ZA200610093B - Compounds and methods for treating dyslipidemia - Google Patents

Description

COMPOUNDS AND METHODS FOR TREATING DYSLIPIDEMIA

FIELD OF THE INVENTION

The current invention relates to the fields of medicinal organic chemistry, pharmacology, and medicine. Further, the current invention relates to a group of compounds and methods for treating pathological states due to dyslipidemia

BACKGROUND OF THE INVENTION

Coronary heart disease (CHD) is one of the major causes of morbidity and mortality worldwide. Despite attempts to modify risk factors such as obesity, smoking, lack of exercise, and treatment of dyslipidemia with dietary modification or drug therapy,

CHD remains the most common cause of death in the U.S. Over 50% of all CHD deaths are due to underlying atherosclerotic coronary heart disease.

Dyslipidemia is a major risk factor for CHD. Low plasma levels of high density lipoprotein (HDL) cholesterol with either normal or elevated levels of low density (LDL) cholesterol is a significant risk factor for developing atherosclerosis and associated coronary artery disease in humans. Indeed, several studies on lipoprotein profiles of

CHD patients have shown that about 50% of the CHD patients have cholesterol levels that are considered to be in the normal range (<200 mg/dl). Furthermore, these studies found low HDL cholesterol in about 40% of the normo-cholesterolemic CHD patients as compared to the general population reported in the National Health and Nutrition

Examination Survey. Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of cardiovascular diseases including, but not limited to, atherosclerosis, CHD, stroke, and peripheral vascular disease.

Cholesterol ester transfer protein (CETP) is a 74 KD glycoprotein that facilitates the exchange of cholesterol esters in HDL for triglycerides in triglyceride-rich lipoproteins (A. R. Tall et. al., (1999) 1999 George Lyman Duss Memorial Lecture: Lipid transfer proteins, HDL metabolism and atherogenesis. Arterio. Thromb. Vasc. Biol. 20:1185-1188.). The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile is believed to be pro- atherogenic, especially in subjects whose lipid profile constitutes an increased risk for

CHD. Niacin can significantly increase HDL, but has serious toleration issues that reduce compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL cholesterol only modestly (~10-12%). As a result, there is a significant unmet medical need for a well- tolerated agent that can significantly elevate plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.

CETP is expressed in multiple tissues and secreted into plasma, where it associates with HDL (X.C. Jiang et al., (1991) Mammalian adipose tissue and muscle are - major sources of lipid transfer protein mRNA. J. Biol. Chem. 266:4631-4639). Humans and monkeys, which express CETP, have relatively low HDL cholesterol, whereas mice and rats do not express CETP and carry nearly all their cholesterol in HDL. Furthermore, transgenic expression of CETP in mice results in significantly reduced HDL cholesterol levels and developed severe atherosclerosis compared to control mice (K.R. Marotti et. al., (1993) Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature: 364, 73-75). Expression of human CETP in Dahl salt-sensitive hypertensive rats led to spontaneous combined hyperlipidemia, coronary heart disease and decreased survival (V.L.M. Herrera et. al., (1999) Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein. Nature : Medicine: 5, 1383-1389).

Antibodies either directly injected into the plasma or generated through vaccine injection can effectively inhibit CETP activity in hamsters and rabbits resulting in elevated HDL cholesterol (C. W. Rittershaus, (1999) Vaccine-induced antibodies inhibit

CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis.

Furthermore, antibody neutralization of CETP in rabbits has been shown to be anti- atherogenic (Arterio. Thromb. Vasc. Biol. 20, 2106-21 12; G.F.Evans et al., (1994)

Inhibition of cholesteryl ester transfer protein in normocholesterolemic and hypercholesterolemic hamsters: effects on HDL subspecies, quantity, and apolipoprotein distribution. J. Lipid Research. 35, 1634-1645). However, antibody and/or vaccine therapy is not currently a viable option for the treatment of large populations of patients in need of treatment for dyslipidemia and resultant or associated disease state manifestations.

There have been several reports of small molecule CETP inhibitors. Barrret et al. (J. Am. Chem. Soc., 188, 7863, (1996)) and Kuo et al. (J. Am. Chem. Soc., 117, 10629, (1995)) describe cyclopropan-containing CETP inhibitors. Pietzonka et al. (Biorg. Med.

Chem. Lett. 6, 1951 (1996)) describe phosphanate-containing analogs as CETP inhibitors.

Coval et al. (Bioorg. Med. Chem. Lett. 5, 60S, (1995)) describe Wiedendiol-A and -B related sesquiterpines as CETP inhibitors. Japanese Patent Application No. 10287662-A describes polycyclic, non-amine containing, polyhydroxylic natural compounds possessing CETP inhibition properties. Lee et al. (J. Antibiotics, 49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. (Lipids, 25, 216- 220 (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and

Zillversmit (J. Lipid Res., 35, 836-47 (1982)) describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP.

Connolly et al. (Biochem. Biophys. Res. Comm. 223, 42-47 (1996)) describe other cysteine modification reagents as CETP inhibitors. Xia et al. Describe 1,3,5-triazines as

CETP inhibitors (Bioorg. Med. Chem. Lett., 6, 919-22 (1996)). Bisgaier et al. (Lipids, 29, 811-8 (1994) describe 4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor.

Oomura et al. disclose non-peptidic tetracyclic and hexacyclic phenols as CETP inhibitors in Japanese Patent Application No. 10287662.

United States patent no. 6,586,448 B1 describes 4-carboxamino-2-substituted- 1,2,3,4-tetrahydroquinolines of the following structure:

RY 1

PIN

R® ON” “OR

RS

' Bee! RZ

ROR wherein R! R?, R® RY R® , RS R” and R® are as defined therein. Similarly, PCT patent applications WO 03/063868A1, WO 00/17164, WO 00/17165, and WO 00/17166,

disclose variously, formulations, methods of preparation and methods of use of compounds tetrahydroquinoline compounds generally related to those in U.S patent no. 6,586,448 B1 from which it derives as a divisional application.

European Patent Application No. 818448 by Schmidt et al. describes certain tetrahydroquinoline derivatives as cholesteryl ester transfer protein inhibitors. European

Patent Application No. 818197 by Schmek et al, describe pyridines with fused heterocycles as cholesteryl ester transfer protein inhibitors. Brandes et al. in German

Patent Application No. 19627430 describe bicyclic condensed pyridine derivatives as cholesteryl ester transfer protein inhibitors. In US Patent 6,207,671 Schmidt et al. describe substituted pyridine compounds as CETP inhibitors. In PCT Patent Applications

WO 03/028727 by Miiller-Gliemann et al. and WO 98/39299 by Gielen et al. certain quinoline derivatives are described as cholesteryl ester transfer protein inhibitors.

The above disclosures notwithstanding, a great need remains, particularly for affluent western societies for effective compounds useful to treat conditions caused by, associated with, or exacerbated by dyslipidemia.

SUMMARY OF THE INVENTION

The present invention provides a compound of Formula 1

R? 3a

H AR

R¥® et ) (RR), (CH LN .

I wherein : nis0,1,2,or3; mis0,1,2,0r3; pislor2; qis0,1,2,3,0r4,;

Y is a bond, C=0, or S(O); wherein tis 0, 1, or 2;

R'is selected from a group consisting of: hydroxy, Ci-Cs alkyl, aryl, C»-Cs alkenyl, C;-Cs haloalkyl, C;-Cs alkylheterocyclic, C3-Cg cycloalkyl, C;-Cs alkylcycloalkyl; C;-Cg alkylaryl, heterocyclyl, Ci-Ce alkylalcohol, C;-Cs alkoxy, aryloxy, -0C,-Cg alkenyl, -OC;-Cs haloalkyl, -OC;-Cs alkylheterocyclic, -OC3-Cs cycloalkyl, -OC;-Cg alkylcycloalkyl, -NRR® and -OC;-Cs alkylaryl, -O-heterocyclic, -OCy-Cs alkylheterocyclic, C;-Cs alkyl-O-C(O)NRR?, C;-Cs alkyl-NR'C(O)NR'R?, and Co-Cs alkylCOOR' 1 provided that R! is not hydroxy when Y is S(O); and wherein each cycloalkyl, aryl and heterocyclic group is optionally substituted with 1 to 3 groups independently selected from oxo, hydroxy, halogen, Ci-Cs alkyl, Co-Cs alkene, C-Cs alkynyl, C;-Cs alkoxy, C;-Cs haloalkyl, C,-Cs alkylalcohol, CONR''R'2, NR''SOR 2, “NR!!'COR2, Cy-C; alkyINR!'R*2, C;-C; alkylCOR'!, Cy-Cs alkylCOOR', cyano, C-Cs alkylcycloalkyl, phenyl, -OC;-Cs alkylcycloalkyl, -OC;-Cs alkylaryl, -OC;-Ce alkylheterocyclic, and C,-Cg alkylaryl;

Each R? is bound only to a carbon atom and is or are if more than one independently selected from the group consisting of: hydrogen, hydroxy, halogen, oxo,

C;-Cs alkyl, Cp-Cs alkene, C,-Cs alkynyl, C;-Cs alkoxy, C;-Cs haloalkyl, CONR''R", -NRUSO,R?, -NR!'COR2, C-Cg alkyINR''R*?, C-Cs alkylCOR"!, Co-Cs alkylCOOR", cyano, nitro, Co-Cs alkylcycloalkyl, phenyl, Co-Cs alkylaryl, heterocyclyl, C3-Cs cycloalkyl, and C;-Ce haloalkyl; and wherein two independently selected R? groups are optionally gem-disubstituted;

R* and R¥ are independently selected from the group consisting of: hydrogen, halogen, C;-Cs alkyl, C;-Cs alkene, C,-Cg alkynyl, C;-Cs alkoxy, and C;-Cs haloalkyl;

R* is a group represented by the formula -NR*R*®; wherein, :

R“ is a heterocyclic, C,-Cs alkylheterocyclic , or Co-Cg alkenylheterocyclic group wherein each heterocyclic group is optionally substituted with 1 to 3 groups independently selected from the group consisting of: hydroxyl, halogen, oxo, -NR!RP,

C1-Cs alkyl, C;-Cs alkenyl, Co-Cs alkylCN, C;-Cg alkoxy, C;-Cs alkylalcohol, Ci-Cs haloalkyl, -OC(O)NR''R?, C;-Cs alkyINR''R'? wherein the C;-Cq alkyl group is optionally substituted with -OR'® or C(O)OR°, C¢-Cs alkyINO,, Co-Cs alkyINR''SO,R™?,

Co-Cs alkylC(O)NR'R, C,-Cs alkyINR''C(O)R'?, Cy-C alkyINR''C(O)OR'2, Co-Cs alkyINR''C(O)NR'®R?, C-Cs alkyINR'CHR°CO,R 2, Co-Cs alkylC(O)OR'!, Co-Cs alkylSO,NR!'R'2, Co-Cs alkylS(O)R'!, C5-Cs cycloalkyl, C,-Cs alkyleycloalkyl, and Co-

Cs alkylheterocyclic wherein the heterocycle of the Co-Ce alkylheterocyclic group is optionally substituted with halo, C;-Cs alkyl, oxo, -CO,R" and -NR!'R'?; and

R*® is selected from the group consisting of: C,-Cg alkylaryl, C;-Cs alkenylaryl,

C,-Cs alkynylaryl, C;-Cs alkylheterocyclic, Co-Cs alkenylheterocyclic, Ci-Cs alkylcycloalkyl, and C;-Cs alkyl-O-C;-Cs alkylaryl, wherein each cycloalkyl, aryl, or heterocyclic group is optionally substituted with 1-3 groups independently selected from the group consisting of hydroxy, oxo, -SC;-Cs alkyl, C;-C alkyl, C,-Cg alkenyl, C;1-Cs alkynyl, C,-Cs haloalkyl, halogen, C;-Cs alkoxy, aryloxy, C-Cs alkenyloxy, Ci-Ce + haloalkoxyalkyl, Co-Ce alkyINR"'R"2, -OC;-C; alkylaryl, nitro, cyano, C1-Cs haloalkylalcohol, and C;-Cs alkyl alcohol;

RS is selected from a group consisting of: hydrogen, hydroxy, halogen, Ci-Cs alkyl, C,-Ce alkenyl, C2-Cs alkynyl, C;-Cs alkoxy, aryloxy, -OC,-Cs alkenyl, -OC;-Ce haloalkyl, C;-Cs haloalkyl, C3-Cs cycloalkyl, C,-Cs alkylaryl, C,-Cs alkytheterocyclic,

C,-Cg alkenylaryl, C,-Cs alkenylheterocyclic, aryl, heterocyclic, cyano, nitro, Co-Cs alkyINRR®, Co-C alkylCOR’, Co-Cs alkylCO,R, Co-Cs alkylCONR'R®, CONR’SO,R®,

NR’SO;R?, -NR’COR?, -N=CR'R?, -OCONRR?, -S(O)R’, -SO,NR'R®, C¢-CsCH,0H, -0C,;-Cg alkylheterocyclic, and -OC;-Cg alkylaryl wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclic group or subgroup is optionally substituted with oxo, alkyloxy, aryloxy; and wherein any two R® groups may combine to form an : optionally substituted 5, 6, or 7-member fused ring with the phenyl ring (A-ring) to which they are attached, wherein the 5, 6, or 7-member fused ring is saturated, partially unsaturated, or fully unsaturated and optionally contains 1, 2, or 3 heteroatoms independently selected from O, N, and S;

RC is independently selected from a group consisting of: hydrogen, Cy-Cs alkyl,

C,-Cg alkenyl, hydroxy, COR’, C,-Cg alkoxy, aryloxy, -OC,-Cs alkenyl, -OC-Cs haloalkyl, C;-Cs alkyINRR?, C3-Cg cycloalkyl, heterocyclic, aryl, C,-Cs alkyl-O-

C(O)NRR?, C;-Cg alkyl-NR'C(O)NRR? and C;-Cq alkyleycloalkyl;

R and R® are each independently selected from a group consisting of: hydrogen,

C;-Cg alkyl, Co-Cs alkenyl, Co-Cs alkynyl, -O C;-Cs alkyl, C;-Cs haloalkyl, -O-aryl, -0C;-Cg cycloalkyl, -O-heterocyclic, -NR'R?, C,-Cs alkylcycloalkyl, -0C;-Cs alkylcycloalkyl, -OC;-Cs alkylheterocyclic, C;-Cs alkylheterocyclic, -O C;-Cg alkylaryl,

-

C5-Cg cycloalkyl, heterocyclic, ary), and Cy-Cs alkylaryl, wherein each alkyl, cycloalkyl, heterocyclic or aryl group is optionally substituted with 1-3 groups independently selected from hydroxy, -CN, halogen, C;-Cs alkyl, C-Cs alkoxy, C;-Cs haloalkyl, and

NR'R™, or R” and R® combine to form a nitrogen containing heterocyclic ring which may have 0, 1, or 2 additional heteroatoms selected from oxygen, nitrogen and sulfur and - wherein the nitrogen-containing heterocycle is optionally substituted with oxo, or C;-Ce alkyl;

R!9 RY, and R* are independently selected from a group consisting of: hydrogen, C;-Cs alkyl, C;-Cs alkenyl, Cs-Cs cycloalkyl, heterocyclic, aryl, Ci-Cs alkylaryl, wherein each alkyl, aryl, cycloalkyl, and heterocyclic group is optionally : substituted with 1-3 groups independently selected from halogen, C;-C¢ alkylheterocyclic, and Cy-Cs haloalkyl, or R!! and R'? combine to form a nitrogen containing heterocyclic ring which may have 0, 1, or 2 additional heteroatoms selected from oxygen, nitrogen or sulfur and is optionally substituted with oxo, C;-Cs alkyl,

COR’, and -SO,R’; or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof.

The present invention also provides a method for modulating CETP activity comprising the use of a compound of Formula I or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof, for the treatment, prevention or amelioration of CETP mediated diseases.

The present invention provides a method for treating or preventing dyslipidemia comprising administering a compound of Formula I, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer, or mixture of diastereomers, or prodrug thereof, to a patient in need thereof.

The present invention provides a method for treating or preventing CHD comprising administering a compound of Formula I, pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer, mixture of diastereomers, or prodrug thereof, to a patient in need thereof.

The present invention provides a method for treating and/or preventing atherosclerosis comprising administering a compound of Formula I, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate diastereomer, mixture of diastereomers, or prodrug thereof, to a patient in need thereof.

The present invention provides a method for treating and/or preventing diseases related to abnormal CETP activity comprising administering a compound of Formula I, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate diastereomer, mixture of diastereomers, or prodrug thereof, to a patient in need thereof.

The present invention provides a method of raising the ratio of plasma HDL- cholesterol to plasma LDL-cholesterol in a mammal comprising administering a therapeutically effective dose of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer, mixture of diastereomers, OF prodrug thereof, to a patient in need thereof.

The present invention provides a method of raising the level of plasma HDL- cholesterol in a mammal comprising administering a therapeutically effective dose of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer, mixture of diastereomers, or prodrug thereof, to a patient in need thereof.

The present invention provides a method of lowering the level of plasma LDL- cholesterol in a mammal comprising administering a therapeutically effective dose of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer, mixture of diastereomers, or prodrug thereof, to a patient in need thereof.

The present invention also provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof, and a carrier.

The present invention also provides a method of treating and/or preventing the pathological sequelae due to low levels of plasma HDL and/or high levels of LDL- cholesterol in a mammal comprising administering an effective dose of a compound of

Formula I, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer, or mixture of diastereomers, thereof, to a patient in need thereof.

The present invention also relates to the use of a compound of Formula I for the manufacture of a medicament for treating and/or preventing atherosclerosis in a mammal comprising administering an effective dose of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer, mixture of diastereomers, or prodrug thereof, to a patient in need thereof.

The present invention also provides a combination therapy involving a compound of Formula I and one or more other cardio protective agents such as for example, statins, leptin, and/or other LXR, CETP, ABC Al, or lipid regulating agents useful for the treatment and/or prevention of atherosclerosis.

DETAILED DESCRIPTION OF THE INVENTION

The current invention provides novel compounds of Formula I useful in modulating CETP activity.

The term “modulation” would include, but not be limited to, up-regulation, down- regulation, inhibition, agonism, antagonism of the CETP receptor as appropriate to achieve HDL raising, or LDL lowering and the resulting biological sequelae from such intervention.

The phrase “diseases” or “diseases related to CETP modulation” or “diseases mediated by CETP activity” refers to pathological states where atherosclerosis and cardiovascular diseases are prone because of dyslipidemia and/or other risk factors and are therefore beneficially affected by down-regulation or modulation of CETP activity.

These diseases include but are not limited to hyperlipidemia and its sequelae such as atherosclerosis, CHD, elevated blood pressure, CHF, stroke, hypertension, hypertriglyceremia, diabetes, obesity, inflammatory diseases including but not limited to dermatitis, arthritis, and pain, and diseases of the central nervous system including but not limited to dementia, cognitive disorders such as Alzheimer’s disease.

The term "treatment" bears its usual meaning which includes prohibiting, inhibiting, ameliorating, halting, restraining, slowing or reversing the progression, or reducing the severity of a pathological symptom related to or resultant from the modulation of CETP activity, especially as related to raising plasma levels of HDL, or lowering LDL-cholesterol levels or raising the HDL/LDL ratio or controlling atherosclerosis, hyperlipidemia and/or hypercholesterolemia. :

Generally, one of skill in the art is aware that valency must be conserved (complete) for all stable molecules. Therefore, the necessary implication that hydrogen atoms are necessary and available to complete valency in all structures including Formula

I unless expressly indicated otherwise, is imputed to the general knowledge of ope of skill in the art.

General chemical terms used in the description of compounds herein described bear their usual meanings. For example, the term "C,¢ alkyl," or “(C1-Ce)alkyl” or “Cy-

Cs alkyl” refers to a straight or branched aliphatic chain of 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, pentyl, and hexyl. Unless otherwise stated, the term “alkyl” means C;-Cg alkyl. Similarly, the term “Co-Cs alkyl” implies an alkyl group as indicated wherein when the term Co applies, the alkyl group is not present, and the remaining group sans carbon attach directly to the rest of the referenced molecule or group.

The terms alkenyl and alkynyl, for example, a C>-Cg alkenyl group or a C>-Cg alkynyl group as used herein mean that the respective groups can include 1, 2, or 3 double bonds or triple bonds, respectively. If more than one double or triple bond is present in the group, the double and triple bonds can be conjugated or non-conjugated.

The invention also contemplates that the term C;-C¢ alkyl or C;-Cg alkenyl or similar terms also encompass the specified alkyl or alkenyl or similar group, which may be chiral, regio or steroisomeric. Such chiral or regio or stereoisomeric groups are also within the scope of the present invention.

The term alkylaryl refers to an alkyl group substituted with an aryl group. For example, C;-Cs alkylaryl indicates that an aryl group is attached to a C;-Cs alkyl group and that the resulting Cy-Cs alkylaryl is attached to the rest of the referenced molecule or group via the alkyl group.

The term "substituted phenyl" or “optionally substituted phenyl” refers to a phenyl group having one or more substituents selected from the group consisting of C;-Cs alkyl,

C;-Cg alkoxy, hydroxy, -COOR’, Co-Cs alkyINR'R®, nitro, chloro, fluoro, bromo, iodo,

C;-Cg haloalkyl, C;-Cg haloalkoxyalkyl, Co-Cs alkylheterocyclic.

The terms “optionally substituted 5-7 member carbocyclic” or “optionally substituted 5-7 member heterocyclic” whether written in the conjunctive or disjunctive style, or in single or in compound sentences, mean a carbocyclic or heterocyclic 5-7 member ring that is optionally substituted with 1-3 groups independently selected from the group consisting of hydroxy, halogen, C1-Cs haloalkyl, C3-Cs cycloalkyl, C;-Cs alkylaryl, C;-C¢ alkylheterocyclic, aryl, heterocyclic, Co-Cs alkylcyano, nitro, C;-Cs alkyl, C;-Cs alkenyl C;-Cs alkoxy, aryloxy, -OCz-Cg alkenyl, -OC,-Cg haloalkyl, Co-Cs alkyINR'R®, Cy-Cs alkylCOR’, Cq-Cs alkylCO,R’, Co-Cs alkyl CONR'R?, CONR’SO.R?, _NR’SO,R®, -NR'COR?, -N=CRR?, -OCONR'R?, -$(0)s2R’, -SO;NR'R’, C-

CsCH,0H, -0OC;-Cs alkylheterocyclic, and -OC,~Cg alkylaryl.

The term “optionally substituted” in general means that the subject group may be substituted, where possible, with 1-3 groups independently selected from the group consisting of hydroxy, halogen, C;-Cg haloalkyl, C3-Cs cycloalkyl, C,-Cs alkylaryl, C1-Cs alkylheterocyclic, aryl, heterocyclic, Co-C; alkylcyano, nitro, C1-C alkyl, C»-Ce alkenyl

C1-Cg alkoxy, aryloxy, -OC;-Cs alkenyl, -OC;-Cs haloalkyl, -Co-Cs alkyINR'R®, Co-Cs alkylCOR”, Co-Cs alkylCOR, Co-Cg alkylCONR'R?, CONR’SO2R?, -NR’SO:R®, -NR’COR®, -N=CR'R?, -OCONR'R?, -S(0).sR, -SO,NR'R®, Co-CsCH,OH, -OC1-Cs alkylheterocyclic, and -OC;-Cs alkylaryl. Where an optionally substituted group is claimed or disclosed, it should be noticed that both the substituted and unsubstituted versions of the subject group are within the purview of the invention unless otherwise indicated.

The term “aryl” refers to a substituted or unsubstituted aromatic or heteroaromatic, or heterocyclic radical (heteroarylaryl groups are subsumed in this term). Hlustrative aryl groups include but is not limited, to napthyl, quinolyl, tetrahydroquinolyl, indazolyl, pyrimidinyl, triaziny), pyrazine, pyridazinyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, pyranyl, tetrazolyl, imidazolyl, 1,2,3-trazolyl, 1,2,4- triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazopyridine, benzimidazolyl, triazolone-yl, imidazolone-yl, imidazolidinone-yl, 2- furyl, 3-furyl, 2-thienyl 3- thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, phenyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5- : benzofuryl, 6-benzofuryl, 7-benzofuryl, 2-benzothieny, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, tetrazole , imidazole, isoxazole, pyrazole, 7-indolyl, and isomers thereof. As used herein the term aryl also encompasses the benzyl group.

The term “carbocycle” as used herein refers to a cyclic group having only carbon and appropriate number of hydrogen atoms. The term encompasses groups such as cycloalkyl, cycloalkene, cycloalkylene, naphthyl, phenyl, and the like.

The term “heterocycle”, "heterocyclyl", or “heterocyclic” refers toa 5, 6, or 7 member saturated, partially unsaturated or aromatic mono-cyclic or a fused bicyclic ring containing 1-5 heteroatoms selected from N, S, or O, wherein said heterocycle is optionally substituted at carbon or nitrogen atom(s) unless otherwise specified. Most preferred heterocyclic groups include pyrolidinyl, piperidinyl, hexamethyleneimmino, morpholino, thiomorpholino, benzthiophene, indolyl, quinolyl, isoquinolyl, tetrazolyl, and pyridinyl. As a corollary, the term “alkylheterocyclic” or “alkylheterocycle” is understood to mean that the alkyl group is attached to the heterocycle and the point of attachment to the rest of the referenced molecule or group.

The term “haloalkyl” as used herein refers to an alkyl (as noted above) substituted with one or more halo atoms selected from F, Br, Cl, and 1.

The term “haloalkoxyalkyl” as used herein include for example trifluoromethoxy, pentafluoroethoxy, trifluoroethoxy (OCH,CFs), and the like. : The term “Prodrugs” describes derivatives of the compounds of the invention that have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative fori often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see,

Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives, such as, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic esters (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. Other preferred esters include morpholinoethyloxy, diethylglycolamide and diethylaminocarbonylmethoxy. In some cases it is desirable to prepare double ester type prodrugs, such as, (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.

As used herein, the term “protecting group” refers to a group useful for masking reactive sites in a molecule to enhance the reactivity of another group or allow reaction at another desired site or sites following which the protecting group may be removed.

Protecting groups are usually used to protect or mask groups including, but not limited to,

-OH, -NH, and ~-COOH. Suitable protecting groups are known to one of skill in the art and are described in Protecting groups in Organic Synthesis, 3™ edition, Greene, T. W.;

Wats, P.G.M. Eds., John Wiley and Sons, New York, 1999.

As used herein, the term “solvate” is a form of the compound of the invention wherein a crystal or crystals of a compound of the invention have been formed from a stoichiometric or non-stoichiometric amount of the compound of Formula I and a solvent.

Typical, non-limiting, solvating solvents include for example, water, methanol, ethanol, acetone and dimethylformamide. The term “hydrate” may be used when the solvent is water.

In those instances where a compound of the invention possesses acidic or basic functional groups, various salts may be formed which are more water soluble and/or more physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts include, but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion-exchange resin.

Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base or acid addition salts of compounds of the present invention. Base addition salts include for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, ef al., “Pharmaceutical Salts,” J. Phar. Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, hydrobromide, camsylate, carbonate, clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrochloride, hydroxynaphthoate, hydroiodide, isothionate, lactate, lactobionate, laureate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.

Preferred salts for the purpose of the invention include the hydrochloride salt, the hydrobromide salt, the bisulfate salt, the methane sulfonic acid salt, the p-toluenesulfonic acid salt, bitartrate, the acetate and the citrate sait.

A compound of the invention as illustrated by Formula I' may occur as any one of its positional isomers, stereochemical isomers or regio-isomers, all of which are included within the scope of the invention. Certain compounds of the invention may possess one or more chiral centers, and thus, may exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group, there exist the possibility of cis and trans isomeric forms of the compounds. The R- and S- isomers and mixtures thereof, including racemic mixtures as well as mixtures of enantiomers or cis- and trans- isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereo-specific reactions with starting materials that contain the asymmetric centers and are already resolved. Alternatively desired stereoisomers may be prepared by methods that lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a racemic mixture may be reacted with a single enantiomer of some other compound i.e. a chiral resolving agent. This changes the racemic form into a mixture of stereoisomers and diastereomers, because they have different melting points, different boiling points, and different solubilities and can be separated by conventional means, such as crystallization.

Preferred Embodiments of the Invention

RA 3a

H R

Rr

RN (Rn (CHR RE

Formula I

Preferred n, m, p, and q

Preferably n is 0, or 1. More preferably, n is 0.

Preferably m is 0, or 1.

Preferably pis 1 or 2.

Preferably, q is 0, 1, 2, or 3. More preferably q is 2 or 3.

Preferably Y is a bond or C(O), or S(O); Where t = 0,1, or 2.

Preferred R}

A preferred R' group is selected from the group consisting of:hydroxy, hydrogen,

C:-Cg alkyl, Co-Cs alkylcycloalkyl, Co-Cs alkylheterocyclic, Ci-Cg haloalkyl, Co-Cs alkylaryl, -Oaryl, -OC,-Cs haloalkyl, -OC;-Cs alkylcycloalkyl, -OC;-Cg cycloalkyl, -C;-

Cs alkyleycloalkyINRRS, -OC;-Cs alkyl, -OCq-Cg alkylaryl, -OC;-Cealkylcyano, -OC;-

Cs alkylCO;R"!, -OCs-Cs cycloalkylCO:R", -OC;-Cealkylhydroxy, -OCy-Cs alkyINR'R? and -OC;-Cg alkylheterocyclic, provided that R! is not -OH when Y is S(O); and wherein each alkyl, cycloalkyl, aryl, or heterocyclic is optionally substituted with 1 or 2 groups selected from halogen, Co-C; alkylalcohol, Co-C3 alkylamine, Co-Cs alkylCOOH, Co-Cs alkylCONH,, Cy-C3 alkylcyano, and Co-C3 alkylC(O)OC;-Cs alkyl.

When p is 1, a more preferred R! group is selected from the group consisting of: hydrogen, hydroxy, Ci-Cs alkyl, Co-Cg alkylaryl, C-Cs alkylcycloalkyl, Co-Cs alkylbeterocyclic, C3-Cgcycloalkyl, -OC;-Cg alkyl, -OCy-Cs alkylcycloalkyl, -OCy-Cs alkylhydroxy, -OC,-Cs alkyINR'R®, and -OC-Cs alkylCO;R", provided that R' is not -OH when Y is S(O); wherein each alkyl, cycloalkyl, heterocyclic and aryl groups are each optionally substituted as described above.

When p is 1, a still more preferred R! is a group represented by C;-Cs alkyl, Co-Cs alkylaryl, Co-Cs alkylheterocyclic, Co-Cg alkylcycloalkyl, -OC;-Cs alkyl and wherein each alkyl, cycloalkyl, aryl, or heterocyclic is optionally substituted with 1 or 2 groups selected from halogen, Cp-C; alkylalcohol, Co-Cs alkylamine, Co-Cs alkylCOOH, Co-Cs, alkylCONH,, Co-C; alkylcyano, and Co-C; alkylC(O)OC,;-C; alkyl.

Preferred R®

A preferred R? group is selected from the group consisting of: hydrogen, Ci-Cs haloalkyl, C;-Cs alkyl, C)-Cs alkylcycloalkyl, Cs-Cg cycloalkyl, Ci-Cg alkylaryl and Co-

Ce alkyINR'R®.

When p is 1, a more preferred R? group is represented by hydrogen.

Preferred R® Groups

Preferred R and R® groups are independently selected from the group consisting of: hydrogen, C;-Cs alkyl, C,-Cs alkenyl, and C,-Cs alkynyl. More preferably, R* and

R%® are independently selected from hydrogen and C;-Cg alkyl. .

Preferred R* Groups

A preferred R* group is NR*R™.

Also preferred, is an R*® group selected from the group consisting of:

RA. RAN AN AR... AN. ’ o Ns

Ned (ed Lv hoa

R

R .

OF BEES 3 ore Or

N-0 N= Nd N-N N-N

R H

OR R. RO, Ne S-N A

Q N N p4 | CN

R R R

Or S ~N Na 6 \ i nN: LJ “N ’ 9 a= Ae rl Me aL A NI $l $) ) ~N ) 0 S —A —Ax a ad Li 2S a Ne ~N N-N ARN - - ’ 7 4 N~

LJ ia 11 ie 43 Lx rl Je a NR R A R he FOO oy

N BR N Ad

Ig ~ $ 7 °N N° NS wherein R is independently selected from the group consisting of: halogen, Co-Cs alkylalcohol, hydrogen, C;-Cs alkyl, C;-Cg alkoxy Co-Cs alkylcycloalkyl , Co-Cs alkylheterocyclic, C1-Cs alkylCN, Cy-Cs haloalkyl, Co-Ce alkyINR''R'? , Ci-Cs alkylC(O)NR'R'2 and C;-Cs alkylC(O)OR'!. Still more preferred is an R group : independently selected from the group consisting of: hydrogen, C;-Ce alkyl, Cr-C¢ alkylNH,, and C,-C; alkylalcohol.

Preferably, R* is selected from C;-Cs alkylaryl, C;-Cs alkylheterocyclic, wherein the heterocyclic and aryl groups are optionally substituted with 1-3 groups selected from the group consisting of: hydroxy, oxo, cyano, -SC;-Cg alkyl, C,-Cg alkyl, C,-Cs alkenyl,

Ci-Cg alkynyl, C;-Cg haloalkyl, halogen, and -OC;-Cg alkyl. More preferably, R*® is benzyl mono or disubstituted with C;-Cs haloalkyl. Still more preferably R® is 3,5- bistrifluorobenzyl. -

Preferred R® groups

R’ is preferably selected from a group consisting of: hydrogen, halogen, C;-Cs alkyl, C,-Cg haloalkyl, -OC-Cs alkyl, -Oaryl, -OC,-Cs alkenyl, -OC;-Cg haloalkyl,

CH,NR'R®, -NH;, -N(C-C4 alkyl)z, -CN, and -NO,. Also preferred are any two R’ groups which combine to form an optionally substituted 5, 6, or 7-member ring fused with the phenyl ring to which they are attached, wherein the 5, 6, or 7-member ring is saturated, partially unsaturated, or fully unsaturated and optionally contains 1, 2,0r3 heteroatoms independently selected from O, N, and S. Optional substituents for the 5, 6, or 7-member fused ring discussed above include preferably, halogen, C-Cs alkyl, C;-Cs haloalkyl, C,-Cs alkoxy, aryloxy, -OCy-Cs alkenyl, -OC\-Cg haloalkyl, -CH,NR'R, -

NH, -N(C;-C3 alkyl), -CN, and -NO;.

Preferred R® groups

Preferred R® groups are independently selected from a group consisting of: hydrogen, C;-Cs alkyl, C,-Cs alkenyl, C3-Cg cycloalkyl, C;-Cs alkylhydroxy, phenyl, and

C,-Cg¢ alkoxy.

Preferred R’ and R®

Preferred R and R® groups are independently selected from a group consisting of: hydrogen, Ci-Cs alkyl, C2-Cs alkenyl, C1-Cs alkylaryl, and C,-Cs alkylheterocyclic, wherein each aryl group is optionally substituted with 1-3 groups independently selected from C1-Cs alkyl, halogen, and C;-Cs haloalkyl.

Preferred R'! and R"

Preferred R!! and R'? groups are independently selected from a group consisting of: hydrogen, C,-Cs alkyl, C2>-Cs alkenyl, C;-Cs alkylaryl, and Ci-Ce alkylheterocyclic, wherein each aryl group is optionally substituted with 1-3 groups independently selected from C;-Cs alkyl, halogen, and C;-Cs haloalkyl.

A particularly preferred compound of the invention is selected from the group consisting of: (S)-(3,5-B istrifluoromethylbenzyl)-(1-cyclopentylmethyl-7 -methyl-8-trifluoromethyl- 2,3.,4,5-tetrahydro-1H-benzo[b] azepin-5-y1)-(2-methyl-2H-tetrazol-5 -yl)amine, 5.[(3,5-Bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-7-methyl-8- rifluoromethyl-2,3,4,5-tetrahydro-benzo[ bazepine-1-carboxylic acid isopropyl ester, (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl- 2H: tetrazol-5-yl)-amino}-7-methyl-8- trifluoromethyl-2,3 4,5-tetrahydro-benzo[blazepine- 1-carboxylic acid ethyl ester, (S)-5-((3,5-Bis-triftuoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- : trifluoromethyl-2,3 4,5-tetrahydro-benzo[blazepine-1-carboxylic acid isopropyl ester, (S)-5-{(3 _5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-y})-amino}-7-methyl-8- trifluoromethyl-2,3 4,5-tetrahydro-benzo[b)azepine-1-carboxylic acid tert-butyl ester, (S)-5-[(3,5-B is-trifluoromethyl-benzyl)-(2-methy)-2H-tetrazol-5-yl)-amino} -7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bjazepine-1-carboxylic acid 1-ethyl-propyl ester, (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]- 7-methyl-3- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepine-1-carboxylic acid cyclopentyl ester, (S)-5-[(3,5-Bis-trifinoromethyl-benzy})-(2-methyl-2H-tetrazol-5-y})-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepine-1-carboxylic acid 1-ethyl-2-methyl- propyl ester,

(8)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino)-7-methyl-3- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepine-1-carboxylic acid tetrahydro-pyran-4-

yl ester,

(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-7-methyl-8- trifluoromethyl-2,3 4,5-tetrahydro- 1H-benzo[b)azepin-5-yl)-amino}-tetrazol-2-yl }- ethanol, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-ethy)-7-methyl-8-trifluoromethyl-2,3,4,5- tetrahydro-1H-benzo{b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bjazepin-1-ylmethyl } -cyclohexyl)-acetic acid, (S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-7-methyl- 8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[blazepin-1-yl }-3,3-dimethyl-pentanoic acid, (S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl- 8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin-1-yl }-ethanol, (+/-)-9-{(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino)-2,2-difluoro-6,7,8,9- tetrahydro-1,3-dioxa-5-aza-cyclohepta[flindene-5-carboxylic acid isopropyl ester, (+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,2~ difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta flindene-5-carboxylic acid isopropyl ester,

(+/-)-Isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(1 H-tetrazol-5-yl)-amino]-8-chloro- 2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate,

(+/-)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-8- chloro-2,3,4,5-tetrahydrobenzo[b)azepine-1-carboxylate,

(+/-) isopropyl -6-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino}-2,3,6,7,8,9- hexahydro-1H-10-aza-cyclohepta[e}indene-10-carboxylate, (+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9- hexahydro- 1 H-5-aza-cyclohepta|f]indene-5-carboxylic acid isopropyl ester, (+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9- hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester, (+/-)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(5-methyl-1H-pyrazol-3-yl)-amino]-8- chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate,

+/-)-isopropyl 5-[(3 S.bistrifluoromethyl-benzyl)-(5-methyl-isoxazol-5-yl)-amino}-8- chloro-2,3 4,5-tetrahydrobenzo[b]azepine-1-carboxylate, (+/-)-isopropy! 5-{(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H -tetrazol-5-yl)-amino}-9- methyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[blazepine-1-carboxylate, (S)- 6-(3.5-Bis-trifluoromethyl-benzy))-(2-methyl-2H-tetrazol-5-yl)-amino] -4-methyl- 2.3.6.7.8,9-hexahydro-1H- 10-aza-cyclohepta[e}indene-10-carboxylic acid isopropyl ester, (S)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-8,9- dimethyl-2,3 4,5-tetrahydrobenzo[b]azepine-1-carboxylate, (S)-isopropyl 5-{ (3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yIl- amino}-8,9-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-catboxylate, (S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-2,3,6,7.8,9- hexahydro-1H-5-aza-cyclohepta[flindene-5-carboxylic acid tert-butyl ester, (S)- 3,5-B is-trifluoromethyl-benzyl)-(5-cyclopentylmethyl- 1,2,3,5,6,7,8,9-octahydro-5- aza-cycloheptaf]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (5)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-3,5,6,7,8,9-hexahydro-1H-2- oxa-5-aza-cyclohepta[flinden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-5-{9-{(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}- 1,3 6,7,8,9-hexahydro-2-oxa-5-aza-cycloheptalf}inden-5-y] }-3,3-dimethyl-pentanoic acid, (S)-5-(9-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl}- amino}-1 3,6,7.8,9-hexahydro-2-oxa-5-aza-cycloheptalflinden-5-y1)-3 ,3-dimethyl- pentanoic acid, (S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-y)-amino}-1,3,6,7.8,9- hexahydro-2-oxa-5-aza-cycloheptaff]indene-5-carboxylic acid isopropyl ester, (3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-2,3 4,5,7,8,9,10-octahydro-1H- naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-anine, 5.[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-2,3,4,5.7,8,9,10- octahydro-naphtho[2,3-b]azepine-1-carboxylic acid isopropyl ester, (S)-9-{(3,5-B is-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl}-amino }- 2.3.6,7,8,9-hexahydro-1H-5-aza-cyclohepta(flindene-5-carboxylic acid isopropyl ester, (R)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-2,3,6,7 ,8,0- hexahydro-1H-5-aza-cyclohepta[flindene-5-carboxylic acid isopropyl ester,

(S)-9-[(3 5. Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3 ,6,7,89- hexahydro-1H-5-aza-cycloheptafflindene-5-carboxylic acid isopropyl ester, (S)-6-{(3,5-Bis-trifluoromethyl-benzyl)- [2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl}-amino }- 2,3,6,7 8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester, (S)-6-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-cthyD)-2H-tetrazol-5-yl]-amino}- 4-methyl-2,3,6,7,8,9-hexahydro-1H-10-aza-cycloheptafelindene- 10-carboxylic acid isopropyl ester, (5)-9-[(3.5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-y))-amino}-2,3.,6,7,8,9- hexahydro-1H-5-aza-cyclohepta[f}indene-5-carboxylic acid 2-methoxycarbonyl-2- methyl-propyl ester, (S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H:tetrazol-5-yl)-amino}-2,3,6,7,8,9- hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid 2-carboxy-2-methyl-propyl ester, (S)-1-{5-[(3,5-B is-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5- yl)-amino)-7-methyl- 8. trifluoromethyl-2,3 4,5-tetrahydro-benzo[blazepin-1-y1}-3-furan-2-ylmethoxy)-propan- 2-one, | : 2-{5-1(3,5-B is-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-y1)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazep in-1-y1}-1-phenyl-ethanol, 2-{5-[(3,5-B is-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino] -7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bjazepin- 1-y1}-2-phenyl-ethanol, (S)-4-{5-1(3,5-B is-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl- 8-trifluoromethyl-2,34,5-tetrahydro-benzo{blazepin-1-ylmethyl} -benzoic acid methyl ester, (S)-4-{ 5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino] -7-methyl- 8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin- 1-ylmethyl }-benzoic acid, (S)-3-{5-{(3,5-B is-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl- 8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl }-benzoic acid methyl ester, (S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl- 8-trifluoromethyl-2,3,4,5-tetrahydro-benzo(b] azepin-1-ylmethyl}-benzoic acid, (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl- 8-trifluoromethyl-2,3 4,5-tetrahydro-benzo[bjazepin-1-yl }-benzoic acid,

4-{5-[(3,5-B is-trifluoromethyl-benzyl)-(3 -methyl-isoxazol-5-yl)-amino] -7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo{blazepin-1-ylmethy }-cyclohexyl)-acetic acid methyl ester, (4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3 -methyl-isoxazol-5-yl)-amino] -7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzofblazepin-1 -ylmethyl}-cyclohexyl)-acetic acid, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-trifluoromethyl- 2,3 4 5-tetrahydro-1H-benzo[bJazepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-trifluoromethyl- 23 4,5-tetrahydro-1H-benzo[blazepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine hydrochloride, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-3-ylmethyl-8-trifluoromethyl- 2.3 4,5-tetrahydro-1H-benzo[bjazepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7 -methyl-8-trifluoromethyl- 2,3,4,5-tetrahydro- 1H-benzo[b]azepin-5-y1)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-2-{5-((3,5-Bis-trifluoromethyl-b enzyl)-(2-methyl-2H-tetrazol-5-yl)-amino] -7-ethyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin-1-yl} -ethanol, (S)-(2-{5-[(3 5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-ethyl- 8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[blazepin-1-yl} -ethyl)-carbamic acid tert-butyl ester, (S)-4-{5-[(3.5-B is-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-ethyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b] azepin-1-ylmethyl }-benzoic acid, (S)5-{9-[(3,5-B is-triftuoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}- 1,3 6.7.8.9-hexahydro-2-oxa-5-aza-cycloheptalflinden- 5-ylmethyl }-thiophene-2- carboxylic acid, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(5-pyridin-4-yimethyl- 3,5,6,7 8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-y})-amine, (S)-(4-{9-[(3,5-B is-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}- 1,3,6,7 8.9-hexahydro-2-oxa-5-aza-cyclohepta[flinden-5-ylmethyl }-cyclohexyl)-acetic acid, (S)-2-{ 9-[(3,5-Bis-trifluoromethyl-benzy!)-(2-methyl-2H-tetrazol-5-yl)-amino]- 1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl} -ethanol,

(S)-9-[[2-(2-Amino-ethyl)-2H-tetrazol-5-y1]-(3,5-bis-trifluoromethyl-benzyl)-amino}- 1,3,6,7 ,8,9-hexahydro-2-oxa-5-aza-cycloheptalf] indene-5-carboxylic acid tert-butyl ester, (S)- [2-(2-Amino-ethyl)-2H-tetrazol-5-y1]-(S-benzyl-3 ,5,6,7,8,9-hexahydro- 1H-2-oxa-5- aza-cyclohepta(flinden-9-yl)-(3,5-bis-trifluoromethyl-benzyl)-amine, (S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-y11-(3,5-bis-trifluoromethyl-benzy})-[5-(3.3,3- triftuoro-propyl)-3,5,6.7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta(flinden-9-yl)-amine, (S)-5-{ 5-{(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]- 2.3,4,5,7.8,9,10-octahydro-naphtho[2,3-bJazepin-1-y1}-3 ,3-dimethyl-pentanoic acid, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl- 11-methy!-2,3,4,5,7,8,9,10- octahydro- 1H-naphtho[2,3-bazepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-5-{5-1(3 5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl- 8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin- 1-ylmethyl}-thiophene-2-carboxylic acid, : (8)-5-{5-[(3,5-B is-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino} -7-methyl- 8-triflusromethyl-2,3,4,5-tetrahydro-benzo[bjazepin- 1-ylmethyl}-2-methyl-propionic acid ethyl ester, (S)-(3.5-Bis-trifluoromethyl-benzyl)-(1,7-dimethyl-8-trifluoromethyl-2,3.4,5-tetrahydro- 1H-benzo[bJazepin-5-y1)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-(3,5-B is-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-y1)-(7 -methyl-1-thiazol-2- ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro- 1H-benzo[blazepin-5-yl)-amine, (S)-(3,5-Bis-trifluoromethyl-benzyl)-[7 -methyl-1-(1-methyl-1H-imidazol-2-ylmethyl)-8- trifluoromethyl-2,3 4, 5-tetrahydro-1H-benzo[blazepin-5-yl]-(2-methyl-2H-tetrazol-5-yl)- amine, (S)-(1-Benzyl-7-methyl-8-trifluoromethyl-2,3 4,5-tetrahydro-1H-benzo[bJazepin-5-y1)- (3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-5-{5-[(3,5-B is-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5 -yl)-amino]-7-methyl- 8-trifluoromethyl-2,3,4,5 -tetrahydro-benzo[b]azepin- 1-ylmethyl}, (S)-(4-{5-((3 5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-y1)-amino) -7- methyl-8-trifluoromethyl-2,3 4,5-tetrahydro-benzo[bazepin-1-ylmethyl } -phenyl)-acetic acid, (S)-4-{ 5.[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl- 8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b] azepin-1-yl}-butyric acid,

(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-ylrethyl- 8-trifluoromethyl-

2,3,4,5-tetrahydro- 1H-benzo[bjazepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-7- methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[blazepin-1-ylmethyl }-piperidin-1-yl)- acetic acid ethyl ester, (S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-7- methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[blazepin-1-ylmethyl }-piperidin-1-yl)- acetic acid, (S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-7-methyl- 8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[blazepin- 1-y! }-2-methyl-propionic acid, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl- 1-pyrrolidin-2-ylmethyl-8- trifluoromethyl-2,3,4,5-tetrahydro- 1 H-benzo[blazepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)- amine, (S)-{5-{(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzofb]azepin-1-yl }-acetic acid, (S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl}-[1-(2-benzyloxy-ethyl)-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[blazepin-5-yl}-(3,5-bis-trifluoromethyl- benzyl)-amine, (8)-2-{5-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl}-(3,5-bis-trifluoromethyl-benzyl)-amino)- 7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin-1-yl } -ethanol,

: (S)-5-[[2-(2- Amino-ethyl)-2H-tetrazol-5-y1]-(3,5-bis-trifluoromethyl-benzyl)-amino)-7- methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[blazepine-1-carboxylic acid tert-butyl ester, (S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-y1}-(3,5-bis-trifluoromethyl-benzyl)-(7-methyl-1- thiazol-2-ylmethyl-8-trifluoromethyl-2,3 ,4,5-tetrahydro- 1H-benzo[bJazepin-5-yl)-amine, (S)-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino)-7- methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[blazepin-1-yl }-ethoxy)-acetic acid, (S)-Acetic acid 2-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)- amino]-7-methyl-8-trifluvoromethyi-2,3,4,5-tetrahydro-benzofblazepin- 1-yl }-ethyl ester, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-[ 7-methyl-1-(2H- tetrazol-5-ylmethyl)-8-trifluoromethyl-2,3,4,5-tetrahydro- 1H-benzo[bJazepin-5-yl}- amine,

(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepine-1-carboxylic acid 2-amino-ethyl ester, (S)-5-[(3 5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-7-methyl-8- trifluoromethyl-2,3 4,5-tetrahydro-benzo[blazepine-1-carboxylic acid 2-carboxy-2- methyl-propyl ester, (S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl}-(3,5-bis-trifluoromethyl-benzyl)-(1- cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3 4,5-tetrahydro-1H-benzo{bJazepin-5- yl)-amine,

S)-[2-(2 -Amino-ethyl)-2H-tetrazol-5-y1}-(3 ,5-bis-trifluoromethyl-benzyl)-(1- cyclopropylmethyl-7 -methyl-8-trifluoromethyl-2,3 4,5-tetrahydro- 1H-benzo{bJazepin-5- yl)-amine hydrochloride, and pharmaceutically acceptable salts solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof.

The geometric isomers associated with the double bonds and the optical isomers associated with asymmetric carbon atoms of compounds of Formula I are also contemplated to be within the scope of the current invention as useful for the treatment of diseases related to CETP modulation.

Synthesis of Compounds of the Invention

The compounds of the instant invention can be synthesized as exemplified in the following Schemes, Examples, and procedures. Anthranilate intermediates of Formula 1 can be chemically prepared, for example, by following the synthetic routes set forth in the

Schemes below. However, the following discussion is not intended to limit the scope of the present invention in any way because one of skill in the art is able to extrapolate without undue experimentation from the Schemes and Examples herein to other specific compounds within the scope of the invention. Many of the reagents and starting materials can be readily obtained from commercial suppliers and are readily available to one of ordinary skill in the art. Other reagents and starting materials may be made by procedures which are selected from standard techniques of organic and heterocyclic chemistry, techniques which are analogous to the syntheses of known similar reagents or starting materials, and the procedures described in the preparations and Examples below, including any novel procedures. This includes, but is not limited to, esterification of a:

carboxylic acid, hydrolysis of a nitrile to a carboxylic acid, and subsequent esterification.

The R, R1, R2, R3, R4, RS, R6, etc, designations used within this section for the purpose of illustrating the various methods of synthesizing compounds of the invention and/or illustrating variability of substituents at the pendent position are not necessarily synonymous in scope or meaning with similar groups used in the generic structure for compounds of Formula I. However, groups in final compounds of the schemes occupying similar positions are co-extensive in scope and meaning compared to groups occupying similar positions as defined for the generic structure of compounds of Formula

L

Intermediate Preparation Scheme 1 0]

R De

RD N R4

R5 . 1

Rl Re RS RI R6

Pe + rN TT CX _R5 r2 > °F R2™ 2 3 4 R6 Zon 1 R6 = CO,R3

In intermediate preparation Scheme 1, the nucleophilic aromatic substitution occurs by methods known ‘in the art, (Wells, K. M. et al. Tetrahedron Letters, 1996, 37(36), 6439-6442). The appropriately substituted amine is dissolved in a suitable solvent, such as DMF or DMSO, with a base, such as cesium carbonate, and the appropriately substituted benzonitrile or fluoro benzoate (R6 = CN or CO,R3). The reaction proceeds at 0 °C to elevated temperatures (up to or about 150 °C) in anywhere from ten minutes to several days depending on the stability of the starting materials and/or reaction conditions. The product of structure 4 (R6 = CN) or 1 (R6 = CO,R3) can then be isolated by a standard aqueous workup, followed by normal phase chromatographic methods or recrystallization techniques commonly employed in the art, : Intermediate Preparation Scheme 2

R1 RG RS A R6

LL pee (XX RS

R2 Br, | R2 IN 8 6 R4 4 R6=CN : 1 R6= CO,R3

In intermediate preparation Scheme 2, the N-aryl coupling occurs by methods known in the art, (Hartwig, J. F. et al. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046- 2067). The appropriately substituted amine is dissolved in a suitable solvent, such as

DMF, with a base, such as cesium carbonate or sodium tert-butoxide, the appropriately substituted benzonitrile or haloalkyl benzoate (R6 = CN or COzR3), and a suitable catalyst complex, such as palladium acetate and diphenyl phospino ferrocene. The reaction proceeds at 0 °C to elevated temperatures in anywhere from ten minutes to several days depending on the stability of the starting materials. The product of structure 4 (R6 = CN) or 1 (R6 = CO,R3) can then be isolated by a standard aqueous workup, followed by normal phase chromatographic methods or recrystallization techniques commonly employed in the art.

Intermediate Preparation Scheme 3

R1 Br R1 i Aa pe RE ed

R2 nN R2 N’ . R4 ; R4

In intermediate preparation Scheme 3, the carbonylation occurs by methods known in the art, (Heck, Palladium Reagents in Organic Synthesis; Academic Press: New

York, 1985, p. 348-358). The appropriately substituted aryl bromide is dissolved in a suitable solvent, such as DMF, with a base, such as cesium carbonate or sodium tert- butoxide, a suitable catalyst complex such as palladium acetate and dipheny! phospino ferrocene, an appropriate alcohol (R3-OH) and saturated with carbon monoxide. The reaction proceeds at 0 °C to elevated temperatures (up to or about 150 °C) in anywhere from ten minutes to several days depending on the stability of the starting materials and/or reaction conditions. The product of structure 1 may then be isolated by a standard aqueous workup, optionally followed by normal phase chromatographic methods or recrystallization techniques commonly employed in the art.

Intermediate Preparation Scheme 4

Ri Br R1 i o R3

Ln R2 No ; R4 ,

In intermediate preparation Scheme 4, the aromatic carboxylation occurs by methods known in the art, (Boger, D. L. et al, Journal of Organic Chemistry, 1994, 59(17), 4943-4949, Volpin et a), Organomet. Reactions, 1975, 5, 313-386). The appropriately substituted aryl bromide is dissolved in a suitable solvent, such as diethyl ether or tetrahydrofuran, with an alkyllithium, such as n-butyl lithium or zert- butyl lithium or magnesium turnings. The resulting anion is quenched with a suitable carbon dioxide source, such as dry ice, or dimethyl carbonate. The reaction proceeds at about 78 °C to about room temperature in anywhere from about five minutes to several hours depending on the stability of the starting materials. The product of structure 1 can then be isolated by a standard aqueous workup, followed by normal phase chromatographic methods or recrystallization techniques commonly employed in the art.

Intermediate Preparation Scheme 5

RY RR COOR

Rea p-TsCl, pyr. be il K,COs, oY R,

NAR Of NPG R, NT" C00R 1 i 64 broimate Br ~~CoOR ss PG :

Re=Re =H 55

Q Q t+BuOK, A §._ coor RY "2 toluene HCI, HOAC PPA or TMS!

N N N R

+ R ! . 2

PG 47 : PG 5 59

R'COCI, base; (0) HO

R'CO,H, _ — carbodiimide reagent; N Ni

R, Pz

A, RS 64 65

Synthetic Scheme 5 shows preparation of exemplary precursor compounds for

Formula I. For example, substituted arylamino esters 1 that are either commercially : available or prepared as set forth in the literature or in Schemes 1 to 4 can be protected with tosyl chloride, isopropyl chloroformate, or other suitable protecting group to provide 54. The compound 54 may in turn be alkylated with appropriately substituted, or unsubstituted 3-bromoethylesters 55 thus affording 56. Dieckmann condensation- cyclization of intermediate 56 yields N-protected benzazepinone 57, which is subjected to acid hydrolysis and decarboxylation to afford ketone derivatives 58. Removal of the protecting group, if necessary, with acid (e.g. PPA (polyphosphoric acid)), TMSI (trimethylsilyliodide), or HCI provides the intermediate 59. N-acylation of 59 by treatment with an appropriately substituted aryl or alkyl chloroformate in the presence of an organic base such as pyridine affords carbamates of structure 64. Alternatively, treatment of 59 with an acid chloride or an appropriate activated ester, affords compounds of formula 64. The intermediate benzazepin-5-ones may be reduced with a reducing :

agent such as sodium borohydride in an appropriate solvent, such as tetrahydrofuran or methanol, to achieve the benzylic alcohol 65 as shown in Scheme S.

Scheme 6 o H LG ’ NaBH, MsCl or TsCl, base

Rs — BR; —_— Rs

N MeOH, rt N Ph,P/CBr, Ng 64 R, 65 R, 66 2

Ay AS, R ro

R

RCA) 1. Lewis acid ®

NH, 2. reduction R w base

R o LL, 8

NH LG n A ‘al

EE ———— a

R

C0) base or R=

N A, Mitsunobu 6 N 68 rt o 67 rR ° Pa

AA) = optionally substituted heterocyclic amine

NH,

Compounds of Formula I may be prepared as shown in Schemes 6 and 7, in which reductive amination chemistry is utilized. Formation of a Schiff base of benzazepin-5- ones 64 with a heterocyclic amine is followed by treatment with a reducing agent such as sodium borohydride in an appropriate solvent, such as tetrahydrofuran or methanol, to achieve the heterocyclic amine adducts. Further elaboration by reaction with an activated benzylic reagent in the presence of base or the use of a Mitsunobu-type displacement reaction affords the corresponding product, a compound of the invention. Alternatively, the benzazepin-3-ones (64) may be reduced to the corresponding carbinol intermediate with a reducing agent such as sodium borohydride in an appropriate solvent, such as tetrahydrofuran or methanol. These adducts may be converted directly to provide disubstituted amine products using the Mitsunobu protocol, or initially converted to activated templates such as a mesylate, tosylate or bromide and displaced with the heterocyclic-substituted benzylamine to achieve trisubstituted amine products as shown in

Scheme 6. A preferred group of potential heterocyclic R-A substituents has been described supra.

Scheme 7

RA :

A. AF a, Pod 550 ROS LET IS ®) R { R, 1. Lewis acid Rs N base of Rs N

R; 0 2. reduction A A R, Mitsunobu p A R. 64 ro to 69 67

A reverse procedure for forming the disubstituted amine is shown in Scheme 7.

Formation of a Schiff base of benzazepin-5-ones (64) with a benzylic amine is followed by treatment with a reducing agent such as sodium borohydride in an appropriate solvent, such as tetrahydrofuran or methanol, to achieve the disubstitued benzylic amine adduct 69. Further elaboration by reaction with an activated heterocylic reagent in the presence of base (or alternatively, Schiff base formation with a heteroaromatic aldehyde followed by reduction) provides a secondary route to disubstituted amine products 67.

Scheme 8 3 a)

R R

NH NH

Ow transformation

N R R — >» R

EN > 2 1. Lewis acid s N 3 " } 2. reduction R 64 A — 2 R A Ry

A 68 “0

Le) R base R Is 9 R or Mitsunobu N

Rd, fa = optionally substitued heterocyclic amine

R NH,

A

La 59 Ey RO} R £0) R NH p tansformation J

Rs A —_— a]

R base N Fe 2 N

Ro At 4 Re : ee 66 67 to * 7

Compounds of Formula I may also be prepared by. transformation of pendant functionality as shown in Scheme 8. Disubstituted amine products, such as, 68 in which the moiety R-A corresponds to reactive functionality such as cyano, carboxylate, and the like may be transformed into heterocyclic moieties such as 71 in intermediate stages of synthesis or at the end of the synthetic preparation. Also, the order of N-substitution may be reversed as shown above. Procedures for transforming pendant functionalities wherein

R-A corresponds to reactive functionality such as nitrile, carboxylate, etc are known to one of skill in the art and may be found in general organic and/or heterocyclic chemistry reference text such as but not limited to Comprehensive Organic Transformations, 2M, ed., by Richard Larock, Wiley-VCH, Publishers, New York.

Scheme 8a a :

Rr R. jor Dy

Hi re OHC R Ne A Neel

N CNBr ad Ra TR ——— EIOH, Hig _ A n° or Misunete ad fe I) { R; RCOCHRX v A; R,

I VE Ao 73 or PhOCN 1. Bu,SnN, of NaN3 HON,

RCOC) 2. RX or ROH

Hee

O—N

AY SN a rT ya Na

R R . \ o R BN av] Rs R

Ry N as R a R, at Fa to ' 0 A, 73b 73d 73 RT : eh .

R

73e oy Fe :

Scheme 8a shows a few examples of transformation reactions to illustrate inter- conversion of functionalities as means of preparing compounds of the invention. Detailed procedures are disclosed in the examples, known to one of skill in the art or may be readily sourced from reference sources by one of skill in the art.

Scheme 9

BR R

Q HN Je! w (3

R ESO 1. amine source 0) R CHO o Ise R

Cad Re 2- reduction . A ol 2 reduction . A Re 64

NOW | base BOW | base

A A Sy : . £0) R CHO R £0) R

N 1. Lewis acid N 68 gr A R, 2. reduction a A R, 67

A JON = Optionally substituted heterocyclic + leaving group

Compounds of the Formula I may also be prepared as shown in Schemes 9 and 10, in which the intermediate benzazepin-5-ones are transformed into benzylic amine adducts. This may be achieved by a number of methods, including reductive amination with a primary amine surrogate (such as, hydroxylamine, hydrazine, ammonium chloride, benzophenoneimine, among others), to provide a primary amine, as shown in Scheme 9, or may be incorporated into the ring construction sequence, as shown in Scheme 10, by chemistry known to one of ordinary skill in the art (Hadden, M.; Nieuwenhuyzen, M.;

Potts, D.; Stevenson, P. J.; Thompson, N. Tetrahedron 2001, 57, 5615; Crousse, B.;

Begue, J.-P.; Bonnet-Delpon, D. J Org Chem 2000, 65, 5009). Schiff base formation by treatment of the amine with a benzaldehyde is followed by treatment with a reducing agent such as sodium borohydride in an appropriate solvent, such as tetrahydrofuran or methanol, to achieve the benzylic amine adducts (or alternatively, displacement of an activated benzylic substrate, such as a mesylate, tosylate or bromide) provides the benzylamine product. This is followed by treatment with an activated heteroaryl (heterocyclic aryl) substrate, such as a mesylate, tosylate or bromide in the presence of a base to produce dibenzylic products, as shown in Scheme 9. In a reverse fashion, formation of a Schiff base of benzazepine-5-amines with a heteroaromatic aldehyde,

followed by treatment with a reducing agent such as sodium borohydride in an appropriate solvent, such as tetrahydrofuran or methanol (or alternatively, displacement of an appropriately activated heteroaryl substrate, such as a mesylate, tosylate or bromide) achieves the benzylic heteroaromatic amine adduct. This is followed by treatment with an activated benzylic substrate, such as a mesylate, tosylate, or bromide, in the presence of a base to produce dibenzylic products, as shown in Scheme 9.

Scheme 10

R

A) o 0 Ra R “N R

Alkylation Ra A » Steps 3b

R; Rg ——e R;

N N N

R R

Rl, a Ard, 64 79 Ce

In Scheme 10, compound 64 can be treated with a base, such as sodium hydride or

Jithium diisopropylamide or lithium bis(trimethylsilyl)amide, in a solvent, such as DMF or tetrahydrofuran. Alkylation with the appropriately substituted halide or mesylate or tosylate may form compound 79 where R3a and R3b can be the same or different.

Conversion of 79 to 67 is as described, for example in scheme 9.

Scheme 11

R R

R R

Ne = N=N _

RN N N=N oo Ne Pi Py © OR; Add S ~ R,CHO -

N -— Rg —

R Rs

A, : R,COCH MR, Ac N or (R,CO),0 H iat a IR 73d 80 ! 82 triphosgene

R,OH of \ / CICO,CCl,

R R

N=N

Ne Ay : by i: 2 0a 81

As shown in Scheme 11, compound 73d may be hydrolyzed to the corresponding amine 80, and may be further acylated using standard procedures known or determined by one skilled in the art to provide 73d. Or alteratively, 80 can be treated with triphosgene or trichloromethylchoroformate to provide 81. Compound 81 can afford compound 73d by reaction with the appropriate alcohols. Also, compound 80 can be alkylated by methods known in the art such as treating 80 with base and an alkyl halide, tosylate or the like, to afford 82. Alternatively compound 82 can be obtained using reductive amination conditions.

© -37-

Scheme 12

R R R R

{ w-NP, ( Yn NH,

NN, bi

MN

N MR

P,N(CH,),-OH oY R, RY Fe

P,N(CH,)X yd 84 85

R R

R R

NN (),-CN iN NIN

N .

Nn — Aon

NC(CH,),-X R

N or

REV NETS NR pl—-Y 83

P,O(CH,),-OH HO(CH,)-X 86 or .

P,O(CH,In-X

R R

7, (,~OP, 7 ; ),~OH

NN, NTN, {NO IN

NN 5 No

TD TD

N N

AY R, r'-Y R, 87 88

As shown in Scheme 12, tetrazole 83 can be alkylated with the appropriate protected aminoalcohol under Mitsunobu conditions or with the appropriate protected aminoalkylbromide, iodide, mesylate, or the like in the presence of base to provide a protected aminoalkyltetrazole 84. Removal of the protecting group, P1, using methods well known in the art can yield compound 85. Alternatively, tetrazole 83 can be alkylated with the appropriate alkylcyano bromide or with the appropriate acrylonitrile under

Michael reaction conditions. Cyano derivative 86 can be then reduced to the corresponding amine 85. Tetrazole 83 can be alkylated using the appropriate alcohol under Mitsunobu conditions, or with the appropriate alkyl halide or the like in the presence of base to provide 87. Removal of P1 (protecting group) using methods well known in the art can yield compound 88. Alternatively hydroxyalkyltetrazole 88 can be obtained by alkylation of 83 with the corresponding halide in the presence of base.

Scheme 14

R

) : J) :

R; — R; S— ® @

N N R le) 5 uo : uo, N o wuo—, 89 90 91

AR R ne : ne ny 0) . meee

Rs Rs N

N

0 RY

Re H 93 92

As shown in Scheme 14, compound 89 can be oxidized to compound 90 with ruthenium oxide in presence of sodium periodate. Compound 90 can be converted to 91 as is described, for example in scheme 9. Deprotection of tertbutoxycarbonyl group by methods well known in the art, can afford amide 92. Alkylation of 92 with the appropriate alkyl halide or tosylate or the like in presence of a base, can give rise compound 93,

Scheme 15 af RLi Po _o

Ee for TEA TR

NHBoc 94 Sd os cat. 0s0,, NalO, . fo} 0

FS OR IS OR

—— R ——— ei Rs ) NHBoc oH TFA NH, OH 97 R 98 ae . 0)

IS EE sg RE — Rg: — A; TTR

OH 3

R,CHO NH 0 No

C, Le nr 99 100 3

As shown in Scheme 15, jodoaryl derivative 94 can be transformed in ketone 95 by lithium exchange reaction followed by addition of a Weinreb amide. Then conversion of compound 95 in the aldehyde 96 and oxidation to the corresponding carboxylic acid can afford compound 97. Hydrolisis of amino protecting group and reductive amination reaction can give rise to compound 99, which can be cyclize to compound 100. Finally compound 93 can be obtained as is described in scheme 14.

Assay

The following assay protocol and result(s) thereof demonstrating the utility and efficacy of the compounds and/or methods of the current invention are given for the purpose of illustration and are not meant to be limiting in any way.

In Vitro CETP Inhibitor Assay: SPA ASSAY

An in vitro Scintillation Proximity Assay (SPA) has been used to evaluate the ability of compounds of this invention to inhibit the transfer of radiolabeled cholesterol esters between HDL and LDL. This assay monitors the inhibition of the transfer of [*H]cholesterol esters from HDL (Amersham) to biotinylated LDL (Amersham) by a

: “0.

CETP source. The CETP source for this assay can be produced by AV-12 cells that have been created to express human CETP. The radiolabeled cholesterol ester is transferred in a HEPES-NaCl based buffer, after thirty minutes incubation the reaction is stopped and the biotinylated LDL is bound to streptavidin/scintillant coated SPA beads (Amersham).

The radioactive signal is measured in a Packard 96-well scintillation TopCounter with window settings fully open. A decrease in radioactive signal from the LDL relative to a standard indicates the ability of compounds to inhibit the activity of CETP. Preferred compounds of the invention evaluated according to this assay protocol exhibit CETP inhibition at concentrations of less than 100 micromolar. : Alternatively, other CETP sources can be used to mediate the transfer of radiolabeled cholesterol ester in this assay. For example, endogenous CETP from human plasma, CETP from mice that express human CETP, and endogenous CETP from hamsters can be used as the CETP source in this assay.

Buffers other than HEPES-NaCl based buffer can be used in this assay, for example, human plasma, mouse plasma or a Tris-bufer that is high in albumin may be used.

It will be understood by those skilled in the art that other sources of radioactivity may be used to track the CETP activity in this assay.

Additionally, radio labeled-LDL may be used in this assay.

In Vivo Assay of CETP Activity.

Syrian Golden Hamsters, which express endogenous CETP, can be used to assess the activity of the compounds in vivo. Test compounds are administered orally in selected aqueous or oil based vehicles for up to one week. At various times after dosing, ranging from 4h to 48h, blood/plasma can be obtained. The CETP activity can be determined by a method similar to that described above for the in vitro CETP activity assay, with the modification that plasma from the treated animals is used as the CETP source in the assay.

A strain of transgenic mice that express human CETP (Taconic, Germantown,

NY) can also be used to test compounds of this invention. Test compounds can be administered orally in selected aqueous or oil based vehicles for up to one week. At various times after dosing, ranging from 4h to 48h, blood/plasma can be obtained. The

CETP activity can be determined by a method similar to that described above for the in vitro CETP activity assay, with the modification that plasma from the treated animals is used as the CETP source in the assay.

Alternatively, a strain of transgenic mice that express both human CETP and human apolipoprotein A-1 (Taconic, Germantown, NY ) can be used to test compounds of this invention. Test compounds can be administered orally in selected aqueous or oil based vehicles for up to one week. At various times after dosing, ranging from 4h to 48h, blood/plasma is obtained. CETP activity can be determined by a method similar to that described for the in vitro CETP activity assay, with the modification that plasma from the treated animals is used as the CETP source in the assay.

In Vivo Assay of Plasma Lipids

Activity of compounds of this invention in vivo can be evaluated by comparing the level of elevation of HDL cholesterol relative to a control by a given amount of a compound in a CETP-containing animal species. A strain of transgenic mice that express both human CETP and human apolipoprotein A-1 (Taconic, Germantown, NY) can be used to evaluate compounds of this invention. Test compounds are administered to the animals once orally in selected aqueous or oil based vehicles. At various times after dosing, ranging from 4h to 24h, blood is obtained. The blood is allowed to clot, and serum is obtained from the clotted blood by centrifugation. The HDL cholesterol levels in the serum can be determined by known procedures using HDL-C plus reagents (Roche/Hitachi, Indianapolis, IN) with a clinical chemistry analyzer (Roche/Hitachi,

Indianapolis, IN). Additional serum lipids can be analyzed by enzymatic methods.

Lipids in the VLDL, LDL and HDL fractions are analyzed by enzymatic methods after precipitation or size exclusion chromatography. An example of the elevation of HDL cholesterol levels at 8hr after administration are summarized in Table 1.

Table 1

Elevation of HDL cholesterol levels at 8 hr

No. (mg/kg) increase

The efficacy of compounds of the invention in vivo can also be evaluated utilizing

Syrian Golden Hamsters. The compounds can be tested in hamsters made hypercholesterolemic by feeding a high fat high cholesterol diet for a minimum of two weeks or in non-hypercholesterolemic hamsters fed normal chow for two weeks. Test compounds can be administered orally in selected aqueous or oil based vehicles for up to 1 week. Serum from the animals can be obtained, and lipids can be analyzed by enzymatic methods. Lipids in the VLDL, LDL and HDL fractions can be analyzed by known enzymatic methods after precipitation or size exclusion chromatography.

Alternatively, a strain of transgenic mice that expresses human CETP (Taconic,

Germantown, NY) can be used to test the efficacy of the compounds of this invention.

The hCETP mice can be made hypercholesterolemic by feeding a high fat chow diet such as TD 88051, as described by Nishina et al. (J Lipid Res., 31, 859-869 (1990)) for at least two weeks before the start of the study. Test compounds can be administered orally to the animals in selected aqueous or oil based vehicles for up to 1 week. Serum can be obtained from the animals. Lipids from the serum can be analyzed by enzymatic methods. Lipids in the VLDL, LDL and HDL fractions are analyzed by enzymatic methods after precipitation or size exclusion chromatography. :

Method of Treatment

As used herein, the term "effective amount” means an amount of compound of the present invention, i.e., Formula J, which is capable of alleviating the symptoms of the various pathological conditions herein described. A specific dose of a compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the case including, for example, but not limited to: the compound administered, the route of administration, the state of being of the patient, and the pathological condition being treated. A typical daily dose will contain a nontoxic dosage level of from about 0.01 mg to about 1000 mg/day of a compound of the present invention. Preferred daily doses generally will be from about 1 mg to about 250 mg/day.

The compounds of this invention may be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds preferably are formulated prior to administration, the selection of which will be decided by the attending physician. Thus, another aspect of the present invention is a pharmaceutical composition comprising an effective amount ofa compound of Formula I, or a pharmaceutically acceptable salt thereof, solvate, prodrug, enantiomer or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. The total active ingredients in such formulations comprises from 0.1% to 99.9% by weight of the formulation.

The term “pharmaceutically acceptable” as used herein means that the carrier, diluent, excipients and salt are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Pharmaceutical formulations of the present invention may be prepared by procedures known in the art using well-known and readily available ingredients. For example, the compounds of Formula I can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like.

Non limiting examples of excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl-pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium, and magnesium stearate, and solid polyethyl glycols.

The compounds also may be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suited to formulation as sustained release dosage forms and the like. The formulations can be so constituted that they release the active ingredient only or preferably in a particular physiological location, possibly over a period of time. The coatings, envelopes, and protective matrices may be made, for example, from polymeric substances or waxes.

Compounds of Formula I, generally, will be administered in a convenient formulation as determined by the attending physician. The following formulation examples are only illustrative and are not intended to limit the scope of the present invention. " Formulations

Compounds of the invention may be formulated following one or more of the formulation examples, procedures, protocols or mixing ratios below. In the formulations which follow, the term “Active Ingredient” as used herein means a compound of Formula

I, a salt, solvate, racemate, enantiomer diastereomer, mixture of diastereomers, prodrug thereof, or a combination of a compound of Formula I and other effective agents for the treatment or prevention of dyslipidemia, atherosclerosis, or other co-morbid conditions and symptoms.

Formulation 1: Gelatin Capsules

Hard gelatin capsules can be prepared according to the following:

EU —

Ingredient Quantity (mg/capsule)

ES

Active ingredient 0.1-1000

Starch, NF 0-650

Starch flowable powder 0-650

Silicone fluid 350 centistokes 0-15

The formulation above may be changed in compliance with the reasonable variations provided. :

Formulation 2: Tablets

A tablet formulation, each tablet containing 2.5 — 1,000 mgs of active ingredient, can be prepared using the ingredients below:

Ingredient Quantity (mg/tablet)

Active ingredient 2.5- 1000

Cellulose, microcrystalline 200 - 650

Silicon dioxide, fumed 10 - 650

Stearate acid 5-15

EET Ee SSeS aad

The components are blended and compressed to form tablets.

Formulation 3: Tablets

Alternatively, tablets, each containing 125 - 1000 mg of active ingredient, can be - prepared according to the following:

I,

Ingredient Quantity (mg/tablet)

Active ingredient 25 - 1000

Starch 45

Cellulose, microcrystalline 35

Polyvinylpyrrolidone 4 (as 10% solution in water)

Sodium carboxymethyl cellulose 4.5

Magnesium stearate 0.5

Talc 1

The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and thoroughly blended. The solution of polyvinylpyrrolidone is mixed with the blended powders. The blended powders are then passed through a No. 14 mesh U.S. sieve and pelletized or formed into granules. The granules so produced are dried at 50°- 60° C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are then added to the granules, which after mixing, are compressed on a tablet machine to yield tablets.

Formulation 4: Suspensions

A suspensions containing 0.1 - 1000 mg of medicament per 5 m! dose can be prepared as follows: — ged Quy (mgm)

Active ingredient 0.1 - 1000 mg

Sodium carboxymethyl cellulose . 50mg

Syrup 125mg

Benzoic acid solution 0.10 mL

Flavor q.v.

Color q.v.

Purified water to 5mL

The active ingredient is passed through a No. 45 mesh U.S. sieve and then blended with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with an amount of purified water and added, with stirring to the paste. Sufficient purified water is then added to provide the suspension with the desired volume (or concentration).

Formulation 5: Aerosol

An aerosol solution can be prepared as follows: ee

Ingredient Quantity (% by weight) —

Active ingredient 0.25

Ethanol 25.75

Propellant 22 (Chlorodifluoromethane) 70.00

The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30 °C, and transferred to a filling device. The desired amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container.

Formulation 6: Intravenous Solution

A solution suitable for intravenous administration can be prepared as follows: ee

Ingredient Quantity a

Active ingredient 50 mg

Isotonic saline 1,000 mL

EE Ed

A solution comparing the above ingredients can be intravenously administered to a patient at a rate of about 1 mL per minute or as prescribed by a physician.

Examples

Compounds of the invention may be prepared following or in analogy to one or more of the Examples and procedure below.

Example 1

Synthesis of (+/-)-Isopropyl 5.[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2 H-tetrazol-5- yl)amino]-7-bromo-2,3,4,5-tetrahydrobenzo[blazepine-1-carboxylate.

N=N CF,

AC

N

Br

CF, hy og L.

Step 1. Preparation of Methyl 5-bromo-2-isopropoxycarbonylaminobenzoate.

Cre

LL

00

Add isopropyl chloroformate (36.9 mL, 36.9 mmol, 1.0 M in toluene) dropwise to a solution of methyl 2-amino-5-bromobenzoate (5.0 g, 24.6 mmol) and pyridine (80.0 mL, 36.9 mmol}) in dichloromethane (80 mL) at room temperature under an atmosphere of nitrogen and stir for 1.5 h. Pour the reaction into water (100 mL) and separate the layers.

Extract the aqueous layer with dichloromethane (2 x 40 mL) and combine the organic extracts and wash with 2 N hydrochloric acid, saturated sodium hydrogen carbonate, and brine (80 mL each). Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to afford the title compound as a pale yellow solid (6.68 g, 86%). 'H NMR (CDCl) & 1.31 (d, J = 6.3 Hz, 6H), 3.92 (s, 3H), 5.03 (septet, J = 6.3 Hz, 1H), 7.61 (dd, /= 1.9, 8.5 Hz, 1H), 8.11 (d, / = 1.9 Hz, 1H), 8.40 (d, J = 8.5 Hz, 1H), 10.31 (br s, 1H). ESIMS m/z 316 [C,H 4BrNO; + H]*.

Step 2. Preparation of Methyl 5-bromo-2-[isopropoxycarbonyl-(3- methoxycarbonylpropyl)aminoJbenzoate.

Cr : Neo iP

Heat a suspension of methyl 5-bromo-2-isopropoxycarbonylaminobenzoate (10.0 g, 31.6 mmol), methyl 4-bromobutyrate (22.9 g, 126 mmol) and cesium carbonate (41.6 g, 126 mmol) in N, N-dimethylformamide (150 mL) under nitrogen at 80 °C for 24 h. Cool the mixture to room temperature and pour into water (200 mL). Extract with ethyl acetate (3 x 100 mL) and wash the organic extracts with water (3 x 100 mL) and brine (100 mL).

Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a colorless oil (11.8 g, 89%). 'H NMR (CDCl;, 300 MHz) 8 1.05-1.07 (m, 4H), 1.30-1.32 (m, 2H), 1.89-1.94 (m ,2H), 2.38-2.44 (m, 2H), 3.46-3.60 (m, 1H), 3.65 (s, 3H), 3.68-3.79 (m, 1H), 3.86 (s, 3H), 4.85-5.01 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 1.7, 8.4 Hz, 1H), 8.07 (brs, 1H); ESIMS m/z 416 [C7H22BINOg + HI.

Step 3. Preparation of (+/-)-Isopropyl 7-bromo-5-0x0-2,3,4,5-tetrahydrobenzo[ b]azepine- 1-carboxylate.

Q

By 0 ol

Add a solution of methyl 5-bromo-2-[methoxycarbonylpropyl)amino] benzoate (11.7 g, 28.1 mmol) in toluene (100 mL) to a suspension of potassium tert-butoxide (6.31 g, 56.2 mmol) in toluene (100 mL) at 70 °C under an atmosphere of nitrogen over a period of 30 min.

After 15 min, cool the mixture to room temperature and pour the suspension into ice water (500 mL). Adjust the pH of the solution to pH =3 with 2 N hydrochloric acid (25 mL) and separate the layers.

Extract the aqueous layer with ethyl acetate (3 x 200 mL) and combine the organic extracts.

Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to provide (+/-)-1-isopropyl-4- methyl-7-bromo-5-ox0-2,3,4,5-tetrahydrobenzo [b}azepine-1,4-dicarboxylate as an orange oil (10.5 g, 98% crude). Dissolve (+/-)-1-isopropyl-4-methyl-7-bromo-5-oxo- 2,3,4,5-tetrahydrobenzo (blazepine-1,4-dicarboxylate (10.5 g, 27.3 mmol) in glacial acetic acid (100 mL) and add water (10 mL) followed by concentrated hydrochloric acid (35 mL) and heat the resulting solution at reflux for 1 h.

Cool the mixture to room temperature and pour into ice water (500 mL). Adjust the to pH = 8 with potassium hydroxide (85 g) in water (200 mL), and extract the mixture with ethyl acetate (3 X 150 mL) and combine the organic extracts.

Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure.

Dissolve the crude material (12.0 g) in dichloromethane (30 mL) and cool to 0 °C.

To the solution add pyridine (2.0 mL, 25.5 mmol) followed by dropwise addition of 1.0 M solution of isopropyl chloroformate in toluene (19.1 mL, 19.1 mmol) and stir for 1.5 h.

Pour the reaction into water (100 mL) and separate the layers.

Extract the aqueous layer with dichloromethane (2 X 40 mL) and combine the organic extracts and wash with 2 N hydrochloric acid, saturated sodium hydrogen carbonate, and brine (80 mL each). Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure.

Chromatograph the residue over silica gel eluting with hexanes/ethyl acetate (60:40), to afford the title compound as a yellow solid (3.5 g, 40% over three steps). '"H NMR (CDCl3, 300 MHz) § 1.30 (d, J = 6.2 Hz, 6H), 2.09-2.21 (m, 2H), 2.75- 2.79 (m, 2H), 3.75-3.80 (m, 2H), 5.05 (septet, J = 6.2 Hz, 1H), 7.38 (m, 1H), 7.61 (dd, J = 1.9, 8.5 Hz, 1H), 7.67 (m, 1H), 7.98 (d, J = 8.5 Hz, 1H); ESI MS m/z 326 [C4H,sBrNO; + HJ".

Claims (20)

1. _ 283 PCT/US2005/022389 may combine to form an optionally substituted 5, 6, or 7-member fused ring with the phenyl ring (A-ring) to which they are attached, wherein the 5, 6, or 7-member fused ring is saturated, partially unsaturated, or fully unsaturated and optionally contains 1, 2, or 3 heteroatoms independently selected from O, N, and S; R® is independently selected from a group consisting of: hydrogen, C,-C¢ alkyl, C,-Cs alkenyl, hydroxy, COR’, C,-Cs alkoxy, aryloxy, -OC,-Cs alkenyl, -OC;-Cs haloalkyl, C,-C¢ alkyINR’R®, C3-Cj cycloalkyl, heterocyclyl, aryl, C,-Cg alkyl-O-C(O)NR'R®, C,-Cg alkyl- NR’C(O)NR'R® and C,-C alkylcycloalkyl; R’ and R® are each independently selected from a group consisting of: hydrogen, C,-Cs alkyl, C,-Cs alkenyl, C,-Cy alkynyl, -OC;-Cy alkyl, C,-C¢ haloalkyl, -O-aryl, -OC;3-Cg cycloalkyl, -O-heterocyclyl, -NR'R8, -C,-C alkylcycloalkyl, -OC,-Cs alkylcycloalkyl, -OC,-Cg alkylheterocyclyl, C;-Cg alkylheterocyclyl, -O-C,-Cq alkylaryl, Cs-Cg cycloalkyl, heterocyclyl, aryl, and C,-Cq alkylaryl, wherein each alkyl, cycloalkyl, heterocyclic or aryl group is optionally substituted with 1-3 groups independently selected from hydroxy, CN, halogen, C,-Cq alkyl, C;- Cs alkoxy, C;-Cs haloalkyl, and -NR! R12 or R” and R® combine to form a nitrogen containing heterocyclic ring which having 0, 1, or 2 additional heteroatoms selected from oxygen, nitrogen and sulfur and wherein the nitrogen-containing heterocycle is optionally substituted with oxo or C,-Cs alkyl; R' R' and R'? are independently selected from a group consisting of hydrogen, C,-C alkyl, C,-C¢ alkenyl, C3-Cg cycloalkyl, heterocyclyl, aryl, C;-Cq alkylaryl, wherein each alkyl, aryl, cycloalkyl, and heterocyclic group is optionally substituted with 1-3 groups independently selected from halogen, C,-Cs alkylheterocyclyl, and C,-C haloalkyl, or R'' and R'? combine to form a nitrogen containing heterocyclic ring which may have 0, 1, or 2 additional heteroatoms selected from oxygen, nitrogen or sulfur and is optionally substituted with oxo, C,-Cs alkyl, COR’, and -SO;R’; or a pharmaceutically acceptable salt, enantiomer, racemate, diastereomer or mixture of diastereomers thereof.
2. 2. A compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, racemate, diastereomer or mixture of diastercomers thereof, wherein p is 1. AMENDED SHEET

   ® 284 PCT/US2005/022389
3. 3. A compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, racemate, diastereomer or mixture of diastereomers thereof, wherein n, m, and q are independently 0, or 1.
4. 4. A compound according to claim 1 wherein pis 1, nis 0, Y is C(O), and R' is selected from a group consisting of: hydroxy, C;-Cg alkyl, Cy-Cs alkylcycloalkyl, Co-Cs alkylheterocyclyl, C,-Cs haloalkyl, Cy-Cy alkylaryl, -Oaryl, -OC;-Cs haloalkyl, -OC,-C¢ alkylcycloalkyl, -OC3-Cg cycloalkyl, -OC,-Cs alkyleycloalkyl, -NR’R®, -OC,-Cg alkyl, -O C,-Cs alkylaryl, -OC;-Cs cycloalkylCO,R'"!, and -OC;-Cs alkylheterocyclyl; and wherein each alkyl, cycloalkyl, aryl, or heterocyclyl is optionally substituted with 1 or 2 groups selected from halogen, Cy-Cs hydroxyalkyl, Cy-Cs alkyINR' R12 Co-C5 alkylCOOH, cyano, and Cy-C; alkylC(O)OC;-C; alky,l or a pharmaceutically acceptable salt, enantiomer, racemate, diastereomer or mixture of diastereomers thereof.
5. 5. A compound according to claim | wherein pis 1, nis 0, Y is a bond, and R'is selected from a group consisting of: C;-Cg alkyl, Cy-Cs alkylcycloalkyl, Ci-Cg alkylheterocyclyl, C,-Cs haloalkyl, Co-Cy alkylaryl, C;-Cs alkylcycloalkylNR'R®, C;-Cs alkylCO,R!!, C}-C alkylcycloalkylCO,R'!, C,-Cq hydroxyalkyl, and -INR’R®; and wherein each alkyl, cycloalkyl, aryl, or heterocyclyl is optionally substituted with 1 or 2 groups selected from halogen, Cy-C; hydroxyalkyl, Co-C; alkyINR''R'2, Cy-C; alkylCOOH, -CONHj, and cyano, or a pharmaceutically acceptable salt, enantiomer, racemate, diastereomer or mixture of diastereomers thereof.
6. 6. A compound compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, racemate, diastereomer or mixture of diastercomers thereof, wherein p is 1, R™* and R* are both hydrogen and R* is NR**R*®; wherein R*" is 3,5-bistrifluoromethylbenzyl and R* is selected from the group consisting of: AMENDED SHEET

   285 PCT/US2005/022389 R N .N .N NTS N° R< RAN 0 Nd or NTF hy R R RE (LN are OF N-O RN N_d N-N N-N R H R R R Da Pa "Non J fo) J J N 7 N RN \ —& \ Le A Le Lhe ek Fate i SU 2 Jy, ee - - R R R ON $ N-N 0 $ 0 $ A NM Ry 3, ~L, re re N-N N~N N-N N-o N-g % 4 8 N- a a R R R R N R pS RSS AS SW & Wn 47 \ ~~ N \ R- ZN N74 SN ~ \ ~ Nx R R < R SP NY Ax wherein each R is independently selected from the group consisting of: halogen, Co-C¢ hydroxyalkyl, hydrogen, C;-Cg alkyl, C,-C¢ alkoxy Cy-Cs alkylcycloalkyl, Co-Cs alkylheterocyclyl, C;-Cg alkylCN, C,-C, haloalkyl, Co-Cs alkyINR''R'2, C,-C alkylC(O)NR''R'?, and C,-Cy alkylC(O)OR'".
7. 7. A compound selected from the group consisting of: (S)-(3,5-Bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-trifluoromethyl- 2,3,4,5-tetrahydro-1H-benzo[bJazepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)amine, 5-[(3,5-Bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl- 2,3,4,5-tetrahydro-benzo[b]azepine- 1 -carboxylic acid isopropyl ester, (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine- 1 -carboxylic acid ethyl ester, (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine- 1-carboxylic acid isopropyl ester, AMENDED SHEET

   ®

   286 PCT/US2005/022389 (8)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methy!-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester, (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJ]azepine- 1-carboxylic acid 1-ethyl-propyl ester, (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepine- 1-carboxylic acid cyclopentyl ester, (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid 1-ethyl-2-methyl-propyl ester, (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJ]azepine- 1-carboxylic acid tetrahydro-pyran-4-yl ester, (S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-7-methyl-8-trifluoromethyl- 2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazol-2-yl} -ethanol, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-ethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro- 1 H- benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin- 1-ylmethyl} -cyclohexyl)-acetic acid, (S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin-1-yl}-3,3-dimcthyl-pentanoic acid, (S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin-1-yl}-ethanol, (+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,2-difluoro-6,7,8,9- tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester, (+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,2-difluoro- 6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester, (+/-)-Isopropyl S-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino}-8-chloro-2,3,4,5- tetrahydrobenzo[b]azepine-1-carboxylate, (+/-)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2 H-tetrazol-5-yl)-amino]-8-chloro- 2,3,4,5-tetrahydrobenzo[ b]azepine-1-carboxylate,

   AMENDED SHEET

   ® 287 PCT/US2005/022389

   (+/-) isopropyl -6-[(3,5-bistrifluoromethyl-benzyl)-(1 H-tetrazol-5-yl)-amino]-2,3,6,7,8,9- hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylate, (+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino)-2,3,6,7,8,9-hexahydro- | H-5- aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester, (+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino}-2,3,6,7,8,9- hexahydro-1H-5-aza-cyclohepta[ f]lindene-5-carboxylic acid isopropyl ester, (+/-)-isopropy! 5-[(3,5-bistrifluoromethyl-benzyl)-(5-methyl-1H-pyrazol-3-yl)-amino]-8-chloro- 2,3,4,5-tetrahydrobenzo[ b]azepine-1-carboxylate, +/-)-1sopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(5-methyl-isoxazol-5-yl)-amino]-8-chloro- 2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate, (+/-)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-9-methyl- 8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine- 1-carboxylate, (S)- 6-{(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-4-methyl- 2,3,6,7,8,9-hexahydro-1H-10-aza-cycloheptafe]indene- 10-carboxylic acid isopropyl ester, (S)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2 H-tetrazol-5-yl)-amino]-8,9- dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine- 1 -carboxylate, (S)-isopropyl 5-{(3,5-Bis-trifluoromethyl-benzyl)-[ 2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl}- amino }-8,9-dimethyl-2,3,4,5-tetrahydrobenzo[bJ]azepine- | -carboxylate, (S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9- hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester, (S)- (3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-1,2,3,5,6,7,8,9-octahydro-5-aza- cyclohepta[ flinden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (8)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-3,5,6,7,8,9-hexahydro- 1H-2-0xa-5- aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9- hexahydro-2-oxa-5-aza-cyclohepta[flinden-5-yl} -3,3-dimethyl-pentanoic acid, (S)-5-(9-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl]-amino} - 1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[ f]inden-5-yl)-3,3-dimethyl-pentanoic acid, (S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9- hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester,

   AMENDED SHEET

   ®

   288 PCT/US2005/022389 (3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-2,3,4,5,7,8,9,10-octahydro-1 H- naphtho(2,3-blazepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, 5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3,4,5,7,8,9,10- octahydro-naphtho[2,3-b]Jazepine- I -carboxylic acid isopropyl ester, (5)-9-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl]-amino} - 2,3,6,7,8,9-hexahydro- I H-5-aza-cyclohepta[ f]indene-5-carboxylic acid isopropyl ester, (R)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9- hexahydro-1H-5-aza-cyclohepta[ f]indene-5-carboxylic acid isopropyl ester, (5)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9- hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester, (S)-6-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl]-amino} - 2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene- 10-carboxylic acid isopropyl ester, (S)-6-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl]-amino} -4- methyl-2,3,6,7,8,9-hexahydro-1H-10-aza-cycloheptafe]indene-10-carboxylic acid isopropyl ester, (S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9- hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid 2-methoxycarbonyl-2-methyl-propyl ester, (S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9- hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid 2-carboxy-2-methyl-propyl ester, (S)-1-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino}-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin-1-yl } -3-furan-2-ylmethoxy)-propan-2-one, 2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJ]azepin-1-yl} -1-phenyl-ethanol, 2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin-1-yl} -2-phenyl-ethanol, (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJ]azepin- 1 -ylmethyl} -benzoic acid methyl ester, (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJ]azepin- 1 -ylmethyl} -benzoic acid,

   AMENDED SHEET

   ®

   289 PCT/US2005/022389 (S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[blazepin-1-ylmethyl} -benzoic acid methyl ester, (S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin- 1 -ylmethyl} -benzoic acid, (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin-1-yl}-benzoic acid, (4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin-1-ylmethyl} -cyclohexyl)-acetic acid methyl ester, (4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-mcthyl-isoxazol-5-yl)-amino]-7-methy]-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin- 1 -ylmethyl} -cyclohexyl)-acetic acid, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl- 1-pyridin-4-ylmethyl-8-trifluoromethyl-2,3,4,5- tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl- 1 -pyridin-4-ylmethyl-8-trifluoromethyl-2,3,4,5- tetrahydro-1H-benzo[b)azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine hydrochloride, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl- 1-pyndin-3-ylmethyl-8-trifluoromethyl-2,3,4,5- tetrahydro-1H-benzo[blazepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5- tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2 H-tetrazol-5-yl)-amino]-7-ethyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJ]azepin-1-yl} -ethanol, (S)-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-ethyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin- 1-yl }-ethyl)-carbamic acid tert-butyl ester, (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]- 7-ethyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl} -benzoic acid, (S)5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9- hexahydro-2-oxa-5-aza-cyclohepta([f]inden-5-ylmethyl} -thiophene-2-carboxylic acid, (S)-(3,5-Bis-triflucromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(5-pyridin-4-ylmethyl- 3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[ f]inden-9-yl)-amine, (S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9- hexahydro-2-oxa-5-aza-cyclohepta[flinden-5-ylmethyl} -cyclohexyl)-acetic acid,

   AMENDED SHEET

   _

   290 PCT/US2005/022389 (S)-2-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9- hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl} -ethanol, (S)-9-[[2-(2-Amino-ethyl)-2H-tetrazol-5-y1]-(3,5-bis-trifluoromethyl-benzyl)-amino}-1,3,6,7,8,9- hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester, (S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(5-benzyl-3,5,6,7,8,9-hexahydro- 1 H-2-oxa-5-aza- cyclohepta[ flinden-9-yl1)-(3,5-bis-trifluoromethyl-benzyl)-amine, (S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-[5-(3,3,3-trifluoro- propyl)-3,5,6,7,8,9-hexahydro- 1 H-2-oxa-5-aza-cyclohepta[f]inden-9-yl]-amine, (8)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tctrazol-5-yl)-amino}-2,3,4,5,7,8,9,10- octahydro-naphtho(2,3-bJazepin-1-yl}-3,3-dimethyl-pentanoic acid, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-11-methyl-2,3,4,5,7,8,9,10- octahydro-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin- 1-ylmethyl} -thiophene-2-carboxylic acid, (S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazcpin- 1 -ylmethyl} -2-methyl-propionic acid ethyl ester,

   (S)-(3,5-Bis-trifluoromethyl-benzyl)-(1,7-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro- 1 H- benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl- I -thiazol-2- ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro- 1 H-benzo[b]azepin-5-yl)-amine, (S)-(3,5-Bis-trifluoromethyl-benzyl)-[ 7-methyl-1-(1-methyl- 1 H-imidazol-2-ylmethyl)-8- trifluoromethyl-2,3,4,5-tetrahydro- 1 H-benzo[b]azepin-5-yl]-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-(1-Benzyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro- 1 H-benzo[b]azepin-5-yl)-(3,5-bis- trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJ]azepin- 1-ylmethyl}, (S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]- 7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin- 1-ylmethyl} -phenyl)-acetic acid, (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b)azepin-1-yl} -butyric acid,

   AMENDED SHEET

   ®

   291 PCT/US2005/022389 (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl- 1 -piperidin-4-ylmethyl-8-trifluoromethyl- 2,3,4,5-tetrahydro-1H-benzo[b)azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl} -piperidin-1-yl)-acetic acid ethyl ester, (5)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]- 7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin- 1 -ylmethyl} -piperidin- 1-yl)-acetic acid, (S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepin- 1 -yl}-2-methyl-propionic acid, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl- 1 -pyrrolidin-2-ylmethyl-8-trifluoromethyl- 2,3,4,5-tetrahydro- 1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine, (S)-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl} -acetic acid, (S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-[ 1-(2-benzyloxy-ethyl)-7-methyl-8-trifluoromethyi- 2,3,4,5-tetrahydro- 1 H-benzo[bJazepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-amine, (S)-2-{5-[[2-(2-Amino-ethyl)-2H-tetrazol-5-y1]-(3,5-bis-trifluoromethyl-benzyl)-amino]-7- methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[bjazepin- 1-yl} -cthanol, (S)-5-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-7-methyl- 8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester, (S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-y1]-(3,5-bis-trifluoromethyl-benzyl)-(7-methyl-1 -thiazol- 2-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro- 1 H-benzo[bJazepin-5-yl)-amine, (S)-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl} -ethoxy)-acetic acid, (S)-Acetic acid 2-{5-{(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7- methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJ]azepin-1-yl} -ethyl ester, (S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-[ 7-methyl- 1-(2H-tetrazol-5- ylmethyl)-8-trifluoromethyl-2,3,4,5-tetrahydro- 1 H-benzo[bJazepin-5-yl]-amine, (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methy1-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid 2-amino-ethyl ester,

   AMENDED SHEET

   PCT/US2005/022389 (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8- trifluoromethyl-2,3,4,5-tetrahydro-benzo[bJazepine-1-carboxylic ~~ acid 2-carboxy-2-methyl- propyl ester, (S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-y1]-(3,5-bis-trifluoromethyl-benzyl)-(1- cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro- 1H-benzo[b]azepin-5-yl)- amine, (S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-y1]-(3,5-bis-trifluoromethyl-benzyl)-(1- cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro- 1 H-benzo[blazepin-5-yl)- amine hydrochloride, and pharmaceutically acceptable salt, enantiomer, racemate, diastereomer or mixture of diastereomers thereof.
8. 8. A pharmaceutical composition comprising a compound according to claim 1 and at least one of: a carrier, diluent, and excipient.
9. 9. Use of a compound according to claim 1, for the manufacture of a medicament for treating atherosclerosis in a mammal comprising administering an effective dose of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer, or mixture of diastereomers thereof to said mammal.
10. 10. Use of a compound according to claim 1, for the manufacture of a medicament for treating dyslipidemia in a mammal comprising administering an effective dose of a compound of Formula I, a pharmaceutically acceptable salt, enantiomer, racemate, diastereomer, or mixture of diastereomers thereof to a patient in need thereof.
11. 11. Use of a compound according to claim 1, for the manufacture of a medicament for treating cardiovascular discases in a mammal comprising administering an effective dose of a compound of Formula I, a pharmaceutically acceptable salt, enantiomer, racemate, diastereomer, or mixture of diastereomers thereof to a patient in need thereof.
12. 12. A compound as claimed according to claim 1 or a pharmaceutically acceptable salt, enantiomer, racemate, diastercomer, or mixture of diastereomers, for use in therapy. AMENDED SHEET

    PCT/US2005/022389
13. 13. The compound of claim 10 for use in treating cardiovascular disease.
14. 14. The compound of claim 10 for use in treating dyslipidemia.
15. 15. The compound of claim 10 for treating low plasma levels of HDL-cholesterol.
16. 16. A compound as claimed according to claim 1 or a pharmaceutically acceptable salt, enantiomer, racemate, diastereomer, or mixture of diastereomers, pathological sequelae due to low levels of plasma HDL-cholesterol in a mammal.
17. 17. A compound substantially as hereinbefore described with reference to any of the examples.
18. 18. A compound according to any one of claims | to 7 or 12 to 16, substantially as herein described with reference to and as illustrated in any of the examples.
19. 19. A composition according to claim 8, substantially as herein described with reference to and as illustrated in any of the examples.
20. 20. Use according to any one of claims 9 to 11, substantially as herein described with reference to and as illustrated in any of the examples. AMENDED SHEET