CN1058709C - Amide compounds for medical treatment - Google Patents

Abstract

Compound of formula I:

The definitions of X, Y and Z are as in the instructions, and the compound is used for reducing the secretion of apoB and treating diseases such as atherosclerosis.

Description

Therapeutic amides

The present invention relates to a class of compounds which are inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion and are therefore useful in the prevention and treatment of atherosclerosis and its clinical sequelae To reduce serum lipids, and prevent and treat related diseases. The present invention also relates to compositions containing such compounds and methods of using such compounds to treat atherosclerosis, obesity and related diseases and/or ailments.

Microsomal triglyceride transfer protein (MTP) catalyzes the transfer of triglycerides, cholestenyl esters, and phospholipids, which as a possible factor affects the assembly of Apo B-containing lipoproteins, active molecules, and promotes atherosclerosis Formation of sclerotic lesions, see European Patent Publication Nos. 0 643 057 A1 and 0 584 446 A2, and Wetterau et al., Science, 258, 999-1001, (1992). Compounds that inhibit MTP and/or inhibit Apo B secretion are of course useful in the treatment of atherosclerosis. This compound is also used in the treatment of other diseases including hypercholesterolemia, hypertriglyceridemia, pancreatitis and obesity due to the reduction of serum cholesterol and triglyceride levels due to inhibition of MTP and/or Apo secretion and hypercholesterolemia, hypertriglycerides and hyperlipidemia associated with pancreatitis, obesity and diabetes.

其中：The present invention provides compounds of formula 1 and pharmaceutically acceptable salts thereof:

in:

X is _CH2 , CO, CS or _SO2 ;

Y is selected from:

direct bonds (i.e. covalent bonds),

Aliphatic hydrocarbylene of up to 20 carbon atoms, which may be replaced by hydroxy, (C ₁ -C ₁₀ )alkoxy, (C ₁ -C ₁₀ )acyl, (C ₁ -C ₁₀ )acyloxy or ( C ₆ -C ₁₀ ) aryl monosubstituted,

NH, and O, with the proviso that if X is _CH2 , then Y is a direct bond;

Z is selected from the following groups:

(1) H, halogen, cyano,

(2) Hydroxy, (C ₁ -C ₁₀ )alkoxy, (C ₁ -C ₁₀ )alkylthio, (C ₁ -C ₁₀ )acyl, thienylcarbonyl, (C ₁ -C ₁₀ )alkoxycarbonyl ,

(3) (C ₁ -C ₁₀ )alkylamino, di(C ₁ -C ₁₀ )alkylamino, (C ₆ -C ₁₀ )aryl(C ₁ -C ₁₀ )alkylamino, with the proviso that Y is not O or NH,

(4) Unsubstituted vinyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl and its fused benzo derivatives, (C ₇ -C ₁₀ ) polycycloalkyl , (C ₄ -C ₈ ) cycloalkenyl, (C ₇ -C ₁₀ ) polycycloalkenyl,

(5) (C ₆ -C ₁₀ ) aryloxy, (C ₆ -C ₁₀ ) arylthio, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₁₀ ) alkoxy, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₁₀ ) alkylthio, (C ₃ -C ₈ ) cycloalkoxy, (C ₄ -C ₈ ) cycloalkenyloxy,

(6) A heterocyclic group selected from a monocyclic group and a fused polycyclic group, said group containing a total of 5-14 ring atoms, containing a total of 1-4 independently selected from oxygen, nitrogen and sulfur heteroatoms, each ring of the group may be saturated, partially unsaturated or aromatic, respectively,

with the proviso that if X is _CH2 , then Z is H or a group selected from (4) and (6),

Wherein, when Z contains one or more rings, each ring may independently have 0-4 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, oxo (O =), thio (S=), aminosulfonyl, phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₁₀ )alkoxy, (C ₁ -C ₁₀ )alkoxycarbonyl, (C ₁ -C ₁₀ )alkylthio, (C ₁ -C ₁₀ )alkylamino, (C ₁ -C ₁₀ )alkane Di(C ₁ -C ₁₀ )alkylaminocarbonyl, Di(C ₁ -C ₁₀ )alkylaminocarbonyl, Di(C ₁ -C ₁₀ )alkylamino(C ₁ -C ₁₀ )alkoxy , (C ₁ -C ₃ ) perfluoroalkyl, (C ₁ -C ₃ ) perfluoroalkoxy, (C ₁ -C ₁₀ ) acyl, (C ₁ -C ₁₀ ) acyloxy, (C ₁ - C ₁₀ )acyloxy(C ₁ -C ₁₀ )alkyl and pyrrolidinyl.

Reference to Z as "heterocyclyl" refers to any monocyclic or fused ring system containing at least one ring heteroatom independently selected from O, N and S, thus, so long as the system also contains at least one fused ring (the The fused ring contains at least one of the above-mentioned heteroatoms), and the polycyclic fused ring system containing one or more carbocyclic fused saturated, partially unsaturated or aromatic rings (usually benzo rings) falls within the definition of the above-mentioned heterocycle . As substituents, these heterocyclic rings can be attached to the residues of carbocyclic (eg benzo) or heterocyclic molecules.

Reference to Z containing "one or more rings" refers to any (single or fused ring) ring moiety in Z, which ring may be carbocyclic or heterocyclic, saturated, partially unsaturated, and aromatic or non- fragrant.

Reference to a fused polycyclic ring system or group means that all rings in the system are fused.

Regarding "halogen" in this specification, unless otherwise specified, fluorine, chlorine, bromine and iodine are included.

Reference to an "aryl" substituent (eg (C ₆ -C ₁₀ )aryl) means that the ring or substituent is carbocyclic, as described above, and as a subclass of the term "heterocyclyl" includes those containing one or Aromatic moieties with multiple heteroatoms.

By "acyl" substituent is meant an aliphatic or cyclic hydrocarbon moiety attached to a carbonyl through which the substituent is bonded.

"Alkyl" and "alkoxy" include both straight chain and branched chain groups, but it should be understood that for individual groups such as "propyl" or "propoxy" only straight chain ("normal Chain") groups, branched isomers such as "isopropyl" or "isopropoxy" are specifically indicated.

The central benzo-heterocyclic ring system of formula 1, that is, the fused bicyclic ring system connected to -XYZ through its monocyclic fluorine atom, is generally referred to herein as "1,2,3,4-tetrahydroisoquinoline" when When the compounds of the present invention are named 2-substituted 1,2,3,4-tetrahydroisoquinolin-6-ylamides, it is customary to use it most often. When named as a substituent in a compound, this central ring system is also referred to as a 6-substituted "3,4-dihydro-1H-isoquinolin-2-yl" moiety, a nomenclature that is not often used.

A group of compounds of formula 1 as defined above includes the following compounds and pharmaceutically acceptable salts thereof: wherein:

X is _CH2 , CO, or _SO2 ;

Y is selected from:

Direct key, NH,

(C ₁ -C ₁₀ )alkylene and (C ₂ -C ₁₀ )alkenylene, any of which may be substituted by phenyl, with the proviso that if X is CH ₂ , then Y is a direct bond;

Z is selected from the following groups:

(1) H,

(2) (C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₁₀ ) alkylthio,

(3) (C ₁ -C ₁₀ )alkylamino, di(C ₁ -C ₁₀ )alkylamino, (C ₆ -C ₁₀ )aryl(C ₁ -C ₁₀ )alkylamino, with the proviso that Y is not NH,

(4) Unsubstituted vinyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₄ -C ₈ ) cycloalkenyl,

(5) (C ₆ -C ₁₀ )aryloxy,

(6) selected from saturated, partially unsaturated or aromatic five- and six-membered heterocyclic groups, and fused benzo derivatives thereof, wherein said groups may contain a total of 1-3 independently a heteroatom selected from oxygen, nitrogen and sulfur,

with the proviso that if X is _CH2 , Z is selected from the groups of (4) and (6),

Wherein, when Z contains one or more rings, each ring may independently have 0-3 substituents independently selected from the following: halogen, hydroxyl, nitro, (C ₁ -C ₆ ) Alkyl, (C ₁ -C ₆ )alkoxy, di(C ₁ -C ₆ )alkylaminocarbonyl, (C ₁ -C ₃ )perfluoroalkoxy, (C ₁ -C ₁₀ )acyl and ( C ₁ -C ₁₀ )acyloxy.

A more specific group includes some compounds of the above group and pharmaceutically acceptable salts thereof, wherein X is methylene, Y is a direct bond, and Z is selected from (C ₆ -C ₁₀ )aryl, (C ₃ -C ₈ )cycloalkyl, and (C ₄ -C ₈ )cycloalkenyl, each of which may have 0-3 independent substituents indicated for Z in the above group, unsubstituted vinyl . The specific meaning of each is explained below.

Another more specific group includes some compounds of the above group and pharmaceutically acceptable salts thereof, wherein X is methylene or CO, Y is a direct bond, and Z is selected from the group consisting of thienyl, pyrrolidinyl, pyrrolyl, Furyl, thiazolyl, isoxazolyl, imidazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, and their fused bicyclic (ortho) benzo derivatives, including benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzothiazolyl, quinolinyl, isoquinolyl and quinazolinyl, each of which may be There are 0-3 independent substituents for Z from the above group.

Specific values for Z as heterocyclyl (which may carry 0-3 independent substituents as indicated for Z in the above group) include 2- and 3-thienyl; 2- and 3-benzo[b] Thienyl; 1-, 2-, and 4-imidazolyl; 2-benzoimidazolyl; 2-, 4-, and 5-thiazolyl; 2-benzothiazolyl; 3-, 4-, and 5-isoxazolyl ; 2-quinoxalinyl; 1-, 2- and -3-pyrrolidinyl; 2-, 3- and 4-pyridyl; 2- and 4-pyrimidinyl; 2-, 3- and 4-quinoline 1-, 3- and 4-isoquinolyl; 1-, 2- and 3-indolyl; 1-, 2- and 3-isoindolyl; 2- and 3-tetrahydrofuranyl; 1- , 2- and 3-pyrrolyl; 2- and 3-furyl; 2- and 3-benzo[b]furyl; 1-, 3- and 4-pyrazolyl and 1,2,4-triazole -3-base.

A preferred group of compounds includes the following compounds and pharmaceutically acceptable salts thereof, wherein:

X is _CH2 or CO,

Y is the direct key,

Z is H, unsubstituted vinyl, phenyl, imidazolyl, thiazolyl, thienyl, 1,2,4-triazolyl, pyridyl and pyrimidinyl. Each of them may carry 0-3 independent substituents as indicated in the above group. Specific values for Z (as heterocyclyl) in this preferred group include the corresponding specific values indicated above.

A subgroup within the above preferred group includes those compounds wherein X is CO.

Another subgroup within the above preferred group includes those compounds wherein X is _CH2 .

The present invention also provides a pharmaceutical composition suitable for the treatment of atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia and diabetes, the composition comprising the compound of formula 1 as defined above and a pharmaceutically acceptable carrier.

The compounds of the present invention may inhibit or reduce the secretion of Apo B by inhibiting MTP, although other mechanisms are also possible. The compound is used in any disease in which Apo B, serum cholesterol, and/or triglyceride levels are elevated. Therefore, the present invention also provides a method for treating atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia and diabetes, which method comprises treating a mammal in need of such treatment , particularly human administration of a compound of formula 1 as defined above in an amount sufficient to reduce secretion of apoprotein B. A subgroup of the aforementioned diseases includes atherosclerosis, obesity, pancreatitis and diabetes, and a more specific subgroup is atherosclerosis.

The term "treatment" as used herein includes prophylactic and disease-modifying treatment.

The present invention further provides a method for reducing ApoB secretion in a mammal, especially a human, which method comprises administering a compound of formula 1 as defined above to reduce the amount of Apo B (secretion) in said mammal.

Another aspect of the present invention also provides certain intermediates:

4'-Trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide,

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [3-(2-hydroxyethyl)-4-hydroxymethyl-phenyl]-amide,

It will be appreciated by those skilled in the art that certain compounds of Formula 1 contain asymmetrically substituted carbon atoms and thus can exist and be isolated in optically active and racemic forms. Polymorphism may exist in some compounds. It is to be understood that the present invention includes any racemic, optically active, polymorphic or stereoisomeric form or mixtures thereof which have properties useful in the treatment of atherosclerosis, obesity and other diseases mentioned above , how to prepare optically active forms (for example, by resolution of racemates by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation with chiral stationary phases) and how to use the following criteria Assays to measure the efficacy of treatments for the above-mentioned diseases are well known to those skilled in the art.

Chemists of ordinary skill will recognize that certain substituents or combinations of moieties described in the present invention determine that certain compounds are unstable under physiological conditions (such as those containing amine linkages or acetal linkages). combined compounds), these compounds are not preferred.

"Aliphatic hydrocarbon subgroup" for the purposes of the present invention refers to a divalent open-chain organic group containing only carbon and hydrogen, which as a linking group refers to the above-mentioned Y, which can be straight-chain or branched Chain, and/or saturated or containing up to three unsaturated bonds (double bond or triple bond or mixture thereof), the two valence bonds may be on different carbon atoms or on the same carbon atom, so "alkylene " falls within this definition, and the group is generally classified as (C ₁ -C ₂₀ )alkylene, (C ₂ -C ₂₀ )alkenylene, or (C ₂ -C ₂₀ )alkynylene. Such groups typically contain 1 to 10 carbon atoms, as shown in the Examples, although longer chain groups are indeed possible and are within the scope of the invention.

Alkylene groups include those saturated hydrocarbon groups having 1-20, preferably 1-10 carbon atoms, obtained by removing two hydrogen atoms from corresponding saturated acyclic hydrocarbons, and specific groups containing 1-10 carbon atoms include the formula (CH ₂ )n, where n is a straight chain group of 1-10, such as methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene , octamethylene, nonamethylene, etc., also include alkylene groups such as ethylene, propylene, butylene and sec-butylene, and also include branched chain isomers such as 1,1-dimethyldi methylene, 1,1-dimethyltetramethylene, 2,2-dimethyltrimethylene and 3,3-dimethylpentamethylene.

Alkenylene includes straight-chain or branched groups having 2-20, preferably 2-10 carbon atoms, obtained by removing two hydrogen atoms from the corresponding acyclic hydrocarbon containing at least one double bond, with one double bond Specific alkenylene groups include ethenylene, propenylene, 1-butenylene, 2-butenylene and isobutenylene. Alkenylene groups containing two double bonds (sometimes referred to in the art as alkenylene groups) include 3-methyl-2,6-heptadienylene; 2-methyl-2,4-heptadiene 2,8-nonadienylene; 3-methyl-2,6-octadienylene and 2,6-decadienylene, alkenylene containing three double bonds (chain triadienylene A specific group of alkenyl) is 9,11,13-heptadecatrienylene.

The alkynylene group includes 2-20, preferably 2-10 carbon atoms, a straight-chain or branched chain group obtained by removing two hydrogen atoms from the corresponding acyclic hydrocarbon containing at least one triple bond, and the specific alkynylene group Including ethynylene, propynylene, 1-butynylene, 1-pentynylene, 1-hexynylene, 2-butynylene, 2-pentynylene, 3,3-dimethyl -1-butynylene, etc.

The following are specific groups of other moieties and other substituents named above, but not as limitations on the present invention. It should be noted through the description that, provided no specific points of attachment are indicated for rings or polycyclic groups which can be attached via different ring atoms, all attachment points, whether via carbon atoms or trivalent nitrogen atoms, are possible. For example, (unsubstituted) "naphthyl" refers to naphthalen-1-yl and naphthalen-2-yl; "pyridyl" refers to 2-, 3- or 4-pyridyl; "indolyl" refers to 1-, 2-, 3-, 4-, 5-, 6-, or 7-linked at any position.

Specific groups of (C ₁ -C ₁₀ )alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy, heptyloxy, Oxygen etc.

Specific groups of (C ₁ -C ₁₀ )alkylthio groups include sulfur-containing compounds corresponding to the above-mentioned (C ₁ -C ₁₀ )alkoxy groups, including methylthio, ethylthio, propylthio, isopropylthio , Butylthio, Isobutylthio, Pentylthio, Hexylthio, Heptylthio, etc.

Particular examples of (C ₁ -C ₁₀ )acyl groups include (C ₁ -C ₁₀ )alkanoyl groups such as formyl, acetyl, propionyl, butyryl and isobutyryl, and also other common cyclic acyl groups such as Benzoyl.

Specific groups of (C ₁ -C ₁₀ )acyloxy groups include (C ₁ -C ₁₀ )alkanoyloxy groups such as formyloxy, acetyloxy, propionyloxy, butyryloxy and isobutyryloxy Acyloxy also includes other common cyclic acyloxy groups such as benzoyloxy.

Specific groups of (C ₁ -C ₁₀ )alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl.

Specific groups of (C ₁ -C ₁₀ )alkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino and isobutylamino.

Specific groups of di-(C ₁ -C ₁₀ )alkylamino include dimethylamino, diethylamino, dipropylamino, dibutylamino and diisobutylamino.

Specific groups of (C ₆ -C ₁₀ )aryl(C ₁ -C ₁₀ )alkylamino are benzylamino, (1-phenethyl)amino and (2-phenethyl)amino.

Particular groups of (C ₆ -C ₁₀ )aryl are phenyl and naphthyl.

Particular groups of (C ₃ -C ₈ )cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Specific fused benzo-derived groups of (C ₃ -C ₈ )cycloalkyl include 1,2,3,4-tetrahydronaphthyl, 2,3-indanyl, fluorenyl.

Particular groups of polycycloalkyl groups include adamantyl and 2-bicyclo[2.2.1]heptyl.

Specific groups of (C ₄ -C ₈ )cycloalkenyl include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl.

Specific groups of polycycloalkenyl include bicyclo[3.1.1.]hept-2-enyl.

Specific groups of (C ₆ -C ₁₀ )aryloxy include phenoxy and naphthyloxy.

Specific groups of (C ₆ -C ₁₀ )arylthio include phenylthio and naphthylthio.

Specific groups of (C ₆ -C ₁₀ )aryl(C ₁ -C ₁₀ )alkoxy include benzyloxy and phenethoxy.

Specific groups of (C ₆ -C ₁₀ )aryl(C ₁ -C ₁₀ )alkylthio include benzylthio and phenethylthio.

Specific groups of (C ₃ -C ₈ )cycloalkenyloxy include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy.

Specific groups of (C ₄ -C ₈ )cycloalkenyloxy groups include cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, and cycloheptenyloxy.

Specific examples of heterocyclic substituents for five-membered monocyclic groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl , 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-thiatriazolyl, etc.

Specific groups of heterocyclic substituents for six-membered monocyclic groups include 2H- and 4H-pyranyl, pyridyl, piperidinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl, Thiolinyl, 1,3,5-triazinyl, etc.

Specific groups of heterocyclic substituents of five-membered heterocyclic fused benzo derivatives include indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, benzimidazolyl , benzothiazolyl, and carbazolyl.

Specific groups of heterocyclic substituents of six-membered heterocyclic fused benzo derivatives include quinolinyl, isoquinolyl, quinazolinyl, 2,3-dichloronaphthyl, phenothiazinyl, Acridyl and phenoxazinyl.

Specific examples of the heterocyclic group of the fused polycyclic group include purinyl and pteridyl, in addition to the fused benzo systems listed above.

Specific groups of (C ₁ -C ₁₀ )alkyl include methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, pentyl, hexyl, and the like.

Specific groups of (C ₁ -C ₃ )perfluoroalkyl include trifluoromethyl, pentafluoroethyl and heptafluoropropyl.

Specific groups of (C ₁ -C ₃ )perfluoroalkoxy include trifluoromethoxy and pentafluoroethoxy.

The compounds of the present invention can often be classified according to the linking group formed together by the ring nitrogen atom of the 1,2,3,4-tetrahydroisoquinoline ring (see formula 1) and the group in -XYZ, the above-mentioned group The XYZ moiety is attached to the ring nitrogen atom. These classes include:

Regarding the linking groups mentioned above, Y is preferably a direct bond or an alkylene group for amides and thioamides (X=CO or CS, respectively). In compounds where Y is a direct bond, the bond is preferably through a carbonyl or thiocarbonyl group to an aliphatic (ie open chain) carbon atom in Z. The aliphatic carbon atom may be part of a chain containing one or more heteroatoms. Bonding may also preferably be through a carbonyl or thiocarbonyl group to a ring carbon atom. "Ring carbon atom" means a saturated or unsaturated carbon atom contained in a (saturated, partially unsaturated or aromatic) carbocyclic or heterocyclic ring. For compounds where Y is alkylene, the bond is through the carbonyl or thiocarbonyl group to the aliphatic carbon atom in Y.

For urea or thiourea where X = CO or CS and Y = NH respectively, the bonding is preferably through (as shown in the rightmost part) the amino group to a ring carbon atom in Z, for some ureas and thioureas (X=CO, Y=direct bond), the amino nitrogen of (far right part) is part of Z. In this case, the preferred linkage is through the amino group of the rightmost moiety to the aliphatic carbon atom in the remainder of Z.

For the sulfonamides of the present invention, X=SO ₂ and Y are preferably alkylene, or directly linked. For sulfonamides where Y is an alkylene group, attachment to the aliphatic carbon atom in Y is through the sulfonyl group. For sulfonamides in which Y is a direct bond, attachment to a ring carbon atom in Z is preferably via the sulfonyl group. For sulfonamides where Y is a direct bond, it can also be attached to the NH that is part of Z, in this case via X directly to the amino nitrogen atom in Z.

N-Alkyls (X= _CH2 , Y=direct bond), preferably attached to a ring carbon atom in Z via a methylene group.

For carbamates where X=CO and Y=O, attachment to the ring carbon atom of the residue of Z is preferably via the oxo (O) moiety of the bond. For carbamates where X = CO, Y = direct bond, the oxo chain is part of Z and is preferably attached to a ring or aliphatic carbon atom in the remainder of Z, most preferably to a on an aliphatic carbon atom.

For compounds of formula 1 wherein Y is alkylene, attachment to Z is through an aliphatic carbon atom in Y, preferably an H or ring carbon or heteroatom in Z.

When classifying compounds by groups below and in the Examples, it refers to the classification by the above structures.

Preferred compounds include the following compounds, which are classified as far as possible by the type of linking group shown in the above partial structures. Amides: 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-phenyl-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4 '-Trifluoromethyl-biphenyl-2-carboxylic acid (2-phenoxy-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4'-tri Fluoromethyl-biphenyl-2-carboxylic acid (2-pentanoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl -2-Carboxylic acid (2-cyclobutane-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4'-trifluoromethyl-biphenyl-2-carboxy Acid [2-(thiophen-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2- Carboxylic acid (2-butyryl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-ethoxy Base-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid {2-[(4-fluoro -phenyl)-acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-( 3-Methyl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-butyl -3-enoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-methoxy- Acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-ethylthio-acetyl- 1,2,3,4-Tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(6-diethyl-carbamoyl -cyclohex-3-enecarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (Cyclopent-1-enyl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-Hex-3-enoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2- (Tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(thiophene -3-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, and 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2- (Pyridine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide; Ureas: 6-[(4′-trifluoromethyl-biphenyl-2- Carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenylamide, 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino] -3,4-dihydro-1 H-isoquinoline-2-carboxylic acid hexylamide, 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4- Dihydro-1H-isoquinoline-2-carboxylic acid benzylamide, 6-[(4′-trifluoromethyl-biphenyl-2-carboxylic acid)-amino]-3,4-dihydro-1H -isoquinoline-2-carboxylic acid [(R)-1-phenyl-ethyl]-amide, and 6-[(4′-trifluoromethyl-biphenyl-2-carboxylic acid)-amino] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyridin-2-ylamide; sulfonamides: 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(propane -2-sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-dimethyl Sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl-amide, and 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-trifluoro Methoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide; Thioureas: 4′-trifluoromethyl-biphenyl-2-carboxylic acid ( 2-Cyclopropylthiocarbamoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide; N-alkyls: 4′-trifluoromethyl-biphenyl- 2-Carboxylic acid [2-(2,6,6-trimethyl-cyclohex-2-enylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,4-dichloro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1,5a,6,9,9a,9b-hexahydro-4H-dibenzofuran-4aylmethyl)- 1,2,3,4-Tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-thiophen-2-ylmethyl-1, 2,3,4-Tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-pyrrol-2-ylmethyl)- 1,2,3,4-Tetrahydroisoquinolin-6-yl]-amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid (2-furan-2-ylmethyl-1, 2,3,4-Tetrahydroisoquinolin-6-yl)-amide, acetic acid 5-{6-[(4′-trifluoromethyl-biphenyl-2-carboxylic acid)-amino]-3, 4-dihydro-1H-isoquinolin-2-ylmethyl}-furan-2-ylmethyl ester, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-thiophene-3- Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,5-di Methoxy-tetrahydrofuran-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-pyridine-2 -ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-quinoline-2- Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-chloro-benzyl Base)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-pyrimidin-2-ylmethyl -1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-nitrobenzyl)- 1,2,3,4-Tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-imidazol-2-ylmethyl )-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1-methyl-pyrrole- 2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H- Benzimidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2 -thiazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (1-Methyl-imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2- Carboxylic acid [2-(1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, and 4′- Trifluoromethyl-biphenyl-2-carboxylic acid [(2-allyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide; carbamates: 6- [(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, particularly preferred compounds include: 4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(thiophen-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide , 6-[(4'-trifluoromethyl-biphenyl-2-carboxy)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (1-phenylethyl) -amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid (2-pyridin-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide , 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl] -amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-thiazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide, and 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4- Tetrahydro-isoquinolin-6-yl]-amide.

Common chemical abbreviations and acronyms used in the following discussion are: Me (methyl); Et (ethyl); THF (tetrahydrofuran); BOC (tert-butoxycarbonyl, protecting group); Acyl); TFA (trifluoroacetic acid); Ac (acetyl); RP (reverse phase); HPLC (high pressure liquid chromatography).

Compounds of formula I can be prepared by methods well known in the chemical art including the preparation of analogous compounds. These processes for the preparation of compounds of formula I as defined above provide a further feature of the invention and are illustrated by the following procedures. Wherein unless otherwise specified, the meanings of the general groups are as above. The method involves treating a compound of formula II with a reagent which forms the XYZ moiety on the right side of the molecule, The compound of formula II constitutes the left part of the molecule, (ie the part consisting of the hydrogen in formula II removed from the nitrogen atom of the tetrahydroisoquinoline ring). Reagents that make up the right-hand portion of the molecule are generally commercially available or can be found in the scientific literature. The compound of formula II is 4'-trifluoromethylbiphenyl-2-carboxylic acid (1,2,3,4-tetrahydroisoquinolin-6-yl)amide, which is abbreviated as "compound II" herein for convenience. Constituting the left part of the molecule of the compound of the present invention is the 6-[(4'-trifluoromethyl)biphenyl-2-ylcarbonylamino]-3,4-dihydro-1H-isoquinolin-2-yl moiety.

This method can generally be carried out according to the following steps:

(a) For compounds of formula I wherein X is carbonyl, by treating compound II with a carboxylic acid of formula Z-Y-COOH in the presence of a coupling agent. The coupling agent generally uses carbodiimide, preferably 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, usually abbreviated as EDC, which can be purchased. EDC binds well to polymers as disclosed in USP 5,416,193. The reaction is usually carried out at room temperature in an inert solvent, but heating can be used if necessary. The reaction period is very wide, from a few minutes to 48 hours, usually overnight.

(b) For compounds of formula I wherein X is carbonyl or thiocarbonyl, compound II is treated with the activated form of the corresponding carboxylic acid or thiocarboxylic acid in the presence of a base. Typical activated forms are the corresponding acid chlorides of formula Z-Y-COCl or Z-Y-CSCl, respectively. The base, such as an amine, binds well to the polymer, simplifying the purification procedure. A typical polymer-bound base is bound morpholino-methylpolystyrene. The reaction is usually carried out at room temperature with stirring, shaking or other forms of stirring for a period of time necessary to allow the reaction to proceed to a suitable extent, generally 2-48 hours, typically overnight.

The types of structures formed by the compounds prepared by the methods disclosed in (a) and (b) above are referred to as amides and thioamides.

(c) For compounds of formula I wherein X is carbonyl or thiocarbonyl and Y is NH, prepared by treating compound II with the corresponding isocyanate of formula Z-N=C=O or the thioisocyanate of formula Z-N=C=S, respectively . The structural type of the compound produced is that of the class of compounds referred to herein as urea or thiourea. The reaction is generally carried out in an inert solvent, typically a halogenated hydrocarbon such as 1,2-dichloroethane, and the typical reaction time is 2-48 hours, usually overnight.

(d) Compounds of formula I, wherein X is sulfonyl, are prepared by treating compounds of formula II with the corresponding sulfonyl chloride of formula ZY- _SO2Cl . The reaction is usually carried out in an inert solvent such as a halogenated hydrocarbon (eg 1,2-dichloroethane) at room temperature for several hours or longer, usually overnight.

(e) Compounds of formula I, wherein X is _CH2 and Y is a direct bond, are prepared by treating compounds of formula II with an aldehyde of formula Z-CHO in the presence of sodium triacetoxyborohydride. This is essentially a reductive amination reaction, reported in Abdel-Magid et. al., Tetrahedron Lett, 31(39), 5595-5598 (1990). The products obtained are of the N-alkyl structural type. The reaction is carried out in a suitable solvent, such as a halogenated hydrocarbon, with shaking or stirring, otherwise at room temperature for hours to days, but heating can be used to speed up the reaction rate if necessary.

(f) For compounds _of formula _I where X is _CH2 and Y is a direct bond, by treating a compound of formula to prepare:

(g) Compounds of formula I, wherein X is thiocarbonyl, are prepared by treating the corresponding compound of formula 1, wherein X is CO, with phosphorus _{pentasulfide P4S10} . The reaction is usually carried out using a stoichiometric amount of _P4S10 (excess if desired) and heating with the corresponding amide in an inert solvent such as pyridine _, xylene, benzene, chlorobenzene or toluene. The reaction is usually refluxed for several minutes to several hours to completion.

Compounds of formula II can be prepared as described in Scheme 1, and as illustrated in Example 1. In scheme 1, 2-(4-bromophenyl)ethylamine hydrobromide and ethyl formate react in the presence of a base to generate N-[2-(4-bromophenyl)ethyl]formamide, which The amide is then cyclized by treatment with phosphorus pentoxide in polyphosphoric acid, followed by treatment with hydrogen halide gas (eg, HCl) to form the hydrohalide salt of 7-bromo-3,4-dihydroisoquinoline. Reduction of the hydrohalide gives 7-bromo-1,2,3,4-tetrahydroisoquinoline. The reduced product is then treated with potassium nitrate in concentrated sulfuric acid for nitration and appropriate fractionation to give 7-bromo-6-nitro-1,2,3,4-tetrahydroisoquinoline. The nitrated product is then reacted with di-tert-butyl carbonate in the presence of a base in order to protect the tetrahydroisoquinoline ring nitrogen atom, thus giving 7-bromo-6-nitro-3,4-dihydro-1H-iso Quinoline-2-carboxylic acid tert-butyl ester. Hydrogenation of this ester in the presence of pd/calcium carbonate affords the corresponding 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate. The amine is then reacted with 4'-trifluoromethylbiphenyl-2-carboxylic acid to give 6-[4'-trifluoromethylbiphenyl-2-carbonylamino]-3,4-dihydro-1H -Isoquinoline-2-carboxylic acid tert-butyl ester, the compound is deprotected by conventional methods to obtain compound II, 4'-trifluoromethylbiphenyl-2-carboxylic acid (1,2,3,4- Tetrahydroisoquinolin-6-yl)amide.

Process 1

Alternatively, the compound of formula II can be prepared by the second route shown in scheme 2. In Scheme 2, nitrobenzoic acid (1) is treated with dimethyl malonate in the presence of base to give compound (2). Compound (2) is hydrolyzed and decarboxylated by treating with an aqueous alcohol-base solution to obtain compound (3). If necessary, compound (3) is treated with acetic anhydride in toluene or other hydrocarbon solvents to obtain anhydride (3a). Reduction of compound (3) or (3a) gives the corresponding diol (4), which is treated with methanesulfonyl chloride to give the dimesylate, followed by cyclization with ammonia to give compound (5). Compound (5) is usually N-protected to yield compound (6), which is then reduced to give the corresponding amine (7). Treatment of amine (7) with 4'-trifluoromethylbiphenyl-2-carboxylic acid chloride (prepared by treating the corresponding free acid with thionyl chloride) affords the corresponding amide analog (8) of compound II. As described in Scheme 1, compound (8) is deprotected by conventional methods to obtain compound II.

Process 2

Compounds of formula III can be prepared as described in Scheme 3, starting from diol (4) in Scheme 2. In Scheme 3, the corresponding aminodiol (9) is prepared by reducing the diol (4) with hydrogen in the presence of a platinum/carbon catalyst, and the aminodiol (9) is treated with 4′-trifluoromethylbiphenyl-2- Acid chloride treatment of the carboxylic acid affords compound III, which is then cyclized with ammonia in the presence of a catalyst to afford compound II as indicated.

Scheme 3 also indicates that compound III can also be directly treated with the corresponding amine of formula Z-CH ₂ -NH ₂ in the presence of a base and a catalyst to prepare a compound of formula I, namely formula Ia referred to in scheme 3, wherein X is CH ₂ and Y is the direct key.

Process 3

Common purification separation methods and techniques well known to those skilled in the art can be used to isolate the compounds of the present invention, these techniques include various types of chromatographic techniques (HPLC, column chromatography using common adsorbents such as silica gel and thin layer chromatography) , recrystallization and fractional extraction techniques (such as liquid-liquid extraction).

The compounds of the present application can form cationic salts such as acid addition salts, and are called "pharmaceutically acceptable salts". These salts can be defined as, but not limited to, the following salts: hydrochloride, hydrobromide, sulfate , hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, methanesulfonate and p-toluenesulfonate. For many compounds multiple addition salts are possible.

Acid addition salts of compounds of the present invention are readily prepared by reacting the corresponding acid and base forms of the compound. When the salt is a monobasic acid salt (such as hydrochloride, hydrobromide, p-toluenesulfonate, acetate), a monohydrogen salt of a dibasic acid (such as hydrogen sulfate, succinate) or a tribasic acid When dihydrogen salts (such as dihydrogen phosphate, citrate) are used, at least one molar equivalent of acid is used, and an excess molar amount of acid is usually used. However, when the desired salt is, for example, sulfate, hemisuccinate, hydrogenphosphate or phosphate, the appropriate and precisely stoichiometric acid is generally used. The free base and acid are generally combined in a co-solvent from which the desired salt is precipitated. Or isolated by concentration and/or addition of non-solvent.

The compound of the present invention can be used for oral administration, so it is combined with a pharmaceutically acceptable carrier or diluent to be used in a dosage form suitable for oral administration. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be presented in the form of the pharmaceutical composition in an amount sufficient to provide the desired dosage in the range described below. Thus, for oral administration, the compounds of the present invention can be combined with suitable solid or liquid carriers or diluents to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical composition may also contain other ingredients such as flavoring agents, sweeteners, excipients and the like, if necessary.

Tablets, pills, capsules, etc. may also contain binders such as tragacanth, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants Such as magnesium stearate; sweeteners such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may also be added as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. Syrups and elixirs may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a coloring and flavoring such as cherry or orange.

These active compounds can also be used for parenteral administration. For parenteral administration. The compound can be combined with sterile water or organic medium to prepare injection solution or suspension. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. The dispersion liquid also can be with sesame oil or peanut oil, ethanol, water, polyhydric alcohol (such as glycerol, propylene glycol, liquid polyethylene glycol) and suitable mixture thereof, vegetable oil, N-methylglucamine, polyvinylpyrrolidone and its Mixtures in oil and aqueous solutions of water-soluble pharmaceutically acceptable salts of the compounds of this invention are prepared. Under ordinary conditions of storage and use, these preparations should contain a preservative so as not to allow the growth of microorganisms. The injection solutions prepared by the above method can be used for intravenous, intraperitoneal, subcutaneous or intramuscular administration.

The dosage forms suitable for parenteral administration include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the dosage form must be sterile and must be fluid so that it can be easily filled into a syringe. It must be stable under the conditions of manufacture and storage and must be free from the contamination by microorganisms such as bacteria and fungi.

The dosage of the compound of formula I is changed according to the principles known in the art, and the general principle is to consider the severity of the disease to be treated and the route of administration. In general, when the compound of formula I is used for administration to warm-blooded animals (such as humans), the usual daily effective dose (one administration or several administrations) is, for example, within the range of about 0.1-15 mg/kg body weight. Accepted, preferably about 1-5 mg/kg body weight. The acceptable total daily dose is generally 1-1000 mg, preferably 5-350 mg.

The compounds of the present invention may also be used in combination with other drugs, including other lipid-lowering agents. These drugs include cholesterol biosynthesis inhibitors, particularly HMG CoA reductase inhibitors and squalene synthesis inhibitors; bile acid sequestrants; fibrates; cholesterol absorption inhibitors and niacin.

A test compound is considered active if it is active in any of the screens described below.

The activity of the compounds of the present invention was assessed by measuring the inhibition of apo B secretion in Hep G2 cells.

HepG2 cells were grown in 96-well culture dishes in Dul-becco's Modified Eagles medium with 10% fetal bovine serum (growth medium; Gibco) in a humidified atmosphere containing 5% carbon dioxide until approximately 70% confluent (confluent). Test compounds were dissolved in dimethyl sulfoxide at 10-20 mM and diluted to 1 [mu]M in growth medium. Prepare a series of 1:1 dilutions of this stock solution in growth medium, add 100 μl per well to each well of a 96-well culture dish containing HepG2 cells, collect the growth medium after 24 hours, and pass through a specific ELISA Concentrations of apo B and apo A1 (as controls) were determined. Inhibitors were identified as compounds that reduced apo B secretion in culture medium but did not affect apo A1 secretion. The ELISA operation for apo B is as follows: the monoclonal antibody to human apo B (Ch-emico) is diluted to 5 μg/ml in phosphate-buffered saline/azide (PBS+0.02% sodium azide), at 96 Add 100 μl to each well of a well culture dish (NVNC Maxisorb). After overnight incubation at room temperature, the antibody solution was removed and the wells were washed 3 times with PBS/azide. Non-specific sites on the plastic were protected by incubating the wells in 1% (w/v) bovine serum albumin (BSA, prepared in PBS/azide) solution for 1-3 hours. Various dilutions of 100 μl of growth medium from Hep G2 cells or apo B standard (prepared in 0.004% Tween 20/1% BSA in PBS/azide) were added to each well and incubated for 18 Hour. Wells were aspirated and washed 3 times (0.1% Tween 20 in PBS) before adding 100 [mu]l of a 1/1000 dilution of the secondary antibody [ie goat anti-human apo B (Chemicon)]. After incubation at room temperature for 3 hours, the solution was aspirated and the wells were washed 3 times as above. Rabbit anti-goat 1 gG 100 μl 1:1600 dilution (in PBS/1%BSA/2mM MgCl ₂ ) (Sigma) combined with alkaline phosphate was added to each well and incubated for 1 hour at room temperature, pumped After aspiration, the wells were washed 4 times as described above, and 100 μl of 1 mg/ml p-nitrophenylbenzyl phosphate (pNPP; Sigma) (pH 9.5) in 25 mM NaHCO3/2 mM _MgCl2 was added to each well. and incubate for 20-30 minutes, and stop the reaction by adding 50 μl of 0.2N NaOH. The absorbance of each well was read at 405 nm and the background at 650 nm was subtracted. Apo B concentrations were calculated from a standard curve consisting of purified LDL standards paralleled in the same assay. Apo A1 was determined in a similar manner, except that the apo A1 antibody (Chemicon) was used instead of the apo B antibody, and the incubation of the antigen was performed at 37°C instead of room temperature.

If the test compound directly inhibits the activity of MTP, its activity can also be confirmed.

Compound inhibition of MTP activity can be quantified by observing the inhibition of radioactive triglyceride transfer from donor vesicles to recipient vesicles in the presence of soluble human MTP. The method for preparing MTP is according to the method of Wetterau and Zilversmit (Biochem, Biophys. Acta (1986) 875:610). Briefly, human liver pieces frozen at -80°C were thawed on ice, minced and washed several times with ice-cold 0.25M sucrose. All subsequent steps were performed on ice. A 50% homogenate in 0.25M sucrose was prepared using a Potter-Elvehjem teflon pestle. Dilute the homogenate to 1:1 with 0.25 M sucrose, centrifuge at 10,000×g for 20 minutes at 4°C, resuspend the pellet in sucrose and centrifuge at 10,000×g for 20 minutes, pool the supernatant, pass through Centrifuge at 105,000×g for 75 minutes to pellet the microsomes, discard the supernatant, suspend the pellets of microsomes in the minimum volume of 0.25M sucrose, and dilute to 3ml/per volume with 0.15M Tris-HCl pH8.0 The suspension was divided into 12 portions and centrifuged at 105,000 xg for 75 minutes to determine the initial liver weight. The supernatant was discarded and the microsomal pellets were stored frozen at -80°C until needed. Prior to completing the above experiments, to prepare MTP, suspend the thawed pellet in 12 ml of cold 50 mM Tris-HCl, 50 mM KCl, 5 mM MgCl (pH 7.4), and slowly add 1.2 ml of 0.54% deoxycholate ( pH 7.4) solution in order to disrupt the membranes of microsomes. After incubation on ice with gentle mixing for 30 minutes, the suspension was centrifuged at 105,000 × g for 75 minutes, and the supernatant containing soluble MTP protein was dialyzed for 2-3 days with 4 changes of the assay buffer (150 mM Tris-HCl, 40 mM NaCl, 1 mM EDTA, 0.02% NaN ₃ , pH 7.4) Human liver MTP was stored at 4°C and diluted 1:5 with assay buffer just before use. Formulations of MTP, no significant loss of transfer activity was found when stored up to 30 days.

Liposomes were prepared by sonicating 400 μM egg phosphocholine (PC), 75 μM bovine tallow and 0.82 μM [14C] triolein (110Ci/mol) in assay buffer under a nitrogen atmosphere at room temperature dispersion. Lipids in chloroform were added in appropriate amounts and dried under nitrogen flow before hydration with assay buffer. The preparation of acceptor liposomes was under nitrogen atmosphere, room temperature bath sonication treatment of 1.2mM PC, 2.3μM triolein and 30 PM [3H]-PC (50 Ci/mol) in the test buffer dispersion. The donor and acceptor liposomes were centrifuged at 160,000 xg for 2 hours at 7°C. The upper 80% of the supernatant containing a small number of unilamellar liposomes was carefully removed and stored at 4°C until used in transfer assays.

MTP activity is determined using a transfer assay that begins by mixing donor and acceptor vesicles with soluble MTP and test compound. To 100 μl of 5% BSA (control) or 5% BSA of test compound was added 500 μl of assay buffer, 100 μl of donor liposomes, 200 μl of acceptor liposomes and 100 μl of diluted MTP protein. After 45 minutes of incubation at 37°C, the transfer of triglycerides was terminated by adding 500 μl of 50% (W/V) DEAE cellulose suspension in assay buffer. Stir for 4 minutes. Donor liposomes bound to DEAE cellulose were selectively pelleted by low speed centrifugation. A portion of the supernatant containing acceptor liposomes was counted and the values for 3H and 14C were used to calculate percent recovery of acceptor liposomes and percent triglyceride transfer using first order kinetics. The inhibitory effect of the test compound on triglyceride transfer is expressed as a decrease in 14C radioactivity when compared to a control group not containing the test compound.

The activity of test compounds as inhibitors of MTR can also be determined in vivo according to the test method described below.

Male mice (20-30 g, different species) were dosed (0.25 ml/25 g body weight) with the test compound suspended in 0.5% methylcellulose aqueous solution by oral gavage, and the compound solution was administered over several days. The blood was collected to prepare serum, and the commercial enzyme sample (Triglyceride G; Wako Fine Ch-emicals) was used to identify the triglyceride concentration in the serum. MTP inhibitors are identified by their ability to lower serum triglycerides compared to control mice dosed with vehicle.

The present invention is illustrated by the following examples, but it should be understood that the invention is not limited to the specific details of these examples.

Example 1

This example illustrates the preparation of the intermediate compound of formula II N-[2-(4-bromo-phenyl)-ethyl]-formamide

Combine 500 g (1.78 mol) of 2-(4-bromo-phenyl)-ethylamine hydrobromide, 1 liter (12.4 mol) of ethyl formyl ester and 248 ml (1.78 mol) of triethylamine, and heat to reflux for 3 hours. The reaction was treated with 1 L each of deionized water and ethyl acetate. The organic layer was separated and washed with 1 liter of water and 1 liter of brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give 378 g of solid.

MS(Cl): 245(M+NH ₄ ⁺ ) 7-bromo-3,4-dihydro-isoquinoline hydrochloride

In a 12-liter three-neck round bottom flask, 4 kg of polyphosphoric acid was heated to 150° C. and stirred. To the stirred polyphosphoric acid was added three 530 g (3.75 mol) portions of phosphorus pentoxide at approximately 176.7 g each. After phosphorus pentoxide was dissolved, 378 g (1.66 mol) of N-[2-(4-bromo-phenyl)-ethyl]-formamide was added. The reaction temperature was then raised to 200°C and held for two hours. At this point, the reaction temperature was cooled to 160°C and poured into 16 liters of ice. The mixture was stirred for 0.5 h, basified to pH 12 with 10N sodium hydroxide solution and extracted three times with 3 L of dichloromethane. The combined organic layers were washed with 1 L of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to an oil. The oil was dissolved in 2.5 L of methanol and saturated with anhydrous HCl gas. The resulting solution was concentrated to a volume of one liter and 1 liter of ether was added. The resulting precipitate was filtered, washed with ether and air dried to give 219 g of a solid.

MS(Cl): 210(M+H ⁺ ) 7-bromo-1,2,3,4-tetrahydroisoquinoline

219 g (0.89 mol) of 7-bromo-3,4-dihydro-isoquinoline hydrochloride and 1.5 liters of water were combined and heated to 50°C. 33.7 g (0.89 mol) of sodium borohydride were added portionwise over 0.5 hours, at which point the temperature rose to 62°C. The reaction was then cooled to ambient temperature and extracted three times with 1 L of dichloromethane. The combined organic layers were washed with 1 liter of saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 173 g of an oil.

MS(Cl): 212(M+H ⁺ ) 7-bromo-6-nitro-1,2,3,4-tetrahydroisoquinoline

In a 5-liter three-necked round-bottom flask, 173 g (0.813 mol) of 7-bromo-1,2,3,4-tetrahydroisoquinoline was carefully dissolved in 950 ml of concentrated hydrochloric acid. The resulting solution was cooled to -5°C and a solution of 82.7 g (0.186 mol) of potassium nitrate in 1 liter of concentrated sulfuric acid was added dropwise. After the addition was complete, the reaction was held at -5°C for 15 minutes and poured into 3 liters of ice. The resulting mixture was basified to pH 14 with 50% sodium hydroxide solution. The basic solution was extracted three times with 1 liter of dichloromethane. The combined organic layers were washed with 1 liter of water and 1 liter of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 201 g of an oil. The oily substance pre-adsorbed on silica gel was loaded on a 4kg silica gel column and eluted with a gradient of 1-5% methanol/dichloromethane. Fractions containing product were combined and concentrated to give 115 g of solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (s, 1H); 7.38 (s, 1H); 4.10 (s, 2H); 3.20 (t, 2H); 2.90 (t, 2H). tert-butyl 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate

115g (0.447mol) 7-bromo-6-nitro-1,2,3,4-tetrahydroisoquinoline, 45.2g (0.447mol) TEA, 97.5g (0.447mol) di-tert-butyl bicarbonate, 3.2 liters of dioxane and 0.5 liters of water were combined and stirred at ambient temperature for 1.5 hours. The reaction was concentrated to remove dioxane, 1 liter of saturated sodium bicarbonate was added and extracted twice with 1 liter of dichloromethane. The organic layer was extracted with brine, dried over magnesium sulfate and concentrated. The obtained solid was recrystallized from isopropanol to obtain 118 g of solid.

¹ H NMR (250MHz, DMSO) δ7.89(s, 1H); 7.81(s, H); 4.58(s, 2H); 3.56(t, 2H); 2.81(t, 2H); ). tert-butyl 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate

59 g (0.16 mol) of 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 5% palladium on calcium carbonate and 10 g of 49 g of ammonium acetate in 1 liter of acetic acid was hydrogenated on a Parr shaker for 5 hours. The reaction was filtered through celite, concentrated, basified to pH 12 with 4N sodium hydroxide, and extracted with dichloromethane. The organic layer was washed with water, brine, dried over magnesium sulfate, and concentrated to give 40 g of an oil.

¹ H NMR (300 MHz, DMSO) δ 4.87 (s, 2H); 4.27 (s, 2H); 3.44 (t, 2H); 2.57 (t, 2H); 1.39 (s, 9H). tert-butyl 6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H- isoquinoline-2-carboxylate

7.6g (29mmol) 4'-trifluoromethyl-biphenyl-2-carboxylic acid, 7.1g (29mmol) 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert Butyl ester, 100 mg DMAP and 6.1 g (32 mmol) EDCI were mixed in 130 ml dichloromethane for 12 hours. The reaction was treated with 2×150ml 1N HCl, 2×150ml 1N NaOH, 150ml water. Brine extraction and concentration afforded 14 g of a beige foam.

MS (Cl): 519 (M+Na ⁺ )

¹ H NMR (250 MHz, CDCl ₃ ) δ 4.49 (s, 2H); 3.60 (t, 2H); 2.77 (t, 2H). 4′-Trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydroisoquinolin-6- yl)-amide

4g (8mmol) 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and 6ml (78mmol) TFA was mixed in 60ml dichloromethane for 5 hours. 40ml dichloromethane was added and the organic phase was extracted with 3 x 50ml saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated to give 3.10 gm of a solid.

MS (Cl): 397 (M+H ⁺ ) The following compound, classified as an amide according to the criteria described above, was synthesized following the procedure described in Method A. Method A

In a glass vial with a screw cap was added 150Ml of a 0.020M solution of acid chloride in 1,2-dichloroethane (3.0μmol), followed by 83μl of 0.030M 4'-trifluoromethyl-biphenyl-2 -A solution of carboxylic acid (1,2,3,4-tetrahydroisoquinolin-6-yl)-amide in 1,2-dichloroethane (2.5 μmol), followed by the addition of 25 mg of morpholino Methyl polystyrene bound polymer (@ 2.5 μmol/gm = 62 μmol). After shaking at 20 °C for 16 h, 10 μl was withdrawn and diluted to 100 μl with methanol for RPHPLC and MS analysis. The polymer was filtered off, and the filtrate was concentrated to dryness in vacuo. Example 2

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2 -(3-Cyclopentyl-propionyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide.

MS (Cl): 521 (M+H ⁺ ) Example 3-39

Following a procedure similar to that described in Example 2, the following compounds were prepared by reacting compound II with the appropriate acid chloride.

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-phenylacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 519 (M+H ⁺ )

¹ H NMR (250 MHz, CDCl ₃ ) δ 4.68 and 4.53 (s, 2H); 3.80 and 3.61 (t, 2H); 2.76 and 2.59 (t, 2H).

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-benzoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 501 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(furan-2-carboxy)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 491 (M+H ⁺ )

4-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-chloro-butyryl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 501 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-benzyloxyacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 545 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-heptyl-benzoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 599 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(bicyclo[2.2.1]hept-5-ene-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline -6-yl]-amide

MS (Cl): 517 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-1,2,3,4-tetrahydroisoquine Lin-6-yl]-amide

MS (Cl): 582 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-tetradecanoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 607 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3,3-dimethyl-butyryl)-1,2,3,4-tetrahydroisoquinolin-6-yl] -amide

MS (Cl): 495 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-phenoxyacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 531 (M+H ⁺ )

Acetic acid 2-oxo-1-phenyl-2-{6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline -2-yl}-ethyl ester

MS (Cl): 573 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 507 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,2,5,7-tetramethyl-1-oxo-1,2-indane-4-carbonyl)- 1,2,3,4-Tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 611 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-octanoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 523 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-octadec-9-enoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 661 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(quinoxaline-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 553 (M+H ⁺ )

4′-Oxo-4-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl} - Methyl butyrate

MS (Cl): 511 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [(2-(biphenyl-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 577 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-pentanoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 481 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-isobutyryl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 467 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-decanoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 551 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-octadecanoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 663 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-hexanoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 495 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-phenyl-propionyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 529 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-cyclohexanecarbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 507 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-cyclobutanecarbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 479 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-ethyl-hexanoyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 523 (M+H ⁺ )

3-oxo-3-{6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}- Methyl propionate

MS (Cl): 497 (M+H ⁺ )

5-Oxo-5-{6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}- Methyl valerate

MS (Cl): 525 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-chloro-propionyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 487 (M+H ⁺ )

5-Oxo-5-{6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}- Ethyl valerate

MS (Cl): 539 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[(3-methoxy-phenyl)-acetyl]-1,2,3,4-tetrahydroisoquinoline-6 -yl}-amide

MS (Cl): 545 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(thiophen-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 521 (M+H ⁺ )

¹ H NMR (250 MHz, CDCl ₃ ) δ 4.68 and 4.60 (s, 2H); 3.97 (s, 2H); 3.80 and 3.69 (t, 2H); 2.71 (m, 2H).

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-butyryl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 467 (M+H ⁺ )

4-Oxo-4-{6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}- methyl butyrate

MS (Cl): 511 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-octadec-11enoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 661 (M+H ⁺ ) Method B polymer bound by EDC

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 gm, 0.104 mol) was partitioned between 400 ml dichloromethane, 200 ml water, and 100 ml concentrated ammonium hydroxide. The aqueous layer was extracted with 2 x 100ml dichloromethane. The combined organic layers were washed with 100ml of 10% ammonium hydroxide solution, 100ml of water, dried over magnesium sulfate, filtered and concentrated in vacuum to obtain a colorless and transparent oil, which was dissolved in 350ml of DMF, and Merrifield resin (100gm , 2% dvb, 200-400 mesh, 1.0 mmol/gm), and the mixture was heated and stirred at 100° C. for 16 hours. After cooling, the resin was filtered, washed with 2 x 100 ml DMF, 2 x 300 ml THF, and dried under vacuum at 50°C for 20 hours. IR 2131cm ^-1 . reaction

In a glass vial with a screw cap was added 50 μl of a 0.050 M acid solution in 1,2-dichloroethane (2.5 μmol), followed by 50 μl of 0.050 M compound II in 1,2 dichloroethane ( 2.5 μmol) solution, followed by adding 30 μl, 0.017MDMAP in 1,2-dichloroethane (0.5 μmol) solution, followed by adding 25 mg of 1-(3-dimethylaminopropyl)-3-ethane Carbodiimide-bound polymer (@1.0 μmol/gm=25 μmol). After shaking at 20 °C for 16 h, 10 μl was withdrawn and diluted to 100 μl with methanol for RPHRLC and MS analysis. The polymer was filtered off, and the filtrate was concentrated to dryness in vacuo.

Example 40

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-( Naphthalen-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide.

MS (Cl): 565 (M+H ⁺ )

Examples 41-97

Following a procedure similar to that described in Example 40, the following compounds were prepared by reacting compound II with the appropriate corresponding carboxylic acid in the presence of the polymer bound by EDC.

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,2-dimethylpropionyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide

MS (Cl): 481 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,2-dimethyl-pentanoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl] -amide

MS (Cl): 509 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-hydroxy-2-phenyl-propionyl)-1,2,3,4-tetrahydroisoquinolin-6-yl ]-amide

MS (Cl): 545 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-phenyl-butyryl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 543 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-methyl-4-oxo-pentanoyl)-1,2,3,4-tetrahydroisoquinoline-6- base]-amide

MS (Cl): 509 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-ethyl-butyryl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 495 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid-(2-ethoxyacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 483 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[(4-fluoro-phenyl)-acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl }-amide

MS (Cl): 533 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-phenylthioacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 547 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-benzylthioacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 561 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-methyl-butyryl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 481 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-chloro-butyryl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 501 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid-(2-but-3-enoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 465 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1-acetyl-pyrrolidine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl] -amide

MS (Cl): 536 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[(4-oxo-2-thio-thiazolidin-3-yl)-acetyl]-1,2,3,4 -Tetrahydroisoquinolin-6-yl}-amide

MS (Cl): 570 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(pyridine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 502 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(quinoline-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 552 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1-phenyl-cyclopentane-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl] -amide

MS (Cl): 569 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(a-methoxy-phenyl-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl] -amide

MS (Cl): 545 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-chloro-2,2-dimethyl-propionyl)-1,2,3,4-tetrahydroisoquinoline- 6-yl]-amide

MS (Cl): 515 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-cyanoacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 464 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-methoxyacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 469 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[(4-chloro-phenyl)-acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl }-amide

MS (Cl): 549 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-ethylthioacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 499 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-phenyl-propan-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl] -amide

MS (Cl): 525 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-hydroxy-butyryl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 483 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[(1H-indol-3-yl)-acetyl]-1,2,3,4-tetrahydroisoquinoline-6 -yl}-amide

MS (Cl): 554 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(6-methyl-pyridine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl] -amide

MS (Cl): 516 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(pyridin-2-yl-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 516 (M+H ⁺ )

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.67 (s, 2H), 399 (s, 2H); 3.77 (m, 2H); 2.76 and 2.65 (t, 2H).

4′-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[(4-nitro-phenyl)-acetyl]-1,2,3,4-tetrahydroisoquinoline-6- base}-amide

MS (Cl): 560 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(6-diethylcarbamoyl-cyclohex-3-enecarbonyl)-1,2,3,4-tetrahydroisoquine Lin-6-yl]-amide

MS (Cl): 604 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(adamantane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 559 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[(3-chloro-phenyl)-acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl )-amide

MS (Cl): 549 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-diphenylacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 591 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[(2,4-dichloro-phenyl)-acetyl]-1,2,3,4-tetrahydroisoquinoline- 6-yl}-amide

MS (Cl): 583 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-phthalimido-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl] -amide

MS (Cl): 584 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(biphenyl-4-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide

MS (Cl): 591 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-O-tolylacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 529 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-m-tolylacetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 529 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-phenyl-but-3-enoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl ]-amide

MS (Cl): 541 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(cyclopent-1-enyl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl] -amide

MS (Cl): 505 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[(3,4,5-trimethoxy-phenyl)-acetyl-1,2,3,4-tetrahydroisoquine Lin-6-yl]-amide

MS (Cl): 605 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(adamantane-1-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide

MS (Cl): 573 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(9H-fluorene-9-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 589 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[(3-trifluoromethyl-phenyl)-acetyl-1,2,3,4-tetrahydroisoquinoline-6 -yl]-amide

MS (Cl): 583 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1-methyl-cyclohexanecarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide

MS (Cl): 521 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[2-(1,3-dioxo-isoindol-2-yl)-propionyl]-1,2,3, 4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 598 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-methyl-2-oxo-pentanoyl-1,2,3,4-tetrahydroisoquinolin-6-yl ]-amide

MS (Cl): 509 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-methoxy-cyclo-hexane-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6- base]-amide

MS (Cl): 537 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-hex-3-enoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 493 (M+H ⁺ )

2-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carbonyl}-pyrrolidine-1- tert-butyl formate

MS (Cl): 594 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(tetrahydro-furan-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 495 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(a-oxo-thiophen-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinoline-6 -yl]-amide

MS (Cl): 552 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(thiophen-3-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 521 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[(6-methoxy-3-oxo-2,3-indan-1-yl)-acetyl]-1 , 2,3,4-Tetrahydroisoquinolin-6-yl)-amide

MS(Cl): 600(M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1-acetyl-pyrrolidine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl )-amide

MS (Cl): 536 (M+H ⁺ )

4'-Trifluoromethoxy-biphenyl-2-carboxylic acid [2-(bicyclo[2.2.1]hept-2-yl-acetyl-1,2,3,4-tetrahydroisoquinoline- 6-yl)-amide

MS (Cl): 533 (M+H ⁺ )

Example 98

Compound II (200 mg, 0.50 mmol), picolinic acid (62 mg, 0.60 mmol) and EDCl (116 mg, 0.60 mmol) were mixed in dichloromethane for 14 hours. The reaction was concentrated and purified by flash chromatography on silica gel (eluent: 70-100% EtOAc/HeX). The product is 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(pyridine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, Yield 98%.

MS (Cl): 502 (M+H ⁺ )

¹ H NMR (250 MHz, CDCl ₃ ) δ 4.81 and 4.69 (s, 2H); 3.92 and 3.73 (t, 2H); 2, 83 (m, 2H). Method C

In a glass vial with a screw cap was added 150 μl of a 0.020M solution of isocyanate in 1,2-dichloroethane (3.0 μmol), followed by 83 μl of 0.030M 4′-trifluoromethyl-biphenyl- A solution (2.5 μmol) of 2-carboxylic acid (1,2,3,4-tetrahydroisoquinolin-6-yl]-amide (compound II) in 1,2-dichloroethane (2.5 μmol). At 20° C. After shaking for 16 hours, 10 μl was removed and diluted to 100 μl with methanol for RPHPLC and MS analysis. The reaction was concentrated to dryness in vacuo.

Example 99

6-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro- 1H-Isoquinoline-2-carboxylic acid phenylamide.

MS (Cl): 516 (M+H ⁺ )

¹ H NMR (250 MHz, DMSO) δ 4.56 (s, 2H); 3.66 (t, 2H); 2.77 (t, 2H). Examples 100-103

Following a procedure similar to that described in Example 99, the following compounds were prepared by reacting compound II with the appropriate isocyanate.

6-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid hexyl

MS (Cl): 524 (M+H ⁺ )

({6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid}-amino)-ethyl acetate ester

MS (Cl): 526 (M+H ⁺ )

6-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzylamide

MS (Cl): 530 (M+H ⁺ )

6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid [(R)-1-phenyl -Ethyl]-amide

NOTE: The product prepared as described in Method C using compound II and (R)-(+)-isocyanate-α-methylbenzyl ester.

MS (Cl): 544 (M+H ⁺ )

¹ H NMR (250 MHz, CDCl ₃ ) δ5.06(m, 1H); 4.66(d, 1H); 4.46(s, 2H); 3.56(t, 2H); 2.78(t, 2H); , 3H).

Example 104

According to a method similar to that described in Ohsawa, A.; Arai, H.; Igeta, H. Chem. -2-Carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyridin-2-ylamide. Yield 23%.

MS (Cl): 517 (M+H ⁺ )

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.60(s, 2H); 3.69(t, 2H); 2.86(t, 2H). Method D

In a glass vial with a screw cap was added 150 μl of a 0.020 M solution of sulfonyl chloride in 1,2-dichloroethane (3.0 μmol), followed by 83 μl of 0.030 M compound II in 1,2-dichloroethane A solution formed in (2.5 μmol) was added, followed by the addition of 25 mg of polymer bound by morpholinomethyl polystyrene (@2.5 μmol/gm=62 μmol). After shaking at 20 °C for 16 h, 10 μl was withdrawn and diluted to 100 μl with methanol for RPHPLC and MS analysis. The polymer was filtered off and the filtrate was concentrated to dryness in vacuo.

Example 105

Compound II was reacted with naphthalene-1-sulfonyl chloride as described in Method D to prepare 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(naphthalene-1-sulfonyl)-1,2 , 3,4-Tetrahydroisoquinolin-6-yl]-amide.

MS (Cl): 604 (M+NH ₄ ⁺ )

Examples 106-111

Following Procedure D as in Example 105, compound II was reacted with the appropriate sulfonyl chloride to prepare the following compounds.

2-{6-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-sulfonyl}-benzoic acid methyl ester

MS (Cl): 595 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(propane-2-sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 520 (M+NH ₄ ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-chloro-propane-1-sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl] -amide

MS (Cl): 555 (M+NH ₄ ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(5-1-sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 534 (M+NH ₄ ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-dimethylaminosulfonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 521 (M+NH ₄ ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-trifluoromethoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl) -amide

MS (Cl): 638 (M+NH ₄ ⁺ )

Example 112

This example illustrates the preparation of compounds wherein the group at XYZ linking XYZ to the tetrahydroisopyridinoline ring is a thiocarbamoyl group.

In a glass vial with a screw cap was added 150 μl of a 0.020 M solution of thioisocyanate (cyclopropyl thioisocyanate) in 1,2-dichloroethane (3.0 μmol), followed by 83 μl of 83 μl 0.030 M 4'-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydroisoquinolin-6-yl)-amide formed in 1,2-dichloroethane solution (2.5 μmol). After shaking at 20 °C for 16 h, 10 μl was withdrawn and diluted to 100 μl with methanol for RPHPLC and MS analysis. The reaction was concentrated to dryness in vacuo to afford 4'-trifluoromethyl-biphenyl-2-carboxylic acid (2-cyclopropylthiocarbamoyl-1,2,3,4-tetrahydroisoquinoline -6-yl)-amide.

MS (Cl): 496 (M+H ⁺ ) Method F

A solution of aldehyde (7.5 μmol), compound II (5 μmol), acetic acid (7.5 μmol) and sodium triacetoxyborohydride (10 μmol) in 300 μl 1,2-dichloroethane was shaken for 60 hours at room temperature. A 7.5 μl sample was removed and diluted with 93 μl methanol for TLC and MS analysis. The remaining sample was evaporated to dryness in vacuo. The crude solid was dissolved in 500 μl ethyl acetate and washed with 300 μl 5% sodium bicarbonate. The organic layer was concentrated to dryness in vacuo.

Example 113

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2, 6,6-Trimethyl-cyclohex-2-enylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide.

MS (Cl): 533 (M+H ⁺ )

Examples 114-162

Following Example 113, the following compounds were prepared by Method F by reacting compound II with the appropriate aldehyde.

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-cyclohex-3-enylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 491 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-methyl-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 501 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-dimethylamino-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 530 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-methoxy-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 517 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-fluoro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 505 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3,4-dichloro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide

MS (Cl): 555 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-isopropyl-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 529 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-biphenyl-4-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 564 (M+2)

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-phenoxy-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS(Cl): 580(M+2)

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-methoxy-naphthalen-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6 -yl]-amide

MS (Cl): 568 (M+2)

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-naphthalen-1-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 538 (M+2)

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-methylthio-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 533 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(9-ethyl-9H-carbazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline -6-yl]-amide

MS(Cl): 605(M+2)

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-tert-butyl-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)- Amide

MS (Cl): 544 (M+2)

3-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-ylmethyl}-cyclohexane ethyl formate

MS (Cl): 566 (M+2)

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-tert-butylthio-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl) -amide

MS (Cl): 576 (M+2)

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-cyclohexylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 494 (M+2)

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-fluoro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 505 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-benzo[1,3]dioxol-5-ylmethyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)-amide

MS (Cl): 531 (M+H ⁺ )

4′-Trioxymethyl-biphenyl-2-carboxylic acid (2-naphthalene-2-methylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 538 (M+2)

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-methoxy-naphthalen-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6 -yl]-amide

MS (Cl): 568 (M+2)

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-benzyloxy-3-methoxy-benzyl)-1,2,3,4-tetrahydroisoquinoline- 6-yl]-amide

MS (Cl): 624 (M+2)

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1,3,4-trimethyl-cyclohex-3-enylmethyl)-1,2,3,4-tetra Hydroisoquinolin-6-yl]-amide

MS (Cl): 533 (M+2)

4'-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[2-(4-chloro-phenylthio)-benzyl)-1,2,3,4-tetrahydroisoquinoline- 6-yl}-amide

MS (Cl): 629 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,4-dichloro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide

MS (Cl): 555 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1,5a,6,9,9a,9b-hexahydro-4H-dibenzofuran-4a-ylmethyl)-1 , 2,3,4-Tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 585 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid {2-[4-(2-diethylamino-ethoxy)-benzyl-1,2,3,4-tetrahydroisoquinoline -6-yl}-amide

MS (Cl): 603 (M+2)

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide

MS (Cl): 555 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-yl-2-ylmethyl)-1,2 , 3,4-Tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 531 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-benzyloxy-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 594 (M+2)

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-phenoxy-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 579 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-dimethylamino-naphthalen-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6 -yl]-amide

MS (Cl): 580 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-pyrrolidin-1-yl-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl ]-amide

MS (Cl): 557 (M+2)

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-thiophen-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 493 (M+H ⁺ )

¹ NMR (250 MHz, DMSO) δ 3.83 (s, 2H); 3.52 (s, 2H); 2.69 (m, 4H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2(1H-indol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide

MS (Cl): 526 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-pyrrol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide

MS (Cl): 476 (M+H ⁺ )

¹ H NMR (300 MHz, DMSO) δ 3.54 (s, 2H); 3.43 (s, 2H); 2.72 (m, 2H); 2.60 (m, 2H).

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-furan-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 477 (M+H ⁺ )

¹ H NMR (250 MHz, DMSO) δ 3.65 (s, 2H); 3.47 (s, 2H); 2.71 (m, 2H); 2.65 (m, 2H).

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 M-pyrazole -4-ylmethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 598 (M+2)

4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-ylmethyl)-1,2,3, 4-Tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 581 (M+2)

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-1,2,3 , 4-Tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 582 (M+2)

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-benzofuran-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 527 (M+H ⁺ )

Acetic acid 5-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-ylmethyl}-furan- 2-ylmethyl ester

MS (Cl): 549 (M+H ⁺ )

¹ H NMR (300MHz, CDCl ₃ ) δ5.02(s, 2H); 3.70(s, 2H); 3.60(s, 2H); 2.83(t, 2H); 2.75(t, 2H); 3H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-methyl-thiophen-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6- base]-amide

MS (Cl): 507 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-thiophen-3-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 493 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-methyl-1H-indol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline -6-yl]-amide

MS (Cl): 540 (M+H ⁺ )

2-Methyl-5-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-ylmethyl }-furan-3-carboxylic acid ethyl ester

MS (Cl): 563 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,5-dimethoxy)-tetrahydrofuran-3-ylmethyl)-1,2,3,4-tetrahydroiso Quinolin-6-yl)-amide

MS (Cl): 541 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1-methyl-1H-indol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline -6-yl)-amide

MS (Cl): 557 (M+NH ₄ ⁺ )

2-{6-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-ylmethyl}-cyclopropanecarboxylic acid ethyl ester

MS (Cl): 523 (M+H ⁺ )

Method G

The following compounds were prepared by reductive amination following procedures analogous to those described by Abdel-Magid, A.F.; Maryanoff, C.A.; Carson, K.G., Tetrahedron Lett. 1990, 31, 5595. This method is essentially the same as Method F and uses sodium triacetoxyborohydride, except for some modifications, generally in the choice of solvent and reaction temperature, all modifications being per compound. Also, unless otherwise indicated, 1.5-2 equivalents of carbonyl compound are used. Compounds prepared in this section were isolated as free bases. In most cases, the free bases used in the field of biology are converted into the single hydrochloride salts by conventional methods.

Example 163

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-benzyl-1,2, 3,4-Tetrahydroisoquinolin-6-yl)-amide solvent: DCE 56% yield

MS (Cl): 487 (M+H ⁺ )

¹ H NMR (250 MHz, DMSO) δ 3.62 (s, 2H); 3.46 (s, 2H); 2.74 (m, 2H); 2.63 (m, 2H).

Examples 164-193

Using a method analogous to Abdel-Magid et al., with the appropriate modifications as indicated, compound II was reacted with the appropriate aldehyde to prepare the following compounds.

4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-pyridin-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide Solvent: THF62 %Yield

MS (Cl): 488 (M+H ⁺ )

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.82 (s, 2H); 3.63 (s, 2H); 2.84 (m, 2H); 2.77 (m, 2H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-pyridin-4-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide Solvent: THF

MS (Cl): 488 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-quinolin-4-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide solvent: THF

MS (Cl): 488 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-quinolin-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide solvent: DCE66% yield

MS (Cl): 538 (M+H ⁺ )

¹ H NMR (250 MHz, CDCl ₃ ) δ 3.99 (s, 2H); 3.67 (s, 2H); 2.82 (m, 4H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(6-methyl-pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6- base]-amide solvent: DCE63% yield

MS (Cl): 502 (M+H ⁺ )

¹ H NMR (250 MHz, CDCl ₃ ) δ 3.79 (s, 2H); 3.63 (s, 2H); 2.81 (s, 2H); 2.76 (s, 2H); 2.55 (s, 3H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(6-bromo-pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl )-amide

MS (Cl): 568 (M+H ⁺ ).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(6-formyl-pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6- base)-amide solvent: DCE; use 10 equivalents of aldehyde

MS (Cl): 516 (M+H ⁺ ).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-chloro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide solvent: DCE

MS (Cl): 521 (M+H ⁺ ).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-chloro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide solvent: DCE69% yield

MS (Cl): 521 (M+H ⁺ )

¹ H NMR (300 MHz, DMSO) δ 3.64 (s, 2H); 3.47 (s, 2H); 2.74 (t, 2H); 2.64 (t, 2H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(4-chloro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide solvent: DCE

MS (Cl): 521 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-pyrimidin-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide Solvent: Di Chloromethane; 61% yield using 6 equivalents of aldehyde

MS (Cl): 489 (M+H ⁺ )

¹ H NMR (250 MHz, DMSO) δ 3.87 (s, 2H); 3.60 (s, 2H); 2.77 (m, 4H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-nitro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide solvent : DCE76% yield

MS (Cl): 532 (M+H ⁺ )

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.75 (s, 2H); 3.58 (s, 2H); 2.84 (t, 2H); 2.73 (t, 2H).

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-methoxy-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide Solvent: DCE

MS (Cl): 517 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-trifluoromethyl-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)- Amide solvent: DCE

MS (Cl): 555 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-cyano-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide solvent : DCE

MS (Cl): 512 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-hydroxy-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide solvent: DCE

MS (Cl): 503 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3,5-dichloro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)- Amide solvent: DCE

MS (Cl): 556 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3,5-di-trifluoromethyl-benzyl)-1,2,3,4-tetrahydroisoquinoline-6 -yl)-amide Solvent: DCE

MS (Cl): 622 (M+H ⁺ )

Acetic acid 3-[6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-ylmethyl}-phenyl Ester solvent: DCE

MS (Cl): 545 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-sulfamoyl-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide Solvent: DCE

MS (Cl): 566 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide solvent: 7:3 THF:DCE 59% yield

MS (Cl): 477 (M+H ⁺ )

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.79 (s, 2H); 3.58 (s, 2H); 2.82 (m, 2H); 2.74 (m, 2H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1-methyl-1H-pyrrol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline- 6-yl]-amide solvent: DCE 57% yield

MS (Cl): 490 (M+H ⁺ )

¹ H NMR (250 MHz, CDCl ₃ ) δ 3.64 (s, 3H); 3.57 (s, 2H); 3.51 (s, 2H); 2.77 (t, 2H); 2.65 (t, 2H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-benzimidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl ]-amide solvent: DCE 83% yield

MS (Cl): 527 (M+H ⁺ )

¹ H NMR (250 MHz, DMSO) δ 3.89 (s, 2H); 3.58 (s, 2H); 2.76 (m, 4H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]- Amide solvent: DCE 66% yield

MS (Cl): 477 (M+H ⁺ )

¹ H NMR (250 MHz, DMSO) δ 3.56 (s, 2H); 3.46 (s, 2H); 2.72 (m, 2H); 2.63 (m, 2H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-thiazol-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide Solvent: DCE38 %Yield

MS (Cl): 494 (M+H ⁺ )

¹ H NMR (250 MHz, DMSO) δ 3.99 (s, 2H); 3.64 (s, 2H); 2.76 (s, 4H).

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-methyl-benzo[b]thiophen-2-ylmethyl)-1,2,3,4-tetrahydroiso Quinolin-6-yl]-amide Solvent: DCE

MS (Cl): 557 (M+H ⁺ )

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1-methyl-1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline- 6-yl)-amide solvent: 7:3 THF:DCE 72% yield

MS (Cl): 491 (M+H ⁺ )

¹ H NMR (300 MHz, DMSO) δ 3.66 (s, 2H); 3.63 (s, 3H); 2.47 (s, 2H); 2.70 (m, 2H); 2.62 (m, 2H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline- 6-yl]-amide Solvent: THF

MS (Cl): 491 (M+H ⁺ )

4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydroiso Quinolin-6-yl]-amide Solvent: EtOH; Temperature: 70°C 42% yield

MS (Cl): 478 (M+H ⁺ )

¹ H NMR (250 MHz, CDCl ₃ ) δ 3.87 (s, 2H); 3.63 (s, 2H), 2.79 (s, 4H).

4'-trifluoromethyl-biphenyl-2-carboxylic acid (2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide Solvent: THF; use 3 equivalents of aldehyde

MS (Cl): 411 (M+H ⁺ )

Example 194

This example illustrates the preparation of compounds of formula II as shown in Scheme 2. The numbers in parentheses of each title compound are the same as those in Scheme 2. a. Dimethyl 2-(carboxy-5-nitro-phenyl)malonate (2)

A solution of 2-chloro-4-nitrobenzoic acid (75 g, 372 mmol) in dimethyl malonate (900 mL) was sparged with nitrogen for 15 minutes. Sodium methoxide (48.3 g, 894 mmol) was added in one portion and the reaction exothermed to 48°C. After fifteen minutes, copper(I) bromide (4.5 g, 37 mmol) was added in one portion and the reaction was heated at 70°C for 24 hours. It can be known by nmr detection that 70% of the reaction is completed, and after heating at 85° C. for 5 hours, the 2-chloro-4-nitrobenzoic acid in the reactant is completely consumed. Water (900 mL) was added to the cooled reactant, followed by hexane (900 mL). The aqueous layer was separated, methyl (900 mL) was added, filtered through celite, and the aqueous layer was separated. Fresh toluene (1800 mL) was added to the aqueous layer, and the biphasic mixture was acidified with 6N aqueous HCl (90 mL). A white precipitate formed, the reaction mixture was stirred for 18 hours, the product was filtered off and dried to give a white solid (78.1 g, 70%), mp = 153°C.

¹ H NMR (CD ₃ ) ₂ )SO δ 8.37 (d, J=2Hz, 1H), 8.30 (d, J=1Hz, 2H), 5.82 (s, 1H), 3.83 (s, 6H).

¹³ C NMR (CD ₃ ) ₂ )SO δ 168.0, 167.3, 149.4, 137.1, 135.8, 132.5, 125.4, 123.7, 54.5, 53.4.

Anal. Calcd. for _C11H10NO8 : C, 48.49; _H , _3.73 ; N, 4.71. Found: C, 48.27; H, 3.72; N, 4.76. b. 2-Carboxymethyl-4-nitro-benzoic acid (3)

A solution of sodium hydroxide (5 g, 125 mmol) in water (200 mL) was added to a solution of dimethyl 2-(carboxy-5-nitro-phenyl)malonate (25.0 g, 84 mmol) in methanol (200 mL) in solution. After 3 hours, the reaction was complete, methanol was removed in vacuo, the reaction was cooled to 0°C and acidified with cone. HCl (37 mL). The aqueous layer was extracted twice with ethyl acetate (200 mL then 100 mL), the combined organic layers were dried over magnesium sulfate, most of the solvent was removed in vacuo, and dichloromethane (30 mL) was added. The white solid was filtered off and dried to give 19.3 g of product as a white solid, mp = 180-83°C. IR (KBr) 3080, 3055, 2983, 1707, 1611, 1585, 1516, 1491, 1424, 1358, 1298, ^{1237 cm -1} .

¹³ C NMR (CD ₃ ) ₂ )SO δ 172.3, 167.5, 149.2, 138.8, 137.3, 132.1, 127.2, 122.4, 39.8. Anal _. Calcd. for _C9H17NO6 : C, 48.01; H, _3.13 ; N, 6.22. Found: C, 47.67; H, 3.19; N, 6.31. c. 2-(2-Hydroxymethyl-5-nitro-phenyl)-ethanol (4)

A solution of 2-carboxymethyl-4-nitro-benzyl alcohol (3.0 g, 13.3 mmol) in THF (60 mL) was treated with borane-THF complex (53.3 mL, 53.3 mmol) at 0° C. for 15 minutes. The reaction was stirred for 18.5 hours, quenched with THF/water (1:1, 30 mL), water (20 mL) was added and the layers were separated. The aqueous layer was re-extracted with THF (30 mL), the combined organic phases were washed with brine, dried over magnesium sulfate, and the solvent was removed in vacuo to give the product as a white solid (2.05 g, 78%) mp = 79-81 °C.

IR (KBr) 3277, 3192, 2964, 2932, 1614, 1525, 1507, 1170, 1134, 1089, 1067 ^{cm -1} .

¹³ C NMR (CD ₃ ) ₂ SO δ 149.1, 146.6, 139.2, 127.8, 124.3, 121.3, 61.2, 60.6, 34.9.

Anal _. Calcd. for _C9H11NO4 : C, 54.82; H, _5.62 ; N, 7.10. Found: C, 54.54; H, 5.49; N, 7.07. c'.2-(2-Hydroxymethyl-5-nitro-phenyl)-ethanol (4), selective preparation method

A mixture of 2-carboxymethyl-4-nitro-benzoic acid (13 g, 57.7 mmol), acetic anhydride (5.45 mL, 57.7 mmol) and toluene (130 mL) was heated at reflux for 5 hours. The solvent was removed in vacuo to afford 6-nitro-isochroman-1,3-dione (compound 3(a) in Scheme 2) as a yellow solid (10.51 g, 88%). To a solution of 6-nitro-isochroman-1,3-dione (2g, 9.66mmol) in THF (40mL) was added dropwise borane tetrahydrofuran complex (35.6 mL, 1M in THF). The reaction was stirred at 25°C for 18 hours, cooled to 0°C, quenched with methanol (30 mL), and stirred for 1 hour. The solvent was removed in vacuo, ethyl alcohol (30 mL) was added and the organic phase was washed with 10% aqueous hydrochloric acid. The acidic aqueous layer was re-extracted with ethyl acetate (30 mL), the combined organic layers were dried over magnesium sulfate, and evaporated in vacuo until only 2 mL of ethyl acetate remained. The solution was filtered through silica gel, washed with dichloromethane (30 mL) to remove impurities. The silica gel was washed with ethyl acetate and the solvent removed in vacuo to give a solid which was slurried in dichloromethane and filtered to give the diol as a white solid, 1.38g, 73%. d. 6-nitro-1,2,3,4-tetrahydroisoquinoline (5)

Add methanesulfonyl chloride (0.9 mL, 11.63 mmol) dropwise into 2-(2-hydroxymethyl-5-nitro-phenyl)-ethanol (1.0 g, 5.07 mmol), triethylamine (1.8 mL, 12.91 mmol) in dichloromethane (20 mL). After 30 minutes, TLC showed the reaction was complete. ¹ H NMR (CD ₃ Cl) δ8.17-11(m, 2H), 7.65(d, J=9Hz, 1H), 5.36(s, 2H), 4.49(t, J=6Hz, 2H), 3.25( t, J=6Hz, 2H), 3.08(s, 3H), 3.98(s, 3H). The reaction mixture was washed with 10% aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate, the dichloromethane was removed in vacuo and rinsed with THF (3 x 100 mL). The product 1.9 g was directly used in the next reaction without further purification. Ammonia (50 mL) was added to a solution of dimesylate (1.9 g) in THF (30 mL) at -78°C. The reaction was warmed at 24°C for 60 hours, the ammonia was evaporated and the solvent was removed in vacuo to give the crude product (786mg, 82%). Toluene was added and the solution was filtered over magnesium sulfonate and the solvent was removed in vacuo to give 721 mg (75%) of an amber oil.

¹ H NMR (CDCl ₃ ) δ7.97(s, 1H), 7.95(d, J=9Hz, 1H), 7.15(d, J=9Hz, 1H), 4.07(s, 2H), 3.15(t, J =6Hz, 2H), 2.89(t, J=6Hz, 2H), 1.98(bs, 1H). e. tert-butyl 6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (6)

BOC-anhydride (1.44 mL, 6.26 mmol) was added to 6-nitro-1,2,3,4-tetrahydroisoquinoline (840 mg, 4.71 mmol) in diethylamine (0.72 mL, 5.17 mmol) solution in methyl chloride (17 mL). After 5 hours, saturated aqueous sodium bicarbonate was added, the two phases were separated, the organic layer was dried over magnesium sulfate, and the solvent was removed in vacuo to give the product as an off-white solid (1.2 g, 92%). mp = 138-41°C.

IR (KBr) 3056, 3018, 2982, 2935, 1734, 1684, 1612, 1522, 1399, 1236 ^{cm -1} . ¹ H NMR (CDCl ₃ ) δ8.04(t, J=5Hz, 1H), 8.01(s, 1H), 7.26(t, J=5Hz, 1H), 4.65(s, 2H), 3.68(t, J =6Hz, 2H), 2.93(t, J=6Hz, 2H), 1.49(s, 9H). f. tert-butyl 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate (7)

6-Nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester in THF (2 mL) was dissolved with 50% Pt-C (50% water wet, 10 mg) at 50 psi (82mg, 0.29mmol) was hydrogenated for 5 hours. The catalyst was filtered off, the solvent removed in vacuo and chromatographed on silica gel eluting with ethyl acetate/hexanes to afford 42 mg (57%) of product.

IR (KBr) 3005, 2975, 2928, 1685, 1627, 1509, 1423, 1365, 1166 ^{cm -1} .

¹ H NMR (CDCl ₃ ) δ6.90 (d, J=6 Hz, 1H), 6.56 (d, J=6 Hz, 1H), 6.48 (s, 1H), 4.47 (s, 2H), 3.60 (m, J=6Hz, 4H), 2.73(t, J=6Hz, 2H), 1.49(s, 9H).

The product obtained in Example 194 above can be reacted with 4'-trifluoromethyl-biphenyl-2-carboxylic acid according to the method disclosed in Example 1 to obtain N-protected compound II, and then deprotected to obtain compound II.

Example 195

This example illustrates the preparation of compounds of formula II as shown in Scheme 3. The numbers in parentheses are the same as those in process 3. a.4'-trifluoromethyl-biphenyl-2-formyl chloride

A solution of 4'-(trifluoromethyl)-2-biphenylcarboxylic acid (9.08 g, 34 mmol), thionyl chloride (12 mL) and dimethylformamide (0.05 mL) was heated at reflux for 2 hours. After the reaction was complete by NMR, the thionyl chloride was distilled off by displacement with toluene (56 mL). The solvent was removed in vacuo to give the acid chloride (9.46 g, 97%) as a white solid.

¹ H NMR (CDCl ₃ ) δ 8.12 (dd, J=1 Hz, J=8 Hz, 1H), 7.70-7.37 (m, 7H). ¹³ C NMR CD ₃ Cl δ(CO)168. b. 4'-Trifluoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxyethyl)-4-hydroxymethyl -phenyl]-amide (10)

Pt-C (50% water-wet, 200 mg) was added to a solution of 2-(2-hydroxymethyl-5-nitrophenyl)-ethanol (1.0 g, 5 mmol) in THF (40 mL) and heated at 50 psi The reaction was hydrogenated for 2 hours. NMR showed that the reaction was complete, generating 2-(5-amino-2-hydroxymethylphenyl)-ethanol (compound (9) in scheme 3);

¹ H NMR (CD ₃ Cl) δ7.08(d, J=2Hz, 1H), 6.54-6.50(m, 2H), 4.51(s, 2H), 3.82(t, J=6Hz, 2H), 3.80- 2.95 (bs, 4H), 2.84 (t, J=6Hz, 2H).

The catalyst was filtered off and triethylamine (1.4 mL, 10 mmol) was added followed by the dropwise addition of 4'-trifluoromethyl-biphenyl-2-carbonyl chloride (1.44 g, 5 mmol) in THF (10 mL) over 1 hour . The reaction was stirred for 24 hours, the solvent was removed in vacuo and ethyl acetate (40 mL) was added. The organic phase was washed with water (2 x 40 mL), dried over magnesium sulfate, the solvent was removed in vacuo and rinsed with toluene (3 x 40 mL). Removal of the solvent gave 2.11 g of a white solid which was redissolved in dichloromethane (21 mL) for 18 hours and the product was filtered off and dried to give the title product as a white solid 1.71 g (81%).

¹ H NMR (CD ₃ ) ₂ SOδ 10.22 (s, 1H), 7.73 (d, J = 8Hz, 2H), 7.62-28 (m, 8H), 7.20 (d, J = 8Hz, 1H), 4.96 ( bs, 1H), 4.96 (bs, 1H), 4.43 (s, 2H), 3.51 (t, J=7Hz, 2H), 2.67 (t, J=7Hz, 2H).

IR (KBr) 3264, 3232, 31278, 3124, 3106, 2956, 2928, 1649, 1613, 1533, 1328, 1129 ^{cm -1} .

¹³ C NMR (CD ₃ ) ₂ SOδ(amide CO) 167.7, aliphatic carbons 62.3, 61.1, 36.0. Anal. Calcd. for _C23F3H20NO3 : C, 66.50; _H , _4.85 ; N, 3.37 _. Found: C, 66.29; H, 4.79; N, 3.27. c. 4'-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydroisoquinolin-6 -yl)-amide (compound II)

Add methanesulfonyl chloride (0.085 mL) to 4′-trifluoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxyethyl)-4-hydroxymethylphenyl]- A solution of the amide (2, 4 mg, 0.51 mmol) and triethylamine (0.18 mL) in THF (8.5 mL). After 30 minutes, TLC showed the reaction was complete. The reaction was cooled to -78°C and ammonia was added, then the reaction was stirred at 25°C for 18 hours. The solvent was removed in vacuo, dichloromethane and 1N aqueous HCl were added, and the reaction was stirred for 1 hour. After phase separation the aqueous phase was basified to pH 12 with aqueous sodium hydroxide solution. The organic phase was extracted with dichloromethane (4 x 10 mL) and the solvent was removed in vacuo to give 108 mg of a white solid which was purified by silica gel chromatography eluting with 5% methanol/dichloromethane containing 0.5% ammonium hydroxide. The product was obtained as a white solid (40 mg, 20%).

¹ H NMR (CDCl ₃ ) δ7.76-6.83 (m, 11H), 3.89 (s, 2H), 3.52 (d, J=7Hz, 0.5H), 3.04 (t, J=6Hz, 2H), 2.74( m, 0.5H), 2.66(t, J=7 Hz, 2H), 2.27(s, 1H).

¹³ C NMR CD ₃ Cl δ (aliphatic carbons only) 47.8, 43.6, 29.1.

Examples 196-197 illustrate the preparation of compounds of the invention as shown in Scheme 3.

Example 196

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-benzyl-1,2,3,4-tetrahydroiso Quinolin-6-yl]-amide

Add methanesulfonyl chloride (0.041 mL) to 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxy-ethyl)-4-hydroxymethyl-phenyl at 0 °C ]-amide (100 mg, 0.24 mmol) and triethylamine (0.084 mL) in THF (2 mL). After 30 minutes, TLC showed the reaction was complete. Benzylamine (0.132 mL) was added and the reaction was stirred at 25°C for 18 hours and at 50°C for 60 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane (15 mL), washed with pH 9 buffer, the phases were separated and the organic phase was dried over magnesium sulfate. The solvent was removed in vacuo to give the crude product as a white solid (204mg), which was redissolved in _CDCl3 , filtered and dried to give the product as a white solid (46mg, 39%). mp = 230-32°C.

¹ H NMR(CD ₃ ) ₂ SOδ7.73(d, J=8Hz, 2H), 7.60-23(m, 12H), 7.17(d, J=8Hz, 1H), 6.87(d, J=8Hz, 1H ), 3.60(s, 2H), 3.43(s, 2H), 2.71(m, 2H), 2.62(m, 2H).

_Anal . _Calcd . _{for C30F3H25N2O :} C, 74.06; H, 5.18; N, 5.76. Found: C, 74.08; H, 5.38; N, 5.76.

Example 197 4′-Trifluoromethyl-biphenyl-2-carboxylic acid (2-allyl-1,2,3,4-tetrahydro Isoquinolin-6-yl]-amide

At -20°C, methanesulfonyl chloride (0.041 mL, 0.53 mmol) was added dropwise into triethylamine (0.084 mL, 0.60 mmol) and 4'-trifluoromethyl-biphenyl-2-carboxylic acid [3-(2 -Hydroxyethyl)-4-hydroxymethyl-phenyl]-amide (0.1 g, 0.24 mmol) in THF (2 mL). Fifteen minutes after the addition was complete, allylamine (0.09 mL, 1.2 mmol) was added and the reaction was stirred at 25°C for 18 hours, then at 60°C for 70 hours. The solvent was removed in vacuo, dichloromethane (10 mL) was added and the organic phase was washed with pH 12 water (10 mL). The organic solvent was removed in vacuo to give 281 mg of crude product. This was purified by silica gel chromatography eluting with 10% methanol/dichloromethane to afford the product as a white solid (91 mg, 87%).

¹ H NMR (CDCl ₃ ) δ7.80(d, J=8Hz, 1H), 7.68(d, J=8Hz, 2H)-7.60-7.42(m, 5H), 6.93-6.83(m, 3H), 6.00 -5.86(m, 1H), 5.27-5.17(m, 2H), 3.55(s, 2H), 3.15(d, J=7Hz, 2H), 2.83(t, J=6Hz, 2H), 2.69(t, J = 6 Hz, 2H), 1.66 (bs, 1H).

¹³ C NMR CD ₃ Cl δ (aliphatic carbons only) 61.4, 55.6, 50.3, 29.1.

Claims (33)

1. Compounds of formula I and pharmaceutically acceptable salts thereof: in: X is _CH2 , CO, CS or _SO2 ; Y is selected from: direct key, Aliphatic hydrocarbylene of up to 20 carbon atoms, which can be replaced by hydroxyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ acyl, C ₁ -C ₁₀ acyloxy, or C ₆ -C ₁₀ aromatic base single substitution, NH and O, with the proviso that if X is _CH2 , then Y is a direct bond; Z is selected from the following groups: (1) H, halogen, cyano, (2) Hydroxy, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylthio, C ₁ -C ₁₀ acyl, thienylcarbonyl, C ₁ -C ₁₀ alkoxycarbonyl, (3) C ₁ -C ₁₀ alkylamino, di-C ₁ -C ₁₀ alkylamino, C ₆ -C ₁₀ aryl C ₁ -C ₁₀ alkylamino, with the proviso that Y is not O or NH, (4) Unsubstituted vinyl, C ₆ -C ₁₀ aryl, C ₃ -C ₈ cycloalkyl or its fused benzo derivatives, C ₇ -C ₁₀ polycycloalkyl, C ₄ -C ₈ Cycloalkenyl, C ₇ -C ₁₀ polycycloalkenyl, (5) C ₆ -C ₁₀ aryloxy, C ₆ -C ₁₀ arylthio, C ₆ -C ₁₀ aryl C ₁ -C ₁₀ alkoxy, C ₆ -C ₁₀ aryl C ₁ -C ₁₀ alkane Thio, C ₃ -C ₈ cycloalkoxy, C ₄ -C ₈ cycloalkenyloxy, (6) A heterocyclic group selected from a monocyclic group and a fused polycyclic group, wherein the group contains a total of 5-14 ring atoms, wherein the total number of ring atoms independently selected from oxygen, nitrogen and sulfur is 1-4 ring heteroatoms, each ring of the group may be saturated, partially saturated or aromatic, respectively, with the proviso that if X is _CH2 , then Z is H or a group selected from (4) and (6), Wherein, when Z contains one or more rings, each ring may independently have 0-4 substituents independently selected from the following: halogen, hydroxyl, cyano, nitro, oxo, sulfur Substitute, aminosulfonyl, phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ - C ₁₀ alkoxycarbonyl, C ₁ -C ₁₀ alkylthio, C ₁ -C ₁₀ alkylamino, C ₁ -C ₁₀ alkylaminocarbonyl, di C ₁ -C ₁₀ alkylamino, di C ₁ -C ₁₀ Alkylaminocarbonyl, diC ₁ -C ₁₀ alkylamino C ₁ -C ₁₀ alkoxy, C ₁ -C ₃ perfluoroalkyl, C ₁ -C ₃ perfluoroalkoxy, C ₁ -C ₁₀ acyl , C ₁ -C ₁₀ acyloxy, C ₁ -C ₁₀ acyloxy C ₁ -C ₁₀ alkyl and pyrrolidinyl. 2. Compounds and pharmaceutically acceptable salts thereof according to claim 1 wherein X is _CH2 , CO, or _SO2 ; Y is selected from: direct bond, NH, C ₁ -C ₁₀ alkylene and C ₂ -C ₁₀ alkenylene, any of which may be substituted by phenyl, provided that if X is CH ₂ , then Y is a direct bond; Z is selected from the following groups: (1) H, (2) C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylthio, (3) C ₁ -C ₁₀ alkylamino, di-C ₁ -C ₁₀ alkylamino, C ₆ -C ₁₀ aryl C ₁ -C ₁₀ alkylamino, with the proviso that Y is not NH, (4) Unsubstituted vinyl, C ₆ -C ₁₀ aryl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, (5) C ₆ -C ₁₀ aryloxy, (6) selected from saturated, partially unsaturated or aromatic 5- and 6-membered heterocyclic groups, and fused benzo derivatives thereof, wherein the group can contain a total of 1-3 independently selected from Ring heteroatoms of oxygen, nitrogen and sulfur, with the proviso that if X is _CH2 , Z is selected from the groups of (4) and (6), Wherein, when Z contains one or more rings, each ring may independently have 0-3 substituents independently selected from the following: halogen, hydroxyl, nitro, C ₁ -C ₆ alkyl , C ₁ -C ₆ alkoxy, di C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₃ perfluoroalkoxy, C ₁ -C ₁₀ acyl and C ₁ -C ₁₀ acyloxy. 3. The compound and the pharmaceutically acceptable salt thereof according to claim 2, wherein X is methylene, Y is a direct bond, and Z is selected from C ₆ -C ₁₀ aryl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, each of them can have 0-3 independent substituents as claimed in claim 2. 4. The compound and the pharmaceutically acceptable salt thereof according to claim 2, wherein X is methylene or CO, Y is a direct bond, and Z is thienyl, pyrrolidinyl, pyrrolyl, furyl, thiazolyl, Isoxazolyl, imidazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl and fused bicyclic ortho-benzo derivatives thereof, each of which may have 0-3 as claimed 2 independent substituents. 5. Compounds and pharmaceutically acceptable salts thereof according to claim 2 wherein X is _CH2 or CO; Y is the direct key; Z is H, unsubstituted vinyl, phenyl, imidazolyl, thiazolyl, thienyl, 1,2,4-triazolyl, pyridyl and pyrimidinyl. 6. A compound according to claim 5, wherein X is CO. 7. A compound according to claim 5, wherein X is _CH2 . 8. The compound according to claim 1, wherein the ring nitrogen atom of 1,2,3,4-tetrahydroisoquinoline in formula 1 and the XYZ moiety attached to the ring nitrogen atom in -XYZ The linking group formed by the group is selected from:

9. A compound according to claim 8, wherein the linking group is an amide. 10. A compound according to claim 9 selected from the group consisting of: 4'-trifluoromethyl-biphenyl-2-carboxylic acid (2-phenyl-acetyl-1,2,3,4-tetrahydroisoquinoline -6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-phenoxy-acetyl-1,2,3,4-tetrahydroisoquinoline-6- Base)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-pentanoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′ -Trifluoromethyl-biphenyl-2-carboxylic acid (2-cyclobutane-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethane Base-biphenyl-2-carboxylic acid [2-(thiophen-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoro Methyl-biphenyl-2-carboxylic acid (2-butyryl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl- 2-Carboxylic acid (2-ethoxy-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxy Acid {2-[(4-fluoro-phenyl)-acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide, 4′-trifluoromethyl-biphenyl -2-Carboxylic acid [2-(3-methyl-butyryl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl -2-Carboxylic acid (2-but-3-enoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2- Carboxylic acid (2-methoxy-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid ( 2-Ethylthio-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-( 6-diethyl-carbamoyl-cyclohex-3-enecarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl Base-2-carboxylic acid [2-(cyclopent-1-enyl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide, 4′-trifluoromethyl -Biphenyl-2-carboxylic acid (2-hex-3-enoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl Base-2-carboxylic acid [2-(tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl- 2-Carboxylic acid [2-(thiophen-3-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide, and 4′-trifluoromethyl-biphenyl Base-2-carboxylic acid [2-(pyridine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide. 11. A compound according to claim 8, wherein said linking group is urea. 12. A compound according to claim 11 selected from the group consisting of 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2 -Carboxylic acid phenylamide, 6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid hexylamide , 6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzylamide, 6-[( 4′-Trifluoromethyl-biphenyl-2-carboxylic acid)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid [(R)-1-phenyl-ethyl ]-amide, and 6-[(4′-trifluoromethyl-biphenyl-2-carboxylic acid)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyridine-2 -yl amides. 13. A compound according to claim 8, wherein said linking group is a sulfonamide. 14. A compound according to claim 13 selected from the group consisting of: 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(propane-2-sulfonyl)-1,2,3,4-tetrahydro -isoquinolin-6-yl]-amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid (2-dimethylsulfamoyl)-1,2,3,4-tetrahydro- Isoquinolin-6-yl]-amide, and 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-trifluoromethoxybenzenesulfonyl)-1,2,3,4 -tetrahydro-isoquinolin-6-yl]-amide. 15. A compound according to claim 8, wherein said linking group is thiourea. 16. A compound according to claim 15 which is 4'-trifluoromethyl-biphenyl-2-carboxylic acid (2-cyclopropylthiocarbamoyl-1,2,3,4-tetrahydro-iso Quinolin-6-yl]-amide. 17. A compound according to claim 8, wherein said linking group is N-alkyl. 18. A compound according to claim 17 selected from the group consisting of: 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,6,6-trimethyl-cyclohex-2-enylmethyl base)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,4-di Chloro-benzyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1, 5a, 6, 9, 9a, 9b-hexahydro-4H-dibenzofuran-4a-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide, 4' -Trifluoromethyl-biphenyl-2-carboxylic acid (2-thiophen-2-ylmethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide, 4'- Trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-pyrrol-2-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide, 4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-furan-2-ylmethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide, acetic acid 5-{6-[(4′-Trifluoromethyl-biphenyl-2-carboxylic acid)-amino]-3,4-dihydro-1H-isoquinolin-2-ylmethyl}-furan- 2-ylmethyl ester, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-thiophen-3-ylmethyl-1,2,3,4-tetrahydro-isoquinoline-6 -yl]-amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,5-dimethoxy-tetrahydrofuran-3-ylmethyl)-1,2,3, 4-tetrahydro-isoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-benzyl-1,2,3,4-tetrahydro-iso Quinolin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-isoquine Lin-6-yl)-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-quinolin-2-ylmethyl-1,2,3,4-tetrahydro-isoquinol Lin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-chloro-benzyl)-1,2,3,4-tetrahydro-isoquinol Lin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-pyrimidin-2-ylmethyl-1,2,3,4-tetrahydro-isoquinoline -6-yl]-amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-nitrobenzyl)-1,2,3,4-tetrahydro-isoquinoline -6-yl]-amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydro- Isoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1-methyl-pyrrol-2-ylmethyl)-1,2,3 , 4-tetrahydro-isoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-benzimidazol-2-ylmethyl)- 1,2,3,4-Tetrahydro-isoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-thiazol-2-ylmethyl)- 1,2,3,4-Tetrahydro-isoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1-methyl-imidazole-2 -ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H- [1.2.4] Triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide, and 4′-trifluoromethyl-biphenyl- 2-Carboxylic acid [(2-allyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide. 19. A compound according to claim 8, wherein said linking group is a carbamate. 20. A compound according to claim 19 which is 6-[(4'-trifluoromethyl-biphenyl-2-carboxy)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxy Acid tert-butyl ester. 21. A compound according to claim 8, wherein said linking group is a thioamide. 22. A compound according to claim 8 selected from the group consisting of 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(thiophen-2-yl-acetyl)-1,2,3,4-tetra Hydrogen-isoquinolin-6-yl]amide, 6-[(4′-trifluoromethyl-biphenyl-2-carboxy)-amino]-3,4-dihydro-1H-isoquinoline-2 -Carboxylic acid ([R]-1-phenylethyl)-amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid (2-pyridin-2-ylmethyl-1,2,3 , 4-tetrahydro-isoquinolin-6-yl]amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-imidazol-2-ylmethyl)-1,2 , 3,4-tetrahydro-isoquinolin-6-yl]amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-thiazol-2-ylmethyl)-1,2, 3,4-tetrahydro-isoquinolin-6-yl]amide, and 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-[1,2,4]triazole- 3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]amide. 23. A compound according to claim 22 which is 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(thiophen-2-yl-acetyl)-1,2,3,4-tetrahydro -isoquinolin-6-yl]-amide. 24. The compound according to claim 22, which is 6-[(4'-trifluoromethyl-biphenyl-2-carboxy)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxy Acid (1-phenyl-ethyl)-amide. 25. A compound according to claim 22 which is 4'-trifluoromethyl-biphenyl-2-carboxylic acid (2-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-isoquine olin-6-yl)-amide. 26. The compound according to claim 22, which is 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-imidazol-2-ylmethyl)-1,2,3,4-tetra Hydrogen-isoquinolin-6-yl]-amide. 27. The compound according to claim 22, which is 4'-trifluoromethyl-biphenyl-2-carboxylic acid (2-thiazol-2-ylmethyl-1,2,3,4-tetrahydro-isoquinone olin-6-yl)-amide. 28. The compound according to claim 22, which is 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-[1,2,4]triazol-3-ylmethyl)-1 , 2,3,4-Tetrahydro-isoquinolin-6-yl]-amide. 29. A pharmaceutical composition comprising the compound of formula 1 as defined in claim 1 and a pharmaceutically acceptable carrier. 30. The compound of formula I of claim 1 is used in the preparation of a drug selected from the group consisting of atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia and diabetes or in the preparation of The use of drugs that reduce the amount of apolipoprotein B secretion. 31. Use according to claim 30, wherein said disease is selected from the group consisting of atherosclerosis, pancreatitis, obesity and diabetes. 32. Use according to claim 31, wherein said disease is selected from atherosclerosis. 33. A compound selected from the group consisting of: 4'-Trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide 4'-Trifluoromethyl-biphenyl-2-carboxylic acid [3-(2-hydroxyethyl)-4-hydroxymethyl-phenyl]-amide