HK1121679A - Preparation and use of aryl alkyl acid derivatives for the treatment of obesity - Google Patents

Description

Aralkyl acid derivative and use thereof

[001] This application claims benefit from U.S. provisional application serial No. 60/673,149, filed on 19/4/2005, which is incorporated herein by reference in its entirety.

Technical Field

[002] The present invention relates to aralkyl acid compounds, compositions and methods for treating or preventing obesity and related diseases.

Background

[003] Obesity, which is a chronic disease very prevalent in modern society, refers to excess body fat relative to fat removal. It not only brings about troubles in social interaction, but also may cause life shortening and various Medical problems including mental retardation, coronary heart disease, hypertension, stroke, diabetes, hyperlipidemia, and some cancers (see, for example, Nishina et al, Metab.43: 554-.

[004] Obesity remains a problem to be solved, and there is a limitation in its treatment. Therefore, there is a need to develop drugs and treatment regimens that are effective in relieving obesity.

[005] Obesity is characterized by an increase in White Adipose Tissue (WAT) mass mainly caused by triacylglycerol accumulation. This increase in WAT mass is a key factor in causing complications associated with obesity. Diacylglycerol O-acyltransferases (DGATs, EC 2.3.1.2) are membrane-bound enzymes that catalyze the finishing step of triacylglycerol biosynthesis. Two enzymes that exhibit DGAT activity are: DGAT-1 (diacylglycerol O-acyltransferase type 1) (see, for example, U.S. Pat. No. 6,100,077; Cases et al, Proc. Nat. Acad. Sci.95: 13018-13023, 1998) and DGAT-2 (diacylglycerol O-acyltransferase type 2) (Cases et al, J.biol. chem.276: 38870-38876, 2001). There is no significant protein sequence identity for DGAT-1 and DGAT-2. Importantly, DGAT-1 deficient mice are not obese relative to wild type siblings when challenged with a high fat diet (Smith et al, Nature genetics 25: 87-90, 2000). DGAT-1 deficient mice display reduced postprandial plasma glucose levels and have increased energy expenditure, but normal levels of serum triglycerides (Smith et al, 2000), which may be attributed to preservation of DGAT-2 activity. Since DGAT-1 is expressed in intestinal and adipose tissues (Cases et al, 1998), there are at least two possible mechanisms that may explain the ability of DGAT-1 deficient mice to tolerate diet-induced obesity. First, clearance of DGAT-1 activity in the intestine can block the reformation of triacylglycerols and their transfer from intestinal cells to the circulation via chylomicrons. Second, elimination of DGAT-1 activity in adipocytes can reduce deposition of triacylglycerols in WAT. The phenotype of DGAT-1 deficient mice, and our findings with DGAT-1 inhibitors in diet-induced obesity (DIO) mice, suggest that DGAT-1 inhibitors are useful for the treatment of obesity and obesity-related complications.

Detailed Description

[006] The present invention relates to aralkanoic acid derivatives and pharmaceutically acceptable salts and esters thereof which are useful for inhibiting DGAT-1 (diacylglycerol O-acyltransferase type 1) and for treating obesity and related diseases.

[007] One embodiment of the present invention are compounds of formula (I)

Wherein

R²And R³Are all hydrogen, and R¹Is hydrogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy radical- (C₂-C₆) Alkyl, phenoxy- (C)₂-C₆) Alkyl, 1-methyl-1H-indol-3-yl, di [ (C)₁-C₆) Alkyl radical]Amino group- (C)₂-C₆) Alkyl, 1-piperidinyl- (C)₂-C₆) Alkyl, 1-pyrrolidinyl- (C)₂-C₆) Alkyl or 1-morpholinyl- (C)₂-C₆) An alkyl group;

or

R¹Is R⁶(CH₂)_mWherein m is 0 to 3, and R⁶Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano, or nitro;

or

R⁶Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro; or

R³Is hydrogen, and R¹And R²Are identical and are each selected from (C)₁-C₆) An alkyl group;

or

R³Is hydrogen, and R¹And R²Together with the carbon atom to which they are attached, form a 3-to 5-membered carbocyclic ring, or are formed of

A 6-membered ring represented by wherein W is CH₂、C(CH₃)₂、O、NH、N(CH₃) S or SO₂；

Or

R¹Is hydrogen, and R²And R³Together with the two carbon atoms to which they are attached, form a 3-to 6-membered carbocyclic ring;

R⁴and R⁵Independently selected from hydrogen, hydroxy, halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl and cyano;

q is R⁷-C (O) -, wherein R⁷Is optionally substituted by one or more of the following groups₁-C₆) Alkyl groups: hydroxy, (C)₁-C₆) Alkoxy, di [ (C)₁-C₆) Alkyl) amino or fluoro;

or

R⁷Is R⁸(CH₂)_nWherein n is 0-3, and R⁸Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁸Is 2-pyridyl, 3-pyrinePyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁷Is R¹⁰C(R⁹)₂Wherein R is⁹Is a methyl group or an ethyl group,

or

C(R⁹)₂Is a 1, 1-cyclopropyl, 1-cyclobutyl, 1-cyclopentyl, or 1, 1-cyclohexyl ring;

R¹⁰is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁰Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro; or

R⁷Is a fragment radical selected from

Wherein R is¹¹Is one or more substituents selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano and nitro;

or

Q is R¹³-N(R¹²) -C (O) -, wherein R¹²Is hydrogen or (C)₁-C₆) Alkane (I) and its preparation methodA base of and

R¹³is optionally substituted by one or more of the following groups₁-C₆) Alkyl groups: hydroxy, (C)₁-C₆) Alkoxy, di [ (C)₁-C₆) Alkyl) amino or fluoro;

or

R¹³Is R¹⁴(CH₂)_pWherein p is 0-3, and R¹⁴Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁴Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹²And R¹³Together with the nitrogen atom to which they are attached form a ring segment selected from

Wherein L is O, C (O) or a bond;

R¹⁵is (C)₁-C₆) An alkyl group;

or

R¹⁵Is R¹⁷(CH₂)_qWherein q is 0 or 1, and R¹⁷Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoroMethyl, cyano or nitro;

or

R¹⁷Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

R¹⁶is one or more substituents selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano and nitro;

or

Q is R¹⁸-S(O)₂-, wherein R¹⁸Is (C)₁-C₆) Alkyl or benzyl;

or

R¹⁸Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

a is OH or NHS (O)₂-R¹⁹

Wherein R is¹⁹Is (C)₁-C₆) Alkyl, trifluoromethyl, benzyl;

or

R¹⁹Is R²⁰(CH₂)_tWherein t is 0 or 1, and R²⁰Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁹Is a fragment radical selected from

V, Y and Z are all carbon; or

V and Y are carbon and Z is nitrogen; or

V and Z are carbon and Y is nitrogen; or

Z is carbon and V and Y are both nitrogen;

and the pharmaceutically acceptable salts and esters thereof,

with the proviso that formula (I) is not 4- [4 ' - (acetylamino) -3 ' -bromobiphenyl-4-yl ] -4-oxobutanoic acid, 4- [4 ' - (acetylamino) biphenyl-4-yl ] -4-oxo-2- (2-phenylethyl) butanoic acid, 4- {4 ' - [ (3, 3-dimethylbutyryl) amino ] biphenyl-4-yl } -4-oxo-2- (2-phenylethyl) butanoic acid, or 4-oxo-4- [4 ' - (pentanoylamino) biphenyl-4-yl ] -2- (2-phenylethyl) butanoic acid.

[008] Examples of the invention can be found in the examples and tables described below. The compounds described in the examples are meant to be representative of the invention, and it will be understood that the scope of the invention is not limited by the scope of the examples. One skilled in the art will recognize that the present invention may be practiced with modification based on the disclosed structures, materials, compositions, and methods, and such modifications are considered to be within the scope of the present invention.

[009] The above terms have the following meanings:

[010] the term "halogen" refers to F, Br, Cl and I.

[011]Term "(C)₁-C₆) Alkyl "and" (C)₂-C₆) Alkyl "refers to straight or branched chain saturated hydrocarbon groups having from about 1 to about 6 carbon atoms or from 2 to about 6 carbon atoms, respectively. The hydrocarbyl group may also include a cyclic alkyl group as part of the alkyl group. Such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, cyclopropylCyclohexyl, cyclopropyl-methyl, and cyclopentyl-methyl.

[012]Term "(C)₁-C₆) Alkoxy "refers to a straight or branched chain saturated hydrocarbon group having from about 1 to about 6 carbon atoms, said group being attached to an oxygen atom. The alkoxy substituent is attached to the rest of the molecule through the oxygen atom. The hydrocarbyl group may also include a cyclic alkyl group as part of the alkyl group. Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-hexyloxy, 3-dimethylpropoxy, cyclopropoxy, cyclopropylmethoxy, cyclopentyloxy, and the like.

[013] The term "optionally substituted" means that the modified group has from 0 to at least the maximum number of substituents shown. Each substituent may replace any hydrogen atom on the modified group, provided that such replacement is chemically possible and stable. When two or more substituents are present on any group, each substituent is selected independently of any other substituent and thus may be the same or different.

[014] When any moiety is described as substituted, the moiety may have one or more of the indicated substituents, which may be located at any possible position on the moiety. When there are two or more substituents on any moiety, each term should be defined independently of any other term appearing in each.

[015] Exemplary salts of the compounds of formula (I) include conventional non-toxic salts and quaternary ammonium salts formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, Thiocyanate, tosylate, and undecanoate.

[016] Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine. In addition, the basic nitrogen-containing groups can be quaternized using various agents, such as: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, and dibutyl sulfates and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl bromide and phenethyl bromide and the like.

[017] The esters of the present invention are non-toxic, pharmaceutically acceptable ester derivatives of the compounds of formula (I). It may include ester derivatives of the compounds of formula (I) containing a hydroxyl group, prepared, for example, with acetic, benzoic, mandelic, stearic, lactic, salicylic, hydroxynaphthoic, glucoheptonic, and gluconic acids. It may also include ester derivatives of carboxylic acid-containing compounds of formula (I), for example, prepared with pharmaceutically acceptable alcohols. Pharmaceutically acceptable alcohols include, but are not limited to, methanol, ethanol, isopropanol, butanol, 2-methylpropanol, 2-methoxyethanol, 2- (dimethylamino) ethanol, 2- (diethylamino) ethanol, 2- (1-piperidinyl) ethanol, 2- (1-morpholinyl) ethanol, glycolic acid, N-dimethyl-2-hydroxyacetamide, hydroxyacetone, and the like. The compounds of formula (I) having a carboxylic acid group may be esterified by various conventional techniques well known to those skilled in the art. One skilled in the art can readily appreciate how to successfully accomplish the above steps as well as other esterification methods.

[018] Certain sensitive or reactive groups on the compounds of formula (I) may require protection in any of the above-described ester-forming processes, and so protecting groups may be added and removed by conventional methods well known in the art.

[019] The compounds of the invention may exist in various isomeric forms due to the nature of the asymmetric center or restricted to rotation. Any isomer may be present, with any one of the asymmetric centers being in each of the (R) -, (S) -or racemic (R, S) configurations.

[020] It will also be appreciated that if two or more asymmetric centers are present in the compounds of the invention, several diastereomers and enantiomers of the exemplified structures are generally possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. This means that pure stereoisomers, pure diastereomers, pure enantiomers and mixtures thereof are within the scope of the invention.

[021] All isomers of the compounds of the present invention, whether isolated, pure, partially pure, or in the form of a racemic mixture, are within the scope of the present invention. Purification of the isomers and separation of the isomeric mixtures may be accomplished by a variety of standard techniques known in the art.

[022] Geometric isomers due to substituents relative to double bonds or rings may exist in either the cis (═ Z-) or trans (═ E-) forms, and both isomeric forms are within the scope of the present invention.

[023] The particular method used in preparing the compounds of the present invention will depend upon the particular compound desired. Factors such as the choice of a particular group and the particular substituents on each group can have a role in preparing a particular compound of the invention. These factors can be readily ascertained by one of ordinary skill in the art.

[024] For the synthesis of any one particular compound, it will be understood by those skilled in the art that the use of protecting groups may be required for the synthesis of compounds containing certain substituents. Suitable protecting Groups and suitable methods for adding and removing such Groups are described, for example, in Protective Groups in Organic Synthesis, Second Edition, T.W.Greene, John Wiley and Sons, New York, 1991.

[025] In the following reaction schemes, it will be understood by those skilled in the art that the various reagents and solvents actually used may be selected from several reagents and solvents known in the art to be reasonably effective. Thus, where specific reagents or solvents are shown in a reaction scheme, they are meant to be illustrative examples of the conditions required to complete that particular reaction scheme. Abbreviations not identified with accompanying sentences are listed subsequently in the "abbreviations and acronyms" of this specification.

[026] The invention also relates to a method for producing the compounds according to the invention. These compounds can be prepared from readily available materials by the methods outlined in the reaction schemes and examples below, with simple modifications.

General preparation of the Compounds of the invention

[027] The preparation of the compounds of the present invention having formula (I) can be accomplished by the methods described in reaction schemes 1-9 below.

[028]In scheme 1, a compound of formula (II) is reacted with a boronic acid or boronic ester of formula (III) in the presence of a palladium catalyst such as PdCl₂(dppf) to form an intermediate of formula (V). Reduction of the nitro group in the compound of formula (V) may be achieved by standard methods, for example iron/acetic acid, to form the corresponding amino compound of formula (VI). An alternative route to form compounds of formula (VI) is to carry out a palladium catalysed coupling reaction of a compound of formula (II) with an optionally amino protected boronic acid or ester of formula (IV), followed by removal of the protecting group if required to form a compound of formula (VI). The nitro or aminoboronic acid/boronic ester reagents (III) and (IV), respectively, are either commercially available or can be prepared from the corresponding readily available halonitrobenzene by methods well known in the art.

[029]Reaction scheme 1

R ═ H or alkyl

X ═ Cl, Br or I

R ″ ═ H or alkyl, and two R ″ may form a ring

Optional protecting group PG ═

[030] An additional process for preparing the compound of formula (VI) is shown in reaction scheme 2, which is useful when the boronic acids or boronic esters of (III) and (IV) are not readily available. The preparation of boronic esters of formula (VII) from the corresponding compounds of formula (II) is accomplished by reacting (II) with a boronic ester reagent such as pinacolborane (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane) to form intermediates of formula (VII). This boronic ester reagent of formula (VII) may then be coupled with an optionally protected compound of formula (VIII) in the presence of a palladium catalyst and a base such as potassium carbonate to form an intermediate of formula (VI).

[031]Reaction scheme 2

R ═ H or alkyl

X ═ Cl, Br or I

R ″ ═ H or alkyl, and two R ″ may form a ring

Optional protecting group PG ═

[032]The compounds of formula (II) can be prepared by various methods described in the literature, for example, variations of the methods described in us patent application 2004/0224997 and us patent 5,789,434. For example, wherein R²And R³Compounds of formula (II) which are both hydrogen may be reacted, for examplePrepared as shown in scheme 3: the malonic acid ester of formula (IX) is alkylated with phenacyl bromide of formula (X) in the presence of a strong base such as sodium hydride to give the intermediate of formula (XI). (XI) is hydrolyzed and decarboxylated to give the compound of formula (IIa) [ wherein R²And R³Are all H (II)]。

[033]Reaction scheme 3

[034] The compounds of formula (II) can also be prepared from readily available anhydrides of formula (XII) or acid chloride-esters of formula (XIII) by Friedel-Crafts acylation as shown in scheme 4.

[035]Reaction scheme 4

[036]Intermediates of formula (XIII) are commercially available or can be prepared from readily available precursors using simple methods. Preparation of formula (XIIIa) [ wherein R³Is H (XIII)]The general procedure of (a) is shown in reaction scheme 5. Esterifying the substituted carboxylic acid of formula (XV) to provide a substituted ester of formula (XVI); the ester is alkylated with tert-butyl bromoacetate to give the diester of formula (XVII). Selective removal of the tert-butyl group under acidic conditions affords the monoacid monoesters of the formula (XVIII) which can be obtained by standard methods (e.g. SOCl)₂) To the ester-acid chloride of formula (XIIIa).

[037]Reaction scheme 5

[038]Wherein R is¹Is hydrogen and R²And R³The preparation of the compounds of formula (II) with the two carbon atoms to which they are attached forming a ring is outlined in reaction scheme 6. This reaction scheme illustrates a general procedure for obtaining compounds of formula (II) in which stereoisomers may be present, and specifically illustrates the preparation of the (R, R) diastereomers of formula (IId) and (IIe).

[039]In scheme 6, the anhydride of formula (XIIb) [ wherein R is¹Is hydrogen, and R²And R³Two carbon atoms attached thereto form a ring of formula (XII)]Converted into the compound of formula (XIIIb). Following the method of scheme 4, the compound of formula (IIb) is prepared from the compound of formula (XIIIb). The compound of formula (IIb) can be converted to the compound of formula (IIc) by basic hydrolysis. If desired, (IIc) can be resolved into its optical antipodes by standard methods, for example by selective crystallization of the diastereomeric salts thereof with a photoactive base such as (R) -or (S) -1-phenylethylamine, and liberating the optically pure compound by acidification of the salt. Thus, compounds of formula (IId) may be prepared and converted to the corresponding esters of formula (IIe).

[040]Reaction scheme 6

[ formulae (IIb) to (IIe) represent wherein R¹Is hydrogen and R²And R³The two carbon atoms to which they are attached form the ring of formula (II). The ring is optionally substituted with up to two R⁸Is substituted by radicals, and n is 1, 2, 3 or 4]

[041] It will be appreciated that different diastereomeric compounds of formula (I) can be prepared by converting intermediates of formulae (IIb) - (IIe) into the corresponding compounds of formula (I) separately by the methods outlined herein.

[042]Can be prepared by methods known in the art and by the methods described herein, examplesE.g. by using compounds1(prepared as described in Jun, et al, Bull. Korean chem. Soc. 9: 206-209, 1988);2(see, for example, the method described in U.S. patent 6,562,828);3and4(see, e.g., Carlon, et al, org.Prep.Proc.Int.9: 94-96, 1977; U.S. Pat. No. 3,256,277; Bushweller, et al, J.org.chem.54: 2404-2409, 1989) to prepare further compounds of formula (II).

[043]In addition, the compounds of formula (II) may be prepared by using other methods known in the art. For example, the following specific compounds of formula (II) are prepared, labeled5-8The following methods may be used:5(see, e.g., WO 9615096 and U.S. Pat. No. 5,789,434);6(see, for example, the process described in WO 9717317);7(see, e.g., methods described by van der Mey, et al, J.Med.chem.44: 2511-2522, 2001; Garre, et al, Acta chem.Scand.51: 1229-1233, 1997; Kuchar, et al, Coll.Czech.chem.Commun.51: 2617-25, 1986); and8(see, for example, the methods described by Kawamatsu, et al, Arzneim. Forsch.30: 454-459, 1980; Bajaj, et al, J.Indian chem.Soc.52: 1076-1078, 1975).

[044]The compound of formula (VI) prepared as described above is then converted to the compound of formula (I) by one of the methods described in reaction scheme 7. For example, a compound of formula (VI) is reacted with a carboxylic acid chloride or fluoride, or with a carboxylic acid plus a coupling agent such as N, N' -dicyclohexylcarbodiimide to form the corresponding carboxylic acid amide, and the ester group-COOR can then be hydrolyzed under standard ester hydrolysis conditions to give a compound of formula(Ia) Compounds [ wherein Q is R⁷-C (O) -and A is OH (I)]。

[045]Alternatively, reacting a compound of formula (VI) with an isocyanate derivative R¹³Reaction of-N ═ C ═ O to form the corresponding urea derivative, and the ester group-COOR can then be hydrolyzed under standard ester hydrolysis conditions to give the compound of formula (Ib) [ wherein Q is R¹³-NH-CO-and A is OH (I)]. Other standard methods of urea formation may be used, for example amine R¹³-NH₂Reaction with carbonyldiimidazole to form an N-acylimidazole intermediate which is then reacted with a compound of formula (VI) and the ester group is subsequently hydrolyzed to give a compound of formula (Ib) [ wherein Q is R¹³-NH-CO-and A is OH (I)]。

[046]Reaction scheme 7

[047]Likewise, the compound of formula (VI) may be reacted with phosgene or a substituent such as triphosgene to form an isocyanate intermediate which is then reacted with a primary or secondary amine (R)¹²R¹³NH) to form the corresponding urea derivative. The ester group-COOR can then be hydrolyzed under standard ester hydrolysis conditions to yield a compound of formula (Ic) [ wherein Q is R¹³-N(R¹²) -CO-and A is OH (I)]。

[048]Furthermore, the compounds of the formula (VI) can be reacted with sulfonyl chlorides (R)¹⁸SO₂Cl) to form the corresponding sulfonamide derivative, and the ester group-COOR can then be hydrolyzed under standard ester hydrolysis conditions to obtain the compound of formula (Id) [ wherein Q is R¹⁸-S(O)₂And A is OH (I)]。

[049]Additional compounds of formula (I) may be prepared by the methods described in reaction scheme 8. In this process, a malonate intermediate of formula (XXIII) is first prepared by a method analogous to that described above. The diester is then treated with a strong base such as sodium hydride, followed by an alkylating agent such as an alkyl iodideOr alkyl tosylate to give an intermediate which is hydrolysed and decarboxylated under standard conditions to give a compound of formula (Ie) [ wherein R²And R³Are both hydrogen and A is OH]The compound (I) of (1).

[050]Reaction scheme 8

R ═ alkyl or benzyl

X ═ Cl, Br or I

R ″ ═ H or alkyl, and two R ″ may form a ring

[051]Wherein A is-NHS (O)₂-R¹⁹The compounds of formula (I) wherein A is OH may be prepared by treating a compound of formula (I) with an alkyl or aryl sulphonamide together with a coupling agent such as N, N' -dicyclohexylcarbodiimide, with the addition of a base such as 4- (dimethylamino). The process is depicted in reaction scheme 9.

[052]Reaction scheme 9

[053] Examples of the invention can be found in the examples and tables described below. The compounds described in these examples are meant to be illustrative of the invention, it being understood that the scope of the invention is not limited to these examples. It will be appreciated by those skilled in the art that various modifications may be made to the disclosed structures, materials, compositions and methods, and such modifications are considered to be within the scope of the present invention.

Preparation of the Compounds of the invention

General knowledge

Mass spectrometry

[054] Chemical ionization mass spectrometry (CI-MS) was obtained using a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 gas chromatograph with a J & W DB-5 column (0.25uM coating; 30m × 0.25 mm). The ion source was maintained at 250 ℃ and the spectrum was scanned at 2 seconds per scan by 50-800 amu.

[055] Liquid chromatography-electrospray mass spectrometry (LC-MS) data were obtained using one of the following two methods. In the examples and tables provided below, the LC-MS data are expressed as HPLC retention time (ret time). Method 1 was used unless otherwise indicated.

[056]Method 1: Hewlett-Packard 1100 HPLC equipped with a quaternary pump, variable wavelength detector set at 254nm, YMC pro C-18 column (2X 23mm, 120A), and Finnigan LCQ ion collection mass spectrometer with electrospray ionization. The spectra were scanned by 120-. The eluent is A: aqueous 2% acetonitrile containing 0.02% TFA, B: a 2% water in acetonitrile containing 0.018% TFA. Elution was from a 10% B gradient to 95% B over 3.5 minutes, using a flow rate of 1.0mL/min, initially for 0.5 minutes and finally for 0.5 minutes at 95% B. The total run time was 6.5 minutes.

[057]Method 2: a Gilson HPLC system equipped with the following instruments: two Gilson 306 pumps, Gilson 215 autosampler, Gilson diode array detector, YMC Pro C-18 column (2X 23mm, 120A) and Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. The spectra were scanned from 120 to 800amu in 1.5 seconds. Elsd (evaporative Light Scattering detector) is also available as a similar channel. The eluent is A: a mixture of 2% acetonitrile in water containing 0.02% TFA, and B: a mixture of 2% water in acetonitrile containing 0.018% TFA. Elution was performed with a gradient from 10% B to 90% B at a flow rate of 1.5 mL/min over a period of 3.5 minutes,hold was started for 0.5 min and finally at 90% B for 0.5 min. The total run time was 4.8 minutes. An additional on-off valve is used for column switching and regeneration.

NMR spectra

[058]Conventional one-dimensional NMR spectroscopy was performed on a 300MHz or 400MHz VarianMercury-plus spectrometer. The sample was dissolved in deuterated solvent obtained from Cambridge Isotrope Labs and transferred to a 5mm ID Wilmad NMR tube. Spectra were taken at 293 ° K. Chemical shifts are recorded on the ppm scale against the appropriate solvent signal, e.g. for¹For H spectrum, 2.49ppm vs. DMSO-d₆1.93ppm vs. CD₃CN, 3.30ppm vs. CD₃OD, 5.32ppm vs. CD₂Cl₂And 7.26 ppm vs. CDCl₃(ii) a For the¹³For the C spectrum, 39.5ppm vs. DMSO-d₆1.3ppm vs. CD₃CN, 49.0ppm vs CD₃OD, 53.8ppm vs. CD₂Cl₂And 77.0ppm vs. CDCl₃。

Chiral chromatography

[059] Chiral chromatography was performed by using Pirkle chromatography (R, R) Whelk-O210/100 from Regis Technologies as the stationary phase. Mobile phases included a ═ hexane (containing 0.1% TFA) and B ═ isopropanol (containing 0.1% TFA). A typical gradient is 10% B to 60% B over 25 minutes. In some cases, a gradient of 10-90% B or 50-90% is used. Quantification and fraction collection were performed based on UV detection at 330nm (also at 280 nm). Prior to injection, the sample is typically dissolved in DMF; for analytical procedures, these samples were further diluted with methanol. For analytical procedures, a 4.6 × 250mm column was used, the flow rate was 1 mL/min, and Shimadzu analytical HPLC. For the preparative run, a 20X 250mm column was used, with a flow rate of 25 mL/min, and Gilson HPLC, the injected amount of sample was typically 50 mg.

Abbreviations and acronyms

[060] When used in this disclosure, the following abbreviations have the following meanings:

CDCl₃deuterated chloroform

DCE Dichloroethane

DCM dichloromethane

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DMSO-d₆Deuterated dimethyl sulfoxide-

EtOAc ethyl acetate

h hours

GC-MS gas chromatography-mass spectrometry

HPLC high pressure liquid chromatography

LC-MS liquid chromatography-mass spectrometry

MeOH methanol

min for

MS mass spectrometry

NMR nuclear magnetic resonance

PdCl₂(dppf) 1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)

Oral administration of p.o. drugs

PS-DIEA diisopropylaminomethyl polystyrene

(available from Argonaut Technologies, San Carlos, CA, USA)

Rf TLC retention factor

rt Room temperature

RT retention time

TFA trifluoroacetic acid

TFFH Tetramethylfluoro-formamidine hexafluorophosphate

(available from Advanced Chemtech, Louisville, KY, USA)

THF tetrahydrofuran

TLC thin layer chromatography

Examples

[061]Example 1

Preparation of 2-benzyl-4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]-butyric acid

[062]Step 1 preparation of 2-benzyl-2- [2- (4-bromophenyl) -2-oxoethyl]Malonic acid Diethyl ester

[063]The process is based on the process described in us patent 5,789,434. To a 500-mL 3-necked round bottom flask equipped with an argon inlet, septum and addition funnel was added sodium hydride (95%, 1.05g, 44mmol) followed by anhydrous tetrahydrofuran (30 mL). The suspension was then cooled to 0 ℃ and diethyl benzylmalonate (10.0g, 40mmol) was added dropwise to tetrahydrofuran over 20 minutesSolution in pyran (20 mL). The ice bath was removed and the reaction mixture was heated to room temperature and then stirred for 45 minutes. A solution of 2, 4' -dibromoacetophenone (11.1g, 40mmol) in tetrahydrofuran (40mL) was then added to the stirred mixture. The reaction mixture was stirred at room temperature under argon overnight, then the reactor was cooled in an ice bath while carefully dropping 75mL of water. The aqueous layer was extracted with 200mL of dichloromethane. The combined organic phases were washed with 10% aqueous hydrochloric acid (50mL) and saturated aqueous sodium bicarbonate (50mL), dried over sodium sulfate, and concentrated under reduced pressure to give 2-benzyl-2- [2- (4-bromophenyl) -2-oxoethyl]Diethyl malonate as a red oil (16.8g, 94.3%). TLC Rf ═ 0.85 (1: 4 ethyl acetate/hexane); LC-MS RT 3.49 min (method 2), m/z 447 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ7.79(d，2H)，7.61(d，2H)，7.19(m，3H)，6.90(m，2H)，4.21(m，4H)，3.50(s，2H)，3.40(s，2H)，1.22(m，6H).

[064]Step 2 preparation of ethyl 2-benzyl-4- (4-bromophenyl) -4-oxobutanoate

[065]To 2-benzyl-2- [2- (4-bromophenyl) -2-oxoethyl]To a solution of diethyl malonate (16.8g, 37.6mmol) in acetone (18.5mL) and ethanol (17.0mL) was added a 1N aqueous solution of sodium hydroxide (37.6mL, 37.6mmol), and the resulting solution was heated at 50 ℃ for 3 hours. The solvent was removed under reduced pressure and the residue was dried under high vacuum for 1 hour. The residue was then redissolved in dichloroethane (46mL) and heated at 80 ℃ for 2.5 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 2-benzyl-4- (4-bromophenyl) -4-oxobutyrate as a red oil (10.0g, 71.5%). TLC Rf ═ 0.80 (1: 4 ethyl acetate/hexane); LC-MS RT 3.37min (method 2), m/z 375 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ7.68(d，2H)，7.50(d，2H)，7.19(m，5H)，4.05(m，2H)，3.25(m，2H)，3.00(m，1H)，2.80(m，2 H)，1.11(t，3H).

[066]Step 3. preparation of 2-benzyl-4- (4 '-nitro-1, 1' -biphenyl-4-yl) -4-oxo Butyric acid ethyl ester

[067]A mixture of ethyl 2-benzyl-4- (4-bromophenyl) -4-oxobutanoate (3.75g, 10.0mmol), 4-nitro-phenylboronic acid (1.8g, 11mmol) and 2N aqueous sodium carbonate (25mL) in toluene/dioxane (65mL/20mL) was degassed with a stream of argon for 20 minutes. Then, add [1, 1' -bis (diphenylphosphino) -ferrocene]Palladium (II) dichloride (1: 1 mixture with dichloromethane, 400mg, 0.5mmol) and the reaction mixture was heated at 85 ℃ for 5 hours. The reaction mixture was cooled to room temperature, filtered, and the organic layer was washed with water (50mL), dried over sodium sulfate, and concentrated under reduced pressure to give ethyl 2-benzyl-4- (4 '-nitro-1, 1' -biphenyl-4-yl) -4-oxobutanoate as a black gum (3.56g, 85%), which was used in the next step without purification. TLC Rf ═ 0.30 (1: 5 ethyl acetate/hexane); LC-MS RT 3.54 min (method 2), m/z 418 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ8.25(d，2H)，8.0(d，2H)，7.68(m，4H)，7.20(m，5H)，4.05(m，2H)，3.40(m，2H)，3.10(m，1H)，2.80-2.90(m，2H)，1.11(t，3H).

[068]Step 4. preparation of 4- (4 '-amino-1, 1' -biphenyl-4-yl) -2-benzyl-4-oxo Butyric acid ethyl ester

[069]To 2-benzyl-4- (4 '-nitro-1, 1'To a solution of ethyl (3.87g, 9.30mmol) of (E) -biphenyl-4-yl) -4-oxobutanoate in 85% ethanol (160mL) was added iron powder (5.0g, 89mmol), followed by 2N aqueous hydrochloric acid (5.0mL), and the resulting mixture was heated at reflux for 3 hours. The mixture was then cooled to room temperature, filtered through a pad of celite, and extracted with ethyl acetate. The combined organic phases were then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 4- (4 '-amino-1, 1' -biphenyl-4-yl) -2-benzyl-4-oxobutanoate as a brown solid (3.0g, 84%). TLC Rf ═ 0.50 (1: 4 ethyl acetate/hexane); LC-MS RT 2.80 min (method 2), m/z 388 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ7.90(m，2H)，7.70-7.35(m，6H)，7.30-7.20(m，3H)，6.70(m，2H)，4.05(m，2H)，3.40(m，2H)，3.10-2.80(m，3H)，1.11(t，3H).

[070]Step 5. preparation of 2-benzyl-4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl Radical-4-radical]Butyric acid

[071]To a solution of ethyl 4- (4 '-amino-1, 1' -biphenyl-4-yl) -2-benzyl-4-oxobutanoate (30mg, 0.078mmol) and valeryl chloride (13.9mg, 0.116mmol) in dichloromethane (1.0mL) was added PS-DIEA (43mg, 0.16mmol) and the resulting suspension was mixed by orbital shaking overnight at room temperature. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The solid residue was redissolved in 1mL of methanol/tetrahydrofuran (1: 1) and 1N aqueous sodium hydroxide (0.3mL) was added. The reaction mixture was shaken at room temperature overnight, then 2N aqueous hydrochloric acid (0.2mL) was added, and the mixture was concentrated under reduced pressure. The solid residue was dissolved in methanol and purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA). The product 2-benzyl-4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl is obtained]Butyric acid as a white solid (20mg, 59%). LC-MS RT 3.14 min (method 2), m/z 444 (MH)⁺)；¹H NMR(300MHz，DMF-d₇)δ12.60(s，1H)，10.10(s，1H)，8.02(d，2H)，7.85(m，4H)，7.75(d，2H)，7.32(m，4H)，7.10(m，1H)，3.37(m，1H)，3.12(m，2H)，2.90(m，2H)，2.40(t，2H)，1.62(m，2H)，1.37(m，2H)，0.94(t，3H).

[072]Example 2

Preparation of 4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]-2- (2-Phenylethyl) Yl) butyric acid

[073]Step 1. preparation of 4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4- Base of]-2- (2-phenylethyl) butanoic acid ethyl ester

[074]To a solution of ethyl 4- (4 '-amino-1, 1' -biphenyl-4-yl) -4-oxo-2- (2-phenylethyl) butyrate (4.63g, 11.5mmol, prepared as described in U.S. 2004/0224997) and valeryl chloride (1.67g, 13.8mmol) in dichloromethane (70mL) was added poly-4-vinylpyridine (3.8g, 34.6 mmol). The resulting suspension was stirred at room temperature for 3 hours and then filtered. The filtrate was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]-ethyl 2- (2-phenylethyl) butyrate (5.47g, 97%). LC-MS RT 3.83 min, m/z 486.5 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ0.91(t，3H)，1.23(t，3H)，1.33-1.41(m，2H)，1.68-1.75(m，2H)，1.82-2.01(m，2H)，2.29(t，2H)，2.64(t，2H)，3.05-3.18(m，2H)，3.41-3.48(m，1H)，4.10(q，2H)，7.15-7.24(m，6H)，7.51-7.62(m，6H)，7.94(d，2H).

[075]Step 2. preparation of 4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4- Base of]-2- (2-phenylethyl) butanoic acid.

[076]To 4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]To a solution of ethyl (2-phenylethyl) butyrate (5.23g, 10.8mmol) in methanol (52mL) was added a 1.0N aqueous solution of sodium hydroxide (37.7mL, 37.7 mmol). Tetrahydrofuran (52mL) was added to dissolve the precipitate formed during stirring. The mixture was heated at 50 ℃ for 2 hours and then concentrated by rotary evaporation. The residue was rapidly treated dropwise with 1.0N aqueous hydrochloric acid to form a thick yellow slurry, which was then filtered. The solid was washed with water and hexane and dried under reduced pressure at 40 ℃ to obtain 4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]-2- (2-phenylethyl) butanoic acid (4.8g, 97%). LC-MS RT 3.44 min, m/z 458.7 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ0.94(t，3H)，1.26-1.40(m，2H)，1.54-1.62(m，2H)，1.79-1.96(m，2H)，2.31(t，2H)，2.67(t，2H)，2.82-2.90(m，1H)，3.20(dd，1H)，3.38-3.46(m，1H)，7.15-7.28(m，5H)，7.70(s，4H)，7.77(d，2H)，8.00(d，2H)，10.01(s，1H)，12.1(s，1H).

[077]Example 3

Preparation of 4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]-2- (2-Phenylethyl) Yl) butyric acid sodium salt

[078]To 4-oxygen4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]A solution of (E) -2- (2-phenylethyl) -butyric acid (900mg, 1.97mmol, prepared as described in example 2) in ethanol (22mL) was added with a 1.0N aqueous solution of sodium hydroxide (1.93mL, 1.93mmol) at 40 deg.C and the resulting solution was stirred for 1 hour. The mixture was concentrated under reduced pressure, and the resulting solid was further dried under reduced pressure at 40 ℃ to obtain 4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Sodium-2- (2-phenylethyl) butyrate (802mg, 85%). LC-MSRT 3.43min., m/z 458.6 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ0.96(t，3H)，1.30-1.1.36(m，2H)，1.54-1.63(m，3H)，1.79-1.83(m，1H)，2.32(t，2H)，2.62-2.79(m，4H)，3.43(m，1H)，7.08-7.25(m，5H)，7.62-7.75(m，6H)，7.97(d，2H)，10.21(s，1H).

[079]Example 4

Preparation of 4-oxo-4- [4 '- (pentanoyl-amino) -1, 1' -biphenyl-4-yl]-2- (2-phenyl) Ethyl) butyric acid single enantiomer

[080]Racemic 4-oxo-4- [4 '- (valerylamino) -1, 1' -biphenyl-4-yl was eluted by preparative chiral chromatography using a Pirkle solvent (R, R) Whelk-O-210/100250X 4.5mm column (from Regis Technologies, Inc.) eluting with a 10-90% isopropanol/hexane gradient]-2- (2-phenylethyl) butanoic acid (prepared as described in example 2) was separated into its two single enantiomers. The two enantiomers were each separated in approximately 30% yield with > 90% enantiomeric purity; LC-MS and¹the H NMR analytical data are essentially as described above for the racemic compound.

[081]Example 5

Preparation of 4- [ 4' - ({ [ (3, 4-dimethylphenyl) amino)Base of]Carbonyl } amino) -1, 1' -biphenyl- 4-radical]-4-oxo-2- (2-phenylethyl) butanoic acid

[082]A mixture of ethyl 4- (4 '-amino-1, 1' -biphenyl-4-yl) -4-oxo-2- (2-phenylethyl) butyrate (25mg, 0.062mmol, prepared as described in U.S. 2004/0224997), 3, 4-dimethylphenyl isocyanate (18mg, 0.120mmol), and dichloromethane (1mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (0.30mL) and methanol (0.30 mL). Then aqueous sodium hydroxide (1N, 0.20mL, 0.20mmol) was added. The resulting mixture was stirred overnight and concentrated. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to give 4- [ 4' - ({ [ (3, 4-dimethyl-phenyl) amino]Carbonyl } amino) -1, 1' -biphenyl-4-yl]-4-oxo-2- (2-phenylethyl) butanoic acid as a white solid (6mg, 19% yield, two steps). LC-MSRT ═ 3.78 min, m/z 521.2 (MH)⁺)；¹H NMR(DMSO-d₆)δ1.75-1.98(m，2H)，2.17(s，3H)，2.19(s，3H)，2.61-2.72(m，2H)，2.78-2.91(m，1H)，3.15(dd，1H)，3.34(dd，1H)，7.01(d，1H)，7.12-7.34(m，7H)，7.57(d，2H)，7.69(d，2H)，7.99(d，2H)，8.04(d，2H)，8.64(brs，1H)，8.93(brs，1H)，12.23(brs，1H).

[083]Example 6

Preparation of 4- { 4' - [ (butylsulfonyl) amino]-1, 1' -biphenyl-4-yl } -4-oxo-2- (2- Phenylethyl) butyric acid

[084]To 4- (4' -amino-1)To a solution of ethyl 1' -biphenyl-4-yl) -4-oxo-2- (2-phenylethyl) butyrate (38.4mg, 0.096mmol, prepared as described in US 2004/0224997) and 1-butanesulfonyl chloride (16.5mg, 0.105mmol) in dichloromethane (0.75mL) was added poly-4-vinylpyridine (32mg, 0.29 mmol). The resulting suspension was stirred at room temperature for 16 hours and then filtered. The filtrate was washed with water and concentrated under reduced pressure. The mixture was then dissolved in methanol (0.6mL) and tetrahydrofuran (0.6mL) and 1.0N aqueous sodium hydroxide (0.4mL, 0.4mmol) was added. The mixture was heated at 50 ℃ for 2 hours and then concentrated under reduced pressure. Purification of the residue by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) gave 4- { 4' - [ (butylsulfonyl) amino]-1, 1' -biphenyl-4-yl } -4-oxo-2- (2-phenyl-ethyl) butanoic acid (12.6mg, 27%). LC-MS RT 4.04 min, m/z 494.2 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ0.88(t，3H)，1.32-1.38(m，2H)，1.73(m，2H)，1.89-1.96(m，1H)，2.08-2.12(m，1H)，2.73(t，2H)，3.02-3.17(m，4H)，3.47-3.53(m，1H)，6.81(s，1H)，7.13-7.28(m，7H)，7.47(d，2H)，7.56(d，2H)，7.95(d，2H).

[085]Example 7

Preparation of 4- [ 4' - ({ [1- (4-methoxyphenyl) cyclopropyl)]Carbonyl } amino) -1, 1' -biphenyl Radical-4-radical]-4-oxo-2- (2-phenylethyl) butanoic acid

[086]In an 8-mL screw-cap vial, 1- (4-methoxyphenyl) cyclopropanecarboxylic acid (100mg, 0.52mmol), TFFH (151mg, 0.57mmol), and PS-DIEA (loading level: 3.50mmol/g, 743mg, 2.6mmol) were combined in 8mL 1, 2-dichloroethane and heated at 35 ℃ while orbital shaking overnight. Formation of acyl fluoride was monitored by LC-MS. To this mixture was added methyl 4- (4 '-amino-1, 1' -biphenyl-4-yl) -4-oxo-2- (2-phenylethyl) butyrate (0.9 eq, 181mg,0.47mmol, prepared as described in us 2004/0224997), and the reaction mixture was again heated at 35 ℃ while shaking orbitally overnight. The mixture was cooled to room temperature, filtered through a filter tube (polypropylene frit) and the filtrate was evaporated under reduced pressure. The crude product residue was redissolved in 1mL MeOH and purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA). The methyl ester obtained was hydrolyzed as described previously and the product was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to yield 37mg of 4- [ 4' - ({ [1- (4-methoxyphenyl) -cyclopropyl ] -4]Carbonyl } amino) -1, 1' -biphenyl-4-yl]-4-oxo-2- (2-phenylethyl) butanoic acid (yield: 13%).¹H NMR(400MHz，DMSO-d₆) δ 12.20(bs, 1H), 9.00(s, 1H), 8.00(d, 2H), 7.80(d, 2H), 7.65(s, 4H), 7.15-7.40(m, 7H), 6.95(d, 2H), 3.75(s, 3H), 3.45(q, 1H), 3.20(m, 1H), 2.85(m, 1H), 2.70(m, 2H), 1.85(m, 2H), 1.40(t, 2H), 1.10(t, 2H); LC-MS (method 2) m/z 548.5 (MH)⁺) The holding time is 3.76min.

[087]Example 8

Preparation of 4- { 4' - [ (4-methoxybenzoyl) amino]-3-methyl-1, 1' -biphenyl-4-yl } -4- Oxo-2- (2-phenylethyl) butanoic acid

[088]A mixture of 4- (4 '-amino-3-methyl-1, 1' -biphenyl-4-yl) -4-oxo-2- (2-phenylethyl) -butyric acid ethyl ester (25mg, 0.060mmol, prepared as described in US 2004/0224997), 4-methoxybenzoyl chloride (20mg, 0.12mmol), diisopropylaminomethyl polystyrene (PS-DIEA) (0.050g, 0.18mmol) and dichloromethane (1mL) was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.30mL) and methanol (0.30mL), and 1N aqueous sodium hydroxide (0.20mL, 0.20mmol) was added. The resulting mixtureStirred overnight, filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to give 4- { 4' - [ (4-methoxybenzoyl) amino]-3-methyl-1, 1' -biphenyl-4-yl } -4-oxo-2- (2-phenylethyl) butyric acid as a white solid (9.6mg, 31% yield in two steps). LC-MS RT 3.63 min, m/z 522.2 (MH)⁺)；¹H NMR(CDCl₃)δ1.85-2.02(m，1H)，2.04-2.21(m，1H)，2.57(s，3H)，2.72-2.81(m，2H)，3.09(dd，1H)，3.14-3.22(m，1H)，3.48(dd，1H)，4.91(s，3H)，6.99(d，2H)，7.16-7.38(m，5H)，7.43-7.52(m，2 H)，7.62(d，2H)，7.72-7.80(m，3H)，7.81-7.93(m，3H).

[089]Example 9

Preparation of 4- { 3-methyl-4' - [ ({ [4- (trifluoromethyl) -phenyl)]-aminocarbonyl) -amino]-1，1′- Biphenyl-4-yl } -4-oxo-2- (2-phenylethyl) butanoic acid

[090]A mixture of ethyl 4- (4 '-amino-3-methyl-1, 1' -biphenyl-4-yl) -4-oxo-2- (2-phenylethyl) butyrate (0.025g, 0.060mmol, prepared as described in U.S. 2004/0224997), 4-trifluoromethylphenyl isocyanate (16mg, 0.12mmol) and dichloromethane (1mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.30mL) and methanol (0.30mL), and 1N aqueous sodium hydroxide (0.20mL, 0.20mmol) was added. The resulting mixture was stirred overnight, filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to give 4- { 3-methyl-4' - [ ({ [4- (trifluoromethyl) -phenyl ] -ethyl- [ ({ [4- (trifluoromethyl) -phenyl- ] -methyl- ] -4 [ (+) -ethyl- ] -methyl-4 { [1- (trifluoromethyl]-aminocarbonyl) -amino]-1, 1' -biphenyl-4-yl } -4-oxo-2- (2-phenyl-ethyl) butyric acid as a white solid (19mg, 56% yield, two steps). LC-MS RT 3.94 min, m/z 575.1 (MH)⁺)；¹H NMR(DMSO-d₆)δ1.73-2.00(m，2H)，2.44(s，3H)，2.61-2.71(m，2H)，2.78-2.92(m，1H)，3.14(dd，1H)，3.33(dd，1H)，7.15-7.34(m，5H)，7.57-7.77(m，10H)，7.89(d，1H)，9.04(s，1H)，9.20(s，1H)，12.29(br s，1H).

[091]Example 10

Preparation of 4- {3 '-fluoro-4' - [ (4-fluoro-3-methylbenzoyl) amino]-1, 1' -biphenyl-4- 2, 2-dimethyl-4-oxobutanoic acid

[092]To a solution of methyl 4- (4 ' -amino-3 ' -fluoro-1, 1 ' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoate (40mg, 0.12mmol, prepared as described in U.S. 2004/0224997) and 4-fluoro-3-methylbenzoyl chloride (25.1mg, 0.15mmol) in dichloromethane (2mL) was added poly-4-vinylpyridine (40mg, 0.36 mmol). The resulting suspension was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure, and the mixture was dissolved in methanol (1mL) and tetrahydrofuran (1mL) and 1.0N aqueous sodium hydroxide (0.5mL, 0.5mmol) was added. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to give 4- {3 '-fluoro-4' - [ (4-fluoro-3-methylbenzoyl) amino]-1, 1' -biphenyl-4-yl } -2, 2-dimethyl-4-oxobutanoic acid (14.4mg, 26% yield, two steps). LC-MS RT 3.36min, m/z452.0 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ1.24(s，6H)，2.32(s，3H)，3.34(s，2H)，7.3 0(t，1H)，7.64(dd，1H)，7.65-7.76(m，2H)，7.84-7.89(m，3H)，7.96(d，1H)，8.02(d，2H)，10.19(s，1H).

[093]Example 11

Preparation of 4- { 4' - [ (4-fluoro-3-methylbenzoyl) amino]-3 '-methyl-1, 1' -biphenyl-4- 2, 2-dimethyl-4-oxobutanoic acid

[094]This compound was prepared in a similar manner to that described in example 10 above using methyl 4- (4 ' -amino-3 ' -methyl-1, 1 ' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoate, prepared as described in us 2004/0224997. LC-MS RT 3.28 min, m/z 448.1 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ1.24(s，6H)，2.33(s，6H)，3.35(s，2H)，7.29(t，1H)，7.47(d，1H)，7.60(dd，1H)，7.67(s，1H)，7.82-7.88(m，3H)，7.94(dd，1H)，8.01(d，2H)，9.91(s，1H).

[095]Example 12

Preparation of 4- [ 4' - ({ [ (2-ethoxyphenyl) amino)]Carbonyl } amino) -3 '-fluoro-1, 1' -bi Phenyl-4-yl]-2, 2-dimethyl-4-oxobutanoic acid

[096]A mixture of methyl 4- (4 ' -amino-3 ' -fluoro-1, 1 ' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoate (40mg, 0.12mmol, prepared as described in U.S. 2004/0224997), 2-ethoxyphenyl isocyanate (24mg, 0.15mmol) in dichloromethane (2mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1mL) and methanol (1 mL). Then aqueous sodium hydroxide (1N, 0.5mL, 0.5mmol) was added. The mixture was then stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to give 4- [ 4' - ({ [ (2-ethoxyphenyl) amino]Carbonyl } amino group)-3 '-fluoro-1, 1' -biphenyl-4-yl]-2, 2-dimethyl-4-oxobutanoic acid (17.6mg, 30% yield, two steps). LC-MSRT 3.42min, m/z 479.5 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ1.24(s，6H)，1.43(t，3H)，3.34(s，2H)，4.15(q，2H)，6.90(t，1H)，7.02(d，1H)，7.57(dd，1H)，7.69(dd，1H)，7.83(d，2H)，8.01(d，2H)，8.11(dd，1H)，8.30(t，1H)，8，65(s，1H)，9.44(s，1H).

[097]Example 13

Preparation of 4- [ 4' - ({ [ (2-ethoxyphenyl) amino)]Carbonyl } amino) -3' -methyl-1, 1- Biphenyl-4-yl]-2, 2-dimethyl-4-oxobutanoic acid

[098]This compound was prepared in a similar manner to that described in example 12 above using methyl 4- (4 ' -amino-3 ' -methyl-1, 1 ' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoate, prepared as described in us 2004/0224997. LC-MS RT 3.37min, m/z 475.0 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ1.24(s，6H)，1.41(t，3H)，2.35(s，3H)，3.34(s，2H)，4.15(q，2H)，6.86-6.94(m，2H)，7.00(d，2H)，7.54(dd，1H)，7.61(s，1H)，7.78(d，2H)，7.92(d，1H)，8.00(d，2H)，8.08(dd，1H)，8.50(s，1H)，8，67(s，1H).

[099]Example 14

Preparation of 4- [ 4' - ({ [ (2-ethoxyphenyl) amino)]Carbonyl } amino) -3' -methoxy-1, 1- Biphenyl-4-yl]-2, 2-dimethyl-4-oxobutanoic acid

[100]A mixture of methyl 4- (4 ' -amino-3 ' -methoxy-1, 1 ' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoate (50mg, 0.15mmol, prepared as described in U.S. 2004/0224997), 2-ethoxyphenyl isocyanate (29mg, 0.18mmol) in dichloromethane (2mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1mL) and methanol (1 mL). Then aqueous sodium hydroxide (1N, 0.5mL, 0.5mmol) was added. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to give 4- [ 4' - ({ [ (2-ethoxyphenyl) amino]Carbonyl } amino) -3 '-methoxy-1, 1' -biphenyl-4-yl]-2, 2-dimethyl-4-oxobutanoic acid (25.8mg, 36% yield, two steps). LC-MS RT 3.46min., m/z 491.0 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ1.24(s，6H)，1.43(t，3H)，3.34(s，2H)，4.15(q，2H)，6.90(t，1H)，7.02(d，1H)，7.57(dd，1H)，7.69(dd，1H)，7.83(d，2H)，8.01(d，2H)，8.11(dd，1H)，8.30(t，1H)，8，65(s，1H)，9.44(s，1H).

[101]Example 15

Preparation of 4-oxo-4- {4- [6- (pentanoylamino) -3-pyridinyl]Phenyl } -2- (2-phenyl) Ethyl) butanoic acid (trifluoroacetate salt)

[102]Step 1 preparation of 4- [4- (6-amino-3-pyridyl) phenyl]-4-oxo-2- (2-) Phenylethyl) -butyric acid ethyl ester

[103]A mixture of ethyl 4- (4-bromophenyl) -4-oxo-2- (2-phenylethyl) butyrate (2.0g, 5.2mmol), bis (pinacol) diboron (1.44g, 5.69mmol) and potassium acetate (1.51g, 15.4mmol) in dioxane (100mL) was degassed with a stream of argon for 20 minutes. Then, add [1, 1' -bis (diphenylphosphino) -ferrocene]Palladium (II) dichloride (1: 1 mixture with dichloromethane, 0.21g, 0.26mmol) and the reaction mixture was heated at 80 ℃ for 3 hours. The mixture was cooled to room temperature, then filtered through a pad of celite and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-oxo-2- (2-phenylethyl) -4- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Ethyl butyrate (3g) was a black oil. A mixture of 0.5g (estd.0.856mmol) of this intermediate, 2-amino-5-bromopyridine (297mg, 1.72mmol) and sodium bicarbonate (963mg, 11.46mmol) in toluene (50mL) and water (9.3mL) was degassed with a stream of argon for 20 minutes. Then, add [1, 1' -bis (diphenylphosphino) -ferrocene]Palladium (II) dichloride (1: 1 mixture with dichloromethane, 94mg, 0.115mmol) and the reaction mixture was heated at 85 ℃ for 3 hours. The mixture was cooled to room temperature, then filtered through a pad of celite and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4- [4- (6-amino-3-pyridyl) phenyl ] amine]-4-oxo-2- (2-phenylethyl) butyric acid ethyl ester as a pale yellow oil (93mg, 27%, total, two steps). LC-MS RT 2.80 min (method 2), m/z 403 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ8.22(s，1H)，7.90(d，2H)，7.55(d，1H)，7.50(d，2H)，7.20-7.10(m，5H)，6.60(d，1H)，4.80(br s，2H)，4.10(q，2H)，3.50(m，1H)，3.00(m，2H)，2.60(m，2H)，2.00(m，2H)，1.20(t，3H).

[104]Step 2. preparation of 4-oxo-4- {4- [6- (pentanoylamino) -3-pyridinyl]Benzene and its derivatives 2- (2-phenylethyl) -butyric acid (trifluoroacetate salt)

[105]To 4- [4- (6-amino-3-pyridyl) phenyl]To a solution of ethyl (4-oxo-2- (2-phenylethyl) butyrate (15mg, 0.037mmol) in dichloroethane (1mL) was added valeryl chloride (6.7mg, 0.056mmol) and PS-DIEA (20mg, 5.7mmol), and the resulting suspension was mixed by orbital shaking overnight at room temperature. The reaction mixture was filtered and then concentrated under reduced pressure (GeneVac evaporator). The solid residue was redissolved in 1: 1 tetrahydrofuran/methanol (1mL), 1N aqueous sodium hydroxide (0.15mL) was added, and the mixture was shaken overnight at room temperature. 2N aqueous hydrochloric acid (0.1mL) was added, and the mixture was dried under reduced pressure (GeneVac evaporator). The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to give 4-oxo-4- {4- [6- (pentanoylamino) -3-pyridinyl]Phenyl } -2- (2-phenylethyl) butanoic acid (trifluoroacetate salt) as a white solid (6.4mg, 37.6%). LC-MS RT 3.00 min (method 2), m/z 459.2 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ12.20(s，1H)，10.50(s，1H)，8.70(s，1H)，8.20(m，2H)，8.05(d，2H)，7.90(d，2H)，7.1-7.3(m，5H)，3.55(dd，1H)，3.22(m，1H)，2.90(m，1H)，2.65(m，2H)，2.40(t，2H)，1.80(m，2H)，1.60(m，2H)，1.37(m，2H)，0.94(t，3H).

[106]Example 16

Preparation of 4- {4- [5- ({ [ (2-chlorophenyl) amino]Carbonyl } amino) -2-pyridyl]Phenyl } - 4-oxo-2- (2-phenylethyl) butanoic acid (trifluoroacetate salt)

[107]Step 1 preparation of 4- [4- (5-amino-2-pyridyl) phenyl]-4-oxo-2- (2-) Phenylethyl) butanoic acid methyl ester

[108]Method and synthesis of 4- [4- (6-amino-3-pyridyl) phenyl]The procedure described for ethyl-4-oxo-2- (2-phenylethyl) butyrate (example 15) is similar, but 3-amino-6-bromopyridine is used instead of 2-amino-5-bromopyridine. The product was obtained as a yellow solid (26% yield).¹H NMR(300MHz，CDCl₃) δ 8.05(d, 3H), 7.90(d, 2H), 7.75(d, 1H), 7.25(m, 2H), 7.20(m, 3H), 6.95(d, 1H), 5.70(s, 2H), 3.55(s, 3H), 3.40(m, 1H), 3.30(m, 1H), 2.95(m, 1H), 2.65(t, 2H), 1.90(m, 2H); LC-MS RT 2.53 min (method 2), m/z 403 (MH)⁺).

[109]Step 2 preparation of 4- {4- [5- ({ [ (2-chlorophenyl) amino]Carbonyl } amino) -2- Pyridyl radical]Phenyl } -4-oxo-2- (2-phenylethyl) butyric acid (trifluoroacetate salt)

[110]The process (urea formation followed by ester hydrolysis) is similar to that described in example 5 above. The product was obtained as a white solid (63% yield).¹H NMR(300MHz，DMSO-d₆) δ 9.80(s, 1H), 8.70(s, 1H), 8.50(s, 1H), 8.20(m, 4H), 8.00(m, 3H), 7.45(d, 1H), 7.25(m, 3H), 7.15(m, 3H), 7.00(m, 1H), 3.55(m, 1H), 3.20(m, 1H), 2.95(m, 1H), 2.65(m, 2H), 1.90(m, 2H); LC-MS RT 3.29 min (method 2), m/z 528.2 (MH)⁺).

[111]Example 17

Preparation of 4- [ 4' - ({ [ (2, 4-difluorophenyl) amino]Carbonyl } amino) -2 '-methyl-1, 1' -bi Phenyl-4-yl]-4-oxo-2- (2-phenylethyl) butanoic acid

[112]Step 1 preparation of 4- (4 ' -amino-2 ' -methyl-1, 1 ' -biphenyl-4-yl) -4-oxo -2- (2-phenylethyl) butanoic acid ethyl ester

[113]Method and synthesis of 4- [4- (6-amino-3-pyridyl) phenyl]The procedure described for ethyl-4-oxo-2- (2-phenylethyl) butyrate (example 15) was similar, but 3-methyl-4-bromoaniline was used instead of 2-amino-5-bromopyridine. The product was obtained as a yellow solid (34% yield).¹H NMR(300MHz，CDCl₃) δ 7.90(d, 2H), 7.30(d, 2H), 7.20(m, 2H), 7.10(m, 3H), 6.95(d, 1H), 6.50(m, 2H), 4.00(m, 2H), 3.70(broad s, 2H), 3.40(m, 1H), 3.00(m, 2H), 2.60(m, 2H), 2.15(s, 3H), 1.95-1.85(m, 2H), 1.20(t, 3H) LC-MS RT 2.89 min (method 2), m/z 416.2 (MH/z 416.2) (MH, 1H) LC-MS RT 2 (method 2)⁺).

[114]Step 2, preparing 4- [ 4' - ({ [ (2, 4-difluorophenyl) amino)]Carbonyl } amino) - 2 '-methyl-1, 1' -biphenyl-4-yl]-4-oxo-2- (2-phenylethyl) butanoic acid

[115]The process (urea formation followed by ester hydrolysis) is similar to that described in example 5 above. The product was obtained as a white solid (62% yield).¹H NMR(300MHz，DMSO-d₆)δ12.2(s，1H)，9.05(s，1H)，8.50(s，1H)，8.00(m，3H)，7.50-7.00(m，12H)，3.40(m, 1H), 3.20(m, 1H), 2.80(m, 1H), 2.60(m, 2H), 2.20(s, 3H), 1.90-1.80(m, 2H); LC-MS RT 4.26 min (method 2), m/z 543.3 (MH)⁺)。

[116]Example 18

Preparation of 2-benzyl-4- {4- [6- ({ [ (3, 4-dimethylphenyl) amino]Carbonyl } amino) -2- Methyl-3-pyridyl]Phenyl } -4-oxobutanoic acid (trifluoroacetate salt)

[117]Step 1 preparation of 4- [4- (6-amino-2-methyl-3-pyridyl) phenyl]-2-benzyl 4-Oxobutyric acid ethyl ester

[118]Method and synthesis of 4- [4- (6-amino-3-pyridyl) phenyl]The procedure described for ethyl-4-oxo-2- (2-phenylethyl) butyrate (example 15) is similar, but 5-bromo-6-methyl-2-pyridylamine is used instead of 2-amino-5-bromopyridine. The product was obtained as a yellow solid (66% yield); LC-MS RT 2.87 min (method 2), m/z 390.2 (MH)⁺).

[119]Step 2 preparation of 2-benzyl-4- {4- [6- ({ [ (3, 4-dimethylphenyl) amino] Carbonyl } amino) -2-methyl-3-pyridyl]Phenyl } -4-oxobutanoic acid (trifluoroacetate salt)

[120]To 4- [4- (6-amino-2-methyl-3-pyridyl) phenyl]-2-benzyl-4-oxobutanTo a solution of ethyl acetate (30mg, 0.077mmol) in DCE (1mL) was added 3, 4-dimethylphenyl isocyanate (17.6mg, 0.12mmol), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure (GeneVac evaporator) and the solid was dissolved in DMF (3 mL). A1N NaOH solution (0.1mL, 0.1mmol) was added, and the mixture was stirred at room temperature overnight. 1N HCl solution (0.1mL, 0.1mmol) and methanol (5mL) were added and the product was purified by preparative reverse phase HPLC separation (water/acetonitrile gradient with 0.1% TFA) to afford 2-benzyl-4- {4- [6- ({ [ (3, 4-dimethylphenyl) amino ] amino]Carbonyl } amino) -2-methyl-3-pyridyl]Phenyl } -4-oxobutanoic acid (trifluoroacetate salt) (62% yield).¹H NMR(300MHz，DMSO-d₆) δ 10.5(bs, 1H), 9.60(s, 1H), 8.00(d, 2H), 7.60(d, 1H), 7.50(d, 2H), 7.30(d, 1H), 7.20(m, 7H), 7.00(d, 2H), 3.40(q, 1H), 3.20(m, 1H), 3.00(m, 2H), 2.90(m, 1H), 2.50(s, 3H), 2.25(s, 3H), 2.20(s, 3H); LC-MS RT 3.42min (method 2), m/z 522.3 (MH)⁺).

[121]Example 19

Preparation of 4-oxo-2- (2-phenylethyl) -4- (4- {2- [ ({ [4- (trifluoromethyl) benzene) Base of]Amino } carbonyl) amino]-5-pyrimidinyl } phenyl) butanoic acid (trifluoroacetate salt)

[122]Step 1 preparation of 4- [4- (2-amino-5-pyrimidinyl) phenyl]-4-oxo-2- (2-) Phenylethyl) butanoic acid methyl ester

[123]Method and synthesis of 4- [4- (6-amino-3-pyridyl) phenyl]-ethyl 4-oxo-2- (2-phenylethyl) butyrate (example 15)The procedure described is similar, but replacing 2-amino-5-bromopyridine with 5-bromo-2-pyrimidineamine. The product was obtained as a brown solid (79% yield); LC-MS RT 2.87 min (method 2), m/z 390.2 (MH)⁺).

[124]Step 2 preparation of 4-oxo-2- (2-phenylethyl) -4- (4- {2- [ ({ [4- (tris) [ (]) Fluoromethyl) phenyl]Amino } carbonyl) amino]-5-pyrimidinyl } phenyl) butanoic acid (trifluoroacetate salt)

[125]To 4- [4- (2-amino-5-pyrimidinyl) phenyl]To a solution of methyl (4-oxo-2- (2-phenylethyl) butyrate (30mg, 0.077mmol) in DCE (1mL) was added 4-trifluoromethylphenyl isocyanate (21.6mg, 0.12mmol), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure (GeneVac evaporator) and the solid was redissolved in DMF (3 mL). A1N NaOH solution (0.1mL, 0.1mmol) was added, and the mixture was stirred at room temperature overnight. 1N HCl solution (0.1mL, 0.1mmol) was added to the reaction mixture and the product was isolated and purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to yield 4-oxo-2- (2-phenylethyl) -4- (4- {2- [ ({ [4- (trifluoromethyl) phenyl ] ethyl) -4]Amino } carbonyl) amino]-5-pyrimidinyl } phenyl) butanoic acid (trifluoroacetate salt) as a white solid (76% yield).¹H NMR (300MHz, DMSO). delta.8.10 (d, 2H), 7.95(d, 2H), 7.80(d, 2H), 7.65(m, 3H), 7.20(m, 6H), 3.50(m, 1H), 3.20(m, 1H), 2.90(m, 1H), 2.60(m, 2H), 1.90(m, 2H); LC-MS RT 3.71 min (method 1), m/z 563.0 (MH)⁺).

[126]Example 20

Preparation of 4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Butyric acid

[127]Step 1 preparation of 2- [2- (4-bromophenyl) -2-oxoethyl]Malonic acid diethyl ester

[128]To a 250mL 3-necked round bottom flask equipped with an argon inlet, septum and addition funnel was added sodium hydride (60% dispersion in mineral oil, 1.75g, 43.7mmol) followed by tetrahydrofuran (25 mL). The suspension was then cooled to 0 ℃ and a mixture of diethyl malonate (7.0g, 43.7mmol) in tetrahydrofuran (20mL) was added dropwise over 20 minutes. The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature over 45 minutes. A solution of 2-bromo-1- (4-bromophenyl) ethanone (8.08g, 43.7mmol) in tetrahydrofuran (35mL) was added quickly, and the resulting yellow mixture was stirred at room temperature for 16 hours, then poured into 20mL of 1.0N aqueous hydrochloric acid. The mixture was stirred for 10 minutes and extracted twice with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2- [2- (4-bromophenyl) -2-oxoethyl group]Diethyl malonate (10.2g, 66%) was used in the next step without further purification. GC-MS RT 3.89 min, m/z 357 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ1.27(t，6H)，3.55(d，2H)，4.02(t，1H)，4.15-4.27(m，4H)，7.59(d，2H)，7.82(d，2H).

[129]Step 2. preparation of 2- [2- (4 '-nitro-1, 1' -biphenyl-4-yl) -2-oxoethyl] Malonic acid diethyl ester

[130]Reacting 2- [2- (4-bromophenyl) -2-oxoethyl]Malonic acid diethyl ester (8.20g, 2)2.9mmol) and 4-nitrophenylboronic acid (4.20g, 25.2mmol) in dry toluene (200mL) and dioxane (50mL) were degassed for 30 minutes. While continuing to degas, saturated aqueous sodium carbonate solution (60mL) and [1, 1' -bis- (diphenylphosphino) -ferrocene were added]Palladium (II) dichloride (1: 1 mixture with dichloromethane, 934mg, 1.14 mmol). The resulting mixture was heated at 85 ℃ for 16 hours and then cooled to room temperature. Water was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Biotage flash 75, 5: 1 ethyl acetate: hexane) to give 2- [2- (4 '-nitro-1, 1' -biphenyl-4-yl) -2-oxoethyl]Malonic acid diethyl ester (4.8g, 53%). LC-MS RT 3.41 min, m/z 400.1 (MH)⁺)；¹HNMR(300MHz，CDCl₃)δ1.30(t，6H)，3.65(d，2H)，4.08(t，1H)，4.22-4.29(m，4H)，7.70-7.79(m，4H)，8.09(d，2H)，8.32(d，2H).

[131]Step 3. preparation of 2- [2- (4 '-amino-1, 1' -biphenyl-4-yl) -2-oxoethyl] Malonic acid diethyl ester

[132]To 2- [2- (4 '-nitro-1, 1' -biphenyl-4-yl) -2-oxoethyl]To a solution of diethyl malonate (3.50g, 8.77mmol) in 85: 15 ethanol/water (115mL) was added iron powder (64.9g), followed by 2N aqueous hydrochloric acid (4.38 mL). The resulting mixture was refluxed for 2.5 hours and then filtered through a pad of celite. The filtrate was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain 2- [2- (4 '-amino-1, 1' -biphenyl-4-yl) -2-oxoethyl]Malonic acid diethyl ester (3.18g, 98%). LC-MS RT 3.23 min, m/z 370.3 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ1.20(t，6H)，3.56(d，2H)，3.8(br s，2H)，4.02(t，1H)，4.18(q，4H)，6.71(d，2H)，7.39(d，2H)，7.54(d，2H)，7.94(d，2H).

[133]Step 4. preparation of 2- { 2-oxo-2- [4 '- (pentanoylamino) -1, 1' -biphenyl-4- Base of]Ethyl-malonic acid diethyl ester

[134]To 2- [2- (4 '-amino-1, 1' -biphenyl-4-yl) -2-oxoethyl]To a solution of diethyl malonate (3.17g, 8.58mmol) and valeryl chloride (1.24g, 103mmol) in dichloromethane (55mL) was added poly-4-vinylpyridine (2.8g, 27.7 mmol). The resulting suspension was stirred at room temperature for 3 hours and then filtered. The filtrate was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give 2- { 2-oxo-2- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Ethyl malonic acid diethyl ester (3.6g, 93%). LC-MS RT 3.99 min, m/z 454.3 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ0.89(t，3H)，1.22(t，6H)，1.32-1.37(m，2H)，1.64-1.69(m，2H)，2.32(t，2H)，3.56(d，2H)，4.00(t，1H)，4.15-4.21(m，4H)，7.14(s，1H)，7.50-7.60(m，6H)，7.95(d，2H).

[135]Step 5. preparation of 2- { 2-oxo-2- [4 '- (pentanoylamino) -1, 1' -biphenyl-4- Base of]Ethyl-malonic acid

[136]To a solution containing 2- { 2-oxo-2- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Ethyl diethyl malonate (1.60g, 3.53mmol) was added ethanol (25mL) to a flask followed by 1.0N aqueous sodium hydroxide (17.6mL) and the resulting mixture was stirred at room temperature for 16 h. The resulting suspension was concentrated under reduced pressure to remove ethanol, and then the aqueous layer was acidified with 1.0N aqueous hydrochloric acid solution and stirred for 10 minutes. Mixing the mixture with acetic acid BThe ester was extracted twice, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2- { 2-oxo-2- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Ethyl } malonic acid (1.34g, 96%). LC-MS RT ═ 3.29 min, m/z 398.5 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ0.90(t，3H)，1.29-1.38(m，2H)，1.53-1.63(m，2H)，2.32(t，2H)，3.52(d，2H)，3.77(t，1H)，7.69(s，4H)，7.78(d，2H)，8.02(d，2H)，10.03(s，1H).

[137]Step 6. preparation of 4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl] Butyric acid

[138]2- { 2-oxo-2- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]A solution of ethyl malonic acid (1.33g, 3.35mmol) in 1, 4-dioxane (60mL) was heated to reflux for 16 h. The mixture was cooled to room temperature and then concentrated under reduced pressure to obtain 4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Butyric acid (1.15g, 98%). LC-MSRT 2.73 min, m/z 354.2 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ0.88(t，3H)，1.27-1.35(m，2H)，1.54-1.59(m，2H)，2.31(t，2H).2.57(t，2H)，3.25(t，2H)，7.70(s，4H)，7.80(d，2H)，8.00(d，2H)，10.01(s，1H)，12.20(s，1H).

[139]Example 21

Preparation of 2- [2- (4-fluorophenyl) ethyl]-4-oxo-4- [4 '- (pentanoylamino) -1, 1' -bi-part Phenyl-4-yl]Butyric acid

[140]Step 1. preparation of 1- (2-iodoethyl) -4-fluorobenzene

[141]To a solution of 1- (2-chloroethyl) -4-fluorobenzene (400mg, 2.52mmol) in acetone (20mL) was added sodium iodide (3.78g, 25.2mmol) and the resulting suspension was heated to reflux for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1- (2-iodoethyl) -4-fluorobenzene (610mg, 97%). GC-MS M/z250 (M)⁺)；RT＝5.53min.；¹H NMR(300MHz，CDCl₃)δ3.14(t，2H)，3.29-3.35(m，2H)，6.97-7.04(m，2H)，7.13-7.18(m，2H).

[142]Step 2. preparation of 2- [2- (4-fluorophenyl) ethyl group]-4-oxo-4- [ 4' - (pentanoyl) Amino) -1, 1' -biphenyl-4-yl]Butyric acid.

[143]To 2- { 2-oxo-2- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Diethyl ethyl malonate (example 15) (100mg, 0.220mmol) in tetrahydrofuran (1.0mL) was added sodium hydride (13.2mg, 0.330mmol, 60% dispersion in mineral oil) and the resulting solution was stirred at room temperature for 30 minutes. A solution of 1- (2-iodoethyl) -4-fluorobenzene (110mg, 0.440mmol) in tetrahydrofuran (1.0mL) was added and the resulting solution was heated at 60 ℃ for 16 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in 2.0% potassium hydroxide ethanol solution (3.0 mL). The resulting mixture was stirred at room temperature for 16 hours, and then concentrated under reduced pressure. The aqueous layer was acidified with 1.0N aqueous hydrochloric acid solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with anhydrous sodium sulfateDried and concentrated under reduced pressure. The residue was dissolved in 1, 4-dioxane (2mL) and heated at 100 ℃ for 16 hours, then cooled to room temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient containing 0.1% TFA) to give 2- [2- (4-fluorophenyl) ethyl]-4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Butyric acid (3.5mg, 4%). LC-MSRT 3.12min, m/z476 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ0.91(t，3H)，1.27-1.35(m，2H)，1.52-1.59(m，2H)，1.80-1.88(m，2H)，2.31(t，2H)，2.64(t，2H)，2.81-2.87(m，1H)，3.15(dd，1H)，3.41-3.49(m，1H)，7.06(t，2H)，7.21-7.26(m，2H)，7.70(s，4H)，7.77(d，2H).8.00(d，2H).

[144]Example 22

Preparation of 2-ethyl-4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Butyric acid.

[145]To 2- { 2-oxo-2- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Diethyl ethyl malonate (example 15) (100mg, 0.220mmol) in tetrahydrofuran (1.0mL) sodium hydride (11mg, 0.26mmol, 60% dispersion in mineral oil) was added and the resulting solution was stirred at room temperature for 30 minutes. A solution of ethyl iodide (49mg, 0.31mmol) in tetrahydrofuran (1.0mL) was added and the resulting solution was heated at 60 ℃ for 16 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (1.5 mL). Aqueous sodium hydroxide (1.0N, 1.1mL) was added, and the resulting mixture was stirred at room temperature for 16 hours. The suspension was concentrated under reduced pressure, and the aqueous layer was acidified with 1.0N aqueous hydrochloric acid. The mixture was then extracted twice with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The mixture was then dissolved in 1, 4-dioxane (2mL) and heated at 100 ℃ for 16 hours, then cooledCooling to room temperature. The mixture was concentrated under reduced pressure and the residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to give 2-ethyl-4-oxo-4- [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Butyric acid (3.7mg, 5%). LC-MS RT 2.99min., m/z 382.1 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ0.91-0.99(m，6H)，1.21-1.37(m，2H)，1.51-1.64(m，4H)，3.32(t，2H)，2.70-2.79(m，2H)，3.10(dd，1H)，3.33-3.43(m，1H)，7.69(s，4H)，7.77(d，2H)，8.00(d，2H)，10.01(s，1H).

[146]Example 23

Preparation of 2- [2- (4' - { [ (4-chlorophenyl) acetyl]Amino } -1, 1' -biphenyl-4-yl) -2- Oxo-ethyl radical]Valeric acid ethyl ester

[147]To a standard amber 4mL vial was added 2- [2- (4 '-amino-1, 1' -biphenyl-4-yl) -2-oxoethyl dissolved in dichloromethane (1mL)]Methyl valerate (35mg, 0.10mmol, prepared as described in U.S. 2004/0224997), then a solution of poly-4-vinylpyridine (34mg, 0.31mmol) and 4-chlorophenylacetyl chloride (17.6mg, 0.093mmol) in dichloromethane (1mL) was added. The resulting suspension was stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated under reduced pressure, and the mixture was dissolved in methanol (1mL) and tetrahydrofuran (1 mL). Aqueous sodium hydroxide (1.0N, 0.31mL) was added, and the reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient containing 0.1% trifluoroacetic acid) to give 2- [2- (4' - { [ (4-chlorophenyl) acetyl ] acetyl]Amino } -1, 1' -biphenyl-4-yl) -2-oxoethyl]Pentanoic acid (8mg, 17%). LC-MS RT 4.01min., m/z 464.2 (MH)⁺)；¹H NMR(300MHz，DMSO-d6)δ0.86(t，3H)，1.25-1.40(m，2H)，1.40-1.64(m，2H)，2.75-2.85(m，1H)，3.07(dd，1H)，3.2-3.45(m，1H)，3.65(s，2H)，7.35(d，4H)，7.70(s，4H)，7.77(d，2H)，8.0(d，2H)， 10.32 s，1H)，12.08(br s，1H).

[148]Example 24

Preparation of 2- {2- [ 4' - ({ [ (2-chlorophenyl) amino)]Carbonyl } amino) -1, 1' -biphenyl-4- Base of]-2-oxoethyl } pentanoic acid

[149]To a standard amber 4mL vial was added 2- [2- (4 '-amino-1, 1' -biphenyl-4-yl) -2-oxoethyl]Methyl valerate (35mg, 0.10mmol, prepared as described in us 2004/0224997), 2-chlorophenyl isocyanate (24mg, 0.15mmol), and dichloromethane (2mL), and the resulting solution was stirred for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the mixture was dissolved in methanol (1mL) and tetrahydrofuran (1mL), followed by addition of 1.0N aqueous sodium hydroxide solution (0.31 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% trifluoroacetic acid) to give 2- {2- [ 4' - ({ [ (2-chlorophenyl) amino ] 2- {2]Carbonyl } amino) -1, 1' -biphenyl-4-yl]-2-oxoethyl } pentanoic acid (15mg, 32%). LC-MSRT 3.43min., m/z 465.2 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ0.9(t，3H)，1.25-1.50(m，2H)，1.50-1.66(m，2H)，2.77-2.92(m，1H)，3.10(dd，1H)，3.22-3.47(m，1H)，7.00-7.08(m，1H)，7.25-7.35(m，1H)，7.46(d，1H)，7.60(d，2H)，7.68-7.85(2d，4H)，8.02(d，2H)，8.16(d，1H)，8.37(s，1H)，9.6(s，1H)，12.1(br s，1H).

[150]Example 25

Preparation of 4- (4' - { [ (4-chlorophenyl) acetyl]Amino } -1, 1' -biphenyl-4-yl) -2- (2- Methoxyethyl group)-4-oxobutanoic acid

[151]To a standard amber 4mL vial was added ethyl 4- (4 '-amino-1, 1' -biphenyl-4-yl) -2- (2-methoxyethyl) -4-oxobutanoate (35mg, 0.10mmol, prepared as described in us 2004/0224997) dissolved in 1mL dichloromethane, followed by poly-4-vinylpyridine (33mg, 0.30mmol) and a solution of 4-chlorophenylacetyl chloride (28.4mg, 0.15mmol) in dichloromethane (1 mL). The resulting suspension was stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (1mL) and tetrahydrofuran (1 mL). Aqueous sodium hydroxide (1N, 0.31mL) was added, and the reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient containing 0.1% trifluoroacetic acid) to give 4- (4' - { [ (4-chlorophenyl) acetyl]Amino } -1, 1' -biphenyl-4-yl) -2- (2-methoxyethyl) -4-oxobutanoic acid (20mg, 41%). LC-MS RT 3.06 min, m/z 480.0 (MH)⁺)；¹HNMR(300MHz，DMSO-d₆) δ: 1.66-1.95 (overlap m, 2H), 2.83-2.97(m, 1H), 3.10-3.20(m, 2H), 3.3-3.47(m, 3H), 7.36(d, 4H), 7.70(s, 4H), 7.79(d, 2H), 8.02(d, 2H), 10.35(s, 1H).

[152]Example 26

Preparation of 4- [ 4' - ({ [ (2-chlorophenyl) amino)]Carbonyl } amino) -1, 1' -biphenyl-4-yl]- 2- (2-methoxyethyl) -4-oxobutanoic acid

[153]2- [2- (4 '-amino-1, 1' -biphenyl-4-yl) -2-oxoethyl]Methyl valerate (30mg, 0.08mmol, prepared as described in U.S. 2004/0224997), 2-chlorophenyl isocyanate (19mg, 0.13mmol), and dichloromethane (2 mL). The resulting solution was stirred for 16 hours and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (1mL) and tetrahydrofuran (1 mL). Aqueous sodium hydroxide (1N, 0.28mL) was added. The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient containing 0.1% trifluoroacetic acid) to give 4- [ 4' - ({ [ (2-chlorophenyl) amino]Carbonyl } amino) -1, 1' -biphenyl-4-yl]-2- (2-methoxyethyl) -4-oxobutanoic acid (15mg, 32%). LC-MS RT 3.19min., m/z 481.0 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ1.67-1.95(2m，2H)，2.85-2.97(m，1H)，3.10-3.20(m，2H)，3.23(s，3H)，3.35-3.49(m，2H)，7.03(t，1H)，7.3(t，1H)，7.45(d，1H)，7.59(d，2H)，7.73(d，2H)，7.80(d，2H)，8.02(d，2H)，8.16(d，1H)，8.35(s，1H)，9.59(s，1H)，12.13(brs，1H).

[154]Example 27

Preparation of 4- (4' - { [ (3, 5-difluorophenyl) acetyl]Amino } -1, 1' -biphenyl-4-yl) - 2, 2-dimethyl-4-oxobutanoic acid

[155]To a solution of ethyl 4- (4 '-amino-1, 1' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoate (60.0mg, 0.190mmol, prepared as described in US 2004/0224997) in dichloromethane (4.0mL) was added 3, 5-difluorophenylacetyl chloride (55.1mg, 0.290mmol) and PS-DIEA (80mg, 0.38 mmol). The solution/suspension was stirred at room temperature overnight. The PS-DIEA polymer was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1: 1 methanol/tetrahydrofuran (1.2mL), aqueous sodium hydroxide (1N, 0.3mL) was added, and the reaction mixture was added toStir at room temperature overnight. The mixture was filtered through a 0.45 PTFE filter and purified by reverse phase HPLC eluting with 20% to 80% gradient acetonitrile/water containing 0.1% trifluoroacetic acid. The combined HPLC fractions containing the desired acid were concentrated under reduced pressure to give 4- (4' - { [ (3, 5-difluorophenyl) acetyl]Amino } -1, 1' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoic acid as a white solid (48.9mg, 84%). LC-MS: RT ═ 3.25 min; m/z 452.2 (MH)⁺)；¹H NMR(400MHz，DMSO-d₆)δ1.20(s，6H)，3.32(s，2H)，3.77(s，2H)，7.01-7.18(m，3H)，7.72(s，4H)，7.78(d，2H)，7.99(d，2H)，10.7(s，1H)，11.98(br s，1H).

[156]Example 28

4- [ 4' - ({ [ (3, 4-dimethylphenyl) amino)]Carbonyl } amino) -1, 1' -biphenyl-4-yl]-2，2- Dimethyl-4-oxobutanoic acid

[157]To a solution of ethyl 4- (4 '-amino-1, 1' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoate (20.0mg, 0.0600mmol, prepared as described in us 2004/0224997) in dichloromethane (1.0mL) was added 3, 4-dimethylphenyl isocyanate (14mg, 0.090mmol), and the solution was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was dissolved in 1: 1 methanol/tetrahydrofuran (0.8 mL). Aqueous sodium hydroxide (1N, 0.3mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a 0.45 μ PTFE filter and purified by reverse phase HPLC eluting with 20% to 80% gradient acetonitrile/water containing 0.1% trifluoroacetic acid. The combined HPLC fractions containing the desired acid were concentrated under reduced pressure to give 4- [ 4' - ({ [ (3, 4-dimethylphenyl) amino group]Carbonyl } amino) -1, 1' -biphenyl-4-yl]2, 2-dimethyl-4-oxobutanoic acid as a white solid (3.5mg, 13%). LC-MS: RT ═ 3.39 min; m/z 445.3 (MH)⁺)；¹H NMR(400MHz，DMSO-d₆) δ 1.23(s, 6H), 2.17(s, 3H), 2.19(s, 3H), 3.34(s, 2H (and H)₂Signal overlap of O), 7.01 (d, 1H), 7.17(d, 1H), 7.25(s, 1H), 7.58(d, 2H), 7.67(d, 2H), 7.78(d, 2H), 7.99(d, 2H), 8.62(br s, 1H), 8.89(br s, 1H).

[158]Example 29

Preparation of 4- (4' - { [ (5-methoxy-1H-indol-2-yl) carbonyl]Amino } -1, 1' -biphenyl-one 4-yl) -2, 2-dimethyl-4-oxobutanoic acid

[159]To a solution of 5-methoxyindole-2-carboxylic acid (61.4mg, 0.32mmol) in N, N-dimethylformamide (1.0mL) was added 1-hydroxybenzotriazole hydrate (86.8mg, 0.640mmol) and N ' - (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (86.2mg, 0.450mmol), followed by a solution of ethyl 4- (4 ' -amino-1, 1 ' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoate (100mg, 0.320mmol, prepared as described in U.S. 2004/0224997) in N, N-dimethylformamide (1.0 mL). The solution was stirred at room temperature overnight. Water (4.0mL) was added and the mixture was extracted three times with ethyl acetate (3mL per extraction). The combined extracts were concentrated under reduced pressure and the residue was dissolved in 1: 1 methanol/tetrahydrofuran (1.0 mL). Aqueous sodium hydroxide (1N, 0.5mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a 0.45 μ PTFE filter and purified by reverse phase HPLC eluting with 20% to 80% gradient acetonitrile/water containing 0.1% trifluoroacetic acid. The combined HPLC fractions containing the desired acid were concentrated under reduced pressure to give 4- (4' - { [ (5-methoxy-1H-indol-2-yl) carbonyl]Amino } -1, 1' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoic acid as a white solid (44.0mg, 29%). LC-MS: RT ═ 3.19 min; m/z 471.0 (MH)⁺)；¹H NMR(400MHz，DMSO-d₆)δ1.25(s，6H)，3.33(s，2H)，3.80(s，3H)，6.89(d，1H)，7.15(s，1H)，7.32-7.42(m，2H)，7.79(d，2H)，7.83(d，2H)，7.94(d，2H)，8.04(d，2H)，10.32(s，1H)，11.62(s，1H)，11.97(br s，1H).

[160]Example 30

Preparation of 4- { 4' - [ (1, 3-dihydro-2H-isoindol-2-ylcarbonyl) amino]-1, 1' -biphenyl-4- 2, 2-dimethyl-4-oxobutanoic acid

[161]Step 1 preparation of 4- } { 4' - [1, 3-dihydro-2H-isoindol-2-ylcarbonyl) ammonia Base of]-1, 1' -biphenyl-4-yl } -2, 2-dimethyl-4-oxobutanoic acid methyl ester

[162]In a three-neck round-bottom flask filled with argon, a suspension of methyl 4- (4 '-amino-1, 1' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoate (0.23g, 0.74mmol, prepared as described in us 2004/0224997) in toluene (3.2mL) was treated with triethylamine (1.0mL) and cooled to 0 ℃. The three-necked flask was charged with a 2N aqueous solution of sodium hydroxide. The stirred suspension was slowly treated with phosgene (20% mixture in toluene, 13.0mL, 81.0mmol) and then stirred at room temperature for 2 hours. The suspension was filtered to remove salts and concentrated under reduced pressure to give methyl 4- (4 '-isocyanato-1, 1' -biphenyl-4-yl) -2, 2-dimethyl-4-oxobutanoate as a dark orange oil. This oil was dissolved in 1, 2-dichloroethane (12.0mL) and used immediately in the subsequent reaction. A portion of the isocyanate solution (2mL, ca.0.12mmol) was treated with isoindoline (0).02g, 0.18mmol) and then stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the crude solid was triturated with ethyl acetate. The mixture was filtered to give the title compound as a white solid (0.04g, 73%).¹H NMR(300MHz，DMSO-d₆) δ 1.23(s, 6H), 3.40(s, 2H), 3.55(s, 3H), 4.79(s, 4H), 7.35-7.32(m, 4H), 7.72-7.70(m, 4H), 7.81(d, 2H), 8.00(d, 2H), 8.53(s, 1H); LC-MS holding time 3.38 min, m/z 457.1 (MH)⁺).

[163]Step 2. preparation of 4- { 4' - [ (1, 3-dihydro-2H-isoindol-2-ylcarbonyl) amino Base of]-1, 1' -biphenyl-4-yl } -2, 2-dimethyl-4-oxobutanoic acid.

[164]To 4- { 4' - [ (1, 3-dihydro-2H-isoindol-2-ylcarbonyl) amino]To a solution of (E) -1, 1' -biphenyl-4-yl } -2, 2-dimethyl-4-oxobutanoic acid ester in methanol (2.0mL) and tetrahydrofuran (1.0mL) was added a 2N sodium hydroxide solution (2.0mL), and the mixture was stirred at room temperature for 16 hours. The reaction was then diluted with water and the pH of the aqueous mixture was adjusted to 2. The product was extracted with ethyl acetate. The organic layer was then washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a white solid (0.040g, 97%). LC-MS Retention time 3.01 min, m/z 443.2 (MH)⁺)；¹H NMR(300MHz，DMSO-d₆)δ1.22(s，6H)，4.79(s，4H)，7.38-7.29(m，4H)，7.75-7.67(m，4H)，7.80(d，2H)，8.00(d，2H)，8.53(s，1H)，11.95(s，1H).

[165]Example 31

Preparation of 4- (2- { 4' - [ (4-fluoro-3-methylbenzoyl) amino)]-1, 1' -biphenyl-4-yl- 2-oxoethyl) tetrahydro-2H-pyran-4-carboxylic acid

[166]To 4- [2- (4 '-amino-1, 1' -biphenyl-4-yl) -2-oxoethyl]To a solution of tetrahydro-2H-pyran-4-carboxylic acid methyl ester (40mg, 0.11mmol, prepared as described in US 2004/0224997) and 4-fluoro-3-methylbenzoyl chloride (24mg, 0.14mmol) in dichloromethane (2mL) was added poly-4-vinylpyridine (38mg, 0.34 mmol). The resulting suspension was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure, the residue was dissolved in methanol (1mL) and tetrahydrofuran (1mL), and 1.0N aqueous sodium hydroxide solution (0.5mL, 0.5mmol) was added. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to give 4- (2- { 4' - [ (4-fluoro-3-methylbenzoyl) amino]-1, 1' -biphenyl-4-yl } -2-oxoethyl) tetrahydro-2H-pyran-4-carboxylic acid (11.9mg, 22%). LC-MS m/z476.0 (MH)⁺)，RT＝3.1min；¹H NMR(300MHz，DMSO-d₆)δ1.62-1.66(m，2H)，1.95-1.99(m，2H)，2.33(s，3H)，3.46(s，2H)，3.59-3.67(m，4H)，7.30(t，1H)，7.78(d，2H)，7.81-7.91(m，4H)，7.93(d，2H)，8.02(d，2H)，10.35(s，1H).

[167]Example 32

Preparation of 4- {2- [ 4' - ({ [ (2-ethoxyphenyl) amino)]Carbonyl } amino) -1, 1' -biphenyl -4-yl]-2-oxoethyl } tetrahydro-2H-pyran-4-carboxylic acid

[168]Reacting 4- [2- (4 '-amino-1, 1' -biphenyl-4-yl) -2-oxoethyl]tetrahydro-2H-pyran-4-carboxylic acid methyl ester (40mg, 0.11mmol, prepared as described in US 2004/0224997) and 2-ethoxyphenyl isocyanA mixture of the acid ester (22mg, 0.14mmol) in dichloromethane (2mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1mL) and methanol (1 mL). Aqueous sodium hydroxide (1N, 0.5mL, 0.5mmol) was added. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to give 4- {2- [ 4' - ({ [ (2-ethoxyphenyl) amino group]Carbonyl } amino) -1, 1' -biphenyl-4-yl]-2-oxoethyl } tetrahydro-2H-pyran-4-carboxylic acid (9.1mg, 16%). LC-MSm/z 503.2 (MH)⁺)，RT＝3.11min；¹H NMR(300MHz，DMSO-d₆)δ11.43(t，3H)，1.61-1.67(m，2H)，1.94-1.99(m，2H)，3.45(s，2H)，3.57-3.69(m，4H)，4.13(q，2H)，6.86-6.94((m，2 H)，7.01(d，2H)，7.60(d，2H)，7.71(d，2H)，7.79(d，2H)，8.01(d，2H)，8.13(d，2H)，9.57(s，1H).

[169]Example 33

Preparation of 1- {2- [ 4' - ({ [ (2-chlorophenyl) amino)]Carbonyl } amino) biphenyl-4-yl]-2- Oxoethyl cyclopentanecarboxylic acid

[170]To 1- [2- (4' -aminobiphenyl-4-yl) -2-oxoethyl]To a solution of methyl cyclopentanecarboxylate (38.4mg, 0.11mmol, prepared as described in US 2004/0224997) in dichloroethane (2mL) was added 2-chlorophenyl isocyanate (21.0mg, 0.14mmol) and the resulting solution was stirred at room temperature for 16 h. The mixture was evaporated to dryness and the residue was dissolved in MeOH (1.0mL) and THF (1.0 mL). Aqueous NaOH (1N, 0.33mL, 0.33mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and then purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to yield 1- {2- [ 4' - ({ [ (2-chlorophenyl) amino]Carbonyl } amino) biphenyl-4-yl]-2-oxoethyl } cyclopentaneFormic acid (20mg, 38%). LC-MSm/z 477.2 (MH)⁺)，RT＝3.52min；¹H NMR(300MHz，DMSO-d₆)δ1.50-1.69(m，6H)，2.03-2.16(m，2H)，3.43(s，2H)，6.96-7.05(m，1H)，7.24-7.36(m，1H)，7.48(d，1H)，7.57(d，2H)，7.72(d，2H)，7.78(d，2H)，7.98(d，2H)，8.16(d，1H)，8.35(s，1H)，9.56(s，1H)，11.85(s，1H).

[171]Example 34

Preparation of trans-2- ({ 4' - [ (4-chlorobenzoyl) amino]-1, 1' -biphenyl-4-yl } carbonyl group) -cyclohexanecarboxylic acid

[172]To cis-2- [ (4 '-amino-1, 1' -biphenyl-4-yl) carbonyl]To a solution of methyl cyclohexanecarboxylate (50mg, 0.15mmol, prepared as described in U.S. 2004/0224997) in dichloromethane (2mL) was added 4-chlorobenzoyl chloride (51.87mg, 0.30mmol) and triethylamine (75.27mg, 0.74mmol), and the resulting solution was stirred at room temperature for 72 hours. The mixture was evaporated to dryness. The residue was dissolved in MeOH and NaOH (1N, 1.5mL, 1.5mmol), and the solution was stirred at 60 deg.C overnight. The solvent was removed under reduced pressure, HCl (2N) was added, then MeOH was added to dissolve the precipitate. The solution was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to afford trans-2- ({ 4' - [ (4-chlorobenzoyl) amino]-1, 1' -biphenyl-4-yl } carbonyl) cyclohexanecarboxylic acid (3.4mg, 5%). LC-MS RT 3.48 min, m/z 462.1 (MH)⁺)；¹H NMR(400MHz，MeOH-d₄)δ1.27(m，1H)，1.35～1.57(m，3H)，1.88(m，2H)，2.06(m，1H)，2.23(m，1H)，2.84(m，1H)，3.6 8(m，1H)，7.54(m，2H)，7.73(m，2H)，7.78(d，2H)，7.84(d，2H)，7.94(m，2H)，8.07(d，2H).

[173]Example 35

Preparation of trans-2- { [ 4' - ({ [ (2, 4-difluorophenyl) amino]Carbonyl } amino) -1, 1' -biphenyl Radical-4-radical]Carbonyl group cyclohexanecarboxylic acid

[174]To cis-2- [ (4 '-amino-1, 1' -biphenyl-4-yl) carbonyl]To a solution of methyl cyclohexanecarboxylate (50mg, 0.15mmol, prepared as described in U.S. 2004/0224997) in dichloromethane (2mL) was added 2, 4-difluorophenyl isocyanate (46mg, 0.30mmol) and the resulting solution was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was suspended in ether. The precipitate was collected by filtration, washed with diethyl ether and dried under high vacuum to give 2- { [ 4' - ({ [ (2, 4-difluorophenyl) amino]Carbonyl } amino) -1, 1' -biphenyl-4-yl]Carbonyl } cyclohexanecarboxylic acid methyl ester (28mg, 36%). LC-MS RT ═ 3.84 min, m/z493.0 (MH)⁺). A sample of this intermediate (24mg, 0.05mmol) was mixed with MeOH and the suspension was heated at 50 ℃ to effect dissolution. Aqueous NaOH (1N, 0.5mL, 0.5mmol) was then added to the solution and the mixture was stirred at 50 ℃ overnight. The mixture was concentrated under reduced pressure, and the residue was dissolved in water. Concentrated HCl was added gradually with stirring until the mixture was acidic. The solution was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to give trans-2- { [ 4' - ({ [ (2, 4-difluorophenyl) amino]Carbonyl } amino) -1, 1' -biphenyl-4-yl]Carbonyl } cyclohexanecarboxylic acid (6.5mg, 28%). LC-MSRT 3.34 min, m/z 479.2 (MH)⁺)；¹H NMR(400MHz，MeOH-d₄)δ1.26(m，1H)，1.37～1.59(m，3H)，1.89(m，2H)，2.06(m，1H)，2.23(m，1H)，2.84(m，1H)，3.67(m，1H)，6.94(m，1H)，7.03(m，1H)，7.56(m，2H)，7.66(m，2H)，7.75(m，2H)，7.99～8.07(m，3H).

[175]Example 36

Preparation ofTrans-2- { [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Carbonyl cyclopropane carboxylic acid ester Acid(s)

[176]Step 1 preparation of trans-2- { [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl] Carbonyl cyclopropanecarboxylic acid methyl ester

[177]To trans-2- [ (4 '-amino-1, 1' -biphenyl-4-yl) carbonyl]To a solution of methyl cyclopropanecarboxylate (45mg, 0.15mmol, prepared as described in us 2004/0224997) in dichloromethane (2mL) was added butyryl chloride (36.7mg, 0.30mmol) and triethylamine (46.7mg, 0.46mmol), and the resulting solution was stirred at room temperature overnight. The mixture was evaporated to dryness under reduced pressure and the residue was suspended in diethyl ether. The precipitate was collected by filtration, washed with diethyl ether and dried under high vacuum to give trans-2- { [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Carbonyl } cyclopropane-carboxylic acid methyl ester (26.4mg, 45%). LC-MSRT 3.25min, m/z 380.3 (MH)⁺)；¹H NMR(400MHz，DMSO-d₆)δ0.90(t，3H)，1.33(sex，2H)，1.50～1.62(m，3H)，2.22(m，1H)，2.33(t，2H)，3.66(s，3H)，7.71(s，4H)，7.81(d，2H)，8.09(d，2H)，10.0(s，1H).

[178]Step 2 preparation of trans-2- { [ 4' - (pentanoylamino) -1, 1-biphenyl-4-yl] Carbonyl group-cyclopropanecarboxylic acid

[179]Trans-2- { [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Carbonyl } cyclopropanecarboxylic acid methyl ester (24.1mg, 0.06mmol) was mixed with MeOH and the suspension was heated at 50 ℃ to effect dissolution. Aqueous NaOH (1N, 1mL, 1mmol) was then added to the solution and the mixture was stirred at 50 ℃ overnight. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water. Concentrated HCl was gradually added with stirring until the mixture was acidic, and the precipitate formed was collected by filtration, washed with diethyl ether and dried under high vacuum to give trans-2- { [4 '- (pentanoylamino) -1, 1' -biphenyl-4-yl]Carbonyl } cyclopropanecarboxylic acid (13.4mg, 57%). LC-MS RT 2.91min, m/z 366.2 (MH)⁺)；¹H NMR(400MHz，DMSO-d₆)δ0.69(t，3H)，1.11(m，2H)，1.27(m，2H)，1.37(m，2H)，1.89(m，1H)，2.11(t，2H)，3.03(m，1H)，7.49(s，4H)，7.60(d，2H)，7.87(d，2H)，9.80(s，1H)，12.36(s，1H).

[180]Example 37

Preparation of trans-2- [ (4' - { [ (3, 4-difluorophenyl) acetyl]Amino } -1, 1' -biphenyl-4- Yl) carbonyl]Cyclopropanecarboxylic acid

[181]To trans-2- [ (4 '-amino-1, 1' -biphenyl-4-yl) carbonyl]To a solution of methyl cyclopropanecarboxylate (94mg, 0.32mmol, prepared as described in U.S. 2004/0224997) in dichloromethane (3mL) was added 3, 4-difluorophenylacetic acid (65.7mg, 0.38mmol), dimethylaminopyridine (1.9mg, 0.02mmol), EDCI (73.2mg, 0.38mmol), and the resulting solution was stirred at room temperature for 3 days. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with aqueous NaOH (1N), HCl (1N), water and brine, and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was mixed and passed through in aqueous HCl (1N)And (5) filtering. The precipitate was washed with water, diethyl ether and dried in a vacuum oven to obtain trans-2- [ (4' - { [ (3, 4-difluorophenyl) acetyl ] methyl acetate]Amino } -1, 1' -biphenyl-4-yl) carbonyl]Cyclopropane-carboxylic acid methyl ester (63.6mg, 44%). LC-MS RT 3.64 min, m/z 450 (MH)⁺)；¹H NMR(400MHz，DMSO-d₆) δ 1.62(m, 2H), 2.36(m, 1H), 3.32(m, 1H), 3.74(s, 5H), 7.12(m, 1H), 7.18-7.30 (m, 2H), 7.62(m, 4H), 7.72(m, 2H), 8.08(m, 2H). A sample of this intermediate (63mg, 0.14mmol) was mixed with MeOH and the suspension was heated at 50 ℃ to complete dissolution. Aqueous NaOH (1N, 1.5mL, 1.5mmol) was then added to the solution and the mixture was stirred at 50 ℃ overnight. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water. Concentrated HCl was gradually added with stirring until the mixture was acidic, and the precipitate formed was collected by filtration, washed with diethyl ether and dried under high vacuum to give trans-2- [ (4' - { [ (3, 4-difluorophenyl) acetyl ] methyl]Amino } -1, 1' -biphenyl-4-yl) carbonyl]Cyclopropanecarboxylic acid (15.8mg, 25%). LC-MS RT 3.01 min, m/z 436.1 (MH)⁺)；¹H NMR(400MHz，DMSO-d₆)δ1.47(m，2H)，2.09(m，1H)，3.24(m，1H)，3.69(s，2H)，7.16(m，1H)，7.38(m，2H)，7.72(m，4H)，7.82(m，2H)，8.09(m，2H)，10.34(s，1H).

[182]Example 38

Preparation of trans-2- { [ 4' - ({ [ (2-chlorophenyl) amino)]Carbonyl } amino) -1, 1' -biphenyl- 4-radical]Carbonyl cyclopropane carboxylic acid ester

[183]To trans-2- [ (4 '-amino-1, 1' -biphenyl-4-yl) carbonyl]To a solution of methyl cyclopropanecarboxylate (45mg, 0.15mmol, prepared as described in U.S. 2004/0224997) in methylene chloride (2mL) was added 2-chlorophenyl isocyanate (46.8mg, 0.30mmol)l), and the resulting solution was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was suspended in diethyl ether. The precipitate was collected by filtration, washed with diethyl ether and dried under high vacuum to give trans-2- { [ 4' - ({ [ (2-chlorophenyl) amino]Carbonyl } amino) -1, 1' -biphenyl-4-yl]Carbonyl } cyclopropanecarboxylic acid methyl ester (22.7mg, 33%). LC-MS RT 3.91 min, m/z 450 (MH)⁺). A sample of this intermediate (24.3mg, 0.05mmol) was mixed with MeOH and the suspension was heated at 50 ℃ to complete dissolution. Aqueous NaOH (1N, 0.5mL, 0.5mmol) was then added to the solution and the mixture was stirred at 50 ℃ overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. Concentrated HCl was added gradually with stirring until the mixture was acidic. The solution was extracted with EtOAc and the combined organic layers were washed with water, brine, and Na₂SO₄Dried and concentrated under reduced pressure. Trans-2- { [ 4' - ({ [ (2-chlorophenyl) amino) is obtained]Carbonyl } amino) -1, 1' -biphenyl-4-yl]Carbonyl } cyclopropanecarboxylic acid (23.5mg, 99%). LC-MS RT 3.32 min, m/z 435.0 (MH)⁺)；¹H NMR(400 MHz，DMSO-d₆)δ1.48(m，2H)，2.10(m，1H)，3.25(m，1H)，7.02(m，1H)，7.29(m，1H)，7.45(m，1H)，7.59(d，2H)，7.73(d，2H)，7.82(d，2H)，8.09(d，2H)，8.15(m，1H)，8.35(s，1H)，9.59(s，1H).

[184]Example 39

Preparation of trans-2- [ (4' - { [ (3-pyridylamino) carbonyl]Amino } -1, 1' -biphenyl-4-yl) Carbonyl radical]Cyclopropanecarboxylic acid (trifluoroacetate)

[185]To trans-2- [ (4 '-amino-1, 1' -biphenyl-4-yl) carbonyl]To a solution of methyl cyclopropanecarboxylate (45mg, 0.15mmol, prepared as described in US 2004/0224997) in dichloromethane (2mL) was added 3-pyridineIsocyanate (92mg, 0.76mmol) and the resulting solution was stirred at room temperature overnight. The mixture was evaporated to dryness under reduced pressure, the residue was dissolved in MeOH, aqueous NaOH (1N, 0.5mL, 0.5mmol) was added to the solution, and the mixture was stirred at 50 ℃ overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. Concentrated HCl was added gradually with stirring until the mixture was acidic. The solution was extracted with EtOAc and the combined organic layers were washed with water, brine, and Na₂SO₄Dried and concentrated. The residue was dissolved in MeOH and purified by preparative reverse phase HPLC (water/acetonitrile gradient containing 0.1% TFA) to give trans-2- [ (4' - { [ (3-pyridylamino) carbonyl ] amino]Amino } -1, 1' -biphenyl-4-yl) carbonyl]Cyclopropanecarboxylic acid (trifluoroacetate) (15.4mg, 26%). LC-MS RT 2.14 min, m/z 402.1 (MH)⁺)；¹H NMR(400MHz，DMSO-d₆)δ1.60(m，2H)，2.26(m，1H)，3.29(m，1H)，7.63(m，2H)，7.70(m，2H)，7.80(m，2H)，7.91(m，1H)，8.11(m，2H)，8.36(m，1H)，8.42(m，1H)，9.26(m，1H).

[186]Example 40

Preparation of trans-2- [ (4' - { [ (4-isopropylphenyl) acetyl)]Amino } -1, 1' -biphenyl-4- Yl) carbonyl]Cyclobutanecarboxylic acid

[187]To trans-2- [ (4 '-amino-1, 1' -biphenyl-4-yl) carbonyl]To a solution of cyclobutane-carboxylic acid methyl ester (100mg, 0.32mmol, prepared as described in US 2004/0224997) in dichloromethane (3mL) was added 4-isopropylphenylacetic acid (89.1mg, 0.39mmol), dimethylaminopyridine (1.97mg, 0.02mmol), EDCI (92.95mg, 0.48mmol) and the resulting solution was stirred at room temperature for 3 days. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with aqueous NaOH (1N), HCl (1N), water and brine, and Na₂SO₄Drying, filtering and concentrating under reduced pressure to obtain trans-2- [ (4' - { [ (4-isopropylphenyl) acetyl group]Amino } -1, 1' -biphenyl-4-yl) carbonyl]Cyclobutane-carboxylic acid methyl ester as an oil. LC-MS RT 3.80 min, m/z 470.1 (MH)⁺)；¹H NMR(400MHz，CD₃OD) δ 1.24(d, 6H), 2.20(m, 2H), 2.35(m, 2H), 2.90(m, 1H), 3.61(m, 1H), 3.65(s, 2H), 3.70(s, 3H), 4.38 (q, 1H), 7.19(d, 2H), 7.26(d, 2H), 7.67(m, 4H), 7.77(d, 2H), 8.01(d, 2H). A sample of this intermediate (90mg, 0.19mmol) was mixed with MeOH and the suspension was heated at 50 ℃ to complete dissolution. Aqueous NaOH (1N, 2.0mL, 2.0mmol) was then added to the solution and the mixture was stirred at 50 ℃ overnight. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water. Concentrated HCl was gradually added under stirring until the mixture was acidic, and the precipitate formed was collected by filtration, washed with diethyl ether, and purified by preparative HPLC to obtain trans-2- [ (4' - { [ (4-isopropylphenyl) acetyl group]Amino } -1, 1' -biphenyl-4-yl) carbonyl]Cyclobutanecarboxylic acid (38.7mg, 44%). LC-MS RT 3.44 min, m/z 456.1 (MH)⁺)；¹H NMR(400MHz，DMSO-d₆)δ1.19(d，6H)，2.11(m，3H)，2.30(m，1H)，2.83(m，1H)，3.40(m，1H)，3.60(s，2H)，4.27(q，1H)，7.16(d，2H)，7.22(d，2H)，7.71(m，4H)，7.79(d，2H)，7.96(d，2H)，10.25(s，1H)，12.23(bs，1H).

[188]EXAMPLE 41

Preparation of trans-2- { [ 4' - ({ [ (2-ethoxyphenyl) amino]Carbonyl } amino) -1, 1' -bi-part Phenyl-4-yl]Carbonyl ester of cyclopentane

[189]To trans-2- [ (4 '-amino-1, 1' -biphenyl-4-yl) carbonyl]Cyclopentanecarboxylic acid methyl ester (47mg, 0.15mmol, e.g. 2004. in the USA0224997) in methylene chloride (2mL) was added 2-ethoxyphenyl isocyanate (47.43mg, 0.30mmol) and the resulting solution was stirred at room temperature overnight. The mixture was evaporated to dryness under reduced pressure and the residue was suspended in diethyl ether. The precipitate was collected by filtration, washed with diethyl ether and dried under high vacuum to give trans-2- { [ 4' - ({ [ (2-ethoxyphenyl) amino]Carbonyl } amino) -1, 1' -biphenyl-4-yl]Carbonyl } cyclopentanecarboxylic acid methyl ester (24.7mg, 34%). LC-MS RT 3.80 min, m/z 487.0 (MH)⁺)；¹H NMR(400MHz，CD₂Cl₂) δ 1.37(t, 3H), 1.67 to 1.90(m, 4H), 2.11(m, 2H), 3.36(m, 1H), 3.57(s, 3H), 4.04(m, 4H), 6.69(s, 1H), 6.82 to 6.96(m, 3H), 7.14(s, 1H), 7.47(d, 2H), 7.57(d, 2H), 7.63(d, 2H), 7.97(d, 2H), 8.03(d, 1H). A sample of this intermediate (24.6mg, 0.05mmol) was mixed with MeOH and the suspension was heated at 50 ℃ to complete dissolution. Aqueous NaOH (1N, 1.0mL, 1.0mmol) was then added to the solution and the mixture was stirred at 50 ℃ overnight. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water. Concentrated HCl was gradually added with stirring until the mixture was acidic, the precipitate formed was collected by filtration, washed with dichloromethane and dried under high vacuum to give trans-2- { [ 4' - ({ [ (2-ethoxyphenyl) amino]Carbonyl } amino) -1, 1' -biphenyl-4-yl]Carbonyl } cyclopentanecarboxylic acid (11.6mg, 48%). LC-MS RT 3.42min, m/z 473.2 (MH)⁺)；¹H NMR(400MHz，DMSO-d₆)δ1.41(t，3H)，1.53～1.84(m，4H)，1.98(m，1H)，2.1 5(m，1H)，3.21(m，1H)，4.13(m，3H)，6.90(m，2H)，7.00(m，1H)，7.60(d，2H)，7.71(d，2H)，7.80(d，2H)，8.05(d，2H)，8.13(m，2H)，9.58(s，1H)，12.18(s，1H).

[190]Example 42

Preparation of trans-2- { [ 4' - ({ [ (2, 4-difluorophenyl) amino]Carbonyl } amino) -1, 1' -biphenyl Radical-4-radical]Carbonyl group cyclopentanecarboxylic acid

[191]To trans-2- [ (4 '-amino-1, 1' -biphenyl-4-yl) carbonyl]To a solution of methyl cyclopentanecarboxylate (47mg, 0.15mmol, prepared as described in US 2004/0224997) in dichloromethane (2mL) was added 2, 4-difluoroisocyanate (45mg, 0.30mmol) and the resulting solution was stirred at room temperature overnight. The mixture was evaporated to dryness under reduced pressure and the residue was dissolved in MeOH. Aqueous NaOH (1N, 0.5mL, 0.5mmol) was added to the solution and the mixture was stirred at 50 ℃ overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. Concentrated HCl was added gradually with stirring until the mixture was acidic. The solution was extracted with EtOAc and the combined organic layers were washed with water and brine, over Na₂SO₄Dried and concentrated under reduced pressure. The residue was dissolved in MeOH and purified by preparative reverse phase HPLC (water/acetonitrile gradient containing 0.1% TFA) to give trans-2- { [ 4' - ({ [ (2, 4-difluorophenyl) amino]Carbonyl } amino) -1, 1' -biphenyl-4-yl]Carbonyl } cyclopentanecarboxylic acid (11.6mg, 15%). LC-MS RT 3.31 min, m/z 465.1 (MH)⁺)；¹H NMR(400MHz，MeOH-d₄)δ1.69～2.0(m，4H)，2.13(m，1H)，2.24(m，1H)，2.37(m，1H)，4.17(m，1H)，6.93(m，1H)，7.02(m，1H)，7.57(m，2H)，7.67(m，2H)，7.76(m，2H)，7.99～8.08(m，3H).

[192]Example 43

Preparation of N- [ 4' - (3- { [ (methylsulfonyl) amino]Carbonyl } -5-phenyl-pentanoyl) -1, 1- Biphenyl-4-yl]Pentamides

[193]Reacting 4-oxo-4- [4 '- (valerylamino) -1, 1' -biphenyl-4-yl]-2- (2-phenylethyl) -butyric acid (26.2mg, 0.057mmol, prepared as described in example 2), methanesulfonamide (5.4mg, 0.057mmol), 1-ethyl-3- [3- (dimethylamino) propyl]A solution of carbodiimide hydrochloride (11mg, 0.057mmol) and 4- (dimethylamino) pyridine (7mg, 0.057mmol) in dichloromethane (1mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative reverse phase HPLC (water/acetonitrile gradient with 0.1% TFA) to afford N- [ 4' - (3- { [ (methylsulfonyl) amino]Carbonyl } -5-phenylpentanoyl) -1, 1' -biphenyl-4-yl]Pentamide (5.8mg, 30%). LC-MS RT 3.52 min, m/z 535.1 (MH)⁺)；¹H NMR(300MHz，CDCl₃)δ0.96(t，3H)，1.41(m，2H)，1.71(m，2H)，1.92(m，1H)，2.18(m，1H)，2.40(t，2H)，2.71-2.86(m，3H)，3.20(dd，1H)，3.28(s，3H)，3.53(m，1H)，7.19-7.34(m，6H)，7.56-7.66(m，6H)，7.95(d，2H)，8.52(s，1H).

[194] Other compounds of the invention may be prepared and characterized by using the methods described above, and by selecting the appropriate starting materials. These compounds and examples 1-43 are summarized in tables 1-6.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

TABLE 5

TABLE 6

[195] By using the methods described above and by selecting the appropriate starting materials, additional compounds of formula (I) as exemplified in table 7 below may be prepared.

TABLE 7

Application method

[196] Various terms used herein are defined as follows.

[197] When introducing elements of the present invention or the preferred embodiments thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[198] The term "subject" as used herein includes mammals (e.g., humans and animals).

[199] The term "treatment" includes any of the steps, effects, uses, treatments, etc., that provide medical assistance to a subject, including a human, with the purpose of directly or indirectly ameliorating the condition of the subject, or slowing the progression of the condition or disorder in the subject.

[200] The term "combination therapy" or "co-therapy" refers to the administration of two or more therapeutic agents to treat a disease, condition, and/or disorder. The administration includes the combined administration of two or more therapeutic agents in a substantially simultaneous manner, e.g., a single capsule with a fixed ratio of active ingredients or multiple separate capsules for each inhibitor. In addition, the administration includes the use of various types of therapeutic agents in a continuous manner.

[201] The phrase "therapeutically effective" refers to the amount of each agent administered for the purpose of achieving an improvement in the severity of a disease, condition, and/or disorder, while avoiding or alleviating the side effects associated with the specified treatment.

[202] The term "pharmaceutically acceptable" refers to a subject suitable for use in the form of a pharmaceutical product.

[203] The compounds of formula (I) of the present invention are expected to be useful as therapeutic agents. Accordingly, embodiments of the invention include methods of treating various conditions in a patient, including a mammal, comprising administering to the patient a composition comprising a compound of formula (I) in an amount sufficient to effectively treat the condition of interest.

[204] It is an object of the present invention to provide methods for treating obesity and inducing weight loss in an individual by administering a compound of the present invention. The methods of the invention comprise administering to a subject a therapeutically effective amount of at least one compound of the invention, or a prodrug thereof, sufficient to induce weight loss. The present invention further includes methods of preventing weight gain in an individual by administering an amount of at least one compound of the present invention, or a prodrug thereof, effective to prevent weight gain.

[205] The invention also relates to the use of compounds of the invention for the treatment of obesity related diseases including disorders associated with dyslipidemia (dyslipemia) and other obesity and overweight related complications, such as cholesterol gallstone, gallbladder disease, gout, cancer (e.g. colon, rectal, prostate, breast, ovarian, endometrial, cervical, gallbladder, and bile duct), abnormal menstruation, infertility, polycystic ovary, osteoarthritis, and sleep apnea, as well as for various other pharmaceutical applications related thereto, such as the modulation of appetite and food intake, dyslipidemia, hypertriglyceridemia, syndrome X, type 2 diabetes (non-insulin dependent diabetes mellitus), atherosclerotic diseases such as heart failure, hyperlipidemia, hypercholesterolemia, low HDL levels, hypertension, cardiovascular diseases including atherosclerosis, hypertension, diabetes mellitus, coronary heart disease, coronary artery disease, and hypertension), cerebrovascular disease such as stroke, and peripheral vascular disease. The compounds of the present invention are also useful in the treatment of physiological disorders associated with, for example, modulation of insulin sensitivity, inflammatory responses, plasma triglyceride, HDL, LDL and cholesterol levels, and the like.

[206] The compounds of formula (I) may be administered alone or in combination with one or more other therapeutic agents. Combination therapy includes administration of a single pharmaceutical formulation containing a compound of formula (I) and one or more other therapeutic agents, as well as administration of the compound of formula (I) and each of the other therapeutic agents in the form of separate pharmaceutical formulations. For example, the compound of formula (I) and the therapeutic agent may be administered to the patient together in a single oral dosage composition, e.g., in the form of a tablet or capsule, or each agent may be administered in separate oral formulations.

[207] If separate formulations are administered, the compound of formula (I) and the one or more other therapeutic agents may be administered substantially simultaneously (e.g., together) or at separately staggered times (e.g., sequentially).

[208]For example, the compounds of formula (I) may be used in combination with other therapeutic agents and drugs useful in the treatment of obesity. For example, anti-obesity drugs include beta-3 adrenergic receptor agonists such as CL 316, 243; cannabinoid (e.g., CB-1) antagonists such as Rimonabant (Rimonabant); a neuropeptide Y receptor antagonist; neuropeptide Y5 inhibitors; apo-B/MTP inhibitors; 11 β -hydroxysteroid dehydrogenase-1 inhibitors; peptide YY_3-36Or an analog thereof; an MCR4 agonist; a CCK-A agonist; monoamine reuptake inhibitors; a sympathomimetic agent; a dopamine agonist; melanocyte stimulating hormone receptor analogs; a melanin concentrating hormone antagonist; leptin (leptin); a leptin analog; a leptin receptor agonist; galanin antagonists; a lipase inhibitor; bombesin agonists; a thyromimetic agent; dehydroepiandrosterone or an analog thereof; a glucocorticoid receptor antagonist; orexin receptor antagonists; ciliary neurotrophic factor; a ghrelin receptor antagonist; a histamine-3 receptor antagonist; a neurointerleukin U receptor agonist; appetite suppressants such as sibutramine (Meridia); and lipase inhibitors such as orlistat (xenoical). The compounds of the present invention may also be used in combination with pharmaceutical compounds that modulate digestion and/or metabolism, such as drugs that modulate thermogenesis, lipolysis, intestinal motility, fat absorption, and satiety.

[209] In addition, the compounds of formula (I) may also be used in combination with one or more agents useful in the treatment of diabetes or diabetes-related disorders, including PPAR ligands (agonists, antagonists), insulin secretagogues such as sulfonylurea drugs and non-sulfonylurea secretagogues, α -glucosidase inhibitors, insulin sensitizers, hepatic glucose output lowering compounds, and insulin derivatives. Such treatment may be administered before, after, or simultaneously with the administration of the compounds of the present invention. Insulin and insulin derivatives include long-acting and short-acting forms and formulations of insulin. The PPAR ligands may include any agonist and/or antagonist of PPAR receptors or a combination thereof. For example, the PPAR ligands may include ligands for PPAR- α, PPAR- γ, PPAR- δ, or any combination of two or three of the PPAR receptors. PPAR ligands include, for example, rosiglitazone, troglitazone, and pioglitazone. Sulfonylurea drugs include, for example, glibenclamide, glimepiride, chlorpropamide, tolbutamide, and glipizide. Alpha-glucosidase inhibitors useful for the treatment of diabetes, when administered with the compounds of the invention, include acarbose, miglitol, and voglibose. Insulin sensitizers which may be used in the treatment of diabetes include PPAR-gamma agonists such as glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, etc.) and other thiazolidinedione and non-thiazolidinedione compounds; biguanides such as metformin and phenformin; inhibitors of protein tyrosine phosphatase-1B (PTP-1B); dipeptidyl peptidase IV (DPP-IV) inhibitors, and 11 β -HSD inhibitors. Hepatic glucose output lowering compounds useful for the treatment of diabetes when administered with the compounds of the present invention include glucagon antagonists and metformin such as Glucophage and Glucophage XR. Insulin secretagogues which are useful in the treatment of diabetes when administered with the compounds of the present invention include sulfonylurea and non-sulfonylurea drugs: GLP-1, GIP, PACAP, secretin, and derivatives thereof; nateglinide, meglitinide, repaglinide, glyburide, glimepiride, chlorpropamide, glipizide. GLP-1 includes GLP-1 derivatives having a longer half-life than native GLP-1, such as fatty acid-derived GLP-1 and exendin.

[210] The compounds of the present invention may also be used in the methods of the present invention in combination with drugs conventionally used to treat lipid disorders in patients. Such agents include, but are not limited to, HMG-CoA reductase inhibitors, niacin, fatty acid lowering compounds (e.g., acipimox); lipid lowering drugs (e.g., stanol esters, sterol glycosides such as tiquinan, and azetidinones such as ezetimibe), ACAT inhibitors (e.g., avasimibe), bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, and fibric acid (fibric acid) derivatives. HMG-CoA reductase inhibitors include, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, cerivastatin, and ZD-4522. Fibric acid derivatives include, for example, clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate, etofibrate, and gemofibrate. Sequestering agents include, for example, cholestyramine, colestipol, and dialkylaminoalkyl derivatives of sephadex.

[211] The compounds of the present invention may also be used in combination with antihypertensive agents such as beta-blockers and ACE inhibitors. Examples of other antihypertensive agents for use in combination with the compounds of the present invention include calcium channel blockers (L-and T-forms; e.g., diltiazem *, verapamil, nifedipine, amlodipine and mybesirasil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlorthiazide, polythiazide, chlorthalidone, furosemide, musolimine, bumetanide, tritranene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, valsartan, ET), receptor antagonists (e.g., sirtataxatase, peptide inhibitors (neutral chain P), and neutral chain P), Vasopeptidase (vasopepsidase) inhibitors (binary NEP-ACE inhibitors) such as omatralat and gemopatrilat, and nitrates.

[212] The compounds of formula (I) may also be used in free base form or in compositions, as well as in research and diagnostics or as analytical reference standards, etc., all of which are known in the art. Accordingly, the present invention includes compositions comprised of an inert carrier and an effective amount of a compound of formula (I), or a salt or ester thereof. Inert carrier refers to a compound that does not interfere with the carried compound and provides support, a means of transport, swelling, a traceable material, etc. for the carried compound. An effective amount of a compound is an amount that produces a result or exerts an effect on the particular step being performed.

[213] It should be noted that prodrug forms of the compounds of the present invention may prove useful in certain situations and, therefore, such compounds are also within the scope of the present invention. Prodrug forms may have advantages over the parent compounds exemplified herein in that they are better absorbed, better distributed, more readily penetrate into the central nervous system, are more slowly metabolized or cleared, and the like. Prodrug forms may also have formulation advantages in terms of crystallinity or water solubility. For example, a compound of the invention having one or more hydroxyl groups may be converted to an ester or carbonate bearing one or more carboxyl, hydroxyl or amino groups, which is hydrolyzed at physiological pH or cleaved in vivo by endogenous esterases or lipases (see, e.g., U.S. Pat. Nos. 4,942,184; 4,960,790; 5,817,840; and 5,824,701, which are incorporated herein by reference in their entirety).

Pharmaceutical composition

[214] Effective dosages of the compounds of the present invention for each of the indications of interest may be conveniently determined by comparing the results with those of known medicaments for treating the condition, in accordance with the above-described tests, or other well-known tests for determining the efficacy of treatment of a given condition in mammals. The amount of active ingredient administered in the treatment of one of the conditions described above may vary depending upon a variety of considerations, such as the particular compound or dosage unit employed, the mode of administration, the time of treatment, the age and sex of the patient being treated, and the nature and extent of the condition being treated.

[215] The total amount of active ingredient administered may generally be, for example, from about 0.001mg/kg to about 200mg/kg, and preferably from about 0.01mg/kg to about 200mg/kg of body weight. The unit dose may contain, for example, from about 0.05 to about 1500mg of the active ingredient, and may be administered one or more times per day. Daily dosages for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injection, as well as using infusion techniques, may be, for example, from about 0.01 to about 200 mg/kg. The daily rectal dosage regimen may be, for example, from 0.01 to 200mg/kg of total body weight. Transdermal concentrations may be required to maintain daily doses of, for example, 0.01-200 mg/kg.

[216] Of course, the specific initial and sustained dosage regimen for each patient may vary with the nature and severity of the condition, the nature of the particular compound employed, the age of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion of the drug, the combination of drugs, and the like, and is determined by the attending diagnostician. The desired treatment pattern and number of doses of a compound of the invention or a pharmaceutically acceptable salt thereof can be determined by one skilled in the art using routine therapeutic testing.

[217] The compounds of the present invention are useful for obtaining a desired pharmacological effect by administration to a subject in need thereof in the form of a suitably formulated pharmaceutical composition. The subject may be, for example, a mammal, including a human, in need of treatment for a particular condition or disease. Accordingly, the present invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt or ester thereof, as determined by the methods described herein. A pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and non-injurious to the patient at concentrations consistent with effective activity of the active ingredient, such that any side effects caused by the carrier do not destroy the beneficial effects of the active ingredient. A pharmaceutically effective amount of a compound is an amount that results in or exerts an effect on the particular condition being treated. The compounds identified by the methods described herein may be administered in effective conventional dosage unit forms, including, for example, immediate and extended release formulations, oral, parenteral, topical, etc., with a pharmaceutically acceptable carrier.

[218] For oral administration, the compounds may be formulated in solid or liquid dosage forms, such as capsules, pills, tablets, lozenges, troches, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known in the art for preparing pharmaceutical compositions. The solid unit dosage form may be a capsule of the type normally found in hard or soft shell gelatin, containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

[219] In another embodiment, the compounds of the present invention may be tableted using conventional tablet bases such as lactose, sucrose, and corn starch in combination with various binders such as acacia, sucrose, corn starch, or gelatin; and disintegrants to aid in disintegration and dissolution of the tablet after administration, such as potato starch, alginic acid, corn starch, and guar gum; lubricants, such as talc, stearic acid, or magnesium, calcium or zinc stearate, for improving tablet granulation flowability and preventing tablet material from sticking to the tablet die and punch surfaces; a dye; a colorant; and flavoring agents to enhance the aesthetics of the tablet and make it more acceptable to patients. Suitable excipients for use in oral liquid dosage forms include diluents, such as water and alcohols, e.g., ethanol, benzyl alcohol, and polyethylene glycol, with or without the addition of pharmaceutically acceptable surfactants, suspending agents, or emulsifying agents. Various other materials may be present in the dosage unit in coated form or otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or a mixture of both.

[220] Dispersible powders and granules are suitable for use in the preparation of aqueous suspensions. They may provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present.

[221] The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a vegetable oil mixture. Suitable emulsifying agents may be (1) naturally-occurring gums, for example gum acacia and gum tragacanth, (2) naturally-occurring phosphatides, for example soya bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and (4) condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

[222] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, such as ethyl or n-propyl paraben; one or more colorants; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

[223] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring agent and a coloring agent.

[224] The compounds of the present invention may also be administered parenterally, i.e., subcutaneously, intravenously, intramuscularly, or intraperitoneally, in the form of an injectable dosage form of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or a mixture of liquids, such as water, saline, aqueous dextrose and related sugar solutions; alcohols such as ethanol, isopropanol or cetyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2, 2-dimethyl-1, 1-dioxolane-4-methanol; ethers such as poly (ethylene glycol) 400; an oil; a fatty acid; fatty acid esters or glycerides; or acetylated fatty acid glycerides, with or without the addition of a pharmaceutically acceptable surfactant such as soap or detergent; suspending agent such as colloid, carbomer, methylcellulose, hydroxypropyl methylcellulose or carboxymethyl cellulose, or emulsifying agent or other pharmaceutical adjuvants.

[225] Exemplary oils which may be used in the parenteral formulations of the invention are petroleum, animal, vegetable or synthetic oils, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, soft paraffin and mineral oil. Suitable fatty acids include oleic acid, stearic acid and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty alkali metal, ammonium and triethanolamine salts, and suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides and alkylamine acetates; anionic detergents such as alkyl, aryl and paraffin sulfonates, alkyl, paraffin, ether and monoglyceride sulfates and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers; and amphoteric cleansers, such as alkyl-beta-aminopropionates and 2-alkylimidazoline quaternary ammonium salts and mixtures.

[226] The parenteral compositions of the invention typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be advantageously employed. To reduce or eliminate irritation at the injection site, such compositions may contain a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of from about 12 to about 17. The surfactant is present in such formulations in an amount of about 5% to about 15% by weight. The surfactant may be a single component having the above-mentioned HLB, or may be a mixture of two or more components having the desired HLB.

[227] Exemplary surfactants for parenteral formulations are polyethylene sorbitan fatty acid esters, e.g., sorbitan monooleate and high molecular weight adducts of ethylene oxide with a hydrophobic group formed by condensing propylene oxide with propylene glycol.

[228] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated in accordance with known procedures using suitable dispersing or wetting agents and suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be naturally occurring phosphatides, for example lecithin, condensation products of ethylene oxide and fatty acids, for example polyoxyethylene stearate, condensation products of ethylene oxide and long chain aliphatic alcohols, for example heptadecaethylene oxide cetyl alcohol (heptadecaethylene oxide), condensation products of ethylene oxide and partial esters derived from fatty acids and a hexitol, and condensation products of hexitol alcohols, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides. Such as polyoxyethylene sorbitan monooleate.

[229] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. Diluents and solvents which can be used are, for example, water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[230] The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycols.

[231] Another formulation for use in the methods of the present invention uses a transdermal delivery device ("patch"). Such transdermal patches may be used to continuously or intermittently infuse controlled amounts of the compounds of the present invention. The construction and use of transdermal patches for delivering pharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No. 5,023,252, which is incorporated herein by reference). Such patches may be configured to deliver the agent continuously, in pulses, or on demand.

[232] It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for delivering pharmaceutical agents is well known in the art. For example, direct methods for administering drugs directly to the brain typically involve placing a drug delivery catheter into the ventricular system of a patient to bypass the blood brain barrier. One such implantable delivery system for delivering an agent to a specific anatomical region of the body is described in U.S. patent No. 5,011,472, the disclosure of which is incorporated herein by reference.

[233] The compositions of the present invention may also contain other conventional pharmaceutically acceptable compounding ingredients, which are commonly referred to as carriers or diluents, if needed or desired. Any of the compositions of the present invention may be preserved by the addition of an antioxidant such as ascorbic acid or other suitable preservative. Conventional procedures for preparing such compositions into suitable dosage forms may be employed.

[234] Commonly used pharmaceutical components of the compositions that may be suitably formulated for their intended route of administration include: acidulants such as, but not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid; and alkalizing agents such as, but not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine.

[235]Other pharmaceutical components include, for example, but are not limited to, adsorbents (e.g., powdered cellulose and activated carbon); aerosol propellants (e.g. carbon dioxide, CCl)₂F₂、F₂ClC-CClF₂And CClF₃) (ii) a Air displacement agents (e.g., nitrogen and argon); antifungal preservatives (e.g., benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate); antibacterial preservatives (e.g., benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylaminopyridine chloride, chlorobutanol, phenol, phenyl ethanol, phenylmercuric nitrate, and sulfur pump sprinkles); antioxidants (e.g. ascorbic acid, ascorbic acid)Ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (e.g., block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, and styrene-butadiene copolymers); buffering agents (e.g., potassium metaphosphate, potassium dihydrogen phosphate, sodium acetate, sodium citrate anhydrous, and sodium citrate dihydrate); carrier agents (e.g., acacia syrup, aromatic elixir, cherry syrup, cocoa syrup, orange peel syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and bacteriostatic water for injection); chelating agents (e.g., edetate disodium and edetic acid); coloring agents (e.g. FD)&C Red No.3、FD&C Red No.20、FD&C Yellow No.6、FD&C Blue No.2、D&C Green No.5、D&C OrangeNo.5、D&C Red No.8, maltose and Red iron oxide); clarifying agents (e.g., bentonite); emulsifying agents (but not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate); forming capsules (e.g., gelatin and cellulose acetate phthalate); flavorants (e.g., anise oil, cinnamon oil, cocoa, menthol, orange peel oil, peppermint oil, and vanillin); humectants (such as propylene glycol and sorbitol); abrasives (e.g., mineral oil and glycerin); oils (e.g., peanut oil, mineral oil, olive oil, peanut oil, sesame oil, and vegetable oil); ointment bases (e.g., lanolin, hydrophilic ointments, polyethylene glycol ointments, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose ointment); permeation enhancers (transdermal delivery) (e.g., monohydric or polyhydric alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones, and ureas); plasticizers (e.g., diethyl phthalate and glycerol); solvents (e.g., alcohol, cottonseed oil, glycerol, isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water, sterile water for injection, and sterile water for rinsing); hardening agents (e.g., cetyl alcohol, methyl ethyl ketone, ethyl methyl ketone,cetyl esters wax and yellow wax); suppository bases (e.g., cocoa butter and polyethylene glycol (mixtures)); surfactants (e.g., benzalkonium chloride, nonoxynol 10, oxoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitan palmitat); suspensions (e.g., agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweeteners (e.g., aspartame, glucose, glycerol mannitol, propylene glycol, sodium saccharin, sorbitol, and sucrose); tablet anti-caking agents (e.g., magnesium stearate and talc); tablet binding agents (e.g., acacia, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone, and pregelatinized starch); tablet and capsule diluents (e.g., dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium phosphate, sorbitol, and starch); tablet coatings (e.g., liquid glucose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, cellulose acetate, and shellac); tablet direct compression excipients (e.g., monocalcium phosphate); tablet disintegrating agents (e.g., alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, potassium-type beralline, sodium alginate, sodium starch glycolate, and starch); tablet glidants (colloidal silica, corn starch and talc); tablet emulsifiers (e.g., calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate); tablets/capsules opaquants (e.g. titanium dioxide); tablet polishing agents (e.g., carnuba wax and white wax); thickeners (e.g., beeswax, cetyl alcohol and paraffin wax); osmotic (tonicity) agents (e.g., glucose and sodium chloride); viscosity increasing agents (e.g., alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, povidone, sodium alginate, and tragacanth); and wetting agents (e.g., heptadecaethylene oxide cetyl alcohol), lecithin, polyethylene sorbitol monooleate, and polyoxyethylene stearate).

[236] The compounds identified by the methods described herein may be administered as a single agent or in combination with one or more other agents, where the combination does not cause unacceptable adverse effects. For example, the compounds of the present invention may be combined with known anti-obesity agents, or with known anti-diabetic or other indications, as well as mixtures or combinations thereof.

[237] The compounds identified by the methods described herein may be used in free base form or in compositions, as well as in research and diagnostics or as analytical reference standards, and the like. Accordingly, the present invention includes compositions comprising an inert carrier and an effective amount of a compound, or a salt or ester thereof, as determined by the methods described herein. Inert carrier refers to not interfere with the carried compound and for the carried compound provides support, transport mode, expansion, can trace material any substance. An effective amount of a compound is an amount that produces a result or exerts an effect on the particular step being performed.

[238] Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; a suitable pharmaceutical carrier; and the formulation and method of administration may be prepared by any of the methods well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing co., Easton, Pa., 20 th edition, 2000).

Biological activity of the Compound

[239] For a better understanding of the present invention, the following examples are given. These examples are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way. The contents of all publications mentioned herein are incorporated herein by reference in their entirety.

[240] Confirmation of the activity of the compounds of the invention may be accomplished by in vitro, ex vivo, and in vivo tests well known in the art. For example, to demonstrate the efficacy of an agent for the treatment of obesity and related disorders, the following test may be used.

Evaluation of Compounds for inhibition of DGAT-1 enzymatic ActivityFunction of

[241] The human DGAT-1 gene (see, e.g., U.S. Pat. No. 6,100,077) was isolated from a human cDNA library by PCR. A recombinant AcNPV baculovirus was constructed in which the gene containing the somatomedin polyhedrin was replaced with the DGAT-1 gene. The DGAT-1 gene sequence was inserted 3' to the AcNPV genome under the transcriptional control of the polyhedrin promoter, replacing the polyhedrin promoter sequence of DGAT-1. Spodoptera frugiperda-derived Sf9 insect cells were infected with a recombinant baculovirus containing DGAT-1 at a multiplicity of 5 and harvested 48 hours post infection. Insect cells expressing DGAT-1 were homogenized in 10mM Tris, 250mM sucrose, pH 7.5 at a concentration of 100mg wet cell biomass/mL. The homogenate was centrifuged at 25,000g for 30 minutes. The 25,000g pellet was discarded and the supernatant was centrifuged at 100,000g for 1 hour. 100,000g of the supernatant was discarded and 100,000g of membrane pellet containing DGAT-1 was resuspended in 10mM Tris, 50% (v/v) glycerol pH 7.5.

[242]DGAT-1 enzyme activity was determined by a phase partition protocol. Specifically, DGAT-1 containing membranes were cultured in 20. mu.M didecanoyl glycerol, 5. mu.M in the presence of variable concentrations of inhibitor¹⁴C-decanoyl-CoA, 2mM MgCl₂0.01% BSA, 20mM HEPES, pH 7.5 buffer. The assay was performed in a volume of 100 μ L in a 96-well microplate with 0.5 μ g total membrane cells/well. The assay was initiated by substrate and gently mixed for 1 hour at ambient temperature. The activity was quenched by addition of 25. mu.L of 0.1% phosphoric acid solution. Selective extraction of the hydrophobic tridecanoyl glycerol product was accomplished by adding 150 μ L of phase partition scintillation fluid Microscmt ® (Packard, Inc.) and vigorously mixing for 30 minutes. Quantification of the product was done by using a MicroBeta ® scintillation counter (Wallac, Inc.) after settling at ambient temperature for approximately 16 hours.

Evaluation of the Effect of Compounds on inhibition of cellular Triglycerides deposition

[243] Cell-based assays for DGAT-1 were performed using human colorectal adenocarcinoma cells HT-29(HTB-38, ATCC). HT-29 cells were grown in 75cm2 plates in DMEM medium with 10% FBS, PSF, glutamine, and 10mM acetate until confluence was-90%. Cells were then replated in 24-well plates to give a 1: 1.2 dilution and grown for approximately 16 hours. Triacylglycerol formation was stimulated by addition of lauric acid to a final concentration of 0.01% in the presence of variable concentrations of inhibitor. After 6 hours, the cells were released from the plate by trypsin, collected by centrifugation, resuspended in water, transferred to a glass HPLC, frozen at-70 ℃ and lyophilized. The lyophilized cell pellet was resuspended in 150 μ LHPLC grade tetrahydrofuran and sealed in a vial. The vials were sonicated for 30 minutes while heating in an ultrasonic water bath (Fisher, Inc.). Cellular triacylglycerols were quantified by HPLC (HP1100, Agilent, Inc.) using evaporative light scattering detection (PL-ELS 1000, Polymer Labs, Inc.). Chromatographic separation was accomplished using a PLRP S100 column (5 microns, 150X 4.6mm, Polymer Labs, Inc.) at 50 deg.C (A: 50% acetonitrile, 2.5% methanol, B: 100% tetrahydrofuran) by 30-100% B buffer for 4 minutes followed by 100% B buffer for 3 minutes. The sample injection was 20 μ L, and the detector was set at 0.4SLM, 40 ℃ sprayer, and 80 ℃ evaporator. The nonpolar fatty acids and glycerolipids were identified and quantified using commercially available standards.

Evaluation of the efficacy of Compounds in weight loss in diet-induced obese mice

[244] The protocol aims to determine the effect of chronic administration of compounds on body weight of mice that are obese as a result of exposure to 45% kcal/g high fat meal for more than 10 weeks. The mice selected for this study were weighed 3 standard deviations above the weight of control mice fed standard low fat (5-6% fat) mice. Food-induced obesity (DIO) animals have been used many times to determine the efficacy of a compound to reduce body weight (see, e.g., Brown, et al, Brit.J.Pharmacol.132: 1898-1904, 2001; Guerre-Millo, et al, J.biol.chem.275 (22): 16638-42, 2000; Han, et al, Intl.J.Obetivity and Related Metabolic disorders 23 (2): 174-79, 1999; Surwit, et al, Endocrinol.141 (10): 3630-37, 2000).

[245] The present animal model has been successfully used to identify and describe efficacy profiles for compounds that are or have been used to control the body weight of obese humans (see, e.g., Brown, et al, 2001; Guerre-Millo, et al, 2000; Han, et al, 1999).

[246] A typical study included 60-80 male C57b1/J6 mice (n-10/treatment group) with an average body weight of approximately 45 g. Mice were kept in a standard animal room under controlled temperature and humidity, and had a 12 hour/12 hour light/dark cycle. Water and food can be continuously obtained. Mice were housed individually. Animals were sham dosed for at least 4 days using the study vehicle, and two-day baseline measurements of body weight and 24-hour food and water consumption were recorded. Mice were assigned to one of 6-8 treatment groups based on baseline body weight. Each group was set so that the mean value of body weight and the standard error of the mean value were similar.

[247]Animals were orally gavaged with the indicated dose/compound (5mL/kg) daily for a predetermined number of days (typically 8-14 days) prior to the dark phase of the light/dark cycle. Body weight, and food and water consumption were measured. After study design, the data were analyzed using appropriate statistical means. On the last day, animals inhale CO₂Euthanasia was performed.

[248] The compounds are generally administered orally at a dose of 5 or 10mg/kg, either once daily as a suspension formulation in 50: 50 PEG/water, or twice daily as a suspension formulation in 0.5% methylcellulose, and are considered effective if statistically significant weight loss is observed in the treated animals after at least seven days of treatment relative to vehicle-treated control animals.

[249] The various structures, materials, compositions and methods described herein are merely representative examples of the invention, and it is to be understood that the scope of the invention is not limited by these examples. It will be appreciated by those skilled in the art that various modifications may be made to the disclosed structures, materials, compositions and methods, and that such modifications are considered to be within the scope of the present invention.

Claims (40)

1. A mixture of the formula (I)

Wherein

R²And R³Are all hydrogen, and R¹Is hydrogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy radical- (C₂-C₆) Alkyl, phenoxy- (C)₂-C₆) Alkyl, aryl, heteroaryl, and heteroaryl,1-methyl-1H-indol-3-yl, di [ (C)₁-C₆) Alkyl radical]Amino group- (C)₂-C₆) Alkyl, 1-piperidinyl- (C)₂-C₆) Alkyl, 1-pyrrolidinyl- (C)₂-C₆) Alkyl or 1-morpholinyl- (C)₂-C₆) An alkyl group;

or

R¹Is R⁶(CH₂)_mWherein m is 0 to 3, and R⁶Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁶Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro; or

R³Is hydrogen, and R¹And R²Are identical and are each selected from (C)₁-C₆) An alkyl group;

or

R³Is hydrogen, and R¹And R²Together with the carbon atom to which they are attached form a 3-5 membered carbocyclic ring, or are formed of

A 6-membered ring represented by wherein W is CH₂、C(CH₃)₂、O、NH、N(CH₃) S or SO₂；

Or

R¹Is hydrogen, and R²And R³Taken together with the two carbon atoms to which they are attached form a 3-6 membered carbocyclic ring;

R⁴and R⁵Independently selected from hydrogen, hydroxy, halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl and cyano;

q isR⁷-C (O) -, wherein R⁷Is optionally substituted by one or more of the following groups₁-C₆) Alkyl groups: hydroxy, (C)₁-C₆) Alkoxy, di [ (C)₁-C₆) Alkyl) amino or fluoro;

or

R⁷Is R⁸(CH₂)_nWherein n is 0-3, and R⁸Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁸Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁷Is R¹⁰C(R⁹)₂Wherein R is⁹Is a methyl group or an ethyl group,

or

C(R⁹)₂Is a 1, 1-cyclopropyl, 1-cyclobutyl, 1-cyclopentyl or 1, 1-cyclohexyl ring;

R¹⁰is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁰Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro; or

R⁷Is a fragment group selected from:

wherein R is¹¹Is one or more substituents selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano and nitro;

or

Q is R¹³-N(R¹²) -C (O) -, wherein R¹²Is hydrogen or (C)₁-C₆) Alkyl radical, and

R¹³is optionally substituted by one or more of the following groups₁-C₆) Alkyl groups: hydroxy, (C)₁-C₆) Alkoxy, di [ (C)₁-C₆) Alkyl) amino or fluoro;

or

R¹³Is R¹⁴(CH₂)_pWherein p is 0-3, and R¹⁴Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁴Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹²And R¹³Together with the nitrogen atom to which they are attached form a ring segment selected from:

wherein L is O, C (O) or a bond;

R¹⁵is (C)₁-C₆) An alkyl group;

or

R¹⁵Is R¹⁷(CH₂)_qWherein q is 0 or 1, and R¹⁷Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁷Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

R¹⁶is one or more substituents selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano and nitro;

or

Q is R¹⁸-S(O)₂-, wherein R¹⁸Is (C)₁-C₆) Alkyl or benzyl;

or

R¹⁸Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

a is OH or NHS (O)₂-R¹⁹

Wherein R is¹⁹Is (C)₁-C₆) Alkyl, trifluoromethyl, benzyl;

or

R¹⁹Is R²⁰(CH₂)_tWherein t is 0 or 1, and R²⁰Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁹Is a fragment radical selected from

V, Y and Z are both carbon; or

V and Y are carbon and Z is nitrogen; or

V and Z are carbon and Y is nitrogen; or

Z is carbon and V and Y are both nitrogen;

and the pharmaceutically acceptable salts and esters thereof,

with the proviso that formula (I) is not 4- [4 ' - (acetylamino) -3 ' -bromobiphenyl-4-yl ] -4-oxobutanoic acid, 4- [4 ' - (acetylamino) biphenyl-4-yl ] -4-oxo-2- (2-phenylethyl) butanoic acid, 4- {4 ' - [ (3, 3-dimethylbutyryl) amino ] biphenyl-4-yl } -4-oxo-2- (2-phenylethyl) butanoic acid or 4-oxo-4- [4 ' - (pentanoylamino) biphenyl-4-yl ] -2- (2-phenylethyl) butanoic acid.

2. The compound of claim 1, wherein

R²And R³Are all hydrogen, and R¹Is hydrogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy radical- (C₂-C₆) Alkyl, phenoxy- (C)₂-C₆) Alkyl, 1-methyl-1H-indol-3-yl, di [ (C)₁-C₆) Alkyl radical]Amino group- (C)₂-C₆) Alkyl, 1-piperidinyl- (C)₂-C₆) Alkyl, 1-pyrrolidinyl- (C)₂-C₆) Alkyl or 1-morpholinyl- (C)₂-C₆) An alkyl group;

or

R¹Is R⁶(CH₂)_mWherein m is 0 to 3, and R⁶Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁶Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy radicalA group, trifluoromethyl, cyano or nitro.

3. The compound of claim 1, wherein

R¹Is hydrogen, and R²And R³Together with the two carbon atoms to which they are attached form a 3-to 6-membered ring

A carbocyclic ring.

4. The compound of claim 1, wherein a is OH.

5. The compound of claim 1, wherein A is NHS (O)₂-R¹⁹

Wherein R is¹⁹Is (C)₁-C₆) Alkyl, trifluoromethyl, benzyl;

or

R¹⁹Is R²⁰(CH₂)_tWherein t is 0 or 1, and R²⁰Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁹Is a fragment radical selected from

6. The compound of claim 1, wherein

V and Y are carbon and Z is nitrogen.

7. The compound of claim 1, wherein

V and Z are carbon and Y is nitrogen.

8. The compound of claim 1, wherein

V and Y are nitrogen and Z is carbon.

9. The compound of claim 1, wherein

R²And R³Are all hydrogen;

and is

R¹Is R⁶(CH₂)_mWherein m is 0 to 3, and R⁶Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁶Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

q is R⁷-C (O) -, wherein R⁷Is optionally substituted by one or more of the following groups₁-C₆) Alkyl groups: hydroxy, (C)₁-C₆) Alkoxy, di [ (C)₁-C₆) Alkyl) amino or fluoro;

or

R⁷Is R⁸(CH₂)_nWherein n is 0-3, and R⁸Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁸Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁷Is R¹⁰C(R⁹)₂Wherein R is⁹Is a methyl group or an ethyl group,

or

C(R⁹)₂Is 1, 1-cyclopropylA 1, 1-cyclobutyl, 1-cyclopentyl or 1, 1-cyclohexyl ring;

R¹⁰is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁰Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro; or

R⁷Is a fragment radical selected from

Wherein R is¹¹Is one or more substituents selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano and nitro;

and is

A is OH.

10. The compound of claim 1, wherein

R³Is hydrogen, and R¹And R²Together with the carbon atom to which they are attached form a 3-5 membered carbocyclic ring, or are formed of

A 6-membered ring represented by wherein W is CH₂、C(CH₃)₂、O、NH、N(CH₃) S or SO₂；

Or

R¹Is hydrogen, and R²And R³Taken together with the two carbon atoms to which they are attached form a 3-6 membered carbocyclic ring;

q is R⁷-C (O) -, wherein R⁷Is optionally substituted by one or more groups selected from (C)₁-C₆) Alkyl groups: hydroxy, (C)₁-C₆) Alkoxy, di [ (C)₁-C₆) Alkyl) amino or fluoro;

or

R⁷Is R⁸(CH₂)_nWherein n is 0-3, and R⁸Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁸Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁷Is R¹⁰C(R⁹)₂Wherein R is⁹Is a methyl group or an ethyl group,

or

C(R⁹)₂Is a 1, 1-cyclopropyl, 1-cyclobutyl, 1-cyclopentyl or 1, 1-cyclohexyl ring;

R¹⁰is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁰Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro; or

R⁷Is a fragment radical selected from

Wherein R is¹¹Is one or more substituents selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano and nitro;

a is OH.

11. The compound of claim 1, wherein

R²And R³Are all hydrogen, and R¹Is hydrogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy radical- (C₂-C₆) Alkyl, phenoxy- (C)₂-C₆) Alkyl, 1-methyl-1H-indol-3-yl, di [ (C)₁-C₆) Alkyl radical]Amino group- (C)₂-C₆) Alkyl, 1-piperidinyl- (C)₂-C₆) Alkyl, 1-pyrrolidinyl- (C)₂-C₆) Alkyl or 1-morpholinyl- (C)₂-C₆) An alkyl group;

or

R¹Is R⁶(CH₂)_mWherein m is 0 to 3, and R⁶Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R⁶Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

q is R¹³-N(R¹²) -C (O) -, wherein R¹²Is hydrogen or (C)₁-C₆) Alkyl radical, and

R¹³is optionally substituted by one or more groups selected from (C)₁-C₆) Alkyl groups: hydroxy, (C)₁-C₆) Alkoxy, di [ (C)₁-C₆) Alkyl) amino or fluoro;

or

R¹³Is R¹⁴(CH₂)_pWherein p is 0-3, and R¹⁴Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁴Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹²And R¹³Together with the nitrogen atom to which they are attached form a ring segment selected from:

wherein L is O, C (O) or a bond;

R¹⁵is (C)₁-C₆) An alkyl group;

or

R¹⁵Is R¹⁷(CH₂)_qWherein q is 0 or 1, and R¹⁷Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁷Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

R¹⁶is one or more substituents selected from the group consisting of: the halogen(s) are selected from the group consisting of,hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano and nitro;

and is

A is OH.

12. The compound of claim 1, wherein

R³Is hydrogen, and R¹And R²Together with the carbon atom to which they are attached form a 3-5 membered carbocyclic ring, or are formed of

A 6-membered ring represented by wherein W is CH₂、C(CH₃)₂、O、NH、N(CH₃) S or SO₂；

Or

R¹Is hydrogen, and R²And R³Taken together with the two carbon atoms to which they are attached form a 3-6 membered carbocyclic ring;

q is R¹³-N(R¹²) -C (O) -, wherein R¹²Is hydrogen or (C)₁-C₆) Alkyl radical, and

R¹³is optionally substituted by one or more groups selected from (C)₁-C₆) Alkyl groups: hydroxy, (C)₁-C₆) Alkoxy, di [ (C)₁-C₆) Alkyl) amino or fluoro;

or

R¹³Is R¹⁴(CH₂)_pWherein p is 0-3, and R¹⁴Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁴Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkane (I) and its preparation methodOxy, trifluoromethyl, cyano or nitro;

or

R¹²And R¹³Together with the nitrogen atom to which they are attached form a ring segment selected from:

wherein L is O, C (O) or a bond;

R¹⁵is (C)₁-C₆) An alkyl group;

or

R¹⁵Is R¹⁷(CH₂)_qWherein q is 0 or 1, and R¹⁷Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

or

R¹⁷Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

R¹⁶is one or more substituents selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano and nitro;

and is

A is OH.

13. A compound according to claim 1, which is a pharmaceutically acceptable salt thereof,

wherein

R³Is hydrogen, and R¹And R²Both are methyl;

or

R¹Is hydrogen, and R²And R³Taken together with the two carbon atoms to which they are attached form a 3-6 membered carbocyclic ring;

R⁴and R⁵Is independently selected fromHydrogen and halogen;

q is R⁷-C(O)-，

Wherein

R⁷Is R⁸(CH₂)_nWherein n is 0-3, and R⁸Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro,

or

R⁸Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

a is OH; and is

V, Y and Z are both carbon.

14. A compound according to claim 1, which is a pharmaceutically acceptable salt thereof,

wherein

R³Is hydrogen, and R¹And R²Both are methyl;

or

R¹Is hydrogen, and R²And R³Taken together with the two carbon atoms to which they are attached form a 3-6 membered carbocyclic ring;

R⁴and R⁵Independently selected from hydrogen and halogen;

q is R¹³-N(R¹²)-C(O)-，

Wherein

R¹²Is hydrogen; and is

R¹³Is R¹⁴(CH₂)_pWherein p is 0-3, and R¹⁴Is phenyl optionally substituted with one or more of the following groups: halogen, hydroxy, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro,

or

R¹⁴Is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethyl, cyano or nitro;

a is OH; and is

V, Y and Z are both carbon.

15. A compound of claim 1 selected from the group consisting of:

trans-2- { [ 4' - ({ [ (4-fluorophenyl) amino ] carbonyl } amino) biphenyl-4-yl ] carbonyl } cyclopentanecarboxylic acid;

trans-2- { [ 4' - ({ [ (4-ethylphenyl) amino ] carbonyl } amino) biphenyl-4-yl ] carbonyl } -cyclopropanecarboxylic acid;

trans-2- { [ 4' - ({ [ (4-ethylphenyl) amino ] carbonyl } amino) biphenyl-4-yl ] carbonyl } -cyclohexanecarboxylic acid;

trans-2- { [ 4' - ({ [ (4-ethoxyphenyl) amino ] carbonyl } amino) biphenyl-4-yl ] carbonyl } -cyclopentanecarboxylic acid; and

trans-2- { [ 4' - ({ [ (3, 4-dimethylphenyl) amino ] carbonyl } amino) biphenyl-4-yl ] carbonyl } -cyclopropanecarboxylic acid.

16. A compound of claim 1 selected from the group consisting of:

trans-2- { [ 4' - ({ [ (2-chlorophenyl) amino ] carbonyl } amino) biphenyl-4-yl ] carbonyl } -cyclopropanecarboxylic acid;

trans-2- { [ 4' - ({ [ (2, 4-difluorophenyl) amino ] carbonyl } amino) biphenyl-4-yl ] carbonyl } -cyclobutanecarboxylic acid;

trans-2- [ (4' - { [ (3, 5-difluorophenyl) acetyl ] amino } biphenyl-4-yl) carbonyl ] cyclopentanecarboxylic acid;

trans-2- [ (4' - { [ (3, 4-dimethoxyphenyl) acetyl ] amino } biphenyl-4-yl) carbonyl ] cyclopentanecarboxylic acid; and

trans-2- ({ 4' - [ (4-fluoro-3-methylbenzoyl) amino ] biphenyl-4-yl } carbonyl) cyclopentanecarboxylic acid.

17. A compound of claim 1 selected from the group consisting of:

trans-2- ({ 4' - [ (4-ethoxybenzoyl) amino ] biphenyl-4-yl } carbonyl) cyclopentanecarboxylic acid;

trans-2- ({ 4' - [ (4-butylbenzoyl) amino ] biphenyl-4-yl } carbonyl) cyclopentanecarboxylic acid;

trans-2- ({ 4' - [ (4-butylbenzoyl) amino ] biphenyl-4-yl } carbonyl) cyclopropanecarboxylic acid;

trans-2- ({ 4' - [ (3, 4-dimethylbenzoyl) amino ] biphenyl-4-yl } carbonyl) cyclopentanecarboxylic acid; and

trans-2- ({ 4' - [ (3, 4-dichlorobenzoyl) amino ] biphenyl-4-yl } carbonyl) cyclohexanecarboxylic acid.

18. A compound of claim 1 selected from the group consisting of:

4- [ 4' - ({ [ (4-ethylphenyl) amino ] carbonyl } amino) biphenyl-4-yl ] -2, 2-dimethyl-4-oxobutanoic acid;

4- [4 '- ({ [ (4-ethylphenyl) amino ] carbonyl } amino) -3' -fluorobiphenyl-4-yl ] -2, 2-dimethyl-4-oxobutanoic acid;

4- [ 4' - ({ [ (3, 4-dimethylphenyl) amino ] carbonyl } amino) biphenyl-4-yl ] -2, 2-dimethyl-4-oxobutanoic acid;

4- [4 '- ({ [ (3, 4-dimethylphenyl) amino ] carbonyl } amino) -3' -fluorobiphenyl-4-yl ] -2, 2-dimethyl-4-oxobutanoic acid; and

4- [4 '- ({ [ (2, 4-difluorophenyl) amino ] carbonyl } amino) -3' -fluorobiphenyl-4-yl ] -2, 2-dimethyl-4-oxobutanoic acid.

19. A compound of claim 1 selected from the group consisting of:

4- [3 '-fluoro-4' - ({ [ (4-fluorophenyl) amino ] carbonyl } amino) biphenyl-4-yl ] -2, 2-dimethyl-4-oxobutanoic acid;

(1R, 2R) -2- { [ 4' - ({ [ (4-ethylphenyl) amino ] carbonyl } amino) biphenyl-4-yl ] carbonyl } -cyclohexanecarboxylic acid;

(1R, 2R) -2- [ (4' - { [ (4-ethoxyphenyl) acetyl ] amino } biphenyl-4-yl) carbonyl ] cyclopentanecarboxylic acid;

(1R, 2R) -2- [ (4' - { [ (3, 5-difluorophenyl) acetyl ] amino } biphenyl-4-yl) carbonyl ] cyclopentanecarboxylic acid;

(1R, 2R) -2- ({ 4' - [ (4-fluoro-3-methylbenzoyl) amino ] biphenyl-4-yl } carbonyl) cyclopentanecarboxylic acid; and

(1R, 2R) -2- ({ 4' - [ (4-ethoxybenzoyl) amino ] biphenyl-4-yl } carbonyl) cyclopentanecarboxylic acid.

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt or ester of claim 1 in combination with a pharmaceutically acceptable carrier.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents.

22. The pharmaceutical composition of claim 21, wherein the drug is an anti-obesity drug selected from the group consisting of: beta-3 adrenergic receptor agonists, cannabinoid antagonists, neuropeptide Y receptor antagonists, neuropeptide Y5 inhibitors, apo-B/MTP inhibitors, 11 beta-hydroxysteroid dehydrogenase-1 inhibitors, peptide YY_3-36Peptide YY_3-36Analogs thereof, MCR4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetics, dopamine agonists, melanocyte stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors, bombesin agonists, thyromimetics, dehydroepiandrosterone analogs, glucocorticoid receptor antagonists, appetite (orexin) receptor antagonists, ciliary neurotrophic factors, ghrelin receptor antagonists, histamine-3 receptor antagonists, interleukin U receptor agonists, appetite suppressors, digestion and/or metabolism modulators, thermogenic modulators, lipolysis modulators, intestinal motility modulators, fat absorption modulators, and satiety modulators.

23. The pharmaceutical composition of claim 21, wherein the drug is a drug for treating diabetes selected from the group consisting of: insulin, insulin derivatives, PPAR ligands, sulfonylurea drugs, alpha-glucosidase inhibitors, biguanides, PTP-1B inhibitors, DPP-IV inhibitors, 11-beta-HSD inhibitors, GLP-1 and GLP-1 derivatives, GIP and GIP derivatives, PACAP and PACAP derivatives, and secretin derivatives.

24. The pharmaceutical composition of claim 21, wherein the drug is a drug for treating a lipid disorder selected from the group consisting of: HMG-CoA inhibitors, nicotinic acid, fatty acid lowering compounds, lipid lowering drugs, ACAT inhibitors, bile chelators, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, and fibric acid derivatives.

25. The pharmaceutical composition of claim 21, wherein the drug is an antihypertensive drug selected from the group consisting of: beta-blockers, calcium channel blockers, diuretics, renin inhibitors, ACE inhibitors, AT-1 receptor antagonists, ET receptor antagonists and nitrates.

26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 2-19, or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier.

27. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 2-19, or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents.

28. A method of treating obesity comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 20.

29. A method of inducing weight loss comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 20.

30. A method of preventing weight gain comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 20.

31. A method of treating an obesity-related disorder comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 20.

32. The method of claim 31, wherein the obesity-related disorder is selected from the group consisting of: dyslipidemia, cholesterol gallstones, cystic disease, gout, cancer, menstrual abnormalities, infertility, polycystic ovary, osteoarthritis, sleep apnea, hypertriglyceridemia, syndrome X, type 2 diabetes, atherosclerotic disease, hyperlipidemia, hypercholesterolemia, low HDL levels, hypertension, cardiovascular disease, coronary heart disease, coronary artery disease, cerebrovascular disease, stroke, and peripheral vascular disease.

33. A method of treating obesity comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutical agents.

34. The method of claim 33, wherein the compound of claim 1 and the one or more agents are administered as a single pharmaceutical dosage form.

35. A method of treating obesity comprising administering to a subject in need thereof a therapeutically effective amount of a composition according to any one of claims 21 to 27.

36. A method of treating an obesity-related disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition according to any one of claims 21 to 27.

37. A compound according to claim 1 for use in the treatment and/or prevention of obesity and obesity related diseases.

38. A medicament containing at least one compound according to claim 1 and at least one pharmaceutically acceptable, pharmaceutically safe carrier and excipient.

39. Use of a compound according to claim 1 for the preparation of a medicament for the treatment and/or prevention of obesity and obesity-related disorders.

40. The medicament according to claim 38 for the treatment and/or prophylaxis of obesity.