MXPA00011094A - 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia - Google Patents

2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia

Info

Publication number
MXPA00011094A
MXPA00011094A MXPA/A/2000/011094A MXPA00011094A MXPA00011094A MX PA00011094 A MXPA00011094 A MX PA00011094A MX PA00011094 A MXPA00011094 A MX PA00011094A MX PA00011094 A MXPA00011094 A MX PA00011094A
Authority
MX
Mexico
Prior art keywords
pharmaceutically acceptable
acid
yloxy
terphenyl
acceptable salt
Prior art date
Application number
MXPA/A/2000/011094A
Other languages
Spanish (es)
Inventor
Joseph Richard Lennox
John Anthony Butera
Robert Emmett Mcdevitt
Craig Eugene Caufield
Russell Francis Graceffa
Alexander Greenfield
Eric Gould Gundersen
Lisa Marie Havran
Alan Howard Katz
Scott Christian Mayer
Original Assignee
American Home Products Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Publication of MXPA00011094A publication Critical patent/MXPA00011094A/en

Links

Abstract

This invention provides compounds of Formula (I) having structure (I) wherein:B and D are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-12 carbon atoms, or heteroaralkyl of 6-12 carbon atoms except where B and D both are hydrogen;R1 is hydrogen, alkyl of 1-6 carbon atoms, -SO2Ph(OH)(CO2H), -CH(R2)W, -CH2CH2Y, or -CH2CH2CH2Y;R2 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, -CH2(1H-imidazol-4-yl), -CH2(3-1H-indolyl), -CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), or -CH2(3-pyridyl);W is -CO2R3, -CONHOH, -CN, -CONHR3, aryl, heteroaryl, -CHO, -CH=NOR3, or -CH=NHNHR3;Y is -W, -OCH2CO2R3, aryl, heteroaryl, -C(=NOH)NH2, -OR3, -O(C=O)NR4R5, -NR3(C=O)OR3, -NR3(C=O)NR4R5, or -NR4R5;R3 is hydrogen or alkyl of 1-6 carbon atoms;R4 and R5 are each, independently, hydrogen, or alkyl of 1-6 carbon atoms or R4 and R5 are, together, -(CH2)n-, or -CH2CH2XCH2CH2-;X is O, S, SO, SO2, NR3, or CH2;n is 2 to 5;C is alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, -CONR6R7, -NR3CONR6R7, -NR3COR6, -OR6, -O2CNR6R7, -NR3CO2R6, -O2CR6, -CH2OR6, -NR6R7, -CR3=CR3R8, -CPh3, -CH2NR6R7, or Formula (1);R6 and R7 are each, independently, hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, cycloalkyl of 3-10 carbon atoms, -(CH2CH2O)nCH3, -(CH2)mA or R6 and R7 are, together, -(CH2)p-, -(CH2)2N(CH3)(CH2)4-, -(CH2)2N(R8)(CH2)2-, or -(CH2)2CH(R8)-(CH2)2-;R8 is hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, cycloakyl or 3-10 carbon atoms, -(CH2CH2O)nCH3, -(CH2CH2CH2O)nCH3, or -(CH2)mA;A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, -CHF2, -CH2F, -CF3, -(CH2CH2O)nCH3, -(CH2CH2CH2O)nCH3, -CO2R3, -O(C=O)NR6R7, aralkyloxy, or heteroaralkyloxy;m is 2 to 16;p is 2 to 12;or apharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

Description

BIPHENYL 2, 3, 5-S0BSTITOSIDES USEFUL IN THE TREATMENT OF INSULIN AND HYPERGLYCEMIA RESISTANCE BACKGROUND OF THE INVENTION The prevalence of insulin resistance in glucose-intolerant subjects has been recognized for a long time. Reaven et al (American Journal oí Medicine 1976, 60, 80), used a continuous infusion of glucose and insulin (insulin / glucose fixation technique) and oral glucose tolerance tests to demonstrate that there is insulin resistance in a diverse group of non-obese non-ketone subjects. These subjects range from the limit of tolerant to glucose to those with hyperglycemia in evident fasting. The diabetic groups in these studies included subjects both insulin dependent (IDDM) and non-insulin dependent (NIDDM). Coincident with sustained insulin resistance is the more easily determined hyperinelinemia, which can be measured by accurate determination of circulating plasma insulin concentration in the plasma of subjects. Hyperinsulinemia may be present as a result of insuf fi cient resistance, such as in obese and / or diabetic subjects (NIDDM) and / or glucose intolerant subjects, or in IDDM subjects, as a consequence of an excessive injection of REF: 1. 380 insulin compared to the normal physiological release of the hormone by the endocrine pancreas. The association of hyperinsulinemia with obesity and ischemic diseases of large blood vessels (for example atherosclerosis) has been well established by numerous experimental, clinical and epidemiological studies (summarized by Stout, MetaJbolism 1985, 34, 7, and in more detail by Pyorala et al. al, Diabetes / Metabolism Reviews 1987, 3, 463). Statistically significant plasma insulin elevations at 1 and 2 hours after oral glucose loading correlate with an increased risk of coronary heart disease. Since most of these studies actually exclude diabetic subjects, there are not many data in relation to the risk of atherosclerotic diseases for the diabetic condition, but they point in the same direction as in non-diabetic subjects (Pyorala et al. ). However, the incidence of atherosclerotic diseases in the morbidity and mortality statistics in the diabetic population exceeds that of the non-diabetic population (Pyorala et al., Jarrett Diabetes / Metabolism Reviews 1989, 5, 547; Harris et al, Mortality from diabetes , in Diabetes in America 1985). The risk factors independent of obesity and hypertension for atherosclerotic diseases are also Associated with insulin resistance. Using a combination of insulin / glucose fixation techniques, tracer glucose infusion and indirect calorimetry, it has been shown that insulin resistance of essential hypertension is localized in peripheral tissues (mainly muscles) and correlates directly with the severity of hypertension ( DePronzo and Ferrannini, Diabetes Care 1991, 14, 173). In the hypertension of the obese, insulin resistance generates hyperinsulinemia, which is recruited as a mechanism to limit the additional weight gain via thermogenesis, but insulin also increases the renal reabsorption of sodium and stimulates the sympathetic nervous system in the kidneys , heart and vasculature, which generates hypertension. It has now been appreciated that insulin resistance is usually the result of a defect in the insulin receptor signaling system, at the site subsequent to the binding of insulin to the recipient. Accumulated scientific evidence demonstrates insulin resistance in the major tissues which respond to insulin (muscle, liver, adipose tissue), strongly suggesting that the defect in insulin signal transduction is at an early stage in this cascade , specifically in the activity of the insulin receptor kinase, which appears to be diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).
Proteins-tyrosine phosphatases (PTPases play a very important role in the regulation of protein phosphorylation.) The interaction of insulin with its receptor leads to the phosphorylation of certain tyrosine molecules within the receptor protein, so the receptor is activated of kinase PTPases dephosphorylate the activated insulin receptor, attenuating tyrosine kinase activity PTPases can also modulate post-receptor signaling by catalyzing the dephosphorylation of cellular substrates of insulin receptor kinase The enzymes that appear most likely to be closely associated with the insulin receptor, and therefore, are more likely to regulate the insulin receptor cmase activity include PTP1B, LAR, PTPalpha and SH-PTP2 (BJ Goldstein, J. Cellular Biochemistry 1992, 48, 33; BJ Goldstein, Receptor 1993, 3, 1-15., - F. Ahmad and BJ Goldstein Biochim, Biophys Acta 1995, 1248, 57-69) McGuire et al. (Diabetes 19 91, 40, 939), demonstrated that non-diabetic glucose intolerant subjects possess significantly higher levels of PTPase activity in muscle tissue versus normal subjects, and that insulin infusion did not suppress PTPase activity as it does in insulin sensitive subjects. . Meyerovitch et al., (J. Clinical Invest., 1989, 84, 976) observed significantly increased PTPase activity in the livers of two IDDM rodent models, the genetically diabetic BB rat and the diabetic rat induced by STZ. Sredy et al (Metabolism, 44, 1074, 1995) observed similar increased PTPase activity in the livers of obese, diabetic, ob / ob mice, the genetic rodent model of NIDDM. The compounds of this invention have been shown to inhibit PTPases derived from rat hepatic microsomes and recombinant human-derived PTPase-lB (hPTP-lB) in vitro. They are useful in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of large and small blood vessels. PN Devine et al (WO 97/21693, June 19, 1997) describes examples D under a preparation method (B, D (independently = halogen, phenyl, alkyl, -X = alkyl, aryl, - Y = (CH2) 0.3CH3, Ph, NH (CH2) 0_3CH3, N ((CH2) 0.3CH3) 2, NH2, N02, NHCO (CHJ, .3CH3, NHC02 (CH2) 0.3CH3, CH20 (CH2) 0_3 CH3, OPh; 0 ( CH2) 1.40 (CH2) 0.5CH3, 0 (CH2) 1.4OPh, 0C02 (CH2) 0.5CH3, CON ((CH2) 0.5CH3) 2, 0 (CHj) 1.40 (CH2) j.jPh) The synthesis process to prepare the compounds represented by the compounds D is different from the process used to prepare the 2, 3, 5-substituted biphenyls of this invention. ; 2¡ ^^^^ g ^ a G. Cain and C. J. Eyermann (U.S. Pat. ,523,302; June 4, 1996) describes examples A (B, D (independently = cycloalkyl, alkyl, aralkyl) as agents which inhibit platelet aggregation, such as t-rombolics and / or for the treatment of thrombolytic disorders. The synthesis for preparing the compounds represented by the compounds A is different from the processes used to prepare the 2,3,5-substituted biphenyls of this invention.
M. Wayne et al (WO 94/22835, WO 94/22834, October 13, 1994) describes examples B (B, D (independently = alkyl, halogen) as agents which inhibit platelet aggregation, such as thrombolytics and / or for the treatment of thromboembolic disorders The synthesis process for preparing the compounds represented by the compounds is different from the process used to prepare the 2, 3, 5-substituted biphenjlcj of this invention.
SW Bagley et al (U.S. Patent 5,334,598; Aug. 2, 1994) discloses examples C (B, D (independently = phenyl, naphthyl, alkyl, halogen) as agents which have endothelin antagonist activity and therefore with useful to treat cardiovascular disorders Our present invention does not claim a composed of this genus, specifically 2-phenyl-2-phenoxyacetic acids. The synthesis process for preparing the compounds represented by the compounds C is different from the processes used to prepare the 3,5-substituted biphenyls of this invention. A similar set of compounds is described in C.M. Harvey et al (WO 96/09818; April 4, 1996), W.J. Greenlee et al (WO 91/11909; August 22, 1991), and. J. Greenlee et al (WO 91/12002, August 22, 1991). A set of similar arguments applies.
DESCRIPTION OF THE INVENTION This invention provides a compound of formula I having the structure * »* - > - --- » (I) wherein: B and D are each independently hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-l2 carbon atoms or heteroaralkyl of 6-12 carbon atoms, except when B and D are both hydrogen; R1 is hydrogen, alkyl of 1-6 carbon atoms, -S02Ph (0H) (C02H), -CH (R) W, -CH2CH2Y, or -CH2CH2CH2Y; R2 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, -CH2 (lH-imidazol-4-yl), -CH2 (3-lh-indolyl), -CH2CH2 (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl), -CH2CH2 (l-oxo-l, 3-dihydro-isoindol-2-) ilo), or -CH2 (3-pyridyl), -W is -C02R3, -CONHOH, -CN, -CONHR3, aryl, heteroaryl, -CHO, -CH = N0R3 or -CH = NHNHR-Y is -W, - OCH2C02R aryl, heteroaryl, -C (= NOH) NH2, 25 -OR -0 (C = 0) NR4R -NR3 (C = 0) ORj -NR3 (C = 0) NR4Rj or -NR4Rj- R3 is hydrogen or alkyl of 1-6 carbon atoms; R4 and R5 are each, independently, hydrogen or alkyl of 1-6 carbon atoms or R4 and R5 are, together, - (CH2) "-, O -CH2CH2XCH2CH2-; X is O, S, SO, S02, NR3 or CH2; n is 2 to 5, - C is alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, -CONR6R -NR3CONRsR -NR3COR -OR -02CNR6R -NR3C02R -02CRJ -CH2ORj -NR5R7, -CR3 = CR3Rβ -CPh3, -CH2NR6R or R6 and R7 are each, independently, hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms carbon, cycloalkyl of 3-10 carbon atoms, - (CH2CH20) "CH3, - (CH2) mA or R6 and R7 are together, - (CH2) _-, - (CH2) 2N (CH3) (CH2) 4- , - (CH2) 2N (Rβ) (CH2) 2-, or - (CH2) 2CH (RB) - (CH2) 2-; Rβ is hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, cycloalkyl of 3-10 carbon atoms, - (CH2CH20) nCH3, - (CH2CH2CH20) nCH3, or - (CH2) "A; A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, aryisulphonyl, heteroarylsulfonyl, -CHF2, -CH2F, -CF3, - (CH2CH20) "CH3, - (CH2CH2CH20) nCH3, -C02R3, -0 (C = 0) NR6R7, aralkyloxy, or heteroaralkyloxy; m is 2 to 16 p is 2 to 12 or a pharmaceutically acceptable salt thereof, which is useful for treating metabolic disorders related to insulin resistance or hyperglycemia. The pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric. , mephulsiform, benzenesulphonic, toluenesulphonic, camphorsulfonic, and acceptable acids, similarly known when a compound of this invention contains a basic portion. The salts can also be formed from organic and inorganic bases, preferably alkali metal salts, for example sodium, lithium or potassium, when a compound of this invention contains a carboxylate or phenolic portion, or a similar portion capable of forming salts of base addition. ü- ^ l «« ^ iÉa - ^ Alkyl includes portions of both straight and branched chain. Halogen means bromine, chlorine, fluorine and iodine. It is preferred that the aryl portion of the aryl aralkyl, aryloxy or aralkyloxy substituent be a phenyl or naphthyl; the phenyl being further preferred. The aryl moiety may optionally be mono-, di- or tri-substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl 2-7 carbon atoms, alkylamino of 1-6 carbon atoms and dialkylamino, in which each of the alkyl groups is 1-6 carbon atoms, nitro, cyano, -C02H, alkylcarbonyloxy of 2-7 carbon atoms carbon and alkylcarbonyl of 2-7 carbon atoms. The heteroaryl portion of the heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkyloxy substituent may be pyridyl, furyl, thienyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, thiazolyl, oxazolyl, imidazolyl, oxadiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, and benzothiazolyl. The heteroaryl portion may be optionally mono-, di- or tri-substituted in the case of pyridyl, furyl, thienyl, quinolinyl, isoquinylinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, optionally it may be mono- or di-substituted on the thiazolyl, oxazolyl or imidazolyl, and optionally it may be monosubstituted in the case of oxadiazolyl, tetrazolyl or triazolyl, the substituent is selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, alkoxy carbonyl of 2-7 carbon atoms, alkylamino of 1 -6 carbon atoms and dialkylamino in which each of the alkyl groups is 1-6 carbon atoms, nitro, cyano, -C02H, alkylcarbonyloxy of 2-7 carbon atoms and alkylcarbonyl of 1-l carbon atoms. The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and thus give rise to optical isomers and diastereomers. Although shown to be without respect to the stereochemistry in formula I, the present invention includes such optical isomers and diastereomers, as well as the enantiomerically pure, racemic, R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts of rn irnos. Preferred compounds are those in which B is aryl and D is aryl or halogen. The most preferred compounds of this invention are: (3,3"-dichloro-5'-dodecylcarbamoyl- [1, 1 ', -3 J 1"] terferl-2'-yloxy) acetic, - acid ( 3-bromo-3'-chloro-5-dodecylcarbamoyl-biphenyl-2-yloxy) acetic acid, - [3, 3"-di-chloro-5 '- (8-f-octylcarbamoyl) - [1,1', -3 ', 1"] terf eni] -2'-yloxylacetic acid; (5 '-octadecyloxy- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid, - (5' -dodecylcarbamoyl-3,3" -bis-trifluoromethy- [1 ', - 3 ', 1"] terfen? L-2'-yloxy) acetic acid (3-bromo-5-dodecylcarbamoyl-3' -trif luoromethyl-biphenyl-2-yloxy) acetic acid (5'- (8-phenyloctylcarbamoyl) -3,3"-bis-trifluoromethyl- {1,1,1 '; 3', 1"] terphenyl-2'-yloxy) -acetic acid (5 '-dodecylcarbamoyl- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) -acetic acid (5'-dodecylcarbamoyl-4,4" -dimethoxy- [1,1 ', -3', 1"] terphenyl-2'-yloxy) -acetic acid, - (3-chloro-5'-dodecylcarbamoyl-4"-methoxy - [1,1 ', -3'] terf-enyl-2'-yloxy) -acetic acid (5'-dodecylcarbamoyl-3,3" - dimethoxy- [1,1 '; 3' 1"] tert-butyl-2'-yloxy) -acetic acid [2 - (3, 3" -dichloro-5'-dodecylcarbamoyl [1,1 ', - 3'] , 1"] -trinyl-2'-yloxy-ethoxy] -acetic acid; {5 '- [6- (4-tert-butyl-benzyloxy) -hexylcarbamoyl] -3,3" -bis-triifluoromethyl [ 1,1 ', - 3', 1"] terphenyl - 2'-yloxy] -acetic, - acid. { 51 - [6- (-benzyloxy-benzyloxy) -hexylcarbamoyl] -3,3-bis-trifluoromethyl [1,1 ', -3' 1"] terphenyl-2'-allyloxy} -acetic; [3"-chloro-4-methoxy-5 '- (8-phenyl-octylcarbamoyl) - [1,1'; 3 ', 1"] terphenyl-2'-yloxy] acetic acid, - acid. { 3"-chloro-4-methoxy-5 '- [methyl- (8-f-enyl-octyl) -carbamoyl] [1,1', -3 ', 1"] terphenyl-2'-allyloxy} -acetic, - [3, 3"-dimethoxy-5 '- (8-phenyl-octylcarbamoyl) - [1,1', -3 ', 1"] terphenyl-2-yloxy] -acetic acid; acid { 2- [5 '- (6-phenyl-hexylcarbamoyl) -3,3-bis-trifluoromethyl- [1, 1', - 3 ', 1"] terphenyl-2'-yloxy] -ethoxy) acetic acid; acid { 5 '- [6- (2, 4-difluoro-benzyloxy) -hexylcarbamoyl] -3,3 -bis -trif luoromethyl [1,1'; 3 '1"] terphenyl-2'-yloxy} -acetic; acid { 5 '- [6- (biphenyl-4-ylmethoxy) -hexylcarbamoyl] -3,3 -bistrif luoromethyl [1,1'; 3 ', 1"] terphenyl-2'-yloxy) -acetic; acid { 3, 3"-dimethoxy-5" - [methyl- (8-f-enyl-octyl) -carbamoyl] - [1,1 '; 3', 1"] terphenyl-21-yloxy} -acetic acid; {.2- [3,5,3", 5" -tetrachloro-5 '- [(6-phenyl-hexyl carbamoyl) - [1, 1', - 3 ', 1"] terf-enyl-2'-ethoxy} -acetic, - [4, 4"-dimethoxy-5 '- (8-phenyl-octyl carbamoyl) - [1,1 J- 3'. 1"] terphenyl-2'-yloxy] acetic acid; sodium salt of the acid (3,3"-dichloro-5 '-dodecylcarbamoyl-4, 4" -dif luoro [1,1'; 3 ', 1"] terphenyl (-2'-yloxy) -acetic acid; 3,3"-dichloro-4-4" difluoro-5 '- (8-phenyl-octylcarbamoyl) [- 1, 1', - 3 ', 1"] terf-enyl-2'-yloxy] -acetic; acid { 3,3"-di-chloro-5 '- (6- (2,5-dimethyl-furan-3-ylmethoxy) -hexylcarbamoyl] -4-4" -dif luoro- [1,1']; 3 ', 1"] terphenyl-2'-yloxy) -acetic acid [3,5-dichloro-5' - (8-f-enyl-octyl carbamoyl) - [1, 1 ', -3', 1"] terphenyl-2'-yloxy] -acetic; [5 '- (8-phenyl-octylcarbamoyl) -3-trifluoromethyl- [ll ", - 3', 1"] terphenyl-2'-yloxy] acetic acid, - acid 4.4"-dif luoro- 5 '- (8 -f -enyl-octylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1 ', - 3', 1"] terphenyl-2'-yloxy] -acetic, - acid. {5 '- [6 - (2,5-dimethyl-ura-3-ylmethoxy) -hexylcarbamoyl] -3,3"-bis-tripif luoromethyl [1,1 '; 3', 1"] terf-enyl-2'-yloxy) - acetic acid (3-bromo-5-dodecylcarbamoyl-4 '-methoxy-biphenyl-2-yloxy) -acetic acid (5' - (2-hexadecylamino-3,4-dioxo-cyclobut-l-enylamino) - [ 1, 1 ', - 3', 1"] terphenyl-2'-yloxy] -acetic acid (3,3" -dichloro-5 '-dodecylcarbamoyl- [1, 1', -3 ', 1"] terfyl -2'-yloxy) -acetic acid - (3-bromo-3'-chloro-5-dodecylcarbamoyl-biphenyl-2-yloxy) -acetic acid [3, 3"-dichloro-5 '- (8-f enyl -oct ilcarbamoyl) - [1,1 ', -3', 1"] terphenyl-2'-yloxy] -acetic acid (5 '-octadecyloxy- [l, l', - 3 ', l"] terphenyl) -2'-iloxy) -acetic, - (5'-benzo [b] naphtho [2,3-d] thiophen-1-yl- [1, 1 ', -3', 1"] terf-enyl-2'-yloxy) -acetic acid; '-Nitro- [1, 1'; 3 ', 1"] terphenyl-2'-yloxy) -acetic; (5 '-methoxy- [1,1'; 3 ', 1"] terf-enyl-2'-yloxy) acetic acid - (5'-bromo- [1,1'; 3 ', 1"] terphenyl) -2'-yloxy) -acetic; [(5'-phenyl [l, l ': 3', 1"-terphenyl] -2'-yl) oxy] acetic acid: (1,3-diphenyl-dibenzofuran-2-yloxy) -acetic acid; (2-benzoyl-4,6-dibromo-benz or furan-5-yloxy) acetic acid, - (5'-butoxy- [1, 1 ', 3', l "] terphenyl-2'-yloxy) acetic acid, - (5 '-octyloxy- [1,1', 3 ', 1"] terf enyl-2'-yloxy) acetic acid (3, 3" -dichloro-5' -octyloxy- [1.1 J-3 J] 1"] terphenyl-2'-yloxy) acetic acid (3, 3" -bi s-acetyl 1-amino-5'-oc t-yloxy - [1,1 ', -3', 1"] terphenyl -2 '-iloxy) acetic, - (5'-octyloxy-3,3"-bis-trifluoromethyl- [1,1', -3 ', 1"] terphenyl-2'-yloxy) -acetic acid, - (3, 3"-dinitro-5'-octyloxy- [1,1 ', -3', 1"] terf-enyl-2'-yloxy) acetic; (3, 3"-dimethoxy-5 '-octyloxy- [1,1', -3 ', 1"] terphenyl-2'-yloxy) acetic acid; [3, 3"-dichloro-5 '- (3-phenyl-propylcarbamoyl) - [1,1'; 3 '1"] terphenyl-2'-yloxy] acetic acid; ['3,3"-dichloro-5' - (2-pyridin-2-yl-ylcarbamoyl) - [1, 1 ', -3' 1"] tert-butyl-2'-yloxy] acetic acid; [5 '- (benzyl-phenethyl-carbamoyl) -3,3-dichloro- [1,1'; 3 '1"] terphenyl-2'-yloxy] acetic acid, - [3, 3" -dichloro-5-acid] '- (4-f-enyl-butyl carbamoyl) - [1, 1'; 3 '1"] terphenyl-21-yloxy] acetic acid; [5- (benzyl-phenethyl-carbamoyl) -3-bromo-3'-chloro-b-phenyl-2-yloxy] -acetic acid, [3-bromo-3'-chloro-5- (2-pyridin- 2-yl-ethylcarbamoyl) -bifinyl-2-yloxy] acetic acid, - [5 '- (benzyl-f-enethyl-carbamoyl) -3"-chloro-3-tr-f-loromethyl- [1,1', -3] '1"] -methyl-2'-yloxy] acetic acid, - [3" -chloro-5' - (2-pyridin-2-yl-ethyl carbamoyl) -3-trifluoromethyl- [1,1 '; 3 '1"] terphenyl-2'-yloxy] acetic acid - [3" -chloro-5' - (3-phenyl-pro and Icarbamoyl) -3-trifluoromethyl- [1,1 ', 3' 1"] erphenyl- 2-yloxy] acetic; [3"-chloro-5 '- (4-phenyl-buyl-Icarbamoyl) -3-trifluoromethyl- [1,1', -3 '1"] terphenyl-2'-yloxy] acetic acid, - [3"- chloro- 5 '- (3-cyclopentyl-propylcarbamo I) -3-trif luoromethyl- [1,1'; 3 '1] -methyl-2'-yloxy] acetic acid; [3-bromo-3'-chloro-5- (3-cyclopentyl-propylcarbamoyl) -bifinyl-2-yloxy] -acetic acid; acid { 5 '- [2- (4-bromo-phenyl) -ethylcarbamoyl] -3"-chloro-3-trifluoromethyl- [1,1'; 3 '1"] terf-enyl-2'-yloxy} acetic; [3, 3"-Dichloro-5 '- (3-cyclopentyl-propylcarbamoyl) - [1,1', - 3 '1"] terphenyl-2'-yloxy] acetic acid; [4"-methoxy-5 '- (2-pyridin-2-yl-ethylcarbamoyl) -3-trif-loromethyl- [1,1', 3 '1"] terphenyl-2'-yloxy] acetic acid; [5 '- (3-cyclopentyl-propylcarbamoyl) -4"-methoxy-3-trif luoromethyl- [1,1'; 3 '1"] terphenyl-2'-yloxy] acetic acid; [5 '- (benzyl-phenethyl-carbamoyl) -4"-met-oxy-3-trifluoromethyl- [1,1', -3 '1"] terphenyl-2'-yloxy] acetic acid, - [5' -] acid (benzyl-phenethyl-carbamoyl) -2-f luoro-4"-methoxy- [1,1 ', - 3' 1"] -terf-enyl-2'-yloxy] -acetic acid - [5- (benzyl-phenethyl-carbamoyl)] ) -3-bromo-2 '-fluoro-b-phenyl-2-yloxy] -acetic acid, [2-fluoro-4"-methoxy-5' - (2-pyridin-2-yl-ylcarbamoyl) - [1] , 1 '; 3' 1"] -terphenyl-2'-yloxy] acetic acid, [2-fluoro-4" -methoxy-5 '- (3-phenyl-propylcarbamoyl) - [1, 1', 3 '] 1"] -terphenyl-2'-yloxy] acetic acid - [3-bromo-2'-fluoro-5- (2-pyridin-2-yl-ethyl-carbamoyl) -bif in? -1-2-yloxy] acetic, - [3-bromo-2'-fluoro-5- (3-phenyl-propylcarbamoyl) -biphenyl-2-yloxy] -acetic acid; [5 '- (3-cyclopentyl-propylcarbamoyl) -2-f-luoro-4"-methoxy- [1,1'; 3 '1"] -terphenyl-2'-yloxy] acetic acid; [3-bromo-5- (3-cyclopentyl-propylcarbamoyl) -2'-fluoro-biphenyl-2-yloxy] -acetic acid, [2-fluoro-4"-methoxy-5 '- (8-phenyl-octylcarbamoyl) acid] ) - [1,1 '; 3' 1"] -terphenyl-2'-yloxy] acetic acid; [3-bromo-2'-fluoro-5- (8-phenyl-octylcarbamoyl) -biphenyl-2-yloxy] -acetic acid, [2-f-luoro-4"-methoxy-5 '- (6-phenyl-) acid hexylcarbamoyl) - [1, 1 ', -3' 1"] -terphenyl-2'-yloxy] acetic acid, [3-bromo-2'-fluoro-5- (6-phenyl-hexylcarbamoyl) -bifenyl- 2-yloxy] -acetic acid - [3, 3"-dichloro-5 '- (6-f-enylhexyl carbamoyl) - [1,1', -3 'l"] terphenyl-2'-yloxy] acetic acid; acid { 4"-methoxy-5 '- [methyl- (8-phenyl-octyl) -carbamoyl] -3-trifluoromethyl- [1, 1', -3 '1") terf enyl-2'-β-loxi} acetic, - acid. { 3, 3"-dichloro -5 '- [methyl- (8-phenyl-octyl) -carbamoyl] - [1,1', -3 '1"] terphenyl-2'-yloxy} acetic, - [3, 3"-dif luoro-5 '- (8-f-enyl-octylcarbamoyl) - [1,1'; 3 '1"] terphenyl-2'-yloxy] acetic acid; acid { 3,3"-difluoro-5 '- [methyl- (8-f-enyl-octyl) -carbamoyl] - [1,1 J-3' 1"] terphenyl-2'-allyloxy} acetic, - [3, 3"-dichloro-5 '- (8-morpholin-4-yl-octylcarbamoyl) - [1,1'; 3 '1"] terfenyl-2'-yloxy] acetic acid; ^^^ ¿^^^ acid { 3,3"-dichloro-5 '- [8- (2,6-dimethoxy-phenoxy) octylcarbamoyl] - [1,1', -3 '1-tert-butyl-2'-yloxy] -acetic acid. {5 '- [8- (benzoxazol-2-ylsulfanyl) • octylcarbamoyl] -3,3-dichloro- [1,1'; 3'1"] -terphenyl-2'-yloxy) acetic acid [3] , 3"-dichloro-5 '- (8-indol-l-yl-octylcarbamoyl) • [1,1'; 3 '1"] terphenyl-21-yloxy] acetic acid; {.3.3"-dichloro} -5 '- [8- (3-cyano-phenoxy) -octylcarbamoyl] - [1,1'; 3 '1"] terphenyl-2'-yloxy} acetic acid - {.3.3" - dichloro-5 '- [8- (4-chloro-benzyloxy) • octylcarbamoyl] - [1,1', -3 '1"] terphenyl-2'-yl-oxyacetic acid - .3,3-dichloro- 5 '- [8- (4-Fluoro-3-methyl-phenoxy) -octylcarbamoyl] - [1,1', 3'1"] terphenyl-2'-yloxy) acetic acid - [3,3" -dichloro] -5 '- (8-imidazol-1-yl-octylcarbamoyl) - [1,1', -3 '1"] terphenyl-2'-yloxy] acetic acid: .3.3" -d? Chloro- 5 '- [6- (naphthalen-1-yl carbamoi loxi) -hexylcarbamoyl] - [1,1', -3'l "] terphenyl-2'-yloxy) acetic acid {3,3"-d? Chloro-5 '- [6- (2,4-difluoro-phenecarbamoyl-oxy) -hexylcarbamoyl [1,1', -3'l"] terphenyl-2'-yloxy) acetic; acid { 3, 3"-dichloro-5 '- [6- (4-phenoxy-f eni Icarbamoyl oxy) -hexylcarbamoyl] - [l, l', - 3'l"] terphenyl-2'-yl oxy} acetic,- acid { 3, 3"-dichloro-5 '- [8- (5-f luoro-indol-1-yl) -octylcarbamoyl] - [1,1', -3 '1"] terphenyl-2'-yloxy} acetic acid - (3, 3"-dichloro-5 '- [8- (5-methoxy-indol-1-yl) -octylcarbamoyl] - [1,1'; 3 '1"] terphenyl-2'-yloxy Acetic acid: {3/3"-dichloro-5 '- [8- (2,5-dimethyl-indol-l-yl) -octylcarbamoyl] - [1,1'; 3'1"] -terphenyl-2'-yloxy) acetic acid. { 3, 3"-dichloro-5 '- [8- (5-methoxy-2-methyl-indol-1-yl) -octylcarbamoyl] - [1,1', -3'l"] terphenyl-2'-yloxy } acetic acid (3,3"-di-chloro-5 '- { [1- (4-f-enyl-but-oxime-tyl) -cyclopropylmethyl] -carbamoyl) [1, 1', -3 '1"] terphenyl-2 '-iloxy) acetic, - [5' - (benzofuran-2-carbonyl) - [1,1 ', -3' 1"] terphenyl-2'-yloxy] acetic acid; 3- [3" - (2 -carboxy vinyl) -2 '-methoxy-5' - (8-phenyl-octylcarbamoyl) - [1, 1 ', -3' 1"] terphenyl -3-yl] -acrylic, - 3- [3" acid - (2-carboxy-ethyl) -2 '-methoxy-5' - (8-phenyl-octylcarbamoyl) - [1,1 ', 3'1"] terphenyl -3-yl] -propionic acid methyl ester. {5 '- [(2-Butyl-benzofuran-3-ylmethyl)) -amino] - [1,1': 3J1"] terphenyl-2'-ylolxy) -acetic acid. { 5 '- [(2-Butyl-benzofuran-3-ylmethyl) -amino] - [1,1': 3 ', 1"] terphenyl-2'-yloxy) acetic acid methyl ester. -dibromo-4- [(2-butyl-benzofuran-3-ylmethyl) -amino-phenoxy] -acetic acid, - {2,6-dibromo-4- [(2-butyl-benzofuran-3-ylmethyl)) -amino] -fenoxijacetic, - [2"-fluoro-5 '- (8-f-enyl -octylcarbamoyl) -3-trif-loromethyl- [1,1', 3 ', 1"] -terphenyl-2'-yloxy) -acetic acid, - ( 5'-dodecylcarbamoyl-2"-fluoro-3-trif luoromethyl- [1,1 '; 3', 1"] terphenyl-2'-yloxy) acetic acid; acid (5'-dodecyl carbamoyl-2, 2"-difluoro- [1,1 '; 3', 1"] terphenyl-2'-yloxy) -acetic acid [2, 2"-dif luoro- '- (8-f-enyl-octylcarbamoyl) - [1,1'; 3 ', 1"] terphenyl-2'-yloxy) -acetic; [2, 2"-di-fluoro-5 '- (6-f-enylhexyl carbamoyl) - [1,1 J-3 J 1"] terphenyl-2'-yloxy] -acetic acid; acid { 5 '- [6- (2, 4-difluoro-f-enoxy) -hexylcarbamoyl] -2, 2"-dif luoro- [1,1', - 3 ', 1"] -terf enyl-2'-yloxy ] -acetic, - (3"-chloro-5 '-dodecylcarbamoyl-2-fluoro- [1,1', -3 ', 1"] terphenyl-2'-yloxy) -acetic acid, - [3"- acid] chloro-2-fluoro-5 '- (8-phenyl-octylcarbamoyl) - [1,1', -3 ', 1"] -terphenyl-2'-yloxy] acetic acid; acid { 3-Chloro-5 '- [6- (2,4-d? -fluoro-phenoxy) -hexylcarbamoyl] -2"-fluoro [1,1', 3 ', l"] terphenyl-2'-yloxy} -acetic, - acid. { 3"-chloro-2-fluoro-5 '- [methyl- (8-f-enyl-octyl) -carbamoyl] - [1,1'; 3 J 1"] -terphenyl-2'-allyloxy} -acetic, - acid. { 2,2"-dif luoro- 5 '- [methyl- (8-f-enyl-octyl) -carbamoyl] - [1,1', - 3 ', 1"] -terphenyl-2'-allyloxy} -acetic, - acid. { 3, 3"-dichloro-5 '- [8- (4-chloro-benzenesulf inyl) -octylcarbamoyl] - [1,1'; 3 J 1"] terphenyl-2'-allyloxy} -acetic; acid { 3,3"-di chloro-5 '- [8- (2,4-difluoro-f-enoxy) -octylcarbamoyl] - [1,1'; 3 ', 1"] terphenyl-2'-yloxy} -acetic acid; {.3.3" -dichloro-5' - [12- (2,4-difluoro-f-enoxy) -dodecylcarbamoyl] - [1, 1 ', 3', 1"] terphenyl-2'-yloxy. -acetic, - acid. {3, 3" -dichloro-5 '- [8 - (4-rif luoromethyl-benzyloxy ) -octylcarbamoyl- [1,1 '; 3', l "] terphenyl-2'-yloxy} -acetic acid - [3, 3" -dichloro-5 '- (8-. {3- 3- [ 3- (3-methoxy-propoxy) -propoxy] -propoxy.] -octylcarbamoyl) - [1,1 ', -3', l "] terphenyl-2'-yloxy] -acetic, - (3, 3"-dichloro-5'-di-cyclohexy Icarbamoyl- [1,1 '; 3', 1"] terphenyl-2'-yloxy) -acetic acid 4- [4, 4"-dimethoxy-5 '- (7 phenyl-heptylcarbamoyl) - [1, 1 ', -3', 1"] -methyl-2'-yloxy] butyric, - 4- [3, 3" -dichloro-5 '- (7-f enyl-heptylcarbamoyl) - [1, 1 ', -' 3 ', 1"] terphenyl-2'-yloxy] butyric acid, - [5' - (7-f eni 1 -heptylcarbamoyl) -3] diethyl ester, 3"-bis -trif luoromethyl- [1,1 ', -3', 1"] - terphenyl-2'-yloxymethyl] -phosphonic acid [5 '- (7-p-enyl-heptylcarb amoyl) -3,3"-bis-tr i f luoromethyl- [1, 1 ': 3', 1"] terphenyl-2'-yloxymethyl] -phosphonic acid; 2, 2-dimethyl-3- [5 '- (7-f-enyl-heptylcarbamoyl) - 3,3"-bis-trifluoromethyl [1,1': 3 ', 1"] -terphenyl-2'-yloxy] -propionic, - 4- [5 '- (7-phenyl-heptyl-Icarbamoyl) -3,3"-bis-t-rif loromethyl- [1,1,13', 1"] terphenyl-2'-yloxymethyl] -benzenesulfonic acid; acid [[4, 4 '- dimet oxy-5' - [4 - [[(7-f-enylheptyl) amino] carbonyl] phenyl] [1, 1 ': 3', 1 'terphenyl] -2' -il ] oxy] acetic; [[5 '- [4- [[(7-f-enylheptyl) amino] carbonyl] phenyl] -3,3'-bis (trifluoromet l) [1, 1': 3 ', 1' terphenyl] -2 '-yl] oxy] acetic; 4 - [[[4, 4'-dimethoxy-5 '- [4 - [[(7-f-enylheptyl) aminol] carbonyl] phenyl] [1,1'-3', 1'-terphyl] -2 '' -yloxymethyl] -benzoic acid; 4 - [5 '- (7-f-enyl-heptylcarbamoyl) -3,3"-bis-trif-loromethyl- [1,1'; 3 ', 1"] terf-enyl-2'-yloxymethyl] -benzoic acid; (3-bromo-3'-chloro-5-dodecylcarbamoyl-4 '-f luoro-bifenyl-2-yloxy) acetic acid; [3'-Cioro-4'-fluoro-5- (8-phenyl-octylcarbamoyl) -bifinyl-2-yloxy] acetic acid; 5-Bromo-6- (2-tetrazol-1-yl-ethoxy) -3'-methoxy acid (3-bis-5-dodecylcarbamoyl-3'-methoxy-biphenyl-2-yl) acetic acid, dodecylamide -bi-enyl -3-carboxylic acid; 5-bromo-3'-chloro-6 - (2-tetrazol-2-yl-ethoxy) -bifinyl-3-carboxylic acid dodecylamide; 5-bromo-3'-chloro-6- (2-tetrazol-1-yl-ethoxy) -bifenyl-3-carboxylic acid dodecylamide, - [3,5,3", 5" -tetramethyl-5 '- (8-phenyl-octylcarbamoyl) - [1,1': 3 1"] terphenyl-2'-yloxy] acetic acid [4,4"] acid -difluoro-3,3"-dimethyl-5 '- (8-phenyloctylcarbamoyl) - [1,1': 3 ', 1"] terphenyl-2'-yloxy] acetic acid; 2'-Hydroxy-3, 5, 3", 5" -tetramethyl- [1,1 ': 3', 1"] terfenyl-5'-carboxylic acid (7-phenylheptyl) amide (7-phenyl-heptyl) ) - 2'-Hydroxy-3, 3"-dimethyl- [1,1 ': 3 J 1"] erphenyl-5'-carboxylic acid amide: [3, 3"-dimethyl-5' - (7- phenyl-heptylcarbamoyl) - [1,1 ': 3,1"] terphenyl-2'-yloxy] acetic acid, 4- [3, 3" -dimethyl-5' - (7-phenyl-heptylcarbamoyl) - [1 , 1 ': 3', 1"] terphenyl-2'-yloxy] butyric acid, [3, 5, 3", 5"-tetramethyl-5 '- (7-phenyl-heptylcarbamoyl) - [1] diethyl ester , 1 ': 3', 1"] terphenyl-2'-yloxymethyl] -phosphonic acid, 4- [3,5,3", 5"-tetramethyl-5l- (7-phenyl-heptylcarbamoyl) - [1, 1 ': 3', 1"] -terphenyl-2'-yloxy] -butyric acid, 3- (3-phenyl-heptyl) -amide -amide of the acid 3, 3" -diformyl-2'-methoxymethoxy- [1, 1 ': 3 J 1"] terphenyl-5'-carboxylic acid 3- (3-phenyl-heptyl) -amide of 3, 3" -diformyl-2'-hydroxy- [1,1 ': 3', 1"] terphenyl-5 '-carboxylic acid, 3,3", 4,4" -bis-me-ilenedioxy-5' - (7-phenyl-heptylcarbamoyl) - [1,1 ': 3', 1"] terphenyl-2'-yloxy] acetic; 3-chloro-butyl ester of 3 '-bromo-2' -hydroxy-5 '- (8-phenyl-octylcarbamoyl) -biphenyl-3-carboxylic acid ester; (3"-chloro-5 '-dodecylcarbamoyl-3-trifluoromethyl- [1, 1', -3 ', 1"] terphenyl-2'-yloxy) acetic acid; acid (5 '-dodecylcarbamoyl-4"-methoxy-3-trif luoromethyl- [1,1', -3 ', 1"] terphenyl-2'-yloxy) acetic acid; (5 '-dodecylcarbamoyl-2"-f luoro-4-ethoxy- [1,1', -3 ', 1"] terphenyl-2'-yloxy) acetic acid, - (3-bromo-5-dodecylcarbamoyl) acid -2 '-f luoro-biphenyl-2-yloxy) acetic; [4"-methoxy-5 '- (6-f-enylhexyl carbamoyl) -3-trifluoromethyl- [1,1'; 3 ', 1"] terf-enyl-2'-yloxy] acetic acid, - [4] "-methoxy -5 '- (8-f-enyl-octylcarbamoyl) -3-trifluoromethyl- [1,1'; 3 ', 1"] terphenyl-2'-yloxy] acetic acid; acid (3,5,3", 5" -tetrachlor-5 '-dodecyl carbamoyl - [1,1', -3 J 1"] -terphenyl-2'-yloxy) acetic acid [3, 5, 3" , 5"-tetrachloro-5 '- (8-f-enyl-octylcarbamoyl) - [1, 1'; 3 ', 1"] terf in? L-2'-yloxy] acetic; [3, 5, 3", 5" -tetrachlor-5 '- (6-phenyl-hexyl carbamoyl) - [1, 1', -3 ', 1"] terphenyl-2'-yloxy] acetic acid; 3, 3"-dichloro-5 '- (4-heptyloxy-benzyl carbamoyl) - [1,1', -3 ', 1"] terphenyl-2'-yloxy] acetic acid methyl ester 8- [( 2'-carboxymethoxy-3, 3"-dichloro- [1,1 ', -3', 1"] terphenyl-5'-carbonyl) -amino] octanoi, 5- [3, 3"-dichloro-5 '] - (8-indol-l-yl-octylcarbamoyl) - [1,1 ', -3', 1"] terphenyl-2'-allyl] pentanoic acid; 4- . { 2- [3,3"-dichloro-5 '- (8-indol-l-yl-octylcarbamoyl) - [1,1': 3 ', 1"] -terphenyl-2'-yloxy] ethoxy) benzoic acid; 6 - [(2'-carboxymethyl-3, 3"-Ichloro- [1,1,1 ', -3', 1"] terphenyl-5'-carbonyl) -amino] -hexyl ester of 4-5-methoxybenzoic acid; [3, 3"-dichloro-5 '- (6-hydroxy-hexylcarbamoyl) - [1,1': 3 J 1"] terphenyl-2'-yloxy] acetic acid; acid { 2- [3, 3"-dichloro-5 '- (8-indol-1-yl-octylcarbamoyl) - [1,1': 3J1"] terphenyl-2'-yloxy] ethoxy} acetic acid, (5 '-hexyl- [1,1', - 3 ', 1"] terf enyl-2'-yloxy) acetic acid (5' -nonyl- [1, 1 ', - 3 ', 1"] terphenyl-2'-yloxy) acetic; (5 '-tridecyl- [1,1'; 3 ', l "] terphenyl-2'-15-yloxy) acetic acid (5'-decyloxy- [l, l' -, 3 ', l"] terphenyl) 2'-yloxy) -acetic acid (5 '-tetradecyloxy- [1,1', -3 ', 1"] terphenyl-2'-yloxy) acetic acid (5'-trityl- [1, 1 ', - 3', 1"] terf enyl-2'-yloxy) acetic; acid (5'-dodecylcarbamoyl-3, 3"-bis-tri-luoromet-il-. {1, 1 '; 3', 1"] terphenyl-2'-yloxy) acetic, - (3-bromo-5) acid dodecylcarbamoyl-3'-trifluoromethyl-25-biphenyl-2-yloxy) -acetic acid, - (5 '- (8-phenyl-octylcarbamoyl-3,3"-bis-trif luoromet il-. {1, 1'; 3 ', 1"] terf-enyl-2'-yloxy) -acetic acid (3-bromo-5- (8-phenyl-octylcarbamoyl) -3'-trifluoromethyl-biphenyl-2-yloxy) -acetic acid 4 - (3-bromo-5-dode-cy-1-carbamoyl 1-3 -trifluoromethyl- biphenyl-2-yloxysulfonyl) -2-hydroxybenzo-co-5-bromo-6- (2- [1, 2, 3] triazol-2-yl-ethoxy) -3 '-trifluoromethyl-biphenyl-3-dodecylamide -carboxylic acid: 5-bromo-6- (2- [1, 2, 3] triazol-1-yl-ethoxy) -3'-trifluoromethyl-bifenyl-3-carboxylic acid dodecylamide; bromo-6- (2-tetrazol-2-yl-ethoxy) -3 '-trif luoromethyl-biphenyl-3-carboxylic acid; -bromo-6- (2-tetrazol-1-yl-ethoxy) -3 '-trif luoromet-1-biphenyl-3-carboxylic acid dodecylamide, 2- [3-bromo-5- (8-phenyl -octylcarbamoyl) -3 '-trif luoromethyl-bifenil-2-yloxy] -ethyl carbamic acid; 5-bromo-6- (2-morpholin-4-yl-ethoxy) -3 '-trif luoromethyl-bifenyl-3-carboxylic acid dodecylamide, 6- (Amino-ethoxy) -5-bromo acid dodecylamide -3 '-trif luoromethyl-bifenyl-carboxylic acid; 5-bromo-3 '-trif luoromethyl-6- (2-ureido-ethoxy) -bifinyl-3-carboxylic acid dodecylamide; [2 - (3-b-norne-5-dodecylcarbamoyl-3 '-trif luoromethyl-biphenyl-2-yloxy) -ethyl] -carbamic acid methyl ester; [5 '- (6-phenyl-hexylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 ', 1"] acid} terf-enyl-2'-yloxy] -acetic acid, - [3-bromo-5- (6-phenyl-hexylcarbamoyl) -3 '-trif luoromethyl-bifenyl-2-yloxy] -acetic acid; (2-Hydroxy-3, 3"-bis-trif-loromethyl- [1,1 ': 3' 1"] terfenyl-5'-carboxylic acid (8-f-enyl-o-ethyl) -amide, - 5- [ 5 '- (8-f-enyl-octylcarbamoyl) -3,3"-bis-trif-loromethyl-1, 1', - 3 '1"] terphenyl-2'-yloxy] -pentanoic acid, - (8-phenyl-o-ethyl) ) 5-bromo-6- (2-piperazin-1-yl-ethoxy) -3 '-trif luoromethyl-biphenyl-3-carboxylic acid amide, 5-bromo- (8-phenyl-octyl) amide 6-Hydroxy-3'-trifluoromethyl-biphenyl-3-carboxylic acid, 4- [3-bromo-5- (8-f-enyl-octylcarbamoyl) -3 '-trif luoromethyl-biphenyl-2-alkoxysulfonyl] -2 -hydroxy-benzoic acid, - 7 - [5 '- (8-f-enyl-octylcarbamoyl) -3,3"-bis trifluoromethyl- [1,1'; 3 ', 1"] terf-enyl-2'-yloxy] -heptanoic; (8-phenyl-octylamide) of 2 '- (2-hydroxy-3,4-d? Oxo-cyclobut-1-enylamino) -ethoxy] -3,3"-bis -trif luoromet il- [1,1 ': 3', 1"] terphenyl-5'-carboxylic acid; 2 '- [4- (lh-tetrazol-5-yl) -butoxy-3, 3"-bis-trif luoromethyl- [1,1': 3 '1"] (8-phenyl-octyl) -amide teril enyl-5'-carboxylic acid; 2-methoxy-4- [5 '- (8-phenyl-octylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 '1"] terphenyl-2'-yloxymethyl] -benzoic acid, - 2-hydroxy-4- [5 '- (8-phenyl-octylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 '1"] terphenyl-2'-yloxymethyl] -benzoic acid; 2-hydroxy-4- [5 '- (8-phenyl-octylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 '1"] terphenyl-2'-yloxymethyl] - methyl ester - benzoic; 4 -? Z [3-bromo-5- (8-phenyl-octylcarbamoyl) -3 '-trifluoromethyl-biphenyl-2-yloxy] ethoxy acid} -2-hydroxy-benzoic; 2-hydroxy-4- [5 '- (8-phenyl-octylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 '1"] -terphenyl-2'-alkoxysulfonyl] -benzoic acid, 4- [3-Bromo-5- (8-phenyl-octylcarbamoyl) -3 '-tpfluoromethyl-biphenyl-2-yloxymethyl] -2-methoxy-benzoic acid, - (8-phenyl-octyl) -amide -bromo-6- (lH-tetra-5-ylmethoxy) -3'-tpfiuoromethyl-biphenyl-3-carboxylic acid; 2 '- (lH-tetrazol-5-ylmethoxy) -3,3-bis-trifluoromethyl- [1,1': 3 '1"] terphenyl-5'-carboxylic acid (8-phenyl-octyl) -amide. , - 4- [3-bromo-5- (8-phenyl-octylcarbamoyl) -3 '-trifluoromethyl-biphenyl-2-) yloxymethyl] -2-hydroxy-benzoic acid methyl ester; a- [3-bromo-5- (8-phenyl-octylcarbamoyl) -3 '-trifluoromethyl-biphenyl-2-yloxymethyl] -2-hydroxy-benzoic acid, - 2'-amino-3, 3"-bis-trifluoromethyl- [1,1 ': 3' 1"] -terphenyl-5'-carboxylic acid (8-phenyl-octyl) -amide; 4- [2-bromo-4- (8-phenyl-octylcarbamoyl) -phenoxysulfonyl] -2-hydroxy-benzoic acid; 2-hydroxy-4- acid. { 2- [5 '- (8-phenyl-octylcarbamoyl) -3,3"-bis-trifluoromethyl [1, 1': 3 ', 1"] terphenyl-2'-yloxy] -ethoxy) -benzoic acid; acid { 3-Bromo-5- [methyl- (8-phenyl-octyl) -carbamoyl] -3'-trifluoromethyl-biphenyl-2-yloxy} -acetic, - acid (3,3"-dichloro-4,4" difluoro-5 '- [methyl- (8-phenyl-octyl) -carbamoyl] - [1, 1', -3 ', l "-terphenyl -2'-yloxy) -acetic; [5-methyl- (8-phenyl-octyl) -carbamoyl] -3,3"-bis-trifluoromethyl- [1,1 ', -3', 1" terphenyl -2 ' -alloxy) -acetic, - [5 '- (3-benzyloxy-benzylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 ', 1"] terphenyl-2'-yloxy] -acetic acid , - (2- (R) -3-phenyl-2- [5- (8-phenyl-octylcarbamoyl) -4'-trifluoromethyl-biphenyl-2-yloxy] propionic acid; 2- (R) -3-phenyl -2- [4'-chloro-5- (8-phenyl-octylcarbamoyl) -bifenil-2-yloxy] propionic acid 2- (R) -3-f-enyl-2- [4'-fluoro-5-] (8-f-enyl-octylcarbamoyl) -bif in α-2-yloxy] ropionic acid 2- (R) -3-phenyl-2- [4'-methoxy-5- (8-phenyl-octylcarbamoyl) -bif) enyl-2-yloxy] propionic acid 2- (R) -3-phenyl-2- [5- (8-phenyl-octylcarbamoyl) -4 '-trif luoromethoxy-bifenyl-2-yloxy] -propionic acid, - or a pharmaceutically acceptable salt thereof.
The compounds of this invention are prepared according to the following reaction schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These reaction schemes show the preparation of representative compounds of this invention.
Reaction scheme 1 z = 1-3 VIb In Reaction Scheme 1, 2-bromophenol (lia; X = H; Y = Br, C = -C02Et, -N02, -CN), available by the Oberhauser method (J. Org. Chem. 1997, 62 , 4504) is treated with two or more equivalents of iodine in an aqueous solution of potassium carbonate / THF at temperatures between 0 ° C and room temperature to provide 2-bromo-6-iodophenol (Ilb; R = H; X = I; Y = Br; C = -C02Et, -N02, -CN). 2-bromo-6-yod? Phenol (Ilb; R = H; X = 1; Y = Br; C = -C02Et, -N02, -CN), 2-chloro-6-bromophenol (He; X = Br Y = Cl; C = -C02Et, -N02, -CN), 2-chloro-6-iodophenol (lid; X = 1; Y = Cl; C = -C02Et, -N02, -CN, -Br) , 2-fluoro-6-bromophenol (He; X = Br; Y = F; C = -C02Et, -N02, -CN), or 2-fluoro-6-iodophenol (lid; X = I; Y = F; C = -C02Et, -N02, -CN, -Br) are subjected to Mitsunobu conditions (for a review see Oyó Mitsunobu Synthesis 1981, 1-27) using ethylene glycol, propane-1,3-diol or butane- 1,4-d? Ol as the nucleophile to provide Illa (R = H; X = I; Y = Br; C = -C02Et, -N02, -CN), 111b (R = H; X = Br; Y = Cl; F; C = -C02Et, -N02, -CN) O Ule (R = H; X = 1; Y = Cl; F; C = -C02Et, -N02, -CN, -Br). The other coreactants necessary to carry out the Mitsunobu reaction include one or more molar equivalents of a lower alkyl azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from -20 ° C to 120 ° C, at temperatures ranging from -20 ° C to 120 ° C. This compound is then subjected to Suzuki or Stille coupling conditions using 1.0 to 1.8 equivalents of a coupling partner to provide IVa (Y = Br; R = H; BH, halogen; C = -C02 Et, -N02, -CN ) and Vía (R = H; BH, halogen; C = -COjEt, -N02, -CN); or IVa (Y = Cl, F; R = H; B H, halogen; C = -COjEt, -N02, -CN). Typical conditions used to carry out the Suzuki reaction include the use of a boronic acid or ester as the coupling partner, a palladium catalyst (2 to 20 mol%) such as Pd (PPh3) 4 or [1, 1 'bis (diphenylphosphino) ferrocene] icloro-palladium (II) and a base such as potassium carbonate, barium hydroxide, potassium phosphate or triethylamine in a suitable solvent such as aqueous dimethoxyethane, THF, acetone or DMF at varying temperatures from 25 ° C to 125 ° C. Typical conditions used to carry out the Stille reaction include the use of an organostannane as the coupling partner. A palladium catalyst (2 to 20 mol%) such as Pd (PPh3) 4 or [1,1'-bis (diphenylphosphino) ferrocene] -dichloro palladium (II) and a salt such as potassium fluoride or lithium chloride in a suitable anhydrous solvent such as dimethoxyethane, THF, acetone or DMF at temperatures ranging from 25 ° C to 125 ° C. To obtain the asymmetric compound Va (R = H, B H, halogen, D H, halogen, C = -C02Et, -N02, -CN), the compound IVa (Y = Br; R = H; BH, halogen; C = -C02Et, -N02, -CN) is again subjected to the above conditions of Suzuki or Stille using 1.0 to 1.8 equivalents of a different boronic acid, ester or organostannane as the coupling partner. Alternatively, 2, 6-dibromophenol (lie; X = Y = Br; C = -C02Et, -N02, -CN) or 2,6-diiodophenol (lid; X = Y = I; -C02Et, -N02, -CN, -Br) can be used as the initial material. The fact of subjecting the Mitsunobu conditions to lie or lid (for a review see Oyó Mitsunobu Synthesis 1981, 1-27) using ethylene glycol, 1,3-propanediol or 1,4-butanediol as the nucleophile provides the derivatives 3,5- dihalo Illb (R = H; X = Y = Br; C = -C02Et, -N02, -CN) or lile (R = H; X = Y = I; C = -C02Et, -N02, -CN, -Br). The other coreactants necessary to carry out the Mitsunobu reaction include one or more molar equivalents of a lower alkyl azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from -20 ° C to 120 ° C, at temperatures ranging from -20 ° C to 120 ° C. This compound is then subjected to Suzuki or Stille coupling conditions using 2.0 coupling partner equivalents to provide VIb (R = H; B H, halogen; C = • - »- * - -» * - • - -C02 Et, -N02, -CN, Br). Typical conditions used to carry out the Suzuki reaction include the use of a boronic acid or an ester such as the coupling partner, a palladium catalyst (2 to 20 mol%) such as Pd (PPh3) 4 or [1, 1 'bis (diphenylphefino) ferrocene] -dichloropalladium (II) and a base such as potassium carbonate, barium hydroxide, potassium phosphate or triethylamine in a suitable solvent such as dimethoxyethane, THF, acetone or DMF in the presence of a small amount of water at temperatures ranging from 25 ° C to 125 ° C. Typical conditions used to carry out the Stille reaction include the use of an organostannane as the coupling partner, ur. palladium catalyst (2 to 20 mol%) such as Pd (PPh3) 4 or [1,1'-bis (diphenyl) phosphino) ferrocene] -dichloropalladium (II), and a salt such as potassium fluoride or lithium in a suitable anhydrous solvent such as dimethoxyethane, THF, acetone or DMF at temperatures ranging from 25 ° C to 125 ° C. In addition, the reaction of Suzuki or Stille of VIb (R = H; BH, halogen; C = Br) can provide the derivative VIb (R = H; BH, halogen; C = alkyl of 1-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms). The protection of the primary alcohol in Illa, Illb, lile, IVa, IVb or V can be carried out by reaction with an electrophile such as tBuMe2SiCl, methoxymethyl chloride (MOM-Cl), or macoxyethoxymethyl chloride (MEM-C1) for provide Illa, Illb or IIIc (R = -SiMe2tBu, -MOM, -MEM), IVa (R = -SiMe2tBu, -MOM, -MEM), VIb (R = -SiMe2tBu, -MOM, -MEM) or Va (R = -SiMe2tBu, -MOM, -MEM) The other coreactants necessary to carry out the protection include an amine base such as pyridine, triethylamine, diisopropylethylamine or 4-dimethylaminopyridine in an appropriate anhydrous solvent such as dichloromethane, DMF or toluene at temperatures ranging from -78 ° C to 125 °. C. Alternatively, protection of the primary alcohol in Illa, Illb, IIIc, IVa, IVb or Va can be obtained by reaction with a reagent such as 3,4-dihydro-2H-pyran in the presence of a moderate acid such as, but not limited to to pyridinium p-toluenesulfonate (PPTS), in a solvent such as dichloromethane, to provide the tetrahydropyranyl ethers Illa, Illb or IIIc (R = -THP), IVa (R = -THP), VIb (R = -THP) , or Va (R = -THP). The conversion of Illa, Illb, IIIc, IVa, IVb or Va (R = H, -SiMe2tBu, -MOM, -MEM, -THFP; C = -CN, -C02Et) to the corresponding aldehydes Illa, Illb, IIIc, IVa , IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -CHO) can be carried out by reaction with diisobutylaluminum hydride in THF or toluene at -78 ° C to -100 ° C. These aldehydes can be converted to the corresponding compounds (Illa, Illb, IIIc, IVa, IVb or Va (R = H, -S? Me2tBu, -MOM, -MEM, -THP; C = alkyl of 1-18 carbon atoms) , aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms) through hydrogenolysis (H2, Pd in C, alcohol solvent, 1 atm, room temperature) of the corresponding compound Illa, Illb, lile, IVa, IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = CR3 = CR3R8) formed by the Wittig or Horner-Emmons reaction with 1.0 to 5.0 equivalents of a suitable phosphonium salt or phosphonate ester. The other co-reactants necessary to carry out the transformation include 1.0 to 5.0 equivalents of a strong base such as potassium t-butoxide, sodium ethoxide, sodium hydride or n-BuLi in a solvent such as THF, DME or Et20 at temperatures They vary from -78 ° C to 25 ° C. The aldehydes Illa, Illb, IIIc, IVa, IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -CHO) can be further elaborated by Bayer-Villager oxidation to the Illa formate esters, Illb, IIIc, IVa, IVb or Va (R = H, -SiMe2tBu, -MOM, -MEM, -THP; C = -OCHO) followed by saponification to the phenols Illa, Illb, IIIc, IVa, IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -ORj- R6 = H). Oxidation of Bayer-Villager is generally carried out with 1.0 to 5.0 equivalents of m-chloroperbenzoic acid or other peracid in a solvent such as dichloromethane, chloroform or benzene at temperatures ranging from 0 ° C to 125 ° C. The saponification of the formate esters is usually carried out in an alcoholic solution of a metal hydroxide, typically sodium hydroxide at temperatures ranging from 0 ° C to 125 ° C. The phenols Illa, Illb, lile, IVa, IVb or Va (R = H, -SiMe2tBu, -MOM, -MEM, -THP; C = -ORJ- R6 = H) can be further elaborated by alkylation with a suitable electrophilic iodide, bromide, tosylate, mesylate or triflate to provide the ethers Illa, Illb, IIIc, IVa, IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -OR -R6 H). The other co-reactants necessary to carry out the transformation include 1.0 to 5.0 equivalents of a base such as cesium carbonate, potassium carbonate, sodium ethoxide or sodium hydride in a solvent such as THF, DME, DMF, DMSO or Et20 a temperatures that vary from 0 ° C to 125 ° C. The phenols Illa, Illb, IIIc, IVa, IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -OR - R6 = H) can be prepared in addition to the corresponding carboxylic acid esters Illa, Illb, lile, IVa, IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP, -C = - 02R6) by reaction with a carboxylic acid halide, carboxylic acid anhydride or reaction with a suitable carboxylic acid in the presence of an activating agent such as dicyclohexyl carbodiimide or isobutyl chloroformate. The other co-reactants necessary to carry out the transformation include 1.0 to 5.0 equivalents of a non-nucleophilic base such as pyridine, triethylamine, dimethylaminopyridine or diisopropylethylamine in a solvent such as dichloromethane, toluene or THF at temperatures ranging from 0 ° C to 125 °. C. The phenols Illa, Illb, lile, IVa, IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -ORJ- R6 = H) can be further elaborate the corresponding carbamates Illa, Illb, IIIc, IVa, IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP, -C = -02CNRβR7) by reaction with a suitable carbamoyl halide or isocyanate. The other co-reactants necessary to carry out the transformation include 1.0 to 5.0 equivalents of a non-nucleophilic base such as pyridine, triethylamine, dimethylaminopyridine or diisopropylethylamine in a solvent such as dichloromethane, toluene or THF at temperatures ranging from 0 ° C to 125 °. C. The conversion of carboxylic acid esters Illa, Illb, lile, IVa, Va or Vía (R = H, -SiMe2tBu, -MOM, -MEM, -THP; C = -C02Et) to primary, secondary or tertiary amides Illa, Illb, IIIc, IVa, Va or Via (R = H, -SiMe2tBu, -MOM, -MEM, -THP; C = -CONRsR7) can be carried out by reaction with 2.0 to 5.0 equivalents of lithium amides (derived from the reaction of the corresponding amines with BuLi in hexanes, in THF or DME at temperatures ranging from -20 ° C to 25 ° C) in THF or DME at temperatures ranging from -20 ° C to 25 ° C. Alternatively, the same conversion can be carried out by treatment of these esters with 2.0 to 5.0 equivalents of aluminum amides (derived from the reaction of AlMe3 with the corresponding amides or their hydrochloride salts in benzene or toluene at temperatures varying from 25 to 50). ° C to 110 ° C) in benzene or toluene at temperatures ranging from 25 ° C to 110 ° C.
The conversion of the carboxylic acid esters Illa, Illb, IIIc, IVa, Va or Via (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -C02Et) to the corresponding benzylic alcohols Illa, Illb, lile, IVa, Va or Via (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -CH2OH) can be carried out by treatment with a suitable reducing agent such as diisobutylaluminum hydride or lithium aluminum hydride in THF or DME at temperatures ranging from -20 ° C to 60 ° C. The benzylic alcohols can be converted to the corresponding ethers Illa, Illb, lile, IVa, Va or Via (R = -? IMe2tBu, -MOM, -MEM, -THP; C = -CH2OR6) by treatment with a suitable base such as Sodium hydride followed by reaction with an electrophilic iodide, bromide, mesylate, tosylate or triflate in a solvent such as THF, DME or DMF at temperatures ranging from -20 ° C to 60 ° C. The conversion of primary, secondary or tertiary amides Illa, Illb, IIIc, IVa, Va or Via (R = -? IMe2tBu, -MOM, -MEM, -THP; C = -CH2NRßR7) to amines Illa, Illb, lile, IVa, Va or Via (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -CH2NRSR7) can be carried out by reaction with 2.0 to 5.0 equivalents of the appropriate reducing agent such as diborane or lithium aluminum hydride in THF or DME at temperatures ranging from -20 ° C to 125 ° C. The conversion of Illa, Illb, lile, IVa, IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -N02) to the corresponding primary anilines Illa, Illb, lile, IVa, IVb or Va (R = H-SiMe2tBu, -MOM, -MEM, -THP; C = -NH2) can be carried out by reduction with an appropriate reducing agent such as iron, sodium dithionite or H2 using a palladium on carbon catalyst in THF or toluene at -78 ° C to 100 ° C. These primary anilines can be alkylated in a gradual manner to provide the secondary and tertiary anilines Illa, Illb, Ule, IVa, IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -NR6R7, - in where P R7 (together) are H). This can be carried out by sequential reaction of the anilines with appropriate aldehydes in the presence of a reducing agent such as sodium cyanoborohydride in a solvent such as EtOH. The primary and secondary anilines Illa, Illb, IIIc, IVa, IVb or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -NR6R7, -Rs = H) can be converted to the corresponding carbamates Illa, Illb, lile, IVa, IVb, or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -NR3C02R6) by reaction with a suitable haloformate. The other coreactants necessary to carry out the transformation include 1.0 to 5.0 equivalents of a non-nucleophilic base such as pyridine, t-butyl amine, dimethyl-minopyridine or diisopropylethylamine in a solvent such as dichloromethane, toluene or THF at temperatures ranging from 0 ° C to 125 ° C. The primary and secondary anilines Illa, Illb, lile, IVa, IVb, or Va (R = -SiMe2th? I, -MOM, -MEM, -THP; C = -NRSR7; Rß = H) can be converted to the corresponding ureas Illa, Illb, lile, IVa, IVb, or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -NR3CONR6R7) by reaction with a suitable carbamoyl halide or isocyanate. The other co-reactants necessary to carry out the transformation include 1.0 to 5.0 equivalents of a non-nucleophilic base such as pyridine, triethylamine, dimethylaminopyridine or diisopropylethylamine in a solvent such as dichloromethane, toluene or THF at temperatures ranging from 0 ° C to 125 °. C. The primary and secondary anilines Illa, Illb, lile, IVa, IVb, or Ja (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -NRSR7; R6 = H) can be converted to the corresponding anilides Illa, Illb, IIIc, IVa, IVb, or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = -NR3COR6) by reaction with a carboxylic acid halide, suitable carboxylic acid anhydride, or by reaction with a carboxylic acid in the presence of an activating agent such as dicyclohexylcarbodiimide. The other co-reactants necessary to carry out the transformation include 1.0 to 5.0 equivalents of a non-nucleophilic base such as pyridine, triethylamine, dimethylaminopyridine or diisopropylethylamine in a solvent such as dichloromethane, toluene or THF at temperatures ranging from 0 ° C to 125 °. C. The primary and secondary anilines Illa, Illb, lile, IVa, IVb, or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = - NRßR7; R6 = H) can be converted to the N-aryl - 1, 2 -diaminocyclobuten-3, 4-diones corresponding Illa, Illb, lile, IVa, IVb, or Va (R = -SiMe2tBu, -MOM, -MEM, -THP; C = jütas lf ..-- Ji- ) by reaction with l-ethoxy-2-aminocyclobuten-3,4-dione substituted with an appropriate solvent such as acetonitrile or ethanol at temperatures ranging from room temperature to 80 ° C. Alternatively, in order to reverse the reaction, where the primary or secondary anilines Illa, Illb, lile, IVa, IVb, or Va (R = -? IMe2tBu, -MOM, -MEM, -THP; C = - NR6R7; R6 = H) can be reacted with diethoxy-ischearic acid in a solvent such as ethanol at temperatures ranging from room temperature to 80 ° C to provide l-amino-2-ethoxycyclobuten-3,4-dione, which , in turn, can be treated with an appropriate amine in an appropriate solvent such as acetonitrile or ethanol at temperatures ranging from room temperature to 80 ° C to provide the same N-aryl-l, 2-d-aminociclobuten-3 , 4-dionas Illa, Illb, lile, IVa, IVb, or Va (R = -SiMe2tBu, -MEM, -THP; C The alcohol protective groups used in the previous transformations Illa, Illb, lile, IVa, IVb, or Va (R = -SiMe2tBu, -MOM, -MEM, -THP) can be removed to provide free alcohol Illa, Illb, IIIc, IVa, IVb, or Va (R = H) in numerous ways. The tBuMe2Si group can be removed by treatment with tetrabutylammonium fluoride in a solvent such as THF at temperatures ranging from 0 ° C to 25 ° C. The group MEM can be removed by treatment with ZnBr2 or TiCl4 in dichloromethane at temperatures ranging from 0 ° C to 25 ° C. The THP and MOM groups can be removed by treatment with aqueous acetic acid in THF at temperatures ranging from room temperature to 60 ° C. Further modifications can be made to the free alcohols of Reaction Scheme 1 (Illa, Illb, lile, IVa, ivb, or Va (R = H)) shown as the free alcohols VII (R = H) as shown in Reaction Scheme 2. Treatment with an oxidizing agent such as tetrapropylammonium perruthenate (TPAP) with 2 or more equivalents of N-methylmorpholine N-oxide (NMMO) or alternatively Cr03 in a solvent such as acetonitrile at room temperature, provides the corresponding oxylic acids VIII (R = OH). Treatment with TPAP and 1 equivalent of NMMO provides the corresponding IX aldehydes. The conversion to free alcohol VII (R = H) to the corresponding mesylate, tosylate or triflate VII (R = -S02Me, -S02PhMe, -S02CF3) can be ied out by treatment with mesyl chloride, tosyl chloride or triflyl chloride in the presence of a non-nucleophilic base such as pyridine, triethylamine, diisopropylethylamine, collidine or 2,6-di-tert-butyl-4-methylpyridine in a solvent such as dichloromethane at temperatures ranging from -78 ° C to 25 ° C. The conversion of the free alcohol VII (R = H) to the corresponding bromide or iodide XI (X = Br, I) can be ied out by treatment with on tetrabromide and triphenylphosphine (X = Br) or with iodine and triphenylphosphine in a solvent such as dichloromethane or THF at temperatures ranging from -20 ° C to 60 ° C. The conversion of VII (R = -S02Me, -S02PhMe, -S02CF3) or XII to nitriles X can be ied out by reaction with an appropriate alkali metal cyanide such as sodium cyanide in a solvent such as DMF, DMSO or THF at temperatures ranging from -20 ° C to 60 ° C. The transformation of the nitrile X to the amide oxime XIII can be ied out by reaction with hydroxylamine hydrochloride and sodium methoxide in methanol at temperatures ranging from -20 ° C to 80 ° C. The amide oximes XII can then be converted to the substituted oxadiazoles XIII (R = CH3, H) by reaction with a oxylic acid chloride, a trialkylortoester, a oxylic acid anhydride or a oxylic acid (in the presence of an activating agent such as dicyclohexylodiimide) in a solvent such as diclromethane, THF, or acetone at temperatures ranging from -20 ° C to 60 ° C followed by dehydration (Dean-Stark trap, refluxing toluene). The conversion of nitriles X to tetrazoles XIV can be ied out by reaction with an appropriate metal azide such as sodium azide in the presence of a tertiary amine hydrochloride salt such as triethylammonium chloride in a solvent such as DMF, DMA or N-methylpyrrolidinone at temperatures ranging from 100 ° C to 160 ° C. The N-alkylated tetrazoles XV (? = T = U = N, X = CR3 and S = T = X = N, U = CR3), N-alkylated 1,2,3-triazoles XV (S = X = CR3, U = T = N; and S = T = N, X = U = CR3), 1, 2, 4-N-alkylated triazoles XV (? = X = N, U = T = CR3, and X = T = N , S = U = CR3) and N-alkylated imidazole XV (S = N, X = T = U = CR3) can be made from VII (R = -S02Me, -S02PhMe, -S02CF3) or XI (X = Br, I) by reaction of the anion formed by the treatment of tetrazole, 1, 2, 3-triazole, 1, 2,4-triazole or imidazole with a strong base such as sodium hydride in a solvent such as THF, DME, DMF or DMSO at temperatures ranging from -20 ° C to 80 ° C. The amines XVI (R4 = H) can be prepared from VII (R = -S02Me, -S02PhMe, -S02CF3) or XI (X = Br, I) by reaction with 2 or more equivalents of pyrrolidine, piperidine, morpholine, N-methylpiperazine or simple disubstituted amines in a solvent such as dichloromethane, THF, DME or DMF at temperatures ranging from -20 ° C to 80 ° C. Alternatively, the reaction of VII (R = -S02Me, -S02PhMe, -S02CF3) or XI (X = Br, I) with an alkali metal azide such as sodium azide in a solvent such such as DMF, DMSO or THF at temperatures ranging from -20 ° C to 80 ° C can provide the azides XI (X = N3). The subsequent treatment of azides XI (X = N3) with triphenylphosphine in Wet THF can provide the primary amines XVI (R4 = R5 = H). The secondary amines XVI (R4 = H; R5 = H) can be made by reaction of the aldehydes IX with primary amines in the presence of a suitable reducing agent such as cyanoborohydride of hatred in a solvent such as ethanol or isopropanol at varying temperatures. -20 ° C to 80 ° C. The aldehydes IX can be further elaborated by reaction with hydroxylamines or hydrazines in a solvent such as methanol or ethanol at temperatures ranging from 0 ° C to 60 ° C to form oximes XVII (X = OR3) and hydrazones XVII (X = NHR3) . Alcohols VII (R = H) can be further elaborated by reaction with an appropriate electrophilic alkylating agent such as an alkyl or carboxyalkyl bromide, iodide, mesylate, tosylate or triflate in the presence of a base such as sodium hydride in a solvent such as THF, DMF or DME at temperatures ranging from -20 ° C to 80 ° C to provide the ethers VII (R = R \ -CH2C02R3). The alcohols VII (R = H) can be further elaborated by reaction with an appropriate isocyanate in a solvent such as dichloromethane at temperatures ranging from 0 ° C to 100 ° C to provide the corresponding carbamates VII (R = CONR4Rs). The primary or secondary amines XVI (R4 = H) can be converted to the carbamates corresponding XI (X = NR5C02R3, R3 = H) by treatment with a suitable haloformate in a solvent such as dichloromethane in the presence of a base such as triethylamine, pyridine or collidine at temperatures ranging from -20 ° C to 50 ° C. Carbamates XI (X = NRSC02RJ R3 = p-nitrophenyl) can be converted to ureas XI (X = NR3CNR4RS) by treatment with a suitable amine in a solvent such as dichloromethane at temperatures ranging from 0 ° C to 100 ° C. Alternatively, ureas XI (X = NR3CNR4R5) can be synthesized from amines XVI (R4 = H) by treatment with a suitable isocyanate in a solvent such as dichloromethane at temperatures ranging from 0 ° C to 100 ° C.
Reaction scheme 2 VII VIII IX XI XIII xv? V? The carboxylic acids VIII (R = OH) can be converted to the carboxylic acid esters VIII (R = OR3, R3 = H) by reaction with a suitable alcohol in the presence of a strong acid catalyst such as sulfuric acid, toluenesulfonic acid or camphorsulfonic acid in a solvent such as toluene under reflux using a Dean-Stark trap for water removal. Alternatively, activating the acid with a reagent such as dicyclohexylcarbodiimide or isobutyl chloroformate in the presence of a non-nucleophilic base such as triethylamine, pyridine, or diisopropylethylamine in a solvent such as dichloromethane at temperatures ranging from -20 ° C to 40 ° C. followed by reaction with a suitable alcohol, can provide the same objective. Esters VIII (R = OR 3, R 3 H, z = 1) can be transformed into the alkylated esters XVIII (R = OR 3, - R 3 = H; R 2 = H) by reaction with a suitable base such as LDA or sodium hexamethyldisilazide followed by reaction with a suitable alkylating agent in a solvent such as THF or DME at temperatures ranging from -78 ° C to 25 ° C. The saponification of the ester can then lead to the alkylated acids. The conditions for carrying out this transformation include an aqueous base in which one or more molar equivalents of the alkali metal hydroxide such as sodium hydroxide, in water, is used with a cosolvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0 ° C to 40 ° C. Alternatively, acidic conditions can also be used in which the carboxylic acid ester mentioned above XVIII (R = OR 3, - R 3 = H) is reacted with one or more molar equivalents of a mineral acid such as HCl or sulfuric acid in water with or without a cosolvent such as THF at temperatures ranging from room temperature up to 80"C. Esters VIII (R = OR3, R3 = H) or XVIII (R = OR3; R3 = H; R2 = H) can be converted to the primary amides VIII (R = NH2) or XVIII (R = NH2; R3 = H; R2 = H) by reacting the initial ester material with gaseous ammonia dissolved in a lower alcohol solvent such as methanol or ethanol at temperatures ranging from 0 ° C to 100 ° C. Alternatively, the carboxylic acids VIII (R = OH) or XVIII (R = OH; R2 = H) can be transformed into their carboxylic acid amide analogs VIII (R = NH2, NHOH, NHR3) or XVIII (R = NH2, NHOH, NHR3; R2 = H). This transformation can be carried out using standard methods to carry out the transformations of carboxylic acid to carboxylic acid amide. These methods include converting the acid to an activated acid and reacting with one or more molar equivalents of the desired amine. Amines in this category include ammonia in the form of ammonium hydroxide, hydroxylamine and 2-aminopropionitrile. Methods for activating the carboxylic acid include reacting the acid with one or more molar equivalents of oxalyl chloride or thionyl chloride to provide the carboxylic acid chloride in a suitable solvent such as dichloromethane, chloroform or diethyl ether. This reaction is often catalyzed by adding small amounts (0.01 to 0.1 molar equivalents) of dimethylformamide. Other methods for activating the carboxylic acid include reacting the acid with one or more molar equivalents of dicyclohexylcarbodiimide, with or without one or more molar equivalents of hydroxybenzotriazole in a suitable solvent such as dichloromethane or dimethylformamide at temperatures ranging from 0 ° C to 60 ° C. ° C. Alternatively, carboxylic acid amide analogs VIII (R = NH2) or XVIII (R = NH2) can be converted to their nitrile analogs XI (X = CN) by the use of reagents that dehydrate the primary carboxamide function to the nitrile function . A set of conditions for carrying out this transformation include reacting the primary carboxylic acid amide with one or more molar equivalents of trifluoroacetic anhydride and two or more molar equivalents of pyridine in a suitable solvent such as dioxane at temperatures varying from 60". C at 120 ° C. The amines of this invention used as reagents in the conversion to the products of this invention can be obtained commercially or can be synthesized by various methods.A carboxylic acid amide can be converted to an amine by reduction with diborane or lithium aluminum hydride in a solvent such as THF, DME or ether a temperatures that vary from -20 ° C to room temperature. A halide can be converted to an amine by reaction with the sodium salt of phthalimide in a solvent such as THF or DMF at temperatures ranging from -20 ° C to room temperature, followed by reaction with hydrazine hydrate in such a solvent as methanol at reflux. Alternatively, the conversion of the azide by reaction with an alkali metal azide such as sodium azide in a food such as DMF or THF at temperatures ranging from -20 ° C to room temperature followed by reaction with triphenylphosphine in aqueous THF Room temperature provides the amine. The compounds of this invention are useful for treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. Therefore, the compounds of this invention are particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful for modulating glucose levels in disorders such as type I diabetes. The ability of the compounds of this invention to treat or inhibit disorders related to insulin resistance or hypergliamymia was established with representative compounds of this invention in the following standard pharmacological test procedure which measures the inhibition of PTPase.
Inhibition of the dephosphorylation of the triphosphorylated insulin receptor dodecaphospeptide. by hPTPIB This standard pharmacological test procedure determines the inhibition of the activity of the recombinant human protein tyrosine phosphatase (PTP) IB. The substrate for the PTPase assay is a dodecaphospeptide corresponding to amino acids 1142-1153 of the receptor and insulin (IR) kinase domain that is synthesized to contain phosphotyrosine at residues 1146, 1150 and 1151. The procedure used and the results obtained they are discussed briefly in the following. Human recombinant PTP1B (hPTPIB) is prepared as described by Goldstein (see Goldstein et al., Mol, Cell, Biochem, 109, 107, 1992). The enzyme preparation used is stored in microtubes containing 4000-10000 μg / ml protein in 10 mM Tris-HCl, 0.2 mM EDTA, 25 mM NaCl, 50% glycerol and 3 mM DTT.
Measurement of PTPase activity. The malachite-molybdate ammonium green method was used for the nanomolar detection of phosphate released by recombinant PTP1B as described (Lanzetta et al Anal Biochem., 100, 95, 1979). The assay is adapted for use with a 96-well microtiter plate reader. The test procedure uses a dodecaphospeptide (TRDIpYETDpYpYRK) synthesized and adapted by AnaSpec, Inc. (San José, CA) corresponding to amino acids 1142-1153 of the β-subunit of the insulin receptor. Phosphotyrosine is incorporated in residues 1146, 1150 and 1151, as indicated. Recombinant hPTPIB is diluted at 1 μg / ml with buffer containing 10 mM Tris-HCl, pH 7.4, 10 mM β-mercaptoethanol and 30% glycerol, which provides an approximate activity of 10000-20000 nmoles of inorganic phosphate released / min / mg of protein. 166.5 μl of diluted enzyme is added to 621 μl of reaction buffer containing HEPES 81.83 M, pH 7.4, 1.1 mM β-mercaptoethanol and then pre-incubated for 5 min at 37 ° C with 2.5 μl of either the test compound or DMSO as a control The dephosphorylation reaction is initiated by adding a 39.5 μl aliquot of the preincubation mixture of recombinant hPTPIB: inhibitor in the appropriate wells of a 96-well microtiter plate containing 10.5 μl of pre-equilibrated IR triphosphopeptide substrate at 37 ° C. A final concentration of 50 mM HEPES, 8.46 mM β-mercaptoethanol and 50 μM IR triphospipeptide is obtained in the well. After 5 min at 37 ° C, the reaction is terminated by the addition of 200 μl of malachite-ammonium molybdate green reagent-Tween 20 reagent (MG / AM / Tw) The retention reagent consists of three parts of malachite green hydrochloride 0.45%, 1 part ammonium molybdate tetrahydrate 4.2% in 4 N HCl and 0.5% Tween 20. sample are prepared by the addition of 200 μl of MG / AM / Tw to wells containing 10.5 μl of triphosphopeptide IR substrate followed by the addition of 39.5 μl of recombinant enzyme pre-incubated either as DMSO or with drug. The color product is allowed to develop at room temperature for 25 min. The absorbance of the sample at 650 nm is determined using a 96-well microtiter plate reader (Bio-Tek). Samples and targets are prepared in quadruplicate.
Calculations: PTPase activities, expressed as nmoles of inorganic phosphate released / min / mg protein is quantified by extrapolation from a standard curve using known amounts of potassium phosphate. The inhibition of recombinant hPTPIB by test compounds as a control percentage (ie, the activity obtained in the presence of only DMSO) is calculated as percent phosphatase control. A nonlinear logistic regression of four parameters of PTPase activities using SAS version 6.08, PROC NLIN, is used to determine the IC 50 values of the test compounds. The following results were obtained. Other examples that are not included in the table below have PTPase inhibitory activity at concentrations less than 50 μM. ammonium olibdate 1.7 tetrahydrate (reference standard) Based on the results obtained in the standard pharmacological test procedure, it has been shown that the representative compounds of this invention inhibit the activity of PTPase and therefore are useful for treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity. or glucose intolerance. More particularly, the compounds of this invention are useful in the treatment of inhibition of type II diabetes and in the modulation of glucose levels in disorders such as type I diabetes.
As used herein, the term "modular" means maintaining glucose levels within clinically normal ranges.
The effective administration of these compounds can be administered at a daily dosage of about 1 mg / kg to about 250 mg / kg, and can be administered in a single dose or in two or more divided doses. Such doses may be administered in a manner useful for targeting the compounds active herein to the bloodstream of the recipient, including orally, by means of implants, parenterally (including injections). intravenous, intraperitoneal and subcutaneous), rectal, vaginal and transdermal. For the purposes of this disclosure, transdermal administrations are understood to include all administrations through body surfaces and interior coatings of body passages that include epithelial and mucosal tissues. Such administrations can be carried out using the present compounds or pharmaceutically acceptable salts thereof in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal). Oral formulations containing active compounds of this invention may comprise any of the conventionally used oral forms, including tablets, capsules, mouth forms, troches, lozenges and liquids, suspensions or oral solutions. The capsules may contain mixtures of the active compounds with inert fillers and / or diluents such as pharmaceutically acceptable starches (eg corn starch, potato or tapioca), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, jellies, gums, etc. Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and can use diluents, binding agents, lubricants, disintegrants, agents that improve the pharmaceutically acceptable suspension or stabilizers including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, cellulose my croccrist al, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium phosphate, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar . Oral formulations herein may use delayed-release or standard-time formulations to alter the absorption of the active compounds. Suppository formulations can be made from traditional materials including cocoa butter, with or without the addition of wax to alter the suppository melting point, and glycerin. Water-soluble suppository bases such as polyethylene glycols of various molecular weights can also be used. It is understood that the dosage, regimen and mode of administration of these compounds will vary according to the disease and the individual being treated and will be submitted to the judgment of the practicing physician involved. It is preferred that administration of one or more of the compounds herein begin at a low dose and increase until the desired effects are obtained.
The s igu e th e m o m e s of s c r ib e in the preparation of representative examples of this invention. 3-bromo-4-hydroxybenzoic acid ethyl ester This procedure is modified from the work of Oberhauser (J. Org. Chem. 1997, 62, 4504). To a solution of 4-hydroxybenzoic acid ethyl ester (57.8 g, 348 mmol) in 480 ml of dry acetonitrile is added HBF4 • Et20 (54% in Et20, 32.9 ml). The solution is cooled to -15 ° C with an ice / methanol bath. N-bromosuccinimide (67.2 g, 378 mmol) is added portionwise at a rate where the temperature does not increase above -10 ° C. After the addition is complete, the cooling bath is removed and the reaction mixture is allowed to stir overnight at room temperature. Work up by pouring the reaction mixture into aqueous sodium bisulfite (38%, 200 ml) and extract it four times with ethyl acetate. The organic layers are combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, decanted and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate / hexane gives the ethyl ester of 3-bromo-4-hydroxybenzoic acid (70.7 g, 83%) as a white solid. 3H-NMR (300 MHz, CDC13) 8 1.39 (t, J = 6.7 Hz, 3H, -C02CH2CH3), 4.34 (t, J = 6.7 Hz, 2H, -C02Ctf2CH3), 7.02 (d, 1H, aromatic), 7.91 (d, 1H, aromatic), 8.19 (d, 1H, aromatic). 3-Bromo-4-hydroxy-5-vedobenzoic acid ethyl ester To a mixture of the ethyl ester of 3-bromo-4-hydroxybenzoic acid (69.2 g, 282 mmol) in 423 ml of 2N aqueous potassium carbonate, sufficient THF is added to completely dissolve the phenol and produce a clear solution (~ 300 to 500 ml). The solution is cooled to 0 ° C and portions I2 (158 g, 621 mmol) are added in portions at such a rate that a large amount of solid I2 does not accumulate in the bottom of the flask. After the addition is complete, the ice bath is removed and the solution allowed to warm to room temperature. The reaction ends in 2 h. Worked by adding solid sodium bisulfite (slowly and with caution) at a rate that allows no excessive foaming to occur. Sodium bisulfite is added until it is completely discolored. The mixture is acidified with concentrated hydrochloric acid, extracted several times with ethyl acetate, the organic layers are combined, washed with brine, dried over anhydrous sodium sulfate, decanted and concentrated in vacuo to give the ethyl ester of the acid. 3-bromo-4-hydroxy-5-iodobenzoic acid (94.6 g, 90% as a light yellow solid.) NMR indicates that it is suitable for use in the next stage sifi additional purification. lH-NMR (300 MHz, CDC13) d 1.39 (t, J = 6.8 Hz, 3H, -C02CH2CH3), 4.32 (t, J = 6.8 Hz, 2H, -C02CH2CH3), 8.14 (d, 1H, aromatic), 8.32 (d, 1H, aromatic). ** Ethyl 3-bromo-4- (2-hydroxyethoxy) -5-iodobenzoic acid ethyl ester To a mixture of the ethyl ester of 3-bromo-4-hydroxy-5-iodobenzoic acid (94.6 g, 255 mmol) in 1 l of dry THF is added ethylene glycol (63.2 ml, 1.02 mol) and triphenylphosphine (87 g, 322 mol). ). The solution is cooled to 0 ° C and diisopropyl azodicarboxylate (60.2 ml, 306 mmol) is added dropwise with stirring. After the addition is complete, the ice bath is removed and the solution allowed to warm to room temperature. The reaction is complete after 3 h. Work by removing 1/2 of THF via concentration in vacuo, add water and extract with ethyl acetate several times, combine the organic layers, wash with saturated brine, dry over anhydrous Na2SO4, decant and concentrate. m vacuo to provide a viscous oil which solidifies upon standing.The main portion of the solid by-products is stirred by stirring with 50% ethyl acetate / hexane.The solid by-product is filtered off and the liquid is concentrated in vacuo to provide a solid which is further purified. Flash chromatography eluting with 5-15% ethyl acetate / hexane gives the ethyl ester of pure 3-bromo-4- (2-hydroxyethoxy) -5-iodobenzoic acid (65 g, 62%). 1 H-NMR (300 MHz, CDC13) d 1.37 (t, J = 6.5 Hz, 3H, -C02CH2CJ / 3), 3.95 (t, J = Hz, 2H, - C02CH2 CH3), 4.19 (t, J = 5 Hz , 2H, -C02CH2CH20H), 4.32 (t, J = 6.5 Hz, 2H, -C02CH2CH3), 8.18 (d, 1H, aromatic), 8.37 (d, 1H, aromatic).
Example 1 (3, 3"-Derloro-5 '-dodecylcarbamoyl- [1,1'; 3 ', 1") terfenyl-2'-yloxy) -acetic acid Stage 1 3,5-bis- (3-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester To a stirred solution of K2CO3 (17.2 g, 124 mmol) in 62 ml of H20 at room temperature is added 490 ml of dioxane, 3-bromo-4- (2-hydroxyethoxy) -5-iodobenzoic acid ethyl ester (17.2 g). , 41.4 mmoles), 3-chlorophenylboronic acid (7 .7 7 g, 4 9 .7 mmoles) and c omp lejo of [1, 1 'bis (diphenylphosphino) ferrocene] dichloropalladium (II), with CH2C12 (0.676 g, 0.828 mmoles). This mixture is stirred at temperature environment for 4 h, and seems to be developing, but is not done by CCD and CLAP. Another amount of 0.1 equivalent of 3-chloro-phenyl-boronic acid (0.647 g) is added and the reaction is stirred for an additional 24 h. During the next 4 days, 0.1 equivalent of boronic acid is added at one-day intervals, until the reaction has been carried out almost completely, determined by CLAP (60% bis-arylated, 25.4% monoarylated and _2.6% SM). The reaction is diluted with HCl (1187 mL, 0.17 M) and the resulting solution is extracted with EtOAc (1 x 300 mL and 3 x 200 mL). The combined organic layers are washed with 0.1 N HCl (2 x 90 ml), H20 (2 x 90 ml) and brine (2 x 90 ml) and then dried (Na2SO4). After concentration, the residue is first purified by flash chromatography (gradient from 0 to 50% EtOAc / hexane) and then by CLAP [CH2C12 60% (methyl t-butyl ether 6%): hexane 40%] to provide the bisarylated product. (6.16 g, 35%) as a viscous light yellow oil (for the mono-aryl product see step 1 of Example 2); 3 H NMR (400 MHz, DMSO-d 6) d 1.31 (t, J = 7 0 Hz, 3 H), 3.12 (c, J = 5.5 Hz, 2 H), 3.28 (t, J = 5.7 Hz, 2 H), 4. ^ 2 (dd, J = 7.0, 14.1 Hz, 2H), 4.45 (t, J = 5.5 Hz, 1H), 7.45-7.53 (m, 4H), 7.53-7.58 (m, 2H), 7.67-7.69 (m 2H); IR (film) 3440, 3090, 2990, 2930, 2860, 1720, 1610, 1570, 1475, 1425, 1390, 1360, 1340, 1310, 1245, 1160, 1120, 1100, 1090, 1065, 1025, 770, 710 and 500 cprj- mass spectrum [(+) APCI], m / z 431/433 (M + H) J 448/450 (M + NH4) *.
Stage 2 N-dodecyl-3,5-bis (3-chlorophenyl) -4- (2-hydroxyethoxy) benzamide A n-BuLi (1.12 ml, 2.5 M in hexane, 2.80 mmoles) is added to a round-bottomed flask, flame-dried, with dodecylamine (0.519 g, 280 mmol) and 8 ml of THF cooled to 0 ° C. during a period of 5 min. The resulting solution is stirred at this temperature for 40 min and then cooled to -45 ° C. To this solution is added dropwise a solution (at 0 ° C) of the 3,5-bis- (3-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester (0.302 g, 0.700 mmol) in ethyl acetate. ml of THF for 5 min. This final mixture is stirred and heated to room temperature for 30 min. At this point, the reaction mixture is suspended with 3 ml of H20 and diluted with 40 ml of EtOAc. The organic layer is dried by 1N HCl (3 x 7 ml), 7 ml of brine and H20: brine (1: 1, 14 ml) and then dried (Na2SO4). After concentration, the residue is purified by flash chromatography (gradient from 0 to 15% EtOAc / hexane) to give the product (0.286 g, 72%) as an oily white solid; 1 H NMR (400 MHz, DMSO-d 6) d 0.86 (t, J = 7.7 Hz, 3H), 1.20-1.37 (m, 18H), 1.46-1.57 (m, 2H), 3.13 (dd, J = 6.9, 11.5 Hz, 2H), 3.20-3.33 (m, 4H), 4.46 (t, J = 6.2 Hz, 1H), 7.43-7.57 (m, 4H), 7.59-7.63 (m, 2H), 7.68-7.73 (m, 2H), 7.89 (s, 2H), 8.67 (t, J = 6.2 Hz, 1H); mass spectrum [(+) APCI], m / z 570 (M + H) *.
Step 3 Acid (3,3"-aichloro-5 '-dodecylcarbamoyl- fl.i', -3 ', 1"! Terfenyl-2'-yloxy) -acetic To an agfatted solution of N-dodecyl-3, 5-bis (-chlorophenyl) -4- (2-hydroxy-ethoxy) -benzamide (0.277 g, 0.485 mmol) CH3CN: CH2C12 (5: 3, 8 ml) at room temperature At room temperature, N-methylmorpholine N-oxide (NMMO) (0.114 g, 0.970 mmol) is added followed by tetrapropylammonium perruthenate (TPAP) (0.017 g, 0.0485 mmol). After 2 h, the reaction mixture still shows the presence of intermediate aldehyde. Another 0.3 equivalents of NMMO (0.017 g) and 0.02 equivalents of TPAP (0.003 g) are added and the reaction is stirred for an additional 3 h. The mixture is suspended with 2 ml of H20, followed by 15 ml of 10% aqueous NaHS03. After stirring for 20 min, the mixture is diluted with 40 ml of EtOAc. The resulting organic layer is washed with 1 N HCl (3 x 7 ml) and brine (2 x 7 ml) and then dried (Na 2 SO 4). After concentration, the residue is purified by preparative plate chromatography (100% EtOAc) to give the product (0.081 g 29%) as a gray solid, m.p. 151-156 ° C; 3 H NMR (400 MHz, DMSO-d 6) d 0.83 (t, J = 6.8 Hz, 3 H), 1.15-1.32 (m, 18 H), 1.46-1.55 (m, 2 H), 3.25 (dd, J = 7.2, 13.2 Hz, 2H), 3.84 (s, 2H), 7.44-7.52 (m, 4H), 7.57 (t, J = 2.0 Hz, 1H), 7.58 (t, J = 1.8 Hz, 1H), 7.67-7.70 (m , 2H), 7.86 (s, 2H), 8.55 (t, J = 5.7 Hz, 1H), 12.54-12.86 (broad s, 1H); IR (KBr) 3360, 2930, 2850, 1725, 1620, 1565, 1465, 1385, 1345, 1245, 1200, 1150, 1075, 1065, 880, 800, 755 and 705 cirf - mass spectrum [(-) ESI], m / z f 582/584/586 (M-H) J; Analysis calculated for C33H39C12N04; C, 67. 80; H, 6.72; N, 2.40, Found: C, 67.63; H, 6.77; N, 2.34.
Example 2 Acid (3-bromo-3'-chloro-5-dodecyl carbamoyl-biphenyl-2-β-10-yloxy) acetic acid Stage 1 3-Bromo-5- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester The 3-bromo-5- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester is prepared as a white solid (5.01 g, 30%) from the ethyl ester of 3-bromo-4- (2-hydroxyethoxy) -5-iodobenzoic acid using the procedure of step 1 of Example 1 (product 2: monoarylation), m.p. 107.5-110.5 ° C; "H NMR (400 MHz, DMSO-d6) dl.33 (t, J = 7.0 Hz, 3H), 3.45 (c, J = 5.5 Hz, 2H), 3.61 (t, J = 5.5 Hz, 2H) , 4.33 (dd, J = 7.2, 14.3 Hz, 2H), 4.69 (t, J = 5.7 Hz, 1H), 7.50-7.56 (m, 3H), 7.64-7.66 (m, 1H), 7.88 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), - IR (KBr) 3240, 3090, 2980, 2930, 1720, 1600, 1570, 1465, 1445, 1380, 1365, 1355, 1305, 1265, 1240, 1180, - li mo, 1080, 1055, 1030, 890, 875, 810, 760 and 705 cm "1; mass spectrum [(+) APCI], m / z 399/401 (M + H) *, 416/418 ( M + NH4) *.
Stage 2 N-dodecyl-3-bromo-5- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzamide N-Dodecyl-3-bromo-5- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzamide is prepared as a colorless oil (0.110 g, 33%) from the 3-bromo-5- ethyl ester (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic using a procedure similar to step 2 of Example 1; * H NMR (400 MHz, DMSO-d6) d 0.86 (t, J = 7.7 Hz, 3H), 1.17-1.36 (m, 18H), 1.46-1.57 (m, 2H), 3.20-3.30 (m, 2H) , 3.46 (dd, J = 5.4, 11.5 Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 4.69 (t, J = 6.2 Hz, 1H), 7.48-7.60 (m, 3H), 7.65- 7.71 (m, 1H), 7.87 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 8.58 (t, J = 6.2 Hz, 1H); mass spectrum [(-) ESI], m / z 536 (M-H) "; 596/598/600 (M + OAc-H)".
Stage 3 Acid (3-bromo-3'-chloro-5-dodecylcarbamoyl-biphenyl-2-yloxy) acetic acid The title compound is prepared as a gray solid (0.051 g, 43%) from N-dodecyl-3-bromo-5- (m-chlorophenyl) -4 - (2-hydroxyethoxy) benzamide using a procedure similar to that of Stage 3 of Example 1, pf > 100 ° C (decomposition); * H NMR (400 MHz, DMSO-d6) d 0.83 (t, J = 6.8 Hz, 3H), 1.18-1.31 (m, 18H), 1.49 (t, J = 6.8 Hz, 2H), 3.23 (dd, J = 6.8, 13.0 Hz, 2H), 3.77 (s, 2H), 7.41-7.47 (m, 2H), 7.57-7.60 (m, 1H), 7.66-7.68 (m, 1H), 7.79 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 8.53 (t, J = 5.3 Hz, 1H); IR (KBr) 3290, 3090, 2930, 2850, 1630, 1555, 1465, 1430, 1325, 1225, 1190, 1110, 1075, 1020, 920, 885, 840, 800, 770, 710, 690 and 600 cm "1 , - mass spectrum [(+) ESI], m / z 552/554/556 (M + H) J-Analysis calculated for C27 H3sBrClN04 1.33 H20: C, 56.21; H, 6.58; N, 2.43, Found: C, 56.01; H, 5.96; N, 2.39.
Example 3 Acid [3,3"-dichloro-5 '- (8-phenyl-octylcarbamoyl) - [1,1'; 3 ', 1"] terphenyl-2'-yloxy] -acetic Step 1 N- (8-phenyl-octyl) -3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) -benzamide To a round-bottom flask, dried to the flame with 8-phenyloctylamine (0.484 ml, 2.43 mmol) and 5 ml of THF cooled to 0 ° C were added n-BuLi (-0.972 ml, 2.5 M in hexane, 2.43 mmoles) dropwise, over a period of 5 min. The resulting solution is allowed to stir for 5 min and then is warmed to room temperature for 30 min. This The solution is then added dropwise to a solution of the 3,5-bis- (m-c 1-orophen-1) -4- (2-hydroxyethoxy) benzoic acid ethyl ester (0.300 g, 0.696 mmoles) in 15 ml of THF a -20 ° C. This final mixture is stirred at -20 ° C for 15 min and then heated at room temperature for 15 min. At this point, the reaction mixture is suspended with 10 ml of H20 and diluted with 200 ml of EtOAc. The organic layer is washed with 20 ml of 1 N HCl, 2 J ml of saturated aqueous NaHCO 3 and 20 ml of brine, and then dried (MgSO 4). After concentration, the residue is purified by Biotage Flash 40 (gradient from 20 to 40% EtOAc / petroleum ether) to provide the product (0.267 g, 65%) as a clear oil; 1 H-NMR (400 MH, CDC13) d 1.09-1.48 (m, 9H), 1.48-1.72 (m, 4H), 2.58 (t, J = 6.8 Hz, 2H), 3.30-3.35 (m, 2H), 3.35 -3.41 (m, 2H), 3.46 (dd, J = 6.8, 13.0 Hz, 2H), 6 07-6.18 (m, 1H), 7.11-7.19 (m, 3H), 7.21-7.31 (m, 2H), 7.35-7.44 (m, 4H), 7.44-7.57 (m, 2H), 7.63 (s, 2H), 7.77 (s, 2H), - mass spectrum [(+) ESI], m / z 590 (M + H) *.
Step 2: Acid [3.3"-dichloro-5 '- (8-phenyl-octylcarbamoyl) -l, l', -3 ', 1'] terphenyl-2'-yloxy-1-acetic acid The title compound is prepared as an off-white solid (0.151 g, 57%) from N- (8-phenyl-octyl) -3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzamide using a procedure similar to that of step 3 of Example 1, mp 165- 167 ° C; ? NMR (400 MHz, DMST-d6) d 1.20-1.32 (m, 8H), 1.46-1.57 (m, 4H), 2.51 (dd, J = 7.7, 15.6 Hz, 2H), 3.25 (dd, J = 6.8, 13.2 Hz, 2H), 3.83 (s, 2H), 7.10-7.17 (m, 3H), 7.21-7.26 (m, 2H), 7.44-7.51 (m, 4H), 7.56-7.59 (m, 2H), 7.67 -7.69 (m, 2H), 7.86 (s, 2H), 8.56 (t, J = 5.5 Hz, 1H), 12.45-12.94 (broad s, 1H); IR (KBr) 3320, 3090, 3030, 2920, 2830, 2520, 1730, 1610, 1565, 1475, 1455, 1390, 1340, 1310, 1245, 1200, 1075, 1055, 875, 800, 780, 755 and 700 cm "J- mass spectrum [(+) ESI], m / z 604 (M + H) *; Analysis calculated for C35H35C12N04 • 0.5 H20: C, 68.51; H, 5.91; N, 2.28, Found: C, 68.36; H, 5.83; N, 2.32.
Example 4 Acid (5-octadecyloxy- [1,1 '; 3', 1"] terphenyl-2'-yloxy) -acetic Stage 1 (5'-Octadedecyloxy-n.1 '. -3', 1"1-tert-butyl-2'-yloxy) acetic acid methyl ester To a stirred 5'-oct solution, adecyloxy - [1,1 J-3 ', 1"] terphenyl-2'-ol (0.250 g, 0.486 mmol, Akzo Chemie, Netherlands, Stabilizer A-2751) and K2C03 (0.0739 g, 0.535 mmol) in 9 ml of DMF and 4 ml of THF at room temperature methyl bromoacetate (0.0922 ml, 0.972 mmol) was added dropwise After 7 days at this temperature, it was diluted with 50 ml of H20, followed by 400 ml of excess EtOAc. The organic layer is washed with 50 ml of 1 N HCl, 50 ml of saturated aqueous NaHCO 3 and 50 ml of brine and then dried (MgSO 4). After concentration, the residue is purified by flash chromatography (gradient from 0 to 15% EtOAc / petroleum ether) to provide the product (0.225 g, 79%) as a white solid), m.p. 66-69 ° C; 1 H NMR (DMSO-d 6) d 0.84 (t, J = 7.0 Hz, 3 H), 1.17-134 (m, 28 H), 1.34-1.43 (m, 2 H), 1.65-1.74 (m, 2 H), 3.36 (s) , 3H), 3.75 (s, 2H), 4.01 (t, J = 6.2 Hz, 2H), 6.86 (s, 2H), 7.33-7.45 (m, 6H), 7.56 (d, J = 7.2 Hz, 4H); IR (KBr) 3420, 3050, 2920, 2860, 1770, 1600, 1575, 1465, 1420, 1365, 1235, 1210, 1200, 1095, 1060, 755 and 710 cm "1; mass spectrum [(+) BAR] , m / z 587 (M + H) *, 609 (M + Na) *; Analysis calculated for C35H54N04; C, 79.82; H, 9.27; N, 0.00, Found: C, 79.47; H, 9.21; N, - 0.01.
Step 2 Acid (5 '-octadecyloxy-fl.1', - 3 ', 1"1-terphenyl-2'-yloxy) -acetic To a stirred solution of the acid methyl ester (5'-Octadecyloxy- [1, 1 ', -3', l "] terphenyl-2'-yloxy-acetic acid (0.182 g, 0.310 mmol) in THF: MeOH (3: 2, 10 mL) at room temperature is added drop 1N KOH (1.55 ml, 1.55 mmole) After 2 h at this temperature, concentrate and dilute with H20, then the solution is acidified to pH 1 with 2 N HCl.
The resulting solid is filtered off, washed with H20 and dried under high vacuum for 18 h to give the product (0.166 g, 93%) as a white solid, m.p. 90.5-92 ° C; 1 H NMR (DMSO-d 6) d 0.83 (t, J = 6.8 Hz, 3 H), 1.16-1.35 (m, 28 H), 1.35-1.44 (m, 2 H), 1.65-1.74 (m, 2 H), 3.63 (s) , 2H), 4.01 (t, J = 6.4 Hz, 2H), 6.86 (s, 2H), 7.32-7.44 (m, 6H), 7.58 (dd, J = 1.5, 8.3 Hz, 4H), 12.20-12.75 ( s broad, 1H); IR (KBr) 3430, 3070, 2920, 2840, 1725, 1600, 1575, 1465, 1410, 1360, 1265, 1220, 1200, 1090, 750 and 695 cm "J- mass spectrum [El], m / z 572 (M) *, - Analysis calculated for C3aHs2N04; C, 79.68; H, 9.15; N, 0.00, Found: C, 79.25; H, 99; N, 0.09.
Example 5 Acid (5 '-dodecylcarbamoyl-3, 3"-bi s-trif luorome il - (1,1'; 3 ', 1"] terphenyl-2'-? Loxi) -acetic Stage 1 3,5-bis- (m-trifluoromethyl phenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester To a stirred solution of K2C03 (2 M in H20) (1.9 ml, 3. 6 microwells) at room temperature add 14.3 ml of dioxane, 3-bromo-4- (2-hydroxyethoxy) -5-iodobenzoic acid ethyl ester (0.503 g, 1.21 mmol) and 3-trif luoromethyl-phenyl-boronic acid ( 0.299 g, 1.57 mmol). The reaction mixture purge with N2 for a few minutes and then add d or l or d [l, l '- b i s (diphenylphosphino) ferrocene] dichloropalladium (II), with CH2C12 (0.030, 0.036 mmol). The reaction is stirred at room temperature for 1.5 h and then heated to reflux for 2 h. After cooling to room temperature, it is poured into a 0.1 N HCl solution and extracted with EtOAc. The combined organic layers are washed with brine and dried over MgSO4. After concentration in vacuo, the residue is purified first by flash chromatography (25% EtOAc: hexane) and then by CLAP [60% CH2C12 (MTBE 6%): 40% hexane to provide the 3,5-bis acid ethyl ester - (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzoic acid (0.215 g, 36%) as a white solid "H-NMR (CDC13) d 8.09 (s, 2H), - 7.94 (m, 2H); -7.80 (m, 2H), 7.7-17.58 (m, 4H), 4.42 (c, 2H) 3.63 (m, 4H), - 1.42 (t, 3H) and 3-bromo-5- ethyl ester (m) -trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzoic acid (0.173 g, 33%) as a white solid 'H-NMR (CDC13) d 8.29 (d, 1H), 7.86 (m, 1H), 7.80-7.55 (m , 3H), 4.40 (c, 2H), 3.74-3.60 (m, 4H) 1.92 (t, 1H), 1.40 (t, 3H).
Step 2 N-dodecyl-3,5-bis (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide To a flame-dried flask containing dodecylamine (0.278 g, 1.5 mmol) in 5 ml of THF cooled to -78 ° C is added n-BuLi (titrated to 2.37 M in hexanes) (0.670 ml, 1.59 mmol) dropwise . The solution is stirred at -78 ° C for 20 min and then warmed to room temperature for 20 min. The reaction is then re-cooled to -40 ° C and the 3,5-bis- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester (0.215 g, 0.43 mmol) in 5 ml is added. of THF. This mixture is allowed to warm to room temperature for 20 min. The reaction mixture is then poured into a 0.1 N HCl solution and extracted with EtOAc. The combined organic layers are washed with a 2N HCl solution (3x), dried over MgSO4 and concentrated m vacuo. The residue is purified by flash chromatography (30% EtOAc: hexane) to give N-dodecyl-3,5-bis (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzamide (0.254 g, 93%), as a solid White. '? -NRM (CDC13) d 7.90 (m, 2H); 7.82-7.76 (m, 4H); 7.65-7.56 (m, 4H); 6.22 (broad t, -1H) 3.45 (dd, 2H); 3.30 (, 4H); 1.60 (m, 2H); 1.25 (m, 18H); 0.84 (m, 3H).
Step 3 Acid (5 '-dodecylcarbamoyl -3.3"-bis-trifluoromethyl-fl.l'.-3 '.1"! Terphenyl-2'-yloxy) -acetic To a solution of N-dodecyl-3, 5-bis (m-5-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzamide (0.254 g, 0.40 mmol) in CH3CN is added NMO (0.145 g, 0.89 mmole) and TPAP (0.014 g, 0.04 mmol). The reaction is stirred at room temperature for _. night. NMO (0.045 g, 0.38 mmol and TPAP (0.013 g, 0.04 mmol) are required, as indicated by CCD After stirring for 48 h, a 10% NaHS03 solution is added and the resulting biphasic mixture is vigorously stirred for 30 minutes, add 2 ml of concentrated HCl and continue stirring for 10 min.The layers are separated and the aqueous layer is extracted with EtOAc. combined organics are washed with brine, dried over Na2SO4 and concentrate in vacuo. The residue is purified by flash chromatography (30% EtOAc: hexane + 1% formic acid) followed by preparative plate chromatography (EtOAc). %: hexane + 1% formic acid) to provide the compound of the title (0.089 g, 34%) as a white solid, m.p. 154.3- 158.2 ° C; X H NMR (DMS0-d 6) d 8.55 (t, 1H); 7.98-7.88 (m, 6H), 7.78-7.67 (m, 4H); 3.57 (s, 2H); 3.25 (m, 2H); 1.50 (m, 2H); 1.23 (m, 18H); 0.82 (t, 3H); IR (KBr) 3275, 2900, 1725, 1600, 1575, 1460, 1325, 1190, 1125, 1075, 775, 725, 700, 625 cm "J- 25 mass spectrum [(-) ESI], m / z 650 (MH) ", - Calculated analysis for C3SH39F6N04; H, 6.03; N, 2.15, Found: C, 62.50; H, 5.99; N, 2.01.
Example 6 Acid (3-bromo-5-dodecylcarbap? Oil-3 '-trif luoromethyl-bifenyl-2-yloxy) -acetic acid Stage 1 N-dodecyl-3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide N-Dodecyl-3-bromo-5- (m-trifluoromethyl-phenyl) -4- (2-hydroxyethoxy) -benzamide is prepared as a white solid (0.116 g, 51%) from the ethyl ether of 3-bromo acid. -5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzoic using a procedure similar to that of Step 2 of Example 1.-NMR (CDC13) d 7.98 (d, 1H); 7.85-7.54 (m, 5H); 6.25 (m, 1H); 3.70-3.58 (m, 4H); 3.48-3.36 (dd, 2H); 1.60 (m, 2H); 1.24 (m, 18H), 0.86 (m, 3H).
Stage 2 Acid (3-bromo-5-dodecylcarbamoyl-3 '-trifluoromethyl-biphenyl-2-yloxy) -acetic acid The title compound is prepared as a white foam (0.058 g, 50%) from N-dodecyl-3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzamide using a procedure similar to step 3 of Example 1. JH NMR (DMSO-d6) 6 13.75 (broad s, 1H); 8.57 (t, 1H); 8.12 (d, 1H), 7.92-7.68 (m, 5H); 4.15 (s, 2H); 3.24 (dd, 2H); 1.49 (m, 2H); 1.26 (m, 18H); 0.83 (m, 3H); IR (KBr) 3350, 2910, 2830, 1740, 1650, 1550, 1460, 1440, 1340, 1175, 1140, 1050, 900, 800, 760, 700, 675 cm "J- mass spectrum [(+) ESI] , m / z 584/586 (MH) J-Analysis calculated for C2eH35BrF3N04: C, 57.34; H, 6.02; N, 2.39, Found: C, 59.34; H, 6.64; N, 2.16.
Example 7 Acid (5 '- (8-f-enyl-octylcarbamoyl-3, 3"-bis-trif-loromethyl- (1,1'; 3 ', 1"] erf enyl-2'-yloxy) -acetic Step 1 N- (8-phenyloctyl) -3,5-bis (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide N- (8-f e n 11 - or c t i 1) - 3, 5-b i s (m -trif luoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide is prepared as a white solid (0.331 g, 74%) from the 3,5-bis- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester and f-enyloctylamine using a procedure similar to step 2 of Example 1. "? -NRM (CDC13) d 7.96-7.50 (m, 10H); 7.35-7.10 (m, 5H); 6.28 (m, 1H); 3.45 (m, 2H), -3.31 (m, 4H), -2.60 (m, 2H), - 1.60 (m, 4H), 1.33 (m, 8H).
Step 2 Acid (5'- (8-phenyl-octylcarbamoyl-3,3"-bis-trifluoromethyl- (1, 1 ', -3', 1" 1-terphenyl-2'-yloxy) acetic The title compound is prepared as a white solid (0.058 g, 50%) from N- (8-phenyloctyl) -3,5-bis- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzamide using a procedure similar to step 3 of Example 1. pf 143-145 ° C H NMR (DMS0-d6) d 12.70 (broad s, 1H); 8.56 (t, 1H); 7.97-7.91 (m, 2H); 7.78-7.69 (m, 4H); 7.25-7.21 (m, 2H); 7.15-7.10 (m, 3H); 3.78 (s, 2H); 3.26 (m, 2H); 2.49 (m, 2H); 1.50 (m, 4H); 1.27 (m, 8H) IR (KBr) 3370, 2920, 2880, 1725, 1625, 1560, 1475, 1340, 1225, 1175, 1125, 1075, 900, 810, 700, 660, 620 cm "J- mass spectrum [(+) ESI], m / z 670 (MH) "; Analysis calculated for C 37 H 35 F 6 N 0 4: C, 66.16; H, 5.25; N, 2.08, Found: C, 65.58; H, 5.37; N, 2.05.
Example 8 Acid (5 '-dodecylcarbamoyl- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) - • acetic acid 5 Stage 1 methyl ester of 3, 5-d i and odo-hydroxybenzoic acid To a stirred solution in 3,5-diiodo-4-hydroxybenzoic acid (10.00 g, 25.65 mmol) in 250 ml of dry methanol is added TiCl, (1.41 ml, 12.82 mmol) in a batch. The reaction is stirred under reflux for 6 h and then stirred at room temperature for 24 h. The mixture is reduced by concentration and the residue is taken up in diethyl ether and filtered through a plug of silica gel. The filtrate is reduced by concentration and the residue is recrystallized from hot methanol to provide 7.84 g (76%) of the ester as white crystalline needles. "H NMR (DMSO-ds) d 10.41 (broad s, 1H), 8.22 (s, 2H), 3.79 (s, 3H).
Stage 2 3, 5-bis-f-4-hydroxybenzoic acid methyl ester To a stirred solution of phenylboronic acid (4.95 g, 40.57 mmoles), Ba (0H2) -H20 (10.48 g, 55.33 mmoles) and Pd (0Ac) 2 (0.414 g, 1.84 mmol) in DME / H20 (110 ml / 20 ml) is added 3,5-diiodo-4-hydroxybenzoic acid methyl ester (7.45 g, 18.44 mmoles). The mixture is stirred at 85 ° C for 3 h and then cooled and concentrated. The residue is partitioned between ethyl acetate / 2N HCl. The organic phase is dried (MgSO4) and concentrated to give a solid which is triturated with diethyl ether / petroleum ether to provide 3.51 g. (62.5%) of product as a white solid. SH NMR (DM? O-ds) d 9. 27 (s, 1H), 7.27 (s, 2H), 7.25-7.40 (m, 10H), 3.81 (s, 3H).
Stage 3 (5'-carbomethoxy-fl, 1 ', 3', 1"1-tert-2-yl) -acetic acid tert-butyl ester To the phenol from step 2 (3.50 g, 11.5 mmol) in 40 ml of acetonitrile is added tertbutyl bromoacetate (3.39 ml, 23 mmol) and K2C03 (1.93 g, 12.65 mmol). The mixture is heated for 2 h at 70 ° C and then cooled to room temperature and concentrated. The residue is partitioned between ethyl acetate / H20. The organic phase is dried (MgSO4) and concentrated to provide the crude product. The compound is purified at Pass it through a short filter column (Si02) using hexane as the eluent. The concentration gives 4.63 g (96%) of the product as a clear oil. * H NMR (DMSO-d6) d 7.86 (s, 2H), 7.60.7.40 (m, 10H), 3.85 (2s, 5H), 1.19 (s, 9H).
Step 4 (5 '-carboxy [1,1: 3'. 1"I!: Erphenyl-2'-yloxy) acetic acid terbutyl ester To a stirring solution of the previous ester (5.95 g, 14.22 mmol) in 100 mL of THF is added aqueous 1.0 N LiOH (15.6 mL, 15.6 mmol). The mixture is stirred overnight at room temperature and then concentrated m vacuo. The resulting residue is partitioned between 0.1 N HCl / diethyl ether. The organic phase is dried (MgSO4) and concentrated to provide the crude product. Purification by CLAP (1: 5 hexanes / ethyl acetate) provides 2.31 g (40%, 59% based on the initial recovered material) of product. XH NMR (DMS0-d6) d 13.02 (broad s, 1H), 7.85 (s, 2 H), 7.60-7.40 (m, 10H), 3.84 (s, 2H;, x.20 (s, 9H).
Step 5 (5 '-dodecylcarbamoyl-fl.1', -3 ', 1"1-ter-2-yl) -acetic acid terbutyl ester To a stirred solution of the above acid (0.50 g, 1236 mmol) and 1-hydroxybenzotriazole hydrate (0.2 g, 1483 mmol) in 8 ml of DMF is added l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.28 g). 1,483 mmoles). After stirring for 2 h at room temperature, dodecylamine (0.412 g, 2225 mmoles) and triethylamine (0.206 ml, 1483 mmoles) are added and the mixture is stirred overnight at room temperature. The mixture is diluted with brine and extracted with diethyl ether. The organic phase is dried (MgSO 4) and concentrated to provide 0.65 g (92%) of the product as an oil. * H NMR (DMS0-d6) d 7.75 (s, 2H), 7.8-7.25 (m, 10H), 6.40 (t, 1H), 3.75 (s, 2H), 2.42 (m, 2H), 1.61 (m, 2H), 1.25 (m, 27H), 0.82 (broad t, 3H).
Step 6: Acid (5 '-dodecylcarbamoyl-1, 1'-3, 1"1-terphenyl-2'-yloxy) -acetic The above terbutyl ester (0.65 g, 1137 mmol) is dissolved in H20 / acetonitrile (1.7 ml / 3.3 ml) and treated with trifluoroacetic acid (0.44 ml, 5.63 mmol). The mixture is heated overnight. The reaction is cooled and concentrated. The residue is divided between brine and acetate ethyl. The organic phase is dried (MgSO4) and concentrated to provide the crude acid. Trituration with diethyl ether / hexanes gives 0.47 g (80%) of the product as a white solid: m.p. 150-153 ° C; JH NMR (DMSO-d6) d 12.57 (broad s, 1H); 8.55 (t, 1H); 7.84 (s, 2H), 7.62 (m, 4H), 7.50-7.35 (m, 6H), 3.84 (s, 2H), 3.26 (c, 2H), 1.51 (m, 2H), 1.22 (m, 18H) 0.84 (t, 3H); IR (KBr) 3350, 2920, 2880, 1730, 1650, 1570, 1200, 700 cm "1; mass spectrum [El], m / z 515 (M) J-Analysis calculated for C33H41N04 • 1.0 H20: C, 74.27; H, 8.12; N, 2.62, Found: C, 74.43; H, 8.04; N, 2.82.
Example 9 Acid (5 '-dodecylcarbamoyl-4, "-dimethoxy- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) -acetic acid Stage 1 3,5-bis- (4-methoxyphenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester To a solution of 108 ml of K2C03 2 N are added 875 ml of dioxane, 3-bromo-4- (2-hydroxyethoxy) -5-iodobenzoic acid ethyl ester (25.34 g, 61.05 mmoles), 4-methoxyphenylboronic acid (12.43 g, 79.37 min) and complex of [1, 1 '-bis (diphenylphosphino) ferrocene] dichloropalladium (II), with CH2C12 (1.49 g, 1.83 mmol). After stirring at room temperature At room temperature for 1 h, the mixture is heated at 60 ° C for 2.5 h. The progress of the reaction is monitored by CCD. Additional amounts of catalyst and 0.5 g of boronic acid are added to drive the reaction to completion. The reaction is cooled and partitioned between ethyl acetate / 0.5 N HCl. The organic phase is washed with 0.5 N HCl and then with brine. It is then dried (MgSO4), decolorized (activated carbon) and concentrated to provide a residue which is filtered through a pad of Si02. Purification by CLAP (ethyl acetate / hexane) gives 11.47 g (47.5%) of the monoarylated product as a white solid [1K NMR (DM? O-d6) d 8.08 (d, 1H), 7.82 (d, 1H), 7.50 (d, 2H), 7.02 (d, 2H), 4.65 (t, 1H), 4.30 (C, 2H), 3.81 (s, 3H), 3.59-3.42 (m, 4H), 1.29 (t, 3H) ] and 6.61 g (25.6%) of the bisarylated product as a brown oil: * H NMR (DMSO-d6) d 7.82 (s, 2H), 7.52 (d, 4H), 7.00 (d, 4H), 4.30 (c, 2H), 3.80 (s, 6H), 3.25 (m, 2H), 3.12 (m, 2H), 1.31 (t, 3H).
Stage 2 5'-Dodecylcarbamoyl-4-4"-dimethoxy-1, 1'-3 '. 1"] terphenyl-2'-yloxy) -acetic acid To an agitated solution of the previous alcohol (0.553 g, 1.31 mmol) in 10 ml of acetone at 0 ° C is added dropwise to Jones reagent (1.04 ml, - 6.7 g of Cr03 / 6 ml of H2SO4 / 13 ml of H2O = 3.27 mmole). The mixture is heated to Room temperature and stirred for 1 h. The reaction is warmed to room temperature and stirred for 1 h. The reaction is suspended by the addition of i-propanol and then divided between ethyl acetate / brine. The organic phase is concentrated and the crude acid is purified by preparative CCD. Yield: 0.314 g (55%) as a white solid. The compound (0.314 g, 0.718 mmol) and dissolved in 8 ml of THF. In a separate flask, n-BuLi (1.01 ml, 2.5 N in hexane, 2.51 mmol) is added dropwise to a stirring solution of dodecylamine (0.466 g, 2.51 mmol) in 8 ml of THF at -40 ° C under N2 . After 15 min, the THF solution of the above ester is added dropwise to a stirred Li salt of dodecylamine. After the addition is complete, the reaction is allowed to stir at room temperature for 15 min and then is suspended by the addition of 20 ml of 1.0 N HCl. The mixture is extracted with ethyl acetate and the organic phase is dried (MgSO4). and concentrates. The product is purified by preparative CCD (10% CH3OH / CH2C12) to provide 0.262 g (63%) of the amide as a white foam: m.p. 65-68 ° C, 'H NMR (DMSO-d6) d 8.51 (t, 1H), 7.76 (s, 2H), 7.55 (d, 4H), 7.00 (d, 4h), 3.81 (s, 6H), 3.75 (s, 2H), 3.23 (m, 2H), 1.51 (m, 2H), 1.22 (m, 18H), 0.85 (t, 3H); IR (KBr) 3350, 2920, 2850, 1510, 1250 cm "J- mass spectrum [(+) APCI], M / Z 576 (M + H) *, - Analysis calculated for C35H45NO6-0.3H2O; C, 72.34; H, 7.91; N, 2.41, Found: C, 72.32; H, 7.94; N, 2.63.
Example 10 Acid (3-chloro-5'-dodecylcarbamoyl- "-methoxy- [1, 1 '; 3'] terphenyl-2'-yloxy) -acetic acid Step 1 N-dodecyl-3- (3-chlorofenyl) -5- (4-methoxy-enyl) -4- (2-hydroxyethoxy) -benzamide In a manner similar to Example 1, Step 2, the title compound is produced, 0.45 g (80%) from the 2- (3-chlorophenyl) -5- (4-methoxy-enyl) -4- ethyl ester. (2-hydroxyethoxy) -benzoic acid (0.422 g, 0.989 mmol) and dodecylamine (0.642 g, 3.46 mmol is). "H-NMR (CDC13) d 7.75 (d, 1H), 7.70 (d, 1H), 7/63 (s, 1H), 7.55 (m, 3H), 7.40 (m, 2H), 7.00 (d, 2H) ), 6.15 (t, 1H), 3.85 (s, 3H), 3.5-3.30 (m, 6H), 1.60 (m, 2H), 1.30 (m, 18H), 0.85 (t, 3H).
Step 2 Acid (3-chloro-5'-dodecylcarbamoyl -4"-methoxy-fl, 1 '; 3' .1" 1 -terphenyl-2'-yloxy) -acetic In a manner similar to Example 1, Step 3, the title compound was made 0.100 g (22%) by oxidation of the above compound: m.p. 114-1170C; l NMR (DMS0-d6) d 12.65 (broad s, 1H), 8.53 (t, 1H), 7.80 (dd, 2H), 7.67 (s, 1H), 7.53 (m, 3H), 7.45 (m, 2H) , 7.03 (d, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 3.25 (m, 2H), 1.50 (m, 2H), 1.21 (m, 18H), 0.83 (t, 3H); IR (KBr) 3330, 2920, 2860, 1730, 1620, 1550, 1250, 1200 cm "J-mass spectrum [-ESI], M / Z 578 (MH) J- Analysis calculated for C34H42C1N05; C, 70.39; H 7.30; N, 2.41, Found: C, 70.29; H, 2.63; N, 2.47.
Example 11 Acid (5 '-dodecylcarbamoyl-3, 3"-dimethoxy- [1,1'; 3 '1"] terphenyl-2'-yloxy-acetic acid Step 1 (N-dodecyl-3, 5-bis- (3-methoxyphenyl) -4- (2-hydroxyethoxy) benzamide In a manner similar to Example 1, Step 2, the title compound (0.386 g, 65%) is prepared from the ethyl ester of the acid (0.44 g, 1.04 mmol) and dodecylamine (0.676 g, 3.65 mmol), "H -NRM (CDC13) d 7.75 (s, 2H), 7.38 (m, 2H), 7.19 (m, 4H), 6.94 (m, 2H), 6.21 (t, 1H), 3.85 (s, 6H), 3.41 ( m, 4H), 3.28 [mu] m, 2H), 1.60 (m, 2H), 1.23 (m, 18 H), 0.85 (t, 3H).
Step 2 Acid (5 '-dodecylbamoyl-3.3"-dimethoxy fl, 1'. 3 ', 1" 1-terphenyl-2'-yloxy) -acetic In a manner similar to Example 1, Step 3, the title compound, 0.108 g, (27%) is prepared by oxidation of the above compound: m.p. 57-58 ° C; "H NMR (DMSO-d6) d 12.60 (broad s, 1H), 8.53 (t, 1H), 7.82 (s, 2H), 7.39 (m, 2H), 7.16 (m, 4H), 6.95 (m, 2H) ), 3.80 (sym, 5h), 3.24 (m, 2H), 1.50 (m, 2H), 1.21 (m, 18H), 0.31 (t, 3H), IR (KBr) 3310, 2920, 2830 1750, 1200 cm "J-mass spectrum [-ESI], M / Z 574 (MH)"; Analysis calculated for C35H4SN06; C, 73.02; H, 7.88; N, 2.43, Found: C, 73.24; H, 8.14; N, 2.36 .
Example 12 Acid [2- (3,3"-dichloro-5 '-dodecylbamoyl- [1, 1'; 3 ', 1"] terphenyl-2'-yloxy-ethoxy] acetic acid Stage 1 F 2 - (3, 3"-dichloro-5'-dodecylbamoyl-3'-3 ', l" lterphenyl-2'-yloxy-ethoxyl-acetic acid methyl ester To a stirred solution of N-dodecyl-3,5-bis (3-chlorofenyl) -4- (2-hydroxy-ethoxy) benzamide (Example 1, Step 2), (0.866 g, 1.52 mmol) in 8 ml of THF is added NaH (0.10 g, 80%, 3.34 mmoles). The mixture is stirred at 60 ° C for 50 min and then cooled to room temperature. Methyl bromoacetate (0.158 ml, 2.67 mmol) is added and the mixture is stirred at 60 ° C overnight. The reaction is cooled, suspended with 1.0 N HCl and extracted with ethyl acetate. The organic phase is dried (MgSO 4) and concentrated. The crude product is purified by CLAP. Yield: 0.177 g (18%) of the product as an oil. '? -NRM (CDC12) d 7.72 (s, 2H), 7.63 (s, 2H), 7.50 (m, 2H), 7.39 (m, 4H), 6.20 (t, 1H), 3.78 (m, 5H), 3.49 (m, 4H), 3.31 (m, 2H), 1.68 (m, 2H), 1.30 (m, 18H), 0.88 (t, 3H).
Step 2 Acid [2- (3,3"-dichloro-5 '-dodecylbamoyl - [1,1', -3 '1" 1-terphenyl-2'-yloxy-ethoxyl-acetic The above ester is dissolved (0.177 g, 0.275 mmole) in THF / MeOH (1 ml / ml). To this is added aqueous NaOH (0.55 ml, 1.0 N, 0.55 mmol). After stirring for 2 h, the reaction is suspended by the addition of 1 N HCl and then extracted with ethyl acetate. The organic phase is dried (MgSO 4) and concentrated. Trituration with hexane / diethyl ether gives 0.133 g (71%) of the product as a light yellow oil:! H NMR (DMSO-D d 12.44 (broad s, 1H), 8.53 (t, 1H), 7.87 (s, 2H ) 7.69 (s, 2H), 7.60 (m, 2H), 7.49 (m, 4H), 3.63 (s, 2H), 3.40-3.20 (m, 6H), 1.51 (m, 2H), 1.21 (m, 18) H), 0.83 (t, 3H); IR (KBr) 3322, 3067, 2925, 2853, 1732, 1633, 1564 cm "1; mass spectrum [+ APCI], M / Z 628 (M + H) *; Analysis calculated for C35H43Cl2NO5-0.3 H20: C, 66.03; H, 6.93; N, 2.21, Found: C, 66.03; H, 6.82; N, 2.44.
Example 13 Acid (5 '- [6- (4-tert-butyl-benzyloxy) -hexylcarbamoyl] -3,3"-b-trifluoromethyl- [1,1'; 3 ', 1"] ter enyl-2'-yloxy .}. -acetic Step 1 N- [6 - (4-tert-butyl-benzyloxy) 1-hexyl-3,5-bis (m-trifluoromethylphenyl) -4- (2-hydroxyethyl) -benzamide In a manner similar to Example 5, Step 2, the title compound, 1.06 g, (98%) is prepared from the 3,5-bis- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) ethyl ester. ) benzoic acid and 6- (4-tert-butyl-benzyloxy) hexylamine (1.27 g, 4.81 mmol).
Stage 2 Acid. { 5'-f 6 - (4-tert-butyl-benzyloxy) -hexylcarbamoyl -3,3"-bis-trif luoromethyl-Fl.1 '; 3' .1"! er phenyl-2'-yloxy I -acetic In a manner similar to Example 5, Step 3, the title compound (0.045 g, 10%) is prepared by oxidation of the previous alcohol: p.f. 156-158 ° C; ? NMR (DMSO-d6) d 12.60 (broad s, 1H), 8.59 (t, 1H), 7.97 (s, 2H), 7.92 (m, 4H), 7.77 (m, 2H), 7.33 (d, 2H), 7.20 (d, 2H), 4.35 (S, 2H), 3.81 (s, 2H), 3.38 (t, 2H), 3.27 (m, 2H), 1.51 (m, 4H), 1.32 (m, 4H), 1.24 (s, 9H); IR (KBr) 3300, 2800, 1730, 1620, 1570, 1330 cm "J-mass spectrum [-ESI], M / Z 728 (M-H)", - Analysis calculated for C40H41FsN05: C, 65.84; H, 5.66; N, 1.92, Found: C, 65.44; H, 5.81; N, 1.79.
Example 14 Acid (5 '- [6- (4-benzyloxy-benzyloxy) -hexylcarbamoyl] -3,3"-bis tri-loromethyl- [1, 1; 3' 1"] er eni-2-yloxy. -acetic acid Step 1 N- [6- (4-benzyloxy-benzyloxy) 1-hexyl-3,5-bis (m-tri luorome-ilphenyl) -4-hydroxy-benzamide A stirring solution of 3,5-bis- (m-trifluoromethylphenyl) -4-hydroxybenzoic acid (0.800 g, 1.87 mol) in 10 ml of S0C12 is refluxed for 1.5 h, then cooled and concentrated in vacuo. The acid chloride is dried idp overnight. The acid chloride is dissolved in 10 ml of CH2C12 and added to a solution of 6- (4-benzyloxy-benzyloxy) hexylamine (0.765 g, 2.44 mmole) and triethylamine (0.92 ml, 6.54 mmole) in 10 ml of CH2C12 a 0 ° C. After Stir for 4 h at 0 ° C, add 1.0 N HCl and extract the mixture with ethyl acetate. The organic phase is washed with brine, dried (MgSO4) and concentrated to provide 1.15 g (85%) of an amide as an oil: "-H NMR (DMS0-d6) d 9.30 (s, 1H), 8.44 ( t, 1H), 7.94-7.70 (m, 10H), 7.41 (m, 4H), 7.20 (d, 2H), 6.95 (d, 2H), 5.08 (s, 2H), 4.35 (s, 2H), 3.42 -3.20 (m, 4H), 1.50 (m, 4H), 1.32 (m, 4H).
Stage 2 Acid methyl ester. { 5 '- [6 - (4-benzyloxy-benzyloxy) -hexylcarbamoyl-3, 3"-bis-trifluorome-il- [1.1'; 3 '. 1" 1-terphenyl-2'-yloxy} -acetic To an agitated solution of above phenol (1.14 g, 1.58 mmol) in 10 ml of DMF is added methyl bromoacetate (0.29 ml, 3.16 mmol) and K2C03 (0.24 g, 1.74 mmol). The mixture is stirred at 60 ° C for 5 h and then overnight at room temperature. The mixture is divided between water and ethyl acetate. The organic phase is dried (MgSO4) and concentrated to give the crude product which is purified by flash column chromatography (2: 1 hexanes / ethyl acetate). Yield: 0.72 g (61%) of product as a clear oil.
Stage 3 Acid. { 5'-f 6- (4-benzyloxy-benzyloxy) -hexylcarbamoyl -3,3"-bis-trifluoromethyl-fl.l ': 3'. 1"] terphenyl-2'-yloxy} -acetic Hydrolysis of the above ester in a manner similar to that described in Example JB-5, Step 2, provides 0. 3007 g (41%) of the title compound as a white solid: m.p. 127-130 ° C; * H NMR (DMS0-d6) d 12.64 (broad s, 1H), 8.57 (t, 1H), 7.92 (s, 2H), 7.92 (m, 4H), 7.75 (m, 4H), 7.42-7.29 (m, 5H), 7.20 (d, 2H), 6.95 (d , 2H), 5.07 (s, 2H), 4. 32 (s, 2H), 3.81 (s, 2H), 3.40-3.30 (m, 4H), 1.51 (m, 4H), 1. 32 (m, 4H); IR (KBr) 3300, 2950, 1730, 1620 cm "1; mass spectrum [-APCI], M / Z 778 (M-H)"; Analysis calculated for C43H39F6N06-H20: C, 64.74; H, 5.18; N, 1.76. Found: C, 64.85; H, 5.02; N, 1.71. Using synthetic routes and experimental procedures identical to those described above, the following terf enyl analogues are prepared: Example 15 Acid [3"-chloro-4-methoxy-5 '- (8-f-enyl-octylcarbamoyl) - [1,1 J-3', l"] terphenyl-2'-ylox] -acetic Using as starting material the ethyl ester of 3 - (m-chlorofenyl) -5- (p -methoxyphenyl) -4- (2-hydroxyethoxy) -benzoic acid and 8-f-enyloctylamine, the title compound is obtained. p.f .: 79-2-80.5; * H NMR (DMS0-d6) d 12.7 (s broad), 8. 55 (t, 1H), 7.80 (d, 2H), 7.68 (s, 1H), 7.55 (m, 4H), 7.48 (m, 2H), 7.10 (m, 3H), 7.00 (d, 2H), 3.80 (2s, 5H), 3.22 (m, 2H), 2.52 (m, 2H), 1.51 (m, 4H), 1.23 (m, 10H); IR (KBr) 3400, 2925, 2840, 1745, 1605, 1250 cm "J- mass spectrum [+ APCI], M / Z 600 (M + H) *; Analysis calculated for C3SH3BC1N05 -H20: C, 69.95; H , 6.52; N, 2.27, Found: C, 69.94; H, 6.27; N, 2.28.
Example 16 Acid (3"-chloro-4-methoxy-5 '- [methyl- (8-phenyl-octyl) -carbamoyl] - [1,1'; 3 ', 1"] terphenyl-2'-ylox) -acetic Using the 3- (m-chlorophenyl) -5- (p-methoxyphenyl) -4- (2-hydroxy-ethoxy) benzoic acid and N- (8-phenyloctyl) -N-methylamine as starting material, the composed of the title. 'H NMR (DMSO-d6) d 7.63 (s, 1H), 7.55 (m, 4H), 7.41 (m, 2H), 7.30 (s, 1H), 7.25 (m, 2H), 7.20 (m, 3H) , 7.00 (d, 2H), 3.78 (2s, 5H), 3.3 (m, 2H), 2.93 (broad s, 3H), 1.60-1.00 (m, 14H); IR (KBr) 3410, 2900, 1620, 1250 cm "J-mass spectrum [+ APCI], M / Z 614 (M + H) *; Calculated analysis for C 37 H 40 ClNO 5 • 1.3 H 20: C, 69.70; H, 6.73; N, 2.20, Found: C, 69.44; H, 6.63; N, 2.30.
Example 17 Acid [3,3"-dimethoxy-5 '- (8-phenyl-octylcarbamoyl) - [1, 1', -3 ', 1"] terphenyl-2-yloxy] -acetic Using as starting material the ethyl ester of 3,5-bis (m-methoxyphenyl) -4- (2-hydroxyethoxy) -benzoic acid and 8-phenyloctylamine, the title compound is obtained. p.f. 67.3-68.7 ° C; * H NMR (DMS0-d6) d 12.75 (s broad, 1H), 8.48 (t, 1H), 7.80 (s, 2H), 7.35 (m, 2H), 7.30-7.10 (m, 9H), 6.92 (dd, 2H), 3.80 (s, 6H), 3.25 (m, 2H), 2.50 (m, 2H), 1.51 (m, 4H), 1.25 (m, 8H), - IR (IBr) 3350, 2910, 2820, 1700, 1600, 1210 cm "J- mass spectrum [+ APCI], M / Z 596 (M + H) *; Analysis calculated for C3H41N06 • 1.5 H20: C, 71.36; H, 7.12; N, 2. 25, Found: C, 71.36; H, 6.72; N, 2.16. ^ &g ^ v ^ & ^^ Example 18 A (2- [5 '- (6-Phenyl-hexylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1'; 3 ', 1"] terphenyl-2'-yloxy] -ethoxy) acetic acid Using the 3,5-bie (m-trifluoromethylphenyl) -4- (2- (hydroxyethoxy) -benzoic acid and 6-phenylethylamine as starting material, the title compound is obtained. 9 10 pf 74.7 -75.9"C;? RMN (DMS0-d6) d 12.50 (s broad, 1H), 8.59 (t, 1H), 7.98 (m, 6H), 7.75 (m, 4H), 7.25 (m, 2H), 7.15 (m, 3H), 3.52 (s, 2H), 3.40-3.15 (m , 6H), 3.52 (m, 2H), 1.53 (m, 4H), 1.30 (m, 4H); IR (KBr) 3400, 2850, 1730, 1630, 1325 cm "J-mass spectrum [-ESI], M / Z 686 (M-H)", - Analysis 15 calculated for CJ7H35F6NOs; C, 64.62; H, 5.13; N, 2.04, Found: C, 64.03; H, 5.18; N, 1.88.
Example 19 Acid (5 '- [6- (2,4-difluoro-benzyloxy) -hexylcarbamoyl] -3,3"-Bbis-tr fluoromethyl- [1,1'; 3'1"] erphen-2'-yloxyacetic Using as starting materials the ethyl ester of 3,5-bis (m-trifluoromethylphenyl) -4- (2- (hydroxyethoxy) - benzoic acid and 6- (2,4-difluorobenzyloxy) hexylamine, the title compound is obtained. • p.f. 149.9-150.6; XH NMR (DMS0-d6) d 12.60 (broad s, 1H), 8.56 (t, 1H), 7.97 (s, 2H), 7.92 (m, 4H), 7.80-7.65 (m, 5 4H), 7.45 (m , 1H), 7.20 (m, 1H), 7.04 (m, 1H), 4.44 (e, 2H), 3.80 (S, 2H), 3.42 (t, 2H), 3.29 (m, 2H), 1.51 (m, 4H), 1.31 (m, 4H); IR (KBr) 3435, 2930, 1725, 1610, 1325 cm "1; mass spectrum [-ESI], M / Z 708 (M-H)"; Analysis calculated for C3ßH31FaN05-H20: C, 59.42; H, 4.57; N, 1.92, Found: C, 59.36; 10 H, 4.22; N, 1.98.
Example 20 Acid (5 '- [6-biphen? L-4-ylmethoxy) -hexylcarbamoyl] -3,3"-bis-trifluoromethyl- [1,1'; 3, 1"] terphenyl-2'-yloxy] -acetic acid Using the 3,5-bis (m-trifluoromethylphenyl) -4- (2- (hydroxyethoxy) -20-benzoic acid and 6- (p-phenylbenzyloxy) -erylamine as starting material, the title compound is obtained. -133.9;? RMN (DMSO-d6) d 12.65 (s broad, 1H), 8.60 (t, 1H), 7.97 (s, 2H), 7.92 (m, 4H), 7.78 (m, 2H), 7. 72 (m, 2H), 7.62 (m, 4H), 7.43 (m, 2H), 7.37 (m, 3H), 4.43 (s, 2H), 3.80 (2H), 3.42 (t, 2H), 3.24 (m, 2H), 1.56 (m, 4H), 1. 35 (m, 4H), - IR (KBr) 3300, 2960, 1730, 1615, 1565, 1325, 1130 cm "J- mass spectrum [-ESI], M / Z 748 (MH) j- Analysis calculated for C42H37F6N05; C, 67.28; H, 4.97; N, 1.87, Found: C, 66.98; H, 5.11; N, 1.79.
Example 21 Acid (3, 3"-dimethoxy-5" - [methyl- (8-phenyl-octyl) carbamol] - [1,1 '; 3', l "] terphenyl-2'-yloxy.
Using the 3,5-bis (m-methoxyphenyl) -4- (2- (hydroxyethoxy) -benzoic acid and N- (8-f-enyloctyl) -N-methylamine as the starting material, the compound of titer, mp 148.9-149-7; ^ NMR (DMS0-d6) d 12.52 (broad s, 1H), 7.52 (m, 4H), 7.23 (m, 2H), 7.17 (m, 7H), 6.90 (dd, 2H), 3.75 (2s, 8H), 2.92 (s, 3H), 2.50 (m, 2H), 1.60-1.00 (m, 12H), IR (KBr) 3400, 2925, 1850, 1700, 1400 cm "J- mass spectrum t-ESI], M / Z 610 (M + H) *, - Analysis calculated for C38H43N06 • 0.5H20: C, 73.76; H, 7.17; N, 2.26. Found: C, 73.50; H, 6.94; N, 2.28.
Example 22 Acid (2- [3,5,3", 5" -tetrachloro-5 '- [(6-phenyl-hexylcarbamoyl) - [1,1'; 3 ', 1"] erphenyl-2'-ethoxy. acetic Using the 3,5-bis (3 ', 5'-dichlorophenyl) -4- (2- (hydroxyethoxy) -benzoic acid and 6-phenylhexylamine ethyl ester as starting material, the title compound is obtained, mp 78.5-79.9; SH NMR (DMSO-ds) d 12.5 (s broad, 1H), 8.52 (t, 1H), 7.92 (s, 2H), 7.73 (s, 4H), 7.65 (s, 4H), 7.22 (m, 2H), 7.14 (m, 3H), 3.63 (s, 2H) ), 3.20 (m, 2H), 3.24 (m, 4H), 2.53 (m, 2H), 1.55 (m, 4H), 1.32 (m, 4H); IR (KBr) 2375, 2925, 1725, 1630, 1560 cm "J-mass spectrum [-ESI], M / Z 688 (M + H) *, - Analysis calculated for C3SH33C14N05: C, 60.97; H, 4.82; N, 2.03, Found: C, 63.17; H, 5.23; N, 2.15.
Example 23 Sodium salt of the acid [4, 4"-dime toxy-5 '- (8-f-enyl-octylcarbamoyl) - [1, 1'; 3 '. 1"] terphenyl-2'-yloxy] -acetic Using the 3,5-bis (p-methoxyphenyl) -4- (2-hydroxyethoxy) -benzoic acid and 8-phenyloctylamine as the starting material, the title compound is obtained. p.f. > 95 ° C; ? NMR (DMSO-ds) d 8.46 (t, lh), 7.73 (s, 2H), 7.57 (d, 4H), 7.24 (m, 2H), 7.15 (m, 3H), 6.97 (d, 4H), 3.78 (s, 6H), 3.58 (s, 2H), 3.22 (c, 2H), 2.58 (m, 2H), 1.50 (m, 4H), 1.27 (m, 8H); IR (KBr) 3410, 2900, 1630, 1600, 1510, 1250 cm "1; mass spectrum [-ESI], M / Z 594 (M-H)"; Analysis calculated for C37H41N06Na: C, 71.83; H, 6.68; N, 2.26. Found: C, 71.30; H, 6.66; N, 2.22.
Example 24 Sodium salt of the acid (3,3"-dichloro-5 '-dodecarbamoyl-4, 4" -difluoro [1,1'; 3 ', 1"] terphenyl (-2'-yloxy) acetic acid Using the 3,5-bis (3'-chloro-4'-fluoro-phenyl) -4- (2- (hydroxyethoxy) -benzoic acid and dodecylamine ethyl ester as starting material, the title compound is obtained, mp 140.2-141.0; H NMR (DMSO-d6) d 8.53 (t, 1H), 7.82 (m, 4H), 7.60 (m, 2H), 7.46 (m, 3H), 3.77 (s, 2H), 3.27 (c, 2H) , 1.47 (m, 2H), 1.17 (m, 18H), 0.79 (t, 3H), IR (KBr) 3375, 2930, 2870, 1720, 1615, 1500 1200 cm "J- mass spectrum [+ APCI], M / Z 620 (M + H) *, - Analysis calculated for C33H37Cl2F2N04Na: C, 61.59; H, 5.80; N, 2.18, Found: C, 61.29; H, 5.57; N, 2.16.
Example 25 Acid [3,3"-dichloro-4-4''difluoro-5 '- (8-f-enyl-octylcatr-amn-i 1) - [1. 1' 3 '. 1"] terphenyl-2'-yloxy] -acetic Using the 3,5-bis (3'-chloro-5'-fluoro-phenyl) -4- (2-hydroxyethoxy) -benzoic acid and 8-phenyloctylamine as the starting material, the title compound is obtained. p.f. 157.0-158.8; * H NMR (DMSO-d6) d 12.5 (s broad, 1H), 8.55 (t, 1H), 7.85 (m, 4H), 7.62 (m, 2H), 7.49 (m, 2H), 7.23 (m, 2H), 7.13 (m, 3H), 3.82 (s, 2H) ), 3.25 (c, 2H), 2.52 (t, 2H), 1.52 (m, 4H), 1.27 (m, 8H), - IR (KBr) 3310, 2915, 1715, 1600, 1550, 1500 cm "J- masae spectrum [-ESI], M / Z 638 (MH) "; Analysis calculated for C35H33C12N0"• 0.7H20: C, 64.36; H, 5.31; N, 2.14. Found: C, 64.22; H, 4.95; N, 2.01.
Example 26 Acid { 3.3"-dichloro-5 '- (6- (2,5-dimethyl-furan-3-ylmethoxy) -hexylcarbamoyl] -4-4" -difluoro- [1.1'; 3 '. 1"] terphenyl-2'-yloxy} -acetic Using 3,5-bi (3'-chloro-4'-fluoro-phenyl) -4- (2- (hydroxyethoxy) -benzoic acid and 6- (2,5-dimethyl-3-furanyloxy) ethyl ester as starting materials. Exilamine, the title compound is obtained, mp 90.0 91.2; "H NMR (DMSO-d6) 6 8.53 (t, 1H), 7.83 (m, 4H), 7.62 (m, 2H), 7.47 (m, 2H), 5.89 (s, 1H), 4.12 (s, 2H), 3.70 (s, 2H), 3.30 (t, 2H), 3.22 (c, 2H), 2.14 (2s, 6H), 1.50 (m, 4H), 1.29 (m, 4H), - IR (KBr) 3400, 1735, 1630, 1500 cm1; spectrum of? sas [-ESI], M / Z 658; (MH) ", - Analysis calculated for C34H33C12F2N06 -H20: C, 60.18; H, 5.20; N, 2.06. Found: C, 59.77; H, 4.77; N, 1.74.
Example 27 Acid [3,5-dichloro-5 '- (8-phenyl-octylcarbamoyl) [1,1' 3 ', 1"1-terfenii-2'-yloxy] -acetic Using the 3- (m-chlorophenyl) -5-phenyl-4- (2- (hydroxyethoxy) -benzoic acid and 8-phenyloctylamine as starting material, the title compound is obtained, mp 82.0-83.1; (DMSO-d6) d 12.7 (broad s, 1H), 8.53 (t, 1H), 7.85 (s, 2H), 7.69 (d, 2H), 7.60 (m, 3H), 7.49 (m, 3H), 7.25 (m, 2H), 7.15 (m, 3H), 3.80 (s, 2H), 3.25 (m, 2H), 2.58 (m, 2H), 1.52 (m, 4H), 1.27 (m, 8H), IR ( KBr) 3392, 2927, 2853, 1737, 1633, 1560 cm "1; mass spectrum [-ESI], M / Z 602 (MH)"; / Analysis calculated for C35H3SNC1204 • 2H20: C, 65.62; H, 6.14; N, 2.19, Found: C, 65.10; H, 5.61; N, 2.10.
Example 28 C5 '- (8-phenyl-octylcarbamoyl) -3-trifluoromethyl-1-yl "; 3'. 1"] erphenyl-2'-yloxy] -acetic acid Using ethyl ester of 3 - (m-tri f luoromethyl-phenyl) -5-phenyl-4 - (2 - (hydroxyethoxy) -benzoic acid and 8-f-enyloctylamine as the starting material, the title compound is obtained. -145.5; H NMR (DMSO-d6) d 8.55 (t, 1H), 7. 46 (s, 1H), 7.86 (m, 3H), 7.75-7.70 (m, 2H), 7.60 (d, 2H), 7. 50-7.38 (m, 3H), 7.23 (m, 2H), 7.12 (m, 3H), 3.77 (s, 2H), 3.24 (m, 2H), 2.59 (m, 2H), 1.52 (m, 4H) , 1.27 (m, 8H); GO (KBr) 3345, 2929, 2855, 1729, 1617; cm "1; mass spectrum [+ ESI], M / Z 604 (M + H) *; Analysis calculated for C35H36F3N04 -H20: C, 69.55; H, 6.16; N, 2.25. Found: C, 69.81; H, 5.95; M, 2.42.
Example 29 4. 4"-dif luoro-5 '- (8-f-enyl-octylcarbamoyl) -3,3" -bis-trif luoromethyl- [1.1'; '.1"] terphenyl-2'-yloxy] -acetic Using as starting material the ethyl ester of 3,5-bromo (3 '-trifluoromethyl-4-fluorophenyl) -4- (2 - (hydroxyethoxy) -benzoic acid and 8-phenyloctylamine, the title compound is obtained. 148; Jl NMR (DMSO-d6) d 12.75 (broad e, 1H), 12. 54 (t, 1H), 8.00 (m, 4H), 7.91 (m, 3H), 7.60 (m, 3H), 7.22 (m, 4H), 7.12 (m, 3H), 3.81 (e, 2H), 3.31 (m, 2H), 2.59 (m, 2H), 1.50 (m, 4H), 1.27 (m, 8H); IR (KBr) 3355, 2930, 2857, 1725, 1622, 1506 cm "J-mass spectrum [+ ESI], M / Z 708 (M + H) J-Analysis calculated for C37H33FBN04; C, 62.80; H, 4.70; N, 1.98, Found: C, 62.29; H, 4.84; N, 2.06.
Example 30 '- [6- (2,5-Dimethyl-furan-3-ylmethoxy) -hexylcarbamoyl] -3.3"-bis-trifluoromethyl- [1,1'; 3 '. 1"] terphenyl-2'-yloxy' acid} -acetic Using the 3,5-bis (m-trifluoromethylphenyl) -4- (2- (hydroxyethoxy) -benzoic acid and 6- (2,5-dimethyl-3-furanyloxy) hexylamine as the starting material, the compound is obtained of the title, mp 107.9-108.5; XH NMR (DMS0-d6) d 12.5 (s broad, 1H), 8.60 (t, 1H), 7.91 (m, 6H), 7.70 (m, 4H), 5.89 (s, 1H), 4.12 (S, 2H), 3.80 (s, 2H), 3.31 (m, 4H) ), 2.14 (2s, 6H), 1.50 (m, 4H), 1.29 (m, 4H); IR (KBr) 3351, 2936, 2861, 1729, 1636 cm-J- mass spectrum [-APCI], M / Z 690 (MH) "; Analysis calculated for C3SH35F6N06- 0.5 H20: C, 61.71; H, 5.18; N, 2.00 Found: C, 61.41, - H, 5.05; N, 1.87.
Example 31 Acid (3-bromo-5-dodecylcarbamoyl-4 '-methoxy-biphenyl-2-yloxy) -acetic acid Using the 3-bromo-5- (p-methoxyphenyl) -4 - (2 - (hydroxyethoxy) -benzoic acid and dodecylamine ethyl ester as starting materials, the title compound is obtained.
NMR (DMSO-ds) d 12.82 (broad s, 1H), 8.54 (t, 1H), 8.03 (dd, 1H), 7.80 (dd, 1H), 7.51 (dd, 2H), 7.02 (dd, 2H), 4.07 (s, 2H), 3.80 (e, 3H), 3.22 (m, 2H), 1.45 (m, 2H), 1.22 (m, 18H), 0.83 (t, 3H9, IR (KBr) 3350, 2915, 2850 , 1745, 1610, 1550, 1510, 1250 cm "1; mass spectrum [-ESI], M / Z 546/548 (MH) '; Analysis calculated for C2íH3βBrNOs: C, 61.31; H, 6.98; N, 2.55. Found: C, 61.08; H, 6.79; N, 2.49.
Example 32 [5 '- (2-hexadecylamino-3,4-dioxo-cyclobut-1-enylamino) -n.l'; 3 '. 1"] erphenyl-2'-yloxy] -acetic acid To a stirring solution of 2,6-diiodo-4-nitrophenol (24.00, 61.40 mmol) in DME / H20 (140 mL, 10: 1) is added phenylboronic acid (16.47 g, 135.08 mmol), Ba (OH) 2 -H20 (34.88 g, 184.2 mmolee) and Pd (OAc) 2 (1.37 g, 6.14 min). The mixture is stirred for 3 h at 80 ° C, cooled, diluted with water and filtered through a pad of Celite. The filtrate is extracted with ethyl acetate. The organic phase is dried (MgSO4) and decolorized (activated carbon). The concentration provides 15.31 g (86%) of the bisaryl product. The compound is treated with methyl bromoacetate (9.96 ml, 105.22 mmol) and K2C03 (8.85 g, 57.87 mmol) in 200 ml of acetonitrile. The mixture is stirred for 4 h at 70 ° C and after overnight at room temperature. Filtration, followed by concentration in vacuo and trituration of the residue with petroleum ether provides 15.01 g (79%) of the f-oxoacetic acid derivative. A portion of this composition (5.00 g, 13.81 mmol) is treated with iron powder (3.7 g, 66.30 mmol) and NH4C1 (0.37 g, 6.91 mmol) in 50 ml of ethanol / 25 ml of water. The mixture is heated at 80 ° C for 18 h, cooled and passed through a short column of Celite. The filtrate is dried (MgSO4) decolorized (activated carbon) and concentrated to provide 3.87 g (84%) of the aniline compound. A portion of this compound (1.50 g, 4.52 mmol) is stirred in pure 3, 4-diethoxy-3-cyclobuten-1,2-dione (2.71 g, 13.55 mmol) overnight at room temperature. The mixture is partitioned between water / ethyl acetate and the crude condensation product is purified by flash column chromatography using 40% ethyl acetate / hexanes to provide 1.25 g (60%) of the product. A portion of this compound (0.100 g, 0.22 mmol) is treated with hexadecylamine (0.08 g, 0.33 mmol) in 20 ml of ethanol at 70 ° C. The mixture is stirred overnight, cooled and filtered to provide 0.14 g (100%) of the methyl ester of [5 '- (2-hexadecylamino-3,4-dioxo-cyclobut-1-enylamino) - [1 , l ', -3', l1] terphenyl-2-yloxy] acetic acid. The ester is dissolved in methanol / THF (8 ml / 12 ml) and treated with aqueous 1 N KOH (1.23 ml, 1.23 mmolee). The reaction is stirred for 18 h, and then concentrate in vacuo and dilute with water. Acidification with HCl l N gives a white precipitate which is collected by filtration and dried in vacuo. Yields of the compound: 0.092 g (58%): m.p. 132.5-133.7; "H NMR (DMSO-d6) d 12.45 (broad s, 1H), 9.78 (broad s, 1H), 7.60 (m, 5H), 7.48-7.30 (m, 8H), 3.70 (s, 2H), 3.60 ( m, 2H), 1.55 (m, 2H), 1.24 (? r "26H), 0.80 (t, 3H), IR (KBr) 3275, 2920, 2810, 1800, 1675, 15/1., 1450 cm" 1; mass spectrum [-ESI], M / Z 637 (MH) "Analysis calculated for C40H50N2Os • H20: C, 73.14; H, 7.98; N, 4.26; N, 4.26 Found: C, 73.74; H, 7.67; N, 4.26.
Example 33 Acid (3,3"-dichloro-5 '-dodecylcarbamoyl- [1,1'; 3 '. 1"] terphenyl-2'-yloxy) -acetic Step 1) 3,5-bie- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoyl acid ethyl ester To a stirred solution of K2C03 (17.2 g, 124 mmol) in 62 ml of H20 at room temperature is added 490 ml of dioxane, 3-bromo-4- (2-hydroxyethoxy) -5-iodobenzoic acid ethyl ester (17.2 < j, 41.4 mmol), 3-chlorophenylboronic acid (7.77 g, 49.7 mmol) and complex or [1, 1 '-bis (diphenylphosphino) ferrocene] icloropalladium (II) with CH2C12 (0.676 g, 0.828 mmol). This mixture is stirred at room temperature for 4 h and seems to advance but not complete by CCD and CLAP. Another 0.1 equivalents of 3-chlorophenylboronic acid (0.647 g) are added and the reaction is stirred for an additional 24 h. In the next 4 days, 0.1 eq of boronic acid are added at intervals of one day until the reaction is almost completely finished, determined by CLAP (60% bis-arylated, 25.4% monoarylated and 12.6% SM). The reaction is diluted with HCl (1187 mL, 0.17 M) and the resulting solution is extracted with EtOAc (1 x 300 mL and 3 x 200 mL). The combined organic layers are washed with 0.1 N HCl (2 x 90 ml), H20 (2 x 90 ml) and brine (2 x 90 ml) and then dry (Na2SO4). After concentration, the residue is first purified by flash chromatography (gradient from 0 to 50% EtOAc / hexane) and then by CLAP [60% CH2C12 (MTBE 6%): 40% hexane] to provide the bis-arylated product ( 6.16 g, 35%) as a light yellow viscous oil (for the mono arylated product, see step 1 of example 33); XH NMR (DMSO-d6) d 1.31 (t, J = 7.0 Hz, 3H), 3.12 (c, J = 5.5 Hz, 2H), 3.28 (t, J = 5.7 Hz, 2H), 4.32 (dd, J = 7.0, 14.1 Hz, 2H), 4.45 (t, J = 5.5 Hz, 1H), 7.45-7.53 (m, 4H), 7.53-7.58 (m, 2H), 7.67-7.69 (m, 2H), 7.91 (8 2H); IR (film) 3440, 3090, 2990, 2930, 2860, 1720, 1610, 1570, 1475, 1425, 1390, 1360, 1340, 1310, 1245, 1160, 1120, 1100, 1090, 1065, 1025, 770, -710 , and 500 cm -1, - mass spectrum [(+) APCI], m / z 431/433 (M + H) J 448/450 (M + NH 4) *.
Step 2) N-dodecyl-3,5-bie (m-chlorophenyl) -4- (2-hydroxyethoxy) -benzamide To a round flamed flask, with dodecylamine (0.519 g, 2.80 mmolee) and 8 ml of THF, cooled to 0 ° C, dropwise added over a period of 5 min n-BuLi (1.12 ml, 2.5 M in hexane, 2.80 mmol). The resulting solution is stirred at this temperature for 40 min and then cooled to -45 ° C. To this solution is added dropwise a solution (at 0 ° C) of the 3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) -benzoic acid ethyl ester (0.302 g, 0.700 mmol) in ethyl acetate. ml of THF for 5 min. This final mixture is stirred and heated at room temperature for 30 min. At this point, the reaction mixture is suspended with 3 ml of H20 and diluted with 40 ml of EtOAc. The organic layer is washed with 1 N HCl (3 x 7 ml), brine (7 ml) and H20: brine (1: 1, 14 ml) and then dried (Na2SO4). After concentration, the residue is purified by flash chromatography (gradient from 0 to 15% EtOAc / hexane) to give the product (0.286 g, 72%) as a white oil oleoeo; KK NMR (DMS0-d6) d 0.86 (t, J = 7.7 Hz, 3H), 1.20-1.37 (m, 18H), 1.46-1.57 (m, 2H), 3.13 (dd, J = 6.9, 11.5 Hz, 2H ), 3.20-3.33 (m, 4H), 4.46 (t, J = 6.2 Hz, 1H), 7.43-7.57 (m, 4H), 7.59-7.63 (m, 2H), 7.68-7.73 (m, 2H), 7.89 (s, 2H), 8.67 (t, J = 6.2 Hz, 1H); mass spectrum [(+) APCI], m / z 570 (M + H) *.
Stage 3 Acid (3, 3"-dichloro-5'-dodecylcarbamoyl-fl.l ': 3' .1" 1-terphenyl-2'-yloxy) -acetic To a stirred solution of N-dodecyl-3,5-bis (m-chlorophenyl) -4- (2-hydroxy-ethoxy) benzamide (0.277 g, 0.485 mmol) in CH3CN: CH2C12 (5: 3.8 ml) Ambient temperature is added NMMO (0.114 g, 0.970 mmol) followed by TPAP (0.017 g, 0.0485 mmol). After 2 h, the reaction mixture still shows the presence of intermediate aldehyde. 0.3 equivalents of NMMO (0.017 g) and 0.02 equivalents of additional TPAP (0.003 g) are added, and the reaction is stirred for an additional 3 h. The mixture is suspended with 2 ml of H20 followed by 15 ml of 10% aqueous NaHS03. After stirring for 20 min, the mixture is diluted with 40 ml of EtOAc. The resulting organic layer is washed with 1 N HCl (3 x 7 ml) and brine (2 x 7 ml) and then dried (Na 2 SO 4). After concentration, the residue is purified by preparative plate chromatography (100% EtOAc) to give the product (0.081 g, 29%) as a gray solid, m.p. 151-156 ° C; "-H NMR (DMSO-d6) d 0.83 (t, J = 6.8 Hz, 3H), 1.15-1.32 (m, 18H), 1.46-1.55 (m, 2H), 3.25 (dd, J = 7.2, 13.2 Hz , 2H), 3.84 (s, 2H), 7.44-7.52 (m, 4H), 7.57 (t, J = 2.0 Hz, 1H), 7.58 (t, J = 1.8 Hz, 1H), 7.67-7.70 (m, 2H), 7.86 (s, 2H), 8.55 (t, J = 5.7 Hz, 1H), 12.54-12.86 (broad s, 1H), - IR (KBr) 3360, 2930, 2850, 1725, 1620, 1565, 1465 , 1385, 1345, 1245, 1200, 1150, 1075, 1065, 880, 800. 755, and 705 crn "1; mass spectrum [(-) ESI], m / z 582/584/586 (M-H) J- Analysis calculated for C33H39C12N04: C, 67.80; H, 6.72; N, 2.40, Found: C, 67.63; H, 6.77; N, 2.34.
Example 34 Acid (3-bromo-3'-chloro-5-dodecylcarbamoyl-biphenyl-2-yloxy) -acetic acid Stage 1 ethyl ester of 3-bromo-5- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid The ethyl ester of 3-bromo-5- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid is prepared as a white solid (5.01 g, 30%) from the ethyl ester of 3-bromo-4 acid. - (2-hydroxyethoxy) -5-iodobenzoic acid using the procedure for step 1 of example 33 (product 2: mono-arylation), mp 107.5-110.5 ° C; 'H NMR (DMS0-d6) d 1.33 (t, J = 7.0 Hz, 3H), 3.45 (c, J = 5.5 Hz, 2H), 3.61 (t, J = 5.5 Hz, 2H), 4.33 (dd, J = 7.2, 14.3 Hz, 2H), 4.69 (t, J = 5.7 Hz, 1H), 7.50-7.56 (m, 3H), 7.64-7.66 (m, 1H), 7.88 (d, J = 2.2 Hz, 1H) , 8.15 (d, J = 2.2 Hz, 1H); IR (KBr) 3240, 3090, 2980, 2930, 1720, 1600, 1570, 1465, 1445, 1380, 1365, 1355, 1305, 1265, 1240, 1180, 1120, 1080, 1055, 1030, 890, 875, 810, 760, and 705 cm "1; mass spectrum [(+) APCI], m / z 399/401 (M + H) J 416/418 (M + NH4) *.
Stage 2 N-dodecyl-3-bromo-5- (m-chlorophenyl) -4- (2-hydroxyethoxy) -benzamide The N-dodecyl-3-bromo-5- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzamide is prepared as a colorless oil (0.110 g, 33%) from the ethyl ether of 3-bromo-5 acid. - (m-chlorofenyl) -4- (2-hydroxyethoxy) benzoic using a procedure similar to step 2 of example 33; XH NMR (DMSO-d6) d 0.86 (t, i = 7.7 Hz, 3H), 1.17-1.36 (m, 18H), 1.46-1.57 (m, 2H), 3.20-3.30 (m, 2H), 3.46 (dd) , J = 5.4, 11.5 Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 4.69 (t, J = 6.2 Hz, 1H), 7.48-7.60 (m, 3H), 7.65-7.71 (m, 1H), 7.87 (d, J 2.3 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 8.58 (t, J = 6.2 Hz, 1H); mass spectrum "(-) ESI], m / z 536 (M-H)", 596/598/600 (M + OAc-H) ".
Stage 3 Acid (3-bromo-3'-chloro-5-dodecylcarbamoyl-biphenyl-2-yloxy) -acetic The title compound is prepared as a gray solid (0.051 g, 43%) from N-dodecyl-3-bromo-5- (m-chlorofenyl) -4 - (2-hydroxyethoxy) benzamide using a procedure similar to stage 3 of example 33, pf > 100 ° C (decompoeition), JH NMR (DMSO-d6) d 0.83 (t, J = 6.8 Hz, 3H), 1. 1 8-1.31 (m, 18H), 1.49 (t, J = 6.8 Hz, 2H) , 3.23 (dd, J = 6.8, 13.0 Hz, 2H), 3.77 (s, 2H), 7.41-7.47 (m, 2H), 7.57-7.60 (m, 1H), 7.66-7.68 (m, 1 H), 7.79 (d, J = 2.2 Hz, 1 H), 8.04 (d, J = 2.2 Hz, 1 H), 8.5 3 (t, J = 5.3 Hz, 1 H); IR (KBr) 3290, 3090, 2930, 2850, 1630, 1555, 1465, 1430, 1325, 1225, 1190, 1110, 1075, 1020, 920, 885, 840, 800, 770, 710, 690, and 600 cm " 1; mass spectrum [(+) ESI], m / e 552/554/556 (M + H) J-Analysis calculated for C27H35BrClN04 1.33H20: C, 56.21; H, 6.58; N, 2.43, Found: C , 56.01; H, 5.96; N, 2.39.
Example 35 Acid [3.3"-dichloro-5 '- (8-phenyl-octylcarbamoyl) -ri.l'; 3 ', 1"] terphenyl-2'-yloxy] -acetic Stage 1 N- (8-pheny-octyl) -3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) -benzairide To a round-bottomed flask flame dried with 8-phenyloctylamine (p.484 ml, 2.43 mmol) and 5 ml of THF, cooled to 0 ° C, dropwise added over a period of 5 min n-BuLi (0.972). ml, 2.5 M in hexane, 2.43 mmol). The resulting solution is allowed to stir for 5 min and then is heated at room temperature for 30 min. This solution is then added dropwise to a solution of the 3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester (0.300 g, 0.696 mmol) er. 15 ml of THF at -20 ° C. This final mixture is ^^ g ^^^^^^^. stir at -20 C, C for 15 min and then warm to room temperature for 15 min. At this point, the mixture Reaction is suspended with 10 ml of H20 and diluted with 200 ml of EtOAc. The organic layer is washed with 20 ml of 1 N HCl, 20 ml saturated aqueous NaHC03 and 20 ml of brine, and then dried (MgSO4). After concentration, the residue is purified by a Biotage Flash 40 apparatus (gradient of 20 to 40% EtOAc / petroleum ether) to provide the product (0.267 g, 65%) as a clear oil:? I NMR (CDC13 ) d 1.09-1.48 10 (m, 9H), 1.48-1.72 (m, 4H), 2.58 (t, J = 6.8 Hz, 2H), 3.30-3.35 (m, 2H), 3.35-3.41 (m, 2H), 3.46 (dd, J = 6.8, 13.0 Hz, 2H), 6. 07-6.18 (m, 1H), 7.11-7.19 (m, 3H), 7.21-7.31 (m, 2H), 7.35-7.44 (m, 4H), 7.44-7.57 (m, 2H), 7.63 (s, 2H) ), 7.77 (e, 2H); mass spectrum [(+) ESI], m / z 590 (M) *. fifteen Stage 2 f3.3"-d? Chloro-5'- (8-phenyl-octylcarbamoyl) - [1.1 '; 3'. l" 1-terphenyl-2'-yloxyl-acetic acid The title compound is prepared as an off-white solid (0.151 g, 57%) from N- (8-phenyl-octyl) -3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzamide using a procedure similar to step 3 of example 33, mp 165- 167 ° C; ? NMR (DMSO-d6) d 1.20-1.32 (m, 8H), 1.46-1.57 (m, 4H), 2.51 (dd, J = 7.7, 15.6 Hz, 2H), 3.25 (dd, J 6.8, 13.2 Hz, 2H), 3. 83 (s, 2H), 7.10-7.17 (m, 3H), 7.21-7.26 (m, 2H), 7.44-7.51 (m, 4H), 7.56-7.59 (m, 2H), 7.67-7.69 (m, 2H) ), 7.86 (s, 2H), 8.56 (t, J = 5.5 Hz, 1H), 12.45-12.94 (broad s, 1H); IR (KBr) 3320, 3090, 3030, 2920, 2830, 2520, 1730, 1610, 1565, 1475, 1455, 1390, 1340, 1310, 1245, 1200, 1075, 1055, 875, 800, 780, 755, and 700 cm "J- mass spectrum [(+) ESI], m / z 604 (M + H) J-Analysis calculated for C3SH35C12N04 0.5H20: C, 68.51; H, 5.91; N, 2.28, Found: C, 68.36; H, 5.83; N, 2.32.
Example 36 (5 '-octadecyloxy-n.l': 3 '. 1"] terphenyl-2'-yloxy) -acetic acid Stage 1 (5'-oc t -aceyloxy-l, 1'-3 '. 1"] terf-enyl-2'-yloxy) acetic acid methyl ester To a stirred solution of 5'-oct adecyloxy - [1, 1 ': 3', 1"] terphenyl-2'-ol (0.250 g, 0.486 immoles, Akzo Chemie, Netherlands, Stabilizer A-2751) and K2C03 (0.0739 g, 0.535 mmol) in 9 ml of DMF and 4 ml of THF at room temperature and methyl bromoacetate (0.0922 ml, 0.972 mmol) was added dropwise after 7 days at this temperature, diluted with 50 ml of H20, followed by 400 ml of excess EtOAc The organic layer is washed with 50 ml of 1 N HCl, 50 ml of saturated aqueous NaHC03 and ml of brine, and then dried (MgSO "). After concentration, the residue is purified by flash chromatography (gradient from 0 to 15% EtOAc / petroleum ether) to provide the product (0.225 g, 79%) as a white solid, m.p. 66-69 ° C, * H NMR (DMS0-d6) d 0.84 (t, J = 7.0 Hz, 3H), 1.17-1.34 (m, 28H), 1.34-1.43 (m, 2H), 1.65-1.74 (m , 2H), 3.36 (s, 3H), 3.75 (s, 2H), 4.01 (t, J = 6.2 Hz, 2H), 6.86 (s, 2H), 7.33-7.45 (m, 6H), 7.56 (d, = J 7.2 Hz, 4H),; IR (KBr) 3420, 3050, 2920, 2860, 1770, 1600. 1575, 1465, 1420, 1365, 1235, 1210, 1200, 1095, 1060, 755, and 710 cm "1; mass spectrum [(+) BAR ], m / z 587 (M + H) J 609 (M + Na) *: Analysis calculated for: C39H54N04 C, 79.82; H, 9.27; N, 0.00, Found: C, 79.47; H, 9.21, N, - 0.01.
Stage 2: acid (5 '-octadecyloxy-fl, 1', - 3 ', 1"1-terphenyl-2'-yloxy) acetic acid To a stirred solution of (5 '-octadecyloxy- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid methyl ester (0.182 g, 0.310 mmol) in THF: MeOH (3: 2) , 10 ml) at room temperature, KOH, 1 N (1.55 ml, 1.55 mmoles) is added dropwise.After 2 h at this temperature, it is concentrated and diluted with H20.The solution is then acidified to pH 1 with 2 N HCl. The resulting solid is separated by filtration, washed with H20, and dried under high vacuum for 18 h to provide the product (0.166 g, 93%) as a white solid, m.p. 90.5-92 ° C; * H NMR (DMS0-d6) d 0.83 (t, J = 6.8 Hz, 3H), 1.16-1.35 (m, 28H), 1.35-1.44 (m, 2H), 1.65-1.74 (m, 2H), 3.63 ( s, 2H), 4.01 (t, J = 6.4 Hz, 2H), 6.86 (s, 2H), 7.32-7.44 (m, 6H), 7.58 (dd, J = 1.5, 8.3 Hz, 4H), 12.20-12.75 (s broad, 1H); IR (KBr) 3430, 3070, 2920, 2840 1725, 1600, 1575, 1465, 1410, 1360, 1265, 1220, 1200, 1090, 750, and 695 cm "1, - mass spectrum [El], m / z 572 (M) J- Analysis calculated for C38Hs2N04: C, 79.68; H, 9.15; N, 0.00, Found: C, 79.25; H, 8.99; N, 0.09.
Example 37 acid (5'-benzo [b] naphtho [2,3-dl iofen-ll-il- [1,1 '; 3'. 1"] terphenyl-2'-yloxy) -acetic step 1 5'-benzo fbl naphtho f 2.3 - d 1 thiof en-ll-il-fl.1 '; 3' .1"! erphenyl-2 '-ol To a stirred solution of phenylboronic acid (0.232 g, 1.90 mmole), Ba (OH) 2.8H20 (1.09 g, 3.46 mmole) and Pd (OAc) 2 (0.004 g, 0.0173 mmole) in DME: H20 (6: 1, 21 ml), 4 '-benzo [b] naphtho [2,3-d] thiophen-ll-yl-2', 6'-diiodophenol (0.500 g, 0.865 mmol) is added at room temperature. The mixture is then heated at 80 ° C for 72 h. At this point, the reaction is acidified with pH 1 with 1 N HCl and diluted with 300 ml of EtOAc.
The organic layer is washed with 30 ml of H20 and 30 ml of brine, and then dried (MgSO4). After concentration, the residue is purified by flash chromatography (gradient from 1 to 16% EtOAc / petroleum ether) to give the product (0.381 g, 92%) as a white glassy solid, m.p. > 78 ° C (decomposition); H NMR (DMSO-d6) d 7.07 d, J = 8.1 Hz, 1 H), 7.22 (td, J = 1.1, 8.1 Hz, 1 H), 7.25 (s, 2H), 7.32 (tt, J = 1. 1, 6.6 Hz, 2H), 7.39-7.52 (m, 6H), 7.56-7.64 (m, 5H), 7.77 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 8.61 (s, 1H), 8.76 (s, 1H); IR (KBr) 3520, 3430, 3050, 2920, 1590, 1495, 1465, 1420, 1380, 1370, 1320, 1220, 1120, 1075, 1030, 755, 735, and 705 cm "1; mass spec [El] , m / z 478 (M) "; Analysis calculated for C34H22OS. 1.6H20: C, 80.48; H, 5.01; N, 0.00, Found: C, 80.26; H, 4.63 N, 0.05.
Stage 2 (5'-benzo fbl naphtho, 3-di thiophene-11-yl- [1,1 '.-3'. 1"1-terphenyl-2'-yloxy) -acetic acid methyl ester The title compound is prepared as a white foam (0.788 g, 85%) from 5'-benzo [b] naphth [2, 3-d] thiophen-11-yl- [1, 1 ', -3' , 1"] terphenyl-2'-ol using a procedure similar to step 1 of example 36, mp> 75 ° C (decomposition); NMR (DMSO-d6) d 3.45 (s, 3H), 4.13 (s, 2H), 6.91 (d, J = 8.1 Hz, 1H), 7.22-7.27 (m, 1H), 7.33-7.38 (m, 2H) , 7.40-7.49 (m, 7H), 7.49-7.56 (m, 1H), 7.58-7.66 (m, 5H), 7.76 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1 H), 8.07 (d, J = 5.1 Hz, 1 H), 8.64 (s, 1 H); IR (KBr) 3430, 3060, 2940, 1760, 1740, 1615, 1590, 1500, 1465, 1420, 1410, 1390, 1380, 1305, 1200, 1070, 1035, 755, 700, and 615 cm "1, - Spectrum mass [El], m / z 550 (M) J Analysis calculated for C37H2603S-0.75H2O C, 78.77; H, 4.9 1; N, 0.00, Found: C, 78.90; H, 4.65; N, 0.06.
Stage 3 Acid (5'-benzo fbl naphtho2.3-dl thiophen-11-yl-fl, 1 ', -3' .1"1-terphenyl-2'-yloxy) -acetic To a stirred solution of the methyl ester of (5 '-benzo [b] naphtho [2,3-d] thiophen-11-yl- [1,1', -3 ', 1"] terphenyl-2'-yloxy) acetic acid (0.094 g, 0.171 mmol) in THF: MeOH (3: 2, 5 ml) at room temperature is added dropwise to 1 N KOH (0.861 ml, 0.861 mmol) After 2 hours this temperature is concentrated and diluted with H20 The solution is then acidified to pH 1 with 2 N HCl. The resulting solid is filtered off, washed with H20 and dried under high vacuum for 18 h, which recrystallizes from MeOH to give the product (0.063). g, 69%) as a whitish solid, pf >136 ° C (decomposition); 3 H NMR (DMSO-d 6) d 4.02 (s, 2 H), 6.91 (d, J = 7.9 Hz, 1 H), 7.22 7.27 (m, 1 H), 7.33-7.38 (m, 2 H), 7.39-7.48 (m, 7H), 7.50-7.55 (m, 1H), 7.58-7.63 (m, 1H), 7.64-7.68 (m, 4H), 7.77 (d, J = 3.6 Hz, 1H), 7.99 (d, J = 7.9 Hz , 1H), 8.07 (d, J = 8.1 Hz, 1H), 8.64 (s, 1H), 12.51-12.70 (broad s, 1H); IR (KBr) 3410, 3070, 2910, 1735, 1680, 1610, 1500, 1465, 1420, A 1395, 1385, 1325, 1210, 1165, 1070, 1040, 755, 735, and 700 cm "1, - Spectrum of mass [(+) BAR], m / z 537 (M + H) J- Analysis 5 calculated for C36H2403S 0.5H20: C, 79.24; H, 4.62; N, 0.00, Found: C, 78.98; H, 4.32; N, 0.02.
Example 38 f 10 (5 '-nitro- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) -acetic acid Stage 1 (5 '-nitro-fl.1' .3 '.1"1-tert-butyl-2-yloxy) -acetic acid methyl ester To a stirred solution of 5 '-nitro- [1, 1'; 3 ', 1"] terphenyl-2'-ol (0.250 g, 0.858 mmolee) and K2C03 (0.130 g, 0.944 mmolee) in 9 ml of DMF at room temperature. Methyl bromoacetate (0.162 ml, 1.72 mmol) is added dropwise. After 72 h at this temperature, it is diluted with 20 ml of H20, followed by 200 ml of excess EtOAc. The organic layer is washed with 50 ml of IN HCl, 50 ml of saturated NaHCO-, aqueous and 50 ml of brine, and then washed (MgSO4). After concentration, the residue is purified by flash chromatography (gradient of 5 to 30% of acetone / hexane) to provide the product (0.309 g, 99%) as a transparent oil; "-H NMR (DMSO-d6) d 3.37 (s, 3H), 4.03 (s, 2H), 7.43-7.53 (pt, 6H), 7.60-7.64 (m, 4H), 8.14 (s, 2H); (film) 3420, 3080, 2950, 1770, 1745, 1590, 1530, 1500, 1455, 1440, 1410, 1350, 1305, 1210, 1110, 1070, 910, 745, and 700 c "J- mass spec [The ], m / z 363 (M) J- Analysis calculated for C21H17N05. 0.75H2O: C, 66.93; H, 4.95; N, 3.72, Found: C, 66.89; H, 4.67; N, 3.51.
Stage 2 acid (5'-nitro-f 1.1 ', - 3'. 1"1-terphenyl-2'-hydroxy) -acetic The title compound is prepared as a white solid (0.229 g, 86%) from the methyl ester of the acid (5 '-nitro- [1, 1', -3 ', 1"] terphenyl-2'-yloxy) acetic using a procedure similar to step 2 of Example 36, mp 153.5-156 ° C; 'HRMN (DMSO-d6) 6 3.92 (s, 2H), 7.42-7.52 (m, 6H), 7.61-7.65 (m, 4H), 8.13 (s, 2H), 12.15-13.20 (s broad, 1 H), - IR (KBr) 3410, 3070, 2910, 2570, 1750, 1705, 1590, 1525, 1500, 1450, 1410, 1395, 1350, 1305, 1290, 1250, 1220, 1110, 1070, 910, 745, 725, and 710 cm "J- mass spectrum [El], m / z 349 (M) J-Analysis calculated for C20H15NO5: C, 68.76; H, 4.33; N, 4.01, Found: C, 68.66; H, 4.33; N, 3.89.
Example 39 acid (5 '-methoxy- (1.1'; 3 '.1"] terphenyl-2'-yloxy) acetic acid Stage 1 2.6-dibromo-4-methoxyphenol To a stirred solution of 4-methoxyphenol (0.500 g, 4.03 mmol) in CH2Cl2: MeOH (5: 2, 70 mL) at room temperature is added BTMABr3 (3.30 g, 8.46 mmol). After 18 h at this temperature, it is concentrated and diluted with 150 ml of EtOAc and 50 ml of H20. The organic layer is washed with 50 ml of brine and then dried (MgSO4). After concentration, the residue is purified by flash chromatography (gradient from 2 to 12% EtOAc / petroleum ether) and recrystallization from MeOH: H20 (1: 3) to give the product (1.00 g, 88%) as a solid cinnamon, pf 83-86 ° C; ? NMR (DMSO-ds) d 3.70 (s, 3H), 7.15 (s, 2H), 9.33 (s, 1H); IR (KBr) 3390, 2960, 2830, 1610, 1575, 1480, 1430, 1410, 1360, 1250, 1210, 1165, 1040, 845, 775, and 745 cm'J- mass spectrum [El], m / z 280 (M) J- Analysis calculated for C7H6Br202: C, 29.82; H, 2.15, N; 0.00, Found: C, 30.04; H, 2.15; N, 0.00 step 2 5'-methoxy-fl.l ': 3' .1"1 terphenyl -2 '-ol To a stirred solution of phenylboronic acid (0.0842 g, 0.691 mmol), Ba (OH) 2.8H20 (0.396 g, 1.26 mmol) and Pd (OAc) 2 (0.0014 g, 0.00628 mmolee) in DME: H20 (6: 1, 7 ml) at room temperature add 2,6-dibromo-4-methoxyphenol (0.0885 g, 0.314 mmolee)). The mixture is then heated at 80 ° C for 18 h. The reaction is 50% complete, and 2.2 additional equivalents of phenylboronic acid and 0.02 equivalents of Pd (OAc) 2 are added and heating is continued for another 24 h. At this point, the reaction is acidified to pH 1 with 1 N HCl and diluted with 100 ml of EtOAc. The organic layer is washed with 10 ml of H20 and 10 ml of brine, and then dried (MgSO4). After concentration, the residue is purified by flash chromatography (gradient from 1 to 5% EtOAc / petroleum ether) to give the product (0.029 g, 33%) as a clear oil; * H NMR (CDC13) 6 3.83 (s, 3H), 5.04 (s, 1H), 6.86 (s, 2H), 7.37-7.42 (m, 2H), 7.45-7.50 (m, 4H), 7.54-7.68 ( m, 4H); IR (film) 3540, 3060, 2930, 2820, 1605, 1580, 1500, 1470, 1425, 1360, 1330, 1210, 1175, 1120, 1060, 1040, 1025, 755, 700, and 500 cm "J- spectrum mass [El], m / z 276 (M) J-Analysis calculated for C19H1602.80H2O: C, 78.49; H, 6.10; N, 0.00, Found: C, 78.19; H, 5.54; N, 0.19.
Step 3: methyl ester of the acid 5'-methoxy- [1,1 ', -3', 1"1-terf-enyl-2'-yloxy) -acetic acid The title compound is prepared as a solid (0.106 g, 99%) from 5 '-methoxy- [1, 1'; 3 ', 1"] terphenyl-2'-ol using a procedure similar to step 1 of the example 36; JH NMR (CDC13) 6 3.46 (8, 3H), 3.77 (e, 2H), 3.86 (s, 3H), 6.89 (s, 2H), 7.32-7.46 (m, 6H), 7.63 (d, J = 8.3 Hz, 4H).
Stage 4 acid (S'-methoxy-fl.l1. -3 ', 1"1-terphenyl-2'-yloxy) acetic acid The title compound is prepared as a white solid (0.099 g, 91%) from the methyl ester of the acid (5 '-methoxy- [1, 1', - 3 ', 1"] terphenyl-2'-yloxy) acetic using a procedure similar to step 2 of example 36, mp 143-145 ° C;? NMR (DMS0-d6) 6 3.65 (s, 2H), 3.80 (s, 3H), 6.89 (s, 2H), 7.33 -7.39 (m, 2H), 7.39-7.45 (m, 4H), 7.57-7.61 (m, 4H), 12.40-12.46 (s broad, 1H); IR (KBr) 3380, 3080, 2920, 2890, 2810, 1770, 1740, 1600, 1575, 1495, 1470, 1425, 1360, 1240, 1210, 1180, 1160, 1070, 1045, 755, and 700 cm "1; mass spectrum [El], m / z 334 (M) J- Analysis calculated for C21Hlβ04. 0.25H20: C, 74.43; H, 5.50; N, 0.00, Found: C, 74.2 1; H, 5.49. N 0.09.
Example 40 (5'-bromo-n.l ': 3', 1"] terphenyl-2'-yloxy) -acetic acid Stage 1 4-bromo-2,6-divodofenol To a stirred solution of 4-bromophenol (0.500 g, 2.89 mmolee) and grit of ground NaOH (0.231 g, 5.78 mmol) in 18 ml of MeOH at 0 ° C is added in portions I2 (1.83 g, 7.23 mmol) for 1 hour. h. After 2 h at this temperature, it is acidified to pH 1 with HCl 2 and then diluted further with 50 ml of H20. The aqueous solution is extracted with 200 ml of EtOAc. The organic layer is ed with 50 ml of 10% aqueous Na2S203, 30 ml of H20 and 30 ml of brine, and then dried (MgSO4). After concentration, the residue is purified by flash chromatography (gradient from 2 to 10% EtOAc / petroleum ether) to give the product (0.525 g, 43%) as a solid, m.p. 122-124 ° C; 1 H NMR (CDC13) 6 5.74 (s, 1 H), 7.79 (s, 2H). step 2 5 '-bromo- fl, 1', -3 ', 1"! terphenyl -2' -ol The title compound is prepared as a solid (0.081 g, 42% product 1: bis-arylated) from 4-bromo-2,6-diiodophenol using the procedure similar to step 1 of Example 37; 1 l NMR (CDC13) 6 5.37 (s, 1 H), 7.34-7.58 (m, 12 H), - (for the aryl tris product see step 1 of example 41).
Stage 3 (5'-bromo-fl.1 ': 3'. 1"1-terphenyl-2'-yloxy) acetic acid methyl ester The title compound is prepared as a solid (0.085 g, 96%) from 5 '-bromo- [1, 1'; 3 ', 1"] terphenyl-2'-ol using a procedure similar to step 1 from the example 36; ? NMR (CDC13) d 3.47 (s, 3H), 3.80 (s, 2H), 7.34-7.50 (m, 8H), 7.59 (d, J = 8.2 Hz, 4H).
Stage 4: acid (5'-bromo-fl, 1 '. -3' .1"1-ter-2-yl) -acetic acid The title compound is prepared as a white solid (0.062 g, 83%) from the methyl ester of the acid (5'-bromo- [1,1 J-3 ', 1"] terphenyl-2'-yloxy) acetic acid using a procedure similar to step 2 of example 36, mp> 50 ° C (decomposition); JH NMR (CDC13) d 3.81 (e, 2H), 7.38-7.50 (m, 7H), 7.52-7.56 (, 5H ); IR (KBr) 3400, 3050, 2900, 1730, 1565, 1495, 1460, 1420, 1210, 1060, 875, 735, 700, and 610 cm "1: mass spectrum [(+) BAR], m / z 382 (M) J 405 (M + Na) *, - Analysis calculated for C20H15BrO3: C, 62.68; H, 3.95; N, 0.00, Found: C, 62.25; H, 4.01; N, 0.01.
Example 41 Acid [(5'-phenyl [1.1 ': 3' .1"-terphenyl] -2'-yl) oxy] acetic acid Step 1 5'-phenyl f1.1 ': 3' .1"-terphenyll-2'-ol The title compound is prepared as a solid (0.055 g, 28%, product 2: tris-arylation) from 4-bromo-2,6-diiodophenol using the procedure of Step 2 of the Example 40; * H NMR (CDC13) d 5.45 (s, 1 H), 7.27-7.57 (m, 11 H), 7. 62 (d, J = 8.3 Hz, 6H).
Step 2: Acid 2 f (5'-phenyl-1, 1'-3'-l "-terphenyl-2-yl) -oxyl-acetic acid The title compound is prepared as a white solid (0.040 g, 72%) using 5'-phenyl [1, 1 ': 3', l "-terphenyl] -2'-ol and a procedure similar to that of Steps 3 and 4 of Example 40, pf >68 ° C (decomposition); 'H NMR (CDC13) d 3.89 (s, 2H), 7.35-7.52 (m, 9H), 7.59 (e, 2H), 7.60-7.65 (m, 6H), IR (KBr) 3420, 3040, 2910, 1730 , 1610, 1495, 1460, 1420, 1215, 1090, 880, 750, and 700 cm "J- mass spectrum [(+) BAR], m / z 380 (M) J 403 (M + Na) * Calculated Analysis for C2SH2003 - 0.25 H20: C, 81.12; H, 5.37; N, 0.00, Found: C, 80.94, H, 5.46; N, 0.03.
Example 42 Acid (l, 3-Diphenyl-dibenzofuran-2-yloxy) acetic acid Stage 1 1.3-Dibromodibenzofuran-2-ol The title compound is prepared as a tan solid (0.840 g, 91%) from 2-hydroxydibenzofuran using a procedure similar to that of Step 1 of Example 39, mp 176-178 ° C; Jl NMR (DMS0-d6) d 7.46 (td, J = 0.88, 8.1 Hz, 1 H), 7.58-7.63 (m, 1 H), 7.72 (d, J = 8.3 Hz, 1 H), 8.05 (s, 1 H), 8.44 (dt, J = 0.44, 7.9 Hz, 1 H), 9.85 (e, 1 H); IR (KBr) 3420, 3110, 1630, 1460, 1425, 1375, 1340, 1230, 1170, 1150, 1120, 880, 860, 845, 745, and 715 cm "J spectrum de maea [El], m / z 340 (M) J Analysis calculated for C12H6Br202: C, 42.14; H, 1.77; N, 0.00, Found: C, 42.11; H, 1.74; N, 0.09.
Stage 2 1.3-Diphenhydibenzofuran-2-ol The title compound is prepared as a light yellow-orange solid (0.058 g, 59%) from 1,3-dibromodibenzofuran-2-ol using a procedure similar to that of Step 2 of Example 39, pf > 46 ° C (decomposition), - XH NMR (CDC13) d 5.14 (s, 1H), 6.99-7.08 (m, 2H), 7.35-7.44 (m, 2H), 7.48-7.68 (m, 1 1H); IR (KBr) 3530, 3060, 1600, 1500, 1460, 1450, 1420, 1320, 1260, 1220, 1160, 1130, 1070, 890, 800, 750, and 700 cm "J- mass spectrum [El], m / z 336 (M) J- Analysis Calculated for C24H1602 - 1.0 H20: C, 81.34; H, 5.12; N, 0.00, Found: C, 81.12; H, 4.79; N, -0.03.
Stage 3 (1,3-Diphenyl-dibenzofuran-2-yloxy) acetic acid methyl ester The title compound is prepared as a solid (0.115 g, 79%) from 1,3-diphenyldibenzofuran-2-ol using a procedure similar to that of Step 1 of Example 36; * H NMR (CDC13) d 3.46 (s, 3H), 3.86 (s, 2H), 7.00- 7.15 (m, 2H), 7.30-7.77 (m, 13H).
Stage 4 Acid (1,3-Diphenyl-dibenzofuran-2-yloxy) acetic acid The title compound is prepared as a white solid (0.091 g, 88%) from (1,3-diphenyl-dibenzofuran-2-yloxy) acetic acid methyl ester using a procedure similar to that of Step 2 of Example 36 , pf > 120 ° C (decomposition); ? NMR (DMS0-d6) d 3.66 (s, 2H), 6.80 (d, J = 7.5 Hz, 1H), 7.09-7.15 (m, 1H), 7.33-7.39 (m, 1H), 7.39-7.47 (m, 3H), 7.48-7.56 (m, 5H), 7.68 (d, J = 8.1 Hz, 1H), 7.70-7.74 (m, 3H), - IR (KBr) 3420, 3070, 2950, 2910, 1730, 1610, 1500, 1465, 1455, 1405, 1330, 1310, 1240, 1220, 1175, 1155, 1070, 750, and 700 cm "J- mass spec [El], m / z 394 (M) J- Analysis Calculated for C26H1804-1. 25 H20: C, 74. 90; H, 4 96; N, 0 00 Found: C, 75. 07; H, 4 89; N, 0 06 Example 43 Acid (2-Benzoyl-4-6-dibromo-benzofuran-5-yloxy) acetic acid Stage 1 Benzofuran-5-ol To a stirred solution of 5-methoxybenzofuran (0.100 g, 0.675 mmol) in CH2C12 (10 ml) at -78 ° C is added dropwise a 1.0M solution of boron tribromide in CH2C12 (2.16 ml, 2.16 mmolee). 1 h at this temperature, it is warmed to room temperature and stirred for an additional 18 h At this point, the reaction is suspended with H20 and diluted with EtOAc (50 ml) The organic layer is washed with brine (10 ml) and it is dried (MgSO 4). After concentration, the residue is purified in a Biotage Flash 40 apparatus (gradient of 15 to 30% acetone / hexane) to give the product (0.064 g, 71%) as a whitish off-white solid, mp. 55-57 ° C; 1 H NMR (CDC13) d 4.53-4.70 (broad s, 1 H), 6.67 (d, J = 0.66, 2.0 Hz, 1 H), 6.81 (dd, J = 2.6, 8.8 Hz, 1 H), 7.01 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H); IR (KBr) 3240, 2960, 1625, 1610 , 1545, 1460, 1410, 1385, 1290, 1195, 1125, 1110, 1030, 865, 810, 765, 735, and 620 cm "J- mass spectrum [El], m / z 134 (M) J- Analysis Calculated for C8Hs02: C, 71.63; H, 4.51; N, 0.00, Found: C, 71.19; H, 4.72; N, 0.05.
Step 2 2-Benzoyl benzofuran-5-ol 5 To a round bottom flask dried to the flame with benzofuran-5-ol (0.100 g, 0.754 mmol) and THF (10.0 ml) cooled to -10 ° C. n-BuLi 0.684 ml, 2.5 M in hexane, 1.71 mmolee) to drop over a period of 10 minutes. The resulting 10 k solution is allowed to stir for 10 minutes while heating to -5 ° C. After cooling, the mixture is again reduced to -20 ° C, and N-methoxy-N-methylbenzamide (0.125 ml, 0.820 mmol) is added dropwise. The solution is stirred at this temperature for 0.5 h and then heated to15 the room temperature for an additional 3 h. At this point, the reaction mixture is suspended with saturated aqueous NH 4 Cl (10 mL) and diluted with EtOAc (100 mL). The organic layer is washed with additional saturated aqueous NH4C1 (10 ml) and brine (10 ml) and then dried (Mg904). After concentration, the residue is purified by flash chromatography (gradient from 10 to 30% EtOAc / petroleum ether) to give the product (0.089 g, 50%) as a yellow powder, mp 159-160 ° C; "-H NMR (DMS0-d6) d 7.02 (d, J = 2.4, 8.8 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.54-7.62 (m, 3H), 7.64 (d, J = 0.66 Hz, 1 H), 7.68-7.73 (m, 1 H), 7.94-7.99 (m, 2H), 9.51 (s, 1 H); IR (KBr) 3380, 2920, 1630, 1600, 1580, 1545, 1470, 1430, 1360, 1335, 1325, 1260, 1200, 1170, 1125, 980, 890, 860, 820, 725, and 630 cm "1; mass spec [El] , m / z 238 (M) J- Analysis Calculated for C15H1003 - 0.25 H20: C, 74.22; H, 4.36; N. 0.00, Found: C, 73.99, H, 4.48; N, 0.13.
Stage 3 Methyl ester of (2-Be n z or i 1-4,6-dibromobenzofuran-5-yloxy) acetic acid ester The title compound is prepared as a solid (0.072 g, 58%) using benzoylbenzofuran-5-ol and a procedure similar to that of Steps 1 and 3 of Example 39; 'H NMR (CDC13) 6 3.92 (s, 3H), 4.68 (s, 2H), 7.47 (e, 1H), 7.57 (t, J = 9.3 Hz, 2H), 7.68 (t, J = 9.3 Hz, 1H ), 7.86 (e, 1H), 8.04 (d, J = 8.5 Hz, 2H); mass spectrum [(+) ESI], m / z 469 (M + H) *.
Stage 4 Acid (2-Benzoyl-4,6-dibromobenzofuran-5-yloxy) acetic acid The title compound is prepared as an off-white solid (0.060 g, 88%) from methyl ether of acid (2-benzoyl-4,6-dibromobenzofuran-5-yloxy) acetic using a procedure similar to that of Step 2 of Example 36, mp 179-181 ° C; "H NMR (DMS0-d6) d 4.54 (s, 2H), 7.58 (d, J = 0.88 Hz, 1H), 7.60-7.65 (m, 2H), 7.74 (tt, J = 1.3, 6.8 Hz, 1H), 7.99-8.03 (m, 2H), 8.31 (d, J = 0.88 Hz, 1H), 12.98-13.32 (s broad, 1H); IR (KBr) 3420, 3080, 2910, 2580, 1740, 1645, 1610, 1540, 1440, 1410, 1330, 1290, 1250, 1175, 1125, 1070, 1000, 970, 915, 860, 800, 715, and 675 cm "J- mass spectrum [(-) ESI], m / z 451 (M - H) *; Analysis calculated for C17HloBr205: C, 44.97; H, 2.22; N, 0.00, Found: C, 44.7 1; , 2.13; N, 0.04.
Example 44 Acid (5 '-Butoxy-1,1': 3 ', 1"-terphenyl-2'-yloxy) acetic acid Stage 1 3, 5-Diiodo-4-methoxyethoxymethoxybenzaldehyde To a stirred solution of 3,5-i and odo-4-hydroxybenzaldehyde (10.0 g, 26.7 mmol) in THF (267 ml) at 0 ° C is added NaH (1.39 g, 34.7 mmol). After 0.5 h at this temperature, MEMC1 (4.88 ml, 42.7 mmoles) is added dropwise. The reaction mixture is stirred for another 15 minutes at 0 ° C and then at room temperature for 18 h. The resulting mixture is suspended with NaOH 0. IN and extracted with Et20 (1000 ml). The organic layer is washed with 0. NaOH (3 x 100 ml) and brine (100 ml), and then dried (MgSO 4). After concentration, the residue is purified by flash chromatography (gradient from 5 to 15% EtOAc / petroleum ether) to provide the product (8.60 g, 69%) as a solid; 1 H NMR (CDC13) d 3.44 (s, 3 H), 3.67 (t, J = 5.5 Hz, 2 H), 4.16 (t, J = 5.5 Hz, 2 H), 5.34 (8, 2 H), 8.29 (e, 2 H) 9.82 (s, 1H).
Step 2 2'-Oxyethoxymethoxy-1: 3 ', 1"1-terphenyl-5'-carboxaldehyde The title compound is prepared as a solid (0.995 g, 84%) from 3,5-diiodo-4-methoxyethoxymethoxy-benzaldehyde using a procedure similar to that of Step 1 of Example 37; XH NMR (CDC13) d 2.83-2.90 (m, 2H), 2.93-2.99 (m, 2H), 3.17 (e, 3H), 4.52 (S, 2H), 7.33.-7.49 (m, 6H), 7.62 ( d, J = 8.3 Hz, 4H), 7.90 (s, 2H), 10. 06 (s, 1H).
Step 3 2'-Methoxyethoxymethoxy- [1.1 ': 3', 1"1 terphenyl-5'-ol To a stirred solution of 2 '-methoxyethoxymethoxy- [1,1': 3 ', 1"] terphenyl-5' -carboxaldehyde (0.836 g, 2.31 mmol) in CH2C12 (25 mL) at room temperature is added MCPBA (0.598 g). 3.46 mmol) The reaction mixture is refluxed for 48 h After concentration, the residue is dissolved in EtOAc (300 mL), the organic layer is washed with saturated aqueous NaHCO3 until the effervescence ceases, followed by brine. (30 ml) and then dried (Na 2 SO 4). After concentration, the residue is dissolved in THF: MeOH (3: 2, 45 ml) followed by addition of additional KOH ÍN drops (11.6 ml, 11.6 mmol). The reaction mixture is stirred at room temperature for 1.5 h and then concentrated. The residue is diluted with H20 (30 ml) and then acidified to pH 4 with IN HCl followed by extraction with EtOAc (300 ml). This organic layer is washed with brine (30 ml) and then dried (MgSO 4). After concentration, the residue is purified in a Biotage Flash 40 apparatus (gradient of 5 to 15% acetone / hexane) to provide the product (0.490). g, 61%) as a solid; 1 H NMR (CDC13) d 2.73-2.86 (m, 2H), 2.90-2.98 (m, 2H), 3.17 (s, 3H), 4.35 (s, 2H), 4.67 (s, 1H), 6.82 (s, 2H) ), 7.27-7.47 (m, 6H), 7.57 (d, J = 9.3 Hz, 4H), -spectrum of mass [(+) ESI], m / z 373 (M + Na) *.
Step 4 (2'-Methoxyethoxymethoxy-fl.l ': 3', 1"1-terphenyl-5'-yloxy) butane To a stirred solution of 2 '-methoxyethoxymethoxy- [1, 1': 3 J 1"] terphenyl-5'-ol (0.240 g, 0.685 mmol) in DMF (10 mL) at room temperature is added K2C03 (0.123 g, 0.890 mmole) followed by the dropwise addition of 1-bromobutane (0.147 ml, 1.37 mmole) The reaction mixture is then heated to 60 ° C. After 4 days at this temperature, the resulting solution is diluted with H20 (10 ml). ml) and an excess of EtOAc (100 ml) The organic layer is washed with IN HCl (10 ml), aqueous NaHCO 3. saturated (10 ml), and brine (10 ml) and then dried (MgSO4). After concentration, the residue is purified by preparative plate chromatography (20% EtOAc / petroleum ether) to give the product (0.257 g, 92%) as a solid; JH NMR (CDC13) 6 0.97 (t, J = 8.1 Hz, 3H), 1.46-1.57 (m, 2H), 1.72-1.82 (m, 2H), 2.80 (t, J = 5.6 Hz, 2H), 2.95 ( t, J = 5.6 Hz, 2H), 3.17 (s, 3H), 3.99 (t, J = 6.9 Hz, 2H), 4.37 (s, 2H), 6.87 (s, 2H), 7.28-7.46 (m, 6H) ), 7.58 (d, J = 7.5 Hz, 4H); eepectro de maea [(+) ESI], m / z 429 (M + Na) *.
Step 5 5 '-Butoxy-fl.l' -.3 ', 1"1 terphenyl -2' -ol To an agitated solution of (2 '-methoxyethoxymethoxy- [1,1', 3 ', 1] terphenyl-5'-yloxy) butane (0.237 g, 0.583 mmol) in CH2C12 (6 mL) at room temperature is added anhydrous ZnBr2. , (0.656 g, 2.92 immoles). After 18 h at this temperature, the resulting mixture is diluted with EtOAc (100 mL). The organic layer is washed with saturated aqueous NaHCO3 (10 ml) and brine (10 ml) and then dried (MgSO4). After concentration, the residue is purified by preparative plate chromatography (10% EtOAc / petroleum ether) to give the product (0.172 g, 92%) as a solid, - 'H NMR (CDC13) 6 0.97 (t, J = 10.9 Hz, 3H), 1.39-1.60 (m, 2H), 1.68-1.87 (, 2H), 3.97 (t, J = 9.5 Hz, 2H), 5.05 (s, 1H), 6.87 (s, 2H) , 7.32-7.62 (m, 10H), - mass spectrum [(+) ESI], m / z 319 (M + H) J 341 (M + Na) *.
Stage 6 (5 '-Butoxy-1: 1': 3 '. 1"! Tert-butyl-2-yloxy) -acetic acid methyl ester The title compound is prepared as a solid (0.203 g, 96%) at par + r of 5 '-butoxy [1, 1': 3 ', 1"] terphenyl-2'-ol using a procedure similar to that of Step 1 of Example 36; 'H NMR (CDC13) d 0.98 (t, J = 10.7 Hz, 3H), 1.41-1.62 (m, 2H), 1.68-1.89 (m, 2H), 3.46 (8, 3H), 3.77 (e, 2H), 4.00 (t, J = 9.3 Hz, 2H), 6.89 (s, 2H), 7.28-7.48 (m, 6H), 7.63 (d, J = 8.6 Hz, 4H), mass spectrum [(+) ESI], m / z 391 (M + H) J 413 (M + Na) *.
Step 7 Acid (5 '-Butoxy-fl.1': 3 '. L "lterphenyl-2'-yloxy) acetic acid The title compound is prepared as an off-white solid (0.167 g, 85%) from (5 '-butoxy- [1, 1': 3 ', 1"] terphenyl-2'-yloxy) acetic using a similar procedure to that of Step 2 of Example 36, mp 92-94 ° C; 'HRMN (DMSO-lJ 6 0.92 (t, J = 7.5 Hz, 3H), 1.38-1.49 (m, 2H), 1.65-1.74 (m, 2H), 3.64 (s, 2H), 4.02 (t, J = 6.6 Hz, 2H), 6.87 (s, 2H), 7.33-7.39 (m, 2H), 7.39-7.44 (m, 4H), 7.57-7.61 (m, 4H), 12.30-12.55 (8 broad, 1H); IR (KBr) 3420, 3060, 2930, 2860, 2770, 2590, 1725, 1590, 1570, 1460, 1420, 1360, 1260, 1235, 1215, 1195, 1075, 1050, 1010, 925, 760, 750, 700, and 620 • cm "J- mass spectrum [(+) ESI], m / z 394 (M + NH4) J- Analysis 5 Calculated for C24H2404: C, 76.57; H, 6.43; N, 0.00, Found: C, 76.33; H, 6.55; N, -0.04.
Example 45 Acid (5'-Octyloxy- [1,1 ': 3'. 1"] terphenyl-2'-yloxy) acetic acid • Stage 1 12'-Methoxyethoxymethoxy-fl. ': 3', l "1-phenyl-5-yloxy) octane The title compound is prepared as a solid (0.305 g, 97%) from 2'-me t-oxy oxy-t-ox i - [1, 1 ': 3', l "] terphenyl-5'-ol using a procedure similar to that of Step 4 of the Example 44; 'H NMR (CDC13) d 0.87 (t, J = 7.7 Hz, 3H), 1.22-1.53 (m, 10H), 1.72-1.96 (m, 2H), 2.81 (t, J = 5.8 Hz, 2H), 2.96 (t, J = 5.8 Hz, 2H), 3.16 (s, 3H), 3.98 (t, J = 7.0 Hz, 2H), 4.36 (e, 2H), 6.88 (s) , 2H), 7.27-7.46 (m, 6H), 7.59 (d, J = 7.7 Hz, 4H); mass spectrum [(+) ESI], m / z 485 (M + Na) *.
Step 2 Acid (5'-Octyloxy-fl.l ': 3', 1"1-terf-enyl-2'-yloxy) acetic acid The title compound is prepared as a white solid (0.121 g, 52%) from (2 '-methoxyethoxymethoxy- [1,1', - 3 ', 1"] ter phenyl-5'-yloxy) octane using a procedure similar to Steps 5-7 of Example 44, mp 82-84 ° C; * H NMR (DMS0-d6) d 0.84 (t, J = 7.0 Hz, 3H), 1.20-1.35 (m, 8H) , 1.35-1.45 (m, 2H), 1.65-1.74 (m, 2H), 3.64 (s, 2H), 4.01 (t, J = 6.6 Hz, 2H), 6.86 (s, 2H), 7.33-7.38 (m , 2H), 7.39-7.44 (m, 4H), 7.56-7.60 (m, 4H), 12.28-12.64 (broad e, 1 H); IR (KBr) 3420, 3060, 2920, 2850, 2580, 1725, 1620 , 1460, 1420, 1360, 1265, 1220, 1200, 1095, 1050, 1030, 860, 845, 750, and 700 cm "J- mass spectrum [(+) ESI], m / z 450 (M + NH4) J- Calculated Analysis for C28H3204: C, 77.75; H, 7.46; N, 0.00, Found: C, 77.37; H, 7.47; N, -0.03.
Example 46 Acid (3,3"-Dichloro-5 '-octyloxy- [1, 1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid The title compound is prepared as a white solid (0.233 g, 39%) from 3, 5-d i and od or 4-hydroxybenzaldehyde using 3-chlorofenylboronic acid and procedures similar to Examples 44 and 45, mp 113-115.5 ° C. "H NMR (DMS0-d6) d 0.84 (t, J = 7.0 Hz, 3H), 1.20-1.36 (m, 8H), 1.36-1.45 (m, 2H), 1.66-1.74 (m, 2H), 3.67 ( s, 2H), 4.03 (t, J = 6.4 Hz, 2H), 6.94 (s, 2H), 7.41-7.48 (m, 4H), 7.56 (dt, J = 2.0, 6.6 Hz, 2H), 7.65-7.68 (m, 2H), 12.45-12.66 (broad s, 1H); IR (KBr) 3420, 2920, 2860, 2590, 1720, 1590, 1560, 1475, 1460, 1 25, 1395, 1350, 1320, 1270, 1240 , 1200, 1150, 1070, 1050, 860, 780, and 695 cm "J- mass spectrum, [El], m / z 500 (M) J- Analysis Calculated for C28H30C1204: C, 67.07; H, 6.03; N, 0.00, Found: C, 67.07; H, 6.16; N, 0.10.
Example 47 Acid (3, 3"-Bis-acetylamino-5 '-octyloxy- [1, 1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid The title compound is prepared as such a tan solid (0.065 g, 7%) from 3,5-diiodo-4-hydroxybenzaldehyde using 3-acetamidobenzeneboronic acid and procedures similar to Examples 44 and 45, pf > 100 ° C (decomposition); JH NMR (DMS0-d6) d 0.86 (t, J = 6.8 Hz, 3H), 1.23-1.37 (m, 8H), 1.37-1.46 (m, 2H), 1.68-1.76 (m, 2H), 2.06 (s) , 6H), 3.72 (s, 2H), 4.01 (t, J = 6.4 Hz, 2H), 6.83 (s, 2H), 7.24 (d, J = 7.7 Hz, 2H), 7.33 (t, J = 7.7 Hz , 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 1.8 Hz, 2H), 10.01 (s, 2H), 12. 33-12.61 (broad s, 1H); IR (KBr) 3320, 2930, 2860, 1740, 1670, 1585, 1555, 1485, 1455, 1420, 1375, 1360, 1320, 1250, 1200, 1075, 860, 785, 710, and 540 cm "J mass spectrum [(+) ESI], m / z 547 (M + H) J 564 (M + NH4) *; Analysis Calculated for 5 C32H38N206 - 0.5 H20: C, 69.17; H, 7.07; N, 5.04, Found: C, 69.34; H, 7.19; N, 4.78.
Example 48 Acid (5'-Octyloxy-3, 3"-bis-trif luoromethyl [1, 1 '; 3', 1"] terphenyl- • 2'-yloxy) acetic acid The title compound is prepared as a white solid (0.136 g, 16%) from 3, 5-diiodo-4-15 hydroxybenzaldehyde using 3 - (trifluoromethyl) phonylboronic and procedures similar to Examples 44 and 45, mp 75-77 ° C, "H NMR (CDC13) d 0.88 (t, J = 6.8 Hz, 3H), 1.23-1.41 (m, 8H), 1.43-1.52 (m, 2H), 1.76-1.85 (m, 2H), 3.75 (s, 2H), 4.01 (t, J = 6.6 Hz, 2H), 6.91 (e, 2H), 7.57 (t, J = 7.9 Hz, 2H), 7.65 (d, J = 7.9 Hz, 2H), 7.80 (d, J = 7.7 Hz, 2H), 7.85 (s, 2H); IR (KBr) 3440, 2930, 2860, 2690, 2580, 1725, 1605, 1590, 1470, 1440, 1410, 1370, 1335, 1270, 1245, 1210, 1170, 1125, 1090, 1070, 1045, 910, 800, and 710 cm "1; mass spectrum [(-) ESI], m / z 567 (M - H) J- Analysis ^ ÍHÉ? ^^ jRg ^ Calculated for C30H30F604: C, 63.38; H, 5.32; N, 0.00, Found: C, 63.41; H, 5.47; N, 0.00 Example 49 Acid (3.3"-Dinitro-5 '-octyloxy- [1, 1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid The title compound is prepared as an off-white solid (0.143 g, 20%) from 3,5-diiodo-4-hydroxybenzaldehyde using 3-nitrophenylboronic acid and procedures similar to Examples 44 and 45, mp 129-132 ° C; "H NMR (DMSO-d6) d 0.86 (t, J = 7.0 Hz, 3H), 1.24-1.38 (m, 8H), 1. 38-1.48 (m, 2H), 1.69-1.78 (m, 2H), 3.70 (s, 2H), 4.08 (t, J = 6.4 Hz, 2H), 7.11 (s, 2H), 7.75 (t, J = 8.1 Hz, 2H), 8.09 (dt, J = 1.3, 7.9 Hz, 2H), 8.26 (ddd, J = 0.88, 2.4, 8.3 Hz, 2H), 8.47 (t, J = 2.0 Hz, 2H), 12.43-12.58 (broad s, 1H); GO (KBr) 3420, 3220, 3120, 2940, 2860, 1745, 1670, 1600, 1570, 1530, 1460, 1410, 1350, 1310, 1235, 1205, 1080, 1070, 865, 815, 735, 720, and 695 cm "1; mass spectrum [(-) ESI], m / z 521 (M - H ) "; Analysis Calculated for C2ßH30N208 - 0.25 H20: C, 63.81; H, . 83; N, 5.32, Found: C, 63.90; H, 5.73; N, 5.24.
Example 50 Acid (3, 3"-Dimethoxy-5 '-octyloxy- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid The title compound is prepared as a clear oil (0.191 g, 35%) from 3,5-diiodo-4-hydroxybenzaldehyde using 3-methoxyphenylboronic acid and procedures similar to Examples 44 and 45; l NMR (DMSO-d6) 6 0.84 (t, J =, 0 Hz, 3H), 1.21-1.35 (m, 8H), 1.35-1.45 (m, 2H), 1.66-1.75 (m, 2H), 3.71 ( s, 2H), 3.78 (s, 6H), 4.01 (t, J = 6.6 Hz, 2H), 6.87 (s, 2H), 6.92 (dd, J = 2.4, 8.1 Hz, 2H), 7.11-7.17 (m , 4H), 7.33 (t, J = 7.9 Hz, 2H), 12.45-12.55 (broad s, 1H); IR (film) 2930, 2880, 2590, 1730, 1595, 1495, 1465, 1415, 1360, 1300, 1240, 1200, 1075, 1050, 870, 780, 750, 710, and 500 cm "J- mass spectrum [ (-) ESI], m / z 491 (M -H) Analysis Calculated for C30H3606 - 0.5 H20: C, 71.83; H, 7.43; N, 0.00, Found: C, 72.17; H, 7.58; N, 0.05.
Example 51 [3, 3"-D? Chloro-5 '- (3-phenyl-propylcarbamoyl) - [1, 1'; 3 ', 1"] terf in? L-2'-yloxy) acetic acid Step 1 N- (3-Fe? Nlpropyl) -3,5-bis (m-chlorophenyl) -4- (2-hydroxyethoxy) -benzamide To a flame-dried round bottom flask with 3-phenyl-1-propylamine (0.404 ml, 2.84 mmol) and THF (5 ml) cooled to -78 ° C, n-BuLi (1.14 ml, 2.5 M) was added dropwise. in hexane, 2.84 mmol) over a period of 5 minutes. The resulting solution is stirred at this temperature for 0.5 h, heated at 0 ° C for 10 minutes, and then cooled back to -40 ° C. This lithiated amine solution is added dropwise to a solution (at -40 ° C) of 3,5-bie- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester (0.350 g, 0.811 mmolee ) in THF (15 ml-) for 5 minutes. The final mixture is stirred at -40 ° C for 15 minutes and then heated to room temperature for 15 minutes. At this point, the reaction mixture is quenched with H20 (20 ml) and diluted with EtOAc (200 ml). The organic layer is washed with IN HCl (20 ml), saturated aqueous NaHC03 (20 ml), and brine (20 ml) and then dried (MgSO4). After concentration, the residue is purified on a Biotage Flash 40 appus (gradient of 20 to 40% EtOAc / hexane) to give the product (0.347 g, 82%) as a solid, - XH NMR (CDC13) d 1.44- 1.68 (broad s, 1 H), 2.01 (t, J = 7.0 Hz, 2H), 2.74 (t, J = 7.7 Hz. 2H), 3.27-3.46 (m, 4H), 3. 53 (dd, J = 7.7, 14.7 Hz, 2H), 5.94-6.08 (broad e, 1H), 7.02-7.13 (m, 1H), 7.13-7.33 (m, 4H), 7.33-7.46 (m, 4H) , 7.46-7.54 (m, 2H), 7.61 (e, 4H); mass spectral [(+) APCI], m / z 520/522 (M + H) *.
Step 2 Acid [3.3"-Dichloro-5 '- (3-phenyl-propylcarbamoyl)-fl.1', -3 ', 1" 1-terphenyl-2'-yloxy-1-acetic acid To a stirred solution of N- (3-phenylpropyl) -3, 5-bie (m-chlorophenyl) -4- (2-hydroxyethoxy) benzamide (0.330 g, 0.634 mmol) in CH3CN (6 mL) at room temperature is added NMMO (0.149 g, 1.27 mmol) followed by TPAP (0.022 g). , 0.0634 immoral). After 2 h, the reaction mixture still shows the presence of intermediate aldehyde. Another 0.3 equivalents of NMMO (0.022 g) and 0.015 equivalents of TPAP (0.003 g) are added, and the reaction is stirred for an additional 1 h. The mixture is suspended with IN HCl (2 ml), followed by 10% aqueous NaHS03 (15 ml). After stirring for ~ 10 minutes, the mixture is diluted with EtOAc (100 mL). The resulting organic layer is washed with IN HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL) and then dried (MgSO4). After concentration, the residue is purified by chromatography on preparation plate (10% MeOH / CHC13) to give the product (0.135 g, 40%) as a gray solid, mp >79 ° C (decomposition); 'H NMR (DMS0-dβ) d 1.79-1.87 (m, 2H), 2.62 (t, J = 7.5 Hz, 2H), 3.27-3.35 (m, 2H), 3.77-3.83 (m, 2H), 7.13- 7.18 (m, 1H), 7.19-7.23 (m, 2H), 7.24-7.29 (m, 2H), 7.44-7.51 (m, 4H), 7.56-7.60 (m, 2H), 7.68-7.70 (m, 2H) ), 7.86 (s, 2H), 8.49 (t, J = 5.5 Hz, 1H), 11.90-13.20 (broad s, 1H); IR (KBr) 3430, 3080, 3020, 2920, 2320, 1735, 1635, 1620, 1570, 1545, 1470, 1450, 1425, 1390, 1350, 1210, 1080, 1055, 875, 755, and 700 cm "J- mass spectrum [(-) ESI], m / z 532/534/536 (M - H)" Calculated Analysis for C30H2sCl2NO4 -H20: C, 65.22; H, 4.93; N, 2.54, Found: C, 65.33; H, 4.43; N, 2.61.
Example 52 Acid [3, 3"-Dichloro-5 '- (2-pyridin-2-yl-ethylcarbamoyl) - [1, 1'; 3 ', l"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.128 g, 32%) from 3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester using 2- (2- aminoethyl) pyridine and a procedure similar to that of Example 51, pf > 94 ° C (decomposition); ! H NMR (DMSO-d6) d 3.01 (t, J = 7.5 Hz, 2H), 3.64 (dd, J = 6.6, 14.3 Hz, 2H), 3.82 (s, 2H), 7.22 (ddd, J = 0.9, 4.8, 7.5 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.46-7.53 (m, 4H), 7.58-7.62 (m, 2H), 7.68-7.73 (m, 3H), 7.85 (s) , 2H), 8.51 (ddd, J = 0.9, 1.8, 4.8 Hz, 1H), 8.72 (t, J = 5.9 Hz, 1H), 11.70-13.15 (broad s, 1H); IR (KBr) 3440, 3090, 2920, 2350, 2340, 1725, 1640, 1610, 1570, 1550, 1475, 1450, 1435, 1400, 1300, 1320, 1245, 1210, 1170, 1100, 1080, 1050, 880, 760, and 700 cm "J- mass spectrum [(-) ESI], m / z 519/521/523 (M - H) J- Calculated Analysis for C28H22C12N204 - 2.0 H20: C, 60.33; H, 4.70; N, 5.03, Found: C, 60.06; H, 3.98; N, 4.84.
Example 53 Acid [5 '- (Benzyl-phenethyl-carbamoyl) -3,3"-Dichloro- [1, 1'; 3 ', 1"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white foamy solid (0.181 g, 37%) from 3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester using N-benzyl ether. 2-phenethylamine and a procedure similar to that of Example 51, pf > 67 ° C (deecomposition), - "H NMR (DMS0-ds) 6 2.73-2.98 (m, 2H), 3.16-3.67 (m, 2H), 3.67-3.80 (m, 2H), 4.42-4.87 (m, 2H), 6.86-6.93 (m, 1H), 6.98-7.14 (m, 3H), 7.14-7.32 (m, 6H), 7.32-7.64 (m, 10H), 12.30-13.40 (s broad, 1H); (KBr) 3420, 3070, 3020, 2920, 2320, 2300, 1750, 1730, 1630, 1600, 1570, 1475, 1450, 1430, 1400, 1370, 1350, 1240, 1210, 1150, 1090, 1075, 1025, 875 , 780, 750, 730, and 705 cm "1; mass spectrum [(-) ESI], m / z 608/610/612 (M-H) ", - Analysis Calculated for C3SH29C12N04 -2.0 H20: C, 66.88; H, 5.14; N, 2.17, Found: C, 66.4 1; H, 4.50; N, 2.28.
Example 54 Acid [3,3"-Dichloro-5 '- (4-phenyl-butylcarbamoyl) - [1,1 J-3', l"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.128 g, 48%) from the 3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester using 4-phenylbutylamine and a procedure similar to Example 51, pf > 164 ° C (decomposition),? NMR (DMSO-d6) d 1.48-1.65 (m, 4H), 2.59 (t, J = 7.2 Hz, 2H), 3.29 (d, J = 6.6, 12.5 Hz, 2H), 3.79 (s, 2H), 7.12 -7.20 (m, 3H), 7.22-7.27 (m, 2H), 7.43-7.50 (m, 4H), 7.56-7.60 (m, 2H), 7.68 (s, 2H), 7.85 (s, 2H), 8.57 (t, J = 5.7 Hz, 1H), 12.25-13.25 (broad s, 1H), - IR (KBr) 3420, 3080, 3020, 2930, 2820, 2320, 1735, 1635, 1620, 1570, 1560, 1475, 1455, 1420, 1390, 1360, 1330, 1245, 1215, 1100, 1080, 1050, 890, 810, 780, 755, and 700 cm "1; mass spectrum [(-) ESI], m / z 546/548 / 550 (M-H) "; Analisis Calculated for C31H27C12N04 - H20: C 65.73; H, 5.16, N, 2.47, Found: C, 65.53; H, 4.40; N, 2.59.
Example 55 [5- (Benzyl-eethyl-carbamoyl) -3-bromo-3'-chloro-biphenyl-2-yloxy] acetic acid The title compound is prepared as an off-white vitreous tanstance (0.043 g, 12%) from ethyl 3-br-orne-5-ethyl ester (m-c 1 or of eni 1) - 4 - (2 - hydroxyethoxy) benzoic using N-benzyl-2-phenethylamine and a procedure similar to that of Example 51, pf > 72 ° C (decomposition); 'H NMR (DMS0-d6) d 2.74-2.96 (m, 2H), 3.20-3.63 (m, 2H), 3.94-4.05 (m, 2H), 4.40-4.84 (m, 2H), 6.90-7.62 (m, 16H), 12.50-13.3, (s broad, 1H), IR (KBr) 3440, 3070, 3020, 2920, 2320, 1755, 1725, 1630, 1600, 1475, 1450, 1420, 1370, 1330, 1220, 1190, 1080, 1030, 885, 755, and 700 cm "1: mass spectrum [(-) ESI ], m / z 576/578/580 (M - H) ", - Analysis Calculated for C30H25BrClNO4-2.5 H20: C, 57.75; H, 4.85; N, 2. 24, Found: C, 57.45; H, 3.85, N, 2.23.
Example 56 [3-Bromo-3'-chloro-5- (2-pyridin-2-yl-ethylcarbamoyl) -biphen-l-2-yloxy] acetic acid The title compound is prepared as a white solid (0.028 g, 9%) from the ethyl ester of 3-bromo-5- (m-chlorofeml) -4- (2-hydroxyethoxy) benzoic acid using 2- (2- aminoethyl) pyridine and a procedure similar to that of Example 51, pf > 102 ° C (decomposition); XH NMR (DMSO-ds) d 3.00 (t, J = 7.5 Hz, 2H), 3.63 (dd, J = 7.5, 13.6 Hz, 2H), 4.02 (s, 2H), 7.23 (dd, J = 6.3, 9. * u * Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.47-7.51 (m, 2H), 7.55-7.60 (m, 1H) , 7.67 (s, 1H), 7.71 (td, J = 1.8, 9.6 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 8.50-8.53 ( m, 1H, 8.73- (t, J = 7.7 Hz, 1H), 11.80-13.30 (8 broad, 1H); IR (KBr) 3430, 3080, 2910, 2330, 1725, 1635, 1605, 1560, 1480, 1450 , 1420, 1370, 1330, 1225, 1190, 1140, 1120, 1080, 1030, 890, 755, and 700 cm "1; mass spectrum [(+) ESI], m / z 489/491 (M + H) *; Calculated Analysis for C22H18BrClN204 - 0.6 CHC13: C, 48.35; H, 3.34; N, 4.99, Found: C, 47.99; H, 3.30; N, 4.87.
Example 57 [5 '- (Benzyl-phenethyl-carbamoyl) -3"-chloro-3-trif-loromethyl- [1,1', 3 ', 1"] terfenyl-2'-yloxy] acetic acid The title compound is prepared as a whitish vitreous substance (0.089 g, 29%) from the 3- (m-chlorophenyl) -4- (2-hydroxyethoxy) -5- (m -trif luoromethylphenyl) ethyl ester. -benzoic using N-benzyl-2-phenethylamine and a procedure similar to that of Example 51, pf > 75 ° C (decomposition), - "-H NMR (DMSO-d6) d 2.77-2.98 (m, 2H), 3.25-3.67 (m, 2H), 3.70-3.80 (m, 2H), 4.45-4.85 (m , 2H), 6.87-7.92 (m, 20H), 12.45-13.05 (s broad, 1H); IR (KBr) 3430, 3070, 3020, 2920, 1755, 1740, 1635, 1610, 1495, 1475, 1450, 1425 , 1365, 1330, 1290, 1240, 1210, 1170, 1130, 1100, 1080, 1030, 890, 800, 755, and 700 cm "J- mass spectrum [(-) ESI], m / z 642/644 (M - H) J- Calculated Analysis for C37H29C1F3N04-1.5 H20: C, 66.22; H, 4.81; N, 2.09, Found: C, 66.07; H, 4.19; N, 2.10.
Example 58 Acid [3"-chloro-5 '- (2-pyridin-2-yl-ethylcarbamoyl) -3-trifluoromethyl- [1,1'; 3 ', 1"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as a light brown glassy material (0.075 g, 29%) from the ethyl ester of 3- (m-chlorofenyl) -4- (2-hydroxyethoxy) -5- (mt rif) luo r orne ti 1 f eni 1) - ben zoi co using 2- (2-aminoethyl) pyridine and a procedure similar to that of Example 51, pf > 92 ° C (decomposition); XH NMR (DMSO-d6) 3.01 (t, J = 7.7 Hz, 2H), 3.64 (dd, J = 6.6, 13.0 Hz, 2H), 3.78 (s, 2H), 7.22 (ddd, J = 0.9, 4.8, 7.5 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.46-7.53 (m, 2H), 7.59-7.62 (m, 1H), 7.67-7.74 (m, 3H), 7.77 (d, J = 7.9 Hz, 1 H), 7.87 (dd, J = 2.2, 5.1 Hz, 2H), 7.94 (d, J = 7.9 Hz, 1 H), 7.98 (s, 1 H), 8.49-8.52 (m, 1H), 8.73 (t, J = 5.3 Hz, 1H), 11.90-13.70 (broad s, 1H); IR (KBr) 3440, 3080, 2920, 1730, 1640, 1605, 1570, 1545, 1475, 1460, 1430, 1410, 1400, 1355, 1325, 1275, 1245, 1210, 1160, 1130, 1110, 1090, 890, 810, 760, and 700 cm "1; mass spectrum [(-) ESI], m / z 553/555 (M-H)", - Analysis Calculated for C29H22C1F3N204 - 0.5 CHC13: C, 57.65; H, 3.69; N, 4.56, Found: C, 57.44; H, 3.54; N, 4.41.
Example 59 Acid [3"-chloro-5 '- (3-phenyl-propylcarbamoyl) -3-trifluoromethyl- [1,1', 3 ', l"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.073 g, 27%) from the 3- (m-chlorophenyl) -4- (2-hydroxyethoxy) -5- (m-trifluoromethylphenyl) -benzoic acid ethyl ester using 3-phenyl-1-propylamine and a procedure similar to that of Example 51, pf > 106 ° C (decomposition); 1U NMR (DMSO-ds) d 1.80-1.88 (m, 2H), 2.64 (t, J = 7.5 Hz, 2H), 3.28-3.37 (m, 2H), 3.78 (s, 2H), 7.14-7.19 (m , 1H), 7.20-7.31 (m, 4H), 7.46-7.53 (m, 2H), 7.59-7.63 (m, 1H), 7.68-7.74 (m, 2H), 7.77 (d, J = 7.7 Hz, 1H ), 7.90 (dd, J = 2.2, 5.1 Hz, 2H), 7.94 (d, J = 7.7 Hz, 1H), 7.99 (s, 1H), 8.62 (t, J = 5.3 Hz, 1H), 11.80-13.50 (? broad, 1H); IR (KBr) 3330, 3080, 3020, 2920, 2860, 1740, 1635, 1620, 1555, 1495, 1455, 1425, 1360, 1325, 1280, 1245, 1210, 1165, 1130, 1095, 1080, 1055, 880, 820, 790, 750, 700, and 670 cm "J- mass spectrum [(+) APCI], m / z 568 (M + H) J- Analysis Calculated even, at C31H2SC1F3N04-1.5 H20: C. 62.58, H, 4.74; N, 2.35, Found: C, 62.32; H, 4.20; N, 2.35.
Example 60 Acid [3"-chloro-5 '- (4-phenyl-butylcarbamoyl) -3-trifluoromethyl- [1,1 J-3', 1"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.105 g, 38%) from the 3- (m-chlorophenyl) -4- (2-hydroxyethoxy) -5- (m-trifluoromethylphenyl) -benzoic acid ethyl ester using 4-phenylbutylamine and a procedure similar to that of Example 51, mp 187-190 ° C; 1K NMR (DMS0-d6) d 1.50-1.67 (m, 4H), 2.61 (t, J = 7.2 Hz, 2H), 3.31 (dd, J = 6.6, 12.7 Hz, 2H), 3.79 (s, 2H), 7.13-7.23 (m, 3H), 7.23-7.29 (m, 2H), 7.45-7.53 (m, 2H), 7.58-7.62 (m, 1H), 7.67-7.74 (m, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.89 (dd, J = 2.0, 5.1 Hz. 2H), 7.93 (di- J = 7.5 -Hz, 1H), 7.98 (s, 1H), 8.60 (t, J = 5.5 Hz, 1H), 11.40-14.10 (broad s, 1H); IR (KBr) 3380, 3080, 3020, 2930, 2850, 1730, 1620, 1570, 1495, 1450, 1400, 1360, 1330, 1280, 1245, 1205, 1165, 1130, 1095, 1080 1050, 890, 815, 790 , 750, and 700 cm "J- mass spectrum [(+) APCI], m / z 582 (M + H) J-Analysis Calculated for C32H27C1F3N04 - H20: C, 64.06; H, 4.87, N, 2.33, Found : C, 63.86; H, 4.45; N, 2.39. • < * «- -? - # - 165 - Example 61 Acid [3"-chloro-5 '- (3-cyclopentyl-propylcarbamoyl) -3-trif luoro- [1, 1'; 3 ', l"] terphenyl-2'-yloxyTacetic acid Stage l 3-cyclopentylprop? Lamina To a stirred solution of condensed liquid ammonia (in excess, saturated at -40 ° C) in Et20 (60 mL) at -40 ° C, 3-cyclopentylpropionyl chloride (10.0 mL, 65.3 mmol) in Et20 (60 mL) is added. ). The reaction mixture is warmed to room temperature and stirred at this temperature for 18 h. The solid that forms is separated by filtration and washed with excess Et20. After concentration, the residue is used directly in the next part without further purification. This intermediate amide is dissolved in Et20: THF (5: 2, 140 ml) and added dropwise to a suspension of LAH (6.36 g, 45.0 mmol) in anhydrous EtOAc (75 ml) at 0 ° C. After stirring at this temperature for 1 h, the mixture (with efficient stirring) is quenched with the dropwise addition of H20 (5.12 ml), 15% aqueous NaOH (5.12 ml), and H20 (15.36 ml) and then stirred for an additional 18 h at room temperature. The dry pellet is dried (NaS04) and then filtered. After concentration, the residue is taken up in hexane. The white solid that forms (excess amide SM) Ijjjpi "¡t ^^^^ Separate by filtration and the resulting filtrate is concentrated. The liquid amine product (4.31 g, 52%) is used directly in subsequent reactions without further purification; ? NMR (DMSO-d6) d 0.95-1.13 (m, 2H), 1.21-1.38 (m, 4H), 1.41-1.62 (m, 4H), 1.63-1.88 (m, 3H), 2.47-2.54 (m, 2H) , overlap with a DMSO peak); mass spectrum [(+) ESI], m / z 128 (M + H) *.
Step 2: Acid [3"- Chloro-5 '- (3-cyclopentyl-propylcarbamoyl) -3-tri uoromethyl-1,11: 3' .1"! terf enyl-2 '- iloxyl acetic The title compound is prepared as an off-white solid (0.064 g, 25%) from the 3- (m-chlorophenyl) -4- (2-hydroxyethoxy) -5- (m-trifluoromethylphenyl) -benzoic acid ethyl ester using 3-cyclopentylpropylamine and a procedure similar to that of Example 51, mp 173-175 ° C; 1 H NMR (DMS0-d6) d 0.97-1.10 m, 2H), 1.27-1.36 (m, 2H), 1.42-1.59 (m, 6H), 1.67-1.79 (m, 3H), 3.25 (dd, J = 6.6, 12.7 Hz, 2H), 3.75 (?, 2H), 7.44-7 51 (m, 2H), 7.59 (d, J = 6.4 Hz, 1H), 7.66-7.71 (m, 2H), 7.75 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 2.6 Hz, 2H), 7.92 (d, J = 7.7 Hz, 1H), 1.97 (s, 1H), 8.57 (t, J = 5.7 Hz, 1H), 12.00-13.90 (broad s, 1H); IR (KBr) 3330, 3090, 2960, 2890, 1735, 1635, 1555, 1460, 1400, 1350, 1325, 1275, 1250, 1220, 1170, 1125, 1095, 1080, 1060, 890, 875, 820, 790, 770, 730, 700, and 675 cm "1; mass spectrum [(-) ESI], m / z 558 (M -H)"; Analysis Calculated for C 30 H 29 ClF 3 NO 4 - 0.75 H 20: C, 62.83; H, 5.36; N, 2.44, Found: C, 62.87; H, 5.04; N, 2.40.
Example 62 [3-Bromo-3'-chloro-5- (3-cyclopentyl-propylcarbamoyl) -biphenyl-2-yloxy] acetic acid The title compound is prepared as an off-white solid (0.057 g, 18%) from the ethyl ester of 3-bromo-5- (m-chlorophenyl) -4- (2-hydroxyethoxy) enzoic acid using 3-cyclopentylpropylamine and a standard procedure. similar to that of Example 51, mp 135 ° C (decomposition); ? NMR (DMSO-ds) d 0.98-1.09 (m, 2H), 1.25-1.34 (m, 2H), 1.42-1.60 (m, 6H), 1.66-1.79 (m, 3H), 3.23 (dd, J = 6.8) , 12.7 Hz, 2H), 4.00 (?, 2H), 7.44-7.49 (m, 2H), 7.53-7.58 (m, 1H), 7.65 (s, 1H), 7.84 (d, J = 2.2 Hz, 1H) , 8.08 (d, J = 2.2 Hz, 1 H), 8.58 (t, J = 5.5 Hz, 1 H), 12.60-14.10 (broad s, 1 H); IR (KBr) 3330, 3090, 2950, 2860, 1740, 1635, 1595, 1555, 1455, 1430, 1325, 1225, 1200, 1080, 1040, 880, 795, 760, and 700 crn'1; mass spectrum [(-) ESI], m / z 492 (M-H) J- Analysis Calculated for C23H2sBrClN04 - 0.5 H20: C, 54.83, H, 5.20; N, 2.78, Found: C, 54.87; H, 5.03; N, 2.74.
L68 - Example 63 Acid (5 '- [2- (-Bromo-phenyl) -ethylcarbamoyl] -3"-chloro-3-trif-loromethyl- [1, 1'; 3 ', 1"] terphenyl-2'-yloxy} acetic acid The title compound is prepared as an off-white solid (0.068 g, 24%) from the 3- (m-chlorophenyl) -4- (2-hydroxyethoxy) -5- (m-trifluoromethylphenyl) -benzoic acid ethyl ester using 4-bromo-phenethylamine and a procedure similar to that of Example 51, pf > 102 ° C (decomposition); 1 H NMR (DMSO-d 6) 6 2.82 (t, J = 6.8 Hz, 2 H), 3.48 (dd, J = 6.8, 13.0 Hz, 2 H), 3.79 (s, 2 H), 7.20 (d, J = 8.3 Hz, 2H), 7.44-7.52 (m, 4H), 7.57-7.60 (m, 1H), 7.67-7.73 (m, 2H), 7.76 (d, J = 7.0 Hz, 1H), 7.84 (d, J = 3.3 Hz , 2H), 7.92 (d, J = 7.7 Hz, 1H), 7.97 (e, 1H), 8.67 (t, J = 7.5 Hz, 1H), 12.40-13.05 (s broad, 1H), IR (KBr) 3400 , 3090, 2930, 1740, 1635, 1610, 1545, 1485, 1460, 1390, 1350, 1325, 1275, 1245, 1215, 1160, 1130, 1100, 1080, 1010, 880, 810, 790, 760, and 700 cm "J- mass spectrum [(-) ESI], m / z 630/632/634 (M - H) \ - Analysis Calculated for C30H22BrClF3NO4 -H20: C, 55.36; H, 3.72, N, 2.15, Found: C , 55.58; H, 3.29; N, 2.17.
Example 64 Acid [3, 3"-Dichloro-5 '- (3-cyclopentyl-propylcarbamoyl) - [1,1 J-3', 1"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.114 g, 27%) from the 3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester using 3-cyclopentylpropylamine and a procedure similar to that of Example 51, pf > 173 ° C (decomposition); ? NMR (DMSO-d6) d 0.99-1.09 (m, 2H), 1.27-1.34 (m, 2H), 1.41-1.60 (m, 6H), 1.67-1.80 (m, 3H), 3.25 (dd, J = 6.6) , 13.0 Hz, 2H), 3.81 (s, 2H), 7.44-7.51 (m, 4H), 7.56-7.60 (m, 2 H), 7.68-7.70 (m, 2H), 7.86 (s, 2H), 8.56 (t, J = 5.9 Hz, 1H), 12.15-13.15 (broad s, 1H); IR (KBr) 3390, 3080, 2S50, 2870, 1740, 1640, 1610, 1570, 1555, 1475, 1450, 1430, 1400, 1360, 1310, 1245, 1215, 1160, 1110, 1080, 1045, 880, 800, 760 and 700 cm "1; mass spectrum [(-) ESI], m / z 524/526/528 (M - H) J- Analysis Calculated for C29H29C12N04 - H20: C, 63.97; H, 5.74; N, 2.57 , Found: C, 63.67; H, 95.38; N, 2.63.
Example 65 Acid [4"-Metoxy-5 '- (2-pyridin-2-yl-ethylcarbamoyl) -3-trifluoromethyl- [1, 1'; 3 ', 1"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.067 g, 28%) from the ethyl ester of the acid 4- (2-hydroxyethoxy) -3- (p-methoxyphenyl) -5- (m-trifluoromethylphenyl) -benzoic acid using 2- (2-aminoe |: il) pyridine and a procedure similar to that of Example 51, pf > 105 ° C (decomposition), 1H NMR (DMS0-d6) d 2.99 (t, J = 7.7 Hz, 2H), 3.62 (dd, J = 6.4, 13.2 Hz, 2H), 3.72 (s, 2H), 3.80 (s, 3H), 7.01 (d, J = 8.6 Hz, 2H,), 7. 10 (dd, J = 4.8, 7.5 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.64-7.74 (m, 3H), 7.80 (dd, J = 2.0, 7.9 Hz, 2H), 7.92 (d, J = 7.7 Hz, 1 H), 7.96 (s) , 1 H), 8.47-8.50 (m, 1 H), 8.68 (t, J = 5.5 Hz, 1 H), 11.70-13.45 (s broad, 1 H); IR (KBr) 3400, 3080, 3000, 2920, 2810, 1730, 1640, 1620, 1560, 1510, 1495, 1455, 1435, 1415, 1360, 1325, 1305, 1280, 1250, 1215, 1160, 1130, 1080, 1030, 890, 835, 800, 755, and 710 cm'1; mass spectrum [(-) ESI], m / z 549 (M - H) ", - Analysis Calculated for C30H25F3N205 -2.5 H20: C, 60.50; H, 5.08; N, 4.70, Found: C, 60.65; H, 4.36; N, 4.64.
Example 66 Acid [5 '- (3-Ci clopen ti 1-propyl carbamoyl) -4"-methoxy-3-trifluoromethyl- [1, 1', 3 ', 1"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.085 g, 35%) from the ethyl ester of the acid 4- (2-hydroxyethoxy) -3- (p-methoxyphenyl) -5- (m-trifluoromethylphenyl) -benzoic acid using 3-cyclopentylpropam and a procedure similar to that of Example 51, pf > 114 ° C (decomposition); Jl NMR (DMSO-d6) 6 0.98-1.07 (m, 2H), 1.27-1.34 (m, 2H), 1.42-1.59 (m, 6H), 1.66-1.79 (m, 3H), 3.25 (dd, J = 6.8, 13.0 Hz, 2H), 3.73 (s, 2H), 3.80 (s, 3H), 7.01 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.66 (t, J = 7.7 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.82 (dd, J = 2.0, 6.8 Hz, 2H), 7.92 (d, J = 7.7 Hz, 1H), 7.96 (s, 1H), 8.54 (t, J = 5.7 Hz, 1H), 12.10-13.50 (broad s, 1H); IR (KBr) 3430, 3090, 2950, 2860, 1740, 1640 1620, 1590, 1560, 1510, 1495, 1455, 1360, 1330, 1310, 1290, 1250, 1220, 1170, 1135, 1100, 1080, 1030, 890 , 840, 800, and 705 cm "1; mass spectrum [(-) ESI], m / z 554 (M - H) J- Calculated Analysis for C31H32F3N05 - 0.75 H20: C, 65.43; H, 5.93; N, 2.46, Found: C, 65.38; H, 5.57; N, 2. 49 Example 67 [5 '- (Benzyl-phenethylcarbamoy 1) -4"-methyl-3-trifluoromethyl- [1,1'; 3 ', 1"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.101 g, 36%) from the 4- (2-hydroxyethoxy) -3- (p-methoxyphenyl) -5- (m-trifluoromethylphenyl) ethyl ester - benzoic using N-benzyl-2-phenethylamine and a procedure similar to that of Example 51, pf > 82 ° C (decomposition), * H NMR (DMSO-d d 2.74-2.97 (m, 2H), 3.23-3.64 (m, 2H), 3.66-3.76 (m, 2H), 3.79 (S, 3H), 4.45 -4.83 (m, 2H), 6.84-7.92 (m, 20H), 11.90-13.40 (broad s, 1H); IR (KBr) 3340,3070.320, 2920, 2820, 1755, 1740, 1635, 1605, 1510 , 1495, 1450, 1420, 1360, 1325, 1300, 1275, 1250, 1210, 1170, 1160, 1125, 1100, 1080, 1030, 890, 830, 800, 750. and 700 cm'J- mass spectrum [( -) ESI], m / z 638 (M-H) "; Calculated Analysis for C38H32F3N05-1.25 H20: C, 68.93; H, 5.25; N, 2.12, Found: C, 68.65; H, 5.04; N, 2.11.
Example 68 [5 '- (Benzyl-eethyl-carbamoyl) -2-fluoro-4"-methoxy- [1,1', 3 ', 1"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.089 g, 27%) from the ethyl ether of 3- (o-fluorophenyl) -4- (2-hydroxyethoxy) -5- (p-methoxyphenyl (benzoic acid using N -benzyl-2-phenethylamine and a procedure similar to that of Example 51, mp> 73 ° C (decomposition); SH NMR (DMSO-d6) 6 2.73-2.94 (m, 2H '? 3.20-3.63 (m, 2H) , 3.70-3.79 (m, 2H), 3.79 (s, 3H), 4.43-4.83 (m, 2H), 6.84-7.53 (m, 20H), 11.30-13.50 (s broad, 1H); IR (KBr) 3440 , 3070, 3020, 2920, 1755, 1735, 1630, 1610, 1510, 1495, 1440, 1420, 1340, 1300, 1250, 1215, 1180, 1100, 1070, 1030, 890, 840, 810, 755, and 700 cm "1; mass spectrum [(+) ESI], m / z 590 (M + H) J 622 (M + Na) *; Calculated for C37H32FN05-1.5 H20: C, 72. 06; H, 5 72; N, 2 27, Found: C, 72. 32; H, 5 32; N, 2 .33.
Example 69 [5- (Benzylphenethyl-carbamoyl) -3-bromo-2'-fluoro-biphenyl-2-yloxy] acetic acid The title compound is prepared as an off-white solid (0.029 g, 8%) from the ethyl ester of 3-bromo-5- (o-fluorophenyl) -4- (2-hydroxyethoxy) benzoic acid using N-benzyl-2 -phenethylamine and a procedure similar to that of Example 51, pf > 85 ° C (decompoiition); XH NMR (DMSO-d6) 6 2.72-2.93 (m, 2H), 3.15-3.63 (m, 2H), 3.88-4.03 (m, 2H), 4.36-4.84 (m, 2H), 6.84-7.00 (m, 2H), 7.00-7.60 (m, 14H), 11.60-13.10 (broad s, 1H); IR (KBr) 3430, 3060, 3020, 2920, 1740, 1635, 1495, 1450, 1420, 1360, 1330, 1260, 1240, 1220, 1120, 1070, 1030, 930, 890, 830, 755, and 700 cm " J- mass spectrum [(-) ESI], m / z 560 (M-H) "; Analysis Calculated for C30H2SBrFN04 - 1.75 H20: C, 60.67; H, 4.84; N, 2.36, Found: C, 60.64; H, 4.41; N, 2.41.
Example 70 Acid [2-Fluoro-4"-methoxy-5 '- (2-pyridin-2-yl-ethylcarbamoyl) - [1,1'; 3 ', l"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as a white solid (0.121 g, 39%) from the 3- (o-fluorophenyl) -4- (2-hydroxyethoxy) -5- (p-methoxyphenyl) benzoic acid ethyl ester using 2 - (2-aminoethyl) pyridine and a procedure similar to that of Example 51, pf > 102 ° C (deecompoeición); XH NMR (DMS0-d6) d 3.00 (t, J = 7.7 Hz, 2H), 3.62 (dd, J = 6.6, 12.7 Hz, 2H), 3.79 (s, 2H), 3.81 (s, 3H), 7.01- 7.06 (m, 2H), 7.22 (ddd, J = 1.1, 4.8, 7.5 Hz, 1H), 7.26-7.32 (m, 3H), 7.42-7.50 (m, 2H), 7.54-7.60 (m, 2H), 7.67-7.73 (m, 2H), 7.85 (d, J = 2.4 Hz, 1H), 8.50 (ddd, J = 0-9, 1.8, 4.8 Hz, 1H), 8.66 (t, J = 5.7 Hz, 1H) 11.75-13.45 (broad s, 1H); IR (KBr) 3420, 3080, 3000, 2930, 2820, 1735, 1640, 1615, 1580, 1550, 1510, 1495, 1450, 1430, 1410, 1370, 1310, 1250, 1215, 1175, 1100, 1070, 1025, 900, 840, 810, 755, and 710 cm "J- mass spectrum [(-) ESI], m / z'4-99 (M -H) J- Analysis Calculated for C29H25FN20;, - 2.5 H20: C, 63.85; H, 5.54; N, 5.13, Found: C, 63.40; H, 4.79; N, 4.93.
Example 71 Acid [2-Fluoro-4"-methoxy-5 '- (3-phenyl-propylcarbamoyl) - [1,1'; 3 ', 1"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.130 g, 42%) from the 3- (o-fluorophenyl) -4- (2-hydroxyethoxy) -5- (p-methoxyphenyl) benzoic acid ethyl ester using phenyl-1-propylamine and a procedure similar to that of Example 51, pf > 89 ° C (decomposition); XH NMR (DMSO-ds) 6 1.77-1.87 (m, 2H), 2.61 (t, J = 7.2 Hz, 2H), 3.27 (dd, J = 6.8, 13.0 Hz, 2H), 3.78 (s, 2H), 3.79 (s, 3H), 6.99-7.04 (m, 2H), 7.13-7.18 (m, 1H), 7.19-7.23 (m, 2H), 7.24-7.30 (m, 4H), 7.41-7.50 (m, 2H) ), 7.54-7.58 (m, 2H), 7.72 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 8.54 (t, J = 5.7 Hz, 1H), 11.85-13.30 (s broad, 1H); IR (KBr) 3420, 3070, 3020, 2940, 1740, 1640, 1620, 1590, 1560, 1510, 1495, 1450, 1415, 1350, 1310, 1250, 1215, 1180, 1100, 1080, 1030, 900, 840, 805, 755, and 700 cm "J- mass spectrum [(-) ESI], m / z 512 (M-H)", - Analysis Calculated for C31H28FN05 -1.25 H20: C, 69.46; H, 5.73; N, 2.61, Found: C. 69.36; H, 5.40; N, 2.56.
Example 72 Acid [3-Bromo-2 '-f luoro-5-pyridin-2-yl-ethylcarbamoyl) -bifinyl-2-yloxy] acetic acid The title compound is prepared as a white solid (0.041 g, 15%) from the ethyl ester of 3-bromo-5- (o-fluorophenyl) -4- (2-hydroxyethoxy) enzoic acid using 2- (2- aminoethyl) pyridine and a procedure similar to that of Example 51, pf > 154 ° C (decomposition); ? NMR (DMS0-ds) d 2.97 (t, J = 7.7 Hz, 2H), 3.59 (dd, J = 6.6, 12.7 Hz, 2H), 3.97 (s, 2H), 7.20 (ddd, J = 0.9, 4.8, 7.5 Hz, 1H), 7.24-7.32 (m, 3H), 7.42-7.50 (m, 2H), 7.68 (td, J = 1.8, 7.7 Hz, 1 H), 7.74 (d, J = 2. 0 Hz, 1 H), 8.10 (d, J = 2.0 Hz, 1 H), 8.48 (dd, J = 0.9, 4.8 Hz, 1H), 8.67 (t, J = 5.3 Hz, 1H), 11.40-13.20 (s broad, 1 HOUR); IR (KBr) 3420, 3080, 2930, 1725, 1630, 1600, 1550, 1495, 1460, 1450, 1435, 1370, 1330, 1245, 1225, 1150, 1120, 1080, 1030, 890, 830, 755, and 710 c "1; mass spectrum [(-) ESI], m / z 471/473 (M-H) J- Calculated Analysis for C22HlßBrFN204 -2.5 H20: C, 50.98; H, 4.47; N, 5.40, Found: C , 50.96; H, 3.81; N, 5.06.
Example 73 [3-Bromo-2'-fluoro-5- (3-phenyl-propylcarbamoyl) -biphenyl-2-yloxy] acetic acid The title compound is prepared as an off-white solid (0.091 g, 32%) from the ethyl ester of 3-bromo-5- (o-fluorophenyl) -4- (2-hydroxyethoxy) benzoic acid using 3-phenyl-1-propylamine and a procedure similar to that of Example 51, pf > 90 ° C (decomposition); ? NMR (DMS0-d6) d 1.77-1.85 (m, 2H), 2.61 (t, J = 7.5 Hz, 2H), 3.26 (dd, J = 6.8, 12.5 Hz, 2H), 4. 08 (?, 2H), 7.13-7.23 (m, 3H), 7.23-7.33 (m, 4H), 7.42-7.51 (m, 2H), 7.78 (d, J = 2.2 Hz, 1H), 8.14 ( d, J = 2.0 Hz, 1H), 8. 58 (t, J = 5.5 Hz, 1H), 11.70-13.90 (broad s, 1H), IR 3350, 3080, 3020, 2940, 2860, 1740, 1630, 1590, 1550, 1495, 1450, 1430, 1325, 1220 , 1200, 1100, 1080, 1050, 890, 830, 755, and 695 (KBr) cm "J- mass spectrum [(-) ESI], m / z 484/486 (M - H) J-Analysis Calculated for C24H21BrFN04-1.25 H20: C, 56.65; H, 4.65; N, 2.75, Found: C, 56.61; H, 4.26; N, 2.65.
Example 74 [5 '- (3-Cyclopentyl-propylcarbamoyl) -2-f luoro-4"-methoxy- [1,1'; 3 ', 1"] terf enyl-2'-yloxy] acetic acid The title compound is prepared as an off white solid (0.100 g, 33%) from 3- (o-fluorofenyl) -4- (2-hydroxyethoxy) -5- (p-methoxyphenyl) benzoic using 3-cyclopentylpropylamine and a procedure similar to that of Example 51, pf > 97 ° C (decomposition); XH NMR (DMSO-d6) d 1.00-1.09 (m, 2H), 1.28-1.36 (m, 2H), 1.42-1.61 (m, 6H), 1.68-1.81 (m, 3H), 3.25 (dd, J = 6.4, 12.7 Hz, 2H), 3.78 (s, 2H), 3.81 (s, 3H), 7.03 (d, J = 9.0 Hz, 2H), 7.25-7.32 (m, 2H), 7.42-7.51 (m, 2H), 7.57 (d, J = 8. 2.2 Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 8.52 (t, J = 5.7 Hz, 1H), 11.85-13.40 (s broad , 1 HOUR); IR (KBr) 3390, 3090, 2950, 2880, 1740, 1635, 1620, 1585, 1565, 1515, 1495, 1450, 1440, 1420, 1360, 1295, 1250, 1215, 1180, 1100, 1075, 1030, 900, 830, 810, 755, and 710 cm "J- mass spectrum [(-) ESI] m / z 504 (M-H)", - Analysis Calculated for C30H32FNO5-H20: C, 68.82, H, 6.55; N, 2.68, Found: C, 68. J, H, 6.14; N, 2.73.
Example 75 [3-Bromo-5- (3-cyclopentyl-propylcarbamoyl) -2'-fluoro-biphenyl-2-yloxy] -acetic acid The title compound is prepared as a off-white solid (0.041 g, 14%) from the ethyl ester of 3-bromo-5- (o-fluoro-phenyl) -4- (2-hydroxyethoxy) benzoic acid using 3-cyclopentylpropyl; and a procedure similar to that of Example 51, pf > 127 ° C (decomposition); 'H NMR (DMS0-ds) d 1.00-1.09 (m, 2H), 1.27-1.34 (m, 2H), 1.43-1.62 (m, 6H), 1.68-1.79 (m, 3H), 3.23 (dd, J = 6.8, 12.7 Hz, 2H), 3.98 (s, 2H), 7.27-7.34 (m, 2H), 7.42-7.52 (m, 2H), 7.78 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 2.2 Hz, 14 !, 8.55 (t, J = 5.7 Hz, 1 H), 1 1.40-13.50 (s broad, 1 H), IR (KBr) 3390, 3090, 2950, 2870, 1735, 1630, 1555 , 1495, 1435, 1425, 1330, 1225, 1100, 1070, 1030, 890, 830, 755. and 705 cm "1; mass spectrum [(-) ESI], m / z 476/478 (M -H) *; Calculated Analysis for C23H25BrFN04-1.5 H20: C, 54.66; H, 5.58; N, 2.77, Found : C, 54.36; H, 4.78; N, 2.75.
Example 76 2-Fluoro- "-methoxy-5 '- (8-enyl-octylcarbamoyl) - [1,1'; 3 ', l"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0. 150 g, 41%) from the 3- (o-fluorophenyl) -4- (2-hydroxyethoxy) -5- (p-methoxyphenyl) benzoic acid ethyl ester. using 8-phenyloctylamine and a procedure similar to that of Example 51, pf > 84 ° C (decomposition); 1 = NMR (DMSO-d6) d 1.23-1.34 (m, 8H), 1.47-1.58 (m, 4H), 2.54 (t, J = 7.5 Hz, 2H), 3.24 (dd, J = 6.8, 12.7 Hz, 2H), 3.81 (s, 5H), 7.03 (d, J = 8.1 Hz, 2H), 7.12-7.18 (m, 3H), 7.22-7.31 (m, 4H), 7.42-7.50 (m, 2H), 7.7 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 8.51 (t, J = 5.5 Hz, 1H), 11.40-13.40 (s broad, 1H); IR (KBr) 3400, 3080, 3020, 2930, 2860, 1735, 1640, 1615, 1590, 1550, 1510, 1495, 1440, 1430, 1400, 1355, 1300, 1250, 1210, 1180, 1100, 1080, 1030, 900, 830, 810, 755, and 695 cm "1; mass spectrum [(-) ESI], m / z 584 (M - H) j- Analysis Calculated for C36H3BFN05 - 0.5 H20: C, 72.95; H, 6.63; N, 2.36, Found: C, 73.04; H, 6.42; N, 2.41.
Example 77 Acid [3-Bromo-2'-fluoro-5- (8-phenyl-octylcarbamoyl) -biphenyl-2-yloxy] acetic acid The title compound is prepared as an off-white solid (0.062 g, 18%) from the ethyl ester of 3-bromo-5- (o-fluorophenyl) -4- (2-hydroxyethoxy) benzoic acid using 8-phenyloctylamine and a procedure similar to that of Example 51, pf > 79 ° C (decomposition); 'H NMR (DMSO-d6) d 1.23-1.33 (m, 8H), 1.45-1.59 (m, 4H), 2.55 (t, J = 7.2 Hz, 2H), 3.23 (dd, J = 6.2, 12.3 Hz, 2H), 4.03 (s, 2H), 7.12-7.19 (m, 3H), 7.23-7.34 (m, 4H), 7.42-7.52 (m, 2H), 7.78 (s, 1H), 8.13-8.17 (, 1H) ), 8.55 (t, J = 5.7 Hz, 1H), 11.70-13.60 (broad s, 1H); IR (KBr) 3360, 3080, 3020, 2930, 2860, 2340, 1740, 1635, 1560, 1495, 1450, 1430, 1370, 1325, 1220, 1100, 1080, 1035, 900, 830, 755, and 700 cm " J- spectrum of maea [(+) ESI], m / z 556 / 5.58 (M + H) * Analysis Calculated for C2SH31BrFN04 - 0.75 H20: C, 61.11; H, 5.75; N, 2.46, Found: C. 61.14; H. 5.19; N, 2.45.
Example 78 Acid [2-Fluoro-4"-methoxy-5 '- (6-pheny1-hexycarbamoyl) [1,1', -3 ', 1"] terphenyl-2'-yloxy] acetic acid 31 -. 31 - The title compound is prepared as an off-white solid (0.155 g, 47%) from 3- (o-fluorophenyl) -4- (2-hydroxyethoxy) -5- (p-methoxyphenyl) benzoic acid ethyl ester using 6-phenylhexylamine and a procedure similar to that of Example 51, pf > 72 ° C (decompoeition); * H NMR (DMSO-d6) 6 1.26-1.37 (m, 4H), 1.45-1.59 (m, 4H), 2.54 (t, J = 7.9 Hz, 2H), 3.23 (dd, J = 6.8, 13.0 Hz, 2H), 3.79 (s, 5H), 6.98-7.04 (m, 2H), 7. 10-7.18 (m, 3H), 7.20-7.30 (m, 4H), 7.40-7.49 (m, 2H), 7.53- 7.57 (m, 2H), 7.72 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 8.49 (t, J = 5.5 Hz, 1H), 12.65-13.30 (s broad, 1 HOUR); IR (KBr) 3400, 3070, 3020, 2940, 2860, 1740, 1635, 1615, 1580, 1550, 1510, 1495, 1445, 1410, 1350, 1305, 1250, 1215, 1185, 1100, 1070, 1030, 900, 830, 810, 755, and 700 cm "1; mass spectrum [(+) ESI], m / z 556 (M + H) J- Calculated Analysis for C34H34FN05 - 0.75 H20: C, 71.75; H, 6.29, N , 2.46, Found: C, 71.72; H, 6.09; N, 2.46.
Example 79 Acid [3-Bromo-2'-fluoro-5- (6-phen-l-hex? Lcarbamoyl) -bifen? L-2-yloxy] acetic acid The title compound is prepared as a white solid (0.077 g, 26%) from the ethyl ester of 3-bromo-5- (o-fluorophenyl) -4- (2-hydroxyethoxy) benzoic acid using 6-phenylhexylamine and a procedure similar to that of Example 51, pf > 84 ° C (decompoiition); Jl NMR (DMS0-d6) d 1.27-1.36 (m, 4H), 1.44-1.59 (m, 4H), 2.54 (t, J 7.2 Hz, 2H), 3.21 (dd, J = 6.4, 12.5 Hz, 2H) , 4.01 (e, 2H), 7.11-7. 1 8 (m, 3H), 7.21-7.32 (m, 4H), 7.41-7.50 (m, 2H), 7.77 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8.53 (t, J = 5.3 Hz, 1 H), 11.80-13.50 (broad e, 1 H); IR (KBr) 3410, 3070, 3020, 2940, 2850, 1740, 1635, 1550, 1495, 1450, 1425, 1330, 1300, 1220, 1115, 1070, 1030, 900, 830, 755, and 700; mass spectrum [(+) ESI], m / z 528/530 (M + H) J- Analysis Calculated for C27H27BrFN04 - 2.5 H20: C, 56.55; H, 5.62. N, 2.44, Found: C, 56.23; H, 4.43; N, 2.56.
Example 80 Acid [3, 3"-Dichloro-5 '- (6-phenyl-hexylcarbamoyl) - [1, 1'; 3 ', 1"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.065 g, 19%) from the ethyl ester of the acid, 5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic using 6-f-enylhexylamine and a procedure similar to that of Example 51, mp 178-181-C; * H NMR (DM? O-d6) d 1.27-1.37 (m, 4H), 1.48-1.59 (m, 4H), 2.55 (t, J = 7.5 Hz, 2H), 3.25 (dd, J = 6.4, 13.0 Hz, 2H), 3.81 (S, 2H), 7.10-7.17 (m, 3H), 7.21-7.26 (m, 2H), 7.44- 7. 51 (m, 4H), 7.56-7.60 (m, 2H), 7.68-7.70 (m, 2H), 7.85 (s, 2H), 8.55 (t, J = 5.3 Hz, 1H), 11.60-13.35 (s broad , 1 HOUR); IR (KBr) 3380, 3070, 3020, 2930, 2860, 2510, 1725, 1620, 1565, 1475, 1450, 1400, 1340, 1320, 1240, 1200, 1170, 1100, 1080, 1050, 880, 790, 770, 750, and 700 cm "1; mass spectrum [(+) ESI], m / z 576 (M + H) J- Analysis Calculated for C33H31C12N04 -0.75 H20: C, 67.18; H, 5.55; N, 2.37, Found : C, 67.35; H, 5.51; N, 2.36.
Example 81 Acid (4"-Me oxy -5 '[methyl- (8-phenyl-octyl) -carbamoyl] -3-tri-loromethyl- [1,1'; 3 ', 1"] terphenyl-2'-yloxy-acetic acid The title compound is prepared as a gray foam (0.399 g, 71%) from the ethyl ester of 4- (2-hydroxyethyl oxy) -3- (p-methoxyphenyl) -5- (m-trif luoromet il- phenyl) benzoic using N-methyl-8-f-enyloctylamine and a procedure similar to that of Example 51, pf > 39 ° C (decomposition); JH NMR (DMSO-ds) d 1.02-1.18 (m, 4H), 1.20-1.36 (m, 4H), 1.40-1.60 (m, 4H), 2.44-2.57 (m, 2H), 2.96 (s, 3H) , 3.22-3.47 (m, 2H), 3.79 (s, 5H), 7.01 (d, J = 8.6 Hz, 2H), 7.10-7.19 (m, 3H), 7.22-7.28 (m, 2H), 7.36 (d , J = 10.5 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.67 (t, J = 7.7 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.96 (s, 1H), 11. 25-13.50 (broad s, 1 H); IR (KBr) 3440, 3070, 3020, 2930, 2860, 1755, 1735, 1610, 1510, 1495, 1455, 1400, 1345, 1330, 1300, 1270, 1250, 1180, 1165, 1125, 1100, 1080, 1060, 1030, 890, 830, 800, 750, and 705 cm "1; mass spectrum [(+) APCI], m / z 648 (M + H) J- Analysis Calculated for C38H40F3NO5 - 0.5 H20: C, 69.50; H , 6.29; N, 2.13, Found: C, 69.09; H, 6.11; N, 2.17.
Example 82 Acid { 3, 3"-Dichloro-5 '- [methyl- (8-phenyl-octyl) -carbamoyl] - [1, 1'; 3 ', 1"] terphenyl-2'-yloxy} acetic This compound is prepared as a whitish foam (0.231 g, 43%) from the 3,5-bis- (bis-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester using N-methyl-8- phenyloctylamine and a procedure similar to that of Example 51, pf > 44 ° C (decompoeition); H NMR (DMS0-d6) d 1.03-1.22 (m, 4H), 1.22-1.37 (m, 4H), 1.41-1.63 (m, 4H), 2.44-2.58 (m, 2H), 2.95 (ñ, 3H) , 3.17-3.54 (m, 2H), 3.79 (s, 2H), 7.12- 7.18 (m, 3H), 7.22-7.28 (m, 2H), 7.39 (s, 2H), 7.43-7.50 (m, 4H), 7.54-7.59 (m, 2H), 7.67 (e, 2H), 10.95-14.15 (s broad, 1 HOUR); IR (KBr) 3440, 3080 3020, 2930, 2870, 1755, 1730, 1630, 1605, 1565, 1495, 1480, 1445, 1400, 1340, 1310, 1215, 1170, 1100, 1085, 1050, 380, 775, 755, and 695 cm'J- spectrum of maea [(+) APCI], m / z 618 (M + H) *, - Analysis Calculated for C36H37C12N04 - 0.5 H20: C, 68.90, H, 6.10; N, 2.23, Found: C, 68.76; H, 5.98; N, 2.25.
Example 83 Acid [3,3"-Difluoro-5 '- (8-phenyl-octyl-1-carbamoyl) - [1,1'; 3 ', l"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as a whitish foam (0.207 g, 37%) from the 3,5-bis- (m-fluorophenyl) -4- (2-hydroxyethoxy) enzoic acid ethyl ester using 8-phenyloctylamine and a procedure similar to that of Example 51, pf > 58 ° C (decomposition); 1 H NMR (DMSO-d 6) d 1.22-1.34 (m, 8H), 1.47-1.59 (m, 4H), 2.54 (t, J = 7.5 Hz, 2H), 3.26 (dd, J = 6.8, 13.0 Hz, 2H ), 3.80 (s, 2H), 7.12-7.19 (m, 3H), 7.20-7.28 (m, 4H), 7.44-7.54 (m, 6H), 7.88 (s, 2H), 8.56 (t, J = 5.3 Hz, 1H), 11.85-13.60 (broad s, 1H); IR (KBr) 3390, 3080, 3020, 2930, 2850, 1740, 1640, 1620, 1585, 1550, 1490, 1455, 1435, 1410, 1340, 1260, 1215, 1195, 1060, 940, 875, 775, 750, and 705 cm'J-mass spectrum [(+) APCI], m / z 572 (M + H) J- Analysis Calculated for C3SH35F2N04 - 0.5 H20: C, 72.40; H, 6.25; N, 2.41, Found: C, 72.14; H, 6.1 1; N, 2.45.
Example 84 Acid (3, 3"-Difluoro-5'- [methyl- (8-phenyl-octyl) -carbamoyl] - [1,1 J-3 ', 1"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as a gray foam (0.240 g, 41%) from 3,5-bie- (m-fluorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester using N-methyl-8 phenyloctylamine and a procedure similar to that of Example 51, pf > 43 ° C (decomposition); * H NMR (DMSO-d6) d 1.02-1.21 (m, 4H), 1.21-1.37 (m, 4H), 1.40-1.63 (m, 4H), 2.44-2.58 (m, 2H), 2.96 (e, 3H) ), 3.22-3.47 (m, 2H), 3.77 (e, 2H), 7.11-7.18 (m 3H), 7.18-7.28 (m, 4H), 7.36-7.51 (m, 8H), 11.25-14.35 (s broad , 1 HOUR); IR (KBr) 3430, 3070, 3020, 2930, 2860, 1755, 1740, 1635, 1615, 1585, 1490, 1445, 1410, 1335, 1260, 1210, 1180, 1120, 1080, 1050, 930, 875, 780, 750, and 700 cm'1, - mass spectrum [(-) ESI], m / z 584 (M - H) ', - Analysis Calculated for C36H37F2N04 - 1.25 H20: C, 71.09; H, 6.55; N, 2.30, Found: C, 71.15; H, 6.09; N, 2.31.
Example 85 [3, 3"-Dichloro-5 '- (8-morpholin-4-] -octylcarbamoyl) [1, 1'; 3 ', 1"] terphenyl-2'-yloxy] acetic acid Stage 1 8 -Morfolin-4 - iloctylamine To a solution of N- (8 -bromooctyl) phthalimide (8.46 g, . 0 mmole) in CH3CN (70 ml) at room temperature is added g ^ morpholine (4.80 g, 55.0 mmoles). After 18 h at this temperature, the reaction mixture is concentrated and then dilute with EtOAc (100 mL). The organic layer is washed with 10% aqueous Na 2 CO 3 (3 x 30 ml), H 2 O (2 x 20 ml), and brine (2 x 20 ml) and then washed (Na 2 SO 4). After concentration, the residue is purified by flash chromatography (gradient from 5 to 10% MeOH / CH2Cl2) to provide the morpholine intermediate ^ k 10 substituted. To this substituted morpholine intermediate (7.40 g, 1.5 mmol) in MeOH (70 ml) at room temperature is added hydrazine monohydrate (1.28 ml, 25.8 mmol) and the resulting mixture is heated to reflux. After 2 hours to this temperature, the reaction is concentrated and then diluted with IN HCl (100 ml). The mixture is stirred for 1 h, and the precipitate that forms during this time is filtered and washed with excess 0.5N HCl. Filtering becomes basic with 50% aqueous NaOH ("7 mL) and stirred for approximately 15 minutes minutes. This aqueous solution is extracted with CHC13 (4 x 50 ml) and the combined organic layers are washed with H20 (3 x 50 ml) and brine (1 x 50 ml). The organic layer after the eeca (Na2SO4) and concentrated to provide the product (4.16 g, 77%) as an oil; 1 H NMR (DMS0-dβ) d 1.18-1.34 (m, 12H), 1.34-1.43 (m, 2H), 2.21 (t, J = 7.0 Hz, 2H), 2.26-2.33 (m, 4H), 2. 46-2.52 (m, 2H), 3.53 (t, J = 4.6 Hz, 4H); IR (film) 3390, 2930, 2860, 28 0, 2790, 2710, 2180, 1640, 1610, 1460, 1390, 1375, 1360, 1320, 1300, 1275, 1200, 1135, 1120, 1080, 1040, 1010, 900 , 870, 815, 800, and 725 cm'J- mass spectrum [(+) APCI], m / z 215 (M + H) *.
Step 2: 3 -3.3 -Dichloro-5 '- (8-morphin-4-yl-octylcarbamoyl) -lfl1'; 3 '.1"1-terphenyl-2'-yloxyl acetic acid The title compound is prepared as a whitish foam (0.147 g, 21%) from the 3,5-bis- (bis-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester benzoic using 8-morpholin-4 ' -iloctylamine and a procedure similar to that of Example 51, pf > 91 ° C (decompoeition); XH NMR (DMSO-d6) 6 1.16-1.32 (m, 8H), 1.32-1.43 (m, 2H), 1.43-1.56 (m, 2H), 2.20 (t, J = 7.2 Hz, 2H), 2.25-2.34 (m, 4H), 3.25 (dd, J = 6.8, 13.0 Hz, 2H), 3.52 (t, J = 4.6 Hz, 4H), 3.76 (s, 2H), 7.43-7.50 (m, 4H), 7.58 ( dt, J = 1.8, 6.6 Hz, 2H), 7.68-7.70 (m, 2H), 7.85 (s, 2H), 8.54 (t, J = 5.7 Hz, 1H), 10.75-13.35 (s broad, 1H); IR (KBr) 3430, 3080, 2940, 2860, 2330, 1720, 1640, 1605, 1560, 1545, 1480, 1460, 1400, 1345, 1310, 1255, 1215, 1160, 1120, 1080, 1030, 875, 755, and 700 cm "J- mass spectrum [(+) ESI], m / z 613/615 (M + H) *; Calculated Analysis for C33H38C12N205 - 0.8 CHC13: C, 57.25; H, 5.52, N, 3.95, Found: C, 57.15; H, 5.41, N, 3.87.
Example 86 Acid (3, 3"-Dichloro-5 '- [8- (2,6-dimethoxy-phenoxy) -octylcarbamoyl] - [1,1'; 3 ', 1"] terphenyl-' -yloxy.
Stage 1 8- (2 '.6' -Dimetoxyphenoxy) octylamine To a round bottom flask with NaH (0.260 g, 6.49 mmol and THF (120 mL) cd to 0 ° C is added 2,6-dimethoxyphenol (1.00 g, 6.49 mmol) .The resulting solution is heated to reflux for 10 minutes After this, the room temperature is again cd to 15 ° C-15 (0.117 ml, 0.589 mmoles), tetrabutylammonium iodide (0.220 g, 0.589 mol), and finally N- (8-bromo-octyl). Phthalimide (2.00 g, 5.89 mmol) The final mixture is heated to reflux for 18 h at which point the reaction mixture is filtered and the filtrate is diluted with EtOAc (400 ml). IN HCl (40 mL), saturated aqueous NaHCO3 (40 mL), and brine (40 mL) and then dried (MgSO4) After concentration, the residue is purified on a Biotage Flash 40 apparatus (5-10% gradient). of EtOAc / petroleum ether) to provide the ether intermediate.
To this intermediate ether (1.23 g, 2.99 mmol) in MeOH (20 ml) at room temperature is added monohydrate A of hydrazine (0.348 ml, 7.18 mmol) and the resulting mixture is heated to reflux. After 5 h at this temperature, the The reaction is concentrated, taken up in EtOAc (200 ml), and filtered to remove insoluble materials. This phthalimide product is washed with excess EtAOc, and the filtrate is washed with H20 (30 ml) and brine (3 ml). The organic layer is then dried (Na2SO4) and concentrated to provide the product (0.833 g, 50% f) as an oil; 'H NMR (CDC13) 6 1.28-1.68 (m, 12H), 1.68-1.82 (m, 2H), 2.69 (t, J = 6.9 Hz, 2H), 3.86 (s, 6H), 3.96 (t, J = 6.9 Hz, 2H), 6.58 (d, J = 8.2 Hz, 2H), 6.97 (t, J = 8.2 Hz, 1H), - maea spectrum [(+) ESI], m / z 282 (M + H) J 304 (M + Na) *. 15 Stage 2 Acid. { 3.3"-Dichloro-5 '- [8- (2,6-dimethoxy-phenoxy) -octylcarbamoill-fl.l', -3 ', 1"! terfenyl-2 '- ^ ilox acé-ico The title compound is prepared as an off-white solid (0.059 g, 11%) from the 3,5-bis- (m-chlorofsyl) -4- (2-hydroxyethoxy (benzoic acid ethyl ester using 8- (2 J 6 '-dimethoxytenoxy) octylamine and a procedure similar to that of Example 51, mp> 70 ° C (decomposition), - 1 H NMR (DMSO-ds) 6 1.24-1.34 (m, 6H), 1.34-1.44 (m, 2H), 1.48-1.63 (m, 4H), 3. 23-3.38 (m, 2H), 3.72 (s, 6H), 3.77 (s, 2H), 3.79 (t, J = 6.4 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 6.94 (t , J = 8.6 Hz, 1H), 7.43-7.50 (m, 4H), 7.56-7.60 (m, 2H), 7.69 (s, 2H), 7.85 (s, 2H), 8.54 (t, J = 5.5 Hz, 1H), 10.95-14.75 (s broad, 1H); IR (KBr) 3375, 3080, 3000, 2930, 2860, 1730, 1595, 1570, 1545, 1495, 1480, 1465, 1430, 1395, 1330, 1295, 1255, 1210, 1110, 1035, 1000, 880, 780, 725, and 700 cm'J- mae spectrum [(+) ESI], m / z 680 (M + H) J- Analysis Calculated for C37H39C12N07 -0.25 CHC13: C, 62.97; H, 5.57; N, 1.97, Found: C, 62.76; H, 5.24; N, 1.87.
Example 87 Acid (5 '- [8- (Benzoxazol-2-ylsulfanyl) -octylcarbamoyl] -3,3'-dichloro- [1,1'; 3 ', 1"] terphenyl-2'-yloxy} acetic acid Stage 1 8- (Benzoxazol-2-ylsulfanyl) -octylamine To a round bottom flask with 2-mercaptobenzoxazole (2.14 g, 14.2 mmolee) and DMF (100 ml) at room temperature is added K2C03 (2.61 g, 18.9 mmol as followed by N- (8-bromooctyl) phthalimide (4.00 g, 11.8 g. The resulting solution is heated at 60 ° C for 0.5 h and then again cooled to room temperature.At this point, the reaction mixture is suspended with H20 (100 ml) and then dilute with EtOAc (600 ml). The organic layer is washed with IN HCl (60 ml), saturated aqueous NaHCO3 (60 ml), and brine (60 ml) and then dried (MgSO4). After concentration, the residue is purified on a Biotage Flash 40 apparatus (gradient of 10 to 20% EtOAc / petroleum ether) to provide thioether intermediate. To this intermediate thioether (3.02 g, 7.39 mmol) in MeOH (40 ml) at room temperature is added hydrazine monohydrate (0.860 ml, 17.7 mmol) and the resulting mixture is heated to reflux. After 18 h at this temperature, the reaction is concentrated, taken up in EtOAc (300 ml), and filtered to remove insoluble materials. This phthalimide by-product is washed with excess EtAOc, and the filtrate is washed with H20 (40 ml) and brine (40 ml). The organic layer is then dried (Na2SO4) and concentrated to give the product (1.87 g, 57%) as an oil; * H NMR (CDC13) d 1.14-1.67 (m, 12H), 1. 72-1.92 (m, 2H), 2.69 (t, J = 9.6 Hz, 2H), 3.32 (t, J = 8.5 Hz, 2H), 7.16-7.34 (m, 2H), 7.38-7.47 (m, 1H), 7.5-7.66 (m, 1 HOUR); mass spectrum [(+) ESI], m / z 279 (M + H) *.
Step 2 (5 '- [8- (Benzoxazol-2-ylsulfanyl) -octylcarbamoyl-3.3"-dichloro fl, 1', -3 ', 1"! Terphenyl-2'-yloxy] -ethanol To a stirred solution of the ethyl ether of 3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid (0.620 g, 1. 44 mmoles) in THF: EtOH (3: 2, 30 ml) at room temperature is added KOH IN (7.20 ml, 7.20 mmoles) dropwise. After 18 h at this temperature, the reaction mixture is concentrated and diluted with H20 (100 ml). The aqueous solution is acidified to pH 1 with 2N HCl. The solid [3,5-bis- (m-chlorophenyl) -4 (2-hydroxyethoxy) benzoic acid that forms is filtered off, washed with excess H20, and then dried in a high vacuum pump ( 0.450 g, 78%). To a round bottom flask cooled to the flame with 8- (benzoxazol-2-ylsulfanyl) octylamine (0.155 g, 0.558 mmol) in benzene: EtOH (1: 1, 6 mL) at room temperature is added 3, 5- bis- (m-chlorophenyl) -4- (2-hydroxyethoxy (benzoic (0.150 g, 0.372 mmol) followed by EEDQ (0.258 g, 1.04 mmol) After 3 days at this temperature, it is diluted with EtOAc (200 ml) This solution is washed with IN HCl (20 ml), saturated aqueous NaHC03 (20 ml), and brine (20 ml) and then dried (MgSO4) After concentration, the residue is purified by chromatography on preparation plate ( 30% EtOAc / petroleum ether) to give the product (0.183 g, 74%) as a solid; JH NMR (CDC1-,) d 1.28-1.42 (m, 6H), 1.42-1.68 (m, 5H), 1.77 -1.97 (m, 2H), 3.27-3.41 (m, 6H), 3.46 (dd, J = 6.1, 13.5 Hz, 2H), 6.09-6.17 (m, 1H), 7.22-7.47 (m, 7H), 7.47 -7.54 (m, 2H), 7.54-7.66 (m, 3H), 7.74 (s, 2H), mass spectrum [(+) ESI], m / z 664 (M + H) *.
Step 3 Acid (5'-Í8- (Benzoxazol-2-ylsulfanyl) -octylcarbamoyl -3,3'-dichloro- [1,1'-3 ', 1"1-terphenyl-2'-cycloalkyl] The title compote is prepared as a white foamy eolid (0.087 g, 47%) from. { 5 '- [8- (benzoxazol-2-ylsulfanyl) -octylcarbamoyl-3, 3"-dichloro- [1,1', -3 '1"] terphenyl-2'-yloxy} ethanol using a procedure similar to that of Step 2 of Example 51, pf > 68 ° C (decompoeition); H NMR (DMSO-d6) 6 1.27-1.34 (m, 6H), 1.36-1.44 (m, 2H), 1.46-1.55 (m, 2H), 1.71-1.80 (m, 2H), 3.22-3.36 (m, 4H), 3.79 (s, 2H), 7.26-7.33 (m, 2H), 7.43-7.50 (m, 4H), 7.56-7.63 (m, 4H), 7.68 (s, 2H), 7.85 (s, 2H) , 8.54 (t, J = 5.3 Hz, 1H), 1 1.55-13.75 (broad s, 1H); IR (KBr) 3410, 3080, 2930, 2860, 1730, 1630, 1600, 1565, 1545, 1500, 1480, 1455, 1430, 1395, 1335, 1300, 1230, 1210, 1170, 1130, 1100, 1080, 1040, 1000, 925, 885, 800, 740, and 700 cm'J- mass spectrum [(+) APCI], m / z 6771679 (M + H) J-Analysis Calculated for C36H34Cl2N2Os? - 1.5 H20: C, 61.36, H, 5.29; N, 3.98, Found: C, 61.37; H, 4.74; N, 4.04.
Example 88 Acid [3, 3"-Dichloro-5 '- (8-indol-l-l-octylcarbamoyl) - [1, 1'; 3 ', l"] terphenyl-2'-yloxy] acetic acid Step 1 f3.3"-Dichloro-5 '- (8-indol-1- i1-octi Icarbamoyl 1-fl, 1'; 3 ', 1" 1 terphenyl-2'-yloxy-1-ethanol To a round-bottomed flask cooled to the flame with 8-indol-1-iloctylamine (0.227 g, 0.930 mmol, preparation similar to that of Step 1 of Example 54) in CH2C12 (10 ml) at room temperature is added 3 acid, 5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) -benzoic acid (0.250 g, 0.620 mmol, prepared in Step 2 of Example 55) followed by Et3N (0.259 mL, 1.86 mmol), HOBT (0.092 g) , 0.682 mmoles), and finally DCC (0.153 g, 0.744 mmolee). After 3 days at this temperature, concentrate and then dilute with EtOAc (200 ml). The white solid (DCU) which is formed is filtered off and washed with excess EtOAc. The organic layer is washed with IN HCl (20 mL), saturated aqueous NaHCO 3 (20 mL), and brine (20 mL) and then dried (MgSO 4). After concentration, the residue is purified on a Biotage Flash 40 apparatus (30 to 50% EtOAc / petroleum ether) to give the product (0.341 g, 87%) as a solid: H NMR (CDC13) d 1.21- 1.38 (m, 8H), 1.46-1.63 (m, 3H), 1.75-1.89 (m, 2H), 3.27-3.49 (m, 6H), 4.11 (t, J = S. 1 Hz, 2H), 6.01- 6.13 (m, 1 H), 6.47 (d, J = 2.2 Hz, 1 H), 7.05-7.13 (m, 2H), 7.19 (t, J = 8.8 Hz, 1H), 7.39-7.46 (m, 5H) , 7.48-7.55 (m, 2H), 7.58-7.66 (m, 3H), 7.74 (s, 2H); mass spectrum [(+) ESI], m / z 629 (M) *.
Step2: Acid [3, 3"-Dichloro-5 '- (8-indol-l-yl-octylcarbamoyl) - [1,1': 3 ', l" f ter nyl-2' - yloxyl acetic The title compound is prepared as an off-white foamy solid (0.051 g, 37%) from [3, 3"-dichloro-5 '- (8-indol-1-yl-octyl carbamoyl) - [l, 1] ', -3'l "] terphenyl-2'-yloxylethanol using a procedure similar to that of Step 2 of Example 51, pf > 84 ° C (decomposition); 1 H NMR (DMS0-d6) d 1.16-1.33 (m, 8H), 1.44-1.54 (m, 2H), 1.68-1.77 (m, 2H), 3.18-3.31 (m, 2H), 3.77 (s, 2H) , 4.12 (t, J = 6.8 Hz, 2H), 6.37 (d, J = 2.9 Hz, 1H) 6.97 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 7.31 ( d, J = 2.9 Hz, 1H), 7.40-7.52 (m, 6H), 7.58- (d, J = 6.6 Hz, 2H), - '. ßß (8, 2H), 7.84 (s, 2H), 8.52 (t, J = 5.9 Hz, 1H), 11.65-13.65 (broad s, 1H); IR (KBr) 3410, 3070, 2930, 2860, 1730, 1635, 1600, 1580, 1570, 1545, 1480, 1460, 1430, 1400, 1330, 1310, 1240, 1210, 1170, 1 100, 1080, 1045, 880 , 795, 760, 740, and 700 cm'J- mass spectrum [(+) APCI], m / z 643/645 (M + H) J- Analysis Calculated for C37H36C12N204-1.5 H20: C, 66.17; H, 5.86; N, 4.18, Found: C, 66.30; H, 5.12; N, 4.14.
Example 89 Acid (3,3"-Dichloro-5 '- [8- (3-cyano-phenoxy) -octylcarbamoyl] - [1,1'; 3 ', 1"] terphenyl-2'-yloxy.
The title compound is prepared as a whitish foam (0.169 g, 50%) from 3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid using 8- (3-cyano-phenoxy). ) octylamine (preparation similar to that of Step 1 of Example 86) and a procedure similar to that of Example 88, pf >61 ° C (decomposition); * H NMR (DMSO-d,) 6 1.28-11.43 (m, 8H), 1.47-1.56 (m, 2H), 1.65-1.74 (m, 2H), 3.23-3.32 (m, 2H), 3.78 (S , 2H), 3.99 (t, J = 6.6 Hz, 2H), 7.25 (dd, J = 2.6, 8.3 Hz, 1H), 7.34-7.39 (m, 2H), 7.42-7.50 (m, 5H), 7.56- 7.60 (m, 2H), 7.68 (s, 2H), 7.85 (s, 2H), 8.56 (t, J = 5.5 Hz, 1H), 12.25-13.55 (broad s, 1H); IR (KBr) 3380, 3080, 2930, 2860. 2240, 1730, 1630, 1600, 1580, 1560, 1535, 1480. 1465, 1430, 1395, 1325, 1290, 1265, 1205, 1160, 1140, 1000, 875, 790, 780, 765, 700, and 680 cm'J- mass spectrum [(+) ESI], miz 645 (M + H) J-Analysis Calculated for C36H34C12N205 - 1.5 H20: C, 64.29, H, 5.54, N , 4.16, Found: C, 64.05; H, 5.01; N, 4.08.
Example 90 Acid. { 3,3"-Dichloro-5'- [8- (4-chloro-benzyloxy) -octylcarbamoyl] - [1,1 '; 3', 1"] terphenyl-2'-yloxy} acetic The title compound is prepared as an off-white solid (0.161 g, 51%) from 3,5-b? S- (m-chlorophenyl) -4- (2-hydroxy-ctoxy) benzoic acid using 8- (4 -chlorobenzyloxy) octylamine (preparation similar to that of Step 1 of Example 86) and a procedure similar to that of Example 88, mp 128-131 ° C; * H NMR (DMSO-d6) d 1.32-1.34 (tn, 8H), 1.47-1.56 (m, 4H), 3.26 (dd, J = 6-8, 13.0 Hz, 2H), 3.39 (t, J = 6.6 Hz, 2H), 3.78 (s, 2H), 4.41 (s, 2H), 7.29-7.33 (m, 2H), 7.36- 7.40 (m, 2H), 7.42-7.51 (m, 4H), 7.58 (dt, J = 2.2, 6.4 Hz, 2H), 7.68-7.71 (m, 2H) 7.86 (e, 2H), 8.56 (t, J = 5.5 Hz, 1H), 11. 75-13.85 (broad s, 1H); IR (KBr) 3320, 3070, 2930, 2860, 1725, 1620, 1600, 1570, 1490, 1480, 1460, 1425, 1400, 1340, 1300, 1280, 1240, 1200, 1170, 1155, 1090, 1050, 1015, 885, 800, 780, 755, and 700 cm "1, - mass spectrum [(+) ESI], m / z 668/670/672 (M + H) J- Analysis Calculated for C36H3SC13N0S - H20: C, 62.93; H, 5.57; N, 2.04, Found: C, 62.95; H, 5.13; N, 1. 96 Example 91 Acid (3,3"-Dichloro-5 '- [8- (4-fluoro-3-methyl-phenoxy) -octylcarbamoyl] - [1, 1'; 3 ', 1"] terphenyl-2'-yloxy acetic acid The title compound is prepared as a white solid (0.193 g, 48%) from 3, 5-bis- (m-chlorophenyl) - 4 - . 4- (2-Hydroxyethoxy) benzoic using 8 - (4-f luoro-3-methylphenoxy) octylamine (preparation similar to that of Step 1 of Example 86) and a procedure similar to that of Example 88, mp 138-140 ° C; XH NMR (DMSO-d6) 6 1.26-1.33 (m, 8H), 1.48-1.57 (m, 2H), 1.63-1.71 (m, 2H), 2.17 (d, J = 1.8 Hz, 3H), 3.27 (dd) , J = 6.6, 12.7 Hz. 2H). 3.81 (e, 2H), 3.88 (t, J = 6.4 Hz, 2H), 6.68-6.73 (m, 1H), 6.81 (dd, J = 3.1, 6.4 Hz. 1H), 6.99 (t, J = 9.2 Hz , 1H), 7.45-7.52 (m, 4H), 7.57-7.60 (m, 2H), 7.69 (s, 2H), 7.87 (S, 2H), 8.57 (t, J = 5.5 Hz, 1H), 12.00- 13.45 (8 broad, 1H); IR (KBr) 3330, 3080, 2930, 2860, 1725, 1625, 1570, 1500, 1485, 1460, 1430, 1395, 1330, 1300, 1280, 1245, 1205, 1165, 1100, 1075, 1050, 885, 795, 770, and 700 cm "1; mass spectrum [(-) ESI], m / z 650 (M - H)", - Analysis Calculated for C36H36C12FN0S - 0.5 H20: C, 65.36; H, 5.64; N, 2.12, Found: C, 65.22, H, 5.56; N, 2.13.
Example 92 Acid [3,3"-Dichloro-5'- (8-imidazol-l -octylcarbamoyl] - [1,1 ', -3', l"] terphenyl-2'-yloxy] acetic acid The title compound is prepared as an off-white solid (0.010 g, 2%) from 3,5-bis- (m-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid using 8-imidazol-1-yloctylamine ( preparation similar to that of Step 1 of Example 86) and a procedure similar to that of Example 88, pf > 109 ° C (decomposition); * H NMR (DMS0-d6) d 1.13-1.32 (m, 8H), 1.44-1.54 (m, 2H), 1.62-1.70 (m, 2H), 3.20-3.36 (m, 2H), 3. 64 (s) , 2H), 3.90 (t, J = 7.0 Hz, 2H), 6.84 (s, 1H), 7.12 (s, 1H), 7.41-7.48 (m, 4H), 7.56-7.62 (m, 3H), 7.71 ( s, 2H), 7.82 (s, 2H), 8.51 (t, J = 5.3 Hz, 1H), 10.75-13.45 (broad s, 1H); IR (KBr) 3420, 3125, 3080, 2930, 2860, 1735, 1630, 1600, 1580, 1565, 1480, 1460, 1425, 1400, 1330, 1300, 1275, 1260, 1240, 1210, 1165, 1085, 1030, 880, 780, 770, and 700 cm'J- mass spectrum [(+) ESI], m / z 594 (M + H) J- Analysis Calculated for C 32 H 33 C 12 N 304 - 6 H 20: C, 54.70; H, 6.46; N, 5.98, Found: C, 54.60; H, 5.34; N, 5.23.
Example 93 Acid (3, 3"-Dichloro-5 '- [6 - (naph alen-1-octylcarbamoyl] - [1, 1', 3 ', 1"] terf-enyl-21-yloxy} acetic acid Stage 1 6- (Naphthalen-1-ylcarbamoyloxy) hexylamine To a round bottom flask with 6-bromo-l-hexanol (0.500 g, 2.76 mmol) and CH2C12 (25 ml) at room temperature is added 1-naphthyl isocyanate (0.595 ml, 4.14 mmol) followed by bis (chloro-dibutyltin) oxide (0.076 g, 0.138 mmol). After stirring at this temperature for 2 h, the The reaction mixture is suspended with MeOH (15 ml) and then diluted with EtOAc (300 ml). The organic layer is washed with IN HCl (30 ml), Saturated aqueous NaHC03 (30 ml), and brine (30 ml) and then dried (MgSO4). After concentration, the residue is diluted with CHC13 (200 ml), and the white polymeric solid which forms is separated by filtration. After a second concentration, the residue is purified in a Biotage Flash 40 apparatus (gradient of 10 to 15% EtOAc / petroleum ether) to provide the bromide carbamate intermediate. To a round bottom flask with the intermediate of bromide carbamate (0.741 g, 2.12 mmol) and DMF (20 ml) at room temperature, add sodium azide (0.689 g, 10.6 mmol) followed by tetrabutylammonium iodide (0.078 g). , 0.212 mmolee). The mixture is heated at 100 ° C for 3 h. At this point, the reaction mixture is concentrated and then diluted with EtOAc (300 ml). The organic layer is washed with IN HCl (30 ml), saturated aqueous NaHCO 3 (30 ml), and brine (30 ml) and then dried (Na 2 SO 4). After concentration, the residue is purified on a Biotage Flash 40 apparatus (gradient of 5 to 15% EtOAc / petroleum ether) to provide the carbamate azide intermediate. To this intermediate of carbamate azide (0.439 g, 1.41 mmol) in THF (14 ml) at room temperature is added H20 (0.028 ml, 1.55 mmole) followed by triphenylphosphine (0.407 g, 1.55 mmole). After stirring at this temperature for 18 h, the reaction has been halved, determined by CCD. Some boiling virutal is added and stirring is continued at room temperature for another 3 days. The solution is diluted with EtOAc in excess (200 ml), dried (Na 2 SO 4), and concentrated to give the product (0.398 g, 65%) as an oil (contaminated with triphenylphosphine oxide which does not cause problems in the Steps). subsequent); ? NMR (CDC13) d 1.31-1.54 (m, 8H), 1.86-1.98 (m, 2H), 2.70 (t, J = 6.8 Hz, 2H), 4.25 (t, J = 6.8 Hz, 2H), 6.98-7.12 (s broad, 1H), 7.26-7.97 (m, 7H), - mass spectrum [(+) ESI], m / z 287 (M + H) *.
Stage 2 2, 6-Divodo-4- 6 '- (naphthalene-1' - iCarbamoyl oxy) - hexylcarbamoyl-phenol To a round bottom flask with 3, 5-diiodo-4-hydroxybenzoic acid (0.420 g, 1.08 mmole) is added S0C12 (3 ml). After 2 h at reflux, the solution is concentrated and pumped at high vacuum for 0.5 h. This acid chloride is then dissolved in THF (3 ml) and added dropwise to a solution of 6- (naph-alen-1-ylcarbamoyloxy) hexylamine (0.402 g, 1.40 mmoles) and Et3N (0.452 ml, 3.24 mmoles). ) in THF (7 ml). After stirring for 1 h at room temperature, the reaction mixture is diluted with EtOAc (250 mL). The organic layer is washed with IN HCl (25 mL), saturated aqueous NaHC03 (25 mL), and brine. (25 ml) and then dried (MgSO4). After concentration, the residue is purified by the Biotage Flash 40 apparatus (30 to 50% EtOAc / petroleum ether) to provide the product (0.394 g, 55%) as a solid; * H NMR (DMSO-ds) d 1.27-1.46 (m, 4H), 1.46-1.58 (m, 2H), 1.58-1.71 (m, 2H), 3.22 (dd, J = 5.7, 13.8 Hz, 2H), 4.12 (t, J = 6.1 Hz, 2H), 7. 5-7.62 (m, 4H), 7.73 (d, J = 8.9 Hz, 1H), 7.88-7.94 (m, 1H), 8.03-8. 10 (m, 1H), 8.23 (S, 2H), 8.43 (t, J - 5.4 Hz, 1H), 9.49 (s, 1 H), 10.03 (s, 1 H); eepectro de maea [(-) ESI], m / z 657 (M - H) ".
Step 3 3.3"-Dichloro-5 '- [6- (naphthalen-l-ylcarbamoyl) -hexylcaraamoill-fl.l', -3 ', 1" 1 terphenyl-2'-ol To a flask with 2,6-diiodo-4 - [6 '- (naphthalene-1'-carbamoyloxy) -hexylcarbamoyl] phenol (0.394 g, 0.599 mmol) is added a 1M solution of K2C03 (1.80 ml, 1.80 mmol) followed by dioxanc (18 ml). To this mixture is added 3-chlorophenylboronic acid (0.25 g, 1.44 mmoles) and then PdCl2 (dppf) (0.010 g, 0.0120 mmcles). The mixture is stirred at room temperature for 0.5 h and then heated at 65 ° C for 3 h. At this point, the reaction is cooled to room temperature, the concertina, and then diluted with EtOAc (250 ml).
The organic layer was washed with IN HCl (25 ml), saturated aqueous NaHCO3 (25 ml), and brine (25 ml) and then dried (MgSO4). After concentration, the residue is purified by the apparatus Biotage Flash 40 (gradient of 30 to 50% EtAOc / petroleum ether) to provide the product (0.337 g, 90%) as a solid; 'HRMN (DMS0-d6) 6 1.30-1.50 (m, 4H), 1.50-1.61 (m, 2H), 1.61-1.72 (m, 2H), 3.19-3.35 (m, 2H), 4.11 (t, J = 6.7 Hz, 2H), 7.43-7.62 (m, 10H), 7.65 (s, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.79 (S, 2H), 7.88-7.94 (m, 1H), 8.03-8.09 (m, 1H), 8.46 (t, J = 5.6 Hz, 1H), 9.18 (s, IH,), 9.50 (s, 1H); mass spectrum [(+) ESI], m / z628 (M + H) J 650 (M + Na) *.
Stage 4 Ethyl acid ester. { 3.3"-Dichloro-5 '- i 6 - (naphthalen-1-ylcarbamoyloxy 1 -hexylcarbamoyl 1-fl, 1', -3 ', 1"! Terphenyl-2'-yloxy I acetic To a stirred solution of 3, 3"-dichloro-5 '- [6 - (naphthalene-1-? Lcarbamoylox?) -hex Icarbamoyl] - [1,1', - 3 '1"] -terphenyl-2' - ol (0.320 g, 0.51 0 mmol) and K2C03 (0.078 g, 0.561 mmol) in DMF (10 mL) at room temperature is added dropwise to ethyl bromoacetate (0.097 mL, 1.02 mmol). After 18 h at this temperature, it is concentrated and then diluted with EtOAc (250 ml) in excess. The organic layer is washed with IN HCl (25 mL), saturated aqueous NaHCO3 (25 mL), and brine (25 mL) and then dried (MgSO4). After concentration, the residue is purified by flash chromatography (gradient of 30 a 50% EtOAc / petroleum ether) to provide the product (0.231 g, 65%) as a solid; "H NMR (DMSO-d6) d 1.32-1.49 (m, 4H), 1.49-1.73 (til, 4H), 3.23-3.35 (m, 2H), 3.44 (s, 3H), 3.99 (S, 2H), 4.11 (t, J = 6.3 Hz, 2H), 7.45-7.63 (m, 10H), 7.69 (s, 2H), 7.73 (d, J = 9.4 Hz, 1H), 7.87-7.94 ( m, 3H), 8.02-8.12 (m, 1H), 8.61 (t, J = 5.5 Hz, 1H), 9.49 (s, 1H); mass spectrum [(+) ESI], m / z 700 (M + H) *.
Stage 5 Acid. { 3.3"-Dichloro-5 '- [6- (naphthalene-1- i) carbamoi loxi l-hexyl carbamoyl l-fl, 1', -3 ', 1" 1 tert-butyl 2'-yloxy lactide To a stirred solution of the ethyl ester of the acid. { 3, 3"-dichloro-5 '- [6- (naphthalen-1-ylcarbamoyloxy) -hexylcarbamoyl] - [1,1', -3 '1"] -terphenyl-2'-yloxy} acetic acid (0.182 g, 0.310 mmol) in THF: MeOH (3: 2, 10 ml) at 0 ° C is added dropwise to IN KOH (1.55 ml, 1.55 mmol). After 0.5 h at this temperature, heat the room temperature for 0.5 h and then concentrate and dilute with H20. The solution is then acidified to pH 1 with 2N HCl. The turbid-white precipitate is filtered off and washed with H20. The re-emerging solid is purified by inert plate chromatography (10% MeOH: CHC13) to give the product (0.151 g, 72%) as an off-white solid, mp: 201-204 ° C; 'H NMR (DMSO-d6) d 1.32-1.45 (m, 4H), 1.51-1.58 (m, 2H), 1.61-1.68 (m, 2H), 3.24-3.35 (m, 2H), 3.77 (s, 2H) ), 4. 1 0 (t, J = 6.6 Hz, 2H), 7.43-7.53 (m, 7H), 7.55-7.60 (m, 3H), 7.68-7.74 (m, 3H), 7. 86 (S, 2H), 7.88-7.92 (m, 1H), 8.02-8.06 (m, 1H), 8.58 (t, J = 5.5 Hz, 1H), 9.48 (s, 1H), 11.65-13.45 (s broad , 1 HOUR); IR (KBr) 3430, 3260, 3060, 2930, 2870, 2720, 2670, 2600, 2510. 2320, 1765, 1690, 1610, 1570, 1535, 1505, 1480, 1465, 1430, 1415, 1390, 1390, 1335, 1300, 1240, 1220, 1195, 1165, 1105, 1080, 1070, 1030, 1010, 900, 895, 785. 780, 765, and 700 cm'1; mass spectral [(-) ESI], m / z 683 (M-H) *, - Analysis Calculated for C38H34C12N206 - 2.25 H20: C, 62.86; H, 5.34; N, 3.86, Found: C, 62.69; H, 4.58: N, 3.79.
Example 94 Acid (3, 3"-Dichloro-5 '- [6- (2,4-difluoro-phenylcarbamoyloxy) -hexylcarbamoyloxy] - [1,1'; 3 ', 1"] terphenyl-2'-yloxy.
The title compound is prepared as a white foamy solid (0.203 g, 30%) from 3,5-diiodo-4-hydroxybenzoic acid using 6- (2,4-difluorophenyl-carbamoyloxy) -hexylamine and a procedure similar to of Example 93, pf > 80 ° C (decompoiition); 'H NMR (DM? O-d6) dl.30-1.42 (m, 4H), 1.48-1.64 (m, 4H), 3.23-3.33 (m, 2H), 3.82 (e, 2H), 4.04 (t, J = 6.8 Hz, 2H), 6.99-7.05 (m, 1H), 7.22-7.29 (m, 1H), 7.44-7.60 (m, 7H), 7.67-7.70 (m, 2H), 7.87 (e, 2H), 8.58 (t, J = 5.5 Hz, 1H), 9.22 (e, 1H), 11.65-13.45 (broad s, 1H); IR (KBr) 3320, 3070, 2930, 2860, 1725, 1620, 1530, 1480, 1460, 1425, 1400, 1330, 1290, 1225, 1200, 1170, 1145, 1100, 1070, 970, 880, 845, 795, 775, and 700 cm'J- mass spectrum [(-) ESI], m / z 669 (M - H) J- Calculated Analysis for C34H30C12F2N206 - 0.75 H20: C, 59.61; H, 4.63; N, 4.09, Found: C, 59.53; H, 4.12; N, 3.99.
Example 95 Acid (3,3"-Dichloro-5 '- [6- (4-phenoxy-phenylcarbamoyloxy) -hexylcarbamoyloxy] - [1,1'; 3 ', 1"] erphenyl-2'-yloxy-acetic acid The title compound is prepared as a white foamy solid (0.494 g, 45%) from 3,5-diiodo-4-hydroxybenzoic acid using 6- (4-phenoxy-phenylcarbamoyloxy) hexylamine and a procedure similar to that of Example 93 , pf > 75 ° C (decomposition); 1K NMR (DMSO-d6) d 1.32-1.43 (m, 4H), 1.50-1.66 (m, 4H), 3.24-3.33 (m, 1H), 3.84 (s, 2H), 4.06 (t, J = 6.6 Hz , 2H), 6.90-6.97 (m, 4H), 7.06 (t, J = 7.2 Hz, 1H), 7.30-7.37 (m, 2H), 7.42-7.52 (m, 6H), 7.58 (dt, J = 2.0 , 6.6 Hz, 2H), 7.67-7.71 (m, 2H), 7.87 (s, 2H), 8.58 (t, J = 5.8 Hz, 1H), 9.59 (s, 1H), 11.50-12.75 (s broad, 1H ); IR (KBr) 3320, 3060, 2930, 2860, 1725, 1705, 1640, 1600, 1545, 1505, 1490, 1465, 1430, 1410, 1330, 1305, 1215, 1170, 1100, 1075, 1010, 980, 835, 795, 765, and 695 cm "J- spectrum of maea [(-) ESI], m / z 725 (M - H) J- Analysis Calculated for C40H36Cl2N2O7 - H20: C, 64.43; H, 5.14; N, 3.76, Found: C, 64.44; H, 4.69; N, 3.53.
Example 96 Acid { 3,3"-Dichloro-5 '- [8- (5-fluoro-indol-l-yl) -octylcarbamoyl] - [1,1'; 3 ', 1"] terphenyl-2'-yloxy) acetic The title compound is prepared as an off-white solid (0.373 g, 48%) from 3,5-diiodo-4-hydroxybenzoic acid using 8- (5-fluoro-indol-1-yl) octylamine (preparation similar to that of Stage 1 of Example 86) and a procedure similar to that of Example 93, mp 141-144 ° C; XH NMR (DMSO-d6) 6 1.16-1.31 (, 8H), 1.44-1.53 (m, 2H), 1.67-1.76 (m, 2H), 3.23 (dd, J = 6.8, 13.2 Hz, 2H), 3.82 ( e, 2H), 4.12 (t, J = 7.0 Hz, 2H), 6.37 (dd, J = 0.7, 3.1 Hz, 1 H), 6.93 (td, J = 2.4, 9.2 Hz, 1 H), 7.26 (dd) , J = 2.2, 9.7 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 7.41-7.51 (m, 5H), 7.57 (dt, J = 2.2, 6.6 Hz. 2H), 7.67-7.69 ( m, 2H), 7.85 (s, 2H), 8.53 (t, J = 5.7 Hz, 1H), 11.55-13.30 (broad s, 1H); IR (KBr) 3340, 3070, 2930, 2860, 2520, 1725, 1625, 1580, 1565, 1490, 1445, 1400, 1375, 1340, 1300, 1280, 1230, 1205, 1150, 1140, 1110, 1100, 1085, 1050, 945, 890, 860, 795, 780, 750, 715, and 695 cm "1; mass spectrum [(+) APCI], m / z 661 (M + H) *; Analysis Calculated for C 37 H 35 C 12 FN 20 4 - H 20: C, 65.39; H, 5.49; N, 4.12, Found: C, 65.44; H, 5.21; N, 3.98.
Example 97 Acid { 3,3"-Dichloro-5'- [8- (5-methoxy-indol-1-yl) -octylcarbaoyloxy] - [1,1 '; 3', 1"] ter enyl-2'-yloxy} acetic The title compound is prepared as a white foamy eolium (0.288 g, 37%) from 3,5-diiodo-4-hydroxybenzoic acid using 8- (5-methoxy-indol-1-yl) octylamine (preparation similar to Stage 1 of Example 86) and a procedure similar to that of Example 93, pf > 70 ° C (decomposition); ? NMR (DMSO-d,) 6 1.15-1.29 (m, 8H), 1.43-1.53, (m, 2H), 1.65-1.74 (m, 2H), 3.23 (dd, J = 6.8, 13.0 Hz, 2H) , 3.72 (?, 3H), 3.82 (s, 2H), 4.07 (t, J = 7.0 Hz, 2H), 6.28 (dd, J = 0.7, 3.1 Hz, 1 H), 6.73 (dd, J = 2.4, 8.8 Hz, 1 H), 7.00 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 3.1 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.44 7.51 (m, 4H) , 7.57 (dt J = 2.2, 6.6 Hz, 2H), 7.67-7.69 (m, 2H), 7.86 (s, 2H), 8.53 (t, J = 5.7 Hz, 1H), 11.65-13.50 (s broad, 1 HOUR); IR (Kbr) 3360, 3070, 2930, 2860, 2520, 1730, 1620, 1600, 1575, 1550, 1490, 1445, 1430, 1395, 1335, 1300, 1230, 1205, 1160, 1145, 1100, 1080, 1050, 1025, 885, 795, 780, 760, and 695 cm "1; mass spectrum [(+) APCI], ni / z 673 (M + H) *, - Analisys Calculated for C38H38C12N205 - 2.0 ^^ ií¿ £ ^ _ H20: C, 64.31; H, 5.97; N, 3.95, Found: C, 64.29; H, 5.56; N, 3.81.
Example 98 Acid (3,3"-Dichloro-5 '- [8- (2,5-dimethyl-indo-1-yl) -octylcarbamoyl] - [1,1'; 3 ', 1"] terphenyl-2' - iloxi acetic The title compound is prepared as a light orange solid (0.138 g, 19%) from 3,5-diiodo-4-hydroxybenzoic acid using 8- (2,5-dimethyl-indol-1-yl) octylamine (preparation similar to that of Step 1 of Example 86) and a procedure similar to that of Example 93, pf > 172 ° C (decomposition); XH NMR (DMS0-d6) d 1.18-1.32 (m, 8H), 1.44-1.53 (m, 2H), 1.55-1.64 (m, 2H), 2.31 (s, 3H), 2.33 (s, 3H), 3.24 (dd, J = 7.0, 13.4 Hz, 2H), 3.81 (s, 2H), 4.01 (t, J = 7.2 Hz, 2H), 6.03-6.05 (m, 1 H), 6.82 (dd, J = 1.5, 8.6 Hz, 1 H), 7.14-7.16 (m, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.43-7.51 (m, 4H), 7.57 (dt, J = 2.2, 6.6 Hz, 2H) , 7.67-7.69 (m, 2H), 7.86 (s, 1H), 8.53 (t, J = 5.7 Hz, 1H), 11.80-13.30 (broad s, 1H); IR (KBr) 3340, 3070, 3010, 2930, 2860, 2740, 2510, 1725, 1620, 1580, 1560, 1485, 1455, 1400, 1345, 1330, 1300, 1240, 1200, 1165, 1100, 1080, 1050, 885, 870, 795, 780, 770, 760, and 700 cm "J- mass spectrum [(+) APCI], m / z 671 (M + H) J- Analysis Calculated for C39H4oCl2N20, -1.5 H20: C, 67. 04; H, 6 twenty; N, 4 01, Found: C, 66. 83; H, 5 94; N, 3 85 Example 99 Acid { 3,3"-Dichloro-5 '- [8- (5-methoxy-2-methyl-? Ndol-1-yl) -octylcarbamoyl] - [1,1'; 3 ', 1"] terphenyl-2' - iloxi} acetic The title compound is prepared as a light orange foaming solid (0.310 g, 41%) from 3,5-diiodo-4-hydroxybenzoic acid using 8- (5-methoxy-methyl-indole-yl) octylamine ( preparation similar to that of Step 1 of Example 86) and a procedure similar to Example 93, pf >75 ° C (decomposition). JH NMR (DMSO-d6) 6 1.22-1.32 (m, 8H), 1.44-1.54 (m, 2H), 1.54-1.64 (m, 2H), 2.33 (S, 3H), 3.24 (dd, J = 6.4, 12.5 I4zJ 2H), 3.70 (s, 3H), 3.85 (e, 2H), 4.00 (t, J = 7.2 Hz, 2H), 6.05-6.07 (m, 1H), 6.64 (dd, J = 2.4, 8.8 Hz , 1H), 6.90 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.44-7.52 (m, 4H), 7.57 (dt, J = 2.2, 6.6 Hz, 2H) , 7.67-7.69 (m, 2H), 7.86 (s, 2H), 8.54 (t, J = 6.9 Hz, 1H), 12.20-12.85 (broad s, 1H); IR (KBr) 3410, 3070, 2930, 2860, 1735, 1635, 1615, 1600, 1580, 1570, 1555, 1490, 1455, 1430, 1400, 1330, 1300, 1210, 1165, 1100, 1075, 1050, 1030, 880, 830, 795, 775, and 700 crn "1; mass spectral [(+) APCI], m / z 687 (M + H) J- Analysis Calculated for C39H40C12N205 - H20: C, 66.38; H, 6.00; N, 3.97, Found: C, 66.62; H, 5.70; N, 3.93.
Example 100 Acid [3,3"-Dichloro-5 '- ([1-phenyl-butoxyphenyl) -cyclopropylmethyl] -carbamoyl.] - [1,1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid Stage 1 3-Hydroxy-2-cyclopropylpropylamine To a suspension of LAH (16.14 g, 425 mol) in THF (300 ml) cooled to 0 ° C is added a suspension of 1- (aminocarbonyl) -1-cyclopropanecarboxylic acid (9.15 g, 70.9 mmol) in THF (100 ml ) drops. After 15 minutes at this temperature, it is warmed to room temperature and stirred for 2.5 h. At this point, the mixture is again cooled to 0 ° C and suspended with efficient stirring by dropwise addition of H20 (16.14 ml), 15% aqueous NaOH (16.14 ml), and H20 (48.42 ml). Then stir an additional 18 h at room temperature. At this time, the solvent is dried (Na 2 SO 4), filtered, and concentrated. The residue is purified by vacuum distillation ("5 mmHg, top temperature of 95-100 ° C) to provide the product (1.40 g, 20%) as an oil; H NMR (DMSO-d6) d 0.24 -0.28 (m, 4H), 2.49 (s, 2H), 3.30 (m, 2H), - IR (film) 3365, 3300, 3080, 3000, 2920, 2870, 1650, 1595, 1465, 1430, 1395, 1310, 1210. 1035, 980, 925, 895, 865, and 720 cm "1; mass spectrum [(+) ESI], m / z 102 (M + H) J Step 2 (3, 3"-Dichloro-5 '- (l- (hydroxymethyl) -cyclopropylmethylcarbamoyl) - [1,1'; 3 '. 1"] terphenyl-2'-yloxy) -methyl methyl ester To a stirred solution of 3,5-bie- (m-chlorophenyl) -4- (2-methoxymethoxy) -benzoic acid ethyl ester (3.18 g, 7.37 mmol) in THF: EtOH (3: 2, 100 ml) At room temperature, add KOH IN (37 ml, 36.9 mmol) dropwise. After 18 h at this temperature, the reaction mixture is concentrated and diluted with H20 (200 ml). The aqueous solution is acidified to pH 1 with 2N HCl. The solid that forms is separated by filtration and washed with excess H20. It is then dissolved in EtOAc (300 ml), washed with brine (30 ml), and dried (Mg 04). After concentration, the residue is purified in a Biotage Flash 40 apparatus (gradient of 1 to 5% MeOH / CHCl 3) to provide the product [2.45 g, 82%, 3, 5-bis- (m-chlorophenyl) - 4- (2-methoxymethoxy) -benzoic acid] as a solid. To a flame-cooled round bottom flask with 3-hydroxy-2-cyclopropyl-propylamine (0.842 g, 8.33 mmol) in CH2C12 (80 ml) at room temperature is added 3, 5-bis- (m-chlorophenyl) -4- (2-Hydroxyethoxy) benzoic acid (2.24 g, 5.55 mmole) followed by Et3N (2.32 ml, 16.7 mmoles), HOBT (0.825 g, 6.11 mmoles), and finally DCC (1.37 g, 6.66 mmoles). After 18 h at this temperature, concentrate and then dilute with EtOAc (400 mL). The white solid (DCU) that forms is filtered off and washed with excess EtOAc. The organic layer is washed with IN HCl (40 ml), saturated aqueous NaHCO 3 (40 ml), and brine (40 ml) and then dried (MgSO 4). After concentration, the residue is purified in a Biotage Flash 40 apparatus (gradient of 30 to 50% EtOAc / petroleum ether) to give the product (2.28 to, 84%) as a solid; 1 H NMR (DMS0-d 6) d 0.34-0.40 (m, * H), 0.43-0.50 (m, 2H), 2.66 (s, 3H), 3.22-3.42 (m, 4H), 4.38 (e, 2H), 4.53 (s, 1H), 7.43-7.66 (m, 6H), 7.72 (s, 2H), 7.89 (s, 2H), 8.61 (t, J = 5.4 Hz, 1H); mass spectrum [(+) ESI], m / z 486 (M) *.
Step 3: (3,3"-Dichloro-5 '- { F 4-phenyl-butoxymethyl) -cyclopropylmethyl] -carbamoyl) -lfl, 3-yl! terfenyl-21-yloxy) -methyl To a solution of 4-phenyl-1-butanol (5.00 g, 33.3 mmol) and CH2C12 (250 ml) at 0 ° C is added triphenylphosphine (13.1 g, 50.0 mmol) followed by NBS (8.90 g, 50.0 mmol). After stirring at this temperature for 2 h, the mixture is separated with H20 (50 ml) and extracted with CH2C12 (150 ml). The organic layer is washed with brine (40 ml) and dried (Na 2 SO 4).
After concentration, the residue is purged through silica gel flash columns eluting with 2% EtOAc / petroleum ether as an eluent to provide 4-phenylbutyl bromide (6.22 g, 88%) as an intermediary. To a round bottom flask with NaH (0.201 g, 5.03 mmol) and THF (50 mL) cooled to 0 ° C is added methyl ether (3,3"-dichloro-5 '- ([1- (hydroxymethyl) - cyclopropylmethyl] -carbamoyl) - [1, 1 ', -3' l] terphenyl-2'-yloxy) methyl (1.88 g, 3.87 mmol) The re-emerging solution is heated to reflux for 10 minutes and then cooled again until the At room temperature, 15-crown-5 (0.308 ml, 1.55 mmol), tetrabutylammonium iodide (0.573 g, 1.55 mmol), and finally 4-phenyl-butyl bromide (3.30 g, 15.5 mmol) were added to this solution. THF (10 ml) The final mixture is heated to reflux for 18 a .. At this point, the reaction mixture is suspended with MeOH (10 ml) and then diluted with EtOAc (400 ml) .The organic layer is washed with IN HCl (40 mL), saturated aqueous NaHC03 (40 mL), and brine (40 mL) and then dehydrated (MgSO4). Deepening concentration, the residue is purified on a Biotage Flash 40 apparatus (10 to 30% gradient) of EtOAc / petroleum ether) to provide the product (0.777 g, 33%) as a solid; H NMR (CDC1 d 0.48-0.58 (m, 2H), 0.58-0.67 (m, 2H), 1.47-1.56 (m, 4H), 2.40 (t, J = 7.5 Hz, 2H), 2.73 (s, 3H) , 3.38 (s, 2H), 3.38-3.48 (m, 4H), 4.40 (s, 2H), 7.07 (d, J = 7.5 Hz, 2H), 7.12-7.26 (m, 3H), 7.31-7.42 (m , 4H), 7.42-7.53 (m, 3H), 7. 62 (s, 2H), 7.77 (s, 2H), - mass spectrum [(+) ESI], m / z 618 (M) *.
Step 4 3.3"-Dichloro-5 '- ([1- (4-phenyl-butoxymethyl) -cyclopropylmethyl -carbamoyl.} - fl. 1', - 3 ', 1" 1 terphenyl-2'-ol To a solution of (3, 3"-dichloro-5 '- ([1- (4-f-enylbutoxymethyl) -cyclopropylamine -carbamoyl] - [1,1', -3'l"] 3-phenyl-2'-yloxy) methyl (0.681 g, 1.10 mmol) in CH2C12 (15 mL) at -30 ° C containing 4 A molecular sieves, trimethylsilyl bromide (0.581 mL, 4.40 mmol) was added. temperature for 1 h, it is heated to 0 ° C and stirred for an additional 5 h.There is only a slight conversion to product, so that it is warmed to room temperature and stirred at this temperature for 18 h. The mixture is suspended with saturated aqueous NaHC03 (10 ml) and extracted with EtOAc (250 ml) The organic layer is washed with brine (25 ml) and then (MgSO4) After concentration, the residue is purified in an apparatus Biotage Flash 40 (10 to 30% EtOAc / petroleum ether) to provide the product (0.455g, 72%) as a solid, JH NMR (DMS0-ds) d 0.32-0.41 (m, 2H), 0.47- 0.55 (m, H), 1.40-1.62 (m, 4H), 2.46-2.58 (m, 2H), 3.28 (s, 2H), 3.28-3.42 (m, 411), 7.11-7.20 (m, 3H), 7.20-7.29 (m, 2H), 7.42 -7.55 (m, 6H), 7.65 (S, 2H), 7.79 (S, 2H), 8.34 (t, J = 6.3 Hz, 1H), 9.19 (s, 1H); mass specimen [(+) ESI], m / z 574 (M) *.
Step 5: Acid (3, 3"-Dichloro-5 '- { Fl- (4-phenyl-butoxymethyl) -cyclopropylmethyl] -carbamoyl) - [1,1': 3 ', l" 1-phenyl-2'-yloxy) acetic The title compound is prepared as a white foamy solid (0.202 g, 47%) from 3,3-dichloro-5 '- ([1- (4-f-enyl-butoxymethyl) -cyclopropylmethylcarbamoyl) - [1, 1 ', -3' 1"] terphenyl-2'-ol using a procedure similar to that of Steps 4-5 of Example 93, pf > 52 ° C (decomposition), JH NMR (DMSO-d6) d 0.36 (dd, J = 4.0, 5.5 Hz, 2H), 0.52 (dd, J = 4.6, 6.2 Hz, 2H), 1.42-1.51 (m, 2H ), 1.51-1.59 (m, 2H), 2.47-2.54 (m, 2H), 3.24-3.39 (m, 6H), 3.83 (s, 2H), 7.10-7.15 (m, 3H), 7.20-7.25 (m , 2H), 7.42-7.51 (m, 4H), 7.57 (dt, J = 2.2, 6.8 Hz, 2H), 7.67-7.69 (m, 2H), 7.86 (s, 2H), 8.47 (t, J = 5.7 Hz, 1H), 11.55-13.35 (broad s, 1H); IR (KBr) 3380, 3070, 3020, 2930, 2860, 1755, 1735, 1630, 1600, 1585, 1570, 1540, 1495, 1485, 1460, 1430, 1395, 1370, 1340, 1300, 1245, 1205, 1165, 1095, 1085, 1050, 885, 795, 780, 770, 755, and 700 cm "J- mass spectrum [(+) APCI], z 632 (M + H) J- Analysis Calculated for C36H35C12N05 - 0.25 H20: C , 67.87; H, 5.62, N, 2.20, Found: C, 67.77; H, 5.51; N, 2.14.
Example 101 Acid [5'- (Benzofuran-2 -carbonyl) - [1,1 ': 3'.1"1-terphenyl-2'-yloxy] acetic acid Stage I5 '- (Benzofuran-2-carbonyl) -Il.l': 3 ', 1"! Terphenyl-2'-illmethoxyethoxymethylether To a flame-dried round bottom flask with 2,3-benzofuran (0.77 ml, 2.51 mmol) and DME (30 ml) cooled to -10 ° C is added n-BuLi (1.10 ml, 2.5 M in hexane, 2.76 mmoles) dropwise over a period of 10 minutes. The resulting solution is stirred for 10 minutes, while heating to -5 ° C, and after cooling down to -20 ° C. To this eeolution 2 '-methoxyethoxymethoxy- [1, 1'; 3 ', 1"] terphenyl-5' -carboxaldehyde (1.00 g, 2.76 mmole) in DME (5 ml) dropwise The final mixture is stirred at -20 ° C for 0.5 h and then warmed to room temperature for 15 h. At this point, the reaction mixture is suspended by pouring into saturated aqueous NH4C1 (100 ml) and diluted with EtOAc (350 ml) The organic layer is washed with additional saturated aqueous NH4C1 (40 ml) and brine (40 ml). ml) and then dried (MgSO 4). After concentration, the residue is purified in a Biotage Flash 40 apparatus (gradient of 10 to 30% EtOAc / petroleum ether) to provide an alcohol intermediate.
To this intermediate alcohol (0.478 g, 0.995 mol) in CH2C12 (20 ml) at room temperature is added NMMO (0.152 g, 1.29 mol) followed by TPAP (0.105 g, 0.299 mmol).
After 1 h at this temperature, the reaction is filtered through a 1"column of silica gel.After concentration of the filtrate, the residue is purified in a Biotage Flash 40 apparatus (gradient from 5 to 15% EtOAc / ether of petroleum) to provide the product (0.430 g, 42%) as a solid; * H NMR (CDC1-,) 6 2.85-2.92 (m, 2H), 2.94-3.00 (m, 2H), 3.18 (s, 3H) ), 4.53 (s, 2H), 7.30-7.42 (, 3H), 7.42-7.54 (m, 5H), 7.58 (s, 1H), 7.61-7.71 (m, 5H), 7.75 (d, J = 8.0 Hz, 1H), 8.07 (s, 2H); ESI mass spectrum], m / z 479 (M + H) J 501 (M + Na) *.
Step 2: 5 '- (Benzofuran-2 -carbonyl) -fl, l'; 3 ', l "1-terphenyl-2'-yloxyl acetic acid The title compound is prepared as a white foam (0.280 g, 79%) from [5 '- (benzofuran-2-carbonyl) - [1, 1'; 3 '1"] terphenyl-2' -il] methoxyethoxymethylether using a procedure similar to Steps 5-7 of Example 44, mp> 73 ° C (decomposition); 'H NMR (DMSO-d6) 63.90 (s, 2H), 7.36-7.44 (m, 3H), 7.45 -7.50 (m, 4H), 7.53-7.59 (m, 1H), 7.65-7.69 (m, 4H), 7.77 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 0.7 Hz, 1H), 7.93 (s, 2H), 11.80-13.40 (s broad, 1H); (ATR) 3110, 3060, 3030, 2910, 1770, 1730, 1640, 1610, 1585, 1545, 1495, 1475, 1465, 1440, 1420, 1410, 1355, 1340, 1290, 1275, 1255, 1205, 1180, 1140 , 1125, 1110, 1070, 1055, 1030, 1000, 985, 910, 890, 830, 750, 730, and 700 cm "1; mass spectrum [(-) APCI], m / z 447 (M-H) J- Analysis Calculated for C29H2005 -0.35 CHC13: C, 71.91; H, 4.18; N, 0.00, Found: C, 71.71; H, 3.91; N, 0.16.
Example 102 3- [3"- (2-Carboxy-vinyl) -2 '-methoxy-5' - (8-phenyl-octylcarbamoyl) -fl, l ': 3', l" 1-terphenyl-3-yl-acrylic acid Stage 1 2, 6-Diiodo-4- (8-phenyloctylcarbamoyl) phenol The title compound is prepared as a solid (0.718 g, 66%) from 3,5-diiodo-4-hydroxybenzoic acid using 8-phenyloctylamine and a procedure similar to Step 2 of Example 93; * H NMR (DMSO-ds) 6 1.17-1.36 (m, 8H), 1.41-1.61 (m, 4H), 2.48-2.60 (m, 2H), 3.20 (dd, J = 5.9, 8.8 Hz, 2H), 7.10-7.21 (m, 3H), 7.21-7.30 (m, 2H), 8.21 (s, 2H), 8.40 (t, J = 4.4 Hz, 1H), 10.06 (s, 1H); mass spectrum [(+) ESI], m / z 578 (M + H) *.
Stage 2 2.6-Divodo-4- (8-phenyl-octylcarbamoyl) phenyl ethyl ether The title compound is prepared as a solid (0.691 94%) from 2,6-diiodo-4- (8-phenyl-1-octylcarbamoyl) phenol using methyl iodide and a procedure similar to that of Step 4 of Example 93; 1K NMR (DMSO-dβ) d 1.19-1.34 (m, 8H), 1.41-1.61 (m, 4H), 2.48-2.59 (m, 2H), 3.21 (dd, J = 6.4, 14.1 Hz, 2H), 3.78 (s, 3H), 7.10-7.21 (m, 3H), 7.21-7.31 m 2H), 8.28 (s, 2H), 8.53 (t, J = 5.6 Hz, 1H), - mass spectrum [(+) ESI], m / z 592 (M + H) J 614 (M + Na) *.
Stage 3 [3.3"-Pifo rmil-5- (8-f-enyl-octylcarbamoyl) - fl.l ', -3', 1" 1 terphenyl -2 '-ill methylether The title compound is prepared as a solid (0.479 g, 75%) from 2, 6-diiodo-4 - - (8 - f eni 1 -oct i 1 carbamoi 1) f enylmet i 1 ether using 3-f ormilbenzeneboronic acid and a procedure similar to the Stage 3 of Example 93; ? NMR (DMSO-d6) 6 1.21-1.35 (m, 8H), 1.46-1.60 (m, 4H), 2.47-2.53 (m, 2H), 3.13 (s, 3H), 3.21-3.32 (m, 2H), 7. 09-7.19 (m, 3H), 7.21-7.30 (m, 2H), 7.54 (t, J = 7.5 Hz, 2H), 7.94-8.03 (m, 6H, S. 17 (s, 2H), 8.61 ( t, J = 5.6 Hz, 1H), 10.14 (s, 2H), mass spectrum [(+) ESI], m / z 548 (M + H) J 570 (M + Na) *. ^^^^^ ¿& s ^ Step 4: 3- f3"- (2-Methoxy-carbon-1-vinyl) -2'-methoxy-5 '- (8-phen-1-ethylcarbamoyl) - fl.l'.-3 '. "] terfenyl -3 -ill-acrylic To a round bottom flask with [3, 3"-diformyl-5 '- (8-phenyl-octylcarbamoyl) - [1, 1'; 3 '1"] terphenyl-2'-yl] methyl ether (0.422 g, 0.770 mmoles) in CH3CN (20 ml) at room temperature add methyl (triphenylphenylanediene) acetate (1.29 g, 3.86 mmoles). After 5 hours at this temperature, concentrate 10 and then dilute with EtOAc (250 ml). The organic layer is washed with IN HCl (25 mL), saturated NaHCO-, aqueous (25 mL), and brine (25 mL) and then dried (Na2SO4). After concentration, the residue is purified in a Biotage Flash 40 apparatus (gradient of 15 to 35% EtOAc / petroleum ether) for provide the product (0.485 g, 89%) as a solid; 1H NMR (DMSO-d6) 6 1.23-1.38 (m, 8H), 1.46-1.62 (m, 4H), 2.47-2.58 (m, 2H), 3.17 (s, 3H), 3.21-3.35 (m, 2H), 3.75 (s, 6H), 6.74 (d, J = 16.5 Hz, 2H), 7.10-7.20 (m, 3H), 7.20-7.29 (m, 2H), 7.55 (t, J = 7.2 Hz, 2H), 7.67 (d, J = 7.2 Hz, 2H), 7.72-7.85 (m, 4H), 7.92 (d, J = 11.5 Hz, 4H), 8.52 (t, J = 5.7 Hz, 1H); mass spectral [(+) ESI], m / z 660 (M + H) *.
Step 5 3-f3"- (2-Carboxy-v nil) -2-methoxy-5 '- (8-phenol-octylcarbamoyl) - fl, 1', -3 ', 1"] terphenyl-3 - ill-acrylic 25 ScJ & _ The title compound is prepared as a whitish foam (0.094 g, 98%) from the methyl ester of the acid 3- [3"- (2-methoxy-carbon-1-vinyl) -2 '-methoxy-5' - (8-phenyl-octylcarbamoyl) - [1,1 '; 3' 1"] -terphenyl -3- il] -acrilicilusing a procedure similar to Step 5 of Example 93, pf > 101 ° C (decomposition); -H NMR (DMS0-d6) d 1.20-1.33 (m, 8H), 1.45-1 58 (m, 4H), 2.45-2.56 (m, 2H), 3.15 (s, 3H), 3.20-3.29 (m, 2H), 6. 61 (d, J 16.0 Hz, 2H), 7.10-7.18 (m, 3H), 7.20-7.26 (m, 2H), 7. 48-7.57 (m, 3H), 7.60-7.78 (m, 5H), 7.87 (s, 4H), 8.47-8.55 (m, 1H), 12.10-12.75 (broad s, 2H); IR (KBr) 3370, 3070, 3020, 2930, 2860, 2660, 2580, 1785, 1730, 1580, 1540, 1490, 1470, 1435, 1405, 1340, 1285, 1230, 1205, 1185, 1095, 1070, 1000, 985, 900, 870, 805, 790, 770, 750, and 700 cm'1; mass spectrum [(+) APCI], m / z 632 (M + H) *, Anal. Calculated for C40H41NO6 -0.5 H20: C, 74.98; H, 6.61; N, 2.19, Found: C, 74.79; H, 6. 62, N, 2.02.
Example 103 3- r3"- (2-Carboxy-et? L) -2 '-methoxy-51 - (8-f-enyl-1-ocylcarbamoyl) - fl, 1', - 3 ', 1" 1 terfyl ester 3 -ill-propionic Into a round bottom flask with Pd / C (0.022 g, 1.05 mmol) and EtOAc: MeOH (1: 1, 7 mL) is added 3- [3"- (2-methoxycarbonyl-vinyl) methyl ester. -2 '-methoxy -5' - (8-f enyl- octyl carbamoyl) - [1,1 '; 3'1"] -terphenyl-3-yl] acrylic (0.230 g, 0.349 mol) in EtOAc: MeOH (1: 1, 3 ml) The flask is purged with H2 (atmospheric) of a balloon and the reaction is stirred at room temperature for 2 h.The reaction mixture is then filtered through Celite, and the Celite is washed with excess EtOAc: MeOH.This solution is concentrated to provide the intermediate saturated methyl ester of acid. {3- [3"- (2-methoxy-carbonyl-ethyl) -2 '-methoxy-5' - (8-phenyl-octylcarbamoyl) - [1,1 ', - 3' 1"] -terphenyl-3-yl] propionic The title compound is prepared as a white foamy solid (0.200 g, 88%) from 3- [3" - (2-methoxy-carbonyl-ethyl) methyl ester ) -2'-methoxy-5 '- (8-phenyl-octylcarbamoyl) - [1,1'; 3 '1"] -terphenyl-3-yl] propionic using a procedure similar to that of Step 5 of Example 61, mp> 53 ° C (decomposition); * H NMR (DMSO-d6) d 1.23-1.31 (m, 8H), 1.44-1.57 (m, 4H), 2.48-2.60 (m, 6H), 2.89 (t, J = 7.5 Hz, 4H), 3.13 (?, 3H), 3.23 (dd, J = 6.6, 13.0 Hz, 2H), 7.10-7.16 (m, 3H), 7.20-7.28 (m, 4H), 7.35-7.41 (m, 4H), 7.43 (s, 2H), 7.79 (s, 2H), 8.49 (t, J = 5.7 Hz, 1H), 11.85-12.30 (s broad, 2H); IR (KBr): 3380, 3020, 2930, 2860, 1710, 1625, 1575, 1540, 1490, 1470, 1465, 1405, 1340, 1280, 1230, 1180, 1155, 1095, 1070, 1005, 900, 805, 750 , amd 705 cm "1; mass spectrum [(+) APCI], m / z 636 (M + H) J- Analysis Calculated for C40H45N06 - 0.5 H20: C, 74.51; H, 7.19; N, 2.17, Found: C, 74.43; H, 7.16; N, 2.10.
Example 104 [5 '- [(2-Butyl-benzofuran-3-ylmethyl) -amino] - [1,1'; 3 ', 1"] ter enyl-2'-yloxy-acetic acid methyl ester Step 1 5 '- [(2-Butyl-benzofuran-3-ylmethyl) -aminol-fl, 1', 3 ', 1"! Terphenyl-2' -ol A mixture of 2-N-Butyl-3-benzofurancarboxaldehyde (2.48 g, 13.3 mmol) and 4-amino-2,6-dipolol in 15 ml of anhydrous methanol is cooled to 0 ° C. 16.6 ml of IN HCl in diethyl ether are added and sodium cyanoborohydride (0.92 g, 14.65 mmolee) is added in portions at a rate such that excess foaming is not allowed. After the addition is complete, remove the ice bath and allow the solution to warm to room temperature overnight. The reaction is quenched with 3N HCl until all the precipitates dissolve and the production of HCN ceases. The reaction is concentrated in vacuo and dissolved in methylene chloride, washed 2 × with saturated sodium bicarbonate and brine and then dried (MgSO). Flash chromatography eluting with 5-15% ethyl acetate / petroleum ether gives the compound of the title as a yellow gum. "H NMR (300 MHz, CDC13) d 0.92 (t, 3H), 1.42 -1.34 (m, 2H), 1.74-1.67 (m, 2H), 2.8 (t, 2H), 3.53 (s, 1H), 4.33 (?, 2H), 4.91 (e, 1H), 6.68 (e, 2H), 7.26 - 7.18 (m, 2H), 7.49-7.36 (m, 7H), 7.58-7.56 (m, 5H). mass spectra (El), m / z 447. / Analysis Calculated for C 31 H 29 N 0 -2 - 0.2 EtOAc: C, 82.11; H, 6.63; N, 3.01. Found: C, 82.15; H, 6.92; N, 2.96.
Stage 2 (5 '- f (2-Butyl-benzofuran-3-methyl) -aminol-fl. 1', -3 ', 1"1-tert-butyl-2'-yloxy lactic acid methyl ester To a mixture of 5 '- [(2-Butylbenzofuran-3-ylmethyl) -amino] - [1, 1' -, 3 ', 1"] -terphenyl-2'-ol (0.81 g, 1.82 mmol) in 10 ml dry acetonitrile, methyl bromoacetate (0.22 ml, 2.27 mol) and a catalytic amount of 18-crown-6 are added.The mixture is stirred at room temperature for 48 h.The reaction is diluted with diethyl ether and filtered. The organic layer is washed with water and then with saturated brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo.Short chromatography eluting with 5-10% acetone / petroleum ether gives pure product as a yellow gum. NMR (300 MHZ, DMSO) d 0.82 (t, 3H), 1.3-1.25 (m, 2H), 1.61-1.53 (m, 2H), 2.81 (t, 2H), 3.32 (s, 2H), 3.68 (8 , 3H), 4.34 (d.2H), 6.09 (t, 1H), 6.6 (s, 2H) 7.49 - 7.16 (m, 13H), 7.71-7. 69 (m, 1H). mass spectra (El), mz 519. Analysis Calculated for C34H33N04: C, 78. 59; H, 6.40; N, 2 70 Found: C, 78 14; H, 6 2. 3; N, 2 68 Example 105 Acid (5 '- [(2-Butyl-benzofuran-3-ylmethyl) -amino] - [1,1'; 3 ', l "] terphenyl-2'-yloxy acetic acid To a stirred solution of (5 '- [(2-Butyl-benzofuran-3-ylmethyl) -amino] - [1,1': 3 '1"] terphenyl-2'-yloxy) acetic acid methyl ester in 2.5 ml of THF and 2.5 ml of MeOH are added 0.84 ml of 5N sodium hydroxide.The reaction is allowed to stir overnight.The solvents are removed in vacuo and the solids are suspended in water and brought to pH 1 with 5N HCl. The aqueous layer is extracted several times with ethyl acetate, dried over anhydrous MgSO 4, filtered, and concentrated in vacuo to give the pure product as a solid coffee. * H PMN (300 MHz, CDC13) d 0.92 (t, 3H), 1.40 - 1.34 (m, 2H), 1.73 - 1.67 (m, 2H), 2.80 (t, 2H), 3.77 (s, 2H), 4. 35 (s, 2 H), 6.6 (d, 2 H), 7.28 - 7.21 (m 2 H), 7.48 - 7.37 (m, 7 H), 7.56 - 7.54 (T., 5 H). mass spectrum (El), m / z 505. Analysis Calculated for C33H31N04 - 1.5 H20: C, 74.42; H, 6.43; N, 2.63. Found: C, 74.39; H, 5.96; N, 2.56.
Example 106 Acid methyl ester (2,6-Dibromo-4- [(2-butyl-benzofuran-3-ylmethyl) -amino-fenj i.) Acetic acid Step 1 2, 6-Dibromo-4- ((2-butyl-benzofuran-3-methylme) -ammo-phenol The title compound is prepared according to the procedure of Step 1 of Example 104 which gives a light brown solid. * H NMR (300 MHz, DMSO) d 0.90 (t, 3H), 1.39-1.33 (m, 2H), 1.68-1.61 (m, 2H), 2.82 (t, 2H), 4.24 (d, 2H), 5.95 (t, 1H), 6.81 (s, 2H), 7.23 - 7.16 (m, 2H), 7.46 -7.44 (m, 1H), 7.64 - 7.62 (m, 1H), 8.74 (s 1H). mass spectrum (El), m / z 451. Analysis Calculated for C19H19Br2N02: C, 50.36; H, 4.23; N, 3.09. Found: C, 49.93; H, 4.29; N, 3.05.
Stage 2 22.6-Dibromo-4- (2-butyl-benzofuran-3-methylmethyl) -amino-phenoxy-1-acetic acid methyl ester The title compound is prepared according to the procedure of Step 2 of Example 104 which provides a clear oil. H NMR (300 MHz, DMSO) d 0.92 (t, 3H), 1.40 -1.35 (m, 2H), 1.S9-1.65 (m, 2H), 2.85 (t, 2H), 3.72 (s, 3H), 4.29 (d, 2H), 4.44 (s, 2H), 6.44 (t, 1H), 6.86 (s, 2H), 7.25 - 7.19 (m, 2H), 7.49 - 7.47 (m, 1H), 7.65 - 7.62) (m, 1H). mass spectrum (El), m / z 523.
Example 107 Acid { 2,6-Dibromo-4- [(2-butyl-benzofuran-3-ylmethyl) -amino] -phenoxy) acetic acid The title compound is prepared according to the procedure of Example 105 which provides a light brown solid. 'H NMR (300 MHz, DM? 0-d6) d 0.90 (t, 3H), 1.40 -1.31 (m, 2H), 1.69-1.61 (m, 2H), 2.83 (t, 2H), 4.16 (2, 2H), 4.27 (d, 2H), 6.35 (broad s, 1H), 6.84 (s, 2H), 7.24 - 7.16 (m, 2H), 7.48 - 7.45 (m, 1H), 7.63 - 7.61 (m, 1H) ). mass spectrum (ESI), (M-H) * m / z 508. Analysis Calculated for C21H21Br2N04 -0.5 H20: C, 48.49; H, 4.26; N, 2.69. Found: C, 48.37; H, 3.99; N, 2.56.
Examples 108 to 124 were prepared in a manner similar to Example 175. Examples 125 to 130 and Example 134 were prepared in a manner similar to Example 179. Examples 131 to 133 were prepared in a manner analogous to Examples 175, 179 and 192 using 4-hydroxy-4 '-carboxymethyldiphenyl as an initial material, instead of 4-hydroxybenzoic acid. Table 1 summarizes the physico-chemical properties of compounds 108 to 134.
Example 135 > Acid (3-Bromo-3'-chloro-5-dodecylcarbamoyl-4 '-fluoro-biphenyl-2-yloxy) acetic acid Stage 1 3-Bromo-4- (2-hydroxyethoxy) -5- (3-chloro-4-chlorophenyl) benzoic acid methyl ester To a stirred solution of K2CO3 (4.99 g, 36.1 mmoles) in 18 ml H20 is added 145 ml of dioxane, 3-bromo-4- (2-hydroxyethoxy) -5-iodobenzoic acid ethyl ester (5.0 g, 12.04 mmoles) , and 3-chloro-4-fluorophenylboronic acid (2.1 g, 12.04 mmol) at room temperature. This mixture is stirred for 5 minutes and after it is degassed twice. Then complex of [1, 1 '-bie- (diphenylphophine) ferrocene] -dichloropalladium (II), with CH2C12 (49 mg, 0.06 mmol) is added. The reaction is stirred for three hours and then 98 mg, 0.12 mmol, of catalyst are added. The reaction is allowed to stir for five days at room temperature before being worked in the following manner. The reaction is diluted with IN HCl and H20 and extracted with EtOAc three times. The combined organic extracts are dried over Na 2 SO 4 and filtered. Removal of the solvent in vacuo gives the crude material which is subjected to preparative CLAP to provide 2 g, 35.5% of this bisarylated product. JH NMR (CDC13) d 1.40 (t, J = 8.18 Hz, 3H); 1.945 (S, 1H); 3.712 (m, 4H); 4.36 (c, J = 8.18 Hz, 2H); 7.19-7.23 (m, 1H), - 7.40-7.45 (m, 1H); 7.60-7.65 (dd, J = 8.18 Hz, 2.73 Hz, 1H); 7.91 (d, J = 2.73 Hz, 1H); 8.24 (d, J = 2.73 Hz, 1H); and 860 mg, 17. 1% of the monoarylated product. NMR (CDC13) d 1.29 (broad s, 1 H), -1.41 (t, J = 8.18 Hz, 3H); 3.40 (m, 4H); 4.40 (C, J = 8.18 Hz, 2H); 7.20-7.28, (m, 2H); 7.454-7.545 (m, 2H); 7.69 (dd, J = 8.18 Hz, 2.73 Hz, 2H); 8.013 (S, 1H); and 38% of MS recovered.
Stage 2 N-Dodecyl-3-bromo-4- (2-hydroxyethoxy) -5- (3-chloro-4-fluorophenyl) benzamide In a flame-dried round bottom flask heated with n-dodecylamine (586 mg, 3.16 mmol) in 7 ml THF at -20 ° C, n-EuLi (1.8 ml, 3.6 mmol) was added as a solution in hexanes. After the addition, the reaction is warmed to room temperature and stirred for half an hour. The solution is then cooled to -20 ° C and added to a solution of 3-bromo-4- (2-hydroxyethoxy) -5- (3-chloro-4-fluoro-phenyDenzoic acid ethyl ester (400 mg, 0.957) mmoles) in 8 ml THF which has previously been cooled to -40 ° C. The resulting mixture is stirred at -40 ° C. for 5 minutes point after which the reaction mixture is allowed to warm to room temperature. it is diluted with water and 2N HCl and then extracted with EtOAc three vecee.
The combined organics are washed with saturated NaHCO 3 and then dried over Na 2 SO 4. After filtration and removal of the solvent in vacuo, a yellow oil is provided which is subjected to column chromatography on silica gel (10% EtOAc: 90% Hexanes followed by 25% EtOAc: 75% Hexanes). 300 mg, 58% of the amide is obtained as a yellow oil. 1 NMR (CDC13) 0.868 (t, J = 8.13 Hz, t); 1.20-1.40 (m, 18H); 1.48-1.67 (m, 2H); 1895-2.00 (broad s, 1H), -3.427 (c, J = 8.13 Hz, 2H); 3.636-7.71 (m, 4H); 6.014 (m, 1H); 7.20-7.24 (m, 1H); 7.40-7.454 (m, 1H); 7,586-7,668 (m, 2H); 7.868 (d, J = 2.04 Hz, 1H).
Step 3 Acid (3-Bromo-3'-chloro-5-dodecylcarbamoyl-4'-fluoro-biphenyl-2-yloxy) acetic acid To a solution of N-odec il-3-br orno-4- (2-hydroxyethoxy) -5- (3-chloro-4-fluorophenyl) benzamide (340 mg, 0.61 mmol) in 5 ml CH2C12 is added NMMO.H20 (165 mg, 1.22 mmol) and TPAP (22 mg, 0.061 mmol). The reaction mixture is stirred overnight and added 2 ml CH3CN and 50 mg, and 0.14 mmole TPAP. The reaction is stirred for about 7 hours and then 90 mg, and 0.665 immoles NMMO.H20 are added and the reaction is stirred overnight. The reaction is worked up by adding H20 and a mixture of sodium bisulfite / sodium dithionite and stirring for 4 hours. The mixture is now greek and acidified with 2N HCl and extracted with EtOAc (3x). The organic layers Combine is dried over Na2SO4 followed by filtration and solvent removal in vacuo. A semi-solid is obtained which is subjected to column chromatography (40% EtOAc: 60% Hexanes) on silica gel pretreated with HCOOH. The yield of the acid is 130 mg, 37% as a dark yellowish-brown oil. * H NMR (DMSO-d6) d 0.84 (t, J = 6.81 Hz, 3H); 1.22-1.27 (m, 18H); 1.50 (t, J = 6.37 Hz, 2H); 3.23 (c, J = 6.81 Hz, 2H); 4.19 (e, 7H); 7.51 (t, J = 8.57 Hz, 1H); 7.57-7.61 (m, 1H); 7.81 (dd, J = 7.25 Hz, 2.20 Hz, 1 H); 7.85 (d, J = 2.2 Hz, 1 H); 8.10 (d, J = 2.20 Hz, 1 H); 8.56 (t, J = 5.49 Hz, 1H), 12.75 (8 broad, 1H); IR 3370, 2930, 1730, 1635, 1400, 1225, 1150, and 700 cm "J- mass spectrum [(+) APCI], m / z 570 [M + H] J-Analysis Calculated for C27H34BrClFN04: C, 56.80; H, 6.00; N, 2.45, Found: C, 54.30; H, 5.73; N, 2.18.
Example 136 [3'-Chloro-4'-fluoro-5- (8-phenyl-octylcarbamoyl) -biphenyl-2-yloxy] acetic acid Step 1 N- (8-Phenyloctyl) -4- (2-hydroxyethoxy) -5- (3-chloro-4-fluorophenyl) -benzamide To a flame-dried round bottom flask loaded with 8-phenyloctylamine (688 mg, 3.35 mmol, 6.68 μl) in 5 ml THF at -78 ° C add n-BuLi (2.2 ml, 4.4 mmolee) as a solution in hexanes. The solution is stirred at -78 ° C for 30 minutes and then stirred at room temperature for 15 minutes. The solution is again cooled to -40 ° C and a cooled solution (-40 ° C) of 3-bromo-4- (2-hydroxyethoxy) -5- (3-chloro-4-fluorophenyl) benzoic acid ethyl ester ( 400 mg, 0.957 mmol) in 10 ml THF via a cannula. After the addition is complete, the reaction is warmed to room temperature, stirred for 10 minutes, and then worked up as in Step 2 of Example 135. The resulting crude yellow oil is dissolved in 1: 1 of EtOAc / Hexanes and filtered through a pad of silica gel with the same solvent system to provide 200 mg, 43% of the amide as a yellow oil. l NMR (CDC13) d 1.25-1.40 (m, 2H); 1.54-1.65 (m, 2H); 1.80 (broad s, 1H), -2.57 (t, J = 8.18 Hz, 2H); 3.41 (c, J = 6.54 Hz, 2H); 3.90 (t, J = 6.13, 2H); 4.12 (t, J = 6.13 Hz, 2H); 6.07 (m, 1H); 6.99 (d, J = 8.13 Hz, 1H); 7.08-7.18 (m, 3H); 7.20-7.27 (m, 2H); 7.33-7.40 (m, 1H); 7.56 (dd, J = 6.54 Hz, 3.27 Hz, 1H); 7.65-7.69 (m, 1H); 7.73 (dd, J = 8.13 Hz, 2.58 Hz, 1H).
Step 2 [3'-Chloro-4'-fluoro-5- (8-f-enyl-oct-il-carbamoyl) -bifinyl-2-yloxyl-acetic acid To a solution of N- (8-f eni 1 oc ti 1) -4- (2-hydroxyethoxy) -5- (3-chloro-4-fluorophenyl) benzamide (200 mg, 0.415 mmolee) in 5 ml of CH2C12 was add NMMO.H20 (96 mg, 0.712 mmol) and TPAP (12.5 mg, 0.0356 mmol). The reaction is stirred overnight and 50 mg, 0.14 mmole of TPAP, 2 ml are added.
CH3CN, and 90 mg, of 0.665 mmol of NMM0.H20, and the reaction is stirred overnight. The reaction is worked up as indicated in Step 3 of Example 135. The crude material is subjected to column chromatography (40% EtOAc: 60% Hexanes) on silica gel pretreated with HCOOH to provide 70 mg, 34% of the acid like a dark yellow oil. JH NMR (DMSO-ds) 1.22-1.27 (m, 8H); 1474-1551 (m, 4H); 2.53 (t, J = 7.47 Hz, t); 3.21 (C, J = 6.59 Hz, 2H); 4.82 (S, 1H); 7.08-7.17 (m, 4H); 7.22-7.26 (m, 2H); 7.48 (t, J = 8.79 Hz, 1H); 7.60-7.64 (m.H.); 7.80-7.85 (m, 2H); 8.36 (t, J = 5.60 Hz, 1H); IR 3400, 2930, 1730, 1600, 1550, 1470, 1210, 1075, and 700 cm "J- mass spectrum [(-) ESI], m / z 510/512 [MH] - Analysis Calculated for C29H30BrClFN04: C, 97.99; H, 6.10; N, 2.73; Found: C, 66.89; H, 6.17; N, 2.61.
Example 137 Acid (3-Bromo-5-dodecylcarbamoyl-3 '-methoxy-bifenyl-2-yloxy) acetic acid Stage 1 3-Bromo-4- (2-hydroxyethoxy) -5- (3-methoxyphenyl) benzoic acid ethyl ester To a solution of K2C03 (4.99 g, 36.1 mmol) in 18 ml H20 is added the ethyl ester of 3-bromo-4- (2-hydroxyethoxy) -5-iodobenzoic acid (5.0 g, 12.04 mmol), 145 ml of dioxane, and 3-methoxyphenylboronic acid (1.83 g, 12.04 mmol) at room temperature. This mixture is stirred for 5 minutes, and then degassed. The [l, -l? -bis (diphenyl-phe- thine) ferrocene] dichloropalladium (II) complex is then added with CH2C12 (49 mg, 0.06 mmolee). The reaction is stirred for three hours and then 98 mg, 0.12 mmol of catalyst are added, and the reaction is allowed to stir for 3 d, at which point 182 mg, 1.2 mmoles of boronic acid are added. The reaction is stirred for an additional 7 d before being worked up as in Step 1 of Example 135. 475 mg, of 10% of the mono-annealed product are obtained; lH NMR (CDC13) d 1.38 (t, J = 8.18 Hz, 3H); 1.83 (broad s, 1H); 3.41 (t, J = 5.43 Hz, 2H); 3 75 (t, J = 5.43 Hz, 2H); 4.84 (s, 3H); 4.37 (c, J = 8.18 Hz, 2H); 6.94 (dd, J = 8.18 Hz, 2.72 Hz, 1H); 7.06-7.14 (m, 2H); 7.35 (t, J = 8.18 Hz, 1H); 7.99 (d, J = 2.73 Hz, 1H); 8.22 (d, J = 2.73 Hz, 1H); 1.3 g, 25% of the bisanlated product and 2.1 g, 42% of MS recovered after the raw material is subjected to preparative CLAP.
Stage 2 N-Dodecyl-3-bromo-4- (2-hydroxyethoxy) -5- (3-methoxy-enyl) -benzamide N-Dodecyl-3-bromo-4- (2-hydroxyethoxy) -5- (3-methoxyphenyl) benzamide is made as a light yellow solid (500 mg, 92%) from the ethyl ester of 3-bromo-4- (2-hydroxyethoxy) -5- (3-methoxy-enyl) -benzoic acid using a similar procedure. to Step 1 in Example 136. 1 H NMR (CDC13) 6 0.80-0.88 (m, 3 H); 1.14-1.40 (m, 19H); 1.48-1.63 (m, 2H); 3.40 (c, J = 7.36 Hz, 2H); 3.60 (t, J = 5.73 Hz, 2H); 3.48 (t, J = 4.91 Hz, 2H); 4.84 (s, 3H); 6.02 (m, 1H); 6.93 (dd, J = 8.18 Hz, 2.73 Hz, 1H); 7.08 (m, 2H); 7.36 (t, J = 8.18 Hz, 1H); 7.67 (d, J = 2.45 Hz, 1H); 7.95 (d, J = 2.45 Hz, 1H).
Step 3 Acid (3-Bromo-5-dodecylcarbamoyl-3 '-methoxy-biphenyl-2-ioxyacetyl) At a concentration of N-dode cy-1,3-bromo-4- (2-hydroxyethoxy) -5- (3-methoxy-phenyl) -benzamide (200 mg, 0.374 mmol) in a mixture of 8 ml of CH 3 CN / 300 μl of THF are added 132 mg, 0.976 immoles of NMMO. The reaction is stirred at 30 minutes and then 132 mg, 0.976 mmolee NMMO are added. The reaction is then stirred overnight. The reaction is diluted with water and sodium metabisulfite / sodium bieulfite and sodium dithionite are added. This mixture is stirred for 1.5 hours and then 2N HCl is added and subsequently the mixture is extracted with EtOAc (3x). The combined organic extracts are dried over Na2SO4 and the solvent is removed under vacuum to provide a black oil. This oil is subjected to flash chromatography (40% EtOAc: 60% hexanes to which 1% HCOOH is added) in treated HCOOH treated silica gel. 60 mg of the acid and 60 mg of the aldehyde intermediate are obtained which is then subjected to reaction conditions again to obtain an additional 40 mg of the acid. The total yield of the acid is 100 mg, 49% of an oily yellow foam. 1 H NMR (DMSO-d 6) d 0.84 (t, J = 6.37 Hz, 3H); 1.15-1.27 (m, 18H); 1.47-1.51 (m, 2H); 3.23 (c, J = 6.59 Hz, 2H); 3.79 (s, 3H); 4.105 (5, 2H); 6.97-7.00 (m, 1H); 7.11-7.14 (m, 2H); 7.38 (t, J = 7.91 Hz, 1H); 7.83 (d, J = 2.20 Hz, 1H); 8.07 (d, J = 2.20 Hz, 1 H); 8.56 (t, J = 5.00 Hz, 1 H), 12.75 (broad s, 1 H); IR 2930, 2850, 1740, 1650, 1550, 1450, 1320, and 1225 cm "J-mass spectrum [(+) ESI], m / z 548/550 [M + H] *; Analysis Calculated for C2, H3BBrN05 : C, 61.51; H, 6.98; N, 2.55; Found: C, 62.44; H, 6.86; N, 2.67; Example 138 -Bromo-6- (2-tetrazol-1-yl-ethoxy) -3 '-methoxy-biphenyl-3-carboxylic acid dodecylamide Stage 1 N-Dodecyl-3-bromo-4- (2-bromoethoxy) -5- (3-methoxyphenyl) benzamide Triphenylphosphine (98 mg, 0.373 mmol) and 1.5 ml of anhydrous THF are added to a flame-dried flask. This is stirred until all of the triphenylphosphine has dissolved. Then add CBr4 (123 mg, 0.373 mmolee). The reaction mixture is stirred for half an hour at room temperature and then cooled to ° C before adding N-dodecyl-3-bromo-4- (2-hydroxyethoxy) -5- (3-methoxyphenyl) benzamide (200 mg, 0.373 immoles). The cooling bath is removed after the addition is complete. After the reaction mixture has warmed to room temperature, 0.2 equivalents of each of triphenylphoephine (19.6 mg, 0.075 mmole) and CBr4 (24.8 mg, 0.075 mmole) are added. The reaction is stirred for half an hour and then the solvent is removed under vacuum to provide a yellow semi-solid. This material is subjected to flash chromatography (25% EtOAc: 75% Hexanes) to provide 150 mg, 67% of a yellow oil. 'H NMR (CDC13) d 1.25 (t, J = 8.13 Hz, 3H); 1.22-1.40 (m, 18H); 1.52-1.63 (m, 2H); 3.35 (t, J = 8.18 Hz, 2H); 3.40 (c, J = 6.54 Hz, 2H); 3.84-3.90 (m, 5H); 6.00 (m, 1H); 6.93 (dd, J = 8.18 Hz, 2.45 Hz, 1 H); 7.07-7.1 1 (m, 2H); 7.35 (t, J = 8. 18 Hz, 1 H); 7.65 (d, J = 2.45 Hz, 1H); 7.93 (d, J = 2.45 Hz, 1H).
Stage 2 5-Bromo-6- (2-tetrazol-1-yl-ethoxy) -3 '-methoxy-biphenyl-3-carboxylic acid Dodecylamide To a solution of 1H-tetrazole (28 mg, 0.4 mmol) in 1 ml of anhydrous THF at 0 ° C is added NaH (10 mg, 0.421 mmol). The reaction mixture is stirred for 10 minutes at 0 ° C, at which point a solution of N-dodecyl-3-bromo-4- (2-bromoethoxy) -5- (3-methoxyphenyl) benzamide (160 mg. , 0.276 mmole) in 2.5 ml of anhydrous THF. The reaction mixture is stirred at 0 ° C for 10 minutes and then allowed to warm to room temperature for half an hour. Then 700 μl of DMSO are added and the reaction is then heated to 65 ° C overnight. The reaction is suspended and diluted with water and extracted with EtOAc (3x). The combined organic layers are dried over Na2SO4 and the solvent removed in vacuo to give a brown-yellow oil. The crude material is subjected to flash column chromatography (25% EtOAc: 75% Hexanes to 40% EtOAc: 60% Hexanes to 50% EtOAc: 50% Hexanes) to provide 40 mg, 25% of a white solid, mp 100- 1 C; -H NMR (DMS0-d6) 6 0.88 (t, J = 6.80 Hz, 3H); 1.25-1.37 (m, 18H); 1.60 (quintet, J = 7.14 Hz, 2H); 3.43 (c, J = 7.14 Hz, 2H); 3.84 (s, 3H); 3.96 (t, J = 4.86 Hz, 2H); 4.57 (t, J = 4.86 Hz, 2H); 6.01 (t, J = 5.00 Hz, 1H); 6.93-6.95 (m, 3H); 7.27-7.32 (m, 1H); 7.64 (d, J = 2.20 Hz, 1H); 7.94 (d, J = 1.98 Hz, 1H), 8.68 (s, 1H); IR 3330, 2900, 2840, 1625, 1600, 1520, 1460, 1310, 1300, 1235, 1175, and 1030 cm "1; mae spectrum [(+) ESI] m / z 586/588 [M + H] +; Calculated Analysis for C29H40BrN503: C, 59.38; H, 6.87; N , 11.94: Found: C, 59.46; H, 6.68; N, 11.77.
Examples 139 and 140 -Bromo-3'-chloro-6- (2-tetrazol-2-yl-ethoxy) -biphenyl-3-carboxylic acid dodecylamide and 5-Bromo-3'-chloro-6- (2 -dodoic acid) dodecylamide -tetrazol-l-yl-ethoxy) -biphenyl-3-carboxylic acid Step 1 Dodecylamide of 5-Bromo-3'-chloro-6 - (2-hydroxy-ethoxy) -biphenyl-3-carboxylic acid To a cooled (0 ° C) solution of dodecylamine (3.22 g, 17.64 mmol) in 50 ml of anhydrous THF, n-BuLi (7.05 ml, 17.64 mmol) was added dropwise. When the addition is complete, the mixture is stirred for 10 minutes at 0 ° C and then at room temperature for 30 minutes. This lithiated amine is added dropwise to a cooled (0 ° C) solution of 5-bromo-3'-chloro-6- (2-hydroxy-ethoxy) -biphenyl-3-carboxylic acid ethyl ester (2.5 g, 5.78 g. mmoles) in 40 ml of anhydrous THF via cannula. The reaction is stirred for 10 minutes at 0 ° C, when the addition is complete and then at room temperature overnight. The reaction mixture is then heated to ° C for 1 hour and then more n-BuLi (0.7 ml, 1.75 mmol) is added. The reaction is then worked up as in Step 2 of Example 135. 2.5 g, 80% of a yellow oil is obtained as the desired product after flash chromatography (25% EtOAc: 75% Hexanes) in silica gel.
Step 2 Dodecylamide of 5-Bromo-3'-chloro-6 - (2-bromoethoxy) -biphenyl-3-carboxylic acid -Bromo-3'-chloro-6- (2-bromoethoxy) -biphenyl-3-carboxylic acid dodecylamide is prepared from 5-bromo-3'-chloro-6- (2-hydroxy-ethoxy) dodecylamide ) -bifenil-3-carboxylic acid as a yellow oil (900 mg, 67%) in a manner similar to that of Step 1 of Example 138. lH NMR (CDC13) d 0.86 (t, J = 8.18 Hz, 3H); 1.23-1.4 (m, 18H); 1.55-1.64 (m, 2H); 3.35-3.64 (m, 4H); 3.88 (t, J = 5.73 Hz, 2H); 6,043 (m, 1H); 7.37-7.40 (m, 2H); 7.43 (quartet, J = 4.09 Hz, 1H); 7.56 (s, 1H); 7.65 (d, J = 2.45 Hz, 1 H); 7.95 (d, J = 2.45 Hz, 1H).
Step 3 Dodecylamide of 5-Bromo-3'-chloro-6- (2-tetrazol-yl-ethoxy) -bifenyl-3-carboxylic acid and 5-Bromo-3'-chloro-6 - (2 -) acid dodecylamide tetrazol-1-yl-ethoxy) -bifinyl-3-carboxylic acid These compounds are prepared from dodecylamide of 5-bromo-3'-chloro-6 - (2-bromoethoxy) -biphenyl-3-I? carboxylic For the dodecylamide of 5-Bromo-3'-chloro-6- (2-tetrazol-2-yl-ethoxy) -biphenyl-3-carboxylic acid (270 mg, 30.6%), follow the spectral data of a yellow oil that crystallizes in a yellow solid, mp 93-5 ° C; ? K NMR (CDC13) 6 0. 88 (t, J = 6.8 Hz, 3H); 1.25-1.38 (m, 18H); 1.60 (quartet, J = 7.03 Hz, 2H); 3., 2 (quartet, J = 7.25 Hz, 2H); 4.12 (t, J = 5.27 Hz, 2H); 4.82 (t, J = 5.27 Hz, 2H); 6.01-6.04 (m, 1H); W 10 7.30-7.32 (m, 2H); 7.35-7.38 (m, 1H); 7.43-7.44 (m, 1H); 7.63 (d, J = 2.20 Hz, 1H); 7.92 (d, J = 2.20 Hz, 1H); 8.48 (s, 1H); IR 3425, 3325, 2915, 2835, 1630, 1550, 1460, 1450, 700 cm "1; mass spectrometer [(+ 1 APCI], m / z 590/592/594 [M + H] +; Calculated for C28H37BrClNs02: C, 56.90; H, 6.31, N, 11.79; Found: C, 56.20; H, 6.04; N, 11.79. For the 5-Bromo-3'-chloro-6- (2-tetrazol-1-yl-ethoxy) -biphenyl-3-carboxylic acid dodecylamide (260 mg, 29.4%) ee show the spectral data fc of a white solid , mp 95-6 ° C; 8 0.87 (t, J = 6.8 Hz, 3H), 1. 25-1.39 (m, 18H); 1.57-1.64 (m, 2H); 3.40 (m, 2H); 3.94 (t, J = 4.83 Hz, 2HJ- 6.11 (t, J = 5.38 Hz, 1H); 7.22-7.32 (m, 2H); 7. 37-7.40 (m, 1H); 7.43 (t, J = 1.86 Hz, 1H); 7.65 (d, J = 2.2 Hz, 1H); 7.94 (d, J = 2.20 Hz, 1H); 8.74 (s, 1H); IR 3375, 3335, 2925, 2835, 1S30, 1545, 1465, 1320, 1230, 1100, 1030, and 700 cm "1; mass spectral [(+ JAPCI], m / z 590/592/594 [M + H] *; Analysis Calculated for C2, H37BrClNs02: C, 56.90; H, 6.31; N, 11.79; Found: C, 56.29; H, 6.26; N, 12.01.
Example 141 Acid [3,5,3", 5" -Tetramethyl-5 '- (8-f-enyl-octylcarbamoyl) - [1,1'; 3 ', l "] terphenyl-2'-yloxy] acetic acid Stage 1 3,5-Bis- (3, 5-dimethylphenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester The 3,5-bis- (3,5-dimethylphenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester is prepared from the ethyl ester of 3-bromo-4- (2-hydroxyethoxy) -5- iodobenzoic acid as a white solid (1.04 g, 20%) in a similar manner to Step 1 of Example 135. 'H NMR (CDC13) d 1.2-1.4 (8 broad, 1H), - 1.37 (t, J = 8.18 Hz , 3H); 2.37 (s, 12H); 3.25 (t, J = 5.45 Hz, 2H); 3.40 (t, J = 5.45 Hz, 2H); 4.37 (quartet, J = 8.18 Hz, 2H); 7.02 (e, 2H), 8.00 (8. 2H).
Step 2 N-8-Phenyl-3-yl, 5-bis- (3,5-dimethyl-phenyl) -4- (2-hydroxyethoxy) benzamide To a cooled solution (0 ° C) of 8-phenyloctylamine (1.56 g, 7.58 mmol, 1.51 mL) in 10 mL of anhydrous THF was i ^^ B add n-BuLi (5.1 ml, 7.96 mmol) as a solution in hexanes, dropwise. After the addition, the reaction is warmed to room temperature and stirred for half an hour at room temperature. Then the lithiated amine is again cooled to 0 ° C and added to a cold (0 ° C) solution of the 3,5-bis- (3,5-dimethylphenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester (1.04 g, 2.49 mmoles) in 10 ml of anhydrous THF. The resulting reaction mixture is stirred for 5 minutes at 0 ° C and then allowed to warm to room temperature. At this point, additional n-BuLi is added (2.04 ml, 3.18 mmol). When the reaction seems to have ended particularly (by CCD), work is done as indicated in Step 2 of Example 135. After flash chromatography (25% EtOAc: 75% Hexanes), ee has a yield of 850 mg, 59.4% of the amide as a yellow oil. lH NMR (CDC13) d 1.25-1.40 (m, 8H); 1.40-1.64 (m, 5H); 2.37 (e, 12H). 2. 57 (t, J = 8.18 Hz, 2H); 3.25 (t, J = 4.09 Hz, 2H); 3.36-3.47 (m, 4H); 6.06 (t, J = 6.54 Hz, 1 H); 7.02 (s, 2H); 7.11-7.19 (m, 4H); 7.20-7.48 (m, 5H); 7.69 (e, 2H). Step 3: Acid [3, 5, 3", 5" -Tetrame il-5 '- (8-phenyl-octylcarbamoyl) -Il. l ', -3', 1"! terfenyl-2 '- iloxyl acetic To a solution of N-8-f-enyloctyl-3, 5 -bs- (3, 5-dimethylphenyl) -4- (2-hydroxyethoxy) benzamide (850 mg, 1.47 mmole) NMMO (415 mg, 3.05 mmol) and TPAP (52 mg, 0. 149 mmol) are added in 15 ml of acetonitrile. The reaction is stirred for 2 hours and then 40 mg of NMMO 0.3 mmol and 52 mg, 0.149 mmol of TPAP are added. The reaction is stirred overnight and an additional 40 mg, 0.3 mmol, of NMMO is added. The reaction is stirred for two additional hours and then water is added, followed by the addition of sodium bisulfite / sodium dithionite. The aqueous mixture is stirred for 1 hour and then extracted with EtOAc (3X). The combined extracts are dried with Na2SO4 and concentrated to provide a black oil. This oil is subjected to flash chromatography (20% EtOAc: 80% Hexanes is acidified with 1% CTJCOOH) on silica gel pretreated with HCOOH. 200 mg of the desired acid plus a fraction consisting of the desired acid plus other impurities are obtained. This fraction is subjected to chromatography again using the same solvent system to provide 30 mg of the acid for a total yield of 230 mg, 26.4% of the desired acid. * H NMR (DMS0-d6) d 1.27 (broad s, 8H); 1.45-1.60 (m, 4H); 2.31 (s, 12H); 2.53 (t, J = 7.58 Hz, 2H); 3.23 (quartet, J = 6.37 Hz, 2H), - 3.81 (e, 2H); 7.00-7.01 (m, 2H); 7.13-7.15 (m, 3H); 7.19-7.25 (m, 6H); 7.76 (S, 2H); 8.48 (t, J = 6.00 Hz, 1H); 12.35 (broad s, 1H); IR 3325, 2935, 2875, 1750, 1645, 1605, 1580, 1545, 1480, 1460, 1430, 1400, 1385, 1380, 1295, 1250, 1200, 1150, 850, and 700 cm "J- mass spectrum t ( +) APCI], m / z 592 [M + H] J- Analysis Calculated for C39H45N04 - C2H402 - C4Hß02: C, 73.03; 7.63; H, 7.63; N, 1.89; Found: C, 73.32, H, 7.88; N, 2.04.
Example 142 Acid [4,4"-Difluoro-3,3" -dimet? L-5 '- (8-phenyloylcarbamoyl) - [1,1 J-3', 1"] terphenyl-2'-yloxy] acetic acid Stage 1 N-8-Phenyloctyl-3,5-bie- (4-fluoro-3-methylphenyl) -2-hydroxyethoxy) -benzoic acid ethyl ester The ethyl ester of N-8-phenyloctyl-3,5-bis- (4-fluoro-3-methylphenyl) -4- (2-hydroxyethoxy) -benzoic acid is made as a brown solid (470 mg, 20%) a from the ethyl ester of 3-bromo-4- (2-hydroxyethoxy) -5-iodobenzoic acid in a manner similar to Step 1 of Example 135. 1 H NMR (CDC13) d 1.40 (t, J = 7.14 Hz, 3H); 1.56 (s broad, 1H); 2.21 (m, 6H); 3.30-3.31 (m, 2H); 3.3'd-3.40 (m, 2H); 4.40 (quartet, J = 7.03 Hz, 2H); 7.09 (t, J = 8.90 Hz, 2H); 7.39-7.44 (m, 4H); 7.99 (s, 1H).
Step 2 N-8-Phenyloctyl-3,5-bis- (4-fluoro-3-methylphenyl) -4- (2-hydroxyethoxy) -benzamide N-8-Fehiloctyl-3,5-bis- (4-f luoro-3-methylphyl) -4- (2-hydroxyethoxy) -benzamide is prepared as a yellow oil (300 mg, 57.4%) from the ester Ethyl acid N-8-phenyloctyl-3,5-bis- (4-fluoro-3-methylphenyl) -4- (2-hydroxyethoxy) benzoic acid in a manner similar to Step 2 of Example 141.? NMR (CDC13) 6 1.40-1.60 (m, 8H); 1.50-1.63 (m, 4H); 1.6-2.2 (broad S, 1H); 2.33 (S, 6H); 3.55 (t, J = 8.18 Hz, 2H), - 3.25 (t, J = 4.91 Hz, 2H); 3.36 (t, J = 4.09 Hz, 2H); 3. 43 (quartet, J = 8.18 Hz, 2H); 6.12 (t, J = 4.09 Hz, 1H); 7.0.4-7.19 (m, 5H); 7.35-7.55 (m, 4H); 7.68 (s, 1H).
Step 3: f4, 4"-Dif luoro- 3, 3" -dimethyl-5 '- (8-f-octylcarbamoyl) - [l. l '.- 3', 1"! terfenyl-2 '- iloxyl acetic To a solution of N-8-phenyloctyl-3, 5-bis- (4-f luoro-3-methylf-enyl) -4- (2-hydroxyethoxy) benzamide (320 mg, 0.546 mmol) in 5 ml of acetonitrile at room temperature environment adds NMMO (162 mg, 1.2 mmolee) and TPAP (38.3 mg, 0.109 mmol). The reaction is stirred for 2 hours and then additional TPAP (38.3 mg, 0.109 mmolee) is added. The reaction is stirred overnight and an additional amount of NMMO (14.7 mg, 0.109 mmol) and TPAP (19 mg, 0.546 mmol) is added. The reaction is then stirred for an additional three hours and aqueous sodium metabisulfite / sodium dithionite is added. After the The reaction is allowed to stir for 1 hour. Subsequently, IN HCl is added. The aqueous solution is extracted with EtOAc (3x). The combined organic extracts are dried over Na2SO4 and the solvent is removed under vacuum to provide a black oil which is subjected to flash column chromatography (20% EtOAc: 80% Acidified Acxa Hexanes) on silica gel which is pretreated with AcOH. 120 mg, 36.6% of the acid cou a yellow oil are obtained. * H NMR (DMSO-ds) d 1.22-1.27 (m, 4H) r 1.53 (quintet, J = 6.59 Hz, 4H); 2.27-2.28 (m, 6H); 2.52 (t, J = 7.69 Hz, 2H), - 3.23 (quartet, J = 6.59 Hz, 2H); 3.82 (s, 2H); 7.11-7.25 (m, 7H); 7.41-7.45 (m, 2H); 7.52 (dd, J = 7.58 Hz, 1.87 Hz, 2H); 7.80 (s, 2H); 8.49 (t, J = 5.60 Hz, 1H); 12.57 (s broad, 1H); IR 3375, 2915, 2835, 1630, 1540, 1500, 1450, 1230, 1120, and 970 cm "J- mass spectrum [(-) ESI], m / z 598 [M-H]"; Analysis Calculated for C37H39F2N04 - 0.17 C6H12 - 0.2 C4Ha02 - 0.88 C2H302: C, 71.16; H, 6.84; N, 2.04; Found: C, 69.55, H, 6.65; N, 2.09.
Example 143 (7-f-enyl-heptyl) -amide of 2'-Hydroxy-3, 5, 3", 5" -tetramethyl- [1, 1 '; ', 1"] erphenyl-5'-carboxylic acid Stage 1 3,5-Bie- (3,5-dimethylphenyl) -4-methoxy-centrioic acid ethyl ester To a solution of K2CO3 (11.39 g, 82.41 mmol) in 41 ml of H2O are added 280 ml dioxane, a 2: 1 mixture of ester (3-bromo-4-methoxymethoxy-5-iodobenzoic acid ethyl ester and ethyl ester of 3,5-dibromo-4-methoxymethoxybenzoic acid (4.85 g, 13.74 mmoles) and 3-methylphenylbenzoic acid (4.1 g, 27.47 mmoles) at room temperature.The reaction is degassed and completes the complex., 1 'bis (dif enylphosphine) ferrocene] dichloropalladium (II), with CH2C12 (224 mg, 0.248 mmol). The reaction is stirred for 2 d and f 10 after adding the catalyst (56 mg, 0.0687 mmol). The reaction is stirred for a further day, and the reaction is worked as in Step 1 of Example 135 to provide the crude material which is subjected to flash column chromatography (5% EtOAc: 95% Hexanes). The core product of the column is further purified by preparative CLAP to provide 1.44 g, 23% of a white solid. E NMR (CDC13) 6 1.33 (t, J = 8.18 Hz, 3H); 2.37 (s, 12 H); 2.69 (S, 3H), 4.33-4.40 (m, 4H); 6.97 (s, 2H); 7.20 (m, 4H); 7.97 (s, 2H).
Step 2 Acid 3, 5-BIS - (3, 5 -dimet ilf enyl) -4-methoxymethoxybenzoic acid To a suspension of 3,5-bis- (3,5-dimethylphenyl) -4-methoxymethoxybenzoic acid (1.4 g, 3.12 mmol) in 4: 1 MeOH / H20 (50 ml total) is added KOH Eolide (150 mg, 2. 67 mmoles) and the reaction mixture is refluxed until all of the ester is consumed. The reaction mixture is then acidified with NaH2P04 to pH 3 and the precipitated product is filtered off and washed with water. It is then placed in a vacuum oven at 60 ° C to 80 ° C for 2 hours and then the material is subjected to flash chromatography (20% EtOAc: 80% Hexanes to 25% EtOAc: 75% Hexanoe) on silica gel. provide 780 mg, 59.5% as a white solid. 1 H NMR (CDC13) d 2.40 (s, 12 H); 2.72 (s, 3H); 4.45 (s, 2H); 7.00 (s, 2H), - 7.24 (m, 4H); 8.08 (e, 2H). 280 mg of the methyl ester are also obtained as a secondary product.
Step 3 N-7-Phenylheptyl-3,5-bie- (3,5-dimethylphenyl) -4-methoxymethoxybenzamide A flame-dried round bottom flask is charged with 7-phenylheptylamine (354 mg, 2.78 mmol) and 20 ml of anhydrous CH2C12. To this is added 3, 5-bis- (3,5-dimethylphenyl) -4-methoxymethoxybenzoic acid (780 mg, 1.85 mmol), triethylamine (563 mg, 5.56 mmol, 726 μl), anhydrous 1-hydroxybenzotriazole (275). mg, 2.04 mmol), and DCC (459 mg, 2.22 mmol), all at room temperature. The reaction mixture is stirred at room temperature for half an hour. After the reaction, work on adding water and extract it with EtOAc (3x). The combined organic extracts are -S-Bh- *. I ^ ta-i dry over Na2SO4 and the solvent is removed in vacuo to give a semi-solid to which CH2C12 is added. This suspeneion is subjected to column chromatography (15% EtOAc: Hexane 85%) to provide 600 mg, 54.5% of the amide as a colorless oil. XH NMR (CDC13) d 1.34 (broad s, 6H), -1.57 (m, 4H); 2.36 (s, 12H); 2.572 (t, J = 8.18 Hz, 2H); 2,681 (s, 3H); 3.414 (quartet, J = 8. 18 Hz, 2H); 4.39 (S, 2H); 6.04 (t, J = 5.73 Hz, 1H); 6.97 (s, 2H); 7.12-7.27 (m, 9H); 7.67 (s, 2H).
Step 4 (7-phenyl-heptyl) -amide of 2'-Hydroxy-3, 5, 3", 5" -tetramethyl- [1,1 ', -3', l "1-phenyl-5'-carboxylic acid To a solution of N-7-phenylheptyl-3,5-bis- (3,5-dimethylphenyl) -4-methoxy-methoxybenzamide (600 mg, 1.01 mmol) in 5 ml of THF is added IN HCl (1.1 ml, 1.1 mmoles) at room temperature. The reaction mixture is refluxed for 1.5 d and a catalytic amount of camphorsulfonic acid is added. The reaction is then stirred at room temperature for 2 d and then refluxed again until the reaction is complete. The reaction is diluted with water and EtOAc. The organic layer is separated and the aqueous layer is extracted with EtOAc (2x). The combined organic layers are dried over Na2SO4 and the solvent is removed in vacuo. Oil The resulting product is passed through silica gel using 25% EtOAc: 75% Hexanes to obtain camphorsulfonic acid. There is a yield of 500 mg, 90% of an oily white foam of the amide. 1.24-1.39 (m, 6H); 1.55-1.63 (m, 4H); 2.38 (s, 12H) 2.60 (t, J = 7.69 Hz, 2H); 3.44 (quartet, J = 7.14 Hz, 2H) 5.78 (s, 1H); 6.05 (t, J = 7.64 Hz, 1H); 7.04-7.05 (m, 2H) 7.14-7.18 (m, 7H); 7.24-7.28 (m, 2H); 7.66 (s, 2H); IR 3520, 3315, 3030, 2930, 2850, 1630, 1600, 1550, 1470, 1200, 850, and 700 cm "1, maea [El] spectrum, m / z 519 [M *], - Analális Calculated for C3SH41N02 : C, 83.20; H, 7.95; N, 2.69; Found: C, 82.66; H, 7.87; N, 2.66; Example 144 (2-phenyl-heptyl) -amide of 2'-Hydroxy-3, 3"-dimethyl- [1,1 '; 3', 1"] terphenyl-5'-carboxylic acid Stage 1 3,5-Bie- (3-methylphenyl) -4-methoxymethoxybenzoic acid ethyl ester The 3,5-Bis- (3-methylphenyl) -4-methoxymethoxybenzoic acid ethyl ester is prepared as a white solid (4.2 g, 30%) in a similar manner to Step 1 of Example 143 from a mixture of 2 : 1 of the ethyl ester of 3-bromo-4-methoxymethoxy-5-iodobenzoic acid and ethyl ether of 3,5- dibromo-4-methoxymethoxybenzoic acid. XH NMR (CDC13) d 1.17 (t, J = 8.18 Hz, 3H); 2.4 (s, 6H); 2.66 (s, 3H); 4.36 (quartet, J = 8.18 Hz, 2H); 4.40 (s, 2H); 7.11-7.20 (m, 2H); 7.20-7.40 (m, 6H); 8.00 (s, 2H).
Stage 2 3, 5-Bis- (3-methylphenyl) -4-methoxymethoxybenzoic acid 3,5-Bie- (3-methylphenyl) -4-methoxymethoxybenzoic acid is prepared as a white solid (900 mg, 50%) in a manner similar to Step 2 of Example 143 from the ethyl ester of acid 3, 5-bis- (3-methylphenyl) -4-methoxymethoxybenzoic acid. JH NMR (CDC13) d 2.40 (s, 6H); 3.67 (s, 3H); 4.40 (S, 2H); 7.14-7.20 (m, 2H); 7.31 (t, J = 6.54 Hz, 2H); 7.37-7.43 (m, 4H); 8.07 (s, 2H).
Step 3 N-7-Phenylheptyl-3,5-bis- (3-methylphenyl) -4-methoxymethoxybenzamide N-7-Phenylheptyl-3,5-bis- (3-methylphenyl) -4-methoxymethoxybenzamide is prepared as a colorless oil (1.04 g, 78.2%) in a manner similar to Step 3 of Example 143 from the acid 3, 5-bie- (3-methyl-enyl) -4-methoxymethoxybenzoic acid. H NMR (CDC13) d 1.26-1.40 (m, 6H); 1.48-1.66 (m, 4H); 2.40 (s, 6H); 2.57 (t, J = 8.18 Hz, 2H); 2.55 (s, 3H); 3.38 (quartet, J = 6.54 Hz, 2H); 4.36 (e, 2H); 6.06 (t, J = 4.91 Hz, 1H); 7.11- 7. 19 (m, 3H); 7.26 (s, 2H); 7.31 (t, J = 8.18 Hz, 2H); 7.35-7.40 (m, 4H); 7.69 (s, 2H).
Step 4 (7-phenyl-heptyl) -amide of 2'-Hydroxy-3, 3"-dimethyl-fl.l ', -3', 1" 1-terphenyl-5'-carboxylic acid To a solution of N-7- phenylheptyl-3,5-bis- (3-methylphenyl) -4-methoxy-methoxybenzamide (1.04 g, 1.94 mmol) in 3.5 mL of THF is added 2N HCl (1.1 mL, 2.2 mmol). at room temperature, and the reaction mixture is refluxed for 2 hours before a catalytic amount of camphorsulfonic acid is added. The reaction is refluxed overnight and the resulting material is dissolved in EtOAc and washed with water. The organic layer is dried over Na2SO4 and the solvent is removed in vacuo. This provides an oil that is passed through a pad of silica gel using? TOAc 20%: 80% Hexanes. 730 mg, 81% of a light yellow viscous oil are obtained. JH NMR (CDC13) 6 1.33-1.39 (m, 6H); 1.59-1.63 (m, 6H); 2.42 (s, 6H); 2.58 (t, J = 7.69 Hz, 2H), 3.44 (quartet, J = 7.03 Hz, 2H); 6.06 (t, J = 7.50 Hz, 1H); 7.14 7.18 (m, 3H); 7.22-7.28 (m, 4H); 7.34-7.40 (m, 6H), - 7.68 (s, 2H); IR 3525, 3025, 2925, 2850, 1630, 1600, 1530, 1460, 1325,? 230, and 700 cm "J- mass spectrum [(+) ESI], m / z 492 [M + H] *; calculated for C34H37N02: C, 83.06; H, 7.59; N, 2.85; Found: C, 83.80; H, 7.62; N, 2.93; - 2 - Example 145 Acid [3,3 '' -Dimethyl-5 '- (7-phenyl-heptylcarbamoyl) - [1,1': 3 ', 1' '] ter enyl-2'-yloxy] acetic acid Step 1: Terbutyl ester of f3, 3 '' -Dimethyl-5 '- (7-phenyl-heptylcarbamoyl) -fl.l': 3 '. 1' '] terphenyl-2'-yloxy] acetic acid ester To a suspension of the 2 'hydroxy-3, 3"-dimethyl- [1,1': 3 ', 1"] terfenyl-5'-carboxylic acid (7-phenyl-heptyl) -amide (240 mg , 0.516 mmoles) in 2.5 ml of anhydrous DMF is added solid K2C03 (84 mg, 0.613 mmol). The reaction mixture is stirred at room temperature for 2 min before t-butyl bromoacetate (158 mg, 0.812 mmol, 812 μl) is added. The reaction is stirred overnight at room temperature, after which it is diluted with water and extracted with EtOAc (3x). The combined organic layers are washed with water to remove DMF. They are then dried with Na 2 SO 4 and the solvent removed in vacuo to give an oil which is subjected to flash column chromatography (15% EtOAc: 85% Hexanes) to give 180 mg, 60% of a colorless oil. * H NMR (CDC13) d 1.25 (s, 9H); 1.25-1.40 (m, 6H), -1.28-1.47 (m, 4H); 2.40 (s, 6H); 2.57 (t, J = 8.18 Hz, 2H); 3.43 (quartet, J = 8.18 Hz, 2H); 3.73 (s, 2H); 6.06 (t, J = 5.73 Hz, aE-Jlfafe. ' 1 HOUR); 7.08-7.20 (m, 5H); 7.20-7.32 (m, 4H); 7.37-7.46 (m, 4H); 7.68 (s, 2H).
Step 2 Acid [3,3 '' -Dimethyl-5 '- (7-phenyl-heptylcarbamoyl) -fl.l': 3 '. 1' '1-terphenyl-2'-ylyl-acetic acid A solution of the [3, 3 '' Dimethyl-5 '- (7-phenyl-heptylcarbamoyl) - [1, 1': 3 ', 1' '] terphenyl-2'-yloxy] acetic acid terbutyl ester (180 mg , 0.311 mmole) in 3.5 ml of HCOOH is stirred at room temperature until all of the ester, as determined by CCD (1: 1 EtOAc: Hexanes), is consumed. Excess HCOOH is removed in vacuo (first with a rotoevaporator and then pumping under high vacuum) and subsequently crystallized from CH2Cl2 / Hexanes to provide 170 mg, 100% acid as a yellow foam. p.f. 58-62 ° C; * H NMR (DMS0-d6) 6 1.21-1.28 (m, 6H); 1.44-1.57 (m, 4H); 2.35 (s, 6H); 2.53 (t, J = 7.69 Hz, 2H); 3.23 (quartet, J = 6.37 Hz, 2H); 3.82 (s, 2H); 7.10-7.24 (m, 7H); 7.30-7.41 (m, 6H); 7.80 (s, 2H); 8.51 (t, J = 5.49 Hz, 1H); 12.60 (s broad, 1 HOUR); IR 3375, 3025, 2925, 2865, 1730, 1630, 1600, 1550, 1450, 1350, 1210, 1195, 1080, and 700 cm "1; Mass spectrum [(-) ESI], m / z 548 [MH] , - Analysis calculated for C36H39N04: C, 78. 66; H, 7 15, -N, 2.55; found: C, 77. 39; H, 7 .42; N, 2 37 Example 146 4- [3, 3 '' -Dimethyl-5 '- (7-phenyl-heptylcarbamoyl) - [1,1': 3 ', 1' '] terphenyl-2'-yloxy] butyric acid Stage 1 Ethyl 4- [3,3 '' -Dimethyl-5 '- (7-phenyl-heptylcarbamoyl) - fl.1': 3 '. 1' '1-terphenyl-2'-ylyl butyric acid ethyl ester The ethyl ether of 4- [3,3 '' - Dimethyl-5 '(7-phenyl-heptylcarbamoyl) - [1,1': 3 ', 1"] terphenyl-2'-yloxy] butyric acid is prepared as a light yellow oil (260 mg, 73.2%) in a manner similar to step 1 of example 145 from the (7-phenyl-heptyl) -amide of 2'-Hydroxy-3, 3"-dimethyl- [1,1 ': 3', 1"] -terphenyl-5'-carboxylic acid. Jl NMR (CDC13) d 1.14 (t, J = 8.18 Hz, 3H); 1.24-1.14 (m, 6H); 1.44 (quintet, J = 6.54 Hz, 2H); 1.48-1.60 (m, 4H); 1.91 (t, J = 7.36 Hz, 2H); 2.55 (t, J = 8.18 Hz, 2H); 3.20 (t, J = 7.36 Hz, 2H); 3.38 (quartet, J = 8.18 Hz, 2H); 3.60 (quartet J = 8.18 Hz, 2H); (t, J = 5.73 Hz, 1H); 7.07-7.17 (m, 6H); 7.18-7.37 (m, 7H), 7.66 (e, 2H). -tea- Step 2: 4- [3,3 '' -Dimethyl-5 '- (7-phenyl-heptylcarbamoyl) - fl.l': 3'.l''1-terphenyl-2'-yloxy] butyric acid To a solution of [3,3 '' - dimethyl-5 '- (7-phenyl-heptylcarbamoyl) - [1,1': 3 ', 1' '] -terphenyl-2'-yloxy] acetic acid methyl ester (260 mg, 0.449 mmoles) in 4 ml of MeOH is added 1 ml of H20 and solid KOH (25 mg, 0.449 mmol). The reaction mixture is refluxed for 2 d and then cooled, acidified with 2N HCl and extracted with EtOAc (3x). The combined organic strains are dried over Na2SO4 and the solvent is removed in vacuo to provide an oil which is subjected to flash column chromatography (20% EtOAc: 80% Hexanes to 100% EtOAc) on silica gel to provide 80 mg of the desired acid and 150 mg of the methyl ester of the desired acid. This ester is subjected to the same reaction conditions to provide more desired acid. The total yield of the desired acid is 150 mg, 60.7% as an oily light yellow foam. "H NMR (DMSO-d6) 6 1.23-1.35 (m, 8H); 1.46-1.55 (m, 4H); 1.83 (t, J = 7.47 Hz, 2H); 2.37 (s, 6H); 2.53 (t, J = 7.58 Hz, 2H), 3.18-3.27 (m, 4H), 7.10-7.15 (m, 3H), 7.19-7.24 (m, 4H), -7.23-7.40 (m, 6H), 7.80 (s, 2H) ), 8.50 (t, J = 5.49 Hz, 1H), 11.87 (s, 1H), IR 3320, 2920, 2850, 1710, 1730, 1560, 1540, 1450, 1380, 1330, 1220, 1050, and 700 cm. J- Eepectro de maeüs. [(-) ESI], m / z 576 [M-H]; Analysis calculated for C38H43N04: C, 79.00; H, 7.50; N, 2.42; found: C, 77.76; H, 7.23; N, 2.69.
Example 147 Acid diethyl ester [3, 5, 3", 5" - Tetramethyl-5 '- (7-enyl-heptylcarbamoyl) - [1,1': 3 ', 1"] erphenyl-2'-yloxymethyl] phosphonic Stage 1 It is a product of the product (trifluoromethyl-sulfonyl) methyl A round-bottom, flame-dried flask is charged with hydroxymethylphosphonate diethyl ester (200 mg, 1.19 mmol, 175 μl) and thiathylamine (157 mg, 1.55 mmol, 216 μl) and 5 ml of CH2C12, and cooled to -70 ° C. Trifluorometalsulfonic anhydride (369 mg, 1.31 mmol, 220 μl) is added dropwise. The reaction is stirred for 10 min while the reaction is warmed to -40 ° C. At this point, the reaction mixture is diluted with EtOAc and extracted with water. The organic layer is dried over Na 2 SO 4 and the solvent removed in vacuo to give 350 mg, 98% orange oil.
Step 2 Diethyl ether of the acid [3, 5.3 '', 5 '' Tetramethyl-5 '- (7-phenyl-heptylcarbamoyl) - fl, l': 3 ', 1"1-terphenyl-21-yloxymethyl phosphonic acid - ^ Aa ..
To a flame-dried round bottom flask is added the 2'-hydroxy-3,5,3", 5" -tetramethyl- (1,1-phenyl-heptyl) -amide. l ''] terphenyl-5'-carboxylic acid (180 mg, 0.327 mmol) and 5 ml of, anhydrous THF. This solution is cooled to 0 ° C and NaH (9 mg, 0.36 mmol) is added: The reaction is stirred for 5 min at 0 ° C and then (trifluoromethylsulfoyl) phosphonate diethyl ester is slowly added to the reaction mixture. iloxy) methyl (98 mg, 0.327 mmol). The reaction is stirred for half an hour while allowing the reaction to warm to room temperature. After the reaction has been stirred at room temperature for 3 hours, 1-2 mg of NaH and 9.8 mg, 0.0327 mmol of the ester are added. The reaction is stirred at room temperature for an additional 2 hours and worked as follows. Water is added to the reaction and the aqueous solution is extracted with EtOAc (3x). The combined organic layers are dried over Na2SO4 and the solvent is removed in vacuo to give a yellow oil which is subjected to flash column chromatography (25% EtOAc: 75% Hexanes up to 50% EtOAc: 50% Hexanes) on silica gel. provide 90 mg, 41% of a colorless oil. Jl NMR (CDC13) d 1.11 (t, J = 7.03 Hz, 6H); 1.32-1.38 (m, 6H); 1.61-1.65 (m, 4H); 2.38 (s, 12H); 2.59 (t, J = 7.69 Hz, 2H); 3.43 (quartet, J = 7.03 Hz, 2H); 3.55-3.64 (m, 4H); 3.73-3.82 (m, 2H), -6.05 (t, J = 6.00 Hz, 1H); 7.01-7.02 (m, 2H); 7.14- 7. 18 (m, 3H), - 7.19-7.20 (m, «&); 7.24-7.28 (m, 2H); 7.65 (s, 2H); IR 3425, 2925, 1540, and 1030 cm "J Mass spectrum [(+) APCI], m / z 670 [M + H] J- Analysis calculated for C41H52N05P: C, 73.52; H, 7.82; N, 2.09; found: C, 73.15; H, 7.90; N, 2.18.
Example 148 4- [3,5,3 '', 5 '' - Tetramethyl-5 '- (7-phenyl-heptylcarbamoyl) - [1,1': 3 ', 1' '] terphenyl-2'-yloxy] butyric acid Step 1: 4-f3.5, 3 '' .5 '' Tetramethyl-5 '- (7-phenyl-heptylcarbamoyl) -fl, l': 3 ', ethyl ester, 1'-terphenyl-2'-yloxy Butyric To a solution of 2'-H-droxy-3,5, 3"5" -tetramethyl- [1,1 ': 3', 1"] terphenyl- (7-phenyl-heptyl) -amide. 5'-carboxylic acid (180 mg, 0.327 mmol) in 2 ml of DMF is added K2C03 (24 mg, 0.174 mmol) and the reaction mixture is stirred for 10 min at room temperature. The ethyl ether of 4-bromobutyric acid (70 mg, 0.36 mmolee) is slowly added to the reaction mixture. The reaction is stirred at room temperature for 2 d, and then heated for 45 min at temperature between 40 ° C and 50 ° C. Afterwards, it works as in stage l of example 146.
JH NMR (CDCl 3) d 1.18 (t, J = 7.36 Hz, 3H); 1.27-1.37 (m, 6H); 1.44-1.64 (m, 6H), - 1.95 (t, J = 8.18 Hz, 2H); 2.54 (s, 12H); 2.57 (t, J = 7.36 Hz, 2H); 3.25 (t, J = 6.54 Hz, 2H); 3.41 (quartet, J = 7.36 Hz, 2H); 4.00 (quartet, J = 8.18 Hz, 2H); 6.04 (m, 1H); 6.00-6.08 (m, 1H) 6.99 (e, 2H); 7.10-7.26 (m, 9H); 7.66 (S, 2H).
Step 2: Acid 4- [3,5,3 '', 5 '' Tetramethyl-5 '- (7-f-enyl-hept-lcarbamoyl) - fl. 1': 3 '. 1' '1-terfen-l-2'-yloxyl Butyric To an euspeneion of the ethyl ether of the acid 4- [3, 5, 3", 5" Te trame til -5 '- (7-phenyl-hepte and Icarbamoyl) - [1, 1': 3 ', 1' '] terphenyl-2'-yloxy] butyric acid (170 mg, 0.256 mmolee) in 4 ml of MeOH / 1 ml of H20 is added solid KOH (12 mg, 0.213 mmol). The reaction mixture is refluxed for 2 d and then the reaction mixture is diluted with 2N HCl and water. The aqueous solution is extracted with EtOAc (3x) and the combined organic extracts are eluted over Na2SO4. The solvent is removed in vacuo to provide an oil which is subjected to flash chromatography (10% EtOAc: 90% Hexanes) on silica gel to provide 70 mg, 43% of the acid as an oily white foam. p.f. 64-66 ° C; * H NMR (DMS0-d6) 6 1.29-1.30 (m, 6H); 1.32-1.39 (m, 2H); 1.46-1.48 (m, 4H); 1.86 (t, J = 7.47 Hz, 2H); 2.33 (s, 12H); 2. 53 (t, J = 7.58 Hz, 2H); 3.19-3.31 (m, 4H); 7.01 (s, 2H); 7.12-7.16 (m, 3H); 7.17-7.19 (m, 4H); 7.21-7.24 (m, 2H); 7.71 (s, 2H); 8.48 (t, J = 7.00 Hz, 1H); 11.86 (s, 1H); IR 3325, 2925, 2875, 1710, 1630, 1600, 1535, 1450, 1290, 1225, 1210, 850, and 700 cm "J- Mass spectrum [(+ JAPCI], m / z 606 [M + H] * , - Analysis calculated for C40H47NO4: C, 79.30; H, 7.82; N, 2.31; found: C, 78.65; H, 7.86; N, 1.87.
Examples 149 and 150 (7-f-enyl-heptyl) -amide of 3, 3"-Dif ormil-2'-methoxymethoxy- [1,1 ': 3', 1"] terphenyl-5'-carboxylic acid and (7-phenyl) -heptyl) -3,3 '' -Dif ormil-2 '-hydroxy- [1,1': 3 ', 1' '] terf enyl-5'-carboxylic acid amide Step 1 3,5-Bis (3-f ormif enyl) -4-met oxime toxibenzoic acid ethyl ester 3,5-Bis (3-formyphenyl) -4-methoxymethoxybenzoic acid ethyl ester is prepared as a white solid (980 mg, 13.7%) in a manner similar to step 1 of example 143 from a mixture 2: 1 of the ethyl ester of 3-bromo-4-methoxymethoxy-5-iodobenzoic acid and the ethyl ether of 3,5-dibromo-4-methoxymethoxybenzoic acid. They also get 1.6 g of ,? ia- > a mixture of benzaldehyde and the initial halogenated compound, and 1.4 g, 20.7% of the mono-aryl material as a white solid. fc Bisarylated compound: Ji NMR (CDC13) d 1.38 (t, J = 7.36 Hz, 3H); 2.59 (e, 5 3H); 4.33-4.42 (m, 4H); 7.62 (t, J = 7.36 Hz, 2H); 7.79 (dd, J = 8.18 Hz, 2.05 Hz, 4H); 7.97 (e, 2H); 8.02 (e, 2H); 10.11 (e, 2H). Monoarylated compound: "H NMR (CDC13) d 1.38 (t, J = 8.18 Hz, 3H), 3.06 (s, f 10 3H), 4.37 (quartet, J = 8.18 Hz, 2H), 4.80 (e, 2H); 7.60 (t, J = 7.36 Hz, 1H), 7.77-7.82 (m, 1H), 7.87-7.91 (m, 1H), 7.96-8.00 (m, 1H), - 8.01-8.06 (m, 1H), 8.26 -8.30 (m, 1H).
Stage 2 3, 5-Bie- (3-formyphenyl) -4-methoxymethoxybenzoic acid Aolution of 3,5-bis- (3-formyphenyl) -4-methoxymethoxybenzoic acid ethyl ether (960 mg, 2.12 mmolee) in 3 ml of MeOH adds 3 ml of solid H20 and KOH (179 mg, 3.18 mmol) ). The reaction is refluxed for 5 to 6 hours and then the reaction mixture is cooled and diluted with 2N HCl and water, the aqueous solution is extracted with EtOAc (3x) and the combined organic layers are dried over Na2SO4. The solvent is removed in vacuo to give an oil which is subjected to flash chromatography (10% MeOH: 90% EtOAc) in a gel. silica. Here 650 mg of the desired acid are obtained together with part of the methyl ester of the desired acid. The methyl ether is again subjected to the reaction conditions to provide more of the desired acid for a total yield of 690 mg, 76.6%. 5 'HEMN (CDC13) 6 2.63 (s, 3H); 4.19 (8, 2H); 7.65 (t, J = 7.36 Hz, 2H); 7.87-7.95 (m, 4H); 8.06-8.26 (m, 4H); 10.10 (s, 2H).
Step 3 (3-phenyl-heptyl) -amide of 3, 3"-Diformyl-2 '-f-10-methoxymethoxy-fl, 1': 3 ', 1" 1-terfen-l-5'-carboxylic acid The 3,3''-D? Form? L-2'-methoxymethyl- [1,1 ': 3', 1 ''] terphenyl-5 '- (7-phenyl-heptyl) -amide is prepared carboxylic as an oily yellow foam (650 mg, 80%) in a manner similar to step 3 of example 143. 'HRMK (CDCl 3) d 1.33-1.40 (m, 6H); 1.59-1.64 (m, 4H); 2. 57-2.61 (m, 5H); 3.45 (quartet, J = 6.81 Hz, 2H); 4.35 (s, 2H); 6.17 (t, J = 7.36 Hz, 1H); 7.14-7.17 (m, 3H); 7.24-7.28 (m, 2H); 7.64 (t, J = 7.58 Hz, 2H); 7.81 (s, 2H); 7.90-7.93 (m, 4H); 8.15 (t, J = 1.43 Hz, 2H); 10.10 (s, 2H); IR 3375, 3075, 3025, 2950, 2825, 2725, 1790, 1700, 1630, 1600, 1580, 1530, 1450, 1150, and 950 cm "1; Mass spectrum [< +) ESI], m / z 564 [M + H] *; Analysis calculated for C36H37NOs: C, 76.71; H, 6.62; 25 N, 2.48; found: C, 74.67; H, 6.35; N, 2.99; Step 4 (7-phenyl-heptyl) -amide of the acid 3.3 '' - faith Diformyl -2 '-hydroxy- [1,1': 3 ', 1"1-terphenyl-5'-carboxylic acid To a solution of the acid (7-phenyl-heptyl) -amide 3,3 '' -diformyl -2 '-methoxymethoxy- [1,1' -3 ', 1"] terphenyl-5'-carboxylic acid (480 mg, 0.80 mmol) in e ml of THF is added 2N HCl ( 400 μl 0.80 mmoles) and a catalytic amount of camphorsulfonic acid. The reaction is heated overnight at about 50 ° C and then cooled and diluted with water. The aqueous solution is extracted with EtOAc (3x)The combined organic layers are dried over Na2SO4 and the solvent is removed in vacuo. The oil obtained is subjected to flash chromatography (20% EtOAc: 80% Hexanes to 40% EtOAc: 60% Hexanes) on silica gel to provide 360 mg, 75% of the desired amide. p.f. 63-S5 ° C; "H NMR (CDCl 3) 6 1.32-1.39 (m, 6H); 1.58-1.65 (m, 4H); 2. 59 (t, J = 7.69 Hz, H); 3.42 (quartet, J = 7.03 Hz, 2H), - 5.668 (s, IH); 6.14 (t, J = 5.60 Hz, 1H); 7.14-7.17 (m, 3H); 7.23-7.28 (m, 2H); 7.67 (t, J = 7.69 Hz, 2H); 7.74 (e, 2H); 7.83 (ddd, J = 8.30 Hz, 1.76 Hz 1.32 Hz, 2H); 7.93 (td, J = 7.87 Hz, 1.43 Hz, 2H); 8.08 (t, J = 1.43 Hz, 2H); 10.07 (e, 2H); IR 3325, 3065, 3025, 2935, 2850, 2725, 1700, 1630, 1600, 1580, 1530, 1470, 1230, 1190, and 700 cm "1; Mass spectrum [(+ JAPCI], m / z 520 [M + H] J- Analysis calculated for C34, H33, N04 Example 151 Acid [3, 3", 4,4" Bis-methylenedioxy-5 '- (7-phenyl-heptylcarbamoyl) - [1,1': 3 '1"] terf enyl-2'. iloxi] acetic Step 1 3,5-Bis-13,4-methylenedioxyphenyl) -4-methoxymethoxybenzoic acid ethyl ester The 3,5-Bis- (3,4-methylenedioxyphenyl) -4-methoxymethoxybenzoic acid ethyl ester is prepared as a white solid (3.1 g, 42.4%) in a manner similar to step 1 of Example 143 from a 2: 1 mixture of the 3-bromo-4-methoxymethoxy-5-iodobenzoic acid ethyl ester and the 3,5-dibromo-4-methoxymethoxybenzoic acid ethyl ester. It also provides 780 mg of the monarylated product. X H NMR (CDCl 3) d 1.37 (t, J = 8. 18 Hz, 3H); 2.80 (s, 3H); 4.36 (quartet, J = 8.18 Hz, 2H); 4.46 (s, 2H), - 6.00 (s, 4H); 6.87 (d, J = 8.18 Hz, 2H); 7.05 (dd, J = 8.18 Hz, 1.63 Hz, 2H); 7.11 (d, J = 1.23 Hz, 2H); 7.95 (s, 2H).
Step 23, 5-Bis- (3,4-methylenedioxyphenyl) -4-methoxymethoxybenzoic acid The synthesis of 3,5-bis- (3,4-methylenedioxyphenyl) -4-methoxymethoxy-benzoic acid is similar to step 2 of examples 149 and 150 from the 3,5-bis- (3-ethyl) ethyl ester , 4-methylenedioxyphenyl) -4-methoxymethoxybenzoic acid. The purification is carried out in this way. The crude acid is dissolved in 2.5N NaOH and extracted 3 times with EtOAc. These combined layers of EtOAc are set aside. The aqueous layer is acidified with 2N HCl and then extracted with EtOAc (3x). These combined layers are dried over Na 2 SO 4 and the solvent removed in vacuo to provide about 1 g of the acid plus a minor amount of AcOH as a broad yellow solid, cured. The solvent is removed from the EtOAc layers that have been left aside and the residue is re-subjected to reaction conditions with a large excess of base. This part is diluted with water, acidified with 2N HCl and extracted with EtOAc. The EtOAc is dried and the solvent removed in vacuo to provide more of the desired acid. The total yield is 1.35 g, 95.7%. 'HRMN (CDC13) 6 2.76 (s, 3H); 4.46 (s, 2H); 6.123 (s, 4H); 7.07 (e, 4H); 7.84 (s, 2H); 13.00 (s broad, 1H).
Step 3 (3,3-f-enyl-heptyl) -amide of 3, 3", 4, 4" -Bis-methylenedioxy-2'-methoxymethoxy-fl, 1 ': 3', 1"1-terphenyl-5 '-carboxylic The 3,3 '' - 4,4"-Bis-methylenedioxy-2'-methoxymethoxy- [1,1 ': 3', 1"] terphenyl ester (7-phenyl-heptyl) -amide is prepared 5'-carboxylic acid as a beige solid (1.2 g, 68.1%) in a manner similar to step 3 of Example 143 from 3,5-bis- (3,4-methylenedioxy-phenyl) -4-methoxymethoxybenzoic acid. "H NMR (CDC13) d 1524-1.386 (m, 6H); 1.51-1.60 (m, 4H); 2.57 (t, J = 8.18 Hz, 2H); 2.80 (s, 3H); 3.41 (quartet, J = 6.54 Hz, 2H); 4.44 (s, 2H); 6.00 (s, 4H); 6.07 (m, 1H); 6.86 (d, J = 8.18 Hz, 2H); 7.03 (dd, J = 8.18 Hz, 1.20 Hz, 2H); 7.08 (s, 2H); 7.10-7.16 (m, 3H); 7.23-7.27 (m, 2H); 7.64 (s, 2H).
Step 4 (7-phenyl-heptyl) -amide of 2'-Hydroxy-3, 4, 3", 4" -bis-methylenedioxyphenyl- [1, 1 ': 3' .1 '' 1 terfenyl-5 '-carboxylic To a solution of the 3, 3", 4, 4" -Bis-methylenedioxy-2'-methoxymethoxy- [1, 1 ': 3 J 1"] (7-f-enyl-heptyl) -amide] Terfenyl-5'-carboxylic acid (1.2 g, 1.9 mmol) in 8 ml THF is added 2N HCl (800 μl, 1.9 mmol) and a catalytic amount of camf or sulfuric acid. The reaction mixture is refluxed until all of the initial material is consumed. The treatment is similar to that of step 4 of examples 149 and 150. Flash chromatography (20% EtOAc: 80% Hexanes to 40% EtOAc: 60% Hexanes) on silica gel provide 870 mg, 74.3% of a light yellow foam as the desired product. 'HEMN (CDC13) d 1.20-1.40 (m, 6H); 1.50-1.67 (m, 4H); 2.57 (t, J = 7.64 Hz, 2H); 3.40 (quartet, J = 7.09 HZ, 2H); 5.70 (S, 1H); 6.00 (s, 5H); 6.86-7.00 (m, 6H); 7.06-7.31 (m, 5H); 7.60 (e, 2H).
Step 5: Terbutyl ether of f3.3", 4,4" -Bie-methylenedioxy-5 '- (7-phenyl-heptylcarbamoyl) -fl.l': 3 ', l'1-terphenyl-2 '-acetyl-acetyl To a solution of the 3, 3", 4, 4" -bie-methylenedioxy-2'-methoxymethoxy- [1,1 ': 3', 1"] - terfeni (7-phenyl-heptyl) -amide. -5'-carboxylic acid (400 mg, 0.648 mmolee) in 5.5 m of anhydrous DMF is stirred at room temperature while solid K2C03 (45 mg, 0.324 mmol) is added. The reaction is stirred for a half hour before t-butyl bromoacetate (139 mg, 0.712 mmole, 105 μL). The reaction is stirred overnight and worked up as step 1 of Example 146. Flash chromatography (10% EtOAc: 90% Hexanes to 30% EtOAc: 70% Hexanes) on silica gel provides 420 mg, 88% of a solid white. 1.28-1.37 (m, 6H); 1.57 (s, 13H); 2.57 (t, J = 8.18 Hz, 2H); 3.41 (quartet, J = 8.18 Hz, 2H); 3.79 (s, 2H); 5.99 (s, 4H); 6.04 (m, 1H); 6.86 (d, J = 9.00 Hz, 2H); 7.05 (dd, J = 8.18 Hz, 1.23 Hz, 2H); 7.10-7.17 (m, 6H); 7.20-7.27 (m, 1H); 7.627 (S, 1H).
Step 6: Acid f3, 3".4.4" -Bis-methylenedioxy-5 '- (7-phenyl-5-heptylcarbamoyl) - fl, l': 3 '. 1"1 -terphenyl-2'-yloxy-1-acetic acid The acid is stirred [3, 3", 4, 4" -Bie-methylenedioxy-5 '- (7-phenyl-heptylcarbamoyl) - [1,1': 3 ', 1"] -terphenyl-2'-yloxy] acetic acid (420 mg, 0.57 mmolee) in 5 ml of HCOOH for 2 d and then the excess of HCOOH is removed in vacuo to yield a cinnamon oil viscoe. The oil is placed under high vacuum to remove the remaining HCOOH and then the oil crystallizes to a beige solid at -78 ° C. 345 mg, 89% of the solid, m.p. 157- 8"C; 15 JH NMR (DMS0-d6) d 1.23-1.29 (m, 6H); 1.47-1.57 (m, 4H); 2.53 (t, J = 7.69 Hz, 2H); 3.23 (quartet, J = 6.59 Hz, 2H), 3.86 (s, 2H); 6.06 (s, 4H); 6.99 (d, J = 8.13 Hz, 2H); 7.06 (td, J = 7.25 Hz, 0.77 Hz, 2H); 7.11-7.17 (m, 4H); 7.21-7.25 (m, 2H); 7.75 (d, J = 0.88 Hz, 2H); 8.12 (s, 1H); 8.49 (t, J = 5.49 Hz, 1H); 20 12.65 (broad s, 1H); IR 3350.2925, 2850, 1730, 1610, 1550, 1500, 1490, 1455, 1430, 1230, 1200, and 1035 cm "1; Mass spectrum [(+) APCI], m / z 610 [M + H] J- Analysis calculated for C36, H35, NOB, C, 70.92, H, 5.79, 25 N, 2.30, found: C, 69.78, H, 5.70, N, 2.30.
Example 152 3 '-Bromo-2' -hydroxy-5 '- (8-phenyl-octylcarbamoyl) -biphenyl-3-carboxylic acid 4-chlorobutyl ester Stage 1 3-Bromo-3-formylphenyl-4-methoxymethoxybenzoic acid To a solution of the ethyl ether of 3-bromo-3-formyphenyl-4-methoxymethoxybenzoic acid (1.4 g, 3.56 mmol) in 10 ml of MeOH / 20 ml of H20 is added solid KOH (220 mg, 3.91 mmol). The reaction mixture is refluxed for 3 h and then additional solid KOH (23 mg, 0.42 mmol) is added and the reaction temperature is lowered to about 50 ° C. point after which the reaction is stirred overnight. Treat the reaction to dilute with water and acidify with 2N HCl to pH 1 and extract with EtOAc (3x). The combined organic layers are dried over Na2SO4 and then the solvent is removed in vacuo to give a beige-colored solid. This solid is subjected to flash chromatography (50% EtOAc: 50% Hexanes to 100% EtOAc to give the desired acid as a beige solid plus a fraction containing the initial ester and the desired acid. provide more acid for a total yield of 920 mg, 70.7%.
* H NMR (CDC13 + DMSO-d6) d 2.91 (s, 3H); 4.67 (s, 2H); 5.2-6.6 (broad s, 1H); 7.26 (t, J = 8.18 Hz, 1H); 7.67 (d, J = 8.18 Hz, 1H) -, 7.73 (d, J = 8.18 Hz, 1H), - 7.83-7.90 (m, 2H); 8.11 (d, J = 1.64 Hz, 1H); 9.90 (s, 1H).
Stage 2 l-Bromo-7-phenylheptane To a solution of 7-phenyl-1-heptanol (29.1 g, 151.3 mmoles) in 800 ml of CH2C12 at room temperature, add CBr4 (60.2 g, 181.6 mmol) and then triphenylphophine (47.6 g, 181.6 mmol). After 30 e, the reaction changes to a light green color. The CCD indicates that the reaction has been completed at this point. The solvent is removed in vacuo to provide a greenish-white emolliol. To this material 10% EtOAc: 90% Hexanes is added and the resulting suspension is filtered through a pad of silica gel, washing well with the same seven solvents. The yield of 57 g of a colorless oil such as the desired bromide and triphenylphosphine oxide. This oil is then subjected to flash chromatography (Hexanes) to provide 38.6 g, 100% of the bromide as a colorless oil. * H NMR (CDC13) 6 1.30-1.49 (m, 6H); 1.60 (quintet, J = 8.18 Hz, 2H); 2.60 (t, J = 8.18 Hz, 2H), - 3.39 (t, J = 8.18 Hz, 2H); 7.13-7.20 (m, 3H); 7.21-7.31 (m, 2H).
Stage 3 7-Phenyl-l-cyanoheptane A dry solid KCN (260 mg, 4 mmol) in a flame-dried round bottom flask is added 1.1 ml of anhydrous THF, 1-bromo-7-phenyl-heptane (510 mg, 2 mmol) and n-BuNHS04 ( 136 mg, 0.4 mmol). The reaction is refluxed for 50 min before 100 μl of anhydrous DMSO is added. The reaction is further heated and an additional 330 μl of anhydrous DMSO are added. The reaction is heated overnight and then cooled. Water is added and the aqueous solution is extracted with EtOAc (3x). The combined organic layers are dried over Na 2 SO 4 and the solvent removed in vacuo to provide an oil which is subjected to flash chromatography (10% EtOAc: 90% Hexanes) to provide 250 mg, 62.5% of the cyanide as a colorless oil. XH NMR (CDC13) 6 1.254-1.482 (m, 6H); 1.51-1.67 (m, H); 2.30 (t, J = 8.18 Hz, 2H); 2.55 (t, J = 8.18 Hz, 2H); 7.10-7.20 (m, 3H); 7.20-7.30 (m, 2H).
Stage 4 8 -Fenyl-heptyl amine A flame-dried round-bottomed flask is charged with 7-fe-1-l-anoheptane (7.67 g, 38.1 mmol) and 180 ml of THF anhydrous. It is added in portions for 3 0 min at room temperature LiAlH4, eolide (2.42 g, 63.8 mmol). The reaction is stirred overnight. Then the treatment is done as follows. 2.4 ml of H20 are added to the stirred reaction mixture. The reaction is cooled to 0 ° C and then 2.4 ml of 15% NaOH are added. Subsequently 7.2 ml of H20 are added. The resulting suspension is diluted with 100 ml of THF and filtered. The filtrate is dried over Na2SO4 and the solvent is removed to provide 6.67 g, 85.3% of a yellow oil such as amine. JH NMR DMSO-d6) d 1.12-1.40 (m, 10H); 1.28-1.60 (m, 2H), -2.26-2.60 (m, 4H), -7.10-7.20 (m, 3H); 7.20-7.28 (m, 2H).
Step 5 N- (8-Phenyl-heptyl) -3-bromo-3-formylphenyl-4-methoxymethoxybenzamide N-7-Phenyl-heptyl-3-bromo-3-formylf-enyl-4-methoxymethoxybenzamide is prepared as a light yellow oil (610 mg, 43. 9%) in a manner similar to step 3 of Example 143 from 3-bromo-3-formyphenyl-4-methoxymethoxybenzoic acid.
* H NMR (CDC13) d 1.26-1.40 (m, 8H); 1.51-1.60 (m, 4H); 2.57 (t, J = 8.18 Hz, 2H); 3.05 (s, 3H); 3.40 (quartet, J = 7.36 Hz, 2H); 5.79 (e, 2H); 6.06-6.13 (m, 1H); 7.10-7.20 (m, 3H); 7.20-7.28 (m, 2H); 7.60 (t, J = 7.36 Hz, 1H); 7.80 (d, J = 8.18 Hz, 1H); 7.97-8.03 (m, 2H); 10.06 (e, 1H).
Step 6 N- (8-Phenyl-heptyl) -3-bromo-3-carboxyphenyl-4-methoxymethoxybenzamide To a solution of N-7-f-enyl-heptyl-3-bromo-3-formyl-phenyl-4-methoxymethoxy-benzamide (300 mg, 0.542 mmol) is added KMn04 (128 mg, 0.813 mmol) at room temperature, and the reaction it is stirred until all the initial aldehyde, determined by CCD, is consumed. The reaction mixture is diluted with water and sodium bisulfite is added. Then 1 ml of IN HCl is added. This mixture is stirred to make it colorless and then extracted with EtOAc (3x). The combined organic layers are washed with 2N HCl, dried over Na 2 SO 4 and the solvent is removed to provide 270 mg, 87.6% of the crude acid as a light yellow oil which is taken directly in the next step. 'H NMR (CDC13) 61.26-1.40 (m, 8H); 1.51-1.64 (m, 4H); 2.57 (t, J = 8.18 Hz, 2H); 3.43 (quartet, J = 8.18 Hz, 2H), - 3.08 (s, 3H); 4.80 (8, 2H); 6.09 (m, 1H); 7.11-7.20 (m, 2H); 7.20-7.28 (m, 3H); 7.54 (t, J = 8.18 Hz, 1H), - 7.68 (d, J = 1.23 Hz, 1H); 7.77 (d, J = 4.09 Hz, 1H); 7.99 (d, J = 1.23 Hz, 1H); 8.10 (d, J = 8.18 Hz, 1H), - 8.27 (e, 1H).
Step 7 3-Chloro-2'-hydroxy-5 '- (8-phenyl-octylcarbamoyl) -biphenyl-3-carboxylic acid ester 4-chlorobutyl? Co To a solution of N- (7-phenylheptyl) -3-bromo-3-carboxyphenyl-4-methoxymethoxybenzamide (270 mg, 0.474 mmol) in ml of THF are added with 150 μl of 2N HCl and a catalytic amount of camphorsulfonic acid. The reaction is refluxed for 3 hours and then stirred at room temperature for 2 d. Then 2 drops of concentrated HCl are added and the reaction mixture is refluxed further until the initial material is consumed. The reaction mixture is cooled, diluted with water and extracted with EtOAc (3x). The combined organic layers are Na2SO4 and the solvent is removed to provide a solid which is subjected to flash chromatography (25% EtOAc: 75% Hexanes) to provide 130 mg, 44.5% of a yellow oil as an ester.
JH NMR (DMS0-d6) d 1.22-1.29 (m, 8H); 1.46-1.56 (m, 4H); 1.84 (t, 3.08 Hz, 4H); 2.53 (t, J = 7.58 Hz, 2H); 3.21 (quartet, J = 6.81 Hz, 2H); 3.70 (t, J = 6.15 Hz 2H); 4.33 (t, J = 6.04 Hz, 2H); 7.12-7.16 (m, 3H), - 7.21-7.25 (m, 2H); 7.62 (t, J = 7.69 Hz, 1H); 7.74-7.79 (m, 2H); 7.97 (dt, J = 7.69 Hz, 1.43 Hz, 1H); 8.05 (d, J = 2.20 Hz, 1H); 8.09 (t, J = 1.65 Hz, 1H), 8.42 (t, J = 5.93 Hz, 1H); 9.78 (s, 1H), - IR 3325, 2925, 2850, 1720, 1630, 1600, 1550, 1470, 1290, 1240, 1010, and 700 cm "J- Eepectro de maeae [(-) ESI], m / z 612/614 [MH] "; Analysis calculated for C32H37BrClN04: C, 62.49; H, 6.06; N, 2.28; found: C, 61.27; H, 6.36; N, 2.09.
Example 153 3 '' - Chloro-5 '-dodecylcarbamoyl-3-trifluoromethyl- [1,1'; 3 ', 1' '] terf enyl-2'-yloxy) acetic acid Stage 1 Ethyl 3- (3-chlorophenyl) -5- (3-trifluoromethyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester To a stirred solution of K2CO3 (2.488 g, 18 mmol) in 9 ml of water are added 71 ml of dioxane, 3-Bromo-5- (m-chlorophenyl) -4- (2-hydroxyethoxy (benzoic acid) 2,3-ethyl ester. g, 6 mmoles), 3- (trifluoromethyl) phenylboronic acid (1367 g, 7.2 mmoles) and c omp lejode [1, 1 '-bie (diphenyl-phepholine) ferrocene] dichloropalladium (II), with CH2C12 (0.098 g, 0.12 mmole) The reaction is stirred at room temperature for 21 h and then heated to 59 ° C. During the course of the day, boronic acid and catalyst are added as needed.The heating is stopped after 7 h. Dilute with 160 ml of 0.2 N HCl and extract with 1 x 100 ml EtOAc, 3 x 50 ml) The combined organic fractions are washed with 0. IN HCl (2 x 30 ml), water (3 x 30 ml). ), brine (2 x 30) and dried over Na 2 SO 4 After concentration, the residue is purified by inantantial chromatography (gradient from 0 to 50% EtOAc / Hex) and purified by CLAP (CH 2). CH2 50% / Hex with methyl t-butyl ether 6%) for provide the product as a colorless oil (2.436 g, 87%); f Jl NMR (400 MHz, DMSO-d d 1.31 (t, J = 7 Hz, 3H); (t, J = 5.7 Hz, 2H), 3.26 (t, J = 5.7 Hz, 2H), 4.33 (c, J = 7.0, 2H), 5 4.42 (broad e, 1H), 7.47-7.54 (m, 2H) ), 7.56-7.60 (m, 1H) 7.69-7.80 (m, 3H), - 7.89-7.98 (m, 3H): IR (film) 3500, 2950, 1720 cm "1; Spectrum of maeae (El), m / z 464 Stage 2 N-dodecyl-3- (3-chlorophenyl) -5- (3-trifluoromethyl) -4- (2-hydroxytoxy) -benzamide The product is prepared as a colorless oil (0.241 g, 84%) from 3- (3-chlorophenyl) -5- (3-trifluoromethyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester using a procedure similar to stage 2 of example 1; * H NMR (300 MHz, DMS0-d5) d 0.85 (t, J = 7.5 Hz, 3H), fc 1.20-1.40 (m, 18H), 1.46-1.60 (m, 2H), 3.14 (c, J = 7.5 , 2H), 3. 20-3.30 (m, 4H), 4.45 (t, J = 7 Hz, 1H), 7.50-7.55 (m, 2H), 7.60-7.66 (m, 1H), 7.70-7.80 (m, 3H), 7.90-8.00 (m, 4H), 8.55 (t, J = Hz, 1H); Mass spectrum [(+) ESI], m / z 604/606 (M + H) *.
Step 3: Acid (3 '' -Cloro-5'-dodecyl carbamoyl-3-trifluoromethyl- [1, 1 ', 3', 1"1-tert-enyl-2'-yloxy) -acetic acid The title compound is prepared as an off-white solid (0.104 g, 42%) from N-dodecyl-3- (3-chlorophenyl) -5- (3-trifluoromethyl) -4- (2-hydroxytoxy) -benzamide using a procedure similar to step 3 of example 1; decomposition > 95 ° C; * H NMR (400 MHz, DMS0-d6) d 0.82 (t, J = 7 Hz, 3H), 1. 18-1.35 (m, 18H), 1.45-1.55 (m, 2H), 3.24 (dd, J = 6.8, 12.7 Hz, 2H), 3.64 (S, 2H), 7.42-7.80 (m, 2H), 7.58-7.74 (m, 4H), 7. 84-7.85 (m, 2H), 7.92-7.98 (m, 2H), 8.53 (t, J = 5.5 Hz, 1H); IR (KBr) 3325, 2925, 2850, 1630 cm "1; Spectrum of maeae [(-) ESI], m / z 616 (MH) J- Analysis calculated for C34H39CIF3N04H20: C, 64.19; H, 6.50; N, 2.20 , found: C, 64.12; H, 6.34; N, 2.20.
Example 154 Acid (5 '-Dodecylcarbamoyl-4"-methoxy-3-trifluoromethyl- [1, 1'; 3 ', 1"] ter enyl-2'-yloxy) acetic acid Stage 1 Ethyl 3- (4-methoxyphenyl) -5- (3-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester The product is prepared as a colorless viscous oil (2609 g, 71%) from the ethyl ester of the acid 3-bromo-5- (4-methoxyphenyl) -4- (2-hydroxyethoxy) benzoic using a procedure similar to that of step 1 of example 153; JH NMR (400 MHz, DMSO-d d 1.30 (t, J = 7 Hz, 3H), 3.10 (dd, J = 5.5, 11.2 Hz, 2H), 3.26 (t, J = 6.2 Hz, 2H), 3.80 ( S, 3H), 4.32 (dd, J = 7.04, 14.3 Hz 2H), 4.39 (t, J = 5.5, 1H), 7.02-7.04 (m, 2H), 7.54-7.58 (m, 2H), 7.68-7.8 (m, 2H), 7.88-7.90 (m, 3H), 7.95 (s, 1H), IR (film) 3500, 2950, 1720, 1625, 1525 cm "J- Species of maeas [(+) APCI], m / z 461 (M + H) *.
Step 2 N-dodecyl-3- (4-methoxyphenyl) -5- (3-trifluoromethylphenyl) -4- (2-hydroxy-ethoxy) benzamide The product is prepared as a colorless oil (0.229 g, 89%) from the 3- (4-methoxyphenyl) -5- (3-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester using a similar procedure to stage 2 of example 1; * H NMR (300 MHz, DMSO- d 0.82 (t, J = 7.5 Hz, 3H); 1. 20-1.35 (m, 18H), 1.50-1.58 (m, 2H), 3.10 (c, J = 7 Hz, 2H), 3.20-3.30 (m, 4H), 3.82 (s, 3H), 4.40 ( s, 1H), 7.02-7.08 (m, 2H), 7.55-7.61 (m, 2H), 7.70-7.80 (m, 2H), 7.85-7.90 (m, 2H), 7. 92-7.99 (m, 2H), 8.55 (t, J = 7.5 Hz, 1H), Mass spectrum [(-) ESI], m / z 598 (M-H) ".
Step 3: Acid (5'-Dodecylcarbamoyl-41'-methoxy-3-trifluoromethyl- [1,1'-3 '. 1"1-terphenyl-2'-yloxy) acetic acid The title compound is prepared as an off-white solid (0.101 g, 44%) from N-dodecyl-3- (4-methoxyphenyl) -5- (3-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide using a procedure similar to step 3 of example 1; decomposition, 90-115 ° C; -H NMR (400 MHz, DMSO-ds) d 0.83 (t, J = 7 Hz, 3H), 1.17-1.30 (m, 18H), 1.47-1.52 (m, 2H), 3.22-3.27 (m, 2H) , 3.57 (s, 2H), 3.79 (s, 3H), 6.97-7.01 (m, 2H), 7.55-7.58 (m, 2H), 7. 61-7.72 (m, 2H), 7.76-7.81 (m, 2H), 7.94-7.99 (m, 2H), 8.50 (t, J = 5.5 1H); IR (KBr) 3300, 2925, 2850, 2630 1520 Cm "1; Mass spectrum [(+) ESI], m / z 614 (M + H) * Analysis calculated for C35H42F3N05. 1.33 H20: C, 65.92; H, 7.06; N 2.20, found: C, 65.88; H, 7.09; N, 2.51.
Example 155 Acid (5 '- Pode ci 1 carbamo i 1 - 2' '- f 1 u or r o - 4 -me toxi - [1, 1'; 3 ', 1' '] ter enyl-2' - 'yloxy) acetic Stage 1 N-dodecyl-3- (2-f luorofenyl) -5- (4-methoxy-enyl) -4- (2-hydroxyethoxy) -benzamide The product is prepared as a colorless viscous oil (0.28 g, 82%) from 3- (2-fluorophenyl) -5- (4-methoxyphenyl) -4- (2-hydroxyethoxy) -benzoic acid ethyl ester using a procedure similar to step 2 of example 1; -H NMR (300 MHz, DMS0-de) 6 0.83 (t, J = 7 Hz, 3H), 1.20-1.30 (m, 18H), 1.45-1.55 (m, 2H), 3.01-3.10 (, 2H), 3.20-3.27 (m, 4H), 3.80 (s, 3H), 4.35 (t, J = 6 Hz, 1H), 7.02-7.08 (m, 2H), 7.25-7.34 (m, 2H), 7.45-7.50 ( m, 2H), 7.55-7.60 (m, 2H), 7.74 (d, J = 3 Hz, 1H), 7.87 (d, J = 3 Hz, 1H), 8.50 (t, J = 5 Hz, 1H); Spectrum of masae [(+) ESI], m / z 550 (M + H) *.
Step 2: Acid (5'-Dodecylcarbamoyl -2"-f luoro-4-methoxy-fl.l '; 3' .1" 1-terphenyl-2'-yloxy) acetic The title compound is prepared as a white solid (0.229 g, 47%) from N-dodecyl-3- (2-fluorophenyl) -5- (4-methoxyphenyl) -4- (2-hydroxyethoxy) -benzamide using a procedure similar to step 3 of example 1. The product is purified by preparative plate chromatography (4% methanol / EtOAc) followed by flash chromatography (15% EtOAc / Hex and 20% EtOAc / Hex, both with 1% formic acid), - 'HEM (400 MHz, DMSO-d d 0.84 (t, J = 6.8 Hz, 3H), -1.17-1.27 (m, 18H), 1.44-1.51 (m, 2H), 3.22 (dd, J = 6.8, 13.0 Hz, 2H), 3.78 (S, 3H), 3.81 (s, 2H), 6.99-7.02 (m, 2H), 7.23-7.28 m, 2H), 7.42-7.47 (m, 2H), 7.50-7.57 (m , 2H), 7.71 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 8.47 (t, J = 5.5, 1H), 12.48 (broad s, 1H); IR (KBr) 3375, 2925, 2850, 1730, 1615, 1200 cm "1; Mass spectrum [(+) ESI], m / z 564 (M + H) J- Analysis calculated for C34H42FN05: C, 72.44; H 7.51, N, 2.48, found, C, 72.48, H, 7.67, N, 2.46.
Example 156 Acid (3-Bromo-5-dodecylcarbamoyl-2 '-f luoro-bifenyl-2-yloxy) acetic acid Stage 1 N-dodecyl-3-bromo-5- (3-f-fluorophenyl) -4- (2-hydroxyethoxy) -benzamide Prepare? the product as a yellow oil (0.256 g, 78%) from the ethyl ester of 3-bromo-5- (3-f luorofenyl) -4- (2-hydroxyethoxy) -benzoic acid using a procedure similar to that of step 2 of example 1, - "H NMR (300 MHz, DMS0-d5) d 0.82 (t, J = 7.5 Hz, 3H), 1.20-1.35 (m, 18H?, 1.45-1.55 (m, 2H), 3.23 (c, J = 7.5 Hz, 2H), 3.30-3.40 (m, 2H), 3.60 (t, J = 6 Hz, 2H), 4.62 (t, J = 7 Hz, 1H), 7.30-7.38 (m, 2H), 7.45-7.55 (m, 2H), 7.81 (d, J = 2 Hz, 1H), 8.15 (d, J = 2 Hz, 1H), 8.55 ( t, J = 5 Hz, 1H); Spectrum of masae [(+) ESI], m / z 522/524 (M + H) *.
Stage 2 Acid (3-Bromo-5-dodecylcarbamoyl-2'-fluoro-biphenyl-2-yloxy) acetic acid The title compound is prepared as a brown solid from N-dodecyl-3-bromo-5- (3-fluorophenyl) -4- (2-hydroxyethoxy) -benzamide using a procedure similar to that of step 3 of example 1; p.f. 128-138 ° C; "H NMR (400 MHz, DMSO-d 6 0.85 (t, J = 7 Hz, 3H), 1.20-1.30 (m, 18H), 1.45-1.55 (m, 2H), 3.20-3.25 (m, 2H), 3.80 (s, 2H), 7.27-7.32 (m, 2H), 7.44-7.50 (m, 2H), 7.74 (d, J = 2 Hz, 1H), 8.11 (d, J = 2 Hz, 1H), 8.51 (t, J = 5.5 Hz, 1H), IR (KBr) 3300, 2925, 2850, 1625 cm "J- Mass Spectrum [(+) E? I], m / z 536/538 (M + H) * Analysis calculated for C27H35BrFN04 2.5H20: C, 55.77; H, 6.93; N, 2.41, found: C, 55.58; H, 6.13; N, 2.40.
Example 157 Acid [4 '' -Metoxy-5 '- (6-phenyl-hexylcarbamoyl) -3-trifluoromethyl- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid Step 1 N- (6-phenylhexyl) -3- (4-methoxyphenyl) -5- (3-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzamide The product is prepared as a yellow gum (0.191 g, 74%) from the 3- (4-methoxyphenyl) -5- (3-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester and 6-phenylhexylamine using a procedure similar to the stage 2 of example 1; JH NMR (300 MHz, DMS0-d £) 6 1.27-1.38 (m, 4H), 1.47-1.60 (m, 4H), 2.55 (t, J = 7.5 Hz, 2H), 3.10 (c, J = 7 Hz , 2H), 3.20-3.30 (m, 4H), 3.80 (S, 3H), 4.38 (t, J = 6 Hz, 1H), 7.01-7.08 (m, 2H), 7.10-7.18 (m, 3H), 7.23-7.26 (m, 2H), 7.55-7.60 (m, 2H), 7.68-7.78 (m, 2H), 7.83-7.88 (m, 2H), 7.91-7.96 (m, 2H), 8.55 (t, J = 4 Hz, 1H); Mass spectrum [< +) ESI], m / z 592 (M + H) *.
Step 2 f4 '' - Methoxy-5 '- (6-phenyl-hexylcarbamoyl) -3-trifluoromethyl-fl.1', -3 ', 1"1-terphenyl-2'-yloxy) acetic acid The title compound is prepared as a white solid (0.067 g, 35%) from N- (6-phenylhexyl) -3- (4-methoxyphenyl) -5- (3-trifluoromethylphenyl) -4- (2 - hydroxyethoxy) benzamide using a procedure similar to step 3 of example 1. The product is purified using chromatography on the preparation plate (40% EtOAc / Hex with 1% formic acid), - m.p. 153-159 ° C; Jl NMR (400 MHz, DMSO-d d 1.30-1.38 (m, 4H), 1.49-1.61 (m, 4H), 2.56 (t, J = 7.5 Hz, 2H), 3.24-3.30 (m, 2H), 3.82 (S, 3H), 3.84 (s, 2H), 7.02-7.07 (m, 2H), 7.12-7.19 (m, 3H), 7.22-7.27 (m, 2H), 7.55-7.59 (m, 2H), 7.68 -7.78 (m, 2H), 7.85 (dd, J = 2.2, 5.7 Hz, 2H), 7.91 (d, J = 7.7, 1H), 7.97 (s, 1H), 8.56 (t, J = 5.7 1H), 12.60 (s broad, 1H), - IR (KBr) 3350, 2925, 1725, 1614 cm "1; Mass spectrum [(+) APCI], m / z 606 (M + H) J- Analysis calculated for C35H34F3NOs: C, 69.41; H, 5.66; N, 2.31, found: C, 69.25; H, 5.68; N, 2.24.
Example 158 Acid [4 '' -Metoxy-5 '- (8-f-enyl-octylcarbamoyl) -3-trif-loromethyl- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid Step 1 N- (8-f-enyloctyl) -3- (4-methoxy-enyl) -5- (3-trifluoromethyl) -4- (2-hydroxyethoxy) benzamide The product is prepared as a yellow viscous oil (0.165 g, 61%) from the 3- (4-methoxyphenyl) -5- (3-trifluoromethylphenyl) -4- (2- hydroxyethoxy) enzoic and 8-phenyloctylamine using a procedure similar to step 2 of example 1; JH NMR (300 MHz, DMSO-d £) d 1.21-1.34 (tn, 8H), 1.45-1.58 (, 4H), 2.50 (t, J = 7.5 Hz, 2H), 3.10 (c, J = 6 Hz, 2H), 3.20-3.30 (m, 4H), 3.80 (s, 3H), 4.38 (t, J = 6 Hz, 1H), 7.01-7.05 (m, 2H), 7.10-7.25 (m, 5H), 7.60 (d, J = 9 Hz, 2H), 7.68-7.78 (m, 2H), 7.84-7.88 (m, 2H), 7.90-7.95 (m, 2H), 8.54 (t, J = 5 Hz, 1H); Mass spectrum [(+) ESI], m / z 620 (M + H) *.Step 2: [4 '' - Methoxy-5 '- (8-phenyl-octylcarbamoyl) -3-trifluoromethyl- [1,1; , -3 ', i' '1 -terphenyl-2'-yloxyl acetic The title compound is prepared as a white solid (0.61 g, 42%) from N- (8-phenyloctyl) -3- (4-methoxyphenyl) -5- (3-trifluoromethylphenyl) -4- (2-hydroxyethoxy) ) -benzamide using a procedure similar to step 3 of example 1. The product is purified by flash chromatography (20% EtOAc / Hex with 1% formic acid) and then by preparative plate chromatography (40% EtOAc / Hex with 1% formic acid); p.f. 139-144 ° C; * H NMR (400 MHz, DMS0-d6) d 1.21-1.30 (m, 8H), 1.45- 1.58 (m, 4H), 2.52 (t, J = 7.2, 2H), 3.24-3.28 (m, 2H), 3.80 (s, 3H), 3.82 (s, 2H), 7.01-7.05 (m, 2H), 7.11-7.17 (, 3H), 7. 20-7.25 (m, 2H), 7.53-7.58 (m, 2H), 7.66-7.76 (m, 2H), 7.83 (dd, J = 2.4, 5.9 Hz, 2H), 7.90 (d, J = 7.7 Hz, 1H), 7.96 (s, 1H), 8.54 (t, J = 6 Hz, 1H), 12.60 (broad s, 1H); IR (KBr) 3350, 2940, 1725, 1200, 1125, 1615 cm "1; Mass spectrum [(+) APCI], m / z 634 (M + H) J- Analysis calculated for C37H3ßF3N05: C, 70.13; H , 6.04; N, 2.21, found: C, 69.80; H, 6.14; N, 2.20.
Example 159 Acid (3,4,3", 5" -Tetrachloro-5'-dodecylcarbamoyl- [1,1 '; 3', 1"] terphenyl-2'-yloxy) acetic acid Stage 1 N-dodecyl-3,5-bis (3,5-dichlorophenyl) -4- (2-hydroxyethoxy) benzamide The product is prepared as a yellow oil (0.468 g, 91%) from the 3,5-bis (3,5-dichlorofenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester using a procedure similar to stage 2 of example 1; -H NMR (300 MHz, DMSO-dj) 6 0.84 (t, J = 7 Hz, 3H), 1.20-1.35 (m, 18H), 1.45-1.55 (m, 2H), 3.15-3.25 (m, 2H) , 3.25-3.30 (m, 4H), 4.51 (broad s, 1H), 7.65 (, 2H), 7.74 (d, J = 2 Hz, 4H), 7.92 (s, 2H), 8.77 (t, J = 6 Hz, 1H): Mass spectrum [(-) ESI], 636 (MH) ".
Step 2 Acid (3.5.3 '', 5 '' -Tetrachlor-5 '-dodecylcarbamoyl-fl.1'; 3 '.1' '1-terphenyl-2'-yloxy) acetic The title compound is prepared as an off-white solid (0.151 g, 32%) from N-dodecyl-3, 5- £ > is (3,5-dichlorophenyl) -4 - (2-hydroxyethoxy) benzamide using a procedure similar to step 3 of Example 1. The product is purified by preparative plate chromatography (20% EtOAc / Hex with 1% formic acid ); p.f. 139-144 ° C; LH NMR (400 MHz, DMSO-ds) 6 0.85 (t, J = 7 Hz, 3H), 1. 18-1.34 (m, 18H), 1.48-1.56 (m, 2H), 3.28 (c, J = 6.6 Hz, 2H), 3.88 (S, 2H), 7.67 (t, J = 2 Hz, 2H), 7.72 (d, J = 2 Hz, 4H), 7.91 (s, 2H), 8.58 (t, J = 5 Hz, 1H), 12.74 (broad s, 1H); IR (KBr) 3370, 2940, 2670, 1725, 1600, 1560, 1200 cm " Analieis calculated for C33H37C14N04: C, 60.66; H, 5, 71; N, 2.14, found: C, 60.78; H, 5.55; N, 2 .08.
Example 160 Acid [3, 5, 3 '', 5 '' - Tetrachlor-5 '- (8-enyl-octylcarbamoyl) - [1, 1'; 3 ', 1"] terf enyl-2'-yloxy] acetic acid Step 1 N- (8-O-phenylphenyl) -3,5 '-bis (3,5-dichlorophenyl) -4- (2-hydroxyethoxy) benzamide The product is prepared as a colorless and loamy oil (0.444 g, 84%) from the 3,5-iis (3,5-dichlorophenyl) -4- (2-hydroxyethoxy-benzoic acid ethyl ether using a procedure similar to step 2 of example 1; "H NMR (3 C MHz, DMS0-d6) d 1.28 (broad s, 8H), 1.45-1.60 (m, 4H), 2.54 (t, J = Hz, 2H), 3.18 ( e broad, 2H), 3.22-3.40 (m, 4H), 4.52 (broad s, 1H), 7.10-7.25 (m, 5H), 7.65 (m, 2H), 7.70 (d, J = 2Hz, 4H), 7.92 (s, 2H), 8.55 (t, J = 4 Hz, 1 HOUR); Mass Spectrum [(-) ESI], m / z 656 (M-H) ".
Step 2: Acid [3,5,3 '', 5"-Tetrachlor-51 - (8-phenyl-octylcarbamoyl)-fl.1 ', -3', 1"] terphenyl-2'-yloxyl acetic The title compound is prepared as a white solid (0.161 g, 36%) from N- (8-octylphenyl) -3,5-i > is (3,5-dichlorophenyl) -4- (2-hydroxyethoxy) benzamide and 8-phenyloctylamine using a procedure similar to step 3 of example 1. The crude product is purified as follows: flash chromatography (EtOac 10% / Hex with formic acid 1%), chromatography on a preparation plate (30% EtOAc / Hex with formic acid 1%), chromatography on preparation (EtOAc), chromatography instantaneous (EtOAc 20% / Hex with formic acid 1%); p.f. 139-149 ° C, solidifies and melts again 175-178 ° C; XH NMR (400 MHz, DMSO-ds) d 1.22-1.32 (, 8H), 1.46-1.57 (m, 4H), 2.53 (t, J = 7.5, 2H), 3.26 (c, J = 6.6, 2H), 3.88 (s, 2H), 7.11-7.16 (m, 3H), 7.21-7.26 (, 2H), 7.66 (t, J = 2 Hz, 2H), 7.69 (d, J = 2 Hz, 4H), 7.89 (s, 2H), (t, J = . 5 Hz, 1H), 12.75 (broad s, 1H); IR (KBr) 3375, 2910, 2850, 1715, 1605, 1560, 1200 cm ' Mass spectrum [(-) ESI], m / z 670 (M-H) "Analysis calculated for C35H33C14N04: C, 62.42; H, 4.94; N, 2.08, found: C, 62.24; H, 4.95; N, 2.01.
Example 161 Acid [3, 5, 3 '', 5 '' - Tetrachlor-5 '- (6-phenyl-hexicarbamoyl) - [1,1'; 3 ', 1' '] terphenyl-2'-yloxy] acetic acid Step 1 N- (6-hexylphenyl) -3,5 '-bis (3,5-dichloro nyl) -4- (2-hydroxyethoxy) benzamide The product is prepared as a colorless oil (0.41 g, 81%) from 3,5-bis (3,5-dichlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester and 6-phenylhexylamine- using a procedure similar to stage 2 of the example 1; JH NMR (300 MHz, DMSO-d6) d 1.25-1.40 (m, 4H), 1.46-1.61 (m, 4H), 2.55 (t, J = 7.5 Hz, 2H), 3.16 (c, 6 Hz, 2H) , 3.22-3.30 (m, 4H), (t, J = 5 Hz, 1H), 7.12-7.25 (m, 5H), 7.65 (m, 2H), 7.77 (d, J = 2 Hz, 4H), 7.90 (e, 2H), (t, J = 5 Hz, 1 HOUR); Spectrum of masae [(+) APCI], m / z 630 (M + H) * ".
Step 2: Acid [3, 5, 3 '', 5 '' - Tetrachlor-51 - (6-phenyl-hexycarbamoyl) - fl, 1 ', -3'. 1 '' 1-terphenyl-2'-yloxy-1-acetic acid The title compound is prepared as a white solid (0.228 g, 56%) from N- (6-hexylphenyl) -3, 5- £ > is (3,5-dichlorofenyl) -4- (2-hydroxyethoxy) benzamide using a procedure similar to step 3 of Example 1. The crude product is first purified by preparative plate chromatography (EtOAc 80% / Hex) and then by flash chromatography (EtOac 20% / Hex with formic acid 1%), mp 151-159 ° C; * H NMR (400 MHz, DMSO-ds) d 1.27-1.36 (m, 4H), 1.46-1.60 (m, 4H), 2.55 (t, J = 7.5, 2H), 3.23-3.28 (m, 2H), 3.88 (s, 2H), 7.11-7.17 (m, 3H), 7.21-7.60 (m, 2H), 7.66 (t, J = 2 Hz, 2H), 7.70 (d, J = 2 Hz, 4H), 7.89 (s, 2H), 8.57 (t, J = 5.3 Hz, 1H), 12.75 (broad s, 1H); IR (KBr) 3375, 2940, 1750, 1610, 1560, 1200, 800 crn "1; Mass spectrum [(-) ESI], m / z 642 (MH) J- Analysis calculated for C33H2SC14N04: C, 61.41; H , 4.53; N, 2.17, found: C, 60.95; H, 4.44; N, 2.17.
Example 162 Acid [3, 3 '' -Dichloro-5 '(4-heptyloxy-benzylcarbamoyl) - [1, 1', -3 ', 1' '] terphenyl-2'-yloxy] acetic acid Stage 1 4- (heptyloxy) benzamide 4- (Hexyloxy) benzoic acid (7.089 g, 30 mmol) in 50 ml of S0C12 is refluxed for 19 h. After refluxing, the mixture is concentrated in vacuo.
The residue is dissolved in Et20 and added dropwise in a saturated solution of NH3 (g) in Et20 at -50"C. After stirring at room temperature overnight, the reaction mixture is concentrated in vacuo and the residue is evaporated. triturate with water and dry The white solid recrystallizes from ethyl acetate to give the desired product (6.15 g, 87%), mp 149-152 ° C; * H NMR (400 MHz, DMS0-de) d 0.87 (t, J = 6.8, 3H), 1.23-1.45 (m, 8H), 1.67-1.75 (m, 2H), 4.01 (t, J = 6.6, 2H), 6.94-6.97 (m, 2H), 7.16 ( s, 1H), 7.79-7.85 (m, 3H), - M * & ^ IR (KBr) 3375, 3170, 2900, 1650, 1605, 1400, 1260, 1175, 625 cm "J- f Mass spectrum [(+ JESI], m / z 236 (M + H) *.
Stage 2 4- (heptyloxy) benzylamine To a stirred suspension of lithium aluminum hydride (1928 g, 52.23 mmol) in 150 mL of THF at room temperature under nitrogen, a suspension of 4-f-10 (heptyloxy) benzamide (6,146 g, 26,117 mmol) is added. After refluxing for 22 h, the reaction is cooled in an ice bath and suspended in the following order: 2.09 ml of water, 2.09 ml of 15% NaOH and 6.26 ml of water. The mixture is stirred for 3 h followed by the addition of Na 2 SO 4. The mixture is filtered and concentrated in vacuo. The residue is taken up in Et20, filtered, concentrated and the remaining residue is taken up in hexane, filtered, concentrated and dried to give the desired product as an opalescent yellow oil (4872 g, 84%); 20 Jl NMR (400 MHz, DMSO-de) 6 0.86 (t, J = 7 Hz, 3H), 1. 22-1.42 (m, 8H), 1.64-1.72 (m, 2H), 1.82 (broad s, 2H), 3.13 (S, 2H), 3.89 (t, J = 6.6 Hz, 2H), 6.80-6.84 (m , 2H), 7.17-7.21 (m, 2H), - IR (film) 2940, 2850, 1510, 1250 cm "J- 25 Mass spectrum [(+) ESI], m / z 222 (M + H) * .
Step 3: Acid [3, 3 '' - Dichloro-5 '(4-heptyloxy-benzylcarbamoyl) - [1,1', -3 ', 1' '] terphenyl-2'-ylyl-acetic acid The title compound is prepared as an off-white solid (0.199 g, 29%) from the ethyl ether of acid 3, 5- £ > is (3-chlorophenyl) -4- (2-hydroxyethoxy) benzoic using a procedure similar to steps 2 and 3 of Example 1. The crude product is first purified by preparative plate chromatography (EtOAc) and deepuée by flash chromatography. (20% EtOAc, 40%, 70% / Hex with 1% formic acid); decomposition 170-175 ° C; * H NMR (400 MHz, DMS0-ds) d 0.85 (t, J = 6.8, 3H), 1.23-1.41 (m, 8H), 1.63-1.71 (m, 2H), 3.84 (e, 2H), 3.91 ( t, J = 6.4 Hz, 2H), 4.41 (d, J = 5.93 Hz, 2H), 6.84-6.87 (m, 2H), 7.20-7.24 (m, 2H), 7.44-7.50 (m, 4H), 7.56 -7.59 (m, 2H), 7.69 (m, 2H), 7.91 (s, 2H), 9.08 (t, J = 5.9 Hz, 1H) 12.65 (broad s, 1H); IR (KBr) 3440, 3310, 1910, 1725, 1610, 1520, 1250, 1200 cm1; Mass Spectrum [(+) APCI], m / z 620 (M + H) *; Analysis calculated for C3SH35C12N05: C, 67.74; H, 5.68, -N, 2.26, found: C, 67.62; H, 5.69; N, 2.22.
Example 163 8- [(2'-Carboxymethoxy-3,3"-dichloro- [1,1 '; 3', 1 ''] terphenyl-5'-carbonyl) -amino] -octanoic acid methyl ester Stage 1 8-amino-octanoic methyl ester To 15 ml of methanol under nitrogen, stirred at -5 ° C, 0.80 ml of thionyl chloride are added dropwise. After 5 minutes, 8-aminooctanoic acid (1592 g, 10 mmolee) is added. The reaction is stirred at -5 ° C for 1 h, at room temperature during < 5 minutes at 40 ° C for 2.25 h After heating, the reaction mixture is concentrated, the residue is taken up in chloroform / water (40 ml / 25 ml) and made basic at pH 9-10 using IN NaOH. The layers are shaken, separated and the aqueous layer is washed with water (2 x 30 ml) The combined organic fractions are dried over Na 2 SO 4 and filtered The filtrate is concentrated m vac and dried to give the product as a solid oil (1.568 g, 90%); 'H NMR (400 MHz, DMSO-d6) d 1.17-1.33 (m, 8H), 1.43- 1.52 (m, 2H), 2.26' t, J = 7.5 Hz, 2H) , 2.44-2.49 (m, 2H), 3.55 (S, 3H); IR (film) 3475, 2930, 2850, 1730 cm "1; Mass spectrum [El], m / z 173 M *.
Stage 2, 3,5-bis (3-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid To a stirred solution of 3,5-bis (3-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ester (2,009 g, 4,658 mmoles) in 30 ml of THF 15 ml of ethanol is added 9.32 ml of KOH IN After 20 h, the reaction is concentrated in vacuo The residue is diluted with 40 ml of water and acidified with 9.32 ml of 2N HCl, After 2 h, the eolids are collected, rinsed with water, dissolved in EtOAc, dried over Na 2 SO 4, filtered, concentrated in vacuo and the residue dried to provide the desired product as a white solid (1,708 g, 91%), - mp 184-192 (partial melt) solidified and melted at 200-202. ° C; "H NMR (400 MHz, DMS0-d6) d 3.12 (c, J = 4 Hz, 2H), 3. 28 (t, J = 4 Hz, 2H), 4.45 (t, J = 4 Hz, 1H), 7.45-7.60 (m, 6H), 7.70 (s, 2H), 7.91 (s, 2H), 13.10 (s) , 1 HOUR) .
Step 3 N- (8-octanoic acid methyl ester) -3,5-bis (3-chlorophenyl) -4- (2-hydroxyethoxy) benzamide A mixture of acid 3, 5- £ > is (3-chlorophenyl) -4- (2-hydroxyethoxy) benzoic acid (0.565 g, 1.4 mmol), 8-amino octanoic acid methyl ethyl (0.364 g, 2.1 mmol), Et3N (0.59 mL, 4.2 mmol), 1- hydroxybenzotriazole (0.208 g, 1.54 mmolee), and 1,3-dicyclohexycarbodiimide (0.347 g, 1.68 mmole) in 16 ml of methylene chloride is stirred under nitrogen at room temperature. After ~20 h, the reaction mixture is concentrated in vacuo. The residue is taken up in EtOAc, stirred and filtered. The filtrate is washed with IN HCl (3 x 15 ml), NaHCO 3 (3 x 15 ml), brine (2 x 15 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (25%, 60% EtOAc / Hex) to provide the desired product as a viscous oil (0.475 g, 61%); "H NMR (400 MHz, DMS0-d5) 6 1.22-1.33 (m, 6H), 1.47- 1.55 (m, 4H), 2.28 (t, J = 7.5 Hz, 2H), 3.13 (t, J = 5.9 Hz , 2h), 3.23-3.30 (m, 4H), 3.56 (s, 3H), 4.43 (s broad, 1H), 7.46-7.53 (m, 4H), 7.59-7.62 (m, 2H), 7.71 (m, 2H), 7.88 (s, 2H), 8.65 (t, J = 5.5 Hz, 1H), Mass spectrum [< +) E? I], m / z 558 M *.
Step 4: 8-f (2'-Carboxymethoxy-3,3"-dichloro fl, 1 ', - 3', 1"] terfenyl-5'-carbonyl) -aminol-octanenoic acid methyl ester The title compound is prepared as a white solid (0.221 g, 46%) from N- (8-octanoic acid methyl ester) -3,5-bis (3-chlorophenyl) -4- (2-hydroxyethoxy) benzamide and 8-amino-octanoic acid methyl ester using a procedure similar to step 3 of example 1. The crude product is purified by preparative plate chromatography. (10% MeOH / EtOAc) and then subjected to flash chromatography (25% EtOAc / Hex with 1% formic acid), -decomposition 131-133 ° C; * H NMR (400 MHz, DMSO-d6) 6 1.20-1.32 (m, 6H), 1.46-1.55 (m, 4H), 2.27 (t, J = 7.5 Hz, 2H), 3.25 (dd, J = 6.8, 13.0, 2H), 3.55 (s, 3H), 3.85 (s, 2H), 7.45-7.52 (m, 4H), 7.56-7.59 (m, 2H), 7.68 (s, 2H), 7.86 (s, 2H) , 8.56 (t, J = 5.7 Hz, 1H), 12.66 (broad s, 1H); IR (KBr) 3400, 2930, 1740, 1630, 1550, 1450, 1200 cm " Mass Spectrum [(-) ESI], m / z 570 (M-H) "Analysis calculated for C30H31C12N06: C, 62.94; H, 5.46; N, 2.45, found: C, 62.86; H, 5.39; N, 2.38.
Example 164 - [3,3 '' -Dichloro-5 '(8-indol-1-yl-oct-lcarbamoyl) - [1,1'; 3 ', 1"] terphenyl-2'-yloxy] pentanoic acid Step 1 N- (8-? Ndol-l-yl-octyl) -3,5-diiodo-4-hydroxybenzamide A mixture of 3,5-diiodo-4-hydroxybenzoic acid (5.037 g, 5.193 mmol) and 45 ml of thionyl chloride were heated at reflux for 2 h. The reaction mixture is then concentrated in vacuo. The residue is dissolved in THF and added to a solution of 8-indoloctylamine (2,631 g, 10,766) and triethylamine (5.25 ml, 37,681 mmole) at 0 ° C. After the admission, the reaction is stirred at room temperature. After 18 h, the reaction is concentrated in vacuo, the residue is taken up in 200 ml of EtOac and 25 ml of 2N HCl. The layers are shaken, washed and the organic layer is washed with 2N HCl (2 x 25 ml), water (3 x 25 ml) and brine (2 x 25 ml), and dried over Na 2 SO 4. After filtration, the filtrate is concentrated in vacuo and dried to provide the crude product which is purified by flash chromatography (25% EtOAc / Hex) to provide the desired product as a gummy foam (4.022 g, 61%); 'HRMN (300 MHz, DMSO-d £) d 1.22 (broad s, 8H), 1.40-1.50 (m, 2H), 1.68-1.79 (m, 2H), 3.15 (c, J = 7 Hz, 2H), 4.13 (t, J = 7 Hz, 2H), 6.40 (d, J = 3 Hz, 1H), 6.95-7.00 (m, 1H), 7.07-7.12 (m, 1H), 7.32 (d, J = 3 Hz , 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 8.21 (s, 2H), 8.37 (t, J = 4 Hz, 1H), 10.04 (s) , 1 HOUR); Mass Spectrum [(+) ESI], m / z 617 (M + H) *.
Step 2 N- (8-indol-l-yl-octyl) -3,5-bis (3-chlorophenyl) -4-hydroxybenzamide A mixture of N- (8-indol-1-yl-octyl) -3,5-diiodo-4-hydroxybenzamide (4,016 g, 6,517 mmol), 2 M K 2 CO 3 (9.8 ml in water), 100 ml of dioxane, 3-hydroxybenzamide -chlorophenylboronic acid (2,242 g, 1 4. 3 3 6 m m or l s), and [1, 1 'bis (diphenylphenefino) ferrocene] dichloropalladium (II), with CH2C12 (0.106 g, 0.130 mmol) is heated to 66 ° C. After 2 h, the reaction mixture is cooled and concentrated ip vac. The residue is taken up in 200 ml of EtOAc and 50 ml of IN HCl. The layers are shaken, separated and the organic layer is washed with IN HCl (2 x 50 ml), brine (2 x 50 ml), dried over Na 2 SO 4, filtered and the filtrate concentrated in vacuo and dried. The crude product is purified by flash chromatography (alumina, hexane to a gradient of 60% EtOAc / Hex) to give a light yellow foam (3.027 g, 79%); 'HRMN (300 MHz, DMSO-d £) d 1.24 (broad s, 8H), 1.43-1.52 (m, 2H), 1.65-1.75 (m, 2H), 3.16-3.26 (c, J = 7.5 Hz, 2H ), 4.12 (t, J = 7.5 Hz, 2H) 6.38 (d, J = 3 Hz, 1H), 6.94-7.00 (m, 1H), 7.05-7-13 (m, 1H), 7.33 (d, J) = 3 Hz, 1H), 7.40-7.53 (m, 8H), 7.62 (s, 2H), 7.76 (s, 2H), 8.40 (t, J = 5 Hz, 1H), 9.19 (s, 1H); Mass spectrum [< +) ESI], m / z 585 (M + H) *.
Step 3: 5- [3, 3 '' - Dichloro-5 '- (8-indol-1-yl-octylcarbamoyl) - Ti 1' 3 '. 1' '1-terphenyl-2'-yloxy-1-ethyl ester pentanoid A mixture of N- (8-indol-l-yl-octyl) -3,5-bis (3-chlorophenyl) -4-hydroxybenzamide (0.399 g, 0.68 mmolee), K2C03 (0.116 g, 0.84 mmol), and ethyl-bromovalerate (0.17606 g, 0. 84 mmole) in DMF is stirred at room temperature under nitrogen. After ~48 h, the reaction mixture was poured into 40 ml of water and extracted with EtOAc (1 x 20 ml, 4 x 10 ml). The combined layers are washed with water (3 x 10 ml), brine (2 x 10 ml), dried over Na 2 SO 4, filtered and the filtrate concentrated in vacuo and dried. The crude product is purified by flash chromatography (alumina, hexane, 10% and 60% EtOAC / Hex) to propoduce the desired product as a light yellow oil (0.432 g, 86%); 'HEMN (400 MHz, DMS0-d £) 6 1.12-1.30 (m, 15H), 1.44- 1.55 (m, 2H), 1.67-1.76 (m, 2H), 1.92 (t, J = Hz, 2H), 3.16-3.27 (m, 4H), 3.98 (c, J = 7 Hz, 2H), 4.12 (t, J = 7.2 Hz, 2H), 6.38 (d, J = 3.1 Hz, 1H), 6.95-6.99 (m , 1H), 7.06-7.10 (m, 1H), 7.32 (d, J = 3.3 Hz, 1H), 7.40-7.52 (m, 6H), 7.56-7.59 (m, 2H), 7.68 (t, J = 1.8 Hz, 2H), 7.87 (s, 2H), 8.53 (t, J = 5.7 Hz, 1H); IR (film) 3320, 2940, 2950, 1730, 1630, 1540 cm "1; Spectrum c'e masses [(+) APCI], m / z 713 (M + H) *.
Step 4: 5- f3, 3 '' -Dichloro-5 '- (8-indol-l-yl-octylcarbamoyl) - fl, 1' 3 ', 1"1-terphenyl-2'-ylyl-pentanoic acid An ethyl ester mixture of 5- [3,3 '' - D? Chloro-5 '- (8-indoI-1-yl-octylcarbamoyl) - [1, 1' 3 ', 1 ''] terfeml-2 '-lloxy] -pentanoic acid (0.409 g, 0.573 mmol) and 1.15 ml of KOH . 'S ?? sse ....... jígg ^ IN 6 ml of THF and 3 ml of methanol were stirred under nitrogen. After ~18 h, the reaction mixture is concentrated ip vac. The residue is suspended in 25 ml of water and acidified with 1.15 ml of 2N HCl and then extracted with EtOAc (3 x 25 ml). The combined organic fractions are washed with water (3 x 10 ml), brine (2 x 10 ml), dried over Na 2 SO 4, filtered and the filtrate concentrated ip vac and dried. The residue is purified by preparative plate chromatography (50% EtOAc / Hex) to give the title compound as a light yellow foam (0.249 g, 63%); decomposition > 50 ° C; 'HRMN (400 MHz, DMSO-d £) d 1.12-1.32 (m, 12H), 1.44-1.53 (m, 2H), 1.67-1.76 (m, 2H), 1.87 (t, J = 7.0 Hz, 2H) , 3.16-3.27 (m, 4H), 4.12 (t, J = 7.0 Hz, 2H), 6.37-6.38 (m, 1H), 6.94-6.99 (m, 1H), 7.06-7.10 (m, 1H), 7.31 (d, J = 3.1 Hz, 1H), 7.40-7.52 (m, 6H), 7.56-7.59 (m, 2H), 7.66-7.69 (m, 2H), 7.87 (s, 2H), 8.52 (t, J) = 5.7 Hz, 1H), 11.85 (s, 1H); IR (KBr) 3400, 2940, 1710, 1630, 1550, 1220 Crn "1; Spectrum of masae [(+) APCI], m / z 685 (M + H) *; Analysis calculated for C40H42Cl2N2O4: C, 70.07; , 6.17; N, 4.09, found: C, 69.66; H, 6.17; N, 3.85.
Example 165 4- (2- [3,3 '' -Dichloro-5 '- (8-indole-1-yl-octylcarbamoyl) - [1,1': 3 '1' '] terphenyl-2'-yloxy] -ethoxy) benzoic Step 1 N- (8-indol-1-yl-octyl) -3,5-bis (3-chlorophenyl) -4- (2-hydroxyethoxy) -banzamide A solution of N- (8-indol-l-yl-octyl) -3,5-b? S (3-chlorophenyl) -4- (2-hydroxybenzamide (0.205 g, 0.35 mmol) in 2 ml of DMF is added ethylene carbomate (0.039 g, 0.438 mmole) and tetraethylammonium bromide (0.007 g, 0.035 mmole).
The reaction mixture is heated to 140 ° C. After 2.5 h, the reaction mixture is poured into 50 ml of water and extracted with EtOAc (3 x 20 ml). The combined organic fractions are washed with water (3 x 10 ml), brine (2 x 10 ml), dried over Na 2 SO 4, filtered and the filtrate is concentrated in vacuo and dried. The residue is purified by preparative plate chromatography (50% EtOAc / Hex) to give the product as a yellow viscous oil (0.185 g, 84%); "H NMR (300 MHz, DMS0-d £) d 1.25 (broad s, 8H), 1.44-1.55 (m, 2H), 1.65-1.77 (m, 2H), 3.07-3.17 (m, 2H), 3.20- 3.30 (m, 4H), 4.14 (t, J = 7.5 Hz, 2H), 4.44 (broad e, 1H), 6.38 (d, J = 3 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H) , 7.09 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 3 Hz, 1H), 7.40-7.52 (m, 6H), 7.56-7.65 (m, 2H), 7.70 (e, 2H), 7.88 (s, 2H), 8.54 (t, J = 4 Hz 1H); Mass spectrum [(+) ESI], m / z 629 (M + H) *.
Step 2: 4-12-f3, 3"-Dichloro-5 '- (8-indol-1-yl-octylcarbamoyl) - [1,1': 3 '1" 1-terphenyl-2'-yloxy] methyl ester -etoxi} benzoic A mixture of N- (8-indol-l-yl-octyl) -3,5-bis (3-chlorophenyl) -4- (2-hydroxyethoxy) benzinamide (0.175 g, 0.278 mmol), methyl 4-hydroxybenzoate ( 0.063 g, 0.417 mmol), triphenylphosphine (0.109 g, 0.417 mmol), and DEAD (0.073 g, 0.417 mmol) in 4 mL of THF, is stirred under nitrogen. After ~18 h, the reaction mixture was concentrated ip vac and purified by preparative plate chromatography (2x) (30% EtOAc Hex) to give the product as a yellow glass-like solid (0.132 g, 62%); -H NMR (400 MHz, DMSO-d £) d 1.15-1.30 (m, 8H), 1.45-1.53 (m, 2H), 1.67-1.76 (m, 2H), 3.21-3.27 (m, 2H), 3.55 -3.60 (m, 2H), 3.72-3.76 (m, 2H), 3.79 (e, 3H), 4.13 (t, J = 7.0 Hz, 2H), 6.38 (dd, J = 0.66, 2.48 Hz, 1H), 6.68-6.72 (m, 2H), 6.94-6.99 (m, 1H), 7.06-7.10 (m, 1H), 7.32 (d, J = 3.1 Hz, 1H), 7.38-7.46 (m, 5H), 7.48- 7.52 (m, 1H), 7.57-7.60 (m, 2H), 7.66-7.68 (m, 2H), 7.78-7.82 (m, 2H), 7.88 (s, 2H), 8.55 (t, J = Hz, 1H ); IR (KBr) 3400 (broad), 2920, 1720, 1630, 1600, 1260 cm Mass spectrum [(+) APCI], m / z 763 (M + H) *.
Step 3: Acid 4- (2-Í3, 3 '' -Dichloro-5 '- (8-indol-l-yl-octylcarbamoyl) -fl.l': 3'1"1-terphenyl-2'-yloxy-1-ethoxy )benzoic The title compound is prepared as a light green solid (0.073 g, 62%) from the methyl ester of Stage 2 acid 4 -. { 2 - [3, 3"-Dichloro-5 '- (8-indol-1-yl-octylcarbamoyl) - [1,1': 3'1"] terphenyl-2'-yloxy] -ethoxy} benzoic using a procedure similar to step 4 of the example 165; decomposition > 65 ° C; 1 H NMR (400 MHz, DMSO-d £) d 1.16-1.30 (m, 8H), 1.44-1.53 (m, 2H), 1.67-1.76 (m, 2H), 3.20-3.26 (m, 2H), 3.56- 3.60 (m, 2H), 3.72-3.76 (m, 2H), 4.12 (t, J = 7.0 Hz, 2H), 6.37 (dd, J = 0.66, 3.1 Hz, 1H), 6.66-6.70 (m, 2H), 6.94-6.99 (m, 1H), 7. 06-7.10 (m, 1H), 7.32 (d, J = 3.1 Hz, 1H), 7.38-7.52 (m, 6H), 7.57-7.60 (m, 2H), 7.67 (t, J = Hz, 2H), 7.76-7.80 (m, 2H), 8. 55 (t, J = 5.7 Hz, 1H), 12.54 (broad s, 1H); IR (KBr) 3420, 2920, 1680, 1600, 1260, 1160 cm "1; Mass spectrum [(-) APCI], m / z 747 (MH) j- Analysis calculated for C44H42C12N205: C, 70.49; H, 5.65; N, 3.74, found: C, 70.12; H, 6.01; N, 3.44.
Example 166 Ester 6- [(2-carboxymethoxy-3,3 [beta]] -dichloro- [1, 1 ': 3' 1 ''] terphenyl-5'-carbonyl) -amino-hexyl 4-methoxybenzoic acid Stage 1 4-methoxybenzoic acid 6-bromohexyl ester ^ fc To a stirred solution of 6-bromo-l-hexanol (1086 g, 6 min) in 8 ml of THF is added p-anisoyl chloride 5 (1.228 g, 7.2 mmol) followed by triethylamine (0.911 g, 9 mmolee ). After ~ 6 o'clock, the mixture is concentrated in vacuo. The residue is taken up in EtOac and washed with water (3 x 10 ml), brine (2 x 10 ml), dried over Na 2 SO 4, filtered and the filtrate concentrated in vacuo and dry. The residue is purified V 10 by flash chromatography (2%, 50% EtOAc / Hex to give the dried product as a colorless oil (1,405 g, 74%); H NMR (400 MHz, DMS0-d6) 6 1.36-1.47 (m, 4H), 1.65-1.73 (m, 2H), 1.77-1.84 (m, 2H), 3.52 (t, J = 6.6 Hz, 2H), 3.82 15 (e, 3H), 4.21 (t, J = 6.6 Hz, 2H), 7.01-7.05 (m, 2H), 7.88-7.92 (m, 2H), IR (film) 2930, 1710, 1605, 1510, 1260 cm "1; fc Mass spectrum [El], m / z 314 (M *).
Stage 2 6-Azidohexyl Ester of 4-methoxybenzoic acid A mixture of 6-bromohexyl ester of 4-methoxybenzoic acid (1384 g, 4,391 mmol) and eodium azide (1427 g, 21,954 mmol) in 15 ml of DMF is stirred at room temperature. environment under nitrogen. After 4 h the reaction mixture it is poured into 100 ml of water and extracted with EtOAc (4 x 10 ml). The combined organic fractions are washed with water ((3 x 15 ml), brine (2 x 15 ml), dried over Na 2 SO 4, filtered and the filtrate is concentrated in vacuo and the residue is purified by inantantial chromatography ( 3% EtOAc / Hex) to provide the desired product as a colorless oil (1136 g, 93%); * H NMR (4GC MHz, DMS0-d £) d 1.36-1.44 (m, 4H), 1.51-1.58 (m , 2H), 1.66-1.72 (m, 2H), 3.31 (t, J = 6.8 Hz, 2H), 3.82 (e, 3H), 4.21 (t, J = 6.6 Hz, 2H), 7.01-7.05 (m, 2H), 7.88-7.92 (m, 2H); IR (film) 2940, 2100, 1720, 1605, 1520, 1260 cm "1, - Mass spectrum [(+) ESI], m / z 278 (M + H ) * Stage 3 6-amhexyl ester of 4-methoxyabenzoic acid A mixture of the 6-azidohexyl ester of 4-methoxybenzoic acid (1119 g, 4.035 mmol), triphenyl-phe- phine (1164 g, 4439 mmol) and 0.08 mL of water in THF is stirred under nitrogen at room temperature. After ~ 144 h, the reaction mixture is diluted with 50 ml of EtOAc, dried over Na 2 SO 4, filtered and the filtrate concentrated in vacuo and dried. The residue is purified by flash chromatography (2x) (alumina, chloroform to 10% MeOH / CHC13, as gradient) to »* -. provide the desired product as a light yellow oil (0.0796 g, 78%); * H NMR (400 MHz, DMSO-d £) d 1.18-1.40 (m, 6H), 1.63-1.71 (m, 2H), 2.50 (t, J = 6.4 Hz, 2H), 3.82 (e, 3H), 4.21 (t, J = 6.6 Hz, 2H), 7.01-7.06 (m, 2H), 7.87-7.92 (m, 2H); IR (KBr) 3410 (broad), 2940, 1710, 1605, 1510, 1260 cm "1, - Mass spectrum [(+ ESI)], m / z 252 (M + H) *.
Step 4: Ester 6- f (4-methoxybenzoic acid 4-methoxybenzoic acid 2'-hydroxyethoxy-3,3"-dichloro-fl, 1'-3 ', 1" 1-tert-enyl-5'-carbonyl) -aminol-hexyl The product is prepared as a colorless viscous oil (6.675 g, 71%) from the acid 3.5-¿> (3-Chlorofenyl) -4- (2-hydroxyethoxy) benzoic acid (0.605 g, 1.5 mmol) and 6-amino-hexyl 4-methoxybenzoic acid ester (0.565 g, 2.25 mmol) using a procedure similar to that of stage 3 of example 164; * H NMR (400 MHz, DMSO-d £) 6 1.33-1.46 (m, 4H), 1.50- 1.58 (m, 2H), 1.65-1.73 (m, 2H), 3.10-3.15 (m, 2H) , 3.22-3.30 (m, 4H), 3.80 (s, 3H), 4.21 (t, J = 6.6 Hz, 2H), 4.44 (t, J = 6.6 Hz, 1H), 6.99-7.03 (m, 2H), 7.45-7.52 (m, 4H), 7.57-7.61 (m, 2H), 7.69 (s, 2H), 7.85-7.91 (m, 4H), 8.56 (t, J = 5.5 Hz, 1H); IR (film) 3350, 2940, 1710, 1640, 1605, 1540, 1510, 1275 cm "1, - Maeas spectrum [< +) ESI], m / z 636 (M + H) *.
Step 5: 4- (2-carboxymethoxy-3,3 '' - dichloro- [1,1 ', -3', 1 '' 1-terphenyl-5'-carbonyl) -aminol-4-methoxybenzoic acid hexyl ester The title compound is prepared as a white solid (0.279 g, 42%) from ether 6- [(2'-hydroxyethoxy-3,3"-dichloro- [1,1 ', -3', 1"] terphenyl -5-carbonyl) -amino] -hexyl of 4-methoxybenzoic acid using a procedure similar to that of step 3 of example 1. The crude product is purified by preparative plate chromatography (10% MeOH / CHC13) and then by chromatography Instant (EtOAc % / Hex with formic acid 1%), - decomposition, 129-133 ° C; * H NMR (400 MHz, DMS0-d £) d 1.34-1.46 (m, 4H), 1.50-1.58 (m, 2H), 1.65-1.73 (m, 2H), 3.24-3.35 (m, 2H) , 3.81 (s, 3H), 3.84 (s, 2H) 4.21 (t, J = 6.6 Hz, 2H), 6.99-7.03 (m, 2H), 7.44-7.51 (m, 4H), 7.55-7.58 (m, 2H), 7.67-7.69 (m, 2H), 7.85-7.90 (m, 4H), 8.56 (t, J = 5.5 Hz, 1H), 12.65 (broad s, 1H); IR (KBr) 3340, 2940, 1710, 1605, 1550, 1260, 1170 cm "1; Spectrum of maeae [(+) APCI], m / z 650 (M + H) *; Analysis calculated for C35H33C12N07 • 0. 25H20: C, 64. 17; H, 5 fifteen; N, 2 14, found: C, 63. 92; H, 5 09; N, 2 04 Example 167 Acid [3,3 '' - Dichloro-5 '- (6-hydroxy-hexyl carbamoyl) - [1, 1': 3 '1' '] erphenyl-' -yloxy] acetic acid The title compound is prepared as a white foam (0.61 g, 46%) from the 6- [(2 '-carboxymethoxy-3,3"-dichloro- [1,1': 3'1 ''] ester] 4-methoxybenzoic acid-4-methoxycarbonyl) -amino] -hexyl using a procedure similar to that of step 4 of Example 165. The crude product is purified by preparative chromatography (3x): first with 10% MeOH / CHC13, the second place with 30% EtOAc / Hex and 1% formic acid, and third with EtOAc: decomposition > 65 ° C; * H NMR (400 MHz, DMS0-d £) 6 1.26-1.33 (m, 4H), 1.35-1.44 (m, 2H), 1.46-1.55 (m, 2H), 3.21-3.38 (m, 4H) , 3.84 (s, 2H), 4.32 (t, J = 5 Hz, 1H), 7.44-7.51 (m, 4H), 7.56-7.59 (m, 2H), 7.68-7.70 (m, 2H), 7.86 (s) , 2H), 8.56 (t, J = 5 Hz, 1H), 12.65 (broad s, 1H); IR (KBr) 3340, 2940, 1740, 1640, 1540, 1450, 1210 cm "1; Mass spectrum [< -) E? I], m / z 514 (M-H)", - Analcale calculated for C27H27Cl2NO50 .5H2O-0. 15EtOAc: C, 61.21; H, 5.46; N, 2 60, found: C, 61.36; H, 5.46; N, 2 51 Example 168 Acid (2- [3,3 '' -Dichloro-5 '- (8-indol-l-yl-octylcarbamoyl) - [1,1': 3'1 ''] terphenyl-2'-yloxy] -ethoxy] acetic Step 1 (2- [3,3 '' - Dichloro-5 '- (8-indol-1-yl-octylcarbamoyl) -fl.l': 3 '1"1-phenyl-2'-yloxy-ethoxylacetic acid methyl ester To a stirred solution of N- (8-indol-1-yl-octyl) -3,5-bis (3-chlorophenyl) -4- (2-hydroxyethoxy) benzamide (0.629 g, 1 mmol) in 10 ml of THF under nitrogen at room temperature, hydride of eodium (0.055 g, 2.3 mmol). The mixture is refluxed for 45 minutes, cooled and methyl bromoacetate (0.189 g, 1.2 mmol) and 15-crown-5 ether (0.022 g, 0.1 mmol) and tetrabutylammonium iodide (0.037 g, 0. 1 mmol). The mixture is refluxed. After 6 h, the reaction mixture is suspended with water and then diluted with 100 ml of water and extracted with EtOAc. This provides a thick emulsion which is removed by acidifying the mixture with IN HCl. The combined layers are washed with water (2 x 15 ml), brine (2 x 15 ml), dried over Na 2 SO 4, filtered and the filtrate concentrated ip vac and dried. The residue is purified by flash chromatography (15%, 20% EtOAc / Hex) and the preparation plate chromatography (50% EtOAc / Hex) to provide the desired product as a viscous, opaque oil (0.400 g, 57%); aH NMR (400 MHz, DMSO-ds) d 1.16-1.31 (m, 8H), 1.45-1.53 (m, 2H), 1.68-1.76 (m, 2H), 3.20-3.26 (m, 4H), 3.45-3.48 (m, 2H), 3.58 (s, 3H), 3.71 (e, 2H) 4.12 (t, J = 6.8 Hz, 2H), 6.37 (dd, J = 0.8, 3.1 Hz, 1H), 6.95-6.99 (m , 1H), 7.06-7.10 (m, 1H), 7.32 (d, J = 3.1 Hz, 1H), 7.40-7.52 (m, 6H), 7.57-7.60 (m, 2H), 7.67-7.70 (m, 2H ), 7.78 (s, 2H), 8.52 (t, J = 4.83 Hz, 1H); IR (film) 3300, 2800, 1750, 1630, 1540, 1470, 1220 cm "1; Mass spectrum [< +) APCI], m / z 701 (M + H) *.
Stage 2 Acid. { 2- [3.3 '' -Dichloro-5 '- (8-indol-l-yl-oc ilcarbamoyl) - fl. l ': 3' 1 '' 1 terf enyl -2 '-i loxi 1 -ethoxy I acetic The title compound is prepared as a white foam (0.172 g, 47%) from the methyl ester of the acid. { 2- [3, 3 '' -Dichloro-5 '- (8-indol-l-yl-octylcarbamoyl) - [1, 1': 3 '1"] terf enyl-2'-yloxy] -ethoxy-acetic acid using a procedure similar to that of step 4 of example 165; deecomposition > 50 ° C; -H NMR (400 MHz, DMSO-d £) d 1.16-1.32 (m, 8H), 1. 44-1.53 (m, 2H), 1.67-1.76 (m, 2H), 3.17-3.42 (m, 6H), 3.61 (e, 2H), 4.12 (t, J = 7 Hz, 2H), 6.37 ( d, J = 3.1 Hz, 1H), 6. 95-6.99 (m, 2H), 7.06-7.10 (m, 2H), 7.32 (m, 1H), 7.32 (m, 1H), 7.41-7.55 (m, 6H), 7.57-7.60 (m, 2H) 7.68-7-77 (m, 2H), 7. 87 (e, 2H), 8.54 t, J = 5.5 Hz, 1H), 12.50 (broad s, 1H); IR (KBr) 3410, 2940, 1625, 1560, 1540, 1460, 1220, 1130 cm "1; Mass spectrum [(+ JAPCI], m / z 687 (M + H) *; Calculated analysis for C39H40Cl2N2O5 • 0.5H20 : C, 67.24; H, 5.93; N, 4.02, found: C, 67.26; H, 6.02; N, 3.96.
Example 169 Acid (5 '-Hexyl- [1,1'; 3 '1' '] terphenyl-2'-yloxy) acetic acid Stage 1 3.5 -diiodo- 4- (2-methoxyethoxymethyloxy) -benzaldehyde To a stirred solution of 3,5-di-4-hydroxybenzaldehyde (18.696 g, 50 mmol) in 360 mL of THF under nitrogen at -0 ° C is added sodium hydride (2.6 g, 1.3 mmol) in portions. After the addition, the mixture is stirred for 20 minutes followed by the dropwise addition of MEMC1 (9.966 g, 80 immoral). The mixture is stirred at ~ 4 ° C for 20 minutes and then at room temperature for 24 h. The reaction mixture was evaporated to dryness and the residue was diluted with 300 ml of EtOAc and washed with IN NaOH (3 x 50 ml), water (2 x 50 ml), brine (2 x 50 ml), dried Na2? 04 is filtered and the filtrate is concentrated ip vac and dried. The residue is purified by flash chromatography (Hex, 10% and 20% EtOAc / Hex) to give the product as a white solid (19.209 g, 83%); p.f. 68-72 ° C; JH NMR (400 MHz, DMS0-d £) d 3.27 (s, 3H), 3.54-3.56 (m, 2H), 4.00-4.04 (m, 2H), 5.24 (s, 2H), 8.34 (e, 2H) 9.85 (s, 1H); IR (KBr) 3410, 2880, 1700, 1540, 1360 cm "J- Mass spectrum [El], m / z 462 M *.
Stage 2 3.5 -diphenyl-4-f (2-methoxyethoxy) methoxy) -benzaldehyde A mixture of 3,5-diiodo-4- (2-methoxyethoxymethyloxy) -benzaldehyde (19,094 g, 41,327 mmol), Pd (OAc) 2 (0.185 g, 0.02 mmol), phenylboronic acid (11,429 g, 90,920 mmol) and Ba (OH) 2-8H20 (39.114 g, 123.981 mmol) in 700 ml of DME and 110 ml of water is refluxed. After 90 minutes, the reaction mixture is cooled, concentrated to approximately 400 ml and the residue extracted with EtOAc (1 x 300 ml, 3 x 100 ml). The combined organic fractions are washed with saturated NaHCO 3 (3 x 75 ml), water (2 x 75 ml), brine (2 x 75 ml), dried over Na 2 SO 4, filtered and the filtrate concentrated m vac and dried. The product is purified by inantantial chromatography (hexane, 5% and 12% EtOAc / Hex) to give the product as a light yellow viscous oil (11.645 g, 78%); "H NMR (400 MHz, DMSO-d £) 6 2.79-2.82 (m, 2H), 2.89-2.92 (m, 2H), 3.02 (s, 3H), 4.42 (s, 2H), 7.42-7.46 (m , 2H), 7.48-7.54 (m, 4H), 7.62-7.66 (m, 4H), 7.91 (s, 2H), 10.07 (s, 1H); IR (film) 3050, 2880, 1690, 1580 cm "1; Eepectro de maeae [El], m / z 362 M *.
Step 31- f3, 5-diphenyl-4-f (2-methoxyethoxy) methoxy-1-ill-exan-1-ol To a stirred solution of n-pentylmagnesium bromide in ethyl ether (3.75 ml of a 2M solution) under nitrogen at 0 ° C, add a solution of 3,5-diphenyl-4 - [(2-methoxyethoxy) methoxy] benzaldehyde (1.812). g, 5 mmolee) in 13 ml of diethyl ether drop. After the addition, the reaction mixture is stirred at room temperature for 3 h, and then poured into a solution of NH 4 Cl (5 g in 30 ml of water). The aqueous layer is extracted with Et20 and the combined extracts are wash with water (2 x 50 ml), brine (2 x 50 ml), dry over Na 2 SO 4, filter and filter the filtrate to ip vac and dry. The residue is purified by flash chromatography (11% and 20% EtOAc / Hex and EtOAc) to give the product as a viscous oil (1394 g, 64%); * H NMR (400 MHz, DMS0-d £) 6 0.82-0.88 (m, 3H), 1.23-1.35 (m, 5H), 1.37-1.46 (m, 1H), 1.58-1.68 (m, 2H), 2.75 -2.78 (m, 2H), 2.86-2.90 (m, 2H), 3.01 (s, 3H), 4.30 (s, 2H), 4.57 (t, J = 6.4 Hz, 1H), 5.16 (broad e, 1H) , 7.29 (e, 2H), 7.34-7.39 (m, 2H), 7.44-7.49 (m, 4H), 7.54-7.59 (m, 4H); IR (film) 3430, 2940, 1450 cm "1; Mass spectrum [El], m / z 434 M *.
Step 4 2, 6-diphenyl-3-hexyl-phenol To a stirred solution of 1- [3,5-diphenyl-4- [(2-methoxyethoxy) methoxy] -1-yl] hexane-1-ol (1361 g, 3,132 mmol) and triethylsilane (3,642 g, 31.32 mmol) in trifluoroacetic acid (7.142 g, 62.64 mmol) is added in 20 ml of methylene chloride under nitrogen. After ~24 h, the reaction mixture is poured into 50 ml of a saturated NaHCO 3 solution, with stirring. The aqueous layer is extracted with methylene chloride (3 x 20 ml). The combined stratuses are washed in a saturated NaHCO solution (2 x 20 ml), brine (1 x 50 ml), dried over Na 2 SO 4, filtered and the filtrate concentrated in vacuo and ee. dry The residue is purified by flash chromatography (hexane and 1% EtOAc / Hex) to give the product as a colorless oil (0.892 g, 86%); 1 NMR (400 MHz, DMSO-d £) d 0.84-0.88 (m, 3H), 1.44-1.36 (m, 6H), 1.55-1.63 (m, 2H), 2.56 (t, J = 7.7 Hz, 2H) , 7.02 (?, 2H), 7.31-7.35 (m, 2H), 7.40-7.45 (m, 4H), 7.52-7.56 (m, 4H), 8.04 (s, 1H); IR (film) 3560, 2940, 1470 cm1- Eepectro de maeae [El], m / z 330 M *.
Step 5 Methyl ester of 15 '-Hexyl- [1,1': 3 '1"1-terphenyl-21-yloxy) acetic acid The product is prepared as a colorless oil (0.883 g, 82%) from 2,6-diphenyl-3-hexyl-phenol (0.879 g, 2.66 mmol) and methyl bromoacetate (0.488 g, 3.192 mmol) using a procedure similar to that of stage 3 of example 165; p.f. 87-89 ° C; Jl NMR (400 MHz, DMS0-d £) 6 1.33-1.38 (m, 3H), 1.25-1.38 (m, 6H), 1.57-1.66 (m, 2H), 2.63 (t, J = 7.5 Hz, 2H) , 3.38 (s, 3H), 3.84 (s, 2H), 7.17 (e, 2H), 7.34-7.39 (m, 2H), 7.41-7.46 (m, 4H), 7.54-7.57 (m, 4H); IR (film) 2930, 1760, 1200 cm "1; Mass spectrum [El], m / z 402 M *. Step 6: Acid (51 -Hexyl- [1, 1 '3' .1 '' 1-terfen-l-21-yloxy) acetic The title compound is prepared as a white solid (0.559 g, 671%) from the methyl ester of the acid (5'Hexyl- [1,1 J-3 Jl ''] terfen? L-2'-yloxy) acetic acid (0.870 g, 2161 mmol) using a procedure similar to step 4 of example 165; "H NMR (400 MHz, DMSO-ds) d 0.82-0.86 (m, 3H), 1.22-1.37 (m, 6H), 1.56-1.64 (m, 2H), 2.61 (t, J = 7.5 Hz, 2H) , 3.71 (s, 2H), 7.16 (s, 2H), 7.32-7.37 (m, 2H), 7.39-7.44 (til, 4H), 7.54-7.59 (m, 4H), 12.47 (broad s, 1H); IR (KBr) 3450, 2920, 1725, 1420, 1210 crn "1; Spectrum of masae [El], m / z 388 MJ- Analysis calculated for C26H2803: C, 80.38; H, 7.26; N, 0.00, found: C, 79.99; H, 7.24; N, 0.13.
Example 170 Acid (5 '-Nonyl- [1,1'; 3 ', 1' '] terphenyl-2'-yloxy) acetic acid The title compound is prepared as a white solid (0.346 g, 20%) from 3, 5 -difenyl -4 - [(2-methoxyethoxy) methoxy] -benzaldehyde (1450 g, 4 mmolee) and bromide of n-octylmagnesium (6 ml of a 1M solution in Et20) using a procedure similar to step 3 to 6 of example 169; p.f. 63-65 ° C; ? H NMR (400 MHz, DMSO-d £) d 0.83 (t, J = 6.8 Hz, 3H), 1.18-1.36 (m, 12H), 1.56-1.64 (m, 2H), 2.61 (t, J = 7.5 Hz, 2H), 3.71 (s, 2H), 7.15 (s, 2H), 7.32-7.37 (m, 2H), 7.39-7.44 (m, 4H), 7.54-7.58 (, 4H), 12.47 (s broad, 1 HOUR); IR (KBr) J450, 2920, 1725, 1430, 1220 cm "1; Mass spectrum [(-) ESI], m / z 429 (M-H) -; Analysis calculated for C29H3403: C, 80.89; H, 7.96; N, 0.00, found. C, 80.71; H, 8.28; N, 0.05.
Example 171 Acid (5 '-Tridecyl- [1,1'; 3 ', 1' '] terfen? L-2'-yloxy) acetic acid The title compound is prepared as a white solid (0.479 g, 20%) from 3, 5-diphenyl -4- [(2-methoxyethoxy) methoxy] benzaldehyde (1.812 g, 5 mmol) and n-dodecylmagnes bromide. or (7.5 ml of IM solution in Et20) using a procedure similar to steps 3 to 6 of example 169; p.f., partially melts at 58-62 ° C, re-solidifies and melts at 69-71 ° C; SH NMR (400 MHz, DMS0-d £) d 0.81-0.86 (m, 3H), 1.17-1.34 (m, 20H), 1.56-1.64 (m, 2H), 2.61 (t, J = 7.5 Hz, 2H) , 3. 71 (s, 2H), 7.15 (e, 2H), 7.32-7.37 (m, 2H), 7.39-7.44 (m, 4H), 7.54-7.58 (m, 4H), 12.47 (broad e, 1H); IR (KBr) 3450, 2920, 1725, 1470, 1220 cm "1; Mass spectrum [(-) ESI], m / z 485 (M-H)", -Analysis calculated for C33H4203: C, 81.44; H, 8.70; N, 0.00, found: C, 81.27; H, 8.68; N, 0.01.
Example 172 Acid (5 '-Decyloxy- [1,1'; 3'1 ''] terphenyl-2'-yloxy) acetic acid Stage 1 3-5-diphenyl-4- [(2-methoxyethoxy) methoxy-1-phenol A solution of 3,5-di-phenyl-4 - [(2-methoxyethoxy) methoxy] -benzaldehyde (7,279 g, 20,084 mmol) and M-CPBA (4,159 g, 24,101 mmol) is refluxed. After After 19 h, the reaction mixture is cooled, concentrated ip vac and the residue is taken up in EtOAc ("80 ml) and washed with a saturated solution of NaHCO 3 (4 x 30 ml), brine (2 x 30 ml), The residue is dissolved in 72 ml of THF and 48 ml of methanol, and 30 ml of IN KOH are added and the reaction mixture is stirred for 1 hour. After 24 hours and then evaporate to approximately 40 ml, the residue is diluted in 50 ml of water, acidified with 2N HCl to pH 3, and extracted with EtOAc (lx). «** ~ * atoa». 50 ml, 3 x 30 ml). The combined organic fractions are washed with water (2 x 20 ml), brine (2 x 20 ml), dried over Na2SO4, filtered and the filtrate concentrated in vacuo and dried. The residue is purified by inert tanning chromatography (10%, 15%, 5 and 20% EtOAc / Hex) to provide an orange solid which is recrystallized from methylene chloride and hexane to give the product as a peach solid (4042 g. 58%); p, f, 103.5-108 ° C; f 10"H NMR (400 MHz, DMS0-d £) 6 2.69-2.72 (m, 2H), 2.84- 2.87 (m, 2H), 3.00 (s, 3H), 4.18 (s, 2H), 6.71 (s) , 2H), 7.31-7.36 (m, 2H), 7.40-7.45 (m, 4H), 7.49-7.54 (m, 4H), 9.48 (e, 1H), IR (KBr) 3340, 2900, 1600, 1425, 1190, 1080 cm "1; 15 Species of maeas [(+) ESI], m / z 368 (M + NH4) *.
Step 2 3, 5-diphenyl-4- (2-methoxyethoxy) methoxy-1-phenyl decyl ether To a stirred solution of 3,5-diphenyl-4 - [(2-20-methoxyethoxy) methoxy] -phenol (0.946 g, 2.7 mmol) in 15 ml of DMF is added K2C03 (0.746 g, 5.4 mmol) and iododecane (1632 g, 5.4 mmol). The reaction mixture is heated to "63 ° C. After ~20 h, additional K2C03 (0.373 g, 2.7 mmol) and iododecane (0.816 g, 2.7 mmol) are added, Heating 25 is continued for an additional 20 h followed by stirring at temperature Environment for ~ 20h. The reaction mixture is concentrated ip vac and the residue is taken up in 50 ml of EtOAc and 20 ml of water. 4fc The layers are stirred and separated, and the organic layer is washed with water (3 x 10 ml), brine (2 x 10 ml), dried over Na 2 SO 4, filtered and the filtrate concentrated in vacuo and dried . The residue is purified by flash chromatography (hexane and 5% EtOAc / Hex) to give the product as a brown oil (0.897 g, 68%); -H NMR (400 MHz, DMS0-66) d 0.83-0.88 (m, 3H), 1.20-f 10 1.37 (m, 12H), 1.37-1.46 (m, 2H), 1.68-1.76 (m, 2H), 2.71-2.75 (m, 2H), 2.86-2.88 (m, 2H), 3.01 (s, 3H), 4.03 (t, J = 6.4 Hz, 2H), 4.22 (e, 2H), 6.87 (e, 2H), 7.34-7.39 (m, 2H), 7.42-7.48 (m, 4H), 7.56-7.60 (m, 4H); IR (film) 2940, 1590, 1460, 1190 cm "1; 15 Mass spectrum [(+) ESI], m / z 508 (M + NH4)".
Step 3 2, 6-diphenyl-4-decyloxy-phenol A mixture of 3, 5-diphenyl -4- [(2-methoxyethoxy) methoxy] -20 phenyl decyl ether (0.880 g, 1793 mol) and ZnBr2 (2.019 g, 8.967 mmol) in 10 ml of methylene chloride under nitrogen and it is stirred at room temperature. After -48 h the reaction mixture was concentrated m vac and the residue was taken up in 60 ml of EtOAc and 20 ml of a saturated NaHCO 3 solution. The layers 25 are stirred and separated, and the organic layer is washed with a , * a & - saturated NaHCO3 solution (2 x 10 ml), water (3 x 10 ml), brine (1 x 10 ml), dried over Na2SO4, filtered and the filtrate was concentrated ip vac and dried. The residue is purified by flash chromatography (hexane and 1% EtOAc / Hex) to give the product as a light brown oil (0.571 g, 79%), - -H NMR (400 MHz, DMSO-d £) d 0.83-0.88. (m, 3H), 1.20-1.36 (m, 12H), 1.36-1.45 (m, 2H), 1.65-1.73 (m, 2H), 3.96 (t, J = 6.6 Hz, 2H), 6.77 (s, 2H) ), 7.31-7.36 (m, 2H), 7.40-7.45 (m, 4H), 7.54-7.58 (m, 4H), 7.80 (s, 1H); IR (film) 3550, 2940, 1600, 1460, 1180 cm "1; Mass spectrum [El], m / z 402 M *.
Step 4: Acid (5 '-Decyloxy-fl, l', 3 ', 1"1-terphenyl-2'-yloxy) acetic The title compound is prepared as a white solid (0.383 g, 65%) from 2,6-diphenyl-4-decyloxy-phenol (0.517 g, 1.284 immoles) using a procedure similar to that of steps 5 and 6 of Example Q; p.f., partially fused to 88-90 ° C, re-solidifies and melts at 98-99 ° C; JH NMR (400 MHz, DMSO-d £) d 0.81-0.87 (m, 3H), 1.17-1.35 (m, 12H), 1.35-1.44 (m, 2H), 1.66-1.74 (m, 2H), 3.64 ( s, 2H), 4.01 (t, J = 6.4 Hz, 2H), 6.86 (s, 2H), 7.33-7.38 (m, 2H), 7.39-7.44 (m, 4H), 7.56-7.60 (m, 4H) , 12.43 (s, 1H); IR (KBr) 3450, 2910, 1725, 1460, 1190 cm "J- Mass Spectrum [(-) ESI], m / z 459 (M-H)"; Analysis calculated for C30H3βO4: C, 78.23; H, 7.88; N, 0.00, found: C, 78.03; H, 7.83; N, 0.10.
Example 173 Acid (5 '-Tetradecyloxy- [1, 1'; 3 ', 1' '] terphenyl-2'-yloxy) acetic acid The title compound is prepared as a white solid (0.556 g, 43%) from 3, 5 -difenyl -4 - [(2-methoxyethoxy) methoxy] -phenol (0.876 g, 2.5 mmol) and 1-bromot et radecano (1387 g, 5 mmol) using a procedure similar to steps 2 to 4 of Example 172; p.f. 89-90 ° C; * H NMR (400 MHz, DMSO-d £) d 0.83 (t, 6.6 Hz, 3H), 1.17-1.35 (m, 20H), 1.35-1.44 (m, 2H), 1.65-1.74 (m, 2H), 3.64 (s, 2H), 4.01 (t, J = 6.4 Hz, 2H), 6.86 (s, 2H), 7.33-7.38 (m, 2H), 7.39-7.44 (m, 4H), 7.56-7.60 (m, 4H), 12.44 (s, 1H); IR (KBr) 3425, 2925, 1725, 1460, 1200 crn "1; Spectrum of masae [El], m / z 516 MJ- Analysis calculated for C34H4404: C, 79.03; H, 8.58; N, 0.00, found: C , 78.66; H, 8.47; N, -0.07.
Example 174 Acid (5 '-Trityl- [1.1'; 3 ', 1' '] terphenyl-2'-yloxy) acetic acid Stage 1 2, 6-dibromo-4-trityl-phenol To a stirred suspension of p-triphenylmethylphenol (5.046 g, 15 mmol / in 25 ml of chloroform, bromine (4.795 g, 30 mmol) is added, the reaction mixture is stirred for 18 h and then concentrated m vac and dried. The residue is recrystallized from hexane to give the product as a white solid (5.837 g, 79%), mp 164-167 ° C; XH NMR (400 MHz, DMSO-dt) d 7.09-7.13 (m, 6H), 7.16 (s, 2H), 7.20-7.25 (, 3H), 7.29-7.35 (m, 6H) -; IR (KBr) 3480, 3020, 1475, 1160 cm'1.
Stage 2 2.6 -d phen] i - 4-tphenyl-phenol A mixture of Pd (OAc) 2 (0.094 g, 0.06 mmolee), phenylboronic acid (2.817 g, 23.1 mmolee), Ba (0H) 2-8H20 (6.625 g, 21 immoles) and 2,6-dibromc-4-trityl Phenol (3.46 g, 7 mmol) in 112 ml of DME and 28 ml of water is refluxed. After ~66 h, the reaction is cooled and concentrated m vac to about 20 ml. The residue is acidified with 35 ml of 2N HCl and extracted with EtOAc (5 x 30 ml). The combined organic fractions are washed with water (3 x 30 ml), brine (2 x 20 ml), dried over Na 2 SO 4, filtered and the filtrate is concentrated in vacuo and dried. The residue is purified by flash chromatography: first on silica (1%, 60% EtOAc / Hex) and then on alumina (33% chloroform / Hexane). This provides a solid which recrystallizes from methyl t-butyl ether to give the product as a white solid (0.910 g, 27%) m.p. 212-215 ° C; XH NMR (400 MHz, DMSO-d6) 6 6.97 (e, 2H), 7.16-7.42 (m, 25H), 8.34 (e, 1H); IR (KBr) 3505, 3025, 1600, 1420 cm "1; Mass spectrum [(+) FAB], m / z 488 MJ- Analysis calculated for C37H280: C, 90.95 H, 5.78; N, 0.00, found: C , 90.76; H, 5.81; N, 0.00.
Stage 3 Acid (5'-Tetradecyloxy-fl, 1 ', -3', 1"1-terphenyl-2'-yloxy-acetic The title compound is prepared as a white solid (0.355 g, 43%) from 2,6-diphenyl-4-trityl-phenol (0.733 g, 1.5 mmol) and methyl bromoacetate (0.281 g, 1.8 mmol) using a procedure similar to steps 3 and 4 of example 165; p.f. 211-214 ° C; Jl NMR (400 MHz, DMSO-dβ) 6 3.77 (s, 2H), 7.10 (s, 2H), 7.17-7.26 (m, 9H), 7.29-7.40 (m, 12H), 7.43-7.47 (m, 4H ), 12.49 (S, 1H); IR (KBr) 3430, 3075, 1730, 1420, 1210 cm "1; Spectrum of maeae [(-) ESI], m / z 545 (M-H)"; Analysis calculated for C 39 H 30 O 3: C, 85.69 H, 5.53; N, 0.00, found: C, 85.54; H. 5.74; N, -0.04.
Example 175 Acid (5 '-Dodecylcarbamoyl-3, 3"-bis-trif luoromethyl- (1,1'; 3 ', 1"] terphenyl-2'-yloxy) -acetic Stage 1 To a stirred solution of K2CO3 (2 M in H20) (1.9 ml, 3.6 mmol) at rt is added 14.3 ml of dioxane, 3-bromo-4- (2-hydroxyethoxy) -5-iodo-benzoic acid ethyl ester ( 0.503 g, 1.21 mmol), and 3-trifluoromethyl-phenyl boronic acid (0.299 g, 1.57 mmol). The reaction mixture is purged with N2 for a few minutes and then complex of [1, 1 bis (diphenylphosphino) ferrocyano] dichloropalladium (II) is added with CH2C12 (0.030 g, 0.036 mmol). The reaction is stirred at rt for 1.5 h and then heated to reflux for 2 h. After cooling to rt, it is poured into a HCl 0. IN solution and extracted with EtOAc. The combined organic layers are washed with brine and dried over MgSO4. After concentration ip vacuo, the residue is purified first by flash chromatography (25% EtOAc: hexane) and then by CLAP [60% CH2C12 (6% MTBE): 40% hexane to provide 3, 5 ethyl ester. -bis- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzoic acid (0.215 g, 36%) as a white solid, -H NMR (CDC13) 6 8.09 (S, 2H); 7.94 (m, 2H); 7.86-7.80 (m, 2H); 7.71-7.58 (m, 4H); 4.42 (c, 2H) 3.63 (m, 4H); 1.42 (t, 3H) and 3-Bromo-5- (m-trifluoromethyl-fyl) -4- (2-hydroxyethoxy) -benzoic acid ethyl ester (0.173 g, 33%) as a white solid, 1 H NMR (CDCl 3) d 8.29 (d, 1H); 8.00 (d, 1H); 7.86 (m, 1H); 7.80-7.55 (m, 3H); 4.40 (c, 2H); 3.74-3.60 (m, 4H); 1. 92 (t, 1H); 1.40 (t, 3H).
Stage 2 To a flame-dried flask containing dodecylamine (0.278 g, 1.5 mmol) in 5 ml of THF, cooled to -78 ° C is added n-BuLi (titrated to 2.37 M in hexanes) (0.670 ml, 1.59 mmol) a drops. The solution is stirred at -78 ° C for 20 min and then heated to rt for 20 minutes. The reaction is subsequently cooled again to -40 ° C and the ester is added Ethyl 3, 5-bis- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzoic acid (0.215 0.43 mmol) in 5 ml THF. Allow this mixture to warm to rt for 20 min. The reaction mixture is poured into a 0. IN HCl solution and extracted with EtOAc. The combined organic layers are washed with a 2N HCl solution (3x), dried over MgSO4 and concentrated ip vacuo. The residue is purified by flash chromatography (30% EtOAc: Hexanes) to give N-dodecyl-3,5-bis (m-tpfluoromethylphenyl) -4- (2-hydroxyethoxy (benzamide (0.254 g, 93%) as a white solid -H-NMR (CDC133) d 7.90 (m, 2H), 7.82-7.76 (m, 4H), 7.65-7.56 (m, 4H), 6.22 (bt, 1H), 3.45 (dd, 2H), 3.30 (m , 4H), 1.60 (m, 2H), -1.25 (m, 18H), 0.84 (m, 3H).
Stage 3 To a solution of N-d or of Ci -3,5-bis (m -trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzamide (0.254 g, 0.40 mmol) in CH3CN is added NMO (0.145 g, 0.89 mmol) and TPAP (0.014 g, 0.04 mmol). The reaction is stirred at rt overnight. NMO (0.045 g, 0.38 mmol) and TPAP (0.013 g, 0.04 mmol) are also required, as indicated by CCD. After stirring for 48 h, a 10% NaHS03 solution is added and the resulting biphasic mixture is stirred vigorously for 30 min. 2 ml of concentrated HCl are added and the stirring for 10 min. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic fractions are washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue is purified by instantaneous chromatography (30% EtOAc: Hexane + 1% formic acid) followed by preparative plate chromatography (30% EtOAc: Hexane + 1% formic acid) to give the title compound (0.089 g, 34% ) as a white solid. p.f. 154.3-158.2 ° C; LH NMR (DMSO-d6) 6 8.55 (t, 1H); 7.98-7.88 (m, 6H); 7. 78-7.67 (m, 4H); 3.57 (s, 2H), -3.25 (m, 2H); 1.50 (m, 2H); 1.23 (m, 18H); 0.82 (t, 3H), - IR (KBr) 3275, 2900, 1725, 1600, 1575, 1460, 1325, 1190, 1125, 1075, 775, 725, 700, 625 cm "1; Mass spectrum [< ) ESI], m / z 650 (MH) "; Analysis calculated for C35H39F6N04: C, 64.51; H, 6.03; N, 2.15, found: C, 62.50; H, 5.99; N, 2.01.
Example 176 Acid (3-Bromo-5-dodecylcarbamoyl-3 '-trifluoromethyl-biphenyl-2-yloxy) -acetic acid Stage 1 N-Dodecyl-3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide is prepared as a white solid (0.116 g, 51%) from the ethyl ester of 3-bromo-5 acid. - (m-trifluoromethylphenyl) -4- (2-hydroxy? ethoxy?) -benzoic acid using a procedure similar to step 2 of example 175. 'HRMN (CDC13) 6 7.98 (d, 1H); 7.85-7.54 (m, 5H); 6.25 (m, 1H); 3.70-3.58 (m, 4H), 3.48-3.36 (dd, 2H); 1.60 (m, 2H); 1.24 (m, 18H), 0.86 (m, 3H).
Step 2 The title compound is prepared as a white foam (0.058 g, 50%) from N-dodecyl-3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide using a procedure similar to step 3 of example 175. 'HRMN (DMS0-ds) 613.75 (broad s, 1H); 8.57 (t, 1H); 8.12 (d, 1H), 7.92- "'68 (m, 5H), - 4.15 (s, 2H), 3.24 (dd, 2H), 1.49 (m, 2H), 1.26 (m, 18H), 0.83 (m , 3H); IR (KBr) 3350, 2910, 2830, 1740, 1650, 1550, 1460, 1440, 1340, 1175, 1140, 1050, 900, 800, 760, 700, 675 crn "1; Eepectro de maeas [(-) ESI], m / z 584/586 (M-H) J- Analysis calculated for C2ßH35BrF3N04: C, 57.34; H, 6.02; N, 2.39, found: C, 59.34; H, 6.64; N, 2.16.
Example 177 Acid (5 '- (8-Phenyl-octylcarbamoyl-3, 3"-bis-trifluoromethyl- (1,1', 3 ', 1"] terphenyl-2'-yloxy) -acetic Stage 1 N- (8-phenyl-octyl) -3,5-bis (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide is prepared as a white solid (0.331 g, 74%) from the ethyl ester of the acid 3, 5-bis- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzoic acid and phenyloctylamine using a procedure similar to step 2 of example 175. aH NMR (CDC13) d 7.96-7.50 (m, 10H); 7.35-7.10 (m, 5H); 6.28 (m, 1H); 3.45 (m, 2H); 3.31 (m, 4H); 2.60 (m, 2H); 1.60 (m, 4H); 1.33 (m, 8H).
Step 2 The title compound is prepared as a white solid (0.058 g, 50%) from N- (8-phenyl-octyl) -3,5-bis (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide using a procedure similar to step 3 of example 175. pf 143-145.4 ° C; 'HRMN (DMS0-d6) d 12.70 (broad s, 1H); 8.56 (t, 1H); 7.97-7.91 (m, 2H); 7.78-7.69 (m, 4H); 7.25-7.21 (m, 2H); 7.15- 7. 10 (m, 3H); 3.78 (s, 2H), -3.26 (m, 2H); 2.49 (m, 2H), -1.50 4H); 1.27 (m, 8H); IR (KBr) 3370, 2920, 2880, 1725, 1625, 1560, 1 75, 1340, 1225, 1175, 1125, 1075, 900, 810, 700, 660, 620 cm "1; Mass spectrum [< -) ESI], m / z 670 (MH) "; Analisis calculated for C 37 H 35 F 6 N 0 4: C, 66.16; H, 5.25; N, 2.08, found: C, 65.58; H, 5.37; N, 2.05.
Example 178 Acid (3-Bromo-5- (8-phenyl-octycarbamoyl) -3'-trifluoromethyl-biphenyl-2-yloxy) -acetic Step 1 N- (8-F-enyl-oc-t-yl) -3-bromo-5- (m-trifluoromethyl-phenyl) -4- (2-hydroxyethoxy) -benzamide is prepared as a white solid (0.221 g, 64%) from 3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzoic acid ethyl ester using a procedure similar to step 2 of example 175. -H NMR (CDC13) d 7.99 (d, 1H); 7.85 (s, 1H); 7.78-7.55 (m, 4H); 7.31-7.13 (m, 5H); 6.14 (bt, 1H); 3.77 (m, 4H); 3.44 (dd, 2H); 2.60 (t, 2H); 1.60 (m, 4H); 1.33 (m, 8H).
Stage 2 The title compound is prepared as a white solid (0.099 g, 44%) from N- (8-phenyl-octyl) -3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) - benzamide using a procedure similar to step 3 of example 175.? NMR (DMSO-d6) d 13.80 (broad s, 1H); 8.58 (t, 1H); 8. 12 (d, 1H); 7.94 (m, 5H); 7.26-7.10 (m, 5H); 4.15 (s, 2H); 3.22 (dd, 2H); 2.52 (t, 2H); 1.51 (m, 4H); 1.27 (m, 8H), - IR (KBr) 3400, 2920, 2850, 1740, 1630, 1550, 1450, 1330, 1160, 1125, 1075, 900, 810, 700 cm "1; Spectrum of masae [< + APCI], m / z 606/608 (M + H) *; Analysis calculated for C30H31BrF3NO4: C, 59.41; H, 5.15; N, 2.31, found: C, 58.96; H, 5.19; N, 2.22.
Example 179 Acid4- (3-Bromo-5-dodecylcarbamoyl-3 '-trifluoromethyl-biphenyl-2-yloxysulfonyl) -2-hydroxy-benzoic acid Stage 1 The ethyl ester of 3-Bromo-4-hydroxy-5 (m-trifluoromethylphenyl) -benzoic acid and 3,5-bis- (m-trifluoromethylphenyl) -4-hydroxy-benzoic acid ethyl ester as white solids (2,445) are prepared g, 34% and 2811 g, 33%, respectively), from 3-bromo-4-hydroxy-5-iodobenzoic acid and 3- trifluoromethyl-phenyl boronic using a procedure similar to step 1 of example 175. 3-Bromo-4-hydroxy-5 (m-trifluoromethylphenyl) benzoic acid ethyl ester. * H, NMR (CDC13) d 8.22 (d, 1H); 7.98 (d, 1H); 7.74 (s, 1H); 7.70 (d, 1H); 7.68-7.53 (m, 2H); 6.10 (s, 1H); 4.38 (c, 2H); 1.40 (t, 3H); 3, 5-bis- (m-trifluoromethylphenyl) -4-hydroxy-benzoic acid ethyl ether; * H NMR (CDC13) d 8.02 (s, 2H); 7.84 (broad s, 2H), -7.77-7.60 (m, 6H); 5.67 (s, 1H); 4.38 (c, 2H); 1.40 (t, 3H).
Stage 2 N-Dodecyl-3-bromo-4-hydroxy-5 - (m-trifluoromethylphenyl) benzamide is prepared as a white solid (0.799 g, 78%) from the ethyl ester of 3-bromo-4-hyhydroxy-5- (m-trifluoromethylphenyl)) -benzoic acid using a procedure similar to step 2 of example 175. * H NMR (CDC13) 6 7.95 (d, 1 HOUR); 7.82-7.50 (m, 5H), -6.26 (bt, 1H); 3.42 (dd, 2H); 1.60 (m, 2H); 1.45-1.18 (m, 18H); 0.86 (t, 3H).
Stage 3 To a suspension of N-dodecyl-3-bromo-4-hydroxy-5- (m-trifluoromethylphenyl) -benzamide (1799 g, 1.51 mmol, 1 equivalent) in 0.05N tris (hydroxymethyl) aminomethane as buffer pH 9 / THF ( 10: 3) (7.5 mL) is added 2.5N NaOH (0.665 mL, 1.66 mmol, 1.1 equivalents) and 10 mL of THF. The reaction is stirred at rt for 30 minutes and then cooled to 5 ° C. 4-Chlorosulfonyl-2-hydroxy-benzoic acid (0.715 g, 3.02 mmol, 2 equivalents) is added in portion while maintaining the pH at 9 by the addition of 2.5 N NaOH. Allow this mixture to warm to rt and shake for 2 days. The reaction is suspended by the addition of a 2M HCl solution and extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4 and concentrated ip vacuo. The residue is purified by flash chromatography (30% EtOAc: Hexane + 1% formic acid) to give the title compound (0.895 g, 79%) as a yellow foam. XH NMR (DMSO-d6) d 11.40 (broad s, 1H); 10.35 (broad e, 1H); 8.70 (t, 1H); 8.22 (d, 1H); 7.85 (d, 1H); 7.72-7.45 (m, 5H); 6.98 (dd, 1H); 6.86 (d, 1H); 3.25 (dd, 2H); 1.50 (dd, 2H); 1.25 (m, 18H); 0.85 (t, 3H); IR (KBr) 3410, 2800, 2700, 1690, 1640, 1605, 1390, 1330, 1180, 1120, 620, 600 cm "J Mass spectrum [< +) APCI], m / z 728/730 (M + H) J-Analysis calculated for C33H37BrF3N07S + 0.25 C4Hβ02: C, 54.40; H, 5.24; N, 1.87, found: C, 53.23; H, 4.77; N, 1.79.
Example 180 -Bromo-6- (2- [1, 2, 3] triazol-2-yl-ethoxy) -3 '-trif luoromethyl-bifenyl-3-carboxylic acid dodecylamide To a solution of N-dodec i 1 -3-bromo-5 - (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide (1508 g, 0.89 mmol, 1 equivalent) in 7 ml of THF is added triphenylphophene ( 0.296 g, 1.13 mmol, 1.27 equivalents) and 1-Hl, 2, 3-triazole (0.210 ml, 1.08 immoles, 1.21 equivalents). The reaction is cooled to 0 ° C and diethyl azodicarboxylate (0.170 ml, 1.08 mmol, 1.21 equivalents) is added. The cold bath is removed and the reaction is stirred overnight at rt. The reaction mixture is poured into a 0. IN HCl solution and extracted with EtOAc. The combined organic layers are washed with a 2N HCl solution, dried over MgSO4 and concentrated ip vacuc. The residue is purified by flash chromatography (30 to 50% EtOAc: hexanes) to give 5-Bromo-6- (2 [1,2,3] triazol-1-yl-ethoxy) -3'-trifluoride dodecylamide. ethyl-β-phen-3-carboxylic acid (see following example) and the title compound (0.247 g, 45%) as a thick oil. a H NMR (DMS0-d5) 6 8.56 (bt, 1H), 8.09 (d, 1H); 7.84 (d, 1H), - 7.78-7.70 (m, 3H); 7.67 (s, 2H); 7.62 (t, 1H); 4.51 (dd, 2H); 4.01 (dd.2H); 3.22 (dd, 2H); 1.48 (dd, 2H), -1.23 (m, 18H); 0.82 (t, 3H); IR (KBr) 3300, 2920, "2850, 1640, 1550, 1460, 1450, 1330, 1170, 1120, 1080, 960, 805 cm" 1; Mass spectrum [(+) APCI], m / z 623 (M + H) *; Analysis calculated for C30H38BrF3N4O2: C, 57.79; H, 6.14; N, 8.99, found: C, 57.84; H, 5.99; N, 8.89.
Example 181 Dodec Lick of 5-Bromo-6- (2- [1,2,3] triazol-1-l-ethoxy?) -3 '-trifluoromethyl-biphenyl-3-carboxylic acid The dodecylamide of 5-Bromo-6- (2- [1, 2, 3] triazol-1-yl-ethoxy?) -3'-trifluoromethyl-biphenyl-3-carboxylic acid is prepared as a white solid (0.172 g, 31%) using the procedure of Example 180. pf 70.5-72.5 ° C; ? NMR (DMSO-d6) d 8.63 (bt, 1H); 8.10 (d, 1H); 7.98 (d, 1H); 7.85 (d, 1H); 7.82-7.72 (m, 3H); 7.66 (d, 1H); 7.60 (m, 1H); 4.51 (dd, 2H), -3.92 (dd, 2H); 3.21 (dd, 2H); 1.48 (dd, 2H); 1.23 (m, 18H); 0.83 (t, 3H); IR (KBr) 3350, 3125, 2900, 2850, 1640, 1620, 1570, 1560, 1430, 1180, 1100 crn "1; Mass spectrum [(-) ESI], m / z 623/625 (M + H) * Analysis calculated for C3H3ßBrF3N402: C, 57.79; H, 6.14; N, 8.99, found: C, 57.56; H, 6.32; N, 8.87.
Example 182 -Bromo-6- (2-tetrazol-yl-ethoxy) -3 '-trifluoromethyl-biphenyl-3-carboxylic acid dodecylamide The title compound is prepared as a white solid (0.296 g, 53%) from N-dodecyl-3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide and 1-H- tetrazole using a procedure similar to that of example 180. pf 75.6-76.2 ° C; * H NMR (DMSO-d6) d 8.88 (s, 1H); 8.53 (bt, 1H); 8.11 (d, 1H), - 7.86 (d, 1H); 7.78 (m, 2H); 7.70 (d, 1H), - 7.63 (dd, 1H); 4.84 (dd, 2H); 4.08 (dd, 2H); 3.22 (dd, 2H); 1.50 (dd, 2H>; 1.23 (m, 18H), 0.84 (t, 3H); IR (KBr) 3400, 3250, 3100, 2900, 2850, 1630, 1550, 1470, 1420, 1330, 1170, 1120, 900 crn "1 Mass spectrum [(+) APCI], m / z 624/626 (M + H) J- Analysis calculated for C29H37BrF3N502: C, 55.77; H, 5.97; N, 11.21, found: C, 55.43; H, 6.03; N, 10.91.
Example 183 -Bromo-6- (2-tetrazol-1-yl-ethoxy) -3'-trifluoromethyl-biphenyl-3-carboxylic acid dodecylamide The title compound is prepared as a white solid (0.189 g, 34%) from N-dodecyl-3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide and lH-tetrazole using a procedure of example 182. mp 91.5-92.6 ° C; * H NMR (DMSO-d6) d 9.34 (s, 1H); 8.58 bt, 1H); 8.11 (d, 1H); 7.88 (d, 1H); 784-7.72 (m, 3H), -7.60 (dd, 1H); 4.63 (dd, 2H); 3.92 (dd, 2H); 3.23 (dd, 2H); 1.50 (dd, 2H); 1.25 (m, 18H); 0.84 (t, 3H); IR (KBr) 3410, 2900, 2850, 1640, 1550, 1470, 1460, 1330, 1170, 1120, 705 cm "1; Mass spectrum [< +) APCI], m / z 624/626 (M + H) *; Analysis calculated for C29H37BrF3N502: C, 55.77; H, 5.97; N, 11.21, found C, 54.08; H, 5.85; N, 10.65.
Example 184 Ester2- [3-bromo-5- (8-phenyl-octylcarbamoyl) -3 '-tri luomomethyl-biphenyl-2-yloxy-ethyl carbamic acid To a solution of N- (8-phenyl-octyl) -3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide (0.463 g, 0. 78 mmoles, 1 equivalent) in 10 ml of CH2C12 is added trichloroacetyl isocyanate (0.100 ml, 0.84 mmolee, 1.1 equivalent). The reaction is stirred at rt 15 minutes and added alumina dried in the oven. The reaction is stirred overnight at rt and concentrated in vacuo, the residue purified by inantaneous chromatography (30 to 60% EtOAc: Hexanes) to give the title compound (0.308 g, 62%) as an oil. ? EMN (DMSO-d6) 6 8.56 (bt, 1H); 8.13 (d, 1H); 7.89 (m, 3H); 7.72 (dd, 1H); 7.24 (m, 2H); 7.14 (m, 3H); 6.40 (broad s, 2H); 3.90 (dd, 2H); 3.70 (dd, 2H); 3.23 (dd, 2H); 2.52 (t, 2H); 1.25 (m, 4H); 1.27 (m, 8H); IR (KBr) 3330, 2920, 2850, 1720, 1640, 1600, 1550, 1460, 1410, 1330, 1180, 1120 cm "1; Spectrum of maeae [(+) ESI], m / z 635/637 (M + H) J- Analysis calculated for C31H34BrF3N204: C, 58.59; H, 5.39; N , 4.41, found C, 57.26; H, 5.46; N, 4.38.
Example 185 Dodecylamine of 5-Bromo-6- (2-morpholin-4-yl-ethoxy) -3 'trifluoromethyl-biphenyl-3-carboxylic acid Stage 1 To a solution of N- ode c i 1 - 3 -bromo-5 - (m-trifluoromethyl-enyl) -4- (2-hydroxyethoxy) -benzamide (0.996 g, 1.74 mmol, 1 equivalent) in 9 ml of CH2C12 is added "A.M. carbon tetrabromide (0.760 g, 2.29 immoles, 1.3 equivalents) and triphenylphosphine (0.603 g, 2.29 mmoles, 1.3 equivalents). The reaction is stirred overnight at rt and concentrated ip vacuo. The residue is purified by flash chromatography (15% EtOAc: Hexane) to give N-dodecyl-3-bromo-4- (2-bromo-ethoxy) -5- (m-trifluoromethylphenyl) -benzamide (0.951 g, 89%) as a colorless oil. "H NMR (CDC13) 67.98 (d, 1H); 7.78-7.40 (m, 5H); 6.20 (bt, 1H); 4.52 (dd, 2H), 3.95 (dd, 2H), - 3.42 (dd, 2H);; 1.50 (m, 2H), - 1.30 (m, 18H); 0.92 (t, 3H).
Stage 2 To a solution of N-dodecyl-3-bromo-4- (2-bromoethoxy) -5- (m-trifluoromethylphenyl) -benzamide (0.294 g, 0.46 mmol, 1 equivalent) in 4 ml of CH3CN is added mofroline (0.50 ml , 0.57 minoles 1.24 equivalents) and K2C03 (0.509 g, 3.68 immoles, 8 equivalents). The reaction is heated to reflux overnight. The solids are separated by filtration and the filtrate is concentrated ip vacuo. The residue is purified by flash chromatography (50% EtOAc: Hexane) to give the title compound (0.296 g, 100%) as a colorless oil. -H NMR (DMS0-d6) 6 8.53 (bt, 1H); 8.11 (d, 1H); 7.88-7.83 (m, 3H); 7.78 (d, 1H); 7.72 (dd, 1H); 3.63 (dd, 2H); 3.40 (dd, 4H); 3.21 (dd, 2H); 2.38 (dd, 2H); 2.15 (dd, 4H); 1.48 (dd, 2H); 1.22 (m, 18H); 0.82 (t, 3H); IR (KBr) 3400, 2900, 2800, 1630, 1540, 1450, 1330, 1310, 1170, 1120, 700 cm "1; Mass spectrum [(+) APCI], m / z 641/643 (M + H) J- Calculation analysis for C32H34BrF3N204: C, 59.90; H, 6.91; N, 4.37, found: C, 58.58; H, 7.01; N, 4.18.
Example 186 6- (Amino-ethoxy) -5-bromo-3'-trifluoromethyl-biphenyl-3-carboxylic acid dodecylamine To a solution of N-dodecyl-3-bromo-4- (2-bromo-ethoxy) -5- (m-trifluoromethylphenyl) -benzamide (1431 g, 2.25 mmol, 1 equivalent) in 2 ml of benzene is added bromide. tetrabutyl ammonium (0.053 g, 0.16 mmoles, 0.07 equivalents) and sodium azide (0.21S g, 3.32 mmoles, 1.48 equivalents). The reaction is heated to reflux overnight. Tetrabucilamonium bromide (0.064 g, 0.20 mmol, 0.09 equivalents) and additional sodium azide (0.224 g, 3.45 mmolee, 1.53 equivalents) are required, as indicated by CCD. The reaction is cooled to rt and the solids are removed by filtration. The filtrate is washed with H20 and dried over MgSO4. Deepuée is added to the filtrate diethyl phosphite (0.390 ml, 2.27 mmmoles, 1.0 equivalent) and the reaction is stirred overnight at rt. Additional triethyl phosphite (0.780 ml, 4.54 mmmol, 2.0 equivalents) is required after 48 hHCl gas is bubbled through the reaction mixture and stirring is continued for 72 h. The reaction is then concentrated in vacuo, dissolved in THF and washed with 2M HCl. The washings are then adjusted to pH 10 with 2.5M NaOH and extracted with CH2C12. All the organic fractions are combined, dried on MgSO4 and concentrated ip vacuo. The residue is purified by flash chromatography (7 to 12% MeoH: CH2Cl2) to give the title compound (0.0738 g, 57%) as a colorless oil. ? RHN (DMS0-d6) 6 8.57 (bt, 1H); 8.12 (d, 1H); 7.90 (m, 3H), -7.80 (d, 1H); 7.73 (dd, 1H); 3.51 (dd, 2H); 3.30 (broad s, 2H), - 3.23 (dd, 2H); 2.58 (dd, 2H); 1450 (dd, 2H); 1.25 (, 18H); 0.83 (t, 3H); IR (film) 3300, 3080, 2920, 2850, 1640, 1600, 1550, 1450, 1330, 1160, 1120, 1080 cm "1; Spectrum of maeae [< +) ESI], m / z 571/573 (M + H) *: Analysis calculated for C2BH3ßBrF3N202: C, 58.84; H, 6.70; N, 4.90, found: C, 56.61; H. 6.61; N, 4.71.
Example 187 -Bromo-3'-tr? Fluoromethyl-6- (2-ureido-ethoxy) -bi-enyl-3-carboxylic acid dodecylamide Stage 1 A solution of 6 - (amino-ethoxy) -5-bromo-3'-trifluoromethyl-biphenyl-3-carboxylic acid (0.257 g, 0.45 mmol, 1 equivalent) in 6 ml of CH2C12 is added chloroacetyl isocyanate (0.060 ml. mmoles, 1.11 equivalents). The reaction is stirred at rt 15 min and then concentrated ip vacuo. The residue is purified by flash chromatography (30% EtOAc: Hexane) to give 5-bromo-N- (8-phenyloctyl) -6- [2- ( { [(2,2,2-trichloroacetic) amino] carbonyl .}. amino) ethoxy] -3 '- (trifluoromethyl) [1,1'-biphenyl] -3-carboxamide (0.273 g, 80%) as a colorless oil. 'HRMN (DMS0-d6) d 11.28 (s,, 1H); 8.60 (bt, 1H); 8.15 (d, 1H); 8.05-7.85 (m, 4H); 7.80-7.64 (m, 2H); 3.64 (t, 2H); 3.24 (m, 4H); 1.52 (m, 2H); 1.26 (m, 18H); 0.87 (t, 3H).
Stage 2 To a solution of 5-bromo-N- (8-phenyloctyl) -6- [2- ( { [(2,2,2-trichloroacetyl) amino] carbonyl) amino) ethoxy] -3 '- (trifluoromethyl) [1,1 '-biphenyl] -3-carboxamide in CH 2 Cl 2 / MeOH (10/4) (14 ml) is added 2 ml of 1M NaOH. The reaction is stirred at rt overnight and concentrated ip vacuo. The residue is extracted with CH2C12, dried over MgSO4 and concentrated ip vacuo. The residue is purified by flash chromatography (3 to 5% of MeOH: CH 2 Cl 2) to provide the title compound (0.203 92%) as a white solid. p.f. 122.5-125.1 ° C; * H NMR (DMSO-d6) d 8.58 (bt, 1H); 8.12 (d, 1H); 7.90 (m, 3H); 7.78 (d, 1H); 7.73 (dd, 1H); 6.95 (t, 1H); 5.44 (s, 2H), 3.48 (dd, 2H); 3.24 (dd, 2H); 3.05 (ddd, 2H); 1.48 (dd, 2H); 1.25 (m, 18H); 0.84 (t, 3H); IR (KBr) 3300, 2950, 2820, 1650, 1600, 1550, 1460, 1330, 1180, 1120, 1080, 1030, 900, 805 cm "1; Mass spectrum [(+) ESI], m / z 614 / 616 (M + H) *; Analysis calculated for C29H39BrF3N303: C, 56.68; H, 6.40; N, 6.84, found: C, 56.37; H, 6.25; N, 6.49.
Example 188 [2- (3-Bromo-5-dodecylcarbamoyl-3 '-tri luoromethyl-biphenyl-2-yloxy) -ethyl] -carbamic acid methyl ester To a solution of 6- (amino-ethoxy) -5-bromo-3'-trifluoromethyl-biphenyl-3-carboxylic acid dodecylamide (0.273 g, 0.48 mmol, 1 equivalent) in 6 ml of THF at 0 ° C is added triethylamine ( 0. 150 mL, 1.08 mmol, 2.25 equivalents) followed by methyl chloroformate (0.040 mL, 0.052 mmol, 1.11 equivalents). The reaction is stirred for 15 min and then poured into a buffer pH 7 and extracted with Et20.
The combined organic fractions are dried over MgSO4 and concentrated ip vacuo. The residue is purified by flash chromatography (30% EtOAc: Hexane) to give the title compound (0.282 g, 93%) as a white solid. p.f. 79.6-80.5 ° C; ? NMR (DMS0-dβ) d 8.56 (bt, 1H); 8.12 (d, 1H); 7.88 (m, 3H); 7.79 (d, 1H); 7.70 (t, 1H); 7.02 (t, 1H); 3.54 (dd, 2H); 3.44 (s, 3H), -3.24 (dd, 2H); 3.08 (ddd, 2H); 1.48 (dd, 2H); 1.23 (m, 18H); 0.83 (t, 3H); IR (KBr) 3330, 2950, 2840, 1695, 1640, 1540, 1340, 1180, 1110, 920, 805 cm'J- Eepectro de maeae [(+) MAT900], m / z 629/631 (M + H) *; Analysis calculated for C3H40BrF3N2O4: C, 57.23; H, 6.40; N, 4.45, found: C, 56.12; H, 6.29; N, 4.29.
Example 189 Acid [5 '- (6-Phenyl-hexylcarbamoyl) -3,3' '-bis-trifluoromethyl- [1,1'; 3 ', 1") terphenyl-2'-yloxy] acetic acid Step 1: To a solution of 3,5-bis- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) benzoic acid ethyl ether (0.560 g, 1. 12 mmol, 1 equivalent) in 25 ml of THF / EtOH (3/2) is added 4 ml of 1M NaOH and the reaction is stirred at rt during the course of the reaction. night. It is then concentrated in vacuo, diluted with H20 and acidified with 2M HCl to pH 1. Extract with CH2C12, dry over MgSO4 and concentrate ip vacuo. To a solution of the residue in 20 ml of CH2C12 is added f-enylhexylamine (0.3 10 ml, 1.69 mmoles 1.5 equivalents), 1-hydroxybenzotriazole (0.174 g, 1.29 mols, 1.15 equivalents), triethylamine (0.500 ml, 3.58 mmoles, 3.2 equivalents) and dicyclohexylcarbodiimide (0.290 g, 1.41 immoral, 1.26 equivalents). The reaction is stirred at rt overnight, diluted with EtOAc, and then washed with a 1M HCl solution, brine, saturated sodium bicarbonate solution and brine. The organic factions are dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (30% EtOAc: Hexane) to give N- (8-phenyl-hexyl) -3,5-bis (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide (0.701 g , 99%) as a white solid. * H NMR (CDCI3) d 7.92 (s, 2H); 7.84 (m, 4H); 7.70-7.54 (m, 4H), - 7.30-7.14 (m, 5H) 6.55 (t, 1H); 3.43 (dd, 2H); 3.32 (m, 4H); 2.59 (t, 2H); 1.64 (m, 4H), 1.38 (m, 4H).
Stage 2 The title compound is prepared as a white solid (0.058 g, 50%) from N- (6-phenyl-hexyl) -3,5-bis (m- trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide using a procedure similar to that of step 3 of example 175. p.p. 166.5-168.8 ° C; 'HEMH (DMSO-dβ) 6 12.60 (s broad, 1H); 8.56 (t, 1H); 7.98 (s, 2H); 7.94-7.90 (m, 4H); 7.80-7.68 (m, 4H); 7.26-7.10 (m, 5H); 3.80 (s, 2H); 3.22 (dd, 2H); 2.54 (t, 2H); 1.54 (m, 4H); 1.06 (m, 4H); IR (KBr) 3.350, 2930, 2860, 1720, 1610, 1570, 1470, 1320, 1200, 1120 cm'1; Mass spectrum [(-) ESI], m / z 642 (M-H) J- Analysis calculated for C3sH3lF6N04: C, 65.32; H, 4.85; N, 2.18, found: C, 64.85; H, 4.92; N, 2.13.
Example 190 Acid [3-Bromo-5- (6-phen? L-hex? Lcarbamoyl) -3 '-trifluoromethyl-biphenyl-2-yloxy] -acetic acid Stage 1 N- (6-hexyl-oc t il) -3-bromo-5 - (m-tpf luoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide is prepared as a white solid (0.221 g, 64%) from of the ethyl ester of 3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) - benzoic using a procedure similar to step 1 of example 189. * H NMR (CDC13) d 7.98 (d, 1H); 7.84-7.50 (m, 5H); 7.30-7.14 (m, 5H); 6.66 (bt, 18); 3.62 (m, 4H); 3.41 (dd, 2H); 2.58 (t, 2H); 2.24 (broad s, 1H) 1.64 (m, 4H); 1.46 (m, 4H).
Stage 2 The title compound is prepared as a white foam (0.099 g, 44%) from N- (6-hexyl-octyl) -3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) - benzamide using a procedure similar to step 3 of example 175.? NMR (DMSO-d6) d 12.85 (broad e, 1H), -8.56 (t, 1H); 8.12 (d, 1H); 7.92-7.84 (m, 3H); 7.77 (d, 1H); 7.69 (t, 1H); 7.22-7.10 (m, 5H); 4.14 (s, 2H); 3.22 (dd, 2H); 2.53 (t, 2H), 1.50 (m, 4H); 1.30 (m, 4H) ¡IR (KBr) 3330, 2950, 2850, 1740, 16301 1550, 1450, 1420 1330, 1180, 1100, 900 cm "1; Spectrum of maeae [< -) ESI], m / z 606/608 (MH) "; Analysis calculated for C2ßH27BrF3N04: C, 58.14; H, 4.7 1; N, 2.42, found: C, 57.62;, H, 4.80; N, 2.35.
Example 191 (8-enyl-octyl) -amide of 2 '-hydroxy-3,3"-bis-trifluoromethyl- [1,1': 3 '1"] terphenyl-5'-carboxylic acid To the ethyl ester of the acid 3, 5- Bis- (m-trifluoromethylphenyl) -4-hydroxybenzoic acid (0.315 g, 0.74 mmol, 1 equivalent) was added 2 ml of thionyl chloride and the reaction was stirred overnight at rt and concentrated ip vacuo. It is then added to a solution of phenyl octylamine (0.222 ml, 1.12 mmoles 1.51 equivalents) and triethylamine (0.470 ml, 337 immoles, 4.6 equivalents). The reaction is stirred at rt 1 h, poured into a 0. IN solution of HCl and extracted with Et20. The combined organic fractions are washed with IN HCl (x3), dried over MgSO4 and concentrated ip vacuo. The residue is purified by inantantial chromatography (20% EtOAc: Hexane) to give the title compound (0.393 g, 86%) as a colorless oil. 'H NMR (DMS0-d6) 6 9.30 (s, 1H); 8.42 (t, 1H) -, 7.91-7.85 (m, 4H); 7.82 (s, 2H); 7.75-7.65 (m, 4H); 7.26-7.10 (m, 5H); 3.23 (dd, 2H); 2.52 (t, 2H); 1.52 (m, 4H); 1.27 (m, 8H); IR (film) 3330, 2980, 2840, 1640, 1600, 1550, 1470, 1320, 1180, 1120, 1080, 900, 805 cm "1; Mass spectrum [(+) APCI], m / z 614 (M + H) J- Analysis calculated for C3SH33FβN02: C, 68.51; H, 5.42; N, 2.28, found: C, 66.76; H, 5.46; N, 2.18.
Example 192 - [5 '- (8-phenyl-octylcarbamoyl) -3.3"-bis-trifluoromethyl-1.1'; 3 '. Ln] terphenyl-2'-yloxy] -pentanoic acid Stage 1 To a solution of 2'-hydroxy-3, 3"-bis-trifluoromethyl- [1,1 ', -3', l"] terphenyl-5'-carboxylic acid (8-phenyloctyl) -amide (0.313 g, 0.64 immoles, 1 equivalent) in 6 ml of acetone is added K2C03 (0.460 g, 3.33 tronols, 5.2 equivalents) and 5-bromromethyl valerate (0.090 ml, 0.63 mmol, 1 equivalent). The reaction is refluxed for 2 days, cooled to rt and concentrated ip vacuo. The residue is partitioned between EtOAc and brine, dried over MgSO4 and concentrated ip vacuo. The residue is purified by flash chromatography (25% EtOAc: hexane) to give N- (8-phenyl-hexyl) -3,5-bis (m-trifluoromethylphenyl) -4-hydroxybenzamide (0.396 g, 85%) as an oil. colorless. JH NMR (CDC13) d 7.91 (s, 2H), 7.80 (m, 4H), 7.66-7.54 (m, 4H), 7.28-7.12 (m, 5H), 6.23 (bt, 1H), 3.59 (8, 3H) ), 3.44 (dd, 2H), 3.17 (t, 2H), 2.58 (t, 2H), 1.95 (t, 2H), 1.60 (m, 4H), 1.52 (m, 12H).
Stage 2 To a solution of N- (8-phenyl-hexyl) -3,5-bis (m- • trifluoromethylphenyl) -4-hydroxybenzamide (0.396 g, 0.54 mmol, l equivalent) in 10 ml of THF / EtOH (3/2) is added 4 ml of 1M NaOH and the reaction is stirred at rt overnight. After concentrating ip vacuo, it is diluted with H20 and acidified with HCl 2M at pH 1. Extract with CH2C12, dry over MgSO4 and concentrate ip vacuo. The residue is purified by flash chromatography (25% EtOAc: hexane + 1% formic acid) to give the title compound (0.367 g, 95%) as a colorless oil. XH NMR (DMS0-dβ) d 11.91 (broad s, 1H), 8.56 (t, 1H), 7.98-7.90 (m, 6H), 7.80-7.70 (m, 4H), 7.26-7.12 (m, 5H), 3.25 (dd, 2H), 3.13 (t, 2H), 2.52 (t, 2H), 1.80 (t, 2H), 1.50 (m, 4H), 1.27 (m, 8H), 1.12 (m, 4H), IR (film) 3300, 2950, 2800, 1710, 1620, 1550, 1490, 1460, 1320, 1160, 1120 cm "1; mass [(+) ESI], m / z 714 (M + H) *, - Analisis calculated for C40H41F6N04: C, 67.31; H, 5.70; N, 1.96, Found: C, 64.95, H, . 99; N, 1.57. 20 Example 193 -Bromo-6- (2-piperazin-1-yl-ethoxy) -3 '-trifluoromethyl-biphenyl-3-carboxylic acid (8-phenyl-octyl) -amide The title compound is prepared as a yellow oil (0.302 g, 45%) from N- (8-phenyl-octyl) -3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) - benzamide and piperazine using a procedure similar to that of Example 185. * H NMR (DM? O-ds) d 8.58 (t, 1H), 8.12 (d, 1H), 7.90-7.84 (m, 3H), 7.96 (d, 1H), 7.52 (dd, 1H), 7.26-7.10 (m, 5H), 3.61 (t, 2H), 3.23 (dd, 2H), 2.62 (t, 4H), 2.52 (t, 2H), 2.36 (t, 2H), 2.18 (m, 5H), 1.50 (m, 4H), 1.24 (m, 8H), IR (film) 3290, 2920, 2850, 1720, 1630, 1600, 1545, 1460, 1330, 1170, 1120, 1080 cm "1, mass spectrum K +) ESI], m / z 660/662 (M + H) J- Calculated analysis for C34H41BrF3N302: C, 61.82; H, 6.26; N, 6. 36; Found: C, 58.20; H, 6.00; N, 5.47.
Example 194 -Bromo-6-hydroxy-3'-trifluoromethyl-bifenyl-3-carboxylic acid (8-f-enyl) -amide The title compound is prepared as a white gum (0.976 g, 58%) from N- (8-f-enyl-octyl) -3,5-bis (m-trifluoromethyl-phenyl) -4-hydroxy-benzamide using a procedure similar to that of Example 191. 1 H NMR (DMS0-d6) d 9.84 (s, 1H), 8.42 (t, 1H), 8.04 (d, 1H), 7.85-7.67 (m, 5H), 7.26-7.10 ( m, 5H), 3.21 (dd, 2H), 2.52 (t, 2H), 1.50 (m, 4H), 1.26 (m, 8H), IR (KBr) 3330, 2950, 2850, 1620, 1550, 1495, 1470, 1330, 1220, 1170, 1120, 1100, 1080 cm "1; spectrum of maea [(+) APCI], m / z 549 (M + H) *; Analysis calculated for C2BH29F3N02: C, 61.32; H, 5.33; N, 2.55; Found: C, 61.02; H, 5.29; N, 2.51.
Example 195 Acid4- [3-bromo-5- (8-phenyl-octylcarbamoyl) -3'-trifluoromethyl-biphenyl-2-yloxysulfonyl-2-hydroxy-benzoic acid The title compound is prepared as an orange foam (0.455 g, 76%) from 5-bromo-6-hydroxy-3'-trifluoromethyl-biphenyl-3-carboxylic acid (8-phenyl-octyl) -amide and 4-chloro-sulfonyl-2-hydroxybenzoic acid using a procedure similar to Step 3 of Example 179. XH NMR (DMS0-d6) d 12.60 (broad s, 1H), 11.60 (broad s, 1H), 8.68 (t, 1H) , 8.21 (d, 1H), 7.84 (d, 1H), 7.71-7.62 (m, 2H), 7.56-7.44 (m, 3H), 7.26-7 10 (m, 5H), 6.96 (dd, 1H), 6.82 (d, 1H), 3.21 (dd, 2H), 2.62 < t, 4H), 2.53 (t, 2H), 1.52 (m, 4H), 1.25 (m, 8H); IR (KBr) 3370, 2950, 2825, 1690, 1640, 1605, 1560, 1540, 1390, 1325, 1195, 1170, 1125 cm'1, - mass spectrum [(-) ESI], m / z 660/662 (MH) "Analysis calculated for C35H33BrF3NO, S: C, 56.16; H, 4.44; N, 1.87; Found: C, 55.65; H, 4.27; N, 1.90; Example 196 7- [5 '- (8-phenyl-octylcarbamoyl) -3.3"-bis-trifluoromethyl-ri.l'; 3 ', 1"] ter enyl-2'-yloxy] -heptanoic acid The title compound is prepared as a colorless oil (0.189 g, 64%) from (2-hydroxy-3, 3"-bis-trifluoromethyl- [1,1 ', 3'] (8-phenyloctyl) -amide. , 1"] terphenyl-5 '-carboxylic acid and ethyl 7-bromoheptanoate using a procedure similar to example 192. XH NMR (DMSO-d6) d 11.90 (broad e, 1H), 8.56 (t, 1H), 7.95-7.90 (m, 6H), 7.80-7.70 (m, 4H), 7.25-7.10 (m, 5H), 3.27 (dd, 2H), 3.14 (t, 2H), 2.52 (t, 2H), 2.02 (t, 2H) ), 1.52 (m, 4H), 1.26 (m, 10H), 1.08 (m, 2H), 0.84 (m, 4H); IR (film) 3375, 2980, 2870, 1705, 1630, 1550, 1460, 1320, 1120, 1080 cm "1; mass spectrum [(-) ESI], m / z 740 (MH); Analysis calculated for C42H45F6N04: C, 68.00; H, 6.11; N, 1.89; Found: C, 66.26; H, 5.14; N, 1.65.
Example 197 (8-phenyl-octyl-amine) of 2 '- (2-hydroxy-3,4-dioxo-cyclobut-1-enylamine) -ethoxy] -3,3"-bis-trifluoromethyl- [1,1' 3 '. 1"] terphenyl-5'-carboxylic acid Stage 1 N- (8-phenyloctyl) -4- (2-amino-ethoxy) -3,5-bis (m-trifluoromethylphenyl) -benzamide is prepared as a colorless oil (0.189 g, 64%) from N- (8 phenyl-octyl) -3,5-bis (-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide using a procedure similar to Example 186. JH NMR (CDC13) d 7.91-7.76 (m, 6H), 7.70- 7.54 (m, 4H), 7.26-7.10 (m, 5H); 6.34 (bt, 1H), 3.45 (dd, 2H); 3.22 (t, 2H); 2.56 (t, 2H), 2.45 (t, 2H); 1.93 (broad s, 2H); 1.60 (m, 4H), 1.32 (m, 8H).
Stage 2 To a solution of diethoxycyclobutane (0.060 ml, 0.41 mmol, 1.6 equivalents) in EtOH (2 ml) is added a solution of N- (8-phenyloctyl) -4- (2-amino-ethoxy) -3,5-bis ( m-trifluoromethylphenyl) benzamide (0.170 g, 0.26 mmol, 1 equivalent) in EtOH (2 mL). The reaction is stirred at rt overnight and then concentrated ip vacuo. The residue is purified by flash chromatography (30 to 50% EtOAc: Hexane + 1% formic acid) to provide a colorless oil. The oil is dissolved in 10% aqueous THF saturated with HCl and stir overnight at rt. It is then concentrated and partitioned between brine and CH2C12 and extracted with CH2C12. The The combined organic fractions are dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (5% ME0H: CH2C12) to give the title compound (0.143 g, 83%) as a purple foam. 3 H NMR (DMSO-dβ) 6 8.56 (t, 1H); 7.78-7.70 (m, 6H); 7.74-7.62 (m, 5H); 7.26-7.12 (m, 5H); 3.60 (s, 1H); 3.31 (t, 2H); 3.25 (dd, 2H); 3.14 (t, 2H); 2.5 (t, 2H); 1.52 (m, 4H); 1.27 (m, 8H); IR (KBr) 3375, 2950, 2840, 1810, 1700, 1600, 1550, 1460, 1410, 1350, 1320, 1210, 1160, 1120, 1080 cm "1, - mass spectrum [(+) APCI], m / z 753 (M + H) *: Analysis calculated for C41H3βF6N205: C, 65.42; H, 5.09; N, 3.72; Found: C, 63.77; H, 4.96; N, 3.63; Example 198 2'- [4- (1H-Tetrazol-5-yl) -butoxy-3, 3"-bis-trifluoromethyl- [1,1 '; 3', 1"] terfen? (8-phenyloctyl) -amide? l-5 '-carboxylic Stage 1 To a solution of (8-phenyl-octyl) -amide of acid 2 '-hydroxy -3,3"-bie -trifluoromethyl- [1,1': 3 '1"] terphenyl-5'-carboxylic acid (0.557 g, 0.91 mmolee, 1 equivalent) in acetone (8 ml) is added K2C03 (0.648 g, 4.68 immoles, 5.14 equivalents) and 5-bromovaleronitrile (0.110 ml, 0.94 mmoles, 1.03 equivalents). The reaction is heated to reflux during night, cool to rt and concentrate in vacuo. The residue is partitioned between EtOAc and brine, dried over MgSO4 and concentrated ip vacuo. The residue is purified by flash chromatography (25% EtOAc: hexane) to give N- (8-phenyl-hexyl) -3,5-bis (m-trifluoromethylphenyl) -4- (4-cyanobutoxy) benzamide (0.527 g , 83%) as a colorless oil. 3 H NMR (CDC13) d 7.98-7.45 (m, 10 H), -7.25-7.10 (m, 5H); 6.25 (bt, 1 H); 3.45 (dd, 2H); 3.18 (t, 2H); 2.58 (t, 2H); 1.97 (t, 2H); 1.62 (m, 4H); 1.54 (m, 12H).
Stage 2 To a solution of N- (8-phenyl-hexyl) -3,5-bis (m-trifluoromethylphenyl) -4- (4-cyano-butoxy) benzamide (0.527 g, 0.76 mmol, 1 equivalent) in 8 ml of xylene sodium azide (0.065 g, 1.0 mmol, 1.3 equivalents) and tributyltin chloride (0.300 ml, l.ll mmolee, 1.46 eq.) are added. The reaction is heated to reflux for 4 days and cooled to rt. 4 ml of a 6M HCl solution is added and the reaction is stirred for three days. It is poured into brine and extracted with EtOAc. The combined organic fractions are dried over MgSO4 and concentrated ip vacuo. The residue is first purified by flash chromatography (5% MeOH: CH2C12) and then by CLAP [85% CH3CN in 0.1% TFA) to give the title compound (0.265 g, 47%) as a white solid. Mp 145.4-150.8 ° C Jl NMR (DMS0-d6) 6 8.55 (t, 1H); 7.97-7.70 (m, 6H); 7.76-7.68 (m, 4H); 7.26-7.20 (m, 2H); 7.16-7.10 (m, 3H); 3.26 (dd, 2H); 3.17 (t, 2H); 2.52 (t, 2H); 1.52 (m, 4H); 1.27 (m, 12H); 1.12 (m, 2H); IR (KBr) 3400, 3300, 2950, 2875, 1680, 1630, 1550, 1450, 1330, 1120, 1080 cm "1; mass spectrum [(+ JAPCI], m / z 738 (M + H) J- Analysis calculated for C40H41F6N502: C, 65.12; H, 5.60; N, 9.49, Found: C, 58.55, H, 5.10; N, 7.98.
Example 199 2-Methoxy- [5 '- (8-enyl-octylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 '' '] terphenyl-2'-yloxymethyl] -benzoic acid Stage l A solution of 2'-hydroxyl-3, 3"-bisp-trifluoromethyl- [1,1 ', - 3' 1 ''] terphenyl-5'-carboxylic acid (8-phenyl-octyl) -amide. (0.755 g, 1.23 mmoles, 1 equivalent) in 12 ml of acetone is added K2C03 (0.857 g, 6.2 mmoles, 5.0 equivalent) and 4-bromomet? L-2-methoxy benzoic acid methyl ester (Julia, M., Chastrette, F .; BSCFAS; Bull, Soc, Chim, Fr.; FR: 1962; 2255-2261). (0.325 g, 1.25 mmol, 1.0 eq). The reaction is refluxed overnight.
Additional methyl ester of 4-bromo-methyl-2-methoxybenzoic acid (0.072 g, 0.28 immoles, 0.2 eq) is added and refluxing is continued for 1H. The reaction is cooled to rt and concentrated ip vacuo. The residue is partitioned between EtOAc and brine, washed with brine, dried over MgSO4 and concentrated ip vacuo. The residue is purified by flash chromatography (20% EtOAc / hexane) to give the methyl ester of 2-methoxy-4- [5 '- (8-phenyl-octylcarbamoyl) -3,3' '-bie-trifluoromethyl- [ 1,1 ': 3' 1"'] terphenyl-2'-yloxymethyl] -benzoic acid (0.847, 87%) as a colorless oil. 1H NMR (CDC13) 6 7.88-7.42 (m, 10H); 7.25-7.10 (m, 5H); 6.24-6.10 (m, 3H); 4. 18 (s, 2H); 3.85 (e, 3H); 3.65 (s, 3H); 3.46 (dd, 2H); 2.58 (t, 2H), - 1.60 (m, 4H); 1.34 (m, 8H).
Stage 2 To a solution of 2-methoxy-4- [5 '- (8-f-enyl-oct-icarbamoyl) -3,3"-bis-trifluoromethyl- [1, 1', -3 '1'] methyl ester. '] terphenyl-2'-yloxymethyl] -benzoic acid (0.352 g, 0.44 mmol, 1 eq) in lOml of THF / EtOH 4 ml of 1M NaOH are added and the reaction is stirred at rt overnight. It is then concentrated ip vacuo, diluted with H20 and acidified with 2M HCl to pHl. Extract with EtOAc, wt. On MgSO4 and concentrate ip vacuo. The residue is purified by flash chromatography (20% EtOAc / hexane + 1% formic acid) to provide the "" - - IWTT compound of the title (0.342g, 865) as a white foam. "H NRM (DMSO-d6) d 12.50 (S aplio, 1H), 8.59 (t, 1H), 7.99-7.92 (m, 6H), 7.80-7.68 (m, 4H), 7.37 (d, 1H), 7.26 -7.10 (m, 5H);; 6.38 (e, 1H); 6.30 (d, 1H); 4.21 (s, 2H), -3.58 (s, 3H); 3.26 (dd, 2H); 1.53 (m, 4H); ); 1.28 (m, 8H); IR (KBr) 3350, 2950, 2850, 1720, 1640, 1620, 1550, 1495, 1475, 1415, 1320, 1160, 1150, 1120, 1095, 1080, 1030 cm "1; mass spectrum [(+) APCI], m / z 778 (M + H) *; analysis calculated for C44H41F6N05: C, 67.95; H, 5.31; N, 1.80; found: C, 67.22; H, 5.22; N, 1.74.
Example 200 2-Hydroxy-4- [5 '- (8-phenyl-octylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 '1"] terphenyl-2'-yloxymethyl] -benzoic acid To a solution of 2-methoxy-4- [5 '- (8-phenyl-octylcarbamoyl) -3,3"-bis-trif-loromethyl- [1,1': 3 '1"] terfenyl methyl ester -2'-yloxymethyl] -benzoic acid (0.418g, 0.53 immoles, 1 equivalent) in 9 ml of CH2C12 cooled to 0 ° C, BBr3 (1M in CH2C12) (O.βOOOO, 0.53 mmol, 1 equivalent) is added. The reaction is stirred at 0 ° C for 40 min., Poured onto ice and extracted with EtOAc. The combined organic fractions are washed with brine, dried over MgSO4 and concentrated ip vacuo. The residue is purified by flash chromatography (20 to 30% EtOAc: hexane + 1% formic acid) to provide 2-hydroxy-4- [5 '- (8-phenyl-octylcarbamoyl) -3,3' '-bie-trifluoromethyl- [1, 1': 3 '1"] terphenyl-2' methyl ester iloxymethyl] -benzoic acid (see example below) and the title compound (0.201 g, 50%) as a white foam. XH NRM (DMSO-d6) 6 13.60 (broad s, 1H); 11.10 (broad e, 1H); 8.59 (broad t, 1H); 7.96-7.92 (m, 6H); 7.78-7.66 (m, 4H); 7.48 (d, lh); 7.26-7.10 (m, 5h); 6.26 (d, 1H); 6.21 (dd, lh); 4.18 (dd, 2H); 3.24 (dd, 2h); 2.52 (t, 2H), 1.52 (m, 4H); 1.27 (m, 8H); IR (film) 3300, 2950, 2800, 1680, 1630, 1590, 1540, 1440, 1320, 1260, 1205, 1160, 1120, 1095, 1080, 990 cm "1; mass spectrum [(-) ESI], m / z 776 (MH) "; analysis calculated for C43H39FsN05: C, 67.62; H, 5.15; N, 1.83; found: C, 67.21; H, 5.11; N, 1.71.
Example 201 Methyl ester of the acid-hydr oxy-4 - [5 '- (8-f-enyl-octylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 '1' '] terphenyl-2'-yloxymethyl ] -benzoic acid The title compound is prepared as a yellow oil (0.198g, 48%) using the procedure of the example 200. 'HNRM (DMSO-ds) d 10.36 (s, 1H); 8.59 (broad t, 1H); 7.94 (m, 6H); 7.76-7.66 (m, 4H); 7.47 (d, 7H); 7.25-7.10 (m, 5H); 6.82 (d, 1H); 6.74 (dd, 1H); 4.18 (dd, 2H); 3.84 (s, 3H); 3.26 (dd, 2H); 2.52 (t, 2H); I, 52 (m, 4H); 1.27 (m, 8H); IR (film) 3330, 2950, 2850, 1680, 1600, 1580, 1550, 1460, 1420, 1320, 1210, 1150, 1115, 1080 cm "1; mass spectrum [(-) ESI], m / z 762 ( MH), analysis calculated for C44H41F6N05: C, 67.95; H, 5.31; N, 1.80, found: C, 67.11; H, 5.29; N, 1.73.
Example 202 4- (- [3-Bromo-5- (8-phenyl-octylcarbamoyl) -3 '-trif luoromethyl-bifenyl-2-yloxy] -ethoxy) -2-hydroxy-benzoic acid Stage 1 To a solution of N- (8-phenyl-octyl) -3-bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide (0.687 g, 1. 16 mmoles, 1 equivalent) in 10 ml of THF is added triphenylphosphine (0.680 g, 2.59 mmolee, 2.23 equivalent) and methyl 2,4-dihydroxybenzoate (0.388 g, 2.30 mmol, 2.0 equivalent). The reaction is cooled to 0 ° C and diethyl azodicarboxylate (0.220 ml, 1.40 mmol, 1.2 equivalent) is added. The cold bath is removed and the reaction is stirred overnight at rt. The reaction mixture is then poured into a 0.1 N HCl solution and extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4 and concentrated ip vacuo. The refund is purified by flash chromatography (20% EtOAc: hexane) to give the methyl ester of 4-acid. { 2 - [3-Bromo-5- (8-phenyl-octylcarbamoyl) -3 '-trifluoromethyl-biphenyl-2-yloxy] -ethoxy} -2-hydroxy-benzoic. ? NRM (CDC13) d 11.90 (s, 1H), -7.97 (d, 1H); 7.84-7.50 (m, 6H); 7.28-7.12 (m, 5H); 6.40 (m, 1H); 6.24 (m, 1H); 6.10 (broad t, 1H); 4.12 (dd, 2H); 4.00 (m, 2H); 3.92 (s, 3H); 3.45 (dd, 2H); 2.59 (t, 2H); 1.60 (m, 4H); 1.33 (m, 8H).
Stage 2 To a solution of the methyl ester of acid 4-. { 2- [3-Bromo-5- (8-phenyl-octylcarbamoyl) -3 '-tpfuoro-methyl-biphenyl-2-yloxy] -ethoxy} -2-Hydroxy-benzoic acid (1.16 mmole, 1 equivalent) in 20 ml of EtOH is added 10 ml of 1M NaOH and the reaction is heated to reflux for 90 minutes. It is then cooled to rt, concentrated ip vacuo, diluted with H20 and acidified with 2 M HCl to pH 1. Extract with EtOAc, dry over MgSO4 and concentrate in vacuo. The residue is purified by flash chromatography (30% EtOAc: hexane + 1% formic acid) to give the title compound (0.607 g, 79%) as a white foam. 1 H NMR (DMSO-d 6) 6 13.55 (broad s, 1H); 11.49 (s aplio, 1H); 8.58 (t, 1H); 8.14 (d, 1H); 7.90-7.84 (m, 3H); 7.73-7.61 (m, 3H); 7.26-7.12 (m, 5H); 6.27-6.23 (m, 2H); 4.00 (m, 2H); 3.92 (m, 2H); 3.23 (dd, 2H); 2.52 (t, 2H); 1.52 (m, 4H); 1.28 (m, 8H); IR (KBr) 3400, 2950, 2850, 1660, 1620, 1550, 1450, 1420, 1330, 1220, 1160, 1120 cm "1; mass spectrum [(-) ESI], m / z 726/728 (MH) '; analysis calculated for C37H37F3N06: C, 60.99; H, 5.12; N, 1.92, found: C, 60.32; H, 5.17; N, 1.83.
Example 203 2-Hydroxy-4- [5 '- (8-f-enyl-octylcarbamoyl) -3,3"-bis-trif-loromethyl- [1,1': 3 '' '] terphenyl-2'-alkoxysulfonyl] - benzoic The title compound is prepared as a white foam (0.541 g, 78%) from 2'-hydroxy-3-3 '' -bie-trifluoromethyl- (1,1-phenyl-octyl) -amide. ': 3'1' '] terphenyl-5'-carboxylic acid and 4-chloro-sulfonyl-2-hydroxy-benzoic acid using a procedure similar to Step 3 of Example 179.' HNRM (DMSO-ds) 6 11.60 (s broad, 2H); 8.70 (t, 1H); 7.94 (e, 2H); 7.88-7.80 (, 4H); 7.69-7.57 (m, 5H); 7.26-7.10 (m, 5H); 6.68 (dd, 1H); 6.57 (d, 1H); 3.25 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H), - 1.28 (m, 8H); IR (KBr) 3400, 2950, 2840, 1690, 1640, 1600, 1550, 1460, 1380, 1320, 1280, 1200, 1170, 1120, 1080 cm "1; mass spectrum [(-) ESI], m / z 812 (mH) ", -analysis calculated for C42H37F6N07S: C, 61.99; H, 4.58; N, 1.72, found: C, 61.40; H, 4.80; N, 1.68.
Example 204 4 - [3-Bromo-5- (8-phenyl-octylcarbamoyl) -3 '-trifluoromethyl-biphenyl-2-yloxymethyl] -2-methoxy-benzoic acid The title compound is prepared as a white foam (0.400 g, 90%) from the (8-phenyl-octyl) -amide of 5-bromo-6-hydru:.? - 3 '-trifluoromethyl-biphenyl- 3-carboxylic using a procedure similar to Example 199. XH NRm (DMSO-d6) 612.50 (broad s, 1H); 8.8 (t, 1H); 8.18 (d, 1H); 7.90 (d, 1H); 7.85 (m, 2H); 7.77 (d, 1H); 7.69 (t, 1H); 7.50 (d, 1H), -7.25-7.10 (m, 5H); 6.80 (d, lh); 6.69 (dd, 1H); 4.63 (s, 2H); 3.70 (s, 3H); 3.24 (dd, 2h); 2.53 (t, 2H); 1.54 (m, 4H); 1.28 (m, 8H); IR (KBr) 3300, 2950, 1720, 1630, 1610, 1550, 1460, 1420, 1380, 1320, 1180, 1120, cm "1; mass spectrum [(-ESI], m / z 710 (MH); calculated for C37H37BrF3N05: C, 62.36; H, 5.23; N, 1.97, found: C, 61.50; H, 5.75; N, 1.91.
Example 205 -bromo-6- (lH-tetra-5-ylmethoxy) -3 '-trif luoromethyl-bifenyl-3-carboxylic acid (8-f-enyl-octyl) -amide.
The 5-bromo-6 - (cyanomethoxy-N- (8-phenyloctyl) -3'-trifluoromethyl) [1,1'-biphenyl] -3-carboxamide is prepared as a white foam (0.400 g, 90%) from of 5-bromo-6-hiroxy-3'-trifluoromethyl-bifenyl-3-carboxylic acid (8-phenyl-octyl) -amide and bromo acetonitrile using a procedure similar to Step 1 of Example 198. XH NRM (CDCl 3) d 8.00 (d, 1H); 7.83-7.58 (m, 5H); 7.28-7.10 (m, 5H); 6.09 (m, 1H); 4.40 (S, 2H); 3.43 (dd, 2H); 2.58 (t, 2H); 1.58 (m, 4H); 1.32 (m, 8H).
Stage 2 To trimethyl aluminum (2M in toluene) (0.380 ml, 0.76 mmol, 1.22 equivalents) was added azido trimethylsilane (0.100 ml, 0.75 mmol, 1.2 equivalents). 5-Bromo-6- (cyanomethoxy) -N- (8-phenyloctyl) -3 '- (trifluoromethyl) [1,1'-biphenyl] -3-carboximide (0.365 g, 0.62 mmol, 1 equivalent) is then added to a solution in 1.5 ml of toluene. The reaction is heated to reflux for 7 days until the LCD indicates the consumption of most of the initial material. The reaction mixture becomes partially solid. It is then cooled to rt and partitioned between toluene and a 6M HCl solution. The aqueous layer is extracted with EtOAc, the combined organic fractions are dried over MgSO, and concentrated in vacuo. The residue is purified by chromatography Instantaneous (30% EtOAc: Hexane + 1% formic acid) to provide the title compound (0.150g, 37%) as a light yellow foam. 'H NRM (DMSO-ds) 6 8.62 (t, 1H); 8.15 (d, 1H); 7.87 (d, 1H); 7.79-7.0 (m, 4H); 7.66-7.61 (t, 1H); 7.26-7.12 (m, 5H); 5.00 (e, 2H); 3.24 (dd, 2H); 2.52 (t, 2H); 1.52 (m, 4H); 1.28 (m, 8H); IR (KBr) 330, 2950, 2850, 1620, 1550, 1460, 1320, 1170, 1120 cm "1; maeas spectrum [(+) APCI], m / z 630 (M + H) *, - analysis calculated for C30H31BrF3N502: C, 57.15; H, 4.96; N, 11.11, found: C, 55.24; H, 4.92; N, 10.50.
Example 206 2 '- (lH-tetrazol-5-ylmethoxy) -3,3"-bis-trifluoromethyl- [1,1': 3 '1' '] terphenyl-5'-carboxylic acid (8-phenyloctyl) -amide.
The title compound is prepared as a white foam (0.486 g, 84%) from the 2'-hydroxy-3-3"-bis-trifluoromethyl- (1,1-phenyl) -amide (8-phenyloctyl) -amide. : 3'1 ''] terphenyl-5'-carboxylic acid using a procedure similar to that of Example 205. "HNRM (DMS0-ds) d 8.59 (t, 1H); 7.93-7.84 (m, 6H); 7.74-7.64 ( m, 5H), 7.25-7.10 (m, 5H), 4.56 (s, 2H), 3.26 (dd, 2H), 2.53 (t, 2H), 1.52 (m, 4H), 1.26 (m, 8H), IR (KBr) 3400, 2950, 2850, 1620, 1550, 1460, 1220, 1260, 1220, 1080 cm "1; mass spectrum [(+) APCI], m / z 696 (M + H) J- analysis calculated for C37H35F6N502: C, 63. 88; H, 5 07; N, 10 07, found: C, 61. 94; H, 5 12; N, 9 75 Example 207 4- [3-Bromo-5- (8-phenyl-octylcarbamoyl) -3 '-trifluoromethyl-biphenyl-2-yloxymethyl] -2-hydroxy-benzoic acid methyl ester The title compound is prepared as a light yellow oil (0.361 g, 37%) from the methyl ester of 4 - [3-bromo-5- (8-phenyl-octylcarbamoyl) -3 '-trifluoromethyl-biphenyl -2- iloxymethyl] -2-methoxy-benzoic using a procedure similar to example 200. 1HNRM (DMSO-d6) d 10.45 (s, 1H); 8.59 (broad t, 1H); 8.18 (d, 1H); 7.90-7.58 (m, 6H); 7.25-7.10 (m, 5H); 6.70-6.60 (m, 2H); 4.60 (s, 2H); 3.88 (s, 3H); 3.24 (dd, 2H); 2.52 (t, 2H); l, 50 (m, 4H); 1.25 (m, 8H); IR (KBr) 3400, 2950, 2850, 1685, 1620, 1550, 1440, 1400, 1180, 1120 cm "1, - spectrum of maeae [(-) APCI], m / z 710 (M-H)"; Analysis calculated for C 37 H 37 BrF 3 N 0 5: C, 61.90; H, 5.05; N, 2.01, found: C, 60.59; H, 5.09; N, 1.86.
Example 208 4- [3-bromo-5- (8-phenyl-octylcarbamoyl) -3'-trifluoromethyl-biphenyl-2-yloxymethyl] -2-hydroxy-benzoic acid The title compound is prepared as a light yellow oil (0.202 g, 22%) from the 4- [3-bromo-5- (8-phenyl-octylcarbamoyl) -3'-trifluoromethyl-biphenyl) methyl ester. -2-yloxymethyl] -2-methoxy-benzoic using the procedure of Example 207. JHNRM (DMSO-d6) d 13.50 s broad, 1); 11.20 (s broad 1H); 9.59 (broad t, 1H); 8.16 (d, 1H); 7. 90-7.62 (m, 6H); 7.25-7.10 (m, 5H); 6.64-6.58 (m, 2H); 4.60 (s, 2H), - 3.23 (dd, 2H); 2.52 (t, 2H); 1.2 (m, 4H); 1.25 (m, 8H), - IR (film) 3400, 2950, 2850, 1660, 1640, 1550, 1495, 1450, 1420, 1320, 1220, 1160, 1120, 1070 cm "1; mass spectrometer [(-) APCI], m / z 690 (M-H) "; analysis calculated for C36H35BrF3N05: C, 61.90; H, 5.05; N 2.01, found: C, 60.59; H, 5.09; N, 1. 86 Example 209 (2-amyl-3, 3"-bis-trifluoromethyl- [1,1 ': 3'1' '] terphenyl-5' carboxylic acid (8-f-enyl-octyl) -amide) Stage 1"-ammo-3, 3" -bis-trif luoromethyl- [1, 1 ', - 3' 1"] terphenyl-5'-carboxylic acid is prepared as a whitish solid (0.992 g, 94%) from 4-amino-3,5-diiodobenzoic acid and 3-trifluoromethyl-phenyl boronic acid using a procedure similar to Step 1 of Example 175. 1K NMR (CDCl 3) d 7.90 (S, 2H); 7.78 (m, 2H); 7.74-7.60 (m, 6H); 4.24 (broad s, 2H).
Stage 2 To a solution of 2'-amino-3, 3"-bis-trifluoromethyl- [1, 1 ': 3'1"] terphenyl-5'-carboxylic acid (0.113 g, 0.27 mmol, 1 equivalent) in 2.7 ml of DMF is added 1,1'-carbonyldiimidazole (0.120 g, 0.74 mmoles, 2.7 equivalents) and phenyl octylamine (0.070 ml, 0.35 mmoles, 1.3 equivalents) and the reaction is stirred overnight at rt. Add 1,1'-carbonyldiimidazole (0.124 g, 0.76 mmolee, 2.8 equivalents) and additional phenyl octylamine (0.070 ml, 0.35 mmoles, 1.3 equivalents), stirring continued at night. The solids are then separated by filtration and washed with EtOAc. The filtrate is washed with a saturated solution of NaHCO 3, 0.1 N HCl and brine. Dry over MgSO4 and concentrate ip vacuo. The residue is purified by flash chromatography (20% EtOAc: Hexane + 1% formic acid) to give the title compound (0.150 g, 37%) as a light yellow oil. XH NMR (DMSO-d6 d 8.20 (t, 1H), 7.81-7.70 (m, 8H), 7.61 (s, 2H), 7.25-7.12 (m, 5H), 4.87 (s, 2H), 3.19 (dd, 2H), 2.52 (t, 2H), 1.50 (m, 4H), 1.28 (m, 8H), IR (KBr) 3540.3350, 2950, 2850, 1620, 1545, 1480, 1420, 1325, 1180, 1120, 1110, 1080 cm "1 mass spectrum [< +) APCI], m / z 613 (M + H) *, - analysis calculated for C35H34F6N20: C, 68.62; H, 5.59; N, 4.57, found: C, 67.66; H, 5.96; N, 4.33.
Example 210 4- [2-Bromo-4- (8-phenyl-octylcarbamoyl) -phenoxy-sulfonyl] -2-hydroxy-benzoic acid Stage 1 3-Bromo-4-hydroxy-N- (8-phenyloctyl) benzamide is prepared as a yellow oil (1.15 g, 61%) from 3-bromo-4-hydroxybenzoic acid and phenyloctylamine using a procedure similar to Example 191. XH NMR (CDC13) 6 7.92 (d, 1H); 7.70 (dd, 1H); 7.27-7.10 (m, 5H); 7.04 (d, 1H); 6.65 (t, 1H); 6.18 (s broad, 1H), -3.41 (dd, 2H); 2.48 (t, 2H); 1.58 (m, 4HJ- 1.32 (, 8H).
Stage 2 The title compound is prepared as a white solid (0.388 g, 0%) from 3-bromo-4-hydroxy-N- (8-phenyloctyl) benzamide and 4-chlorosulfonyl-2-hydroxy-benzoic acid using a procedure eimilar to Stage 3 of Example 179. H NMR (DMS0-d6) d 8.57 (bt, 1H); 8.50 (d, 1H), 7.99 (dd, 1H); 7.86 (dd, 1H); 7.38-7.32 (m, 3H); 7.26-7. 1 0 (m, 5H); 3.50 (broad s, 2H); 3.20 (dd, 2H); 2.53 (t, 2H); 1.50 (m, 4H); 1.28 (m, 8H); IR (KBr) 3480, 3350, 2950, 2850, 1900, 1690, 1630, 1600, 1580, 1540, 1480, 1450, 1360, 1285, 1250, 1205, 1180, 1110, 1080, 1040, 930, 860 cm.3 , - maea [(+) APCI] spectrum, m / z 604 (M + H); Analysis Calculated for C28H30BrNO7S: C, 55.63, H, 5.00; r., 2.32, Found: C, 54.33; H, 5.11; N, 1.95.
Example 211 2-Hydroxy-4- acid. { 2- [5'- (8-phenyl-octylcarbamoyl) -3,3"-bis-trifluorome-yl- [1,1 '; 3', 1"] ter enyl-2'-yloxy] -ethoxy) -benzoic acid Stage 1 N- (8-Phenyl-octyl) -4- (2-bromo-ethoxy) -3,5-bie (m-trifluoromethyl-phenyl) -benzamide is prepared as a colorless oil (1.48 g, 95%) from N- (8-f-enyl-octyl) -3,5-bis (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide using a procedure similar to Step 1 of Example 185. 1 H NMR (CDC13) d 7.95 -7.78 (m, 6H); 7.72-7.54 (m, 4H); 7.32-7.10 (m, 5H); 6.18 (bt, 1H); 3.45 (m, 4H); 2.98 (t, 2H); 2.55 (t, 2H); 1.60 (m, 4H); 1.30 (m, 8H).
Stage 2 To a solution of N- (8-phenyl octyl) -4- (2-bromo-ethoxy) -3,5-bis (m-trifluoromethylphenyl) benzamide (1.48 g, 2.05 mmol, l equivalent) in acetone (21 ml) K2C03 (1.42 g, 10.25 mmol, 5 equivalents) and methyl 2,4-dihydroxybenzoate (0.340 g, 2.05 mmol, 1.0 equivalent) are added. The reaction is heated to reflux overnight, cooled to room temperature and concentrated ip vacuo. The residue is partitioned between EtOAc and brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (30% EtOAc: hexane) to give 2-hydroxy-4-methyl ester. { 2- [5 '- (8-f-enyl-octylcarbamoyl) -3,3"-bis-trifluoromethyl- [1, 1': 3 ', 1"] terphenyl-2'-yloxy] -ethoxy-benzoic acid (0.98 g , 60%) as a colorless oil. JH NMR (CDC13) d 10.90 (e, 1 H); 7.92-7.78 (m, 7H); 7.66-7.50 (m, 4H); 7.27-7.12 (m, 5H); 6.18-6. 10 (m, 3H); 3.92 (s, 3H); 3.66-3.40 (m, 6H); 2.58 (t, 2H); 1.60 (m, 4H); 1.28 (m, 8H).
Stage 3 To a solution of 2-hydroxy-4- (2- [5 '- (8-phenyl-octylcarbamoyl) -3,3"-bis-trif luoromethyl [1,1': 3 ', 1"] methyl ester 2-phenyloxy] -ethoxy] -benzoic acid (0.980 g, 1.21 mmol, 1 equivalent) in EtOH (20 mL) was add 50% NaOH (10 mL) and the reaction is refluxed overnight. It is cooled to room temperature, diluted with H20 and acidified with 2M HCl to pH 1. It is extracted with EtOAc, dry ee over MgSO4 and concentrated ip vacuo. The residue is purified by flash chromatography (30% EtOAc: hexane) to give the title compound (0.92 96%) as a white foam. ? NMR (DMSO-d6) d 13.60 (broad s, 1H); 11.40 (broad, 1H); 8.59 (bt, 1H); 8.00-7.92 (m, 6H); 7.74-7.65 (m, 4H); 7.56 (d, 1 H); 7.25-7.10 (m, 5H); 6.08-6.00 (m, 2H); 3.66 (bd, 2H), 3.52 (bd, 2H); 3.25 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H); 1.27 (m, 8H); IR (KBr) 3350, 2950, 2850, 1670, 1620, 1550, 1500, 1460, 1320, 1230, 1220, 1160, 1120, 1095, cm "1; mass spectrum [(-) APCI], m / z 792 (MH) ", - Calculated Analysis for C44H41F6N06: C, 66.58; H, 5.21; N, 1.76, Found: C, 64.86; H, 5.22; N, 1.68.
Example 212 Acid (3-Bromo-5- [methyl- (8-phenyl-octyl) -carbamoyl] -3'-trifluoromethyl-bi-enyl-2-yloxy} -acetic acid Stage l To a solution of 8-phenyloctanoic acid (28.6 g, 129.8 mmol, 1 equivalent) in CH2C12 (100 mL) is cooled to 0 ° C and oxalyl chloride (17 ml, 195 mmol, 1.5 equivalent) is added dropwise via an addition funnel for 30 minutes. Upon completion of the addition, the ice bath is removed and the reaction is stirred at rt for 2 h. It is then heated to reflux for 30 minutes. The reaction is cooled to rt and concentrated ip vacuo to give a yellow oil. It is added as a solution of Et20 (100 ml) to a solution of condensed methylamine ("20 ml) in Et20 (200 ml) at -78 ° C. Immediately a white precipitate forms, the cold bath is removed and allowed to the reaction is stirred overnight while heating to rt under a stream of N2.The residue is washed with Et20 and concentrated to give N-methyl-8-phenyloctanamide (25.2 g, 83%) as a yellow-white solid. NMR (CDC13) d 7.68-7.10 (m, 5H), 5.42 (broad s, 1H), 3.80 (m, 3H), -2.60 (m, 2H), 2.18 (m, 2H), 1.60 (m, 4H) 1.30 (m, 8H).
Stage 2 To a solution of N-methyl-8-phenyloctanamide (25.2 g, 108. 0 mmole, 1 equivalent) in THF (500 ml) cooled to 0 ° C add lithium aluminum hydride (12.3 g, 466.8 mmoles, 4.3 equivalents) in portions for 20 minutes. The cold bath is removed and the reaction is stirred at rt for 3 hours. The reaction is heated to reflux for 2 hours. Later it is cooled to rt and suspended by the slow addition of H20 (30 ml). EtOAc (300 mL) is added followed by 2M NaOH (40 mL). The solids are then separated by filtration and washed with EtOAc.
The filtrate is dried over MgSO4 and concentrated ip vacuo to give N-methyl-N- (8-phenyloctyl) amine (19.7 g, 83%) as a light yellow oil. X H NMR (CDC13) d 7.30-7.14 (m, 5H); 2.63-2.52 (m, 4H); 2.43 (s, 3H); 2.05 (e, 1H); 1.62 (m, 4H); 1.30 (m, 8H).
Stage 3 -Bromo-6- (2-hydroxyethoxy) -N-methyl-N- (8-phenloctyl) [1,1'-biphenyl-3-carboxanamide is prepared as a colorless oil (0.200 g, 56%) from of ethyl ester of acid 3-Bromo-5- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzoic acid and N-methyl-N- (8-phenyloctyl) amine using a procedure similar to Step 2 of Example 175. JH NMR ( CDC13) d 7.87-7.54 (m, 5H); 7.38-7.12 (m, 6H); 3.65 (m, 4H); 3.50 and 3.03 (2bt, 2H); 3.03 (2s, 3H); 2.58 (m, 2H); 1.98 (s broad, 1H), 1.60 (m, 4H); 1.40-1.22 (m, 8H).
Stage 4 The title compound is prepared as a foam 25 (0.108 g, 44%) from 5-bromo-6- (2-hydroxyethoxy) -N-methyl- N- (8-phenyloctyl) [1,1 '-biphenyl-3-carboxamide using a procedure similar to Step 3 of Example 175. "H NMR (DMS0-d6) d 12.87 (broad s, 1H); 7.92-7.62 (m, 5H); 7.43 (m, 1H); 7.26-7.08 (m, 5H); 4.12 (s, 2H); 3.40 and 3.18 (2m, 2H); 2.90 (e, 3H); 2.52 (m, 2H); 1.53 (m, 4H), 1.30-1.12 (m, 8H) IR (film) 2930, 2850, 1735, 1640, 1600, 1495, 1400, 1270, 1150, 1130 cm "1; maea spectrum [(-) ESI], m / z 618/620 (M-H)" ; Analysis Calculated for C31H33BrF3N04: C, 60.01; H, 5.36; N, 2.26, Found: C, 59.96; H, 5.43; N, 2.22.
Example 213 Acid (3, 3"-Dichloro-4, 4" -difluoro-5 '- [methyl- (8-phenyl-octyl) -carbamoyl] - [1,1'; 3 ', 1"] terphenyl-2' - iloxi) -acetic Stage 1 N-Methyl-N- (8-phenyloctyl) -3,5-bis [m-chloro-p-fluoro-phenyl] is prepared. -4- (2-hydroxyethoxy) -benzamide as a white solid (0.313 g, 78%) from the ethyl ester of 3,5-bis [(m-chloro) - (p-fluoro) -phenyl) -4 - (2-hydroxyethoxy) -benzoic acid and N-methyl-N- (8-phenyloctyl) amine using a procedure similar to Step 2 of Example 175. XH NMR (CDC13) d 7.71-7.66 (dd, 2H); 7.52-7.45 (m, 2H); 7.36 (m, 2H); 7.30-7.12 (m, 7H); 3.52 and 3.28 (2bt, 2H); 3.27 (m, 4H); 3.04 (2s, 3H); 2.58 (m, 2H); 1.60 (, 4H); 1.42-1.10 (m.H. 9H).
Stage 2 The title compound is prepared as a white foam (0.177 g, 62%) from N-methyl-N- (8-phenyloctyl) -3,5-bis [(m-chloro) - (p-fluoro) - phenyl) -4- (2-hydroxyethoxy) -benzamide using a procedure similar to Step 3 of Example 175. "H NMR (DMSO-de) d 12.60 (broad s, 1H); 7.82 (d, 2H); 7.62- 7.56 (m, 2H), 7.51-7.32 (m, 4H), 7.26-7.06 (m, 5H), 3.82-3.64 (2s, 2H), 3.40 and 3.24 (2m, 2H), 2.94 (2s, 3H); 2.52 (m, 2H), -1.55 (m, 4H), 1.33-1.00 (m, 8H), IR (KBr) 3450, 2955, 2860, 1750, 1640, 1600, 1500, 1440, 1400, 1375, 1260, 1150, 1060 cm "1; mass spectrum [(+) ESI], m / z 654 (M + H) *; Analysis Calculated for C36H3SC12F2N04: C, 66.06; H, 5.39; N, 2.14, Found: C, 65.30; H, 5.44; N, 2.09.
Example 214 [5-Methyl- (8-fatyl-oethyl) -carbamoyl] -3,3"-bis-trif-loromethyl- [1,1 '; 3', l" terphenyl-2'-yloxy] -acetic acid Stage l N-Methyl-N- (8-phenyloctyl) -3,5-bie (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzamide is prepared as a white solid (0.238 g, 67%) from the ethyl ester of 3,5-bis- (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) -benzoic acid and N-methyl-N- (8-phenyloctyl) amine using a procedure similar to Step 2 of Example 175. JH NMR (CDC13) d 7.94 (S, 2H); 7.84 (d, 2H); 7.68-7.56 (m, 4H); 7.44 (S, 2H); 7.30-7.12 (m, 5H); 3.24 (t, 2H); 3.52 and 3.33 (2bt, 2H); 3.40 (t, 2H); 3.08 (2e, 3H), 2.58 (bt, 2H); 1.60 (m, 4H); 1.42-1.12 (m, 8H).
Stage 2 The title compound is prepared as a foam (0.149 g, 57%) from N-methyl-N- (8-phenyloctyl) -3,5-bis (m-trifluoromethylphenyl) -4- (2-hydroxyethoxy) - benzamide using a procedure similar to Step 3 of Example 175. JH NMR (DMSO-d £) d 12.60 (broad s, 1H); 7.96 (s, 2H); 7.90 (d, 2H); 7. 78-7.65 (m, 4H); 7.46 (m, 2H); 7.26-7.08 (m, 5H); 3.78 (s, 2H); 3.41 and 3.28 (2m, 2H); 2.95 (s, 3H); 2.50 (m, 2H); 1.55 (m, 4H); 1.30-1.00 (m, 8H) IR (KBr) 3400, 2950, 2850, 1760, 1740, 1630, 1600, 1490, 1450, 1405, 1320, 1170, 1160, 1120, 1080, 1050 cm "1; mass spectrum [< +) ESI], m / z 686 (M + H) *; Calculated for C38H37F6N04: C, 66.56; H, 5.44; N, 2.4, Found: C, 65.83; H, 5.50; N, 1.99.
Example 215 Acid [5 '- (3-Benzyl lox i -benz Icarbamoyl) -3, 3"-bis-trif luoromethyl- [1,1'; 3 ', 1"] terf enyl-2'-yloxy] -acetic Stage 1 4- (Benzyloxy) benzylamine (3.00 g, 67%) is prepared from 4 - (benzyloxy) -benzoic acid using a procedure similar to step 1 and 2 of Example 212. 1H NMR (CDC13) 6 8.10 (e, 4H); 7.38 -7.22 (m, 5H); 6.90 (d, 2H); 4. 98 (S, 2H); 4.00 (s, 2H).
Stage 2 2'-Hydroxy-3, 3"-bis-trifluoromethyl- [1,1 ': 3' 1"] terphenyl-5'-carboxylic acid (3-benzyloxy-benzylcarbamoyl) -amide (0.460 g, 72%) is prepared ) from the 3,5-bis- (m-trifluoromethylphenyl) -4- (hydroxy) -benzoic acid and 4- (benzyloxy) -benzylamine ethyl ester using a procedure similar to Example 190.? NMR (CDC13) 6 7.78-7.54 (m, 10H); 7.48-7.22 (m, 7H); 6.95 (d, 2H); 6.32 '(m, 1H); 5.52 (s, 1H); 5.05 (s, 2H); 4.40 (d, 2H).
Stage 3 aafc - '"iflfa .., -J-Bfc_ The [5 '- (3-Benzyloxy-benzyl carbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 ', 1"] terphenyl-2'-yloxy] -acetic acid methyl ester is prepared (0.513 g, 92%) from (2-benzyloxy-benzylcarbamoyl) -amide of 2 '-hydroxy -3,3"-bis-trifluoromethyl- [1,1': 3 '1"] terphenyl-5 '-carboxylic acid and methylbromoacetic acid using a procedure similar to Step 1 of Example 192. * H NMR (CDC13) 67.92 (m, 6H); 7.70-7.52 (m, 5H), - 7.44-7.21 (m, 6H), -6.96 (d.2H), -6.35 (m, 1H); 5.08 (e, 2H), 4.60 (d, 2H); 3.80 (e, 2H), 3.45 (e, 3H).
Stage 4 The title compound is prepared as a white foam (0.286 g, 74%) from [5 '- (3-benzyloxy-benzylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1'] methyl ester. : 3 ', l "] terphenyl-2'-yloxy] -acetic using a procedure similar to Step 2 of Example 192. 1T? NMR (DMSO-d6) 6 12.60 (broad s, 1H), -9.50 (bt, 1H); 8.00-7.92 (m, 6H); 7.80-7.68 (m, 4H); 7.44-7.22 (m, 7H), 6.98-6.94 (m, 2H); 5.08 (s, 2H); 4.42 (s, 2H); 3.81 (s, 2H) IR (KBr) 3350, 2950, 1720, 1630, 1610, 1540, 1510, 1460, 1320, 1230, 1210, 1180, 1160, 1120, 1080cm "J- mass spectrum [(-) ESI ], m / z 678 (MH) 'Calculated Analysis for C37H27F6N05: C, 65.39; H, 4.00; N, 2.06, Found: C, 63.35; H, 4.3 1; N, 2.59.
Example 216 Acid (2- (R) -3-Phenyl-2- [5- (8-phenyl-octylcarbamoyl) -4'-trifluoromethyl-biphenyl-2-yloxy] -propionic Step-1: 3- Vodo-4-hydroxybenzoic acid To a stirring solution of 4-hydroxybenzoic acid (6.91 g, 50.03 mol) in dry acetonitrile (250 ml) at 10 ° C at -20 ° C under an atmosphere of N2 and add HBF4-Et20 (10.50 g, 9.50 ml, 55.00 mmoles) drop by means of a syringe. The solution is stirred at 0 ° C for 0.5 hours at which time solid N-iodosuccinimide (13.5 g, 60 mmol) is added in one go. The solution is left stirring for 16 hours and Then it is filtered to remove the precipitated succinimide. The solution is diluted with 500 ml of water and extracted with ethyl acetate (2 x 250 ml). The organic portions are combined and washed with 10% sodium bisulfite (250 ml), water (2 x 250 ml) and saturated aqueous NaCl (250 ml). The solvent is removed in vacuo to provide 8.76 g of the crude solid. The crude solid is purified by column chromatography (6: 4: 0.1 hexane: ethyl acetate: formic acid) to provide 7.54 g (57%) of the desired product as white crystals. JH NMR (DMSO-d6) d 12.74 (broad s, 1 H), 11.18 (s, 1 H), 8.20 (s, 8.20, 1 H), 7.79 (d, 1 H), 6.94 (d, 1 H).
Stage 2 N- (8-Phenyloctyl) -3-iodo-4-hydroxybenzamide To a stirred solution of 3-iodo-4-hydroxy-benzoic acid (2.64 g, 10.00 mmol) in fresh DMF (50 ml) at room temperature under an atmosphere of N2 is added EDC (2.11 g, 11.00 mmolee), HOBt (1.49 g, 11.00 mmolee) and DIPEA (1.94 g, 2.61 ml, 15.00 mmolee). The solution is allowed to stir at room temperature for 1 hour, at which time 8-phenyl-octylamine (2.46 g, 2.39 ml, 12 mmol) is added in one go. The solution is allowed to stir for an additional 4 hours, at which time it is diluted with 250 ml of water and extracted with 250 ml of ethyl acetate. The organic phase is washed with water (2 x 250 ml), saturated aqueous NaHCO3 (250 ml) and saturated aqueous NaCl (250 ml). The solvent is removed in vacuo to provide 4.62 g of the crude oil. The crude oil is purified by column chromatography (7: 3 hexane: ethyl acetate) to provide 4.47 g (99%) of the desired product as a clear oil, which crystallizes upon standing. "H NMR (CDC13) d 8.19 (dd, 2H), 7.60 (dd, 1H), 7.20 (m, 4H), 6.97 (d, 1H), 6.32 (t, 1H), 3.39 (c, 2H), 2.57 (t, 2H), 1.58 (m, 4H), 1.30 (m, 8H).
Stage 3 2- (R) -3-Phenol-2- [2-vodo-4- (8-phenyl-octylcarbamoyl) -phenyl-2-yloxy-1-methyl propionate To a stirred solution of N- (8-phenyloctyl) -3-iodo-4-hydroxybenzamide (4.47 g, 9.90 mmol), methyl ester of L-f-1-amino acid (2.68 g, 15.00 mmol) and triphenylphosphine (3.91 g, 15.00 mmol) in freshly distilled THF (250 ml) at 0 ° C under an atmosphere of N2 is added DEAD (2.60 g, 2. 35 ml, 15.00 mmol) dropwise by means of a syringe. The solution is left to stand for 4 hours, at which time it is diluted with 500 ml of water and extracted with ethyl acetate. (2 x 250 ml). The organic portions are combined and washed with water (2 x 250 ml) and 250 ml of saturated aqueous NaCl. The solvent is removed ip vacuo to provide 5.27 g of the crude oil. The crude oil is purified by column chromatography (7: 3 hexane: ethyl acetate) to provide 4.34 g (71%) of the desired product as a clear oil, which recrystallizes upon standing. XH NMR (DMSO-d £) d 8.36 (t, 1H), 7.55 (m, 13H), 5.30 (dd, 1H), 3.64 (e, 3H), 3.23 (m, 4H), 2. 55 (t, 2H), 1.50 (m, 4H), 1.27 (m, 8H).
Step 4: 2- (R) -3-Phenyl-2- [5- (8-phenyl-octylcarbamoyl) -4'-trifluoromethyl-bifenyl-2-yloxy-propionic acid A 25 ml round bottom flask is charged with 2 - (R) -3-Phenyl-2 - [2-iodo-4- (8-f-enyl-octylcarbamoyl) -phenyl-2-yloxy] -methyl propionate ( 0.225 g, 0.37 immoles), 4-trif luoromethylbenzanboronic acid (0.106 g, 0.56 mmoles), 2N aqueous potassium carbonate (0.55 ml, 1.10 mmol), complex of [1, 1'-bis (diphenylphosphino) ferrocene] -dichloro-palladium (II) with dichloromethane (1: 1) (0.016 g, 0.019 mol) and dioxane freshly distilled (10 ml) and heated to 70 ° C with stirring for 16 h. The reaction mixture is then cooled and diluted with ethyl acetate (150 ml), washed with water (2 x 150 ml), saturated aqueous sodium bicarbonate (150 ml), saturated aqueous sodium chloride (150 ml) and The organic phase is filtered through Celite. The solvent is removed ip vacuo to provide 0.251 g of the crude oil. The crude oil is purified by column chromatography (8: 2 hexane: ethyl acetate) to provide 0.172 g of the desired intermediate which is then dissolved in 10 ml of 2: 1 tetrahydrofuran / methanol and stirred with aqueous KOH. (1.1 ml, 1.10 mmol) for 1 hour. The solution is acidified to pH 2 with IN HCl and filtered. The solvent is removed ip vacuo to give 0.142 g of the crude solid which is subjected to column chromatography (4: 6: 0.1 hexane: ethyl acetate: formic acid). The solvent is removed ip vacuo to give 0.120 g (53%) of the desired product as a white solid: mp 78-80 ° C, XH NMR (DMSO-ds) d 8.33 (t, 1H), 7.41 (m, 17H) , 5.20 (dd, 1H), 3.21 (m, 4H), 3.06 (m, 1H), 2.53 (m, 1 H), 1.50 (m, 4H), 1.26 (m, 8H); IR (KBr) 3450, 2930, 2850, 1740, 1620, 1600, 1560, 1490, 1320, 1160, 1130, 1070, 700 cm "1; mass spectrum [(-) APCI] m / z 616 [(MH) "]; Analysis Calculated for C37H3ßF3N04 - 0.25 H20: C, 71.42; H, 6.24; N, 2.25; Found: C, 71.47; H, 6.66, N, 2.18.
Example 217 2- (R) -3-Phenyl-2- ['-chloro-5- (8-phenyl-octylcarbamoyl) -bi-enyl-2-yloxy] propionic acid In a manner similar to Example 216, Step 4, the title compound (0.210 g, 36%) is prepared from propionate of 2- (R) -3-Feni 1 - 2 - [2-iodo-4 - ( 8-f eni-1-octylcarbamoyl) -phenyl-2-yloxy] -methyl (0.614 g, 1.00 mol) and 4-chlorobenzanboronic acid (0.188 g, 1.20 mmol): mp 99-100 ° C; 'HRMN (DMS0-d6) d 8.33 (t, 1H), 7.36 (m, 17H), 5.18 (dd, 1H), 3.27 (m, 4H), 3.05 (m, 1H), 2.53 (m, 1H), 1.51 (m, 4H), 1. 25 (m, 8H); IR (solid ATR) 3350, 2940, 2870, 1720, 1600, 1560, 1500, 1480, 1200, 1070, 830, 700 cm "J- mass specimen [(-) APCI] m / z 582 [(M-H) "], - Analysis Calculated for C36H38C1N04 - 0.5 H20: C, 72.90; H, 6.63; N, 2.36; Found: C, 72.92; H, 6.43; N.2.35.
Example 218 2- (R) -3-Phenyl-2- [4 '- luoro-5- (8-phenyl-octylcarbamoyl) -biphenyl-2-yloxy] -propionic acid jtff- ~ 1n 4 ^ 4 In a manner similar to Example 216, Step 4, the title compound (0.356 g, 61%) is prepared from propionate of 2- (R) -3-Feni 1 - 2 - [2-iodo-4 - ( 8-f-enyl-octylcarbamoyl) -phenyl-2-yloxy] -methyl (0.614 g, 1.00 mmol) and 4-fluorobenzeneboronic acid (0.168 g, 1.20 mmol): mp 105-106 ° C; XH NMR (DMS0-d6) 6 8.33 (t, 1 H), 7.41 (m, 17H), 5.20 (dd, 1H), 3.21 (m, 4H), 3.06 (m, 1H), 2.53 (m, 1H), 1.50 (m, 4H), 1.26 (m, 8H); IR (solid ATR) 3350, 2940, 2870, 1720, 1600, 1560, 1490, 1220, 1200, 1080, 840, 700 cm "1; mass spectrum [(+) APCI] m / z 568 [(M + H)"]; Calculated Analysis for C36H38FN04 - 0.5 H20: C, 74.98; H, 6.82; N, 2.43; Found: C, 75. twenty; H, 6.72; N, 2.41.
Example 219 2- (R) -3-Phenyl-2- [4 '-metox? -5- (8-phenyl-octylcarbamoyl) -biphenyl-2-yloxy] -propionic acid In a manner similar to Example 216, Step 4, the title compound (0.225 g, 39%) is prepared from propionate of 2- (R) -3-Feni 1 - 2 - [2-iodo-4 - ( 8-f-enyl-octylcarbamoyl) -phenyl-2-yloxy] -methyl (0.614 g, 1.00 mmolee) and 4-methoxybenzanboronic acid (0.182 g, 1.20 mmolee) and ee aiela as a traneparent oil: JH NMR (DMSO-dß) 6 8.31 (t, 1 H), 7.32 (m, 17H), 5.13 (dd, 1H), 3.81 (e, 3H), 3.25 (m, 4H), 3. 05 (m, 1H), 2.5 (m, 1H), 1.51 (m, 4H), 1.26 (m, 8H); IR (solid ATR) 2920, 2850, 1730, 1600, 1480, 1240, 1180, 840, 700 cm "1; mass spectrum [(-) APCI] m / z 578 [(M-H)"]; Analysis Calculated for C37H41N05 - 0.5 H20: C, 75.48; H, 7.19; N, 2.37; Found: C, 75.36; H, 7.16; N, 2.38.
Example 220: Acid 2 - (R) -3-Fene-1 - 2 - [5 - (8-f-enyl -octylcarbamoyl) -4'-trifluoromethoxy-biphenyl-2-yloxy] -propionic acid In a manner similar to Example 216 Step 4, the title compound (0.163 g, 26%) is prepared from 2 - (R) -3-Phenyl-2 - [2-iodo-4- (8-f-phenyl-o-ethylcarbamoyl) -phenyl propionate. -2-yloxy] -methyl (0.614 g, 1.00 mmol) and 4-trifluoromethoxybenzeneboronic acid (0.247 g, 1.20 mmol) and it is added as a tranepant oil: XH NMR (DMS0-d6) 6 8.33 (t, 1 H), 7.37 (m, 17H), 5.17 (dd, 1H), 3.25 (m, 4H), 3.05 (m, 1H), 2.53 (m, 1H), 1.51 (m, 4H), 1.25 (m, 8H); IR (ATR solid) 2930, 2850, 1730, 1600, 1490, 1250, 1230, 1160, 1080, 700; mass spectral [(+) ESI] m / z 634 ([M + H] *); Analysis Calculated for C37H3BF3N0s -0.25 H20: C, 69.63; H, 6.08; N, 2.19; Found: C, 69. 5; H, 5.89; N, 2.18. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (227)

CLAIMS Having described the invention as above, property is claimed as contained in the following:
1. A compound of formula I, characterized in that it has the structure (I) wherein: B and D are each independently hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-12 carbon atoms or heteroaralkyl of 6-12 carbon atoms, except when B and D are both hydrogen, - R1 is hydrogen, alkyl of 1-6 carbon atoms, -S02Ph (OH) (C02H), -CH (RJ, -CH2CH2Y, or -CH2CH2CH2Y; R2 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, -CH2 (lH-imidazol-4-yl), -CH2 (3-1H- indolyl), -CH2CH2 (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl), -CH2CH2 (l-oxo-l, 3-dihydro-isoindol-2-yl), or -CH2 (3 -pyridyl), -W is -C02R3, -C0NH0H, -CN, -CONHRJ aryl, heteroaryl, -CHO, -CH = NOR3 or -CH = NHNHR3; Y is -W, -OCH2C02R \ aryl, heteroaryl, -C (= NOH) NH2, -ORj -0 (C = 0) NR4Rj -NR3 (C = 0) 0R3, -NR3 (C = 0) NR4Rj O -NR "Rj-R3 is hydrogen or alkyl of 1-6 carbon atoms, -R * and R5 are each, independently, hydrogen or alkyl of 1-6 carbon atoms or R4 and R5 are, together, - (CH2) n -, or -CH2CH2XCH2CH2-; X ee 0, S, SO, S02, NR3 or CH2; n ee 2 to 5, - C is alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms; carbon, heteroaralkyl of 6-20 carbon atoms, -C0NR6R -NR3CONR6R -NRCOR -OR -02CNR6RJ -NR3C02R -02CR -CH2OR -NR6RJ R6 and R7 are each, independently, hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atom, cycloalkyl of 3-10 carbon atom , - (CH2CH20) nCH3, - (CH2) "A or Rd and R7 are together, - (CH2) p-, - (CH2) 2N (CH3) (CH2) 4-, - (CH2) 2N (R8) (CH2) 2-, O - (CH2) 2CH (Rj - (CH2) 2-; Rs is hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, cycloalkyl of 3-10 carbon atoms, - (CH2CH20) nCH3, - (CH2CH2CH20) "CH3, or - (CH2) _A; A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, -CHF2, -CH2F, -CF3, - (CH2CH20) "CH3, - (CH2CH2CH20) nCH3, -C02R3, -0 ( C = 0) NR6R7, aralkyloxy, or heteroaralkyloxy; m is 2 to 16 p ee 2 to 12 or a pharmaceutically acceptable salt thereof.
2. The compound in accordance with the claim 1, characterized in that it is -C02H or a pharmaceutically acceptable salt thereof.
3. The compound in accordance with the claim 2, characterized in that B and D are each, independently, aryl or halogen or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1, which is (3, 3"-dichloro-5'-dodecylcarbamoyl- [1, 1 '; 3', 1"] terphenyl-2'-yloxy) acetic acid or a salt pharmaceutically acceptable thereof.
5. The compound according to claim 1, which is (3-bromo-3'-chloro-5-dodecylcarbamoyl-biphenyl-2-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1, which is the acid [3,3"-dichloro-5 '- (8-phenyl-octylcarbamoyl) - [1,1', -3 1"] terphenyl-2'-yloxy ] acetic acid or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1, which is (5 '-octadecyloxy- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1, which is (5 '-dodecylcarbamoyl-3, 3"-bis-trifluoromethyl- [1,1'; 3 ', 1"] erphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1, which is (3-bromo-5-dodecylcarbamoyl-3'-trifluoromet il-bifenyl-2-yl oxy) acetic acid or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1, which is the acid (5 '- (8-f-enyloctylcarbamoyl-3, 3"-bis-trif luoromethyl-, {1, 1', -3 ', 1"] terphenyl -2'-yloxy) -acetic or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1, which is (5 '-dodecylcarbamoyl- [1,1', - 3 ', 1"] terphenyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1, which is the acid (5'-dodecylcarbamoyl -4,4"-dimethoxy- [1,1 ', -3', 1"] terphenyl-2'-i-loxy (-acetic acid or a pharmaceutically acceptable salt thereof.
13. The composition according to claim 1, which is (3-chloro-5'-dodecylcarbamoyl-4"-methoxy- [1,1 ', -3'] terphenyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1, which is (5 '-dodecylcarbamoyl-3, 3"-dimethoxy- [1,1', -3 '1") terf enyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1, which is [2 - (3, 3"- dic 1 -o-5 '-dodecylcarbamoyl [1, +, -3', 1"] -terphenyl-2'-yloxy acid -ethoxy] -acetic or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 1, which is the acid. { 5 '- [6- (4-tert-Butyl-benzyloxy) -hexylcarbamoyl] -3,3"-bis-trifluoromethyl [1, 1', -3 ', 1"] terphenyl-2'-yloxy] -acetic or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 1, which is the acid. { 5 '- [6- (4-benzyloxy-benzyloxy) -hexylcarbamoyl] -3,3"-bie-trifluoromethyl [1,1'; 3'1"] terphenyl-2'-yloxy} -acetic or a pharmaceutically acceptable salt of the mole.
18. The compound according to claim 1, which is [3"-chloro-4-methoxy-5 '- (8-phenyl-octylcarbamoyl) - [1, 1', -3 ', 1"] terphenyl- 2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 1, which is the acid. { 3"-chloro-4-methoxy-5 '- [methyl- (8-phenyl-octyl) -carbamoyl] [1, 1'; 3 ', 1"] terphenyl-2'-yloxy} -acetic or a pharmaceutically acceptable salt thereof.
20. The compound according to claim 1, which is the acid [3, 3"-dimethoxy-5 '- (8-phenyl) -octylcarbamoyl) - [1,1J-3 J 1"] terphenyl-2-yloxy] -acetic or a pharmaceutically acceptable eal of the mole.
21. The compound according to claim 1, which is the acid. { 2- [5 '- (6-phenyl-hexylcarbamoyl) -3,3-pythomethyl- [1, 1', -3 ', 1"] terphenyl-2'-yloxy] -ethoxy) acetic acid or a salt pharmaceutically acceptable thereof.
22. The compound in accordance with the claim 1, which is the acid. { 5 '- [6- (2,4-difluoro-benzyloxy) -hexylcarbamoyl] -3,3"-bis-trifluoromethyl [1,1', - 3 '1"] terphenyl-2'-yloxy} -acetic or a pharmaceutically acceptable salt thereof.
23. The compound in accordance with the claim 1, which is the acid. { 5 '- [6 - (biphenyl-4-ylmethoxy) -hexylcarbamoyl] -3,3-bis-trifluoromethyl [1,1'; 3 ', 1"] terphenyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt acceptable of it.
24. The compound according to claim 1, which is the acid. { 3, 3"-dimethoxy-5" - [methyl- (8-phenyloctyl) -carbamoyl] - [1,1 ', -3', 1"] terphenyl-2'-yloxy} -acetic acid or a pharmaceutically acceptable salt acceptable of it.
25. The compound according to claim 1, which is the acid. { 2- [3, 5, 3", 5" -tetrachloro-5 '- [(6-phenyl-hexylcarbamoyl) - [1,1'; 3 ', 1"] terphenyl-2'-ethoxy} -acetic or a pharmaceutically acceptable salt thereof.
26. The compound according to claim 1, which is the [4,4"-dimethoxy-5 '- (8-phenyl-octylcarbamoyl) - [1, 1'; 3 '. 1"] terphenyl-2'-yloxy acid. ] acetic acid or a pharmaceutically acceptable salt thereof.
27. The compound according to claim 1, which is the acid (3, 3"-dichloro-5 '-dodecylcarbamoyl-4, 4" -difluoro [1, 1', -3 ', 1"] terphenyl (-2 '-iloxy) acetic acid or a pharmaceutically acceptable salt thereof.
28. The compound according to claim 1, which is [3, 3"-dichloro-4-4" difluoro-5 '- (8-phenyl-octylcarbamoyl) [-1,1', -3 ', 1] "] terphenyl-2'-yloxy] -acetic acid or a pharmaceutically acceptable salt thereof.
29. The compound in accordance with the claim 1, which is the acid. { 3, 3"-dichloro-5 '- (6- (2, 5-dimethyl-furan-4fc-3-ylmethoxy) -hexylcarbamoyl] -4-4" -difluoro- [1,1', -3 ', 1" ] tert-butyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt of the 5 same.
30. The compound according to claim 1, which is [3, 5-dichloro-5 '- (8-f-enyl-octylcarbamoyl) - [1, 1', -3 ', l "] terphenyl-2' acid. -yloxy] -acetic or a pharmaceutically acceptable salt thereof.
31. The compound according to claim 1, which is [5 '- (8-phenyl-octylcarbamoyl) -3-trifluoromethyl- [1, 1"; 3', 1"] terphenyl-2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
32. The compound in accordance with the claim ^ k 1, which is 4,4"-difluoro-5 '- (8-phenyl-octylcarbamoyl) -3,3" -bis-trifluoromethyl- [1,1'; 3 ', 1"] terphenyl-20-2'-yloxy] -acetic or a pharmaceutically acceptable salt thereof.
33. The compound according to claim 1, which is the acid. { 5 '- [6- (2,5-dimethyl-furan-3-ylmethoxy) - hexylcarbamoyl] -3,3-β-trifluoromethyl [1, 1 ', 3', 1"] terphenyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
34. The compound according to claim 1, which is (3-bromo-5-dodecylcarbamoyl-4'-methoxy-biphenyl-2-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
35. The compound according to claim 1, which is the acid (5 '- (2-hexadecylamino-3,4-dioxo-cyclobut-1-enylamino) - [1, 1', -3 ', 1"] terphenyl -2'-yloxy] -acetic acid or a pharmaceutically acceptable salt thereof.
36. The compound according to claim 1, which is (3, 3"-dichloro-5'-dodecylcarbamoyl- [1, 1 ', - 3', l"] terphenyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
37. The compound according to claim 1, which is (3-bromo-3'-chloro-5-dodecylcarbamoyl-biphenyl-2-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
38. The compound according to claim 1, which is the acid [3, 3"- di cl oro-5 '- (8-f-enyl- octylcarbamoyl) - [1,1 '; 3', 1"] erphenyl-2'-yloxy] -acetic acid or a pharmaceutically acceptable salt thereof.
39. The compound according to claim 1, which is (5 '-octadecyloxy- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
40. The compound according to claim 1, which is the acid (5'-benzo [b] naphtho [2,3-d] thiophen-1-yl- [1, 1 '; 3', 1"] terf in i 1 - 2 '- i 1 ox i) - acyclic or a pharmaceutically acceptable salt thereof.
41. The compound according to claim 1, which is the (5'-nitro- [1,1 '; 3', 1"] terphenyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
42. The compound in accordance with the claim 1, which is (5 '-methoxy- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
43. The compound according to claim 1, which is the (5'-bromo- [1,1 '; 3', 1"] terphenyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
44. The compound according to claim 1, which is [(5'-phenyl [1,1 ': 3', 1"-terphenyl] -2'-yl) oxy] acetic acid or a pharmaceutically acceptable salt thereof .
45. The compound in accordance with the claim 1, which is the (1,3-diphenyl-dibenzofuran-2-ylox?) -acetic acid or a pharmaceutically acceptable salt thereof.
46. The compound according to claim 1, which is the (2-benzoyl-4,6-dibromo-benzofuran-5-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
47. The compound in accordance with the claim 1, which is (5 '-butoxy [1, 1', -3 ', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
48. The composition according to claim 1, which is the acid (5 '-octyloxy- [1, 1', 3 ', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof. .
49. The compound according to claim 1, which is (3, 3"-dichloro-5'-octyloxy- [1,11, -3 ', 1"] terphenyl-21-yloxy) acetic acid or a salt pharmaceutically acceptable thereof.
50. The compound according to claim 1, which is (3, 3"-bie-acetylamino-5 '-octyloxy- [1, l'; 3 ', l"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable mole.
51. The composition according to claim 1, which is (5 '-octyloxy-3, 3"-bie-trif-loromethyl- [l, l'; 3 ', l"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
52. The compound according to claim 1, which is (3, 3"-dinitro-5 '-octyloxy- [1, 1', -3 ', l"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
53. The compound according to claim 1, which is (3, 3"-dimethoxy-5 '-octyloxy- [1, 1', -3 ', l"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
54. The compound according to claim 1, which is the acid [3,3"-dichloro-5 '- (3-phenyl-propylcarbamoyl) - [1, 1'; 3 '1"] terf enyl-2' - iloxy] acetic acid or a pharmaceutically acceptable salt thereof.
55. The compound according to claim 1, which is [3, 3"-dichloro-5 '- (2-pyridin-2-yl-ethylcarbamoyl) - [1, 1', -3 '1"] terphenyl -2'-yloxy] acetic or a pharmaceutically acceptable eal of the mole.
56. The composition according to claim 1, which is [5 '- (benzyl-phenethyl-carbamoyl) -3,3-dichloro- [1,1', - 3 '1"] terphenyl-2'-yloxy acid. ] acetic acid or a pharmaceutically acceptable salt thereof.
57. The compound according to claim 1, which is [3,3"-dichloro-5 '- (4-phenyl-butylcarbamoyl) - [1,1'; 3 '1"] terphenyl-2'-allyloxy] ] acetic acid or a pharmaceutically acceptable salt thereof.
58. The compound according to claim 1, which is [5- (benzyl-phenethyl-carbamoyl) -3-bromo-3'-chloro-biphenyl-2-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
59. The compound according to claim 1, which is [3-bromo-3'-chloro-5- (2-pyridin-2-yl-et-il-carbamoyl) -bifinyl-2-yl-oxy] -acetic acid. ico or a pharmaceutically acceptable salt thereof. ^ ^ ^
60. The compound according to claim 1, which is [5 '- (benzyl-phenethyl-carbamoyl) -3"-chloro-3-trifluoromethyl- [1, 1'; 3 '1"] -terphenyl-2 acid. '-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
61. The compound in accordance with the claim 1, which is [3"-chloro-5 '- (2-pyridin-2-yl-ethylcarbamoyl) -3-trifluoromethyl- [1,1'; 3'l"] terphenyl-2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
62. The compound in accordance with the claim 1, which is [3"-chloro-5 '- (3-phenyl-propylcarbamoyl) -3-trifluoromethyl- [1,1', 3 '1"] terphenyl-2'-yloxy] acetic acid or a pharmaceutically acceptable salt of the same.
63. The compound in accordance with the claim 1, which is [3"-chloro-5 '- (4-phenyl-butylcarbamoyl) -3-trifluoromethyl- [1,1', -3 '1"] terphenyl-2'-yloxy] acetic acid or a salt pharmaceutically acceptable thereof.
64. The compound in accordance with the claim 1, which is [3"-chloro-5 '- (3-cyclopentyl-propylcarbamoyl) -3-trifluoromethyl- [1,1', - 3 '1"] -terphenyl-2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
65. The compound according to claim 1, which is [3-bromo-3'-chloro-5- (3-cyclopentyl-propyl carbamoyl) -bi-phenyl-2-yloxy] -acetic acid or a pharmaceutically acceptable salt thereof. same.
66. The compound according to claim 1, which is the acid. { 5 '- [2- (4-Bromo-phenyl) -ethylcarbamoyl] -3"-chloro-3-trifluoromethyl- [1,1', -3 '1"] terphenyl-2'-yloxy} acetic acid or a pharmaceutically acceptable salt thereof.
67. The compound according to claim 1, which is [3, 3"-dichloro-5 '- (3-cyclopentyl-propylcarbamoyl) - [1, 1': 3 '1"] terphenyl-2' - acid. iloxy] acetic acid or a pharmaceutically acceptable salt thereof.
68. The compound according to claim 1, which is the acid [4"-methoxy-5 '- (2-pyridin-2-yl-ethylcarbamoyl) -3-trif luoromethyl- [1,1', -3'l] "] terphenyl-2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
69. The compound according to claim 1, which is [5 '- (3-cyclopentyl-propylcarbamoyl) -4"-methoxy-3-trifluoromethyl- [1,1', -3 '1"] terphenyl -2 '-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
70. The compound according to claim 1, which is [5 '- (benzyl-phenethyl-carbamoyl) -4"-methoxy-3-trifluoromethyl- [1, 1'; 3 '1"] terphenyl-2' acid. -yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
71. The compound according to claim 1, which is [5 '- (benzyl-phenethyl-carbamoyl) -2-fluoro-4"-methoxy- [1, 1', -3 '1"] -terphenyl- 2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
72. The compound according to claim 1, which is [5- (benzylphenethyl-carbamoyl) -3-bromo-2'-fluoro-biphenyl-2-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
73. The composition according to claim 1, which is the acid [2-fluoro-4"-methoxy-5 '- (2-pyridin-2-l-ethylcarbamoyl) - [1,1', -3 '] "] -terphenyl-2'-yloxy] acetic or a pharmaceutically acceptable eal of the mole.
74. The compound according to claim 1, which is [2-fluoro-4"-methoxy-5 '- (3-phenyl-propylcarbamoyl) - [1, 1', 3 '1"] -terphenyl-2 acid. '-ioxy] acetic acid or a pharmaceutically acceptable salt thereof.
75. The compound according to claim 1, which is [3-bromo-2 '-f-luoro-5- (2-pyridin-2-yl-yl-carbamoyl) -bi-phenyl-2-yloxy] -acetic acid. co or a pharmaceutically acceptable salt thereof.
76. The compound according to claim 1, which is [3-bromo-2'-fluoro-5- (3-phenyl-propyl carbamoyl) -i ^ ifnyl-2-yloxy] acetic acid or a pharmaceutically salt acceptable of it.
77. The compound according to claim 1, which is [5 '- (3-cyclopentyl-propylcarbamoyl) -2-f luoro-4"-methoxy- [1, 1', -3 '1"] -terphenyl ester -2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
78. The compound according to claim 1, which is [3-bromo-5- (3-cyclo-1-opent-1-propylcarbamoyl) -2 '-f-luoro-biphenyl-2-yloxy] -acetic acid or a salt pharmaceutically acceptable thereof.
79. The compound according to claim 1, which is the acid [2-f luoro-4"-methoxy-5 '- (8-f-enyl-octylcarbamoyl) - [1, l'; 3 '1"] -terphenyl -2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
80. The compound according to claim 1, which is [3-bromo-2'-fluoro-5- (8-phenyl-octylcarbamoyl) -bifinyl-2-yloxy] acetic acid or a pharmaceutically acceptable salt thereof .
81. The compound according to claim 1, which is the acid [2-f luoro-4"-methoxy-5 '- (6-f-enyl-hexylcarbamoyl) - [1, 1'; 3 '1"] -terphenyl -2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
82. The compound according to claim 1, which is [3-bromo-2'-f-luoro-5- (6-f-enyl-hexyl-1-carbamoyl) -bi-phenyl-2-yl-oxy] -acetic acid. or a pharmaceutically acceptable salt of the mole.
83. The compound according to claim 1, which is the acid [3,3"-dichloro-5 '- (6-phenyl-hexylcarbamoyl) - [1,1', -3 '1"] terphenyl -2' - iloxy] acetic acid or a pharmaceutically acceptable salt thereof.
84. The compound according to claim 1, which is the acid. { 4"-methoxy-5 '- [methyl- (8-f-enyl-octyl) -carbamoyl] -3-trifluoromethyl- [1,1', -3'l"] terphenyl-2'-yloxy} acetic acid or a pharmaceutically acceptable salt thereof.
85. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [methyl- (8-phenyl-octyl) -carbamoyl] - [1, 1', 3 '1"] terphenyl-2'-yloxy} acetic acid or a pharmaceutically acceptable salt thereof.
86. The compound according to claim 1, which is the acid [3, 3"-dif luoro-5 '- (8-f-enyl-octylcarbamoyl) - [1, 1', -3 '1"] terphenyl-2 '-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
87. The compound according to claim 1, which is the acid. { 3, 3"-difluoro-5 '- [methyl- (8-phenyloctyl) -carbamoyl] - [1, 1', - 3 '1"] terphenyl-2'-yloxy} acetic acid or a pharmaceutically acceptable salt thereof.
88. The composition according to claim 1, which is [3, 3"-dichloro-5 '- (8-morpholin-4-yl-octylcarbamoyl) - [1, 1'; 3 '1"] terphenyl- 2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
89. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [8- (2,6-dimethoxy-phenoxy) -octylcarbamoyl] - [1,1', -3 '1-terphenyl-2'-yloxy} acetic acid or a salt pharmaceutically acceptable thereof.
90. The compound in accordance with the claim 1, which is the acid. { 5 '- [8- (benzoxazol-2-ylsulfanyl) -octylcarbamoyl] -3,3"-dichloro- [1,1'; 3'1"] -terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof same.
91. The composition according to claim 1, which is [3, 3"-dichloro-5 '- (8-indol-l-yl-octylcarbamoyl) - [1,1', -3 '1"] terphenyl acid -2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
92. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [8- (3-cyano-phenoxy) -octylcarbamoyl] - [1, 1', -3 '1"] terphenyl-2'-yloxyacetic acid or a pharmaceutically acceptable salt thereof.
93. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [8- (4-chloro-benzyloxy) -octylcarbamoyl] - [1,1', -3 '1"] terphenyl-2'-yloxy} acetic acid or a pharmaceutically acceptable salt thereof.
94. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [8- (4-fluoro-3-methyl-phenoxy) -octylcarbamoyl] - [1, 1'; 3 '1"] terphenyl-2'-yloxy) acetic acid or a salt pharmaceutically acceptable thereof.
95. The compound according to claim 1, which is [3, 3"-dichloro-5 '- (8-imidazol-1-yl-octylcarbamoyl) - [1,1'; 3 '1"] terphenyl- 2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
96. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [6- (naphthalen-1-i learbamoi loxi) -hexylcarbamoyl] - [1,1', -3'l"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically salt acceptable of it.
97. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [6- (2,4-difluorophenylcarbamoyloxy) -hexylcarbamoyl [1,1', -3'l"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
98. The composition according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [6 - (4-phenoxy-phenycarbamoyloxy) -hexylcarbamoyl] - [1,1', -3'l"] terphenyl-2'-yloxy} acetic or a pharmaceutically acceptable mole.
99. The composition according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [8- (5-fluoro-indol-1-yl) -octylcarbamoyl] - [l, l'; 3 'l"] terphenyl-2'-yloxy} acetic acid or a pharmaceutically acceptable salt thereof.
100. The compound according to claim 1, which is (3, 3"-dichloro-5 '- [8- (5-methoxy-mdol-1-yl) -octylcarbamoyl] - [1,1'; 3 '1"] terphenyl-2'-yloxy. Acetic acid or a pharmaceutically acceptable salt thereof.
101. The composition according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [8- (2, 5-dimethyl-indol-1-yl) -octylcarbamoyl] - [1,1'; 3 '1"] -terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
102. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [8- (5-methoxy-2-methyl-mdol-1-yl) -octylcarbamoyl] - [1,1', -3 '1"] terf enyl-2' - iloxi} acetic or a pharmaceutically acceptable mole.
103. The compound in accordance with the claim 1, which is the acid (3, 3"-dichloro-5 '- { [1 - (4-f-enyl-butoxymethyl) -cyclopropylmethyl] -carbamoyl) [1,1'; 3 '1"] terphenyl-2'-hydroxy) acetic acid or a pharmaceutically acceptable salt thereof.
104. The compound according to claim 1, which is [5 '- (benzofuran-2-carbonyl) - [1, 1'; 3 '1"] terphenyl-2'-yloxy] acetic acid or a pharmaceutically salt acceptable of it.
105. The compound according to claim 1, which is 3- [3"- (2-carboxy-vinyl) -2 '-methoxy-5' - (8-phenyl-octylcarbamoyl) - [1,1 '; 3 '1"] terphenyl-3-yl] -acrylic acid or a pharmaceutically acceptable salt thereof.
106. The compound according to claim 1, which is 3- [3"- (2-carboxy-ethyl) -2 '-methoxy-5' - (8-phenyl-octylcarbamoi +, - [1,1 ', 3'1"] terphenyl-3-yl] -propionic acid or a pharmaceutically acceptable salt thereof.
107. The compound according to claim 1, which is the methyl ester of the acid. { 5 '- [(2-Butyl-benzofuran-3-ylmethyl)) -amino] - [1,1': 3 ', 1"] terphenyl-2'-yloxy} acetic acid or a pharmaceutically acceptable salt thereof.
108. The compound according to claim 1, which is the acid. { 5 '- [(2-Butyl-benzofuran-3-ylmethyl) -amino] - [1, 1': 3 ', 1'] erphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
109. The compound according to claim 1, which is the methyl ester of the acid. { 2,6-dibromo-4- [(2-butyl-benzofuran-3-ylmethyl) -amino-phenoxyacetic acid or a pharmaceutically acceptable salt thereof.
110. The compound according to claim 1, which is the acid. { 2, 6-dibromo-4- [(2-butyl-benzofuran-3-ylmethyl) -amino] -phenoxyacetic acid or a pharmaceutically acceptable salt thereof.
111. The compound according to claim 1, which is the acid [2"-fluoro-5 '- (8-phenyl-octylcarbamoyl) -3-trifluoromethyl- [1,1', 3 ', 1"] -terphenyl- 2'-yloxy) -acetic or a pharmaceutically acceptable eal of the mole.
112. The composition according to claim 1, which is (5 '-dodecylcarbamoyl-2"-fluoro-3-trifluoromethyl- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
113. The compound according to claim 1, which is (5 '-dodecylcarbamoyl-2, 2"-difluoro- [1,1', - 3 ', i"] terphenyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
114. The compound according to claim 1, which is [2, 2"- dif luoro-5 '- (8-f-enyl -octylcarbamoyl) - [1, 1', -3 ', 1"] terphenyl- 2'-yloxy) -acetic or a pharmaceutically acceptable salt thereof.
115. The compound according to claim 1, which is the acid [2, 2"-dif luoro-5 '- (6-f-enyl-hexylcarbamoyl) - [1, 1', -3 ', l"] terphenyl- 2'-yloxy] -acetic or a pharmaceutically acceptable salt thereof.
116. The composition according to claim 1, which is the acid. { 5 '- [6 - (2,4-dif luoro-f enoxi) -hexylcarbamoyl] -2, 2"-difluoro- [1,1'; 3 ', 1"] -terphenyl-2'-yloxy] -acetic or a pharmaceutically acceptable eal thereof.
117. The compound according to claim 1, which is (3"-chloro-5 '-dodecylcarbamoyl-2-fluoro- [1,1', - 3 ', l"] terphenyl-2'-yloxy) - acetic acid or a pharmaceutically acceptable salt thereof.
118. The compound according to claim 1, which is the acid [3"-chloro-2-fluoro-5 '- (8-phenyl-octylcarbamoyl) - [1,1'; 3 ', 1"] -terphenyl- 2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
119. The compound according to claim 1, which is the acid. { 3-Chloro-5 '- [6- (2, 4-difluoro-phenoxy) -hexylcarbamoyl] -2"-fluoro [1, 1', 3 ', 1"] terphenyl-2'-yloxy} -acetic or a pharmaceutically acceptable salt thereof.
120. The compound according to claim 1, which is the acid. { 3"-chloro-2-fluoro-5 '- [methyl- (8-phenyloctyl) -carbamoyl] - [1,1'; 3 ', 1"] -terphenyl-2'-yloxy} -acetic or a pharmaceutically acceptable salt thereof.
121. The compound according to claim 1, which is the acid. { 2, 2"-difluoro-5 '- [methyl- (8-phenyl-octyl) -carbamoyl] - [1,1', -3 ', 1"] -terphenyl-2'-yloxy} -acetic or a pharmaceutically acceptable salt thereof.
122. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [8 - (4-chloro-benzene-sulfonyl) -octylcarbamoyl] - [1,1', -3 ', 1"] terphenyl-2'-yloxy} -acetic or a pharmaceutically acceptable eal thereof.
123. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [8- (2,4-difluoro-phenoxy) -octylcarbamoyl] - [1, 1', 3 ', 1"] terphenyl-2'-yloxy} -acetic or a pharmaceutically acceptable salt thereof.
124. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [12- (2,4-difluoro-phenoxy) -dodecylcarbamoyl] - [1,1'; 3 ', 1"] terphenyl-2'-allyloxy} -acetic or a pharmaceutically acceptable salt thereof.
125. The compound according to claim 1, which is the acid. { 3, 3"-dichloro-5 '- [8- (4-trifluoromethyl-benzyloxy) -octylcarbamoyl- [1,1'; 3 ', 1"] terphenyl-2'-allyloxy} -acetic or a pharmaceutically acceptable salt thereof.
126. The compound in accordance with the claim 1, which is [3, 3"-dichloro-5 '- (8-. {3- [3- (3-methoxy-propoxy) -propoxy] -propoxy] -octylcarbamoyl) - [1 , 1 ', 3', 1"] terphenyl-2'-yloxy] -acetic acid or a pharmaceutically acceptable salt thereof.
127. The compound according to claim 1, which is (3, 3"-dichloro-5'-dicyclohexylcarbamoyl- [1, 1 ', - 3', l"] terphenyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
128. The compound according to claim 1, which is 4- [4, 4"-dimethoxy-5 '- (7-f-enyl-heptylcarbamoyl) - [1,1'; 3 ', 1"] -terphenyl- 2'-yloxy] butyric acid or a pharmaceutically acceptable salt thereof.
129. The composition according to claim 1, which is 4 - [3, 3"- dichloro-5 '- (7-f-enyl-heptylcarbamoyl) - [1, 1', - '3', 1"] terphenyl-2'-yloxy] butyric acid or a pharmaceutically acceptable salt thereof.
130. The compound according to claim 1, which is the diethyl ester of [5 '- (7-phenyl-heptylcarbamoyl) -3,3"-bis-tpfluoromethyl- [1,1', -3 ', 1"] ] -terphenyl-2'-yloxymethyl] -phosphonic acid or a pharmaceutically acceptable salt thereof.
131. The compound according to claim 1, which is [5 '- (7-phenyl-heptylcarbamoyl) -3,3"-bis-trifluoromethyl- [1, 1': 3 ', 1"] terphenyl -2 acid. '-yloxymethyl] -phosphonic acid or a pharmaceutically acceptable salt thereof.
132. The compound in accordance with the claim 1, which is 2, 2-dimethyl-3 - [5 '- (7-f-enyl-heptylcarbamoyl) -3,3"-bis-trifluoromethyl [1,1': 3 ', 1"] - acid terphenyl-2'-yloxy] -propionic acid or a pharmaceutically acceptable salt thereof.
133. The compound in accordance with the claim 1, which is 4- [5 '- (7-f-enyl-heptylcarbamoyl) -3,3-trifluoromethyl- [1, 1' 3 ', 1"] terphenyl-2'-yl oxime] il] -benzenesulfonic acid or a pharmaceutically acceptable salt thereof.
134. The compound according to claim 1, which is [[4, 4 '- dimet oxy-5' - [4 - [[(7 - - 4S f-enylheptyl) amino] carbonyl] phenyl] [1,1 ': 3', 1 '-terphenyl] -2'-yl] oxy] acetic acid or a pharmaceutically acceptable salt thereof.
135. The compound according to claim 1, wherein the [[5 '- [4 - [[(7-f-enylheptyl) amino] carbonyl] -fenyl] -3,3'-bis (trifluoromethyl) [ 1,1 ': 3', 1 '-terphenyl] -2'-yl] oxy] acetic acid or a pharmaceutically acceptable salt thereof.
136. The compound in accordance with the claim 1, which is 4 - [[[4, 4'-dimethoxy-5 '- [4 - [[(7-f-enylheptyl) amino] carbonyl] phenyl] [1, l': 3 ', l'] -terphenyl] -2'-yloxymethyl] -benzoic acid or a pharmaceutically acceptable salt thereof.
137. The compound according to claim 1, which is 4- [5 '- (7-phenyl-heptylcarbamoyl) -3,3"-bis-trifluoromethyl-IX, 1'; 3 ', 1"] terphenyl- 2'-yloxymethyl] -benzoic acid or a pharmaceutically acceptable salt thereof.
138. The composition according to claim 1, which is the acid (3-bromo-3'-chloro-5-dodecylcarbamoyl-4'-fluoro-biphenyl-2-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
139. The composition according to claim 1, which is [3'-chloro-4'-f-loro-5- (8-f-enyl-6-ylcarbamoyl) -bifinyl-2-yloxy] -acetic acid or a salt pharmaceutically acceptable thereof.
140. The compound according to claim 1, which is (3-bromo-5-dodecylcarbamoyl-3'-methoxy-biphenyl-2-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
141. The composition according to claim 1, which is the dodecylamide of 5-bromo-6- (2-tetrazol-1-yl-ethoxy) -3'-methoxy-bifenyl-3-carboxylic acid or a pharmaceutically eal acceptable of the member.
142. The composition according to claim 1, which is the dodecylamide of 5-bromo-3'-chloro-6- (2-tetrazol-2-yl-ethoxy) -bifinyl-3-carboxylic acid or a pharmaceutically acceptable salt of the member.
143. The composition according to claim 1, which is the dodecylamide of 5-bromo-3'-chloro-6- (2-tetrazol-1-yl-ethoxy) -bifinyl-3-carboxylic acid or an eal pharmaceutically acceptable thereof.
144. The compound according to claim 1, which is the acid [3, 5, 3", 5" -tetramethyl-5 '- (8-phenyl-octylcarbamoyl) - [1, 1': 3 ', 1"] terphenyl-2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
145. The compound according to claim 1, which is the acid [4, 4"-difluoro-3, 3" -dimethyl-5 '- (8-phenyloctylcarbamoyl) - [1,1': 3 ', 1"] terphenyl-2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
146. The compound according to claim 1, which is the (7-phenyl-heptyl) -amide of 2 '-hydroxy-3,5,3", 5" -tetramethyl- [1, 1': 3 ', 1"] terphenyl-5'-carboxylic acid or a pharmaceutically acceptable salt thereof.
147. The compound according to claim 1, which is (2-phenyl-heptyl) -amide of 2'-hydroxy-3, 3"-dimethyl- [1, 1 ': 3', 1"] terphenyl- 5'-carboxyl or a pharmaceutically acceptable salt thereof.
148. The composition according to claim 1, which is [3, 3"-dimet il-5 '- (7-f-enyl-heptylcarbamoyl) - [1,1': 3, l"] terphenyl-2 'acid. -yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
149. The compound according to claim 1, which is 4 - [3, 3"- dimet il-5 '- (7-f-enyl-heptylcarbamoyl) - [1,1': 3 ', 1"] terphenyl -2'-yloxy] butyric or a pharmaceutically acceptable salt thereof.
150. The compound in accordance with the claim 1, which is the [3, 5,3", 5" - tetramethyl-5 '- (7-phenyl-heptylcarbamoyl) - [1,1': 3J1"] terphenyl-2'-yloxymethyl] diethyl ester] -phosphonic or a pharmaceutically acceptable salt thereof.
151. The compound according to claim 1, which is 4- [3, 5, 3", 5" -tetramethyl-5 '- (7-phenyl-heptylcarbamoyl) - [1,1': 3 ', 1"] -terphenyl-2'-yloxy] -butyric acid or a pharmaceutically acceptable salt thereof.
152. The compound according to claim 1, which is the 3,3-diphenyl-2'-methoxymethoxy- [1,1 ': 3', 1"] terfenyl (7-phenyl-heptyl) -amide. -5'-carboxylic acid or a pharmaceutically acceptable salt thereof.
153. The compound according to claim 1, which is the 3,3-diformyl-2'-hydroxy- [1, 1 ': 3', 1"] terphenyl- (7-phenyl-heptyl) -amide. 51 -carboxylic acid or a pharmaceutically acceptable salt thereof.
154. The compound according to claim 1, which is 3, 3", 4,4" -bis-methylenedioxy-5 '- (7-phenyl-heptylcarbamoyl) - [1, 1': 3 J 1"] terphenyl-2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
155. The compound according to claim 1, which is the 4-chloro-butyl ether of 3'-bromo-2'-hydroxy-5 '- (8-phenyl-octylcarbamoyl) -biphenyl-3-carboxylic acid or an eal pharmaceutically acceptable thereof.
156. The compound according to claim 1, which is (3"-chloro-5 '-dodecylcarbamoyl-3-trifluoromethyl- [1, 1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
157. The compound according to claim 1, which is (5 '-dodecylcarbamoyl-4"-methoxy-3-trifluoromethyl- [1,1', - 3 ', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
158. The compound according to claim 1, which is (5 '-dodecylcarbamoyl-2"-fluoro-4-methoxy- [1,1', -3 ', 1"] terphenyl-21-yloxy) acetic acid or a pharmaceutically acceptable eal thereof.
159. The compound according to claim 1, which is (3-bromo-5-dodecylcarbamoyl-2'-fluoro-biphenyl-2-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
160. The compound according to claim 1, which is ["-methoxy-5 '- (6-phenyl-hexylcarbamoyl) -3-trifluoromethyl- [1, 1'; 3 ', 1"] terphenyl-2' acid. -alkoxy] acetic or a pharmaceutically acceptable eal of the mole.
161. The compound according to claim 1, which is ["-methoxy-5 '- (8-phenyl-octylcarbamoyl) -3-trifluoromethyl- [1, 1'; 3 ', 1"] terphenyl-2' acid. -yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
162. The compound according to claim 1, which is the acid (3,5,3", 5" -tetrachlor-5 '-dodecylcarbamoyl- [1, 1', -3 ', 1"] -terphenyl-2' -yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
163. The compound according to claim 1, which is the acid [3, 5, 3", 5" -tetrachloro-5 '- (8-phenyl-octylcarbamoyl) - [1, 1'; 3 ', 1"] terphenyl-2'-yloxy] acetic acid or a pharmaceutically acceptable salt thereof.
164. The compound according to claim 1, which is the acid [3, 5, 3", 5" -tetrachloro-5 '- (6-phenyl-hexylcarbamoyl) - [1,1'; 3 ', 1"] terphenyl-2'-yloxy] acetic acid or a salt • pharmaceutically acceptable thereof.
165. The compound according to claim 1, which is [3, 3"-dichloro-5 '- (4-heptyloxy-benzylcarbamoyl) - [1, -.'; 3 ', 1"] terphenyl-2 acid. '-yloxy] acetic acid or a pharmaceutically acceptable salt thereof. 10
166. The compound according to claim 1, which is the methyl ester of 8- [(2'-carboxyethoxy-3,3"-dichloro- [1, 1 ', -3', 1"] terphenyl ester. -5'-carbonyl) -amino] octanoic or a pharmaceutically acceptable salt thereof.
167. The compound according to claim 1, which is 5- [3, 3"-dichloro-5 '- (8-indol-1-yl-octylcarbamoyl) - [1, 1', - 3 ', 1"] terphenyl-2'-yloxy] pentanoic acid or a pharmaceutically acceptable salt thereof.
168. The compound according to claim 1, which is 4- acid. { 2- [3, 3"-dichloro-5 '- (8-indol-l-yl-octylcarbamoyl) - [i, 1': 3 ', 1"] -terphenyl-2'-yloxy] ethoxy} benzoic acid or a pharmaceutically acceptable salt thereof. 25
169. The compound in accordance with the claim 1, which is the 6- [(2 '-carboxymethoxy-3, 3"-dichloro- [1,1'; 3 ', 1"] terphenyl-5'-carbonyl) -amino] -hexyl ester of 4 -methoxybenzoic acid or a pharmaceutically acceptable salt thereof.
170. The compound according to claim 1, which is [3, 3"-dichloro-5 '- (6-hydroxy-hexylcarbamoyl) - [1, 1': 3 ', 1"] terphenyl-2' - iloxy] acetic acid or a pharmaceutically acceptable salt thereof.
171. The composition according to claim 1, which is the acid. { 2- [3, 3"-dichloro-5 '- (8-indol-1-yl] -octylcarbamoyl) - [1, 1': 3 ', 1"] terphenyl-2'-yloxy] ethoxy} acetic or a pharmaceutically acceptable mole.
172. The composition according to claim 1, which is (5'-hexyl- [1, 1 ', -3', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
173. The compound in accordance with the claim 1, which is (5 '-nonyl- [1, 1', -3 ', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt of the moiety.
174. The compound according to claim 1, which is (5 '-tridecyl- [1,1'; 3 ', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
175. The compound in accordance with the claim 1, which is (5 '-decyloxy- [1,1', 3 ', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
176. The compound according to claim 1, which is (5'-tetradecyloxy- [1,1 '; 3', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
177. The compound according to claim 1, which is (5'-trityl- [1,1 '; 3', 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
178. The compound according to claim 1, which is the acid (5'-dodecylcarbamoyl-3, 3"-bis-trifluoromethyl-, {1, 1 ', -3 J 1"] terphenyl-2'-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.
179. The compound according to claim 1, which is the acid (3-bromo-5-dodecylcarbamoyl-3 '- tri luoromethyl-bifenyl-2-yloxy) -acetic or a pharmaceutically acceptable salt thereof.
180. The compound according to claim 1, which is the acid (5 '- (8-f-enyl-octylcarbamoyl-3, 3"-bis-trif luoromethyl -. {1.1 J-3', 1"] terphenyl-2'-yloxy) -acetic or a pharmaceutically acceptable salt thereof.
181. The compound according to claim 1, which is (3-bromo-5- (8-phenyl-octylcarbamoyl) -3'-tr if luoromet il-bifenyl-2-yloxy) -acetic acid or a salt pharmaceutically acceptable thereof.
182. The compound according to claim 1, which is 4- (3-bromo-5-dodecylcarbamoyl-3'-tr? Fluoromethyl-biphenyl-2-yloxysulfonyl) -2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof.
183. The compound according to claim 1, which is the dodecylamide of 5-bromo-6 - (2 - [1, 2,3] triazol-2-yl-ethoxy) -3 '-trif luoromethyl-bifenyl- 3-carboxylic acid or a pharmaceutically acceptable salt thereof.
184. The compound according to claim 1, which is the dodecylamide of 5-bromo-6- (2 - [1,2,3] triazol-1-yl-ethoxy) -3'-trifluoromethyl-biphenyl-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
185. The compound according to claim 1, which is the dodecylamide of 5-bromo-6- (2-tetrazol-2-yl-ethoxy) -3'-trifluoromethyl-biphenyl-3-carboxylic acid or a pharmaceutically acceptable salt thereof. same.
186. The compound according to claim 1, which is the dodecylamide of 5-bromo-6- (2-tetrazol-1-yl-ethoxy) -3'-trifluoromethyl-biphenyl-3-carboxylic acid or a pharmaceutically acceptable salt of the same.
187. The compound according to claim 1, which is the 2- [3-bromo-5- (8-phenyl-octylcarbamoyl) -3 '-trifluoromethyl-biphenyl-2-yloxy] -ethyl ester of carbamic acid or a salt pharmaceutically acceptable thereof.
188. The compound according to claim 1, which is the dodecylamide of 5-bromo-6- (2-morpholin-4-yl-ethoxy) -3'-trifluoromethyl-biphenyl-3-carboxylic acid or a pharmaceutically acceptable salt thereof. same.
189. The compound according to claim 1, which is the dodecylamide of 6- (amino-ethoxy) -5- acid bromine-3 '-trif luoromethyl-bifenyl-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
190. The compound according to claim 1, which is the dodecylamide of 5-bromo-3'-trifluoromethyl-6- (2-ureido-ethoxy) -bifenil-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
191. The compound according to claim 1, which is [2- (3-bromo-5-dodecylcarbamoyl-3 '-trif luoromethyl-bifenil-2-yloxy) -ethyl] -carbamic acid methyl ester or a salt pharmaceutically acceptable thereof.
192. The compound according to claim 1, which is [5 '- (6-phenyl-hexylcarbamoyl) -3,3"-bis-trif luoromethyl- [1, 1': 3 ', 1"} terphenyl-2'-yloxy] -acetic acid or a pharmaceutically acceptable salt thereof.
193. The composition according to claim 1, which is [3-bromo-5- (6-f-enyl-hexylcarbamoyl) -3'-tpf luoromethyl-bifenil-2-yloxy] -acetic acid or a pharmaceutically acceptable salt. of the same.
194. The compound according to claim 1, which is the (8-phenyl-octyl) -amide of 2'-hydroxy acid. 3, 3"-bis-trifluoromethyl- [1,1 ': 3' 1"] terphenyl-5'-carboxylic acid or a pharmaceutically acceptable salt thereof.
195. The compound according to claim 1, which is 5- [5'- (8-phenyl-octylcarbamoyl) -3,3"-b 's-trifluoromethyl-1, 1'; 3 '1"] terphenyl acid. -2'-yloxy] -pentanoic acid or a pharmaceutically acceptable salt thereof.
196. The compound according to claim 1, which is the (8-phenyl-octyl) -amide of 5-bromo-6- (2-piperazin-1-yl-ethoxy) -3 '-trifluoromethyl-biphenyl-3 acid -carboxylic acid or a pharmaceutically acceptable eal thereof.
197. The compound according to claim 1, which is the 5-bromo-6-hydroxy-3'-trifluoromethyl-biphenyl-3-carboxylic acid (8-phenyl-octyl) amide or a pharmaceutically acceptable salt thereof.
198. The compound according to claim 1, which is 4- [3-bromo-5- (8-phenyl-octylcarbamoyl) -3'-trifluoromethyl-biphenyl-2-yloxysulfonyl] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
199. The compound according to claim 1, which is 7- [5 '- (8-phenyl-octylcarbamoyl) -3, 3"-bis trifluoromethyl- [1, 1 ', 3', 1"] terphenyl-2'-yloxy] -heptanoic acid or a pharmaceutically acceptable salt thereof.
200. The compound according to claim 1, which is the (8-phenyl-octylamide) of 2 '- (2-hydroxy-3,4-dioxo-cyclobut-1-enylamino) -ethoxy] -3,3" β-trifluoromethyl- [1, 1 ': 3', 1"] terphenyl-5'-carboxylic acid or a pharmaceutically acceptable moiety thereof.
201. The compound in accordance with the claim 1, which is the 2 '- [4- (lH-tetrazol-5-yl) -butoxy-3, 3"-bis-trif luoromethyl- [1,1'] (8-phenyl-octyl) -amide. : 3 '1"] terphenyl-5'-carboxylic acid or a pharmaceutically acceptable salt thereof.
202. The compound according to claim 1, which is 2-methoxy-4- [5 '- (8-phenyl-octylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 '1] acid "] terphenyl-2'-yloxymethyl] -benzoic acid or a pharmaceutically acceptable salt thereof.
203. The compound in accordance with the claim 1, which is 2-Hydr oxy-4 - [5 '- (8-f-en-1-octylcarbamoyl) -3,3"-bis-trifluoromethyl- [1,1': 3 '1"] terphenyl- 2'-yloxymethyl] -benzoic acid or a pharmaceutically acceptable salt thereof.
204. The compound in accordance with the claim 1, which is the methyl ester of 2-hydroxy-4- [5 '- (8-phenyl-octylcarbamoyl) -3,3"-bis-trif luoromethyl- [1, 1': 3 '1"] terf enyl-2'-yloxymethyl] -benzoic acid or a pharmaceutically acceptable salt thereof.
205. The compound in accordance with the claim 1, which is the acid 4 -. { 2 - [3-bronene-5 - (8-f in i 1 -octylcarbamoyl) -3 '-trif luoromethyl-bifenyl-2-yloxy] ethoxy} -2-hydroxy-benzoic or a pharmaceutically acceptable salt of the same.
206. The compound in accordance with the claim 1, which is 2-hydroxy-4 - [5 '- (8-f eni 1 -octylcarbamoyl) -3,3"-bis -trif luoromethyl- [1,1': 3" l "] - terf acid enyl-2'-yloxy-sulfonyl] -benzoic acid or a pharmaceutically acceptable moiety thereof.
207. The composition according to claim 1, which is 4- [3-bromo-5- (8-phenyl-octylcarbamoyl) -3'-trifluoromethyl-biphenyl-2-yloxymethyl] -2-methoxy-benzoic acid or a pharmaceutically acceptable mole.
208. The compound according to claim 1, which is the 5-bromo-6- (8-f-enyl-octyl) -amide of the acid (lH-tetra-5-ylmethoxy) -3'-trifluoromethyl-biphenyl-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
209. The compound according to claim 1, which is the (8-phenyl-octyl) -amide of 2 '- (lH-tetrazol-5-ylmethoxy) -3,3"-bis-trif luoromethyl- [1, 1 ': 3' 1"] terphenyl-5'-carboxylic acid or a pharmaceutically acceptable salt thereof.
210. The compound in accordance with the claim 1, which is 4- [3-bromo-5- (8-f-enyl-octylcarbamoyl) -3'-trifluoromethyl-biphenyl-2-yloxymethyl] -2-hydroxy-benzoic acid methyl ester or a pharmaceutically acceptable salt of mine. Saint .
211. The compound according to claim 1, which is 4- [3-bromo-5- (8-phenyl-octylcarbamoyl) -3'-trifluoromethyl-biphenyl-2-yloxymethyl] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
212. The compound according to claim 1, which is the (8-phenyl-octyl) -amide of the 2'-amino-3, 3"-bie-trifluoromethyl- [1, 1 ': 3' 1"] - terphenyl-5'-carboxylic acid or a pharmaceutically acceptable salt thereof.
213. The compound according to claim 1, which is 4- [2-bromo-4- (8-phenyl-octylcarbamoyl) -phenoxy-sulfonyl] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
214. The compound in accordance with the claim 1, which is 2-hydroxy-4 - acid. { 2 - [5 '- (8-f-enyl-octylcarbamoyl) -3,3"-bie-trifluoromethyl [1,1': 3 ', 1"] terphenyl-2'-yloxy] -ethoxy) -benzoic acid or a salt pharmaceutically acceptable thereof.
215. The compound according to claim 1, which is the acid. { 3-Bromo-5- [methyl- (8-phenyl-octyl) -carbamoyl] -3'-trifluoromethyl-biphenyl-2-yloxy} -acetic or a pharmaceutically acceptable salt thereof.
216. The compound according to claim 1, which is (3, 3"-dichloro-4,4" difluoro-5 '- [methyl- (8-phenyl-octyl) -carbamoyl] - [1, 1'] , -3 ', l "-terphenyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
217. The compound according to claim 1, which is [5-methyl- (8-phenyl-octyl) -carbamoyl] - oS,. .. < ., ... 3, 3"-bis-trif luoromethyl- [1, 1 ', -3', l" terf-enyl-2'-yloxy) -acetic acid or a pharmaceutically acceptable salt thereof.
218. The compound according to claim 1, which is [5 '- (3-benzyloxy-benzylcarbamoyl) -3, 3"-bie-trif-loromethyl- [1,1': 3 ', 1"] terphenyl- 2'-yloxy] -acetic or a pharmaceutically acceptable eal of the mole.
219. The composition according to claim 1, which is the acid (2 - (R) -3-phenyl-2 - [5 - (8-f-enyl-octylcarbamoyl) -4 '-trif-luromethyl-bifenyl-2- iloxy] propionic or a pharmaceutically acceptable salt thereof.
220. The compound according to claim 1, which is 2- (R) -3-f-enyl-2- [4'-chloro-5- (8-phenyl-octylcarbamoyl) -bifinyl-2-yloxy]] propionic or a pharmaceutically acceptable salt of the mole.
221. The compound according to claim 1, which is 2- (R) -3-phenyl-2- [4 '-fluoro-5- (8-f-enyl-octylcarbamoyl) -bifinyl-2-yloxy]] propionic or a pharmaceutically acceptable salt thereof.
222. The composition according to claim 1, which is 2- (R) -3-phenol-2- [4'-methoxy-5- (8-phenyl- octylcarbamoyl) -biphenyl-2-yloxy] propionic acid or a pharmaceutically acceptable salt thereof.
223. The compound according to claim 1, which is 2 - (R) -3-phenyl-2 - [5 - (8-f-enyl-octylcarbamoyl) -4'-trifluoromethoxy-biphenyl-2-yloxy] - propionic or a pharmaceutically acceptable salt thereof.
224. A method for treating metabolic disorders mediated by insulin resistance or hyperglycemia in a mammal in need thereof, characterized in that it comprises administering to the mammal a compound of formula I, according to claim 1.
225. A method for treating or inhibiting type II diabetes in a mammal in need thereof, characterized in that it comprises administering to the mammal a compound of formula I, according to claim 1.
226. A method for modulating glucose levels in a mammal in need thereof, characterized in that it comprises administering to the mammal a compound of formula I, according to claim 1.
227. A pharmaceutical composition, characterized in that it comprises a compound of formula I, according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. SUMMARY OF THE INVENTION The present invention provides compounds of formula (I) having the structure (I) wherein: B and D are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-12 carbon atoms or heteroaralkyl of 6-12 carbon atoms, except where B and D are both hydrogen; R1 is hydrogen, alkyl of 1-6 carbon atoms, -? 02Ph (OH) (C02H), -CH (Rj, -CH2CH2Y, or -CH2CH2CH2Y; R2 ee hydrogen, alkyl of 1-6 carbon atom, aralkyl of 6-12 carbon atoms, -CH2 (lH-imidazol-4-yl), -CH2 (3-1H-indolyl), -CH2CH2 (1,3-dioxo-1,3-dihydro-orindole-2-yl) , -CH2CH2 (1-oxo-l, 3-dihydro-io-soindol-2-yl), or -CH2 (3-pyridyl), is -C02R? -CHOHO, -CN, -CONHR3, aryl, heteroaryl, -CHO , -CH = NOR or -CH = NHNHR3; Y is -W, OCH2C02R3, aryl, heteroaryl, -C (= NOH) NH2, -OR3, -0 (C = 0) NR4R -NR3 (C = 0) OR3, -NR3 (C = 0) NR4Rj or -NR4R5; R3 is hydrogen or alkyl of 1-6 carbon atoms: R4 and R5 are each independently, hydrogen or alkyl of 1-6 carbon atoms, or R1 and R5 are, together, - (CH2) n-, or -CH2CH2XCH2CH2-; X is O, S, SO, S02, NR3 or CH2; n is 2 to 5; C is alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, -CONR6R7, -NR3C0NRsR7, -NR3C0Rj -OR6, -02CNRsR7, -NR3C02R- 02CRj -CH20Rj -NR6R7, -CR3 = CR3Rj -CPh3, -CH2NRSR7, or formula (I), -R6 and R7 are each independently hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms , cycloalkyl of 3-10 carbon atoms, - (CH2CH20) "CH3, - (CH2) mA or R6 and R7 are together, - (CH2) p-, - (CH2) 2N (CH3) (CH2) 4 -, - (CH2) 2N (RJ (CH2) 2-, or - (CH2) 2CH (RJ - (CH2) 2-; Rβ is hydrogen, alkyl of 1-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atom, heteroaralkyl of 6-20 carbon atom, cycloalkyl of 3-10 carbon atom, - (CH2CH20) nCH3, - (CH2CH2CH20) nCH3, or - (CH2) A; A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroaryl, heteroaryl sulphonyl, heteroarylsulfonyl, -CHF2, -CH2F, -CF3, - (CH2CH20) nCH3, - (CH2CH2CH20) "CH3 , -C02R3, -O (C = 0) NR6R7, aralkyloxy or heteroaralkyloxy; m is 2 to 16, - p is 2 to 12, - or a pharmaceutically acceptable salt thereof, which are useful for treating metabolic disorders related to insulin resistance or hyperglycemia.
MXPA/A/2000/011094A 1998-05-12 2000-11-10 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia MXPA00011094A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US09/076,709 1998-05-12

Publications (1)

Publication Number Publication Date
MXPA00011094A true MXPA00011094A (en) 2001-07-31

Family

ID=

Similar Documents

Publication Publication Date Title
US6214877B1 (en) 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
CA2363145C (en) Oxamic acids and derivatives as thyroid receptor ligands
RU2280025C2 (en) New derivatives of aminodicarboxylic acids possessing pharmaceutical properties
US4010189A (en) Alkanolamine derivatives
CA2720096A1 (en) Pai-1 inhibitor
JP4619791B2 (en) Histone deacetylase inhibitor
PL183549B1 (en) Substituted 4-biarylobutyric and 4-biarylopentanic acids and their derivatives as inhibitors of intracellular substance metaloprotease
AU2003211384A1 (en) Substituted phenylalkanoic acid derivative and use thereof
EP1392637A2 (en) Modulators of peroxisome proliferator activated receptors
WO2007009083A2 (en) Compounds with activity at retinoic acid receptors
JPWO2009072581A1 (en) Lactam compound or salt thereof and PPAR activator
US20090326263A1 (en) Process for the preparation of aniline-derived thyroid receptor ligands
EA016129B1 (en) Substituted biphenyl carboxylic acids and derivatives thereof
FR2901792A1 (en) PPAR ACTIVATOR DERIVATIVES, PREPARATION METHOD AND THERAPEUTIC APPLICATION
CA2068076A1 (en) Substituted carboxylic acid derivaties
AU2006244709A1 (en) Benzoic acid derivatives that are modulators or agonists of GLYR
IE911732A1 (en) Oxidant sensitive and insensitive aromatic esters as¹inhibitors of human neutrophil elastase
ES2315911T3 (en) NEW BIOAROMATIC COMPOUNDS THAT ACTIVATE RECEPTORS OF PPAR TYPE AND ITS USE IN PHARMACEUTICAL OR COSMETIC COMPOSITIONS.
MXPA04006203A (en) Aromatic thioether liver x-receptor modulators.
US4083992A (en) Alkanolamine derivatives
EP0512352A2 (en) Substituted carboxylic acid derivatives
ES2401833T3 (en) Y-secretase carbon bonded modulators
MXPA04013000A (en) Amide linker peroxisome proliferator activated receptor modulators.
US20040044258A1 (en) Substituted phenylalkanoic acid derivatives and use thereof
US6451827B2 (en) 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia