Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein

FIELD OF THE INVENTION

[0002] The present invention relates to inhibitors of the adipocyte fatty acid binding protein (aP2), and to dual inhibitors of aP2 and keratinocyte fatty acid binding protein (k-FABP), especially aryl carboxylic acids and tetrazoles of Formula I. The present invention further relates to a method for treating diabetes, especially Type II diabetes, as well as hyperglycemia, hyperinsulinemia, obesity, Syndrome X, diabetic complications, atherosclerosis and related diseases, and other chronic inflammatory and autoimmune/inflammatory diseases, employing the compounds of the present invention alone or in combination with one or more types of therapuetic agents.

BACKGROUND OF THE INVENTION

[0003] Fatty acid binding proteins (FABPs) are small cytoplasmic proteins that bind to fatty acids such as oleic acids which are important metabolic fuels and cellular regulators. Dysregulation of fatty acid metabolism in adipose tissue is a prominent feature of insulin resistance and the transition from obesity to non-insulin dependent diabetes mellitus (NIDDM or Type II diabetes).

[0004] aP2 (adipocyte fatty binding protein), an abundant 14.6 KDa cytosolic protein in adipocytes, and one of a family of homologous intracellular fatty acid binding proteins (FABPs), is involved in the regulation of fatty acid trafficking in adipocytes and mediates fatty acid fluxes in adipose tissue. G. S. Hotamisligil et al, “Uncoupling of Obesity from Insulin Resistance Through a Targeted Mutation in aP2, the Adipocyte Fatty Acid Binding Protein”, Science, Vol. 274, Nov. 22, 1996, pp. 1377-1379, report that aP2-deficient mice placed on a high fat diet for several weeks developed dietary obesity, but, unlike control-mice on a similar diet, did not develop insulin resistance or diabetes. Hotamisligil et al conclude “aP2 is central to the pathway that links obesity to insulin resistance” (Abstract, page 1377).

[0005] Also, it has been shown by Uysal et al in “Improved glocose and lipid metabolism in genetically obese mice lacking aP2” in Endocrinology, Vol. 141, 2000, pp. 3388-3396 that ob/ob mice deficient of aP2 had lower plasma glucose, improved peripheral insulin resistance, and beneficial effects on lipid metabolism.

[0006] Additionally, Makowski et. al. in “Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis” in Nature Medicine, Vol. 7, 2001, pp. 699-705 showed that Apoe-/- mice with either total aP2 deficiency or aP2-/- macrophage deficiency showed reductions in the formation of atherosclerotic plague, as well as reduction of TNF-alpha and a variety of inflammatory cytokines, as compared to aP2 replete ApoE-/- mice.

[0007] Since it is known that both aP2 and k-FABP (mal-1), both intracellular fatty acid binding proteins, are expressed in both adipocyte and macrophage cells, concommitant inhibition of both FABPs should be expected to have greater effects in treating the diseases such as diabetes, obesity, atherosclerosis, inflammation, and those previously mentioned.

[0008] DIALOG ALERT DBDR928 dated Jan. 2, 1997, Pharmaprojects No. 5149 (Knight-Ridder Information) discloses that a major drug company “is using virtual screening techniques to identify potential new antidiabetic compounds.” It is reported that “the company is screening using aP2, a protein related to adipocyte fatty acid binding protein.”

[0009] PCT applications WO 00/15229 and WO 00/59506 disclose methods for treating diabetes employing an aP2 inhibitor.

SUMMARY OF THE INVENTION

[0010] In accordance with the present invention, aryl compounds are provided which are aP2 inhibitors and/or dual aP2/k-FABP inhibitors having the structure of formula I

[0011] including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof wherein

[0012] A is

[0013] a bond,

[0014] a C1-C3 alkylene group optionally independently substituted on available atoms with one to six halo, hydroxy, alkoxy, hydroxyalkyl, SR4, alkyl, alkenyl, cyano, CONHR4, COOR4, oxo, NHOR4, ═NOR4 or N(R8)COR4; or

[0015] a C2-C3 alkenylene group optionally independently substituted on available atoms with one to four halo, hydroxy, alkoxy, hydroxyalkyl, SR4, alkyl, alkenyl, cyano, CONHR4, COOR4, oxo, NHOR4, ═NOR4, or N(R8)COR4;

[0016] B is carboxyl or tetrazole;

[0017] X and Y are independently

[0018] —O(CR5R6)q—,

[0019] —(CR5R6)qO—,

[0020] —(CR5R6)qN(R7)CO—,

[0021] —N(R7)CO(CR5R6)q—,

[0022] —N(R7)CO(CR5R6)qO—,

[0023] —N(R7)CO(CR5R6)qC(O)O—,

[0024] —N(R7)CO—CR5═CR6—,

[0025] —(CR5R6)qN(R7)SO2—,

[0026] —N(R7)SO2(CR5R6)q—,

[0027] —O—CO(CR5R6)q—,

[0028] —O(CR5R6)qCO—,

[0029] —(CR5R6)qO—CO—, or

[0030] —(CR5R6)qS(O)t—;

[0031] R1 is aryl, heteroaryl, alkyl, cycloalkyl, aralkyl, heteroarylalkyl, cylcoalkenyl or heterocyclo any of which may be optionally substituted with Z1a, Z2a and one or more Z3a;

[0032] R2 is aryl, heteroaryl, alkyl, cycloalkyl, aralkyl, heteroarylalkyl, cylcoalkenyl or heterocyclo any of which may be optionally substituted with Z1b, Z2b and one or more Z3b;

[0033] R3 is H, OH, alkyl, hydroxyalkyl, aryl, nitro, halo, amino, alkylamino, alkoxy, cyano, thioalkyl, carboxyl, COOR4, NR7COR4, or NR7COOR4;

[0034] R4 is

[0035] (1) H; or

[0036] (2) alkyl, haloalkyl (especially di- or trihaloalkyl), aminoalkyl, alkoxyalkyl, hydroxyalkyl, aryl or heteroaryl any of which may be optionally substituted with Z1c, Z2c and one or more Z3c;

[0037] R5 and R6 are independently

[0038] (1) H, OH, halo, cyano or oxo; or

[0039] (2) alkoxy, alkyl, alkenyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylthio, aryloxy or heteroaryloxy any of which may be optionally substituted with Z1d, Z2d and one more Z3d;

[0040] R7 is

[0041] (1) H, OH, or cyano; or

[0042] (2) alkoxy, alkyl, alkenyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylthio, aryloxy or heteroaryloxy any of which may be optionally substituted with Z1e, Z2e and one more Z3e;

[0043] R8 is

[0044] (1) H, OH; or

[0045] (2) alkyl, aryl, heteroaryl, alkoxy, aryloxy, or alkenyl any of which may be optionally subtituted with Z1f, Z2f and one or more Z3f;

[0046] t is 0, 1 or 2;

[0047] q is 0 to 5.

[0048] Z1a-1f, Z2a-2f, and Z3a-3f are optional substituents independently selected from

[0049] (1) V, where V is

[0050] (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;

[0051] (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or

[0052] (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of Z1a,

[0053] (2) —OH or —OV,

[0054] (3) —SH or —SV,

[0055] (4) —C(O)pH, —C(O)pV, or —O—C(O)V, where p is 1 or 2,

[0056] (5) —SO3H, —S(O)pV, or S(O)pN(V1)V,

[0057] (6) halo,

[0058] (7) cyano,

[0059] (8) nitro,

[0060] (9) —U1—NV2V3,

[0061] (10) —U1—N(V1)—U2—NV2V3,

[0062] (11) —U1—N(V4)—U2—V,

[0063] (12) —U1—N(V4)—U2—H,

[0064] (13) oxo;

[0065] U1 and U2 are each independently

[0066] (1) a single bond,

[0067] (2) —U3—S(O)p—U4—,

[0068] (3) —U3—C(O)—U4—,

[0069] (4) —U3—C(S)—U4—,

[0070] (5) —U3—O—U4—,

[0071] (6) —U3—S—U4—,

[0072] (7) —U3—O—C(O)—U4—,

[0073] (8) —U3—C(O)—O—U4—,

[0074] (9) —U3C(═NV1a)—U4—, or

[0075] (10) —U3—C(O)—C(O)—U4—;

[0076] V1, V1a, V2, V3 and V4

[0077] (1) are each independently hydrogen or a group provided in the definition of Z1a; or

[0078] (2) V2 and V3 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z1a; or

[0079] (3) V2 or V3, together with V1, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z1a; or

[0080] (4) V2 and V3 together with the nitrogen atom to which they are attached may combine to form a group —N═CV5V6 where V5 and V6 are each independently H or a group provided in the definition of V; and

[0081] U3 and U4 are each independently

[0082] (1) a single bond,

[0083] (2) alkylene,

[0084] (3) alkenylene, or

[0085] (4) alkynylene.

[0086] In addition, in accordance with the present invention, a method is provided for treating diabetes, especially Type II diabetes, and related diseases such as insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hypertriglyceridemia, atherosclerosis, inflammation, diabetic retinopathy, diabetic neuropathy and diabetic nephropathy wherein a therapeutically effective amount of a compound of formula I is administered to a human patient in need of treatment.

[0087] In addition, in accordance with the present invention, a method is provided for treating diabetes and related diseases as defined above and hereinafter, wherein a therapeutically effective amount of a combination of a compound of formula I and another type antidiabetic agent is administered to a human patient in need of treatment.

[0088] In the above method of the invention, the compound of structure I will be employed in a weight ratio to another antidiabetic agent (depending upon its mode of operation) within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 10:1.

[0089] Preferred compounds of formula I include compounds where

[0090] A is a bond, an optionally substituted C1-C2 alkylene group, or an optionally substituted C2 alkenylene group;

[0091] B is carboxyl or tetrazole;

[0092] X and Y are independently —O(CR5R6)q—, —(CR5R6)qO—, —N(R7)CO(CR5R6)q—, —N(R7)CO(CR5R6)qO—, —N(R7)CO(CR5R6)qC(O)O—, —N(R7)CO—CR5═R6—, —N(R7)SO2(CR5R6)q—, or —O(CR5R6)qCO—

[0093] where

[0094] q is 0, 1 or 2;

[0095] R1 is aryl, heteroaryl (including N-oxides thereof), cycloalkyl or alkyl, any of which may be optionally substituted with Z1a, z2a and one more Z3a (especially where Z1a, Z2a and Z3a are independently halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryloxy, aralkoxy, aryl, arylcarbonyl, carboxyl, cyano, nitro, oxo, arylsulfonylalkyl or alkylsulfonyl);

[0096] R2 is aryl, heteroaryl (including N-oxides thereof), cycloalkyl or alkyl, any of which may be optionally substituted with Z1b, Z2b and one more Z3b (especially where Z1b, Z2b and Z3b are independently halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryloxy, aralkoxy, aryl, arylcarbonyl, carboxyl, cyano, nitro, oxo, arylsulfonylalkyl or alkylsulfonyl);

[0097] R3 is H, OH, halo, alkyl, haloalkyl or hydroxyalkyl;

[0098] R5 and R6 are independently

[0099] (1) H or OH; or

[0100] (2) alkyl, aryl, aralkyl or heteroarylalkyl any of which may be optionally substituted with Z1d, Z2d and one or more Z3d; and

[0101] R7 is

[0102] (1) H or OH; or

[0103] (2) alkyl, aryl, aralkyl or heteroarylalkyl any of which may be optionally substituted with Z1e, Z2e and one or more Z3e.

[0104] More preferred compounds of formula I include compounds where

[0105] A is a bond, or a C1-C2 alkylene group optionally substituted with one OH, SH, NH2, or ═NHOR4, or optionally substituted with at least one COOR4, halogen or oxo;

[0106] B is carboxyl or prodrug ester thereof;

[0107] X and Y are independently —O(CR5R6)q—, —(CR5R6)qO—, —N(R7)CO(CR5R6)q—, or —N(R7)SO2(CR5R6)q—

[0108] where

[0109] q is 0 or 1, and

[0110] R1 is aryl (preferably phenyl, napthyl, benzodioxolyl, benzodioxinyl, or anthracenyl), heteroaryl (including N-oxides thereof) (preferably, (pyridinyl, benzimidazolyl, quinoxalinyl, furanyl, thienyl, benzothiophenyl, or isothiozolyl) or, C3-C6 cycloalkyl any of which may be optionally substituted with one or more Z1a, Z2a and one or more Z3a (especially where Z1a, Z2a and Z3a are selected from halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryloxy, aralkoxy, aryl, arylcarbonyl, carboxyl, cyano, nitro, oxo, arylsulfonylalkyl or alkylsulfonyl);

[0111] R2 is aryl (preferably phenyl, napthyl, benzodioxolyl, benzodioxinyl, or anthracenyl), heteroaryl (including N-oxides thereof) (preferably, (pyridinyl, benzimidazolyl, quinoxalinyl, furanyl, thienyl, benzothiophenyl, or isothiozolyl) or, C3-C6 cycloalkyl any of which may be optionally substituted with one or more Z1b, Z2b and one or more Z3b (especially where Z1b, Z2b and Z3b are selected from halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryloxy, aralkoxy, aryl, arylcarbonyl, carboxyl, cyano, nitro, oxo, arylsulfonylalkyl or alkylsulfonyl);

[0112] R3 is H, OH, halo, alkyl, or haloalkyl;

[0113] R5 and R6 are independently

[0114] (1) H; or

[0115] (2) alkyl, aralkyl, or heteroarylalkyl any of which may be optionally substituted with Z1d, Z2d and one or more Z3d; and

[0116] R7 is

[0117] (1) H; or

[0118] (2) alkyl, aralkyl, or heteroarylalkyl any of which may be optionally substituted with Z1d, Z2d and one or more Z3d.

[0119] Most preferred compounds of formula I include compounds where

[0120] A is a hydroxy-substituted C1 alkylene group (preferably the (S) isomer);

[0121] B is carboxyl;

[0122] X and Y are —O(CR5R6)q—,

[0123] where

[0124] q is 1, and

[0125] R1 is phenyl or pyridinyl either of which may be optionally substituted with Z1a, Z2a and one or more Z3a (especially where Z1a, Z2a and Z3a are selected from halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryloxy, aralkoxy, aryl, arylcarbonyl, carboxyl, cyano, nitro, oxo, arylsulfonylalkyl or alkylsulfonyl);

[0126] R2 is phenyl optionally substituted with Z1b, Z2b and one or more Z3b (especially where Z1b, Z2b and Z3b are selected from one or more halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryloxy, aralkoxy, aryl, arylcarbonyl, carboxyl, cyano, nitro, oxo, arylsulfonylalkyl or alkylsulfonyl);

[0127] R3 is H, or halo; and

[0128] R5 and R6 are H;

DETAILED DESCRIPTION OF THE INVENTION

[0129] Compounds of the invention of general structure I may be synthesized as illustrated generically in the schemes set forth below, and as further illustrated by the examples set forth herein.

[0130] Benzoate 1 is converted to bis ether 2 by reaction with an appropriate halide. Saponification provides compound Ia.

[0131] Alternatively, catechol 3 can be monoprotected to provide phenol ether 4 and reacted with an appropriate halide to provide 5. Transesterification of 5 with sodium ethoxide gives phenol 6 which is reacted with an appropriate halide, resulting in ester 7. Saponification as before provided Ib.

[0132] Additional compounds within formula I can be generated via solid phase synthesis. For example, Merrifield resin can be reacted with phenol 8, the resulting aldehyde 9 reduced to alcohol 10 and reacted with 2-hydroxy-3-nitrobenzoic acid to provide phenol 11. Reaction with the appropriate alkyl halide resulted in ether 12. Reduction of the nitro group provided aniline 13. Acylation or sulfonylation (Scheme 4) followed by removal from the resin resulted in amide Ic or sulfonamide Id.

[0133] Compound Ia was also obtained by reaction of catechol 14 to give bis ether 15 followed by oxidation.

[0134] In addition, aldehyde 15 can be converted to cyanohydrin 16 by standard methods and the cyanohydrin converted to ester 17. Saponification resulted in mandelic acid Ie.

[0135] The enantiomers of compound Ie can be readily separated by the use of a chiral auxillary. Thus, alcohol 17 was esterified with (S)-t-butyloxycarbonyl proline and the resulting diastereomers 18a and 18b were isolated by normal phase chromatography. Subsequent saponification provided (R)-Ie and (S)-Ie in high enantiomeric purity.

[0136] Phenylacetic acids If could be prepared from aldehyde 15. By known methods alcohol 19 led to bromide 20 and to nitrile 21. Alcoholic acidolysis provided ester 22 and saponification gave If.

[0137] Alternatively, If could be prepared from aldehyde 15 by condensation with either methyl sulfinyl methyl sulfoxide or ethyl sulfinyl ethyl sulfide and an appropriate base to give vinyl thioacetal 23. Methanolic acidolysis provided ester 24 and saponification led to If.

[0138] Treatment of If with two equivalents of lithium diisopropyl amide followed by carbon dioxide provides malonate Ig.

[0139] Treatment of the dianion of If followed by DMPU (N,N-dimethyl propylene urea) and gaseous formaldehyde provides β-hydroxyacid Ih.

[0140] Aldehyde 15 could also be used to prepare cinnamate 25, which upon hydrolysis provideds unsaturated acid Ii.

[0141] The corresponding saturated acid Ij can be prepared from bromide 20 by alkylation with diethyl malonate, followed by saponification and pyrolysis.

[0142] Treatment of the mandelate 17 with oxidizing agents (for example, Jones reagent or AcNHTEMPO) provided ketoester 28; saponification led to ketoacid Ik. Reaction of 28 with hydroxylamine or methoxylamine hydrochloride followed by saponification provided oximes Il as separable geometric isomers.

[0143] Alcohol 17 on treatment with one equivalent of DAST provides fluoride 30 and saponification yields α-fluorophenylacetic acid Im. Analogously, ketoester 28 on reaction with excess DAST provides difluoride 31 and then In.

[0144] Benzoic acid Ia can be used to prepare α-methyl mandelic acid Io by preparation of amide 32 and subsequent addition of methyl magnesium chloride to provide acetophenone 33. Cyanohydrin 34 derived from 33 was then hydrolyzed to prepare ester 35 and saponification led to Io.

[0145] Amino acid Ip and acylated derivatives Iq can be prepared from aldehyde 15 or hydroxyester 17 as described in Schemes 17, 18 and 19. A modified Strecker procedure provides amino ester 37, hydrolysis of which provides Ip. Alternatively, 37 could be prepared from azide 39 and subsequent Staudinger reaction. Acylation of 37 using a variety of methods gave acetomido ester 38, saponification then providing Iq.

[0146] Benzoic acid Ir can be prepared from 2,3-dimethylbenzoate. Double radical bromination of 42 leads predominantly to 43. Displacement of the bromides with an appropriate alcohol anion gives 44 and saponification provides Ir.

[0147] Mandelic acid Is can be prepared from 2,3-dimethylbenzoic acid 45. The acid is converted into dibromo amide 46. Displacement with an appropriate oxide gives 47, reduction of which provides aldehyde 48. Cyanohydrin formation and hydrolyses, analogous to Scheme 1, provides Is.

[0148] An alternative chiral synthesis of (R) or (S)-1e can be shown as follows: cinnamate 25 is reduced to allylic alcohol 49. Sharpless epoxidation with chiral diisopropyltartrate provides epoxide 50 with high enantiomeric excess, which, upon ring-opening with titanium (IV) acetoxytriisopropoxide gives diol 51. Oxidative cleavage of the diol leads to O-(acetyl) mandelate 52 and saponification provides (R) or (S)-1e.

[0149] Preparation of tetrazole 1t proceeds from cyanohydrin 16, by treatment with a trialkyltinazide at reflux in xylene.

[0150] A dual aP2/k-FABP inhibitor (or dual k-FABP/aP2 inhibitor) is defined herein as any compound which has a Kivalue in both an aP2 and K-FABP assay of less than 500 nM (preferably less than 100 nM and more preferably less than 50 nM) and wherein the Ki of the compound in the k-FABP assay differs no more than 100 times the Ki of the compound in the aP2 assay (more preferably the Ki of the compound in the k-FABP assay differs no more than 10 times the Ki of the compound in the aP2 assay). Dual aP2/k-FABP inhibitors will preferably contain less than 60 carbon atoms, more preferably less than 45 carbon atoms, and will contain less than 20 heteroatoms, more preferably less than 12 heteroatoms.

[0151] Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents such as halo, for example F, Br, Cl or I or CF3, alkoxy, haloalkoxy, (alkoxy)alkoxy, alkoxyalkyl, (hydroxy)alkoxyalkyl, (alkoxy)alkoxyalkyl, aryl, aryloxy, (aryl)aryl or diaryl, (aryl)alkoxyaryl, diaryl, arylalkyl, (aryl)alkoxy, (aryl)alkoxyalkyl, (aryloxy)aralkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, substituted amino, alkylamino, hydroxy, hydroxyalkyl, hydroxycarbonyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, acyl, heterocylo, (heterocyclo)alkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, (amino)carbonyl, (substituted amino)carbonyl, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/or alkylthio (where the alkyl radical is optionally substituted), arylthio (where the aryl radical is optionally substituted), sulfonylaryl, arylsulfonylalkyl, alkylsulfonyl, COOR4, COR4 or SR4. Where particular substituted alkyl groups are identified herein they are named by adding the term “alkyl” at the end of the name of the substituent radical (e.g., aralkyl, heteroaralkyl etc.).

[0152] The term “cycloalkyl” as used herein by itself or as part of another group refers to saturated and partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 7 carbons, forming the ring. The rings of multi-ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro union to 1 or 2 aromatic, cycloalkyl or heterocyclo rings. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl,

[0153] and the like any of which groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, aryl, aryloxy, arylalkoxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol, alkylthio, arylsulfonylalkyl, alkylsulfonyl, COOR4, COR4, and/or SR4.

[0154] The term “cycloalkylene” as employed herein refers to a “cycloalkyl” group which includes free bonds and thus is a linking group such as

[0155] and the like, and may optionally be substituted as defined above for “cycloalkyl”.

[0156] The term “alkanoyl” as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.

[0157] Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, heterocyclo, alkanoylamino, alkylamido, arylcarbonyl-amino, nitro, cyano, thiol, alkylthio and/or any of the alkyl substituent groups.

[0158] Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, heterocyclo, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, and/or any of the alkyl substituents.

[0159] The terms “arylalkenyl” and “arylalkynyl” as used alone or as part of another group refer to alkenyl and alkynyl groups as described above having an aryl substituent.

[0160] Where alkyl groups as defined above have single bonds for attachment to two other groups from the same or different, they are termed “alkylene” groups and may optionally be substituted as defined above for “alkyl”.

[0161] Where alkenyl groups as defined above and alkynyl groups as defined above, respectively, have single bonds for attachment to two other groups, they are termed “alkenylene groups” and “alkynylene groups”, respectively, and may optionally be substituted as defined above for “alkenyl” and “alkynyl”.

[0162] Suitable alkylene, alkenylene or alkynylene groups (CH2)x or (CH2)y (where, y is 1 to 8, preferably 1 to 5, and x is 1 to 5, preferably 1 to 3, which includes alkylene, alkenylene or alkynylene groups) as defined herein, may optionally include 1, 2, or 3 substituents which include alkyl, alkenyl, halogen, cyano, hydroxy, alkoxy, amino, thioalkyl, keto, C3-C6 cycloalkyl, alkylcarbonylamino or alkylcarbonyloxy.

[0163] Examples of (CH2)x or (CH2)y, alkylene, alkenylene and alkynylene include

[0164] The term “halogen” or “halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF3, with chlorine, bromine or fluorine being preferred.

[0165] Unless otherwise indicated, the terms “aryl” or “ar” as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or heterocyclo rings for example

[0166] and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, substituted alkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, (aryl)alkyl, aryloxy, (aryloxy)alkyl, (aryl)alkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, aminocarbonyl, (substituted amino)carbonyl, (alkyl)aminocarbonyl, (substituted alkyl)aminocarbonyl, (aryl)aminocarbonyl, (substituted aryl)aminocarbonyl, alkoxycarbonyl, (amino)alkoxycarbonyl, (substituted amino)alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonylaminocarbonyl , sulfonylaryl, (alkyl)sulfonylaryl, sulfonylarylalkyl, (alkyl)sulfonylaralalkyl, arylsulfonylalkyl, alkylsulfonyl, COOR4, COR4 and/or SR4.

[0167] Unless otherwise indicated, the term “lower alkoxyl”, “alkoxy”, “aryloxy” or “aralkoxy” as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.

[0168] Unless otherwise indicated, the term “substituted amino” as employed herein alone or as part of another group refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl (optionally substituted), aryl (optionally substituted), arylalkyl (optionally substituted), arylalkyl (optionally substituted), heteroaryl (optionally substituted), heteroarylalkyl (optionally substituted), heterocyclo (optionally substituted), (heterocyclo)alkyl (optionally substituted), cycloalkyl (optionally substituted), cycloalkylalkyl (optionally substituted), haloalkyl (optionally substituted), hydroxyalkyl (optionally substituted), alkoxyalkyl (optionally substituted) or thioalkyl (optionally substituted). In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-l-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, substituted alkyl, alkoxy, alkylthio, halo, trifluoromethyl, hydroxy, aryl or substituted aryl.

[0169] Unless otherwise indicated, the term “lower alkylthio”, alkylthio”, “arylthio” or “aralkylthio” as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.

[0170] Unless otherwise indicated, the term “lower alkylamino”, “alkylamino”, “arylamino”, or “arylalkylamino” as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.

[0171] Unless otherwise indicated, the term “acyl” as employed herein by itself or part of another group, as defined herein, refers to an organic radical linked to a carbonyl group (i.e.,

[0172] ); examples of acyl groups include any of the R1 groups attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, heterocycloalkanoyl and the like. Such groups may also be identified by adding the term “carbonyl” at the end of the name of the organic radical R bonded to the acyl group (e.g., alkylaminocarbonyl, alkoxycarbonyl, etc).

[0173] Unless otherwise indicated, the term “heterocycle” or “heterocyclo” as used herein alone or as part of another group refers to a 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 or more hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)x, such as

[0174] and the like. The above groups may include 1 to 4 substituents such as alkyl, substituted alkyl, halo, alkoxy, haloalkoxy, aryloxy, cyano, nitro, oxo, aryl, substituted aryl, aralkyl, substituted aralkyl, arylsulfonylalkyl, alkylsulfonyl, COOR4, COR4, and/or SR4. In addition, any of the heterocyclo rings can be fused to a cycloalkyl, aryl, heteroaryl or heterocyclo ring. In addition, any of the heterocyclo rings can be joined by spiro union to cycloalkyl rings or other heterocyclo rings.

[0175] Unless otherwise indicated, the term “heteroaryl” as used herein alone or as part of another group refers to monocyclic and bicyclic aromatic rings containing from 5 to 10 atoms, which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl or heterocyclo ring (e.g. benzothiophenyl, indolyl), where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heteroaryl group may optionally include 1 to 4 substituents such as halo, haloalkyl, alkyl, substituted alkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclo, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonylaminocarbonyl , sulfonylaryl, sulfonylarylalkyl, arylsulfonylalkyl, alkylsulfonyl, COOR4, COR4 and/or SR4. Examples of heteroaryl groups include the following:

[0176] and the like.

[0177] The term “heterocycloalkyl” as used herein alone or as part of another group refers to heterocyclo groups as defined above linked to a (CH2)x chain.

[0178] The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein alone or as part of another group refers to a heteroaryl group as defined above linked to a —(CH2)x— chain, alkylene or alkenylene as defined above.

[0179] The term “polyhaloalkyl” as used herein refers to an “alkyl” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2, CF3 or CF3CF2CH2.

[0180] The term “polyhaloalkyloxy” as used herein refers to an “alkoxy” or “alkyloxy” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2O, CF3O or CF3CF2CH2O.

[0181] The compounds of formula I form salts which are also within the scope of this invention. Reference to a compound of the formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of formula I contains a both a basic moiety and an acidic moiety, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0182] The compounds of formula I which contain a basic moiety may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0183] The compounds of formula I which contain an acidic moiety may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.

[0184] Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

[0185] Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term “prodrug”, as employed herein, denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, or a salt and/or solvate thereof. Solvates of the compounds of formula I are preferably hydrates.

[0186] To the extent that compounds of the formula I, and salts thereof, may exist in their tautomeric form, all such tautomeric forms are contemplated herein as part of the present invention.

[0187] All stereoisomers of the present compounds, such as those which may exist due to asymmetric carbons on the various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons) and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.

[0188] Thus, where desired, the compounds of the present invention may be used in combination with one or more hypolipidemic agents or lipid-lowering agents, or lipid agents, or lipid modulating agents, and/or one or more other types of therapeutic agents including antidiabetic agents, anti-obesity agents, antihypertensive agents, platelet aggregation inhibitors, anti-Alzheimer's agents, anti-dementia agents, and/or other cardiovascular agents (including anti-anginal agents, anti-arrhythmic agents, anti-atherosclerosis agents, anti-inflammatory agents, anti-platelet agents, anti-heart failure agents), which may be administered orally in the same dosage form or in a separate oral dosage form, or by injection.

[0189] The hypolipidemic agent or lipid-lowering agent or other lipid agent or lipid modulating agent which may be optionally employed in combination with the compounds of the present invention may include 1,2,3 or more MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, PPAR α agonists, PPAR dual α/γ agonists, PPAR δ agonists, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal Na+/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, cholesteryl ester transfer protein inhibitors, bile acid sequestrants, and/or nicotinic acid and derivatives thereof.

[0190] MTP inhibitors employed herein include MTP inhibitors disclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No. 5,885,983 and U.S. Pat. No. 5,962,440. Preferred are each of the preferred MTP inhibitors disclosed in each of the above patents and applications.

[0191] All of the above U.S. Patents and applications are incorporated herein by reference.

[0192] Most preferred MTP inhibitors to be employed in accordance with the present invention include preferred MTP inhibitors as set out in U.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

[0193] The most preferred MTP inhibitor is 9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

[0194] The hypolipidemic agent may be an HMG CoA reductase inhibitor which includes, but is not limited to, mevastatin and related compounds as disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, pitavastatin (Nissan/Sankyo's nisvastatin (NK-104) or itavastatin), disclosed in U.S. Pat. No. 5,011,930, Shionogi-Astra/Zeneca rosuvastatin (visastatin (ZD-4522)) disclosed in U.S. Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat. No. 5,753,675, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives as disclosed in PCT application WO 86/03488, 6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivatives thereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed in French Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin) as disclosed in European Patent Application No. 0,142,146 A2, and quinoline and pyridine derivatives disclosed in U.S. Pat. No. 5,506,219 and 5,691,322.

[0195] In addition, phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837.

[0196] The squalene synthetase inhibitors suitable for use herein include, but are not limited to, α-phosphonosulfonates disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinylmethyl)phosphonates as well as other known squalene synthetase inhibitors, for example, as disclosed in U.S. Pat. No. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996).

[0197] In addition, other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987, 109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, Summary.

[0198] Other hypolipidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex and cholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterol lowering agents.

[0199] The other hypolipidemic agent may be an ACAT inhibitor (which also has anti-atherosclerosis activity) such as disclosed in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters”, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; “The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals”, Krause et al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd), as well as F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8-434.

[0200] The hypolipidemic agent may be an upregulator of LDL receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

[0201] The hypolipidemic agent may be a cholesterol absorption inhibitor preferably Schering-Plough's SCH48461 (ezetimibe) as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

[0202] The other lipid agent or lipid-modulating agent may be a cholesteryl transfer protein inhibitor (CETP) such as Pfizer's CP-529,414 as well as those disclosed in WO/0038722 and in EP 818448 (Bayer) and EP 992496, and Pharmacia's SC-744 and SC-795, as well as CETi-1 and JTT-705.

[0203] The hypolipidemic agent may be an ileal Na+/bile acid cotransporter inhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).

[0204] The ATP citrate lyase inhibitor which may be employed in the combination of the invention may include, for example, those disclosed in U.S. Pat. No. 5,447,954.

[0205] The other lipid agent also includes a phytoestrogen compound such as disclosed in WO 00/30665 including isolated soy bean protein, soy protein concentrate or soy flour as well as an isoflavone such as genistein, daidzein, glycitein or equol, or phytosterols, phytostanol or tocotrienol as disclosed in WO 2000/015201;

[0206] a beta-lactam cholesterol absorption inhibitor such as disclosed in EP 675714;

[0207] an HDL upregulator such as an LXR agonist, a PPAR α-agonist and/or an FXR agonist;

[0208] an LDL catabolism promoter such as disclosed in EP 1022272;

[0209] a sodium-proton exchange inhibitor such as disclosed in DE 19622222;

[0210] an LDL-receptor inducer or a steroidal glycoside such as disclosed in U.S. Pat. No. 5,698,527 and GB 2304106;

[0211] an anti-oxidant such as beta-carotene, ascorbic acid, α-tocopherol or retinol as disclosed in WO 94/15592 as well as Vitamin C and an antihomocysteine agent such as folic acid, a folate, Vitamin B6, Vitamin B12 and Vitamin E;

[0212] isoniazid as disclosed in WO 97/35576;

[0213] a cholesterol absorption inhibitor, an HMG-CoA synthase inhibitor, or a lanosterol demethylase inhibitor as disclosed in WO 97/48701;

[0214] a PPAR δ agonist for treating dyslipidemia;

[0215] or a sterol regulating element binding protein-I (SREBP-1) as disclosed in WO 2000/050574, for example, a sphingolipid, such as ceramide, or neutral sphingomyelenase (N-SMase) or fragment thereof.

[0216] Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin and rosuvastatin, as well as niacin and/or cholestagel.

[0217] The above-mentioned U.S. patents are incorporated herein by reference. The amounts and dosages employed will be as indicated in the Physician's Desk Reference and/or in the patents set out above or as otherwise known in the art.

[0218] The compounds of the present invention will be employed in a weight ratio to the hypolipidemic agent (were present), within the range from about 500:1 to about 1:500, preferably from about 100:1 to about 1:100.

[0219] The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.

[0220] The dosages and formulations for the hypolipidemic agent or other lipid agent or lipid modulating agent will be as disclosed in the various patents and applications discussed above.

[0221] The dosages and formulations for the other hypolipidemic agent or other lipid agent or lipid modulating agent to be employed, where applicable, will be as set out in the latest edition of the Physicians' Desk Reference.

[0222] For oral administration, a satisfactory result may be obtained employing the MTP inhibitor in an amount within the range of from about 0.01 mg to about 500 mg and preferably from about 0.1 mg to about 100 mg, one to four times daily.

[0223] A preferred oral dosage form, such as tablets or capsules, will contain the MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, one to four times daily.

[0224] For oral administration, a satisfactory result may be obtained employing an HMG CoA reductase inhibitor, for example, pravastatin, lovastatin, simvastatin, atorvastatin, or fluvastatin in dosages employed as indicated in the Physician's Desk Reference, such as in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.

[0225] The squalene synthetase inhibitor may be employed in dosages in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.

[0226] A preferred oral dosage form, such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount from about 0.1 to about 100 mg, preferably from about 0.5 to about 80 mg, and more preferably from about 1 to about 40 mg.

[0227] A preferred oral dosage form, such as tablets or capsules will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.

[0228] The anti-atherosclerotic agent includes a lipoxygenase inhibitor including a 15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives as disclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613, isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors as disclosed by Sendobry et al “Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties,” Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al, “15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.

[0229] The compounds of the present invention and the hypolipidemic agent may be employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.

[0230] The compositions described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination.

[0231] The antidiabetic agent which may be optionally employed in combination with the compounds of the present invention may be 1,2,3 or more antidiabetic agents or antihyperglycemic agents including insulin secretagogues or insulin sensitizers, which may include biguanides, sulfonyl ureas, glucosidase inhibitors, aldose reductase inhibitors, PPAR γ agonists such as thiazolidinediones, PPAR α agonists (such as fibric acid derivatives), PPAR δ antagonists or agonists, PPAR α/γ dual agonists, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors, glycogen phosphorylase inhibitors, and/or meglitinides, as well as insulin, and/or glucagon-like peptide-1 (GLP-1), and/or a PTP-1B inhibitor (protein tyrosine phosphatase-1B inhibitor).

[0232] The antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof, preferably metformin HCl.

[0233] Where the antidiabetic agent is a biguanide, the compounds of the present invention will be employed in a weight ratio to biguanide within the range from about 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1.

[0234] The antidiabetic agent may also preferably be a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, other known sulfonylureas or other antihyperglycemic agents which act on the ATP-dependent channel of the beta-cells, with glyburide and glipizide being preferred, which may be administered in the same or in separate oral dosage forms.

[0235] The compounds of the present invention will be employed in a weight ratio to the sulfonyl urea in the range from about 0.01:1 to about 100:1, preferably from about 0.02:1 to about 5:1.

[0236] The oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosed in U.S. Pat. No. 4,639,436), which may be administered in the same or in a separate oral dosage forms.

[0237] The compounds of the present invention will be employed in a weight ratio to the glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.05:1 to about 10:1.

[0238] The compounds of the present invention may be employed in combination with a PPAR γ agonist such as a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016), Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone.

[0239] The compounds of the present invention will be employed in a weight ratio to the thiazolidinedione in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.05:1 to about 10:1.

[0240] The sulfonyl urea and PPAR γ agonists in amounts of less than about 150 mg oral antidiabetic agent may be incorporated in a single tablet with the compounds of the present invention.

[0241] The compounds of the present invention may also be employed in combination with a antihyperglycemic agent such as insulin or with glucagon-like peptide-1 (GLP-1) or mimetic such as GLP-1 (1-36) amide, GLP-1(7-36) amide, GLP-1 (7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of which is incorporated herein by reference), as well as AC2993 (Amylen) and LY-315902 (Lilly), which may be administered via injection, intranasal, inhalation or by transdermal or buccal devices.

[0242] Where present, metformin, the sulfonyl ureas, such as glyburide, glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and the glucosidase inhibitors acarbose or miglitol or insulin (injectable, pulmonary, buccal, or oral) may be employed in formulations as described above and in amounts and dosing as indicated in the Physician's Desk Reference (PDR).

[0243] Where present, metformin or salt thereof may be employed in amounts within the range from about 500 to about 2000 mg per day which may be administered in single or divided doses one to four times daily.

[0244] Where present, the PPAR anti-diabetic agent may be employed in amounts within the range from about 0.01 to about 2000 mg/day which may be administered in single or divided doses one to four times per day.

[0245] Where present insulin and other anti-diabetic agents as set out above may be employed in formulations, amounts and dosing as indicated by the Physician's Desk Reference.

[0246] Where present GLP-1 peptides or mimetics may be administered in oral buccal formulations, by nasal administration or parenterally as described in U.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which are incorporated herein by reference.

[0247] The antidiabetic agent or other lipid agent may also be a PPAR modulator such as a PPAR alpha/gamma dual agonist such as AR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck) as well as those disclosed by Murakami et al, “A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation-Activated Receptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847 (1998), and in U.S. Pat. No. 6,414,002, the disclosure of which is incorporated herein by reference, employing dosages as set out therein, which compounds designated as preferred are preferred for use herein.

[0248] The antidiabetic agent may be an SGLT2 inhibitor such as disclosed in U.S. Pat. No. 6,414,126, employing dosages as set out therein. Preferred are the compounds designated as preferred in the above application.

[0249] The antidiabetic agent may be a DP4 inhibitor such as disclosed in U.S. Pat. No. 6,395,767, WO99/38501, WO99/46272, WO99/67279, WO99/67278, WO99/61431, NVP-DPP728A (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis) (preferred) as disclosed by Hughes et al, Biochemistry, 38(36), 11597-11603, 1999, TSL-225 (tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (disclosed by Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540, 2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth et al, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and 2745-2748 (1996) employing dosages as set out in the above references.

[0250] The meglitinide which may optionally be employed in combination with the compounds of the present invention may be repaglinide, nateglinide (Novartis) or KAD1229 (PF/Kissei), with repaglinide being preferred.

[0251] The antidiabetic compound may be a melanocortin receptor agonist such as a spiropiperidine as disclosed in WO 99/64002.

[0252] The compounds of the present invention will be employed in a weight ratio to the meglitinide, PPAR modulator such as a PPAR gamma agonist, PPAR α agonist, PPAR δ agonits or antagonist, PPAR alpha/gamma dual agonist, DP4 inhibitor or SGLT2 inhibitor or other antidiabetic agent within the range from about 0.01:1 to about 100:1, preferably from about 0.05:1 to about 10:1.

[0253] The other type of therapeutic agent which may be optionally employed with the compounds of the present invention may be 1, 2, 3 or more of an anti-obesity agent including a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, an aP2 inhibitor, a thyroid receptor beta drug, a PTP-1B inhibitor, an anorectic agent, a PPAR modulator including PPAR γ antagonists, PPAR α agonists, PPAR δ antagonists, a CCKA agonist, a leptin inhibitor such as a leptin receptor activator, a neuropeptide Y antagonist, a melanocortin-4-receptor (MC4R) agonist, or a fatty acid oxidation upregulator or inducer such as Famoxin (Genset).

[0254] The beta 3 adrenergic agonist which may be optionally employed in combination with the compounds of the present invention may be AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648 being preferred.

[0255] The neuropeptide Y antagonists which may be optionally employed in combination with the compounds of the present invention include those described in WO 01/13917, in U.S. Pat. No. 6,218,408 and in WO 01/14376.

[0256] The lipase inhibitor which may be optionally employed in combination with compounds of the present invention may be orlistat or ATL-962 (Alizyme), with orlistat being preferred.

[0257] The serotonin (and dopoamine) reuptake inhibitor which may be optionally employed in combination with compounds of the present invention may be sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramine and topiramate being preferred.

[0258] The thyroid receptor beta compound which may be optionally employed in combination with compounds of the present invention may be a thyroid receptor ligand as disclosed in WO97/21993, WO99/00353, GB98/284425, and WO 01/60784.

[0259] The anorectic agent which may be optionally employed in combination with compounds of the present invention may be dexamphetamine, phentermine, phenylpropanolamine or mazindol, with dexamphetamine being preferred.

[0260] The CCKA agonists which may be employed herein include Glaxo-SmithKline's GI-181,771 and Sanofi's SR146,131.

[0261] The PTP-LB inhibitor which may be an anti-oesity and/or an antidiabetic agent include those disclosed in WO 99/585,521, WO 99/58518, WO 99/58522 and WO 99/61435.

[0262] The anti-obesity agent employed may also be Pfizer's P57 or CP-644,673.

[0263] The various anti-obesity agents described above may be employed in the same dosage form with the compounds of the present invention or in different dosage forms, in dosages and regimens as generally known in the art or in the PDR.

[0264] The antihypertensive agents which may be employed in combination with the compounds of the invention include ACE inhibitors, angiotensin II receptor antagonists, NEP inhibitors such as candoxatril, NEP/ACE inhibitors, as well as calcium channel blockers (such as verapamil and amlodipine besylate), T-channel calcium antagonists (such as mibefradil), β-adrenergic blockers, diuretics, α-adrenergic blockers (such as doxazosin mesylate and terazosin HCl), dual ET/AT receptor antagonists, heart failure drugs such as digoxin, and other types of antihypertensive agents.

[0265] The angiotensin converting enzyme inhibitor which may be employed herein includes those containing a mercapto (—S—) moiety such as substituted proline derivatives, such as any of those disclosed in U.S. Pat. No. 4,046,889 to Ondetti et al mentioned above, with captopril, that is, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred, and mercaptoacyl derivatives of substituted prolines such as any of those disclosed in U.S. Pat. No. 4,316,906 with zofenopril being preferred.

[0266] Other examples of mercapto containing ACE inhibitors that may be employed herein include rentiapril (fentiapril, Santen) disclosed in Clin. Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivopril and YS980.

[0267] Other examples of angiotensin converting enzyme inhibitors which may be employed herein include any of those disclosed in U.S. Pat. No. 4,374,829 mentioned above, with N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is, enalapril, being preferred, any of the phosphonate substituted amino or imino acids or salts disclosed in U.S. Pat. No. 4,452,790 with (S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline or (ceronapril) being preferred, phosphinylalkanoyl prolines disclosed in U.S. Pat. No. 4,168,267 mentioned above with fosinopril being preferred, any of the phosphinylalkanoyl substituted prolines disclosed in U.S. Pat. No. 4,337,201, and the phosphonamidates disclosed in U.S. Pat. No. 4,432,971 discussed above.

[0268] Other examples of ACE inhibitors that may be employed herein include Beecham's BRL 36,378 as disclosed in European Patent Application Nos. 80822 and 60668; Chugai's MC-838 disclosed in C.A. 102:72588v and Jap. J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824 (3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1 acetic acid HCl) disclosed in U.K. Patent No. 2103614 and CGS 16,617 (3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoic acid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril, Dainippon) disclosed in Eur. Therap. Res. 39:671 (1986); 40:543 (1986); ramipril (Hoechsst) disclosed in Euro. Patent No. 79-022 and Curr. Ther. Res. 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung 34:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc. Pharmacol. 9:39 (1987); R 31-2201 (Hoffman-LaRoche) disclosed in FEBS Lett. 165:201 (1984); lisinopril (Merck), indalapril (delapril) disclosed in U.S. Pat. No. 4,385,051; indolapril (Schering) disclosed in J. Cardiovasc. Pharmacol. 5:643, 655 (1983), spirapril (Schering) disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986); perindopril (Servier) disclosed in Eur. J. clin. Pharmacol. 31:519 (1987); quinapril (Warner-Lambert) disclosed in U.S. Pat. No. 4,344,949 and CI925 (Warner-Lambert) ([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid HCl)disclosed in Pharmacologist 26:243, 266 (1984), WY-44221 (Wyeth) disclosed in J. Med. Chem. 26:394 (1983).

[0269] Preferred ACE inhibitors are captopril, fosinopril, enalapril, lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.

[0270] NEP/ACE inhibitors may also be employed herein in that they possess neutral endopeptidase (NEP) inhibitory activity and angiotensin converting enzyme (ACE) inhibitory activity. Examples of NEP/ACE inhibitors suitable for use herein include those disclosed in U.S. Pat. Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688, U.S. Pat. No. 5,552,397, U.S. Pat. No. 5,504,080, U.S. Pat. No. 5,612,359,U.S. Pat. No. 5,525,723, European Patent Application 0599,444, 0481,522, 0599,444, 0595,610, European Patent Application 0534363A2, 534,396 and 534,492, and European Patent Application 0629627A2.

[0271] Preferred are those NEP/ACE inhibitors and dosages thereof which are designated as preferred in the above patents/applications which U.S. patents are incorporated herein by reference; most preferred are omapatrilat, gemopatrilat ([S[(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-acetic acid) and CGS 30440.

[0272] The angiotensin II receptor antagonist (also referred to herein as angiotensin II antagonist or AII antagonist) suitable for use herein includes, but is not limited to, irbesartan, losartan, valsartan, candesartan, tasosartan or eprosartan, with irbesartan, losartan or valsartan being preferred.

[0273] A preferred oral dosage form, such as tablets or capsules, will contain the ACE inhibitor or AII antagonist in an amount within the range from abut 0.1 to about 500 mg, preferably from about 5 to about 200 mg and more preferably from about 10 to about 150 mg.

[0274] For parenteral administration, the ACE inhibitor, angiotensin II antagonist or NEP/ACE inhibitor will be employed in an amount within the range from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.01 mg/kg to about 1 mg/kg.

[0275] Where a drug is to be administered intravenously, it will be formulated in conventional vehicles, such as distilled water, saline, Ringer's solution or other conventional carriers.

[0276] It will be appreciated that preferred dosages of ACE inhibitor and AII antagonist will be as set out in the latest edition of the Physician's Desk Reference (PDR).

[0277] Dual ET/AT receptor antagonists suitable for use herein include those disclosed in WO 01/44239.

[0278] Other examples of preferred antihypertensive agents suitable for use herein include omapatrilat, gemopatrilat, amlodipine besylate, prazosin HCl, verapamil, nifedipine, diltiazem, felodipine, nisoldipine, isradipine, nicardipine, beta blockers such as nadolol, atenolol, sotalol, terazosin, doxazosin, carvedilol, and propranolol, and clonidine HCl.

[0279] Diuretics which may be employed in combination with compounds of the present invention include hydrochlorothiazide, torasemide, furosemide, spironolactone, and indapamide.

[0280] Antiplatelet agents which may be employed in combination with compounds of the present invention include aspirin, clopidogrel, ticlopidine, dipyridamole, abciximab, tirofiban, eptifibatide, anagrelide, and ifetroban, with clopidogrel and aspirin being preferred.

[0281] The antihypertensive agents, diuretics and antiplatelet drugs may be employed in amounts as indicated in the PDR. Ifetroban may be employed in amounts as set out in U.S. Pat. No. 5,100,889.

[0282] Anti-Alzheimer's agents or anti-dementia agents suitable for use herein include tacrine HCl and donepezil, as well as γ-secretase inhibitors, β-secretase inhibitors and/or antihypertensive agents. Dosages employed will be as set out in the PDR.

[0283] a cyclooxygenase (COX)-2 inhibitor, such as celecoxib, rofecoxib or paracoxib or a glycoprotein IIa/IIIb receptor antagonist such as disclosed in WO 99/45913 and tirofiban or abciximab;

[0284] a 5-HT reuptake inhibitor such as disclosed in WO 99/44609;

[0285] anti-anginal agents such as vasodilators, for example, isosorbide dinitrate, or nitroglycerin;

[0286] anti-atherosclerosis agents such as ACAT inhibitors and lipoxygenase inhibitors as described herein and phospholipase A-2 inhibitors such as S-3013 and SB-435,495 (which are also anti-inflammatory agents); or

[0287] an immunosuppressant (for use in transplantations) such as cyclosporine, mycophenolate mofetil, azathioprine and the like.

[0288] It will be appreciated that unless otherwise specified the dosage regiment for therapeutic agents used in combination with the compounds of the invention will be as specified in the PDR.

[0289] In carrying our the method of the invention, a pharmaceutical composition will be employed containing the compounds of structure I, with or without another therapeutic agent, in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The compounds can be administered to mammalian species including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations. The dose for adults is preferably between 20 and 2,000 mg per day, which can be administered in a single dose or in the form of individual doses from 1-4 times per day.

[0290] A typical capsule for oral administration contains compounds of structure I (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

[0291] A typical injectable preparation is produced by aseptically placing 250 mg of compounds of structure I into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.

[0292] The aP2/mal-1 inhibitor activity of the compounds of the invention may be determined using methods well known to those of skill in the art.

[0293] The following Examples illustrate embodiments of the present invention, and are not intended to limit the scope of the claims. Abbreviations employed herein are defined below. Compounds of the Examples are identified by the example and step in which they are prepared (for example, “1A” denotes the title compounds of step A of Example 1), or by the example only where the compound is the title compound of the example (for example “4” denotes the title comound of Example 4).

[0294] 9-BBN=9-borabicyclo[3.3.1]nonane

[0295] Calc=calculated

[0296] DiBAl=diisobutylaluminum hydride

[0297] DMAP=Dimethylaminopyridine

[0298] DMF=dimethylformamide

[0299] DMSO=dimethylsulfoxide

[0300] Et=ethyl

[0301] Fnd=found

[0302] h=hours

[0303] LC/MS=liquid chromatography/mass spectrometry

[0304] LDA=lithium diisopropylamide

[0305] Me=methyl

[0306] Ms=mesyl=methanesulfonyl

[0307] OAc=acetate

[0308] Ph=phenyl

[0309] TFA=trifluoroacetic acid

[0310] THF=tetrahydrofuran

[0311] TMS=trimethylsilyl

EXAMPLE 1

2,3-Bis[(2-Chlorophenyl)Methoxy]-α-Hydroxybenzeneacetic Acid

[0312]

[0313] To a stirred slurry of 2,3-dihydroxybenzaldehyde (6.91 g, 50.0 mmol) and potassium carbonate (17.2 g, 125 mmol) in EtOH (60 mL) at room temperature under argon was added 2-chlorobenzyl chloride (15 mL, 120 mmol). The reaction mixture was heated to reflux for 16 h, then cooled and poured into water (150 mL). The resulting solids were collected, washed with water, air-dried and recrystallized from methanol to give the title compound as white needles (16.28 g, 71% yield), mp 98-100° C. LC/MS gave the correct molecular ion [(M+H)+=387] for the desired compound.

[0314] To a stirred solution of part A compound (5.01 g, 12.9 mmol) in CH2Cl2 (50 mL) at room temperature under argon was added trimethylsilylcyanide (1.725 mL, 12.9 mmol) and triethylamine (200 μL, 1.4 mmol). The resulting yellow solution was stirred for 3 h and then evaporated. The residuum was then dissolved in EtOH (25 mL) and trimethylsilyl chloride (25 mL) was added. The colorless solution was heated to 50° C. for 48 h. The solution was cooled, evaporated and the residuum was stirred rapidly for 1 h with CH2Cl2 (50 mL), EtOH (25 mL) and saturated sodium bicarbonate solution (50 mL). The mixture was partially evaporated to remove the ethanol and the remainder partitioned with CH2Cl2. The organic extract was dried (MgSO4) and evaporated. Purification by flash chromatography (5×25 cm column, 1:49 Et2O/CH2Cl2) provided the title compound as a colorless oil which slowly solidified (4.97 g, 84% yield), mp 47-49° C. LC/MS gave the correct molecular ion [(M+H)+=461] for the desired compound.

[0315] A solution of part B compound (1.40 g, 3.03 mmol) in THF (10 mL) was stirred at room temperature under argon, as 1 M NaOH solution (5 mL, 5.0 mmol) was added. After 24 h, the reaction mixture was diluted with water (20 mL) and extracted twice with Et2O. The aqueous phase was acidified with 1 M hydrochloric acid (5.5 mL, 5.5 mmol), extracted twice with CH2Cl2, the extracts dried (MgSO4) and evaporated. A portion of the resulting gummy solid (1.10 g) was dissolved in Et2O (20 mL) and extracted once with 0.1 M sodium hydroxide solution (23 mL, 2.3 mmol). The aqueous layer was purged with nitrogen gas for 15 min and then lyophilized to give the title compound as a white powder, 988 mg, 87% yield. LC/MS gave the correct molecular ion [(M+H)+=433] for the desired compound as its free acid.

EXAMPLE 2

α(R)-2,3-Bis[(2-Chlorophenyl)Methoxy]-α-Hydroxybenzeneacetic Acid

[0316]

[0317] To a stirred slurry of Example 1, Part B compound (1.334 g, 2.89 mmol), N-t-butyloxycarbonyl-(S)-proline (646 mg, 3.00 mmol), triethylamine (210 μL, 1.5 mmol) and DMAP (122 mg, 1.0 mmol) in CH2Cl2 (10 mL) at room temperature under argon was added N-Ethyl N′,N′-diisoproylaminoethyl carbodiimide (573 mg, 3.0 mmol). After 16 h, the reaction mixture was diluted with CH2Cl2 and washed once with 5% potassium hydrogren sulfate solution. The organic phase was dried (Na2SO4) and evaporated. Purification by flash chromatography (5×25 cm column, 1.5 L 1:24 Et2O/CH2Cl2, then 1:16 Et2O/CH2Cl2) gave two fractions. The first product to elute was the title compound as a colorless oil. LC/MS gave the correct molecular ion [(M+H)+=659] for the desired compound.

[0318] To a stirred solution of part A compound (2.18 g, 3.30 mmol) in dioxane (10 mL) at room temperature under argon was added KOH solution (10.0 mL, 1 M, 10.0 mmol). The resulting solution was heated to 70° C. for 4 h and then cooled to room temperature. After acidifying with 5% potassium hydrogen sulfate solution, the reaction mixture was extracted twice with CH2Cl2. The extracts were combined, washed once with brine, dried (MgSO4) and evaporated. The oily residue was dissolved in 4 N HCl/dioxane (10 mL), stirred under argon for 2 h and then evaporated and re-evaporated twice from hexanes. The residual oil was dissolved in ether (10 mL) and washed twice with water (10 mL) and then extracted with 0.1 M NaOH (30.0 mL, 3.00 mmol). The aqueous layer was frozen and lyophilized to provide the title compound as a white powder, 1.30 g (100% yield). LC/MS gave the correct molecular ion [(M+H)+=433] for the desired compound. Chiral purity was determined by chromatography of the methyl ester (prepared from a 3 mg sample of the title compound using trimethylsilyl-diazomethane in Et2O/CH3OH) on a normal-phase OD column (hexane/isopropanol as the elutent). Optical purity was determined to be 96.7%.

EXAMPLE 3

α(S) -2,3-Bis[(2-Chlorophenyl)Methoxy]-α-Hydroxybenzeneacetic Acid

[0319]

[0320] To a stirred slurry of Example 1, Part B compound (1.334 g, 2.89 mmol), N-t-butyloxycarbonyl-(S)-proline (646 mg, 3.00 mmol), triethylamine (210 μL, 1.5 mmol) and DMAP (122 mg, 1.0 mmol) in CH2Cl2 (10 mL) at room temperature under argon was added N-Ethyl N′,N′-diisoproylaminoethyl carbodiimide (573 mg, 3.0 mmol). After 16 h, the reaction mixture was diluted with CH2Cl2 and washed once with 5% potassium hydrogren sulfate solution. The organic phase was dried (Na2SO4) and evaporated. Purification by flash chromatography (5×25 cm column, 1.5 L 1:24 Et2O/CH2Cl2, then 1:16 Et2O/CH2Cl2) gave two fractions. The first product to elute was Example 2 Part C compound. The second was the title compound as a colorless oil. LC/MS gave the correct molecular ion [(M+H)+=659] for the desired compound.

[0321] To a stirred solution of part A compound (2.56 g, 3.90 mmol) in dioxane (10 mL) at room temperature under argon was added KOH solution (10.0 mL, 1 M, 10.0 mmol). The resulting solution was heated to 70° C. for 4 h and then cooled to room temperature. After acidifying with 5% potassium hydrogen sulfate solution, the reaction mixture was extracted twice with CH2Cl2. The extracts were combined, washed once with brine, dried (MgSO4) and evaporated. The oily residue was dissolved in 4 N HCl/dioxane (10 mL), stirred under argon for 2 h and then evaporated and re-evaporated twice from hexanes. The residual oil was dissolved in ether (10 mL) and washed twice with water (10 mL) and then extracted with 0.1 M NaOH (33.0 mL, 3.30 mmol). The aqueous layer was frozen and lyophilized to provide the title compound as a white powder, 1.50 g (100% yield). LC/MS gave the correct molecular ion [(M+H)+=433] for the desired compound. Chiral purity was determined by chromatography of the methyl ester (prepared from a 3 mg sample of the title compound using trimethylsilyl-diazomethane in Et2O/CH3OH) on a normal-phase OD column (hexane/isopropanol as the elutent). Optical purity was determined to be 96.5%.

EXAMPLE 4

2-(E)-3-[2,3-Bis[(2-Chlorophenyl)Methoxy]phenyl]-2-Propenoic Acid

[0322]

[0323] To a stirred solution of triethyl phosphonoacetate (561 mg, 2.50 mmol) in THF (5.0 mL) at room temperature under argon was added sodium hydride (60% mineral-oil dispersion, 96 mg, 2.4 mmol). The reaction mixture was warmed to 50° C. for 1 h and then cooled to room temperature. Example 1 Part A compound (775 mg, 2.00 mmol) was added in one portion. The resulting mixture was stirred for 30 min, quenched with saturated sodium bicarbonate solution and extracted with CH2Cl2. The organic extract was dried (MgSO4) and evaporated. Recrystallization from CH2Cl2/hexanes gave title compound as a white solid (715 mg, 78% yield), mp 95-97° C. LC/MS gave the correct molecular ion [(M+H)+=457] for the desired compound.

[0324] To a stirred solution of part A compound (700 mg, 1.53 mmol) in THF (3 mL) at room temperature under argon was added NaOH solution (3.0 mL, 1 M, 3.0 mmol). The resulting solution was heated to 50° C. for 14 h and then cooled to room temperature. After acidifying with 1 M HCl, the resulting solids were collected, washed with water and air-dried to provide the title compound as a white solid, 648 mg (99% yield), mp 187-189° C. LC/MS gave the correct molecular ion [(M+H)+=430] for the desired compound.

EXAMPLE 5

2,3-Bis[(2-Chlorophenyl)Methoxy]Benzeneacetic Acid

[0325]

[0326] To a stirring slurry Example 1 Part A compound (1.00 g, 2.58 mmol) in EtOH (10 mL) at room temperature was added powdered sodium borohydride (100 mg, 2.6 mmol) over 1 min. The resulting mixture was stirred for 16 h, quenched with saturated sodium bicarbonate solution (20 mL) and stirred 20 min. The resulting solids were collected, washed with water and air-dried to give the title compound as a white solid (930 mg, 93% yield), mp 102-104° C. LC/MS gave the correct molecular ion [(M+H)+=389] for the desired compound.

[0327] To a stirred solution of part A compound (930 mg, 2.4 mmol) in CH2Cl2 (10 mL) at 0° C. under argon was added phosphorous tribromide solution (5.0 mL, 1 M in CH2Cl2, 5.0 mmol) over 1 min. The resulting solution was warmed to room temperature. After 3 h, the reaction was quenched with saturated sodium bicarbonate solution (20 mL) and then treated with solid sodium bicarbonate to bring to pH 7. The mixture was extracted twice with EtOAc, dried (MgSO4) and evaporated to provide the title compound as a white amorphous solid, 1.05 g (97% yield). LC/MS gave the correct molecular ion [(M+H)+=451] for the desired compound.

[0328] To a stirred solution of part B compound (875 mg, 1.94 mmol) in DMSO (8 mL) at room temperature under argon was added potassium cyanide (1.30 g, 20 mmol). The resulting solution was warmed to 65° C. After 3 h, the reaction was quenched with water and the resulting gummy solid was collected, washing with water. The solid was dissolved in CH2Cl2, washed with water, dried (MgSO4) and evaporated. Purification by flash chromatography provided the title compound as a light yellow amorphous solid, 343 mg (44% yield). LC/MS gave the correct molecular ion [(M+H)+=398] for the desired compound.

[0329] To a stirred solution of part C compound (340 mg, 0.85 mmol) in EtOH (4 mL) at room temperature under argon was added chlorotrimethylsilane (4 mL). The resulting solution was warmed to 50° C. After 34 h, the reaction was cooled to room temperature and evaporated. The residue was stirred vigorously with saturated sodium bicarbonate solution (10 mL) for 30 min and then extracted three times with CH2Cl2. The extracts were combined, dried (MgSO4) and evaporated. Purification by flash chromatography provided the title compound as a colorless oil, 223 mg (59% yield). LC/MS gave the correct molecular ion [(M+H)+=445] for the desired compound.

[0330] To a stirred solution of part D compound (220 mg, 0.49 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (1.5 mL, 1.0 M, 1.5 mmol). The resulting solution was heated to 50° C. for 15 h. The reaction mixture was cooled, diluted with water (3 mL) and extracted once with Et2O. The aqueous phase was acidified with 1 N HCl to pH 2 and extracted twice with CH2Cl2. The CH2Cl2 extracts were combined, dried (MgSO4) and concentrated to ˜2 mL. Hexanes were added, the flask scratched and the resulting white solid was collected and air-dried to give the title compound as a white solid, 198 mg, 94% yield, mp 105-107° C. LC/MS gave the correct molecular ion [(M+H)+=417] for the desired compound.

EXAMPLE 6

2,3-Bis[(2-Chlorophenyl)Methoxy]Benzeneacetic Acid Alternative Synthesis

[0331]

[0332] To a stirred solution of Example 1 Part A compound (1.94 g, 5.00 mmol) and methylthiomethyl methylsulfoxide (0.58 mL, 5.6 mmol) in THF (5 mL) at room temperature under argon was added Trit-on-B (0.5 mL, 40% in MeOH). The resulting solution was heated to gentle reflux for 16 h and then evaporated and re-evaporated twice from hexanes. The residue was purified by flash chromatography to give the thioketene S-oxide as a colorless oil, 2.06 g (83% yield).

[0333] This oil was dissolved in MeOH (100 mL) and HCl gas was bubbled into the solution as the temperature rose to 66° C. before subsiding to room temperature. After 30 min more, the reaction was evaporated and re-evaporated from CH2Cl2. Purification by flash chromatography gave the title compound as a white solid, 1.66 g, 93% yield. LC/MS gave the correct molecular ion [(M+H)+=431] for the desired compound.

[0334] By the method of Example 5 Part E, Part A compound (1.00 g, 2.32 mmol) was hydrolyzed to give the title compound as a white solid, 964 mg, 100% yield, mp 105-107° C.

EXAMPLE 7

[[2,3-Bis[(2-Chlorophenyl)Methoxy]Phenyl]Methyl]Propanedioic Acid

[0335]

[0336] To a stirred solution of Example 5 Part A compound (1.00 g, 2.57 mmol) and triphenylphosphine (674 mg, 2.57 mmol) in THF (2.5 mL) at room temperature under argon was added carbon tetrachloride (15 mL) and the reaction heated to 50° C. After 24 h, the reaction evaporated and purified by flash chromatography to provide the title compound as a white solid, 517 mg (49% yield), mp 96-98° C. LC/MS gave the correct molecular ion [(M+H)+=407] for the desired compound.

[0337] To a stirred slurry of sodium hydride (60% mineral oil dispersion, 75 mg, 1.88 mmol) in THF (5 mL) at room temperature under argon was added a solution of diethyl malonate (300 μL, 2.0 mmol) in THF (5 mL). After 30 min, a solution of Part A compound (500 mg, 1.23 mmol) in THF (2 mL) was added in one portion. After 14 h, the reaction mixture was quenched with 5% potassium hydrogen sulfate solution and extracted twice with EtOAc. The organic extracts were combined, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 524 mg (80% yield). LC/MS gave the correct molecular ion [(M+H)+=531] for the desired compound.

[0338] A stirred mixture of part B compound (520 mg, 0.99 mmol) in potassium hydroxide solution (246 mg, 4.4 mmol in 4 mL of water) was heated to reflux under argon for 24 h. The reaction mixture was cooled, diluted with water (3 mL) and extracted once with Et2O. The aqueous phase was brought to pH 2 with 3 N HCl and the resulting solids filtered, washed with water and air-dried to give the title compound as a white solid, 365 mg (77% yield), mp 148-150° C. (dec). LC/MS gave the correct molecular ion [(M+H)+=475] for the desired compound.

EXAMPLE 8

2,3-Bis[(2-Chlorophenyl)Methoxy]Benzenepropanoic Acid

[0339]

[0340] Example 7 Part C compound (256 mg, 0.54 mmol) was heated to 155° C. at a pressure of 1 Torr for 3 h. The reaction mixture was cooled and recrystallized directly from hexanes/toluene to provide the title compound as a white solid (225 mg, 97% yield), mp 131-132° C. LC/MS gave the correct molecular ion [(M+H)+=431] for the desired compound.

EXAMPLE 9

2,3-Bis[(2-Chlorophenoxy)Methyl]Benzoic Acid

[0341]

[0342] To a stirred solution of methyl 2,3-dimethylbenzoate (1.75 g, 10.7 mmol) in carbon tetrachloride (35 mL) under argon was added freshly recrystallized N-bromosuccinimide (3.90 g, 21.9 mmol) and AIBN (50 mg). The reaction mixture was heated to reflux under argon for 4 h and then cooled and filtered. Evaporation gave a yellow oil, 3.53 g, predominantly methyl 2,3-bis(bromomethyl)benzoate.

[0343] To a stirred solution of 2-chlorophenol (2.83 g, 22.0 mmol) in DMF (20 mL) at room temperature under argon was added sodium hydride (60% mineral oil dispersion, 880 mg, 22 mmol) over 5 min. The resulting clear solution was stirred 30 min and a solution in DMF (5 mL) of the dibromide prepared above was added. After 14 h, the reaction mixture was quenched with water and extracted three times with Et2O. The extracts were combined and washed twice with water, once with brine, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a white solid, 2.03 g (46% yield), mp 107-109° C. LC/MS gave the correct molecular ion [(M+H)+=417] for the desired compound.

[0344] To a solution of Part A compound (270 mg, 0.647 mmol) in EtOH (2 mL) at room temperature under argon was added sodium hydroxide solution (2.0 mL, 1 M, 2.0 mmol). The mixture was heated to 50° C. for 1 h. The reaction mixture was cooled, diluted with water (3 mL) and extracted once with Et2O. The aqueous phase was brought to pH 2 with 1 N HCl and the resulting solids filtered, washed with water and air-dried to give the title compound as a white solid, 238 mg (91% yield), mp 172-174° C. LC/MS gave the correct molecular ion [(M+H)+=403] for the desired compound.

EXAMPLE 10

3-[(2-Chlorophenoxy)Methyl]-2-[(2-Chlorophenyl)Methoxy]Benzoic Acid

[0345]

[0346] To a stirred solution of 2-bromophenol (3.42 g, 19.8 mmol) in DMF (10 mL) under argon was added propargyl bromide (80% in toluene, 4.12 g, 27.7 mmol) and potassium carbonate (3.80 g, 27.5 mmol). The reaction mixture was stirred for 90 min, then diluted with water and extracted twice with Et2O. The extracts were combined, washed once with water, three times with 1 M NaOH (25 mL portions) and once with brine, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 3.93 g (94% yield). LC/MS gave the correct molecular ion [(M+H)+=211] for the desired compound.

[0347] A stirred slurry of Part A compound (3.00 g, 14.2 mmol) and cesium fluoride (3.02 g, 20 mmol) in N,N-diethylaniline (24 mL) under argon was heated to 210° C. for 4 h. The reaction mixture was then cooled, diluted with hexanes and washed three times with 1 M HCl (100 mL portions). The organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography (hexanes as the elutant) provided the title compound as a colorless oil, 1.94 g (67% yield). LC/MS gave the correct molecular ion [(M+H)+=211] for the desired compound.

[0348] A stirred solution of Part B compound (1.94 g, 9.19 mmol) in CH2Cl2 (100 mL) protected from atmospheric moisture by a calcium chloride drying tube was cooled to −78° C. and a 3% O3/O2 gas mixture is bubbled through the solution until a blue color persists (˜35 min). The solution was purged with nitrogen gas and then dimethylsulfide (5 mL) was added and the reaction allowed to warm to room temperature. After 4 h, the solution was evaporated and the residue redissolved in MeOH (8 mL) to which was added water (8 mL) and potassium carbonate (1.1 g, 80 mmol). The mixture was heated to 55° C. under argon for 1 h and then cooled, neutralized with 1 M potassium hydrogen sulfate to pH 7 and extracted twice with CH2Cl2. The organic extracts were combined, dried (MgSO4) and evaporated. Purification by flash chromatography provided the title compound as a light yellow crystalline solid, 1.47 g (80% yield). LC/MS gave the correct molecular ion [(M+H)+=201] for the desired compound.

[0349] To a solution of Part C compound (638 mg, 3.17 mmol) in DMF (10 mL) at room temperature under argon was added sodium hydride (60% mineral oil dispersion, 140 mg, 3.5 mmol). After 20 min, 2-chloro-benzyl chloride (0.50 mL, 4.0 mmol) and tetrabutylammonium iodide (200 mg, 0.5 mmol) was added and the reaction was heated to 60° C. After 14 h the reaction mixture was cooled, diluted with Et2O and washed once with 5% potassium hydrogen sulfate solution, twice with water, once with brine, dried (MgSO4) and evaporated. Purification by flash chromatography provided the title compound as a white solid, 734 mg (71% yield), mp 96-98° C. LC/MS gave the correct molecular ion [(M+H)+=325] for the desired compound.

[0350] To a solution of Part D compound (672 mg, 2.06 mmol) in CH2Cl2 (10 mL) at room temperature under argon was added diisobutylaluminum hydride solution (1 M in toluene, 2.3 mL, 2.3 mmol). After 1 h, the reaction mixture was quenched with 1 M potassium sodium tartrate solution (4 mL) and stirred for 1 h. The reaction mixture was extracted twice with EtOAc. The organic extracts were combined, dried (MgSO4) and evaporated to provide the title compound as a white solid, 675 mg (100% yield). LC/MS gave the correct molecular ion [(M+H)+=327] for the desired compound.

[0351] To a solution of Part E compound (407 mg, 1.24 mmol) in CH2Cl2 (5 mL) at 0° C. under argon was added phosphorous tribromide solution (1 M in CH2Cl2, 2.5 mL, 2.5 mmol). After 15 min, the reaction mixture was warmed to room temperature for 1 h and then diluted with CH2Cl2, washed once with water, once with saturated sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and evaporated. The product was unstable and therefore used immediately by dissolving in DMF (1 mL) and adding to a solution prepared from 2-chlorophenol (0.2 mL, 1.3 mmol) and sodium hydride (60% mineral oil dispersion, 50 mg, 1.25 mmol) in DMF (3 mL) at room temperature under argon. The reaction mixture was stirred for 16 h. The reaction was quenched with water and extracted three times with hexanes. The hexanes extracts were combined, washed once with water, dried (MgSO4) and evaporated. Purification by flash chromatrography on silica gel provided the title compound as a colorless oil, 115 mg (21% yield). LC/MS gave the correct molecular ion [(M+H)+=437] for the desired compound.

[0352] To a solution of Part F compound (110 mg, 0.25 mmol) in methanol (1.5 mL) and DMF (2 mL) was added Pd(OAc)2 (12 mg, 0.05 mmol), dppf (21 mg, 0.05 mmol) and triethylamine (70 μL, 0.5 mmol). The stirred solution was purged twice with carbon monoxide gas and then heated under a CO-filled balloon at 80° C. After 18 h, the reaction mixture was cooled, diluted with water and brought to pH3 with 10% aqueous potassium hydgrogen sulfate. The mixture was extracted twice with ether and the organic extract dried (MgSO4). Flash chromatography on silica gel gave the title compound as a colorless oil, 51 mg (49% yield). LC/MS gave the correct molecular ion [(M+H)+=417] for the desired compound.

[0353] To a solution of Part G compound (50 mg, 0.12 mmol) in THF (1 mL) at room temperature under argon was added sodium hyroxide solution (1 mL, 1 M, 1 mmol). After 14 h, the solution was acidified (1 M HCl) and partially evaporated. The resulting solids were filtered, washed with water and air-dried to give the title compound as a white solid, 45 mg, 93% yield, mp 172-174° C. LC/MS gave the correct molecular ion [(M+H)+=403] for the desired compound.

EXAMPLE 11

(Alternate Synthesis of Example 10) 3-[(2-Chlorophenoxy)Methyl]-2-[(2-Chlorophenyl)Methoxy]Benzoic Acid

[0354]

[0355] To a solution of Example 10 Part F compound (208 mg, 0.474 mmol) in THF (4 mL) at −78° C. under argon was added n-butyllithium solution (200 μL, 2.5 M in hexane, 0.5 mmol) over 10 min. After 3 h, dry carbon dioxide gas was bubbled into the reaction mixture as the reaction was allowed to warm to room temperature. After 1 h at room temperature, the reaction mixture was quenched with 1 M NaOH (1 mL, 1 mmol) and extracted twice with hexanes. The aqueous phase was brought to pH 2 with 1 N HCl and the resulting solids filtered, washed with water and air-dried to give the title compound as a white solid, 16.5 mg (9% yield), mp 172-174° C. LC/MS gave the correct molecular ion [(M+H)+=403] for the desired compound.

EXAMPLE 12

α-Amino-2,3-Bis[(2-Chlorophenyl)Methoxy]Benzeneacetic Acid

[0356]

[0357] To a stirred solution of Example 1 Part B compound (1.009 g, 2.19 mmol) in CH2Cl2 (20 mL) under argon at room temperature was added a solution prepared from benzotriazole (570 mg, 4.8 mmol) and thionyl chloride (570 mg, 4.8 mmol) in CH2Cl2 (5 mL) over 2 min. The reaction mixture was stirred for 90 min, then diluted with water and extracted twice with CH2Cl2. The extracts were combined, washed once with water, once with 0.5 M NaOH (25 mL) and once with brine, dried (MgSO4) and evaporated. The residuum was immediately dissolved in DMF (8 mL), treated with sodium azide (570 mg, 8.8 mmol) and stirred at room temperature under argon for 1 h. The reaction mixture was quenched with water and extracted twice with Et2O. The extracts were combined, washed twice with water, once with brine dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 657 mg (62% yield). LC/MS gave the correct molecular ion [(M+H)+=486] for the desired compound.

[0358] A stirred solution of Part A compound (652 mg, 1.34 mmol) under argon at room temperature in THF(4 mL) was treated with triphenylphosphine (352 mg, 1.34 mmol). After 15 h, the reaction mixture was evaporated and re-evaporated twice from hexanes to give the title compound as a colorless oil, 965 mg (100% yield). LC/MS gave the correct molecular ion [(M+H)+=720] for the desired compound.

[0359] To a stirred solution of Part B compound (880 mg, 1.22 mmol) in THF (8 mL) at room temperature under argon was added sodium hydroxide solution (2.5 mL, 1 M, 2.5 mmol). After 14 h, the solution was diluted with water and extracted once with CH2Cl2. The aqueous phase was cooled and the resulting precipitate was filtered. The filtrate was lyophilized and the residue was purified by reverse phase preparative HPLC (YMC S5 ODS 20×250 mm column, MeOH/water-TFA elutant) to give the title compound as its trifluoroacetic acid salt, 450 mg (82% yield). LC/MS gave the correct molecular ion [(M+H)+=432] for the desired compound as its free base.

EXAMPLE 13

α-(Acetylamino)-2,3-Bis[(2-Chlorophenyl)Methoxy]Benzeneacetic Acid

[0360]

[0361] A stirred slurry of Example 1 Part A compound (4.00 g, 10.33 mmol) in MeOH (10 mL) saturated with ammonia gas under argon at 40-45° C. was treated with additional ammonia gas for 1 h. The slurry was cooled to 5° C. and trimethylsilylcyanide (2.1 mL, 15.7 mmol) was added over 10 min. The temperature was then raised to 45° C. as a yellow solution formed. After 7 h, the reaction mixture was evaporated, re-dissolved in EtOH (60 mL) and hydrogen chloride gas was used to saturate the solution. After 14 h, the reaction mixture was treated with thionyl chloride (0.8 mL) and warmed to 55° C. for 2 h. The solution was cooled to room temperature, evaporated and the resulting solids triturated in Et2O to give the title compound as an orange solid, usable without further purification.

[0362] To a stirred solution of Part A compound (197 mg, 0.4 mmol) under argon at room temperature in THF (2 mL) was added triethylamine (0.2 mL, 1.6 mmol), DMAP (2 mg, 0.02 mmol) and acetic anhydride (60 μL, 0.6 mmol). After 15 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 167 mg (83% yield). LC/MS gave the correct molecular ion [(M+H)+=502] for the desired compound.

[0363] To a stirred solution of Part B compound (167 mg, 0.33 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (0.5 mL, 1 M, 0.5 mmol). After 14 h, the solution was diluted with water and extracted once with Et2O. The aqueous phase was cooled, acidified to pH 2 with 1 N HCl and the resulting precipitate was filtered, washed with water and air-dried to give the title compound as a white amorphous solid, 104 mg (55% yield). LC/MS gave the correct molecular ion [(M+H)+=474] for the desired compound.

EXAMPLE 14

2,3-Bis[(2-Chlorophenyl)Methoxy]-α-[(2-Methyl-1-Oxopropyl)Amino]Benzeneacetic Acid

[0364]

[0365] To a stirred solution of Example 13 Part A compound 15 (197 mg, 0.4 mmol) under argon at 0-5° C. in THF (1.5 mL) was added triethylamine (0.2 mL, 1.6 mmol), DMAP (2 mg, 0.02 mmol) and isobutyryl chloride (65 μL, 0.6 mmol). The reaction mixture was allowed to warm to room temperature and after 15 h, it was diluted with EtOAc, washed once 20 with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 156 mg (74% yield). LC/MS gave the correct molecular ion [(M+H)+=530] for the desired compound.

[0366] To a stirred solution of Part B compound (155 mg, 0.29 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (0.5 mL, 1 M, 0.5 mmol). After 24 h, the solution was diluted with water and extracted once with Et2O. The aqueous phase was cooled, acidified to pH 2 with 1 N HCl and the resulting precipitate was filtered, washed with water and air-dried to give the title compound as a white amorphous solid, 156 mg (100% yield). LC/MS gave the correct molecular ion [(M+H)+=502] for the desired compound.

EXAMPLE 15

α-(Benzoylamino)-2,3-Bis[(2-Chlorophenyl)Methoxy]Benzeneacetic Acid

[0367]

[0368] To a stirred solution of Example 13 Part A compound (197 mg, 0.4 mmol) under argon at 0-5° C. in THF(1.5 mL) was added triethylamine (0.2 mL, 1.6 mmol), DMAP (2 mg, 0.02 mmol) and benzoyl chloride (70 μL, 0.6 mmol). The reaction mixture was allowed to warm to room temperature and after 15 h, it was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 161 mg (71% yield). LC/MS gave the correct molecular ion [(M+H)+=564] for the desired compound.

[0369] To a stirred solution of Part B compound (160 mg, 0.28 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (0.5 mL, 1 M, 0.5 mmol). After 24 h, the solution was diluted with water and extracted once with Et2O. The aqueous phase was cooled, acidified to pH 2 with 1 N HCl and the resulting precipitate was filtered, washed with water and air-dried to give the title compound as a tan amorphous solid, 142 mg (95% yield). LC/MS gave the correct molecular ion [(M+H)+=536] for the desired compound.

EXAMPLE 16

2,3-Bis[(2-Chlorophenyl)Methoxy]-α-[(Difluoroacetyl)Amino]Benzeneacetic Acid

[0370]

[0371] To a stirred solution of Example 13 Part A compound (222 mg, 0.45 mmol) under argon at room temperature in CH2Cl2 (2.5 mL) was added triethylamine (85 μL, 0.6 mmol), HOAt (69 mg, 0.5 mmol) and difluoroacetic acid (48 mg, 0.5 mmol) was added EDAC (96 mg, 0.5 mmol). After 16 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 156 mg (64% yield). LC/MS gave the correct molecular ion [(M+H)+=538] for the desired compound.

[0372] To a stirred solution of Part B compound (153 mg, 0.28 mmol) in THF (1.5 mL) at room temperature under argon was added a solution of lithium hydroxide monohydrate (13 mg, 0.32 mmol) in water (1 mL). After 24 h, the solution was diluted with water and extracted once with Et2O. The aqueous phase was cooled, acidified to pH 2 with 1 N HCl and the resulting precipitate was filtered, washed with water and air-dried to give the title compound as an off-white amorphous solid, 144 mg (100% yield). LC/MS gave the correct molecular ion [(M+H)+=510] for the desired compound.

EXAMPLE 17

α-[(Aminoacetyl)Amino]-2,3-Bis[(2-Chlorophenyl)Methoxy]Benzeneacetic Acid Hydrochloride

[0373]

[0374] To a stirred solution of N-t-butyloxycarbonyl glycine under argon at −5° C. in THF (2 mL) was added triethylamine (60 μL, 0.5 mmol) and then isobutyl chloroformate (67 μL, 0.52 mL). The resulting slurry was stirred 20 min and a solution of Example 13 Part A compound (222 mg, 0.45 mmol) and triethylamine (70 μL, 0.6 mmol) in THF (1 mL) was added over 1 min. The reaction was allowed to warm to room temperature and stirred. After 1 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 102 mg (37% yield). LC/MS gave the correct molecular ion [(M+H)+=617] for the desired compound.

[0375] To a stirred solution of Part B compound (102 mg, 0.17 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (0.3 mL, 1 M, 0.3 mmol). After 20 h, the reaction mixture was acidified to pH 2 with 1 N HCl and extracted with CH2Cl2. The extract was dried (MgSO4), evaporated and then stirred with 4 N HCl/dioxane (1 mL) for 4 h. The solution was evaporated, the residue triturated with Et2O and collected to provide the title compound as an off-white amorphous solid, 90 mg (100% yield). LC/MS gave the correct molecular ion [(M+H)+=489] for the desired compound.

EXAMPLE 18

2,3-Bis[(2-Chlorophenyl)Methoxy]-α-[(Methoxyacetyl)Amino]Benzeneacetic Acid

[0376]

[0377] To a stirred solution of Example 13 Part A compound (222 mg, 0.45 mmol) under argon at room temperature in CH2Cl2 (1.5 mL) was added triethylamine (85 μL, 0.6 mmol), HOAt (69 mg, 0.5 mmol) and methoxyacetic acid (46 mg, 0.5 mmol) was added EDAC (96 mg, 0.5 mmol). After 16 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 153 mg (74% yield). LC/MS gave the correct molecular ion [(M+H)+=518] for the desired compound.

[0378] To a stirred solution of Part B compound (153 mg, 0.29 mmol) in THF (2 mL) at room temperature under argon was added a solution of lithium hydroxide monohydrate (13 mg, 0.32 mmol) in water (1 mL). After 24 h, the solution was diluted with water and extracted once with Et2O. The aqueous phase was cooled, acidified to pH 2 with 1 N HCl and the resulting precipitate was filtered, washed with water and air-dried to give the title compound as an off-white amorphous solid, 120 mg (82% yield). LC/MS gave the correct molecular ion [(M+H)+=504] for the desired compound.

EXAMPLE 19

[2,3-Bis[(2-Chlorophenyl)Methoxy]Phenyl]Propanedioic Acid

[0379]

[0380] To a stirred solution of diisopropylamine (160 μL, 1.14 mmol) under argon at −5° C. in THF (3 mL) was added n-butyllithium solution (0.43 mL, 2.5 M in hexanes, 1.08 mmol). After 15 min, a solution of Example 5 Part E compound (209 mg, 0.5 mmol) in THF (1 mL) was added over 2 min. After 40 min, dry CO2 gas was bubbled through the solution for 20 min. The reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by reverse phase preparative HPLC (YMC S5 ODS 20×250 mm column, acetonitrile/water−0.1% TFA gradient) provided the title compound as a light yellow oil, 164 mg (71% yield). LC/MS gave the correct molecular ion [(M+H)+=461] for the desired compound.

EXAMPLE 20

[[2,3-Bis[(2-Chlorophenyl)Methoxy]Phenyl]Methyl]-α-(Hydroxymethyl)Benzeneacetic Acid

[0381]

[0382] To a stirred solution of diisopropylamine (160 μL, 1.14 mmol) under argon at −5° C. in THF (3 mL) was added n-butyllithium solution (0.43 mL, 2.5 M in hexanes, 1.08 mmol). After 15 min, the reaction mixture was cooled to −78° C. and a solution of Example 5 Part E compound (209 mg, 0.5 mmol) in THF (1 mL) was then added over 2 min. After an additional 15 min, DMPU was added (2 mL) and the solution warmed to 0° C. Formaldehyde gas (by the pyrolysis of paraformaldehyde [300 mg, 10 mmol] at 190° C.) was introduced to the reaction mixture by a gas inlet tube. The reaction mixture was stirred for 1 h, diluted with EtOAc, washed once with 5% potassium hydrogen sulfate, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (1:39:360 HOAc/MeOH/CH2Cl2 as elutent) provided the title compound as a white solid, 136 mg (61% yield). LC/MS gave the correct molecular ion [(M+H)+=447] for the desired compound.

EXAMPLE 21

3-[1-(2-Chlorophenyl)Ethoxy]-2-[(2-Chlorophenyl)Methoxy]-α-Hydroxybenzeneacetic Acid

[0383]

[0384] To a stirred solution of diisopropylamine (170 μL, 1.21 mmol) under argon at −5° C. in THF (3 mL) was added n-butyllithium solution (483 μL, 2.5 M in hexanes, 1.21 mmol). After 15 min, the reaction mixture was cooled to −78° C. and a solution of Example 1 Part B compound (248 mg, 0.537 mmol) in THF (1 mL) was then added over 2 min. After an additional 15 min, DMPU was added (2 mL) and then methyl iodide (42 μL, 0.68 mmol). The reaction mixture was stirred for 2 h and then warmed to −40° C. After 14 h, the reaction was quenched with sodium hydroxide solution (1 M), warmed to room temperature and stirred for 1 h. The reaction mixture was acidified with 5% potassium hydrogen sulfate, extracted with CH2Cl2, dried (MgSO4) and evaporated. Purification by reverse phase preparative HPLC (YMC S5 ODS 20×250 mm column, acetonitrile/water−0.1% TFA gradient) provided the title compound, a colorless oil, as a 1:1 mixture of diastereomers, 75 mg (31% yield). LC/MS gave the correct molecular ion [(M+H)+=447] for the desired compound.

EXAMPLE 22

2,3-Bis[(2-Chlorophenoxy)Methyl]-α-Hydroxybenzeneacetic Acid

[0385]

[0386] To a stirred solution of 2,3-dimethylbenzoic acid (1.50 g, 10 mmol) in CH2Cl2 (10 mL) under argon at room temperature was added oxalyl chloride solution (8.0 mL, 2 M in CH2Cl2, 16 mmol) and then DMF (0.2 mL). After 2 h, the solution was evaporated and re-evaporated twice from CH2Cl2 and then dissolved in CH2Cl2 (10 mL). This solution was added, over 30 min, to a stirred slurry of N-methoxy-N-methylammonium chloride (1.10 g, 11 mmol), DMAP (5 mg, 0.04 mmol) and triethylamine (3.0 mL, 21.4 mmol) in CH2Cl2 (15 mL) at 10° C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was then diluted with CH2Cl2, washed once with 10% citric acid, once with water and once with brine. The organic extract was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 1.38 g (71% yield). LC/MS gave the correct molecular ion [(M+H)+=194] for the desired compound.

[0387] To a stirred solution of part A compound (1.32 g, 6.83 mmol) in carbon tetrachloride (20 mL) under argon was added freshly recrystallized N-bromosuccinimide (3.10 g, 13.7 mmol) and AIBN (50 mg). The reaction mixture was heated to reflux under argon for 3 h and then cooled and filtered. Purification by flash chromatography on silica gel provided predominantly N-methoxy-N-methyl 2,3-bis(bromomethyl) benzamide as a colorless oil, 1.08 g (45% yield).

[0388] To a stirred solution of 2-chlorophenol (1.06 mL, 10.2 mmol) in DMF (10 mL) at room temperature under argon was added sodium hydride (60% mineral oil dispersion, 385 mg, 9.6 mmol) over 5 min. The resulting clear solution was stirred 30 min and a solution in DMF (5 mL) of the dibromide prepared above was added and the reaction mixture heated to 65° C. After 1 h, the reaction mixture was quenched with water and extracted three times with Et2O. The extracts were combined and washed twice with water, once with brine, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a light yellow oil, 1.11 g (83% yield). LC/MS gave the correct molecular ion [(M+H)+=446] for the desired compound.

[0389] To a solution of Part B compound (2.56 g, 5.75 mmol) in THF (30 mL) at −78° C. under argon was added diisobutylaluminum hydride solution (7.6 mL, 1.5 M in toluene, 11.4 mmol) over 10 min. The reaction was stirred for 1 h and then warmed to room temperature and stirred for 2 h. The reaction mixture was then quenched with water (2 mL) and then stirred with potassium sodium tartrate solution (20 mL, 1 M) for 1 h. The mixture was extracted twice with EtOAc, the organic phases combined, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a white solid, 1.58 g (71% yield), mp 101-103° C. LC/MS gave the correct molecular ion [(M+H)+=387] for the desired compound.

[0390] By the method of Example 1 Part B, Part C compound (532 mg, 1.37 mmol) was converted to the title compound as an amorphous white solid, 425 mg (67% yield). LC/MS gave the correct molecular ion [(M+H)+=461] for the desired compound.

[0391] By the method of Example 1 Part C, Part D compound (413 mg, 0.90 mmol) was converted to the title compound as a white powder, 410 mg (100% yield). LC/MS gave the correct molecular ion [(M+H)+=433] for the desired compound as the protonated acid.

EXAMPLE 23

2,3-Bis[(2-Chlorophenyl)Methoxy]-α-Mercaptobenzeneacetic Acid

[0392]

[0393] To a stirred solution of Example 1 Part B compound (462 mg, 1.00 mmol) in CH2Cl2 (5 mL) under argon at room temperature was added thionyl chloride (80 μL, 1.1 mmol) and then DMF (80 μL, 1.0 mmol) over 2 min. The reaction mixture was stirred for 1 h, then quenched with saturated sodium bicarbonate solution and extracted twice with CH2Cl2. The extracts were combined, dried (MgSO4) and evaporated. The residuum was immediately dissolved in EtOH (5 mL) and added to a solution prepared from thiolacetic acid (0.35 mL, 4.9 mmol) and potassium t-butoxide (539 mg, 4.8 mmol) in EtOH (5 mL). After 16 h, the reaction mixture was quenched with water and extracted three times with EtOAc. The organic extracts were combined, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 330 mg (64% yield). LC/MS gave the correct molecular ion [(M+H)+=519] for the desired compound.

[0394] To a stirred solution of part A compound (330 mg, 0.64 mmol) in nitrogen-purged THF (5 mL) at room temperature was added sodium hydroxide solution (3.0 mL, 1 M, 3.0 mmol). After 24 h, the reaction was quenched with 10% citric acid and extracted twice with EtOAc. The extracts were combined, dried (MgSO4) and evaporated to provide predominantly the title compound as a colorless oil, 255 mg (89% yield). LC/MS gave the correct molecular ion [(M+H)+=894] for the desired compound.

[0395] To a solution of Part B compound (52 mg, 0.058 mmol) in THF (2 mL) and water (2 mL) at room temperature under argon was added tributylphosphine (50 μL, 0.2 mmol). The reaction was stirred for 5 min and then purified directly by reverse phase preparative HPLC (YMC S5 ODS 20×250 mm column, acetonitrile/water−TFA elutant) to give the title compound as a colorless oil, 32 mg, 62% yield. LC/MS gave the correct molecular ion [(M+H)+=449] for the desired compound.

EXAMPLE 24

2,3-Bis[(2-Chlorophenyl)Methoxy]-α-Fluorobenzeneacetic Acid

[0396]

[0397] To a stirred solution of Example 1 Part B compound (461 mg, 1.00 mmol) in CH2Cl2 (10 mL) under argon at 0° C. was added a solution of diethylaminosulfur trifluoride [DAST] (265 μL, 2.0 mmol) in CH2Cl2 (5 mL) over 20 min. The reaction mixture was stirred for an additional 45 min, then quenched with saturated sodium bicarbonate solution and extracted twice with CH2Cl2. The extracts were combined, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a light yellow oil, 218 mg (47% yield). LC/MS gave the correct molecular ion [(M+H)+=463] for the desired compound.

[0398] To a stirred solution of part A compound (218 mg, 0.47 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature under argon was added sodium hydroxide solution (2.0 mL, 1 M, 2.0 mmol). After 14 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 5% potassium hydrogen sulfate solution. The resulting solids were collected, washed with water and air-dried to give the title compound as a white solid, 202 mg (98% yield), mp 92-94° C. LC/MS gave the correct molecular ion [(M+H)+=435] for the desired compound.

EXAMPLE 25

[0399] 3-[(2-Chlorophenyl)Methoxy]-2-Hydroxybenzoic Acid Ethyl Ester

[0400] To a stirred solution of trifluoroacetic acid (200 mL) and trifluoroacetic anhydride (100 mL) at −4° C. was added 2,3-dihydroxybenzoic acid (20.0 g, 130 mmol) over 5 min. To this slurry was added acetone (34 mL, 460 mmol) over the course of 1 h. After an additional 3 h, the reaction was allowed to warm to room temperature in situ and stirred 4 h. The resulting solution was evaporated and the resulting residue poured into ice water (300 mL). Solid sodium bicarbonate was added portionwise until the solution reached ˜pH 9. The gummy residue was extracted into EtOAc (300 mL) and the aqueous phase was extracted twice with EtOAc. The extracts were combined, washed once with brine, dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound 9.87 g (39% yield). LC/MS gave the correct molecular ion [(M+H)+=197] for the desired compound.

[0401] To a stirred solution of part A compound (3.0 g, 15.4 mmol) in DMF (26 mL) at room temperature under argon was added 2-chlorobenzyl chloride (2.3 mL, 18.2 mmol), potassium carbonate (3.2 g, 23 mmol) and tetrabutylammonium iodide (57 mg, 0.15 mmol). The mixture was heated to 50° C. and stirred for 2 h. After cooling to room temperature, the reaction was filtered through Celite® and poured into Et2O (250 mL). The solution was washed three times with water and once with brine. After drying (Na2SO4) and evaporation, the title compound was isolated and used in part C without further purification (5.47 g, >100% yield).

[0402] To a stirred solution of part B compound (5.47 g, ˜15.4 mmol) in THF (100 mL) at room temperature under argon was added a 25% solution of sodium ethoxide in ethanol (4.5 mL, 16 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was then diluted with water (400 mL) and ethyl acetate (400 mL). The suspension was treated with 50 mL of 1 N hydrochloric acid and the organic fraction was washed with brine, dried (MgSO4) and evaporated to an oil (4.65 g, 85% yield.

EXAMPLE 26

2,3-Bis[(2-Chlorophenyl)Methoxy]-α-Oxobenzeneacetic Acid

[0403]

[0404] To a stirred solution of Example 1 Part B compound (400 mg, 0.867 mmol) in DMSO (1 mL) at 90° C. was added acetic anhydride (0.1 mL, 1 mmol) over 1 h. After an additional 3 h, the reaction mixture was cooled, diluted with water and extracted three times with ether. The organic extracts were combined, washed with brine, dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound, 382 mg (96% yield). LC/MS gave the correct molecular ion [(M+Na)+=481] for the desired compound.

[0405] To a stirred solution of Part A compound (67 mg, 0.15 mmol) in THF (0.3 mL) at room temperature under argon was added sodium hydroxide solution (0.3 mL, 1 M, 0.3 mmol). After 18 h, the reaction mixture was diluted with water and extracted three times with ether. The aqueous layer was cooled to 5° C., acidified to pH 3 with 1 M hydrochloric acid and extracted three times with ether. The acidicified organic extracts were combined, dried (Na2SO4) and evaporated to provide the title compound as a white solid, 55 mg (86% yield), mp 116-118° C. LC/MS gave the correct molecular ion [(M+H)+=431] for the desired compound.

EXAMPLE 27

2,3-Bis[(2-Chlorophenyl)Methoxy]-α,α-Difluorobenzeneacetic Acid

[0406]

[0407] To a stirred solution of Example 26 Part A compound (256 mg, 0.557 mmol) in CH2Cl2 (100 μL) under argon at room temperature was added DAST (160 μL, 1.2 mmol). The reaction mixture was stirred for 22 h, the reaction mixture was quenched with water and extracted three times with CH2Cl2. The organic extracts were combined, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a white solid, 197 mg (74% yield), mp 55-57° C. LC/MS gave the correct molecular ion [(M+H)+=481] for the desired compound.

[0408] To a stirred solution of part A compound (195 mg, 0.41 mmol) in THF (2 mL) at room temperature under argon was added sodium hydroxide solution (0.6 mL, 1 M, 0.6 mmol). After 15 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 5% potassium hydrogen sulfate solution. The resulting solids were collected, washed with water and air-dried to give the title compound as a white solid, 168 mg (92% yield), mp 113-115° C. LC/MS gave the correct molecular ion [(M+H)+=453] for the desired compound.

EXAMPLES 28-336

[0409]

100

[0410] Sealable reaction vessels were each charged with potassium carbonate (32 mg, 0.23 mmol), tetrabutylammonium iodide (˜1 mg) and DMF (244 μL). A solution of Example 25 Part C compound (489 μL, 0.2 M in DMF, 0.0978 mmol) and of R-X (0.147 mmol, 0.2 M in THF) was added and the reaction vessels were agitated and heated to 60° C. After 14 h, the reactions were cooled to room temperature and EtOH (2 mL) was added to each reaction, followed by a solution of sodium hydroxide in ethanol (733 μL, 0.3 M, 0.2 mmol). The reactions were heated again at 60° C. for 5 h and cooled to room temperature. The contents of each reaction vessel were diluted with MeOH (˜2 mL) and purified by reverse phase preparative HPLC (YMC S5 ODS 20×100 mm column, MeOH/water−TFA elutant) to give the title compound. Mass spectrometric and HPLC data were collected for all compounds.

[0411] Following the above procedure, the following compounds of the invention were prepared:

1Massion typeEx.CAS NameElemental formulaSpec, m/zinferred282-[(2-Bromophenyl)methoxy]-3-C21 H16 Br Cl O4466[M + NH4][(2-chlorophenyl)methoxy]benzoicacid293-[(2-Chlorophenyl)methoxy]-2-C22 H19 Cl O4400[M + NH4][(2-methylphenyl)methoxy]benzoic acid303-[(2-Chlorophenyl)methoxy]-2-C22 H19 Cl O4400[M + NH4][(3-methylphenyl)methoxy]benzoic acid312-[(4-Bromophenyl)methoxy]-3-C21 H16 Br Cl O4466[M + NH4][(2-chlorophenyl)methoxy]benzoicacid323-[(2-Chlorophenyl)methoxy]-2-C25 H25 Cl O4442[M + NH4][[4-(1,1-dimethylethyl)phenyl]methoxy]benzoic acid333-[(2-Chlorophenyl)methoxy]-2-C22 H19 Cl O4400[M + NH4][(4-methylphenyl)methoxy]benzoic acid343-[(2-Chlorophenyl)methoxy]-2-C21 H16 Cl F O4404[M + NH4][(2-fluorophenyl)methoxy]benzoicacid353-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4422[M + NH4][(2,6-difluorophenyl)methoxy]benzoic acid363-[(2-Chlorophenyl)methoxy]-2-C21 H16 Cl F O4404[M + NH4][(3-fluorophenyl)methoxy]benzoicacid373-[(2-Chlorophenyl)methoxy]-2-C21 H16 Cl F O4404[M + NH4][(4-fluorophenyl)methoxy]benzoicacid383-[(2-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O4454[M + NH4][[3-(trifluoromethyl)phenyl]methoxy]benzoic acid393-[(2-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O4454[M + NH4][[4-(trifluoromethyl)phenyl]methoxy]benzoic acid403-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(2,6-dichlorophenyl)methoxy]benzoic acid412-[(3-Chlorophenyl)methoxy]-3-C21 H16 Cl2 O4420[M + NH4][(2-chlorophenyl)methoxy]benzoicacid423-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid432-[(2-Chloro-6-fluorophenyl)C21 H15 Cl2 F O4438[M + NH4]methoxy]-3-[(2-chlorophenyl)methoxy]benzoic acid443-[(2-Chlorophenyl)methoxy]-2-C24 H23 Cl O4428[M + NH4][(2,4,6-trimethylphenyl)methoxy]benzoic acid453-[(2-Chlorophenyl)methoxy]-2-C23 H21 Cl O4414[M + NH4][(2,5-dimethylphenyl)methoxy]benzoic acid463-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(3,4-dichlorophenyl)methoxy]benzoic acid473-[(2-Chlorophenyl)methoxy]-2-C22 H19 Cl O5416[M + NH4][(3-methoxyphenyl)methoxy]benzoic acid483-[(2-Chlorophenyl)methoxy]-2-C22 H19 Cl O5416[M + NH4][(4-methoxyphenyl)methoxy]benzoic acid493-[(2-Chlorophenyl)methoxy]-2-C28 H23 Cl O5492[M + NH4][[4-(phenylmethoxy)phenyl]methoxy]benzoic acid502-([1,1′-Biphenyl]-4-ylmethoxy)-3-C27 H21 Cl O4462[M + NH4][(2-chlorophenyl)methoxy]benzoicacid513-[(2-Chlorophenyl)methoxy]-2-C22 H16 Cl N O4411[M + NH4][(2-cyanophenyl)methoxy]benzoicacid523-[(2-Chlorophenyl)methoxy]-2-C22 H16 Cl N O4411[M + NH4][(3-cyanophenyl)methoxy]benzoicacid533-[(2-Chlorophenyl)methoxy]-2-C22 H16 Cl N O4411[M + NH4][(4-cyanophenyl)methoxy]benzoicacid543-[(2-Chlorophenyl)methoxy]-2-C25 H19 Cl O4436[M + NH4](1-naphthalenylmethoxy)benzoicacid553-[(2-Chlorophenyl)methoxy]-2-C26 H21 Cl O4450[M + NH4][(2-methyl-1-naphthalenyl)methoxy]benzoic acid563-[(2-Chlorophenyl)methoxy]-2-C25 H19 Cl O4436[M + NH4](2-naphthalenylmethoxy)benzoicacid572-[[3,4-Bis(phenylmethoxy)C35 H29 Cl O6598[M + NH4]phenyl]methoxy]-3-[(2-chlorophenyl)methoxy]benzoicacid582-[(6-Chloro-1,3-benzodioxol-5-C22 H16 Cl2 O6464[M + NH4]yl)methoxy]-3-[(2-chlorophenyl)methoxy]benzoic acid593-[(2-Chlorophenyl)methoxy]-2-C22 H18 Cl N O6445[M + NH4][(2-methyl-3-nitrophenyl)methoxy]benzoic acid603-[(2-Chlorophenyl)methoxy]-2-C21 H16 Cl N O6431[M + NH4][(2-nitrophenyl)methoxy]benzoicacid613-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl2 N O6446[M − H][(4-chloro-2-nitrophenyl)methoxy]benzoic acid623-[(2-Chlorophenyl)methoxy]-2-C21 H16 Cl N O6431[M + NH4][(3-nitrophenyl)methoxy]benzoicacid633-[(2-Chlorophenyl)methoxy]-2-C22 H18 Cl N O7461[M + NH4][(2-methoxy-5-nitrophenyl)methoxy]benzoic acid643-[(2-Chlorophenyl)methoxy]-2-C22 H18 Cl N O6445[M + NH4][(5-methyl-2-nitrophenyl)methoxy]benzoic acid653-[(2-Chlorophenyl)methoxy]-2-C21 H16 Cl N O6412[M − H][(4-nitrophenyl)methoxy]benzoicacid663-[(2-Chlorophenyl)methoxy]-2-C28 H23 Cl O6 S540[M + NH4][[2-[(phenylsulfonyl)methyl]phenyl]methoxy]benzoicacid673-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4403[M − H][(3,4-difluorophenyl)methoxy]benzoic acid683-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4422[M + NH4][(2,5-difluorophenyl)methoxy]benzoic acid692-[[3,5-Bis(trifluoromethyl)C23 H15 Cl F6 O4522[M + NH4]phenyl]methoxy]-3-[(2-chlorophenyl)methoxy]benzoicacid703-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4422[M + NH4][(3,5-difluorophenyl)methoxy]benzoic acid713-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4422[M + NH4][(2,4-difluorophenyl)methoxy]benzoic acid723-[(2-Chlorophenyl)methoxy]-2-C23 H21 Cl O4414[M + NH4][(3,5-dimethylphenyl)methoxy]benzoic acid733-[(2-Chlorophenyl)methoxy]-2-C25 H25 Cl O4442[M + NH4][(2,3,5,6-tetramethylphenyl)methoxy]benzoic acid743-[(2-Chlorophenyl)methoxy]-2-C23 H21 Cl O4395[M − H][(2,4-dimethylphenyl)methoxy]benzoic acid753-[(2-Chlorophenyl)methoxy]-2-C24 H23 Cl O4409[M − H][[4-(1-methylethyl)phenyl]methoxy]benzoic acid763-[(2-Chlorophenyl)methoxy]-2-C21 H16 Cl I O4512[M + NH4][(3-iodophenyl)methoxy]benzoicacid772-[(4-Carboxyphenyl)methoxy]-3-C22 H17 Cl O6411[M − H][(2-chlorophenyl)methoxy]benzoicacid783-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4435[M − H][(2,3-dichlorophenyl)methoxy]benzoic acid793-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(2,5-dichlorophenyl)methoxy]benzoic acid803-[(2-Chlorophenyl)methoxy]-2-C23 H21 Cl O4395[M − H][(4-ethylphenyl)methoxy]benzoicacid812-[(4-Chlorophenyl)methoxy]-3-C21 H16 Cl2 O4420[M + NH4][(2-chlorophenyl)methoxy]benzoicacid822-[(3-Bromophenyl)methoxy]-3-C21 H16 Br Cl O4466[M + NH4][(2-chlorophenyl)methoxy]benzoicacid833-[(2-Chlorophenyl)methoxy]-2-C27 H21 Cl O5478[M + NH4][(3-phenoxyphenyl)methoxy]benzoic acid843-[(2-Chlorophenyl)methoxy]-2-C22 H18 Cl F O4418[M + NH4][(2-fluoro-3-methylphenyl)methoxy]benzoic acid853-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4422[M + NH4][(2,3-difluorophenyl)methoxy]benzoic acid862-[(3-Chloro-2-C21 H15 Cl2 F O4438[M + NH4]fluorophenyl)methoxy]-3-[(2-chlorophenyl)methoxy]benzoicacid873-[(2-Chlorophenyl)methoxy]-2-C29 H19 Cl O6516[M + NH4][(9,10-dihydro-9,10-dioxo-2-anthracenyl)methoxy]benzoic acid883-[(2-Chlorophenyl)methoxy]-2-C22 H18 Cl N O6445[M + NH4][(4-methyl-3-nitrophenyl)methoxy]benzoic acid892-[(3-Benzoylphenyl)methoxy]-3-C28 H21 Cl O5490[M + NH4][(2-chlorophenyl)methoxy]benzoicacid903-[(2-Chlorophenyl)methoxy]-2-C21 H15 Br2 Cl O4544[M + NH4][(3,5-dibromophenyl)methoxy]benzoic acid913-[(2-Chlorophenyl)methoxy]-2-C22 H19 Cl O5416[M + NH4][(2-methoxyphenyl)methoxy]benzoic acid923-[(2-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(3,5-dichlorophenyl)methoxy]benzoic acid933-[(2-Chlorophenyl)methoxy]-2-C22 H15 Cl F4 O4472[M + NH4][[2-fluoro-5-(trifluoromethyl)phenyl]methoxy]benzoic acid943-[(2-Chlorophenyl)methoxy]-2-C22 H15 Cl F4 O4472[M + NH4][[3-fluoro-5-(trifluoromethyl)phenyl]methoxy]benzoic acid953-[(2-Chlorophenyl)methoxy]-2-C22 H15 Cl F4 O4472[M + NH4][[4-fluoro-2-(trifluoromethyl)phenyl]methoxy]benzoic acid963-[(2-Chlorophenyl)methoxy]-2-C22 H15 Cl F4 O4472[M + NH4][[4-fluoro-3-(trifluoromethyl)phenyl]methoxy]benzoic acid973-[(2-Chlorophenyl)methoxy]-2-C21 H14 Cl F3 O4440[M + NH4][(2,3,6-trifluorophenyl)methoxy]benzoic acid983-[(2-Chlorophenyl)methoxy]-2-C21 H14 Cl F3 O4440[M + NH4][(2,4,5-trifluorophenyl)methoxy]benzoic acid993-[(2-Chlorophenyl)methoxy]-2-C21 H14 Cl F3 O4440[M + NH4][(2,4,6-trifluorophenyl)methoxy]benzoic acid1003-[(2-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O5470[M + NH4][[4-(trifluoromethoxy)phenyl]methoxy]benzoic acid1013-[(2-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O5470[M + NH4][[3-(trifluoromethoxy)phenyl]methoxy]benzoic acid1023-[(2-Chlorophenyl)methoxy]-2-C23 H21 Cl O6446[M + NH4][(3,5-dimethoxyphenyl)methoxy]benzoic acid1032-([1,1′-Biphenyl]-2-ylmethoxy)-3-C27 H21 Cl O4462[M + NH4][(2-chlorophenyl)methoxy]benzoicacid1043-[(2-Chlorophenyl)methoxy]-2-C22 H19 Cl O6 S464[M + NH4][[4-(methylsulfonyl)phenyl]methoxy]benzoic acid1053-[(2-Chlorophenyl)methoxy]-2-C23 H20 Cl N O8491[M + NH4][(4,5-dimethoxy-2-nitrophenyl)methoxy]benzoic acid1063-[(2-Chlorophenyl)methoxy]-2-C21 H16 Cl I O4512[M + NH4][(4-iodophenyl)methoxy]benzoicacid1072-[(2-Bromophenyl)methoxy]-3-C21 H15 Br Cl2 O4499[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid1083-[(2,4-Dichlorophenyl)methoxy]-C22 H18 Cl2 O4453[M + NH4]2-[(2-methylphenyl)methoxy]benzoic acid1093-[(2,4-Dichlorophenyl)methoxy]-C22 H18 Cl2 O4434[M + NH4]2-[(3-methylphenyl)methoxy]benzoic acid1102-[(4-Bromophenyl)methoxy]-3-C21 H15 Br Cl2 O4498[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid1113-[(2,4-Dichlorophenyl)methoxy]-C25 H24 Cl2 O4476[M + NH4]2-[[4-(1,1-dimethylethyl)phenyl]methoxy]benzoic acid1123-[(2,4-Dichlorophenyl)methoxy]-C22 H18 Cl2 O4434[M + NH4]2-[(4-methylphenyl)methoxy]benzoic acid1133-[(2,4-Dichlorophenyl)methoxy]-C21 H15 Cl2 F O4438[M + NH4]2-[(2-fluorophenyl)methoxy]benzoic acid1143-[(2,4-Dichlorophenyl)methoxy]-C21 H14 Cl2 F2 O4456[M + NH4]2-[(2,6-difluorophenyl)methoxy]benzoic acid1153-[(2,4-Dichlorophenyl)methoxy]-C21 H15 Cl2 F O4438[M + NH4]2-[(3-fluorophenyl)methoxy]benzoic acid1163-[(2,4-Dichlorophenyl)methoxy]-C21 H15 Cl2 F O4438[M + NH4]2-[(4-fluorophenyl)methoxy]benzoic acid1173-[(2,4-Dichlorophenyl)methoxy]-C22 H15 Cl2 F3 O4488[M + NH4]2-[[3-(trifluoromethyl)phenyl]methoxy]benzoic acid1183-[(2,4-Dichlorophenyl)methoxy]-C22 H15 Cl2 F3 O4488[M + NH4]2-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid1192-[(2,6-Dichlorophenyl)methoxy]-C21 H14 Cl4 O4488[M + NH4]3-[(2,4-dichlorophenyl)methoxy]benzoic acid1202-[(3-Chlorophenyl)methoxy]-3-C21 H15 Cl3 O4454[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid1212-[(2-Chlorophenyl)methoxy]-3-C21 H15 Cl3 O4454[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid1222-[(2-Chloro-6-C21 H14 Cl3 F O4472[M + NH4]fluorophenyl)methoxy]-3-[(2,4-dichlorophenyl)methoxy]benzoicacid1233-[(2,4-Dichlorophenyl)methoxy]-C23 H20 Cl2 O4448[M + NH4]2-[(2,5-dimethylphenyl)methoxy]benzoic acid1242-[(3,4-Dichlorophenyl)methoxy]-C21 H14 Cl4 O4488[M + NH4]3-[(2,4-dichlorophenyl)methoxy]benzoic acid1252-([1,1′-Biphenyl]-4-ylmethoxy)-3-C27 H20 Cl2 O4496[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid1262-[(2-Cyanophenyl)methoxy]-3-C22 H15 Cl2 N O4445[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid1273-[(2,4-Dichlorophenyl)methoxy]-C25 H18 Cl2 O4470[M + NH4]2-(1-naphthalenylmethoxy)benzoic acid1283-[(2,4-Dichlorophenyl)methoxy]-C26 H20 Cl2 O4484[M + NH4]2-[(2-methyl-1-naphthalenyl)methoxy]benzoic acid1293-[(2,4-Dichlorophenyl)methoxy]-C25 H18 Cl2 O4470[M + NH4]2-(2-naphthalenylmethoxy)benzoic acid1302-[(6-Chloro-1,3-benzodioxol-5-C22 H15 Cl3 O6498[M + NH4]yl)methoxy]-3-[(2,4-dichlorophenyl)methoxy]benzoicacid1313-[(2,4-Dichlorophenyl)methoxy]-C22 H17 Cl2 N O6479[M + NH4]2-[(2-methyl-3-nitrophenyl)methoxy]benzoic acid1323-[(2,4-Dichlorophenyl)methoxy]-C21 H15 Cl2 N O6465[M + NH4]2-[(3-nitrophenyl)methoxy]benzoicacid1333-[(2,4-Dichlorophenyl)methoxy]-C22 H17 Cl2 N O7495[M + NH4]2-[(2-methoxy-5-nitrophenyl)methoxy]benzoic acid1343-[(2,4-Dichlorophenyl)methoxy]-C28 H22 Cl2 O6 S574[M + NH4]2-[[2-[(phenylsulfonyl)methyl]phenyl]methoxy]benzoicacid1353-[(2,4-Dichlorophenyl)methoxy]-C21 H14 Cl2 F2 O4456[M + NH4]2-[(3,4-difluorophenyl)methoxy]benzoic acid1363-[(2,4-Dichlorophenyl)methoxy]-C21 H14 Cl2 F2 O4456[M + NH4]2-[(2,5-difluorophenyl)methoxy]benzoic acid1372-[[3,5-Bis(trifluoromethyl)C23 H14 Cl2 F6 O4556[M + NH4]phenyl]methoxy]-3-[(2,4-dichlorophenyl)methoxy]benzoicacid1383-[(2,4-Dichlorophenyl)methoxy]-C21 H14 Cl2 F2 O4456[M + NH4]2-[(3,5-difluorophenyl)methoxy]benzoic acid1393-[(2,4-Dichlorophenyl)methoxy]-C21 H14 Cl2 F2 O4456[M + NH4]2-[(2,4-difluorophenyl)methoxy]benzoic acid1403-[(2,4-Dichlorophenyl)methoxy]-C23 H20 Cl2 O4448[M + NH4]2-[(3,5-dimethylphenyl)methoxy]benzoic acid1413-[(2,4-Dichlorophenyl)methoxy]-C22 H15 Cl2 F3 O4488[M + NH4]2-[[2-(trifluoromethyl)phenyl]methoxy]benzoic acid1423-[(2,4-Dichlorophenyl)methoxy]-C23 H20 Cl2 O4448[M + NH4]2-[(2,4-dimethylphenyl)methoxy]benzoic acid1433-[(2,4-Dichlorophenyl)methoxy]-C21 H15 Cl2 I O4546[M + NH4]2-[(3-iodophenyl)methoxy]benzoicacid1442-[(2,3-Dichlorophenyl)methoxy]-C21 H14 Cl4 O4488[M + NH4]3-[(2,4-dichlorophenyl)methoxy]benzoic acid1452-[(2,5-Dichlorophenyl)methoxy]-C21 H14 Cl4 O4488[M + NH4]3-[(2,4-dichlorophenyl)methoxy]benzoic acid1463-[(2,4-Dichlorophenyl)methoxy]-C23 H20 Cl2 O4448[M + NH4]2-[(4-ethylphenyl)methoxy]benzoic acid1472-[(4-Chlorophenyl)methoxy]-3-C21 H15 Cl3 O4454[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid1482-[(3-Bromophenyl)methoxy]-3-C21 H15 Br Cl2 O4498[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid1493-[(2,4-Dichlorophenyl)methoxy]-C27 H20 Cl2 O5512[M + NH4]2-[(3-phenoxyphenyl)methoxy]benzoic acid1503-[(2,4-Dichlorophenyl)methoxy]-C22 H17 Cl2 F O4452[M + NH4]2-[(2-fluoro-3-methylphenyl)methoxy]benzoic acid1513-[(2,4-Dichlorophenyl)methoxy]-C21 H14 Cl2 F2 O4456[M + NH4]2-[(2,3-difluorophenyl)methoxy]benzoic acid1522-[(3-Chloro-2-fluorophenyl)C21 H14 Cl3 F O4472[M + NH4]methoxy]-3-[(2,4-dichlorophenyl)methoxy]benzoic acid1533-[(2,4-Dichlorophenyl)methoxy]-C22 H17 Cl2 N O6479[M + NH4]2-[(4-methyl-3-nitrophenyl)methoxy]benzoic acid1542-[(3-Benzoylphenyl)methoxy]-3-C28 H20 Cl2 O5524[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid1552-[(3,5-Dibromophenyl)methoxy]-C21 H14 Br2 Cl2 O4576[M + NH4]3-[(2,4-dichlorophenyl)methoxy]benzoic acid1562-[(6-Chloro-4H-1,3-benzodioxin-C23 H17 Cl3 O6512[M + NH4]8-yl)methoxy]-3-[(2,4-dichloro-phenyl)methoxy]benzoic acid1572-[(3,5-Dichlorophenyl)methoxy]-C21 H14 Cl4 O4488[M + NH4]3-[(2,4-dichlorophenyl)methoxy]benzoic acid1583-[(2,4-Dichlorophenyl)methoxy]-C22 H14 Cl2 F4 O4506[M + NH4]2-[[2-fluoro-5-(trifluoromethyl)phenyl]methoxy]benzoic acid1593-[(2,4-Dichlorophenyl)methoxy]-C22 H14 Cl2 F4 O4506[M + NH4]2-[[3-fluoro-5-(trifluoromethyl)phenyl]methoxy]benzoic acid1603-[(2,4-Dichlorophenyl)methoxy]-C22 H14 Cl2 F4 O4506[M + NH4]2-[[4-fluoro-2-(trifluoromethyl)phenyl]methoxy]benzoic acid1613-[(2,4-Dichlorophenyl)methoxy]-C22 H14 Cl2 F4 O4506[M + NH4]2-[[4-fluoro-3-(trifluoromethyl)phenyl]methoxy]benzoic acid1623-[(2,4-Dichlorophenyl)methoxy]-C21 H13 Cl2 F3 O4474[M + NH4]2-[(2,3,6-trifluorophenyl)methoxy]benzoic acid1633-[(2,4-Dichlorophenyl)methoxy]-C21 H13 Cl2 F3 O4474[M + NH4]2-[(2,4,5-trifluorophenyl)methoxy]benzoic acid1643-[(2,4-Dichlorophenyl)methoxy]-C21 H13 Cl2 F3 O4474[M + NH4]2-[(2,4,6-trifluorophenyl)methoxy]benzoic acid1653-[(2,4-Dichlorophenyl)methoxy]-C22 H15 Cl2 F3 O5504[M + NH4]2-[[4-(trifluoromethoxy)phenyl]methoxy]benzoic acid1663-[(2,4-Dichlorophenyl)methoxy]-C22 H15 Cl2 F3 O5504[M + NH4]2-[[3-(trifluoromethoxy)phenyl]methoxy]benzoic acid1673-[(2,4-Dichlorophenyl)methoxy]-C23 H20 Cl2 O6480[M + NH4]2-[(3,5-dimethoxyphenyl)methoxy]benzoic acid1682-([1,1′-Biphenyl]-2-ylmethoxy)-3-C27 H20 Cl2 O4496[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid1693-[(2,4-Dichlorophenyl)methoxy]-C22 H18 Cl2 O6 S498[M + NH4]2-[[4-(methylsulfonyl)phenyl]methoxy]benzoic acid1703-[(2,4-Dichlorophenyl)methoxy]-C21 H15 Cl2 I O4546[M + NH4]2-[(4-iodophenyl)methoxy]benzoicacid1713-[(2,4-Dichlorophenyl)methoxy]-C22 H18 Cl2 O5450[M + NH4]2-[(3-methoxyphenyl)methoxy]benzoic acid1723-[(2-Bromophenyl)methoxy]-2-C22 H19 Br O4444[M + NH4](1-phenylethoxy)benzoic acid1732,3-Bis[(2-bromophenyl)C21 H16 Br2 O4508[M + NH4]methoxy]benzoic acid1743-[(2-Bromophenyl)methoxy]-2-C22 H19 Br O4444[M + NH4][(2-methylphenyl)methoxy]benzoic acid1753-[(2-Bromophenyl)methoxy]-2-C22 H19 Br O4444[M + NH4][(3-methylphenyl)methoxy]benzoic acid1762-[(4-Bromophenyl)methoxy]-3-C21 H16 Br2 O4508[M + NH4][(2-bromophenyl)methoxy]benzoicacid1773-[(2-Bromophenyl)methoxy]-2-C25 H25 Br O4486[M + NH4][[4-(1,1-dimethylethyl)phenyl]methoxy]benzoic acid1783-[(2-Bromophenyl)methoxy]-2-C22 H19 Br O4444[M + NH4][(4-methylphenyl)methoxy]benzoic acid1793-[(2-Bromophenyl)methoxy]-2-C21 H16 Br F O4448[M + NH4][(2-fluorophenyl)methoxy]benzoicacid1803-[(2-Bromophenyl)methoxy]-2-C21 H15 Br F2 O4466[M + NH4][(2,6-difluorophenyl)methoxy]benzoic acid1813-[(2-Bromophenyl)methoxy]-2-C21 H16 Br F O4448[M + NH4][(4-fluorophenyl)methoxy]benzoicacid1823-[(2-Bromophenyl)methoxy]-2-C22 H16 Br F3 O4498[M + NH4][[4-(trifluoromethyl)phenyl]methoxy]benzoic acid1833-[(2-Bromophenyl)methoxy]-2-C21 H15 Br Cl2 O4498[M + NH4][(2,6-dichlorophenyl)methoxy]benzoic acid1843-[(2-Bromophenyl)methoxy]-2-C21 H16 Br Cl O4464[M + NH4][(3-chlorophenyl)methoxy]benzoicacid1853-[(2-Bromophenyl)methoxy]-2-C21 H16 Br Cl O4464[M + NH4][(2-chlorophenyl)methoxy]benzoicacid1863-[(2-Bromophenyl)methoxy]-2-C21 H15 Br Cl2 O4498[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid1873-[(2-Bromophenyl)methoxy]-2-C21 H15 Br Cl F O4482[M + NH4][(2-chloro-6-fluorophenyl)methoxy]benzoic acid1883-[(2-Bromophenyl)methoxy]-2-C21 H16 Br I O4556[M + NH4][(2-iodophenyl)methoxy]benzoicacid1893-[(2-Bromophenyl)methoxy]-2-C24 H23 Br O4472[M + NH4][(2,4,6-trimethylphenyl)methoxy]benzoic acid1903-[(2-Bromophenyl)methoxy]-2-C23 H21 Br O4458[M + NH4][(2,5-dimethylphenyl)methoxy]benzoic acid1913-[(2-Bromophenyl)methoxy]-2-C21 H15 Br Cl2 O4498[M + NH4][(3,4-dichlorophenyl)methoxy]benzoic acid1922-([1,1′-Biphenyl]-4-ylmethoxy)-3-C27 H21 Br O4506[M + NH4][(2-bromophenyl)methoxy]benzoicacid1933-[(2-Bromophenyl)methoxy]-2-C25 H19 Br O4480[M + NH4](1-naphthalenylmethoxy)benzoicacid1943-[(2-Bromophenyl)methoxy]-2-C25 H19 Br O4480[M + NH4](2-naphthalenylmethoxy)benzoicacid1952-[[3,4-Bis(phenylmethoxy)C35 H29 Br O6642[M + NH4]phenyl]methoxy]-3-[(2-bromophenyl)methoxy]benzoicacid1963-[(2-Bromophenyl)methoxy]-2-C22 H16 Br Cl O6508[M + NH4][(6-chloro-1,3-benzodioxol-5-yl)methoxy]benzoic acid1973-[(2-Bromophenyl)methoxy]-2-C21 H16 Br N O6475[M + NH4][(3-nitrophenyl)methoxy]benzoicacid1983-[(2-Bromophenyl)methoxy]-2-C22 H18 Br N O7505[M + NH4][(2-methoxy-5-nitrophenyl)methoxy]benzoic acid1993-[(2-Bromophenyl)methoxy]-2-C21 H15 Br F2 O4466[M + NH4][(3,4-difluorophenyl)methoxy]benzoic acid2003-[(2-Bromophenyl)methoxy]-2-C21 H15 Br F2 O4466[M + NH4][(2,5-difluorophenyl)methoxy]benzoic acid2012-[[3,5-Bis(trifluoromethyl)C23 H15 Br F6 O4566[M + NH4]phenyl]methoxy]-3-[(2-bromophenyl)methoxy]benzoicacid2023-[(2-Bromophenyl)methoxy]-2-C21 H15 Br F2 O4466[M + NH4][(3,5-difluorophenyl)methoxy]benzoicacid2033-[(2-Bromophenyl)methoxy]-2-C23 H21 Br O4446[M + NH4][(3,5-dimethylphenyl)methoxy]benzoicacid2043-[(2-Bromophenyl)methoxy]-2-[[2-C22 H16 Br F3 O4498[M + NH4](trifluoromethyl)phenyl]methoxy]benzoic acid2053-[(2-Bromophenyl)methoxy]-2-C21 H16 Br I O4556[M + NH4][(3-iodophenyl)methoxy]benzoicacid2063-[(2-Bromophenyl)methoxy]-2-C21 H15 Br Cl2 O4498[M + NH4][(2,3-dichlorophenyl)methoxy]benzoic acid2073-[(2-Bromophenyl)methoxy]-2-C21 H15 Br Cl2 O4498[M + NH4][(2,5-dichlorophenyl)methoxy]benzoic acid2083-[(2-Bromophenyl)methoxy]-2-C23 H21 Br O4458[M + NH4][(4-ethylphenyl)methoxy]benzoicacid2093-[(2-Bromophenyl)methoxy]-2-C21 H16 Br Cl O4464[M + NH4][(4-chlorophenyl)methoxy]benzoicacid2102-[(3-Bromophenyl)methoxy]-3-C21 H16 Br2 O4508[M + NH4][(2-bromophenyl)methoxy]benzoicacid2113-[(2-Bromophenyl)methoxy]-2-C27 H21 Br O5522[M + NH4][(3-phenoxyphenyl)methoxy]benzoic acid2123-[(2-Bromophenyl)methoxy]-2-C22 H18 Br F O4462[M + NH4][(2-fluoro-3-methylphenyl)methoxy]benzoic acid2133-[(2-Bromophenyl)methoxy]-2-C21 H15 Br F2 O4466[M + NH4][(2,3-difluorophenyl)methoxy]benzoic acid2143-[(2-Bromophenyl)methoxy]-2-C21 H15 Br Cl F O4482[M + NH4][(3-chloro-2-fluorophenyl)methoxy]benzoic acid2153-[(2-Bromophenyl)methoxy]-2-C22 H18 Br N O6489[M + NH4][(4-methyl-3-nitrophenyl)methoxy]benzoic acid2162-[(3-Benzoylphenyl)methoxy]-3-C28 H21 Br O5534[M + NH4][(2-bromophenyl)methoxy]benzoicacid2173-[(2-Bromophenyl)methoxy]-2-C21 H15 Br3 O4586[M + NH4][(3,5-dibromophenyl)methoxy]benzoic acid2183-[(2-Bromophenyl)methoxy]-2-C23 H18 Br Cl O6522[M + NH4][(6-chloro-4H-1,3-benzodioxin-8-yl)methoxy]benzoic acid2193-[(2-Bromophenyl)methoxy]-2-C22 H15 Br F4 O4516[M + NH4][[2-fluoro-5-(trifluoromethyl)phenyl]methoxy]benzoic acid2203-[(2-Bromophenyl)methoxy]-2-C22 H15 Br F4 O4516[M + NH4][[3-fluoro-5-(trifluoromethyl)phenyl]methoxy]benzoic acid2213-[(2-Bromophenyl)methoxy]-2-C22 H15 Br F4 O4516[M + NH4][[4-fluoro-2-(trifluoromethyl)phenyl]methoxy]benzoic acid2223-[(2-Bromophenyl)methoxy]-2-C22 H15 Br F4 O4516[M + NH4][[4-fluoro-3-(trifluoromethyl)phenyl]methoxy]benzoic acid2233-[(2-Bromophenyl)methoxy]-2-C21 H14 Br F3 O4484[M + NH4][(2,3,6-trifluorophenyl)methoxy]benzoic acid2243-[(2-Bromophenyl)methoxy]-2-C21 H14 Br F3 O4484[M + NH4][(2,4,5-trifluorophenyl)methoxy]benzoic acid2253-[(2-Bromophenyl)methoxy]-2-C21 H14 Br F3 O4484[M + NH4][(2,4,6-trifluorophenyl)methoxy]benzoic acid2263-[(2-Bromophenyl)methoxy]-2-C22 H16 Br F3 O5514[M + NH4][[4-(trifluoromethoxy)phenyl]methoxy]benzoic acid2273-[(2-Bromophenyl)methoxy]-2-C22 H16 Br F3 O5514[M + NH4][[3-(trifluoromethoxy)phenyl]methoxy]benzoic acid2283-[(2-Bromophenyl)methoxy]-2-C23 H21 Br O6490[M + NH4][(3,5-dimethoxyphenyl)methoxy]benzoic acid2292-([1,1′-Biphenyl]-2-ylmethoxy)-3-C27 H21 Br O4506[M + NH4][(2-bromophenyl)methoxy]benzoicacid2303-[(2-Bromophenyl)methoxy]-2-C22 H19 Br O6 S508[M + NH4][[4-(methylsulfonyl)phenyl]methoxy]benzoic acid2313-[(2-Bromophenyl)methoxy]-2-C21 H16 Br I O4556[M + NH4][(4-iodophenyl)methoxy]benzoicacid2323-[(2-Bromophenyl)methoxy]-2-C22 H19 Br O5460[M + NH4][(3-methoxyphenyl)methoxy]benzoic acid2333-[(2-Bromophenyl)methoxy]-2-C18 H19 Br O4396[M + NH4](2-methylpropoxy)benzoic acid2343-[(2-Bromophenyl)methoxy]-2-C16 H15 Br O4368[M + NH4]ethoxybenzoic acid2353-[(2-Bromophenyl)methoxy]-2-C18 H19 Br O4396[M + NH4]butoxybenzoic acid2363-[(2-Bromophenyl)methoxy]-2-C20 H23 Br O4424[M + NH4](hexyloxy)benzoic acid2373-[(2-Bromophenyl)methoxy]-2-C22 H27 Br O4452[M + NH4](octyloxy)benzoic acid2383-[(2-Bromophenyl)methoxy]-2-C21 H23 Br O4436[M + NH4](cyclohexylmethoxy)benzoic acid2393-[(3-Chlorophenyl)methoxy]-2-C21 H17 Cl O4386[M + NH4](phenylmethoxy)benzoic acid2402-[(2-Bromophenyl)methoxy]-3-C21 H16 Br Cl O4464[M + NH4][(3-chlorophenyl)methoxy]benzoicacid2413-[(3-Chlorophenyl)methoxy]-2-C22 H19 Cl O4400[M + NH4][(2-methylphenyl)methoxy]benzoic acid2423-[(3-Chlorophenyl)methoxy]-2-C22 H19 Cl O4400[M + NH4][(3-methylphenyl)methoxy]benzoic acid2432-[(4-Bromophenyl)methoxy]-3-C21 H16 Br Cl O4464[M + NH4][(3-chlorophenyl)methoxy]benzoicacid2443-[(3-Chlorophenyl)methoxy]-2-C25 H25 Cl O4442[M + NH4][[4-(1,1-dimethylethyl)phenyl]methoxy]benzoic acid2453-[(3-Chlorophenyl)methoxy]-2-C22 H19 Cl O4400[M + NH4][(4-methylphenyl)methoxy]benzoic acid2463-[(3-Chlorophenyl)methoxy]-2-C21 H16 Cl F O4404[M + NH4][(2-fluorophenyl)methoxy]benzoicacid2473-[(3-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4422[M + NH4][(2,6-difluorophenyl)methoxy]benzoic acid2483-[(3-Chlorophenyl)methoxy]-2-C21 H16 Cl F O4404[M + NH4][(3-fluorophenyl)methoxy]benzoicacid2493-[(3-Chlorophenyl)methoxy]-2-C21 H16 Cl F O4404[M + NH4][(4-fluorophenyl)methoxy]benzoicacid2503-[(3-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O4454[M + NH4][[3-(trifluoromethyl)phenyl]methoxy]benzoic acid2513-[(3-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O4454[M + NH4][[4-(trifluoromethyl)phenyl]methoxy]benzoic acid2523-[(3-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(2,6-dichlorophenyl)methoxy]benzoic acid2532-[(2-Chlorophenyl)methoxy]-3-C21 H16 Cl2 O4420[M + NH4][(3-chlorophenyl)methoxy]benzoicacid2543-[(3-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(2,4-dichlorophenyl)methoxy]benzoic acid2552-[(2-Chloro-6-C21 H15 Cl2 F O4438[M + NH4]fluorophenyl)methoxy]-3-[(3-chlorophenyl)methoxy]benzoicacid2563-[(3-Chlorophenyl)methoxy]-2-C21 H16 Cl I O4512[M + NH4][(2-iodophenyl)methoxy]benzoicacid2573-[(3-Chlorophenyl)methoxy]-2-C23 H21 Cl O4414[M + NH4][(2,5-dimethylphenyl)methoxy]benzoic acid2583-[(3-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(3,4-dichlorophenyl)methoxy]benzoic acid2593-[(3-Chlorophenyl)methoxy]-2-C28 H23 Cl O5492[M + NH4][[4-(phenylmethoxy)phenyl]methoxy]benzoic acid2602-([1,1′-Biphenyl]-4-ylmethoxy)-3-C27 H21 Cl O4462[M + NH4][(3-chlorophenyl)methoxy]benzoicacid2613-[(3-Chlorophenyl)methoxy]-2-C22 H16 Cl N O4411[M + NH4][(2-cyanophenyl)methoxy]benzoicacid2623-[(3-Chlorophenyl)methoxy]-2-C25 H19 Cl O4436[M + NH4](1-naphthalenylmethoxy)benzoicacid2633-[(3-Chlorophenyl)methoxy]-2-C26 H21 Cl O4450[M + NH4][(2-methyl-1-naphthalenyl)methoxy]benzoic acid2643-[(3-Chlorophenyl)methoxy]-2-C25 H19 Cl O4436[M + NH4](2-naphthalenylmethoxy)benzoicacid2652-[(6-Chloro-1,3-benzodioxol-5-C22 H16 Cl2 O6464[M + NH4]yl)methoxy]-3-[(3-chlorophenyl)methoxy]benzoic acid2663-[(3-Chlorophenyl)methoxy]-2-C22 H18 Cl N O6444[M + NH4][(2-methyl-3-nitrophenyl)methoxy]benzoic acid2673-[(3-Chlorophenyl)methoxy]-2-C21 H16 Cl N O6431[M + NH4][(3-nitrophenyl)methoxy]benzoicacid2683-[(3-Chlorophenyl)methoxy]-2-C22 H18 Cl N O7461[M + NH4][(2-methoxy-5-nitrophenyl)methoxy]benzoic acid2693-[(3-Chlorophenyl)methoxy]-2-C28 H23 Cl O6 S540[M + NH4][[2-[(phenylsulfonyl)methyl]phenyl]methoxy]benzoicacid2703-[(3-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4422[M + NH4][(2,5-difluorophenyl)methoxy]benzoic acid2713-[(3-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4422[M + NH4][(3,5-difluorophenyl)methoxy]benzoic acid2723-[(3-Chlorophenyl)methoxy]-2-C23 H21 Cl O4414[M + NH4][(3,5-dimethylphenyl)methoxy]benzoic acid2733-[(3-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O4454[M + NH4][[2-(trifluoromethyl)phenyl]methoxy]benzoic acid2743-[(3-Chlorophenyl)methoxy]-2-C21 H16 Cl I O4512[M + NH4][(3-iodophenyl)methoxy]benzoicacid2753-[(3-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(2,3-dichlorophenyl)methoxy]benzoic acid2763-[(3-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(2,5-dichlorophenyl)methoxy]benzoic acid2772-[(4-Chlorophenyl)methoxy]-3-C21 H16 Cl2 O4420[M + NH4][(3-chlorophenyl)methoxy]benzoicacid2782-[(3-Bromophenyl)methoxy]-3-C21 H16 Br Cl O4464[M + NH4][(3-chlorophenyl)methoxy]benzoicacid2793-[(3-Chlorophenyl)methoxy]-2-C27 H21 Cl O5478[M + NH4][(3-phenoxyphenyl)methoxy]benzoic acid2803-[(3-Chlorophenyl)methoxy]-2-C22 H18 Cl F O4418[M + NH4][(2-fluoro-3-methylphenyl)methoxy]benzoic acid2813-[(3-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4422[M + NH4][(2,3-difluorophenyl)methoxy]benzoic acid2822-[(3-Chloro-2-C21 H15 Cl2 F O4438[M + NH4]fluorophenyl)methoxy]-3-[(3-chlorophenyl)methoxy]benzoicacid2833-[(3-Chlorophenyl)methoxy]-2-C22 H18 Cl N O6444[M + NH4][(4-methyl-3-nitrophenyl)methoxy]benzoic acid2842-[(3-Benzoylphenyl)methoxy]-3-C28 H21 Cl O5490[M + NH4][(3-chlorophenyl)methoxy]benzoicacid2853-[(3-Chlorophenyl)methoxy]-2-C21 H15 Br2 Cl O4542[M + NH4][(3,5-dibromophenyl)methoxy]benzoic acid2862-[(6-Chloro-4H-1,3-benzodioxin-C23 H18 Cl2 O6478[M + NH4]8-yl)methoxy]-3-[(3-chlorophenyl)methoxy]benzoic acid2873-[(3-Chlorophenyl)methoxy]-2-C22 H19 Cl O5416[M + NH4][(2-methoxyphenyl)methoxy]benzoic acid2883-[(3-Chlorophenyl)methoxy]-2-C22 H15 Cl F4 O4472[M + NH4][[2-fluoro-5-(trifluoromethyl)phenyl]methoxy]benzoic acid2893-[(3-Chlorophenyl)methoxy]-2-C22 H15 Cl F4 O4472[M + NH4][[3-fluoro-5-(trifluoromethyl)phenyl]methoxy]benzoic acid2903-[(3-Chlorophenyl)methoxy]-2-C22 H15 Cl F4 O4472[M + NH4][[4-fluoro-2-(trifluoromethyl)phenyl]methoxy]benzoic acid2913-[(3-Chlorophenyl)methoxy]-2-C22 H15 Cl F4 O4472[M + NH4][[4-fluoro-3-(trifluoromethyl)phenyl]methoxy]benzoic acid2923-[(3-Chlorophenyl)methoxy]-2-C21 H14 Cl F3 O4440[M + NH4][(2,3,6-trifluorophenyl)methoxy]benzoic acid2933-[(3-Chlorophenyl)methoxy]-2-C21 H14 Cl F3 O4440[M + NH4][(2,4,5-trifluorophenyl)methoxy]benzoic acid2943-[(3-Chlorophenyl)methoxy]-2-C21 H14 Cl F3 O4440[M + NH4][(2,4,6-trifluorophenyl)methoxy]benzoic acid2953-[(3-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O5470[M + NH4][[4-(trifluoromethoxy)phenyl]methoxy]benzoic acid2963-[(3-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O5470[M + NH4][[3-(trifluoromethoxy)phenyl]methoxy]benzoic acid2973-[(3-Chlorophenyl)methoxy]-2-C23 H21 Cl O6446[M + NH4][(3,5-dimethoxyphenyl)methoxy]benzoic acid2982-([1,1′-Biphenyl]-2-ylmethoxy)-3-C27 H21 Cl O4462[M + NH4][(3-chlorophenyl)methoxy]benzoicacid2993-[(3-Chlorophenyl)methoxy]-2-C22 H19 Cl O6 S464[M + NH4][[4-(methylsulfonyl)phenyl]methoxy]benzoic acid3003-[(3-Chlorophenyl)methoxy]-2-C22 H19 Cl O5416[M + NH4][(3-methoxyphenyl)methoxy]benzoic acid3013-[(3-Chlorophenyl)methoxy]-2-C18 H19 Cl O4352[M + NH4](2-methylpropoxy)benzoic acid3022-Butoxy-3-[(3-chlorophenyl)C18 H19 Cl O4352[M + NH4]methoxy]benzoic acid3033-[(3-Chlorophenyl)methoxy]-2-C20 H23 Cl O4380[M + NH4](hexyloxy)benzoic acid3042-[(2-Bromophenyl)methoxy]-3-C21 H16 Br Cl O4464[M + NH4][(4-chlorophenyl)methoxy]benzoicacid3052-[(4-Bromophenyl)methoxy]-3-C21 H16 Br Cl O4464[M + NH4][(4-chlorophenyl)methoxy]benzoicacid3063-[(4-Chlorophenyl)methoxy]-2-C25 H25 Cl O4442[M + NH4][[4-(1,1-dimethylethyl)phenyl]methoxy]benzoic acid3073-[(4-Chlorophenyl)methoxy]-2-C22 H19 Cl O4400[M + NH4][(4-methylphenyl)methoxy]benzoic acid3083-[(4-Chlorophenyl)methoxy]-2-C21 H16 Cl F O4404[M + NH4][(2-fluorophenyl)methoxy]benzoicacid3093-[(4-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4422[M + NH4][(2,6-difluorophenyl)methoxy]benzoic acid3103-[(4-Chlorophenyl)methoxy]-2-C21 H16 Cl F O4404[M + NH4][(3-fluorophenyl)methoxy]benzoicacid3113-[(4-Chlorophenyl)methoxy]-2-C21 H16 Cl F O4404[M + NH4][(4-fluorophenyl)methoxy]benzoicacid3123-[(4-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O4454[M + NH4][[3-(trifluoromethyl)phenyl]methoxy]benzoic acid3133-[(4-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O4454[M + NH4][[4-(trifluoromethyl)phenyl]methoxy]benzoic acid3143-[(4-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(2,6-dichlorophenyl)methoxy]benzoic acid3152-[(3-Chlorophenyl)methoxy]-3-C21 H16 Cl2 O4420[M + NH4][(4-chlorophenyl)methoxy]benzoicacid3162-[(2-Chloro-6-C21 H15 Cl2 F O4438[M + NH4]fluorophenyl)methoxy]-3-[(4-chlorophenyl)methoxy]benzoicacid3173-[(4-Chlorophenyl)methoxy]-2-C21 H16 Cl I O4512[M + NH4][(2-iodophenyl)methoxy]benzoicacid3183-[(4-Chlorophenyl)methoxy]-2-C23 H21 Cl O4514[M + NH4][(2,5-dimethylphenyl)methoxy]benzoic acid3193-[(4-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(3,4-dichlorophenyl)methoxy]benzoic acid3202-([1,1′-Biphenyl]-4-ylmethoxy)-3-C27 H21 Cl O4462[M + NH4][(4-chlorophenyl)methoxy]benzoicacid3213-[(4-Chlorophenyl)methoxy]-2-C25 H19 Cl O4436[M + NH4](1-naphthalenylmethoxy)benzoicacid3222-[(2-Chlorophenyl)methoxy]-3-C21 H16 Cl2 O4420[M + NH4][(4-chlorophenyl)methoxy]benzoicacid3233-[(4-Chlorophenyl)methoxy]-2-C25 H19 Cl O4436[M + NH4](2-naphthalenylmethoxy)benzoicacid3243-[(4-Chlorophenyl)methoxy]-2-C22 H18 Cl N O6445[M + NH4][(2-methyl-3-nitrophenyl)methoxy]benzoic acid3253-[(4-Chlorophenyl)methoxy]-2-C21 H15 Cl F2 O4422[M + NH4][(2,5-difluorophenyl)methoxy]benzoic acid3262-[[3,5-Bis(trifluoromethyl)C23 H15 Cl F6 O4522[M + NH4]phenyl]methoxy]-3-[(4-chlorophenyl)methoxy]benzoicacid3273-[(4-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O4454[M + NH4][[2-(trifluoromethyl)phenyl]methoxy]benzoic acid3283-[(4-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(2,3-dichlorophenyl)methoxy]benzoic acid3293-[(4-Chlorophenyl)methoxy]-2-C21 H15 Cl3 O4454[M + NH4][(2,5-dichlorophenyl)methoxy]benzoic acid3302-[(6-Chloro-4H-1,3-benzodioxin-C23 H18 Cl2 O6478[M + NH4]8-yl)methoxy]-3-[(4-chlorophenyl)methoxy]benzoic acid3313-[(4-Chlorophenyl)methoxy]-2-C21 H14 Cl F3 O4440[M + NH4][(2,3,6-trifluorophenyl)methoxy]benzoic acid3323-[(4-Chlorophenyl)methoxy]-2-C22 H16 Cl F3 O5470[M + NH4][[3-(trifluoromethoxy)phenyl]methoxy]benzoic acid3333-[(4-Chlorophenyl)methoxy]-2-C23 H21 Cl O6446[M + NH4][(3,5-dimethoxyphenyl)methoxy]benzoic acid3342-Butoxy-3-[(4-C18 H19 Cl O4352[M + NH4]chlorophenyl)methoxy]benzoicacid3353-[(4-Chlorophenyl)methoxy]-2-C20 H23 Cl O4380[M + NH4](hexyloxy)benzoic acid3363-[(4-Chlorophenyl)methoxy]-2-C21 H23 Cl O4392[M + NH4](cyclohexylmethoxy)benzoic acid

EXAMPLE 337

2,3-Bis[(2-Chlorophenyl)Methoxy]-α-Methoxybenzeneacetic Acid

[0412]

101

[0413] To a stirred solution of Example 1 Part B compound (112 mg, 0.243 mmol) in DME (1 mL) under argon at room temperature was added sodium hydride (60% mineral oil dispersion, 9.7 mg, 0.24 mmol). After 30 min, methyl iodide (15 μL, 0.24 mmol) was added, the reaction mixture was stirred for 18 h and then diluted with saturated ammonium chloride solution. The mixture was extracted three times with Et2O. The organic extracts were combined, washed once with water, once with brine, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 67 mg (58% yield). LC/MS gave the correct molecular ion [(M+H)+=475] for the desired compound.

102

[0414] To a stirred solution of part A compound (65 mg, 0.14 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (1.0 mL, 1 M, 1.0 mmol). After 15 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 1 M hydrochloric acid and extracted three times with Et2O. The acidified organic extracts were combined, washed with water, brine, dried (Na2SO4) and evaporated to give the title compound as a colorless oil, 49 mg (80% yield). LC/MS gave the correct molecular ion [(M+H)+=447] for the desired compound.

EXAMPLE 338

(E)-2,3-Bis[(2-Chlorophenyl)Methoxy]-α-(Hydroxyimino)Benzeneacetic Acid and (Z)-2,3-Bis[(2-Chlorophenyl)Methoxy]-α-(Hydroxyimino)Benzeneacetic Acid

[0415]

103

[0416] To a stirred solution of Example 26 Part B compound (105 mg, 0.23 mmol) in EtOH (1 mL) under argon at room temperature was added sodium acetate (20.6 mg, 0.25 mmol) and hydroxylamine hydrochloride (17.3 mg, 0.25 mmol). The reaction mixture was heated to reflux for 3 h, cooled, diluted with EtOH and filtered. The filtrate was evaporated and water (5 mL) was added to give a gummy solid. The solid was dissolved in Et2O, washed with water, brine, dried (Na2SO4) and evaporated title compound as a 5:4 mixture of geometric isomers, colorless oil, 100 mg (93% yield). LC/MS gave the correct molecular ion [(M+H)+=474] for the desired compound.

104

[0417] To a stirred solution of part A compound (100 mg, 0.22 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (1.0 mL, 1 M, 1.0 mmol). After 15 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 1 M hydrochloric acid and extracted three times with Et2O. The acidified organic extracts were combined, washed with water, brine, dried (Na2SO4) and evaporated. Purification by reverse phase HPLC (YMC S5 ODS 20×250 mm column, acetonitrile/ water−0.1% TFA gradient) gave the title compounds as separate white amorphous solids, both geometric isomers of the oxime. LC/MS gave the correct molecular ion [(M+H)+=446] for each of the desired compounds.

EXAMPLE 339

(E)-2,3-Bis[(2-Chlorophenyl)Methoxy]-α-(Methoxyimino)Benzeneacetic Acid and (Z)-2,3-Bis[(2-Chlorophenyl)Methoxy]-α-(Methoxyimino)Benzeneacetic Acid

[0418]

105

[0419] To a stirred solution of Example 26 Part B compound (105 mg, 0.23 mmol) in EtOH (1 mL) under argon at room temperature was added sodium acetate (20.6 mg, 0.25 mmol) and methoxylamine hydrochloride (20.8 mg, 0.25 mmol). The reaction mixture was heated to reflux for 17 h, and additional portions of sodium acetate and methoxylamine hydrochloride were added and the reaction refluxed for an additional 5 h. The mixture was cooled, diluted with EtOH and filtered. The filtrate was evaporated and water (5 mL) was added to give a gummy solid. The solid was dissolved in Et2O, washed with water, brine, dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel provided the title compounds: Isomer A (first eluting) as colorless oil, 49 mg (44% yield) and Isomer B as a colorless oil, 34 mg, 34%. LC/MS gave the correct molecular ion [(M+H)+=478] for each of the desired compounds.

EXAMPLE 340

(E or Z)-2,3-Bis[(2-Chlorophenyl)Methoxy]-α-(Methoxyimino)Benzeneacetic Acid

[0420]

106

[0421] To a stirred solution of Example 339 (Isomer A) compound (49 mg, 0.1 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (1.0 mL, 1 M, 1.0 mmol). The reaction was heated to 50° C. After 16 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 1 M hydrochloric acid and extracted three times with Et2O. The acidified organic extracts were combined, washed with water, brine, dried (Na2SO4) and evaporated to provide the title compound as a white solid, 37 mg, (80% yield), mp 140-141° C. LC/MS gave the correct molecular ion [(M+H)+=460] for the desired compound.

EXAMPLE 341

(E or Z)-2,3-Bis[(2-Chlorophenyl)Methoxy]-α-(Methoxyimino)Benzeneacetic Acid

[0422]

107

[0423] To a stirred solution of Example 339 (Isomer B) compound (37 mg, 0.075 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (1.0 mL, 1 M, 1.0 mmol). The reaction was heated to 50° C. After 16 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 1 M hydrochloric acid and extracted three times with Et2O. The acidified organic extracts were combined, washed with water, brine, dried (Na2SO4) and evaporated to provide the title compound as a white solid, 32 mg, (91% yield), mp 97-99° C. LC/MS gave the correct molecular ion [(M+H)+=460] for the desired compound.

EXAMPLE 342

3-[(2-Chlorophenyl)Methoxy]-2-(Cyclohexylmethoxy)-α-Hydroxybenzeneacetic Acid

[0424]

108

[0425] To a stirred slurry of sodium hydride (60% mineral oil dispersion, 3.68 g, 92 mmol) in DMSO (40 mL) at room temperature under argon was added a solution of 2,3-dihydroxybenzaldehyde (5.53 g, 40.0 mmol) in DMSO (20 mL). After 1 h, a solution of 2-chlorobenzylchloride (5.05 mL, 40.0 mmol) in DMSO (10 mL) was added, the reaction mixture was stirred for 60 h and then diluted with water. The mixture was extracted three times with Et2O. The organic extracts were combined, washed once with water, once with brine, dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound, 5.6 g (53% yield). LC/MS gave the correct molecular ion [(M+H)+=263] for the desired compound.

109

[0426] To a stirred solution of part A compound (1.31 g, 5.00 mmol) in EtOH (15 mL) at room temperature under argon was added potassium carbonate (1.04 g, 7.5 mmol) and then cyclohexylmethyl bromide (0.98 mL, 7.0 mmol). After 16 h at reflux, the reaction was diluted with water, extracted with CH2Cl2, dried (Na2SO4) and evaporated. Purification by flash chromatography gave the title compound as a colorless oil, 400 mg (22% yield). LC/MS gave the correct molecular ion [(M+H)+=359] for the desired compound.

110

[0427] By the method of Example 1, Part B compound (340 mg, 0.95 mmol) was converted to the title compound as a white amorphous solid, 170 mg, 47% yield. LC/MS gave the correct molecular ion [(M+H)+=405] for the desired compound.

EXAMPLE 343

3-[(2-Chlorophenyl)Methoxy]-α-Hydroxy-2-[(2-Methoxyphenyl)Methoxy]Benzeneacetic Acid

[0428]

111

[0429] By the method of Example 342 Part B, but using 2-methoxybenzyl chloride in place of cyclohexylmethyl bromide, the title compound was prepared. LC/MS gave the correct molecular ion [(M+H)+=383] for the desired compound.

112

[0430] By the method of Example 1, Part A compound (110 mg, 0.29 mmol) was converted to the title compound as a white amorphous solid. LC/MS gave the correct molecular ion [(M+H)+=429] for the desired compound.

EXAMPLE 344

3-[(2-Chlorophenyl)Methoxy]-α-Hydroxy-2-(4-Pyridinylmethoxy)Benzeneacetic Acid

[0431]

113

[0432] By the method of Example 342 Part B, but using the free base of 4-picolyl chloride in place of cyclohexylmethyl bromide, the title compound was prepared. LC/MS gave the correct molecular ion [(M+H)+=354] for the desired compound.

114

[0433] By the method of Example 1, Part A compound (581 mg, 1.54 mmol) was converted to the title compound as a white solid, mp 181-183° C. LC/MS gave the correct molecular ion [(M+H)+=400] for the desired compound.

EXAMPLE 345

2,3-Bis[(3,5-Dichlorophenyl)Methoxy]Benzoic Acid

[0434]

115

[0435] A solution of 2,3-dihydroxybenzoic acid (3.00 g, 19.46 mmol) and 96% sulfuric acid (3 mL, 55 mmol) in methanol (60 mL) at room temperature under argon was stirred for 1 h. The reaction mixture was heated to reflux for 16 h, then cooled, concentrated to half the volume and poured into water (150 mL) and ethyl acetate (150 mL). The organic fraction was washed with water, aqueous NaHCO3 solution, dried (MgSO4) and concentrated to give the title compound as a white solid (2.90 g, 89%). mp 77-78° C. LC/MS gave the correct molecular ion [(M−H)−=167] for the desired compound.

116

[0436] To a stirred solution of part A compound (0.17 g, 1.00 mmol) in DMF (13 mL) at room temperature under argon was added K2CO3 (1.10 9, 8.00 mmol), tetrabutylammonium iodide (0.05 g, 0.14 mmol) and 3,5-dichlorobenzyl chloride (0.78 g, 4.00 mmol). The mixture was stirred at RT for 0.5 h and then at 60° C. for 1.5 h. The mixture was cooled, filtered through a pad of Celite and poured into diethyl ether. The ether fraction was washed with brine, dried over MgSO4 and concentrated. The title compound was then crystallized from 1:9 THF/methanol to give the title compound as a white solid (0.25 g, 51%), mp 150-151° C.

117

[0437] A solution of part B compound (0.12 g, 0.25 mmol) in a THF:methanol (3 mL:0.5 mL) solution was stirred at room temperature under argon, as 10 M NaOH solution (0.05 mL, 0.5 mmol) was added. After 4 h, the reaction mixture was concentrated and diluted with water (5 mL). The mixture was acidified to pH=1 with 1N HCl and the white solid collected (0.10 g, 85%). LC/MS gave the correct molecular ion [(M−H)−=471−] for the title compound. mp 219-220° C.

EXAMPLES 346-352

[0438] The following compounds were prepared according to the methods outlined in Example A, utilizing 2,4-dichlorobenzyl chloride, 2-chlorobenzyl chloride, 3-chlorobenzyl chloride, 4-chlorobenzyl chloride, 3,5-bis(trifluoromethyl)benzyl chloride, 2,5-dimethylbenzyl chloride, and 3,5-dimethylbenzyl chloride.

118

m/zEx.Rm.p. (° C.)(−ions)Name346

119

168-169]M-H 471−]2,3-Bis[(2,4- dichlorophenyl) methoxy]benzoic acid347

120

156-157]M-H 401−]2,3-Bis[(2- chlorophenyl) methoxy]benzoic acid348

121

126-127]M-H 401−]2,3-Bis[(3- chlorophenyl) methoxy]benzoic acid349

122

174-175]M-H 401−]2,3-Bis[(4- chlorophenyl) methoxy]benzoic acid350

123

156-158]M-H 605−]2,3-Bis[[3,5- bis(trifluoro methyl)phenyl]metho xy]benzoic acid351

124

114-116]M-H 389−]2,3-Bis[(2,5- dimethylphenyl) methoxy]benzoic acid352

125

117-118]M-H 389−]2,3-Bis[(3,5- dimethylphenyl) methoxylbenzoic acid

EXAMPLE 353

2-[(2,4-Dichlorophenyl)Methoxy]-3-(Phenylmethoxy)Benzoic Acid

[0439]

126

[0440] For preparation of part A compound, see example 25 part A.

127

[0441] To a stirred solution of part A compound (0.19 g, 1.00 mmol) in DMF (5 mL) at room temperature under argon was added K2CO3 (0.27 g, 2.00 mmol) and benzyl bromide (0.14 mL, 1.20 mmol). The mixture was stirred at RT for 0.5 h and then at 60° C. for 4 h. The mixture was cooled, filtered through a pad of celite and poured into diethyl ether. The ether fraction was washed with brine, dried over MgSO4 and concentrated. The crude compound was triturated with hot hexane to give the title compound (0.20 g, 70%) as an off white solid. MS gave the correct molecular ion [(M+H)+=285+] for the desired compound.

128

[0442] To a stirred solution of part B compound (0.14 g, 0.50 mmol) in THF (10 mL) at room temperature under argon was added a 25% solution of sodium methoxide in methanol (0.15 mL, 0.69 mmol) and the mixture was stirred at RT for 1 h. The mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The suspension was treated with 2 mL of 1 N HCl solution and the organic fraction was washed with HCl solution, brine, dried over MgSO4 and concentrated to an oil (0.13 g, 96%). MS gave the correct molecular ion [(M+H)+=259+] for the desired compound.

129

[0443] To a stirred solution of part C compound (0.05 g, 0.20 mmol) in DMF (2 mL) at room temperature under argon was added K2CO3 (0.11 g, 0.80 mmol), tetrabutylammonium iodide (3 mg, catalyst) and 2,4-dichlorobenzyl chloride (0.06 mL, 0.40 mmol). The mixture was stirred at RT for 0.5 h and then at 60° C. for 4 h. The mixture was cooled, filtered through a pad of celite and poured into diethyl ether. The ether fraction was washed with brine, dried over MgSO4 and concentrated. The crude compound was crystallized from hot hexane to give the title compound (0.06 g, 72%) as a white solid. MS gave the correct molecular ion [(M+H)+=417+] for the desired compound.

130

[0444] A solution of part D compound (0.05 g, 0.12 mmol) in a THF:methanol (1 mL:1 mL) solution was stirred at room temperature under argon, as 10 M NaOH solution (0.1 mL, 1.00 mmol) was added. After 4 h, the reaction mixture was concentrated and diluted with water (5 mL). The mixture was acidified to pH=1 with 1N HCl and the white solid collected (0.03 g, 60%). LC/MS gave the correct molecular ion [(M−H)−=401−] for the title compound. mp 140-142° C.

EXAMPLE 354

3-[(2,4-Dichlorophenyl)Methoxy]-2-(Phenylmethoxy)Benzoic Acid

[0445]

131

[0446] To a stirred solution of Example 25 part A compound (0.19 g, 1.00 mmol) in DMF (5 mL) at room temperature under argon was added K2CO3 (0.28 g, 2.00 mmol), tetrabutylammonium iodide (17 mg, catalyst) and 2,4-dichlorobenzyl chloride (0.17 mL, 1.20 mmol). The mixture was stirred at RT for 0.5 h and then at 60° C. for 4 h. The mixture was cooled, filtered through a pad of celite and poured into diethyl ether. The ether fraction was washed with brine, dried over MgSO4 and concentrated. The crude compound was triturated with hexane to give the title compound (0.23 9, 65%) as a white solid. MS gave the correct molecular ion [(M+H)+=353+] for the desired compound.

132

[0447] To a stirred solution of part A compound (0.18 g, 0.50 mmol) in THF (10 mL) at room temperature under argon was added a 25% solution of sodium methoxide in methanol (0.15 mL, 0.65 mmol) and the mixture was stirred at RT for 1 h. The mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The suspension was treated with 2 mL of 1 N HCl solution and the organic fraction was washed with HCl solution, brine, dried over MgSO4 and concentrated to an off white solid (0.15 g, 92%). MS gave the correct molecular ion [(M+H)+=327+] for the desired compound.

133

[0448] To a stirred solution of part B compound (0.10 g, 0.30 mmol) in DMF (3 mL) at room temperature under argon was added K2CO3 (0.17 g, 1.20 mmol), and benzyl bromide (0.07 mL, 0.60 mmol). The mixture was stirred at RT for 0.5 h and then at 60° C. for 4 h. The mixture was cooled, filtered through a pad of celite and poured into diethyl ether. The ether fraction was washed with brine, dried over MgSO4 and concentrated. The crude compound was purified by flash column chromatography on silica gel with ethyl acetate:hexane 7:93 to give the title compound (0.11 g, 93%) as a white solid. mp 166-168° C.

134

[0449] A solution of part C compound (0.03 g, 0.07 mmol) in a THF:methanol (1 mL:1 mL) solution was stirred at room temperature under argon, as 10 M NaOH solution (0.06 mL, 0.60 mmol) was added. After 4 h, the reaction mixture was concentrated and diluted with water (5 mL). The mixture was acidified to pH=1 with 1N HCl and the white solid collected (0.02 g, 71%). LC/MS gave the correct molecular ion [(M−H)−=401−] for the title compound. mp 151-153° C.

EXAMPLE 355

5-Bromo-2,3-Bis[(2-Chlorophenyl)Methoxy]Benzoic Acid

[0450]

135

[0451] A solution of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (1.03 g, 4.33 mmol) and sulfamic acid (563 mg, 5.78 mmol) in THF:H2O (1:2, 15.9 mL) was treated dropwise with a solution of sodium hypochlorite (519 mg, 4.59 mmol) in water (2.6 mL) and the resulting orange solution stirred at room temperature for 3.0 h. The mixture was treated with 5 % KHSO4 (6.6 mL), extracted with EtOAc (2×70 mL) and the organic phase was washed with brine (14 mL), dried (MgSO4) and concentrated to give a light brown solid. Trituration of the crude product with CH2Cl2:hexane (1:1, 10 mL) and hexane (10 mL) gave the title compound as a light brown solid (753 mg, 70%), mp 195-198° C. LC/MS gave the correct molecular ion [(M−H)−=245] for the desired compound.

136

[0452] A cooled (0° C.) solution of part A compound (753 mg, 3.05 mmol) in dry CH2Cl2 (9.0 mL) was treated with 1.0 M BBr3/CH2Cl2 (6.2 mL, 6.1 mmol), stirred at 0° C. for 3.0 h then allowed to come up to room temperature overnight (J. Med. Chem. 1995, 38, 4937-4943). The reaction mixture was quenched by the dropwise addition of water (19 mL), stirred for 30 min then extracted with EtOAc (3×100 mL). The extracts were washed with water (3×20 mL), brine (20 mL) and dried (MgSO4) to give the title compound as a light brown solid (626 mg, 88%), mp 211-213° C. LC/MS gave the correct molecular ion [(M−H)−=231] for the desired compound.

137

[0453] A mixture of thionyl chloride (0.35 mL, 4.8 mmol) and methanol (5.4 mL) was stirred at room temperature for 30 min then treated with part B compound (600 mg, 2.57 mmol). The reaction mixture was stirred at room temperature for 2.0 hr. refluxed for 7.0 hr, cooled and concentrated to a brown solid. Purification by column chromatography (2.5×25 cm column, 1:4 EtOAc/hexane, then 1:1 EtOAc) gave the title compound (500 mg, 78%).

138

[0454] To a mixture of part C compound (205 mg, 0.83 mmol), potassium carbonate (900 g, 6.64 mmol) and Bu4NI (cat) in dry DMF (3.4 mL) was added 2-chlorobenzylchloride (0.42 mL, 3.32 mmol). The reaction mixture was heated at 60° C. for 4 hr and partitioned between water (25 mL) and Et2O (3×60 mL). The organic extracts were washed with water (3×25 mL) and brine (25 mL) and dried (MgSO4) to give a syrup. Purification by flash chromatography (2.5×25 cm column, 1:9 EtOAc/hexane) gave the title compound as a white solid (392 mg, 95%), mp 100-101° C.

139

[0455] A solution of part D compound (387 mg, 0.78 mmol) in THF:CH3OH (1:1, 3.0 mL) was treated with 10.0 N sodium hydroxide (0.17 mL, 1.7 mmol) and stirred at room temperature for 18 h. The mixture was concentrated and the solids obtained were suspended in water (5.0 mL), acidified to pH 1 with 1.0 N hydrochloric acid (2.1 mL) and extracted with EtOAc (2×60 mL). The organic phase was washed with water (3×5.0 mL) and brine (5.0 mL), dried (MgSO4) and concentrated to give a white solid. Trituration of the solid with CH2Cl2 (4.0 mL) and hexane (25 mL) gave the title compound as a white solid (346 mg, 92%), mp 186-187° C. LC/MS gave the correct molecular ion [(M−H)−=479] for the desired compound.

EXAMPLE 356

5-Bromo-2,3-Bis(Phenylmethoxy)Benzoic Acid

[0456]

140

[0457] Example 356 was prepared by the method of Example 355. The title compound was obtained as a white solid (128 mg, 94%), mp 151-153° C. LC/MS gave the correct molecular ion [(M+H)+=413] for the desired compound.

EXAMPLES 357-372

[0458] The following compounds were prepared according to the methods outlined in Example 345.

141

m.p.Ex.R1MS(° C.)Name357

142

1/45383 [M-H]107-1091/453-[(2- Chlorophenyl) methoxy]-2-[(3- methylphenyl) methoxy]benzoic acid358

143

1/45387 [M-H]152-1541/453-[(2- Chlorophenyl) methoxy]-2-[(3- fluorophenyl) methoxy]benzoic acid359

144

1/45437 [M-H]128-1291/453-[(2- Chlorophenyl) methoxy]-2-[[3- trifluoromethyl) phenyl]methoxy]benzoic acid360

145

1/45473 [M-H]107-1091/453-[(2- Chlorophenyl) methoxy]-2-[[4- (phenylmethoxy) phenyl]methoxy]benzoic acid361

146

1/45397 [M-H]122-1231/453-[(2- Chlorophenyl) methoxy]-2-[(3,5- dimethylphenyl) methoxy]benzoic acid362

147

1/45399 [M-H]110-1121/453-[(2- Chlorophenyl) methoxy]-2-[(2- methoxyphenyl) methoxy]benzoic acid363

148

1/45370 [M-H]168-1701/453-[(2- Chlorophenyl) methoxy]-2-[(2- pyridinylmethoxy) benzoic acid364

149

1/45370 [M-H]157-1591/453-[(2- Chlorophenyl) methoxy]-2-[(4- pyridinylmethoxy) benzoic acid365

150

1/45370 [M-H]181-1821/453-[(2- Chlorophenyl) methoxy]-2-[(3- pyridinylmethoxy) benzoic acid366

151

1/45404 [M-H]183-1841/453-[(2- Chlorophenyl) methoxy]-2-[(2- chloro-3- pyridinyl)methoxy) benzoic acid367

152

1/45386 [M-H]189-1911/453-[(2- Chlorophenyl) methoxy]-2-[(1- oxido-2- pyridinyl)methoxy]benzoic acid368

153

1/45386 [M-H]177-1791/453-[(2- Chlorophenyl) methoxy]-2-[(1- oxido-3- pyridinyl)methoxy]benzoic acid369

154

1/45386 [M-H]186-1881/453-[(2- Chlorophenyl) methoxy]-2-[(1- oxido-4- pyridinyl)methoxy]benzoic acid370

155

1/45420 [M-H]145-1481/453-[(2- Chlorophenyl) methoxy]-2-[(2- chloro-1-oxido-3- pyridinyl)methoxy]benzoic acid371

156

1/45409 [M-H]197-2011/452-(1H- Benzimidazol-2- ylmethoxy)-3- [(2-chlorophenyl) methoxyl]benzoic acid, monohydrochloride372

157

1/45423 [M-H]179-1821/453-[(2- Chlorophenyl) methoxy]-2-[(1- methyl-1H- benzimidazol]-2- yl)methoxy]benzoic acid

EXAMPLE 373

6-Bromo-2,3-Bis[(2-Chlorophenyl)Methoxy]Benzoic Acid

[0459]

158

[0460] A cooled (0° C.) solution of 2,3-dimethoxybenzoic acid (1.0 g, 5.5 mmol) in 1.4 M NaOH (8.63 mL, 12.1 mmol) was treated portionwise with N-bromosuccinimide (1.185 g, 6.59 mmol), brought to room temperature and stirred for 48.0 hr (Tet. Lett, 1993, 34 (6), 931-934). The mixture was quenched with 5% NaHSO3 solution (30 mL), acidified with 12 N hydrochloric acid to pH 1 and extracted with Et2O (2×50 mL). The organic phase was washed with H2O (3×10 mL) and brine (10 mL), dried (MgSO4) and concentrated to give the title compound as a syrup (1.43 g, 100%).

159

[0461] A cooled (0° C.) solution of part A compound (1.43 g, 5.49 mmol) in dry dichloromethane (6.0 mL) was treated with 1.0 M BBr3/CH2Cl2 (11.0 mL, 11.0 mmol), stirred at 0° C. for 3.0 h then allowed to come up to room temperature overnight (J. Med. Chem. 1995, 38, 4937-4943). The reaction mixture was quenched by the dropwise addition of water (35 mL) followed by 1.0 N hydrochloric acid (70 mL), stirred for 15 min then extracted with EtOAc (3×100 mL). The extracts were washed with water (2×50 mL), brine (25 mL) and dried (MgSO4) to give the title compound as a solid (1.163 g, 91%). LC/MS gave the correct molecular ion [(M−H)−=231] for the desired compound.

160

[0462] A mixture of thionyl chloride (0.60 mL, 8.2 mmol) and methanol (10.0 mL) was stirred at room temperature for 30 min then treated with part B compound (1.15 g, 4.94 mmol). The reaction mixture was stirred at room temperature for 1 h, refluxed for 7 h, cooled and concentrated to a brown solid. Purification by column chromatography (2.5×25 cm column, 1:9 EtOAc/hexane, then 1:4 EtOAc/hexane) gave the title compound (550 mg, 45%). LC/MS gave the correct molecular ion [(M−H)−=245] for the desired compound.

161

[0463] To a mixture of part C compound (200 mg, 0.83 mmol), potassium carbonate (900 mg, 6.64 mmol) and Bu4NI (cat) in dry DMF (3.4 mL) was added 2-chlorobenzyl chloride (0.42 mL, 3.32 mmol) (J. Med. Chem. 1997, 40, 105-111). The reaction mixture was heated at 60° C. for 4 h and partitioned between water (25 mL) and Et2O (3×60 mL). The organic extracts were washed with water (3×25 mL) and brine (25 mL) and dried (MgSO4) to give a syrup. Purification by flash chromatography (2.5×25 cm column, 1:9 EtOAc/hexane) gave the title compound as a clear thick syrup (421 mg, 100%).

162

[0464] A solution of part D compound (421 mg, 0.83 mmol) in 1:1:1 THF/CH3OH/H2O (11 mL) was treated with 10.0 N sodium hydroxide (0.58 mL, 5.8 mmol) and stirred at room temperature for 24 h and then refluxed for 48 h. The mixture was concentrated and the solids obtained were suspended in water (6.0 mL), acidified to pH 1.0 with 1.0 N hydrochloric acid and extracted with EtOAc (2×65 mL). The organic phase was washed with water (3×6.0 mL) and brine (6.0 mL), dried (MgSO4) and concentrated to give a white solid. Trituration of the solid with CH2Cl2 (5 mL) and hexane (25 mL) gave the title compound as a white solid (335 mg, 94%), mp 156-158° C. LC/MS gave the correct molecular ion [(M−H)−=479] for the desired compound.

EXAMPLE 374

6-Bromo-2,3-Bis(Phenylmethoxy)Benzoic Acid

[0465]

163

[0466] Example 374 was prepared using the method of Example 373. The title compound was obtained as a white solid (65 mg, 65%), mp 164-166° C. LC/MS gave the correct molecular ion [(M+H)+=415] for the desired compound.

EXAMPLE 375

2-(Benzoylamino)-3-(Phenylmethoxy)Benzoic Acid

[0467]

164

[0468] To a stirred mixture of methanol (55 mL) and thionyl chloride (3.19 mL, 43.7 mmol) was added 3-hydroxy-2-nitrobenzoic acid (5.0 g, 27.3 mmol). The reaction mixture was stirred at room temperature for 2 h, refluxed for 7 h then evaporated. Purification by flash chromatography (2.5×10 cm column, 1:3 EtOAc/hexane) gave the title compound as a light yellow solid (5.03 g, 93% yield), mp 114-116° C. LC/MS gave the correct molecular ion [(M−H)−=196] for the desired compound.

165

[0469] A mixture of part A compound (1.0 g, 5.07 mmol) and potassium carbonate (700 mg, 5.07 mmol) in dry DMF (10 mL) was treated with benzyl bromide (992 mg, 5.8 mmol) and heated at 100° C. for 2 h. The mixture was concentrated and partitioned between EtOAc (3×50 mL) and water (10 mL). The organic phase was washed with H2O ( 3×10 mL) and brine (10 mL), dried (MgSO4) and evaporated. Purification by flash chromatography (2.5×25 cm column, 1:4 EtOAc/hexane) provided the title compound as a white solid (1.32 g, 91% yield), mp 96-98° C.

166

[0470] A solution of part B compound (6.12 g, 21.3 mmol) in glacial HOAc (120 mL) was cooled to 0° C., treated with zinc powder (13.71 g, 210 mmol), brought to room temperature and stirred for 2 h (J. Med. Chem. 1997, 40, 105-111). The mixture was filtered, washing the powder with glacial HOAc (25 mL), and the reddish-brown solution concentrated and re-evaporated several times with toluene. The crude product was partitioned between water (40 mL) and CH2Cl2 (2×150 mL) followed by extraction with EtOAc (150 mL). The organic extracts were washed with water (2×40 mL) and brine (40 mL), dried (MgSO4) and concentrated to a syrup. Purification by flash chromatography (2.5×10 cm column, 1:9 EtOAc/hexane, then 1:4 EtOAc/hexane) gave the desired compound as a white solid (3.36 g, 87%), mp 81-82° C. LC/MS gave the correct molecular ion [(M+H)+=258] for the title compound.

167

[0471] To a solution of part C compound (300 mg, 1.17 mmol) in dry CH2Cl2 (6.0 mL) was added dry pyridine (119 mg, 1.5 mmol) followed by a solution of benzoyl chloride (181 mg, 1.29 mmol) in dry CH2Cl2 (6.0 mL) (J. Med. Chem 1994, 37, 4251-4257). The reaction mixture was stirred at room temperature for 19 h, diluted with CH2Cl2 (13 mL) and washed with 1.0 N hydrochloric acid (2.0 mL). The aqueous phase was back-extracted with CH2Cl2 (25 mL) and the organic fractions were washed with 5% sodium bicarbonate solution (2.0 mL), water (2×2.0 mL) and brine (2.0 mL), dried (MgSO4) and concentrated to a white solid. Purification by flash chromatography (2.5×25 cm column, 1:9 EtOAc/Hexane, then 1:4 EtOAc/Hexane) gave the title compound as a white solid (357 mg, 85%), mp 126-128° C.

168

[0472] A solution of part D compound (100 mg, 0.28 mmol) in dry CH3OH (5.0 mL) was treated with 1.0 N sodium hydroxide solution (0.8 mL) and stirred at room temperature for 5.0 h, then heated to reflux for 30 min. The solution was concentrated and the crude product dissolved in water (2.0 mL), acidified to pH 1 with 1.0 N hydrochloric acid (0.9 mL) and extracted with EtOAc (3×10 mL). The organic extracts were washed with water (3×2 mL) and brine (2 mL), dried (MgSO4) and concentrated to give the title compound as a white solid (96.9 mg, 100%), mp 167-168° C. LC/MS gave the correct molecular ion [(M+H)+=348 ] for the desired compound.

EXAMPLES 376-391

[0473] The following compounds were prepared according to the methods outlined in Example 375.

169

m/zm.p.Ex.R1R2[M-H]−(° C.)Name376

170

171

398153-155]2-[[(4- Methylphenyl) sulfonyl]amino]-3- (phenylmethoxy) benzoic acid377

172

173

362184-186]2- (Benzoylmethylamino)-3- (phenylmethoxy) benzoic acid378

174

175

382161-163]2-[(3- Chlorobenzoyl)amino]-3- (phenylmethoxy) benzoic acid379

176

177

382170-172]2-[(4- Chlorobenzoyl)amino]-3- (phenylmethoxy) benzoic acid380

178

179

438161-163]2- [Benzoyl(phenyl methyl)amino]-3- (phenylmethoxy) benzoic acid381

180

181

414208-210]2-[(2,4- Dichlorobenzoyl) amino]-3- (phenylmethoxy) benzoic acid382

182

183

414202-204]2-[(3,5- Dichlorobenzoyl) amino]-3- (phenylmethoxy) benzoic acid383

184

185

414145-147]2- (Benzoylamino)- 3-(2,6-dichlorophenyl) methoxy]benzoic acid384

186

187

414187-189]2- (Benzoylamino)- 3-(2,5- dichlorophenyl) methoxy]benzoic acid385

188

189

382180-182]2- (Benzoylamino)- 3-[(2- chlorophenyl) methoxy]benzoic acid386

190

191

38290-92]2- (Benzoylamino)- 3-(3- chlorophenyl) methoxy]benzoic acid387

192

193

414182-184]2- (Benzoylamino)- 3-[(2,4- dichlorophenyl) methoxy]benzoic acid388

194

195

382142-144]2- (Benzoylamino)- 3-[(4- chlorophenyl) methoxy]benzoic acid389

196

197

416225-227]2-[(2- Chlorobenzoyl) amino]-3-[(2- chlorophenyl) methoxy]benzoic acid390

198

199

388196-198]3-[(2- Chlorophenyl) methoxy]-2- [(cyclohexylcarb onyl)amino]benzoic acid391

200

201

451171-174]3-[(2- Chlorophenyl) methoxy]-2-[[2- chlorophenyl) sulfonyl]amino]benzoic acid

EXAMPLE 392

3-[(2-Chlorobenzoyl)Amino]-2-[(2-Chlorophenyl)Methoxy]Benzoic Acid

[0474]

202

[0475] A mixture of thionyl chloride (1.15 mL, 15.8 mmol) and methanol (20.0 mL) was stirred at room temperature for 30 min then treated with 3-amino-2-hydroxybenzoic acid (1.5 g, 9.79 mmol). The reaction mixture was stirred at room temperature for 2 h, refluxed for 20 h, cooled and concentrated. The crude product was partitioned between EtOAc (100 mL) and 5% NAHCO3 solution (65 mL), back-extracting the aqueous phase with EtOAc (4×100 mL). The organic phase was washed with water (2×20 mL) and brine (20 mL) , dried (MgSO4), filtered and concentrated to give a dark red solid (381 mg, 19%).

203

[0476] To a solution of part A compound (381 mg, 1.9 mmol) and dry pyridine (0.18 mL) in dry CH2Cl2 (11.0 mL) was added 2-chlorobenzoylchloride (0.29 mL, 2.18 mmol) (J. Med. Chem. 1994, 37, 4251-4257). The reaction mixture was stirred at room temperature for 24 h and then partitioned between 1.0 N hydrochloric acid (3.0 mL) and CH2Cl2 (2×25 mL). The organic phase was washed with water (2×3.0 mL) and brine (3 mL), dried (MgSO4) and concentrated to give a semi-solid. Purification by flash chromatography (2.5×25 cm column, 1:9 EtOAc/hexane) gave the title compound as an off-white solid (569 mg, 99%). LC/MS gave the correct molecular ion [(M+H)+=306] for the desired compound.

204

[0477] A mixture of part B compound (100 mg, 0.33 mmol), potassium carbonate (92 mg, 0.66 mmol) and Bu4NI (˜5 mg) in dry dimethyformamide (1.5 mL) was treated with 2-chlorobenzylchloride (0.05 mL, 0.43 mmol) and stirred at 60° C. for 3 h. The mixture was concentrated and the slurry partitioned between water (2.0 mL) and EtOAc (2×20 mL). The organic phase was washed with water (2×2.0 mL) and brine (2 mL), dried (MgSO4) and concentrated to give a syrup. Purification by flash chromatography (2.5×25 cm column, 1:9 EtOAc/Hexane) gave the title compound as a clear syrup (125 mg, 88%).

205

[0478] A solution of part C compound (125 mg, 0.29 mmol) in CH3OH (4.7 mL) was treated with 1.0 N sodium hydroxide solution (0.8 mL, 0.8 mmol) and refluxed for 2 h. The mixture was concentrated and the solids were dissolved in water (2.0 mL), acidified with 1.0 N hydrochloric acid (0.89 mL) to pH 1 and partitioned between water (2 mL) and EtOAc (2×50 mL). The organic phase was washed with water (2×4.0 mL) and brine (4.0 mL), dried (MgSO4) and concentrated to give the title compound as a white solid (125 mg, 100%), mp 182-183° C. LC/MS gave the correct molecular ion [(M+H)+=418] for the desired compound.

EXAMPLE 393

3-[(2-Chlorobenzoyl)Amino]-2-[(4-Methoxyphenyl)Methoxy]Benzoic Acid

[0479]

206

[0480] Example 393 was prepared by the method of Example 392. The title compound was obtained as a white solid (47 mg, 88%), mp 115-117° C. This compound was acid-labile and an LC/MS or HPLC could not be obtained.

EXAMPLES 394-571

[0481] The compounds of examples 394-571 were prepared as part of a solid-phase library run using the following procedure.

207

208

[0482] To a stirred suspension of sodium hydride (60% mineral oil dispersion, 10.5 g, 0.263 mol) in DMF (100 mL) at 4° C. was added a solution of 2-methoxy-4-hydroxy-benzaldehyde (40.0 g, 0.263 mol) in DMF (200 mL) over 2 h. The reaction mixture was warmed to room temperature and stirred for 1 h, whereupon tetrabutylammonium iodide (13.0 g, 35.2 mmol) and Merrifield polystyrene resin (100 g, 1.24 mmol chloride/g, 124 mmol) was added in two batches. The reaction mixture was heated to 61° C. for 19 h. The resulting solid was collected and washed with the following sequence: five times with 1:1 DMF-water, five times with DMF, once with DMF-water, once with DMF, three times with THF, once with methanol and once with THF. The solids were dried in vacuum at room temperature to constant weight to give the title compound (117.1 g). Elemental analysis showed a residual chloride content of 0.15% by weight. The calculated loading was 1.084 mmol/g.

209

[0483] To an agitated suspension (at 150 rpm) of Part A resin (53.3 g, 57.6 mmol) in THF (150 mL) and ethanol (150 mL) at room temperature was added solid sodium borohydride (11.48 g, 317 mmol). After 20 h, the resulting solid was collected and washed with the following sequence: four times with 1:1 DMF-water, three times with DMF, four times with 1:19 acetic acid/THF, twice with THF and four times with dichloromethane. The solids were dried in vacuum at room temperature to constant weight to give the title compound (52.35 g).

210

[0484] To a solution of triphenylphosphine (45.3 g, 173 mmol) in CH2Cl2 (200 mL) at 4° C. was added triphosgene (46.6 g, 173 mmol) portionwise over 30 min. After an additional 10 min, the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was evaporated re-evaporated once from CH2Cl2 and the resulting solid redissolved in CH2Cl2 (90 mL). This solution was added to an agitated suspension (at 150 rpm) of Part B resin (35.0 g, 37.9 mmol) in CH2Cl2 (150 mL). After 3 h, the resulting solid was collected and washed twice with anhydrous DMF. The washed solid was suspended in DMF (200 mL) and 3-hydroxy-2-nitro-benzoic acid (17.0 g, 92.8 mmol), sodium bicarbonate (11.23 g, 139 mmol) and tetra-n-butylammonium iodide (1.4 g, 3.8 mmol) were added and the mixture agitated at 150 rpm. After 40 h, the solid was collected and washed five times with 1:1 DMF/water followed by DMF, then four times with THF and four times with CH2Cl2. Drying in vacuum at room temperature to constant weight gave the title compound (38.83 g).

211

[0485] A suspension of Part C resin (1.0 g, 0.91 mmol), finely ground potassium carbonate (1.26 g, 9.1 mmol), tetrabutylammonium iodide (100 mg, 0.9 mmol) and R2-X (4.6 mmol) in DMF (11.5 mL) at 68° C. was agitated at 300 rpm. After 33 h, the solid was washed four times with 1:1 DMF/water, then four times with DMF and four times with THF (15 mL portions). Drying in vacuum at room temperature to constant weight gave the title compounds. The following R2-X were included: (1-bromoethyl)benzene, benzyl bromide, 2-bromobenzyl bromide, α-bromo-o-xylene, α-bromo-m-xylene, α-bromo-p-xylene, 4-bromobenzyl bromide, 4-(trifluoromethyl) benzyl bromide, 3-chlorobenzyl bromide, 2-chlorobenzyl chloride, 2,4-dichlorobenzyl chloride, 4-methoxybenzyl chloride, 4-benzyloxybenzyl chloride, 4-biphenylmethyl chloride, 2-chloroacetophenone, 2,2′,4′-trichloroacetophenone, 1-iodobutane, bromomethylcyclo-hexane, 1-(chloromethyl)naphthalene, 2-(bromomethyl) naphthalene, 2,4′-dichloroacetophenone, 4-chlorobenzyl bromide, 3-phenoxybenzyl chloride and 3-methoxybenzyl bromide.

212

[0486] A suspension of Part D resin in THF (10 mL) was agitated at 270 rpm and then water (4.4 mL) was added, followed by potassium carbonate (1.26 g, 9.1 mmol), tetrabutylammonium hydroxide solution (0.60 mL, 1.53 M, 0.9 mmol) and sodium hydrosulfite (3.12 g, 18.2 mmol). After 76 h, the solid was washed six times with 1:1 DMF/water, then four times with DMF, three times with THF and twice with CH2Cl2 (15 mL portions) gave the title compounds.

213

[0487] A suspension of Part D resin (60 mg) in ClCH2CH2Cl (500 μL) was treated with a solution of DMAP in pyridine (0.5 mL, 0.1 M, 0.05 mmol) and then a solution of R1—X(O)n—Cl (0.5 mL, 1 M). The vessels were agitated at 580 rpm for 14 h. Each resin was washed twice with DMF, three times with 1:1 DMF/water, three times with THF, twice with CH2Cl2 (1 mL portions) and then treated with 1% TFA in ClCH2CH2Cl for 40 min at 550 rpm. The solution was evaporated and the residues were dissolved in isopropanol (0.5 mL), filtered and evaporated to give the title compounds.

[0488] The following R1—X(O)n—Cl were included: benzoyl chloride, 2-chlorobenzoyl chloride, o-anisoyl chloride, 3-chlorobenzoyl chloride, m-anisoyl chloride, heptanoyl chloride, cyclohexanecarbonyl chloride, 2-quinoxaloyl choride, benzenesulfonyl chloride, 2-chloronicotinyl chloride, 3-chorobenzenesulfonyl chloride and 6-chloronicotinyl chloride.

5Massion typeEx.CAS NameElemental formulaSpec, m/zinferred3943-[[(3-C21 H18 Cl N O5 S432(M + H)Chlorophenyl)sulfonyl]amino]-2-(1-phenylethoxy)benzoicacid3952-[(2-C21 H16 Cl N O4382(M + H)Chlorobenzoyl)amino]-3-(phenylmethoxy)benzoicacid3962-[(2-C22 H19 N O5379(M + H)Methoxybenzoyl)amino]-3-(phenylmethoxy)benzoicacid3972-[(1-Oxoheptyl)amino]-C21 H25 N O4356(M + H)3-(phenylmethoxy)benzoicacid3982-C21 H23 N O4354(M + H)[(Cyclohexylcarbonyl)amino]-3-(phenylmethoxy)benzoicacid3993-(Phenylmethoxy)-2-[(2-C23 H17 N3 O4400(M + H)quinoxalinylcarbonyl)amino]benzoic acid4003-(Phenylmethoxy)-2-C20 H17 N O5 S384(M + H)[(phenylsulfonyl)amino]benzoic acid4012-[[(6-Chloro-3-C20 H15 Cl N2 O4383(M + H)pyridinyl)carbonyl]amino]-3-(phenylmethoxy)benzoicacid4022-(Benzoylamino)-3-[(2-C21 H16 Br N O4426(M + H)bromophenyl)methoxy]benzoic acid4033-[(2-21 H15 Br Cl N O4460(M + H)Bromophenyl)methoxy]-2-[(3-chlorobenzoyl)amino]benzoic acid4043-[(2-C21 H22 Br N O4432(M + H)Bromophenyl)methoxy]-2-[(cyclohexylcarbonyl)amino]benzoic acid4053-[(2-C23 H16 Br N3 O4478(M + H)Bromophenyl)methoxy]-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid4062-(Benzoylamino)-3-[(2-C22 H19 N O4362(M + H)methylphenyl)methoxy]benzoic acid4072-[(2-C23 H21 N O5392(M + H)Methoxybenzoyl)amino]-3-[(2-methylphenyl)methoxy]benzoic acid4082-[(3-C22 H18 Cl N O4396(M + H)Chlorobenzoyl)amino]-3-[(2-methylphenyl)methoxy]benzoic acid4093-[(2-C22 H27 N O470(M + H)Methylphenyl)methoxy]-2-[(1-oxoheptyl)amino]benzoicacid4102-C22 H25 N O4368(M + H)[(Cyclohexylcarbonyl)amino]-3-[(2-methylphenyl)methoxy]benzoic acid4113-[(2-C24 H19 N3 O414(M + H)Methylphenyl)methoxy]-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid4122-[[(6-Chloro-3-C21 H17 Cl N2 O4397(M + H)pyridinyl)carbonyl]amino]-3-[(2-methylphenyl)methoxy]benzoic acid4132-[(2-C22 H18 Cl N O4396(M + H)Chlorobenzoyl)amino]-3-[(3-methylphenyl)methoxy]benzoic acid4142-[(2-C23 H21 N O5392(M + H)Methoxybenzoyl)amino]-3-[(3-methylphenyl)methoxy]benzoic acid4152-[(3-C22 H18 Cl N O4396(M + H)Chlorobenzoyl)amino]-3-[(3-methylphenyl)methoxy]benzoic acid4162-[(3-C23 H21 N O5392(M + H)Methoxybenzoyl)amino]-3-[(3-methylphenyl)methoxy]benzoic acid4173-[(3-C22 H27 N O4370(M + H)Methylphenyl)methoxy]-2-[(1-oxoheptyl)amino]benzoicacid4182-C22 H25 N O4368(M + H)[(Cyclohexylcarbonyl)amino]-3-[(3-methylphenyl)methoxy]benzoic acid4193-[(3-C24 H19 N3 O4414(M + H)Methylphenyl)methoxy]-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid4203-[(3-C21 H19 N O5 S398(M + H)Methylphenyl)methoxy]-2-[(phenylsulfonyl)amino]benzoic acid4212-[[(2-Chloro-3-C21 H17 Cl N2 O4398(M + H)pyridinyl)carbonyl]amino]-3-[(3-methylphenyl)methoxy]benzoic acid4222-[[(3-C21 H18 Cl N O5 S432(M + H)Chlorophenyl)sulfonyl]amino]-3-[(3-methylphenyl)methoxy]benzoic acid4232-[[(6-Chloro-3-C21 H17 Cl N2 O4397(M + H)pyridinyl)carbonyl]amino]-3-[(3-methylphenyl)methoxy]benzoic acid4242-(Benzoylamino)-3-[(4-C21 H16 Br N O4426(M + H)bromophenyl)methoxy]benzoic acid4253-[(4-C21 H15 Br Cl N O4460(M + H)Bromophenyl)methoxy]-2-[(2-chlorobenzoyl)amino]benzoic acid4263-[(4-C22 H18 Br N O5456(M + H)Bromophenyl)methoxy]-2-[(2-methoxybenzoyl)amino]benzoic acid4273-[(4-C21 H15 Br Cl N O4460(M + H)Bromophenyl)methoxy]-2-[(3-chlorobenzoyl)amino]benzoic acid4283-[(4-C22 H18 Br N O5456(M + H)Bromophenyl)methoxy]-2-[(3-methoxybenzoyl)amino]benzoic acid4293-[(4-C21 H24 Br N O4434(M + H)Bromophenyl)methoxy]-2-[(1-oxoheptyl)amino]benzoicacid4303-[(4-C21 H22 Br N O4432(M + H)Bromophenyl)methoxy]-2-[(cyclohexylcarbonyl)amino]benzoic acid4313-[(4-C23 H16 Br N3 O4478(M + H)Bromophenyl)methoxy]-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid4323-[(4-C20 H16 Br N O5 S462(M + H)Bromophenyl)methoxy]-2-[(phenylsulfonyl)amino]benzoic acid4333-[(4-C20 H14 Br Cl N2 O4461(M + H)Bromophenyl)methoxy]-2-[[(2-chloro-3-pyridinyl)carbonyl]amino]benzoic acid4343-[(4-C20 H15 Br Cl N O5 S496(M + H)Bromophenyl)methoxy]-2-[[(3-chlorophenyl)sulfonyl]amino]benzoic acid4353-[(4-C20 H14 Br Cl N2 O4461(M + H)Bromophenyl)methoxy]-2-[[(6-chloro-3-pyridinyl)carbonyl]amino]benzoic acid4362-[(2-C23 H21 N O5392(M + H)Methoxybenzoyl)amino]-3-[(4-methylphenyl)methoxy]benzoic acid4372-[(3-C22 H18 Cl N O4397(M + H)Chlorobenzoyl)amino]-3-[(4-methylphenyl)methoxy]benzoic acid4382-[(3-C23 H21 N O5392(M + H)Methoxybenzoyl)amino]-3-[(4-methylphenyl)methoxy]benzoic acid4393-[(4-C22 H27 N O4370(M + H)Methylphenyl)methoxy]-2-[(1-oxoheptyl)amino]benzoicacid4402-C22 H25 N O4368(M + H)[(Cyclohexylcarbonyl)amino]-3-[(4-methylphenyl)methoxy]benzoic acid4413-[(4-C24 H19 N3 O4414(M + H)Methylphenyl)methoxy]-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid4422-[[(2-Chloro-3-C21 H17 Cl N2 O4397(M + H)pyridinyl)carbonyl]amino]-3-[(4-methylphenyl)methoxy]benzoic acid4432-[[(3-C21 H18 Cl N O5 S432(M + H)Chlorophenyl)sulfonyl]amino]-3-[(4-methylphenyl)methoxy]benzoic acid4442-[[(6-Chloro-3-C21 H17 Cl N2 O4397(M + H)pyridinyl)carbonyl]amino]-3-[(4-methylphenyl)methoxy]benzoic acid4452-(Benzoylamino)-3-[[4-C22 H16 F3 N O4414(M + H)(trifluoromethyl)phenyl]methoxy]benzoic acid4462-[(2-C22 H15 Cl F3 N O4450(M + H)Chlorobenzoyl)amino]-3-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid4472-[(2-C23 H18 F3 N O5446(M + H)Methoxybenzoyl)amino]-3-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid4482-[(3-C22 H15 Cl F3 N O4450(M + H)Chlorobenzoyl)amino]-3-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid4492-[(3-C23 H18 F3 N O5446(M + H)Methoxybenzoyl)amino]-3-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid4502-[(1-Oxoheptyl)amino]-C22 H24 F3 N O4424(M + H)3-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid4512-C22 H22 F3 N O4422(M + H)[(Cyclohexylcarbonyl)amino]-3-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid4522-[(2-C24 H16 F3 N3 O4468(M + H)Quinoxalinylcarbonyl)amino]-3-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid4532-C21 H16 F3 N O5 S452(M + H)[(Phenylsulfonyl)amino]-3-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid4542-[[(2-Chloro-3-C21 H14 Cl F3 N2 O4451(M + H)pyridinyl)carbonyl]amino]-3-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid4552-[[(3-C21 H15 Cl F3 N O5 S486(M + H)Chlorophenyl)sulfonyl]amino]-3-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid4562-[[(6-Chloro-3-C21 H14 Cl F3 N2 O4451(M + H)pyridinyl)carbonyl]amino]-3-[[4-(trifluoromethyl)phenyl]methoxy]benzoic acid4572-[(2-C21 H15 Cl2 N O4416(M + H)Chlorobenzoyl)amino]-3-[(3-chlorophenyl)methoxy]benzoic acid4583-[(3-C22 H18 Cl N O5412(M + H)Chlorophenyl)methoxy]-2-[(2-methoxybenzoyl)amino]benzoic acid4592-[(3-C21 H15 Cl2 N O4416(M + H)Chlorobenzoyl)amino]-3-[(3-chlorophenyl)methoxy]benzoic acid4603-[(3-C22 H18 Cl N O5412(M + H)Chlorophenyl)methoxy]-2-[(3-methoxybenzoyl)amino]benzoic acid4613-[(3-C21 H24 Cl N O4390(M + H)Chlorophenyl)methoxy]-2-[(1-oxoheptyl)amino]benzoicacid4623-[(3-C21 H22 Cl N O4388(M + H)Chlorophenyl)methoxy]-2-[(cyclohexylcarbonyl)amino]benzoic acid4633-[(3-C20 H16 Cl N O5 S418(M + H)Chlorophenyl)methoxy]-2-[(phenylsulfonyl)amino]benzoic acid4643-[(3-C20 H14 Cl2 N2 O4417(M + H)Chlorophenyl)methoxy]-2-[[(2-chloro-3-pyridinyl)carbonyl]amino]benzoic acid4653-[(3-C20 H15 Cl2 N O5 S452(M + H)Chlorophenyl)methoxy]-2-[[(3-chlorophenyl)sulfonyl]amino]benzoic acid4663-[(2-C22 H18 Cl N O5412(M + H)Chlorophenyl)methoxy]-2-[(2-methoxybenzoyl)amino]benzoic acid4672-[(3-C21 H15 Cl2 N O4416(M + H)Chlorobenzoyl)amino]-3-[(2-chlorophenyl)methoxy]benzoic acid4683-[(2-C22 H18 Cl N O5412(M + H)Chlorophenyl)methoxy]-2-[(3-methoxybenzoyl)amino]benzoic acid4693-[(2-C21 H24 Cl N O4390(M + H)Chlorophenyl)methoxy]-2-[(1-oxoheptyl)amino]benzoicacid4703-[(2-C21 H22 Cl N O4388(M + H)Chlorophenyl)methoxy]-2-[(cyclohexylcarbonyl)amino]benzoic acid4713-[(2-C23 H16 Cl N3 O4434(M + H)Chlorophenyl)methoxy]-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid4723-[(2-C20 H14 Cl2 N2 O4417(M + H)Chlorophenyl)methoxy]-2-[[(2-chloro-3-pyridinyl)carbonyl]amino]benzoic acid4733-[(2-C20 H14 Cl2 N2 O4417(M + H)Chlorophenyl)methoxy]-2-[[(6-chloro-3-pyridinyl)carbonyl]amino]benzoic acid4742-[(2-C21 H14 Cl3 N O4450(M + H)Chlorobenzoyl)amino]-3-[(2,4-dichlorophenyl)methoxy]benzoic acid4753-[(2,4-C22 H17 Cl2 N O5446(M + H)Dichlorophenyl)methoxy]-2-[(2-methoxybenzoyl)amino]benzoic acid4762-[(3-C21 H14 Cl3 N O4450(M + H)Chlorobenzoyl)amino]-3-[(2,4-dichlorophenyl)methoxy]benzoic acid4773-[(2,4-C22 H17 Cl2 N O5446(M + H)Dichlorophenyl)methoxy]-2-[(3-methoxybenzoyl)amino]benzoic acid4783-[(2,4-C21 H23 Cl2 N O4424(M + H)Dichlorophenyl)methoxy]-2-[(1-oxoheptyl)amino]benzoicacid4793-[(2,4-C21 H21 Cl2 N O4423(M + H)Dichlorophenyl)methoxy]-2-[(cyclohexylcarbonyl)amino]benzoic acid4803-[(2,4-C20 H15 Cl2 N O5 S452(M + H)Dichlorophenyl)methoxy]-2-[(phenylsulfonyl)amino]benzoic acid4812-[[(2-Chloro-3-C20 H13 Cl3 N2 O4452(M + H)pyridinyl)carbonyl]amino]-3-[(2,4-dichlorophenyl)methoxy]benzoic acid4822-(Benzoylamino)-3-C27 H21 N O4424(M + H)([1,1′-biphenyl]-4-ylmethoxy)benzoic acid4833-([1,1′-Biphenyl]-4-C27 H20 Cl N O4458(M + H)ylmethoxy)-2-[(2-chlorobenzoyl)amino]benzoic acid4843-([1,1′-Biphenyl]-4-C28 H23 N O5454(M + H)ylmethoxy)-2-[(2-methoxybenzoyl)amino]benzoic acid4853-([1,1′-Biphenyl]-4-C27 H20 Cl N O4458(M + H)ylmethoxy)-2-[(3-chlorobenzoyl)amino]benzoic acid4863-([1,1′-Biphenyl]-4-C28 H23 N O5454(M + H)ylmethoxy)-2-[(3-methoxybenzoyl)amino]benzoic acid4873-([1,1′-Biphenyl]-4-C27 H29 N O4432(M + H)ylmethoxy)-2-[(1-oxoheptyl)amino]benzoicacid4883-([1,1′-Biphenyl]-4-C27 H27 N O4430(M + H)ylmethoxy)-2-[(cyclohexylcarbonyl)amino]benzoic acid4893-([1,1′-Biphenyl]-4-C29 H21 N3 O4476(M + H)ylmethoxy)-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid4903-([1,1′-Biphenyl]-4-C26 H19 Cl N2 O4459(M + H)ylmethoxy)-2-[[(2-chloro-3-pyridinyl)carbonyl]amino]benzoic acid4913-([1,1′-Biphenyl]-4-C26 H19 Cl N2 O4459(M + H)ylmethoxy)-2-[[(6-chloro-3-pyridinyl)carbonyl]amino]benzoic acid4922-[(2-C22 H16 Cl N O5410(M + H)Chlorobenzoyl)amino]-3-(2-oxo-2-phenylethoxy)benzoicacid4932-[(2-C23 H19 N O6406(M + H)Methoxybenzoyl)amino]-3-(2-oxo-2-phenylethoxy)benzoicacid4942-(Benzoylamino)-3-C18 H19 N O4314(M + H)butoxybenzoic acid4953-Butoxy-2-[(2-C19 H21 N O5344(M + H)methoxybenzoyl)amino]benzoic acid4963-Butoxy-2-[(3-C18 H18 Cl N O4348(M + H)chorobenzoyl)amino]benzoic acid4973-Butoxy-2-[(3-C19 H21 N O5344(M + H)methoxybenzoyl)amino]benzoic acid4983-Butoxy-2-[(1-C18 H27 N O4322(M + H)oxoheptyl)amino]benzoicacid4993-Butoxy-2-C18 H25 N O4320(M + H)[(cyclohexylcarbonyl)amino]benzoic acid5003-Butoxy-2-[(2-C20 H19 N3 O4366(M + H)quinoxalinylcarbonyl)amino]benzoic acid5013-Butoxy-2-C17 H19 N O5 S350(M + H)[(phenylsulfonyl)amino]benzoic acid5023-Butoxy-2-[[(2-chloro-3-C17 H17 Cl N2 O4349(M + H)pyridinyl)carbonyl]amino]benzoic acid5033-Butoxy-2-[[(3-C17 H18 Cl N O5 S384(M + H)chlorophenyl)sulfonyl]amino]benzoic acid5043-Butoxy-2-[[(6-chloro-3-C17 H17 Cl N2 O4349(M + H)pyridinyl)carbonyl]amino]benzoic acid5052-(Benzoylamino)-3-C21 H23 N O4354(M + H)(cyclohexylmethoxy)benzoic acid5062-[(2-C21 H22 Cl N O4388(M + H)Chlorobenzoyl)amino]-3-(cyclohexylmethoxy)benzoic acid5073-(Cyclohexylmethoxy)-C22 H25 N O5384(M + H)2-[(2-methoxybenzoyl)amino]benzoic acid5082-[(3-C21 H22 Cl N O4388(M + H)Chlorobenzoyl)amino]-3-(cyclohexylmethoxy)benzoic acid5093-(Cyclohexylmethoxy)-C22 H25 N O5384(M + H)2-[(3-methoxybenzoyl)amino]benzoic acid5103-(Cyclohexylmethoxy)-C21 H31 N O4362(M + H)2-[(1-oxoheptyl)amino]benzoicacid5112-C21 H29 N O4360(M + H)[(Cyclohexylcarbonyl)amino]-3-(cyclohexylmethoxy)benzoic acid5123-(Cyclohexylmethoxy)-C23 H23 N3 O4406(M + H)2-[(2-quinoxalinylcarbonyl)amino]benzoic acid5133-(Cyclohexylmethoxy)-C20 H23 N O5 S390(M + H)2-[(phenylsulfonyl)amino]benzoic acid5142-[[(2-Chloro-3-C20 H21 Cl N2 O4389(M + H)pyridinyl)carbonyl]amino]-3-(cyclohexylmethoxy)benzoic acid5152-[[(3-C20 H22 Cl N O5 S424(M + H)Chlorophenyl)sulfonyl]amino]-3-(cyclohexylmethoxy)benzoic acid5162-[[(6-Chloro-3-C20 H21 Cl N2 O4389(M + H)pyridinyl)carbonyl]amino]-3-(cyclohexylmethoxy)benzoic acid5172-(Benzoylamino)-3-(1-C25 H19 N O4398(M + H)naphthalenylmethoxy)benzoic acid5182-[(2-C25 H18 Cl N O4432(M + H)Chlorobenzoyl)amino]-3-(1-naphthalenylmethoxy)benzoic acid5192-[(2-C26 H21 N O5428(M + H)Methoxybenzoyl)amino]-3-(1-naphthalenylmethoxy)benzoic acid5202-[(3-C25 H18 Cl N O4432(M + H)Chlorobenzoyl)amino]-3-(1-naphthalenylmethoxy)benzoic acid5212-[(3-C26 H21 N O5428(M + H)Methoxybenzoyl)amino]-3-(1-naphthalenylmethoxy)benzoic acid5223-(1-C25 H27 N O4406(M + H)Naphthalenylmethoxy)-2-[(1-oxoheptyl)amino]benzoicacid5232-C25 H25 N O4404(M + H)[(Cyclohexylcarbonyl)amino]-3-(1-naphthalenylmethoxy)benzoic acid5243-(1-C27 H19 N3 O4450(M + H)Naphthalenylmethoxy)-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid5252-[[(2-Chloro-3-C24 H17 Cl N2 O4433(M + H)pyridinyl)carbonyl]amino]-3-(1-naphthalenylmethoxy)benzoic acid5262-[[(6-Chloro-3-C24 H17 Cl N2 O4433(M + H)pyridinyl)carbonyl]amino]-3-(1-naphthalenylmethoxy)benzoic acid5272-(Benzoylamino)-3-(2-C25 H19 N O4398(M + H)naphthalenylmethoxy)benzoic acid5282-[(2-C25 H18 Cl N O4432(M + H)Chlorobenzoyl)amino]-3-(2-naphthalenylmethoxy)benzoic acid5292-[(2-C26 H21 N O5428(M + H)Methoxybenzoyl)amino]-3-(2-naphthalenylmethoxy)benzoic acid5302-[(3-C25 H18 Cl N O4432(M + H)Chlorobenzoyl)amino]-3-(2-naphthalenylmethoxy)benzoic acid5312-[(3-C26 H21 N O5428(M + H)Methoxybenzoyl)amino]-3-(2-naphthalenylmethoxy)benzoic acid5323-(2-C25 H27 N O4406(M + H)Naphthalenylmethoxy)-2-[(1-oxoheptyl)amino]benzoicacid5332-C25 H25 N O4404(M + H)[(Cyclohexylcarbonyl)amino]-3-(2-naphthalenylmethoxy)benzoic acid5343-(2-C27 H19 N3 O4450(M + H)Naphthalenylmethoxy)-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid5352-[[(2-Chloro-3-C24 H17 Cl N2 O4433(M + H)pyridinyl)carbonyl]amino]-3-(2-naphthalenylmethoxy)benzoic acid5362-[[(6-Chloro-3-C24 H17 Cl N2 O4433(M + H)pyridinyl)carbonyl]amino]-3-(2-naphthalenylmethoxy)benzoic acid5372-[(2-C21 H15 Cl2 N O4416(M + H)Chlorobenzoyl)amino]-3-[(4-chlorophenyl)methoxy]benzoic acid5383-[(4-C22 H18 Cl N O5412(M + H)Chlorophenyl)methoxy]-2-[(2-methoxybenzoyl)amino]benzoic acid5392-[(3-C21 H15 Cl2 N O4416(M + H)Chlorobenzoyl)amino]-3-[(4-chlorophenyl)methoxy]benzoic acid5403-[(4-C22 H18 Cl N O5412(M + H)Chlorophenyl)methoxy]-2-[(3-methoxybenzoyl)amino]benzoic acid5413-[(4-C21 H24 Cl N O4390(M + H)Chlorophenyl)methoxy]-2-[(1-oxoheptyl)amino]benzoicacid5423-[(4-C21 H22 Cl N O4388(M + H)Chlorophenyl)methoxy]-2-[(cyclohexylcarbonyl)amino]benzoic acid5433-[(4-C23 H16 Cl N3 O4434(M + H)Chlorophenyl)methoxy]-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid5443-[(4-C20 H14 Cl2 N2 O4417(M + H)Chlorophenyl)methoxy]-2-[[(2-chloro-3-pyridinyl)carbonyl]amino]benzoic acid5453-[(4-C20 H14 Cl2 N2 O4417(M + H)Chlorophenyl)methoxy]-2-[[(6-chloro-3-pyridinyl)carbonyl]amino]benzoic acid5462-(Benzoylamino)-3-[(3-C27 H21 N O5440(M + H)phenoxyphenyl)methoxy]benzoic acid5472-[(2-C27 H20 Cl N O5474(M + H)Chlorobenzoyl)amino]-3-[(3-phenoxyphenyl)methoxy]benzoic acid5482-[(2-C28 H23 N O6470(M + H)Methoxybenzoyl)amino]-3-[(3-phenoxyphenyl)methoxy]benzoic acid5492-[(3-C27 H20 Cl N O5474(M + H)Chlorobenzoyl)amino]-3-[(3-phenoxyphenyl)methoxy]benzoic acid5502-[(3-C28 H23 N O6470(M + H)Methoxybenzoyl)amino]-3-[(3-phenoxyphenyl)methoxy]benzoic acid5512-[(1-Oxoheptyl)amino]-C27 H29 N O5448(M + H)3-[(3-phenoxyphenyl)methoxy]benzoic acid5522-C27 H27 N O5446(M + H)[(Cyclohexylcarbonyl)amino]-3-[(3-phenoxyphenyl)methoxy]benzoic acid5533-[(3-C29 H21 N3 O5492(M + H)Phenoxyphenyl)methoxy]-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid5542-[[(2-Chloro-3-C26 H19 Cl N2 O5475(M + H)pyridinyl)carbonyl]amino]-3-[(3-phenoxyphenyl)methoxy]benzoic acid5552-[[(6-Chloro-3-C26 H19 Cl N2 O5475(M + H)pyridinyl)carbonyl]amino]-3-[(3-phenoxyphenyl)methoxy]benzoic acid5562-(Benzoylamino)-3-[(3-C22 H19 N O5378(M + H)methoxyphenyl)methoxy]benzoic acid5572-[(2-C22 H18 Cl N O5412(M + H)Chlorobenzoyl)amino]-3-[(3-methoxyphenyl)methoxy]benzoic acid5582-[(2-C23 H21 N O6408(M + H)Methoxybenzoyl)amino]-3-[(3-methoxyphenyl)methoxy]benzoic acid5592-[(3-C22 H18 Cl N O5412(M + H)Chlorobenzoyl)amino]-3-[(3-methoxyphenyl)methoxy]benzoic acid5603-[(3-C22 H27 N O5386(M + H)Methoxyphenyl)methoxy]-2-[(1-oxoheptyl)amino]benzoicacid5612-C22 H25 N O5384(M + H)[(Cyclohexylcarbonyl)amino]-3-[(3-methoxyphenyl)methoxy]benzoic acid5623-[(3-C24 H19 N3 O5430(M + H)Methoxyphenyl)methoxy]-2-[(2-quinoxalinylcarbonyl)amino]benzoic acid5633-[(3-C21 H19 N O6 S414(M + H)Methoxyphenyl)methoxy]-2-[(phenylsulfonyl)amino]benzoic acid5642-[[(2-Chloro-3-C21 H17 Cl N2 O5413(M + H)pyridinyl)carbonyl]amino]-3-[(3-methoxyphenyl)methoxy]benzoic acid5652-[[(6-Chloro-3-C21 H17 Cl N2 O5413(M + H)pyridinyl)carbonyl]amino]-3-[(3-methoxyphenyl)methoxy]benzoic acid5662-(Benzoylamino)-3-C21 H17 N O4348(M + H)(phenylmethoxy)benzoicacid5672-[(3-C21 H16 Cl N O4382(M + H)Chlorobenzoyl)amino]-3-(phenylmethoxy)benzoicacid5682-(Benzoylamino)-3-[(2-C21 H16 Cl N O4382(M + H)chlorophenyl)methoxy]benzoic acid5692-[(2-C21 H15 Cl2 N O4416(M + H)Chlorobenzoyl)amino]-3-[(2-chlorophenyl)methoxy]benzoic acid5702-(Benzoylamino)-3-C21 H15 Cl2 N O4416(M + H)[(2,4-dichlorophenyl)methoxy]benzoic acid5712-(Benzoylamino)-3-[(4-C21 H16 Cl N O4382(M + H)chlorophenyl)methoxy]benzoic acid

EXAMPLES 572-728

[0489] The title compounds were prepared as part of a solid-phase library run employing the method of Examples 394-571, but using 2-hydroxy-3-nitrobenzoic acid instead of 3-hydroxy-2-nitrobenzoic acid.

6Massion typeEx.CAS NameElemental formulaSpec, m/zinferred5723-[(2-C21 H15 Br Cl N O4460[M + H]Bromobenzoyl)amino]-2-[(2-chlorophenyl)methoxy]benzoic acid5732-[(2-C21 H15 Cl F N O4400[M + H]Chlorophenyl)methoxy]-3-[(2-fluorobenzoyl)amino]benzoic acid5742-[(2-C21 H14 Cl F2 N O4418[M + H]Chlorophenyl)methoxy]-3-[(2,4-difluorobenzoyl)amino]benzoic acid5752-[(2-C22 H18 Cl N O5412[M + H]Chlorophenyl)methoxy]-3-[(2-methoxybenzoyl)amino]benzoic acid5762-[(2-C22 H18 Cl N O4396[M + H]Chlorophenyl)methoxy]-3-[(2-methylbenzoyl)amino]benzoic acid5773-[(3-C21 H15 Br Cl N O4461[M + H]Bromobenzoyl)amino]-2-[(2-chlorophenyl)methoxy]benzoic acid5782-[(2-C21 H15 Cl F N O4401[M + H]Chlorophenyl)methoxy]-3-[(3-fluorobenzoyl)amino]benzoic acid5793-[(3-C21 H15 Cl2 N O4416[M + H]Chlorobenzoyl)amino]-2-[(2-chlorophenyl)methoxy]benzoic acid5802-[(2-C22 H18 Cl N O5412[M + H]Chlorophenyl)methoxy]-3-[(3-methoxybenzoyl)amino]benzoic acid5812-[(2-C22 H18 Cl N O4396[M + H]Chlorophenyl)methoxy]-3-[(3-methylbenzoyl)amino]benzoic acid5822-[(2-C21 H15 Cl F N O4400[M + H]Chlorophenyl)methoxy]-3-[(4-fluorobenzoyl)amino]benzoic acid5833-[(4-C21 H15 Cl2 N O4416[M + H]Chlorobenzoyl)amino]-2-[(2-chlorophenyl)methoxy]benzoic acid5842-[(2-C22 H18 Cl N O5412[M + H]Chlorophenyl)methoxy]-3-[(4-methoxybenzoyl)amino]benzoic acid5853-[(4-C25 H24 Cl N O5454[M + H]Butoxybenzoyl)amino]-2-[(2-chlorophenyl)methoxy]benzoic acid5863-[([1,1′-Biphenyl]-4-C27 H20 Cl N O4458[M + H]ylcarbonyl)amino]-2-[(2-chlorophenyl)methoxy]benzoic acid5872-[(2-C22 H15 Cl F3 N O4450[M + H]Chlorophenyl)methoxy]-3-[[4-(trifluoromethyl)benzoyl]amino]benzoic acid5882-[(2-C22 H18 Cl N O4396[M + H]Chlorophenyl)methoxy]-3-[(4-methylbenzoyl)amino]benzoic acid5892-[(2-C24 H22 Cl N O4424[M + H]Chlorophenyl)methoxy]-3-[(4-propylbenzoyl)amino]benzoic acid5902-[(2-C18 H18 Cl N O4348[M + H]Chlorophenyl)methoxy]-3-[(2-methyl-1-oxopropyl)amino]benzoicacid5912-[(2-C22 H18 Cl N O5412[M + H]Chlorophenyl)methoxy]-3-[(phenoxyacetyl)amino]benzoic acid5922-[(2-C23 H18 Cl N O4408[M + H]Chlorophenyl)methoxy]-3-[[(2E)-1-oxo-3-phenyl-2-propenyl]amino]benzoicacid5932-[(2-C17 H16 Cl N O4334[M + H]Chlorophenyl)methoxy]-3-[(1-oxopropyl)amino]benzoicacid5942-[(2-C23 H20 Cl N O4410[M + H]Chlorophenyl)methoxy]-3-[(1-oxo-3-phenylpropyl)amino]benzoic acid5952-[(2-C21 H24 Cl N O4390[M + H]Chlorophenyl)methoxy]-3-[(1-oxoheptyl)amino]benzoicacid5962-[(2-C21 H15 Cl I N O4508[M + H]Chlorophenyl)methoxy]-3-[(4-iodobenzoyl)amino]benzoic acid5972-[(2-C18 H16 Cl N O4346[M + H]Chlorophenyl)methoxy]-3-[(cyclopropylcarbonyl)amino]benzoic acid5982-[(2-C20 H20 Cl N O4374[M + H]Chlorophenyl)methoxy]-3-[(cyclopentylcarbonyl)amino]benzoic acid5992-[(2-C22 H24 Cl N O4402[M + H]Chlorophenyl)methoxy]-3-[(3-cyclopentyl-1-oxopropyl)amino]benzoicacid6002-[(2-C21 H22 Cl N O4388[M + H]Chlorophenyl)methoxy]-3-[(cyclohexylcarbonyl)amino]benzoic acid6012-[(2-C19 H14 Cl N O5372[M + H]Chlorophenyl)methoxy]-3-[(2-furanylcarbonyl)amino]benzoic acid6022-[(2-C20 H16 Cl N O4 S402[M + H]Chlorophenyl)methoxy]-3-[(2-thienylacetyl)amino]benzoic acid6032-[(2-C20 H16 Cl N O5 S418[M + H]Chlorophenyl)methoxy]-3-[(phenylsulfonyl)amino]benzoic acid6042-[(2-C20 H15 Cl N2 O4383[M + H]Chlorophenyl)methoxy]-3-[(4-pyridinylcarbonyl)amino]benzoic acid6053-[(1,3-Benzodioxol-5-C22 H16 Cl N O6426[M + H]ylcarbonyl)amino]-2-[(2-chlorophenyl)methoxy]benzoic acid6063-[(Benzo[b]thiophen-2-C23 H16 Cl N O4 S434[M + H]ylcarbonyl)amino]-2-[(2-chlorophenyl)methoxy]benzoic acid6072-[(2-C20 H14 Cl2 N2 O4417[M + H]Chlorophenyl)methoxy]-3-[[(2-chloro-3-pyridinyl)carbonyl]amino]benzoic acid6082-[(2-C20 H15 Cl2 N O5 S452[M + H]Chlorophenyl)methoxy]-3-[[(3-chlorophenyl)sulfonyl]amino]benzoic acid6092-[(2-C20 H14 Cl2 N2 O4417[M + H]Chlorophenyl)methoxy]-3-[[(6-chloro-3-pyridinyl)carbonyl]amino]benzoic acid6103-[[(3-C23 H15 Cl2 N O4 S472[M + H]Chlorobenzo[b]thiophen-2-yl)carbonyl]amino]-2-[(2-chlorophenyl)methoxy]benzoic acid6113-[[(5-Bromo-3-C20 H14 Br Cl N2 O4461[M + H]pyridinyl)carbonyl]amino]-2-[(2-chlorophenyl)methoxy]benzoic acid6123-[[[3,5-Bis(methylthio)-4-C20 H17 Cl N2 O4 S3481[M + H]isothiazolyl]carbonyl]amino]-2-[(2-chlorophenyl)methoxy]benzoic acid6132-[(2-C21 H15 Br F N O4444[M + H]Bromophenyl)methoxy]-3-[(2-fluorobenzoyl)amino]benzoic acid6142-[(2-C21 H14 Br F2 N O4462[M + H]Bromophenyl)methoxy]-3-[(2,4-difluorobenzoyl)amino]benzoic acid6152-[(2-C21 H14 Br Cl2 N O4494[M + H]Bromophenyl)methoxy]-3-[(2,4-dichlorobenzoyl)amino]benzoic acid6162-[(2-C22 H18 Br N O5456[M + H]Bromophenyl)methoxy]-3-[(2-methoxybenzoyl)amino]benzoic acid6172-[(2-C22 H18 Br N O4440[M + H]Bromophenyl)methoxy]-3-[(2-methylbenzoyl)amino]benzoic acid6183-[(3-C21 H15 Br2 N O4504[M + H]Bromobenzoyl)amino]-2-[(2-bromophenyl)methoxy]benzoic acid6192-[(2-C21 H15 Br F N O4444[M + H]Bromophenyl)methoxy]-3-[(3-fluorobenzoyl)amino]benzoic acid6202-[(2-C21 H15 Br Cl N O4460[M + H]Bromophenyl)methoxy]-3-[(3-chlorobenzoyl)amino]benzoic acid6212-[(2-C22 H18 Br N O5456[M + H]Bromophenyl)methoxy]-3-[(3-methoxybenzoyl)amino]benzoic acid6222-[(2-C22 H18 Br N O4440[M + H]Bromophenyl)methoxy]-3-[(3-methylbenzoyl)amino]benzoic acid6232-[(2-C21 H15 Br F N O4444[M + H]Bromophenyl)methoxy]-3-[(4-fluorobenzoyl)amino]benzoic acid6242-[(2-C21 H15 Br Cl N O4460[M + H]Bromophenyl)methoxy]-3-[(4-chlorobenzoyl)amino]benzoic acid6252-[(2-C22 H18 Br N O5456[M + H]Bromophenyl)methoxy]-3-[(4-methoxybenzoyl)amino]benzoic acid6262-[(2-C25 H24 Br N O5498[M + H]Bromophenyl)methoxy]-3-[(4-butoxybenzoyl)amino]benzoic acid6273-[([1,1′-Biphenyl]-4-C27 H20 Br N O4502[M + H]ylcarbonyl)amino]-2-[(2-bromophenyl)methoxy]benzoic acid6282-[(2-C22 H15 Br F3 N O4494[M + H]Bromophenyl)methoxy]-3-[[4-(trifluoromethyl)benzoyl]amino]benzoic acid6292-[(2-C22 H18 Br N O4440[M + H]Bromophenyl)methoxy]-3-[(4-methylbenzoyl)amino]benzoic acid6302-[(2-C24 H22 Br N O4468[M + H]Bromophenyl)methoxy]-3-[(4-propylbenzoyl)amino]benzoic acid6312-[(2-C18 H18 Br N O4392[M + H]Bromophenyl)methoxy]-3-[(2-methyl-1-oxopropyl)amino]benzoicacid6322-[(2-C22 H18 Br N O5456[M + H]Bromophenyl)methoxy]-3-[(phenoxyacetyl)amino]benzoic acid6332-[(2-C23 H18 Br N O4452[M + H]Bromophenyl)methoxy]-3-[[(2E)-1-oxo-3-phenyl-2-propenyl]amino]benzoicacid6342-[(2-C19 H18 Br N O6436[M + H]Bromophenyl)methoxy]-3-[(3-ethoxy-1,3-dioxopropyl)amino]benzoicacid6352-[(2-C17 H16 Br N O4378[M + H]Bromophenyl)methoxy]-3-[(1-oxopropyl)amino]benzoicacid6362-[(2-C23 H20 Br N O4454[M + H]Bromophenyl)methoxy]-3-[(1-oxo-3-phenylpropyl)amino]benzoic acid6372-[(2-C21 H24 Br N O4434[M + H]Bromophenyl)methoxy]-3-[(1-oxoheptyl)amino]benzoicacid6382-[(2-C21 H15 Br I N O4552[M + H]Bromophenyl)methoxy]-3-[(4-iodobenzoyl)amino]benzoic acid6392-[(2-C20 H20 Br N O4418[M + H]Bromophenyl)methoxy]-3-[(cyclopentylcarbonyl)amino]benzoic acid6402-[(2-C22 H24 Br N O4446[M + H]Bromophenyl)methoxy]-3-[(3-cyclopentyl-1-oxopropyl)amino]benzoicacid6412-[(2-C21 H22 Br N O4432[M + H]Bromophenyl)methoxy]-3-[(cyclohexylcarbonyl)amino]benzoic acid6422-[(2-C19 H14 Br N O5416[M + H]Bromophenyl)methoxy]-3-[(2-furanylcarbonyl)amino]benzoic acid6432-[(2-C20 H16 Br N O4 S446[M + H]Bromophenyl)methoxy]-3-[(2-thienylacetyl)amino]benzoic acid6442-[(2-C20 H16 Br N O5 S462[M + H]Bromophenyl)methoxy]-3-[(phenylsulfonyl)amino]benzoic acid6452-[(2-C23 H20 Br N O5470[M + H]Bromophenyl)methoxy]-3-[[(3-methoxyphenyl)acetyl]amino]benzoic acid6462-[(2-C20 H15 Br N2 O4427[M + H]Bromophenyl)methoxy]-3-[(3-pyridinylcarbonyl)amino]benzoic acid6472-[(2-C20 H15 Br N2 O4427[M + H]Bromophenyl)methoxy]-3-[(4-pyridinylcarbonyl)amino]benzoic acid6483-[(1,3-Benzodioxol-5-C22 H16 Br N O6470[M + H]ylcarbonyl)amino]-2-[(2-bromophenyl)methoxy]benzoic acid6493-[(Benzo[b]thiophen-2-C23 H16 Br N O4 S482[M + H]ylcarbonyl)amino]-2-[(2-bromophenyl)methoxy]benzoic acid6502-[(2-C20 H15 Br Cl N O5 S496[M + H]Bromophenyl)methoxy]-3-[[(3-chlorophenyl)sulfonyl]amino]benzoic acid6512-[(2-C20 H14 Br2 N2 O4505[M + H]Bromophenyl)methoxy]-3-[[(5-bromo-3-pyridinyl)carbonyl]amino]benzoic acid6523-[(2-C21 H15 Br2 N O4504[M + H]Bromobenzoyl)amino]-2-[(4-bromophenyl)methoxy]benzoic acid6532-[(4-C22 H18 Br N O5456[M + H]Bromophenyl)methoxy]-3-[(2-methoxybenzoyl)amino]benzoic acid6542-[(4-C22 H18 Br N O4440[M + H]Bromophenyl)methoxy]-3-[(2-methylbenzoyl)amino]benzoic acid6553-[(3-C21 H15 Br2 N O4504[M + H]Bromobenzoyl)amino]-2-[(4-bromophenyl)methoxy]benzoic acid6562-[(4-C21 H15 Br Cl N O4460[M + H]Bromophenyl)methoxy]-3-[(3-chlorobenzoyl)amino]benzoic acid6572-[(4-C22 H18 Br N O5456[M + H]Bromophenyl)methoxy]-3-[(3-methoxybenzoyl)amino]benzoic acid6582-[(4-C22 H18 Br N O4440[M + H]Bromophenyl)methoxy]-3-[(3-methylbenzoyl)amino]benzoic acid6593-[(4-C21 H15 Br2 N O4504[M + H]Bromobenzoyl)amino]-2-[(4-bromophenyl)methoxy]benzoic acid6602-[(4-C21 H15 Br F N O4444[M + H]Bromophenyl)methoxy]-3-[(4-fluorobenzoyl)amino]benzoic acid6612-[(4-C21 H15 Br Cl N O4460[M + H]Bromophenyl)methoxy]-3-[(4-chlorobenzoyl)amino]benzoic acid6622-[(4-C22 H18 Br N O5456[M + H]Bromophenyl)methoxy]-3-[(4-methoxybenzoyl)amino]benzoic acid6632-[(4-C25 H24 Br N O5498[M + H]Bromophenyl)methoxy]-3-[(4-butoxybenzoyl)amino]benzoic acid6642-[(4-C22 H18 Br N O4440[M + H]Bromophenyl)methoxy]-3-[(4-methylbenzoyl)amino]benzoic acid6652-[(4-C24 H22 Br N O4468[M + H]Bromophenyl)methoxy]-3-[(4-propylbenzoyl)amino]benzoic acid6662-[(4-C22 H18 Br N O5456[M + H]Bromophenyl)methoxy]-3-[(phenoxyacetyl)amino]benzoic acid6672-[(4-C23 H18 Br N O4452[M + H]Bromophenyl)methoxy]-3-[[(2E)-1-oxo-3-phenyl-2-propenyl]amino]benzoicacid6682-[(4-C17 H16 Br N O4378[M + H]Bromophenyl)methoxy]-3-[(1-oxopropyl)amino]benzoicacid6692-[(4-C23 H20 Br N O4454[M + H]Bromophenyl)methoxy]-3-[(1-oxo-3-phenylpropyl)amino]benzoic acid6702-[(4-C21 H24 Br N O4434[M + H]Bromophenyl)methoxy]-3-[(1-oxoheptyl)amino]benzoicacid6712-[(4-C20 H20 Br N O4418[M + H]Bromophenyl)methoxy]-3-[(cyclopentylcarbonyl)amino]benzoic acid6722-[(4-C22 H24 Br N O4446[M + H]Bromophenyl)methoxy]-3-[(3-cyclopentyl-1-oxopropyl)amino]benzoicacid6732-[(4-C21 H22 Br N O4432[M + H]Bromophenyl)methoxy]-3-[(cyclohexylcarbonyl)amino]benzoic acid6742-[(4-C19 H14 Br N O5416[M + H]Bromophenyl)methoxy]-3-[(2-furanylcarbonyl)amino]benzoic acid6752-[(4-C20 H16 Br N O4 S446[M + H]Bromophenyl)methoxy]-3-[(2-thienylacetyl)amino]benzoic acid6762-[(4-C20 H16 Br N O5 S462[M + H]Bromophenyl)methoxy]-3-[(phenylsulfonyl)amino]benzoic acid6772-[(4-C20 H15 Br N2 O4427[M + H]Bromophenyl)methoxy]-3-[(3-pyridinylcarbonyl)amino]benzoic acid6782-[(4-C20 H15 Br N2 O4427[M + H]Bromophenyl)methoxy]-3-[(4-pyridinylcarbonyl)amino]benzoic acid6793-[(1,3-Benzodioxol-5-C22 H16 Br N O6470[M + H]ylcarbonyl)amino]-2-[(4-bromophenyl)methoxy]benzoic acid6803-[(Benzo[b]thiophen-2-C23 H16 Br N O4 S482[M + H]ylcarbonyl)amino]-2-[(4-bromophenyl)methoxy]benzoic acid6812-[(4-C20 H14 Br Cl N2 O4461[M + H]Bromophenyl)methoxy]-3-[[(2-chloro-3-pyridinyl)carbonyl]amino]benzoic acid6822-[(4-C23 H15 Br Cl N O4 S516[M + H]Bromophenyl)methoxy]-3-[[(3-chlorobenzo[b]thiophen-2-yl)carbonyl]amino]benzoicacid6833-[[[3,5-Bis(methylthio)-4-C20 H17 Br N2 O4 S3525[M + H]isothiazolyl]carbonyl]amino]-2-[(4-bromophenyl)methoxy]benzoic acid6843-[(2-C21 H22 Br N O4432[M + H]Bromobenzoyl)amino]-2-(cyclohexylmethoxy)benzoic acid6852-(Cyclohexylmethoxy)-3-C21 H21 F2 N O4390[M + H][(2,4-difluorobenzoyl)amino]benzoic acid6863-[(2-C21 H22 Cl N O4388[M + H]Chlorobenzoyl)amino]-2-(cyclohexylmethoxy)benzoic acid6872-(Cyclohexylmethoxy)-3-C21 H21 Cl2 N O4422[M + H][(2,4-dichlorobenzoyl)amino]benzoic acid6882-(Cyclohexylmethoxy)-3-[(2-C22 H25 N O5384[M + H]methoxybenzoyl)amino]benzoic acid6892-(Cyclohexylmethoxy)-3-[(2-C22 H25 N O4368[M + H]methylbenzoyl)amino]benzoic acid6903-[(3-C21 H22 Br N O4432[M + H]Bromobenzoyl)amino]-2-(cyclohexylmethoxy)benzoic acid6912-(Cyclohexylmethoxy)-3-[(3-C21 H22 F N O4372[M + H]fluorobenzoyl)amino]benzoic acid6923-[(3-C21 H22 Cl N O4388[M + H]Chlorobenzoyl)amino]-2-(cyclohexylmethoxy)benzoic acid6932-(Cyclohexylmethoxy)-3-C22 H25 N O5384[M + H][(3-methoxybenzoyl)amino]benzoic acid6942-(Cyclohexylmethoxy)-3-[(3-C22 H25 N O4368[M + H]methylbenzoyl)amino]benzoic acid6953-[(4-C21 H22 Br N O4432[M + H]Bromobenzoyl)amino]-2-(cyclohexylmethoxy)benzoic acid6962-(Cyclohexylmethoxy)-3-C21 H22 F N O4372[M + H][(4-fluorobenzoyl)amino]benzoic acid6973-[(4-C21 H22 Cl N O4388[M + H]Chlorobenzoyl)amino]-2-(cyclohexylmethoxy)benzoic acid6982-(Cyclohexylmethoxy)-3-[(4-C22 H25 N O5384[M + H]methoxybenzoyl)amino]benzoic acid6993-[(4-C25 H31 N O5426[M + H]Butoxybenzoyl)amino]-2-(cyclohexylmethoxy)benzoic acid7003-[([1,1′-Biphenyl]-4-C27 H27 N O4430[M + H]ylcarbonyl)amino]-2-(cyclohexylmethoxy)benzoic acid7012-(Cyclohexylmethoxy)-3-C22 H22 F3 N O4422[M + H][[4-(trifluoromethyl)benzoyl]amino]benzoic acid7022-(Cyclohexylmethoxy)-3-C22 H25 N O4368[M + H][(4-methylbenzoyl)amino]benzoic acid7032-(Cyclohexylmethoxy)-3-C24 H29 N O4396[M + H][(4-propylbenzoyl)amino]benzoic acid7042-(Cyclohexylmethoxy)-3-C18 H25 N O4320[M + H][(1-0x0-2-methylpropyl)amino]benzoic acid7052-(Cyclohexylmethoxy)-3-C22 H25 N O5384[M + H][(phenoxyacetyl)amino]benzoic acid7062-(Cyclohexylmethoxy)-3-C23 H25 N O4380[M + H][[(2E)-1-oxo-3-phenyl-2-propenyl]amino]benzoicacid7072-(Cyclohexylmethoxy)-3-[(1-C17 H23 N O4306[M + H]oxopropyl)amino]benzoicacid7082-(Cyclohexylmethoxy)-3-C23 H27 N O4382[M + H][(1-oxo-3-phenylpropyl)amino]benzoic acid7092-(Cyclohexylmethoxy)-3-[(1-C21 H31 N O4362[M + H]oxoheptyl)amino]benzoicacid7102-(Cyclohexylmethoxy)-3-C18 H23 N O4318[M + H][(cyclopropylcarbonyl)amino]benzoic acid7112-(Cyclohexylmethoxy)-3-C20 H27 N O4346[M + H][(cyclopentylcarbonyl)amino]benzoic acid7122-(Cyclohexylmethoxy)-3-C22 H31 N O4374[M + H][(3-cyclopentyl-1-oxopropyl)amino]benzoicacid7133-C21 H29 N O4360[M + H][(Cyclohexylcarbonyl)amino]-2-(cyclohexylmethoxy)benzoic acid7142-(Cyclohexylmethoxy)-3-C19 H21 N O5344[M + H][(2-furanylcarbonyl)amino]benzoic acid7152-(Cyclohexylmethoxy)-3-C20 H23 N O4 S374[M + H][(2-thienylacetyl)amino]benzoic acid7162-(Cyclohexylmethoxy)-3-C20 H23 N O5 S390[M + H](phenylsulfonyl)amino]benzoic acid7172-(Cyclohexylmethoxy)-3-[[(3-C23 H27 N O5398[M + H]methoxyphenyl)acetyl]amino]benzoic acid7182-(Cyclohexylmethoxy)-3-[(3-C20 H22 N2 O4355[M + H]pyridinylcarbonyl)amino]benzoic acid7192-(Cyclohexylmethoxy)-3-C20 H22 N2 O4355[M + H][(4-pyridinylcarbonyl)amino]benzoic acid7203-[(1,3-Benzodioxol-5-C22 H23 N O6398[M + H]ylcarbonyl)amino]-2-(cyclohexylmethoxy)benzoic acid7213-[(Benzo[b]thiophen-2-C23 H23 N O4 S410[M + H]ylcarbonyl)amino]-2-(cyclohexylmethoxy)benzoic acid7223-[[(2-Chloro-3-C20 H21 Cl N2 O4389[M + H]pyridinyl)carbonyl]amino]-2-(cyclohexylmethoxy)benzoic acid7233-[[(3-C20 H22 Cl N O5 S424[M + H]Chlorophenyl)sulfonyl]amino]-2-(cyclohexylmethoxy)benzoic acid7243-[[(6-Chloro-3-C20 H21 Cl N2 O4389[M + H]pyridinyl)carbonyl]amino]-2-(cyclohexylmethoxy)benzoic acid7253-[[(5-Bromo-3-C20 H21 Br N2 O4433[M + H]pyridinyl)carbonyl]amino]-2-(cyclohexylmethoxy)benzoic acid7263-(Benzoylamino)-2-[(2-C21 H16 Br N O4426[M + H]bromophenyl)methoxy]benzoic acid7273-(Benzoylamino)-2-[(2-C21 H16 Cl N O4382[M + H]chlorophenyl)methoxy]benzoic acid7283-(Benzoylamino)-2-C21 H23 N O4354[M + H](cyclohexylmethoxy)benzoic acid

Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein

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