# Patent

## Title
Vitamin D receptor modulators

## Abstract

The present invention relates to novel, non-secosteroidal, diaryl compounds with vitamin D receptor (VDR) modulating activity that are less hypercalcemic than 1α,25 dihydroxy vitamin D3. These compounds are useful for treating bone disease and psoriasis.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This patent application claims the benefit of priority under Title 35 United States Code, section 119(e), of Provisional Patent Application No. 60/429,041 filed Nov. 22, 2002, the disclosure of which is incorporated herein by reference and PCT Application Serial No. PCT/US2003/035055, filed Nov. 20, 2003.


BACKGROUND OF THE INVENTION
Vitamin D3 Receptor (VDR) is a ligand dependent transcription factor that belongs to the superfamily of nuclear hormone receptors. The VDR protein is 427 amino acids, with a molecular weight of  ̃50 kDa. The VDR ligand, 1α,25-dihydroxyvitamin D3 (the hormonally active form of Vitamin D) has its action mediated by its interaction with the nuclear receptor known as Vitamin D receptor (“VDR”). The VDR ligand, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) acts upon a wide variety of tissues and cells both related to and unrelated to calcium and phosphate homeostasis.
The activity 1α,25-dihydroxyvitamin D3 in various systems suggests wide clinical applications. However, use of conventional VDR ligands is hampered by their associated toxicity, namely hypercalcemia (elevated serum calcium). Currently, 1α,25(OH)2D3, marketed as Rocaltrol® pharmaceutical agent (product of Hoffmann-La Roche), is administered to kidney failure patients undergoing chronic kidney dialysis to treat hypocalcemia and the resultant metabolic bone disease. Other therapeutic agents, such as Calcipotriol® (synthetic analog of 1α,25(OH)2D3) show increased separation of binding affinity on VDR from hypercalcemic activity.
Chemical modifications of 1α,25(OH)2D3 have yielded analogs with attenuated calcium mobilization effects (R. Bouillon et. al., Endocrine Rev. 1995, 16, 200-257). One such analog, Dovonex® pharmaceutical agent (product of Bristol-Meyers Squibb Co.), is currently used in Europe and the United States as a topical treatment for mild to moderate psoriasis (K. Kragballe et. al., Br. J. Dermatol. 1988, 119, 223-230).
Other Vitamin D3 mimics have been described in the publication, Vitamin D Analogs: Mechanism of Action of Therapeutic Applications, by Nagpal, S.; Lu, J.; Boehm, M. F., Curr. Med. Chem. 2001, 8, 1661-1679.
Although some degree of separation between the beneficial action and calcium raising (calcemic) effects has been achieved with these VDR ligands, to date the separation has been insufficient to allow for oral administration to treat conditions such as osteoporosis, cancers, leukemias, and severe psoriasis.
One example of a major class of disorder that could benefit from VDR mediated biological efficacy in the absence of hypercalcemia is osteoporosis. Osteoporosis is a systemic disorder characterized by decreased bone mass and microarchitectural deterioration of bone tissue leading to bone fragility and increased susceptibility to fractures of the hip, spine, and wrist (World Health Organization WHO 1994). Osteoporosis affects an estimated 75 million people in the United States, Europe, and Japan.
Within the past few years, several antiresorptive therapies have been introduced. These include bisphosphonates, hormone replacement therapy (HRT), a selective estrogen receptor modulator (SERM), and calcitonins. These treatments reduce bone resorption, bone formation, and increase bone density. However, none of these treatments increase true bone volume nor can they restore lost bone architecture.
Another major disorder that could benefits from VDR mediated biological activity is psoriasis. Psoriasis is one of the most common dermatologic diseases and is a chronic inflammatory skin condition characterized by erythematous, sharply demarcated papules and rounded plaques, covered by silvery micaceous scale.
Synthetic VDR ligands with reduced calcemic potential have been synthesized. For example, a class of bis-phenyl compounds stated to mimic 1α,25-dihydroxyvitamin D3 is described in U.S. Pat. No. 6,218,430 and the article; “Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1α,25-Dihydroxyvitamin D3” by Marcus F. Boehm, et. al., Chemistry & Biology 1999, Vol 6, No. 5, pgs. 265-275.
Synthetic VDR ligands having an aryl-thiophene nucleus are described in U.S. provisional patent application Ser. No. 60/384,151, filed 29 May 2002.
There remains a need for improved treatments using alternative or improved pharmaceutical agents that mimic 1α,25-dihydroxyvitamin D3 to stimulate bone formation, restore bone quality, and treat other diseases without the attendant disadvantage of hypercalcemia.
SUMMARY OF THE INVENTION
Novel compounds having a nucleus of formula “(A)” have been found effective as Vitamin D Receptor (VDR) modulators:




The compounds of the invention with VDR modulating activities are represented by formula (I)





wherein the variables R, R′, R1, R2, ZB, and ZC are as hereinafter defined. It is a discovery of this invention that compounds described herein display the desirable cell differentiation and antiproliferative effects of 1,25(OH)2D3 with reduced calcium mobilization (calcemic) effects if substituent ZC possesses a carbon atom linked group that is directly connected (i.e., with no intervening non-carbon atom) to the aryl nucleus.

In another aspect, the present invention is directed towards pharmaceutical compositions containing pharmaceutically effective amounts of compounds of formulae (I) or a pharmaceutically acceptable salt or prodrug thereof, either singly or in combination, together with pharmaceutically acceptable carriers and/or auxiliary agents.
Another aspect of the invention is a pharmaceutical formulation for treatment or prevention of osteoporosis containing pharmaceutically effective amounts of the vitamin D receptor modulator compound of formula (I) alone or together with pharmaceutically effective amounts of co-agents conventionally used for the treatment of osteoporosis.
Another aspect of the invention is a pharmaceutical formulation for treatment or prevention of psoriasis containing pharmaceutically effective amounts of the vitamin D receptor modulator compound of formula (I) alone or together with pharmaceutically effective amounts of co-agents conventionally used for the treatment of psoriasis.
Another aspect of the invention is a pharmaceutical formulation for treatment or prevention of prostate cancer containing pharmaceutically effective amounts of the vitamin D receptor modulator compound of formula (I) alone or together with pharmaceutically effective amounts of co-agents conventionally used for the treatment of prostate cancer.
Another aspect of the invention is to use the compounds of the invention to treat disease states responsive to Vitamin D receptor ligands.
Another aspect of the invention is the prevention and treatment of acne, actinic keratosis, alopecia, Alzheimer's disease, autoimmune induced diabetes, bone fracture healing, breast cancer, Crohn's disease, colon cancer, Type I diabetes, host-graft rejection, hypercalcemia, Type II diabetes, leukemia, multiple sclerosis, insufficient sebum secretion, osteomalacia, insufficient dermal firmness, insufficient dermal hydration, myelodysplastic syndrome, psoriatic arthritis, renal osteodystrophy, rheumatoid arthritis, scleroderma, seborrheic dermatitis, skin cancer, systemic lupus erythematosis, ulcerative colitis and wrinkles; by administering to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula I.


DETAILED DESCRIPTION OF THE INVENTION
Definitions:
The term, “abscess” refers to adverse complications often associated with surgery, trama, or diseases that predispose the host to abscess formation from encapsulated bacteria lymphocytes, macrophages, and etc.
The term, “adhesion” refers to the adverse and abnormal union of surfaces normally separate by the formation of new fibrous tissue resulting from an inflammatory process.
The term, “Mustard” is inclusive of both sulfur mustards and nitrogen mustards, either alone or in any combination. Exemplary of such compounds are the vesicants; bis(2-chloroethyl) sulfide (Chemical Agent Symbol HD), Cl(CH2)2S(CH2)2Cl 1,2-bis(2-chloroethylthio)ethane (Chemical Agent Symbol Q), Cl(CH2)2S(CH2)2S(CH2)2Cl; bis(2-chloroethylthioethyl)ether, Cl(CH2)2S(CH2)O(CH2)2S(CH2)2Cl (Chemical Agent Symbol T); tris(2-chloroethyl)amine (Chemical Agent Symbol HN3) N(CH2CH2Cl)3; N-methyl-2,2′-dichlorodiethylamine (Chemical Agent Symbol NH2); and 2,2′-dichlorotriethylamine, CH3CH2N(CH2CH2Cl)2 (Chemical Agent Symbol NH1).
The term “branched C3-C5 alkyl” is an alkyl group selected from 1-methylethyl; 1-methylpropyl; 2-methylpropyl; 1,1-dimethylethyl; 1,1-dimethylpropyl; 1,2-dimethylpropyl; or 2,2-dimethylpropyl. Preferred branched C3-C5 alkyl groups are 2-methylpropyl and 1,1-dimethylethyl, with the 1,1-dimethylethyl group being most preferred.
The term, “branched alkyl terminal group” is used to identify the substituent ZB of Formula I of the Invention. The defining characteristic of the branched alkyl terminal group is that it is placed on the diphenyl nucleus other than on the phenyl ring bearing the substituent ZC as shown, for example, in the structural formula (B);




The term, “carbon atom linked group” is used to identify the chemical substituent ZC in the Formula I definition of compounds of the invention. Its defining characteristic is a carbon atom as the first atom and point of attachment to the aryl ring to which it is attached. For example in the structural formula (C):




the arrow identifies the carbon atom linked directly to the aryl nucleus of formula (I). All compounds of the invention contain a carbon atom linked group as the ZC substituent.

The term “alkenyl” refers to aliphatic groups wherein the point of attachment is a carbon-carbon double bond, for example vinyl, 1-propenyl, and 1-cyclohexenyl. Alkenyl groups may be straight-chain, branched-chain, cyclic, or combinations thereof, and may be optionally substituted. Suitable alkenyl groups have from 2 to about 20 carbon atoms.
The term “C1-C5 alkyl” refers to saturated aliphatic groups including straight-chain, branched-chain, and cyclic groups and any combinations thereof. Alkyl groups may further be divided into “primary”, “secondary”, and “tertiary” alkyl groups. In primary alkyl groups, the carbon atom of attachment is substituted with zero (methyl) or one organic radical. In secondary alkyl groups, the carbon atom of attachment is substituted with two organic radicals. In tertiary alkyl groups, the carbon atom of attachment is substituted with three organic radicals. Examples of C1-C5 alkyl groups are methyl, ethyl, n-propyl, 1-methylethyl; n-butyl, 1-methylpropyl; 2-methylpropyl; 1,1-dimethylethyl; n-amyl, 1,1-dimethylpropyl; 1,2-dimethylpropyl; and 2,2-dimethylpropyl.
The term, “bond” when used to describe a divalent linking group indicates the absence of a divalent atom, for example in the group




when L1 is —O—, L2 is a bond, L3 is —CH2—, and RB is tBu the structural formula is





The term “cycloalkyl” includes organic radicals such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term, “cycloalkenyl” includes organic radicals such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.
The term, “C1-C5 fluoroalkyl” is an alkyl group containing fluorine and includes organic radicals such as —CF3, —CHF2, —CH2F, —CF2CF3, —CHFCF3, —CH2CF3, —CH2CHF2, and —CH2CH2F, with —CF3 being preferred.
The abbreviation, “Me” means methyl.
The abbreviation, “Et” means ethyl.
The abbreviation, “iPr” means 1-methylethyl.
The abbreviation, “tBu” means 1,1-dimethylethyl.
The abbreviation, “3Me3OH44DiMe-Pentyl” means 3-methyl-3-hydroxy-4,4-dimethylpentyl.
The abbreviation, “3Me3OH44DiMe-Pentenyl” means 3-methyl-3-hydroxy-4,4-dimethylpentenyl.
The abbreviation, “3Me3OH44DiMe-Pentynyl” means 3-methyl-3-hydroxy-4,4-dimethylpentyl.
The abbreviation, “3Et3OH44DiMe-Pentyl” means 3-ethyl-3-hydroxy-4,4-dimethylpentyl.
The abbreviation, “3Et3OH44DiMe-Pentenyl” means 3-ethyl-3-hydroxy-4,4-dimethylpentenyl.
The abbreviation, “3Et3OH44DiMe-Pentynyl” means 3-ethyl-3-hydroxy-4,4-dimethylpentynyl.
The term, “—CH2—C(O)—N-pyrrolidine” refers to the radical represented by the structural formula:




The term, “—CH2—N-pyrrolidin-2-one” refers to the radical represented by the structural formula:




The term, “—CH2-(1-methylpyrrolidin-2-one-3-yl)” refers to the organic radical represented by the structural formula:




The term, “1,3,4-oxadiazolin-2-one-5-yl” refers to the organic radical represented by the structural formula:




The term, “1,3,4-oxadiazolin-2-thione-5-yl” refers to the organic radical represented by the structural formula:




The term, “imidazolidine-2,4-dione-5-yl” refers to the organic radical represented by the structural formula:




The term, “isoxazol-3-ol-5-yl” refers to the organic radical represented by the structural formula:




The term, “3-methyl-3-hydroxy-4,4-dimethylpentyl” refers to the radical having the structural formula:




The term, “3-methyl-3-hydroxy-4,4-dimethylpentenyl.” refers to the radical having the structural formula (both cis and trans isomers):




The term, “3-methyl-3-hydroxy-4,4-dimethylpentyl” refers to the radical having the structural formula:




The term, “3-ethyl-3-hydroxy-4,4-dimethylpentynyl” refers to the radical having the structural formula:




The term, “3-ethyl-3-hydroxy-4,4-dimethylpentenyl” refers to the radical having the structural formula (both cis and trans isomers):




The term, “3-ethyl-3-hydroxy-4,4-dimethylpentynyl” refers to the radical having the structural formula:




The term, “-5-ethylidene-1,3-thiazolidine-2,4-dione, refers to the radical represented by the structural formula:




The dotted line symbol crossing a solid line representing a bond




means that the bond so marked is the bond of attachment.

The structural formula representing the compounds of the invention with or without open display of all pendant hydrogen atoms are equivalent, for example:




is the same compound as




The term, “mammal” includes humans.
The term “ester” refers to compounds of the general formula; RO—C(O)R′, prepared for example, where a hydroxy group of an acid is replaced with an alkoxide group. For example, a carboxylic ester is one in which the hydroxy group of a carboxylic acid is replaced with an alkoxide. Esters may derive from any acid comprising one or more hydroxy groups: for example, carbonic acid, carbamic acids, phosphonic acids, and sulfonic acids.
The term “halo” refer to fluorine, chlorine, bromine, and iodine.
The term, “C1-C5 fluoroalkyl” is an alkyl group containing fluorine and includes organic radicals such as —CF3, —CHF2, —CH2F, —CF2CF3, —CHFCF3, —CH2CF3, —CH2CHF2, and —CH2CH2F, with —CF3 being preferred.
The term, “(Acidic Group)” means a carbon atom linked organic group that acts as a proton donor capable of hydrogen bonding. Illustrative of an (Acidic Group) is a group selected from the following:







Compounds of the Invention:

The compounds of the invention with vitamin receptor modulating (VDRM) activities are represented by formula (I) or a pharmaceutically acceptable salt or a prodrug derivative thereof:




wherein;

R and R′ are independently C1-C5 alkyl, C1-C5 fluoroalkyl, or together R and R′ form a substituted or unsubstituted, saturated or unsaturated carbocyclic ring having from 3 to 8 carbon atoms;
R1 and R2 are independently selected from the group consisting of hydrogen, halo, C1-C5 alkyl, C1-C5 fluoroalkyl, —O—C1-C5 alkyl, —S—C1-C5 alkyl, —O—C1-C5 fluoroalkyl, —CN, —NO2, acetyl, —S—C1-C5 fluoroalkyl, C2-C5 alkenyl, C3-C5 cycloalkyl, and C3-C5 cycloalkenyl;
ZB is a group represented by the formula:




wherein

-(L1), -(L2)-, and -(L3)- is each a divalent linking groups independently selected from the group consisting of




where m is 0, 1, or 2, and each R40 is independently hydrogen, C1-C5 alkyl, or C1-C5 fluoroalkyl;

RB is a branched C3-C5 alkyl;
ZC is a carbon atom linked group selected from



















In the preceding formula (I) the divalent linking groups -(L1)- and -(L2)- and -(L3)- are understood (in the case of those having more than one substituent) to be oriented in either direction, for example, where divalent linker (L1) has the identity —(CH2)m—O—, it may be configured:




Preferred compounds of the invention with VDR modulating activities are represented by formula (I) or a pharmaceutically acceptable salt or a prodrug derivative thereof:




wherein;

R and R′ are independently methyl, ethyl, propyl, or 1-methylethyl;
R1 and R2 are independently selected from the group consisting of hydrogen, fluoro, —Cl, —CF3, —CH2F, —CHF2, methoxy, ethoxy, vinyl, methyl, ethyl, propyl, 1-methylethyl, 1,1-dimethylethyl, butyl, 1-methylpropyl, 2-methylpropyl, or cyclopropyl;
ZB is a branched alkyl terminated group represented by the formula:




RB is 1-methylethyl; 1-methylpropyl; 2-methylpropyl; 1,1-dimethylethyl; 1,1-dimethylpropyl; 1,2-dimethylpropyl; 2,2-dimethylpropyl; 3-methyl-3-hydroxy-4,4-dimethylpentyl; 3-methyl-3-hydroxy-4,4-dimethylpentenyl; 3-methyl-3-hydroxy-4,4-dimethylpentyl; 3-ethyl-3-hydroxy-4,4-dimethylpentynyl; 3-ethyl-3-hydroxy-4,4-dimethylpentenyl; or 3-ethyl-3-hydroxy-4,4-dimethylpentynyl;
(L1) and (L2) and (L3) are independently divalent linking groups where
L1 is —O—, —CH2—, —CHOH—, —CH(Me)—, —C(O)—, or —C(Me)OH—;
L2 is —CH2—, —CHOH—, —CH(Me)—, —C(O)—, or —C(Me)OH—; or
L1 and L2 taken together is the group




L3 is a bond, —CH2—, —CHOH—, —CH(Me)— —C(O)—, or —C(Me)OH—;
ZC is a group selected from

    
    
        —C(O)CH2S(O)Me,
        —C(O)CH2S(O)Et,
        —C(O)CH2S(O)2Me,
        —C(O)CH2S(O)2Et,
        —C(O)CH2CH2S(O)Me,
        —C(O)CH2CH2S(O)Et,
        —C(O)CH2CH2S(O)2Me,
        —C(O)CH2CH2S(O)2Et,
        —C(O)CH(Me)CH2CO2H,
        —C(O)CH(Me)CH2CO2Me,
        —C(O)CH(Me)CH2CO2Et,
        —C(O)CH(Me)CH2CO21Pr,
        —C(O)CH(Me)CH2CO2tBu,
        —C(O)CH(Me)CH(Me)CO2H,
        —C(O)CH(Me)CH(Me)CO2Me,
        —C(O)CH(Me)CH(Me)CO2Et,
        —C(O)CH(Me)CH(Me)CO2iPr,
        —C(O)CH(Me)CH(Me)CO2tBu,
        —C(O)CH(Me)C(Me)2CO2H,
        —C(O)CH(Me)C(Me)2CO2Me,
        —C(O)CH(Me)C(Me)2CO2Et,
        —C(O)CH(Me)C(Me)2CO21Pr,
        —C(O)CH(Me)C(Me)2CO2tBu,
        —C(O)CH(Me)CH(Et)CO2H,
        —(O)CH(Me)CH(Et)CO2Me,
        —C(O)CH(Me)CH(Et)CO2Et,
        —C(O)CH(Me)CH(Et)CO2iPr,
        —C(O)CH(Me)CH(Et)CO2tBu,
        —C(O)C(O)OH,
        —(C(O)C(O)NH2,
        —C(O)C(O)NHMe,
        —C(O)C(O)NMe2,
        —C(O)NH2,
        —C(O)NMe2,
        —C(O)NH—CH2—C(O)OH,
        —C(O)NH—CH2—C(O)OMe,
        —C(O)NH—CH2—C(O)OEt,
        —C(O)NH—CH2—C(O)OiPr,
        —C(O)NH—CH2—C(O)OtBu,
        —C(O)NH—CH(Me)—C(O)OH,
        —C(O)NH—CH(Me)—C(O)OMe,
        —C(O)NH—CH(Me)—C(O)OEt,
        —C(O)NH—CH(Me)—C(O)iPr,
        —C(O)NH—CH(Me)—C(O)tBu,
        —C(O)NH—CH(Et)C(O)OH,
        —C(O)NH—C(Me)2—C(O)OH,
        —C(O)NH—C(Me)2—C(O)OMe,
        —C(O)NH—C(Me)2—C(O)OEt,
        —C(O)NH—C(Me)2—C(O)iPr,
        —C(O)NH—C(Me)2—C(O)tBu,
        —C(O)NH—CMe(Et)-C(O)OH,
        —C(O)NH—CH(F)—C(O)OH,
        —C(O)NH—CH(CF3)—C(O)OH,
        —C(O)NH—CH(OH)—C(O)OH,
        —C(O)NH—CH(cyclopropyl)-C(O)OH,
        —C(O)NH—C(Me)2—C(O)OH,
        —C(O)NH—C(Me)2—C(O)OH,
        —C(O)NH—CF(Me)-C(O)OH,
        —C(O)NH—C(Me)(CF3)—C(O)OH,
        —C(O)NH—C(Me)(OH)—C(O)OH,
        —C(O)NH—C(Me)(cyclopropyl)CO2H,
        —C(O)NMe-CH2—C(O)OH,
        —C(O)NMe-CH2—C(O)OMe,
        —C(O)NMe-CH2—C(O)OEt,
        —C(O)NMe-CH2—C(O)OiPr,
        —C(O)NMe-CH2—C(O)tBu,
        —C(O)NMe-CH(Me)-C(O)OH,
        —C(O)NMe-CH(F)—C(O)OH,
        —C(O)NMe-CH(CF3)—C(O)OH,
        —C(O)NMe-CH(OH)—C(O)OH,
        —C(O)NMe-CH(cyclopropyl)-C(O)OH,
        —C(O)NMe-C(Me)2—C(O)OH,
        —C(O)NMe-CF(Me)-C(O)OH,
        —C(O)NMe-C(Me)(CF3)—C(O)OH,
        —C(O)NMe-C(Me)(OH)—C(O)OH,
        —C(O)NMe-C(Me)(cyclopropyl)-C(O)OH, or
        —C(O)—N(Me)-5-tetrazolyl.
    
    


Other preferred compounds of the invention are those represented by formula (I) or a pharmaceutically acceptable salt or a prodrug derivative thereof:




wherein;

R and R′ are independently methyl or ethyl;
R1 and R2 are independently selected from the group consisting of hydrogen, fluoro, —Cl, —CF3, —CH2F, —CHF2, methoxy, ethoxy, vinyl, methyl, or cyclopropyl;
ZB is a branched alkyl terminated selected from the formulae:







ZC is selected from







Particularly preferred is a compound or a pharmaceutically acceptable salt or ester prodrug derivative thereof represented by structural formulae (AA) to (DB) as follows:



















Other particularly preferred compounds of the invention are those shown by the structural formulae C-1 to C-54 set out below. Pharmaceutically acceptable salts for prodrug derivatives of these compounds are also preferred.



















Most preferred are the individual enantiomers or a mixture of enantiomers represented by the formulae:





Additional particularly preferred are compounds or a pharmaceutically acceptable salt or prodrug derivative thereof selected from (TBU-1) to (TBU-86), as follows:
A compound or a pharmaceutically acceptable salt or an ester prodrug derivative thereof selected from (TBU-1) to (TBU-86), as follows:








































Particularly preferred as a compound of the invention is the compound or a pharmaceutically acceptable salt or ester prodrug derivative of the compound represented by the formula:




Particularly preferred as a compound of the invention is the compound or a pharmaceutically acceptable salt or ester prodrug derivative of the compound represented by the formula:




For all of the above compounds of the invention defined by Formula (I) the preferred prodrug derivative is a methyl ester, ethyl ester N,N-diethylglycolamido ester or morpholinylethyl ester. In addition, for all of the above compounds of the invention the preferred salt is sodium or potassium.
Other specific compounds that are preferred embodiments of this invention and are preferred for practicing the method of treatment of the invention are set out in the following Tables. All numbers in the Tables cells reciting chemical species are to be understood as subscripts in chemical formulae, for example, in the first row of Table 1, Compound No. 1, the symbol, “CO2Me” is to be understood as the conventional chemical nomenclature, —CO2H—. Each row of the Tables 1 and 2 represents a single compound having an identifying defining the specific substituents in the structural formula displayed above each Tables, as follows:
Among other preferred compounds of the invention are those represented by the formula:




    and pharmaceutically acceptable salts thereof; wherein;

said compound is selected from a compound code numbered 1 thru 468, with each compound having the specific selection of substituents RB, RC, L1, L2, and L3 shown in the row following the compound code number, as set out in the following Table 1:















TABLE 1





No.
RB
L3
L2
L1
RC




















1
tBu
C(O)
CH2
O
C(O)CH(Me)CH2CO2H


2
tBu
CHOH
CH2
O
C(O)CH(Me)CH2CO2H


3
tBu
C(Me)OH
CH2
O
C(O)CH(Me)CH2CO2H


4
tBu
C(O)
CH(Me)
O
C(O)CH(Me)CH2CO2H


5
tBu
CHOH
CH(Me)
O
C(O)CH(Me)CH2CO2H


6
tBu
C(Me)OH
CH(Me)
O
C(O)CH(Me)CH2CO2H


7
tBu
C(O)
CH2
O
CO2H


8
tBu
CHOH
CH2
O
CO2H


9
tBu
C(Me)OH
CH2
O
CO2H


10
tBu
C(O)
CH(Me)
O
CO2H


11
tBu
CHOH
CH(Me)
O
CO2H


12
tBu
C(Me)OH
CH(Me)
O
CO2H


13
tBu
C(O)
CH2
O
C(O)NH2


14
tBu
CHOH
CH2
O
C(O)NH2


15
tBu
C(Me)OH
CH2
O
C(O)NH2


16
tBu
C(O)
CH(Me)
O
C(O)NH2


17
tBu
CHOH
CH(Me)
O
C(O)NH2


18
tBu
C(Me)OH
CH(Me)
O
C(O)NH2


19
tBu
C(O)
CH2
O
C(O)NMe2


20
tBu
CHOH
CH2
O
C(O)NMe2


21
tBu
C(Me)OH
CH2
O
C(O)NMe2


22
tBu
C(O)
CH(Me)
O
C(O)NMe2


23
tBu
CHOH
CH(Me)
O
C(O)NMe2


24
tBu
C(Me)OH
CH(Me)
O
C(O)NMe2


25
tBu
C(O)
CH2
O
5-tetrazolyl


26
tBu
CHOH
CH2
O
5-tetrazolyl


27
tBu
C(Me)OH
CH2
O
5-tetrazolyl


28
tBu
C(O)
CH(Me)
O
5-tetrazolyl


29
tBu
CHOH
CH(Me)
O
5-tetrazolyl


30
tBu
C(Me)OH
CH(Me)
O
5-tetrazolyl


31
tBu
C(O)
CH2
O
C(O)—NH-5-tetrazolyl


32
tBu
CHOH
CH2
O
C(O)—NH-5-tetrazolyl


33
tBu
C(Me)OH
CH2
O
C(O)—NH-5-tetrazolyl


34
tBu
C(O)
CH(Me)
O
C(O)—NH-5-tetrazolyl


35
tBu
CHOH
CH(Me)
O
C(O)—NH-5-tetrazolyl


36
tBu
C(Me)OH
CH(Me)
O
C(O)—NH-5-tetrazolyl


37
tBu
C(O)
CH2
O
C(O)NHCH2SO2Me


38
tBu
CHOH
CH2
O
C(O)NHCH2SO2Me


39
tBu
C(Me)OH
CH2
O
C(O)NHCH2SO2Me


40
tBu
C(O)
CH(Me)
O
C(O)NHCH2SO2Me


41
tBu
CHOH
CH(Me)
O
C(O)NHCH2SO2Me


42
tBu
C(Me)OH
CH(Me)
O
C(O)NHCH2SO2Me


43
tBu
C(O)
CH2
O
C(O)NHCH2S(O)Me


44
tBu
CHOH
CH2
O
C(O)NHCH2S(O)Me


45
tBu
C(Me)OH
CH2
O
C(O)NHCH2S(O)Me


46
tBu
C(O)
CH(Me)
O
C(O)NHCH2S(O)Me


47
tBu
CHOH
CH(Me)
O
C(O)NHCH2S(O)Me


48
tBu
C(Me)OH
CH(Me)
O
C(O)NHCH2S(O)Me


49
tBu
C(O)
CH2
O
C(O)NHCH2CH2SO2Me


50
tBu
CHOH
CH2
O
C(O)NHCH2CH2SO2Me


51
tBu
C(Me)OH
CH2
O
C(O)NHCH2CH2SO2Me


52
tBu
C(O)
CH(Me)
O
C(O)NHCH2CH2SO2Me


53
tBu
CHOH
CH(Me)
O
C(O)NHCH2CH2SO2Me


54
tBu
C(Me)OH
CH(Me)
O
C(O)NHCH2CH2SO2Me


55
tBu
C(O)
CH2
O
C(O)NHCH2CH2S(O)Me


56
tBu
CHOH
CH2
O
C(O)NHCH2CH2S(O)Me


57
tBu
C(Me)OH
CH2
O
C(O)NHCH2CH2S(O)Me


58
tBu
C(O)
CH(Me)
O
C(O)NHCH2CH2S(O)Me


59
tBu
CHOH
CH(Me)
O
C(O)NHCH2CH2S(O)Me


60
tBu
C(Me)OH
CH(Me)
O
C(O)NHCH2CH2S(O)Me


61
tBu
C(O)
CH2
O
C(O)NHSO2Me


62
tBu
CHOH
CH2
O
C(O)NHSO2Me


63
tBu
C(Me)OH
CH2
O
C(O)NHSO2Me


64
tBu
C(O)
CH(Me)
O
C(O)NHSO2Me


65
tBu
CHOH
CH(Me)
O
C(O)NHSO2Me


66
tBu
C(Me)OH
CH(Me)
O
C(O)NHSO2Me


67
tBu
C(O)
CH2
O
C(O)NHS(O)Me


68
tBu
CHOH
CH2
O
C(O)NHS(O)Me


69
tBu
C(Me)OH
CH2
O
C(O)NHS(O)Me


70
tBu
C(O)
CH(Me)
O
C(O)NHS(O)Me


71
tBu
CHOH
CH(Me)
O
C(O)NHS(O)Me


72
tBu
C(Me)OH
CH(Me)
O
C(O)NHS(O)Me


73
tBu
C(O)
CH2
O
C(O)NHSO2Et


74
tBu
CHOH
CH2
O
C(O)NHSO2Et


75
tBu
C(Me)OH
CH2
O
C(O)NHSO2Et


76
tBu
C(O)
CH(Me)
O
C(O)NHSO2Et


77
tBu
CHOH
CH(Me)
O
C(O)NHSO2Et


78
tBu
C(Me)OH
CH(Me)
O
C(O)NHSO2Et


79
tBu
C(O)
CH2
O
C(O)NHS(O)Et


80
tBu
CHOH
CH2
O
C(O)NHS(O)Et


81
tBu
C(Me)OH
CH2
O
C(O)NHS(O)Et


82
tBu
C(O)
CH(Me)
O
C(O)NHS(O)Et


83
tBu
CHOH
CH(Me)
O
C(O)NHS(O)Et


84
tBu
C(Me)OH
CH(Me)
O
C(O)NHS(O)Et


85
tBu
C(O)
CH2
O
C(O)NHSO2iPr


86
tBu
CHOH
CH2
O
C(O)NHSO2iPr


87
tBu
C(Me)OH
CH2
O
C(O)NHSO2iPr


88
tBu
C(O)
CH(Me)
O
C(O)NHSO2iPr


89
tBu
CHOH
CH(Me)
O
C(O)NHSO2iPr


90
tBu
C(Me)OH
CH(Me)
O
C(O)NHSO2iPr


91
tBu
C(O)
CH2
O
C(O)NHS(O)iPr


92
tBu
CHOH
CH2
O
C(O)NHS(O)iPr


93
tBu
C(Me)OH
CH2
O
C(O)NHS(O)iPr


94
tBu
C(O)
CH(Me)
O
C(O)NHS(O)iPr


95
tBu
CHOH
CH(Me)
O
C(O)NHS(O)iPr


96
tBu
C(Me)OH
CH(Me)
O
C(O)NHS(O)iPr


97
tBu
C(O)
CH2
O
C(O)NHSO2tBu


98
tBu
CHOH
CH2
O
C(O)NHSO2tBu


99
tBu
C(Me)OH
CH2
O
C(O)NHSO2tBu


100
tBu
C(O)
CH(Me)
O
C(O)NHSO2tBu


101
tBu
CHOH
CH(Me)
O
C(O)NHSO2tBu


102
tBu
C(Me)OH
CH(Me)
O
C(O)NHSO2tBu


103
tBu
C(O)
CH2
O
C(O)NHS(O)tBu


104
tBu
CHOH
CH2
O
C(O)NHS(O)tBu


105
tBu
C(Me)OH
CH2
O
C(O)NHS(O)tBu


106
tBu
C(O)
CH(Me)
O
C(O)NHS(O)tBu


107
tBu
CHOH
CH(Me)
O
C(O)NHS(O)tBu


108
tBu
C(Me)OH
CH(Me)
O
C(O)NHS(O)tBu


109
tBu
C(O)
CH2
O
CH2NHSO2Me


110
tBu
CHOH
CH2
O
CH2NHSO2Me


111
tBu
C(Me)OH
CH2
O
CH2NHSO2Me


112
tBu
C(O)
CH(Me)
O
CH2NHSO2Me


113
tBu
CHOH
CH(Me)
O
CH2NHSO2Me


114
tBu
C(Me)OH
CH(Me)
O
CH2NHSO2Me


115
tBu
C(O)
CH2
O
CH2NHS(O)Me


116
tBu
CHOH
CH2
O
CH2NHS(O)Me


117
tBu
C(Me)OH
CH2
O
CH2NHS(O)Me


118
tBu
C(O)
CH(Me)
O
CH2NHS(O)Me


119
tBu
CHOH
CH(Me)
O
CH2NHS(O)Me


120
tBu
C(Me)OH
CH(Me)
O
CH2NHS(O)Me


121
tBu
C(O)
CH2
O
CH2NHSO2Et


122
tBu
CHOH
CH2
O
CH2NHSO2Et


123
tBu
C(Me)OH
CH2
O
CH2NHSO2Et


124
tBu
C(O)
CH(Me)
O
CH2NHSO2Et


125
tBu
CHOH
CH(Me)
O
CH2NHSO2Et


126
tBu
C(Me)OH
CH(Me)
O
CH2NHSO2Et


127
tBu
C(O)
CH2
O
CH2NHS(O)Et


128
tBu
CHOH
CH2
O
CH2NHS(O)Et


129
tBu
C(Me)OH
CH2
O
CH2NHS(O)Et


130
tBu
C(O)
CH(Me)
O
CH2NHS(O)Et


131
tBu
CHOH
CH(Me)
O
CH2NHS(O)Et


132
tBu
C(Me)OH
CH(Me)
O
CH2NHS(O)Et


133
tBu
C(O)
CH2
O
CH2NHSO2iPr


134
tBu
CHOH
CH2
O
CH2NHSO2iPr


135
tBu
C(Me)OH
CH2
O
CH2NHSO2iPr


136
tBu
C(O)
CH(Me)
O
CH2NHSO2iPr


137
tBu
CHOH
CH(Me)
O
CH2NHSO2iPr


138
tBu
C(Me)OH
CH(Me)
O
CH2NHSO2iPr


139
tBu
C(O)
CH2
O
CH2NHS(O)iPr


140
tBu
CHOH
CH2
O
CH2NHS(O)iPr


141
tBu
C(Me)OH
CH2
O
CH2NHS(O)iPr


142
tBu
C(O)
CH(Me)
O
CH2NHS(O)iPr


143
tBu
CHOH
CH(Me)
O
CH2NHS(O)iPr


144
tBu
C(Me)OH
CH(Me)
O
CH2NHS(O)iPr


145
tBu
C(O)
CH2
O
CH2NHSO2tBu


146
tBu
CHOH
CH2
O
CH2NHSO2tBu


147
tBu
C(Me)OH
CH2
O
CH2NHSO2tBu


148
tBu
C(O)
CH(Me)
O
CH2NHSO2tBu


149
tBu
CHOH
CH(Me)
O
CH2NHSO2tBu


150
tBu
C(Me)OH
CH(Me)
O
CH2NHSO2tBu


151
tBu
C(O)
CH2
O
CH2NHS(O)tBu


152
tBu
CHOH
CH2
O
CH2NHS(O)tBu


153
tBu
C(Me)OH
CH2
O
CH2NHS(O)tBu


154
tBu
C(O)
CH(Me)
O
CH2NHS(O)tBu


155
tBu
CHOH
CH(Me)
O
CH2NHS(O)tBu


156
tBu
C(Me)OH
CH(Me)
O
CH2NHS(O)tBu


157
tBu
C(O)
CH2
O
CH2—N-pyrrolidin-2-one


158
tBu
CHOH
CH2
O
CH2—N-pyrrolidin-2-one


159
tBu
C(Me)OH
CH2
O
CH2—N-pyrrolidin-2-one


160
tBu
C(O)
CH(Me)
O
CH2—N-pyrrolidin-2-one


161
tBu
CHOH
CH(Me)
O
CH2—N-pyrrolidin-2-one


162
tBu
C(Me)OH
CH(Me)
O
CH2—N-pyrrolidin-2-one


163
tBu
C(O)
CH2
O
CH2-(1-methylpyrrolidin-2-







one-3-yl)


164
tBu
CHOH
CH2
O
CH2-(1-methylpyrrolidin-2-







one-3-yl)


165
tBu
C(Me)OH
CH2
O
CH2-(1-methylpyrrolidin-2-







one-3-yl)


166
tBu
C(O)
CH(Me)
O
CH2-(1-methylpyrrolidin-2-







one-3-yl)


167
tBu
CHOH
CH(Me)
O
CH2-(1-methylpyrrolidin-2-







one-3-yl)


168
tBu
C(Me)OH
CH(Me)
O
CH2-(1-methylpyrrolidin-2-







one-3-yl)


169
tBu
C(O)
CH2
O
CH2CO2Me


170
tBu
CHOH
CH2
O
CH2CO2Me


171
tBu
C(Me)OH
CH2
O
CH2CO2Me


172
tBu
C(O)
CH(Me)
O
CH2CO2Me


173
tBu
CHOH
CH(Me)
O
CH2CO2Me


174
tBu
C(Me)OH
CH(Me)
O
CH2CO2Me


175
tBu
C(O)
CH2
O
CH2CO2H


176
tBu
CHOH
CH2
O
CH2CO2H


177
tBu
C(Me)OH
CH2
O
CH2CO2H


178
tBu
C(O)
CH(Me)
O
CH2CO2H


179
tBu
CHOH
CH(Me)
O
CH2CO2H


180
tBu
C(Me)OH
CH(Me)
O
CH2CO2H


181
tBu
C(O)
CH2
O
CH2C(O)NH2


182
tBu
CHOH
CH2
O
CH2C(O)NH2


183
tBu
C(Me)OH
CH2
O
CH2C(O)NH2


184
tBu
C(O)
CH(Me)
O
CH2C(O)NH2


185
tBu
CHOH
CH(Me)
O
CH2C(O)NH2


186
tBu
C(Me)OH
CH(Me)
O
CH2C(O)NH2


187
tBu
C(O)
CH2
O
CH2C(O)NMe2


188
tBu
CHOH
CH2
O
CH2C(O)NMe2


189
tBu
C(Me)OH
CH2
O
CH2C(O)NMe2


190
tBu
C(O)
CH(Me)
O
CH2C(O)NMe2


191
tBu
CHOH
CH(Me)
O
CH2C(O)NMe2


192
tBu
C(Me)OH
CH(Me)
O
CH2C(O)NMe2


193
tBu
C(O)
CH2
O
CH2C(O)—N-pyrrolidine


194
tBu
CHOH
CH2
O
CH2C(O)—N-pyrrolidine


195
tBu
C(Me)OH
CH2
O
CH2C(O)—N-pyrrolidine


196
tBu
C(O)
CH(Me)
O
CH2C(O)—N-pyrrolidine


197
tBu
CHOH
CH(Me)
O
CH2C(O)—N-pyrrolidine


198
tBu
C(Me)OH
CH(Me)
O
CH2C(O)—N-pyrrolidine


199
tBu
C(O)
CH2
O
CH2-5-tetrazolyl


200
tBu
CHOH
CH2
O
CH2-5-tetrazolyl


201
tBu
C(Me)OH
CH2
O
CH2-5-tetrazolyl


202
tBu
C(O)
CH(Me)
O
CH2-5-tetrazolyl


203
tBu
CHOH
CH(Me)
O
CH2-5-tetrazolyl


204
tBu
C(Me)OH
CH(Me)
O
CH2-5-tetrazolyl


205
tBu
C(O)
CH2
O
C(O)C(O)OH


206
tBu
CHOH
CH2
O
C(O)C(O)OH


207
tBu
C(Me)OH
CH2
O
C(O)C(O)OH


208
tBu
C(O)
CH(Me)
O
C(O)C(O)OH


209
tBu
CHOH
CH(Me)
O
C(O)C(O)OH


210
tBu
C(Me)OH
CH(Me)
O
C(O)C(O)OH


211
tBu
C(O)
CH2
O
CH(OH)C(O)OH


212
tBu
CHOH
CH2
O
CH(OH)C(O)OH


213
tBu
C(Me)OH
CH2
O
CH(OH)C(O)OH


214
tBu
C(O)
CH(Me)
O
CH(OH)C(O)OH


215
tBu
CHOH
CH(Me)
O
CH(OH)C(O)OH


216
tBu
C(Me)OH
CH(Me)
O
CH(OH)C(O)OH


217
tBu
C(O)
CH2
O
C(O)C(O)NH2


218
tBu
CHOH
CH2
O
C(O)C(O)NH2


219
tBu
C(Me)OH
CH2
O
C(O)C(O)NH2


220
tBu
C(O)
CH(Me)
O
C(O)C(O)NH2


221
tBu
CHOH
CH(Me)
O
C(O)C(O)NH2


222
tBu
C(Me)OH
CH(Me)
O
C(O)C(O)NH2


223
tBu
C(O)
CH2
O
CH(OH)C(O)NH2


224
tBu
CHOH
CH2
O
CH(OH)C(O)NH2


225
tBu
C(Me)OH
CH2
O
CH(OH)C(O)NH2


226
tBu
C(O)
CH(Me)
O
CH(OH)C(O)NH2


227
tBu
CHOH
CH(Me)
O
CH(OH)C(O)NH2


228
tBu
C(Me)OH
CH(Me)
O
CH(OH)C(O)NH2


229
tBu
C(O)
CH2
O
C(O)C(O)NMe2


230
tBu
CHOH
CH2
O
C(O)C(O)NMe2


231
tBu
C(Me)OH
CH2
O
C(O)C(O)NMe2


232
tBu
C(O)
CH(Me)
O
C(O)C(O)NMe2


233
tBu
CHOH
CH(Me)
O
C(O)C(O)NMe2


234
tBu
C(Me)OH
CH(Me)
O
C(O)C(O)NMe2


235
tBu
C(O)
CH2
O
CH(OH)C(O)NMe2


236
tBu
CHOH
CH2
O
CH(OH)C(O)NMe2


237
tBu
C(Me)OH
CH2
O
CH(OH)C(O)NMe2


238
tBu
C(O)
CH(Me)
O
CH(OH)C(O)NMe2


239
tBu
CHOH
CH(Me)
O
CH(OH)C(O)NMe2


240
tBu
C(Me)OH
CH(Me)
O
CH(OH)C(O)NMe2


241
tBu
C(O)
CH2
O
CH2CH2CO2H


242
tBu
CHOH
CH2
O
CH2CH2CO2H


243
tBu
C(Me)OH
CH2
O
CH2CH2CO2H


244
tBu
C(O)
CH(Me)
O
CH2CH2CO2H


245
tBu
CHOH
CH(Me)
O
CH2CH2CO2H


246
tBu
C(Me)OH
CH(Me)
O
CH2CH2CO2H


247
tBu
C(O)
CH2
O
CH2CH2C(O)NH2


248
tBu
CHOH
CH2
O
CH2CH2C(O)NH2


249
tBu
C(Me)OH
CH2
O
CH2CH2C(O)NH2


250
tBu
C(O)
CH(Me)
O
CH2CH2C(O)NH2


251
tBu
CHOH
CH(Me)
O
CH2CH2C(O)NH2


252
tBu
C(Me)OH
CH(Me)
O
CH2CH2C(O)NH2


253
tBu
C(O)
CH2
O
CH2CH2C(O)NMe2


254
tBu
CHOH
CH2
O
CH2CH2C(O)NMe2


255
tBu
C(Me)OH
CH2
O
CH2CH2C(O)NMe2


256
tBu
C(O)
CH(Me)
O
CH2CH2C(O)NMe2


257
tBu
CHOH
CH(Me)
O
CH2CH2C(O)NMe2


258
tBu
C(Me)OH
CH(Me)
O
CH2CH2C(O)NMe2


259
tBu
C(O)
CH2
O
CH2CH2-5-tetrazolyl


260
tBu
CHOH
CH2
O
CH2CH2-5-tetrazolyl


261
tBu
C(Me)OH
CH2
O
CH2CH2-5-tetrazolyl


262
tBu
C(O)
CH(Me)
O
CH2CH2-5-tetrazolyl


263
tBu
CHOH
CH(Me)
O
CH2CH2-5-tetrazolyl


264
tBu
C(Me)OH
CH(Me)
O
CH2CH2-5-tetrazolyl


265
tBu
C(O)
CH2
O
CH2S(O)2Me


266
tBu
CHOH
CH2
O
CH2S(O)2Me


267
tBu
C(Me)OH
CH2
O
CH2S(O)2Me


268
tBu
C(O)
CH(Me)
O
CH2S(O)2Me


269
tBu
CHOH
CH(Me)
O
CH2S(O)2Me


270
tBu
C(Me)OH
CH(Me)
O
CH2S(O)2Me


271
tBu
C(O)
CH2
O
CH2S(O)Me


272
tBu
CHOH
CH2
O
CH2S(O2Me


273
tBu
C(Me)OH
CH2
O
CH2S(O)Me


274
tBu
C(O)
CH(Me)
O
CH2S(O)Me


275
tBu
CHOH
CH(Me)
O
CH2S(O)Me


276
tBu
C(Me)OH
CH(Me)
O
CH2S(O)Me


277
tBu
C(O)
CH2
O
CH2CH2S(O)2Me


278
tBu
CHOH
CH2
O
CH2CH2S(O)2Me


279
tBu
C(Me)OH
CH2
O
CH2CH2S(O)2Me


280
tBu
C(O)
CH(Me)
O
CH2CH2S(O)2Me


281
tBu
CHOH
CH(Me)
O
CH2CH2S(O)2Me


282
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)2Me


283
tBu
C(O)
CH2
O
CH2CH2S(O)Me


284
tBu
CHOH
CH2
O
CH2CH2S(O)Me


285
tBu
C(Me)OH
CH2
O
CH2CH2S(O)Me


286
tBu
C(O)
CH(Me)
O
CH2CH2S(O)Me


287
tBu
CHOH
CH(Me)
O
CH2CH2S(O)Me


288
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)Me


289
tBu
C(O)
CH2
O
CH2CH2CH2S(O)2Me


290
tBu
CHOH
CH2
O
CH2CH2CH2S(O)2Me


291
tBu
C(Me)OH
CH2
O
CH2CH2CH2S(O)2Me


292
tBu
C(O)
CH(Me)
O
CH2CH2CH2S(O)2Me


293
tBu
CHOH
CH(Me)
O
CH2CH2CH2S(O)2Me


294
tBu
C(Me)OH
CH(Me)
O
CH2CH2CH2S(O)2Me


295
tBu
C(O)
CH2
O
CH2CH2CH2S(O)Me


296
tBu
CHOH
CH2
O
CH2CH2CH2S(O)Me


297
tBu
C(Me)OH
CH2
O
CH2CH2CH2S(O)Me


298
tBu
C(O)
CH(Me)
O
CH2CH2CH2S(O)Me


299
tBu
CHOH
CH(Me)
O
CH2CH2CH2S(O)Me


300
tBu
C(Me)OH
CH(Me)
O
CH2CH2CH2S(O)Me


301
tBu
C(O)
CH2
O
CH2S(O)2Et


302
tBu
CHOH
CH2
O
CH2S(O)2Et


303
tBu
C(Me)OH
CH2
O
CH2S(O)2Et


304
tBu
C(O)
CH(Me)
O
CH2S(O)2Et


305
tBu
CHOH
CH(Me)
O
CH2S(O)2Et


306
tBu
C(Me)OH
CH(Me)
O
CH2S(O)2Et


307
tBu
C(O)
CH2
O
CH2S(O)Et


308
tBu
CHOH
CH2
O
CH2S(O)Et


309
tBu
C(Me)OH
CH2
O
CH2S(O)Et


310
tBu
C(O)
CH(Me)
O
CH2S(O)Et


311
tBu
CHOH
CH(Me)
O
CH2S(O)Et


312
tBu
C(Me)OH
CH(Me)
O
CH2S(O)Et


313
tBu
C(O)
CH2
O
CH2CH2S(O)2Et


314
tBu
CHOH
CH2
O
CH2CH2S(O)2Et


315
tBu
C(Me)OH
CH2
O
CH2CH2S(O)2Et


316
tBu
C(O)
CH(Me)
O
CH2CH2S(O)2Et


317
tBu
CHOH
CH(Me)
O
CH2CH2S(O)2Et


318
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)2Et


319
tBu
C(O)
CH2
O
CH2CH2S(O)Et


320
tBu
CHOH
CH2
O
CH2CH2S(O)Et


321
tBu
C(Me)OH
CH2
O
CH2CH2S(O)Et


322
tBu
C(O)
CH(Me)
O
CH2CH2S(O)Et


323
tBu
CHOH
CH(Me)
O
CH2CH2S(O)Et


324
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)Et


325
tBu
C(O)
CH2
O
CH2CH2CH2S(O)2Et


326
tBu
CHOH
CH2
O
CH2CH2CH2S(O)2Et


327
tBu
C(Me)OH
CH2
O
CH2CH2CH2S(O)2Et


328
tBu
C(O)
CH(Me)
O
CH2CH2CH2S(O)2Et


329
tBu
CHOH
CH(Me)
O
CH2CH2CH2S(O)2Et


330
tBu
C(Me)OH
CH(Me)
O
CH2CH2CH2S(O)2Et


331
tBu
C(O)
CH2
O
CH2CH2CH2S(O)Et


332
tBu
CHOH
CH2
O
CH2CH2CH2S(O)Et


333
tBu
C(Me)OH
CH2
O
CH2CH2CH2S(O)Et


334
tBu
C(O)
CH(Me)
O
CH2CH2CH2S(O)Et


335
tBu
CHOH
CH(Me)
O
CH2CH2CH2S(O)Et


336
tBu
C(Me)OH
CH(Me)
O
CH2CH2CH2S(O)Et


337
tBu
C(O)
CH2
O
CH2S(O)2iPr


338
tBu
CHOH
CH2
O
CH2S(O)2iPr


339
tBu
C(Me)OH
CH2
O
CH2S(O)2iPr


340
tBu
C(O)
CH(Me)
O
CH2S(O)2iPr


341
tBu
CHOH
CH(Me)
O
CH2S(O)2iPr


342
tBu
C(Me)OH
CH(Me)
O
CH2S(O)2iPr


343
tBu
C(O)
CH2
O
CH2S(O)iPr


344
tBu
CHOH
CH2
O
CH2S(O)iPr


345
tBu
C(Me)OH
CH2
O
CH2S(O)iPr


346
tBu
C(O)
CH(Me)
O
CH2S(O)iPr


347
tBu
CHOH
CH(Me)
O
CH2S(O)iPr


348
tBu
C(Me)OH
CH(Me)
O
CH2S(O)iPr


349
tBu
C(O)
CH2
O
CH2CH2S(O)2iPr


350
tBu
CHOH
CH2
O
CH2CH2S(O)2iPr


351
tBu
C(Me)OH
CH2
O
CH2CH2S(O)2iPr


352
tBu
C(O)
CH(Me)
O
CH2CH2S(O)2iPr


353
tBu
CHOH
CH(Me)
O
CH2CH2S(O)2iPr


354
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)2iPr


355
tBu
C(O)
CH2
O
CH2CH2S(O)iPr


356
tBu
CHOH
CH2
O
CH2CH2S(O)iPr


357
tBu
C(Me)OH
CH2
O
CH2CH2S(O)iPr


358
tBu
C(O)
CH(Me)
O
CH2CH2S(O)iPr


359
tBu
CHOH
CH(Me)
O
CH2CH2S(O)iPr


360
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)iPr


361
tBu
C(O)
CH2
O
CH2S(O)2tBu


362
tBu
CHOH
CH2
O
CH2S(O)2tBu


363
tBu
C(Me)OH
CH2
O
CH2S(O)2tBu


364
tBu
C(O)
CH(Me)
O
CH2S(O)2tBu


365
tBu
CHOH
CH(Me)
O
CH2S(O)2tBu


366
tBu
C(Me)OH
CH(Me)
O
CH2S(O)2tBu


367
tBu
C(O)
CH2
O
CH2S(O)tBu


368
tBu
CHOH
CH2
O
CH2S(O)tBu


369
tBu
C(Me)OH
CH2
O
CH2S(O)tBu


370
tBu
C(O)
CH(Me)
O
CH2S(O)tBu


371
tBu
CHOH
CH(Me)
O
CH2S(O)tBu


372
tBu
C(Me)OH
CH(Me)
O
CH2S(O)tBu


373
tBu
C(O)
CH2
O
CH2CH2S(O)2tBu


374
tBu
CHOH
CH2
O
CH2CH2S(O)2tBu


375
tBu
C(Me)OH
CH2
O
CH2CH2S(O)2tBu


376
tBu
C(O)
CH(Me)
O
CH2CH2S(O)2tBu


377
tBu
CHOH
CH(Me)
O
CH2CH2S(O)2tBu


378
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)2tBu


379
tBu
C(O)
CH2
O
CH2CH2S(O)tBu


380
tBu
CHOH
CH2
O
CH2CH2S(O)tBu


381
tBu
C(Me)OH
CH2
O
CH2CH2S(O)tBu


382
tBu
C(O)
CH(Me)
O
CH2CH2S(O)tBu


383
tBu
CHOH
CH(Me)
O
CH2CH2S(O)tBu


384
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)tBu


385
tBu
C(O)
CH2
O
CH2CH2S(O)2NH2


386
tBu
CHOH
CH2
O
CH2CH2S(O)2NH2


387
tBu
C(Me)OH
CH2
O
CH2CH2S(O)2NH2


388
tBu
C(O)
CH(Me)
O
CH2CH2S(O)2NH2


389
tBu
CHOH
CH(Me)
O
CH2CH2S(O)2NH2


390
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)2NH2


391
tBu
C(O)
CH2
O
CH2CH2S(O)NH2


392
tBu
CHOH
CH2
O
CH2CH2S(O)NH2


393
tBu
C(Me)OH
CH2
O
CH2CH2S(O)NH2


394
tBu
C(O)
CH(Me)
O
CH2CH2S(O)NH2


395
tBu
CHOH
CH(Me)
O
CH2CH2S(O)NH2


396
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)NH2


397
tBu
C(O)
CH2
O
CH2CH2S(O)2NMe2


398
tBu
CHOH
CH2
O
CH2CH2S(O)2NMe2


399
tBu
C(Me)OH
CH2
O
CH2CH2S(O)2NMe2


400
tBu
C(O)
CH(Me)
O
CH2CH2S(O)2NMe2


401
tBu
CHOH
CH(Me)
O
CH2CH2S(O)2NMe2


402
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)2NMe2


403
tBu
C(O)
CH2
O
CH2CH2S(O)NMe2


404
tBu
CHOH
CH2
O
CH2CH2S(O)NMe2


405
tBu
C(Me)OH
CH2
O
CH2CH2S(O)NMe2


406
tBu
C(O)
CH(Me)
O
CH2CH2S(O)NMe2


407
tBu
CHOH
CH(Me)
O
CH2CH2S(O)NMe2


408
tBu
C(Me)OH
CH(Me)
O
CH2CH2S(O)NMe2


409
tBu
C(O)
CH2
O
C(O)CH2S(O)2Me


410
tBu
CHOH
CH2
O
C(O)CH2S(O)2Me


411
tBu
C(Me)OH
CH2
O
C(O)CH2S(O)2Me


412
tBu
C(O)
CH(Me)
O
C(O)CH2S(O)2Me


413
tBu
CHOH
CH(Me)
O
C(O)CH2S(O)2Me


414
tBu
C(Me)OH
CH(Me)
O
C(O)CH2S(O)2Me


415
tBu
C(O)
CH2
O
C(O)CH2S(O)Me


416
tBu
CHOH
CH2
O
C(O)CH2S(O)Me


417
tBu
C(Me)OH
CH2
O
C(O)CH2S(O)Me


418
tBu
C(O)
CH(Me)
O
C(O)CH2S(O)Me


419
tBu
CHOH
CH(Me)
O
C(O)CH2S(O)Me


420
tBu
C(Me)OH
CH(Me)
O
C(O)CH2S(O)Me


421
tBu
C(O)
CH2
O
C(O)CH2CH2S(O)2Me


422
tBu
CHOH
CH2
O
C(O)CH2CH2S(O)2Me


423
tBu
C(Me)OH
CH2
O
C(O)CH2CH2S(O)2Me


424
tBu
C(O)
CH(Me)
O
C(O)CH2CH2S(O)2Me


425
tBu
CHOH
CH(Me)
O
C(O)CH2CH2S(O)2Me


426
tBu
C(Me)OH
CH(Me)
O
C(O)CH2CH2S(O)2Me


427
tBu
C(O)
CH2
O
C(O)CH2CH2S(O)Me


428
tBu
CHOH
CH2
O
C(O)CH2CH2S(O)Me


429
tBu
C(Me)OH
CH2
O
C(O)CH2CH2S(O)Me


430
tBu
C(O)
CH(Me)
O
C(O)CH2CH2S(O)Me


431
tBu
CHOH
CH(Me)
O
C(O)CH2CH2S(O)Me


432
tBu
C(Me)OH
CH(Me)
O
C(O)CH2CH2S(O)Me


433
tBu
C(O)
CH2
O
CH2CH2CH2S(O)2NH2


434
tBu
CHOH
CH2
O
CH2CH2CH2S(O)2NH2


435
tBu
C(Me)OH
CH2
O
CH2CH2CH2S(O)2NH2


436
tBu
C(O)
CH(Me)
O
CH2CH2CH2S(O)2NH2


437
tBu
CHOH
CH(Me)
O
CH2CH2CH2S(O)2NH2


438
tBu
C(Me)OH
CH(Me)
O
CH2CH2CH2S(O)2NH2


439
tBu
C(O)
CH2
O
CH2CH2CH2S(O)NH2


440
tBu
CHOH
CH2
O
CH2CH2CH2S(O)NH2


441
tBu
C(Me)OH
CH2
O
CH2CH2CH2S(O)NH2


442
tBu
C(O)
CH(Me)
O
CH2CH2CH2S(O)NH2


443
tBu
CHOH
CH(Me)
O
CH2CH2CH2S(O)NH2


444
tBu
C(Me)OH
CH(Me)
O
CH2CH2CH2S(O)NH2


445
tBu
C(O)
CH2
CH2
1,3,4-oxadiazolin-2-one-5-yl


446
tBu
CHOH
CH2
CH2
1,3,4-oxadiazolin-2-one-5-yl


447
tBu
C(Me)OH
CH2
CH2
1,3,4-oxadiazolin-2-one-5-yl


448
tBu
C(O)
CH(Me)
CH2
1,3,4-oxadiazolin-2-one-5-yl


449
tBu
CHOH
CH(Me)
CH2
1,3,4-oxadiazolin-2-one-5-yl


450
tBu
C(Me)OH
CH(Me)
CH2
1,3,4-oxadiazolin-2-one-5-yl


451
tBu
C(O)
CH2
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


452
tBu
CHOH
CH2
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


453
tBu
C(Me)OH
CH2
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


454
tBu
C(O)
CH(Me)
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


455
tBu
CHOH
CH(Me)
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


456
tBu
C(Me)OH
CH(Me)
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


457
tBu
C(O)
CH2
CH2
imidazolidine-2,4-dione-5-yl


458
tBu
CHOH
CH2
CH2
imidazolidine-2,4-dione-5-yl


459
tBu
C(Me)OH
CH2
CH2
imidazolidine-2,4-dione-5-yl


460
tBu
C(O)
CH(Me)
CH2
imidazolidine-2,4-dione-5-yl


461
tBu
CHOH
CH(Me)
CH2
imidazolidine-2,4-dione-5-yl


462
tBu
C(Me)OH
CH(Me)
CH2
imidazolidine-2,4-dione-5-yl


463
tBu
C(O)
CH2
CH2
isoxazol-3-ol-5-yl


464
tBu
CHOH
CH2
CH2
isoxazol-3-ol-5-yl


465
tBu
C(Me)OH
CH2
CH2
isoxazol-3-ol-5-yl


466
tBu
C(O)
CH(Me)
CH2
isoxazol-3-ol-5-yl


467
tBu
CHOH
CH(Me)
CH2
isoxazol-3-ol-5-yl


468
tBu
C(Me)OH
CH(Me)
CH2
isoxazol-3-ol-5-yl









Among other preferred compounds of the invention are also those represented by the formula:




    and pharmaceutically acceptable salts thereof; wherein;

said compound is selected from a compound code numbered 1A thru 468A, with each compound having the specific selection of substituents RB, RC, L1, L2, and L3 shown in the row following the compound code number, as set out in the following Table 2:
















TABLE 2







RB
L3
L2
L1
RC





















 1A
tBu
C(O)
CH2
CH2
C(O)CH(Me)CH2CO2H


 2A
tBu
CHOH
CH2
CH2
C(O)CH(Me)CH2CO2H


 3A
tBu
C(Me)OH
CH2
CH2
C(O)CH(Me)CH2CO2H


 4A
tBu
C(O)
CH(Me)
CH2
C(O)CH(Me)CH2CO2H


 5A
tBu
CHOH
CH(Me)
CH2
C(O)CH(Me)CH2CO2H


 6A
tBu
C(Me)OH
CH(Me)
CH2
C(O)CH(Me)CH2CO2H


 7A
tBu
C(O)
CH2
CH2
CO2H


 8A
tBu
CHOH
CH2
CH2
CO2H


 9A
tBu
C(Me)OH
CH2
CH2
CO2H


 10A
tBu
C(O)
CH(Me)
CH2
CO2H


 11A
tBu
CHOH
CH(Me)
CH2
CO2H


 12A
tBu
C(Me)OH
CH(Me)
CH2
CO2H


 13A
tBu
C(O)
CH2
CH2
C(O)NH2


 14A
tBu
CHOH
CH2
CH2
C(O)NH2


 15A
tBu
C(Me)OH
CH2
CH2
C(O)NH2


 16A
tBu
C(O)
CH(Me)
CH2
C(O)NH2


 17A
tBu
CHOH
CH(Me)
CH2
C(O)NH2


 18A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NH2


 19A
tBu
C(O)
CH2
CH2
C(O)NMe2


 20A
tBu
CHOH
CH2
CH2
C(O)NMe2


 21A
tBu
C(Me)OH
CH2
CH2
C(O)NMe2


 22A
tBu
C(O)
CH(Me)
CH2
C(O)NMe2


 23A
tBu
CHOH
CH(Me)
CH2
C(O)NMe2


 24A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NMe2


 25A
tBu
C(O)
CH2
CH2
5-tetrazolyl


 26A
tBu
CHOH
CH2
CH2
5-tetrazolyl


 27A
tBu
C(Me)OH
CH2
CH2
5-tetrazolyl


 28A
tBu
C(O)
CH(Me)
CH2
5-tetrazolyl


 29A
tBu
CHOH
CH(Me)
CH2
5-tetrazolyl


 30A
tBu
C(Me)OH
CH(Me)
CH2
5-tetrazolyl


 31A
tBu
C(O)
CH2
CH2
C(O)—NH-5-tetrazolyl


 32A
tBu
CHOH
CH2
CH2
C(O)—NH-5-tetrazolyl


 33A
tBu
C(Me)OH
CH2
CH2
C(O)—NH-5-tetrazolyl


 34A
tBu
C(O)
CH(Me)
CH2
C(O)—NH-5-tetrazolyl


 35A
tBu
CHOH
CH(Me)
CH2
C(O)—NH-5-tetrazolyl


 36A
tBu
C(Me)OH
CH(Me)
CH2
C(O)—NH-5-tetrazolyl


 37A
tBu
C(O)
CH2
CH2
C(O)NHCH2SO2Me


 38A
tBu
CHOH
CH2
CH2
C(O)NHCH2SO2Me


 39A
tBu
C(Me)OH
CH2
CH2
C(O)NHCH2SO2Me


 40A
tBu
C(O)
CH(Me)
CH2
C(O)NHCH2SO2Me


 41A
tBu
CHOH
CH(Me)
CH2
C(O)NHCH2SO2Me


 42A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHCH2SO2Me


 43A
tBu
C(O)
CH2
CH2
C(O)NHCH2S(O)Me


 44A
tBu
CHOH
CH2
CH2
C(O)NHCH2S(O)Me


 45A
tBu
C(Me)OH
CH2
CH2
C(O)NHCH2S(O)Me


 46A
tBu
C(O)
CH(Me)
CH2
C(O)NHCH2S(O)Me


 47A
tBu
CHOH
CH(Me)
CH2
C(O)NHCH2S(O)Me


 48A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHCH2S(O)Me


 49A
tBu
C(O)
CH2
CH2
C(O)NHCH2CH2SO2Me


 50A
tBu
CHOH
CH2
CH2
C(O)NHCH2CH2SO2Me


 51A
tBu
C(Me)OH
CH2
CH2
C(O)NHCH2CH2SO2Me


 52A
tBu
C(O)
CH(Me)
CH2
C(O)NHCH2CH2SO2Me


 53A
tBu
CHOH
CH(Me)
CH2
C(O)NHCH2CH2SO2Me


 54A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHCH2CH2SO2Me


 55A
tBu
C(O)
CH2
CH2
C(O)NHCH2CH2S(O)Me


 56A
tBu
CHOH
CH2
CH2
C(O)NHCH2CH2S(O)Me


 57A
tBu
C(Me)OH
CH2
CH2
C(O)NHCH2CH2S(O)Me


 58A
tBu
C(O)
CH(Me)
CH2
C(O)NHCH2CH2S(O)Me


 59A
tBu
CHOH
CH(Me)
CH2
C(O)NHCH2CH2S(O)Me


 60A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHCH2CH2S(O)Me


 61A
tBu
C(O)
CH2
CH2
C(O)NHSO2Me


 62A
tBu
CHOH
CH2
CH2
C(O)NHSO2Me


 63A
tBu
C(Me)OH
CH2
CH2
C(O)NHSO2Me


 64A
tBu
C(O)
CH(Me)
CH2
C(O)NHSO2Me


 65A
tBu
CHOH
CH(Me)
CH2
C(O)NHSO2Me


 66A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHSO2Me


 67A
tBu
C(O)
CH2
CH2
C(O)NHS(O)Me


 68A
tBu
CHOH
CH2
CH2
C(O)NHS(O)Me


 69A
tBu
C(Me)OH
CH2
CH2
C(O)NHS(O)Me


 70A
tBu
C(O)
CH(Me)
CH2
C(O)NHS(O)Me


 71A
tBu
CHOH
CH(Me)
CH2
C(O)NHS(O)Me


 72A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHS(O)Me


 73A
tBu
C(O)
CH2
CH2
C(O)NHSO2Et


 74A
tBu
CHOH
CH2
CH2
C(O)NHSO2Et


 75A
tBu
C(Me)OH
CH2
CH2
C(O)NHSO2Et


 76A
tBu
C(O)
CH(Me)
CH2
C(O)NHSO2Et


 77A
tBu
CHOH
CH(Me)
CH2
C(O)NHSO2Et


 78A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHSO2Et


 79A
tBu
C(O)
CH2
CH2
C(O)NHS(O)Et


 80A
tBu
CHOH
CH2
CH2
C(O)NHS(O)Et


 81A
tBu
C(Me)OH
CH2
CH2
C(O)NHS(O)Et


 82A
tBu
C(O)
CH(Me)
CH2
C(O)NHS(O)Et


 83A
tBu
CHOH
CH(Me)
CH2
C(O)NHS(O)Et


 84A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHS(O)Et


 85A
tBu
C(O)
CH2
CH2
C(O)NHSO2iPr


 86A
tBu
CHOH
CH2
CH2
C(O)NHSO2iPr


 87A
tBu
C(Me)OH
CH2
CH2
C(O)NHSO2iPr


 88A
tBu
C(O)
CH(Me)
CH2
C(O)NHSO2iPr


 89A
tBu
CHOH
CH(Me)
CH2
C(O)NHSO2iPr


 90A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHSO2iPr


 91A
tBu
C(O)
CH2
CH2
C(O)NHS(O)iPr


 92A
tBu
CHOH
CH2
CH2
C(O)NHS(O)iPr


 93A
tBu
C(Me)OH
CH2
CH2
C(O)NHS(O)iPr


 94A
tBu
C(O)
CH(Me)
CH2
C(O)NHS(O)iPr


 95A
tBu
CHOH
CH(Me)
CH2
C(O)NHS(O)iPr


 96A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHS(O)iPr


 97A
tBu
C(O)
CH2
CH2
C(O)NHSO2tBu


 98A
tBu
CHOH
CH2
CH2
C(O)NHSO2tBu


 99A
tBu
C(Me)OH
CH2
CH2
C(O)NHSO2tBu


100A
tBu
C(O)
CH(Me)
CH2
C(O)NHSO2tBu


101A
tBu
CHOH
CH(Me)
CH2
C(O)NHSO2tBu


102A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHSO2tBu


103A
tBu
C(O)
CH2
CH2
C(O)NHS(O)tBu


104A
tBu
CHOH
CH2
CH2
C(O)NHS(O)tBu


105A
tBu
C(Me)OH
CH2
CH2
C(O)NHS(O)tBu


106A
tBu
C(O)
CH(Me)
CH2
C(O)NHS(O)tBu


107A
tBu
CHOH
CH(Me)
CH2
C(O)NHS(O)tBu


108A
tBu
C(Me)OH
CH(Me)
CH2
C(O)NHS(O)tBu


109A
tBu
C(O)
CH2
CH2
CH2NHSO2Me


110A
tBu
CHOH
CH2
CH2
CH2NHSO2Me


111A
tBu
C(Me)OH
CH2
CH2
CH2NHSO2Me


112A
tBu
C(O)
CH(Me)
CH2
CH2NHSO2Me


113A
tBu
CHOH
CH(Me)
CH2
CH2NHSO2Me


114A
tBu
C(Me)OH
CH(Me)
CH2
CH2NHSO2Me


115A
tBu
C(O)
CH2
CH2
CH2NHS(O)Me


116A
tBu
CHOH
CH2
CH2
CH2NHS(O)Me


117A
tBu
C(Me)OH
CH2
CH2
CH2NHS(O)Me


118A
tBu
C(O)
CH(Me)
CH2
CH2NHS(O)Me


119A
tBu
CHOH
CH(Me)
CH2
CH2NHS(O)Me


120A
tBu
C(Me)OH
CH(Me)
CH2
CH2NHS(O)Me


121A
tBu
C(O)
CH2
CH2
CH2NHSO2Et


122A
tBu
CHOH
CH2
CH2
CH2NHSO2Et


123A
tBu
C(Me)OH
CH2
CH2
CH2NHSO2Et


124A
tBu
C(O)
CH(Me)
CH2
CH2NHSO2Et


125A
tBu
CHOH
CH(Me)
CH2
CH2NHSO2Et


126A
tBu
C(Me)OH
CH(Me)
CH2
CH2NHSO2Et


127A
tBu
C(O)
CH2
CH2
CH2NHS(O)Et


128A
tBu
CHOH
CH2
CH2
CH2NHS(O)Et


129A
tBu
C(Me)OH
CH2
CH2
CH2NHS(O)Et


130A
tBu
C(O)
CH(Me)
CH2
CH2NHS(O)Et


131A
tBu
CHOH
CH(Me)
CH2
CH2NHS(O)Et


132A
tBu
C(Me)OH
CH(Me)
CH2
CH2NHS(O)Et


133A
tBu
C(O)
CH2
CH2
CH2NHSO2iPr


134A
tBu
CHOH
CH2
CH2
CH2NHSO2iPr


135A
tBu
C(Me)OH
CH2
CH2
CH2NHSO2iPr


136A
tBu
C(O)
CH(Me)
CH2
CH2NHSO2iPr


137A
tBu
CHOH
CH(Me)
CH2
CH2NHSO2iPr


138A
tBu
C(Me)OH
CH(Me)
CH2
CH2NHSO2iPr


139A
tBu
C(O)
CH2
CH2
CH2NHS(O)iPr


140A
tBu
CHOH
CH2
CH2
CH2NHS(O)iPr


141A
tBu
C(Me)OH
CH2
CH2
CH2NHS(O)iPr


142A
tBu
C(O)
CH(Me)
CH2
CH2NHS(O)iPr


143A
tBu
CHOH
CH(Me)
CH2
CH2NHS(O)iPr


144A
tBu
C(Me)OH
CH(Me)
CH2
CH2NHS(O)iPr


145A
tBu
C(O)
CH2
CH2
CH2NHSO2tBu


146A
tBu
CHOH
CH2
CH2
CH2NHSO2tBu


147A
tBu
C(Me)OH
CH2
CH2
CH2NHSO2tBu


148A
tBu
C(O)
CH(Me)
CH2
CH2NHSO2tBu


149A
tBu
CHOH
CH(Me)
CH2
CH2NHSO2tBu


150A
tBu
C(Me)OH
CH(Me)
CH2
CH2NHSO2tBu


151A
tBu
C(O)
CH2
CH2
CH2NHS(O)tBu


152A
tBu
CHOH
CH2
CH2
CH2NHS(O)tBu


153A
tBu
C(Me)OH
CH2
CH2
CH2NHS(O)tBu


154A
tBu
C(O)
CH(Me)
CH2
CH2NHS(O)tBu


155A
tBu
CHOH
CH(Me)
CH2
CH2NHS(O)tBu


156A
tBu
C(Me)OH
CH(Me)
CH2
CH2NHS(O)tBu


157A
tBu
C(O)
CH2
CH2
CH2—N-pyrrolidin-2-one


158A
tBu
CHOH
CH2
CH2
CH2—N-pyrrolidin-2-one


159A
tBu
C(Me)OH
CH2
CH2
CH2—N-pyrrolidin-2-one


160A
tBu
C(O)
CH(Me)
CH2
CH2—N-pyrrolidin-2-one


161A
tBu
CHOH
CH(Me)
CH2
CH2—N-pyrrolidin-2-one


162A
tBu
C(Me)OH
CH(Me)
CH2
CH2—N-pyrrolidin-2-one


163A
tBu
C(O)
CH2
CH2
CH2-(1-methylpyrrolidin-2-







one-3-yl)


164A
tBu
CHOH
CH2
CH2
CH2-(1-methylpyrrolidin-2-







one-3-yl)


165A
tBu
C(Me)OH
CH2
CH2
CH2-(1-methylpyrrolidin-2-







one-3-yl)


166A
tBu
C(O)
CH(Me)
CH2
CH2-(1-methylpyrrolidin-2-







one-3-yl)


167A
tBu
CHOH
CH(Me)
CH2
CH2-(1-methylpyrrolidin-2-







one-3-yl)


168A
tBu
C(Me)OH
CH(Me)
CH2
CH2-(1-methylpyrrolidin-2-







one-3-yl)


169A
tBu
C(O)
CH2
CH2
CH2CO2Me


170A
tBu
CHOH
CH2
CH2
CH2CO2Me


171A
tBu
C(Me)OH
CH2
CH2
CH2CO2Me


172A
tBu
C(O)
CH(Me)
CH2
CH2CO2Me


173A
tBu
CHOH
CH(Me)
CH2
CH2CO2Me


174A
tBu
C(Me)OH
CH(Me)
CH2
CH2CO2Me


175A
tBu
C(O)
CH2
CH2
CH2CO2H


176A
tBu
CHOH
CH2
CH2
CH2CO2H


177A
tBu
C(Me)OH
CH2
CH2
CH2CO2H


178A
tBu
C(O)
CH(Me)
CH2
CH2CO2H


179A
tBu
CHOH
CH(Me)
CH2
CH2CO2H


180A
tBu
C(Me)OH
CH(Me)
CH2
CH2CO2H


181A
tBu
C(O)
CH2
CH2
CH2C(O)NH2


182A
tBu
CHOH
CH2
CH2
CH2C(O)NH2


183A
tBu
C(Me)OH
CH2
CH2
CH2C(O)NH2


184A
tBu
C(O)
CH(Me)
CH2
CH2C(O)NH2


185A
tBu
CHOH
CH(Me)
CH2
CH2C(O)NH2


186A
tBu
C(Me)OH
CH(Me)
CH2
CH2C(O)NH2


187A
tBu
C(O)
CH2
CH2
CH2C(O)NMe2


188A
tBu
CHOH
CH2
CH2
CH2C(O)NMe2


189A
tBu
C(Me)OH
CH2
CH2
CH2C(O)NMe2


190A
tBu
C(O)
CH(Me)
CH2
CH2C(O)NMe2


191A
tBu
CHOH
CH(Me)
CH2
CH2C(O)NMe2


192A
tBu
C(Me)OH
CH(Me)
CH2
CH2C(O)NMe2


193A
tBu
C(O)
CH2
CH2
CH2C(O)—N-pyrrolidine


194A
tBu
CHOH
CH2
CH2
CH2C(O)—N-pyrrolidine


195A
tBu
C(Me)OH
CH2
CH2
CH2C(O)—N-pyrrolidine


196A
tBu
C(O)
CH(Me)
CH2
CH2C(O)—N-pyrrolidine


197A
tBu
CHOH
CH(Me)
CH2
CH2C(O)—N-pyrrolidine


198A
tBu
C(Me)OH
CH(Me)
CH2
CH2C(O)—N-pyrrolidine


199A
tBu
C(O)
CH2
CH2
CH2-5-tetrazolyl


200A
tBu
CHOH
CH2
CH2
CH2-5-tetrazolyl


201A
tBu
C(Me)OH
CH2
CH2
CH2-5-tetrazolyl


202A
tBu
C(O)
CH(Me)
CH2
CH2-5-tetrazolyl


203A
tBu
CHOH
CH(Me)
CH2
CH2-5-tetrazolyl


204A
tBu
C(Me)OH
CH(Me)
CH2
CH2-5-tetrazolyl


205A
tBu
C(O)
CH2
CH2
C(O)C(O)OH


206A
tBu
CHOH
CH2
CH2
C(O)C(O)OH


207A
tBu
C(Me)OH
CH2
CH2
C(O)C(O)OH


208A
tBu
C(O)
CH(Me)
CH2
C(O)C(O)OH


209A
tBu
CHOH
CH(Me)
CH2
C(O)C(O)OH


210A
tBu
C(Me)OH
CH(Me)
CH2
C(O)C(O)OH


211A
tBu
C(O)
CH2
CH2
CH(OH)C(O)OH


212A
tBu
CHOH
CH2
CH2
CH(OH)C(O)OH


213A
tBu
C(Me)OH
CH2
CH2
CH(OH)C(O)OH


214A
tBu
C(O)
CH(Me)
CH2
CH(OH)C(O)OH


215A
tBu
CHOH
CH(Me)
CH2
CH(OH)C(O)OH


216A
tBu
C(Me)OH
CH(Me)
CH2
CH(OH)C(O)OH


217A
tBu
C(O)
CH2
CH2
C(O)C(O)NH2


218A
tBu
CHOH
CH2
CH2
C(O)C(O)NH2


219A
tBu
C(Me)OH
CH2
CH2
C(O)C(O)NH2


220A
tBu
C(O)
CH(Me)
CH2
C(O)C(O)NH2


221A
tBu
CHOH
CH(Me)
CH2
C(O)C(O)NH2


222A
tBu
C(Me)OH
CH(Me)
CH2
C(O)C(O)NH2


223A
tBu
C(O)
CH2
CH2
CH(OH)C(O)NH2


224A
tBu
CHOH
CH2
CH2
CH(OH)C(O)NH2


225A
tBu
C(Me)OH
CH2
CH2
CH(OH)C(O)NH2


226A
tBu
C(O)
CH(Me)
CH2
CH(OH)C(O)NH2


227A
tBu
CHOH
CH(Me)
CH2
CH(OH)C(O)NH2


228A
tBu
C(Me)OH
CH(Me)
CH2
CH(OH)C(O)NH2


229A
tBu
C(O)
CH2
CH2
C(O)C(O)NMe2


230A
tBu
CHOH
CH2
CH2
C(O)C(O)NMe2


231A
tBu
C(Me)OH
CH2
CH2
C(O)C(O)NMe2


232A
tBu
C(O)
CH(Me)
CH2
C(O)C(O)NMe2


233A
tBu
CHOH
CH(Me)
CH2
C(O)C(O)NMe2


234A
tBu
C(Me)OH
CH(Me)
CH2
C(O)C(O)NMe2


235A
tBu
C(O)
CH2
CH2
CH(OH)C(O)NMe2


236A
tBu
CHOH
CH2
CH2
CH(OH)C(O)NMe2


237A
tBu
C(Me)OH
CH2
CH2
CH(OH)C(O)NMe2


238A
tBu
C(O)
CH(Me)
CH2
CH(OH)C(O)NMe2


239A
tBu
CHOH
CH(Me)
CH2
CH(OH)C(O)NMe2


240A
tBu
C(Me)OH
CH(Me)
CH2
CH(OH)C(O)NMe2


241A
tBu
C(O)
CH2
CH2
CH2CH2CO2H


242A
tBu
CHOH
CH2
CH2
CH2CH2CO2H


243A
tBu
C(Me)OH
CH2
CH2
CH2CH2CO2H


244A
tBu
C(O)
CH(Me)
CH2
CH2CH2CO2H


245A
tBu
CHOH
CH(Me)
CH2
CH2CH2CO2H


246A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2CO2H


247A
tBu
C(O)
CH2
CH2
CH2CH2C(O)NH2


248A
tBu
CHOH
CH2
CH2
CH2CH2C(O)NH2


249A
tBu
C(Me)OH
CH2
CH2
CH2CH2C(O)NH2


250A
tBu
C(O)
CH(Me)
CH2
CH2CH2C(O)NH2


251A
tBu
CHOH
CH(Me)
CH2
CH2CH2C(O)NH2


252A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2C(O)NH2


253A
tBu
C(O)
CH2
CH2
CH2CH2C(O)NMe2


254A
tBu
CHOH
CH2
CH2
CH2CH2C(O)NMe2


255A
tBu
C(Me)OH
CH2
CH2
CH2CH2C(O)NMe2


256A
tBu
C(O)
CH(Me)
CH2
CH2CH2C(O)NMe2


257A
tBu
CHOH
CH(Me)
CH2
CH2CH2C(O)NMe2


258A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2C(O)NMe2


259A
tBu
C(O)
CH2
CH2
CH2CH2-5-tetrazolyl


260A
tBu
CHOH
CH2
CH2
CH2CH2-5-tetrazolyl


261A
tBu
C(Me)OH
CH2
CH2
CH2CH2-5-tetrazolyl


262A
tBu
C(O)
CH(Me)
CH2
CH2CH2-5-tetrazolyl


263A
tBu
CHOH
CH(Me)
CH2
CH2CH2-5-tetrazolyl


264A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2-5-tetrazolyl


265A
tBu
C(O)
CH2
CH2
CH2S(O)2Me


266A
tBu
CHOH
CH2
CH2
CH2S(O)2Me


267A
tBu
C(Me)OH
CH2
CH2
CH2S(O)2Me


268A
tBu
C(O)
CH(Me)
CH2
CH2S(O)2Me


269A
tBu
CHOH
CH(Me)
CH2
CH2S(O)2Me


270A
tBu
C(Me)OH
CH(Me)
CH2
CH2S(O)2Me


271A
tBu
C(O)
CH2
CH2
CH2S(O)Me


272A
tBu
CHOH
CH2
CH2
CH2S(O2Me


273A
tBu
C(Me)OH
CH2
CH2
CH2S(O)Me


274A
tBu
C(O)
CH(Me)
CH2
CH2S(O)Me


275A
tBu
CHOH
CH(Me)
CH2
CH2S(O)Me


276A
tBu
C(Me)OH
CH(Me)
CH2
CH2S(O)Me


277A
tBu
C(O)
CH2
CH2
CH2CH2S(O)2Me


278A
tBu
CHOH
CH2
CH2
CH2CH2S(O)2Me


279A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)2Me


280A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)2Me


281A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)2Me


282A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)2Me


283A
tBu
C(O)
CH2
CH2
CH2CH2S(O)Me


284A
tBu
CHOH
CH2
CH2
CH2CH2S(O)Me


285A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)Me


286A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)Me


287A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)Me


288A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)Me


289A
tBu
C(O)
CH2
CH2
CH2CH2CH2S(O)2Me


290A
tBu
CHOH
CH2
CH2
CH2CH2CH2S(O)2Me


291A
tBu
C(Me)OH
CH2
CH2
CH2CH2CH2S(O)2Me


292A
tBu
C(O)
CH(Me)
CH2
CH2CH2CH2S(O)2Me


293A
tBu
CHOH
CH(Me)
CH2
CH2CH2CH2S(O)2Me


294A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2CH2S(O)2Me


295A
tBu
C(O)
CH2
CH2
CH2CH2CH2S(O)Me


296A
tBu
CHOH
CH2
CH2
CH2CH2CH2S(O)Me


297A
tBu
C(Me)OH
CH2
CH2
CH2CH2CH2S(O)Me


298A
tBu
C(O)
CH(Me)
CH2
CH2CH2CH2S(O)Me


299A
tBu
CHOH
CH(Me)
CH2
CH2CH2CH2S(O)Me


300A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2CH2S(O)Me


301A
tBu
C(O)
CH2
CH2
CH2S(O)2Et


302A
tBu
CHOH
CH2
CH2
CH2S(O)2Et


303A
tBu
C(Me)OH
CH2
CH2
CH2S(O)2Et


304A
tBu
C(O)
CH(Me)
CH2
CH2S(O)2Et


305A
tBu
CHOH
CH(Me)
CH2
CH2S(O)2Et


306A
tBu
C(Me)OH
CH(Me)
CH2
CH2S(O)2Et


307A
tBu
C(O)
CH2
CH2
CH2S(O)Et


308A
tBu
CHOH
CH2
CH2
CH2S(O)Et


309A
tBu
C(Me)OH
CH2
CH2
CH2S(O)Et


310A
tBu
C(O)
CH(Me)
CH2
CH2S(O)Et


311A
tBu
CHOH
CH(Me)
CH2
CH2S(O)Et


312A
tBu
C(Me)OH
CH(Me)
CH2
CH2S(O)Et


313A
tBu
C(O)
CH2
CH2
CH2CH2S(O)2Et


314A
tBu
CHOH
CH2
CH2
CH2CH2S(O)2Et


315A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)2Et


316A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)2Et


317A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)2Et


318A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)2Et


319A
tBu
C(O)
CH2
CH2
CH2CH2S(O)Et


320A
tBu
CHOH
CH2
CH2
CH2CH2S(O)Et


321A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)Et


322A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)Et


323A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)Et


324A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)Et


325A
tBu
C(O)
CH2
CH2
CH2CH2CH2S(O)2Et


326A
tBu
CHOH
CH2
CH2
CH2CH2CH2S(O)2Et


327A
tBu
C(Me)OH
CH2
CH2
CH2CH2CH2S(O)2Et


328A
tBu
C(O)
CH(Me)
CH2
CH2CH2CH2S(O)2Et


329A
tBu
CHOH
CH(Me)
CH2
CH2CH2CH2S(O)2Et


330A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2CH2S(O)2Et


331A
tBu
C(O)
CH2
CH2
CH2CH2CH2S(O)Et


332A
tBu
CHOH
CH2
CH2
CH2CH2CH2S(O)Et


333A
tBu
C(Me)OH
CH2
CH2
CH2CH2CH2S(O)Et


334A
tBu
C(O)
CH(Me)
CH2
CH2CH2CH2S(O)Et


335A
tBu
CHOH
CH(Me)
CH2
CH2CH2CH2S(O)Et


336A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2CH2S(O)Et


337A
tBu
C(O)
CH2
CH2
CH2S(O)2iPr


338A
tBu
CHOH
CH2
CH2
CH2S(O)2iPr


339A
tBu
C(Me)OH
CH2
CH2
CH2S(O)2iPr


340A
tBu
C(O)
CH(Me)
CH2
CH2S(O)2iPr


341A
tBu
CHOH
CH(Me)
CH2
CH2S(O)2iPr


342A
tBu
C(Me)OH
CH(Me)
CH2
CH2S(O)2iPr


343A
tBu
C(O)
CH2
CH2
CH2S(O)iPr


344A
tBu
CHOH
CH2
CH2
CH2S(O)iPr


345A
tBu
C(Me)OH
CH2
CH2
CH2S(O)iPr


346A
tBu
C(O)
CH(Me)
CH2
CH2S(O)iPr


347A
tBu
CHOH
CH(Me)
CH2
CH2S(O)iPr


348A
tBu
C(Me)OH
CH(Me)
CH2
CH2S(O)iPr


349A
tBu
C(O)
CH2
CH2
CH2CH2S(O)2iPr


350A
tBu
CHOH
CH2
CH2
CH2CH2S(O)2iPr


351A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)2iPr


352A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)2iPr


353A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)2iPr


354A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)2iPr


355A
tBu
C(O)
CH2
CH2
CH2CH2S(O)iPr


356A
tBu
CHOH
CH2
CH2
CH2CH2S(O)iPr


357A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)iPr


358A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)iPr


359A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)iPr


360A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)iPr


361A
tBu
C(O)
CH2
CH2
CH2S(O)2tBu


362A
tBu
CHOH
CH2
CH2
CH2S(O)2tBu


363A
tBu
C(Me)OH
CH2
CH2
CH2S(O)2tBu


364A
tBu
C(O)
CH(Me)
CH2
CH2S(O)2tBu


365A
tBu
CHOH
CH(Me)
CH2
CH2S(O)2tBu


366A
tBu
C(Me)OH
CH(Me)
CH2
CH2S(O)2tBu


367A
tBu
C(O)
CH2
CH2
CH2S(O)tBu


368A
tBu
CHOH
CH2
CH2
CH2S(O)tBu


369A
tBu
C(Me)OH
CH2
CH2
CH2S(O)tBu


370A
tBu
C(O)
CH(Me)
CH2
CH2S(O)tBu


371A
tBu
CHOH
CH(Me)
CH2
CH2S(O)tBu


372A
tBu
C(Me)OH
CH(Me)
CH2
CH2S(O)tBu


373A
tBu
C(O)
CH2
CH2
CH2CH2S(O)2tBu


374A
tBu
CHOH
CH2
CH2
CH2CH2S(O)2tBu


375A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)2tBu


376A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)2tBu


377A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)2tBu


378A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)2tBu


379A
tBu
C(O)
CH2
CH2
CH2CH2S(O)tBu


380A
tBu
CHOH
CH2
CH2
CH2CH2S(O)tBu


381A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)tBu


382A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)tBu


383A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)tBu


384A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)tBu


385A
tBu
C(O)
CH2
CH2
CH2CH2S(O)2NH2


386A
tBu
CHOH
CH2
CH2
CH2CH2S(O)2NH2


387A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)2NH2


388A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)2NH2


389A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)2NH2


390A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)2NH2


391A
tBu
C(O)
CH2
CH2
CH2CH2S(O)NH2


392A
tBu
CHOH
CH2
CH2
CH2CH2S(O)NH2


393A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)NH2


394A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)NH2


395A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)NH2


396A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)NH2


397A
tBu
C(O)
CH2
CH2
CH2CH2S(O)2NMe2


398A
tBu
CHOH
CH2
CH2
CH2CH2S(O)2NMe2


399A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)2NMe2


400A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)2NMe2


401A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)2NMe2


402A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)2NMe2


403A
tBu
C(O)
CH2
CH2
CH2CH2S(O)NMe2


404A
tBu
CHOH
CH2
CH2
CH2CH2S(O)NMe2


405A
tBu
C(Me)OH
CH2
CH2
CH2CH2S(O)NMe2


406A
tBu
C(O)
CH(Me)
CH2
CH2CH2S(O)NMe2


407A
tBu
CHOH
CH(Me)
CH2
CH2CH2S(O)NMe2


408A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2S(O)NMe2


409A
tBu
C(O)
CH2
CH2
C(O)CH2S(O)2Me


410A
tBu
CHOH
CH2
CH2
C(O)CH2S(O)2Me


411A
tBu
C(Me)OH
CH2
CH2
C(O)CH2S(O)2Me


412A
tBu
C(O)
CH(Me)
CH2
C(O)CH2S(O)2Me


413A
tBu
CHOH
CH(Me)
CH2
C(O)CH2S(O)2Me


414A
tBu
C(Me)OH
CH(Me)
CH2
C(O)CH2S(O)2Me


415A
tBu
C(O)
CH2
CH2
C(O)CH2S(O)Me


416A
tBu
CHOH
CH2
CH2
C(O)CH2S(O)Me


417A
tBu
C(Me)OH
CH2
CH2
C(O)CH2S(O)Me


418A
tBu
C(O)
CH(Me)
CH2
C(O)CH2S(O)Me


419A
tBu
CHOH
CH(Me)
CH2
C(O)CH2S(O)Me


420A
tBu
C(Me)OH
CH(Me)
CH2
C(O)CH2S(O)Me


421A
tBu
C(O)
CH2
CH2
C(O)CH2CH2S(O)2Me


422A
tBu
CHOH
CH2
CH2
C(O)CH2CH2S(O)2Me


423A
tBu
C(Me)OH
CH2
CH2
C(O)CH2CH2S(O)2Me


424A
tBu
C(O)
CH(Me)
CH2
C(O)CH2CH2S(O)2Me


425A
tBu
CHOH
CH(Me)
CH2
C(O)CH2CH2S(O)2Me


426A
tBu
C(Me)OH
CH(Me)
CH2
C(O)CH2CH2S(O)2Me


427A
tBu
C(O)
CH2
CH2
C(O)CH2CH2S(O)Me


428A
tBu
CHOH
CH2
CH2
C(O)CH2CH2S(O)Me


429A
tBu
C(Me)OH
CH2
CH2
C(O)CH2CH2S(O)Me


430A
tBu
C(O)
CH(Me)
CH2
C(O)CH2CH2S(O)Me


431A
tBu
CHOH
CH(Me)
CH2
C(O)CH2CH2S(O)Me


432A
tBu
C(Me)OH
CH(Me)
CH2
C(O)CH2CH2S(O)Me


433A
tBu
C(O)
CH2
CH2
CH2CH2CH2S(O)2NH2


434A
tBu
CHOH
CH2
CH2
CH2CH2CH2S(O)2NH2


435A
tBu
C(Me)OH
CH2
CH2
CH2CH2CH2S(O)2NH2


436A
tBu
C(O)
CH(Me)
CH2
CH2CH2CH2S(O)2NH2


437A
tBu
CHOH
CH(Me)
CH2
CH2CH2CH2S(O)2NH2


438A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2CH2S(O)2NH2


439A
tBu
C(O)
CH2
CH2
CH2CH2CH2S(O)NH2


440A
tBu
CHOH
CH2
CH2
CH2CH2CH2S(O)NH2


441A
tBu
C(Me)OH
CH2
CH2
CH2CH2CH2S(O)NH2


442A
tBu
C(O)
CH(Me)
CH2
CH2CH2CH2S(O)NH2


443A
tBu
CHOH
CH(Me)
CH2
CH2CH2CH2S(O)NH2


444A
tBu
C(Me)OH
CH(Me)
CH2
CH2CH2CH2S(O)NH2


445A
tBu
C(O)
CH2
CH2
1,3,4-oxadiazolin-2-one-5-yl


446A
tBu
CHOH
CH2
CH2
1,3,4-oxadiazolin-2-one-5-yl


447A
tBu
C(Me)OH
CH2
CH2
1,3,4-oxadiazolin-2-one-5-yl


448A
tBu
C(O)
CH(Me)
CH2
1,3,4-oxadiazolin-2-one-5-yl


449A
tBu
CHOH
CH(Me)
CH2
1,3,4-oxadiazolin-2-one-5-yl


450A
tBu
C(Me)OH
CH(Me)
CH2
1,3,4-oxadiazolin-2-one-5-yl


451A
tBu
C(O)
CH2
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


452A
tBu
CHOH
CH2
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


453A
tBu
C(Me)OH
CH2
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


454A
tBu
C(O)
CH(Me)
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


455A
tBu
CHOH
CH(Me)
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


456A
tBu
C(Me)OH
CH(Me)
CH2
1,3,4-oxadiazolin-2-thione-5-







yl


457A
tBu
C(O)
CH2
CH2
imidazolidine-2,4-dione-5-yl


458A
tBu
CHOH
CH2
CH2
imidazolidine-2,4-dione-5-yl


459A
tBu
C(Me)OH
CH2
CH2
imidazolidine-2,4-dione-5-yl


460A
tBu
C(O)
CH(Me)
CH2
imidazolidine-2,4-dione-5-yl


461A
tBu
CHOH
CH(Me)
CH2
imidazolidine-2,4-dione-5-yl


462A
tBu
C(Me)OH
CH(Me)
CH2
imidazolidine-2,4-dione-5-yl


463A
tBu
C(O)
CH2
CH2
isoxazol-3-ol-5-yl


464A
tBu
CHOH
CH2
CH2
isoxazol-3-ol-5-yl


465A
tBu
C(Me)OH
CH2
CH2
isoxazol-3-ol-5-yl


466A
tBu
C(O)
CH(Me)
CH2
isoxazol-3-ol-5-yl


467A
tBu
CHOH
CH(Me)
CH2
isoxazol-3-ol-5-yl


468A
tBu
C(Me)OH
CH(Me)
CH2
isoxazol-3-ol-5-yl









Among other preferred compounds of the invention are also those represented by the formula:




    and pharmaceutically acceptable salts thereof;
    wherein;
    
        said compound is selected from a compound code numbered 1B thru 81B, with each compound having the specific selection of substituents RB, RC, L1, L2, and L3 shown

in the row following the compound code number, as set out in the following Table 3:

    
    















TABLE 3







RB
L3
L2
L1
RC





















 1B
tBu
C(O)
CH2
O
—C(O)NH—CH2—C(O)OH


 2B
tBu
CHOH
CH2
O
—C(O)NH—CH2—C(O)OH


 3B
tBu
C(Me)OH
CH2
O
—C(O)NH—CH2—C(O)OH


 4B
tBu
C(O)
CH(Me)
O
—C(O)NH—CH2—C(O)OH


 5B
tBu
CHOH
CH(Me)
O
—C(O)NH—CH2—C(O)OH


 6B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—CH2—C(O)OH


 7B
tBu
C(O)
CH2
O
—C(O)NH—CH(Me)—C(O)OH


 8B
tBu
CHOH
CH2
O
—C(O)NH—CH(Me)—C(O)OH


 9B
tBu
C(Me)OH
CH2
O
—C(O)NH—CH(Me)—C(O)OH


 10B
tBu
C(O)
CH(Me)
O
—C(O)NH—CH(Me)—C(O)OH


 11B
tBu
CHOH
CH(Me)
O
—C(O)NH—CH(Me)—C(O)OH


 12B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—CH(Me)—C(O)OH


 13B
tBu
C(O)
CH2
O
—C(O)NH—CH(Et)—C(O)OH


 14B
tBu
CHOH
CH2
O
—C(O)NH—CH(Et)—C(O)OH


 15B
tBu
C(Me)OH
CH2
O
—C(O)NH—CH(Et)—C(O)OH


 16B
tBu
C(O)
CH(Me)
O
—C(O)NH—CH(Et)—C(O)OH


 17B
tBu
CHOH
CH(Me)
O
—C(O)NH—CH(Et)—C(O)OH


 18B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—CH(Et)—C(O)OH


 19B
tBu
C(O)
CH2
O
—C(O)NH—C(Me)2—C(O)OH


 20B
tBu
CHOH
CH2
O
—C(O)NH—C(Me)2—C(O)OH


 21B
tBu
C(Me)OH
CH2
O
—C(O)NH—C(Me)2—C(O)OH


 22B
tBu
C(O)
CH(Me)
O
—C(O)NH—C(Me)2—C(O)OH


 23B
tBu
CHOH
CH(Me)
O
—C(O)NH—C(Me)2—C(O)OH


 24B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—C(Me)2—C(O)OH


 25B
tBu
C(O)
CH2
O
—C(O)NH—CMe(Et)—C(O)OH


 26B
tBu
CHOH
CH2
O
—C(O)NH—CMe(Et)—C(O)OH


 27B
tBu
C(Me)OH
CH2
O
—C(O)NH—CMe(Et)—C(O)OH


 28B
tBu
C(O)
CH(Me)
O
—C(O)NH—CMe(Et)—C(O)OH


 29B
tBu
CHOH
CH(Me)
O
—C(O)NH—CMe(Et)—C(O)OH


 30B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—CMe(Et)—C(O)OH


 31B
tBu
C(O)
CH2
O
—C(O)NH—CH(F)—C(O)OH


 32B
tBu
CHOH
CH2
O
—C(O)NH—CH(F)—C(O)OH


 33B
tBu
C(Me)OH
CH2
O
—C(O)NH—CH(F)—C(O)OH


 34B
tBu
C(O)
CH(Me)
O
—C(O)NH—CH(F)—C(O)OH


 35B
tBu
CHOH
CH(Me)
O
—C(O)NH—CH(F)—C(O)OH


 36B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—CH(F)—C(O)OH


 37B
tBu
C(O)
CH2
O
—C(O)NH—CH(CF3)—C(O)OH


 38B
tBu
CHOH
CH2
O
—C(O)NH—CH(CF3)—C(O)OH


 39B
tBu
C(Me)OH
CH2
O
—C(O)NH—CH(CF3)—C(O)OH


 40B
tBu
C(O)
CH(Me)
O
—C(O)NH—CH(CF3)—C(O)OH


 41B
tBu
CHOH
CH(Me)
O
—C(O)NH—CH(CF3)—C(O)OH


 42B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—CH(CF3)—C(O)OH


 43B
tBu
C(O)
CH2
O
—C(O)NH—CH(OH)—C(O)OH


 44B
tBu
CHOH
CH2
O
—C(O)NH—CH(OH)—C(O)OH


 45B
tBu
C(Me)OH
CH2
O
—C(O)NH—CH(OH)—C(O)OH


 46B
tBu
C(O)
CH(Me)
O
—C(O)NH—CH(OH)—C(O)OH


 47B
tBu
CHOH
CH(Me)
O
—C(O)NH—CH(OH)—C(O)OH


 48B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—CH(OH)—C(O)OH


 49B
tBu
C(O)
CH2
O
—C(O)NH—CH(cyclopropyl)-C(O)OH


 50B
tBu
CHOH
CH2
O
—C(O)NH—CH(cyclopropyl)-C(O)OH


 51B
tBu
C(Me)OH
CH2
O
—C(O)NH—CH(cyclopropyl)-C(O)OH


 52B
tBu
C(O)
CH(Me)
O
—C(O)NH—CH(cyclopropyl)-C(O)OH


 53B
tBu
CHOH
CH(Me)
O
—C(O)NH—CH(cyclopropyl)-C(O)OH


 54B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—CH(cyclopropyl)-C(O)OH


 55B
tBu
C(O)
CH2
O
—C(O)NH—CH(Me)—C(O)OH


 56B
tBu
CHOH
CH2
O
—C(O)NH—CH(Me)—C(O)OH


 57B
tBu
C(Me)OH
CH2
O
—C(O)NH—CH(Me)—C(O)OH


 58B
tBu
C(O)
CH(Me)
O
—C(O)NH—CH(Me)—C(O)OH


 59B
tBu
CHOH
CH(Me)
O
—C(O)NH—CH(Me)—C(O)OH


 60B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—CH(Me)—C(O)OH


 61B
tBu
C(O)
CH2
O
—C(O)NH—C(Me)2—C(O)OH


 62B
tBu
CHOH
CH2
O
—C(O)NH—C(Me)2—C(O)OH


 63B
tBu
C(Me)OH
CH2
O
—C(O)NH—C(Me)2—C(O)OH


 64B
tBu
C(O)
CH(Me)
O
—C(O)NH—C(Me)2—C(O)OH


 65B
tBu
CHOH
CH(Me)
O
—C(O)NH—C(Me)2—C(O)OH


 66B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—C(Me)2—C(O)OH


 67B
tBu
C(O)
CH2
O
—C(O)NH—CF(Me)—C(O)OH


 68B
tBu
CHOH
CH2
O
—C(O)NH—CF(Me)—C(O)OH


 69B
tBu
C(Me)OH
CH2
O
—C(O)NH—CF(Me)—C(O)OH


 70B
tBu
C(O)
CH(Me)
O
—C(O)NH—CF(Me)—C(O)OH


 71B
tBu
CHOH
CH(Me)
O
—C(O)NH—CF(Me)—C(O)OH


 72B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—CF(Me)—C(O)OH


 73B
tBu
C(O)
CH2
O
—C(O)NH—C(Me)(CF3)—C(O)OH


 74B
tBu
CHOH
CH2
O
—C(O)NH—C(Me)(CF3)—C(O)OH


 75B
tBu
C(Me)OH
CH2
O
—C(O)NH—C(Me)(CF3)—C(O)OH


 76B
tBu
C(O)
CH(Me)
O
—C(O)NH—C(Me)(CF3)—C(O)OH


 77B
tBu
CHOH
CH(Me)
O
—C(O)NH—C(Me)(CF3)—C(O)OH


 78B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—C(Me)(CF3)—C(O)OH


 79B
tBu
C(O)
CH2
O
—C(O)NH—C(Me)(OH)—C(O)OH


 80B
tBu
CHOH
CH2
O
—C(O)NH—C(Me)(OH)—C(O)OH


 81B
tBu
C(Me)OH
CH2
O
—C(O)NH—C(Me)(OH)—C(O)OH


 82B
tBu
C(O)
CH(Me)
O
—C(O)NH—C(Me)(OH)—C(O)OH


 83B
tBu
CHOH
CH(Me)
O
—C(O)NH—C(Me)(OH)—C(O)OH


 84B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—C(Me)(OH)—C(O)OH


 85B
tBu
C(O)
CH2
O
—C(O)NH—C(Me)(cyclopropyl)CO2H


 86B
tBu
CHOH
CH2
O
—C(O)NH—C(Me)(cyclopropyl)CO2H


 87B
tBu
C(Me)OH
CH2
O
—C(O)NH—C(Me)(cyclopropyl)CO2H


 88B
tBu
C(O)
CH(Me)
O
—C(O)NH—C(Me)(cyclopropyl)CO2H


 89B
tBu
CHOH
CH(Me)
O
—C(O)NH—C(Me)(cyclopropyl)CO2H


 90B
tBu
C(Me)OH
CH(Me)
O
—C(O)NH—C(Me)(cyclopropyl)CO2H


 91B
tBu
C(O)
CH2
O
—C(O)NMe—CH2—C(O)OH


 92B
tBu
CHOH
CH2
O
—C(O)NMe—CH2—C(O)OH


 93B
tBu
C(Me)OH
CH2
O
—C(O)NMe—CH2—C(O)OH


 94B
tBu
C(O)
CH(Me)
O
—C(O)NMe—CH2—C(O)OH


 95B
tBu
CHOH
CH(Me)
O
—C(O)NMe—CH2—C(O)OH


 96B
tBu
C(Me)OH
CH(Me)
O
—C(O)NMe—CH2—C(O)OH


 97B
tBu
C(O)
CH2
O
—C(O)NMe—CH(Me)—C(O)OH


 98B
tBu
CHOH
CH2
O
—C(O)NMe—CH(Me)—C(O)OH


 99B
tBu
C(Me)OH
CH2
O
—C(O)NMe—CH(Me)—C(O)OH


100B
tBu
C(O)
CH(Me)
O
—C(O)NMe—CH(Me)—C(O)OH


101B
tBu
CHOH
CH(Me)
O
—C(O)NMe—CH(Me)—C(O)OH


102B
tBu
C(Me)OH
CH(Me)
O
—C(O)NMe—CH(Me)—C(O)OH


103B
tBu
C(O)
CH2
O
—C(O)NMe—CH(F)—C(O)OH


104B
tBu
CHOH
CH2
O
—C(O)NMe—CH(F)—C(O)OH


105B
tBu
C(Me)OH
CH2
O
—C(O)NMe—CH(F)—C(O)OH


106B
tBu
C(O)
CH(Me)
O
—C(O)NMe—CH(F)—C(O)OH


107B
tBu
CHOH
CH(Me)
O
—C(O)NMe—CH(F)—C(O)OH


108B
tBu
C(Me)OH
CH(Me)
O
—C(O)NMe—CH(F)—C(O)OH


109B
tBu
C(O)
CH2
O
—C(O)NMe—CH(CF3)—C(O)OH


110B
tBu
CHOH
CH2
O
—C(O)NMe—CH(CF3)—C(O)OH


111B
tBu
C(Me)OH
CH2
O
—C(O)NMe—CH(CF3)—C(O)OH


112B
tBu
C(O)
CH(Me)
O
—C(O)NMe—CH(CF3)—C(O)OH


113B
tBu
CHOH
CH(Me)
O
—C(O)NMe—CH(CF3)—C(O)OH


114B
tBu
C(Me)OH
CH(Me)
O
—C(O)NMe—CH(CF3)—C(O)OH


115B
tBu
C(O)
CH2
O
—C(O)NMe—CH(OH)—C(O)OH


116B
tBu
CHOH
CH2
O
—C(O)NMe—CH(OH)—C(O)OH


117B
tBu
C(Me)OH
CH2
O
—C(O)NMe—CH(OH)—C(O)OH


118B
tBu
C(O)
CH(Me)
O
—C(O)NMe—CH(OH)—C(O)OH


119B
tBu
CHOH
CH(Me)
O
—C(O)NMe—CH(OH)—C(O)OH


120B
tBu
C(Me)OH
CH(Me)
O
—C(O)NMe—CH(OH)—C(O)OH


121B
tBu
C(O)
CH2
O
—C(O)NMe—CH(cyclopropyl)-C(O)OH


122B
tBu
CHOH
CH2
O
—C(O)NMe—CH(cyclopropyl)-C(O)OH


123B
tBu
C(Me)OH
CH2
O
—C(O)NMe—CH(cyclopropyl)-C(O)OH


124B
tBu
C(O)
CH(Me)
O
—C(O)NMe—CH(cyclopropyl)-C(O)OH


125B
tBu
CHOH
CH(Me)
O
—C(O)NMe—CH(cyclopropyl)-C(O)OH


126B
tBu
C(Me)OH
CH(Me)
O
—C(O)NMe—CH(cyclopropyl)-C(O)OH


127B
tBu
C(O)
CH2
O
—C(O)NMe—C(Me)2—C(O)OH


128B
tBu
CHOH
CH2
O
—C(O)NMe—C(Me)2—C(O)OH


129B
tBu
C(Me)OH
CH2
O
—C(O)NMe—C(Me)2—C(O)OH


130B
tBu
C(O)
CH(Me)
O
—C(O)NMe—C(Me)2—C(O)OH


131B
tBu
CHOH
CH(Me)
O
—C(O)NMe—C(Me)2—C(O)OH


132B
tBu
C(Me)OH
CH(Me)
O
—C(O)NMe—C(Me)2—C(O)OH


133B
tBu
C(O)
CH2
O
—C(O)NMe—CF(Me)—C(O)OH


134B
tBu
CHOH
CH2
O
—C(O)NMe—CF(Me)—C(O)OH


135B
tBu
C(Me)OH
CH2
O
—C(O)NMe—CF(Me)—C(O)OH


136B
tBu
C(O)
CH(Me)
O
—C(O)NMe—CF(Me)—C(O)OH


137B
tBu
CHOH
CH(Me)
O
—C(O)NMe—CF(Me)—C(O)OH


138B
tBu
C(Me)OH
CH(Me)
O
—C(O)NMe—CF(Me)—C(O)OH


139B
tBu
C(O)
CH2
O
—C(O)NMe—C(Me)(CF3)—C(O)OH


140B
tBu
CHOH
CH2
O
—C(O)NMe—C(Me)(CF3)—C(O)OH


141B
tBu
C(Me)OH
CH2
O
—C(O)NMe—C(Me)(CF3)—C(O)OH


142B
tBu
C(O)
CH(Me)
O
—C(O)NMe—C(Me)(CF3)—C(O)OH


143B
tBu
CHOH
CH(Me)
O
—C(O)NMe—C(Me)(CF3)—C(O)OH


144B
tBu
C(Me)OH
CH(Me)
O
—C(O)NMe—C(Me)(CF3)—C(O)OH


145B
tBu
C(O)
CH2
O
—C(O)NMe—C(Me)(OH)—C(O)OH


146B
tBu
CHOH
CH2
O
—C(O)NMe—C(Me)(OH)—C(O)OH


147B
tBu
C(Me)OH
CH2
O
—C(O)NMe—C(Me)(OH)—C(O)OH


148B
tBu
C(O)
CH(Me)
O
—C(O)NMe—C(Me)(OH)—C(O)OH


149B
tBu
CHOH
CH(Me)
O
—C(O)NMe—C(Me)(OH)—C(O)OH


150B
tBu
C(Me)OH
CH(Me)
O
—C(O)NMe—C(Me)(OH)—C(O)OH


151B
tBu
C(O)
CH2
O
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


152B
tBu
CHOH
CH2
O
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


153B
tBu
C(Me)OH
CH2
O
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


154B
tBu
C(O)
CH(Me)
O
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


155B
tBu
CHOH
CH(Me)
O
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


156B
tBu
C(Me)OH
CH(Me)
O
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


157B
tBu
C(O)
CH2
O
—C(O)—N(Me)-5-tetrazolyl


158B
tBu
CHOH
CH2
O
—C(O)—N(Me)-5-tetrazolyl


159B
tBu
C(Me)OH
CH2
O
—C(O)—N(Me)-5-tetrazolyl


160B
tBu
C(O)
CH(Me)
O
—C(O)—N(Me)-5-tetrazolyl


161B
tBu
CHOH
CH(Me)
O
—C(O)—N(Me)-5-tetrazolyl


162B
tBu
C(Me)OH
CH(Me)
O
—C(O)—N(Me)-5-tetrazolyl









Among other preferred compounds of the invention are also those represented by the formula:




    and pharmaceutically acceptable salts thereof;
    wherein;
    
        said compound is selected from a compound code numbered 1C thru 162C, with each compound having the specific selection of substituents RB, RC, L1, L2, and L3 shown

in the row following the compound code number, as set out in the following Table 4:

    
    















TABLE 4







RB
L3
L2
L1
RC





















1C
tBu
C(O)
CH2
CH2
—C(O)NH—CH2—C(O)OH


2C
tBu
CHOH
CH2
CH2
—C(O)NH—CH2—C(O)OH


3C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—CH2—C(O)OH


4C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—CH2—C(O)OH


5C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—CH2—C(O)OH


6C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—CH2—C(O)OH


7C
tBu
C(O)
CH2
CH2
—C(O)NH—CH(Me)—C(O)OH


8C
tBu
CHOH
CH2
CH2
—C(O)NH—CH(Me)—C(O)OH


9C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—CH(Me)—C(O)OH


10C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—CH(Me)—C(O)OH


11C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—CH(Me)—C(O)OH


12C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—CH(Me)—C(O)OH


13C
tBu
C(O)
CH2
CH2
—C(O)NH—CH(Et)—C(O)OH


14C
tBu
CHOH
CH2
CH2
—C(O)NH—CH(Et)—C(O)OH


15C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—CH(Et)—C(O)OH


16C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—CH(Et)—C(O)OH


17C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—CH(Et)—C(O)OH


18C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—CH(Et)—C(O)OH


19C
tBu
C(O)
CH2
CH2
—C(O)NH—C(Me)2—C(O)OH


20C
tBu
CHOH
CH2
CH2
—C(O)NH—C(Me)2—C(O)OH


21C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—C(Me)2—C(O)OH


22C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—C(Me)2—C(O)OH


23C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—C(Me)2—C(O)OH


24C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—C(Me)2—C(O)OH


25C
tBu
C(O)
CH2
CH2
—C(O)NH—CMe(Et)—C(O)OH


26C
tBu
CHOH
CH2
CH2
—C(O)NH—CMe(Et)—C(O)OH


27C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—CMe(Et)—C(O)OH


28C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—CMe(Et)—C(O)OH


29C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—CMe(Et)—C(O)OH


30C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—CMe(Et)—C(O)OH


31C
tBu
C(O)
CH2
CH2
—C(O)NH—CH(F)—C(O)OH


32C
tBu
CHOH
CH2
CH2
—C(O)NH—CH(F)—C(O)OH


33C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—CH(F)—C(O)OH


34C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—CH(F)—C(O)OH


35C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—CH(F)—C(O)OH


36C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—CH(F)—C(O)OH


37C
tBu
C(O)
CH2
CH2
—C(O)NH—CH(CF3)—C(O)OH


38C
tBu
CHOH
CH2
CH2
—C(O)NH—CH(CF3)—C(O)OH


39C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—CH(CF3)—C(O)OH


40C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—CH(CF3)—C(O)OH


41C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—CH(CF3)—C(O)OH


42C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—CH(CF3)—C(O)OH


43C
tBu
C(O)
CH2
CH2
—C(O)NH—CH(OH)—C(O)OH


44C
tBu
CHOH
CH2
CH2
—C(O)NH—CH(OH)—C(O)OH


45C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—CH(OH)—C(O)OH


46C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—CH(OH)—C(O)OH


47C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—CH(OH)—C(O)OH


48C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—CH(OH)—C(O)OH


49C
tBu
C(O)
CH2
CH2
—C(O)NH—CH(cyclopropyl)-C(O)OH


50C
tBu
CHOH
CH2
CH2
—C(O)NH—CH(cyclopropyl)-C(O)OH


51C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—CH(cyclopropyl)-C(O)OH


52C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—CH(cyclopropyl)-C(O)OH


53C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—CH(cyclopropyl)-C(O)OH


54C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—CH(cyclopropyl)-C(O)OH


55C
tBu
C(O)
CH2
CH2
—C(O)NH—CH(Me)—C(O)OH


56C
tBu
CHOH
CH2
CH2
—C(O)NH—CH(Me)—C(O)OH


57C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—CH(Me)—C(O)OH


58C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—CH(Me)—C(O)OH


59C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—CH(Me)—C(O)OH


60C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—CH(Me)—C(O)OH


61C
tBu
C(O)
CH2
CH2
—C(O)NH—C(Me)2—C(O)OH


62C
tBu
CHOH
CH2
CH2
—C(O)NH—C(Me)2—C(O)OH


63C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—C(Me)2—C(O)OH


64C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—C(Me)2—C(O)OH


65C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—C(Me)2—C(O)OH


66C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—C(Me)2—C(O)OH


67C
tBu
C(O)
CH2
CH2
—C(O)NH—CF(Me)—C(O)OH


68C
tBu
CHOH
CH2
CH2
—C(O)NH—CF(Me)—C(O)OH


69C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—CF(Me)—C(O)OH


70C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—CF(Me)—C(O)OH


71C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—CF(Me)—C(O)OH


72C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—CF(Me)—C(O)OH


73C
tBu
C(O)
CH2
CH2
—C(O)NH—C(Me)(CF3)—C(O)OH


74C
tBu
CHOH
CH2
CH2
—C(O)NH—C(Me)(CF3)—C(O)OH


75C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—C(Me)(CF3)—C(O)OH


76C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—C(Me)(CF3)—C(O)OH


77C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—C(Me)(CF3)—C(O)OH


78C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—C(Me)(CF3)—C(O)OH


79C
tBu
C(O)
CH2
CH2
—C(O)NH—C(Me)(OH)—C(O)OH


80C
tBu
CHOH
CH2
CH2
—C(O)NH—C(Me)(OH)—C(O)OH


81C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—C(Me)(OH)—C(O)OH


82C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—C(Me)(OH)—C(O)OH


83C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—C(Me)(OH)—C(O)OH


84C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—C(Me)(OH)—C(O)OH


85C
tBu
C(O)
CH2
CH2
—C(O)NH—C(Me)(cyclopropyl)CO2H


86C
tBu
CHOH
CH2
CH2
—C(O)NH—C(Me)(cyclopropyl)CO2H


87C
tBu
C(Me)OH
CH2
CH2
—C(O)NH—C(Me)(cyclopropyl)CO2H


88C
tBu
C(O)
CH(Me)
CH2
—C(O)NH—C(Me)(cyclopropyl)CO2H


89C
tBu
CHOH
CH(Me)
CH2
—C(O)NH—C(Me)(cyclopropyl)CO2H


90C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NH—C(Me)(cyclopropyl)CO2H


91C
tBu
C(O)
CH2
CH2
—C(O)NMe—CH2—C(O)OH


92C
tBu
CHOH
CH2
CH2
—C(O)NMe—CH2—C(O)OH


93C
tBu
C(Me)OH
CH2
CH2
—C(O)NMe—CH2—C(O)OH


94C
tBu
C(O)
CH(Me)
CH2
—C(O)NMe—CH2—C(O)OH


95C
tBu
CHOH
CH(Me)
CH2
—C(O)NMe—CH2—C(O)OH


96C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NMe—CH2—C(O)OH


97C
tBu
C(O)
CH2
CH2
—C(O)NMe—CH(Me)—C(O)OH


98C
tBu
CHOH
CH2
CH2
—C(O)NMe—CH(Me)—C(O)OH


99C
tBu
C(Me)OH
CH2
CH2
—C(O)NMe—CH(Me)—C(O)OH


100C
tBu
C(O)
CH(Me)
CH2
—C(O)NMe—CH(Me)—C(O)OH


101C
tBu
CHOH
CH(Me)
CH2
—C(O)NMe—CH(Me)—C(O)OH


102C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NMe—CH(Me)—C(O)OH


103C
tBu
C(O)
CH2
CH2
—C(O)NMe—CH(F)—C(O)OH


104C
tBu
CHOH
CH2
CH2
—C(O)NMe—CH(F)—C(O)OH


105C
tBu
C(Me)OH
CH2
CH2
—C(O)NMe—CH(F)—C(O)OH


106C
tBu
C(O)
CH(Me)
CH2
—C(O)NMe—CH(F)—C(O)OH


107C
tBu
CHOH
CH(Me)
CH2
—C(O)NMe—CH(F)—C(O)OH


108C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NMe—CH(F)—C(O)OH


109C
tBu
C(O)
CH2
CH2
—C(O)NMe—CH(CF3)—C(O)OH


110C
tBu
CHOH
CH2
CH2
—C(O)NMe—CH(CF3)—C(O)OH


111C
tBu
C(Me)OH
CH2
CH2
—C(O)NMe—CH(CF3)—C(O)OH


112C
tBu
C(O)
CH(Me)
CH2
—C(O)NMe—CH(CF3)—C(O)OH


113C
tBu
CHOH
CH(Me)
CH2
—C(O)NMe—CH(CF3)—C(O)OH


114C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NMe—CH(CF3)—C(O)OH


115C
tBu
C(O)
CH2
CH2
—C(O)NMe—CH(OH)—C(O)OH


116C
tBu
CHOH
CH2
CH2
—C(O)NMe—CH(OH)—C(O)OH


117C
tBu
C(Me)OH
CH2
CH2
—C(O)NMe—CH(OH)—C(O)OH


118C
tBu
C(O)
CH(Me)
CH2
—C(O)NMe—CH(OH)—C(O)OH


119C
tBu
CHOH
CH(Me)
CH2
—C(O)NMe—CH(OH)—C(O)OH


120C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NMe—CH(OH)—C(O)OH


121C
tBu
C(O)
CH2
CH2
—C(O)NMe—CH(cyclopropyl)-C(O)OH


122C
tBu
CHOH
CH2
CH2
—C(O)NMe—CH(cyclopropyl)-C(O)OH


123C
tBu
C(Me)OH
CH2
CH2
—C(O)NMe—CH(cyclopropyl)-C(O)OH


124C
tBu
C(O)
CH(Me)
CH2
—C(O)NMe—CH(cyclopropyl)-C(O)OH


125C
tBu
CHOH
CH(Me)
CH2
—C(O)NMe—CH(cyclopropyl)-C(O)OH


126C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NMe—CH(cyclopropyl)-C(O)OH


127C
tBu
C(O)
CH2
CH2
—C(O)NMe—C(Me)2—C(O)OH


128C
tBu
CHOH
CH2
CH2
—C(O)NMe—C(Me)2—C(O)OH


129C
tBu
C(Me)OH
CH2
CH2
—C(O)NMe—C(Me)2—C(O)OH


130C
tBu
C(O)
CH(Me)
CH2
—C(O)NMe—C(Me)2—C(O)OH


131C
tBu
CHOH
CH(Me)
CH2
—C(O)NMe—C(Me)2—C(O)OH


132C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NMe—C(Me)2—C(O)OH


133C
tBu
C(O)
CH2
CH2
—C(O)NMe—CF(Me)—C(O)OH


134C
tBu
CHOH
CH2
CH2
—C(O)NMe—CF(Me)—C(O)OH


135C
tBu
C(Me)OH
CH2
CH2
—C(O)NMe—CF(Me)—C(O)OH


136C
tBu
C(O)
CH(Me)
CH2
—C(O)NMe—CF(Me)—C(O)OH


137C
tBu
CHOH
CH(Me)
CH2
—C(O)NMe—CF(Me)—C(O)OH


138C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NMe—CF(Me)—C(O)OH


139C
tBu
C(O)
CH2
CH2
—C(O)NMe—C(Me)(CF3)—C(O)OH


140C
tBu
CHOH
CH2
CH2
—C(O)NMe—C(Me)(CF3)—C(O)OH


141C
tBu
C(Me)OH
CH2
CH2
—C(O)NMe—C(Me)(CF3)—C(O)OH


142C
tBu
C(O)
CH(Me)
CH2
—C(O)NMe—C(Me)(CF3)—C(O)OH


143C
tBu
CHOH
CH(Me)
CH2
—C(O)NMe—C(Me)(CF3)—C(O)OH


144C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NMe—C(Me)(CF3)—C(O)OH


145C
tBu
C(O)
CH2
CH2
—C(O)NMe—C(Me)(OH)—C(O)OH


146C
tBu
CHOH
CH2
CH2
—C(O)NMe—C(Me)(OH)—C(O)OH


147C
tBu
C(Me)OH
CH2
CH2
—C(O)NMe—C(Me)(OH)—C(O)OH


148C
tBu
C(O)
CH(Me)
CH2
—C(O)NMe—C(Me)(OH)—C(O)OH


149C
tBu
CHOH
CH(Me)
CH2
—C(O)NMe—C(Me)(OH)—C(O)OH


150C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NMe—C(Me)(OH)—C(O)OH


151C
tBu
C(O)
CH2
CH2
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


152C
tBu
CHOH
CH2
CH2
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


153C
tBu
C(Me)OH
CH2
CH2
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


154C
tBu
C(O)
CH(Me)
CH2
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


155C
tBu
CHOH
CH(Me)
CH2
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


156C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)NMe—C(Me)(cyclopropyl)-C(O)OH


157C
tBu
C(O)
CH2
CH2
—C(O)—N(Me)-5-tetrazolyl


158C
tBu
CHOH
CH2
CH2
—C(O)—N(Me)-5-tetrazolyl


159C
tBu
C(Me)OH
CH2
CH2
—C(O)—N(Me)-5-tetrazolyl


160C
tBu
C(O)
CH(Me)
CH2
—C(O)—N(Me)-5-tetrazolyl


161C
tBu
CHOH
CH(Me)
CH2
—C(O)—N(Me)-5-tetrazolyl


162C
tBu
C(Me)OH
CH(Me)
CH2
—C(O)—N(Me)-5-tetrazolyl









Method of Making the Compounds of the Invention:

Compounds of the invention represented by formula (I) may be prepared by the methods set out below. It will be understood by one skilled in the chemical arts that the reactants may be varied to analogous molecules to provide desired substitutions in the final reaction product.
Definitions of Symbols Used in the Schemes:


    
    
        (PhO)2P(O)N3—diphenyl phosphorus azide
        BBr3—boron tribromide
        BF3-OEt2—boron trifluoride etherate
        BnBr—benzyl bromide
        CH3CN—acetonitrile
        DMAP—4-(dimethylamino)pyridine
        DMF—N,N-dimethylformamide
        DMSO—dimethylsulfoxide
        DPPF—dichloro[1,1′-bis(diphenylphosphino)ferrocene
        DPPB—1,4-bis(diphenylphosphino)butane
        EDCI—3-Ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride
        Et3N—triethylamine
        EtOH—ethanol
        H2NCH2CO2Me—methyl glycinate
        HN(OMe)Me—N-methyl-O-methyl hydroxylamine
        HNMe2—dimethyl amine
        K2CO3—potassium carbonate
        KOH—potassium hydroxide
        LAH—lithium aluminum hydride
        LiHMDS—lithium hexamethyldisilazide
        mCPBA—meta-chloroperbenzoic acid
        MeI—methyl iodide
        MeOH—methanol
        NaBH4—sodium borohydride
        NaH—sodium hydride
        NaI—sodium iodide
        NMP—N-methylpyrrolidin-2-one
        Na—S—R3—sodium alkylmercaptide
        PBr3—phosphorus tribromide
        Pd(OAc)2— palladium (II) acetate
        Pd—C—palladium on carbon
        pTSA—para-toluenesulfonic acid
        Pyr—pyridine
        R2MgBr—alkyl magnesium bromide
        R3MgBr—alkyl magnesium bromide
        R5MgBr—alkyl magnesium bromide
        R2S(O)2NH2—alkylsulfonamide
        tBuC(O)CH2Br—2-bromopinacolone
        Tf2O—triflic anhydride
        TFA—trifluoroacetic acid
        THF—tetrahydrofuran

Description of the Schemes:

Preparation of diphenyl acid and diphenyl acylaminotetrazole (Scheme 1).

    
    


A mixture of 3-substituted-4-hydroxy benzoic acid 1a and methanol is treated with HCl (gas) to yield methyl benzoate ester 1. Methyl benzoate ester 1 is reacted with excess alkyl magnesium bromide to produce tertiary alcohol 2. Tertiary alcohol 2 is converted to phenol 4 by reaction with O-benzyl-2-substituted phenol 3a and BF3-Et2O. O-benzyl-2-substituted phenol 3a is derived from the reaction of 2-substituted phenol 3 with benzylbromide and NaH. Phenol 4 is reacted with triflic anhydride/pyridine to give triflate 5 which is subjected to methoxycarbonylation with Pd(OAc)2, DPPF, CO (689-6895 KPa), methanol and triethylamine in either DMF or DMSO at 80-100° C. to yield methyl ester 6. DPPB may be used instead of DPPF for the methoxycarbonylation reaction. Methyl ester 6 is subjected to palladium catalyzed hydrogenolysis and alkylated with NaH/pinacolone bromide to give ketone 7. Ketone 7 is sequentially reacted with sodium borohydride/MeOH and potassium hydroxide/EtOH/H2O/80° C. to produce acid 8. Acid 8 is coupled with EDCI, DMAP and 5-aminotetrazole to give acylamino tetrazole 9. Acid 8 is also coupled with EDCI, DMAP and alkylsulfonamide to give acylsulfonamide 9a.
Preparation of functionalized sidechain analogs (Scheme 2).
Ester 6 is reduced with LAH to give benzyl alcohol 10. Benzyl alcohol 10 is converted to benzylic bromide 11 with PBr3 and alklylated with the enolate of pinacolone to afford ketone 12. Ketone 12 is transformed into keto-ester 14 via Pd—C catalyzed hydrogenolysis, triflate formation with triflic anhydride/pyridine and palladium catalyzed methoxycarbonylation. Keto-ester 14 is subjected to sodium borohydride reduction and potassium hydroxide hydrolysis to produce alcohol-acid 15. Alcohol-acid 15 is coupled with EDCI/Et3N/DMAP/R4NHCH2CO2Me and hydrolyzed with LiOH/EtOH/H2O to afford amide-acid 15a.
Preparation of alkylated pinacolol sidechain (Scheme 3).
Ketone 7 is alkylated with LiHMDS/MeI and reduced with NaBH4/MeOH to give alcohol 16. Alcohol 16 is hydrolyzed with potassium hydroxide to afford alcohol-acid 17. Alcohol-acid 17 is reacted sequentially with 1) EDCI/Et3N/DMAP/R4NHCH2CO2Me; and 2) LiOH/EtOH/H2O to give amide-acid 17a.
Preparation of alkylsulfonylmethyl sidechain analogs (Scheme 4).
Benzylic bromide 11 is reacted with sodium alkylmercaptide and oxidized with mCPBA to give sulfone 18. Sulfone 18 is hydrogenolyzed with Pd—C/H2 and alkylated with pinacolone chloride, potassium carbonate and sodium iodide to produce ketone sulfone 19. Ketone sulfone 19 is reduced with sodium borohydride to afford alcohol sulfone 20.
Preparation of unsymmetrical central link diphenyl scaffold (Scheme 5).
3-Substituted-4-hydroxybenzoic acid is coupled with EDCI/N-methyl-N-methoxyamine/DMAP and alkylated with benzyl bromide to give amide 21. Amide 21 is sequentially reacted with R2MgBr and R3MgBr Grignard reagents to afford tertiary alcohol 23. Alcohol 23 is reacted with 2-substituted phenol 3 and BF3-OEt2 to produce diphenylalkane 24. Diphenylalkane 24 is reacted with triflic anhydride/pyridine and methoxycarbonylated with Pd(OAc)2, (DPPF or DPPB), carbon monoxide, MeOH, and Et3N to give ester 26. Ester 26 is hydrogenolyzed with Pd—C/H2 and alkylated with pinacolone bromide to yield ketone ester 27. Ketone ester 27 is reduced with sodium borohydride and hydrolyzed with potassium hydroxide to afford alcohol-acid 28. Alcohol-acid 28 is coupled with EDCI/Et3N/DMAP/R4NHCH2CO2Me and hydrolyzed with LiOH/EtOH/H2O to afford amide-acid 28a.
Preparation of tertiary alcohol sidechain analog (Scheme 6).
Phenol 4 is alkylated with pinacolone bromide and reacted with MeMgBr or EtMgBr to give alcohol 29. Alcohol 29 is hydrogenolyzed with Pd—C/H2, reacted with triflic anhydride/pyridine and methoxycarbonylated to afford ester 30. Ester 30 is hydrolyzed with potassium hydroxide, coupled with EDCI/Et3N/DMAP/R4NHCH2CO2Me, and hydrolyzed to produce tertiary alcohol amide-acid 31.
Preparation of direct linked tetrazole (Scheme 7).
Acid 8 is reacted with formamide and sodium methoxide to give primary amide 32. Primary amide 32 is treated with trifluoroacetic acid and methylene chloride followed by 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate to give nitrile 33. Nitrile 33 is reacted with sodium azide and triethylammonium hydrochloride in N-methylpyrrolidin-2-one to afford tetrazole 34.
Preparation of amide (Scheme 8).
Acid 8 is reacted with diphenyl phosphorus azide and triethylamine followed by treatment with dimethylamine and 4-(dimethylamino)pyridine to yield amide 35.
Preparation of esters (Scheme 9).
Acid 8 is treated with sodium iodide and N,N-dimethyl-2-chloroacetamide to give ester 36. Acid 8 is treated with sodium iodide and N-morpholinocarbonylmethyl chloride to give ester 37.
Alternative Synthesis of Diphenylalkyl Scaffold (Scheme 10).
Phenol 2 is heated with pTSA to give olefin 38. Olefin 38 is alkylated with 2-chloropinacolone and reacted with a 2-substituted phenol/BF3-OEt2 to yield phenol 40. Phenol 40 is converted to the corresponding phenolic triflate and reduced to alcohol 41. Alcohol 41 is methoxycarbonylated to afford ester 42. Ester 42 is hydrolyzed to produce acid 8.
Synthesis of Pentynol Phenyl alkyl Phenyl Acids (Scheme 11).
Ester 26 is hydrogenolyzed with Pd—C/H2 and reacted with Tf2O/pyridine to give triflate 43. Triflate 43 is sequentially reacted with 1) TMS-acetylene, PdCl2(PPh3)2, Et3N, and DMF and 2) CsF and water to afford acetylene 44. Acetylene 44 is treated with Zn(OTf)2/t-butyl aldehyde/chiral auxiliary (with or without) to give alcohol 46. Alternatively, acetylene 44 is reacted with LiHMDS/ketone 45 to give alcohol 46. Alcohol 46 is hydrolyzed with KOH/EtOH/H2O to afford acid 47. Acid 47 is sequentially reacted with 1) EDCI/Et3N/DMAP/R4NHCH2CO2Me and 2) LiOH/EtOH/H2O to give amide-acid 48.
Synthesis of Cis-Pentenol Phenyl alkyl Phenyl Acids (Scheme 12).
Amide-acid 48 is hydrogenated with Lindlar catalyst to afford cis-pentenol amide-acid 49.
Synthesis of trans-Pentenol Phenyl Alkyl Phenyl Acids (Scheme 13).
Triflate 25 is sequentially reacted with 1) TMS-acetylene, PdCl2(PPh3)2, Et3N, and DMF and 2) CsF and water to afford acetylene 50. Acetylene 50 is treated with Zn(OTf)2/t-butyl aldehyde/chiral auxiliary (with or without) to give alcohol 51. Alternatively, acetylene 50 is reacted with LiHMDS/ketone 45 to give alcohol 51. Alcohol 51 is reduced with LAH or DiBAH to afford trans-pentenol 52. Trans-pentenol 52 is sequentially reacted with 1) Pd—C/H2; 2) Tf20/pyridine; 3) Pd(OAc)2, DPPF, CO, MeOH, Et3N, DMF; 4) KOH/EtOH/H2O; 5) EDCI/Et3N/DMAP/R4NHCH2CO2Me; and 6) LiOH/EtOH/H2O to give trans-pentenol amide-acid 53. For reaction step 3, DPPB and DMSO.


























































EXAMPLES
Abbreviations:
The following examples use several standard abbreviations, for example;

    “RT” is room temperature, “Rt” or tret are symbols for retention time, and “Hex” refers to hexanes
    Concentration is performed by evaporation from RT to about 70° C. under vacuum (1-10 mm)


Example 1
Preparation of racemic 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane




A. 3′,3′-Bis[4-hydroxy-3-methylphenyl]pentane




To a mixture of o-cresol (196 g, 1.81 mol) and 3-pentanone (60 ml, 0.57 mol) is added methanesulfonic acid (45 ml, 0.69 mol) and stirred for 3 days. The reaction is basified to pH 8 with satd Na2CO3 and extracted with EtOAc. The organic layer is washed with water (6×500 ml), Na2SO4 dried, concentrated, chromatographed (2 kg SiO2, Hex to 80% EtOAc/Hex), and triturated with Hex to give the title compound as a white solid (100 g, 61%).
NMR 400 mHz (DMSO): δ 0.49 (t, J=7.3 Hz, 6H), 1.91 (q, J=7.3 Hz, 4H), 2.02 (s, 6H), 6.61 (d, J=8.3 Hz, 2H), 6.73 (d, J=8.3 Hz, 2H), 6.76 (s, 2H), 8.94 (s, 2H).
High Res. EI-MS: 284.1794; calc. for C19H24O2: 284.1776
B. 3′-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl)]-3′-[4-hydroxy-3-methylphenyl]pentane




To a mixture of 60% NaH disp (8.0 g, 200 mmol) and DMF (600 ml) is added 3,3-bis[4-hydroxy-3-methylphenyl]pentane (56.88 g, 200 mmol) and stirred for 2 h. To the reaction is added 3,3-dimethyl-1-bromo-2-butanone (26.93 ml, 200 mmol) dropwise and stirred overnight. The solvent is removed in-vacuo. To the resulting residue is added EtOAc/water (800 ml/200 ml), acidified to pH 3 with 5N HCl, and partitioned. The organic layer is washed with water (2×), brine, Na2SO4 dried, concentrated, and chromatographed (3 kg SiO2, hex to 15% EtOAc/hex) to give the title compound as a white solid (35 g, 46%).
NMR (300 mHz, DMSO): δ 0.52 (t, J=7.3 Hz, 6H), 1.16 (s, 9H), 1.95 (q, J=7.3 Hz, 4H), 2.04 (s, 3H), 2.12 (s, 3H), 5.05 (s, 2H), 6.57 (d, J=9.1 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.81 (m, 2H), 8.97 (s, 1H).
ES-MS: 400 (M+NH4).
C. 3′-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane




To a 0° C. solution of 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl)]-3′-[4-hydroxy-3-methylphenyl]pentane (20 g, 52 mmol), pyridine (30 ml) is added Tf2O (9.7 ml, 57 mmol). The mixture is warmed to RT and stirred 14 h. The reaction is concentrated. The residue is partitioned between Et2O/1N HCl. The organic layer is washed with water, brine, Na2SO4 dried, concentrated, and chromatographed (hex to 10% EtOAc/hex) to give the title compound as an oil (26.3 g, 98%).
NMR (300 mHz, DMSO): δ 0.53 (t, J=7.3 Hz, 6H), 1.16 (s, 9H), 2.04 (q, J=7.3 Hz, 4H), 2.14 (s, 3H), 2.28 (s, 3H), 5.07 (s, 2H), 6.61 (d, J=8.8 Hz, 1H), 6.86 (dd, J=2.2, 8.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 7.10 (dd, J=2.2, 8.8 Hz, 1H), 7.25 (m, 2H).
ES-MS: 532.5 (M+NH4).
D. 3′-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane




To a 0° C. mixture of 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane (25.5 g, 49.5 mmol) and MeOH (200 ml) is added NaBH4 (2.63 g, 59.4 mol) in portions. After stirring for 15 m, the reaction is allowed to warm to RT and stirred for 16 h. The reaction is concentrated and partitioned between Et2O/1N HCl. The organic layer is washed with water, Na2SO4 dried, and concentrated to give the title compound as an oil (26.0 g, quant).
NMR (300 mHz, DMSO): δ 0.55 (t, J=7.3 Hz, 6H), 0.92 (s, 9H), 2.04 (q, J=7.3 Hz, 4H), 2.11 (s, 3H), 2.28 (s, 3H), 3.46 (m, 1H), 3.76 (m, 1H), 4.03 (m, 1H), 4.78 (d, J=5.5 Hz, 1H), 6.89 (m, 3H), 7.10 (dd, J=1.8, 8.8 Hz, 1H), 7.23 (m, 2H).
High Res. EI-MS, m/e: 516.2171; calc. for C26H35F3O5S: 516.2157.
E. 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane
A mixture of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane (27 g, 52.2 mmol), Pd(OAc)2 (1.2 g, 5.22 mmol), Dppf (5.8 g, 10.4 mmol), MeOH (21 ml, 522 mmol), Et3N (22 ml, 157 mmol), and DMF (100 ml) is pressurized with carbon monoxide (1000 psi) and heated to 110° C. for 48 h. After cooling, the reaction is filtered through diatomaceous earth with EtOAc wash. The filtrate is diluted with 1:1 Et2O:EtOAc, washed with 1N HCl, and filtered through diatomaceous earth, Na2SO4 dried, concentrated, and chromatographed (hex to 10% EtOAc/hex) to give the title compound (14 g, 63%).
NMR 300 MHz(DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 0.92 (s, 9H), 2.04 (q, J=7.3 Hz, 4H), 2.09 (s, 3H), 2.46 (s, 3H), 3.45 (m, 1H), 3.76 (m, 4H), 4.02 (m, 1H), 4.78 (d, J=5.5 Hz, 1H), 6.83 (m, 2H), 6.92 (dd, J=2.2, 8.4 Hz, 1H), 7.07 (m, 2H), 7.74 (d, J=8.1 Hz, 1H).
High Res. FAB-MS: 426.2750; calc. for C27H38O4: 426.2770.
Example 2
Preparation of racemic 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane




A mixture of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane (8.3 g, 19.4 mmol), EtOH (100 ml), water (100 ml) is added KOH (10.8 g, 97 mmol) and heated to 75° C. for 8 h. The reaction is concentrated with a stream of nitrogen and the residue is partitioned between 1:1 Et2O:EtOAc and 1N HCl. The organic layer is washed with water, Na2SO4 dried, concentrated, and chromatographed (gradient 20% EtOAc/MeCl2 to 30% EtOAc/CHCl3) to give the title compound as a white foam (7.85 g, 95%).
NMR mHz(DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 0.92 (s, 9H), 2.05 (q, J=7.3 Hz, 4H), 2.10 (s, 3H), 2.47 (s, 3H), 3.45 (m, 1H), 3.76 (m, 1H), 4.02 (dd, J=3.3, 9.9 Hz, 1H), 4.78 (d, J=5.1 Hz, 1H), 6.83 (m, 2H), 6.92 (dd, J=1.8, 8.4 Hz, 1H), 7.05 (m, 2H), 7.72 (d, J=8.1 Hz, 1H), 12.60 (br s, 1H).
High Res. ES-MS: 435.2498; calc. for C26H36O4+Na: 435.2511
Example 3A and Example 3B
Preparation of enantiomers of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl)]pentane




A mixture of racemic 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl)]pentane, Example 3, is chromatographed with a ChiralPak AD column to give enantiomer 1, Example 3A (110 mg, 37%) and enantiomer 2, Example 3B (110 mg, 37%).
Enantiomer 1, Example 3A
HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow rate); Rt=6.2 m
NMR eq. To Example 2.
High Res. ES-MS: 411.2521; calc. for C26H36O4—H: 411.2535
Enantiomer 2, Example 3B
HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow rate); Rt=7.3 m
NMR eq. To Example 2.
High Res. ES-MS: 413.2728; calc. for C26H36O4+H, 413.2692
Example 3A Alternate Method
Preparation of enantiomer 1 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane from enantiomer 1 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane
Using a procedure analogous to Example 2, enantiomer 1 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane, Example 4A, gave the title compound as a glassy solid (1.3 g, quant).
Enantiomer 1, Example 3A
HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow rate); Rt=7.0 m
NMR eq. To Example 2.
High Res. ES-MS: 435.2533; calc. for C26H36O4+Na: 435.2511
High Res. ES-MS: 430.2943; calc. for C26H36O4+NH4: 430.2943
HPLC correlation of Example 3A (derived from chiral HPLC of 2) and 3A (derived from the hydrolysis of 4A):

    A mixture of Example 3A (1 mg) (derived from chiral HPLC of 2) and 3A (1 mg) (derived from the hydrolysis of 4A) is dissolved in TFA/20% IPA/80% and analyzed by HPLC;
    ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow rate); to give a single peak with Rt=7.0 m.

Example 3B Alternate Method



Preparation of enantiomer 2 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane from enantiomer 2 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane
Using a procedure analogous to Example 2, enantiomer 2 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane, Example 4B, gave the title compound as a glassy solid (1.3 g, quant).
Enantiomer 2, Example 3B
HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow rate); Rt=8.0 m
NMR eq. To Example 2.
High Res. ES-MS: 435.2536; calc. for C26H36O4+Na: 435.2511
HPLC correlation of Example 3B (derived from chiral HPLC of 2) and 3B (derived from the hydrolysis of 4B): A mixture of Example 3B (1 mg) (derived from chiral HPLC of 2) and 3B (1 mg) (derived from the hydrolysis of 4B) is dissolved in TFA/20% IPA/80% and analyzed by HPLC; ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow rate); to give a single peak with Rt=8.16 m.
Example 4A and 4B
Preparation of enantiomers of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane




A mixture of racemic 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane, Example 1, is chromatographed with a ChiralPak AD column to give enantiomer 1, Example 4A (1.72 g, 49%) and enantiomer 2, Example 4B (1.72 g, 49%).
Enantiomer 1, Example 4A
HPLC: ChiralPak AD (4.6×250 mm); 15% IPA/80% heptane; 1 ml/m (flow rate); Rt=5.4 m
NMR eq. To Example 1.
High Res. ES-MS: 444.3130; calc. for C27H38O4+NH4: 444.3114
Enantiomer 2, Example 4B
HPLC: ChiralPak AD (4.6×250 mm); 15% IPA/80% heptane; 1 ml/m (flow rate); Rt=8.0 m
NMR eq. To Example 1.
High Res. ES-MS: 444.3134; calc. for C27H38O4+NH4: 444.3114
Example 5
Preparation of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methylsulfonylaminocarbonyl-3-methylphenyl)]pentane




To a mixture of methane sulfonamide (92 mg, 0.97 mmol), EDCI (186 mg, 0.97 mmol), DMAP (118 mg, 0.97 mmol) and CH2Cl2 (7 ml) is added 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane, Example 1, (400 mg, 0.97 mmol) and stirred overnight. The reaction is diluted with CH2Cl2, washed with 1N HCl (4×20 ml), Na2SO4 dried, concentrated, and chromatographed (gradient CHCl3 to 10% CH3CN/CHCl3) to give the title compound as a solid (240 mg, 51%).
NMR mHz(DMSO): δ 0.60 (t, J=7.3 Hz, 6H), 1.01 (s, 9H), 2.06 (q, J=7.3 Hz, 4H), 2.17 (s, 3H), 2.42 (d, J=2.9 Hz, 1H), 2.49 (s, 3H), 3.43 (s, 3H), 3.70 (d, J=8.8 Hz, 1H), 3.86 (t, J=8.8 Hz, 1H), 4.09 (dd, J=2.4, 9.3 Hz, 1H), 6.71 (d, 8.8 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.91 (dd, J=2.4, 8.8 Hz, 1H), 7.09 (m, 2H), 7.37 (d, J=7.8 Hz, 1H), 12.30 (s, 1H).
High Res. ES-MS: 490.2633; calc. for C27H39NO5S+H, 490.2627
Example 6
Preparation of 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-carboxylethyl)-3-methylphenyl]pentane




A. 3′-[4-Benzyloxy-3-methylphenyl]-3′-[4-hydroxy-3-methylphenyl]pentane




To a solution of 3,3-bis[4-hydroxy-3-methylphenyl]pentane (10 g, 35.2 mmol) and DMF (180 ml) is added 60% NaH disp (1.4 g, 35.2 mmol). After stirring for 30 m, to the reaction is added benzyl bromide (4.2 ml, 35.2 mmol). The mixture is stirred for 14 h and concentrated in vacuo. The residue is partitioned between Et2O/water. The organic layer is washed with 1N HCl, water, brine, Na2SO4 dried, concentrated, and chromatographed (MeCl2) to give the title compound as an oil (6.5 g, 49%).
NMR 300 MHz(DMSO): δ 0.52 (t, J=7.3 Hz, 6H), 1.96 (q, J=7.3 Hz, 4H), 2.04 (s, 3H), 2.12 (s, 3H), 5.05 (s, 2H), 6.63 (d, J=8.1 Hz, 1H), 6.75 (dd, J=2.2, 8.1 Hz, 1H), 6.79 (s, 1H), 6.89 (m, 3H), 7.44 (m, 5H), 8.96 (s, 1H).
High Res. FAB-MS: 374.2237; calc. for C26H30O2: 374.2246
B. 3′-[4-Benzyloxy-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane




Using a procedure analogous to Example 1C, 3′-[4-benzyloxy-3-methylphenyl]-3′-[4-hydroxy-3-methylphenyl]pentane gives the title compound as an oil (21.5 g, 91%).
NMR 300 MHz(DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 2.05 (q, J=7.3 Hz, 4H), 2.14 (s, 3H), 2.28 (s, 3H), 5.06 (s, 2H), 7.10 (dd, J=2.2, 8.8 Hz, 1H), 7.26 (m, 2H), 7.34 (d, J=7.0 Hz, 1H), 7.39 (m, 4H).
High Res. FAB-MS: 506.1743; calc. for C27H29F3O4S: 506.1739
C. 3′-[4-Benzyloxy-3-methylphenyl]-3′-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentane




To a mixture of 3′-[4-benzyloxy-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane (5.3 g, 10.5 mmol) and THF (5 ml) is sequentially added Pd(dppf)Cl2 (860 mg, 1.05 mmol), LiCl (1.78 g, 42 mmol), and 0.5 M BrZnCH2CH2CO2Et in THF (63 ml, 31.4 mmol). The mixture is heated to 60° C. for 18 h. After cooling to RT, the mixture is concentrated in-vacuo, partitioned between Et2O/EtOAc/1N HCl. The organic layer is washed with 1N HCl, water, Na2SO4 dried, concentrated, and chromatographed (hex to 10% EtOAc/hex) to give the title compound (2.5 g, 52%).
NMR 400 MHz(DMSO): δ 0.51 (t, J=7.3 Hz, 6H), 1.14 (t, J=7.1 Hz, 3H), 2.00 (q, J=7.3 Hz, 4H), 2.10 (s, 3H), 2.18 (s, 3H), 2.52 (t, J=8.1 Hz, 2H), 2.75 (t, J=8.1 Hz, 2H), 4.01 (q, J=7.1 Hz, 2H), 5.03 (s, 2H), 6.87 (m, 5H), 6.98 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.3 Hz, 1H), 7.37 (m, 2H), 7.43 (d, J=7.1 Hz, 2H).
High Res. ES-MS: 476.3178; calc. for C31H38O3+NH4: 476.3165
D. 3′-[4-Hydroxy-3-methylphenyl]-3′-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentane




A mixture of 3′-[4-benzyloxy-3-methylphenyl]-3′-[4-(2-ethoxycarbonyl ethyl)-3-methylphenyl]pentane (2.4 g, 5.45 mmol), EtOH (20 ml), and 10% Pd/C (250 mg) is hydrogenated at atmospheric pressure for 18 h. The reaction is filtered through diatomaceous earth with EtOAc wash. The filtrate is concentrated to give the title compound (2 g, quant).
NMR 400 MHz(DMSO): δ 0.49 (t, J=7.3 Hz, 6H), 1.12 (t, J=7.1 Hz, 3H), 1.95 (q, J=7.3 Hz, 4H), 2.01 (s, 3H), 2.18 (s, 3H), 2.52 (t, J=7.7 Hz, 2H), 2.75 (t, J=7.7 Hz, 2H), 4.01 (q, J=7.1 Hz, 2H), 6.61 (d, J=8.3 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 6.77 (s, 1H), 6.86 (m, 2H), 6.97 (d, J=7.8 Hz, 1H), 8.98 (s, 1H).
High Res. ES-MS: 391.2218; calc. for C24H32O3+Na: 391.2249
E. 3′-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentane




Using a procedure analogous to Example 1B, 3′-[4-hydroxy-3-methylphenyl]-3′-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentane and 1-bromo-3,3-dimethyl-2-butanone gave the title compound (2.1 g, 83%).
1H NMR 400 MHz (DMSO-d6): δ 0.50 (t, J=7.3 Hz, 6H), 1.05-1.14 (m, 12H), 1.98 (q, J=7.3 Hz, 4H), 2.10 (s, 3H), 2.18 (s, 3H), 2.52 (t, J=7.7, 2H), 2.75 (t, J=7.7, 2H), 4.02 (q, J=7.2 Hz, 2H), 5.04 (s, 2H), 6.55 (d, J=8.3 Hz, 1H), 6.82-6.89 (m, 4H), 6.98 (d, J=8.1, 1H).
High Res. ES-MS: 489.2990; calc. for C30H42O4+Na: 489.2981
F. 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxylethyl-3-methylphenyl]pentane
Using a procedure analogous to Example 2,3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentane gives the title compound (1.8 g, 95%).
1H NMR 300 MHz (DMSO-d6): δ 0.52 (t, J=7.3 Hz, 6H), 1.16 (s, 9H), 2.01 (q, J=7.32 Hz, 4H), 2.13 (s, 3H), 2.20 (s, 3H), 2.46 (t, J=7.3 Hz, 2H), 2.74 (t, J=7.3 Hz, 2H), 5.06 (s, 2H), 6.58 (d, J=8.4 Hz, 1H), 6.89 (m, 4H), 7.01 (d, J=7.7 Hz, 1H).
High Res. ES-MS: 461.2669; calc. for C28H38O4+Na: 461.2668
Example 7
Preparation of 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-dimethylcarbamoylethyl)-3-methylphenyl]pentane




To a 0° C. mixture of 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-carboxylethyl)-3-methylphenyl]pentane (500 mg, 1.14 mmol), pyridine (101 ul, 1.25 mmol), DMF (4.4 ul, 0.057 mmol) and MeCl2 (4 ml) is added oxalyl chloride (104 ul, 1.2 mmol). After stirring for 10 m, to the mixture is added 2M Me2NH/THF (2.3 ml, 4.56 mmol). To the reaction is added MeCl2 (4 ml) and stirred at RT for 2 h. The mixture is concentrated and partitioned between Et2O/1N HCl. The organic layer is washed with water, Na2SO4 dried, concentrated, and chromatographed (hex to CH2Cl2 to 15% EtOAc/MeCl2) to give the title compound as a solid (85 mg, 16%).
1H NMR 400 MHz (DMSO-d6): δ 0.51 (t, J=7.3 Hz, 6H), 1.14 (s, 9H), 1.96 (q, J=7.3 Hz, 4H), 2.11 (s, 3H), 2.19 (s, 3H), 2.48 (t, J=7.2, J=8.8 Hz, 2H, under DMSO peak), 2.69 (t, J=7.2, J=8.8 Hz, 2H), 2.79 (s, 3H), 2.88 (s, 3H), 5.05 (s, 2H), 6.55 (d, J=8.8 Hz, 1H), 6.84-6.87 (m, 4H), 6.99 (d, J=8.3 Hz, 1H).
ES-MS: 466.2 (M+H)
Example 8
Preparation of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-dimethylcarbamoylethyl)-3-methylphenyl]pentane




Using a procedure analogous to Example 1D, 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-dimethylcarbamoylethyl)-3-methylphenyl]pentane gives the title compound as a white glassy solid (65 mg, quant).
1H NMR 300 MHz (DMSO-d6): δ 0.53 (t, J=7.0 Hz, 6H), 0.92 (s, 9H), 6.96 (q, J=6.96 Hz, 4H), 2.10 (s, 3H), 2.20 (s, 3H), 2.50 (t, J=6.9, J=8.4 Hz, 2H, under DMSO peak), 2.71 (t, J=6.9, J=8.4 Hz, 2H), 2.80 (s, 3H), 2.90 (s, 3H), 3.45 (m, 1H), 3.75 (m, 1H), 4.01 (dd, J=2.9, J=6.9 Hz, 1H), 6.80 (d, J=8.4, 1H), 6.89 (m, 4H), 7.01 (d, J=8.0 Hz, 1H).
High Res. ES-MS: 490.3301; calc. for C30H45NO3+Na: 490.3297
Example 9
Preparation of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-dimethylcarbamoyl-t-ethylidene)-3-methylphenyl]pentane




To a mixture of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane (640 mg, 1.24 mmol), Pd(OAc)2 (14 mg, 0.062), DPPP (51 mg, 0.124 mmol), and DMF (2.5 ml) is added Et3N (0.69 ml, 4.96 mmol). The mixture is purged with N2 and N,N-dimethylacrylamide (0.39 ml, 3.71 mmol) is added. The reaction is heated to 80° C. for 14 h and then cooled. The mixture is partitioned between EtOAc/water. The organic layer is washed with 1N HCl, water, brine, Na2SO4 dried, concentrated, and chromatographed (MeCl2 to 60% EtOAc/MeCl2) to give the title compound as a white foam (90 mg, 16%).
1H NMR 300 MHz (DMSO-d6): δ 0.55 (t, J=7.0 Hz, 6H), 0.92 (s, 9H), 2.04 (q, J=7.0 Hz, 4H), 2.10 (s, 3H), 2.31 (s, 3H), 2.92 (s, 3H), 3.13 (s, 3H), 3.45 (m, 1H), 3.75 (dd, J=7.4, 9.9 Hz, 1H), 4.02 (dd, J=3.3, 9.9 Hz, 1H), 4.78 (d, J=5.1 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.87 (s, 1H), 6.96 (m, 3H), 7.01 (s, 1H), 7.62 (m, 2H).
High Res. ES-MS: 466.3328; calc. for C30H44NO3+H, 466.3321
Preparation of enantiomers of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane




A. 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane




Using a procedure analogous to Example 1B, 3′-[4-hydroxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane gave the title compound as a white solid (19.5 g, 88%).
NMR 300 mHz(DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 1.16 (s, 9H), 2.05 (q, J=7.3 Hz, 4H), 2.13 (s, 3H), 2.47 (s, 3H), 3.79 (s, 3H), 5.07 (s, 2H), 6.59 (d, J=9.1 Hz, 1H), 6.86 (m, 2H), 7.06 (d, J=8.1 Hz, 1H), 7.11 (s, 1H), 7.72 (d, J=8.1 Hz, 1H).
High Res. ES-MS: 442.2953; calc. for C27H36O4+NH4: 442.2957.
B. 3′-[4-(2-oxo-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane




To a −78° C. mixture of 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-methoxycarbonyl-3-methylphenyl)]pentane (2.0 g, 4.7 mmol) in THF (10 ml) is added 1M LiHMDS/THF (5.2 ml, 5.2 mmol). The reaction is warmed to −45° C., stirred for 1.25 h, added MeI (351 ul, 5.6 mmol). After warming to RT and stirred overnight, the reaction is diluted with Et2O, washed with 1N HCl, water, and Na2SO4 dried. The organic solution is concentrated and chromatographed (50% CHCl3/hex) to give the title compound (1.75 g, 85%).
NMR 300 mHz(DMSO): δ 0.53 (t, J=7.3 Hz, 6H), 1.10 (s, 9H), 1.34 (d, J=6.6 Hz, 3H), 2.04 (q, J=7.3 Hz, 4H), 2.10 (s, 3H), 2.46 (s, 3H), 3.79 (s, 3H), 5.32 (q, J=6.6 Hz, 1H), 6.88 (m, 3H), 7.05 (d, J=8.4 Hz, 1H), 7.10 (s, 1H), 7.71 (d, J=8.1 Hz, 1H).
High Res. ES-MS: 456.3107; calc. for C28H38O4+NH4: 456.3114
C. 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane




Using a procedure analogous to Example 1D, 3′-[4-(2-oxo-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane gives the title compound (1.6 g, 100%).
NMR 300 mHz(DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 1.19 (d, J=5.9 Hz, 3H), 2.07 (m, 7H), 2.48 (s, 3H), 3.08 (dd, J=1.1, 7.7 Hz, 1H), 3.79 (s, 3H), 4.35 (d, J=7.7 Hz, 1H), 4.57 (br q, J=5.9 Hz, 1H), 6.84 (m, 3H), 7.06 (br d, J=8.4 Hz, 1H), 7.14 (s, 1H), 7.72 (d, J=8.4 Hz, 1H).
High Res. ES-MS: 456.3107; calc. for C28H38O4+NH4: 456.3114.
D. Enantiomers of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane
Using a procedure analogous to Example 1D, 3′-[4-(2-oxo-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane gave a racemic mixture of the title compound. The mixture is chromatographed (Chiralpak AD) to give enantiomer 1 (543 mg, 36%, Rt=) and enantiomer 2 (822 mg, 55%, Rt=).
Enantiomer 1 Example 10Da
NMR 300 mHz (DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 1.20 (d, J=6.2 Hz, 3H), 2.07 (m, 7H), 2.48 (s, 3H), 3.08 (dd, J=1.5, 7.7 Hz, 1H), 3.79 (s, 3H), 4.35 (d, J=7.7 Hz, 1H), 4.57 (m, 1H), 6.84 (m, 3H), 7.06 (dd, J=1.1, 8.4 Hz, 1H), 7.14 (s, 1H), 7.72 (d, J=8.4 Hz, 1H).
High Res. ES-MS: 458.3257; calc. for C28H40O4+NH4: 458.3270.
Enantiomer 2 Example 10Db
NMR 300 mHz (DMSO): eq. to enantiomer 1.
MS: 440.29 (M+).
High Res. ES-MS: calc. for C27H39NO5S+H:
Example 11
Preparation of enantiomer 1 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane




Using a procedure analogous to Example 2, enantiomer 1 of 3′-[4-(1-methyl-2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane, Example 10Da, gave the title compound (420 mg, 96%).
HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow rate); Rt=m
NMR 300 mHz (DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), d, J=5.9 Hz, 3H), 2.07 (m, 7H), 2.48 (s, 3H), 3.08 (dd, J=1.1, 7.7 Hz, 1H), 4.35 (d, J=7.7 Hz, 1H), 4.57 (m, 1H), 6.84 (m, 3H), 7.04 (d, J=8.1 Hz, 1H), 7.10 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 12.60 (br s, 1H).
High Res. ES-MS: 875.5439; calc. for [C27H38O4+Na]+C27H38O4: 875.5438.
Example 12
Preparation of enantiomer 2 of 3′-[4-(2-hydroxy-3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl)]pentane




Using a procedure analogous to Example 2, enantiomer 2 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane, Example 10Db, gave the title compound (680 mg, 94%).
HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow rate); Rt=m
NMR 300 mHz (DMSO): eq. to enantiomer 1.
High Res. ES-MS: 449.2657; calc. for C27H38O4+Na: 449.2668.
Example 12a
Preparation enantiomer 1 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane




Using a procedure analogous to Example 5, enantiomer 1 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane, Example 3A, and 5-aminotetrazole give the title compound (440 mg, 95%).
NMR 300 mHz (DMSO): 0.57 (t, J=7.3 Hz, 6H), 0.92 (s, 9H), 2.09 (m, 7H), 2.40 (s, 3H), 3.46 (m, 1H), 3.76 (dd, J=7.3, 10.2 Hz, 1H), 4.03 (dd, J=3.3, 10.2 Hz, 1H), 4.79 (d, J=5.5 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.12 (s, 1H), 7.52 (d, J=8.1 Hz, 1H), 12.23 (s, 1H), 16.00 (br s, 1H).
High Res. ES-MS: 480.2983; calc. for C27H37N5O3+H, 480.2975.
Example 12b
Preparation enantiomer 2 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane




Using a procedure analogous to Example 5, enantiomer 2 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane, Example 3B, and 5-aminotetrazole gives the title compound (385 mg, 83%).
NMR 300 mHz (DMSO): eq. to enantiomer of 1.
High Res. ES-MS: 480.2968; calc. for C27H37N5O3+H, 480.2975.
Example 13
Preparation of 1-[4-(1-ethyl-1-{4-[(2-methanesulfonyl-ethylamino)-methyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-3,3-dimethyl-butan-2-one




A. Methyl 4-(1-{4-[2-(tert-Butyldimethylsilanyloxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methyl-benzoate




To a solution of the methyl 4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoate (4.79 g, 11.24 mmol), Example 1, in DMF (40 mL) is added imidazole (1.14 g, 16.87 mmol) followed by the addition of TBSCl (1.78 g, 11.80 mmol). The mixture is stirred at RT overnight and concentrated. The mixture is partitioned between 0.1 M HCl (100 mL) and EtOAc (100 mL). The aqueous layer is extracted with EtOAC. The combined organic layers is MgSO4 dried, concentrated, and chromatographed (10% EtOAc/Hex) to give the title compound (4.37 g, 72%).
1H NMR (CDCl3): δ 0.04 (s, 3H), 0.10 (s, 3H), 0.60 (t, J=7.0 Hz, 6H), 0.89 (s, 9H), 0.96 (s, 9H), 2.04-2.09 (m, 4H), 2.16 (s, 3H), 2.55 (s, 3H), 3.66 (dd, J=5.6, 3.6 Hz, 1H), 3.82-3.86 (m, 4H), 3.97 (dd, J=10.0, 3.2 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.83-7.06 (m, 4H), 7.79 (d, J=7.6 Hz, 1H). ES-MS (m/z): calcd for C33H52O4Si (M+): 540.9; found: 541.2.
B. [4-(1-{4-[2-(tert-Butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylphenyl]-methanol




To a 0° C. solution of the methyl 4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methyl-benzoate (4.37 g, 8.09 mmol) in THF (50 mL) is added LiAlH4 (0.31 g, 8.09 mmol). The reaction is stirred for 10 m and allowed to warm to RT overnight. The mixture is cooled to 0° C. and quenched successively with H2O (0.3 mL), 15% NaOH (0.3 mL) and H2O (0.9 mL). The mixture is stirred for 10 m, warmed to RT, stirred for 20 m, filtered through celite with EtOAc (100 mL) wash, and concentrated to give the title compound (4.14 g, 8.08 mmol, 99%).
1H NMR (CDCl3): δ 0.04 (s, 3H), 0.10 (s, 3H), 0.59 (t, J=7.1 Hz, 6H), 0.89 (s, 9H), 0.94 (s, 9H), 2.05 (q, J=7.1 Hz, 4H), 2.17 (s, 3H), 2.31 (s, 3H), 3.66 (dd, J=6.0, 3.6 Hz, 1H), 3.70 (t, J=5.6 Hz, 1H), 3.84 (dd, J=9.8, 5.2 Hz, 1H), 3.97 (dd, J=9.8, 3.6 Hz, 1H), 4.67 (s, 2H), 6.65 (d, J=8.4 Hz, 1H), 6.88-7.02 (m, 4H), 7.21 (d, J=8.0 Hz, 1H). ES-MS (m/z): calcd for C32H56NO3Si (M+NH4)+: 530.9; found: 530.2.
C. 4-(1-{4-[2-(t-Butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzaldehyde




To a solution of [4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylphenyl]methanol (0.25 g, 0.48 mmol) in CH2Cl2 (4 mL) is added powdered 4 Å molecular sieves (250 mg) followed by the addition of NMO (84 mg, 0.72 mmol), and TPAP (8.4 mg, 0.02 mmol). The resulting mixture is stirred at RT for 5 m, filtered through silica gel, washed with EtOAc, and the combined filtrate is concentrated to give the title compound (0.20 g, 83%).
1H NMR (CDCl3): δ 0.04 (s, 3H), 0.10 (s, 3H), 0.61 (t, J=7.2 Hz, 6H), 0.89 (s, 9H), 0.96 (s, 9H), 2.09 (q, J=7.2 Hz, 4H), 2.17 (s, 3H), 2.62 (s, 3H), 3.67 (dd, J=5.4, 3.4 Hz, 1H), 3.85 (dd, J=9.8, 5.4 Hz, 1H), 3.97 (dd, J=9.8, 3.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.84-6.92 (m, 2H), 7.08 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 10.21 (s, 1H). ES-MS (m/z): calcd for C32H51O3Si (M+H)+: 511.8; found: 511.2.
D. [4-(1-{4-[2-(t-Butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzyl]-(2-methanesulfonylethyl)amine




To a mixture of 4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzaldehyde (2.40 g, 4.71 mmol), Et3N (0.9 ml, 6.12 mmol), and 2-aminoethylmethylsulfone hydrochloride (0.78 g, 5.18 mmol) is treated with Ti(OiPr)4 (1.8 ml, 6.12 mmol). The mixture is stirred for 1 h, diluted with CH3OH (20 mL), then NaBCNH3 (0.33 g, 5.18 mmol) is added. The mixture is stirred overnight, quenched with H2O (3 mL), stirred for 1 h., and filtered through SiO2 with EtOAc (100 mL) wash. The filtrate is concentrated and chromatographed (75-80% EtOAc) to give the title compound (1.47 g, 2.38 mmol, 51%).
1H NMR (CDCl3), δ 0.05 (s, 3H), 0.12 (s, 3H), 0.61 (t, J=7.4 Hz, 6H), 0.91 (s, 9H), 0.97 (s, 9H), 2.05 (q, J=7.4 Hz, 4H), 2.19 (s, 3H), 2.33 (s, 3H), 2.99 (s, 3H), 3.21-3.27 (m, 3.5 H), 3.66-3.72 (m, 1.5H), 3.83 (s, 2H), 3.86 (t, J=5.9 Hz, 1H), 3.98 (dd, J=9.8, 3.4 Hz, 1H), 6.65 (d, J=8.3 Hz, 1H), 6.86-6.88 (m, 1H), 6.92 (dd, J=8.3, 2.4 Hz, 1H), 6.99 (s, 1H), 7.00 (bs, 1H), 7.14 (d, J=8.2 Hz, 1H). ES-MS (m/z): calcd for C35H60O4SSi (M+H)+: 619.0; found: 619.6.
E. 1-[4-(1-Ethyl-1-{4-[(2-methanesulfonylethylamino)methyl]-3-methylphenyl}propyl)-2-methylphenoxy]-3,3-dimethylbutan-2-ol




To a mixture of [4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzyl]-(2-methanesulfonylethyl)amine (1.47 g, 2.43 mmol) in THF (30 mL) is added 1M TBAF (2.7 mL, 2.7 mmol), and refluxed for 2 h. After cooling to RT, the mixture is diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers are MgSO4 dried, concentrated, and chromatographed (80% EtOAc/Hex) to give the title compound (0.97 g, 1.93 mmol, 79%).
1H NMR (CDCl3), δ 0.60 (t, J=7.4 Hz, 6H), 1.02 (s, 9H), 2.05 (q, J=7.4 Hz, 4H), 2.18 (s, 3H), 2.34 (s, 3H), 3.01 (s, 3H), 3.32 (bs, 4H), 3.71 (dd, J=8.8, 2.4 Hz, 1H), 3.86 (t, J=9.3 Hz, 1H), 3.88 (s, 2H), 4.09 (dd, J=9.3, 2.4 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 6.89 (bs, 1H), 6.90-6.96 (m, 1H), 6.98 (s, 1H), 7.00 (s, 1H), 7.13 (d, J=7.5 Hz, 1H). ES-MS (m/z): calcd for C29H46O4S (M+H)+: 504.8; found: 504.4.
F. t-Butyl (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzyl)-(2-methanesulfonylethyl)carbamate




To a mixture of 1-[4-(1-ethyl-1-{4-[(2-methanesulfonylethyl-amino)methyl]-3-methylphenyl}propyl)-2-methylphenoxy]-3,3-dimethylbutan-2-ol (0.97 g, 1.92 mmol), NaHCO3 (0.32 g, 3.84 mmol), H2O (10 mL), and THF (5 mL), is added (Boc)2O (0.46 g, 2.11 mmol). The reaction is stirred overnight, diluted with H2O (10 mL), and extracted with EtOAc (2×20 mL). The combined organic layers are washed with 0.1 M HCl (15 mL), brine (10 mL); MgSO4 dried, and chromatographed (40% EtOAc/Hex) to give the title compound (0.86 g, 1.43 mmol, 74%).
1H NMR (CDCl3), δ 0.61 (t, J=7.3 Hz, 6H), 1.02 (s, 9H), 1.45 (bs, 9H), 2.05 (q, J=7.3 Hz, 4H), 2.19 (s, 3H), 2.24 (s, 3H), 2.44 (bs, 1H), 2.70-3.20 (b, 5H), 3.58 (bs, 2H), 3.71 (dd, J=8.8, 2.9 Hz, 1H), 3.86 (t, J=8.8 Hz, 1H), 4.10 (dd, J=8.8, 2.9 Hz, 1H), 4.47 (s, 2H), 6.71 (d, J=8.4 Hz, 1H), 6.80-7.01 (m, 5H). ES-MS (m/z): calcd for C34H57N2O6S (M+NH4)+: 621.9; found: 621.3.
G. t-Butyl (4-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-2-methylbenzyl)-(2-methanesulfonylethyl)carbamate




Using a procedure analogous to Example 13C, from t-butyl (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzyl)-(2-methanesulfonylethyl)carbamate (0.26 g, 0.43 mmol) to give the title compound (0.25 g, 0.42 mmol, 95%).
1H NMR (CDCl3), δ 0.60 (t, J=7.5 Hz, 6H), 1.26 (s, 9H), 1.48 (bs, 9H), 2.05 (q, J=7.5 Hz, 4H), 2.23 (s, 3H), 2.25 (s, 3H), 2.60-3.20 (m, 5H), 3.57 (bs, 2H), 4.46 (s, 2H), 4.84 (s, 2H), 6.50 (d, J=8.1 Hz, 1H), 6.80-7.01 (m, 5H). ES-MS (m/z): calcd for C34H51O6S: 601.9; found: 602.2.
H. 1-[4-(1-Ethyl-1-{4-[(2-methanesulfonylethylamino)-methyl]-3-methylphenyl}propyl)-2-methylphenoxy]-3,3-dimethylbutan-2-one




To a mixture of t-butyl (4-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-2-methylbenzyl)-(2-methanesulfonylethyl)carbamate (0.25, g, 0.41 mmol) and CH2Cl2 (5 mL) is added TFA (5 mL,), stirred for 10 m, and concentrated. The residue is diluted with EtOAc (100 mL), washed with sat.d NaHCO3 (2×30 mL); MgSO4 dried, and chromatographed (90% EtOAc) to give the title compound (0.19 g, 0.39 mmol, 95%).
1H NMR (CDCl3), δ 0.61 (t, J=7.2 Hz, 6H), 1.27 (s, 9H), 2.05 (q, J=7.2 Hz, 4H), 2.25 (s, 3H), 2.32 (s, 3H), 2.99 (s, 3H), 3.25 (s, 4H), 3.81 (s, 2H), 4.84 (s, 2H), 6.49 (d, J=8.3 Hz, 1H), 6.85-7.00 (m, 4H), 7.13 (d, J=7.7 Hz, 1H). ES-MS (m/z): calcd for C29H44NO4S (M+H)+: 502.7; found: 502.2.
Example 14
Preparation of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-N-(2-methanesulfonylethyl)-2-methylbenzamide




To a mixture of 4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoic acid, Example 1, (0.53 g, 1.29 mmol), 2-aminoethylmethylsulfone hydrochloride (0.21 g, 1.29 mmol), HOBt (0.19 g, 1.43 mmol), Et3N (0.72 mL, 5.19 mmol) and CH2Cl2 (10 mL) is added EDCI (0.249 g, 1.29 mmol) and stirred overnight. The reaction is diluted with CH2Cl2 (50 mL), washed with 1M HCl (2×30 mL), H2O (20 mL), satd NaHCO3 (2×20 mL), and brine (20 mL). The organic layer is MgSO4 dried, concentrated, and chromatographed (75% EtOAc/Hex) to give the title compound (0.51 g, 76%).
1H NMR (CDCl3), δ 0.59 (t, J=7.8 Hz, 6H), 1.01 (s, 9H), 2.00-2.28 (m, 4H), 2.17 (s, 3H), 2.41 (s, 3H), 3.00 (s, 3H), 3.35 (t, J=5.6 Hz, 1H), 3.70 (bd, J=8.6 Hz, 1H), 3.85 (t, J=9.1 Hz, 1H), 3.97 (dd, J=12.3, 5.6 Hz, 2H), 4.09 (dd, J=9.1, 3.0 Hz, 1H), 6.53 (t, J=5.9 Hz, 1H), 6.69 (d, J=7.8 Hz, 1H), 6.85 (s, 1H), 6.91-7.01 (m, 2H), 7.25-7.29 (m, 2H). ES-MS (m/z): calcd for C29H44NO5S (M+H)+: 518.7; found: 518.3.
Example 15A & 15B
Preparation of enantiomer 1 and 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-N-(2-methanesulfonylethyl)-2-methylbenzamide




A racemic mixture of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-N-(2-methanesulfonylethyl)-2-methylbenzamide (0.34 g), Example 14, is chromatographed (HPLC: ChiralPak AD, 60% EtOH/Hept) to give enantiomer 1 (0.10 g, 29%, rt=4.9 m) and enantiomer 2 (0.125 g, 37%, rt=6.3 m).
Example 15A, 2071445 (enantiomer 1):
HPLC: ChiralPak AD (4.6×250 mm); 60% EtOH/Hept; 1.0 mL/m (flow rate); rt=4.9 m; @ 240 nm.
NMR & LC/MS: equivalent to the racemate, Example 14.
Example 15B, 2071447 (enantiomer 2):
HPLC: ChiralPak AD (4.6×250 mm); 60% EtOH/Hept; 1.0 mL/m (flow rate); rt=6.3 m; @ 240 nm.
NMR & LC/MS: equivalent to the racemate, Example 14.
Example 16
Preparation of 4-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-N-(2-methanesulfonylethyl)-2-methylbenzamide




Using a procedure analogous to Example 13C, from 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-N-(2-methanesulfonylethyl)-2-methylbenzamide, Example 14, (0.08 g, 0.16 mmol), NMO (27 mg, 0.24 mmol), and TPAP (2.8 mg, 0.08 mmol) are reacted for 1 h to give the title compound (0.06 g, 76%).
1H NMR (CDCl3): δ 0.60 (t, J=7.4 Hz, 6H), 1.27 (s, 9H), 2.05 (q, J=7.4 Hz, 4H), 2.24 (s, 3H), 2.42 (s, 3H), 3.01 (s, 3H), 3.36 (t, J=6.0 Hz, 2H), 3.94-4.02, (m, 2H), 4.82 (s, 2H), 6.46-6.57 (m, 2H), 6.82-7.23 (m, 5H). ES-MS (m/z): calcd for C29H42NO5S (M+H)+: 516.7; found: 516.4.
Example 17
Preparation of 4-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-2-methylbenzoic acid




To a mixture of 4-{1-[4-(3,3-dimethyl-2-hydroxybutoxy)-3-methylphenyl]-1-ethylpropyl}-2-methylbenzoic acid, Example 1, (0.50 g, 1.22 mmol) in CH2Cl2 (10 mL) is added a solution of the Dess-Martin reagent (0.57 g, 1.34 mmol) in CH2CL2 (10 mL) dropwise and stirred for 2 h. The reaction is diluted with EtOAc (100 mL), washed with 10% Na2SO3 (2×20 ml), 0.1 M HCl (20 ml), and H2O (20 ml). The organic layer is MgSO4 dried, and concentrated to give the title compound (0.48 g, 1.17 mmol, 95%).
1H NMR (CDCl3), δ 0.62 (t, J=7.2 Hz, 6H), 1.27 (s, 9H), 2.09 (q, J=7.2 Hz, 4H), 2.25 (s, 3H), 2.61 (s, 3H), 4.85 (s, 2H), 6.51 (d, J=8.8 Hz, 1H), 6.85-6.91 (m, 2H), 7.05-7.10 (m, 2H), 7.93 (d, J=9.0 Hz, 1H). ES-MS (m/z): calcd for C26H38NO4 (M+NH4)+: 428.6; found: 428.3.
Example 18
Preparation of enantiomer 1 of [(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid




A. Enantiomer 1 of [(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester




Using a procedure analogous to Example 5, from enantiomer 1 of 4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoic acid, Example 3A, (1.28 g, 3.17 mmol) and N-methyl glycine methyl ester hydrochloride (0.48 g, 3.41 mmol) to give the title compound (1.43 g, 2.88 mmol, 93%). 1H NMR (CDCl3), δ 0.57-0.65 (m, 6H), 1.02 (s, 9H), 2.00-2.11 (m, 4H), 2.18 (s, 3H), 2.25 (s, 0.80H), 2.32 (s, 2.20H), 2.89 (s, 2.20H), 3.15 (s, 0.80H), 3.70 (s, 0.8H), 3.72 (d, J=2.6 Hz, 1H), 3.79 (s, 2.2H), 3.86 (t, J=8.8 Hz, 1H), 3.91 (s, 0.52H), 4.09 (dd, J=7.0, 2.6 Hz, 1H), 4.32 (bs, 1.48H), 6.70 (d, J=8.3 Hz, 1H), 6.85-7.11 (m, 5H). ES-MS (m/z): calcd for C30H44NO5 (M+H)+: 498.7; found: 498.3.
B. Enantiomer 1 of [(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid




Using a procedure analogous to Example 2, from enantiomer 1 of [(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester (1.43 g, 2.88 mmol) to give the title compound (1.24 g, 2.57 mmol, 90%). 1H NMR (CDCl3), δ 0.56-0.63 (m, 6H), 1.02 (s, 9H), 2.01-2.09 (m, 4H), 2.11 (s, 0.7H), 2.18 (s, 2.3H), 2.23 (s, 0.70H), 2.29 (s, 2.30H), 2.91 (s, 2.30H), 3.14 (s, 0.70H), 3.71 (dd, J=8.8, 2.6 Hz, 1H), 3.86 (t, J=8.8 Hz, 1H), 3.92 (s, 0.47H), 4.09 (dd, J=8.8, 2.6 Hz, 1H), 4.33 (bs, 1.53H), 6.69 (d, J=8.8 Hz, 0.23H), 6.70 (d, J=8.3 Hz, 0.77H), 6.85-7.11 (m, 5H). ES-MS (m/z): calcd for C29H40NO5 (M−H)−: 482.7; found: 482.3.
Example 19
Enantiomer 2 of [(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid




A. Enantiomer 2 of [(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester




Using a procedure analogous to Example 5, from enantiomer 2 of 4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoic acid, Example 3B, (1.08 g, 2.62 mmol) to give the title compound (1.16 g, 2.33 mmol, 89%).
1H NMR & LC/MS: equivalent to Example 18A.
B. Enantiomer 2 of [(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid
Using a procedure analogous to Example 2, from enantiomer 2 of [(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester (0.58 g, 1.16 mmol) gives the title compound (0.53 g, 1.10 mmol, 95%). 1H NMR & LC/MS: equivalent to Example 18B.
Example 20
A. 2-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-2-methyl-propionic acid methyl ester




Using the procedure analogous to Example 5, from enantiomer 1 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid, Example 3A, (0.40 g, 0.97 mmol) and 2-aminoisobutyric acid methyl ester hydrochloride (0.15 g, 1.07 mmol) to furnish the title compound (0.36 g, 0.70 mmol, 72%). 1H NMR (CDCl3), δ 0.60 (t, J=7.6 Hz, 6H), 1.01 (s, 9H), 1.64 (s, 6H), 2.01-2.09 (m, 4H), 2.17 (s, 3H), 2.40 (s, 3H), 2.70 (d, J=9.0 Hz, 1H), 3.77 (s, 3H), 3.85 (t, J=9.1 Hz, 1H), 4.09 (d, J=9.6 Hz, 1H), 6.28 (s, 1H), 6.70 (dd, J=8.9, 2.6 Hz, 1H), 6.85 (s, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.95-7.02 (m, 2H), 7.27 (dd, J=7.9, 2.6 Hz, 1H). ES-MS (m/z): calcd. for C31H46NO5 (M+H)+: 512.3; found: 512.3.
B. 2-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-2-methyl-propionic acid




Enantiomer 1
Using a procedure analogous to Example 2, from enantiomer 1 of 2-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-2-methyl-propionic acid methyl ester (0.36 g, 0.70 mmol) to furnish the titled compound (0.35 g, 0.70 mmol, 92%). 1H NMR (CDCl3), δ 0.59 (t, J=7.3 Hz, 6H), 1.01 (s, 9H), 1.67 (s, 6H), 2.05 (q, J=7.3 Hz, 4H), 2.17 (s, 3H), 2.40 (s, 3H), 3.70 (dd, J=8.7, 2.7 Hz, 1H), 3.86 (t, J=8.9 Hz, 1H), 4.09 (dd, J=9.1, 2.7 Hz, 1H), 6.28 (s, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 6.93 (dd, J=8.5, 2.3 Hz, 1H), 6.98-7.03 (m, 2H), 7.26 (d, J=7.9 Hz, 1H). ES-MS (m/z): calcd. for C30H44NO5 (M+H)+: 498.3; found: 498.3.
Example 21
Preparation of 4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzoic acid




A. 4-(Z/E-2-Penten-3-yl)-O-trifluoromethylsulfonyl-phenol




To a mixture of 4-(Z/E-2-penten-3-yl)phenol (7.45 g, 45.9 mmol), CH2Cl2 (150 mL), and Tf2O (13.4 g, 47.5 mmol) is added DIPEA (6.13 g, 47.5 mol) drop wise. After stirring overnight, the reaction is poured into ice water (100 mL) and separated. The organic layer is washed with cold water (2×50 mL), Na2SO4 dried, filtered and concentrated to give the title compound as an oil (10.5 g, 78%) which is used as is.
B. 4-[(1-Ethyl-1-(3-methyl-4-hydroxyphenyl)propyl]-O-trifluoromethylsulfonylphenol




To 4-(Z/E-2-penten-3-yl)-O-trifluoromethylsulfonyl-phenol (5.25 g, 17.8 mmol) and O-cresol (7.7 g, 71.4 mmol) in CH2Cl2 (20 mL) at −20° C. is added BF3.Et2O (240 μL, 1.9 mmol), and the mixture is allowed to come to RT and stirred 16 h. To the reaction is added ethylene glycol (5 mL), and the CH2Cl2 is evaporated under vacuum. The residue is vacuum distilled up to 70° C. at 0.116 mm to remove the excess phenol and ethylene glycol. The residue is partitioned between Et2O (50 mL) and water (50 mL). The organic layer is washed with water (3×50 mL), saturated brine, Na2SO4 dried, filtered and concentrated. The residue is chromatographed to give the title compound (3.9 g, 54%).
H-NMR ppm in CDCl3: 7.24 (2H, d, J=9.0 Hz); 7.14 (2H, d, J=9.2 Hz); 6.84 (1H, s); 6.83 (1H, d, J=8.0 Hz); 6.66 (1H, d, J=8.0 Hz); 4.70 (1H, s); 2.20 (3H, s); 2.05 (4H, q, J=7.2 Hz); 0.61 (6H, t, J=7.2 Hz). LC-MS: 401.1 (M−1).
C. 4-[(1-Ethyl-1-(3-methyl-4-hydroxyphenyl)propyl]-benzoic acid, methyl ester




Using a procedure analogous to Example 1E, from 4-[(1-ethyl-1-(3-methyl-4-hydroxyphenyl)propyl]-O-trifluoromethylsulfonylphenol (2.5 g, 6.2 mmol) gives the title compound (1.08 g, 56%).
1H-NMR ppm in CDCl3: 7.89 (2H, d, J=8.0 Hz); 7.23 (2H, d, J=8.0 Hz); 6.84 (1H, s); 6.83 (1H, d, J=8.2 Hz); 6.65 (1H, d, J=8.2 Hz); 4.58 (1H, s); 3.89 (3H, s); 2.18 (3H, s); 2.08 (4H, q, J=7.2 Hz); 0.61 (6H, t, J=7.2 Hz). LC/MS: 313.1 (M+1), 311.1 (M−1).
D. 4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzoic acid methyl ester




Using a procedure analogous to Example 1B, from 4-[(1-ethyl-1-(3-methyl-4-hydroxyphenyl)propyl]-benzoic acid, methyl ester (0.88 g, 2.81 mmol) gives the title compound (0.95 g, 2.32 mmol, 95%). 1H NMR (CDCL3), δ 0.61 (t, J=7.4 Hz, 6H), 1.26 (s, 9H), 2.09 (q, J=7.4 Hz, 4H), 2.24 (s, 3H), 3.89 (s, 3H), 4.84 (s, 2H), 6.49 (d, J=8.8 Hz, 1H), 6.85-6.89 (m, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.91 (d, J=9.4 Hz, 2H). ES-MS (m/z): calcd for C26H38NO4 (M+NH4)+: 428.6; found: 428.3.
E. 4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-benzoic acid methyl ester




Using a procedure analogous to Example 1D, from 4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzoic acid methyl ester (0.94 g, 2.29 mmol) to give the title compound (0.93 g, 2.26 mmol, 99%). 1H NMR (CDCl3), δ 0.62 (t, J=7.6 Hz, 6H), 1.02 (s, 9H), 2.10 (q, J=7.6 Hz, 4H), 2.17 (s, 3H), 3.71 (dd, J=8.8, 2.9 Hz, 1H), 3.86 (t, J=8.6 Hz, 1H), 3.90 (s, 3H), 4.09 (dd, J=9.3, 2.9 Hz, 1H), 6.71 (d, J=8.3 Hz, 1H), 6.86 (d, J=2.1 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.94 (d, J=2.6 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.6 Hz, 2H). ES-MS (m/z): calcd for C26H37O4 (M+H)+: 413.6; found: 413.3.
F. 4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}benzoic acid




Using a procedure analogous to Example 2, from 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-benzoic acid methyl ester (0.93 g, 2.25 mmol) gives the title compound (0.81 mmol, 2.02 mmol, 90%). 1H NMR (CDCl3), δ 0.63 (t, J=7.2 Hz, 6H), 1.02 (s, 9H), 2.12 (q, J=7.2 Hz, 4H), 2.18 (s, 3H), 3.71 (dd, J=8.7, 2.4 Hz, 1H), 3.86 (t, J=9.3 Hz, 1H), 4.09 (dd, J=9.3, 2.4 Hz, 1H), 6.71 (d, J=8.3 Hz, 1H), 6.87 (d, J=1.9 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.8 Hz, 2H). ES-MS (m/z): calcd for C25H33O4 (M−H)−: 397.6; found: 397.2.
G. 4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzoic acid
Using a procedure analogous to Example 17, from 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}benzoic acid (0.31 g, 0.79 mmol) and Dess-Martin reagent (366 mg, 0.86 mmol) gives the title compound (0.27 g, 0.69 mmol, 88%). %). 1H NMR (CDCl3), δ 0.62 (t, J=7.0 Hz, 6H), 1.27 (s, 9H), 2.10 (q, J=7.0 Hz, 4H), 2.24 (s, 3H), 4.85 (s, 2H), 6.50 (d, J=9.1 Hz, 1H), 6.85-6.90 (m, 2H), 7.28 (d, J=8.1 Hz, 2H), 7.96 (d, J=8.2 Hz, 2H). ES-MS (m/z): calcd for C25H31O4 (M−H)−: 395.6; found: 395.2.
Example 22 and 23
Preparation of enantiomer 1 and 2 of 4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}benzoic acid




A racemic mixture of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}benzoic acid (500 mg) is chromatographed (CHIRALPAK AD column, Heptane, 90%; EtOH, 9.5%, CH3OH, 0.5%, TFA, 0.1%) to give enantiomer 1 (rt=7.4 m), Example 22 (231 mg, 46%) and enantiomer 2 (rt=9.4 m), Example 23 (230 mg, 46%).
Example 22(Enantiomer 1)
rt=7.4m
NMR & LC/MS: Identical to the racemic material, Example 21F.
Example 23(Enantiomer 2)
rt=9.4m
NMR & LC/MS: Identical to the racemic material, Example 21F.
Example 24
Preparation of (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzoylamino)acetic acid




A. Methyl (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-2-methylbenzoylamino)acetate




Using a procedure analogous to Example 5, from 4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoic acid (0.50 g, 1.22 mmol) and glycine methyl ester hydrochloride (0.15 g, 1.22 mmol) give the title compound (0.587 g, 1.21 mmol, 99%).
1H NMR (CDCl3), δ 0.62 (t, J=7.5 Hz, 6H), 1.03 (s, 9H), 2.07 (q, J=7.5 Hz, 4H), 2.19 (s, 3H), 2.43 (s, 3H), 3.71 (dd, J=8.8, 2.9 Hz, 1H), 3.80 (s, 3H), 3.87 (t, J=8.8 Hz, 1H), 4.08-4.12 (m, 1H), 4.24 (d, J=5.4 Hz, 1H), 6.26 (t, J=5.4 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 6.94 (dd, J=8.5, 2.5 Hz, 1H), 6.99-7.04 (m, 2H), 7.32 (d, J=7.8 Hz, 1H). ES-MS (m/z): calcd for C29H42NO5 (M+H)+: 484.7; found: 484.2.
B. (4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzoylamino)acetic acid
A mixture of methyl (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-2-methylbenzoylamino)acetate (0.43 g, 0.89 mmol), CH3OH (10 ml), NaOH (0.18 g, 4.46 mmol), and H2O (1 mL) is refluxed for 2 h. The reaction is concentrated, diluted with H2O (5 ml), acidified (pH 3-4) with 0.1 M HCl and extracted with EtOAc (3×15 mL). The combined organic layers are MgSO4 dried, and concentrated to give the title compound (0.29 g, 71%).
1H NMR (CD3OD), δ 0.66 (t, J=7.2 Hz, 6H), 1.05 (s, 9H), 2.15 (q, J=7.2 Hz, 4H), 2.20 (s, 3H), 2.42 (s, 3H), 3.63-3.68 (m, 1H), 3.91 (dd, J=10.0, 7.8 Hz, 1H), 4.09 (s, 2H), 4.16 (dd, J=10.0, 2.9 Hz, 1H), 6.81 (d, J=9.3 Hz, 1H), 6.86 (d, J=2.1 Hz, 1H), 7.02 (dd, J=8.4, 2.1 Hz, 1H), 7.09 (s, 1H), 7.11 (s, 1H), 7.37 (d, J=8.1 Hz, 1H). ES-MS (m/z): calcd for C28H40NO5 (M+H)+: 470.6; found: 470.2.
Example 25A and Example 25B
Preparation of enantiomer 1 and 2 of (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzoylamino)acetic acid




A racemic mixture of (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzoylamino)acetic acid (0.217 g), Example 24, is chromatographed (HPLC: ChiralPak AD, 0.1% TFA in 0.75:14.25:85 CH3OH:EtOH:Hept) to give enantiomer 1 (80.6 mg, 37%, rt=8.0 m) and enantiomer 2 (81.1 mg, 37%, rt=10.1 μm).
(Enantiomer 1) Example 25A
HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA in 0.75:14.25:85 CH3OH:EtOH:Hept; 1.0 mL/m (flow rate); rt=8.0 m; @ 280 nm; 97.8% ee.
NMR & LC/MS: equivalent to the racemate, Example 24.
(Enantiomer 2) Example 25B
HPLC: ChiralPac AD (4.6×250 mm); 0.1% TFA in 0.75:14.25:85 CH3OH:EtOH:Hept; 1.0 mL/m (flow rate); rt=10.1 m; @ 280 nm; 95.2% ee.
NMR & LC/MS: equivalent to the racemate, Example 24.
Example 26
Preparation enantiomer 1 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane




Using a procedure analogous to Example 5, enantiomer 1 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane and 5-aminotetrazole give the title compound (440 mg, 95%).
NMR 300 mHz (DMSO): 0.57 (t, J=7.3 Hz, 6H), 0.92 (s, 9H), 2.09 (m, 7H), 2.40 (s, 3H), 3.46 (m, 1H), 3.76 (dd, J=7.3, 10.2 Hz, 1H), 4.03 (dd, J=3.3, 10.2 Hz, 1H), 4.79 (d, J=5.5 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.12 (s, 1H), 7.52 (d, J=8.1 Hz, 1H), 12.23 (s, 1H), 16.00 (br s, 1H).
High Res. ES-MS: 480.2983; calc. for C27H37N5O3+H, 480.2975.
Example 27
Preparation enantiomer 2 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane




Using a procedure analogous to Example 5, enantiomer 2 of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane and 5-aminotetrazole gives the title compound (385 mg, 83%).
NMR 300 mHz (DMSO): eq. to enantiomer of 1.
High Res. ES-MS: 480.2968; calc. for C27H37N5O3+H, 480.2975.
Preparation of 4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid




Using a procedure analogous to Example 2, from racemic 4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid methyl ester, Example 10C, (4.70 g, 10.68 mmol) gives the title compound (2.93 g, 6.87 mmol, 64%).
1H NMR and ES-MS: equivalent to the pure enantiomer 1, Example 11.
Example 29
Preparation enantiomer 1 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane




Using a procedure analogous to Example 5, enantiomer 1 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane, Example 11, and 5-aminotetrazole give the title compound (125 mg, 72%).
1H NMR 400 MHz (DMSO-d6): δ 0.57 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 1.20 (d, J=6.3 Hz, 3H), 2.07 (m, 7H), 2.41 (s, 3H), 3.07 (br s, 1H), 4.37 (br s, 1H), 4.57 (q, J=5.8, 1H), 6.87 (m, 3H), 7.06 (d, J=7.8 Hz, 1H), 7.15 (s, 1H), 7.50 (d, J=7.8 Hz, 1H), 12.24 (s, 1H), 16.0 (s, 1H).
High Res ES(+)MS m/z: 494.3127; calc. for C28H39N5O3+H, 494.3131
Example 30
Preparation enantiomer 2 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane




Using a procedure analogous to Example 5, enantiomer 2 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane, Example 12, and 5-aminotetrazole give the title compound (150 mg, 74%).
High Res ES(+)MS m/z: 494.3144; calc. for C29H39N5O3+H, 494.3131
Example 31
Preparation enantiomer 1 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(carboxymethylaminocarbonyl)-3-methylphenyl]pentane




A. Enantiomer 1 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane




Using a procedure analogous to Example 5, enantiomer 1 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane, methyl glycinate hydrochloride, and DMAP (2.5 eq) give the title compound (150 mg, 86%).
1H NMR 400 MHz (DMSO-d6): δ 0.55 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 1.20 (d, J=5.9 Hz, 3H), 1.98-2.07 (m, 7H), 2.32 (s, 3H), 3.07 (s, 1H), 3.65 (s, 3H), 3.93 (d, J=6.3 Hz, 2H), 4.36 (br s, 1H), 4.55 (q, J=7.2 Hz, 1H), 6.80-6.84 (m, 2H), 6.89 (d, J=8.3 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.05 (s, 1H), 7.24 (d, J=8.3 Hz, 1H), 8.61 (t, J=5.9 Hz, 1H).
High Res ES(+)MS m/z: 498.3224; calc. for C30H43NO5+H, 498.3219.
B. Enantiomer 1 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(carboxymethylaminocarbonyl)-3-methylphenyl]pentane
Using a procedure analogous to Example 2 but reacted at RT, enantiomer 1 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane gives the title compound (130 mg, 99%).
1H NMR 400 MHz (DMSO-d6): δ 0.55 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 1.20 (d, J=5.9 Hz, 3H), 1.98-2.07 (m, 7H), 2.32 (s, 3H), 3.07 (s, 1H), 3.84 (d, J=5.8 Hz, 2H), 4.37 (br s, 1H), 4.56 (q, J=6.3 Hz, 1H), 6.80-6.84 (m, 2H), 6.89 (dd, J=2.4, J=8.3 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 7.04 (s, 1H), 7.25 (d, J=7.8 Hz, 1H), 8.48 (t, J=5.9 Hz, 1H)
High Res ES(+)MS m/z: 484.3041; calc. for C29H41NO5+H, 484.3063
Example 32
Preparation enantiomer 2 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(carboxymethylaminocarbonyl)-3-methylphenyl]pentane




A. Enantiomer 2 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane




Using a procedure analogous to Example 5, enantiomer 2 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane, methyl glycinate hydrochloride, and DMAP (2.5 eq) give the title compound (160 mg, 78%).
NMR equivalent to Example 31A.
High Res ES(+)MS m/z: 498.3200; calc. for C30H43NO5+H, 498.3219
B. Enantiomer 2 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(carboxymethylaminocarbonyl)-3-methylphenyl]pentane
Using a procedure analogous to Example 2 but reacted at RT, enantiomer 2 of 3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane gives the title compound (145 mg, quant).
NMR equivalent to Example 31B.
High Res ES(+)MS m/z: 484.3080; calc. for C29H41NO5+H, 484.3063
Example 33
Preparation of enantiomer 1 of (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyloxy)-acetic acid




A. Enantiomer 1 of 4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-benzoic acid methyl ester




Using a procedure analogous to Example 13A, from enantiomer 1 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid methyl ester (1.90 g, 4.45 mmol to furnish the title compound (2.40 g, 4.45 mmol, >99%).
1H NMR & ES-MS: equivalent to (Example 13A).
B. Enantiomer 1 of [4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-methanol




Using a procedure analogous to 13B, from enantiomer 1 of 4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-benzoic acid methyl ester (2.40 g, 4.45 mmol) to furnish the title compound (2.10 g, 4.09 mmol, 91%).
1H NMR & ES-MS: equivalent to (Example 13B).
C. [4-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-benzyloxy]-acetic acid methyl ester




To a solution of enantiomer 1 of [4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-methanol, (2.10 g, 4.10 mmol) and PhCH3 (10 mL) is added methyl glycolate (6.5 mL, 81.89 mmol) and MeReO3 (0.02 g, 0.082 mmol). The solution is heated at a reflux for 2 hours with the use of a Dean-Stark trap. The solution is concentrated and chromatographed to give the title compound (0.96 g, 1.64 nmol, 40%).
1H NMR (CDCl3), δ 0.06 (s, 3H), 0.11 (s, 3H), 0.61 (t, J=7.3 Hz, 6H), 0.90 (s, 9H), 0.97 (s, 9H), 2.05 (q, J=7.3 Hz, 4H), 2.18 (s, 3H), 2.33 (s, 3H), 3.67 (dd, J=5.7, 3.2 Hz, 1H), 3.77 (s, 3H), 3.85 (dd, J=9.7, 5.7 Hz, 1H), 3.98 (dd, J=9.7, 3.5 Hz, 1H), 4.12 (s, 2H), 4.60 (s, 2H), 6.65 (d, J=8.4 Hz, 1H), 6.87 (d, J=2.1 Hz, 1H), 6.92 (dd, J=8.4, 2.6 Hz, 1H), 6.97-7.01 (m, 2H), 7.17 (d, J=8.4 Hz, 1H).).
D. Enantiomer 1 of (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyloxy)-acetic acid
To a solution of enantiomer 1 of [4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-benzyloxy]-acetic acid methyl ester (0.96 g, 1.64 mmol) and THF (10 mL) is added 1M TBAF (3.3 mL, 3.28 mmol). The solution is heated at a reflux overnight and concentrated. The residue is dissolved in MeOH (5 mL) and water (1 mL), NaOH (0.33 g, 8.21 mmol) is added and the solution is heated at reflux for 3 hours. The solution is concentration, dissolved in EtOAc (20 mL), washed with 1M HCl (15 mL), water (15 mL), brine (15 mL), dried over MgSO4, and concentrated. The residue is chromatographed to furnish the title compound (0.45 g, 0.99 mmol, 60%).
1H NMR (CDCl3), δ 0.60 (t, J=7.3 Hz, 6H), 1.02 (s, 9H), 2.05 (q, J=7.3 Hz, 4H), 2.17 (s, 3H), 2.31 (s, 3H), 3.71 (dd, J=8.8, 2.6 Hz, 1H), 3.86 (t, J=8.8 Hz, 1H), 4.09 (dd, J=8.8, 2.6 Hz, 1H), 4.13 (s, 2H), 4.62 (s, 2H), 6.70 (d, J=8.3 Hz, 1H), 6.90-7.02 (m, 4H), 7.16 (d, J=7.5 Hz, 1H).
ES-MS (m/z): calcd. for C28H41O6 (M−H)−: 455.6; found: 455.2.
Example 34
Preparation of epimer 1 of D-2-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid




A. Epimer 1 of D-2-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester
D-Epimer 1
Using a procedure analogous to Example 5, from enantiomer 1 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.40 g, 0.97 mmol) and D-alanine methyl ester hydrochloride (0.15 g, 1.07 mmol) to furnish the title compound (0.36 g, 0.72 mmol, 75%).
1H NMR (CDCl3), δ 0.60 (t, J=7.2 Hz, 6H), 1.00 (s, 9H), 1.49 (d, J=7.1 Hz, 3H), 2.05 (q, J=7.2 Hz, 4H), 2.17 (s, 3H), 2.40 (s, 3H), 3.69 (dd, J=8.5, 2.7 Hz, 1H), 3.76 (s, 3H), 3.84 (t, J=9.1 Hz, 1H), 4.07 (dd, J=9.1, 2.5 Hz, 1H), 4.72-4.81 (m, 1H), 6.42 (d, J=7.9 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.92 (dd, J=8.4, 2.4 Hz, 1H), 6.96-7.01 (m, 2H), 7.28 (d, J=8.1 Hz, 1H).
ES-MS (m/z): calcd. for C30H44NO5 (M+H)+: 498.3; found: 498.3.
B. Epimer 1 of D-2-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid
Using a procedure analogous to Example 2, from epimer 1 of D-2-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester (0.36 g, 0.72 mmol) to furnish the titled compound (0.31 g, 0.64 mmol, 89%).
1H NMR (CDCl3), δ 0.60 (t, J=7.5 Hz, 6H), 1.01 (s, 9H), 1.50 (d, J=7.3 Hz, 3H), 2.05 (q, J=7.5 Hz, 4H), 2.17 (s, 3H), 2.41 (s, 3H), 3.71 (dd, J=8.4, 2.5 Hz, 1H), 3.85 (t, J=8.9 Hz, 1H), 4.09 (dd, J=9.3, 2.7 Hz, 1H), 4.74-4.83 (m, 1H), 6.33 (d, J=7.8 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.93 (dd, J=8.2, 2.2 Hz), 6.98-7.03 (m, 1H), 7.01 (s, 1H), 7.30 (d, J=8.0 Hz, 1H).
ES-MS (m/z): calcd. for C29H42NO5 (M+H)+: 484.3; found: 484.3.
Example 35
Preparation of racemic 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[4-carboxyphenyl]pentane




A. 3-(3-Chloro-4-hydroxyphenyl)-3-pentanol




To a solution of methyl 3-chloro-4-hydroxybenzoate (25.0 g, 133 mmol) in THF (250 mL) is added dropwise 1.0 M ethylmagnesium bromide/THF (442 mL, 442 mmol) at a rate maintaining the temperature below 27° C. The brownish grey reaction is stirred for 72 h. The reaction mixture is cooled in an ice bath and quenched with satd ammonium chloride (1 ml portions) until evolution of ethane subsides. Additional satd NH4Cl solution is added (total of 50 mL) and the mixture is concentrated to remove most of the THF. The residue is added to water and ether, filtered through diatomaceous earth, and partitioned. The organic layer is washed with brine (3×), MgSO4 dried, and concentrated to give the title compound (28.6 g, 99%).
H-NMR (300 mHz, CDCl3): δ 7.38 (1H, d, J=1.6 Hz), 7.07 (1H, dd, J=8.4 Hz, J=1.6 Hz), 6.95 (1H, d, J=8.4 Hz), 5.53 (1H, br s), 1.80 (4H, m), 0.76 (6H, t, J=7.6 Hz).
IR (CHCl3): 3600 cm−1, 3540 cm−1.
EI (+) TOF MS: Observed m/z 214.076; Calc. m/z. 214.0761
B. [E,Z]-3-(3-Chloro-4-hydroxyphenyl)-3-pentene




A mixture of 3-(3-chloro-4-hydroxyphenyl)-3-pentanol (10.0 g, 46.5 mmol), pTSA monohydrate (20 mg, catalytic amount), and toluene (300 mL) is heated on a steam bath for 3 h. Analysis by TLC indicates the loss of starting material and formation of a much less polar compound. The toluene solution is cooled to RT, washed with satd sodium carbonate solution (25 mL), MgSO4 dried, and concentrated to give the title compounds as a [E:Z] isomeric mixture of [85:15] (9.2 g, quant).
TLC (CHCl3): Rf ̃0.7
H-NMR (300 mHz, DMSO-d6): δ 6.85-7.30 (3H, m), 5.65 (0.85H, q, J=6.8 Hz), 5.43 (0.15H, q, J=6.8 Hz), 2.43 ((1.7H, q, J=7.6 Hz), 2.28 (0.3H, q, J=7.6 Hz), 1.72 (2.55H, d, J=7.6 Hz), 1.52 (0.45H, d, J=7.6 Hz), 0.90 (2.55H, t, J=7.6 Hz) 0.85 (0.45H, t, J=7.6 Hz)
C. [E,Z]-3-[3-Chloro-4-(2-oxo-3,3-dimethylbutoxy)phenyl]-3-pentene




A mixture of [E,Z]-3-(3-chloro-4-hydroxyphenyl)-3-pentene (4.00 g, 20.3 mmol) and 1-chloropinacolone (2.73 g, 20.3 mmol), anhydrous KI (0.17 g, 1.0 mmol), K2CO3 (14.0 g, 102 mmol) and acetonitrile (80 mL) is refluxed for 3 h. The reaction is cooled to RT and concentrated. The residue is partitioned between methylene chloride (50 mL) and ice water (50 mL). The organic layer is MgSO4 dried, concentrated, and chromatographed (40% to 70% chloroform in hexane) to give the title compounds as an 85:15 [E. Z] mixture (5.07 g, 85%).
H-NMR (300 mHz, DMSO-d6): δ 7.37 (0.85H, d, J=2.1 Hz), 7.22 (0.85H, dd, J=2.1, J=8.6 Hz), 7.18 (0.15H, d, J=2.1 Hz), 7.03 (0.15H, dd, J=2.0 Hz, J=8.4 Hz), 6.88 (0.15H, d, J=8.4 Hz), 6.85 (0.85H, d, J=8.6 Hz), 5.71 (0.85H, m), 5.52 (0.15H, m), 5.25 (2H, s), 2.45 (1.70H, q, J=7.6 Hz), 2.30 (0.30H, q, J=7.6 Hz), 1.75 (2.55H, d, J=7.6 Hz), 1.53 (0.45H, d, J=7.6 Hz), 1.17 (9H, s), 0.91 (2.55H, t, J=7.6 Hz), 9.88 (0.45H, t, J=7.6 Hz).
EI (+) TOF MS: Observed m/z 294.139; Calc. m/z 294.1387.
D. 3′-[3-Chloro-4-(2-oxo-3.3-dimethylbutoxy)phenyl]-3′-(4-hydroxyphenyl)pentane




A −20° C. solution of [E,Z]-3-[3-chloro-4-(2-oxo-3,3-dimethylbutoxy)phenyl]-3-pentene (4.5 g, 15.2 mmol), phenol (17.2 g, 183 mmol) and methylene chloride (30 mL) is treated with BF3-etherate (0.863 g, 6.1 mmol) and stirred for 30 m while maintaining the temperature near −20° C. The resulting light reddish brown solution is allowed to warm to 0° C. and kept at that temperature for 16 h. The reaction is distilled at 45° C./0.04 mm to remove most of the excess phenol. The residue is treated with powderized NaHCO3 (600 mg), ethylene glycol (15 ml), and distilled to remove the last of the phenol and almost all of the glycol. The resulting viscous tan oily residue is cooled to RT and distributed between sat NaHCO3 (25 mL) and ethyl acetate (200 mL). The organic layer is separated, washed with water (5×50 mL), Na2SO4 dried, and concentrated to give the title compound as an oil (5.8 g, 98%).
H-NMR (300 mHz, CDCl3): 7.21 (1H, d, J=2.3 Hz), 6.99 (2H, d, J=8.7 Hz), 6.95 (1H, dd, J=2.3 Hz, J=8.6 Hz), 6.75 (2H, d, J=8.7 Hz), 6.62 (1H, d, J=8.6 Hz), 4.91 (2H, s), 4.86 (1H, s), 2.02 (4H, q, J=7.3 Hz), 1.28 (9H, s), 0.62 (6H, t, J=7.3 Hz).
ES(+) MS m/z: 389.3 [M+H]; calc. m/z 389.1883 [M+H].
E. 3′-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)]-3′-(4-trifluoromethylsulfonyloxyphenyl)pentane




Using a procedure analogous to Example 1C with isopropyldiethylamine as the base, allowing the reaction to warm from 0 to RT overnight, and with potassium phosphate monobasic/sodium hydroxide buffer quench, 3′-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)phenyl]-3′-(4-hydroxyphenyl)pentane and triflic anhydride give the title compound as a colorless oil (3.7 g, 69%).
H-NMR (300 mHz, DMSO-D6): δ 7.40 (2H, d, J=8.7 Hz), 7.33 (2H, d, J=8.7 Hz), 7.15 (1H, d, J=2.1 Hz), 6.98 (1H, dd, J=2.1 Hz, J=8.6 Hz), 6.78 (2H, d, J=8.6 Hz), 5.22 (2H, s), 2.07 (4H, q, J=7.3 Hz), 1.17 (9H, s), 0.55 (6H, t, J=7.3 Hz).
FAB+MS m/z: 521.0 [M+H]; calc. 521.1376 [M+H].
ES MS: 521.3 [M+1], 538.3 [M+NH4], 543.2 [M+Na].
F. 3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-chloro-phenyl]-3′-4-carbomethoxyphenyl)-pentane




To 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-chlorophenyl]-3′-(4-trifluoromethyl-sulfonyloxy-phenyl)-pentane (3.7 g 7.1 mmol), palladium acetate (64 mg, 0.28 mmol), dppf (315 mg, 0.28 mmol), and triethylamine (4 mL) are heated in the absence of air under an atmosphere of carbon monoxide (initial 100 psig) in DMF (20 mL) and methanol (2 mL) at 110° C. for 48 h. The reaction mixture is cooled to room temperature, vented, and filtered. The filtrate is partitioned between EtOAc and water. The organic phase is washed 3 times with water, once with sat brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue is chromatographed on 10 g silica gel with 8% EtOAc in hexanes to give the title compound (1.12 g, 37%).
H-NMR (400 mHz, CDCl3): δ 7.91 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz), 7.16 (1H, s), 6.88 (1H, d, J=8.8 Hz), 6.59 (1H, d, J=8.8 Hz), 4.90 (2H, s), 3.89 (3H, s), 2.07 (4H, q, J=7.2 Hz), 1.25 (9H, s), 0.61 (6H, t, J=7.2 Hz).
FAB(+) MS m/z [M]: 431.1; calc. m/z 431.3.
ES (+) MS: m/z 431.3 [M+H], 448.3 [M+NH4].
G. Racemic 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[4-carbomethoxyphenyl]pentane




A solution of 3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-chloro-phenyl]-3′-(4-methoxycarbonyl-phenyl)-pentane (0.825 g, 1.91 mmol) in MeOH (10 mL) under a N2 atmosphere is cooled to 0° C. Sodium borohydride (0.076 g, 2.01 mmol) is added in one portion and the reaction mixture is stirred for 15 minutes. Acetone (1 mL) followed by potassium phosphate monobasic/sodium hydroxide buffer (3 mL) are added and the resulting mixture is concentrated to remove most of the MeOH. The residue is distributed into water and CH2Cl2 and the organic layer is separated and dried over anhydrous MgSO4. The desired product is obtained as a colorless oil, (0.816 g, 98.5%).
H-NMR (300 mHz, CDCl3): δ 7.92 (2H, d, J=8.8 Hz), 7.22 (2H, m), 7.15 (1H, d, J=2.3), 6.93 (1H, dd, J=2.3 Hz, J=8.8 Hz), 6.84 (1H, d, J=8.8 Hz), 4.17 (1H, dd, J=2.6 Hz, J=9.0 Hz), 3.89 (s, 3H), 3.87 (t, J=8.9 Hz,), 3.62 (1H, dt, J=2.6, J=8.9, J=3.0), 2.60, (1H, d, J=3.0 Hz), 2.09 (4H, q, J=7.3 Hz), 1.01 (9H, s), 0.61 (6H, t, J=7.3 Hz).
FAB(+) MS m/z [M]: 432.2; calc. for C25H33ClO4: m/z 432.2.
IR(CHCl3): 1718 cm−1
H. Racemic 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[4-carboxyphenyl]pentane, sodium salt




The methyl ester of 3′-[3-chloro-4-(2-hydroxy-3,3-dimethyl-butoxy)phenyl]-3′-[4-(carboxy)phenyl]pentane (0.600 g, 1.38 mmol) and 2N NaOH (3.46 mL, 6.93 mmol) are refluxed in EtOH (15 mL) under a N2 atmosphere for 1 h. TLC (SiO2; CHCl3) shows the loss of the starting material and appearance of a more polar compound spot near the origin. The reaction is allowed to cool to near RT and subsequently it is concentrated under reduced pressure to remove EtOH and provide a white residue. The residue is dissolved in a minimum amount of hot water (approx. 20 mL) and cooled and scratched to provide the desired sodium salt as white crystals (0.582 g, 96%).
H-NMR (300 mHz, DMSO): δ 7.73 (2H, d, J=8.7 Hz), 7.00 to 7.06 (5H, m), 4.88 (1H, d, J=5.1 Hz), 4.10 (1H, dd, J=3.0 Hz, J=10.2 Hz), 3.86 (1H, dd, J=3.1 Hz, J=10.2 Hz), 3.47 (1H, m), 2.04 (4H, q, J=7.3 Hz), 0.92 (9H, s), 0.55 (6H, t, J=7.3 Hz).
ES (+) MS m/z 436.2 [M+NH4], 441.1 [M+Na]
ES (−) MS m/z 417.2 [M−H].
IR(CHCl3): 1601 cm−1.
I. Racemic 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[4-carboxyphenyl]pentane
A portion of the above 3′-[3-chloro-4-(2-hydroxy-3,3-dimethyl-butoxy)phenyl]-3′-[4-(carboxy)phenyl]pentane, sodium salt (0.182 g, 0.413 mmol) is dissolved in 50 ml of hot water. After the solution is allowed to cool to near to RT it is acidified with dropwise addition of 5N HCl. The resulting white precipitate is collected and washed with ice water and subsequently vacuum dried to provide the desired free acid (0.169 g, 98%).
H-NMR (300 mHz, DMSO): δ 7.85 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3) 7.00 to 7.12 (3H, m), 4.85 (1H, d, J=5.1 Hz), 4.11 (1H, dd, J=3.0 Hz, J=10.2 Hz), 3.87 (1H, dd, J=3.1 Hz, J=10.2 Hz), 3.47 (1H, m), 2.08 (4H, q, J=7.3 Hz), 0.94 (9H, s), 0.56 (6H, t, J=7.3 Hz).
ES (+) MS: 436.2 [M+NH4], 441.1 [M+Na]
ES (−) MS: 417.2 [M−1].
IR (CHCl3): 1691 cm−1.
Example 36 and 37
Separation of optical isomers of 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[4-carboxyphenyl]pentane




A racemic mixture of the Na salt of 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-4-carboxyphenyl)pentane (350 mg) is chromatographed with a Chiralpak AD column to give enantiomer 1, Example 36 (120 mg, 36%) and enantiomer 2, Example 37 (117 mg, 35%).
Example 36, Enantiomer 1
HPLC: Chiralpak AD (4.6×150 mm); 100% 3A Alcohol; 0.6 mL/m (flow rate); rt=7.3 m; 240 nm; ee 99.7% by HPLC.
H-NMR (300 mHz, DMSO): δ 7.85 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3) 7.00 to 7.12 (3H, m), 4.85 (1H, d, J=5.1 Hz), 4.11 (1H, dd, J=3.0 Hz, J=10.2 Hz), 3.87 (1H, dd, J=3.1 Hz, J=10.2 Hz), 3.47 (1H, m), 2.08 (4H, q, J=7.3 Hz), 0.94 (9H, s), 0.56 (6H, t, J=7.3 Hz).
ES (+) MS: 436.2 [M+NH4], 441.1 [M+Na]
ES (−) MS: 417.2 [M−1].
Example 37,Enantiomer 2
HPLC: Chiralpak AD (4.6×150 mm); 100% 3A Alcohol; 0.6 mL/m (flow rate); rt=10.5 m; 240 nm; ee 99.0% by HPLC.
H-NMR (300 mHz, DMSO): δ 7.85 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3) 7.00 to 7.12 (3H, m), 4.85 (1H, d, J=5.1 Hz), 4.11 (1H, dd, J=3.0 Hz, J=10.2 Hz), 3.87 (1H, dd, J=3.1 Hz, J=10.2 Hz), 3.47 (1H, m), 2.08 (4H, q, J=7.3 Hz), 0.94 (9H, s), 0.56 (6H, t, J=7.3 Hz).
ES (+) MS: 436.2 [M+NH4], 441.1 [M+Na]
ES (−) MS: 417.2 [M−1].
Example 38
Preparation of racemic 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carboxy)phenyl]pentane




A. [E,Z]-3-[3-Chloro-4-(trifluoromethylsulfonyloxy)phenyl)-3-pentene




Using a procedure analogous to Example 1C, [E,Z]-3-(3-chloro-4-hydroxyphenyl)-3-pentene, triflic anhydride, and diisopropylethylamine are reacted at RT for 3 h to give the title compound as a yellow oil in a [E:Z] ratio of 9:1 (16.7 g, 98%). Chromatography over silica gel using 10% chloroform in hexane as the eluent provided 11.72 g (71. %) of purified material.
H-NMR (300 mHz, CDCl3): δ 7.01-7.39 (3H, m), 5.70 (0.9H, q, J=6.9 Hz), 5.53 (0.1H, q, J=6.9 Hz), 2.41 ((1.8H, q, J=7.6 Hz), 2.24 (0.2H, q, J=7.6 Hz), 1.74 (2.7H, d, J=7.6 Hz), 1.48 (0.3H, d, J=7.6 Hz), 0.91 (2.7H, t, J=7.6 Hz)), 0.89 (0.3H, t, J=7.6 Hz).
ES GC MS m/z 328.0; Calc. for C12H12ClF3O3S m/z 328.0148.
B. 3′-(4-hydroxy-3-methylphenyl)-3′-[3-chloro-4-(trifluoromethylsulfonyloxy)-phenyl]pentane




Using a procedure analogous to Example 35D, [E,Z]-3-[3-chloro-4-(trifluoromethylsulfonyloxy)phenyl]-3-pentene and o-cresol are reacted at RT overnight to give the title compound as a pale tan oil (4.29 g, 38%).
H-NMR (300 mHz, CDCl3): 6.5 to 7.3 (6H, m) 4.57 (1H, s), 2.21 (3H, s), 2.05 (4H, q, J=7.3 Hz), 0.62 (6H, t, J=7.3 Hz).
ES (−) MS m/z 435.1 [M−H].
C. 3′-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)-phenyl]-3′-[3-methyl-4-(trifluoromethylsulfonyloxy)phenyl]pentane
Triflate Rearrangement Procedure.




Using a procedure analogous to Example 35C, 3′-(3-chloro-4-hydroxyphenyl)-3′-[3-methyl-4-(trifluoromethylsulfonyloxy)phenyl]pentane, 1-chloropinacolone, anhydrous KI, and K2CO3 are reacted in acetonitrile to give the title compound (2.61 g, 53%) following chromatographies (30% to 50% chloroform/Hex; Hex to 10% EtOAc/Hex).
H-NMR (300 mHz, CDCl3): δ 7.15 (1H, d, J=2.3 Hz), 7.11 (1H, d, J=8.4 Hz), 7.04 (1H, d, J=2.3 Hz), 7.02 (1H, dd, J=2.3 Hz, J=8.4 Hz), 6.89 (1H, dd, J=8.6 Hz, J=2.3 Hz), 6.62 (1H, d, J=8.6 Hz), 4.91 (2H, s), 2.32 (3H, s), 2.03 (4H, q, J=7.2 Hz), 1.26 (9H, s), 0.60 (6H, t, J=7.2 Hz).
ES (+) MS m/z, [M+NH4]: 552.2.
Further NMR data: COSY data allowed the spin systems of the two aromatic rings to be grouped together. When the OCH2 was selectively excited, a NOE is observed with a resonance at 6.62δ which is ortho only coupled. When the aromatic methyl (at 2.32δ) was excited, a NOE is observed to a meta coupled proton at 7.04δ. These resonances are not part of the same spin system, requiring the OCH2 and aromatic methyl to be on different rings. Therefore the triflate has migrated during the reaction and the isolated product has the structure shown above. (HMBC data also supports this conclusion.)
D. 3′-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carbomethoxy)phenyl]pentane




Using a procedure analogous to Example 35F, 3′-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)-phenyl]-3′-[3-methyl-4-(trifluoromethylsulfonyl-oxy)phenyl]pentane, MeOH, dppb, DMSO, Et3N, and Pd(OAc)2 under an atmosphere of CO are reacted to provide the title compound as a colorless oil (938 mg, 73%).
H-NMR (300 mHz, CDCl3): δ 7.82 (1H, d, J=8.8 Hz), 7.20 (1H, d, J=2.3 Hz), 7.03-7.05 (2H, m), 6.92 (1H, dd, J=2.3 Hz, J=8.6 Hz), 6.63 (1H, d, J=8.6 Hz), 4.92 (2H, s), 3.89 (3H, s), 2.57 (3H, s), 2.08 (4H, q, J=7.3 Hz), 1.27 (9H, s), 0.63 (6H, t, J=7.3 Hz).
ES (+) MS m/z: 462.4 [M+NH4].
FAB (+) MS m/z [M+H]: 445.2; calc. m/z 445.1.
E. Racemic 3′-[3-chloro-4-(2-hydroxy-3.3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carbomethoxy)phenyl]pentane




Using a procedure analogous to Example 35G, 3′-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carbomethoxy)phenyl]pentane was reduced by NaBH4 to provide the title compound as a colorless oil (735 mg, 98%).
H-NMR (300 mHz, CDCl3): δ 7.89 (1H, d, J=8.8 Hz), 7.13 (1H, d, J=1.78 Hz), 7.00 (2H, m), 6.93 (1H, dd, J=2.2 Hz, J=8.8 Hz), 6.80 (1H, d, J=8.8 Hz), (4.17 (1H, dd, J=2.6 Hz, J=9.0 Hz), 3.86 (1H, m), 3.85 (3H, s), 3.74 (1H, m), 2.60, (1H, d, J=3.0 Hz), 2.54 (3H, s), 2.06 (4H, q, J=7.3 Hz), 1.01 (9H, s), 0.61 (6H, t, J=7.3 Hz).
FAB (+) MS m/z [M+H]: 447.1; calc m/z 447.2.
IR (CHCl3): 1717 cm−1 
F. Racemic 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carboxy)phenyl]pentane




Using a procedure analogous to Example 35H&I, racemic 3′-[3-chloro-4-(2-hydroxy-3.3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carbomethoxy)-phenyl]pentane was saponified by aqueous NaOH in EtOH to form the Na salt corresponding to the desired compound. After removal of the EtOH under reduced pressure, the residue containing the Na salt was dissolved in water and acidified in a manner analogous to the procedure of Example CDJ-3 to provide the title compound as a white solid (470 mg, 97%).
H-NMR (300 mHz, DMSO): δ 7.72 (1H, d, J=8.0 Hz), 7.00 to 7.10 (5H, m), 4.84 (1H, d, J=5.6 Hz), 4.09 (1H, dd, J=2.8 Hz, J=10.4 Hz), 3.85 (1H, dd, J=7.0 Hz, J=10.4 Hz), 3.45 (1H, m), 2.47 (3H, s), 2.06 (4H, q, J=7.3 Hz), 0.91 (9H, s), 0.55 (6H, t, J=7.3 Hz).
ES (+) MS m/z 450.2 [M+NH4], 455.2 [M+Na].
ES (−) MS m/z 431.1 [M−1].
IR (CHCl3): 1689 cm−1.
Example 39
Preparation of Racemic 3′-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane




A. [E,Z]-3-[3-Chloro-4-carbomethoxyphenyl)-3-pentene




Using a procedure similar to Example 35F, a mixture of [E,Z]-3-[3-chloro-4-(trifluoromethylsulfonyloxy)phenyl)-3-pentene, MeOH, dppb, DMSO (instead of DMF), Et3N, and Pd(OAc)2 under an atmosphere of CO at 80° C. for 4 h are reacted to provide the title compound as a colorless liquid in a [E:Z] ratio of 9:1 (1.99 g, 92%).
H-NMR (300 mHz, CDCl3): δ 7.06-7.85 (3H, m), 5.85 (0.9H, q, J=6.9 Hz), 5.60 (0.1H, q, J=6.9 Hz), 3.94 (0.3H, s), 3.93 (2.7H, s), 2.50 (1.8H, q, J=7.6 Hz), 2.32 (0.2H, q, J=7.6 Hz), 1.82 (2.7H, d, J=7.6 Hz), 1.53 (0.3H, d, J=7.6 Hz), 0.97 (2.7H, t, J=7.6 Hz), 0.94 (0.3H, t, J=7.6 Hz).
IR (CHCl3): 1726 cm−1
ES GC MS m/z 238.1, M+; Calc. C13H15ClO2 m/z 238.1
B. 3′-(4-hydroxy-3-methylphenyl)-3′-[3-chloro-4-carbomethoxyphenyl]pentane




Using a procedure analogous to Example 35D, [E,Z]-3-[3-chloro-4-carbomethoxyphenyl)-3-pentene and o-cresol are reacted at RT overnight to give the title compound as a thick, pale yellow oil (3.54 g, 99%).
H-NMR (300 mHz, CDCl3): δ 7.74 (1H, d, J=8.2 Hz), 7.29 (1H, d, J=1.7 Hz), 7.08 (1H, dd, J=1.7 Hz, J=8.2 Hz), 6.81 (2H, m), 6.63 (1H, d, J=8.9 Hz), 3.91 (3H, s), 2.20 (3H, s), 2.09 (4H, q, J=7.3 Hz), 1.27 (9H, s), 0.70 (6H, t, J=7.3 Hz).
ES (+) MS m/z 347.1 [M+1].
IR (CHCl3): 1725 cm−1.
C. 3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-methyl-phenyl]-3′-(3-chloro-4-carbomethoxyphenyl)-pentane




Using a procedure analogous to Example 35C, 3′-(4-hydroxy-3-methylphenyl)-3′-[3-chloro-4-carbomethoxyphenyl]pentane, 1-chloropinacolone, anhydrous KI, and K2CO3 are reacted in acetonitrile to give the title compound as a clear colorless oil (3.46 g, 90%).
H-NMR (300 mHz, CDCl3): δ 7.70 (1H, d, J=8.2 Hz), 7.28 (1H, d, J=1.8 Hz), 7.07 (1H, dd, J=1.8, J=8.2), 6.858-6.87 (2H, m), 6.50 (1H, d, J=9.2 Hz), 4.84 (2H, s), 3.91 (3H, s), 2.23 (3H, s), 2.05 (4H, q, J=7.3 Hz), 1.53 (9H, s), 0.61 (6H, t, J=7.3 Hz).
FAB(+) MS m/z [M+H]: 445.2 Calc. m/z 445.2.
IR (CHCl3): 1725 cm−1.
D. Racemic 3′-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carbomethoxyoxyphenyl)pentane




Using a procedure analogous to Example 35G, 3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-methyl-phenyl]-3′-(3-chloro-4-carbomethoxyphenyl)-pentane was reduced by NaBH4 to provide the title compound as a colorless oil (2.75 g, 91%).
H-NMR (300 mHz, CDCl3): δ 7.75 (1H, d, J=8.8 Hz), 7.27 (1H, d, J=1.8 Hz), 7.16 (1H, d, J=2.0 Hz), 7.07 (1H, dd, J=1.8 Hz, J=8.8 Hz), 6.94 (1H, dd, J=2.0 Hz, J=8.8 Hz), 6.83 (1H, d, J=8.8 Hz), 4.18 (1H, dd, J=2.6 Hz, J=9.0 Hz), 3.92 (3H, s), 3.89 (1H, m), 3.74 (1H, m), 2.60, (1H, broad s), 2.06 (4H, q, J=7.3 Hz), 1.04 (9H, s), 0.63 (6H, t, J=7.3 Hz).
FAB(+) MS m/z [M+H]: 447.3; calc. m/z 447.2
IR (CHCl3): 1733 cm−1 
E. Racemic 3′-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane
Using a procedure analogous to Example 35H, racemic 3′-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carbomethoxyoxyphenyl)pentane was saponified by aqueous NaOH in EtOH to form the Na salt corresponding to the desired compound. After removal of the EtOH under reduced pressure, the residue containing the Na salt was dissolved in water and acidified in a manner analogous to the procedure of Example 39I to provide the title compound as a white solid (1.84 g, 93%).
H-NMR (300 mHz, DMSO): δ 7.69 (1H, d, J=8.0 Hz), 7.10 to 7.20 (2H, m), 6.80 to 6.95 (3H, m), 4.78 (1H, d, J=5.6 Hz), 4.02 (1H, dd, J=2.8 Hz, J=10.4 Hz), 3.76 (1H, dd, J=7.0 Hz, J=10.4 Hz), 3.44 (1H, m), 2.10 (3H, s), 2.04 (4H, q, J=7.3 Hz), 0.93 (9H, s), 0.56 (6H, t, J=7.3 Hz).
ES (+) MS m/z 433.2 [M+H], 450.1 [M+NH4], 455.1 [M+Na].
ES (−) MS m/z 431.2 [M−H].
IR(CHCl3): 1701 cm−1.
Example 40
Preparation of racemic 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane




A. 3′-(4-hydroxy-3-chlorophenyl)-3′-(3-chloro-4-carbomethoxy-phenyl)pentane




Using a procedure analogous to Example 35D, [E,Z]-3-[3-chloro-4-carbomethoxyphenyl]-3-pentene and o-chlorophenol are reacted (initially at RT overnight, then at 70° C. for 20 h, and finally at 90° C. overnight) to give the title compound as an oil (886 mg, 58%).
H-NMR (300 mHz, CDCl3): 6.90 to 7.76 (6H, m), 5.45 (1H, s), 3.93 (3H, s), 2.06 (4H, q, J=7.3 Hz), 0.64 (6H, t, J=7.3 Hz).
ES (+) MS m/z 367.0 [M+H].
IR (CHCl3): 1726 cm−1 
B. 3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-chlorophenyl]-3′-(3-chloro-4-carbomethoxyphenyl)-pentane




Using a procedure analogous to Example 35C, 3′-(4-hydroxy-3-chlorophenyl)-3′-(3-chloro-4-carbomethoxy-phenyl)pentane, 1-chloropinacolone, anhydrous KI, and K2CO3 are reacted in acetonitrile to give the title compound as a clear, nearly colorless oil (919 mg, 89%).
H-NMR (300 mHz, CDCl3): δ 7.72 (1H, d, J=8.2 Hz), 7.26 (1H, m), 7.17 (1H, d, J=2.3, 7.06 (1H, dd, J=1.8 Hz, J=8.2 Hz), 6.90 (1H, dd, J=8.7 Hz, J=2.3 Hz), 4.91 (2H, s), 3.92 (3H, s), 2.05 (4H, q, J=7.3 Hz), 1.26 (9H, s), 0.62 (6H, t, J=7.3 Hz).
ES (+) MS m/z 465.1 [M+H], 482.1 [M+NH4].
C. Racemic 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carbomethoxyphenyl)pentane




Using a procedure analogous to Example 35G, 3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-chlorophenyl]-3′-(3-chloro-4-carbomethoxyphenyl)-pentane was reduced by NaBH4 to provide the title compound as a colorless oil (738 mg, 98%).
H-NMR (300 mHz, CDCl3): δ 7.89 (1H, d, J=8.8 Hz), 7.13 (1H, d, J=1.78 Hz), 7.00 (2H, m), 6.93 (1H, dd, J=2.2 Hz, J=8.8 Hz), 6.80 (1H, d, J=8.8 Hz), (4.17 (1H, dd, J=2.6 Hz, J=9.0 Hz), 3.86 (1H, m), 3.85 (3H, s), 3.74 (1H, m), 2.60, (1H, d, J=3.0 Hz), 2.06 (4H, q, J=7.3 Hz), 1.01 (9H, s), 0.61 (6H, t, J=7.3 Hz).
ES (+) MS m/z 489.2 (M+Na).
IR (CHCl3): 1717 cm−1
D. Racemic 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane
Using a procedure analogous to Example 35H, racemic 3′-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carbomethoxy-phenyl)pentane was saponified by aqueous NaOH in EtOH to form the Na salt corresponding to the desired compound. After removal of the EtOH under reduced pressure, the residue containing the Na salt was dissolved in water and acidified in a manner analogous to the procedure of Example 391 to provide the title compound as a white solid (517 mg, 94%).
H-NMR (300 mHz, DMSO): δ 7.74 (1H, d, J=8.0 Hz), 7.04 to 7.30 (5H, m), 4.88 (1H, d, J=5.6 Hz), 4.14 (1H, dd, J=2.8 Hz, J=10.4 Hz), 3.89 (1H, dd, J=7.0 Hz, J=10.4 Hz), 3.49 (1H, m), 2.04 (4H, q, J=7.3 Hz), 0.95 (9H, s), 0.58 (6H, t, J=7.3 Hz).
ES (+) MS m/z 475.2 [M+Na].
IR (CHCl3): 1701 cm−1.
Example 41 and Example 42
Separation of optical isomers of 3′-[3-chloro-4-(2-hydroxy-3,3-dimethyl-butoxy)phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane




A racemic mixture 3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)-phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane. (490 mg) is chromatographed with a ChiralpakAD column to give enantiomer 1, Example 41 (192 mg, 39%) and enantiomer 2, Example 42 (185 mg, 38%).
Enantiomer 1, Example 41
HPLC: Chiralpak AD (4.6×250 mm); 3:2 heptane:isopropyl alcohol with 0.1% TFA; 1.0 mL/m (flow rate); rt=7.8 m; 270 nm; ee 99.9% by HPLC.
H-NMR (300 mHz, DMSO): δ 7.74 (1H, d, J=8.0 Hz), 7.04 to 7.30 (5H, m), 4.88 (1H, d, J=5.6 Hz), 4.14 (1H, dd, J=2.8 Hz, J=10.4 Hz), 3.89 (1H, dd, J=7.0 Hz, J=10.4 Hz), 3.49 (1H, m), 2.04 (4H, q, J=7.3 Hz), 0.95 (9H, s), 0.58 (6H, t, J=7.3 Hz).
ES (+) MS m/z 475.2 [M+Na].
Enantiomer 2, Example 42
HPLC: Chiralpak AD (4.6×250 mm); 3:2 heptane:isopropyl alcohol with 0.1% TFA; 1.0 mL/m (flow rate); rt=10.6 m; 270 nm; ee 99.5% by HPLC.
H-NMR (300 mHz, DMSO): δ 7.74 (1H, d, J=8.0 Hz), 7.04 to 7.30 (5H, m), 4.88 (1H, d, J=5.6 Hz), 4.14 (1H, dd, J=2.8 Hz, J=10.4 Hz), 3.89 (1H, dd, J=7.0 Hz, J=10.4 Hz), 3.49 (1H, m), 2.04 (4H, q, J=7.3 Hz), 0.95 (9H, s), 0.58 (6H, t, J=7.3 Hz).
ES (+) MS m/z 475.1 [M+Na].
Example 43
Preparation of racemic 1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol




A. 3′-(4-Iodophenyl)-3′-pentanol.




To ethyl, p-iodobenzoate (11.04 g, 40 mmol) in diethylether (100 mL) at −20° C. under nitrogen is added 1M ethylmagnesium bromide (91 mL, 91 mmol) dropwise with mechanical stirring, and the mixture is allowed to come to R.T. and stirred over night. The mixture is quenched with satd. sodium bicarbonate and triturated with diethylether six times. The organic layers are combined; washed with water; dried over anhydrous sodium sulfate; and evaporated under vacuum to give the title compound as an oil (10.4 g, 90%) which is used as is.
1H NMR (400 mHz, CDCl3), δ 7.64 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 1.74-1.85 (m, 4H), 0.75 (t, J=7.4 Hz, 6 h).
B. 1-{4-[1]-Ethyl-1-(4-iodophenyl)-propyl]}-2-methyl-phenol




To 3′-(4-iodophenyl)-3′-pentanol (10.4 g, 36 mmol) and o-cresol (15.5 g, 143 mmol) in methylene chloride (5 mL) is added borontrifluoride etherate (0.96 mL, 7.2 mmol), and the mixture is allowed to stir at room temperature overnight. The mixture is quenched with satd. sodium bicarbonate, and extracted into diethylether. The organic phase is washed with water; dried over anhydrous sodium sulfate; and evaporated under vacuum. The residue is vacuum distilled (0.5 mm) to 80° C. to remove excess o-cresol, and the residue is partitioned between diethylether and water. The organic layer is dried over anhydrous sodium sulfate, and evaporated under vacuum to give the title compound as an oil (13 g, 95%) which is used as is.
1H NMR (400 mHz, CDCl3), δ 7.53 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.84 (s, 1H), 6.83 (d. J=8.9 Hz, 1H), 6.64 (d, J=8.9 Hz, 1H), 4.50 (s, 1H), 2.20 (s, 3H), 2.01 (q, J=7.2 Hz, 4H), 0.60 (t, J=7.2 Hz, 6H).
C. 1-{4-[1-Ethyl-1-(4-iodophenyl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one




In a procedure analogous to Example 35C, 1-{4-[1-Ethyl-1-(4-iodophenyl)-propyl]}-2-methyl-phenol (13 g, 34 mmol) gave the title compound as an oil (13.9 g, 85%) which is used as is.
1H NMR (400 mHz, CDCl3), δ 7.53 (d, J=8.4 hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.87 (s, 1H), 6.86 (d, J=8.8 hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 4.83 (s, 2H), 2.23 (s, 3H), 2.01 (q, J=7.2 Hz, 4H), 1.25 (s, 9H).
D. 4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzonitrile




To a mixture of 1-{4-[1-ethyl-1-(4-iodo-phenyl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (3.0 g 6.27 mmol) and DMF (30 mL) is added Zn(CN)2 (0.44 g, 3.76 mmol), Pd2(dba)3 (0.29 g, 0.31 mmol), and DPPF (0.42 g, 0.75 mmol). The solution is heated at 100° C. overnight, diluted with Et2O (200 mL), washed with 4:1:4 sat NH4Cl:Conc. NH4OH:water (100 mL), water (100 mL), brine (100 mL), dried MgSO4, filtered and concentrated. The residue is purified by ISCO (10%-2-% EtOAc gradient) to furnish the title compound (1.1 g, 2.91 mmol, 46%).
1H NMR (CDCl3), δ 0.52-0.63 (m, 6H), 1.26 (s, 9H), 2.03-2.10 (m, 4H), 2.24 (s, 3H), 4.85 (s, 2H), 6.50 (d, J=9.4 Hz, 1H), 6.82-6.86 (m, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.9 Hz, 2H).
LC/MS (m/z): calcd. for C25H31NO2 (M+H)+: 378.6; found: 395.3.
E 1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one




To a mixture of 4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzonitrile (0.50 g, 1.32 mmol), and DMF (5 mL) is added NaN3 (0.26 g, 3.95 mmol) and Et3N.HCl (0.54 g, 3.95 mmol). The slurry is heated at 110° C. overnight. The slurry is diluted with EtOAc (50 mL), washed with 1M HCl (40 mL) water (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (20%-40% [89% EtOAc: 10% MeOH: 1% ACOH] gradient) to furnish the title compound (0.37 g, 0.88 mmol, 66%).
1H NMR (CDCl3), δ 0.57-0.62 (m, 6H), 1.27 (s, 9H), 2.02-2.11 (m, 4H), 2.17 (s, 3H), 4.87 (s, 2H), 6.50 (d, J=9.4 Hz, 1H), 6.82-6.88 (m, 2H), 7.22-7.28 (m, 3H), 7.94 (d, J=7.9 Hz, 2H).
LC/MS (m/z): calcd. for C25H32N4O2 (M+H)+: 421.7; found: 421.2.
F. 1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol
To a mixture of 1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one (0.37 g, 0.88 mmol) and EtOH (5 mL) was added NaBH4 (0.037 g, 0.97 mmol) and the solution stirred for 1 hour. The solids were removed by filtration and the solution concentrated. The residue was purified by ISCO (10-30 [89% EtOAc:10% MeOH:1% AcOH] gradient) to furnish the title compound (0.32 g, 0.76 mmol, 86%).
1H NMR (CDCl3), δ 0.59-0.64 (m, 6H), 1.02 (s, 9H), 2.05-2.12 (m, 4H), 2.13 (s, 3H), 3.75 (dd, J=2.8, 8.8 Hz, 1H), 3.89 (t, J=8.8 Hz, 1H), 4.10 (dd, J=2.8, 8.8 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.92 (dd, J=2.2, 8.7 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H).
LC/MS (m/z): calcd. for C25H34N4O2 (M+H)+: 423.7; found: 423.2.
Example 44 and Example 45
Separation of enantiomers of 1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol




A racemic mixture of 1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol (0.32 g) is chromatographed (CHIRALPAK ADH column, 0.1% TFA, 20% i-PrOH/Hept) to give enantiomer 1, (0.168 g, 0.40 mmol, 45%) and enantiomer 2, (0.150 g, 0.35 mmol, 41%).
Example 44, Enantiomer 1
Rt=7.7m
1H NMR (CDCl3), δ 0.57-0.67 (m, 6H), 1.02 (s, 9H), 2.05-2.12 (m, 4H), 2.14 (s, 3H), 3.74 (dd, J=2.2, 8.8 Hz, 1H), 3.89 (t, J=8.8 Hz, 1H), 4.10 (dd, J=2.2, 8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.86 (s, 1H), 6.93 (d, J=8.8 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.99 (d, J=8.0 Hz, 2H). LC/MS (m/z): calcd. for C25H34N4O2 (M+H)+: 423.7; found: 423.3.
Example 45, enantiomer 2
Rt=11.6 m
1H NMR (CDCl3), δ 0.59-0.66 (m, 6H), 1.01 (s, 9H), 2.05-2.15 (m, 4H), 2.16 (s, 3H), 3.71 (dd, J=2.5, 8.7 Hz, 1H), 3.87 (t, J=9.0 Hz, 1H), 4.09 (dd, J=2.5, 9.0 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.87 (d, J=1.7 Hz, 1H), 6.95 (dd, J=2.2, 8.5 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 8.01 (d, J=8.2 Hz, 2H). LC/MS (m/z): calcd. for C25H34N4O2 (M+H)+: 423.7; found: 423.3.
Example 46
Preparation of epimer 1 of (D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid




A. Preparation of epimer 1 of (D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy) -3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester




Using a procedure analogous to Example 5, isomer 1 of 4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.55 g, 1.29 mmol). (D)-alananine methyl ester hydrochloride (198 mg, 1.42 mmol), EDCI (276 mg, 1.44 mmol), and 1-hydroxybenzotriazole hydrate (195 mg, 1.44 mmol) furnish the title compound (0.42 g, 0.82 mmol, 63%).
1H NMR (CDCl3), δ 0.62 (t, J=7.3 Hz, 6H), 0.97 (S, 9H), 1.35 (d, J=6.3 Hz, 3H), 1.51 (d, J=7.5 Hz, 3H), 2.06 (q, J=7.3 Hz, 4H), 2.14 (s, 3H), 2.43 (s, 3H), 3.18 (bs, 1H), 3.79 (s, 3H), 4.58 (q, J=6.3 Hz, 1H), 4.79 (m, 1H), 6.32 (d, J=8.1 Hz, 1H), 6.69 (d, J=8.3 Hz, 1H), 6.84-7.05 (m, 4H), 7.30 (d, J=8.3 Hz, 1H).
ES-MS (m/z): calcd. for C31H46NO5 (M+H)+: 511.7; found: 512.3.
B. Preparation of epimer 1 of (D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid
Using a procedure analogous to Example 2, epimer 1 of (D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester (0.42 g, 0.82 mmol) and LiOH give the title compound (0.41 g, 0.82 mmol, 100%).
1H NMR (CDCl3), δ 0.62 (t, J=7.5 Hz, 6H), 0.97 (S, 9H), 1.36 (d, J=6.2 Hz, 3H), 1.57 (d, J=7.0 Hz, 3H), 2.06 (q, J=7.5 Hz, 4H), 2.14 (s, 3H), 2.44 (s, 3H), 3.19 (d, J=0.9 Hz, 1H), 4.58 (dq, J=6.2, 0.9 Hz, 1H), 4.74-4.82 (m, 1H), 6.28 (d, J=7.0 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.84-7.06 (m, 4H), 7.31 (d, J=7.9 Hz, 1H). ES-MS (m/z): calcd. for C31H46NO5 (M+H)+: 511.7; found: 512.3.).
ES-MS (m/z): calcd for C30H42NO5 (M−H)−: 496.7; found: 496.3.
Example 47
Preparation of epimer 1 of (L)-2-(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid




A. Preparation of epimer 1 of (L)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester




Using the procedure analogous to Example 46A, isomer 1 of 4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.55 g, 1.29 mmol) and (L)-alananine methyl ester hydrochloride (198 mg, 1.42 mmol) furnish the title compound (0.56 g, 1.09 mmol, 85%).
1H NMR (CDCl3), δ 0.62 (t, J=7.2 Hz, 6H), 0.97 (s, 9H), 1.36 (d, J=6.1 Hz, 3H), 1.51 (d, J=7.4 Hz, 3H), 2.06 (q, J=7.2 Hz, 4H), 2.15 (s, 3H), 2.43 (s, 3H), 3.18 (bs, 1H), 3.79 (s, 3H), 4.58 (dq, J=6.1, 0.9 Hz, 1H), 4.79 (m, 1H), 6.32 (d, J=7.3 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.84-7.05 (m, 4H), 7.30 (d, J=8.3 Hz, 1H).
ES-MS (m/z): calcd. for C31H46NO5 (M+H)+: 511.7; found: 512.3.
B. Preparation of epimer 1 of (L)-2-(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid
Using a procedure analogous to Example 46B, epimer 1 of (D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester (0.56 g, 1.09 mmol) gives the title compound (0.54 g, 1.09 mmol, 100%).
1H NMR (CDCl3), δ 0.62 (t, J=7.0 Hz, 6H), 0.97 (S, 9H), 1.36 (d, J=6.1 Hz, 3H), 1.57 (d, J=7.4 Hz, 3H), 2.06 (q, J=7.0 Hz, 4H), 2.14 (s, 3H), 2.44 (s, 3H), 3.19 (d, J=1.3 Hz, 1H), 4.59 (q, J=6.1, Hz, 1H), 4.74-4.82 (m, 1H), 6.29 (d, J=7.0 Hz, 1H), 6.69 (d, J =8.8 Hz, 1H), 6.84-7.07 (m, 4H), 7.31 (d, J=8.4 Hz, 1H).
ES-MS (m/z): calcd for C30H42NO5 (M−H)−: 496.7; found: 496.3.
Example 48
Preparation of epimer 2 of (D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid




A. Preparation of epimer 2 of (D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester




Using the procedure analogous to Example 46A, isomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.50 g, 1.17 mmol) and (D)-alananine methyl ester hydrochloride (180 mg, 1.29 mmol) furnish the title compound (0.47 g, 0.92 mmol, 79%). 1H NMR) & ES-MS (m/z): identical to that of Example 47A.
B. Preparation of epimer 2 of (D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid
Using a procedure analogous to Example 46B, from epimer 2 of (D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester (0.47 g, 0.92 mmol) to give the title compound (0.39 g, 0.79 mmol, 86%). 1H NMR & ES-MS: identical to that of Example 47B.
Example 49
Preparation of epimer 2 of (L)-2-(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid




A. Preparation of epimer 2 of (L)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester




Using the procedure analogous to Example 46A, isomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.50 g, 1.17 mmol) and (L)-alananine methyl ester hydrochloride (180 mg, 1.29 mmol) furnish the title compound (0.47 g, 0.92 mmol, 79%). 1H NMR) & ES-MS (m/z): identical to that of Example 46A.
B. Preparation of epimer 2 of (L)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid
Using a procedure analogous to Example 24B, epimer 2 of (L)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester (0.47 g, 0.92 mmol) give the title compound (0.44 g, 0.88 mmol, 96%). 1H NMR & ES-MS: identical to that of Example 46B.
Example 50
Preparation of enantiomer 1 of 5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyl)-thiazolidine-2,4-dione




A. Enantiomer 1 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide




To a mixture of enantiomer 1 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (1.11 g, 2.69 mmol) and DMF (5 mL) is added hydroxylamine hydrochloride (0.29 g, 2.96 mmol), EDCI (0.57 g, 2.96 mmol), HOBt (0.40 g, 2.96 mmol), and NEt3 (1.65 mL, 11.84 mmol). The mixture is stirred at ambient temperature overnight, diluted with EtOAc (40 mL), washed with 1M HCl (40 mL), water (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated.
The residue is purified by ISCO (10%-40% EtOAc gradient) to furnish the title compound (1.0 g, 2.19 mmol, 81%).
1H NMR (CDCl3), δ 0.57-0.64 (m, 6H), 1.02 (s, 9H), 2.02-2.10 (m, 4H), 2.17 (s, 3H), 2.29 (s, 3H), 3.28 (bs, 3H), 3.53 (bs, 1H), 3.71 (dd, J=2.7, 8.8 Hz, 1H), 3.86 (t, J=8.8 Hz, 1H), 4.10 (dd, J=2.7, 8.8 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.94 (dd, J=2.2, 8.1 Hz, 1H), 6.97-7.02 (m, 3H), 7.14 (d, J=8.4 Hz, 1H). LC/MS (m/z): calcd. for C28H41NO4 (M+H)+: 456.7; found: 456.2.
B. Enantiomer 1 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzaldehyde




To a mixture of enantiomer 1 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide (1.0 g, 2.42 mmol) and THF (10 mL) is added 1M in THF LAH (2.5 mL, 2.55 mmol) with cooling.
THF (5 mL) was added and the solution stirred for 1 hour. The solution is diluted with Et2O (100 mL) and washed with 1M HCl (50 mL). The aqueous phase is extracted with Et2O (50 mL). The combined organic layers are washed with 1M HCl (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.64 g, 1.61 mmol, 67%).
1H NMR (CDCl3), δ 0.59-0.66 (m, 6H), 1.02 (s, 9H), 2.05-2.15 (m, 4H), 2.18 (s, 3H), 2.62 (s, 3H), 3.71 (dd, J=1.9, 9.1 Hz, 1H), 3.86 (t, J=9.1 Hz, 1H), 4.10 (dd, J=1.9, 9.1 Hz, 1H), 6.72 (d, J=8.2 Hz, 1H), 6.87 (s, 1H), 6.93 (d, J=8.7 Hz, 1H), 7.06 (s, 1H), 7.17 (d, J=8.2 Hz, 1H) 7.67 (dd, J=1.7, 8.0, 1H), 10.20 (s, 1H).
LC/MS (m/z): calcd. for C26H36O3 (M+H)+: 397.7; found: N/A.
C. Enantiomer 1 of 5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione




To a mixture of enantiomer 1 of 4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzaldehyde (0.64 g, 1.61 mmol) and toluene (20 mL) is added 90% 2,4-thiazolidinedione (0.25 g, 1.94 mmol), and piperidine acetate (0.04 g, 0.24 mmol). The solution is heated to a reflux overnight and the water removed by a Dean-Stark trap. The solution is diluted with EtOAc (60 mL), washed with water (50 mL), saturated NaHCO3 (50 mL), dried over MgSO4, filtered and concentrated. Purified by ISCO (20%-50% EtOAc gradient) to furnish the title compound (0.75 g, 1.51 mmol, 94%).
1H NMR (CDCl3), δ 0.60-0.67 (m, 6H), 1.03 (s, 9H), 2.04-2.13 (m, 4H), 2.19 (s, 3H), 2.42 (s, 3H), 2.50 (d, J=2.0 Hz, 1H), 3.72 (d, J=8.8 Hz, 1H), 3.86 (t, J=8.9 Hz, 1H), 4.10 (dd, J=2.7, 9.4 Hz, 1H), 6.72 (d, J=8.1 Hz, 1H), 6.88 (d, J=1.7 Hz, 1H), 6.94 (dd, J=2.3, 8.7 Hz, 1H), 7.08 (s, 1H), 7.11 (dd, J=1.8, 8.4 Hz, 1H), 7.33 (d, J=8.4, 1H), 8.06 (s, 1H), 8.97 (bs, 1H).
LC/MS (m/z): calcd. for C29H37NO4S (M+H)+: 494.5; found: 494.2.
D. Enantiomer 1 of 5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyl)-thiazolidine-2,4-dione
To a mixture of enantiomer 1 of 5-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione (0.35 g, 0.71 mmol) and MeOH (10 mL) is added Mg (0.17 g, 7.1 mmol). The solution is heated at a reflux for 4 hours. The solution is filtered thru Celite®, rinsed with MeOH (2 mL), and the solution concentrated. The residue is purified by ISCO (15%-30% EtOAc gradient) to furnish the title compound (0.13 g, 0.26 mmol, 37%).
1H NMR (CDCl3), δ 0.57-0.65 (m, 6H), 1.02 (s, 9H), 2.01-2.10 (m, 4H), 2.19 (s, 3H), 2.31 (s, 3H), 2.50 (d, J=2.6 Hz, 1H), 2.97-3.06 (m, 1H), 3.65 (dd, J=3.8, 14.5 Hz, 1H), 3.69-3.75 (m, 1H), 3.87 (t, J=8.8 Hz, 1H), 4.10 (dd, J=2.7, 9.3 Hz, 1H), 4.52 (dd, J=3.8, 11.2 Hz, 1H), 6.70 (dd, J=2.3, 8.5 Hz, 1H), 6.87-7.04 (m, 5H), 8.56 (bs, 1H).
LC/MS (m/z): calcd. for C29H39NO4S (M+H)+: 496.6; found: 496.2.
Example 51
Preparation of enantiomer 2 of 5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyl)-thiazolidine-2,4-dione




A. Enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide




To mixture of enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.70 g, 1.70 mmol) and DMF (5 mL) is added hydroxylamine hydrochloride (0.18 g, 1.87 mmol), EDCI (0.33 g, 1.87 mmol), HOBt (0.23 g, 1.87 mmol), and NEt3 (0.95 mL, 6.79 mmol). The mixture is stirred at ambient temperature overnight, diluted with EtOAc (40 mL), washed with 1M HCl (40 mL), water (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.76 g, 2.19 mmol, 81%).
1H NMR (CDCl3), δ 0.57-0.64 (m, 6H), 1.02 (s, 9H), 2.01-2.10 (m, 4H), 2.17 (s, 3H), 2.28 (s, 3H), 3.28 (bs, 3H), 3.54 (bs, 1H), 3.71 (dd, J=2.6, 8.8 Hz, 1H), 3.86 (t, J=8.8 Hz, 1H), 4.10 (dd, J=2.6, 8.8 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H), 6.94 (dd, J=2.2, 8.6 Hz, 1H), 6.97-7.02 (m, 3H), 7.13 (d, J=8.3 Hz, 1H). LC/MS (m/z): calcd. for C28H41NO4 (M+H)+: 456.7; found: 456.3.
B. Enantiomer 2 of 4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzaldehyde




To a mixture of enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide (0.76 g, 1.75 mmol) and THF (20 mL) is added 1M LAH in THF (1.75 mL, 1.75 mmol) with cooling, and the solution stirred for 1 hour. The solution is diluted with Et2O (100 mL) and washed with 1M HCl (50 mL). The aqueous phase is extracted with Et2O (50 mL). The combined organic layers are washed with 1M HCl (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.48 g, 1.21 mmol, 73%).
1H NMR (CDCl3), δ 0.60-0.65 (m, 6H), 1.02 (s, 9H), 2.07-2.14 (m, 4H), 2.18 (s, 3H), 2.62 (s, 3H), 3.58-3.74 (m, 1H), 3.87 (t, J=8.9 Hz, 1H), 4.10 (dd, J=2.6, 9.2 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 6.87 (d, J=2.5, 8.6, 1H), 7.06 (s, 1H), 7.17 (dd, J=1.8, 8.2 Hz, 1H), 7.67 (d, J=8.4, 1H), 10.20 (s, 1H).
LC/MS (m/z): calcd. for C26H36O3 (M+H)+: 397.7; found: 397.3.
C. Enantiomer 2 of 5-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione




To a mixture of enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzaldehyde (048 g, 1.21 mmol) and toluene (15 mL) is added 90% 2,4-thiazolidinedione (0.19 g, 1.45 mmol), and piperidine acetate (0.03 g, 0.18 mmol). The solution is heated to a reflux overnight and the water removed by a Dean-Stark trap. The solution is diluted with EtOAc (60 mL), washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. Purified by ISCO (20%-40% EtOAc gradient) to furnish the title compound (0.50 g, 1.00 mmol, 83%).
1H NMR (CDCl3), δ 0.60-0.67 (m, 6H), 1.03 (s, 9H), 2.05-2.12 (m, 4H), 2.19 (s, 3H), 2.42 (s, 3H), 2.51 (d, J=2.5 Hz, 1H), 3.70-3.75 (m, 1H), 3.88 (t, J=8.8 Hz, 1H), 4.10 (dd, J=2.7, 9.2 Hz, 1H), 6.72 (d, J=8.3 Hz, 1H), 6.88 (d, J=1.8 Hz, 1H), 6.94 (dd, J=2.2, 8.6 Hz, 1H), 7.08 (s, 1H), 7.11 (dd, J=1.8, 8.0 Hz, 1H), 7.33 (d, J=8.0, 1H), 8.06 (s, 1H), 9.02 (bs, 1H).
LC/MS (m/z): calcd. for C29H37NO4S (M+H)+: 494.5; found: 494.2.
D. Enantiomer 2 of 5-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyl)-thiazolidine-2,4-dione
To a mixture of enantiomer 2 of 5-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione (example Rupp-7) (0.25 g, 0.50 mmol) and MeOH (10 mL) is added Mg (0.12 g, 5.04 mmol). The solution is heated at a reflux for 4 hours. The solution is filtered thru Celite®, rinsed with MeOH (2 mL), and the solution concentrated. The residue is purified by ISCO (15%-30% EtOAc gradient) to furnish the title compound (0.084 g, 0.17 mmol, 34%).
1H NMR (CDCl3), δ 0.56-0.63 (m, 6H), 1.02 (s, 9H), 2.00-2.10 (m, 4H), 2.18 (s, 3H), 2.31 (s, 3H), 2.51 (d, J=2.1 Hz, 1H), 2.97-3.06 (m, 1H), 3.65 (dd, J=3.9, 14.7 Hz, 1H), 3.69-3.75 (m, 1H), 3.86 (t, J=8.9 Hz, 1H), 4.09 (dd, J=2.7, 9.4 Hz, 1H), 4.52 (dd, J=3.8, 11.2 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.86-7.03 (m, 5H), 8.56 (bs, 1H). LC/MS (m/z): calcd. for C29H39NO4S (M+H)+: 496.6; found: 496.2.
Example 52 and 53
Enantiomer 1 and 2 of [(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid




A. Racemic [(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester




Using a procedure analogous to Example 46A, from racemic 4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (1.46 g, 3.43 mmol) and sascoine methyl ester hydrochloride (0.52 g, 3.76 mmol) to give the title compound (1.74 g, 3.40 mmol, 99%).
1H NMR (CDCl3), δ 0.58-0.65 (m, 6H), 0.97 (s, 6H), 1.02 (s, 3H), 1.33 (d, J=6.2 Hz, 1H), 1.36 (d, J=6.2 Hz, 2H), 2.00-2.10 (m, 4H), 2.14 (s, 3H), 2.25 (s, 1H), 2.33 (s, 2H), 2.57 (d, J=9.6 Hz, 0.33H), 2.58 (d, J=9.6 Hz, 0.66H), 2.89 (s, 3H), 3.18 (dd, J=9.6, 1.3 Hz, 1H), 3.69 (s, 1H), 3.79 (s, 2H), 3.91 (s, 0.66H), 4.32 (bs, 1.34H), 4.59 (dq, J=6.2, 1.3 Hz, 1H), 6.69 (d, J=8.3 Hz, 1H), 6.84-7.11 (m, 5H).
ES-MS (m/z): calcd for C31H45NO5 (M+H)+: 512.7; found: 512.3.
B. Separation of enantiomers of [(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester
A racemic mixture of [(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester (1.73 g), is chromatographed (HPLC: ChiralPak AD, 0.1% TFA in iPrOH:Hept=5:95) to give enantiomer 1 (0.636 g, 38%, rt=21.8 m) and enantiomer 2 (0.72 g, 42%, rt=26.7 m).
(Enantiomer 1)
HPLC: ChiralPak AD, 0.1% TFA in iPrOH:Hept=5:95; 0.6 mL/m (flow rate); rt=21.8 m; @ 240 nm;
NMR & LC/MS: equivalent to the racemate.
(Enantiomer 2)
HPLC: ChiralPak AD, 0.1% TFA in iPrOH:Hept=5:95; 0.60 mL/m (flow rate); rt=26.7 m; @240 nm;
NMR & LC/MS: equivalent to the racemate
C. Enantiomer 1 of [(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid
Using a procedure analogous to Example 46B, enantiomer 1 of [(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester (0.63 g, 1.24 mmol) gives the title compound (0.58 g, 1.16 mmol, 93%).
1H NMR (CDCl3), δ 0.58-0.65 (m, 6H), 0.98 (s, 9H), 1.36 (d, J=6.2 Hz, 3H), 2.06 (q, J=7.1 Hz, 4H), 2.14 (s, 3H), 2.25 (s, 0.9H), 2.31 (s, 2.1H), 2.93 (s, 3H), 3.16 (bs, 1H), 3.18 (d, J=1.3 Hz, 1H), 3.95 (s, 1H), 4.35 (s, 1H), 4.59 (q, J=6.2 Hz, 1H), 6.68-7.11 (m, 6H).
ES-MS (m/z): calcd for C30H42NO5 (M−H)−: 496.7; found: 496.3.
D. Enantiomer 2 of [(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid
Using a procedure analogous to Example 46B, enantiomer 2 of [(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester (0.72 g, 1.41 mmol) gives the title compound (0.64 g, 1.28 mmol, 91%). 1H NMR & ES-MS (m/z): identical to enantiomer 1 of [(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid.
Example 54
Preparation of 3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane




A. 3′-[4-benzyloxy-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane




Using a procedure analogous to Example 1E, 3′-[4-benzyloxy-3-methylphenyl]-3′-[4-trifluoromethanesulfonyloxy-3-methylphenyl]pentane gives the title compound (30 g, 77%).
1H NMR 300 MHz (DMSO-d6): δ 0.54 (t, J=6.9 Hz, 6H), 2.05 (q, J=6.9 Hz, 4H), 2.12 (s, 3H), 2.47 (s, 3H), 3.78 (s, 3H), 5.06 (s, 2H), 6.91 (m, 3H), 7.05 (d, J=8.41 Hz, 1H), 7.11 (s, 1H), 7.29-7.47 (m, 5H), 7.72 (d, J=8.05, 1H).
B. 3′-[4-benzyloxy-3-methylphenyl]-3′-[4-hydroxymethyl-3-methylphenyl]pentane




Using a procedure analogous to Example 13B, 3′-[4-benzyloxy-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane gives the title compound (6.0 g, quant).
1H NMR 400 MHz (DMSO-d6): δ 0.54 (t, J=7.2 Hz, 6H), 2.02 (q, J=7.2 Hz, 4H), 2.12 (s, 3H), 2.17 (s, 3H), 4.42 (d, J=6.0 Hz, 2H), 4.94 (t, J=5.6 Hz, 1H), 5.05 (s, 2H), 6.87-6.94 (m, 5H), 7.19 (d, J=8.0 Hz, 1H), 7.31 (d, J=7.6, 1H), 7.38 (t, J=7.2 Hz, 2H), 7.44 (d, J=7.2 Hz, 2H).
High Res. FAB-MS: 388.2397; calc. for C27H32O2: 388.2402.
C. 3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-benzyloxy-3-methylphenyl]pentane




To a 0° C. mixture of 3′-[4-benzyloxy-3-methylphenyl]-3′-[4-hydroxymethyl-3-methylphenyl]pentane (6.0 g, 15.4 mmol) and Et2O (40 ml) is added PBr3 (1.6 ml, 17.0 mmol). The reaction is stirred for 2 h and allowed to warm to RT. The reaction is diluted with Et2O, washed with minimal amount of water, brine, Na2SO4 dried, concentrated, and azeotrope to dryness with toluene. The resulting residue is dissolved in THF (4 ml) and cooled to −78° C. to afford the bromide/THF solution. In a separate flask is charged with 1M LiHMDS (31 ml, 30.8 mmol), cooled to −78 C, and added pinacolone (3.9 ml, 30.8 mmol). The reaction is stirred for 1.5 h, warmed to −55 C and transferred (via syringe) to the −78° C. solution of bromide/THF. The reaction is allowed to warm to RT and stirred for 16 h. The reaction is diluted with Et2O and washed with 1N HCl. The organic layer is Na2SO4 dried and chromatographed (70% CHCl3/Hex) to give the title compound (5.2 g, 71%).
1H NMR 400 MHz (DMSO-d6): δ 0.48 (t, J=7.6 Hz, 6H), 0.97 (s, 9H), 1.93 (q, J=7.2 Hz, 4H), 2.05 (s, 3H), 2.13 (s, 3H), 2.60 (t, J=8.0 Hz, 2H), 2.69 (t, J=8.4 Hz, 2H), 4.98 (d, J=4.4 Hz, 2H), 6.77-6.84 (m, 5H), 6.90 (d, J=8.0 Hz, 1H), 7.24-7.26 (m, 1H), 7.32 (t, J=7.2 Hz, 2H), 7.38 (d, J=7.2 Hz, 2H).
D. 3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-hydroxy-3-methylphenyl]pentane




Using a procedure analogous to Example 6D, 3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-benzyloxy-3-methylphenyl]pentane gives the title compound (3.1 g, 74%).
1H NMR 400 MHz (DMSO-d6): δ 0.51 (t, J=6.8 Hz, 6H), 1.03 (s, 9H), 1.96 (q, J=7.2 Hz, 4H), 2.03 (s, 3H), 2.19 (s, 3H), 2.66 (t, J=6.4 Hz, 2H), 2.74 (t, J=6.4 Hz, 2H), 6.61 (d, J=8.0 Hz, 1H), 6.73 (dd, J=2.0 Hz, J=8.0 Hz, 2H), 6.83-6.86 (m, 2H), 6.95 (d, J=8.0 Hz, 1H), 8.97 (s, J=8.0 Hz, 1H).
E. 3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-(trifluoromethylsulfonyloxy)-3-methylphenyl]pentane




Using a procedure analogous to Example 1C, 3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-hydroxy-3-methylphenyl]pentane gives the title compound (4.2 g, quant).
1H NMR 400 MHz (DMSO-d6): δ 0.53 (t, J=7.2 Hz, 6H), 1.03 (s, 9H), 2.05 (q, J=7.2 Hz, 4H), 2.21 (s, 3H), 2.27 (s, 3H), 2.66 (t, J=8.4 Hz, 2H), 2.74 (t, J=8.0 Hz, 2H), 6.84 (dd, J=1.6 Hz, J=6.4 Hz, 1H), 6.91 (s, 1H), 7.00 (d, J=7.6 Hz, 1H), 7.07 (dd, J=2.0 Hz, J=6.4 Hz, 1H), 7.21-7.24 (m, 2H).
ES-MS: 530.25 (M+NH4).
F. 3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-(methoxycarboxyl)-3-methylphenyl]pentane




Using a procedure analogous to Example 1E, 3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-(trifluoromethylsulfonyloxy)-3-methylphenyl]pentane gives the title compound as a white foam (2.1 g, 67%).
1H NMR 400 MHz (DMSO-d6): δ 0.53 (t, J=7.2 Hz, 6H), 1.03 (s, 9H), 2.07 (q, J=7.2 Hz, 4H), 2.20 (s, 3H), 2.46 (s, 3H), 2.69 (t, J=7.6 Hz, 2H), 2.75 (t, J=6.4 Hz, 2H), 3.78 (s, 3H), 6.84 (d, J=8.4 Hz, 1H), 6.88 (s, 1H), 6.98 (d, J=8.0 Hz, 1H), 7.03 (dd, J=1.6 Hz, J=6.8 Hz, 1H), 7.08 (s, 1H), 7.70 (d, J=8.4 Hz, 1H).
High Res ES(+)MS m/z: 440.3167; calc. for C28H38O3+NH4: 440.3165
G. 3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane
Using a procedure analogous to Example 2,3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-(methoxycarboxyl)-3-methylphenyl]pentane gives the title compound as a white foam (1.5 g, 97%).
1H NMR 300 MHz (DMSO-d6): δ 0.54 (t, J=7.0 Hz, 6H), 1.03 (s, 9H), 2.07 (q, J=6.6 Hz, 4H), 2.20 (s, 3H), 2.46 (s, 3H), 2.68 (d, J=7.0 Hz, 2H), 2.73 (d, J=5.9, 2H), 6.85-6.90 (m, 2H), 6.99-7.06 (m, 3H), 7.72 (d, J=8.4 Hz, 1H).
High Res ES(+)MS m/z: 426.3003; calc. for C27H36O3+NH4: 426.3008
Example 55
Preparation of racemic 3′-[4-(3-hydroxy-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane




Using a procedure analogous to Example 1D, 3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane gives the title compound as a white foam (1.5 g, quant).
1H NMR 300 MHz (DMSO-d6): δ 0.54 (t, J=7.3 Hz, 6H), 0.80 (s, 9H), 1.30-1.36 (m, 1H), 1.58-1.64 (m, 1H), 2.07 (q, J=6.9 Hz, 4H), 2.20 (s, 3H), 2.47 (s, 3H), 2.74-2.82 (m, 1H), 2.99-3.04 (m, 1H), 4.41 (d, J=6.2, 1H), 6.85-6.89 (m, 2H), 7.02-7.08 (m, 3H), 7.72 (d, J=8.0 Hz, 1H),
High Res ES(+)MS m/z: 428.3145; calc. for C27H38O3+NH4: 428.3165
Compounds of the Invention—Salts, Stereoisomers, & Prodrugs
Salts of the compounds represented by formulae (I) are an additional aspect of the invention. The skilled artisan will also appreciate that the family of compounds of formulae I include acidic and basic members and that the present invention includes pharmaceutically acceptable salts thereof.
In those instances where the compounds of the invention possess acidic or basic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, ammonium, calcium, magnesium, aluminum, zinc, and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin. For example, a carboxylic acid substituent on the compound of Formula I may be selected as —CO2H and salts may be formed by reaction with appropriate bases (e.g., NaOH, KOH) to yield the corresponding sodium and potassium salt.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar. Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, choline, clavulanate, citrate, chloride, chloroprocaine, choline, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate, estolate, esylate, ethylenediamine, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, bromide, chloride, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, malseate, mandelate, meglumine, mesylate, mesviate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate, polygalacturonate, procane, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.
Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans-isomeric forms of the compounds. The R— and S— isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans-isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a chiral column may be used such as those sold by Daicel Chemical Industries identified by the trademarks:

    CHIRALPAK AD, CHIRALPAK AS, CHIRALPAK OD, CHIRALPAK OJ,
    CHIRALPAK OA, CHIRALPAK OB, CHIRALPAK OC, CHIRALPAK OF,
    CHIRALPAK OG, CHIRALPAK OK, and
    CHIRALPAK CA-1.


By another conventional method, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers. These diastereomers, because they have different melting points, different boiling points, and different solubilities can be separated by conventional means, such as crystallization.
Compounds of the Invention—Salts, Stereoisomers, & Prodrugs:
Salts of the compounds represented by formulae (I) are an additional aspect of the invention. The skilled artisan will also appreciate that the family of compounds of formulae I include acidic and basic members and that the present invention includes pharmaceutically acceptable salts thereof.
In those instances where the compounds of the invention possess acidic or basic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, ammonium, calcium, magnesium, aluminum, zinc, and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin. For example, a carboxylic acid substituent on the compound of Formula I may be selected as —CO2H and salts may be formed by reaction with appropriate bases (e.g., NaOH, KOH) to yield the corresponding sodium and potassium salt.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar. Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, choline, clavulanate, citrate, chloride, chloroprocaine, choline, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate, estolate, esylate, ethylenediamine, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, bromide, chloride, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, malseate, mandelate, meglumine, mesylate, mesviate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate, polygalacturonate, procane, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.
Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans-isomeric forms of the compounds. The R- and S-isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans-isomers, are contemplated by this invention.
Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a chiral column may be used such as those sold by Daicel Chemical Industries identified by the trademarks:

    CHIRALPAK AD, CHIRALPAK AS, CHIRALPAK OD, CHIRALPAK OJ,
    CHIRALPAK OA, CHIRALPAK OB, CHIRALPAK OC, CHIRALPAK OF,
    CHIRALPAK OG, CHIRALPAK OK, and
    CHIRALPAK CA-1.


By another conventional method, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers. These diastereomers, because they have different melting points, different boiling points, and different solubilities can be separated by conventional means, such as crystallization.
The present invention is also embodied in mixtures of compounds of formulae I.
Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo.
Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred esters to use as prodrugs are; methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N-diethylglycolamido.
N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-chloro-N,N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).
Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C5,220-3).
Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula I (in a medium such as dimethylformamide) 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C5,220-3). The prodrugs, for example, may be prepared by reaction of the sodium salt for a compound of Formula I with;




and sodium iodide to provide the ester prodrug pendent group




Also, lower alkyl (viz., C1-C8) ester prodrugs may be prepared by conventional means such as reacting the sodium or potassium salt (derived by forming the salt of any acidic compound of the invention, viz., reaction of a base such as KOH with an acidic group such as —CO2H) of a compound of Formula I with an alkyl iodide such as methyl iodide, ethyl iodide, n-propyl iodide, isopropyl iodide. Typical ester prodrug substituents are




Pharmaceutical Formulations Containing the Novel Compounds of the Invention:

Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the compound of the invention (compounds of Formula I) together with a pharmaceutically acceptable carrier or diluent. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients.
In making the compositions of the present invention, the compounds of Formula I will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10% by weight of the compound. The compounds of the present invention are preferably formulated prior to administration.
The compounds of the invention may also be delivered by suitable formulations contained in a transderm patch. Alternatively, the compounds of the invention may be delivered to a patient by sublingual administration.
For the pharmaceutical formulations any suitable carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc.
In powders the carrier is a finely divided solid which is in admixture with the finely divided Active ingredient. In tablets the compound of Formula I is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the compound which is the novel compound of this invention.
Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.
Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs.
The compounds of the invention may be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The compounds can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the finely divided compounds of the invention in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
Methods of Using the Compounds of the Invention:
Generic disease states benefited by treatment with the compounds of Formula I include, but are not limited to:

    
    
        disease states characterized by abnormal calcium regulation
        disease states characterized by abnormal cell proliferation
        disease states characterized by abnormal cell differentiation
        disease states characterized by abnormal immune response
        disease states characterized by abnormal dermatological conditions
        disease states characterized by neurodegenerative condition
        disease states characterized by inflammation
        disease states characterized by vitamin D sensitivity
        disease states characterized by hyperproliferative disorders.
    
    


Specific disease states benefited by treatment of the compounds of Formula I and II include, but are not limited to:

    
    
        Acne
        Actinic keratosis
        Alopecia
        Alzheimer's disease
        Bone maintenance in zero gravity
        Bone fracture healing
        Breast cancer
        Chemoprovention of Cancer
        Crohn's disease
        Colon cancer
        Type I diabetes
        Host-graft rejection
        Hypercalcemia
        Type II diabetes
        Leukemia
        Multiple sclerosis
        Myelodysplastic syndrome
        Insufficient sebum secretion
        Osteomalacia
        Osteoporosis
        Insufficient dermal firmness
        Insufficient dermal hydration
        Psoriatic arthritis
        Prostate cancer
        Psoriasis
        Renal osteodystrophy
        Rheumatoid arthritis
        Scleroderma
        Skin cancer
        Systemic lupus erythematosus
        Skin cell protection from Mustard vesicants
        Ulcerative colitis
        Vitiligo
        Wrinkles
    
    


Particularly preferred is the treatment of psoriasis and osteoporosis by administration to a mammal (including a human) of a therapeutically effective amount of compounds of Formulae I. By “pharmaceutically effective amount” it is meant that quantity of pharmaceutical agent corresponding to formulae I which prevents, removes or reduces the deleterious effects of a disease state in mammals, including humans.
The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a pharmaceutically effective amount typically in the range of from about 0.0001 mg/kg/day to about 50 mg/kg/day of body weight of an active compound of this invention. Preferably the dose of compounds of the invention will be from 0.0001 to 5 mg/kg/day of body weight.
Preferably compounds of the invention (e.g., per Formula I) or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of Active ingredient in a unit dose of composition may be varied or adjusted from about 0.0001 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it is necessary to make routine variations to the dosage depending on the age and condition of the patient. Dosage will also depend on the route of administration. The compounds of the invention may be administered by a variety of routes including oral, aerosol, rectal, transdermal, sublingual, subcutaneous, intravenous, intramuscular, and intranasal. Particularly preferred is the treatment of psoriasis with an ointment type formulation containing the compounds of the invention. The ointment formulation may be applied as needed, typically from one to 6 times daily.
Treatment of psoriasis is preferably done with topical application by a formulation in the form of a cream, oil, emulsion, paste or ointment containing a therapeutically effective amount of a compound defined by Formula (I), and in particular those compounds set out in Tables 1 or 2 or those compounds identified as “AA” to “BQ”, supra. The formulation for topical treatment contains from 0.5 to 0.00005 weight percent, preferably from 0.05 to 0.0005 weight percent, and most preferably from 0.025 to 0.001 of a compound defined by formula (I).
For example, two semisolid topical preparations useful as vehicles for VDR modulators in treatment and prevention of psoriasis are as follows:

    
    
        Polyethylene Glycol Ointment USP (p. 2495)
        Prepare Polyethylene Glycol Ointment as Follows:
    
    


















Polyethylene Glycol 3350
400 g.



Polyethylene Glycol 400
600 g.



To make
1000 g. 










    
    
        Heat the two ingredients on a water bath to 65 C. Allow to cool, and stir until congealed. If a firmer preparation is desired, replace up to 100 g of the polyethylene glycol 400 with an equal amount of polyethylene glycol 3350.
        Hydrophilic Ointment USP (p. 1216)
        Prepare Hydrophilic Ointment as Follows:
    
    


















Methylparaben
0.25 g. 



Propylparaben
0.15 g. 



Sodium Lauryl Sulfate
 10 g.



Propylene Glycol
120 g.



Stearyl Alcohol
250 g.



White Petrolatum
250 g.



Purified Water
370 g.



To make about
1000 g. 










The Stearyl Alcohol and White Petrolatum are melted on a steam bath, and warmed to about 75 C. The other ingredients, previously dissolved in the water are added, warmed to 75 C, and the mixture stirred until it congeals.
For each of the above formulations the compound of formula (I) is added during the heating step in an amount that is from 0.5 to 0.00005 weight percent, preferably from 0.05 to 0.0005 weight percent, and most preferably from 0.025 to 0.001 weight percent of the total ointment weight. (Source: —United States Pharmacopoeia 24, United States Pharmacopeial Convention, 1999)
Conventional therapy for osteoporosis includes; (i) estrogens, (ii) androgens, (iii) calcium supplements, (iv) vitamin D metabolites, (v) thiazide diuretics, (vi) calcitonin, (vii) bisphosphonates, (viii) SERMS, and (ix) fluorides (see, Harrison's Principles of Internal Medicine, 13th edition, 1994, published by McGraw Hill Publ., ISBN 0-07-032370-4, pgs. 2172-77; the disclosure of which is incorporated herein by reference.). Any one or combination of these conventional therapies may be used in combination with the method of treatment using compounds of Formulae I as taught herein. For example, in a method of treating osteoporosis, the vitamin D receptor modulator compounds of the invention (e.g., as defined by formula I) may be administered separately or simultaneously with a conventional therapy. Alternatively, the vitamin D receptor modulator compounds of the invention may be combined with conventional therapeutic agents in a formulation for treatment of osteoporosis such as set out below:
A formulation for treating osteoporosis comprising:

    
    
        Ingredient (A1): a vitamin D receptor modulator represented by formula (I), or a pharmaceutically acceptable salt or aliphatic ester prodrug derivative thereof;
        Ingredient (B1):
        
            one or more co-agents that are conventional for treatment osteoporosis selected from the group consisting of:
            
                a. estrogens,
                b. androgens,
                c. calcium supplements,
                d. vitamin D metabolites,
                e. thiazide diuretics,
                f. calcitonin,
                g. bisphosphonates,
                h. SERMS, and
                i. fluorides.
            
            
        
        
        Ingredient (C1): optionally, a carrier or diluent.

Typically useful formulations are those wherein the weight ratio of (A1) to (B1) is from 10:1 to 1:1000 and preferably from 1:1 to 1:100.

Combination Therapy for Psoriasis:

    
    


Conventional therapy for psoriasis includes topical glucocorticoids, salicylic acid, crude coal tar, ultraviolet light, and methotrexate (see, Harrison's Principles of Internal Medicine, 13th edition, 1994, published by McGraw Hill Publ., ISBN 0-07-032370-4, pgs. 2172-77). Any one or combination of these conventional therapies may be used in combination with the method of treatment using compounds of Formulae I as taught herein. For example, in a method of treating osteoporosis, the vitamin D receptor modulator compounds of the invention (e.g., as defined by formula I) may be topically administered separately or simultaneously with a conventional therapy. Alternatively, the vitamin D receptor modulator compounds of the invention may be combined with conventional therapeutic agents in a topically applied formulation for treatment of osteoporosis such as set out below:
A formulation for treating osteoporosis comprising:

    
    
        Ingredient (A2): a vitamin D receptor modulator represented by formula (I), or a pharmaceutically acceptable salt or aliphatic ester prodrug derivative thereof;
        Ingredient (B2):
        
            one or more co-agents that are conventional for treatment osteoporosis selected from the group consisting of:
            
                a. topical glucocorticoids,
                b. salicylic acid, or
                c. crude coal tar.
            
            
        
        
        Ingredient (C2): optionally, a carrier or diluent.

Typically useful formulations are those wherein the weight ratio of (A2) to (B2) is from 1:10 to 1:100000 and preferably from 1:100 to 1:10000.

Experimental Results:

    
    









TABLE 3







Summary of Experimental Results












RXR-VDR
VDR
OCN
Mouse


Test
heterodimer2
EC50 (nM)
Promoter4
Hypercal5


Cmpd.1
EC50 (nM)
(Caco-2 cells)3
EC50 (nM)
μg/Kg/d














Ex. 1


21



Ex. 3A
149/51 
1261
15/18
1000


Ex. 3B
396/292
2869
57/83
3000


Ex. 4A


3


Ex. 4B


15


Ex. 5

3000
42
100


Ex 6
20/1 
300
0.3
10


Ex. 7

63
4


Ex. 8
1
35
4/1
100


Ex. 9
4
4
7/6


Ex. 10Da
218/25 
538
 8/46


Ex. 10Db
86
935
15


Ex. 11
186
1011
7
3000


Ex. 12
562/206
1261
20/25
4000


Ex. 12a
67
651
1
300


Ex. 12b
335/55 
960
13/23
300


Ex. 13
22/30
1009
 89/167
3000


Ex. 14


306
3000


Ex. 15A
229/17 
662
35/43
1500


Ex. 15B


163


Ex. 16


35
>5000


Ex. 17
275/101
990
56/15
>3000


Ex. 18
38/4 
430
1/3
1000


Ex. 19
96/12
613
12/16
2000


Ex. 20B
9/3
101
0.8/0.2
300


Ex. 21
226/77 
935
 8/27
6000


Ex. 22
80/23
467
7/3
1000


Ex. 23
283/230
805
13/40
3000


Ex. 24
3
368
0.2


Ex. 25A
8/2
340
0.4
<300


Ex. 25B
83/25
982
2/3
1000


Ex. 26
 6/67
651
1
300


Ex. 27
335/55 
960
13/23
300


Ex. 28
171/337
72
106/84 


Ex. 29
93/60
958
 2/11
3000


Ex. 30
101/48 
698
1/3
1000


Ex. 31
19/33
410
1
3000


Ex. 32
89/9 
345
4/1
1000


Ex. 33
 1/55
418
3/1
<300


Ex. 34
15/5 
303
9/1
<300


Ex. 35


27


Ex. 36
242/293
698
135/37 
>300


Ex. 37
60
698
12
1000


Ex. 38
266/137
863
41


Ex. 39
302/204
979
74/61


Ex. 40
138
694
70


Ex. 41
523

421


Ex. 42
 56/316
1227
98/19


Ex. 44
0.4

0.1
<300


Ex. 45
2

0.7
300


Ex. 46
6
400
2/3
3000


Ex. 47
59
816
22/6 
3000


Ex. 48
44
433
9/4
<1000


Ex. 49
92
859
14/40


Ex. 50
10
83
0.2
300


Ex. 51
4

1.4
300


Ex. 52
81
813
4
>3000


Ex. 53
236/210

12/34
>3000


Ex. 54
396

119
>3000


Ex. 55
9
920
6


AA
5.02
16
5
0.06


BB
10.32
169.81
8.24
20


CC
2427.7

>1000


DD
109.44

31.1
1000


EE
429.99
891.16
341.25
1000


FF
3
57
















TABLE 4







Summary of Experimental Results











Test
Kera. Prolif.
IL-10.



Cmpd.1
IC50 (nM)
IC50 (nM)















Ex. 1





Ex. 3A



Ex. 3B



Ex. 4A



Ex. 4B



Ex. 5
375



Ex 6
2
55



Ex. 7
18



Ex. 8
330



Ex. 9
985



Ex. 10Da
1000



Ex. 10Db
1000



Ex. 11
308
478



Ex. 12



Ex. 12a
4
52



Ex. 12b



Ex. 13



Ex. 14



Ex. 15A
117



Ex. 15B



Ex. 16



Ex. 17
1000



Ex. 18
1000
47



Ex. 19
82
142



Ex. 20B
3
4



Ex. 21
223
1050



Ex. 22
4
39



Ex. 23
40
27



Ex. 24



Ex. 25A
1105
40



Ex. 25B
26
158



Ex. 26
4
52



Ex. 27



Ex. 28
240



Ex. 29
49
153



Ex. 30
20
123



Ex. 31
21
295



Ex. 32
1000
106



Ex. 33
6
19



Ex. 34
25
45



Ex. 35
40



Ex. 36
139



Ex. 37
55
229



Ex. 38



Ex. 39
508



Ex. 40
1000



Ex. 41



Ex. 42
50



Ex. 44
28
6



Ex. 45
32
15



Ex. 46
21
33



Ex. 47
1000



Ex. 48
1000



Ex. 49
1000



Ex. 50
3
4



Ex. 51
26
19



Ex. 52
52
154



Ex. 53
224



Ex. 54



Ex. 55



AA
120
1.2



BB
10
28



CC



DD
1060



EE



FF
103
0.5










Explanation of Table 5 and 6 Column Numerical Superscripts:

1. Test Compound numbers refer to the products of the corresponding Example Nos. that is, compounds within the scope of the invention. For example, the number “Ex. 2” refers to the compound, 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane, prepared in Example 2. The control experiments are done with the double letter coded compounds identified as follows:
“AA”=1α,25-dihydroxyvitamin D3 
“BB”=3-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1,2-diol
“CC”=1-(4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-cyclohexyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one
“DD”=compound represented by the formula:




“EE”=compound represented by the formula:




“FF”−=calcipotriol (structural formula below):




2. The RXR-VDR heterodimerization (SaOS-2 cells) test is described in the “Assay” section of the Description, infra.
3. The VDR CTF (Caco-2 cells) test is described in the “Assay” section of the Description, infra.
4. The OCN Promoter test is described in the “Assay” section of the Description, infra.
5. The Mouse Hypercalcemia test is described in the “Assay” section of the Description, infra.
6. The keratinocyte proliferation assay is described in the “Assay” section of the Description, infra.
7. The IL-10 induction assay is described in the “Assay” section of the Description, infra.
Assay Methods
Use of the Assay Methods:
The evaluation of the novel compounds of the invention for osteoporosis and other related diseases is done using a plurality of test results. The use of multiple assays is necessary since the combined properties of (i) high activity for the vitamin D receptor, and (ii) prevention of hypercalcemia must be achieved to have utility for the methods of treating diseases, which are also, aspects of this invention. Some of the tests described below are believed related to other tests and measure related properties of compounds. Consequently, a compound may be considered to have utility in the practice of the invention if is meets most, if not all, of the acceptance criteria for the above described tests.
The evaluation of the novel compounds of the invention for psoriasis is done using the Keratinocyte Proliferation Assay in combination with other assays that measure inhibition of IL-2 production and stimulation of IL-10 production in peripheral blood mononuclear cells (PBMCs).
Brief Description, Utility and Acceptance Criteria for the Assay Methods:
1. The RXR-VDR heterodimerAssay:
This assay provides the VDR activity of a test compound. It is desirable to have low EC50 values for a compound in this assay. The lower the EC50 value, the more active the compound will be as a VDR agonist. Desired assay results are EC50 values less than or equal to 600 nM. Preferred assay results are less than 250 nM, and most preferably less than 150 nM.
2. The Caco-2 cell Co-transfection Assay:
The Caco-2 cell assay is an indicator for the undesirable condition of hypercalcemia. This co-transfection assay is a surrogate assay for in vivo calcemic activity of VDR ligands. It is desirable to have high EC50 values for a test compound in this assay. The higher the EC50 values for a compound the less calcemic it will be in vivo. Desired assay results are EC50 greater than or equal to 300 mM. Preferred assay results are greater than 1000 nM.
3. The OCN (osteocalcin) Promoter Assay
The OCN Promoter Assay is an indicator and marker for osteoporosis. Desired assay results are EC50 less than or equal to 325 nM. Preferred assay results are less than 50 nM.
4. The Mouse Hypercalcemia Assay
The Mouse Hypercalcemia Assay is a six day hypercalcemia test for toxicity and selectivity. Acceptable test results are levels greater than 300 μg/kg/day. Preferred assay results are levels greater than 1000 μg/kg/day.
5. The Keratinocyte Proliferation Assay
This Assay is indicative for the treatment of psoriasis. An acceptable test result is IC50 value of less than or equal to 300 nM. Preferred assay results are IC50 values of less than 100 nM.
6. The IL-10 Induction Assay
This is an in vitro efficacy assay for psoriasis, abscess and adhesion. Psoriasis involves both keratinocytes and immune cells. IL-10 is a unique cytokine because it is anti-inflammatory and immunosuppressive. This assay tells us whether a VDRM is able to function as an agonist in PBMCs (primary blood mononuclear cells) or not. A lower EC50 value is desirable in this assay since a compound with a lower EC50 value will be a better agonist in PBMCs. An acceptable test result is an EC50 value of less than 200 nM. Preferred assay results are EC50 values of less than 100 nM.
7. Other Compound Assay Standards
An alternative measure of the therapeutic index (bone efficacy vx. Hypervcalcemia) of compounds of the invention for treatment of osteoporosis is a numerical ratio calculated as follows:

Dose Threshold needed to induce hypercalcemia divided by Dose Threshold needed for bone efficacy

An alternative measure of the therapeutic index (in vivo keratinocyte proliferation vs. hypercalcemia) of compounds of the invention for treatment of psoriasis is a numerical ratio calculated as follows:

Dose Threshold needed to induce hypercalcemia divided by Dose Threshold needed to induce keratinocyte proliferation

For the above ratios, Dose Thresholds are determined from dose response curve data.

Details of the Assay Methods:

(1) Materials and Method for RXR-VDR Heterodimerization Assay:

Transfection Method:

    
    
        FuGENE 6 Transfection Reagent (Roche Cat # 1 814 443)
    
    
    Growth Media:
    
        D-MEM High Glucose (Gibco BRL Cat # 11054-020), 10% FBS, 1% antibiotic-antimycotic (Ab-Am)
    
    
    FBS heat inactivated (Gibco BRL Cat # 10092-147)
    Ab-Am (Gibco BRL Cat # 15240-062)

Cells:
    
        Grow SaOs-2 cells in T-152 cm2 culture flasks in growth media.
        Keep the density at 5-6×105 cells/ml
        Passage cells 1:3 twice a week
        Add Trypsin EDTA (Gibco BRL Cat # 25300-020) and incubate
        Resuspend cells in plating media and transfer into growth media.

Wash Media:

        HBSS Low Glucose Without Phenol Red (Gibco BRL Cat # 14175-095), 1% Ab-Am

Plating Media:

        D-MEM Low Glucose Without Phenol Red (Gibco BRL Cat # 11054-020), 1% Ab-Am
    
    
    D-MEM
    Stripped FBS (Hyclone Cat# SH30068.03 Lot # AHM9371)
    Ab-Am

Transfection/Treatment Media:
    
        D-MEM Low Glucose Without Phenol Red only
    
    
    T-152 cm2 culture flask:
    
        Use Corning Coastar T-152 cm2 culture flask (Cat # 430825) to grow the cells

Flat well Plates:

        Use well plate to plate cells
        Use Deep well plate sterile to make up treatment media.

Luciferase Assay Reagent:

        Use Steady-Glo Luciferase Reagent from Promega (Cat # E2550) Consists of:
    
    
    a. E2533 Assay Substrate, lypholized product and
    b. E2543 Assay Buffer.
    
        Thaw at room temperature
        Store

DAY 1: Cell Plating:

    
    
    Cell Harvesting
    Aspirate media from culture flask, rinse cells with HBSS and aspirate.
    Add trypsin and incubate.
    When cells appear detached, resuspend cells in growth media.
    Transfer into a new flask with fresh growth media for passaging the cells.
    Plate well plates and two extra plates

D. Cell Count

    Mix the cell suspension using pipette
    Use Hematocytometer to count the cells
    Load cell suspension onto the hemocytometer chamber
    Count cells.

Plate seeding:

    Use plating media 10% Stripped FBS in D-MEM Low Glucose, Without Phenol Red, 1% Ab-Am
    Plate 14 plates @ 165 μl/well.
    In sterile flask add cell suspension to plating media.
    Mix.
    Add cells/well.
    Place the cells in the incubator.
    Cells should be about 75% confluent prior to transfection.

Step 1: DNA and Media

    Add plain DMEM media to tubes for mixing the DNA
    Add the Reporter gene pFR-LUC
    Add the Gal4—RXR-DEF and VP16-VDR-LBD

Step 2: FuGENE and Media

    Prepare plain DMEM media in a ubes for mixing FuGENE
    Add FuGENE 6 Transfection Reagent
    Incubate

Step 3: FuGENE, DNA and Media Complex

    Add FuGENE Media complex from step 2 to DNA Media complex from step 1
    Incubate

Step 4: FuGENE, DNA and Media Complex to-well plate

    Add FuGENE-DNA-Media complex from step 3 to each plate
    Incubate.


Day 3: Dosing
Treatment Preparation


    Allow for transfection time
    Make a stock solution of the compounds in DMSO Vortex until all the compounds has been dissolved.
    Further dilute in D-MEM (Low Glucose—With out Phenol Red)
    Add compounds in quadruplicate to give final volume Incubate.


Day 4: Luciferase Assay


    Read the plates after drug treatment
    Remove part of media from all the wells and leave remainder
    Add Steady-Glo Luciferase Reagent mixture/wells
    Incubate
    Count each well using a Luminescence counter, Top Count NXT by Packard
    
        Set a delay between plates to reduce the background.

(2) Materials and Method for The Caco-2 Cell Assay:

    
    


Caco-2 cells, grown in phenol red free, DMEM (Invitrogen, Carlsbad, Calif.) containing 10% charcoal-stripped FCS (Hyclone, Logan, Utah), were transfected with Fugene 6 reagent (Roche Diagnostics, Indianapolis, Ind.). Cells (5000/well) were plated 18 h before transfection in a 96 well plate. The Cells were transfected with Gal4-responsive reporter pFRLuc (150 ng, Stratagene, La Jolla Calif.) and the receptor expression vector pGal4-VDR-LBD (10 ng), along with Fugene 6 reagent (0.2 μl/well). The DNA-Fugene complex was formed by incubating the mixture for 30 min at room temperature. The cells were transfected in triplicate for 5 h, and treated with various concentrations of VDR ligands (form 0.01 nM to 10,000 nM concentration range) 18 h post-transfection. The luciferase activity was quantified using Steady-Glo reagent kit (Promega, Madison, Wis.) as per manufacturer's specifications.
(3) Materials and Method for The OCN Promoter Assay:
The activation of osteocalcin by VDR ligands was evaluated in a rat osteoblast-like cell line RG-15 (ROS 17/2.8) stably expressing rat osteocalcin promoter fused with luciferase reporter gene. The stable cell lines were established as reported before (Activation of Osteocalcin Transcription involves interaction of protein kinase A- and Protein kinase C-dependent pathways. Boguslawski, G., Hale, L. V., Yu, X.-P., Miles, R. R., Onyia, J. E., Santerre R. F., Chandrasekhar, S. J. Biol. Chem. 275, 999-1006, 2000). Confluent RG-15 cells maintained in DMEM/F-12 medium (3:1) containing 5% FBS, 300 □g/ml G418 and at 37° C. under 5% CO2/95% air atmosphere were trypsinized (0.25% trypsin) and plated into white opaque 96-well cell culture plates (25000 cells/well). After 24 hr, cells (in DMEM/F-12 medium+2% FBS) were treated with various concentrations of compounds, dissolved in DMSO. The final DMSO concentration remained at 0.01% (v/v). After 48 hr treatment, the medium was removed, cells were lysed with 50 □l of lysis buffer (From Luciferase reporter assay system, Roche Diagnostics, Indianapolis, Ind.) and assayed for luciferase activity using the Luciferase Reporter Gene Assay kit from Boehringer Mannheim as per manufacturer's specifications.
(4) Materials and Method for the Mouse Hypercalcemia Assay:
Weanling, virus-antibody-free, five to six weeks old female DBF mice (Harlan, Indianapolis, Ind.) are used for all the studies. Animals are allowed to acclimate to local vivarium conditions for 2 days. Mice are maintained on a 12 hr light/dark cycle at 22° C. with ad lib access to food (TD 5001 with 1.2% Ca and 0.9% P, Teklad, Madison, Wis.) and water. The animals then are divided into groups with 4-5 mice per group. Different doses of test compounds prepared in 10% Ethanol and 90% sesame oil are administered to mice orally via gavage for 6 days. 1α-25(OH)2D3 0.5 μg/kg/d was also given to one group of mice as the positive control. Serum ionized calcium is evaluated at 6 hours after the last dosing under isoflurane anesthesia by Ciba-Corning Ca++/PH Analyzer, (Model 634, Chiron Diagnostics Corp., East Walpole, Mass.). Raw data of group differences is assessed by analysis of variance (ANOVA) using Fisher's protected least significant difference (PLSD) where the significance level was P<0.05.
(5) The Keratinocyte Proliferation Assay:
KERtr cells (Human skin keratinocyte transformed with a retrovirus vector, obtained from ATCC) were plated in 96-well flat-bottomed plates (3000 cells/well) in 100 □l keratinocyte serum free medium supplemented with bovine pituitary extract in the absence of EGF (Life Technologies, Rockville, Md.) and incubated at 37° C. for two days. The cells were treated with various concentrations of VDR ligands (ten-fold serial dilution from 10,000 nM to 0.1 nM in triplicate), dissolved in 100 □l keratinocyte serum free medium supplemented with bovine pituitary extract in the absence of EGF and incubated at 37° C. for 72 hr. BrdU (5-bromo-2′-deoxyuridine) incorporation was analyzed as a measure of DNA replication (Cell proliferation ELISA kit, Roche Diagnostics, Indianapolis, Ind.) and absorbance was measured at 405 nm. Potency values (IC50) values were determined as the concentration (nM) of compound that elicited a half-maximal response.
(6) Materials and Method for human IL-10 Induction Assay:


    Isolation of peripheral blood mononuclear cells (PBMCs):
    
        A. Collect 50 ml of human blood and dilute with media, RPMI-1640.
        B. Prepare sterile tubes with ficol.
        C. Add diluted blood to tubes.
        D. Centrifuge.
        E. Discard the top layer and collect the cells from middle layer.
        F. Divide all cells into four tubes and add media.
        G. Centrifuge.
        H. Aspirate off media and resuspend.
        I. Collect all cells
        J. Centrifuge. at 1200 rpm for 10 minutes.
        K. Resuspend in RPMI-1640 with 2% FBS and count cells Stimulation of PBMC:
        L. Prepare TPA in DMSO.
        M. Dissolve PHA in water.
        N. Plate TPA/PHA treated PBMCs in well plates.
        O. Incubate.
        Treatment:
        P. Prepare all compound dilutions in plain RPMI-1640 media.
        Q. Add diluted compound.
        R. Incubate.
        Sample Collection and assay:
        S. Remove all the cells by centrifugation and assay the supernatant for IL-10 by immunoassay.
    
    
    1) T. Perform IL-10 assay using anti-human IL-10 antibody coated beads, as described by the manufacturer (Linco Research Inc., St. Charles, Mo.).

## Claims

1. A compound or a pharmaceutically acceptable salt represented by the formula:




or a mixture thereof.

2. The salt derivative of a compound of claim 1 wherein the salt is sodium or potassium.

3. A pharmaceutical formulation comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.

4. A formulation according to claim 3 for treating osteoporosis comprising:
Ingredient (A1): a vitamin D receptor modulator of claim 1, or a pharmaceutically acceptable salt thereof;
Ingredient (B1):
one or more co-agents selected from the group consisting of:
a. estrogens,
b. androgens,
c. calcium supplements,
d. vitamin D metabolites,
e. thiazide diuretics,
f. calcitonin,
g. bisphosphonates,
h. SERMS, and
i. fluorides.

5. The formulation of claim 3 wherein the weight ratio of (A1) to (B1) is from 10:1 to 1:1000.

6. A formulation according to claim 3 for treating psoriasis comprising:
Ingredient (A2): a vitamin D receptor modulator of claim 1;
Ingredient (B2):
one or more co-agents that are conventional for treatment psoriasis selected from the group consisting of:
a. topical glucocorticoids,
b. salicylic acid,
c. crude coal tar.

7. The formulation of claim 6 wherein the weight ratio of (A2) to (B2) is from 1:10 to 1:100000.

8. A compound according to claim 1 represented by the formula:




or a pharmaceutically acceptable salt thereof.

9. A compound represented by the formula:




or a pharmaceutically acceptable salt thereof.

10. A compound represented by the formula:




or a mixture thereof,
wherein R is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N, diethylglycolamide.

11. A pharmaceutical formulation according to claim 3 provided for oral administration.

12. A method of treating osteoporosis by administration to a mammal a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. A method according to claim 12 comprising administrating a dose between 0.0001 mg/kg/day to 5 mg/kg/day of body weight.

14. A method of treating a mammal to alleviate the pathological effects of at least one of: osteoporosis, leukemia, and psoriasis.