The present invention is directed toward 2-aryloxyethyl glycine derivatives that exhibit activity as inhibitors of the glycine type-1 transporter, to pharmaceutical compositions containing them and to their use in the treatment of neurological and neuropsychiatric disorders.

BACKGROUND OF THE INVENTION

Glutamic acid is the major excitatory amino acid in the mammalian central nervous system (CNS), and acts through two classes of receptors, the ionotropic and metabotrobic receptors, respectively. The ionotropic glutamate receptors are divided into three subtypes based on the affinities of agonists for these receptors, namely iV-methyl-D- aspartate (NMDA), (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) and kainic acid (or kainite) receptors. The NMDA receptor contains binding sites for co-agonists (glycine, D-serine) as well as modulators such as polyamines and Mg2+. NMDA receptor activation requires binding of both glutamate and glycine. Based on both preclinical and clinical data, functional NMDA receptor activation is a potential target for the treatment of schizophrenia and other diseases linked to NMDA receptor dysfunction. Activation of NMDA receptors can be achieved by an inhibitor of the glycine transporter.

The NMDA receptor is blocked by compounds such as phencyclidine which induce a psychotic state which resembles schizophrenia. Likewise, the NMDA. antagonists, such as ketamine, induce negative and cognitive symptoms similar to schizophrenia. This indicates that NMDA receptor dysfunction is involved in the pathophysiology of schizophrenia. The NMDA receptor has been associated with a number of diseases, such as pain (Yaksh Pain 1989, 37, 111-123), spasticity, myuoclonus and epilepsy (Truong et. al. Movement Disorders 1988, 3, 77-87), learning and memory (Rison et. al. Neurosci. Biobehav. Rev. 1995, 19, 533-522), and with schizophrenia (Javitt D. C. and Zukin S.R., Recent advances in the phencyclidine model of schizophrenia, American Journal of Psychiatry, 148, 1301-8, 1991). It is reported that the negative symptoms of schizophrenic patients are ameliorated with a high dose of glycine (Heresco- Levy U., et al., Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia, Br. J. Psychiatry, 169, 610-7. 1996)-, (Biol. Psychiatry 2004; 55:165-171).

Additionally, the activation of NMDA receptor is involved in the formatioin of long-term potentiation (LTP) considered as a memory and learning model at the n_euron level (Collingridge G.L. and Bliss T.V., NMDA receptors-their role in long-term potentiation. Trends. Neurosi., 10, 288-93, 1987). Still additionally, the adminisixation of an NMDA receptor antagonist to animals induces an amnesia therein (Morris R-.. G., Andersen E., Lynch G.S. and Braudy M., Selective impairment of learning and blockade of long-term potentiation by an iV-methyl-D-aspartate receptor antagonist, AP5, Nature, 319, 774-6, 1986; and Mark Benvenga and Theodore C. Spaulding, Amnesic effect of the novel anticonvulsant MK-801, Pharmacol Biochem Behav., 30, 205-207, 1988). Hence, it is suggested that NMDA receptor plays a very significant role in memory and learning.

Further, the deterioration of the function of NMDA receptor has been reported even in humans, namely in patients with Alzheimer-type dementia (Ninomiya, H._, et. al., [3H]-N-[l-(2-thienyl)cyclo-hexyl]-3,4-piperidine ([3H]-TCP) binding in human frontal cortex: decreases in Alzheimer-type dementia., J. Neurochem., 54, 526-32, 1990; and Tohgi, H., et. al., A selective reduction of excitatory amino acids in cerebrospinal fluid of patients with Alzheimer type dementia compared with vascular dementia of the Binswanger type., Neurosci. lett, 141, 5-8, 1992).

Alternatively, a number of papers report an anti-amnesia action of glycine— site agonist in animal models (Matsuoka N. and Aigner T. G., D-Cycloserine, a partial agonist at the glycine site coupled to iV-methyl-D-aspartate receptors, improves visual recognition memory in rhesus monkeys, J. Exp. Pharmacol. Ther., 278, 891-7, 1996; Ohno M-, et. al., Intraphippocampal administration of glycine site antagonist impairs working menαory performance of rats. Eur. J. Pharmacol., 253, 183-7, 1994; and Fishkin R.J., et. aL., D-cycloserine attenuates scopolamine-induced learning and memory deficits in rarts, Behav. Neural. Biol., 59, 150-7, 1993). These findings suggest that drugs which would enhance extracellular levels of glycine at the NMDA receptor by inhibiting the activity of glycine transporters are useful as therapeutic agents of dementia, schizophrenia and other cognitive disorders. Molecular cloning has revealed the existence of two types of glycine receptors, glycine type-1 (GIyT-I) (Borowsky B. Hoffman BJ. Analysis of a gene encoding two glycine transporter variants reveals alternative promoter usage and a novel gene structure. Journal of Biological Chemistry. 273(44) :29077-85, 1998 Oct 30. Kim K-M. Kingsmore SF. Han H. Yang-Feng TL. GodinotN. Seldin MF. Caron MG. Giros B. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Molecular Pharmacology. 45(4):608-17, 1994. Borowsky B. Mezey E. Hoffman BJ. Two glycine transporter variants with distinct localization in the CNS and peripheral tissues are encoded by a common gene. Neuron. 10(5):851-63, 1993.. Guastella J. Brecha N. Weigmann C. Lester HA. Davidson N. Cloning, expression, and localization of a rat brain high-affinity glycine transporter. Proceedings of the National Academy of Sciences of the United States of America. 89(15):"/ 7189-93, 1992. Liu QR. Nelson H. Mandiyan S. Lopez-Corcuera B. Nelson N. Cloning and expression of a glycine transporter from mouse brain. FEBS Letters. 305(2): 110-4, 1992. Smith KE. Borden LA. Hartig PR. Branchek T. Weinshank RL. Cloning and expression of a glycine transporter reveal colocalization with NMDA receptors. Neuron. 8(5):927-35, 1992 May. Borowsky B. Hoffman BJ. Neurotransmitter transporters: molecular biology, function, and regulation. International Review of Neurobiology. 38:139-99, 1995.) ) and glycine type-2 (GIy T-2) (Liu QR. Lopez-Corcuera B. Mandiyan S. Nelson H. Nelson N. Cloning and expression of a spinal cord- and brain-specific glycine transporter with novel structural features. Journal of Biological Chemistry. 268(30) :22802-8, 1993. Evans J. Herdon H. Cairns W. O'Brien E. Chapman C. Terrett J. Gloger I. Cloning, functional characterisation and population analysis of a variant form of the human glycine type 2 transporter. [Journal Article] FEBS Letters. 463(3) :301-6, 1999. Morrow JA. Collie IT. Dunbar DR. Walker GB. Shahid M. Hill DR. Molecular cloning and functional expression of the human glycine transporter GIy T2 and chromosomal localisation of the gene in the human genome. FEBS Letters. 439(3): 334-40, 1998). Recent studies have demonstrated that GIyTl inhibitors are effective in pre¬ clinical models of schizophrenia. (Le Pen G. Kew J. Alberati D. Borroni E. Heitz MP. Moreau JL. Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal-lesioned rats: reversal by glycine and a glycine transporter inhibitor. Biological Psychiatry. 54(11): 1162-70, 2003. Kinney GG. Sur C. Burno M. Mallorga PJ. Williams JB. Figueroa DJ. Wittmann M. Lemaire W. Conn PJ. The glycine transporter type 1 inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior. Journal o/Neuroscience. 23(20): 7586-91, 2003.. Chen L. Muhlhauser M. Yang CR. Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. Journal of Neurophysiology. 89 (2): 691- 703. Bergeron R. Meyer TM. Coyle JT. Greene RW. Modulation of N-methyl-D- aspartate receptor function by glycine transport. Proceedings of the National Academy of Sciences of the United States of America. 95 (26): 15730-4, 1998.

WO 97/45115 discloses a class of substituted amines, pharmaceutical compositions and methods of treating neurological and neuropsychiatric disorders

WO 99/34790 discloses a class of substituted amino acids, pharmaceutical compositions and methods of treating neurological and neuropsychiatric disorders.

WO 03/000646 Al discloses substituted aromatic ethers as inhibitors of glycine transport.

Expert Opin. Ther. Patents (2004) 14(2): 201-214 discloses recent progress in the use of glycine transporter -1 inhibitors for the treatment of central and peripheral nervous system diseases.

WO 2004/096761 Al discloses aromatic oxyphenyl and aromatic sulfanylphenyl derivatives.

The novel compounds of the present invention are inhibitors of the GIyT-I transporter and thus useful for the treatment of neurological and neuropsychiatric disorders. DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides for a compound of Formula 1

wherein

X is hydrogen, halo, C1-C10 alkyl, (C1-C10 alkyl) aryl, CF3, cycloalkyl, aryl, substituted aryl, CO-aryl, fused arylcycloalkyl, substituted fused arylcycloalkyl, heteroaryl, substituted heteroaryl or fused arylheterocyclyl;

Z is C1-C10 alkyl, C2-C10 alkenyl, Y, COY, CH(OH)Y, OY, (Ci-Ci0 alkyl) Y, (C1-C10 alkyl) OY, SY, CF2Y or NR2Y;

Y is Ci-Ci0 alkyl, (CH2)nCF3, CF3, C2F5, C3F7, aryl, substituted aryl, heteroaryl, substituted heteroraryl, cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl;

n is 1 to 10;

A is aryl, substituted aryl, hydrogen, or -0(C1-C10 alkyl);

R is Ci-Ci0 alkyl; and

R is hydrogen or Ci-Cio alkyl; wherein aryl or substituted aryl is phenyl or napthyl each of which may. be substituted by one or more (C1-C10 alkyl) phenyl, (C1-C10 alkyl) napthyl, pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole, 1,2,4-triazinyl, benzyl, napthalenemethyl, thienylmethyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, hydroxy, C1-C10 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C10 hydroxyalkyl, -0(C1-C10 alkyl), phenyl, phenoxy, napthyloxy, benzyloxy, 1- or 2-napthalenemethoxy, CHO, (C1-C3 alkyl)CO, benzoyl, 1- or 2- napthoyl, fluoro, bromo, chloro, iodo, NO2, CN, COOH, (C1-C10 atkyl)OCO, phenoxycarbonyl, napthoxycarbonyl, (C1-C10 alkyl)SO2, -S(C1-C1O alkyl), phenylsulfinyl, napthylsulfϊnyl, benzylthio, cyclohexyl, cyclopentyl, cycloheptyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomoφholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl cyano, CF3, OCF3, phenyl, S(C1-C10 alkyl), amino, methylamino or dimethylamino substituents;

heteroaryl or substituted heteroaryl is pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2- a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole or 1,2,4-triazinyl each of which may be substituted by one or more (C1-C10 alkyl) phenyl, (C1-C10 alkyl) napthyl, pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole or 1,2,4-triazinyl, benzyl, napthalenemethyl, thienylmethyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, hydroxy, C1-C10 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C10 hydroxy alkyl, 0(C1-C10 alkyl), phenoxy, napthyloxy, benzyloxy, 1- or 2- napthalenemethoxy, HCO, (C1-C3 alkyl)CO, benzoyl, 1- or 2-napthoyl, fluoro, bromo, chloro, iodo, NO2, CN5 COOH, (C1-C10 alkyl)OCO, phenoxycarbonyl, napthoxycarbonyl, (C1-CiO alkyl)SO2, phenylsulfinyl, napthyl sulfinyl, benzylthio, cyclohexyl, cyclopentyl, cycloheptyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomoφholinyl. thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, cyano, CF3, phenyl, S(C1-C10 alkyl), amino, methylamino or dimethylamino substituents;

fused arylcarbocyclyl is a fused aryl and carbocyclyl wherein aryl is as defined above and carbocyclyl is a non-aromatic monocyclic ring system of 3 to 10 carbon atoms, which may bear an oxo (=O) moiety;

fused arylheterocyclyl is a fused aryl and heterocyclyl wherein aryl is as defined above and heterocyclyl is a non-aromatic monocyclic ring system of 3 to 10 carbon atoms in which one or more atoms in the ring system is nitrogen, oxygen or sulfur, which may be substituted by one or more Ci-C10 alkyl substituents;

cycloalkyl or substituted cycloalkyl is a non-aromatic monocyclic or multicyclic ring system of 3 to 10 carbon atoms each of which may be substituted by one or more (C1-C10 alkyl) phenyl, (C1-C10 alkyl) napthyl, pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2- ajpyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole, 1,2,4-triazinyl, benzyl, napthalenemethyl, thienylrnethyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, hydroxy, Ci-C10 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C10 hydroxyalkyl, 0(C1-C10 alkyl), phenoxy, napthyloxy, benzyloxy, 1- or 2-napthalenemethoxy, CHO, (C1-C3 alkyl)CO, benzoyl, 1- or 2- napthoyl, fluoro, bromo, chloro, iodo, NO2, CN, COOH, (C1- C10 alkyl)OCO, phenoxycarbonyl, napthoxycarbonyl, (Ci-C10 alkyl)SO2, phenylsulfinyl, napthyl sulfinyl, benzylthio, cyclohexyl, cyclopenyl, cycloheptyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, cyano, CF3, phenyl, S(C1- C10 alkyl)., amino, methylamino or dimethylamino substituents; and

heterocyclyl or substituted heterocyclyl is a non-aromatic saturated monocyclic or multicyclic ring system of 3 to 10 carbon atoms in which one or more of the carbon atoms in the ring system are nitrogen, oxygen or sulfur each of which may be substituted by one or more (C1-C10 alkyl) phenyl, (C1-C10 alkyl) napthyl, pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l52-a]pyτidine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole, 1,2,4-triazinyl, benzyl, napthalenemethyl, thienylmethyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, hydroxy, Ci-C1O alkyl, C2-C4 alkenyl, C2-C4 alkynyl, . C1-C1O hydroxyalkyl, 0(C1-C10 alkyl), phenoxy, napthyloxy, benzyloxy, 1- or 2-napthalenemethoxy, CHO, (C1-Ca alkyl)CO, benzoyl, 1- or 2- napthoyl, fluoro, bromo, chloro, iodo, NO2, CN5 COOH, (Ci-C1O alkyl)OCO, phenoxycarbonyl, napthoxycarbonyl, (Ci-C1O alkyl)SO2, phenylsulfinyl, napthyl sulfmyl, benzylthio, cyclohexyl, cyclopenyl, cycloheptyl, piperidyl, pyrrolidinyl; piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, cyano, CF3, phenyl, S(Ci-C1O alkyl), amino, methylamino or dimethylamino substituents;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of Formula 1 above wherein

X is hydrogen, halo, Ci-Cjo alkyl, CF3, aryl, substituted aryl, heteroaryl, substituted heteroaryl or fused arylheterocyclyl;

Z is Y, COY, CH(OH)Y, OY, (Ci-Ci0 alkyl) Y, SY or NR2Y; Y is Ci-C10 alkyl, (CH2)nCF3; CF3, C2F5, C3F7, aryl, substituted aryl, heteroaryl, substituted heteroraryl, cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl;

n is 1 to 10;

A is aryl, substituted aryl or hydrogen;

R is Ci-Cio alkyl; and

R is hydrogen or Ci-Cio alkyl;

wherein aryl or substituted aryl is phenyl or napthyl each of which may be substituted by one or more (C1-C1O alkyl) phenyl, (C1-C10 alkyl) napthyl, pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole, 1 ,2,4-triazinyl, benzyl, napthalenemethyl, tliienyl methyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, hydroxy, C1-C10 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C10 hydroxy alkyl, 0(C1-C10 alkyl), phenoxy, napthyloxy, benzyloxy, 1- or 2-napthalenemethoxy, CHO, (C1-C3 alkyl)CO, benzoyl, 1- or 2- napthoyl, fluoro, bromo, chloro, iodo, NO2, CN, COOH, (C1-C10 alkyl)OCO, phenoxycarbonyl, napthoxycarbonyl, (C1-C10 alkyl)SO2, phenylsulfinyl, napthyl sulfinyl, benzylthio, cyclohexyl, cyclopenyl, cycloheptyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl or tetrahydrothiopyranyl;

heteroaryl or substituted heteroaryl is pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2- a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole, 1,2,4-triazinyl each of which may be substituted by one or more (C1-C1O alkyl) phenyl, (C1-C10 alkyl) napthyl, pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, berrzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole or 1,2,4-triazinyl, benzyl, napthalenemethyl, thienyl methyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, hydroxy, C1-C10 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C10 hydroxyalkyl, 0(C1-C10 alkyl), phenoxy, napthyloxy, benzyloxy, 1- or 2- napthalenemethoxy, HCO5 (C1-C3 alkyl)CO, benzoyl, 1- or 2-napthoyl, fluoro, bromo, chloro, iodo, NO2, CN, COOH, (C1-C10 alkyl)OCO, phenoxycarbonyl, napthoxycarbonyl, (C1-C10 alkyl)SO2, phenylsulfmyl, napthyl sulfϊnyl, benzylthio, cyclohexyl, cyclopenyl, cycloheptyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl or tetrahydrothiopyranyl;

fused arylheterocyclyl is a fused aryl and heterocyclyl wherein aryl is as defined above and heterocyclyl is a non-aromatic saturated monocyclic ring system of 3 to 10 carbon atoms in which one or more atoms in the ring system is nitrogen, oxygen or sulfur;

cycloalkyl or substituted cycloalkyl is a non-aromatic monocyclic or multicyclic ring system of 3 to 10 carbon atoms each of which may be substituted by one or more (C1-C10 alkyl) phenyl, (C1-C1O alkyl) napthyl, pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2- a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole, 1,2,4-triazinyl, benzyl, napthalenemethyl, thienyl methyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, hydroxy, C1-C10 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C10 hydroxy alkyl, 0(C1-C10 alkyl), phenoxy, napthyloxy, benzyloxy, 1- or 2-napthalenemethoxy, CHO, (C1-C3 alkyl)CO, benzoyl, 1- or 2- napthoyl, fluoro, bromo, chloro, iodo, NO2, CN, COOH, (C1- C10 alkyl)OCO, phenoxycarbonyl, napthoxycarbonyl, (C1-CiO alkyl)SO2, phenylsulfinyl, napthyl sulfinyl, benzylthio, cyclohexyl, cyclopenyl, cycloheptyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetraliydrothiophenyl or tetrahydrothiopyranyl; and

heterocyclyl or substituted heterocyclyl is a non-aromatic saturated monocyclic or multicyclic ring system of 3 to 10 carbon atoms in which one or more of the carbon atoms in the ring system are nitrogen, oxygen or sulfur each of which may be substituted by one or more (Ci-C10 alkyl) phenyl, (C1-C10 alkyl) napthyl. pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, qυinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole, 1,2,4-triazinyl, benzyl, napthalenemethyl, thienyl methyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, hydroxy, C1-C1O alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C10 hydroxy alkyl, 0(C1-C10 alkyl), phenoxy, napthyloxy, benzyloxy, 1- or 2-napthalenemethoxy, CHO, (C1-C3 alkyl)CO, benzoyl, 1- or 2- napthoyl, fluoro, bromo, chloro, iodo, NO2, CN, COOH, (CI-C10 alkyl)OCO, phenoxycarbonyl, napthoxycarbonyl, (C1-Ci0 alkyl)SO2, phenylsulfinyl, napthyl sulfinyl, benzylthio, cyclohexyl, cyclopenyl, cycloheptyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl or tetrahydrothiopyranyl;

or a pharmaceutically acceptable salt thereof.

Yet a further embodiment of the present invention provides a compound of Formula 1 above wherein Y is Ci-C10 alkyl, CF3 or -(CH2) CF3.

In a further embodiment, the present invention provides for a Compound of Formula 1 wherein Z is C1-C10 alkyl, C2-C10 alkenyl, Y, COY, CH(OH)Y, (Ci-CiOalkyl)Y Or NR2Y. In. a further embodiment, the present invention provides a compound of Formula 1 above wherein

X is aryl, substituted aryl, halo, CF3; hydrogen, heteroaryl or fused arylheterocyclyl;

Z is COY5 OY, Y or -CH2Y;

Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl or cycloalkyl;

A is hydrogen or aryl; and

R is methyl;

or a pharmaceutically acceptable salt thereof.

The compounds of the present invention and their pharmaceutically acceptable salts inhibit the activity of the glycine type-1 transporter.

Accordingly, the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof for use in therapy. In particular, the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof for use as an inhibitor the glycine type-1 transporter.

In another embodiment, the present invention provides a method for inhibiting the uptake of glycine type-1 transporter in a patient, comprising administering to a patient in need of such inhibition an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof. In particular, the present invention provides a method for treating a disorder which is caused by or linked to decreased neurotransmission of the glycine type-1 transporter in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof. Such disorders include, for example, schizophrenia, cognitive impairment associated with schizophrenia, Alzheimer's disease, Parkinson's disease or dementia. In another alternative embodiment, the present invention provides for the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the glycine type-1 transporter. In particular, the present invention provides for the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disorder which is caused by or linked to decreased neurotransmission of glycine type-1. Such disorders include, for example, schizophrenia, cognitive impairment associated with schizophrenia, Alzheimer's disease, Parkinson's disease or dementia.

"C1-C1O alkyl" means an aliphatic hydrocarbon group which may be straight or branched. AUkyl groups have 1 to 10 carbons in the chain.

"C2-C io alkenyl" means an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be straight or branched having 2 to 10 carbon atoms in the chain.

"Alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having 2 to 15 carbon atoms in the chain.

"AraUkyl" means an aryl-alkyl- group wherein the aryl and alkyl are as herein described. Particular aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.

"AratkylsulfonyT means an aralkyl-SO2- group wherein the aralkyl group is as herein described.

"Aralkylsulfinyl" means an aralkyl-SO- group wherein the aralkyl group is as herein described.

"Aryl" means an aromatic monocyclic or multicyclic ring system of 6 to 14 carbon atoms, preferably of 6 to 10 carbon atoms. Representative aryl groups include phenyl or naphthyl. "Substituted aryl" means aryl substituted with one or more "ring system substituents" which may be the sane or different, as defined herein. Representative substituted aryl groups are substituted phenyl or substituted napthyl. "Substituted phenyl" means a phenyl group, as herein described, substituted by one or more ring system substituents. "Substituted naphthyl" means a 1- or 2-naphthyl group substituted by one or more ring system substituents.

"Aryloxy" means an aryl-O- group wherein the aryl group is as defined herein. Representative groups include pherxoxy and 2-naphthyloxy.

"Aryloxyalkyl" means an aryl-O-alkyl- group wherein the aryl or alkyl groups are as herein described. Representative aryloxyalkyl groups are phenoxypropyl.

"Arylsulfonyl" means an aryl-SCh- group wherein the aryl group is as defined herein.

"Arylsulfmyl" means an aryl-SO- group wherein the aryl group is as defined herein.

"Arylthio" means an aryl-S- group wherein the aryl group is as herein described. Representative arylthio groups include phenylthio and naphthylthio.

"Carboxy" means a HO(O)C- (carboxylic acid) group.

"Compounds of the invention", and equivalent expressions, are meant to embrace compounds of general Formula 1 as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances Λvhen the context so permits.

"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system of 3 to IO carbon atoms, preferably of 5 to 10 carbon atoms. Preferred ring sizes of rings of the ring system include 5 to 6 ring atoms. The term "substituted cycloalkyl" means cycloalkyl substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Representative monocyclic cycloalkyl include cyclohexyl, cyclopentyl, cycloheptyl, and the like.

"Fused arylcarbocyclyl" is a. non-aromatic monocyclic ring system of 3 to 10 carbon atoms fused. Fused aryl carbocyclyl may bear an oxo (=0) moiety. A particular fused arylcarbocyclyl group is lH-oxoindane.

"Heteroaralkyl" means a heteroaryl-alkyl- group wherein the heteroaryl and alkyl are as herein described. Particular kieteroaralkyls contain 1 to 4 carbon atoms in the alkyl chain. Particular heteroaralkyl groups are, for example, thienylmethyl, pyridylmethyl, imidazolylmethyl and pyrazinylmefhyl.

"Heteroaryl" means an aromatic monocyclic or multicyclic ring system of 5 to 14 carbon atoms, preferably 5 to 10 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero elenxent(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred ring sizes of rings of the ring system include 5 to 6 ring atoms. The term "substituted heteroaryl" means heteroaryl be substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The designation of the aza, oxa or ttiia as a prefix before heteroaryl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. A nitrogen atom of an heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide. Representative heteroaryl and substituted heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole or 1 ,2 r4-triazinyl.

"Fused arylheterocyclyl" means a fused aryl and heterocyclyl as defined herein. Preferred fused arylheterocyclyls are those wherein the aryl thereof is phenyl and the heterocyclyl consists of 5 to 6 ring atoms. A fused arylheterocyclyl as a variable may be bonded through any atom of the ring system thereof capable of such. The designation of the aza, oxa or thia as a prefix before heterocyclyl portion of the fused arylheterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused arylheterocyclyl may be optionally substituted by one or more ring system substituent, wherein the "ring system substituent" is as defined herein. The nitrogen atom of a fused arylheteroaryl may be a basic nitrogen atom. Representative fused aryllheterocylyl ring systems include benzothiophene, benzodioxol, dihydrobenzodioxin, indole, dihydrobenzodioxyl, benzothdophene, benzofuran, dihydrobenzofuran, oxoindane or dihydroindole and the like.

"Ring system substituents" mean substituents attached to aromatic or non- aromatic ring systems inclusive of hydrogen, alkylaryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfinyl, aralkylthio, cycloalkyl or heterocyclyl.

"Acyl" means an H-CO- or alkyl-CO- group wherein the alkyl group is as herein described. Representative acyls contain a lower alkyl. Additional representative acyl groups include formyl, acetyl, propanoyl, 2-methylproparjLoyl, butanoyl and palmitoyl.

"Alkoxy" means an alkyl-O- group wherein the alkyl group is as herein described. Representative alkoxy groups include methoxy, ethoxy, ra-propoxy, /-propoxy, rø-butoxy and heptoxy.

"Alkoxycarbonyl" means an alkyl-O-CO- group, wherein the alkyl group is as herein defined. Representative alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, or t-butyloxycarbonyl.

"Aralkoxy" means an aralkyl-O- group wherein the aralkyl groups is as herein described. Representative aralkoxy groups include benzyloxy and 1- or 2- naphthalenemethoxy.

"Aroyl" means an aryl-CO- group wherein the aryl group is as herein described. Exemplary groups include benzoyl and 1- and 2-naphthoyl. "Effective amount" is means an amount of a compound/composition according to the present invention effective in producing the desired therapeutic effect.

"Halo" means fluoro, chloro, bromo or iodo.-

"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system of 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms, in W7WcIi one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred ring sizes of rings of trie ring system include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a. prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is pxesent respectively as a ring atom. The term "substituted heterocyclyl" means heterocycLyl optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen atom of an heterocyclyl may t>e a basic nitrogen atom. The nitrogen or sulphur atom of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

Representative mono-, di- or trifluoro- substituted lower alkyl groups include -CF35 -C2F5 Or -C3F7.

In a particular embodiment, X is aryl or substituted aryl. When X is aryl, X is more particularly phenyl or napthyl. When X is substituted aryl, X is more particularly phenyl which may be substituted by one or more methoxy, ethoxy, cyano, fluoro, chloro, bromo, acetyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, butyl, hydroxy, phenyl, nitro, methanesulfonyl, ethylsulfanyl, t-butyl, isopropyl, ethylsulfonyl, dimethylamino or isopropoxy substituents. Still more particularly wlαen X is substituted aryl, X is is 4-chlorophenyl, 4-methylphenyl, 3-(trifluoromethyl)pherxyl, 2- (trifluoromethyl)phenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 3- (phenyl)phenyl, 2-methylphenyl, 3-bromophenyl, (3-nitro-4-methyl)phenyl, 2,5- dichlorophenyl,3-methoxyphenyl, 2,4-difluorophenyl, 4-(ethyl)phenyl, 4- (hydroxy)phenyl, 2,5-(dimethyl)phenyl, 3-acetylphenyl, 4-(txifluorornethyl)phenyl, 3,4- (dimethoxy)phenyl, 2,4-(dichloro)phenyl, 3,4-(difluoro)phenyl, 4-fluιorophenyl, (3- memyl~4-fluoro)phenyl, 4-(ethylsulfonyl)phenyl, 4-(t-butyl)phenyl, 4-(isopropyl)phenyl, 3,5-(dimethyl)phenyl, 4-(ethanesulfonyl)phenyl, 3,5-(dichloro)phenyl, (3-chloro-4- fluoro)phenyl, 3,4-(dichloro)phenyl, 3-ethoxyphenyl, S-methylphenyd, 3- (trifluoromethoxy)phenyl5 4-(acetyl)phenyl, 2-(cyano)phenyl, 3-cyanophenyl, 4- cyanophenyl, 2-fluorophenyl, 3 -fluorophenyl, (3-methyl-4-fluoro)ph.enyl, 4-(methanesulfonyl)phenyl, 4-(dimethylamino)phenyl, 4-ethylsulfkryl, 4-ethanesulfonyl, 3-methyl-4-methoxyphenyl, 3-(isopropyl)phenyl, 4-(isopropoxy)phenyl, 3,5- (difluoro)phenyl, 3,4-(dimethyl)phenyl, 4-(ethoxy)phenyl, 3 -methyl— 4-methoxyphenyl, 3- (isopropoxy)phenyl or 3-chloro-4-fluorophenyl.

In another particular embodiment, X is halo. In a more partioular embodiment, X is bromo or chloro. In another particular embodiment X is fluoro.

In another particular embodiment, X is CF3.

In another particular embodiment, X is hydrogen.

In another particular embodiment, X is cycloalkyl. In a more particular embodiment X is cyclohexyl.

In another particular embodiment, X is CO-aryl. In a more particular embodiment, X is -CO-phenyl.

In another particular embodiment, X is (Ci-Qoalkytyaryl. In a more particular embodiment X is -CH2-phenyl.

In a particular embodiment X is heteroaryl or substituted heteroaryl. In yet another particular embodiment X is thiophen-2-yl, furan-3-yl or lH-indol-6-yl.

In another particular embodiment, X is fused arylheterocyclyl. When X is fused arylheterocyclyl particular values of X are benzodioxol, dihydrobenzodioxin, indole, dihydrobenzodioxyl, benzothiophene, benzofuran, dihydrobenzofuran., oxoindane or dihydroindole. Even more particular values of X are benzo[b]thioherjL-3-yl or benzo[b]thiophen-2-yl. More particular values of X include benzo[l,3]dioxol-5-yl, 2,3— dihydrobenzo [ 1 ,4] dioxol-6-yl, 2,3 -dihydrobenzo [ 1 ,4] dioxin-6-yl, benzo [b]thiophen-3 -yi, benzo[b]thiophen-2-yl, benzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, l-oxo-indan-5-yl_, 2,3-dihydro-lH-indol-5-yl, 2,3-dihydrobenzofuran-5-yl, benzofuran-2-yl, benzofuran-5 - yl, lH-indol-6-yl or benzo[l,4]dioxin-6-yl.

In a particular embodiment, Z is (Ci-Ci o alkyl)Y. When Z is (Ci-Ci o alkyl)Y, Υ is particularly aryl or heteroaryl and Ci-Cio alkyl is preferably -CH2-. A more preferred heteroaryl group is thiophen-2-yl. A more particular aryl group is phenyl. Also when Z is (Ci-Cio alkyl) Y, Y is particularly cycloalkyl or substituted cycloalkyl. More particularly, Y is cyclopropylmethyl, cyclohexyl or cyclopropyl. In yet another particular embodiment when Z is (Ci -C 10 alkyl) Y, Y is phenyl which may be substituted by one or more methyl, ethyl, bromo, chloro or fluoro substituents. More particularly, Y is 2- or

3-methylphenyl or 2- or 3-chlorophenyl. In yet a further embodiment when Z is (Ci-Cj 0 alkyl) Y, Z is -(CHa)2Y.

In another particular embodiment, Z is Y. When Z is Y, a particular value for Y is heteroaryl, substituted heteroaryl, aryl or substituted aryl. When Z is Y and Y is heteroaryl, a more particular heteroaryl group is thiophen-2-yl. Another particular heteroaryl group is thiazolyl. When Z is Y and Y is substituted heteroaryl, a particular value for Y is 3 -(methyl) thiophen-2-yl.

When Z is Y and Y is aryl, a particular value for Y is phenyl.

When Z is Y and Y is substituted aryl, a particular value for Y is phenyl which may be substituted by one or more methyl, fluoro, methoxy or chloro substituents. Moire particular values for Y include 3,4-(dimethyl)phenyl, (3-methyl-4-fluoro)phenyl, 2,4- difluorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2-methoxyphenyl, 2,4-dichlorophenyl., 2- (methyl)phenyl, 3-chlorophenyl, or 4-chlorophenyl. When Z is Y particular values for Y also include 2-chlorophenyl, 3-methylphenyl, 4-chlorophenyl, 3-chlorophenyl or 2- methylphenyl. When Z is Y and Y is Ci-Ci0 alkyl, Y is particularly isopropyl, t-butyl, isobutyl, 1,2-dimethylpropyl or 2,2-dimethylpropyl.

When Z is Y and Y is cycloalkyl, a particular value for Y is cyclohexyl.

When Z is OY5 a particular value for Y is aryl. When Z is OY, a more particular aryl group for Y is phenyl. Other particular values of Y when Z is OY include butyl, CH2CF3, isopropyl or CF3.

When Z is COY, a particular value for Y is heteroaryl, aryl, substituted aryl, fused arylheterocyclyl or cycloakyl. When Z is COY and Y is heteroaryl, a particular value for Y is thiophen-2-yl. When Z is COY and Y is aryl, a particular value for Y is phenyl or napthelen-2-yl. When Z is COY and Y is substituted aryl, a more particular value for Y is 4-(methoxy)phenyl, 4-chlorophenyl, 3 -(methyl) phenyl or 3-chlorophenyl. When Z is COY and Y is cycloalkyl, a particular value for Y is cyclohexyl. When Z is COY and Y is Ci-Cio alkyl, a particular Ci-Cio alkyl is t-butyl.

A particular value for R is methyl.

Particular values for A are hydrogen or aryl. When A is aryl, a more preferred value is phenyl. Yet another particular value for A is methoxy.

In a particular embodiment, Z is (Ci-Cio alkyl)OY. A particular Ci-Cio alkyl is - CH2-. A particular value for Y, when Z is (Ci-Cio alkyl)OY , is isopropyl or cycloalkyl.

In a particular embodiment, Z is isopropenyl.

In another particular embodiment, Z is NR2Y. When Z is NR2Y a particular value for R is hydrogen and a particular value for Y is phenyl.

When Y is cycloalkyl, a particular value or Y is cyclohexyl.

When Z is Y and Y is Ci-Ci0 alkyl, a particular value for Y is CH2C(CH3) 3.

A particular value for n is 1. Prefejred compounds of Formula 1 include {methyl[2-(3-thiophen-2-yl-biphenyl- 4-yloxy)ethyl]amino} -acetic acid, { [2-(4-benzo[l ,3]dioxol-5-yl-2-tert-butylphenoxy]- ehtyl] -methylamino } -acetic acid, ( { 2- [3 -(2,2-dimethylpropyl-biphenyl-4-yloxy] ethyl} - methylamino)-acetic acid or { [2-(3 -tert-butylbiphenyl-4-yloxy)ethyl] -methylamino } - acetic acid.

The present invention includes pharmaceutically acceptable salts of the compounds of Formula 1. "Pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts, and salts made with a base of compounds of the present invention, for example hydrochloride salt. (See, for example S.M. Berger, et al, "Pharmaceutical Salts," J. Pharm. Sci., 66: p. 1-19 (1977))

Compounds of Formula 1 may also be administered as a zwitterionic form without any additional acid or basic species.

"Pharmaceutically acceptable" means it is, within the scope of sound medical judgement, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.

It will be appreciated that compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of Formula 1 hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates.

The compounds of the present invention and their pharmaceutically acceptable salts are useful in treating neurological and neuropsychiatric disorders which are caused or linked to decreased levels or decreased half-life of extracellular glycine or dysfunction of the NMDA receptor. Such disorders are remedied by inhibition of the GIyT-I transporter. Compounds of the present invention alter the functional activity of glycine transporters and therefore result in changes in extracellular glycine levels which can be useful in the treatment or prevention of a number of neurological and neuropsychiatric disorders. Such disease states include those associated with decreased or exaggerated function of NMDA receptors, namely schizophrenia, cognitive impairment associated with schizophrenia, mood disorders, learning disorders, psychosis, depression, dementia and other forms of impaired cognition, such as attention deficit disorders. Compounds of Formula 1 may also be useful as an adjunctive treatment with other antipsychotic treatments. NMDA receptors have further been implicated in disorders arising from neuronal cell death and neurodegeneration and therefore compounds of Formula 1 may be useful in the treatment or prevention of stroke, head trauma, Alzheimer's disease, pain, Parkinson's disease and Huntington's disease. Enhanced inhibitory glycinergic transmission resulting from inhibition of GIyT-I activity by compounds of the present invention may be useful in the treatment of muscle hyperactivity associated with spasticity, myoclonus or epilepsy. Compounds of the present invention may also elevate spinal glycine and thus possess analgesic properties. Compounds of Formula 1 may also be useful in enhancing memory or learning.

In the context of the present specification the terms "treating" and "treatment" include prophylactic treatment as well as curative treatment.

The compounds may be administered by various routes and are usually employed in the form of a pharmaceutical composition.

Accordingly, in a further embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.

The compositions indicated can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colorants, flavorings and/or one or more further active compounds. Compositions of the invention may be formulated so as to provide, quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 500 mg of the active ingredient.

In the context of the present specification, the term "unit dosage form" refers to physically discrete units suitable as unitary doses for human subjects and other mammals, each unit containing a predetermined quantity of one or more compounds of Formula 1 or pharmaceutically acceptable salts thereof, calculated to produce the desired therapeutic effect, together with a pharmaceutically acceptable diluent or carrier.

"Patient" includes human and other mammals.

While it is possible for the compounds of the invention to be administered alone it is preferably to present them as pharmaceutical compositions. The pharmaceutical compositions, both for veterinary and for human use, of the present invention comprise at least one compound of the invention, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.

Compound IC5O values were determined using a whole cell transport assay formatted as a solid-scintillant based assay using the Amersham 96-well Cytostar-T plate technology. Briefly, 16-20 hours prior to initiation of the assay, human medulloblastoma cell, BE(2)-C, stably expressing a human GIyTIa cDNA were trypsinized, counted and plated at a cell density of 60,000 cells/well in culture medium (1 : 1 mixture of Eagle's minimum essential medium with non-essential amino acids and Ham's F12 medium, 90% and fetal bovine serum, 10%). After washing the cell layer with assay buffer (25 rnM Hepes, 125 rnM NaCl, 4.8 mM KCl, 1.2 mM KH2PO4, 1.2 mM MgSO4, 5.6 mM glucose and 4 mM alanine), assay buffer and test compounds at various concentrations were added to the cell layer. The uptake assay was initiated by addition of 14C-glycine or 14C- sarcosine (7.5 μM final) and allowed to proceed at 25°C for 4-5 hours prior to counting on a.Wallac MicroBeta liquid scintillation spectrometer. Non-specific uptake was defined using 10 mM sarcosine (for 14C-glycine) or 10 mM glycine (for 14C-sarcosine). Data was analyzed using standard software. Advantageously, compounds of the present invention which were tested according to the assay described above exhibit an IC50 of < lμM. The in vivo effects of some of the compounds of Formula 1 were also evaluated in mice. Compounds were administered systemically up to two hours before a dose of phencyclidme or a dose of another NMDA receptor antagonist and locomotor activity was recorded for 60 minutes according to the methods of Gleason and Shannon (Gleason, S. C. and Shannon, H.E.: Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine, and 5-HT antagonists in mice. Psychopharmacology 1997,129:79-84). Compounds, when administered to mice, reversed the locomotor activity-increasing effects of phencyclidine or another NMDA receptor antagonist.

Preparation of Compounds of the Invention

The starting materials and intermediates of compounds of the invention may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their chemical equivalents which are apparent to one of ordinary skill in the art.

Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

The invention also provides for a process for preparing a compound of Formula 1 (or a pharmaceutically acceptable salt thereof) which comprises:

(a) decomposing the ester of a compound of Formula II

C in which R is a carboxy protecting group; (b) for a compound of Formula 1 in which Z is -CH2 Y, reducing the carbonyl group a compound of Formula 1 wherein Z is CO-Y;

whereafter, for any of the above procedures, when a pharmaceutically acceptable salt of a compound of Formula 1 is required, it is obtained by reacting the basic form of such a compound of Formula 1 with an acid affording a physiologically acceptable counterion, or, for a compound of Formula 1 which bears an acidic moiety, reacting the acidic form of such a compound of Formula 1 with a base which affords a pharmaceutically acceptable cation, or the compound may be isolated as zwitterionic species, or by any other conventional procedure; and wherein, unless more specifically described, the values of Y, Z, X, A and Ri are as defined above.

"Carboxy protecting groups" are those where the acidic hydrogen atom has been replaced with a suitable protecting group, to block or protect the acid functionality while the reactions involving other functional sites of the compound are carried out. Such protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups. For suitable protecting groups see T. W. Green and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991. ' Exemplary acidic functional groups include carboxyl (and acid bioisosteres), hydroxy, mercapto and imidazole. Examples of carboxylic acid protecting groups include esters such as methoxymethyl, tert-butyl and the like.

The compounds of the present invention can be prepared by a variety of procedures, some of which are illustrated in the Schemes below. It will be recognized by one of skill in the art that the individual steps in the. following schemes may be varied to provide the compounds of Formula 1. The particular order of steps required to produce the compounds of Formula 1 is dependent upon the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties. Some substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Compounds of Formula 1 may be prepared as illustrated in the following schemes. The skilled artisan will also appreciate that many of the steps outlined below will require standard extractive and chromatographic techniques to isolate the compounds.

Certain compounds of Formula 1 may be prepared as described in Scheme 1 where Z1 is CO-Y, OY, (Ci-Cio alkyl)Y, and SY. G is defined as a leaving group, such as halogen or boronic ester.

Scheme 1

Compound (a) when G is a halogen may be reacted in a Suzuki coupling with an aryl-boronic acid, heteroaryl-boronic acid or a suitable alkyl-boronic acid in a suitable solvent, such as 1,4-dioxane, with potassium fluoride, a source of palladium, such as palladium acetate, and a phosphine reagent, preferably 2-(dicylohexylphosphino)-2'- methylbiphenyl or tricyclohexylphospine. When. G is a boronic ester, compound (a) may be displaced with an aryl halogen, such as 2-bromothiazole, in 1,4-dioxane with a suitable base, such as potassium carbonate with triphenylphosphine and bis(dibenzylideneacetone)palladium (0). These reactions are generally heated at a temperature of 65 0C to 100 0C for about 2-72 h to give the coupled product (b) where Z1 is Y. The methoxy ether of (b) may be cleaved using boron tribromide in dichloromethane at about -75 0C, or using sodium ethanethiolate in N5N- dimethylformamide at 110 0C to give the hydroxy analog (c). In a standard Mitsunobu reaction the hydroxy analog (c) is reacted with [(2-hydroxyethyl)-alkyl-amino]acetic acid tert-butyl ester using l,r-(azodicarbonyl)-dipiperidine to give the ester (d). The tert- butyl ester may be removed using two different procedures. Compound (d) can be heated in 2 N sodium hydroxide in a solvent such, as 1,4-dioxane, or treated with trifluoroacetic acid in dichloromethane at room temperature. Either process will give the final product (Ia) as either the zwitterion or hydrochloride or other salt depending on how the acid is isolated.

In a similar fashion, when G is a halogen, an alcohol, such as cyclohexanol, with copper (I), 1,10-phenanthroline and a base like cesium carbonate may be heated in a sealed tube at about 120 0C to give the ether compound where Z1 is OY. In a Heck type reaction when G is a halogen, the aryl halogen compound may be reacted with bis(triphenylphosphine)palladium(II) chloride, copper(I) iodide in triethylarnine with an aryl-acetylene heated at about 45 0C for about 18 h gives an alkyne intermediate which is catalytically reduced to the saturated compound 5% palladium on carbon under am atmosphere of hydrogen to give a compound where Z1 is (Ci-Cio alkyl)Y.

The keto analogs may be prepared as described in Scheme 2 where A, Y and X are as previously described. G is defined as a leaving group, such as halogen or boronic ester.

Scheme 2

(e) (f) (g)

(h) (i) (J)

Oxidizing the benzaldehyde (e) with an oxidant such as potassium permanganate in tert-butanol produces the acid (f). The acid is reacted with 1,1 '-carbonyldiimadazole and N,O-dimethylhydroxylamine hydrochloride in a suitable solvent, such as dichloromethane, to give the Weinreb amide (g). A Suzuki coupling with an aryl-boronic acid or hetero-boronic acid gives compound (h) prepared essentially as previously described. Reaction of the Weinreb amide with an alkyl or an aryl Grignard reagent prepared using standard conditions giye the keto analog (i). Compound (i) may be further converted to the saturated compound by reducing the ketone utilizing such conditions as triethylsilane in trifluoroacetic acid to give analog Q). Intermediates (i) or (j) may then be processed similarly to intermediate (b) as shown in Scheme 1.

The disubstitued analogs may be prepared as described in Scheme 3 where X and Y are as previously described.

Scheme 3 (k) (I)

The substituted dichloroanisole (k) is reacted in a Suzuki coupling as previously

defined using two equivalents of the aryl-boronic acid or heteroaryl-boronic acid gives

the disubstituted compound (1). Intermediate (1) may then be processed similarly to

intermediate (b) as shown in Scheme 1.

The advanced intermediate (n) may also be prepared as described in Scheme 4

where A, X, Z and R1 are as previously described.

Scheme 4

Treating substituted aryl-fluorine compound (m) with [(2-hydroxyethyl)-alkyl-

amino] acetic acid tert-butyl ester that has been reacted at 0 0C with sodium hydride in

N,N-dimethylformamide gives the advanced intermediate compound (n). This compound

may be hydrolyzed as previously described to give compound Oa)- The advanced intermediates (q) and (r) may also be prepared using Rapid Parallel Synthesis as described in Scheme 5. G is defined as a leaving group, such as halogen or boronic ester. In this scheme A, X, Z and R1 are as previously described and R is a varied substituent on a phenyl ring.

Scheme 5

Reacting {[2-(3-iodobiphenyl-4-yloxy)ethyl]-methylamino)acetic acid tert-butyl ester compound (o) in a Suzuki reaction using conditions previously described with substituted aryl-boronic acid or heteroaryl-boronic acid reagents, such as 2- methylphenylboronic acid, in a Greenhouse™ reaction vessel quicldy generates many analogs shown as compoiind (p). Similarly, ({2-[4-bromo-2-(thiophene-2- carbonyl)phenoxy]emyl}-methylamino)acetic acid tot-butyl ester (q) can be reacted in a similar fashion to give compound (r). Both compounds (p) and (r) may then be converted to compound (Ia) after treatment with trifluoroacetic acid.

The ether and thiol ether may be prepared as described in Scheme 6 where X and A are as previously described.

Scheme 6

(U) (V)

React compound (s) in a suitable solvent, such as THF, at about -20 0C to a mixture of N,N,N',N'-tetramethylethylenediamine (TMEDA) and butyllithium. After about 30 minutes, a solution of phenyl disulfide in THF is added to give compound (t). Intermediate (t) may then be processed similarly to compound (Ia) as shown in Scheme 1. Also compound (s) may be reacted with sec-butyllithium in cyclohexane at -78 0C followed by the addition of an aldehyde, such as cyclohexanecarboxaldehyde, in THF to give the alcohol (u). Reductive cleavage of the alcohol using triethylsilane in trifluoroacetic acid gives compound (v). Intermediate (v) may then be processed similarly to compound (Ia) as shown in Scheme 1.

The ketone analogs may be prepared as described in Scheme 7 where X and A are as previously described.

Scheme 7

(W) (*) (y)

Treat an aldehyde (w) with a Grignard reagent, such as isopropylmagnesium chloride, in THF to give the alcohol (x). Oxidation of compound (x) with an oxidizing agent, such as manganese dioxide, in refluxϊng toluene gives the ketone compound (y). Alternatively compound (x) may be treated -with a reducing agent, such as triethylsilane in trifluoroacetic acid, or under hydrogenolysis conditions, to give a compound similar in structure to compound (v). Intermediate (y) may be processed similarly to compound (Ia) as shown in Scheme 1.

The following Examples are provided to further describe the invention and are not to be construed as limitations thereof".

The abbreviations, symbols and terms used in the examples have the following meanings.

CHCl3 = chloroform DMSO = dimethylsulfoxide eq = equivalent(s) GC-MS = gas chromatography mass spectroscopy h = hour(s) HPLC = high performance liquid chromatography HRMS = high resolution mass spectroscopy LC-MS = liquid chromatography mass spectroscopy min = minute(s) NMR = nuclear magnetic resonance

The compounds of the invention, their methods or preparation and their biological activity will appear more clearly from the examination of th.e folio wing examples which are presented as an illustration only and are not to be considered as limiting the invention in its scope. EXAMPLES Preparation 1 {Methyl- [2-(3-thiophen-2-ylbiphenyl-4-yloxy)ethyl] -at_αino}-acetic acid tert-butyl ester

2-(4~Methoxybiphenyl-3-yl)thiophene Stir a solution of commercially available 3-iodo-4-raethoxybiphenyl (9.91 g, 31.95 mmol) in 1,4-dioxane (160 niL) and add 2-thiopheneb>oronic acid (4.91 g, 38.34 mmol), palladium acetate (0.359 g, 1.60 mmol), 2-(dicycloh.exylphosphino)-2'- methylbiphenyl (2.33 g, 6.39 mmol), and potassium fluoride (5.57 g, 95.86 mmol). Heat to 105 0C for about 17 h, cool to room temperature and filtered through filtering agent, rinsing with ethyl acetate (400 mL). Wash the filtrate with O.2 N hydrochloric acid (2 x 200 mL), dilute aqueous sodium bicarbonate (2 x 200 mL), saturated aqueous sodium chloride (2 x 200 mL) dry (sodium sulfate), concentrate and jpurify (HPLC5 eluting with 85:15 hexanes:dichloromethane) to give the title compound as a pale yellow solid which is used in the next step without further purification (8.59 g). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, I H1 J = 2.2 Hz), 7.58 (d, 2 H5 J = 8.3 Hz), 7.54 (d, 1 H, J = 2.6 Hz), 7.49-7.41 (m, 3 H), 7.34-7.30 (m, 2 H)5 7.11-7.O9 (m, 1 H), 7.04 (d, 1 H, J = 8.8 Hz), 3.95 (s, 3 H); HRMS m/∑ Calculated: 267.0844; Fouxid: 267.0867

3-Thiophen-2-yl-biphenyl-4-ol Stir a solution of 2-(4-methoxybiρhenyl-3-yl)thiophene (8.59 g, 31.95 mmol) in N,N-dimethylformamide (70 mL) and add sodium ethanethiolate (6.72 g, 79.88 mmol). Heat to 110 0C for 2.5 h, cool to room temperature, dilute with ethyl acetate (300 mL) and wash with 0.5 N hydrochloric acid (2 x 200 mL), dilute aqueous sodium bicarbonate (2 x 200 mL), saturated aqueous sodium chloride (2 x 200 mL) dry (sodium sulfate), concentrate and purify (HPLC, eluting with 85:15 hexanes:ethyl acetate) to give the title compound as a tan solid (7.77 g, 96% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, 1 H, J = 2.2 Hz), 7.56 (d, 2 U, J = 7.0 Hz), 7.47- 7.40 (m, 4 H), 7.34-7.29 (m, 2 H), 7.17-7.15 (m, 1 H), 7.03 (d, 1 H5 J = 8.3 Hz), 5.54 (br s, 1 H); HRMS m/z Calculated: 251.0531; Found: 251.0544

{Methyl-[2-(3-thiophen-2-ylbiphenyl-4-yloxy)ethyl]-amino} -acetic acid tert- butyl ester Stir a solution of (3-thioρhen-2-ylbiphenyl-4-ol) (0.700 g, 2.77 mmol), [(2- hydroxyethyl)-methylamino]acetic acid tert-butyl ester (0.630 g, 3.33 mmol), 1,1'- (azodicarbonyl)-dipiperidine (1.40 g, 5.5 mmol) in toluene (30 mL) and add tri-n- butylphosphine (1.22 g, 5.55 mmol). Heat to 90 0C for 3h and cool to room temperature. Add diethyl ether (200 mL) and stir for 30 min. Filter precipitate and rinse with diethyl ether (200 mL). Dilute filtrate with ethyl acetate (200 mL), and wash with dilute aqueous sodium bicarbonate (2 x 300 mL) and saturated aqueous sodium chloride (2 x 200 mL). Dry (sodium sulfate), concentrate and purify (HPLC, eluting with 3:1 hexanes:ethyl acetate) to give the title compound as an oil (1.14 g). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 2.1 Hz, 1 H), 7.64-7.60 (irα, 3 H), 7.52-7.45 (m, 3 H), 7.39-7.34 (m, 2 H), 7.14 (dd, J = 5.3, 3.8 Hz, 1 H), 7.10 (d, J = 8.4 Hz, 1 H), 4.29 (t, J = 6.0 Hz, 2 H), 3.37 (s, 2 H), 3.17 (t, J = 6.0 Hz, 2 H), 2.56 Cs, 3 H), 1.50 (s, 9 H)

Preparation 2 4-Chloro-2-phenoxy-l-methoxybenzene

Heat a mixture of commercially available 2-bromo-4-chloro-l-methoxybenzene (8.0 g, 36.1 mmol,), phenol (6.80 g, 72.2 mmol), cesium carbonate (23.54 g, 72.2 mmol), copper (I) chloride (1.79 g, 18.1 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (1.66 g, 9.00 mmol) in rø-memyl-2-pyrrolidinone (80 mL) at 120 0C for 20 h. Cool to room temperature, filter and quench the filtrate with 1 N hydrochloric acid (50 mL). Dilute the filtrate with diethyl ether and extract with water. Dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 90:10 hexanesrethyl acetate) to give the title compound 7.42 g (88%).- 1HNMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 2 H), 7.12-7.05 (m, 2 H), 6.98-6.95 (m, 2 H), 6.93-6.89 (m, 2 H), 3.85 (s, 3 H)

Preparation 3 (Methyl{2-[3-(thiophene-2-carbonyl)biphenyI-4-yIoxy]ethyl}am ino)acetic acid tert-butyl ester

5-Bromo-2-methoxybenzoic acid Suspend commercially available 5-bromo-2-methoxybenzaldehy^de (100 g, 465 mmol) in acetone (700 mL) and water (1100 mL) and stir at 5 0C. Treat with potassium permanganate (88.2 g, 558 mmol) in portions over a 2 h period. Remove ice bath and stir at room temperature for about 20 h. Filter mixture through a pad of filtering agent and acidify filtrate to about pH = 1 with 5 N hydrochloric acid. Filter precipitate, air dry, redissolve in dichloromethane (300 mL), dry (magnesium sulfate), filter, and concentrate to give the title compound as a yellow solid (40.0 g, 37% yield). 1H NMR (CDCl3) δ 10.7 (br s, IH), 8.28 (d, J = 2.6 Hz, IH), 7.66 (dd, T = 8.8, 2.6 Hz5 IH), 6.96 (d, J = 8.8 Hz, IH), 4.08 (s, 3H); MS (ES): m/z = 212

5-Bromo-2-N-dimethoxy-N-methylbenzamide Treat a solution of 5-bromo-2-methoxybenzoic acid (40.0 g, 173 mmol) in anhydrous dichloromethane (400 mL) with neat l,r-carbonyldiimidazole (28.2 g, 173 mmol). Add N,O-dimethylhydroxylamine hydrochloride (16.9 g, 173 rrumol) after about 15 min and stir for about 72 h. Transfer to a separatory funnel and wash with 1 N hydrochloric acid (2 x 100 mL), saturated sodium bicarbonate (2 x 100 mL), saturated aqueous sodium chloride (100 mL), dry (magnesium sulfate), filter and concentrate to give the title compound as an off-white solid (41.3 g, 87% yield). 1H NMR (CDCl3) δ 7.44 (dd, J = 8.8, 2.4 Hz, IH), 7.4 (br s, IH), 6.80 (d, J = 8.8 Hz, IH), 3.83 (s, 3H), 3.5 (br s, 3H), 3.4 (br s, 3H); MS (ES): m/z = 275.9

(5-Bromo-2-methoxyphenyl)thiophen-2-ylmethanone Add neat 2-bromothiophene (15.6mL, 25.6 g, 162 mmol) to magnesium turnings (5.2 g, 210 mmol) in diethyl ether (100 mL) under a nitrogen atmosphere at such a rate as to initiate and maintain reflux (about 20 min). Stir for 1 h after complete addition and transfer mixture to an addition funnel and add to a solution of 5-bromo-2— N-dimethoxy- N-methylbenzamide (33 g, 120 mmol) in diethyl ether (150 mL). Quencli reaction after 3 h by the slow addition of 1 N hydrochloric acid (200 mL) and stir for 20 xniή. Transfer to a separatory funnel, separate layers, and extract the aqueous layer with eChyl acetate. Wash organic layers with saturated sodium bicarbonate (2 x 100 mL), saturated aqueous sodium chloride (100 mL), dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 33:67 dichloromethane:ethyl acetate) "to give the title compound as an off-white solid (25.7 g, 72% yield). 1H NMR (CDCl3) δ 7.72 (dd, J = 4.8, 1.2 Hz, IH), 7.54 (dd, J = 8.8, 2.O Hz, IH), 7.49 (d, J = 2.4 Hz, IH), 7.46 (dd, J = 4.0, 1.2 Hz, IH), 7.10 (dd, J = 4.8, 4.0 Hz, IH), 6.89 (d, J = 8.8 Hz, IH), 3.79 (s, 3H); MS (ES): m/z = 298.8

(5-Phenyl-2-methoxyphenyl)thiophen-2-ylmethanone Stir a mixture of palladium acetate (210 mg, 0.94 mmol), tricyclohexylphosphine (260 mg, 0.93 mmol), potassium fluoride (3.60 g, 62.0 mmol), and pherrylboronic acid (2.48 g, 20.3 mmol) in tetrahydrofuran (75 ml). Degas twice with nitrogen, then treat with a solution of (5-bromo-2-methoxyphenyl)thiophen-2-ylmethanone (5.50 g, 18.5 mmol) in tetrahydrofuran (30 mL), and gently reflux overnight. Cool to room temperature, dilute with ethyl acetate (100 mL), filter through a pad of filtering agent, concentrate and purify (silica gel chromatography, eluting with 1:1 dichloromethane:hexanes) to give the title compound (4.2 g, 77% yield) - 1H NMR (CDCl3) δ 7.7 (m, 3H), 7.5 (m, 3H), 7.42 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.4 Hz, IH), 7.1 (m, 2H), 3.86 (s, 3H); MS (ES): m/z = 295.0

(4-HydroxybiphenyI-3-yl)thiophen-2-ylmethanone Treat a solution of (5-phenyl-2-methoxyphenyl)thiophen-2-ylmethanone (14.0 g, 47.6 mmol) in dichloromethane (150 mL) at -75 ° with boron tribromide (5.2 mL, 52.3 mmol) via syringe over 30-min. After 1 h pour the mixture into an aqueous slurry of cracked ice and allow to stand for 2 h. Separate layers and extract with dichloromethane (100 mL). Wash the organic layer with brine (200 mL), dry (magnesium, sulfate), concentrate and purify (silica gel chromatography, eluting with 33 :67 dichloromethane:hexanes) to give the title compound (11.7 g, 88% yieli). 1HNMR (CDCl3) δ 11.56 (s, IH), 8.47 (d, J = 2.4 Hz, IH), 7.6 (m, 3H), 7.44 (t, J = 7.2 Hz, 2H), 7.35 (t, J = 7.2 Hz, IH), 7.2 (m, 2H), 7.16 (d, J = 8.0 Hz, IH); MS (ES): m/z = 298

(Methyl{2-[3-(thiophene-2-carbonyl)biphenyI-4-yloxy]ethyl }amino)- acetic acid tert- butyl ester

Treat a solution of (4-hydroxybiphenyl-3-yl)thiophen-2-ylmethanone (1.58 g, 5.66

mmol), [(2-hydroxyethyl)-methylamino]acetic acid tert-butyl ester (2.13 g, 11.25 mniolX

and l,l?-(azodicarbonyl)-dipiperidine (2.85 g, 11.29 mmol) in tetrahydrofuran (50 mL)

with tri-n-butylphosphine (2.82 mL, 11.28 mmol). Stir overnight at reflux, concentrate

and filter the dihydroazodicarboxylate dipiperidine and purify (silica gel chromatography,

eluting with 15:85 to 70:30 ethyl acetate :cyclohexane) to give the title compound (1.6g,

63%).

1H NMR (CDCl3) δ 7.7 (m, 3H), 7.55 (d, J = 3.2 Hz, 2H), 7.51 (d, J = 1.4 Hz, IH), 7.42

(t, J = 3.2 Hz, 2H)5 7.3 (m, IH), 7.10 (t, J = 1.8 Hz, IH), 7.05 (d, J = 3.4 Hz, IH), 4.1 (m_,

2H), 3.47 (br s, 2H), 2.69 (br s, 3H), 1.44 (s, 9H); MS (ES): m/∑ = 438

The compounds of Preparations 4-8 may be prepared essentially as described in

Preparation 3.

Preparation 9

{Methyl-[2-(3-thiophen-2-yImethyIbiphenyl-4-yIoxy)ethyI]a mino}-acetic add tert-butyl ester

2-(5-Bromo-2-hydroxybenzyl)thiophene Heat at 120-140 0C a solution of (5-bromo-2-hydroxyphenyl)-thiophen-2- ylmetlianone (1.63 g; 5.74 mmol) following a literature procedure (J. Chem. Research (M), 1991, 2333-2347) in ethylene glycol (16 niL) with hydrazine monohydrate (1.4 niL, 28.7 mmol) for 45 min. Cool to 90 0C and add a solution of potassium hydroxide (1.3 g, 22.9 mmol) in ethylene glycol (6.5 mL) and stir overnight at 150 0C and for 8 h at 190- 200 0C. Cool to room temperature, pour into water and extract with diethyl ether. Concentrate and redissolve in ethyl acetate, dry over magnesium sulfate, concentrate and purify (silica gel chromatography, eluting with 5:95 to 30:70 of ethyl acetatexyclohexane) to give the title compound as a yellow oil (1.1 g; 71%).

{[2-(4-Bromo-2-thiophen-2-yImethyIphenoxy)ethyl]methyIami no}-acetic acid tert- butyl ester Treat a solution of 4-bromo-2-thiophen-2-ylmethylphenol (1.1 g; 4.09 mmol) in tetrahydrofuran (40 mL) with l,r-(azodicarboxylate)-dipiperidine (1.55 g; 6.14 mmol), [(2-hydroxyethyl)-methylamino]acetic acid tert-butyl ester (1.16 g; 6.14 mmol) in tetrahydrofuran (2 mL), and neat tributylphosphine (1.53 mL, 6.14 mmol) and stir at 65 0C for about 24 h. Add a second aliquot of reagents (0.75 eq) and heat for 65 0C for 2 h. Concentrate and redissolve in cyclohexane. Filter away the precipitate and concentrate the filtrate. Purify by silica gel chromatography, eluting with 5:95 to 40:60 ethyl acetatexyclohexane) to give the title compound as a yellow oil (1.55 g; 86%). LC-MS: m/z -= 442 {Methyl- [2-(3-thiophen-2-ylmethylbiphenyI-4-yloxy)ethyl] amino}-acetic acid tert- butyl ester Treat a solution of {[2-(4-bromo-2-thiophen-2-ylmethylphenoxy)ethyl]- methylamino} acetic acid tert-butyl ester (0.375 g, 0.851 mmol) in tetrahydrofuran (6 mL) with phenylboronic acid (0.124 g; 1.02 mmol), tricyclohexylphosphine (0.028g, 0.10 mmol), potassium fluoride (0.163 g, 2.80 mmol) and palladium acetate (0.019 g, 0.085 mmol). Degas twice with nitrogen and stir at reflux for 3 h. Cool to room temperature, dilute with dichloromethane, filter through a pad of filtering agent and concentrate. Redissolve in methanol and purify by ion exchange chromatography to give the title compound (0.365 g; 98%) as a yellow oil. LC-MS: m/z = 43S

Preparation 10 [(2-Hy droxyethyl)-methylamino] -acetic acid tert-butyl ester

Add triethylamine (1000 mL, 7.17 mol) to a solution of 2-(methylamino)ethanol (504 g, 6.71 mol) in tetrahydrofuran (5000 mL). Slowly add tert-butyl bromoacetate (1000 g, 5.13 mol) over about 30 min, the temperature rises to about 50 °C and continues to rise once the addition is complete to about 65 0C. Stir for 5 h, after which time the solution has reached room temperature. Add water (5000 mL) and extract the mixture with ethyl acetate (5000 mL, then 2500 mL). Combine the ethyl acetate solutions, wash with water (5000 mL), then saturated aqueous sodium chloride (2500 mL), dry (magnesium sulfate) and concentrate to give the title compound as a clear, straw colored oil (794 g, 82%) 1H NMR (300 MHz, CDCl3) δ 3.57 (2H, t, J = 5.1 Hz), 3.21 (2H, s), 2.69 (2H, t, J = 5.1 Hz)5 2.42 (3H, s), 1.47 (9H, s)

Preparation 11 {[2-(2'-Fluoro-3-thiophen-2-yIbiphenyl-4-yloxy)ethyl]-methyl amino}-acetic acid tert- butyl ester

Treat a solution of {[2-(4-cliloro-2-thiophen-2-ylphenoxy)ethyl]-

methylamino} acetic acid tert-butyl ester prepared essentially as described in Preparations

21-23 (0.300 g, 0.785 mmol) in tetrahydrofuran (4.0 mL) in a microwave tube (10 mL

tube, CEM Microwave) with 2-fluorophenylboronic acid (0.132g, 0.934 mmol), [(2-

(dicyclohexylphosphino)-2', 4', 6'-triisopropyl-l,r-biphenyl) (0.075 g, 0.157 mmol ),

palladium acetate (0.018 g, 0.079 mmol) and potassium fluoride (0.137 g, 2.35 mmol).

Stir and heat to 80 0C at 300 W for 30 min. Cool to room temperature and filter through a

filtering agent, wash with ethyl acetate (200 mL). Wash filtrate with water (3 x 100 mL),

saturated aqueous sodium chloride (1 x 100 mL), dry (sodium sulfate), filter, concentrate

and purify (HPLC, eluting with 85:15 hexanes:ethyl acetate) to give the title compound

(0.240 g, 0.347 mmol) as an oil.

HRMS m/z Calculated: 442.1852; Found: 442.1865

The compounds of Preparations 12-20 may be prepared essentially as described in

Preparation 11.

Preparation 21

2-(5-Chloro-2-methoxyphenyl)thiophene

Add to a solution of 4-chloro-2-iodoanisole (10 g, 37.24 mmol) in 1,4-dioxane (50

inL) is 2-thiopheneboronic acid (5.71 g, 44.66 mmol), (2-dicyclohexylphosphino)-2'-

methylbiphenyl (2.71 g, 7.44 mmol), palladium acetate (0.418 g, 1.86 mmol) and

potassium fluoride (6.49 g, 111.7 mmol). Stir at 95 0C for 18 h, cool to room

temperature, filter through a filtering agent and wash with ethyl acetate (400 mL). Wash

organic layer with water (3 x 100 mL), saturated aqueous sodium chloride (1 x 100 mL),

dry over sodium sulfate, filter, concentrate and purify (HPLC, eluting with hexanes) to

give the titled compound as an oil (5.4g).

HRMS m/z Calculated: 225.0141; Found: 225.0132

Preparation 22

[l,l';4',l']Terphenyl-2'-ol

2'-Methoxy-[l,l\ 4', l']terphenyl Add to a solution of 2,5-dichloroanisole (3.0 g, 16.94 mmol) in 1,4-dioxane (50 mL) is added phenylboronic acid (4.95 g, 40.0 mmol), (2-dicyclohexylphosphino)-2'- methylbiphenyl (2.46 g, 6.77 mmol), palladium acetate (0.380 g, 1.69 mmol), and potassium fluoride (5.89 g, 101.67 mmol). Heat to 95 0C for about 78 h, cool to room temperature, filter through Celite® and rinse with, ethyl acetate (400 mL). Wash the filtrate with 0.2 N. hydrochloric acid (2 x 200 mL), dilute NaHCO3, saturated aqueous sodium chloride (2 x 200 mL), dry (sodium sulfate), concentrate and purify (HPLC, eluting with 9:1 hexanes:dichloromethane) to give the title compound as a white solid (4.26 g). MS (FAB) = 261

[l,l';4',l']Terphenyl-2'-ol Treat a solution of 2'-methoxy-[l,l';4',r]terρhenyl (0.700 g, 2.68 mmol) in dichloromethane (25 mL) cooled to -78 0C with boron tribromide (2.95 mL, 2.95 mmol) added dropwise over 10 min. Warm to room temperature and stir for 3 h. Pour over ice and dilute with dichloromethane (100 mL) and wash with water (100 mL) and saturated aqueous sodium chloride (50 mL). Dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 9:1 hexanes: dichloromethane) to give the title compound as a white solid (0.650 g). HRMS m/z Calculated: 245.0967; Found: 245.0985.

Preparation 23 {[2-(3-CyclohexanecarbonyIbiphenyl-4-yloxy)ethyl]-methyIamin o}-acetic acid tert- butyl ester

Cyclohexyl-(4-hydroxybiphenyl-3-yl)-methanone Treat a solution of cyclohexyl(4-methoxybiphenyl-3-yl)methanone (0.581 g; 1.983 mmol) prepared as described in J. Labelled Cpd. Radiopharm., 42, 949-57, (1999) in dichloromethane (20 niL), with boron tribromide (1 M solution in dichloromethane, 2.18 mL), at -78 0C via syringe. Pour mixture after 20 min into an aqueous slurry of cracked ice, separate the layers and extract the aqueous layer with dichloromethane. Wash the combined organic layers with saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel column chromatography, eluting with 0:100 to 30:70 dichloromethane xyclohexane) to give the title compound as an oil (0.512 g; 93%). 1H NMR (300 MHz, CDCl3) δ 12.50 (s, IH), 7.83 (d, J = 2.3 Hz, IH), 7.55 (dd, J = 8.5, 2.3 Hz, IH), 7.43-7.23 (m, 5H), 6.94 (d, J = 8.5 Hz, IH), 3.29-3.22 (m, IH), 1.83-1.72 (m, 4H), 1.67-1 .62 (m, IH), 1.53-1.14 (m, 5H)

{[2-(3-CycIohexanecarbonyIbiphenyl-4-yIoxy)ethyl]-methyIa mino}-acetic acid tert- butyl ester Treat a solution of cyclohexyl-(4-hydroxybiphenyl-3-yl)-methanone (0.51 g; 1.83 mmol) in tetrahydrofuran (20 mL), with l5l'-(azodicarbonyl)-dipiperidine (0.788 g, 3.12 mmol, 1.7 eq), [(2-hydroxyethyl)-methylamino]acetic acid tert-butyl ester (0.591 g, 3.12 mmol) and neat tri-n-butylphosphine (0.78 mL, 3.12 mmol). Stir at 65 0C overnight and treat with an excess of reagents, l,r-(azodicarbonyl)-dipiperidine (0.394 g, 1.56 mmol), [2-hydroxyethyl)-methylamino]acetic acid tert-butyl ester (0.296 g, 1.56 mmol) and neat tri-n-butylphosphine (0.39 mL, 1.56 mmol) for 24 h and concentrate. Take up the residue in cyclohexane and the dihydroazodicarboxylate dipiperidine solid is filtered away. Concentrate and purify the residue (silica gel chromatography, eluting with 5:95 to 40:60 ethyl acetatexyclohexane) to give the title product as an oil (0.397 g; 48%). LC-MS: m/z= 452

Preparation 24 ^MethyI-{2-[3-(thiophene-2-carbonyl)-[l,l';3',l"]terphenyl-4 -yloxy]ethyl}-amino)- acetic acid tert-butyl ester

General Procedure for Rapid Parallel Synthesis: Treat a stirring mixture of potassium fluoride (6.6 eq), palladium acetate (0.20 eq) and tricyclohexylphosphine (0.24 eq) in tetrahydrofuran (2 mL) at room temperature with a solution of 3-biphenylboronic acid (78.4 mg, 0.396 mmol, 1.2 eq) in tetrahydrofuran (0.5ml). After 15 min, add a stock solution of ({2-[4-bromo-2-(thiophene-2- carbonyl)phenoxy]ethyl}-methylamino)acetic acid tert-butyl ester (150 mg, 0.33 mmol, 1 eq) in tetrahydrofuran (prepared essentially as described in Preparation 58). Heat the reaction to 65 0C overnight in a Greenhouse™ reaction vessel containing consisting of 24 tubes each with a total volume of about 3 mL of solvent. Add extra potassium fluoride (2 eq), palladium acetate (0.06 eq), tricyclohexylphosphine (0.07 eq), and 3-biphenylboronic acid (1 eq) and heat the reaction mixture for a further 24 h. Allow the reactions to cool to room temperature. Filter the inorganics through a Whatman Filtertube (5μm), and further wash with tetrahydrofuran (2 x 1 mL). Evaporate the solvent in a Reacti-Therm™ under a stream of nitrogen with heat, take up the residue in methanol, load onto an ion exchange column, wash with methanol and elute with 2 M ammonia in methanol. Evaporate solvent in a Reacti-Therm™ under a stream of nitrogen with heat to give the title compound (130.9 mg, 79%). LC-MS: m/* = 528

The compounds of Preparations 25-57 may be prepared essentially as described in Preparation 24. Prep Compound Name & Data (Methyl-{2-[2'-methyl-3-(thiophene-2-carbonyl)biphenyl-4-ylo xy]ethyl}-amino)- 25 acetic acid tert-butyl ester LC-MS: m/z = 466 ( {2- [3 ' -Bromo-3 -(thiophene-2-carbonyl)biphenyl-4-yloxy] ethyl } -methylamino)- 26 acetic acid tert-butyl ester

Prep Compound Name & Data ({2-[4'-Acetyl-3-(thiophene-2-carbonyl)biphenyl-4-yloxy]ethy l}-methylammo)- 57 acetic acid tert-butyl ester LC-MS: m/z = 494

Preparation 58 ({2-[4-Bromo-2-(thiophene-2-carbonyl)phenoxy]ethyl}-methyIam ino)-acetic acid tert-butyl ester

2-ThienyImagnesium bromide, 2 M solution in ether Add neat 2-bromothiophene (17.2 mL, 177.65 mmol) dropwise to a suspension of preactivated magnesium turnings (5.2 g, 214 mmol) in diethyl ether (90 mL) with a catalytic amount of iodine. Apply heat at such a rate as to initiate and maintain reflux (about 20 min). Continue stirring for 1 h after complete addition and use in the next step without further purification.

(5-Bromo-2-methoxyphenyl)thiophen-2-ylmethanone Add a solution of 2-thienyl magnesium bromide (26.5 mL, 53.4 mmol) to a solution of 5-bromo-2,N-dimethoxy-N-methylbenzamide (prepared as an intermediate as described in Preparation 3) (9.65 g, 35.6 mmol) in tetrahydrofuran (50 mL) over a 15-min period. Keep stirring the reaction at 50 0C for 1 h. Cool to room temperature, add ethyl acetate to the reaction mixture and wash the organic phase with saturated aqueous ammonium chloride (2 x 50 mL), saturated aqueous sodium chloride (50 mL), dry (magnesium sulfate), filter, and concentrate the filtrate to give the title compound (11.081 g) which is used directly in the next step without further purification. 1H NMR (CDCl3) δ 7.72 (dd, J = 4.8, 1.2 Hz, IH), 7.54 (dd, J = 8.8, 2.0 Hz, IH), 7.49 (d, J = 2.4 Hz, IH), 7.46 (dd, J = 4.0, 1.2 Hz, IH), 7.10 (dd, J = 4.8, 4.0 Hz, IH), 6.89 (d, J = 8.8 Hz, IH), 3.79 (s, 3H) (5-Bromo-2-hydroxyphenyl)thiophen-2-ylmethanone Add a solution of (5-bromo-2-methoxyphenyl)thiophen-2-yl-methanone (11.081 g) in dichloromethane 100 mL) to a solution of boron tribromide (1 M solution in dichloromethane, 39.2 mL, 39.16 mmol) at -78 0C dropwise through a cannula over 30 min. Stir the reaction for 30 min and pour into ice. Separate the two phases and the aqueous phase is extracted with dichloromethane. Combine the organic phases and concentrate to give the title compound (10.24 g) which is used directly in the net step without further purification. 1H NMR CCDCl3) δ 11.47 (s, IH), 8.05 (d, J = 2.45 Hz, IH), 7.78 (dd, J = 5.1, 1.1 Hz, IH), 7.75 Cdd, J = 3.8, 1.1 Hz5 IH), 7.59 (dd, J = 2.45, 8.85 Hz, IH), 7.24 (dd, J = 3.8, 4.9 Hz, IH), 6.89 (d, J = 9 Hz, IH)

({2-[4-Bromo-2-(thiophene-2-carbonyl)phenoxy]ethyl}-methy lamino)-acetic acid tert-butyl ester Treat (5-bromo-2-hydroxyphenyl)thiophen-2-ylmethanone (8.627 g, 30.81 mmol) and l-r-(azodicarbonyl)-dipiperidine (11.66 g, 46.2 mmol) in tetrahydrofuran (80 mL) with [(2-hydroxyethyl)-methylamino] acetic acid tert-butyl ester (8.75 g, 46.23 mmol) in tetrahydrofuran (10 mL) and neat tri-n-butylphosphine (11.5 mL, 82.0 mmol). Reflux overnight, cool and concentrate to near dryness. Filter the precipitate, wash with cyclohexane and concentrate. Purify (silica gel chromatography, eluting with 90:10 to 27:75 cyclohexane: ethyl acetate) to give the title compound (10.38 g; 75%). 1H NMR CCDCl3) δ 7.70 (broad d, J = 4.9 Hz, IH), 7.53 (dd, J = 8.8, 2.2 Hz, IH), 7.49 (d, J = 2.5 Hz, IH), 7.46 (d, J = 3.9 Hz, IH), 7.10 (t, J = 4.4 Hz, IH), 6.89 (d, J = 8.8 Hz, IH), 4.06 (t, J = 5.9 Hz, 2H), 3.08 (s, 2H), 3.01 (t, J = 5.9 Hz, 2H), 2.29 (s, 3H), 1.43 (s, 9H); LC-MS: m/z = 456

Preparation 59 {[2-(2"-Cliloro[14';3%l'']te2^phenyI-4'-yloxy)ethyl]-methyla mino}-acetic acid tert- butyl ester 3-Iodobiphenyl-4-ol Add sodivtm ethanethiolate (3.39 g, 40.3 mmol) to a solution of commercially available 3-iodo-4-methoxybiphenyl (5.00 g, 16.1 mmol) in N,N-dimethylformamide (80 s- :M$έ|HlM%W' 6C for 4 h- c°o1 10 room temperature. Dilute with ethyl acetate (200 mL) and wash with water (3 x 100 niL), and saturated aqueous sodium chloride (1 x 100 mL). Dry (sodium sulfate), filter and concentrate the filtrate to give the title compound (4.1 g, 86%) which was used directly in the next step without further purification. HRMS: m/z Calculated: 294.9620; Found: 294.9636

{[2-(3-Iodobiphenyl-4-yIoxy)ethyl]-methylamino}-acetic acid tert-butyl ester Add tri-n-lDUtylphosphine (6.90 mL, 27.0 mmol) to a solution of 3-iodobiphenyl- 4-ol (4.00 g, 13.5 mmol). [(2-hydroxyethyl)-methylamino] acetic tert-butyl ester (2.81 g, 14.8 mmol) and 1 ,r-azodicarbonyl)-dipiperidine (6.81 g, 27.0 mmol) in toluene (67 mL). Heat to 90 0C for 3 h and cool to room temperature. Add diethyl ether (250 mL) and stir for 30 min. Filter and wash with diethyl ether (50 mL). Dilute with ethyl acetate (200 mL) and wash with water (3 x 100 mL), saturated aqueous sodium chloride (1 x 100 mL). Dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 7:3 hexanes:ethyl acetate) to give the title compound as a pale yellow oil (6.0 g). HRMS: m/z Calculated: 468.1035; Found: 468.1063

{[2-(2"-Chloro-[l,l';3',l"]tejrtphenyI-4'-yIoxy)ethyl]-me thyl-amino}-acetic acid tert- butyl ester General Procedure for Rapid Parallel Synthesis: Treat a stirring mixture of potassium fluoride (6.6 eq), palladium acetate (0.20 eq) and 2-(dicyclohexylphosphino)-2'-methylbiphenyl (0.24 eq) in tetrahydrofuran (2 mL) at room temperature with a solution of 2-chlorophenylboronic acid (1.2 eq) in

tetrahydrofuran (0.5 niL). After 15 min, add a stock solution of {[2-(3-iodobiphenyl-4-

yloxy)ethyl]-methylamino} acetic acid tert-butyl ester (180 mg, 0.43 mmol, 1 eq) in

tetrahydrofuran. Heat the reaction to 65 0C overnight in a Greenhouse™ reaction vessel

containing consisting of 24 tubes each with a total volume of about 3 mL of solvent. Add

extra potassium fluoride (2 eq), palladium acetate (0.06 eq), 2-(dicyclohexylphosphino)-

2'-methylbiphenyl (0.07 eq), and 2-chlorophenylboronic acid (1 eq) and heat the reaction

mixture for a further 24 h. Allow the reactions to cool to room temperature. Filter the

inorganics through a Whatman Filtertube (5μm), and further wash with tetrahydrofuran (2

x 1 mL). Evaporate the solvent in a Reacti-Therm™ under a stream of nitrogen with

heat, take up the residue in methanol, load onto an ion exchange column, wash with

methanol and elute with 2 M ammonia in methanol. Evaporate solvent in a Reacti-

Therm™ under a stream of nitrogen with heat to give the title compound (145 mg, 75%) .

LC-MS: m/z = 454

The compounds of Preparations 60-71 may be prepared essentially as described in

Preparation 59.

Preparation 72

{[2-(2-Benzoyl-4-bromophenoxy)ethyl]-me*hylamino}-acetic acid tert-butyl ester

Add tri-n-butylphosphine (5.5 mL, 22.0 mmol) portionwise to a solution of

commercially available 5~bromo-2-hydroxybenzophenone (5.0 g, 118.3 mmol), 1,1'-

(azodicarbonyl)-dipiperidine (5.56 g, 22.0 mmol) and [(2-hydroxyethyl)-

methylamino] acetic acid tert-butyl ester (4.16 g, 22.0 mmol) in toluene (200 mL). Stir at

room temperature for 30 min and heat at 90 0C overnight. Cool to room temperature and

dilute with diethyl ether. Filter precipitate, concentrate the filtrate and purify (silica gel

chromatography, eluting with a gradient of 25:75 to 100:0 ethyl acetate :hexanes) to give

the title compound (1.75 g, 21%) as a yellow oil.

1HNMR (300 MHz5 CDCl3) δ 1.39 (s, 9H), 2.19 (s, 3H), 2.59 (t, 2H, J = 5.6 Hz), 2.97 (s,

2H), 3.97 (t, 2H, J = 5.6 Hz), 6.83 (d, IH, J = 8.9 Hz), 7.37-7.53 (m, 5H), 7.73 (d, 2H, J =

7.9 Hz); MS (ES): m/z = 450 The compounds of Preparations 73-74 may be prepared essentially as described in Preparation 72 using the appropriately substituted prxenols. Prep Compound Name & Data {[2-(2-Benzyl-4-chlorophenoxy)ethyl]-methylamino} -acetic acid tert-butyl ester

73 1HNMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 2.48 (s, 3H)5 2.98 (t, 2H, J = 5.6 Hz), 3.29 (s, 2H), 3.92 (s, 2H)5 4.07 (t, 2H5 J = 5.6 Hz)5 6.77 (d, IH5 J = 8.6 Hz)5 7.01 (d, IH5 J = 2.6 Hz), 7.11 (dd, IH5 J = 2.6, 8.6 Hz)5 7.16-7.20 (m, 3H)5 7.24-7.30 (m, 2H); MS (ES): m/z = 390 {[2-(2-Benzoyl-4-chloro-phenoxy)ethyl]-methylammo}-acetic acid tert-butyl ester 74 1H NMR (300 MHz, CDCl3) δ 1.42 (s, 9H), 2.21 (s, 3H)5 2.62 (t, 2H5 J = 5.6 Hz)5 2.99 (s, 2H), 4.01 (t, 2H5 J = 5.6 Hz)5 6.91 (d, IH5 J = 8.6 Hz)5 7.36-7.45 (m, 4H), 7.53-7.58 (m, IH), 7.74-7.78 (m, 2H); MS (BS): m/z = 404

Preparation 75 {Methyl- [2-(3-thiazol-2-yl-biphenyl-4-yloxy)ethyl] -amino}-acetic acid tert-butyl ester

3-Iodobiphenyl-4-ol Add sodium ethanethiolate (3.39 g, 40.30 mrnol) to a solution of 3-iodo-4- methoxybiphenyl (5.0 g, 16.2 mmol) in N5N-dimethylformamide (80 niL). Heat to 110 0C for 4 h in an oil bath. Cool to room temperature, dilute with ethyl acetate (200 niL) and washed with water (3 x 100 mL), saturated aqueous sodium chloride (100 mL)5 dry (sodium sulfate) filter and concentrate to give the title compound as a pale yellow oil which solidifies upon standing. This compound is used directly in the next step. HRMS m/z Calculated: 294.9620; Found: 294.9636

{[2-(3-Iodobiphenyl-4-yloxy)ethyl]-methylamino}— acetic acid tert-butyl ester Add a solution of 3-iodobiphenyl-4-ol (4.0 g. 13.51 mmol), [(2-hydroxyethyl)- methylamino] acetic acid tert-butyl ester (2.81 g, 14.86 mmol) and l,l'-azodicarbonyl dipiperidine (ADDP) (6.82 g, 27.02 mmol) in toluene ( 67 mL) to tri-n-butylphosphine (6.9 mL, 27.02 mmol). Heat to 90 0C for 3 h. Cool to room temperature. Add diethyl ether (250 mL) and let stir for 30 min. Filter off by-product and wash with diethyl ether (50 mL). Dilute with ethyl acetate (200 mL) and wash with water (3 x 100 mL), saturated aqueous sodium chloride 100 mL, dry (sodium sulfate), filter and concentrate and purify (HPLC eluting with 7:3 hexanesrethyl acetate) to give the title compound as a pale yellow oil (6.O g). HRMS m/z Calculated: 468.1035; Found: 468.1063 (Methyl-{2-[3-(4,4,5,5-tetramethyI-[l,3,2]dioxaborolan-2-yl) -l)iphenyl-4- yloxy]ethyl}-amino)-acetic acid tert-butyl ester Add to a solution of {[2-(3-iodobiphenyl-4-yloxy)ethyl]-methylamino}-acetic acid tert-butyl ester (4.0 g, 8.56 mmol) in N,N-dimethylformamide (4-3 mL), [1,1'- bis(diphenylphosphino)-ferrocene)-dichloropalladium (II) complex (DPPF) in dichloromethane (0.699 g, 0.855 mmol) with bis(ρinacolato)diboron and potassium acetate (3.36 g, 34.24 mmol) (J. Org. Chem., 63, 9300-9305, (1998)). Heat to 95 0C for 18 h. Cool to room temperature and filter through a plug of Celrte® . Dilute filtrate with ethyl acetate (150 mL), wash with water (3 x 50 mL), saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), filter and purify (HPLC, eluting with 7:3 hexanes:ethyl acetate) to give the title compound as an oil (2.2 g).

{Methyl- [2-(3-thiazol-2-ylbiphenyl-4-yloxy)ethyl]-amino}-ace tic acid tert-butyl ester Add to a solution of (methyl-[{2-[3-(4,4,5,5-tetramethyl[l,3,2]dioxaborolan-2-yl) - biphenyl-4-yloxy] ethyl }-amino)-acetic tert-butyl ester (0.400 g, 0.856 mmol) in 1,4- dioxane (4.3 mL) under nitrogen 2-bromothiazole (0.140 g, 0.856 mmol), 2 N potassium carbonate, and triphenylphosphine (0.027 g, 0.103 mmol). Degas, add bis(dibenzylideneacetone)palladium (0) (0.024 g, 0.026 mmol) and heat to 110 0C for 3 h. Cool to room temperature, filter through a plug of Celite®, rinse Λvith ethyl acetate (100 mL). Wash with water (3 x 100 mL), saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filter and purify (HPLC, eluting with 1:1 hexanes:ethyl acetate) to give the title compound as a yellow oil (181.0 mg, 49.8 %) HRMS m/z Calculated: 424.1821; Found: 424.1821 Preparation 76 {[2-(4-Benzoyl-2-thiophen-2-ylphenoxy)ethyl]-methylamino}-ac etic acid tert-butyl ester

3-Bromo-4-methoxybenzoic acid methyl ester Add iodomethane (45.5 niL, 731.4 mmol) to a rapidly stirring solution of commercially available 3-bromo-4-methoxybenzoic acid (33 g, 146.3 mmol) in N5N- dimethylformamide (400 mL). Add cesium carbonate (95.3 g, 292.6 xnmol and stir at room temperature for 21 h. Dilute with ethyl acetate (800 mL) and water (500 mL). Wash the organic layer 1 N sodium hydroxide (2 x 400 mL), saturated aqueous sodium chloride (2 x 400 mL), dry (sodium sulfate), filter and concentrate to give the title compound as a tan solid which is used directly in the next step without further purification (33.44 g, 93%). LC-MS mZz = 245

4-Methoxy-3-thiophen-2-ylbenzoic acid methyl ester Add to a solution of 3-bromo-4-methoxybenzoic acid methyl ester (33.4 g, 136.5 mmol) in 1,4-dioxane (650 mL) under nitrogen 2-thiopheneboronic acid (34.9 g, 272.9 mmol), 2 N potassium carbonate (682 mL), and triphenylphosphine (4.29 g, 16.37 mmol). Degas, add bis(dibenzylideneacetone)palladium (0) (3.75 g, 4.09 mmol) and heat at 110 0C for 2.5 h. Cool to room temperature, filter through a plug of Celite®, wash with ethyl acetate (600 mL). Wash the filtrate with sodium bicarbonate (2 x 40O mL), water (2 x 400 mL), saturated aqueous sodium chloride (400 mL), dry (sodium sulfate), filter, concentrate and purify (slica gel chromatography, eluting with 1:1 he:xanes:ethyl acetate to give the title compound as a pale yellow oil (8.8 g). 1H NMR (CDCl3) δ 8.37 (IH, s), 8.02 (IH, dd, J = 1.3, J = 8.5 Hz)5 7.59 (IH, d, J = 9 Hz)5 7.38 (IH5 d, J = 9 Hz)5 7.14 (IH5 dd, J = 3.6 Hz, J = 5.2 Hz), 7.02 (IH5 d, J=4.0 Hz), 4.02 (3H, s), 3.95 (3H, s)

4-Methoxy-3-thiophen-2-ylbenzoic acid Add to a solution of 4-methoxy-3-thiophen-2-ylbenzoic acid methyl ester (11.07 g, 45.0 mmol) in 1 ,4-dioxane (200 niL) 2 N sodium hydroxide (200 mL). Heat to 1 L 5 0C for 2 h and cool to room temperature. Dilute with water (100 mL) and wash with diethyl ether (2 x 200 mL). Wash the aqueous layer with 5 N hydrochloric acid (85 mL) and ethyl acetate (300 mL). Separate the layers and wash the organic layer with saturated aqueous sodium chloride (300 mL), dry (sodium sulfate), filter and concentrate to grve the title compound as an off white solid which is used directly in the next step witho~ut further purification (9.47 g).

4,N-Dimethoxy-N-methyl-3-thiophen-2-yIbenzamide Add to a solution of 4-methoxy-3-thiophen-2-ylbenzoic acid (9.4 g, 40.0 rrnnol) in tetrahydrofuran (400 mL) N,O-dimethylhydroxylamine (4.29 g, 44.0 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.44 g, 44.0 mmol), 1- hydroxybenzotriazole hydrate (5.95, 44.0 mmol) and diisopropylethylamine (15.3 πxL, 88.0 mmol). Stir for 15 min and add N,N-dimethylformamide (10 mL). Stir at room temperature for 21 h, dilute with ethyl acetate (600 mL), wash with 0.2 N aqueous hydrochloric acid (2 x 300 mL), and saturated aqueous sodium chloride (300 mL), dory (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 6:4 hexanes:ethyl acetate) to give the title compound as a teal colored oil (4.57 g, 41 %). HRMS m/z Calculated: 278.0851; Found: 278.0836

(4-Methoxy-3-thiophen-2-ylphenyl)-phenylmethanone Add to a solution of 4,N-dimethoxy-N-methyl-3-thiophen-2-ylbenzamide (0_5 g, 1.80 mmol) in tetrahydrofuran (5 mL) 3 M phenylmagnesium bromide in diethyl etfcier (0.90 mL, 2.70 mmol) dropwise. Stir at room temperature for 3 h, cool to 0 0C and quench with 1 N hydrochloric acid (3 mL). Dilute with ethyl acetate (100 mL) and washed with water (3 x 50 mL), saturated aqueous sodium chloride (2 x 50 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 8:2 hexanes:ethyl acetate) to give the title compound as an oil (531.0 mg, 96%). HRMS m/z Calculated: 295.0793; Found: 295.0823

(4-Hydroxy-3-thiophen-2-ylphenyl)-phenylmethanone Prepare (4-hydroxy-3-thiophen-2-ylphenyl)-phenylmethanone essentially as decribed in Preparation 75. HRMS m/z Calculated: 281.0636; Found: 281.0651

{[2-(4-Benzoyl-2-thiophen-2-ylphenoxy)ethyl]-methylamino} -acetic acid tert-butyl ester Prepare {[2-(4-benzoyl-2-thiophen-2-ylphenoxy)ethyl]-methylamino}-ac etic acid tert-butyl ester essentially as decribed in Preparation 75. HRMS m/z Calculated: 452.1895; Found: 452.1894

Preparation 77 {[2-(3-Cyclohexylmethylbiphenyl-4-yloxy)ethyl]-methylamino}- acetic acid tert-butyl ester

Cyclohexyl-(4-methoxybiphenyI-3-yl)-methanol Add to a solution of 4-methoxybiphenyl (2.0 g, 11 mmol) in tetrahydrofuran (15.6 g, 217 mmol) at -78 0C 1.40 M of sec-butyllithium in cyclohexane (8.5 niL) dropwise. Stir for 1 h at -78 0C, then add dropwise a solution of cyclohexanecarboxaldehyde (1.4 mL, 0.012 mol) in tetrahydrofuran (5 mL). Warm to room temperature and stir for 1 h, cool to 0 0C and quench with a saturated solution of ammonium chloride (10 mL). Wash with ethyl acetate (100 mL), water (3 x 50 mL), saturated aqueous sodium chloride (2 x 50 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 8:2 hexanes: ethyl acetate) to give the title compound as a clear oil (1.38 g). HRMS m/z Calculated: 296.1758; Found: 279.1759

3-Cyclohexylmethyl-4-methoxybiphenyl Add triethylsilane (4.20 mL, 26.3 mmol) to a solution of cyclohexyl-(4- methoxybiphenyl-3-yl)-methanol (1.3 g, 4.4 mmol)in trifluoroacetic acid (20 mL). Stir at room temperature for 1 h, pour into ice and dilute with water (25 mL). Wash with ethyl acetate (120 mL), water (3 x 50 mL), saturated aqueous sodium chloride (2 x 50 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with hexanes) to give the title compound as a clear oil (731.0 mg). HRMS m/z Calculated: 281.1905; Found: 281.1908

3-Cyclohexylmethylbiphenyl-4-ol Add to a solution of 3-(cyclohexylmethyl)-4-methoxybiphenyl (0.700 g, 2.50 mmol) in N,N-dimethylformamide (15.5 mL, 200 mmol) sodium ethanethiolate (0.52 g, 6.2 mmol) and heat to 110 0C for 12 h. Cool to room temperature, wash with ethyl acetate (100 mL), water (3 x 50 mL), saturated aqueous sodium chloride (2 x 50 mL). dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 8:2 hexanes:ethyl acetate) to give the title compound as a white solid (440 mg, 66 %). MS (ES): m/z = 266.17

{[2-(3-CyclohexylmethylbiphenyI-4-yIoxy)ethyl]-methylamin o}-acetic acid tert-butyl ester { [2-(3-Cyclohexylmethylbiphenyl-4-yloxy)ethyl]-methylamino}-a cetic acid tert- butyl ester was prepared essentially as described in Preparation 75. HRMS m/z Calculated: 438.3008; Found: 438.3038

Preparation 78 {[2-(3-Cyclopropylmethyl-biphenyl-4-yloxy)ethyl]-methylamino }-acetic acid tert- butyl ester 3-CycIopropylmethyl-4-methoxybiphenyl Add to a 1-neck round-bottom flask under nitrogen 10% palladium on carbon (1.20 g, 9.80 mmol), ethyl acetate (40.0 rnL, 410 mmol), ethanol (40.0 mL, 685 mmol), acetic acid (1.2 mL, 21 mmol), and cyclopropyl-(4-methoxybiphenyl-3-yl)methanol, prepared essentially as described in Preparation 77 using cyclopropanecarboxaldehyde, (2.00 g, 7.86 mmol) and place under a blanket of hydrogen gas (3.0 L, 130 mmol) using a balloon. Stir at 45 0C over night, cool to room temperature, wash with ethyl acetate (130 mL), water (100 mL), saturated aqueous sodium chloride (100 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with hexanes) to give the title compound as a white solid (1.0 Ig). HRMS m/z Calculated: 239.1436; Found: 239.1472

3-Cyclopropylmethylbiphenyl-4-oI Staring with 3-cyclopropylmethyl-4-methoxybiphenyl, 3- cyclopropylmethylbiphenyl-4-ol is prepared essentially as described in Preparation 77. MS (ES): m/z = 224.12

{[2-(3-CyclopropylmethylbiphenyI-4-yloxy)ethyl]-methylami no}-acetic acid tert- butyl ester The preparation of {[2-(3-cyclopropylmethylbiphenyl-4-yloxy)ethyl]- methylamino} -acetic acid tert-butyl ester is preparared essentially as described in Preparation 77 staring with 3-cyclopropylmethylbiphenyl-4-ol. MS (ES): m/z = 396.26

Preparation 79 l-MethylcycIopropanecarbaldehyde

Add to a slurry of pyridinium chlorochroniate (5.5 g, 26 mmol) in dihcloromethane (60 mL, 900 mmol) commercially available 1- methylcyclopropanemethanol (2.00 g, 23.2 mmol). After a small exotherm, stir at room temperature for for 2 h. Add diethyl ether (200 mL), filter through a plug of silica gel and concentrate to give the title compound which is directly in the next step without further purification (1.1 g). 1H NMR (CDCl3) δ 8.637 (IH, s), 1.248 (4H, s), 1.169-1.146 (2H, m), 0.943-0.908 (2H, m)

Preparation 80 {Methyl-[2-(3-phenylethynylbiphenyl-4-yloxy)ethyl]-amino}-ac etic acid tert-butyl ester

Add phenylacetylene (0.014 g, 0.14 mmol) to a solution of {[2-(3-iodobiphenyl-4- yloxy)ethyl]-methylamino} -acetic acid tert-butyl ester prepared as described in Preparation 75 (0.500 g, 1.07 mmol), bis(triphenylphosphine)palladium (II) chloride (0.05 g, 0.00007 mol), copper (I) iodide (0.020 g, 0.10 mmol) in triethylamine (10.0 mL, 71.7 mmol). Heat at 45 0C for 18 h. Cool to room temperature and wash with ethyl acetate (100 mL), water (3 x 50 mL), saturated aqueous sodium chloride (2 x 50 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 1:1 hexanes: ethyl acetate) to give the title compound as an amber colored oil (410 mg, 87%). HRMS m/z Calculated: 442.2382; Found: 442.2393 Preparation 81 ({2-[4-(2,3-Dihydrobenzo[l,4]dioxin-6-yl)-2-thioρhen-2-ylph enoxy]ethyl}- methylamino)-acetic acid tert-butyl ester

2-Iodo-4-bromophenoI Dissolve 4-bromophenol (100 g, 0.578 mol), sodium iodide (86.6 g, 0.578 mol) and sodium hydroxide (23.1 g, 0.578 mol) in methanol (1500 mL) and cool to 0 °C. Add aqueous sodium hypochlorite (5% active chlorine, 900 mL) dropwise keeping the temperature below 2 °C and allow the reaction to stir for 20 min. Add 10% aqueous sodium thiosulphate solution (800 mL). Acidify to pH = 2 with 1 N hydrochloric acid. Extract the mixture with dichloromethane (3 x 1000 mL). Combine the organic phases, wash "with saturated aqueous sodium chloride, dry (magnesium sulphate) and concentrate to give the crude title compound as a white solid which is used directly without further purification (171 g). 1H NMR (300 MHz; CDCl3) δ 7.77 (IH, d, J=2.4 Hz), 7.35 (IH, dd, J=2.4, 8.6 Hz), 6.87 (IH, d, J=8.6 Hz)5 5.35 (IH, s)

{[2-(4-Bromo-2-iodophenoxy)ethyl]-methylamino}-acetic acid tert-butyl ester Prepared essentially as described in Preparation 75 using 2-iodo-4-bromophenol. HRMS m/z Calculated: 469.9828; Found: 469.9800

{[2-(4-Bromo-2-thiophen-2-ylphenoxy)ethyl]-methylamino}-a cetic acid tert-butyl ester Add to a 1-neck round-bottom flask under nitrogen triphenylphosphine (1.14 g, 4.36 rαmol), {[2-(4-bromo-2-iodophenoxy)ethyl]-methylamino} -acetic acid tert-butyl ester (8.55 g, 18.2 mmol), 2-thiopheneboronic acid (2.67 g, 18.2 mmol) in 1,4-dioxane (200 niL, 2 mol) and 2 N aqueous potassium carbonate (200 niL). Degas and add tris(dibenzylideneacetone)dipalladium (0) (1.0 g, 1.1 mmol) and heat to 110 0C for 4 h. Cool to room temperature, filter through Celite®, wash with ethyl acetate (200 mL). Wash the filtrate with water (3 x 50 mL), saturated aqueous sodium chloride (2 x 50 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 7:3 hexanes:ethyl acetate) to give the title compound as a clear oil (4.8 g, 62.0%). LC-MS: m/z = 425.0, 427.0

MethyI-{2-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-y l)-2-thiophen-2-yl- phenoxy]ethyl}-amino)-aeetic acid tert-butyl ester Add potassium acetate (0.92 g, 9.4 mmol) to a solution of {[2-(4-bromo-2- thiophen-2-ylphenoxy)ethyl]-methylamino}-acetic acid tert-butyl ester (1.0 g, 2.3 mmol), (1:1) [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (0.19 g, 23 mmol) and bis(pinacolato)diboron (0.774 g, 3.05 mmol) in N,N-dimetliylformamide (100.0 mL, 1.291 mol). Heat at 95 0C for 3 h. Cool to room temperature, filter through a plug of Celite®. Diluted with ethyl acetate (200 mL), wash with water (3 x 100 mL), saturated aqueous sodium chloride (2 x 100 mL) dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 7:3 hexanes:ethyl acetate) to give the title compound as an amber oil (770 mg, 69.0%). HRMS m/z Calculated: 474.2407; Found: 474.2502

({2-[4-(2,3-Diliydrobenzo[l,4]dioxm-6-yl)-2-thiophen-2-yl -phenoxy]ethyl}- methylamino)-acetic acid tert-butyl ester Add to a 1 -neck round-bottom flask (100 mL) under nitrogen triphenylphosphine (0.0997 g, 0.380 mmol), methyl-{2-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- 2- thiophen-2-yl-phenoxy]ethyl}-amino)-acetic acid tert-butyl ester (0.600 g, 1.27 mmol), 6- bromo-l,4-benzodioxane (0.136 g, 0.634 mmmol) in 1,4-dioxane (20 mL, 0.2 mol) and 2 N aqueous potassium carbonate (20 mL). Degas reaction, add tris(dibenzylideneacetone)diρalladium (0) (0.07 g, 0.08 mmol) heat to 110 0C for 2 h. Col to room temperature, filter through Celite® and wash with ethyl acetate (200 mL). Wash The filtrate with water (3 x 50 mL), saturated aqueous sodium chloride (2 x 50 mL) dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 6:4 hexanes:ethyl

acetate) to give the title compound as a clear oil (500 mg, 82.0%).

HRMS m/z Calculated: 482.2001; Found: 482.1980

The compounds of Preparations 82-84 may be prepared essentially as described as

Preparation 81 using 5-bromo-l-indanone, 5-bromoindoline or 5-iodo-2,3-

dihydrobenzofuran respectively.

Preparation 85

({2-[4-(2,3-Dihydrobenzofuran-6-yl)-2-thiophen-2-ylphenox y]ethyl}-methylamino)-

acetic acid tert-butyl ester

Acetic acid 3-oxo-2,3-dih.ydrobenzofuran-6-yl ester

Add dropwise acetyl chloride (1.04 mL, 14.653 mmol) to a solution of 6-hydroxy-

2H-benzofuran-3-one (2.0 g, 13.32 mmol) and diisopropylethylarnine (2.55 mL, 14.653

mmol) in dichloromethane (100 mL) and stir for 2 h at room temperature. Dilute with

dichloromethane (100 mL) and wash with water (2 x 100 mL), saturated aqueous sodium

chloride (100 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting

with 3:7 hexanes:ethyl acetate) to give the title compound as white solid (1.53 g, 59 %).

HRMS m/z Calculated: 193.0500; Found: 193.0496 Acetic acid 2,3-dihydrobenzofuran-6-yl ester Add 5% palladium on carbon (454 mg, 30% wt) into a Parr bottle containing acetic acid 3-oxo-2,3-dihydrobenzofuran-6-yl ester (1.5 g, 7.81 mmol) in ethyl acetate (100 niL) and acetic acid (9.8 niL). Hydrogenate at 55 psi hydrogen at 60 0C for 18 h. Cool to room temperature and filter through Celite®. Dilute the filtrate with ethyl acetate (100 mL). Wash with water (2 x 100 niL), saturated aqueous sodium chloride (100 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 3:7 hexanes:ethyl acetate) to give the title compound as white solid (350.0 mg, 25%). HRMS m/z Calculated: 179.0708; Found: 179.0

2,3-Dihydrobenzofuran-6-ol Add a saturated solution of potassium carbonated (3.5 mL) to a solution of acetic acid 2,3-dihydrobenzofuran-6-yl ester (0.250, 1.403 mmol) in tetrahydrofuran (7.0 mL) and stir at room temperature for 3 h. Dilute with ethyl acetate (100 mL) and wash with water (2 x 100 mL), saturated aqueous sodium chloride (100 mL), dry (sodium sulfate), filte, concentrate and purify (HPLC, eluting with 8:2 hexanes:ethyl acetate) to give the title compound as pale yellow oil (189.0 mg, 99%). HRMS m/z Calculated: 137.0602; Found: 137.0575

Trifluoromethanesulfonic acid 2,3-dihydrobenzofuran-6-yl ester Add to a solution of 2,3-dihydrobenzofuran-6-ol (0.180 g, 1.32 mmol) and N-phenyl- bis(trifluoromethanesulfonimide) (0.520 g, 1.45 mmol) in tetrahydrofuran (6.61 mL). Cool to 0 0C was added sodium tert-butoxide (0.140 g, 1.45 mmol) and stir at 0 0C for for 1 h. Warm to room temperature and stir for 1 h. Dilute with ethyl acetate (100 mL) and wash with water (3 x 50 mL), saturated aqueous sodium chloride (2 x 50 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 9:1 hexanes:ethyl acetate) to give the title compound as a pale yellow oil (340 mg, 96.0%). HRMS m/z Calculated: 269.0095; Found: 269.0099

({2-[4-(2,3-Dihydrobenzofuran-6-yl)-2-thiophen-2-ylphenox y]ethyl}-methylamino)- acetic acid tert-butyl ester Add to a solution of trifluoromethanesulfonic acid 2,3-dmydrobenzofuran-6-yl ester (550 mg, 16.2 mmol), [14'bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.088 g, 0.35 mmol) in N,N-dimethylformamide (12 mL), {[2-(4-bromo-2-thiophen-2-ylphenoxy)ethyl]-metliylamino}-ace tic acid tert- butyl ester (0.4O g3 1.27 mmol) and 2 N aqueous potassium carbonate (2.9 mL, 58 mmol). Heat at 95 0C for 18 h. Cool to room temperature and filter through a plug of Celite® . Diltue the filtrate with ethyl acetate (200 mL) and wash with water (3 x 100 mL), saturated aqueous sodium chloride (2 x 100 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 7:3 hexanes: ethyl acetate) to give the title compound as an amber pale yellow oil (280 mg, 51.7%.) HRMS m/z: 488.1855

Preparation 86 {[2-(4-Furan-2-yl-2-thiophen-2-ylphenoxy)ethyl]-methylamino} -acetic acid tert-butyl ester

Add 2-furanboronic acid (0.275 g, 1.42 mmol) and 2 N aqueous potassium carbonate (3.1 mL, 0.064 mol) to a solution of {[2-(4-bromo-2-thiophen-2- ylphenoxy)ethyl]-methylamino} -acetic acid tert-butyl ester prepared as described in Preparation 81 (0.550 g, 16.2 mmol) and [l,l'bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.098 g, 0.39 mmol) in N9K-dimethylformamide (13 mL). Heat at 95 °C for 4 h. Cool to room temperature and filter through a plug of Celite®. Dilute the filtrate with ethyl acetate (200 mL) and wash with, water (3 x 100 mL), saturated aqueous sodium chloride (2 x 100 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 7:3 hexanes:ethyl acetate) to give the title compound as a pale yellow oil (450 mg, 84.3%). HRMS m/z Calculated: 414.1739; Found: 414.1722 The compound of Preparations 87-89 may be prepared essentially as described in Preparation 81 using 3-furanboronic acid, 2-benzylfuranboronic acid, or 3- chlorophenylboronic acid.

Preparation 90 {[2-(3-Isopropenylbiphenyl-4-yloxy)ethyl]-methylamino}-aceti c acid ethyl ester

{2-[3-(l-Hydroxy-l-methylethyl)-biphenyl-4-yloxy]ethyl}-m ethylcarbamic acid tert- butyl ester Add methylmagnesium bromide (3 M in diethyl ether, 1.0 mL, 3.0 mmol) over 2 min to a solution of 4-[2-(tert-butoxycarbonyl-methylamino)-ethoxy]-biphenyl-3- carboxylic acid methyl ester (0.385 mg, 1.0 mmol) in tetrahydrofuran (10 mL) under nitrogen at-78 0C. Stir for 1 h, warm to 0 0C and stir for 45 min. Quench with saturated aqueous ammonium chloride, dilute with ethyl acetate (100 mL) and separate the phases. Wash the organic phase with water (50 mL) and saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 3:1 hexanes:ethyl acetate) to give the title compound as a white solid (350.9 mg, 91%) HRMS m/z Calculated: 408.1270; Found: 408.1276, 1H NMR (CDCl3) δ 7.64-7.60 (3H, m), 7.5-7.4 (3H, m), 7.34-7.45 (3H, m), 7.02 (IH, d, J = 8.7 Hz), 4.27 (2H, t, J = 7.5 Hz), 3.75 (2H5 t, J = 5.4 Hz), 3.02 (2H, s), 1.71 (3H5 s), 1.53 (9H5 s) {2-[3-(l-Methoxy-l-methyIethyl)-biphenyl-4-yloxy]ethyI}-meth ylcarbamic acid tert- butyl ester Add iodomethane (0.1 niL, 0.00155 mol) to a solution of {2-[3-(l -hydroxy- 1- methylethyl)-biphenyl-4-yloxy] ethyl }-methylcarbamic acid tert-butyl ester (0.460 g, 1.19 mmol), silver trifluoromethanesulfonate (0.337 g, 1.31 mol), 2,6-di-tert-butyl pyridine (0.401 mL, 1.79 mmol) in dichloromethane (3 rnL). After about 6 h add more iodomethane (0.1 mL, 1.55 mmol) and silver trifluoromethanesulfonate (0.337 g, 1.31 mmol) and stir another 2 h. Dilute with dichloromethane (100 mL) and wash with 0.1 N hydrochloric acid (2 x 50 mL), dilute aqueous sodium bicarbonate (2 x 50 mL), water (2 x 50 mL), saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), filter, concentrateand purify (HPLC, eluting with 7:3 hexanes: ethyl acetate) to give the title compound as a clear oil (250 mg, 52%). 1H NMR (CDCl3) δ 7.72 (IH, d, J = 2.4 Hz), 7.61 (2H, dd, 1 = 1.6 Hz, J=8.8 Hz), 7.51- 7.42 (3H, m), 7.36-7.31 (IH, m), 4.16 (2H, t, J = 7.2 Hz), 3.71 (2H, s), 3.29 (3H, s), 3.04 (3H, s), 1.67 (6H, s), 1.51 (9H, s)

[2-(3-IsopropenylbiphenyI-4-yloxy)ethyl]-methylamine hydrochloride Add 4 N hydrochloric acid in 1,4-dioxane (14 mL, 56.31 mmol) to a solution of {2-[3-(l-methoxy-l-methylethyl)-biphenyl-4-yloxy]ethyl}-meth ylcarbamic acid tert- butyl ester (225.0 mg, 0.563 mmol) in 1,4-dioxane (5.63 mL). Stir for 3 h at room temperature. Concentrate and add ether. Filter solid and dry in a vacuum oven to give the title compound as a white solid (150 mg, 87%) HRMS m/∑ Calculated: 268.1701; Found: 268.1701

{[2-(3-Isopropenylbiphenyl-4-yloxy)ethyl]-methylamino}-ac etic acid ethyl ester Add to a solution of [2-(3-isopropenylbiphenyl-4-yloxy)ethyl]-methylamine hydrochloride (150.0 mg, 0.494 mmol) in acetonitrile, potassium carbonate (136.0 mg, 0.987 mmol) and ethyl bromoacetate (0.07 mL, 0.592 mmol) and stir for 2 h at room temperature. Dilute with ethyl acetate (100 mL) and wash with water (3 x 100 mL), saturated aqueous sodium chloride (100 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 3:7 hexanes:ethyl acetate) to give the title compound as clear oil (130 mg, 75.5%). HRMS m/z Calculated: 354.2069; Found: 354.2062 Preparation 91 ({2-[3-(l,2-Dimethylpropyl)-lbiphenyl-4-yloxy]ethyl}-methyla mmo)-acetic acid tert- butyl ester

Add phenylboronic acid (0.259g, 2.124 mmol) and 2 N potassium carbonate (4.83 mL, 9.65 mmol) to a solution of ({2-[4-bromo-2-(l,2-dimethylpropyl)-phenoxy] ethyl}- methylamino)-acetic acid tert-bxityl ester prepared as decribed in Preparation 102 (0.8O g, 1.93 mmol), [l,rbis(diphenylphLθsphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.473 g, 0.579 mmol) in tetrahydrofuran (20 mL). Heat at 95 °C for 1 h (monitor by LC-MS), cool to room temperature and filter through a plug of Celite®. Dilute with ethyl acetate (200 mL) and wash water (3 x 100 mL), saturated aqueous sodium chloride (2 x 1 OO mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 7:3 hexanes: ethyl acetate) to give the mixture of isomers as a yellow oil (780 mg, 98%). HRMS m/z Calculated: 412.2852; Found: 412.2849

The compounds of Preparations 92-93 may be prepared essentially as described as Preparation 90 using (3,4-methylenedioxyphenyl)boronic acid or (3,4- difluorophenyl)boronic acid respectively. Prep Compound & Data ({2-[4-Benzo[l,3]dioxol-5-yl-2-(l,2-dimethylproρyl)-ρhenox y]etliyl}- methylamino)-acetic acid tert-butyl ester 92 1U NMR (CDCl3) δ 7.80 (d, IH, J = 2.7 Hz), 7.58 (d, IH, J = 3.7 Hz), 7.43-7.36 (m, 2H), 7.14-7.05 (m, 4H), 6.92 (d, IH), J = 7.6 Hz, IH), 6.03 (s, 2H)5 4.29 (bt, 2H), 3.37 (bs, 2H), 3.18 (bs, 2H), 2.57 (s, 3H), 1.50 (s, 9H) ({2-[3-(l52-Dimethylpropyl)-3lJ4'-difluorobiphenyl-4-yloxy]e thyl}-methylainino)- acetic acid tert-butyl e

HRMS m/z 448.2655

Preparation 94 ({2-[4-Cyclohexyl-2-(2,2-dimethyl-propyI)-phenoxy]ethyl}-met hylamino)-acetic acid- tert-butyl ester

4-Cyclohexyl-2-(2,2-dimethylpropyl)-l-methoxybenzene Add to a Parr bottle 10^o palladium on carbon (6.5 g), acetic acid, ethanol (171 niL) with l-(4-methoxybiphenyl-3-yl)-2,2-dimethylpropan-l-ol (6.0 g, 22.35 mmol). Charge the bottle with hydrogen to 60 psi. Stir at room temperature for 18 h and filter through Hyflo Super Cel® and the filtrate diluted with ethyl acetate (1.0 L) and wash with water (200 mL), saturated aqueous sodium chloride (200 mL), dry (sodium sulfate), filter and concentrate. Thin layer chromatography indicates no reaction. Redissolve in ethyl acetate (200 mL) and add palladium hydroxide and hydrogenate again. Add palladium black and heat to 50 ° C for 18 h. Filter, concentrate and purify (HPLC, ehiting with 80:20 hexanes:ethyl acetate) to give totally reduced phenyl ring compound (3 g) and the title compound (3 g) as a clear oil. 1H NMR (DMSO-d6) δ 7.47 (IH, dd, J = 2.0 Hz, J = 5.6 Hz)5 6.80 (IH, d, J = 2.8 Hz), 6.64 (IH, d, J - 8.4 Hz), 3.72 ( 3H, s), 2.49 (2H, s), 2.44-2.34 (1 H, m), 1.88-1.66 (5H, m), 1.40-1.24 (5H, m), 0.968 (9H, s)

4-CyclohexyI-2-(2,2-dimethylp3ropyl)-phenol 4-Cyclohexyl-2-(2,2-dimethylpropyl)-phenol is prepared essentially as described in Preparation 75. MS (ES): m/z = 246.4 ({2-[4-Cyclohexyl-2-(2,2-dimethylpropyl)-phenoxy]ethyl}-meth ylamino)-acetic acid- tert-butyl ester ({2-[4-Cyclohexyl-2-(2,2-dimethylpropy'l)-phenoxy]ethyl}-met hylamino)-acetic acid-tert-butyl ester is prepared essentially as described in Preparation 75. HRMS m/z Calculated: 418.3321; Found: 418.3311

Preparation 95 (Methyl-{2-[4-(l-methyl-lH-indol-6-yl)-2-tliiophen-2-yl-phen oxy]ethyl}-amino)- acetic acid tert-butyl ester

6-Bromo-l-methyI-lH-indole Add 5-bromoindole (0.500 g, 2.55 rnmol) dropwise to a stirred slurry of sodium hydride (0.098 g, 4.08 mmol) in tetrahydrofuran. (12.75 mL) and stir for 1 h at room temperature. Add iodomethane (0.18 mL, 2.805 mmol) and let stir overnight. Pour over ice and dissolve further with water (100 mL) and extract into ethyl acetate (100 mL), wash with water (3 x 250 mL), saturated aqueous sodium chloride (2 x 250 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 7:3 hexanes:ethyl acetate) to give the title compound as a white solid (210 mg). HRMS m/z Calculated: 209.9901; Found: 209.9901

(Methyl-{2-[4-(l-methyl-lH-indol-6-yl)-2-thi»phen-2-yl-p henoxy]ethyl}-amino)- acetic acid tert-butyl ester Add (methyl-{2-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl) -2-thiophen-2- yl-phenoxy] ethyl} -amino)-acetic acid tert-butyl ester prepared as described in Preparation 81 (0.400g, 0.845 mmol) and 2 N aqueous potassium carbonate (2.1 mL, 4.22 mmol) to a solution of 6-bromo-l -methyl- lH-indole (0.195g, 0.92 mmol), [l,rbis(diphenylphosphino)ferrocene]dichloropalladiuEn (II) complex with dichloromethane (1:1) (0.064 g, 0.253 mmol) in tetrahy drofuran (0.5 mL). Heat at 95 0C for 4 h. Cool to room temperature and filter through a plug of Celite® . Dilute with ethyl acetate (100 mL), water (50 mL), saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 7:3 hexanes: ethyl acetate) to give the title compound as a pale yellow oil O 50.0 mg). HRMS m/z Calculated: 477.2212; Found: 477.2191

Preparation 96 {[2-(2-Benzoyl-4-bromophenoxy)ethyl]-methylamϊno}-acetic acid tert-butyl ester

Stir a solution of 5-bromo-2-hydroxybenzophen.one (5.0 g, 118.3 mmol), 1,1'- (azodicarbonyl)dipiperidide (ADDP) (5.56 g, 22.0 mmol), [(2-hydroxyethyl)- methylamino] -acetic acid tert-butyl ester (4.16 g, 22.0 mmol) and tri-n-butylphosphine (5.5 mL, 4.45 g, 22.0 mmol) in toluene (200 mL) at room temperature for 30 min. Heat at 90 0C overnight. Dilute with diethyl ether and cool to room temperature. Filter the white precipitate, concentrate and purify (silica gel chromatography, eluting with 25:75 to 100:0 ethyl acetate:hexanes) to give (1.75 g, 21%) of the title compound as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.39 (9H, s), 2.19 (3H, s), 2.59 (2H5 1, J = 5.6 Hz), 2.97 (2H, s), 3.97 (2H, t, J = 5.6 Hz), 6.83 (IH, d, J = 8.9 Hz), 7.37-7.53 (5H, m), 7.73 (2H, d, J = 7.9 Hz); MS (ES): 448, 450

The compounds of Preparations 97-98 may be prepared essentially as described in Preparation 96 using the appropriate phenols. Prep Compound Name & Data {[2-(2-Benzyl-4-chlofophenoxy)ethyl]-metliylaπnino}-acetic acid tert-butyl ester 97 1H NMR (300 MHz, CDCl3) δ 1.45 (9H, s), 2.4S (3H, s), 2.98 (2H, t, J = 5.6 Hz),

Preparation 99 {Methyl-[2-(3-phenylaminobiphenyl-4-yloxy)ethyl]-amino}-acet ic acid tert-butyl ester

[2-(3-Bromobiphenyl-4-yloxy)ethyl]-methylcarbamic acid tert-butyl ester Stir a solution of 3 -bromobiphenyl-4-ol (0.50 g, 2.00 mmol), 1,1'- (azodicarbonyl)dipiperidide (ADDP) (0.76 g, 3.00 mmol) and (2-rrydroxyethyl)- methylcarbamic acid tert-butyl ester (0.53 g, 3.00 mmol) in toluene (20 mL) at room temperature. Next add tri-n-butylphosphine (747 μL, 3.00 mmol) portionwise via syringe. Stir at room temperature for 30 min amd heat at 80 °C overnight. Dilute with diethyl ether and allow to cool to room temperature. Filter the white precipitate, concentrate the filtrate and purify (silica gel chromatography, eluting with 10:90 to 50:50 ethyl acetate:hexanes) to give the title compound (0.54 g, 66%). 1HNMR (300 MHz, CDCl3) δ 1.51 (9H5 s), 3.13 (3H, s), 3.71 (2H= t, J = 5.6 Hz), 4.22 (2H, t, J = 5.6 Hz), 6.97 (IH, d, J = 8.6 Hz), 7.36-7.58 (6H, m), 7.83 (IH, d, J = 1.9 Hz); MS (ES): 306, 308

Methyl-[2-(3-phenylaminobiphenyl-4-yloxy)ethyl]-carbamic acid tert-butyl ester In a sealed tube add a solution of aniline (0.07 g, 0.74 mmol) and [2-(3- bromobiphenyl-4-yloxy)ethyl]-methylcarbamic acid tert-butyl ester (0.25 g, 0.62 rnmol) in toluene (10 mL) and stir at room temperature. Add consecutively tris(dibenzylidene acetone)dipallaium (0) (0.11 g, 0.12 mmol), 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (0.15 g, 0.25 mmol), and sodium tert-butoxide (0.12 g, 1.24 mmol) and heat the sesaled tube at 120 0C for 6 h. Cool, dilute with ethyl acetate, filter through Celite®, concentrate and purify (silica gel chromatography eluting with 10:90 to 25:75 ethyl acetate :hexanes) to give the title compound (0.17 g, 66%). 1H NMR (300 MHz, CDCl3) δ 1.49 (9H, s), 3.02 (3H, s), 3.72 (2H, t, J = 5.3 Hz), 4.24 (2H, t, J = 5.3 Hz), 6.96-7.02 (2H, m), 7.07-7.11 (IH, m), 7.22-7.28 (2H, m), 7.29-7.36 (3H, m), 7.39-7.46 (2H, m), 7.54-7.59 (3H, m); MS (ES): 319, 419

(2-Methylaminoethoxy)-biphenyl-3-yl]-phenyIamine Stir a solution of methyl- [2-(3-phenylaminobiphenyl-4-yloxy)ethyl]-carbaαiic acid tert-butyl ester (0.15 g, 0.36 mmol) in chloroform (3 mL) at 0 °C. Add a 1 : 1 mixture of chloroform:trifluoroacetic acid (6 mL total volume) in one portion. Remove cooling bath stir at room temperature for 1 h. Dilute with ethyl acetate (~700 mL) and wash with 0.5 N sodium hydroxide (twice), saturated aqueous sodium chloride, dry (potassium carbonate) and concentrate to give the title compound as a thick yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.57 (3H, s), 3.09 (2H, t, J = 4.9 Hz), 4.24 (2H, t, J = 5.3 Hz), 6.95-7.02 (2H, m), 7.06-7.10 (IH, m), 7.24-7.36 (5H, m), 7.39-7.46 (2H, m), 7.52- 7.60 (3H, m); MS (ES): 319

{Methyl-[2-(3-phenylamino-biphenyl-4-yIoxy)ethyl]-amino}- acetic acid ethyl ester Stir a solution of [4-(2-methylaminoethoxy)-biphenyl-3-yl]-phenylamine (0.18 g, 0.56 mmol), potassium carbonate (0.10 g, 0.68 mmol), ethyl bromoacetate (0.11 g, 0.68 mmol) in N,N-dimethylformamide (5 mL) at room temperature for 4 h. Dilute with ethyl acetate (-500 mL), wash with water (3x), saturated aqueous sodium chloride, dry (potassium carbonate) and purify (silica gel chromatography, eluting with 10:90 to 1 :1) to give of the title compound as a light yellow oil (0.20 g, 88%). 1H NMR (300 MHz5 CDCl3) δ 1.28 (3H, t, J = 7.3 Hz), 2.62 (3H, bs), 3.06-3:20 (2H, m), 3.53 (2H, bs), 4.21 (2H, q, J = 7.3, 14.2 Hz), 4.22-4.27 (2H, m), 6.75 (1H, bs), 6.97-7.02 (2H5 m), 7.06-7.10 (IH5 m), 7.25-7.36 (5H5 m), 7.38-7.46 (2H, m)5 7.53-7.61 (3H, rn); MS (ES): 405

Preparation 100 {[2-(3-Isopropoxymethylbiphenyl-4-yloxy)ethyl]-methyIamino}- acetic acid ethyl ester

4-Hydroxybiphenyl-3-carboxylic acid methyl ester Stir a solution of methyl 5-bromosalicylate (10.0 g, 43.3 mmol) in 1,4-dioxaαie (-200 niL) at room temperature with phenylboronic acid (6.3 g, 51.9 mmol), palladium (II) acetate (1.90 g, 8.7 mmol), 2-(dicyclohexylphosphino)-2'-methylbiphenyl (6.30 g, 17.3 mmol) and potassium fluoride (7.60 g, 130 mmol). Heat at 100 0C overnight. Cool and dilute with diethyl ether and filter through Celite®. Transfer the filtrate to a separatory funnel, further dilute with diethyl ether, wash with water (3x), and satura-ted aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica g&l chromatography, eluting with 100:0 to 80:20 hexanes:ethyl acetate) to give the title compound as a pale yellow solid (8.12 g, 82%). 1HNMR (300 MHz5 CDCl3) δ 4.02 (3H, s), 7.10 (IH, d, J = 8.6 Hz)5 7.33-7.40 (IH3 m), 7.43-7.50 (2H5 m), 7.56-7.61 (2H5 m), 7.75 (IH5 dd5 J = 2.3, 8.6 Hz), 8.11 (IH5 d, J = 2.6 Hz), 10.80 (IH5 s); MS (ES): m/z = 227

(4-[2-(tert-Butoxycarbonylmethylamino)-ethoxy]-biphenyI-3 -carboxyIic acid methyl ester Stir at 0 °C a solution of 4-hydroxybiphenyl-3-carboxylic acid methyl ester (13.04 g, 57.1 mmol), l,l*-(azodicarbonyl)diρiρeridide (ADDP) (28.80 g, 114 mmol) and Ql- hydroxyethyl)-methylcarbamic acid tert-butyl ester (11.0 g, 62.8 mmol) in toluene ( 1 L). Add portionwise via syringe tri-n-butylphosphine (28.5 niL, 114 mmol) and stir at room temperature for 30 min. Heat at 90 0C for 4 h. Pour the reaction mixture into diethyl ether (1 L) at room temperature and stir for 1 h. Filter the white precipitate, concentrate the filtrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate :hexanes) to give the title compound as a white solid (10.06 g, 46%). 1H NMR (300 MHz5 CDCl3) δ 1.50 (9H, s), 3.09 (3H5 s), 3.70 (2H t, J = 4.9 Hz)5 3.94 (3H5 s), 4.24 (2H5 t, J = 5.3 Hz)5 7.07 (IH5 d, J = 8.6 Hz)5 7.33-7.39 (IH5 m), 7.44-7.50 (2H5 m)5 7.58-7.62 (2H5 m), 7.72 (IH, dd, J = 2.6, 8.6 Hz)5 8.07 (IH5 d, J = 2.6 Hz); MS (ES): m/z = 386

[2-(3-Hydroxymethylbiphenyl-4-yloxy)ethyl]-methylcarbamic acid tert-butyl ester Chill a stirring solution of 4- P-(tert-butoxycarbonyl-memγlamino)-ethoxy| - biphenyl-3-carboxylic acid methyl ester (1.96 g5 5.08 mmol) in tetrahydrofuran (30 mL) to 0 °C. Add 1.0 M solution of lithium aluminum hydride (5.0 mL) in tetrahydrofuran via syringe to maintain internal reaction temperature at <15 °C. Upon complete addition, stir at 0 °C for 30 min. Quench by portionwise addition of sodium sulfate decahydrate. Dilute with diethyl ether and stirr vigorously at room temperature for 1 h. Filter the solids and concentrate the filtrate to give the title compound without need of further purification. 1H NMR (300 MHz5 CDCl3) δ 1.52 (9H5 s)5 2.54 (IH, bs), 3.02 (3H5 s), 3.65-3.80 (2H5 m)5 4.20 (2H5 1, J = 4.9 Hz)5 4.76 (2H5 s), 6.96 (IH5 d5 J = 8.6 Hz)5 7.29-7.37 (IH5 m), 7.41-7.60 (6H5 m); MS (ES): m/z = 380

[2-(3-Bromomethylbiphenyl-4-yloxy)ethyI]-methyIcarbamic acid tert-butyl ester Add to a solution of [2-(3-hydroxymethylbiphenyl-4-yloxy)ethyl]-methylcarbamic acid tert-butyl ester (0.50 g5 1.40 mmol) and diiopropylethylamine (0.91 g, 7.0 mmol) in chloroform (30 mL) at 0 °C with dibromotriphenylphosphorane (0.89 g, 2.1 mmol) in one portion. Stir at 0 °C for 15 min. Partition between aqueous sodium bicarbonate and ethyl acetate. Extract the product with ethyl acetate. Combine the organics, wash with saturated aqueous sodium chloride, dry (potassium carbonate), concentrate and purify (silica gel chromatography, eluting with 10:90 ethyl to 1:1 acetate :hexanes) to give of the title compound as a clear colorless oil (0.56 g, 95%). 1HNMR (300 MHz, CDCl3) δ 1.45 (9H, s), 3.04 (3H5 s), 3.60-3.71 (2H5 m), 4.10-4.25 (2H, m), 4.58 (2H, s), 6.90-6.93 (IH, m), 7.27-7.31 (IH, m), 7.37-7.42 (2H, m), 7.46-7.56 (4H, m)

[2-(3-Isopropoxymethylbiphenyl-4-yloxy)ethyl]-methylcarba mic acid tert-butyl ester Add silver (II) oxide (0.22 g, 1.70 mmol) in one portion to a solution of [2-(3- bromomethylbiphenyl-4-yloxy)ethyl]-methylcarbamic acid tert-butyl ester (0.12 g, 0.29 mmol) in 2-propanol at room temperature (10 mL). Heat to reflux for 4 h and stir at room temperature overnight. Filter through Celite® and concentrate the filtrate to give the title compound without further purification (0.11 g, 95%). 1H NMR (300 MHz, CDCl3) δ 1.26 (6H, d), 1.48 (9H, s), 3.03 (3H, s), 3.60-3.68 (2H, m), 3.70-3.80 (IH, m), 4.15 (2H, t, J = 5.3 Hz), 4.61 (2H, s), 6.92 (IH, d, J = 8.5 Hz), 7.29-7.34 (IH, m), 7.40-7.48 (3H, m), 7.56-7.59 (2H, m), 7.69 (lH,d, J - 2.2 Hz); MS (ES): m/z = 422

[2-(3-Isopropoxymethylbiphenyl-4-yloxy)ethyI]-methylamine Treat a solution of [2-(3-isopropoxymethylbiphenyl-4-yloxy)ethyl]~ methylcarbamic acid tert-butyl ester (0.10 g, 0.25 mmol) in chloroform (5 mL) with trifluoroacetic acid (0.74 g, 6.5 mmol) in one portion. Stir at room temperature for 1 h and dilute with ethyl acetate and wash with 0.5 N sodium hydroxide (3x), saturated aqueous sodium chloride, dry (potassium carbonate) and concentrate to give the title compound as a thick yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.26 (6H, d), 2.06 (IH, bs), 2.55 (3H, s), 3.05 (2H, t, J = 5.3 Hz), 3.73-3.77 (IH5 m), 4.18 (2H, t, J = 5.3 Hz), 4.60 (2H, s), 6.95 (IH, d, J = 8.4 Hz), 7.29-7.33 (IH, m), 7.40-7.51 (3H, m), 7.56-7.59 (2H, m), 7.63 (IH5 d, J = 2.6 Hz); MS (ES): m/z = 300

{[2-(3-IsopropoxymethylbiphenyI-4-yIoxy)ethyI]-methyIamin o}-acetic acid ethyl ester Add to solution of [2-(3-isopropoxymethylbiphenyl-4-yloxy)ethyl]-methylamine (0.09 g, 0.30 mmol) in acetonitrile (10 mL) potassium carbonate (0.10 g, 0.75 mmol) and ethylbromoacetate (0.062 g5 0.38 mmol). Stir at room temperature overnight. Partition with water and extract the product with ethyl acetate. Combine the organic layers, wash with saturated aqueous sodium chloride, dry (potassium carbonate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 1:1 ethyl acetate:hexanes) to give the title compound as a clear colorless glass (0.11 g, 95%). 1HNMR (300 MHz5 CDCl3) δ 1.26 (6H, d), 1.29 (3H, t, J = 7.0 Hz)5 2.61 (3H, s), 3.10- 3.20 (2H, m), 3.47-3.58 (2H, m), 3.70-3.80 (IH, m), 4.21 (2H, q, J = 7.0, 14.5 Hz), 4.23- 4.30 (2H, m), 4.60 (2H5 s), 6.93 (IH, d, J = 8.4 Hz), 7.28-7.33 (IH, m), 7.39-7.48 (3H, m), 7.56-7.59 (2H, m), 7.67 (IH, d, J = 2.6 Hz); MS (ES): m/∑ = 386

The compound of Preparation 101 may be prepared essentially as described in Preparation 100 using cyclohexanol. Prep Compound Name & Data { [2-(3 -Cyclohexyloxymethylbiphenyl-4-yloxy)ethyl] -methylamino } -acetic acid ethyl ester

1H NMR (300 MHz, CDCl3) δ 1.25 (3H, t, J = 7.0 Hz), 1.20-1.40 (5H5 m), 1.45- 101 1.50 (IH5 m)5 1.70-1.80 (2H5 m), 1.90-2.00 (2H5 m), 2.53 (3H5 s), 3.00-3.10 (2H5 m), 3.30-3.40 (IH5 m), 3.44 (2H5 s), 4.16 (2H, q, J = 7.0, 14.5 Hz), 4.10-4.20 (2H5 m), 4.60 (2H5 s), 6.88 (IH, d, J = 8.4 Hz), 7.24-7.29 (IH5 m), 7.36-7.44 (3H5 m), 7.52-7.56 (2H5 m), 7.65 (IH, d5 J = 2.2 Hz); MS (ES): m/z = 426

Preparation 102 ({2-[4-Bromo-2-(l,2-dimethylpropyI)-phenoxy]ethyl}-methyIami no)-acetic acid tert- butyl ester

l-(5-Bromo-2-methoxyphenyl)-2,2-dimethylpropan-l-ol Add a solution of tert-butylmagnesium chloride (20% w/w in tetrahydrofuran; 300 mL, 0.477 mol) to a solution of 5-bromo-2-methoxybenzaldehyde (67.4 g5 0.313 mol) in anhydrous tetrahydrofuran (600 mL) at about 0 °C. Warm slowly to room temperature and stir for 16 h. Cool to about 5 °C and add saturated aqueous ammonium chloride (600 mL). Extract with dichloromethane (2000 mL), dry (magnesium sulfate), filter, concentrate, selectively crystallize starting material from ethanol, concentrate and purify (silica gel chromatography, eluting with dichloromethane). Further purify impure fractions by twice selectively crystallizing starting material from diethyl ether to give the title compound as a yellow oil (45.5 g, 53%). 1H NMR (300 MHz, CDCl3) δ 7.44 (IH, d, J = 2.5 Hz), 7.32 (IH, dd, J = 2.5, 8.8), 6.72 (IH, d, J = 8.8), 4.74 (IH5 d, J = 4.1 Hz), 3.78 (3H, s), 2.37 (IH, br), 0.92 (9H, s)

4-Bromo-2-(l,2-dimethylpropyl)-l-methoxybenzene Add triethylsilane (140 mL, 0.876 mol) slowly to a solution of l~(5-bromo-2- methoxyphenyl)-2,2-dimethylpropan-l-ol (45.0 g, 0.165 mol) in trifluoroacetic acid (180 mL) at about 0 0C. Stir for 2 h, concentrate at 40 °C and partition the residue between dichloromethane and water. Dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with dichloromethane, then purify by silica gel chromatography, eluting with cyclohexane) to give a mixture of the title compound and the by-product 4-bromo-2-(2,2-dimethylpropyl)-l~methoxybenzene (ratio ~3:7, 15.6 g). 1H NMR (300 MHz, (CDCl3) δ minor: 7.16-7.28 (2H, m), 6.7 (IH, d, J 8.8), 3.78 (3H, s), 2.90 (IH, quintet, J = 7.0), 1.70-1.85 (IH, m), 1.14 (3H, d, J = 7.0), 0.90 (3 H, partly bidden under major), 0.76 (3H, d, 6.6); major: 7.16-7.28 (2H, m), 6.8 (IH, d, J 8.8), 3.75 (3H, s), 2.50 (2H, s), 0.89 (9H, s)

4-Bromo-2-(l,2-dimethylpropyl)-phenol Add a solution of boron tribromide (1.0 M in dichloromethane; 121 mL, 0.121 mol) to a mixture of 4-bromo-2-(l,2-dimethylpropyl)-l-methoxybenzene and 4-bromo-2- (2,2-dimethylpropyl)-l-methoxybenzene (15.6 g, 0.0607 mol) in dichloromethane (250 mL) in a dry ice bath. Warm to room temperature over 3 h, pour onto ice, separate the phases, dry (magnesium sulfate) and concentrate to give a mixture of the title compound and the by-product 4-bromo-2-(2,2-dimethylpropyl)-phenol as a green oil (ratio -3:7, 13.5 g). 1H NMR (300 MHz, CDCl3) δ minor: 7.12-7.23 (2H5 m), 6.61-6.70 (IH, m), 4.68 (IH, br), 2.75 (IH, quintet, J = 7.2), 1.75-1.89 (IH, m), 1.20 (3H, d, J = 7.2), 0.95 (3H, d, J = 6.7), 0.81 (3H, d, J = 6.7); major: 7.12-7.23 (2H, m), 6.61-6.70 (IH, m), 4.68 (IH, br), 2.48 (2H, s), 0.95 (9H, s) ({2-[4-Bromo-2-(l,2-dimethyIpropyl)-phenoxy]ethyl}-methyIami no)-acetic acid tert- butyl ester Add sequentially, [(2-hydroxyethyl)-methylamino] -acetic acid tert-butyl ester (11.6 g, 61.1 mmol) and l,l'-azodicarbonyl dipiperidine (ADDP) (28.0 g, 111 mmol) to a mixture of 4-bromo-2-(l,2-dimethyrpropyl)-phenol and 4-bromo-2-(2,2-dimethylpropyl)- phenol (13.5 g, 55.6 mmol) in toluene (280 mL). Add rapidly tributylphosphine (27.7 niL, 111 mmol) and heat to 90 °C for 4 h. Cool to room temperature, slurry in diethyl ether (700 mL) and stir for 30 min. Filter, concentrate and purify (silica gel chromatography, eluting form 3:7 to 1:1 diethyl ether:2-methylpentane) to give a mixture of the title compound and ({2-[4-bromo-2-(2,2-dimethylpropyl)-phenoxy]ethyl}-methylami no)- acetic acid tert-butyl ester (ratio ~3:7, 17.1 g). Further purify 580 mg by HPLC, eluting with 9:1 hexanes:ethyl acetate to separate the by-product ({2-[4-bromo-2-(2,2- dimethylpropyl)-phenoxy] ethyl }-methylamino)-acetic acid tert-butyl ester (360 mg) and the title compound as a clear oil (150 mg).

Preparation 103 ({2-[3'-Isopropyl-3-(thiophene-2-carbonyl)-biphenyI-4-yloxy] ethyl}-methylamino)- acetic acid tert-butyl ester

({2-[4-Bromo-2-(thiophene-2-carbonyl)-phenoxy]ethyl}-meth ylamino)-acetic acid tert-butyl ester Stir a mixture of (5-bromo-2-liydroxyphenyl)-thiophen-2-ylmethanone (6.71 g, 23.7 mmol), l,r-(azodicarbonyl)-dipiperidine (11.9 g, 47.4 mmol), [(2-hydroxyethyl)- methylamino] -acetic acid tert-butyl ester (8.97 g, 47.4 mmol) in anhydrous tetrahydrofuran, and add tri-n-butylphosphine (11.84 mL, 47.4 mmol). Heat to reflux for 3 h and cool to room temperature. Concentrate and add cyclohexane to residue and filter white precipitate. Further wash precipitate with cyclohexane. Combine filtrate, concentrate, and purify (Isco automated chromatography, eluting with 40:60 to 80:20 ethyl acetate: cyclohexane) to give the title compound as a oil (10.08 g, 93.6%). LC-MS: m/z 454/ 456.0

({2-[3'-Isopropyl-3-(thiophene-2-carbonyl)-biphenyI-4-ylo xy]ethyl}-methylamino)- acetic acid tert-butyl ester Stir a mixture of tricyclohexylphosphine (74 mg, 0.26 mmol), palladium acetate (49.3 mg, 0.22 mmol), potassium fluoride (0.38 g, 6.61 mmol), 3-isopropylphenylboronic acid (216.8 mg, 1.32 mmol) in anhydrous tetrahydrofuran (11 mL), and add ({2-[4- bromo-2-(thiophene-2-carbonyl)-phenoxy] ethyl } -methylamino)-acetic acid tert-butyl ester, (prepared essentially as described in Preparation 58), (0.5 g, 1.10 mmol). Heat to reflux over night under nitrogen. Add extra equivalents of tricyclohexylphosphine (37 mg, 0.13 mmol). palladium acetate (24.6 mg, 0.11 mmol), and potassium fluoride (191.4 mg, 3.3 mmol) and heat to reflux over weekend. Cool to room temperature, filter inorganics, concentrate and purify (ion exchange chromatography, eluting with 2 M ammonia in methanol, followed by automated chromatography, eluting with solvent gradient 0:100 to 40:60 ethyl acetate: cyclohexane) to give the title compound (181 mg,

LC-MS: m/z 494.5

The compounds of Preparations 104-105 may be prepared essentially as described as Preparation 103 using 4-isopropoxyphenylboronic acid or 3,4-methylenedioxyphenyl boronic acid respectively.

General Procedure for Rapid Parallel Synthesis: Preparation 106 ({2-[3',5'-Difluoro-3-(thiophene-2-carbonyl)-biphenyl-4-ylox y]ethyl}-methylamino)- acetic acid tert-butyl ester

Treat a stirring mixture of potassium fluoride (6eq), palladium acetate (0.20 eq) and tricyclohexylphosphine (0.24 eq) in tetrahydrofuran (2 mL) at room temperature with a solution of 3,5-difluorophenylboronic acid (112.4 mg, 0.396 mmol, 1.2 eq) in tetrahydrofuran (0.5 mL). After 15 min, add a stock solution of ({2-[4-bromo-2- (thiophene-2-carbonyl)-phenoxy]ethyl}-methylamino)-acetic acid tert-butyl ester prepared essentially as described in Preparation 58 (150 mg, 0.33 mmol, 1 eq) in tetrahydrofuran. Heat the reaction to 65 0C overnight in a Greenhouse™ reaction vessel consisting of 24 tubes each with a total volume of about 3 mL of solvent. Add extra potassium fluoride (2 eq), palladium acetate (0.06 eq), tricyclohexylphosphine (0.07 eq), and 3,5-difluorophenylboronic acid (0.6 eq) and heat the reaction mixture for a further 24 h. Allow the reactions to cool to room temperature. Filter the inorganics through a Whatman Filtertube (5 μm), and further wash with tetrahydrofuran (2 x 1 mL). Evaporate the solvent in a Reacti-Therm™ under a stream of nitrogen with heat, take up the residue in methanol, load onto an ion exchange column, wash with methanol and elute with 2 M ammonia in methanol. Evaporate solvent in a Reacti-Therm™ under a stream of nitrogen with heat to give the title compound (103.1 mg, 64.1%). LC-MS: m/z = 488.5

The compounds of Preparations 107-115 may be prepared essentially as described as Preparation 106 using the appropriate boronic acids.

Preparation 115

{[2-(2"-Chloro-3,4-difluoro-[l,l';3',l"]terphenyI-4'-ylox y)ethyl]-methylammo}-

acetic acid tert-butyl ester

3 ' ,4 r-Difluorobiphenyl-4-ol

Stir a mixture of tricyclohexylphosphine (777 mg, 2.77 mmol), palladium acetate

(518 mg, 2.31 mmol), potassium fluoride (4.43 g, 76.3 mmol), 3,4-difluorophenyllboronic

acid (2.17 g, 13.9 mmol) in anhydrous tetrahydrofuran (3OmL) for 15min, and add p_-

bromophenol (2 g, 11.6 mmol). Heat to 65 0C overnight. Cool to room temperature, filter

organics through a pad of Celite® and further wash with ethyl acetate. Concentrate

filtrate and purify (automated Isco chromatography, eluting with 0:100 to 30:70 ethyl

acetate xyclohexane) to give the title compound (1.72 g, 72%).

LC-MS: m/z 205.0

3-Bromo-3',4'-difluorobiphenyI-4-ol Add a solution of bromine (0.28 mL, 5.4 mmol) in chloroform to 3 ',4'- difluorobiphenyl-4-ol (2.22 g, 10.8 mmol) in chloroform at 60 0C under nitrogen. Continue to heat at 60 0C overnight under nitrogen. Cool to room temperature and dilute with water (20 mL). Separate the two phases and further wash chloroform layer with water, collect the chloroform layer through a phase frit, concentrate and purify (automated Isco chromatography, eluting with 0: 100 to 20:80 ethyl acetate: cyclohexane) to give the title compound as a solid (1.58 g, 51%). LC-MS: m/z 281/ 283.2

{[2-(3-Bromo-3',4'-difluorobiphenyl-4-yIoxy)ethyI]-methyl amino}-acetic acid tert- butyl ester Stir a mixture of 3-bromo-3',4t-difluorobiphenyl-4-ol (0.5 g, 1.75 mmol), 1,1'- (azodicarbonyl)-dipiperidine (883 mg, 3.50 mmol), [(2-hydroxyethyl)-methylamino]- acetic acid tert-butyl ester (662 mg, 3.50 mmol) in anhydrous tetrahydrofuran (17.5 mL) for 15 min, and add tri-n-butylphosphine (0.87 mL, 3.50 mmol). Heat to 65 0C overnight and cool to room temperature. Concentrate and add cyclohexane to the residue and filter the white precipitate. Further wash the precipitate with cyclohexane. Combine filtrate, concentrate and purify (automated Isco chromatography, eluting 0:100 to 30:70 ethyl acetate: cyclohexane) to give the title compound (0.476 g, 60%). LC-MS: m/z 454.0/ 456.0

{[2-(2M-Chloro-3,4-difluoro-[l,l';3',lM]terpheαyl-4f-ylo xy)ethyI]-methylamino}- acetic acid tert-butyl ester Stir a mixture of triphenylphosphine (45.5 mg, 0.174 mmol), tris(dibenzylideneacetone)dipalladium (0) (132.4 mg, 0.14 mmol), potassium carbonate (0.659 g, 4.77 mmol), 2-chlorophenylboronic acid (136.1 mg, 0.87 mmol) in anhydrous 1,4-dioxane (7.5mL) for 15 min, and add {[2-(3-bromo-3',4'-difluorobiphenyl-4- yloxy)ethyl]-methylamino}-acetic acid tert-butyl ester (330 mg, 0.723 mmol). Heat to reflux overnight under nitrogen. Add extra equivalent of triphenylphosphine (22.8 mg, 0.087 mmol), tris(dibenzylideneacetone)dipalladium (0) (66.2 mg, 0.072 mmol), potassium carbonate (0.329 g, 2.39 mmol), 2-chlorophenylboronic acid (68 mg, 0.43 mmol), and further heat to reflux for 4 h under nitrogen. Cool to room temperature, filter inorganics through a pad of Celite®, concentrate and purify (ion exchange chromatography, eluting with 2 M ammonia in methanol, followed by automated Isco chromatography, eluting with 0:100 to 40:60 ethyl acetatexyclohexane) to give the title compovmd (180 mg, 51%). LC-MS: m/z 488.1

Preparation 116 {[2-(3-Isopropylbiphenyl-4-yloxy)ethyI]-methylamino}-acetic acid tert-butyl ester

4-Brom.o~2~isopropylpb.enol Stir a solution of 2-isopropylphenol (1.48 mL, 11.0 rnrnol) in anhydrous chloroform and add tetra-n-butylammonium tribromide (5.31 g, 11.0 mmol) in anhydrous chloroform. Stir at room temperature for 2.5 h under nitrogen. Quench with aqueous sodium sulfate (50 mL) and dilute with dichloromethane. Separate the two layers, wash the organic layer with water, saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (automated Isco chromatography, eluting with 0:100 to 30:70 ethyl acetatexyclohexane) to give the title compound as a colourless liquid (2.16 g, 91%). 1HNMR (300 MHz, CDCl3) δ 1.23 (d, 6 H), 3.09-3.25 (m, 1 H), 4.79 (s, 1 H), 6.62 (d, 1 H), 7.15 (dd, J = 8.48, 2.45 Hz, 1 H), 7.28 (d, J = 2.45 Hz, 1 H)

{[2-(4-Bromo-2-isopropylphenoxy)ethyl]-methyIamino}-aeeti c acid tert-butyl ester Stir a mixture of 4-bromo-2-isopropylphenol (2.1 g, 9.76 mmol), 1,1'- (azodicarbonyl)-dipiperidine (4.93 g, 19.5 mmol), [(2-hydroxyethyl)-methylamino]-acetic acid tert-butyl ester (2.22 g, 11.7 mmol) in anhydrous tetraliydrofuran (25mL) for 15min, and add tri-n-butylphosphine (4.88 mL, 19.5 mmol). Heat to 70 0C overnight and cool to room temperature. Concentrate and add cyclohexane to residue and filter white precipitate. Wash precipitate with cyclohexane. Combine filtrate, concentrate and purify (automated Isco chromatography, eluting with 0:100 to 40:60 ethyl acetate: cyclohexane) to give the title compound (1.42 g, 38%). LC-MS: m/∑ 386/ 388.2

{[2-(3-IsopropyIbiphenyI-4-yIoxy)ethyl]-methylamino}-acet ic acid tert-butyl ester Stir a mixture of tricyclohexylphosphine (86.9 mg, 0.31 mmol), palladium acetate (58.0 mg, 0.26 mmol), potassium fluoride (0.45 g, 7.77 mmol), phenylboronic acid (189.5 mg, 1 .55 mmol) in anhydrous tetrahydrofuran (13mL) for 15 min, and add {[2-(4-bromo- 2-isopropylphenoxy)ethyl]-methylamino}-acetic acid tert-butyl ester (0.5 g, 1.29 mmol). Heat to 70 °C overnight under nitrogen. Add extra equivalents of tricyclohexylphosphine (43 rng, 0.15 mmol), palladium acetate (29 mg, 0.13 mmol), potassium fluoride (225 mg, 3.87 mmol), phenylboronic acid (95 mg, 0.77 mmol), and heat to 70 0C for 1 h under nitrogen. Cool to room temperature, filter inorganics, concentrate and purify (ion exchange chromatography, eluting with 2 M ammonia in methanol, followed by Isco automated chromatography, eluting with solvent gradient 0:100 to 20:80 ethyl acetate: cyclohexane) to give the title compound (311 mg, 63%). LC-MS: m/z 384.4

Preparation 117 {[2-C5-Bromo-2'-chlorobiphenyl-2-yloxy)ethyI]-methylamino}-a cetic acid tert-butyl ester

2'-Chloro-2-methoxybiphenyI Stir a mixture of 2-(dicyclohexylphosphino)-2-2'-methylbiphenyl (1.49 g, 4.10 mmol), palladium acetate (765.7 mg, 3.42 mmol), potassium fluoride (6.5 g, 112.8 mmol), 2-chlorophenylboronic acid (189.5 mg, 1.55 mmol) in anhydrous 1,4-dioxane for 15 min, and add 2-iodoanisole (4 g, 17.1 mmol). Heat to 110 0C overnight under nitrogen. Add extra equivalents of 2-(dicyclohexylphosphino)-2-2'-methylbiphenyl (4 g, 2.05 mmol), palladium acetate (382.9 mg, 1.71 mmol), potassium fluoride (3.25 g, 56.1 mmol), 2-chlorophenylboronic acid (1.6 g, 10.3 mmol) in anhydrous 1 ,4-dioxane, and heat to 70 0C overnight under nitrogen. Add extra equivalents of palladium acetate (382.9 mg, 1.71 mmol), potassium fluoride (3.25 g, 56.1 mmol), 2-chlorophenylboronic acid (1.6 g, 10.3 mmol) in anhydrous 1,4-dioxane, and heat to 1100C for 3 days under nitrogen. Cool to room temperature, filter inorganics, concentrate and purify (Isco automated chromatography, eluting Λvith 0:100 to 15:85 ethyl acetatexyclohexane) to give the title compound as a black oil (3.595 g, 96%). GC-MS: 218

5-Bromo-2'-chIoro-2-methoxybiphenyI Add a solution of bromine (0.41 mL, 8.0 mmol) in chloroform (5 mL) to T- chloro-2-methoxybiphenyl (3.52 g, 16.1 mmol) in chloroform (30 mL) at 60 0C under nitrogen. Continue to heat at 60 0C. After 3 h add extra equivalent of bromine (0.41 mL, 8 mmol) in chloroform and continue to heat for 1 h under nitrogen. Cool to room temperature and quench with water (35 mL). Separate two phases and further wash chloroform layer with water, collect the chloroform layer through a phase frit. Concentrate and purify (automated Isco chromatography, eluting with solvent gradient 0:100 ethyl to 10:90 acetatexyclohexane) to give the title compound as a yellow liquid (2.75 g, 57%). GC-MS: 296/ 298

5-Bromo-2'-chIorobipheαyl-2-ol Stir a solution of boron tribromide (1 M in dichloromethane, 10.2 mL, 10.2 mmol) in dichloromethane at 0 0C and add 5-bromo-2'-chloro-2-methoxybiphenyl (2.75 g, 9.24 mmol) under nitrogen. Stir at 0 0C for 4 h and quench with ice water (-10 mL). Separate the two layers and further wash aqueous layer with dichloromethane. Concentrate and purify (automated Isco chromatography, eluting with 0:100 to 30:70 ethyl acetatexyclohexane) to give the title compound as a yellow oil (1.80 g, 69%). GC-MS: 282/ 284 {[2-(5-Bromo-2'-chIorobipheMiyl-2-yloxy)ethyI]-inethylamino} -acetic acid tert-butyl ester Stir amixture of 5-bromo-2'-chlorobiphenyl-2-ol (1.80 g, 6.34 mmol), 1,1 '- (azodicarbonyl)-dipiperidine (3.20 g, 7.62 mmol), [(2-liydroxyethyl)-methylamήio]-acetic acid tert-butyl ester (1.44 g, 7.62 mmol) in anhydrous tetrahydrofuran (20 niL) for 15min5 and add tri-n-butylphosphine (3.17 mL, 12.68 mmol). Heat to 70 0C for 1.5 h and cool to room temperature. Concentrate and add cyclohexane to residue and filter the white precipitate. Wash precipitate with cyclohexane. Combine filtrate, concentrate arid purify (automated Isco chromatography, eluting with solvent gradient 0:100 to 40:60 ethyl acetate: cyclohexane ) to give the title compound as a yellow oil (2.73 g, 94%). LC-MS: m/z 454.0/ 456.0

General Procedure for Rapid Parallel Synthesis: Preparation 118 {[2-(2M-Chloro-3-fluoro-[l,l';3',l"]terphenyl-4'-yloxy)ethyl ]-methylamino>-acetic acid tert-butyl ester

Treat a stirring mixture of potassium fluoride (6.6 eq), palladium acetate (O.20 eq) and tricyclohexylphosphine (0.24 eq) in tetrahydrofuran (2 mL) at room temperature with a solution of 3-fluorophenylboronic acid (58.8 mg, 0.422 mmol, 1.2 eq) in 1,4-dioxane (0.5 mL). After 15 min, add a stock solution of {[2-(5-bromo-2'-chlorobiphenyl-2- yloxy)ethyl]-methylamino} -acetic acid tert-butyl ester prepared as described in Preparation 117 (160 mg, 0.35 rnmol, 1 eq) in 1,4-dioxane. Heat the reaction to 1 10 0C overnight in a Greenhouse™ reaction vessel containing consisting of 24 tubes each with a total volume of about 3.5 mL of solvent. Add extra potassium fluoride (3.3 eq), palladium acetate (0.1 eq), tricyclohexylphosphine (0.12 eq), and 3-fluorophenylboronic

acid (0.6 eq) and heat the reaction mixture for a further 5 h. Allow the reactions to cool

to room temperature. Filter the inorganics through a Whatman Filtertube (5 μm), and

further wash with 1,4-dioxane (2 x 1 niX). Concentrate the solvent in a Reacti-Therm™

under a stream of nitrogen with heat, take up the residue in methanol and purify (ion

exchange chromatography, eluting with. 2 M ammonia in methanol) to give the title

compound (152.6 mg, 93%).

LC-MS: m/z 470.1

The compounds of Preparations 119-130 may be prepared essentially as described

as Preparation 118 using the appropriate boronic acids.

General Procedure for Rapid Parallel Synthesis:

Preparation 131 {[2-(3,2M-Dichloro-[l,l';3',l"]terphenyl-4'-yloxy)ethιyl]-m ethylamino}-acetic acid tert-butyl ester

Treat a stirring mixture of potassium fluoride (6.6 eq), palladium acetate (0.20 eq) and tricyclohexylphosphine (0.24 eq) in tetrahydrofuran (11 mL) at room temperature with a solution of 3-chlorophenylboronic acid (206.4 mg, 1.32 mmol, 1.2 eq) in 1,4- dioxane (0.5 mL). After 15 min, add a stock solution of {[2-(5-bromo-2'~chlorobiphenyl- 2-yloxy)ethyl]-methylamino} -acetic acid tert-butyl ester (0.5 g, 1.10 mmol, 1 eq) in tetrahydrofuran. Heat the reaction to 70 0C overnight in a 6-position carousel reaction vessel containing containing a total volume of 11.0 mL of solvent. Add extra potassium fluoride (3 eq), palladium acetate (0.1 eq), tricyclohexylphosphine (0.12 eq), and 3- chlorophenylboronic acid (0.6 eq) and heat the reaction mixture overnight at 70 0C. Cool to room temperature over the weekend. Add extra potassium fluoride (3 eq), palladium acetate (0.1 eq), tricyclohexylphosphine (0.12 eq), and 3-chlorophenylboronic acid (0.6 eq) and heat the reaction mixture overnight at 70 0C. Allow the reactions to cool to room temperature. Filter the inorganics through a Whatman Fϊltertube (5 μm), and further wash with tetrahydrofuran (2 x 5 mL). Concentrate and purify (ion exchange chromatography, eluting with 2 M ammonia in methanol) to give the title product (473 mg, 89%). LC-MS: m/z 486.2/ 488.2

The compounds of Preparations 132-136 may be prepared essentially as described as Preparation 131 using the appropriate boronic acids.

General Procedure for Rapid Parallel Synthesis:

Preparation 137

{[2-(3-tert-Butyl-2'-fluorobiphenyl-4-yloxy)ethyl]-rnethy lamino}-acetic acid tert-

butyl ester

Stir a mixture of potassium fluoride (6.6 eq), palladium acetate (0.20 eq),

tricyclohexylphosphine (0.24 eq) and 2-fluorophenylboronic acid (167.88 mg, 1.20 mmol,

1.2 eq) in 1,4-dioxane for 20 min and add a stock soluti&n of { [2-(4-bromo-2-tert-

butylphenoxy)ethyl]-methylamino}-acetic acid tert-butyl ester prepared as described in

Preparation 164 (0.4 g, 1.00 mmol, 1 eq) in 1,4-dioxane. Heat the reaction to 110 0C for 2

days in a 6-position carousel reaction vessel containing containing 11.0 mL of solvent.

Add extra potassium fluoride (6eq), palladium acetate (0_2 eq), tricyclohexylphosphine

(0.24 eq), and 2-fluorophenylboronic acid (1.2 eq) and heat the reaction mixture for 5 h at

110 0C. Allow the reactions to cool to room temperature . Filter the inorganics through a

Whatman Filtertube (5 μm), and further wash with 1,4-dioxane (5 mL). Dilute with

methanol (3 mL) and purify (ion exchange chromatograpliy, eluting with 2 M ammonia in methanol, followed by ion exchange chromatography, collecting noneluting product) to

give the title product (260 mg, 63%)

LC-MS: m/z 416.4

The compounds of Preparations 138-147 may be prepared essentially as described

as Preparation 137 using the appropriate boronic acids.

General Procedure for Rapid Parallel Synthesis:

Preparation 148

({2-[3-(2,2-Dimethylpropyl)-2'-fluorobiphenyl-4-yloxy]etI iyl}-methyIamiMθ)-acetic

acid tert-butyl ester Stir a mixture of potassium fluoride (6.6 eq), palladium acetate (0.20 eq), tricyclohexylphosphine (0.24 eq) and 2-fluorophenylboronic acid (181.87 mg, 1.30 mmol, 1.2 eq) in 1,4-dioxane (1OmL) for 15 min and add a stock solution of ({2-[2-(2,2- dimethylpropyl)-4-iodophenoxy] ethyl }-methylamino)-acetic acid tert-butyl ester prepared as decribed in Preparation 179 (0.5 g, 1.08 mmol, 1 eq) in 1,4-dioxane (ImL). Heat "the reaction to 110 0C overnight in a 6-position carousel reaction vessel containing a total volume of 11.0 mL of solvent. Add extra potassium fluoride (3 eq), palladium aceta~te (0.1 eq), tricyclohexylphosphine (0.12 eq), and 2-fluorophenylboronic acid (0.6 eq) and heat the reaction mixture for 4 days at 110 0C. Add extra potassium fluoride (3 eq), palladium acetate (0.1 eq), 2-(dicyclohexylphosphino)-2'-methylbiphenyl (0.24 eq), and 2-fluorophenylboronic acid (0.6 eq) and heat the reaction mixture overnight at 110 0C Allow the reactions to cool to room temperature. Filter the inorganics through a Whatman Filtertube (5 μm), wash with methanol (2 x 2 mL) and purify (ion exchange chromatography, eluting with 2 M ammonia in methanol) to give the title compound (445 mg, 96%). LC-MS: m/z 430.4

The compounds of Preparations 149-157 may be prepared essentially as described as Preparation 148 using the apprpriate boronic acids.

Preparation 158 {[2-(3-tert-ButyI-3',5'-difluoro-4'-methoxybiphenyl-4-yloxy) ethyl]-methylamino}- acetic acid tert-butyl ester

Stir a mixture of ({2-[2-tert-butyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan -2- yl)-phenoxy] ethyl }-methylamino)-acetic acid tert-butyl ester prepared essentially as decribed in Preparation 180 (0.4 mg, 0.89 rnmol, leq), potassium phosphate (5 eq) and [l,l'bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.1 eq) in 1,2- dimethoxyethane for 15 min at room temperature under nitrogen and add 4-bromo-2,6- difluoroanisole (1.5 eq) in 1,2-dimethoxyethane. Heat to reflux over night under nitrogen. Add extra 4-bromo-2,6-difluoroanisole (0.75 eq), potassium phosphate (2.5 eq) and [l,rbis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.05eq) in 1,2- dimethoxyethane (5 mL) and heat for a further 24 h. Cool to room temperature, filter inorganics on Celite® washing with methanol and concentrate. Take up residue in methanol and purify (ion exchange chromatography, eluting with 2 M ammonia in methanol, followed by automated Isco chromatography, eluting with solvent gradient 0:100 to 30:70 cyclohexane: ethyl acetate) to give the title compound as a oil (123 mg,

LC-MS: m/z = 464.2

Preparation 159 ({2- [3-(2,2-Dimethylpropyl)-biphenyl-4-yloxy] ethyl}-methylamino)-acetic acid tert- butyl ester

l-(4-Methoxybiphenyl-3-yl)-2,2-dimethylpropan-l-ol Add a solution of sec-butyllithium (1.4 M in cyclohexane, 232 mL, 0.325 mol) to a cooled stirred solution of 4-methoxybiphenyl (50.0 g; 0.271 mol) in dry tetrahydrofuran (1400 mL) maintaining the temperature at -50 0C. Stir at this temperature for about 45min, remove the cooling bath and allow the mixture to warm up to -30 0C prior to cooling again to -50 0C. Add trimethylacetaldehyde (45.6 mL, 0.420 mol) dropwise. Remove the cooling bath and allow the mixture to warm to 0 0C. Quench with a saturated solution of ammonium chloride (400 mL), then water (400 mL). Dilute with ethyl acetate (500 mL) and partition the phases. Wash the organic phase with water (600 mL), saturated aqueous sodium chloride (300 mL), dry (magnesium sulfate), filter and concentrate. Purify by chromatography (silica gel chromatography, eluting with 1:19 to 10:90 diethyl ether: 2-methylρentane) to give the title compound (80 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 7.56-7.53 (m, 3H), 7.48-7.38 (m, 3H), 7.32-7.27 (m, IH), 6.94 (d, J = 8.5 Hz, IH), 4.78 (d, J = 5.5 Hz5 IH), 3.85 (s, 3H), 2.60 (d, J = 5.5 Hz, IH), 0.97 (s, 9H)

3-(l-ChIoro-2,2-dimethylpropyl)-4-methoxybiphenyl Add thionyl chloride (18.9 mL, 259 mmol) dropwise to a solution of l-(4- methoxybiphenyl-3-yl)-2,2-dimethyl-propan-l-ol (35.0 g, 129 mmol) in dichloromethane (850 mL) and triethylamine (36.0 mL, 259 mmol) at 0 0C (J. Org. Chem., 66, 954-961, (2001)). Stir at 0 0C for 30 min and then at reflux for 1 h. Pour the mixture over ice (500 g) and water (500 mL), dilute with dichloromethane (1 L) and separate the organic layer. Dry (magnesium sulfate), filter through a pad of silica, washing the pad well with additional dichoromethane. Concentrate to give the title compound as an orange solid (34.2 g, 91%). 1H NMR (CDCl3) δ 7.76 (d, J = 2.2 Hz, IH), 7.57-7.53 (m, 2H)5 7.48-7.39 (m, 3H), 7.34- 7.28 (m, IH), 6.91 (d, J = 8.6 Hz, IH)5 5.49 (s, IH), 3.86 (s, 3H), 1.06 (s, 9H)

3-(2,2-Dimethylpropyl)-4-methoxybiphenyl Add 2,2'-azobisisobutyronitrile (0.725 g, 4.415 mmol) and tributyltin hydride (15.83 niL, 58.86 mmol) to a solution of 3-(l-chloro-2,2-dimethylproρyl)-4- methoxybiphenyl (8.5 g, 29.43 mmol) in toluene (676 mL) and stir at reflux for 3 h. Pour over ice, dilute with ethyl acetate (1 L) and wash with water (200 mL). Dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 100% hexanes) to give the title compound as an amber pale yellow oil contaminated with tin residues which is used directly without further purification in the next step (15 g). 1H NMR (CDCl3) δ 7.57-7.52 (m, 2H), 7.44-7.35 (m, 3H), 7.31-7.25 (m, 2H), 6.92 (d, J = 8.5 Hz, IH), 3.82 (s, 3H), 2.61 (s, 2H), 0.94 (s, 9H)

3-(2,2-Dimethylpropyl)-biphenyl-4-ol Add sodium ethane thiolate (6.61 g, 78.641 mmol) to a solution of 3-(2,2- dimethylpropyl)-4-methoxybiphenyl (8 g, 31.456 mmol) in N,N-dimethylformamide (157.28 mL) and keep at 110 0C for 4 h. Cool to room temperature, dilute with ethyl acetate (200 mL), wash with water (3 x 100 mL), saturated aqueous sodium chloride (1 x 100 mL), dry (sodium sulfate), filter and concentrate, purify (HPLC, eluting with 10:90 ethyl acetate:hexanes) to give the title compound as pale yellow oil (6.59 g, 87%). 1H NMR (400 MHz, CDCl3) δ 7.53-7.50 (m, 2H), 7.40-7.37 (m, 2H), 7.32-7.25 (m, 3H), 6.88 (d, J = 8 Hz, IH), 4.75 (s, IH), 2.57 (s, 2H), 0.97 (s, 9H)

({2-[3-(2,2-Dimethylpropyl)-biphenyl-4-yloxy]ethyl}-methy lamino)-acetic acid tert- bufyl ester Add l,r-(azodicarbonyl)-dipiperidine (13.87 g, 54.97 mmol), [(2-hydroxyethyl)- methylamino] -acetic acid tert-butyl ester (10.37 g, 54.84 mmol) in tetrahydrofuran (20 mL) and neat tri-n-butylphosphine (13.5 mL, 54.71 mmol) to a solution of 3-(2,2- dimethylpropyl)-biphenyl-4-ol (6.59 g, 27.41 mmol) in tetrahydrofuran (100 mL). Stir at reflux overnight and let cool to room temperature. Filter off the precipitate of 1,1 '- (azodicarbonyl)-dipiperidme-2H and wash the residue with hexanes, dilute with ethyl acetate, wash with water, dry (sodium sulfate), filter, concentrate and purify (twice by HPLC, eluting with 15:85 ethyl acetate :hexanes) to give the title compound (5.65 g, 50%). 1H NMR (400 MHz, CDCl3) δ 7.53-7.50 (m, 2H), 7.39-7.35 (m, 3H), 7.29-7.23 (m, 2H), 6.89 (d, J = 9.2 Hz, IH), 4.09 (t, J = 6 Hz, 2H,), 3.32 (s, 2H), 3.03-3.00 (m, 2H)5 2.59 (s, 2H), 2.51 (s, 3H)5 1.45 (s, 9H), 0.86 (s, 9H); LC-MS: m/z = 412.0, 434.0 Preparation 160 ({2-[3-(2)2-Dimethylpropionyl)-biphenyl-4-yloxy]ethyl}-methy Iamino)-acetic acid tert-butyl ester

l-(4-Methoxybiphenyl-3-yl)-2,2-dimethylpropan-l-ol Add dropwise over 20 min at 0 0C (ice bath) a solution of tert-butylmagnesium chloride (20% wt solution ~0.17 M, 7.99 mmol, 47 mL, 1.5 eq) to a solution of 4- methoxybiphenyl-3-carbaldehyde (1.126 g, 5.33 mmol) in tetrahydrofuran (dry, 20 mL). Stir overnight at room temperature. Quench by adding water dropwise (5 mL) and dilute with dichloromethane (20 mL). Separate via a phase separator cartridge and concentrate to give the title compound which is used directly in the next step without further purification (1.082 g). GC-MS: 270 [M].

l-(4-Methoxybiphenyl-3~yl)-2,2-dimethylpropan-l-one Add manganese dioxide (53.28 mmol, 4.63 g) to a solution of l-(4- methoxybiphenyl-3 -yl)-2,2-dimethylpropan- 1 -ol ( 1.082 g, ~5.33 mmol) in toluene (dry, 50 mL) and heat to 80 0C under nitrogen overnight. Add an excess of manganese dioxide (4.65 g, 53.3 mmol) after 24 h and stir overnight. Filter the solids through a wet Celite® pad and concentrate to give the title compound as a white solid which is is used directly in the next step without further purification (759 mg). 1H NMR (300 MHz, CDCl3): δ 7.49-7.44 (m, 3H), 7.37-7.32 (m, 2H), 7.27-7.21 (IH, m), 7.18 (d, J = 1.7 Hz, IH)5 6.90 (d, J = 8.6 Hz, IH), 3.77 (s, 3H), 1.18 (s, 9H); GC-MS: 268

l-(4-Hydroxybiphenyl-3-yl)-2,2-dimethylpropan-l-one Add at —78 0C a solution of boron tribromide (I M solution in dichloromethane, 4.1 mmol, 4.1 mL, 1.2 eq) to a solution of l-(4-methoxy-biphenyl-3-yl)-2,2-dimethyl- propan-1-one (0.912 g, 3.40 mmol) in dichloromethane (50 mL). Monitor the evolution of the reaction by thin layer chromatography and after 30 min pour the reaction mixture onto ice and wash the organic phase with water, dry (magnesium sulfate), filter and concentrate to give the title compound which crystallizes on standing (0.607 g, 43% over 3 steps). 1H NMR (300 MHz, CDCl3) δ 12.65 (s, IH), 8.23 (d, J = 2.26 Hz5 IH)5 7.66 (dd, J - 2.26 Hz5 J = 8.66 Hz5 IH)5 7.53-7.31 (m5 5H), 7.09 (d, J = 8.66 Hz, IH), 1.51 (s, 9H)

({2- [3-(2,2-Dimethylpropionyl)-biphenyl-4-yloxy] ethyl}-methylamino)-acetic acid tert-butyl ester Add l,l'-(azodicarbonyl)-dipiperidine (3.50 mmol, 0.883 g), a solution of [(2- hydroxyethyl)-meώylamino]-acetic acid tert-butyl ester (3.5 mmol, 0.662 g) in tetrahydrofuran (30 mL) and neat tri-n-butylphosphine (3.50 mmol, 0.88 mL) to a solution of l-(4-hydroxybiphenyl-3-yl)-2,2-dimethylpropan-l -one (2.33 mmol, 0.593 g) in dry tetrahydrofuran (20 mL). Leave stirring at 65 0C overnight, then add an excess of [1 ,r-(azodicarbonyl)-dipiperidine (3.6 mmol, 0.907 g) and tri-n-butylphosphine (3.50 mniol, 0.88 mL) and monitor by Flow Injection Analysis (FIA) and LC-MS. Add a third excess of [l5r-(azodicarbonyl)-dipiperidine (3.6 mmol, 0.90 g), tri-n-butylphosphine (3.50 mmol, 0.88 mL) and [(2-hydroxyethyl)-methylamino]-acetic acid tert-butyl ester (3.5 mmol, 0.662 g) in tetrahydrofuran (1 mL) and leave stirring overnight at 65 0C. Concentrate, filter off the l,r-(azodicarbonyl)-dipiperidine-2H, and wash the residue with cyclohexanes. Combine the organic phases, concentrate and purify (silica gel chromatography, eluting with 5:95 to 40:60 ethyl acetate :cyclohexane) to give the title compound as a clear oil (0.867 g, 87%). 1HNMR (300 MHz, CDCl3) δ 7.54-7.51 (m, 3H), 7.41 (t, J = 7.8 Hz, 2H), 7.32 (t, J = 7.3 Hz, IH), 7.23 (d, J = 2.45 Hz, IH), 6.97 (d, J = 8.8 Hz, IH), 4.12 (t, J = 6.1 Hz, 2H)5 3.25 (s, 2H), 2.96 (t, J = 6.1Hz, 2H)5 2.46 (s, 3H), 1.49 (s, 9H)5 1.25 (s, 9H)

Preparation 161 {[2-(5-Benzoyl-2-methoxybiphenyl-4-yloxy)ethyl]-methylamino} -acetic acid tert- butyl ester

{[2-(2-Benzoyl-4-bromo-5-methoxyphenoxy)ethyl]-methylamin o}-acetic acid tejrt- butyl ester Add 1,1 '-(azodicarbonyl)-dipiperidine (1.025 mmol, 0.258 g), [(2-hydroxyethyl)- methyl-amino] -acetic acid tert-butyl ester (1.025 mmol, 0.194 g) in tetrahydrofuran (5 mL) and neat tri-n-butylphosphine (1.025 mmol, 0.25 mL) to a solution of (5-bromo-2- hydroxy-4-methoxyphenyl)-phenylmethanone (0.68 mmol, 0.209 g) in tetrahydrofuran (10 mL). Heat at 60 0C overnight. Concentrate and take up the residue in cyclohexane, filter off l,l'-(azodicarbonyl)-dipiperidine-2H and purify (ion exchange chromatography and then silica gel chromatography, eluting with 20:80 to 60:40 ethyl acetatexyclohexane) to give the title compound contaminated with [(2-hydroxyethyl)- methylamino]-acetic acid tert-butyl ester (85 mg). Take the mixture onto the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.73 (dd, J= 1.5 Hz, J=7 Hz, 2H), 7.66 (s, IH), 7.53 (t, J=7.3 Hz, IH), 7.41 (t, J=7.3 Hz, 2H), 6.55 (s, IH), 4.00 (t, J=5.84 Hz, 2H), 3.95 (s, 3H), 2.99 (s, 2H), 2.54 (t, J= 5.84 Hz, 2H), 2.23 (s, 3H), 1.43 (s, 9H); LC-MS: 478.3, 480.3

{[2-(5-Benzoyl-2-methoxybiphenyI-4-yloxy)ethyl]-methyIami no}-acetic acid tert- butyl ester Add palladium acetate (0.1 eq; 0.0178 mmol, 4 mg), tricyclohexylphosphine (0.12 eq; 0.0213 mmol, 6 mg), phenyl boronic acid (0.266 mmol, 1.5 eq; 33 mg) and potassium fluoride (0.586 mmol, 3.3 eq; 34 mg) to a solution of {[2-(2-benzoyl-4-bromo-5- methoxyphenoxy)ethyl]-methylamino}-acetic acid tert-butyl ester (0.177 mmol, 85 mg) in tetrahydrofuran (dry, 5 mL). Leave stirring at 65 0C overnight and add more palladium acetate (0.3 eq; 12 mg), tricyclohexylphosphine (0.36 eq; 18.6 mg), phenyl boronic acid (0.266 mmol, 1.5 eq; 33 mg) and potassium fluoride (0.586 mmol, 3.3 eq; 34 mg). Monitor the reaction by LC-MS. After 1 h, stop the reaction and concentrate. Take up the residue in dichloromethane (30 mL) and wash the organic phase with water. Wash the aqueous phase with dichloromethane (30 mL), combine the organic phases and concentrate. Take up the residue in methanol (10 mL) and purify by ion exchange chromatography to give the title compound which is used directly in the next step without further purification (71 mg, -85% pure). 1H NMR (300 MHz, CDCl3) δ 7.79-7.76 (m, 2H), 7.54-7.47 (m, 4H), 7.43-7.26 (m, 5H), 6.61 (s, IH), 4.07 (t, J=5.84 Hz, 2H)5 3.87 (s, 3H), 3.01 (s, 2H), 2.59 (t, J= 5.84 Hz, 2H), 2.26 (s, 3H), 1.44 (s, 9H)

Preparation 162 {Methyl- [2-(3-phenylsulfanylbiphenyl-4-yloxy)ethyl]-amino}-acetic acid tert-butyl ester

4-Methoxy-3-phenylsuIfanylbiphenyl Add a solution of 4-rnethoxybiphenyl (19.9 mmol, 3.66 g) in tetrahydrofuran (dry, 30 mL) at -20 0C drop wise (exothermic reaction) to a stirred mixture of N,N,N',N'- tetramethylethylenediamine (25 mmol, 3.77 mL) and butyllithium (2.5M in hexanes, 26 mmol, 10.4 mL). Add a solution of phenyl disulfide (22 mmol, 4.80 g) in tetrahydrofuran (dry, 20 mL after 30 min). Leave stirring 2 h 45 min, quench with water (5 mL) and observe a rapid discoloration of the solution. Warm to room temperature and partition the two phases. Dilute the organic phase with ethyl acetate (50 mL), wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetatexyclohexane) to give the title compound (1.939 g, 33%). 1HNMR (300 MHz5 CDCl3) δ 7.56 (d, J = 2.4 Hz, IH), 7.48 (d, J = 7.3 Hz, 2H), 7.34 (t, J = 7.3 Hz, 2H), 7.32-7.26 (m, IH), 7.18 (t, J = 7.3 Hz, IH), 7.09-7.00 (m, 5H), 6.44 (d, J = 8.3 Hz, IH), 3.84 (s, 3H)

3-Phenylsulfanylbiphenyl-4-ol Dispatch a solution of 4-methoxy-3-phenylsulfanylbiphenyl (6.07 mmol, 1.77 g) in N,N'-dimethylformamide (dry 16 mL) in equal amounts (4 mL) to 4 microwave reaction vessels containing sodium thiomethoxide (15.15 mmol, 10 eq; 1.06 g per reaction vessel). Seal the reaction vessels and microwave the solution at 110 0C with a run time of 5 min; hold time of 10 min and power set at 150 W with a maximum pressure set at 300 psi. Submit the reaction vessels to a second run, using the same conditions, after which the methoxy analogue could not be detected by GC-MS analysis. Filter off the solids and wash withN,N'-dimethylformamide (2 x 20 mL). Combine the solutions and concentrate in vacuo. Add acetone to remove the remaining sodium thiomethoxide and filter. Concentrate and purify (silica gel chromatography, eluting with 20:80 to 60:40 ethyl acetate :cyclohexane) to give title compound (1.336g, 79%). GC-MS: 278

{Methyl- [2-(3-phenylsulfanylbipheπtyl-4-yloxy)ethyI]-amino}-acetic acid tert-butyl ester Add [(2-hydroxyethyl)-methylamino]-acetic acid tert-butyl ester (2.94 mmol, 0.557 g), l,r-(azodicarbonyl)-dipiperidine (2.92 mmol, 0.738 g) and tri-n- butylphosphine (2.92 mmol, 0.73 mL) to a solution of 3-phenylsulfanylbiphenyl-4-ol (1.94 mmol, 0.54 g) in tetrahydrofuran (dry, 30 mL). Upon addition heat the reaction to about 65 0C for 1 h. Cool to room temperature, filter off the precipitate of 1,1'- (azodicarbonyl)-dipiperidine-2H, wash with cyclohexane (50 mL), concentrate and purify (ion exchange chromatography, then silica gel chromatography, eluting with 15:85 to 40:60 ethyl acetatexyclohexane) to give the title compound (0.706 g, 81%). 1H NMR (300 MHz, CDCl3) δ 7.93-7.23 (m, 12H), 6.97 (d, J = 8.5 Hz, IH)5 4.16 (t, J = 5.8 Hz, 2H), 3.27 (s, 2H), 2.92 (t, J = 5.8 Hz, 2H)5 2.46 (s, 3H), 1.46 (s, 9H); LC-MS: m/z = 450.5, 472.5

Preparation 163 {[2-(3-Isobutyrylbiphenyl-4-yloxy)ethyl]-methyIamino}-acetic acid tert-butyl ester

4-Methoxybiphenyl-3-carbaldehy de Add palladium acetate (0.05 eq; 0.512 g), tricyclohexylphosphine (0.06 eq; 780 mg), phenylboronic acid (50 mtnol, 6.12 g) and potassium fluoride (152 mmol, 3.3 eq; 8.8g) to a solution of 5-bromo-2-methoxybenzaldehyde (46 mmol, 10 g) in tetrahydrofuran (dry, 150 mL). Stir at 65 0C and add after 24 h more palladium acetate (512 mg), tricyclohexylphosphine (780 mg), phenylboronic acid (3.1 g) and potassium fluoride (4.4 g). Monitor the reaction by LC-MS. After 12 h, stop the reaction, add water, and extract the aqueous phase with ethyl acetate. Flush the organic layer through a plug of silica gel to obtain a yellow oil and purify by Isco automated chromatography, eluting with 20:80 to 80:20 ethyl acetate xyclohexane to give the title compound (6.3 g, 65%). LC-MS: w/z = 213, 235

1 -(4-Methoxybiphenyl-3-yl)-2-methylpropan- 1 -ol Add a solution of isopropylmagnesium chloride (15 mmol, 15 mL) to a solution of the 4-methoxybiphenyl-3-carbaldehyde (10 mmol, 2.12 g) in tetrahydrofuran (30 mL). After 2 h, add an excess of reagent (5 mmol) and stir for 2 h. Quench with saturated aqueous sodium chloride, extract the aqueous layers with ethyl acetate, Dry (magnesium sulfate), filter, concentrate and purify (Isco automated chromatography, eluting with 5:95 to 50:50 ethyl acetate:cyclohexane) to give the title compound as a yellow oil (1.3 g). GC-MS: m/z = 256

l-(4-Methoxybiphenyl-3-yl)-2-methyIpropan-l-one Add manganese dioxide (51 mmol, 864 mg) to a solution of l-(4-methoxy- biphenyl-3-yl)-2-methylpropan-l-ol (5.1 mmol, 1.3 g) in toluene (75 mL). Stir at reflux for 18 h. Filter the manganese residues through a plug of Celite® and concentrate to give the ketone product contaminated with the alcohol (~1 : 1). Add more manganese dioxide (1.2 g) and stir at reflux for 48 h. Add more manganese dioxide (0.6 g) and stir overnight. Filter the manganese residues through a plug of Celite® and concentrate to give the title compound yellow oil (0.6 g, 45%). 1H NMR (300 MHz5 CDCl3) δ 7.75 (d, J = 2.4 Hz, IH), 7.66 (dd, J = 2.4Hz, J = 8.8 Hz, IH), 7.56 (d, J - 7.3 Hz, 2H), 7.42 (t, J = 7.3 Hz, 2H), 7.32 (t, J = 7.3 Hz, IH), 7.02 (d, J = 8.8 Hz, IH), 3.92 (s, 3H), 3.55-3.47 (m, IH), 1.17 (d, J = 6.8 Hz, 6H)

l-(4-Hydroxybiphenyl-3-yI)-2-methyIpropan-l-one Add at —78 0C a solution of boron tribromide (I M solution in dichloromethane, 2.6 mmol, 2.6 mL) to a solution of l-(4-methoxybiphenyl-3-yl)-2-methylpropan-l-one (2.36 mmol, 0.6 g) in dichloromethane (10 mL). Monitor the evolution of the reaction by thin layer chromatography and after 3 h, add ice and wash the organic phase with saturated aqueous sodium chloride. Extract the aqueous layer with dichloromethane then ethyl acetate. Combine the organic phases, dry (magnesium sulfate), filter and concentrate to give the title compound which is used directly in the next step without further purification (0.6 g). 1H NMR (300 MHz, CDCl3) δ 12.51 (s, IH), 7.97 (d, J = 2.1Hz, IH), 7.70 (dd, J = 2.3Hz5 J = 8.7Hz, IH), 7.56-7.52 (m, 2H)5 7.49-7.41 (m, 2H)5 7.39-7.32 (m, IH)5 7.02 (d, J = 8.7 Hz, IH)5 3.80-3.63 (m, IH)5 1.29 (d, J = 6.8 Hz5 6H)

{[2-(3-Isobutyrylbiphenyl-4-yloxy)ethyl]-methylammo}-acet ic acid tert-butyl ester Add [(2-hydroxyethyl)-methylamino]-acetic acid tert-butyl ester (5 mmol, 0.94 g), l,r-(azodicarbonyl)-dipiperidine (5 mmol, 1.26 g) and neat tri-n-butylphosphine (5 mmol, 1.35 mL) to a solution of l-(4-hydroxybiphenyl-3-yl)-2-methylpropan-l-one (2.5 mmol, 0.6 g) in tetrahydrofuran. Heat to about 65 0C for 12 h then stir at room temperature for 12 h. Cool to room temperature, add water (50 mL) and ethyl acetate (50 niL). Extract the aqueous layer with ethyl acetate (50 mL), combine the organic phases, dry (magnesium sulfate), filter and concentrate to give a solid. Take up the solid in dichloromethane; triturate with cyclohexane and filter away the precipitate. Concentrate the filtrate and purify by silica gel chromatography, eluting with 5:95 to 60:40 ethyl acetate :cyclohexane) to give the title compound (0.57 g, 56%). LC-MS: m\z = 412

Preparation 164 {[2-(3-tert-Butylbiphenyl-4-yloxy)ethyl]-methylamino}-acetic acid tert-butyl ester

4-Bromo-2-tert-butylphenol Add a solution of tetrabutylammonium tribromide (207 mmol, 100 g) in chloroform (23 O mL) to a solution of 2-tert-butylphenol (207 mmol, 31.9 mL) in chloroform (45 O mL) and stir for 2 hours at RT. Add a solution of 5% aqueous sodium thiosulfate (500 mL), separate the aqueous phase and extract with dichloromethane (400 mL). Wash the combined organic phase with water (250 mL), then saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 100% 2-methylpentane to 1:1 diethyl ether :2- methylpentane) to give the title compound contaminated with trace diethyl ether (47.3 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 2.45 Hz, IH), 7.16 (dd, J = 2.45 Hz, J = 8.4 Hz, IH), 6.55 Cd, J = 8.4 Hz, IH), 1.38 (s, 9H)

{[2-(4-Bromo-2-tert-butylphenoxy)ethyl]-methylamino}-acet ic acid tert-butyl ester Add sequentially [(2-hydroxyethyl)-methylamino] -acetic acid tert-butyl ester (62.7 g, 331 mmol), 1,1 '-(azodicarbonyl)-dipiperidine (110 g, 435 mmol) and tri-n- Butylphosphine (108 mL, 435 mmol) to a solution of 4-bromo-2-tejt-butylpheiiol (69.1 g, 302 mmol) in dry toluene (1500 mL). Heat to 90 °C and stir for 4 h. Cool to 80 °C and pour into rapidly stirring diethyl ether (3000 mL). Stir the mixture for 30 min and filter off the white precipitate. Concentrate the filtrate and purify (silica gel chromatography, eluting with 100% 2-methylpentane to 1:3 diethyl ether:2-methylpentane) to give tiie title compound (97.6 g, 81%). 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 2.45 Hz, IH), 7.27-7.22 (m, IH + CHCl3), 6.74 (d, J = 9.0 Hz, IH), 4.07 (t, J = 6.4 Hz, 2H), 3.28 (s, 2H), 3.02 0, J = 6.4 Hz, 2H), 2.50 (s, 3H), 1.47 (s, 9H)5 1.35 (s, 9H); LC-MS: m\z = 400.1/402.1

{[2-(3-tert-ButyIbiphenyI-4-yloxy)ethyl]-methyIamino}-ace tic acid tert-butyl ester Add 2-phenylboronic acid (3.35 g, 27.48 mmol) and potassium carbonate (62.4 mL) to a solution of {[2-(4-bromo-2-tert-butylphenoxy)ethyl]-methylamino}-acetic acid tert-butyl ester (10.0 g, 27.47mmol), [l,rbis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (6.19 g, 7.49 mmol) dissolved in tetrahydrofuran (250 mX). Heat at 95 °C for 5 h (monitor by LC-MS). Cool to room temperature and filter through a plug of Celite® . Dilute with ethyl acetate (100 mL), and wash with water (50 mL), then saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 7:3 hexanes:ethyl acetate) to give the title compound as a pale yellow solid (7.7 g, 77.54%). HRMS m/z Calculated: 398.2695; Found: 398.2692

The compounds of Preparations 165-168 may be prepared essentially as described in Preparation 164. For Preparation 165, the starting material of 4-bromo-2- trifluoromethoxyphenol may be prepared essentially as described in Can. J. Chem., 67, 2061-2066, (1989). Preparation 169

{[2-(4'-FIuoro-3-thiophen-2-ylmethylb»iphenyl-4-ylosy)et hyl]-methylamino}-acetic

acid tert-butyl ester

Add an aliquot (2 niL, 0.482 mmol) of a solution of {[2-(4-bromo-2-thiophen-2-

ylmethyl-phenoxy)ethyl]-methylamino}-a.cetic acid tert-butyl ester (850 mg, 1.93 mmol)

in tetrahydrofuran (8 mL) to 4-fluorobenzeneboronic acid (101 mg, 0.722 mmol), [1,1'-

bis(diphenylphosphino)-ferrocene)-dicliloropalladium (II) complex (DPPF) (118 mg,

0.144), 2 N aqueous potassium carbonate (1.2 mL, 2.4 mmol) in tetrahydrofuran (2 mL).

Stir at 65 0C for 3.5 h and cool to room temperature. Filter through a wet Celite® pad to

remove the palladium residues, dilute with, ethyl acetate (20 mL), wash with water (2 x 20

mL), saturated aqueous sodium chloride (20 mL), dry (magnesium sulfate), filter,

concentrate and purify (HPLC, eluting with 15:85 to 25:75 ethyl acetate :hexanes) to give

the title compound.

LC-MS: m\z = 456.0

The compounds of Preparations 170-171 may be prepared essentially as described

as Preparation 169 using the appropriate boronic acids.

Preparation 172 {[2-(3-IsobutyI-4'-methoxy-3'-methylbiphenyl-4-yloxy)ethyl]- methylainino}-acetic acid tert-butyl ester

l-(5-Bromo-2-methoxyphenyl)-2-methyIj>ropan-l-ol Add at room temperature a solution of isopropyl magnesium chloride (2 M in tetrahydrofuran, 95 mL, 0.19 mole) to a solution of 5-bromo-2-methoxybenzaldehyde (25.24 g, 0.117 mole) in dry tetrahydrofuran (160 mL) and stir overnight at room temperature under nitrogen. Quench with crushed ice, filter away the salts, concentrate and purify (silica gel chromatography, elutirtg with 2:98 to 20:80 ethyl acetatexyclohexane) to give the title compound (10.89 g, 36%). GC-MS: 258/260

4-Bromo-2-isobutyl-l-methoxybenzene Add triethylsilane (33.3 mL, 5eq) to a solution of l-(5-bromo-2-methoxyphenyl)- 2-methylpropan-l-ol (10.8g, 41.70 mmol) in trifluoroacetic acid (100 mL) and stir overnight. Concentrate, add methanol (2 x 5 O mL), concentrate, take up the rsidue in dichloromethane (100 mL) and wash the organic phase with water (2 x 100 mL) and saturated aqueous sodium chloride (100 mL). Dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with cyclohexane) to give the title compound (5.37 g, 53%). 1H NMR (300 MHz5 CDCl3) 7.25 (dd, J = 2.45 Hz, J = 8.67 Hz5 IH)5 7.19 (J = 2.45 Hz5 IH)5 6.67 (d, J = 8.67 Hz5 IH), 3.78 (s, 3H)3 2.43 (d, J = 7.16 Hz)5 1.95-1.79 (m, IH)5 0.88 (d, J = 6.7 Hz5 6H)

4-Bromo-2-isobutylphenol Treat 4-bromo-2-isobutyl-l-methoxybenzene (5.35 g, 22.01 mmol) with boron tribromide (48 niL) in dichloromethane (50 rnL). Monitor the evolution of the reaction by thin layer chromatography and after 3 h, add ice and wash ttie organic phase with saturated aqueous sodium chloride. Extract the aqueous layer with dichloromethane, then ethyl acetate. Combine the organic phases, dry (magnesium sulfate), filter, and concentrate. Oil crystallising on standing after workup to give the title compound (5.04 g, 97%). 1H NMR (300 MHz5 CDCl3) δ 7.19-7.17 (m, IH)5 7.15 (d, J = 2.4 Hz5 IH)5 6.64 (d, J = 8.3 Hz5 IH)5 4.61 (s, IH)5 2.43 (d, J = 7.2 Hz, 2H5), 2.00-1.82 (rn, IH), 0.93 (d, J = 6.8 Hz, 6H5); LC-MS: m\∑ = 227, 229

{[2-(4-Bromo-2-isobutylphenoxy)ethyl]-methyIamino}-acetic acid tert-butyl ester Add [(2-hydroxyethyl)-methylamino] -acetic acid tert-butyl ester (42.79 mmol, 8.10 g), l,r-(azodicarbonyl)-dipiperidine (42.76 mmol, 10.79 g) and tri-n- butylphosphine (42.83 mmol, 10.7 mL) to a solution of 4-brom.o-2-isobutylph.enol (21.39 mmol, 4.9 g) in tetrahydrofuran (150 mL) and stir 2 h at 65 0C. Cool to room temperature and concentrate. Take up the mixture in cyclohexane (30 mL) and filter away the 1,1'- (azodicarbonyl)-dipiperidine-2H. Concentrate and purify (silica, gel chromatography, eluting with 10:90 to 30:70 ethyl acetate: cyclohexane) to give the title compound (7.3g, 85%).

{[2-(3-Isobutyl-4'-methoxy-3'-methyIbiphenyl-4-yloxy)ethy l]-methylamino}-acetic acid tert-butyl ester Dissolve {[2-(4-bromo-2-isobutylphenoxy)ethyl]-meth>^lamino}-aceti c acid tert- butyl ester (2 g, 4.99 mmol) in dry tetrahydrofuran (20 mL). Deliver an aliquot of this stock solution (4 mL, 0.999 mmol) under nitrogen to a solution in tetrahydrofuran (5 mL) of the appropriate arylboronic acid (1.5 eq), palladium acetate (22 mg, 0.1 eq; 0.099 mmol), tricyclohexylphosphine (34 mg, 0.12 eq; 0.1198 mmol) and potassium fluoride (180 mg, 3.1 eq; 3.098 mmol). Stir at reflux for 66 h. Monitor the progress of the reactions after 66 h and treat each reaction then individually as described. Deliver an aliquot of {[2-(4-bromo-2-isobutylphenoxy)ethyl]-methylamino} -acetic acid tert-butyl ester (0.999 mmol of the stock solution), along with (4-methoxy-3 -methyl) boronic acid (248 mg, 1.4939 mmol, 95% pure), palladium acetate (22 mg), tricyclohexylphosphine (34 mg, 0.12 eq; 0.1214 mmol) and potassium fluoride (180 mg, 3.098 mmol). Add a second aliquot of reagents after 66 h (4-methoxy-3 -methyl) boronic acid (248 mg, 1.4939 mmol), tricyclohexylphosphine (37 mg, 0.1319 mmol), palladium acetate (24 mg) and potassium fluoride (186 mg, 3.20 mmol). Stir for another 24 h. Dilute with tetrahydrofuran (dry, 4 mL) and treat with [l,l'-bis(diphenylphosphino)-ferrocene)- dichloropalladium (II) complex (DPPF) (76 mg, 0.093 eq), 2 N aqueous potassium carbonateaq (5 eq, 2.5 mL) and (4-methoxy-3 -methyl) boronic acid (166 mg) and stir at reflux for 24 h until total consumption of the starting material as indicated by thin layer chromatography and LC-MS. Filter the crude reaction mixture through a "wet Celite® pad, dilute with ethyl acetate (50 mL), wash the organic phase with water (50 mL), dry (magnesium sulfate), filter, concentrate and purify (HPLC, eluting with 10:90 ethyl acetate :hexanes) to give the title compound (302.8 mg, 62%). 1HNMR (400 MHz, CDCl3) δ 7.36-7.32 (m, 3H), 7.28-7.27 (m, IH), 6.8 S (d, J = 8.3 Hz, 2H), 4.13 (m, 2H), 3.87 (s, 3H), 3.36 (s, 2H), 3.05 (t, J = 5.7 Hz, 2H), 2.55-2.53 (m, 5H), 2.29 (s, 3H), 1.96 (q, J = 6.6 Hz, IH,), 1.49 (s, 9H), 0.94 (d, J = 6.6 Hz, 6£L); LC-MS: m\z = 442.0

The compounds of Preparations 173-177 may be prepared essentially as described in Preparation 172 using the appropriate boronic acids. Prep Compound Name & Data ({2-[4-(2,3-Dihydrobenzofuran-5-yl)-2-isobutylplienoxy]ethyl }-n3.ethylammo)- acetic acid tert-butyl ester

1H NMR (400 MHz, CDCl3,) δ 7.38 (broad d, J = 1.3 Hz, IH), 732-7.28 (m, 2H), 173 7.27-7.26 (m, IH), 6.88 (d, J = 8.8 Hz, IH), 6.84-6.82 (d, J = 8.3 Hz, IH,), 4.61 (t, J = 8.8 Hz, 2H), 4.14 (t, J = 5.7 Hz, 2H), 3.36 (s, 3H), 3.27 (t, J = 8.8Hz, 2H,), 3.06 (m, 2H), 2.56-2.53 (m, 5H), 2.06-1.94 (m, IH), 1.49 (s, 9H), 0.93 (d, J = 6.6 Hz, 6H); LC-MS: m\z = 440.0

Preparation 178

({2-[2-(2,2-Dimethylpropyl)-4-iodophenoxy]ethyl}-methylam ino)-acetIc acid tert-

butyl ester

l-(2-Methoxyphenyl)-2,2-dimethylpropan-l-ol Add a solution of tert-butylmagnesium chloride (2.0 M in diethyl ether; 800 niL, 1.6 mol) to a solution of 2-methoxybenzaldehyde (100.0 g, 0.73 mol) in anhydrous diethyl ether (1000 niL) at 0 °C. Allow the solution to warm slowly to room temperature and stir for 60 h. Cool the solution to 0 °C and carefully add saturated aqueous ammonium chloride until no more reaction is evident, then add water (500 mL). Decant the liquid and filter through Celite®. Wash the residue with diethyl ether (3 x 500 mL), filter the combined washings through Celite®. Combine the organic portions, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:40 diethyl ether:2-methylpentane) to give the title compound as a yellow oil (74.0 g, 52%). 1H NMR (300 MHz, CDCl3) δ 7.32-7.19 (2H, m), 6.98-6.85 (2H, m), 4.73 (IH, d, J = 6.0 Hz), 3.81 (3H5 s), 2.61 (IH, d, J = 6.0 Hz), 0.93 (9H, s)

l-(2,2-Dimethylpropyl)-2-methoxybenzene Add a slurry of 10% palladium on carbon (50.0 g) in methanol (1000 mL) to a solution of l-(2-methoxyphenyl)-2,2-dimethylpropan-l-ol (50.0 g, 0.258 mol) in ethyl acetate (750 mL) and hydrogenate the mixture for 90 h (60 psi of hydrogen gas, 50 °C). Filter the reaction mixture through Celite®, wash the filter cake with ethyl acetate (250 mL) and concentrate. Dissolve the residue in diethyl ether (1000 mL) and wash with saturated aqueous potassium carbonate (500 mL), water (500 mL) and saturated aqueous sodium chloride. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with about 1:19 diethyl ether:2-methylpentane) to give the title compound as a clear colorless oil (30.8 g, 67%). 1H NMR (300 MHz, CDCl3) δ 7.21-7.05 (2H, m), 6.90-6.83 (2H, m), 3.78 (3H, s), 2.55 (2H, s), 0.90 (9H, s)

2-(2,2-Dimethylpropyl)-phenol Add boron tribromide (32 mL, 0.337 mol) dropwise to l-(2,2-dimethylpropyl)-2- methoxybenzene (30.0 g, 0.168 mol) in dichloromethane (1000 mL) at about -78 0C. Stir for 10 min, then remove the cooling bath and allow the solution to warm to room temperature. After 16 h pour the mixture onto crushed ice (1000 g), separate the phases and extract the aqueous phase with dichloromethane (500 mL). Dry (magnesium sulfate) and concentrate to give the title compound (26.1 g, 94%). 1H NMR (300 MHz, CDCl3) δ 7.13-7.04 (2H, m), 6.89-6.75 (2H5 m), 4.64 (IH, s), 2.52 (2H, s), 0.95 (9H, s)

2-(2,2-Dimethylpropyl)-4-iodophenol Add sodium iodide (23.9 g, 0.159 mol) and sodium hydroxide (6.36 g, 0.159 mol) to a solution of 2-(2,2-dimethylpropyl)-phenol (26.1 g, 0.159 mol) in methanol (400 mL). Cool the solution to 0 0C and add sodium hypochlorite (4% available chlorine, 300 g) keeping the temperature to about 0 °C. Stir the reaction for a further 70 min at about 1 °C, then add 10% aqueous sodium thiosulphate (400 mL) and acidify the mixture to about pH = 5 with 2 N hydrochloric acid. Extract the mixture with diethyl ether (500 mL, then 300 mL), dry the combined extracts (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 diethyl ether:2-methylρentane) to give the title compound as a brown oil (8.6 g, 28%). 1HNMR (300 MHz, CDCl3) δ 7.39-7.34 (2H, m), 6.56 (1 H, d, J = 9.0 Hz), 4.74 (IH, s), 2.46 (2H, s), 0.94 (9H, s)

({2-[2-(2,2-Dimethylpropyl)-4-iodophenoxyJethyl}-methylam ino)-acetic acid tert- butyl ester Add sequentially, [(2-hydroxyethyl)-methylamino]-acetic acid tert-butyl ester (9.39 g, 50.0 mmol) and l,l'-azodicarbonyl dipiperidine (ADDP) (22.8 g, 90 mmol) to 2- (2,2-dimethylpropyl)-4-iodophenol (13.1 g, 45 mmol) in toluene (220 mL). Rapidly add tributylphosphine (22.5 mL, 90 mmol) and heat to 90 0C for 4 h. Cool the mixture to room temperature, slurry in diethyl ether (700 mL) and stir for 30 min. Filter and concentrate the filtrate. Purify the residue by silica gel chromatography, eluting with 10:90 to 20:80 diethyl ether:2-methylpentane) to give the title compound as a yellow tinted clear oil (16.2 g, 78%). 1H NMR (300 MHz, CDCl3) δ 7.43 (IH, dd, J = 8.6, 2.4 Hz), 7.36 (IH, d, J = 2.4 Hz), 6.61 (IH, d, J = 8.6 Hz), 4.01 (2H, t, J = 6.0 Hz), 3.29 (2H5 s), 2.97 (2H, t, J = 6.0 Hz), 2.50-2.48 (2H, m), 1.46 (9H5 s), 0.89 (9H, s) Preparation 179 ({2-[2-tert-Butyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaboroIan -2-yl)-phenoxy]ethyl}- methylamino)~acetic acid tert-butyl ester

Add bispinicolato diboron (24.4 g, 96.3 mmol) to a solution of {[2-(4-bromo-2- tert-butylphenoxy)ethyl]-methylamino} -acetic acid tert-butyl ester prepared essentially as described in Preparation 164 (35.0 g, 87.5 mmol) in 1,4-dioxane (175 mL). To this mixture add sequentially potassium acetate (25.8 g, 263 mmol), 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium (II), complex with dichloromethane (3.57 g, 4.38 mmol) and 1,1' -bis(diphenylphosphino)ferrocene (2.42 g, 4.38 mmol). Heat to 80 °C and stir for 6. Cool to room temperature, concentrateand purify (silica gel chromatography, eluting with 0:100 to 50:50 diethyl ether:2-methylpentane) to give the title compound as a pale yellow oil (32.3 g, 83%). 1H NMR (400 MHz, CDCl3) δ 7.71 (IH, d, J = 1.5 Hz), 7.64 (IH, dd, J = 1.5, 8.0 Hz), 6.87 (IH, d, J = 8.0 Hz), 4.14 (2H, t, J = 6.4 Hz), 3.30 (2H, s), 3.06 (2H, t, J = 6.4 Hz), 2.50 (3H, s), 1.47 (9H, s), 1.39 (9H, s), 1.32 (12H, s)

Preparation 180 ({2-[2,4-Bis-(l,l-dimethylpropyl)-phenoxy]ethyl}-methylamino )-acetic acid tert- butyl ester

Prepare essentially as described in Preparation 75 using commercially available 2,4-bis-(l , 1 -dimethylpropyl)-phenol. LC-MS: m/z = 406.2

Preparation 181 {Methyl-[2-(3-phenoxymethylbiphenyl-4-yloxy)ethyI]-amino}-ac etic acid ethyl ester

[4-(2-Methylaminoethoxy)~biphenyl-3-yl]-methanol Dissolve [2-(3-hydroxymethylbiphenyl-4-yloxy)ethyl]-methylcarbamic acid tert- butyl ester (10.0 g, 24.4 mmol) in dichloromethane (80 mL). Cool to 0 °C and add portionwise trifluoroacetic acid (10 mL). Warm to room temperature while stirring for 2 h. Dilute with ethyl acetate, wash with 0.5 N sodium hydroxide (twice), dry (potassium carbonate), filter and concentrate. Triturate the residue with diethyl ether and filter to give the title compound as a white solid (5.95 g, 95%).

{[2-(3-Hydroxymethylbiphenyl-4-yloxy)ethyl]-methyIamino}- acetic acid ethyl ester Stir [4-(2-methylaminoethoxy)-biphenyl-3-yl]-methanol in acetonitrile (100 mL) and dichloromethane (50 mL). Add potassium carbonate (7.43 g, 53.8 mmol) and ethyl bromoacetate (2.62 mL, 23.7 mmol) and stir at room temperature for 3 h. Dilute with ethyl acetate and 0.5 N sodium hydroxide, extract with ethyl acetate, combine organic washes, wash with saturated aqueous sodium chloride, dry (potassium carbonate), filter, concentrate and purify (silica gel chromatography, eluting with 10:90 to 1:1 ethyl acetate :hexanes) to give the title compound as a colorless oil (3.94 g, 53%).

{Methyl-[2-(3-phenoxymethylbiphenyl-4-yloxy)ethyl]-amino} -acetic acid ethyl ester Add phenol (0.06 g, 0.66 mmol) to a solution of {[2-(3-hydroxymethylbiphenyl-4- yloxy)ethyl]-methylamino} -acetic acid ethyl ester (0.15 g, 0.44 mmol) in toluene (15 mL). Add l,l'-azodicarbonyl dipiperidine (ADDP) (0.17 g, 0.66 mmol) andtri-n- butylphosphine (164 μL, 0.66 mmol) and stir at room temperature for 30 min and heat at 80 °C for 4 h. Pour the warm reaction into diethyl ether (-200 mL) and stir vigorously while cooling to room temperature. Filter the precipitate and concentrate the filtrate to give as thick oil. Purify using silica gel chromatography, eluting with 25:75 to 75:25 ethyl acetate:hexanes to give the title compound as a colorless oil.

EXAMPLE 1 {Methyl[2-(3-thiophen-2-yl-biphenyl-4-yloxy)ethyl]amino}-ace tic acid

Add to a solution of ({methyl [2-(3-thiophen-2-ylbipheny 1-4- yloxy)ethyl]amino}acetic acid tert-butyl ester prepared essentially as described in Preparation 1 (2.86 g, 6.75 mmol) in 1,4-dioxane (135 mL) 2 N sodium hydroxide (67.52 mL). Heat to 115 0C for 3 h and cool to room temperature. Dilute with water (200 mL) and wash with diethyl ether (1 L). Acidify to about pH = 4 by the drop wise addition of 5 N hydrochloric acid. Collect the precipitate by vacuum filtration and wash with water (20 mL). Dry in a vacuum oven to give the title compound as white solid (2.4 g). HRMS m/z Calculated: 368.1320; Found: 368.1331

The compounds of EXAMPLES 2-12 may be prepared essentially as described in EXAMPLE l. EX Compound Name & Data { [2-(2,4-Dithiophen-2-ylphenoxy)ethyl]-methylamino}-acetic acid

MS (ES): m/z = 31 A

EXAMPLE 13

(Methyl{2-[3-(thiophene-2-carbonyl)biphenyl-4-yloxy]ethyl }amino)-acetic add

hydrochloride

Reflux a solution of methyl- {2- [3 -(thiophene-2-carbonyl)biphenyl-4-yloxy] ethyl} amino)-acetic acid tert-butyl ester prepared essentially as described in Preparation 3 (3.54 g; 7.849 mmol) in ethanol (40 mL), water (40 mL) and 2 N sodium hydroxide (40 mL) for 3 h. Cool to room temperature, concentrate, dilute with water (20 mL) and acidify to about pH = 3-4 using 2 N hydrochloric acid. Take up the residue in ethanol (30 mL) and the sodium chloride precipitate is filtered away. Concentrate filtrate and redissolve the residue in 1 : 1 acetonitrile: water and lyophilize to give the title compound as an off-white solid (2.893 g; 85%). 1H NMR (300 MHz, CH3OH-d4) δ 2.96 (s, 3 H)5 3.63 (2 H, d, J = 3.58 Hz), 4.04 (s, 2 H), 4.53 (2 H, d, J = 3.77 Hz), 7.12-7.26 (m, 1 H), 7.27-7.50 (m, 4 H), 7.51-7.62 (m, 3 H), 7.64-7.72 (m, 1 H), 7.76-7.88 (m, 1 H), 7.90-8.09 (m, 1 H); LC-MS: m/z = 396

EXAMPLE 14 may be prepared essentially as described in EXAMPLE 13.

EXAMPLE 15 [Methyl(2-{[3-(thien-2-ylmethyl)[l,l'-biphenyl]-4-yl]oxy}eth yl)amino]-acetic acid Treat a solution of {methyl- [2-(3-thiophen-2-ylmethylbiphenyl-4-

yloxy)ethyl]amino}-acetic acid tert-butyl ester prepared essentially as described in

Preparation 9 (0.365 g; 0.835 mmol) in dichloromethane (5 rnL) with trifluoroacetic acid

(4.6 rnL) added portionwise over 48 h. Concentrate and purify by ion exchange

chromatography, eluting with 2 M triethylamine solution in acetonitrile, to give the title

compound as an off-white solid (224.2 mg; 70%).

1H NMR (400 MHz, DMSOd6) δ 2.44 (s, 3 H), 3.02 (t, J = 5.62 Hz, 2 H), 3.31 (s, 2 H),

4.10-4.19 (m, 4 H), 6.86-6.95 (m, 2 H)5 7.07 (d, J = 9.05 Hz, 1 H), 7.22-7.33 (m, 2 H),

7.40 (t, J = 7.70 Hz5 2 H), 7.45-7.52 (m, 2 H), 7.55 (d, J - 7.34 Hz5 2 H); LC-MS: m/z =

382

The compounds of EXAMPLES 16-19 may be prepared essentially as described

in EXAMPLE 15.

({2-[4-(23-Dihydrobenzo[l,4]dioxin-6-yl)-2-thiophen-2-ylmeth ylphenoxy]ethyl}- methylamino)-acetic acid 28K-3456-140-005 2341644

18 1H NMR (400 MHz5 DMSO-d6) δ 45-7.39 (m, 2H), 7.27 (dd, J = 1.2 Hz, J = 4.9 Hz, IH), 7.04-7.00 (m, 3H), 6.94-6.87 (m, 3H), 4.25 (s, 4H)5 4.14-4.11 (m, 4H), 3.28 (s, 2H)5 3.02 (t, J = 5.6 Hz5 2H,)5 2.36 (s, 3H); LC-MS: m/z = 440.1 {[2-(4-Benzo[l,3]dioxol-5-yl-2-thioρhen-2-yl-methylρlienox y)ethyl]- methylamino}-acetic acid 28K-3456-138-005 2341643

19 1H NMR (400 MHz, DMSO-d6) δ 7.44-7.41 (m, 2H), 7.27 (dd, J = 1.2 Hz, J = 5.1 Hz5 IH), 7.14 (d, J = 1.7 Hz, IH), 7.03 (d, J = 8.1 Hz5 IH), 6.97-6.89 (m, 3H), 6.03 (s, 2H), 4.15-4.12 (m, 4H), 3.34 (s, 2H)5 3.02 (d, J = 5.6 Hz, 2H), 2.45 (s, 3H); LC- MS: m/z = 426.1

EXAMPLE 20

{[2-(2'-Cyano-3-thiophen-2-yIbiphenyl-4-yloxy)ethyl]-meth ylamino}-acetic acid

Add trifluoroacetic acid (1.12 mL, 14.48 mmol) to a solution of {[2-(2'-cyano-3-

thiophen-2-ylbiphenyl-4-yloxy)ethyl]-methylamino} -acetic acid tert-butyl ester (0.130 g,

0.290 mmol) in dichloromethane (2.9 mL) and heat to 40 0C for 4 h. Concentrate,

redissolve the residue in 1,4-dioxane (10 mL), and water (10 mL) and made basic with 1

N sodium hydroxide to about pH = 10. Wash with diethyl ether (20 mL), acidify aqueous

layer with 1 N hydrochloric acid to about pH = 4, concentrate, redissolve the residue in

1,4-dioxane (15 mL) and filter away the sodium chloride. Concentrate the filtrate and stir

the residue in diethyl ether (20 mL) to precipitate out a tan solid. Filter and dry in a

vacuum oven to give the title compound (0.030 g).

HRMS m/z Calculated: 393.1273; Found: 393.1272

The compounds of EXAMPLES 21-22 may be prepared essentially as described

in EXAMPLE 20. EX Compound Name & Data

{[2-(3'-Cyano-3-thiophen-2-ylbiphenyl-4-yloxy)ethyl]-meth ylamino}-acetic acid 21 HRMS m/z Calculated: 393.1273; Found: 393.1272 { [2-(4 ' -Cyano-3 -thiophen-2-ylbiphenyl-4-yloxy)ethyl] -methylamino } -acetic acid 22 HRMS m/z Calculated: 393.1273; Found: 393.1288

EXAMPLE 23

{MethyI-[2-([l,l';3%l']terphenyl-4'-yloxy)ethyl]-amino}-a cetic acid hydrochloride

Treat a solution of methyl-[2-([l,r;3',r]terphenyl-4'-yloxy)ethyl]-amino}-acetic

acid tert-butyl ester prepared essentially as described in Preparation 59 using {[2-(3-

iodobiphenyl-4-yloxy)ethyl] -methylamino} acetic acid tert-butyl ester and phenylboronic

acid (0.235 g, 0.562 mmol) in 1,4-dioxane (3.4 mL) with 2 N sodium hydroxide (5.62

mL, 11.2 mmol). Heat to 115 ° C for 3 h. Cool to room temperature, dilute with water

(10 mL) and wash with diethyl ether (200 mL). Acidify aqueous layer to about pH = 4 by

the dropwise addition of 5 N hydrochloric acid. Decant the water layer from the gummy

residue and triturate the gum with water (10 mL) for 30 min. Decant the water and

redissolve the residue in 1,4-dioxane, concentrate and dry in a vacuum oven to give the

title compound as a white solid (0.120 g, 0.301 mmol).

HRMS m/z Calculated: 362.1756; Found: 362.1771

The compounds of EXAMPLES 24-30 may be prepared essentially as described

in EXAMPLE 23

EX Compound Name & Data

{Methyl-[2-(2-tbiophen-2-yl-4-trifluoromethylphenoxy)ethy l]-amino}-acetic acid hydrochloride 24

HRMS m/z Calculated: 360.0881; Found: 360.0871 {Methyl- [2-(2 ' -methyl-3 -thiophen-2-ylbiphenyl-4-yloxy)ethyl] -amino } -acetic acid 25 HRMS m/z Calculated: 382.1477; Found: 382.1480 {Meώyl-[2-(3'-methyl-3-thiophen-2-ylbiphenyl-4-yloxy)ethyl] -amino}-acetic acid 26 HRMS m/z Calculated: 382.1477; Found: 382.1475 {Metiiyl-[2-(4'-me1iiyl-3-tiiiophen-2-ylbiphenyl-4-yloxy)eth yl]-amino}-acetic acid 27 HRMS m/z Calculated: 382.1477; Found: 382.1480 {[2-(3'-Fluoro-3-tMophen-2-ylbiphenyl-4-yloxy)ethyl]-inethyl aniino}-acetic acid 28 HRMS m/z Calculated: 386.1226; Found: 386.1233 {[2-(4'-Fluoro-3-tbiophen-2-ylbiphenyl-4-yloxy)ethyl]-metliy lammo}-acetic acid 29 HRMS m/z Calculated: 386.1226; Found: 386.1233 {Methyl-[2-([l,l';4',l"]terphenyl-2'-yloxy)ethyl]-amiαo}-ac etic acid hydrochloride 30

HRMS m/z Calculated: 362.1226; Found: 362.1757

EXAMPLE 31

({2-[3-(3-ChIorobenzoyl)-biphenyl-4-yloxy]ethyl}-methyIam ino)-acetic acid

hydrochloride

Reflux a solution of {2-[3-(3-chlorobenzoyl)biphenyl~4-yloxy]ethyl}-

methylamino)-acetic acid tert-butyl ester (1.58 g, 3.29 mmol) in 2 N sodium hydroxide

(33 mL) and 1,4-dioxane (16.5 niL) for 4 h. Cool to room temperature, concentrate,

acidify to pH = 2-3 using 2 N hydrochloric acid. The residue is taken up in ethanol and

the NaCl is filtered away and the filtrate is concentrated. Take up in the residue in 1 : 1

acetonitrile: water and lyophilize to give the title compound as an off-white solid (1.35 g,

96%).

1H NMR (400 MHz5 CH3OH-d4) δ 2.62 (s, 3 H)5 3.43-3.49 (m, 2 H)5 3.51 (s, 2 H)5 4.37-

4.44 (m, 2 H)5 7.18-7.24 (m, 1 H)5 7.30 (q, J = 7.50 Hz5 1 H)5 7.33-7.46 (m, 6 H)5 7.48- 7.54 (m, 1 H)5 7.58 (d, J = 7.82 Hz5 2 H)5 7.66 (dd, J = 8.56, 2.45 Hz5 1 H); LC-MS: m/z

= 424

The compounds of EXAMPLES 32-35 may be prepared essentially as described

in EXAMPLE 31.

EX Compound Name & Data

{ [2-(3 -Benzoylbiphenyl-4-yloxy)ethyl] -methylamino } -acetic acid

32 1HNMR (300 MΗz, CH3OH-d4) δ 2.67 (s5 3 H)5 3.24-3.46 (m5 2 H), 3.54 (s, 2 H)5 4.33-4.62 (m, 2 H), 122-1.Id (m, 10 H)5 7.77-8.04 (m, 3 H); LC-MS: m/z = 390 ({2-[(3-{[4-(Methyloxy)phenyl]carbonyl)[l,r-biphenyl]-4-yl]o xy}etliyl)- methylamino] -acetic acid

33 1HNMR (300 MHz5 CH3OH-d4) δ 2.73 (s, 3 H)5 3.39-3.53 (m5 2 H)5 3.58 (s, 2 H)5 3.86-4.04 (m, 3 H)5 4.36-4.58 (m, 2 H)5 7.00-7.15 (m, 2 H)5 7.23-7.52 (m5 4 H), 7.53-7.69 (m, 3 H), 7.76-7.97 (m, 3 H); LC-MS: m/z 420.1 ({2-[(3-{[4-Chlorophenyl)carbonyl][l5r-biphenyl]-4-yl]oxy}et hyl)-methylamino]- acetic acid

34 1HNMR (300 MHz5 CH3OH-d4) δ 2.83 (s, 3 H)5 3.44-3.56 (m5 2 H), 3.83 (s, 2 H), 4.43-4.56 (m, 2 HQ5 7.27-7.39 (m5 2 H)5 7.40-7.49 (m5 2 H)5 7.51-7.71 (rn5 5 H)5 7.77-7.94 (m, 3 H); LC-MS: m/z 424 (Methyl- { 2- [3 -(3 -methylbenzoyl)-biphenyl-4-yloxy] ethyl } -amino)-acetic acid

35 H NMR (300 MHz5 CH3OH-d4) δ 2.42 (3 H5 s), 2.70 (3 H5 s)5 3.38-3.44 (2 H, m), 3.55-3.62 (2 H5 nx), 4.44-4.50 (2 H5 m), 7.28-7.53 (6 H, m), 7.58-7.72 (5 H, m), 7.85 (1 H5 dd, J = 8.67 Hz); LC-MS: m/z = 404

EXAMPLE 36

{[2-(3-Ben.cylbiphenyl-4-yloxy)ethyl] -methylamino}-acetic acid

Add neat triethylsilane (0.5 mL) to a solution of {[2-(3-benzoylbiphenyl-4-

yloxy)ethyl]-methylamijno}-acetic acid (0.270 g; 0.63 mmol) in trifluoroacetic acid (6

mL). Add triethylsilane in excess (2 TnL) portionwise over 3 h and stir at room

temperature overnight. Combine this reaction mixture with a second similarly prepared batch of { [2-(3 -benzylbiphenyl-4-yloxy)ethyl] -methylamino } -acetic acid. Concentrate the combined solutions and wash the crude residue with water and methanol. Concentrate and purify the residue by ion exchange chromatography to give the title compound as the free base as a white solid (250 mg, 87%). 1H NMR (300 MHz, DMSOd6) δ 2.44 (s, 3 H)5 3.01 (t, J = 5.46 Hz, 2 H), 3.33 (s, 2 H)5 3.96 (s, 2 H), 4.13 (t, J = 5.46 Hz5 2 H)5 7.01-7.10 (m, 1 H), 7.11-7.20 (m, 1 H)5 7.20-7.35 (m, 5 H), 7.41 (t, J = 7.63 Hz5 2 H)5 7.45-7.52 (m, 2 H)5 7.52-7.63 (m5 2 H); LC-MS: m/z = 376

EXAMPLE 37 [{3-[3-(CyclohexyIcarbonyl)[l,l'-biphenyl]-4-yl]ethyl)-methy lamino]-acetic acid

Add trifluoroacetic acid (15 mL) to a solution of {{[2-(3- cyclohexanecarbonylbiphenyl-4-yloxy)ethyl] -methylamino} acetic acid tert-butyl ester prepared essentially as described in Preparation 23 (0.397 g; 0.88 mmol) in dichloromethane (10 mL) at O °C and stir at room temperature overnight. Purify by ion exchange chromatography, dissolving in methanol and eluting with a 2 M triethylamine solution in acetonitrile, to give the title compound as an off-white solid (304 mg) along with its methyl ester. Purify "by preparative LC-MS to give (98 mg) pure of the title compound. Treat the remaining material contaminated with the methyl ester analogue with 1 N lithium hydroxide (1 mL), to a solution of tetrahydrofuran (4 mL) and water (2 mL). Stir at room temperature overnight. Concentrate and combined with the first batch of material. Purify by ion exchange chromatography to give the title compound as an off- white solid (0.238 g; 68%). 1H NMR (300 MHz, DMSO-d6) δ 1.08-1.44 (m, 4 H)5 1.50-1.92 (m, 6 H), 2.46 (s, 3 H), 2.98-3.09 (m, 2 H), 3.21-3.32 (m, 1 H)5 3.35 (s, 2 H)5 4.23 (t, J = 5.56 Hz5 2 H)5 7.25 (d, J = 8.67 Hz, 1 H), 7.33 (t, J = 7.35 Hz, 1 H), 7.45 (t, J = 7.54 Hz, 2 H), 7.56-7.68 (m, 3 H)5 7.78 (dd, J = 8.67, 2.45 Hz, 1 H); LC-MS: m/z = All

EXAJMPLE 38 [(2-{[4'-Chloro-3-(thien-2-ylcarbonyl)[l,l'-biphenyl]-4yl]ox y}ethyl)-methyIamino]- acetic acid

Prepare a stock solution of ({2-[4-bromo-2-(thiophene-2- carbonyl)phenoxy]ethyl}-methylamino)-acetic acid tert-butyl ester prepared essentially as described in Preparation 58 (1.93 g; 4.25 rnmol) in dry tetrahydrofuran (32 niL). Take an aliquot (1.062 mmol in tetrahydrofuran, 8 mL) and add 4-chlorophenylboronic acid (1.1 eq; 0.183 mg), palladium acetate (0.05 eq), tricyclohexylphosphine (0.06 eq) and potassium fluoride (3.3 eq). Degas the mixture twice with nitrogen and stir at reflux for 48 h at 65 0C. Add more reagents ([4-chlorophenyl boronic acid (0.55 eq), palladium acetate (0.025 eq), tricyclohexylphosphine (0.03 eq) and potassium fluoride (1.65 eq) and reflux overnight. Cool to room temperature, dilute with dichloromethane and filter through a pad of filtering agent. Concentrate and redissolve the residue in methanol. Purify by ion exchange chromatography to give the desired compound which is used directly in the next step. Dissolve in ethanol (4 mL), water (4 mL) and treat with 2 N sodium hydroxide (4 mL). Heat to reflux for 72 h. Cool to room temperature and dissolve the residue in methanol. Purify by ion exchange chromatography followed by preparative LC-MS and lyophilization (1:1 acetonitrile: water) to give the title compound. 1H NMR (300 MHz, DMSOd6) δ 2.72 (s, 3 H), 3.41-3.53 (m, 2 H), 4.03 (s, 2 H), 4.42- 4.58 (m, 2 H), 7.23 (dd, J = 4.90, 3.77 Hz, 1 H), 7.35 (d, J = 8.67 Hz, 1 H), 7.47-7.53 (m, 2 H), 7.56 (dd, J = 3.77, 0.94 Hz, 1 H), 7.69-7.72 (m, 1 H), 7.72-7.78 (m, 2 H), 7.89 (dd, J = 8.76, 2.35 Hz, 1 H), 8.12 (dd, J = 4.90, 1 .13 Hz, 1 H); LC-MS: m/z = 430 The compounds of EXAMPLES 39-43 may be prepared essentially as described

in EXAMPLE 38 except that in the hydrolysis step 1,-4-dioxane (5 mL) and 2 N sodium

hydroxide (10 mL) are used at reflux temperature instead of the ethanol, water and 2 N

sodium hydroxide combination.

EXAMPLE 44 {[2-(2-Benzoyl-4-trifluoromethyIphenoxy)ethyI]-methylamino}- acetic acid

Add a solution of [(2-hydroxyethyl)-methylamino]-acetic acid tert-butyl ester (0.7 g; 2 eq) in N,N-dimethylformaniide (3 mL) at 0 0C to a suspension of sodium hydride (60% dispersion in oil, 2.1 eq; 155 mg) in N,N-dimethylformamide (2 mL). Stir for 10 min at 0 0C and add a solution of commercially available 2-fluoro-5- (trifluoromethyl)benzophenone (0.5 g; 1.86 mmol) in N~.N-dimethylforrnamide (12 mL). Stir for 1 h at room temperature and then reflux overnight. Cool to room temperature and quench with water. Dilute with diethyl ether, wash successively with water and saturated aqueous sodium chloride and concentrate the organic phase. Purify residue by ion exchange chromatography to give a mixture of the {[2-(j2-benzoyl-4- trifluoromethylphenoxy)ethyl]-methylamino} acetic acicfl tert-butyl ester and the title compound (925 mg) which is directly without further purification. Next add trifiuoroacetic acid (3 mL) at 00C to a solution of the mixture of {[2-(2-benzoyl-4- trifluoromethylphenoxy)ethyl]-methylamino}acetic acidl tert-butyl ester and the title compound (925 mg) in dichloromethane (2 mL). Stir 1 Ii at room temperature. Concentrate and purify by ion exchange chromatography and preparative LC-MS to give the acid as a clear pale yellow oil. Dissolve the residue in 1 :1 acetonitrile: water and lyophilize to give the title compound as an off-white solid (109 mg; 11 % over two steps). 1H NMR (400 MHz, CDCl3) δ 2.20 (s, 3 H), 2.88 (t, J = 4.6 Hz, 2 H), 3.05 (s, 2 H), 4.10 (t, J = 4.6 Hz, 2 H), 6.79 (d, J = 8.56 Hz, 1 H), 7.18-7.27 (m, 2H), 7.31-7.45 (m, 2 H), 7.48-7.62 (m, 3 H); LC-MS: m/z = 382

• EXAMPLE 45 (Methyl- {2- [3-(tbiophene-2-carbonyl)- [1,1 ' ;3 ',1"] te*-phenyl-4-yloxy] ethyl}-amino)- acetic acid Treat a solution of (memyl-{2-[3(thiophene-2-carbonyl)-[l,l';3 *,l"]terphenyl~4-

yloxy]ethyl}-amino)-acetic acid tert-butyl ester prepared essentially as described in

Preparation 24 (130.9 mg, 0.26 mmol) in dichloromethane (2 mL) with trifluoroacetic

acid (0.6 mL, 30 eq). Stir the reaction for about 2 days at room temperature in a

Greenhouse™ reaction vessel containing consisting of 24 reaction tubes each containing

dichloromethane (2 mL). Evaporate the solvents in an EZ-2 Genevac™ system under

vacuum, take up the residue in acetonitrile (1 mL), load onto an ion exchange column,

wash with methanol and elute with 2 M ammonia in methanol. Evaporate the solvent in a

Reacti-Therm™ under a stream of nitrogen with heat and purify by preparative LC-MS to

give the title compound (45 mg, 37%).

1H NMR (300 MHz, CH3OH-d4) δ 7.87-8.01 (m, 2 H)5 7.74-7.85 (m, 2 H), 7.42-7.72 (m,

8 H), 7.31-7.42 (m, 2 H), 7.24 (dd, J = 4.9, 4.0 Hz, 1 H), 4.48-4.55 (m, 2 H), 3.65 (s, 2 H),

3.49-3.57 (m, 2 H), 2.84 (s, 3 H); LC-MS: m/z = All

The compounds of EXAMPLES 46-78 may be prepared essentially as described

in EXAMPLE 45.

EX Compound Name & Data

( {2- [3 ' -Bromo-3 -(thiophene-2-carbonyl)biphenyl-4-yloxy] ethyl} -methylamino)- acetic acid

46 1H NMR (400 MHz, DMSOd6) δ 8.06 (d, J = 4.9 Hz, 1 H), 7.82-7.90 (m, 2 H), 7.66-7.73 (m, 2 H), 7.47-7.56 (m, 2 H), 7.39 (t, J = 7.9 Hz, 1 H), 7.30 (d, J = 8.8 Hz, 1 H), 7.18-7.23 (m, 1 H), 4.15 (t, J = 5.6 Hz, 2 H), 3.06 (s, 2 H), 2.77 (t, J=5.7 Hz, 2 H), 2.24 (s, 3 H); LC-MS: m/z = 476 (Methyl- { 2- [2 ' -methyl-3 -(thiophene-2-carbonyl)biphenyl-4-yloxy] ethyl } -amino)- acetic acid

47 1HNMR (400 MHz, DMSOd6) δ 2.26 (6 H, s), 2.80 (2 H, t, J = 5.75 Hz), 3.13 (2 H, s), 4.16 (2 H, t, J = 5.62 Hz), 7.19-7.32 (7 H, m), 7.48 (1 H, dd, J = 8.56, 2.45 Hz), 7.51-7.56 (1 H, m), 8.06 (1 H, d, J = 4.89 Hz) EX Compound Name & Data

(Methyl- {2-[4 ' -methyl-3 ' -nitro-3 -(thiophene-2-carbonyl)biphenyl-4-yloxy] etlryl } - amino)-acetic acid

48 1H NMR (400 MHz, DMSOd6) δ 8.24 (d, J = 2.0 Hz, 1 H), 8.07 (d, J = 4.2 Hz5 1 H), 7.85-8.01 (m, 2 H)5 7.78 (d, J = 2.4 Hz, 1 H), 7.46-7.62 (m, 2 H)5 7.33 (d, J" = 8.6 Hz, 1 H), 7.16-7.27 (m, 1 H)5 4.15 (t, J = 5.9 Hz, 2 H), 2.98 (s, 2 H), 2.75 (t, J = 5.9 Hz5 2 H), 2.14-2.25 (br S5 3 H)5 2.07 (s, 3 H); LC-MS: m/z = 476 ({2-[2',5'-Dichloro-3-(thioρhene-2-carbonyl)biρhenyl-4-ylo xy]ethyl}- methylamino)-acetic acid

49 Η NMR (400 MHz5 DMSO-d6) δ 2.25 (s, 3 H)5 2.79 (t, J - 5.75 Hz5 2 H)5 3.07 (s, 2 H)5 4.17 (t, J = 5.62 Hz5 2 H)5 7.18-7.26 (m, 1 H)5 7.31 (d, J = 8.80 Hz5 1 H)5 7_42- 7.65 (m, 6 H)5 8.07 (d, J = 4.65 Hz5 1 H); LC-MS: m/z 464 (Methyl- { 2- [3 ' -methoxy-3 -(thiophene-2-carbonyl)biphenyl-4-yloxy] ethyl} -anαino)- acetic acid

50 1HNMR (400 MHz5 DMSOd6) δ 2.26 (s, 3 H)5 2.80 (t, J = 5.62 Hz, 2 H), 3.14 (s, 2 H)5 3.81 (s, 3 H)5 4.16 (t, J = 5.75 Hz, 2 H)5 6.90 (dd, J = 8.19, 2.32 Hz5 1 H)5 7.15- 7.40 (m5 5 H)5 7.52 (d, J = 3.67 Hz, 1 H)5 7.67 (d, J = 2.20 Hz5 1 H), 7.83 (dd5 J = 8.685 2.32 Hz5 1 H)5 8.06 (d, J = 4.89 Hz, IH); LC-MS: m/z = 426 ({2-[2'54'-Difluoro-3-(thiophene-2-carbonyl)biphenyl-4-yloxy ]ethyl}- methylamino)-acetic acid

51 1HNMR (400 MHz5 DMSOd6) δ 2.25 (s, 3 H)5 2.79 (t, J = 5.62 Hz5 2 H)5 3.12 (s, 2 H)5 4.17 (t, J = 5.62 Hz5 2 H)5 7.13-7.24 (m5 2 H)5 7.29-7.39 (m, 2 H), 7.50-7.72 (m, 4 H)5 8.07 (d, J = 4.89 Hz5 1 H); LC-MS: m/z = 432.3 (Methyl- { 2- [4 ' -ethyl-3 ~(thiophene-2-carbonyl)biphenyl-4-yloxy] ethyl } -amino)~ - acetic acid

52 1H NMR (400 MHz, DMSOd6) δ 1.20 (t, J = 7.58 Hz, 3 H)5 2.25 (s, 3 H)5 2.63 (q, J = 7.66 Hz5 2 H)5 2.79 (t, J = 5.62 Hz, 2 H), 3.11 (s, 2 H), 4.15 (t, J = 5.75 Hz5 2 H)5 7.19-7.31 (m5 4 H)5 7.50-7.63 (m, 4 H)5 7.79 (dd, J = 8.68, 2.32 Hz5 1 H), 8.06 (d, J = 4.89 Hz5 1 H); LC-MS: m/z = 424 ({2-[4'-Hydroxy-3-(thiophene-2-carbonyl)biphenyl-4-yloxy]eth yl}-methylamino)- acetic acid

53 1H NMR (400 MHz5 DMSOd6) δ 2.24 (s, 3 H)5 2.77 (t, J = 5.62 Hz5 2 H)5 3.05-3.08 (m, 2 H)5 4.12 (t, J = 5.75 Hz5 2 H)5 6.82 (d, J = 8.56 Hz5 2 H)5 7.17-7.27 (m, 2 H)5 7.43-7.56 (m, 4 H)5 7.71 (dd5 J = 8.68, 2.32 Hz, 1 H), 8.05 (d, J = 4.89 Hz, 1 IT); LC- MS: m/z = 412 (Methyl-{2-[2',5'-dimethyl-3-(thiophene-2-carbonyl)biphenyl- 4-yloxy]ethyl}- amino)-acetic acid

54 1H NMR (400 MHz5 DMSOd6) δ 2.21 (s, 3 H)5 2.27 (s, 3 H), 2.29 (s, 3 H)5 2.S 1 (t5 J = 5.62 Hz5 2 H)5 3.15 (s, 2 H)5 4.16 (t, J = 5.62 Hz5 2 H)5 7.01-7.30 (m, 6 H)5 7_44- 7.54 (m, 2 H), 8.06 (d, J = 4.89 Hz, 1 H); LC-MS: m/z = 424

EXAMPLE 79

{[2-(2"-Chloro[l,l';3',l"]terphenyl-4'-yloxy)ethyl]-methy Iamino}-acetic acid Treat a solution of {[2-(2"-chloro-[l,l';3',l"]tertphenyl-4'-yloxy)e%l]-

methylamino} acetic acid tert-butyl ester prepared essentially as described in Preparation

59 (145 mg, 0.32 rnmol) in dichloromethane (2 mL) with trifluoroacetic acid (0.6 rnL, 30

eq). Stir the reaction overnight at room temperature and at 40 0C for 2.5 h in a

Greenhouse™ reaction vessel containing consisting of 24 reaction tubes each containing

of dichloromethane (2 mL). Evaporate the solvents in an EZ-2 Genevac™ system under

vacuum, take up the residue in acetonitrile (1 mL), load onto an ion exchange column,

wash with methanol and elute with 2 M ammonia in methanol. Evaporate the solvent in a

Reacti-Therm™ under a stream of nitrogen with heat and purify by preparative LC-MS to

give the title compound (17.7 mg, 14%).

1H NMR (400 MHz, CH3OH-d4) δ 2.62 (s, 3 H), 3.43-3.49 (m, 2 H), 3.51 (s, 2 H), 4.36-

4.44 (m, 2 H), 7.17-7.23 (m, 1 H), 7.26-7.45 (m, 6 H), 7.29 (t, J = 7.34 Hz, 1 H), 7.47-

7.54 (m, 1 H), 7.58 (d, J = 7.82 Hz, 2 H), 7.66 (dd, J = 8.56, 2.45 Hz, 1 H); LC-MS: m/z

= 396.1

The compounds of EXAMPLES 80-91 may be prepared essentially as described

in EXAMPLE 79.

EX Compound Name & Data

{Methyl-[2-(3 "-methyl-[l , 1 ';3 ', 1 "]teφhenyl-4'-yloxy)ethyl]-amino}-acetic acid

80 1H NMR (400 MHz, CH3OH-d4) δ 3.30 (3 H, s), 3.62 (3 H, s), 4.39-4.43 (2 H, m), 4.50 (2 H, s), 5.26-5.30 (2 H, m), 8.04-8.14 (2 H, m), 8.17-8.26 (4 H, m), 8.31 (2 H, t, J = 7.70 Hz), 8.41 (1 H, d, J = 2.20 Hz), 8.50 (3 H, d5 J = 7.82 Hz); LC-MS: m/z = 376 { [2-(4"-Chloro-[ 1 , l';3 ', 1 "]terphenyl-4'-yloxy)ethyl] -methylamino } -acetic acid

81 1H NMR (300 MHz, DMSOd6) δ 2.07 (s, 3 H), 2.92 (t, J = 5.46 Hz, 2 H), 3.17 (s, 2 H), 4.16 (t, J = 5.65 Hz, 2 H), 7.22 (d, J = 8.67 Hz, 1 H), 7.28-7.37 (m, 1 H), 7.39- 7.51 (m, 4 H), 7.57 (d, J = 2.26 Hz, 1 H), 7.60-7.73 (m, 5 H); LC-MS: m/z = 396 {[2-(3"-Chloro-[l,r;3!,l"]terphenyl-4t-yloxy)ethyl]-methylam ino}-acetic acid

82 1H NMR (300 MHz, DMSOd6) δ 2.36 (s, 3 H), 2.92 (t, J = 5.27 Hz, 2 H), 3.17 (s, 2 H)5 4.17 (t, J = 5.56 Hz, 2 H), 7.23 (d, J = 8.48 Hz, 1 H), 7.28-7.50 (m, 5 H), 7.56- 7.76 (m, 6 H); LC-MS: m/z = 396 {Methyl-[2-(2"-methyl-[l,r;3',rι]terphenyl-4'-yloxy)ethyl]- amino}-acetic acid

83 1H NMR (300 MHz, DMSO-d6) δ 2.12 (s, 3 H), 2.21 (s, 3 H), 2.80 (t, J = 5.37 Hz, 2 H), 3.17 (s, 2 H), 4.10 (t, J = 5.84 Hz, 2 H), 7.13-7.27 (m, 5 H), 7.30 (t, J = 7.35 Hz, 1 H), 7.35-7 '.47 (m, 3 H), 7.65 (d, J = 7.16 Hz, 3 H); LC-MS: m/z = 376

EXAMPLE 92 {Methyl- [2-(3-thiazol-2-yl-biphenyl-4-yloxy)ethyl]-amino}-acetic acid hydrochloride

Add to a solution of {methyl-[2-(3-thiazol-2-ylbiphenyl-4-yloxy)ethyl]-amino}- acetic acid tot-butyl ester (0.170 g, 0.400mmol) in 1,4-dioxane (8.0 mL) was added 2 N sodium hydroxide (4.0 mL). Heat to 115 0C for 3 h. Cool to room temperature, dilute with water (10 mL) and wash with diethyl ether (200 mL). Acidify to about pH = 1 by the dropwise addition of 5 N hydrochloric acid. Concentrate to a dry powder. Slurry the powder in ethanol, filter, concentrate at room temperature, and dry in a vacuum oven to give the title compound as a pale yellow solid (150 mg, 93%). HRMS m/z Calculated: 369.1273; Found: 369.1268

The compounds of EXAMPLES 93-94 may be prepared essentially as described as EXAMPLE 92.

EXAMPLE 95 {[2-(4-Benzyl-2-thiophen-2-ylphenoxy)ethyl]-methylamino}-ace tic acid trifluoroacetate

Add triethylsilane (0.295 mL. 1.84 mmol) to a solution of {[2-(4-benzoyl-2- thiophen-2-ylphenoxy)ethyl]-methylamino} -acetic acid hydrochloride (0.1328 g, 0.3075 mmol) in trifluoroacetic acid (1 mL, 0.02 mol). Stir at room temperature for 18 h (monitored by LC-MS), pour into ice and dilute with water (5 mL). Adjust to about pH = 9 with 2 N sodium hydroxide and wash with diethyl ether (50 mL). Acidify the aqueous layer to about pH = 1 by the dropwise addition of 5 N hydrochloric acid. Concentrate to a dry powder and slurry in 1,4-dioxane (20 mL), filter, concentrate and dry in a vacuum oven to give 60 mg of the hydrochloride salt as a beige solid. Reverse phase chromatography eluting with acetonitrile/water with 0.1 % trifluoroacetic acid gives the title compound (18 mg, 12.0%). HRMS m/z Calculated: 382.1477; Found: 382.1483

EXAMPLE 96 {[2-(3-CyclohexyImethylbiphenyl-4-yloxy)ethyl]-methylamino}- acetic acid

Add 2 N sodium hydroxide (1O.0 mL) to a solution of {[2-(3- cyclohexylmethylbiphenyl-4-yloxy)ethyl]-methylamino}-acetic acid tert-butyl ester (0.480 g, 1.10 mmol) in 1,4-dioxane (20 mL). Heat to 115 °C for 3 h. Cool to room temperature, dilute with water (40 mL) and wash with diethyl ether (90 mL). Acidify the water layer to about pH = 4 by the dropwise addition of 5 N hydrochloric acid. Filter the solid and dry to give the title compound as a white solid (401.0 mg). HRMS m/z Calculated: 382.2382; Found: 382.2391

The compounds of EXAMPLES 97-117 may be prepared essentially as described

as EXAMPLE 96. For EXAMPLES 111-112, after the deprotection step, separate the

two isomers using reverse phase chiral chromatography, eluting with a buffer containing

0.1% trifluoroacetic acid to give the final products as the trifluoroacetate salt.

EXAMPLE 118

{Methyl- [2-(3-phenethynylbiphenyl-4-yloxy)ethyl] -amino}-acetic acid

trifluoroacetate

Add 5% palladium on carbon (0.0214 g) to a solution of {methyl- [2-(3-

phenethynyl-biphenyl-4-yloxy)ethyl] -amino} -acetic acid tert-butyl ester prepared as

described in Preparation 80 (0.17 g, 0.40 mmol) in tetrahydrofuran and hydrogenate in a

Parr shaker under 60 psi hydrogen gas for 8 h at room temperature. Filter through Hyflo

Super Cell®, concentrate and purify (reverse phase chromatography, eluting with

acetonitrile/water with 0.1 % trifluoroacetic acid) to give {methyl-[2-(3-

phenethynylbiphenyl-4-yloxy)ethyl] -amino} -acetic acid tert-butyl ester. The free acid is

prepared essentially as described in EXAMPLE 96. Purification by reverse phase chromatograpliy, eluting with a buffer containing 0.1% trifluoroacetic acid, gives the title compound as the trifluoroacetate salt as a white solid (29.0 mg, 14 %). MS (ES): m/z = 388.1

EXAMPLE 119 {[2-(3-IsopropenylbiphenyI-4-yloxy)ethyl]-methylamino}-aceti c acid

Add 2 N sodium hydroxide (3.4 mL) to a solution of { [2-(3-isopropenylbiphenyl- 4-yloxy)ethyl]-methylamino} -acetic acid ethyl ester (0.120 mg, 0.340 mmol) in 1,4- dioxane (3.4 rnL). Heat to 115 0C for 3 h. Cool to room temperature, dilute with water (10 mL) and wash with diethyl ether (50 mL). Acidify the water layer to about pH = 4 by the dropwise addition of 5 N hydrochloric acid. Concentrate to a dry powder, slurry and filter off the sodium chloride. Concentrate the filtrate and dry to give the title compound as a white solid (30 mg). HRMS m/z Calculated: 326.1756; Found: 326.1769

EXAMPLE 120 (Methyl-{2-[4-(l-methyl-lH-indol-6-yI)-2-thiophen-2-ylphenox ^]ethyl}-amino)-acetic acid hydrochloride Add 2 N sodium hydroxide (1.36 niL) to a solution of (methyl- {2-[4-(l -methyl- lH-indol-6-yl)-2-thiophen-2-ylphenoxy] ethyl }-amino)-acetic acid tert-butyl ester in 1,4- dioxane (2.73 niL). Heat to 115 0C for 4 h. Cool to room temperature, dilute with water (10 iriL) and wash with diethyl ether (50 mL). Acidify the water layer to about pH = 4 by the drop wise addition of 5 N hydrochloric acid. Filter the precipitate and dry to give the title compound as a white solid (85 mg). HRMS m/z Calculated: 421.1586; Found: 421.1572

EXAMPLE 121 {[2-(2-BenzoyI-4-chlorophenoxy)ethyl]-methylamino}-acetic acid

Treat a solution of {[2-(2-benzoyl-4-chlorophenoxy)ethyl]-methylainino}-acetic acid tert-butyl ester (0.29 g, 0.72 mmol) in 1,4-dioxane (5 mL) with 2 N sodium hydroxide (5 mL, 10 mmol) and heat at reflux overnight. Concentrate and redissolve in water. Acidify the "water to about pH = 2 with 1 N hydrochloric acid and purify on Dowex® 50 x 8-10O cation exchange resin, eluting with 10:90 pyridine:water. Dissolve product in water and lyophilize overnight to give the title compound as a white solid (0.104 g, 42%). 1H NMR (300 MHz, CH3OH-d4) δ 2.65 (3H, s), 3.36 (2H, t, J = 5.0 Hz), 3.55 (2H, s), 4.42 (2H, t, J = 4.9 Hz)5 7.25 (IH, d, J = 8.9 Hz), 7.42 (IH, d, J = 2.6 Hz), 7.53-7.62 (3H,- m). 7.67-7.70 (IH, rn). 7.82-7.84 (2H, m); MS (ES): 348

EXAMPLE 122 {Methyl-[2-(3-phenyIaminobiphenyI-4-yloxy)ethyl]-amino}-acet ic acid Stir {methyl-[2-(3-phenylaminobiphenyl-4-yloxy)ethyl]-amino}-acet ic acid ethyl ester (0.19 g, 0.47 mmol) in a 1:1 mixture of 1 N sodium hydroxide :tetrahydrofuran (6 mL total volume) at room temperature overnight. Acidify to about pH = 7 with 1 N hydrochloric acid and concentrate. Redissolve in water and acidify to pH = 4 with 1 1ST hydrochloric acid and stirred vigorously for 1 h. Filter the white precipitate via vacuum filtration and air dry to give the title compound (0.14 g, 79%). 1H NMR (300 MHz5 D2O w/KOD) δ 1.84 (3H, s, br), 2.20-2.24 (2H5 m)5 2.75 (2H, s5 br), 3.20-3.42 (2H5 m), 6.05-6.15 (IH5 m), 6.20-6.33 (2H5 m)5 6.40-6.63 (7H5 m), 6.65-6.80 (2H5 m), 6.90-7.00 (IH, m); MS (ES): m/z = 399, 375

EXAMPLE 123 {[2-(3-Isopropoxymethylt>iphenyl-4-yloxy)ethyl]-methylami no}-acetic acid

Add 1 N sodium hydroxide (2 mL) in one portion to a solution of {[2-(3- isopropoxymethylbiphenyl-4-yloxy)ethyl]-methylamino} -acetic acid ethyl ester (0.11 g5 0.29 mmol) in tetrahydrofuran (5 mL). Stir at room temperature overnight. Acidify to about pH = 2 with 1 N hydrochloric acid and concentrate to dryness. Triturate solid with acetone and filter. Concentrate filtrate to a tacky white foam. Reconstitute foam in water and lyophillize overnight to give the title compound as a fluffy white solid (0.045 g, o . 1H NMR (300 MHz, CH3OH-d4) δ 1.24 (3H, s), 1.25 (3H, s), 3.13 (3H, s), 3.76-3.82 (3H, m), 4.18 (2H5 s), 4.49 (2H, t, J = 4.8 Hz), 4.67 (2H5 s), 7.11 (IH5 d, J = 8.4 Hz)5 7.28- 7.33 (IH5 m), 7.40-7.42 (2H5 m), 7.56-7.59 (3H5 m)5 7.66 (IH5 d5 J = 2.6 Hz); MS (ES): m/∑ = 358, 380

EXAMPLE 124 {[2-(3-CyclohexyloxymethylbiphenyI-4-yloxy)ethyl]-methyIamin o}-acetic acid

Add 1 N sodium hydroxide (1 mL) in one portion to a solution of {[2-(3- cyclohexyloxymethylbiphenyl-4-yloxy)ethyl]-methylamino} -acetic acid ethyl ester (0.09 g, 0.21 mmol) in tetrahydrofuran (2 mL). Stir at room temperature overnight. Acidify to about pH = 4 with 1 N hydrochloric acid and stir vigorously for 1 h. Filter the precipitate and dry overnight in a vacuum oven to give the title compound as a fluffy white solid (0.075 g, 90%). 1H NMR (300 MHz5 CH3OH-d4) δ 1.20-1.40 (5H5 m), 1.50-1.58 (IH5 m), 1.70-1.80 (2H, m), 1.90-2.00 (2H5 m), 3.03 (3H, s), 3.40-3.45 (IH5 m), 3.66 (2H5 t, J = 4.8 Hz)5 3.75 (2H5 s)5 4.43 (2H, U = 4.8 Hz)54.67 (2H5 s), 7.06 (IH5 d5 J = 8.4 Hz)5 7.24-7.29 (IH5 m), 7.36-7.40 (2H5 m), 7.50-7.55 (3H, m), 7.62 (IH5 d5 J = 2.2 Hz); MS (ES): m/z = 398, 420

EXAMPLE 125 ({2-[3'-Isopropyl-3-(thiophene-2-carbonyl)-biphenyl-4-yloxy] ethyI}-methyl-amino)- acetic acid Add neat trifluoroacetic acid (0.54 niL, 7.33 rnmol) to ({2-[3'-isopropyl-3- (thiophene-2-carbonyl)-biphenyl-4-yloxy]ethyl}-metliylamino) -acetic acid tert-butyl ester (181 mg, 0.367 mmol) in dichloromethane at room temperature. Stir overnight at room temperature. Add extra equivalents of trifluoroacetic acid (0.54 niL, 7.33 mmol) and stir overnight at room temperature. Add extra equivalent of trifluoroacetic acid (0.27 mmol, 3.67 mmol) and stir overnight at room temperature. Concentrate and purify (ion exchange chromatography, eluting with 2 M ammonia in methanol). Lyophilize to give the title compound as a white solid (125.3 mg, 78.0%»). 1H NMR (400 MHz, CDCl3) δ 1.28 (d, 6 H), 1.29 (S5. 3 H), 2.61 (s, 3 H), 2.90-2.99 (m, 1 H), 3.27 (t, J = 4.41 Hz, 2 H), 3.40 (s, 2 H), 4.35 (t, J = 4.44 Hz, 2 H), 7.05-7.12 (m, 2 H), 7.17-7.24 (m, 1 H), 7.31-7.41 (m, 3 H), 7.49 (dd, J = 3.91, 0.98 Hz, 1 H), 7.61-7.72 (m, 3 H); LC-MS: m/z 438.4

The compounds of EXAMPLES 126-128 may be prepared essentially as described in EXAMPLE 125. EX Compound Name & Data ({2-[4'-Isopropoxy-3-(thiophene-2-carbonyl)-biphenyl-4-yloxy ]ethyl}- methylamino)-acetic acid

126 1H NMR (400 MHz, CDCl3) δ 4.84 (d, 6 H), 4.85 (s, 3 H)5 6.28 (s, 3 H), 6.76-6.92 (m, 2 H), 6.98 (s, 2 H), 7.89 (s, 2 H), 7.99-8.17 (m, 1 H), 10.40 (d, J = 7.09 Hz, 2 H)5 10.54-10.68 (m, 2 H), 10.77-10.92 (m, 2 H), 10.95-11.12 (m, 2 H)5 11.16 (dd, J = 8.80, 1.71 Hz, 1 H), 11.30 (d, J = 4.89 Hz, 1 H); LC-MS: m/z 454.4 ( {2- [4-Benzo [1,3] dioxol-5 -yl-2-(thiophene-2-c arbonyl)-phenoxy] ethyl } - methylamino)-acetic acid 127 1H NMR (400 MHz, CDCl3) δ 2.59 (s, 3 H)5 3- 17-3.33 (m, 2 H)5 3.45 (s, 2 H)5 4.26- 4.39 (m, 2 H)5 5.96 (s, 2 H)5 6.81 (d, J = 8.31 Hz5 1 H), 6.89-6.98 (m, 2 H), 7.01- 7.15 (m, 2 H), 7.45 (d, J = 3.18 Hz, 1 H)5 7.47-7.54 (m, 2 H), 7.68 (d, J = 4.40 Hz5

EXAMPLE 129 ({2-[3',5f-Difluoro-3-(thiophene-2-carbonyl)-biphenyl-4-ylo& gt;xy]ethyl}-methylammo)- acetic acid

Treat a solution of ({2-[3',5'-difluoro-3-(thiophene-2-caxbonyl)-biphenyl-4- yloxy]ethyl}-methylamino)-acetic acid tert-butyl ester prepared, essentially as described in Preparation 106 (103.1 mg, 0.21 mmol) in dichloromethane ζ2 mL) with trifluoroacetic acid (0.5 mL, ~20 eq). Stir the reaction overnight at room temperature in a sealed disposable carousel tube, 24 position carousel each containing dichloromethane (2 mL). Add extra equivalents of trifluoroacetic acid (0.5mL, -20 eq) and stir overnight at room temperature. Evaporate the solvent in a Reacti-Therm™ under a stream of nitrogen with heat, take up the residue in acetonitrile, load onto an ion exchange column, wash with acetonitrile and elute with 2 M ammonia in methanol. Evaporate solvent in a Reacti- Therm™ under a stream of nitrogen with heat and purify by preparative LC-MS to give the title compound (41 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J = 4.9 Hz, 1 H), 7.92 (dd, J = 2.3 Hz, 1 H)5 7.79 (d, J = 2.4 Hz, 1 H), 7.42-7.55 (m, 3 H)5 7.30 (d, J = 8.9 HDz5 1 H), 7.11-7.25 (m, 2 H), 4.17 (t, J = 5.7 Hz5 2 H)5 3.10 (s, 2 H), 2.77 (t, J = 5.7 Hz5 Z H)5 2.23 (s, 3 H); LC-MS: m/z = 432.1 The compounds of EXAMPLES 130-137 may be prepared essentially as

described in EXAMPLE 129.

EX Compound Name & Data

({2-[3',4'-Dimethyl-3-(tliiophene-2-carbonyl)-biphenyl-4- yloxy]ethyl}- methylamino)-acetic acid

130 1H NMR (300 MHz, DMSOd6) δ 8.06 (d, J - 4.9 Hz5 1 H), 7.78 (dd, J = 8.7 Hz, 1 H), 7.61 (d, J = 2.4 Hz, 1 H), 7.49-7.54 (m, 1 H), 7.45 (s, 1 H)3 7.37 (dd, J = 7.8 Hz, 1 H), 7.27 (d, J = 8.7 Hz, 1 H), 7.14-7.24 (m, 2 H), 4.14 (t, J = 5.7 Hz, 2 H), 3.12 (s, 2 H), 2.77 (t, J = 5.5 Hz, 2 H), 2.27 (s, 3 H), 2.24 (s, 6 H); LC-MS: m/z = 424.1 ( {2- [4'-Ethoxy-3 -(thiophene-2-carbonyl)-biphenyl-4-yloxy] ethyl } -methylamino)- acetic acid

131 1H NMR (300 MHz, DMSO-d6) δ 8.06 (dd, J = 5.0, 1.0 Hz5, 1 H)5 7.75 (dd, J = 8.7, 2.4 Hz, 1 H)5 7.54 - 7.62 (m, 3 H)5 7.51 (dd, J = 3.8, 0.9 Hz= 1 H)5 7.15-7.30 (m, 2 H)5 6.97 (d, J = 8.9 Hz, 2 H), 4.14 (t, J = 5.7 Hz5 2 H)5 4.05 (q, J=7.0 Hz, 2 H), 3.08 (S5 2 H), 2.76 (t, J = 5.5 Hz5 2 H)5 2.22 (s, 3 H)5 1.33 (t, J = 7.0 Hz5 3 H); LC-MS: m/z = 440.1 ( { 2- [4'-Methoxy-3 '-methyl-3 -(trriophene-2-carbonyl)-biphe;nyl-4-yloxy] ethyl } - methylamino)-acetic acid

1H NMR (300 MHz5 DMSO-d6) δ 8.06 (dd5 J = 4.9, 1.1 Hz5, 1 H), 7.75 (dd, J = 8.7, 132 2.4 Hz, 1 H)5 7.58 (d, J = 2.4 Hz5 1 H), 7.51 (dd, J = 3.8, 1.1 Hz5 1 H), 7.41-7.49 (m, 2 H), 7.16-7.29 (m, 2 H)5 6.94-7.02 (m, 1 H), 4.14 (t, J = 5.7 Hz5 2 H)5 3.81 (s, 3 H)5 3.12 (S5 2 H), 2.77 (t, J = 5.6 Hz5 2 H)5 2.24 (s, 3 H)5 2.20 (s, 3 H); LC-MS: m/z = 440.1 ( { 2- [3 '-Isopropoxy-3 -(thiophene-2-carbonyl)-biphenyl-4-yl oxy] ethyl } - methylamino)-acetic acid

1H NMR (300 MHz5 DMSOd6) δ 8.06 (dd, J = 4.9, 1.1 Hz5, 1 H), 7.81 (dd, J = 8.7, 133 2.3 Hz, 1 H), 7.65 (d, J = 2.4 Hz, 1 H), 7.51 (dd, J = 3.8, 1.1 Hz5 1 H)5 7.24-7.37 (m, 2 H), 7.11-7.24 (m5 3 H)5 6.88 (dd, J = 8.1, 1.7 Hz, 1 H), 4.65-4.78 (m, 1 H), 4.15 (t, J = 5.7 Hz5 2 H), 3.11 (s, 2 H), 2.78 (t, J - 5.7 Hz5 2 H)5 2.24 (s, 3 H)5 1.28 (s, 3 H), 1.26 (s, 3 H); LC-MS: m/z = 454.1 ({2-[3'-Fluoro-3-(thiophene-2-carbonyl)-biphenyl-4-yloxy] ethyl}-methylamino)- acetic acid

134 1H NMR (300 MHz, DMSOd6) δ 8.02-8.12 (m, 1 H), 7.69-7.79 (m, 1 H)5 7.45-7.58 (m, 3 H)5 7.37 (dd, J = 8.3, 1.9 Hz, 1 H), 7.11-7.29 (m, 3 H), 6.81 (d, J = 8.3 Hz, 1 H)5 4.14 (t, J = 5.7 Hz, 2 H)5 3.13 (s, 2 H)5 2.78 (t, J = 5.6 Hz5 2 H)5 2.25 (s, 3 H); LC-MS: m/z = 414.1 EX Compound Name & Data

({2-[4'-Chloro-3'-methyl-3-(tliiopliene-2-carbonyl)-biphe nyl-4-yloxy] etliyl}- methylamino)-acetic acid

135 1HNMR (300 MHz, DMSO-d6) δ 8.07 (dd, J = 5.0, 1.0 Hz, 1 H), 7.83 (dd, J = 8.7, 2.4 Hz, 1 H), 7.68 (dd, J = 5.5, 2.1 Hz, 2 H)5 7.40-7.56 (m, 3 H), 7.29 (d, J = 8.7 Hz, 1 H), 7.21 (dd, J = 4.9, 3.8 Hz, 1 H), 4.15 (t, J = 5.7 Hz, 2 H), 3.10 (s, 2 H), 2.77 (t, J = 5.6 Hz, 2 H), 2.38 (s, 3 H), 2.23 (s, 3 H); LC-MS: m/z = 444.1 ( {2-[4'-Butyl-3 -(thiophene-2-carbonyl)-biphenyl-4-yloxy] ethyl} -metixylamino)- acetic acid

136 1H NMR (300 MHz, DMSOd6) δ 8.06 (dd, J = 5.1, 1.1 Hz, 1 H), 7.80 (dd, J = 8.7, 2.4 Hz, 1 H), 7.46-7.65 (m, 4 H), 7.16-7.32 (m, 4 H), 4.15 (t, J = 5.7 HLz, 2 H), 3.13 (s, 2 H), 2.78 (t, J = 5.7 Hz, 2 H), 2.60 (t, J = 7.6 Hz, 2 H), 2.25 (s, 3 H), 1.50-1.64 (m, 2 H), 1.23-1.41 (m, 2 H), 0.90 (t, J = 7.3 Hz, 3 H) (Methyl-{2-[2-(thiophene-2-carbonyl)-4-thioρhen-3-ylphenoxy ]ethyl)- -amino)- acetic acid

137 1H NMR (300 MHz, DMSO-d6) δ 8.06 (dd, J = 4.9, 1.1 Hz, 1 H), 7.81 -7.90 (m, 2 H), 7.72 (d, J = 2.4 Hz, 1 H), 7.59-7.65 (m, 1 H), 7.53-7.59 (m, 1 H), 7.44-7.53 (m, 1 H), 7.15-7.29 (m, 2 H), 4.13 (t, J = 5.7 Hz, 2 H), 3.10 (s, 2 H), 2.76 (t, J = 5.7 Hz, 2 H), 2.23 (s, 3 H); LC-MS: m/z = 402.4

EXAMPLE 138

(Methyl- {2- [3-(3-methylbenzy l)~biphenyl-4-yloxy] ethyl}-ammo)-acetic acid

Add triethylsilane (0.5 niL) to (methyl-{2-[3-(3-methylbenzoyl)-biphLenyl-4-

yloxy] ethyl }-amino)-acetic acid (200 mg, 0.496 mmol) in neat trifluoroacetic acid (5.5

mL). Stir overnight at room temperature. Add extra equivalents of triethylsilane (0.5

mL) and stir for 2 days at room temperature. Concentrate triethylsilane and

trifluoroacetic acid in Reacti-Therm under a stream of nitrogen with heat, and purify (ion

exchange chromatography, eluting with 2 M ammonia in methanol) to give tlae title

compound as an off white solid (161.4 mg, 83%). 1HNMR (400 MHz, CDCl3) δ 2.21 (s, 3 H)5 2.53 (s, 3 H), 3.18 (t, J = 4.62 Hz, 2 H), 3.36 (s, 2 H), 3.92 (s, 2 H)5 4.16 (t5 J = 4.70 Hz5 2 H), 6.83 (d, J = 8.56 Hz, 1 H), 6. S6- 6.95 (m, 3 H), 7.06 (t, J = 7.83 Hz, 1 H), 7.18-7.27 (m, 1 H), 7.27-7.38 (m, 4 H), 7.-10- 7.51 (m, 2 H); LC-MS: m/z 390.2

EXAMPLE 139 ({2-[3-(3-ChlorobenzyI)-biphenyl-4-yloxy]ethyl}-methylamino) -acetic acic3

Add triethylsilane (0.5 mL) to ({2-[3-(3-chlorobenzoyl)-biphenyl-4-yloxy]ethyl}- methylamino)-acetic acid hydrochloride prepared essentially as described in EXAMPLE 31 (200 mg, 0.496 mmol) in neat trifluoroacetic acid (5.5 mL). Stir overnight at room temperature. Concentrate triethylsilane and trifluoroacetic acid in Reacti-Therm under a stream of nitrogen with heat and purify (ion exchange chromatography, eluting with. 2 M ammonia in methanol) to give the title compound as a yellow solid (164.0 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3 H), 3.07 (t, J = 4.77 Hz, 2 H), 3.15 (s, 2 II), 3.9 (s, 2 H), 4.15-4.24 (m, 2 H), 6.90-6.95 (m, 1 H), 7.03 (d, J = 8.56 Hz, 1 H), 7.25-737 (m, 5 H), 7.41-7.50 (m, 3 H), 7.52-7.62 (m, 2 H); LC-MS: m/z 410.1, 412.1

EXAMPLE 140 {[2-(2"-Chloro-3,4-difluoro-[l,l1;31,l"]terphenyl-4'-yloxy)e thyl]-methylamiΛo}- acetic acid

Add neat trifluoroacetic acid (0.52 niL, 7.01 mmol) to {[2-(2"-chloro-3,4-difluoro- [l,r;3'5r']terphenyl-4'-yloxy)ethyl]-methylamino}-acetic acid tert-butyl ester (171 mg, 0.35 mmol) in dichloromethane at room temperature. Stir overnight at room temperature under nitrogen. Add extra equivalents of trifluoroacetic acid (0.52 mL, 7.01 mmol) and stir overnight at room temperature. Concentrate in Reacti-Therm under a stream of nitrogen with heat and purify (ion exchange chromatography, eluting with 2 M ammonia in methanol, followed by preparative LC-MS) to give title compound as a gum (93.3 mg,

1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3 H), 3.08 (t, J = 4.89 Hz, 2 H)5 3.16 (s, 2 H), 4.12-4.28 (m, 2 H), 7.02 (d, J = 8.56 Hz, 1 H), 7.13-7.25 (m, 1 H), 7.24-7.30 (m, 2 H), 7.30-7.40 (m, 4 H), 7.43-7.55 (m, 2 H); LC-MS: m/z 432.1, 433.1

EXAMPLE 141 {[2-(3-Cyclohexyloxybiphenyl-4-yIoxy)ethyl]-methyIamino}-ace tic acid

Stir a solution of {[2-(3-iodo-biphenyl-4-yloxy)ethyl]-methylamino} -acetic acid tert-butyl ester (0.5 g, 1.07 mmol) in cyclohexanol (1 mL) in a microwave tube, and add copper (I) iodide (20.4 mg, 0.107 mmol), 1,10-phenanthroline (38.6 mg, 0.214 mmol) and cesium carbonate (697.3 mg, 2.14 mmol). Seal the tube and heat to 120 0C overnight. Add extra equivalent of cyclohexanol (1 mL), copper (I) iodide (20.4 mg, 0.107 mmol), 1,10-phenanthroline (38.6 mg, 0.214 mmol) and cesium carbonate (697.3 mg, 2.14 mmol)

and heat to 120 0C overnight. Add extra equivalent of cyclohexanol (1 mL), copper (I)

iodide (20.4 mg, 0.107 mmol), 1,10-phenanthroline (38.6 mg, 0.214 mmol) and cesium

carbonate (697.3 mg, 2.14 mmol) and further heat to 120 0C overnight. Cool to room

temperature and pour into diethyl ether (10 mL). Filter and concentrate and purify (ion

exchange chromatography, eluting with 2 M ammonia in methanol followed by

preparative LC-MS) to give the title compound (82.4 mg, 20.1%).

1H NMR (400 MHz, CDCl3) δ 1.25-1.42 (m, 3 H)5 1.50-1.63 (m, 3 H), 1.80 (dd, J = 9.78,

4.89 Hz5 2 H)5 1.96-2.09 (m5 2 H), 2.45 (none, 1 H), 2.83 (s, 3 H), 3.34-3.38 (m, 2 H),

3.59 (s, 2 H), 4.22-4.33 (m, 3 H)5 6.95 (d, J = 8.07 Hz, 1 H), 7.05-7.14 (m, 2 H)5 7.29-

7.35 (m, 1 H), 7.38-7.46 (m, 2 H), 7.48-7.54 (m, 2 H); LC-MS: m/z 384.2

The compounds of EXAMPLES 142-144 may be prepared essentially as

described in EXAMPLE 141 using the appropriate alcohol.

EX Compound Name & Data

{ [2-(3 -Butoxybiphenyl-4-yloxy)ethyl] -methylamino } -acetic acid

142 1H NMR (400 MHz5 CDCl3) δ 0.98 (t5 J = 7.34 Hz5 3 H)5 1.41-1.55 (m, 2 H)5 1.74- 1.87 (m, 2 H)5 3.03 (s, 3 H), 3.55 (t, J = 5.30 Hz5 2 H), 3.69 (s, 2 H), 4.06 (t, J = 6.72 Hz, 2 H)5 4.37 (t, J = 5.30 Hz5 2 H)5 6.95-7.03 (m, 1 H)5 7.07-7.15 (m, 2 H), 7.27-7.37 (m, 1 H), 7.38-7.47 (m, 2 H), 7.50-7.57 (m, 2 H); LC-MS: m/z 358.2

(Methyl-{2-[3-(2,2,2-trifluoroethoxy)-biphenyl-4-yloxy]et hyl}-amino)-acetic acid

1H NMR (400 MHz5 CH3OH-d4) δ 3.30 (s, 3 H)5 3.86 (t5 J = 4.86 Hz, 2 H), 3.98 (s, 143 2 H)5 4.68 (t, J = 5.03 Hz5 2 H), 4.89 (q5 J = 8.56 Hz5 2 H), 7.39 (d, J = 8.80 Hz5 1 H)5 7.48-7.59 (m, 3 H)5 7.64 (t, J = 7.70 Hz, 2 H)5 7.75-7.88 (m, 2 H); LC-MS: m/z 384.1 {[2-(3-Isopropoxybiphenyl-4-yloxy)ethyl]-methylamino}-acetic acid

144 1H NMR (400 MHz5 CDCl3) δ 1.37 (d, 6 H)5 1.38 (s, 3 H)5 2.81 (s5 3 H), 3.35 (t, J = 4.88 Hz, 2 H)5 3.59 (s, 2 H)5 4.28 (t, J = 4.96 Hz, 2 H), 4.54-4.65 (m, 1 H)5 6.95 (d5 J = 8.31 Hz, 1 H), 7.05-7.14 (m, 2 H), 7.28-7.36 (m, 1 H), 7.38-7.45 (m, 2 H), 7.46- 7.54 (m, 2 H); LC-MS: m/z 344.2

EXAMPLE 145

{[2-(2"-Chloro-3-fluoro-[l,l';3',lM]terphenyl-4'-yloxy)et hyl]-methylamino}-acetic

acid Treat a solution of {[2-(2"-chloro-3-fluoro-[l,l';3'5l"]terphenyl-4l-yloxy)ethyl ]-

methylamino} -acetic acid tert-butyl ester prepared essentially as described in Preparation

118 (152.6 mg, 0.32 mmol) in dichloromethane (2 mL) with trifluoroacetic acid (0.52

niL, -20 eq). Stir the reaction for about 1.5 h at room temperature in a disposable

carousel tube, 24 position, each containing a total volume of 2 mL of dichloromethane.

Add extra equivalent of trifluoroacetic acid (0.52 mL, 20 eq) and stir overnight at room

temperature. Concentrate the solvents in an Reacti-Therm under a stream of nitrogen

with heat, take up the residue in acetonitrile (2 mL) and purify (ion exchange

chromatography, eluting with 2 M ammonia in methanol, followed by preparative LC-

MS) to give the title compound as a white solid (92.3 mg, 70%).

1 NMR (400 MHz, CDCl3) δ 2.46 (s, 3 H), 3.21-3.30 (m, 4 H), 4.23-4.34 (m, 2 H), 6.95-

7.04 (m, 2 H), 7.22-7.40 (m, 6 H), 7.42-7.47 (m, 2 H), 7.56 (dd5 J = 8.56, 2.45 Hz, 1 H);

LC-MS: m/z 414.1, 416.1

The compounds of EXAMPLES 146-155 may be prepared essentially as

described in EXAMPLE 145.

EX Compound Name & Data

{[2-(2"-Chloro-2-methyl-[l,r;31,r']terphenyl-41-yloxy)eth yl]-methylamino}-acetic acid

146 1H NMR (400 MHz, CDCl3) δ 2.31 (s, 3 H), 2.46 (s, 3 H), 3.20-3.25 (m, 2 H), 3.26 (s, 2 H), 4.21-4.31 (m, 2 H), 7.00 (d, J = 8.56 Hz, 1 H), 7.16-7.35 (m, 9 H)5 7.42- 7.47 (m, 1 H); LC-MS: m/z 410.1, 412.1 { [2-(2"-Chloro-3 -methyl- [ 1 , l';3 ', 1 "]terphenyl-4'-yloxy)ethyl] -methylarnmo } -acetic acid

147 1HNMR (400 MHz, CDCl3) δ 2.25 (s, 3 H), 2.35 (s, 3 H), 2.84 (t, J = 5.86 Hz, 2 H), 3.14 (s, 2 H)5 4.13 (t, J = 5.86 Hz5 2 H), 7.10-7.15 (m, 1 H)5 7.21 (d, J = 8.80 Hz5 1 H)5 7.31 (t, J = 7.88 Hz5 1 H)5 7.35-7.49 (m, 6 H)5 7.50-7.55 (m, 1 H), 7.65- 7.70 (m, 1 H); LC-MS: m/z 410.1, 412.1

EX Compound Name & Data

{[2-(2"-Chloro-4-fluoro-3-methyl-[l,lt;3t5l"]terphenyl-4' -yloxy)ethyl]- methylamino} -acetic acid

154 1HNMR (400 MHz, DMSO-d6) δ 2.25 (s, 3 H), 2.28 (d, J = 1.47 Hz, 3 H), 2.84 (t, J = 5.75 Hz, 2 H), 3.14 (s, 2 H), 4.08-4.16 (m, 2 H), 7.12-7.25 (m, 2 H), 7.34-7.41 (m, 3 H), 7.43 (d, J = 2.20 Hz, 1 H), 7.45-7.56 (m, 2 H), 7.59 (dd, J = 7.34, 1.96 Hz, 1 H), 7.66 (dd, J = 8.56, 2.45 Hz, 1 H); LC-MS: m/z 428.1, 430.1 {[2-(2"-Chloro-3,4-dimethyl-[l,r;3',l"]terphenyl-4'-yloxy)et hyl]-methylamino}- acetic acid

155 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3 H), 2.25 (s, 3 H), 2.27 (s, 3 H), 2.84 (t, J = 5.87 Hz, 2 H), 3.14 (s, 2 H), 4.12 (t, J = 5.62 Hz, 2 H), 7.18 (dd, J = 8.44, 4.52 Hz, 2 H), 7.34-7.42 (m, 5 H), 7.43-7.45 (m, 1 H), 7.49-7.54 (m, 1 H), 7.65 (dd, J = 8.56, 2.45 Hz, 1 H); LC-MS: m/z 424.1, 426.1

EXAMPLE 156

{[2-(5-Benzo[l,3]dioxoI-5-yl-2'-chlorobiphenyl-2-yIoxy)et hyl]-methylamino}-acetic

acid

Add 2 N sodium hydroxide (4.5 mL) to {[2-(5-benzo[l,3]dioxol-5-yl-2'-

chlorobiphenyl-2-yloxy)ethyl]-methylamino} -acetic acid tert-butyl ester (219 mg, 0.44

mmol) in 1,4-dioxane. Heat to reflux overnight under nitrogen. Cool to room

temperature and dilute with water (4.5 mL). Wash with diethyl ether and acidify aqueous

layer with 2 N hydrochloric acid to about pH = 5. Filter precipitate and purify (ion

exchange chromatography, eluting with 2 M ammonia in methanol, followed by

preparative LC-MS). Freeze dry over 2 days to give the title compound (135.0 mg, 70%).

1H NMR (400 MHz, CDCl3) δ 2.45 (s, 3 H), 3.19-3.25 (m, 2 H), 3.26 (s, 2 H), 4.19-4.30

(m, 2 H), 5.98 (s, 2 H), 6.85 (d, J = 7.82 Hz, 1 H), 6.95-7.07 (m, 3 H), 7.27-7.32 (m, 3 H),

7.36 (d, J = 2.45 Hz, 1 H), 7.42-7.51 (m, 2 H); LC-MS: m/z 440.1, 442.1 EXAMPLE 157 {[2-(3,2"-Dichloro-[l,l';3',lM]terphenyl-4'-yloxy)ethyl]-met hylamino}-acetic acid

Treat a solution of {[2-(3,2"-dichloro-[l,r;3',l"]terphenyl-4'-yloxy)ethyl]- methylamino} -acetic acid tert-butyl ester (473 mg, 0.975 mmol) in dichloromethane (5 niL) with trifluoroacetic acid (1.69 rnL, ~20 eq). Stir overnight at room temperature. Add extra equivalents of trifluoroacetic acid (1.69 mL, 20 eq) and stir overnight at room temperature. Concentrate, take up the residue in acetonitrile and purify (ion exchange chromatography, eluting with 2 M ammonia in methanol followed by preparative LC- MS) to give the title (78.6 mg, 19%) 1H NMR (400 MHz, CDC13) δ 2.40 (s, 3 H), 3.07 (t, J = 4.77 Hz, 2 H), 3.15 (s, 2 H), 4.15-4.25 (m, 2 H), 7.03 (d, J = 8.56 Hz, 1 H), 7.24-7.28 (m, 1 H), 7.28-7.37 (m, 4 H), 7.41-7.50 (m, 3 H), 7.53-7.60 (m, 2 H); LC-MS: m/z 430.0, 432.1

The compounds of EXAMPLES 158-162 may be prepared essentially as described in EXAMPLE 157. EX Compound Name & Data { [2-(2"-Chloro-4-methoxy-3-methyl-[l , l';3 ', 1 "]terphenyl-4'-yloxy)ethyl]- methylamino} -acetic acid

158 1H NMR (400 MHz, CDCl3) δ 2.26 (s, 3 H) 2.46 (s, 3 H) 3.20-3.26 (m, 2 H) 3.27 (s, 2 H) 3.85 (s, 3 H) 4.19-4.30 (m, 2 H) 6.86 (d, J = 9.29 Hz, 1 H) 6.98 (d, J = 8.31 Hz, 1 H) 7.27-7.32 (m, 3 H) 7.33-7.38 (m, 2 H) 7.40 (d, J = 2.45 Hz, 1 H) 7.42-7.48 (m, 1 H) 7.53 (dd, J = 8.80, 2.45 Hz, 1 H); LC-MS: m/z 440.1, 442.1 { [2-(2"-Chloro-4-fluoro-[ 1 , 1 ';3 ', 1 M]terphenyl-4'~yloxy)ethyl] -methylamino } -acetic acid 159 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3 H), 2.83 (t, J = 5.75 Hz, 2 H), 3.13 (s, 2 H), 4.12 (t, J = 5.62 Hz, 2 H), 7.19-7.28 (m, 3 H), 7.35-7.45 (m, 4 H), 7.49-7.55 (m, 1 H), 7.64-7.72 (m, 3 H); LC-MS: m/z 414.1, 416.1 EX Compound Name & Data

{ [2-(2"-Chloro-2-fluoro-[ 1 , l';3 ', 1 "]terphenyl-4'-yloxy)ethyl] -methylamino } -acetic acid

160 1H NMR (400 MHz5 CDCl3) δ 2.45 (s, 3 H)5 3.19-3.24 (m, 2 H)5 3.25 (s, 2 H)5 4.22- 4.34 (m, 2 H)5 7.02 (d, J = 8.56 Hz', 1 H)5 7.09-7.22 (m, 2 H)5 7.26-7.33 (m, 4 H)5 7.39-7.49 (m, 3 H)5 7.54-7.60 (m, 1 H); LC-MS: m/z 414.1, 416.1 ({2-[2'-Chloro-5-(253-dihydrobenzofuran-5-yl)-biphenyl-2-ylo xy]ethyl}- methylamino)-acetic acid

161 1H NMR (400 MHz5 DMSOd6) δ 2.25 (s, 3 H)5 2.83 (t, J = 5.75 Hz5 2 H)5 3.13 (s, 2 H)5 3.21 (t, J = 8.68 Hz5 2 H), 4.10 (t, J = 5.62 Hz5 2 H)5 4.54 (t, J - 8.68 Hz5 2 H)5 6.80 (d, J = 8.31 Hz5 1 H)5 7.17 (d, J = 8.80 Hz5 1 H)5 7.31-7.44 (m, 5 H)5 7.47- 7.54 (m, 2 H)5 7.59 (dd5 J = 8.56, 2.45 Hz5 1 H); LC-MS: m/z 438.1 ({2-[2'-Chloro-5-(253-dihydrobenzo[l54]dioxin-6-yl)-biphenyl -2-yloxy]ethyl}- methylamino)-acetic acid

162 1H NMR (400 MHz5 DMSOd6) δ 2.22 (s, 3 H)5 2.79 (t5 J = 6.11 Hz5 2 H)5 3.03 (s, 2 H)5 4.08 (t, J = 5.87 Hz5 2 H)5 4.26 (s, 4 H)5 6.89 (d, J = 8.31 Hz5 1 H)5 7.06-7.20 (m, 3 H)5 7.32-7.41 (m5 4 H)5 7.47-7.53 (m, 1 H), 7.59 (dd, J = 8.56, 2.45 Hz5 1 H); LC-MS: m/z 454.1, 456.1

EXAMPLE 163

{[2-(3-tert-ButyI-2'-fluorobiphenyl-4-yloxy)ethyl]-methyl amino}-acetic acid

Treat a solution of { [2-(3 -tert-butyl-2'-fluorobiphenyl-4-yloxy)ethyl] -

methylamino} -acetic acid tert-butyl ester (260 mg, 0.627 mmol) in dichloromethane (4

mL) with trifluoroacetic acid (1.54 HiL5 ~20 eq). Stir overnight at room temperature. Add

extra equivalents of trifluoroacetic acid (1.69 mL5 20 eq) and stir for 5 h at room

temperature. Concentrate the solvents in a Reacti-Therm under a stream of nitrogen with

heat, take up the residue in acetonitrile (2 mL) and purify (ion exchange chromatography,

eluting with 2 M ammonia in methanol followed by preparative LC-MS) to give the title

compound (94.7 mg, 42%). 1H NMR (400 MHz5 DMSOd6) δ 1.38 (s, 9 H), 2.46 (s, 3 H), 3.05 (t, J = 5.99 Hz, 2 H),

3.33 (s, 2 H), 4.14 (t, J = 6.11 Hz, 2 H), 7.09 (d, J = 8.31 Hz, 1 H), 7.23-7.31 (m, 2 H),

7.31-7.40 (m, 3 H), 7.46-7.53 (m, 1 H); LC-MS: m/z 360.2

The compounds of EXAMPLES 164-171 may be prepared essentially as

described in EXAMPLE 163.

EX Compound Name & Data

{[2-(3-tert-Butyl-3'-fluorobiphenyl-4-yloxy)ethyl]-methyl amino}-acetic acid

164 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.45 (m, 9 H), 2.46 (s, 3 H), 3.04 (t, J = 5.99 Hz, 2 H), 3.33 (s, 2 H), 4.14 (t, J = 5.99 Hz, 2 H), 7.02-7.20 (m, 2 H), 7.37- 7.52 (m, 5 H); LC-MS: m/z 360.2 {[2-(3-tert-Butyl-4'-fluorobiphenyl-4-yloxy)ethyl]-methylami no}-acetic acid

165 1H NMR (400 MHz, DMSOd6) δ 1.39 (s, 9 H), 2.46 (s, 3 H), 3.04 (t, J = 6.11 Hz, 2 H), 3.32 (s, 2 H), 4.13 (t, J = 6.11 Hz, 2 H), 7.07 (d, J = 9.05 Hz, 1 H), 7.19-7.31 (m, 2 H), 7.37-7.46 (m, 2 H), 7.56-7.67 (m, 2 H); LC-MS: m/z 360.2 { [2-(3 -tert-Butyl-3 ',4!-difluorobiphenyl-4-yloxy)ethyl] -methylamino } -acetic acid

166 1H NMR (400 MHz, DMSO-d6) δ 1.39 (s, 9 H), 2.46 (s, 3 H), 3.03 (t, J = 5.99 Hz, 2 H), 3.33 (s, 2 H), 4.13 (t, J = 5.99 Hz, 2 H), 7.08 (d, J = 8.56 Hz, 1 H), 7.40-7.54 (m, 4 H), 7.63-7.73 (m, 1 H); LC-MS: m/z 378.2 { [2-(3-tert-Butyl-3 '-chlorobiphenyl-4-yloxy)ethyl] -methylamino } -acetic acid

1H NMR (400 MHz, DMSOd6) δ 1.28-1.43 (m, 9 H), 2.46 (s, 3 H), 3.04 (t, J = 167 5.99 Hz, 2 H), 3.33 (s, 2 H)5 4.14 (t, J = 6.11 Hz, 2 H), 7.09 (d, J = 8.56 Hz, 1 H), 7.35 (dd, J = 7.95, 1.10 Hz, 1 H), 7.40-7.52 (m, 3 H), 7.57 (d, J = 8.07 Hz, 1 H), 7.64 (t, J = 1.83 Hz, 1 H); LC-MS: m/z 316.2, 378.2 { [2-(3 -tert-Butyl-4'-methoxybiphenyl-4-yloxy)ethyl] -methylamino } -acetic acid

168 1H NMR (400 MHz, DMSOd6) δ 1.39 (s, 9 H), 2.45 (s, 3 H), 3.03 (t, J = 6.11 Hz, 2 H), 3.31 (s, 2 H), 3.78 (s, 3 H), 4.11 (t, J = 6.11 Hz, 2 H), 6.94-7.08 (m, 4 H), 7.34-7.41 (m, 2 H), 7.51 (d, J = 8.56 Hz, 2 H); LC-MS: m/z 372.2 {[2-(3-tert-Butyl-4'-methoxy-3'-methylbiphenyl-4-yloxy)ethyl ]-methylamino}- acetic acid

169 1H NMR (400 MHz, DMSOd6) δ 1.39 (s, 9 H), 2.20 (s, 3 H), 2.46 (s, 3 H), 3.03 (t, J = 6.11 Hz, 2 H), 3.32 (s, 2 H), 3.80 (s, 3 H), 4.11 (t, J = 6.11 Hz, 2 H), 6.93-7.00 (m, 1 H), 7.03 (d, J = 8.31 Hz, 1 H), 7.32-7.43 (m, 4 H); LC-MS: m/z 386.2 EX Compound Name & Data

( {2-[2-tert-Butyl-4-(2,3 -dihydrobenzofuran-5 -yl)-phenoxy] ethyl} -methylamino)- acetic acid

170 1H NMR (400 MHz, DMSO-d6) δ 1.38 (s, 9 H), 2.46 (s, 3 H), 3.03 (t, J = 6.11 Hz, 2 H), 3.22 (t, J = 8.68 Hz5 2 H), 3.32 (s, 2 H), 4.11 (t, J = 6.11 Hz, 2 H), 4.54 (t, J = 8.68 Hz, 2 H), 6.79 (d, J = 8.31 Hz5 1 H)5 7.03 (d, J = 8.31 Hz5 1 H)5 7.28 (dd, J = 8.3I5 1.96 Hz5 1 H)5 7.32-7.39 (m, 2 H), 7.44 (s, 1 H); LC-MS: m/z 384.2 ({2-[2-tert-Butyl-4-(2,3-dihydrobenzo[l54]dioxin-6-yl)-pheno xy]ethyl}- methylamino)-acetic acid

171 1H NMR (400 MHz5 DMSO-d6) δ 1.38 (s, 9 H), 2.45 (s, 3 H)5 3.03 (t, J = 5.99 Hz5 2 H)5 3.32 (s, 2 H), 4.11 (t, J = 6.11 Hz, 2 H)5 4.26 (s, 4 H)5 6.86-6.92 (m, 1 H)5 6.99-7.07 (m, 3 H)5 7.32-7.39 (m5 2 H); LC-MS: m/z 400.2

EXAMPLE 172

{[2-(4-Benzo[l,3]dioxol-5-yl-2-tert-bufylphenoxy)ethyl]-m ethylamino}-acetic acid

Add 2 N sodium hydroxide (7.5 mL) to { [2-(4-benzo[l ,3]dioxol-5-yl-2-tert-

butylphenoxy)ethyl]-methylamino} -acetic acid tert-butyl ester (340 mg, 0.77 mmol) in

1,4-dioxane (7.5 mL). Heat to reflux overnight under nitrogen. Cool to room

temperature and dilute with water (15 mL). Wash with diethyl ether and acidify aqueous

layer with 2 N hydrochloric acid to about pH = 5-6. Concentrate and wash residue with

1,4-dioxane. Filter sodium chloride precipitate, concentrate filtrate and purify (ion

exchange chromatography, eluting with 2 M ammonia in methanol, followed by

preparative LC-MS), to give the title compound (61.7 mg, 21%).

1H NMR (400 MHz5 DMSOd6) δ 1.38 (s, 9 H), 2.45 (s, 3 H)5 3.03 (t, J = 6.11 Hz5 2H)5

3.32 (s, 2 H), 4.11 (t, J = 5.99 Hz5 2 H), 6.03 (s, 2 H), 6.90-6.99 (m, 1 H)5 6.99-7.08 (m, 2

H), 7.15 (d, J = 1.71 Hz5 1 H)5 7.32-7.41 (m, 2 H); LC-MS: m/z 386.2 EXAMPLE 173

({2-[3-(2,2-Dimethylpropyl)-2'-fluorobiphenyl-4-yloxy]eth yl}-methylamino)-acetic

acid

Treat a solution of ({2-[3-(252-dimethylpropyl)-2'-fluorobiphenyl-4-yloxy]ethyl} -

methylamino)-acetic acid tert-butyl (445 mg, 1.04 mmol) in dichloromethane (4 mL) with

trifluoroacetic acid (1.66 mL, ~20 eq). Stir for 5 h in a sealed carousel tube. Add extra

equivalents of trifluoroacetic acid (1.42 mL, 5 eq) and stir overnight at room temperature.

Concentrate the solvents in a Reacti-Therm under a stream of nitrogen with heat, take up

the residue in acetonitrile (2 mL) and purify (ion exchange chromatography, eluting with

2 M ammonia in methanol followed by preparative LC-MS) to give the title compound

(98.3 mg, 25%).

1H NMR (400 MHz, DMSOd6) δ 0.90 (s, 9 H), 2.50 (s, 3 H), 2.56 (s, 2 H), 3.01 (t, J =

5.75 Hz, 2 H), 3.32 (s, 2 H), 4.09 (t, J = 5.75 Hz, 2 H)5 7.07 (d, J = 8.56 Hz, 1 H), 7.23-

7.30 (m, 3 H), 7.32-7.40 (m, 2 H), 7.44-7.51 (m,-l H); LC-MS: m/∑ 374.2

The compounds of EXAMPLES 174-181 may be prepared essentially as

described in EXAMPLE 173.

EX Compound Name & Data

({2-[3-(2,2-Dimethylpropyl)-3'-fluorobiphenyl-4-yloxy]eth yl}-methylamino)-acetic acid

174 1H NMR (400 MHz, DMSO-d6) δ 0.90 (s, 9 H), 2.47 (s, 3 H), 2.58 (s, 2 H), 3.01 (t, J = 5.75 Hz, 2 H), 3.32 (s, 2 H), 4.09 (t, J = 5.87 Hz, 2 H)5 7.01-7.17 (m, 2 H), 7.35-7.55 (m, 5 H); LC-MS: m/z 374.2 ({2- [3 -(2,2-Dimethylpropyl)-4'-fluorobiphenyl-4-yloxy] ethyl} -methylamino)-acetic acid

175 1H NMR (400 MHz, DMSO-d6) δ 0.90 (s, 9 H)5 2.48 (s, 3 H)5 2.57 (s, 2 H), 3.01 (t, J = 5.87 Hz5 2 H)5 3.33 (s, 2 H), 4.09 (t5 J = 5.75 Hz5 2 H)5 7.04 (d, J = 8.56 Hz, 1 H)5 7.16-7.37 (m, 3 H), 7.44 (dd, J = 8.56, 2.45 Hz5 1 H)5 7.56-7.66 (m5 2 H); LC- EX Compound Name & Data

MS: m/z 374.2 ({2-[3'-Chloro-3-(2,2-dimethylρroρyl)-biphenyl-4-yloxy]eth yl}-methylamino)- acetic acid

176 1H NMR (400 MHz5 DMSOd6) δ 0.90 (s, 9 H)5 2.47 (s, 3 H)5 2.58 (s, 2 H)5 3.01 (t5 J = 5.75 Hz5 2 H)5 3.32 (s, 2 H)5 4.09 (t, J = 5.87 Hz5 2 H), 7.06 (d, J - 8.56 Hz5 1 H), 7.33-7.40 (m, 2 H)5 7.45 (t, J = 7.82 Hz, 1 H)5 7.51 (dd, J = 8.56 Hz, 1 H)5 7.57 (d, J = 7.82 Hz5 1 H), 7.63 (t, J = 1.71 Hz5 1 H); LC-MS: m/z 390.2, 392.2 ({2-[3-(252-Dimethylpropyl)-4'-methoxybiphenyl-4-yloxy]ethyl }-methylammo)- acetic acid

177 1H NMR (400 MHz5 DMSOd6) δ 0.90 (s, 9 H), 2.48 (s, 3 H)5 2.56 (s, 2 H)5 3.02 (t5 J = 5.75 Hz, 2 H), 3.35 (s5 2 H)5 3.78 (s, 3 H)5 4.08 (t, J = 5.62 Hz5 2 H), 7.00 (t, J = 9.41 Hz5 3 H), 7.28 (d, J = 2.20 Hz5 1 H)5 7.40 (dd, J = 8.56, 2.20 Hz, 1 H)5 7.51 (d, J = 8.80 Hz, 2 H); LC-MS: m/z 386.2 ({2- [3 -(252-Dimethylρropyl)-4'-methoxy-3 '-methylbiphenyl-4-yloxy] ethyl} - methylamino)-acetic acid

178 1H NMR (400 MHz5 DMSOd6) δ 0.90 (s, 9 H), 2.20 (s, 3 H), 2.48 (s, 3 H)5 2.56 (s, 2 H), 3.01 (t, J = 5.75 Hz5 2 H), 3.33 (s, 2 H), 3.78-3.83 (m, 3 H)5 4.07 (t, J = 5.75 Hz5 2 H), 6.95-7.03 (m, 2 H)5 7.27 (d, J = 2.45 Hz5 1 H), 7.34-7.41 (m, 3 H); LC- MS: m/z 400.3 ({2-[4-(253-Dihydrobenzofuran-5-yl)-2-(252-dimethypropyl)-ph enoxy]ethyl}- methylamino)-acetic acid

179 1H NMR (400 MHz, CDCl3) δ 7.22-7.38 (m, 4 H)5 6.85 (dd, J= 16.4, 8.3 Hz5 2 H)5 4.60 (t, J = 8.7 Hz5 2 H)5 4.14 (t, J = 5.0 Hz, 2 H), 3.41 (s, 2 H)5 3.26 (t, J = 8.7 Hz, 2 H)5 3.13 (t, J = 5.0 Hz, 2 H)5 2.63 (s, 3 H), 2.60 (s, 2 H), 0.94 (s, 9 H); LC-MS: m/z = 398.2 ({2-[4-(2,3-Dib.ydrobenzo[l54]dioxin-6-yl)-2-(252-dimethylpr opyl)-phenoxy]ethyl}- methylamino)-acetic acid

180 1H NMR (400 MHz, DMSOd6) δ 7.37 (dd5 J = 8.6, 2.4 Hz5 1 H)5 7.25 (d, J = 2.2 Hz5 1 H)5 6.96-7.06 (m, 3 H)5 6.87-6.93 (m, 1 H), 4.26 (s, 4 H), 4.07 (t, J=5.7 Hz5 2 H)5 3.34 (s, 2 H), 3.00 (t, J = 5.6 Hz5 2 H), 2.55 (s, 2 H), 2.47 (s, 3 H), 0.89 (s., 9 H); LC-MS: m/z = 414.2 ({2-[3-(2,2-Dimethylpropyl)-3l54l-difluorobiphenyl-4-yloxy]e thyl}-methylamino)- acetic acid

1H NMR (400 MHz5 CDCl3) δ 7.08-7.39 (m, 5 H), 6.90 (d, 1 H), 4.20 (t, J = 5.1 Hz, 2 H), 3.47 (s, 2 H)5 3.19 - 3.27 (m, 2 H)5 2.71 (s, 3 H)5 2.60 (s, 2 H), 0.94 (s, 9 H); LC-MS: m/z = 392.2

EXAMPLE 182 ({2-[4-Benzo[l,3]dioxol-5-yl-2-(2,2-dimethylpropyl)-phenoxy] ethyl}-methylamino)- acetic acid

Add 2 N sodium hydroxide (11 mL) to ({2-[4-benzo[l,3]dioxol-5-yl-2-(2,2- dimethylpropyl)-phenoxy] ethyl }-methylamino)-acetic acid tert-butyl ester (496 mg, 1.09 mmol) in 1 54-dioxane (11 mL). Heat to reflux overnight under nitrogen. Cool to room temperature and dilute with water (22 mL). Wash with diethyl ether and acidify the aqueous layer with 2 N hydrochloric acid to about pH = 3. Concentrate solution, wash residue with 1,4-dioxane, filter sodium chloride precipitate, concentrate filtrate and purify (ion exchange chromatography, eluting with 2 M ammonia in methanol, followed by preparative LC-MS), to give the title compound (149 mg, 34%). 1HNMR C400 MHz, DMSO-d6) δ 0.90 (s, 9 H), 2.48 (s, 3 H), 2.56 (s, 2 H), 3.02 (t, J = 5.75 Hz, 2 H), 3.34 (s, 2 H), 4.08 (t, J = 5.75 Hz, 2 H), 6.03 (s, 2 H), 6.88-7.09 (m, 3 H)5 7.14 (d, J = 1.71 Hz, 1 H), 7.27 (d, J = 2.45 Hz, 1 H), 7.39 (dd, J = 8.56, 2.45 Hz, 1 H); LC-MS: m/z 400.2

EXAMPLE 183 {[2-(3-tert-Butyl-3',5'-difluoro-4'-methoxybiphenyl-4-yloxy) ethyl]-methylamino}- acetic acid

Treat a solution of { [2-(3-tert-butyl-3',5 -difluoro-4'-methoxybiphenyl-4- yloxy)ethyl]-methylamino} -acetic acid prepared essentially as described in Preparation 158 (126 mg, 0.27 mmol) in dichloromethane (2.5 mL) with trifluoroacetic acid (0.42 mL, 20 eq). Stir the reaction overnight at room temperature in a sealed tube. AxId extra equivalents of trifluoroacetic acid (0.2ImL, 10eq) and stir overnight at room temperature. Evaporate the solvent in a Reacti-Therm™ under a stream of nitrogen with heat, take up the residue in acetonitrile, load onto an ion exchange column, wash with acetonitrile and elute with 2 M ammonia in methanol. Evaporate solvent in a Reacti-Therm™ under a stream of nitrogen with heat and purify by preparative LC-MS to give the title compound (86 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J - 2.2 Hz, 1 H), 7.29 (dd, J = 8.4, 2.3 Hz, 1 H), 6.99-7.09 (m, 2 H), 6.94 (d, J = 8.3 Hz, 1 H), 4.30 (t, J = 5.4 Hz, 2 H)5 4.01 (s, 3 H), 3.51 (s, 2 H), 3.34 (t, J = 5.3 Hz5 2 H), 2.75 (s, 3 H), 1.42 (s, 9 H); LC-MS: m/z = 4O8.2

EXAMPLE 184 ({2-[3-(2,2-Dimethylpropyl)-biphenyl-4-yloxy]ethyl}-methylam ino)-acetic acid

Add 2 N sodium hydroxide (70 mL, 140 mmol) to a solution of ({2-[3-(2,2- dimethylpropyl)-biphenyl-4-yloxy]ethyl}-methylamino)-acetic acid text-butyl ester (5.65 g, 13.72 mmol) in 1,4-dioxane (140 mL). Stir at 110-115 0C for 4 h. Cool to room temperature, dilute with water (15 mL and 10 mL) and wash the aqueous layer with diethyl ether (300 mL). Wash, the organic phase with water (3O mL). Combine the aqueous layers and acidify by dropwise addition of 5 N hydrochloric acid over 30 min to about pH = 3-3.5. Apply a gentle nitrogen stream over the reaction mixture to concentrate the aqueous/ 1,4-dioxane solution by 10-15% and leave stirring 30-40 min. Filter and dry under high vacuum to give the title compound (4.495 g, 92%). 1HNMR (400 MHz5 CDCl3,) δ 7.55-7.53 (m, 2H), 7.43 (dd, J = 8 Hz5 J = 2.8 Hz5 2H), 7.38 (t, J = 8Hz, IH), 7.3 1 (d, J = 2.8 Hz5 IH)5 7.28-7.24 (m, IH), 7.01 (d, J = 8.4 Hz5 IH), 4.14 (t, J = 5.6 Hz, 2H), 3.57 (s, 2H), 3.16 (t, J = 5.6 Hz5 2H)5 2.59 (s, 2H)5 2.54 (s, 3H), 0.86 (s, 9H); LC-MS: m/z = 356.0, 3 78.O5 354.2, 709.0

EXAMPLE 185 ({2- [3-(2,2-Dimethylpropionyl)-biphenyl-4-yloxy] ethyl}-methylamino)-acetic acid

Add trifluoroacetic acid (5 mL) to a solution of the ({2-[3-(2,2- dimethylpropionyl)-biphenyl-4-yloxy] ethyl } -methylamino)-acetic acid tert-butyl e ster (2.02 mmol, 0.86 g) in dichloromethane (5 mL) and leave stirring at room temperature overnight monitoring by Flow injection Analysis (FIA). Add more trifluoroacetic acid (2 mL) and stir 4 h. Concentrate, wash the residue with dichloromethane (2 x 20 mL) and concentrate. Take up the residue in acetonitrile (2 x 20 mL) and purify by ion exchange chromatography to give the free acid as an oil (0.842 g) crystallizing partially on standing. Triturate the residue with diethyl ether (~20 mL) and filter to give the first batch of title compound. (0.473 g) as a white solid. Take up the remaining materiel in dichloromethane and concentrate to give a second batch of the title compound (0.2 g) (90%, total combined yield). 1H NMR (400 MHz5 CDCl3) δ 7.47-7.42 (m, 3H)5 7.37-7.32 (m, 2H)5 7.28-7.22 (m5 IH), 7.19-7.15 (m, IH)5 6.93 Cd, J = 8.47 Hz, IH)5 4.19 (t, J = 5.1 Hz, 2H), 3.34 (s, 2H)5 3.13 (t, J = 5.1 Hz5 2H), 2.58 Cs, 3H), 1.17 (s, 9H); LC-MS: m/z = 370.4, 392.4

EXAMPLE 186 ({2- [3-(Hy droxypheny Imethyl)-biphenyl-4-yloxy] ethyl}-methylamino)-acetic acid Add sodium borohydride (1.1 mg, 0.029 mmol) to a solution of {[2-(3- benzoylbiphenyl-4-yloxy)ethyl]-methylainino} acetic acid (22 mg, 0.0564 mmol) in methanol/acetonitrile (2 mL) and stir for 20 min at room temperature. Quench by adding water and purify by ion exchange chromatography. Lyophilize (1 : 1 water: acetonitrile) to give the title compound (10.6 mg, 48%). 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 2.45 Hz, IH), 7.55 (broad d, J = 7.3 Hz, 2H), 7.48-7.39 (m, 5H), 7.27 (q, J = 5.3 Hz, 3H), 7.17-7.13 (m, IH), 7.04 (d, J = 8.7 Hz, IH3), 6.1 (s, IH), 4.07 (t, J = 5.7 Hz, 2H)5 2.84-2.80 (m, 4H), 2.31 (s, 3H); LC-MS: m/z = 374, 414

EKAMPLE 187 {[2-(5-Benzoyl-2-methoxybipheαyl-4-yloxy)ethyl]-methylamino }-acetic acid

Add trifluoroacetic acid (2 mL) to a solution of {[2-(5-benzoyl-2- methoxybiphenyl-4-yloxy)ethyl]-methylamino} -acetic acid tert-butyl ester (71 mg, 85% pure) in dichloromethane (2 mL). Leave stirring overnight at room temperature. Concentrate, take up the residue in dichloromethane (10 mL), wash the organic phase with water (2 mL), separate and concentrate. Purify by ion exchange chromatography and preparative LC-MS and lyophilize (^1:1 wateπacetonitrile) to give the title compound as a white solid (38.5 mg). 1H NMR (400 MHz, DMSO-d6) δ 7.70-7.66 (m, 2H), 7.63-7.58 (m, IH), 7.51-7.46 (m, 4H), 7.42-7.37 (m, 2H), 7.33-7.26 (m, 2H)5 6.89 (s, IH), 4.12 (t, J = 5.7 Hz, 2H), 3.90 (s, 3H), 3.04 (s, 2H), 2.53 (t, 5.7 Hz, 2H), 2.16 (s, 3H); LC-MS: m/z = 420, 442

EXAIMPLE 188 {Methyl-[2-(3-phenylsuIfanylbipbιenyl-4-yloxy)ethyl]-ainino }-acetic acid

Add trifluoroacetic acid (1 mL) to a solution of {methyl-[2-(3- phenylsulfanylbiphenyl-4-yloxy)ethyl]-amino} -acetic acid tert-butyl ester (0.962 mmol, 0.432 g) in dichloromethane (2 mL). Stir overnight at room temperature. Add more trifluoroacetic acid (2 mL) over the course of 6 h and concentrate. Wash the residue with dichloromethane (10 mL), concentrate and purify by ion exchange chromatography. A small trace of protected acid being detected, redissolve the residue in 3:1 trifluoroacetic acid:dichloromethane (10 mL), stir at room temperature and after 3 h purify by ion exchange chromatography. Lyophilize (1 : 1 wateπacetonitrile) to give the title compound as a powder (363.7 mg, 96%). 1R NMR (300 MHz, CDCl3) δ 7.57 (dd, J = 2.3 Hz, J = 8.5 Hz, IH), 7.49-7.26 (m, 1 IH), 7.19 (d, J = 8.5 Hz, IH), 4.17 (t, J = 5.6 Hz, 2H), 3.29 (s, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.27 (s, 3H); LC-MS: m/z = 394.4, 416.3

EXAMPLE 189 {[2-(3-Isobutyrylbiphenyl-4-yloxy)ethyl]-methylamino}-acetic acid Dissolve {[2-(3-isobutyrylbiphenyl-4-yloxy)etiiyl]-methylamino} -acetic acid tert- butyl ester (1.49 mmol, 0.613 g) in a 1:1 trifluoroacetic acid:dichloromethane solution (20 mL) and stir at room temperature overnight. Concentrate and take up the residue in acetonitrile and purity by ion exchange chromatography to give the title compound (526 mg, 99%). 1H NMR (400 MHz5 DMSO-d6) δ 7.79 (dd, J = 2.5 Hz, J = 8.6 Hz, 2H), 7.66 (d, J = 2.5 Hz, IH), 7.64 (dd, J = 1.2 Hz, J = 8.6 Hz, IH), 7.45 (broad t, J = 7.6 Hz, 2H), 7.33 (broad t, J = 7.6 Hz, IH), 7.26 (d, J = 78.6 Hz, IH), 4.22 (t, J = 5.6 Hz, 2H), 3.59-3.51 (m, IH), 3.35 (s, 2H), 2.99 (t, J = 5.6 Hz, 2H), 2.42 (s, 3H), 1.08 (d, J = 7.1 Hz, 6H); LC-MS: m\z = 356.2, 378.1

EXAMPLE 190 {[2-(3-tert-Butylbiphenyl-4-yloxy)ethyl]-m- ethylamino}-acetic acid

Add 2 N sodium hydroxide (95.6 mL, 192.0 mmol) to a solution of {[2-(3-tert- butylbiphenyl-4-yloxy)ethyl]-methylamino}-acetic acid tert-butyl ester (7.6 g, 19.11 mmol) in 1,4-dioxane (190 mL). Heat to 115 0C for 4 Ia. Cool to room temperature, dilute with water (10 mL) and wash with diethyl ether (50 mL). Acidify the aqueous layer to about pH = 4 by the dropwise addition of 5 N hydrochloric acid. Filter the precipitate and dry to give the title compound as a white solid (6.2 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ 7.60-7.57 (m, 2H), 7.46-7.40 (rn, 4H), 7.30 (t, J = 7.3

Hz, IH5), 7.09-7.07 (m, IH), 4.13 (t, J = 6.1 Hz, 2H5), 3.32 (s, 2H)3 3.04 (t, J = 6.1 Hz,

2H), 2.46 (s, 3H), 1.40 (s, 9H); HRMS m/z Calculated: 342.2069; Found: 342.2071

Alternatively, add trifluoroacetic acid (10 mL) to a solution of crude {[2-(3-tert-

butylbiphenyl-4-yloxy)ethyl]-methylamino} -acetic acid tert-butyl ester (0.448 g) in

dichloromethane (10 mL) with a catalytic amount of water and stir overnight at room

temperature. Concentrate and purify by preparative LC-MS to give the title compound

(213 mg).

LC-MS: m/z = 342.2

The compounds of EXAMPLES 191-194 may be prepared, essentially as

described in EXAMPLE 190.

EX Compound Name & Data

{Methyl-[2-(3-trifluoromethoxybiphenyl-4-yloxy)ethyl]-ani ino}-acetic acid

191 1H NMR (400 MHz, DMSO-d6) δ 7.69-7.62 (m, 4H), 7.46 (jt, J = 7.6 Hz, 2H), 7.38- 7.34 (m, 2H), 4.23 (t, J = 5.6 Hz, 2H), 3.33 (s, 2H), 3.00 (t, J - 5.6 Hz, 2H,), 2.45 (s, 3H,); LC-MS: m\z = 370.1, 392.1 {[2-(4'-Fluoro-3-isobutylbiphenyl-4-yloxy)ethyl]-methylamLin o}-acetic acid

192 1H NMR (400 MHz, DMSO-d6) δ 7.65-7.61 (m, 2H), 7.44 Cdd, J = 2.4 Hz, J = 8.6 Hz, IH), 7.36 (d, J = 2.4 Hz, IH)5 7.24 (t, J = 8.8 Hz, 2H), 7.03 (d, J = 8.6 Hz, IH), 4.12 (t, J = 5.4 Hz, 2H), 3.30 (s, 2H), 3.02 (t, J = 5.4 Hz, 2HQ, 2.52-2.48 (m, 5H), 1.96-1.87 (m, IH), 0.87 (d, J = 6.6 Hz, 6H); LC-MS: m\z =360.2 {[2-(3',4'-Difluoro-3-isobutylbiphenyl-4-yloxy)ethyl]-methyl ammo}-acetic acid

193 1H NMR (400 MHz, DMSO-d6) δ 7.72-7.65 (m, IH), 7.50-7.41 (m, 4H), 7.03 (d, J = 8.5 Hz, IH), 4.12 (t, J = 5.5 Hz, 2H), 3.34 (s, 2H), 3.02 (t, J = 5.5 Hz, 2H), 2.51- 2.47 (m, 5H), 1.98-1.85 (m, IH), 0.87 (d, J = 6.6 Hz, 6H)); LC-MS: m\z = 378.2 { [2-(4-Benzo [1,3] dioxol-5 -yl-2-isobutylphenoxy)ethyl] -methylamino } -acetic acid

1H NMR (400 MHz5 DMSO-d6) δ 7.38 (dd, J = 2.4 Hz, J = 8.5 Hz, IH), 7.31 (d, J = 194 2.4 Hz, IH), 7.16 (d, J = 1.7 Hz5 IH)5 7.06 (dd, J = 1.7 Hz, 8.1 Hz, IH), 6.98 (d, J = 8.5 Hz, IH), 6.95 (d, J = 8.1 Hz, IH), 4.11 (t, J = 5.6 Hz, 2H), 3.34 (s, 2H), 3.01 (t, J = 5.6 Hz, 2H), 2.50-2.46 (m, 5H), 1.95-1.84 (m, IH), 0.87 (d, J = 6.6 Hz, 6H); LC-MS: m\z = 386.2

EXAMPLE 195

{[2-(3-IsobutyIbiphenyl-4-yIoxy)ethyl]-methylamino}-aceti c acid ' O Treat {[2-(3-isobutyrylbiphenyl-4-yloxy)ethyl]-methylanαino}-acet ic acid (0.937 mmol, 0.333 g) with triethylsilane (31.3 mmol, 0.54 niL) and trichloroacetic acid (5 mL). Stir overnight, concentrate, purify by ion exchange chromatography and lyophilize (1:1 wateπacetonitrile) to give the title compound as a white powder (245.64 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ 7.59 (broad d, J = 7.3 Hz, 2H5), 7.47-7.37 (m, 4H), 7.29 (t, J = 7.3 Hz, IH5), 7.03 (d, J = 8.6 Hz3 IH5), 4.12 (t, J = 5.6 Hz, 2H,)5 3.35 (s, 2H), 3.03 (t, J = 5.6 Hz, 2H), 2.50-2.49 (m, 5H), 1.94-1.87 (m, IH)5 0.88 (d, J = 6.6 Hz, 6H5); LC-MS: m\z = 342.2, 365.1

EXAMPLE 196 {[2-(4'-Fluoro-3-thiophen-2-ylmethylbiphenyl-4-yloxy)ethyl]- methylamino}-acetic acid

Add 2 N sodium hydroxide (2 mL) to a solution of { [2-(4-'-fluoro-3-thiophen-2- ylmethyl-biphenyl-4-yloxy)ethyl]-methylamino} -acetic acid tert-butyl ester in 1,4- dioxane (4 mL). Stir at about 115 0C for 5 h. Cool to room temperature, dilute with water (10 mL) and wash the aqueous layer with diethyl ether (30 mL). Dilute with acetonitrile (10 mL) and purify by ion exchange chromatography. Concentrate and dissolve the residue in 1 :1 water: acetonitrile (5 mL) and lyophilize to give the title compound (83.3 mg, 43% over two steps). 1H NMR (400 MHz, DMSO-d6) δ 7.57-7.53 (m, 2H)5 7.46-7.41 (m, 2H)5 7.25-7.17 (m5

3H), 7.02 (d, 8.8 Hz3 IH), 6.92-6.85 (m, 2H)5 4.09 (s, 2H)5 4.04 (t, 6.4 Hz, 2H), 2.28 (t,

6.4 Hz5 2H), 2.76 (s, 2H)5 2.27 (s, 3H); LC-MS: m\z = 400.0, 421.7

The compounds of EXAMPLES 197-198 may be prepared essentially as

described in EXAMPLE 196.

EX Compound Name & Data

{ [2-(3 ' ,4'-Difluoro-3 -thiopb.en-2-ylmethylbiphenyl-4-yloxy)ethyl]-met]iylamino } - acetic acid

197 1HNMR (400 MHz5 DMSO-d6) δ 7.69-7.62 (m, IH), 7.57-7.38 (m, 4H)5 7.23 (dd, J = 4.8 Hz5 J - 1.2 Hz, IH), 7.04 (d, J = 8 Hz, IH), 6.89-6.85 (m, 2H), 4,13-4.09 (m, 4H), 3.28(s, 2H)5 2.98 (t, J = 5.6 Hz, 2H)5 2.4 (s, 3H); LC-MS: m\∑ = 418.0, 439.7 ({2-[4-(2,3-Dihydrobenzoruran-5-yl)-2-tMophen-2-ylmethylphen oxy]etliyl}- methylamino)-acetic acid

198 1H NMR (400 MHz5 DMSO-d6) δ 7.38-7.33 (m, 3H), 7.24-7.21 (m, 2H), 6.99-6.96 (m, IH)5 6.89-6.85 (m, 2H)5 6.74 (d, J = 8 Hz, IH), 4.49 (t, J = 9 Hz, 2HT) 4.07 (s, 2H)5 4.00 (broad s, 2H), 3.16 (t, J = 9 Hz, 2H), 2.84 (broad s, 2H), 2.79 Cs3 2H), 2.28 (s, 3H); LC-MS: m\z = 424.0, 445.8

EXAMPLE 199

{[2-(3-IsobutyI-4'-methoxy-3'-methylbiphenyl-4-yIoxy)ethy l]-methylamino}-acetic

acid

Add 2 N sodium hydroxide (3.4 mL, 6.8 mmol) to a solution of {[2-(3— isobutyl-4'-

methoxy-3'-methylbiphenyl-4-yloxy)ethyl]-methylamino}-ace tic acid tert-but^l ester

(302.8 mg, 0.685 mmol) in 1,4-dioxane (6.8 mL) and stir at 110 0C for 7.5 h. Cool to

room temperature, dilute with water (~6 mL) and wash with diethyl ether (15O to 200 mL). Wash he organic phase twice with water (~ 4 mL), combine the aqueous ph_ases,

acidify by dropwise addition of 5 N hydrochloric acid to about pH = 3.5-4 to precipitate

out the solid. Filter off the white solid and dry under high vacuum to give the title

compound as a white powder (180.8 mg, 68%).

1H NMR (400 MHz, DMSO-d6) δ 7.36-7.34 (m, 2H), 7.32 (d, J = 2.6 Hz, IH), 7.26 (d, J

= 2.6 Hz, IH5), 6.93 (broad t, J = 8.1 Hz, 2H5), 4.06 (t, J = 5.71 Hz, 2H5), 3.76 (s, 3H), 3.3

(s, 2H), 2.97 (t, J = 5.71 Hz, 2H), 2.47-2.43 (m, 5H), 2.15 (s, 3H), 1.89-1.82 (m, L H), 0.83

(d, J = 6.6 Hz, 6H); LC-MS: m\z = 386.0, 408.0

The compounds of EXAMPLES 200-203 may be prepared essentially as

described in EXAMPLE 199. EXAMPLE 203 is isolated as the trifluoroacetate salt after

additional HPLC purification.

EX Compound Name & Data

({2-[4-(2,3-Dihydrobenzofuran-5-yl)-2-isobutylphenoxy]eth yl}-methylamirio)- acetic acid

200 1H NMR (400 MHz, DMSO-d6) δ 7.42-7.40 (m, IH), 7.32-7.24 (m, 3H), 6.93 (d, J = 8.35 Hz, IH), 6.74 (d, J = 8.35 Hz, IH), 4.50 (t, J = 8.8 Hz, 2H), 4.05 (t, T = 5.7 Hz, 2H), 3.30 (s, 3H), 3.17 (t, J = 8.8 Hz, 2H), 2.97 (t, J = 5.7 Hz, 2H,), 2.47-2.42 (m, 5H), 1.85 (s, 3H), 1.89-1.82 (m, IH), 0.83 (d, J = 6.6 Hz, 6H); LC-MS: m\z = 384.0, 406.0, 382.0, 765 {[2-(3'-Fluoro-3-isobutylbiphenyl-4-yloxy)ethyl]-methylammo} -acetic acid-

1H NMR (400 MHz, DMSO-d6) δ 7.46 (dd, J = 8.8 Hz, J = 2.8 Hz, IH), 7.4-2-7.38 201 (m, 4H), 7.09-7.04 (m, IH), 6.99 (d, J = 8.4 Hz, IH), 4.08 (t, J = 5.6 Hz, IHC), 3.32 (s, 2H), 2.99 (t, J = 5.6 Hz, 2H), 2.47-2.44 (m, 5H), 1.89-1.84 (m, IH), 0.83 (d, J = 6.8 Hz, 6H); LC-MS: m\z = 360.0, 358.3, 717.2 {2-[4-(2,3-Dihydrobenzo[l,4]dioxin-6-yl)-2-isobutylphenoxy]e thyl}- methylamino)-acetic acid

202 1H NMR (400 MHz, DMSO-d6) δ 7.32 (br dd, J = 8.4 Hz, J = 1.2 Hz, IH), 7.26 (br s, IH), 7.01-6.83 (m, 4H), 4.21 (s, 4H), 4.11 (br s, 2H), 3.55 (s, 2H), 3.10 (h»r s, 2H), 2.54 (s, 3H), 2.43 (d, J = 6.8 Hz, 2H), 1.87-1.81 (m, IH), 0.82 (d, J = 6.8 Hz, 6H); LC-MS: m\z = 400.0, 422.0

EXAMPLE 204

{[2-(2'-Fluoro-3-isobutylbiphenyl-4-yloxy)ethyl]-methylam ino}-acetic acid

Add 2 N sodium hydroxide (3.6 niL, 7.2 rnmol) to a solution of {[2-(2'-fluoro-3-

isobutylbiphenyl-4-yloxy)ethyl]-methylamino}-acetic acid tert-butyl ester (299 mg, 0.719

mmol) in 1,4-dioxane (7.2 mL) and stir at 110 0C for 7.5 h. Cool to room temperature,

dilute with water (~6 mL), wash with diethyl ether (-200 mL). Wash the organic phase

twice with water (~4 mL) and combine the aqueous phases, acidify by dropwise addition

of 5 N hydrochloric acid to about pH = 3.5-4. Concentrate and take up the residue in. 1,4-

dioxane; triturate the insoluble sodium chloride salt and filter away. Dilute with water

(~6 mL), basify to about pH = 8-9 with 2 N sodium hydroxide, wash with diethyl ether

(200 mL). Repeat this procedure a second time in order to isolate the desired compound.

Concentrate and take up the residue in 1,4-dioxane (30 mL) and ethanol (5 mL). Triturate

the hygroscopic material in tetrahydrofuran (20 mL) and 1,4-dioxane (10 mL) and filter

off the remaining insoluble salts. Concentrate to give an off-white hygroscopic foanx.

Dissolve the material in acetonitrile/water and lyophilize. Purify by ion exchange ■

chromatography to give the title compound (83.3 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ 7.45 (t, J = 8 Hz5 IH)5 7.33-7.29 (m, 5H)5 7.00 (d, J = 9.2 Hz, IH)5 4.08 (t, J = 5.6 Hz5 2H), 3.32 (s, 2H)5 2.97 (t, J = 5.6 Hz5 2H)5 2.46-2.42 (m, 5H)5 1.87-1.84 (m, IH)5 0.83 (d, J = 6.4 Hz5 6H); LC-MS: m\z = 360.0, 382.0

EXAMPLE 205 {MethyI-[2-(3-phenoxymethylbiphenyl-4-yloxy)ethyI]-amino}-ac etic acid

Dissolve {methyl-[2-(3-phenoxymethylbiphenyl-4-yloxy)ethyl]-amino}-ac etic acid ethyl ester (0.15 g, 0.36 mmol) in tetrahydrofuran (5 mL) and add 1 N sodium hydroxide (3 mL, 3 mmol). Stir at room temperature overnight, reduce the volume of tetrahydrofuran, and acidify the reaction using 1 N hydrochloric acid to about pH = 9. Filter the precipitate, wash with water and dry under vacuum to give the title compound as a white solid (0.135 g5 96%). LC-MS: m/z = 392.0