AU2004224082A1 - 1,2,4-substitute 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as CETP inhibitors for the treatment of atherosclerosis and obesity - Google Patents

1,2,4-substitute 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as CETP inhibitors for the treatment of atherosclerosis and obesity Download PDF

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AU2004224082A1
AU2004224082A1 AU2004224082A AU2004224082A AU2004224082A1 AU 2004224082 A1 AU2004224082 A1 AU 2004224082A1 AU 2004224082 A AU2004224082 A AU 2004224082A AU 2004224082 A AU2004224082 A AU 2004224082A AU 2004224082 A1 AU2004224082 A1 AU 2004224082A1
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Australia
Prior art keywords
trifluoromethyl
methyl
bis
phenyl
optionally
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AU2004224082A
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Bruce Michael Bechle
George Chang
Mary Theresa Didiuk
Jari Ilmari Finneman
Ravi Shanker Garigipati
Ryan Michael Kelley
David Austen Perry
Michael P. Pollastri
Roger Benjamin Ruggeri
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Pfizer Products Inc
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Pfizer Products Inc
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Description

WO 2004/085401 PCT/IB2004/000836 -1 1,2,4-SUBSTITUERTE 1, 2,3,4-TETRAHYDRO-AND 1,2 DIHYDRO-QUINOLINE AND 1,2,3,4 TETRAHYDRO-QUINOXALINE DERIVATIVES AS CETP INHIBITORS FOR THE TREATMENT OF ATHEROSCLEROSIS AND OBESITY BACKGROUND OF INVENTION This invention relates to quinoline and quinoxaline compounds, 5 pharmaceutical compositions containing such inhibitors and the use of such inhibitors to elevate certain plasma lipid levels, including high density lipoprotein (HDL)-cholesterol and to lower certain other plasma lipid levels, such as low density lipoprotein (LDL)-cholesterol and triglycerides and accordingly to treat diseases which are affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol 10 and triglycerides, such as atherosclerosis and cardiovascular diseases in certain mammals (i.e., those which have CETP in their plasma), including humans. Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of 15 dyslipidemia with dietary modification and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the U.S., where cardiovascular disease accounts for 44% of all deaths, with 53% of these associated with atherosclerotic coronary heart disease. Risk for development of this condition has been shown to be strongly 20 correlated with certain plasma lipid levels. While elevated LDL-C may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to CHD. Low 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). 25 High LDL-cholesterol and triglyceride levels are positively correlated, while high levels of HDL-cholesterol are negatively correlated with the risk for developing cardiovascular diseases. Thus, dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations. Among the many factors controlling plasma levels of these disease 30 dependent principles, cholesteryl ester transfer protein (CETP) activity affects all three. The role of this 70,000 dalton plasma glycoprotein found in a number of animal WO 2004/085401 PCT/IB2004/000836 -2 species, including humans, is to transfer cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), and chylomicrons. The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. 5 This effect on lipoprotein profile is believed to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD. No wholly satisfactory HDL-elevating therapies are on the market today. Niacin can significantly increase HDL, but has serious toleration issues which reduce compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL-C, but in 10 some patients, the result is an increase of modest porportions (-10-12%). As a result, there is an unmet medical need for an approved therapeutic agent that elevates plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis. Thus, although there are a variety of anti-atherosclerosis therapies, there is a 15 continuing need and a continuing search in this field of art for alternative therapies. SUMMARY OF THE INVENTION This invention is directed to compounds according to Formula I
R
4
R
3 5 1N R N R 7 1 R R 20 Formula I Wherein C3 is carbon; J is nitrogen or carbon, wherein if J is carbon, then the bond between C3 and J is a single or double bond and if J is nitrogen, then the bond between C3 and J is a 25 single bond; R' is Y, W-X or W-Y 1 ; wherein W is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl; X is -O-Y, -S-Y, -N(H)-Y or -N-(Y) 2 ; Y for each occurrence is independently Z or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein each carbon, other than the connecting 30 carbon, may optionally be replaced with one or two heteroatoms selected WO 2004/085401 PCT/IB2004/000836 -3 independently 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-, 5 or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z; and Y' for each occurrence is independently Z or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur 10 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 Z; wherein Z is a partially saturated, 15 fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and 20 said Z substituent is optionally mono-, di- or tri-substituted independently with halo,
(C
2
-C
6 )alkenyl, (Cr C6) alkyl, hydroxy, (C-C 6 )alkoxy, (C-C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C-C)alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said (C-C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (0 1
-C
6 )alkoxy, (C-C4)alkylthio, amino, nitro, cyano, 25 oxo, carboxy, (0 1
-C
6 )alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino, said
(C-C
6 )alkyl or (C-CB)alkoxy substituent is also optionally substituted with from one to nine fluorines;
R
2 is a partially saturated, fully saturated or fully unsaturated one to six membered straight or branched carbon chain wherein each carbon, other than the 30 connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen and sulfur, and said carbon is optionally mono-, di- or tri substituted independently with halo, said carbon chain is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo,; or said R 2 is a partially saturated, fully WO 2004/085401 PCT/IB2004/000836 -4 saturated or fully unsaturated three to seven membered ring optionally having one to two heteroatoms selected independently from oxygen and sulfur, wherein said R 2 ring is optionally attached through (C-C4)alkyl; wherein said R 2 ring is optionally mono-, di- or tri-substituted independently with halo, (C 2
-C
6 )alkenyl, (C-C 6 ) alkyl, 5 hydroxy, (C-C 6 )alkoxy, (C-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C
C
6 )alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said (C-C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy,
(C-C
6 )alkoxy, (C-C4)alkylthio, oxo or (C-C 6 )alkyloxycarbonyl;
R
3 is a fully saturated, partially unsaturated or fully unsaturated one to six 10 membered straight or branched carbon chain containing C4a, wherein C4a is a carbon atom that connects to J, wherein each carbon in the carbon chain may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono 15 substituted with oxo or nitrogen, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with hydrogen or oxo, and said carbon chain is mono, di-, or tri-substituted with V at C4a or the R 3 carbon adjacent to C4a; provided that in R 3 , when J is carbon, it is other than C4a that is optionally replaced with one heteroatom; and provided that in R 3 , when J is nitrogen, 20 it is other than C4a that is optionally replaced with a heteroatom and it is other than C4a that is optionally mono-substituted with hydroxy or nitrogen; wherein V is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen such that V is not imidazolyl or a fully saturated heterocyclic 25 nitrogen-containing ring wherein nitrogen of the ring is connected to the R 3 group; a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; or a tricyclic ring consisting of three fused partially saturated, fully saturated or fully 30 unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said V substituent is optionally mono-, di-, tri-, tetra- or penta-substituted independently with V 1 , (CrC 6 )alkyl-V 1 , C(O)-V, 0-(Co-C 6 )alkyl-Vl, (C 1 -C)alkyl-O-V', C(O)-mono-N- or di-N,N-(C 1
-C
6 )alkyl-V 1 , halo, (C -C 6 )alkyl, (C 2
-C
6 )alkenyl, hydroxy, WO 2004/085401 PCT/IB2004/000836 -5 (Cl-C 6 )alkoxy, (C-C4)alkylthio, (C-C4)alkylsulfinyl, (C-C 4 )alkylsulfonyl, mono-N- or di-N,N-(C-C 6 )alkylsulfonyl, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di
N,N-(C-C
6 ) alkylcarboxamoyl, carboxy, (C-C 6 )alkyloxycarbonyl, mono-N- or di-N,N (C-Ce)alkylamino, wherein said (C-Ce)alkyl or (C 2
-C
6 )alkenyl substituent is 5 optionally mono-, di- or tri-substituted independently with hydroxy, (C-CS)alkoxy, (C
C
4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C-C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C-Ca)alkylamino, wherein each (C-C)alkyl, (C-C 6 )alkoxy, (C-C4)alkylthio, (C-C4)alkylsulfonyl or (C 2
-C
6 )alkenyl substituents are also optionally substituted with from one to nine fluorines; wherein V 1 is a partially saturated, fully saturated or fully 10 unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said V 1 substituent is 15 optionally mono-, di-, tri-, tetra- or penta-substituted independently with halo, (C
C
6 )alkyl, (C-C 6 )alkoxy, hydroxy, oxo, amino, nitro, cyano, (C-C)alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said (C-C 6 )alkyl substituent is optionally mono-substituted with oxo, said (C-C 6 )alkyl or (C-C 6 )alkoxy substituent is also optionally substituted with from one to nine fluorines; and 20 each of R4, R9, R and R are independently hydrogen, a bond, nitro or halo wherein said bond is substituted with T or a partially saturated, fully saturated or fully unsaturated (C-C 1 2 ) straight or branched carbon chain wherein each carbon may optionally be replaced with one or two heteroatoms per carbon chain wherein the heteroatoms are selected independently from oxygen, sulfur and nitrogen, wherein 25 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 or nitrogen, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with hydrogen or oxo, and said carbon chain is optionally mono-substituted with T; wherein T is a partially 30 saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, WO 2004/085401 PCT/IB2004/000836 -6 sulfur and oxygen; and said T substituent is optionally mono-, di- or tri-substituted independently with halo, (Cl-C 6 )alkyl, (C 2
-C
6 )alkenyl, hydroxy, (C-C 6 )alkoxy, (C C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C-C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said (C-C 6 )alkyl substituent is optionally mono-, 5 di- or tri-substituted independently with hydroxy, (0 1
-C
6 )alkoxy, (C-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (0 1
-C
6 )alkyloxycarbonyl, mono-N- or di-N,N-(C
C
6 )alkylamino, said (C-C 6 )alkyl or (C-C 6 )alkoxy substituent also optionally has from one to nine fluorines;
R
4 and R 5 , R 5 and R 6 , and/or R' and R 7 may optionally be taken together and 10 can form at least one ring that is a partially saturated or fully unsaturated four to eight membered ring optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein each ring formed by R 4 and R 5 , or R' and R , and/or R and R 7 is optionally mono-, di- or tri-substituted independently with halo, (C-C 6 )alkyl, (C-C 4 )alkylsulfonyl, (C 2
-C
6 )alkenyl, hydroxy, (C-C 6 )alkoxy, (C 15 C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (0 1
-C
6 )alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said (CrC 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (Cr-C 6 )alkoxy, (C-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C-Cs)alkyloxycarbonyl, mono-N- or di-N,N-(Cr
C
6 )alkylamino, said (C-C 6 )alkyl substituent also optionally has from one to nine 20 fluorines; or a pharmaceutically acceptable salt or prodrug thereof; with the following provisos: a) when there is a single bond between C3 and J, and R 3 is a fully saturated one to six membered straight or branched carbon chain substituted on C4a with V then R, 25 is other than C(O)-(C-C4)alkyl optionally mono-, di- or tri-substituted with halo and R' is other than C(O)-monocyclicaromatic ring; or b) when there is a single bond between C3 and J, and R 3 is -C(O)-O-V, and R2 is phenyl then R 1 is other than (C-C 4 )alkyl; and c) when there is a double bond between C3 and J, and R 2 is methyl then R 3 is other 30 than -CH 2 -O-V, -CH 2 -V or -CH 2
-CH
2 -V. Furthermore, the present invention is directed to compounds according to Formula Il WO 2004/085401 PCT/IB2004/000836 -7
R
4
R
3 R6 Rb N R2
R
7 R Formula II wherein
R
1 is W-X; 5 W is carbonyl; X is -O-Y; Y for each occurrence is independently (C-C 6 )alkyl, said ( 1 -Cr 6 )alkyl optionally having one to nine fluorines or said (Cl-C 6 )alkyl optionally mono substituted with Z; 10 wherein Z is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C-C4)alkyl, (Cr C 4 )alkoxy, (C-C 4 )alkylthio, nitro, cyano, 15 oxo, or (C-C 4 )alkyloxycarbonyl, said (Cl-C 4 )alkyl optionally substituted with from one to nine fluorines;
R
2 is a partially saturated, fully saturated or fully unsaturated (C1C4) straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one heteroatom selected independently from oxygen 20 and sulfur wherein said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon chain is optionally mono-substituted with oxo, said carbon is optionally mon-substituted with hydroxy, said sulfur is optionally mono or di-substituted with oxo,; or said R 2 is a partially saturated, fully saturated or fully unsaturated three to five membered ring optionally having one heteroatom selected 25 independently from oxygen and sulfur; wherein said R 2 ring is optionally mono-, di- or tri-substituted independently with halo or (Cr-C 6 )alkoxy; wherein R 3 is -CH 2
NR
8
R
9 or -C(O)NR 8
R
9 ; wherein R"and R 9 are independently hydrogen or a (CrC2) straight carbon 30 chain wherein at least one of R 8 and R are not hydrogen and wherein said carbon is WO 2004/085401 PCT/IB2004/000836 -8 optionally mono-, di- or tri-substituted independently with halo, said carbon, other than the connecting carbon, is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, and said carbon chain is optionally mono, di-, or tri-substituted with V 3 , wherein either R 8 or R 9 is substituted with V3, or both R 8 and 5 R 9 is substituted with V 3 ; wherein V 3 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken 10 independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said V 3 substituent is optionally mono-, di-, tri-, tetra- or penta substituted independently with V 4 , (C-C 6 )alkyl-V 4 , C(O)-V 4 , 0-(Co-C 6 )alkyl-V 4 , (Cr
C
6 )alkyl-0-V 4 , halo, (C-Ce)alkyl, (C-C 6 )alkoxy, hydroxy, oxo, amino, nitro, cyano, 15 (Cr-C 4 )alkylthio, (C-C 4 )alkylsulfinyl, (C-C 4 )alkylsulfonyl, mono-N- or di-N,N-(C
C
6 )alkylsulfonyl, (C-C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(Cj-C 6 )alkylamino, wherein said (C-C 6 )alkyl substituent is optionally mono-substituted with oxo, wherein said (C-C 6 )alkyl substituent is optionally mono-substituted with hydroxy, said (C
C
6 )alkyl or (C-C 6 )alkoxy substituents are also optionally substituted with from one to 20 nine fluorines; wherein V 4 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken 25 independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said V4 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C-C)alkyl, (C-CB)alkoxy, hydroxy, oxo, amino, nitro, cyano, (C-C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said 30 (C-C 6 )alkyl substituent is optionally mono-substituted with oxo, said (C-C 6 )alkyl or
(C-C
6 )alkoxy substituent is also optionally substituted with from one to nine fluorines; or wherein Rand R 9 are taken together to form a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to WO 2004/085401 PCT/IB2004/000836 -9 four heteroatoms selected independently from oxygen, sulfur, and nitrogen or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, selected independently from nitrogen, sulfur and oxygen; 5 R 4 is hydrogen;
R
5 and R 6 are each independently hydrogen, halo, T, (C-C 6 )alkoxy or (C
C
6 )alkyl, said (C-C 6 )alkoxy or (C-C 6 )alky substituent optionally having from one to nine fluorines or said (C-C 6 )alkoxy or (C-C 6 )alkyl substituent optionally mono substituted with T; 10 wherein T is a partially saturated, fully saturated or fully unsaturated five to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said T substituent is optionally mono-, di- or tri-substituted independently with halo, (C-C 6 )alkyl, hydroxy, (C-C 6 )alkoxy, (C-C4)alkylthio, amino, 15 oxo, carboxy, (Cr-C 6 )alkyloxycarbony, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said (C-C 6 )alkyl substituent optionally has from one to nine fluorines;
R
7 is hydrogen; or a pharmaceutically acceptable salt or prodrug thereof. In addition, the present invention provides compounds of Formula Ill
R
1 (R ), C >3 R6 N R2 /
OR
1 0 20 Formula Ill wherein C3 is carbon; J is carbon, wherein the bond between C3 and J is a single or double bond; 25 n is zero if the bond between C3 and J is a double bond or one if the bond between C3 and J is a single bond;
R
2 is (C-C 4 )alkyl, cyclopropyl or cyclobutyl;
R
5 is CF 3 ;
R
6 is hydrogen; WO 2004/085401 PCT/IB2004/000836 -10
R'
0 is a fully saturated (C-C 4 ) straight or branched carbon chain; R" is halo, hydroxy, -C(O)(O(C-C4)alkyl), -C(O)C(O)(O(C-C4)alkyl), C(O)NH(O(C-C 4 )alkyl), or -C(O)N((C-C 4 )alkyl)(O(C-C 4 )alkyl); R1 2 is hydrogen or halo, wherein R" is not halo when R 12 is halo; 5 or R" and R are taken together to form oxo or N 2 ; or a pharmaceutically acceptable salt or prodrug thereof. In addition, the present invention provides methods for treating atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, 10 hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia or myocardial infarction in a mammal by administering to a mammal in need of such treatment an atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, 15 hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction treating amount of a compound of the present invention, or a pharmaceutically acceptable form of said compound. In addition, the present invention provides pharmaceutical compositions which comprise a therapeutically effective amount of a compound of the present 20 invention, or a pharmaceutically acceptable form of said compound and a pharmaceutically acceptable vehicle, diluent or carrier. In addition, the present invention provides pharmaceutical compositions for the treatment of atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, 25 hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction in a mammal which comprise a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable form of said compound and a pharmaceutically acceptable vehicle, diluent or carrier. 30 Moreover, the present invention provides pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of the present invention, or a pharmaceutically acceptable form of said compound; WO 2004/085401 PCT/IB2004/000836 -11 a second compound, said second compound being an HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a PPAR modulator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion-exchange 5 resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant (preferably an HMG-CoA reductase inhibitor, a PPAR modulator, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin); and a pharmaceutical vehicle, diluent or carrier. This composition may be used to treat the aforementioned diseases, including atherosclerosis. 10 Also, the present invention provides a kit for achieving a therapeutic effect in a mammal comprising packaged in association a first therapeutic agent comprising a therapeutically effective amount of a compound of claim 1, 8, 12, or 13, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, a second therapeutic agent comprising a 15 therapeutically effective amount of an HMG CoA reductase inhibitor, a PPAR modulator, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier and directions for administration of said first and 20 second agents to achieve the therapeutic effect. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. 25 DETAILED DESCRIPTION OF THE INVENTION The present invention may be understood more readily by reference to the following detailed description of exemplary embodiments of the invention and the examples included therein. Before the present compounds, compositions and methods are disclosed and 30 described, it is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
WO 2004/085401 PCT/IB2004/000836 -12 The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the present invention. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, 5 ie, salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (Le, 10 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)) salts. The invention also relates to base addition salts of the compounds of the present invention. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the present invention that are acidic in nature are those that form non-toxic base salts with such 15 compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (g.., potassium and sodium) and alkaline earth metal cations (eq, calcium and magnesium), ammonium or water-soluble amine addition salts such as N methylglucamine-(meglumine), and the lower alkanolammonium and other base 20 salts of pharmaceutically acceptable organic amines. The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may 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. Hydrates and 25 solvates of the compounds of this invention are also included. Where the compounds of the present invention possess two or more stereogenic centers and the absolute or relative stereochemistry is given in the name, the designations R and S refer respectively to each stereogenic center in ascending numerical order (1, 2, 3, etc.) according to the conventional IUPAC number schemes 30 for each molecule. Where the compounds of the present invention possess one or more stereogenic centers and no stereochemistry is given in the name or structure, it is understood that the name or structure is intended to encompass all forms of the compound, including the racemic form.
WO 2004/085401 PCT/IB2004/000836 -13 The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. The term "cis" refers to the orientation of two substituents with reference to each other and the plane of the ring (either both 5 "up" or both "down"). Analogously, the term "trans" refers to the orientation of two substituents with reference to each other and 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 reference to the plane of the ring. Beta is above the plane of the ring and Alpha is below the plane of 10 the ring. This invention also includes isotopically-labeled compounds, which are identical to those described by formulas I and II, except for the fact that one or more atoms are replaced by one or more atoms having specific atomic mass or mass numbers. Examples of isotopes that can be incorporated into compounds of the 15 invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 18,170, 1 8 F, and 36Ci respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or of the prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope 20 of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and "C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., 3 H), and carbon-14 (i.e., 14C), isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 25 2 H), can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the Examples below, by substituting 30 a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings: As used herein, the term mammals is meant to refer to all mammals which contain CETP in their plasma, for example, rabbits and primates such as monkeys WO 2004/085401 PCT/IB2004/000836 -14 and humans, including males and females. Certain other mammals e.g., dogs, cats, cattle, goats, sheep and horses do not contain CETP in their plasma and so are not included herein. The term "treating", "treat" or "treatment" as used herein includes 5 preventative (e.g., prophylactic) and palliative treatment. By "pharmaceutically acceptable" is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof. "Compounds" when used herein includes any pharmaceutically acceptable 10 derivative or variation, including conformational isomers (eq., cis and trans isomers) and all optical isomers (eg, enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. By "tautomers" is meant chemical compounds that may exist in two or more forms of different 15 structure (isomers) in equilibrium, the forms differing, usually, in the position of a hydrogen atom. Various types of tautomerism can occur, including keto-enol, ring chain and ring-ring tautomerism. The expression "prodrug" refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the 20 physiological pH or through enzyme action is converted to the desired drug form). Exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of the present invention include but are not limited to those having a carboxyl moiety wherein the free hydrogen is replaced by (C-C 4 )alkyl, (C 2
-C
7 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl 25 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 30 (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4 crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C-C 2 )alkylamino(C 2
-C
3 )alky (such as p-dimethylaminoethyl), carbamoyl-(C-C 2 )alkyl, N,N-di(Cl
C
2 )alkylcarbamoyl-(C-C 2 )alkyl and piperidino-, pyrrolidino- or morpholino(C 2
-C
3 )alkyl.
WO 2004/085401 PCT/IB2004/000836 -15 The following paragraphs describe exemplary ring(s) for the generic ring descriptions contained herein. Exemplary five to six membered aromatic rings optionally having one or two heteroatoms selected independently from oxygen, nitrogen and sulfur include 5 phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl and pyrazinyl. Exemplary partially saturated, fully saturated or fully unsaturated five to eight membered rings optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen include cyclopentyl, cyclohexyl, cycloheptyl, 10 cyclooctyl and phenyl. Further exemplary five membered rings include 2H-pyrrolyl, 3H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazoly, 1,2,3 15 triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazoly, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 3H-1,2,3-dioxazoly, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5 oxathiazolyl and 1,3-oxathiolyl. Further exemplary six membered rings include 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, 20 thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4 triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 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, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6 oxathiazinyl, 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl. 25 Further exemplary seven membered rings include azepinyl, oxepinyl, and thiepinyl. Further exemplary eight membered rings include cyclooctyl, cyclooctenyl and cyclooctadienyl. Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, 30 optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen include indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1 H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, I H-indazolyl, indoxazinyl, benzoxazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, WO 2004/085401 PCT/IB2004/000836 -16 cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b) pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4 benzoxazinyl, 1 H-2,3-benzoxazinyl, 4H-3,1 -benzoxazinyl, 2H-1,2-benzoxazinyl and 5 4H-1,4-benzoxazinyl. By "alkylene" is meant saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of two adjacent carbons. Exemplary of such groups (assuming the designated length encompasses the particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene, 10 heptylene). By "halo" or "halogen" is meant chloro, bromo, iodo, or fluoro. By "alkyl" is meant straight chain saturated hydrocarbon or branched chain saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, 15 butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1 methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl. "Alkenyl" referred to herein may be linear or branched, and they may also be cyclic (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl) or bicyclic or contain cyclic groups. They contain 1-3 carbon-carbon double bonds, which can be cis or trans. 20 By "alkoxy" is meant straight chain saturated alkyl or branched chain saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy. 25 As used herein the term "mono-N-" or "di-N,N-(C 1 -Cx)alkyl" refers to the (C Cx)alkyl moiety taken independently when it is di-N,N-(C-C2)alkyl (x refers to integers). References (e.g., claim 1) to "said carbon" in the phrase "said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is 30 optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo" refers to each of the carbons in the carbon chain including the connecting carbon. References to a "nitrogen... di-substituted with oxo" herein (e.g., claim 1) refer to a terminal nitrogen which constitutes a nitro functionality.
WO 2004/085401 PCT/IB2004/000836 -17 It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For 5 example, the term "pyridyl" means 2-, 3- or 4-pyridyl, the term "thienyl" means 2- or 3-thienyl, and so forth. DTT means dithiothreitol. DMSO means dimethyl sulfoxide. EDTA means ethylenediamine tetraacetic acid. As used herein, the expressions "reaction-inert solvent" and "inert solvent" 10 refer to a solvent or a mixture thereof which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. In one embodiment of formula I compounds of the present invention, J is carbon; 15 R 1 is W-X; W is carbonyl; X is -O-Y; Y for each occurrence is independently (C-C)alkyl, said (C-Ce)alkyl optionally having one to nine fluorines or said (C-C)alkyl optionally mono-substituted with Z; 20 wherein Z is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C-C 4 )alkyl, (C-C 4 )alkoxy, (C-C 4 )alkylthio, nitro, cyano, 25 oxo, or (C-C4)alkyloxycarbonyl, said (Cr-C4)alkyl or (Cr-C4)alkoxy is optionally substituted with from one to nine fluorines;
R
2 is beta and is a partially saturated, fully saturated or fully unsaturated (C
C
4 ) straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one heteroatom selected 30 independently from oxygen and sulfur wherein said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon chain is optionally mono substituted with oxo or hydroxy, said sulfur is optionally mono- or di-substituted with oxo,; or said R 2 is a partially saturated, fully saturated or fully unsaturated three to WO 2004/085401 PCT/IB2004/000836 -18 five membered ring optionally having one heteroatom selected independently from oxygen and sulfur; wherein said R 2 ring is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C-C)alkoxy, amino, nitro, (C-C 4 )alkyloxycarbonyl or carboxy; 5 wherein R 3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein each carbon, other than C4a, may optionally be replaced with one 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 10 with hydroxy, said carbon is optionally mono-substituted with cyano, said carbon is optionally mono-substituted with oxo or nitrogen, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with hydrogen or oxo, and said carbon chain is optionally mono, di-, or tri-substituted with V at C4a or at the R 3 carbon adjacent to C4a; V is a three, four, five or six 15 membered partially saturated, fully saturated or fully unsaturated ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen such that V is not imidazolyl or a fully saturated heterocyclic nitrogen containing ring wherein nitrogen of the ring is connected to the R 3 group; wherein said V ring is optionally mono-, di-, tri-, tetra- or penta-substituted 20 independently with halo, (C-C 8 )alkyl, hydroxy, (Cl-C 6 )alkoxy, (C-C 6 )alkoxycarbonyl, nitro, cyano or oxo, wherein said (C-C 6 )alkyl or (C-C 6 )alkoxy substituent optionally has from one to nine fluorines;
R
4 is hydrogen;
R
5 and R 6 are each independently hydrogen, halo, T, (C 1 -Ce)alkoxy or (C 25 C 6 )alkyl, said (C-C 6 )alkoxy or (C-C 6 )alkyl substituent optionally having from one to nine fluorines or said (Cr-C 6 )alkoxy or (C-C 6 )alkyl substituent optionally mono substituted with T; wherein T is a partially saturated, fully saturated or fully unsaturated five to six membered ring optionally having one to two heteroatoms selected independently 30 from oxygen, sulfur and nitrogen; wherein said T substituent is optionally mono-, di- or tri-substituted independently with halo, (C 1 -Cf)alkyl, hydroxy, (C-C 6 )alkoxy, (C-C 4 )alkylthio, amino, oxo, carboxy, (C-C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein WO 2004/085401 PCT/IB2004/000836 -19 said (C-Ce)alkyl or (C-Ca)alkoxy substituent optionally has from one to nine fluorines; and
R
7 is hydrogen. In another embodiment of formula I compounds of the present invention, 5 Y is (C-C4)alkyl, wherein said (C-C4)alkyl substituent optionally has one to nine fluorines;
R
2 is (C-C4)alkyl, cyclopropyl or cyclobutyl;
R
3 is -((C-C 4 )alkyl)(NH 2 )(V), -((C-C3)alkyl)(NH(C-C 2 )alkyl))(V), -((Ci C4)alkyl)(OH)(V), -((C 1 -C4)alkyl)(F)(V), -((C-C 2 )alkyl)(O-C(O)(C-C 2 )alkyl)(V), -C(O) 10 V, -C(OH)(C(O)O(C-C 3 )akyl)(V), -CF 2 (V), -((C-C 2 )alkyl)(NHC(O)(C-C 2 )alkyl)(V), CH2(V), -((Cr-C2)alkyl)(C(O)O(Cr-C2)alkyl)(V), -((Cr-C4)alkyl)(C(0)NH2)(V),-((Cr C4)alkyl)(CN)(V), or-((C-C 3 )alkyl)((Cl-C 3 )alkoxy)(V), V is phenyl optionally mono-, di- or tri-substituted independently with halo, (C-C)alkyl, hydroxy, (CI-C)alkoxy, nitro, cyano or oxo wherein said (C-C 6 )alkyl or 15 (CI-C 6 )alkoxy substituent optionally has from one to nine fluorines;
R
5 and R 6 are each independently hydrogen, halo, (C-C 3 )alkoxy or (C
C
6 )alkyl, said (C-C 3 )alkoxy optionally having from one to seven halo, said (C
C
6 )alkyl optionally having from one to nine halo. In a further embodiment of formula I compounds of the present invention, 20 Y is methyl, ethyl, 1 -propyl, 2-propyl or tert-butyl; R2 is methyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl;
R
3 is -C(O)-V, -C(OH)(C(O)OCH 3 )(V), -CH(F)(V), -CF 2 (V), -CH(OCH 3 )(V), CH(C(O)OCH 3 )(V), -CH(CN)(V), -CH(OH)(V), -CH 2 (V), -CH(NH 2 )(V), CH(NH(CHs))(V), -CH(C(O)NH 2 )(V), -CH(CH 2 OH)V, -CH(CH 2 0CH 3 )V, 25 CH(CH 2 0C(O)CH 3 )V, -CH(CH 2 F)V, or -CH(CH 2
NH
2 )V; and V is phenyl optionally mono-, di- or tri-substituted independently with halo, nitro, or (C-C 2 )alkyl, wherein said (C-C 2 )alkyl optionally has from one to five fluorines; R9 and R are each independently hydrogen, methyl, methoxy or chloro; said 30 methoxy optionally having from one to three fluorines, said methyl optionally having from one to three fluorines. In another embodiment of the present invention, formula I compounds include substituents wherein Y is ethyl; WO 2004/085401 PCT/IB2004/000836 -20 R2 is ethyl or methyl;
R
3 is (3,5-bis-(trifluoromethyl)-phenyl)-hydroxy-methoxycarbonyl-methyl; (3,5 bis-trifluoromethyl-phenyl)-methoxycarbony-methyl; (3,5-bis-trifluoromethyl-phenyl) cyano-methyl, 3,5-bis-trifluoromethyl-benzoyl; (3,5-bis-trifluoromethyl-phenyl) 5 hydroxy-methyl; (3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl; (3,5-bis trifluoromethyl-phenyl)-difluoro-methyl; (3,5-bis-(trifluoromethyl)-benzyl); (3,5-bis trifluoromethyl-phenylcarbamoyl)-methyl; amino-(3,5-bis-(trifluoromethyl)-phenyl) methyl; (3,5-bis-(trifluoromethyl)-phenyl)-methylamine-methyl; 1-(3,5-bis (trifluoromethyl)-phenyl)-2-amino-ethyl; 1-(3,5-bis-(trifluoromethyl)-phenyl)-2-fluoro 10 ethyl; 1-(3,5-bis-(trifluoromethyl)-phenyl)-2-methoxy-ethyl; 1-(3,5-bis-(trifluoromethyl) phenyl)-2-hydroxy-ethyl; or 2-acetoxy-1 -(3,5-bis-(trifluoromethyl)-phenyl)-ethyl;
R
5 is methoxy or trifluoromethyl; and
R
6 is hydrogen or methoxy. In another embodiment of compounds of formula 1, the bond between C3 and 15 J is a single bond. In yet another embodiment of compounds of formula I, the bond between C3 and J is a double bond. In another embodiment, the compounds of formula I are selected from the group consisting of: 20 (R, R, S)-4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R)-4-(3,5-bis-trifluoromethyl-benzyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro 25 2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 30 (R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl] 6,7-dimethoxy-2-methyl-2H-quinoline-1-carboxylic acid ethyl ester; (R, S)- 4 -[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl] 6,7-dimethoxy-2-methyl-2H-quinoline-1-carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -21 (R, S, R)- 4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl- methoxycarbonyl methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl 5 methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 10 (R, R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl 15 ester; (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl 20 methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 25 (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl-6,7 dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R)- 4 -[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl] 30 2-ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (R, S)- 4 -[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl] 2-ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -22 (R, S, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[2-Acetoxy-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 5 (R, S, S)-4-[2-Acetoxy-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6 10 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-fluoro-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-fluoro-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 15 (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-amino-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-amino-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2-ethyl-6 20 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -23 (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2-ethyl 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 5 (RS,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 10 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; 15 (R,S)-4-(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 20 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; 25 (R,S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,R)-4-(3,5-bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester; (R,S)-4-(3,5-bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro 30 2H-quinoline-1 -carboxylic acid ethyl ester; (R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -24 (R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 5 (R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 10 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; and (R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt or prodrug thereof. In a further embodiment of compounds of formula I of the present invention, 15 J is nitrogen; the bond between C3 and J is a single bond; R' is W-X; W is carbonyl; X is -O-Y; 20 Y for each occurrence is independently (C-C 6 )alkyl, said (C-C 6 )alkyl optionally having one to nine fluorines or said (Cj-Cc)alkyl optionally mono substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently 25 from oxygen, sulfur and nitrogen; wherein said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C-C 4 )alkyl, (C-C 4 )alkoxy, (C-C 4 )alkylthio, nitro, cyano, oxo, or (C-C4)alkyloxycarbonyl, said (C-C 4 )alkyl or (C-C 4 )alkoxy optionally substituted with from one to nine fluorines; 30 R 2 is a partially saturated, fully saturated or fully unsaturated (C-C 4 ) straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one heteroatom selected independently from oxygenand sulfur wherein said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon chain is optionally mono-substituted with oxo, WO 2004/085401 PCT/IB2004/000836 -25 said carbon is optionally monosubstituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo,; or said R 2 is a partially saturated, fully saturated or fully unsaturated three to five membered ring optionally having one heteroatom selected independently from oxygenand sulfur; wherein said R 2 ring is optionally 5 mono-, di- or tri-substituted independently with halo, hydroxy, (C-Ce)alkoxy, amino, nitro, (C-C 4 )alkyloxycarbonyl or carboxy; wherein R 3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein each carbon, other than C4a or the R 3 carbon adjacent to C4a, may optionally be replaced with one 10 heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon, other than C4a, is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with cyano, said carbon is optionally mono-substituted with oxo or nitrogen, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono 15 or di-substituted with hydrogen or oxo, and said carbon chain is optionally mono, di-, or tri-substituted with V at C4a or at the the R 3 carbon adjacent to C4a; V is a five or six membered partially saturated, fully saturated or fully unsaturated ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen such that V is not imidazolyl or a fully saturated 20 heterocyclic nitrogen-containing ring wherein nitrogen of the ring is connected to the
R
3 group; wherein said V ring is optionally mono-, di-, tri-, tetra- or penta-substituted independently with halo, (0 1
-C
6 )alkyl, hydroxy, (C-C)alkoxy, (C-C 6 )alkoxycarbonyl, nitro, cyano or oxo, wherein said (C-C 6 )alkyl or (C-Ce)alkoxy substituent optionally has from one to nine fluorines; 25 R 4 is hydrogen;
R
5 and R 6 are each independently hydrogen, halo, T, (C-C 6 )alkoxy or (C C)alkyl, said (C-C 6 )alkoxy or (C-C 6 )alkyl substituent optionally having from one to nine fluorines or said (C-C 6 )alkoxy or (C-Ca)alkyl substituent optionally mono substituted with T; 30 wherein T is a partially saturated, fully saturated or fully unsaturated five to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said T substituent is optionally mono-, di- or tri-substituted independently with halo, (C-Ce)alkyl, hydroxy, (C-C)alkoxy, (C-C4)alkylthio, amino, WO 2004/085401 PCT/IB2004/000836 -26 oxo, carboxy, (C-C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said (C-C 6 )alkyl or (0 1
-C
6 )alkoxy substituent optionally has from one to nine fluorines;
R
7 is hydrogen. 5 In a further embodiment of compounds of formula I of the present invention, Y is (C-C 4 )alkyl, wherein said (C-C 4 )alkyl substituent optionally has one to nine fluorines;
R
2 is (C-C 4 )alkyl, cyclopropyl or cyclobutyl;
R
3 is -C(O)-V, -CH(C(O)O(C-C 3 )alky)(V), or -CH(CN)(V); 10 V is phenyl optionally mono-, di- or tri-substituted independently with halo, (C-Ca)alkyl, hydroxy, (Cl-C 6 )alkoxy, nitro, cyano or oxo wherein said (C-C 6 )alkyl substituent optionally has from one to nine fluorines; R and R 6 are each independently hydrogen, (C-C 3 )alkoxy or (C-C)alkyl, said (C-C 3 )alkoxy optionally having from one to nine fluorines, said (C-C 6 )alkyl 15 optionally having from one to seven fluorines; or a pharmaceutically acceptable salt thereof. In a further embodiment of compounds of formula I of the present invention, Y is methyl, ethyl, 1-propyl, 2-propyl or tert-butyl;
R
2 is methyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl; 20 R 3 is 3,5-bis-trifluoromethyl-benzoyl, (3,5-bis-trifluoromethyl-phenyl)-cyano methyl, or (3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl;
R
5 is methyl or trifluoromethyl;
R
6 is hydrogen or methyl. In yet another embodiment of formula I compounds, the compound is 25 selected from the group consisting of: (R)-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethy-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl 3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; 30 (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl 3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -27 (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid methyl ester; 5 (RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid methyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyI 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 10 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyi-methyl]-2-ethyl-6 trifluoromethy-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; and (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; 15 or a pharmaceutically acceptable salt or prodrug thereof. Moreover, one embodiment of the present invention includes a method for treating atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, 20 hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction in a mammal by administering to a mammal in need of such treatment an atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial 25 hypercholesterolemia or myocardial infarction treating amount of a compound of formula I or II, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. In another embodiment, atherosclerosis is treated. In another embodiment, peripheral vascular disease is treated. 30 In another embodiment, dyslipidemia is treated. In another embodiment, hyperbetalipoproteinemia is treated. In another embodiment, hypoalphalipoproteinemia is treated. In another embodiment, familial-hypercholesterolemia is treated. In another embodiment, coronary artery disease is treated.
WO 2004/085401 PCT/IB2004/000836 -28 In another embodiment, myocardial infarction is treated. Furthermore, the present invention includes a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula I or II, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said 5 prodrug and a pharmaceutically acceptable vehicle, diluent or carrier. In one embodiment, the present invention is a pharmaceutical composition for the treatment of atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, 10 hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction in a mammal which comprises a therapeutically effective amount of a compound of formula I or 11, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable vehicle, diluent or carrier. 15 In another embodiment, the present invention is a pharmaceutical composition for the treatment of atherosclerosis in a mammal which comprises an atherosclerosis treating amount of a compound of formula I or II, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable vehicle, diluent or carrier. 20 In another embodiment, the present invention includes a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising: a first compound, said first compound being a compound of formula I or II, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; a second compound, said second compound being an 25 HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a PPAR modulator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant; and a pharmaceutical vehicle, diluent or carrier. 30 In another embodiment, the present invention includes a pharmaceutical combination composition wherein the second compound is an HMG-CoA reductase inhibitor or a PPAR modulator.
WO 2004/085401 PCT/IB2004/000836 -29 In another embodiment, the present invention includes a pharmaceutical combination composition wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin. In another embodiment, the present invention includes a pharmaceutical 5 combination composition further comprising a cholesterol absorption inhibitor. In another embodiment, the cholesterol absorption inhibitor is ezetimibe. One further embodiment of the present invention includes a method for treating atherosclerosis in a mammal comprising administering to a mammal in need of treatment thereof; a first compound, said first compound being a compound of 10 formula (I), a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; and a second compound, said second compound being an HMG CoA reductase inhibitor, a PPAR modulator, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an 15 ACAT inhibitor or a bile acid sequestrant; wherein the amounts of first and second compounds result in a therapeutic effect. In another embodiment, the present invention includes a method for treating atherosclerosis wherein the second compound is an HMG-CoA reductase inhibitor or a PPAR modulator. 20 In another embodiment, the present invention includes a method for treating atherosclerosis wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin. In another embodiment, the present invention includes a method for treating atherosclerosis wherein the method further comprises administering a cholesterol 25 absorption inhibitor. In another embodiment, the cholesterol absorption inhibitor is ezetimibe. A further embodiment of the present invention includes a kit for achieving a therapeutic effect in a mammal comprising packaged in association a first therapeutic agent comprising a therapeutically effective amount of a compound of 30 claim 1, 8, 12, or 13, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, a second therapeutic agent comprising a therapeutically effective amount of an HMG CoA reductase inhibitor, a PPAR modulator, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of WO 2004/085401 PCT/IB2004/000836 -30 niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier and directions for administration of said first and second agents to achieve the therapeutic effect. In another embodiment, the present invention includes a kit wherein said 5 second compound is an HMG-CoA reductase inhibitor or a PPAR modulator. In a further embodiment, the present invention includes a kit wherein said second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin. In another embodiment, the present invention includes a kit that further 10 comprises a cholesterol absorption inhibitor. In another embodiment, the cholesterol absorption inhibitor is ezetimibe. Specific compounds of formula Ill include: 2-Ethyl-4-iodo-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; 2-Ethyl-4-iodo-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; 15 4-Chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 4-Bromo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; 4-Diazo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl 20 ester; 4-Chloro-2-ethy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1,4-dicarboxylic acid 1-ethyl ester 4-methyl ester; 2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1,4-dicarboxylic acid-1-ethyl ester-4-methyl ester; 25 2-Ethyl-4-(methoxy-methyl-carbamoyl)-6-trifluoromethyll-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester; 2-Ethyl-6-trifluoromethyl-2H-quinoline-1,4-dicarboxylic acid-1-ethyl ester-4-methyl ester; 4-Chloro-2-ethyl-4-methoxycarboncarbonyl-6-trifluoromethyl-3,4-dihydro-2H 30 quinoline-1-carboxylic acid ethyl ester; 2-Ethyl-4-methoxycarboncarbonyl-6-trifluoromethyl-2H-quinoline-I -carboxylic acid-ethyl ester; 4-Diazo-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -31 6,7-Dimethoxy-4-methoxycarboncarbonyl-2-methyl- 2H-quinoline-1-carboxylic acid-ethyl ester; 6,7-Dimethoxy- 2-methyl- 3,4-dihydro-2H-quinoline-1,4-dicarboxylic acid-1 -ethyl ester-4-methyl ester; 5 6,7-Dimethoxy-4-(methoxy-methyl-carbamoyl)-2-methyl-3,4-dihydro-2H-quinoline 1-carboxylic acid ethyl ester; 2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl 10 ester; 2-Ethyl-4-hyIroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid methyl ester; 2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid methyl ester; 15 2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid 1-propyl ester; 2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid 1 propyl ester; 2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 2 20 propyl ester; 2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 2 propyl ester; 2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester; 25 2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ted butyl ester; and 2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1,4-dicarboxylic acid-1 -ethyl ester-4-methyl ester. In general, the compounds of this invention can be made by processes which 30 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. Other processes may be described in the experimental section. Analogous processes are disclosed in the following U.S.
WO 2004/085401 PCT/IB2004/000836 -32 patents, which are hereby incorporated by reference herein in their entirety: U.S. Patent 6,140,342; U.S. Patent 6,362,198; U.S. Patent 6,147,090; U.S. Patent 6, 395,751; U.S. Patent 6,147,089; U.S. Patent 6,310,075; U.S. Patent No. 6,197,786; U.S. Patent 6,140,343; U.S. Patent 6,489,478; and International Publication No. WO 5 00/17164. The Reaction Schemes herein described are intended to provide a general description of the methodology employed in the preparation of many of the Examples given. However, it will be evident from the detailed descriptions given in the Experimental section that the modes of preparation employed extend further 10 than the general procedures described herein. In particular, it is noted that the compounds prepared according to these Schemes may be modified further to provide new Examples within the scope of this invention. For example, an ester functionality may be reacted further using procedures well known to those skilled in the art to give another ester, an amide, a carbinol or a ketone. 15 SCHEME 1 WO 2004/085401 PCT/IB2004/000836 -33
R
4 0 R 4
NNH
2
R
4
N
2 R RR R KCOL R5 N R 2 RG ~ N R 2 R 6 N R 2
R
7
R
1 R R R 7 R' IX VIll VI L L
R
4 K a 0 R5R 5 + 2 N R 2 N R R R R VII V M L 4 OH RL 0 R4 K Z 5 RR R6 N R2 R N R R N R
R
7
R
1 R R X111 xil XI M L V L V
R
4 OH
R
5
R
5 R N R 2 R N R 2 N R 2 RRT XIV X IV 11 1 HO L L V R4 0 R4
R
5 R5 -~ R 5
R
6 ) N R 2 & R N R N R 2 7 RN R 7 1 7
R
1 RR R R XV 1II XI SCHEME I 5 According to reaction Scheme 1, the desired compounds wherein J is carbon, the optional double bond is absent, R 3 is a group CH(V)(L) wherein L is a N R2 R7N R (CI-CR) alkoxycarbonyl group and V, R1, R , R 4 , R 5 , R 6 , and R are as described above (depicted in Scheme 1 as Formula 11 compounds) may be prepared as a mixture of diastereoisomers from the corresponding Scheme 1, Formula III 10 compounds by reduction of the double bond or L is R 3 as defined herein. This may WO 2004/085401 PCT/IB2004/000836 -34 be achieved by hydrogenation in a reaction inert solvent such as methanol, ethanol or acetic acid with a catalyst such as palladium or rhodium on carbon under a hydrogen pressure equal to 15-50 psi for a period between 2-24hrs, or by transfer hydrogenation using ammonium formate in refluxing methanol in the presence of a 5 catalyst such as palladium on carbon in a reaction inert solvent such as methanol or ethanol at a temperature between 00C to 800C, typically 250C to 600C. This method of preparing these particular Formula I compounds typically provides a preponderance of those diastereoisomers in which the R 2 and R 3 groups are cis to one another. 10 The desired Formula IlII compounds wherein L, V, R', R 2 , R 4 , R 5 , R 6 , and R' are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula IV compounds by removal of the hydroxyl group. This may be achieved by treatment with a chlorinating agent such as phosphorus (Ill) chloride or thionyl chloride in a reaction inert solvent such as methylene chloride or chloroform 15 optionally containing a base such as pyridine, diisopropylethylamine or 2,6-di-tert butyl-4-methylpyridine at a temperature between 00C to 600C, typically ambient, for a period between 1 to 24hr. The chloro-derivative thus formed is then treated with a finely divided metal such as zinc in the presence of an acid, or mixture of acids, such as acetic acid or hydrochloric acid in a suitable solvent, or mixture of solvents such as 20 methanol, water or tetrahydrofuran at a temperature between 250C to 600C, typically ambient, to provide the desired product of Formula Ill. The desired Formula IV compounds wherein L is a (0 1
-C
6 ) alkoxycarbonyl group and V, R', R 2 , R 4 , R', R 6 , and R' are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula V compounds by 25 reaction with a suitable organometallic derivative of the V group such as a magnesium or lithium derivative, prepared in turn from a compound V-Hal where Hal represents a chlorine, bromine or iodine atom, using methods well known to those skilled in the art, for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995. 30 This reaction is conducted in a suitable reaction inert solvent such tetrahydrofuran or diethyl ether at a temperature between -780C to 250C, typically -781C, to provide the desired product of Formula IV. The desired Formula V compounds wherein L is a (CrC6) alkoxycarbonyl group and R 1 , R 2 , R 4 , R , RO, and R are as described above may be prepared from WO 2004/085401 PCT/IB2004/000836 -35 the corresponding Formula VI compounds by reaction with an acyl compound KCOL wherein K is a leaving group such as chlorine or bromine, at a temperature between 0*C to 250C, typically ambient, in a reaction inert solvent such as acetonitrile or toluene optionally in the presence of a base such as diisopropylethylamine or 5 triethylamine to remove traces of HK which may be present. Depending on the nature of the substitutents on the Formula VI compounds and the nature of L, the Formula V compound may be obtained as a mixture with the corresponding Formula VIl compound. The desired Formula VI compounds wherein R', R 2 , R 4 , R 5 , R 6 , and R are as 10 described above may be prepared from the corresponding Formula VIII compounds by reaction with a suitable oxidizing agent, typically manganese (IV) oxide, in a suitable reaction inert solvent such as diethyl ether at a temperature between 00C to 250C, typically ambient. Since this reaction produces an equivalent of water, which may be deleterious in the subsequent step, this may optionally be removed by 15 addition of a solvent suitable for the next reaction such as acetonitrile or toluene and evaporation of the solvent mixture to a volume somewhat less than that of the added solvent, but not to dryness. The desired Formula VIII compounds wherein R', R 2 , R 4 , R', R 6 , and R 7 are as described above may be prepared from the corresponding Formula IX compounds 20 by reaction with hydrazine hydrate in a suitable reaction inert solvent such as ethanol or toluene at a temperature between 25*C to 1800C, typically 80*C to 170*C. The hydrazone formation may be assisted by continuous removal of water, such as by the use of a Dean-Stark apparatus, or by heating in a closed vessel to a temperature beyond the boiling point of the solvent such as by a microwave oven. 25 An alternative preparation of the desired Formula II compounds wherein L is a (Cr1C6) alkoxycarbonyl group and V, R', R , R 4 , R, R , and R 7 are as described above may be accomplished from the corresponding Formula X compounds by treatment with a chlorinating agent such as phosphorus (Ill) chloride or thionyl chloride in a reaction inert solvent such as methylene chloride or chloroform optionally 30 containing a base such as pyridine, diisopropylethylamine or 2,6-di-tert-butyl-4 methylpyridine at a temperature between 00C to 600C, typically ambient, for a period between 1 to 24hr. The chloro-derivative thus formed as a mixture of diastereoisomers is then treated with a finely divided metal such as zinc in the presence of an acid, or mixture of acids, such as acetic acid or hydrochloric acid in a WO 2004/085401 PCT/IB2004/000836 -36 suitable solvent, or mixture of solvents such as methanol, water or tetrahydrofuran at a temperature between 250C to 60 0 C, typically ambient, to provide the desired product of Formula II. The desired Formula X compounds wherein L is a (C1C6) alkoxycarbonyl 5 group and V, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula XI compounds by reaction with a suitable organometallic derivative of the V group such as a magnesium or lithium derivative, prepared in turn from a compound V-Hal where Hal represents a chlorine, bromine or iodine atom, using methods well known to those 10 skilled in the art, for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995. This reaction is conducted in a suitable reaction inert solvent such tetrahydrofuran or diethyl ether at a temperature between -78*C to 250C, typically -78*C, to provide the desired product of Formula X. 15 The desired Formula XI compounds wherein L is a (CrC6) alkoxycarbonyl group and R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula V compounds by reduction of the double bond. This may be achieved by hydrogenation in a reaction inert solvent such as methanol, ethanol or acetic acid with a catalyst such as 20 palladium or rhodium on carbon under a hydrogen pressure equal to 15-50 psi for a period of 2-24hrs, or by transfer hydrogenation using ammonium formate in refluxing methanol in the presence of a catalyst such as palladium on carbon in a reaction inert solvent such as methanol or ethanol at a temperature between 00C to 80*C, typically 250C to 600C. 25 An alternative preparation of the desired Formula X compounds wherein L is a (Cr1C6) alkoxycarbonyl group and V, R 1 , R 2 , R 4 , R , R', and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula XII compounds, wherein K is a leaving group such as chlorine or bromine, by hydrogenation in a reaction inert solvent such as methanol, ethanol or acetic acid 30 with a catalyst such as palladium or rhodium on carbon under a hydrogen pressure equal to 15-50 psi for a period between 2-24hrs, or by transfer hydrogenation using ammonium formate in refluxing methanol in the presence of a catalyst such as palladium on carbon in a reaction inert solvent such as methanol or ethanol at a WO 2004/085401 PCT/IB2004/000836 -37 temperature between 0*C to 800C, typically 25 0 C to 600C to provide the desired product of Formula X. Another alternative preparation of the desired Formula X compounds wherein L is a (C1-C) alkoxycarbonyl group and V, R', R 2 , R 4 , R 5 , R 6 , and R are as described 5 above may be prepared as a mixture of diastereoisomers from the corresponding Formula IV compounds by reduction of the double bond. This may be accomplished by hydrogenation in a reaction inert solvent such as methanol, ethanol or acetic acid with a catalyst such as palladium or rhodium on carbon under a hydrogen pressure equal to 15-50 psi for a period between 2-24hrs, or by transfer hydrogenation using 10 ammonium formate in refluxing methanol in the presence of a catalyst such as palladium on carbon in a reaction inert solvent such as methanol or ethanol at a temperature between 00C to 800C, typically 250C to 600C to provide the desired product of Formula X. An alternative method of reduction involves treatment with diimide which is generated in situ in a reaction-inert solvent in the presence of the 15 Formula IV compounds by a number of methods known to those skilled in the arts, such as those described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995. The desired Formula XII compounds wherein L is a (C0-C6) alkoxycarbonyl group, K is a leaving group such as chlorine or bromine, and V, R 1 , R 2 , R 4 , R 5 , R 6 , 20 and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula VII compounds by reaction with a suitable organometallic derivative of the V group such as a magnesium or lithium derivative, prepared in turn from a compound V-Hal where Hal represents a chlorine, bromine or iodine atom. This reaction is conducted in a suitable reaction inert solvent such 25 tetrahydrofuran or diethyl ether at a temperature between -78*C to 250C, typically 780C, to provide the desired product of Formula XII. As referred to above, the desired Formula VII compounds wherein L is a (C C6) alkoxycarbonyl group, K is a leaving group such as chlorine or bromine, and R 1 ,
R
2 , R 4 , R 5 , RG, and R 7 are as described above may be prepared as a mixture of 30 diastereoisomers from the corresponding Formula VI compounds by reaction with an acyl compound KCOL at a temperature between 00C to 250C, typically ambient, in a reaction inert solvent such as acetonitrile or toluene, optionally in the presence of a base such as diisopropylethylamine or triethylamine to remove traces of HK which may be present. Depending on the nature of the substitutents on the Formula VI WO 2004/085401 PCT/IB2004/000836 -38 compounds and the nature of L, the Formula VII compound may be obtained as a mixture with the corresponding Formula V compound. The desired Formula XIII compounds wherein M is a (CrC6) alkoxy group and R', R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of 5 diastereoisomers from the corresponding Formula VI compounds by reaction with phosgene at a temperature between 0"C to 250C, typically ambient, in a reaction inert solvent such as acetonitrile or toluene in the presence of a base such as diisopropylethylamine or triethylamine. Addition of the desired alcohol MOH to the acid chloride in the presence of excess base then provides the desired Formula XIlI 10 compound. The desired Formula XIV compounds wherein M is a (C6) alkoxy group and R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula X111 compounds by hydrogenolysis. This may be achieved by hydrogenation in a reaction inert solvent 15 such as methanol, ethanol or acetic acid with a catalyst such as palladium or rhodium on carbon under a hydrogen pressure equal to 15-50 psi for a period between 2 24hrs, or by transfer hydrogenation using ammonium formate in refluxing methanol in the presence of a catalyst such as palladium on carbon in a reaction inert solvent such as methanol or ethanol at a temperature between 00C to 800C, typically 251C to 20 600C. Alternatively, the Formula XIII compounds may be treated with a finely divided metal such as zinc in the presence of an acid, or mixture of acids, such as acetic acid or hydrochloric acid in a suitable solvent, or mixture of solvents such as methanol, water or tetrahydrofuran at a temperature between 250C to 600C, typically ambient, to provide the desired Formula XIV compounds. 25 The desired Formula XV compounds wherein R', R 2 , R 4 , R , R", and R are as described above may be prepared by hydrolysis of the ester group of the Formula XIV compounds, using methods well known to those skilled in the arts, such as can be found in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995, for example, by treatment with an 30 aqueous base, preferably, lithium, sodium, or potassium hydroxide, in a polar solvent, preferably dioxane, at a temperature between 00C and 100*C (preferably room temperature) for between 1 to 20 hours to provide the desired Formula XV compounds. SCHEME 2 WO 2004/085401 PCT/IB2004/000836 -39
R
4
NH
2
R
4 OMe
R
6 N R 2 R N R2
R
7
R
1 R XXIX IXXX
R
4 Q
R
4 0
R
4 O R6 R 2 2 2 R2 R5 L V R R XNV R 6 N' R R N R 2 7 R 7 R 1
R
7 1 R R F 1 0
R
4 Q
R
4 ON O4 0 H
R
5
R
5
R
5 R N R R N R2 R N R2
R
7 1 R R R 0 2 6SCHEME 2 N R v R 1 XVI R, 0 2 6 - 2 R5 N R R N R
R
7 1 1R 7
R
1 R4 N-R 9 X 6 2
R
7 Ii 6 4 N R 2 RFEVF R~ 4 1 R7XRVI R5 XXVII RtD'5 N R 2
R
7 I1 SCHEME 2 WO 2004/085401 PCT/IB2004/000836 -40 According to reaction Scheme 2, the desired compounds wherein J is carbon, the optional double bond is absent, R 3 is a group CH(V)(L) wherein L is a (C-Ce) alkoxycarbonyl group or a cyano group and V, R', R 2 , R 4 , R 5 , R', and R are as described above (depicted as Formula XVI compounds) may be prepared as a 5 mixture of diastereoisomers from the corresponding Formula XVII compounds by reaction with a compound VCH 2 L in the presence of a suitable base such as 1,8 diazabicyclo[5.4.0]undec-7-ene , diisopropylethylamine, triethylamine or sodium hydride in a reaction inert solvent such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile or toluene at a temperature between 0*C to 60"C, typically ambient. 10 The desired Formula XVII compounds wherein Q is a leaving group such as chlorine, bromine, methanesulfonyloxy or p-toluenesulfonyloxy and R 1 , R 2 , R 4 , R, R 6 , and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula XVIII compounds by reaction with the appropriate reagent such as methanesulfonyl chloride or toluenesulfonyl chloride in the presence 15 of a suitable base such as diisopropylethylamine or triethylamine in a reaction inert solvent such as N,N-dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride or toluene at a temperature between 00C to 600C, typically ambient. Other suitable reagents for formation of the Formula XVII compounds include phosphorus (Ill) chloride, phosphorus (Ill) bromide and thionyl chloride optionally in a reaction 20 inert solvent such as chloroform, methylene chloride, pyridine or toluene at a temperature between 0"C to 60"C, typically ambient. The desired Formula XVIII compounds wherein R', R 2 , R 4 , R 5 , R6, and R 7 are as described above may be prepared as a mixture of diastereoisomers from the corresponding Formula IX compounds by reduction of the carbonyl group using 25 methods and reagents well known to those skilled in the arts, such as can be found in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995, for example using sodium borohydride in an alcohol solvent such as methanol of ethanol at a temperature between 00C to 60*C, typically ambient or using potassium tri-sec-butylborohydride (K-Selectride@) in a 30 reaction inert solvent such as tetrahydrofuran or diethyl ether at a temperature between -78*C to 250C, typically 00C. In an alternative procedure, the desired Formula XVIII compounds wherein R', R 2 , R 4 , R 6 , R , and R 7 are as described above may be obtained by treatment of the corresponding Formula XIX compounds with sodium nitrite in the presence of an WO 2004/085401 PCT/IB2004/000836 -41 acid, preferably acetic acid, followed by hydrolysis with a suitable base such as lithium, sodium, or potassium hydroxide, preferably sodium hydroxide in a suitable hydroxylic solvent such as ethanol to give the desired Formula XIX compounds. Methods for the preparation of Formula XIX compounds are described in US Patent 5 6197786 and International Application WO 0140190. The desired Formula IX compounds wherein R' is an alkoxycarbonyl group and R 2 , R, R 5 , R", and R are as described above may be prepared from the corresponding 4-methoxyquinoline compounds of Formula XX by treatment with an organomagnesium derivative of the R2 group together with an acylating agent such 10 as ethyl chloroformate at a temperature between -1 00*C to 70 0 C, typically -78*C in a reaction inert solvent such as tetrahydrofuran followed by warming to a temperature between 0*C and about 700C (preferably ambient) for between 0.1 and 24hr, preferably 1 hr, followed by hydrolysis in aqueous acid, preferably IN hydrochloric acid to give the desired Formula IX compounds, as described in US Patent 6197786. 15 In an alternative procedure, the desired Formula IX compounds wherein R 1 , R, R 4 , R 5 , R 6 , and R 7 are as described above may be obtained by oxidation of the corresponding Formula XVIII compounds using a variety of methods and reagents well known to those skilled in the arts, such as can be found in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, 20 England, 1995, for example pyridinium chlorochromate, aqueous sodium hypochlorite in the presence of a catalytic amount of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) free radical and catalytic potassium bromide in a suitable reaction inert solvent such as methylene chloride, or alternatively with acetic anhydride and dimethylsulfoxide. The desired Formula XXI compounds wherein R 1 , R 2 , R 4 , R , R , R are as 25 described above may be prepared from the corresponding Formula IX compounds by treatment with trimethylsilylcyanide in an inert solvent such as an aromatic hydrocarbon (e.g.,benzene, toluene, xylene) in the presence of a catalytic amount of Lewis acid, preferably zinc iodide, at a temperature of about 25 IC to about 140 C, preferably about 80 0C to about 100 0C, for 1-12 hours , preferably 5 hours. The 30 resulting solution is concentrated to dryness and added directly without further purification to a polar solvent (e.g., methanol, ethanol). A solution of acid (preferably hydrochloric) in a polar aprotic solvent (preferably dioxane) is added to the solution and the mixture is stirred at a temperature from 0 0C to about 100 OC, preferably WO 2004/085401 PCT/IB2004/000836 -42 room temperature, for 1 to 24 hours, preferably 12 hours, to yield the Formula XXI compounds. The desired Formula XXII compounds wherein R 1 , R 2 , R 4 , R 5 , R', R 7 are as described above may be prepared from the corresponding Formula XXI compounds 5 by treatment with a reducing agent such as sodium borohydride or sodium cyanoborohydride in a reaction inert solvent such as methanol or ethanol, preferably ethanol, at a temperature of about 0 0C to about 100 0C (preferably reflux temperature) for 0.1 to 5 hours (preferably 0.75 hour) to provide the desired Formula XXII compounds. 1 2 4 5 6 10 Alternatively, the desired Formula XXII compounds wherein R', R , R4, R5, R , R7 are as described above may be prepared from the corresponding Formula XVII compounds, wherein Q is a leaving group as described above, by treatment with a cyanide salt such as lithium, sodium, potassium or a tetraalkylammonium cyanide in a reaction inert solvent such as dimethylformamide at a temperature between 0 OC to 15 100 C for 1 to 12 hours, to provide the Formula XXII compounds. The desired Formula XXIII compounds wherein R', R 2 , R 4 , R 5 , R 6 , R 7 are as described above may be prepared from the corresponding Formula XXII compounds by dissolving in concentrated sulfuric acid containing five equivalents of water at a temperature from 00C to 100 C (preferably room temperature) for 1 to 20 hours. The 20 resulting amide is then dissolved in a polar solvent (preferably methylene chloride) and treated with trimethyloxonium tetrafluoroborate at a temperature from 00C to 100 C (preferably room temperature) for 1-20 hours (preferably 12 hours). The resulting imino ester is then treated with an aqueous base, preferably, lithium, sodium, or potassium hydroxide, in a polar solvent, preferably dioxane, at a 25 temperature between 00C and 1000C (preferably room temperature) for between 1 to 20 hours to provide the Formula XXIII Compounds. The desired Formula XXIV compounds wherein R', R 2 , R 4 , R 5 , R 6 , R , R and
R
9 are as described above may be prepared from the corresponding Formula XXIII compounds by treating the acid in a reaction inert solvent (preferably 30 dichloromethane) with the corresponding amine (NHR 8
R
9 ) in the presence of 1 hydroxybenzotriazole hydrate (HOBT) and 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride (EDCI) at a temperature between 00C to 1000C (preferably ambient temperature) for 1 to 24 hours (preferably 12 hours).
WO 2004/085401 PCT/IB2004/000836 -43 The desired Formula XXV compounds wherein R', R2, R , R , R 6 , R are as described above and V2 is a group V or CH 2 V where V is as described above may be prepared from the corresponding Formula XXIV compounds when R 8 is methyl and
R
9 is methoxy (the 'Weinreb' amide) by treatment with a variety of V 2 Met compounds 5 where Met is a metal, preferably magnesium or lithium, to produce the desired Formula XXV compounds. The desired Formula XXVI compounds wherein R', R 2, R4, RI, RI, R, R' and R2 (which are within the scope of the present invention) are as described above may be prepared from the corresponding Formula XXIV compounds by reduction with a 10 hydride source, preferably sodium borohydride, in the presence of an acid such as trifluoroacetic acid in a reaction inert solvent (preferably tetrahydrofuran) at a temperature of between 0 OC and 100 OC for I to 20 hours (preferably 12 hour). When R" and/or R is H, the amine may be acylated using standard amide coupling conditions known to those skilled in the art such as those described in L.A. Paquette 15 (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995, to produce further Formula XXVI compounds. An alternative preparation of the desired Formula XXVI compounds wherein
R
1 , R-, R 4 , R 5 , R 6 and R are as described above and R 8 and R 9 are H involves reduction of the corresponding Formula XXII compounds using procedures known to 20 those skilled in the art, such as those described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995, for example using borane-tetrahydrofuran complex in a reaction inert solvent. These primary amines may subsequently be converted to amides as described above to produce further compounds within the scope of the present invention. 25 The desired Formula XXVII compounds wherein R', R 2, R4, R , R , Rand V 2 are as described above and X 1 is OH, F, or H, may be prepared from the corresponding Formula XXV compounds by treatment with a reducing agent such as sodium borohydride in a polar solvent such as methanol or ethanol at a temperature of about 0 0 C to about 100 OC for 1 to 10 hours (preferably 1 hour) to produce Formula XXVII 30 compounds wherein X 1 is OH. Formula XXVII compounds when X 1 =N may be prepared from the corresponding alcohol (X=OH) which is converted to the mesylate and displaced with sodium azide. The azide is hydrogenated to NH 2 . One skilled in the art can convert
NH
2 to NR'H by standard reductive amination conditions using the correspounding WO 2004/085401 PCT/IB2004/000836 -44 aldehyde and reducing agent, such as sodium borohydride or sodium cyano borohydrite. NR'H can be converted to NR'R2 using the same conditions of reductive amination to produce NR1R 2 . Moreover, when X 1 is NH 2 , the corresponding alcohol (X=OH) may be 5 converted to the mesylate, displaced with an azide and reduced with hydrogen to produce one single diastereomer. When X 1 is NHR (R 1 =Me), the corresponding primary amine NH 2 may be converted to NHR 1 by treatment with ethyl formate at a temperature between 0 0C to 100 0C between 1-24 hours (preferably 12 hours). The resulting formamide is added directly without further purification to a nonpolar solvent 10 (e.g., benzene, toluene, preferably toluene) and a reducing agent such as borane methyl sulfide complex at a temperature between 0 0C to 100 0C between 1-24 hours (preferably 12 hours) to provide the desired mono methyl amine product. When X' is NHR', the corresponding primary amine NH 2 may be converted to NHR 1 by standard reductive amination conditions by treatment with an aldehyde R 1 in a polar solvent 15 such as methanol or ethanol in the presence of sodium borohydride or sodium cyanoborohydride at a temperature between 0 0C to 100 0C between 1-24 hours (preferably 12 hours). When X 1 is NR 1
R
2 , the corresponding secondary amine NHR 1 may be converted to NR 1
R
2 by standard reductive as described above. Compound XXV may also be converted to NH 2 , NHR 1 , and NR 1
R
2 by standard reductive 20 amination conditions with the corresponding aldehyde or ketone as described above. This method produces a mixture of amine diastereomers that may be separated by silica gel chromatography. These may be converted to the corresponding Formula XXVII compounds where X 1 is F by treatment with a fluorinating agent, such as diethylaminosulfur 25 trifluoride (DAST) or [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxyfluor) in a reaction inert solvent such as dichloromethane or 1,2 dichloroethane at a temperature between -78 C to about 100 C (preferably ambient temperature) for 0.1 to 10 hours (preferably 1 hour). These may be converted to the corresponding Formula XXVII compounds wherein X' is H by reduction with a suitable hydride 30 source such as diisobutyl aluminum hydride in a reaction inert solvent such as tetrahydrofuran at a temperature between -78 0C to about 100 C, preferably about 0 C, for 0.1 to 10 hours.
WO 2004/085401 PCT/IB2004/000836 -45 The desired Formula XXVIII compounds wherein R', R 2 , R 4 , R 5 , R 6 , Rare as described above and V 2 is a group V or CH 2 V where V is as described above may be prepared from the corresponding Formula XXV compounds by treatment with a fluorinating agent, such as diethylaminosulfur trifluoride (DAST) or [bis(2 5 methoxyethyl)amino]sulfur trifluoride (Deoxyfluor) in a reaction inert solvent such as dichloromethane or 1,2-dichloroethane at a temperature between -78 0C to about 100*C (preferably ambient temperature) for 0.1 to 24 hours (preferably 12 hours). SCHEME 3
R
5
R
4 H R4 R N H 2 R_____ N 0I 1 6 N R, 6 - 02 R N 2 R N R 7
NH
2 7 R 7XXXI XXX XXIX H R 4 Boc R N R 2 RD N R2 H -H R 7 H R7 XXXII XXXIII
R
4 Boc H
R
5 5 2 N R 2 RD *'N R 2 7 R1*
R
7
R
1 R R XXXIV XXXV 10 SCHEME 3 According to Scheme 3, the desired Formula XXIX compounds wherein J is nitrogen, the optional double bond is absent, and R 2 , R 4 , RE, R , and R are as described above, may be prepared from the corresponding Formula XXX compounds 15 by reaction with an alpha-ketocarboxylic acid R2COC 2 H in a protic solvent, such as ethanol or methanol at high temperature. These temperatures can be conveniently and safely achieved using a microwave apparatus familiar to one skilled in the art, such as a Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) or Milestone microwave (Milestone Laboratories, Sorisole, Italy). The resulting reaction mixture is WO 2004/085401 PCT/IB2004/000836 -46 concentrated to dryness and the Formula XXIX compounds can be usually crystallized or alternatively can be purified by flash chromatography on silica gel. The desired Formula XXXI compounds wherein R 2 , R 4 , R 5 , R 6 , and R are as described above may be prepared from the corresponding Formula XXIX compounds 5 by treatment with a chlorinating agent such as phosphorus (Ill) chloride, phosphorus (V) oxychloride, thionyl chloride or triphenylphosphine/carbon tetrachloride. Typically Formula XXIX compounds are dissolved in excess phosphorus oxychloride and the mixture is heated to about 1 000C, for 12-18h. After cooling excess phosphorus (V) oxychloride is distilled off and the residue is carefully quenched with saturated 10 NaHCO 3 . The resulting aqueous suspension is extracted with an appropriate organic solvent, preferably methylene chloride. The desired Formula XXXII compounds wherein R 2 , R 4 , R 5 , R 6 , and R are as described above may be prepared from the corresponding Formula XXXI compounds by catalytic hydrogenation in the presence of standard catalysts well known to those 15 skilled in the art, for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995. Typically, the compound is dissolved in an organic solvent, preferably a polar solvent such as acetic acid. Additives such as sodium acetate are usually added to improve the reaction rate. An appropriate catalyst is chosen, such as palladium on carbon. 20 Hydrogenation is carried out at elevated pressures in an appropriate apparatus, preferably for about 6 h. The catalyst is filtered off to yield the Formula XXXII compound, which is typically isolated after chromatography on silica gel. The desired Formula XXXIII compounds wherein R 2 , R 4 , R 5 , R 6 , and R' are as described above may be prepared from the corresponding Formula XXXII 25 compounds by reaction with boc-anhydride as described in the T. W. Greene and G.M. Wuts, Protective Groups in Organic Synthesis, Wiley Interscience, 1991. Typically, the reaction is carried out in a solvent such as methylene chloride at -78 0 C to 00C, typically -40*C. In general, in this procedure, there is a selective functionalization of the less hindered nitrogen in Formula XXXII compounds. The 30 Formula XXXIII compounds can be purified by standard silica gel chromatography, if needed. The desired Formula XXXIV compounds wherein R', R , R4, R5, R , and R' are as described above may be prepared from the corresponding Formula XXXIII compounds by introducing the acyl, carbamoyl, sulfinyl or sulfonyl group R 1 . This may WO 2004/085401 PCT/IB2004/000836 -47 be achieved by treatment with an appropriate reagent, for example, ethyl chloroformate or isopropyl chloroformate, in a suitable reaction inert solvent such as methylene chloride or chloroform optionally containing a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine at 5 a temperature between 0"C to 60*C, typically ambient, for a period of I to 24hr. At times, the reaction is carried out in pyridine as a solvent. The product is usually isolated by standard extractive workup and flash chromatography on silica gel. The desired Formula XXXV compounds wherein R', R 2 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding Formula XXXIV 10 compound by treatment with an acid as described in the T. W. Greene and G.M. Wuts, Protective Groups in Organic Synthesis, Wiley Interscience, 1991. In a typical procedure, the bis-carbamate is treated with trifluoroacetic acid at ambient temperature for 1-24hr, typically 3hr. Upon completion, the acid is removed by evaporation and the residue is partitioned between an organic solvent, preferably 15 methylene chloride and aqueous sodium hydrogen carbonate. Evaporation of the organic solvent affords the desired Formula XXXV compounds.
WO 2004/085401 PCT/IB2004/000836 -48 SCHEME 4 OMe R4 YV OH R5 N R4 R 6 N R 2 R N
R
7 Ri R R N R 2 OAc
R
7 R R4 V XXXIX R 5 N
R
6 _ N R 2 R 7 Ri RI LI MeO 2 v
R
4
R
3 R4
R
4 H
R
5 N
R
5 N
R
5 N R 6 *- R 26*N
R
2 N R 2 R - N R 2 R 7 Ri R Ri R 7 RI XXXVIII XXXV XXXVII
R
4
R
3
R
5 N RN R 2
R
7 1 I RR XXXVI SCHEME 4 5 According to Scheme 4, the desired compounds wherein J is nitrogen, the optional double bond is absent, R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are as described above and
R
3 is as described above wherein the connecting carbon is oxo substituted (depicted as Formula XXXVI compounds) may be prepared from the corresponding Formula WO 2004/085401 PCT/IB2004/000836 -49 XXXV compounds by reaction with an acid chloride, in a solvent such as methylene chloride or chloroform, optionally containing a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine, at a temperature between 00C to 600C, typically ambient, for a period of 1 to 24hr. 5 Upon completion of the reaction, the mixture is washed with aqueous acid and brine to afford the Formula XXXVI compounds after silica gel chromatography. If desired, the acid chloride can be generated in situ, from the corresponding carboxylic acid and triphenylphosphine in conjunction with agents such as carbon tetrachloride, hexachloroethane or trichloroacetonitrile. This latter procedure can be carried out with 10 resin bound triphenylphosphine which makes it amenable to automated chemistry. Filtration of the resin followed by evaporation and purification on silica gel yields the required compound of Formula XXXVI. The desired Formula XXXVII compounds wherein R', R 2 , R 4 , R , R 6 , and R 7 are as described above and R 3 is as described above, wherein the group V is 15 attached to the connecting carbon, may be prepared from the corresponding Formula XXXV compounds by alkylation with the appropriate alkyl bromides. These alkylations are typically carried out in a polar solvent such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone etc. in the presence of a base (e.g., potassium carbonate, triethylamine, pyridine, 4-dimethylaminopyridine, lutidine) at a 20 temperature between 250C to 2000C, typically 1500C. Due to the unreactivity of quinoxalines, heating in the microwave at the appropriate temperature is particularly suitable for this procedure. Alkylations can be performed with a variety of alkyl bromides, such as arylmethyl bromides or alpha-substituted arylmethyl bromides. Use of suitable microwave equipment such as the Emrys Optimizer (Personal 25 Chemistry, Uppsala, Sweden) or Milestone microwave (Milestone Laboratories, Sorisole, Italy) facilitates these reactions. The desired Formula XXXVIII compounds, wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and V are as described above may be prepared from the corresponding alpha bromoester VCHBrCO 2 Me compounds. These alkylations are typically carried out in a 30 polar solvent such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone etc. in the presence of a base (e.g., potassium carbonate, triethylamine, pyridine, 4 dimethylaminopyridine, lutidine) at a temperature between 250C to 2000C, typically 1500C. Due to the unreactivity of quinoxalines, heating in the microwave at the appropriate temperature is particularly suitable for this procedure. Use of suitable WO 2004/085401 PCT/IB2004/000836 -50 microwave equipment such as the Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) or Milestone microwave (Milestone Laboratories, Sorisole, Italy) facilitates these reactions. The desired Formula XXXIX compounds, wherein R', R2, R4, R 5 , R 6 , R 7 and V 5 are as described above may be prepared from the corresponding Formula XXXVIII compounds by the reduction of the ester functionality using reagents and conditions well known to those skilled in the art. For example, Formula XXXVIII compounds can be treated with lithium aluminum hydride in anhydrous ethereal solvents such as tetrahydrofuran and ether at temperatures ranging between -78*C and 0 0 C. Typically 10 treating the reaction mixture with sodium sulfate hexahydrate or silica gel/chloroform and removal of the solids by filtration gives a crude product from which Formula XXXIX compounds are typically isolated by silica gel chromatography. The desired Formula L compounds, wherein R', R 2 , R 4 , R , R , R and V are as described above may be prepared from the corresponding Formula XXXIX 15 compounds by using an appropriate alkylating agent, such as an alkyl iodide or bromide and a base, such as sodium hydride, in a reaction inert solvent such as tetrahydrofuran or dimethylformamide to obtain the desired Formula L compounds. The desired Formula LI compounds, wherein R', R 2 , R 4 , R 5 , R 6 , R 7 and V are as described above and Ac is an acyl group (which are within the scope of the 20 present invention) may be prepared from the corresponding Formula XXXIX compounds by using a suitable acyl chloride and a base such as pyridine, triethylamine or 4-dimethylaminopyridine in an anhydrous solvent such as dichloromethane. Depending on the reactivity of the acyl chloride, one can use the base, such as pyridine, as the solvent. The products can usually be isolated by 25 concentrating the reaction mixture and purifying the product by silica gel chromatography.
WO 2004/085401 PCT/IB2004/000836 -51 SCHEME 5 P40 R40 R4 H R R R- RR2
R
7 R6 LIII L LIV 40 V
R
4
/
3 R N R2R2 R N R LRV H 5 N 5 V N R R N4R R V R5 RN R 3 I RR R NNR2 LVI R H R4 O V 4 R R R2 R N R 6 N IR 2 6 R 7 H' R N) R2 LVII LX SCHEME 5 5 Scheme 5 describes the preparation of further compounds, in which J is nitrogen and the optional double bond is absent (i.e. quinoxalines), using soiid phase chemistry similar to that described by V. Krchnak eta., Tetrahedron Lett. 42, 2443 2446 (2001), and which offers several advantages. This chemistry can also be WO 2004/085401 PCT/IB2004/000836 -52 carried out in the solution phase by substituting the resin with an electron rich arylmethyl group, such as 4-methoxybenzyl or 2,4-dimethoxybenzyl and using it like a protecting group and cleaving under appropriate conditions as described in T.W. Greene and G.M. Wuts, Protective Groups in Orqanic Synthesis, Wiley Interscience, 5 1991. In particular, this scheme provides a method for preparation of chiral quinoxalines from chiral aminoalcohols, which are readily prepared from widely available chiral aminoacids using methods and reagents well known to those skilled in the art. The resin bound Formula LII compounds wherein R , R, R , Rand Rare as 10 described above can be prepared from the corresponding aminoalcohol R 2CH(CH 2
OH)NH
2 which is first bound to a resin by the method described by V. Krchnak et.aL., Tetrahedron Lett. 42, 2443-2446 (2001). This is then treated with the corresponding Formula LlII compounds typically in a polar solvent such as dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone or dimethylacetamide which is 15 capable of allowing polystyrene based resin to swell as known to one skilled in the art. The reaction is carried out for 12-36h, and the resin is then washed to isolate the desired resin bound Formula LII compounds. The desired resin bound Formula LIV compounds, wherein R 2 , R 4 , R 5 , R 6 , and R7 are as described above may be prepared from the corresponding resin bound 20 alcohol of Formula LlI compounds by activating the alcohol functionality as familiar to one skilled in the art. This involves the conversion of the alcohol to a sulfonate (such as a methanesulfonate or toluenesulfonate), halide (such as chloride or bromide) or an acetate. Preferably the reaction is carried out by treatment of the resin bound Formula LII compounds with methanesulfonyl chloride in the presence of a base such 25 as pyridine, 4-dimethylaminopyridine or proton sponge in solvents such as dichloromethane or dichloroethane in which case the reaction is typically carried out for 1-5 h. The resulting resin bound sulfonate is washed of all the reagents and the nitro group can be reduced by a variety of reducing agents well known to those skilled in the art, for example as described in L.A. Paquette (Ed), Encyclopedia of 30 Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995. For example, one can use tin (II) chloride in a polar solvent such as N methylpyrrolidone or dimethylformamide, which are capable of swelling a polystyrene based resin. The reaction is typically carried out for 1-5h, the reagents are washed away and the resulting primary amine undergoes an intramolecular ring closure to WO 2004/085401 PCT/IB2004/000836 -53 afford the resin bound Formula LIV compounds. If one uses an activating group other than a methanesulfonate as described above, the reaction times for the ring closure might be longer as known to one skilled in the art. The resin bound Formula LV compounds wherein R 2 , R 4 , R', R 6 , R' and V are 5 as described above may be prepared from the corresponding Formula LIV compounds, by reaction with an acid chloride VOCI, in a solvent such as methylene chloride or chloroform optionally containing a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine at a temperature between 00C to 600C, typically ambient, for a period of 1 to 24hr. The 10 resin bound Formula LV compound is subsequently filtered and repeatedly washed with solvents such as dichloromethane, methanol and water to remove the excess reagents. The desired Formula LVI compounds wherein R 2 , R 4 , R5, R 6 , R 7 and V are as described above may be prepared from the corresponding resin bound Formula LV 15 compounds, by treatment with a strong acid well known to those skilled in the art, such as trifluoroacetic acid or hydrofluoric acid, optionally in a reaction-inert solvent such as dichloromethane or dichloroethane. Typically the desired Formula LVI compounds can be isolated by filtration and washing of the resin with an appropriate organic solvent such as dichloromethane, dichloroethane or tetrahydrofuran. If 20 necessary, the Formula LVI compounds can be further purified by silica gel chromatography under standard conditions. The desired Formula LVII compounds wherein R', R 2 , R4, R 5 , R 6 , R 7 and V are as described above may be prepared from the corresponding Formula LVI compounds by treatment with an appropriate reagent, for example, ethyl 25 chloroformate or isopropyl chloroformate, in a reaction inert solvent such as methylene chloride or chloroform, optionally containing a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine at a temperature between 0*C to 60*C, typically ambient, for a period of 1 to 24hr. At times, the reaction is carried out in pyridine as a solvent. In the particular case where 30 R' is a carbamate or urea, the product can be obtained by treating Formula LVI compounds with phosgene in toluene, optionally containing a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine at a temperature between 00C to 600C, followed by treatment with, respectively, an alcohol or an amine to afford the desired carbamate or urea of Formula LVIl. The WO 2004/085401 PCT/IB2004/000836 -54 product is usually isolated by standard extractive workup and flash chromatography on silica gel. The desired resin bound Formula LVIII compounds, wherein R', R 2 , R 4 , R 5 , R', and R 7 are as described above and R3 is as described above, wherein the group 5 V is attached to the connecting carbon, may be prepared from the corresponding resin bound Formula LIV compounds by alkylation with the appropriate alkyl bromides or iodides. These alkylations are typically carried out in a polar solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone in the presence of a base (triethylamine, pyridine, 4-dimethylaminopyridine, lutidine). The solvents used in 10 this reaction are capable of allowing the polystyrene resin to swell as familiar to one skilled in the art. These reactions are usually carried out from ambient temperatures to about 150 0 C. Due to the unreactivity of quinoxalines, heating in a microwave oven at an appropriate temperature is preferred. Alkylations can be performed with a variety of alkyl bromides such as arylmethyl bromides or alpha-substituted arylmethyl 15 bromides. The alkylation reactions typically proceed in better yield if the bromides are substituted with an alpha electron-withdrawing group (such as in the preparation of the Formula XXXVIII compounds in Scheme 4). The quinoxaline compounds of Formula LIX wherein R1, R2, R 4, R, R', and R are as described above may be prepared from the corresponding resin bound 20 Formula LVIII compounds, by treatment with strong acids well known to those skilled in the art, such as trifluoroacetic acid or hydrofluoric acid, with or without additional solvents (such as dichloromethane or dichloroethane). Typically, the quinoxaline compounds of Formula LIX, can be isolated by filtration and washing of the resin with an appropriate organic solvent such as dichloromethane, dichloroethane or 25 tetrahydrofuran. Evaporation of the solvent usually affords clean desired Formula LIX compounds. If necessary, the isolated products can be further purified by silica gel chromatography under standard conditions. The desired Formula LX compounds wherein R', R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as described above may be prepared from the corresponding Formula LIX 30 compound by treatment with an acylating/sulfonating agent solvent, for example ethyl or isopropyl chloroformate in a reaction-inert solvent such as methylene chloride or chloroform optionally containing a base such as pyridine, diisopropylethylamine, 4 dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine at a temperature between 0 0 C to 60*C, typically ambient, for a period of 1 to 24hr. At times, the reaction is WO 2004/085401 PCT/IB2004/000836 -55 carried out in pyridine as a solvent. In the particular case when R' is a carbamate or urea, the product can be obtained by treating Formula LX compound with phosgene in toluene optionally containing a base such as pyridine, diisopropylethylamine, 4 dimethylaminopyridine 2,6-di-tert-butyl-4-methylpyridine at a temperature between 5 00C to 600C, followed by treatment with, respectively, an alcohol or an amine to afford the desired carbamate or urea Formula LX compound. The product is usually isolated by standard extractive workup and flash chromatography on silica gel. An alternative preparation of the desired Formula LVI compounds wherein R 2 ,
R
4 , R 5 , RO, R 7 and V are as described above may be achieved from the 10 corresponding Formula XXXV compounds by reaction with an acylating agent such as acid chloride VOCI, in a solvent such as methylene chloride or chloroform optionally containing a base such as pyridine, diisopropylethylamine, 4 dimethylaminopyridine or 2,6-di-tert-butyl-4-methylpyridine at a temperature between 00C to 600C, typically ambient, for a period of I to 24hr. Typically under these 15 conditions, when R2 is other than hydrogen, the less hindered nitrogen atom of the quinoxaline preferentially undergoes acylation to give the desired Formula LVI compounds. The desired compounds of Formula LVII wherein R', R 2 , R 4 , R 5 , R 6 , R 7 are as described above and R 3 is as described above, wherein the group V is attached to the connecting carbon, may be achieved from the corresponding Formula 20 LVI compounds by alkylation or acylation, using procedures as described above. An alternative preparation of the desired Formula LIX compounds wherein R 2
R
4 , R 5 , R 6 , R 7 are as described above and R 3 is as described above, wherein the group V is attached to the connecting carbon, may be achieved from the corresponding Formula XXXV compounds, via the compounds of Formula LIX, by 25 alkylation with the appropriate alkyl bromides or iodides. These alkylations are typically carried out in a polar solvent such as dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone in the presence of a base (e.g., triethylamine, pyridine, 4 dimethylaminopyridine, lutidine). These reactions are usually carried out from ambient temperatures to about 1500C. Due to the unreactivity of quinoxalines, heating in a 30 microwave oven at an appropriate temperature is preferred. Alkylations can be performed with a variety of alkyl bromides such as arylmethyl bromides, alpha substituted arylmethyl bromides. Typically under these conditions, when R 2 is other than hydrogen, the less hindered nitrogen atom of the quinoxaline preferentially undergoes alkylation to give the desired Formula LIX compounds.
WO 2004/085401 PCT/IB2004/000836 -56 The desired Formula XXXV compounds wherein R2, R4, R5, R6, and R are as described above may be prepared from the corresponding resin bound Formula LIV compounds by treatment with strong acids well known to those skilled in the art, such as trifluoroacetic acid or hydrofluoric acid, optionally in a reaction inert solvent such 5 as dichloromethane or dichloroethane. SCHEME 6 4~4 V OH
R
4
NNH
2 R4I OH
R
5 NN -1 R ' R u
R
6 6 2R 2 N R 2 R N R 2
R
7
R
1
R
7
R
1 R R VIll LXI LXII L V 0 R4 OH R 4 R 5
R
5 R) N R2 Rb N R 2 R R R IV LXIII 10 SCHEME6 According to reaction Scheme 6, the desired compounds wherein J is carbon, the optional double bond is present, R 3 is a group COV and V, R 1 , R 2 , R 4 , R , R 6 , and R are as described above (depicted as Formula LXIII compounds) can be prepared from the corresponding Formula LXII compounds by oxidation of the alcohol. This 15 may be achieved by a wide variety of methods well known to those skilled in the art, for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, England, 1995. For example the Formula LXII compounds can be treated with activated manganese (IV) oxide in a suitable reaction inert solvent such as tetrahydrofuran, diethyl ether or 20 dichloromethane at a temperature between 0*C to 25*C, typically ambient, to provide the desired product of Formula LXIII. The desired Formula LXII compounds wherein V, R', R 2 , R 4 , R , R 6 , and R 7 are as described above can be prepared as a mixture of diastereoisomers from the corresponding Formula LXI compounds by treatment with a suitable transmetallating WO 2004/085401 PCT/IB2004/000836 -57 agent such as an alkyllithium compound, such as n-butyllthium or s-butyllithium, or an alkylmagnesium halide such as isopropylmagnesium chloride in a suitable reaction inert solvent such as tetrahydrofuran or diethyl ether at a temperature between 1200C to 00C, typically -78"C, to provide a vinyllithium species which is then reacted 5 with the appropriate aldehyde of formula VCHO at a temperature between -1201C to 00C, typically -781C to -23*C, to provide the desired product of Formula LXII. In some cases, it is convenient to add the transmetallation agent to a mixture of the aldehyde and the iodide. The desired Formula LXI compounds wherein R', R 2 , R 4 , R 5 , R 6 , and R 7 are 10 as described above can be prepared from the corresponding Formula VIII compounds (prepared as described in Scheme 1) using the general procedure described by D.H.R. Barton et al. (Tetrahedron Letters 1983 24, 1605) in which the hydrazone is reacted with iodine in the presence of a suitable hindered base such as 1,1,3,3-tetramethylguanidine in a suitable reaction inert solvent such as 15 tetrahydrofuran at a temperature between 250C to 100*C, typically 25*C to 85"C, removing the solvent in the course of the reaction, to provide the desired product of Formula LXI. An alternative preparation of the desired Formula IV compounds wherein L is a (C 1
-C
6 )alkoxycarbonyl group and V, R1, R 2, R4, R5, R6, and R are as described 20 above can be accomplished in a manner similar to that described for the preparation of the Formula LXII compounds from the corresponding Formula LXI compounds by treatment with a suitable transmetallating agent such as an alkyllithium compound such as n-butyllthium or s-butyllithium, or an alkylmagnesium halide such as isopropylmagnesium chloride in a suitable reaction inert solvent such as 25 tetrahydrofuran or diethyl ether at a temperature between -1200C to 00C, typically 780C, to provide a vinyllithium species, which is then reacted with the appropriate ketone of formula VCOL at a temperature between -1200C to 00C, typically -780C to 230C, to provide the desired product of Formula IV. In some cases, it is convenient to add the transmetallation agent to a mixture of the ketone and the iodide. 30 As an initial note, in the preparation of compounds, it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in intermediates). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation WO 2004/085401 PCT/IB2004/000836 -58 methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. 5 For example, in the reaction schemes, certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid 10 protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl, benzyloxycarbony, and 9 fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other 15 functionality in the compound. Prodrugs of the compounds of the present invention may be prepared according to methods known to those skilled in the art. Exemplary processes are described below. Prodrugs of this invention where a carboxyl group in a carboxylic acid of the 20 compounds is replaced by an ester may be prepared by combining the carboxylic acid with the appropriate alkyl halide 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 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 25 concentrated sulfuric acid at a temperature of about 20 to 1000C, preferably at a reflux, for about 1 hour to about 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 concomitant removal of the water being produced by physical (e.g., Dean-Stark trap) or chemical (e.g., 30 molecular sieves) means. Prodrugs of this invention where an alcohol function has been derivatized as an ether may 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 I WO 2004/085401 PCT/IB2004/000836 -59 to about 24 hours. Alkanoylaminomethyl ethers may 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 method described in US 4,997,984. Alternatively, these compounds may be prepared by the methods 5 described by Hoffman et al. in J. Org. Chem. 1994, 59, 3530. Glycosides are prepared by reaction of 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 alternate procedure is the reaction of the alcohol with a suitably protected glycosyl halide in 10 the presence of base followed by deprotection. N-(1-hydroxyalkyl) amides, N-(1-hydroxy-1-(alkoxycarbonyl)methyl) amides may be prepared by the reaction of the parent amide with the appropriate aldehyde under neutral or basic conditions (e.g., sodium ethoxide in ethanol) at temperatures between 25 and 70*C. N-alkoxymethyl or N-1-(alkoxy)alkyl derivatives can be 15 obtained by 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 (e.g., LDL-cholesterol lowering agents, triglyceride lowering agents) for the treatment of the disease/conditions described herein. For example, 20 they may be used in combination with a HMG-CoA reductase inhibitor, a cholesterol synthesis inhibitor, a cholesterol absorption inhibitor, a MTP/Apo B secretion inhibitor, a PPAR modulator and other cholesterol lowering agents such as a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor, and a bile acid sequestrant. Other pharmaceutical agents would also include the following: a bile 25 acid reuptake inhibitor, an ileal bile acid transporter inhibitor, an ACC inhibitor, an antihypertensive (such as NORVASC@), a selective estrogen receptor modulator, a selective androgen receptor modulator, an antibiotic, an antidiabetic (such as metformin, a PPARy activator, a sulfonylurea, insulin, an aldose reductase inhibitor (ARI) and a sorbitol dehydrogenase inhibitor (SDI)), and aspirin (acetylsalicylic acid). 30 A slow-release form of niacin is available and is known as Niaspan. Niacin may also be combined with other therapeutic agents such as statins, i.e. lovastatin, which is an HMG-CoA reductase inhibitor and described further below. This combination therapy is known as ADVICOR@ (Kos Pharmaceuticals Inc.) In combination therapy WO 2004/085401 PCT/IB2004/000836 -60 treatment, both the compounds of this invention and the other drug therapies are administered to mammals (e.g., humans, male or female) by conventional methods. Any HMG-CoA reductase inhibitor may be used in the combination aspect of this invention. The term HMG-CoA reductase inhibitor refers to compounds which 5 inhibit the bioconversion of hydroxymethylglutaryl-coenzyme A to mevalonic acid catalyzed by the enzyme HMG-CoA reductase. Such inhibition is readily determined by those skilled in the art according to standard assays (e.g., Meth. Enzymol. 1981; 71:455-509 and references cited therein). A variety of these compounds are described and referenced below however other HMG-CoA reductase inhibitors will 10 be known to those skilled in the art. U.S. Pat. No. 4,231,938 (the disclosure of which is hereby incorporated by reference) discloses certain compounds isolated after cultivation of a microorganism belonging to the genus Aspergillus, such as lovastatin. Also, U.S. Pat. No. 4,444,784 (the disclosure of which is hereby incorporated by reference) discloses synthetic derivatives of the aforementioned compounds, such 15 as simvastatin. Also, U.S. Pat. No. 4,739,073 (the disclosure of which is incorporated by reference) discloses certain substituted indoles, such as fluvastatin. Also, U.S. Pat. No. 4,346,227 (the disclosure of which is incorporated by reference) discloses ML-236B derivatives, such as pravastatin. Also, EP-491226A (the disclosure of which is incorporated by reference) discloses certain 20 pyridyldihydroxyheptenoic acids, such as cerivastatin. In addition, U.S. Pat. No. 5,273,995 (the disclosure of which is incorporated by reference) discloses certain 6 [2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones such as atorvastatin and any pharmaceutically acceptable form thereof (i.e. LIPITOR@). Additional HMG-CoA reductase inhibitors include rosuvastatin and pitavastatin. 25 Any PPAR modulator may be used in the combination aspect of this invention. The term PPAR modulator refers to compounds which modulate peroxisome proliferator activator receptor (PPAR) activity in mammals, particularly humans. Such modulation is readily determined by those skilled in the art according to standard assays known in the literature. It is believed that such compounds, by 30 modulating the PPAR receptor, regulate transcription of key genes involved in lipid and glucose metabolism such as those in fatty acid oxidation and also those involved in high density lipoprotein (HDL) assembly (for example, apolipoprotein Al gene transcription), accordingly reducing whole body fat and increasing HDL cholesterol. By virtue of their activity, these compounds also reduce plasma levels of triglycerides, WO 2004/085401 PCT/IB2004/000836 -61 VLDL cholesterol, LDL cholesterol and their associated components such as apolipoprotein B in mammals, particularly humans, as well as increasing HDL cholesterol and apolipoprotein Al. Hence, these compounds are useful for the treatment and correction of the various dyslipidemias observed to be associated with 5 the development and incidence of atherosclerosis and cardiovascular disease, including hypoalphalipoproteinemia and hypertriglyceridemia. A variety of these compounds are described and referenced below, however, others will be known to those skilled in the art. International Publication Nos. WO 02/064549 and 02/064130 and U.S. patent application 10/720942, filed November 24, 2003 (the disclosures of 10 which are hereby incorporated by reference) disclose certain compounds which are PPARa activators. Any MTP/Apo B (microsomal triglyceride transfer protein and or apolipoprotein B) secretion inhibitor may be used in the combination aspect of this invention. The term MTP/Apo B secretion inhibitor refers to compounds which inhibit 15 the secretion of triglycerides, cholesteryl ester, and phospholipids. Such inhibition is readily determined by those skilled in the art according to standard assays (e.g., Wetterau, J. R. 1992; Science 258:999). A variety of these compounds are described and referenced below however other MTP/Apo B secretion inhibitors will be known to those skilled in the art, including imputapride (Bayer) and additional 20 compounds such as those disclosed in WO 96/40640 and WO 98/23593, (two exemplary publications). For example, the following MTP/Apo B secretion inhibitors are particularly useful: 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1 H-[1,2,4,]triazol-3-ylmethyl) 25 1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide; 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-acetylamino-ethyl)-1,2,3,4 tetrahydro-isoquinolin-6-yl]-amide; (2-{6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1 H isoquinolin-2-yl}-ethyl)-carbamic acid methyl ester; 30 4'-trifluoromethyl-biphenyl-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-y]-amide; and WO 2004/085401 PCT/IB2004/000836 -62 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-ethoxy-ethyl)-1,2,3,4 tetrahydro-isoquinolin-6-yl]-amide. Any HMG-CoA synthase inhibitor may be used in the combination aspect of this invention. The term HMG-CoA synthase inhibitor refers to compounds which 5 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 readily determined by those skilled in the art according to standard assays (Meth Enzymol. 1975; 35:155-160: Meth. Enzymol. 1985; 110:19-26 and references cited therein). A variety of these compounds are described and 10 referenced below, however other HMG-CoA synthase inhibitors will be known to those skilled in the art. U.S. Pat. No. 5,120,729 (the disclosure of which is hereby incorporated by reference) discloses certain beta-lactam derivatives. U.S. Pat. No. 5,064,856 (the disclosure of which is hereby incorporated by reference) discloses certain spiro-lactone derivatives prepared by culturing a microorganism (MF5253). 15 U.S. Pat. No. 4,847,271 (the disclosure of which is hereby incorporated by reference) discloses certain oxetane compounds such as 11 -(3-hydroxymethyl-4 oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undeca-dienoic acid derivatives. Any compound that decreases HMG-CoA reductase gene expression may be used in the combination aspect of this invention. These agents may be HMG-CoA 20 reductase transcription inhibitors that block the transcription of DNA or translation inhibitors that prevent or decrease translation of mRNA coding for HMG-CoA reductase into protein. Such compounds may either affect transcription or translation directly, or may be biotransformed to compounds that have the aforementioned activities by one or more enzymes in the cholesterol biosynthetic cascade or may 25 lead to the accumulation of an isoprene metabolite that has the aforementioned activities. Such compounds may cause this effect by decreasing levels of SREBP (sterol receptor binding protein) by inhibiting the activity of site-1 protease (S1P) or agonizing the oxzgenal receptor or SCAP. Such regulation is readily determined by those skilled in the art according to standard assays (Meth. Enzymol. 1985; 110:9 30 19). Several compounds are described and referenced below, however other inhibitors of HMG-CoA reductase gene expression will be known to those skilled in the art. U.S. Pat. No. 5,041,432 (the disclosure of which is incorporated by reference) discloses certain 15-substituted lanosterol derivatives. Other oxygenated WO 2004/085401 PCT/IB2004/000836 -63 sterols that suppress synthesis of HMG-CoA reductase are discussed by E.I. Mercer (Prog.Lip. Res. 1993;32:357-416). Any squalene synthetase inhibitor may be used in the combination aspect of this invention. The term squalene synthetase inhibitor refers to compounds which 5 inhibit the condensation of 2 molecules of farnesylpyrophosphate to form squalene, catalyzed by the enzyme squalene synthetase. Such inhibition is readily determined by those skilled in the art according to standard assays (Meth. Enzymol. 1969; 15: 393-454 and Meth. Enzymol. 1985; 110:359-373 and references contained therein). A variety of these compounds are described in and referenced below however other 10 squalene synthetase inhibitors will be known to those skilled in the art. U.S. Pat. No. 5,026,554 (the disclosure of which is incorporated by reference) discloses fermentation products of the 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). 15 Any squalene epoxidase inhibitor may be used in the combination aspect of this invention. The term squalene epoxidase inhibitor refers to compounds which inhibit the bioconversion of squalene and molecular oxygen into squalene-2,3 epoxide, catalyzed by the enzyme squalene epoxidase. Such inhibition is readily determined by those skilled in the art according to standard assays (Biochim. 20 Biophys. Acta 1984; 794:466-471). A variety of these compounds are described and referenced below, however other squalene epoxidase inhibitors will be known to those skilled in the art. U.S. Pat. Nos. 5,011,859 and 5,064,864 (the disclosures of which are incorporated by reference) disclose certain fluoro analogs of squalene. EP publication 395,768 A (the disclosure of which is incorporated by reference) 25 discloses certain substituted allylamine derivatives. PCT publication WO 9312069 A (the disclosure of which is hereby incorporated by reference) discloses certain amino alcohol derivatives. U.S. Pat. No. 5,051,534 (the disclosure of which is hereby incorporated by reference) discloses certain cyclopropyloxy-squalene derivatives. Any squalene cyclase inhibitor may be used as the second component in the 30 combination aspect of this invention. The term squalene cyclase inhibitor refers to compounds which inhibit the bioconversion of squalene-2,3-epoxide to lanosterol, catalyzed by the enzyme squalene cyclase. Such inhibition is readily determined by those skilled in the art according to standard assays (FEBS Lett. 1989;244:347 350.). In addition, the compounds described and referenced below are squalene WO 2004/085401 PCT/IB2004/000836 -64 cyclase inhibitors, however other squalene cyclase inhibitors will also be known to those skilled in the art. PCT publication W09410150 (the disclosure of which is hereby incorporated by reference) discloses certain 1,2,3,5,6,7,8,8a-octahydro 5,5,8(beta)-trimethyl-6-isoquinolineamine derivatives, such as N-trifluoroacetyl 5 1,2,3,5,6,7,8,8a-octahydro-2-allyl-5,5,8(beta)-trimethyl-6(beta)-isoquinolineamine. French patent publication 2697250 (the disclosure of which is hereby incorporated by reference) discloses certain beta, beta-dimethyl-4-piperidine ethanol derivatives such as 1-(1,5,9-trimethyldecyl)-beta,beta-dimethyl-4-piperidineethano Any combined squalene epoxidase/squalene cyclase inhibitor may be used 10 as the second component in the combination aspect of this invention. The term combined squalene epoxidase/squalene cyclase inhibitor refers to compounds that inhibit the bioconversion of squalene to lanosterol via a squalene-2,3-epoxide intermediate. In some assays it is not possible to distinguish between squalene epoxidase inhibitors and squalene cyclase inhibitors, however, these assays are 15 recognized by those skilled in the art. Thus, inhibition by combined squalene epoxidase/squalene cyclase inhibitors is readily determined by those skilled in art according to the aforementioned standard assays for squalene cyclase or squalene epoxidase inhibitors. A variety of these compounds are described and referenced below, however other squalene epoxidase/squalene cyclase inhibitors will be known 20 to those skilled in the art. U.S. Pat. Nos. 5,084,461 and 5,278,171 (the disclosures of which are incorporated by reference) disclose certain azadecalin derivatives. EP publication 468,434 (the disclosure of which is incorporated by reference) discloses certain piperidyl ether and thio-ether derivatives such as 2-(1-piperidyl)penty isopentyl sulfoxide and 2-(1-piperidyl)ethyl ethyl sulfide. PCT publication WO 25 9401404 (the disclosure of which is hereby incorporated by reference) discloses certain acyl-piperidines such as 1-(1-oxopentyl-5-phenylthio)-4-(2-hydroxy-1-methyl) ethyl)piperidine. U.S. Pat. No. 5,102,915 (the disclosure of which is hereby incorporated by reference) discloses certain cyclopropyloxy-squalene derivatives. The compounds of the present invention can also be administered in 30 combination with naturally occurring compounds that act to lower plasma cholesterol levels. These naturally occurring compounds are commonly called nutraceuticals and include, for example, garlic extract and niacin. A slow-release form of niacin is available and is known as Niaspan. Niacin may also be combined with other therapeutic agents such as lovastatin, or another is an HMG-CoA reductase inhibitor.
WO 2004/085401 PCT/IB2004/000836 -65 This combination therapy with lovastatin is known as ADVICORTM (Kos Pharmaceuticals Inc.). Any cholesterol absorption inhibitor can be used as an additional in the combination aspect of the present invention. The term cholesterol absorption 5 inhibition refers to the ability of a compound to prevent cholesterol contained within the lumen of the intestine from entering into the intestinal cells and/or passing from within the intestinal cells into the lymph system and/or into the blood stream. Such cholesterol absorption inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Lipid Res. (1993) 34: 377-395). 10 Cholesterol absorption inhibitors are known to those skilled in the art and are described, for example, in PCT WO 94/00480. An example of a recently approved cholesterol absorption inhibitor is ZETIA TM (ezetimibe) (Schering-Plough/Merck). Any ACAT inhibitor may be used in the combination therapy aspect of the present invention. The term ACAT inhibitor refers to compounds that inhibit the 15 intracellular esterification of dietary cholesterol by the enzyme acyl CoA: cholesterol acyltransferase. Such inhibition may be determined readily by one of skill in the art according to standard assays, such as the method of Heider et al. described in Jouma/ of Lipid Research., 24:1127 (1983). A variety of these compounds are known to those skilled in the art, for example, U.S. Patent No. 5,510,379 discloses certain 20 carboxysulfonates, while WO 96/26948 and WO 96/10559 both disclose urea derivatives having ACAT inhibitory activity. Examples of ACAT inhibitors include compounds such as Avasimibe (Pfizer), CS-505 (Sankyo) and Eflucimibe (Eli Lilly and Pierre Fabre). A lipase inhibitor may be used in the combination therapy aspect of the 25 present invention. A lipase inhibitor is a compound that inhibits the metabolic cleavage of dietary triglycerides or plasma phospholipids into free fatty acids and the corresponding glycerides (e.g. EL, HL, etc.). Under normal physiological conditions, lipolysis occurs via a two-step process that involves acylation of an activated serine moiety of the lipase enzyme. This leads to the production of a fatty 30 acid-lipase hemiacetal intermediate, which is then cleaved to release a diglyceride. Following further deacylation, the lipase-fatty acid intermediate is cleaved, resulting in free lipase, a glyceride and fatty acid. In the intestine, the resultant free fatty acids and monoglycerides are incorporated into bile acid-phospholipid micelles, which are subsequently absorbed at the level of the brush border of the small WO 2004/085401 PCT/IB2004/000836 -66 intestine. The micelles eventually enter the peripheral circulation as chylomicrons. Such lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231). Pancreatic lipase mediates the metabolic cleavage of fatty acids from 5 triglycerides at the 1- and 3-carbon positions. The primary site of the metabolism of ingested fats is in the duodenum and proximal jejunum by pancreatic lipase, which is usually secreted in vast excess of the amounts necessary for the breakdown of fats in the upper small intestine. Because pancreatic lipase is the primary enzyme required for the absorption of dietary triglycerides, inhibitors have utility in the 10 treatment of obesity and the other related conditions. Such pancreatic lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231). Gastric lipase is an immunologically distinct lipase that is responsible for approximately 10 to 40% of the digestion of dietary fats. Gastric lipase is secreted in 15 response to mechanical stimulation, ingestion of food, the presence of a fatty meal or by sympathetic agents. Gastric lipolysis of ingested fats is of physiological importance in the provision of fatty acids needed to trigger pancreatic lipase activity in the intestine and is also of importance for fat absorption in a variety of physiological and pathological conditions associated with pancreatic insufficiency. See, for example, 20 C.K. Abrams, et al., Gastroenterology, 92,125 (1987). Such gastric lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231). A variety of gastric and/or pancreatic lipase inhibitors are known to one of ordinary skill in the art. Preferred lipase inhibitors are those inhibitors that are 25 selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), valilactone, esterastin, ebelactone A, and ebelactone B. The compound tetrahydrolipstatin is especially preferred. The lipase inhibitor, N-3-trifluoromethylphenyl-N'-3-chloro-4' trifluoromethylphenylurea, and the various urea derivatives related thereto, are disclosed in U.S. Patent No. 4,405,644. The lipase inhibitor, esteracin, is disclosed in 30 U.S. Patent Nos. 4,189,438 and 4,242,453. The lipase inhibitor, cyclo-O,O'-[(1,6 hexanediyl)-bis-(iminocarbonyl)]dioxime, and the various bis(iminocarbonyl)dioximes related thereto may be prepared as described in Petersen et al., Liebig's Annalen, 562, 205-229 (1949).
WO 2004/085401 PCT/IB2004/000836 -67 A variety of pancreatic lipase inhibitors are described herein below. The pancreatic lipase inhibitors lipstatin, (2S, 3S, 5S, 7Z, 10Z)-5-[(S)-2-formamido-4 methyl-valeryloxy]-2-hexyl-3-hydroxy-7,1 0-hexadecanoic acid lactone, and tetrahydrolipstatin (orlistat), (2S, 3S, 5S)-5-[(S)-2-formamido-4-methyl-valeryloxy] 5 2-hexyl-3-hydroxy-hexadecanoic 1,3 acid lactone, and the variously substituted N formylleucine derivatives and stereoisomers thereof, are disclosed in U.S. Patent No. 4,598,089. For example, tetrahydrolipstatin is prepared as described in, e.g., U.S. Patent Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874. The pancreatic lipase inhibitor, FL-386, 1-[4-(2-methylpropyl)cyclohexyl]-2-[(phenylsulfonyl)oxy] 10 ethanone, and the variously substituted sulfonate derivatives related thereto, are disclosed in U.S. Patent No. 4,452,813. The pancreatic lipase inhibitor, WAY 121898, 4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and the various carbamate esters and pharmaceutically acceptable salts related thereto, are disclosed in U.S. Patent Nos. 5,512,565; 5,391,571 and 5,602,151. The pancreatic 15 lipase inhibitor, valilactone, and a process for the preparation thereof by the microbial cultivation of Actinomycetes strain MG147-CF2, are disclosed in Kitahara, et al., J. Antibiotics, 40 (11), 1647-1650 (1987). The pancreatic lipase inhibitors, ebelactone A and ebelactone B, and a process for the preparation thereof by the microbial cultivation of Actinomycetes strain MG7-G1, are disclosed in Umezawa, 20 et al., J. Antibiotics, 33, 1594-1596 (1980). The use of ebelactones A and B in the suppression of monoglyceride formation is disclosed in Japanese Kokai 08-143457, published June 4, 1996. Other compounds that are marketed for hyperlipidemia, including hypercholesterolemia and which are intended to help prevent or treat atherosclerosis 25 include bile acid sequestrants, such as Welchol*, Colestid*, LoCholest* and Questran*; and fibric acid derivatives, such as Atromid*, Lopid® and Tricor*. Diabetes can be treated by administering to a patient having diabetes (especially Type 11), insulin resistance, impaired glucose tolerance, metabolic syndrome, or the like, or any of the diabetic complications such as neuropathy, 30 nephropathy, retinopathy or cataracts, a therapeutically effective amount of a compound of the present invention in combination with other agents (e.g., insulin) that can be used to treat diabetes. This includes the classes of anti-diabetic agents (and specific agents) described herein.
WO 2004/085401 PCT/IB2004/000836 -68 Any glycogen phosphorylase inhibitor can be used as the second agent in combination with a compound of the present invention. The term glycogen phosphorylase inhibitor refers to compounds that inhibit the bioconversion of glycogen to glucose-1-phosphate which is catalyzed by the enzyme glycogen 5 phosphorylase. Such glycogen phosphorylase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Med. Chem. 41 (1998) 2934-2938). A variety of glycogen phosphorylase inhibitors are known to those skilled in the art including those described in WO 96/39384 and WO 96/39385. 10 Any aldose reductase inhibitor can be used in combination with a compound of the present invention. The term aldose reductase inhibitor refers to compounds that inhibit the bioconversion of glucose to sorbitol, which is catalyzed by the enzyme aldose reductase. Aldose reductase inhibition is readily determined by those skilled in the art according to standard assays (e.g., J. Malone, Diabetes, 29:861-864 (1980). 15 "Red Cell Sorbitol, an Indicator of Diabetic Control"). A variety of aldose reductase inhibitors are known to those skilled in the art. Any sorbitol dehydrogenase inhibitor can be used in combination with a compound of the present invention. The term sorbitol dehydrogenase inhibitor refers to compounds that inhibit the bioconversion of sorbitol to fructose which is 20 catalyzed by the enzyme sorbitol dehydrogenase. Such sorbitol dehydrogenase inhibitor activity is readily determined by those skilled in the art according to standard assays (e.g., Analyt. Biochem (2000) 280: 329-331). A variety of sorbitol dehydrogenase inhibitors are known, for example, U.S. Patent Nos. 5,728,704 and 5,866,578 disclose compounds and a method for treating or preventing diabetic 25 complications by inhibiting the enzyme sorbitol dehydrogenase. Any glucosidase inhibitor can be used in combination with a compound of the present invention. A glucosidase inhibitor inhibits the enzymatic hydrolysis of complex carbohydrates by glycoside hydrolases, for example amylase or maltase, into bioavailable simple sugars, for example, glucose. The rapid metabolic action of 30 glucosidases, particularly following the intake of high levels of carbohydrates, results in a state of alimentary hyperglycemia which, in adipose or diabetic subjects, leads to enhanced secretion of insulin, increased fat synthesis and a reduction in fat degradation. Following such hyperglycemias, hypoglycemia frequently occurs, due to the augmented levels of insulin present. Additionally, it is WO 2004/085401 PCT/IB2004/000836 -69 known chyme remaining in the stomach promotes the production of gastric juice, which initiates or favors the development of gastritis or duodenal ulcers. Accordingly, glucosidase inhibitors are known to have utility in accelerating the passage of carbohydrates through the stomach and inhibiting the absorption of 5 glucose from the intestine. Furthermore, the conversion of carbohydrates into lipids of the fatty tissue and the subsequent incorporation of alimentary fat into fatty tissue deposits is accordingly reduced or delayed, with the concomitant benefit of reducing or preventing the deleterious abnormalities resulting therefrom. Such glucosidase inhibition activity is readily determined by those skilled in the art 10 according to standard assays (e.g., Biochemistry (1969) 8: 4214). A generally preferred glucosidase inhibitor includes an amylase inhibitor. An amylase inhibitor is a glucosidase inhibitor that inhibits the enzymatic degradation of starch or glycogen into maltose. Such amylase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods 15 Enzymol. (1955) 1: 149). The inhibition of such enzymatic degradation is beneficial in reducing amounts of bioavailable sugars, including glucose and maltose, and the concomitant deleterious conditions resulting therefrom. A variety of glucosidase inhibitors are known to one of ordinary skill in the art and examples are provided below. Preferred glucosidase inhibitors are those 20 inhibitors that are selected from the group consisting of acarbose, adiposine, voglibose, miglitol, emiglitate, camiglibose, tendamistate, trestatin, pradimicin-Q and salbostatin. The glucosidase inhibitor, acarbose, and the various amino sugar derivatives related thereto are disclosed in U.S. Patent Nos. 4,062,950 and 4,174,439 respectively. The glucosidase inhibitor, adiposine, is disclosed in U.S. 25 Patent No. 4,254,256. The glucosidase inhibitor, voglibose, 3,4-dideoxy-4-[[2 hydroxy-1-(hydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epi-inositol, and the various N-substituted pseudo-aminosugars related thereto, are disclosed in U.S. Patent No. 4,701,559. The glucosidase inhibitor, miglitol, (2R,3R,4R,5S)-1-(2 hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol, and the various 3,4,5 30 trihydroxypiperidines related thereto, are disclosed in U.S. Patent No. 4,639,436. The glucosidase inhibitor, emiglitate, ethyl p-[2-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2 (hydroxymethyl)piperidino]ethoxyl-benzoate, the various derivatives related thereto and pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Patent No. 5,192,772. The glucosidase inhibitor, MDL-25637, 2,6-dideoxy-7-0-p- WO 2004/085401 PCT/IB2004/000836 -70 D-glucopyrano-syl-2,6-imino-D-glycero-L-gluco-heptitol, the various homodisaccharides related thereto and the pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Patent No. 4,634,765. The glucosidase inhibitor, camiglibose, methyl 6-deoxy-6-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2 5 (hydroxymethyl)piperidino]-a-D-glucopyranoside sesquihydrate, the deoxy nojirimycin derivatives related thereto, the various pharmaceutically acceptable salts thereof and synthetic methods for the preparation thereof, are disclosed in U.S. Patent Nos. 5,157,116 and 5,504,078. The glycosidase inhibitor, salbostatin and the various pseudosaccharides related thereto, are disclosed in U.S. Patent 10 No. 5,091,524. A variety of amylase inhibitors are known to one of ordinary skill in the art. The amylase inhibitor, tendamistat and the various cyclic peptides related thereto, are disclosed in U.S. Patent No. 4,451,455. The amylase inhibitor Al-3688 and the various cyclic polypeptides related thereto are disclosed in U.S. Patent No. 15 4,623,714. The amylase inhibitor, trestatin, consisting of a mixture of trestatin A, trestatin B and trestatin C and the various trehalose-containing aminosugars related thereto are disclosed in U.S. Patent No. 4,273,765. Additional anti-diabetic compounds, which can be used as the second agent in combination with a compound of the present invention, includes, for example, the 20 following: biguanides (e.g., metformin), insulin secretagogues (e.g., sulfonylureas and glinides), glitazones, non-glitazone PPARy agonists, PPARs agonists, inhibitors of DPP-IV, inhibitors of PDE5, inhibitors of GSK-3, glucagon antagonists, inhibitors of f 1,6-BPase(Metabasis/Sankyo), GLP-1/analogs (AC 2993, also known as exendin-4), insulin and insulin mimetics (Merck natural products). Other examples would include 25 PKC-p inhibitors and AGE breakers. The compounds of the present invention can be used in combination with other anti-obesity agents. Any anti-obesity agent can be used as the second agent in such combinations and examples are provided herein. Such anti-obesity activity is readily determined by those skilled in the art according to standard assays known 30 in the art. Suitable anti-obesity agents include phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, P3 adrenergic receptor agonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (e.g., WO 2004/085401 PCT/IB2004/000836 -71 sibutramine), sympathomimetic agents, serotoninergic agents, cannabinoid receptor antagonists (e.g., rimonabant (SR-141,716A)), dopamine agonists (e.g., bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, 5 leptin receptor agonists, galanin antagonists, lipase inhibitors (e.g., tetrahydrolipstatin, i.e. orlistat), bombesin agonists, anorectic agents (e.g., a bombesin agonist), Neuropeptide-Y antagonists, thyroxine, thyromimetic agents, dehydroepiandrosterones or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, 10 glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (e.g., AxokineTM), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists, and the like. Any thyromimetic can be used as the second agent in combination with a 15 compound of the present invention. Such thyromimetic activity is readily determined by those skilled in the art according to standard assays (e.g., Atherosclerosis (1996) 126: 53-63). A variety of thyromimetic agents are known to those skilled in the art, for example those disclosed in U.S. Patent Nos. 4,766,121; 4,826,876; 4,910,305; 5,061,798; 5,284,971; 5,401,772; 5,654,468; and 5,569,674. 20 Other antiobesity agents include sibutramine which can be prepared as described in U.S. Patent No. 4,929,629. and bromocriptine which can be prepared as described in U.S. Patent Nos. 3,752,814 and 3,752,888. The compounds of the present invention can also be used in combination with other antihypertensive agents. Any anti-hypertensive agent can be used as the 25 second agent in such combinations and examples are provided herein. Such antihypertensive activity is readily determined by those skilled in the art according to standard assays (e.g., blood pressure measurements). Examples of presently marketed products containing antihypertensive agents include calcium channel blockers, such as Cardizem*, Adalat*, Calan*, Cardene*, 30 Covera*, Dilacor®, DynaCirc*' Procardia XL*, Sular®, Tiazac®, Vascor®, Verelan®, Isoptin®, Nimotop*' Norvasc®, and Plendil®; angiotensin converting enzyme (ACE) inhibitors, such as Accupril®, Altace*, Captopril*, Lotensin*, Mavik*, Monopril*, Prinivil*, Univasc*, Vasotec® and Zestril®.
WO 2004/085401 PCT/IB2004/000836 -72 Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 5 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated. The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture 10 incidence is forecasted to increase three-fold over the next 60 years, and one study has estimated that there will be 4.5 million hip fractures worldwide in 2050. Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle 15 and low calcium intake. Those skilled in the art will recognize that anti-resorptive agents (for example progestins, polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists, estrogen, estrogen/progestin combinations, Premarin*, estrone, estriol or 17a- or 17p-ethynyl estradiol) may be used in conjunction with the compounds of the present 20 invention. Exemplary progestins are available from commercial sources and include: algestone acetophenide, altrenogest, amadinone acetate, anagestone acetate, chiormadinone acetate, cingestol, clogestone acetate, clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone, dydrogesterone, ethynerone, 25 ethynodiol diacetate, etonogestrel, flurogestone acetate, gestaclone, gestodene, gestonorone caproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, melengestrol acetate, methynodiol diacetate, norethindrone, norethindrone acetate, norethynodrel, norgestimate, norgestomet, norgestrel, oxogestone phenpropionate, 30 progesterone, quingestanol acetate, quingestrone, and tigestol. Preferred progestins are medroxyprogestrone, norethindrone and norethynodrel. Exemplary bone resorption inhibiting polyphosphonates include polyphosphonates of the type disclosed in U.S. Patent 3,683,080, the disclosure of WO 2004/085401 PCT/IB2004/000836 -73 which is incorporated herein by reference. Preferred polyphosphonates are geminal diphosphonates (also referred to as bis-phosphonates). Tiludronate disodium is an especially preferred polyphosphonate. Ibandronic acid is an especially preferred polyphosphonate. Alendronate and resindronate are especially preferred 5 polyphosphonates. Zoledronic acid is an especially preferred polyphosphonate. Other preferred polyphosphonates are 6-amino-1 -hydroxy-hexylidene-bisphosphonic acid and 1 -hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid. The polyphosphonates may be administered in the form of the acid, or of a soluble alkali metal salt or alkaline earth metal salt. Hydrolyzable esters of the polyphosphonates 10 are likewise included. Specific examples include ethane-1-hydroxy 1,1-diphosphonic acid, methane diphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic acid, methane dichloro diphosphonic acid, methane hydroxy diphosphonic acid, ethane-1 amino-1,1 -diphosphonic acid, ethane-2-amino-1, 1 -diphosphonic acid, propane-3 amino-1 -hydroxy-1, 1 -diphosphonic acid, propane-N, N-dimethyl-3-amino-1 -hydroxy 15 1,1-diphosphonic acid, propane-3,3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenyl amino methane diphosphonic acid,N,N-dimethylamino methane diphosphonic acid, N(2-hydroxyethyl) amino methane diphosphonic acid, butane-4 amino-i -hydroxy-1, 1 -diphosphonic acid, pentane-5-amino-1 -hydroxy-1,1 diphosphonic acid, hexane-6-amino-1-hydroxy-1,1-diphosphonic acid and 20 pharmaceutically acceptable esters and salts thereof. In particular, the compounds of this invention may be combined with a mammalian estrogen agonist/antagonist. Any estrogen agonist/antagonist may be used in the combination aspect of this invention. The term estrogen agonist/antagonist refers to compounds which bind with the estrogen receptor, inhibit 25 bone turnover and/or prevent bone loss. In particular, estrogen agonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and mimicking the actions of estrogen in one or more tissue. Estrogen antagonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and blocking the actions of 30 estrogen in one or more tissues. Such activities are readily determined by those skilled in the art of standard assays including estrogen receptor binding assays, standard bone histomorphometric and densitometer methods, and Eriksen E.F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S.J. et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, WO 2004/085401 PCT/IB2004/000836 -74 31(1):50-62; Wahner H.W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296). A variety of these compounds are described and referenced below. Another preferred estrogen agonist/antagonist is 3-(4-(1,2-diphenyl-but-1 5 enyl)-phenyl)-acrylic acid, which is disclosed in Willson et al., Endocrinology, 1997, 138, 3901-3911. Another preferred estrogen agonist/antagonist is tamoxifen: (ethanamine,2-( 4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl, (Z)-2-, 2-hydroxy-1,2,3 propanetricarboxylate(1:1)) and related compounds which are disclosed in U.S. 10 patent 4,536,516, the disclosure of which is incorporated herein by reference. Another related compound is 4-hydroxy tamoxifen, which is disclosed in U.S. patent 4,623,660, the disclosure of which is incorporated herein by reference. A preferred estrogen agonist/antagonist is raloxifene: (methanone, (6 hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl)(4-(2-(1 -piperidinyl)ethoxy)phenyl) 15 hydrochloride) which is disclosed in U.S. patent 4,418,068, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist/antagonist is toremifene: (ethanamine, 2 (4-(4-chloro-1,2-diphenyl-i-butenyl)phenoxy)-N, N-dimethyl-, (Z)-, 2-hydroxy-1,2,3 propanetricarboxylate (1:1) which is disclosed in U.S. patent 4,996,225, the 20 disclosure of which is incorporated herein by reference. Another preferred estrogen agonist/antagonist is centchroman: 1-(2-((4 (-methoxy-2,2, dimethyl-3-phenyl-chroman-4-yl)-phenoxy)-ethyl)-pyrrolidine, which is disclosed in U.S. patent 3,822,287, the disclosure of which is incorporated herein by reference. Also preferred is levormeloxifene. 25 Another preferred estrogen agonist/antagonist is idoxifene: (E)-1-(2-(4-(1-(4 iodo-pheny)-2-pheny-but-1-enyl)-phenoxy)-ethyl)-pyrrolidinone, which is disclosed in U.S. patent 4,839,155, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist/antagonist is 2-(4-methoxy-phenyl)-3-[4 (2-piperidin-1-yi-ethoxy)-phenoxy]- benzo[b]thiophen-6-ol which is disclosed in U.S. 30 Patent No. 5,488,058, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist/antagonist is 6-(4-hydroxy-phenyl)-5-(4 (2-piperidin-1-yl-ethoxy)-benzyl)-naphthalen-2-ol, which is disclosed in U.S. patent 5,484,795, the disclosure of which is incorporated herein by reference.
WO 2004/085401 PCT/IB2004/000836 -75 Another preferred estrogen agonist/antagonist is (4-(2-(2-aza bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl)-(6-hydroxy-2-(4-hydroxy-phenyl) benzo[b]thiophen-3-yl)-methanone which is disclosed, along with methods of preparation, in PCT publication no. WO 95/10513 assigned to Pfizer Inc. 5 Other preferred estrogen agonist/antagonists include the compounds, TSE 424 (Wyeth-Ayerst Laboratories) and arazoxifene. Other preferred estrogen agonist/antagonists include compounds as described in commonly assigned U.S. patent 5,552,412, the disclosure of which is incorporated herein by reference. Especially preferred compounds described therein 10 are: cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1 -yl-ethoxy)-phenyl)-5,6,7,8 tetrahydro-naphthalene-2-ol; (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro naphthalene-2-ol (also known as lasofoxifene); 15 cis-6-phenyl-5-(4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro naphthalene-2-ol; cis-1 -(6'-pyrrolodinoethoxy-3'-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4 tetrahydronaphthalene; 1-(4'-pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyl)-6-hydroxy-1,2,3,4 20 tetrahydroisoquinoline; cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1 -yl-ethoxy)-phenyl)-5,6,7,8 tetrahydro-naphthalene-2-ol; and 1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4 tetrahydroisoquinoline. 25 Other estrogen agonist/antagonists are described in U.S. patent 4,133,814 (the disclosure of which is incorporated herein by reference). U.S. patent 4,133,814 discloses derivatives of 2-phenyl-3-aroyl-benzothiophene and 2-phenyl-3 aroylbenzothiophene-1 -oxide. Other anti-osteoporosis agents, which can be used as the second agent in 30 combination with a compound of the present invention, include, for example, the following: parathyroid hormone (PTH) (a bone anabolic agent); parathyroid hormone (PTH) secretagogues (see, e.g., U.S. Patent No. 6,132,774), particularly calcium receptor antagonists; calcitonin; and vitamin D and vitamin D analogs.
WO 2004/085401 PCT/IB2004/000836 -76 Any selective androgen receptor modulator (SARM) can be used in combination with a compound of the present invention. A selective androgen receptor modulator (SARM) is a compound that possesses androgenic activity and which exerts tissue-selective effects. SARM compounds can function as androgen 5 receptor agonists, partial agonists, partial antagonists or antagonists. Examples of suitable SARMs include compounds such as cyproterone acetate, chlormadinone, flutamide, hydroxyflutamide, bicalutamide, nilutamide, spironolactone, 4 (trifluoromethyl)-2(1 H)-pyrrolidino[3,2-g] quinoline derivatives, 1,2-dihydropyridino [5,6-g]quinoline derivatives and piperidino[3,2-g]quinolinone derivatives. 10 Cypterone, also known as (1b,2b)-6-chloro-1,2-dihydro-17-hydroxy-3'H cyclopropa[l,2]pregna-1,4,6-triene-3,20-dione is disclosed in U.S. Patent 3,234,093. Chlormadinone, also known as 17-(acetyloxy)-6-chloropregna-4,6-diene-3,20-dione, in its acetate form, acts as an anti-androgen and is disclosed in U.S. Patent 3,485,852. Nilutamide, also known as 5,5-dimethyl-3-[4-nito-3 15 (trifluoromethyl)phenyl]-2,4-imidazolidinedione and by the trade name Nilandron@ is disclosed in U.S. Patent 4,097,578. Flutamide, also known as 2-methyl-N-[4-nitro-3 (trifluoromethyl)phenyl] propanamide and the trade name Eulexin@ is disclosed in U.S. Patent 3,847,988. Bicalutamide, also known as 4'-cyano-a',a',a'-trifluoro-3-(4 fluorophenylsulfonyl)-2-hydroxy-2-methylpropiono-m-toluidide and the trade name 20 Casodex@ is disclosed in EP-100172. The enantiomers of biclutamide are discussed by Tucker and Chesterton, J. Med. Chem. 1988, 31, 885-887. Hydroxyflutamide, a known androgen receptor antagonist in most tissues, has been suggested to function as a SARM for effects on IL-6 production by osteoblasts as disclosed in Hofbauer et al. J. Bone Miner. Res. 1999, 14, 1330-1337. Additional SARMs have been disclosed 25 in U.S. Patent 6,017,924; WO 01/16108, WO 01/16133, WO 01/16139, WO 02/00617, WO 02/16310, U.S. Patent Application Publication No. US 2002/0099096, U.S. Patent Application Publication No. US 2003/0022868, WO 03/011302 and WO 03/011824. All of the above refences are hereby incorporated by reference herein. The starting materials and reagents for the above described compounds, are 30 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 to, or are derived from compounds in which there is a large scientific interest and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from WO 2004/085401 PCT/IB2004/000836 -77 other commonly available substances by methods which are reported in the literature. Some of the compounds of this invention or intermediates in their synthesis have asymmetric carbon atoms and therefore are enantiomers or diastereomers. 5 Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known per se, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by, for example, chiral HPLC methods or converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound 10 (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, an enantiomeric mixture of the compounds or an intermediate in their synthesis which contain an acidic or basic moiety may be separated into their corresponding pure enantiomers by forming a diastereomic salt with an optically pure chiral base or acid 15 (e.g., 1-phenyl-ethyl amine or tartaric acid) and separating the diasteromers 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 as part of this invention for all of the compounds of the present invention, including the compounds of the present 20 invention. Also, some of the compounds of this invention are atropisomers (e.g., substituted biaryls) and are considered as part of this invention. More specifically, the compounds of this invention may be obtained in enantiomerically enriched form by resolving the racemate of the final compound or an intermediate in its synthesis, employing chromatography (preferably high 25 pressure liquid chromatography [HPLC]) on an asymmetric resin (preferably ChiralcelTM 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). 30 Concentration of the product containing fractions affords the desired materials. Some of the compounds of this invention are acidic and they form a salt with a pharmaceutically acceptable cation. Some of the compounds of this invention are basic and they form a salt with a pharmaceutically acceptable anion. All such salts are within the scope of this invention and they can be prepared by conventional WO 2004/085401 PCT/IB2004/000836 -78 methods such as combining the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous 5 solutions, by lyophilization, as appropriate. The compounds can be obtained in crystalline form by dissolution in an appropriate solvent(s) such as ethanol, hexanes or water/ethanol mixtures. In addition, when the compounds of this invention form hydrates or solvates they are also within the scope of the invention. 10 The compounds of this invention, their prodrugs and the salts of such compounds and prodrugs are all adapted to therapeutic use as agents that inhibit cholesterol ester transfer protein activity in mammals, particularly humans. Thus, the compounds of this invention elevate plasma HDL cholesterol, its associated components, and the functions performed by them in mammals, particularly humans. 15 By virtue of their activity, these agents also reduce plasma levels of triglycerides, VLDL cholesterol, Apo-B, LDL cholesterol and their associated components in mammals, particularly humans. Moreover, these compounds are useful in equalizing LDL cholesterol and HDL cholesterol. Hence, these compounds are useful for the treatment and correction of the various dyslipidemias observed to be associated with 20 the development and incidence of atherosclerosis and cardiovascular disease, including coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, familial hypercholesterolemia, low HDL and associated components, elevated LDL and 25 associated components, elevated Lp(a), elevated small-dense LDL, elevated VLDL and associated components and post-prandial lipemia. Further, introduction of a functional CETP gene into an animal lacking CETP (mouse) results in reduced HDL levels (Agellon, L.B., et al: J. Biol. Chem. (1991) 266: 10796-10801.) and increased susceptibility to atherosclerosis.(Marotti, K.R., et 30 al: Nature (1993) 364: 73-75.). Also, inhibition of CETP activity with an inhibitory antibody raises HDL-cholesterol in hamster (Evans, G.F., et al: J. of Lipid Research (1994) 35: 1634-1645.) and rabbit (Whitlock, M.E., et al: J. Clin. Invest. (1989) 84: 129-137). Suppression of increased plasma CETP by intravenous injection with antisense oligodeoxynucleotides against CETP mRNA reduced atherosclerosis in WO 2004/085401 PCT/IB2004/000836 -79 cholesterol-fed rabbits (Sugano, M., et al: J. of Biol. Chem. (1998) 273: 5033-5036.) Importantly, human subjects deficient in plasma CETP, due to a genetic mutation possess markedly elevated plasma HDL-cholesterol levels and apolipoprotein A-1, the major apoprotein component of HDL. In addition, most demonstrate markedly 5 decreased plasma LDL cholesterol and apolipoprotein B (the major apolipoprotein component of LDL. (Inazu, A., Brown, M.L., Hesler, C.B., et al.: N. Engl. J. Med. (1990) 323: 1234-1238.) Given the negative correlation between the levels of HDL cholesterol and HDL associated lipoproteins, and the positive correlation between triglycerides, LDL 10 cholesterol, and their associated apolipoproteins in blood with the development of cardiovascular, cerebral vascular and peripheral vascular diseases, the compounds of this invention, their prodrugs and the salts of such compounds and prodrugs, by virtue of their pharmacologic action, are useful for the prevention, arrestment and/or regression of atherosclerosis and its associated disease states. These include 15 cardiovascular disorders (e.g., angina, ischemia, cardiac ischemia and myocardial infarction), complications due to cardiovascular disease therapies (e.g., reperfusion injury and angioplastic restenosis), hypertension, elevated cardiovascular risk associated with hypertension, stroke, atherosclerosis associated with organ transplantation, cerebrovascular disease, cognitive dysfunction (including, but not 20 limited to, dementia secondary to atherosclerosis, transient cerebral ischemic attacks, neurodegeneration, neuronal deficient, and delayed onset or procession of Alzheimer's disease), elevated levels of oxidative stress, elevated levels of C Reactive Protein, Metabolic Syndrome and elevated levels of HbA1 C. Because of the beneficial effects widely associated with elevated HDL levels, 25 an agent which inhibits CETP activity in humans, by virtue of its HDL increasing ability, also provides valuable avenues for therapy in a number of other disease areas as well. Thus, given the ability of the compounds of this invention, their prodrugs and the salts of such compounds and prodrugs to alter lipoprotein composition via 30 inhibition of cholesterol ester transfer, they are of use in the treatment of vascular complications associated with diabetes, lipoprotein abnormalities associated with diabetes and sexual dysfunction associated with diabetes and vascular disease. Hyperlipidemia is present in most subjects with diabetes mellitus (Howard, B.V. 1987. J. Lipid Res. 28, 613). Even in the presence of normal lipid levels, diabetic WO 2004/085401 PCT/IB2004/000836 -80 subjects experience a greater risk of cardiovascular disease (Kannel, W.B. and McGee, D.L. 1979. Diabetes Care 2, 120). CETP-mediated cholesteryl ester transfer is known to be abnormally increased in both insulin-dependent (Bagdade, J.D., Subbaiah, P.V. and Ritter, M.C. 1991. Eur. J. Clin. Invest. 21, 161) and non-insulin 5 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 results in changes in lipoprotein composition, particularly for VLDL and LDL, that are more atherogenic (Bagdade, J.D., Wagner, J.D., Rudel, L.L., and Clarkson, T.B. 1995. J. Lipid Res. 36, 759). These changes would not 10 necessarily be observed during routine lipid screening. Thus the present invention will be useful in reducing the risk of vascular complications as a result of the diabetic condition. The described agents are useful in the treatment of obesity and elevated cardiovascular risk associated with obesity. In both humans (Radeau, T., Lau, P., 15 Robb, M., McDonnell, M., Ailhaud, G. and McPherson, R., 1995. Journal of Lipid Research. 36 (12):2552-61) and nonhuman primates (Quinet, E., Tall, A., Ramakrishnan, R. and Rudel, L., 1991. Journal of Clinical Investigation. 87 (5):1559 66) mRNA for CETP is expressed at high levels in adipose tissue. The adipose message increases with fat feeding (Martin, L. J., Connelly, P. W., Nancoo, D., 20 Wood, N., Zhang, Z. J., Maguire, G., Quinet, E., Tall, A. R., Marcel, Y. L. and McPherson, R., 1993. Journal of Lipid Research. 34 (3):437-46), and is translated into functional transfer protein and through secretion contributes significantly to plasma CETP levels. In human adipocytes the bulk of cholesterol is provided by plasma LDL and HDL (Fong, B. S., and Angel, A., 1989. Biochirnica et Biophysica 25 Acta. 1004 (1):53-60). The uptake of HDL cholesteryl ester is dependent in large part on CETP (Benoist, F., Lau, P., McDonnell, M., Doelle, H., Milne, R. and McPherson, R., 1997. Journal of Biological Chemistry. 272 (38):23572-7). This ability of CETP to stimulate HDL cholesteryl uptake, coupled with the enhanced binding of HDL to adipocytes in obese subjects (Jimenez, J. G., Fong, B., Julien, P., Despres, 30 J. P., Rotstein, L., and Angel, A., 1989. International Journal of Obesity. 13 (5):699 709), suggests a role for CETP, not only in generating the low HDL phenotype for these subjects, but in the development of obesity itself by promoting cholesterol accumulation. Inhibitors of CETP activity that block this process therefore serve as useful adjuvants to dietary therapy in causing weight reduction.
WO 2004/085401 PCT/IB2004/000836 -81 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 in large part due to endotoxin, a lipopolysaccharide (LPS) released from the outer surface of the bacteria, which causes an extensive 5 inflammatory response. Lipopolysaccharide can form complexes with lipoproteins (Ulevitch, R.J., Johnston, A.R., and Weinstein, D.B., 1981. J. Clin. Invest. 67, 827 37). In vitro studies have demonstrated that binding of LPS to HDL substantially reduces the production and release of mediators of inflammation (Ulevitch, R.J., Johhston, A.R., 1978. J. Clin. Invest. 62, 1313-24). In vivo studies show that 10 transgenic mice expressing human apo-Al and elevated HDL levels are protected from septic shock (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, administration of reconstituted HDL to humans challenged with endotoxin resulted in a decreased inflammatory response (Pajkrt, D., Doran, J.E., Koster, F., Lerch, P.G., Arnet, B., 15 van der Poll, T., ten Cate, J.W., and van Deventer, S.J.H. 1996. J. Exp. Med. 184, 1601-08). The CETP inhibitors, by virtue of the fact that they raise HDL levels, attenuate the development of inflammation and septic shock. These compounds would also be useful in the treatment of endotoxemia, autoimmune diseases and other systemic disease indications, organ or tissue transplant rejection and cancer. 20 The utility of the compounds of the invention, their prodrugs and the salts of such compounds and prodrugs as medical agents in the treatment of the above described disease/conditions in mammals (e.g. humans, male or female) is demonstrated by the activity of the compounds of this invention in conventional assays and the in vivo assay described below. The in vivo assay (with appropriate 25 modifications within the skill in the art) may be used to determine the activity of other lipid or triglyceride controlling agents as well as the compounds of this invention. The combination protocol described below is useful for demonstrating the utility of the combinations of the lipid and triglyceride agents (e.g., the compounds of this invention) described herein. Such assays also provide a means whereby the 30 activities of the compounds of this invention, their prodrugs and the salts of such compounds and prodrugs (or the other agents described herein) can be compared to each other and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
WO 2004/085401 PCT/IB2004/000836 -82 The following protocols can of course be varied by those skilled in the art. The hyperalphacholesterolemic activity of the compounds can be determined by assessing the effect of these compounds on the action of cholesteryl ester transfer protein by measuring the relative transfer ratio of radiolabeled lipids between 5 lipoprotein fractions, essentially as previously described by Morton in J. Biol. Chem. 256, 11992, 1981 and by Dias in Clin. Chem. 34, 2322, 1988. CETP IN VITRO ASSAY The following is a brief description of assays of cholesteryl ester transfer in 97% (whole) or diluted human plasma (in vitro) and animal plasma (ex vivo): CETP 10 activity in the presence or absence of drug is assayed by determining the transfer of 3 H-labeled cholesteryl oleate (CO) from exogenous tracer HDL or LDL to the nonHDL or HDL lipoprotein fraction in human plasma, respectively, or from 3
H
labeled LDL to the HDL fraction in animal plasma. Labeled human lipoprotein substrates are prepared similarly to the method described by Morton in which the 15 endogenous CETP activity in plasma is employed to transfer 3 H-CO from phospholipid liposomes to all the lipoprotein fractions in plasma. 3H-labeled LDL and HDL are subsequently isolated by sequential ultracentrifugation at the density cuts of 1.019-1.063 and 1.10-1.21 g/ml, respectively. For the 97% or whole plasma activity assay, 3 H-labeled HDL is added to 20 plasma at 10-25 nmoles CO/ml and the samples incubated at 370 C for 2.5-3 hrs. Non-HDL lipoproteins are then precipitated by the addition of an equal volume of 20% (wt/vol) polyethylene glycol 8000 (Dias). The samples are centrifuged 750 g x 20 minutes and the radioactivity contained in the HDL-containing supernatant determined by liquid scintillation counting. Introducing varying quantities of the 25 compounds of this invention as a solution in dimethylsulfoxide into human plasma, before addition of the radiolabeled cholesteryl oleate, and comparing the amounts of radiolabel transferred compared to incubations containing no inhibitor compounds allows the cholesteryl ester transfer inhibitory activities to be determined. When a more sensitive assay is desirable, an in vitro assay using diluted 30 human plasma is utilized. For this assay, 3 H-labeled LDL is added to plasma at 50 nmoles CO/ml and the samples incubated at 370 C for 7 hrs. Non-HDL lipoproteins are then precipitated by the addition of potassium phosphate to 100 mM final concentration followed by manganese chloride to 20 mM final concentration. After vortexing, the samples are centrifuged 750 g x 20 minutes and the radioactivity WO 2004/085401 PCT/IB2004/000836 -83 contained in the HDL-containing supernatant determined by liquid scintillation counting. Introducing varying quantities of the compounds of this invention as a solution in dimethylsulfoxide into diluted human plasma, before addition of the radiolabeled cholesteryl oleate, and comparing the amounts of radiolabel transferred 5 compared to incubations containing no inhibitor compounds allows the cholesteryl ester transfer inhibitory activities to be determined. This assay has been adapted to run in microtiter plate format with liquid scintillation counting accomplished using a Wallac plate reader. CETP IN VIVO ASSAY 10 Activity of these compounds in vivo can be determined by the amount of agent required to be administered, relative to control, to inhibit cholesteryl ester transfer activity by 50% at various time points ex vivo or to elevate HDL cholesterol by a given percentage in a CETP-containing animal species. Transgenic mice expressing both human CETP and human apolipoprotein Al (Charles River, Boston, 15 MA) may be used to assess compounds in vivo. The compounds to be examined are administered by oral gavage in an emulsion vehicle containing 20% (v:v) olive oil and 80% sodium taurocholate (0.5%). Blood is taken from mice retroorbitally before dosing, if a predose blood sample is desirable. At various times after dosing, ranging from 4h to 24h, the animals are sacrificed, blood obtained by heart puncture, and 20 lipid parameters measured, including total cholesterol, HDL and LDL cholesterol, and triglycerides. CETP activity is determined by a method similar to that described above except that 3H-cholesteryl oleate-containing LDL is used as the donor source as opposed to HDL. The values obtained for lipids and transfer activity are compared to those obtained prior to dosing and/or to those from mice receiving vehicle alone. 25 PLASMA LIPIDS ASSAY The activity of these compounds may also be demonstrated by determining the amount of agent required to alter plasma lipid levels, for example HDL 30 cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels or triglycerides, in the plasma of certain mammals, for example marmosets that 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 mean ±SD for total, HDL, and/or LDL plasma WO 2004/085401 PCT/IB2004/000836 -84 cholesterol concentrations. After group assignment, marmosets are dosed daily with compound as a dietary admix or by intragastric intubation for from one to eight days. Control marmosets receive only the dosing vehicle. Plasma total, LDL VLDL and HDL cholesterol values can be determined at any point during the study by obtaining 5 blood from an antecubital vein and separating plasma lipoproteins into their individual subclasses by density gradient centrifugation, and by measuring cholesterol concentration as previously described (Crook et al. Arteriosclerosis 10, 625, 1990). IN VIVO ATHEROSCLEROSIS ASSAY 10 Anti-atherosclerotic effects of the compounds can be determined by the amount of compound required to reduce the lipid deposition in rabbit aorta. Male New Zealand White rabbits are fed a diet containing 0.2% cholesterol and 10% coconut oil for 4 days (meal-fed once per day). Rabbits are bled from the marginal ear vein and total plasma cholesterol values are determined from these samples. 15 The rabbits are then assigned to treatment groups so that each group has a similar mean ±SD for total plasma cholesterol concentration, HDL cholesterol concentration, triglyceride concentration and/or cholesteryl ester transfer protein activity. After group assignment, rabbits are dosed daily with compound given as a dietary admix or on a small piece of gelatin based confection. Control rabbits receive only the 20 dosing vehicle, be it the food or the gelatin confection. The cholesterol/coconut oil diet is continued along with the compound administration throughout the study. Plasma cholesterol values and cholesteryl ester transfer protein activity can be determined at any point during the study by obtaining blood from the marginal ear vein. After 3-5 months, the rabbits are sacrificed and the aortae are removed from 25 the thoracic arch to the branch of the iliac arteries. The aortae are cleaned of adventitia, opened longitudinally and then analyzed unstained or stained with Sudan IV as described by Holman et. al. (Lab. Invest. 1958, 7, 42-47). The percent of the lesioned surface area is quantitated by densitometry using an Optimas Image Analyzing System (Image Processing Systems). Reduced lipid deposition is 30 indicated by a reduction in the percent of lesioned surface area in the compound receiving group in comparison with the control rabbits. ANTIOBESITY PROTOCOL The ability of CETP inhibitors to cause weight loss can be assessed in obese human subjects with body mass index (BMI) > 30 kg/m 2 . Doses of inhibitor are WO 2004/085401 PCT/IB2004/000836 -85 administered sufficient to result in an increase of > 25% in HDL cholesterol levels. BMI and body fat distribution, defined as waist (W) to hip (H) ratio (WHR), are monitored during the course of the 3-6 month studies, and the results for treatment groups compared to those receiving placebo. 5 IN VIVO SEPSIS ASSAY In vivo studies show that transgenic mice expressing human apo-Al and elevated HDL levels are protected from septic shock. Thus the ability of CETP inhibitors to protect from septic shock can be demonstrated in transgenic mice 10 expressing both human apo-Al and human CETP transgenes (Levine, D. M., Parker, T.S., Donnelly, T. M., Walsh, A. M. and Rubin, A.L., 1993. Proc. Natl. Acad. Sci. 90, 12040-44). LPS derived from E. coli is administered at 30mg/kg by i.p. injection to animals which have been administered a CETP inhibitor at an appropriate dose to result in elevation of HDL. The number of surviving mice is determined at times up to 15 48h after LPS injection and compared to those mice administered vehicle (minus CETP inhibitor) only. Administration of the compounds of this invention can be via any method which delivers a compound of this invention systemically and/or locally. These methods include oral routes, parenteral, intraduodenal routes, etc. Generally, the 20 compounds of this invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, subcutaneous or intramedullary) may be utilized, for example, where oral administration is inappropriate for the target or where the patient is unable to ingest the drug. In general an amount of a compound of this invention is used that is sufficient 25 to achieve the therapeutic effect desired (e.g., HDL elevation). In general an effective dosage for the compounds of this invention is about 0.001 to 100 mg/kg/day of the compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. An especially preferred dosage is about 0.01 to 10 mg/kg/day of the compound, a prodrug thereof, or a 30 pharmaceutically acceptable salt of said compound or of said prodrug. A dosage of the combination pharmaceutical agents to be used in conjuction with the CETP inhibitors is used that is effective for the indication being treated.
WO 2004/085401 PCT/IB2004/000836 -86 For example, typically an effective dosage for HMG-CoA reductase inhibitors is in the range of 0.01 to 100 mg/kg/day. In general an effect dosage for a PPAR modulator is in the range of 0.01 to 100 mg/kg/day. The compounds of the present invention are generally administered in the 5 form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable vehicle, diluent or carrier as described below. Thus, the compounds of this invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form. 10 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 citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with 15 binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high 20 molecular weight polyethylene glycols. A preferred formulation is a solution or suspension in an oil, for example, a vegetable oil, such as olive oil; triglycerides such as those marketed under the name, MiglyolTM; or mono- or diglycerides such as those marketed under the name, CapmulTM, for example, in a soft gelatin capsule. Antioxidants may be added to prevent long-term degradation as appropriate. When 25 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, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. 30 Pharmaceutical compositions comprising a solid amorphous dispersion of a cholesteryl ester transfer protein (CETP) inhibitor and a concentration-enhancing polymer are described in International Publication No. WO 02/11710, which is hereby incorporated by reference herein. Self-emulsifying formulations of cholesteryl ester transfer protein (CETP) inhibitors are described in International Publication No.
WO 2004/085401 PCT/IB2004/000836 -87 WO 03/000295, which is hereby incorporated by reference herein. Methods for depositing small drug crystals on excipients are set forth in the literature, such as in J. Pharm. Pharmacol. 1987, 39:769-773, which is hereby incorporated by reference herein. 5 For purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for 10 intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art. For purposes of transdermal (e.g.,topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), 15 otherwise similar to the above parenteral solutions, are prepared. Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack Publishing 20 Company, Easter, Pa., 15th Edition (1975). Pharmaceutical compositions according to the invention may contain 0.1% 95% of the compound(s) of this invention, preferably 1%-70%. In any event, the composition or formulation to be administered will contain a quantity of a compound(s) according to the invention in an amount effective to treat the 25 disease/condition of the subject being treated, e.g., atherosclerosis. Since the present invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate 30 pharmaceutical compositions: a compound of the present invention, a prodrug thereof or a salt of such compound or prodrug and a second compound as described above. The kit comprises means for containing the separate compositions such as a container, a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is WO 2004/085401 PCT/IB2004/000836 -88 particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician. 5 An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are 10 formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and 15 the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. It may be desirable to provide a memory aid on the kit, e.g., in the form of 20 numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, ... etc.... Second Week, Monday, Tuesday,..." etc. Other variations of memory aids will be readily apparent. A "daily dose" can be 25 a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of compounds of the present invention can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this. In another specific embodiment of the invention, a dispenser designed to 30 dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory WO 2004/085401 PCT/IB2004/000836 -89 coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken. The compounds of this invention either alone or in combination with each 5 other or other compounds generally will be administered in a convenient formulation. The following formulation examples only are illustrative and are not intended to limit the scope of the present invention. In the formulations which follow, "active ingredient" means a compound of this invention. 10 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 Starch flowable powder 0-50 Silicone fluid 350 centistokes 0-15 A tablet formulation is prepared using the ingredients below: Formulation 2: Tablets Ingredient Quantity (mg/tablet) Active ingredient 0.25-100 Cellulose, microcrystalline 200-650 Silicon dioxide, fumed 10-650 Stearate acid 5-15 The components are blended and compressed to form tablets. 15 Alternatively, tablets each containing 0.25-100 mg of active ingredients are made up as follows: WO 2004/085401 PCT/IB2004/000836 -90 Formulation 3: Tablets Ingredient Quantity (mg/tablet) Active ingredient 0.25-100 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone (as 10% solution in water) 4 Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1 The active ingredients, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. 5 The granules so produced are dried at 500 - 60 0 C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets. Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose 10 are made as follows: Formulation 4: Suspensions Ingredient Quantity (mg/5 ml) Active ingredient 0.25-100 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 mL Flavor q .v. Color q .v. Purified Water to 5 mL The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, 15 with stirring. Sufficient water is then added to produce the required volume. An aerosol solution is prepared containing the following ingredients: WO 2004/085401 PCT/IB2004/000836 -91 Formulation 5: Aerosol Ingredient Quantity (% by weight) Active ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 70.00 The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30 0 C, and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the 5 remaining propellant. The valve units are then fitted to the container. Suppositories are prepared as follows: Formulation 6: Suppositories Ingredient Quantity (mg/suppository) Active ingredient 250 Saturated fatty acid glycerides 2,000 The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimal 10 necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. An intravenous formulation is prepared as follows: Formulation 7: Intravenous Solution Ingredient Quantity Active ingredient dissolved in ethanol 1% 20 mg Intralipid T M emulsion 1,000 mL The solution of the above ingredients is intravenously administered to a 15 patient at a rate of about 1 mL per minute. Soft gelatin capsules are prepared using the following: Formulation 8: Soft Gelatin Capsule with Oil Formulation Ingredient Quantity (mg/capsule) Active ingredient 10-500 Olive Oil or Miglyo T M Oil 500-1000 The active ingredient above may also be a combination of agents.
WO 2004/085401 PCT/IB2004/000836 -92 GENERAL EXPERIMENTAL PROCEDURES The following examples are put forth so as to provide those of ordinary skill in the art with a disclosure and description of how the compounds, compositions, and 5 methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Unless indicated otherwise, percent is percent by weight given the component and the total weight of the composition, temperature is in 0C or is at ambient temperature, and pressure is at or near atmospheric. 10 Commercial reagents were utilized without further purification. Room or ambient temperature refers to 20-25 0C. All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields. Concentration in vacuo means that a rotary evaporator was used. The names for the compounds of the invention were created by the Autonom 2.0 PC-batch version from Beilstein 15 Informationssysteme GmbH (ISBN 3-89536-976-4). The chemical structures depicted may be only exemplary of the general structure or of limited isomers, and not include specific stereochemistry as recited in the chemical name. NMR spectra were recorded on a Varian Unity 400 (Varian Co., Palo Alto, CA) NMR spectrometer at ambient temperature. Chemical shifts are expressed in parts 20 per million (6) relative to an external standard (tetramethylsilane). The peak shapes are denoted as follows: s, singlet; d, doublet, t, triplet, q, quartet, m, multiplet with the prefix br indicating a broadened signal. The coupling constant (J) data given have a maximum error of ±0.41Hz due to the digitization of the spectra that are acquired. Mass spectra were obtained by (1) atmospheric pressure chemical ionization (APCI) 25 in alternating positive and negative ion mode using a Fisons Platform 11 Spectrometer or a Micromass MZD Spectrometer (Micromass, Manchester, UK) or (2) electrospray ionization in alternating positive and negative ion mode using a Micromass MZD Spectrometer (Micromass, Manchester, UK) with a Gilson LC-MS interface (Gilson Instruments, Middleton, WI) or (3) a QP-8000 mass spectrometer (Shimadzu 30 Corporation, Kyoto, Japan) operating in positive or negative single ion monitoring mode, utilizing electrospray ionization or atmospheric pressure chemical ionization. Where the intensity of chlorine- or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3:1 for 35
CI/
3 7 Cl-containing ions WO 2004/085401 PCT/IB2004/000836 -93 and 1:1 for 7 Br/ 8 Br-containing ions) and the position of only the lower mass ion is given. Column chromatography was performed with either Baker Silica Gel (40 pm) (J.T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (40-63 pm)(EM Sciences, Gibbstown, 5 N.J.). Flash chromatography was performed using a Flash 12 or Flash 40 column (Biotage, Dyar Corp., Charlottesville, VA). Preparative HPLC purification was performed on a Shimadzu 1OA preparative HPLC system (Shimadzu Corporation, Kyoto, Japan) using a model SIL-1 OA autosampler and model 8A HPLC pumps. Preparative HPLC-MS was performed on an identical system, modified with a QP 10 8000 mass spectrometer operating in positive or negative single ion monitoring mode, utilizing electrospray ionization or atmospheric pressure chemical ionization. Elution was carried out using water/acetonitrile gradients containing either 0.1% formic acid or ammonium hydroxide as a modifier. In acidic mode, typical columns used include Waters Symmetry C8, 5pm, 19x50mm or 30x5Omm, Waters XTerra 15 C18, 5pm, 50x50 (Waters Corp, Milford, MA) or Phenomenex Synergi Max-RP 4pm, 5Ox5Omm (Phenomenex Inc., Torrance, CA). In basic mode, the Phenomenex Synergi Max-RP 4pm, 21.2x50mm or 30x5Omm columns (Phenomenex Inc., Torrance, CA) were used. Optical rotations were determined using a Jasco P-1 020 Polarimeter Jasco 20 Inc., Easton, MD) Dimethylformamide, tetrahydrofuran, toluene and dichloromethane were the anhydrous grade supplied by Aldrich Chemical Company (Milwaukee, WI). Unless otherwise specified, reagents were used as obtained from commercial sources. The terms "concentrated" and "evaporated" refer to removal of solvent at 1-200 mm of 25 mercury pressure on a rotary evaporator with a bath temperature of less than 450C. The abbreviation "min" stand for "minutes" and "h" or "hr" stand for "hours." The abbreviation "gm" or "g" stand for grams. The abbreviation "pl" or "pL" stand for microliters. Preparation 1 30 (R, S)-2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Method 1) To a solution of (RS)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester (1294gm, 4.09mol, prepared according to the procedure described in WO 0140190) in glacial acetic acid (3882ml) was added a WO 2004/085401 PCT/IB2004/000836 -94 solution of sodium nitrite (582gm, 8.18mol) in water (1618ml), maintaining a temperature of 20 to 25 0 C. The solvent was removed under vacuum, the residue dissolved in methylene chloride (2006ml), and the solution was washed with saturated sodium hydrogen carbonate solution. The solvent was removed by 5 distillation at atmospheric pressure and the residue was dissolved in anhydrous ethanol (2688ml) and treated with aqueous sodium hydroxide (62.2gm, 1.55mol). The solvent was removed under vacuum, the residue dissolved in methylene chloride (2000 ml), washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under vacuum to give the title compound as an oil (1219gm) 10 which was used without further purification in the following procedure. Preparation 2 (RS)-2-Ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of (RS)-2-ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H 15 quinoline-1-carboxylic acid ethyl ester (1208gm, 3.81mol) in methylene chloride (4663mi) was added 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), free radical (6.1gm, 0.038mol), and a solution of potassium bromide (45.8gm, 0.381mol) dissolved in water (191 ml). A 6 % aqueous sodium hypochlorite solution (7748ml), which had been buffered to pH 8.6 to 9.5 with solid sodium hydrogen carbonate 20 (78gm), was slowly added at 0 to 50C. The aqueous layer was washed with methylene chloride (1 208mi). The combined organic layers were washed with 1.4N hydrochloric acid (1493ml) to which potassium iodide (12.8gm, 0.076moles) had been added, then aqueous sodium thiosulfate (60.8gm, 0.381 mol) dissolved in water (1208ml) and finally water (1691 ml). The organic layer was dried over anhydrous 25 magnesium sulfate and evaporated to dryness under vacuum to give the title compound as a yellow oil (1193gm). 'H-NMR (DMSO-de) 8 8.03 (m, 2H), 7.91 (dd, J=9.12, 2.49Hz, 1H), 4.79 (m, 1H), 4.23 (q, J=7.05Hz, 2H), 3.25 (dd, J=17.42, 5.81Hz, 1H), 2.61 (dd, J=17.42, 1.66Hz, 1 H), 1.42 (m, 2H), 1.25 (t, J=7.05Hz, 3H), 0.76 (t, J=7.05Hz, 3H). 30 Preparations 3 and 4 (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (3) and (S)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (4) WO 2004/085401 PCT/IB2004/000836 -95 (RS)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-d ihydro-2H-q uinoline-1 -carboxylic acid ethyl ester was resolved by chiral chromatography on a 10cm x 25cm column packed with Chiralcel OD (Chiral Technologies Inc., Exton, PA). The racemic ketone (300mg) in methanol (0.84mL) was injected onto the column and eluted with 5 heptane:isopropanol 99:1 at a flow rate of 275mL/min to give the title compounds: (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (3), retention time 7.82 min, [a]D ~139.81" (c=0.438, chloroform). (S)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (4), retention time 8.93 min, [a]D = +139.70 (c=0.41, chloroform). 10 Preparation 5 4-Hydrazono-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A mixture of 6,7-dimethoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester (1.00gm, 3.41 mmol, prepared according to the procedure 15 described in German Patent DE 2461050), hydrazine hydrate (330pl, 6.80mmol) and ethanol (4.5mL) were heated together in a crimp-topped vial at 150'C for 30 min in a microwave oven (Emrys Optimizer, Personal Chemistry, Uppsala, Sweden). The solvent was removed under vacuum, the residue dissolved in ethanol (4.5mL), hydrazine hydrate (330pl, 6.80mmol) added and the solution was heated as before at 20 150"C for 30 min. The solvent was evaporated under vacuum to give the title compound as a pale yellow solid. MS: 308.2 [M+H]+ found 'H-NMR (CDC1 3 ) 5 7.39 (s, 1H), 7.03 (brs, 1H), 5.21 (s, 2H), 5.04 (m, 1H), 4.27 (m, 1H), 4.15 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.61 (dd, J=17, 5.81Hz, 1H), 25 2.53 (dd, J=17, 1.66Hz, 1H), 1.28 (t, J=7.47Hz, 3H), 1.08 (d, J = 6.64Hz, 3H). Preparation 6 (R)-2-Ethyl-4-hydrazono-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester A mixture of (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 30 carboxylic acid ethyl ester (Preparation 3, 1.13gm, 3.58mmol), hydrazine hydrate (348pl, 7.16mmol) and ethanol (10mL) were heated in a Dean-Stark apparatus under conditions allowing for slow distillation of the solvent. After 5h approximately 5mL of distillate had been collected. The solution was diluted with an equal volume of WO 2004/085401 PCT/IB2004/000836 -96 toluene and the solvent was evaporated under vacuum to give a pale green solid which was triturated and rinsed with a little hexanes to give the title compound as a nearly colorless solid (1.07g). MS: 330.2 [M+H]* found 5 'H-NMR (CDCIq) 8 8.23 (s, 1H), 7.62 (brd, J=8.30Hz, 1H), 7.46 (dd, J=8.30, 1.66Hz, 1H), 5.45 (brs, 2H), 4.82 (m, 1H), 4.28 (m, 1H), 4.24 (m, IH), 2.64 (m, 2H), 1.36 (m, 2H), 1.31 (t, J=7.47Hz, 3H), 0.84 (t, J = 7.47Hz, 3H). Preparation 7 4-Diazo-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl 10 ester To a solution of 4-hydrazono-6,7-dimethoxy-2-methyl-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester (Preparation 5, 200mg, 0.65mmol) in diethyl ether (20mL) was added manganese (IV) oxide (400mg, activated, -85%, Aldrich Chemical Company, Milwaukee, WI). The suspension was stirred at ambient 15 temperature under nitrogen in the dark for 30 min then the solid removed by filtration through Celite@D to give the title compound as a fuchsia colored solution which was typically used immediately. Preparation 8 (R)-4-Diazo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl 20 ester To a solution of (R)-2-ethyl-4-hydrazono-6-trifluoromethyl-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester (Preparation 6, 317mg, 0.962mmol) in diethyl ether (6mL) was added manganese (IV) oxide (1.1g, activated, -85%, Aldrich Chemical Company, Milwaukee, WI). The suspension was stirred at ambient 25 temperature under nitrogen in the dark for 1.5 h then the solid removed by filtration through Celite@. The filtrate was diluted with toluene (1 5mL) prior to evaporation to a final volume of approximately 1 OmL (never to dryness) to give the title compound as a fuchsia colored solution which was typically used immediately. Preparations 9 and 10 30 (R)-4-Chloro-2-ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester (9) and (R)-2-ethyl-4 methoxycarbonecarbonyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester (10) WO 2004/085401 PCT/IB2004/000836 -97 To a solution of (R)-4-diazo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline 1-carboxylic acid ethyl ester (Preparation 8) prepared from Preparation 6 (317mg, 0.962mmol) as a solution in toluene as described above was added N,N diisopropylethylamine (335pl, 1.92mmol) followed, dropwise, by methyl 5 chlorooxoacetate (0.962mmol, 88.4pl). The mixture was allowed to stir at room temperature under nitrogen. Gas evolution was observed and the fuchsia color changed to yellow-orange within about 10 min. The solution was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution then water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was 10 chromatographed on silica eluting with a hexanes:ethyl acetate gradient from 19:1 to 4:1 to give the title compounds: (R)-4-Chloro-2-ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-3,4-dihydro 2H-quinoline-1 -carboxylic acid ethyl ester (earlier eluting diastereoisomer, 82mg) MS: 422.0 [M+H]+ found 15 1 H-NMR (CDCl 3 ) 6 7.72 (d, J=9.13Hz, IH), 7.58 (m, 1H), 7.54 (s. 1H), 4.57 (m, 1H), 4.27 (m, 1H), 4.25 (m, 1H), 3.95 (s, 3H), 2.85 (dd, J=14.11, 6.64Hz, IH), 2.77 (dd, J=14.11, 6.92Hz, IH), 1.61 (m, IH), 1.52 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 0.87 (t, J = 7.47Hz, 3H). (R)-4-Chloro-2-ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-3,4-dihydro 20 2H-quinoline-1-carboxylic acid ethyl ester (later eluting diastereoisomer, 73mg) MS: 422.0 [M+H]* found 'H-NMR (CDC1 3 ) 6 7.88 (s, 1H), 7.60 (m, 2H), 7.54 (s. IH), 4.57 (m, 1H), 4.22 (m, 1H), 4.20 (m, 1H), 3.73 (s, 3H), 3.26 (dd, J=13.8, 7.47 Hz, 1H), 2.23 (dd, J=13.8, 6.75 Hz, IH), 1.65 (m, 1H), 1.53 (m, IH), 1.27 (t, J=7.47 Hz, 3H), 0.89 (t, J = 7.47 Hz, 25 3H). (R)-2-Ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-2H-quinoline-1 carboxylic acid ethyl ester, 133mg MS: 384.1 [M-H]~ found 'H-NMR (CDC1 3 ) 6 8.27 (s, 1H), 7.71 (brd, J=8.3OHz, 1H), 7.56 (dd, J=8.30, 30 1.66Hz, IH), 7.20 (d, J=6.64Hz, 1H), 5.21 (m, 1H), 4.28 (m, 2H), 3.95 (s, 3H), 1.57 (m, 1H), 1.41 (m, 1H), 1.32 (t, J=7.47Hz, 3H), 0.91 (t, J = 7.47Hz, 3H).
WO 2004/085401 PCT/IB2004/000836 -98 Preparation 11 2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Method 2) To a solution of 2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 5 carboxylic acid ethyl ester (0.89gm, 2.83mmol) in methanol (20mL) was added solid sodium borohydride (102mg, 2.8mmol). After 10 min acetone was added to quench the reaction and the mixture was stirred for 2h before evaporating the solvent under vacuum. The residue was dissolved in methylene chloride and the solution was washed with 0.05N hydrochloric acid. The organic layer was dried over anhydrous 10 sodium sulfate, diluted with toluene and evaporated to dryness to give the title compound as a mixture of diastereoisomers which were carried forward unseparated. MS: 318.0 [M+H]+ found (trans isomer- minor) 'H-NMR (CDC1 3 ) 6 7.80 (d, J=8.3OHz, 1 H), 7.69 (s, 1 H), 15 7.49 (dd, J=8.30, 1.66Hz, 1H), 4.86 (m, 1H), 4.58 (m, iH), 4.25 (m, 2H), 2.16 (m, 2H), 1.60 (m, 1 H), 1.50 (m, 1 H), 1.32 (t, J=7.47Hz, 3H), 0.90 (t, J=7.47Hz, 3H). MS: 318.0 [M+H]* found (cis isomer- major) 'H-NMR (CDC1 3 ) 8 7.73 (s, 1H), 7.58 (d, J=9.13Hz, 1H), 7.50 (dd, J=9.13, 1.66Hz, 1H), 4.55 (m, 1H), 4.41 (m, 1H), 4.24 (m, 2H), 2.52 (ddd, 20 J=13.28, 7.47, 4.98Hz, 1H), 1.67 (m, 1H), 1.60 (m, 1H), 1.48 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 0.85 (t, J=7.47Hz, 3H). Preparation 12 4-Chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Method 1) 25 The product from the previous preparation (Preparation 11, 2.83mmol) was dissolved in anhydrous methylene chloride (30mL), cooled to OC and triethylamine (1.0mL, 7.17mmol) followed by methanesulfonyl chloride (245p1, 3.16mmol) were added. After 2h, a further aliquot of triethylamine (1.0mL, 7.17mmol) was added, and the mixture stirred at ambient temperature for 15h then washed with water 30 containing 2N hydrochloric acid (1 OmL). The organic layer was dried over anhydrous sodium sulfate, evaporated to dryness and purified by chromatography on silica eluting with hexanes:acetone 25:1 to give title compound as an unequal mixture of diastereoisomers (590mg) which typically were carried forward unseparated.
WO 2004/085401 PCT/IB2004/000836 -99 Diastereoisomer 1 (Major) MS: 336.0 [M+H]* found 'H-NMR (CDCl 3 ) 5 7.69 (d, J=8.29Hz, 1H), 7.60 (s, 1H), 7.63 (d, J=8.29Hz, IH), 5.12 (dd, J=6.64, 4.98Hz, IH), 4.60 (m, 1H), 4.27 (m, 2H), 2.60 (ddd, J=14.11, 5 6.64, 6.64Hz, 1H), 2.13 (ddd, J=14.11, 6.64, 4.98Hz, 1H), 1.64 (m, 1H), 1.54 (m, 1H), 1.31 (t, J=7.47Hz, 3H), 0.89 (t, J=7.47Hz, 3H). Diastereoisomer 2 (Minor) MS: 336.0 [M+H]+ found 1 H-NMR (CDC 3 ) 5 7.82 (s, 1H), 7.68 (d, J=8.30Hz, 1H), 7.51 (dd, J=8.30, 10 1.66Hz, 1H), 5.08 (dd, J=5.81, 5.81Hz, 1H), 4.55 (m, 1H), 4.25 (m, 2H), 2.71 (ddd, J=14.11, 5.81, 5.81Hz, 1H), 2.18 (ddd, J=14.11, 5.81, 5.81Hz, 1H), 1.74 (m, 1H), 1.60 (m, IH), 1.31 (t, J=7.47Hz, 3H), 0.91 (t, J=7.47Hz, 3H). Preparation 13 (R, S)-2-Ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid 15 ethyl ester (Method 3) To a solution of (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline 1-carboxylic acid ethyl ester (1.1gm, 3.49mmol) in anhydrous tetrahydrofuran at 0*C under nitrogen was added potassium triisobutylborohydride (K-Selectride@, IM in tetrahydrofuran, 8.0mL, 8mmol). After 1.5h the mixture was allowed to warm to 20 ambient temperature, stirred for 16h then an additional aliquot of K-Selectride@ (3.49mL, 3.49mmol) was added. After 1.5h the solvent was removed under vacuum, the residue was dissolved in ethyl acetate (50mL) and this solution was washed with 2N sodium hydroxide solution (20mL) followed by hydrogen peroxide (30%, 15mL), dried over anhydrous magnesium sulfate and concentrated to low volume. The 25 residue was taken up in acetonitrile and evaporated to dryness (x3) to remove residual water to give the title compound (100%), identical to the cis isomer of the product described above (Preparation 11). Preparation 14 (R)-4-Chloro-2-ethyl-6-trifluoromethy-3,4-dihydro-2H-quinoline-1-carboxylic acid 30 ethyl ester (Method 2) (R, S)-2-ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester (Preparation 13, 1.1gm, 3.47mmol) was dissolved in thionyl chloride (20mL) at ambient temperature under nitrogen. After 1 h N,N dimethylformamide (2 drops) was added and the mixture allowed to stir at ambient WO 2004/085401 PCT/IB2004/000836 -100 temperature for 15h. The solvent was removed under reduced pressure and the residue was chromatographed on silica eluting with ethyl acetate-hexanes 50:1 to give the title compound as a yellow oil (405mg) with a proton NMR spectrum very similar to that obtained for Preparation 12 except that the major and minor 5 components of the mixture were reversed. Example 1 F F F 0 F F 0 F O N 4-(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-2H-quinoline-1-carboxylic acid ethyl ester 10 A solution of 4-diazo-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester (Preparation 7, 0.65mmol) prepared as a solution in diethyl ether as described above was added to a solution of 3,5-bistrifluoromethylbenzoyl chloride (180mg, 0.65mmol) and N,N-diisopropylethylamine (120il, 0.65mmol) in diethyl ether (15mL) and allowed to stir at room temperature under nitrogen in the 15 dark for 15h. The solvent was removed under vacuum and the residue was chromatographed on silica eluting with hexanes:ethyl acetate 3:1 to give a partially purified product which was further purified by reverse phase chromatography (linear acetonitrile:water gradient, 55% to 100% acetonitrile, both phases containing 0.1 % formic acid) to give the title compound as a lemon yellow solid (90mg). 20 MS: 518.1 [M+H]* found 'H-NMR (CDCl 3 ) 5 8.26 (s, 2H), 8.07 (s, 1H), 7.25 (brs, 1H), 7.04 (s, 1H), 6.32 (d, J=6.64Hz, 1H), 5.31 (m, 1H), 4.33 (m, 1H), 4.23 (m, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 1.33 (t, J=7.47Hz, 3H), 1.20 (d, J=6.64Hz, 3H).
WO 2004/085401 PCT/IB2004/000836 -101 Example 2 F F F OH FF FEF F F N (R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester 5 A solution of 3,5-bis(trifluoromethylphenyl)magnesium bromide was prepared by dropwise addition of a solution of 3,5-bistrifluoromethylbromobenzene (0.818mL, 4.74mmol) in anhydrous tetrahydrofuran (0.7mL) to a stirred suspension of magnesium powder (116mg, 4.74mmol) in anhydrous tetrahydrofuran (4.7mL) at 35 0 C. The mixture was then heated under reflux for 1 h to give a dark colored 10 solution. A portion of this solution (1.5mL) was added dropwise to a solution of (R) 2-ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester (Preparation 10, 133mg, 0.345mmol) in anhydrous tetrahydrofuran (4mL) at -78*C. After 30 min the mixture was warmed to 0*C and poured into water and extracted with ethyl acetate, adding a few drops of 2N hydrochloric acid to facilitate 15 separation of the layers. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. This procedure was repeated in an exactly similar manner using (R)-2-ethyl-4-methoxycarbonecarbonyl-6-trifluoromethyl-2H-quinoline 1-carboxylic acid ethyl ester (Preparation 10, 235mg, 0.609mmol) in anhydrous tetrahydrofuran (5mL) and adding the solution of 3,5 20 bis(trifluoromethylphenyl)magnesium bromide (2mL). The combined crude product was chromatographed on silica eluting with an ethyl acetate-hexanes gradient from 5% to 30% to give the title compound as a mixture of diastereoisomers (463mg) which were carried forward unseparated. MS: 597.9 [M-H]- found 25 Diastereoisomer 1: 1 H-NMR (CDC1s) 3 7.92 (s, 2H), 7.75 (s, IH), 7.67 (s, 1H), 7.65 (d, J=8.30Hz, 1H), 7.34 (dd, J=8.30, 1.66Hz, 1H), 5.97 (d, J=6.64Hz, 1H), 5.04 WO 2004/085401 PCT/IB2004/000836 -102 (m, 1H), 4.53 (s, 1H), 4.27 (m, 2H), 3.87 (s, 3H), 1.47 (m, 1H), 1.35 (m, 1H), 1.28 (t, J=7.47Hz, 3H), 0.85 (d, J=6.64Hz, 3H). MS: 597.9 [M-H]~ found Diastereoisomer 2: 1 H-NMR (CDC13) 6 8.16 (s, 2H), 7.90 (s, 1H), 7.65 (d, 5 J=8.30, 1H), 7.63 (s, 1H), 7.45 (dd, J=8.30, 1.66Hz, 1H), 5.82 (d, J=6.42Hz, 1H), 4.96 (m, 1H), 4.34 (s, 1H), 4.27 (m, 2H), 3.78 (s, 3H), 1.47 (m, 1H), 1.35 (m, 1H), 1.33 (t, J=7.47Hz, 3H), 0.83 (d, J=7.47Hz, 3H). Examples 3 and 4 F F F o H~ F 0 0o F F F F N N 10 (R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester F F F 0H I F O O F F F F F N N o o (R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester 15 To a solution of (R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester (Example 2, 125mg, 0.208mmol) and 2,6-di-tert-butyl-4-methylpyridine (256mg, 1.248mmol) in chloroform (7mL) was added thionyl chloride (30.4pal, 0.417mmol). After stirring for 18h at ambient temperature the mixture was diluted 20 with methylene chloride, washed with water and dried over anhydrous sodium WO 2004/085401 PCT/IB2004/000836 -103 sulfate. After removal of the solvent under vacuum the residue was chromatographed on silica eluting with an ethyl acetate-hexanes gradient from 0% to 40% to give 4-[(3,5-bis-trifluoromethyl-phenyl)-chloro-methoxycarbonyl-methy]-2 ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester as a mixture of 5 diastereoisomers. This material (128mg) was dissolved in a mixture of tetrahydrofuran (2mL) and acetic acid (2mL). Zinc dust (200mg, 3.05mmol) was added followed by 2N hydrochloric acid (1.5mL). The suspension was stirred at ambient temperature for 3h then diluted with methylene chloride and washed with water. The organic layer was dried with anhydrous sodium sulfate and evaporated 10 to dryness under vacuum. The residue was chromatographed on silica eluting with a methylene chloride-hexanes gradient from 60% to 80% to give the title compounds: Diastereoisomer 1: 44mg MS: 584.0 [M+H]* found 'H-NMR (CDCI,) 5 7.79 (s, 1H), 7.76 (s, 2H), 7.74 (d, J=8.30Hz, 1H), 7.47 (d, 15 J=8.3OHz, 1H), 7.41 (s, 1H), 6.02 (d, J=6.64Hz, 1H), 5.12 (s, IH), 5.01(m, 1H), 4.26 (m, 2H), 3.82 (s, 3H), 1.53 (m, 1H), 1.40 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 0.87 (d, J=7.47Hz, 3H). Diastereoisomer 2: 16mg MS: 584.0 [M+H]* found 20 1 H-NMR (CDCi 3 ) 6 7.88 (s, 2H), 7.87 (s, 1H), 7.77 (d, J=8.30Hz, 1H), 7.49 (d, J=8.30Hz, I H), 7.33 (s, 1 H), 5.96 (d, J=5.81 Hz, 1 H), 5.07 (s, 1 H), 5.00 (m, 1 H), 4.29 (m, 2H), 3.74 (s, 3H), 1.47 (m, 1H), 1.36 (m, 1H), 1.34 (t, J=7.47Hz, 3H), 0.84 (d, J=7.47Hz, 3H). Examples 5 and 6 F F F F 0 F F F H F F F N 25 (RS, SR, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -104 F F F 0 F F H F F F H '-H F N (RS, SR, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methy]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of 4-chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 5 carboxylic acid ethyl ester (Preparation 12, 275mg, 0.82mmol) and 3,5 bis(trifluoromethylphenyl)acetic acid methyl ester (286mg, 1 mmol) in anhydrous dimethylformamide (2mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, -100mg). The mixture was stirred at ambient temperature for 24h then at 50*C for 15h. The mixture was poured into water, acidified by the addition of a little 2N 10 hydrochloric acid and extracted with methylene chloride (x3). The extract was dried over anhydrous sodium sulfate, evaporated to dryness and the residue purified initially by reverse phase chromatography and finally by chromatography on silica eluting with hexanes-ethyl acetate 6:1 to give the title compounds. (RS, SR, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2 15 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-I -carboxylic acid ethyl ester (13.8mg, first eluting diastereoisomer) MS: 586.0 [M+H]* found 1 H-NMR (CDC 3 ) 5 7.90 (s, 2H), 7.87 (s, 1H), 7.59 (d, J=8.30Hz, IH), 7.62 (d, J=8.30Hz, 1H), 7.61 (s, 1H), 4.39-4.27 (m, 2H), 4.27-4.18 (m, 1H), 3.78 (d, 20 J=11.61Hz, 1H), 3.59 (m, 1H), 3.48 (s, 3H), 1.76 (ddd, J=14.10, 8.30, 3.30Hz, 1H), 1.61-1.55 (m, 1H),1.57-1.50 (m, IH), 1.48-1.40 (m, 1H), 1.35 (t, J=7.47Hz, 3H), 0.73 (t, J=7.47Hz, 3H). (RS, SR, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (33.7mg, 25 second eluting diastereoisomer) MS: 586.0 [M+H]* found 1 H-NMR (CDCl 3 ) 3 7.66 (s, 1H), 7.42 (d, J=8.3OHz, 1H), 7.40 (s, 2H), 7.33 (dd, J=8.30, 1.66Hz, 1 H), 6.47 (d, J=1.66Hz, 1 H), 4.55-4.47 (m, 1 H), 4.34 (m, 1 H), WO 2004/085401 PCT/IB2004/000836 -105 4.32 (m,1H), 3.83 (d, J=11.61 Hz, 1H), 3.80 (s, 3H), 3.43 (ddd, J=11.61, 4.98, 2.49Hz, 1H), 2.44 (ddd, J=14.11, 8.30, 2.49Hz, 1H), 1.81 (ddd, J=14.10, 8.30, 4.98Hz, 1H), 1.67 (m, 1H),1.51 (m, 1H), 1.33 (t, J=7.47Hz, 3H), 0.85 (t, J=7.47Hz, 3H). Examples 7 and 8 F F F 0H F F 0 F F FF1 N o o 5 (RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester F F F F F O F F\ H 11 F H F N O' O (2S, RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 10 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A mixture of (RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester and (RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester (prepared by a procedure 15 exactly similar to that described for Examples 3 and 4 with the exception that racemic starting material was used and the mixture of diastereoisomers produced were not separated) (20mg, 0.0342mmol) in ethanol (5mL) containing palladium hydroxide (20% on carbon, 20mg) was hydrogenated in a Parr shaker (Parr Instrument Company, Moline, Illinois) at 40psi for 5h. The catalyst was removed by filtration WO 2004/085401 PCT/IB2004/000836 -106 through Celite@ and the solvent was removed under vacuum. The residue was chromatographed on silica eluting with an ethyl acetate - hexanes gradient from 0% to 10% to give the title compounds. (RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2 5 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (first eluting diastereoisomer, 8mg) MS: 586.0 [M+H]* found 1 H-NMR (CDC1 3 ) 8 7.89 (s, 1 H), 7.88 (s, 2H), 7.53 (m, 2H), 7.39 (s, 1 H), 4.55 4.47 (m, 1H), 4.34-4.24 (m, 2H), 4.24-4.18 (m, 1H), 4.03 (d, J=11.62Hz, IH), 3.77 (s, 10 3H), 3.38 (m, 1H), 1.75 (m, 1H), 1.49 (m, 1H), 1.38 (m, 1H), 1.31 (t, J=7.47Hz, 3H), 0.96 (m, 1H), 0.71 (t, J=7.47Hz, 3H). (RS, RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (second eluting diastereoisomer, 5mg) 15 MS: 586.0 [M+H]* found 1 H-NMR (CDCl3) 6 7.93 (s, 2H), 7.84 (s, 1H), 7.53 (d, J=8.29Hz, 1H), 7.43 (dd, J=8.29Hz, 1H), 7.07 (s, 1H), 4.42 (m, 1H), 4.27 (d, J=9.96Hz, 1H), 4.26 (m, 2H), 4.32 (m,IH), 3.76 (s, 3H), 3.28 (m, IH), 2.36 (m, IH), 1.65 (m, IH), 1.62 (m, IH),1.45 (m, 1 H), 1.31 (t, J=7.47Hz, 3H), 0.84 (t, J=7.47Hz, 3H). 20 Examples 9 and 10 F F F F F F N F F H '"'H F N (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -107 F F F FN F F H "H F F F N )-o (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester Sodium hydride (60% dispersion in mineral oil, 34mg, 0.85mmol) was added 5 to a solution of 3,5-bis(trifluoromethylphenyl)acetonitrile (212mg, 0.84mmol) in anhydrous dimethylformamide (1.5mL). After stirring under nitrogen for 30 min at ambient temperature a solution of (R)-4-chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester (Preparation 14, 188mg, 0.56mmol) in anhydrous dimethylformamide (2mL) was added. The mixture was stirred at ambient 10 temperature for 16h then poured into water (20mL) and extracted with diethyl ether (3x2OmL). The extract was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. This material was purified by chromatography on silica eluting initially with ethyl acetate - hexanes (1:19) to obtain one diastereoisomer of the desired compound in an impure form which was further purified by reverse phase 15 chromatography to obtain the title compound Example 9 as a clear oil (69mg). Further elution of the silica column with ethyl acetate - hexanes (1:4) provided the title compound of Example 10 as a yellow oil (54mg). (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 20 MS: 553 [M+H]* found 'H-NMR (CDCl 3 ) 5 7.80 (s, 1H), 7.60 (d, J=8.3OHz, IH), 7.49 (dd, J=8.30, 1.66Hz, 1H), 7.40 (s, 2H), 6.60 (d, J=1.66Hz, IH), 4.59 (m, IH), 4.33 (m, 2H), 4.06 (d, J=9.96, IH), 3.20 (m, 1H), 2.78 (m, 1H), 1.89 (m, 1H), 1.65 (m, 1H), 1.53 (m, 1H), 1.34 (t, J=7.47Hz, 3H), 0.96 (m, 1H), 0.88 (t, J=7.47Hz, 3H). 25 (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS: 553 [M+H]* found WO 2004/085401 PCT/IB2004/000836 -108 'H-NMR (CDC1 3 ) 8 7.89 (s, 1H), 7.62 (s, 2H), 7.62 (d, J=8.30Hz, 1H), 7.55 (d, J=8.3OHz, 1H), 7.38 (s, 1H), 4.41 (m, 1H), 4.24 (m, 2H), 4.16 (m, 1H), 4.15 (d, J=8.3OHz, 1H), 3.48 (m, 1H), 2.01 (m, 1H), 1.95 (m, IH), 1.48 (m, 1H), 1.41 (m, 1H), 1.29 (t, J=7.47Hz, 3H), 0.77 (t, J=7.47Hz, 3H). 5 Preparation 15 CN MeO OTMS MeO N Me CO 2 Et [(R, S), (S, R)] and [(R, R), (S, S)]-4-Cyano-6,7-dimethoxy-2-methyl-4 trimethylsilanyloxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester [(RS)]-6,7-Dimethoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1 -carboxylic 10 acid ethyl ester (8.02gm, 27.3mmol, 1 eq) and zinc iodide (0.43gm, 1.37mmol, 0.05 eq) were added to a dry round bottomed flask equipped with a magnetic stir bar and reflux condenser under a nitrogen atmosphere. Toluene (20mL) was added to the flask followed by trimethylsilyl cyanide (4.40mL, 33.Ommol, 1.2 eq). The reaction was heated to 80 OC. After 5 hr, the reaction mixture was concentrated to dryness to 15 afford the title compounds (1 0.7gm, 27.2mmol, 100% yield) that were used without further purification. LCMS (ESI+): 393 (MH+). Preparation 16 CN MeO MeO N Me CO 2 Et 20 (RS) -4-Cyano-6,7-dimethoxy-2-methyl-2H-quinoline-1-carboxylic acid ethyl ester [(R, S), (S, R)] and [(R, R), (S, S)]-4-cyano-6,7-dimethoxy-2-methyl-4 trimethylsilanylqxy-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (10.7gm, 27.37mmol) was placed in a 100mL round bottomed flask and dissolved in ethanol 25 (25 mL). Hydrochloric acid in dioxane (21.0mL of a 4.0 M solution) was added to the mixture. After 12 hr at room temperature, the reaction mixture was concentrated, quenched with a saturated aqueous sodium hydrogen carbonate solution and extracted 3 times with ethyl acetate. The combined organic layers were dried over WO 2004/085401 PCT/IB2004/000836 -109 anhydrous sodium sulfate, filtered and concentrated. Flash chromatography eluting with 80/20 hexanes/ethyl acetate the title compounds (5.49gm, 18.1mmol, 67% yield). LCMS (ESI+): 303 (MH+). 5 1 H-NMR (CDCl): 8 1.13 (d, 3H), 1.33 (t, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 4.30 (m, 2H), 5.25 (m, 1H), 6.65 (d, 1H), 6.91 (s, 1H), 7.24 (br s, 1H). Preparations 17 and 18 CN MeO MeO N Me CO 2 Et [(R, S), ((S, R)] and [(R, R), (S, S)]-4-Cyano-6,7-dimethoxy-2-methyl-3,4-dihydro-2H 10 quinoline-1-carboxylic acid ethyl ester (RS) -4-Cyano-6,7-dimethoxy-2-methyl-2H-quinoline-1-carboxylic acid ethyl ester (4.99gm, 16.5mmol) was placed in a round bottomed flask equipped with a magnetic stir bar, dissolved in 47mL of ethanol, and was combined with sodium borohydride (3.18gm, 84.3mmol, 5.1 eq). After 45 min of heating at reflux, the 15 mixture was concentrated to dryness, quenched with water, and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered and concentrated to afford the title compounds (4.91gm, 16.1mmol, 98% yield). cis isomer: 20 LCMS (ESI+): 305 (MH+). (R, S) and (S, R) 1 H-NMR (CDCl3): 5 1.23 (d, 3H), 1.29 (t, 3H), 1.78 (m, 1H), 2.65 (m, 1H), 3.74 (m, 1H), 3.86 (s, 3H), 3.90 (s, 3H), 4.22 (m, 2H), 4.61 (m, IH), 6.92 (s, IH), 7.10 (s, 1H). trans isomer: 25 LCMS (ESI+): 305 (MH+). (R, R) and (S, S) 1 H-NMR (CDC13): 6 1.16 (d, 3H), 1.32 (t, 3H), 2.03 (m, 1H), 2.42 (m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 3.94 (m, 1H), 4.26 (m, 2H), 4.86 (m, 1H), 6.77 (s, 1H), 7.30 (s, 1H). Preparations 19 and 20 WO 2004/085401 PCT/IB2004/000836 -110 o
NH
2 MeO MeO N Me
CO
2 Et [(R, S), (S, R)] and [(R, R), (S, S)]-4-Carbamoyl-6,7-dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester [(R, S), (S, R)] and [(R, R), (S, S)]-4-cyano-6,7-dimethoxy-2-methyl-3,4 5 dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.22gm, 7.32mmol, 1 eq) was dissolved in concentrated sulfuric acid (12mL) and water (0.66mL, 36.6mmol, 5 eq). After 12 hr at ambient temperature the reaction was quenched into solid sodium bicarbonate, dissolved in water and extracted 3 times with ethyl acetate. Organic layers were collected, dried over anhydrous sodium sulfate, filtered, and concentrated 10 to provide the title compounds (2.25gm, 6.98mmol, 95% yield). LCMS (ESI+): 323 (MH+). [(R, S), (S, R)]: 1 H-NMR (CDCI 3 ): 6 1.20 (d, 3H), 1.30 (t, 3H), 1.89 (m, 1H), 2.41 (m, 1 H), 3.37 (m, 1 H), 3.84 (s, 3H), 3.86 (s, 3H), 4.22 (m, 2H), 4.55 (m, 1 H), 5.70 (s, 1H), 5.80 (s, IH), 6.70 (s, iH), 7.21 (s, 1H). 15 LCMS (ESI+): 323 (MH+). [(R, R), (S, S)]: 1 H-NMR (CDC 3 ): 5 1.17 (d, 3H), 1.30 (t, 3H), 1.74 (m, 1H), 2.67 (m, 1 H), 3.55 (m, 1 H), 3.86 (s, 3H), 3.87 (s, 3H), 4.21 (m, 2H), 4.58 (m, 1 H), 5.36 (s, 1H), 5.49 (s, IH), 6.65 (s, IH), 7.15 (s, IH). Preparations 21 and 22 o OMe MeO MeO N Me 20
CO
2 Et [(R, S), (S, R)] and [(R, R), (S, S)]-6,7-Dimethoxy-2-methyl-3, 4-dihydro-2H quinoline-1,4-dicarboxylic acid-I-ethyl ester-4-methyl ester [(R, S), ((S, R)] and [(R, R), (S, S)]-4-Carbamoyl-6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.24gm, 6.95mmol, 1 eq) was 25 placed in a 1 OOmL round bottomed flask equipped with a stir bar and was dissolved in methylene chloride (56.5mL). Trimethyloxonium tetrafluoroborate (1.29gm, 8.76mmol, 1.26 eq) was added to the solution followed by 12.2mL more of methylene WO 2004/085401 PCT/IB2004/000836 -111 chloride. After 12 hr at ambient temperature the reaction mixture was concentrated to dryness and used without further purification. The product (2.84gm, 6.95mmol, I eq) was dissolved in water (20mL) and stirred for several hours at room temperature. The mixture was saturated with sodium chloride solution, extracted 3 times with ethyl 5 acetate, dried over sodium sulfate, filtered and concentrated to dryness. Flash chromatography eluting with 80/20 hexanes/ethyl acetate provided the title compounds (1.65gm, 4.88mmol, 70% yield). LCMS (ESI+): 338 (MH+). [(R, S) (S, R)] 'H-NMR (CDC13): 8 1.17 (d, 3H), 1.29 (t, 3H), 1.81 (m, IH), 2.46 10 (m, 1H), 3.56 (m, 1H), 3 .81 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 4.21 (m, 2H), 4.55 (m, 1H), 6.60 (s, 1H), 7.11 (s, 1H). LCMS (ESI+): 338 (MH+). [(R, R) (S, S)]: 'H-NMR (CDC13): 8 1.13 (d, 3H), 1.29 (t, 3H), 1.78 (m, 1H), 2.54 (m, 1H), 3.67 (s, 3H), 3.71 (m, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 4.21 (m, 2H), 4.74 15 (m, 1H), 6.66 (s, 1H), 7.13 (s, 1H). Preparations 23 and 24 0 OH MeO MeO N Me
CO
2 Et [(R, S), (S, R)] and [(R, R), (S, S)]-6,7-Dimethoxy-2-methyl-3,4-dihydro-2H-quinoline 1,4-dicarboxylic acid-1-ethyl ester 20 [(R, S), (S, R)] and [(R, R), (S, S)]-6,7-Dimethoxy-2-methyl-3,4-dihydro-2H quinoline-1,4-carboxylic acid ethyl ester-4-methyl ester (0.62gm, 1.73mmol, I eq) was dissolved in dioxane (12mL) and water (12mL) in round bottomed flask with a magnetic stir bar. Sodium hydroxide (0.13gm, 3.48mmol, 2 eq) was added and stirred at room temperature. After 12 hr, the reaction mixture was concentrated and 25 partitioned between 1.0 N aqueous sodium hydroxide and diethyl ether. The aqueous layer was collected, acidified with concentrated hydrochloric acid, and extracted with ether. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated to provide the title compounds (0.536gm, 1.65mmol, 90% yield) as a mixture of diastereoisomers. 30 LCMS (ESI+): 324 (MH+).
WO 2004/085401 PCT/IB2004/000836 -112 [(R, S), (S, R)]: 'H-NMR (CDC1 3 ): 5 1.18 (d, 3H), 1.30 (t, 3H), 1.89 (m, 1H), 2.48 (m, 1H), 3.61 (m, IH), 3.84 (s, 3H), 3.85 (s, 3H), 4.21 (m, 2H), 4.60 (m, IH), 6.75 (s, 1H), 7.15 (s, 1H). LCMS (ESI+): 324 (MH+). 5 [(R, R), (S, S)]: 'H-NMR (CDCl 3 ): 3 1.14 (d, 3H), 1.29 (t, 3H), 1.83 (m, 1H), 2.56 (m, 1H), 3.74 (m, 1H), 3.85 (s, 6H), 4.21 (m, 2H), 4.76 (m, 1H), 6.70 (s, 1H), 7.14 (s, 1H). Examples 11 and 12
F
3 C H o N "
CF
3 MeO MeO N Me
CO
2 Et 10 [(R, S), (S, R)] and [(R, R), (S, S)]-4-(3,5-Bis-trifluoromethyl-benzylcarbamoyl)-6,7 dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester [(R, S), (S, R)] and [(R, R), (S, S)]-6,7-Dimethoxy-2-methyl-3,4-dihydro-2H quinoline-1,4-dicarboxylic acid-I-ethyl ester (0.229gm, 0.71Ommol) was placed in a 25mL round bottomed flask equipped with a stir bar. Methylene chloride (7.OmL) was 15 added followed by the addition of 3,5-bis(trifluoromethyl)benzylamine (0.519gm, 2.14mmol, 3.0 eq). To this reaction, 1-hydroxybenzotriazole hydrate (0.022gm, 0.146mmol, 0.2 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.232gm, 1.21 mmol, 1.7 eq) were added. The reaction mixture was stirred at room temperature. After 12 hr, the reaction was quenched with water and extracted 3 20 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered, concentrated to provide the title compounds (0.1225gm, 0.223mmol, 58% yield) as a mixture of diastereoisomers. LCMS (ESI+): 549 (MH+). 1 H NMR [(R, R), (S, S) and (R, S) (S, R)] (CDC 3 ): 5 1.16 (d, 3H), 1.24 (t, 3H), 25 1.80 (m, 1H), 2.66 (m, 1H), 3.64 (m, 1H), 3.81 (s, 3H), 3.86 (s, 3H), 4.11 (m, 2H), 4.29 (m, 1H), 4.56 (m, 2H), 4.70 (m, 2H), 6.05 (m, 1H), 6.40 (m, 1H), 6.65 (s, 1H), 6.60 (s, 1H), 7.13 (s, 1H), 7.66 (s, 2H), 7.75 (s, 1H), 7.80 (s, 1H). LCMS (ESI+): 549 (MH+).
WO 2004/085401 PCT/IB2004/000836 -113 Preparations 25 and 26 [(R, S), (S, R)] and [(R, R), (S, S)]-6,7-Dimethoxy-4-(methoxymethyl-carbamoyl)-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester [(R, S), (S, R)] and [(R, R), (S, S)]-6,7-Dimethoxy-2-methyl-3,4-dihydro-2H 5 quinoline-1,4-dicarboxylic acid-I -ethyl ester (0.536gm, 1.55mmol) was placed in a 25mL round bottomed flask equipped with a stir bar and dissolved in methylene chloride (1OmL). The reaction mixture was cooled to 0 0C, and di-iso propylethylamine (0.18gm, 2.Ommol, 1.3 eq) was added followed by addition of N,O di-methyihydroxylamine hydrochloride (1.1 eq), 4-dimethylaminopyridine (0.1 eq), and 10 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 eq). The reaction mixture was stirred at room temperature. After 12 hr, the reaction mixture was quenched with water and extracted 3 times with ethyl acetate. The organic layers were collected, dried, filtered, and concentrated to provide the title compounds (0.56gm, 1.52mmol, 98% yield) that were used without further purification. 15 LCMS (ESI+): 367 (MH+). [(R, R), (S, S)] 1 H-NMR (CDCI 3 ): 6 1.10 (d, 3H), 1.28 (t, 3H), 1.83 (m, I H), 2.41 (m, 1H), 3.16 (s, 3H), 3.38 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 4.06 (m, 1H), 4.21 (in, 2H), 4.84 (m IH), 6.55 (s, IH), 7.16 (s, IH). LCMS (ESI+): 367 (MH+). 20 [(R, S), (S, R)] 1 H-NMR (CDCi 3 ): 6 1.32 (d, 3H), 1.65 (t, 3H), 1.75 (m, 1H), 2.39 (m, IH), 3.16 (s, 3H), 3.35 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 4.06 (m, 1H), 4.21 (m, 2H), 4.84 (m 1H), 6.45 (s, 1H), 7.05 (s, 1H). Examples 13 and 14
CF
3 MeO
CF
3 MeO N Me
CO
2 Et 25 [(R, S), (S, R)] and [(R, R), (S, S)]-4-(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy 2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester [(R, S), (S, R)] and [(R, R), (S, S)]-6,7-Dimethoxy-4-(methoxy-methyl carbamoyl)-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.56gm, 1.45mmol, 1 eq) was dissolved in tetrahydrofuran (12mL) in a round bottomed flask WO 2004/085401 PCT/IB2004/000836 -114 equipped with a magnetic stir bar. The reaction was cooled to 0 OC. 3,5 Bis(trifluoromethyl)phenyl magnesium bromide (13.6mL of 0.5 M solution) was added drop wise, and the reaction mixture was stirred at room temperature. After 12 hr, the reaction mixture was quenched with aqueous ammonium chloride, further 5 saturated with NaCI and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered and concentrated to dryness. Flash chromatography eluting with 90/10 hexanes/ethyl acetate provided the title compounds (0.556gm, 1.07mmol, 73% yield). LCMS (ESI+): 520 (MH+). 10 [(R, S), (S, R)]: 1 H NMR (CDCl 3 ): 5 1.24 (d, 3H), 1.35 (t, 3H), 1.81 (m, 1 H), 2.52 (m, 1 H), 3.63 (s, 3H), 3.88 (s, 3H), 4.29 (m, 2H), 4.42 (m, 1 H), 4.57 (m, 1 H), 6.21 (s, 1H), 7.15 (s, 1H), 8.13 (s, 1H), 8.45 (s, 2H). LCMS (ESI+): 520 (MH+). [(R, R), (S, S)] 1 H NMR (CDCI 3 ): 5 1.18 (d, 3H), 1.28 (t, 3H), 1.88 (m, IH), 15 2.67 (m, 1 H), 3.79 (s, 3H), 3.84 (s, 3H), 4.21 (m, 2H), 4.45 (t, I H), 4.88 (m, I H), 6.59 (s, IH), 7.07 (s, IH), 7.97 (s, 1H), 8.25 (s, 2H). Example 15
CF
3 CF 3 F F F CF 3 F CF 3 MeO H MeO .H MeO N Me MeO N "'Me
CO
2 Et CO 2 Et [(R, R), (S, S)]- 4-(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-methyl-5,6 20 dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester [(R, R), (S, S)]-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-6,7-dimethoxy-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.062gm, 0.120mmol) was dissolved in methylene chloride (0.25mL) in a vial equipped with a magnetic stir bar. [Bis(2-methoxyethyl)amino]sulfur trifluoride (0.22mL, 1.20mmol, 10 eq) was added to 25 this solution and the reaction mixture was stirred at room temperature. After 12 hr, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted 3 times with ethyl acetate. The organic layers were collected, dried over magnesium sulfate, filtered, concentrated and purified by chromatography WO 2004/085401 PCT/IB2004/000836 -115 on silica eluting with 90/10 hexanes/ethyl acetate to provide the title compound (0.045gm, 0.08mmol, 66% yield). LCMS (ESI+): 542 (MH+). [(R, R), (S, S)]: 'H NMR (CDCIs): 5 1.10 (d, 3H), 1.22 (t, 3H), 1.95 (m, 1H), 5 2.45 (m, 1H), 3.55 (m, 1H), 3.75 (s, 3H), 3.87 (s, 3H), 4.00 (m, 1H), 4.19 (m, 1H), 4.60 (m, 1H), 6.45 (s, 1H), 6.99 (s, IH), 7.6 (s, 2H), 7.90 (s, IH). Examples 16 and 17
CF
3 CF 3 HO I HO MeO H CF 3 MeO .,\H CF 3 MeO N Me MeO N Me
CO
2 Et
CO
2 Et [(R, R, R), (S, S, S)] and [(R, R, S), (S, S, R)]-4-[(3,5-Bis-trifluoromethyl-phenyl) 10 hydroxy-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester [(R, R), (S, S)]-4-(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-i-carboxylic acid ethyl ester (0.302gm, 0.58mmol, 1 eq) was placed in a round bottomed flask equipped with a magnetic stir bar. Methanol (1 2mL) 15 was added followed by the addition of sodium borohydride (0.131gm, 3.48mmol, 6 eq) at room temperature. After 1 hour, the reaction mixture was quenched with a brine solution, extracted 3 times with ethyl acetate and dried over sodium sulfate. The material was purified by flash chromatography eluting with 75/25 hexanes/ethyl acetate to provide the title compounds (0.271gm, 0.52mmol, 89% yield). 20 Diastereoisomer 1 (29% yield) LCMS (ESI+): 522 (MH+). 'H NMR (CDC 3 ): 8 1.12 (d, 3H), 1.29 (t, 3H), 1.39 (m, 1H), 2.52 (m, 1H), 2.81 (br s, 1H), 2.94 (m, 1H), 3.65 (s, 3H), 3.83 (s, 3H), 4.21 (m, 2H), 4.67 (m, 1H), 5.04 (d, 1H), 6.18 (s, 1H), 7.02 (s, 1H), 7.64 (s, 2H), 7.72 (s, 1H). 25 Diastereoisomer 2 (60% yield) LCMS (ESI+): 522 (MH+). 'H NMR (CDCs): 8 1.14 (d, 3H), 1.34 (t, 3H), 1.56 (m, 1H), 1.86 (m, 1H), 2.97 (m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 4.26 (m, 2H), 4.49 (m, 1H), 4.77 (d, 1H), 6.70 (s, IH), 7.09 (s, 1H), 7.84 (s, 3H).
WO 2004/085401 PCT/IB2004/000836 -116 Examples 18 and 19
CF
3
CF
3 F
CF
3 F
CF
3 MeO H MeO H MeO N Me MeO N "'Me
CO
2 Et CO 2 Et [(R, R, R), (S, S, S) and (R, R, S), (S, S, R)]-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 5 [(R, R, R), (S, S, S) and (R, R, S), (S, S, R)]-4-[(3,5-Bis-trifluoromethyl phenyl)-hydroxy-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoine-1 carboxylic acid ethyl ester (0.06gm, 0.115mmol) was placed in a small round bottomed flask containing a magnetic stir bar and dissolved in dichloromethane (0.25mL). To this reaction, (diethylamino)sulfur trifluoride (0.152mL) was added 10 dropwise at room temperature. After 2 hr, the reaction was quenched with the addition of aqueous ammonium chloride solution and extracted 3 times with EtOAc. Organics were collected, dried over Na 2
SO
4 , filtered and concentrated to afford the title compounds in 40% isolated yield (0.024gm, 0.046mrnol). LCMS (ESI+): 524 (MH+). 15 1 H NMR (CDC 3 ): 5 1.19 (d, 3H), 1.30 (t, 3H), 2.02 (m, IH), 2.95 (m, 1H), 3.95 (s, 3H), 3.97 (s, 3H), 4.26 (m, 2H), 4.49 (m, iH), 6.40 (s, IH), 6.9 (s, 1H), 7.1 (s, 1H), 7.8 (s, 3H), 7.95 (s, 1 H). Preparation 27 o 0 F OMe F FOMe FFCl C F F N Me N Me
CO
2 Et
CO
2 Et 20 [(R, S) and (R, R)]-4-Chloro-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1,4 dicarboxylic acid-1 -ethyl ester-4-methyl ester (R)-2-Ethyl-4-hydrazono-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester (Preparation 6, 1.22gm, 3.70mmol) was placed in a 250mL round bottomed flask equipped with a stir bar. Diethyl ether (100mL) was 25 added followed by the addition of MnO 2 (22.2mmol, 6 eq). The reaction was WO 2004/085401 PCT/IB2004/000836 -117 protected from light and stirred at room temperature for 90 min. The solution was filtered through Celite@ and concentrated to a final volume of 30mL. Additional toluene (1OOmL) was added and concentrated to 40mL. To this solution was added of di-iso-propylethylamine (3.25mL, 18.5mmol), followed by the addition of 20% 5 phosgene solution in toluene (7.5mL). The reaction mixture was stirred for 45 min before anhydrous methanol (1OmL) was added. After 2 hr, the reaction was concentrated down to 20mL, extracted into methylene chloride and washed with 0.1 N HCI. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated to dryness to obtain the title compound (1.43gm, 3.66mmol, 98% 10 yield). LCMS (ESI+): 394 (MH+). (R, S), (R, R): 'H NMR (CDCI 3 ): 5 0.95 (t, 3H), 1.25 (m, 2H), 1.30 (t, 3H), 2.60 (dd, 1H), 2.79 (dd, 1H), 3.99 (s, 3H), 4.23 (m, 2H), 4.62 (m, H), 7.61 (d, 1H), 7.70 (d, I H). 15 Preparation 28 and 29 0 0 F F OMe F OMe H FH N Me /N Me
CO
2 Et CO 2 Et Preparation of [(R, S) and (R, R)]-2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline 1,4-dicarboxylic acid-i -ethyl ester-4-methyl ester [(R, S) and (R, R)]-4-Chloro-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1,4-dicarboxylic acid-1 -ethyl ester-4 20 methyl ester (1.40 grams, 3.56 mmol) was dissolved in 30 mL of methanol before 0.15 grams of 10% Pd/C was added and the mixture was hydrogenated at 45 psi on the par shaker for 2 hours. The reaction mixture was filtered through Celite and concentrated. The crude mixture was then dissolved in dichloromethane and the organics were collected, dried over magnesium sulfate and concentrated. The 25 product was isolated after purification by column chromatography eluting with a solution of 90:10 hexane-acetone to yield 83% (2.98 mmol) of the title compound. (R, S): 1 H NMR (CDCI 3 ): S? 0.84 (t, 3H), 1.30 (t, 3H), 1.40 (m, 2H), 1.95 (m, IH), 2.47 (m, 1H), 3.61 (m, 1H), 3.80 (s, 3 H), 4.3 (m, 2H), 4.42 (m, 1H), 7.40 (s, 1H), 7.60 (d, 1H), 7.70 (d, 1H). 30 LCMS (ESI+): 360 (MH+) WO 2004/085401 PCT/IB2004/000836 -118 (R, R): 'H NMR (CDCI 3 ): 8? 0.86 (t, 3H), 1.28 (t, 3H), 1.38 (m, 2H), 2.1 (m, 1H), 2.56 (m, 1H), 3.69 (s, 3H), 3.90 (t, 1H), 4.30 (m, 2H), 4.58 (m, 1H). 7.46 (s, 1H), 7.50 (d, 1H), 7.70 (d, 1H) LCMS (ESI+): 360 (MH+) 5 Preparation 30 0o F F OH F F OH H FEH F F N Me / N Me
CO
2 Et CO 2 Et [(R, S) and (R, R)]-2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1,4-dicarboxylic acid-1 -ethyl ester [(R, S) and (R, R)]-2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1,4 10 dicarboxylic acid-1-ethyl ester-4-methyl ester (Preparation 28 and 29, 0.070gm, 0.195mmol, 1 eq) was dissolved in a round bottomed flask with magnetic stir bar containing dioxane (1.5mL) and water (1.5mL). Sodium hydroxide (0.016gm, 0.409mmol, 2.1 eq) was added and stirred at room temperature. After 12 hr, the reaction mixture was concentrated to a minimum volume and partitioned between 1.0 15 N aqueous sodium hydroxide and diethyl ether. The aqueous layer was collected, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated to provide the title compounds (0.067gm, 0.194mmol, 99% yield). LCMS (ESI+): 346 (MH+). 20 [(R, S), (R, R)]: 'H-NMR (CDCI 3 ): 6 0.84 (t, 3H), 1.23 (t, 3H), 1.39 (m, 2H), 1.94 (m, 1H), 2.59 (m, IH), 3.84 (t, 1H), 4.19 (m, 2H), 4.62 (m, H), 7.49 (m, 2H), 7.63 (d, IH). Preparation 31 O OMe O OMe F F N'Me FF N'Me H .nH F F Me Me N N
CO
2 Et CO 2 Et 25 [(R, S) and (R, R)]-2-Ethyl-4-(methoxy-methyl-carbamoyl)-6-trifluoromethyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -119 [(R, S) and (R, R)]-2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1,4 dicarboxylic acid-1-ethyl ester (0.066gm, 0.239mmol) was placed in a 5mL round bottomed flask equipped with stir bar. Methylene chloride (3mL) was added. The reaction mixture was cooled to 0 OC. Di-iso-propylethylamine (0.032gm, 0.248mmol, 5 1.3 eq) was added followed by addition of N,O-dimethylhydroxylamine HCI salt (0.239mmol), 4-dimethylaminopyridine (0.019mmol) and 1-(3-dimethylaminopropy) 3-ethylcarbodiimide hydrochloride (0.210mmol). The reaction was stirred at room temperature. After 12 hr, the reaction was quenched with water and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium 10 sulfate, filtered, concentrated to provide the title compounds (0.065gm, 0.167mmol, 88% yield). LCMS (ESI+): 389 (MH+). [(R, S), (R, R)]: 'H-NMR (CDC 3 ): 5 0.90 (t, 3H), 1.33 (t, 3H), 1.39 (m, 2H), 2.0 (m, 1H), 2.55 (m, 1H), 3.20 (s, 3H), 3.40 (s, 3H), 4.19 (m, 2H), 4.62 (m, 1H), 7.21 15 (s, 1H), 7.40 (s, 2H), 7.62 (d, 2H). Examples 20 and 21
CF
3
CF
3 0 CF 3 CF 3
F
3 C Me F 3 C H N Me N Me
CO
2 Et
CO
2 Et [(R, S)] and [(R, R)]-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4 dihydro-2H-quinoline-1 -carboxylic acid ethyl ester 20 [(R, S), (R, R)]-2-Ethyl-4-(methoxy-methyl-carbamoyl)-6-trifluoromethyl-3,4 dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.564gm 1.45mmol, 1 eq) was dissolved in tetrahydrofuran (12mL) in a round bottomed flask equipped with a stir bar. The reaction was cooled to 0 IC. 3,5-Bis(trifluoromethyl)phenyl magnesium bromide (13.6mL of 0.5M solution) was added dropwise, and the reaction mixture 25 was stirred at room temperature. After 12 hr, the reaction mixture was quenched with aqueous ammonium chloride solution, further saturated with NaCl and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered and concentrated to dryness. Flash chromatography eluting with WO 2004/085401 PCT/IB2004/000836 -120 90/10 hexanes/ethyl acetate provided the title compounds (0.556gm, 1.02mmol, 70% yield). trans isomer: LCMS (ESI+): 542 (MH+). 5 (R, R): 'H-NMR (CDCI 3 ): 5 0.98 (t, 3H), 1.29 (t, 3H), 1.52 (m, 2H), 2.05 (m, 1H), 2.64 (m, 1H), 4.24 (m, 2H), 4.66 (m, 2H), 7.40 (s, IH), 7.55 (d, 1H), 7.60 (d, 1H), 8.05 (s, 2H), 8.24 (s, 1H). cis isomer: LCMS (ESI+): 542 (MH+). 10 (R, S): 'H-NMR (CDC 3 ): 3 0.91 (t, 3H), 1.39 (t, 3H), 1.43 (m, 2H), 1.78 (m, 1H), 1.99 (m, 1H), 2.60 (m, 1H), 4.34 (m, 2H), 4.56 (m, 2H), 7.05 (s, 1H), 7.55 (d, IH), 7.65 (d, 1H), 8.20 (s, 1H), 8.44 (s, 2H). Examples 22, 23, 24 and 25
CF
3 CF 3
CO
2 Et CO 2 Et
CF
3
CF
3 H I H I HO E CF 3 HO CF 3
F
3 C H F3C H N Me N Me
CO
2 Et CO 2 Et 15 [(R, R, R)], [(R, R, S)], [(R, S, S)], and [(R, S, R)]-4-(3,5-bis-trifluoromethyl-phenyl) hydroxy-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-q uinoline-1 -carboxylic acid ethyl ester [(R, S)] and [(R, R)]-4-(3,5-Bis-trifluoromnethyl-benzoyl)-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.182gm, 20 0.34mnmol, 1 eq) was placed in a round bottomed flask equipped with a magnetic stir bar. Methanol (6.8mL) was added followed by the addition of (0.077gm, 2.05mmiol, 6 WO 2004/085401 PCT/IB2004/000836 -121 eq) sodium borohydride at room temperature. After 1 hour, the reaction mixture was quenched with brine solution, extracted 3 times with ethyl acetate and dried over sodium sulfate. The material was purified by flash chromatography eluting with 90/10 hexanes/ethyl acetate to provide the title compounds in three fractions. 5 (R,S,R): LCMS (ESI+): 544 (MH+). 'H-NMR (CDCI): 5 0.81 (t, 3H), 1.27 (t, 3H), 2.04 (m, 1H), 4.22 (m, 3H), 7.86 (s, 1H), 7.90 (s, 1H). (R,S,S): 10 LCMS (ESI+): 544 (MH+). 1 H-NMR (CDCI 3 ): 8 0.73 (t, 3H), 1.09 (m, 1H), 1.27 (t, 3H), 1.43 (m, 2H), 1.67 (m, 1H), 2.44 (d, 1H), 2.87 (m, 1H), 4.24 (m, 3H), 5.17 (dd, 1H), 7.26 (s, IH), 7.50 (m, 2H), 7.90 (s, 2H), 7.92 (s, 1 H). (R,R,R) and (R,R,S): This mixture was separated on a 10 cm by 50 cm, 15 Chiralpak AD column eluting in heptane/IPA 98//2 at a flow rate of 275 mL/min. (R,R,R): 1 H-NMR (CDCl 3 ): 5 0.77 (t, 3H), 1.31 (t, 3H), 1.41 (m, 2H), 2.21 (d, 1H), 3.19 (m, 1H), 4.23 (m, 2H), 4.37 (m, 1H), 4.83 (d, IH), 7.65 (s, 2H), 7.79 (s, IH). LCMS (ESI+): 544 (MH+). (R,R,S): 1 H-NMR (CDCI 3 ): B 0.81 (t, 3H), 1.33 (t, 3H), 1.6 (m, 2H), 2.22 (d, 20 1H), 3.05 (m, 1H), 4.30 (m, 2H), 4.62 (m, 1H), 5.19 (d, 1H), 7.01 (s, 1H), 7.40 (s, 2H), 7.85 (s, I H). LCMS (ESI+): 544 (MH+). Preparations 32 and 33 [(R, R), (S, S)] and [(S, R), (R, S)]-4-Aminomethyl-6,7-dimethoxy-2-methyl-3,4 25 dihydro-2H-quinoline-1-carboxylic acid ethyl ester Sodium borohydride (0.828gm, 21.9mmol) was suspended in tetrahydrofuran (1 3.5mL) in a dry 50mL round-bottomed flask equipped with stir bar. In another flask trifluoroacetic acid (1.68mL, 21.8mmol) was dissolved in tetrahydrofuran (5mL). The 50mL reaction flask was cooled to O0C and the trifluoroacetic acid solution was added 30 slowly. The reaction was allowed to stir at room temperature. After 30 min, [(R, R), (S, S)] and [(S, R), (R, S)]-4-cyano-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline 1-carboxylic acid ethyl ester (1.33gm, 4.37mmol) in tetrahydrofuran (5mL) was added drop wise to the reaction. After 12 hr, the reaction was cooled back to 0 0C and WO 2004/085401 PCT/IB2004/000836 -122 carefully quenched with water. The aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography eluting with 97/2/1 methylene chloride/methanol/triethylamine to afford the title compounds 5 (0.982gm, 3.18mmol, 73% yield). LCMS (ESI+): 309 (MH+). [(R, S), (S, R)] 'H-NMR (CDCI 3 ): 8 1.18 (d, 3H), 1.27 (t, 3H), 2.47 (m, 2H), 2.92 (m, 1H), 3.29 (m, 1H), 3.84 (s, 3H), 3.86 (s, 3H), 4.19 (m, 2H), 4.47 (m, 1H), 6.69 (s, 1H), 7.02 (s, 1H). 10 LCMS (ESI+): 309 (MH+). [(R, R), (S, S)] 1 H-NMR (CDC 3 ): 81.15 (d, 3H), 1.31 (t, 3H), 1.76 (m, 1H), 2.18 (m, 1H), 2.94 (m, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 4.22 (m, 2H), 4.61 (m, 1H), 6.69 (s, 1H), 7.12 (s, 1H). Example 26 F H N ,& F MeO 0 MeO N Me 15
CO
2 Et [(R, S), (R, R)j and [(S, S), (S, R)]-4-[(3,5-Difluoro-benzoylamino)-methyl]-6,7 dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of [(R, S), (R, R)] and [(S, S), (S, R)]-4-aminomethyl-6,7 dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.012gm, 20 0.039mmol) in methylene chloride (1.OmL) was added 3,5-difluorobenzoic acid (0.0065gm, 0.041mmol, 1.0 eq) followed by 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride (0.012gm, 0.065mmol, 1.6 eq) and 1 hydroxybenzotriazole hydrate (0.005gm, 0.039mmol, 1 eq). The reaction was stirred at ambient temperature for 12 hr. The mixture was concentrated, dissolved in 25 dimethylsulfoxide and purified by HPLC to provide the title compound (0.008gm, 0.019mmol). LCMS (ESI+): 449 (MH+).
WO 2004/085401 PCT/IB2004/000836 -123 [(R, S), (R, R)] and [(S, S), (S, R)]: 'H-NMR (CDC1 3 ): 5 1.15 (d, 3H), 1.30 (t, 3H), 1.79 (m, IH), 2.16 (m, IH), 3.16 (m, 1H), 3.63 (m, 2H), 3.82 (s, 3H), 3.87 (s, 3H), 4.22 (m, 2H), 4.63 (m, 1H), 6.13 (m, 1H), 6.63 (s, 1H), 6.92 (m, 1H), 7.13 (s, 1H), 7.19 (m, 2H). 5 Examples 27 and 28
F
3 C H N ~
CF
3 MeO MeO N Me CO 2 Et [(R, S), (S, R)] and [(R, R), (S, S)]-4-[(3,5-Bis-trifluoromethyl-benzylamino)-methy] 6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester [(R, S), (S, R)] and [(S, S), (R, R)]-4-Aminomethyl-6,7-dimethoxy-2-methyl 10 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.131gm, 0.428mmol) was dissolved in dichloroethane (2.OmL) in a 1OmL round bottomed flask equipped with a stir bar. To this solution, 3,5-bis(trifluoromethyl)benzaldehyde (0.071 mL, 0.431 mmol) was added followed by sodium triacetoxyborohydride (0.272gm, 1.28mmol). After stirring at ambient temperature for 12 hr, the reaction mixture was 15 quenched with a 1.0 N aqueous sodium hydroxide solution and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography eluting with 80/20 hexanes/ethyl acetate provided the title compounds (0.063gm, 0.1 2mmol, 28% yield). 20 LCMS (ESI+): 535 (MH+). [(R, S) (S, R)] 'H-NMR (CDCl 3 ): 5 1.09 (m, IH), 1.17 (d, 3H), 1.28 (t, 3H), 2.47 (m, 1H), 2.61 (m, 1H), 2.83 (m, 1H), 3.16 (m, 1H), 3.83 (s, 3H), 3.84 (s, 3H), 4.02 (s, 2H), 4.20 (m, 2H), 4.47 (m, 1 H), 6.81 (s, 1 H), 7.01 (s, 1 H), 7.82 (s, 1 H), 7.87 (s, 2H). 25 LCMS (ESI+): 535 (MH+). [(R, R) (S, S)] 1 H-NMR (CDC13): 5 1.14 (d, 3H), 1.28 (t, 3H), 1.74 (m, IH), 2.21 (m, 1H), 2.79 (m, 2H), 2.93 (m, 1H), 3.83 (s, 3H), 3.84 (s, 3H), 3.88 (s, 2H), 4.20 (m, 2H), 4.56 (s, 1H), 6.69 (s, 1H), 7.11 (s, 1H), 7.75 (s, 1H), 7.79 (s, 2H).
WO 2004/085401 PCT/IB2004/000836 -124 Examples 29 and 30
F
3 C F 3 C N N
CF
3 N.. N
CF
3 MeO MeO MeO N Me MeO N "Me
CO
2 Et
CO
2 Et [(R, S), (S, R)] and [(R, R), (S, S)]-4-[(3,5-Bis-trifluoromethyl-benzyl) methoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 5 carboxylic acid ethyl ester [(R, S), (S, R)] and [(S, S), (R, R)]-4-[(3,5-Bis-trifluoromethyl-benzylamino) methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.020gm, 0.037mmol) was dissolved in tetrahydrofuran (2.OmL) in a 1OmL round bottomed flask equipped with a stir bar. To this solution, potassium carbonate 10 (0.134gm, 0.972mmol) was added followed by the addition of methyl chloroformate (0.030mL, 0.388mmol). The reaction mixture was stirred at room temperature. After 12 hr, the reaction mixture was quenched with 1.0 N aqueous sodium hydroxide and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography 15 eluting with 65/35 hexanes/ethyl acetate provided the title compounds (0.005gm, 0.008mmol, 30% yield). LCMS (ESI+): 593 (MH+). (R, S) (S, R)] 'H-NMR (CDC 3 ): 3 1.17 (d, 3H), 1.29 (t, 3H), 2.30 (m, 1H), 2.75 (m, 1H), 3.60 (m, 1H), 3.78 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 4.22 (m, 2H), 20 4.39 (m, 1H), 7.03 (s, IH). LCMS (ESI+): 593 (MH+). [(R, R) (S, S)] 'H-NMR (CDC 3 ): 6 1.15 (d, 3H), 1.24 (m, 3H), 1.63 (m, 1H), 2.15 (m, 1H), 3.78 (s, 3H), 3.83 (s, 3H), 3.86 (s, 3H), 4.17 (m, 2H), 4.53 (m, 1H), 7.06 (s, IH). 25 The following examples were prepared from analogous starting materials using methods analogous to those described in the examples above: Example 31 WO 2004/085401 PCT/IB2004/000836 -125
CF
3 CF 3 O CF 3 0 CF 3 MeO 4,H MeO H MeO N Me MeO N "'Me
CO
2 Et CO 2 Et [(R, S), (S, R)]-4-[(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester 'H-NMR (CDCI 3 ): 5 1.2 (d, 3H), 1.35 (t, 3H), 1.95 (m, 1H), 2.55 (m, 1H), 3.60 5 (s, 3H), 3.97 (s, 3H), 4.20 (m, 1 H), 4.22 (m, 1 H), 4.40 (m, 1 H), 4.62 (m, 1 H), 6.2 (s, 1H), 7.1 (s, 1H) 8.19 (s, 1H), 8.45 (s, 2H). LCMS (ESI+): 522 (MH+). Example 32
CF
3 CF 3 HO
CF
3 HO
CF
3 MeO H MeO .,6H MeO N Me MeO N "Me
CO
2 Et CO 2 Et 10 [(R, S, S), (S, R, R), (R, S, R), (S, R, S)]-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 1 H-NMR (CDCl 3 ): 5 1.13 (d, 3H), 1.34 (t, 3H), (m, 1H), 2.97 (m, IH), 3.87 (s, 3H), 3.88 (s, 3H), 4.26 (m, 2H), 4.40 (m, 1H), 5.05 (d, 1H), 6.89 (s, 1H), 6.99 (s, 1H), 7.84 (s, 3H). 15 LCMS (ESI+): 522 (MH+). Example 33
CF
3 0
CF
3
F
3 C I%\H N Me
CO
2 Et WO 2004/085401 PCT/IB2004/000836 -126 (R, S)-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester (R, S)]- cis: 'H-NMR (CDCl 3 ): 6 0.91 (t, 3H), 1.39 (t, 3H), 1.43 (m, 2H), 1.78 (m, 1H), 1.99 (m, IH), 2.60 (m, 1H), 4.34 (m, 2H), 4.56 (m, 2H), 7.05 (s, 1H), 7.55 5 (d, 1H), 7.65 (d, 1H), 8.20 (s, IH), 8.44 (s, 2H). LCMS (ESI+): 542 (MH+). Example 34
CF
3 CF 3 0 Me O YMe 0
CF
3 0
CF
3 MeO H MeO MeO N Me MeO N "'Me
CO
2 Et CO 2 Et [(R, R, S), (S, S, R), (R, R, R), (S, S, S)]-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl) 10 methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 1 H-NMR (CDC 3 ): 5 1.10 (d, 3H), 1.29 (t, 3H), 1.62 (m, 1H), 1.87 (m, IH), 2.00 (s, 3H), 3.22 (m, 1H), 3.84 (s, 3H), 3.86 (s, 3H), 4.21 (m, 2H), 4.47 (m, 1H), 5.89 (d, 1 H), 6.62 (s, 1 H), 7.03 (s, I H), 7.66 (s, 2H), 7.80 (s, 1 H). LCMS (ESI+): 564 (MH+). 15 Example 35
CF
3 CF 3 F
CF
3 F
CF
3 MeO H MeO .,0 H MeO N Me MeO N "'Me
CO
2 Et CO 2 Et [(R,R,R) (S,S,S) and (R,R,S) and (S,S,R)]-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 'H-NMR (CDC 3 ): 6 1.19 (d, 3H), 1.30 (t, 3H), 2.02 (m, 1H), 2.95 (m, 1H), 20 3.95 (s, 3H), 3.97 (s, 3H), 4.26 (m, 2H), 4.49 (m, 1H), 6.40 (s, IH), 6.9 (s, 1H), 7.1 (s, I H), 7.8 (s, 3H), 7.95 (s, I H). LCMS (ESI+): 524 (MH+).
WO 2004/085401 PCT/IB2004/000836 -127 Example 36 j OH I MeO MeO N Me CO 2 Et [(R, R), (S, S), (R, S), (S, R)]-4-(Hydroxy-diphenyl-methyl)-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 5 'H-NMR (CDC): 5 1.0 (d, 3H), 1.32 (t, 3H), 2.2 (m, 1H), 3.90 (s, 3H), 3.95 (s, 3H), 4.26 (m, 2H), 4.6 (m, 1H), 6.60 (s, 1H), 6.9 (s, 1H), 7.0 (s, 1H), 7.2-7.4 (m, 1OH). LCMS (ESI+): 444 (MH+) (minus 17 OH group). Example 37 MeO MeO Z H MeO N Me MeO N "Me 10
CO
2 Et CO 2 Et [(R, R), (S, S)-4-benzoyl-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester H-NMR (CDCl 3 ): 5 1.19 (d, 3H), 1.25 (t, 3H), 2.4 (m, 1H), 3.75 (s, 3H), 3.85 (s, 3H), 4.30 (m, 2H), 4.6 (m, 1H), 4.9 (m, IH), 6.50 (s, IH), 7.2 (s, 1H), 7.4 (m, 2H), 15 7.5 (t, 1H), 7.9 (d, 2H). LCMS (ESI+): 384 (MH+). Example 38 HO HO MeO H MeO MeO N Me MeO N "Me
CO
2 Et
CO
2 Et [(R, S, S), (R, S, R), (S, R, R), (S, R, S)] 4-(Hydroxy-phenyl-methyl)-6,7 20 dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester LCMS (ESI+): 386(MH+) WO 2004/085401 PCT/IB2004/000836 -128 Examples 39-169 in Table A were prepared as racemic mixtures using analogous methods as described above from the appropriate starting materials and have the following structure:
R
3 MeO MeO N Me 5
CO
2 Et Table A Ex. R3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 39 F (4-[(3,5-Bis-trifluoromethyl-benzyl)- 563 F F F methyl-carbamoyl]-6,7-dimethoxy 2-methyl-3,4-dihydro-2H-quinol F ine-i -carboxylic acid ethyl ester) N 40 0- 4-{[(3,5-Bis-trifluoromethyl-benzyl)- 593 o methoxycarbonyl-amino]-methyl} * N F 6,7-dimethoxy-2-methyl-3,4 2 C F dihydro-2H-quinoline-1-carboxylic F
-
F acid ethyl ester F F 41 0 CH 2 * 4-[(3,5-Bis-trifluoromethyl-phenyl)- 579 N methoxy-carbonyl-amino]-methyl} 0F 6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic F F acid ethyl ester F F WO 2004/085401 PCT/IB2004/000836 -129 Ex. R3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 42 0 4-{[(3,5-Bis-trifluoromethyl-benzyl)- 593 0 methoxy-carbonyl-amino]-methyl} *H2/ F 6,7-dimethoxy-2-methyl-3,4
H
2 C /F dihydro-2H-quinoline-1-carboxylic F F acid ethyl ester F F 43F F 4-(3,5-Bis-trifluoromethyl- 549 F F benzylcarbamoy)-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 F carboxylic acid ethyl ester IF NH CC=O 44 6,7-Dimethoxy-2-methyl-4-(4- 481 F HNC F NC trifluoromethyl-benzylcarbamoyl) F F -3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester 45 F 4-(2-Fluoro-4-trifluoromethyl- 499 - F benzylcarbamoyl)-6,7-dimethoxy-2 -C-NH F methyl-3,4-dihydro-2H-quinoline-1 O carboxylic acid ethyl ester 46 . F 4-(2-Fluoro-benzylcarbamoyl)-6,7- 431 C "N dimethoxy-2-methyl-3,4-dihydro H 2H-quinoline-1 -carboxylic acid ethyl ester 47 4-(3-Fluoro-benzylcarbamoyl)-6,7- 431 dimethoxy-2-methyl-3,4-dihydro F C 2H-quinoline-1 -carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -130 Ex. R 3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 48 NH 4-(4-Fluoro-benzylcarbamoyl)-6,7- 431 1 dimethoxy-2-methyl-3,4-dihydro F e 0 2H-quinoline-1-carboxylic acid ethyl ester 49 . Cl 4-(2-Chloro-benzylcarbamoyl)-6,7- 447 0 N dimethoxy-2-methyl-3,4-dihydro H 2H-quinoline-1-carboxylic acid ethyl ester 50 4-(3-Chloro-benzylcarbamoyl)-6,7- 447 N o dimethoxy-2-methyl-3,4-dihydro ClI C 2H-quinoline-1-carboxylic acid ethyl ester 51 NH 4-(4-Chloro-benzylcarbamoyl)-6,7- 447 1 dimethoxy-2-methyl-3,4-dihydro CI O 2H-quinoline-1-carboxylic acid ethyl ester 52 CI 4-(2,4-Dichloro-benzylcarbamoyl)- 481 0CN 6,7-dimethoxy-2-methyl-3,4 H dihydro-2H-quinoline-1-carboxylic CI acid ethyl ester 53 Cl NH 4-(2,5-Dichloro-benzylcarbamoyl)- 481 | 6,7-dimethoxy-2-methyl-3,4 Cl*C O dihydro-2H-quinoline-1-carboxylic acid ethyl ester 54 Cl 4-(3,4-Dichloro-benzylcarbamoyl)- 481 H 6,7-dimethoxy-2-methyl-3,4 CN C dihydro-2H-quinoline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -131 Ex. R 3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 55 F 4-(3,5-Difluoro-benzylcarbamoyl)- 449 O, 'Ce 6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic HN F acid ethyl ester 56 . F 4-(2,4-Difluoro-benzylcarbamoyl)- 449 O C N 6,7-dimethoxy-2-methyl-3,4 H dihydro-2H-quinoline-1-carboxylic F acid ethyl ester 57 F NH 6,7-Dimethoxy-2-methyl-4-(4- 497 F OK trifluoromethoxy F 0 benzylcarbamoyl)-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester 58 F F 4-(3,5-Bis-trifluoromethyl- 549 F F benzylcarbamoyl)-6,7-dimethoxy F 2-methyl-3,4-dihydro-2H F quinoline-1 -carboxylic acid ethyl NH ester 'C=0 59 CI 4-(3,5-Dichloro-benzylcarbamoyl)- 481 O C* 6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic HN Cl acid ethyl ester 60 F 6,7-Dimethoxy-2-methyl-4-(3- 497 F O C,0 trifluoromethoxy F benzylcarbamoyl)-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -132 Ex. R 3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 61 F 4-(3,4-Difluoro-benzylcarbamoyl)- 449 H 6,7-dimethoxy-2-methyl-3,4 F N dihydro-2H-quinoline-1-carboxylic acid ethyl ester 62 F 6,7-Dimethoxy-2-methyl-4-(3,4,5- 467 F trifluoro-benzylcarbamoyl)-3,4 H dihydro-2H-quinoline-l-carboxylic F C acid ethyl ester 63 F NH 6,7-Dimethoxy-2-methyl-4-(2,4,5- 467 trifluoro-benzylcarbamoyl)-3,4 F F 0 dihydro-2H-quinoline-1 -carboxylic acid ethyl ester 64 H 4-[2-(1 H-Indol-3-yl)- 466 N HN-C ethylcarbamoyll-6,7-dimethoxy-2 0 methyl-3,4-dihydro-2H-quinoline 1 -carboxylic acid ethyl ester 65 0, 6,7-Dimethoxy-2-methyl-4- 419 H 1 [(thiophen-2-ylmethyl)-carbamoy] H N S 3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester 66 O C* 6,7-Dimethoxy-2-methyl-4-[(5- 417 H1 methyl-furan-2-ylmethyl) HN carbamoyl]-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester 67 0 4-[(Furan-2-ylmethyl)-carbamoyl]- 403 6,7-dimethoxy-2-methyl-3,4 HN dihydro-2H-quinoline-1 -carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -133 Ex. R3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 68 0 6,7-Dimethoxy-2-methyl-4- 407 [(tetrahyd ro-furan-2-ylmethyl) HN carbamoyl]-3,4-dihydro-2H 0 quinoline-1-carboxylic acid ethyl ester 69 0- 4-{[(3,5-Bis-trifluoromethyl-benzyl)- 593 O methoxy-carbonyl-amino]-methyl} N *C F 6,7-dimethoxy-2-methyl-3,4 F dihydro-2H-quinoline-1-carboxylic F ? F acid ethyl ester F F 70 F F 4-(3,5-Bis-trifluoromethyl- 535 F F phenylcarbamoyl)-6,7-dimethoxy F 2-methyl-3,4-dihydro-2H F quinoline-1-carboxylic acid ethyl \\C ester 0 71 0 F F 4-[(2,4-Bis-trifluoromethyl- 549 H/ F benzoylamino)-methyl]-6,7 dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1-carboxylic acid F F FF ethyl ester F 72 HN 0 4-[(3,5-Bis-trifluoromethyl- 549 'H2C F benzoylamino)-methyl]-6,7 /F F dimethoxy-2-methyl-3,4-dihydro F 2H-quinoline-1-carboxylic acid F F ethyl ester WO 2004/085401 PCT/IB2004/000836 -134 Ex. R3(- denotes link to Compound LCMS structure) ESI+ (MH+) 73 CI 4-[(2-Chloro-benzoylamino)- 447 o methyl]-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1 H 2 C-NH carboxylic acid ethyl ester 74 CI 4-[(2,4-Dichloro-benzoylamino)- 481 O
-
methyl]-6,7-dimethoxy-2-methyl CI 3,4-dihydro-2H-quinoline-1 'H 2 C-NH carboxylic acid ethyl ester 75 cI 4-[(3,5-Dichloro-benzoylamino)- 481 o - methyl]-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1 *H 2 C-NH carboxylic acid ethyl ester cl 76 F 4-[(2,4-Difluoro-benzoylamino)- 449 methyl]-6,7-dimethoxy-2-methyl F 3,4-dihydro-2H-quinoline-1
*H
2 C-NH carboxylic acid ethyl ester 77 F 4-[(3,5-Difluoro-benzoylamino)- 449 o _ methyl]-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1
*H
2 C-NH carboxylic acid ethyl ester F 78 F F 4-{[(2,4-Bis-trifluoromethyl- 593 F F benzyl)-methoxycarbonyl-amino] O F methyl}-6,7-dimethoxy-2-methyl N F 3,4-dihydro-2H-quinoline-1 S H 2 ' carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -135 Ex. R3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 79 *H 2 C 0 4-{[(2-Chloro-benzyl)- 491 N methoxycarbonyl-amino]-methyl} o 6,7-dimethoxy-2-methyl-3,4 / dihydro-2H-quinoline-1 -carboxylic ci acid ethyl ester 80 0 CH 2 * F 4-{[(3,5-Difluoro-benzyl)- 493 N methoxycarbonyl-amino]-methyl} 0 6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1 -carboxylic F acid ethyl ester 81 F 4-{[(2,4-Difluoro-benzyl)- 493 o N methoxycarbonyl-amino]-methyl}
I
2 6,7-dimethoxy-2-methyl-3,4 CH2' F dihydro-2H-quinoline-1-carboxylic acid ethyl ester 82 4-{[(3,5-Dimethyl-isoxazol-4- 476 ylmethyl)-methoxycarbonyl amino]-methyl}-6,7-dimethoxy-2 N--N methyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester o
CH
2 * 83 4-Benzylcarbamoyl-6,7-dimethoxy- 413 2-methyl-3,4-dihydro-2H-quinoline -C~ 1-carboxylic acid ethyl ester 84 F F 4-[Benzyl-(3,5-bis-trifluoromethyl- 639 F F benzyl)-carbamoyl]-6,7-dimethoxy F - 2-methyl-3,4-dihydro-2H FN quinoline-1-carboxylic acid ethyl -C=0 ester WO 2004/085401 PCT/IB2004/000836 -136 Ex. R 3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 85 F 4-[(3,5-Bis-trifluoromethyl-benzyl)- 658 F F (3,5-dimethyl-isoxazol-4-ylmethyl) F NC /N carbamoyl]-6,7-dimethoxy-2 N 7 F methyl-3,4-dihydro-2H-quinoline-1 F carboxylic acid ethyl ester 86 F 6,7-Dimethoxy-2-methyl-4-[(3,4,5- 467 O trifluoro-benzoylamino)-methyl] F 3,4-dihydro-2H-quinoline-1 *H 2 C-NH F carboxylic acid ethyl ester 87 F 4-[(3,4-Difluoro-benzoylamino)- 449 O methyl]-6,7-dimethoxy-2-methyl F 3,4-dihydro-2H-quinoline-1
+H
2 C-NH carboxylic acid ethyl ester 88 F F 6,7-Dimethoxy-2-methyl-4-[(2,3,5- 467 0 trifluoro-benzoylamino)-methyl] 3,4-dihydro-2H-quinoline-1 *H 2 C-NH carboxylic acid ethyl ester F 89 F F 6,7-Dimethoxy-2-methyl-4- 503 0 - [(2,3,4,5,6 F pentafluorobenzoylamino)-methyl] H 3,4-dihydro-2H-quinoline-1
*H
2 C F F carboxylic acid ethyl ester 90 F 4-[(3-Fluoro-5-trifluoromethyl- 499
CH
2 * benzoylamino)-methyl]-6,7 I dimethoxy-2-methyl-3,4-dihydro F NH F 2H-quinoline-1-carboxylic acid Fel F O ethyl ester WO 2004/085401 PCT/IB2004/000836 -137 Ex. R3(- denotes link to Compound LCMS structure) ESI+ (MH+) 91 0 4-[(3-Fluoro-4-trifluoromethyl- 499 HN F benzoylamino)-methyl]-6,7 I Idimethoxy-2-methyl-3,4-dihydro
CH
2 ' 'F 2H-quinoline-1-carboxylic acid ethyl F F ester 92 F 4-[(5-Fluoro-2-trifluoromethyl- 499
CH
2 . benzoylamino)-methyl]-6,7 N H dimethoxy-2-methyl-3,4-dihydro 0 2H-quinoline-1-carboxylic acid F F F ethyl ester 93 6,7-Dimethoxy-2-methyl-4-[(3- 497 N trifluoromethoxy-benzoylamino) HC 0 methyl]-3,4-dihydro-2H-quinoline F F I -carboxylic acid ethyl ester F 94 0 4-{[(4-Fluoro-naphthalene-1- 481 F carbonyl)-amino]-methyl}-6,7 oH 2 C-NH dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester 95 F 6,7-Dimethoxy-2-methyl-4-{[(5- 536 0 F F trifluoromethoxy-1 H-indole-2 carbonyl)-amino]-methyl}-3,4
-H
2 C' N dihydro-2H-quinoline-1-carboxylic 0 acid ethyl ester 96 0 4-[(2-Chloro-4-methanesulfonyl- 525 / NCH2 benzoylamino)-methyl]-6,7 0 Cl dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -138 Ex. R 3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 97 F F 4-[(3-Fluoro-4-trifluoromethyl- 499 F benzoylamino)-methyl]-6,7 o NH > dimethoxy-2-methyl-3,4-dihydro
-H
2 C F 2H-quinoline-1-carboxylic acid 0 ethyl ester 98 0 4-[(2,4-Dimethoxy-benzoylamino)- 473 NH methyl]-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1 / carboxylic acid ethyl ester 99 0 4-[(4-Fluoro-benzoylamino)- 431 N/CH2' methyl]-6,7-dimethoxy-2-methyl F 3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester 100 0 6,7-Dimethoxy-2-methy-4-[(2- 481 NHCH2" trifluoromethyl-benzoylamino) IF methyl]-3,4-dihydro-2H-quinoline 1-carboxylic acid ethyl ester F F 101 0 4-[(2-Chloro-4-fluoro- 465 NICH2' benzoylamino)-methyl]-6,7 F dimethoxy-2-methyl-3,4-dihydro CI 2H-quinoline-1-carboxylic acid ethyl ester 102 0 6,7-Dimethoxy-2-methyl-4-[(4- 497 F / NH trifluoromethoxy-benzoylamino) methyl]-3,4-dihydro-2H-quinoline 1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -139 Ex. R3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 103 0 4-[(2-Fluoro-4-trifluoromethyl- 499 / NH benzoylamino)-methyl]-6,7 FF F dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1 -carboxylic acid ethyl ester 104 F 6,7-Dimethoxy-2-methyl-4-[(2,3,6- 467
-CH
2 . trifluoro-benzoylamino)-methyl] / NH 3,4-dihydro-2H-quinoline-1 F carboxylic acid ethyl ester F 105 0 4-[(2-Fluoro-3-trifluoromethyl- 499 NCH2' benzoylamino)-methyl]-6,7 '' dimethoxy-2-methyl-3,4-dihydro F F F 2H-quinoline-1-carboxylic acid F ethyl ester 106 CI O 4-[(2-Chloro-4,5-difluoro- 483
ICH
2 g benzoylamino)-methyl]-6,7 F dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1 F carboxylic acid ethyl ester 107 0 4-[(4-Fluoro-2-trifluoromethyl- 499
NH
2 benzoylamino)-methyl]-6,7 F F dimethoxy-2-methyl-3,4-dihydro F 2H-quinoline-1-carboxylic acid ethyl ester 108 0 4-[(4-Fluoro-3-trifluoromethyl- 499 NI CH2 benzoylamino)-methyl]-6,7 F dimethoxy-2-methyl-3,4-dihydro F 2H-quinoline-1-carboxylic acid F F ethyl ester WO 2004/085401 PCT/IB2004/000836 -140 Ex. R3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 109 0 4-[(3,5-Dimethyl-benzoylamino)- 441
NNCH
2 ' methyl]-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester 110 0 4-[(3-Fluoro-4-methyl- 445 NH'CH2 benzoylamino)-methyl]-6,7 / Idimethoxy-2-methyl-3,4-dihydro F 2H-quinoline-1-carboxylic acid ethyl ester 111 4-[(3-Fluoro-benzoylamino)- 431 H methyl]-6,7-dimethoxy-2-methyl F ICH 2 * 3,4-dihydro-2H-quinoline-I 0 carboxylic acid ethyl ester 112 0 6,7-Dimethoxy-4-[(3-methoxy-4- 457 NNCH2' methyl-benzoylamino)-methyl]-2 methyl-3,4-dihydro-2H-quinoline 1 -carboxylic acid ethyl ester 113 0 4-[(3-Chloro-2-fluoro- 465
NNCH
2 ' benzoylamino)-methyl]-6,7 dimethoxy-2-methyl-3,4-dihydro F 2H-quinoline-1-carboxylic acid CI ethyl ester 114 0 6,7-Dimethoxy-2-methyl-4-[(2- 497 NNCH2' trifluoromethoxy-benzoylamino) 0 O methyl]-3,4-dihydro-2H-quinoline F F 1-carboxylic acid ethyl ester
F
WO 2004/085401 PCT/IB2004/000836 -141 Ex. R3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 115 4-[(3-Ethoxy-benzoylamino)- 457 NH CH2' methyl]-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1 Q0 carboxylic acid ethyl ester 116 0 4-[(3-Chloro-4-methoxy- 477 NH benzoylamino)-methyl]-6,7 dimethoxy-2-methyl-3,4-dihydro Cl 2H-quinoline-1 -carboxylic acid ethyl ester 117 o 4-[(3-Isopropoxy-4-methoxy- 501 NH benzoylamino)-methyl]-6,7 dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1 -carboxylic acid ethyl ester 118 F F 6,7-Dimethoxy-4-{[5-methoxy-2- 541 F (2,2,2-trifluoro-ethoxy) O benzoylanino]-methyl}-2-methyl 0 3,4-dihydro-2H-quinoline-1 H2-N Hcarboxylic acid ethyl ester oH 2 C-NHcaoyicaietyesr 0 119 0 4-[(3-Difluoromethoxy- 479 N 1H 2 benzoylamino)-methyl]-6,7 dimethoxy-2-methyl-3,4-dihydro O F 2H-quinoline-1-carboxylic acid ethyl F ester WO 2004/085401 PCT/IB2004/000836 -142 Ex. R3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 120 4-[(4-Dipropylsulfamoyl- 576 0 benzoylamino)-methyl]-6,7 N NH dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1 -carboxylic acid ethyl ester 121 0 4-{[3-(2-tert-Butoxycarbonylamino- 556 ethyl)-benzoylamino]-methyl}-6,7 dimethoxy-2-methyl-3,4-dihydro 0 N 2H-quinoline-1-carboxylic acid ethyl o ester 122 N 6,7-Dimethoxy-2-methyl-4-[(3- 479 N O pyrazol-1 -yl-benzoylamino) N CH 2 methyl]-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester 123 0 4-[(4-Methanesulfonyl- 491 \ N ~H2* benzoylamino)-methyl]-6,7 OS ~ dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester 124 4-{[3-(3,5-Dimethyl-pyrazol-1 -yl)- 507 N-N 0 benzoylamino]-methyl}-6,7 NNCH2 dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester 125 0 4-{[(3'-Fluoro-biphenyl-4-carbonyl)- 507 FN O / NH GH2 amino]-methyl}-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -143 Ex. R 3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 126 0 4-{[(2'-Fluoro-biphenyl-3-carbonyl)- 507 I -CH 2 * NH amino]-methyl}-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 F r / \carboxylic acid ethyl ester 127 0 4-{[(3'-Fluoro-biphenyl-3-carbonyl)- 507 N'C' amino]-methyl}-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester F 128 0 4-{[(4'-Fluoro-biphenyl-3-carbonyl)- 507 N amino]-methyl}-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester F 129 CI O 4-[(2,6-Dichloro-benzoylamino)- 481 - CH 2 . methyl]-6,7-dimethoxy-2-methyl NH 3,4-dihydro-2H-quinoline-1 C carboxylic acid ethyl ester 130 0 6,7-Dimethoxy-2-methyl-4-[(3- 481
NHICH
2 ' trifluoromethyl-benzoylamino) methyl]-3,4-dihydro-2H-quinoline-1 IF F carboxylic acid ethyl ester
F
WO 2004/085401 PCT/IB2004/000836 -144 Ex. R3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 131 0 4-[(3-Methanesulfonyl- 491 S0 o
CH
2 . benzoylamino)-methy]-6,7 NH dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester 132 0 6,7-Dimethoxy-4-[(3-methoxy- 443
NOCH
2 ' benzoylamino)-methyl]-2-methyl 3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester ~~0 133 0 4-[(3,4-Dichloro-benzoylamino)- 481 N H2 methyl]-6,7-dimethoxy-2-methyl Cl 3,4-dihydro-2H-quinoline-1 cl carboxylic acid ethyl ester 134 F 4-[(2-Chloro-6-fluoro- 465
-CH
2 * benzoylamino)-methyl]-6,7 / NH dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester 135 F 0 4-[(2,5-Difluoro-benzoylamino)- 449
NNCH
2 ' methyl]-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1 F carboxylic acid ethyl ester 136 0 4-[(2,3-Difluoro-benzoylamino)- 449
NNCH
2 ' methyl]-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1 F carboxylic acid ethyl ester
F
WO 2004/085401 PCT/IB2004/000836 -145 Ex. Rd(- denotes link to Compound LCMS structure) ESI+ (MH+) 137 F 4-[(2,4-Difluoro-benzoylamino)- 449 methyl]-6,7-dimethoxy-2-methyl NH H2C H 3,4-dihydro-2H-quinoline-1 O F carboxylic acid ethyl ester 138 F 4-[(3,5-Difluoro-benzoylamino)- 449 methyl]-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1 NH 'H2C F carboxylic acid ethyl ester 0 139 F 0 4-[(2,5-Bis-trifluoromethyl- 449
/H
2 * FF N benzoylamino)-methyl]-6,7 F H dimethoxy-2-methyl-3,4-dihydro F 2H-quinoline-1-carboxylic acid ethyl F F ester 140 F O 6,7-Dimethoxy-2-methyl-4-[(2,4,5- 467 -CH2. trifluoro-benzoylamino)-methyl] F NH 3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester F 141 F 4-[(2-Fluoro-6-trifluoromethyl- 499 NI'CH2 * benzoylamino)-methyl]-6,7 dimethoxy-2-methyl-3,4-dihydro - F 2H-quinoline-1-carboxylic acid ethyl F F ester 142 F 6,7-Dimethoxy-2-methyl-4-[(2,3,4- 467
-CH
2 . trifluoro-benzoylamino)-methyl] F/ NH 3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -146 Ex. Rd (- denotes link to Compound LCMS structure) ESI+ (MH+) 143 0 6,7-Dimethoxy-2-methyl-4-{[(4'- 557 NCH2' trifluoromethyl-biphenyl-2 NH carbonyl)-amino]-methyl}-3,4 dihydro-2H-quinoline-1 -carboxylic F acid ethyl ester - F F F 144 0 4-[(3-Fluoro-4-methoxy- 461 NH benzoylamino)-methyl]-6,7 dimethoxy-2-methyl-3,4-dihydro F 2H-quinoline-1-carboxylic acid ethyl ester 145 0 4-[(3-Chloro-4-fluoro- 465 NCH2' benzoylamino)-methyl]-6,7 F dimethoxy-2-methyl-3,4-dihydro Cl 2H-quinoline-1-carboxylic acid ethyl ester 146 F 4-[(3-Fluoro-5-trifluoromethyl- 499 benzoylamino)-methyl]-6,7 dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1 -carboxylic acid ethyl 'H2C F ester 0 147 F 0 4-[(4-Difluoromethoxy- 479 F ONHC benzoylamino)-methyl]-6,7 dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1 -carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -147 Ex. R3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 148 0 4-[(3-Chloro-benzoylamino)- 447 N CH2' methyl]-6,7-dimethoxy-2-methyl I NH3,4-dihydro-2H-quinoline-1 Cl carboxylic acid ethyl ester 149 / 6,7-Dimethoxy-2-methyl-4-[(3,4,5- 503 o O 0CH 2 . trimethoxy-benzoylamino)-methyl] N 3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester 0\ 150 / 4-[(4-Fluoro-3-methoxy- 461 o 0 benzoylamino)-methy]-6,7 / ACH 2 c F NH dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester 151 4-[(5-Chloro-2-methyl- 461
CH
2 e benzoylamino)-methyl]-6,7 / IH dimethoxy-2-nethyl-3,4-dihydro 2H-quinoline-1 -carboxylic acid ethyl Cl ester 152 / 4-[(3,5-Dimethoxy-4-methyl- 487 o 0 CH2' benzoylamino)-methyl]-6,7 NH dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1 -carboxylic acid ethyl 0 ester 153 / Ca 4-[(2-Chloro-3,4-dimethoxy- 507 -CH2, benzoylamino)-methyl]-6,7 o / NH dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -148 Ex. R 3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 154 o O CH2' 4-[(3-Cyclopentyloxy-4-methoxy- 527 / \ NN benzoylamino)-methyl]-6,7 dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1 -carboxylic acid ethyl ester 155 0 6,7-Dimethoxy-4-[(4-methoxy-3- 501 SNHCH2' propoxy-benzoylamino)-methyl]-2 Omethyl-3,4-dihydro-2H-quinoline-1 /9 o carboxylic acid ethyl ester 156 4-[(2-Chloro-4,5-dimethoxy- 507
-CH
2 benzoylamino)-methyl]-6,7 O / NH dimethoxy-2-methyl-3,4-dihydro c 2H-quinoline-1 -carboxylic acid ethyl ester 157 6,7-Dimethoxy-4-[(4-methoxy-3- 457 0 0 methyl-benzoylamino)-methyl]-2
H
2 C-NH \ methyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester 158 0 4-{[(Benzo[1,3]dioxole-5-carbonyl)- 457 amino]-methyl}-6,7-dimethoxy-2
*H
2 C-NH methyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester 159 N H 4-{[4-(1-tert-Butoxycarbonyl- 498 O N'CH2' pyrrolidin-3-yloxy)-benzoylamino] 0 methyl}-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl WO 2004/085401 PCT/IB2004/000836 -149 Ex. R 3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 160 H 6,7-Dimethoxy-2-methyl-4-{[3-(2- 496 SN, CH2* oxo-pyrrolidin-1 -yl)-benzoylamino] OO methyll-3,4-dihydro-2H-quinoline 0 1-carboxylic acid ethyl ester 161 0 4-{[3-(3,5-Dimethyl-pyrazol-1 - 521 HN N ylmethyl)-benzoylamino]-methyl} N 6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1 -carboxylic acid ethyl ester 162 N 4-{[3-(1 -tert-Butoxycarbonyl- 496 -o piperidin-4-yl)-benzoylamino] O \CH methyl}-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester 163 H 4-{[(Biphenyl-3-carbonyl)-amino]- 489 'N methyl}-6,7-dimethoxy-2-methyl
H
2 C O 3,4-dihydro-2H-quinoline-1 0 carboxylic acid ethyl ester 164 ci 4-{[(3',4'-Dichloro-biphenyl-4- 557 -ci carbonyl)-amino]-methyl}-6,7
'H
2 c-NH dimethoxy-2-methyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester 165 *H 2 C\ 0 6,7-Dimethoxy-2-methyl-4-{[3-(5- 495 HN/ bN methyl-[1,2,4]oxadiazol-3-yl) benzoylamino]-methyl}-3,4-dihydro N' 2H-quinoline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -150 Ex. R 3 (- denotes link to Compound LCMS structure) ESI+ (MH+) 166 *H2C 0 4-{[3-(5-Ethyl-[1,2,4]oxadiazol-3-yl)- 509 HN N ~ benzoylamino]-methyl}-6,7 -o dimethoxy-2-methyl-3,4-dihydro 2H-luinoline-1 -carboxylic acid ethyl ester 167 S 4-{[(Benzothiazole-6-carbonyl)- 470
HN-CH
2 ' amino]-methyl}-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester 168 Cl 4-[(3-Chloro-4-methyl- 461 0 benzoylamino)-methyl]-6,7 dimethoxy-2-methy-3,4-dihydro
H
2 C-NH 2H-quinoline-1-carboxylic acid ethyl ester 169 CI 4-[(2-Chloro-benzoylamino)- 447 0 - methyl]-6,7-dimethoxy-2-methyl 3,4-dihydro-2H-quinoline-1 eH 2 C-NH carboxylic acid ethyl ester Preparation 34 3-Ethyl-6,7-dimethyl-3,4-dihydro-1 H-quinoxalin-2-one A mixture of 5,6-dimethyl phenylenediamine (22.45gm, 165mmol, 1eq), 2 5 ketobutyric acid (16.83gm, 165mmol, 1eq) and ethanol (75mL) were irradiated in the Milestone microwave (Milestone Laboratories, Sorisole, Italy) for 5 min at 180 0 C. The solid product upon cooling was filtered and washed with ethanol. Concentration of the filtrate and further crystallization provided the desired quinoxalin-2-one (18.45gm, 55.2%). 10 1 H-NMR (dmso-d6): 6 1.17 (t, J=7.05Hz, 3H), 2.25 (s, 3H), 2.26 (s, 3H), 2.74 (q, J=7.05Hz, 2H), 7.00 (s, 1H), 7.48 (s, 1H), 12.15 (brs, 1H). ESI-MS: 203 (MH+).
WO 2004/085401 PCT/IB2004/000836 -151 Preparation 35 3-Chloro-2-ethyl-6,7-dimethyl-1,2-dihydro-quinoxaline 3-Ethyl-6,7-dimethyl-3,4-dihydro-1 H-quinoxalin-2-one (1 8.45g, 91.2mmol) was dissolved in 180mL phosphorus oxychloride and the mixture was heated overnight at 5 110 C under a drying tube charged with potassium hydroxide and Drierite@. After cooling, the phosphorus (V) oxychloride was carefully distilled off, and residue was carefully quenched with ice, followed by saturated sodium hydrogen carbonate. The aqueous suspension was extracted several times with methylene chloride. The combined organics were washed 1 time with brine, dried over anhydrous sodium 10 sulfate, filtered, and evaporated to give the title compound (19.3gm, 81%), which was carried forward without further purification. 'H-NMR (dmso-d6): 8 1.30 (t, J=7.47Hz, 3H), 3.04 (q, J=7.47Hz, 2H), 7.74, (s, 1H), 7.83 (s, IH).
WO 2004/085401 PCT/IB2004/000836 -152 Preparation 36 2-Ethyl-6,7-dimethyl-1,2,3,4-tetrahydro-quinoxaline The residue containing 3-chloro-2-ethyl-6,7-dimethyl-1,2-dihydro-quinoxaline was dissolved in 200mL acetic acid and 18.2g sodium acetate was added (222mmol, 5 3eq). After flushing with nitrogen, the vessel was charged with palladium on carbon (10%, 7.86gm, 0.1eq Pd, 7.39mmol). The reaction was subjected to hydrogenation at 45psi for 5 hr whereupon hydrogen uptake ceased. The reaction was filtered through Celite@ and evaporated. The residue was azeotroped 3 times with heptane to remove further acetic acid. The residue was then partitioned between ethyl acetate and 10 saturated aqueous sodium hydrogen carbonate. The organic layer was washed 3 times with saturated aqueous sodium hydrogen carbonate, 1 time with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Flash chromatography eluting with a 20-50% ethyl acetate /hexanes gradient provided the desired quinoxaline (10.56gm, 63% yield.) as a fluffy pinkish solid. 15 1 H-NMR (dmso-d6): 3 0.89 (t, J=7.46Hz, 3H), 1.35 (m, 2H), 1.89, (s, 3H), 1.94 (s, 3H), 2.75 (m, IH), 2.96 (m, 1H), 3.14 (m, 1H), 6.12, (s, IH), 6.17 (s, IH). Preparation 37 3-Ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid tert-butyl ester 2-Ethyl-6,7-dimethyl-1,2,3,4-tetrahydro-quinoxaline (1 0.56g, 55.6mmol, 1 eq) 20 was dissolved in anhydrous methylene chloride and cooled to -30'C in an ethylene glycol/dry ice bath. A solution of di-tert-butyl dicarbonate (12.13gm, 55.6mmol, Ieq) in methylene chloride (50mL) was added dropwise, and the reaction was allowed to slowly warm to room temperature overnight. The reaction was evaporated to dryness and repartitioned between ethyl acetate and 0.1M HCI. The organic layer was 25 washed 3 times with 0.1M HCI, 1 time with saturated sodium hydrogen carbonate, 1 time with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Silica chromatography eluting with 10% ethyl acetate /hexane provided the desired compound (10.35g, 64%). 1 H-NMR (dmso-d6): 3 0.90 (t, J=7.47Hz, 3H), 1.34 (m, 2H), 1.41 (s, 9H), 2.02 30 (s, 6H), 3.09 (m, 1H), 3.24 (m, 1H), 3.58 (m, 1H), 5.74 (s, 1H), 6.34 (s, 1H), 7.05 (brs, 1 H). ESI-MS: 290 (M+), 235 (MH+ - isobutylene).
WO 2004/085401 PCT/IB2004/000836 -153 Preparation 38 2-Ethyl-6,7-dimethyl-2,3-dihydro-quinoxaine-1,4-dicarboxylic acid 4-tert-butyl ester 1-ethyl ester A solution of 3-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic 5 acid tert-butyl ester (10.35gm, 35.7mmol, 1eq) and 4-dimethylaminopyridine (436mg, 3.57mmol , 0.1eq) in anhydrous pyridine (250mL) was cooled to 00C and ethyl chloroformate (17.OmL, 178.3mmol, 5eq) was added dropwise. The reaction was allowed to warm to room temperature overnight. The solvents were evaporated under vacuum and azeotroped 3 times with heptanes. The residue, after drying under 10 vacuum, was partitioned between ethyl acetate and 0.1 M HCI. The organic layer was extracted with 0.1 M HCI until the extracts were acidic, then was washed 1 time with saturated aqueous sodium hydrogen carbonate, I time with water, 1 time with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to provide the desired compound (100%). 15 'H-NMR (dmso-d6): 5 0.77 (t, J=7.05Hz, 3H), 1.20 (t, J=7.05Hz, 3H), 1.25 (m, 2H), 1.44 (s, 9H), 2.13 (s, 6H), 3.55 (dd, J=13.35, 4.98Hz, 1H), 3.78 (dd, J=13.1, 3.32Hz, 1H), 4.12 (m, 2H), 4.39 (m, 1H), 7.41 (s, 1H), 7.44 (s, 1H). ESI-MS: 307 (MH+-isobutylene), 263 (MH+ - boc). Preparation 39 20 2-Ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester: To 2-Ethyl-6,7-dimethyl-2,3-dihydro-quinoxaline-1,4-dicarboxylic acid 4-tert butyl ester 1-ethyl ester (12.93g) was added trifluoroacetic acid (200mL), the mixture was stirred until a solution had formed and then evaporated to dryness under vacuum. The residue was azeotroped 3 times with heptane and dried under vacuum. 25 The residual oil was then partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The aqueous layer was extracted 3 times with methylene chloride. The combined methylene chloride extracts were dried over anhydrous sodium sulfate, filtered and evaporated, giving the desired quinoxaline (100%). 30 'H-NMR (dmso-d6): 5 0.77 (t, J=7.47Hz, 3H), 1.19 (t, J=7.05Hz, 3H), 1.24 (m, 2H), 2.02 (s, 6H), 3.14 (m, 2H), 4.08 (m, 2H), 4.24 (m, 1H), 5.72 (m, 1H), 7.11 (brs, 1 H). ESI-MS: 263 (MH+).
WO 2004/085401 PCT/IB2004/000836 -154 This racemic quinoxaline was subjected to preparative chiral separations using a ChiralcelOD 1 Ox25cm chiral preparative column. The eluent was 5% ethanol in heptane, at a flow rate of 275mL/min, observing at 300nm. The sample was loaded on the column using 2:1 methanol/dichloromethane. Retention time of the S 5 enantiomer was 16min, the R-enantiomer was 22min. A 25g sample was subjected to these conditions, resulting in 1 Og of the R-enantiomer, 99.4%ee, and 11 g of the S enantiomer, 95.1%ee. Examples 170, 171, 172 and 173 F F F F F H0 1 H'c')~.' F F 0
H
3 CN F F
H
3 C'N FF H 3 CH
H
3 C O CH CH 3 CH3 10 (RR, RS, SR and SS) -4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl methyl]-2-ethyl-6,7-dinethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester Method A: A mixture of (RS)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 1-carboxylic acid ethyl ester (652mg, 1eq, 2.5mmol), bromo-4.-(3,5-bis-trifluoromethyl 15 phenyl)-acetic acid methyl ester (1.0gm, 1.1eq, 2.74mmol) and 2,6-lutidine (0.87mL, 3eq, 7.47mmol) in dimethylformamide (3mL) were heated at 1400C for 20 min by microwave irradiation in an Emrys Optimizer (Personal Chemistry, Uppsala, Sweden). The mixture was partitioned between methylene chloride and water, and the phases were separated. The aqueous phase was extracted 3 times with methylene chloride, 20 and the combined organic extracts were washed 2 times with water, 1 time with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Chromatography on silica gel using 10% ethyl acetate in hexanes as eluant provided the title compounds as a mixture of two diastereoisomers (900mg, 66%). Method B: A mixture of (RS)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 25 1-carboxylic acid ethyl ester (652mg, 1eq, 2.5mmol), bromo-4-(3,5-bis-trifluoromethyl phenyl)-acetic acid methyl ester (1.0gm, 1.1eq, 2.74mmol) and 2,6-lutidine (0.87mL, 3eq, 7.47mmol) in dimethylformamide (3mL) were stirred at room temperature for 24 WO 2004/085401 PCT/IB2004/000836 -155 hours. The mixture was partitioned between methylene chloride and water, and the phases were separated. The aqueous phase was extracted 3 times with methylene chloride, and the combined organic extracts were washed 2 times with water, 1 time with brine, dried over anhydrous sodium sulfate, filtered and evaporated. 5 Chromatography on silica gel using 10% ethyl acetate in hexanes as eluant provided the title compounds as a mixture of two diastereoisomers (900mg, 66%). Diastereoisomer 1 'H-NMR (CDC 3 ): 5 0.71 (t, J=7.57Hz, 3H), 1.30 (t, J=7.05Hz, 3H), 1.46 (m, 2H), 2.18 (s, 3H), 2.20 (s, 3H), 2.77 (dd, J=9.54, 2.08Hz,1H), 3.37 (dd, J=11.38, 3.32Hz, IH) 3.82 (s, 3H), 4.20 (m, 2H), 4.26 (m, 1H), 5.82 (s, IH), 10 6.58 (s,1H), 7.49 (brs, 1H) 7.75 (s,2H), 7.88 (s,1H). LCMS (ESI+): 547 (MH+) Diastereoisomer 2: 'H-NMR (CDC 3 ): 5 0.87 (t, J=7.47Hz, 3H), 1.28 (t, J=6.64Hz, 3H), 1.43 (m, 2H), 2.18 (s, 3H), 3.11 (dd, J=11.35, 4.98Hz, 1H), 3.22 (dd, J=10.79, 1.66Hz, 1H), 3.83 (s, 3H), 4.19 (m, 2H), 4.44 (m, 1H), 5.66 (s, 1H), 6.41 (s, 15 1H), 7.28 (brs, 1H), 7.73 (s, 2H), 7.86 (s, IH). LCMS (ESI+): 547 (MH+). This racemic mixture of diastereoisomers could be further resolved by chiral HPLC on a Pirkle Covalent (S,S)Whelk-O I column (Regis Technologies, Inc., Morton Grove, IL) (5 x 25cm) eluting at 1 OOmL/min with 5% ethanol/heptane to 20 provide three fractions: Isomer 1, Retention time =18min Isomers 2 and 3, Retention time =25min Isomer 4, Retention time =37min Examples 174 and 175 F F F
H
3 C O F H3C N FF
H
3 C N O O1 CHI 25 CH 3 Preparation of 4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid methyl ester WO 2004/085401 PCT/IB2004/000836 -156 This compound was prepared using the procedure as described above for 4 [(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6,7-dimethyl-3,4 dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester, but using methyl chloroformate in the place of ethyl chloroformate. 5 Diastereoisomer 1 1 H-NMR (CDCI 3 ): 5 0.86 (t, J=7.47Hz, 3H), 1.43 (m, 2H), 2.18 (s, 6H), 3.10 (dd, J=11.48, 4.98Hz, 1H), 3.22 (dd, J=11.17Hz 1.66Hz, 1H), 3.75 (s, 3H), 4.43 (m, I H), 3.82 (s, 3H), 5.66 (s, 1 H), 6.41 (s, I H), 7.22 (brs, 1 H), 7.72 (s, 2H), 7.86 (s, 1H). LCMS (ESI+): 532 (M+). 10 Diastereoisome'r 2 'H-NMR (CDCI 3 ): 6 0.71 (t, J=7.47Hz, 3H), 1.19 (m, 1H), 1.43 (m, 1H), 2.19 (s, 3H), 2.20 (s, 3H), 2.77 (dd, J=11.47, 1.65Hz, 1H), 3.38 (dd, J=11.30, 3.74Hz, 1H), 3.77 (s, 3H), 3.81 (s, 3H), 4.38 (m, 1H), 5.83 (s, 1H), 6.58 (s, 1H), 7.37 (s, 1H), 7.75 (s, 2H), 7.88 (s, IH). LCMS (ESI+): 532 (M+). 15 Examples 176 and 177 F F F H 0 F' H N F F 0'o OCHa H3C CH3 Preparation of 4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester This compound was prepared using the procedure as described above for 20 compound 4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethy-6,7 dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester, but using isopropyl chloroformate in the place of ethyl chloroformate. Diastereoisomer 1 1 H-NMR (CDCl 3 ): 6 0.86 (t, J=7.47Hz, 3H), 1.16 (dd, J=6.22, 6.22Hz, 3H), 1.26 (dd, J=1 5.07, 6.22Hz, 3H), 1.50 (m, 2H), 2.17, (s, 6H), 25 3.10, (m, 1H), 3.2 (m, IH), 3.82 (s, 3H), 4.42 (m, IH), 5.00 (m, IH), 5.65 (s, 1H), 6.40 (s, 1H), 7.31 (brs, 1H), 7.64 (s, 1H), 7.74 (s, IH). ). LCMS (ESI+): 560 (M+).
WO 2004/085401 PCT/IB2004/000836 -157 Diastereoisomer2 1 H-NMR (CDC 3 ): 5 0.71 (t, J=7.47, 3H), 1.16 (m, 1H), 1.26 (d, J=6.23Hz), 1.29 (d, J=5.81Hz), 1.44 (m, 1H), 2.18 (s, 3H), 2.20 (s, 3H), 2.76 (dd, J=11.52, 2.07Hz, 1H), 3.37 (dd, J=11.52, 3.32Hz), 3.82 (s, 3H), 4.38 (m, 1H), 5.01 (m, IH), 5.82 (s, 1H), 6.58 (s, 1H), 7.47 (brs, IH), 7.75 (s, 2H), 7.88 (s, 1H). 5 LCMS (ESI+): 561 (MH+). Preparation 40 (3,5-Bis-trifluoromethyl-phenyl)-bromo-acetonitrile To a solution of (3,5-bis-trifluoromethyl-phenyl)-acetonitrile (2.0g, 7.9mmol) in carbon tetrachloride (20mL) was added dibenzoyl peroxide (0,076g, 0.3mmol) and N 10 bromosucinnimide (1.4g, 7.9mmol). This reaction mixture was refluxed for 24h then diluted with methylene chloride and washed with brine. The organic layer was dried and concentrated to afford the crude product which was purified by silica gel chromatography using 2% ethyl acetate in hexanes as eluant to afford the title compound (2.0g, 75%). 15 LCMS (ESI+): 333 (MH+). Example 178 F F F NA F
H
3 C N F F H 3 C N H3C O- 0CH 3 4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl-3,4-dihydro 2H-quinoxaline-1-carboxylic acid ethyl ester 20 Method A: A mixture of 2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester (1g, 1eq, 3.81mmol), 3,5-bis-(trifluoromethyl-phenyl) bromo-acetonitrile (Preparation 40, 1.27gm, 1eq, 3.81mmol) and potassium carbonate (1.58gm, 3eq, 11.43mmol) in acetonitrile (5mL) was subjected to microwave irradiation in the Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) 25 at 1400C for 20 min. The reaction was partitioned between ethyl acetate and water, and the phases were separated. The aqueous phase was extracted 3 times with ethyl acetate, and the combined organic extracts were washed 2 times with water, 1 time WO 2004/085401 PCT/IB2004/000836 -158 with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Chromatography on silica gel using a gradient of 10-30% ethyl acetate in hexanes as eluant provided the desired nitrile as a mixture of two diastereoisomers (1.5:1)(900mg, 29%). 5 Method B: A mixture of 2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester (1 g, 1 eq, 3.81 mmol), 3,5-bis-(trifluoromethyl-phenyl) bromo-acetonitrile (Preparation 40,1.27gm, 1eq, 3.81mmol) and 2,6-lutidine (3eq, 11.43mmol) in N,N-dimethylformamide (5mL) was stirred at room temperature for 24 hours. The reaction was partitioned between ethyl acetate and water, and the phases 10 were separated. The aqueous phase was extracted 3 times with ethyl acetate, and the combined organic extracts were washed 2 times with water, 1 time with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Chromatography on silica gel using a gradient of 10-30% ethyl acetate in hexanes as eluant provided the desired nitrile as a mixture of two diastereoisomers (1.5:1)(900mg, 29%). 15 LCMS (ESI+): 514 (MH+) Example 179 F HO F
H
3 c N F F Hac N oi ocH 3
CH
3 Preparation of 4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6,7 dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester 20 To a solution of the 4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl methyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester (0.14g, 0.26mmol) in tetrahydrofuran (5mL) at -78 0 C was added a solution of lithium aluminum hydride (1M in tetrahydrofuran, 0.16mL) dropwise. This solution was slowly warmed to room temperature over 3 h. The reaction mixture was quenched with 25 sodium sulfate hexahydrate (2gm) and the mixture was stirred for 30 min. The reaction mixture was filtered and concentrated to afford the crude product (mixture of WO 2004/085401 PCT/IB2004/000836 -159 diastereoisomers) which was purified by silica gel chromatography eluting with 10% ethyl acetate in hexanes to give the title compound (0.08g, 70%). 'H-NMR (CDCi 3 ): 5 0.71 (t, J=7.57Hz, 3H), 0.95 (t, J=7.05Hz, 3H), 1.26 (m, 2H), 2.20 (bs, 6H), 2.97 (dd, 1H), 3.25 (m, 1H), 3.37 (m, 1H), 3.85 (m, 2H), 4.15 (m, 5 3H), 4.5 (bm, IH), 4.62(m, 1H), 4.70 (m, 1H), 5.82 (s, 1H), 6.58 (s, IH), 7.49 (brs, 1 H) 7.75 (s, 2H), 7.88 (s, 1 H). LCMS (ESI+): 518 (MH+) Example 180 F F F ICH 3 F
H
3 C N F F HaC N
CH
3 CH 3 10 Preparation of 4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-methoxy-ethylj-2-ethyl-6,7 dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester To a solution of 4-[1-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester (0.044gm, 0.13mmol) in anhydrous dimethylformamide (93mL), was added sodium hydride 15 (60% suspension, 0.005gm, 0.27mmol) and the mixture was stirred for 20 min. Excess of methyl iodide was added and the reaction was stirred for 1 h and quenched with saturated ammonium chloride. The mixture was extracted with ether (3x2OmL) and concentrated. Silica gel chromatography of the crude product using a gradient of 10-30% ethyl acetate in hexanes as eluant provided the desired product as an oil 20 (0.015gm, 35%). 1 H-NMR (CDC13): 5 0.71 (t, J=7.57Hz, 3H), 1.30 (t, J=7.05Hz, 3H), 1.46 (m, 2H), 2.20 (brs, 6H), 2.97 (dd, 1H), 3.25 (m, IH), 3.37 (m, IH), 3.4 (s, 3H), 3.85 (m, 2H), 4.26 (m, 1H), 4.5 (bm, 1H), 4.62(m, 1H), 4.70 (m, 1H), 5.82 (s, 1H), 6.58 (s, 1H), 7.49 (brs, 1H), 7.75 (s,2H), 7.88 (s,IH). 25 LCMS (ESI+): 532 (MH+).
WO 2004/085401 PCT/IB2004/000836 -160 Example 181 F F O F F
H
3 C N F F
H
3 C N O o 0CH 3 KCH Preparation of 4-[2-Acetoxy-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6,7 dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester 5 4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6,7-dimethyl-3,4 dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester was dissolved in a 1:1 mixture of acetic anhydride and pyridine (4mL) and the mixture was stirred at ambient temperature for 1 Oh. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to afford the desired acetate (25 mg, 58%; mixture of 10 diastereoisomers) "H-NMR (CDCI 3 ): 8 0.71 (t, J=7.57Hz, 3H), 1.30 (t, J=7.05Hz, 3H), 1.46 (m, 2H), 1.98 (s, 3H) 2.18 (s, 3H), 2.20 (s, 3H), 2.77 (dd, 1H), 3.05 (m, 1H), 3.37 (m, IH), 4.20 (m, 2H), 4.26 (m, I H), 4.5 (m, 1 H), 4.62(m, 1 H), 4.70 (m, I H), 5.82 (s, 1 H), 6.58 (s, 1H), 7.49 (brs, 1H), 7.75 (s,2H), 7.88 (s,1H). 15 LCMS (ESI+): 560 (MH+) Example 182 F F F O1 F
H
3 c N F F H3C N O OLl CHa. Hc Preparation of 4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro 2H-quinoxaline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -161 A room-temperature solution of 2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester (0.1gm, 1eq, 0.38mmol) in 5mL methylene chloride was treated with the acid chloride formed by combination of 3,5-bis (trifluoromethyl)benzoic acid (147mg, 1.5eq, 0.57mmol), oxalyl chloride (0.05mL, 5 1.5eq, 0.57mmoI) and a drop of anhydrous dimethylformamide. The reaction was allowed to stir overnight at room temperature, at which time the reaction was quenched with saturated sodium hydrogen carbonate and extracted 3 times with methylene chloride. The combined organic extracts were washed I time with 1 M HCI, 1 time with saturated sodium hydrogen carbonate, I time with brine, dried over 10 anhydrous sodium sulfate, filtered and evaporated. Chromatography on silica gel using a 10-20% ethyl acetate in hexanes gradient provided 4-(3,5-Bis-trifluoromethyl benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester (1 30mg, 68%). 'H-NMR (CDCI 3 ): 6 0.91 (t, J=7.47Hz, 3H), 1.30 (t, J=7.04Hz, 3H), 1.50 (m, 15 1H), 1.60 (m, 1H), 1.94 (s, 3H), 2.20 (s, 3H), 3.39 (m, 1H), 4.26 (q, J=6.22Hz, 2H), 4.68 (m, 2H), 6.29 (brs, IH), 7.41 (brs, IH), 7.78 (s, 2H), 7.85 (s, IH). FIA-MS (APCI+): 503 (MH+). Preparation 41 6-Trifluoromethyl-1,2,3,4-tetrahydro-quinoxaline 20 This desired quinoxaline was prepared using the method described by V. Krchnak etaL (Tetrahedron Lett. 42, 2443-2446 (2001)), using 3-(R)-amino-pentan-1 ol and 2-fluoro-5-trifluoromethyl-nitrobenzene. 1 H-NMR (dmso-d6): 6 1.06 (t, J=7.48Hz, 3H), 1.73 (m, J=7.9OHz, 2H), 3.19 (dd, J=9.96Hz, 1H), 3.68 (dd, J=9.55Hz, 1H), 3.71 (m, 1H), 6.98 (d, J=8.3Hz, 1H), 25 7.25 (dd, 1H), 7.43 (s, 1H). ESI-MS: 231 (MH+).
WO 2004/085401 PCT/IB2004/000836 -162 Example 183 CH, O CH, F F F F ON N F F F F CH 3 F 4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester 5 A solution of 6-trifluoromethyl-1,2,3,4-tetrahydro-quinoxaline (Preparation 41, .01g, 0.04mmol, 1eq), 3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl bromide (0.017g, 0.044mmol, 1.1eq), and 2,6-lutidine (.014g, 0.12mmol 3eq) in dimethylformamide (0.5mL) were irradiated in the Milestone microwave (Milestone Laboratories, Sorisole, Italy) for 10 min at 1400C. The solvent was removed under 10 reduced pressure to yield a dark oil which was used without further purification. ESI-MS: 542 (MH*). This residue was combined with 2,6-lutidine (0.018g, 0.16mmol, 2eq) and ethyl chloroformate (0.0175g, 0.16mmol, 2eq) in dimethylformamide (0.5mL) and heated at 1400C for 10 min by irradiation in a Milestone microwave (Milestone 15 Laboratories, Sorisole, Italy). The solution was purified by preparative HPLC eluting with water 0.1%NH 4 0H, 70 - 0% with acetonitrile, 0.1%NH 4 0H, 6min gradient time, and8min run time to yield the title compound. ESI-MS: 587 (MH+) General procedure for parallel synthesis of amides: 20 The required benzoic acids (0.06mmol, 1eq) were combined with PS-PPh 3 (115mg, 1.51mmol/g, 3eq, 0.18mmol) (Argonaut Technologies, Inc., Foster City, CA) in septum-capped 2 dram vials. To this solid mixture was added dichloroethane (1 mL) via a Tecan US (Research Triangle Park, NC) liquid handler. To this suspension was added via the Tecan a solution of trichloroacetonitrile (0.0072mL, 25 1.2eq, 0.07mmol) in dichloroethane (1 mL) and the reactions were gently agitated by means of an orbital shaker for 3h. To this solution was added PS-DIPAM (56mg, WO 2004/085401 PCT/IB2004/000836 -163 3.2mmol/g, 3eq, 0.18mmol)(Polymer Laboratories, Amherst, MA) and a solution of 2 ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester (15mg, 0.06mmol, 1.Oeq) in dichloroethane (1 mL) was added via the Tecan. The reactions were agitated overnight. The reactions were filtered through filter tubes using the 5 Tecan liquid handler, and the resins were washed 3 times with dichloroethane. The solutions were evaporated using a Genevac Mega660 centrifugal evaporator (Genevac Ltd.. Suffolk, UK) and the residues were redissolved in dimethyl sulfoxide (0.2mL) and purified using the Shimadzu preparative HPLC system (Shimadzu Corporation, Kyoto, Japan) eluting with a 30-100% acetonitrile/water/0.1 % formic acid 10 gradient on a 19x5Omm Waters Symmetry Column (Waters Corp, Milford, MA) 8 min run, 6 min gradient, 25mL/min, UV triggered collection, observing at 21 Onm. The product-containing fractions were evaporated to dryness using the Genevac Mega660 centrifugal evaporator (Genevac Ltd., Suffolk, UK). Using the appropriate starting materials, Examples 184-409 were made as 15 racemic mixtures in an analogous manner to Example 183: Example 184 H3C' N.-N CH3 O CH o O- C CH
CH
3
H
3 C N
H
3 C aN 0 j- CH 3 KCH3 4-(5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 20 LC-MS (ESI+): 427 (MH+).
WO 2004/085401 PCT/IB2004/000836 -164 Example 185 F N N HC N O- O CH, CH, 2-Ethyl-4-[2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-6,7-dimethyl-3,4-dihydro 2H-quinoxaline-1 -carboxylic acid ethyl ester 5 LC-MS (ESI+): (MH+). Example 186 F F 0;110 H 3 C NN H 3 C aN O 0 CH 3 CH3 4-(2-Difluoromethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 478 (MH+). Example 187 WO 2004/085401 PCT/IB2004/000836 -165 F F O
H
3 CaN H 3 C ''N 0O O CH 3
CH
3 4-(3-Difluoromethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 433 (MH+). 5 Example 188 F F H 3 C N
CH
3 KCH3 2-Ethyl-6,7-dimethyl-4-(2-trifluoromethyl-[i1,8]naphthyridine-3-carbonyl)-3,4-dihydro 2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 487 (MH+). 10 Example 189 F F N H 3 C N C H 3 C N OJ o H 3 KCH, 2-Ethyl-6,7-dimethyl-4-(2-trifluoromethyl-[1,6]naphthyridine-3-carbonyl)-3,4-dihydro 2H-quinoxaline-1 -carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -166 LC-MS (ESI+): 487 (MH+). Example 190 F F F H 3 C N H 3 C aN o1o CH 3
CH
3 2-Ethyl-6,7-dimethyl-4-(5-trifluoromethyl-thieno[3,2-b]pyridine-6- carbonyl)-3,4 5 dihydro-2H-quinoxaline-1- carboxylic acid ethyl ester LC-MS (ESI+): 492 (MH+). Example 191 F F N
H
3 C N 0 OH 3 : CHa 2-Ethyl-6,7-dimethyl-4-(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-3,4-dihydro 10 2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 502 (MH+). Example 192 WO 2004/085401 PCT/IB2004/000836 -167 0\\ S "O 0" N
CH
3 H 3 C ~ N H 3 C
H
3 C "! N o O CH 3
CH
3 4-(4-Dipropylsulfamoyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 530 (MH+). 5 Example 193 o
H
3 C N 0-/
H
3 C N O O CCH 3
CH
3 4-(2,3-Dihydro-benzofuran-7-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 409 (MH+). 10 Example 194 Br 7 CI o 'N H 3 C N
H
3 Ca N O'O CH 3
CH
3 4-(3-Bromo-4-chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -168 LC-MS (ESI+): 480 (MH+). Example 195
CH
3 CH
H
3 C N
H
3 C aN 0 o H 3 KCH3 4-(2-Chloro-3-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 415 (MH+). Example 196 S O C 3
H
3 0 0
H
3 C N o o H 3 CH3 4-(2-Chloro-4-methanesulfonyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H 10 quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 479 (MH+). Example 197 WO 2004/085401 PCT/IB2004/000836 -169 0
H
3 C N CI
H
3 C N O O-Ll CH 3
CH
3 4-(2,6-Dichloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 436 (MH+). 5 Example 198 0 C H 3 0 H 3 C N d 3 C N O H H 3 CH3 2-Ethyl-4-(4-methoxy-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-i -carboxylic acid ethyl ester LC-MS (ESI+): 397 (MH+). 10 Example 199
CH
3 o N 0 3 H N o oI CH 3 CH3 2-Ethyl-4-(2-methoxy-pyridine-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -170 LC-MS (ESI+): 398 (MH+). Example 200 F F' F N oa1 N
H
3 C><N CH, 2-Ethyl-6,7-dimethyl-4-(1 -phenyl-5-trifluoromethyl-1 H-pyrazole-4-carbonyl)-3,4 5 dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 501 (MH+). Example 201 O CH 0 0 H 3 C N o1 'o
CH
3
CH
3 2-Ethyl-6, 7 -dimethyl-4-(3-methyl-benzofuran-2-carbonyl)-3,4-dihydro-2H-quinoxaline 10 1-carboxylic acid ethyl ester LC-MS (ESI+): 421(MH+).
WO 2004/085401 PCT/IB2004/000836 -171 Example 202 O H3C N S=O
OH
3
H
3 C N O O CH 3 CH3 2-Ethyl-4-(2-methanesulfonyl-benzoy)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+): 445 (MH+). Example 203 o
H
3 C N CH 3
CH
3 2-Ethyl-4-(9H-fluorene-4-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 455 (MH+).
WO 2004/085401 PCT/IB2004/000836 -172 Example 204 F H ON H 3 C N F O ~O CH 3 CH3 2-Ethyl-6,7-dimethyl-4-(2,3,6-trifluoro-benzoyl)-3,4-dihydro-2H- quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+): 421 (MH+). Example 205 C1 O N
H
3 C N
H
3 C : N O O COH 3 CH3 4-(4,5-Dichloro-isothiazole-3-carbonyl)-2-ethyl-6,7-dimethy-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 10 LC-MS (ESI+): 443 (MH+).
WO 2004/085401 PCT/IB2004/000836 -173 Example 206 N'N,
H
3 C N CH 3 H3C N o 0O CH 3
CH
3 2-Ethyl-6,7-dimethyl-4-(5-methyl-2-phenyl-2H[1,2,3]triazole-4-carbonyl)-3,4-dihydro 2H-quinoxaline-1 -carboxylic acid ethyl ester 5 LC-MS (ESI+): 448 (MH+). Example 207 o
H
3 CZaN H3K ' OHN CH 2-Ethyl-6,7-dimethyl-4-(2-phenoxymethyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 473 (MH+).
WO 2004/085401 PCT/IB2004/000836 -174 Example 208 4-(3-Chloro-benzo[blthiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1 -carboxylic acid ethyl ester 5 LC-MS (ESI+): 457 (MH+). Example 209 C I OI I CH3 o o CH 3 CH 3 4-(3-Chloro-4-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 415 (MH+). Example 210 WO 2004/085401 PCT/IB2004/000836 -175
CH
3 Br I 0~,
H
3 C N O' O1O
CH
3
CH
3 4-(3-Bromo-2,6-dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro- 2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 506 (MH+). 5 Example 211
CH
3 oyq0
H
3 C N CI OH 3
H
3 C N H3COH 3 O' O CH 3 CH3 4 -(2-Chloro-3,4-dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 1-carboxylic acid ethyl ester LC-MS (ESI+): 461 (MH+). 10 Example 212 Cl F F F I N H 'C N O,50 CH KCH3 4-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1 H-pyrazole-4-carbonyl]-2-ethyl-6,7-dimethyl 3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -176 LC-MS (ESI+): 535 (MH+). Example 213 H 3 C N 0 CH 3 o 1-o CH3
CH
3 4
-(
3 -Ethoxy-thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 5 1-carboxylic acid ethyl ester LC-MS (ESI+): 417 (MH+). Example 214 S 0 ci
H
3 C N o'CH
H
3 C N O OI CH 3
CH
3 4 -(5-Chloro-4-methoxy-thiophene-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H 10 quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 437 (MH+). Example 215 /S _ N 0
H
3 C N
H
3 C N o o CH 3 CH3 4-[2-(2,3-Dihydro-benzo[1, 4 ]dioxin-2-yl)-thiazole-4-carbonyl]-2-ethyl-6,7-dimethyl-3,4 15 dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 508 (MH+).
WO 2004/085401 PCT/IB2004/000836 -177 Example 216
OH
3 0
H
3 C N
I
H
3 C G N o <o CH 3
CH
3 4-(3-Cyclopentyloxy-4-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 5 LC-MS (ESI+): 481 (MH+). Example 217
CH
3 o CH, H C N H~H, H3C'HN CH, 2-Ethyl-4-(4-methoxy-3-propoxy-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 455 (MH+). Example 218
CH
3 OCH H3Cac N O O CH3 CH3 2-Ethyl-4-(3-isopropoxy-4-methoxy-benzoy)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -178 LC-MS (ESI+): 455 (MH+). Example 219
CH
3 o CH HaC N HaC N CH, 4-(3-Butoxy-4-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihyd ro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 469 (MH+). Example 220 0O-CHa3 ooCH 3 CH, 2-Ethyl-4-(5-methoxycarbonyl-pyridine-2-carbonyl)-6,7-dimethyl-3,4-dihydro-2H 10 quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 426 (MH+). Example 221 WO 2004/085401 PCT/IB2004/000836 -179 N o H C N F F 3 F
H
3 C N O O CHa CH 2-Ethyl-6,7-dimethyl-4-(4-trifluoromethyl-pyridine-3-carbonyl)-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 436 (MH+). 5 Example 222 FF F 0 H0 N Hac N
H
3 C - N oH<o cH 3 CH3 2-Ethyl-6,7-dimethyl-4-[6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+):466 (MH+). 10 Example 223 CH3
LH
3 C O -N N
H
3 C O 0
CH
3 F F F 2-Ethyl-4-[5-methoxy-2-(2,2,2-trifluoro-ethoxy)-benzoyl]-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+):495 (MH+).
WO 2004/085401 PCT/IB2004/000836 -180 Example 224
H
3 C 0 HaC N HaC N
CH
3 KCH 2-Ethyl-6,7-dimethyl-4-(2-methyl-5-phenyl-furan-3-carbonyl)-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 5 LC-MS (ESI+): 447 (MH+). Example 225 F F F 1~ 0 H Oo )CH , o CH3
CH
3 2-Ethyl-6,7-dimethyl-4-(5-methyl-2-trifluoromethyl-furan-3-carbonyl)-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 10 LC-MS (ESI+): 439 (MH+). Example 226
CH
3 N N
H
3 C CH 3
H
3 C N o'<o CH 3 CH3 2-Ethyl-4-(2-ethyl-5-methyl-2H-pyrazole-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 15 LC-MS (ESI+): 399 (MH+).
WO 2004/085401 PCT/IB2004/000836 -181 Example 227 Hac CH 3 Hac N-N
H
3 C N o o CHa
CH
3 4-(2-tert-Butyl-5-methyl-2H-pyrazole-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1 -carboxylic acid ethyl ester 5 LC-MS (ESI+): 427 (MH+). Example 228 CH, o'-9 o N HaC 3 H 3C N2 H KCHa 2-Ethyl-4-[2-(4-ethyl-benzoyl)-benzoyl]-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 499 (MH+). Example 229
H
3 C H ,C N H C N N
H
3 C N O OCH, CH, 4-(2-Ethoxy-naphthalene-1 -carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -182 LC-MS (ESI+): 461 (MH+). Example 230 Br H
H
3 C -a N 0
H
3 C N O O oCH 3
CH
3 4-(5-Bromo-2,3-dihydro-benzofuran-7-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H 5 quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 488 (MH+). Example 231 C1 HaC N
H
3 C N
H
3 C CH CH, 4
-[
2
-(
4 -Chloro-phenoxy)-pyridine-3-carbonyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H 10 quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 494 (MH+). Example 232 WO 2004/085401 PCT/IB2004/000836 -183 0N
H
3 C>a N CH, HOHC C H 3 2-Ethyl-6,7-dimethyl-4-(2-p-tolyloxy-pyridine-3-carbonyl)-3,4-dihydro-2H-quinoxaline 1-carboxylic acid ethyl ester LC-MS (ESI+): 474 (MH+). 5 Example 233 N--O o C
H
3 C N H 3 C
H
3 C N O O CH 3 CH3 2-Ethyl-4-(5-isobutyl-isoxazole-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 1 -carboxylic acid ethyl ester LC-MS (ESI+):414 (MH+). 10 Example 234 OH N,CH, OO CHN H c
H
3 C3 CH3 2-Ethyl-4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzoyl}-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 440 (MH+).
WO 2004/085401 PCT/IB2004/000836 -184 Example 235 HN CH 3 H 3 C N CH 3
H
3 C N O Io CH 3 CH3 4-(3,5-Dimethyl-1 H-indole-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1 -carboxylic acid ethyl ester 5 LC-MS (ESI+): 434 (MH+). Example 236 O-
-H
3 N C O0N,0 HNC N
H
3 C N 0 0CHN <CH, 2-Ethyl-4-[4-(5-ethyl-[1,2,4]oxadiazol-3-yl)-benzoyl]-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 10 LC-MS (ESI+): 463 (MH+). Example 237 H C N "'6 H,C N H3CXYN O) O CHa CH, 2-Ethyl-6,7-dimethyl-4-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoyl]-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -185 LC-MS (ESI+): 449 (MH+). Example 238
N-
0 O CH 3 H 3 C N
H
3 C N
CH
3 2-Ethyl-6,7-dimethyl-4-(5-propyl-isoxazole-3-carbonyl)-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+)400 (MH+). Example 239 CH, O N CH, N
H
3 C N CH, HC N CH, CH3 2-Ethyl-4-(5-isobutyl-2-methyl-2H-pyrazole-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H 10 quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 427 (MH+). Example 240 WO 2004/085401 PCT/IB2004/000836 -186
CH
3 CH, N
H
3 C N CH,
H
3 C N O- 0 CH,
CH
3 2-Ethyl-4-(5-methoxymethyl-furan-2-carbonyl)-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 401 (MH+). 5 Example 241 HN-N CH 3 H 3 C N 0 O CH 3
CH
3 2-Ethyl-4-(5-isopropyl-2H-pyrazole-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 399 (MH+). 10 Example 242 ro N
H
3 C N HC~a- N
CH
3 2-Ethyl-6,7-dimethyl-4-(4-morpholin-4-yl-benzoyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 452 (MH+). 15 WO 2004/085401 PCT/IB2004/000836 -187 Example 243 HN \ / CI o c H 3 C N CH 3
H
3 C aN
CH
3 cHa 4-(5-Chloro-3-methyl-1 H-indole-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 5 LC-MS (ESI+): 454 (MH+). Example 244 CH 3 HN O
H
3 C N CH 3 H C N 0o'^1o CH 3
CH
3 4-(3,5-Dimethyl-i H-pyrrole-2-carbonyl)-2-ethyl-6,7-dinethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 10 LC-MS (ESI+): 384 (MH+). Example 245 NH 0 H3CH 3 o o H, KCHa 2-Ethyl-6,7-dimethyl-4-(6,7,8,9-tetrahydro-5H-carbazole-3-carbonyl)-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -188 LC-MS (ESI+): 460 (MH+). Example 246 ICCa H3C NN
H
3 C N KCH, 4-[4-(2,5-Dimethoxy-benzoyl)-benzoyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H 5 quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 531 (MH+). Example 247 O -- N CH3 S H3I/OH 3 HSC N OJ O CH 3
CH
3 2-Ethyl-6,7-dimethyl-4-(2-methyl-thiazole-4-carbonyl)-3,4-dihydro-2H-quinoxaline-1 10 carboxylic acid ethyl ester LC-MS (ESI+):388 (MH+). Example 248 WO 2004/085401 PCT/IB2004/000836 -189 N' 'N
CH
3
H
3 C N
H
3 C
H
3 C N O o CH 3 CH3 4-[3-(3,5-Dimethyl-pyrazol-1 -yl)-benzoyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 461 (MH+). 5 Example 249
CH
3 N H N O j O CH 3 CH, 2-Ethyl-6,7-dimethyl-4-(2-p-tolyl-quinoline-4-carbonyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 508 (MH+). 10 Example 250 CH O N H3C N \ N N
CH
3 2-Ethyl-6,7-dimethyl-4-(5-methyl-1,3-diphenyl-1 H-pyrazole-4-carbonyl)-3,4-dihydro 2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 523 (MH+). 15 Example 251 WO 2004/085401 PCT/IB2004/000836 -190 N
H
3 C: N
H
3 C N O O1 CH,
CH
3 2 -Ethyl-6,7-dimethyl-4-(4-piperidin-1-yl-benzoyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 450 (MH+). 5 Example 252 CH
N
CHa H C N H3C a5N O- O CH, 1CH3 4-[3-(3,5-Dimethyl-pyrazol-1 -ylmethyl)-benzoyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 475 (MH+). 10 Example 253 H 3 C N
CH
3 2-Ethyl-6,7-dimethyl-4-(quinoline-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 418 (MH+).
WO 2004/085401 PCT/IB2004/000836 -191 Example 254 o~fl
H
3 C N OH O O CHaN CH 2-Ethyl-4-(furan-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester 5 LC-MS (ESI+): 357 (MH+). Example 255 a Br H 3 C N OH
CH
3 4-(5-Bromo-2-chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 480 (MH+). Example 256 0 o cH 3
H
3 C N ocH 3 KCH3 4-(4-Acetyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester 15 LC-MS (ESI+): 409 (MH+).
WO 2004/085401 PCT/IB2004/000836 -192 Example 257 o
H
3 C N F
H
3 C N O'LO CH 3 CH3 4-(2-Chloro-6-fluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-I carboxylic acid ethyl ester 5 LC-MS (ESl+): 419 (MH+). Example 258 o oN 7~
H
3 C N
H
3 CC N
CH
3 2-Ethyl-6,7-dimethyl-4-(naphthalene-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 417 (MH+). Example 259 Br
H
3 0 N K-1
H
3 C aN
CH
3
OH
3 4-(3-Bromo-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -193 LC-MS (ESI+): 446 (MH+). Example 260 CH 0 CH 3 3 0O
H
3 H 3 C N
H
3 C N 0 O CH,
CH
3 2-Ethyl-6,7-dimethyl-4-(2,3,4-trimethoxy-benzoyl)-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 457 (MH+). Example 261 C
H
3
H
3 N CHM CH CH3 2-Ethyl-4-(4-ethyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid 10 ethyl ester LC-MS (ESI+):395 (MH+). Example 262 WO 2004/085401 PCT/IB2004/000836 -194 N HN
H
3 C N o o CH,
CH
3 2-Ethyl-6,7-dimethyl-4-(2-pheny-quinoline-4-carbonyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 494 (MH+). 5 Example 263 F F F H 3 C N O O oCH 3 CH3 2-Ethyl-6,7-dimethyl-4-(2-trifluoromethyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 435 (MH+). 10 Example 264 F F O N F 0 H 3 C N 0o,4o CH3
CH
3 2-Ethyl-6,7-dimethyl-4-(4-trifluoromethyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -195 LC-MS (ESI+): 435 (MH+). Example 265 C1 o N o .
0- 0 CH, CH, 4-[2-(4-Chloro-benzoyl)-benzoyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 506 (MH+). Example 266 CH O H 0 H3HC N oj0CH, CH, 4-(3,4-Diethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 10 carboxylic acid ethyl ester LC-MS (ESI+): 455 (MH+). Example 267 WO 2004/085401 PCT/IB2004/000836 -196
H
3 C N O O CH 3 CH3 4-(2-Chloro-5-methylsulfanyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 448 (MH+). 5 Example 268 0
H
3 C N CH 3
H
3 C N
OH
3
CH
3 2-Ethyl-6,7-dimethyl-4-(3-methyl-thiophene-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 387 (MH+). 10 Example 269
CH
3 00 O N
H
3 C N H 3 C
H
3 C N
OCH
3
CH
3 4-(2,5-Dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 427 (MH+). 15 Example 270 WO 2004/085401 PCT/IB2004/000836 -197 oF
H
3 C N H3COH 3 oJo CHK
CH
3 4-(2,4-Difluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 403 (MH+). 5 Example 271 F F
H
3 C "Z~ N
H
3 C ON
CH
3 4-(3,4-Difluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+):403 (MH+). 10 Example 272 Br
CH
3 0
H
3 C N
H
3 0~ N O O0 CH3
CH
3 4-(3-Bromo-4-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+).
WO 2004/085401 PCT/IB2004/000836 -198 Example 273
CH
3 o
CH
3 H 3 C 'NN H 3 N o o CH 3 CH3 2 -Ethyl-4-(4-isopropyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester 5 LC-MS (ESI+): 409 (MH+). Example 274 oH C o 'o C H 3 HC N
CH
3 2-Ethyl-4-(2-methoxy-4-methylsulfanyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 10 LC-MS (ESI+):443 (MH+). Example 275 F O, F
H
3 C -N N
H
3 C N o -o CHs CHS 4-(3,5-Difluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester 15 LC-MS (ESI+): 403 (MH+).
WO 2004/085401 PCT/IB2004/000836 -199 Example 276 C F o oH H 3 C N
CH
3 CH C 3 4-(2-Chloro-4-fluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+):419 (MH+). Example 277 0 H3C N H 3C N O' 0 H3 CH, 2-Ethyl-6,7-dimethyl-4-(9-oxo-9H-fluorene- I -carbonyl)-3,4-d ihydro-2H-q uinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 469 (MH+). Example 278 0 /
H
3 C N H~3C N H)L1 CH N CH3 4-(Benzofuran-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -200 LC-MS (ESI+): 407 (MH+). Example 279
H
3 CO O O 0
H
3 C N
H
3 C N
CH
3 2-Ethyl-4-(2-methoxycarbonyl-benzoyl)-6,7-dimethy-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 425 (MH+). Example 280 F O F
H
3 C NN F
H
3 CX : N O O 0CH 3
CH
3 2-Ethyl-6,7-dimethy-4-(2,4,5-trifluoro-benzoyl)-3,4-dihydro-2H-quinoxaline-1 10 carboxylic acid ethyl ester LC-MS (ESI+): 421 (MH+). Example 281 WO 2004/085401 PCT/IB2004/000836 -201
CH
3
H
3 0) : - N
H
3 C < N 0O 0CH3 CH3 2-Ethyl-6,7-dimethyl-4-(4-propyl-benzoyl)-3,4-dihyd ro-2H-q uinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 409 (MH+). 5 Example 282 O F
H
3 C N F
H
3 C' N cOO CH 3
CH
3 2-Ethyl-6,7-dimethyl-4-(2,3,4-trifluoro-benzoyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 421 (MH+). 10 Example 283 F F F F o;
H
3 C N O OI CH3
CH
3 2-Ethyl-4-(2-fluoro-3-trifluoromethyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 453 (MH+).
WO 2004/085401 PCT/IB2004/000836 -202 Example 284 CH, o N o / HCAN H 'C N o3o H 3 CH, 2-Ethyl-6,7-dimethyl-4-[2-(4-methyl-benzoy)-benzoyl]-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+): 485 (MH+). Example 285 F F F
H
3 Ca_ N
H
3 C N 1 CH 3 cH 3 2-Ethyl-6,7-dimethyl-4-(4'-trifluoromethyl-biphenyl-2-carbonyl)-3,4-dihydro-2H quinoxaline-11-carboxylic acid ethyl ester 10 LC-MS (ESI+):511 (MH+). Example 286 WO 2004/085401 PCT/IB2004/000836 -203 F 0 C H 3 H 3 C N o CH 3
CH
3 2-Ethyl-4-(3-fluoro-4-methoxy-benzoyl)-6,7-dimethyl-3,4-dihyd ro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+):415 (MH+). 5 Example 287 0 CH 3 H 3 CCH 3 I H 3 C N IIo OCH3 CH 2-Ethyl-4-(4-isopropoxy-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 425 (MH+). 10 Example 288
H
3 1 N
-
H
H
3 C N HOCCH 0 o CH3 CH3 2-Ethyl-6,7-dimethyl-4-(4-propoxy-benzoyl)-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 425 (MH+).
WO 2004/085401 PCT/IB2004/000836 -204 Example 289 CI F 0
H
3 C lN
H
3 C N O o CH 3
CH
3 4-(3-Chloro-4-fluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+):419 (MH+). Example 290 F F F o
H
3 C N F F F
H
3 C N O 1O CH 3 CH3 4-(2,4-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 503 (MH+). Example 291
CH
3 O N 0O o 'CH 3
H
3 0 N
H
3 C~ N O O CH 3 CH3 4-(2,6-Dimethoxy-pyridine-3-carbonyl)-2-ethy WO 2004/085401 PCT/IB2004/000836 -205 -6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 428 (MH+). Example 292 o;ao
H
3 C N
CH
3
H
3 C N O O 0CH 3
CH
3 5 4-(2-Bromo-5-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 476 (MH+). Example 293 0
H
3 C N
H
3 C aN
CH
3 10 2-Ethyl-4-(2-fluoro-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 385 (MH+). Example 294 WO 2004/085401 PCT/IB2004/000836 -206
H
3 C o O
CH
3 H 3 C N
H
3 C aN 0 O0 CH 3 CH3 4-(2,5-Dimethyl-furan-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 385 (MH+). 5 Example 295 F F F F 0 H C N
H
3 0- "-N o o cH 3
CH
3 2-Ethyl-4-(4-fluoro-3-trifluoromethyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 453 (MH+). 10 Example 296 H3C NJ: HC ,N O O H CH, 4-(2-Benzoyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 471 (MH+).
WO 2004/085401 PCT/IB2004/000836 -207 Example 297 0 o o cH3
CH
3 4-(4-Benzoyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1 -carboxylic acid ethyl ester 5 LC-MS (ESI+): 471 (MH+). Example 298 0 HaC N
H
3 C N HCcH, CHa 4-(Biphenyl-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 10 LC-MS (ESI+): 443 (MH+). Example 299 07
H
3 C N CH, 4-(Biphenyl-4-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -208 LC-MS (ESI+): 443 (MH+). Example 300 ci
H
3 O N 0.1 CH 3
CH
3 4-(3-Chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic 5 acid ethyl ester LC-MS (ESI+):401 (MH+). Example 301 CH3 N C H C N
H
3 C N ci h CH 3
CH
3 4-(2.-Cyano-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1 -C-rboxylic 10 acid ethyl ester LC-MS (ESI+):392 (MH+). Example 302 CH CH, o 1 1
H
3 C N
H
3 C N 0 CH, K CH, 4 -(2, 3- D imeth oxy- be nzoyl)-2-et hyl -6 ,7-d im et hyl -3,4- d ihyd ro-2 H-q u inoxaIi n e- 1 15 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -209 LC-MS (ESI+): 427 (MH+). Example 303 CH ' o , N
CH
3 H 3 C N o,, o cHa
CH
3 4-(2,4-Dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+):427 (MH+). Example 304 H0C,0 o0 CH,
H
3 C N
H
3 C N o o CH,
CH
3 4-(3,4-Dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 10 carboxylic acid ethyl ester LC-MS (ESI+): 427 (MH+). Example 305 0-CH, H C N C H '
H
3 C N oj o CH,
KCH
3 4-(3,5-Dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 15 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -210 LC-MS (ESI+): 427 (MH+). Example 306
CH
3 CH,
H
3 o N CHa 1,OH 3 4-(3,4-Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+):395 (MH+). Example 307 CH, --- CH, H3C N
H
3 C N O O CH,
CH
3 4-(3,5-Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 10 carboxylic acid ethyl ester LC-MS (ESI+): 395 (MH+). Example 308 F
CH
3 o OH 3 CH 3 2-Ethyl-4-(3-fluoro-4-methyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 15 carboxylic acid ethyl ester LC-MS (ESI+): 399 (MH+).
WO 2004/085401 PCT/IB2004/000836 -211 Example 309
H
3 C N
H
3 C aN o -o H 3 CH3 2-Ethyl-4-(furan-2-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester 5 LC-MS (ESI+): 357 (MH+). Example 310 F
H
3 C KN
H
3 CX N o)o
CH
3
CH
3 2-Ethyl-4-(3-fluoro-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid ethyl ester 10 LC-MS (ESI+): 385 (MH+). Example 311 O CH,
H
3 C aN
H
3 C N O O CH, 1CH3 2-Ethyl-4-(3-methoxy-4-methyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1 carboxylic acid ethyl ester 15 LC-MS (ESI+): 411 (MH+).
WO 2004/085401 PCT/IB2004/000836 -212 Example 312
CH
3
K
H
3 C N C
CH
3 2-Ethyl-6,7-dimethyl-4-(5-methyl-thiophene-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+): 387 (MH+). Example 313 o H C N
H
3 C N O Io CH 3
CH
3 2-Ethyl-6,7-dimethyl-4-(naphthalene-I -carbonyl)-3,4-dihydro-2H-quinoxaline-I carboxylic acid ethyl ester 10 LC-MS (ESI+):417 (MH+). Example 314
CH
3 o!
H
3 C N H 3 C N oCH 3 1,
OH
3 2-Ethyl-6,7-dimethyl-4-(6-methyl-pyridine-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 15 LC-MS (ESI+):382 (MH+).
WO 2004/085401 PCT/IB2004/000836 -213 Example 315 CH 1 3 0;P 'U CH 3
H
3 C N 0'CH3
H
3 Ca N o, o CH 3 CH3 2-Ethyl-6,7-dimethyl-4-(2,4,6-trimethoxy-benzoyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+): 457 (MH+). Example 316
H
3 C 0 o \IN
H
3 Ca N O -O CH 3
CH
3 4-[3-(2-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-ethyl-6,7-dimethyl-3,4 dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester 10 LC-MS (ESI+): 482 (MH+). Example 317 Ci OY
H
3 C N Br
H
3 C N O H 3
CH
3 4-(2-Bromo-5-chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 15 LC-MS (ESI+): 480 (MH+).
WO 2004/085401 PCT/IB2004/000836 -214 Example 318 Br O CH 8
H
3 C I N N O o CH3
CH
3 4-(3-Bromo-4-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+):476 (MH+). Example 319
H
3 C N
H
3 C aN CH, 4-(4-Benzyloxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 10 LC-MS (ESI+):473 (MH+). Example 320
H
3 C N o< o OH 3 CH3 2-Ethyl-6,7-dimethyl-4-(thiophene-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -215 LC-MS (ESI+):373 (MH+). Example 321 HC
H
3 0
H
3 C N 0 1 O CH 3
CH
3 2-Ethyl-6,7-dimethyl-4-(2-methyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic 5 acid ethyl ester LC-MS (ESI+): 381 (MH+). Example 322
CH
3 o
H
3 C N
H
3 C0 N 0)-O CH 3
CH
3 2-Ethyl-6,7-dimethyl-4-(3-methyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1 -carboxylic 10 acid ethyl ester LC-MS (ESI+): 381 (MH+). Example 323
CH
3
H
3 C N H3 CXOH 3 O O ' CH3
CH
3 2-Ethyl-6,7-dimethyl-4-(4-methyl-benzoyl)-3,4-dihydro-2H-quinoxaline-1 -carboxylic 15 acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -216 LC-MS (ESI+): (MH+). Example 324 Hac H 'cH0 H 0 CH, 0
H
3 C N O) O CH, CH, 2-Ethyl-6,7-dimethyl-4-(3,4,5-trimethoxy-benzoyl)-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 457 (MH+). Example 325 N
H
3 C N
CH
3
CH
3 2-Ethyl-4-(isoquinoline-1-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 10 carboxylic acid ethyl ester LC-MS (ESI+): 418 (MH+). Example 326 H0
H
3 C N CH 3
H
3 C N OS
CH
3
CH
3 4-(2,6-Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 15 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -217 LC-MS (ESI+): 395 (MH+). Example 327 F F F 0 F HC N F F
H
3 c N
H
3 c 4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 503 (MH+). Example 328
H
3 C N
H
3 C aN O <o CH 3
CH
3 4-Benzoyl-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl 10 ester LC-MS (ESI+): 367 (MH+). Example 329 WO 2004/085401 PCT/IB2004/000836 -218 HN CI
H
3 C ~ N o: a
H
3 C N o -o CH 3
CH
3 4-(5-Chloro-3-phenyl-1 H-indole-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 517 (MH+). 5 Example 330 F 0
H
3 C N
CH
3 CH, 2-Ethyl-4-(4'-fluoro-biphenyl-4-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+):461 (MH+). 10 Example 331 0 F HC N o 0 CHa CH, 2-Ethyl-4-(3'-fluoro-biphenyl-4-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 461 (MH+). 15 Example 332 WO 2004/085401 PCT/IB2004/000836 -219 F 0 H C N 1CH3 2-Ethyl-4-(2'-fluoro-biphenyl-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+):461 (MH+). 5 Example 333 F O H C N H,C NI 0 0 H ICH 2-Ethyl-4-(3'-fluoro-biphenyl-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+):461 (MH+). 10 Example 334 F H C N H 3CI:N CH3 2-Ethyl-4-(4'-fluoro-biphenyl-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 461 (MH+).
WO 2004/085401 PCT/IB2004/000836 -220 Example 335 N HO N
H
3 C N O O CH 3
CH
3 2-Ethyl-6,7-dimethyl-4-([1,2,5]thiadiazole-3-carbonyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+):375 (MH+). Example 336 CHS H3C O# H0 N 2-Ethyl-6,7-dimethyl-4-(2-pyrazol-1 -yl-benzoyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 433 (MH+). Example 337 N, N HaC N
H
3 C aN o, o CH, CHa 2-Ethyl-6,7-dimethyl-4-(4-pyrazol-1-yl-benzoyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 15 LC-MS (ESI+): 433 (MH+).
WO 2004/085401 PCT/IB2004/000836 -221 Example 338 oN H G N
H
3 C N CH, 2-Ethyl-6,7-dimethyl-4-(3-phenyl-isoxazole-5-carbonyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+): 434 (MH+). Example 339 CH
H
3 C N 3
H
3 C N o- o CH 3 CH3 2-Ethyl-4-[5-(4-methoxy-phenyl)-furan-2-carbonyl]-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester 10 LC-MS (ESI+): 463 (MH+). Example 340 CH, O N H3C N CH 3 o CH, CH, 2-Ethyl-6,7-dimethyl-4-(2-methyl-5-propyl-2H-pyrazole-3-carbonyl)- 3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -222 LC-MS (ESI+): 413(MH+). Example 341
CH
3 0 N' H 3 C N CH 3 OAO CH 3
CH
3 2-Ethyl-4-(5-ethyl-2-methyl-2H-pyrazole-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H 5 quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):399 (MH+). Example 342 N-N H C N
H
3 C N
CH
3 2-Ethyl-6,7-dimethyl-4-(pyrazolo[1,5-a]quinoline-2-carbonyl)-3,4-dihydro-2H 10 quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 457 (MH+). Example 343 WO 2004/085401 PCT/1B2004/000836 -223 HN\/
H
3 C _N K'I CH 3 2-Ethyl-6 ,7-dimethyl-4-(3-phenyl-1 H-indole-2-carbonyl)-3,4-dihydro-2H-q uinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+):482 (MH+). 5 Example 344 a- CH, H3HN 2 -Ethyl- 4 -[5-(4-methoxy-pheny)-thiophene-2carbonyl]6,7-dimethyl-3,4dihydro2H q uinoxaline-I -carboxylic acid ethyl ester LC-MS (ESI+):479 (MH+). 10 Example 345
GH
3 o N Br H 3 0 N
H
3 C N
OH
3 4 -(5-Bromo-2-methoxy-pyridine-3-carbonyl)-2-ethyl-6 ,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 477 (MH+). 15 Example 346 WO 2004/085401 PCT/IB2004/000836 -224
CH
3 0- H C N
H
3 C~a N oQo CH, CH 2-Ethyl-4-(3-methoxy-benzoyl)-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 397 (MH+). 5 Example 347 F
H
3 C N o <o CH 3
CH
3 2-Ethyl-4-(4-fluoro-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 385 (MH+). 10 Example 348
H
3 C 0 0 o IN
H
3 C N
H
3 C N oJ o
CH
3
CH
3 2-Ethyl-6,7-dimethyl-4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 448 (MH+). 15 Example 349 WO 2004/085401 PCT/IB2004/000836 -225 o o CH3
CH
3 4-(2-Chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+): 401 (MH+). 5 Example 350 C1
H
3 C: a N
H
3 C N O O CH 3
CH
3 4-(4-Chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+):401 (MH+). 10 Example 351 F o N. H,C N H3C N do O CH, KCH, 2-Ethyl-4-[2-(4-fluoro-benzoyl)-benzoyl]-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 489 (MH+). 15 Example 352 WO 2004/085401 PCT/IB2004/000836 -226 o Ko
H
3 C , ~ N
H
3 C N OH O O CH3 CH3 4-(2-Bromo-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 446 (MH+). 5 Example 353 C1 CI ClI o H 3 C N O O CH3
CH
3 4-(2,4-Dichloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 436 (MH+). 10 Example 354 Cl oC
H
3 C 'NN H 3 C N, o Lo CH 3
CH
3 4-(3,4-Dichloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 436 (MH+).
WO 2004/085401 PCT/IB2004/000836 -227 Example 355 ON
CH
3
H
3 C N O O CH 3 CH3 4-(4-Ethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester 5 LC-MS (ESI+): 411 (MH+). Example 356 S CH S
H
3 C N CH3 CH3 2-Ethyl-6,7-dimethyl-4-(4-methylsulfanyl-benzoyl)-3,4-dihydro-2H- quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 413 (MH+). Example 357
CH
3 0 C
H
3 C 'NN
H
3 C aN O O oCH 3
CH
3 4-(4-Chloro-2-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 15 LC-MS (ESI+): 431 (MH+).
WO 2004/085401 PCT/IB2004/000836 -228 Example 358 HaC o
H
3 C: a N
H
3 C N oj o CH, CHa 4-(2-Ethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester 5 LC-MS (ESI+): 411 (MH+). Example 359 C 0;)
H
3 C N
CH
3 KCH3 4-(2,3-Dichloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester 10 LC-MS (ESI+): 436 (MH+). Example 360
H
3 C N 3 o CH 3 CH3 2-Ethyl-6,7-dimethyl-4-(thiophene-3-carbonyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 15 LC-MS (ESI+): 373 (MH+).
WO 2004/085401 PCT/IB2004/000836 -229 Example 361 F HOCa N H 3 C N
CH
3 4-(2,3-Difluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-I -carboxylic acid ethyl ester 5 LC-MS (ESI+): 403 (MH+). Example 362 F o
H
3 Cs N
H
3 C N o -o CH 3
CH
3 2-Ethyl-4-(4-fluoro-naphthalene-1-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 1-carboxylic acid ethyl ester 10 LC-MS (ESI+): 435 (MH+). Example 363 0 F F H 3 C - N
H
3 C N 0)o CH 3
CH
3 2-Ethyl-6,7-dimethyl-4-(4-trifluoromethoxy-benzoyl)-3,4-dihydro-2H-quinoxaline-1 15 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -230 LC-MS (ESI+): 451 (MH+). Example 364 F F O;C:- F
H
3 C N N
H
3 )
CH
3 KCH3 2-Ethyl-4-(2-fluoro-4-trifluoromethyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H 5 quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 453 (MH+). Example 365 F F F 0 H3C N F F F d 0 oCH, CH, 4-(2,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 10 carboxylic acid ethyl ester LC-MS (ESI+): 503 (MH+). Example 366 WO 2004/085401 PCT/IB2004/000836 -231 FF F
H
3 C N F
H
3 C N 0 o CH 3 CH3 2-Ethyl-4-(2-fluoro-6-trifluoromethyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 453 (MH+). 5 Example 367 F OHo CH3
CH
3 2-Ethyl-4-(3-fluoro-2-methyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 399 (MH+). 10 Example 368 F o ci
H
3 C N CI
H
3 C N
CH
3
CH
3 4-(2,4-Dichloro-5-fluoro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 454 (MH+).
WO 2004/085401 PCT/IB2004/000836 -232 Example 369 O F
H
3 C N F
H
3 C N O O C~aN
CH
3 2-Ethyl-6,7-dimethyl-4-(2,4,6-trifluoro-benzoyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+): 421 (MH+). Example 370 F
H
3 C N CHS
H
3 C N O -O CH 3
CH
3 2-Ethyl-4-(5-fluoro-2-methyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 399 (MH+). Example 371 o N CH CH3 2-Ethyl-4-(2-fluoro-5-methyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-=quinoxaline-1 15 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -233 LC-MS (ESI+): 399 (MH+). Example 372 Br
H
3 C N 0)"o CH 3
CH
3 4-(5-Bromo-thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 452 (MH+). Example 373 0 YF o Ox F
H
3 -:_ N 0 o CH3
CH
3 4-(4-Difluoromethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 10 carboxylic acid ethyl ester LC-MS (ESI+):433 (MH+). Example 374 CH, 0 Y
H
3 N N o'0H N O CH 3
,CH
3 4-(2,6-Dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 15 carboxylic acid ethyl ester LC-MS (ESI+): 427 (MH+).
WO 2004/085401 PCT/1B2004/000836 -234 Example 375
OH
3 H 3 C N - CH 3 KCH 2 -Ethyl-6,7-dimethyl-4-(4-methyl-naphthalene-1 -carbony)-3,4-dihydro-2H quinoxaline-1 -carboxylic acid ethyl ester 5 LC-MS (ESI+): 431 (MH+). Example 376
OH
3 CI 0 H 3 C N 0, CH
H
3 C, OH 3 4
-(
3 -Chloro- 2
,
6 -dimethoxy-benzoyl)2ethy67dimethyl3,4dihydro-2H-quinoxaline 1 -carboxylic acid ethyl ester 10 LC-MS (ESI-i):461 (MH+). Example 377 CI
H
3 O N
H
3 C) ~N
OH
3 4
-(
3 -Chloro- 2 -fluoro-benzoyl)2ethy,7dimethyl34dihydro-2H-quinoxalinel carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -235 LC-MS (ESI+): 419 (MH+). Example 378 HGC N HCa N O Oo CH 3
CH
3 4-(3-Chloro-thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 407 (MH+). Example 379 F F}F 0 oacN.
H
3 C N HP N 3 CH 2-Ethyl-6,7-dimethyl-4-(2-trifluoromethoxy-benzoyl)-3,4-dihydro-2H-quinoxaline- 1 10 carboxylic acid ethyl ester LC-MS (ESI+):451 (MH+). Example 380 WO 2004/085401 PCT/IB2004/000836 -236 N'-O o / CH 3
H
3 C N O O CH 3
CH
3 2-Ethyl-6,7-dimethyl-4-(5-methyl-isoxazole-3-carbonyl)-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 372 (MH+). 5 Example 381 H Br
H
3 C N o : o CH3
CH
3 2-Ethyl-6,7-dimethyl-4-(3-methyl-furan-2-carbonyl)-3,4-dihydro-2H-quinoxalinel carboxylic acid ethyl ester LC-MS (ESI+): 371 (MH+). 10 Example 382 C Br Hp N 01,--o CH3
CH
3 4-(4-Bromo-2-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+).
WO 2004/085401 PCT/IB2004/000836 -237 Example 383 CI Br H 3 C N o o CH 3
CH
3 4-(4-Bromo-2-chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 5 LC-MS (ESI+): 480 (MH+). Example 384
CH
3 Br
H
3 C N
H
3 ) N
CH
3 4-(4-Bromo-3-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 10 LC-MS (ESI+): 460 (MH+). Example 385 ci
H
3 q
H
3 C -' N H o Co H 3 4-(5-Chloro-thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 15 LC-MS (ESI+): 407 (MH+).
WO 2004/085401 PCT/IB2004/000836 -238 Example 386 'CH, HCH ICHa 4-(3-Benzyloxy-4-methoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 1-carboxylic acid ethyl ester 5 LC-MS (ESI+): 503 (MH+). Example 387 H3C, 0 CH,
H
3 C N
CH
3
H
3 C N
CM
3 CH, 4-(3,5-Dimethoxy-4-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 1-carboxylic acid ethyl ester 10 LC-MS (ESI+): 441 (MH+). Example 388
H
3 C N
H
3 C aN CHS 4-(Benzo[b]thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -239 LC-MS (ESI+): 423 (MH+). Example 389
CH
3 CI 0
H
3 C N
H
3 C aN
CH
3 4-(4-Chloro-3-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 415 (MH+). Example 390 o C H3C N
H
3 C N O O CH 3
CH
3 4-(2-Bromo-4-chloro-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 10 carboxylic acid ethyl ester LC-MS (ESI+): 480 (MH+). Example 391 WO 2004/085401 PCT/IB2004/000836 -240
CH
3 Br O o )
H
3 C N OH OCH CH3 4-(2-Bromo-3-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+). 5 Example 392 O; CHS O O CH3
CH
3 4-(2-Bromo-5-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-uinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 460 (MH+). 10 Example 393 Br H3C 0
H
3 C N H 3 OH 3 O 'JO CH3
CH
3 4-(3-Bromo-2-methyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -241 LC-MS (ESI+): 460 (MH+). Example 394 0 CH 0
H
3 C N OH 3
H
3 C N O <O CH 3 CH 4-(2-Chloro-4,5-dimethoxy-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 5 1-carboxylic acid ethyl ester LC-MS (ESI+):461 (MH+). Example 395 0
H
3 0 0 -N OH
H
3 C N CH3 H, C N o o CH 3 CH, 4-(7-Ethoxy-benzofuran-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 10 1-carboxylic acid ethyl ester LC-MS (ESI+): 451 (MH+). Example 396
CH
3 HC OAN N
H
3 C 0 NH
CH
3 H 3 C N. 2-Ethyl-6,7-dimethyl-4-[2-(1 -phenyl-ethylcarbamoyl)-benzoyl]-3,4-dihydro-2H 15 quinoxaline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -242 LC-MS (ESI+): 514 (MH+). Example 397 0 NY'a 0 H 3 C N O O C~H 3
CH
3 4-(Benzo[1,3]dioxole-5-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 411 (MH+). Example 398
H
3 C
OH
3
CH
3 H3OH 3 10 4-(4-tert-Butyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-I -carboxylic acid ethyl ester LC-MS (ESI+):423 (MH+). Example 399 WO 2004/085401 PCT/IB2004/000836 -243 0 HaC~a H N o OH CH 2-Ethyl-6,7-dimethyl-4-(2-phenoxy-benzoyl)-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 459 (MH+). 5 Example 400 F F N N O F F 0 F 4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 503 (MH+). 10 Example 401 F O F N F N O F F 0 F 4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -244 LC-MS (ESI+): 503 (MH+). Example 402 \ 0 N N N NO 0 2-Ethyl-6,7-dimethyl-4-(1 -methyl-1 H-indole-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1 5 carboxylic acid ethyl ester LC-MS (ESI+): 420 (MH+). Example 403 O 0 N N S 4-(Benzo[b]thiophene-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 10 carboxylic acid ethyl ester LC-MS (ESI+): 423 (MH+). Example 404 WO 2004/085401 PCT/IB2004/000836 -245 o 0 N o, 2-Ethyl-4-(2-methoxy-benzoyl)-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1 -carboxylic acid ethyl ester LC-MS (ESI+):3977 (MH+). 5 Example 405 o o 0 0 4 -(2,3-Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+):395 (MH+). 10 Example 406
N
WO 2004/085401 PCT/IB2004/000836 -246 4
-(
2
,
4 -Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+):395 (MH+). Example 407 0 N# N O 0 5 4
-(
2 ,5-Dimethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESI+): 395 (MH+). Example 408 0 0< N O-N 0 10 0 2-Ethyl-4-(4-methoxy-3-methyl-benzoyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester LC-MS (ESl+):411 (MH+). Example 409 F F F F
H
3 C N FF
H
3 c N 0 CH 15
CH,
WO 2004/085401 PCT/IB2004/000836 -247 Preparation of 4-(3,5-Bis-trifluoromethyl-benzyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1 -carboxylic acid ethyl ester A solution of 2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester (0.05g, 1eq, 0.19mmol), 3,5-bis-(trifluoromethyl)benzyl bromide 5 (0.038mL, 2.2eq, 0.42mmol) and triethylamine (0.062mL, 3eq, 0.57mmol) in acetonitrile (2mL) was treated with catalytic potassium iodide and subjected to two ten minute cycles on the Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) chemical microwave at 180 0 C. The reaction was evaporated to dryness and purified on the Shimadzu Corporation (Kyoto, Japan) preparative HPLC system using a 40 10 100% acetonitrile/water 6 min gradient, 8min total run time to provide the title compound (0.0045mg, 5%). 1 HNMR (CDC3): 8 0.90 (t, J=7.47Hz, 3H), 1.31 (t, J=7.05Hz, 3H), 1.46 (m, 2H), 2.11 (s, 3H), 2.16 (s, 3H), 3.17 (dd, J=11.28, 1.24Hz, 1H), 3.49 (dd, J=11.16, 4.15Hz, 1H), 4.19 (m, 1H), 4.28 (m, 1H), 4.46 (d, J=17.43Hz), 4.52 (m, IH), 4.66 (d, 15 J=17.01Hz, 1H), 6.31 (s, 1H), 7.29 (brs, 1H), 7.71 (s, 2H), 7.78 (s, 1H). LCMS (ESI+): 489 (MH+). The prophetic examples 410-427 may be prepared in optically enriched form by resolution of the corresponding racemate indicated, or an intermediate in its synthesis, using methods analogous to those described herein: 20 Example 410 (Stereo-Isomers of Example 2) F F F F F F o OH FFO F H3 F F FF F 0 F F F F F N H N CH 3 3~o N 0~ O0 o o cH 3 CH3 (R, R)-4-[(3,5-Bis-trifluoromethyl-pheny)-hydroxyl-methoxycarbony-methyl] 2-ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbony-methyl] 25 2-ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl] 2-ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; or WO 2004/085401 PCT/IB2004/000836 -248 (S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl] 2-ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. Example 411 (Stereo-Isomers of Examples 3 and 4) F F F F F F F F F F 0 / o C F 0 F F O F F O F F
F
3 H 0 F3C F F Fl F F F F F F F FN FH N N H C*N N c_)_a O O0H 5 0 0 CH CH 3 (S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2 ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; or (S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; or a pharmaceutically 10 acceptable salt of said compound. Example 412 (Stereo-Isomers of Examples 5, 6, 7 and 8) F F F F F F F H O FF F F F H F F I -3C F 0F0 F0 kH F H -H F F F H H SCH F N cH 3 N N ' cN H J1 CH3 0 o CH3 CH 3 (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2 15 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -249 (R, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 5 (S, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or (S, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2 10 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. Example 413 (Stereo-Isomers of Examples 9 and 10) F F F F F F F F N F F N F F H NH F N"H -FF F FFF F FN N-- N I N CH3 / N CH3 0 0 H 3C O- H 3C -O 15 (R, R, R)-4-[(3,5-Bis-trifiuoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 20 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -250 (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 5 (S, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (S, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl 10 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl-2H quinoline-1-carboxylic acid ethyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; 15 (RR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (S,R)-4-[(3,5-Bis-tifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; or (SS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 20 trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. Example 414 (Stereo-Isomers of Examples 13 and 14)
CF
3 o i CF 3 MeO MeO N Me
CO
2 Et (R,S)-4-[(3,5-bis-trifluoromethyl-benzoyl)]-6,7-dimethoxy-2-methyl-3,4 25 dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-benzoyl)]-6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -251 (S,R)-4-[(3,5-bis-trifluoromethyl-benzoyl)]-6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or (S,S)-4-[(3,5-Bis-trifluoromethyl-benzoyl)]-6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 5 or a pharmaceutically acceptable salt thereof. Example 415 (Stereo-Isomers of Examples 18, 19 and 35)
CF
3 F
CF
3 MeO MeO N Me
CO
2 Et (R,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 10 (R,RS)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 15 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (S,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (S,R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; 20 (S,SR)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or (S,S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. 25 Example 416 (Stereo-Isomers of Examples 20 and 21) WO 2004/085401 PCT/IB2004/000836 -252
CF
3 CF 3 O CF 3 O CF 3
F
3 C , aH F 3 C H N Me N Me
CO
2 Et
CO
2 Et (S,R)-4-[(3,5-bis-trifluoromethyl-benzoyl)]-2-ethyl-6-trifluoromethyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or (S, S)-4-[(3,5-bis-trifluoromethyl-benzoyl)]-2-ethyl-6-trifluoromethy-3,4 5 dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. Example 417 (Stereo-Isomers of Examples 16 and 17)
CF
3 HO
CF
3 MeO MeO N Me CO 2 Et (R,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 10 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 15 (R,S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S,R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 20 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or WO 2004/085401 PCT/IB2004/000836 -253 (S,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. Example 418 (Stereo-Isomers of Example 34)
CF
3 o Me I O CF 3 MeO MeO N Me 5
CO
2 Et (R,S,S)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,S)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 10 (R,S,R)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,R)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S,S,S)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]-6,7-dimethoxy-2 15 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S,R,S)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S,S,R)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or 20 (S,RR)-4-[Acetoxy-(3,5-Bis-trifluoromethyl-phenyl)-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
WO 2004/085401 PCT/IB2004/000836 -254 Example 419 (Stereo-Isomers of Examples 22, 23, 24 and 25)
CF
3 HO
CF
3
F
3 C N Me CO 2 Et (R,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 5 (R,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethy-6 10 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S,S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S,SR)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 15 (S,RS)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-i-carboxylic acid ethyl ester; or (S,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. 20 Example 420
CF
3 F I F
CF
3
F
3 C H N Me
CO
2 Et 4-[(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -255 (R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethy-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 5 (SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or (S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. 10 Example 421 (Stereo-Isomers of Example 15)
CF
3 F I F
CF
3 MeO H MeO N Me CO 2 Et (RR)-4-[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-methyl-6,7 dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-methyl-6,7 15 dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-methy-6,7 dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; or (S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-methyl-6,7 dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 20 or a pharmaceutically acceptable salt of said compound. Example 422 (Stereo-Isomers of Example 182) F F F o F
H
3 c N F F
H
3 c N
H
3 c WO 2004/085401 PCT/IB2004/000836 -256 (R)-4-[(3,5-Bis-trifluoromethyl-benzoyl)]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester; or (S)-4-[(3,5-Bis-trifluoromethyl-benzoyl)]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester; 5 or a pharmaceutically acceptable salt of said compound. Example 423 (Stereo-Isomers of Example 178) F F F F
H
3 C N FF
H
3 CxxN H3C O 0 (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl 3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; 10 (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl 3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; (S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl 3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; or (SS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl 15 3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
WO 2004/085401 PCT/IB2004/000836 -257 Example 424 (Stereo-Isomers of Examples 170, 171, 172, and 173) F F FF F F H3C N F
H
3 C. N F ' H No CH CH 3CH F F F F SFF O CH 7 F,0 3 c N F HHc N H
OH
3 F FF FF FF ,~ C C3 IH H3C,0 F H CNF H 3C N F HH CNF F CH o CH 3 9 CHO C Ha (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 5 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; (S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; or 10 (SS)- 4 -[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound.
WO 2004/085401 PCT/IB2004/000836 -258 Example 425 (Stereo-Isomers of Examples 174 and 175) F F F
H
3 C O F
H
3 C N FE
H
3 C N O O ,CH 3
CH
3 (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid methyl ester; 5 (RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid methyl ester; (S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid methyl ester; or (S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 10 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid methyl ester; or a pharmaceutically acceptable salt of said compound. Example 426 (Stereo-Isomers of Examples 176 and 177) F F F Hc 0 F
H
3 C N F F Hac N 01 OCH 3
H
3 C CHa 15 (RR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester; (S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 20 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester; or WO 2004/085401 PCT/IB2004/000836 -259 (S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester; or a pharmaceutically acceptable salt of said compound. Example 427 (Stereo-Isomers of Example 183) F N FF F F F F 5 F (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; (R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; 10 (SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; or (S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compound. 15 Examples 428 and 429 F F F N F F
H
3 C N F
H
3 C N H3 C O O CH3 (R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl-3,4 dihydro-2H-quinoxaline-1 -carboxylic acid ethyl ester and WO 2004/085401 PCT/IB2004/000836 -260 (R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl-3,4 dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester A mixture of 2-ethyl-6,7-dimethyl-3,4-dihydro-2(R)-H-quinoxaline-1-carboxylic acid ethyl ester (1g, 1 eq, 3.81 mmol), 3,5-bis-(trifluoromethyl-phenyl)-bromo 5 acetonitrile (Preparation 40, 1.27gm, 1eq, 3.81mmol) and 2,6-lutidine (3eq, 11.43mmol) in N,N-dimethylformamide (5mL) was stirred at room temperature for 24 hours. The reaction was partitioned between ethyl acetate and water, and the phases were separated. The aqueous phase was extracted 3 times with ethyl acetate, and the combined organic extracts were washed 2 times with water, 1 time with brine, 10 dried over anhydrous sodium sulfate, filtered and evaporated. Chromatography on silica gel using a gradient of 10-30% ethyl acetate in hexanes as eluant provided the desired nitrile diastereoisomers (1.5:1) (1.0g. and 0.7g, 60%). Isomer 1: LCMS (ESI+): 514 (MH+) 15 1 H-NMR (CDC 3 ) 8 0.88 (t, J=7.5Hz, 3H), 1.29 (t, J=7.1Hz, 3H), 1.49 (m, 2H), 2.21 (s, 3H), 2.22 (s, 3H), 3.03 (dd, J 1 =11.0Hz, J 2 =2.9Hz, IH), 3.19 (dd,
J
1 =11.0Hz, J 2 =5.4Hz, 1H), 4.19 (m, 1H), 4.27 (m, 1H), 4.50 (brm, 1H), 6.05 (s, 1H), 6.59 (s, IH), 7.33 (brs, IH), 7.94 (s, IH), 7.97 (s, 2H). Isomer2: 20 LCMS (ESI+): 514 (MH+) 1 H-NMR (CDCI 3 ) 5 0.76 (t, J=7.48 Hz, 3H), 1.31 (t, J=7.06Hz, 3H), 1.52 (m, 2H), 2.21 (s, 3H), 2.23 (s, 3H), 2.75 (dd, J 1 =11.0Hz, J 2 =2.1Hz, 1H), 3.29 (dd,
J
1 =11.Hz, J 2 =3.73Hz, 1H), 4.19-4.30 (m, 2H), 4.52 (brm, 1H), 6.19 (s, 1H), 6.70 (s,IH), 7.47 (brs, IH), 7.96 (s, 1H), 8.00 (s, 2H). 25 Preparation 42 F I F N 0 0 (R)-2-Ethyl-4-iodo-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester The title compound was prepared using the general procedure described by D.H.R. Barton et al. (Tetrahedron Letters 1983 24, 1605). To a solution of iodine WO 2004/085401 PCT/IB2004/000836 -261 (3.0gm, 9.1mmol) in anhydrous tetrahydrofuran (30mL) under nitrogen was slowly added a solution of 1,1,3,3-tetramethylguanidine (63.7mmol, 8mL) in anhydrous tetrahydrofuran (30mL). The mixture was stirred at room temperature for 10min before addition of (R)-2-ethyl-4-hydrazono-6-trifluoromethyl-3,4-dihydro-2H-quinoline 5 1-carboxylic acid ethyl ester (Preparation 6, 9.1mmol, 3gm) in anhydrous tetrahydrofuran (30mL). After 15min the solvent was removed under vacuum and the residue heated under nitrogen at 850C for 90min. The residue was dissolved in ethyl acetate, washed with 2N hydrochloric acid, aqueous sodium sulfite solution (2.5%), saturated sodium hydrogen carbonate solution and dried over anhydrous sodium 10 sulfate. The crude product was purified by chromatography on silica gel eluting with hexanes/ethyl acetate from 19:1 to 85:15 to give the title compound as a yellow solid (2.8gm, 72%). MS: 426.3 [M+H]* found. 1 H-NMR (CDCIs) 5 7.69 (brs, 1H), 7.61 (brd, J = 8.14Hz, 1H), 7.49 (brd, J = 15 8.14Hz, IH), 6.85 (d, J = 6.64Hz, 1H), 4.87 (m, 1H), 4.27 (m, 2H), 4.15 (m, IH), 1.50 (m, IH), 1.38 (m, 1H), 1.32 (t, J=7.47Hz, 3H), 0.87 (t, J=7.47Hz, 3H). Example 430 F F F HO F F F F N cH F N
CH
3 0 o CH, (RS, RS) and (RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 20 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester To a solution of (RS)-2-ethyl-4-iodo-6-trifluoromethyl-2H-quinoline-1 carboxylic acid ethyl ester (814mg, 1.91 mmol, prepared as described above for the (R) isomer except that racemic starting material was used) in anhydrous tetrahydrofuran (4mL) under nitrogen at -78"C was added dropwise n-butyllithium 25 (2.5M in hexanes, 2.87mmol, 1.15mL). After 5min 3,5 bis(trifluoromethyl)benzaldehyde (6.06mmol, 1 mL) was added dropwise. After 45min at -780C the mixture was allowed to warm to room temperature and after 1hr water WO 2004/085401 PCT/IB2004/000836 -262 was added. The mixture was acidified by addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate from 9:1 to 4:1 5 then further purified by chromatography on silica gel eluting with dichloromethane to give the title compounds as a mixture of diastereoisomers (60mg). MS: 540.3 [M-H]* found. Example 431 F F F cH, / o N~ F F F F F F F / N CHa o 0 cH3 10 (RS, RS) and (RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxy-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester To a solution of the diastereoisomeric mixture (RS, RS) and (RS, SR)-4-[(3,5 bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6-trifluoromethy-2H-quinoline-1 carboxylic acid ethyl ester (Example 430, 32mg, 0.059mmol) in dimethylsulfoxide 15 (3mL) under nitrogen was added powdered potassium hydroxide (0.236mmol, 13mg) followed immediately by iodomethane (0.118mmol, 7.4[tL). The mixture was stirred at room temperature for 2hr then diluted with 2N hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under 20 vacuum. The crude product was purified by chromatography on silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 then 85:15 to give the title compound (13mg) as a mixture of diastereoisomers. Example 432 WO 2004/085401 PCT/IB2004/000836 -263 F F F o N F F F F F F /N o <o CH 3
CH
3 (RS)-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-2H-quinoline-1 carboxylic acid ethyl ester To a solution of the diastereoisomeric mixture (RS, RS) and (RS, SR)-4-[(3,5 5 bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline- 1 carboxylic acid ethyl ester (Example 430, 11mg, 0.020mmol) in anhydrous diethyl ether (1mL) was added manganese (IV) oxide (22mg, activated, -85%, Aldrich Chemical Company, Milwaukee, WI). The suspension was stirred at ambient temperature for 90 min. A second aliquot of manganese (IV) oxide (20mg) was 10 added and stirring was continued for a further 1hr before a third aliquot of manganese (IV) oxide (30mg) was added. After 10min the solid was removed by filtration through Celite@, the solvent was removed under vacuum and the residue was chromatographed on Baker Silica Gel (1gm, 40 pm) (J.T. Baker, Phillipsburg, N.J.) eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 then 85:15 then 15 4:1 to give the title compound (6.6mg). MS: 540.3 [M+H]* found. 1 H-NMR (CDCl 3 ) 8 8.27 (s, 2H), 8.11 (s, 1H), 7.79 (brd, J=8.3Hz, 1H), 7.77 (brs, 1H), 7.57 (brd, J=8.3Hz, IH), 6.56 (d, J=6.64Hz, 1H), 5.18 (m, IH), 4.31 (m, 2H), 1.64 (m, 1H), 1.55 (m, IH), 1.33 (t, J=7.47Hz, 3H), 0.96 (t, J=7.47Hz, 3H). 20 Examples 433 and 434 WO 2004/085401 PCT/IB2004/000836 -264 F F F O H FFO F F H FF F N (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester F F F 0 ' 'FO F H F FF FF0 H FEF F " N 0 0 5 (S, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 7) was resolved on a Pirkle Covalent (S,S)Whelk-0 1 column (Regis 10 Technologies, Inc., Morton Grove, IL) (5 x 25cm) eluting at 1 OOmL/min with 5% ethanol/heptane to provide two fractions: First eluting: (S, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 15 MS: 585.8 [M+H]* found. Second eluting: (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl) methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester; MS: 586.2 [M+H] found.
WO 2004/085401 PCT/IB2004/000836 -265 Examples 435 and 436 F F F 0H F 0 F F 0 5 N (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester F F IFI F F F 5 (R, R, R)-4(,--[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A mixture of (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl 10 ester (Example 433, 98mg, 0.167mmol), aqueous sodium hydroxide (1N, 1mL, 1 mmol) and anhydrous tetrahydrofuran (2.4mL) was stirred at room temperature for 5 days before adding 2N hydrochloric acid to acid pH. The mixture was extracted with ethyl acetate, the organic solution washed with water (x3) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue 15 chromatographed on Baker Silica Gel (1gm, 40 pm) (J.T. Baker, Phillipsburg, N.J.) eluting with a hexanes-ethyl acetate gradient from 0% to 80% ethyl acetate to give the title compounds: First eluting: (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (67mg); WO 2004/085401 PCT/IB2004/000836 -266 MS: 572.4 [M+H]* found. 'H-NMR (CDC 3 ) 5 7.90 (s, 1H), 7.89 (s, 2H), 7.54 (m, 2H), 7.46 (brs, IH), 4.28 (m, 2H), 4.22 (m, 1H), 4.08 (d, J=11.2Hz, 1H), 3.37 (m, 1H), 1.76 (m, 1H), 1.48 (m, 1H), 1.38 (m, 1H), 1.31 (t, J=7.05Hz, 3H), 0.95 (m, 1H), 0.70 (t, J=7.47Hz, 3H). 5 Second eluting: (R, R, R)-4-[(3,5-Bis-tifluoromethyl-phenyl)-carboxy-methyl] 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (29.5mg) MS: 572.3 [M+H]* found "H-NMR (CDCI 3 ) 8 7.94 (s, 2H), 7.83 (s, 1H), 7.50 (d, J=8.14Hz, 1H), 7.41 (brd, 10 J=8.14Hz, 1H), 7.01 (brs, 1H), 4.42 (m, 1H), 4.22 (m, 2H), 4.21 (m, 1H), 3.32 (m,1H), 2.45 (m, 1H), 1.58 (m, 1H), 1.41 (m, 1H), 1.41 (m, 1H), 1.28 (t, J=7.47Hz, 3H), 0.79 (t, J=7.47Hz, 3H). Example 437 F F F OH I FFF F F N C
CH
3 15 (R, R) and (R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester To a solution of (R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester and (R, S) 4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl 20 2H-quinoline-1-carboxylic acid ethyl ester (Examples 3 and 4, used as the mixture obtained prior to separation, 329mg, 0.563mmol) in anhydrous tetrahydrofuran (6mL) under nitrogen at -40*C was added dropwise a solution of lithium aluminum hydride (1 M in tetrahydrofuran, 8 4 5pL, 0.845mmol). After 30min an excess of ethyl acetate was added to quench the reaction and the mixture was allowed to warm to room 25 temperature. The mixture was shaken with water/ethyl acetate, the organic layer washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum. The crude product was purified by chromatography on silica gel eluting with WO 2004/085401 PCT/IB2004/000836 -267 hexanes then hexanes/ethyl acetate 9:1 then 4:1 then 7:3 to give the title compounds as a mixture of diastereoisomers (243mg). MS: 556.3 [M+H]* found. Example 438 F F F H ' F O FF N 5 (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A mixture of (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxy-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 10 (Example 435, 110mg, 0.193mmol) and thionyl chloride (ImL) was stirred at room temperature under nitrogen for 3 days then the excess thionyl chloride was removed under vacuum. To the residue was added a solution of ammonia in dioxane (0.5M, 6mL, 3mmol). After 12hr the mixture was diluted with ethyl acetate, washed with water (x2) and the organic layer was dried over anhydrous sodium sulfate then 15 evaporated to dryness under vacuum. The crude product was purified by chromatography on silica gel eluting with dichloromethane/ethyl acetate 39:1 then 19:1 to give the title compound (1 03mg). MS: 571.3 [M+H]* found. 1 H-NMR (CDCl 3 ) 87.88 (s,1H), 7.88 (s, 2H), 7.51 (m, 2H), 7.46 (brs, 1H), 5.80 20 (brs, 1H), 5.53 (brs, 1H), 4.26 (m, 1H), 4.26 (m, 1H), 4.19 (m, 1H), 3.82 (d, J=10.79Hz, IH), 3.45 (m, 1H), 1.68 (m, 1H), 1.49 (m, 1H), 1.39 (m, 1H), 1.29 (t, J=7.06Hz, 3H), 0.95 (m, IH), 0.70 (t, J=7.47Hz, 3H). The two following compounds were prepared by an analogous procedure utilizing, respectively, methylamine and dimethylamine in place of ammonia: 25 Example 439 WO 2004/085401 PCT/IB2004/000836 -268 F F F N F F O F FA F F N (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methylcarbamoy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS: 585.3 [M+H]* found. 5 Example 440 F F F H FF ~ F /,,,\H F F F I N (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-dimethylcarbamoy-methyl]-2-ethy-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS: 599.3 [M+H]* found. 10 Examples 441 and 442 WO 2004/085401 PCT/IB2004/000836 -269 FF F F F F F F Hll"' N F N (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester F F F N- F FF F FF N\ 5 (R, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carbamoyl methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 438, 30mg, 0.053mmol) in anhydrous dichloromethane (1 mL) was 10 added (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess reagent, 37mg, 0.157mmol). The mixture was stirred at room temperature for 72hr under nitrogen then evaporated under vacuum. The crude product was purified by chromatography on silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 to give the title compounds: 15 First eluting compound: (R, R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (8mg); MS: 553.3 [M+H]* found; WO 2004/085401 PCT/IB2004/000836 -270 'H-NMR (CDCl 3 ) 5 7.96 (s, 1H), 7.90 (s, 2H), 7.60 (m, 2H), 7.56 (brs, 1H), 4.88 (d, J=3.32Hz, 1H), 4.28 (m, 1H), 4.22 (m, 1H), 4.22 (m, 1H), 2.93 (m, 1H), 2.22 (m, 1H), 1.63 (m, 1H), 1.62 (m, IH), 1.51 (m, IH), 1.27 (t, J=7.47Hz, 3H), 0.83 (t, J=7.47Hz, 3H). 5 Second eluting compound: (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (20mg); MS: 553.3 [M+H]* found; 1 H-NMR (CDCl 3 ) 6 7.96 (s, 1H), 7.92 (s, 2H), 7.59 (brs, 1H), 7.57 (m, 2H), 10 4.36 (m, 1H), 4.30 (m, 1H), 4.27 (d, J=8.3Hz, 1H), 4.22 (m, IH), 3.23 (m, IH), 2.08 (m, IH), 1.55 (m, 1H), 1.43 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 1.27 (m, 1H), 0.79 (t, J=7.47Hz, 3H). Preparation 43 (R)-4-Bromo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 15 ethyl ester To a solution of (R, S)-2-ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester (Preparation 13, 3.29gm, 10.37mmo) in dichloromethane (25mL) at ambient temperature under nitrogen was added pyridine (1.58mL) followed dropwise by a solution of phosphorus (111) bromide (1.1mL) in 20 dichloromethane (1 OmL). The mixture was allowed to stir at ambient temperature for 15h then partitioned between water and dichloromethane. The organic layer was washed with saturated sodium hydrogen carbonate solution (2 x 15mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the title compound as a yellow oil (3.79gm) containing an approximately 5:1 25 mixture of diastereoisomers and a variable amount of (R)-2-ethyl-6-trifluoromethyl 2H-quinoline-1-carboxylic acid ethyl ester formed by elimination of hydrogen bromide. The crude bromide was used directly without further purification or stored in the refrigerator to arrest further decomposition. MS: 379, 381 [M].* found (GC-MS). 30 Examples 443 and 444 WO 2004/085401 PCT/IB2004/000836 -271 CI H F F N Cl F N o-0>==o (R, R, R)-4-[Cyano-(3,5-dichloro-phenyl)-methyl]-2-ethyl-6-trifluoromethyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester CI H CVN F7= F N 5 (R, R, S)-4-[Cyano-(3,5-dichloro-phenyl)-methyl]-2-ethyl-6-trifluoromethy-3,4 dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of 3,5-dichlorophenylacetonitrile (134mg, 0.72mmol, prepared according to the procedure described in W00/58292) in anhydrous N,N dimethylformamide (1mL) was added sodium hydride (60% mineral oil dispersion, 10 0.925mmol, 37mg) and the mixture was stirred at room temperature for 30min. A solution of (R)-4-bromo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester (Preparation 43, 250mg, mixture of isomers as prepared above) in anhydrous N,N-dimethylformamide (1.5mL) was added and the mixture was stirred at room temperature for 5min. Water was added and the mixture was 15 extracted with diethyl ether (3 x 20mL) and the organic extract was diluted with heptane and evaporated to dryness to give the crude product as a yellow oil (-400mg). Initial purification was achieved by purified by chromatography on silica gel eluting with hexanes/ethyl acetate 9:1. Fractions containing the title compounds were further purified using radial chromatography (Chromatron model 7924T, Harrison WO 2004/085401 PCT/IB2004/000836 -272 Research, Palo Alto, CA) with a 2mm silica gel rotor eluting with hexanes/ethyl acetate 9:1 to give the title compounds: First eluting compound: (R, R, R)-4-[cyano-(3,5-dichloro-phenyl)-methyl]-2-ethyl-6-trifluoromethyl-3,4 5 dihydro-2H-quinoline-1-carboxylic acid ethyl ester (14mg); 'H-NMR (CDCI 3 ) 6 7.59 (s, 2H), 7.54 (s, 1 H), 7.43 (t, J=1.95Hz, 1 H), 7.35 (d, J=1.95Hz, 2H), 4.69 (d, J=3.52Hz, 1H), 4.28 (m, 1H), 4.22 (m, 1H), 4.22 (m, 1H), 2.90 (m, I H), 2.27 (m, I H), 1.61 (m, I H), 1.50 (m, 1 H), 1.49 (m, 1 H), 1.29 (t, J=7.03Hz, 3H), 0.84 (t, J=7.42Hz, 3H). 10 Second eluting compound: (R, R, S)-4-[cyano-(3,5-dichloro-phenyl)-methyl]-2-ethyl-6-trifluoromethyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester (5mg); MS: 485.2 [M+H]* found; 1 H-NMR (CDC1 3 ) 6 7.59 (s, 1H), 7.55 (s, 2H), 7.42 (t, J=1.66Hz, 1H), 7.33 (d, 15 J=1.66Hz, 2H), 4.34 (m, IH), 4.27 (m, IH), 4.22 (m, 1H), 4.01 (d, J=9.13Hz, 1H), 3.13 (m, 1H), 2.07 (m, 1H), 1.53 (m, IH), 1.42 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 1.16 (m, 1 H), 0.78 (t, J=7.47Hz, 3H). Example 445 F F F 0 ' H FI 20 (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-ethoxycarbony-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A solution of (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxy-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 435, 33mg, 0.058mmol) in anhydrous ethanol (5mL) containing 25 concentrated sulfuric acid (4 drops) was heated under reflux for 18hr then the solvent was evaporated under vacuum. The residue was partitioned between water and ethyl WO 2004/085401 PCT/IB2004/000836 -273 acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel eluting with hexanes then a hexanes/ethyl acetate gradient from 9:1 to 4:6 to give the title compound (1 7.5mg) as a gum. 5 MS: 600.6 [M+H]* found. 1 H-NMR (CDC1 3 ) 8 7.88 (s, 2H), 7.88 (s, 1H), 7.53 (m, 2H), 7.44 (brs, 1H), 4.35 (m, 1 H), 4.27 (m, 2H), 4.22 (m, 1 H), 4.06 (m, 1 H), 4.01 (d, J=1 1.62Hz, 1 H), 3.37 (m, 1H), 1.73 (m, 1H), 1.48 (m, 1H), 1.38 (m, 1H), 1.30 (t, J=7.06Hz, 3H), 1.27 (t, J=7.06Hz, 3H), 0.94 (m, 1H), 0.70 (t, J=7.47Hz, 3H). 10 Example 446 F F F FE F F FE N (R)-4-(3,5-Bis-trifluoromethyl-benzyl)-2-ethyl-6-trifluoromethyl-2H-quinoline-1 carboxylic acid ethyl ester To a solution of (R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl 15 methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester and (R, S) 4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl 2H-quinoline-1-carboxylic acid ethyl ester (Examples 3 and 4, used as the mixture obtained prior to separation, 148mg, 0.253mmol) in tetrahydrofuran (3mL) under nitrogen was added aqueous sodium hydroxide solution (1 M, 250pL, 0.25mmol). 20 After stirring at room temperature for 72hr an additional aliquot of aqueous sodium hydroxide solution (1M, 100 1., 0.1mmol) was added. After 72hr the mixture was acidified by addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under vacuum and the residue was purified by chromatography on silica gel eluting with 25 dichloromethane/hexanes 1:1 then 3:1 followed by dichloromethane then WO 2004/085401 PCT/IB2004/000836 -274 dichloromethane/methano 9:1 then a hexanes/ethyl acetate gradient from 9:1 to 4:6 to give the title compound (4.5mg). MS: 526.3 [M+H]* found. 1 H-NMR (CDC 3 ) 8 7.76 (s, 1H), 7.74 (m, 1H), 7.68 (s, 2H), 7.48 (m, 1H), 7.42 5 (brs, 1H), 5.76 (d, J=5.81Hz, 1H), 4.93 (m, 1H), 4.27 (m, 2H), 3.92 (m, IH), 3.88(m, 1H), 1.48 (m, 1H), 1.38 (m, 1H), 1.32 (t, J=7.47Hz, 3H), 0.85 (t, J=7.47Hz, 3H). Example 447 F F F H HH F F ,,,H F F N F 0 0 (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6 10 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of (R, R, S)-4-[(3,5-bis-trifluoromethyl-pheny)-carboxy-methyl] 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 435, 67mg, 0.11 7mmol) in tetrahydrofuran (1 mL) under nitrogen was added borane-dimethylsulfide complex (22.2pL, 0.234mmol). After 24hr aqueous 15 sodium hydroxide (1M, 4 drops) was added to quench the reaction and the mixture was allowed to stir for 1 hr. The mixture was acidified by addition of 2N hydrochloric acid, stirred for 10min and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated under vacuum. The crude product was purified by chromatography on 20 silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 then 4:1 then 3:7 and finally 2:3 to give the title compound (54mg). MS: 558.3 [M+H]* found. 'H-NMR (CDCI 3 ) 8 7.83 (s, 1H), 7.80 (s, 2H), 7.60 (brs, 1H), 7.52 (m, 2H), 4.27 (m, 1H), 4.24 (m, 2H), 4.20 (m, 1H), 4.00 (m, 1H), 3.54 (m, IH), 2.84 (m, 1H), 25 1.82 (m, 1H), 1.63 (brs, 1H), 1.46 (m, 1H), 1.32 (m, 1H), 1.31 (t, J=7.05Hz, 3H), 0.87 (m, 1H), 0.69 (t, J=7.47Hz, 3H).
WO 2004/085401 PCT/IB2004/000836 -275 Preparation 44 Methyl (3,5-dichloro)-phenylacetate A mixture of 3,5-dichlorophenylacetonitrile (2gm, prepared according to the procedure described in WOOO/58292), ethanol (25mL), potassium hydroxide 5 (3.95gm) and water (1 OmL) was heated under reflux for 4hr then evaporated to dryness under vacuum. The residue was partitioned between water (20mL) and diethyl ether and the aqueous layer was acidified to pHI by addition of concentrated hydrochloric acid. The mixture was extracted with diethyl ether (3 x 25mL), the organic layer dried over anhydrous sodium sulfate and evaporated under vacuum. 10 The carboxylic acid was dissolved in methanol (20mL) and trimethylsilyldiazomethane (2M solution in hexanes, 30mL, Aldrich Chemical Company, Milwaukee, WI) was added slowly. After 1 hr the solvent was removed under vacuum, the residue dissolved in diethyl ether, washed with aqueous sodium carbonate solution (2M), dried over anhydrous sodium sulfate and evaporated to dryness to give the title 15 compound (2.1gm). H-NMR (CDCl 3 ) 8 7.27 (s,1H), 7.17 (s, 2H), 3.71 (s, 3H), 3.57 (s, 2H). Examples 448, 449, 450 and 451 Cl 0 F OCI IFN H O O (R, S, R)-4-[(3,5-Dichloro-phenyl)-methoxycarbony-methyl]-2-ethyl-6-trifluoromethyl 20 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -276 C1 O CI H F -C F ,H F N O O0 (R, R, S)-4-[(3,5-Dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester Ci 0 Cl | H F 0 FF HO F N 0O 5 (R, S, S)-4-[(3,5-Dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester CI CI HO F O F H F (R, R, R)-4-[(3,5-Dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 10 To a solution of methyl (3,5-dichloro)-phenylacetate (311 mg, 1.42mmol) in anhydrous N,N-dimethylformamide (3mL) was added sodium hydride (60% mineral oil dispersion, 1.93mmol, 77mg) and the mixture was stirred at room temperature for 30min. A solution of (R)-4-bromo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline I -carboxylic acid ethyl ester (490mg, mixture of isomers, Preparation 43) in WO 2004/085401 PCT/IB2004/000836 -277 anhydrous N,N-dimethylformamide (5mL) was added and the mixture was stirred at room temperature for 5min. Water was added and the mixture was extracted with diethyl ether (3 x 20mL) and the organic extract was diluted with heptane and evaporated to dryness to give the crude product as a yellow oil (-460mg). Purification 5 was achieved using radial chromatography (Chromatron model 7924T, Harrison Research, Palo Alto, CA) with a 4mm silica gel rotor eluting with hexanes/ethyl acetate 9:1 and subsequently rechromatographing appropriate fractions eluting with dichloromethane/hexanes 45:55 to give the title compounds: (R, S, R)-4-[(3,5-dichloro-phenyl)-methoxycarbony-methyl]-2-ethyl-6 10 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (10mg); MS: 518.3 [M+H]* found; 'H-NMR (CDCl 3 ) 6 7.55 (brd, J=8.30Hz, 1 H), 7.49 (brd, J=8.3OHz, 1 H), 7.48 (brs, 1 H), 7.33 (m, 2H), 7.33 (m, I H), 4.33 (m, I H), 4.31 (m, 1 H), 4.24 (m, 1 H), 3.56 (d, J=1 1.62Hz, 1 H), 3.52 (m, I H), 3.46 (s, 3H), 1.86 (m, 1 H), 1.53 (m, 1 H), 1.47 (m, 15 2H), 1.34 (t, J=7.47Hz, 3H), 0.74 (t, J=7.47Hz, 3H). (R, R, S)-4-[(3,5-dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (24mg); MS: 518.3 [M+H]* found; 1 H-NMR (CDCl 3 ) 6 7.52 (m, 1H), 7.50 (m, IH), 7.35 (t, J=1.66Hz, 1H), 7.32 20 (brs, 1H), 7.30 (d, J=1.66Hz, 2H), 4.30 (m, 1H), 4.27 (m, 1H), 4.20 (m, 1H), 3.78 (d, J=11.61Hz, 1H), 3.74 (s, 3H), 3.28 (m, 1H), 1.85 (m, iH), 1.49 (m, 1H), 1.39 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 0.91 (m, 1 H), 0.72 (t, J=7.47Hz, 3H). (R, S, S)-4-[(3,5-dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (29mg); 25 MS: 518.3 [M+H]* found; 'H-NMR (CDCl 3 ) 6 7.43 (d, J=8.30Hz, 1H), 7.36 (dd, J=8.30, 1.66Hz, 1H), 7.15 (t, J=1.66, 1H), 6.88 (d, J=1.66Hz, 2H), 6.69 (brs, 1H), 4.45 (m, 1H), 4.32 (m, 1H), 4.31 (m, 1H), 3.75 (s, 3H), 3.62 (d, J=10.79Hz, 1H), 3.40 (m, 1H), 2.88 (m, IH), 1.75 (m, 1H), 1.64 (m, 1H),1.48 (m, IH), 1.34 (t, J=7.47Hz, 3H), 0.83 (t, J=7.47Hz, 30 3H). (R, R, R)-4-[(3,5-dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (18mg); MS: 518.3 [M+H]* found; WO 2004/085401 PCT/IB2004/000836 -278 'H-NMR (CDCi 3 ) 6 7.51 (brd, J=8.59Hz, 1H), 7.43 (brd, J=8.59Hz, 1H), 7.33 (m, 2H), 7.31 (m, 1H), 7.10 (brs, 1H), 4.40 (m, 1H), 4.28 (m, IH), 4.23 (m, 1H), 4.06 (d, J=10.15Hz, 1H), 3.74 (s, 3H), 3.24 (m, IH), 2.32 (m, IH), 1.64 (m, IH), 1.47 (m, 1H),1.37 (m, 1H), 1.32 (t, J=7.02Hz, 3H), 0.83 (t, J=7.47Hz, 3H). 5 Example 452 F O C l F FH F N o-O (R, R, S)-4-[(3,4-Dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of methyl (3,4-dichloro)-phenylacetate (1.22gm, 5.57mmol) in 10 anhydrous N,N-dimethylformamide (5mL) was added sodium hydride (60% mineral oil dispersion, 7mmol, 280mg) and the mixture was stirred at room temperature for 5min. A solution of (R)-4-bromo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester (798mg, mixture of isomers, Preparation 43) in anhydrous N,N-dimethylformamide (4mL) was added and the mixture was stirred at room 15 temperature for 15min. Water was added and the mixture was acidified by addition of 2N hydrochloric acid then extracted with dichloromethane (x 3) and the organic extract was dried over anhydrous sodium sulfate and evaporated to dryness to give a yellow oil. This was dissolved in tetrahydrofuran (10mL) and water (5mL) and aqueous sodium hydroxide (2N, 1 OmL) was added. The mixture was stirred at room 20 temperature for 24hr then partitioned between hydrochloric acid (0.1 N) and dichloromethane. The organic extract was dried over anhydrous sodium sulfate and evaporated to dryness to give a mixture of carboxylic acids. This material was purified by chromatography on silica gel eluting with hexanes/ethyl acetate 5:1 then 4:1. Fractions containing the first carboxylic acid to elute (with the desired R, R, S 25 stereochemistry) were combined, evaporated to dryness under vacuum and dissolved in methanol (25mL). Trimethylsilyldiazomethane (2M solution in hexanes, Aldrich Chemical Company, Milwaukee, WI) was added slowly until effervescence ceased and a yellow color persisted. This was discharged by addition of a small WO 2004/085401 PCT/IB2004/000836 -279 amount of acetic acid then the solvent was removed under vacuum and the residue was purified by chromatography on silica gel eluting with a hexanes/dichioromethane gradient from 2:1 to 1:2. Final purification was achieved using reverse phase HPLC using the Shimadzu preparative HPLC system (Shimadzu Corporation, Kyoto, Japan) 5 eluting with a 30-100% acetonitrile/water/0. 1 % formic acid gradient on a 19x5Omm Waters Symmetry Column (Waters Corp, Milford, MA) 8 min run, 6 min gradient, 25mL/min, UV triggered collection, observing at 21Onm. The product-containing fractions were evaporated to dryness to give the title compound (75mg). MS: 518.3 [M+H]* found. 10 1 H-NMR (CDCI 3 ) 5 7.52 (m, 1H), 7.51 (m, IH), 7.50 (m, IH), 7.47 (d, J=8.3Hz, 1H), 7.34 (brs, 1H), 7.25 (dd, J=8.3, 2.49Hz, 1H), 4.28 (m, IH), 4.27 (m, IH), 4.20 (m, 1H), 3.80 (d, J=11.62Hz, 1H), 3.73 (s, 3H), 3.29 (m, 1H), 1.86 (m, 1H), 1.50 (m, 1H), 1.37 (m, 1H), 1.30 (t, J=7.47Hz, 3H), 0.90 (m, 1H), 0.71 (t, J=7.47Hz, 3H). Example 453 F F 0-F F F F FF F F N o o CH 3 15 cHa (R, S) and (R, R)-4-[2-Acetoxy-1 -(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of the diastereoisomeric mixture (R, R) and (R, S)-4-[1-(3,5-bis trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1 20 carboxylic acid ethyl ester (Example 437, 57mg, 0.102mmol) in dichloromethane (1 mL) under nitrogen was added triethylamine ( 4 3plL, 0.306mmol) followed by acetyl chloride (9pL, 0.132mmol). After 3hr the mixture was partitioned between water and dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by chromatography 25 on silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 then 4:1 then 3:7 and finally 2:3 to give the title compound as a mixture of diastereoisomers (51mg).
WO 2004/085401 PCT/IB2004/000836 -280 MS: 598.3 [M+H]* found. Example 454 F F F H F F H FF F N 0 O (R, R, S)-4-[2-Acetoxy-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6 5 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of (R, R, S)-4-[1-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 447, 50mg, 0.0896mmol) in dichloromethane (1 mL) under nitrogen was added triethylamine (37pL, 0.269mmol) followed by acetyl chloride (8.3pL, 10 0.11 6mmol). After 30min the mixture was partitioned between water and dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 then 4:1 to give the title compound (41mg). 15 MS: 600.4 [M+H]* found. 1 H-NMR (CDCi 3 ) S 7.88 (s, 1H), 7.85 (s, 1H), 7.73 (s, 2H), 7.64 (m, IH), 7.62 (m, 1H), 4.80 (dd, J=11.62, 4.15Hz, 1H), 4.29 (m, 1H), 4.25 (m, 1H), 4.23 (m, 1H), 4.20 (m, 1H), 3.72 (ddd, J=9.13, 9.13, 3.32Hz, IH), 2.79 (m, IH), 1.97 (s, 3H), 1.84 (m, 1H), 1.46 (m, 1H), 1.32 (m, IH), 1.31 (t, J=7.47Hz, 3H), 0.87 (m, IH), 0.69 (t, 20 J=7.47Hz, 3H). Example 455 WO 2004/085401 PCT/IB2004/000836 -281 F F F -F pHF F F 0 0 (R, R, S)-4-[I-(3,5-Bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of (R, R, S)-4-[1-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy 5 ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (Example 447, 20mg, 0.035mmol) in tetrahydrofuran (1mL) under nitrogen was added sodium hydride (60% mineral oil dispersion, 0.043mmol, 1.7mg) followed after 5min by iodomethane (2 drops). After stirring for 16hr additional aliquots of sodium hydride (2mg) and iodomethane (3 drops) were added. The mixture was stirred at 10 room temperature for 48hr then diluted with ethyl acetate. The mixture was washed with water, the organic layer separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The crude product was purified by chromatography on silica gel eluting with hexanes then hexanes/ethyl acetate 19:1 then 9:1 to give the title compound (19mg). 15 MS: 572.5 [M+H]* found. 1 H-NMR (CDCI 3 ) 5 7.81 (s, 1H), 7.76 (s, 2H), 7.61 (brs, 1H), 7.52 (m, 2H), 4.27 (m, 1H), 4.24 (m, 1H), 4.21 (m, IH), 3.89 (dd, J=9.96, 3.32Hz, 1H), 3.74 (dd, J=9.13, 7.47Hz, 1H), 3.55 (m, 1H), 3.29 (s, 3H), 2.85 (m, 1H), 1.80 (m, 1H), 1.47 (m, 1H), 1.32 (m, 1H), 1.31 (t, J=7.47Hz, 3H), 0.87 (m, 1H), 0.69 (t, J=7.47Hz, 3H). 20 Example 456 WO 2004/085401 PCT/IB2004/000836 -282 F F F F H F F FF N FF F 0)0 (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-fluoro-ethyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of (R, R, S)-4-[1-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy 5 ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 447, 20mg, 0.035mmol) in dichloromethane (1mL) under nitrogen was added diethylaminosulfur trifluoride (47pL, 0.358mmol). The mixture was stirred at room temperature for 3hr then a further aliquot of diethylaminosulfur trifluoride (47pL, 0.358mmol) was added. After 1 hr the mixture was partitioned between water and 10 dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was initially purified by chromatography on silica gel eluting with hexanes/ethyl acetate 19:1 then 19:1 then 9:1 and finally purified by reverse phase hplc using the Shimadzu preparative HPLC system (Shimadzu Corporation, Kyoto, Japan) eluting with a 30-100% 15 acetonitrile/water/0. 1% formic acid gradient on a 19x50mm Waters Symmetry Column (Waters Corp, Milford, MA) 8 min run, 6 min gradient, 25mL/min, UV triggered collection, observing at 21 Onm. The product-containing fractions were evaporated to dryness to give the title compound (3mg). MS: 560.3 [M+H]* found. 20 'H-NMR (CDC1s) 5 7.86 (s, 1H), 7.80 (s, 2H), 7.55 (m, 2H), 7.54 (s, 1H), 4.93 (ddd, J=46.47, 9.96, 4.14Hz, 1H), 4.82 (ddd, J=46.47, 9.96, 6.64Hz, 1H), 4.28 (m, 1H), 4.27 (m, 1H), 4.23 (m, IH), 3.72 (m, 1H), 2.91 (m, 1H), 1.88 (m, 1H), 1.48 (m, 1H), 1.34 (m, 1H), 1.32 (t, J=7.47Hz, 3H), 0.92 (m, IH), 0.71 (t, J=7.47Hz, 3H). Example 457 WO 2004/085401 PCT/IB2004/000836 -283 F F IF NH2 H2 F F F F H FF ,,H N (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-amino-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carbamoyl 5 methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 438, 25mg, 0.0438mmol) in tetrahydrofuran (3mL) under nitrogen was added borane-dimethylsulfide complex (8.3tL, 0.0876mmol). The mixture was heated at 70 0 C for 48hr then water (2.5mL) and saturated aqueous sodium carbonate solution (1 mL) was added. The mixture was heated at 70 0 C for 1 hr then partitioned 10 between water and dichloromethane. The organic layer was evaporated to dryness under vacuum and the residue dissolved in diethyl ether (5mL) and 2N hydrochloric acid (1mL) added. After 24hr the mixture was diluted with water, sodium carbonate solution added and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under 15 vacuum. The crude product was purified by chromatography on silica gel eluting with hexanes/ethyl acetate 3:1 then ethyl acetate give the title compound (18.5mg). MS: 557.4 [M+H]* found. 1 H-NMR (CDCl 3 ) 6 7.84 (s, 1 H), 7.77 (s, 2H), 7.58 (brs, I H), 7.52 (m, 2H), 4.27 (m, 1H), 4.23 (m, 1H), 4.22 (m, 1H), 3.44 (dd, J=13.28, 3.32Hz, 1H), 3.35 (m, 20 1H), 3.09 (dd, J=13.28, 9.13Hz, 1H), 2.76 (m, 1H), 1.76 (m, 1H), 1.45 (m, 1H), 1.34 (m, 1H), 1.31 (t, J=7.47Hz, 3H), 0.84 (m, 1H), 0.69 (t, J=7.47Hz, 3H). Examples 458, 459, 460 and 461 WO 2004/085401 PCT/IB2004/000836 -284
CF
3 H I HO
CF
3
F
3 C %H N
-
Me N
CO
2 Et [(R, S, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester
CF
3 H I HO :: - CF 3
F
3 C H N Me
CO
2 Et 5 [(R, R, R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester
CF
3 H I HO
CF
3
F
3 C N M NI Me
CO
2 Et [(R, R, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester
CF
3 H I HO~ 7 CF 3
F
3 C CF3 N Me 10 CO 2 Et [(R, S, R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -285 These compounds (previously prepared in Examples 22, 23, 24 and 25) were prepared in optically enriched form by resolution of the corresponding racemate indicated, or an intermediate in its synthesis, using methods analogous to those described herein. 5 Examples 462, 463, 464 and 465
CF
3
H
2 N
CF
3
F
3 C N Me CO 2 Et Preparation of [(R, R, R)], [(R, R, S)], [(R, S, S)], and [(R, S, R)]-4-[Amino-(3,5-bis trifluoromethyl-phenyl)-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester 10 General procedure to make amine compounds: [(R, R, R)J-4-(3,5-bis trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester (0.527 grams, 0.971 mmol, I eq) was placed in a round bottomed flask equipped with a magnetic stir bar. Methylene chloride (20 mL) was added followed by the addition of triethylamine (0.456 mL, 3.37 mmol, 3.37 15 eq) and mesyl chloride (0.150 mL, 1.94 mmol, 2.0 eq) at room temperature and the reaction mixture was stirred overnight. The reaction mixture was quenched with water, extracted 4 times with ethyl acetate. The organic layer was washed with 0.1 M HCl, followed by saturated bicarbonate solution and dried over sodium sulfate. The solution was filtered, concentrated and dried on the high vacuum to provide [(R, R, 20 R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-methanesulfonyloxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoine-1 -carboxylic acid ethyl ester (0.599 grams, 99% yield) as a white solid, MS (ES+) m/z=622 (M+1). [(R, R, R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-methanesulfonyloxy-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.313 25 grams, 0.504 mmol, 1 eq) was placed in a round bottomed flask equipped with a magnetic stir bar. DMF (12 mL) was added followed by the addition of sodium azide (0.201 grams, 0.3.10 mmol, 6.1 eq). The reaction mixture was heated to 700C for 12 hours. The reaction mixture was cooled to room temperature, diluted into 200 mL of WO 2004/085401 PCT/IB2004/000836 -286 EtOAc and washed 4 times with brine and water. The EtOAc was collected, dried over sodium sulfate, filtered and concentrated. The material was purified on a Biotage flash 40s to provide [(R, R, S)]-4-[Azido-(3,5-bis-trifluoromethyl-phenyl) methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl 5 ester 0.202 grams, 71% yield) MS (ES+) m/z=569 (M+1). [(R, R, S)]-4-[Azido-(3,5-bis-trifluoromethyl-phenyl)-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester ( 0.202 grams, 0.356 mol, 1 eq) was placed in a round bottomed flask and equipped with a magnetic stir bar and reflux condenser. NH 4
CO
2 H (0.226 grams, 3.58 mol, 10.1 eq) 10 and Pd/C (0.113 grams, 0.107 mol, 0.30 eq) was added followed by the addition of a 2:1 solution of methanol and ethyl acetate (8.80 mL). The reaction mixture was refluxed for 2 hours and then filtered through Celite. The fitrate was concentrated but not to dryness and partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was collected, dried over sodium sulfate, 15 filtered and concentrated. The crude material was purified on Biotage Flash 40 M to provide the desired compound, [(R, R, S)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl) methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.162 grams, 83% yield) MS (ES+) m/z=543 (M+1). 'H NMR (CDC3l): 5 0.82 (t, 3H), 1.32 (t, 3H), 1.34-1.57 (m, 3H), 2.53 (m, 20 1H), 3.00 (m, 1H), 4.28 (q, 2H), 4.50 (d, 1H), 4.54 (m, IH), 7.03 (s, 1H), 7.42 (d, IH), 7.60 (d, IH), 7.66 (s, 2H), 7.72 (s, 1H). MS (ES+) m/z=543 (M+1). These additional compounds were prepared using analogous procedures to those described herein:
CF
3 H I
H
2 N
CF
3
F
3 C HMe N Me 25 CO 2 Et [(R, S, S)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester: WO 2004/085401 PCT/IB2004/000836 -287 'H NMR (CDCIa): 8 0.71 (t, 3H), 1.00 (m, 1H), 1.29 (t, 3H), 1.33-1.52 (m, 2H), 1.67 (m, IH & H 2 0), 2.70 (m, IH), 4.15-4.31 (m, 3H), 4.47 (d, IH), 7.51 (m, 2H), 7.84 (s, IH), 7.89 (s, 2H), 7.91 (s, 1H); MS (ES+) m/z=543 (M+1).
CF
3 H I
H
2 N :
CF
3
F
3 C H N Me 5
CO
2 Et [(R, R, R)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester: HNMR (CDCl 3 ): 8 0.75 (t, 3H), 1.33 (t, 3H), 1.37-1.62 (m, 3H), 1.82 (m, IH), 2.98 (m, 1H), 4.17-4.36 (m, 4H), 7.51 (s, 1H), 7.53-7.61 (m, 2H), 7.83 (s, 1H), 7.86 10 (s, 2H); MS (ES+) m/z=543 (M+I).
CF
3 H I
H
2 N - &
CF
3
F
3 C "'C (N Me
CO
2 Et [(R, S, R)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-ethyl-6-2 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester: 15 HNMR (CDCl 3 ): 5 0.82 (t, 3H), 1.27 (t, 3H), 1.40-1.64 (m, 3H), 2.07 (m, 1H), 2.76 (m, 1H), 4.09-4.27 (m, 3H), 5.07 (m, 1H), 7.55 (q, 2H), 7.66 (s, IH), 7.83 (s, 1 H), 7.96 (s, 2H); MS (ES+) m/z=543 (M+1). Example 466, 467, 468 and 469 20 The following compounds were prepared from starting materials and procedures analogous to those described above, particularly in Examples 18, 19, and 456.
WO 2004/085401 PCT/IB2004/000836 -288
CF
3 H I F i
CF
3
F
3 C ,%H N' Me
CO
2 Et [(R, S, R)]-4-(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester 'H-NMR (CDC 3 ): 5 7.92 (s, 1H), 7.83 (s, 2H), 7.67 (s, 1H), 7.57 (s, 2H), 6.5 5 (d, 1H), 4.24 (m, 3H), 2.91(dd, 1H), 2.08 (m, 1H), 1.51 (m, 3H), 1.27 (t, 3H), 0.80 (t, 3H); MS: 546.3 [M+H]+ found.
CF
3 H F
CF
3
F
3 C Mvje N M
CO
2 Et [(R, S, S)]-4-(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-2-ethyl-6 10 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester 1 H-NMR (CDC 3 ): 5 7.96 (s, 1H), 7.88 (s, 2H), 7.76 (s, 1H), 7.55 (s, t, 2H), 5.86 (dd, J=9.13 Hz, 1H), 4.25 (m, 3H), 3.10 (m, 1H), 1.75 (m, 1H), 1.47 (m, 2H), 1.29 (t, 3H), 1.18 (t, 3H), 0.77 (t, 3H); MS: 546.4 [M+H]+ found.
CF
3 H F
CF
3
F
3 C H N Me 15 CO 2 Et [(R, R, S)]-4-(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -289 'H-NMR (CDCI 3 ): 8 7.8 (s, IH), 7.59 (d, IH), 7.47 (d, IH), 7.43 (s, 2H), 6.86 (s, 1H), 5.65 (dd, J=7.88 Hz, 1H), 4.60 (m, 1H), 4.28 (m, 2H), 3.21 (m, IH), 2.65 (m, 3H), 1.74 (m, 1H), 1.41-1.62 (m, 2H), 1.31 (t, 3H), 0.86 (t, 3H); MS: 546.3 [M+H]+ found
CF
3 F CF3
F
3 C H N Me 5
CO
2 Et [(R, R, R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 'H-NMR (CDCIs): 5 7.88 (s, 1H), 7.63 (s, d, 3H), 7.52 (d, 1H), 7.41(s, 1H), 5.58 (dd, J=7.47 Hz, 1H), 4.42 (m, 1H), 4.24 (m, 2H), 3.40 (m, 1H), 1.97 (m, 1H), 10 1.74 (m, IH), 1.41 (m, 2H), 1.27 (t, 3H), 0.79 (t, 3H); MS: 546.3 [M+HJ+ found. Examples 470, 471, 472 and 473 The following compounds were prepared from starting materials and procedures analogous to those described above, as shown in Scheme 2 whereby 15 the addition of a suitable organometallic derivative such as magnesium or lithium derivative, prepared from a compound alkyl-Hal, wherein Hal represents a chlorine, bromine or iodine atom to XXV produced compounds shown in examples 470, 471, 472 and 473. [(R,R), (S,S)]-4-[(3,5-Bis-trifluoromethyl-benzoyl)]-6,-trifluoromethy -2-ethyl 20 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.015 grams, 0.028 mmol) was placed in a small round bottomed flask containing a magnetic stir bar and dissolved in 0.50 mL of tetrathydrofuran. Methyl magnesium bromide solution (0.028 mL of 3.0 M in diethylether) was added to the reaction mixture at room temperature and stirred for 2 hours. The reaction mixture was then quenched with saturated 25 ammonium chloride solution and extracted into ethyl acetate. The organic layer was washed with water, dried over magnesium sulafte, filtered and concentrated to provide the desired products as an crude oil. The alcohol diastereomers were separated by silica gel chromatography to provide [(R, R, R)],-4-[(3,5-bis- WO 2004/085401 PCT/IB2004/000836 -290 trifluoromethyl-phenyl)-1-hydroxyl- ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H quinoline-1-carboxylic acid ethyl ester and [(R, R, S)]-4-[(3,5-bis-trifluoromethyl phenyl)-1-hydroxyl- ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 carboxylic acid ethyl ester.
CF
3 CF 3 OH I OH I Me
CF
3 Me-
CF
3
F
3 C H F 3 C H N Me N Me 5
CO
2 Et
CO
2 Et [(R, R, R)], (R, R, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-1-hydroxyl- ethyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester First eluting compound: 1 H-NMR (CDC 3 ): 5 7.86 (s, 2H), 7.80 (s, 1 H), 7.53 (dd, 2H), 7.34 (s, IH), 4.3 (m, 2H), 4.18 (m, 1H), 3.18 (m, 1H), 1.95 (m, 1H), 1.80 (s, 10 1H), 1.5-1.63 (m, 4H), 1.24 - 1.45 (m, 5H), 0.70 (t, 3H); MS: 588.3 [M+H]+ found. Second eluting compound:'H-NMR (CDC 3 ): 5 7.76 (m, 3H), 7.53 (d, 1 H), 7.42 (d, 1H), 7.06 (s, 1H), 4.41 (m, IH), 4.2 (q, 2H), 3.18 (m, 1H), 2.30 (m, 1H), 1.91 (br s, 1 H), 1.62-1.74 (m, 4H), 1.24 - 1.43 (m, 5H), 0.77 (t, 3H); 15 MS: 588.3 [M+H]+ found.
CF
3 CF 3 OH I OH I Me CF 3 Me CF 3
F
3 C o\H
F
3 C N Me / N',Me
CO
2 Et
CO
2 Et [(R, S, R)], (R, S, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-1 -hydroxyl- ethyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester First eluting compound: 1 H-NMR (CDCl 3 ): 8 7.86 (s, 1 H), 7.80 (s, 1 H), 7.70 20 (s, 1H), 7.55 (m ,2H), 7.35 (s, 1H), 4.3 (m, 2H), 4.19 (m, 1H), 3.20 (m, 1H), 1.91 (m, IH), 1.60 (s, 3H), 1.30 (t, 3H), 0.70 (t, 3H); MS: 556.2 [M-H]~ found.
WO 2004/085401 PCT/IB2004/000836 -291 Second eluting compound:H-NMR (CDC 3 ): 5 8.0 (s, 2H), 7.80 (s, 1H), 7.50 (brs, I H), 7.40 (dd, 2H), 4.4 (br m, I H), 4.20 (m, 2H), 3.05 (d, 1 H), 2.55 (br m, 1 H), 1.74 (s, 3H), 1.63 (m, 1 H), 1.43 (m, 2H), 1.30 (t, 3H), 0.90 (t, 3H); MS: 558.3 [M+H]* found. 5 Example 474 and 475 The following compounds were prepared from starting materials and procedures analogous to those described in Scheme 1 above, particularly in Example 2.
CF
3 CF 3 OOH OOH MeO CF 3 MeO CF 3 MeO MeO MeO N Me MeO t N Me
CO
2 Et CO 2 Et 10 [(R, R)], (R, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-1-hydroxyl methoxycarbonyl-methyl]- 6,7-dimethoxy-2-methyl-2H-quinoline-1-carboxylic acid ethyl ester Diastereomer 1: 1 H-NMR (CDC 3 ): 8 7.92 (s, 2H), 7.73 (s, 1H), 6.81 (s, 1H), 5.80 (d, IH), 5.20 (br m, 1H), 4.40 (brs, IH), 4.30 (m, IH), 4.20 (br m, 1H), 3.84 (s, 15 3H), 3.80 (s, 3H), 3.50 (s, 3H), 1.34 (m, 4H), 1.09 (d, 3H); MS: 578.5 [M+H]+ found. Diastereomer 2: 'H-NMR (CDC 3 ): 6 8.18 (s, 2H), 7.87 (s, 1H), 6.67 (s, IH), 5.65 (br s, 1 H), 5.15 (br s, 1 H), 4.31 (brm, 1 H), 4.20 (br m, 1 H), 3.86 (s, 3H), 3.80 (s, 3H), 3.58 (s, 3H), 1.33 (t, 3H), 1.09 (d, 3H); 20 MS: 578.6 [M+H]+ found. (Examples 476 and 477 The following compounds were prepared from starting materials and procedures analogous to those described in Scheme 1 above, particularly in Examples 7 and 8.
WO 2004/085401 PCT/IB2004/000836 -292
CF
3 OH I MeO
CF
3 MeO MeO N Me
CO
2 Et [(R, S, R), (R, S, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl- methoxycarbonyl methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 5 First Eluting: 1 H NMR (CDC 3 ): 8 8.18 (s, 2H), 7.88 (s, 1H), 7.03 (br s, 1H), 6.73 (s, 1H), 4.31 (m, 1H), 4.20 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.81 (s, 3H), 3.30 (d, 1H), 1.70 (m, 2H), 1.21 -1.30 (t, m, 4H), 1.09 (d, 3H); MS: 580.6 [M+H]+ found. Second Eluting: 1 H NMR (CDC 3 ): 6 8.25 (s, 2H), 7.84 (s, 1H), 6.92 (br s, 10 1H), 6.30 (s, 1H), 4.55 (m, 1H), 4.30 (m, IH), 4.20 (m, 1H), 3.88 (s, 3H), 3.80 (s, 3H) 3.60 (d, IH), 3.40 (s, 3H), 2.03 (m, 2H), 1.55 (m, 1H), 1.32 (t, 3H) 1.09 (d, 3H); MS: 580.5 [M+H]+ found. Examples 478 and 479 The following compounds were prepared from starting materials and 15 procedures analogous to those described above, particularly in Examples 448, 449, 450 and 451. [(R, R, R)], (R, R, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester F F F 0 F HO'3C 0 F HC F N
CH
3
H
3 C O O CH 20 0 H WO 2004/085401 PCT/IB2004/000836 -293 'H NMR (CDC[,): S 7.97 (s, 2H), 7.83 (s, 1H), 7.0 (brs, 1H), 6.20 (s, 1H), 4.50 (m, 1H), 4.30 (m, 1H), 4.30 (m, 1H), 4.19 (m, 1H), 4.17 (d, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.51 (s, 3H), 3.32 (m, 1H), 2.30 (m, 1H), 1.31 (t, 3H), 1.20 (d, 3H); MS: 564.5 [M+H]+ found. F F F S,0 F~
H
3 C O F
H
3 0 F N
CH
3 5 ,H3C O O CH 3 1 H NMR (CDC13): 6 7.87 (s, 3H), 7.03 (br s, 1H), 6.72 (s, 1H), 4.31 (m, 2H), 4.20 (m, 1H), 3.98 (d, IH), 3.86 (s, 6H), 3.75 (s, 3H), 3.32 (t, 1H), 1.70 (m, 1H), 1.30 (t, 3H), 1.07 (d, 3H), 0.80 (m, 1H); MS: 564.4 [M+H]+ found. 10 Example 480 The following compound was prepared from starting materials and procedures analogous to those described above, particularly in Examples 470, 471, 472 and 473. [(R, R, R)], (R, R, S)]-4-[(3,5-bis-trifluoromethyl-phenyl)-1-hydroxyl- ethyl] 15 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.079 grams, 0.142 mmol) was placed in a small round bottomed flask containing a magnetic stir bar and dissolved in 1.5 mL of anhydrous chloroform. To this reaction solution, 2,6-di-t-butyl-4-methylpyridine (0.117 grams, 0.568 mmol) and thionyl chloride (0.051 grams, 0.425 mmol) was added and allowed to stir at room 20 temperature for four hours. The reaction mixture was quenched with water and extracted into methylene chloride. The organic layers was washed with 0.1 N HCl, dried over magnesium sulfate, filtered and concentrated to provide [(R, R, R)], (R, R, S)]-4-[1-(3,5-bis-trifluoromethyl-phenyl)-1 -chloro-ethyl]-2-ethyl-6-trifluoromethyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester as an oil which was used without 25 further purification. [(R, R, R)], (R, R, S)]-4-[1-(3,5-bis-trifluoromethyl-phenyl)-1 chloro-ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.085 grams, 0.142 mmol) was placed in a small round bottomed flask WO 2004/085401 PCT/IB2004/000836 -294 containing a magnetic stir bar and dissolved in 0.48 mL THF. This solution was added glacial acetic acid (0.48 mmol), HCI (0.80 mmol), and zinc dust ((0.093 grams, 1.42 mmol). The reaction mixture was stirred at room temperature for three hours. The reaction mixture was quenched with water and extracted three times with ethyl 5 actetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated to provide [(R, R)-4-[1-(3,5-bis-trifluoromethyl-phenyl)-vinyl] 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as an oil. [(R,R)-4-[1-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-2-ethyl-6-trifluoromethyl-3,4 10 dihydro-2H-quinoline-1-carboxylic acid ethyl ester (15 mg) was placed in a small round bottomed flask and dissolved in 10 mL of methanol. To this solution was added 10 mg of 10% Pd/C. The reaction mixture was hydrogenated at 45 psi for 12 hours. The reaction mixture was then filtered through Celite@ and washed with methanol. The filtrate was concentrated to an oil and purified by silica gel 15 chromatography to provide [(R, R, R)], (R, R, S)]-4-[1-(3,5-bis-trifluoromethyl phenyl)-ethyl]- 6,7-trifluoromethyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in 66% yield. F F F FF H C / FH F F F N CH,
H
3 C [(R, S, R)], (R, S, S)]-4-[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl- 6,7 20 trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester 'H NMR (CDC 3 ): 5 7.78 (s, 1H), 7.65 (s, 2H), 7.59 (dd, 2H), 7.41 (s, 1H), 4.30 (m, 1H), 4.20 (m, 2H), 2.95 (m, 2H), 1.80 (m, 1H), 1.58 (m, 2H), 1.40 (m, 1H), 1.30 (t, 3H), 1.20 (d, 3H), 0.72 (t, 3H); MS: 542.3 [M+H]+ found. 25 Example 481 (Stereo-Isomers of Examples 462, 463, 464 and 465) WO 2004/085401 PCT/IB2004/000836 -295
CF
3
H
2 N
CF
3
F
3 C s N Me
CO
2 Et [(S, R, S)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [(S, S, S)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6 5 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; [(S, R, R)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [(S, S, R)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 10 or a pharmaceutically acceptable salt of said compound. The above stereo-isomers of examples 462, 463, 464 and 465 are prophetic and may be prepared in optically enriched form by resolution of the corresponding racemate indicated, or an intermediate in its synthesis, using methods analogous to those described herein. 15 Examples 482 and 483 F F F o -/ OH F F O F F F N (R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl] 2-ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl] 20 2-ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester The mixture of two diastereoisomers (Example 2, 1.0g) was chromatographed on silica (Flash 40M column, Biotage, Dyar Corp., Charlottesville, WO 2004/085401 PCT/IB2004/000836 -296 VA) eluting with a methylene chloride -hexanes gradient from 2:3 to 4:1 to give the title compounds as white solids. First eluting diastereoisomer (4a stereochemistry not determined): MS: 597.9 [M-H]~ found 5 'H-NMR (CDC1 3 ) 6 7.92 (s, 2H), 7.75 (s, 1H), 7.67 (s, 1H), 7.65 (d, J=8.3OHz, 1H), 7.34 (dd, J=8.30, 1.66Hz, 1H), 5.97 (d, J=6.64Hz, 1H), 5.04 (m, 1H), 4.53 (s, 1H), 4.27 (m, 2H), 3.87 (s, 3H), 1.47 (m, 1H), 1.35 (m, 1H), 1.28 (t, J=7.47Hz, 3H), 0.85 (d, J=6.64Hz, 3H). Second eluting diastereoisomer (4a stereochemistry not determined): 10 MS: 597.9 [M-H]~ found 1 H-NMR (CDCi 3 ) 6 8.16 (s, 2H), 7.90 (s, 1H), 7.65 (d, J=8.30, 1H), 7.63 (s, 1H), 7.45 (dd, J=8.30, 1.66Hz, 1H), 5.82 (d, J=6.42Hz, 1H), 4.96 (m, 1H), 4.34 (s, 1H), 4.27 (m, 2H), 3.78 (s, 3H), 1.47 (m, 1H), 1.35 (m, 1H), 1.33 (t, J=7.47Hz, 3H), 0.83 (d, J=7.47Hz, 3H). 15 Example 484
CF
3
CF
3
F
3 C ~N. 0 O OEt (R, R)- 4-(3,5-bis-trifluoromethyl-benzyl)-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H 20 quinoline-1-carboxylic acid ethyl ester. [(R, R, R)]-4-[(3,5-bis-trifluoromethyl-phenyl)-methanesulfonyloxy-methy]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.045 mmol, 0.0278 g) was placed in a 5 mL reaction flask. To this 1.3 mL of DMF followed by sodium borohydride (0.526 mmol, 0.019 g) was added. The reaction was heated 25 to 85 OC for twelve hours. The reaction mixture was then diluted with ethyl actetate and washed with an aqueous brine solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to dryness. The crude reaction mixture was purified on silica gel chromatography to provide 18.5 mg of the desired product WO 2004/085401 PCT/IB2004/000836 -297 (R, R)- 4-(3,5-bis-trifluoromethyl-benzy)-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H quinoline-1-carboxylic acid ethyl ester in 78% yield. 1 H NMR (CDCI 3 ): 0.80 ppm (t, 3H), 1.10 (m, 1H), 1.29 (t, 3H), 1.41-1.62 (m, 2H & H 2 0), 2.16 (m, 1H), 2.76-2.87 (m, 2H), 3.64 (d, 1H), 4.15-4.32 (m, 3H), 7.47 5 (s, 1H), 7.51-7.57 (m, 2H), 7.70 (s, 2H), 7.80 (s, 1H). MS (ES+) mlz=528 (M+1). Example 485
CF
3 H H I Me'N H CF 3
F
3 C H N 10 0 OEt (R, R, S) 4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl]-2-ethyl-6 trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. (R, R, S) 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)-methyl]-2-ethyl-6 15 trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.193 g, 0.357 mmol) was placed in a sealed tube that contained 7 mL of ethyl formate. The tube was sealed and heated for twelve hours at 100 OC. The reaction mixture was then concentrated and purified on silica gel chromatography to provide 0.165 g of the formamide in 81% yield. This product was then placed in a round bottomed flask 20 equipped with a magnetic stir bar and dissolved in 7.3 mL of toluene. To this solution, 2.92 mL of borane methyl sulfide complex in toluene (2.0 M) was added. A reflux condenser was attached to the flask and the reaction was heated to 74 0C for twelve hours. The reaction mixture was then quenched with methanol and a few drops of HCl. This mixture was then heated for 1 hour. After cooling to room 25 temperature, the mixture was quenched with aqueous NaHCO 3 and extracted 3 times with ethyl acetate. The organics were collected, dried over sodium sulfate and concentrated to dryness. The crude oil was purified on silica gel chromatography to provide (R, R, S) 4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl]-2-ethyl-6 trifluoromethyl-3, 4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester in 41 % yield.
WO 2004/085401 PCT/IB2004/000836 -298 'H NMR (CDCI 3 ): 0.81 ppm (t, 3H), 1.33 (t, 3H), 1.36-1.52 (m, 3H), 2.25 (s, 3H), 2.52 (m, 1H), 2.97 (m, 1H), 3.99 (d, 1H), 4.28 (m, 2H), 4.52 (m, 1H), 7.04 (s, 1H), 7.41 (m, 1H), 7.59-7.61 (m, 3H), 7.72 (s, 1H). MS (ES+) m/z=557 (M+1). 5 Examples 486 - 499 These compounds were prepared from appropriate starting materials procedures analogous to those described in Examples 9, 10, 433, 434, 438, 443, 444, 452, 454, 457 and described generally in Scheme 2. The appropriately substituted bromo intermediates designated as Formula XVII in Scheme 2, were 10 prepared using procedures described by Matsugi in Tetrahedron Lett 2000, 41, 8523 and Hardy in U.S. patent 6,288,075. Example 486
CF
3 0
CF
3 F N 0 0 (RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6-fluoro- 2 15 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester GCMS (El): 535 (M+) 'H-NMR (CDCIs): 5 0.87 (m, I H), 1.04 (d, 3H), 1.25 (m, 3H), 1.32 (d, 3H), 1.69 (m, 1H), 3.33 (m, IH), 3.76 (s, 3H), 3.92 (d, 1H), 4.29 (m, 1H), 5.03 (m, 1H), 6.81 (dd, 1H), 6.87 (m, 1H), 7.38 (bs, 1H), 7.85 (s, 2H), 7.87 (s, 1H). 20 Example 487
CF
3 F
CF
3 N 010 WO 2004/085401 PCT/IB2004/000836 -299 (R, R, S)-4-[ 3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6-fluoro-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester GCMS (El): 535 (M+) 1 H-NMR (CDC13): 8 0.83 (m, 1H), 1.04 (d, 3H), 1.26 (d, 3H), 1.32 (d, 3H), 1.72 5 (m, IH), 3.33 (m, 1H), 3.77 (s, 3H), 3.91 (d, IH), 4.28 (m, 1H), 5.03 (m, 1H), 6.82 (dd, 1H), 6.95 (m, 1H), 7.38 (bs, 1H), 7.84 (s, 2H), 7.87 (s, 1H). Example 488
CF
3 SH I O H CF 3 H N 00O (S, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6-fluoro-2 10 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester GCMS (El): 535 (M+) 1 H-NMR (CDCI 3 ): 3 0.83 (m, 1H), 1.04 (d, 3H), 1.26 (d, 3H), 1.32 (d, 3H), 1.69 (m, IH), 3.33 (m, 1H), 3.77 (s, 3H), 3.91 (d, 1H), 4.28 (m, 1H), 5.03 (m, 1H), 6.82 (dd, 1H), 6.95 (m, 1H), 7.38 (bs, 1H), 7.84 (s, 2H), 7.87 (s, IH). 15 Example 489
CF
3 0H I
CF
3 F O N (RS, RS, PS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-6-fluoro-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester GCMS (El): 535 (M+) WO 2004/085401 PCT/IB2004/000836 -300 'H-NMR (CDCl 3 ): 5 0.87 (m, 1H), 1.17 (d, 3H), 1.26 (m, 3H), 1.32 (d, 3H), 2.31 (m, IH), 3.28 (m, 1H), 3.74 (s, 3H), 4.17 (d, 1H), 4.46 (m, 1H), 5.04 (m, IH), 6.44 (dd, IH), 6.87 (m, 1H), 7.38 (m, 1H), 7.84 (s, 1H), 7.89 (s, 2H). Example 490
CF
3
H
2 N CF3 F F N 00O 5 (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoyl-methyl]-6-fluoro-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic acid isopropyl ester GCMS (El): 520 (M+) 1 H-NMR (CDCI 3 ): 5 0.85 (m, 1H), 1.05 (d, 3H), 1.25 (d, 3H), 1.30 (d, 3H), 1.64 10 (m, IH), 3.38 (m, 1H), 3.71 (d, 1H), 4.26 (m, 1H), 5.01 (m, 1H), 5.53 (bs, 1H), 5.78 (bs, IH), 6.93 (m, 2H), 7.37 (m, 1H), 7.85 (s, 2H), 7.87 (s, IH). Example 491
CF
3 H I N ::
CF
3 F H N 00O (RS, RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-6-fluoro-2-methyl-3,4 15 dihydro-2H-quinoline-1-carboxylic acid isopropyl ester LCMS (ESI+): 503 (MH+) 'H-NMR (CDCIl): 5 1.19 (d, 3H), 1.24 (d, 3H), 1.28 (d, 3H), 1.45 (m, 1H), 2.18 (m, 1H), 2.87 (m, 1H), 4.31 (m, 1H), 4.77 (d, 1H), 4.99 (m, 1H), 7.04 (bs, 1H), 7.06 (bs, 1H), 7.45 (m, 1H), 7.90 (s, 2H), 7.96 (s, 1H).
WO 2004/085401 PCT/IB2004/000836 -301 Example 492
CF
3 H I O CF 3
F
3 C H N (RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2-methyl 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester 5 GCMS (El): 585 (M+) 'H-NMR (CDCI): 8 0.91 (m, 1 H), 1.09 (d, 3H), 1.29 (d, 3H), 1.34 (d, 3H), 1.75 (m, 1H), 3.38 (t, 1H), 3.77 (s, 3H), 4.02 (d, 1H), 4.31 (m, 1H), 5.06 (m, 1H), 7.38 (s, 1H), 7.55 (m, 2H), 7.88 (bs, 3H). Example 493
CF
3 H O
CF
3
F
3 C H 00- 10 (RS, RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-methyl 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester LCMS (ESI+): 585 (M+) 1 H-NMR (CDC 3 ): 8 1.22 (d, 3H), 1.28 (d, 3H), 1.33 (d, 3H), 1.39 (m, 1H), 2.36 15 (m, 1H), 3.27 (m, 1H), 3.76 (s, 3H), 4.27 (d, IH), 4.46 (m, 1H), 5.06 (m, 1H), 7.08 (s, 1H), 7.43 (d, 1H), 7.57 (d, IH), 7.85 (s, 1H), 7.93 (s, 2H). Example 494 WO 2004/085401 PCT/IB2004/000836 -302
CF
3 SH I
H
2 N CF 3
F
3 C H N (RS, RS, SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoyl-methyl]-2-methyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester LCMS (ESI+): 571 (MH+) 5 'H-NMR (CDC13): 5 0.91 (m, 1H), 1.09 (d, 3H), 1.27 (d, 3H), 1.33 (d, 3H), 1.68 (m, 1H), 3.46 (t, 1H), 3.81 (d, 1H), 4.28 (m, IH), 5.04 (m,1H), 5.54 (bs, 1H), 5.82 (bs, 1H), 7.46 (s, 1H), 7.50 (d, 1H), 7.56 (d, 1H), 7.88 (s, 3H). Example 495
CF
3 0H I
H
2 N H
CF
3
F
3 C N 10 (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoyl-methyl]-2-methyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester LCMS (ESI+): 571 (MH+) 1 H-NMR (CDC13): 5 0.87 (m, 1H), 1.09 (d, 3H), 1.26 (d, 3H), 1.33 (d, 3H), 1.69 (m, 1H), 3.45 (t, 1H), 3.83 (d, IH), 4.27 (m, 1H), 5.03 (m,1H), 5.65 (bs, 1H), 5.99 (bs, 15 1H), 7.46 (s, 1H), 7.49 (d, 1H), 7.55 (d, 1H), 7.88 (s, 3H). Example 496 WO 2004/085401 PCT/IB2004/000836 -303
CF
3 0 H
H
2 N H
CF
3
F
3 C N 00 (S, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoyl-methyl]-2-methyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester LCMS (ESI+): 571 (MH+) 5 'H-NMR (CDC 3 ): 6 0.87 (m, 1H), 1.08 (d, 3H), 1.26 (d, 3H), 1.32 (d, 3H), 1.68 (m, 1H), 3.44 (t, 1H), 3.84 (d, 1H), 4.26 (m, 1H), 5.02 (m,1H), 5.69 (bs, 1H), 6.01 (bs, 1H), 7.47 (s, 1H), 7.49 (d, 1H), 7.54 (d, 1H), 7.87 (s, 3H). Example 497
CF
3 0 H~ H2N CF 3
F
3 C H 00- 10 (RS, RS, RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carbamoy-methyl]-2-methyl- 6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester LCMS (ESI+): 571 (MH+) 'H-NMR (CDCI 3 ): 8 0.87 (m, IH), 1.18 (d, 3H), 1.24 (d, 3H), 1.28 (d, 3H), 2.54 (m, IH), 3.37 (t, 1H), 4.00 (d, 1H), 4.48 (m, 1H), 5.04 (m,1H), 6.02 (bs, 1H), 6.33 (bs, 15 1H), 7.00 (s, 1H), 7.36 (d, 1H), 7.55 (d, 1H), 7.81 (s, 1H), 7.98 (s, 2H). Example 498 WO 2004/085401 PCT/IB2004/000836 -304
CF
3 H I
H
2 N H CF 3
F
3 C N 00O (RS, RS, SR)-4-[2-Amino-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester LCMS (ESI+): 557 (MH+) 5 'H-NMR (CDCI 3 ): 8 0.80 (m, 1H), 1.04 (d, 3H), 1.28 (d, 3H), 1.34 (d, 3H), 1.76 (m, IH), 2.75 (t, IH), 3.11 (m, IH), 3.35 (m, IH), 3.46 (m,1H), 4.26 (m, 1H), 5.06 (m, 1H), 7.54 (m, 3H), 7.77 (s, 2H), 7.84 (s, 1H). Example 499 0
CF
3 ,A H IH
F
3 C CF3 00 10 (RS, RS, SR)-4-[2-Acetylamino-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester LCMS (ESI+): 599 (MH+) 1 H-NMR (CDC 3 ): 5 0.78 (m, 1 H), 1.04 (d, 3H), 1.28 (d, 3H), 1.34 (d, 3H), 1.76 (m, 1H), 1.93 (s, 3H), 2.68 (s, IH), 3.01 (m, 1H), 3.72 (m, 1H), 4.26 (m, 1H), 4.37 (m, 15 1H), 5.06 (m, 1H), 5.40 (m, 1H), 7.53 (s, 2H), 7.70 (s, 2H), 7.85 (s, 1H), 8.41 (s, 1H).
WO 2004/085401 PCT/IB2004/000836 -305 Examples 500 and 501 F F F 0 F F 0 H F N 50 (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester F F F F OF F F F H -H F 5 (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester To a solution of 3,5-bis(trifluoromethylphenyl)acetic acid methyl ester (1.41 g, 4.93mmol) in anhydrous N,N-dimethylformamide (3mL) was added sodium hydride 10 (60% mineral oil dispersion, 6.55mmol, 262mg) and the mixture was stirred at room temperature for 60min. A solution of (R)-4-chloro-2-ethyl-6-trifluoromethyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester (1.10g, 3.28mmol, mixture of isomers, Preparation 14) in anhydrous N,N-dimethylformamide (1.5mL) was added and the mixture was stirred at room temperature for 72hr. Water (20mL) was added 15 and the mixture was extracted with diethyl ether (3 x 50mL) and the organic extract was dried over anhydrous sodium sulfate and the solvent was removed under vacuum to give the crude product as a yellow oil (-2g). Purification was achieved using radial chromatography (Chromatron model 7924T, Harrison Research, Palo Alto, CA) with a 4mm silica gel rotor eluting with hexanes/ethyl acetate 9:1 to give the 20 title compounds: WO 2004/085401 PCT/IB2004/000836 -306 (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (first eluting diastereoisomer) MS: 586.0 [M+H]* found 5 1 H-NMR (CDC1 3 ) 8 7.90 (s, 2H), 7.87 (s, 1H), 7.59 (d, J=8.3OHz, 1H), 7.62 (d, J=8.30Hz, 1H), 7.61 (s, 1H), 4.39-4.27 (m, 2H), 4.27-4.18 (m, 1H), 3.78 (d, J=11.61Hz, 1H), 3.59 (m, 1H), 3.48 (s, 3H), 1.76 (ddd, J=14.10, 8.30, 3.30Hz, IH), 1.61-1.55 (m, 1H),1.57-1.50 (m, 1H), 1.48-1.40 (m, 1H), 1.35 (t, J=7.47Hz, 3H), 0.73 (t, J=7.47Hz, 3H). 10 (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (536mg, second eluting diastereoisomer) MS: 586.0 [M+H]* found 'H-NMR (CDCl 3 ) S 7.66 (s, 1 H), 7.42 (d, J=8.30Hz, 1 H), 7.40 (s, 2H), 7.33 (dd, 15 J=8.30, 1.66Hz, 1H), 6.47 (d, J=1.66Hz, IH), 4.55-4.47 (m, IH), 4.34 (m, IH), 4.32 (m,1H), 3.83 (d, J=11.61Hz, IH), 3.80 (s, 3H), 3.43 (ddd, J=11.61, 4.98, 2.49Hz, 1H), 2.44 (ddd, J=14.11, 8.30, 2.49Hz, 1H), 1.81 (ddd, J=14.10, 8.30, 4.98Hz, 1H), 1.67 (m, IH),1.51 (m, 1H), 1.33 (t, J=7.47Hz, 3H), 0.85 (t, J=7.47Hz, 3H). Examples 502 and 503 F F F OH 1 F O F F N H H F F 20 (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester WO 2004/085401 PCT/IB2004/000836 -307 F F F OH H F 0 F F __F H F F ,H N (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2-ethyl-6-trifluoromethyl 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester A mixture of (R, S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl 5 methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 501, 100mg, 0.171mmol), aqueous sodium hydroxide (2N, 0.512mL, 1.024mmol) and anhydrous tetrahydrofuran (2mL) was stirred at room temperature for 2 days before adding 2N hydrochloric acid (1.5mL). The mixture was diluted with acetonitrile and evaporated to dryness under vacuum to give the crude product as an 10 oil (128mg). Purification was achieved using radial chromatography (Chromatron model 7924T, Harrison Research, Palo Alto, CA) with a 4mm silica gel rotor eluting with hexanes/ethyl acetate 55:45 to give the title compounds: First eluting: (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (14mg); 15 'H-NMR (CDCI 3 ) 5 7.88 (s, 1H), 7.88 (s, 2H), 7.55 (m, 1H), 7.51 (m, 1H), 7.49 (m, 1H), 4.32 (m, 1H), 4.27 (m, 1H), 4.21 (m, 1H), 3.80 (d, J=10.79Hz, 1H), 3.57 (m, I H), 1.78 (m, 1 H), 1.55 (m, 2H), 1.43 (m, 1 H), 1.32 (t, J=7.47Hz, 3H), 0.71 (t, J=7.47Hz, 3H). Second eluting: (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-carboxy-methyl] 20 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (32mg) 1 H-NMR (CDC1 3 ) 8 7.67 (s, 1H), 7.45 (s, 2H), 7.41 (m, 1H), 7.34 (m, 1H), 6.51 (brs, 1H), 4.55 (m, 1H), 4.32 (m, 2H), 3.85 (d, J=I0.79Hz, 1H), 3.43 (m, 1H), 2.55 (m, IH), 1.81 (m, IH), 1.63 (m, 1H), 1.60 (m, 1H), 1.31 (t, J=7.47Hz, 3H), 0.84 (t, J=7.47Hz, 3H). 25 Examples 504 and 505 WO 2004/085401 PCT/IB2004/000836 -308 F F 'F OH F F F O H F H F ,,\H FF N O 0O (R, S, R)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester F F F FF FF OF O 5 (R, S, S)-4.-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-l-carboxylic acid ethyl ester To a solution of (R, S, R)- and (R, S, S)- 4-[(3,5-bis-trifluoromethyl-phenyl) carboxy-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Examples 502 and 503 as prepared above but isomers not separated, 10 143mg, 0.25mmol) in tetrahydrofuran (3mL) under nitrogen was added borane dimethylsulfide complex (2M in tetrahydrofuran, 0.25mL, 0.5mmol). After 24hr the mixture was diluted with methanol (1 mL) and evaporated to dryness under vacuum. To the residue was added 2N hydrochloric acid (3mL), the mixture was stirred for 1 0min and then extracted with diethyl ether (3 x 15mL). The organic layer was dried 15 over anhydrous sodium sulfate and the solvent was evaporated under vacuum to give the crude product as an oil (175mg). Purification was achieved using radial chromatography (Chromatron model 7924T, Harrison Research, Palo Alto, CA) with WO 2004/085401 PCT/IB2004/000836 -309 a 1mm silica gel rotor eluting with a hexanes/ethyl acetate gradient from 4:1 to 7:3 to give the title compounds: First eluting: (R, S, R)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (9mg) 5 MS: 558.3 [M+H]* found. 'H-NMR (CDC1 3 ) 5 7.83 (s, 1H), 7.79 (s, 2H), 7.60 (m, 1H), 7.53 (brs, 1H), 7.52 (m, 1H), 4.35 (m, 1H), 4.24 (m, 1H), 4.16 (m, IH), 3.71 (m, 2H), 3.34 (m, IH), 2.99 (m, 1 H), 1.78 (m, 1 H), 1.57 (m, 2H), 1.57 (m, 1 H), 1.45 (m, 1 H), 1.33 (t, J=7.47Hz, 3H), 0.71 (t, J=7.47Hz, 3H). 10 Second eluting: (R, S, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (30mg) MS: 558.5 [M+H]* found. 1 H-NMR (CDC 3 ) 6 7.63 (s, 1H), 7.40 (m, 1H), 7.39 (s, 2H), 7.32 (m, IH), 6.62 15 (brs, 1H) 4.48 (m, IH), 4.25 (m, 2H), 4.15 (m, 2H), 3.13 (m, 2H), 2.60 (m, IH), 1.69 (m, 3H), 1.50 (m, I H), 1.29 (t, J=7.47Hz, 3H), 0.86 (t, J=7.47Hz, 3H). Example 506 F F F H F MeO F H F F F N 20
CO
2 Et (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester [(R, R, S)]- 4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyll-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (0.030 grams, 25 0.055 mmol, 1 eq) was placed in a round bottomed flask equipped with a magnetic stir bar. DMSO (1.0 mL) was added followed by the addition of (0.012gramsO.221 mmol, 4 eq) potassium hydroxide and (0.016 grams, 0.110 mmol, 2 eq) methyl iodide at room temperature. After 1.5 hour, the reaction mixture was quenched with IN WO 2004/085401 PCT/IB2004/000836 -310 HCI, extracted 3 times with ethyl acetate and dried over sodium sulfate. The crude material was purified on silica gel chromatography to provide the title compound. LCMS (ESI+): 551 (MH+). 'H NMR (CDCi 3 ): 8? 0.95 (t, 3H), 1.31 (t, 3H), 1.41 (m, 1H), 1.60 (m, 1H), 2.6 (m, 1H), 5 2.90 (m, IH), 3.20 (s, 3H), 4.33 (m, 2H), 4.45 (m, IH), 6.60 (s, 1H), 7.2- (s, 2H), 7.30 (d, 1H).7.5 (d, 1H) 7.70 (s, IH). Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by 10 reference into this application for all purposes. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the 15 invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. 20

Claims (15)

1. A compound according to Formula I R 4 R 3 R 5 1C3 6
2 R N R R 7 R Formula 1 5 Wherein C3 is carbon; J is nitrogen or carbon, wherein if J is carbon, then the bond between C3 and J is a single or double bond and if J is nitrogen, then the bond between C3 and J is a single bond; 10 R 1 is Y, W-X or W-Y'; wherein W is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl; X is -O-Y, -S-Y, -N(H)-Y or -N-(Y) 2 ; Y for each occurrence is independently Z or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected 15 independently 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 20 Z; and Y' for each occurrence is independently Z or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently 25 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 Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having 30 one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or WO 2004/085401 PCT/IB2004/000836 -312 a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said Z substituent is optionally mono-, di- or tri-substituted independently with halo, 5 (C 2 -C 6 )alkenyl, (C-C 6 ) alkyl, hydroxy, (C-C 6 )alkoxy, (C-C4alkylthio, amino, nitro, cyano, oxo, carboxy, (0 1 -C)alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said (C-C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (CrCe)alkoxy, (C-C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C-C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino, said 10 (C-C 6 )alkyl or (C-C)alkoxy substituent is also optionally substituted with from one to nine fluorines; R 2 is a partially saturated, fully saturated or fully unsaturated one to six membered straight or branched carbon chain wherein each carbon, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected 15 independently from oxygen and sulfur, and said carbon is optionally mono-, di- or tri substituted independently with halo, said carbon chain is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo,; or said R 2 is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to 20 two heteroatoms selected independently from oxygen and sulfur, wherein said R 2 ring is optionally attached through (C-C4)alkyl; wherein said R 2 ring is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C-C 6 ) alkyl, hydroxy, (C-C 6 )alkoxy, (C-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C C)alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said (C-C 6 )alkyl 25 substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C-C 6 )alkoxy, (C-C 4 )alkylthio, oxo or (C-C)alkyloxycarbonyl; R 3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain having C4a, wherein C4a is a carbon atom that connects to J, wherein each carbon in the carbon chain may optionally be 30 replaced with one heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo or nitrogen, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with hydrogen or oxo, and said carbon chain is WO 2004/085401 PCT/IB2004/000836 -313 mono, di-, or tri-substituted with V at C4a or the R 3 carbon adjacent to C4a; provided that in R 3 , when J is carbon, it is other than C4a that is optionally replaced with one heteroatom; and provided that in R , when J is nitrogen, it is other than C4a that is optionally replaced with a heteroatom and it is other than C4a that is optionally 5 mono-substituted with hydroxy or nitrogen; wherein V is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen such that V is not imidazolyl or a fully saturated heterocyclic nitrogen-containing ring wherein nitrogen of the ring is connected to the R 3 group; a bicyclic ring consisting of two 10 fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; or a tricyclic ring consisting of three fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected 15 independently from nitrogen, sulfur and oxygen; and said V substituent is optionally mono-, di-, tri-, tetra- or penta-substituted independently with V 1 , (C 1 -C 6 )alkyl-V', C(O)-V 1 , 0-(Co-C 6 )alkyl-V', (C 1 -C 6 )alkyl-O-V', C(O)-mono-N- or di-N,N-(C-C 6 )alkyl V 1 , halo, (C-C 6 )alkyl, (C 2 -C)alkenyl, hydroxy, (C-C)alkoxy, (C-C4)alkylthio, (C C4)alkylsulfinyl, (C-C4)alkylsulfonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylsulfonyl, amino, 20 nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C-C 6 ) alkylcarboxamoyl, carboxy, (C 1 -C)alkyloxycarbonyl, mono-N- or di-N,N-(Cq-C 6 )alkylamino, wherein said (C-C 6 )alkyl or (C 2 -C 6 )alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (Cl-r)alkoxy, (C-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C-C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino, wherein 25 each (C-C 6 )alkyl, (C-C)alkoxy, (C-C 4 )alkylthio, (C-C 4 )alkylsulfony or (C2 C 6 )alkenyl substituents are also optionally substituted with from one to nine fluorines; wherein V 1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two 30 fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said V 1 substituent is optionally mono-, di-, tri-, tetra- or penta-substituted independently with halo, (C-C)alkyl, (C C 6 )alkoxy, hydroxy, oxo, amino, nitro, cyano, (C-C 6 )alkyloxycarbonyl, mono-N- or di- WO 2004/085401 PCT/IB2004/000836 -314 N,N-(C-C 6 )alkylamino wherein said (C-C 6 )alkyl substituent is optionally mono substituted with oxo, said (C-C)alkyl or (C-C 6 )alkoxy substituent is also optionally substituted with from one to nine fluorines; and each of R 4 , R, R' and R 7 are independently hydrogen, a bond, nitro or halo 5 wherein said bond is substituted with T or a partially saturated, fully saturated or fully unsaturated (C-C 1 2 ) straight or branched carbon chain wherein each carbon may optionally be replaced with one or two heteroatoms per carbon chain wherein the heteroatoms are selected independently from oxygen, sulfur and nitrogen, wherein said carbon is optionally mono-, di- or tri-substituted independently with halo, said 10 carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono substituted with oxo or nitrogen, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with hydrogen or oxo, and said carbon chain is optionally mono-substituted with T; wherein T is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring 15 optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said T substituent is optionally mono-, di- or tri-substituted 20 independently with halo, (C-C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C-C 6 )alkoxy, (C C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (0 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said (CrC 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C-C 6 )alkoxy, (C-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C-C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 25 C 6 )alkylamino, said (C-C 6 )alkyl or ( 1 -C 6 )alkoxy substituent also optionally has from one to nine fluorines; R 4 and R 5 , R 5 and R8, and/or R 6 and R 7 may optionally be taken together and can form at least one ring that is a partially saturated or fully unsaturated four to eight membered ring optionally having one to three heteroatoms independently selected 30 from nitrogen, sulfur and oxygen; wherein each ring formed by R 4 and R6, or R 5 and R6, and/or R'and R7 is optionally mono-, di- or tri-substituted independently with halo, (C-C 6 )alkyl, (C-C 4 )alkylsulfonyl, (C 2 -C 6 )alkenyl, hydroxy, (C-C 6 )alkoxy, (C C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C-C)alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein said (C-C 6 )alkyl substituent is optionally mono-, WO 2004/085401 PCT/IB2004/000836 -315 di- or tri-substituted independently with hydroxy, (C-C 6 )alkoxy, (C-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(Cr C 6 )alkylamino, said (C-C 6 )alkyl substituent also optionally has from one to nine fluorines; 5 or a pharmaceutically acceptable salt or prodrug thereof; with the following provisos: a) when there is a single bond between C3 and J, and R 3 is a fully saturated one to six membered straight or branched carbon chain substituted on C4a with V then R, is other than C(O)-(C-C 4 )alkyl optionally mono-, di- or tri-substituted with halo and 10 R 1 is other than C(O)-monocyclicaromatic ring; or b) when there is a single bond between C3 and J, and R3 is -C(O)-O-V, and R2 is phenyl then R 1 is other than (C-C4)alkyl; and c) when there is a double bond between C3 and J, and R 2 is methyl then R 3 is other than -CH 2 -O-V, -CH 2 -V or -CH 2 -CH 2 -V. 15 2. A compound of claim I wherein J is carbon; R 1 is W-X; W is carbonyl; X is -O-Y; 20 Y for each occurrence is independently (CI-C 6 )alkyl, said (C-Ce)alkyl optionally having one to nine fluorines or said (C-C 6 )alkyl optionally mono-substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; 25 wherein said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C-C4)alkyl, (C-C4)alkoxy, (C-C 4 )alkylthio, nitro, cyano, oxo, or (Cr 1 C 4 )alkyloxycarbonyl, said (C-C 4 )alkyl or (C-C4)alkoxy is optionally substituted with from one to nine fluorines; R2 is beta and is a partially saturated, fully saturated or fully unsaturated (C 30 C4) straight or branched carbon chain wherein one carbon, other than the connecting carbon, may optionally be replaced with oxygen or sulfur and wherein said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon chain is optionally mono-substituted with oxo or hydroxy, said sulfur is optionally mono- or di substituted with oxo,; or said R 2 is a partially saturated, fully saturated or fully WO 2004/085401 PCT/IB2004/000836 -316 unsaturated three to five membered ring optionally having one heteroatom selected independently from oxygen and sulfur; wherein said R 2 ring is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C-C 6 )alkoxy, amino, nitro, (C-C 4 )alkyloxycarbonyl or carboxy; 5 wherein R 3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein each carbon, other than C4a, may optionally be replaced with one 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 10 with hydroxy, said carbon is optionally mono-substituted with cyano, said carbon is optionally mono-substituted with oxo or nitrogen, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with hydrogen or oxo, and said carbon chain is optionally mono, di-, or tri-substituted with V at C4a or at the R 3 carbon adjacent to C4a; V is a three, four, five or six 15 membered partially saturated, fully saturated or fully unsaturated ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen such that V is not imidazolyl or a fully saturated heterocyclic nitrogen containing ring wherein nitrogen of the ring is connected to the R 3 group; wherein said V ring is optionally mono-, di-, tri-, tetra- or penta-substituted 20 independently with halo, (C-C 6 )alkyl, hydroxy, (C-C 6 )alkoxy, (C-CB)alkoxycarbonyl, nitro, cyano or oxo, wherein said (C-C 6 )alkyl or (C-C 6 )alkoxy substituent optionally has from one to nine fluorines; R 4 is hydrogen; R6 and RO are each independently hydrogen, halo, T, (C-C 6 )alkoxy or (C 25 C 6 )alkyl, said (C-C 6 )alkoxy or (C-C 6 )alkyl substituent optionally having from one to nine fluorines or said (C-C 6 )alkoxy or (C-C 6 )alkyl substituent optionally mono substituted with T; wherein T is a partially saturated, fully saturated or fully unsaturated five to six membered ring optionally having one to two heteroatoms selected independently 30 from oxygen, sulfur and nitrogen; wherein said T substituent is optionally mono-, di- or tri-substituted independently with halo, (C-C 6 )alkyl, hydroxy, (CI-Ce)alkoxy, (C-C4)alkylthio, amino, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C-C 6 )alkylamino wherein WO 2004/085401 PCT/IB2004/000836 -317 said (C-C 6 )alkyl or (C-C 6 )alkoxy substituent optionally has from one to nine fluorines; R 7 is hydrogen; or a pharmaceutically acceptable salt thereof. 5
3. A compound of claim 2 wherein Y is methyl, ethyl, 1-propyl, 2-propyl or tert-butyl; R 2 is methyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl; R 3 is -C(O)-V, -C(OH)(C(O)OCH 3 )(V), -CH(F)(V), -CF 2 (V), -CH(OCH 3 )(V), CH(C(O)OCH 3 )(V), -CH(CN)(V), -CH(OH)(V), -CH 2 (V), -CH(NH 2 )(V), 10 CH(NH(CH 3 ))(V), -CH(C(O)NH 2 )(V), -CH(CH 2 OH)V, -CH(CH 2 0CH 3 )V, CH(CH 2 0C(O)CH 3 )V, -CH(CH 2 F)V, or -CH(CH 2 NH 2 )V; and V is phenyl optionally mono-, di- or tri-substituted independently with halo, nitro, or (C-C 2 )alkyl, wherein said (C-C 2 )alkyl optionally has from one to five fluorines; 15 R 5 and Ra are each independently hydrogen, methyl, methoxy or chloro; said methoxy optionally having from one to three fluorines, said methyl optionally having from one to three fluorines; or a pharmaceutically acceptable salt thereof.
4. A compound of claim 3 wherein 20 Y is ethyl; R 2 is ethyl or methyl; R 3 is (3,5-bis-(trifluoromethyl)-phenyl)-hydroxy-methoxycarbonyl-methyl; (3,5 bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl; (3,5-bis-trifluoromethyl-phenyl) cyano-methyl, 3,5-bis-trifluoromethyl-benzoyl; (3,5-bis-trifluoromethyl-phenyl) 25 hydroxy-methyl; (3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl; (3,5-bis trifluoromethyl-phenyl)-difluoro-methyl; (3,5-bis-(trifluoromethyl)-benzyl); (3,5-bis trifluoromethyl-phenylcarbamoyl)-methyl; amino-(3,5-bis-(trifluoromethyl)-phenyl) methyl; (3,5-bis-(trifluoromethyl)-phenyl)-methylamine-methyl; 1-(3,5-bis (trifluoromethyl)-phenyl)-2-amino-ethyl; 1-(3,5-bis-(trifluoromethyl)-phenyl)-2-fluoro 30 ethyl; 1-(3,5-bis-(trifluoromethyl)-phenyl)-2-methoxy-ethyl; 1-(3,5-bis-(trifluoromethyl) phenyl)-2-hydroxy-ethyl; or 2-acetoxy-1-(3,5-bis-(trifluoromethyl)-phenyl)-ethyl; R 5 is methoxy or trifluoromethyl; and R 6 is hydrogen or methoxy; or a pharmaceutically acceptable salt thereof. WO 2004/085401 PCT/IB2004/000836 -318
5. A compound of claim I wherein J is nitrogen; the bond between C3 and J is a single bond; R 1 is W-X; 5 W is carbonyl; X is -O-Y; Y for each occurrence is independently (C-C 6 )alkyl, said (C-Ce)alkyl optionally having one to nine fluorines or said (C-C)alkyl optionally mono substituted with Z; 10 wherein Z is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C-C4)alkyl, (C-C4)alkoxy, (C-C4)alkylthio, nitro, cyano, 15 oxo, or (C-C 4 )alkyloxycarbonyl, said (C-C 4 )alkyl or (C-C4)alkoxy optionally substituted with from one to nine fluorines; R 2 is a partially saturated, fully saturated or fully unsaturated (C-C 4 ) straight or branched carbon chain wherein one carbon, other than the connecting carbon, may optionally be replaced with oxygen or sulfur and wherein said carbon is 20 optionally mono-, di- or tri-substituted independently with halo, said carbon chain is optionally mono-substituted with oxo, said carbon is optionally monosubstituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo,; or said R 2 is a partially saturated, fully saturated or fully unsaturated three to five membered ring optionally having one heteroatom selected independently from oxygenand sulfur; 25 wherein said R 2 ring is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (0 1 -C 6 )alkoxy, amino, nitro, (C-C4)alkyloxycarbonyl or carboxy; wherein R 3 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein each carbon, other than C4a or the R3 carbon adjacent to C4a, may optionally be replaced with one 30 heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon, other than C4a, is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with cyano, said carbon is optionally mono-substituted with oxo or nitrogen, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- WO 2004/085401 PCT/IB2004/000836 -319 or di-substituted with hydrogen or oxo, and said carbon chain is optionally mono, di-, or tri-substituted with V at C4a or at the the R 3 carbon adjacent to C4a; V is a five or six membered partially saturated, fully saturated or fully unsaturated ring optionally having one to three heteroatoms selected independently 5 from oxygen, sulfur and nitrogen such that V is not imidazolyl or a fully saturated heterocyclic nitrogen-containing ring wherein nitrogen of the ring is connected to the R 3 group; wherein said V ring is optionally mono-, di-, tri-, tetra- or penta-substituted independently with halo, (C-C 6 )alkyl, hydroxy, (C-C 6 )alkoxy, (C-Ce)alkoxycarbonyl, nitro, cyano or oxo, wherein said (C-C 6 )alkyl or (C-C)alkoxy substituent optionally 10 has from one to nine fluorines; R 4 is hydrogen; R5 and R' are each independently hydrogen, halo, T, (Cl-C 6 )alkoxy or (C C 6 )alkyl, said (Cl-Ce)alkoxy or (C-C 6 )alkyl substituent optionally having from one to nine fluorines or said (C-C 6 )alkoxy or (C-C 6 )alkyl substituent optionally mono 15 substituted with T; wherein T is a partially saturated, fully saturated or fully unsaturated five to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said T substituent is optionally mono-, di- or tri-substituted 20 independently with halo, (C-C 6 )alkyl, hydroxy, (C-C 6 )alkoxy, (C-C 4 )alkylthio, amino, oxo, carboxy, (Cr-C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C-C 6 )alkyl or (C-C 6 )alkoxy substituent optionally has from one to nine fluorines; R 7 is hydrogen; 25 or a pharmaceutically acceptable salt thereof.
6. A compound of claim 5 wherein Y is (C-C4)alkyl, wherein said (Cr-C 4 )alkyl substituent optionally has one to nine fluorines; R 2 is (C-C 4 )alkyl, cyclopropyl or cyclobutyl; 30 R 3 is -C(O)-V, -CH(C(O)O(C-C 3 )alkyl)(V), or -CH(CN)(V); V is phenyl optionally mono-, di- or tri-substituted independently with halo, (C-C)alkyl, hydroxy, (C-C 6 )alkoxy, nitro, cyano or oxo wherein said (C-C 6 )alkyl substituent optionally has from one to nine fluorines; WO 2004/085401 PCT/IB2004/000836 -320 R 5 and R 6 are each independently hydrogen, (C-C 3 )alkoxy or (C-C 6 )alkyl, said (C-C 3 )alkoxy optionally having from one to nine fluorines, said (C-C6)alkyl optionally having from one to seven fluorines; or a pharmaceutically acceptable salt thereof. 5
7. A compound of claim 6 wherein Y is methyl, ethyl, 1-propyl, 2-propyl or tert-butyl; R2 is methyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl; R 3 is 3,5-bis-trifluoromethyl-benzoyl, (3,5-bis-trifluoromethyl-phenyl)-cyano methyl, or (3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl; 10 R 5 is methyl or trifluoromethyl; R 6 is hydrogen or methyl.
8. A compound according to claim 1, selected from the group consisting of: (R, R, S)-4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 15 (R, S, S)-4-[Amino-(3,5-bis-trifluoromethyl-phenyl)- methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R)-4-(3,5-bis-trifluoromethyl-benzyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl]-2-ethyl-6 20 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl] 6,7-dimethoxy-2-methyl-2H-quinoline-1 -carboxylic acid ethyl ester; 25 (R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbony-methyl] 6,7-dimethoxy-2-methyl-2H-quinoline-1 -carboxylic acid ethyl ester; (R, S, R)- 4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl- methoxycarbonyl methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 30 (R, S, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -321 (R, R, S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R, R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl 5 methyl]- 6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; 10 (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl 15 ester; (R, R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6,7 20 dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl] 2-ethyl-6-trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; 25 (R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxyl-methoxycarbonyl-methyl] 2-ethyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-2-ethyl-6 30 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[2-Acetoxy-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[2-Acetoxy-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -322 (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 5 (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-fluoro-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-fluoro-ethy]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, R, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-amino-ethy]-2-ethyl-6 10 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-amino-ethyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; 15 (RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (R, S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2-ethyl 20 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R, S, R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 25 (RR,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 30 trifluoromethyl-2H-quinoline-1 -carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6 trifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester; (R,S)-4-(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -323 (R,R)-4-[(3,5-Bis-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-3,4 dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; 5 (R,R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,S,R)-4-1(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2 10 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,R)-4-(3,5-bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester; (R,S)-4-(3,5-bis-trifluoromethyl-benzoyl)-2-ethyl-6-trifluoromethyl-3,4-dihydro 2H-quinoline-1 -carboxylic acid ethyl ester; 15 (R,RR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R, S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methylj-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 20 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2 methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,S,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; 25 (R,SR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethy-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-hydroxy-methy]-2-ethyl-6 30 trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester; (R)-4-(3,5-Bis-trifluoromethyl-benzoyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H quinoxaline-1-carboxylic acid ethyl ester; (RR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl 3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; WO 2004/085401 PCT/IB2004/000836 -324 (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl 3,4-dihydro-2H-quinoxaline-l-carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; 5 (RS)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid methyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methy]-2-ethyl 10 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid methyl ester; (R,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester; (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester; 15 (RR)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbony-methyl]-2-ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; and (R,S)-4-[(3,5-Bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethy-6 trifluoromethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt or prodrug thereof. 20
9. A method for treating atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction in a mammal by administering to a mammal in need of such treatment an 25 atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia or myocardial infarction treating amount of a compound of any of claims 1 to 8, a prodrug thereof, or a pharmaceutically acceptable salt of said 30 compound or of said prodrug.
10. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of any of claims 1 to 8, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable vehicle, diluent or carrier. WO 2004/085401 PCT/IB2004/000836 -325
11. A pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of any of claims 1 to 8, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of 5 said prodrug; a second compound, said second compound being an HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a PPAR modulator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion-exchange 10 resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant; and a pharmaceutical vehicle, diluent or carrier.
12. A pharmaceutical combination composition as recited in claim 11 wherein the second compound is an HMG-CoA reductase inhibitor or a PPAR modulator.
13. A pharmaceutical combination composition as recited in claim 12 wherein the 15 second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.
14. A kit for achieving a therapeutic effect in a mammal comprising packaged in association a first therapeutic agent comprising a therapeutically effective amount of a compound of any of claims 1 to 8, a prodrug thereof, or a pharmaceutically 20 acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, a second therapeutic agent comprising a therapeutically effective amount of an HMG CoA reductase inhibitor, a PPAR modulator, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, 25 an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier and directions for administration of said first and second agents to achieve the therapeutic effect.
15. A compound of Formula Ill 5 R (R12n R6 N R2 / OR 10 WO 2004/085401 PCT/IB2004/000836 -326 Formula Ill wherein C3 is carbon; J is carbon, wherein the bond between C3 and J is a single or double bond; 5 n is zero if the bond between C3 and J is a double bond or one if the bond between C3 and J is a single bond; R 2 is (C-C 4 )alkyl, cyclopropyl or cyclobutyl; R 5 is CF 3 ; R 6 is hydrogen; 10 R 10 is a fully saturated (Cr1C4) straight or branched carbon chain; R" is halo, hydroxy, -C(O)(O(C-C 4 )alkyl), -C(O)C(O)(O(C-C4)akyl), C(O)NH(O(C-C4)alkyl), or -C(O)N((CI-C 4 )alkyl)(O(C-C4)alkyl); R 12 is hydrogen or halo, wherein R" is not halo when R 1 2 is halo; or R and R 12 are taken together to form oxo or N 2 ; 15 or a pharmaceutically acceptable salt or prodrug thereof.
AU2004224082A 2003-03-28 2004-03-15 1,2,4-substitute 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as CETP inhibitors for the treatment of atherosclerosis and obesity Abandoned AU2004224082A1 (en)

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