NZ569415A

NZ569415A - Selective benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors

Info

Publication number: NZ569415A
Application number: NZ569415A
Authority: NZ
Inventors: Anima Baruah; Dibyendu De; Ish Kumar Khanna; Sivaram Pillarisetti; Christopher W Alexander; Jennepali Sreenu; Santanu Maitra; Shanavas Alikunju
Original assignee: Reddy Us Therapeutics Inc
Priority date: 2005-12-28
Filing date: 2006-06-29
Publication date: 2011-07-29

Abstract

Disclosed is a tertiary benzyl amide of formula (I) or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: A, R1 - R3 and Z is defined in the specification and m represents 0-2, inclusive; p is an integer from 0 to 3, inclusive; Rr and Rs independently represents isopropyl or -CF3 and Rt represents hydrogen or hydroxyl.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 569415 WO 2007/075194 PCT/US2006/025427 SELECTIVE BENZYLAMINE DERIVATIVES AND THEIR UTILITY AS CHOLESTEROL ESTER-TRANSFER PROTEIN INHIBITORS 5 FIELD OF THE INVENTION The present invention relates to selective benzylamine compounds, methods and compositions for making and using the benzylamine compounds, and compositions and methods for treating or preventing conditions or diseases 10 associated with lipoprotein metabolism. BACKGROUND OF THE INVENTION Cholesteryl ester-transfer protein (CETP) is an important player in metabolism of lipoproteins such as, for example, a high density lipoprotein (HDL). 15 CETP is a 70 kDa plasma glycoprotein that is physically associated with HDL particles. It facilitates the transport of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins. This transfer is accompanied by transfer of triglycerides in the opposite direction. Thus, a decrease in CETP activity can result in an increase in the level of HDL cholesterol and a decrease in the level of 20 very low density lipoprotein (VLDL) and low density lipoprotein (LDL). CETP can therefore simultaneously affect the concentrations of pro-atherogenic (e.g., LDL) and anti-atherogenic (e.g., HDL) lipoproteins. Human and clinical studies have shown that inhibitors of CETP can be effective in elevating HDL levels by 30-60%. And, epidemiological studies have 25 shown that decreased high-density lipoprotein cholesterol (HDL-C) is a powerful risk factor for coronary artery disease (CAD). Gordon et al., Circulation, 79, pp. 8-15, 1989; Despres et al., Atherosclerosis 153: 263-272, 2000. Elevating HDL-C has been shown to decrease this risk and it is estimated that each 1 mg/dl (0.02 mmol/1) elevation of HDL-C is associated with a 2-3% reduction in coronary heart 30 disease (CHD) risk, a magnitude comparable to that for low density lipoprotein -1 - WO 2007/075194 PCT/US2006/025427 (LDL) lowering. It has been recommended that serum HDL-C levels of >40 mg/dl be considered as a therapeutic target in primary and secondary prevention. This goal appears to be particularly important in patients with low serum HDL-C levels and ischemic heart disease (IHD) or its equivalents, even if the therapeutic target 5 for serum low-density lipoprotein cholesterol (LDL-C) levels (<100 mg/dl) has been achieved. It is believed that the anti-atherogenic role of HDL is in part due its ability to promote the efflux of free cholesterol from cells and to transport it to the liver, a process termed reverse cholesterol transport. HDL could protect against 10 atherosclerosis by several other mechanisms. For example, several studies showed HDL to have antioxidant and anti-inflammatory effects. Oxidative products of lipid metabolism induce inflammatory cell recruitment in vascular cells. HDL particles carry enzymes that retard LDL oxidation, including paraoxonase, platelet-activating factor acetylhydrolase, and lecithin-cholesterol acyltransferase. These 15 enzymes degrade pro-inflammatory, oxidized phospholipids, limiting their accumulation in LDL. In addition, apoA-I can bind oxidized lipids and remove them from LDL. Further, HDL also can act as a carrier vehicle for small molecules, including bacterial lipopolysaccharide (LPS) thus regulating the inflammatory effects of LPS. In animal models of endotoxic shock, HDL 20 attenuates organ injury and adhesion molecule expression. Thus elevating HDL is not only anti-atherogenic but it could also potentially be anti-inflammatoiy. Existing therapies such as, for example, HDL-elevating therapies and anti-atherosclerosis therapies have limitations including serious toleration issues. There is a present need to find alternative therapies including methods of preventing or 25 treating conditions or diseases associated with lipoprotein metabolism such as, for example, atherosclerosis. -2- WO 2007/075194 PCT/US2006/025427 SUMMARY OF THE INVENTION The present invention is directed to novel benzylamine compounds, novel compositions comprising these benzylamine compounds, and novel methods employing such benzylamine compounds and their compositions. Disclosed herein 5 are methods for making benzylamine compounds compounds, compositions comprising these benzylamines, and methods and compositions for using these benzylamines. The benzylamine compounds and compositions comprising these compounds have utility in treatment of a variety of diseases. Certain aspects of benzylamine compounds have been disclosed in PCT Publication WO 10 2004/020393, and in U.S. Patent Numbers 6,710,089 and 6,723,753. In one aspect, the present invention provides for compounds and compositions comprising these compounds, in which the compounds have the following formula: or a salt, including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: 20 A is selected from 15 -3 - WO 2007/075194 PCT/US2006/025427 Wherein R1, in each occurrence, is selected independently from hydrogen, halogen, alkyl, haloalkyl, alkoxy; R11, in each occurrence, is selected independently from hydrogen or alkyl; or alkoxy; Rlv, in each occurrence, is selected independently from hydrogen, alkyl, or -COR4 or CO2R5", Rv, in each occurrence, is selected independently from alkyl, aryl, or 10 -(CH2)mcycloalkyl; Rvl, in each occurrence, is selected independently from halogen, alkyl or aryl; R4 represents cycloalkyl; R5 represents alkyl; 15 m represents 0-2, inclusive; 5 Rm, in each occurrence, independently represents halogen, alkyl, haloalkyl p is an integer from 0 to 3, inclusive; 20 R1 and Rs independently represents -C(CH3)3 or -CF3; Rl represents hydrogen or hydroxyl; R3, in each occurrence, is selected independently from (i) a cyclic group selected from (ii) -C02Et, when ZR1 moiety represents S, SO, or SO2; -4- WO 2007/075194 PCT/US2006/025427 20 Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, - X CH2CH(CI-I3)OH, -CH2C02Et; (ii) V , ^ or"< Rc and Rf, in each occurrence, is selected independently from (i) hydrogen, 5 halogen, alkyl, heterocyclyl comprising at least one heteroatom selected independently from >0, >N, or >S,, any of which having up to 6 carbon atoms; or (ii) NRyRz, wherein Ry and Rz independently represents hydrogen or alkyl group; Rd, in each occurrence, is selected independently from hydrogen, halogen, -jlV ^D -1-f/ ^N-CH3 (Ci-C3)alkyl, -N(CH3)2> W or ? W ; 10 Re independently represents halogen; Z represents N; or the ZR1 moiety represents S, SO or S02; or the ZR*R2 moiety independently represents (i) -C(0)Z1Rg wherein Rg is hydrogen, cycloallcyl, aryl or (cycloallcyl)alkyl, Z1 represents O or NRh, wherein Rh is hydrogen, alkyl, cycloallcyl, or 15 (cycloalkyl)alkyl; or -l-N7 Yl-(CH2)COR5 , (ii) 5 \ / , R represents heterocyclyl comprises comprising at least one heteroatom selected independently from >0, >N, or >S; R1 and R2, in each occurrence, is selected independently from ethyl In another aspect, the present invention provides for compounds and compositions, in which the compounds have the following formula: r—*3 ,-m- -5- WO 2007/075194 PCT/US2006/025427 or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein all symbols are as defined above. Various aspects of the invention are provided. In yet another aspect, the present invention is also directed to methods or 5 processes for the preparation of the benzylamine compounds disclosed herein, including compounds of the general formula (I). In another aspect, this invention is also directed to compositions comprising the benzylamine compounds disclosed herein, including compounds of the general formula (I). When the composition is a pharmaceutical compositions, the composition also comprises a pharmaceutically 10 acceptable carrier and at least one compound according to this invention, and further comprises: optionally, a pharmaceutically acceptable auxiliary; optionally, a pharmaceutically acceptable preservative; optionally, a pharmaceutically acceptable excipient; optionally, a pharmaceutically acceptable diluent; and optionally, a pharmaceutically acceptable solvate. 15 The present invention also is directed to a method for treating a condition or disease in a mammalian subject, including a human. In some aspects, the method comprises administering to the subject a composition comprising a therapeutically-effective amount of at least one compound disclosed herein, or their pharmaceutically-acceptable salts thereof. Besides being useful for treating a 20 human subject, the methods and compositions of the present invention are useful for treating a variety of mammals such as, for example, companion animals such as cats or dogs, primates, ruminant animals, and rodents. The present invention also is directed to a method for treating or preventing a condition or disease in a human or an animal subject, the method comprising 25 administering to the subject a composition comprising a prophylactically- or therapeutically-effective amount of at least one compound disclosed herein, or their pharmaceutically-acceptable salts thereof. In some aspects, for example, this invention provides methods for the treatment and/or prevention of conditions or disease states in a human or anminal, such as dyslipidemia, atherosclerosis, 30 peripheral vascular disease, hypertryglyceridemia, hypercholesterolemia, -6- WO 2007/075194 PCT/US2006/025427 hyperbetalipoproteinemia, hypoalphalipoprotenemia, cardiovascular disorders such as angina, ischemia, stroke, myocardial infarction (MI), reperfusion injury, restenosis and hypertension, and diabetic vascular diseases such as diabetic retinopathy, and endotoxemia, comprising administering a therapeutically-effective 5 amount of at least one compound disclosed herein. In accordance with the present invention, novel benzylamine compounds and novel compositions comprising these benzylamine compounds are described. 10 In one aspect, compounds in accordance with the present invention can comprise benzylamine compounds having the following formula: or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: DETAILED DESCRIPTION OF THE INVENTION 15 A is selected from Wherein R1, in each occurrence, is selected independently from hydrogen, halogen, 20 alkyl, haloalkyl, alkoxy; R11, in each occurrence, is selected independently from hydrogen or alkyl; -7- WO 2007/075194 PCT/US2006/025427 Rm, in each occurrence, independently represents halogen, alkyl, haloalkyl or alkoxy; RIV, in each occurrence, is selected independently from hydrogen, alkyl, or -COR4 or C02Rs; 5 Rv, in each occurrence, is selected independently from alkyl, aryl, or -(CH2)mcycloalkyl; RVI, in each occurrence, is selected independently from halogen, alkyl or aryl; R4 represents cycloalkyl; 10 R5 represents alkyl; m represents 0-2, inclusive; p is an integer from 0 to 3, inclusive; Rr and Rs independently represents -C(CH3)3 or -CF3; R1 represents hydrogen or hydroxyl; 15 R3, in each occurrence, is selected independently from (i) a cyclic group selected from KRVrpAR- NyN N-^N N^N \AAA/ _ • _ _ \AAA> vVW lAA/V 1 or i ; or (ii) -C02Et, when ZR1 moiety represents S, SO, or SO2; Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, 20 -(CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NI-I2, - X CH2CH(CH3)OH, -CH2C02Et; (ii) V , or^ Rc and Rf, in each occurrence, is selected independently from (i) hydrogen, halogen, alkyl, heterocyclyl comprising at least one heteroatom selected independently from >0, >N, or >S,, any of which having up to 6 carbon atoms; or 25 (ii) NRyRz, wherein Ry and Rz independently represents hydrogen or alkyl group; -8- wo 2007/075194 pct/us2006/025427 Rd, in each occurrence, is selected independently from hydrogen, halogen, -l-l/ ^0 -i-t/ Yl-CH3 (C,-C3)alkyl, -N(CH3)2, V_V or * V_/ ; Re independently represents halogen; Z represents N; or the ZR1 moiety represents S, SO or SO2; or 5 the ZR'R2 moiety independently represents (i) -C(0)Z'R8 wherein Rg is hydrogen, cycloalkyl, aryl or (cycloalkyl)alkyl, Z1 represents O or NRh, wherein Rh is hydrogen, alkyl, cycloalkyl, or 5 -i-N N-(CHz)CORl -(cycloalkyl)alkyl; or (ii) ? \—/ , R represents heterocyclyl comprises comprising at least one heteroatom selected independently from >0, >N, 10 or >S; R1 and R2, in each occurrence, is selected independently from X ethyl, V ? V or O Another aspect of the present invention provides benzylamine compounds 15 according to formula (I), having the formula: -cf3 or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein all symbols are as defined above. 20 -9- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compounds according to formula (la), wherein A is selected from Rilrt RVI N / or 10 15 Another aspect of the present invention provides benzylamine compounds according to formula (la), having the following formula: or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R\ is CI, -OCH3, -CH3, -CH(CH3)2, or -CF3; Rb represents a) methyl, isopropyl, -CH2-CH2-OH, -CH2-CH2-OCH3, -CI-I2-CH2-NH-C02CH(CH3)3, -CH2-CH2-NH2, -CH2-CH(CH3)-OH, or -CH2-C02Et; b) X , "V , or Another aspect of the present invention provides benzylamine compound according to formula (II), wherein R1 and Rb independently represent -CH3. -10- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (II), which is (5)-(+)-(3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]methyl} -8-methyl-quinolin-2-yl)-ethyl- (tetrahydro-furan-2-ylmethyl)-amine. 10 15 Another aspect of the present invention provides benzylamine compound according to formula (II), which is (i?)-(-)-(3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]methyl}~8-methyl-quinolin-2-yl)-ethyl-(tetrahydro-furan-2-ylmethyl)-amine. Another aspect of the present invention provides benzylamine compounds according to formula (la), having the following formula: or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R'" is -CH3, CF3, CI, -OC.H3, or-CH(CH3)2; R" is H or -CH3; Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, - X 20 CH2CH(CH3)OH, -CH2C02Et; (ii) or"^ Another aspect of the present invention provides benzylamine compound according to formula (III), wherein R11 is hydrogen. -11 - WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (III), which is (3-{[3,5-bis trifluoromethyl-benzyl)-(2-cyclopropylmethyl-2H-tetrazole-5-yl)-amino]-methyl}-8-methyl-quinoline-2-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an 5 enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (III), which is (3~{[3,5 -bis trifluoromethyl-benzyl )-(2-cyclopentyl -2H-tetrazole -5-yl)-amino]methyl-}~8-methyl-quinoline-2-yl)- bis-10 cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (III), which is (3-{[3,5-bis trifluoromethyl-benzyl )-(2-15 cyclohexyl -2H-tetrazole -5-yl)-amino]-methyl}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound 20 according to formula (III), which is (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-isopropyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 25 Another aspect of the present invention provides benzylamine compound according to formula (III), which is (2-{5-[[2-(bis-Cyclopropylmethyl-amino)-8-methyl-quinolin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethyl)-carbamic acid tert-butyl ester; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 30 -12- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (III), which is (3-{[[2-amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bistrifluoromethyl-benzyl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an 5 enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (III), which is l-{5-[[2-(bis-cyclopropylmethyl-amino)8-methyl-quinoline-3-ylmethyl]-(3,5-bistrifluoro methyl-benzyl)-amino]-tetrazol-2-10 yl}-propane-2-ol; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (III), which is (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-15 methyl-2H-tetrazol-5-yl)-amino]-methyl} -8-trifluoromethyl-quinolin-2-yl)-bis- cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound 20 according to formula (III), which is (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-Chloro-quinoline-2-yl)- bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 25 Another aspect of the present invention provides benzylamine compound according to formula (III), which is 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methoxy-quinoline-2-yl)- bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 30 -13- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (III), which is 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-} -8-isopropyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an 5 enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (III), which is 2-{5-[[2-(bis-cyclopropylmethyl-amino)-8-methyl-quinoline-3-ylmethyl]-(3,5-bis trifluoromethyl-benzyl)-amino]-tetrazol-2-10 yl}-ethanol; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (III), which is [3-({(3,5-bis-trifluoromethyl-benzyl)-[2-(2-15 methoxy-ethyl)-2H-tetrazol-5-yl]-amino}-methyl)-8-methyl-quinolin-2-yl]-bis- cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (III), which is 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl 20 -2H-tetrazole -5-yl)-amino]-methyl-}-7,8-dimethyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound 25 according to formula (III), which is {5-[[2-(bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl} -acetic acid ethyl ester; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. -14- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compounds according to formula (la), having the following formula: or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic 5 mixture, or any combination thereof, wherein: Another aspect of the present invention provides benzylamine compound according to formula (IV), which is (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(4-chloro-[ 1,3,5]triazin-2-yl)-amino]-methyl} -8-methyl-quinolin-2-yl)-bis-15 cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (IV), which is N-[2-(Bis-cyclopropylmethyl-amino)-8-20 methyl-quinolin-3-ylmethyl]-N-(3,5-bis-trifluoromethyl-benzyl)-N',N'-dimethyl-[l,3,5]triazine-2,4-diamine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. R1, is CI, -OCH3, -CH3, -CH(CH3)2, or -CF3; Rc represents halogen, -N(CH3)2, or Another aspect of the present invention provides benzylamine compound 10 according to formula (IV), wherein R1 is -CH3. -15- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (IV), which is (3-{[(3,5-Bis-trifhioromethyl-benzyl)-(4-morpholin-4-yl-[l,3,5]triazin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an 5 enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compounds according to formula (la), having the following formula: 10 or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R', is CI, -OCH3, -CH3, -CH(CH3)2, -CF3; , -l-l/ P ^N-CH3 R represents hydrogen, -Br, - CH2CH3, -N(CH3)2, \—/ or 5 \—/ ; 15 Another aspect of the present invention provides benzylamine compound according to formula (V), wherein R1 represents -CH3. Another aspect of the present invention provides benzylamine compound according to formula (V), which is (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-20 pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. -16- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (V), which is (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an 5 enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (V), which is (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-ethyl-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-10 amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (V), which is A^-[2-(bis-cyclopropylmethyl-amino)-8-methyl-15 quinolin-3 -ylmethyl] -N-(3,5-bis-trifluoromethyl-benzyl)-/^ ,iV -dimethyl- pyrimidine-2,5-diamine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound 20 according to formula (V), which is [3-({((3,5-bis-trifluoromethyl-benzyl)-[5-(4-methyl-piperazin-l-yl)-pyrimidin-2-yl]-amino}-methyl)-8-methyl-quinolin-2-yl]-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 25 Another aspect of the present invention provides benzylamine compound according to formula (V), which is (3 - {[(3,5-bis-trifluoromethyl-benzyl)-pyrimidin-2-yl-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 30 -17- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: 5 or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R\ is CI, -OCH3, -CH3, -CH(CH3)2, -CF3; S, / \ / \ N O -1-N N-CH3 R represents hydrogen, -Br, -N(CH3)2, \—/ or 5 \—/ ; 10 Another aspect of the present invention provides benzylamine compound according to formula (VI), wherein R1 is -OCH3 and Rd is -Br. Another aspect of the present invention provides benzylamine compound according to formula (VI), which is (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-15 bromo-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-cyclobutylmethyl-ethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. -18- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic 5 mixture, or any combination thereof, wherein: 10 according to formula (VII), wherein R1 is -CH3 and Re is -Br. Another aspect of the present invention provides benzylamine compound according to formula (VII), which is (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyridin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-15 cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: Rb (VII); R1, is CI, -OCH3, -CH3, -CH(CH3)2, or -CF3; Re represents -Br. Another aspect of the present invention provides benzylamine compound 20 -19- WO 2007/075194 PCT/US2006/025427 or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: Rvi, is F, CI, -CH3, -CH2CH3, -CH(CH3)2 or phenyl; R", is H or -CH3; 5 Rbis -CH3. Another aspect of the present invention provides benzylamine compound according to formula (VIII), wherein Rvi, is F, -CH2CH3, -CH(CH3)2 or phenyl; 10 R", is H or -CH3; Rbis -CH3. Another aspect of the present invention provides benzylamine compound according to formula (VIII), which is (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-15 methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-isopropyl-5-methyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound ) 20 according to formula (VIII), which is (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5 -yl)-amino] -methyl} -6-isopropyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 25 Another aspect of the present invention provides benzylamine compound according to formula (VIII), which is (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-ethyl-5-methyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 30 -20- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (VIII), which is (3-{[3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-5-methyl-6-phenyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an 5 enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (VIII), which is (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5 -yl)-amino] -methyl} -6-fluoro-pyridin-2-yl)-bis-10 cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: 15 Rv, is -CH3, -CH2CH3, -CH(CH3)2, phenyl, or R" is -H or -CH3; 20 -21 - WO 2007/075194 PCT/US2006/025427 10 Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, - X CH2CH(CH3)OH,-CH2C02Et; (ii) V , ^ or^ Another aspect of the present invention provides benzylamine compound according to formula (IX), wherein Rv, is -CH3 or phenyl; R" is -H or -CH3; Rb is methyl. Another aspect of the present invention provides benzylamine compound according to formula (IX), which is (5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl} -1 -phenyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an 15 enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: R\ \x R1 h n^n (X); 20 or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: X Rv, is -CH3, -CH2CH3, -CH(CH3)2, phenyl, or -22- WO 2007/075194 PCT/US2006/025427 5 Ru is -H or -CH3; Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, - X CH2CH(CH3)OH, -CH2C02Et; (ii) V , ^ or'K Another aspect of the present invention provides benzylamine compound according to formula (X), wherein X Rv is R" is -H or -CH3; 10 Rbis methyl. Another aspect of the present invention provides benzylamine compound according to formula (X), which is 5- {[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5 -yl)-amino]methyl} -1 -cyclopropylmethyl-1 H-pyrazolo[3,4-b]pyridin-15 6-yl)-cyclobutylmethyl-ethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: 20 V (XI); or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: -23 - WO 2007/075194 PCT/US2006/025427 10 X Rv, is -CH3, -CH2CH3, -CH(CH3)2, phenyl, or R" is -H or -CH3; , -^-N7 ^0 -l-U ^N-CH3 R represents hydrogen, -Br, -N(CH3)2, \—/ or 5 \—/ ; Another aspect of the present invention provides benzylamine compound according to formula (XI), wherein Rv, is -CH3 or -CH2CH3; R" is -H or -CH3; . -iV p R is-Br or \—/ . Another aspect of the present invention provides benzylamine compound according to formula (XI), which is (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino] -methyl} -1,3 -dimethyl-1 H-pyrazolo [3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an 15 enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (XI), which is (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino] -methyl} -1 -ethyl-1 H-pyrazolo [3,4-b]pyridin-6-yl)-20 bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (XI), which is (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-(4-25 morpholin-4-yl-phenyl)-pyrimidin-2-yl] -amino } -methyl)-1 -ethyl-1 H-pyrazolo [3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. -24- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: (XII); or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: Rv is -CH3, -CH2CH3, -CH(CH3)2, phenyl, or R" is -H or -CH3; R° represents halogen, -N(CH3)2, -n o -f-n / or 5 \ n-ch3 10 Another aspect of the present invention provides benzylamine compound according to formula (XII), wherein Rv is -CH3; R" is -CH3; Rc is -N(CH3)2.. 15 Another aspect of the present invention provides benzylamine compound according to formula (XII), which is (5-{[(3,5-Bis-trifluoromethyl-benzyl)-(4-N,N dimethylamino-[ 1,3,5]triazin-2-yl)-amino]-methyl} -1,3-dimethyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric 20 mixture, an enantiomer, a tautomer, or a racemic mixture. -25- WO 2007/075194 PCT/US2006/025427 10 Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: Rb\ CF3 0-Rg (XIII); or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R1V is H, -CH3, -CH2CH3, -CH2CH2CH3, -CO2CH2CI-I3, 7 , or O A/. Rb is -CH3; Rg is -CH2CH3. Another aspect of the present invention provides benzylamine compound according to formula (XIII), which is 3-{[( 3,5-Bis-trifluormethyl-benzyl )- ( 2-methyl-2H-tetrazol-5-yl)-amino]-methyl } -lH-indole-2-carboxylic acid ethyl ester; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a 15 racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (XIII), which is 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl} -1 -methyl-1 H-indole-2-carboxylic acid 20 ethyl ester; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. -26- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (XIII), which is 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl} -1 -propyl-1 H-indole-2-carboxylic acid ethyl ester; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a 5 tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (XIII), which is 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino] -methyl} -1 -cyclopentanecarbonyl-1 H-indole-2-10 carboxylic acid ethyl ester; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (XIII), which is 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-15 methyl-2H-tetrazol-5-yl)-amino] -methyl} -1 -ethyl-1 H-indole-2-carboxylic acid ethyl ester; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound 20 according to formula (XIII), which is 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino] -methyl} -indole-1,2-carboxylic acid ethyl ester; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 25 Another aspect of the present invention provides benzylamine compound according to formula (XIII), which is 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino] -methyl} -1 -cyclopropanecarbonyl-1 H-indole-2-carboxylic acid ethyl ester; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 30 -27- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: Rb\ (XIV); or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic 5 mixture, or any combination thereof, wherein: O O V R1V is H, -CH3, -CH2CH3, -CH2CH2CH3, C02 CH2CH3, ' , or Rb is -CH3; Rg is -CH2CH3 or 10 Rh is-CH2CH3 or Another aspect of the present invention provides benzylamine compound according to formula (XIV), wherein Riv is H, -CH3 or -CH2CH2CH3. 15 Another aspect of the present invention provides benzylamine compound according to formula (XIV), which is 3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-3H-indole-2-carboxylic acid diethylamide; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 20 -28- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (XIV), which is 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-methyl-lH-indole-2-carboxylic acid diethylamide; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a 5 tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (XIV), which is 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino] -methyl} -1 -methyl-1 H-indole-2-carboxylic acid bis-cyclopropylmethyl-amide; or a salt, a prodrug, a diastereomeric mixture, an 10 enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (XTV), which is 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino] -methyl} -1 -propyl-1 H-indole-2-carboxylic acid 15 bis-cyclopropylmethyl-amide; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: R1 (XV) or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R1 is hydrogen or -CH3; ZR1 moiety represents S, SO or SO2; R2 is -CH3, -CH2CH3 or -CH2CH2CH3. 20 -29- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (XV), wherein R' is -CH3; R2 is -CH2CH3. 5 Another aspect of the present invention provides benzylamine compound according to formula (XV), which is (3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-carbamic acid ethyl ester; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (XV), which is (3,5-Bis-trifluoromethyl-benzyl)-[8-methyl-2-(propane-l-sulfonyl)-quinolin-3-ylmethyl]-carbarnic acid ethyl ester; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic 15 mixture. Another aspect of the present invention provides benzylamine compound according to formula (XV), which is (3,5-Bis-trifluoromethyl-benzyl)-[8-methyl-2-(propane-l-sulfinyl)-quinolin-3-ylmethyl]-carbamic acid ethyl ester; or a salt, a 20 prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: 10 25 -30- WO 2007/075194 PCT/US2006/025427 or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R11' in each occurrence, independently represent hydrogen, -CH3, -CH2CH3, or -CH(CH3)2; 5 Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, - X CH2CH(CH3)OH,-CH2C02Et; (ii) V , ^ or^ Another aspect of the present invention provides benzylamine compound 10 according to formula (XVI), wherein Ru is -CH3, Rb is methyl. Another aspect of the present invention provides benzylamine compound according to formula (XVI), which is (6-{[(3,5-Bis-trifhioromethyl-benzyl)-(2-15 methyl-2H-tetrazol-5-yl)-amino]-methyl}-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 20 Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: (XVII) or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: -31 - WO 2007/075194 PCT/US2006/025427 Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, - X CH2CH(CH3)OH, -CH2C02Et; (ii) V or^v Another aspect of the present invention provides benzylamine compound according to formula (XVI), which is 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-benzo[h]quinolin-2-yl)- bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an 10 enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compounds according to formula (la), having the formula: (XVIII) 15 or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein Rh is H, -CH3 or -CH(CH3)2; Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, - X. 20 CH2CH(CH3)OH, -CH2C02Et; (ii) V , or^ -32- WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (XVIII), wherein: Rh is H or -CH3; Rb is methyl. 5 Another aspect of the present invention provides benzylamine compound according to formula (XVIII), which is 3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-methyl-quinolin-4-yl)-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an 10 enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (XVIII), which is (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-quinolin-4-yl)-bis-cyclopropylmethyl-15 amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (I), which is 2-[4-(3-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-20 bromo-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-piperazin-l-yl]-l-pyrrolidin-1 -yl-ethanone; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound 25 according to formula (I), which is [3-({((3,5-bis-trifluoromethyl-benzyl)-[(4-morpholin-4-yl-phenyl)-amino]-methyl)-8-methyl-quinolin-2-yl]-bis-cyclopropylmethyl-amine; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. -33 - WO 2007/075194 PCT/US2006/025427 Another aspect of the present invention provides benzylamine compound according to formula (I), which is 4-{[[2-(bis-cyclopropylmethyl-amino)8-methyl-quinoline-3-yknethyl]-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-2,6-di-/er/-butyl-phenol; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a 5 tautomer, or a racemic mixture. Another aspect of the present invention provides benzylamine compound according to formula (I), which is selected from (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-cyclopropylmethyl -2H-tetrazole -5-yl)-10 amino]-methyl-}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-cyclopentyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; 15 (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-cyclohexyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-isopropyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; 20 (2-{5-[[2-(bis-Cyclopropylmethyl-amino)-8-methyl-quinolin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethyl)-carbamic acid tert-butyl ester; (3 - {[ [2-amino-ethyl)-2H-tetrazol-5 -yl] -(3,5-bistrifluoromethyl-benzyl)-amino] -25 methyl} -8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; 1 - {5-[[2-(bis-cyclopropylmethyl-amino)8-methyl-quinoline-3-ylmethyl]- (3,5-bistrifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-propane-2-ol; 30 (3 - {[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino] -methyl} -8-trifluoromethyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-Chloro-quinoline-2-yl)- bis-cyclopropylmethyl-amine; 35 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methoxy-quinoline-2-yl)- bis-cyclopropylmethyl-amine; 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-40 methyl-}-8-isopropyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; -34- WO 2007/075194 PCT/US2006/025427 2-{5-[[2-(bis-cyclopropylmethyl-amino)-8-methyl-quinoline-3-ylmethyl]- (3,5- bistrifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethanol; [3-({(3,5-bis-trifluoromethyl-benzyl)-[2-(2-methoxy-ethyl)-2H-tetrazol-5-yl]-5 amino}-methyl)-8~methyl-quinolin-2-yl]-bis-cyclopropylmethyl~amine; 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-7,8-dimethyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; 10 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-} -benzo[h]quinolin-2-yl)- bis-cyclopropylmethyl-amine; (S)-(+)-(3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]methyl}-8-methyl-quinolin-2-yl)-ethyl-(tetrahydro-furan-2-ylmethyl)-amine; 15 (R)-(-)-(3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazoI-5-yI)-amino]methyl}-8-methyl-quinolin-2-yl)-ethyl-(tetralaydro-furan-2-ylmethyl)-amine; (5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-20 1 -phenyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-l,3-dimethyl-lH-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; 25 (5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]methyl}-l-cyclopropylmethyl-lH-pyrazolo[3,4-b]pyridin-6-yl)-cyclobutylmethyl-ethyl-amine; (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5~bromo-pyrimidin-2-yl)-amino]-methyl}-l-30 ethyl-lH-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-(4-morpholin-4-yl-phenyl)-pyrimidin-2-yl] -amino } -methyl)-1 -ethyl-1 H-pyrazolo [3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; 35 (3 - {[(3,5 -bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl} - 8-methyl-quinolin-2-yl)-cyclobutylmethyl-ethyl-amine; (3 - {[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino] -methyl} -8-40 methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholm-4-yl-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; -35- WO 2007/075194 PCT/US2006/025427 (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-ethyl-pyrimidin-2-yl)-amino]-methyl}-8- methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; N-[2-(bis-cyclopropyhiiethyl-amino)-8-methyl-quinolin-3-ylmethyl]-N-(3,5-bis-5 trifluoromethyl-benzyl)-N' ,N'-dimethyl-pyrimidine-2,5-diamine; [3-({((3,5-bis-trifluoromethyl-benzyl)-[5-(4-methyl-piperazin-l-yl)-pyrimidin-2-yl]-amino}-methyl)-8-methyl-quinolin-2-yl]-bis-cyclopropylmethyl-amine; 10 (3-{[(3,5-bis-trifluoromethyl-benzyl)-pyrimidin-2-yl-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyridin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; 15 (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-isopropyl-5-methyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[(3,5-Bis-trifhioromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-20 6-isopropyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-ethyl-5-methyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; 25 (3-{[3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-5-methyl-6-phenyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; {5-[[2-(bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-acetic acid ethyl ester; 30 (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(4-chloro-[l,3,5]triazin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; N-[2-(Bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-ylmethyl]-N-(3,5-bis-35 trifluoromethyl-benzyl)-N',N'-dimethyl-[l,3,5]triazine-2,4-diamine; (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(4-morpholin-4-yl-[l,3,5]triazin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; 40 (5-{[(3,5-Bis-trifluoromethyl-benzyl)-(4-N,N,dimethylamino-[l,3,5]triazin-2-yl)-amino] -methyl} -1,3-dimethyl-1 H-pyrazolo [ 3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; 3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-45 6-methyl-quinolin-4-yl)-bis-cyclopropylmethyl-amine; -36- WO 2007/075194 PCT/US2006/025427 (3 - {[(3,5-Bis-trifhioromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl} - quinolin-4-yl)-bis-cyclopropylmethyl-amine; 5 (6- {[(3,5-Bis-trifhioromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl} -2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-bis-cyclopropylmethyl-amine; 3-{[( 3,5-Bis-trifluormethyl-benzyl )- ( 2-methyl-2H-tetrazol-5-yl)-amino]-methyl } -lH-indole-2-carboxylic acid ethyl ester; 10 3-{[(3,5-bis-trifhioromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-methyl-lH-indole-2-carboxylic acid ethyl ester; 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-15 1 -propyl-1 H-indole-2-carboxylic acid ethyl ester; 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-cyclopentanecarbonyl-lH-indole-2-carboxylic acid ethyl ester; 20 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-ethyl-lH-indole-2-carboxylic acid ethyl ester; 3 - {[(3,5 -bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5 -yl)-amino] -methyl} -indole-1,2-carboxylic acid ethyl ester; 25 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-cyclopropanecarbonyl-lH-indole-2-carboxylic acid ethyl ester; 3 - {[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5 -yl)-amino] -methyl} -30 3H-indole-2-carboxylic acid diethylamide; 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-methyl-lH-indole-2-carboxylic acid diethylamide; 35 3 - {[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino] -methyl} -1 -methyl-lH-indole-2-carboxylic acid bis-cyclopropylmethyl-amide; 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1 -propyl-1 H-indole-2-carboxylic acid bis-cyclopropylmethyl-amide; 40 (3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-carbamic acid ethyl ester; (3,5-Bis-trifluoromethyl-benzyl)-[8-methyl-2-(propane-l-sulfonyl)-quinolin-3-45 ylmethyl]-carbamic acid ethyl ester; -37- WO 2007/075194 PCT/US2006/025427 (3,5-Bis-trifluoromethyl-benzyl)-[8-methyl-2-(propane-l-sultinyl)-quinolin-3-" ylmethyl]-carbamic acid ethyl ester; 5 (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-fluoro-pyridin-2-yl)-bis-cyclopropylmethyl-amine; 2-[4-(3-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl} -8-methyl-quinolin-2-yl)-piperazin-l -yl]-l -pyrrolidin-1 -yl-ethanone; 10 [3-({((3,5-bis-trifhioromethyl-benzyl)-[(4-morpholin-4-yl-phenyl)-amino]-methyl)-8-methyl-quinolin-2-yl]-bis-cyclopropylmethyl-amine; 4-{[[2-(bis-cyclopropylmethyl-amino) -8-methyl-quinolin-3-ylmethyl]-(2-methyl-15 2F[-tetrazol-5-yl)-amino]-methyl}-2,6-di-fert-butyl-phenol; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. hi still a further aspect of the present invention, this disclosure provides 20 benzylamine compounds. By the disclosure of these specific compounds, it is intended to include any salt, including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, any prodrug, and any stereoisomer, including diastereomeric mixtures, enantiomers, tautomers, racemic mixtures, or any combinations thereof, of the disclosed compounds. 25 The present invention also encompasses any combination of compounds provided herein, including any salts, including pharmaceutically acceptable and non-pharmaceutically acceptable salts, or any mixture thereof. The present invention also encompasses any stereoisomers of compounds provided herein, including any combination of stereoisomers. 30 In this aspect of the present invention, compounds provided herein can be chiral or achiral, or they may exist as racemic mixtures, diastereomers, pure enantiomers, a prodrug, a tautomer or any mixture thereof. For chiral compounds, separate enantiomers, separate diastereomers, and any mixture of enantiomers, diastereomers, or both are encompassed herein, such as, for example, (R), (S), or a 35 mixture of (R) and (S) isomers. In this aspect, individual optical isomers or a -38- WO 2007/075194 PCT/US2006/025427 particular desired isomer may be obtained by using chiral reagents to obtain a single isomeric form in a resolution process wherever applicable, or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric or diasteromeric form. 5 In one aspect, methods for the resolution of racemic compounds include, but are not limited to: using microbial resolution; resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable; or resolving the diastereomeric salts formed with chiral bases such as brucine, cinchona alkaloids and their 10 derivatives; and the like. Commonly used methods are compiled in Jaques, et al. in Enantiomers, Racemates and Resolution; Wiley-Interscience, 1981. For example, where appropriate, compounds of formula (I) can be resolved by treating with chiral amines, aminoacids, or aminoalcohols derived from aminoacids; by using conventional reaction conditions to convert an acid into an amide; by 15 separation of diastereomers by fractional crystallization or by chromatography; or by preparing the stereoisomers of formula (I) by hydrolyzing the pure diastereomeric amide. As used herein, the terms "pharmaceutically acceptable" salt or "pharmacologically acceptable" salt refers generally to a salt or complex of the 20 compound or compounds in which the compound can be either anionic or cationic, and have associated with it a counter cation or anion, respectively, that is generally considered suitable for human or animal consumption. For example, a pharmaceutically acceptable salt can refer to a salt of a compound disclosed herein that forms upon reaction or complexation with an acid whose anion is generally 25 considered suitable for human or animal consumption. In this aspect, pharmacologically acceptable salts include salts with organic acids or inorganic acids. Examples of pharmacologically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, propionate, lactate, maleate, malate, succinate, tartarate, and the like. -39- WO 2007/075194 PCT/US2006/025427 Salts may also be formed by deprotonating an acid moiety of the compound, such as a carboxylic acid moiety, OH, or NH, and the like, using a base such as an organic base, an inorganic base, an organometallic base, a Lewis base, a Bransted base, or any combination thereof, hi cases where compounds carry an 5 acidic moiety, suitable pharmaceutically acceptable salts can include alkali metal salts, alkaline earth metal salts, or salts with organic basis, and the like. In this aspect, examples of alkali metal salts include, but are not limited to, sodium and potassium salts, and examples of salts with organic basis include, but are not limited to, meglumine salts, and the like. The pharmacologically acceptable salts 10 can be prepared by conventional means. Additional examples of pharmaceutically acceptable salts, and methods of preparing such salts, are found, for example, in Berg et.al., J. Pharma. Sci, 66, 1-19 (1977). In a further aspect, this invention also provides a composition comprising at least one compound as disclosed herein, including a composition comprising a 15 pharmaceutically acceptable carrier and at least one compound as disclosed herein. In this aspect, the at least one compound can be present as a neutral compound, as a salt, or as any combination thereof. This invention also encompasses a composition comprising at least one compound as disclosed herein, and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an 20 auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof. In another aspect, this invention encompasses a pharmaceutical composition comprising at least one compound as disclosed herein, and optionally further comprising an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, an anti-inflammatory 25 agent, an antidyspilidemic agent, an antirheumatic agent, a cardiovascular agent, or any combination thereof. Further, this invention encompasses a pharmaceutical composition, comprising at least one compound as disclosed herein, and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, 30 an excipient, a preservative, a solvate, or any combination thereof, wherein the -40- WO 2007/075194 PCT/US2006/025427 pharmaceutical composition is in the form of a tablet, a capsule, a syrup, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, or a transdermal patch. 5 In another aspect of this invention, alternatively, the compounds can be formulated and administered in a prodrug form. In general, prodrugs comprise functional derivatives of the claimed compounds which are capable of being enzymatically activated or converted into the more active parent form. Thus, in the treatment methods of the present invention, the term "administering" encompasses 10 the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Wihnan, 14 Biochem. Soc. Trans. 375-82 15 (1986); Stella et al., Prodrugs: A Chemical Approach to Targeted Drug Delivery, in Directed Drug Delivery 247-67 (1985). Thus, in one aspect, "prodrugs" of the compounds disclosed herein refers to species that have chemically- or metabolically-cleavable groups wherein, under physiological conditions, the species become, provide, release, or are transformed 20 into the compounds disclosed herein. In this manner, prodrugs can release the pharmaceutically in vivo active compounds disclosed herein. For example, prodrugs of present invention include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, 0-25 lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs, optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine or other 5-fluorouridine prodrugs which may be converted into the more active species, and the like. In another aspect, prodrugs of present invention include, but are not limited to derivatives of carboxylic acid, sulfonamide, amine, -41 - WO 2007/075194 PCT/US2006/025427 hydroxyl, and the like, including other functional groups and including any combination thereof. In another aspect, this invention provides a pharmaceutical composition, comprising one or more compounds of any formula in any combination described 5 above and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof. In a related aspect, this invention affords a method of treating a condition or disease state such as dyslipidemia, atherosclerosis, peripheral vascular disease, hypertryglyceridemia, hypercholesterolemia, hyperbetalipo-10 proteinemia, hypoalphalipoprotenemia, cardiovascular disorders such as angina, ischemia, stroke, myocardial infarction (MI), reperfusion injury, restenosis and hypertension, and diabetic vascular diseases such as diabetic retinopathy, and endotoxemia, comprising administering an effective amount of at least one compound as disclosed herein. 15 SYNTHETIC METHODS General reaction schemes are provided herein that detail the synthetic approaches to the benzylamine compounds disclosed herein. Thus, compounds in accordance with this disclosure could be prepared as shown in the specific 20 Schemes and/or as illustrated in the Examples by using standard synthetic methods and starting materials, which are either commercially available or can be synthesized from commercially available precursors using synthetic methods known in the art, or variations thereof as appreciated by those skilled in the art. Each variable in the following schemes refer to any group consistent with the 25 description of the compounds provided herein. In each synthetic scheme or example provided, substitutents in any structure that are illustrated in the scheme or example that are not specified are selected as disclosed according to the general formulas of the compounds provided herein. -42- WO 2007/075194 PCT/US2006/025427 The following general procedures could be used in the reactions schemes and in the Examples provided herein. Halogenation could be carried out by using reagents such as phosphorus oxychloride (POCI3), thionyl chloride (SOClo), and the like, for example, at a 5 temperature from about 80°C to about 120°C, for about 4 to about 8 hours, followed by pH adjustment of resultant mixture to a pH from about 6 to about 7. Amination could be carried out by using amines in presence of a solvent chosen from acetone, acetonitrile, dimethylformamide, dimethylacetamide and the like, with or with out a base. Suitable bases include triethylamine, N,N-diisopropyl 10 ethyl amine, potassium carbonate, sodium carbonate, sodium hydride, and the like. The reaction temperature was typically from about 20°C to about 120°C, and the duration of the reaction was typically in the range of from about 4 hours to about 20 hours. Thus one further aspect of the invention relates to the processes of 15 preparing compounds of formulas provided herein. Any compound of any formula disclosed herein can be obtained using procedures provided in the reaction Schemes, as well as procedures provided in the Examples, by selecting suitable starting materials and following analogous procedures. Thus, any compound of any formula disclosed or exemplified herein, can be obtained by using the 20 appropriate starting materials and appropriate reagents, with the desired substitutions, and following procedures analogous to those described herein. Therefore, it will be readily understood by one of ordinary skill, that the reaction schemes disclosed herein can be adapted to prepare any compound of this disclosure, therefore any discussion of a particular step in a reaction scheme is 25 intended to reflect one method or one set of considitions that can be used to carry out that step. This discussion of a particular step is not intended to be limiting, but rather exemplary, of one particular method and set of conditions by which that step can be effected. -43 - WO 2007/075194 PCT/US2006/025427 In one aspect of this invention, compounds of formula (I) according to this invention could be prepared as illustrated in at least one of the following Schemes 1-5. In some cases, the relevant reagents and starting materials were commercially available. In other cases, the relevant reagents and starting materials were made by 5 standard synthetic procedures in organic and heterocyclic chemistry, and known by one of ordinary skill in the relevant art. These techniques were analogous to the synthesis of known structurally similar intermediates or starting materials and the procedures described in preparations and examples below. For example the following references disclosed the exact procedures or analogues procedures for 10 the preparation of many of the intermediates described in Schemes 1-5: Synlett., 2001, No: 2, 251-253; Synthesis 2001, 1185-1196; Journal of Heterocyclic Chemistry, 1987, 351-355; Journal of Organic Chemistry Vol: 30, 1965, 3593-3596; Journal of Heterocyclic Chemistry 1982, 809-811. Such known procedures include the reduction of aldehydes, cyanation, alkylation of amines, benzylation, 15 acylation of amines, sulfonylation of amines, reductive amination, hydrolysis of nitriles, esterification of carboxylic acids and carboxylic acids to amide conversions, and the like. Thus, in the following representative synthetic schemes, the starting materials were either commercially available or readily prepared using well known 20 procedures, using starting materials and/or reagents having the appropriate substitution. As the context of any scheme or Example demands or allows, substitutents in any structure that are not specified are selected as provided herein in the general description of the disclosed compounds. In one aspect, compounds according to the present invention could be 25 prepared according to the following scheme. .44. WO 2007/075194 PCT/US2006/025427 In one aspect, compounds according to the present invention could be prepared according to the following scheme: Scheme 1 Representative steps of Scheme 1 include the following. The compound of formula (la') could be converted to a compound of formula (lb) by an amination reaction using HNR'R2, in a polar solvent such as N,N-dimethylformamide (DMF) 10 and a base such as sodium carbonate or potassium carbonate. The reaction could also be carried out in the presence of a solvent such as acetonitrile, tetrahydroforan, or toluene. The base could also be selected from cesium carbonate, potassium tertiary butoxide, and the like. -45- WO 2007/075194 PCT/US2006/025427 Reductive amination of compound of formula (lb) with a compound of formula (Ic), in presence of a reducing agent such as Na(CN)BH3, Na(OAc)3BH, NaBH4 and the like, in a (C1-C10) alcohol solvent such as methanol, ethanol, propanol, isopropanol, and the like, or a chlorinated solvent such as 5 dichloromethane, chloroform, 1,2-dichloroethane, and the like, along with an acid such as acetic acid or diluted hydrochloric acid, yields a compound of formula (I), wherein R3 is typically hydrogen. In one aspect, the temperature of the reaction could be maintained from about 25 °C to about 35 °C, and the duration of the reaction typically could range from about 30 minutes to about 5 hours. 10 The compound of formula (Id), could be converted to a compound of formula (Ie), in the presence of cyanogen bromide (CNBr), by using a suitable solvent such as dimethylformamide, acetonitrile, a (Ci-Cio) alcohol, or the like, along with a base such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, and the like. In one aspect, 15 the temperature of the reaction could be maintained from about 25 °C to about 55 °C, and the duration of the reaction typically could range from about 20 minutes to about 5 hours. The compound of formula (Ie), can be converted to a compound of formula (If), by reacting the cyano compound with sodium azide or potassium azide, in the 20 presence zinc salts such as ZnBr2. Suitable solvents for this reaction include N,N-dimethylformamide, acetonitrile, (Ci-Cio) alcohols, and the like. Compounds of formula (If) could be converted into a compound of formula (Ig) where Rb is as defined above, by reacting the tetrazolyl compound with corresponding reagents such as alkyl halides or dialkyl sulphates, in the presence of 25 a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydride and the like, along with a phase-transfer catalyst such as tetraalkylammoniumhalide or tetraarylammoiumhalide, in a solvent medium such as water, dimethylformamide, acetonitrile, and the like. -46- WO 2007/075194 PCT/US2006/025427 In yet another aspect, compounds according to the present invention could be prepared according to the following scheme. Scheme 2 (RC)PW <RVn R (Ir) Rr ,R1 Rs H. rV""1?' V^JIK,,R1 RS N' R2 (Id) (IP) "L N^N Rr R1 R1 RS N (Is) R2 rl Where in R is -halogen, alkyl RdH (lu) N N N Rr ,R1 Rs (Is) Where in Rd is -N(CH3)2, morpholinyl, N-methyl piperazinyl 10 The compound of formula (Id) could be converted to a compound of formulae (Ir), (Is) and (It) by reacting with a compound of formulae (Io), (Ip) and (Iq) respectively wherein L represents a leaving group such as halide. The base such as triethylamine, disiopropylethylamine, potassium carbonate, sodiumcarbonate can be used. The reaction could also be carried out in the presence of different solvents, including but not limited to, acetone, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide and the like. -47- WO 2007/075194 PCT/US2006/025427 The compound of formula (Is) wherein Rd is halogen could be coverted to a compound of formula (Is), wherein Rd is -N(CH3)2, morpholinyl, N-methyl piperazinyl by reacting with compound of formula (Iu) wherein Rd is -N(CIi3)2, morpholinyl, N-methyl piperazinyl by known reactions like Buchwald-Hartwig 5 Cross Coupling Reaction. hi yet another aspect, compounds according to the present invention could be prepared according to the following scheme: Scheme 3 CHO NaBH4/R.T CHpOH MsCI/TEA DCM Representative steps of Scheme 3 include the following: The compound of formula (Ha) could be converted to a compound of formula (lib) by earring out reduction, in a polar solvent such as methanol and a 15 reagent such as sodiumborohydrate. The compound of formula (lib) could be converted to a compound of formula (lie), wherein L is leaving group, by recting with a reagent such as methansulfonylchlride or p-toluensulfonylchloride, in a solvent such as dichloromethane. -48- WO 2007/075194 PCT/US2006/025427 The compound of formula (lie) could be converted to a compound of formula (He) by recting with sodiumazide or potasiumazide, followed by coverting azide group to -NH2 group by conventional methods. The compound of formula (He) could be converted to a compound of 5 formula (Ilg) by carrying out reductive amination with compound of formula (Ilf). Compounds disclosed herein to control CETP activity can be used for preventing or treating a variety of conditions or diseases such as ones associated with lipoprotein metabolism. Without being held to a particular theory, it is believed that CETP activity can affect the level of circulating cholesterol-10 containing HDL. Increased CETP can produce a decrease in HDL-C levels relative to LDL-C and/or VLDL-C levels. For example, CETP plays a role in transferring cholesteryl ester from HDL to VLDL and LDL, and thereby in altering the relative profile of circulating lipoproteins to one which is associated with an increased risk of cardiovascular disease (for example, decreased levels of HDL-C and increased 15 levels of VLDL-C and LDL-C). Further, increased levels of CETP activity can be predictive of increased risk of cardiovascular disease. Modulation or inhibition of CETP activity, therefore, can be a prophylactic or therapeutic method for modulating the relative levels of lipoproteins to reduce or prevent the progression of, to induce regression of, or reduce risk of development of a variety of conditions 20 or diseases including cardiovascular diseases, such as atherosclerosis. Effective amounts are administered to the subject in dosages and formulations that are safe and effective, including, but not limited to, the ranges taught herein. As disclosed herein, compositions comprising at least one compound having a formula as disclosed herein, and/or their pharmaceutically-25 acceptable salts, can be used in conjunction with other prophylactic or therapeutic agents or in methods optionally comprising steps such as altered patient activities, including, but not limited to, changes in exercise or diet. In one aspect, the present invention provides a method of treating or preventing a condition or disease in a mammalian subject, the method comprising 30 administering to the subject a composition comprising a prophylactically- or -49- WO 2007/075194 PCT/US2006/025427 therapeutically-effective amount of at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts. In various aspects, the condition or disease is dyslipidemia, atherosclerosis, a peripheral vascular disease, hypertryglyceridemia, hypercholesterolemia, hyperbetalipoproteinemia, 5 hypoalphalipoprotenemia, a cardiovascular disorder (i.e., angina, ischemia, stroke, myocardial infarction (MI), reperfusion injury, restenosis, hypertension) or diabetic vascular diseases (i.e., diabetic retinopathy, endotoxemia). In one other aspect, the present invention provides a method of decreasing or inhibiting CETP activity in a mammalian subject, the method comprising 10 administering to the subject an amount of a composition comprising at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts, wherein the amount is sufficient to decrease or inhibit CETP activity in the subject. In still another aspect, the present invention provides a method of 15 increasing high density lipoprotein (HDL) in a mammalian subject, the method comprising administering to the subject an amount of a composition comprising at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts, wherein the amount is sufficient to increase high density lipoprotein (HDL) in the subject. 20 In another aspect, the present invention provides a method of elevating the ratio of circulating HDL to circulating LDL, VLDL, or total cholesterol in a mammalian subject, the method comprising administering to the subject a prophylactically- or therapeutically-effective amount of at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable 25 salts. In yet another aspect, the present invention provides a method of altering catabolism of HDL-cholesterol to decrease development of atherosclerotic lesions in a mammalian subject, the method comprising administering to the subject an amount of a composition comprising at least one compound having a formula as 30 disclosed herein, and/or their pharmaceutically-acceptable salts, wherein the -50- WO 2007/075194 PCT/US2006/025427 amount is sufficient to alter the catabolism of HDL-cholesterol thereby leading to decreased development of atherosclerotic lesions. In still another aspect, the present invention provides a method of decreasing low density lipoprotein (LDL) in a mammalian subject, the method 5 comprising administering to the subject an amount of a composition comprising at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts, wherein the amount is sufficient to decrease low density lipoprotein (LDL). In another aspect, the present invention provides a method of treating or 10 preventing atherosclerosis in a mammalian subject, the method comprising administering to the subject a prophylactically- or therapeutically-effective amount of at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts. In yet another aspect, the present invention provides a method of treating or 15 preventing hyperlipidemia in a mammalian subject, the method comprising administering to the subject a prophylactically- or therapeutically-effective amount of at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts. In another aspect of the present invention, this invention provides a method 20 of treating or preventing a CETP-mediated disorder in a mammalian subject, the method comprising administering to the subject a prophylactically- or therapeutically-effective amount of at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts. In yet another aspect, the present invention provides a method of treating or 25 preventing dyslipidemia, atherosclerosis, a peripheral vascular disease, hypertryglyceridemia, hypercholesterolemia, hyperbetalipoproteinemia, hypoalphalipoprotenemia, a cardiovascular disorder, a diabetic vascular disease, or endotoxemia. In one aspect, the cardiovascular disorder is angina, ischemia, stroke, myocardial infarction (MI), reperfusion injury, restenosis or hypertension. -51 - WO 2007/075194 PCT/US2006/025427 The compounds of the present invention are useful in the treatment and / or prophylaxis of the above said diseases in combination / concomittant with one or more LDL-cholesterol lowering agents such as HMG CoA reductase inhibitors; cholesterol absorption inhibitors; antiobesity drugs; lipoprotein disorder treatment 5 drugs; hypoglycemic agents: insulin; biguanides; sulfonylureas; thiazolidinediones; dual PPAR agonists; and/or mixtures thereof. The compounds of the present invention in combination with HMG CoA reductase inhibitors, microsomal triglyceride transfer protein (MTP) /ApoB secretion inhibitors, cholesterol absorption inhibitors, antiobesity drugs, hypoglycemic agents can be administered 10 together or within in such a period of time so as to act synergistically. In one aspect, the present invention provides a prophylactic or therapeutic composition comprising at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts and, optionally an antihypertensive agent. Hypertension can be characterized as persistently high 15 blood pressure. Illustratively, an adult having a systolic blood pressure that is persistently at least about 140 mmHg or a diastolic blood pressure that is at least about 90 mmHg can be classified as hypertensive. Hyperlipidemic conditions such as atherosclerosis can have an affect on hypertension. The dosage regimen utilizing, the compounds of the present invention is 20 selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount 25 of the drug required to prevent, counter or arrest the progress of the condition. Compounds and compositions of the present invention can be administered by any appropriate route, including, for example, orally, parenterally, intravenously, intradermally, intramuscularly, subcutaneously, sublingually, transdermally, bronchially, pharyngolaryngeal, intranasally, topically such as by a 30 cream or ointment, rectally, intraarticular, intracisternally, intrathecally, -52- WO 2007/075194 PCT/US2006/025427 intravaginally, intraperitoneally, intraocularly, by inhalation, bucally or as an oral or nasal spray. Oral dosages of compositions of the present invention, when used for the indicated effects, will range from about 0.01 mg per kg of body weight per day 5 (mg/kg/day) to about 100 mg/lcg/day. Advantageously, compounds of the present invention can be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using 10 those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be substantially continuous rather than intermittent throughout the dosage regimen. In the methods of the present invention, the compounds herein described in 15 detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. 20 For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be 25 combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums 30 such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, -53 - WO 2007/075194 PCT/US2006/025427 polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. 5 In one aspect, the present invention provides a composition comprising at least one compound as disclosed herein. In another aspect, this invention provides a pharmaceutical composition, comprising: at least one compound as disclosed herein; and 10 optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof. In yet another aspect, this invention provides a pharmaceutical composition, comprising: 15 at least one compound as disclosed herein; and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof; wherein the pharmaceutical composition is in the form of a tablet, a 20 capsule, a syrup, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, or a transdermal patch. In still another aspect, this invention provides a pharmaceutical composition, comprising: 25 at least one compound as disclosed herein; optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof; and further comprising an agent selected from a chemotherapeutic agent, an 30 immunosuppressive agent, a cytokine, a cytotoxic agent, an anti-inflammatory -54- WO 2007/075194 PCT/US2006/025427 agent, an antirheumatic agent, an antidyspilidemic agent, a cardiovascular agent, or any combination thereof. Accordingly, in addition to the compounds disclosed herein, the pharmaceutical compositions of the present invention can further comprise at least 5 one of any suitable auxiliary such as, but not limited to, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant, or the like. In one aspect of the present invention, pharmaceutically acceptable auxiliaries are employed. Examples and methods of preparing such sterile solutions are well known in the art and can be found in well known texts such as, but not limited to, remington's 10 Pharmaceutical Sciences (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990)). Pharmaceutically acceptable carriers can be routinely selected that are suitable for the mode of administration, solubility and/or stability of the compound. For oral administration in the form of a tablet or capsule, a compound can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such 15 as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents may also be incorporated into the mixture. Suitable binders include, without limitation, starch; gelatin; natural sugars such as glucose or beta-lactose; corn sweeteners; natural and synthetic gums such as acacia, tragacanth, or sodium alginate, 20 carboxymethylcellulose; polyethylene glycol; waxes; and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. 25 The pharmaceutical preparations contain at least one compound of the present invention represented by any formula disclosed herein, and/or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit CETP activity and prevent or treat the various conditions or diseases attributable to CETP activity. One skilled in the art can easily determine such an effective amount. The -55- WO 2007/075194 PCT/US2006/025427 preparations optionally can contain other ingredients including, for example, an antihypertensive drug. Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets, or tablets each containing a 5 predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus, and the like. The invention further relates to the administration of at least one compound disclosed herein by the following routes, including, but not limited to oral, 10 parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, 15 intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, iontophoretic means, or transdermal means. A composition comprising at least one compound of the present invention can be administered at a frequency and for a period of time effective to achieve a 20 therapeutic effect, which should be understood in the context of a regimen of repeated administration at such a frequency and over such a period. In some aspects, a composition is administered at a frequency and for a period of time effective to increase a HSPG expression. In some aspects, a composition can be administered in a single daily dose, or a total daily dosage can be administered in 25 divided doses of two, three, or four times daily. Typically and most conveniently, a composition is administered at least once daily, but in certain situations less frequent, e.g., twice weekly or weekly, administration can be effective. For greatest benefit, administration should continue for a prolonged period, for example at least about 3 months, or at least about 6 months, or at least about 1 30 year, or at least about 2 years, or at least about 3 years. In one aspect, - 56 - WO 2007/075194 PCT/US2006/025427 administration continues from a time of initiation for substantially the remainder of the mammal's life. The selection and/or amounts of individual compounds can, if desired vary over the period of administration. In one aspect, a single composition of this 5 invention is administered to a mammal for the entire period of administration. In other aspects, different compositions comprising at least one compound are administered to the mammal at different times. The dosages of compounds can be adjusted on a per body weight basis and may thus be suitable for any subject regardless of the subject's size. 10 In one aspect of this invention, daily oral dose comprises a total compound amount of at least about 0.0001 mg per kg body weight, illustratively about 0.0001 mg to about 1000 mg, about 0.001 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.1 mg to about 5 mg, or about 1 to about 3 mg per kg body weight. In another aspect, a daily intravenous injection comprises a total compound 15 amount of at least about 0.0001 mg per kg body weight, illustratively about 0.0001 mg to about 0.5 mg, about 0.001 mg to about 0.25, or about 0.01 to about 0.03 mg per kg body weight. Illustratively, a tablet for oral administration can be manufactured to comprise a total compound amount of about 0.001 mg, about 0.1 mg, about 0.2 mg, 20 about 0.5 mg, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In one aspect, a composition comprises an active ingredient content of at 25 least about 0.01% by weight of the composition, illustratively about 0.01% to about 99%, about 0.05% to about 90%, about 0.1% to about 80%, about 0.5% to about 50% by weight of the composition. The amount of active ingredient that can be combined with other materials to produce a single dosage form varies depending upon the subject treated and the particular mode of administration. -57- WO 2007/075194 PCT/US2006/025427 All effective amount of the drag is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 20 mg/kg of body weight per day. In one aspect, the range is from about 0.2 mg/kg to about 10 mg/kg of body weight per day. In another aspect, the range is from about 0.5 mg/kg to about 10 mg/kg of body 5 weight per day. The compounds can be administered on a regimen of about 1 to about 10 times per day. Co-administration or sequential administration of the compounds of the present invention and other therapeutic agents can be employed, such as chemotherapeutic agents, immunosuppressive agents, cytokines, cytotoxic agents, 10 nucleolytic compounds, radioactive isotopes, receptors, and pro-drug activating enzymes, which can be naturally occurring or produced by recombinant methods. The combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both 15 (or all) active therapeutic agents simultaneously exert their biological activities. It is to be understood that this invention is not limited to the particular methodology, syntheses, formulations, protocols, cell lines, constructs, and reagents described herein and as such can vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, 20 and is not intended to limit the scope of the present invention. All publications, patents, and other references mentioned herein are provided for the purpose of describing and disclosing, for example, the constructs and methodologies that are described in these references, which might be used in connection with the presently described invention. 25 -58- WO 2007/075194 PCT/US2006/025427 DEFINITIONS AND TERMINOLOGY The groups defined for various symbols used in the formulas of this disclosure, as well as the optional substituents defined on those groups, can be defined as follows. Unless otherwise specified, any recitation of the number of 5 carbon atoms in a particular group is intended to refer to the unsubstituted "base" group, therefore, any substituent recited on a base group is described by its own definition, including its own limitation of the number of carbon atoms. Unless otherwise specified, all structural isomers of a given structure, for example, all enantiomers, diasteriomers, and regioisomers, are included within this definition. 10 The terms "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine. The term "alkyl" group is used to refer to both linear and branched alkyl groups. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, and the like. Unless 15 otherwise specified, an alkyl group has from 1 to 12 carbon atoms. Also unless otherwise specified, all structural isomers of a given structure, for example, all enantiomers and all diasteriomers, are included within this definition. For example, unless otherwise specified, the term propyl is meant to include w-propyl and zso-propyl, while the term butyl is meant to include «-butyl, iso-butyl, /-butyl, 20 see-butyl, and so forth. The term "aryl" refers to an optionally substituted monocylic or polycyclic aromatic ring system of 6 to 14 carbon atoms. Exemplary groups include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, indane, fluorene, and the like. Unless otherwise specified, an aryl group typically has from 6 to 14 carbon atoms. 25 The term "haloalkyl" refers to a group containing at least one halogen and an alkyl portion as define above, that is, a haloalkyl is a substituted alkyl group that is substituted with one or more halogens. Unless otherwise specified, all structural isomers of a given structure, for example, all enantiomers and all diasteriomers, are included within this definition. Exemplary haloalkyl groups include fluoromethyl, -59- WO 2007/075194 PCT/US2006/025427 chloromethyl, fluoroethyl, chloroethyl, trifluoromethyl, and the like. Unless otherwise specified, a haloalkyl group has from 1 to 12 carbon atoms. A "cycloalkyl" group refers to a cyclic alkyl group which can be mono or polycyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, 5 cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Unless otherwise specified, a cycloalkyl group has from 3 to 15 carbon atoms. An "alkoxy" group refers to an -O(alkyl) group, where alkyl is as defined herein. Therefore, unless otherwise specified, all isomers of a given structure are included within a definition. Exemplary alkyl groups include methoxy, ethoxy, n-10 propoxy, iso-propoxy, n-butoxy, iso-butoxy, £-butoxy, and the like. Unless otherwise specified, an alkoxy group has from 1 to 12 carbon atoms. Unless otherwise specified, all structural isomers of a given structure, for example, all enantiomers and all diasteriomers, are included within this definition. For example, unless otherwise specified, the term propoxy is meant to include n-15 propoxy and zso-propoxy. "Heterocyclyl" is a non-aromatic, saturated or unsaturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from -0-, >N-, -S-, >NR, >S02, >CO, and the like, wherein R is hydrogen or a substituted or an unstubstituted alkyl, aryl, or acyl, as defined 20 herein. Exemplary heterocyclyl groups include aziridinyl, imidazolidinyl, 2,5-dihydro-[l,2,4]oxadiazolenyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl, piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, 2,5-dihydro-lH-imidazolyl, and the like. Unless otherwise specified, a heterocyclyl group typically has from 2 to 10 carbon atoms. 25 A heterocyclyl group can be bonded through a heteroatom that is formally deprotonated or a heterocyclyl group can be bonded through a carbon atom of the heterocyclyl group. A "cyclic" moiety, including a monocyclic moiety or a bicyclic moiety, unless otherwise specified, is intended to be inclusive of all the cyclic groups -60- WO 2007/075194 PCT/US2006/025427 disclosed herein, for example, a heteroaryl group, a heterocyclyl group, a heterocycloalkyl group, and/or a heteroaryloxy group. A "(cycloalkyl)allcyl" group, refers to an alkyl group that is substituted with a cycloalkyl substituent, wherein alkyl and cycloalkyl are defined herein. Thus, the 5 cycloalkyl group portion can be a mono or polycyclic alkyl group. Unless otherwise specifed, a (cycloalkyl)alkyl group can have up to 20 carbon atoms, regardless of how the carbon atoms are distributed between the alkyl portion and the cycloalkyl portion of the group, and including all possible sterochemistries and all regiochemistries. For example, in one aspect, a cycloalkyl-substitued alkyl can 10 comprise a (C3-C10) cycloalkyl bonded to a C1-C10 alkyl group, wherein the cycloalkyl portion can be mono or polycyclic. Exemplary (cycloalkyl)alkyl groups include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, 15 cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, cyclooctylmethyl, cyclooctylethyl, cyclooctylpropyl, and the like. Further, the meaning of certain additional terms and phrases employed in the specification, can be defined as follows. As used herein, the term "compound" includes both the singular and the 20 plural, and includes any single entity or combined entities that have at least the affect disclosed herein and combinations, fragments, analogs or derivatives of such entities. As used herein, the term "substance" refers broadly to any material of a particular kind or constitution. Examples of a "substance" can include, without 25 limitation, a chemical element, a molecule, a compound, a mixture, a composition, an emulsion, a chemotherapeutic agent, a pharmacological agent, a hormone, an antibody, a growth factor, a cellular factor, a nucleic acid, a protein, a peptide, a peptidomimetic, a nucleotide, a carbohydrate, and combinations, fragments, analogs or derivatives of such entities. -61 - WO 2007/075194 PCT/US2006/025427 The terms "treatment", "treating", "treat", and the like are used herein to refer generally to any process, application, therapy, etc., wherein a mammal is subject to medical attention with the object of obtaining a desired pharmacological and/or physiological effect for improving the mammal's condition or disease, 5 directly or indirectly. The effect can be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease. The effect also can include, for example, inhibition of disease symptom (i.e., arresting its development) or relieving disease symptom (i.e., causing regression of the disease or symptom). 10 A used herein, the term "therapeutically-effective amount" refers to that amount of at least one compound as disclosed herein, or their pharmaceutically-acceptable salts thereof, that is sufficient to bring about the biological or medical effect that is being sought in a mammal, system, tissue, or cell. The term "preventing", "prevent", "prevention", and the like are used 15 herein to refer generally to any process, application, therapy, etc., wherein a mammal is subject to medical attention with the object of obtaining a desired pharmacological and/or physiological effect for preventing onset of clinically evident condition or disease or preventing onset of a preclinically evident stage of a condition or disease. The effect can be prophylactic in terms of completely or 20 partially preventing or reducing the risk of occurance of a condition or disease or symptom thereof. A used herein, the term "prophylactically-effective amount" refers to that amount of a drug or pharmaceutical agent that will prevent or reduce the risk of occurrence of the biological or medical effect that is sought to be prevented in the 25 cell, tissue, system, or mammal. As used herein, the term "activation" refers to any alteration of a signaling pathway or biological response including, for example, increases above basal levels, restoration to basal levels from an inhibited state, and stimulation of the pathway above basal levels. -62- WO 2007/075194 PCT/US2006/025427 Generally a skill in the art is known that valance must be conserved for all the stable molecules. Therefore, the necessary implication that hydrogen atoms are necessary and available to complete the valance in all structures including Formula I unless expressly indicated otherwise. 5 Publications and patents mentioned herein are disclosed for the purpose of describing, for example, the constructs and methodologies that are provided in the publications and patents, which might be used in connection with the present invention. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such publications, patents, or other disclosure by virtue of 10 prior invention. To the extent that any definition or usage provided by any document incorporated herein by reference conflicts with the definition or usage provided herein, the definition or usage provided herein controls. When Applicants disclose or claim a range of any type, for example a range IS of temperatures, a range of numbers of atoms, a molar ratio, or the like, Applicants' intent is to disclose or claim individually each possible number that such a range could reasonably encompass, as well as any sub-ranges and combinations of subranges encompassed therein. For example, when the Applicants disclose or claim a chemical moiety having a certain number of carbon atoms, Applicants' intent is to 20 disclose or claim individually every possible number that such a range could encompass, consistent with the disclosure herein. For example, the disclosure that R is selected independently from an alkyl group having up to 12 carbon atoms, or in alternative language a Q to C12 alkyl group, as used herein, refers to an R group that can be selected independently from a hydrocarbyl group having 1, 2, 3, 4, 5, 6, 25 7, 8, 9, 10, 11, or 12 carbon atoms, as well as any range between these two numbers for example a C3 to Cg alkyl group, and also including any combination of ranges between these two numbers for example a C3 to C5 and C7 to C10 hydrocarbyl group. In another example, by the disclosure that the molar ratio typically spans the range from about 0.1 to about 1.1, Applicants intend to recite 30 that the molar ratio can be selected from about 0.1:1, about 0.2:1, about 0.3:1, -63 - WO 2007/075194 PCT/US2006/025427 about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1.0:1, or about 1.1:1. Applicants reserve the right to proviso out or exclude any individual members of any such group, including any sub-ranges or combinations of sub-5 ranges within the group, that may be claimed according to a range or in any similar manner, if for any reason Applicants choose to claim less than the full measure of the disclosure, for example, to account for a reference that Applicants may be unaware of at the time of the filing of the application. Further, Applicants reserve the right to proviso out or exclude any individual substituents, compounds, ligands, 10 structures, or groups thereof, or any members of a claimed group, if for any reason Applicants choose to claim less than the full measure of the disclosure, for example, to account for a reference that Applicants may be unaware of at the time of the filing of the application. The following references disclose certain heterocyclic compounds. 15 Table-1. References disclosing heterocyclic compounds. Publication or Patent No. Title W02005097806 Preparation of heterocyclic piperidine derivatives as inhibitor of cholesterol ester transfer protein W02005095395 Preparation of 1,2,3,4-tetrahydro-l,5-naphthyridin-4-amines as cholesteryl ester transfer protein inhibitors W02005095409 Preparation of 1,2,3,4-tetrahydroquinolin-4-amines as cholesteryl ester transfer protein inhibitors W02005030185 Method using cholesteryl ester transfer protein (CETP) inhibitors for inhibiting remnant lipoprotein production US2004039018 Use of cholesteryl ester transfer protein (CETP) inhibitors and antihypertensive agents and optional HMG-CoA reductase inhibitors for the treatment of cardiovascular conditions W02000017165 Preparation of 4-amino-substituted 2-substituted 1,2,3,4-tetrahydroquinolines as CEPT inhibitors -64- WO 2007/075194 PCT/US2006/025427 US2004053842 Therapeutic use and pharmaceutical compositions of cholesterol ester transfer protein (CETP) inhibitors and optional HMG-CoA reductase inhibitors and/or antihypertensive agents W02003000295 Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors and surfactants W02002011710 Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors US2003198674 Controlled release dosage forms containing cholesteryl ester transfer protein inhibitor W02003063832 Pharmaceutical compositions comprising a solid amorphous dispersion of CETP inhibitors US2003104063 Pharmaceutical compositions containing a solid dispersion of a poorly-soluble drug in a matrix and a solubility-enhancing polymer US2003054037 Pharmaceutical compositions of adsorbates of amorphous drug US2003170309 Pharmaceutical compositions containing polymer and drug assemblies US2003072801 Pharmaceutical compositions comprising concentration-enhancing polymers US2004185102 Dosage forms comprising a CETP inhibitor and an HMG-CoA reductase inhibitor W02005000811 Preparation of 3-aminopyrrolidines as inhibitors of monoamine uptake US2005049239 Preparation of aroylpiperidines and related compounds as selective inhibitors of the type 2 glycine transporter (GlyT2) W02005021525 Preparation of aroylpiperidines and related compounds as selective inhibitors of the type 2 glycine transporter (GlyT2) W02004078169 Use of EP2 selective receptor agonists in medical treatment of pulmonary hypertension and other conditions W02004078128 Preparation of pyridine-containing diaryl ureas useful in the treatment of cancer and other disorders W02004073709 Preparation of tertiary amino compounds as antimicrobial agents W02003087088 Preparation of pyridone and pyrimidone compounds as inhibitors of the enzyme Lp-PLA2 -65- WO 2007/075194 PCT/US2006/025427 W02003030909 Preparation of 2- and 4-aminopyrimidines N-substituted by a bicyclic ring for use as kinase inhibitors in the treatment of cancer W02002090349 Pyridylmethylanthranilamide N-oxides as inhibitors of VEGFRII kinase W02002070462 Preparation of aminodicarboxylic acids for the treatment of cardiovascular diseases W02002068417 Heteropolycyclic compounds, particularly pyridyl- and phenyl-substituted 1,2,4-oxadiazoles and analogs, and their use as metabotropic glutamate receptor antagonists for inhibiting neuronal damage W02002042273 Preparation of aromatic acid derivatives useful as serine protease inhibitors W02002022584 Preparation of substituted heterocyclic aryl-alkyl-aryl compounds as thrombin inhibitors W02001085671 Preparation of (heterocyclyl)anthranylamides as inhibitors of vascular endothelial growth factor receptors W0200106045 8 Piperazine inhibitors of prenyl-protein transferase for antitumor use W02001060369 Piperazine inhibitors of prenyl-protein transferase for antitumor therapy W02001056560 Preparation of substituted amino acids as neutral sphingomyelinase inhibitors W02001022954 Indolyl-3-glyoxylic acid derivatives comprising therapeutically valuable properties W02001000623 Method of producing nitroguanidine and nitroenamine derivatives JP2001163779 Prostaglandin receptor agonists and prodrugs for treatment of male erectile disorder EP1108426 Prostaglandin receptor agonists and prodrugs for treatment of male erectile disorder DE19962300 Preparation ofN-(pyridin-4-yl) [l-(4-aminobenzyl)indol-3-yl]glyoxylamides as antitumor agents US2001014690 Preparation of N-(pyridin-4-yl) [l-(4-aminobenzyl)indol-3-yl]glyoxylamides as antitumor agents US6432987 Preparation ofN-(pyridin-4-yl) [l-(4-aminobenzyl)indol-3-yl]glyoxylamides as antitumor agents -66- WO 2007/075194 PCT/US2006/025427 CA2395259 Preparation of N-(pyridin-4-yl) [l-(4-aminobenzyl)indol-3-yl]glyoxylamides as antitumor agents W02001047913 Preparation of N-(pyridin-4-yl) [l-(4-aminobenzyl)indol-3-yl]glyoxylamides as antitumor agents DEI 9930075 Preparation of aminoarylsulfonamides as antivirals W02001002350 Preparation of aminoarylsulfonamides as antivirals W02000050398 Preparation of phenyl and pyridinyl derivatives as NK-1 receptor antagonists US6121271 Preparation of naphtho[2,3-b]heteroar-4-yl derivatives for treating metabolic disorders related to insulin resistance or hyperglycemia DEI 9845202 Hair growth atimulant W02000019969 Hair growth atimulant W09951224 Preparation of indolylglyoxylamides as antitumor agents W09919300 Preparation of prostaglandin agonists and their use to treat bone disorders US6008362 Elevation of HDL cholesterol by 2-(4-chloro-l-aryl-butylidene)- hydrazinecarbothioamides US5977170 Preparation of 4- [(aminothioxomethyl)hydrazono]-4-arylbutyl carbamates as elevators of HDL cholesterol JP11209366 Preparation of chromans and pharmaceuticals for treatment of heart failure W09857928 Elevation of HDL cholesterol by 2-(4-chloro-l-aryl-butylidene)hydrazinecarbothioamides W09857927 Elevation of HDL cholesterol by 4- [(aminothioxomethyl)hydrazono]-4-arylbutyl carbamates W09857925 Elevation of HDL cholesterol by 2- [(aminothioxomethyl)hydrazono]-2-arylethyl carbamates W09827053 Preparation of sulfonamide and carboxamide derivatives as drugs W09809946 Preparation of new, N-substituted indole-3-glyoxylamides as antiasthmatics, antiallergic agents and immunosuppressants/immunomodulators DE19615262 Phenylglycinol amides as antiatherosclerotic agents EP802188 Phenylglycinol amides as antiatherosclerotic agents -67- WO 2007/075194 PCT/US2006/025427 W09616650 Antibacterial or bactericide comprising 2-aminothiazole derivative and salts thereof US5491152 ACAT-inhibiting derivatives of cyclic ethers and sulfides for the treatment of atherosclerosis JP08092225 Preparation of 0-( 1,2,4-triazol-5-yl)glycolamide derivatives as herbicides JP08092224 Preparation of 3,5-diphenyl-l,2,4-triazole derivatives as insecticides and acaricides W09505363 Amidine derivatives with nitric oxide synthetase activities US5422355 Antidepressant (arylalkyl)amines as GABA autoreceptor agonists DD294706 Antidepressant (arylalkyl)amines as GABA autoreceptor agonists US5086073 Antidepressant (arylalkyl)amines as GABA autoreceptor agonists US5260331 Antidepressant (arylalkyl)amines as GABA autoreceptor agonists JP07285962 Preparation of (pyridyloxy)pyrazole derivatives as herbicides W09413636 Preparation of N-carbamoyl-2-[(aminoalkyl)carbamoylalkoxy] azetidinones and analogs as elastase inhibitors US5348953 Preparation of azetidinones as antiinflammatory and antidegenerative agents CN1068815 Preparation of azetidinones as antiinflammatory and antidegenerative agent ZA9204659 Preparation of azetidinones as antiinflammatory and antidegenerative agent AU9218582 Preparation of azetidinones as antiinflammatory and antidegenerative agent AU660026 Preparation of azetidinones as antiinflammatory and antidegenerative agent W09413636 Preparation of azetidinones as antiinflammatory and antidegenerative agent EP604798 N-arylhydrazine derivatives as insecticides and acaricides EP585500 Diaryl piperazineacetamides as antimuscarinic agents W09405648 Diaryl piperazineacetamides as antimuscarinic agents W09310099 Pyrazoleglycolamide derivatives as agrochemicals -68- WO 2007/075194 PCT/US2006/025427 EP553016 Preparation of naphthalene amides and sulfonamides, their pharmaceutical formulations, and their affinity for serotoninergic receptors JP01104052 Preparation of pyridine derivatives as leukotriene antagonists and vasodilators Applicants reserve the right to proviso out or to restrict from any claim currently presented, or from any claim that may be presented in this or any further application based upon this disclosure, including claims drawn any genus or 5 subgenus disclosed herein, any compound or group of compounds disclosed in any reference, including any reference provided herein. The following acronyms, abbreviations, terms and definitions have been used throughout this disclosure. The following acronyms, abbreviations, terms and definitions have been used throughout the experimental section. Acronyms and 10 abbreviations: THF (tetrahydrofuran), DMF (TV, A/"-dimethylformamide), IP A (iso-propanol), TBAB (tetra-n-butylammonium bromide), TBTU [0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate] DIPEA (diisopropylethylamine) DCM (dichloromethane), DCE (dichloroethane), EDCI [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride], DIBAL (diisobutyl 15 aluminum hydride), LAH (lithium aluminum hydride), POCI3 (phosphorousoxychloride) g or gm (grams), L (liter), mL (milliliters), mp (melting point), rt or RT (room temperature 20-40 °C), overnight (8-12 hours) aq (aqueous), min (minute), h or hr (hour), min (minutes), atm (atmosphere), conc. (concentrated), MS or mass spec (mass spectroscopy/spectrometry), NMR (nuclear 20 magnetic resonance), IR (infrared spectroscopy), RB (round bottom), RBF (round bottom flask). In addition to these abbreviations, standard chemical abbreviations for chemical moieties, such as Me for methyl, Et for ethyl, and the like, are used throughout. NMR abbreviations: br (broad), apt (apparent), s (singlet), d (doublet), t (triplet), q (quartet), dq (doublet of quartets), dd (doublet of doublets), 25 dt (doublet of triplets), m (multiplet). -69- WO 2007/075194 PCT/US2006/025427 General Synthetic Procedures. Room temperature is defined as an ambient temperature range, typically from about 20°C to about 35°C. An ice bath (crushed ice and water) temperature is defined as a range, typically from about -5°C to about 0 °C. Temperature at reflux 5 is defined as ±15°C of the boiling point of the primary reaction solvent. Overnight is defined as a time range of from about 8 to about 16 hours. Vacuum filtration (water aspirator) is defined as occurring over a range of pressures, typically from about 5 mm Hg to about 15 mm Hg. Dried under vacuum is defined as using a high vacuum pump at a range of pressures, typically from about 0.1 mm Hg to 10 about 5 mm Hg. Neutralization is defined as a typical acid-based neutralization method and measured to a pH range of from about pH 6 to about pH 8, using pH-indicating paper. Brine is' defined as a saturated aqueous sodium chloride. Nitrogen atmosphere is defined as positive static pressure of nitrogen gas passed through a Drierite™ column with an oil bubbler system. Concentrated ammonium 15 hydroxide is defined as an approximately 15 M solution. Melting points were measured against a mercury thermometer and are not corrected. All eluents for column or thin layer chromatography were prepared and reported as volume:volume (v:v) solutions. The solvents, reagents, and the quantities of solvents and/or reagents used for reaction work-up or product 20 isolation can be those that typically would be used by one of ordinary skill in organic chemical synthesis, as would be determined for the specific reaction or product to be isolated. For example: 1) crushed ice quantity typically ranged from about 10 g to about 1000 g depending on reaction scale; 2) silica gel quantity used in column chromatography depended on material quantity, complexity of mixture, 25 and size of chromatography column employed and typically ranged from about 5 g to about 1000 g; 3) extraction solvent volume typically ranged from about 10 mL to about 500 mL, depending upon the reaction size; 4) washes employed in compound isolation ranged from about 10 mL to about 100 mL of solvent or aqueous reagent, depending on scale of reaction; and 5) drying reagents (potassium -70- WO 2007/075194 PCT/US2006/025427 carbonate, sodium carbonate or magnesium sulfate) ranged from about 5 g to about 100 g depending on the amount of solvent to be dried and its water content. Spectroscopic and other Instrumental Procedures NMR. The *H spectra described herein were obtained using Varian Gemini 5 200 MHz spectrometers. Spectrometer field strength and NMR solvent used for a particular sample are indicated in the examples, or on any NMR spectra that are shown as Figures. Typically, !H NMR chemical shifts are reported as 8 values in parts per million (ppm) downfield from tetramethylsilane (TMS) (8 = 0 ppm) as an internal standard. Solid or liquid samples were dissolved in an appropriate NMR 10 solvent (typically CDCI3 or DMSO-dg), placed in a NMR sample tube, and data were collected according to the spectrometer instructional manuals. Most samples were analyzed in Variable Temperature mode, typically at about 55 °C, though some data for some samples were collected with the probe at ambient probe temperature. NMR data were processed using the software provided by Varian, 15 VNMR 6.1 G version. The present invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope of this disclosure, but rather are intended to be illustrative only. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, 20 modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to one of ordinary skill in the art without departing from the spirit of the present invention. Thus, the skilled artisan will appreciate how the experiments and Examples may be further implemented as disclosed by variously altering the following examples, substituents, reagents, or conditions, hi the 25 specification, including the following examples, in the disclosure of any measurements, including temperatures, pressures, times, weights, percents, concentrations, ranges, chemical shifts, frequencies, molar ratios, and the like, it is to be understood that such measurements are respectively, "about." -71 - WO 2007/075194 PCT/US2006/025427 10 15 20 Example 1 Synthesis of (3-{[3,5-bis trifluoromethyl-benzyl )-(2-cyclopropyImethyI-2H- DMF (1.22 g, 16.7 mmol) was taken in a flask equipped with a drying tube and POCI3 (7.32 g, 46.7 mmol) was added dropwise with stirring at 0° C. To this solution, 7V-o-Tolyl acetamide (1.00 g, 6.7 mmol) was added and the solution was refluxed for 6 h at 90° C. The excess POCI3 was distilled off, water was added to the residue and this was stirred at room temperature for 10 min. The solid was filtered and dried under vacuum. .This crude compound was purified over silica gel (100-200 mesh) using 6% ethyl acetate and petroleum ether to give the product as a yellowish solid (yield: 78%). 'H NMR (CDC13, 200 MHz): 5 10.5 (s, 1H), 8.71 (s, 1H), 7.83- 7.79 (m, 1H), 7.74-7.70 (m, 1H), 7.56-7.49 (m, 1H), 2.79 (s, 3H); m/z (EI-MS): 206 (M+, 100%). Step (ii): Synthesis of 2-(bis(cyclopropylmethyl)amino)-8-methylquinoline-3-carbaldehyde: 2-Chloro-8-methyl-quinoline-3-carbaldehyde (.115 g, 0.559 mmol), and potassium carbonate (0.231 g, 1.67 mmol) were put in a 25 mL two necked RB flask. To this, 3 mL of DMF was added followed by dropwise addition of bis-cyclopropylmethyl amine (0.083 g, 0.67 mmol). The reaction mixture was refluxed for 2 h and was cooled to RT. It was then poured on crushed ice (10 mL) and extracted with EtOAc (3x10 mL). The organic layer was washed with brine and tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)-bis- cyclopropylmethyl-amine Step (i): Synthesis of 2-chloro-8-methyl-quinoline-3-carbaldehyde "'HO -72- WO 2007/075194 PCT/US2006/025427 dried over sodium sulphate. The solvent was evaporated under vacuum to give a yellow colored oil (0.081 g, 50%). 'H NMR (CDC13, 400 MHz): 8 10.5 (s, 1H), 8.71 (s, 1H), 7.83- 7.79 (m, 1H), 7.74-7.70 (m, 1H), 7.56-7.49 (m, 1H), 3.55-3.47 (m, 4H), 2.79 (s, 3H), 1.73-1.72 5 (m, 2H), 1.70-1.46 (m, 4H), 1.20-1.11 (m, 4H); m/z (ES-MS ): 295 (M++l, 100%); IR (neat, cm"1): 3385, 2948,1691. Step (iii): Synthesis of 3-((3,5-bis(trifluoromethyl)benzylamino)methyl)-N,N-bis(cyclopropylmethyl)-8-methylquinolin-2-amine 2-(Bis(cyclopropylmethyl)amino)-8-methylquinoline-3-carbaldehyde (0.081 g, 0.39 mmol), 3,5-bis-trifluoromethylbenzylamine (0.096 g, 0.39 mmol) and acetic acid (0.047 g, 0.78 mmol) were put in a 25 mL RB flask. To this, 2 mL of methanol was added and stirred at RT for 15 min. Sodium cyanoborohydride 15 (0.075 g, 0.77 mmol) was added portionwise and stirring was continued at RT for another 1 h. Methanol was removed from the reaction mixture under vacuum, water was added to this crude and was extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with saturated NaHC03 solution, brine and dried over sodium sulphate. The solvent was evaporated and the crude residue was 20 purified by column chromatography over silica gel (100-200 mesh) eluting with 4% ethyl acetate in petroleum ether to give the title amine (0.142 g, yield: 99%). lR NMR (CDCI3, 400 MHz): 6 7.89-7.86 (m, 1H), 7.80 (m, 1H), 7.75-7.74 (m, 1H), 7.60-7.40 (m, 3H), 7.30-7.26 (111,1H), 4.12 (s, 2H), 3.88 (s, 2H), 3.24-3.22 (m, 4H), 2.72 (s, 3H), 0.99-0.92 (m, 2H), 0.44-0.35 (m, 4H), 0.11-0.05 (m, 4H); m/z 25 (EI-MS ): 522 (M++l, 100%); IR (neat, cm"1): 3357, 2929, 2851. Step (iv): Synthesis of N-(3,5-bis(trifluoromethyl)benzyl)-N-((2-(bis(cyclopropylmethyl)amino)-8-methylquinolin-3-yl)methyl)cyanamide 10 -73 - WO 2007/075194 PCT/US2006/025427 nc cf3 To a solution of 3-((3,5-bis(triiluoromethyl)benzylamino)methyl)-N,N-bis(cyclopropylmethyl)-8-methylquinolin-2-amine (0.176 g , 0.33 mmol ), obtained in step (iii) , in MeOH (4 mL) under N2 atmosphere was added sodium 5 bicarbonate (0.056 g, 0.67 mmol ) followed by the addition of cyanogen bromide (0.063 g, 0.60 mmol). The reaction mixture was stirred at RT for 2 h. The solvent was removed under vacuum to give the crude residue which was dissolved in water, extracted with ethyl acetate and dried over sodium sulphate. The solvent was evaporated and concentrated in vacuo to afford N-(3,5-bis(trifluoromethyl)benzyl)-10 N-((2-(bis(cyclopropylmethyl)amino)-8-methylquinolin-3-yl)methyl)cyanamide (0.118 g, 64%). 'H NMR (CDCI3, 400 MHz ): 8 8.07 (s, 1H), 7.82 (s, 1H), 7.70 (s, 2H), 7.56-7.55 (m, 1H), 7.50-7.49 (m, 1H), 4.49 (s, 2H), 4.23 (s, 2H), 3.17 -3.15 (m, 4H), 2.71 (s, 3H), 0.097-0.085 (m, 2H), 0.405-0.401 (m, 4H), 0.385-0.381 (m, 4H); m/z (ES-15 MS): 547 (M++l, 100%); IR(KBr ,cm"'): 2273, 1280. Step (v): Synthesis of (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine 20 8-methylquinolin-3-yl)methyl)cyanamide (0.118 g, 0.216 mmol), sodium azide (0.70 g 1.08 mmol) and ammonium chloride (.058 g, 1.08 mmol) were put in a RB flask under N2 atmosphere. To this reaction mixture, DMF (2 mL) was added and was refluxed for 1 h. The reaction mixture was cooled to RT and ice was added to n=n / \ HN^N 7V-(3,5-Bis(trifluoromethyl)benzyl)-N-((2-(bis(cyclopropylmethyl)amino)- -74- WO 2007/075194 PCT/US2006/025427 this and extracted with ethylacetate (3x10 mL). The combined organic layer was washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford of (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine as a yellow 5 solid (0.125 g, 99%). ]H NMR (CDC13, 400 MHz ): 8 7.99 (s, 1H), 7.79 -7.74 (m, 4H ), 7.41-7.40 (m, 1H ), 7.33-7.31 (m, 1H), 4.99 (s, 2H), 4.80 (s, 2H), 3.68 (s, 4H), 2.16 (s, 1H) 1.56-1.06 (m, 11H); m/z (ES-MS): 578 (M++l, 100%); IR (KBr , cm"1) 3680 , 2922 , 1660,1616. 10 Step (vi): Synthesis of (3-{[3,5-bis trifluoromethyl-benzyl )-(2-cyclopropylmethyl-2H-tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)-bis- cyclopropylmethyl-amine (3-{[(3,5-Bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-8-15 methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine (0.4 g, 0.679 mmol) and potassium carbonate (0.28 g, 2.03 mmol) were taken in a 25 mL RB . To this, 4 mL of DMF was added and the reaction mixture was stirred at RT for 0.5 h. Then cycloproanelmethylbromide (O.llg, 0.814 mmol) was added dropwise. The reaction temperature was raised to 60°C and stirring was continued for another 2 h. 20 The reaction mixture was cooled to RT, ice was added to this and was extracted with ethyl acetate (3x10 mL). The combined organic layer was washed with brine, dried over sodium sulphate and was concenterated under vacuum to afford the crude which was purified over silica gel (100-200 mesh) using 4% ethyl acetate and petroleum ether to give the desired product (0.25 g, yield: 57%). -75- WO 2007/075194 PCT/US2006/025427 .'H NMR (CDCI3, 400 MHz): 5 7.87 (s, 1H), 7.70 (s, 2H), 7.44-7.39 (m, 2H), 7.23-7.19 (m, 1H), 4.93 (s, 2H), 4.64 (s, 2I-I), 4.30 (d, J= 7.25 Hz, 2H), 3.20-3.18 (m, 4H), 2.71 (s, 3H), 1.04-0.99 (m, 2H), 0.98-0.95 (m, 1H), 0.69-0.64 (m, 2H), 0.48-0.44 (m, 2H), 0.39-0.36 (m, 4H), 0.08-0.07 (m, 4H); (ES-MS): m/z 644 (M++l, 5 100%); IR (neat, cm"1) 3384, 1618,1580,1278. Example 2 Synthesis of (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-cyclopentyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine (3-{[(3,5-Bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-S-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine (0.4 g, 0.679 mmol) and potassium carbonate (0.28 g, 2.03 mmol) were taken in a 25 mL RB. To this, 4 mL of DMF was added and the reaction mixture was stirred at RT for 0.5 h.Then 15 cyclopentylbromide (0.12g, 0.814 mmol) was added dropwise. The reaction temperature was raised to 60°C and stirring was continued for another 2 h. The reaction mixture was cooled to RT, ice was added to this and was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with brine, dried over sodium sulphate and was concenterated under vacuum to afford the 20 crude which was purified over silica gel (100-200 mesh) using 4% ethylacetate and petroleum ether to afford the required product (0.3 g, yield: 67%). JH NMR (CDCI3, 400 MHz): 5 7.87 (s, 1H), 7.70 (s, 3H), 7.44-7.41 (m, 2H), 7.23-7.20 (m, 1H), 5.09-5.05 (m, 1H), 4.92 (s, 2H), 4.62 (s, 2H), 3.20-3.19 (m, 4H), 2.71 (s, 3H), 2.23-2.18 (m, 4H), 1.94-1.89 (m, 2H), 1.76-1.71 (m, 2H), 1.03-0.99 10 -76- WO 2007/075194 PCT/US2006/025427 (m, 2H), 0.39-0.35 (m, 4H), 0.09-0.07 (m, 4H); (ES-MS): m/z 658 (M++l, 100%); IR (neat, cm"'): 3383,1578, 1278. Example 3 5 Synthesis of (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-cyclohexyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine (3-{[(3,5-Bistrifluoromethyl-benzyl)-(2H-tetrazoI-5-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine (0.275 g, 0.46 mmol) and 10 potassium carbonate (0.19 g, 1.40 mmol) were taken in a 25 mL RB. To this, 4 mL of DMF was added and the reaction mixture was stirred at RT for 0.5 h. Then cyclohexylbromide (0.09 g, 0.552 mmol) was added dropwise. The reaction temperature was raised to 60°C and stirring was continued for another 2 h. The reaction was cooled to RT, ice was added to this and was extracted with ethyl 15 acetate (3x10 mL). The combined organic layer was washed with brine, dried over sodium sulphate and was concentrated under vacuum to afford the crude which was purified over silica gel (100-200 mesh) using 4% ethyl acetate and petroleum ether to get the required product (0.125 g, yield: 39%). *H NMR (CDC13, 400 MHz): 8 7.87 (s, 1H), 7.70 (s, 3H), 7.44-7.40 (m, 2H), 7.23-20 7.19 (m, 1H), 4.92 (s, 2H), 4.62 (s, 2H), 4.56-4.50 (m, 1H), 3.20-3.19 (m, 4H) 2.71 (s, 3H), 2.24-2.20 (m, 2H), 1.98-1.66 (m, 4H), 1.76-1.71 (m, 2H), 1.53-1.24 (m, 2H), 1.05-0.98 (m, 2H), 0.39-0.35 (m, 4H), 0.09-0.06 (m, 4H); (ES-MS): m/z 672 (M++l, 100%); IR (neat, cm"1): 3417,1576,1278. 25 -77- WO 2007/075194 PCT/US2006/025427 Example 4 Synthesis of (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-isopropyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine procedure as in Example 1 by using -isopropylbromide instead of cyclopropanemethyl bromide. NMR (CDCls, 400 MHz): 8 7.87 (s, 1H), 7.71 (s, 3H), 7.43-7.41 (m, 2H), 7.22-7.20 (m, 1H), 4.93 (s, 2H), 4.92-4.88 (m, 1H), 4.63 (s, 2H), 3.20 (d, J= 6.4 Hz, 10 4H), 2.72 (s, 3H), 1.62 (d, 6.7 Hz, 6H), 1.04-1.00 (m, 2H), 0.40-0.38 (m, 4H), 0.10-0.07 (m, 4H). (ES-MS): m/z 632 (M"'"+l, 100%); IR (neat, cm"1): 3079, 2925, 1578, 1278, 1135. Example 5 15 Synthesis of (2-{5-[[2-(bis-cyclopropylmethyl-amino)-8-methyI-quinolin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethyl)-carbamic acid tert-butyl ester V 5 This compound (0.12 g, yield: 44%) was prepared following the same -78- WO 2007/075194 PCT/US2006/025427 This compound (0.35 g, yield: 95%) was prepared following the same procedure as in Example 1 by using (2~bromoethyl)-carbamic acid-ter£-butyl ester instead of cyclopropanemethyl bromide. 'H NMR (CDC13, 400 MHz): 5 7.84 (s, 1H), 7.70 (s, 1H), 7.68 (s, 2H), 7.44-7.42 5 (m, 2H), 7.24-7.20 (m, 1H), 4.92 (s, 2H), 4.8 (br s, 1H), 4.66 (s, 2H), 4.59-4.56 (m, 2H), 3.73-3.69 (m, 2H), 3.19-3.12 (m, 4H), 2.71 (s, 3H), 1.53 (s, 9H), 0.89-0.85 (m, 2H), 0.39-0.35 (m, 4H), 0.09-0.05 (m, 4H); (ES-MS): m/z 733 (M++l, 100%); IR (neat, cm'1): 3358, 2927,1582, 1278. 10 Example 6 Synthesis of (3-{[[2-amino-ethyl)~2H-tetrazol-5-yl]-(3,5-bistrifluoromethyl-benzyl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine 15 (3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethyl)-carbamic acid tert-butyl ester (Example 5) (0.242 g, 0.33 mmol ) was dissolved in 1 mL of DCM in a 25 mL RB. This solution was cooled to 0°C, and was added 0.4 mL of a mixture of TFA and DCM (1:1). Stirring was continued for 1 h at RT. Then water was added to reaction mixture and this was extracted with DCM (3x10 mL). The combined 20 organic layer was washed with brine and was concentrated under vacuum to get pure compound (0.15 g, yield: 72%). 'H NMR (CDCI3, 400 MHz): 8 7.85 (s, 1H), 7.70-7.69 (m, 3H), 7.44-7.41 (m, 2H), 7.24-7.20 (m, 1H), 4.93 (s, 2H), 4.66 (s, 2H), 4,54-4.51 (m, 2H) 3.31-3.28 (m, 2H), (2-{5-[[2-(bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-ylmethyl]- -79- WO 2007/075194 PCT/US2006/025427 3.20-3.18 (m, 4H), 2.71 (s, 3H), 0.99-0.86 (m, 2H), 0.40-0.35 (m ,4H), 0.10-0.07 (m, 4H); (ES-MS): m/z 633 (MM, 100%); IR (neat, cm"1): 2926,1580,1278. Example 7 5 Synthesis of l-{5-[[2-(bis-cyclopropylmethyl-amino)8-methyl-quinoline-3-ylmethyl]- (3,5-bistrifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-propane-2-ol 3-{[(3,5-Bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-8-methyl-quinolin~2-yl)-bis-cyclopropylmethyl-amine (0.4g, 0.679 mmol), tris-^-10 butyl tin oxide (0.202 g, 0.33 mmol) were refluxed in ethanol for 4 h. Ethanol was removed from the reaction mixture under vacuum and diethyl ether was added followed by the addition of methyl propylene oxide (0.058g, 1.00 mmol). The reaction was refluxed for overnight and ether was removed under vacuum. The crude was purified by column chromatography over silica gel (100-200 mesh) 15 using chloroform to afford the required compound (0.1 g, yield: 23%). 'H NMR (CDC13, 400 MHz): 6 7.97 (s, IH), 7.79 (s, 2H), 7.74 (s, IH), 7.50-7.47 (m, 2H), 7.30-7.28 (m, IH), 4.95-4.85 (m, 2H), 4,74-4.69 (m, H), 4.36-4.31 (m ,1H), 4.14-4.10 (m, IH), 4.00-3.94 (m, IH), 3.21-3.11 9(m, 4H), 2.71 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.02-0.96 (m, 2H), 0.41-0.36 (m, 4H); (ES-MS): m/z 648 20 (M++l, 100%); IR (neat, cm"1) :3411,1593,1281. -80- WO 2007/075194 PCT/US2006/025427 Example 8 Synthesis of (3-{[(3,5-2?is-trifluoromethyl-benzyl)-(2~methyl-2H~tetrazol-5-yl)-amino]-methyl}-8-trifluoromethyl-quinolm-2~yl)-bis~cyclopropylmethyl-amine Step (i): Synthesis of 3-phenyl-7V-(2-trifhioromethyl-phenyl)-acrylamide A mixture of cinnamoyl chloride (20.7g, 124.3 mmol), 2-trifluoromethylamine (20.0g, 124.2 mmol), and potassium carbonate (25.6g, 185.5 mmol) in 60 mL of acetone and 50 mL of water were stirred at 0 °C for 2 h. The reaction mixture was poured into ice and stirred for 10 min. The solid was filtered 10 and dried under vacuum to afford the said compound (25 g, yield: 69%). 'H NMR (CDCls, 400 MHz): 8 8.37 (d, J = 8.06, IH), 7.79-7.75 (m,lH), 7.64-7.55 (m, 4H), 7.42-7.38 (m, 3H), 7.25-7.22 (m, IH), 6.55-6.51 (m, IH); (ES-MS): m/z 292 (M+l, 100%);.IR (KBr, cm"1): 3227, 3012,1632,1318. Step (ii): Synthesis of 8-trifluoromethyl -lH-quinolin-2-one 3-Phenyl-A-(2-trifluoromethyl~phenyl)-acrylamide (18.0 g, 61.8 mmol), which was obtained in step (i), and aluminium chloride (49.3 g, 371.1mmol) were taken in a 250 mL RB flask containing 50 mL of chlorobenzene. The reaction mixture was refluxed for 2 h and then cooled to room temperature. The mixture 20 was poured in ice cold water. The precipitate was filtered off, washed with water and dried under vacuum to afford the title compound (9.0 g, yield: 68%). *H NMR (CDCI3, 200 MHz): 8 12.01 (bs, IH), 7.98-7.95 (m, IH), 7.63-7.56 (m, IH), 7.43-7.28 (m, 2H), 6.88 (s, IH); (ES-MS): m/z 302 (M+89, 100%); IR (KBr, cm"1): 3007, 2850,1664. 5 'O 15 -81 - WO 2007/075194 PCT/US2006/025427 Step (iii): Synthesis of 2-chloro-8-trifluoromethyl-quinoline cf3 8-Trifluoromethyl -1 H-quinolin-2-one(8.35g, 39.2 mmol ) was taken in a 25 mL RB POCI3 (10 mL) was added, and then refluxed for 1 h. The excess POCl3 5 was distilled off and ice was added to the reaction mixture. This was stirred for 15 min, the precipitate was filtered off and then dried under vacuum to afford the title compound (3 g, yield: 33%). (ES-MS): m/z 197(M-34, 100%); IR (KBr, cm"1): 3061,1575,1145. Step (iv): Synthesis of 2-chloro-8-trifluoromethyl-quinoline-3-carbaldehyde 10 cp3 To a cold solution of butyllithium (0.498g, 1.7 mmol) in 2 mL dry THF at -20C was added diisopropyl amine (0.192g, 1.9mmol) drop wise and reaction mixture was allowed to stir at 0 °C for 1 h. then rection mixture was again cooled to -78 °C and a solution of 2-chloro-8-trifluoromethyl-quinoline(0.4g, 1.70 mmol) 15 in 4 mL dry THF was added drop wise continued stirring for 5-10 min then added ethyl formate (0.12 g, 1.7 mmol ) drop wise, continued stirring for 0.5 h. n-Butyllithium was quenched with ammonium chloride solution and extracted with ether (3x10 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, concentrated under vacuum to get the crude compound. 20 The crude residue was purified over silica gel (100-200 mesh) using 10% ethyl acetate: petroleum ether to afford the desired compound (0.15g, 34%). 'H NMR (CDCI3, 200 MHz): 8 10.6 (s,lH), 8.40 (d, J=7.5 Hz, IH), 8.07 (d, J=7.9 Hz, , IH), 7.96-7.88 (m,lH), 7.79-7.71 (m,lH); (ES-MS): m/z 260 (M+l, 60%), 258 (M-l, 100%); IR (KBr, cm"1): 1710, 1580. 25 Step (v): Synthesis of 2-(bis(cyclopropylmethyl)amino)-8- trifhioromethylquinoline-3-carbaldehyde -82- WO 2007/075194 PCT/US2006/025427 This compound (0.92 g, 69 %) was prepared by following same procedure as given in step (ii) of Example 1 by using 2-chloro-8-trifluoromethyl-quinoline-3-carbaldehyde instead of 2-Chloro-8-methyl-quinoline-3-carbaldehyde. 5 'H NMR (CDC13, 400 MHz): 5 10.47 (s,1H), 8.12-8.10 (m,lH), 7.96-7.94 (m,lH), 7.74-7.70 (m,lH), 7.52-7.48 (m,lH), 3.48-3.46 (m,4H), 1.25-1.05 (m, 2H), 0.87-0.45 (m, 4H), 0.10-0.06 (m, 4H); (ES-MS): m/z 314 (M-34, 100%); IR (neat, cm"1): 3075,1693,1021. Step (vi): Synthesis of 3-((3,5-bis(trifluoromethyl)benzylamino)methyl)-N,N-10 bis(cyclopropylmethyl)-8-trifluoromethylquinolin-2-amine This compound (yield: 98%) was prepared by following same procedure as in step (iii) of Example 1 by using 2-(bis(cyclopropylmethyl)amino)-8- 15 (bis(cyclopropylmethyl)amino)-8-methylquinoline-3-carbaldehyde. NMR (CDCI3, 400 MHz): 8 8.20-8.18 (m, IH), 7.97-7.94 (m, IH), 7.91-7.88 (m, 3H), 7.73-7.69 (m,lH), 7.52-7.48 (m, IH), 4.98 (s, 2H), 4.77 (s,2H), 3.17-3.15 (m, 4H), 0.79-0.73 (m, 2H), 0.28-0.26 (m, 4H), 0.003-.001 (m, 4H); (ES-MS): m/z 542 (M-33,40%), 299 (M-276, 100%); IR (neat, cm"1): 3005, 1278,1134, 1018. 20 Step (vii): Synthesis of A-(3,5-bis(trifluoromethyl)benzyl)-N-((2-(bis(cyclopropylmethyl)amino)-8-trifluoromethylquinolin-3-yl)methyl)cyanamide trifluoromethylquinoline-3-carbaldehyde instead of 2- -83 - WO 2007/075194 PCT/US2006/025427 This compound (1.5 g, yield: 85%) was prepared following the same procedure as mentioned in step (iv) of Example 1 by using 3-((3,5-bis(trifluoromethyl)benzylamino)methyl)-iY,7V-bis(cyclopropylmethyl)-8-5 trifluoromethylquinolin-2-amine instead of 3-((3,5- bis(trifluoromethyl)benzylamino)methyl)-jV,Ar-bis(cyclopropylmethyl)-8-methylquinolin-2-amine. 'H NMR (CDCI3, 400 MHz): 8 8.03-8.00 (m,2H), 7.91-7.90 (m, 3H), 7.73-7.69 (m,lH), 7.54-7.50 (m, IH), 4.60 (s,2H) 4.53 (s,2H), 3.28-3.26 (m, 4H), 0.94-0.87 10 (m, 2H), 0.043-0.032 (m, 4H). 0.019-0.004 (m, 4H); (ES-MS): m/z 567 (M-33, . 100%); IR (Neat, cm"1): 3006, 2210, 1276,1012. Step (viii): Synthesis of (3-{[(3,5-bistrifhxoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyI}-8-trifluoromethyI-quinolin-2-yl)-bis-cyclopropylmethyl-amine F3Q h vv^ "-N \J 15 This compound (0.8 g, yield: 56 %) was prepared by following the same procedure as mentioned in step (v) of Example 1 by using N-(3,5-bis(trifluoromethyl)benzyl)-A7-((2-(bis(cyclopropylrnethyl)amino)-8-trifluoromethylquinolin-3-yl)methyl)cyanamide instead of N-( 3,5-bis(trifluoromethyl)benzyl)-iV-((2-(bis(cyclopropylmethyl)amino)-8-20 methylquinolin-3 -yl)methyl)cyanamide. -84- WO 2007/075194 PCT/US2006/025427 lll NMR (CDCI3, 400 MHz): 5 8.69 (d, J=8.3 Hz, IH), 8.18-8.13 (111,IH), 8.00-7.98 (m, IH), 7.88-7.84 (m, IH), 7.72-7.64 (m, 3H), 7.52-7.48 (m, IH), 5.28 (s, 2H), 5.12 (s, 2H), 3.27-3.25 (m, 4H), 0.90-0.73 (m, 2H), 0.43-0.26 (m, 4H), 0.03-0.002 (m, 4H); (ES-MS): m/z 617 (M-26, 80%), 574 (M-69, 100%); IR (KBr, cm" 5 '): 3680,2922, 1660, 1616. Step (ix): Synthesis of (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-trifluoromethyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine amino]-methyl}~8-trifluoromethyl-quinolin~2-yl)-bis-cyclopropylmethyl-amine (0.5 g, 0.77 mmol) in water (4 mL), sodium hydroxide (0.062 g, 1.55 mmol) was added and stirred for 15 min at RT followed by the addition of dichloromethane (4 mL). To this reaction mixture, dimethyl sulphate (0.117 g, 0.933 mmol) was added 15 followed by the addition of tetra butyl ammonium bromide (0.012 g, 0.038 mmol). The reaction was stirred for 1 h. The organic layer was separated from aqueous layer and the aqueous layer was extracted with DCM (3x10 mL), the combined organic layer was washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by 20 column chromatography over 100-200 mesh silica gel using 8% ethyl acetate and petroleum ether to afford Synthesis of (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole ~5-yl)-amino]-methyl-}-8-trifiuoromethyl-quinoline-2-yl)-bis-cyclopropylmethyl-amine (0.1 g, 20%).. 10 To a suspension (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)- -85- WO 2007/075194 PCT/US2006/025427 fH NMR (CDCI3, 400 MHz): 8 8.67-8.65 (m, IH), 8.19-8.17 (m, IH), 7.83-7.79 (m, IH), 7.66-7.64 (m, 4H). 5.36 (s, 2H), 5.05 (s, 2H), 4.15 (s, 3H), 3.28 (s, 4H), 0.99-0.93 (m, 2H), 0.40-0.3 l(m, 4H), 0.03-0.01 (m, 4H); (ES-MS): m/z 631 (M-26, 100%); IR (KBr, cm"1): 3428, 3082, 2925; 1618. 5 Example 9 Synthesis of (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-Chloro-quinoline-2-yl)- bis-cyclopropylmethyl-amine Example 8 by using (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino] -methyl} -8-chloro-quinolin-2 -yl)-bis-cyclopropylmethyl-amine instead of (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-trifluoromethyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine. 15 lK NMR (CDCI3, 400 MHz): 8 7.83 (s, IH), 7.71-7.67 (m, 4H), 7.47-7.45 (m,lH), 7.25-7.18 (m,lH), 4.88 (s, 2H), 4.64 (s, 2H), 4.22 (s, 3H), 3.27-3.25 (m, 4H), 0.89-0.83 (m, 2H), 0.43-0.38 (m, 4H), 0.15-0.07 (m, 4H); (ES-MS): m/z 624 (M+1, 100%); IR (KBr, cm"1): 2926,1578,1280. ci 10 This compound was prepared by following same procedure as in step (ix) of -86- WO 2007/075194 PCT/US2006/025427 Example 10 Synthesis of 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methoxy-quinoline-2-yl)- bis-cyclopropylmethyl-amine Step (i): Synthesis of (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-5 amino]-methyl}-8-methoxy-quinolin-2-yl)-bis-cyclopropylmethyl-amine N=N / \ This compound was prepared by following the same procedure except using Ar-(2-methoxy phenyl) acetamide instead of iV-o-tolyl acetamide in step (i) of Example 1. 10 Step (ii): Synthesis of 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methoxy-quinoline-2-yl)- bis- cyclopropylmethyl-amine / N-N // \ This compound was prepared by following the same procedure by using 3-15 {[(3,5-bi strifluoromethyl-b enzyl) - (2H-tetrazol- 5 -yl) - amino] -methyl} - 8 -methoxy-quinolin-2-yl)-bis-cyclopropylmethyl-amine in step (ix) of Example 8 Purity 98.43% (HPLC: Symmetry Shield RP8 (150x4.6) 20:80 [0.01M KH2P04: CH3CN], 217 nm, Rt 11.095 min); !H NMR (CDC13, 400 MHz): 5 7.82 (s, IH), 7.71 (s, IH), 7.65 (s, 2H), 7.24-7.22 (m, IH), 7.17-7.15 (m, IH), 6.98-6.96 (m, 20 IH), 4.91 (s, 2H), 4.65 (s, 2H), 4.21 (s, 3H), 4.03 (s, 3H), 3.22 -3.20 (m, 4H), 1.27-1.25 (m, 2H), 0.40-0.35 (m, 4H), 0.12-0.09 (m, 4H); (ES-MS): m/z 618 (M+-l, 100%); IR (neat, cm"1) 3422, 1581, 1279. -87- WO 2007/075194 PCT/US2006/025427 Example 11 Synthesis of 3-{[3,5-bis trifluoromethyl-benzyl )-(2-methyl-2H-tetrazole-5-yl) amino]-methyl-}-8-isopropyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine / n-n 5 This compound was prepared as pale yellow oil (yield: 53%) by following the same procedure except using N-(2-isopropyl phenyl) acetamide instead of N-(2-methoxy phenyl) acetamide in step (i) of Example 10. Purity 98.01% (HPLC: Symmetry Shield RP8 (150x4.6) 20:80 [0.01M KH2P04: CH3CN], 217 nm, Rt 11.608 min); lB. NMR (CDC13, 400 MHz): 8 7.84 (s, IH), 10 7.71-7.69 (m, 3H), 7.48-7.47 (m, IH), 7.44-7.41 (m, IH), 7.32-7.28 (m, IH), 4.91 (s, 2H), 4.68 (s, 2H), 4.19-4.14 (m, IH), 3.96 (s, 3H), 3.18 (d, J= 5.4 Hz, 4H), 1.37 (d, J= 6.7 Hz, 6H), 0.95-0.93 (m, 2H), 0.38-0.34 (m, 4H), 0.07-0.04 (m, 4H); (ES-MS): m/z 632 (M++l, 100%); IR (neat, cm"1) 3079, 2960,1279. 15 Example 12 Synthesis of 2-{5-[[2-(bis-cyclopropylmethyl-amino)-8-methyl~quinoline-3-ylmethyl]- (3,5-bistrifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethanol This compound (yield: 56%) was prepared following the same procedure as 20 in Example 1 except using 2-bromoethanol instead of cyclopropanemethyl bromide. -88- WO 2007/075194 PCT/US2006/025427 'H NMR (CDCI3, 400 MHz): 3 7.84 (s,lH), 7.69 (d, J= 9.4 Hz, 3H), 7.44-7.41 (m, 2H), 7.24-7.20 (m, IH), 4.67 (s, 2H), 4.63 (s, 2H), 4.62-4.60 (m, 2H), 4.16-4.09 (ra, 2H), 3.19-3.18 (m, 4H), 2.71 (s, 3H), 1.02-1.00 (m, 2H), 0.40-0.35 (in, 4H), 0.09-0.07 (m, 4H). 5 (ES-MS): m/z 634 (M'"+l, 100%); IR (neat, cm"1): 3415,1583. Example 13 Synthesis of [3-({(3,5-bis-trifluoromethyl-benzyl)-[2-(2-methoxy-ethyl)-2H-tetrazol-5-yl]-amino}-methyl)-8-methyl-quinolin-2-yl]-bis-cyclopropylmethyl-10 amine To the 2- {5-[[2-(bis-cyclopropylmethyl-amino)-8-methyl-quinoline-3-ylmethyl]- (3,5-bistrifhioromethyl-benzyl)-amino]-tetrazol-2-yl}-ethanol (0.08 g, 0.126 mmol) , (example 12), was added NaOH (0.010 g, 0.25 mmol) and water (1 15 mL). The reaction was stirred at room temperature for 15 min and then DCM (1 mL) was added followed by the addition of DMS (0.019 g, 0.15 mmol) and TBAB (0.002 g, 0.006 mmol). The reaction was continued for overnight. The solvent was evaporated and the aqueous layer was back extracted with DCM (2x10 mL). The combined organic layer was washed with brine and dried over sodium sulfate. The 20 sovent was evaporated on rotavapor. The residue obtained was purified by preparative thin layer chromatography and eluted with 15% ethyl acetate and petroleum ether to get the desired product (0.30 g, 56%). *H NMR (CDCI3, 400 MHz): 5 7.83 (s,lH), 7.69-7.67 (m, 4H), 7.44 -7.42 (m, IH), 7.23-7.21 (m, IH), 4.91 (s, 2H), 4.76-4.74 (m, 2H), 4.66-4.63 (m, 4H), 3.75 (s, \ .0 n-n -89- WO 2007/075194 PCT/US2006/025427 3H), 3.18 (d, J= 6.7 Hz, 4H), 2.71 (s, 3H), 0.89-0.83 (m, 2H), 0.39-0.35 (m, 4H), 0.09-0.07 (m, 4H). (ES-MS): m/z 648 (M+, 100%), 692 (M++ 45,100%). IR (neat, cm"1): 2925, 1279. Example 14 Synthesis of 3-{[3,5 -bis trifluoromethyl-benzyl )-(2~methyl -2H-tetrazole -5-yl)-amino]-methyl-}-7,8-climethyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine This compound was prepared as a light green oil (yield: 32%) by following the same procedure except using 7V-(2,3-dimethyl-phenyl)- acetamide instead of N-(2-methoxy phenyl) acetamide in step (i) of Example 10 Purity 99.31% (HPLC: Symmetry Shield RP8 (150x4.6) 20:80 [0.01M KH2P04: 15 CH3CN], 220 nm, Rt 11.88 min); XH NMR (CDC13, 400 MHz): 5 7.78 (s, IH), 7.69-7.67 (m, 2H), 7.34-7.32 (m, IH), 7.16-7.14 (m, IH), 4.90 (s, 2H), 4.64 (s, 2H), 4.21 (s, 3H), 3.17 (d, J= 7.0 Hz, 4H), 2.67 (s, 3H), 2.45 (s, 3H), 1.02-0.98 (m, 2H), 0.37-0.36 (m, 4H), 0.35-0.34 (m, 4H); (ES-MS): m/z 618 (M++l, 100%); IR (neat, cm"1) 2926,1582,1185. 5 \ n-n ,CF 10 20 -90- WO 2007/075194 PCT/US2006/025427 Example 15 Synthesis of 3-{ [3,5-bis trifluoromethyl-benzyl)-(2-methyl -2H-tetrazole -5-yl)~ amino]-methyl-}-benzo[h]quinolin-2-yl)- bis-cyclopropylmethyl-amine \ 5 This compound was prepared as oil (0.2 g, 25%) by following the same procedure except using iV-naphthalen-1 -yl-acetamide instead of JV-(2-methoxy phenyl) acetamide in step (i) of Example 10. Purity 97.96% (HPLC: Symmetry Shield RP8 (150x4.6) 20:80 [0.01M KH2P04: CI-I3CN], 210 nm, Rt 11.69 min); lH NMR (CDC13, 400 MHz): 8 9.21-9.18 (m, 10 IH), 7.91 (s, 2H), 7.86-7.64 (m, 6H), 7.62-7.49 (m, IH), 4.96 (s, 2H), 4.60 (s, 2H), 4.20 (s, 3H), 3.27 (d, J = 7.0 Hz, 4H), 1.06-1.01 (m, 2H), 0.99-0.85 (m, 4H), 0.86-0.35 (m, 4H) (ES-MS): m/z 640 (M++l, 100%); IR (neat, cm-1) 2927,1582,1134. 15 Example 16 Synthesis of (*S)-(+)-(3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H- tetrazol-5-yl)-amino]methyl}-8-methyl-quinolin-2-yl)-ethyl-(tetrahydro-furan- 2-ylmethyI)-amine -91 - WO 2007/075194 PCT/US2006/025427 The title compound was obtained as a colorless thick liquid (yield: 40%) carbaldehyde by following analogues procedure as described in Example 1. Purity 98.58 % (HPLC: YMC C8, 20:80 [ICH2P04 (0.01 M, pH 3.2):CH3CN], Rt 5 8.66 min); 'H NMR (CDCI3, 300 MHz): 5 7.83 (s, IH), 7.70-7.67 (m, 3H), 7.45-7.39 (m, 2H), 7.22-7.19 (m, IH), 4.89 (s, 2H), 4.70 (d,J = 8.5 Hz, 2H), 4.21 (s, 3H), 4.18-4.08 (m, IH), 3.86-3.76 (m, IH), 3.69-3.60 (m, IH), 3.56-3.43 (m, 2H), 3.36-3.22 (m, 2H), 2.69 (s, 3H), 1.86-1.78 (m, 3H), 1.55-1.46 (m, IH), 1.11 (t, J = 6.81 Hz, 3H); [D]d +15.2°, c = 0.25% in MeOH; MS (ESI) m/z 608 (M+l)+. Example 17 Synthesis of (i?)-(-)-(3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]methyl}-8-methyl-quinolin-2-yl)-ethyl-(tetrahydro-furan-2-ylmethyl)~amine The title compound was obtained as a colorless thick liquid (10%) in a similar manner described in Example 16. Purity: 92.36 % (HPLC: YMC C8, 20:80 [KH2P04 (0.01 M, pH 3.2):CH3CN], Rt 40.98 min); *H NMR (CDC13, 300 MHz): 8 7.83 (s, IH), 7.70-7.67 (m, 3H), 7.45-20 7.39 (m, 2H), 7.22-7.19 (m, IH), 4.89 (s, 2H), 4.70 (d, J = 8.5 Hz, 2H), 4.21 (s, 3H), 4.18-4.08 (m, IH), 3.86-3.76 (m, IH), 3.69-3.60 (m, IH), 3.56-3.43 (m, 2H), 3.36-3.22 (m, 2H), 2.69 (s, 3H), 1.86-1.78 (m, 3H), 1.52-1.46 (m, IH), 1.10 (t, J= 6.81 Hz, 3H); [D]d -10.0°, c = 0.25% in MeOH; MS (ESI) m/z 608 (M+l)+. from 2-[ethyl-(tetrahydro-furan-2-ylmethyl)-amino]-8-methyl-quinoline-3- 10 15 -92- WO 2007/075194 PCT/US2006/025427 Example 18 Synthesis of (5-{[(3,5~bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazoI-5-yl)- amino]-methyl}-l-phenyI-lH-pyrazolo[3,4-b]pyridin-6-yl)-bis- cyclopropylmethyi-amine The title compound was obtained as a colorless thick liquid (63%) in a similar manner described in Example 8, by using 6-chloro-l -phenyl-lH-pyrazole[3,4-b]pyridine-5-carbaldehyde (starting material synthesized according to the procedure described in US 2858309). 10 Purity: 99.03 % (HPLC: YMC C8, 20:80 [KH2P04 (0.01 M, pH 3.2): CH3CN], Rt 10.78 min); 'H NMR (CDC13, 300 MHz): 8 8.40 (d, J = 7.72 Hz, 2H), 7.95 (s, IH), 7.85 (s, IH), 7.72-7.68 (m, 3H), 7.53-7.47 (m, 2H), 7.29-7.24 (m, IH), 4.87 (s, 2H), 4.65 (s, 2H), 4.22 (s, 3H), 3.19 (d, J = 6.60 Hz, 2H), 1.0-0.95 (m, 2H), 0.40-0.37 (m, 4H), 0.081-0.047 (m, 4H); MS (ESI) m/z 656 (M+l)+. Example 19 Synthesis of (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)- amino]-methyl}-l,3-dimethyl-lH-pyrazolo[3,4-b]pyridin-6-yl)-bis~ cyclopropylmethyl-amine 5 15 20 -93- WO 2007/075194 PCT/US2006/025427 The title compound was obtained as a colorless thick liquid (yield: 44%), heating a solution of {5-[(3,5-bis-trifluoromethyl-benzylamino)-methyl-l,3-dimethyl-lH-pyrazolo[3,4-b]pyridin-6-yl}-bis-cyclopropylmethyl-amine (0.3 g, 0.6 mmol), 5-bromo-2-chloropyrimidine (0.09 g, 0.5 mmol), diisopropylethylamine (1 5 mmol) in isopronaol at 80-100 °C for 4-6 h followed by evaporation of volatiles and purification of the crude by chromatography using silica gel. Purity: 97.06 % (HPLC: YMC C8, 20:80 [KH2P04 (0.01 M, pH 3.2):CH3CN], Rt 22.71 min); !H NMR (CDC13, 300 MHz): 5 8.4 (s, 2H), 7.72-7.58 (m, 4H), 5.03 (s, 2H), 4.77 (s, 2H), 3.95 (s, 3H), 3.13 (d, J= 6.0 Hz, 4H), 2.39 (s, 3H), 0.98-0.82 (m, 10 2H), 0.46-0.35 (m, 4H), 0.18-0.08 (m, 4H); MS (ESI) m/z 683 (M+l)+, 684 (M+2)+. Example 20 Synthesis of (5-{ [(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-15 amino]metliyl}-l-cyclopropyImethyl-lH-pyrazolo[3,4-b]pyridin-6-yl)~ cyclobutylmethyl-ethyl-amine The title compound was obtained as a colorless thick liquid (yield: 27%) in a similar method described in Example 18, except using 6-chloro-l-20 cyclopropylmethyl-lH-pyrazolo[3,4~b]pyridine-5-carbaldehyde (starting material prepared in a similar method described in US 2965643). Purity: 97.84 % (HPLC: YMC C8, 20:80 [KH2P04 (0.01 M, pH 3.2):CH3CN], Rt 3.30 min); lH NMR (CDC13, 300 MHz): 8 7.77-7.63 (m, 5H), 4.77 (s, 2H), 4.62 (s, 2H), 4.27 (d, J= 7.04 Hz, 2H), 4.22 (s, 3H), 3.22-3.52 (m, 4H), 1.88-1.69 (m, 4H), -94- WO 2007/075194 PCT/US2006/025427 1.54-1.30 (m, 4H), 1.03 (t, J= 7.04 Hz, 3H), 0.55-0.46 (m, 4H); MS (ESI) m/z 622 (M+l)+. Example 21 5 Synthesis of (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-l-ethyI-lH-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine: The title compound was obtained as a colorless thick liquid (0.25 g, yield: Purity: 93.48 % (HPLC: YMC C8, 20:80 [KH2P04 (0.01 M, pH 3.2):CH3CN], Rt 11.97 min); *H NMR (CDC13, 300 MHz): 5 8.39 (s, 2H), 7.74-7.67 (m, 5H), 5.01 (s, 2H), 4.77 (s, 2H), 4.48 (q, J= 7.26 Hz, 2H), 3.13 (d, J= 6.58 Hz, 4H), 1.53 (t, J = 7.26 Hz, 3H), 0.82-0.96 (m, 2H), 0.40-0.36 (m, 4H), 0.07-0.04 (m, 4H); MS 15 (ESI) m/z 683 (M+l)+, 684 (M+2)+. 10 66%) in a similar manner described in Example 19. -95- WO 2007/075194 PCT/US2006/025427 Example 22 Synthesis of (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5~(4-morpholin-4-yl- phenyl)-pyrimidin-2-yl]-amino}-methyl)-l-ethyl-lH-pyrazolo[3,4-b]pyridin-6- yl)-bis-cyclopropylmethyl-amine A mixture of (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo~pyrimidin-2-yl)-amino]-methyl}-l-ethyl-lH-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine 0.21 g, 0.3 mmol), tris(dibenzylideneacetone)dipalladium (0.05 g, 0.05 mmol), (2-biphenyl)-di-tert-10 butylphosphine (0.01 g, 0.03 mmol), sodium tert-butoxide (0.06 g, 0.6 mmol), morpholine (0.05 ml, 0.6 mmol) in toluene was stireed at ambient temperature for 24 h. Thereafter, the reaction mixture was quenched with water and extracted with ethyl acetate (2x30 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude was purified by 15 chromatography using silica gel to afford the title compound as a pale yellow liquid (0.085 g, 40%). Purity: 96.84 % (HPLC: YMC C8, 20:80 [KH2P04 (0.01 M, pH 3.2):CH3CN], PDA 264 nm, flow rate 1.2 mL/min, Rt 11.57 min); 'H NMR (CDC13, 300 MHz): 5 8.18 (s, 2H), 7.76-7.66 (m, 5H), 5.03 (s, 2H), 4.80 (s, 2H), 4.48 (q, J= 7.27 Hz, 20 2H), 3.89 (t, J = 4.77 Hz, 2H), 3.28-3.05 (m, 8H), 1.52 (t, J = 1.21 Hz, 3H), 0.82-0.96 (m, 2H), 0.42-0.33 (m, 4H), 0.09-0.05 (m, 4H); MS (ESI) m/z 689 (M+l)+. -96- WO 2007/075194 PCT/US2006/025427 Example 23 Synthesis of (3-{ [(3,5-bis-trifluoromethyl~benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-cyclobutylmethyl-ethyl-amine Step (i): Preparation of 2-(cyclobutylmethyl-ethyl-amino)-8-methyl-quinoline-3-5 carbaldehyde: Potassium carbonate (0.62 g, 4.5 mmol) was added to a solution of 2-chloro-8-methyl-quinoline-3-carbaldehyde (0.45 g, 2.2 mmol) and cyclobutylmethyl-ethyl-amine (0.47 g, 4.1 mmol) in anhydrous dimethyl 10 formamide (5 mL) under nitrogen. After stirring for 0.5 h at RT, the reaction mixture was heated for 20 h at 80-95 °C. Thereafter, the reaction was cooloed to RT, water (30 mL) and ethyl acetate (30 mL) were added, and the organic layer was separated from the aqeous mixture. The organic extract was washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The 15 residue was purified by chromatography using silica gel to afford the title compound as a pale yellow liquid (0.46 g, 75%); JH NMR (CDCI3, 300 MHz): 8 10.13 (s, IH), 8.41 (s, IH), 7.61 (d, J= 8.17, IH), 7.53 (d, J= 7.72, IH), 7.61 (t, J = 7.72, IH), 3.55-3.46 (m, 4H), 2.80-2.74 (m, IH), 2.65 (s, 3H), 2.01-1.67 (m, 6H), 1.23 (t, J = 7.04 Hz, 3H). 20 Step (ii): Preparation of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-8-methyl-quinolin-2-yl}-cyclobutylmethyl-ethyl-amine O -97- WO 2007/075194 PCT/US2006/025427 To a solution of 2-(cyclobutylmethyl-ethyl-amino)-8-methyl-quinoline-3-carbaldehyde (0.45 g, 1.6 mmol) and bis-trifluoromethyl-benzylamine (0.39 g, 1.6 mmol) in anhydrous dichloroethane (10.0 mL) was added glacial acetic acid (0.4 mL) and stirred for 20 min at RT. Sodium triacetoxyborohydride (0.68 g, 3.2 5 mmol) was added slowly and the reaction was stirred overnight at RT. After evaporation of volatiles in vacuo, water (30 mL) and ethyl acetate (30 mL) were added to the residue and the organic layer was allowed to separate. The organic layer was collected and washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography 10 using silica gel to afford the desired compound as a colorless liquid (0.485 g, yield: 60%). 1HNMR (CDCI3, 300 MHz): 8 7.89-7.75 (m, 4H), 7.53-7.44 (m, 2H), 7.28-7.23 (m, IH), 3.94 (s, 2H), 3.79 (s, 2H), 3.37-3.24 (m, 4H), 2.70 (s, 3H), 2.69-2.58 (m, IH), 1.88-1.57 (m, 6H), 1.16 (t, J= 7.04 Hz, 3H). 15 Step (iii): Preparation of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-cyclobutylmethyl-ethyl-amine 20 quinolin-2-yl}-cyclobutylmethyl-ethyl-amine (0.23 g, 0.46 mmol), 5-bromo-2-chloropyrimidine (0.09 g, 0.46 mmol), and potassium fluoride (0.11 g, 1.8 mmol) in dimethyl formamide (10 ml) was heated at 80 °C overnight. After cooling the reaction to ambient temperature water (10 mL) and EtOAc (20 mL) were added and stirred for 0.5 h. Thereafter, the organic layer was separated, washed with 25 brine, dried over sodium sulfate, filtered and solvent evaporated in vacuo. The A mixture of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-8-methyl- -98- WO 2007/075194 PCT/US2006/025427 crude was purified by chromatography using silica gel to afford the title compound as a colorless liquid (0.14 g, 47%). Purity: 96.74 % (HPLC: YMC C8, 20:80 [KH2P04 (0.01 M, pH 3.2):CH3CN], PDA 240 nm, flow rate 1.2 mL/min, Rt 65.59 min); 1HNMR (CDC13, 300 MHz): 5 5 8.40 (s, 2H), 7.71-7.66 (m, 4H), 7.43-7.38 (m, 2H), 7.22-7.17 (m, IH), 4.96 (s, 2H), 4.75 (s, 2H), 3.30 (d, J = 7.04 Hz, 2H), 3.2 (q, J = 7.04 Hz, 2H), 2.69 (s, 3H), 2.67-2.60 (m, IH), 1.87-1.54 (m, 6H), 1.10 (t, J= 7.04 Hz, 3H). MS (ESI) m/z 667 (M+1)"1"; 668 (M+2)+. 10 Example 24 Synthesis of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine: The title compound was obtained as a colorless liquid in a similar manner 15 described in Example 23 (0.32 g, 82%). Purity: 9S.60 % (HPLC: YMC C8, 20:80 [KH2P04 (0.01 M, pH 3.2): CH3CN], PDA 254 min, flow rate 1.2 mL/min, Rt 51.49 min); !H NMR (CDC13, 300 MHz): 8 8.40 (s, 2H), 7.24-7.68 (m, 4H), 7.44-7.38 (m, 2H), 7.22-7.18 (m, IH), 5.06 (s, 2H), 4.78 (s, 2H), 3.21 (d, J = 6.4 Hz, 4H), 2.71 (s, 3H), 1.04-0.97 (m, 2H), 0.39-20 0.34 (m, 4H), 0.09-0.06 (m, 4H); MS (ESI) m/z 619 (M+l)+; 680 (M+2)+. -99- WO 2007/075194 PCT/US2006/025427 Example 25 Synthesis of (3- {[ (3,5-bis-trifluoromethyl-benzyl)-(5-morpholin~4-yl- pyriniidin-2-yl)-amino]-methyl}-8-methyl-qumolm-2-yl)-bis- cyclopropylmethyl-amine A mixture of (3-{[(3,5-bis-trifhioromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine (0.32 g, 0.47 mmol), tris(dibenzylideneacetone)dipalladium (0.07 g, 0.08 mmol), (2-biphenyl)-di-fer/S-butylphosphine (0.02 g, 0.06 mmol), sodium tert-butoxide (0.09 10 g, 1 mmol), morpholine (0.08 ml, 0.9 mmol) in toluene was stirred at ambient temperature for 24 h. Therafter, the reaction mixture is quenched with water and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified by chromatography using silica gel to afford the title 15 compound as a colorless solid (0.11 g, 35%). Mp: 123-124 °C; Purity: 99.46 % (HPLC: YMC Pro C8, 20:80 [KH2P04 (0.01 M, pH 3.2):CH3CN], PDA 264 nm, flow rate 1.2 mL/min, Rt 31.71 min)]; lH NMR (CDC13, 300 MHz): 8 8.18 (s, 2H), 7.75-7.67 (m, 4H), 7.43-7.38 (m, 2H), 7.22-7.18 (m, IH), 5.05 (s, 2H), 4.79 (s, 2H), 3.91-3.85 (m, 4H), 3.21 (d, J= 6.0 Hz, 20 4H), 3.09-3.06 (m, 4H), 2.71 (s, 3H), 1.03-.099 (m, 2H), 0.39-0.34 (m, 4H), 0.09-0.07 (m, 4H); MS (ESI) m/z 685 (M+l)+. 5 -100- WO 2007/075194 PCT/US2006/025427 Example 26 Synthesis of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-ethyl-pyrimidin-2-yl)-amino]-methyl}-8-inethyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine: 5 A mixture of (3-{[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-8-methyl-quinolin-2-yl}-bis-cyclopropylmethyl-amine (0.32 g, 0.61 mmol) and 2-chloro-5-ethylpyrimidine (0.4 mL, 3 mmol) in l,3-dimethyl-2-imidazolidinone (5-10 mL) was stirred overnight at 100 °C. After evaporation of volatiles the crude was purified by chromatography using silica gel to afford the title compound as a 10 colorless liquid (0.06 g, 16%). Purity: 91.67 % (HPLC: YMC Pro C8), 20:80 [KH2P04(0.01 M, pH 3.2):CH3CN], PDA 240 nm, flow rate 1.2 mL/min, PDA 240 nm; Rt 44.76 min)]; *H NMR (CDC13, 300 MHz): 5 8.28 (s, 2H), 7.76-7.69 (m, 4H), 7.43-7.38 (m, 2H), 7.22-7.17 (m, IH), 5.08 (s, 2H), 4.81 (s, 2H), 3.22 (d, 6.36 Hz, 4H), 2.71 (s, 3H), 15 2.56 (q, 7.5 Hz, 2H), 1.29 (t,J= 7.5 Hz, 3H), 1.08-0.98 (m, 2H), 0.39-0.34 (m, 4H), 0.12-0.06 (m, 4H); MS (ESI) m/z 628 (M+l)+. -101 - WO 2007/075194 PCT/US2006/025427 Example 27 Synthesis of N- [2-(bis-cyclopropyImethyI-amino)-8-methyl-quinolin-3- ylmethyl]-iV-(3,5-bis-trifluoromethyl-benzyl)-iV^V-dimethyI-pyrimidine-2,5- diamine The title compound was obtained in a similar manner described in Example 25 as a colorless liquid (0.10 g, 37%). Purity: 99.43 % (HPLC: YMC Pro C8, 20:80 [KH2P04 (0.01 M, pH 3.2):CH3CN], PDA 264 nm, flow rate 1.2 mL/min, Rt 31.35 min); *H NMR (CDC13, 300 MHz): 10 8 8.11 (s, 2H), 7.75-7.66 (m, 4H), 7.42-7.37 (m, 2H), 7.22-7.18 (m, IH), 5.04 (s, 2H), 4.78 (s, 2H), 3.22 (d, J= 6.3 Hz, 4H), 2.88 (s, 6H), 2.71 (s, 3H), 1.20-.098 (m, 2H), 0.39-0.34 (m, 4H), 0.10-0.06 (m, 4H); MS (ESI) m/z 643 (M+l)+. Example 28 15 Synthesis of [3-({((3,5-bis-trifluoromethyl-benzyl)-[5-(4-methyl-piperazin-l-yI)-pyrimidin-2-yl]-amino}-methyl)-8-methyl-quinolin-2-yl]-bis-cyclopropylmethyl-amine 5 The title compound was obtained in a similar manner described in Example 20 25 as a colorless liquid (0.07 g, 32%). -102- WO 2007/075194 PCT/US2006/025427 Purity: 93.53 % (HPLC: YMC Pro C8, 20:80 [KH2P04 (0.01 M, pH 3.2):CH3CN], flow rate 1.2 mL/min, Rt 9.8 min); 'H NMR (CDC13, 300 MHz): 8 8.19 (s, 2H), 7.74-7.67 (m, 4H), 7.41-7.39 (m, 2H), 7.21-7.17 (m, IH), 5.04 (s, 2H), 4.78 (s, 2H), 3.21 (d, J= 6.6 Hz, 4H), 3.16-3.13 (m, 4H), 2.71 (s, 3H), 2.67-2.61 (m, 4H), 5 2.04 (s, 3H), 1.03-.099 (m, 2H), 0.38-0.33 (m, 4H), 0.10-0.06 (m, 4H). MS (ESI) m/z 698 (M+l)+. Example 29 Synthesis of (3- {[(3,5-bis-trifluor omethyl-benzyl)-py rimidin-2-yl-amino] -10 methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine The title compound was prepared in a similar manner described in Example 26 as a colorless liquid (0.14 g, 36%). Purity: 97.20% (HPLC: YMC Pro C8), 20:80 [KH2P04(0.01 M, pH 3.2):CH3CN], 15 PDA 240 nm, flow rate 1.2 mL/min, Rt 28.96 min)]; *H NMR (CDC13, 300 MHz): 8 8.43 (d, J = 4.5 Hz, 2H), 7.58-7.70 (m, 4H), 7.43-7.39 (m, 2H), 7.22-7.17 (m, IH), 6.86 (t, J= 4.5 Hz, IH), 5.10 (s, 2H), 4.82 (s, 2H), 3.22 (d, J= 6.3 Hz, 4H), 2.71 (s, 3H), 1.08-0.99 (m, 2H), 0.41-0.34 (m, 4H), 0.11-0.06 (m, 4H). MS (ESI) m/z 600 (M+l)+. 20 -103 - WO 2007/075194 PCT/US2006/025427 10 15 Example 30 Synthesis of (3-{[(3,5~bis-trifluoromethyl-benzyl)-(5-bromo-pyridin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine A mixture of (3-{[(3,5-bis-trifhioromethyl-benzylamino)-methyl]-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine (0.3 g, 0.57 mmol), tris(dibenzylideneacetone)dipalladium (0.015 g, 0.016 mmol), 4,5-bis-diphenylphosphino-9,9-dimethylxanthine (0.03 g, 0.05 mmol), sodium tert-butoxide (0.08 g, 0.86 mmol), 2,5-dibromopyridine (0.17 gl, 0.74 mmol) in toluene was stirred at 80-100° C for 4 h. Therafter, the reaction was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude was purified by chromatography using silica gel to afford the title compound as a colorless liquid (0.055 g, 14%). Purity: 99.56 % (HPLC: YMC Pro C8, 20:80 [KH2P04 (0.01 M, pH 3.2):CH3CN], PDA 240 nm, flow rate 1.2 mL/min, Rt 52.70 min)]; !H NMR (CDCI3, 300 MHz): 8 8.22 (d, J = 2.4 Hz, IH), 7.77-7.32 (m, 4H), 7.46-7.40 (m, 3H), 7.26-7.23 (m, IH), 6.34 (d, 6.9 Hz, IH), 5.01 (s, 2H), 4.79 (s, 2H), 3.18 (d, J= 6.0 Hz 4H), 2.71 (s, 3H), 1.05-.099 (m, 2H), 0.41-0.36 (m, 4H), 0.10-0.07 (m, 4H). MS (ESI) m/z 678 (M+l)+, 679 (M+2)+. -104- WO 2007/075194 PCT/US2006/025427 Example 31 Synthesis of (3-{[(3,5-bis-trifluoromethyI-benzyl)-(2-methyl-2H~tetrazol-5-yl)- amino]-methyl}-6-isopropyl-5-methyl-pyridin-2-yl)-bis-cyclopropylmethyl- amine The title compound was prepared from 2-(bis-cyclopropyhnethyl-amino)-6-isopropyl-5-methyl-pyridine-3-carbaldehyde by following the similar experimental procedure mentioned in the Example 8, (0.2 g, 38.0%). Purity 96.43% (HPLC: Symmetry Shield RP8, [0.01M KH2P04 (pH 6.5 with 10 KOH): CH3CN], 210 nm, Rt 9.156 min); !H NMR (CDC13, 400 MHz): 5 7.72 (s, IH), 7.68 (s, 2H), 7.17 (s, IH), 4.79 (s, 2H), 4.64 (s, 2H), 4.18 (s, 3H), 3.14-3.09 (m, IH), 2.95 (d, 7.0 Hz, 4H), 2.16 (s, 3H), 1.19 (d, J= 6.1 Hz, 6H), 0.84 - 0.77 (m, 2H), 0.30 - 0.07 (m, 4H), -0.02-0.01 (m, 4H); CI MS: m/z 595 (M+, 100%); IR (neat, cm"1) 2963, 1583 Example 32 Synthesis of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-metliy]-2H-tetrazol-5-yl)-amino]-methyl}-6-isopropyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine / N-N ii <• N x,N 5 15 / n-n 20 The title compound was prepared by following similar experimental procedure mentioned in the Example 31, (0.2 g, 25.0%). -105- WO 2007/075194 PCT/US2006/025427 Purity 98.49% (HPLC: Symmetry Shield RP8, [O.OIM KH2P04 (pH 6.5 with KOH): CH3CN], 210 nm, Rt 8.281 min); 'H NMR (CDC13, 400 MHz): 5 7.77 (s, IH), 7.73 (s, 2H), 7.43 (d, J= 7.0 Hz, IH), 6.78 (d, J= 7.0 Hz, IH), 4.83 (s, 2H), 4.68 (s, 2H), 4.22 (s, 3H), 3.03 (d, J= 6.0 Hz, 4H), 3.00-2.94 (m, IH), 1.28 (d, J= 5 6.8 Hz, 6H), 0.91 - 0.84 (m, 2H), 0.37 - 0.32 (m, 4H), 0.10-0.01 (m, 4H); CI MS: m/z 581 (M+, 100%); IR (neat, cm"1) 2964,1583. Example 33 Synthesis of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5~yl)-10 amino]-methyl}-6-ethyl-5-methyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine / n-n The title compound was prepared by following the similar experimental procedure mentioned in the Example 31,(0.2 g, 24.0%). Purity 95.41% (HPLC: Symmetry Shield RP8, [0.01M KH2P04 (pH 6.5 with 15 KOH): CH3CN], 210 nm, Rt 7.534 min); 'H NMR (CDC13, 400 MHz): 5 7.75 (s, IH), 7.71 (s, 2H), 7.21 (S, IH), 4.85 (s, 2H), 4.68 (s, 2H), 4.20 (s, 3H), 2.98 (d, J = 7.0 Hz, 4H), 2.74-2.69 (m, 2H), 2.08 (s, 3H), 1.25 (d, 7.5 Hz, 3H), 0.92 - 0.82 (m, 2H), 0.36 - 0.31 (m, 4H), 0.10-0.01 (m, 4H); CI MS: m/z 581 (M+, 100%); IR (neat, cm"1) 2964, 1583. 20 -106- WO 2007/075194 PCT/US2006/025427 Example 34 Synthesis of (3-{[3,5-bis-trifluoromethyl-benzyl)~(2H-tetrazol~5-yl)-amino]~ methyl}-5-methyl-6-phenyI-pyridin-2-yl)-bis-cycIopropylmethyI-amine \ 5 The title compound (0.24 g, 34%) was prepared by following the similar experimental procedure mentioned in the Example 31. Purity: 97.41% (HPLC Symmetry Shield RP8 (150X4.6) {0.01M KH2P04:ACN} 210 nm, RT: 11.73 min; ]H NMR (CDC13, 400 MHz): 5 7.73 (s,3H), 7.5 (d, J = 1.6Hz, 2H), 7.53-7.33 (m,4H),4.88 (s,2H), 4.71 (s,2H), 4.20 (s,3H), 2.99 (d J = 10 6.7Hz, H), 2.23 (s,3H), 0.89-0.82 (m,4H), 0.35-0.32 (m,4H) ,0.01-0.001 (m,4H); ES-MS: m/z: 630 (100%, M+1). Example 35 Synthesis of {5- [ [2-(bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-15 ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl}~acetic acid ethyl ester This compound (yield: 66%) was prepared following the same procedure as in Example 1 by using ethylbromoacetate instead of cyclopropanemethyl bromide. -107- WO 2007/075194 PCT/US2006/025427 'H NMR (CDCI3, 400 MHz): 5 7.84 (s, IH), 7.69 (s, IH), 7.67 (s, 2H), 7.44-7.41 (m, 2H), 7.23-7.21 (m, IH), 5.25 (s, 2H), 4.93 (s, 2H), 4.66 (s, 2H), 4.30-4.25 (m, 2H), 3.19-3.17 (m, 4H), 2.70 (s, 3H), 1.30-1.21 (m, 3H), 0.88-0.85 (m, 2H), 0.39-0.34 (m, 4H), 0.09-0.05 (m, 4H); (ES-MS): m/z 616 (M++l, 100%); IR (neat, cm" 5 '): 3003, 2925,1760. Example 36 Synthesis of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(4-chloro-[l,3,5]triazin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine 10 Step (i): Synthesis of iV-cyanochloroformamidine Concentrated hydrochloric acid (125 mL) was cooled to -18 °C. Sodium cyanamide (15 g, 160 mmol) was dissolved in 20 mL of water and added quickly to the hydrochloric acid. The temperature of the flask was maintained at -20 0 - 35 °C 15 and the contents were stirred for 30 min. The flask was warmed to 40 °C and again cooled to -10 °C. The precipitate obtained (iV-cyanochloroformamidine) was filtered, washed with water (5 mL), and dried under vacuum to give 10 g of material that was used directly for the next step without any purification (yield: 57.8 %). 20 Step (ii): Synthesis of 2,4-dichloro-[l,3,5]triazine Af-Cyanochloroformamidine (6 g, 50 mmol) was taken in dichloromethane (50 mL) and cooled to 0 °C. To this, POCI3 (4.1 mL, 50 mmol) was added followed by DMF (50 mmol). Contents of the flask were stirred overnight from 0 °C at room 25 temperature. Water (100 mL) was added to the flask and the compound was extracted with dichloromethane (100 mL X 3). The organic layer was dried over sodium sulfate and concentrated under vacuum to afford 4.2 g of colorless solid (yield: 48.8%). n - 108- WO 2007/075194 PCT/US2006/025427 *H NMR (CDC13> 400 MHz): 5 8.2 (s, IH). Step (iii): Synthesis of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(4-chloro-[l,3,5]triazin-2~yl)-amino]methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine A mixture of 3-((3,5-bis(trifluoromethyl)benzylamino)methyl)-iV,iV-bis(cyclopropylmethyl)-8-methylquinolin-2-amine (Example 1 step-iii) (0.2 g, 0.38 mmol), diisopropyl ethylamine (54 |J.L, 0.42 mmol) was taken in DMF (20 mL) and stirred at 0 °C for 5 min. To this 2,4-dichloro-[l,3,5]triazine (84 mg, 0.57 10 mmol) was added to the flask at 0 °C and the contents were stirred for 30 min. The reaction mixture was taken in ethyl acetate (100 mL) and washed with water (100 mL X 3). The organic layer was separated, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified on column chromatography (silica gel 230- 400 mesh). Elution with 2 % ethyl acetate in 15 hexane afforded as a colorless gummy mass (yield: 67.9%). Purity: 98.66%; *H NMR (CDC13): 8 8.53- 8.51 (m,lH), § 7.77- 7.70 (m, 4H), 7.47- 7.43 (m, 2H), 7.24 (s,lH), 5.14- 5.11 (m, 2H), 4.82- 4.77 (m, 2H), 3.20-3.19 (m, 4H), 2.71 (s, 3H), 1.03- 0.86 (m, 2H), 0.41-0.39 (m,4H), 0.11- 0.0.06 (m, 4H); ES-MS: m/z 635(M4', 100 %) IR (neat) cm"1: 3386, 2925, 1566, 1498, 1421, 1383, 20 1354,1278,1174,1135, 977, 900, 806, 763, 706, 682, 617. -109- WO 2007/075194 PCT/US2006/025427 10 15 20 Example 37 Synthesis of N-[2-(Bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3~ ylmethyl]-N-(3,5-bis-trifluoromethyl-benzyl)-N',N'-dimethyl-[l,3,5]triazine- 2,4-diamine Step (i): Synthesis of (4-chloro-[l,3,5]triazin-2-yl)-dimethyl-amine N^N Cl^N^N^ I iV-Cyanochloroformamidine (2.4 g, 20 mmol) was taken in dichloromethane (50 mL) and cooled to 0 °C, POCI3 (3.2 mL, 40 mmol) was added followed by DMF (40 mmol). Contents of the flask were stirred overnight starting at 0 °C and then slowly warming up to room temperature. Water (100 mL) was added to the flask and the compound was extracted with dichloromethane (100 mL X 3). The organic layer was dried over sodium sulfate and concentrated under vacuum to afford 0.8 g of colorless solid (yield: 22.2%). 'H NMR (CDCI3, 400 MHz): 5 8.34 (s,lH), 3.22-3.90 (2s, 6H); (EI-MS) m/z: 159 (M++l, 100 %). Step (ii): Synthesis of N-[2-(Bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3- ylmethyl]-N-(3,5-bis-trifluoromethyl-benzyl)-N',N'-dimethyl-[l,3,5]triazine-2,4- diamine A mixture of 3-((3,5-bis(trifluoromethyl)benzylamino)methyl)-N,N-bis(cyclopropylmethyl)-8-methylquinolin-2-amine (Example 1, step-iii) (0.3 g, 0.57 mmol), diisopropyl ethylamine (81jaL, 0.69 mmol) was taken in DMF (20 mL) and stirred at 0 °C for 5 min. To this (4-chloro-[l,3,5]triazin-2-yl)-dimethyl- -110- WO 2007/075194 PCT/US2006/025427 amine (100 mg, 0.69 mmol) was then added and the contents were stirred for 30 min at 60 °C . The reaction mixture was taken in ethyl acetate (100 mL) and washed with water (100 mL X 3). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified on 5 column chromatography (silica gel 230- 400 mesh). Elution with 2 % ethyl acetate in hexane afforded 265 mg of colorless solid (yield: 71.6 %). Purity: 99.24 %; 'H NMR (CDC13): 5 8.32-8.31 (m, IH), 7.77-7.71 (m, 4H), 7.43-7.42 (m, 2H), 7.24 (s,lH), 5.08-4.98 (m, 2H), 4.84- 4.6 7(m, 2H), 3.21- 3.09 (m, 10H), 2.71- 2.62 (m, 4H), 2.17 (s, 3H), 1.14- 0.84,(m, 2H), 0.38- 0.36 (m, 4H), 10 0.07-0.04 (m, 4H). ES-MS: m/z 644 (M++l, 100%); IR (neat) cm"1: 3385, 2926,1618, 1572, 1510, 1482, 1408, 1381, 1353, 1278, 1234, 1176, 1135, 1006, 971, 898, 813, 762, 706, 682, 590. 15 Example 38 Synthesis of (3-{ [(3,5-bis-trifluoromethyl-benzyl)-(4-morpholin-4-yl- [l,3,5]triazin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis- cv clop r opyl me thyl-a mine 2-yl)-amino]methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine (Example 36) (60 mg, 0.09 mmol), diisopropyl ethylamine (13]_lL, 0.1 mmol) was taken in DMF (10 mL). The flask was cooled to 0 °C and the contents were stirred for 5 min. To this, morpholine (12 |j,L, 0.13 mmol) was added and the stirring was 25 continued for 30 min at 0 °C and then warming up to room temperature. Contents 20 A mixture of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(4-chloro-[l,3,5]triazin- - Ill - WO 2007/075194 PCT/US2006/025427 of the flask were taken in 100 mL EtOAc and washed with water (100 mL X 3). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography; (silica gel 230- 400 mesh). Elution with 2% EtOAc in hexane afforded 58 mg of colorless 5 mass (yield: 78%). Purity: 97.34%; lH NMR (CDC13): 8 8.33- 8.30 (m, IH), 7.78- 7.72 (m, 4H), 7.44-.42 (m, 2H), 7.24 (s, 1H), 5.09- 4.65 (m, 4H), 3.715 (m, 8H), 3.20-3.19 (m, 4H), 2.7 (s,3H), 1.14-0.83 (m, 2H), 0.40-0.38 (m, 4H), 0.07- 0.0 6 (m, 4H); ES-MS: m/z 686 (M+'+l ,100%); IR (neat) cm"1: 3395, 2925, 2855, 1618, 1509, 1515, 1493, 10 1445, 1383, 1351, 1278, 1225, 1176, 1136, 1136, 1019, 991, 972, 897, 858, 812, 761, 706, 682, 582. Example 39 Synthesis of (5-{[(3,5-bBis-trifluoromethyl-benzyl)-(4-N,N dimethylamino-15 [l,3,5]triazin-2-yl)-amino]-methyI}-l,3-dimethyI-lH-pyrazoIo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine A mixture of {5-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-l,3-dimethyl-1 H-pyrazolo[3,4-b]pyridin-6-yl} -bis-cyclopropylmethyl-amine (400 mg, 20 0.76 mmol) and diisopropylethylamine(197 mg, 1.5 mmol) in DMF (25 mL) was stirred for 5 min at 0 °C. Then (4-chloro-[ 1,3,5]triazin-2-yl)-dimethyl-amine (144 mg, 0.91 mmol) was added and the flask was heated for 1 h at 60 °C. The reaction mixture was taken in EtOAc (200 mL) and washed with water (200 mL X 4) and finally with brine (100 mL). The crude product was purified by column n n N y -112- WO 2007/075194 PCT/US2006/025427 chromatography (silica gel 230- 400 mesh). Elution with 1.5% EtOAc in hexane afforded 160 mg of gummy compound (yield: 32.45%). Purity: 93%; 'H NMR (CDC13): 8 8.32- 8.29 (m,lH), 7.70- 7.62 (m,4H), 7.24 (s,lPI), 5.05- 4.95 (m, 2H), 4.82-4.67 (m,2H), 43.97 (s,3H), 3.21-3.09(m, 10H), 2.4 5 (s,3H), 0.94-0.85 (m, 2H), 0.39-0.36 (m, 4H), 0.07-0.04 (m,4H); ES-MS: m/z 648 (M+'+l, 100%). IR (neat) cm"1: 3416, 3080, 3004, 2931,1610,1573,1510,1318, 1278, 1175,1135, 1005, 813, 682. 10 Example 40 Synthesis of (3-{ [(3,5-bis-trifIuoromethyl-benzyl)-(2-methyI-2H-tetrazol-5-yl)-amino]-methyl}-6-methyl-quinolin-4-yl)-bis-cyclopropylmethyl-amine Step (i): Synthesis of 2-(p-tolylamino-methylene)-malonic acid diethyl ester diethyl ester (24.2 g, 0.11 mol) and heated at 110 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove the liberated ethanol from the reaction. The residue (25.8 g, 100 %) was carried out for the next reaction without any purification. 20 Step(ii): Synthesis of 4-chloro-6-methyl-quinoline-3-carboxylic acid ethyl ester CI COOEt Phosphorous oxychloride (83.6 mL, 900 mmol) was added slowly to 2-(p-tolylamino-methylene)-malonic acid diethyl ester (28 g, 90 mmol) at 0 °C for 20 min and then heated at 115 °C for 5h. The excess POCI3 was distilled off under 25 reduced pressure the residue was neutralized with saturated sodium carbonate and extracted with ethyl acetate (500 mL X 3) and washed with water (500 mL) and sodium chloride (500 mL). The organic layer was concentrated and purified uuutt 7>Toludine (10 g, 0.093 mol) was taken in 2-ethoxymethylene-malonic acid 15 -113 - WO 2007/075194 PCT/US2006/025427 through column chromatography using 100-200 mesh silica gel; elution was with 5% ethyl acetate in petroleum ether as light yellow solid (12.0 g, yield: 51 %). 'H NMR (CDC13, 200 MHz): 8 9.1 (s, IH), 8.1(s, IH), 8.02-7.98 (d, 8.5Hz IH), 7.66-7.62 (d, J= 8.5Hz IH), 4.54-4.44 (q,J= 7.2Hz 2H), 2.58 (s, 3H), 1.50- 1.42 (t, 5 J = 7.1Hz, 3H); (CI-MS) m/z : 250 (M+l+) 100%). Step(iii): Synthesis of (4-chloro-6-methyl-quinolin-3-yl)-methanol 4-Chloro-6-methyl-quinoline-3-carboxylic acid ethyl ester (4 g, 16 mmol) was taken in dry THF (150 mL) under nitrogen atmosphere and DIBAL-H (20% 10 solution in toluene) (12.5 mL, 100 mmol) was added at -78 °C over a 30 min period. The flask was stirred from -78 °C to room temperature for 48 h and then cooled back down to 0 °C. Excess DIBAL-H was quenched with saturated ammonium chloride (150 mL) solution. The precipitate was filtered and washed with ethyl acetate. The filtrate was washed with water (500 mL X 3). The organic 15 layer was separated, dried over sodium sulfate and concentrated under vacuum. The solid obtained was washed with 1% EtOAc in hexane (150 mL X 3) to remove the unreacted ester. The resultant white solid was filtered and dried under vacuum to give 1.7 g of material (yield: 51.5%). *H NMR (CDCI3, 200 MHz): 8 8.88(s, IH), 7.99- 7.95 (m,2H), 7. 58 -7.54 (d, J= 20 8.5Hz IH), 5.00 (s,2H), 2.57 (s, 3H); (CI-MS): m/z 207 (M+> 100%). Step (iv): Synthesis of 4-chloro-6-methyl-quinoline-3-carbaldehyde (4-Chloro-6-methyl-quinolin-3-yl)-methanol (500 mg, 2.42 mmol) was taken in dichloromethane and activated manganese (IV) oxide (6.6 g, 70 mmol) 25 was added to it. The contents were stirred for 1 h. Manganese oxide was filtered CI CI O H -114- WO 2007/075194 PCT/US2006/025427 and washed with dichloromethane (300 mL). The filtrate was concentrated under vacuum to afford 422 mg of colorless solid (yield: 85.2%). ]H NMR (CDCI3, 200 MHz): 5 10.70 (s, IH), 9.20 (s, IH) 8.16- 8.04 (m, 2H), 7.77- 7.72 (d, 8.5Hz,lH), 2.63 (s, 3H); (CI-MS): m/z 205 (M+' 100%). 5 Step (v) Synthesis of 4-(bis-cyclopropylmethyl-amino)-6-methyl-quinoline-3-carbaldehyde To a mixture of N bis-cyclopropyl methylamine (263 mg, 2 mmol) and potassium carbonate (484 mg, 3 mmol) was added in DMSO (25 mL), 4-Chloro-6-10 methyl-quinoline-3-carbaldehyde (360 mg, 1.7 mmol) was added and the contents of the flask were stirred at 130 °C for 3 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (200 mL X 4) and finally with brine (100 mL). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica 15 gel 230-400 mesh). Elution with 10% EtOAc in hexane afforded the compound as a yellow oil (0.325 gm, yield: 62%). *H NMR (CDCI3, 400 MHz): 5 10.53 (s, IH), 9.09 (s, IH), 8.00- 7.98 (d, J= 8.5Hz, IH), 7.86 (s,lH),7.60-7.58 (d, J= 8.5Hz, IH) 3.54- 3.52( d,J= 6.7Hz, 4H), 2.58 (s, 3H), 1.40-1.25 (m, 2H), 0.49- 0.47 (m, 4H), 0.08- 0.06 (m, 4H); (CI-MS): m/z 295 20 (M+r-100%). Step (vi) Synthesis of {3-[(3,5-bis-trifhioromethyl-benzylamino)-methyl]-6-methyl-quinolin-4-yl}-bis-cyclopropylmethyl-amine cf3 -115- WO 2007/075194 PCT/US2006/025427 A mixture of 4-(bis-cyclopropyhnethyl-amino)-6-methyl-quinoline-3-carbaldehyde (310 mg, 1 mmol), 3,5-bis-trifluoromethyl-benzylamine (334 mg, 1.3 mmol) and acetic acid (63 |iL, 1 mmol) was taken in methanol (20 mL) and stirred at 0 °C for 30 min. Sodium borohydride (130 mg, 2 mmol) was added to it at room 5 temperature portion wise over a period of 5 min. The contents were stirred at room temperature for 1 h and then taken in EtOAc (250 mL) and washed with water (200 mL X 3). Organic layer separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (Silica gel 100- 200 mesh). Elution with 2 % EtOAc in hexane afforded 0.490 gm (yield: 10 89.2 %) of gummy oil. NMR (CDClj, 400 MHz): 5 8.86 (s, IH), 8.00- 7.75 (m, 6H), 7.48-7.45 (d, 8.3Hz, IH) 4.08- 4.01 (m, 4H),3.24- 3.20 (m, 4H), 2.53 (s, 3H), 0.96-0.93 (m, 2H), 0.37- 0.35 (m, 4H), 0.07- 0.01 (m, 4H); (CI-MS): m/z 522 (M+l+'100%). Step(vii) Synthesis of [4-(bis-cyclopropylmethyl-amino)-6-methyl-quinolin-3-15 ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide A mixture of {3-[(3,5-bis-trifiuoromethyl-benzylamino)-methyl]-6-methyl-quinolin-4-yl}-bis-cyclopropylmethyl-amine (490 mg, 0.94 mmol) and sodium hydrogen carbonate (159 mg, 1.87 mmol) in methanol (10 mL) was stirred at room 20 temperature for 5 min. To this, cyanogen bromide (149 mg, 1.40 mmol) was added and the contents were stirred at room temperature for 30 min. Reaction mixture was diluted with EtOAc (200 mL) and washed with water (200 mL X 3). Organic layer separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified with column chromatography (silica gel 230-400 mesh). 25 Elution with 0.5% methanol in dichloromethane afforded 0.460 gm of oily compound (yield: 89.6%). - 116- WO 2007/075194 PCT/US2006/025427 'H NMR (CDCI3, 400 MHz): 5 8.86 (s, IH), 8.00- 7.75 (m, 6H), 7.53-7.52 (d,J= 6.7Hz IH) 4.08- 4.01 (m, 4H), 3.21-3.19 (m,J= 6.7Hz, 4H), 2.53 (s, 3H), 0.96-0.93 (m, 2H), 0.37- 0.35 (m, 4H), 0.07- 0.01 (m, 4H); (CI-MS): m/z 547 (M+1+', 100%). Step (viii): Synthesis of (3-{[(3,5-bis-trifhioromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-6-methyl-quinolin-4-yl)~bis-cyclopropylmethyl-amine HN-N CF3 A mixture of [4-(bis-cyclopropylmethyl-amino)-6-methyl-quinolin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide (450 mg, 0.824 mmol), zinc 10 bromide (222 mg, 0.986 mmol) and sodium azide (74 mg, 1.138 mmol) in water (50 mL) was heated under reflux for 5 h. The flask was cooled to room temperature and 5 % hydrochloric acid was added to it. The reaction mixture was extracted with EtOAc (100 mL X 3). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum to afford 700 mg of the crude compound and it 15 was directly used for the next step without any purification. Scheme (ix) Synthesis of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H- tetrazol-5-yl)-amino]-methyl}-6-methyl-quinolin-4-yl)-bis-cyclopropylmethyl- amine 20 A mixture of (3-{[(3,5-bBis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)- amino]-methyl}-6-methyl-quinolin-4-yl)-bis-cyclopropylmethyl-amine (700 mg, 1.18 mmol) and sodium hydride (60 %) (61 mg, 1.5 mmol) in DMF (25 mL) was -117- WO 2007/075194 PCT/US2006/025427 stirred at 0 °C for 5 min. To this, methyl iodide (337 g, 2 mmol) was then added and stirring was continued for another 30 min. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (200 mL X 4) and finally with brine (100 mL). The organic layer was separated, dried over sodium sulphate and 5 concentrated under vacuum. The crude product was purified by column chromatography (silica gel 230- 400 mesh). Elution with 1.5 % EtOAc in hexane afforded 0.205 gm of gummy mass (yield: 28.63%). Purity: 95%; 'H NMR (CDC13): 5 8.61 (s, IH), 7.97-7.95 (d, J= 8.3Hz IH), 7.78-767 (m, 4H), 7.48-7.46 (d, J= 6.7Hz, IH), 5.10 (s, 2H), 4.79 (s, 2H), 4.18 s,3H), 10 3.18-3.16 (d, J= 6.7Hz,4H) 2.53 (s, 3H), 0.81- 0.77 (m, 2H), 0.31-0.29 (m, 4H), -0.008- -0.02 (m, 4H). ES-MS: m/z 604 (M++l, 100%); IR (neat) cm"1: 3004, 1575, 1505, 1508, 1426, 1379,1279, 1173, 1134,1019, 903, 827, 754, 706, 682. 15 Example 41 Synthesis of (3-{ [(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)- amino]-methyl}-quinolin-4-yl)-bis-cyclopropylmethyl-amine Step (i): Synthesis of 2-phenylaminomethylene-malonic acid diethyl ester diethyl ester (27.8 g, 128 mmol) was heated at 110 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove the liberated ethanol from the reaction. The residue (28.2 g) was carried out for the next reaction without any purification. 25 Step (ii): Synthesis of 4-chloro-quinoline-3-carboxylic acid ethyl ester C02Et 20 A mixture of aniline (10 g, 107 mmol), 2-ethoxymethylene-malonic acid CI -118- WO 2007/075194 PCT/US2006/025427 Phosphorous oxychloride (98,6 mL, 1.06 mol) was added slowly to 2-phenylaminomethylene-malonic acid diethyl ester (28 g, 106 mmol) at 0 °C for 20 min and then heated at 115 °C for 5h. The excess POCI3 was distilled off under reduced pressure and the residue was neutralized with saturated sodium carbonate 5 and extracted with ethyl acetate (500 mL X 3) and washed with water (500 mL) and sodium chloride (500 mL). The organic layer was concentrated and purified through column chromatography using 100-200 mesh silica gel, elution with 5% ethyl acetate in petroleum ether afforded 12.5 g of product (yield: 50%) as a light yellow solid. 10 ES-MS: m/z 236 (M++l,100%). Step (iii): Synthesis of 4-(Bis-cyclopropylmethyl-amino)-quinoline-3-carboxylic acid ethyl ester A mixture of 4c-quinoline-3-carboxylic acid ethyl ester (5 g, 20 mmol) and 15 bis-cyclopropylmethyl-amine (3.98 g, 30 mmol) were taken in isopropanol (50 mL) and the reaction mixture was refluxed for 10 h. Isopropanol was removed under reduced pressure then the crude was washed with petroleum ether and dried to afford 5.4 g (yield: 79%) of yellow colored gummy mass. ES-MS: m/z 325 (M++l, 100 %). 20 Step (iv): Synthesis of [4-(bis-cyclopropylmethyl-amino)-quinolin-3-yl]-methanol 4-(Bis-cyclopropylmethyl-amino)-quinoline-3-carboxylic acid ethyl ester (1 g, 3.0 mmol) was taken in DCM at -78 °C under nitrogen atmosphere and DIB ALII (8.76 mL (20 % solution in toluene), 12 mmol) was added at the same -119- WO 2007/075194 PCT/US2006/025427 temperature over a period of 20 min. The reaction mixture was continued to stir at room temperature for 48 h. It was again cooled to -78 °C and saturated potassium sodium tartrate solution (15 mL) was added slowly for 20 mins and extracted with ethyl acetate (100 mL X 3) and washed with water (100 mL). The organic layer 5 was dried over sodium sulfate, concentrated under reduced pressure and purified through column chromatography using 100-200 mesh silica gel. Elution with 1 % methanol in dichloromethane afforded 0.450 gm (yield: 45%) of yellow colored gummy mass. !H NMR (CDC13) 5: 8.89 (s, IH), 8.13-8.10 (d, J= 9.134, IH), 8.07-8.04 (d,, J = 10 9.40, IH) 7.67 (dd, .7=1.48, 1.34 Hz, IH), 7.49 (dd, 7=1.6, 1.4 Hz, IH), 5.00 (s, 2H), 3.32-3.31 (d, J= 6.99, 4H), 1.03-0.96 (m, 2H), 0.45-0.40 (m, 4H), 0.06-0.02 (m, 4H); ES-MS m/z: 283 (M++l, 100%). Step (v): Synthesis of 4-(bis-cyclopropylmethyl-amino)-quinoline-3-carbaldehyde 15 A mixture of [4-(bis-cyclopropylmethyl-amino)-quinolin-3-yl]-methanol (450 mg, 1.5 mmol) and Mn02 (1.3 g, 15 mmol) in methylene chloride (15 mL) was stirred at room temperature for 30 min. The reaction mixture was filtered through celite with methylene chloride. The filtrate was concentrated under reduced pressure to afford 400 mg (yield: 90%) of yellow colored gummy mass. 20 (CI-MS): m/z: 281 (M++l, 100 %). Step (vi): Synthesis of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-quinolin-4-yl}-bis-cyclopropylmethyl-amine N cf3 -120- WO 2007/075194 PCT/US2006/025427 A mixture of 4-(bis~cyclopropylmethyl-amino)-quinoline-3-carbaldeliyde (400 mg, 1.4 mmol), 3,5-bis-trifluorometliyl-benzylamine (380 mg, 1.5 mmol) in methanol (20 mL) was added acetic acid (2 drops). The contents were stirred at room temperature for 30 min and sodium cyano borohydride (176 mg, 2.8 mmol) was 5 added to it at 0 °C over a period of 5 min. The flask was wanned to room temperature and continued to stir for 1 h. Methanol was removed under vacuum and water (15 mL) added to the residue. The crude product was extracted with ethyl acetate (100 mL X 3); the organic layer was washed with water (100 mL X 3) and dried over sodium sulfate. Concentration under vacuum afforded 0.468 gm 10 (yield: 65%) of yellow colored gummy mass. 'ii NMR (CDCI3) 5: 8.93 (s, IH), 8.11-8.06 (m, 2H), 7.87-7.75 (m, 3H), 7.63 (t, ■7=4.2 Hz, IH), 7.48 (t, <7=4.2 Hz), IH), 4.09 (s, 2H), 4.02 (s, 2H), 3.26-3.24 (m, 4H), 0.95-0.86 (m, 2H), 0.41-0.34 (m, 4H), 0.06-0.02 (m, 4H); ES-MS: m/z 508 (M++l, 100 %). 15 Step (vii): Synthesis of [4-(bis-cyclopropylmethyl-amino)-quinolin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide A mixture of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-quinolin-4-yl}-bis-cyclopropylmethyl-amine (460 mg, 0.9 mmol) and sodium hydrogen 20 carbonate (151 mg, 1.8 mmol) in methanol (20 mL) was stirred at 0 °C for 30 min then cyanogen bromide (190 mg, 1.8 mmol) was added and the resulting reaction mixture was stirred at room temperature for 1 h. Methanol was removed under vacuum and water (50 mL) was added to the reaction mixture; the crude product was extracted with ethyl acetate (100 mL X 3) and washed with water (100 mL X 25 3) then the combined organic layer was dried over sodium sulfate and concentrated to afford 0.360 gm (yield: 7 %) of light yellow solid. cf3 - 121 - WO 2007/075194 PCT/US2006/025427 'H NMR (CDCI3) 8: 8.91 (s, IH), 8.13-8.11 (d,/= 8.33, IH), 8.05-8.03 (d, IH, J= 9.14), 7.90 (s, IH), 7.81 (s, 2H), 7.70 (t, IH), 7.52 (t, 12H), 4.62 (s, 2H), 4.39 (s, 2H), 3.23-3.21 (d, ,7=6.71 Hz, 4H), 0.88-0.81 (m, 2H), 0.39-0.37 (m, 4H), 0.08-0.04 (m, 4H); ES-MS: m/z 533 (M++l, 100%). 5 Step (viii): Synthesis of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-quinolin-4-yl)-bis-cyclopropylmethyl-amine A mixture of [4-(bis-cyclopropylmethyl-amino)-quinolin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide (350 mg, 0.65 mmol), sodium azide (51 10 mg, 0.78 mmol) and zinc bromide (175 mg, 0.78 mmol) were taken in water (15 mL) and refluxed for 1 h. 5% Hydrochloric acid was added and the crude product was extracted with ethyl acetate (100 mL X 3) and washed with water (75 mL); the organic layer was dried over sodium sulfate and concentrated to afford 0.300 gm (yield: 80 %) of yellow colored gummy mass. This was directly carried for the next 15 reaction. Step (ix): Synthesis of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-quinolin-4-yl)-bis-cyclopropylmethyl-amine A mixture of (3 - {[ (3,5 -bis-trifluoromethyl-benzyl)-(2H-tetrazol- 5-yl)-20 amino]-methyl}-quinolin-4-yl)-bis-cyclopropylmethyl-amine (300 mg, 0.52 mmol) and sodium hydride (31 mg, 0.78 mmol) were taken in DMF (10 mL) at 0 °C and stirred for 20 min, then methyl iodide (0.067 mL, 1.04 mmol) was added at that N-NH CF3 n-n cf3 \ 3 - 122- WO 2007/075194 PCT/US2006/025427 temperature and stirred for 1 h. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (100 mL X 3) and the organic layer was washed with water (75 mL). Drying over sodium sulfate and concentration under vacuum yielded the crude product that was purified by column chromatography using 230-5 400 mesh silica gel eluting with 5% ethyl acetate in petroleum ether to afford 0.107 gm (yield: 35%) of yellow colored gummy mass. Purity: 94%; ]H NMR (CDC13): 8 8.68 (s,lH), 8.09-8.04 (m,2H), 7.75-7.47 (m, 5H), 5.09 (s, 2H) 4.80 (s,2H), 4.18 (s,3H), 3.20-3.18 (d, J=6.7 Hz, 4H), 0.91- 0.76 (m,2H), 0.31-0.30 (m,4H), -0.008- -0.05 (m, 4H); ES-MS: m/z 590 (MN-1,100%); 10 IR (neat) cm"1: 3385, 2926, 1567, 1500, 1380, 1279, 1174, 1134, 1020, 903, 843, 766, 706, 682. Example 42 Synthesis of (6-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyI-2H-tetrazol-5-yl)-15 amino]-methyl}-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-bis-cyclopropylmethyl-amine Step (i): Synthesis of A/-(2,3-dimethyl-3H-imidazol-4-yl)-acetamide 5% Palladium on carbon (7.5 g) was taken in to 500 mL round bottom flask 20 and to that 1,4-dioxane (450 mL) was added. l,2-dimethyl-5-nitro-lH-imidazole (15.0 g, 106.2 mmol.) was added to it and stirred gently at room temperature under hydrogen atmosphere for 12 h. Acetic anhydride (30.1 mL, 318.6 mmol.) was added very slowly and continued to stir at room temperature for 5 h; then the reaction mixture was then passed through celite and washed with dichloromethane 25 (500 mL) and the filtrate was concentrated under vacuum to yield 15.0 g (yield: 92%) of dark yellow oily liquid. !H NMR (CDCls): 8 8.57 (bs, IH), 6.65 (s,lH), 3.39-3.34 (s, 3H), 2.37-2.31 (s, 3H), 2.28-2.24 (s, 3H); (CI-MS): m/z 153 (M+100%), 110. - 123 - WO 2007/075194 PCT/US2006/025427 Step (ii): Synthesis of 5-chloro-2,3-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbaldehyde iV-(2,3-Dimethyl-3H-imidazol-4-yl)-acetamide (15.0 g, 988.0 mmol) was 5 taken in P0C13 (54.8 mL, 588 mmol.) at 0 °C and stirred for 3 h at 90 °C then DMF (22.72 mL, 294 mmol.) was added to it slowly at the same temperature over a period of 30 min. the reaction was continued to stir at the same temperature for 1.5 h. The excess POCI3 was distilled off under reduced pressure then the residue was neutralized with saturated solution of sodium carbonate and extracted with ethyl 10 acetate (600 mL X 3) and washed with water (300 mL) and the organic layer was dried over sodium sulfate and concentrated under vacuum. The crude compound was purified through column chromatography using 100-200 mesh silica gel. Elution was 1% methanol in dichloromethane to yield 5.25 g (yield: 25.6%) of colorless solid. 15 'H NMR (CDCI3): 5 10.5 (s, IH), 8.46 (s,lH), 3.83 (s, 3H), 2.67 (s, 3H); (CI-MS): m/z 210 (M+r-, 100%). Step (iii): Synthesis of 5-chloro-2,3-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbaldehyde oxime 20 To a mixture of 5-chloro-2,3-dimethyl-3H-imidazo[4,5-b]pyridine-6- carbaldehyde (4.2 g, 20 mmol.) and hydroxylamine hydrochloride (2.8 g, 40 mmol.) in methanol was added triethylamine (5.415 mL, 40 mmol.) at 0 °C then the reaction mixture was stirred at room temperature for 12 h. Methanol was distilled off under reduced pressure and then the residue was taken in ice cold 25 water (500 mL) and stirred for 15 min. The resulting solid was filtered out and washed with water (500 mL) and then dried under vacuum to yield 3.0 g (yield: 66.9%) of color less solid. - 124- WO 2007/075194 PCT/US2006/025427 (CI-MS): m/z 225 (M+1K, 100 %),207,178,129. Step (iv): Synthesis of 5-chloro-2, 3-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile 5 5-Chloro-2 ,3-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbaldehyde oxime (2.2 g, 9.8 mmol.) was taken in acetic anhydride (40 mL, excess) and refluxed for 14 h in nitrogen atmosphere. The reaction mixture was then taken in water (250 mL) and extracted with ethyl acetate (100 mL X 3), washed with saturated sodium bicarbonate solution (100 mL) followed by water (250 mL) and concentrated 10 under vacuum. Upon purification by column chromatography using 230-400 mesh silica gel using 2 % acetone in dichloromethane yielded 1.1 g (yield: 54.4 %) of pure colorless solid. 'H NMR (CDCI3, 200 MHz): 5 8.67 (s, IH), 3.75 (s, 3H), 2.66 (s, 3H); (CI-MS): m/z 207 (M+'l, 100%). 15 Step (v): Synthesis of 5-(bis-cyclopropylmethyl-amino)-2,3-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile A mixture of 5-chloro-2,3-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile (1.0 g, 4 mmol.), bis-cyclopropylmethyl-amine (1.213 g, 9 mmol.) and 20 potassium carbonate (1.339 g, 9 mmol.) were taken in DMF (20 mL) in a 80 mL microwave vessel and subjected to microwave irradiation at 250 W, 120 °C for 60 min. Then the reaction mixture was taken in to ethyl acetate (250 mL) and washed with water (250 mL X 3), the organic layer dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by column 25 chromatography using 230-400 mesh silica gel. Elution with 1% isopropanol in dichloromethane yielded 0.350 gm (yield: 24.4%) of colorless solid. -125- WO 2007/075194 PCT/US2006/025427 10 15 'H NMR (CDC13, 200 MHz): 5 7.97 -7.96 (s, IH), 3.68-3.67 (s, IH), 3.62-3.61 (d, .7=6.7 Hz 4H) 2.56-2.54 (s, 3H), 0.87-0.81 (m, 2H) 0.57-0.47 (m, 4H), 0.29-0.22 (m, 4H); (CI-MS): m/z295 (M+l, 100 %). Step (vi): Synthesis of 5-(bis-cyclopropylmethyl-amino)-2,3-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbaldehyde 5-(Bis-cyclopropylmethyl-amino)-2,3-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile ( 0.220 g, 0.7 mmol.) was taken in dichloromethane at -75 °C and DIBAL-H (20% solution in toluene) (0.630 mL, 0.8 mmol.) was added dropwise over a period of 20 min and then stirred at room temperature for 12 h. The reaction mixture was quenched with saturated solution of potassium sodium tartrate at 0 °C and the crude product was extracted with ethyl acetate (250 mL X 3), washed with water (250 mL X 3) and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.220 gm of yellow oily liquid. (CI-MS) m/z: 299 (M+ l, 100 %). Step (vii): Synthesis of {6-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl}-bis-cyclopropylmethyl-amine To a mixture of 5-(bis-cyclopropylmethyl-amino)-2,3-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbaldehyde (0.220 g, 0.73 mmol.) and 3, 5-bis-trifluoromethyl-benzylamine (215 mg, 0.87 mmol) in methanol (8 mL) was added acetic acid (0.042 mL, 0.073 mol) at 0 °C and the resulting reaction mixture was stirred for 15 min at the same temperature. NaCNBH3 (0.069 g, 0.011 mmol.) -126- WO 2007/075194 PCT/US2006/025427 was added and the mixture was stirred at room temperature for 45 min. Methanol was removed under reduced pressure and the crude was extracted with ethyl acetate (250 mL) and washed with water (250 mL X 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.220 g 5 of colorless gummy compound. Step (viii): Synthesis of [5-(Bis-cyclopropylmethyl-amino)-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-6-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide 10 dimethyl-3H-imidazo[4,5-b]pyridin-5-yl}-bis-cyclopropylmethyl-amine (0.220 g, 0.41 mol) and sodium bicarbonate (0.071 mg, 0.83 mol.) in methanol (8 mL) was stirred at 0 °C for 15 min. Cyanogen bromide (0.053 g, 0.05 mol) was added and continued to stir at room temperature for 1.5 h. Methanol was removed under reduced pressure, extracted with ethyl acetate (250 mL), washed with water (250 15 mL X 2) and the organic layer was dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 0.220 g of colorless gummy compound. Step (ix): Synthesis of (6-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-bis-20 cyclopropylmethyl-amine A mixture of {6-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-2,3- HN-N - 127- WO 2007/075194 PCT/US2006/025427 A mixture of [5-(bis-cyclopropylmethyl-amino)-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-6-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide (0.220 g, 0.04 mmol), sodium azide (0.130 g, 2 mmol.) and ammonium chloride (0.106 g, 2 mmol) were taken in DMF (15 mL) and heated at 90 °C for 2 h. The 5 reaction mixture was taken in ethyl acetate (250 mL) and washed with water (250 mL X 4) and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.220 g of colorless gummy liquid. Step (x): Synthesis of (6-{[(3,5-bis-trifluoromethyl-benzyl) - (2-methyl-2H-tetrazol-5-yl)-amino] -methyl} - 2,3 -dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-bis-10 cyclopropylmethyl-amine To a solution of (6-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-bis-cyclopropylmethyl-amine (0.220 g, 3.7 mmol.) in DMF (8 mL) was added 60 % 15 sodium hydride (0.017 g, 0.741 mmol.) at 0 °C and the resulting reaction mixture was stirred at the same temperature for 15 min. and then methyl iodide (0.046 mL, 0.0741 mmol.) was added and continued to stir for 30 min. The crude product was extracted with ethyl acetate (250 mL), washed with water (250 mL X 2) and the organic layer was dried over anhydrous sodium sulfate and concentrated under 20 reduced pressure. Purification by column chromatography using 230-400 mesh silica gel eluting with 1:1 hexane: ethyl acetate yielded 0.010 gm (yield: 4.4%) of pure colorless gummy compound. Purity: 90.28%; *H NMR (CDC13): 8 7.76-7.65 (m, 4H), 4.94 (s,2H), 4.64 (s, 2H), 4.8 (s, 3H), 3.73 (s, 3H), 3.01(d, J=6 Hz, 4H), 2.57 (s, 3H), 0.92-0.81 (m, 2H), 25 0.33-0.29 (m, 4H), 0.00- -0.09 (m, 4H); ES-MS m/z: 608 (M+l\ 100%); IR (neat) \ n-n -128- WO 2007/075194 PCT/US2006/025427 cm"1: 3358, 2925, 1688, 1578, 1484, 1382, 1279, 1174, 1135, 1049, 902, 752, 706, 682. Example 43 5 Synthesis of 3-{[(3, 5-Bis-trifluormethyl-benzyl)- (2-methyI-2H-tetrazol-5-yl)-amino]-methyl} -lH-indole-2-car boxy lie acid ethyl ester Step (i): Synthesis of lH-indole-2-carboxylic acid ethyl ester: OK lH-indole-2-carboxylic acid (1 g, 6.2 mmol) was dissolved in 20 mL of 10 ethanol. To this thionyl chloride (5.86 g, 49.68 mmol) was added drop wise with stirring at 0° C and stirring was continued for 30 h at room temperature. Excess of SOCL was evaporated, water was added to the residue and the suspension was filtered to afford the title compound (1.0 g, yield: 85.5%). lH NMR (CDCI3) □ 8.85 (br s, IH), 7.71-7.67 (m, IH), 7.44-7.28 (m, 2H), 7.23-15 7.12 (m, 2H), 4.41 (q, J= 7.2 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H); m/z (CI-MS): 190 (Mf+1,100%). Step (ii): Synthesis of 3-formyl-lH-indole-2-carboxylic acid ethyl ester: A solution of iV-methyl formanilide (1.18 g, 8.73 mmol) and POCI3 (1.26 g, 20 8.2 mmol) was stirred at room temperature for 0.5 h under nitrogen atmosphere. Dry 1,2-dichloroethane (10 mL) and 1 H-indole-2-carboxylic acid ethyl ester (1 g, 5.29 mmol) were added, and the suspension was stirred at 80°C for 6 h. The reaction mixture was poured into a 50% aqueous solution of NaOAc (50 mL) and filtered the suspension to afford the title compound (0.890 g, yield: 77.4%). 25 'H NMR (CDCla)D 10.76 (s, IH), 9.31 (br s, IH), 8.50-8.47 (m, IH), 7.45-7.32 (m, 3H), 4.53 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H); (CI-MS): m/z 218 (M++l, 100%). -129- WO 2007/075194 PCT/US2006/025427 10 15 Step (iii): Synthesis of 3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]~lH-indole-2-carboxylic acid ethyl ester 3-Formyl-lH-indole-2-carboxylic acid ethyl ester (2 g, 9.21 mmol), obtained in step (ii), 3,5-bis-trifluoromethylbenzylamine (2.23 g, 9.21 mmol) and acetic acid (1.66 g, 18.43 mmol) were put in a 50 mL RB flask. To this was added 10 mL of methanol and stirred at RT for 15 min. Sodium cyanoborohydride (2.61 g, 27.64 mmol) was added portionwise and stirring was continued at RT for another 1 h. Methanol was removed from the reaction mixture under vacuum, water was added to this crude and was extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with saturated NaHC03 solution, brine and dried over sodium sulphate and then evaporated the solvent to get the required compound (3.8 g, yield: 93%). (CI-MS): m/z 445 (M++l, 90%). Step (iv): Synthesis of 3-{[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-methyl}-lH-indole-2-carboxylic acid ethyl ester To a solution of 3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-lH-indole-2-carboxylic acid ethyl ester (0.1 g , 0.22 mmol ), obtained in step (iii), in MeOH (10 mL) under N2 atmosphere was added sodium bicarbonate (0.38 g, 0.45 mmol) followed by the addition of cyanogen bromide (0.028 g, 0.26 mmol). -130- WO 2007/075194 PCT/US2006/025427 The reaction mixture was stirred at RT for 4 h. The solvent was removed under vacuum to get the crude material. The residue was dissolved in water and was extracted with ethyl acetate and dried over sodium sulphate. The solvent was evaporated and concentrated in vacuo which was purified by column 5 chromatography over 100-200 mesh silica gel using 20% ethyl acetate and petroleum ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-methyl}-1 H-indole-2-carboxylic acid ethyl ester (0.08 g, yield: 80%). 'H NMR (CDCls, 400 MHz ): 5 8.89 (br s, IH), 7.76-7.73 (m, 2H), 7.60 (s, 2H), 7.39-7.37 (m, 2H) ,7.25-7.22 (m, IH), 4.88 (s, 2H), 4.43-4.37 (m, 2H), 4.30 (s, 10 2H), 1.43-1.39 (m, 3H); m/z (CI-MS) 202 (Mf-268, 90%), 269(M+-202, 40%), 469 (M+,10%). Step (v): Synthesis of 3-{[(3,5-bis-trifluoromethyl-benzyl)-(lH-tetrazol-5-yl)-amino]-methyl}-lH-indole-2-carboxylic acid ethyl ester carboxylic acid ethyl ester (0.5 g, 1.06mmol), obtained in step (iv), sodium azide (0.381 g, 5.33mmol) and ammonium chloride (0.316 g, 5.33 mmol) were taken in a 25 mL RB flask with dry DMF (5 mL). The reaction was refluxed under nitrogen atmosphere for 1 h. The reaction mixture was cooled to room temperature and the 20 aqueous solution was extracted with ethyl acetate (3x10 mL) and the combined organic layer was washed with brine. The solvent was dried over sodium sulphate and concentrated under vacuum to afford the title compound (0.3 g, yield: 56%). 'H NMR (CDCls, 400 MHz ):5 8.89 (br s, IH), 7.70 (s, IH), 7.61 (s, 2H), 7.51-7.49 (m, IH), 7.42-7.35 (m, 2H), 7.17-7.13 (m, IH), 5.08 (s, 2H), 5.05 (s, 2H), 25 4.32 (q, J = 7.2 Hz, 2H), 4.23 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H); (CI-MS): m/z 526 (M+, 100%). 15 h 3-{[(3,5-Bis-trifluoromethyl-benzyl)-cyano-amino]-methyl}-lH-indole-2- -131 - WO 2007/075194 PCT/US2006/025427 Step (vi): Synthesis of 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-lH-tetrazol-5-yl)-amino]-methyl) -1 H-indole-2-carboxylic acid ethyl ester 5 amino]-methyl} -1 H-indole-2-carboxylic acid ethyl (0.19 g, 0.37 mmol) in water (4 mL) was added sodium hydroxide (0.03 g, 0.742 mmol) and stirred for 15 min at RT followed by the addition of dichloromethane (4 mL). To this reaction mixture was added dimethyl sulphate (0.051 g, 0.241 mmol) and tetra-butylammonium bromide (0.006 g, 0.018 mmol). The reaction was stirred for 15 min. The organic 10 layer was separated from aqueous layer, aqueous layer was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate and pet ether to afford 3-{[(3,5-bis-15 trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5 -yl)-amino] -methyl} -1 H-indole-2-carboxylic acid ethyl ester (0.18 g, 94%). Mp: 130 °C; Purity: 97.37% (Symmetry shield RP 8 [0.01M KH2P04, ACN], 210.nm, Rt=5.81); lH NMR (CDC13, 400 MHz ):5 8.69 (br s, IH), 7.70-7.68 (d, J = 7.8 Hz, IH), 7.54 (s, IH), 7.39 (s, 2H) ,7.32-7.20 (m, 2H), 7.11-7.09 (m, IH), 20 5.35 (s, 2H), 4.67 (s, 2H), 4.31 (q, 7= 7.2 Hz, 2H), 1.46 (t, J= 7.0 Hz, 3H); (CI-MS): m/z 202 (M+-311,100%), 512 (M+, 50%); IR (neat, cm"1): 1708,1583, 1278. To a suspension of 3- {[(3,5-bis-trifluoromethyl-benzyl)-( 1 H-tetrazol-5-yl)- -132- WO 2007/075194 PCT/US2006/025427 Example 44 Synthesis of 3-{[(3,5-bis-trifluoromethyl-benzyI)-(2-methyl-2H-tetrazol-5-yI)-amino]-methyl}-l-methyl-lH-indole-2-carboxylic acid ethyl ester 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-lH-tetrazol-5-yl)-amino]-methyl}-lH-indole-2-carboxylic acid ethyl ester (0.03 g, 0.05 mmol), obtained in step (vi) of Example 43, at 0°C, and stirred for 15 min. Methyl iodide (0.016 g, 0.114 mmol) was added to this at the same temperature and the reaction was stirred for 10 another 1 h. The aqueous layer was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate and petroleum ether to afford 3-{[(3,5-bis-trifhioromethyl-benzyl)-(2-methyl-2H- 15 tetrazol-5-yl)-amino]-methyl}-1 H-indole-2-carboxylic acid ethyl ester (0.35 g, 70%). Mp: 83 °C; Purity: 94.57% (Inertsil ODS [0.01M KH2P04, ACN], 210.nm, Rt =8.06). 'H NMR (CDCls, 400 MHz ):5 7.65 (m, IH), 7.53-7.52 (m, IH), 7.33-7.26 (m, 20 4H),7.11-7.07 (m, IH), 5.29 (s, 2H), 4.64 (s, 2H), 4.78 (q, J= 7.2 Hz, 2H), 4.23 (s, 3H), 1.27-1.23 (m, 3H); (CI-MS): m/z 541 (M++l, 100%); IR (neat, cm"1): 1708, 1583,1278. 5 \ To a suspension of NaH (0.003 g, 0.114 mmol) in DMF (2 mL) was added -133 - WO 2007/075194 PCT/US2006/025427 Example 45 Synthesis of 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-propyl-lH-indole~2-carboxylic acid ethyl ester {[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-lH-indole-2-carboxylic acid ethyl ester (0.03 g, 0.05 mmol), obtained in step (vi) of Example 43, at 0°C, and stirred for 15 min. Bromopropane (0.23 g, 1.9 mmol) was added to this at the same temperature and the reaction was stirred for another 1 10 h. The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 10% ethyl acetate and pet ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5- 15 yl)-amino]-methyl}-1 -propyl-1 H-indole-2-carboxylic acid ethyl ester (0.2 g, yield: 38%). Purity: 98.49% (Symmetry shield RP8 [0.01M KH2P04, ACN], 227.nm, Rt=8.96); ]H NMR (CDCls, 400 MHz ):5 7.67-7.65 (m, IH), 7.53-7.52 (m, IH), 7.34-7.30 (m, 4H,7.11-7.08 (m, IH), 5.29 (s, 2H), 4.64 (s, 2H), 4.37-4.30 (m, 2H), 4.28-4.24 20 (m, 2H), 4.22 (s, 2H), 1.72-1.64 (m, 2H), 1.28-1.23 (m, 3H), 0.87-0.83 (m, 3H); (CI-MS): m/z 541 (M++l, 100%); IR (neat, cm"1): 1708, 1583, 1278. cf3 5 To a suspension of NaH (0.23 g, 1.9 mmol) in DMF (5 mL) was added 3- - 134- WO 2007/075194 PCT/US2006/025427 Example 46 Synthesis of 3-{ [(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-cyclopentanecarbonyl-lH-indole-2-carboxylic acid ethyl ester To a suspension of NaH (0.01 g, 0.45 mmol) in DMF (5 mL) was added 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-lH-indole-2-carboxylic acid ethyl ester (0.2 g, 0.38mmol), obtained in step (vi) of Example 43, at 0°C, and stirred for 15 min. Cyclopropane carbonyl chloride (0.05 10 g, 0.38 mmol) was added to this at the same temperature. The reaction was stirred for 1 h. The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 12% ethyl acetate and 15 petroleum ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-cyclopentanecarbonyl-lH-indole-2-carboxylic acid ethyl ester (0.1 g, yield: 42.3%). Purity: 93.78% (Symmetry shield RP8 [0.01M KH2P04, ACN], 280 nm, Rt=7.77). ]H NMR (CDC13, 400 MHz ):5 7.73-7.71 (m, IH), 7.67-7.65 (m, IH), 7.55 (s, 20 IH), 7.48 (s, 2H), 7.40-7.36 (m, IH), 7.21-7.17 (m, IH) , 5.14 (s, 2H), 4.73 (s, 2H), 4.30 (q, J= 7.2 Hz, 2H), 4.22 (s, 3H), 3.30-3.26 (m, IH), 1.91-1.77 (m, 6H), 1.64-1.62 (m, 2H), 1.28 (m, 3H); IR (neat, cm"1): 1713,1578,1279. 5 -135 - WO 2007/075194 PCT/US2006/025427 Example 47 Synthesis of 3-{ [(3,5-bis-trifhioromethyl-benzyl)-(2~methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-ethyl-lH~indole-2-carboxyIic acid ethyl ester {[(3,5-bis-trifhioromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1 H-indole-2-carboxylic acid ethyl ester (0.1 g, 0.19 mmol), obtained in step (vi) of Example 43, at 0 C, and stirred for 15 min. Ethyl iodide (0.09 g, 1.08 mmol) was added to this at the same temperature and this reaction was stirred for 1 h. The 10 aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate and pet ether to afford 3-{[(3,5-bis-trifhioromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-15 methyl}-1 -ethyl-1 H-indole-2-carboxylic acid ethyl ester (0.08 g, 80%); Purity: 98.49% (Inertsil ODS 3V [0.01M KH2P04, ACN], 210nm, Rt =8.44); !H NMR (CDC13, 400 MHz ):S 7.68-7.65 (m, IH), 7.52 (m, IH), 7.33-7.30 (m, 4H), 7.11-7.07 (m, IH), 5.29 (s, 2H), 4.65 (s, 2H), 4.43 (q, J= 6.9 Hz, 2H), 4.31-4.25 (m, 2H), 4.22 (s, 3H), 1.30-1.22 (m, 6H); (CI-MS): m/z 554 (M+-2, 10%); IR (neat, 20 cm"1): 1708,1583,1278. 5 To a suspension of NaH (0.01 g, 0.38 mmol) in DMF (5 mL) was added 3- - 136- WO 2007/075194 PCT/US2006/025427 Example 48 Synthesis of 3-{ [(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-indole-l,2-carboxylic acid ethyl ester 5 To a suspension of NaH (0.01 g, 0.38 mmol) in DMF (5 mL) was added 3- {[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1 H-indole-2-carboxylic acid ethyl ester (0.1 g, 0.19 mmol), obtained in step (vi) of Example 43, at 0°C, and stirred for 15 min. Ethyl chloroformate (0.02 g, 0.22 mmol) was added to this at the same temperature. The reaction was stirred for 4 h. 10 The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 20% ethyl acetate and petroleum ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-15 tetrazol-5-yl)-amino]-methyl}-indole-l,2-carboxylic acid ethyl ester (0.05 g, 45%). Purity: 90.58% (Inertsil ODS [0.01M KH2P04, ACN], 210nm, Rt =13.19); *H NMR (CDC13, 400 MHz ):5 7.96-7.94 (m, IH), 7.52-7.50 (m, 4H), 7.36-7.26 (m, IH) ,7.17-7.13(m, IH), 4.99 (s, 2H), 4.72 (s, 2H), 4.46 (q,J= 7.2 Hz, 2H), 4.33 (q, J= 7.2 Hz, 2H), 4.23 (s, 3H), 1.31-1.29 (m, 3H); m/z (CI-MS) 598 (M++l, 20 100%). -137- WO 2007/075194 PCT/US2006/025427 Example 49 Synthesis of 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H~tetrazol-5-yl)-amino]-methyl}-l-cyclopropanecarbonyl-lH-indole-2-carboxylic acid ethyl ester To a suspension of NaH (0.004 g, 0.18 mmol) in DMF (5 mL) was added 3 - {[ (3,5 -bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol- 5 -yl)-amino] -methyl} -lH-indole-2-carboxylic acid ethyl ester (0.05 g, 0.095 mmol), obtained in step (vi) of Example 43, at 0°C, and stirred for 15 min. Cyclopropanecarbonyl chloride 10 (0.012 g, 0.11 mmol) was added to this at the same temperature and the reaction was stirred for 6 h. The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate 15 and petroleum ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-cyclopropanecarbonyl-lH-indole-2-carboxylic acid ethyl ester (0.04 g, yield: 71%). Purity: 98.45% (Inertsil ODS [0.01M KH2P04, ACN], 210nm, Rt =9.448.85); lH NMR (CDCls, 400 MHz ):S 7.89 (m, IH), 7.67 (m, IH), 7.53 (s, 2H), 7.38-7.31 20 (m, 2H) ,7.2 (m, IH), 5.35 (s, 2H), 4.75 (s, 2H), 4.32-4.27 (m, 2H), 4.20 (s, 3H), 2.04-1.96 (m, IH), 1.29-1.24 (m, 4H), 1.14-1.12 (m, 3H); m/z (CI-MS) 595 (M++l, 100%); IR (neat, cm"1): 1711,1581, 1279. 5 - 138- WO 2007/075194 PCT/US2006/025427 Example 50 Synthesis of 3-{[(3,5-bis-trifluoromethyI-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyI}-3H-indoIe-2-carboxyIic acid diethylamide Step(i): Synthesis of 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol~5-5 yl)-amino]-methyl} -1 H-indole-2-carboxylic acid To the solution of 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-lH-indole~2-carboxylic acid ethyl ester (0.2 g, 0.38 mmol) in 5 mL ethanol, was added NaOH (0.076 g, 1.9 mmol). The reaction was 10 refluxed under nitrogen atm for 1 h. The reaction mixture was acidified and the suspension was filtered to afford the title compound (0.1 g, 53%) 'H NMR (CDC13, 400 MHz ):S 11.33 (br s, IH), 7.73 (s, IH), 7.59-7.57 (m, 3H), 7.35-7.33 (m, IH) ,7.17-7.13 (m, IH), 6.97-6.93 (m, IH), 5.30 (s, 2H), 4.71 (s, 2H), 4.19 (s, 3H); m/z (CI-MS) 499 (M++l, 100%); IR (neat, cm"1): 1578, 1278, Step (ii): Synthesis of 3- {[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1 H-indole-2-carboxylic acid diethylamide n oh h 15 1133 - 139- WO 2007/075194 PCT/US2006/025427 To a solution of 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-lH-indole-2-carboxylic acid (0.05 g , 0.10 mmol), obtained in step (i), in DCM (5 mL) under N2 atmosphere was added EDC (0.36 g, 0.12 mmol ) at 0°C followed by the addition of TBTU ( 0.035 g, 0.12 mmol). 5 The reaction mixture was stirred for 10 min, DIPEA (0.04 g, 0.3 mmol) was added followed by diethylamine (0.008 g, 0.10 mmol) and stirring was continued at RT for 4 h. Water was added to the reaction mixture and extracted with DCM (3x10 mL). The combined organic layers were washed with brine, dried over sodium sulphate. The solvent was evaporated and concentrated in vacuo which was 10 purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate and petroleum ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino] -methyl} -1 H-indole-2-carboxylic acid diethylamide (0.035 g, yield: 64%). Mp 98 °C; Purity: 97.76% (Inertsil ODS 3 V [0.01M KH2PO4, ACN], 215 nm, Rt 15 =7.81). !H NMR (CDCI3, 400 MHz): 8 8.14 (bs, IH), 7.52 (s, 2H), 7.45-7.43 (m, 2H), 7.23-7.17 (m, IH), 7.15-6.98 (m, IH), 4.66 (s, 2H), 4.22 (s, 2H), 3.46-3.41 (m, 4H), 1.12 (t, J= 7.1Hz, 6H); m/z (CI-MS) 553 (M+,100% ). 20 -140- WO 2007/075194 PCT/US2006/025427 Example 51 Synthesis of 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-aniino]-methyl}-l-methyl~lH-indole-2-carboxylic acid diethylamide {[(3,5 -bis-trifhioromethyl-benzyl)-(2-methyl-2H-tetrazol-5 -yl)-amino] -methyl} -1 H-indole-2-carboxylic acid diethylamide (0.1 g, 0.18 mmol), obtained in Example 50, at 0°C, and stirred for 15 min. Methyl iodide (0.031 g, 0.216 mmol) was added to this at the same temperature. The reaction was stirred for 6 h and the aqueous 10 layer was extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate and petroleum ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-15 1-methyl-lH-indole-2-carboxylic acid diethylamide (0.07 g, 60%). Purity: 99.11% (Symmetry shield RP 8 [0.01M KH2P04, ACN], 220 nm, Rt=6.71); 'H NMR (CDC13, 400 MHz ): 5 7.56 (s, 2H), 7.44-7.39 (m, 2H), 7.20-7.18 (m, 2H), 7.00-6.97 (m, IH), 5.38-5.34 (m, IH), 4.74-4.70 (m, IH), 4.56-4.52 (m, IH), 4.36-4.32 (m, IH), 4.22 (s, 2H), 3.65 (s, 3H), 3.62-3.56 (m, 2H), 3.34-3.29 (m, 20 IH), 3.15-3.09 (m, IH), 1.21-1.17 (m, 3H), 1.03 (t, 7.0 Hz, 3H); m/z (CI-MS) 567 (M+, 20%); IR (neat, cm"1): 2933,1278,1132. 5 To a suspension of NaH (0.01 g, 0.36 mmol) in DMF (5ml) was added 3- -141 - WO 2007/075194 PCT/US2006/025427 Example 52 Synthesis of 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-X-methyl-lII-indole-2-carboxylic acid bis-cyclopropylmethyl- 3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-methyl-lH-indole-2-carboxylic acid (0.08 g, 0.156 mmol) and bis cyclopropylmethylamine (0.02 g, 0.156 mmol) were used to synthesize the title compound instead of using 3~{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-10 tetrazol-5-yl)-amino]-methyl}~lH-indole-2-carboxylic acid and diethylamine in step (ii) of example 50 (0.05 g, yield: 62%). Purity: 98.43% (Symmetry shield RP 8 [0.01M KH2P04, ACN], 220 nm, Rt =7.315); *H NMR (CDC13, 400 MHz ):8 7.53-7.51 (m, IH), 7.42-7.40 (m, 2H), 7.19-7.17 15 (m, 2H), 7.00-6.96 (m, IH), 5.39-5.36 (m, IH), 4.73-4.69 (m, 1H); 4.54-4.50 (m, IH), 4.38-4.34 (m, IH), 4.22 (s, 3H), 3.67 (s, 3H), 3.65-3.55 (m, IH), 3.54-3.52 (m, IH), 3.17-3.15 (m, 2H), 0.88-0.83 (m, 2H), 0.49-0.30 (m, 2H), 0.53-0.50 (m, 4H); (CI-MS): m/z 620 (M++l, 90%). amide CF. 5 -142- WO 2007/075194 PCT/US2006/025427 Example 53 Synthesis of 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)~ amino]~methyl}-l-propyl-lH-indoIe-2-carboxylic acid bis-cyclopropylmethyl-amide 3-{[(3,5-Bis-trifhioromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1 -propyl-1 H-indole-2-carboxylic acid (0.16g, 0.29 mmol) and bis cyclopropylmethylamine (0.37 g, 0.29 mmol) were used to synthesize the title compound instead of using 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-10 tetrazol-5-yl)-amino]-methyl}-lH-indole-2-carboxylic acid and diethylamine in step (ii) of example 50 (0.08 g, 42%) Purity: 98.49% (Symmetry shield RP18 [0.01M KH2P04, ACN], 220 nm, Rt =8.85). 'H NMR (CDC13, 400 MHz ): 5 7.51-7.48 (m, 3H), 7.24-7.21 (m, 2H), 7.19-7.17 15 (m, IH), 7.04-7.00 (m, IH), 4.69-4.58 (q, J=16.1Hz, 2H), 4.20 (s, 3H), 4.15-4.08 (m, IH), 3.92-3.85 (m, IH), 3.70-3.64 (m, IH), 3.55-3.45 (m, IH), 3.13-3.12 (m, 4H), 1.82-1.660.88-0.83 (m, 2H), 1.29-1.22 (m, 2H), 0.86 (t, J = 7.3Hz, 3H), 0.51-0.47 (m, 4H), 0.01 (m, 4H); (CI-MS) m/z: 648 (M++l, 60%). 5 -143 - WO 2007/075194 PCT/US2006/025427 Example 54 Synthesis of (3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-carbamic acid ethyl ester Step (i): Synthesis of 8-methyl-2-propylsulfanyl-quinoline-3-carbaldehyde To 2-chloro-8-methylquinoline-3-carboxaldehyde (2.055 g, 10 mmol) in ethanol (25 mL) was added anhydrous potassium carbonate (2.76 g, 20 mmol) followed by the addition of n-propanethiol (1.12 mL, 13 mmol). The reaction mixture was heated at reflux under a nitrogen atmosphere with stirring for 1.75 h. 10 Then water (30 mL) was added and the mixture was stirred approximately 15 h at room temperature. The mixture was extracted 3 times diethyl ether, and the combined ether phases were sequentially washed one time with 10% sodium hydroxide and brine. The organic phase was dried over potassium carbonate, filtered and concentrated by rotary evaporation. The material was purified by 15 chromatography. (Biotage Horizon HPFC chromatography system, SiC>2, 80:20 hexanes: ethyl acetate) gave a yellow solid (1.979 g, 80%). No further purification was completed and the material was used as is for the next step. HPLC: Inertsil ODS-3V CI8, 30:70 [KH2P04 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 27 min, 77.5% purity; lR NMR (300 MHz, CDC13, TMS): □ 10.33 (s, IH), 8.42 20 (s, IH), 7.62-7.10 (m, 2H), 7.38 (t,J= 7.5 Hz, IH), 3.37 (t, J= 7.2 Hz, 2H), 2.75 (s, 3H), 1.87 (sextet, J= 7.2 Hz, 2H), 1.11 (t,J= 7.5 Hz, 3H). Step (ii): Synthesis of (3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3 -ylmethyl)-amine O 5 -144- WO 2007/075194 PCT/US2006/025427 3,5-Bis-(trifluoromethyl) benzylamine (1.014 g, 4.2 mmol) and 8-methyl-2-propylsulfanyl-quinoline-3-carbaldehyde (1.006 g, 4.0 mmol) was dissolved in anhydrous methanol (12 mL). Acetic acid (0.5 mL, 8.8 mmol) was added and the mixture was stirred for approximately 1 h at RT under a nitrogen atmosphere. 5 Sodium cyanoborohydride (0.800 g, 12.6 mmol) was added and the mixture was stirred for an additional 24 h at RT. The reaction was quenched with saturated sodium bicarbonate and then stirred for 15-20 min at RT. The mixture was extracted 3 times with diethyl ether. The combined ether layers were then washed 2 times with brine, then dried over anhydrous potassium carbonate, filtered and 10 concentrated in vacuo. The material was purified by chromatography. (Biotage Horizon HPFC chromatography system, SiC>2, 90:10 hexanes: ethyl acetate) gave an oil (1.13 g, 58.6%). HPLC: Inertsil ODS-3V CI8, 30:70 [KH2P04 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 50.7 min, 99.5% purity; *H NMR (300 MHz, CDC13, TMS): □ 7. 69-7.88 (m, 4 15 H), 7.48-7.57 (m, 2 H), 7.29-7.34 (m, IH), 3.97 (s, 2H), 3.96 (s, 2H), 3.37 (t, J = 7.2H, 2H), 2.75 (s, 3H), 1.85 (sextet, J = 7.5 Hz, 3 H; DiO exchange, overlap of NH), 1.09 (t, J= 7.5Hz, 3H); Mass: LC-MSD (ES+): m/z 473 (M+H, 100). Step (iii): Synthesis of (3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-carbamic acid ethyl ester To ethyl chloroformate (0.4 ml, 4.2 mmol) and potassium carbonate (0.875 g, 6.3 mmol) were added to (3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-amine (1.058 g, 2.1 mmol) which was dissolved in anhydrous THF (10 mL). The resulting mixture was stirred at room 25 temperature for overnight. The mixture was diluted with methylene chloride, and was washed one time with water. The organic phase was dried over potassium 20 -145- WO 2007/075194 PCT/US2006/025427 carbonate and concentrated by rotary evaporation. The resulting sample was dried under vacuum gave a light yellow solid (1.18 g, 97%). M.P.: 42 °C; HPLC: Inertsil ODS-3V CI8, 30:70 [KH2P04 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 61.9 min, 99.6% purity; ]H NMR (300 MHz, CDC13, TMS): 5 □ 7.65-7.32 (brm, 3H), 7.51 (t, J=7.2 Hz, 2H), 7.32 (t, J =7.5 Hz, IH), 4.67-4.58 (m, 4H), 4.3 (q, J =12 Hz, 2H), 3.34 (t, J =1.5 Hz, 2H), 2.74 (s, 3H), 1.87-1.79 (m, 2H), 1.30 (t, J= 7.2 Hz, 3H), 1.07 (t, J= 1.5 Hz, 3H); Mass: LC-MSD (ES+): m/z 545 (M+H, 100). 10 Example 55 Synthesis of (3,5-Bis-trifluoromethyl-benzyl)-[8-methyl~2-(propane-l-sulfonyl)-quinolin-3-ylmethyl]-carbamic acid ethyl ester 15 ylmethyl)-carbamic acid ethyl ester (Example 54) (504 mg, 0.9 mmol) was dissolved in methanol (15 mL) and water (10 mL) then OXONE (5.54 g, 9 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride, and was washed one time with water and one time with brine. The organic phase was dried over sodium sulfate and 20 concentrated by rotary evaporation. The resulting sample was dried under vacuum. (Biotage Horizon HPFC chromatography system, Si02, 80:20 hexanes: ethyl acetate) gave a white solid (274 mg, 51%). M.P.: 98°C; HPLC: Inertsil ODS-3V CI8, 30:70 [KH2P04 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 40.9 min, 95.3% purity; ]H NMR (300 MHz, CDC13, TMS): 25 □ 8.2-8.0 (brm, IH), 7.73-7.54 (m, 6H), 5.20-5.24 (m, 2H, rotomers), 4.68 (s, 2H), (3,5-Bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3- -146- WO 2007/075194 PCT/US2006/025427 4.31 (brs, 2H), 3.81-3.76 (m, 2H), 2.74 (s, 3H), 2.11-1.99 (m, 2H ), 1.306-1.23 (m, 3H), 1.20 (t, J= 7.5 Hz, 3H); Mass: LC-MSD (ES+): m/z 599 (M+Na, 100). Example 56 5 Synthesis of (3, 5-bis-trifluoromethyl-benzyl)-[8-methyl-2-(propane-l-sulfinyl)-quinolin-3-ylmethyl]-carbamic acid ethyl ester ylmethyl)-carbamic acid ethyl ester (Example 54) (116 mg, 0.18 mmol) was 10 dissolved in methanol (2 mL) and water (2 mL) followed by the addition of magnesium bis(mono peroxy phthalate hexahydrate) (MMPP) (267.1 mg, 0.54 mmol). The resulting mixture was stirred at room temperature overnight. The sample was diluted with methylene chloride and washed one time with water and one time with brine. The organic phase was dried, filtered and concentrated by 15 rotary evaporation. The resulting sample was dried overnight under vacuum. (Biotage Horizon HPFC chromatography system, SiC>2, 70:80 hexanes: ethyl acetate) gave a whit solid (80 mg, 72%). M.P.: 86°C; HPLC: Inertsil ODS-3V C18, 20:80 [KH2P04 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 20.7 min, 99.8% purity; 'H NMR (300 MHz, CDC13, TMS): 20 □ 8.18-7.99 (m, IH), 7.7 (brs, 3H), 7.65-7.60 (m, 2H), 7.54-7.49 (m, IH), 5.24-5.10 (brm, 2H, rotomers), 4.72 (s, 2H), 4.28 (q, J= 6.9 Hz, 2H), 3.30 (t, /= 7.2 Hz, 2H), 2.77 (s, 3H), 1.95-1.72 (m, 2H), 1.27 (t, J = 6.6 Hz, 3H), 1.11 (t, J= 7.5 Hz, 3H); Mass: LC-MSD (ES+): m/z 561 (M+H, 100). r (3,5-Bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3- -147- WO 2007/075194 PCT/US2006/025427 Example 57 Synthesis of (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-fluoro-pyridin-2-yl)-bis-cyclopropylmethyl-amine Step (i): Synthesis of 2-(bis-cyclopropylmethyl-amino)-6-fluoro-pyridine-3- Diisopropylamine (1.4 mL, 9.6 mmol) was stirred in ether (10 mL). The solution is cooled -78°C with dry ice and acetone. n-Butyllithium (4 mL, 9.6 mmol) was added and the resulting solution was allowed to stir at -78°C for about 10 15 minutes. 2,6-Difluoropyridine (0.8 mL, 8.7 mmol) was added and the solution was allowed to stir at -78°C for about 2 hours. A/',A/-bis-cyclopropylmethyl formamide (1.71g, 10.9 mmol) was added and the solution was allowed to stir at -78°C for about 1 hour. The solution was quenched with 10% potassium phosphate. The solution was extracted with ether (2 x 20 mL). The combined organic layers 15 were washed with water and brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give an orange oily product. Purification by silica gel chromatography and eluting with 20% ethyl acetate in hexanes afforded the title compound as an orange oil (224 mg, yield: 10.3%). 1HNMR (CDC13, 300 MHz): □ 9.96 (s, IH), 8.08 (t, J= 8.4 Hz, IH), 6.34 (dd, J= 20 5.1, 3.3 Hz, IH), 3.48 (d, J= 6.6 Hz, 4H), 1.16-1.07 (m, 2H), 0.574-0.513 (m, 4H), 0.245-0.193 (m, 4H); Mass: LC-MSD (ES+): m/z 248 (M+l, 100%). Step (ii): Synthesis of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-6-fluoro-pyridin-2-yl}-bis-cyclopropylmethyl-amine 5 carbaldehyde O -148- WO 2007/075194 PCT/US2006/025427 To 2-(bBis-cyclopropyhuethyl-amino)-6-fluoro-pyridine-3-carbaldehyde (200 mg, 0.8 mmol) stirred in THF (10 mL) was added 3,5-bis-(trifluoromethyl) benzylamine (198.1 mg, 0.8 mmol) and acetic acid (0.05 mL, 0.8 mmol). After stirring at room temperature for about 1 hour, sodium triacetoxyborohydride (237.5 5 mg, 1.12 mmol) was added and the solution was allowed to stir at room temperature overnight. The solution was extracted with ether (2x10 mL). The combined organic layers were washed with water and brine, dried over potassium carbonate, filtered, and then concentrated under vacuum to give the title compound an orange oily product (361 mg, yield: 95%). Used as is with no purification. 10 *H NMR (CDC13, 300 MHz): □ 7.82-7.74 (m, 3H), 7.67 (t, J = 8.4 Hz, IH), 6.52 (dd, J - 4.5, 3.3 Hz, IH), 4.90 (s, IH), 3.85 (d, J= 13.5 Hz, 4H), 3.10 (d, J= 6.9 Hz, 3H), 0.948-0.851 (m, 2H), 0.419-0.358 (m, 4H), 0.069-0.011 (m, 4H); Mass: LC-MSD (ES+): m/z 476 (M+l, 99.7%). Step (iii): Synthesis of [2-(bis-cyclopropylmethy-amino)-6-fluoro-pyridin-3-15 ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide To {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-6-fTuoro-pyridin-2-yl}-bis-cyclopropylmethyl-amine (302 mg, 0.64 mmol) stirred in methanol (10 mL) was added sodium bicarbonate (139.6 mg, 1.24 mmol). After stirring at room 20 temperature for about 15 minutes, cyanogen bromide (237.5 mg, 1.12 mmol) was added and the solution was allowed to stir at room temperature for about 4 hours. The solution was extracted with ethyl acetate (2x15 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and then concentrated under vacuum to give the title compound as an orange oily 25 product (284 mg, yield: 87%) and was used as is without purification. - 149- WO 2007/075194 PCT/US2006/025427 !H NMR (CDCI3, 300 MHz): □ 7.89 (s, IH), 7.81-7.73 (m, 3H), 6.61 (dd, J= 4.5, 3.6 Hz, IH), 4.27 (broad d, /= 23.4 Hz, 4H), 3.28 (d, /= 6.9 Hz, IH), 3.04 (d, J= 6.6 Hz, 2H); Mass: LC-MSD (ES+): m/z 501 (M + 1, 81%). Step (iv): Synthesis of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(lH-tetrazol-5-yl)-5 amino]-methyl}-6-fluoro-pyridine-2-yl)-bis-cyclopropylmethyl-amine N"N^N-^vj-^YCF3 Q7 To [2-(bis-cyclopropylmethy-amino)-6-fluoro-pyridin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide (244 mg, 0.5 mmol) stirred in isopropanol (5 mL) and water (10 mL) was added sodium azide (38.4 mg, 0.55 mmol) and zinc 10 bromide (115.6 mg, 0.5 mmol). After stirring at reflux overnight, the solution was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give the title compound as an orange oily product (248 mg, yield: 91%) and was used as is without purification. 15 Mass: LC-MSD (ES+): m/z 544 (M + 1, 82%). Step (v): Synthesis of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H- tetrazol-5-yl)-amino]-methyl}-6-fluoro-puridine-2-yl)-bis-cyclopropylmethyl- amine \ n-n Q7 20 To sodium hydroxide (33.6 mg, 0.8 mmol) stirred in water (2 mL) was added (3-{[(3,5-bis-trifluoromethyl-benzyl)-(lH-tetrazol-5-yl)-amino]-methyl}-6-fluoro-pyridine-2-yl)-bis-cyclopropylmethyl-amine (222 mg, 0.4 mmol) in -150- WO 2007/075194 PCT/US2006/025427 dichloromethane (5 mL). After stirring for 15 minutes, dimethyl sulfate (0.05 mL, 0.44 mmol) and tetrabutylammonium bromide (7.5 mg, 0.0176 mmol) was added and the solution was left to stir at room temperature for 1 hour. The solution was extracted with dichloromethane (2x15 mL). The combined organic layers were 5 washed with water and brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give an orange oily product. Purification by silica gel chromatography and eluting with 30% ethyl acetate in hexanes afforded the title compound as an orange oil (124.6 mg, yield: 56%). *H NMR (CDC13, 300 MHz): □ 7.75-7.67 (m, 3H), 7.56 (t,J= 8.1 Hz, 3H), 6.45 10 (dd, J = 4.5, 3.6 Hz, IH), 4.67 (broad d, J= 39.9 Hz, 4H), 4.20 (s, 3H), 3.03 (d, J= 6.6 Hz, 4H), 0.900-0.809 (m, 2H), 0.399-0.338 (m, 4H), 0.063-0.025 (m, 4H); Mass: LC-MSD (ES+): m/558 (M+l, 90%). Example 58 15 Synthesis of 2-[4-(3-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yI)-amino]-methyl}-8-methyl-quinolin-2-yl)-piperazin-l-yl]-l-pyrrolidin-l-yl-ethanone Step (i): Synthesis of 8-methyl-2-[4-(2-oxo-2-pyrrolidin-1 -yl-ethyl)-piperazin-1 -yl] -quinoline-3 -carbaldehyde To 2-chloro-8-methylquionline-3-carboxaldehyde (0.2034 g, 1 mmol) dissolved in N, N-dimethylformamide (7 mL) was added l-[2-(piperazine-l-yl)acetyl] pyrrolidine (0.2271 g, 1.15 mmol) followed by potassium carbonate (0.1395 g, 1 mmol). After stirring at reflux overnight under nitrogen, the solution 25 was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over potassium carbonate, filtered and then concentrated under vacuum. Purification by silica gel chromatography and eluting O 20 -151 - WO 2007/075194 PCT/US2006/025427 with 90:9:1 (methylene chloride: methanol: NH4OH) afforded the title compound as a yellow gummy liquid. (166 mg, yield: 46%). HPLC: YMC Pro C-8, 40:30:30 [KH2P04 (0.01M, pH 3.2): CH3CN: methanol], 264 nm, Rt 2.5 min, 97.6% purity. 5 'l-I NMR (300 MHz, CDC13, TMS): □ 10.15 (s, IH), 8.50 (s, IH), 7.68-7.58 (m, 2H), 7.34-7.29 (m, IH), 3.97-3.46 (brm, 14H), 2.06-1.97 (m, 2H), 1.94-1.85 (m, 2H). Mass: LC-MSD (ES+): m/z 367 (M+l, 100). Step (ii): Synthesis of 2-(4-{3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-8-10 methyl-quinolin-2-yl} -piperazin-1 -yl)-1 -pyrrolidin-1 -yl-ethanone To of 8-methyl-2-[4-(2-oxo-2-pyrrolidin-1 -yl-ethyl)-piperazin-1 -yl]-quinoline-3-carbaldehyde (152 mg, 0.4 mmol) stirred in THF (7 mL) was added 3,5-bis-(trifluoromethyl) benzylamine (0.0995 mg, 0.4 mmol) and acetic acid (0.02 15 mL, 0.4 mmol). After stirring at room temperature for about 1 hour, sodium triacetoxyborohydride (0.1201 mg, 0.56 mmol) was added and the solution was allowed to stir at room temperature overnight under nitrogen. The solution was extracted with ether (2x10 mL). The combined organic layers were washed with water and brine, dried over potassium carbonate, filtered, and then concentrated 20 under vacuum. Purification by silica gel chromatography and eluting with 90:9:1 (methylene chloride: methanol: NH4OH) afforded the title compound as a brown liquid (144 mg, yield: 60%) and was used without further purification. HPLC: YMC Pro C-8, 40:30:30 [KH2P04 (0.01M, pH 3.2): CH3CN: methanol], 254 nm, Rt 5.0 min, 89.8% purity; Mass: LC-MSD (ES+): m/z 594 (M+l, 100). 25 Step (iii): Synthesis of 2-[4-(3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl} -8-methyl-quinolin-2-yl)-piperazin-1 -yl]-1 -pyrrolidin-1 -yl-ethanone -152- WO 2007/075194 PCT/US2006/025427 To 8-methyl-2-[4-(2-oxo-2-pyrrolidin-1 -yl-ethyl)-piperazin-1 -yl] -quinoline-3-carbaldehyde (121 mg, 0.2 mmol) stirred in N, A'-dimethylfomiamide (5 mL) was added 5-bromo-2-chloropyrimidine (0.0587 mg, 0.3 mmol) and 5 diisopropylethylamine (0.03 mL, 0.2 mmol). After stirring at reflux overnight under nitrogen, the solution was extracted with dichloromethane. The combined organic layers were washed with water two times and brine one time, dried over potassium carbonate, filtered and then concentrated under vacuum. Purification by silica gel chromatography and eluting with 95:5 (methylene chloride: methanol) 10 afforded the title compound as a brown semi-solid. (140 mg, yield: 92%). HPLC: YMC Pro C-8, 30:70 [KH2P04 (0.01M, pH 3.2): CH3CN], 254 nm, Rt 4.1 min, 95.3% purity; lH NMR (300 MHz, CDC13, TMS): □ 8.41 (s, 2H), 7.70-7.69 (brm, 2H), 7.62 (s, 2H), 7.42 (t, J = 8.4 Hz, 2H), 7.26-7.20 (m, IH), 5.00 (s, 2H), 4.78 (s, 2H), 3.50 (q, Jx = 9.3 Hz, 4H), 3.33 (brt, J= 4.5 Hz, 4H), 3.20 (s, 2H), 2.73 15 (brs, 4H), 2.69 (s, 3H), 2.01-1.92 (m, 2H), 1.90-1.81 (m, 2H); Mass: LC-MSD (ES+): m/z 752 (M+l, 100). -153 - WO 2007/075194 PCT/US2006/025427 Example 59 Synthesis of [3-({((3,5-bis-trifluoromethyl-benzyl)- [(4-morpholin-4-yl-phenyl)-amino]-methyl)-8-methyl-quinolin-2-yl]-bis-cyclopropylmethyl-amine (0.01 M, pH 3.2):CH3CN], flow rate 1.2 mL/min, Rt 23.5 min) was obtained in a similar manner described in Example 25 as a pale yellow thick liquid (0.1 lg, 36%). ]H NMR (CDCI3, 300 MHz): 5 7.88 (s, IH), 7.77-7.72 (m, 3H), 7.46-7.39 (m, 2H), 7.24-7.19 (m, IH), 6.82-6.77 (m, 2H), 6.69-6.63 (m, 2H), 4.72-4.69 (m, 4H), 10 3.85-3.80 (m, 4H), 3.21 (d, J= 6.6 Hz, 4H), 3.08-2.98 (m, 4H), 2.72 (s, 3H), 1.09-1.0 (m, 2H), 0.43-0.35 (m, 4H), 0.13-0.06 (m, 4H); MS (ESI) m/z 683 (M+l)+. Example 60 Synthesis of 4-{ [ [2-(bis-cyclopropylmethyl-amino)8-methyl-quinoline-3-yImethyl]-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-2,6-di-fer£-butyl-phenoI 15 Step (i): Synthesis of [2-(bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-yl]-methanol To a solution of of 2-(bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-carbaldehyde (0.276 g, 0.938 mmol) obtained in step (ii) of Example 57 in 5mL 20 THF was added sodiumborohydride (0.042 g, 1.12 mmol ). The reaction mixture was stirred at RT for 5 min, then water was added to reaction mixture and this was o-^ 5 The title compound of 97.0 % purity (HPLC: YMC Pro C8, 20:80 [KH2PO4 OH -154- WO 2007/075194 PCT/US2006/025427 extracted with ethyl acetate (3x10 mL). The combined organic layer was washed with water and brine respectively and the solution was dried over sodium sulfate. The volatiles were removed under vacuum to get the pure compound (0.25 g, yield: 93%). 5 'H NMR (CDC13, 400 MHz): 8 7.88 (s, IH), 7.58 (m, IH), 7.56 (m, IH), 7.48-7.46 (m, IH), 5.18 (br s, IH), 4.89 (s, 2H), 3.22-3.20 (m, 4H), 2.73 (s, 3H), 1.08-1.01 (m, 2H), 0.14-0.10 (m ,4H), 0.14-0.11 (m, 4H); m/z (ES-MS): 297 (M++l, 100%); IR (neat, cm"1):3382, 1618, 1050. Step (ii): Synthesis of (3-azidomethyl-8-methyl-quinolin-2-yl-bis-10 cyclopropylmethyl-amine Triethylamine (1.75 mL, 12.62 mmol ) was added to a solution of of [2-(bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-yl]-methanol (1.2 g, 4.05 mmol), obtained in step (i) in 15 mL DCM. This solution was cooled to 0°C, and 15 mesyl chloride (0.47 mL, 12.62 mmol) was added over a period of 15 min. The reaction mixture was stirred at RT for overnight and the solvent was evaporated to get the required methanesulfonic acid 2-(bis- cyclopropylmethyl-amino)-8-methyl-quinolin-3-yl methyl ester (1.5 g, yield: 90%). 20 a 25 mL RB flask. To this solution, sodium azide (0.786 g, 12.09 mmol) was added and stirring was continued for 1 h at 40°C. The reaction mixture was cooled to RT and then water was added to this which was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water and brine and the volatile was removed under vacuum to get the crude which was purified by column 25 chromatography over silica gel (100-200 mesh) using 2% ethyl acetate and + The methanesulfonate (1.5 g, 4.03 mmol) was dissolved in 4 mL of DMF in -155 - WO 2007/075194 PCT/US2006/025427 petroleum ether to give (3-azidomethyl-8-methyl-quinolin-2-yl-bis-cyclopropylmethyl-amine (0.4 g, yield: 30%). ]H NMR (CDC13, 400 MHz): 8 8.0 (s, IH), 7.60-7.56 (m, IH), 7.49-7.45 (m, IH), 7.28-7.24 (m, IH), 4.6 l(s, 2H), 3.27-3.25 (m, 4H), 2.71 (s, 3H), 1.12-1.04 (m, 2H), 5 0.45-0.40 (m ,4H), 0.14-0.11 (m, 4H); m/z (ES-MS): 322 (M++l, 10%), 225 (M+-42,100%) Step (iii): Synthesis of (3-aminomethyl-8-methyl-quinolin-2-yl-bis-cyclopropylmethyl-amine g, 1.09 mmol) was dissolved in 3 mL of THF in a 25 mL RB. Triphenyl phosphine followed by one drop of water was added to this and then stirring was continued for 1 h at 40°C. The reaction mixture was cooled to RT and then poured in IN HC1 (10 mL) solution which was diluted with ethyl acetate and basified with potassium 15 carbonate where pH was adjusted to 9. This was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water and brine and the volatile was removed under vacuum to give the required amine (0.4 g, yield: 60%) 'H NMR (CDCI3, 400 MHz): 8 7.95 (s, IH), 7.56-7.54 (m, IH), 7.45-7.44 (m, IH), 7.29-7.26 (m, IH), 4.15-4.11 (m, 2H), 3.24-3.17 (m, 2H), 2.72 (s, 3H), 1.07-1.03 20 (m, 2H), 0.46-0.41 (m ,4H), 0.14-0.10 (m, 4H); m/z (ES-MS): 296 (M++l, 80%). Step (iv): Syntheis of 4-({[2-(bis-cyclopropylmethyl-amino) -8-methyl-quinolin-3-ylmethyl]-amino}-methyl)-2,6-di-/er/-butyl-phenol 10 (3-Azidomethyl-8-methyl-quinolin-2-yl-bis-cyclopropylmethyl-amine (0.35 -156- WO 2007/075194 PCT/US2006/025427 (3-Aminomethyl-8~methyl-quinolin-2-yl-bis-cyclopropyhnethyl-amine (0.05 g, 0.17 mmol) obtained in step (iii), 3,5-di-fcrt-butyl-4-hydroxy-benzaldehyde (0.096 g, 0.041 mmol) and acetic acid (0.02 g, 0.338 mmol) were put in a 25 mL RB flask. To this, 2 mL of methanol was added and stirred at RT for 15 5 min. Sodium cyanoborohydride (0.021 g, 0.39 mmol) was added portion wise and stirring was continued at RT for another 1 h. Methanol was removed from the reaction mixture under vacuum, water was added to this crude and was extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with saturated NaHCC>3 solution, brine and dried over sodium sulphate. The solvent was 10 evaporated and the crude residue was purified by column chromatography over silica gel (100-200 mesh) eluting with 4% ethyl acetate in petroleum ether to give the title amine (0.05 g, yield: 69%); 'H NMR (CDCI3, 400 MHz): 5 8.09 (s, IH), 7.72 (m, 2H), 7.68-7.66 (m, IH), 7.58-7.57 (m, IH), 7.45-7.43 (m, IH), 4.35 (s, 2H), 4.03 (s, 2H), 3.08-3.06 (m, 15 4H), 2.73 (s, 3H), 1.44 (s, 18H), 0.75 (m, 2H), 0.39-0.35 (m ,4H), 0.07-0.00 (m, 4H); m/z (ES-MS): 514 (M++l, 100%). Step (v): Synthesis of [2-(bis-cyclopropylmethyl-amino) -8-methyl-quinolin-3-ylmethyl]-(3,5-di-fcr£-butyl-4-hydroxy-benzyl)-cyanamide 3-ylmethyl]-amino}-111 ethyl)-2,6-di-terf-butyl-phenol (0.05 g, 0.097 mmol ), obtained in step (iv), in MeOH (4 mL) under N2 atmosphere was added sodium bicarbonate (0.016 g, 0.195 mmol) followed by the addition of cyanogen bromide (0.018 g, 0.175 mmol). The reaction mixture was stirred at RT for 2 h. The solvent 25 was removed under vacuum to give the crude residue which was dissolved in 20 To a solution of 4-( {[2-(bis-cyclopropylmethyl-amino) -8-methyl-quinolin- -157- WO 2007/075194 PCT/US2006/025427 water, extracted with ethyl acetate and dried over sodium sulphate. The solvent was evaporated and concentrated in vacuo to afford [2-(bis-cyclopropylmethyl-amino) -8-methyl-quinolin-3-ylmethyl]-(3,5-di-fer£-butyl-4-hydroxy-benzyl)-cyanamide (0.035 g, yield: 66.7%). 5 'H NMR (CDC13, 400 MHz): 8 8.05 (s, IH), 7.57 (m, IH), 7.48 (m, IH), 7.30 (s, IH), 7.03 (s, 2H), 4.40 (s, 2H), 4.06 (s, 2H), 3.18 (m, 4H), 2.71 (s, 3H), 1.44 (s, 3H), 1.02 (m, 2H), 0.40 (m, 4H), 0.09 (m, 4H); m/z (ES-MS): 539 (M++l, 100%); IR (KBr, cm"1): 3377, 2211, and 1434. Step (vi): Synthesis of 4-{[[2-(bis-cyclopropylmethyl-amino) -8-methyl-quinolin-10 3-ylmethyl]-(2H-tetrazol-5-yl)-amino]-methyl}-2,6-di-fer/-butyl-phenol [2-(Bis-cyclopropylmethyl-amino) -8-methyl-quinolin-3-ylmethyl]-(3,5-di-fer£-butyl-4-hydroxy-benzyl)-cyanamide (0.035 g, 0.065 mmol) obtained in step (v), sodium azide (0.021 g, 0.325 mmol) and ammonium chloride (0.175 g, 0.325 15 mmol ) were put in a RB flask under N2 atmosphere. To this reaction mixture, DMF (2 mL) was added and heated at 100°C for 1 h. The reaction mixture was cooled to RT and ice was added to this and was extracted with ethyl acetate (3x10 mL). The combined organic layer was washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford of 4-{[[2-(bis-20 cyclopropylmethyl-amino) -8-methyl-quinolin-3-ylmethyl]-(2H-tetrazol-5-yl)-amino]-methyl}-2,6-di-ter/-butyl-phenol (0.02 g, yield: 52.9%.). 'H NMR (CDCI3, 400 MHz ): 8 7.48-7.46 (s, IH) , 7.35 -7.27 (m, 3H ), 7.20 (s, 2H ), 4.83 (s, 2H), 4.55 (s, 2H), 3.30-3.29 (m, 4H), 2.69 (s, 3H) 1.4 (s, 18H), 1.21-1.10 (m, 2H), 0.54-0.49 (m, 4H), 0.19-0.15 (m, 4H); m/z (ES-MS): 582 (M++l, 25 100%); IR (KBr, cm"1) 3637, 2923,1434. -158- WO 2007/075194 PCT/US2006/025427 Step (vii): Synthesis of 4- {[[2-(bis-cyclopropylmethyl-amino) -8-methyl-quinolin-3-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-2,6-di-fe/t-butyl-phenol \ To a suspension of 4-{[[2-(bis-cyclopropylmethyl-amino) -8-methyl-quinolin-5 3-ylmethyl]-(2H-tetrazol-5-yl)-amino]-methyl}-2,6-di-te/-/-butyl-phenol (0.3 g, 0.51mmol) in water (5 mL), sodium hydroxide (0.041 g, 1.032 mmol) was added and was stirred for 15 min at RT followed by the addition of dichloromethane (5 mL). To this reaction mixture, dimethyl sulphate (0.12 g, 1.032 mmol) was added followed by the addition of tetra butyl ammonium bromide (0.008 g, 0.02 mmol). 10 The reaction was stirred for 1 h. The organic layer was separated from aqueous layer and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 8% ethyl acetate and 15 petroleum ether to afford 4-{[[2-(bis-cyclopropylmethyl-amino) -8-methyl-quinolin-3-yhnethyl]-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-2,6-di-fe7t- butyl-phenol (0.03g, yield: 13%). Purity 94.36% (HPLC: Symmetry Shield RP8 (150x4.6) [0.01M KH2P04: CH3CN], 218nM, Rt 12.55 min); *H NMR (CDC13, 400 MHz): 5 7.74 (s, IH), 7.42-20 7.39(m, 2H), 7.20-7.17 (m, IH), 7.03 (s, 2H), 5.17(s, IH), 4.82 (s, 2H), 4.53 (s, 2H), 4.17 (s, 3H), 3.21 -3.19 (m, 4H), 2.70 (s, 3H), 1.33 (s, 18H), 1.08-1.00 (m,2H), 0.38-0.34 (m, 4H), 0.10-0.06 (m, 4H); m/z (ES-MS): 596 (M++l, 100%); IR (neat, cm"1) 3628, 3383, 1210. -159- </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 2007/075194 PCT/US2006/025427 Example 61 Determination of in vitro activity An in vitro fluorescence-based assay to identify CETP inhibitors was developed from modifications of the protocols outlined in Bisgaier et al., J Lipid 5 Res., 34(9): 1625-34 (1993) and Epps et al., Chem Phys Lipids., 77(1): 51-63 (1995). Acceptor and donor lipid microemulsions were prepared according to Bisgaier et al., 1993, except that the buffer was prepared with 0.67 ug/mL human HDL (Calbiochem). Donor microemulsions contained the fluorescent cholesteryl ester analog BODIPY-CE (Molecular Probes), characterized by excitation and 10 emission maxima at 503 nm and 518 nm, respectively. The CETP-mediated transfer of fluorescent cholesteryl ester to acceptor particles was monitored over a 2-hour time period using the FAM filter set (excitation 492 nm, emission 516 nm) in an MX3000P fluorescent plate reader (Stratagene). Recombinant CETP enzyme (Cardiovascular Targets) was used at 0.14 ng/pl, final concentration, to achieve 15 lipid transfer. CETP inhibition by compounds was compared to DMSO controls and graphed as a percentage of the control CETP activity over 2 hours. The IC50 curves for CETP inhibition were generated from the activity profiles. Active compounds were also tested for CETP inhibition as above, but in the presence of 3% human serum albumin, fraction V (Calbiochem). 20 Using this protocol, compounds given in Examples 2, 3, 43, 44, 45 and 49 were shown to exhibit a CETP activity with an IC50 of less than or equal to 5 pM; compounds given in Examples 1, 4, 5, 6, 9 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 42 and 46, have shown CETP activity with an IC50 of less than or equal to 1 pM. 25 - 160- RECIEVED IPONZ 03 JUNE 2011 We Claim: 1. A compound of formula (I) Rr Rl (I) or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: A is selected from R ii—^ X RV ^Rl r RVi^N^V. wherein R1, in each occurrence, is selected independently from hydrogen, halogen, alkyl, haloalkyl, alkoxy; R", in each occurrence, is selected independently from hydrogen or alkyl; R111, in each occurrence, independently represents halogen, alkyl, haloalkyl or alkoxy; R1V, in each occurrence, is selected independently from hydrogen, alkyl, or -COR4 or C02R5; Rv, in each occurrence, is selected independently from alkyl, aryl, or -(CH2)mcycloalkyl; RV1, in each occurrence, is selected independently from halogen, alkyl or aryl; R4 represents cycloalkyl; R5 represents alkyl; m represents 0-2, inclusive; p is an integer from 0 to 3, inclusive; Rr and Rs independently represents -C(CH3)3 or -CF3; Rl represents hydrogen or hydroxyl; R3, in each occurrence, is selected independently from (i) a cyclic group selected from - 161 - RECIEVED IPONZ 03 JUNE 2011 N-N;R rN.4pp ^ F N^N NyN NfN ^ , T , , 1 or l ; or (ii) -C02Et, when ZR1 moiety represents S, SO, or S02; Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, (CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, -CH2CH(CH3)OH, X CH2C02Et; (ii) V , or ^ Rc and Rf, in each occurrence, is selected independently from (i) hydrogen, halogen, alkyl, heterocyclyl comprising at least one heteroatom selected independently from >0, >N, or >S, , any of which having up to 6 carbon atoms; or (ii) NRyRz, wherein Ry and Rz independently represents hydrogen or alkyl group; Rd, in each occurrence, is selected independently from hydrogen, halogen, (Ci- -\-N \> -l-N \l-CH3 C3)alkyl, -N(CH3)2, 5 or * ; Re independently represents halogen; Z represents N; or the ZR1 moiety represents S, SO or S02; or , lr>2 the ZR R moiety independently represents (i) -C(0)Z'Rg wherein Rg is hydrogen, cycloalkyl, aryl or (cycloalkyl)alkyl, Z1 represents O or NRh, wherein Rh is hydrogen, alkyl, cycloalkyl, or (cycloalkyl)alkyl; or -|-N^ \l-(CH2)COR5 5 (ii) 5 \ / , R represents heterocyclyl comprising at least one heteroatom selected independently from >0, >N, or >S; 1 2 ^ R and R , in each occurrence, is selected independently from ethyl, or O" 2. The compound as claimed in claim (I), having the formula: XF3 - 162- RECIEVED IPONZ 03 JUNE 2011 or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein A is selected from R'r R Rv , Rvl or R' , R symbols are as explained in claim 1. 3. The compound as claimed in claim 2, having the formula: and other N» II N^n CF, CF, (II); or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R', is CI, -OCH3, -CH3, -CH(CH3)2, or -CF3; Rb represents a) methyl, isopropyl, -CH2-CH2-OH, -CH2-CH2-OCH3, -CH2-CH2-NH-C02CH(CH3)3, -CH2-CH2-NH2, -CH2-CH(CH3)-OH, or -CH2-C02Et; b) or "N, 4. The compound as claimed in claim 3, wherein R1 and R independently represent -CH3. 5. The compound as claimed in claim 2, having the formula (III) or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R'" is -CH3, CF3, CI, -OCH3, or -CH(CH3)2; - 163 - RECIEVED IPONZ 03 JUNE 2011 R11 is H or -CH3; Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, (CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, -CH2CH(CH3)OH, X CH2C02Et; (ii) V , or 6. The compound as claimed in claim 5, wherein R" is hydrogen. 7. The compound as claimed in claim 2, having the following formula \? ^ (IV); or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R', is CI, -OCH3, -CH3, -CH(CH3)2, or -CF3; -\-N Rc represents halogen, -N(CH3)2, or \—/ . 8. The compound as claimed in claim 7, wherein R1 is -CH3. 9. The compound as claimed in claim 2, having the formula: (V); or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R', is CI, -OCH3, -CH3, -CH(CH3)2, -CF3; , -iV \i-ch3 R represents hydrogen,-Br, - CH2CH3,-N(CH3)2, \ / or 5 \ / 10. The compound as claimed in claim 9, wherein R1 represents -CH3. 11. The compound as claimed in claim 2, having the formula - 164- RECIEVED IPONZ 03 JUNE 2011 N^\ .CF- (VI); or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R', is CI, -OCH3, -CH3, -CH(CH3)2, -CF3; -\-N -\-N \l-CH3 R represents hydrogen, -Br, -N(CH3)2, \—/ or 5 \—/ 12. The compound as claimed in claim 11, wherein R1 is -OCH3 and Rd is -Br. 13. The compound as claimed in claim 2, having the formula: or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R', is CI, -OCH3, -CH3, -CH(CH3)2, or -CF3; Re represents -Br. 14. The compound as claimed in claim 13, wherein R1 is -CH3 and Re is -Br. 15. The compound as claimed in claim 2, having the formula or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: Rvi, is F, CI, -CH3, -CH2CH3, -CH(CH3)2 or phenyl; R", is H or -CH3; Rb is -CH3. 16. The compound as claimed in claim 15, wherein (VII); I (VIII); - 165 - RECIEVED IPONZ 03 JUNE 2011 RV1, is F, -CH2CH3, -CH(CH3)2 or phenyl; R", is H or -CH3; Rb is -CH3. 17. The compound as claimed in claim 2, having the formula (IX) or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: Rv, is -CH3, -CH2CH3, -CH(CH3)2, phenyl, or R" is -H or -CH3; Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, (CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, -CH2CH(CH3)OH, X CH2C02Et; (ii) V , or ^ 18. The compound as claimed in claim 17, wherein Rv, is -CH3 or phenyl; R" is -H or -CH3; Rb is methyl. 19. The compound as claimed in claim 2, having the formula N Is Ji PF CFs (X); or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: yC Rv, is -CH3, -CH2CH3, -CH(CH3)2, phenyl, or - 166- RECIEVED IPONZ 03 JUNE 2011 R11 is -H or -CH3; Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, (CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, -CH2CH(CH3)OH, X CH2C02Et; (ii) V , ^ or 20. The compound as claimed in claim 19, wherein Ry is R" is -H or -CH3; Rb 1S methyl. 21. The compound as claimed in claim 2, having the formula R, ^ N> /\ C Fq N N N R ^ (XI); or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: x Rv, is -CH3, -CH2CH3, -CH(CH3)2, phenyl, or R" is -H or -CH3; -\-N \l-CH3 R represents hydrogen, -Br, -N(CH3)2, \ / or 6 \ / ; 22. The compound as claimed in claim 21, wherein Rv, is -CH3 or -CH2CH3; R" is -H or -CH3; d -t_Nf P R is -Br or \ / . 23. The compound as claimed in claim 2, having the formula: R° N^N r ii N N N- .A /\ CF3 N^N 3 Rv ^ (XII); - 167- RECIEVED IPONZ 03 JUNE 2011 or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: Rv is -CH3, -CH2CH3, -CH(CH3)2, phenyl, or V ; R" is -H or -CH3; -\-n \) \l-ch3 Rc represents halogen, -N(CH3)2, \ / or 5 \ / 24. The compound as claimed in claim 23, wherein Rv is -CH3; R" is -CH3; Rc is -N(CH3)2. 25. The compound as claimed in claim 2, having the formula: Ri (XV) or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R1 is hydrogen or -CH3; ZR1 moiety represents S, SO or S02; R2 is -CH3, -CH2CH3 or -CH2CH2CH3. 26. The compound as claimed in claim 25, wherein R' is -CH3; R2 is -CH2CH3. 27. The compound as claimed in claim 2, having the formula: Rb\ (XVII) or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: - 168- RECIEVED IPONZ 03 JUNE 2011 Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, (CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, -CH2CH(CH3)OH, X CH2C02Et; (ii) V , orK 28. The compound as claimed in claim 1, having the formula: (XIII); or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: ° H Ad...^V R is H, -CH3, -CH2CH3, -CH2CH2CH3, -C02CH2CH3, \—/, or Rb is -CH3; Rg is -CH2CH3. 29. The compound as claimed in claim 1, having the formula Rb\ n n; cf3 N~~n ^ /=\ y_f cp3 n n-rh Riv Rg (XIV); or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: O O VY) V R1V is H, -CH3, -CH2CH3, -CH2CH2CH3, C02 CH2CH3, N—' , or Rb is -CH3; Rg is -CH2CH3 or Rh is -CH2CH3 or 30. The compound as claimed in claim 29, wherein R1V is H, -CH3 or -CH2CH2CH3. 31. The compound as claimed in claim 1, having the formula - 169 - RECIEVED IPONZ 03 JUNE 2011 ,n~n cf3 No I] n' V \ // Rii^3fX CF3 n^-n^n- r" (XVI) or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein: R"' in each occurrence, independently represent hydrogen, -CH3, -CH2CH3, or -CH(CH3)2; Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, -CH2CH(CH3)OH, - X CH2C02Et; (ii) V , orK 33. The compound as claimed in claim 31, wherein R" is -CH3, Rb is methyl. 33. The compound as claimed in claim 1, having the formula: (XVIII) or a salt, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein R" is H, -CH3 or -CH(CH3)2; Rb, in each occurrence, is selected independently from (i) methyl, isopropyl, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2NHC02CH(CH3)3, -(CH2)2NH2, -CH2CH(CH3)OH, - X CH2C02Et; (ii) V , or ^ 34. The compound as claimed in claim 33, wherein R" is H or -CH3; Rb is methyl. - 170- RECIEVED IPONZ 03 JUNE 2011 35. The compound as claimed in claim 1, is selected from (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-cyclopropylmethyl -2H-tetrazole -5-yl)-amino]-methyl-} -8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-cyclopentyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-cyclohexyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-isopropyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; (2-{5-[[2-(bis-Cyclopropylmethyl-amino)-8-methyl-quinolin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethyl)-carbamic acid tert-butyl ester; (3-{ [[2-amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bistrifluoromethyl-benzyl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; 1-{5-[[2-(bis-cyclopropylmethyl-amino)8-methyl-quinoline-3-ylmethyl]- (3,5-bistrifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-propane-2-ol; (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-8-trifluoromethyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-Chloro-quinoline-2-yl)- bis-cyclopropylmethyl-amine; 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-methoxy-quinoline-2-yl)- bis-cyclopropylmethyl-amine; 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-8-isopropyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; 2-{5-[[2-(bis-cyclopropylmethyl-amino)-8-methyl-quinoline-3-ylmethyl]- (3,5-bistrifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethanol; [3-({(3,5-bis-trifluoromethyl-benzyl)-[2-(2-methoxy-ethyl)-2H-tetrazol-5-yl]-amino}-methyl)-8-methyl-quinolin-2-yl]-bis-cyclopropylmethyl-amine; 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-7,8-dimethyl-quinoline-2-yl)- bis-cyclopropylmethyl-amine; 3-{[3,5 -bis trifluoromethyl-benzyl )-(2-methyl -2H-tetrazole -5-yl)-amino]-methyl-}-benzo[h]quinolin-2-yl)- bis-cyclopropylmethyl-amine; (S)-(+)-(3-{[(3,5-bis-trifhioromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]methyl}-8-methyl-quinolin-2-yl)-ethyl-(tetrahydro-furan-2-ylmethyl)-amine; - 171 - RECIEVED IPONZ 03 JUNE 2011 (R)-(-)-(3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]methyl}-8-methyl-quinolin-2-yl)-ethyl-(tetrahydro-furan-2-ylmethyl)-amine; (5-{ [(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl }-l-phenyl-lH-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-l,3-dimethyl-1 H-pyrazolo [3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; (5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]methyl}-l-cyclopropylmethyl-lH-pyrazolo[3,4-b]pyridin-6-yl)-cyclobutylmethyl-ethyl-amine; (5 - {[(3,5-bis-trifluoromethyl-benzyl)-(5 -bromo-pyrimidin-2-yl)-amino] -methyl} -1 -ethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-(4-morpholin-4-yl-phenyl)-pyrimidin-2-yl]-amino}-methyl)-l-ethyl-lH-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine; (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-cyclobutylmethyl-ethyl-amine; (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-ethyl-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; N-[2-(bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-ylmethyl]-N-(3,5-bis-trifluoromethyl-benzyl)-N' ,N' -dimethyl-pyrimidine-2,5-diamine; [3-({((3,5-bis-trifluoromethyl-benzyl)-[5-(4-methyl-piperazin-1-yl)-pyrimidin-2-yl]-amino}-methyl)-8-methyl-quinolin-2-yl]-bis-cyclopropylmethyl-amine; (3-{[(3,5-bis-trifluoromethyl-benzyl)-pyrimidin-2-yl-amino]-methyl }-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyridin-2-yl)-amino]-methyl }-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-isopropyl-5-methyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-isopropyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; - 172- RECIEVED IPONZ 03 JUNE 2011 (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-ethyl-5-methyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; (3-{[3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-5-methyl-6-phenyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine; {5-[[2-(bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-acetic acid ethyl ester; (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(4-chloro-[l,3,5]triazin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; N- [2-(Bis-cyclopropylmethyl-amino)- 8-methyl-quinolin-3 -ylmethyl] -N-(3,5 -bis-trifluoromethyl-benzyl)-N',N'-dimethyl-[l,3,5]triazine-2,4-diamine; (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(4-morpholin-4-yl-[l,3,5]triazin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine; (5-{[(3,5-Bis-trifluoromethyl-benzyl)-(4-N,N,dimethylamino-[l,3,5]triazin-2-yl)-amino]-methyl} -1,3 -dimethyl-1 H-pyrazolo [3,4-b] pyridin-6-yl)-bis-cyclopropylmethyl-amine; 3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-methyl-quinolin-4-yl)-bis-cyclopropylmethyl-amine; (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-quinolin- 4-yl)-bis-cyclopropylmethyl-amine; (6-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-bis-cyclopropylmethyl-amine; 3-{[( 3,5-Bis-trifluormethyl-benzyl )- ( 2-methyl-2H-tetrazol-5-yl)-amino]-methyl } -1H-indole-2-carboxylic acid ethyl ester; 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-methyl-lH-indole-2-carboxylic acid ethyl ester; 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-propyl-lH-indole-2-carboxylic acid ethyl ester; 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl }-l-cyclopentanecarbonyl-lH-indole-2-carboxylic acid ethyl ester; 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl }-l-ethyl-lH-indole-2-carboxylic acid ethyl ester; 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-indole-1,2-carboxylic acid ethyl ester; - 173 - RECIEVED IPONZ 03 JUNE 2011 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-cyclopropanecarbonyl-lH-indole-2-carboxylic acid ethyl ester; 3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-3H-indole- 2-carboxylic acid diethylamide; 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-methyl-lH-indole-2-carboxylic acid diethylamide; 3-{[(3,5-bis-trifhioromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-l-methyl-lH-indole-2-carboxylic acid bis-cyclopropylmethyl-amide; 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl }-l-propyl-lH-indole-2-carboxylic acid bis-cyclopropylmethyl-amide; (3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-carbamic acid ethyl ester; (3,5-Bis-trifluoromethyl-benzyl)-[8-methyl-2-(propane-l-sulfonyl)-quinolin-3-ylmethyl]-carbamic acid ethyl ester; (3,5-Bis-trifluoromethyl-benzyl)-[8-methyl-2-(propane-l-sulfinyl)-quinolin-3-ylmethyl]-carbamic acid ethyl ester; (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-6-fluoro-pyridin-2-yl)-bis-cyclopropylmethyl-amine; 2-[4-(3-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-piperazin-1 -yl] -1 -pyrrolidin-1 -yl-ethanone; [3 -({((3,5 -bis-trifluoromethyl-benzyl)-[(4-morpholin-4-yl-phenyl)-amino] -methyl)- 8-methyl-quinolin-2-yl]-bis-cyclopropylmethyl-amine; 4-{[[2-(bis-cyclopropylmethyl-amino) -8-methyl-quinolin-3-ylmethyl]-(2-methyl-2H-tetrazol- 5-yl)-amino]-methyl}-2,6-di-fer^-butyl-phenol; or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture. 36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound having the formula (I) as claimed in any one of claims 1 to 35. 37. The pharmaceutical composition according to Claim 36, further comprising at least one of the following: a pharmaceutically acceptable auxiliary; a pharmaceutically acceptable preservative; a pharmaceutically acceptable excipient; a pharmaceutically acceptable diluent; a pharmaceutically acceptable solvate; or - 174- RECIEVED IPONZ 03 JUNE 2011 any combination thereof. 38. The pharmaceutical composition according to Claim 36, wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash. 39. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound having the formula (I) as claimed in claim 35. 40. The pharmaceutical composition according to Claim 39, further comprising at least one of the following: a pharmaceutically acceptable auxiliary; a pharmaceutically acceptable preservative; a pharmaceutically acceptable excipient; a pharmaceutically acceptable diluent; a pharmaceutically acceptable solvate; or any combination thereof. 41. The pharmaceutical composition according to Claim 39, wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash. 42. A compound as claimed claim 1, is a cholesteryl ester transfer protein (CETP) inhibitor 43. A compound as claimed claim 35, is a cholesteryl ester transfer protein (CETP) inhibitor. 44. A compound according to claim 1 or claim 35, substantially as herein described with reference to any one of the accompanying examples thereof. 45. A pharmaceutical composition according to claim 36, substantially as herein described with reference to any one of the accompanying examples thereof. - 175 - </div>