# Patent

## Title
4-Biarylyl-1-phenylazetidin-2-ones

## Abstract

4-Biarylyl-1-phenylazetidin-2-ones useful for the treatment of hypercholesterolemia are disclosed. The compounds are of the general formula




in which





represents an aryl or heteroaryl residue; Ar represents an aryl residue; U is a two to six atom chain; and the R's represent substituents.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority from U.S. provisional applications Ser. Nos. 60/518,698; 60/549,577; 60/592,529; and 60/614,005, filed Nov. 10, 2003; Mar. 3, 2004; Jul. 30, 2004; and Sep. 28, 2004, respectively. The entire disclosures of all are incorporated herein by reference.


FIELD OF THE INVENTION
The invention relates to a chemical genus of 4-biarylyl-1-phenylazetidin-2-ones useful for the treatment of hypercholesterolemia and cholesterol-associated benign and malignant tumors.
BACKGROUND OF THE INVENTION
1,4-Diphenylazetidin-2-ones and their utility for treating disorders of lipid metabolism are described in U.S. Pat. No. 6,498,156, USRE37,721 and PCT application WO02/50027, the disclosures of which are incorporated herein by reference as they relate to utility.
SUMMARY OF THE INVENTION
In one aspect the invention relates to compounds of formula:




which comprises compounds of two closely related genera, Φ and Ψ:





wherein





represents an aryl or heteroaryl residue; Ar represents an aryl residue; R1 represents one, two, three, four or five residues chosen independently from H, halogen, —OH, loweralkyl, OCH3, OCF2H, OCF3, CH3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, —PO3H2, —SO3H, —B(OH)2, a sugar, a polyol, a glucuronide and a sugar carbamate; R2 represents one, two, three, four or five residues chosen independently from H, halogen, —OH, loweralkyl, OCH3, OCF2H, OCF3, CH3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO3H2, —SO3H, —B(OH)2, a sugar, a polyol, a glucuronide and a sugar carbamate; R4 represents one, two, three or four residues chosen independently from H, halogen, —OH, loweralkyl, —O-loweralkyl, hydroxyloweralkyl, —CN, CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO3H2, —SO3H, —B(OH)2, a sugar, a polyol, a glucuronide and a sugar carbamate; R4f is —OH, —SH or —B(OH)2; R5g represents one, two, three, four or five residues on Ar chosen independently from halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO3H2, —SO3H, —B(OH)2, a sugar, a polyol, a glucuronide and a sugar carbamate; R5h represents one, two, three, four or five residues on Ar chosen independently from hydrogen, halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO3H2, —SO3H, —B(OH)2, a sugar, a polyol, a glucuronide and a sugar carbamate; U is (C2-C6)-alkylene in which one or more —CH2— may be replaced by a radical chosen from —S—, —S(O)—, —SO2—, —O—, —C(═O)—, —CHOH—, —NH—, CHF, CF2, —CH(O-loweralkyl)-, —CH(O-loweracyl)-, —CH(OSO3H)—, —CH(OPO3H2)—, —CH(OB(OH)2)—, or —NOH—, with the provisos that (1) adjacent —CH2— residues are not replaced by —S—, —S(O)—, —SO2— or —O—; and (2)—S—, —S(O)—, —SO2—, —O— and —NH— residues are not separated only by a single carbon; Ua is the same as U except that Ua excludes —CH2CH2CH(OH)—.

The genera Φ and Ψ exclude compounds in which R5g is —CN; 2,5-dimethoxy; 2,6-dimethoxy or halogen when neither ring of the biphenyl residue is further substituted.

The genera Φ and Ψ also exclude compounds in which R5g is 2-hydroxy when





represents a 2,5-thienyl residue.

Subgenera include biphenyl compounds of general formulae I-VII:







In formula I, R1 and R2 represent one or two residues chosen independently from H, halogen, —OH, loweralkyl, OCH3, OCF2H, OCF3, CH3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, a sugar, a glucuronide and a sugar carbamate; R3 is chosen from H, —OH, fluoro, —O-loweralkyl and —O-acyl; R4 represents one, two, three or four residues chosen independently from H, halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, a sugar, a glucuronide and a sugar carbamate; R5f represents one, two, three, four or five residues chosen independently from halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, a sugar, a glucuronide a sugar carbamate and —N+R6R7R8X−; R6 is C1 to C20 hydrocarbon or forms a five- to seven-membered ring with R7; R7 is alkyl or forms a five- to seven-membered ring with R6; R8 is alkyl or together with R6 or R7 forms a second five- to seven-membered ring; and X is an anion.
In formula II one of R1a, R4a and R5a is -Q-A-N+R9R10R11X− and the other two of R1a, R4a and R5a are chosen independently from hydrogen, halogen, —OH, loweralkyl, OCH3, OCF2H, OCF3, CH3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy. R2a represents one or two residues chosen independently from H, halogen, —OH, loweralkyl, OCH3, OCF2H, OCF3, CH3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy and benzyloxy. R3 is chosen from H, —OH, fluoro, —O-loweralkyl and —O-acyl. Q is chosen from a direct bond, —O—, —S—, —NH—, —CH2O—, —CH2NH—, —C(═O)—, —CONH—, —NHCO—, —O(C═O)—, —(C═O)O—, —NHCONH—, —OCONH— and —NHCOO—. A is chosen from C2 to C20 hydrocarbon, substituted alkyl of 2 to 20 carbons, substituted aryl, substituted arylalkyl, and oxaalkyl of four to fifty carbons; and, when Q is a direct bond, —C(═O) or —O(C═O)—, A may additionally be methylene. R9 is C1 to C20 hydrocarbon or forms a five- to seven-membered ring with A or R10; R10 is alkyl, forms a double bond with A or forms a five- to seven-membered ring with R9; R11 is alkyl or together with R10 or R9 forms a second five- to seven-membered ring; and X is an anion.
In formula III, R2b represents one or two residues chosen independently from H, halogen, —OH, loweralkyl, OCH3, OCF2H, OCF3, CH3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy. R3 is chosen from H, —OH, fluoro, —O-loweralkyl and —O-acyl. One of R1b, R4b and R5b is R12 and the other two of R1b, R4b and R5b are chosen independently from hydrogen, halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, a sugar, a glucuronide, and a sugar carbamate; R12 is (C0 to C30)alkylene-Gn in which one or more —CH2— residues in said alkylene may be replaced by —S—, —SO—, SO2—, —O—, —NH—, —N(alkyl)-, —N(phenyl)-, —N(alkylphenyl)-, —N+(alkyl)2—, —N+(phenyl)2—, —N+(alkylphenyl)2—, —C(═O)—, —C(═S), CH═CH—, —C═C—, phenylene or —N[(C═O)alkyleneCOOH]—; G is chosen from —SO3H, —PO3H2, —O—PO3H2, —COOH, —C(N═H)NH2, a polyol, a sugar, a glucuronide, a sugar carbamate, —N+R6aR7aR8aX−, and a mono or bicyclic trialkylammoniumalkyl residue; R6a is C1 to C20 hydrocarbon; R7a is alkyl; R8a is alkyl; n is one, two, three, four or five and X is an anion.
In compounds of formula IV, R1c and R2c represent one or two residues chosen independently from H, halogen, —OH, loweralkyl, OCH3, OCF2H, OCF3, CH3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, hydroxyamidino, guanidino, dialkylguanidino, phenyl, benzyl, phenoxy, benzyloxy, a glucuronide, and a sugar carbamate. R3 is chosen from H, —OH, fluoro, —O-loweralkyl and —O-acyl. R4c represents one, two, three or four residues chosen independently from H, halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, a glucuronide and a sugar carbamate; and R5f represents one, two, three, four or five residues chosen independently from halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, a sugar, a glucuronide a sugar carbamate and —N+R6R7R8X−.
In compounds of formula V, R1a, R2a and R4a each represents one or two residues chosen independently from H, halogen, —OH, loweralkyl, OCH3, OCF2H, OCF3, CH3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy. R3 is chosen from H, —OH, fluoro, —O-loweralkyl and —O-acyl. R5c is -Q-A-N+R9R10R11R11X−; Q is chosen from a direct bond, —O—, —S—, —NH—, —CH2O—, —CH2NH—, —C(═O)—, —CONH—, —NHCO—, —CH2NH(C═O)—, —O(C═O)—, —(C═O)O—, —NHCONH—, —OCONH— and —NHCOO—; and A is chosen from C2 to C20 hydrocarbon, substituted alkyl of 2 to 20 carbons, substituted aryl, substituted arylalkyl, and oxaalkyl of four to fifty carbons; and, when Q is a direct bond, —C(═O) or —O(C═O)—, A may additionally be methylene.
In compounds of formula V1, R2b represents one or two residues chosen independently from H, halogen, —OH, loweralkyl, OCH3, OCF2H, OCF3, CH3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy. R3 is chosen from H, —OH, fluoro, —O-loweralkyl and —O-acyl. One of Rd, R4d and R5d is R12a and the other two of R1d, R4d and R5d are chosen independently from hydrogen, halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy and R12a;
R12a is




or, when R5d is R12a, R12a may additionally be (C0 to C30)alkylene-Gn in which one or more —CH2— residues in said alkylene may be replaced by —S—, —SO—, SO2—, —O—, —NH—, —N(alkyl)-, —N(phenyl)-, —N(alkylphenyl)-, —N+(alkyl)2—, —N+(phenyl)2—, —N+(alkylphenyl)2—, —C(═O)—, —C(═S), CH═CH—, —C═C—, phenylene or —N[(C═O)alkyleneCOOH]—; G is chosen from —SO3H, —PO3H2, —O—PO3H2, —COOH, —C(N═H)NH2, a polyol, a sugar, a glucuronide, a sugar carbamate, —N+R6aR7aR8aX−, and a mono or bicyclic trialkylammoniumalkyl residue; R13 is chosen from a direct bond, —C═C—, —OCH2, —C(═O)— and —CHOH—; R14 is chosen from —OH and —OC(═O)alkyl; R15 is chosen from —CH2OH, —CH2C(═O)alkyl and —COOalkyl; j is 1-5; k is zero or 1-5; and n is 1-5.

In compounds of formula VII, R1e, R2a and R4e each represents one or two residues chosen independently from H, halogen, —OH, loweralkyl, OCH3, OCF2H, OCF3, CH3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy. R3 is chosen from H, —OH, fluoro, —O-loweralkyl and —O-acyl. R5e is chosen from




and (C0 to C30)alkylene-Gn in which one or more —CH2— residues in said alkylene may be replaced by —S—, —SO—, SO2—, —O—, —NH—, —N(alkyl)-, —N(phenyl)-, —N(alkylphenyl)-, —N+(alkyl)2-, —N+(phenyl)2-, —N+(alkylphenyl)2—, —C(═O)—, —C(═S), CH═CH—, —C═C—, phenylene or —N[(C═O)alkyleneCOOH]—.

In a second aspect the invention relates to pharmaceutical formulations comprising a pharmaceutically acceptable carrier and a compound of the invention having a pharmaceutically acceptable counter anion and, optionally additionally comprising one or more of (1) an inhibitor of cholesterol biosynthesis; (2) a cholesterol ester transfer protein (CETP) inhibitor; (3) a bile acid sequestrant; (4) a nicotinic acid or derivative thereof; (5) a peroxisome proliferator-activator receptor alpha agonist; (6) an acylcoenzyme A:cholesterol acyltransferase (ACAT) inhibitor; (7) an obesity control medication; (8) a hypoglycemic agent; (9) an antioxidant and (10) an antihypertensive compound.
In a third aspect, the invention relates to methods for preventing and/or treating a disorder of lipid metabolism, including hyperlipidemia, sitosterolemia and arteriosclerotic symptoms; inhibiting the absorption of cholesterol from the intestine; reducing the blood plasma or serum concentrations of LDL cholesterol; reducing the concentrations of cholesterol and cholesterol ester in the blood plasma or serum; reducing blood plasma or serum concentrations of C-reactive protein (CRP), reducing blood plasma or serum concentrations of triglycerides; reducing blood plasma or serum concentrations of apolipoprotein B; increasing blood plasma or serum concentrations of high density lipoprotein (HDL) cholesterol; increasing the fecal excretion of cholesterol; treating a clinical condition for which a cholesterol absorption inhibitor is indicated; reducing the incidence of cardiovascular disease-related events; reducing plasma or tissue concentration of at least one non-cholesterol sterol or 5α-stanol; treating or preventing vascular inflammation; preventing, treating, or ameliorating symptoms of Alzheimer's Disease; regulating the production or level of at least one amyloid β peptide in the bloodstream and/or brain of a subject; regulating the amount of ApoE isoform 4 in the bloodstream and/or brain; preventing and/or treating obesity; and preventing or decreasing the incidence of xanthomas. The methods comprise administering a compound described herein.
In a fourth aspect, the invention relates to methods and compositions for prevention or treatment of a cholesterol-associated tumor. The methods comprise administering a therapeutically effective amount of a compound of the invention to a patient at risk of developing a cholesterol-associated tumor or already exhibiting a cholesterol-associated tumor. The method also includes coadministering a therapeutically effective amount of a compound of the invention and at least one other anticancer agent.
In a fifth aspect, the invention relates to an article of manufacture comprising a container, instructions, and a pharmaceutical formulation as described above. The instructions are for the administration of the pharmaceutical formulation for a purpose chosen from: the prevention or treatment of a disorder of lipid metabolism; inhibiting the absorption of cholesterol from the intestine; reducing the plasma or tissue concentration of at least one non-cholesterol sterol or 5α-stanol; reducing the blood plasma or serum concentrations of LDL cholesterol; reducing the concentrations of cholesterol and cholesterol ester in the blood plasma or serum; increasing the fecal excretion of cholesterol; reducing the incidence of cardiovascular disease-related events; reducing blood plasma or serum concentrations of C-reactive protein (CRP); treating or preventing vascular inflammation; reducing blood plasma or serum concentrations of triglycerides; increasing blood plasma or serum concentrations of HDL cholesterol; reducing blood plasma or serum concentrations of apolipoprotein B; preventing, treating, or ameliorating symptoms of Alzheimer's Disease; regulating the production of amyloid β peptide; regulating the amount of ApoE isoform 4 in the bloodstream and/or brain; preventing and/or treating obesity; preventing or decreasing the incidence of xanthomas; and preventing or treating a cholesterol-associated tumor.


DETAILED DESCRIPTION OF THE INVENTION
Compounds of the genus represented by formulae Φ, Ψ, and I-VII above are inhibitors of cholesterol absorption from the intestine. As such they have utility in treating and preventing lipid disorders, such as hypercholesterolemia and hyperlipidemia. Because of their effect in lowering serum lipids, the compounds are useful in the treatment and prevention of atherosclerosis. The compounds can be used advantageously in combination with other hypolipidemic agents, including inhibitors of cholesterol biosynthesis, such as HMG-CoA reductase inhibitors. HMG-CoA reductase inhibitors include the “statins”: lovastatin, simvastatin, pravastatin, rosuvastatin, mevastatin, atorvastatin, cerivastatin, pitavastatin, fluvastatin, bervastatin, crilvastatin, carvastatin, rivastatin, sirrivastatin, glenvastatin and dalvastatin. A further listing of non-limiting examples of antihyperlipidemic agents that may be used in combination with the compounds of the present invention may be found in columns 5-6 of U.S. Pat. No. 6,498,156, and in PCT WO 04/004778, the disclosures of which are incorporated herein by reference. As described above, the formulation may additionally contain at least one bile acid sequestrant. Sequestrants include cholestyramine, colestipol and colesevelam hydrochloride. The formulation may also contain a nicotinic acid or derivative thereof. Nicotinic acid derivatives include niceritrol, nicofuranose and acipimox. The formulation may also contain a peroxisome proliferator-activator receptor alpha agonist, which may be a fibric acid derivative. Fibric acids include fenofibrate, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, clinofibrate, binifibrate and lifibrol. The formulation may also contain a CETP inhibitor. Examples of such are the compounds identified as JTT-705 in Nature. 406, (6792):203-7 (2000) and CP-529,414 (torcetrapib), described in US20030186952 and WO2000017164. Examples of CETP inhibitors are also found in Current Opinion in Investigational Drugs. 4(3):291-297 (2003). The formulation may also contain an ACAT inhibitor. Examples of such are the compounds identified as avasimibe in Current Opinion in Investigational Drugs. 3(9):291-297 (2003), and CL-277,082 in Clin Pharmacol Ther. 48(2):189-94 (1990). The formulation may also contain an obesity control medication. Examples of obesity control medications include gut hormone fragment peptide YY3-36 (PYY3-36)(N. Engl. J. Med. 349:941, 2003; IKPEAPGE DASPEELNRY YASLRHYLNL VTRQRY) or a variant thereof, glp-1 (glucagon-like peptide-1), exendin-4 (an inhibitor of glp-1), sibutramine, phentermine, phendimetrazine, benzphetamine hydrochloride (Didrex), orlistat (Xenical), diethylpropion hydrochloride (Tenuate), fluoxetine (Prozac), bupropion, ephedra, chromium, garcinia cambogia, benzocaine, bladderwrack (focus vesiculosus), chitosan, nomame herba, galega (Goat's Rue, French Lilac), conjugated linoleic acid, L-camitine, fiber (psyllium, plantago, guar fiber), caffeine, dehydroepiandrosterone, germander (teucrium chamaedrys), B-hydroxy-β-methylbutyrate, ATL-962 (Alizyme PLC), T71 (Tularik, Inc.; Boulder Colo.), a ghrelin antagonist, Acomplia (rimonabant), AOD9604, alpha-lipoic acid (alpha-LA), and pyruvate. The formulation may also contain a hypoglycemic agent. Examples of of classes of hypoglycemic agents include the peroxisome proliferator-activator receptor gamma agonists (including, e.g. rosiglitazone, pioglitazone, ciglitazone; and metformin, phenformin, carbutamide, tolbutamide, acetohexamide, tolazamide, chlorpropamide, glyburide [glibenclamide], glipizide, and gliclazide). The formulation may also contain an antioxidant. Examples of antioxidants include probucol and AGI-1067.
The formulation may also contain an antihypertensive compound. Examples of classes of antihypertensive compounds include thiazide derivatives, β-adrenergic blockers, calcium-channel blockers, angiotensin-converting-enzyme (ACE) inhibitor, and angiotensin II receptor antagonists. Examples of thiazide derivatives include hydrochlorothiazide, chlorothiazide, and polythiazide. Examples of β-adrenergic blockers include atenolol, metoprolol, propranolol, timolol, carvedilol, nadolol, and bisoprolol. Examples of calcium-channel blockers include isradipine, verapamil, nitrendipine, amlodipine,nifedipine, nicardipine, isradipine, felodipine, nisoldipine, and diltiazem. Examples of angiotensin-converting-enzyme (ACE) inhibitors include delapril, captopril, enalopril, lisinopril, quinapril, perindopril, benazepril, trandolapril, fosinopril, ramipril, and ceranapril. Examples of angiotensin II receptor antagonists include candesartan, irbesartan, olmesartan, telmisartan, and aprosartan.
In one embodiment, the invention comprises a compound of the invention together with a statin. In another embodiment, the invention further comprises an agent chosen from niacin, a sequestrant and a fibrate. In another embodiment, the invention comprises a compound of the invention together with a statin, niacin, a sequestrant and a fibrate.
The present invention is also directed to methods of prevention or treatment of a cholesterol-associated tumor in patients who are either at risk of developing a cholesterol-associated tumor or already exhibit a cholesterol-associated tumor. The tumor may be either a benign or a malignant tumor of the prostate, breast, endometrium or colon. The compounds of the invention may be co-administered with at least one other anticancer agent, which may be a steroidal antiandrogen, a non-steroidal antiandrogen, an estrogen, diethylstilbestrol, a conjugated estrogen, a selective estrogen receptor modulator (SERM), a taxane, or an LHRH analog. Tests showing the efficacy of the therapy and the rationale for combination therapy are presented in PCT application WO 2004/010948, the disclosure of which is incorporated herein by reference.
The compounds of the invention may reduce both cholesterol levels in vivo and epoxycholesterol formation and thereby inhibit initiation and progression of benign and malignant cholesterol-associated tumors or cholesterol-associated cell growth or cell-masses. Compositions disclosed herein, for example, are useful for the treatment and/or prevention of benign prostatic hypertrophy, as well as tumors associated with prostate, colon, endometrial, or breast tissues.
Compositions of the invention comprise an effective dose or a pharmaceutically effective amount or a therapeutically effective amount of a compound described above and may additionally comprise at least one other anticancer agent, for the treatment or prevention of benign prostatic hypertrophy or other cholesterol-related benign or malignant tumors, particularly those associated with prostate, breast, endometrial or colon tissues. Examples of agents for use in compositions and methods of the invention include steroidal or non steroidal antiandrogens such as finasteride (PROSCAR®), cyproterone acetate (CPA), flutamide (4′-nitro-3′-trifluorormethyl isobutyranilide), bicalutamide (CASODEX®), and nilutamide; estrogens, diethylstilbestrol (DES); conjugated estrogens (e.g., PREMARIN®); selective estrogen receptor modulator (SERM) compounds such as tamoxifen, raloxifene, droloxifene, idoxifene; taxanes such as paclitaxel (TAXOL®) and docetaxel (TAXOTERE®); and LHRH analogs such as goserelin acetate (ZOLADEX®), and leuprolide acetate (LUPRON®).
Methods of the invention parallel the compositions and formulations. The methods comprise co-administering to a patient in need of treatment a therapeutically effective amount of an azetidinone according to the invention and one or more of: (a) a steroidal or non steroidal antiandrogen; (b) an estrogen; (c) diethylstilbestrol (DES); (d) a conjugated estrogen; (e) a selective estrogen receptor modulator (SERM); (f) a taxane; and (g) an LHRH analog. The term “selective estrogen receptor modulator” includes both estrogen agonist and estrogen antagonists and refers to compounds that bind with the estrogen receptor, inhibit bone turnover and prevent bone loss. In particular, estrogen agonists are compounds capable of binding to the estrogen receptor sites in mammalian tissue and mimicking the actions of estrogen in that tissue. Estrogen antagonists are compounds capable of binding to the estrogen receptor sites in mammalian tissue and blocking the actions of estrogen in that tissue. Exemplary SERMs are: tamoxifen (U.S. Pat. No. 4,536,516); 4-hydroxytamoxifen (U.S. Pat. No. 4,623,660); raloxifene (U.S. Pat. No. 4,418,068); idoxifene (U.S. Pat. No. 4,839,155; and droloxifene. For the taxanes see U.S. Pat. Nos. 6,395,770; 6,380,405; and 6,239,167. Azetidinones of the invention may also be combined with a steroidal or non steroidal antiandrogen, as described above.
Certain compounds of the invention may have the additional advantage that they suppress serum cholesterol and/or LDL levels while themselves not being appreciably absorbed into the mammalian circulation upon oral administration. As a result of the low-to-insignificant serum levels, fewer side-effects, such as drug-drug interactions, are observed.
Subgenera according to the invention include compounds of formulae Φ and Ψ in which U is chosen from —CH2CH2CH(OH)—, —SCH2CH2—, —S(O)CH2CH2—, —SCH2C(═O)—, —SCH2CH(OH)—, —CH(OH)CH2CH2— and —(CH2)4—, wherein the left end of the string is the point of attachment to the azetidinone ring and the right end of the string is the point of attachment to the phenyl ring. Other subgenera of compounds of formulae Φ and Ψ include ΦA and ΨA




Futher subgenera include compounds of formulae ΦA and ΨA in which the ring bearing R5 is in the para position, e.g.:




In another subgenus R1 may be H or 4-fluoro; R2 may be 4-fluoro; and R4 may be H or hydroxy. In another subgenus, R4 and R5 are both hydroxy.

Other subgenera according to the invention include compounds in which R1, R1a, R2, R2a, R4 and R4a are chosen independently from H, halogen, —OH, and methoxy; compounds in which R1, R2, R4 and R5 are chosen from H, a sugar, a glucuronide and a sugar carbamate; compounds in which R3 is chosen from hydrogen and hydroxy; compounds in which R4 or R4a is hydrogen; compounds in which R5 or R5a is chosen from halogen, hydroxy, loweralkyl, —O-loweralkyl, CF3, alkylsulfonyl and arylsulfonyl. Examples of compounds of formula II include those in which one of R1a, R1a and R5a is -Q-A-N+R9R10R11X− and -Q-A- is chosen from (C2 to C20 hydrocarbon), —O—(C2 to C20 hydrocarbon), —NH(C2 to C20 hydrocarbon), —NHCO(C2 to C20 hydrocarbon) and oxaalkyl of four to twenty carbons. In this series of compounds, R9, R10 and R11 are (1) loweralkyl or benzyl, or (2) R9, R10 and R11 taken together form a diazabicyclooctane quat:




or (3) R9, R10 and R11 taken together form a quinuclidinium quat:





Some of the compounds of the invention are quaternary salts, i.e. cationic species. Therefore they will always be presented as salts. Other compounds of formula I may contain basic or acidic residues, allowing them to be presented as salts. In the claims, reference to the acid includes its salts. Thus, for example, a claim to 4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid is intended to encompass as well sodium 4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonate. The term “pharmaceutically acceptable salt” refers to salts whose counter ion derives from pharmaceutically acceptable non-toxic acids and bases. When the compounds contain a quat or a basic residue, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include inorganic acids, organic acids and, in the case of quats, water (which formally furnishes the hydroxide anion). Examples include hydroxide, acetate, benzenesulfonate (besylate), benzoate, bicarbonate, bisulfate, carbonate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, glycolate, bromide, chloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, trifluoroacetate, p-toluenesulfonate, acetamidobenzoate, adipate, alginate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, calcium edetate, camphorate, camsylate, caprate, caproate, caprylate, cinnamate, cyclamate, dichloroacetate, edetate (EDTA), edisylate, embonate, estolate, esylate, fluoride, formate, gentisate, gluceptate, glucuronate, glycerophosphate, glycolate, glycollylarsanilate, hexylresorcinate, hippurate, hydroxynaphthoate, iodide, lactobionate, malonate, mesylate, napadisylate, napsylate, nicotinate, oleate, orotate, oxalate, oxoglutarate, palmitate, pectinate, pectinate polymer, phenylethylbarbiturate, picrate, pidolate, propionate, rhodamide, salicylate, sebacate, stearate, tannate, theoclate, tosylate, and the like. When the compounds contain an acidic residue, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include ammonium, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Other base addition salts includes those made from: arecoline, arginine, barium, benethamine, benzathine, betaine, bismuth, clemizole, copper, deanol, diethylamine, diethylaminoethanol, epolamine, ethylenediamine, ferric, ferrous, glucamine, glucosamine, histidine, hydrabamine, imidazole, isopropylamine, manganic, manganous, methylglucamine, morpholine, morpholineethanol, n-ethylmorpholine, n-ethylpiperidine, piperazine, piperidine, polyamine resins, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trolamine, and tromethamine.
In certain subgenera of compounds of formulae III, VI and VII, R1b is R12; R2b and R4b are chosen from H, halogen, —OH, and methoxy; R12 is (C6 to C20)alkylene-G in which one or more —CH2— residues in said alkylene may be replaced by —O—, —NH—, —N(alkyl)-, —C(═O)— or —CH═CH—; and G is chosen from —SO3H, a polyol, and a sugar. In a further embodiment, R5 is R12; R1, R2 and R4 are chosen from H, halogen, —OH, and methoxy; R12 is (C6 to C20)alkylene-G in which one or more —CH2— residues in said alkylene may be replaced by —O—, —NH—, —N(alkyl)-, —C(═O)— or —CH═CH—; and G is chosen from —SO3H, a polyol, and a sugar.
Definitions
Throughout this specification the terms and substituents retain their definitions.
Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. When not otherwise restricted, the term refers to alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like. Methyl is preferred. Preferred alkyl and alkylene groups are those of C20 or below (e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20). Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5, 6, 7, and 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.
C1 to C20 Hydrocarbon (e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20) includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. The term “phenylene” refers to ortho, meta or para residues of the formulae:




Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. Methoxy is preferred.
Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like. The term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, ¶196, but without the restriction of ¶127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds). Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
Polyol refers to a compound or residue having a plurality of —OH groups. Polyols may be thought of as alkyls in which a plurality of C—H bonds have been replaced by C—OH bonds. Common polyol compounds include for example glycerol, erythritol, sorbitol, xylitol, mannitol and inositol. Linear polyol residues will generally be of the empirical formula —CyH2y+1Oy, and cyclic polyol residues will generally be of the formula —CyH2y+1Oy. Those in which y is 3, 4, 5 and 6 are preferred. Cyclic polyols also include reduced sugars, such as glucitol.
Acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include, acetyl, propionyl, isobutyryl, t-butoxycarbonyl, benzoyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to four carbons.
Aryl and heteroaryl refer to aromatic or heteroaromatic rings, respectively, as substituents. Heteroaryl contains one, two or three heteroatoms selected from O, N, or S. Both refer to monocyclic 5- or 6-membered aromatic or heteroaromatic rings, bicyclic 9- or 10-membered aromatic or heteroaromatic rings and tricyclic 13- or 14-membered aromatic or heteroaromatic rings. Aromatic 6, 7, 8, 9, 10, 11, 12, 13 and 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5, 6, 7, 8, 9 and 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl and the like.
Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.
The term “halogen” means fluorine, chlorine, bromine or iodine.
The term “sugar” is used in its normal sense, as defined in Hawley's Condensed Chemical Dictionary 12th Edition, Richard J. Lewis, Sr.; Van Nostrand Reinhold Co. New York. It encompasses any carbohydrate comprised of one or two saccharose groups. The monosaccharide sugars (often called simple sugars) are composed of chains of 2-7 carbon atoms. One of the carbons carries aldehydic or ketonic oxygen, which may be combined in acetal or ketal forms. The remaining carbons usually have hydrogen atoms and hydroxyl groups (or protecting groups for hydroxyl, such as acetate). Among monosaccharides which would be considered within the term “sugars” as intended in this application, are arabinose, ribose, xylose, ribulose, xylulose, deoxyribose, galactose, glucose, mannose, fructose, sorbose, tagatose, fucose, quinovose, rhamnose, manno-heptulose and sedoheptulose. Among the disaccharides are sucrose, lactose, maltose, and cellobiose. Unless specifically modified, the general term “sugar” refers to both D-sugars and L-sugars. The sugar may also be protected. The sugar may be attached through oxygen (as in U.S. Pat. No. 5,756,470) or through carbon (as in PCT WO 2002066464), the disclosures of both of which are incorporated herein by reference.
Reduced C-attached sugars or C-glycosyl compounds are also encompassed by the invention. The reduced sugars (e.g. glucitol), which could be classed either as polyols or as sugars, are also known as alditols. Alditols are polyols having the general formula HOCH2[CH(OH)]nCH2OH (formally derivable from an aldose by reduction of the carbonyl group.
The term “glucuronide” is also used in its normal sense to refer to a glycoside of glucuronic acid.
The term “sugar carbamate” refers to mono-, di- and oligosaccharides in which one or more hydroxyls have been derivatized as carbamates, particularly as phenyl carbamates and substituted phenyl carbamates. [See Detmers et al. Biochim Biophys. Acta 1486, 243-252 (2000), which is incorporated herein by reference.] A preferred sugar carbamate is:




Examples of quats that fall within the definition of monocyclic and bicyclic trialkylammoniumalkyl residues include:




The term “prodrug” refers to a compound that is made more active in vivo. Commonly the conversion of prodrug to drug occurs by enzymatic processes in the liver or blood of the mammal. Many of the compounds of the invention may be chemically modified without absorption into the systemic circulation, and in those cases, activation in vivo may come about by chemical action (as in the acid-catalyzed cleavage in the stomach) or through the intermediacy of enzymes and microflora in the gastrointestinal GI tract.
In the characterization of the variables, it is recited that R9 may form a five- to seven-membered ring with A or R10; that R10 may form a double bond with A or may form a five- to seven-membered ring with R9; and that R11 may form a second five- to seven-membered ring. It is intended that these rings may exhibit various degrees of unsaturation (from fully saturated to aromatic), may include heteroatoms and may be substituted with lower alkyl or alkoxy.
In the characterization of the variables, it is recited that R-groups, such as R5, represent one, two, three, four or five residues chosen independently from a list of variable definitions. The structure below illustrates the intent of that language. In this example, R5 represents three residues: —CH3, —OH and —OCH3.




The variables are defined when introduced and retain that definition throughout. Thus, for example, R3 is always chosen from H, —OH, fluoro, —O-loweralkyl and —O-acyl, although, according to standard patent practice, in dependent claims it may be restricted to a subset of these values. Superscripts are added to distinguish among residues that are attached similarly and that have overlapping Markush groups. For example, the substituent attached to the phenyl ring at the 1-position (i.e. on the nitrogen) of the azetidinone is always labeled R1, but can be R1, R1a, R1b or R1c depending on the members of the Markush group defining it. For simplicity, the dependent claims, when multiply dependent, may refer to R1 etc. This is intended to modify the appropriate value of the corresponding variable R1, R1a, R1b, R1c etc. in each claim from which it depends. Thus a claim that recites “a compound according to any of claims 1 to 8 wherein R1 is chosen from H, halogen, —OH and methoxy” intends to further limit, for example, the corresponding R1a substituent in claim 6, the R1b substituent in claim 7 and the R1c substituent in claim 8.
It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include 3H, 14C, 35S, 18F, and 36Cl, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. 3H, and carbon-14, i.e., 14C, radioisotopes are particularly preferred for their ease in preparation and detectability. Radiolabeled compounds of Formulas I-VIII of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
The terms “methods of treating or preventing” mean amelioration, prevention or relief from the symptoms and/or effects associated with lipid disorders. The term “preventing” as used herein refers to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition to diminish the likelihood or seriousness of the condition. The person of ordinary skill in the medical art (to which the present method claims are directed) recognizes that the term “prevent” is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended in applicants' claims. As used herein, reference to “treatment” of a patient is intended to include prophylaxis. Throughout this application, various references are referred to. The disclosures of these publications in their entireties are hereby incorporated by reference as if written herein.
The term “mammal” is used in its dictionary sense. The term “mammal” includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats, and horses, monkeys, dogs (e.g., Canis familiaris), cats, rabbits, guinea pigs, and primates, including humans.
The compounds may be use to treat or prevent vascular inflammation, as described in US published application 20030119757; to prevent, treat, or ameliorate symptoms of Alzheimer's Disease and to regulate the production or level of amyloid β peptide and ApoE isoform 4, as described in U.S. Pat. No. 6,080,778 and US published application 20030013699; and to prevent or decrease the incidence of xanthomas, as described in US published application 20030119809. The disclosures of all are incorporated herein by reference.
The compounds described herein contain two or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as ®- or (S)—. The present invention is meant to include all such possible isomers, as well as, their racemic and optically pure forms. Optically active ®- and (S)—, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines and single thin lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. Thus, the formula XI is intended to encompass both of the pure enantiomers of that pair:




Means either pure R,S:





or pure S,R:





whereas





refers to a racemic mixture of R,S and S,R, i.e. having a trans relative configuration on the beta lactam ring.

The term “enantiomeric excess” is well known in the art and is defined for a resolution of ab into a+b as




  
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The term “enantiomeric excess” is related to the older term “optical purity” in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, zero being racemic and 100 being pure, single enantiomer. A compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee; in other words, a 90% ee reflects the presence of 95% of one enantiomer and 5% of the other in the material in question.
The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as E may be Z, E, or a mixture of the two in any proportion.
Terminology related to “protecting”, “deprotecting” and “protected” functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as “protecting groups”. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T. W. Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference. Particular attention is drawn to the chapters entitled “Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols” (pages 10-86).
The abbreviations Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluenesulfonyl and methanesulfonyl respectively. A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled “Standard List of Abbreviations” is incorporated herein by reference.
While it may be possible for the compounds of formulae Φ, Ψ and I-VIII to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula Φ, Ψ or I-VIII or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula Φ, Ψ and I-VIII or a pharmaceutically acceptable salt or solvate thereof (“active ingredient”) with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
The pharmaceutical compositions may include a “pharmaceutically acceptable inert carrier”, and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, “Pharmaceutically acceptable carrier” also encompasses controlled release means.
Compositions of the present invention may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must, of course, be compatible with the compound of the invention to insure the stability of the formulation.
Examples of excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to:
BINDERS: corn starch, potato starch, other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch (e.g., STARCH 1500® and STARCH 1500 LM®, sold by Colorcon, Ltd.), hydroxypropyl methyl cellulose, microcrystalline cellulose (e.g. AVICELTM, such as, AVICEL-PH-101TM, -103TM and -105TM, sold by FMC Corporation, Marcus Hook, Pa., USA), or mixtures thereof;
FILLERS: talc, calcium carbonate (e.g., granules or powder), dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, or mixtures thereof;
DISINTEGRANTS: agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums, or mixtures thereof;
LUBRICANTS: calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g. peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, syloid silica gel (AEROSIL 200, W. R. Grace Co., Baltimore, Md. USA), a coagulated aerosol of synthetic silica (Degussa Co., Plano, Tex. USA), a pyrogenic silicon dioxide (CAB-O-SIL, Cabot Co., Boston, Mass. USA), or mixtures thereof;
ANTI-CAKING AGENTS: calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, or mixtures thereof;
ANTIMICROBIAL AGENTS: benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride, cresol, chlorobutanol, dehydroacetic acid, ethylparaben, methylparaben, phenyl, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimersol, thymo, or mixtures thereof; and
COATING AGENTS: sodium carboxymethyl cellulose, cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose phthalate, methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnuba wax, microcrystalline wax, or mixtures thereof.
The dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
Combination therapy can be achieved by administering two or more agents, each of which is formulated and administered separately, or by administering two or more agents in a single formulation. Other combinations are also encompassed by combination therapy. For example, two agents can be formulated together and administered in conjunction with a separate formulation containing a third agent. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so. Combination therapy can also include two or more administrations of one or more of the agents used in the combination. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.
In Vivo Assay of Hypolipidemic Agents using the Rat Cholesterol Absorption Model. This model is based on models described by Burnett et al (2002), Bioorg. Med. Chem. Lett. 2002 Feb. 11;12(3):315-8 and J. Lipid Res. 1999 October;40(10):1747-57. Female Sprague-Dawley rats weighing 150-250 g are separated into groups of 3 and fasted overnight. The animals (4-6/group) are dosed perorally with 300 μL test compounds in olive oil or suitable vehicle. Thirty minutes later, 3-5 microCuries 3H-cholesterol per rat are delivered perorally in 300 μL olive oil. After three hours, 200 μL serum is collected, vortexed with scintillation fluid, and measured for radioactivity in a scintillation counter. Percent inhibition is defined as 100*(1−Ctest/Cctrl), where Ctest and Cctl refer to 3H levels in serum for the test compound and for the vehicle only control, respectively. Percent inhibition values are reported for a fixed dose. The ED50 is the dose at which the half-maximal effect on serum 3H levels is observed for a given test compound.
In Vivo Assay of Hypolipidemic Agents using the Mouse Cholesterol Absorption Model. Female CD-1 mice weighing 20-30 g are separated into groups of 3-8 and fasted overnight. The animals (3-8/group) are dosed perorally with 200 μL test compound in olive oil or suitable vehicle. Thirty minutes later, 3-5 microCuries 3H-cholesterol per mouse are delivered perorally in 200 μL olive oil. After three hours, 100 μL serum is collected, vortexed with scintillation fluid, and measured for radioactivity in a scintillation counter. Percent inhibition and ED50 are defined as in the Rat Cholesterol Absorption Model above.
In Vivo Assay of Hypolipidemic Agents Using the Hyperlipidemic Hamster: Hamsters are separated into groups of six and given a controlled cholesterol diet (Purina Chow #5001 containing 0.5% cholesterol) for seven days. Diet consumption is monitored to determine dietary cholesterol exposure in the face of test compounds. The animals are dosed with the test compound once daily beginning with the initiation of diet. Dosing is by oral gavage of 0.2 mL of corn oil alone (control group) or solution (or suspension) of test compound in corn oil. All animals moribund or in poor physical condition are euthanized. After seven days, the animals are anesthetized by intramuscular (IM) injection of ketamine and sacrificed by decapitation. Blood is collected into vacutainer tubes containing EDTA for plasma lipid analysis and the liver excised for tissue lipid analysis. Lipid analysis is conducted as per published procedures [Schnitzer-Polokoff, R., et al, Comp. Biochem. Physiol., 99A, 4, 665-670 (1991)] and data are reported as percent reduction of lipid versus control.
In Vivo Assay of Hypolipidemic Agents using the Hamster Acute Cholesterol Absorption Model. Male Syrian Hamsters weighing 120 g are separated into groups of 3-6 and fasted overnight. The animals (3-6/group) are dosed perorally with 200 μL test compound in olive oil or suitable vehicle. Thirty minutes later, 3-5 microCuries 3H-cholesterol per hamster are delivered perorally in 200 μL olive oil. After three hours, 100-200 μL serum is collected, vortexed with scintillation fluid, and measured for radioactivity in a scintillation counter. Percent inhibition and ED50 are defined as in the Rat Cholesterol Absorption Model above.
The bioabsorption of the compounds herein described may be examined using the Caco-2 cell monolayer model of Hilgers et al. [Pharm. Res. 7, 902 (1990)].
Pharmacokinetics. To study the pharmacokinetics of compounds, bioavailability studies are carried out in rats. Compounds are prepared in suitable formulations: 5% ethanol in olive oil for oral administration and 2% DMSO: 20% cyclodextrins in H2O for intravenous administration. Compounds are administered intravenously via tail vein injection and orally by gavage to independent groups of CD rats (200-250 g). Serum is collected at various time points and assayed for the presence of compounds using an LC/MS/MS detection method. Samples are diluted 15-fold in 30% acetonitrile in water, then injected (35 mL) into a 3.2 ml/min flow of 5% methanol in water onto a sample extraction cartridge (Waters Oasis HLB Direct Connect), washed for 30 seconds, then loaded onto a reverse phase HPLC column (Thermo Electron Betasil C18 Pioneer 50×2.1 mm, 5 um particle size). Samples are eluted from the reverse phase HPLC column with a gradient: (Mobile Phase A: 5 mM ammonium acetate in dH2O, Mobile Phase B: 20% methanol in acetonitrile; 40% B ramping to 95% B over 4 minutes, and holding for 3 minutes, then returning to initial conditions to re-equilibrate the column for 1 min, all at a flow rate of 0.3 ml/min.). A Micromass Quattro Micro (Waters Corp.; Milford, Mass.) triple quadrupole mass spectrometer operated in MRM mode is used for detection. Concentrations are calculated based on standard concentration curves of compounds. MassLynx software (Waters, Corp.; Milford, Mass.) is used to calculate the absolute concentration of test compound in each serum sample. A concentration versus time plot is generated from the data in Microsoft Excel, Summit Software PK Solutions 2.0 or GraphPad Prism (GraphPad Software, Inc., San Diego, Calif.) to generate pharmacokinetic curves. An area under the curve (AUCn, n=length of experiment in minutes or hours) is calculated from the concentration vs. time data by the software using the trapezoid method for both the orally and intravenously dosed animals. Oral Bioavailability (F) over the length of the experiment is calculated using the equation:

F=(AUCoral*Dosei.v. )/(AUCi.v.*Doseoral)

Representative compounds of the invention were tested in the Rat Cholesterol Absorption model above. The compounds of the invention exhibited inhibition as shown below in Tables 1 and 2







TABLE 1













 



















%


Exam-





inhibition


ple





at 1


#
R51
R52
R53
R54
R55
mg/kg
















2


OH


541


3





151


4

OH



72


5


OMe


261


7
OH




30


8


SO2Me


53


9

OMe
OMe
OMe

40


10

SO2Me



542


11
OMe
OMe



28


12

OMe



70


13

CHO



70


14

CN



323


15


SO2NMe2


 8


16

CH2OH



72


17


NMe2


43


18


CH2OH


48


19

OH


Br
66


20

O-glucuronide



59


21

CO2H



68


22


CO2H


52


23

NO2



541


26

NHAc



761


28


NH2


56


56

P═O(OH)2



59


76

O—C6-



56




glucopyranose


77

O—C6-methyl



70




glucopyranoside


78

O—C6-glucitol



51


81

OMe
OMe


17


82

SMe



28


83

NMe2



38


84


CH═CH2


51


85

OMe


CHO
15


86

NH2



35












87

O—CH2—CH2—O


59













88


CH2CO2H


30


89


CO2Me


45


90

Me

Me

27












91

β-naphthyl


56













92

CF3



17


93

Me



28


94

Me
F


30


95

O-glucopyranose



57


96
OMe
OMe
OMe


69


97
OMe

OMe


40


98
Me




 7


99


CHO


38


100

OEt



54


101


OEt


41


102

OMe
OH


56


103

O—nPr



21


104

OH


CHO
52


105

O—iPr



15


106

CO2H
OH


66


107

OMe

OMe

49


108
OH

OH


69


109

O—nBu



52


110

OH
CO2H


72


111

OMe

F

72


112

OH

F

75


113

C1-glucitol



67


114

OH

OH

72


115

B(OH)2



70


116


C1-gluco-


81





pyranose


117

C1-CH2-



26




glucopyranose


118

SO3H



61


119

SH



56


120

NMe3+



23





1% inhibition at 10 mg/kg


2% inhibition at 3 mg/kg


3% inhibition at 5 mg/kg













TABLE 2













 













Example#
R51
R52
R53
R1




% inhibitionat 1 mg/kg
















42

OH

H




87


 


44

OH

F




24


 


46


OH
F




30


 


49

OH

H




30


 


50

OH

H




27


 


51


OH
H




39


 


53

SO3H

H




78


 


57

OH

H




73


 


59

B(OH)2

H




70


 


61

P═O(OH)2

H




583


 


64

C1-glucitol

H




67


 


65

C1-glucitol

H




605


 


66


C1-glucitol
H




716


 


71

C6-S-glucopyranose

H




65


 


72

C6-R-glucopyranose

H




276


 


73

C6-S-glucopyranose

H




59


 


74

C6-R-glucopyranose

H




67


 


75

C6-S-glucitol

H




68


 


121

OH

F




72


 


122

P═O(OH)2

H




67


 


123

SO2Me

H




72


 


124

OH

Ph




48


 


125


OH
H




64


 


127


P═O(OH)2
H




58


 


128


SO3−Na+





60





4The asterisk indicates the point of attachment to the azetidine ring.


5% inhibition at 0.1 mg/kg


6% inhibition at 0.3 mg/kg


7the asterisk indicates the point of attachment to the azetidine ring






In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
The starting materials, in the case of suitably substituted azetidinones, may be obtained by the methods described in WO 02/50027, WO 97/16424, WO 95/26334, WO 95/08532 and WO 93/02048, the disclosures of which are incorporated herein by reference.
Processes for obtaining the compounds of the invention are presented below. Although detailed syntheses are not presented for every example in Tables 1 and 2, the procedures below illustrate the methods. The other compounds were made in analogous fashion to those whose synthesis is exemplified.
EXAMPLE 1
Preparation of the Intermediate 4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl trifluoromethanesulfonate




(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one (150.4 mg, 0.367 mmol) and 4-dimethylaminopyridine (9.4 mg, 0.077 mmol) were dissolved in methylene chloride (10.0 mL). Triethylamine (100 μL, 72.6 mg, 0.717 mmol) was added via syringe followed by N-phenyltrifluoromethanesulfonimide (143.6 mg, 0.402 mmol) added as a solid. The reaction was stirred for 3.5 h at room temperature and then poured into water (40 mL) and extracted with 1:1 ethyl acetate-hexane (75 mL). The organic layer was washed with water (40 mL) and brine (40 mL), then dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 10% to 90% ethyl acetate-hexane) to afford 4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl trifluoromethanesulfonate (190.8 mg, 96% yield) as a clear film (eventually becomes a while solid); mp 121.6° C.; Rf 0.38 (2:3 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.41 (d, J=8.7 Hz, 2H), 7.31-7.26 (m, 4H), 7.19 (dd, J=9.0, 4.6 Hz, 2H), 7.01 (t, J=8.7 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 4.71 (t, J=6.0 Hz, 1H), 4.67 (d, J=2.3 Hz, 1H), 3.10-3.04 (m, 1H), 2.08-1.86 (m, 4H) ppm; MS [M−OH] 524.5.

EXAMPLE 2
Preparation of (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxybiphenyl-4yl)azetidin-2-one




4-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl trifluoromethanesulfonate (162.5 mg, 0.30 mmol) and tetrakis(triphenylphosphine)palladium(0) (17.3 mg, 0.015 mmol) were dissolved in toluene (2.5 mL). 2.0 M aqueous potassium carbonate (0.3 mL) and a solution of 4-hydroxyphenylboronic acid (57.9 mg, 0.42 mmol) in ethanol (1.0 mL) were added. The reaction was stirred vigorously for 5 h at refluxing temperature under a nitrogen atmosphere and then diluted with water (2.5 mL), extracted with ethyl acetate (3×10 mL), washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 10% to 100% ethyl acetate-hexane) to afford (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxybiphenyl-4-yl)azetidin-2-one (112 mg, 77% yield) as a clear film; mp 110° C.; Rf 0.5 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.5 (d, J=9.0 Hz, 2H) 7.4 (d, J=9.0 Hz, 2H) 7.3 (m, 6H), 6.9 (m, 6H), 4.7 (m, 1H), 4.6 (s, 1H), 3.15 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS [M+H] 486.5.

In the same manner was obtained:
EXAMPLE 3
(3R,4S)-4-Biphenyl-4-yl-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one




(3R,4S)-4-Biphenyl-4-yl-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (11.8 mg, 54% yield) as a clear film; purification by chromatography (4 g silica gel, 10% to 100% ethyl acetate-hexane) and then by reverse-phase HPLC (21 mm column, 50% to 100% acetonitrile-0.1% trifluoroacetic acid in water); Rf 0.47 (3:2 ethyl acetate-hexane); 1H NMR (300 MHz, CD3OD) δ 7.63 (d, J=8.3 Hz, 2H), 7.61-7.58 (m, 2H), 7.45-7.39 (m, 4H), 7.35-7.28 (m, 5H), 7.02 (t, J=8.8 Hz, 2H), 7.00 (t, J=8.8 Hz, 2H), 4.63 (t, J=5.7 Hz, 1H), 3.15-3.00 (m, 1H), 2.05-1.84 (m, 5H) ppm; MS [M−OH] 452.5.

EXAMPLE 4
(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one




(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one (110 mg, 76% yield using a reaction time of 4 h) as an off white solid; purification by chromatography (12 g silica gel, 10% to 100% ethyl acetate-hexane); mp 107° C.; Rf 0.50 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.6 (d, J=8.9 Hz, 2H), 7.3 (d, J=8.9 Hz, 2H), 7.2 (m, 6H), 6.9 (m, 6H), 4.7(m, 1H), 4.6(s, 1H), 3.15 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS [M+H] 486.5.

EXAMPLE 5
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-methoxybiphenyl-4-yl)azetidin-2-one




(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-methoxybiphenyl-4-yl)azetidin-2-one (86 mg, 67% yield using a reaction time of 16 h) as a white solid; purification by chromatography (12 g silica gel, 10% to 100% ethyl acetate-hexane); mp 103° C.; Rf 0.75 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.4 (m, 4H), 7.3 (m, 6H), 6.9 (m, 6H), 4.75 (m, 1H), 4.65 (s, 1H), 3.85 (s, 3H), 3.2 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS [M−OH] 482.5.

EXAMPLE 6
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(6-hydroxybiphenyl-3-yl)azetidin-2-one




(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(6-hydroxybiphenyl-3-yl)azetidin-2-one (36 mg, 40% yield using a reaction time of 16 h) as a white solid; purification by chromatography (12 g silica gel, 10% to 100% ethyl acetate-hexane); mp 113° C.; Rf 0.70 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.5-6.9 (m, 16H), 4.75 (m, 1H), 4.65 (s, 1H), 3.2 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS [M+H] 486.5.

EXAMPLE 7
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2′-hydroxybiphenyl-4-yl)azetidin-2-one




(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2′-hydroxybiphenyl-4-yl)azetidin-2-one (74 mg, 51% yield using a reaction time of 2 h) as a white solid; purification by chromatography (12 g silica gel, 10% to 100% ethyl acetate-hexane); mp 101° C.; Rf 0.50 (1:1 ethyl acetate-hexane);1H NMR (300 MHz, CDCl3) δ 7.6 (d, J=9.0 Hz, 2H), 7.4 (d, J=9.0 Hz, 2H), 7.25 (m, 6H), 6.9 (m, 6H), 6.3 (s, 1H), 4.65 (m, 2H), 3.1 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS [M+H] 486.5.

EXAMPLE 8
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4′-(methylsulfonyl)biphenyl-4-yl]azetidin-2-one




(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4′-(methylsulfonyl)biphenyl-4-yl]azetidin-2-one (80 mg, 79% yield using a reaction time of 4 h) as a white solid; purification by chromatography (12 g silica gel, 10% to 100% ethyl acetate-hexane); mp 111° C.; Rf 0.40 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 8.1 (d, J=9.3 Hz, 2H), 7.8 (d, J=9.3 Hz, 2H), 7.6 (d, J=8.1 Hz, 2H), 7.5 (d, J=8.1 Hz, 2H), 7.3 (m, 5H), 6.9 (m, 3H), 6.3 (s, 1H), 4.7 (m, 1H), 4.6 (s, 1H), 3.1 (s, 4H), 2.1-1.9 (m, 4H) ppm; MS [M−OH] 530.6.

EXAMPLE 9
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′,4′,5′-trimethoxybiphenyl-4-yl)azetidin-2-one




(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′,4′,5′-trimethoxybiphenyl-4-yl)azetidin-2-one (93 mg, 90% yield using a reaction time of 2 h) as a white solid; purification by chromatography (12 g silica gel, 10% to 100% ethyl acetate-hexane); mp 103° C.; Rf 0.4 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.6 (d, J=9.0 Hz, 2H), 7.5 (d, J=9.0 Hz, 2H), 7.3 (m, 4H), 7.0 (m, 4H), 6.8 (s, 2H), 4.7 (m, 1H), 4.6 (s, 1H), 3.9 (s, 9H), 3.1 (s, 1H), 2.1-1.9 (m, 4H) ppm; MS [M−OH] 542.6.

EXAMPLE 10
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3′-(methylsulfonyl)biphenyl-4-yl]azetidin-2-one




(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3′-(methylsulfonyl)biphenyl-4-yl]azetidin-2-one (92 mg, 90% yield using a reaction time of 2 h) as a white solid; purification by chromatography (12 g silica gel, 10% to 100% ethyl acetate-hexane); mp 104° C.; Rf 0.45 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 8.2-6.8 (m, 15H), 4.7 (m, 1H), 4.65 (s, 1H), 3.2 (m, 1H), 3.1 (s, 3H), 2.1-1.9 (m, 4H) ppm; MS [M−OH] 530.6.

EXAMPLE 11
(3R,4S)-4-(2′,3′-dimethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one




(3R,4S)-4-(2′,3′-dimethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (132.0 mg, 90% yield using a reaction time of 2 h) as a white solid; purification by chromatography (12 g silica gel, 10% to 100% ethyl acetate-hexane); mp 101° C.; Rf 0.70 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.6 (d, J=8.5 Hz, 2H), 7.4 (d, J=8.5 Hz, 2H), 7.3 (m, 5H), 7.0 (m, 6H), 4.7 (m, 1H), 4.6 (s, 1H), 3.9 (s, 3H), 3.7 (s, 3H), 3.3 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS [M−OH] 512.6.

EXAMPLE 12
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-methoxybiphenyl-4-yl)azetidin-2-one




(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-methoxybiphenyl-4-yl)azetidin-2-one (36.1 mg, 77% yield) as a clear foam; purification by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane); Rf 0.52 (40% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.7 Hz, 2H), 7.30 (m, 7H), 7.15 (dt, J=13.5, 1.5 Hz, 1H), 7.09 (t, J=2.4 Hz, 1H), 7.00 (t, J=10.4 Hz, 2H), 6.92 (m, 3H), 4.73 (t, J=6.2 Hz, 1H), 4.67 (d, J=2.1 Hz, 1H), 3.86 (s, 3H), 1.95 (m, 4H); MS [M−OH] 482.5.

EXAMPLE 13
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-carbaldehyde




4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-carbaldehyde (32.7 mg, 67% yield) as a clear foam; purification by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane); Rf 0.72 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 10.09 (s, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.85 (m, 2H), 7.62 (m, 3H), 7.44 (d, J=7.8 Hz, 2H), 7.27 (m, 4H), 7.03 (t, J=8.6 Hz, 2H), 6.95 (t, J=8.8 Hz, 2H), 4.74 (m, 1H), 4.70 (d, J=2.4 Hz, 1H), 3.14 (m, 1H), 1.97 (m, 4H) ppm; MS [M−OH] 480.5.

EXAMPLE 14
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-carbonitrile




4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-carbonitrile (32.5 mg, 57% yield) as a clear foam; purification by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane); Rf 0.69 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.84 (m, 1H), 7.79 (m, 1H), 7.64 (m, 1H), 7.55 (m, 3H), 7.44 (d, J=6.6 Hz, 2H), 7.28 (m, 4H), 7.02 (t, J=8.9 Hz, 2H), 6.95 (t, J=8.9 Hz, 2H), 4.75 (t, J=6.2 Hz, 1H), 4.68 (d, J=2.1 Hz, 1H), 3.13 (m, 1H), 2.01 (m, 4H) ppm; MS [M−OH] 477.5.

EXAMPLE 15
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-N,N-dimethylbiphenyl-4-sulfonamide




4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-N,N-dimethylbiphenyl-4-sulfonamide (39.6 mg, 73% yield) as a faint yellow foam; purification by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane); Rf 0.50 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=5.4 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.25 (m, 4H), 7.02 (t, J=8.4, 9.0 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 4.74 (t, J=5.5 Hz, 1H), 4.69 (d, J=1.8 Hz, 1H), 3.13 (m, 1H), 2.75 (s, 6H), 2.01 (m, 4H) ppm; MS [M−OH] 559.7.

EXAMPLE 16
(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-(hydroxymethyl)biphenyl-4-yl)azetidin-2-one




(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-(hydroxymethyl)biphenyl-4-yl)azetidin-2-one (37.3 mg, 80% yield) as a clear foam; purification by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane); Rf 0.43 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.59 (m, 3H), 7.49 (m, 2H), 7.37 (m, 3H), 7.27 (m, 4H), 7.02 (t, J=8.7 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 4.74 (m, 1H), 4.67 (d, J=2.4 Hz, 1H), 3.14 (m, 1H), 1.99 (m, 4H) ppm; MS [M−OH] 482.5.

EXAMPLE 17
(3R,4S)-4-[4′(dimethylamino)biphenyl-4-yl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one




(3R,4S)-4-[4′(dimethylamino)biphenyl-4-yl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (35.4 mg, 79% yield) as a white foam; purification by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane); Rf 0.78 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.53 (m, 4H), 7.31 (m, 8H), 7.02 (t, J=8.7 Hz, 2H), 6.94 (t, J=8.7 Hz, 2H), 4.73 (m, 1H), 4.64 (d, J=2.1 Hz, 1H), 3.14 (m, 1H), 3.10 (s, 6H) 1.97 (m, 4H) ppm; MS [M+H] 513.6.

EXAMPLE 18
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(hydroxymethyl)phenyl]azetidin-2-one




(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(hydroxymethyl)phenyl]azetidin-2-one (37.2 mg, 75% yield with a 7% impurity) as a clear film; purification by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane); Rf 0.43 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.57 (m, 4H), 7.44 (d, J=8.4, 2H), 7.38 (d, J=8.4, 2H), 7.27 (m, 4H), 7.02 (t, J=8.9 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 4.73 (m, 3H), 4.66 (d, J=2.4 Hz, 1H), 3.12 (m, 1H), 1.97 (m, 4H) ppm; MS [M−OH] 482.5.

EXAMPLE 19
Preparation of (3R,4S)-4-(2′-bromo-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one




(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one (19.2 mg, 0.04 mmol) was dissolved in chloroform (0.4 mL) and tetrabutylammonium tribromide (18.8 mg, 0.04 mmol) was added at room temperature. After 10 minutes, saturated aqueous sodium thiosulfate (2 mL) was added to quench the reaction. The mixture was poured into a seperatory funnel, extracted with dichloromethane (4×10 mL), dried over sodium sulfate, filtered and concentrated. (3R,4S)-4-(2′-bromo-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one was purified by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) and then by reverse-phase HPLC (21 mm column, 50% to 100% acetonitrile-0.1% trifluoroacetic acid in water) to afford (3R,4S)-4-(2′-bromo-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (8.0 mg, 34% yield) as a clear foam; Rf 0.51 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J=8.7 Hz, 1H), 7.40 (m, 4H), 7.29 (m, 4H), 7.02 (t, J=8.7 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 6.80 (d, J=3.3, 1H), 6.73 (dd, J=3.0, 3.0 Hz, 1H), 4.74 (t, J=6.2 Hz, 2H), 4.67 (d, J=2.1 Hz, 1H), 3.14 (m, 1H) 1.99 (m, 4H) ppm; MS [M−OH] 547.4.

EXAMPLE 20
Preparation of 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl β-L-glucopyranosiduronic Acid




Step 1: Preparation of (1S)-1-(4-fluorophenyl)-3-[(3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-{[(trifluoromethyl)sulfonyl]oxy}-phenyl)azetidin-3-yl]propyl acetate

4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl trifluoromethanesulfonate (0.16 g, 0.35 mmol) was dissolved in dichloromethane (2 mL). To this was added acetic anhydride (0.04 mL, 0.45 mmol), triethylamine (0.08 mL, 0.60 mmol) and 4-dimethylaminopyridine (18.3 mg, 0.15 mmol). The reaction was stirred at room temperature for 18 h after which time it was diluted with water (5 mL) and extracted with dichloromethane (10 mL). The aqueous layer was re-extracted with dichloromethane (3×10 mL) and the organic fractions were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford (1S)-1-(4-fluorophenyl)-3-[(3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-[(trifluoromethyl)sulfonyl]oxy}-phenyl)azetidin-3-yl]propyl acetate (0.20 g, 0.35 mmol, 100%) as a clear film.
Step 2: Preparation of (1S)-1-(4-fluorophenyl)-3-[(2S,3R)-1-(4-fluorophenyl)-2-(3′-hydroxybiphenyl-4-yl)-4-oxoazetidin-3-yl]propyl acetate
The product of step 1 (0.20 g, 0.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.3 mg, 0.018 mmol) were dissolved in toluene (10 mL). 2.0 M aqueous potassium carbonate (0.35 mL) and a solution of 4-hydroxyphenylboronic acid (67.8 mg, 0.49 mmol) in ethanol (2.5 mL) was added. The reaction was stirred vigorously for 4 h at refluxing temperature under a nitrogen atmosphere and then diluted with water (2.5 mL), extracted with ethyl acetate (3×10 mL), washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford (1S)-1-(4-fluorophenyl)-3-[(2S,3R)-1-(4-fluorophenyl)-2-(3′-hydroxybiphenyl-4-yl)-4-oxoazetidin-3-yl]propyl acetate (157 mg, 85% yield) as a clear film.
Step 3: Preparation of (1S)-1-(4-fluorophenyl)-3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-{3′-[(2,3,4-tri-O-acetyl-6-hydroperoxy-β-L-gluco-hexodialdo-1,5-pyranosyl)oxy]biphenyl-4-yl}azetidin-3-yl)propyl acetate
The product of step 2 (69.4 mg, 0.132 mmol) and methyl 2,3,4-tri-O-acetyl-1-O-(2,2,2-trifluoroethanimidoyl)-D-glucopyranuronate (49.0 mg, 0.110 mmol) were azeotroped with toluene (3×15 mL) and dried in vacuo for 18 h. The dried syrup was suspended in dichloromethane (1.1 mL) and the reaction was cooled to −25° C. Freshly distilled (over calcium hydride) boron trifluoride diethyl etherate was added and the reaction was maintained at −25° C. for 2 h and warmed to 10° C. over about 3.5 h. The mixture was diluted with saturated aqueous ammonium chloride (2 mL), extracted with ethyl acetate (3×10 mL), washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford (1S)-1-(4-fluorophenyl)-3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-{3′-[(2,3,4-tri-O-acetyl-6-hydroperoxy-β-L-gluco-hexodialdo-1,5-pyranosyl)oxy]biphenyl-4-yl}azetidin-3-yl)propyl acetate (57.2 mg, 87% based on recovered starting material) as a white foam.
Step 4: Preparation of 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl β-L-glucopyranosiduronic acid
The product of step 3 (57.2 mg, 0.068 mmol) was dissolved in 1:1 methanol-triethylamine (2.8 mL). To this solution was added water (4.25 mL). The reaction progress was monitored by TLC (5% acetic acid and 15% methanol in dichloromethane) and was complete after 19 hours. The methanol and triethylamine were evaporated in vacuo, the residue was acidified with 1 N aqueous hydrochloric acid (1.4 mL), extracted with ethyl acetate (20 mL), washed with brine (5 mL), dried over sodium sulfate, filtered, concentrated and purified by chromatography (10 g silica gel, 5% acetic acid and 15% methanol in dichloromethane) to afford 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl β-L-glucopyranosiduronic acid (32.6 mg, 73%) as an off-white foam; Rf 0.37 (5% acetic acid and 15% methanol in dichloromethane); 1H NMR (300 MHz, CD3OD) δ 7.63 (d, J=7.8 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.33 (m, 7H), 7.06 (m, 5H), 5.03 (m, 1H), 4.63 (t, J=5.1, 5.1 Hz, 2H), 3.94 (m, 3H), 3.13 (m, 1H) 1.91 (m, 4H) ppm; MS [M−H] 660.6.
EXAMPLE 21
Preparation of 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]biphenyl-3-carboxylic acid




4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl trifluoromethanesulfonate (51.1 mg, 0.094 mmol) and 3-carboxyphenylboronic acid (21.9 mg, 0.132 mmol) were dissolved in 1:1 toluene:ethanol (2 mL). 2.0 M aqueous potassium carbonate (0.14 mL) was added and the solution degassed. Tetrakis(triphenylphosphine)palladium(0) (5.1 mg, 0.005 mmol) was added and the reaction stirred vigorously for 2 h at refluxing temperature under a nitrogen atmosphere. The cooled reaction was diluted into dichloromethane (15 mL), water (3 mL) was added and the pH was adjusted to 3 with 5% aqueous sodium bisulfate. The layers were separated and the aqueous layer extracted with dichloromethane (2×5 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 5% methanol in dichloromethane) to afford 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]biphenyl-3-carboxylic acid (41.9 mg, 86% yield) as a colorless foam; Rf 0.15 (5% methanol in dichloromethane); 1H NMR (300 MHz, CDCl3) δ?8.31 (m, 1H), 8.09 (dt, J=7.8, 1.5 Hz, 1H), 7.79-7.39 (m, 6H), 7.23-7.32 (m, 4H), 6.90-7.02 (m, 4H), 4.75 (t, J=5.7 Hz, 1H), 4.69 (d, J=2.1 Hz), 3.12 (m, 1H), 2.10-1.90 (m, 4H) ppm; MS [M−H] 512.5.

In the same manner was obtained:

EXAMPLE 22
4′-{(2S,3R)-1-(4-fluorophenyl)3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]biphenyl-4-carboxylic acid




4′-{(2S,3R)-1-(4-fluorophenyl)3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]biphenyl-4-carboxylic acid (21.0 mg, 67% yield) as a white foam; purification by chromatography (12 g silica gel, 5% methanol in dichloromethane); Rf 0.14 (5% methanol in dichloromethane); 1H NMR (300 MHz, CDCl3) δ ?8.17 (d, J=8.4 Hz, 2H), 7.65 (t, J=8.1 Hz, 4H), 7.43 (d, J=8.4 Hz, 2H), 7.33-7.24 (m, 4H), 7.04-6.92 (m, 4H), 4.77 (t, J=5.7 Hz, 1H), 4.70 (d, J=2.1 Hz, 1H), 3.15 (m, 1H), 1.92-2.09 (m, 4H) ppm; MS [M−H] 512.5.

EXAMPLE 23
Preparation of (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-nitrobiphenyl-4-yl)azetidin-2-one




4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl trifluoromethanesulfonate (50.0 mg, 0.092 mmol) and 3-nitrophenylboronic acid (21.6 mg, 0.129 mmol) were dissolved in 1:1 toluene:ethanol (2 mL). 2.0 M aqueous potassium carbonate (0.092 mL) was added and the solution degassed. Tetrakis(triphenylphosphine)palladium(0) (5.7 mg, 0.005 mmol) was added and the reaction stirred vigorously for 2 h at refluxing temperature under a nitrogen atmosphere. The cooled reaction was diluted into dichloromethane (15 mL). The layers were separated and the aqueous layer further extracted with dichloromethane (2×5 mL). The combined extracts were dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 5% to 50% ethyl acetate-hexane) to afford (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-nitrobiphenyl-4-yl)azetidin-2-one (45.0 mg, 95% yield) as a clear film; Rf 0.33 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ ?8.42 (m, 1H), 8.21 (ddd, J=8.1, 2.4, 1.2 Hz, 1H), 7.89 (ddd, J=7.9, 1.5, 1.2 Hz, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.33-7.22 (m, 4H), 7.04-6.92 (m, 4H), 4.76 (t, J=6.0 Hz, 1H), 4.71 (d, J=2.1 Hz, 1H), 3.14 (m, 1H), 1.91-2.11 (m, 4H) ppm; MS [M−OH] 497.5.

In the same manner was obtained:
EXAMPLE 26
N-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)acetamide




N-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)acetamide (18.8 mg, 44% yield) as a white foam; purification by chromatography (12 g silica gel, 50% ethyl acetate-hexane); Rf 0.07 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.81 (b, 1H), 7.72-7.19 (m, 12H), 6.99 (t, J=8.7 Hz, 2H), 6.93 (t, J=9.0 Hz, 2H), 4.72 (t, J=5.7 Hz, 1H), 4.65 (d, J=2.1 Hz, 1H), 3.13 (m, 1H), 2.17 (s, 3H), 2.04-1.88 (m, 4H) ppm; MS [M−OH] 509.6.

EXAMPLE 28
(3R,4S)-4-(4′-aminobiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one




(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-aminobiphenyl-4-yl)azetidin-2-one (42.0 mg, 95% yield) as a brown film; purification by chromatography (12 g silica gel, 50% ethyl acetate-hexane); Rf 0.32 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=8.1 Hz, 2H), 7.39-7.23 (m, 8H), 7.00 (t, J=8.7 Hz, 2H), 6.92 (t, J=8.7 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H), 4.72 (t, J=5.7 Hz, 1H), 4.63 (d, J=2.4 Hz, 1H), 3.14 (m, 1H), 2.11-1.91 (m, 4H) ppm; MS [M+H] 485.5.

EXAMPLE 29
(3R,4S)-1-(2′,3′-difluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′,4′-difluorobiphenyl-4-yl)azetidin-2-one




(3R,4S)-1-(2′,3′-difluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′,4′-difluorobiphenyl-4-yl)azetidin-2-one (36.9 mg, 86% yield) as a clear film; purification by chromatography (12 g silica gel, 5% to 50% ethyl acetate-hexane); Rf 0.51 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.55 (dd, J=8.3, 1.5 Hz, 2H), 7.41 (d, J=6.9 Hz, 2H), 7.32-7.22 (m, 4H), 7.19-7.12 (m, 3H), 7.01 (t, J=8.7 Hz, 2H), 6.95 (t, J=9.0 Hz, 2H), 4.74 (t, J=6.0 Hz, 1H), 4.68 (d, J=2.7 Hz, 1H), 3.14 (m, 1H), 2.07-1.90 (m, 4H) ppm; MS [M−OH] 488.5.

EXAMPLE 31
1-[4-(4-{(2S,3R)-2-(3′-hydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-1-yl}phenyl)butyl]-1-azoniabicyclo[2.2.2]octane chloride.




A quaternary salt is made in the following manner. (3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)boronic acid and 4-bromostyrene are coupled under Suzuki conditions with tetrakis(triphenylphosphine)palladium(0) and 2.0 M aqueous potassium carbonate in toluene-ethanol solvent. The product is reacted with chlorosulfonyl isocyanate in ethereal solvent followed by alkali aqueous work-up to generate a β-lactam. The amide proton is exchanged for an aryl group by reaction with 4-iodophenylcarbonylallyl (generated from the commercially available acid by borane reduction and protected with allyl chloroformate) using trans-1,2-cyclohexanediamine and copper (I) iodide in decane-dioxane as solvent. Deprotonation of the 3-position of the β-lactam with a suitable base, such as lithium diisopropylamide, and subsequent quenching with tert-butyl {[(1S)-4-iodo-1-phenylbutyl]oxy}dimethylsilane (generated from the commercially available (S)-(−)-3-chloro-1-phenyl-1-propanol by protection with tert-butyldimethylchlorosilane and Finkelstein reaction with sodium iodide) provide the 3-substituted intermediate. The allyloxycarbonate protecting group is removed with ammonium formate and tetrakis(triphenylphosphine)palladium(0) in tetrahydrofuran and the resulting alcohol converted into the bromide using carbon tetrabromide and triphenylphosphine in dichloromethane. The silyl protecting groups are removed from the benzyl alcohol and the phenyl using 48% hydrofluoric acid in acetonitrile. The resulting compound is reacted with a tertiary amine, such as quinuclidine, purified by HPLC and passed through a chloride ion-exchange column to afford 1-[4-(4-{(2S,3R)-2-(3′-hydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-1-yl}phenyl)butyl]-1-azoniabicyclo[2.2.2]octane chloride.
EXAMPLE 32
Illustrated in Scheme I below is the general method for the preparation of cholesterol absorption inhibitors of general formula 32. Imines 2 are made by refluxing 4-cyanoaniline with the appropriate aldehyde in isopropanol. Condensation of imine 2 with the benzyloxazolidinone compound 3 using titanium tetrachloride, and subsequent cyclization using N,O-bistrimethylacetamide and catalytic tetra-n-butylammonium fluoride, affords the azetidinone 4. Reduction of the cyano group in 4 to the amine 5 is accomplished under hydrogen atmosphere over excess Raney-Nickel in ethanol and ammonium hydroxide. Acylation with the appropriate acid chloride [Br(CH2)nCOCl], followed by reaction with hydrofluoric acid in acetonitrile to remove the silyl protecting groups, and subsequent reaction with taurine provides the finally product 32. It is noted that in this scheme the taurine is for illustration and that a large variety of functional groups can be substituted in its place.







EXAMPLE 33
Illustrated in Scheme II below is the general method for the preparation of cholesterol absorption inhibitors of general formula 33. The aldehyde 7 is made by Suzuki coupling of 4-bromobenzaldehyde with 3-cyanophenylboronic acid. Refluxing 4-fluoroaniline with the aldehyde 7 in isopropanol makes the imine 8. Condensation of imine 8 with benzyloxazolidinone compound 3 using titanium tetrachloride and subsequent cyclization, using N,O-bistrimethylacetamide and catalytic tetra-n-butylammonium fluoride, affords the azetidinone 9. Reduction of the cyano group in 9 to the amine 10 is accomplished under hydrogen atmosphere over excess Raney-Nickel in ethanol and ammonium hydroxide. Acylation with the appropriate acid chloride [Br(CH2)nCOCl], followed by reaction with hydrofluoric acid in acetonitrile to remove the silyl protecting groups, and reaction with taurine provides the final product 11. It is noted that in this scheme the taurine is for illustration and that a large variety of functional groups can be substituted in its place.







EXAMPLE 34
Illustrated in Scheme III below is the general method for the preparation of cholesterol absorption inhibitors of general formula 34. An imine is made by condensing 4-bromobenzaldehyde with 4-cyanoaniline, followed by condensation with the benzyloxazolidinone compound 3 using titanium tetrachloride, and subsequent cyclization, using N,O-bistrimethylacetamide and catalytic tetra-n-butylammonium fluoride, to afford the azetidinone 12. Hydrofluoric acid in acetonitrile is used to remove the silyl protecting group, and coupling to bis(pinacolato)diboron using catalytic palladium affords compound 13. Suzuki coupling with intermediate 20 affords compound 14. Reduction of the cyano group is accomplished under hydrogen atmosphere over excess Raney-Nickel in ethanol and ammonium hydroxide, and acetate groups are removed with triethylamine-methanol-water to provide 15. Acylation with the appropriate acid chloride [Br(CH2)nCOCl] followed by reaction with taurine provides the final product 16. It is noted that in this scheme the taurine is for illustration and that a large variety of functional groups can be substituted in its place.







Synthesis of Intermediate 20: 3-Allyloxyphenyl lithium is reacted with glucopyranolactone 17, followed by reductive cleavage of the hemiketal with triethylsilane and boron trifluoride diethyl etherate to provide benzyl-protected glycoside 18. Removal of the allyl group with palladium catalyst and tri-n-butyltin hydride followed by hydrogenation using palladium on carbon under a hydrogen atmosphere provides phenyl glycoside 19. Reaction with N-phenyltrifluoromethanesulfonimide provides the triflate and peracetylation using acetic anhyride in pyridine afford intermediate 20.




EXAMPLE 35
(4S)-4-Benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one




5-(4-Fluorophenyl)-5-oxopentanoic acid (10.08 g, 47.9 mmol) and triethylamine (6.8 mL, 4.94 g, 48.8 mmol) were dissolved in tetrahydrofuran (50 mL). The reaction was cooled to −5° C. (ice/brine bath), trimethylacetyl chloride (6.0 mL, 5.87 g, 48.7 mmol) was added quickly drop-wise and the mixture was warmed to room temperature and stirred for 1.5 h. The reaction was cooled to −5° C. (ice/brine bath) again for 30 min, filtered through Celite®, washed with cold 1:1 hexane-tetrahydrofuran (60 mL) and hexane (120 mL). The filtrate was concentrated, dissolved in N,N-dimethylformamide (16 mL) and to this mixture was added (S)-benzyl-2-oxazolidinone (8.47 g, 47.8 mmol) and 4-dimethylaminopyridine (8.57 g, 70.2 mmol) as solids. The reaction was stirred at room temperature for 20 h, poured into 1.0 N hydrochloric acid (400 mL) and extracted with ethyl acetate (2×300 mL). The organic layer was washed with water (400 mL), quarter saturated sodium bicarbonate solution (400 mL), brine (200 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by crystallization from hot isopropyl alcohol (75 mL) with slow cooling to room temperature over 16 h. The crystals were filtered cold and washed with cold isopropyl alcohol (50 mL) to afford (4S)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (13.87 g, 78% yield) as a white crystalline solid; mp 114.5° C.; Rf 0.29 (1:2 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 8.03-7.98 (m, 2H), 7.37-7.19 (m, 5H), 7.14 (t, J=8.7 Hz, 2H), 4.72-4.64 (m, 1H), 4.25-4.15 (m, 2H), 3.32 (dd, J=13.3, 3.4 Hz, 1H), 3.12-3.01 (m, 4H), 2.78 (dd, J=13.3, 9.6 Hz, 1H), 2.15 (quint., J=7.2 Hz, 2H) ppm.

EXAMPLE 36
(4S)-4-Benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3-oxazolidin-2-one




(4S)-4-Benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (13.87 g, 37.54 mmol) was dissolved in dichloromethane (40 mL). Into a separate flask were added borane-methyl sulfide complex (3.6 mL,  ̃38 mmol), 1.0 M®-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole in toluene (1.9 mL, 1.9 mmol) and dichloromethane (20 mL). This mixture was cooled to −5° C. (ice/methanol bath) and the ketone solution was added drop-wise via cannula over 5 min. The reaction was stirred at −5° C. for 5.5 h and then quenched by slow addition of methanol (9 mL), 5% hydrogen peroxide solution (30 mL) and 1 M aqueous sulfuric acid (20 mL) respectively. The reaction was poured into water (500 mL) and extracted with ethyl acetate (500 mL). The organic layer was washed with water (500 mL), 0.1 N hydrochloric acid (300 mL) and brine (300 mL), dried over sodium sulfate, filtered, and concentrated to afford (4S)-4-benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3-oxazolidin-2-one, which was used in subsequent reactions without further purification; Rf 0.14 (1:2 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.37-7.24 (m, 5H), 7.19 (d, J=7.3 Hz, 2H), 7.02 (t, J=8.9 Hz, 2H), 4.72-4.61 (m, 2H), 4.21-4.13 (m, 2H), 3.27 (dd, J=13.2, 3.0 Hz, 1H), 2.99-2.94 (m, 2H), 2.74 (dd, J=13.2, 9.6 Hz, 1H), 2.27 (br s, 1H), 1.88-1.66 (m, 4H) ppm; MS [M−OH]+354.0.

EXAMPLE 37
(4S)-4-Benzyl-3-[(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-1,3-oxazolidin-2-one




(4S)-4-Benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3-oxazolidin-2-one (37.54 mmol) was dissolved in N,N-dimethylformamide (40 mL) and then imidazole (2.97 g, 43.6 mmol) and tert-butyldimethylsilyl chloride (6.12 g, 40.6 mmol) were added. The reaction was stirred at room temperature for 19 h, poured into 0.1 N hydrochloric acid (500 mL) and extracted with 1:1 ethyl acetate-hexane (500 mL). The organic layer was washed with water (2×500 mL), brine (300 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by crystallization from methanol (55 mL) by heating to a light boil and cooling slowly to room temperature over 18 h. The crystals were filtered cold and washed with cold methanol (45 mL) to afford (4S)-4-benzyl-3-[(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-1,3-oxazolidin-2-one (16.04 g, 88% yield) as a white crystalline solid; mp 87.6° C.; Rf 0.66 (1:2 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.36-7.18 (m, 7H), 6.99 (t, J=8.7 Hz, 2H), 4.69-4.61 (m, 2H), 4.18-4.13 (m, 2H), 3.27 (dd, J=13.5, 3.2 Hz, 1H), 2.96-2.89 (m, 2H), 2.73 (dd, J=13.5, 9.7 Hz, 1H), 1.82-1.63 (m, 4H), 0.88 (s, 9H), 0.04 (s, 3H), −0.15 (s, 3H) ppm; MS [M−OSi(CH3)2C(CH3)3]+354.0.

EXAMPLE 38
N-{(1E)-[2-(Allyloxy)-4-bromophenyl]methylene}aniline




4-Bromosalicylaldehyde (4.02 g, 20.0 mmol) [prepared from 3-bromophenyl analogous to the procedure of Casiraghi, et. al. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1978), 318-21] was dissolved in anhydrous N,N-dimethylformamide (13 mL). Potassium carbonate (3.9 g, 28.0 mmol) was added as a solid to give a yellow suspension. Allyl bromide (2.6 mL, 3.63 g, 30.0 mmol) was added via syringe. The reaction stirred for 17 h at room temperature and was then diluted with water and extracted three times with 1:1 ethyl acetate-hexane. The combined organic layers were washed with water (5×), brine, dried over sodium sulfate, filtered and concentrated to afford 2-(allyloxy)-4-bromobenzaldehyde (4.83 g, 100% yield) as a yellow solid which was used without further purification in the next step; Rf 0.38 (1:9 ethyl acetate-hexane); MS [M+H]+241.0.

2-(Allyloxy)-4-bromobenzaldehyde (5.05 g, 20.9 mmol) was dissolved with warming in isopropanol (18 mL). Freshly distilled aniline (1.99 g, 21.3 mmol) was added with isopropanol (4 mL) and the reaction was heated to 50° C. A yellow precipitate formed within 30 min and isopropanol (5 mL) was added to aid stirring. The reaction was stirred at 50° C. for 16 h, by which time proton NMR showed no aldehyde present. The reaction was cooled with stirring. The mixture was diluted with hexane (20 mL), the solid was filtered and washed with the mother liquor, washed with hexane and air dried to afford N-{(1E)-[2-(allyloxy)-4-bromophenyl]methylene}aniline (5.69 g, 86% yield) as a light yellow powder; 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.43-7.36 (m, 2H), 7.27-7.17 (m, 4H), 7.099 (d, J=1.8 Hz, 1H), 6.06 (ddt, J=17.2, 10.5, 5.3 Hz, 1H), 5.43 (AB q, J=17.3, 3.0 Hz, 1H), 5.33 (AB q, J=10.5, 2.8 Hz, 1H), 4.62 (ddd, J=5.2, 1.5, 1.5 Hz, 2H) ppm.
EXAMPLE 39
(3R,4S)-4-(4-Bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one




2-(Allyloxy)-4-bromobenzaldehyde (2.79 g, 8.83 mmol) and (4S)-4-Benzyl-3-[(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-1,3-oxazolidin-2-one (3.3 g, 6.8 mmol) were combined in a 100-mL 3-neck round bottom flask fitted with a thermometer and nitrogen inlet. Anhydrous dichloromethane (60 mL) was added to give a light yellow solution which was cooled to −30° C. Diisopropylethylamine (2.3 mL, 1.71 g, 13.2 mmol) was added via syringe. Titanium tetrachloride (0.86 mL, 1.48 g, 7.82 mmol) was added dropwise over 6 min at an internal temperature between −28° to −26° C. to give a reddish brown solution. The reaction stirred under nitrogen for 3 h between −30 to −25° C. and was then cooled to −35° C. and quenched slowly with glacial acetic acid (6 mL) over 6 min. The reaction was poured into a cold (0° C.) 7% tartaric acid solution (125 mL). Ethyl acetate (200 mL) was added and the mixture was warmed to room temperature with stirring. A 5% sodium sulfite solution (60 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with a saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (120 g silica gel, 1% to 90% ethyl acetate-hexane) to afford (4S)-3-[(2R,5S)-2-[(S)-[2-(allyloxy)-4-bromophenyl](anilino)methyl]-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-4-benzyl-1,3-oxazolidin-2-one (4.54 g, 83% yield); Rf 0.38 (1:4 ethyl acetate-hexane); MS [M+H]+ 801.0.

(4S)-3-[(2R,5S)-2-[(S)-[2-(Allyloxy)-4-bromophenyl](anilino)methyl]-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-4-benzyl-1,3-oxazolidin-2-one (1.2 g, 1.5 mmol) was dissolved in anhydrous methyl tert-butyl ether (10 mL) and stirred at room temperature under nitrogen. N,O-bistrimethylsilylacetamide (1.1 mL, 4.5 mmol) was added followed by a catalytic amount ( ̃5 mg) of tetrabutylammonium fluoride trihydrate. The reaction was stirred at room temperature for 19 h, quenched at room temperature with glacial acetic acid (160 μL) and partitioned between ethyl acetate and water and separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (120 g silica gel, 1% to 85% ethyl acetate-hexane) to afford (3R,4S)-4-[2-(allyloxy)-4-bromophenyl]-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (816 mg, 87% yield); Rf 0.56 (1:4 ethyl acetate-hexane).
(3R,4S)-4-[2-(Allyloxy)-4-bromophenyl]-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.34 g, 2.15 mmol) was dissolved in deoxygenated tetrahydrofuran (20 mL). Morpholine (1.8 mL, 1.8 g, 20.6 mmol) was added with additional deoxygenated tetrahydrofuran (5 mL). The reaction was purged with nitrogen and tetrakis(triphenylphosphine)palladium(0) (220 mg, 0.19 mmol) was added. The reaction was purged with nitrogen again. After 1.5 h at room temperature the reaction was diluted with ethyl acetate, washed twice with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and filtered. The solution was treated with activated charcoal, filtered, concentrated and purified by chromatography (40 g silica gel, 6% to 80% ethyl acetate-hexane) to afford (3R,4S)-4-(4-bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.04 g, 83% yield); Rf 0.38 (1:4 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.28-7.18 (m, 6H), 7.09-6.92 (m, 6H), 5.91 (s, 1H), 4.93 (d, J=2.3 Hz, 1H), 4.65 (t, J=5.4 Hz, 1H), 3.06 (ddd, J=4.8, 2.3, 2.3 Hz, 1H), 1.98-1.77 (m, 4H), 0.86 (s, 9H), 0.006 (s, 3H), −0.16 (s, 3H) ppm; MS [M−H]+581.7.
EXAMPLE 40
(3R,4S)-4-(4-Bromo-2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one




(3R,4S)-4-(4-Bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.04 g, 1.79 mmol) was dissolved in anhydrous dichloromethane (5 mL), anhydrous N,N-dimethylformamide (5 mL) and stirred under nitrogen at room temperature. 2,6-Lutidine (1.0 mL, 920 mg, 8.6 mmol) was added followed by drop-wise addition of tert-butyldimethylsilyl trifluromethane sulfonate (1.2 mL, 1.38 g, 5.22 mmol). The reaction was stirred under nitrogen at room temperature for 2.25 h. 2,6-Lutidine (0.25 mL, 230 mg, 2.15 mmol) was added followed by addition of tert-butyldimethylsilyl trifluromethane sulfonate (0.4 mL, 460 mg, 1.74 mmol) and after a total of 4.5 h at room temperature the reaction was diluted with ethyl acetate and water and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with 0.5 N hydrochloric acid, saturated sodium bicarbonate solution, water (4 times) and brine, dried over sodium sulfate, filtered, concentrated and purified by chromatography (40 g silica gel, 1% to 85% ethyl acetate-hexane) to afford (3R,4S)-4-(4-bromo-2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.23 g, 99% yield); Rf 0.57 (1:4 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.33-7.14 (m, 6H), 7.09-6.91 (m, 6H), 4.99 (d, J=2.3 Hz, 1H), 4.62 (t, J=5.6 Hz, 1H), 3.06 (ddd, J=4.9, 2.5, 2.3 Hz, 1H), 1.97-1.69 (m, 4H), 1.03 (s, 9H), 0.84 (s, 9H), 0.33 (s, 3H), 0.29 (s, 3H), −0.01 (s, 3H), −0.20 (s, 3H) ppm.

EXAMPLE 41
5-Bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenyl acetate




(3R,4S)-4-(4-Bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (293 mg, 0.50 mmol) was dissolved in anhydrous dichloromethane (3 mL). 4-Dimethylaminopyridine (183 mg, 1.5 mmol) was added followed by acetic anhydride (280 μL, 302 mg, 3.0 mmol). After 1 h the reaction was filtered through a plug of silica gel and eluted with dichloromethane. The solvent was concentrated, azeotroped with toluene and purified by chromatography (40 g silica gel, 1% to 85% ethyl acetate-hexane) to afford 5-bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenyl acetate (245 mg, 78% yield); Rf 0.47 (1:4 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.38-7.16 (m, 9H), 7.14-6.94 (m, 3H), 4.69 (t, J=5.4 Hz, 1H), 4.64 (d, J=2.3 Hz, 1H), 3.06 (ddd, J=4.7, 2.3, 2.2 Hz, 1H), 2.30 (s, 3H), 1.97-1.78 (m, 4H), 0.89 (s, 9H), 0.032 (s, 3H), −0.14 (s, 3H) ppm; MS [M−OSi(CH3)2C(CH3)3]+ 493.8.

EXAMPLE 42
(3R,4S)-4-(3,3′-Dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one




Using Suzuki coupling methodology, 5-Bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenyl acetate (100 mg, 0.16 mmol) was combined with 3-hydroxyphenyl boronic acid (29 mg, 0.21 mmol) with deoxygenated toluene (3 mL) and deoxygenated ethanol (1 mL). 2.0 M aqueous potassium carbonate (0.31 mL, 0.31 mmol) was added and the vessel was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol) was added and the vessel purged again. The reaction was heated to 70° C. for 1.5 h, cooled, diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, concentrated and purified by chromatography (40 g silica gel, 20% to 90% ethyl acetate-hexane) to afford 4-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl acetate (70 mg, 69% yield)); Rf 0.34 (1:2 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 10H), 7.06-6.90 (m, 5H), 6.79 (ddd, J=8.1, 2.5, 0.8 Hz, 1H), 6.03 (br s, 1H), 4.67 (d, J=2.3 Hz, 1H), 4.64 (t, J=5.6 Hz, 1H), 3.26 (ddd, J=4.8, 2.5, 2.4 Hz, 1H), 2.27 (s, 3H), 1.94-1.73 (m, 4H), 0.84 (s, 9H), −0.02 (s, 3H), −0.19 (s, 3H) ppm; MS [M−OSi(CH3)2C(CH3)3]+ 508.0.
4-{(2S,3R)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl acetate (70 mg, 0.11 mmol) was dissolved in methanol (2.45 mL). Water (0.73 mL) was added dropwise followed by triethylamine (2.2 mL) and the reaction stirred at room temperature for 1 h. Toluene (3 mL) and methanol (5 mL) were added and the reaction was concentrated to give 69 mg of crude (3R,4S)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3,3′-dihydroxybiphenyl-4-yl)-1-phenylazetidin-2-one which was used without further purification.
(3R,4S)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3,3′-dihydroxybiphenyl-4-yl)-1-phenylazetidin-2-one (73 mg, 0.122 mmol) was dissolved in acetonitrile (5 mL) and transferred to a polypropylene conical vial. 48% Hydrofluoric acid (1 mL) was added dropwise and the reaction stirred at room temperature for 1 h. The reaction was quenched with 1 N sodium hydroxide (24 mL) and transferred to a flask containing pH 7.4 phosphate buffer (24 mL). The pH of the solution was adjusted to 7.5-8.0 with saturated sodium bicarbonate solution then extracted with ethyl acetate (3×). The combined organic layers were washed with saturated sodium bicarbonate solution (2×), water, brine, dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 40% to 100% ethyl acetate-hexane) to afford (3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (53 mg, 69% yield)); 1H NMR (300 MHz, CDCl3) δ 7.30-7.13 (m, 7H), 7.08-6.85 (m, 8H), 6.78 (ddd, J=8.1, 2.3, 0.9 Hz, 1H), 5.04 (d, J=2.3 Hz, 1H), 4.61 (t, J=5.9 Hz, 1H), 3.07 (ddd, J=5.7, 1.8, 1.5 Hz, 1H), 2.08-1.80 (m, 4H) ppm; MS [M+H]+ 584.0 [M−H]− 582.0.
EXAMPLE 43
(3R,4S)-4-(3-bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one




Synthesized using a similar procedure as Example 39 starting from 4-fluoroaniline and 3-bromobenzaldehyde. The benzylic TBDMS protecting group was removed using 48% hydrofluoric acid as described in Example 42. Purified by chromatography (silica gel, 10% to 60% ethyl acetate-hexane) to afford (3R,4S)-4-(3-bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (86 mg); 1H NMR (300 MHz, CDCl3) δ 7.50-7.45 (m, 2H), 7.33-7.18 (m, 6H), 7.07-6.91 (m, 4H), 4.72 (t, J=5.8 Hz, 1H), 4.57 (d, J=2.4 Hz, 1H), 3.10 (ddd, J=4.8, 2.4, 2.4 Hz, 1H), 2.12 (br s, 1H), 2.06-1.86 (m, 4H) ppm; MS [M+HCO2−]− 516.0.

EXAMPLE 44
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-3-yl)azetidin-2-one




(3R,4S)-4-(3-Bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (43 mg, 0.091 mmol) was coupled with 3-hydroxyphenyl boronic acid (18 mg, 0.13 mmol) under standard Suzuki conditions illustrated by Example 42. Purified by chromatography (silica gel, 10% to 90% ethyl acetate-hexane) to afford (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-3-yl)azetidin-2-one (19.7 mg, 45% yield); Rf 0.30 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.57-7.40 (m, 3H), 7.34-7.22 (m, 6H), 7.10 (ddd, 7.7, 1.6, 0.9 Hz 1H), 7.04-6.90 (m, 5H), 6.84 (ddd, J=8.2, 2.6, 0.9 Hz, 1H), 5.10 (br s, 1H), 4.72 (t, J=5.9 Hz, 1H), 4.67 (d, J=2.4 Hz, 1H), 3.16 (ddd, J=5.0, 2.6, 2.4 Hz, 1H), 2.26 (br s, 1H), 2.08-1.88 (m, 4H) ppm.

EXAMPLE 45
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxybiphenyl-3-yl)azetidin-2-one




(3R,4S)-4-(3-Bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (42 mg, 0.089 mmol) was coupled with 4-hydroxyphenyl boronic acid (18 mg, 0.13 mmol) under standard Suzuki conditions illustrated by Example 42. Purified by chromatography (silica gel, 10% to 90% ethyl acetate-hexane) to afford (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxybiphenyl-3-yl)azetidin-2-one (27 mg, 63% yield); Rf 0.31 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.54-7.37 (m, 6H), 7.32-7.22 (m, 4H), 7.04-6.87 (m, 6H), 5.24 (br s, 1H), 4.72 (t, J=6.0 Hz, 1H), 4.67 (d, J=2.4 Hz, 1H), 3.17 (ddd, J=5.3, 2.5, 2.4 Hz, 1H), 2.26 (br s, 1H), 2.09-1.88 (m, 4H) ppm.

EXAMPLE 46
(3R,4S)-4-(4-Bromophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one




Synthesized using a similar procedure as Example 39 starting from aniline and 4-bromobenzaldehyde. The benzylic TBDMS protecting group was removed using 48% hydrofluoric acid as described in Example 42. Purification by chromatography (40 g silica gel, 10% to 90% ethyl acetate-hexane) afforded (3R,4S)-4-(4-bromophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (982.6 mg, 75% overall yield) as a clear film; Rf 0.45 (2:3 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J=8.3 Hz, 2H), 7.31-7.19 (m, 8H), 7.07-6.98 (m, 3H), 4.70 (t, J=6.1 Hz, 1H), 4.61 (d, J=2.5 Hz, 1H), 3.04 (dt, J=7.4, 2.3 Hz, 1H), 2.24 (br s, 1H), 2.03-1.86 (m, 4H) ppm.

EXAMPLE 47
(3R,4S)-4-(5-Bromopyridin-2-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one




Synthesized using the same procedure as Example 39 starting from aniline and 5-bromo-2-pyridinecarboxaldehyde (prepared using a procedure described by Wang et. al., Tetrahedron Letters 41 (2000), 4335-4338). The benzylic TBDMS protecting group was removed using 48% hydrofluoric acid as described in Example 42. Purification by chromatography (12 g silica gel, 15% to 90% ethyl acetate-hexane) afforded (3R,4S)-4-(5-bromopyridin-2-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (23.3 mg, 3% overall yield) as a clear film; Rf 0.07 (1:4 ethyl acetate-hexane); 1H NMR 300 MHz, CDCl3) δ 8.66 (d, J=2.3 Hz, 1H), 7.80 (dd, J=8.3, 2.3 Hz, 1H), 7.34-7.29 (m, 3H), 7.24-7.17 (m, 4H), 7.09-6.99 (m, 3H), 4.82 (d, J=2.5 Hz, 1H), 4.75-4.71 (m, 1H), 3.21 (dt, J=7.0, 2.3 Hz, 1H), 2.31-1.89 (m, 5H) ppm.

EXAMPLE 48
(3R,4S)-4-(5-Bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one




Synthesized using the same procedure as Example 39 starting from aniline and 5-bromo-2-thiophenecarboxaldehyde. The benzylic TBDMS protecting group was removed using 48% hydrofluoric acid as described in Example 42. Purification by chromatography (40 g silica gel, 15% to 90% ethyl acetate-hexane) afforded (3R,4S)-4-(5-bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (212.4 mg, 23% overall yield) as a white solid; Rf 0.13 (1:4 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.36-7.21 (m, 6H), 7.10-7.06 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.89 (dd, J=19.7, 3.8 Hz, 2H), 4.83 (d, J=2.4 Hz, 1H), 4.71 (t, J=5.7 Hz, 1H), 3.25-3.19 (m, 1H), 2.20 (br s, 1H), 2.01-1.83 (m, 4H) ppm.

EXAMPLE 49
(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)pyridin-2-yl]-1-phenylazetidin-2-one




(3R,4S)-4-(5-Bromopyridin-2-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (23 mg, 0.051 mmol) was coupled with 3-hydroxyphenyl boronic acid (9.2 mg, 0.067 mmol) under standard Suzuki conditions illustrated by Example 42. Purification by chromatography (4 g silica gel, 15% to 100% ethyl acetate-hexane) afforded (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)pyridin-2-yl]-1-phenylazetidin-2-one (20.7 mg, 87% yield) as a clear film; Rf 0.14 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 8.88 (d, J=2.2 Hz, 1H), 7.88 (dd, J=8.2, 2.3 Hz, 1H), 7.86-7.80 (m, 1H), 7.39-7.22 (m, 7H), 7.12-7.02 (m, 3H), 6.96 (t, J=8.7 Hz, 2H), 6.96-6.91 (m, 1H), 4.97 (d, J=2.3 Hz, 1H), 4.76-4.72 (m, 1H), 3.28-3.22 (m, 1H), 3.20 (br s, 1H), 2.17-1.90 (m, 4H), 1.80 (br s, 1H) ppm; MS [M+H]+ 469.0.

EXAMPLE 50
(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one




(3R,4S)-4-(5-Bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (90.2 mg, 0.196 mmol) was coupled with 3-hydroxyphenyl boronic acid (32.2 mg, 0.233 mmol) under standard Suzuki conditions illustrated by Example 42. Purification by chromatography (12 g silica gel, 15% to 100% ethyl acetate-hexane) afforded (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one (77.6 mg, 84% yield) as a clear foam; Rf 0.36 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CD3OD) δ 7.31-6.93 (m, 14H), 6.70 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 4.89-4.88 (m, 1H), 4.64-4.59 (m, 1H), 3.77 (br s, 2H), 3.25-3.21 (m, 1H), 1.97-1.83 (m, 4H) ppm; MS [M−OH]+ 456.0.

EXAMPLE 51
(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-[5-(4-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one




(3R,4S)-4-(5-Bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (69.8 mg, 0.152 mmol) was coupled with 4-hydroxyphenyl boronic acid (25.2 mg, 0.183 mmol) under standard Suzuki conditions illustrated by Example 42. Purification by chromatography (12 g silica gel, 15% to 100% ethyl acetate-hexane) afforded (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(4-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one (40.7 mg, 56% yield) as a clear foam; Rf 0.39 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.64-7.60 (m, 4H), 7.56-7.48 (m, 5H), 7.33-7.27 (m, 2H), 7.25-7.20 (m, 2H), 7.07 (d, J=8.6 Hz, 2H), 6.81 (br s, 1H), 5.14 (d, J=2.3 Hz, 1H), 5.00-4.95 (m, 1H), 3.57-3.50 (m, 1H), 2.29-2.11 (m, 4H) ppm; MS [M+H]+ 474.0.

EXAMPLE 53
Sodium 4′-{(2S,3R)-3-[(3S/R)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonate




5-Bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenyl acetate (140.0 mg, 0.223 mmol) was dissolved in acetonitrile (8.0 mL) and 48% hydrofluoric acid (0.8 mL) into a polypropylene Falcon® tube. The reaction was stirred for 4 h at room temperature and then poured into 0.5 M potassium phosphate (50 mL), extracted with 1:1 ethyl acetate-hexane (50 mL), washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 15% to 90% ethyl acetate-hexane) to afford 5-bromo-2-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}phenyl acetate (114.5 mg, 100% yield) as a clear foam; Rf 0.11 (1:4 ethyl acetate-hexane).

5-Bromo-2-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}phenyl acetate (114.5 mg, 0.223 mmol) and 3-thioanisoleboronic acid (48.3 mg, 0.287 mol) were dissolved in toluene (3.0 mL) and ethanol (1.5 mL). A solution of 2.0 M aqueous sodium carbonate (0.215 mL, 0.43 mmol) and solid tetrakis(triphenylphosphine)palladium(0) (14.4 mg, 0.0125 mmol) were added and the vessel was vacuum/nitrogen purged (3×). The reaction was stirred vigorously for 4 h at 60° C. under a nitrogen atmosphere and then poured into 0.2 N hydrochloric acid (50 mL), extracted with 1:1 ethyl acetate-hexane (75 mL), washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford a mixture of products which was used directly in the next step; Rf 0.79 (2:1 ethyl acetate-hexane) for (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3-hydroxy-3′-(methylthio)biphenyl-4-yl]-1-phenylazetidin-2-one and 0.84 (2:1 ethyl acetate-hexane) for 4-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-(methylthio)biphenyl-3-yl acetate.
A 1:1 mixture of (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3-hydroxy-3′-(methylthio)biphenyl-4-yl]-1-phenylazetidin-2-one and 4-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-(methylthio)biphenyl-3-yl acetate (0.223 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. 3-Chloroperoxybenzoic acid (64.3 mg, 0.373 mmol) was added in portions while monitoring by LCMS to make the arylsulfoxide. Once addition was complete the reaction was poured into quarter saturated sodium bicarbonate solution (50 mL), extracted with 1:1 ethyl acetate-hexane (75 mL), washed brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane (10 mL) and the Pummerer rearrangement was effected by the addition of trifluoroacetic anhydride (100 μL, 148.7 mg, 0.708 mmol). The reaction was stirred at room temperature for 4 h and then 3-chloroperoxybenzoic acid (121.7 mg, 0.705 mmol) was added to convert to the sulfone. The mixture was stirred for 15 min at room temperature, concentrated and dissolved in 3:3:1 methanol-triethylamine-water (7 mL) to hydrolyze the acetate and trifluoroacetate groups. The reaction was stirred for 2 h at room temperature, concentrated and dissolved in dichloromethane (10 mL). 3-Chloroperoxybenzoic acid (49.2 mg, 0.285 mmol) was added to oxidize the compound to the sulfonic acid. The reaction was stirred for 10 min at room temperature, diluted with 1:1 ethyl acetate-hexane (50 mL) and extracted with 1% saturated sodium bicarbonate solution (3×50 mL). The aqueous layer was acidified with 1.0 N hydrochloric acid ( ̃10 mL), extracted with ethyl acetate (2×75 mL), diluted with triethylamine (1.0 mL), concentrated, purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 25% to 100% acetonitrile-0.1% trifluoroacetic acid in water) and passed through Dowex® sodium ion exchange resin to afford sodium 4′-{(2S,3R)-3-[(3S/R)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonate (45.3 mg, 36% yield) as an off-white solid; 1H NMR (300 MHz, CD3OD) δ 8.04-6.98 (m, 16H), 5.17 (d, J=2.2 Hz, 0.66H), 5.14 (d, J=2.2 Hz, 0.33H), 4.70-4.60 (m, 1H), 3.21-3.14 (m, 1H), 2.09-1.89 (m, 4H) ppm; MS [M−Na]− 546.0.
EXAMPLE 54
(3R,4S)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one




(3R,4S)-4-(3′-{[tert-Butyl(dimethyl)silyl]oxy}biphenyl-4-yl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (0.60 g, 0.86 mmol) was stirred at room temperature in dry methanol (20 mL) under a nitrogen atmosphere. Potassium fluoride (0.10 g, 1.72 mmol) was added and the reaction mixture was stirred 1.5 h at room temperature. The solution was poured into ethyl acetate and washed successively with water (2×), 10% aqueous sodium bicarbonate, water and brine. The organic solution was dried over sodium sulfate, filtered, concentrated and purified by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 50%) to afford (3R,4S)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one (0.46 g, 92%) as a white foam; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.2, Hz, 2H,) 7.37 (d, J=8.2 Hz, 2H), 6.9-7.4 (m, 12H), 6.8 (m, 1H), 4.9 (br s, 1H), 4.67 (t, J=6.0 Hz, 1H), 4.63 (d, J=2.5 Hz, 1H), 3.0-3.1 (m, 1H), 1.8-2.0 (m, 4H), 0.87 (s, 9H), 0.02 (s, 3H), −0.16 (s, 3H).

EXAMPLE 55
4′-{(2S,3R)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl trifluoromethanesulfonate




(3R,4S)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one (0.46 g, 0.79 mmol) was stirred at room temperature in dry dichloromethane (15 mL) under a nitrogen atmosphere. N-Phenyltrifluoromethanesulfonimide (0.39 g, 1.09 mmol), triethylamine (0.23 mL, 1.65 mmol) and 4-(dimethylamino)pyridine (0.02 g, 0.2 mmol) were added in succession and the reaction mixture was stirred 2 h at room temperature. The solution was poured into 0.5N aqueous hydrochloric acid (20 mL) and extracted with ethyl acetate. The organic phase was washed successively with water, 10% aqueous sodium bicarbonate, water and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford 4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl trifluoromethanesulfonate as a white foam (0.56 g, 100%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 50%) 1H NMR (300 MHz, CDCl3) δ 6.9-7.3 (m, 17H), 4.68 (t, J=5.7 Hz, 1H), 4.65 (d, J=2.5 Hz, 1H), 3.0-3.1 (m, 1H), 1.8-2.0 (m, 6H), 0.88 (s, 9H), 0.02 (s, 3H), −0.16 (s, 3H).

EXAMPLE 56
(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonic acid




This reaction was performed using a PersonalChemistryTM microwave instrument set at normal absorbance, fixed hold time and 30 sec pre-stirring. A 10-mL reaction vial was charged with 4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl trifluoromethanesulfonate (0.27 g, 0.38 mmol), dimethyl phosphite (0.070 mL, 0.76 mmol) and triethylamine (0.15 mL, 1.08 mmol) in toluene (4 mL). Nitrogen was bubbled through the stirred solution for 5 min, tetrakis(triphenylphosphine)palladium(0) (0.1 g) was added, and the solution was covered with a blanket of nitrogen and sealed. The reaction mixture was heated for 11 min at 160° C., then cooled to room temperature and diluted with ethyl acetate. The yellow solution was washed successively with 0.5 M hydrochloric acid (20 mL) water (3×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure dimethyl (4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate was obtained as a white foam (0.26 g, 65%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 100%). 1H NMR (300 MHz, CDCl3) δ 8.00 (dt, J=14.2, 1.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.40(d, J=8.5 Hz, 2H), 6.9-7.8 (m, 12H), 4.68 (t, J=5.7 Hz, 1H), 4.64 (d, J=2.4 Hz, 1H), 3.81 (d, J=0.9 Hz, 1H), 3.77 (d, J=0.9 Hz, 1H), 3.0-3.1 (m, 1H), 1.8-2.2 (m, 4H), 0.88 (s, 9H), 0.02 (s, 3H), −0.16 (s, 3H) ppm
A solution of dimethyl (4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate (0.32 g, 0.47 mmol) in dry dichloromethane (15 mL) under nitrogen was cooled in an ice bath and bromotrimethylsilane (0.30 mL, 2.27 mmol) was dripped in over 5 min. The reaction mixture was stirred at room temperature for 3 h, then poured into ice water (20 m]L) and extracted with ethyl acetate. The organic solution was washed successively with water (2×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 20% to 70% acetonitrile-0.1% trifluoroacetic acid in water) to afford (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonic acid (0.25 g, 99%) as a white powder; 1H NMR (300 MHz, CD3OD) δ 8.04 (br d, J=14.2 Hz, 1H) 7.68 (d, J=8.5 Hz, 2H), 7.50(d, J=8.5 Hz, 2H), 7.0-7.8 (m, 12H), 4.93 (d, J=2.2 Hz, 1H), 4.63 (t, J=5.2 Hz, 1H), 3.1-3.2 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS [M−H]− 531, [2M-H]− 1061.
EXAMPLE 57
(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one




(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one was synthesized in a manner similar to that described in Example 42. (3R,4S)-4-(3′-{[tert-Butyl(dimethyl)silyl]oxy}biphenyl-4-yl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (0.60 g, 0.86 mmol) was stirred at room temperature in acetonitrile (18 mL) in a 40 ml polypropylene vial fitted with a screw cap. Hydrogen fluoride (48% aqueous, 2.0 mL, 48 mmol) was dripped in and stirring was continued at room temperature overnight. The reaction mixture was poured into an aqueous solution of 1 N sodium hydroxide (45 mL) buffered with 1 M sodium phosphate (45 mL, pH 7.4), then the pH of the solution was brought to pH 8 with the addition of aqueous 10% sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the organic solution was washed successively with 10% sodium bicarbonate solution (2×), water (2×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one was obtained as a white foam (0.35 g, 87%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 10% ethyl acetate to 60%) 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=8.2, Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.0-7.3 (m, 12H), 6.80-6.86 (m, 1H), 5.00 (br s, 1H), 4.74 (t, J=6.2 Hz, 1H), 4.69 (d, J=2.2 Hz, 1H), 3.1-3.2 (m, 1H), 2.20 (br s, 1H), 1.8-2.1 (m, 4H) ppm; MS [M+HCO2−]− 512.

EXAMPLE 58
4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl trifluoromethanesulfonate




(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one (0.353 g, 0.77 mmol) was stirred at room temperature in dry dichloromethane (15 mL) under a nitrogen atmosphere.

Phenyltrifluoromethanesulfonimide (0.38 g, 1.69 mmol), triethylamine (0.23 mL, 1.65 mmol) and 4-dimethylaminopyridine (0.02 g, 0.2 mmol) were added in succession and the reaction mixture was stirred 1 h at room temperature. The solution was poured into 0.5 N hydrochloric acid (20 mL) and extracted with ethyl acetate. The organic phase was washed successively with water, 10% aqueous sodium bicarbonate, water and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure 4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl trifluoromethanesulfonate was obtained as a white foam (0.35 g, 76%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 50%); 1H NMR (300 MHz, CDCl3) δ 7.0-7.6 (m, 17H), 4.74 (t, J=6.4 Hz, 1H), 4.72 (d, J=2.2 Hz, 1H), 3.1-3.2 (m, 1H), 2.16 (br s, 1H), 1.9-2.1 (m, 4H) ppm; MS [M+HCO2−]− 644.
EXAMPLE 59
(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)boronic acid




4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl trifluoromethanesulfonate (0.15 g, 0.25 mmol), bis(pinacolato)diboron (0.70 g, 0.27 mmol), potassium acetate (0.80 g, 0.81 mmol) and dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II) (0.020 g, 0.03 mmol) were combined in dimethylsulfoxide (7 mL) in a 40-mL screw-cap vial at room temperature. The mixture was covered with a nitrogen atmosphere, the vial was sealed and the reaction was heated overnight at 80° C. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic phase was washed successively with water (2×) and brine, dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl]azetidin-2-one was obtained as a white foam (0.097 g, 67%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 70%) 1H NMR (300 MHz, CDCl3) δ 8.01(br s, 1H), 7.75-7.85 (m, 1H), 7.0-7.7 (m, 15H), 4.74 (t, J=6.2 Hz, 1H), 4.69 (d, J=2.2 Hz, 1H), 3.0-3.2 (m, 1H), 1.50 (br s, 1H), 1.8-2.1 (m, 4H), 1.35 (s, 6H), 1.24 (s, 6H) ppm; MS [M+HCO2−]− 577

(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl]azetidin-2-one (0.020 g, 0.034 mmol) was dissolved in ethanol (3 mL) and water (1 mL) at room temperature. Solid sodium carbonate (0.10 g, 1.2 mmol) was added and the mixture was rapidly stirred 2 h at room temperature. The solution was poured into 0.5 N hydrochloric acid (4 mL) and extracted with ethyl acetate. The organic phase was washed successively with water (2×) and brine, then dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 40% to 75% acetonitrile-0.1% trifluoroacetic acid in water) to afford (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)boronic acid as a white powder (0.012 g, 70%); 1H NMR (300 MHz, CD3OD) δ 7.83 (br s, 1H), 7.0-7.7 (m, 16H), 4.92 (d, J=2.7 Hz, 1H), 4.63 (t, J=6.2 Hz, 1H), 3.1-3.2 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS [M+HCO2−]− 540.
EXAMPLE 60
Dimethyl [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate




3-Chlorophenyl (0.50 g, 3.89 mmol) was stirred at room temperature in dry dichloromethane (20 mL) under a nitrogen atmosphere.

Phenyltrifluoromethanesulfonimide (1.80 g, 5.0 mmol), triethylamine (0.90 mL, 6.4 mmol) and 4-dimethylaminopyridine (0.10 g, 0.8 mmol) were added in succession and the reaction mixture was stirred 2 h at room temperature. The solution was poured into 0.5 N hydrochloric acid (20 mL) and extracted with ethyl acetate. The organic phase was washed successively with water, 10% aqueous sodium bicarbonate and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure 3-chlorophenyl trifluoromethanesulfonate was obtained as a colorless oil (0.92 g, 91%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% to 50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.16-7.50 (m) ppm
This reaction was performed using a PersonalChemistryTM microwave instrument set at normal absorbance, fixed hold time and 30 sec pre-stirring. A 10-mL reaction vial was charged with 3-chlorophenyl trifluoromethanesulfonate (0.60 g, 2.30 mmol), dimethyl phosphite (0.42 mL, 4.58 mmol) and triethylamine (0.64 mL, 4.59 mmol) in toluene (4 mL). Nitrogen was bubbled through the stirred solution for 5 min, the tetrakis(triphenylphosphine)palladium(0) (0.1 g) was added, the solution was covered with a blanket of nitrogen and sealed. The reaction mixture was heated 11 min at 160° C., then cooled to room temperature and diluted with ethyl acetate. The yellow solution washed successively with water (3×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure dimethyl (3-chlorophenyl)phosphonate was obtained as a colorless oil (0.27 g, 57%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 100%). 1H NMR (300 MHz, CDCl3) δ 7.77 (br d, J=13.7 Hz, 1H), 7.68 (ddt, J=13.0, 7.5, 1.4 Hz, 1H), 7.53 (dquint., J=8.0, 1.1 Hz, 1H), 7.38-7.45 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H) ppm; MS [M+H]+ 221, [2M+H]+ 441
Bis(dibenzylidineacetone)palladium(0) (0.10 g, 0.17 mmol and tricyclohexylphosphine (0.12 g, 0.43 mmol) were stirred 30 min in dry dioxane (1.0 mL) under an atmosphere of nitrogen at room temperature. Dimethyl (3-chlorophenyl)phosphonate (0.50 g, 2.26 mmol), bis(pinacolato)diboron (0.70 g, 0.27 mmol) and potassium acetate (0.30 g, 0.30 mmol) were mixed in dry dioxane (3.0 mL) at room temperature under a nitrogen atmosphere in a separate flask. A portion of the palladium catalyst solution (0.20 mL) was syringed into the flask containing the chlorophosphonate and this mixture was heated at 80° C. Additional 0.2 mL portions of the catalyst solution were syringed into the reaction mixture after 4 h and 8 h of heating at 80° C., then heating was continued overnight at 80° C. The reaction mixture was filtered through Celite® and the solvent was removed by rotary evaporation under reduced pressure. Chromatography over silica gel using ethyl acetate-hexane (gradient: 0% ethyl acetate to 80%) dimethyl [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate as a colorless oil (0.41 g). 1H NMR showed a 60:40 mixture of product plus recovered starting material. This mixture was used as is in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J=13.2 Hz, 1H), 7.95-8.00 (m, 1H), 7.88 (ddt, J=13.0, 7.5, 1.4 Hz, 1H), 7.43-7.50 (m, 1H), 3.76 (s, 3H), 3.73 (s, 3H) ppm; MS [M+H]+ 312, [2M+H]+ 625.
EXAMPLE 61
(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic Acid




(3R,4S)-4-(4-Bromo-2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (0.080 g, 0.11 mmol), crude dimethyl [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate (0.054 g total, 0.030 g calculated, 0.096 mmol) and aqueous 2 M potassium carbonate (0.12 mL, 0.24 mmol) were mixed in ethanol (1.0 mL) and toluene (3.0 mL). The solution was deoxygenated by bubbling nitrogen through the mixture for 5 min while stirring. Tetrakis(triphenylphosphine)palladium(0) (0.05 g) was added and the reaction was heated for 3 h at 70° C. under an atmosphere of nitrogen. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated by rotary evaporation under reduced pressure. The product was purified by chromatography over silica gel using ethyl acetate-hexane (gradient: 10% ethyl acetate to 80%) to afford dimethyl (3′-{[tert-butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate as a colorless syrup (0.065 g, 84%). 1H NMR (300 MHz, CDCl3) δ 6.9-8.0 (m, 16H), 5.09 (d, J=2.2 Hz, 1H), 4.64 (d, J=6.1 Hz, 1H), 3.79 (d, J=2.4 Hz, 3H), 3.76 (d, J=2.4 Hz, 3H), 3.05-3.15 (m, 1H), 1.8-2.0 (m, 4H), 1.06 (s, 9H), 0.85 (s, 9H), 0.36 (s, 3H), 0.33 (s, 3H), 0.00 (s, 3H), −0.20 (s, 3H) ppm

Dimethyl(3′-{[tert-butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate (0.047 g, 0.058 mmol) was stirred at room temperature in dry methanol (2 mL) under a nitrogen atmosphere. Potassium fluoride (0.02 g, 0.34 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. The solution was poured into ethyl acetate and washed successively with water (2×), and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Dimethyl(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonate was obtained as a colorless glass (0.041 g, 100%) was used directly in the next reaction without further purification; MS [M−H]+ 688
A solution of dimethyl(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonate (0.041 g, 0.059 mmol) in dry dichloromethane (5 mL) under nitrogen was cooled in ice and bromotrimethylsilane (0.030 mL, 0.30 mmol) was dripped in over 5 min. The reaction mixture was stirred at room temperature for 3 h, then methanol (1 mL) was added and the reaction was partitioned between water and ethyl acetate. The organic solution was washed successively with water (2×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 59% acetonitrile-0.1% trifluoroacetic acid in water) to afford (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid as a white powder (0.014 g, 44%); 1H NMR (300 MHz, CD3OD) δ 8.0 (d, J=13.6 Hz, 1H), 6.9-7.8 (m, 15H), 5.17 (d, J=2.1 Hz, 1H), 4.63 (d, J=5.2 Hz, 1H), 3.15-3.25 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS [M−H]+ 546, [2M−H]+ 1093.
EXAMPLE 62
(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol




D-Glucopyranose (1.0 g, 5.55 mmol) was dissolved in 5 mL of acetic anhydride and 7 mL of pyridine at 0° C. To this mixture was added 4-dimethylaminopyridine (200 mg, 1.63 mmol), and the reaction was stirred while warming to room temperature. TLC (40% ethyl acetate-hexane) after 18 h showed complete consumption of the starting material and formation of a higher running spot. The reaction was poured into 50 mL of water and extracted into dichloromethane (3×50 mL). The organic layers were combine, washed with 1 N hydrochloric acid (3×20 mL), dried over sodium sulfate, filtered, concentrated and purified by column chromatography (50 g silica gel, 40% ethyl acetate-hexane) to afford 1,2,3,4,6-penta-O-acetyl-α-D-glucopyranose (2.10 g, 5.37 mmol).

1,2,3,4,6-penta-O-acetyl-α-D-glucopyranose (1.0 g, 2.60 mmol) was dissolved in 20 mL of dichloromethane and 1.90 mL of hydrobromic acid (33% in acetic acid) at 0° C., and the reaction was stirred while warming to room temperature. TLC (40% ethyl acetate-hexane) after 18 h showed complete consumption of the starting material and formation of a higher running spot. The reaction was slowly diluted with saturated sodium bicarbonate (25 mL), extracted into dichloromethane (2×100 mL), dried over sodium sulfate, filtered and concentrated to afford 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide which was used without purification.
Magnesium (0) (400 mg) was suspended in 17 mL of anhydrous diethyl ether, and to the suspension was added 100 μL of 1,2-dibromoethane. 1,3-dibromobenzene (3.8 g, 16.08 mmol) was added at a rate to keep a moderate reflux. After Grignard formation was complete (magnesium consumed and the reaction cooled), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (0.34 g, 0.80 mmol in 8 mL of anhydrous diethyl ether) was added drop-wise. The reaction was refluxed for 5 h, cooled to room temperature and poured into a separatory funnel with 20 mL of water. The flask was rinsed with 50 mL of diethyl ether and 3 mL of acetic acid (to dissolve the magnesium salts) and added to the seperatory funnel. The layers were separated and the aqueous layer was collected and concentrated in vacuo. The white pasty solid was dissolved in 15 mL of pyridine and 10 mL of acetic anhydride. After 20 h at room temperate the reaction was poured into 150 mL of water and extracted into dichloromethane (3×150 mL). The organic layers were combine, washed with 1 N hydrochloric acid (3×50 mL), dried over sodium sulfate, filtered, concentrated and purified by column chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol (0.178 g, 0.36 mmol, 45% yield) as a white foam; Rf 0.4 (40% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.44 (m, 2H) 7.25 (m, 2H), 5.27-5.35 (m, 1H), 5.21 (t, J=9.6 Hz, 1H), 5.03 (t, J=9.7 Hz, 1H), 4.36 (d, J=9.9 Hz, 1H), 4.23-4.32 (m, 1H) 4.08-4.18 (m, 1H) 3.80-3.85 (m, 1H) 2.09 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H), 1.84 (s, 3H) ppm; MS [M+H]+ 488.4.
EXAMPLE 63
Synthesized in the Same Manner as Example 62, but Replacing 1,3 Dibromobenzene with 1,4 Dibromobenzene




(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1-(4-bromophenyl)-D-glucitol was obtained (45% yield, white wax). Rf 0.3 (40% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.47 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.7, 2H), 5.31 (d, J=9.3 Hz, 1H), 5.21 (t, J=9.9 Hz, 1H), 5.09 (t, J=9.6 Hz, 1H), 4.37 (d, J=9.9 Hz, 1H), 4.12-4.33 (m, 2H), 3.83 (m, 1H), 2.09 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.83 (s, 3H) ppm; MS [M+H]+ 488.4.

EXAMPLE 64
(1S)-1,5-Anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol




(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one (51.3 mg, 0.102 mmol) and (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol (35.5 mg, 0.073 mmol) were dissolved in 2.0 mL of toluene and 0.25 mL of ethanol. 0.075 mL of 4 N potassium carbonate was added to the mixture followed by 5.0 mg of tetrakis(triphenylphosphine)palladium(0). The entire reaction was degassed three times with argon then heated to reflux for 4 h. The reaction was cooled to room temperature, diluted with 5 mL of water, and extracted with ethyl acetate (3×25 mL). The organic layers were combine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford 10.5 mg (13%) of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol as a clear oil.

(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol (10.5 mg, 0.013 mmol) was dissolved in 0.30 mL of methanol and 0.30 mL of triethylamine followed by drop-wise addition of water (0.80 mL). The yellowish mixture stirred at room temperature overnight. LCMS of the solution confirmed complete consumption of the starting material and formation of the fully deprotected material. The mixture was concentrated in vacuo, and purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) to afford 2.8 mg (35%) of the desired (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol as a white powder; 1H NMR (300 MHz, CD3OD) δ 7.65 (d, J=11.1 Hz, 2H), 7.54-7.23 (m, 10H), 7.05-6.89 (m, 3H), 4.61 (t, J=6.3 Hz, 1H), 4.19 (d, J=9.0 Hz, 1H), 3.87 (d, J=10.7 Hz, 1H), 3.73-3.63 (m, 1H), 3.49-3.36 (m, 3H) 3.22-3.18 (m, 2H), 1.89 (m, 4H) ppm; MS [M−OH]+ 596.5.
EXAMPLE 65
(1S)-1,5-Anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol




(3R,4S)-4-(4-Bromo-2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (0.42 g, 0.60 mmol) was dissolved in 15 mL of dioxane in a sealed tube. Bis(pinacolato)diboron (0.17 g, 0.66 mmol), potassium acetate (0.18 g, 1.83 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium(II) dichloromethane adduct (14.6 mg, 0.018 mmol) were added and the reaction was degassed with argon and heated to 85° C. for 24 h. The mixture was cooled to room temperature diluted with 50 mL of 1:1 ethyl acetate-hexane, washed with 100 mL of 0.1 N hydrochloric acid and 2×100 mL of brine. The organic layers were collected, partially concentrated to half the volume, filtered through 10 g of silica gel, washed with 50 mL of ethyl acetate and concentrated in vacuo.

The resulting brown oil which is (3R,4S)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-[2-{[tert-butyl(dimethyl)silyl]oxy}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-phenylazetidin-2-one was dissolved with (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol in 4.0 mL of toluene and 0.5 mL of ethanol. 0.150 mL of 4 N potassium carbonate was added followed by 7 mg of tetrakis(triphenylphosphine)palladium(0). The entire reaction was degassed three times with argon then heated to reflux for 1.5 h. After this time the reaction was cooled to room temperature and diluted with 25 mL of water and extracted with 1:1 hexane-ethyl acetate (3×75 mL). The organic layers were combine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford 41.6 mg (27%) of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3′-{[tert butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol as a clear oil.
This material was immediately dissolved in 0.80 mL of methanol and 0.80 mL of triethylamine followed by dropwise addition of water (2.3 mL). The yellow mixture was stirred at room temperature for 24 h, extracted with 1:1 ethyl acetate-hexane (3×100 mL), dried with sodium sulfate, and concentrated in vacuo to afford (1S)-1,5-anhydro-1-(3′-{[tert-butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol.
The final deprotection was accomplished by dissolving (1S)-1,5-anhydro-1-(3′-{[tert-butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-4-yl)-D-glucitol in 5 mL of acetonitrile, and adding 2.5 mL of 48% hydrofluoric acid. The mixture stirred at room temperature of 1.5 h, neutralized with 70 mL of 1 N sodium hydroxide and 50 mL of 1 M sodium phosphate buffer pH 7.4, extracted into ethyl acetate (2×100 mL), washed with saturated sodium bicarbonate (2×25 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The crude sample was purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) to afford 7.9 mg (74%) of the desired (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol as a white solid; 1H NMR (300 MHz, CD3OD) δ 7.49 (dd, J=6.6 Hz, 4H), 7.34-7.21 (m, 7H), 7.15 (d, J=7.8 Hz, 1H), 7.07-6.97 (m, 5H), 5.13 (d, J=2.1 Hz, 1H), 4.61 (m, 1H), 4.15 (d, J=9.3 Hz, 1H) 3.90 (d, J=12 Hz, 1H), 3.70 (m, 1H) 3.41 (m, 4H), 3.16 (m, 1H), 1.99-1.93 (m, 4H) ppm; MS [M−OH]+ 612.6.
EXAMPLE 66
(1S)-1,5-Anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol




Obtained in a manner similar to Example 65, but using (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(4-bromophenyl)-D-glucitol in place of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol. (1S)-1,5-Anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol (20% yield, white solid). 1H NMR (300 MHz, CD3OD) δ 7.49 (dd, J=8.1 Hz, 4H), 7.35-7.16 (m, 8H), 7.05-6.97 (m, 4H), 5.15 (d, J=1.8 Hz, 1H), 4.61 (m, 1H), 4.16 (d, J=9.6 Hz, 1H), 3.90 (d, J=11.1 Hz, 1H), 3.71 (m, 1H), 3.42 (m, 4H), 3.16 (m, 1H), 2.02-1.93 (m, 4H) ppm; MS [M−OH]+ 612.6. 

EXAMPLE 67
(2S/2R,3S,4S,6R,7R,8S)-3-O-tert-Butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-dioxa-2-(3-bromophenyl)-bicyclo [3.3.0]octane




n-Butyllithium (31.5 mL, 41.0 mmol, 1.3 M hexane) was added via addition funnel to 1,3-dibromobenzene (9.64 g, 41.0 mmol, 4.94 mL) dissolved in anhydrous tetrahydrofuran (30 mL) at −78° C. over 30 min. The addition funnel was rinsed with anhydrous tetrahydrofuran (15 mL) and the reaction was allowed to stir for 30 min at −78° C. To this solution was added 5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-α-D-glucuronolactone (4.5 g, 13.6 mmol) [prepared according to Tetrahedron Asymmetry 7:9, 2761, (1996)] dissolved in 30 mL of anhydrous tetrahydrofuran at −78° C. and the reaction stirred for 2 h. The reaction was quenched by the addition of saturated ammonium chloride (20 mL) followed by warming to room temperature. The reaction was poured into ethyl acetate (30 mL) and water (10 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated and purified by chromatography (1:1 diethyl ether-hexane) to afford a diastereomeric mixture of (2S12R,3S,4S,6R,7R,8S)-3-O-tert-butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-dioxa-2-(3-bromophenyl)-bicyclo[3.3.0]octane (4.77 g, 72% yield) as a colorless viscous oil. Rf 0.51 (3:1 hexane-ethyl acetate).

EXAMPLE 68
(6S)-6-C-(3-Bromophenyl)-6-O-[tert-butyl(dimethyl)silyl]-1,2-O-(1-methylethylidene)-α-D-glucofuranose




Sodium borohydride (11.1 mg, 0.29 mmol) was added to (2S/2R,3S,4S,6R,7R,8S)-3-O-tert-butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-dioxa-2-(3-bromophenyl)-bicyclo[3.3.0]octane dissolved in absolute ethanol (4 mL) at room temperature. The reaction was stirred at room temperature for 1 h. TLC analysis (3:1 hexane-ethyl acetate) indicated that all the starting lactol had been consumed. 1 mL of saturated ammonium chloride solution was added and the reaction was stirred until the effervescence ceased. The reaction was poured into ethyl acetate (30 mL) and water (10 mL) and the layers separated. The aqueous layer was extracted 2×20 mL with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated and purified by chromatography (3:1 hexane:ethyl acetate) to afford (6S)-6-C-(3-bromophenyl)-6-O-[tert-butyl(dimethyl)silyl]-1,2-O-(1-methylethylidene)-α-D-glucofuranose (125 mg, 88% yield) as a white waxy solid. mp 76-77° C.; Rf 0.24 (3:1 hexane:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.51-7.17 (m, 4H), 5.95 (d, J=3.6 Hz, 1H), 4.90 (s, 1H), 4.53 (d, J=3.9 Hz, 1H), 4.32 (d, J=2.7 Hz, 1H), 4.09 (dd, J=2.7 Hz, J=8.4 Hz, 1H), 3.75 (d, J=7.2 Hz, 1H), 2.76-2.68 (br s, 2H), 1.46 (s, 3H), 1.31 (s, 3H), 0.92 (s, 9H), 0.11 (s, 3H), −0.10 (s, 3H) ppm.
EXAMPLE 69
(6R)-6-C-(3-Bromophenyl)-1,2-O-(1-methylethylidene)-α-D-glucofuranose




Tetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.14 mL) was added dropwise to (2S/2R,3S,4S,6R,7R,8S)-3-O-tert-butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-dioxa-2-(3-bromophenyl)-bicyclo[3.3.0]octane (1.53 g, 3.14 mmol) and glacial acetic acid (188.4 mg, 3.14 mmol, 180 μL) in anhydrous tetrahydrofuran (30 mL) at 0° C. The reaction was stirred for 30 min at 0° C. then warmed to room temperature and stirred an additional 30 min. TLC analysis (3:1 hexane-ethyl acetate) indicated that the starting material had been completely consumed. The reaction was poured into ethyl acetate (30 mL), washed with saturated sodium bicarbonate (10 mL) and brine (2×10 mL). The aqueous layer was back extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated and purified by chromatography (35 g, 40% ethyl acetate-hexane isocratic) to afford (2S/2R,3S,4S,6R,7R,8S)-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-oxa-2-(3-bromophenyl)-bicyclo[3.3.0]octane (1.146 g, 98% yield) as a white solid; Rf 0.18 (3:1 hexane-ethyl acetate).
Sodium borohydride (116 mg, 3.1 mmol) was added to (2S/2R,3S,4S,6R,7R,8S)-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-oxa-2-(3-bromophenyl)-bicyclo[3.3.0]octane (1.15 g, 3.1 mmol) dissolved in absolute ethanol (5 mL) at room temperature. The reaction was stirred at room temperature for 1 h. TLC analysis (2:1 ethyl acetate-hexane) indicated that all the starting lactol had been consumed. 1 mL of saturated ammonium chloride solution was added and the reaction stirred until the effervescence ceased. The reaction was poured into ethyl acetate (30 mL) and water (10 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated and purified by chromatography (2:1 ethyl acetate-hexane to elute the first diastereomer then 100% ethyl acetate) to afford (6R)-6-C-(3-bromophenyl)-1,2-O-(1-methylethylidene)-α-D-glucofuranose (511 mg, 89% yield) as a white solid; mp 172-173° C.; Rf 0.19 (2:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3/CD3OD) δ 7.62-7.61 (m, 1H), 7.42-7.38 (m, 1H), 7.21 (t, J=7.5 Hz, 1H), 5.94 (d, J=3.9 Hz, 1H), 4.86 (d, J=4.5 Hz, 1H), 4.48 (d, J=3.3 Hz, 1H), 4.24 (d, J=2.4 Hz, 1H), 4.14-4.10 (m, 1H), 3.79-3.74 (m, 1H), 1.38 (s, 3H), 1.30 (s, 3H) ppm.
EXAMPLE 70
(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one




(3R,4S)-4-(4-Bromophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (45.1 mg, 0.10 mmol), bis(pinacolato)diboron (27.7 mg, 0.11 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (2.4 mg, 0.003 mmol), and potassium acetate (29.7 mg, 0.30 mmol) were dissolved in anhydrous dimethyl sulfoxide (600 μL). The vessel was evacuated and flushed with argon three times then sealed and heated at 80° C. for 16 h. LCMS analysis indicated that some starting material remained so an additional aliquot of catalyst and bis(pinacolato)diboron were added, the solution degassed and heating continued for 2 h. The reaction was diluted into dichloromethane (30 mL) and filtered through a plug of Celite®. The filtrate was washed 2×10 mL with water. The combined aqueous washed were back extracted with 3×10 mL dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (12 g silica gel, 20-50% ethyl acetate-hexane) to afford (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one (41.9 mg, 85% yield) as a tan foam; Rf (1:1 hexane-ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.1 Hz, 1H), 7.35-7.18 (m, 9H), 7.04-6.97 (m, 3H), 4.70 (t, J=5.7 Hz, 1H), 4.65 (d, J=2.1 Hz, 1H), 3.08 (dt, J=7.7, 2.5, 1H), 2.02-1.87 (m, 4H), 1.33 (s, 12H) ppm.

EXAMPLE 71
(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose




(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one (26.8 mg, 0.05 mmol), (6S)-6-C-(3-bromophenyl)-6-O-[tert-butyl(dimethyl)silyl]-1,2-O-(1-methylethylidene)-α-D-glucofuranose (18.1 mg, 0.04 mmol), and potassium carbonate (40 μL, 4 N aqueous) were dissolved in 1:1 toluene:ethanol (1 mL total volume). The solution was degassed by evacuating the vessel and flushing with argon three times.

Tetrakis(triphenylphosphine)palladium(0) (2.2 mg, 0.002 mmol) was added and the solution was degassed twice. The reaction was heated at 85° C. for 1 h. LCMS and TLC (1:1 hexane-ethyl acetate) analysis indicated consumption of the starting glycoside. The reaction was diluted into ethyl acetate (30 mL) and washed with water (2×10 mL). The combined aqueous washes were back extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by chromatography (12 g silica gel, 20-50% ethyl acetate-hexane) to afford (6S)-6-O-[tert-butyl(dimethyl)silyl]-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-1,2-O-(1-methylethylidene)-α-D-glucofuranose (13.5 mg, 45% yield) as a white foam; Rf 0.23 (1:1 hexane-ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.58-7.22 (m, 13H), 7.07-6.98 (m, 4H), 5.97 (d, J=3.9 Hz, 1H), 4.98 (d, J=2.4 Hz, 1H), 4.73 (t, J=6.3 Hz, 1H), 4.69 (d, J=2.1 Hz, 1H), 4.54 (d, J=3.9 Hz, 1H), 4.37 (d, J=2.4 Hz, 1H), 3.87-3.86 (m, 1H), 3.13-3.09 (m, 1H), 2.04-1.86 (m, 4H), 1.43 (s, 3H), 1.31 (s, 3H), 0.94 (s, 9H), 0.12 (s, 3H), −0.09 (s, 3H) ppm.
(6S)-6-O-[tert-Butyl(dimethyl)silyl]-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-1,2-O-(1-methylethylidene)-α-D-glucofuranose (13.5 mg, 0.017 mmol) was dissolved in acetonitrile (5 mL) in a polypropylene centrifuge tube. 48% Hydrofluoric acid (500 μL) was added at room temperature and the reaction was stirred for 16 h monitoring by LCMS. Upon completion, 1 equivalent of solid sodium carbonate (1.27 g, 12 mmol) was added and just enough water to dissolve the solid. The reaction was diluted into ethyl acetate (20 mL) and the layers separated. The aqueous solution was extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with saturated sodium carbonate (2×10 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) to afford (6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose (5.5 mg, 51%); 1H NMR (300 MHz, CDCl3/CD3OD) δ 7.64-7.58 (m, 2H), 7.48-7.21 (m, 12H), 7.08-6.98 (m, 3H), 5.12-5.07 (m, 1.4H), 4.73 (d, J=2.4 Hz, 1H), 4.66 (t, J=5.7 Hz, 1H), 4.39 (d, J=7.5 Hz, 0.6H), 4.00 (dd, J=1.5 Hz, J=9.6 Hz, 0.6H), 3.76-3.56 (m), 3.23-3.10 (m, 1.5H), 2.01-1.90 (m, 4H) ppm; MS [M+H]+ 630.0.
EXAMPLE 72
(6R)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose




Obtained in a manner similar to Example 71 but using as starting materials the products from Examples 68 and 70. (6R)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose (2.4 mg, 53% yield); 1H NMR (300 MHz, CDCl3/0.1% CD3OD) δ 7.64-7.58 (m, 2H), 7.49-7.23 (m, 12H), 7.08-6.98 (m, 3H), 5.06 (d, J=3.6 Hz, 0.6H), 4.91 (d, J=6.0 Hz, 1H), 4.72 (d, J=4.8 Hz, 1H), 4.66 (t, J=5.4 Hz, 1H), 4.42 (d, J=7.8 Hz, 0.4H), 4.07-4.02 (m, 1H), 3.69-3.66 (m, 1H), 3.16-3.11 (m, 1H), 1.96-1.91 (m, 4H) ppm; MS [M+H]+ 630.0.
EXAMPLE 73
(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose




(3R,4S)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-[2-{[tert-butyl(dimethyl)silyl]oxy}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-phenylazetidin-2-one (53.0 mg, 0.07 mmol), (6S)-6-C-(3-bromophenyl)-6-O-[tert-butyl(dimethyl)silyl]-1,2-O-(1-methylethylidene)-α-D-glucofuranose (24.1 mg, 0.05 mmol), and potassium carbonate (50 μL, 4 N aqueous solution) were dissolved in 1:1 toluene:ethanol (1 mL total volume). The solution was degassed by evacuating the vessel and flushing with argon three times. Tetrakis(triphenylphosphine)palladium (4.0 mg, 0.003 mmol) was added and the solution degassed twice. The reaction was heated at 85° C. for 1 h. LCMS and TLC (1:1 hexane-ethyl acetate) analysis indicated consumption of the starting glycoside. The reaction was diluted into ethyl acetate (30 mL) and washed with water (2×10 mL). The combined aqueous washes were back extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by chromatography (12 g silica gel, 5-50% ethyl acetate-hexane) to afford (6S)-6-O-[tert-butyl(dimethyl)silyl]-6-C-(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-1,2-O-(1-methylethylidene)-α-D-glucofuranose (10.5 mg, 20% yield) as a white foam; 1H NMR (300 MHz, CDCl3) δ 7.44-7.18 (m, 13H), 7.05-6.93 (m, 3H), 5.97 (d, J=3.9 Hz, 1H), 5.03 (d, J=2.1 Hz, 1H), 4.95 (d, J=2.4 Hz, 1H), 4.67 (m, 1H), 4.56 (t, J=4.8 Hz, 1H), 4.38 (m, 1H), 4.10 (dd, J=7.6, 3.0 Hz, 1H), 3.87 (m, 1H), 3.12 (m, 1H), 1.94-1.89 (m, 4H), 1.44 (s, 3H), 1.31 (s, 3H), 0.93 (s, 9H), 0.86 (s, 9H), 0.11 (s, 3H), 0.01 (s, 3H), −0.11 (s, 3H), −0.16 (s, 3H) ppm.

(6S)-6-O-[tert-Butyl(dimethyl)silyl]-6-C-(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-1,2-O-(1-methylethylidene)-α-D-glucofuranose was dissolved in acetonitrile (5 mL) in a polypropylene centrifuge tube. 48% Hydrofluoric acid (750 μL) was added at room temperature and the reaction stirred for 16 h monitoring progress by LCMS. Upon completion, 1 equivalent of solid sodium carbonate (1.91 g, 18 mmol) was added and just enough water to dissolve the solid. The reaction was diluted into ethyl acetate (20 mL) and the layers separated. The aqueous solution was extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with saturated sodium carbonate (2×10 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) to afford (6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose (17.8 mg); 1H NMR (300 MHz, CDCl3/CD3OD) δ 7.52-6.83 (m, 16H), 5.05-5.00 (m, 2H), 4.50 (m, 1H), 4.34 (m, 1H), 3.94 (m, 1H), 3.72-3.59 (m, 2H), 2.91 (m, 1H), 1.95-1.77 (m, 4H) ppm; MS [M−OH]+ 627.8.
EXAMPLE 74
(6R)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose




Obtained in a manner similar to Example 73. Purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) to afford (6R)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose (4.1 mg, 70% yield); 1H NMR (300 MHz, CDCl3/CD3OD) δ 7.55-6.90 (m, 16H), 5.08-2.06 (m, 1H), 5.01-5.00 (m, 1H), 4.86 (d, J=4.5 Hz, 1H), 4.60 (t, J=5.1 Hz, 1H), 4.39 (d, J=8.1 Hz, 1H), 4.02-3.97 (m, 1H), 3.70-3.64 (m, 1H), 3.52-3.49 (m, 1H), 1.96-1.85 (m, 4H) ppm; MS [M−OH]+ 627.8.
EXAMPLE 75
(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol




(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose (7.1 mg, 0.01 mmol) was dissolved in 80:20 acetonitrile-water (1 mL). Sodium borohydride (0.4 mg, 0.01 mmol) was added at room temperature and the reaction was stirred for 30 min monitoring by LCMS. Upon completion, the reaction was diluted with 80:20 acetonitrile:water (3 mL) then filtered through a Whatman 0.45 μM glass microfiber filter and purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) to afford (6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol (1.4 mg, 22% yield). 1H NMR (300 MHz, CDCl3/CD3OD) δ 7.37-6.89 (m, 16H), 5.08 (d, J=2.4 Hz, 1H), 4.97-4.95 (m, 1H), 4.60 (t, J=6.0 Hz, 1H), 3.92 (m, 1H), 3.76-3.56 (m, 6H), 2.01-1.82 (m, 4H) ppm; MS [M−OH]+ 629.8.

EXAMPLE 76
6-O-(4′-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose




Diethylazodicarboxylate (192.4 mg, 1.11 mmol, 172 μL) was added drop-wise at 0° C. to 1,2,3,4-tetra-O-acetyl-β-D-glucopyranose (350.0 mg, 1.01 mmol), 3-bromophenyl (174.0 mg, 1.11 mmol), and triphenylphosphine (115.0 mg, 0.44 mmol) dissolved in dry tetrahydrofuran (2 mL). The reaction was stirred for 16 h warming to room temperature. The reaction was diluted into diethyl ether (30 mL) and washed with 5% sodium bisulfate (2×10 mL). The separated organic solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by chromatography (20% ethyl acetate-dichloromethane) to afford 1,2,3,4-tetra-O-acetyl-6-O-(3-bromophenyl)-β-D-glucopyranose (357 mg, 71% yield).

Triethylamine (1 mL) was added at room temperature to 1,2,3,4-tetra-O-acetyl-6-O-(3-bromophenyl)-β-D-glucopyranose (200 mg, 0.40 mmol) dissolved in 5: I methanol-water (6 mL). The reaction progress was monitored by LCMS and TLC (20% ethyl acetate-dichloromethane). Upon completion, the solvents were removed in vacuo to afford 6-O-(3-bromophenyl)-β-D-glucopyranose which was carried on without further purification.
tert-Butyldimethylsilyl trifluoromethanesulfonate (442 mg, 1.67 mmol, 383 μL) was added dropwise at 0° C. to 6-O-(3-bromophenyl)-β-D-glucopyranose and 4-dimethylaminopyridine (219 mg, 1.79 mmol) dissolved in dichloromethane (3 mL). The reaction was stirred for 16 h warming to room temperature. The reaction was diluted into dichloromethane (30 mL) and washed with 5% sodium bisulfate (2×10 mL). The separated organic solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by chromatography (50% ethyl acetate:hexane) to afford a 6-O-(3-bromophenyl)-β-D-glucopyranose bis-O-[tert-butyl(dimethyl)silyl]ether (98.9 mg, 44% yield); Rf=0.14 (50% ethyl acetate-hexane).
(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one (141.5 mg, 0.27 mmol), 6-O-(3-bromophenyl)-β-D-glucopyranose bis-O-[tert-butyl(dimethyl)silyl]ether (98.9 mg, 0.18 mmol), and potassium carbonate (175 μL, 2 M aqueous solution) were dissolved in 1:1 toluene-ethanol (1 mL total volume). The solution was degassed by evacuating the vessel and flushing with argon three times.
Tetrakis(triphenylphosphine)palladium (10.0 mg, 0.009 mmol) was added and the solution degassed twice. The reaction was heated at 85° C. for 1 h. LCMS and TLC (1:1 hexane-ethyl acetate) analysis indicated consumption of the starting glycoside. The reaction was diluted into ethyl acetate (30 mL) and washed with water (2×10 mL). The combined aqueous washes were back extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by chromatography (12 g silica gel, 50% ethyl acetate-hexane) to afford 6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-β-D-glucopyranose bis-O-[tert-butyl(dimethyl)silyl]ether (113 mg, 74% yield). 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=7.8 Hz, 2H), 7.36-7.10 (m, 8H), 7.01-6.80 (m, 6H), 4.70 (t, J=5.4 Hz, 1H), 4.64 (d, J=1.8 Hz, 1H), 4.56 (d, J=6.9 Hz, 1H), 4.35-4.32 (m, 1H), 4.16-4.07 (m, 1H), 3.68-3.58 (m, 2H), 3.51-3.46 (m, 1H), 3.38-3.32 (m, 1H), 3.11-3.09 (m, 1H), 1.98-1.88 (m, 4H), 0.91 (s, 9H), 0.91 (s, 9H), 0.14 (s, 6H), 0.13 (s, 6H) ppm.
6-O-(4′-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranose bis-O-[tert-butyl(dimethyl)silyl]ether (82.3 mg, 0.09 mmol) was dissolved in acetonitrile (10 mL) in a polypropylene centrifuge tube. 48% Hydrofluoric acid (1 mL) was added at room temperature and the reaction monitored by LCMS. Upon completion, 1 equivalent of solid sodium carbonate (2.54 g, 24 mmol) was added and just enough water to dissolve the solid. The reaction was diluted into ethyl acetate (20 mL) and the layers separated. The aqueous solution was extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with saturated sodium carbonate (2×10 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by reverse phase preparative HPLC (Polaris C18-A 10 μ 50×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) to afford 6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranose (54.3 mg, 89% yield). 1H NMR (300 MHz, CDCl3/1% CD3OD) δ 7.58 (d, J=7.8 Hz, 2H), 7.39-7.24 (m, 7H), 7.17-7.14 (m, 2H), 7.04-6.92 (m, 5H), 5.23 (d, J=3.9 Hz, 0.6H), 4.71 (d, J=1.8 Hz, 1H), 4.66 (t, J=5.7 Hz, 1H), 4.58 (d, J=8.1 Hz, 0.4H), 4.40-4.30 (m, 1H), 4.25-4.14 (m, 1H), 3.57-3.48 (m, 2H), 3.16-3.11 (m, 1H), 2.04-1.85 (m, 4H) ppm; MS [M−OH]+ 630.0.
EXAMPLE 77
Methyl 6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranoside




Diethylazodicarboxylate (76.2 mg, 0.44 mmol, 68 μL) was added drop-wise to methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (184.8 mg, 0.40 mmol), 3-bromophenyl (72.3 mg, 0.42 mmol), and triphenylphosphine (115.0 mg, 0.44 mmol) dissolved in dry tetrahydrofuran (2 mL) at 0° C. The reaction was stirred for 16 h warming to room temperature. The reaction was diluted into dichloromethane (30 mL) and washed with 5% sodium bisulfate (2×10 mL). The separated organic solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by chromatography (20% ethyl acetate-dichloromethane) to afford methyl 2,3,4-tri-O-benzyl-6-O-(3-bromophenyl)-α-D-glucopyranoside (216 mg, 87% yield).

(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one (64.1 mg, 0.12 mmol), methyl 2,3,4-tri-O-benzyl-6-O-(3-bromophenyl)-D-glucopyranoside (54.6 mg, 0.09 mmol), and potassium carbonate (88 μL, 2 M aqueous solution) were dissolved in 1:1 toluen-ethanol (1 mL total volume). The solution was degassed by evacuating the vessel and flushing with argon three times. Tetrakis(triphenylphosphine)palladium (5.1 mg, 0.004 mmol) was added and the solution degassed twice. The reaction was heated at 85° C. for 1 h. LCMS and TLC (1:1 hexane-ethyl acetate) analysis indicated consumption of the starting glycoside. The reaction was diluted into ethyl acetate (30 mL) and washed with water (2×10 mL). The combined aqueous washes were back extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by chromatography (12 g silica gel, 20% to 50% ethyl acetate-hexane) to afford methyl 2,3,4-tri-O-benzyl-6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranoside (70.0 mg, 85% yield). 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=8.1 Hz, 2H), 7.39-6.84 (m, 29H), 5.01 (d, J=10.8 Hz, 1H), 4.89-4.80 (m, 3H), 4.73-4.64 (m, 4H), 4.52 (d, J=11.1 Hz, 1H), 4.15-4.12 (m, 2H), 4.08-4.-1 (m, 1H), 3.94-3.90 (m, 1H), 3.77-3.71 (m, 1H), 3.62 (dd, J=3.6 Hz, J=9.6 Hz, 1H), 3.39 (s, 3H), 3.13-3.10 (m, 1H), 2.03-1.89 (m, 4H) ppm.
Methyl 2,3,4-tri-O-benzyl-6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranoside (70 mg, 0.08 mmol) was dissolved in absolute ethanol (3 mL). 10% Pd/C (wet, 14% w/w) was added and the vessel sealed. The solution was degassed by evacuation and flushing with hydrogen gas at balloon pressure. The reaction was monitored by TLC (1:1 hexane-ethyl acetate). Upon completion, the catalyst was filtered by passing through a plug of Celite® and washing with additional ethanol. The filtrate was concentrated in vacuo and purified by preparative HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) affording methyl 6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranoside (18.1 mg, 36% yield); 1H NMR (300 MHz, CDCl3/1% CD3OD) δ 7.58 (d, J=8.4 Hz, 2H), 7.38-7.23 (m, 7H), 7.17-7.14 (m, 2H), 7.04-6.92 (m, 5H), 4.80 (d, J=3.9 Hz, 1H), 4.70 (d, J=2.4 Hz, 1H), 4.67 (t, J=5.7 Hz, 1H), 4.37-4.33 (m, 1H), 4.26-4.21 (m, 1H), 3.92-3.87 (m, 1H), 3.74-3.45 (m, 3H), 3.42 (s, 3H), 3.18-3.10 (m, 1H), 2.01-1.88 (m, 4H) ppm; MS [M−OH]+ 644.0.
EXAMPLE 78
6-O-(4′-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucitol




Sodium borohydride (1.6 mg, 0.04 mmol) was added to 6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose (26.3 mg, 0.04 mmol) dissolved in 80:20 acetonitrile-water (1 mL) at room temperature. The reaction was stirred for 10 min at room temperature monitoring by LCMS. Upon completion, the reaction was diluted with 50:50 acetonitrile:water (3 mL) and filtered through a Whatman 0.45 μM glass microfiber filter then purified by preparative HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) affording 6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucitol (21.2 mg, 80% yield). 1H NMR (300 MHz, CDCl3/1% CD3OD) δ 7.58 (d, J=8.1 Hz, 2H), 7.39-7.24 (m, 7H), 7.17-7.15 (m, 2H), 7.04-6.92 (m, 5H), 4.71 (d, J=2.1 Hz, 1H), 4.68 (t, J=6.3 Hz, 1H), 4.31-4.27 (m, 1H), 0.19-4.14 (m, 1H), 4.08-4.02 (m, 1H), 3.97-3.95 (m, 1H), 3.86-3.65 (m, 4H), 3.14-3.12 (m, 1H), 2.01-1.88 (m, 4H) ppm; MS [M+HCO2−]− 694.0.





Illustrated in Scheme IV is the general method for the preparation of cholesterol absorption inhibitors of general formula IV-3. Imines IV-2 are made by refluxing anilines with the appropriate aldehydes in isopropanol. Condensation of imine IV-2 with the ester enolate of compound IV-1 affords the azetidinone IV-3. In the case where X is sulfur, one equivalent of an appropriate oxidizing agent such as MCPBA can be used to convert to the sulfoxide, two equivalents can be used to synthesize the sulfone. Where X is nitrogen, one equivalent of an appropriate oxidizing agent can be used to convert the secondary amine to a hydroxylamine (following deprotection).




The following examples were also prepared according to the methods described above:
EXAMPLE 81
(3R,4S)-4-(3′,4′-dimethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 82
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3′-(methylthio)biphenyl-4-yl]azetidin-2-one
EXAMPLE 83
(3R,4S)-4-[3′-(dimethylamino)biphenyl-4-yl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 84
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-vinylbiphenyl-4-yl)azetidin-2-one
EXAMPLE 85
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-5-methoxybiphenyl-2-carbaldehyde
EXAMPLE 86
(3R,4S)-4-(3′-aminobiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 87
(3R,4S)-4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 88
(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-4-yl)acetic Acid
EXAMPLE 89
methyl 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-4-carboxylate
EXAMPLE 90
(3R,4S)-4-(3′,5′-dimethylbiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 91
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(2-naphthyl)phenyl]azetidin-2-one
EXAMPLE 92
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3′-(trifluoromethyl)biphenyl-4-yl]azetidin-2-one
EXAMPLE 93
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-methylbiphenyl-4-yl)azetidin-2-one
EXAMPLE 94
(3R,4S)-4-(4′-fluoro-3′-methylbiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 95
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl β-L-glucopyranoside
EXAMPLE 96
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2′,3′,4′-trimethoxybiphenyl-4-yl)azetidin-2-one
EXAMPLE 97
(3R,4S)-4-(2′,4′-dimethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 98
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2′-methylbiphenyl-4-yl)azetidin-2-one
EXAMPLE 99
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-4-carbaldehyde
EXAMPLE 100
(3R,4S)-4-(3′-ethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 101
(3R,4S)-4-(4′-ethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 102
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxy-3′-methoxybiphenyl-4-yl)azetidin-2-one
EXAMPLE 103
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-propoxybiphenyl-4-yl)azetidin-2-one
EXAMPLE 104
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-5-hydroxybiphenyl-2-carbaldehyde
EXAMPLE 105
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-isopropoxybiphenyl-4-yl)azetidin-2-one
EXAMPLE 106
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-4-hydroxybiphenyl-3-carboxylic Acid
EXAMPLE 107
(3R,4S)-4-(3′,5′-dimethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 108
(3R,4S)-4-(2′,4′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 109
(3R,4S)-4-(3′-butoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 110
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-3-hydroxybiphenyl-4-carboxylic Acid
EXAMPLE 111
(3R,4S)-4-(3′-fluoro-5′-methoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 112
(3R,4S)-4-(3′-fluoro-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 113
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-L-glucitol
EXAMPLE 114
(3R,4S)-4-(3′,5′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 115
(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)boronic Acid
EXAMPLE 116
(1R)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-4-yl)-L-glucitol
EXAMPLE 117
2,6-anhydro-1-deoxy-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-ylbiphenyl-3-yl)-D-glycero-D-gulo-heptitol
EXAMPLE 118
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-sulfonic Acid
EXAMPLE 119
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-mercaptobiphenyl-4-yl)azetidin-2-one
EXAMPLE 120
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-N,N,N-trimethylbiphenyl-3-aminium
EXAMPLE 121
(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one
EXAMPLE 122
(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonic Acid
EXAMPLE 123
(3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3-hydroxy-3′-(methylsulfonyl)biphenyl-4-yl]-1-phenylazetidin-2-one
EXAMPLE 124
(3R,4S)-1-biphenyl-4-yl-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one
EXAMPLE 125
(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one
EXAMPLE 126
Dimethyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate




prepared in analogous manner to dimethyl [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate (Example 60) starting with 4-chlorophenyl instead of 3-chlorophenyl. Dimethyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate product was obtained as a light yellow oil (90%); 1H NMR (300 MHz, CDCl3) δ 7.86-7.95 (m, 2H), 7.84-7.82 (m, 2H), 7.43-7.50 (m, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 1.34 (s, 12H) ppm; MS [M+H] 312, [2M+H] 625.

EXAMPLE 127
(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic Acid




prepared in analogous manner to Example 61 using dimethyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate (Example 126) in the reaction scheme instead of dimethyl [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate (Example 60). Final purification by reverse-phase HPLC (Polaris C18-A 10±250×21.2 mm column, 30% to 59% acetonitrile-0.1% trifluoroacetic acid in water) afforded (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid as a white powder (62%); 1H NMR (300 MHz, CD3OD) δ 7.8 (dd, J=8.0, 13.0 Hz, 1H), 7.68 (dd, J=3.2, 8.0 Hz, 1H), 6.9-7.4 (m, 14H), 5.17 (d, J=2.1 Hz, 1H), 4.60-4.66 (m, 1H), 3.13-3.22 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS [M−H] 546, [2M−H] 1093.

EXAMPLE 128
Sodium 4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonate




5-Bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenyl acetate (850 mg, 1.36 mmol) and 4-thioanisoleboronic acid (252 mg, 1.50 mmol) were dissolved in dioxane (13.6 mL). Cesium carbonate (882 mg, 2.71 mmol) and solid bis(1-adamantylamine)palladium(0) (113 mg, 0.21 mmol) were added and the vessel was vacuum/nitrogen purged (3×). The reaction was stirred vigorously for 4 h at 80° C. under a nitrogen atmosphere and then cooled and reacted with acetic anhydride (0.70 mL, 7.3 mmol) and 4-dimethylamino-pyridine (185.6 mg, 1.52 mmol). After 15 min, the mixture was poured into 1.0 N hydrochloric acid (60 mL), extracted with 1:1 ethyl acetate-hexane (60 mL), washed with brine (60 mL), dried over sodium sulfate, filtered, concentrated and purified by chromatography (40 g silica gel, 5% to 50% ethyl acetate-hexane) to afford 4-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-4′-(methylthio)biphenyl-3-yl acetate (478 mg, 52% yield) as a white foam; Rf 0.41 (1:4 ethyl acetate-hexane).

4-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-4′-(methylthio)biphenyl-3-yl acetate (478 mg, 0.713 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0° C. 3-Chlorobenzenecarbo-peroxoic acid (134.5 mg, 0.779 mmol) was added in portions while monitoring by TLC and LCMS to make the arylsulfoxide. Once addition was complete the reaction was poured into quarter saturated sodium bicarbonate solution (60 mL), extracted with dichloromethane (60 mL) and ethyl acetate (60 mL), the combined organic layers were dried over sodium sulfate, filtered and concentrated with toluene. The residue was dissolved in dichloromethane (10 mL) and the Pummerer rearrangement was effected by the addition of trifluoroacetic anhydride (250 μL, 372 mg, 1.77 mmol). The reaction was stirred at room temperature for 8.5 h and then concentrated with toluene and diluted with a solution of degassed methanol (3.0 mL), triethylamine (3.0 mL) and water (1.0 mL). After 2.75 h the golden yellow solution was concentrated, transferred into a polypropylene Falcon® tube with acetonitrile (10.0 mL) and diluted with 48% hydrofluoric acid (1.0 mL). The reaction was stirred for 4 h at room temperature and then poured into 0.5 M potassium phosphate (50 mL), extracted with ethyl acetate (60 mL), washed with water (60 mL) and brine (60 mL), dried over sodium sulfate, filtered, concentrated and purified by chromatography (40 g silica gel, 10% to 100% ethyl acetate-hexane) to afford a mixture of compounds (some impurities and oxidized desired material). The residue was used as is in the next step.
The residue was dissolved in dichloromethane (10 mL) and added drop-wise to a solution of 3-chlorobenzenecarboperoxoic acid (489 mg, 2.83 mmol) in dichloromethane (10 mL). Dichloromethane (5 mL) was used to help transfer the material and the mixture was stirred at room temperature for 15 min. The reaction was quenched by addition of triethylamine (4 mL), concentrated, dissolved in methanol, filtered through a 0.45 μl Whatman® filter, concentrated again, purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 5% to 100% acetonitrile-0.1% triethylamine in water) and treated with Dowex® sodium ion exchange resin to afford sodium 4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonate (249.0 mg, 57% yield) as a light pale purple solid; 1H NMR 300 MHz, CD3OD) δ 7.88 (d, J=8.6 Hz, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.35-7.19 (m, 7H), 7.14-7.11 (m, 2H), 7.03-6.97 (m, 3H), 5.14 (d, J=2.2 Hz, 1H), 4.63-4.59 (m, 1H), 3.17-3.08 (m, 1H), 2.04-1.87 (m, 4H) ppm; MS [M−Na] 546.0.
Also within the invention are compounds described by Table 3, together with Table 4 and Formula VIII which is shown below.




In these embodiments, R1 and R2 are independently chosen from H, F, CN, Cl, CH3, OCH3, OCF3, OCF2H, CF3, CF2H, and CH2F; R4 is chosen from H, Cl, CH3, OCH3, OH, B(OH)2, and SH; R5 is chosen from OH, SO3H, PO3H2, CH2OH, COOH, CHO, D-glucitol, a C-glysosyl compound and a sugar and only one R substitution is allowed on any aromatic ring. For example, where R5 is —OH, all of the other substituents on the corresponding aromatic ring are H. Of course, where a given R group is H (e.g., R1) all of the substituents on the corresponding aromatic ring are also H. In Table 4 when the R4 substituent position is defined as 3-, the substitution occurs at the position ortho to the azetidinone ring. In Table 4 when the R4 substituent position is defined as 2-, the substitution occurs at the position meta to the azetidinone ring.
Each row in Table 3 defines a unique subset of R group substituents which can be systematically substituted in an iterative fashion into Formula VIII at the positions specified by each row of Table 4 to generate specific compounds within Formula VIII. For example, in Table 3, row 1, R1 is H, R2 is F, R4 is OH, and R5 is OH. Substituting this set of R groups into Formula VIII according to the placement defined by row 1 of Table 4 (i.e., R1 is ortho, R2 is ortho, R4 is 3- and R5 is ortho) yields




(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one
Similarly, (3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one is disclosed by the using values in Table 3, row 1 to substitute Formula VIII according to Table 4, row 2. Tables 5-20 comprise the compounds disclosed by substituting the substituents listed in Tables 3 rows 1-16 into Formula VIII according to the placement defined by each row in Table 4. It should be understood that the compounds listed in Tables 5-20 are only a small subset of the compounds described by the systematic iterative substitution of the substituents in each row of Table 3 into generic Formula VIII according to the placement defined by each row of Table 4.











TABLE 3





Row
R1
R2
R4
R5



















1
H
F
OH
OH


2
H
F
OH
D-glucitol


3
H
F
OH
SO3H


4
H
F
OH
PO3H2


5
H
H
OH
OH


6
H
H
OH
D-glucitol


7
H
H
OH
SO3H


8
H
H
OH
PO3H2


9
H
Cl
OH
OH


10
H
Cl
OH
D-glucitol


11
H
Cl
OH
SO3H


12
H
Cl
OH
PO3H2


13
F
H
OH
OH


14
F
H
OH
D-glucitol


15
F
H
OH
SO3H


16
F
H
OH
PO3H2


17
F
F
OH
OH


18
F
F
OH
D-glucitol


19
F
F
OH
SO3H


20
F
F
OH
PO3H2


21
F
Cl
OH
OH


22
F
Cl
OH
D-glucitol


23
F
Cl
OH
SO3H


24
F
Cl
OH
PO3H2


25
Cl
H
OH
OH


26
Cl
H
OH
D-glucitol


27
Cl
H
OH
SO3H


28
Cl
H
OH
PO3H2


29
Cl
F
OH
OH


30
Cl
F
OH
D-glucitol


31
Cl
F
OH
SO3H


32
Cl
F
OH
PO3H2


33
Cl
Cl
OH
OH


34
Cl
Cl
OH
D-glucitol


35
Cl
Cl
OH
SO3H


36
Cl
Cl
OH
PO3H2


37
H
H
H
OH


38
H
H
H
D-glucitol


39
H
H
H
SO3H


40
H
H
H
PO3H2


41
H
H
H
CHO


42
H
H
H
COOH


43
H
H
H
CH2OH


44
H
H
H
sugar


45
H
H
H
C-glycosyl compound


46
H
H
OH
CHO


47
H
H
OH
COOH


48
H
H
OH
CH2OH


49
H
H
OH
sugar


50
H
H
OH
C-glycosyl compound


51
H
H
CH3
OH


52
H
H
CH3
D-glucitol


53
H
H
CH3
SO3H


54
H
H
CH3
PO3H2


55
H
H
CH3
CHO


56
H
H
CH3
COOH


57
H
H
CH3
CH2OH


58
H
H
CH3
sugar


59
H
H
CH3
C-glycosyl compound


60
H
H
Cl
OH


61
H
H
Cl
D-glucitol


62
H
H
Cl
SO3H


63
H
H
Cl
PO3H2


64
H
H
Cl
CHO


65
H
H
Cl
COOH


66
H
H
Cl
CH2OH


67
H
H
Cl
sugar


68
H
H
Cl
C-glycosyl compound


69
H
H
B(OH)2
OH


70
H
H
B(OH)2
D-glucitol


71
H
H
B(OH)2
SO3H


72
H
H
B(OH)2
PO3H2


73
H
H
B(OH)2
CHO


74
H
H
B(OH)2
COOH


75
H
H
B(OH)2
CH2OH


76
H
H
B(OH)2
sugar


77
H
H
B(OH)2
C-glycosyl compound


78
H
H
SH
OH


79
H
H
SH
D-glucitol


80
H
H
SH
SO3H


81
H
H
SH
PO3H2


82
H
H
SH
CHO


83
H
H
SH
COOH


84
H
H
SH
CH2OH


85
H
H
SH
sugar


86
H
H
SH
C-glycosyl compound


87
H
H
OCH3
OH


88
H
H
OCH3
D-glucitol


89
H
H
OCH3
SO3H


90
H
H
OCH3
PO3H2


91
H
H
OCH3
CHO


92
H
H
OCH3
COOH


93
H
H
OCH3
CH2OH


94
H
H
OCH3
sugar


95
H
H
OCH3
C-glycosyl compound


96
H
F
H
OH


97
H
F
H
D-glucitol


98
H
F
H
SO3H


99
H
F
H
PO3H2


100
H
F
H
CHO


101
H
F
H
COOH


102
H
F
H
CH2OH


103
H
F
H
sugar


104
H
F
H
C-glycosyl compound


105
H
F
OH
CHO


106
H
F
OH
COOH


107
H
F
OH
CH2OH


108
H
F
OH
sugar


109
H
F
OH
C-glycosyl compound


110
H
F
CH3
OH


111
H
F
CH3
D-glucitol


112
H
F
CH3
SO3H


113
H
F
CH3
PO3H2


114
H
F
CH3
CHO


115
H
F
CH3
COOH


116
H
F
CH3
CH2OH


117
H
F
CH3
sugar


118
H
F
CH3
C-glycosyl compound


119
H
F
Cl
OH


120
H
F
Cl
D-glucitol


121
H
F
Cl
SO3H


122
H
F
Cl
PO3H2


123
H
F
Cl
CHO


124
H
F
Cl
COOH


125
H
F
Cl
CH2OH


126
H
F
Cl
sugar


127
H
F
Cl
C-glycosyl compound


128
H
F
B(OH)2
OH


129
H
F
B(OH)2
D-glucitol


130
H
F
B(OH)2
SO3H


131
H
F
B(OH)2
PO3H2


132
H
F
B(OH)2
CHO


133
H
F
B(OH)2
COOH


134
H
F
B(OH)2
CH2OH


135
H
F
B(OH)2
sugar


136
H
F
B(OH)2
C-glycosyl compound


137
H
F
SH
OH


138
H
F
SH
D-glucitol


139
H
F
SH
SO3H


140
H
F
SH
PO3H2


141
H
F
SH
CHO


142
H
F
SH
COOH


143
H
F
SH
CH2OH


144
H
F
SH
sugar


145
H
F
SH
C-glycosyl compound


146
H
F
OCH3
OH


147
H
F
OCH3
D-glucitol


148
H
F
OCH3
SO3H


149
H
F
OCH3
PO3H2


150
H
F
OCH3
CHO


151
H
F
OCH3
COOH


152
H
F
OCH3
CH2OH


153
H
F
OCH3
sugar


154
H
F
OCH3
C-glycosyl compound


155
H
Cl
H
OH


156
H
Cl
H
D-glucitol


157
H
Cl
H
SO3H


158
H
Cl
H
PO3H2


159
H
Cl
H
CHO


160
H
Cl
H
COOH


161
H
Cl
H
CH2OH


162
H
Cl
H
sugar


163
H
Cl
H
C-glycosyl compound


164
H
Cl
OH
CHO


165
H
Cl
OH
COOH


166
H
Cl
OH
CH2OH


167
H
Cl
OH
sugar


168
H
Cl
OH
C-glycosyl compound


169
H
Cl
CH3
OH


170
H
Cl
CH3
D-glucitol


171
H
Cl
CH3
SO3H


172
H
Cl
CH3
PO3H2


173
H
Cl
CH3
CHO


174
H
Cl
CH3
COOH


175
H
Cl
CH3
CH2OH


176
H
Cl
CH3
sugar


177
H
Cl
CH3
C-glycosyl compound


178
H
Cl
Cl
OH


179
H
Cl
Cl
D-glucitol


180
H
Cl
Cl
SO3H


181
H
Cl
Cl
PO3H2


182
H
Cl
Cl
CHO


183
H
Cl
Cl
COOH


184
H
Cl
Cl
CH2OH


185
H
Cl
Cl
sugar


186
H
Cl
Cl
C-glycosyl compound


187
H
Cl
B(OH)2
OH


188
H
Cl
B(OH)2
D-glucitol


189
H
Cl
B(OH)2
SO3H


190
H
Cl
B(OH)2
PO3H2


191
H
Cl
B(OH)2
CHO


192
H
Cl
B(OH)2
COOH


193
H
Cl
B(OH)2
CH2OH


194
H
Cl
B(OH)2
sugar


195
H
Cl
B(OH)2
C-glycosyl compound


196
H
Cl
SH
OH


197
H
Cl
SH
D-glucitol


198
H
Cl
SH
SO3H


199
H
Cl
SH
PO3H2


200
H
Cl
SH
CHO


201
H
Cl
SH
COOH


202
H
Cl
SH
CH2OH


203
H
Cl
SH
sugar


204
H
Cl
SH
C-glycosyl compound


205
H
Cl
OCH3
OH


206
H
Cl
OCH3
D-glucitol


207
H
Cl
OCH3
SO3H


208
H
Cl
OCH3
PO3H2


209
H
Cl
OCH3
CHO


210
H
Cl
OCH3
COOH


211
H
Cl
OCH3
CH2OH


212
H
Cl
OCH3
sugar


213
H
Cl
OCH3
C-glycosyl compound


214
H
CN
H
OH


215
H
CN
H
D-glucitol


216
H
CN
H
SO3H


217
H
CN
H
PO3H2


218
H
CN
H
CHO


219
H
CN
H
COOH


220
H
CN
H
CH2OH


221
H
CN
H
sugar


222
H
CN
H
C-glycosyl compound


223
H
CN
OH
OH


224
H
CN
OH
D-glucitol


225
H
CN
OH
SO3H


226
H
CN
OH
PO3H2


227
H
CN
OH
CHO


228
H
CN
OH
COOH


229
H
CN
OH
CH2OH


230
H
CN
OH
sugar


231
H
CN
OH
C-glycosyl compound


232
H
CN
CH3
OH


233
H
CN
CH3
D-glucitol


234
H
CN
CH3
SO3H


235
H
CN
CH3
PO3H2


236
H
CN
CH3
CHO


237
H
CN
CH3
COOH


238
H
CN
CH3
CH2OH


239
H
CN
CH3
sugar


240
H
CN
CH3
C-glycosyl compound


241
H
CN
Cl
OH


242
H
CN
Cl
D-glucitol


243
H
CN
Cl
SO3H


244
H
CN
Cl
PO3H2


245
H
CN
Cl
CHO


246
H
CN
Cl
COOH


247
H
CN
Cl
CH2OH


248
H
CN
Cl
sugar


249
H
CN
Cl
C-glycosyl compound


250
H
CN
B(OH)2
OH


251
H
CN
B(OH)2
D-glucitol


252
H
CN
B(OH)2
SO3H


253
H
CN
B(OH)2
PO3H2


254
H
CN
B(OH)2
CHO


255
H
CN
B(OH)2
COOH


256
H
CN
B(OH)2
CH2OH


257
H
CN
B(OH)2
sugar


258
H
CN
B(OH)2
C-glycosyl compound


259
H
CN
SH
OH


260
H
CN
SH
D-glucitol


261
H
CN
SH
SO3H


262
H
CN
SH
PO3H2


263
H
CN
SH
CHO


264
H
CN
SH
COOH


265
H
CN
SH
CH2OH


266
H
CN
SH
sugar


267
H
CN
SH
C-glycosyl compound


268
H
CN
OCH3
OH


269
H
CN
OCH3
D-glucitol


270
H
CN
OCH3
SO3H


271
H
CN
OCH3
PO3H2


272
H
CN
OCH3
CHO


273
H
CN
OCH3
COOH


274
H
CN
OCH3
CH2OH


275
H
CN
OCH3
sugar


276
H
CN
OCH3
C-glycosyl compound


277
H
CH3a
H
OH


278
H
CH3a
H
D-glucitol


279
H
CH3a
H
SO3H


280
H
CH3a
H
PO3H2


281
H
CH3a
H
CHO


282
H
CH3a
H
COOH


283
H
CH3a
H
CH2OH


284
H
CH3a
H
sugar


285
H
CH3a
H
C-glycosyl compound


286
H
CH3a
OH
OH


287
H
CH3a
OH
D-glucitol


288
H
CH3a
OH
SO3H


289
H
CH3a
OH
PO3H2


290
H
CH3a
OH
CHO


291
H
CH3a
OH
COOH


292
H
CH3a
OH
CH2OH


293
H
CH3a
OH
sugar


294
H
CH3a
OH
C-glycosyl compound


295
H
CH3a
CH3
OH


296
H
CH3a
CH3
D-glucitol


297
H
CH3a
CH3
SO3H


298
H
CH3a
CH3
PO3H2


299
H
CH3a
CH3
CHO


300
H
CH3a
CH3
COOH


301
H
CH3a
CH3
CH2OH


302
H
CH3a
CH3
sugar


303
H
CH3a
CH3
C-glycosyl compound


304
H
CH3a
Cl
OH


305
H
CH3a
Cl
D-glucitol


306
H
CH3a
Cl
SO3H


307
H
CH3a
Cl
PO3H2


308
H
CH3a
Cl
CHO


309
H
CH3a
Cl
COOH


310
H
CH3a
Cl
CH2OH


311
H
CH3a
Cl
sugar


312
H
CH3a
Cl
C-glycosyl compound


313
H
CH3a
B(OH)2
OH


314
H
CH3a
B(OH)2
D-glucitol


315
H
CH3a
B(OH)2
SO3H


316
H
CH3a
B(OH)2
PO3H2


317
H
CH3a
B(OH)2
CHO


318
H
CH3a
B(OH)2
COOH


319
H
CH3a
B(OH)2
CH2OH


320
H
CH3a
B(OH)2
sugar


321
H
CH3a
B(OH)2
C-glycosyl compound


322
H
CH3a
SH
OH


323
H
CH3a
SH
D-glucitol


324
H
CH3a
SH
SO3H


325
H
CH3a
SH
PO3H2


326
H
CH3a
SH
CHO


327
H
CH3a
SH
COOH


328
H
CH3a
SH
CH2OH


329
H
CH3a
SH
sugar


330
H
CH3a
SH
C-glycosyl compound


331
H
CH3a
OCH3
OH


332
H
CH3a
OCH3
D-glucitol


333
H
CH3a
OCH3
SO3H


334
H
CH3a
OCH3
PO3H2


335
H
CH3a
OCH3
CHO


336
H
CH3a
OCH3
COOH


337
H
CH3a
OCH3
CH2OH


338
H
CH3a
OCH3
sugar


339
H
CH3a
OCH3
C-glycosyl compound


340
H
OCH3b
H
OH


341
H
OCH3b
H
D-glucitol


342
H
OCH3b
H
SO3H


343
H
OCH3b
H
PO3H2


344
H
OCH3b
H
CHO


345
H
OCH3b
H
COOH


346
H
OCH3b
H
CH2OH


347
H
OCH3b
H
sugar


348
H
OCH3b
H
C-glycosyl compound


349
H
OCH3b
OH
OH


350
H
OCH3b
OH
D-glucitol


351
H
OCH3b
OH
SO3H


352
H
OCH3b
OH
PO3H2


353
H
OCH3b
OH
CHO


354
H
OCH3b
OH
COOH


355
H
OCH3b
OH
CH2OH


356
H
OCH3b
OH
sugar


357
H
OCH3b
OH
C-glycosyl compound


358
H
OCH3b
CH3
OH


359
H
OCH3b
CH3
D-glucitol


360
H
OCH3b
CH3
SO3H


361
H
OCH3b
CH3
PO3H2


362
H
OCH3b
CH3
CHO


363
H
OCH3b
CH3
COOH


364
H
OCH3b
CH3
CH2OH


365
H
OCH3b
CH3
sugar


366
H
OCH3b
CH3
C-glycosyl compound


367
H
OCH3b
Cl
OH


368
H
OCH3b
Cl
D-glucitol


369
H
OCH3b
Cl
SO3H


370
H
OCH3b
Cl
PO3H2


371
H
OCH3b
Cl
CHO


372
H
OCH3b
Cl
COOH


373
H
OCH3b
Cl
CH2OH


374
H
OCH3b
Cl
sugar


375
H
OCH3b
Cl
C-glycosyl compound


376
H
OCH3b
B(OH)2
OH


377
H
OCH3b
B(OH)2
D-glucitol


378
H
OCH3b
B(OH)2
SO3H


379
H
OCH3b
B(OH)2
PO3H2


380
H
OCH3b
B(OH)2
CHO


381
H
OCH3b
B(OH)2
COOH


382
H
OCH3b
B(OH)2
CH2OH


383
H
OCH3b
B(OH)2
sugar


384
H
OCH3b
B(OH)2
C-glycosyl compound


385
H
OCH3b
SH
OH


386
H
OCH3b
SH
D-glucitol


387
H
OCH3b
SH
SO3H


388
H
OCH3b
SH
PO3H2


389
H
OCH3b
SH
CHO


390
H
OCH3b
SH
COOH


391
H
OCH3b
SH
CH2OH


392
H
OCH3b
SH
sugar


393
H
OCH3b
SH
C-glycosyl compound


394
H
OCH3b
OCH3
OH


395
H
OCH3b
OCH3
D-glucitol


396
H
OCH3b
OCH3
SO3H


397
H
OCH3b
OCH3
PO3H2


398
H
OCH3b
OCH3
CHO


399
H
OCH3b
OCH3
COOH


400
H
OCH3b
OCH3
CH2OH


401
H
OCH3b
OCH3
sugar


402
H
OCH3b
OCH3
C-glycosyl compound


403
F
H
H
OH


404
F
H
H
D-glucitol


405
F
H
H
SO3H


406
F
H
H
PO3H2


407
F
H
H
CHO


408
F
H
H
COOH


409
F
H
H
CH2OH


410
F
H
H
sugar


411
F
H
H
C-glycosyl compound


412
F
H
OH
CHO


413
F
H
OH
COOH


414
F
H
OH
CH2OH


415
F
H
OH
sugar


416
F
H
OH
C-glycosyl compound


417
F
H
CH3
OH


418
F
H
CH3
D-glucitol


419
F
H
CH3
SO3H


420
F
H
CH3
PO3H2


421
F
H
CH3
CHO


422
F
H
CH3
COOH


423
F
H
CH3
CH2OH


424
F
H
CH3
sugar


425
F
H
CH3
C-glycosyl compound


426
F
H
Cl
OH


427
F
H
Cl
D-glucitol


428
F
H
Cl
SO3H


429
F
H
Cl
PO3H2


430
F
H
Cl
CHO


431
F
H
Cl
COOH


432
F
H
Cl
CH2OH


433
F
H
Cl
sugar


434
F
H
Cl
C-glycosyl compound


435
F
H
B(OH)2
OH


436
F
H
B(OH)2
D-glucitol


437
F
H
B(OH)2
SO3H


438
F
H
B(OH)2
PO3H2


439
F
H
B(OH)2
CHO


440
F
H
B(OH)2
COOH


441
F
H
B(OH)2
CH2OH


442
F
H
B(OH)2
sugar


443
F
H
B(OH)2
C-glycosyl compound


444
F
H
SH
OH


445
F
H
SH
D-glucitol


446
F
H
SH
SO3H


447
F
H
SH
PO3H2


448
F
H
SH
CHO


449
F
H
SH
COOH


450
F
H
SH
CH2OH


451
F
H
SH
sugar


452
F
H
SH
C-glycosyl compound


453
F
H
OCH3
OH


454
F
H
OCH3
D-glucitol


455
F
H
OCH3
SO3H


456
F
H
OCH3
PO3H2


457
F
H
OCH3
CHO


458
F
H
OCH3
COOH


459
F
H
OCH3
CH2OH


460
F
H
OCH3
sugar


461
F
H
OCH3
C-glycosyl compound


462
F
F
H
OH


463
F
F
H
D-glucitol


464
F
F
H
SO3H


465
F
F
H
PO3H2


466
F
F
H
CHO


467
F
F
H
COOH


468
F
F
H
CH2OH


469
F
F
H
sugar


470
F
F
H
C-glycosyl compound


471
F
F
OH
CHO


472
F
F
OH
COOH


473
F
F
OH
CH2OH


474
F
F
OH
sugar


475
F
F
OH
C-glycosyl compound


476
F
F
CH3
OH


477
F
F
CH3
D-glucitol


478
F
F
CH3
SO3H


479
F
F
CH3
PO3H2


480
F
F
CH3
CHO


481
F
F
CH3
COOH


482
F
F
CH3
CH2OH


483
F
F
CH3
sugar


484
F
F
CH3
C-glycosyl compound


485
F
F
Cl
OH


486
F
F
Cl
D-glucitol


487
F
F
Cl
SO3H


488
F
F
Cl
PO3H2


489
F
F
Cl
CHO


490
F
F
Cl
COOH


491
F
F
Cl
CH2OH


492
F
F
Cl
sugar


493
F
F
Cl
C-glycosyl compound


494
F
F
B(OH)2
OH


495
F
F
B(OH)2
D-glucitol


496
F
F
B(OH)2
SO3H


497
F
F
B(OH)2
PO3H2


498
F
F
B(OH)2
CHO


499
F
F
B(OH)2
COOH


500
F
F
B(OH)2
CH2OH


501
F
F
B(OH)2
sugar


502
F
F
B(OH)2
C-glycosyl compound


503
F
F
SH
OH


504
F
F
SH
D-glucitol


505
F
F
SH
SO3H


506
F
F
SH
PO3H2


507
F
F
SH
CHO


508
F
F
SH
COOH


509
F
F
SH
CH2OH


510
F
F
SH
sugar


511
F
F
SH
C-glycosyl compound


512
F
F
OCH3
OH


513
F
F
OCH3
D-glucitol


514
F
F
OCH3
SO3H


515
F
F
OCH3
PO3H2


516
F
F
OCH3
CHO


517
F
F
OCH3
COOH


518
F
F
OCH3
CH2OH


519
F
F
OCH3
sugar


520
F
F
OCH3
C-glycosyl compound


521
F
Cl
H
OH


522
F
Cl
H
D-glucitol


523
F
Cl
H
SO3H


524
F
Cl
H
PO3H2


525
F
Cl
H
CHO


526
F
Cl
H
COOH


527
F
Cl
H
CH2OH


528
F
Cl
H
sugar


529
F
Cl
H
C-glycosyl compound


530
F
Cl
OH
CHO


531
F
Cl
OH
COOH


532
F
Cl
OH
CH2OH


533
F
Cl
OH
sugar


534
F
Cl
OH
C-glycosyl compound


535
F
Cl
CH3
OH


536
F
Cl
CH3
D-glucitol


537
F
Cl
CH3
SO3H


538
F
Cl
CH3
PO3H2


539
F
Cl
CH3
CHO


540
F
Cl
CH3
COOH


541
F
Cl
CH3
CH2OH


542
F
Cl
CH3
sugar


543
F
Cl
CH3
C-glycosyl compound


544
F
Cl
Cl
OH


545
F
Cl
Cl
D-glucitol


546
F
Cl
Cl
SO3H


547
F
Cl
Cl
PO3H2


548
F
Cl
Cl
CHO


549
F
Cl
Cl
COOH


550
F
Cl
Cl
CH2OH


551
F
Cl
Cl
sugar


552
F
Cl
Cl
C-glycosyl compound


553
F
Cl
B(OH)2
OH


554
F
Cl
B(OH)2
D-glucitol


555
F
Cl
B(OH)2
SO3H


556
F
Cl
B(OH)2
PO3H2


557
F
Cl
B(OH)2
CHO


558
F
Cl
B(OH)2
COOH


559
F
Cl
B(OH)2
CH2OH


560
F
Cl
B(OH)2
sugar


561
F
Cl
B(OH)2
C-glycosyl compound


562
F
Cl
SH
OH


563
F
Cl
SH
D-glucitol


564
F
Cl
SH
SO3H


565
F
Cl
SH
PO3H2


566
F
Cl
SH
CHO


567
F
Cl
SH
COOH


568
F
Cl
SH
CH2OH


569
F
Cl
SH
sugar


570
F
Cl
SH
C-glycosyl compound


571
F
Cl
OCH3
OH


572
F
Cl
OCH3
D-glucitol


573
F
Cl
OCH3
SO3H


574
F
Cl
OCH3
PO3H2


575
F
Cl
OCH3
CHO


576
F
Cl
OCH3
COOH


577
F
Cl
OCH3
CH2OH


578
F
Cl
OCH3
sugar


579
F
Cl
OCH3
C-glycosyl compound


580
F
CN
H
OH


581
F
CN
H
D-glucitol


582
F
CN
H
SO3H


583
F
CN
H
PO3H2


584
F
CN
H
CHO


585
F
CN
H
COOH


586
F
CN
H
CH2OH


587
F
CN
H
sugar


588
F
CN
H
C-glycosyl compound


589
F
CN
OH
OH


590
F
CN
OH
D-glucitol


591
F
CN
OH
SO3H


592
F
CN
OH
PO3H2


593
F
CN
OH
CHO


594
F
CN
OH
COOH


595
F
CN
OH
CH2OH


596
F
CN
OH
sugar


597
F
CN
OH
C-glycosyl compound


598
F
CN
CH3
OH


599
F
CN
CH3
D-glucitol


600
F
CN
CH3
SO3H


601
F
CN
CH3
PO3H2


602
F
CN
CH3
CHO


603
F
CN
CH3
COOH


604
F
CN
CH3
CH2OH


605
F
CN
CH3
sugar


606
F
CN
CH3
C-glycosyl compound


607
F
CN
Cl
OH


608
F
CN
Cl
D-glucitol


609
F
CN
Cl
SO3H


610
F
CN
Cl
PO3H2


611
F
CN
Cl
CHO


612
F
CN
Cl
COOH


613
F
CN
Cl
CH2OH


614
F
CN
Cl
sugar


615
F
CN
Cl
C-glycosyl compound


616
F
CN
B(OH)2
OH


617
F
CN
B(OH)2
D-glucitol


618
F
CN
B(OH)2
SO3H


619
F
CN
B(OH)2
PO3H2


620
F
CN
B(OH)2
CHO


621
F
CN
B(OH)2
COOH


622
F
CN
B(OH)2
CH2OH


623
F
CN
B(OH)2
sugar


624
F
CN
B(OH)2
C-glycosyl compound


625
F
CN
SH
OH


626
F
CN
SH
D-glucitol


627
F
CN
SH
SO3H


628
F
CN
SH
PO3H2


629
F
CN
SH
CHO


630
F
CN
SH
COOH


631
F
CN
SH
CH2OH


632
F
CN
SH
sugar


633
F
CN
SH
C-glycosyl compound


634
F
CN
OCH3
OH


635
F
CN
OCH3
D-glucitol


636
F
CN
OCH3
SO3H


637
F
CN
OCH3
PO3H2


638
F
CN
OCH3
CHO


639
F
CN
OCH3
COOH


640
F
CN
OCH3
CH2OH


641
F
CN
OCH3
sugar


642
F
CN
OCH3
C-glycosyl compound


643
F
CH3a
H
OH


644
F
CH3a
H
D-glucitol


645
F
CH3a
H
SO3H


646
F
CH3a
H
PO3H2


647
F
CH3a
H
CHO


648
F
CH3a
H
COOH


649
F
CH3a
H
CH2OH


650
F
CH3a
H
sugar


651
F
CH3a
H
C-glycosyl compound


652
F
CH3a
OH
OH


653
F
CH3a
OH
D-glucitol


654
F
CH3a
OH
SO3H


655
F
CH3a
OH
PO3H2


656
F
CH3a
OH
CHO


657
F
CH3a
OH
COOH


658
F
CH3a
OH
CH2OH


659
F
CH3a
OH
sugar


660
F
CH3a
OH
C-glycosyl compound


661
F
CH3a
CH3
OH


662
F
CH3a
CH3
D-glucitol


663
F
CH3a
CH3
SO3H


664
F
CH3a
CH3
PO3H2


665
F
CH3a
CH3
CHO


666
F
CH3a
CH3
COOH


667
F
CH3a
CH3
CH2OH


668
F
CH3a
CH3
sugar


669
F
CH3a
CH3
C-glycosyl compound


670
F
CH3a
Cl
OH


671
F
CH3a
Cl
D-glucitol


672
F
CH3a
Cl
SO3H


673
F
CH3a
Cl
PO3H2


674
F
CH3a
Cl
CHO


675
F
CH3a
Cl
COOH


676
F
CH3a
Cl
CH2OH


677
F
CH3a
Cl
sugar


678
F
CH3a
Cl
C-glycosyl compound


679
F
CH3a
B(OH)2
OH


680
F
CH3a
B(OH)2
D-glucitol


681
F
CH3a
B(OH)2
SO3H


682
F
CH3a
B(OH)2
PO3H2


683
F
CH3a
B(OH)2
CHO


684
F
CH3a
B(OH)2
COOH


685
F
CH3a
B(OH)2
CH2OH


686
F
CH3a
B(OH)2
sugar


687
F
CH3a
B(OH)2
C-glycosyl compound


688
F
CH3a
SH
OH


689
F
CH3a
SH
D-glucitol


690
F
CH3a
SH
SO3H


691
F
CH3a
SH
PO3H2


692
F
CH3a
SH
CHO


693
F
CH3a
SH
COOH


694
F
CH3a
SH
CH2OH


695
F
CH3a
SH
sugar


696
F
CH3a
SH
C-glycosyl compound


697
F
CH3a
OCH3
OH


698
F
CH3a
OCH3
D-glucitol


699
F
CH3a
OCH3
SO3H


700
F
CH3a
OCH3
PO3H2


701
F
CH3a
OCH3
CHO


702
F
CH3a
OCH3
COOH


703
F
CH3a
OCH3
CH2OH


704
F
CH3a
OCH3
sugar


705
F
CH3a
OCH3
C-glycosyl compound


706
F
OCH3b
H
OH


707
F
OCH3b
H
D-glucitol


708
F
OCH3b
H
SO3H


709
F
OCH3b
H
PO3H2


710
F
OCH3b
H
CHO


711
F
OCH3b
H
COOH


712
F
OCH3b
H
CH2OH


713
F
OCH3b
H
sugar


714
F
OCH3b
H
C-glycosyl compound


715
F
OCH3b
OH
OH


716
F
OCH3b
OH
D-glucitol


717
F
OCH3b
OH
SO3H


718
F
OCH3b
OH
PO3H2


719
F
OCH3b
OH
CHO


720
F
OCH3b
OH
COOH


721
F
OCH3b
OH
CH2OH


722
F
OCH3b
OH
sugar


723
F
OCH3b
OH
C-glycosyl compound


724
F
OCH3b
CH3
OH


725
F
OCH3b
CH3
D-glucitol


726
F
OCH3b
CH3
SO3H


727
F
OCH3b
CH3
PO3H2


728
F
OCH3b
CH3
CHO


729
F
OCH3b
CH3
COOH


730
F
OCH3b
CH3
CH2OH


731
F
OCH3b
CH3
sugar


732
F
OCH3b
CH3
C-glycosyl compound


733
F
OCH3b
Cl
OH


734
F
OCH3b
Cl
D-glucitol


735
F
OCH3b
Cl
SO3H


736
F
OCH3b
Cl
PO3H2


737
F
OCH3b
Cl
CHO


738
F
OCH3b
Cl
COOH


739
F
OCH3b
Cl
CH2OH


740
F
OCH3b
Cl
sugar


741
F
OCH3b
Cl
C-glycosyl compound


742
F
OCH3b
B(OH)2
OH


743
F
OCH3b
B(OH)2
D-glucitol


744
F
OCH3b
B(OH)2
SO3H


745
F
OCH3b
B(OH)2
PO3H2


746
F
OCH3b
B(OH)2
CHO


747
F
OCH3b
B(OH)2
COOH


748
F
OCH3b
B(OH)2
CH2OH


749
F
OCH3b
B(OH)2
sugar


750
F
OCH3b
B(OH)2
C-glycosyl compound


751
F
OCH3b
SH
OH


752
F
OCH3b
SH
D-glucitol


753
F
OCH3b
SH
SO3H


754
F
OCH3b
SH
PO3H2


755
F
OCH3b
SH
CHO


756
F
OCH3b
SH
COOH


757
F
OCH3b
SH
CH2OH


758
F
OCH3b
SH
sugar


759
F
OCH3b
SH
C-glycosyl compound


760
F
OCH3b
OCH3
OH


761
F
OCH3b
OCH3
D-glucitol


762
F
OCH3b
OCH3
SO3H


763
F
OCH3b
OCH3
PO3H2


764
F
OCH3b
OCH3
CHO


765
F
OCH3b
OCH3
COOH


766
F
OCH3b
OCH3
CH2OH


767
F
OCH3b
OCH3
sugar


768
F
OCH3b
OCH3
C-glycosyl compound


769
Cl
H
H
OH


770
Cl
H
H
D-glucitol


771
Cl
H
H
SO3H


772
Cl
H
H
PO3H2


773
Cl
H
H
CHO


774
Cl
H
H
COOH


775
Cl
H
H
CH2OH


776
Cl
H
H
sugar


777
Cl
H
H
C-glycosyl compound


778
Cl
H
OH
CHO


779
Cl
H
OH
COOH


780
Cl
H
OH
CH2OH


781
Cl
H
OH
sugar


782
Cl
H
OH
C-glycosyl compound


783
Cl
H
CH3
OH


784
Cl
H
CH3
D-glucitol


785
Cl
H
CH3
SO3H


786
Cl
H
CH3
PO3H2


787
Cl
H
CH3
CHO


788
Cl
H
CH3
COOH


789
Cl
H
CH3
CH2OH


790
Cl
H
CH3
sugar


791
Cl
H
CH3
C-glycosyl compound


792
Cl
H
Cl
OH


793
Cl
H
Cl
D-glucitol


794
Cl
H
Cl
SO3H


795
Cl
H
Cl
PO3H2


796
Cl
H
Cl
CHO


797
Cl
H
Cl
COOH


798
Cl
H
Cl
CH2OH


799
Cl
H
Cl
sugar


800
Cl
H
Cl
C-glycosyl compound


801
Cl
H
B(OH)2
OH


802
Cl
H
B(OH)2
D-glucitol


803
Cl
H
B(OH)2
SO3H


804
Cl
H
B(OH)2
PO3H2


805
Cl
H
B(OH)2
CHO


806
Cl
H
B(OH)2
COOH


807
Cl
H
B(OH)2
CH2OH


808
Cl
H
B(OH)2
sugar


809
Cl
H
B(OH)2
C-glycosyl compound


810
Cl
H
SH
OH


811
Cl
H
SH
D-glucitol


812
Cl
H
SH
SO3H


813
Cl
H
SH
PO3H2


814
Cl
H
SH
CHO


815
Cl
H
SH
COOH


816
Cl
H
SH
CH2OH


817
Cl
H
SH
sugar


818
Cl
H
SH
C-glycosyl compound


819
Cl
H
OCH3
OH


820
Cl
H
OCH3
D-glucitol


821
Cl
H
OCH3
SO3H


822
Cl
H
OCH3
PO3H2


823
Cl
H
OCH3
CHO


824
Cl
H
OCH3
COOH


825
Cl
H
OCH3
CH2OH


826
Cl
H
OCH3
sugar


827
Cl
H
OCH3
C-glycosyl compound


828
Cl
F
H
OH


829
Cl
F
H
D-glucitol


830
Cl
F
H
SO3H


831
Cl
F
H
PO3H2


832
Cl
F
H
CHO


833
Cl
F
H
COOH


834
Cl
F
H
CH2OH


835
Cl
F
H
sugar


836
Cl
F
H
C-glycosyl compound


837
Cl
F
OH
CHO


838
Cl
F
OH
COOH


839
Cl
F
OH
CH2OH


840
Cl
F
OH
sugar


841
Cl
F
OH
C-glycosyl compound


842
Cl
F
CH3
OH


843
Cl
F
CH3
D-glucitol


844
Cl
F
CH3
SO3H


845
Cl
F
CH3
PO3H2


846
Cl
F
CH3
CHO


847
Cl
F
CH3
COOH


848
Cl
F
CH3
CH2OH


849
Cl
F
CH3
sugar


850
Cl
F
CH3
C-glycosyl compound


851
Cl
F
Cl
OH


852
Cl
F
Cl
D-glucitol


853
Cl
F
Cl
SO3H


854
Cl
F
Cl
PO3H2


855
Cl
F
Cl
CHO


856
Cl
F
Cl
COOH


857
Cl
F
Cl
CH2OH


858
Cl
F
Cl
sugar


859
Cl
F
Cl
C-glycosyl compound


860
Cl
F
B(OH)2
OH


861
Cl
F
B(OH)2
D-glucitol


862
Cl
F
B(OH)2
SO3H


863
Cl
F
B(OH)2
PO3H2


864
Cl
F
B(OH)2
CHO


865
Cl
F
B(OH)2
COOH


866
Cl
F
B(OH)2
CH2OH


867
Cl
F
B(OH)2
sugar


868
Cl
F
B(OH)2
C-glycosyl compound


869
Cl
F
SH
OH


870
Cl
F
SH
D-glucitol


871
Cl
F
SH
SO3H


872
Cl
F
SH
PO3H2


873
Cl
F
SH
CHO


874
Cl
F
SH
COOH


875
Cl
F
SH
CH2OH


876
Cl
F
SH
sugar


877
Cl
F
SH
C-glycosyl compound


878
Cl
F
OCH3
OH


879
Cl
F
OCH3
D-glucitol


880
Cl
F
OCH3
SO3H


881
Cl
F
OCH3
PO3H2


882
Cl
F
OCH3
CHO


883
Cl
F
OCH3
COOH


884
Cl
F
OCH3
CH2OH


885
Cl
F
OCH3
sugar


886
Cl
F
OCH3
C-glycosyl compound


887
Cl
Cl
H
OH


888
Cl
Cl
H
D-glucitol


889
Cl
Cl
H
SO3H


890
Cl
Cl
H
PO3H2


891
Cl
Cl
H
CHO


892
Cl
Cl
H
COOH


893
Cl
Cl
H
CH2OH


894
Cl
Cl
H
sugar


895
Cl
Cl
H
C-glycosyl compound


896
Cl
Cl
OH
CHO


897
Cl
Cl
OH
COOH


898
Cl
Cl
OH
CH2OH


899
Cl
Cl
OH
sugar


900
Cl
Cl
OH
C-glycosyl compound


901
Cl
Cl
CH3
OH


902
Cl
Cl
CH3
D-glucitol


903
Cl
Cl
CH3
SO3H


904
Cl
Cl
CH3
PO3H2


905
Cl
Cl
CH3
CHO


906
Cl
Cl
CH3
COOH


907
Cl
Cl
CH3
CH2OH


908
Cl
Cl
CH3
sugar


909
Cl
Cl
CH3
C-glycosyl compound


910
Cl
Cl
Cl
OH


911
Cl
Cl
Cl
D-glucitol


912
Cl
Cl
Cl
SO3H


913
Cl
Cl
Cl
PO3H2


914
Cl
Cl
Cl
CHO


915
Cl
Cl
Cl
COOH


916
Cl
Cl
Cl
CH2OH


917
Cl
Cl
Cl
sugar


918
Cl
Cl
Cl
C-glycosyl compound


919
Cl
Cl
B(OH)2
OH


920
Cl
Cl
B(OH)2
D-glucitol


921
Cl
Cl
B(OH)2
SO3H


922
Cl
Cl
B(OH)2
PO3H2


923
Cl
Cl
B(OH)2
CHO


924
Cl
Cl
B(OH)2
COOH


925
Cl
Cl
B(OH)2
CH2OH


926
Cl
Cl
B(OH)2
sugar


927
Cl
Cl
B(OH)2
C-glycosyl compound


928
Cl
Cl
SH
OH


929
Cl
Cl
SH
D-glucitol


930
Cl
Cl
SH
SO3H


931
Cl
Cl
SH
PO3H2


932
Cl
Cl
SH
CHO


933
Cl
Cl
SH
COOH


934
Cl
Cl
SH
CH2OH


935
Cl
Cl
SH
sugar


936
Cl
Cl
SH
C-glycosyl compound


937
Cl
Cl
OCH3
OH


938
Cl
Cl
OCH3
D-glucitol


939
Cl
Cl
OCH3
SO3H


940
Cl
Cl
OCH3
PO3H2


941
Cl
Cl
OCH3
CHO


942
Cl
Cl
OCH3
COOH


943
Cl
Cl
OCH3
CH2OH


944
Cl
Cl
OCH3
sugar


945
Cl
Cl
OCH3
C-glycosyl compound


946
Cl
CN
H
OH


947
Cl
CN
H
D-glucitol


948
Cl
CN
H
SO3H


949
Cl
CN
H
PO3H2


950
Cl
CN
H
CHO


951
Cl
CN
H
COOH


952
Cl
CN
H
CH2OH


953
Cl
CN
H
sugar


954
Cl
CN
H
C-glycosyl compound


955
Cl
CN
OH
OH


956
Cl
CN
OH
D-glucitol


957
Cl
CN
OH
SO3H


958
Cl
CN
OH
PO3H2


959
Cl
CN
OH
CHO


960
Cl
CN
OH
COOH


961
Cl
CN
OH
CH2OH


962
Cl
CN
OH
sugar


963
Cl
CN
OH
C-glycosyl compound


964
Cl
CN
CH3
OH


965
Cl
CN
CH3
D-glucitol


966
Cl
CN
CH3
SO3H


967
Cl
CN
CH3
PO3H2


968
Cl
CN
CH3
CHO


969
Cl
CN
CH3
COOH


970
Cl
CN
CH3
CH2OH


971
Cl
CN
CH3
sugar


972
Cl
CN
CH3
C-glycosyl compound


973
Cl
CN
Cl
OH


974
Cl
CN
Cl
D-glucitol


975
Cl
CN
Cl
SO3H


976
Cl
CN
Cl
PO3H2


977
Cl
CN
Cl
CHO


978
Cl
CN
Cl
COOH


979
Cl
CN
Cl
CH2OH


980
Cl
CN
Cl
sugar


981
Cl
CN
Cl
C-glycosyl compound


982
Cl
CN
B(OH)2
OH


983
Cl
CN
B(OH)2
D-glucitol


984
Cl
CN
B(OH)2
SO3H


985
Cl
CN
B(OH)2
PO3H2


986
Cl
CN
B(OH)2
CHO


987
Cl
CN
B(OH)2
COOH


988
Cl
CN
B(OH)2
CH2OH


989
Cl
CN
B(OH)2
sugar


990
Cl
CN
B(OH)2
C-glycosyl compound


991
Cl
CN
SH
OH


992
Cl
CN
SH
D-glucitol


993
Cl
CN
SH
SO3H


994
Cl
CN
SH
PO3H2


995
Cl
CN
SH
CHO


996
Cl
CN
SH
COOH


997
Cl
CN
SH
CH2OH


998
Cl
CN
SH
sugar


999
Cl
CN
SH
C-glycosyl compound


1000
Cl
CN
OCH3
OH


1001
Cl
CN
OCH3
D-glucitol


1002
Cl
CN
OCH3
SO3H


1003
Cl
CN
OCH3
PO3H2


1004
Cl
CN
OCH3
CHO


1005
Cl
CN
OCH3
COOH


1006
Cl
CN
OCH3
CH2OH


1007
Cl
CN
OCH3
sugar


1008
Cl
CN
OCH3
C-glycosyl compound


1009
Cl
CH3a
H
OH


1010
Cl
CH3a
H
D-glucitol


1011
Cl
CH3a
H
SO3H


1012
Cl
CH3a
H
PO3H2


1013
Cl
CH3a
H
CHO


1014
Cl
CH3a
H
COOH


1015
Cl
CH3a
H
CH2OH


1016
Cl
CH3a
H
sugar


1017
Cl
CH3a
H
C-glycosyl compound


1018
Cl
CH3a
OH
OH


1019
Cl
CH3a
OH
D-glucitol


1020
Cl
CH3a
OH
SO3H


1021
Cl
CH3a
OH
PO3H2


1022
Cl
CH3a
OH
CHO


1023
Cl
CH3a
OH
COOH


1024
Cl
CH3a
OH
CH2OH


1025
Cl
CH3a
OH
sugar


1026
Cl
CH3a
OH
C-glycosyl compound


1027
Cl
CH3a
CH3
OH


1028
Cl
CH3a
CH3
D-glucitol


1029
Cl
CH3a
CH3
SO3H


1030
Cl
CH3a
CH3
PO3H2


1031
Cl
CH3a
CH3
CHO


1032
Cl
CH3a
CH3
COOH


1033
Cl
CH3a
CH3
CH2OH


1034
Cl
CH3a
CH3
sugar


1035
Cl
CH3a
CH3
C-glycosyl compound


1036
Cl
CH3a
Cl
OH


1037
Cl
CH3a
Cl
D-glucitol


1038
Cl
CH3a
Cl
SO3H


1039
Cl
CH3a
Cl
PO3H2


1040
Cl
CH3a
Cl
CHO


1041
Cl
CH3a
Cl
COOH


1042
Cl
CH3a
Cl
CH2OH


1043
Cl
CH3a
Cl
sugar


1044
Cl
CH3a
Cl
C-glycosyl compound


1045
Cl
CH3a
B(OH)2
OH


1046
Cl
CH3a
B(OH)2
D-glucitol


1047
Cl
CH3a
B(OH)2
SO3H


1048
Cl
CH3a
B(OH)2
PO3H2


1049
Cl
CH3a
B(OH)2
CHO


1050
Cl
CH3a
B(OH)2
COOH


1051
Cl
CH3a
B(OH)2
CH2OH


1052
Cl
CH3a
B(OH)2
sugar


1053
Cl
CH3a
B(OH)2
C-glycosyl compound


1054
Cl
CH3a
SH
OH


1055
Cl
CH3a
SH
D-glucitol


1056
Cl
CH3a
SH
SO3H


1057
Cl
CH3a
SH
PO3H2


1058
Cl
CH3a
SH
CHO


1059
Cl
CH3a
SH
COOH


1060
Cl
CH3a
SH
CH2OH


1061
Cl
CH3a
SH
sugar


1062
Cl
CH3a
SH
C-glycosyl compound


1063
Cl
CH3a
OCH3
OH


1064
Cl
CH3a
OCH3
D-glucitol


1065
Cl
CH3a
OCH3
SO3H


1066
Cl
CH3a
OCH3
PO3H2


1067
Cl
CH3a
OCH3
CHO


1068
Cl
CH3a
OCH3
COOH


1069
Cl
CH3a
OCH3
CH2OH


1070
Cl
CH3a
OCH3
sugar


1071
Cl
CH3a
OCH3
C-glycosyl compound


1072
Cl
OCH3b
H
OH


1073
Cl
OCH3b
H
D-glucitol


1074
Cl
OCH3b
H
SO3H


1075
Cl
OCH3b
H
PO3H2


1076
Cl
OCH3b
H
CHO


1077
Cl
OCH3b
H
COOH


1078
Cl
OCH3b
H
CH2OH


1079
Cl
OCH3b
H
sugar


1080
Cl
OCH3b
H
C-glycosyl compound


1081
Cl
OCH3b
OH
OH


1082
Cl
OCH3b
OH
D-glucitol


1083
Cl
OCH3b
OH
SO3H


1084
Cl
OCH3b
OH
PO3H2


1085
Cl
OCH3b
OH
CHO


1086
Cl
OCH3b
OH
COOH


1087
Cl
OCH3b
OH
CH2OH


1088
Cl
OCH3b
OH
sugar


1089
Cl
OCH3b
OH
C-glycosyl compound


1090
Cl
OCH3b
CH3
OH


1091
Cl
OCH3b
CH3
D-glucitol


1092
Cl
OCH3b
CH3
SO3H


1093
Cl
OCH3b
CH3
PO3H2


1094
Cl
OCH3b
CH3
CHO


1095
Cl
OCH3b
CH3
COOH


1096
Cl
OCH3b
CH3
CH2OH


1097
Cl
OCH3b
CH3
sugar


1098
Cl
OCH3b
CH3
C-glycosyl compound


1099
Cl
OCH3b
Cl
OH


1100
Cl
OCH3b
Cl
D-glucitol


1101
Cl
OCH3b
Cl
SO3H


1102
Cl
OCH3b
Cl
PO3H2


1103
Cl
OCH3b
Cl
CHO


1104
Cl
OCH3b
Cl
COOH


1105
Cl
OCH3b
Cl
CH2OH


1106
Cl
OCH3b
Cl
sugar


1107
Cl
OCH3b
Cl
C-glycosyl compound


1108
Cl
OCH3b
B(OH)2
OH


1109
Cl
OCH3b
B(OH)2
D-glucitol


1110
Cl
OCH3b
B(OH)2
SO3H


1111
Cl
OCH3b
B(OH)2
PO3H2


1112
Cl
OCH3b
B(OH)2
CHO


1113
Cl
OCH3b
B(OH)2
COOH


1114
Cl
OCH3b
B(OH)2
CH2OH


1115
Cl
OCH3b
B(OH)2
sugar


1116
Cl
OCH3b
B(OH)2
C-glycosyl compound


1117
Cl
OCH3b
SH
OH


1118
Cl
OCH3b
SH
D-glucitol


1119
Cl
OCH3b
SH
SO3H


1120
Cl
OCH3b
SH
PO3H2


1121
Cl
OCH3b
SH
CHO


1122
Cl
OCH3b
SH
COOH


1123
Cl
OCH3b
SH
CH2OH


1124
Cl
OCH3b
SH
sugar


1125
Cl
OCH3b
SH
C-glycosyl compound


1126
Cl
OCH3b
OCH3
OH


1127
Cl
OCH3b
OCH3
D-glucitol


1128
Cl
OCH3b
OCH3
SO3H


1129
Cl
OCH3b
OCH3
PO3H2


1130
Cl
OCH3b
OCH3
CHO


1131
Cl
OCH3b
OCH3
COOH


1132
Cl
OCH3b
OCH3
CH2OH


1133
Cl
OCH3b
OCH3
sugar


1134
Cl
OCH3b
OCH3
C-glycosyl compound


1135
CN
H
H
OH


1136
CN
H
H
D-glucitol


1137
CN
H
H
SO3H


1138
CN
H
H
PO3H2


1139
CN
H
H
CHO


1140
CN
H
H
COOH


1141
CN
H
H
CH2OH


1142
CN
H
H
sugar


1143
CN
H
H
C-glycosyl compound


1144
CN
H
OH
OH


1145
CN
H
OH
D-glucitol


1146
CN
H
OH
SO3H


1147
CN
H
OH
PO3H2


1148
CN
H
OH
CHO


1149
CN
H
OH
COOH


1150
CN
H
OH
CH2OH


1151
CN
H
OH
sugar


1152
CN
H
OH
C-glycosyl compound


1153
CN
H
CH3
OH


1154
CN
H
CH3
D-glucitol


1155
CN
H
CH3
SO3H


1156
CN
H
CH3
PO3H2


1157
CN
H
CH3
CHO


1158
CN
H
CH3
COOH


1159
CN
H
CH3
CH2OH


1160
CN
H
CH3
sugar


1161
CN
H
CH3
C-glycosyl compound


1162
CN
H
Cl
OH


1163
CN
H
Cl
D-glucitol


1164
CN
H
Cl
SO3H


1165
CN
H
Cl
PO3H2


1166
CN
H
Cl
CHO


1167
CN
H
Cl
COOH


1168
CN
H
Cl
CH2OH


1169
CN
H
Cl
sugar


1170
CN
H
Cl
C-glycosyl compound


1171
CN
H
B(OH)2
OH


1172
CN
H
B(OH)2
D-glucitol


1173
CN
H
B(OH)2
SO3H


1174
CN
H
B(OH)2
PO3H2


1175
CN
H
B(OH)2
CHO


1176
CN
H
B(OH)2
COOH


1177
CN
H
B(OH)2
CH2OH


1178
CN
H
B(OH)2
sugar


1179
CN
H
B(OH)2
C-glycosyl compound


1180
CN
H
SH
OH


1181
CN
H
SH
D-glucitol


1182
CN
H
SH
SO3H


1183
CN
H
SH
PO3H2


1184
CN
H
SH
CHO


1185
CN
H
SH
COOH


1186
CN
H
SH
CH2OH


1187
CN
H
SH
sugar


1188
CN
H
SH
C-glycosyl compound


1189
CN
H
OCH3
OH


1190
CN
H
OCH3
D-glucitol


1191
CN
H
OCH3
SO3H


1192
CN
H
OCH3
PO3H2


1193
CN
H
OCH3
CHO


1194
CN
H
OCH3
COOH


1195
CN
H
OCH3
CH2OH


1196
CN
H
OCH3
sugar


1197
CN
H
OCH3
C-glycosyl compound


1198
CN
F
H
OH


1199
CN
F
H
D-glucitol


1200
CN
F
H
SO3H


1201
CN
F
H
PO3H2


1202
CN
F
H
CHO


1203
CN
F
H
COOH


1204
CN
F
H
CH2OH


1205
CN
F
H
sugar


1206
CN
F
H
C-glycosyl compound


1207
CN
F
OH
OH


1208
CN
F
OH
D-glucitol


1209
CN
F
OH
SO3H


1210
CN
F
OH
PO3H2


1211
CN
F
OH
CHO


1212
CN
F
OH
COOH


1213
CN
F
OH
CH2OH


1214
CN
F
OH
sugar


1215
CN
F
OH
C-glycosyl compound


1216
CN
F
CH3
OH


1217
CN
F
CH3
D-glucitol


1218
CN
F
CH3
SO3H


1219
CN
F
CH3
PO3H2


1220
CN
F
CH3
CHO


1221
CN
F
CH3
COOH


1222
CN
F
CH3
CH2OH


1223
CN
F
CH3
sugar


1224
CN
F
CH3
C-glycosyl compound


1225
CN
F
Cl
OH


1226
CN
F
Cl
D-glucitol


1227
CN
F
Cl
SO3H


1228
CN
F
Cl
PO3H2


1229
CN
F
Cl
CHO


1230
CN
F
Cl
COOH


1231
CN
F
Cl
CH2OH


1232
CN
F
Cl
sugar


1233
CN
F
Cl
C-glycosyl compound


1234
CN
F
B(OH)2
OH


1235
CN
F
B(OH)2
D-glucitol


1236
CN
F
B(OH)2
SO3H


1237
CN
F
B(OH)2
PO3H2


1238
CN
F
B(OH)2
CHO


1239
CN
F
B(OH)2
COOH


1240
CN
F
B(OH)2
CH2OH


1241
CN
F
B(OH)2
sugar


1242
CN
F
B(OH)2
C-glycosyl compound


1243
CN
F
SH
OH


1244
CN
F
SH
D-glucitol


1245
CN
F
SH
SO3H


1246
CN
F
SH
PO3H2


1247
CN
F
SH
CHO


1248
CN
F
SH
COOH


1249
CN
F
SH
CH2OH


1250
CN
F
SH
sugar


1251
CN
F
SH
C-glycosyl compound


1252
CN
F
OCH3
OH


1253
CN
F
OCH3
D-glucitol


1254
CN
F
OCH3
SO3H


1255
CN
F
OCH3
PO3H2


1256
CN
F
OCH3
CHO


1257
CN
F
OCH3
COOH


1258
CN
F
OCH3
CH2OH


1259
CN
F
OCH3
sugar


1260
CN
F
OCH3
C-glycosyl compound


1261
CN
Cl
H
OH


1262
CN
Cl
H
D-glucitol


1263
CN
Cl
H
SO3H


1264
CN
Cl
H
PO3H2


1265
CN
Cl
H
CHO


1266
CN
Cl
H
COOH


1267
CN
Cl
H
CH2OH


1268
CN
Cl
H
sugar


1269
CN
Cl
H
C-glycosyl compound


1270
CN
Cl
OH
OH


1271
CN
Cl
OH
D-glucitol


1272
CN
Cl
OH
SO3H


1273
CN
Cl
OH
PO3H2


1274
CN
Cl
OH
CHO


1275
CN
Cl
OH
COOH


1276
CN
Cl
OH
CH2OH


1277
CN
Cl
OH
sugar


1278
CN
Cl
OH
C-glycosyl compound


1279
CN
Cl
CH3
OH


1280
CN
Cl
CH3
D-glucitol


1281
CN
Cl
CH3
SO3H


1282
CN
Cl
CH3
PO3H2


1283
CN
Cl
CH3
CHO


1284
CN
Cl
CH3
COOH


1285
CN
Cl
CH3
CH2OH


1286
CN
Cl
CH3
sugar


1287
CN
Cl
CH3
C-glycosyl compound


1288
CN
Cl
Cl
OH


1289
CN
Cl
Cl
D-glucitol


1290
CN
Cl
Cl
SO3H


1291
CN
Cl
Cl
PO3H2


1292
CN
Cl
Cl
CHO


1293
CN
Cl
Cl
COOH


1294
CN
Cl
Cl
CH2OH


1295
CN
Cl
Cl
sugar


1296
CN
Cl
Cl
C-glycosyl compound


1297
CN
Cl
B(OH)2
OH


1298
CN
Cl
B(OH)2
D-glucitol


1299
CN
Cl
B(OH)2
SO3H


1300
CN
Cl
B(OH)2
PO3H2


1301
CN
Cl
B(OH)2
CHO


1302
CN
Cl
B(OH)2
COOH


1303
CN
Cl
B(OH)2
CH2OH


1304
CN
Cl
B(OH)2
sugar


1305
CN
Cl
B(OH)2
C-glycosyl compound


1306
CN
Cl
SH
OH


1307
CN
Cl
SH
D-glucitol


1308
CN
Cl
SH
SO3H


1309
CN
Cl
SH
PO3H2


1310
CN
Cl
SH
CHO


1311
CN
Cl
SH
COOH


1312
CN
Cl
SH
CH2OH


1313
CN
Cl
SH
sugar


1314
CN
Cl
SH
C-glycosyl compound


1315
CN
Cl
OCH3
OH


1316
CN
Cl
OCH3
D-glucitol


1317
CN
Cl
OCH3
SO3H


1318
CN
Cl
OCH3
PO3H2


1319
CN
Cl
OCH3
CHO


1320
CN
Cl
OCH3
COOH


1321
CN
Cl
OCH3
CH2OH


1322
CN
Cl
OCH3
sugar


1323
CN
Cl
OCH3
C-glycosyl compound


1324
CN
CN
H
OH


1325
CN
CN
H
D-glucitol


1326
CN
CN
H
SO3H


1327
CN
CN
H
PO3H2


1328
CN
CN
H
CHO


1329
CN
CN
H
COOH


1330
CN
CN
H
CH2OH


1331
CN
CN
H
sugar


1332
CN
CN
H
C-glycosyl compound


1333
CN
CN
OH
OH


1334
CN
CN
OH
D-glucitol


1335
CN
CN
OH
SO3H


1336
CN
CN
OH
PO3H2


1337
CN
CN
OH
CHO


1338
CN
CN
OH
COOH


1339
CN
CN
OH
CH2OH


1340
CN
CN
OH
sugar


1341
CN
CN
OH
C-glycosyl compound


1342
CN
CN
CH3
OH


1343
CN
CN
CH3
D-glucitol


1344
CN
CN
CH3
SO3H


1345
CN
CN
CH3
PO3H2


1346
CN
CN
CH3
CHO


1347
CN
CN
CH3
COOH


1348
CN
CN
CH3
CH2OH


1349
CN
CN
CH3
sugar


1350
CN
CN
CH3
C-glycosyl compound


1351
CN
CN
Cl
OH


1352
CN
CN
Cl
D-glucitol


1353
CN
CN
Cl
SO3H


1354
CN
CN
Cl
PO3H2


1355
CN
CN
Cl
CHO


1356
CN
CN
Cl
COOH


1357
CN
CN
Cl
CH2OH


1358
CN
CN
Cl
sugar


1359
CN
CN
Cl
C-glycosyl compound


1360
CN
CN
B(OH)2
OH


1361
CN
CN
B(OH)2
D-glucitol


1362
CN
CN
B(OH)2
SO3H


1363
CN
CN
B(OH)2
PO3H2


1364
CN
CN
B(OH)2
CHO


1365
CN
CN
B(OH)2
COOH


1366
CN
CN
B(OH)2
CH2OH


1367
CN
CN
B(OH)2
sugar


1368
CN
CN
B(OH)2
C-glycosyl compound


1369
CN
CN
SH
OH


1370
CN
CN
SH
D-glucitol


1371
CN
CN
SH
SO3H


1372
CN
CN
SH
PO3H2


1373
CN
CN
SH
CHO


1374
CN
CN
SH
COOH


1375
CN
CN
SH
CH2OH


1376
CN
CN
SH
sugar


1377
CN
CN
SH
C-glycosyl compound


1378
CN
CN
OCH3
OH


1379
CN
CN
OCH3
D-glucitol


1380
CN
CN
OCH3
SO3H


1381
CN
CN
OCH3
PO3H2


1382
CN
CN
OCH3
CHO


1383
CN
CN
OCH3
COOH


1384
CN
CN
OCH3
CH2OH


1385
CN
CN
OCH3
sugar


1386
CN
CN
OCH3
C-glycosyl compound


1387
CN
CH3a
H
OH


1388
CN
CH3a
H
D-glucitol


1389
CN
CH3a
H
SO3H


1390
CN
CH3a
H
PO3H2


1391
CN
CH3a
H
CHO


1392
CN
CH3a
H
COOH


1393
CN
CH3a
H
CH2OH


1394
CN
CH3a
H
sugar


1395
CN
CH3a
H
C-glycosyl compound


1396
CN
CH3a
OH
OH


1397
CN
CH3a
OH
D-glucitol


1398
CN
CH3a
OH
SO3H


1399
CN
CH3a
OH
PO3H2


1400
CN
CH3a
OH
CHO


1401
CN
CH3a
OH
COOH


1402
CN
CH3a
OH
CH2OH


1403
CN
CH3a
OH
sugar


1404
CN
CH3a
OH
C-glycosyl compound


1405
CN
CH3a
CH3
OH


1406
CN
CH3a
CH3
D-glucitol


1407
CN
CH3a
CH3
SO3H


1408
CN
CH3a
CH3
PO3H2


1409
CN
CH3a
CH3
CHO


1410
CN
CH3a
CH3
COOH


1411
CN
CH3a
CH3
CH2OH


1412
CN
CH3a
CH3
sugar


1413
CN
CH3a
CH3
C-glycosyl compound


1414
CN
CH3a
Cl
OH


1415
CN
CH3a
Cl
D-glucitol


1416
CN
CH3a
Cl
SO3H


1417
CN
CH3a
Cl
PO3H2


1418
CN
CH3a
Cl
CHO


1419
CN
CH3a
Cl
COOH


1420
CN
CH3a
Cl
CH2OH


1421
CN
CH3a
Cl
sugar


1422
CN
CH3a
Cl
C-glycosyl compound


1423
CN
CH3a
B(OH)2
OH


1424
CN
CH3a
B(OH)2
D-glucitol


1425
CN
CH3a
B(OH)2
SO3H


1426
CN
CH3a
B(OH)2
PO3H2


1427
CN
CH3a
B(OH)2
CHO


1428
CN
CH3a
B(OH)2
COOH


1429
CN
CH3a
B(OH)2
CH2OH


1430
CN
CH3a
B(OH)2
sugar


1431
CN
CH3a
B(OH)2
C-glycosyl compound


1432
CN
CH3a
SH
OH


1433
CN
CH3a
SH
D-glucitol


1434
CN
CH3a
SH
SO3H


1435
CN
CH3a
SH
PO3H2


1436
CN
CH3a
SH
CHO


1437
CN
CH3a
SH
COOH


1438
CN
CH3a
SH
CH2OH


1439
CN
CH3a
SH
sugar


1440
CN
CH3a
SH
C-glycosyl compound


1441
CN
CH3a
OCH3
OH


1442
CN
CH3a
OCH3
D-glucitol


1443
CN
CH3a
OCH3
SO3H


1444
CN
CH3a
OCH3
PO3H2


1445
CN
CH3a
OCH3
CHO


1446
CN
CH3a
OCH3
COOH


1447
CN
CH3a
OCH3
CH2OH


1448
CN
CH3a
OCH3
sugar


1449
CN
CH3a
OCH3
C-glycosyl compound


1450
CN
OCH3b
H
OH


1451
CN
OCH3b
H
D-glucitol


1452
CN
OCH3b
H
SO3H


1453
CN
OCH3b
H
PO3H2


1454
CN
OCH3b
H
CHO


1455
CN
OCH3b
H
COOH


1456
CN
OCH3b
H
CH2OH


1457
CN
OCH3b
H
sugar


1458
CN
OCH3b
H
C-glycosyl compound


1459
CN
OCH3b
OH
OH


1460
CN
OCH3b
OH
D-glucitol


1461
CN
OCH3b
OH
SO3H


1462
CN
OCH3b
OH
PO3H2


1463
CN
OCH3b
OH
CHO


1464
CN
OCH3b
OH
COOH


1465
CN
OCH3b
OH
CH2OH


1466
CN
OCH3b
OH
sugar


1467
CN
OCH3b
OH
C-glycosyl compound


1468
CN
OCH3b
CH3
OH


1469
CN
OCH3b
CH3
D-glucitol


1470
CN
OCH3b
CH3
SO3H


1471
CN
OCH3b
CH3
PO3H2


1472
CN
OCH3b
CH3
CHO


1473
CN
OCH3b
CH3
COOH


1474
CN
OCH3b
CH3
CH2OH


1475
CN
OCH3b
CH3
sugar


1476
CN
OCH3b
CH3
C-glycosyl compound


1477
CN
OCH3b
Cl
OH


1478
CN
OCH3b
Cl
D-glucitol


1479
CN
OCH3b
Cl
SO3H


1480
CN
OCH3b
Cl
PO3H2


1481
CN
OCH3b
Cl
CHO


1482
CN
OCH3b
Cl
COOH


1483
CN
OCH3b
Cl
CH2OH


1484
CN
OCH3b
Cl
sugar


1485
CN
OCH3b
Cl
C-glycosyl compound


1486
CN
OCH3b
B(OH)2
OH


1487
CN
OCH3b
B(OH)2
D-glucitol


1488
CN
OCH3b
B(OH)2
SO3H


1489
CN
OCH3b
B(OH)2
PO3H2


1490
CN
OCH3b
B(OH)2
CHO


1491
CN
OCH3b
B(OH)2
COOH


1492
CN
OCH3b
B(OH)2
CH2OH


1493
CN
OCH3b
B(OH)2
sugar


1494
CN
OCH3b
B(OH)2
C-glycosyl compound


1495
CN
OCH3b
SH
OH


1496
CN
OCH3b
SH
D-glucitol


1497
CN
OCH3b
SH
SO3H


1498
CN
OCH3b
SH
PO3H2


1499
CN
OCH3b
SH
CHO


1500
CN
OCH3b
SH
COOH


1501
CN
OCH3b
SH
CH2OH


1502
CN
OCH3b
SH
sugar


1503
CN
OCH3b
SH
C-glycosyl compound


1504
CN
OCH3b
OCH3
OH


1505
CN
OCH3b
OCH3
D-glucitol


1506
CN
OCH3b
OCH3
SO3H


1507
CN
OCH3b
OCH3
PO3H2


1508
CN
OCH3b
OCH3
CHO


1509
CN
OCH3b
OCH3
COOH


1510
CN
OCH3b
OCH3
CH2OH


1511
CN
OCH3b
OCH3
sugar


1512
CN
OCH3b
OCH3
C-glycosyl compound


1513
CH3a
H
H
OH


1514
CH3a
H
H
D-glucitol


1515
CH3a
H
H
SO3H


1516
CH3a
H
H
PO3H2


1517
CH3a
H
H
CHO


1518
CH3a
H
H
COOH


1519
CH3a
H
H
CH2OH


1520
CH3a
H
H
sugar


1521
CH3a
H
H
C-glycosyl compound


1522
CH3a
H
OH
OH


1523
CH3a
H
OH
D-glucitol


1524
CH3a
H
OH
SO3H


1525
CH3a
H
OH
PO3H2


1526
CH3a
H
OH
CHO


1527
CH3a
H
OH
COOH


1528
CH3a
H
OH
CH2OH


1529
CH3a
H
OH
sugar


1530
CH3a
H
OH
C-glycosyl compound


1531
CH3a
H
CH3
OH


1532
CH3a
H
CH3
D-glucitol


1533
CH3a
H
CH3
SO3H


1534
CH3a
H
CH3
PO3H2


1535
CH3a
H
CH3
CHO


1536
CH3a
H
CH3
COOH


1537
CH3a
H
CH3
CH2OH


1538
CH3a
H
CH3
sugar


1539
CH3a
H
CH3
C-glycosyl compound


1540
CH3a
H
Cl
OH


1541
CH3a
H
Cl
D-glucitol


1542
CH3a
H
Cl
SO3H


1543
CH3a
H
Cl
PO3H2


1544
CH3a
H
Cl
CHO


1545
CH3a
H
Cl
COOH


1546
CH3a
H
Cl
CH2OH


1547
CH3a
H
Cl
sugar


1548
CH3a
H
Cl
C-glycosyl compound


1549
CH3a
H
B(OH)2
OH


1550
CH3a
H
B(OH)2
D-glucitol


1551
CH3a
H
B(OH)2
SO3H


1552
CH3a
H
B(OH)2
PO3H2


1553
CH3a
H
B(OH)2
CHO


1554
CH3a
H
B(OH)2
COOH


1555
CH3a
H
B(OH)2
CH2OH


1556
CH3a
H
B(OH)2
sugar


1557
CH3a
H
B(OH)2
C-glycosyl compound


1558
CH3a
H
SH
OH


1559
CH3a
H
SH
D-glucitol


1560
CH3a
H
SH
SO3H


1561
CH3a
H
SH
PO3H2


1562
CH3a
H
SH
CHO


1563
CH3a
H
SH
COOH


1564
CH3a
H
SH
CH2OH


1565
CH3a
H
SH
sugar


1566
CH3a
H
SH
C-glycosyl compound


1567
CH3a
H
OCH3
OH


1568
CH3a
H
OCH3
D-glucitol


1569
CH3a
H
OCH3
SO3H


1570
CH3a
H
OCH3
PO3H2


1571
CH3a
H
OCH3
CHO


1572
CH3a
H
OCH3
COOH


1573
CH3a
H
OCH3
CH2OH


1574
CH3a
H
OCH3
sugar


1575
CH3a
H
OCH3
C-glycosyl compound


1576
CH3a
F
H
OH


1577
CH3a
F
H
D-glucitol


1578
CH3a
F
H
SO3H


1579
CH3a
F
H
PO3H2


1580
CH3a
F
H
CHO


1581
CH3a
F
H
COOH


1582
CH3a
F
H
CH2OH


1583
CH3a
F
H
sugar


1584
CH3a
F
H
C-glycosyl compound


1585
CH3a
F
OH
OH


1586
CH3a
F
OH
D-glucitol


1587
CH3a
F
OH
SO3H


1588
CH3a
F
OH
PO3H2


1589
CH3a
F
OH
CHO


1590
CH3a
F
OH
COOH


1591
CH3a
F
OH
CH2OH


1592
CH3a
F
OH
sugar


1593
CH3a
F
OH
C-glycosyl compound


1594
CH3a
F
CH3
OH


1595
CH3a
F
CH3
D-glucitol


1596
CH3a
F
CH3
SO3H


1597
CH3a
F
CH3
PO3H2


1598
CH3a
F
CH3
CHO


1599
CH3a
F
CH3
COOH


1600
CH3a
F
CH3
CH2OH


1601
CH3a
F
CH3
sugar


1602
CH3a
F
CH3
C-glycosyl compound


1603
CH3a
F
Cl
OH


1604
CH3a
F
Cl
D-glucitol


1605
CH3a
F
Cl
SO3H


1606
CH3a
F
Cl
PO3H2


1607
CH3a
F
Cl
CHO


1608
CH3a
F
Cl
COOH


1609
CH3a
F
Cl
CH2OH


1610
CH3a
F
Cl
sugar


1611
CH3a
F
Cl
C-glycosyl compound


1612
CH3a
F
B(OH)2
OH


1613
CH3a
F
B(OH)2
D-glucitol


1614
CH3a
F
B(OH)2
SO3H


1615
CH3a
F
B(OH)2
PO3H2


1616
CH3a
F
B(OH)2
CHO


1617
CH3a
F
B(OH)2
COOH


1618
CH3a
F
B(OH)2
CH2OH


1619
CH3a
F
B(OH)2
sugar


1620
CH3a
F
B(OH)2
C-glycosyl compound


1621
CH3a
F
SH
OH


1622
CH3a
F
SH
D-glucitol


1623
CH3a
F
SH
SO3H


1624
CH3a
F
SH
PO3H2


1625
CH3a
F
SH
CHO


1626
CH3a
F
SH
COOH


1627
CH3a
F
SH
CH2OH


1628
CH3a
F
SH
sugar


1629
CH3a
F
SH
C-glycosyl compound


1630
CH3a
F
OCH3
OH


1631
CH3a
F
OCH3
D-glucitol


1632
CH3a
F
OCH3
SO3H


1633
CH3a
F
OCH3
PO3H2


1634
CH3a
F
OCH3
CHO


1635
CH3a
F
OCH3
COOH


1636
CH3a
F
OCH3
CH2OH


1637
CH3a
F
OCH3
sugar


1638
CH3a
F
OCH3
C-glycosyl compound


1639
CH3a
Cl
H
OH


1640
CH3a
Cl
H
D-glucitol


1641
CH3a
Cl
H
SO3H


1642
CH3a
Cl
H
PO3H2


1643
CH3a
Cl
H
CHO


1644
CH3a
Cl
H
COOH


1645
CH3a
Cl
H
CH2OH


1646
CH3a
Cl
H
sugar


1647
CH3a
Cl
H
C-glycosyl compound


1648
CH3a
Cl
OH
OH


1649
CH3a
Cl
OH
D-glucitol


1650
CH3a
Cl
OH
SO3H


1651
CH3a
Cl
OH
PO3H2


1652
CH3a
Cl
OH
CHO


1653
CH3a
Cl
OH
COOH


1654
CH3a
Cl
OH
CH2OH


1655
CH3a
Cl
OH
sugar


1656
CH3a
Cl
OH
C-glycosyl compound


1657
CH3a
Cl
CH3
OH


1658
CH3a
Cl
CH3
D-glucitol


1659
CH3a
Cl
CH3
SO3H


1660
CH3a
Cl
CH3
PO3H2


1661
CH3a
Cl
CH3
CHO


1662
CH3a
Cl
CH3
COOH


1663
CH3a
Cl
CH3
CH2OH


1664
CH3a
Cl
CH3
sugar


1665
CH3a
Cl
CH3
C-glycosyl compound


1666
CH3a
Cl
Cl
OH


1667
CH3a
Cl
Cl
D-glucitol


1668
CH3a
Cl
Cl
SO3H


1669
CH3a
Cl
Cl
PO3H2


1670
CH3a
Cl
Cl
CHO


1671
CH3a
Cl
Cl
COOH


1672
CH3a
Cl
Cl
CH2OH


1673
CH3a
Cl
Cl
sugar


1674
CH3a
Cl
Cl
C-glycosyl compound


1675
CH3a
Cl
B(OH)2
OH


1676
CH3a
Cl
B(OH)2
D-glucitol


1677
CH3a
Cl
B(OH)2
SO3H


1678
CH3a
Cl
B(OH)2
PO3H2


1679
CH3a
Cl
B(OH)2
CHO


1680
CH3a
Cl
B(OH)2
COOH


1681
CH3a
Cl
B(OH)2
CH2OH


1682
CH3a
Cl
B(OH)2
sugar


1683
CH3a
Cl
B(OH)2
C-glycosyl compound


1684
CH3a
Cl
SH
OH


1685
CH3a
Cl
SH
D-glucitol


1686
CH3a
Cl
SH
SO3H


1687
CH3a
Cl
SH
PO3H2


1688
CH3a
Cl
SH
CHO


1689
CH3a
Cl
SH
COOH


1690
CH3a
Cl
SH
CH2OH


1691
CH3a
Cl
SH
sugar


1692
CH3a
Cl
SH
C-glycosyl compound


1693
CH3a
Cl
OCH3
OH


1694
CH3a
Cl
OCH3
D-glucitol


1695
CH3a
Cl
OCH3
SO3H


1696
CH3a
Cl
OCH3
PO3H2


1697
CH3a
Cl
OCH3
CHO


1698
CH3a
Cl
OCH3
COOH


1699
CH3a
Cl
OCH3
CH2OH


1700
CH3a
Cl
OCH3
sugar


1701
CH3a
Cl
OCH3
C-glycosyl compound


1702
CH3a
CN
H
OH


1703
CH3a
CN
H
D-glucitol


1704
CH3a
CN
H
SO3H


1705
CH3a
CN
H
PO3H2


1706
CH3a
CN
H
CHO


1707
CH3a
CN
H
COOH


1708
CH3a
CN
H
CH2OH


1709
CH3a
CN
H
Sugar


1710
CH3a
CN
H
C-glycosyl compound


1711
CH3a
CN
OH
OH


1712
CH3a
CN
OH
D-glucitol


1713
CH3a
CN
OH
SO3H


1714
CH3a
CN
OH
PO3H2


1715
CH3a
CN
OH
CHO


1716
CH3a
CN
OH
COOH


1717
CH3a
CN
OH
CH2OH


1718
CH3a
CN
OH
sugar


1719
CH3a
CN
OH
C-glycosyl compound


1720
CH3a
CN
CH3
OH


1721
CH3a
CN
CH3
D-glucitol


1722
CH3a
CN
CH3
SO3H


1723
CH3a
CN
CH3
PO3H2


1724
CH3a
CN
CH3
CHO


1725
CH3a
CN
CH3
COOH


1726
CH3a
CN
CH3
CH2OH


1727
CH3a
CN
CH3
sugar


1728
CH3a
CN
CH3
C-glycosyl compound


1729
CH3a
CN
Cl
OH


1730
CH3a
CN
Cl
D-glucitol


1731
CH3a
CN
Cl
SO3H


1732
CH3a
CN
Cl
PO3H2


1733
CH3a
CN
Cl
CHO


1734
CH3a
CN
Cl
COOH


1735
CH3a
CN
Cl
CH2OH


1736
CH3a
CN
Cl
sugar


1737
CH3a
CN
Cl
C-glycosyl compound


1738
CH3a
CN
B(OH)2
OH


1739
CH3a
CN
B(OH)2
D-glucitol


1740
CH3a
CN
B(OH)2
SO3H


1741
CH3a
CN
B(OH)2
PO3H2


1742
CH3a
CN
B(OH)2
CHO


1743
CH3a
CN
B(OH)2
COOH


1744
CH3a
CN
B(OH)2
CH2OH


1745
CH3a
CN
B(OH)2
sugar


1746
CH3a
CN
B(OH)2
C-glycosyl compound


1747
CH3a
CN
SH
OH


1748
CH3a
CN
SH
D-glucitol


1749
CH3a
CN
SH
SO3H


1750
CH3a
CN
SH
PO3H2


1751
CH3a
CN
SH
CHO


1752
CH3a
CN
SH
COOH


1753
CH3a
CN
SH
CH2OH


1754
CH3a
CN
SH
sugar


1755
CH3a
CN
SH
C-glycosyl compound


1756
CH3a
CN
OCH3
OH


1757
CH3a
CN
OCH3
D-glucitol


1758
CH3a
CN
OCH3
SO3H


1759
CH3a
CN
OCH3
PO3H2


1760
CH3a
CN
OCH3
CHO


1761
CH3a
CN
OCH3
COOH


1762
CH3a
CN
OCH3
CH2OH


1763
CH3a
CN
OCH3
sugar


1764
CH3a
CN
OCH3
C-glycosyl compound


1765
CH3a
CH3a
H
OH


1766
CH3a
CH3a
H
D-glucitol


1767
CH3a
CH3a
H
SO3H


1768
CH3a
CH3a
H
PO3H2


1769
CH3a
CH3a
H
CHO


1770
CH3a
CH3a
H
COOH


1771
CH3a
CH3a
H
CH2OH


1772
CH3a
CH3a
H
sugar


1773
CH3a
CH3a
H
C-glycosyl compound


1774
CH3a
CH3a
OH
OH


1775
CH3a
CH3a
OH
D-glucitol


1776
CH3a
CH3a
OH
SO3H


1777
CH3a
CH3a
OH
PO3H2


1778
CH3a
CH3a
OH
CHO


1779
CH3a
CH3a
OH
COOH


1780
CH3a
CH3a
OH
CH2OH


1781
CH3a
CH3a
OH
sugar


1782
CH3a
CH3a
OH
C-glycosyl compound


1783
CH3a
CH3a
CH3
OH


1784
CH3a
CH3a
CH3
D-glucitol


1785
CH3a
CH3a
CH3
SO3H


1786
CH3a
CH3a
CH3
PO3H2


1787
CH3a
CH3a
CH3
CHO


1788
CH3a
CH3a
CH3
COOH


1789
CH3a
CH3a
CH3
CH2OH


1790
CH3a
CH3a
CH3
sugar


1791
CH3a
CH3a
CH3
C-glycosyl compound


1792
CH3a
CH3a
Cl
OH


1793
CH3a
CH3a
Cl
D-glucitol


1794
CH3a
CH3a
Cl
SO3H


1795
CH3a
CH3a
Cl
PO3H2


1796
CH3a
CH3a
Cl
CHO


1797
CH3a
CH3a
Cl
COOH


1798
CH3a
CH3a
Cl
CH2OH


1799
CH3a
CH3a
Cl
sugar


1800
CH3a
CH3a
Cl
C-glycosyl compound


1801
CH3a
CH3a
B(OH)2
OH


1802
CH3a
CH3a
B(OH)2
D-glucitol


1803
CH3a
CH3a
B(OH)2
SO3H


1804
CH3a
CH3a
B(OH)2
PO3H2


1805
CH3a
CH3a
B(OH)2
CHO


1806
CH3a
CH3a
B(OH)2
COOH


1807
CH3a
CH3a
B(OH)2
CH2OH


1808
CH3a
CH3a
B(OH)2
sugar


1809
CH3a
CH3a
B(OH)2
C-glycosyl compound


1810
CH3a
CH3a
SH
OH


1811
CH3a
CH3a
SH
D-glucitol


1812
CH3a
CH3a
SH
SO3H


1813
CH3a
CH3a
SH
PO3H2


1814
CH3a
CH3a
SH
CHO


1815
CH3a
CH3a
SH
COOH


1816
CH3a
CH3a
SH
CH2OH


1817
CH3a
CH3a
SH
sugar


1818
CH3a
CH3a
SH
C-glycosyl compound


1819
CH3a
CH3a
OCH3
OH


1820
CH3a
CH3a
OCH3
D-glucitol


1821
CH3a
CH3a
OCH3
SO3H


1822
CH3a
CH3a
OCH3
PO3H2


1823
CH3a
CH3a
OCH3
CHO


1824
CH3a
CH3a
OCH3
COOH


1825
CH3a
CH3a
OCH3
CH2OH


1826
CH3a
CH3a
OCH3
sugar


1827
CH3a
CH3a
OCH3
C-glycosyl compound


1828
CH3a
OCH3b
H
OH


1829
CH3a
OCH3b
H
D-glucitol


1830
CH3a
OCH3b
H
SO3H


1831
CH3a
OCH3b
H
PO3H2


1832
CH3a
OCH3b
H
CHO


1833
CH3a
OCH3b
H
COOH


1834
CH3a
OCH3b
H
CH2OH


1835
CH3a
OCH3b
H
sugar


1836
CH3a
OCH3b
H
C-glycosyl compound


1837
CH3a
OCH3b
OH
OH


1838
CH3a
OCH3b
OH
D-glucitol


1839
CH3a
OCH3b
OH
SO3H


1840
CH3a
OCH3b
OH
PO3H2


1841
CH3a
OCH3b
OH
CHO


1842
CH3a
OCH3b
OH
COOH


1843
CH3a
OCH3b
OH
CH2OH


1844
CH3a
OCH3b
OH
sugar


1845
CH3a
OCH3b
OH
C-glycosyl compound


1846
CH3a
OCH3b
CH3
OH


1847
CH3a
OCH3b
CH3
D-glucitol


1848
CH3a
OCH3b
CH3
SO3H


1849
CH3a
OCH3b
CH3
PO3H2


1850
CH3a
OCH3b
CH3
CHO


1851
CH3a
OCH3b
CH3
COOH


1852
CH3a
OCH3b
CH3
CH2OH


1853
CH3a
OCH3b
CH3
sugar


1854
CH3a
OCH3b
CH3
C-glycosyl compound


1855
CH3a
OCH3b
Cl
OH


1856
CH3a
OCH3b
Cl
D-glucitol


1857
CH3a
OCH3b
Cl
SO3H


1858
CH3a
OCH3b
Cl
PO3H2


1859
CH3a
OCH3b
Cl
CHO


1860
CH3a
OCH3b
Cl
COOH


1861
CH3a
OCH3b
Cl
CH2OH


1862
CH3a
OCH3b
Cl
sugar


1863
CH3a
OCH3b
Cl
C-glycosyl compound


1864
CH3a
OCH3b
B(OH)2
OH


1865
CH3a
OCH3b
B(OH)2
D-glucitol


1866
CH3a
OCH3b
B(OH)2
SO3H


1867
CH3a
OCH3b
B(OH)2
PO3H2


1868
CH3a
OCH3b
B(OH)2
CHO


1869
CH3a
OCH3b
B(OH)2
COOH


1870
CH3a
OCH3b
B(OH)2
CH2OH


1871
CH3a
OCH3b
B(OH)2
sugar


1872
CH3a
OCH3b
B(OH)2
C-glycosyl compound


1873
CH3a
OCH3b
SH
OH


1874
CH3a
OCH3b
SH
D-glucitol


1875
CH3a
OCH3b
SH
SO3H


1876
CH3a
OCH3b
SH
PO3H2


1877
CH3a
OCH3b
SH
CHO


1878
CH3a
OCH3b
SH
COOH


1879
CH3a
OCH3b
SH
CH2OH


1880
CH3a
OCH3b
SH
sugar


1881
CH3a
OCH3b
SH
C-glycosyl compound


1882
CH3a
OCH3b
OCH3
OH


1883
CH3a
OCH3b
OCH3
D-glucitol


1884
CH3a
OCH3b
OCH3
SO3H


1885
CH3a
OCH3b
OCH3
PO3H2


1886
CH3a
OCH3b
OCH3
CHO


1887
CH3a
OCH3b
OCH3
COOH


1888
CH3a
OCH3b
OCH3
CH2OH


1889
CH3a
OCH3b
OCH3
sugar


1890
CH3a
OCH3b
OCH3
C-glycosyl compound


1891
OCH3b
H
H
OH


1892
OCH3b
H
H
D-glucitol


1893
OCH3b
H
H
SO3H


1894
OCH3b
H
H
PO3H2


1895
OCH3b
H
H
CHO


1896
OCH3b
H
H
COOH


1897
OCH3b
H
H
CH2OH


1898
OCH3b
H
H
sugar


1899
OCH3b
H
H
C-glycosyl compound


1900
OCH3b
H
OH
OH


1901
OCH3b
H
OH
D-glucitol


1902
OCH3b
H
OH
SO3H


1903
OCH3b
H
OH
PO3H2


1904
OCH3b
H
OH
CHO


1905
OCH3b
H
OH
COOH


1906
OCH3b
H
OH
CH2OH


1907
OCH3b
H
OH
sugar


1908
OCH3b
H
OH
C-glycosyl compound


1909
OCH3b
H
CH3
OH


1910
OCH3b
H
CH3
D-glucitol


1911
OCH3b
H
CH3
SO3H


1912
OCH3b
H
CH3
PO3H2


1913
OCH3b
H
CH3
CHO


1914
OCH3b
H
CH3
COOH


1915
OCH3b
H
CH3
CH2OH


1916
OCH3b
H
CH3
sugar


1917
OCH3b
H
CH3
C-glycosyl compound


1918
OCH3b
H
Cl
OH


1919
OCH3b
H
Cl
D-glucitol


1920
OCH3b
H
Cl
SO3H


1921
OCH3b
H
Cl
PO3H2


1922
OCH3b
H
Cl
CHO


1923
OCH3b
H
Cl
COOH


1924
OCH3b
H
Cl
CH2OH


1925
OCH3b
H
Cl
sugar


1926
OCH3b
H
Cl
C-glycosyl compound


1927
OCH3b
H
B(OH)2
OH


1928
OCH3b
H
B(OH)2
D-glucitol


1929
OCH3b
H
B(OH)2
SO3H


1930
OCH3b
H
B(OH)2
PO3H2


1931
OCH3b
H
B(OH)2
CHO


1932
OCH3b
H
B(OH)2
COOH


1933
OCH3b
H
B(OH)2
CH2OH


1934
OCH3b
H
B(OH)2
sugar


1935
OCH3b
H
B(OH)2
C-glycosyl compound


1936
OCH3b
H
SH
OH


1937
OCH3b
H
SH
D-glucitol


1938
OCH3b
H
SH
SO3H


1939
OCH3b
H
SH
PO3H2


1940
OCH3b
H
SH
CHO


1941
OCH3b
H
SH
COOH


1942
OCH3b
H
SH
CH2OH


1943
OCH3b
H
SH
sugar


1944
OCH3b
H
SH
C-glycosyl compound


1945
OCH3b
H
OCH3
OH


1946
OCH3b
H
OCH3
D-glucitol


1947
OCH3b
H
OCH3
SO3H


1948
OCH3b
H
OCH3
PO3H2


1949
OCH3b
H
OCH3
CHO


1950
OCH3b
H
OCH3
COOH


1951
OCH3b
H
OCH3
CH2OH


1952
OCH3b
H
OCH3
sugar


1953
OCH3b
H
OCH3
C-glycosyl compound


1954
OCH3b
F
H
OH


1955
OCH3b
F
H
D-glucitol


1956
OCH3b
F
H
SO3H


1957
OCH3b
F
H
PO3H2


1958
OCH3b
F
H
CHO


1959
OCH3b
F
H
COOH


1960
OCH3b
F
H
CH2OH


1961
OCH3b
F
H
sugar


1962
OCH3b
F
H
C-glycosyl compound


1963
OCH3b
F
OH
OH


1964
OCH3b
F
OH
D-glucitol


1965
OCH3b
F
OH
SO3H


1966
OCH3b
F
OH
PO3H2


1967
OCH3b
F
OH
CHO


1968
OCH3b
F
OH
COOH


1969
OCH3b
F
OH
CH2OH


1970
OCH3b
F
OH
sugar


1971
OCH3b
F
OH
C-glycosyl compound


1972
OCH3b
F
CH3
OH


1973
OCH3b
F
CH3
D-glucitol


1974
OCH3b
F
CH3
SO3H


1975
OCH3b
F
CH3
PO3H2


1976
OCH3b
F
CH3
CHO


1977
OCH3b
F
CH3
COOH


1978
OCH3b
F
CH3
CH2OH


1979
OCH3b
F
CH3
sugar


1980
OCH3b
F
CH3
C-glycosyl compound


1981
OCH3b
F
Cl
OH


1982
OCH3b
F
Cl
D-glucitol


1983
OCH3b
F
Cl
SO3H


1984
OCH3b
F
Cl
PO3H2


1985
OCH3b
F
Cl
CHO


1986
OCH3b
F
Cl
COOH


1987
OCH3b
F
Cl
CH2OH


1988
OCH3b
F
Cl
sugar


1989
OCH3b
F
Cl
C-glycosyl compound


1990
OCH3b
F
B(OH)2
OH


1991
OCH3b
F
B(OH)2
D-glucitol


1992
OCH3b
F
B(OH)2
SO3H


1993
OCH3b
F
B(OH)2
PO3H2


1994
OCH3b
F
B(OH)2
CHO


1995
OCH3b
F
B(OH)2
COOH


1996
OCH3b
F
B(OH)2
CH2OH


1997
OCH3b
F
B(OH)2
sugar


1998
OCH3b
F
B(OH)2
C-glycosyl compound


1999
OCH3b
F
SH
OH


2000
OCH3b
F
SH
D-glucitol


2001
OCH3b
F
SH
SO3H


2002
OCH3b
F
SH
PO3H2


2003
OCH3b
F
SH
CHO


2004
OCH3b
F
SH
COOH


2005
OCH3b
F
SH
CH2OH


2006
OCH3b
F
SH
sugar


2007
OCH3b
F
SH
C-glycosyl compound


2008
OCH3b
F
OCH3
OH


2009
OCH3b
F
OCH3
D-glucitol


2010
OCH3b
F
OCH3
SO3H


2011
OCH3b
F
OCH3
PO3H2


2012
OCH3b
F
OCH3
CHO


2013
OCH3b
F
OCH3
COOH


2014
OCH3b
F
OCH3
CH2OH


2015
OCH3b
F
OCH3
sugar


2016
OCH3b
F
OCH3
C-glycosyl compound


2017
OCH3b
Cl
H
OH


2018
OCH3b
Cl
H
D-glucitol


2019
OCH3b
Cl
H
SO3H


2020
OCH3b
Cl
H
PO3H2


2021
OCH3b
Cl
H
CHO


2022
OCH3b
Cl
H
COOH


2023
OCH3b
Cl
H
CH2OH


2024
OCH3b
Cl
H
sugar


2025
OCH3b
Cl
H
C-glycosyl compound


2026
OCH3b
Cl
OH
OH


2027
OCH3b
Cl
OH
D-glucitol


2028
OCH3b
Cl
OH
SO3H


2029
OCH3b
Cl
OH
PO3H2


2030
OCH3b
Cl
OH
CHO


2031
OCH3b
Cl
OH
COOH


2032
OCH3b
Cl
OH
CH2OH


2033
OCH3b
Cl
OH
sugar


2034
OCH3b
Cl
OH
C-glycosyl compound


2035
OCH3b
Cl
CH3
OH


2036
OCH3b
Cl
CH3
D-glucitol


2037
OCH3b
Cl
CH3
SO3H


2038
OCH3b
Cl
CH3
PO3H2


2039
OCH3b
Cl
CH3
CHO


2040
OCH3b
Cl
CH3
COOH


2041
OCH3b
Cl
CH3
CH2OH


2042
OCH3b
Cl
CH3
sugar


2043
OCH3b
Cl
CH3
C-glycosyl compound


2044
OCH3b
Cl
Cl
OH


2045
OCH3b
Cl
Cl
D-glucitol


2046
OCH3b
Cl
Cl
SO3H


2047
OCH3b
Cl
Cl
PO3H2


2048
OCH3b
Cl
Cl
CHO


2049
OCH3b
Cl
Cl
COOH


2050
OCH3b
Cl
Cl
CH2OH


2051
OCH3b
Cl
Cl
sugar


2052
OCH3b
Cl
Cl
C-glycosyl compound


2053
OCH3b
Cl
B(OH)2
OH


2054
OCH3b
Cl
B(OH)2
D-glucitol


2055
OCH3b
Cl
B(OH)2
SO3H


2056
OCH3b
Cl
B(OH)2
PO3H2


2057
OCH3b
Cl
B(OH)2
CHO


2058
OCH3b
Cl
B(OH)2
COOH


2059
OCH3b
Cl
B(OH)2
CH2OH


2060
OCH3b
Cl
B(OH)2
sugar


2061
OCH3b
Cl
B(OH)2
C-glycosyl compound


2062
OCH3b
Cl
SH
OH


2063
OCH3b
Cl
SH
D-glucitol


2064
OCH3b
Cl
SH
SO3H


2065
OCH3b
Cl
SH
PO3H2


2066
OCH3b
Cl
SH
CHO


2067
OCH3b
Cl
SH
COOH


2068
OCH3b
Cl
SH
CH2OH


2069
OCH3b
Cl
SH
sugar


2070
OCH3b
Cl
SH
C-glycosyl compound


2071
OCH3b
Cl
OCH3
OH


2072
OCH3b
Cl
OCH3
D-glucitol


2073
OCH3b
Cl
OCH3
SO3H


2074
OCH3b
Cl
OCH3
PO3H2


2075
OCH3b
Cl
OCH3
CHO


2076
OCH3b
Cl
OCH3
COOH


2077
OCH3b
Cl
OCH3
CH2OH


2078
OCH3b
Cl
OCH3
sugar


2079
OCH3b
Cl
OCH3
C-glycosyl compound


2080
OCH3b
CN
H
OH


2081
OCH3b
CN
H
D-glucitol


2082
OCH3b
CN
H
SO3H


2083
OCH3b
CN
H
PO3H2


2084
OCH3b
CN
H
CHO


2085
OCH3b
CN
H
COOH


2086
OCH3b
CN
H
CH2OH


2087
OCH3b
CN
H
sugar


2088
OCH3b
CN
H
C-glycosyl compound


2089
OCH3b
CN
OH
OH


2090
OCH3b
CN
OH
D-glucitol


2091
OCH3b
CN
OH
SO3H


2092
OCH3b
CN
OH
PO3H2


2093
OCH3b
CN
OH
CHO


2094
OCH3b
CN
OH
COOH


2095
OCH3b
CN
OH
CH2OH


2096
OCH3b
CN
OH
sugar


2097
OCH3b
CN
OH
C-glycosyl compound


2098
OCH3b
CN
CH3
OH


2099
OCH3b
CN
CH3
D-glucitol


2100
OCH3b
CN
CH3
SO3H


2101
OCH3b
CN
CH3
PO3H2


2102
OCH3b
CN
CH3
CHO


2103
OCH3b
CN
CH3
COOH


2104
OCH3b
CN
CH3
CH2OH


2105
OCH3b
CN
CH3
sugar


2106
OCH3b
CN
CH3
C-glycosyl compound


2107
OCH3b
CN
Cl
OH


2108
OCH3b
CN
Cl
D-glucitol


2109
OCH3b
CN
Cl
SO3H


2110
OCH3b
CN
Cl
PO3H2


2111
OCH3b
CN
Cl
CHO


2112
OCH3b
CN
Cl
COOH


2113
OCH3b
CN
Cl
CH2OH


2114
OCH3b
CN
Cl
sugar


2115
OCH3b
CN
Cl
C-glycosyl compound


2116
OCH3b
CN
B(OH)2
OH


2117
OCH3b
CN
B(OH)2
D-glucitol


2118
OCH3b
CN
B(OH)2
SO3H


2119
OCH3b
CN
B(OH)2
PO3H2


2120
OCH3b
CN
B(OH)2
CHO


2121
OCH3b
CN
B(OH)2
COOH


2122
OCH3b
CN
B(OH)2
CH2OH


2123
OCH3b
CN
B(OH)2
sugar


2124
OCH3b
CN
B(OH)2
C-glycosyl compound


2125
OCH3b
CN
SH
OH


2126
OCH3b
CN
SH
D-glucitol


2127
OCH3b
CN
SH
SO3H


2128
OCH3b
CN
SH
PO3H2


2129
OCH3b
CN
SH
CHO


2130
OCH3b
CN
SH
COOH


2131
OCH3b
CN
SH
CH2OH


2132
OCH3b
CN
SH
sugar


2133
OCH3b
CN
SH
C-glycosyl compound


2134
OCH3b
CN
OCH3
OH


2135
OCH3b
CN
OCH3
D-glucitol


2136
OCH3b
CN
OCH3
SO3H


2137
OCH3b
CN
OCH3
PO3H2


2138
OCH3b
CN
OCH3
CHO


2139
OCH3b
CN
OCH3
COOH


2140
OCH3b
CN
OCH3
CH2OH


2141
OCH3b
CN
OCH3
sugar


2142
OCH3b
CN
OCH3
C-glycosyl compound


2143
OCH3b
CH3a
H
OH


2144
OCH3b
CH3a
H
D-glucitol


2145
OCH3b
CH3a
H
SO3H


2146
OCH3b
CH3a
H
PO3H2


2147
OCH3b
CH3a
H
CHO


2148
OCH3b
CH3a
H
COOH


2149
OCH3b
CH3a
H
CH2OH


2150
OCH3b
CH3a
H
sugar


2151
OCH3b
CH3a
H
C-glycosyl compound


2152
OCH3b
CH3a
OH
OH


2153
OCH3b
CH3a
OH
D-glucitol


2154
OCH3b
CH3a
OH
SO3H


2155
OCH3b
CH3a
OH
PO3H2


2156
OCH3b
CH3a
OH
CHO


2157
OCH3b
CH3a
OH
COOH


2158
OCH3b
CH3a
OH
CH2OH


2159
OCH3b
CH3a
OH
sugar


2160
OCH3b
CH3a
OH
C-glycosyl compound


2161
OCH3b
CH3a
CH3
OH


2162
OCH3b
CH3a
CH3
D-glucitol


2163
OCH3b
CH3a
CH3
SO3H


2164
OCH3b
CH3a
CH3
PO3H2


2165
OCH3b
CH3a
CH3
CHO


2166
OCH3b
CH3a
CH3
COOH


2167
OCH3b
CH3a
CH3
CH2OH


2168
OCH3b
CH3a
CH3
sugar


2169
OCH3b
CH3a
CH3
C-glycosyl compound


2170
OCH3b
CH3a
Cl
OH


2171
OCH3b
CH3a
Cl
D-glucitol


2172
OCH3b
CH3a
Cl
SO3H


2173
OCH3b
CH3a
Cl
PO3H2


2174
OCH3b
CH3a
Cl
CHO


2175
OCH3b
CH3a
Cl
COOH


2176
OCH3b
CH3a
Cl
CH2OH


2177
OCH3b
CH3a
Cl
sugar


2178
OCH3b
CH3a
Cl
C-glycosyl compound


2179
OCH3b
CH3a
B(OH)2
OH


2180
OCH3b
CH3a
B(OH)2
D-glucitol


2181
OCH3b
CH3a
B(OH)2
SO3H


2182
OCH3b
CH3a
B(OH)2
PO3H2


2183
OCH3b
CH3a
B(OH)2
CHO


2184
OCH3b
CH3a
B(OH)2
COOH


2185
OCH3b
CH3a
B(OH)2
CH2OH


2186
OCH3b
CH3a
B(OH)2
sugar


2187
OCH3b
CH3a
B(OH)2
C-glycosyl compound


2188
OCH3b
CH3a
SH
OH


2189
OCH3b
CH3a
SH
D-glucitol


2190
OCH3b
CH3a
SH
SO3H


2191
OCH3b
CH3a
SH
PO3H2


2192
OCH3b
CH3a
SH
CHO


2193
OCH3b
CH3a
SH
COOH


2194
OCH3b
CH3a
SH
CH2OH


2195
OCH3b
CH3a
SH
sugar


2196
OCH3b
CH3a
SH
C-glycosyl compound


2197
OCH3b
CH3a
OCH3
OH


2198
OCH3b
CH3a
OCH3
D-glucitol


2199
OCH3b
CH3a
OCH3
SO3H


2200
OCH3b
CH3a
OCH3
PO3H2


2201
OCH3b
CH3a
OCH3
CHO


2202
OCH3b
CH3a
OCH3
COOH


2203
OCH3b
CH3a
OCH3
CH2OH


2204
OCH3b
CH3a
OCH3
sugar


2205
OCH3b
CH3a
OCH3
C-glycosyl compound


2206
OCH3b
OCH3b
H
OH


2207
OCH3b
OCH3b
H
D-glucitol


2208
OCH3b
OCH3b
H
SO3H


2209
OCH3b
OCH3b
H
PO3H2


2210
OCH3b
OCH3b
H
CHO


2211
OCH3b
OCH3b
H
COOH


2212
OCH3b
OCH3b
H
CH2OH


2213
OCH3b
OCH3b
H
sugar


2214
OCH3b
OCH3b
H
C-glycosyl compound


2215
OCH3b
OCH3b
OH
OH


2216
OCH3b
OCH3b
OH
D-glucitol


2217
OCH3b
OCH3b
OH
SO3H


2218
OCH3b
OCH3b
OH
PO3H2


2219
OCH3b
OCH3b
OH
CHO


2220
OCH3b
OCH3b
OH
COOH


2221
OCH3b
OCH3b
OH
CH2OH


2222
OCH3b
OCH3b
OH
sugar


2223
OCH3b
OCH3b
OH
C-glycosyl compound


2224
OCH3b
OCH3b
CH3
OH


2225
OCH3b
OCH3b
CH3
D-glucitol


2226
OCH3b
OCH3b
CH3
SO3H


2227
OCH3b
OCH3b
CH3
PO3H2


2228
OCH3b
OCH3b
CH3
CHO


2229
OCH3b
OCH3b
CH3
COOH


2230
OCH3b
OCH3b
CH3
CH2OH


2231
OCH3b
OCH3b
CH3
sugar


2232
OCH3b
OCH3b
CH3
C-glycosyl compound


2233
OCH3b
OCH3b
Cl
OH


2234
OCH3b
OCH3b
Cl
D-glucitol


2235
OCH3b
OCH3b
Cl
SO3H


2236
OCH3b
OCH3b
Cl
PO3H2


2237
OCH3b
OCH3b
Cl
CHO


2238
OCH3b
OCH3b
Cl
COOH


2239
OCH3b
OCH3b
Cl
CH2OH


2240
OCH3b
OCH3b
Cl
sugar


2241
OCH3b
OCH3b
Cl
C-glycosyl compound


2242
OCH3b
OCH3b
B(OH)2
OH


2243
OCH3b
OCH3b
B(OH)2
D-glucitol


2244
OCH3b
OCH3b
B(OH)2
SO3H


2245
OCH3b
OCH3b
B(OH)2
PO3H2


2246
OCH3b
OCH3b
B(OH)2
CHO


2247
OCH3b
OCH3b
B(OH)2
COOH


2248
OCH3b
OCH3b
B(OH)2
CH2OH


2249
OCH3b
OCH3b
B(OH)2
sugar


2250
OCH3b
OCH3b
B(OH)2
C-glycosyl compound


2251
OCH3b
OCH3b
SH
OH


2252
OCH3b
OCH3b
SH
D-glucitol


2253
OCH3b
OCH3b
SH
SO3H


2254
OCH3b
OCH3b
SH
PO3H2


2255
OCH3b
OCH3b
SH
CHO


2256
OCH3b
OCH3b
SH
COOH


2257
OCH3b
OCH3b
SH
CH2OH


2258
OCH3b
OCH3b
SH
sugar


2259
OCH3b
OCH3b
SH
C-glycosyl compound


2260
OCH3b
OCH3b
OCH3
OH


2261
OCH3b
OCH3b
OCH3
D-glucitol


2262
OCH3b
OCH3b
OCH3
SO3H


2263
OCH3b
OCH3b
OCH3
PO3H2


2264
OCH3b
OCH3b
OCH3
CHO


2265
OCH3b
OCH3b
OCH3
COOH


2266
OCH3b
OCH3b
OCH3
CH2OH


2267
OCH3b
OCH3b
OCH3
sugar


2268
OCH3b
OCH3b
OCH3
C-glycosyl compound





aoptionally substituted with one, two or three F


boptionally substituted with two or three F

















TABLE 4





row number
R1
R2
R4
R5



















1
ortho
ortho
3-
ortho


2
ortho
ortho
3-
meta


3
ortho
ortho
3-
para


4
ortho
ortho
2-
ortho


5
ortho
ortho
2-
meta


6
ortho
ortho
2-
para


7
ortho
meta
3-
ortho


8
ortho
meta
3-
meta


9
ortho
meta
3-
para


10
ortho
meta
2-
ortho


11
ortho
meta
2-
meta


12
ortho
meta
2-
para


13
ortho
para
3-
ortho


14
ortho
para
3-
meta


15
ortho
para
3-
para


16
ortho
para
2-
ortho


17
ortho
para
2-
meta


18
ortho
para
2-
para


19
meta
ortho
3-
ortho


20
meta
ortho
3-
meta


21
meta
ortho
3-
para


22
meta
ortho
2-
ortho


23
meta
ortho
2-
meta


24
meta
ortho
2-
para


25
meta
meta
3-
ortho


26
meta
meta
3-
meta


27
meta
meta
3-
para


28
meta
meta
2-
ortho


29
meta
meta
2-
meta


30
meta
meta
2-
para


31
meta
para
3-
ortho


32
meta
para
3-
meta


33
meta
para
3-
para


34
meta
para
2-
ortho


35
meta
para
2-
meta


36
meta
para
2-
para


37
para
ortho
3-
ortho


38
para
ortho
3-
meta


39
para
ortho
3-
para


40
para
ortho
2-
ortho


41
para
ortho
2-
meta


42
para
ortho
2-
para


43
para
meta
3-
ortho


44
para
meta
3-
meta


45
para
meta
3-
para


46
para
meta
2-
ortho


47
para
meta
2-
meta


48
para
meta
2-
para


49
para
para
3-
ortho


50
para
para
3-
meta


51
para
para
3-
para


52
para
para
2-
ortho


53
para
para
2-
meta


54
para
para
2-
para









Table 5 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is F, R4 is OH and R5 is OH (i.e. Table 3, row 1) according to the positions defined by all rows of Table 4.













1
(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


2
(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


3
(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


4
(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


5
(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


6
(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


7
(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


8
(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


9
(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


10
(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


11
(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


12
(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


13
(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


14
(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


15
(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


16
(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


17
(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one


18
(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-1-



phenylazetidin-2-one









Table 6 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is F, R4 is OH and R5 is D-glucitol (i.e. Table 3, row 2) according to the positions defined by all rows of Table 4.













1
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)-D-glucitol


2
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol


3
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol


4
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)-D-glucitol


5
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)-D-glucitol


6
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(2-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)-D-glucitol


7
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)-D-glucitol


8
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol


9
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol


10
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)-D-glucitol


11
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)-D-glucitol


12
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(3-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)-D-glucitol


13
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)-D-glucitol


14
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol


15
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol


16
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)-D-glucitol


17
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)-D-glucitol


18
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-



3-(4-fluorophenyl)-3-hydroxypropyl]-4-



oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)-D-glucitol









Table 7 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is F, R4 is OH and R5 is SO3H (i.e. Table 3, row 3) according to the positions defined by all rows of Table 4.













1
4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-2-sulfonic acid


2
4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-3-sulfonic acid


3
4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-4-sulfonic acid


4
4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-2-sulfonic acid


5
4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-3-sulfonic acid


6
4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-4-sulfonic acid


7
4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-2-sulfonic acid


8
4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-3-sulfonic acid


9
4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-4-sulfonic acid


10
4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-2-sulfonic acid


11
4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-3-sulfonic acid


12
4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-4-sulfonic acid


13
4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-2-sulfonic acid


14
4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-3-sulfonic acid


15
4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-4-sulfonic acid


16
4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-2-sulfonic acid


17
4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-3-sulfonic acid


18
4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-4-sulfonic acid









Table 8 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is F, R4 is OH and R5 is PO3H2 (i.e. Table 3, row 4) according to the positions defined by all rows of Table 4.













1
(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid


2
(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid


3
(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid


4
(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid


5
(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid


6
(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid


7
(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid


8
(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid


9
(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid


10
(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid


11
(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid


12
(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid


13
(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid


14
(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid


15
(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid


16
(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid


17
(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid


18
(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-



3-hydroxypropyl]-4-oxo-1-phenylazetidin-



2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid









Table 9 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is H, R4 is OH and R5 is OH (i.e. Table 3, row 5) according to the positions defined by all rows of Table 4.













1
(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]-1-phenylazetidin-2-one


2
(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]-1-phenylazetidin-2-one


3
(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]-1-phenylazetidin-2-one


4
(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]-1-phenylazetidin-2-one


5
(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]-1-phenylazetidin-2-one


6
(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]-1-phenylazetidin-2-one









Table 10 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is H, R4 is OH and R5 is D-glucitol (i.e. Table 3, row 6) according to the positions defined by all rows of Table 4.













1
(1S)-1,5-anhydro-1-(3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-



phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-2-yl)-D-glucitol


2
(1S)-1,5-anhydro-1-(3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-



phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol


3
(1S)-1,5-anhydro-1-(3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-



phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-4-yl)-D-glucitol


4
(1S)-1,5-anhydro-1-(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-



phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-2-yl)-D-glucitol


5
(1S)-1,5-anhydro-1-(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-



phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol


6
(1S)-1,5-anhydro-1-(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-



phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-4-yl)-D-glucitol









Table 11 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is H, R4 is OH and R5 is SO3H (i.e. Table 3, row 7) according to the positions defined by all rows of Table 4.













1
3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-2-sulfonic acid


2
3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-3-sulfonic acid


3
3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-4-sulfonic acid


4
2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-2-sulfonic acid


5
2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-3-sulfonic acid


6
2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-4-sulfonic acid









Table 12 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is H, R4 is OH and R5 is PO3H2 (i.e. Table 3, row 8) according to the positions defined by all rows of Table 4.













1
(3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-2-yl)phosphonic acid


2
(3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-3-yl)phosphonic acid


3
(3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-4-yl)phosphonic acid


4
(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-2-yl)phosphonic acid


5
(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-3-yl)phosphonic acid


6
(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-



phenylazetidin-2-yl}biphenyl-4-yl)phosphonic acid









Table 13 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is Cl, R4 is OH and R5 is OH (i.e. Table 3, row 9) according to the positions defined by all rows of Table 4.













1
(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


2
(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


3
(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


4
(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


5
(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


6
(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


7
(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(3-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


8
(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(3-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


9
(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(3-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


10
(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(3-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


11
(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(3-cjlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


12
(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(3-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


13
(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(4-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


14
(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(4-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


15
(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(4-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


16
(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(4-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


17
(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(4-chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one


18
(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-



3-[(3S)-3-(4chlorophenyl)-3-



hydroxypropyl]-1-phenylazetidin-2-one









Table 14 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is Cl, R4 is OH and R5 is D-glucitol (i.e. Table 3, row 10) according to the positions defined by all rows of Table 4.













1
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



3′-hydroxybiphenyl-2-yl)-D-glucitol


2
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



3′-hydroxybiphenyl-3-yl)-D-glucitol


3
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



3′-hydroxybiphenyl-4-yl)-D-glucitol


4
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



2′-hydroxybiphenyl-2-yl)-D-glucitol


5
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



2′-hydroxybiphenyl-3-yl)-D-glucitol


6
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



2′-hydroxybiphenyl-4-yl)-D-glucitol


7
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



3′-hydroxybiphenyl-2-yl)-D-glucitol


8
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



3′-hydroxybiphenyl-3-yl)-D-glucitol


9
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



3′-hydroxybiphenyl-4-yl)-D-glucitol


10
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



2′-hydroxybiphenyl-2-yl)-D-glucitol


11
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



2′-hydroxybiphenyl-3-yl)-D-glucitol


12
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



2′-hydroxybiphenyl-4-yl)-D-glucitol


13
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



3′-hydroxybiphenyl-2-yl)-D-glucitol


14
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



3′-hydroxybiphenyl-3-yl)-D-glucitol


15
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



3′-hydroxybiphenyl-4-yl)-D-glucitol


16
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



2′-hydroxybiphenyl-2-yl)-D-glucitol


17
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



2′-hydroxybiphenyl-3-yl)-D-glucitol


18
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-



hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-



2′-hydroxybiphenyl-4-yl)-D-glucitol









Table 15 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is Cl, R4 is OH and R5 is SO3H (i.e. Table 3, row 11) according to the positions defined by all rows of Table 4.













1
4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid


2
4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid


3
4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid


4
4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid


5
4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid


6
4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid


7
4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid


8
4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid


9
4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid


10
4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid


11
4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid


12
4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid


13
4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid


14
4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid


15
4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid


16
4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid


17
4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenlyazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid


18
4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid









Table 16 lists the compounds disclosed by substitution of Formula VIII wherein R1 is H, R2 is Cl, R4 is OH and R5 is PO3H2 (i.e. Table 3, row 12) according to the positions defined by all rows of Table 4.













1
(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid


2
(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid


3
(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid


4
(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid


5
(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid


6
(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid


7
(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid


8
(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid


9
(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid


10
(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid


11
(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid


12
(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid


13
(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid


14
(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid


15
(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid


16
(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid


17
(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid


18
(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-



phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid









Table 17 lists the compounds disclosed by substitution of Formula VIII wherein R1 is F, R2 is H, R4 is OH and R5 is OH (i.e. Table 3, row 13) according to the positions defined by all rows of Table 4.













1
(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-1-(2-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


2
(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-1-(2-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


3
(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-1-(2-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


4
(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-1-(2-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


5
(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-1-(2-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


6
(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-1-(2-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


7
(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-1-(3-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


8
(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-1-(3-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


9
(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-1-(3-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


10
(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-1-(3-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


11
(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-1-(3-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


12
(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-1-(3-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


13
(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


14
(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


15
(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


16
(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


17
(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one


18
(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-



3-hydroxy-3-phenylpropyl]azetidin-2-one









Table 18 lists the compounds disclosed by substitution of Formula VIII wherein R1 is F, R2 is H, R4 is OH and R5 is D-glucitol (i.e. Table 3, row 14) according to the positions defined by all rows of Table 4.













1
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-



2-yl)-D-glucitol


2
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-



3-yl)-D-glucitol


3
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-



4-yl)-D-glucitol


4
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-



2-yl)-D-glucitol


5
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-



3-yl)-D-glucitol


6
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-



4-yl)-D-glucitol


7
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-



2-yl)-D-glucitol


8
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-



3-yl)-D-glucitol


9
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-



4-yl)-D-glucitol


10
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-



2-yl)-D-glucitol


11
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-



3-yl)-D-glucitol


12
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-



4-yl)-D-glucitol


13
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-



2-yl)-D-glucitol


14
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-



3-yl)-D-glucitol


15
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-



4-yl)-D-glucitol


16
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-



2-yl)-D-glucitol


17
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-



3-yl)-D-glucitol


18
(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-



hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-



4-yl)-D-glucitol









Table 19 lists the compounds disclosed by substitution of Formula VIII wherein R1 is F, R2 is H, R4 is OH and R5 is SO3H (i.e. Table 3, row 15) according to the positions defined by all rows of Table 4.













1
4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid


2
4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid


3
4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid


4
4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid


5
4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid


6
4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid


7
4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid


8
4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid


9
4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid


10
4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid


11
4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid


12
4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid


13
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid


14
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid


15
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid


16
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid


17
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid


18
4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-



oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid









Table 20 lists the compounds disclosed by substitution of Formula VIII wherein R1 is F, R2 is H, R4 is OH and R5 is PO3H2 (i.e. Table 3, row 16) according to the positions defined by all rows of Table 4.













1
(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid


2
(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid


3
(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid


4
(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid


5
(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid


6
(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid


7
(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid


8
(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid


9
(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid


10
(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid


11
(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid


12
(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid


13
(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid


14
(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid


15
(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid


16
(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid


17
(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid


18
(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-



4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid

## Claims

1. A compound of formula:



wherein





represents an aryl or heteroaryl residue;
Ar represents an aryl residue;
R1 represents one, two, three, four or five residues chosen independently from H, halogen, —OH, loweralkyl, OCF2H, OCF3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, —PO3H2, —SO3H, and —B(OH)2,
R2 represents one, two, three, four or five residues chosen independently from H, halogen, —OH, loweralkyl, OCF2H, OCF3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO3H2, —SO3H, and —B(OH)2,;
R4 represents one, two, three or four residues chosen independently from H, halogen, —OH, loweralkyl, —O-loweralkyl, hydroxyloweralkyl, —CN, CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO3H2, —SO3H, and —B(OH)2,
R5g represents one, two, three, four or five residues on Ar chosen independently from halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO3H2, —SO3H, and —B(OH)2;
U is (C2-C6)-alkylene in which one or more individual —CH2— may be replaced by a radical chosen from —S—, —S(O)—, —SO2—, —O—, —C(═O)—, —CHOH—, —NH—, CHF, CF2, —CH(O-loweralkyl)-, —CH(O-loweracyl)-, —CH(OSO3H)—, —CH(OPO3H2)—, —CH(OB(OH)2)—, or —NOH—;
with the provisos that
R5g cannot be —CN; 2,5-dimethoxy; 2,6-dimethoxy or halogen when neither of R4 and R5g includes an —OH, amino, loweralkyl, O-loweralkyl, alkoxycarbonyl, —B(OH)2, —PO3H2 or —SO3H group;
R5g cannot be 2-hydroxy when





represents a 2,5-thienyl residue;
adjacent —CH2— residues in U cannot be replaced by —S—, —S(O)—, —SO2— or —O—; and
—S—, —S(O)—, —SO2—, —O— and —NH— residues in U cannot be separated only by a single carbon.

2. A compound of formula:



wherein





represents an aryl or heteroaryl residue;
Ar represents an aryl residue;
R1 represents one, two, three, four or five residues chosen independently from H, halogen, —OH, loweralkyl, OCF2H, OCF3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, —PO3H2, —SO3H, and —B(OH)2,
R2 represents one, two, three, four or five residues chosen independently from H, halogen, —OH, loweralkyl, OCF2H, OCF3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO3H2, —SO3H, and —B(OH)2,
R4f is —OH, —SH or —B(OH)2;
R5h represents one, two, three, four or five residues on Ar chosen independently from hydrogen, halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, —CF3, nitro, —SH, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, —PO3H2, —SO3H, and —B(OH)2,
U is (C2-C6)-alkylene in which one or more —CH2— may be replaced by a radical chosen from —S—, —S(O)—, —SO2—, —O—, —C(═O)—, —CHOH—, —NH—, CHF, CF2, —CH(O-loweralkyl)-, —CH(O-loweracyl)-, —CH(OSO3H)—, —CH(OPO3H2)—, —CH(OB(OH)2)—, or —NOH—,
with the provisos that:
adjacent —CH2— residues in U cannot be replaced by —S—, —S(O)—, —SO2— or —O—; and
—S—, —S(O)—, —SO2—, —O— and —NH— residues in U cannot be separated only by a single carbon.

3. A compound according to claim 1 wherein U is chosen from —CH2CH2CH(OH)—, —SCH2CH2—, —S(O)CH2CH2—, —S(O)CH2CH(OH)—, —SCH2C(═O)—, —SCH2CH(OH)—, —CH(OH)CH2CH2—, —CH(OH)CH2CH(OH)—, —(CH2)3CH(OH)— and —(CH2)4—, wherein the left end of the string is the point of attachment to the azetidinone ring and the right end of the string is the point of attachment to the phenyl ring.

4. A compound according to claim 3 wherein U is —CH2CH2CH(OH)—.

5. A compound of formula:



wherein
R2b represents one or two residues chosen independently from H, halogen, —OH, loweralkyl, OCF2H, OCF3, CF2H, CH2F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy;
R3 is chosen from H, —OH, fluoro, —O-loweralkyl and —O-acyl;
one of R1b, R4b and R5b is R12 and the other two of R1b, R4b and R5b are chosen independently from hydrogen, halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF3, nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, and benzyloxy;
R6a is C1, to C20 hydrocarbon;
R7a is alkyl;
R8a is alkyl;
R12 is (C0 to C30)alkylene-Gn in which one or more —CH2— residues in said alkylene may be replaced by —S—, —SO—, SO2—, —O—, —NH—, —N(alkyl)-, —N(phenyl)-, —N(alkylphenyl)-, —C(═O)—, —C(═S), CH═CH—, —C≡C—, phenylene or —N[(C═O)alkyleneCOOH]—;
G is chosen from —SO3H, —PO3H2, —O—PO3H2, —COOH, —C(N═H)NH2, —N+R6aR7aR8aX−;
n is 1, 2, 3, 4 or 5 and
X is an anion.

6. A compound according to claim 1 wherein R1, R2 and R4 are chosen from H, halogen, —OH, and methoxy.

7. A compound according to claim 1 wherein at least one of R1, R2, R4 and R5g is chosen from SO3H and PO3H2.

8. A compound according to claim 5 wherein R3 is chosen from hydrogen and hydroxy.

9. A compound according to claim 1 wherein R4 is hydrogen.

10. A compound according to claim 1 wherein R4 is OH.

11. A compound according to claim 1 of formula

12. A compound according to claim 11 of formula

13. A compound according to claim 12 of formula

14. A compound according to claim 12 of formula

15. A compound according to claim 14 of formula

16. A compound according to claim 15 wherein R1 is H.

17. A compound according to claim 1 of formula



wherein
R1i and R2i are independently chosen from H, F, Cl, CH3, CN, OCH3, OCF3, OCF2H, CF3, CF2H, and CH2F;
R4i is chosen from H, F, Cl, CH3, OCH3, OH, B(OH)2, and SH; and
R5i is chosen from OH, SO3H, PO3H2, CH2OH, COOH, and CHO.

18. A compound according to claim 17 wherein R5i is —OH of formula

19. A compound according to claim 17 wherein R5i is —SO3H of formula

20. A compound according to claim 17 wherein R5i is —PO3H2 of formula

21. A compound according to claim 18 wherein R5i is —OH of formula

22. A compound according to claim 19 wherein R5i is —SO3H of formula

23. A compound according to claim 20 wherein R5i is —PO3H2 of formula

24. A compound according to claim 21 wherein R5i is —OH of formula

25. A compound according to claim 21 wherein R5i is —OH of formula

26. A compound according to claim 22 wherein R5i is —SO3H of formula

27. A compound according to claim 22 wherein R5i is —SO3H of formula

28. A compound according to claim 23 wherein R5i is —PO3H2 of formula

29. A compound according to claim 23 wherein R5i is —PO3H2 of formula

30. A compound according to claim 17 wherein R4i is OH.

31. A compound according to claim 30 wherein R4i is ortho to the azetidine ring.

32. A compound according to claim 17 wherein R5i is an ortho substituent.

33. A compound according to claim 17 wherein R5i is a meta substituent.

34. A compound according to claim 17 wherein R5i is a para substituent.

35. A compound according to claim 17 wherein R1i and R2i are chosen from H, Cl and F.

36. A compound according to claim 35 wherein R1i is H.

37. A compound according to claim 1 of formula




wherein
R1 and R2 are chosen from H, halogen, —OH, and methoxy;
R3 is chosen from hydrogen and hydroxy; and
R5 is chosen from halogen, hydroxy, loweralkyl, —O-loweralkyl, CF3, alkylsulfonyl and arylsulfonyl.

38. A compound according to claim 37 of formula

39. A compound according to claim 38 of formula

40. A compound according to claim 5 wherein
R1b is R12;
R2b and R4b are chosen from H, halogen, —OH, and methoxy;
R12 is (C6 to C20)alkylene-G in which one or more —CH2— residues in said alkylene may be replaced by —O—, —NH—, —N(alkyl)-, —C(═O)— or —CH═CH—; and
G is chosen from —SO3H, and —PO3H2.

41. A compound according to claim 1 wherein the substituents at positions 3 and 4 of the azetidin-2-one are in a cis relative configuration.

42. A compound according to claim 1 wherein the substituents at positions 3 and 4 of the azetidin-2-one are in a trans relative configuration.

43. A compound according to claim 42 wherein the substituent at position 3 of the azetidin-2-one is of the R absolute configuration and the substituent at position 4 of the azetidin-2-one is of the S absolute configuration.

44. A compound according to claim 1 wherein U is (C2-C6)-alkylene in which at least one —CH2— is replaced by —CHOH—.

45. A compound chosen from the group consisting of:
(6) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2′,3′,4′-trimethoxybiphenyl-4-yl)azetidin-2-one,
(7) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one,
(8) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-mercaptobiphenyl-4-yl)azetidin-2-one,
(9) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-methoxybiphenyl-4-yl)azetidin-2-one,
(10) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-nitrobiphenyl-4-yl)azetidin-2-one,
(11) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxy-3′-methoxybiphenyl-4-yl)azetidin-2-one,
(12) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-vinylbiphenyl-4-yl)azetidin-2-one,
(13) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3′-(hydroxymethyl)biphenyl-4-yl]azetidin-2-one,
(14) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3′-(methylsulfonyl)biphenyl-4-yl]azetidin-2-one,
(15) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(2-naphthyl)phenyl]azetidin-2-one,
(16) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4′-(hydroxymethyl)biphenyl-4-yl]azetidin-2-one,
(17) (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4′-(methylsulfonyl)biphenyl-4-yl]azetidin-2-one,
(18) (3R,4S)-1-biphenyl-4-yl-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one,
(19) (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one,
(20) (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3-hydroxy-3′-(methylsulfonyl)biphenyl-4-yl]-1-phenylazetidin-2-one,
(21) (3R,4S)-4-(2′,3′-difluorobiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(22) (3R,4S)-4-(2′,4′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(23) (3R,4S)-4-(2′-bromo-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(24) (3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(26) (3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one,
(27) (3R,4S)-4-(3′,5′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(28) (3R,4S)-4-(3′,5′-dimethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(29) (3R,4S)-4-(3′-butoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(30) (3R,4S)-4-(3′-ethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(31) (3R,4S)-4-(3′-fluoro-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(32) (3R,4S)-4-(3′-fluoro-5′-methoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(33) (3R,4S)-4-(4′-aminobiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(34) (3R,4S)-4-(4′-ethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(35) (3R,4S)-4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(36) (3R,4S)-4-[4′-(dimethylamino)biphenyl-4-yl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one,
(37) (4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)boronic acid,
(38) (4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)phosphonic acid,
(39) (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid,
(40) (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)boronic acid,
(41) (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonic acid,
(47) 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-3-hydroxybiphenyl-4-carboxylic acid,
(48) 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-4-hydroxybiphenyl-3-carboxylic acid,
(49) 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-5-hydroxybiphenyl-2-carbaldehyde,
(50) 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-carbaldehyde,
(51) 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-carboxylic acid,
(55) 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-4-carboxylic acid,
(59) methyl 4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-4-carboxylate,
(61) N-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)acetamide, and
(62) (4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid.

46. A compound according to claim 5 wherein X is a pharmaceutically acceptable anion.

47. A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

48. A pharmaceutical formulation according to claim 47 additionally comprising an inhibitor of cholesterol biosynthesis.

49. A pharmaceutical formulation according to claim 48 wherein said inhibitor of cholesterol biosynthesis is an HMG-CoA reductase inhibitor.

50. A pharmaceutical formulation according to claim 49 wherein said HMG-CoA reductase inhibitor is chosen from the group consisting of lovastatin, simvastatin, pravastatin, rosuvastatin, mevastatin, atorvastatin, cerivastatin, pitavastatin, fluvastatin, bervastatin, crilvastatin, carvastatin, rivastatin, sirrivastatin, glenvastatin and dalvastatin.

51. A pharmaceutical formulation according to claim 47 additionally comprising at least one bile acid sequestrant.

52. A pharmaceutical formulation according to claim 51 wherein the at least one bile acid sequestrant is selected from the group consisting of cholestyramine, colestipol, colesevelam hydrochloride and mixtures thereof.

53. A pharmaceutical formulation according to claim 47 additionally comprising at least one nicotinic acid or derivative thereof selected from the group consisting of nicotinic acid, niceritrol, nicofuranose, acipimox and mixtures thereof.

54. A pharmaceutical formulation according to claim 47 additionally comprising at least one peroxisome proliferator-activated receptor alpha activator.

55. A pharmaceutical formulation according to claim 54 wherein said peroxisome proliferator-activated receptor alpha activator is a fibric acid derivative.

56. A pharmaceutical formulation according to claim 55 wherein said fibric acid derivative is selected from the group consisting of fenofibrate, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, clinofibrate, binifibrate, lifibrol and mixtures thereof.

57. A pharmaceutical formulation according to claim 47 additionally comprising at least one cholesterol ester transfer protein (CETP) inhibitor.

58. An article of manufacture comprising a container, instructions, and a pharmaceutical formulation according to claim 47, wherein the instructions are for the administration of the pharmaceutical formulation for a purpose chosen from: the prevention or treatment of a disorder of lipid metabolism; reducing the plasma or tissue concentration of at least one 5α-cholestanol or cholest-5-enol other than (3β)-cholest -5ene-3-ol; reducing the blood plasma or serum concentrations of LDL cholesterol; reducing the concentrations of cholesterol and cholesterol ester in the blood plasma or serum; increasing the fecal excretion of cholesterol; reducing the incidence of coronary heart disease-related events; reducing blood plasma or serum concentrations of C-reactive protein (CRP); treating or preventing vascular inflammation; reducing blood plasma or serum concentrations of triglycerides; increasing blood plasma or serum concentrations of HDL cholesterol; reducing blood plasma or serum concentrations of apolipoprotein B.

59. A method for treating a disorder of lipid metabolism comprising administering to a mammal a therapeutically effective amount of a compound having the formula show in claim 1, wherein said disorder is chosen from hypercholesterolemia, hyperlipidemia, arteriosclerosis, and sitosterolemia.

60. A method according to claim 59, wherein said disorder of lipid metabolism is hyperlipidemia.

61. A method according to claim 59, wherein said disorder of lipid metabolism is arteriosclerosis.

62. A method according to claim 59, wherein said disorder of lipid metabolism is sitosterolemia.

63. A method for inhibiting the absorption of cholesterol from the intestine of a mammal, which comprises administering an effective cholesterol-absorption-inhibiting amount of a compound according to claim 1 to the mammal.

64. A method of reducing plasma or tissue concentration of at least one non-cholesterol sterol or 5α-stanol comprising administering to a mammal in need of such treatment an effective amount of a compound according to any of claims claim 1.

65. A method for reducing the blood plasma or serum concentrations of LDL cholesterol in a mammal, which comprises administering an effective cholesterol reducing amount of a compound according to claim 1 to the mammal.

66. A method for reducing the concentrations of cholesterol and cholesterol ester in the blood plasma or serum of a mammal, which comprises administering an effective cholesterol and cholesterol ester reducing amount of a compound according to claim 1 to the mammal.

67. A method for increasing the fecal excretion of cholesterol in a mammal, which comprises administering an effective cholesterol fecal excretion increasing amount of a compound according to claim 1 to the mammal.

68. A compound of formula




wherein
U is (C2-C6)-alkylene in which one or more —CH2— may be replaced by a radical chosen from —S—, —S(O)—, —SO2—, —O—, —C(═O)—, —CHOH—, —NH—, CHF, CF2, —CH(O-loweralkyl)-, —CH(O-loweracyl)-, —CH(OSO3H)—, —CH(OPO3H2)—, —CH(OB(OH)2)—, or —NOH—;
R1j and R2j are independently chosen from H, F and Cl; and
R5j is chosen from SO3H, and PO3H2.

69. A compound according to claim 68 wherein R1j is H.

70. A compound according to claim 68 wherein R2j is F.

71. A method according to claim 59, wherein said diaorder of lipid metabolism is hypercholestetolemia.