TW201200505A - GPR120 receptor agonists and uses thereof - Google Patents

Abstract

GPR120 agonists are provided. These compounds are useful for the treatment of metabolic diseases, including Type II diabetes and diseases associated with poor glycemic control.

Description

201200505 VI. Description of the invention: [Prior Art] Diabetes can be divided into two clinical syndromes, type 糖尿病 and type π diabetes, type I diabetes, or TB-dependent diabetes, which is characterized by chronic autoimmune diseases. It is the vast number of cold cells in the Langerhans' small island that produces insulin (hereinafter referred to as "islet cells" or "pancreatic islet cells"). Because these cell lines are progressively destroyed, the amount of insulin secreted is reduced, so when the amount of secretion falls below the level required for normal blood glucose (normal blood sugar content), it will eventually lead to hyperglycemia (abnormally high). The amount of glucose in the blood). Although it is not known that the immune response is indeed the beginning, patients with type 1 diabetes have high levels of resistance to pancreatic cells (hereinafter referred to as π-point cells. But 'not all diseases with high levels of these antibodies Type I diabetes develops in both cases. Type II diabetes, or non-insulin-dependent diabetes, develops when muscle, fat, and liver cells fail to respond normally to insulin. This failure to respond (called insulin resistance) Sexuality may be attributed to a decrease in the number of Luteng's genus on these cells, or a dysfunction in the cell's signaling pathway, or both. No cells initially compensate for this insulin resistance by increasing their insulin output. Over time, these cells became unable to produce enough insulin to maintain normal glucose levels, indicating progression to type DIA sy ry SE, as (2000) 1 〇 8 supplement 6a, 2S-8S). Fasting hyperglycemia characterized by Type II diabetes occurs due to combined damage of insulin resistance and no cell dysfunction. No cell defects have two components: the first component, the increase in basal insulin release (occurring in the presence of low non-stimulation 149105-sp-20100806.doc 201200505 glucose concentration), was found in obese insulin-resistant diabetes Pre-stage and type II diabetes. The second component is a failure to increase the release of insulin above the elevated substrate output in response to hyperglycemia. This damage. The system does not exist in the pre-diabetes and is shown to shift from a normal glycoside resistance state to significant diabetes. There is currently no cure for diabetes. Therapeutic treatments for diabetes are extremely limited and focus on attempts to control blood glucose levels to minimize or delay complications. The current treatment is insulin resistant (metformin, pyrazolidinedione ("tzd")) or release from/5 cells of insulin (sulfonylurea, exopeptide) )) as the target. Sulfonylureas and other compounds which act by depolarizing the cells have side effects of hypoglycemia, which cause secretion of the tampondin which is not related to glucose. One licensed drug, Byetta (exenatide), stimulates insulin secretion only in the presence of high glucose, but is not orally effective, but must be injected.奴奴维(Μ—(sitagliptin) is another blood that has recently been added to the intestinal (IV) hormonal hormone, which can increase the secretion of glucocorticoids, and has other Fully characterized, however, allosterivir and other dipeptidyl peptidase inhibitors can also affect other: the tissue content of the peptides and peptides' and the long-term results of this broader effect: not fully studied. (4) The sugar-dependent way to stimulate the oral drug secreted by Tengdaosu, which has not met the demand. Progressive tamsin resistance and insulin-secreting pancreatic "cell loss" are the main features of type II diabetes. Under normal circumstances The decrease in insulin sensitivity in muscle and fat is compensated by the increase in the secretion of the cell pancreas 149105-sp-20100806.doc 201200505. However, the loss of /3 cell function and quality will Causes insulin dysfunction and diabetes (Kahn BB, Ce// 92: 593-596, 1998; Cavaghan MK et al., /«vesi 106: 329-333, 2000; Saltiel AR, Ce// 104: 517_529, 2001; PrentkiM With NolanCJ, / C/w/m; eiill6: 1802-1812 (2006); and Kahn SE,>/C7z>7 86 : 4047-4058, 2001). Hyperglycemia further accelerates the decline of 3 cell function (UKPDS Group,

281: 2005-2012, 1999; LevyJ et al., 290-296, 1998; and Zhou YP et al., 75,·ο/ CTzem 278: 51316-23, 2003). Several genes in which the duality variant is associated with an increased risk of type 2 diabetes are selectively expressed in cold cells (Bell GI and Polonsky KS, /Vaiwre 414: 788-791 (2001); Saxena R Et al., Scz·(9)ce (2007) April 26; and Valgerdur Steinthorsdottir et al., iVaiwre G(9) eh'cs (2007) April 26 曰). Insulin secretion from pancreatic islets/3 cells is induced by increased blood glucose levels. The glucose system is mainly dissolved in /? cells by point cells and the liver selective transporter GLUT2 (Thorens B, Mo/sports/October/December 2001; 18(4): 265-73). Once inside the cell, glucose is phosphorylated by glucokinase, which is the major glucose sensor in the /3 cell, as it catalyzes the irreversible rate-limiting step on glucose metabolism (Matschinsky FM, Cwrr and India 2005) June; 5(3): 171-6). The rate of glucose-6-acid production by glucokinase is determined by the glucose concentration around the/5 cells. Therefore, this enzyme allows direct glucose content in the blood and the overall rate of glucose oxidation by the cells. relationship. Mutations in glucokinase produce an abnormality in glucose-dependent insulin secretion in humans, which is further evidence that this hexokinase family member plays a key role in the response to glucose islet responses 149105-sp-20100806.doc 201200505 (Gloyn AL et al., /WC/^m April 8, 2005; 280(14): 14105-13, Epub January 25, 2005). Small molecule activators of glucokinase enhance insulin secretion and provide therapeutics for the use of this enzyme (Guertin KR and Grimsby J, Cwrr Mei/ CTiem 2006; 13(15): 1839-43; with Matschinsky FM et al., DiWeto 2006 January; 55(1): 1-12) A way of acting on diabetes. Glucose metabolism via glycogenolysis and mitochondrial oxidative phosphorylation ultimately results in ATP production, and the amount of ATP produced in the /3 cells is directly related to the glucose concentration exposed by the cold cells. Glucose-dependent insulin secretion from self-calling cells depends on a variety of neurotransmitters and hormones with blood, as well as local islet factors. CNS activation of the vagus nerve distribution of islets can lead to the release of small molecules such as acetylcholine and peptides, such as vascular intestinal polypeptide (VIP), gastrin releasing peptide (GRP), and pituitary gland #acid cyclase Activated peptide (PACAP). Phospholipase C undergoes activation of the intracellular storage of Ca2+ via the Ga q-coupled GPCRM3 muscarinic receptor (Gilon P and Henquin JC, five rn/ocr October 2001; 22 (5) : 565-604) ^ Cholinergic agonists also lead to ingenious Na+-dependent serosal depolarization, which works synergistically with the depolarization induced by glucose to enhance insulin release (GilonP and HenquinJC, Office cr, October 2001; 22(5): 565-604). The overlapping combination of VIP and PACAP binding to Ga-coupled GPCRs (PAC1, VIPR1, and VIPR2) on /3 cells results in stimulation of ghrelin cyclase and increase in intracellular cAMP (Filipsson K et al, September 2001; 50(9): 1959-69; Yamada Η et al., Pepi / Pepi December 15, 2014; 123(1-3): 147-53; and Qader SS et al., / 149105 -sp-20100806.doc 201200505 May; 292(5): E1447-55). Intestinal stimulating hormone, such as glucagon peptide 1 (GLP-1) and glucose-dependent insulin polypeptide (GIP, also known as gastric inhibitory polypeptide), will also bind to the island of Tendo; 5 cell surface Specific coupling of GPCR receptors and elevation of intracellular cAMP (Drucker DJ, C7 Plus / «vesi January 2007; 117(1): 24-32). Although the system of hormone receptors is present in other cells and tissues, the overall sum of the effects of these peptides has been shown to be beneficial in controlling glucose metabolism in organisms (Hansotia T et al., JC//« Vesi January 2007; 117(1): 143-52, Epub December 21, 2006). GIP and GLP-1 are produced and secreted separately from intestinal K and L cells, and these peptide hormones are released in response to three meals, by the direct action of nutrients in the intestinal lumen, and due to food feeding. The nerve stimulation of the formation. GIP and GLP-1 have a short half-life in the human circulation due to the action of the protease dipeptidyl-peptidase IV (DPPIV), and this protease inhibitor can lower blood sugar, which is due to its promotion of intestine Due to the ability of the active form of the insulin peptide. However, the glucose reduction system that can be obtained with DPPIV inhibitors is somewhat limited because these drugs rely on endogenous release of incretin hormones. A peptide that binds to the GIP or GLP-1 receptor but is resistant to serum protease cleavage (such as exanatide (Byetta)) and the peptide, can also substantially lower blood sugar (Gonzalez C et al., Experi (9pm /we young DrMg·? August 2006; 15(8): 887-95), but these incretins must be injected and tend to cause high nausea, so no It is an ideal therapy for the general population of patients with type 2 diabetes. The clinical success of DPPIV inhibitors and incretin mimetic, although not ideal, does indicate that it will increase 149105-sp-20100806.doc 201200505 blood Potential use of compounds in the incretin activity of the intestine. Some studies have shown a decrease in the cytotoxicity of GIP in type II diabetes (Nauck MA et al, JC/plus/«νπ/91: 301-307) (1993); and Elahi D et al., E.gw/ 51: 63-74 (1994)). This responsive restoration (Meneilly GS et al., DzMeies Care, January 1993; 16(1): 110-4) A promising way to improve /5 cell function in vivo. Due to increased incretin Activity has a positive effect on glucose-dependent insulin secretion and other mechanisms that may lead to lowering blood glucose, so it is also of interest to explore therapeutic pathways that increase intestinal insulin release from intestinal K and L cells. GLP-1 secretion The line is shown to be attenuated in type 2 diabetes (Vilsboll T et al., eg 50: 609-613), so improving incretin release can correct this metabolic dysfunction component. Nutrients, such as in the intestinal lumen Glucose and fat promote insulin secretion by interaction with apical receptors (Vilsboll T et al, 50 '· 609-613). GLP-1 and GIP release can also be caused by nerve stimulation; Insulin secretion, acetylcholine and GRP may be similar to the way these neurotransmitters act on/5 cells, enhancing intestinal glandular release (Brubaker P, July 2006; 1070: 10-26; with Reimann F et al., December 2006; 55 (Supplement 2): S78-S85). Growth hormone releasing inhibitors, leptin and free fatty acids are also shown to modulate incretin secretion (Brubaker P, # r 2006) July of the year; 1070: 10-26; with Reimann F et al., December 2006; 55 (Supplement 2): S78-S85). However, there has not been a way to selectively attack these pathways to promote incretin secretion that provides therapeutic benefits. There is a need for oral drugs that stimulate insulin secretion to treat diabetes I49105-sp-20100806.doc 201200505. Incretin is also available in animal models (Farilla L et al., Cold-secreted shoots, November 2002; 143(11): 4397-408) and in vitro human islets (FariUaL et al., Fragmentation 2, December 2003) 144(12): 5 M9-58) increases the rate of /3 cell proliferation and reduces the cell wilting rate of stone cells. The net result of these changes is an increase in the number of /3 cells and islet mass, and this should provide increased insulin secretion capacity, which is another desirable goal of anti-diabetic therapy. GLP-1 has also been shown to protect the islets from the destructive effects of #agents (such as streptavidin) by blocking cell dying (Li Y et al., C/zem, January 3, 2003) ;278(1) : 471-8). Cyclin D1, a key regulator of cell cycle progression, is regulated by GLP-1 and has a similar effect on other agents that increase cAMP and PKA activity (Friedrichsen BN et al., J Vwcccrwi?/ 2006 3 Month; 188(3): 481-92; with Kim MJ et al., J V. WocWw/March 2006; 188(3): 623-33). Increased cyclin D1 gene transcription occurs in response to PKA phosphorylation of CREB (cAMP-responsive element binding) transcription factors (Hussain MA et al, Mo/Ce//)/October 2006; • 26 (20 ): 7747-59). There is a need for oral medications that increase the number of cells/3 and the quality of islets to treat diabetes. G protein-coupled receptors (GPCRs) are cell surface receptors that play an important physiological role by transducing and amplifying extracellular messages such as hormones, growth factors, neurotransmitters, and physiologically active substances. Character. The GPCR line is associated with a change in intracellular Ca2+ concentration and an increase in intracellular inositol 1,4,5-triphosphate (IP3) concentration. These second messengers are used to focus on message transduction events and stimulate other avenues. Therefore, GPCR is an important target species in the pharmaceutical industry for the treatment of 149105-sp-20100806.doc 201200505. GPR120 is a GPCR for unsaturated long-chain free-state fatty acid (FFA), and is highly expressed in lung, intestine, adipocytes and taste cells, as well as in enteroendocrine cell lines such as STC-1 and GLUTag. (Hirasawa et al., Atowre MetZ/cme January 2005; 11: 90-94; and Iakoubov et al., Qiao Secretology March 2007; 148(3): 1089-1098; and Katsuma et al., C/2em May 2005; 280: 19507-19515; Matsumura et al., February 2007; 28(1) 49-55). Stimulation of GPR120 by FFA increased Ca2+ release from intracellular storage, indicating that GPR120 is a Gaq-coupled receptor. GPR120 is a mediator of unsaturated long-chain free fatty acids that stimulates the secretion of GLP-1 and CCK, increases the activation of plasma insulin, extracellular signal-regulated kinase (ERK) cascade, pancreatic/3 cells. Inhibition of cell dying and lipogenesis induced by hyperplasia and serum deprivation (Katsuma et al., /.) / C/zem. May 2005; 280: 19507-19515; and Rayasam et al., five xperiC) ;?/". 77zer· May 2007; 11(5): 661-671; and Tanaka et al., iSc/wm.eifeftergJrc/i /Vzamizco/ June 2008; 377(4-6): 515- 22; and Gotoh et al., oc/ie/w. 〇/?/^· /? Batch. Cowmim. March 2007; 354(2): 591-597). Free-state fatty acids have been confirmed as Recently identified orphan GPCR ligands (Rayasam et al., Experi 77zer Thrgeto 2007 May; 11(5): 661-671). GPR120 is a ligand-specific ligand with other fatty acid receptors and needs to be developed. Small molecule agent, which is a specific modulator of GPR120 function. In particular, GPR120 is for the treatment of diabetes, obesity and metabolic syndrome It is desirable to consider the important role of GLP-1 and CCK in insulin secretion, gastric emptying, and appetite feeding control. 149105-sp-20100806.doc -10· 201200505 SUMMARY OF THE INVENTION The present invention provides novel GPR120 compound agonism. Agents, methods for their preparation, and related synthetic intermediates and compositions.This novel GPR120 agonist can be used to treat diabetes and other related diseases, including metabolic syndrome, lipodystrophy, insulin resistance, and diabetic complications. Methods of treating diseases such as type π diabetes and other diseases and conditions using one or more of such compounds or compositions, as further detailed below. The invention also provides for the use of one or more of the compounds described herein to enhance A method for intracellular content of Ca2+. Further, the compound can be used to stimulate insulin production in mammals, particularly humans, and to stimulate insulin, glucagon-like peptide 1 (GLP1), and glucose-dependent insulin polypeptides ( Secretion of GIP). In addition, the compounds described herein are administered when they are administered to reduce blood sugar. In animals, it can be used to lower blood sugar. DETAILED DESCRIPTION OF THE INVENTION Abbreviations used herein are conventional, unless otherwise defined: AcOH: acetic acid; nBuLi: n-butyl lithium; Cs2 C03: carbonic acid planing; CH2 Cl2 or DCM: Dichlorodecane; CH3MgI: methyl magnesium iodide; CuCl2: copper chloride; DAST: (diethylamino) sulfur trifluoride; DEAD: diethyl azodicarboxylate; DIBAL: diisobutyl hydride Aluminum; DIPEA: diisopropylethylamine; DMF: dimethylformamide; DMSO: diterpenoid; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; g: gram; H2: hydrogen; HBr: hydrogen bromide; HC1: hydrogenated hydrogen; H20: water; H2〇2: hydrogen peroxide; HPLC: high performance liquid chromatography; KCN: potassium cyanide; LHMDS: hexa Lithium bismuth lithium nitride; LiAlH4: lithium aluminum hydride; LiOH: lithium hydroxide; M: molar concentration; MeCN: acetonitrile; £149105-sp-20100806.doc 201200505

Mel: sulphuric acid; MeOH: methanol; MgS04: magnesium sulfate; MgC03: phenolic acid; mg: house gram; MsCl; cesium chloride smoldering; mmol: millimolar; mL: cc; NaHS〇3; mCPBA: m-chloroperoxybenzoic acid; N··equivalent concentration; N2: nitrogen; Na2 C03: sodium carbonate; NaHC03: sodium hydrogencarbonate; NaN02: sodium nitrite; NaOH: sodium hydroxide; Na2 S2 03 : acid sodium sulfate; Na2 S04: sodium sulfate; NBS: N-bromosuccinimide; NH4 C1: chloride; NH4 OAc: acetic acid; NMR: nuclear magnetic resonance; Pd/C: palladium/carbon; : triphenylphosphine; iPrOH: isopropanol; s〇Cl2: sulfinium dichloride; THF: tetrahydrofuran; TLC: thin layer chromatography; A: microliter. Unless otherwise stated, the following terms used in this specification and claims have the meanings set forth below. "alkyl base" means a monovalent saturated aliphatic nicotine having from 1 to 10 carbon atoms, and in some embodiments 'from 1 to 6 carbon atoms. "Cu_valkyl" means an alkyl group having from u to v carbon atoms. By way of example, the term includes both linear and branched hydrocarbon radicals such as fluorenyl (CH3-), ethyl (CH3CH2-), n-propyl (ch3ch2ch2), isopropyl ((ch3)2ch-) 'positive- Butyl (ch3ch2ch2ch2-), isobutyl ((ch3)2chch2-), second-butyl ((ch3)(ch3ch2)ch-), tert-butyl((CH3)3C-), n-pentyl Base (CH3CH2CH2CH2CH2-) and neopentyl ((CH3)3CCH2-). "Substituted alkyl" and "substituted cu_v alkyl" means alkyl, having from 1 to 5, and in some embodiments, from 1 to 3 or from 1 to 2 substituents a group selected from the group consisting of alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, decyl, decylamino, decyloxy, Amine, substituted amino group, aminocarbonyl group, aminothio group I49105-sp-20100806.doc •12· 201200505 Group, amino group amino group, aminothio group, amine group Alkoxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, decyl, aryl, substituted aryl, aryloxy, substituted aryloxy, Arylthio, substituted arylthio, azide, carboxyl, carboxy ester, (carboxy ester) amine, (carboxy ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, Cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, fluorenyl, substituted fluorenyl, functional, hydroxy, hydroxylamine, alkoxy Amine, Substituted, substituted fluorenyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, hetero Ring group, substituted heterocyclic group, heterocyclic oxy group, substituted heterocyclic oxy group, heterocyclic thio group, substituted heterocyclic thio group, nitro group, spirocycloalkyl group, S03 Η Substituted sulfonyl, sulfonyloxy, thiol, thiocyanate, thiol, alkylthio and substituted alkylthio, wherein the substituents are as defined herein. "Alkenyl" Is a linear or branched hydrocarbon radical having from 2 to 10 carbon atoms, and in some embodiments, from 2 to 6 carbon atoms or from 2 to 4 carbon atoms, and having at least one ethylenic unsaturation ( >C=C<) position. "Cu_valkenyl" means an alkenyl group having from u to v carbon atoms, and is meant to include, for example, ethenyl, propenyl, 1,3-butadienyl and the like. "Substituted alkenyl π and ''substituted oxime-alkenyl" means an alkenyl group having from 1 to 3 substituents, and in some embodiments, from 1 to 2 substituents selected from the group consisting of Group consisting of: alkoxy, substituted alkoxy, decyl, decylamino, decyloxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amine, via Substituted amine group, aminocarbonyl group, aminothiocarbonyl group, 149105-sp-20100806.doc -13 - 201200505 Aminomethylamino group, aminothiomethylamino group, amine group #yloxy group, amine Sulfosyl, aminosulfonyloxy, aminosulfonylamino, carbaryl 'aryl, substituted aryl, aryloxy 'substituted aryloxy, arylthio' Substituted arylthio, carboxyl, carboxy ester, (carboxy ester) amine, (carboxy carboxy)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted Cycloalkyloxy 'cycloalkylthio, substituted cycloalkylthio, fluorenyl, substituted fluorenyl, dentate, hydroxy, heteroaryl, substituted heteroaryl, heteroaryl Oxygen, substituted Heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclyl Thio group, substituted heterocyclic thio group, nitro group, S〇3H, substituted sulfonyl group, sulfonyloxy group, thiol group, thiol, alkylthio group and substituted alkylthio group, wherein The substituents are all as defined herein, with the proviso that any hydroxyl or thiol substitution is not attached to the acetylene carbon atom. "alkynyl" means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one reference bond. The term "alkynyl" is also meant to include a hydrocarbyl group having one key and one double bond. "CU-V alkynyl" means an alkynyl group having from u to v carbon atoms, and the system is intended to include B. Base, C-base, etc. , substituted alkynyl, and "substituted Cu_v alkynyl" means an alkynyl group having from 1 to 3 substituents, and in some embodiments, from 丨 to 2 substituents, selected Groups from the group consisting of alkoxy, substituted alkoxy, decyl, decylamino, decyloxy, amine, substituted amine, amine carbonyl, amine thiocarbonyl, amine Alkylcarbonylamino 'amino thiocarbonylamino group, aminocarbonyloxy group, aminosulfonyl group, aminosulfonyl fluorenyl group, aminosulfonylamino group, 149105-sp-20l00806.doc •14 - 201200505 Mercapto, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxy, carboxy ester, (carboxy ester) amine , (wei), oxy, carbyl, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted naphthenic Thiothio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, fluorenyl, hydrazine a sulfhydryl group, a hydryl group, a hydroxy group, a heteroaryl group, a substituted heteroaryl group, a heteroaryloxy group, a substituted heteroaryloxy group, a heteroarylthio group, a substituted heteroarylthio group, Heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, S03 oxime, substituted a sulfonyl group, a sulfonyloxy group, a sulfonyl group, a thiol group, an alkylthio group, and a substituted alkylthio group, wherein the substituent is defined herein, and the proviso is that any hydroxy or thiol substitution is not Attached to an acetylene carbon atom. "Alkoxy" refers to the group - fluorene-alkyl, wherein alkyl is defined herein. For example, alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, second-butoxy and n-pentane. Oxygen. "Cu_v alkoxy" means an alkoxy group having from u to ν carbon atoms. "Substituted alkoxy' and ''substituted Cu_v alkoxy" means a group -0-( Substituted alkyl) wherein the substituted alkyl is as defined herein. '• Mercapto' refers to the group HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl -C(O)-, alkynyl-C(O)-, substituted alkynyl-c(o)-, cycloalkyl-c(o)-, substituted cycloalkyl-C(O)- , aryl-c(o)-, substituted aryl-c(o)-, substituted fluorenyl-c(o)-, heteroaryl £149105-sp-20100806.doc • 15 - 201200505 - c(o)-, substituted heteroaryl-c(0)-, heterocyclic-c(o)-, and substituted heterocyclic-c(o)-, wherein alkyl, substituted alkane Base, alkenyl group, substituted dilute group, alkynyl group, substituted alkynyl group, cycloalkyl group, substituted cycloalkyl group, aryl group, substituted aryl group, substituted fluorenyl group, heteroaryl group, The substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Indenyl includes "ethinyl" "CH3 c(o). "Mercaptoamine" refers to a group -nr2Gc(o)h, -NR20C(O)alkyl, c(o) substituted alkyl, -nr2Gc(o)cycloalkyl, -NR2gC(0) substituted Cycloalkyl, -nr2Gc(o) dilute, -nr2Gc(o) substituted dilute, _NR2GC(0) alkynyl, -NR2()C(0) substituted alkynyl, -NR20C(O)aryl , -Nyoqo) substituted aryl, -NR2.C(O)heteroaryl, -NR2 0 C(O) substituted heteroaryl, -NR2 0 c(〇) heterocyclic and -NR2GC(0) substituted a heterocyclic group wherein R 2 hydrazine is hydrogen or an alkyl group, and wherein a thiol group, a substituted aryl group, a dilute group, a substituted fluorenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, or a substituted group thereof A cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. "醯oxy" HC(0)0-, alkyl (;; (〇)〇_, substituted alkyl-c(o)o-, alkenyl-c(o)o-, substituted alkenyl_c ( 0) 0_, alkynyl _c(〇)〇_, substituted alkynyl-c(o)o-, aryl-C(0)0·, substituted aryl _c(〇)〇_, Cycloalkyl-c(o)o-, substituted cycloalkyl-c(0)0_, heteroaryl_c(0)0_, substituted Aryl-c(o)o-, heterocyclic group _c(0)0· and substituted heterocyclic group -C(0)0-, wherein alkyl, substituted alkyl, dilute, substituted Alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cyclo, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and 149105-sp-20100806.doc -16- 201200505 The heterocyclic group is as defined herein. "Amine" refers to the group _Nh2. '"Disubstituted amine group" refers to the group-NR21 R2 2 wherein R 2 1 and R 2 2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, _s(〇)2-alkyl, _s( 〇) 2_substituted alkyl, -s(o)2-alkenyl, _s(0)2_substituted alkenyl, _s(〇)2_cycloalkyl, _s(〇)2_substituted decane , _S(0)2-aryl, -S(0)2_substituted aryl, -s(0)2-heteroaryl, -s(o)2-substituted heteroaryl, _s(〇 2) Heterocyclic group a _s(〇)2 _ substituted heterocyclic group, and wherein R 2 1 and R 22 are bonded together with the nitrogen bonded thereto as appropriate to form a heterocyclic group or a substituted heterocyclic group, provided that R 2 I And R22 are not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aromatic The aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are all as defined herein. When R2 1 is hydrogen and R22 is an alkyl group, the substituted amine is sometimes referred to herein as an alkylamine group. When R2j and R22 are alkyl groups, the substituted amines are sometimes referred to herein as dialkylamine groups. When referring to a monosubstituted amine group, it means that R2 or R22 is hydrogen, but not both. When referring to a disubstituted amine group, it means neither R2丨 nor R22 is hydrogen. "Hydroxylamine" refers to the group -NHOH. The π alkoxyamino group " refers to the group -NHO-alkyl, wherein alkyl is defined herein. 149105-sp-20100806.doc -17- 201200505 , Diyl refers to the group _c(0)nr23r24, where r23 is independent of r24 ^, group: hydrogen, alkyl, substituted alkyl

Substituted alkenyl, alkyne, technology & A, and 'the fast base of the earth, aryl, substituted aryl = agricultural 'mono-a substituted ring-based, heteroaryl' substituted : ring =, heterocyclic group 'passage group, hospital oxygen and substituted house oxygen soil" R Xiao R24 is optionally bonded to the nitrogen bonded thereto

Starting to form a heterocyclic or substituted heterocyclic group, wherein the alkyl group, the substituted alkyl group substituted by a dilute group, an alkynyl group, a substituted block group, a cyclofilament, a substituted ring Pit-based, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic 'substituted heterocyclic, trans-, alkoxy and substituted alkanoyl are as herein definition. "Aminothiocarbonyl" refers to the group _C(8) cis 23圮4, wherein r23 and r24 are independently selected from the following group of groups: hydrogen, alkyl group, substituted alkyl group, dilute base , alkynyl, substituted silk 1 , substituted aryl, yl, substituted cycloalkyl, heteroaryl 'substituted heteroaryl, heterocyclic and substituted hydrazine, hydrazine <Heterocyclic private and where R23 and R24 are as appropriate

And a nitrogen bonded to the same, to form a heterocyclic or substituted heterocyclic group, wherein the alkyl group, the substituted leukoxene, the dilute group, the substituted county, the alkynyl group, The silk, the ring, the substituted ring, the aryl, the substituted aryl, the heteroaryl, the substituted heteroaryl ring, and the substituted heterocyclic are all as defined herein. "Aminocarbonylamino" refers to the group _NR2〇C(〇)NR23R24, which is _R2〇 hydrogen or alkyl, and R" and ... are independently selected from the group consisting of: hydrogen: Substituted minus, alkenyl, substituted dilute, block, 149105-sp-20I00806.doc '18· 201200505 alkynyl, aryl, substituted aryl, cycloalkyl, substituted naphthenic a heterocyclic group or a substituted heterocyclic group, wherein the R23 and R24 are bonded to the nitrogen bonded thereto a substituted heterocyclic group wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl The substituted, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are all as defined herein, wherein the amine thiocarbonylamino group is a hydrogen group. Or a base, and the furnace and the core are independently selected from the group consisting of: gas, alkyl, substituted alkyl, alkenyl, substituted dilute, block, substituted alkynyl, An aryl group, a substituted aryl group, a cycloalkyl group, a substituted cycloalkyl group, a heteroaryl group, a substituted (tetra) group, a heterocyclic group, and a substituted heterocyclic group, and wherein W and - are as appropriate The gas bonded thereto is joined together to form a heterocyclic or substituted heterocyclic group, wherein a leuco group, a substituted alkyl group, an alkenyl group, a substituted phenyl group, a fast group, a substituted group The aryl group, the cycloalkyl group, the fluorenyl group, the substituted group, the heteroaryl group, the substituted heteroaryl group, the heterocyclic group and the substituted heterocyclic group are all as defined herein. "Aminomethyloxy" refers to the group _〇_c(〇)nr23r24, preferably center and ... are independently selected from the group consisting of nitrogen, alkyl, substituted alkyl, and dilute Substituted dilute group, fast group, substituted fast group, aryl group, selly substituted aryl group, cycloalkyl group, substituted cycloalkyl group, heteroaryl group, substituted heteroaryl group, heterocyclic group And a substituted heterocyclic group, wherein W and r24 are optionally bonded to the nitrogen bonded thereto. ', L according to the group, to form a heterocyclic group of the heterocyclic group, and let p Its 't-decyl group, substituted alkyl, alkenyl group, substituted by 149I05-sp-20100806.doc -19-201200505, alkynyl, alkynyl, substituted alkynyl, cyclodextrin' substituted r Anthracene, aryl, fluorenyl, heteroaryl, substituted cloxin, and substituted heterocyclic are as defined herein. "Amine base continued at base" refers to the group s(0)2NR23r24, its towel r23 and the core are selected from the following sub-forms, substituted n-based, substituted alkyl, rare, substituted alkene Base, silk, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl 'substituted heteroaryl, heterocyclic and substituted heterocyclic And the flakes R23 and r24 are bonded to the nitrogen to which the soil is bound, as in the case, to form a heterocyclic or substituted heterocyclic group, wherein the substituted group, the substituted base, the woman Substituted: alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl 'substituted heteroaryl, heterocyclic And substituted heterocyclic groups are as defined herein. , "Aminosulfonyloxy", refers to the group _0_S(0)2NR23R24, wherein r23 and R24 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, and Substituted dilute, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and a substituted heterocyclic group, wherein R23 and R24 are bonded together with the nitrogen bonded thereto, as appropriate, to form a heterocyclic or substituted heterocyclic group, wherein the alkyl group, the substituted alkyl group Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Both a heterocyclic group and a substituted heterocyclic group are as defined herein. Amine-based hydrazino group " refers to a group which is R2〇l49J05-sp-20100806.doc -20- 201200505

Is hydrogen or alkyl, and R23 and R24 are independently selected from the group consisting of hydrogen, alkyl, substituted U group 1, substituted county, block group, substituted fast group, aryl group, Substituted aryl, ring-based, substituted ring-based, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein ... and R24 are The nitrogen thereon is bonded together to form a heterocyclic or substituted heterocyclic group, wherein the alkyl group, the substituted substituent, the material, the substituted group, the (IV), the substituted block, the ring The alkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are all as defined herein. "曱脒基" refers to the group -C(=NR25)NR23R24, wherein r25, r23 and r24 are independently selected from the group consisting of hydrogen, burn/, substituted base, and baked base Substituent, alkynyl, substituted block, aryl, aryl, ring, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted a heterocyclic group, and wherein π; 盥KM is optionally bonded to a nitrogen bonded thereto to form a heterocyclic or substituted heterocyclic group, wherein the alkyl group, the substituted alkyl group , alkenyl, substituted county, alkynyl, substituted block, benzyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic Both a family and a substituted heterocyclic group are as defined herein. "Aryl" means an aromatic group of 6 to 14 carbon atoms and has no ring heteroatoms, but has a single ring (eg phenyl) or multiple condensations ( a fused) ring (eg, a naphthyl or fluorenyl group h for a multiple ring system, including a chelating, bridging, and spiro ring system having a bimodal and non-aromatic ring without a ring heteroatom "Aryl" or " language suitable for operation when the attachment point on the line when the aromatic carbon atom (e.g., 5,6,7,8-tetrahydro-149105-sp-21 201〇〇8〇6id〇c

S 201200505 Tea-2-yl is an aryl group because its attachment point is in the 2_ position of the aromatic benzene ring). "substituted aryl" refers to an aryl group which is 1 to 8 and, in some embodiments, 1 to 5, 1 to 3, or 1 to 2 substituents, The substituent is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl alkoxy, substituted alkoxy, fluorenyl , mercaptoamine, oxime 'amine, substituted amine, amine carbonyl, amine thiocarbonyl, aminocarbonylamino, amine thiocarbonylamino 'aminocarbonyloxy, amine Sulfosyl, aminosulfonyloxy, amino (tetra)ylamino, carbenyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, Substituted arylthio 'azido group, carboxyl group, carboxy ester, (carboxy ester) amine group, (carboxy ester)oxy 'cyano group, cycloalkyl group, substituted cycloalkyl group, cycloalkyloxy group Substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, fluorenyl, substituted fluorenyl 'halo, thio, amino, alkoxyamino, Substituted Mercapto, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted Heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio 'nitro, s〇3H, substituted sulfonyl, indeed Alkoxy, thiol, thiocyanate, thiol, sulfonyl and substituted alkylthio, wherein the substituents are all defined herein. Aralkyl" or "aryl(c 〖-Cz)alkyl" refers to the group _RURV, wherein RU is an alkyl group (having 8 or fewer backbone carbon atoms), and An aryl group as defined herein. Thus, "aralkyl" refers to a group such as a fluorenyl group and a phenyl group. Similarly, an aralkenyl group means a group _RURV, wherein ru is Stretching 149105-sp-20100806.doc •22·201200505 base (extension alkyl group having 1 or 2 double bonds), and RV is an aryl group as defined herein, such as stupid vinyl, 3-phenyl-2 - Propylene or the like. "aryloxy" refers to a group aryl group, wherein the aryl group is as defined herein, and exemplarily includes 'phenoxy group and decyloxy group. Substituted aryloxy group' refers to a group - 〇 - (substituted aryl) wherein the substituted aryl is as defined herein.

"Arylthio" refers to the group -S_aryl, wherein aryl is as defined herein. Substituted arylthio" refers to a group -s-(substituted aryl) wherein the substituted aryl is as defined herein. "Azido" refers to the group -N3. "胼基" refers to the group _NHNH2. "Substituted thiol" refers to the group -NR26NR27R28, wherein RW, R27 and R28 are independently selected from the group consisting of hydrogen, alkyl, substituted alkylalkenyl, substituted alkenyl , alkynyl, substituted alkynyl, aryl, 'star substituted aryl, carboxy ester, cycloalkyl, substituted cycloalkyl, heteroaryl* substituted heteroaryl, heterocyclic, via Substituted heterocyclic and substituted: aryl, and wherein &27 and r28 are bonded to the nitrogen interface bonded thereto, to form a heterocyclic or substituted heterocyclic group, The conditions 疋R and R28 are not hydrogen, and wherein cyclyl, substituted leukoyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, cyclized ring Alkyl, cycloalkenyl 'substituted cycloaliphatic, aryl, substituted =, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and substituted sulfonyl Both are as defined herein. Cyano or "carbonitrile 11 refers to the group -CN. 149105-SP-20 ] 00806.doc •23- 201200505 “Carbonyl” refers to the divalent group -c(o)-, which is equivalent to -c(=o)-. "carboxy" or "carboxy" means -COOH or a salt thereof. ••carboxy ester” or "carboxylate" refers to the group -c(o)o-alkyl, -c(o)o-substituted alkyl, -c(o)o-alkenyl, -c (o) o-substituted alkenyl, -c(o)o-alkynyl, -c(o)o-substituted alkynyl, -c(o)o-aryl, -c(o)o-substituted Aryl, -c(o)o-cycloalkyl, -c(o)o-substituted cycloalkyl'-c(〇)o-heteroaryl, -c(o)o-substituted heteroaryl a heterocyclic group of -c(o)o-heterocyclic and -c(o)o-substituted, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted Alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. "(Carboxy ester)amine group π refers to the group -nr2()-c(o)o-alkyl, -nr2G-c(o)o-substituted alkyl, -nr2G-c(o)o- Alkenyl, -nr2Q-c(o)o-substituted alkenyl, -NR20-C(O)O-alkynyl, -NR20-C(O)O-substituted alkynyl, -nr2()-c() o) o-aryl, -nr2G-c(o)o-substituted aryl, -nr2Q-c(o)o-cycloalkyl, -nr2G-c(o)o-substituted cycloalkyl, - nr2G-c(o)o-heteroaryl, -nr2G-c(o)o-substituted heteroaryl, -NR2 G-C(0)0-heterocycle And -NR2 0 -C(0)0-substituted heterocyclic, wherein R20 is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted Alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. "(Carboxy ester)oxy" refers to the group -〇-c(o)o-alkyl, -oc(o)o-substituted alkyl, -oc(o)o-alkenyl, -oc(o O-substituted alkenyl, -oc(o)o-alkynyl, -oc(o)o-substituted alkynyl, -oc(o)o-aryl, -oc(o)o-substituted aryl , -oc(o)o-cycloalkyl'-oc(o)o-substituted cycloalkyl, -oc(o)o-heteroaryl, 149105-sp-20100806.doc -24- 201200505 -〇 _c(o)o-substituted heterozygous gamma, heterocyclic group, -0<(0)0-heterocyclic group and -〇-c(o)〇-substituted heterocyclic group: wherein the alkyl group is substituted Dylenyl, alkenyl, substituted dilute, fast-radical, substituted alkynyl, cycloalkyl, substituted ring, cycloalkenyl, I: % alkenyl, aryl, substituted Aryl, heteroaryl, substituted heteroaryl, heterocyclic And the substituted heterocyclic are as defined herein Si. "π-cycloalkyl" means 3 to a group and has no ring hetero atom or a saturated or partially saturated cyclic group of one carbon atom and has a single or multiple ring, including a fused, bridged

Pick up and wear clothes%. For aromatic and non-aromatic oxime systems without ring heteroatoms, the term "% alkyl" is used when the point of attachment is on a non-aromatic, carbon atom (eg 5,6,7,8_) The term tetrahydronaphthalene _5_ kib, cycloalkyl" includes cycloalkenyl. Examples of the alkyl group include, for example, adamantylcyclopropylcyclobutyl, cyclopentyl, cyclooctyl and cyclohexyl. "C" is a cycloalkyl group having from 0 to ν carbon atoms as a ring member. "Cu vcycloalkenyl" means a cycloolefin having from 0 to V carbon atoms as a ring member. "% alkenyl" means a partially saturated cycloalkyl ring having at least one >C=C<ring-unsaturated position. Substituted cycloalkyl" means a cycloalkyl group as defined herein, Having from i to 8, or from 1 to 5, or in some embodiments, from 1 to 3 substituents selected from the group consisting of keto, thioketone, alkyl, substituted olefinic Substituted dilute group, alkynyl group, substituted alkynyl group, alkoxy group, substituted alkoxy group, fluorenyl 'mercaptoamine group, decyloxy group, amine group, red substituted amine group, amine group Carbonyl group, amine group Thiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, methylidene, Aryl, substituted aryl 149105-sp-20l00806.doc •25- 201200505 aryloxy, substituted aryloxy, arylthio, substituted arylthio, azide, carboxyl, carboxyl Cool, (carboxy carboxylic acid) amine group, (carboxy ester) oxy group, cyano group, cycloalkyl group, substituted cycloalkyl group, cycloalkyloxy group, substituted cycloalkyloxy group, cycloalkylthio group Substituted cycloalkylthio, fluorenyl, substituted fluorenyl, hydrazine, hydroxy, hydroxylamine, alkoxyamino, fluorenyl, substituted fluorenyl, heteroaryl, substituted Aryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, Substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio 'nitro, S〇3H, substituted sulfonyl, sulfonyloxy, thiol, thiocyanate Ester, sulfur An alkylthio group and a substituted alkylthio group, wherein the substituent is as defined herein. "Substituted cycloalkyl, the term includes substituted cycloalkenyl. "cycloalkyloxy" Means - 〇-cycloalkyl, wherein cycloalkyl is as defined herein. Substituted cycloalkyloxy" means - 〇 (substituted cycloalkyl), wherein a substituted cyclocyl group is as "N-alkylthio" means -S-cycloalkyl, wherein substituted cycloalkyl is as defined herein. Substituted cycloalkylthio" means -S- (substituted The cycloalkyl group, wherein the substituted cycloalkyl group is as defined herein. "胍基" refers to the group ΝΗ(χ=ΝΗ)ΝΗ2. "Substituted thiol" means _NR29C(=NR29)N(R29)2, wherein each R29 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and 149105-sp-20100g Q6.doc 26· 201200505 substituted heterocyclic group, and attached to two of the common nucleus nitrogen atoms The 9 group is bonded to the nitrogen bonded thereto as appropriate to form a heterocyclic or substituted heterocyclic group, provided that at least one R29 is not hydrogen, and wherein the S substituent is As defined herein. ' "Halo" or "halogen" means fluoro, chloro, bromo and iodo. Haloalkyl means that the alkyl group is deuterated to 5 or, in some embodiments, 1 to Substituted by three halo groups, for example, -CH2C-CH2F, -CH2Br, -CFaBr, -CH2CH2C1, -CH2CH2F, -CF3, -CH2CF3, -CH2CC13, etc., and further including an alkyl group such as an all-gas alkyl group, wherein all hydrogen Atoms are each replaced by a fluorine atom. 'Haloalkoxy' means that the alkoxy group is up to 5 or, in some embodiments, '1 to 3 halo, for example _〇CH2C卜_〇CH2F 〇 CH2CH2Br, -OCH2CH2Cl, -〇cf3, etc. "" or "yl radical" refers to the group -OH. Heteroalkyl'' means an alkyl group as defined herein, having 1, 2 or 3 substituents independently selected from cyano, -ORw, -NRxRy, -SRZ, -S(0)Rz, and -S(0)2R (wherein n is ruthenium, osmium or 2), and The point of attachment is through a carbon atom of a heteroalkyl group. RW is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamide or Mono- or di-alkylamine fluorenyl. Rx is hydrogen, Alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or aralkyl. Ry is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, alkoxycarbonyl, An aryloxycarbonyl group, a carboxy oxime amino group, a mono- or di-alkylaminecarbamyl group or an alkylsulfonyl group. RZ is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aromatic Alkyl, amine, mono-alkylamino, di-alkylamino or 149105-sp-20100806.doc -27 201200505. Representative examples include, for example, 2-ethyl, 2,3-dihydroxy Propyl, 2-methoxyethyl, decyloxy, 2-cyanoethyl and 2-methylsulfonyl-ethyl. With respect to each of the above, Rw, Rx, Ry and Rz may be further Substituted with an amine group, a fluorine, an alkylamino group, a di-alkylamino group, an OH group or an alkoxy group. Further, the prefix of the reverse atomic number of the stone (for example, q -Ci 〇) is used to mean a carbon atom in the heteroalkyl moiety. The total number 'excludes cyano, -ORw, -NRXRy, _SRZ, _s(〇)R^_s(〇)2RZ moiety. Heteroaryl, which refers to an aromatic group of 1 to 14 carbon atoms and 丨 to 6 heteroatoms. a group, a hetero atom selected from the group consisting of oxygen, nitrogen, and sulfur, and including 5 to 18 members Or a ring system comprising a monocyclic (eg imidazolyl) or polycyclic (eg benzimidazol-2-yl and benzimidazole-6-yl). For polycyclic systems, including aromatic and non-aromatic rings A fused, bridged, and spiro ring system, if at least one ring heteroatom, and the point of attachment is attached to an atom of an aromatic ring, the term "heteroaryl" is used (eg ^3,4-tetrahydro) Porphyrin·6-based and 5,6,7,8-tetrahydroporphyrin-3-yl). The nitrogen of the heteroaryl group and the sulfur ring atom are oxidized as appropriate in order to extract the oxide (the NH(tetra) group or the base group is more clearly defined as the 'heteroaryl group'. Including but not limited to pyridyl, furyl, pyrenyl, oxazolyl, isoxazolyl, tetrazolyl, 2azolyl, imidazolyl, isodecyl, oxime, "base," Benzophenoxyl group, tetrahydrobenzopyranyl, iso-p-(tetra)yl, stupidinyl, benzoisomeric, benzotrienyl, phenyl, benzoyl, benzoxyl a 'tetrahydrocarbyl group', an iso-W group, a 4-mercapto, a benzimidazolyl group, a benzisoxazolyl group or a benzothienyl group. A HI group containing a HI group in which a point is attached to a nitrogen-containing group. 149105-sp-2010〇8〇6.d( •28· 201200505 nitrogen atom. For example, "N-linked tetrazolyl" is a group in which the point of attachment is a nitrogen atom of a tetrazolyl group. The triazole group, the N-linked imidazolyl group, the N-linked pyrazolyl group and the N-linked pyrrolyl group are the nitrogen atoms of the triazole, imidazole, pyrazole and pyrrole. Group. Similarly, &quo "N-linked imidazolyl" means an imidazole in which the point of attachment is to a nitrogen atom. "Substituted heteroaryl" means that it is deuterium to 8, or in some embodiments, 1 to 5, or 1 to 3, or a substituent-substituted heteroaryl group, the substituent being selected from the group consisting of: as defined for a substituted aryl group: a substituent; a heteroaryloxy group Is a hetero-aryl group, as defined herein. "Substituted heteroaryloxy" means a group _〇_(substituted heteroaryl), wherein heteroaryl Is defined as follows. "heteroarylthio" refers to the group .S•heteroaryl, wherein heteroaryl is as herein

Substituted heteroarylthio&quot; refers to a group substituted with a heteroaryl group as defined herein. &quot;Heterocycle&quot; or &quot;Heterocyclic, hydrazine, </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; 1 to 6 heteroatoms, selected from the following 纟B/, s ^ ^ , , , , and groups: nitrogen, sulfur or oxygen, and including early % and more mourning systems, including single people. ^ ^ ^ 1 - σ, bridging and spiro ring systems. For the versatile and / or non-family ring Rong Lu μ Ε „ „ clothing, first, &quot;heterocyclic", "heterocyclic", ", heterozygous", "heterocyclic burning a "heterocyclic" heterocyclic heteropolyatom with a ring heteroatom, and a point of attachment of two =: suitable for use on atoms having at least a non-family ring (eg

S J49105-sp-20J00806.doc -29- 201200505 1,2,3,4-Tetra-Ammonia Junction Forest f, base, 5,6,7,8-tetrahydro-portal Kuai Jilong) In a specific embodiment, the heterogeneous group has a base and a phosgene such as "the nitrogen and/or sulfur atomic group of the oxidative read group as appropriate. &amp; The hexahydropyridyl group of the hydrazone is not limited to tetrahydropiperidinyl,

^ 八八虱pyridine_3·yl, hexahydropyridinyl, A tetrapyridin-3-extension, q — N &quot; * I β , tetrazepyrrolyl, 2_tetrahydropyrrole-- Base, ruthenium and tetrahydropyrrolyl. Refers to the thousands of hemorrhoids &amp; * horse porphyrins, the date is not only the atomic number of the first Η丨 ^ ring base part (such as C3-C10) refers to the total number of hetero atoms, except for the number of heteroatoms. ''Substituted Heterocycle&quot;Red&quot; 铋戍, 士 substituted heterocyclic ''or &quot; substituted 瑷 瑷 and • ' or &quot; replaced by heterogeneous p I , ', 衣戈' Substituted heterocyclic group•• means a heterocyclic group as in the present meaning, which is 1 to 5, or in some embodiments '1 to 3 as defined for substituted haloalkyl The substituent is substituted. A heterocyclic oxy group "sandyl group" a heterocyclic group, wherein the heterocyclic group is as defined herein. &quot;Substituted heterocyclyloxy" means a group _〇_(substituted heterocyclic group Wherein the heterocyclic group is as defined herein. Heterocyclylthio&quot; refers to a group _S_heterocyclyl, wherein the heterocyclic group is as defined in the '''Substituted heterocyclic thio group'' Refers to a group _s_(substituted heterocyclic group), wherein the hetero aryl group is as defined herein. Examples of heterocyclic and heteroaryl groups include, but are not limited to, tetrahydro, anthracene, oxazole, pyrazole, Pyridine, pyridinium, well, pyrimidine, sorghum, sorghum, isoindole, hydrazine, dihydroanthracene, carbazole, anthraquinone, sorghum, isoporphyrin, porphyrin, sorghum, 30. 149105-sp .2〇l〇〇806d〇c 201200505

Thiofoline base (also known as thiophyllinyl), 虱兵嗤琳, 4,5,6,7-tetrahydrobenzino[b]thiophene, morpholinyl, 1 lyophilyl , 1,1-diketothiomorpholinyl, hexahydropyridyl, tetrahydropyrrole and tetrahydrofuranyl. "Nitro" refers to the group -N02. " Keto" refers to an atom. "Oxide" means an example of a product formed by oxidation of - or a plurality of heteroatoms including N-oxides, sub-categories, and sarcases.

&quot;Spirocycloalkyl" means a 3 to 10 membered cyclic substituent formed by the replacement of two hydrogen atoms on a common carbon atom by a stretching group having 2 to 9 carbon atoms. The column structure is exemplified by the following: wherein the fluorene group attached to the bond indicated by the wavy line is substituted with a spirocycloalkyl group as follows: &quot;sulfonyl group means a divalent group _S(〇)2 _. &quot;Substituted sulfonyl, refers to the group _S(0)2-alkyl, -S(0)2-substituted alkyl, -S(0)2-alkenyl, ·8(〇 2-substituted alkenyl, -S(0)2-alkynyl, -S(indenyl)2-substituted alkynyl, -S(0)2-cycloalkyl, -S(0)2-substituted Cycloalkyl, -s(o)2-aryl, -S(0)2-substituted aryl, -s(0)2-heteroaryl, -s(o)2-substituted heteroaryl, -S(0)2-heterocyclic, -S(0)2-substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyne Base, cycloalkane 149105-sp-20100806.doc -31- 201200505 base, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted The heterocyclic groups are as defined herein. The substituted sulfonyl group includes a group such as methyl-S(0)2-, phenyl-S(0)2- and 4-mercaptophenyl-S(0)2-. '• sulfonyloxy π refers to the group -os(o)2-alkyl, -os(o)2-substituted alkyl, -os(o)2-alkenyl, -os(o)2 - Substituted alkenyl, -os(o)2-cycloalkyl, -os(o)2-substituted cycloalkyl, -os(o)2-aryl, -os(o)2-substituted aryl , -os(o)2-heteroaryl, -os(o)2-substituted heteroaryl, -os(o)2-heterocyclic, -os(o)2-substituted heterocyclic ring, wherein Alkyl, substituted alkyl, dilute, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl The substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. • 'Thionyl' refers to the group HC(S)-, alkyl-C(S)-, substituted alkyl-c(s)-, alkenyl-c(s)-, substituted Alkenyl-c(s)-, alkynyl-c(s)-, substituted alkynyl-c(s)-, cycloalkyl-c(s)-, substituted cycloalkyl-c(s -, aryl-c(s)-, substituted aryl-c(s)-, heteroaryl-c(s)-, substituted heteroaryl-c(s)-, heterocyclic -c(s)- and substituted heterocyclic-c(s)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, naphthenic The substituted, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are all as defined herein. &quot;thiol&quot; refers to the group -SH. &quot;alkylthio" refers to the group -S-alkyl, wherein alkyl is as defined herein. "Substituted alkylthio" refers to the group -s-(substituted alkyl) wherein the radicals substituted by 149105-sp-20100806.doc •32·201200505 are as defined herein. , 'thiol-based' means the divalent group _颂_, its &quot;thione, hydrazine refers to the atom (=s). , 田于-c(=s)- 〇 &quot;thiocyanate&quot; refers to the group _SCN. As used herein, &quot;compound&quot; and &quot;誃 reveals that the general chemical &lt; m1~ ^ σ物&quot; refers to the compound of the ι化干式8所, 何亚属, and by- Generally, it is a pharmaceutically acceptable salt of the formula " Except. Any form of matter further includes - or a plurality of compounds = = then the term construct and tautomer. "Buddha, stereoisotope" means a pharmaceutically acceptable substance, wherein the combination of the genomically labeled polymorphism and the Ej atomic sequence, usually in the absence of the atom, but the atomic mass of the agar, The isotopes of different atomic masses found in the above are replaced by white mats. Suitable species include isotopes of wind, such as 2H and 3H. Age (4), Tiandai, Ruru, and sound 2 are heavier isotopes. It can be mentioned that some treatment benefits, heart drawing, and large metabolic stability result in a dish such as an increased half-life/required amount in the living body, JL ® tl· y·L dry J or a reduced dose. Therefore, it may be preferred in some cases. "Racemate" is a mixture of metabolites. A "solvate" or a stoichiometric or non-chemical P ^ species of a compound is defined as a compound which is bound to a non-chemical amount of a non-chemical leaf amount. The chemical compound A, The solvate of the substance includes all the compounds, such as the solvent of the "form of the solvent", which is not disclosed in the general and sub-chemical formulas.

Body music or pharmacy can be used as a 丨 丨 丨 之 杈 杈 杈 杈 杈 杈 杈 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂 溶剂. The invention provides a solvate of the compound 149l〇5.sp.2〇j〇〇8〇6d〇cg ·33· 201200505 disclosed herein. &quot;stereoisomers&quot; or, stereoisomers &quot; refers to a compound that differs in the palm of one or more centers. Stereoisomers include palmomers and diastereomers. If the compound of the invention has one or more asymmetry Or eight asymmetrically substituted double bonds, which may exist in stereoisomeric form: 'There may be individual stereoisomers or mixtures thereof. Unless otherwise stated, the description is intended to include individual stereoisomers. And mixtures. The methods for determining stereochemistry and isolating stereoisomers are known in the art (see Chapter 4 of the High School, 帛 4 Edition). March,

John Wiley &amp; Sons, New York, 1992). ' &quot;Tautomers'' refers to alternating forms of compounds that differ in the position of a proton, such as an enol-keto group and an imine-enamine tautomer, or a tautomeric form of a heteroaryl group, It contains a ring atom attached to both the ring_NH_ moiety and the ring=n_ moiety, such as oxime, sputum, stupid, sputum, and sputum. "Rigid body drug" means any derivative of a compound of a specific embodiment which, when administered to a patient, provides, directly or indirectly, a compound of the specific embodiment or an active metabolic product or residue thereof. The prodrug system of the compound of the present invention By modifying the functional group present in the compound in such a manner that the modified substance can be cleaved in vivo to release the parent compound or the active metabolic product. For example, the prodrug includes some compounds, wherein The hydroxy, amine or thiol group in the compound is individually bonded to any group which can be cleaved in vivo to regenerate the free hydroxy, amine or thiol group. Particularly advantageous derivatives and prodrugs, When this compound 149105-sp-20l00806.doc • 34 - 201200505 is administered to a patient, the bioavailability of the compound of the specific example will be increased (for example, by allowing the compound to be administered orally to be more easily Absorbed into the bloodstream, or relative to the parent species', which enhances the transmission of the parent compound to the biological compartment (eg (IV) or lymphatic system). 16 includes an ester, a guanamine, and a urethane (e.g., N,N-dimethylamine carbonyl) form of a hydroxy functional group of the compound of the present invention. Examples of ester prodrugs include formate, acetate, and acetonitrile. From butyric acid, acrylate and diethyl succinate derivatives. The general introduction to prodrugs is provided in τ twisting and 乂%丨la, Weiwei not as new 痹## J, 统, ACS Volume 14 of the series, edited by Edward BR〇che, in the ## diagnosis of Yin Zhilan, y, Dai Dai, American Medical Association and Pergam〇n Press, 1987, both of which are incorporated herein by reference. "Acceptable salt" means a pharmaceutically acceptable salt derived from a variety of organic and inorganic counterions well known in the art, and by way of example only, includes sodium, potassium, calcium, magnesium, ammonium and tetraoxane. Alkyl ammonium. When the molecule contains an organic functional group, it is an acid addition salt of an organic or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or an organic acid such as acetic acid or C. Acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxyphenylindenyl)benzoic acid, cinnamic acid, stupid glycolic acid, decanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, Benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, oxalic acid, 4-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, 4-methylcyclohexyl [2.2.2]-oct-2- Baked-1-Resin, glucoheptonic acid, 3-phenylpropionic acid, dimethylacetic acid, t-butyl acetate, lauryl sulfate, gluconic acid, glutamine I49l05-sp-20100806.doc •35· 201200505 Acid, wish formic acid, salicylic acid, stearic acid, turtle and so on. When the acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth ion or an aluminum ion; or when coordinating with an organic base, such as ethanolamine, diethanolamine, 1 ethanolamine, trimethylamine, and methyl glucose Amine or the like can also form a salt. A pharmaceutically acceptable salt is suitable for administration in a patient's order and has the desired pharmacological properties. Appropriate salt intake – including P. Heinrich Stahl, CamiUe G. Wermuth (ed.), doctors and poor, choose the hand of the Capricorn; 2, 2. Unless otherwise indicated, the nomenclature of substituents, which are not explicitly defined herein, is achieved by referring to the terminal portion of the functional group, followed by the orientation toward the adjacent functional groups of the junction. For example, the 'substituent, aralkyloxycarbonyl group' refers to the group (aryl)-(alkyl)_〇_C(〇)_. It should be understood that in all of the substituted groups defined above, by substituting a substituent for a further substituent to itself (for example, a substituted aryl group, = a substituted aryl group as a substituent, The basic body is replaced by a substituted aryl group which is further substituted by a substituted aryl group, etc., and is not intended to be included herein. In this case t, the maximum number of such substituents is three. For example, a substituted aryl group is substituted with a sequence of two other substituted aryl groups to the _substituted aryl group &lt;substituted aryl)-substituted aryl group. Similarly, it should be understood that the above definition is not intended to include an unacceptable substitution pattern (e.g., a fluorenyl group substituted with five fluoro groups). Such an unacceptable substitution pattern is known to the skilled artisan. Use the &quot;or&quot;as appropriate&quot; terminology, when used throughout this patent specification, I49105-sp-20100806.doc 36 - 201200505, meaning that the events or conditions described below may, but do not necessarily occur, and when described It is the case where the event or condition occurs, and the situation in which 2 is not issued. For example, the &quot;heterocyclic group is optionally mono- or disubstituted by an alkyl group, and ^ means that the alkyl group may but not necessarily be present' and the description includes the case where the heterocyclic group is mono- or disubstituted by a burning group, And a state in which the heterocyclic group is not substituted by an alkyl group. Turning next to the compositions of the present invention, the term "pharmaceutically acceptable carrier or excipient," means a carrier or form that can be used to prepare a pharmaceutical composition that is generally safe and has acceptable toxicity. An acceptable carrier or a second agent includes those acceptable for veterinary use as well as human medical use. &quot;Pharmaceutically acceptable carrier or excipient&quot;, as used in this patent specification and in the item: When included, one or more than one such carrier or excipient. With reference to the methods of the present invention, the following terms are used in conjunction with the indicated meaning: The term "treatment" or "treatment" refers to the inhibition of the disease, that is, to suppress or reduce the disease or its clinical signs. Developing, or relieving the disease, is intended to cause degradation of the disease or its clinical signs. - Preferred embodiments of the invention are for treating a disease comprising mitigating the disease. &quot;Diagnostics&quot; Refers to the determination of the presence or absence of a particular disease or condition. Furthermore, the term refers to determining the extent or severity of a particular disease or condition, and monitoring the disease or condition to determine its response to a particular treatment. &quot;1 The term "3-dioxo" refers to cyclic acetal: I49I05-sp-20100806.doc 201200505

The therapeutically effective amount means the amount of the subject compound that will elicit a biological or medical response from the tissue, system, animal or human being sought by a researcher, veterinarian, doctor or other clinician. "Therapeutically effective amount: includes the amount of the compound that is sufficient to achieve such treatment of the disease when administered to a mammal to treat the disease." The therapeutically effective amount &quot;compounding compound, disease and its severity, and The term "mammal" of a mammal to be treated includes, but is not limited to, humans, domestic animals (such as dogs or cats), farm animals (dairy cows, horses or pigs), and laboratory animals (rats, large). White rats, large rats, scorpion gas, pigs, rabbits, dogs or monkeys, and the words can be defined as glucose metabolism. More specifically, 1 island resistance can be Defined as the reduced biological effect of the application of insulin over a broad range of concentrations, resulting in a lower than expected biological effect (see, for example, Re followed by GM, yc ά • (1998) 9 : 387 4〇6 and FUe j, - finely called ... 0) insulin k-sex has the ability to reduce the proper metabolism of glucose bio- and will respond poorly to insulin therapy, that is, the appearance of insulin resistance is also included in the muscles of the Portuguese Insufficient islet absorption, oxidation, and storage of inadequate oxytocin, as well as lipolysis in adipose tissue and inappropriate production and secretion of glucose in the liver, can prevent or contribute to Cystic ovarian sign box 'attenuates glucose threshold, gestational diabetes' metabolic syndrome, hypertension, fertilizer 149l05-sp-20i00806.doc

•38- 201200505 Fat, atherosclerosis and a variety of other conditions. Finally, the insulin resistant individual can progress to the point in time when the diabetic state is reached. "diabetes mellitus," or "diabetes" refers to a disease or condition that is generally characterized by a metabolic defect in the production and utilization of glucose that causes failure to remain adequate in the body. Blood sugar content. The result of these defects is the increased blood sugar 'called 'hyperglycemia'. The two main forms of diabetes are type 2 diabetes and type _ diabetes. As mentioned above, type 2 diabetes is usually the result of absolute deficiency of tamsin. Tengdao is a hormone that regulates the utilization of glucose. Type I diabetes often occurs in normal or even elevated levels of insulin, and can be caused by the inability of tissues to respond appropriately. Patients with type π diabetes mellitus are resistant to tensin and have relatively inferior insulin, because insulin II cannot compensate for the resistance of peripheral tissues to insulin response. In addition: Xu Xi type II diabetes patients are *'' 'Fat. Other types of stable diseases such as glucose include attenuated glucose tolerance and diabetes. (4) The metabolic system is in the middle of the "glycosidic stable and ancient phase, with gestational diabetes, which is in the unsweetened Not allowed. Urinary disease - the grape in the pregnant women with a history of "metabolic syndrome" - "words refer to fat, Tennessin resistance, glucose does not: U cluster, including abdominal fat disorder. Pre-existing, diabetes , high blood pressure and fat floating / positive r. It is known that these different fΛ &quot; belly, ', one plus the risk of vascular events are related. Sexual (10) centimeters of the heart ^ male waist heart 1 〇 2 cm and Female assessment and treatment of high blood biliary... as directed by the National Cholesterol Education Program Professional Group on Sex Measurements in Adults

S 149105-sp-20100806.doc -39- 201200505 The third report is recommended (NCEP/ATP Hi group). Guidelines for the diagnosis of type η diabetes, impaired glucose tolerance, and surrogate diabetes have been presented by the American Diabetes Association (see, for example, the Expert Committee on Diagnosis and Classification of Diabetes, such as ^, (^第...Supplement 1) : S5 -19) The term “secretin” means a substance or compound that stimulates secretion. For example, insulin secretagogues are 'diabetes that stimulate insulin secretion', and the term includes, but is not limited to, polyuria, thirst = as used herein, incorporated into its usual practice. For example, “polyuria,” means a large amount of urine excretion during a specific period; &quot;thirst&quot; means chronic excessive thirst; and “Buzzard” means overeating. Other symptoms of diabetes include 2 cases of increased susceptibility to certain infections (especially fungal and staphylococcal infections), nausea and ketoacidosis (enhanced ketone body production in liquids). The term "complications" of diabetes includes, but is not limited to, microvascular complications and macrovascular complications. Microvascular complications are complications that generally cause small blood vessel damage. Such complications include, for example, retinopathy (visual attenuation or loss due to vascular injury in the eye); neuropathy (because of nerve damage and foot problems caused by damage to the nervous system); and kidney disease (due to kidneys) Kidney disease caused by injury in the enterprise) Giant vascular complications are generally complications due to macrovascular injury. Such complications include, for example, cardiovascular disease and peripheral vascular disease. Cardiovascular disease refers to a disease of the heart's blood vessels. See, for example, KaplanRM et al., in the syllabus of the genus &quot;Cardiovascular Diseases', pp. 206-242 (McGraw-Hill, New York 1993). Cardiovascular disease is usually one of several forms, including, for example, high pressure (also known as high gray hydraulic pressure 149105-sp-20100806.doc •40· 201200505 heart disease. peripheral vascular disease is often used to transport jk fluid to the foot force), coronary Heart disease, stroke and rheumatism refer to diseases of any blood vessel outside the heart. The blood vessels of the arms and arms are narrowed. The term "atherosclerosis" refers to the disease and symptoms of oily blood, which is recognized and understood by the physicians in the medical field. Atherosclerotic vascular disease, coronary heart disease (also known as coronary artery disease or cardiovascular disease), cerebrovascular disease and peripheral vascular disease are atherosclerotic

The clinical appearance is therefore covered by &quot;atherosclerosis&quot; and &quot;atherosclerotic disease.&quot; The term "anti-lipidemia" refers to reducing the concentration of excess lipids in the blood to a level. "Modulation" or "modulation" refers to the treatment, prevention, inhibition, enhancement or induction of a function or symptom. For example, The compound can inhibit hyperglycemia by increasing insulin in humans to modulate type π diabetes. Compounds can also modulate GPR12〇 by acting as a GPR120 agonist. As used herein, triglyceride &quot;(&quot; The term TG&quot;) is incorporated into its commonly used method. TG contains three fatty acid molecules that are esterified to glycerol molecules. tg is used to store fatty acids, which are used by muscle cells for energy production, or are dissolved. And stored in adipose tissue. Because cholesterol and TG are water-insoluble, they must be packaged in a special molecular complex called &quot;lipoprotein&quot; for delivery in plasma. Lipoproteins can be in plasma. Accumulation, due to overproduction and/or lack of removal. There are at least five unique lipoproteins in size, composition, density and function. In the cells of the small intestine Lipid-based food packaging to be called &quot; chylomicrons ,, the

S 149105-sp-20l00806.doc -41- 201200505 Large lipoprotein complex A, which has high content of butyl and low cholesterol. In the liver, TG and cholesterol are packaged and released into blood. The TG of the very low-density lipoprotein (&quot;VLDL&quot; is rich in lipoprotein, its main function is endogenously transported in the liver or TG released by adipose tissue. VLDL can be Reduced and absorbed by the liver, or converted to intermediate density lipoprotein (&quot;IDL&quot;). IDL is sequentially absorbed by the liver, or further modified to form low-density lipoprotein (&quot;LDL&quot;). LDL is liver Absorbs and decomposes, or is absorbed by extrahepatic tissues. High-density lipoprotein (&quot;HDL&quot;) helps to remove cholesterol from peripheral tissues during a process called reverse cholesterol delivery. • The term 'lipidemia disorder' An abnormal amount of lipoprotein in plasma includes reduced and/or increased levels of lipoprotein (eg, increased levels of ldl and/or VLDL, and reduced levels of hdl). The term "excessive gold fat" includes but is not limited to Description: (1) Family from A large number of bloody cockroaches, a rare genetic disorder, which causes the lack of an enzyme that breaks down fat molecules. The lipase deficiency can cause a large amount of fat or lipoprotein to accumulate in the blood; (2) Family From the high mushroom, a relatively common genetic disorder caused by 'subordinate defects is a series of mutations in the LDL receptor gene, which will cause LDL receptor dysfunction and / or lDL receptors. This will lead to the LDL receptor's ineffective clearance, which will increase the LDL and total cholesterol content in the sputum; (3) the family itch itch cover too much waste, also known as multiple lipoprotein type hyperlipidemia , is a genetic disorder, in which the patient and its effects can be expressed at high time with high cholesterol and high triglyceride as 149105-sp-20100806.doc -42· 201200505. HDL cholesterol content It is often moderately reduced; (4) The domestic child has a relatively large number of positive chromosomal dominant gene abnormalities. This defect is caused by the substitution of glutamine to replace the single nucleus of arginine. Glycosylate Caused by mutations, which can cause a decrease in the affinity of LDL particles for LDL styles. Therefore, this can cause high plasma LDL and total cholesterol levels; (5) Family prion disorders, also known as m-type lipids Too much protein is a rare genetic disorder, causing a moderate to severe increase in serum sputum and cholesterol levels, accompanied by abnormal apolipoproteins. HDL levels are usually normal; and (6) home hydroxy ▲ 鑀 鑀 甘 甘It is mostly a common genetic disorder in which the concentration of plasma VLDL is increased. This can result in a mild to moderately elevated TG content (and usually not a cholesterol content) and can often be accompanied by a low plasma HDL content. Risk factors for hyperlipidemia include, but are not limited to, the following: (i) disease risk factors, such as the first! Type 2 diabetes, type 3 diabetes, (3) also a history of stagnation syndrome, hypogonadism, and certain types of renal failure; (2) drug risk factors, including birth control pills; hormones, such as estrogen, and Corticosteroids; certain diuretics; and various y5 blockers; (3) food risk factors include food fat intake greater than 40% per total calorie; saturated fat intake per total calories greater than 10%; daily cholesterol intake greater than 300 Mg; habits and excessive alcohol use; and obesity. The term 'obese' and 'obese', according to the World Health Organization, refers to the body mass index (&quot;BMI") for males greater than 27.8 kg/m2, while for females]49105-sp-20100806. Doc -43- 201200505 The sex is 27.3 kg / m 2 (BMI is equal to the weight (kg) / height (m2). Obesity is linked to a variety of medical symptoms, including diabetes and hyperlipidemia. Obesity is also about the development of type II diabetes. Known risk factors (Zhu Yue, for example, Barrett-Conner E, Assisted Chichi/., v. (1989) 11: 172-181; and others, Jw···· C/z&gt; 2. (1991) 53 : 1543-1551) The term “dirty” refers to the glandular organs in the digestive and endocrine systems of vertebrates (including mammals). The pancreas secretes both digestive enzymes and hormones, such as insulin, GLP- 1 and GIP 'and other hormones. &quot;islet or "Langhans's islet&quot; The term refers to the endocrine cells of the pancreas, which are clustered in the island, and secrete lycopene and other hormones. &quot;石细胞" A t-system refers to the islet of Langerhans The discovered cells, which secrete insulin, dextrin and other hormones. "Endocrine cells, - words refer to cells that secrete hormones into the bloodstream. Endocrine cell lines are found in various glandular and organ systems of the body, including The pancreas, intestines, and other organs. The term "L cells" refers to the secretory cells that produce gum intestines. &quot;K-cells--the words refer to the endocrine cells that produce GIP. &quot;Intestinal Teng Island The term “main” refers to increasing the secretion of 姨 素 以 in response to food: Take the hormone group 1 促 岛 包括 包括 包括 包括 包括 包括 G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G姨 素 素 会 结合 结合 素 素 素 素 素 素 素 素 素 素 素 素 素 素 素 素 149 149 149 149 素 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 素 149 149 素 素 素 149 Sp-20100806.doc 201200505 GUM&quot; or &quot;glucagon-like peptide

Secretion increases the absence of cell mass and the expression of the gonadotropin gene, inhibits acid secretion and gastric emptying in the stomach, and reduces food intake by increasing satiety. &quot;GIP&quot; or &quot;stomach-inhibiting peptide&quot; or &quot;glucose-dependent insulin polypeptide, the term refers to a peptide hormone produced primarily by kappa cells. GIP stimulates the secretion of temsin. GIP also has significant lipid metabolism. &quot;CAMP&quot; or &quot;cyclic AMP&quot; or &quot;cyclic adenosine monophosphate&quot; term refers to intracellular signaling molecules involved in many biological processes, including glucose and lipid metabolism. A scorpion refers to a compound that binds to a receptor and triggers a response in the cell. An agonist mimics the action of an endogenous ligand, such as a hormone, and produces a physiological response similar to that produced by the endogenous ligand. The term "partial agonist" refers to a compound that binds to a receptor and triggers a partial response in a cell. Partial agonists only produce a partial physiological response to the endogenous ligand. In the examples, the compound of formula (I) is provided w^\

Or a pharmaceutically acceptable salt thereof, wherein: A], A2, A3 and A4 are independently selected from the group consisting of N and C, with the proviso that only 0, 1 of A1, 2, 3 and A4 2 is N; 149105-sp-20100806.doc •45· 201200505 One of X and Y is a bond or _CH2_, _C2H4_, and the other of 乂 and γ is selected from the group consisting of: -CH2 -, -C(O)-, -C(P)NRa, -NR3 -, -〇-, _S-, -S(〇)_ and -S(0)2-; E1, E and E3 are independently selected from c a group consisting of N; one of W^w^w3 and W4 is independently selected from the group consisting of: bonding, NRa, CR1 R2, 〇, s, S(O), and S(0)2, The rest, W2, w3 and W4 are all cWR2; L is -(CR4 R5 )q _, where one _(CR4 Rs)_ is replaced by each or another; subscript k is 〇, 1, 2 or 3 Subscript m is 0, 1, 2 or 3; subscript q is 0, 1, 2, 3 or 4; G is selected from the group consisting of the following

0 Each z is independently selected from the group consisting of η, alkyl and substituted alkyl; each R1 and R2 are independently selected from the group consisting of hydrazine, halo, alkyl, substituted alkane Base, cycloalkyl, substituted cycloalkyl, alkenyl, substituted phenyl, fast-radical, substituted block, keto, CN, -ORa, -NRaRb ' -C(0)Ra ' - C(0)0Ra ' -C(0)NRaRb ' -NRaC(0)Rb ' -SRa, -S(0)Ra and -S(O)2 Ra, and Ri and R2 may be cyclized as appropriate to form 3,4-,5- or 6-membered heterocyclic or cycloalkyl ring; 149105-sp-20100806.doc •46· 201200505 Each R3 is independently selected from the group consisting of hydrazine, halo, alkane a substituted alkyl group, an alkoxy group, a substituted alkoxy group, an amine group, a substituted amine group, an aryloxy group, and -CN; each of R4 and R5 is independently selected from the group consisting of: Η , a fluoro group, an alkyl group, a substituted alkyl group and an alkoxy group, and optionally R4 and R5 may be cyclized to form a 3-, 4-, 5- or 6-membered heterocyclic or cyclodeptyl ring; Each R6 is independently selected from the group consisting of hydrazine, halo, alkyl, substituted alkyl, cyclohexyl, substituted ring-fired , Dilute, Dilute®, Alkynyl, Substituted Block, CN, -〇Ra, -NRa Rb, -C(0)Ra, -C(0)0Ra, -C(0) NRaRb, _NRac(〇)Rb, _SRa, _s(〇)Ra and -S(0)2Ra; each of 1^ and Rb are independently selected from the group consisting of H, alkyl, substituted alkyl, ring Alkyl, heterocyclyl, substituted heterocyclyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl are provided in the specific embodiment. Π) or a compound of formula (III)

(R3)/ E2 or a pharmaceutically acceptable salt thereof, wherein: In some aspects, W4 is 〇, W3 is a bond, and W1 and W2 are both CR1 R2. In a further aspect, W1 is 〇 and W2 is bonding And (7) are both CRlR2 and A are independently selected from the group consisting of N and c, with the accompanying bars ^, A, 八2 and A4 only 〇, 1 or 2 are N; 149105-SP -20100806.doc -47- 201200505 One of X and Y is a bond or -CH2 -, -c2 H4 -, and the other of x and γ is selected from the group consisting of -CH2-, -c(0&gt ;,,_ma... -Ο-, -S-, -S(O)-, and -S(0)2,; E], E2 and E3 are independently selected from the group consisting of C and N; One of W2, W3 and W4 is independently selected from the group consisting of: bonding, NRa, CWR2, 0, S, S(O) and S(0)2, while the rest &lt; w2, w3 and W4 are all Is CR1 R2 ; L is -(CR4R5)q- ' where one _(CR4R5)_ is replaced by 〇_ or _s_; subscript k is 0, 1, 2 or 3; subscript m is 0 , 1, 2 or 3; subscript q is 0, 1, 2 or 3; G is selected from the group consisting of -|-C(0)02 , -|-C(0)NZ2

, 9 n~〇z ο S-^v Ρ, Ν Ύ and ΛΑΑ0Ζ ο Each Ζ is independently selected from the group consisting of η, alkyl and substituted alkyl; each R1 and R2 are independently selected from the following Group consisting of: anthracene, halo, dean, substituted alkyl, cycloalkyl 'substituted cycloalkyl, alkenyl' substituted alkenyl, alkynyl, substituted alkynyl, keto , CN, -〇Ra, -NRaRb, _C(〇)Ra, -C(0)0Ra, _c(〇)NRaRb, _NRaC(〇)Rb, -SRa, 4(0)1^ and _s(〇) 2Ra 'and optionally R 丨 and R 2 may be cyclized to form a 3-, 4-, 5- or 6-membered heterocyclic or cycloalkyl ring at 149105-sp-20100806.doc 201200505; each R3 is independently selected from a group consisting of hydrazine, a halogen group, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, an amine group, a substituted amino group, an aryloxy group, and -CN; R5 is independently selected from the group consisting of hydrazine, fluoro, alkyl, substituted alkyl and alkoxy' and optionally R4 and R5 can be cyclized to form 3-, 4-, 5- or a 6-membered heterocyclic or cycloalkyl ring; each R6 is independently selected from the group consisting of hydrazine, halo, alkyl, and Alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted dilute, alkynyl, substituted alkynyl, CN, 〇Ra, _NRaRb, -C(0)Ra, -C (0) 0Ra, _C(〇)NRaRb, 视 aC(〇)Rb, _SRa, s(〇)Ra and -S(0)2Ra; each Ra and Rb are independently selected from the group consisting of H, alkane Alkyl, substituted alkyl, % alkyl, heterocyclyl, substituted heterocyclyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In some implementations, W, 〇, w3 are bonding, and ... and 舻 are both CR 丨 R2. In some aspects, G is _c(9)〇z. In some of these respects, Z is Η. In some embodiments, W丨 is Ο, W2 is 鐽, and w, w4 are all CR1R2 (7), and G is -C(9)OZ. In some of these respects, Z is Η. In some embodiments, the respective R1 and R2 systems are independently selected from the group consisting of hydrazine, fluoro, _CH3, and _CF3.

S 149105-sp-20100806.doc -49- 201200505 Λ ilb Μ .. 2 /, π know, R1 and R2 are cyclized to form a 3- to 6-membered heterocyclic or cycloalkyl ring ^ &amp; In some embodiments, the E1, E2, and E3 systems are all C. In some embodiments, a, A2, A3, and A4 are all c. In some embodiments, the A1, A2, and A4 systems are all C.爯 爯 - - - - 万 万 万 万 万 万 万 万 万 万 Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο c. In some embodiments, the X and Y lines are selected from the group consisting of C and hydrazine. In some aspects, χ is _CH2_ and γ is 〇. In some embodiments, R3 is independently selected from the group consisting of: fluoro, gas, _CH3, -OCH3, -OCH2CH3, -〇CF3, _CH(CH3)2, and -CF3. In some aspects, m is i. In some embodiments, the 'R6 is independently selected from the group consisting of: fluoro, gas, _CH3, -CH2CH3, - 〇CH3' - 〇CH2CH3 and -CF3. In some respects, k is ο, 1 or 2. In some embodiments, the subscript q is 1 or 2. In some embodiments, R4 and R5 are independently selected from the group consisting of: 9 and (:^13. In some embodiments, R4 and R5 are cyclized to form a cyclopropyl ring. In a specific embodiment, an ester of a compound of formula 1, („) and (ΠΙ) is provided. In some embodiments, the ester is a compound wherein the carboxylic acid group is derivatized to an ester, such as in the chemical formula When 2 is an alkyl group or a substituted alkyl group. In some aspects of the compound of formula (I), W4 is hydrazine; W3 is a bond; and wl and I49105-sp-20100806.doc -50- 201200505 w^^ Cr1r2; e1, e^b3, ^4c; a1) A2jA3^a4#^^c XA_〇V; γ is the subscript "2; and (10) meaning (9) 〇 z. , in some aspects of the compounds of formula (9) and (iv), w, 〇; w3 is a bondage. and w%w2 are 〇^2; "2 and _ are all ^, heart ^ is all C; X is even-; Y is the subscript q is 1; and G is OZ. In a specific embodiment, the compound of formula (A) is provided

(RV

Or a pharmaceutically acceptable salt thereof, wherein: the group J is absent or selected from the group consisting of the following

W2-^ X W1 M W1 \Λ vv, v_y

and

Wherein Q is replaced by (R6)k as appropriate; A, A2, A3 and A4 are independently selected from the group consisting of N and C, with the proviso that A1, A2, A3 and A4 are only 〇, 1 or 2 are N; T1, T2, T3 and T4 are independently selected from the group consisting of N, 〇, CR1 and CR1 R2 'with the proviso that T1, T2, D3 and T4 are only 〇, 1 or Two lines are selected from N and 〇; W1, W2, W3 and W4 are independently selected from the group consisting of N, NRa, 149105-sp-20100806.doc • 51 · 201200505 CRl, CRl R2, 0, s ' s(〇) and s(o)2, with the proviso that ring J is not 1,3-dioxobic;

Ei, E2 and E3 are independently selected from the group consisting of: (1 and 1); one of X and Y is a bond, -ch2-, -CHD_4_CD2-, and the other of X and Y is selected from the following components. Group: -CH2 -, -CHD-, -CD2 -, -C(O), -(:(0) Cong, -NRa-, -〇_, _s·, ___ and __2 ; L is -( CR4R5)q-, where optionally _(CR4R5)_ is replaced by _N_, _〇_, _S_, _Ql4=CR5_ or -phenyl·; G is selected from _C(0)〇Z and -C (〇) a group consisting of NZ2; each Z series is independently selected from the group consisting of H, alkyl and substituted alkyl; each R and R2 are independently selected from the group consisting of: Η, 氘, halo, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl 'substituted alkenyl, alkynyl, substituted alkynyl, keto, alkoxy, Substituted alkoxy, CN, 〇Η, _NRaRb, _c(())Ra, -C(0)〇Ra, _(:(〇辉中, _NRac(〇)Rb, _SRa, 8(聊和- S(〇)2Ra, and as the case may be cyclized to form a hydrazone 37 heterocyclic group, substituted (: 3-7 heterocyclic group, spiro c: 37 heterocyclic group, substituted snail Cs-7 hetero Cyclic group, c:3·7 cycloalkyl Substituted q??cycloalkyl, spiro C3.7 cycloalkyl or spiro substituted c3-7 cycloalkyl; each R3 is independently selected from the group consisting of H, halo, alkyl, Substituted alkyl, alkoxy, substituted alkoxy, -NRaC(0)Rb, -NRaRb, _S(〇)2Ra, cycloalkyl, substituted cycloalkyl, aryl, substituted Aryl, heteroaryl, substituted heteroaryl 149105-sp-20100806.doc • 52· 201200505 aryl, aryloxy, substituted aryloxy and _CN; each R4 and R5 are independently selected from the following Group: H, anthracene, fluoro, leucoyl, substituted alkyl, alkoxy and substituted alkoxy, and optionally R4 and R5 may be cyclized to form a heterocyclic group. Substituted C3·7 heterocyclic group, spiro C; J_7 heterocyclic group, substituted spiro C3 7 heterocyclic group, A·7 cycloalkyl group, substituted C3 7 cycloalkyl group, spiro C3_7 cycloalkyl group or spiro Substituted c3_7 cycloalkyl; each R6 is independently selected from the group consisting of hydrazine, halo, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted Aryl, cycloalkyl, substituted cycloalkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, CN, _〇Ra, -C(0)Ra, -C(0)0Ra, _C(〇)NRaRb, Na c(〇)Rb, _s (〇)Ra and _S(0)2Ra; each R and R are independently selected from the group consisting of H, _c(〇)〇Ra, alkyl, substituted thio, cycloalkyl, heterocyclic a substituted heterocyclic group, an alkenyl group, an alkynyl group, an aryl group, a substituted aryl group, a heteroaryl group, and a substituted heteroaryl group. The subscript k is 〇, 1, 2 or 3; the subscript m is 〇, 1, 2 or 3; and the subscript q is 0, 1, 2, 3 or 4. In a specific embodiment, the compound of formula (A) is not a formula (A-D compound 149105-sp-20100806.doc -53- 201200505

G or a pharmaceutically acceptable salt thereof, wherein: W2-^^W2 w1 'w1 vy1, #基v/ii is not in or selected from the group consisting of 'A (10) gas and ring 5 series r, selected From the group consisting of: aryl, heteroaryl, Λ3^-Τ1 a3^VT1-_, soil

Wherein Q is replaced by (R6)k as appropriate; AW, A3 and A4 are independently selected from the group consisting of ^^ and 〇: the group consisting of only 0, 1 in A'A^A3 and A4 or 2 are N; τ1, τ2, τ3 and τ4 are independently selected from the group consisting of N, 〇, and CRiR2, with the proviso that Tl, T2, T3 and ρ are only...丨 or? The lines are selected from N and 〇; W1, W2, W3 and W4 are independently selected from the group consisting of n, CR1, CR1!^, 〇, s, S(O) and S(0)2, With the proviso that ring J is not 1,3-dioxobic; E1, E2 and E3 are independently selected from the group consisting of C and N; one of X and Y is a bond, -CH2-, -CHD - or -CD2_, and the other of X and γ is selected from the group consisting of -CH2-, -CHD-, -CD2-, -C(O), _C(0)NRa, -NRa_, -ο -, -S-, -S(O)- and -S(〇)2-; 149105-sp-20100806.doc -54· 201200505 L is _(CR4R5)q_, where one -(CR4R5)- Substituted by -N-, -Ο-, -S-, -CR4 =CR5 - or -phenyl-; G is selected from the group consisting of -C(0)0Z and -C(0)NZ2; each Z Each of the R1 and R2 groups is independently selected from the group consisting of ruthenium, osmium, halo, alkyl, substituted alkyl, Cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, keto, alkoxy, substituted methoxy, CN '-NRaRb, _c (〇)Ra, _c(〇)〇Ra,, -C(0)NRaRb, -NRa C(0)Rb, -SRa, -S(0)Ra&amp;-S(0)2Ra, and optionally R1 and R2 may be cyclized to form a C3-7 heterocyclic group, a substituted -7 heterocyclic group. , spiro C3 -7 heterocyclyl, substituted spiro c3 · 7 heterocyclyl, A-7 cycloalkyl, substituted c: 3·7 cycloalkyl, spiro c3-7 cycloalkyl or spiro substituted c3_7 ring Alkyl; each R3 is independently selected from the group consisting of hydrazine, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, ®-NRaC(0)Rb, _NRaRb , aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy and _CN; each R4 and R5 are independently selected from the group consisting of: Η , gas, fluoro, alkyl, substituted alkyl, alkoxy and substituted alkoxy, and optionally R4 and R5 may be cyclized to form A7 heterocyclyl' substituted A-7 heterocyclic , snail c: 3 heterocyclic group, substituted snail q? heterocyclic group, c3-7 cyclodyl group, substituted c3 7 cycloalkyl group, spiro c3 7 ring yard group or spiro substituted (: 3- 7-cycloalkyl; 149105-sp-20100806.doc •55- 201200505 Each R6 is independently selected from the group consisting of hydrazine and halogen. , alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, Alkynyl, substituted alkynyl, CN, -0Ra, _NRaRb, -C(0)R^, -C(0)0Ra ^ -C(0)NRaRb ^ -NRaC(0)Rb , .SRa . _S( 〇)Ra and -S(〇)2Ra; each R and Rb are independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, heterocyclic, substituted heterocyclic An alkenyl group, an alkynylaryl group, a substituted aryl group, a heteroaryl group, and a substituted heteroaryl group. The subscript k is 〇, 1, 2 or 3; the subscript m is 〇, 1, 2 or 3; and the subscript q is 0, 1, 2, 3 or 4.

In another embodiment, the compound of formula (A) is not a compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein:

Ai, A2, A3 and A4 are independently selected from the group consisting of N and c, with the proviso that A, A2, A3 and A4 are only 〇, 1 or 2 are N;

•Ο-, -S·, -; , -S(〇)- and _s(0)2_ ; 149105-sp-20100806.doc -56, 201200505

Ei, E and E3 are independently selected from the group consisting of c and N; one of W'W^W3 and W4 is independently selected from the group consisting of: bonding, NRa, CRiR2, 〇, S, S ( O) and S(0)2, while the remaining Wi, W3 and W4 are all CR1 R2; L is _(cr4r5 V, where one - (CR4R5)- is replaced by -〇 or -S-;

The subscript k is 〇, 1, 2 or 3; the subscript m is 〇, 1, 2 or 3; the subscript q is 0, 1, 2, 3 or 4; the G is selected from the group consisting of the following groups - (o&gt;oz, |c(0>NZ2

ο i Η -Η~οζ Ο · ο Ίοζ S*^ Ρ, Ν ζ and -vwz ο Each 独立 is independently selected from the group consisting of hydrazine, alkyl and substituted alkyl;

Each of R1 and R2 is independently selected from the group consisting of hydrazine, halo, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, dilute, substituted alkenyl, alkynyl Substituted alkynyl group, _*, CN, _〇Ra, -NRaRb, -C(0)Ra, -C(0)0Ra, _c(0)NRaRb, -NRaC(0)Rb, -SRa, _s (0) Ra and -S(O)2 Ra 'and depending on the case, Ri and R2 may be cyclized to form a 3-, 4-, 5- or 6-membered heterocyclic or cycloalkyl ring; each R3 is independently a group selected from the group consisting of hydrazine, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amine, substituted amine, aryloxy, and -CN; 57· 149105-sp-20l00806.doc 201200505 Each R4 and R5 are independently selected from the group consisting of hydrazine, oxy, decyl, substituted alkyl and alkoxy, and optionally 尺5 Cyclization to form a 3-, 4-, 5- or 6-membered heterocyclic or cycloalkyl ring; each R6 is independently selected from the group consisting of hydrazine, fluorenyl, alkyl, substituted alkane Base, cycloalkyl, substituted cycloalkyl, alkenyl 'substituted alkenyl, alkynyl, substituted alkynyl, CN, 〇Ra ' _N RaRb ' -C(0)Ra ^ -C(0)0Ra . -C(0)NR^Rb . -NRaC(〇)Rb ^ _gRa ^ s(〇)Ra and -S(0)2Ra ; Rb is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, heterocyclyl, substituted heterocyclyl, alkenyl, alkynyl, aryl, substituted aryl Base, heteroaryl and substituted heteroaryl. In still another specific embodiment, the compound of formula (A) is not a compound of formula (11) or formula (III)

Or a pharmaceutically acceptable salt thereof, wherein: A, 2 and V are 'independently selected from the group consisting of N#c, the condition is 'A〗, only 0 in A2 and A4, and U2 are N; The X and Y are either a bond or even _, d, and the other of my is selected from the group consisting of -CH2-, -C(O)-, -C(0)NRa, -NRa-ο- , -s-, ·8(0)_ and ·s(〇)2; E丨, E2 and E3 are independently selected. Group consisting of entanglements; 149105-sp-20100806.doc -58- 201200505 One of w1, w2, W3 and W4 is independently selected from the group consisting of: bonding, NRa, CR1 R2, Ο, S, s (0) and S(〇)2, while the remaining W1, W2, W3 and W4 are all CR1 R2; L is -(CR4R5)q-, where a _(CR4R5)- is _〇· or each Substitution; subscript k is 0, 1, 2 or 3; subscript m is 0, 1, 2 or 3;

The subscript q is 0, 1, 2 or 3; the G system is selected from the group consisting of -|-c(o)oz, +c(o)nz2

'Vz. 斗* Each 独立 is independently selected from the group consisting of η, alkyl and substituted alkyl;

Each of R1 and R2 is independently selected from the group consisting of hydrazine, halo, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkyne Substituted, substituted alkynyl, keto, CN, -ORa, -NRaRb, -C(;0)Ra, -C(0)0Ra, -C(〇)NRaRb, -SRa, -S(0) Ra and -S(O)2 Ra 'and depending on the case, r1 and R2 may be cyclized to form a 3-, 4-, 5- or 6-membered heterocyclic or cyclic ring; each R3 is independently selected from the following Group consisting of: hydrazine, hydrazine, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amine, substituted amine, aryloxy, and -CN; 149105-sp- 20100806.doc •59- i^· 201200505 Each R4 and R5 are independently selected from the group consisting of hydrazine, fluoro, alkyl, substituted alkyl and alkoxy, and optionally R4 and R5 To form a 3-, 4-, 5- or 6-membered heterocyclic or cycloalkyl ring; each R6 is independently selected from the group consisting of hydrazine, halo, alkyl, substituted alkyl , cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl' substituted alkynyl, CN, -ORa, -NRaR b, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -NRaC(0)Rb, -SRa, -S(0)Ra and -SC〇)2Ra; each Ra and Rb Is a group independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, alkynyl, aryl, substituted aryl , heteroaryl and substituted heteroaryl. In another specific embodiment, the compound of formula (A) is not a compound of formula (A-1), (I), (II) and/or (III), or a pharmaceutically acceptable salt thereof. In another embodiment, it is expressly intended that the compounds disclosed in Taiwan Application No. 098143781, filed on Dec. 18, 2009, are hereby incorporated herein by reference. This exclusion applies not only to the general chemical formula, but also to the individual types disclosed in the application of 098143781. In another specific embodiment, a compound of formula (B) is provided. 149105-sp-20100806.doc • 60· 201200505 R2

Or a pharmaceutically acceptable salt thereof, wherein r, r2, R3, R6, w], w3, e1, e2, 纪, \乂(^'1^0, 111 and 1^ are as in formula (VIII) The definition is that |1 and W3 are not all 0. '

In some embodiments of the compound of formula (B) '^(10) is independently selected from the group consisting of CR1 R2 and hydrazine. In some embodiments, a compound of formula (c) is provided: R2

Qm and k are as defined in some embodiments, &lt;(8)" (the hydrazine compound is not a compound of formula (I), (II) and/or (III), or a pharmaceutically acceptable salt thereof. In a particular embodiment, a compound of formula (c) is provided wherein the El, E2 and E3 systems are all C. In certain aspects, the lanthanide is selected from the group consisting of _CH2_, _chd_ and -CD2 - and Y is In a further aspect, in L, the subscript q is 2 or 3. In some respects

S 149105-sp-20I00806.doc -61- 201200505 The standard q is 2. In terms of progress, G is -C(0)〇z. In some respects, B is alkyl or Ηβ. In terms of progress, the subscript m is 1 or 2, and each R3 is independently selected from the following composition. a substituted, substituted 9 group, an alkoxy group, and a substituted alkoxy group. In some aspects, each R3 is independently selected from the group consisting of Fα, -CH3, -ch2 CH3 -, -CH(CH3)2, -CF3, -〇CH3, -och2ch3, and -OCH3. In terms of the step-by-step, R and r2 are independently selected from the group formed by the Ci3 yard and the _CF3. In some aspects, both R1 and R2 are _CH3. In a further aspect, the subscript k is 0342. Fluoro Group In a further aspect, each R6 is independently selected from the group consisting of the following groups of gas groups, -ch3, -c2H5, .OCh3, _0CH2CH3, and _CF3. In the specific embodiment of the formula (A), Q is in some aspects, the ring J is absent, and each R3 is independently selected from the group of (4): alkoxy groups, substituted oxygen Base and self base. In some embodiments, it is implemented. The compound is not a compound selected from the group consisting of the following compounds: or a pharmaceutically acceptable salt thereof; 2 chloro- 2,2-dimethyl-dihydrobenzopyryl)methoxy)6-fluoro Base-2,3-monohydrogen-1Η-茚-〗 _) acetic acid (29); 3-(4-((2,2·di-f-yloxy)_3,5_:fluorophenyl (31) 3-(4-((2,3-dihydrobenzopyran)-7-methoxy)&gt;3,5_di-gas substrate methyl 149105-sp-20100806.doc •62- 201200505 Propionic acid (32); methyl-2,3-dihydrobenzoxanthene-7-yl)methoxy)benzene 2-methyl-3-(4-((2,2,5-triyl)) Propionic acid (33); • 3-(3,5-difluoro-4-((2,2,5-phenyl)-2-mercaptopropionic acid (34); Benzylfuran-7-yl) Oxy) 3-(4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzopyranoyl-7-yl)methoxy)-3-methyl stupid 2-methylpropionic acid (35); 3-(4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran)

Methoxyphenyl)-2-methylpropionic acid (36); &quot; 3-(3-fluoro-4-((5-fluoro)-2,2-dimercapto-2,3-di t stupid And astringent _7_yl)methoxy)phenyl)-2-methylpropionic acid (37); 3-(4-((5-chloro-2,2-dimethyl-2,3_) Dihydro benzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)_2-mercaptopropionic acid (38); 3-(4-((5-chloro)-2, 2-monodecyl-2,3-dihydrobenzop-amyl-7-yl)methoxy)___fluorophenyl)-2-mercaptopropionic acid (39); 3-(4-( (5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuranyl)methoxy&gt; 3-methylphenyl)-2-methylpropionic acid (40); 3-( 3-Chloro-4-((5-chloro-2,2-dimercapto-2,3-dihydrobenzofuran; yl)foxy)phenyl)-2-methylpropionic acid (41 3-(3,5-Dichloro-4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7) methoxy)phenyl) -2-methylpropionic acid (42); 3-(3'5-dichloro-4-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzofuranyl)) Oxy)phenyl)-2-methylpropionic acid (43); 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) )methoxy)_3·

S I49105-sp-20100806.doc -63- 201200505 methoxyphenyl)-2-methylpropionic acid (44); 3-(4-((5-fluoro-2,2-dimethyl-2, 3-dihydrobenzofuran-7-yl)decyloxy)phenyl)-2-mercaptopropionic acid (45); 3-(4-((2,2-dimethyl-2,3-di) Hydrogen benzofuran _4•yl) decyloxy)phenyl)2·methylpropionic acid (46); methyl-2,3-dihydro benzofuran-7-yl)methyl fluorenyl-2,3 - dihydro benzofuran _7, yl) hydrazine benzofuran-7-yl) decyloxy) benzene 3-(3,5-difluoro-4-((5-carbyl-2,2-di) Oxy)phenyl)-2-mercaptopropionic acid (47); 2-(3,5-difluoro-4-((5-1-yl-2,2-dioxy)phenyl)cyclopropanecarboxylate Acid (48); 3-(3,5-difluoro-4-((2-methyl-2,3~yl)-2-mercaptopropionic acid (49); 3-(4-((2, 2-Dimethyl-2,3-dihydroindolyl^_4•yl)decyloxy)_3,5-di-phenylphenyl-2-mercaptopropionic acid (50); 2- (4-(( 2,2_Dimethyl·2,3-dihydroindolyl _4•yl)decyloxy)_3,5-di-phenylphenyl)cyclopropanecarboxylic acid (51); 3- (4-((2) ,2-dimercapto-2,3-dihydrobenzopyrene _7-yl)nonyloxy)_3,5-di-phenylphenyl-2-mercaptopropionic acid (52); 2- (4- ((2,2-Dimethyl-2,3-dihydrobenzofuranyl)methoxy group阳-二说phenyl)cyclopropanecarboxylic acid (S3); 3-(4-((2,2-dimercapto-2,3·dihydro cuminium, 7-yl)methoxy) Dioxophenyl)propionic acid (54); 3-(2-ranyl-4-((5-chloro-2,2-dimethyl)phenyl)-2-mercaptopropionic acid (55) ; '2,3_dihydrobenzofuran_7-yl)oxime 2-(3,5-di-I-4-((4-carbyl-2,2-dimethyl-3-hydrobenzofuran)- 7-yl) A 149105-sp-20100806.doc • 64 - 201200505 Oxy)phenyl) Cyclopropanone (56); 3-(3,5-Difluoro-4-((4-fluoro)- 2,2-Dimethyl 2,3-dioxy)phenyl)-2-mercaptopropionic acid (57); Hydrobenzobenzopyran-7-yl)methyl 3-(3-Denyl-4- ((4-mercapto-2,2-diinyl at the second gas stupid and succinyl) methoxy)phenyl)-2-methylpropionic acid (58);

3_(Guidyl-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)methoxy)phenyl)-2-mercaptopropionic acid (59); Dimethyl-4-(trimethylmethyl&gt;2,3-dihydrobenzopyrano-7-yl)methoxy)-3,5-difluorophenyl)cyclopropanecarboxylic acid (6 〇) 3-(4-((2,2-Dimethyl-4-(trifluoromethyl)2,3-diazino-p-xyl)-methoxy)-3,5-« One gas base) -2 -methylpropionic acid (61); 3-(4-((2,2-difyl-4-(trifluoromethyl) R3_dihydro benzoate _7_yl) Methoxy)-3-fluorophenyl)·2-methylpropionic acid (62); 3-(4-((2,2-dimethyl-4-(trimethyl)&gt;2,3_ Diazobenzonitrile % _7_yl)methoxy)phenyl)-2-methylpropionic acid (63); 2-(4-((5-carbyl-2,2_difyl-2, 3_Dihydrobenzofuran_7•yl)methoxy--, gas-based Cyclopropanone (64); 2-(5-((5-Chloro-2,2-dimethyl) Base 2,3_dihydrobenzopyran%) methoxy like diphos-1H-ind-1-yl)acetic acid (65); occupation (10) group · 2,2 • dimethyl 2,3_ Dihydrobenzo^ _7•yl)methoxy like diterpene-lH-k--1-yl)acetic acid (66); 3-(4-((5-carbyl-2,2-dimethyl-2) Dihydrobenzofuran (South difluorophenyl)-2-methyl Acid (67); -7-yl)methoxy)-3,5- 3-(4-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzofuran_7) _ base) methoxy)_2_

S 149I05-sp-20100806.doc •65· 201200505 曱Phenylphenyl)-2-methylpropionic acid (68); gas-based)-3,5-difluorobenzofuran-7-yl) oxime 3-( 4-((2,3·Dimethyl-2,3-dihydrobenzofuran π)methyl)·2-mercaptopropionic acid (69); 2-(2-(4-((5- Gas-based-2,2-dimethyl-2,3-dihydrobenzo)-3,5-difluorophenyl)cyclopropyl)acetic acid (70); N-7-yl) oxime 3 -(4-((5,6-difluoro-2,2-dimercapto-2,3-dihydroindolizine)-3,5-difluorophenyl)-2-mercaptopropionic acid ( 71); 3-(4-((5,6-Difluoro-2,2,didecyl-2,3-dihydrobenzofuran π)methoxy)phenyl)-2-methylpropane Acid (72); 3-(4-((2,2-dimethyl-2,3-dihydrobenzopyran-7)yloxy)methyl)_3_fluorophenyl)-2 -methylpropionic acid (73); 3-(4-((6-fluoro-4H-benzo[d][l,3]dioxolyl-8-yl) decyloxy)phenyl) -2-methylpropionic acid (74); 3-(4-((5-It-based-2,2-indolyl-2,3-dihydrobenzopfunan-7-yl) oxime Base)_2·methylphenyl)propionic acid (75); 3-(2-chloro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzopyran) -7-yl)decyloxy)phenyl)propionic acid (76); 3_(2-fluoro-4-((5-fluoro-2,2-) 2-(2,6-difluoro-4-((5-fluoro)-) 2-Dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)propionic acid (78); 3-(4_((5-fluoro-2,2-difluorene) Benzyl-2,3-dihydrobenzofuran-7-yl)decyloxy)_2·nonyloxyphenyl)propionic acid (79); 3-(4-((5-alkyl-2,2-di) Methyl-2,3-dihydrobenzofuran-7-yl)decyloxy)_2_ 149105-sp-20100806.doc -66 · 201200505

Methylphenyl)propionic acid (80); 3-(2-carbyl-4-((5-carbyl-2,2-dimercapto-2,3)yl)phenyl)-propionic acid (81 3-(4-((5-Gasyl-2,2-dimethyl-2,3·dihydro cuminium 咕〆"ββ失失的'7-yl) 曱oxy)-2-fluoro Phenyl)-propionic acid (82); 3-(4-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzoquinone A lactyl-furan-7-yl)) Oxy)·2,6-difluorophenyl)propionic acid (83); 3-(4-((5-carbyl-2,2-dimethyl-2,3-dihydro 袈旄 风 风 本Open-furan-7-yl)methoxy)-2-oxooxyphenyl)propionic acid (84); 3-(2-bromo-4-((5-fluoro-2,2-dimethyl) 2,3_-gas '- 虱 开 呋 喃 -7 -7-yl) methoxy)-5-methoxyphenyl) propionic acid (85); 3-(tetra)-based gas-based dimethyl dihydrogen And chewing silk) methoxy)-5-methoxyphenyl)propionic acid (86); 2-((4-((5-fluoro)-2,2-dimethyl-2,3-. )thio)-acetic acid (87); 2-((4-((5-chloro-2,2-didecyl-2,3-)yl)thio)-acetic acid (88); '-( 2-ethyl-4-((5-aeroyl·2,2-dimercapto-2,3-dihydrobenzo^_7-yl) methoxy)phenyl)acrylic acid (89); 3- ( 4-((5-Fluoro-2,2-dimethyl-2,3-yl)_2-(trifluoromethyl)phenyl)propane (90); 3-(4-((5-Chloro-2,2-dimethyl-2,3-yl)-2·(trifluoromethyl)phenyl)propanoic acid (91); 3- (Gas-based 2,2-dimethyl-2,3-dihydrobenzobenzoin-7-yl)methoxy-oxygen benzofuran-7-yl)hydroxanthene-7- Methoxy) phenylhydrobenzofuran-7-yl) methoxy) phenylhydro benzofuran-7-yl) oxime oxo benzo-7-yl) methoxy 149105-sp-20100806. Doc -67- 201200505 monoterpene-1H-indol-4-yl)propionic acid (92); 3 (7-((5-carbyl-2,2-monomethyl-2,3-dihydrobenzindole)南南_7_yl)methoxy)_2 3_dihydro-1H-indol-4-yl)propionic acid (93); (R) -3-(4-((5-fluoro-2,2-) Dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-mercaptopropionic acid (94); (S) -3-(4-((5-fluoro) Base-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropionic acid (95); 3-(4-((( 5-Alkyl-2,2-indenyl-2,3-dihydrobenzo-[Nan-7-yl)methyl)amino)phenyl)-2-mercaptopropionic acid (96); -(4-(5-fluoro-2,2-monomethyl-2,3-difluorenyl p-amyl-7-amidino)phenyl)-2-mercaptopropionic acid (97) ; 3-(3,5-I il -4-((5-oxy-2,2-di) Benzyl-2,3-dihydrobenzobenzoin-7-yl)methoxy)phenyl)-2-ethoxypropionic acid (98); 2-(4-(2-(5-fluoro)- 2,2-Dimethyl-2,3-dihydrobenzopyranyl-7-yl)ethyl)aloxy)acetic acid (99); 3-(5-((5-)yl-2,2 - dimethyl-2,3-dihydrobenzifuryl-7-yl)decyloxybiphenyl]yl)propionic acid (1〇〇); 3-(5-((5-fluoro)-2, 2-Dimethyl-2,3·dihydrobenzofuran-7-yl)methoxy)-[1,Γ-biphenyl]-2-yl)propionic acid (1〇1); 3-( 4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran; yl)methoxy)-5-fluoro-2-propylphenyl)propanoic acid (102); 3-(5-Fluoro-4-((5-fluoro-2,2·didecyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2-propylphenyl Propionic acid (103); 3-(4-((5-carbyl-2,2-dimethyl-3,yl-2,3-dihydrobenzofuran-7-yl)oxime 149105-sp -20100806.doc •68- 201200505 keto-2-ethyl-3-fluorophenyl)propionic acid (104); 3-(4-((5-ranyl-2,2-methylketone)- 2,3--oxo-p-pyrano-7-yl)methoxy)-2-propylphenyl)propionic acid (105); 3-(4_((5_气基·2,2·二) Methyl-3-yl-keto-2,3-dihydroindolofuranyl)methoxy)- 3-fluorophenyl)-2-methylpropionic acid (106); 3-(3-fluoro-4-((5-fluoro-2,2-didecyl-3-keto-2,3) -Dihydrobenzopyrene-7 (meth) methoxy)phenyl)-2-methylpropionic acid (107); 3-(4-((5-carbyl-2,2-dimethyl-3) -keto-2,3-dihydrobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)-2-methylpropionic acid (108); 3-(4- ((5-Alkyl-3-transyl-2,2-dimethyl-2,3-dihydrobenzifuryl-7-yl)methoxy)-3-fluorophenyl)-2-indenyl Propionic acid (109); 3-(4_((5-indolyl-2,2-dimethyl-2,3-dihydrobenzofuranyl)methoxy)phenyl)-2-mercaptopropyl Acid (110); 3-(4-((5-(4-chlorophenyl)-2,2-dimercapto-2,3-dihydrobenzofuran; yl)methoxy)phenyl)- 2-mercaptopropionic acid (111); 3_(4_((5_(4_1phenyl)&gt;2,2-diindenyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl -2-methylpropionic acid (112); 3-(4-((5-(3-chlorophenyl)-2,2-dimethyl-2,3-dihydrobenzofuranyl)methoxy Phenyl)-2-methylpropionic acid (113); 3-(4-((5-(2-chlorophenyl)-2,2-dimethyl-2,3-dihydrobenzofuran) _7_yl)methoxy)phenyl)-2-mercaptopropionic acid (114); 3-(4-((5-(3-) Phenyl)-2,2·dimethyl-2,3-dihydrobenzofuranj-yl)methoxy)phenyl)-2-methylpropionic acid (Π5); 3-(4-((2) ,2-dimethyl-(trifluoromethyl)phenyl)2,3-dioxbenzotrienyl 149105-sp-20100806.doc •69·201200505 yl)methoxy)phenyl)-2-methyl Propionic acid (116); 3-(4-((5-chloro-2,2-dimercapto-2,3-dihydrobenzf). _7_yl) methoxy)_3 ((dimethylamino)methyl)phenyl)-2-methylpropionic acid (117); 3-(4-((5-(diethylamino)) -2,2-dimercapto-2,3-dihydrobenzofuranyl-7-yl)methoxy)phenyl)-2-methylpropionic acid (118); 3-(4-((2) ,2-dimercaptotetrazole-l-yl>2,3-dihydrobenzifuryl-7-yl)methoxy)phenyl)-2-methylpropionic acid (119); 3-(4 -((7-Fluoro-2,2-monomethyl-2,3-monohydrobenzofuran-4-yl)methoxy)phenyl)-2-methylpropionic acid (120); -(3,5-difluoro-4-((7-1-yl-2,2-dimercapto-2,3-dihydro benzofuran-4-yl)methoxy)phenyl&gt;2- Mercaptopropionic acid (121); 2-(3,5-difluoro-4·((7-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran) methoxy Phenyl)cyclopropanecarboxylic acid (122); 2-(5-((7-fluoro-2,2·dimethyl-2,3-dihydrobenzofuran-4-yl)methoxy) · 2,3 dihydro-1 Η-indol-1-yl)acetic acid (123); ' 3- (3,5-di 14-((5-glycol dimethyl-2,3-dihydrobenzo)吱4_yl)methoxy)phenyl)-2-mercaptopropionic acid (124); 3-(4-((5-f-yl-2,2-dimethyl-2,3-di) (2-)-methylpropionic acid (125); (R)-3-(3,5-difluoro-4-((5-mercapto-2,2-di) Methoxy)phenyl)-2-methylpropionic acid (126); 3-(4-((5-chloro-2,2-dimethyl-2,3-dioxaphenyl)-2) - mercaptopropionic acid (127); hydrogen benzofuran-4-yl) decyloxy) benzyl-2,3-dihydrobenzopyranyl) hydrogen benzofuran-7-yl) methoxy Base)_2_ 2-(3,5-difluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzindazinyl). 149105-sp-20100806. Doc -70· 201200505 oxy)phenyl)cyclopropanecarboxylic acid (128); 3-(4-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzofuranyl) )methoxy)-3,5-difluorophenyl)-2-methylpropionic acid (129); 3-(3,5-difluoro_4_((6-fluoro-2-,2-dimethyl) _2,3-dihydrobenzofuranyl)methoxy)phenyl)-2-mercaptopropionic acid (130); 3-(4-((5-carbyl-2,2-dimethyl) -2,3-dihydrobenzofuranyl)methoxy)phenyl)-2.methylpropionic acid (131); 2-(4-((5-carbyl-2,2-dimethyl) -2,3-dihydrobenzofuran-7-yl)methoxy)dong# mercaptophenoxy)acetic acid (132); 2-(4-((4-carbyl-2,2-dioxin) Benzyl-2,3-dihydrobenzofuran-7-yl)methoxy)_2_methylphenyloxy)acetic acid (133); 2-(4-((5-carbyl-2,2-dimethyl) Base-2,3 -dihydrobenzofuran-7-yl)methoxy)phenoxy)acetic acid (134); 3-(4-((5-carbyl-2,2-dimethyl-2,3-dihydro) Benzofuran-7-yl)methoxy)_3,5-difluorophenyl)butyric acid (135); 3-(3,5-difluoro-4-((5-methoxy-2,2-) Dimethyl-2,3-dihydrobenzofuran-7-yl) anthraceneoxy)phenyl)-2.methylpropionic acid (136); 3-(4-((5-methoxy)- 2,2-monomethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropionic acid (137); 3-(4-((5-gas) Base-2,3,3-tridecyl-2,3-dihydrobenzofuran-7-yl)methoxy)·3,5-difluorophenyl)-2-methylpropionic acid (138) 3-(4-((5-ethoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)-3,5·difluorophenyl) 2-methylpropionic acid (139); 3-(4-((5-(benzyloxy)-2,2-dimethyl-2,3-dihydrobenzifuryl-7-yl)methoxy 149105-sp-20100806.doc 201200505 base-3,5-difluorophenyl)-2-mercaptopropionic acid (140) ·, 5-((5-carbyl-2,2-dimethyl-2) , 3-dihydrobenzofuran_7 side) methoxy 3 _ hydrogen-1H-indole-2-carboxylic acid (141); 5-((5-fluoro-2,2-dimethyl-2, 3-dihydrobenzofuranyl)methoxy)_2 3 monohydro-1H-indole-2- Acid (142); 6-((5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)-methanecarboxylic acid (143); 3-( 4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzoc-yl-7-yl)methoxy)_2isopropoxyphenyl)propanoic acid (144); 3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxyisopropoxyphenyl)propanoic acid (145); 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran,7-yl)methoxy)_2-ethoxyphenyl)propanoic acid (146); 3-(2-ethoxy-4-((5-methoxy-2,2-dimethyl-2,3·dihydrobenzofuranyl)methoxy)phenyl)propionic acid (147 3-(4-((5-Alkyl-2-methyl benzofuran-7-yl)methoxy)-2 ethylphenyl)propanoic acid (148); 3-(4_((5- Chloro-2-methylbenzofuran-7-yl)methoxy)_3_fluorophenyl)_2-methylpropionic acid (149); 3-(4-((5-fluoro-2,2) -dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)indol-1-yl)propionic acid (150); 3-(2-((dimethylamino)methyl) -4·((5-Fluoro 2,2-diindenyl 2,3-dihydrobenzobenzo-7-yl)methoxy)phenyl)propionic acid (151); 3-(4 -((5-Acetylamino-2,2-dimethyl -2,3-dihydrobenzofuran-7-yl)methoxy-I49105-sp-20100806.doc •72- 201200505 phenyl)-2-methylpropionic acid (152); 3-(4-( (2,2-Dimethyl-5-(trifluoromethoxy)_2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-T-propionic acid (1S3); 3-(4-((5-Fluoro-2,2-methyl-2,3-dihydrobenzoin-7-yl)methoxy)_2_methylbenzofuran-7-yl) Propionic acid (154); 3-(4-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)methoxy)_3_ (trifluoromethyl) 2-(4-((5-chloro-2,2-dimethyl-2,3-di) Hydrobenzofuran-7-yl)hydrazino)amino)phenyl)propionic acid (156); 3-(4-(((5-fluoro) 2,2-dimethyl-2,3-dihydro) Stupid and furan·7·yl)hydrazino)amino)phenyl)propionic acid (157); 3-(4-((5-chloro-2,2-dimethyl-3-keto-2), 3-dihydrobenzofuran; yl)methoxy)phenyl)-2-mercaptopropionic acid (158); 3-(4-((5-chloro-3-yl)-2,2-di Methyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropionic acid (159); 2-(4-((5-fluoro-2,2) -Dimethyl-2,3-diqibenzopyrene _7_yl) decyloxy) phenyl yl) cyclopropanecarboxylic acid (160); 3-(4-((5-fluoro-2,2-indolyl-2,3-·-indole benzopyrene)喃-7-yl)decyloxy)phenyl)propionic acid (161); 2-(4-((5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran) _ yl)methoxy)phenyl)acetic acid (162); M2·ethyl-4-((5.fluoro-2-,2-dimercapto-2,3-dihydroindolyl) anthracene Phenyl)propionic acid (163); 3-(4-((5,2-yl-2,2-indolyl 2,3-)-) _2_ £149l05-sp-20100806.doc -73- 201200505 Isopropylphenyl)propionic acid (164); 3-(4-((5-fluoro-2,2-didecyl-2,3-di) Hydrogen benzofuran _7-yl) methoxy) 2 - (trifluoromethoxy) phenyl) propionic acid (165); 3_(4-((5-)- 2,2-dimethyl- 2,3-dihydrobenzifuranyl-7-yl)decyloxy)_2-isopropylphenyl)propionic acid (166); 3-(4-((5-carbyl-2,2-dimethyl) -2,3-dihydrobenzofuran-7-yl)methoxy)_2_ethylphenyl)propionic acid (167); 3-(4-((5-a)-2,2-didecyl -2,3-dihydrobenzofuran-7-yl)decyloxy)_2_(trifluoromethoxy)phenyl)propanoic acid (168); 3-(4-((2,2-didecyl) -2,3-two Benzofuran-4-yl)methoxy)_2-ethylphenyl)propionic acid (169); (R)-3-(4-((5-chloro-2,2-didecyl-2) ,3·dihydrobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpropionic acid (170); (S) -3-(4-((5-) -2,2-dimethyl-2,3-dihydrobenzofuran) methoxy)-3-fluorophenyl)-2-methylpropionic acid (171); (foot)-3-( 4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)-2- Mercaptopropionic acid (Π2) (S)-3-(4-((5-Chloro-2,2-dimethyl-2,3-diazabenzofuran-7-yl)decyloxy)- 3-(4-((3,3-diodes-5-fluoro-2,2-dimethyl-)-(3-((3,3-didecyl-5-fluoro-2,2-dimethyl-) 2,3-dihydrobenzo-c-amyl-7-yl) decyloxy)phenyl)-2-methylpropanoic acid (174); 3-(4_((3,3-diindole-5- gas) Base 2,2·dimethyl-2,3-dihydrobenzopyran-yl) methoxy)-3-fluorophenyl)-2-methylpropionic acid (175); 3-(4_ ((3,3-dioxane-based 2,2-dimethyl-2,3-dihydrobenzopyrene)-based 149105-sp-20100806.doc _ 74 - 201200505 methoxy)- 3-(trifluoromethyl)phenyl)_2-methylpropionic acid (176); 3-(4-((5) -lacyl-3,3-dimethyl-2,3-dihydrobenzo-dozen 0-n-7-yl)methoxy)phenyl)-2-mercaptopropionic acid (177); 3 (4 ( (5-muro-3,3-monomethyl-2,3-dihydrobenzop-am-7-yl)methoxy)_3·fluorophenyl)-2-methylpropionic acid (178) ; 3 (4 ((2,2-monomethyl-2,3-monohydrobenzopyran-4-yl)decyloxy)_2,3-dimethylphenyl)propanoic acid (179); 3 -(3,5-difluoro-4-((2-methylbenzo[b]sulfonyl-7-yl)methoxy)phenyl)_2-methylpropionic acid (180); soil 2-( 5-((2-mercaptobenzo[b>pyrene; yl) oxime)_2,3_dihydro-ih茚+yl)acetic acid (181); soil 2-(6-((5-fluoro) Base-2,2-dimethyl-2,3_dibenzobenzofuran-7-yl)methoxy^1,2,3,4-tetrahydroindolyl-acetic acid (see 2); 2_(6·((5-Alkyl-2,2-dimethyl-23--浒, '上+ 1 « 丞, j 一虱本开furan-7-yl)methoxy)_ 1, 2,3,4-tetrahydrosol-i-yl)acetic acid (183); M3-carbyl-4-((5-fluoro-based 2,2-diamino 2,3 dihydrobenzofuran) (meth) methoxy) benzyl) 2-mercaptopropionic acid (184); 3- (4-((5-a)-2,2-diinyl-23-- § wild t 1 poem, Monomethylfuran-7-yl)methoxy)benzene (3)-mercaptobutyric acid (18S); (((5-fluoro 2,2-indolyl 2,3-dihydrobenzo-peptyl-7-yl)methoxy)phenyl)-3 -methylbutyric acid (186); methyl 3 (4 ((2,2,5--methyl-2,3-dihydro benzofuran-7-yl)methoxy)phenyl)butyric acid ( 187); 3-(4-((5-Gasyl-3H-spiro[benzopyrene_2, Γ_cyclopentan]_7-yl)methoxy)benzene 149105-sp-20100806.doc ^ 201200505 4-methylpropionic acid (188); 4-(4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy) Butyryl) butyric acid (189); 4-(3,5-difluoro-4-((5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl) Methoxy)phenyl)butyric acid (190); MMO fluoro-3H-spiro[benzofuran.2, fluorene-cyclopentane]-7-yl)nonyloxy)phenyl)-2-methyl Propionic acid (191); 2- 0-((5-1--3H-spiro[benzofuran]. South _2,1,-cyclodecane]_7-yl)decyloxy)_2,3_dihydro-1H-indol-1-yl)acetic acid (192); 3-(4-((5-fluoro)- 3H-spiro[benzofuran_2, Γ_cyclopentane]_7_yl) decyloxy)phenyl)propionic acid (193); 2-(4-((5-fluoro)-3Η- snail [stupid] And furan 'polycyclodecane] _7_yl) decyloxy) phenyl) cyclopropanecarboxylic acid (194); 3- (4-((5-alkyl-3H-spiro [stuppyfuran-2, 1L) Cyclopentane]_7-yl)decyloxy)phenyl)propionic acid (195); 4-(4-((2,2,5·trimethyl-2,3-dihydrobenzopyrene. South_ 7-based) methoxy)phenyl)butyric acid (196); 4-(4-((5-carbyl-2,2-dimethyl-2 3-- τ 丞 虱 虱 开 开 _ _ 7 _ yl) methoxy) phenyl) butyric acid (197); - hydrogen benzopyrano-7-yl) methoxy) 4-(3,5-difluoro-4-((2,2,5) -trimethyl-2,3-phenyl)butyric acid (198); 4-(4-((5-chloro-2,2-difluorenyldifluorophenyl)butanoic acid (199); , 3-dihydro benzofuran-7-yl)methoxy)3,5_ 4-(4-((5-fluoro-2,2-difyl-2,3-dihydroindolefuran) 7_yl)methoxy)benzene 149105-sp-20100806.doc •76· 201200505 yl)-2-mercaptobutyric acid (200); 4-(4-((5-ranyl-2,2-a) Mercapto-2,3-dihydrobenzene N-(7-yl)methoxy)phenyl)-2-methylbutyric acid (201); 3-(4-((5-fluoro-2,2-dimethyl-2,3_2) Hydroxybenzofuran-7-yl)methoxy)_3. oxirane phenyl)propionic acid (202); 3-(4-((5-alkyl-2,2-dimethyl-2,3- Dihydrobenzofuran-7-yl)methoxy)·3. methoxyphenyl)propionic acid (203); (S)-2-(5-((5-fluoro-2,2-dimethyl) Base 2,3-dihydrobenzofuran; yl)methoxy)_2,3_-wind-1H-ind-1-yl)acetic acid (2〇4); (S)-2-(5-(( 5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuranyl)methoxy-l-indole-1-yl)acetic acid (2〇5); 3-(4-( (5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)propionic acid (206); (R)-2-(5- ((5-Gasyl-2,2-dimethyl-2,3-dihydroindolofuran-7-yl)methoxy)-2,3-dihydro-1H-ind-1-yl)acetic acid (2〇7); (8)-2-(5-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzop-fyl)methoxy)-2,3- Dihydro-1H-indol-1-yl)acetic acid (2〇8); 2 (3 gas-based-4_((5-fluoro-2,2-dimethyl-2,3-dihydrobenz-p) _7-yl)methoxy)phenyl)cyclopropanecarboxylic acid (209); 2-(4-((5-carbyl-2,2-dimethyl-2,3·2) Benzofuran-7-yl)methoxy)_3·fluorophenyl)cyclopropanecarboxylic acid (210); 4 (4-((5-carbyl-2,2-methyl-2,3·) Dihydrobenzop-pyrene-7-yl)decyloxy)phenyl)-3-indolylbutyric acid (211); 4_(4_((5_(2)-(2)- 2,2-indolyl-2, 3·Dihydrobenzopyran·7_yl)methoxy)benzene 149105-sp-20100806.doc -77- 201200505 benzyl-3-methylbutyric acid (212); 2-(3,5-di Fluoro-4-((5-fluoro-2,2-dimethyl-2,3·dihydrobenzofuran-7-yl)methoxy)henyl)cyclopropanecarboxylic acid (213); 2- (4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)_3 5_difluoroindolyl)cyclopropanecarboxylic acid (214) 3-(4-((2,2-Dimethyl-5-phenyl-2,3-dihydrobenzopyrano-7-yl)decyloxy)phenyl)propanoic acid (215); -(5-((2,2-Dimethyl-5-phenyl-2,3-dihydrobenzofuran-7-yl)decyloxy)·2 3_Dihydro-1Η-茚-1-yl Acetic acid (216); (R)-2-(5-((6-fluoro-2,2-dimethyl-2,3-dihydrobenzofuranyl)methoxy)-2,3 -dihydro-1Η-indol-1-yl)acetic acid (217); 3-(2-fluoro-4-((5-fluoro)-3H-spiro[benzofuran-2,1'-cyclopentane Methoxy)phenyl)propionic acid (218); 3-(4 -((5-Fluoro-3H-spiro[benzofuran-2,1,-cyclopentane]-7-yl)nonyloxy)_2-methoxyphenyl)propionic acid (219); 2-(4 -((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)benzyl)cyclopropanecarboxylic acid (220); 2- (4- ((5-Chloro-2,2-dimethyl-2,3·dihydrobenzofuran-7-yl)methoxy)indolyl)cyclopropanecarboxylic acid (221); 3- (4-( (5-Chloro-3H-spiro [stupylfuran·2&gt;1,·cyclopentanol]_7_yl) methoxylates are described as stupid) propionic acid (222); 3-(4-((5- Gas-based 3-indole-spiro[plumhydrofuran·21,-cyclopentane]_7-yl)methoxymethoxyphenyl)propionic acid (223); 3-(2_carbyl-4-((5- Fluoryl·3Η-spiro[benzofuran_2,Γ_cyclopentane]_7yl)methoxy 149105-sp-20100806.doc •78· 201200505 base) stupid) propionic acid (224); 3-(2 - gas-based 4-((5-alkyl-3H-spiro[p-oxafuran-2, oxime-cyclopentane]-7-yl)methoxy)phenyl)propanoic acid (225); 3-( 2,6-monochloro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)propanoic acid (226) 3-(2,6·Dichloro_4·((5·3,3 dihydrobenzobenzoin-7)methoxy)phenyl)propionic acid (227);

2-(2-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)cyclopropyl)acetic acid ( 228乂; 2-(2-(4-((5-Alkyl-2'2-dimethyl-2'3 digas benzo) methoxy-7) methoxy) stupyl) cyclopropyl Acetic acid (229); noisy (four) (four) based. snail [benzoh ^ 2, Γ _ cyclopentan] _7_ yl) methoxy) stupyl) cyclopropyl) acetic acid (230); 2 Yang I gas base · 3 Η snail [benzo bite. South _2,1L Cyclopentyl) methoxy) phenyl)cyclopropyl)acetic acid (231); 3-(2-ethyl-4-((5-Denyl·3Η- snail [stupid and 吱Taste _2, Γ_cyclopentan] 7-yl) fluorenyl) phenyl) propionic acid (232); ΗΜ (5-fluoro-2,2-dimercapto-2,3_ two gas stupid Furan _7_yl) oxime _ dimethylphenyl) propionic acid (233); 3-(4-((5-carbyl-2,2-dimercapto-2,3-dihydrobenzene) And furan _7-yl) decyloxy)·2,6· dimethylphenyl)propionic acid (234); 3-(4-((5-carbyl-2,2-dimercapto-2,3) _ II gas stupid and furan _7 • base 曱 戍 5 曱 _ ) ) ) 丙 丙 235 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3_Dihydrobenzofuran-7-yl)methoxy 149105-sp-20100806.doc -79· 201200505 Dimercaptophenyl)propionic acid (236); methoxy)-2,3- 3 -(4~((5-fluoro-2,2-dimercapto-2,3-dihydrobenzo-[1]-N-dimethylphenyl)propionic acid (237); oxy)-2,3 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran)) _7_yi)methyl dimethyl phenyl)propanoic acid C 238); _7_yl)methyl 2-(2-(2-fluoro-based 4-((5-fluoro-2,2-dimethyl-2,3-dihydroindolyl).) Cyclopropyl)acetate 239); 2-(2-(4-((5-Alkyl-2,2-dimercapto-2,3·di-ar-benzofuran-7-yl)methoxy)-2-phenyl) Cyclopropyl)acetic acid (240); 3-(4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) anthracene) 2 propyl Phenyl)propionic acid (241); 3-(4-((5-carbyl-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)_2-propyl Phenyl)propionic acid (242); 3-(5-IL-based 4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzo-[beta]-N-7-yl) Methoxy)-2-mercaptophenyl)propionic acid (243); 3-(4-((5-carbyl-2,2-indolyl-2,3-dioxabenzopyrene) 7-yl)nonyloxy)_5 fluoro-2-methylphenyl)propionic acid (244); 3-(2-ethyl-3-fluoro-4-((5-fluoro)-2,2 -Dimethyl-2,3-dihydrobenzofuranyl)nonyloxy)phenyl)propionic acid (245); 3-(4-((5-lactyl-2,2-indenyl)_2 , 3_2-gas benzophenone 〇南·7_yl)methoxy)_2 ethyl-3-fluorophenyl)propionic acid (246); 3-(4-((5-fluoro-2,2) -dimercapto-2,3-dihydroindolofuran-7-yl)decyloxy)-5,6,7,8-tetrahydroindol-1-yl)propionic acid (247); 3-(4 -((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuranyl)methoxy)_ 149105_sp-201008 06.doc -80- 201200505 5,6,7,8-tetrahydronaphthalen-1-yl)propionic acid (248); 3-(2-ethyl-5-fluoro-4-((5-fluoro) -2,2-dih-yl)methoxy)phenyl)propionic acid (249); Hydrobenzofuran-7-

3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydromosa 4 + habenfuran-7-yl)methoxy)-2-ethyl-5 -fluorophenyl)propionic acid (250); 3-(3-fluoro-4-((5-fluoro-2,2-dimethyl-2,3-dif 1 +) -yl)nonyloxy)-2-propylphenyl)propionic acid (251); 3-(4-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzindole)咕 喃 -7-7-yl)methoxy)-3_fluoro-2-propylphenyl)propionic acid (252); 3-(3-fluoro-4-((5-fluoro)-2, 2-dimercapto-2,3-dioxin-poor ugly + oxime-openfuran-7-yl)nonyloxy)-2-pentylphenyl)propionic acid (253); 3-(4-(( 5-oxo-2,2-dimethyl-2,3-dihydroindolofuryl)methoxypyridyl-2-pentylphenyl)propionic acid (254); 3-(2-B 3-fluoro-4-((5-fluoro-2,2-di-2-yl-2,3dihydrophenyl)methoxy)phenyl)-2-methylpropanoic acid (255) 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuranyl)methoxy-ethyl-3-fluorophenyl)-2-methyl Propionic acid (256); 3-(4-(difluoro-(5-fluoro-2,2-dimethyl-2,3-yl)-3-Iso-2-ethylphenyl)propanoic acid (257); 3-(4-(difluoro-(5-fluoro-2,2-dimethyl-2,3-yl)-3-I-yl-2- Phenyl)propionic acid (258); 3·(4_(di-deuterated (5-fluoro-2-,2-dimethyl-2,3-dihydrobenzifuryl-7)methoxy)- 3-fluorophenyl)-2-methylpropionic acid (259); 3-(4-(disintegrated (5-carbyl-2,2-dimethyl-2,3-dioxin-poor ugly milk) Ben 唤 _ 7 7 _ _ _ _ _ _ _ _ _ 呋 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 (trifluoromethyl)phenyl)-2.methylpropionic acid (260); 3-(3-fluoro-4-((5-fluoro-2,2-dimethyl-2,3-di) Hydrobenzofuran-7-yl)methoxy)-2-isopentylphenyl)propionic acid (261); 3-(4-((5-carbyl-2,2-dimethyl-2, 3-dihydrobenzofuran-7-yl)methoxy&gt; 3-fluoro-2-isopentylphenyl)propionic acid (262); 3-(4-(di-dimethylated (5-chloro) -2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)nonyloxy)-3-fluoro-2-ethylphenyl)propionic acid (263); 3-(4 -(Di-deuterated (5-carbyl-2,2-dimercapto-2,3-dihydro acnefuran-7-yl)methoxy)-3-fluoro-2-propylphenyl) Propionic acid (264); 3-(4-(two gasification (5-carbyl-2,2-dimercapto-2,3-dihydrobenzoate). _7_yl)methoxy)-3-fluorophenyl)-2-mercaptopropionic acid (265); di-negative (5-chloro-2,2·didecyl_2,3_2 Hydrogen stupid and 吱7_yl) decyloxy)-3-(trifluoromethyl)phenyl)-2-methylpropionic acid (266); 3-(2-butyl-3-fluoro- 4-((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzoc.South-7-yl)methoxy)phenyl)propionic acid (267); 3-(2- Butyl-4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzifuryl-7-yl)methoxy)-3-fluorophenyl)propanoic acid (268) 3-(4-((5-oxy-2,2-dimercapto-2,3-dihydrobenzop. Nan-7)-methoxy)3(trifluoromethyl)benzene 2-mercaptopropionic acid (269); 3-(4-((5-carbyl·2,2·didecyl-2,3-dihydrobenzofuran, 7-yl)methoxy) Fluorophenyl)-2,2,3,3-tetrahydropropionic acid (270); 3-(3-f-yl-4-((5-fluoro-2,2-didecyl-2,3) -dihydrobenzofuran-7-yl)nonyloxy)-2-propylphenyl)-2,2,3,3-tetrahydropropionic acid (271); 3-(2-ethyl-3- Fluoro-4-((5-fluoro-2,2-indolyl-2,3-dihydrobenzopyrano 7 149105-sp-20100806.doc -82· 201200505) methoxy)benzene -2,2,3,3-tetrahydropropionic acid (272); 3-(3-fluoro-4-((5-fluoro)-2,2- Dimethyl-2,3-dihydrobenzifuryl π-yl)methoxy)-2-methylphenyl)propionic acid (273); 3-(4-((5-carbyl-2,2-) Dimercapto-2,3-dihydrobenzofuranyl)oxy)_3 fluoro-2-indenylphenyl)propionic acid (274); 3-(3-ethyl-4-((5- Acetyl-2,2-dimethyl-2,3-dihydro benzopyrazine 7-yl)methanyl)phenyl)propionic acid (275);

3-(4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy-ethylphenyl)propanoic acid (276); ^ 3-(3-Ethyl-4-((tetra)yl.2,2 dimethyl dihydro benzoxanyl)methoxy)phenyl)-2-mercaptopropionic acid (277); 3- (4-((5-Chloro-2,2-didecyl dihydro benzofuran-7-yl)methoxyethylphenyl)-2-methylpropanoic acid (278) ; ^ 3- (2-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran) methoxy)phenyl)propanoic acid (279); 3-(3-(( 5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-mercaptopropionic acid (280); 3-(4 -((2,2-dimethyl&amp;-2,3-dihydrobenzofuranyl)methoxy)phenyl)propionic acid (281); 3-(4-((2,2-dimethyl) Benzyl-2,3-dihydrobenzopyrene _7-yl)methoxy)phenylated methylpropionic acid (282); 3-(4-((5-fluoro-2,2-dimethyl) Base-2,3-dihydrobenzofuran. Nanfuyl)methoxy) 2,3,5-tridecylphenyl)propionic acid (283); chloro-2,2-didecyl-2 , 3_ dihydro benzofuranyl) methoxy)_

S 149105-sp-20100806.doc -83- 201200505 2,3,5-trimethylphenyl)propionic acid (284); 3-(4-((5-fluoro-3H-spiro[benzofuran, 2, Γ_cyclopentyl]-7-yl)methoxy dimethylphenyl)propionic acid (285); 2-(5-((5-chloro-2-isopropoxybenzyl)oxy) 6-fluoro 2-, 3-dihydro-indole-1-yl)acetic acid (286); 2-(5-((5-ylyl-2-isopropoxybenzyl)oxy)2 3 dihydrogen _m茆小基)acetic acid (287); 2-(5-((2-isopropoxypyridin-3-yl)decyloxy)_2,3_dihydro-exe_printing) acetic acid (288 3_(4_((1H, oxazol-7-yl)methoxy) 3,5-difluorophenyl)2·methylpropionic acid (289); 3-(3,5-difluoro-4 -((2-methylbenzo[d]carbazole-7-yl)methoxy)phenyl)-2-methylpropionic acid (290); 2-(6-((5-fluoro-2,2) -Dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)benzofuran-3-yl)acetic acid (291); 2-(7-((5-fluoro)-2, 2-Dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)_2-keto-2H-nonen-4-yl)acetic acid (292); 3- (4-((5) -fluoro-2,2-dimercapto-2,3-dihydrobenzop-amyl-7-yl)decyloxy)phenyl)-N-yl-2-methylpropanamide (293 ); 3-(4·((5- Base-2,2-dimercapto-2,3-dihydrobenzopyranyl-7-yl)methoxy)phenyl)-N-hydroxypropionamide (294); 3-(4-(( 5-Chloro-2,2-dimethyl-2,3-dihydrobenzopyranyl-7-yl)decyloxy)phenyl)-4-methylpentanoic acid (295); 3-(4 -((6-ranyl-2,2-monomethyl-2,3-dihydroindole oxime. South_4_yl) decyloxy)_2,3·dimethylphenyl)propionic acid (296 ); and 149105-sp-20100806.doc -84· 201200505 &quot;3-(2-ethoxylated stomach 4·((5-fluoro-based 2,2-dimethyl-2,3-dihydro benzoate) Squeezing _7-based oxy)phenyl)propionic acid (297). In another embodiment, a synthetic intermediate or compound, or a pharmaceutically acceptable salt thereof, as described in the Examples is provided. In other specific examples, a compound agonist, or a pharmaceutically acceptable salt thereof, or a synthetic intermediate thereof, is provided as exemplified in the Chemical Examples section below. In some embodiments, the formula (1&gt; (111) and (A)(C) compounds and pharmaceutically acceptable salts thereof have resistance to human GpR12, such as Μ" or less. In other respects, the compounds have EC5 〇 greater than i - and below or Equal to 10 (10). In other aspects, the compound has an EC50 of 1 - or less. Preparation of the Compounds of the Invention The compounds of the present invention can be prepared in a variety of ways familiar to those skilled in the art of organic chemical synthesis. The synthetic route of the compounds of the present invention is not limited to the methods outlined herein or as provided in the Examples. Individual compounds may require manipulation of the conditions to conform to various functional groups and may require the appropriate use of protecting groups. If necessary, the purification can be carried out on the Shi Xizheng column and dissolved in a suitable organic solvent system. Reverse phase HPLC or recrystallization can also be employed. In a specific implementation, the invention is directed to the novel intermediates for the preparation of the compounds of the invention. Compositions and Methods of Treatment In accordance with the present invention, there is provided a treatment for a disease selected from the group consisting of type I diabetes, type II diabetes, and metabolic syndrome. This method comprises administering to a patient in need of such treatment a therapeutically effective amount of the invention 149105-sp-20100806.doc -85 - 201200505 on the other hand providing a cell that promotes Ca2+ in cells expressing GPR120 The method of internal content. This method involves exposing cells that exhibit GpR12 〇 to the compounds of the invention. The Ca2+ content is determined by the method disclosed in the Examples section herein. In one embodiment, the cells that exhibit GPR120 are pancreatic cells, islet cells, or/5 cells, enteroendocrine cells, L cells, or kappa cells. Another aspect of the invention provides a method of stimulating the production of tamsin in a mammal, particularly a human. This method comprises administering to the mammal a therapeutically effective amount of a compound of the invention. In response to the administration of the compound to the patient, the Tengdao system is provided by the W cell. Example 4 provides a detailed method. The skilled artisan can measure the insulin secretion in the laboratory animal in response to the administration of the compound of the present invention. Putian 丨玉Α and Kong Lei, especially the method of stimulating insulin secretion in humans. In this method, Wanling has been administered to the mammal, and the compound is a response compound to the patient. The insulin is secreted into the bloodstream by the cells. A further aspect of the invention provides a stimulation in a mammalian human. Glucose-dependent insulin secretion is administered to a mammal; Θ, this method includes the compound of the present invention which is only effective (7). After the sputum, the insulin is glucose-dependent. 4 The beautiful pile + fly by the secretion of stone cells to the blood sugar lowering effect, , the system does not show the compound of the present invention in another specific embodiment is provided in the mammal preferably 149105-sp-20100806. Jo, '86 ' 201200505 LL ^ ^ for lowering blood sugar in humans 仏 This method includes (iv) money animal administration: therapeutically effective! The compound of the invention. In response to: Le, blood sugar content is reduced. This includes the steps of measuring the blood glucose level before and after administration of the compound. The gold sugar contains (4) is easily measured by a number of commercially available glucose monitoring devices, which are: ^: :::: The amount of gray sugar can also be set by the commercially available glucose meter, which does not require blood ass to collect urine samples. Biological example 3 provides guidance on how to measure diabetes parameters ', monitoring. The method, including blood glucose, is a method for stimulating incretin production in a feeding animal, particularly a human, in a further aspect of the invention. This is a method comprising administering to the mammal &gt; A therapeutically effective amount of a compound of the present invention. In response to a compound's interest in the patient, the glucagon peptide i and the (iv) sugar-dependent insulin-producing polypeptide are produced by enteroendocrine cells. A detailed method is provided by which a skilled technician can measure the production of invitrogen in response to administration of a compound of the invention in a laboratory animal. TC Therapy As described above, in some cases, the compound of the present invention will be combined with other therapeutic agents to produce the desired The role of other agents is based on the desired therapy (see, for example, Tumer N et al, Pr〇g ~ & (Μ% 51: 33-94; HaffnerS, test toC (10) (1998) 21 : 16 fingers And (4)^ et al. (eds.), Qianming Minghui (1997), Vol. 5, No. 4, many studies have studied the benefits of combination therapy with oral agents (see, for example, 丨erR, / d• her site) (1999) 84: 1165_71; UK Prospective Diabetes Study 149105-sp.20100806.doc -87 - 201200505 Group: UKPDS 28, Care (1998) 21: 87-92; Bardin CW (ed.), Department of Secretion and Metabolism Current Therapy, % 6; Company, St. Louis, MO 1997), Chiasson J et al., J. / 咐em Afei. (1994) 121: 928-935; ConiffR et al., C//«. 77/er· (1997) 19 : 16-26 ; ConiffR et al., Jw. /· Met/· (1995) 98 : 443-451; and Iwamoto Y et al., /^'&lt;30 over ^/!^ · (1996) 13: 365-370; Kwiterovich P, Am. J. Cardiol (1998) 82(12A): 3U-17U). These studies show that diabetes modulation can be further improved by adding a second agent to the therapeutic regimen. Combination therapy comprises administering a single pharmaceutical dosage formulation containing a compound as provided herein, and one or more additional active agents, and administering the compound and active agent as provided herein in its own individual pharmaceutical dosage formulation. . For example, a compound as provided herein and a DPP4 inhibitor can be administered to a human patient, such as a tablet or capsule, together with a single oral dosage composition, or each agent can be administered in an individual oral dosage formulation. In the case of individual dosage formulations, the compounds as provided herein and one or more other active agents may be administered at substantially the same time (ie, collectively), or at individual staggered times (ie, sequentially). . It should be understood that the combination therapy system includes all such usages. Examples of combination therapies can be seen in modulating (preventing the development of symptoms or complications associated with diabetes) diabetes (or treating, preventing or reducing the risk of developing diabetes and its associated signs, complications, and conditions), as in this document The compounds provided can be effectively used in combination with, for example, bifolds (such as metformin), sputum bites, two steels (such as ciglitazone, pioglitazone, zhuo Troglitazone and rosiglitazone; dipeptidyl-peptidase-4 (&quot;DPP4&quot;) inhibitor 149105-sp-20100806.doc -88- 201200505 (eg, weidae Vildagliptin and sitagliptin; a high blood-glycopeptide-1 (&quot;GLP-1&quot;) agonist (such as exanatide) (or GLP-1) Analogy; PPARt* agonist or partial agonist; dual PPARa, PPARt agonist or partial agonist; dual PPAR6, PPARj agonist or partial agonist; total PPAR agonist or partial agonist; dehydrogenation Epiandroxin (also known as DHEA, or its conjugation Acid ester DHEA-S04); anti-cortisol; TNFa inhibitor; glucosidase inhibitors (such as acarbose, miglitol and voglibose); Base ureas (such as chlorpropamide, tolbutamide, acesulfame hexazone, methotrexate, glyburide, gliclazide, griclas) Glynase), glimepiride and glipizide; pramlintide (synthetic analogue of human hormone dextrin); other gonadotropin-promoting hormones Repaglinide, gliquidone, and nateglinide; insulin (or mitomycin mimic); gonadotropin receptor antagonist; gastric inhibitory peptide (&quot;GIP) Or GIP mimics; and active agents discussed below for the treatment of obesity, hyperlipidemia, atheroma, and/or metabolic syndrome. Another example of combination therapy can be seen in the treatment of obesity or obesity-related disorders. And wherein the compound as provided herein is effective in combination with And use, for example, phenylpropanolamine, phenteramine; diethylamine benzene; chlorinated mazindol; fenfluramine; dexfenfluramine; Phentiramine, /3-3 adrenergic receptor agonist; sibutramine; gastrointestinal lipase inhibitor (such as orlistat); and Lepasol. Other agents for the treatment of obesity or obesity-related diseases 149105-sp-20100806.doc-89·201200505, wherein the compounds as provided herein can be effectively used in combination with, for example, marijuana-like-1 (&quot;CB -1&quot;) receptor antagonist (such as rimonabant); PPAR &lt;5 agonist or partial agonist; double PPAR alpha, PPAR5 agonist or partial agonist; double PPAR6, PPAR &lt;r Agonist or partial agonist; total PPAR agonist or partial agonist; neuropeptide Y; enter bacteriocin; chosome stimulating hormone; bombesin; dextrin; histamine H3 receptor; dopamine D2 Receptor; melanocyte stimulating hormone; corticotropin releasing factor; galangin; and 7* aminobutyric acid (GABA). Yet another example of combination therapy can be seen in the modulation of hyperlipidemia (treatment of hyperlipidemia and its associated complications), wherein a compound as provided herein can be effectively used in combination with, for example, bacteriocin ( Such as atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin, CETP Inhibitors (such as torcetrapib); cholesterol absorption inhibitors (such as ezetimibe); PPAR alpha agonists or partial agonists; PPAR &lt; 5 agonists or partial agonists; Dual PPARa, PPAR5 agonist or partial agonist; dual PPARa, PPARr agonist or partial agonist; dual PPAR (5, PPAR7 agonist or partial agonist; total PPAR agonist or partial agonist; Fibric acid derivatives (such as gemfibrozil, clofibrate, fenofibrate and bezafibrate); bile acid-binding resins (such as Lesbian (c〇iestip〇l) or biliary (cholestyramine)); final acid; probucol; carotenoid; vitamin E; or vitamin C. Further examples of combination therapy can be seen in the modulation of atherosclerosis, 149105-sp-20100806. Doc -90· 201200505 wherein a compound as provided herein is administered in combination with one or more of the following active agents: an antihyperlipidemic agent; a plasma HDL enhancer; an antihypercholesterolemia agent, such as a cholesterol biosynthesis inhibitor, for example Hydroxymethylpentamethylene (HMG) CoA reductase inhibitors (also known as bacteriocins, such as lovastatin, simvastatin, prasin) Pravastatin), fluvastatin and atorvastatin; HMG-CoA synthetase inhibitor; squalene epoxidase inhibitor; or squalene synthase inhibitor Agent (also known as synthase inhibitor); brewing base-coenzyme A cholesterol thiol transferase (ACAT) inhibitors, such as melinamide; probucol Acid test with its salt and nicotinamide; cholesterol absorption Inhibitors, such as /5-sulphonol; bile acid sequestrant anion exchange resins, such as cholestyramine, colestipol or cross-linked dextran dialkylaminoalkane Base derivatives; LDL receptor inducers; fiber esters such as clofibrate, bezafibrate, fenofibrate and gemfibrizol; vitamins B6 (also known as pyridoxine), and pharmaceutically acceptable salts thereof, such as ® HC1 salt; vitamin B] 2 (also known as cyanocobalamic acid); vitamin β3 (also known as niacin and nicotine) Amines; antioxidant vitamins such as vitamins C and E and cold carotene; blockers; angiotensin II antagonists; angiotensin converting enzyme inhibitors; PPARa agonists or partial agonists; PPAR5 agonists or Partial agonist; PPAR7 agonist or partial agonist; dual PPARa, PPAR&lt;5 agonist or partial agonist; dual PPARa, PPAR«r agonist or partial agonist; dual PPAR3, PPARt agonist or minis Agonist; total PPAR agonist or partial agonist; and platelet Set inhibitors, such as fibrin 3 I49105-sp-20100806.doc -91 - 201200505 fibrinogen receptor antagonists (meaning glycoprotein Ilb / IIIa fibrinogen receptor antagonists) and aspirin. As stated above, a compound as provided herein can be administered in combination with more than one other active agent, for example, a compound as provided herein, and a HMG-CoA reductase inhibitor (eg, atorvastatin, effluent) Fluvastatin, lovastatin, pravastatin and simvastatin, and aspirin, or a compound as provided herein Combination with HMG-CoA reductase inhibitor and /3 blocker. Furthermore, a therapeutically effective amount of a compound as provided herein and a therapeutically effective amount of one or more of the active agents may be used together in the preparation of a pharmaceutical composition for use in the treatment described above, the active agent being selected from the group consisting of : anti-hyperlipidemic agents; plasma HDL-boosting agents; anti-hypercholesterolemia agents, such as cholesterol biosynthesis inhibitors, such as HMG-CoA reductase inhibitors; HMG-CoA synthetase inhibitors; squalene epoxidase inhibition Agent or squalene synthase inhibitor (also known as synthase inhibitor); thiol-coenzyme A cholesterol thiol transferase inhibitor; probucol; Acid and its salts; CETP inhibitors, such as torcetrapib; cholesterol absorption inhibitors, such as ezetimibe; PPAR alpha agonists or partial agonists; PPAR agonists or parts Agonist; dual PPARa, PPAR5 agonist or partial agonist; dual PPARa, PPARr agonist or partial agonist; dual PPAR (5, PPAR &lt;r agonist or partial agonist; total PPAR agonist or part Agonist; nickamine; Sterol absorption inhibitor; bile acid sequestrant anion exchange resin; LDL receptor inducer; clofibrate, fenofibrate and geifab 149105-sp-20100806.doc - 92- 201200505 Gemfibrozil; Vitamin B6 and its pharmaceutically acceptable salts; Vitamin B! 2; Antioxidant vitamins; Blockers; Angiotensin II antagonists; Angiotensin converting enzyme inhibitors; Aggregation inhibitor; fibrinogen receptor antagonist; aspirin; phentiramine, /5-3 adrenergic receptor agonist; sulfonyl urea, bifist, alpha - Glucosidase inhibitors, other insulin secretagogues and insulin. Another example of combination therapy can be seen in the modulation of metabolic syndrome (or treatment of metabolic syndromes and their associated signs, complications, and conditions), such as this article The compounds provided herein can be used effectively in combination with, for example, the modulation or treatment of diabetes, obesity, hyperlipidemia, atherosclerosis and/or its associated symptoms, complications, and In the specific embodiment, the compound of the present invention can be administered in combination with another compound of halofenic acid, an ester of halo-based acid or a halo-based acid, preferably And (-)-(4-phenylphenyl)-(3-trifluorodecylphenoxy)-acetic acid 2-acetamidoethyl ester. In particular, the present invention is provided by administration as herein A method of treating a mammal, particularly a human, with a compound provided and a DPP4 inhibitor. The DPP4 inhibitors which can be used in the present invention are sitagliptin (Merck), vildagliptin (Novartis), BMS-477118 (saxagliptin) (Bristol) -Myers Squibb), R143 8 (Amino-mercapto ρ ratio) (Roche), NVPDPP728 (Novartis), PSN9301 (Prosidion), P32/98 (Probiodrug), GSK823093C ( Denagliptin (Glaxo Smithkline), SYR-322 (Alogliptin) (Takeda) 'NN-7201 (NovoNordisk) ' ALS2-0426 (Alantos) ° (Green BD, 149105 -sp-20100806.doc -93- 201200505

Flatt PR, Bailey CJ, dipeptidyl peptidase IB (DPP4) inhibitor: an emerging class of drugs for the treatment of type 2 diabetes, 2006, 3: 159-165). Preferred DPP4 inhibitors are sitagliptin, vildagliptin, denagliptin, saxagliptin, and alogliptin. ). Further preferred CPP4 inhibitors are sitagliptin and vildagliptin. The compounds as provided herein and the DPP4 inhibitor are administered in a single dose or in individual doses. A single dose is administered once a day or multiple times a day. When a compound as provided herein and a DPP4 inhibitor are administered in separate doses, the dose can be administered once a day or multiple times a day. The compound as provided herein and the DPP4 inhibitor can be administered simultaneously, in a few minutes or divided into several hours. For example, a compound as provided herein and a DPP4 inhibitor can be taken together in the morning, with no further medication for the remainder of the day. Alternatively, in the morning, a compound as provided herein and a DPP4 inhibitor are administered, followed by a second dose of the compound and/or DPP4 inhibitor as provided herein at night or after meal. It may be necessary to administer a dose of a compound and/or a DPP4 inhibitor as provided herein, once a day or more than once a day, or before or after a meal, as is known to those skilled in the art. Furthermore, it should be noted that the clinician or treating physician will cooperate with the response of individual patients to know how and when to start, interrupt, adjust or terminate treatment. In a specific embodiment, when a compound as provided herein and a DPP4 inhibitor are administered in a single dose, the compound is formulated as a single pill with the DPP4 inhibitor I49105-sp-20100806.doc •94-201200505 A single tablet or a single capsule, when the compound is administered in a single dose with a DPP4 inhibitor, the compound is formulated into a pill, tablet or capsule, and the DPP4 inhibitor is formulated into another pill or capsule. When a compound as provided herein and a Dpp4 inhibitor are administered in separate doses, the compound can be administered first, and after administration of the compound, a DPP4 inhibitor can be administered. Alternatively, the Dpp4 inhibitor can be administered first, and then the compound can be administered at the time of the first administration and the second administration.

The interval can be changed by skilled practitioners. In one embodiment, the first administration (such as a compound provided herein or a Dpp4 inhibitor) is followed by a second administration (such as a compound provided herein or a Dpp4 inhibitor). In another specific embodiment, the second administration is 2 minutes, 5 minutes, 1 minute, 15 minutes, 3 minutes or 6 minutes, 2 hours, 3 hours, 3 hours after the first administration. 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, n hours or 12 hours. Yet another embodiment provides a compound and/or a Dpp4 inhibitor as provided herein for administration in the morning, followed by a compound as provided herein and a /4 Dpp4 inhibitor for administration at night. Furthermore, the present invention provides kits having unit dosages of the compounds and/or DPP4 inhibitors as provided herein for oral or injectable doses. In addition to containers containing unit doses, the use of descriptive drugs in the treatment of type 2H diabetes, obesity, hyperlipidemia, atherosclerosis and metabolic syndrome, and/or its associated symptoms, complications, and conditions The package of interest is packaged. Preferred compounds and unit dosages are as described above in 149 I05-sp-20I00806.doc-95-201200505. Another aspect of this month provides a method for lowering blood glucose levels in a patient's condition by administering a compound as provided herein and a DPP4 inhibitor. This method comprises administering to the mammal a therapeutically effective amount of the compound and a DPP4 inhibitor. The method further comprises the step of measuring the blood glucose level before and after administration of the compound as provided herein and the DPP4 inhibitor. = Sugar content is readily measurable by a number of commercially available glucose monitoring devices, either from blood or urine samples, or as measured herein. Blood glucose can also be measured by commercially available glucose meters, which do not require blood or urine samples. Another aspect of the invention provides a method of reducing the blood content of insulin in a patient by administering a compound as provided herein and a DPP4 inhibitor. The method comprises administering to the Wei animal a therapeutically effective amount of the compound and a DPP4 inhibitor. The method further comprises the step of measuring the blood tetanol content before and after administration of the compound and the pengic inhibitor. The blood sputum content is readily measurable by conventional insulin monitoring assays, either from blood or bodily fluid samples, or as measured as described herein. In another aspect, the invention provides a method of increasing the blood content of incretin in a patient by administering a compound of the invention and a DPP4 inhibitor. Intestinal insulin is GUM and GIP. This method comprises administering to the mammal a therapeutically effective amount of a compound as provided herein and a Dpp4 inhibitor. The method further comprises the step of measuring the blood incretin content before and after administration of the compound as provided herein and the Dpp4 inhibitor. Blood Intestinal Insulin Levels are readily detectable by conventional incretin monitoring, or as measured herein as 149105-sp-20100806.doc • 96· 201200505. Still another method of the present invention, wherein the method of administering a compound as claimed herein and a Congconin inhibitor to lower the blood triglyceride content in a patient, comprises administering a mammal to the mammal. Give (iv) an effective amount of the compound and the inhibitor. The method further comprises the step of measuring the blood triglyceride content before and after administration of the compound and the inhibitor. The blood triglyceride lysate is readily measurable by a number of commercially available devices which measure the glycerol triglyceride content from a blood sample. A further aspect of the invention provides a method of reducing gastric emptying by administering a compound of the invention and a de-inhibiting inhibitor in a patient. This method comprises administering to the mammal a therapeutically effective amount of a compound as provided herein and a DPP4 inhibitor. Another aspect of the invention provides a method and method for the production of a compound and a therapeutic agent, as described herein, in a islet cell of a patient, comprising administering to a mammal a therapeutically effective effect. A compound and a destructive inhibitor as provided herein. The method further comprises the step of measuring the production of temsin in the islet cells or sputum stone cells before and after administration of the compound and the DPH inhibitor. The insulin production line of the 姨 Island and 々 cells is readily measurable by conventional detection or as set forth herein. In still another aspect, the invention provides a method of maintaining islet function in a patient by administering a compound as provided herein and a Dpp4 inhibitor. The method comprises administering to the mammal a therapeutically effective amount of a compound as provided herein and a DPP4 inhibitor. The method further comprises measuring the function of the island or the 10,000 cell production before and after administering the compound and the leg inhibitor.

S I49I05-sp-20I00806.doc -97- 201200505 The step of the ability to produce insulin, the islet and $cell insulin production is readily measured by conventional detection or as set forth herein. The compounds used in the methods of the invention can be incorporated into a variety of formulations and agents' for therapeutic administration. More specifically, a compound as provided herein can be formulated into a pharmaceutical composition by combining with a suitable pharmaceutically acceptable carrier or diluent, and can be formulated into a solid, semi-solid, liquid or In the form of a gas, such as tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions, suppositories, injections, drugs, and aerosols. Thus, administration of the compound can be accomplished in a variety of ways, including oral, cheek, rectal, parenteral, intraperitoneal, intradermal, transdermal, and/or intratracheal administration. Further, the compound can be administered in a localized rather than systemic manner in a stored or sustained release formulation. In addition, the compound can be administered as a liposome. The compound can be formulated with excipients, diluents or carriers, and compressed into tablets, or formulated as a vehicle or solution for oral administration, by intramuscular or intravenous route. The compound can be administered transdermally and can be formulated into a sustained release dosage form or the like. The compounds can be administered alone or in combination with each other, or they can be used in combination with other known compounds. Suitable formulations for use in the present invention are described in (10) Medical Sciences (Mack Publishing Company (1985) Philadelphia, pA, 17th Edition), which is incorporated herein by reference. Further, for a brief reinstatement page for the drug delivery method, see Langer, ed. (9) ce (l990) 249: 1527-1S33', which is incorporated herein by reference. The pharmaceutical compositions described herein can be prepared by methods known to those skilled in the art, by conventional mixing, dissolving, granulating, dragee manufacturing, grinding, emulsification, encapsulation, capture or lyophilization methods. The following methods and excipients are only examples of I49105-sp_20100806.doc •98·201200505, and are by no means limiting. For injection, the compound and a DPP4 inhibitor selected may be formulated into a formulation by dissolving, suspending or emulsifying them in an aqueous or non-aqueous solvent, such as a plant or other similar oil, a synthetic fatty acid glyceride, Esters of high carbon aliphatic acids or propylene glycol; and if necessary, conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives. Preferably, the compound of the present invention is formulated in an aqueous solution, preferably in a physiologically compatible buffer such as a solution such as Ringer's® or a physiological saline buffer. For transmucosal administration, a suitable permeation agent for the barrier to be infiltrated is used in the formulation. Such penetrants are generally known in the art. For oral administration, the compound and a DPP4 inhibitor of choice may be conveniently formulated by combining with a pharmaceutically acceptable carrier as is known in the art. Such carriers enable the compounds to be formulated into tablets, pills, dragees, capsules, emulsions, lipophilic and hydrophilic suspensions, liquids, gels, syrups, slurries, suspensions, and the like, for the patient to be treated Oral feeding. The pharmaceutical preparation for oral use can be obtained by mixing the compound with a solid excipient, grinding the formed mixture as appropriate, and treating the mixture of the granules, and if necessary, obtaining a tablet or after adding an appropriate adjuvant. Sugar clothing record: core. Suitable excipients are, in particular, fillers, such as sugars, including lactose, sucrose, mannitol or sterol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, scutellaria, medlar Cellulose, hydroxypropionyl-cellulose, sodium carboxymethylcellulose and/or polyvinyltetrahydropyrrolidone. If necessary, a disintegrating agent such as 149105.sp-20J00806.doc •99· 201200505 cross-linked polyvinyltetrahydropyrrolidone, agar or alginic acid or a salt thereof, such as sodium sulphate, may be added. The dragee core has a suitable coating. For this project, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinyl tetrahydrofuranone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solution and appropriate Organic solvent or solvent mixture. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as gelatin and gelatin. A soft, sealed capsule made of a plasticizer such as glycerol or sterol. The push-fit capsules may contain the active ingredient in admixture with a filler such as lactose, a binder, such as a starch, and/or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid sarcophagus or liquid polyethylene glycol. In addition, a stabilizer can be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the composition may be in the form of a tablet or lozenge formulated in a conventional manner. For administration by inhalation, the compound for use according to the present invention is conveniently delivered from a pressurized pack or atomized can.

A dosage unit is delivered to deliver a metered amount. In the form of an aerosol spray, using a suitable propellant, such as two wraps, or from a propellant-free, dry condition, can be used for inhalation or insufflation via a valve provided 149105-sp-20100806.doc -100 · 201200505 capsules and cartridges, such as a gelatin, can be formulated to contain a mixture of a compound and a suitable base, such as lactose or starch. The compound can be formulated for parenteral injection by injection, for example by injection or continuous infusion of a bolus. Formulations for injection may be presented in unit dosage form, such as in ampoules or in multi-dose vials with added preservatives. The composition may take some form, such as a suspension of water, a solution or an emulsion, in an oily or aqueous vehicle, and may contain a right-handed formulation, such as a suspension, stabilization, and/or dispersant.

The pharmaceutical formulation for parenteral administration is g, and (4) includes an aqueous solution of the active compound in a water-soluble form. In addition, 'activated people'. The suspension of the substance can be made into a suitable oily injection suspension. Suitable lipophilic solvents or vehicles include fatty oils, 鐾 &gt; sesame oil or blends such as oleic acid or triacetin, or vesicles. For water-containing injections, people with sputum, sputum, and liquids have substances that increase the viscosity of the suspension, such as carboxymethyl cellulose, a ginolone sterol or dextran. Suspensions may also contain suitable stabilizers, as appropriate, or as a proprietary compound to allow for the preparation of the desired solution. Seven soils t simple agent. Alternatively, the active ingredient may be in the form of a powder which is suitably formulated for use in the field, such as sterile, pyrogen-free water, prior to use. The compounds may also be formulated in rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter, carbon quinone, polyethylene glycol or other glycerin, all at body temperature, It is cured at room temperature. In addition to the foregoing formulations, the compounds may also be formulated as a stocking formulation. This long-acting formulation can be implanted (eg subcutaneously or intramuscularly) or

S -101 - 1491〇5-sp-2〇l〇〇g〇6d〇c 201200505 Use an appropriate emulsion) for injection administration. Thus, for example, a compound may be formulated as a polys- or hydrophobic material (for example, as an ion-exchange resin in an acceptable oil or as a controllable soluble salt). Others for hydrophobic pharmaceutical compounds _ micro-moon granules and &lt; chemical liquids are transport agents or carriers for hydrophobic drugs. Example:: - In the preferred embodiment before the project, long can be used Circulation: w is secret in microfilaments. Such vesicles are generally described in Idle et al., U.S. Patent 5, Pair. The compounds of the invention may also be administered by controlled release and/or delivery devices. For example, in the U.S. Patent No. 5, 〇; 3'916'899; 3,536,8〇9; 3 598 123; and 4 〇〇8 719.,, or some organic solvents, such as Dimethyl hydrazine (&quot;DMSO&quot;). In addition, the compounds can be delivered using a sustained release system, such as a semipermeable matrix of a solid 巟X-poly conjugate containing a therapeutic agent. Various types of sustained release substances have been established. 'And it is familiar to those skilled in the art. Continuous release of capsules, according to While hydrazine, the compound can be released over a period of hours up to more than 100 days. The sigma can also contain a suitable solid or gel phase carrier or excipient. Examples of seed carriers or screaming agents include However, it is not limited to calcium carbonate, calcium phosphate, various sugar powders, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. Pharmaceutical compositions suitable for use in the present invention include those in which the active ingredients are therapeutically effective. The composition to be included. The amount of the composition to be administered will of course depend on the patient being treated, the weight of the patient, the severity of the condition, the mode of administration, and the judgment of the physician 149105-sp-20100806.doc 201200505 The ability of the effective amount of the decision-makers &amp; 弋, 弋 is well after the knowledge of this art. + The detailed disclosure of the ribs of the ribs == any compound used in the method, therapeutically effective agent = The toxicity and therapeutic efficacy of the compounds described herein from cell culture assays, animal models or human patients can be determined in standard cell cultures or experimental animals, as determined by standard pharmaceutical procedures, for example by assay (up to 50% of the individual's lethal dose) and sputum (therapiously effective doses in the individual group). The dose ratio between toxicity and therapeutic effect: for the therapeutic index 'and can be LD5. Between ED5. The ratio is expressed as a compound showing a high therapeutic index. Data from such cell culture assays and animal studies can be used to formulate doses that are not toxic in humans. Within the range of circulating concentrations, which include ED5G with little or no toxicity. The dosage can vary within this range, depending on the agent used and the route of administration used. Proper formulation of the drug route and dosage Individual physicians can choose from the symptoms of the patient (see, for example, Fingl et al., 1975, in Chapter 1 of the Science and Technology Foundation). The amount of the compound as provided herein, which may be combined with the carrier materials to produce a single dosage form, will vary depending upon the condition being treated, the mammalian species, and the particular mode of administration. However, as a general guideline, a suitable unit dose of the compound of the invention may, for example, preferably contain between 0.1 mg to about 1000 mg, between 1 mg to about 500 mg, and between 1 mg to about 3 mg. U9105_sp_20100806.doc -103 - 201200505 Sex compounds. In the other item will add rf» mg of the door. The M unit dose is between 1 mg and about 100 homes. This early agent - 2 3 4 5 -3⁄4 ή &gt;&gt; , ° technology for more than once, such as one day, ', 5 or 6: person, but preferably for each illusion or 2 times, so that 7 〇 The total dose of kilograms of adult is in the range of 0.001 to about 15 milligrams per 8 kg of adult ''mother's weight of each dose. The preferred dose is 15 grams per A", and the therapy can be::: The mother kilogram of the patient's weight _ to the approximate path can be extended by a few or a few dollars, while the 纟一^ is several years. It is clear that the degree of any particular agent depends on a variety of factors, including the age, weight, general health status, gender and diet of the treated individual; time and route of administration; rate of excretion; The other drugs administered, and the severity of the particular disease being treated, are well known to those skilled in the art. Typical dosages may range from 1 mg to about 1 (9) mg tablets or i mg to about 300 mg. Take it once or twice a day, or release a capsule or tablet on time, once a day and contain a proportionally higher amount of active ingredient. The release of the capsule can be achieved by dissolving the capsule at different pH values. , obtained by a capsule that is slowly released by osmotic pressure, or by any other known controlled release method. In some cases, it may be necessary to use doses outside of these ranges, as is well known to those skilled in the art. Should pay attention to The clinician or therapist will cooperate with the response of individual patients to know how and when to start, interrupt, adjust or terminate the treatment. With regard to the compositions, methods and kits provided above, those skilled in the art will be aware of the use of each The preferred compound in one is a compound indicated above as preferably 149105-SP-20100806.doc • 104· 201200505. Further preferred compounds for the compositions, methods and kits are as follows. The compounds provided in the examples. [Embodiment] Chemical Examples General Methods · All operations involving moisture and/or oxygen-sensitive substances are carried out in a dry nitrogen atmosphere in a pre-dried glassware. It was noted that the material was obtained from a commercially available source and used without further purification. The flash chromatography was performed on a Isco Combiflash-related article using a RediSep /?f stone cartridge, by Teledyne Isco. The thin layer chromatography method was carried out using a pre-coated plate (silicone 60 PF254, 0.25 mm) purchased from E. Merck, and the light spot was expressed by long-wave ultraviolet light. Coloring reagent tracking. The NMR (&quot;NMR&quot;) spectroscopy was recorded on a Varian Inova-400 resonance spectrometer. The iH NMR chemical shift is in parts per million of the low magnetic field from tetramethyl decane (&quot;TMS"). The number (5) indicates that the TMS or residual solvent signal (CHC13 = (5 7.24, DMSO = 6 2.50) is used as the internal standard. The 1 H NMR message is listed in the following format: multiplicity (s, singlet; d , doublet; t, triplet; q, quartet; m, multiplet), coupling constant (J), expressed in Hertz, proton number. The prefix app is sometimes applied to the true signal multiplicity. In the case of analysis, the br system indicates that the signal in the discussion is widened. Compounds were named using ChemBioDraw Ultra version 11.0. LCMS analysis was performed using a PE SCIEX API 2000 mass spectrometer with a Phenomenex Luna 5 micron Ci8 column. Preparative HPLC was performed on a Gilson HPLC 215 liquid handler with a Phenomenex column (Gemini 10 a, (3丨8, 149105-sp-20100806.doc -105· 201200505 110A) and UV/VIS I56 detector) The microwave reaction is carried out in Biotage Intiator EXP US. When the manufacture of the starting materials is not specifically described, the compounds are known or may be similar to those known in the art or as prepared in the intermediates or examples. It will be apparent to those skilled in the art that the synthetic procedures described herein are merely representative of the methods for preparing the compounds of the present invention, and other conventional methods can be used similarly. The present invention is further described to illustrate the preparation. The following examples of the compounds of the present invention are exemplified, but are not limited thereto. Intermediates for the preparation of intermediates 1

Cl

5-Alkyl-7-(methyl-methyl&gt;2,2-dimethyl-2,3-dihydrobenzofuran OH 0 'V } K2C〇3 II J DMF Step W A

Step A: To a solution of methyl 5-oxo-2-hydroxybenzoate (25 g, 134 mmol) in dimethyl decylamine (25 mL), EtOAc (EtOAc) Mohr) with 3_Chloro-2-methylpropanoid-ene (1 gram, 16 丨 millimolar). The suspension was heated at 7 (TC for 8 hours, cooled to room temperature, diluted with water (5 mL) and extracted with ethyl acetate (2×25 mL).

The soda is dehydrated and dried, (iv), and concentrated in vacuo. The residue is purified by chromatography (0-2G% EtOAe in hexane), and the desired product (1) is provided. • 106· 149105-sp-20100806.doc 3 201200505 Step B: 'Add compound (1) (2 gram, 8 31 耄 mol) and N-methyltetrahydro p piroxime (15) in a 20 ml microwave tube ML). The tube was sealed and heated in a microwave at 200 C for 8 hours. The solution was cooled to room temperature, diluted with water (5 mL) andEtOAc. The organic layers were combined, dried over sodium sulfate &lt The residue was purified by chromatography (0-30%EtOAcEtOAc) Step C. Compound (2) (2.00 g &lt; 8.31 mmol) was dissolved in EtOAc (1 mL) and water (1 mL) and refluxed for 18 hours. The solution was cooled to room temperature, diluted with water (50 mL) and EtOAc EtOAc. The residue was purified by chromatography (0-30%EtOAcEtOAcEtOAc) Step D. Compound (3) (2.00 g, 8.31 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and cooled to EtOAc. The hydrogenation of tetrahydrofuran was added (1.0 M, 8.31 ml, 8.31 mmol) over a period of ten minutes. After the addition was completed, the solution was allowed to warm to room temperature and stirred for another six and ten minutes. The solution was cooled to 0 ° C. and was quenched by ethyl acetate (1 mL). The mixture was diluted with ethyl acetate and filtered through a pad of Celite. The combined filtrate was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (0-100% EtOAc in hexane) to afford the desired alcohol (4). Step E: To a solution of compound (4) (1.00 g, 47 EtOAc) in acetonitrile (2 mL), EtOAc (. The solution was stirred for 4 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate 149105 ep-20100806.doc -107 - 201200505 ethyl acetate and washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography ( EtOAc EtOAc (EtOAc) Intermediate 2 3·(3,5-Difluoro-4-hydroxyphenyl)-2-methylpropionic acid ethyl ester (9)

Step A: refluxing a solution of 2,6-difluorophenol (25 g, 192 mmol), hexamethylenetetramine (26 g '192 mmol) and trifluoroacetic acid (19 mM millimolar) Through the instrument. The reaction was cooled and diluted with water (2 mL) and EtOAc (EtOAc) The organic layer was washed with 1% aqueous potassium carbonate solution (2 χ 1 Torr). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 3,5-fluoro-4-hydroxybenzobenzene as a white solid. Upon standing, the desired product begins to precipitate from the initial aqueous layer and is extracted with dichloromethane. The filtrate layer was filtered to provide product (6)' as a long white crystal. Step B: 3,5-Difluoro-4-hydroxybenzaldehyde (6) (8 26 g, 522 mmol) with potassium carbonate (14.4 g, 104.4 mmol) in dimethylformamide (1 〇〇) Add cesium chloride (7.2 ml, 62.7 mmol) to the mixture in ML) and mix at 50 c overnight. The reaction was diluted with water and extracted with ethyl acetate (3.times.ss.sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss The residue was purified by flash column chromatography (% EtOAc in hexane) to give 4-(benzyloxy)_3&gt;difluorophenylfurfural (7). Step C: 4-(decyloxy)_3,5-difluorobenzate (7) (1 32 g, 5% mmol) with (1-ethoxycarbonylethylidene)triphenylphosphane (232 The solution in THF (53 mL) was refluxed for 2 hours. The reaction was concentrated in vacuo and purified by flash column chromatography eluting eluting eluting eluting , 5-difluorophenyl)·2-ethyl methacrylate (8). Step D · (Ε)-3-(4-(Hexyloxy)_3,5-difluorophenyl)_2-methyl methacrylate (8) (1.4 g, 4.21 mmol) in ethanol ( Add Pd/C (140 mg, 10% Degussa type) to the solution in 25 ml). A nitrogen bottle was added and the reaction was evacuated and backfilled three times with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere at room temperature, filtered through Shixiazao soil, and concentrated in vacuo to give 3-(3,5•difluoro-4-phenyl)-2-methyl Ethyl propyl propionate (9). Intermediate 3

Pd(OAc)2 P(Zou-tolyl&gt;3 Et3N, DMF Step A 3-(3,5--murine-4-Phenylphenyl)propionic acid B g(11)

H2, Pd/C F

OEt Step A: In a 350 ml pressure glass tube, add 4_glycol-2,6-difluorophenol (23.82 g, 0.11 mol), triethylamine (55 ml, 〇·39 mol) under n2 Ethyl acrylate (34.27 g, 0.34 mol), DMF (50 ml), acetic acid (11) (1.29 g, 5.75 mmol), followed by tri-o-tolylphosphine (2·34 g, 7.6 millimoles). The mixture was stirred in a sealed glass tube under u〇〇c overnight (21 h), cooled to room temperature, and Et EtOAc (15 mL) was added and stirred 3 〇 149105-sp-20100806.doc -109- It was filtered through celite and rinsed with EtOAc (3 x 100 mL). The filtrate was acidified to pH~2 with 2N HCl. The organic layer was separated and EtOAc (EtOAc &EtOAc The combined organic layers were washed with water (2×1 mL), brine (1···· After filtration, heptane (2 mL) was added and the solution was concentrated in vacuo. The precipitate formed was filtered, washed with a hept (2 x 50 mL) and dried to give the desired product as a pale yellow solid. The mother liquor was concentrated in vacuo to give the desired product (10)' as a pale yellow solid. 1 H NMR (400 MHz, CDC13) (5: 7.50 (d, J = 15.9)

Hz, 1H), 7.09 (d, J = 8.3 Hz, 2H), 6.29 (d, J = 15.9 Hz, 1H), 5.54 (br, 1H), # 4.26 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). Step B: a solution of ethyl (E)-3-(3,5-difluoro-4-hydroxyphenyl)acrylate (ίο) (〇.75i gram ' 3.29 mmol) in ethanol (20 mL) Inside, add p to ◦ (8i mg, 10% DegUSSa type). A hydrogen cylinder was added and the reactants were evacuated&apos; and backfilled three times with hydrogen. The reaction was stirred under a hydrogen atmosphere at room temperature overnight, filtered through a pad of Celite, and concentrated in vacuo to give ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (11) ).

F intermediate 4 2-(3,5-difluoro·4·phenyl)cyclopropanecarboxylic acid ethyl ester (12)

Step A: In a 350 ml pressure tube, add bromodifluorophenol (23.82 g '0.11 mol), triethylamine (55 ml, 0.39 mo 149105-sp-20100806.doc • 110-201200505) under the armpit Ethyl acrylate (34.27 g, 〇·34 mol), DMF (50 ml), palladium acetate (II) (1_29 g ' 5.75 mmol) and tri-o-p-phenylphosphine (2.34 g, 7.6 mmol) The mixture was sealed in a glass tube and stirred overnight (21 h) at 11 ° C. The reaction was cooled to room temperature and Et EtOAc (150 mL). It was filtered through celite and washed with EtOAc (3 EtOAc). The filtrate was acidified to EtOAc EtOAc EtOAc (EtOAc) The layers were washed with water (2 mL 1 mL), brine (100 mL) and dried over sodium sulfate. The precipitate formed was filtered, washed with heptane (50 mL of EtOAc) and dried to give the desired product as pale yellow. Solid. Concentrate the mother liquor in vacuo to give the desired product (10) as a pale yellow solid. iHNMR (400 MHz, CDCl3) d: 7.50 (d, J - 15.9 Hz, 1H), 7.09 (d, J = 8.3 Hz, 2H), 6.29 (d, J = 15.9 Hz, 1H), 5.54 (br, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). B: in N-mercapto-indolyl-nitro-N-nitrosoguanidine (TCI-US catalog #M0527, 10 g, on a dry weight basis, 0068 mol) in ether (15 ml) A cold solution of potassium hydroxide (12.6 g) in water (7 ml) was added to the mixture at 〇 °C. After stirring for 2 minutes, a portion of the formed heavy gas-burning yellow ether-containing solution was added to 3-(3,5-difluoro-4-hydroxyphenyl)propanate ethyl ester (TC). 10) (2.28 g, 0.010 mol) in a solution of ether (1 mL). Add one portion of palladium(II) acetate (0.372 g, 1.66 mmol), followed by another portion of diazomethane This procedure was continued until all the diazomethane solution was added with palladium (II) acetate. The dark mixture formed was stirred at 0-5 for 4 hours and acetic acid (6 drops) was added to quench any excess reagent. After 149105-sp-20100S06.doc 201200505 was removed in vacuo, the residue was purified eluting eluted elut elut elut elut elut elut 1 H NMR (400 MHz, CDC13) δ : 6.67 (d, J = 8.4 Hz, 2H), 5.05 (br, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.45-2.40 (m, 1H ), 1.87-1.74 (m, 1H), 1.39-1.14 (m, 5H). Intermediate 5 (2,2-dimercapto-8-yl)methanol (16)

Step A: Add coumarin (114 ml, 9 〇 mmol) in tetrahydrofuran (20 ml) in a solution of vaporized bismuth-based magnesium (3M in THF, 6 mM, 180 mM). ) Let the solution last for forty minutes. The reaction was stirred for 18 hours. The solution was quenched with ice cold water (20 mL) andEtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired compound (13) as white powder. Step B: The alcohol (13) (7.6 g, 42.2 mmol) was dissolved in acetic acid (45 mL) and 20% sulfuric acid (17 mL). The solution was heated at 1 ° C for 45 minutes. After the solution was allowed to cool to room temperature, ice (2 g) was added. The mixture was extracted with ethyl acetate (2×25 mL). The residue was purified by vacuum distillation (8) seven oil 149105-sp-20100806.doc • 112-201200505 bath, 5 mm Hg) to provide (14). Step C: To a solution of n-butyllithium (26 mL, 2.5 M in hexanes). A solution of compound (14) (4.2 g, 26 mmol) in 30 mL of dry diethyl ether was added dropwise. After the addition was completed, the reaction was refluxed for 90 minutes. The solution was allowed to cool to room temperature and poured into a flask containing a slurry of dry ice in anhydrous water. Water (5 mL) was added and the solution was extracted with ethyl acetate (2 X 50 mL). The combined organic extracts were dried over sodium sulfate, dried and evaporated and evaporated Step D: Compound (15) (0.230 g, 丨 12 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and cooled to EtOAc. Lithium aluminum hydride (1.0 M '1.2 ml, 1.2 mmol) in tetrahydrofuran was added over a period of ten minutes. After the addition was completed, the solution was allowed to warm to room temperature and stirred for another sixty minutes. The solution was cooled to 0 C and quenched by ethyl acetate (1 mL) thenEtOAcEtOAcEtOAc The mixture was diluted with ethyl acetate and filtered through a pad of Celite. The combined filtrate was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc EtOAc) Intermediate 6 2-(6-Fluoro-5-carbyl-2,3-dihydro-1H-indol-1-yl)acetic acid ethyl ester (22) 149I05-sp-20100806.doc -113 - 201200505

Step A: In malonic acid (21.5 g, 2 〇 7 mmol) in 峨. Into a solution of (5 mL), 4-fluoro--3-methoxybenzoic acid (16 g, 1 〇 4 mmol) and hexahydropyridine (1.5 mL) were added. The reaction was refluxed for 13 hours. Add water in milliliters), followed by concentrated HC1 (40 ml by filtration to collect the precipitated product (17) and wash with water. Step B: at (17) (25 g, 127 mmol) in ethanol (4 mL) In the solution, Pd7C (2 g, 10% Degussa type) was added. A hydrogen bottle was added, and the reaction was evacuated and backfilled with hydrogen three times. The reaction was stirred overnight at room temperature under a nitrogen bottle. Filtration through a pad of Shiyoshi, and concentration in vacuo to provide compound (18). Step C: Add compound (μ) (2.00 g, 1 (U millimolar) and methyl) to a 20 ml microwave tube. Sulfonic acid (15 ml). The tube was sealed and heated at 9 ° C for 10 minutes. The resulting solution was poured into an ice bath and neutralized with a Na〇H aqueous solution to pH 7. formed by concentrated collection. The sinker' is washed with water to provide compound (19). Step D: ketone (19) (3.56 g, 19.8 mmol) in benzene/tetrahydrofuran 149105-sp-20100806.doc •114· Add Zn powder (2.6 g, 39.6 mmol) to vaporized copper (I) (0.4 g '3.9) in a solution of 201200505 (50:1 '4〇ml) 6 mmol.) This suspension was heated at 9 (TC for 3 Torr. After cooling to room temperature, ethyl bromoacetate (3.4 mL, 316 mM) was added. (3 hours heating for 4 hours. After cooling to room temperature, add HCl aqueous solution (50 ml, 2N), and extract the solution with ethyl acetate (2 X 50 ml). Filtration and concentration in vacuo. Purify the residue by flash column chromatography (〇_5〇0/〇)

EtOAc was added in hexanes to afford the desired ester (2 s) as a mixture.

Step E. Add Pd/C (0.08 g &apos; 1% Degussa type) to a solution of (20) (0.79 g, 3.2 mmol) in ethanol (1 mL). A hydrogen cylinder was added and the reactants were evacuated&apos; and backfilled three times with hydrogen. The reaction was stirred under a hydrogen atmosphere at rt overnight, filtered over Celite pad and concentrated in vacuo to afford compound (21). Step F: Add three desertification butterfly (10) ml in a liquid of dichloromethane (40 ml) in a solution (21) (1.06 g, 4.2 mmol), 9 m. The solution was scrambled for 2 hours, and the reaction was quenched with ethanol (5 mL) and a saturated aqueous solution (5 mL). The organic layer was separated, dried over sodium sulfate, and passed in vacuo to yield the desired product (22). Intermediate 7

Br

NH Me, 义ΜΛ • \*1Γ- τ Name EW dmf Step A

______ an OEt

Pd(〇7^ F 笨基h H〇 J49105-sp-20100806.doc •115- 201200505

Step A: Add 4-bromo-2,6-difluorophenol (23.82 g, 0.11 mol), triethylamine (55 ml, 0.39 mol), acrylic acid B in a 350 ml pressure tube under N2. Ester (34.27 g, 0.34 mol), DMF (50 ml), palladium (II) acetate (1.29 g, 5.75 mmol) and tri-o-tolylphosphine (2.34 g, 7.6 mmol). The mixture was sealed in a glass tube and stirred at ll ° C overnight (21 h). The reaction was cooled to room rt and EtOAc (150 mL). The mixture was stirred for 30 min, filtered over EtOAc (EtOAc)EtOAc The filtrate was acidified to pH~2 with 2N HCl. The organic layer was separated and aqueous brine evaporated with EtOAc EtOAc The combined organic layers were washed with water (100 mL EtOAc) After filtration, heptane (200 mL) was added and the solution was concentrated in vacuo. The precipitate formed was filtered, washed with EtOAc (EtOAc)EtOAc The mother liquor was concentrated to give the desired product (4·29 g) as a pale yellow solid. 1HNMR (400MHz, CDC13) (5: 7.50 (d, J = 15.9 Hz, 1H), 7.09 (d, J = 8.3 Hz, 2H), 6.29 (d, J = 15.9 Hz, 1H), 5.54 (br, 1H) ), 4.26 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7,1 Hz, 3H) Step B: N-methyl-Ν'-nitro-N-nitrosoguanidine ( TCI-US catalog #M0527, 10 g, on a dry weight basis, 0.068 mol) in a mixture of ether (150 ml) 149105-sp-20100806.doc -116- 201200505, at 0 ° C, add ΚΟΗ (12.60 g) cold solution in water (21 ml). After stirring for 2 minutes, add the yellow mystery solution of diazonate formed to 3_(3,5) _Difluoroicyloxyphenyl)ethyl acrylate (10) (2.28 g, 0.010 mol) in a solution of ethereal hydrazine. Add a portion of palladium acetate (II) (0-372 g, 1.66 m) Mohr), followed by another diazomethane solution. Continue this procedure' until all the diazol solution and palladium acetate (II) are added. The dark mixture formed is mixed under 〇5〇c. Hours, • Add acetic acid (6 drops) to quench any excess reagent. After removing the solvent The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 6.67 (d, J = 8.4 Hz, 2H), 5.05 (br, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.45-2.40 (m, 1H), 1.87-1.74 (m, 1H), 1.39 -1.14 (m, 5H). Step C: Ethyl 2-(3,5-difluorobuhydroxyphenyl)cyclopropanecarboxylate (12) (2 〇 4 g '8.4 mmol) with carbonic acid ( ι·69 g, 12.2 mmol.) benzyl bromide (1.88 g, 11 mmol) was added to a mixture of DMF (15 mL). The mixture was stirred at room temperature overnight. The organic extract was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. Purified by flash chromatography on silica gel (0-20% Et. Ac is in the house)' Obtained 2J6g of desired product (500) as a white solid. iHNMR (400 MHz, CDCI3) δ: 7.50-7.43 (m, 2H), 7.38-7.32 (m, 3H), 6.62 ( d, J = 9.0 Hz, 2H), 5.12 (s, 2H), 4.19-4.11 (m, 2H), 2.43-2.38 (m, 1H), 1.89-1.76 (m, 1H) 1.65-1.58 (m, 1H), 1.29-1.15 (m, 4H). Step D: Ethyl 2-(4-(henryoxy)·3,5-difluorophenyl)cyclopropanecarboxylate (500) 149I05-sp-20100806.doc -117- 201200505 (2.74 g ' 8.24 m A solution of UAIH4 (IN, 12.5 mL in ether) was added in a solution of tetrahydrofuran (1 mL). After mixing for 2 hours at room temperature, 8 ml of EtOAc was added and the solution was stirred for 1 Torr. Water (10 mL) was added and the mixture was stirred for additional 1 min. The filtrate was partitioned between EtOAc and EtOAc / EtOAc (EtOAc)EtOAc. The product is sufficiently pure to be used directly in subsequent Swem oxidation. 1 η NMR (400 MHz, CDC13) ^ : 7.49-7.39 (m, 2H), 7.39-7.33 (m, 3H), 6.59 (d, J = 9.2 Hz, 2H), φ 5.10 (s, 2H), 3.68 -3.51 (m, 2H), 1.81-1.68 (m, 1H), 1.47-1.20 (m, 1H), 1.02-0.83 (m, 2H). Step E: DMSO (2.5 mL) was added to a solution of gasified grasshopper (2.12 g '16'7 mmol) in anhydrous dichloromethane (15 mL) at -78 ° C, then added ( 2-(4-(Benzyloxy)-3,5-difluorophenyl)-cyclopropyl) decyl alcohol (501) (2.25 g, 7.75 mmol) in dioxane (5 mL) The solution was followed by Et3N (5,6 mL). Purification by flash chromatography on oxime (〇_3〇%) gave 2.07 g of desired product (S02) s as colorless liquid.丨η NMR (400 MHz, CDC13) accounted for: 9.37 Lu (s, 1H), 7.47-7.41 (m, 2H), 7.40-7.29 (m, 3H), 6.65 (d, J = 7.1 Hz, 2H), 5.13 (s, 2H), 2.59-2.45 (m, 1H), 2.19-2.10 (m, 1H), 1.78-1.65 (m, 1H), 1.51-1.36 (m, 1H) 〇Steps F, G, and H: The reaction is carried out according to the proposal described in the U.S. Patent (US 2004/0092538, pages 40-41). Step I: Ethyl 2-(2-(4-(decyloxy)-3,5-difluorophenyl)cyclopropyl)acetate (505) (0.782 g, 2.25 mmol) in EtOAc / EtOH 149105-sp-20100806.doc •118· 201200505 in solution (5 ml/10 ml), 159 mg of 10% Pd/C was added, and the mixture was stirred under a hydrogen cylinder overnight. After filtration through celite and washing with EtOH, the filtrate was concentrated in vacuo to give &lt;RTI ID=0.0&gt;&gt; The product is sufficiently pure' to be used directly for subsequent coupling. 1Η 彳4〇〇MHz, CDC13) δ : 6.67 (d, J = 8.4 Hz, 2H), 4.96 (br, 1H), 4.23-4.05 (m, 2H), 2.50-2.26 (m, 2H), 1.70- 1.66 (m, 1H), 1.33-1.19 (m, 4H), 0.97-0.79 (m, 2H). Intermediate 8 2-(4-Hydroxyphenylthio)acetic acid ethyl ester (507)

HO

Br, ^C〇2Et

CsjCOj Step A

507

Step A: Adding carbonic acid (128 mg, 0.39 mmol) to ethyl bromoacetate (44 μl) in a solution of 4-cyanophenol (49.7 mg, 0.39 mmol) in tetrahydrofuran (2 mL) , 0.39 mmol, and the reaction was stirred at 5 yc overnight. The reaction was quenched with water and extracted with ethyl acetate (3 EtOAc). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) Intermediate 9

·· butyl lithium co2&lt;gas carrier) 7-(gasmethyl)-2-methylbenzomethane (511)

Step B 509 610

Step C

Step A. A solution of 7-bromo-2-methylbenzo[b] porphin (5〇8) (〇9〇8 g, 4 〇 mmol) in tetrahydrofuran (16 ml) under nitrogen Cool to _78t:. n-Butyllithium (2·40 mL, 6 〇 mmol, 丨〇M, in hexane) was added dropwise. g· 149105^sp-20]00806.doc • 119·201200505 After the addition was completed, the reaction mixture was stirred at _78 ° C for 1 hour, then poured onto a mixture of dry ice in diethyl ether (30 ml). The reaction was stirred to room temperature over 5 h then washed with 1N EtOAc, brine and dried over NaH. The white solid obtained was washed with hexane to give 2-methyl succinyl[b]-indole carboxylic acid (5 〇9) (0.240 g, 31.2%). LC-MS ESI m/z: Found. Step B: The carboxylic acid (509) (0.240 g, EtOAc) was dissolved in anhydrous tetrahydrofurane (12 mL) and cooled to hydr. Hey. Slowly add BH3 tetrahydroanthracene. South complex (3.12 ml ' 3.12 mmol, lom, in tetrahydroanthracene). After the addition was completed, the solution was allowed to warm to room temperature and stirred for an additional hour. The solution was cooled to (TC) and quenched with EtOAc (EtOAc) (EtOAc) Dehydrated, dried, and concentrated in vacuo to provide (2-mercaptobenzothiophene-7-yl) decyl alcohol (51 〇) (〇2〇3 g '91.2%) as a colorless oil. C. Slowly add the second gasified stearite (〇 415 ml, 5.69 mmol) to the alcohol (510) (0.203 g, 1.14 mmol) in ice-cold solution in di-methane (6 mL) The reaction mixture was stirred and warmed to room temperature over 1 hr. The resulting solution was quenched slowly with saturated sodium bicarbonate (10 mL) and extracted with m. Dehydrated to dryness, filtered, and concentrated in vacuo to give Intermediate <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 2-(6-Hydroxy-1,2,3,4-tetrahydronaphthalenyl)ethyl acetate (S14) I49105-sp-20100806.doc •120· 201200505

Step A: Slowly add sodium hydride (0.5 g, 12.5 mmol) to 6-methoxytetralone (0.881 g '5.0 mmol) and phosphonic acid acetate at 0 °C. Ethyl ester (2.5 mL '12.5 mmol) in a mixture of anhydrous tetrahydrofuran (25 mL). The reaction was allowed to warm to rt and reflux under nitrogen for 48 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate sulfate The residue was purified by flash chromatography on silica gel (4% 〇 〇Ac in hexane) to provide 2-(6-decyloxy-3,4-dihydronaphthalene-1 (211) )-Based ethyl acetate (512) (〇 792 g ^ 64.3%) * is a yellow oil. Procedure: To a solution of olefin (512) (0.792 g, 3.22 mmol) in ethanol (53 ml) was added Pd/C (100 mg, 1%%). A hydrogen cylinder was added and the reaction was evacuated and backfilled three times with hydrogen. The reaction was stirred under a hydrogen atmosphere at room temperature overnight, then filtered through a pad of Celite, and concentrated in vacuo to give 2-(6-methoxy-i,2,3,4-tetrahydronaphthalene. Ethyl acetate (513) (0.708 g '88.7%) as a colorless oil. £ Step C · 2-(6-foxy-indole, 2, "hydrogen tea small base" ethyl acetate (si3) (0.708 g ' 2.85 mmol) in dichloromethane (28 mL) The solution was placed underneath this solution, and boron tribromide (〇.8〇9 ml, 8.56 mmol) was added. The solution was stirred for 2 hours and then with ethanol (5 ml), followed by saturated sodium bicarbonate solution (5 149 149 - Sp-20100806.doc -121 - 201200505 liter) The reaction was quenched. The organic layer was separated, dried over sodium sulfate, filtered, and dried in vacuo to give the intermediate 2-(6-carbazyl). 2,3,4-tetrahydronaphthalene]. Ethyl acetate (514) (0.600 g, 90.0%) as an oil residue. Intermediate 11 3-(3-carbyl-4-phenyl) Ethyl 2-methylpropionate (516a)

Step A: 3-Chloro-4-hydroxybenzaldehyde (0·783 g, 5 mmol) with 2 (triphenylphosphoranylidene) propionate (2.72 g, 7.5 mmol) The mixture in anhydrous tetrahydrofuran (25 mL) was evaporated in EtOAc EtOAc EtOAc. (3-Chloro-4 hydroxyphenyl) 2-methyl propyl ethyl acrylate (S1S) (1. u g, 95.2 ° /.) as a white solid. &gt; Step B: in a dilute hydrocarbon _ _ i gram, 2. 〇 millimol) In a solution of ethyl acetate (2 〇 ml), add Pd / C (48 mg, add hydrogen, and pump the reaction, and backfill with hydrogen three times The reaction was stirred at room temperature overnight under a rolling flask, then filtered through a pad of diatomaceous earth and concentrated in vacuo to provide the medium „3_(3_chlorophenyl)phenyl)propanoic acid ethyl vinegar (pass) (〇.g, 96.9%), as a color solid. Lc_MsEsim/z : found 243.2 [M+H]+. Intermediate 12 - gas group _7-(methyl-methyl)|spiro[benzene And 吱.South _2J,·銭銭](522) 149105-sp-20100806.doc -122. 201200505 Ο

522

Step: Add potassium carbonate (14 5 g, 1 〇 5 亳 mol) to a solution of ethyl 2 bromo pirone (1 〇 9 g, 52 5 mmol) in acetone (105 ml). )' followed by 2-isocyclopentanone (6,3 ml, 63 mmol). The mixture was refluxed overnight at 1 〇〇C. then filtered over EtOAc (EtOAc) elute EtOAc (EtOAc) (2-Bromo-4-indolyloxy)cyclopentanone (516B) (10.8 g, 71.0%) as a yellow oil. Step B: In a mixture of methyltriphenylphosphonium bromide (16.0 g, 44.8 mmol) in anhydrous tetrahydrofuran (125 mL). Potassium tert-butoxide (5.0 g, 44.8 mmol) was added in portions under nitrogen and nitrogen. After stirring for 30 minutes at TC, 2-(2-bromo-4-cyclophenoxy)cyclopentanone (516B) (10.8 g, 37.3 mmol) was added slowly in tetrahydrofuran (40 mL). The mixture was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over sodium sulfate and dried. Concentration by pressure. The residue was purified by flash chromatography (5-10% EtOAc in hexane) to afford 2-bromo-4. -20100806.doc • 123 - 201200505 Cyclopentyloxy)benzene (517) (6.2 g, 58.2%) as a colorless oil. Step C: 2-bromo-4-nitro-1-(2-) Indole cyclopentyloxy)benzene (517) (6.2 g '21.7 house moles) was heated at 150 ° C for 6 hours. The residue was purified by flash chromatography on EtOAc (5-10% EtOAc) In hexanes to provide 2-methyl-4-pyry-6-(cyclopentenyl) carboxylic acid (SIS) (5.7 g, 53.0%) as a yellow oil. Step D: Bromo-4-yl-6-(cyclopentenylmethyl)phenol (518) (5.7 g, 19.8 mmol) A mixture of Amberlyst® I5 ion exchange resin (5.2 g) in toluene (1 ml) was heated at 80 ° C for 3 hours. Then, 15 resin 'filtered 'and the filtrate was concentrated in vacuo' to give 7_ Bromo group _5 gas group _3 snail [benzofuran-2,1,·cyclopentane] (519) (5.4 g, 94_9%) as a yellow oil. Step E: use about (5〇9 Synthesizing a similar manner to synthesize 5-gas--3H-spiro[benzofuran-2, fluorene-cyclopentane]-7-rebel (52 〇) (ί ο, 44 5%), It is an off-white solid. Step F: Using a similar manner as described for the synthesis of (510), to synthesize (5_ gas-based 3 snail [本吱 吱 _2 2, ι 衣 烧 烧 】 】 /々ο克, 67.8%) 'is a colorless oil. Way to synthesize intermediate _2,1'-cyclopentane] (522) Step G: use the analog of (511) to synthesize the 5-chloro group - 7-(Alkylmethyl)_3Η-spiro [benzofuran (0.630 g, 91.4%), a yellow oil. Intermediate 13

Step C

149I05-sp-20100806.doc -124- 525 201200505

Br

n-Butyllithium

Step E

A similar reaction route as used for the synthesis of (522) was used to synthesize the intermediate 7-(chloromethyl)-5-fluoro- _ snail [benzofuran _21, cyclopentane] (529).

Step A: 2-(2-Bromo-4-fluorophenoxy)cyclopentanone (523) (13.3 g, 92.7%). Step B. 2-Bromo-4-ylfluoro-indole-(2-methylcyclopentyloxy)benzene (9.7 g, 73.4 °/.) was provided as a colorless oil. Step C: 2-Bromo-6-(cyclopentenylmethyl)-4-ylphenol (525) (8 2 g, 62.2%). Step D: Providing 7-bromo-5-fluoro-methyl-snail [stupyl-furan-21, cyclopentane] (526) (8.2 g, 100%), yellow oil. Step Ε: 5-Fluoro-3-indole-spiro[p-xanhydrofuran-2, hydrazine-cyclopentane]-7-bound acid (527) (1.75 g, 86.6%). Step F ·· Provided (5-fluoro-3H-spiro[benzofuran-2, oxime-cyclopentane]-7-yl) decyl alcohol (528) (0.610 g, 37.0%) as a colorless oil. Step G: Providing the intermediate 7_(chloromethyl) group but _ snail [stupid and biting -2,1'-cyclopenta] (529) (0,610 g '92.3%) as a yellow oil. Intermediate 14 (S)-2-(5-transyl-2,3-monohydro-ih-茚-i-yl)ethyl acetate (533) 149105-sp-20100806.doc -125- 201200505

530 ΗζΝ^Ο 1)

631

Et〇H, H2S〇4 Step B

532 2) HCI step iA BBr3

Step A: Slowly add palmitic base (3) small phenylethylamine (46 mA * ^ / house mole) to 2-(5-methoxy-2,3_dihydro_1H# small base) acetic acid (s3〇) (7 grams, 34_0 millimoles) in the mixing mixture in C_7〇 ml): After the addition is complete, add another acetone (1 ml) and continue to stir for 1 hour. . The precipitate was collected by filtration, washed with acetone and dried under vacuum. The solid was resuspended in acetone (100 mL) and allowed to warm to reflux until all solids dissolved. The resulting reaction mixture was allowed to cool slowly to room temperature overnight, during which time a precipitate formed. Allow this suspension to cool to 0,

The white solid was collected by filtration and washed with cold acetone. The solid was dissolved in 1N EtOAc and extracted with EtOAc. The organic phase was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo to afford (s) </ </ "> </ </ </ </ 531) (1.65 g, 23.5%, 99.9% ee), as an oil residue. Step B·(S)-2-(5-Methoxy-2,3-dihydro-1H-indol-1-yl)acetic acid (531) (1.65 g '8.0 mmol) with 咏8〇4 (0.111 ml, 4. 〇 mmol) mixture in ethanol (5 ml) was refluxed for 2 hr under TC. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. Washing. Separate the organic layer, dehydrated with sodium sulfate, filtered and concentrated in vacuo to afford (s) </ </ </ </ "> (532) (1.8 g, 96.0%), 149105-sp-20100806.doc -126. 201200505 oil. Step c: using a similar method described in (514) synthesis 'to synthesize (S)_2_( Ethyl 5-hydroxy-2,3-dihydro-1H-indol-1-yl)acetate (533) (I.6 g, 94.5%) as an oil residue. Intermediate 15 (S)-2-( 5-Phenyl-2,3-dihydro-1H-indol-1-yl)ethyl acetate (536)

The intermediate (S)-2-(5-hydroxy-2,3-dihydro-1H-indol-1-yl)acetate (536) was synthesized using a similar reaction scheme used for the (533) synthesis. Step A: Providing (R)-2-(5-decyloxy-2,3-dihydro-1H-indol-1-yl)acetic acid (534) (2.67 g, 38.1%, 92.0% ee pure) as Oil residue. Step B: Providing (R)-2-(5-decyloxy-2,3-dihydro-1H-inden-1-yl)acetate (535) (2.9 g, 96.9%) as an oil residue . Step C: Providing the intermediate (R)-2-(5-hydroxy-2,3-dihydro-1H-indole-1-yl)ethyl acetate (536) (1.7 g '61.1%) as an oil residue . Intermediate 16 ethyl 2-(3-fluoro-4-hydroxyphenyl)cyclopropanecarboxylate (539) NH Μθ'Ν^Ν-Ν〇2

F 537 149105-sp-20100806.doc •127- 201200505

Step A: 3-Fluoro-4-indolylbenzaldehyde (51 g, 33 〇 mmol) with (ethoxycarbonyl fluorenylene) triphenyl sinter (Π. 2 g, 49.5 mmol) A mixture of anhydrous toluene (165 mL) was taken in EtOAc (EtOAc (EtOAc) (E)-3-(3-Fluoro-4-methoxyphenyl)propanoic acid ethyl ester (537) (65 g, 87.6%) as a white solid. Step B: N-methyl-indole '-Nitro-N-nitrosoguanidine (τα-US catalog # Μ0527, 3.7 g, 25.0 mmol on dry weight basis) in a mixture of ether (5 mL) at 0 ° C Add 25% aqueous hydrazine solution (20 ml). After stirring for 2 minutes, add a portion of the formed diazonium salt-containing ether solution to olefin (537) (u, 5 〇mol) in a solution of ether (25 ml), add a portion of palladium acetate (11) (〇 112 g, 〇 5 〇 millimoles), followed by another portion of the diazomethane solution. Procedure until all diazomethane solution and palladium acetate are added ( 11). The resulting mixture was mixed for 0 hours under 0-5X: and acetic acid (6 drops) was added to quench any excess reagent. The resulting mixture was concentrated in vacuo to provide 2 ( Ethyl 3-fluoroamino-4_methoxyphenyl)cyclopropanecarboxylate (538) (0 990 g, 83.0%) as a yellow oil. Step C: using a similar procedure as described for the synthesis of (514) Intermediate 2_(3·Fluoro-4-hydroxyphenyl)cyclopropanecarboxylate (S39) (〇85 g, Μ, as a colorless oil. Intermediate 17 149l05-sp-20100806.doc •128· 201200505

4-(4-Phenylphenyl)·3·methylbutanoic acid ethyl ester (542). iXrr N〇xxrrc

Ph, .OEt

Step A 540 541 XTYV0E, Step c 〇 542 Step A: Using a similar manner as described for the synthesis of (537) to synthesize ethyl 4-(4-methoxyphenyl)-3-methylbut-2-enoate (540 (4.5 g, 64.3%), a colorless oil. The step is referred to as β·· using a similar manner as described in the synthesis of (513) to synthesize ethyl 4-(small methoxyphenyl)-3-methylbutanoate (541) (2.0 g, 98, 4%) as Colorless oil. Step C: A similar procedure as described for the synthesis of (514) was used to synthesize the intermediate 4-(4-hydroxyphenyl)-3. decanoic acid ethyl ester (542) (〇·8 g, 42 5% ), for colorless oil 0

Intermediate 18 7-(Chloroindenyl)-2,2-dimethyl-5-phenyl-2,3-dihydrobenzofuran. South (547) 0Η

Cl c丨 people. TiClJ step c

Ph 545

Step A Ph 543 NMP, heating Step B

Step A: A similar manner as described for the synthesis of (516B) was used to synthesize 4 (2 - decallyloxy)biphenyl (543) (5.9 g &apos; 89.5%) as a white solid. Step B: 4-Alllyloxy)biphenyl (S43) (5.9 g, 26.4 mmol)

S 149105-sp-20100806.doc -129- 201200505 The mixture in N-methyl-2-tetrahydropyrrolidone was microwaved at 21 ° C for 8 hours. The residue was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on EtOAc (5-10%EtOAcEtOAcEtOAc (3.6 g, 60.8%) as a white solid. Step C: 2,2-dimethyl-7-phenyl-2,3-dihydrobenzofuran (544) (2 24 g, 10.0 mmol) in dioxane (15 mL) Titanium tetraoxide (2 ml, 18 mmol) was slowly added to the ice-cold solution. After stirring for 5 minutes, dichloro(methoxy)decane (1 mL, 11 mmol) was added slowly. The resulting mixture was stirred at 〇r for 3 hours, and the reaction was quenched slowly with ice water. The product was extracted with dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on EtOAc (5-10%EtOAcEtOAcEtOAc Carboxaldehyde (545). Step D. in 2,2-dimethyl-5-phenyl-2,3-dihydrobenzopyrano-7-carboxaldehyde (S4S) (1 g, 3.96 mmol) in decyl alcohol ( Sodium borohydride (179.9 mg, 4.76 mmol) was added in portions to ice cold solution in 20 mL). The resulting mixture was stirred at 0 ° C for 3 hours, and the reaction was quenched slowly with water. The product was extracted with dioxane. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on Shishijiao (2% by weight)

EtOAc was added in hexanes to give (2,2-dimethyl-5-phenyl),3,dihydrobenzofuran-7-yl)methanol (546). Step E: using a similar manner as described for the synthesis of (511) to synthesize intermediate I49105-sp-20100806.doc -130· 201200505 7-(Chloromethyl)-2,2-dimercapto-5-benzene Base-2,3-dihydro benzofuran (547). Intermediate 19 6-Alkyl-4-(chloroindenyl)_2,2-dimercapto-2,3-dihydro cumin cough South (552)

Step A: In a mixture of methyl 2-amino-3-methoxybenzoate (10 g, 55 mmol) in DMF (200 mL), N. The imine (8. 08 g, 60, 5 mmol) was added and the resulting mixture was stirred at 5 ° C for 2 hours. The reaction was cooled to room temperature, diluted with water (3 mL) andEtOAc. The combined organic layers were washed with water (2 EtOAc EtOAc EtOAc). The residue is purified by chromatography to afford the desired product (548). Step by step: in 2-amino-5-yl-3-methoxybenzoic acid methyl ester (548) (5.2 g, 24 mmol) in water (25 mL) and sulphuric acid (2.7 mL) A solution of sodium nitrite (1.7 g, 24 mmol) in water (25 mL) was added at room temperature. The mixture was stirred at room temperature for 30 minutes and added to a mixture of copper bromide (5.2 g, 36 mmol) in concentrated hydrogen bromide (1 mL) and water (2 mL) at room temperature. . The mixture was stirred at room temperature overnight and passed through a crucible.

S I49105-sp-20100806.doc -131 - 201200505 The celite pad was filtered and rinsed with EtOAc (3 x 100 mL). The organic layer was separated and aqueous brine evaporated elut The combined organic layers were washed with water (2 &lt;RTI ID=0.0&gt;&gt;&gt; The residue is purified by chromatography to give the desired product (S49). Step C · Methyl 2-bromo-5-yl-3-methoxybenzoate (549) (1.1 g, 4 mmol), 4,4,5,5-tetradecyl-2- (2-mercaptopropene+ene·i•yl)+3}dioxaboron (0.72 g, 4 mmol), Pd(pph3)4 (138 mg, 0.12 mmol), 2N sodium carbonate aqueous solution (8 ml), a mixture of decyl alcohol (1 ml) and toluene (6 ml), heated in a pressure-resistant tube at 12 (rc overnight). Add ethyl acetate and water, and separate the liquid layer. The phases are extracted with ethyl acetate, and the combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound is subjected to flash column chromatography on silica gel with hexane and Et. 4, the desired product (55 〇). Step D · 5-Hydroxy-3-poxy-2-(2-f-propyl-propionyl)-benzoic acid formazan (550) (0.6 g, 2.3 mmol) in a solution of trimethyl ketone (2 〇 ml), under the addition of three desert boron (〇67 ml, 69 mAh to warm the solution to room temperature) And (4) overnight, with methanol (5 ml), followed by saturated sodium bicarbonate (5 ml) Should be + extinguished. &gt; From the organic layer, dehydrated and dried with sodium chlorate; and concentrated in vacuo. The crude compound was subjected to flash column chromatography on hexanes, with hexane and Et. Purification affords the desired product (551). Step K: The compound network is made in a similar manner as described for the synthesis of (4) and (5). 149105-sp-20100806.doc -132- 201200505 t interstitial 20 〇H 2-(4-Ethyl 2-cyclopropanecarboxylate (556)

DMSO, (COCI)2 〇,

NH Μθ'ν·^ν-ν〇2

I I

NO H

Pd(OA〇2 /KOH water soluble ig Step C &quot; wv 5δβ Step Α·2DMS 二氯甲烷 (5.2 ml, 72.6 mmol) in dichloromethane (145 ml) was added to the gas at -7 ° C under nitrogen.醯草醯(31 ml, 36 3 mmol) in a solution of dichloromethane (83 ml). After stirring for 5 minutes, add 2_(4) dissolved in dichloromethane (33 ml) _Methoxyphenyl)ethanol (5 gram, 33.0 mmol) (2 〇 min). Stirring was continued for 2 Torr, and triethylamine (9.7 liters, 69.3 mmol) was added and the reaction mixture was Stir and slowly warm to room temperature for 1 hour. Dilute the reaction mixture with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(4-methoxyphenyl) Aldehyde (553) (2.2 g, 44.4%) as an oil residue. Step B: Using a similar procedure as described for the synthesis of (537) to synthesize (6) 4-(indolylphenyl)but-2-enoic acid Ethyl ester (554) (1.1 g, 38.2%) as a colorless oil. Step c: using a similar procedure as described for the synthesis of (538) to synthesize 2 &lt;4_methoxybenzyl)cyclopropane Carboxylate (555) (1.2 g, 99.0%) as a colorless oil. Step D: An intermediate of 2-(4-hydroxybenzyl)cyclopropanecarboxylate (556) (0.945 g, 80.1%) was obtained as a colorless oil.

E I49105-sp-20100806.doc -133 - 201200505 Intermediate 21 2-(2-(4-Hydroxyphenyl)cyclopropyl)acetate (562)

Step A: bromination of (2-carboxyethyl)triphenyl scale (2 〇 0 g, ". ο mmol") with 4-methoxy quinone (6.5 g, 53.5 mmol) in anhydrous The mixture in DMSO (64 mL) was slowly added to a suspension of 60% NaH (4.3 g, 107 mmol) from EtOAc (EtOAc) After 30 minutes, then warmed to room temperature for 4 hours. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. Concentration under reduced pressure. Purification of the residue on silica gel by flash chromatography (50 〇 / 〇Et〇Ac in hexane) to provide (E)-4-(4-methoxyphenyl)- 3-enoic acid (5S7) (5.7 g, 55.0%), as a yellow solid. Step B: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Bismuth fluoroborate-(benzotriazole small group)_ν,ν,ν,,ν,·θ methyl hydrazine (9·5 g, 29.5 mol). After 5 minutes of mixing, add ν〇_二曱Base amine.HC1 (2.9 g, 29 .5 millimoles)' followed by Et N (8 2 ml, 58.9 mmol). The reaction mixture was spoiled at room temperature for 3 hours and diluted with water, 149l05-sp.20100806.doc •134· 201200505 This was extracted with ethyl acetate. The organic phase was washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (E)-N-Methoxy-4-(4-methoxyphenyl)-N-methylbut-3-enylamine (558) (2.1 g, 29.6%) was obtained as a yellow solid. C: a solution of diethylzinc in hexane (1 M, 17.4 ml, 17.4 mmol), slowly added to iodonane (2.5 ml, 34.9 mmol), dimethyl at -15 °C. Ethyloxyethane (1.82 ml) in a mixture of dichloromethane (25 ml). After stirring for 20 min, (E)-N-decyloxy-4-(4-indoleoxyphenyl)-N - a solution of mercapto-3-ene decylamine (558) (2.0 g of '8_7 mmol) in dichlorohydrazine (ml) was added to the reaction mixture. The resulting mixture was allowed to warm to room temperature. After 24 hours, the reaction mixture Diluted with water and extracted with dioxane. The organic phase was washed with water, brine, dried over sodium sulfate sulfate In hexanes to provide N-decyloxy-2-(2-(4-methoxyphenyl)cyclopropyl)-N-methylacetamide (559) (1.8 g, 85.2%), It is yellow oil. Step D: N-Methoxy-2-(2-(4-methoxyphenyl)cyclopropyl&gt; N-methylacetamide (559) (1.8 g ' 7.4 house Moer), 2.5 N A mixture of NaOH (15 ml) and EtOH (15 mL) was stirred at 60 ° C for 24 hours. The reaction mixture was acidified with EtOAc and extracted with EtOAc. The organic phase was washed with water, brine and dried over sodium sulfate. Concentrate in vacuo to provide 2-(2-(4-indoleoxyphenyl)cyclopropyl)acetic acid (560) (1.5 g, 96.1%) as a yellow solid. Step E: using (532) In a similar manner, to synthesize 2 (2-(4-methoxyphenyl)cyclopropyl)acetate (561) (1.2 g, 71.3%) as a colorless oil. Step F: use (514) In a similar manner, to synthesize _ 149I05-sp-20100806.doc • 135- 201200505 2-(2-(4-hydroxyphenyl)cyclopropyl)acetate (562) (〇488 g, 43.6% ), as a colorless oil. Intermediate 22 ethyl 3-(4-hydroxy-2,6-dimethylphenyl)propanoate (564)

Step A: Synthesis of ethyl (E)-3-(4-hydroxy-2,6-dimethylphenyl)acrylate (563) using a similar manner as described for the synthesis of (537) (3 4 g, 1 〇〇〇/0), as a white solid. Step B: A similar procedure as described for the synthesis of (513) was used to synthesize the intermediate 3-(4-carbo-2,6-dimethylphenyl)propanoic acid ethyl ester (564) (lo, 97.8%) ), is a colorless oil. Intermediate 23 ethyl 3-(4-hydroxy-2,5-diamidinophenyl)propanoate (567)

OEt Ha, Pd/C Step B Step A: Synthesis of (E)-3-(4-methoxy-2,5-dianonylphenyl) propylene using a similar manner as described for the synthesis of (537) Ethyl acetate (5 dip) (32 g, 91.0%) as a white solid. Step B: Using a similar manner as described for the synthesis of (S13), to synthesize ethyl 3(4_ methoxy-2-,5-methylphenyl)propanoate (5 sec) 〇j g, Μ 7〇/ 〇), for no 149105-sp-20100806.doc -136- 201200505 color oil. Step c - Using a similar manner as described for the synthesis of (514) to synthesize the intermediate 3-(4-light-based 2,5-dimethylphenyl)propionic acid ethyl ester (9) is (〇克, 89丨(6) , is a colorless oil. Intermediate 24 3-(4-hydroxy-2,6-

Monomethyl (meth) propionate ethyl vinegar (570)

569 h2, Pd/c step b

Step A: Using a similar reaction route for the synthesis of (537) to synthesize ethyl (E)-3-(4-methoxy-2,3-dimethylphenyl)acrylate (568) (3.2 g , 90.7%), as a white solid. Step B: Synthesis of ethyl 3-(4-decyloxy-2,3-dimercaptophenyl)propanoate (569) using a similar reaction scheme for the (513) synthesis (1.3 g, 86.0% ), as a white solid.

Step C: Using the similar reaction scheme used for the synthesis of (514) to synthesize the intermediate ethyl 3-(4-hydroxy-2,3-didecylphenyl)propanoate (570) (1.2 g, 89.3%) ), as a white solid. Intermediate 25 2-(2-(2-Fluoro-4-hydroxyphenyl)cyclopropyl)acetic acid ethyl ester (576)

149105-sp-20100806.doc -137· 201200505

Cl^/i

A similar reaction route for the synthesis of (562) was used to synthesize the intermediate 2-(2-(2-fluoro-4-hydroxyphenyl)cyclopropyl)acetate (576). Step A. Provided (E)-4-(2-Fluoro-4-methoxyphenyl)butane-3-ylic acid (571) (5 g, 47.4%) as a yellow oil. Step B: Providing (E)-4-(2-Fluoropiperidinyl)-N-decyloxy_N-methylbut-3-enylamine (572) (3.4 g, 56.7%) as Yellow oil. Step C: Providing 2-(2-(2-fluoro-4-methoxyphenyl)cyclopropyl)-N-methoxy-N-methylacetamide (573) (3.5 g, 96.7%) Yellow oil. Step D: 2-(2-(2-Fluoro-4-oxophenyl)cyclopropyl)acetic acid (574) (27 g, 92.4%). Step E · Known for 2-(2-(2-yl-4-oxophenyl)cyclopropyl)acetate (gw) (1.9 g, 62.8%), yellow oil. Step F. An intermediate of 2-(2-(2-fluoro-4, phenyl)cyclopropyl)acetic acid ethyl acetate (576) (1.4 g, 78.6%). Intermediate 26 3-(5-Fluoro-4-alkyl-2-methylphenyl)propanoic acid ethyl ester (57%

〆0 CI

CI TiCI4

ΗΟ^ Step A

F 149105-sp-20100806.doc -138- 201200505 Ο

Step C

F 579 Step A: Synthesis of 5-fluoro-4-pyridyl-2-methylbenzaldehyde (577) (0.240 g, 6 5%) as a white solid using a similar procedure as described in (545). . Step B · Using a similar manner as described for the synthesis of (537) to synthesize ethyl (E)-3-(5-fluoro-4-hydroxy-2-methylphenyl)acrylate (578) (〇33 〇克, 94.5%), as a white solid.

Step C: Using a similar manner as described for the synthesis of (513) to synthesize ethyl 3-(5-fluoro-4-pyridyl-2-decylphenyl)propanoate (579) (〇325 g, 97 6 %) is a colorless oil.

Intermediate 27 3-(5-Fluoro-4-alkyl-2-methylphenyl)propanoic acid ethyl ester (58_

Step A: A similar manner as described for the synthesis of (517) was used to synthesize 2-hydroxyl-1-methoxy-3-ethphenylbenzene (580) (3.5 g, 88.5%) as A 1 J. The heat is already oily. Step B: Using a similar manner as described for the synthesis of (513) to synthesize 丨_ethyl-2-yl-3-methoxybenzene (581) (3.2 g, 89.7%) as colorless, by step C : In a similar manner as described for the synthesis of (545), octaethyl 2-ethyl-3-fluoro-4-methoxybenzaldehyde (582) (2.7 g, 73·2 〇/〇) was used as the colorless.

S 149105-sp-20100806.doc -139- 201200505 Step D ··Use the similar method described in (537) synthesis to synthesize (E)-3-(2-ethyl_3_fluoroyl_4_A Oxyphenyl) acetoacetate (5 phantom) (丨3 g, 89.4%) as a white solid. Step E: Ethyl 3-(2-ethyl-3-fluoro-4-tetramethoxyphenyl)propanoate (584) (1.3 g, 98.5%) was synthesized in a similar manner as described for the synthesis of (513). , is a colorless oil. Step F. A similar procedure as described for the synthesis of (514) was used to synthesize the intermediate 3-(5-fluoropiperidin-2-methylphenyl)propanoate (585) (1 2 g, 98.2 °/.)' is a colorless oil beta intermediate 28

A similar reaction route as used for the synthesis of (567) was used to synthesize the intermediate ethyl 3-(5-fluoro-4-hydroxy-2-mercaptophenyl)propanoate (588). Step A: Ethyl (E)-3-(4-decyloxy-5,6,7,8-tetrahydroindenyl) acrylate (586) (0.540 g &apos; 78.3%). Step B: Ethyl 3-(4-decyloxy-5,6,7,8-tetrahydroindol-1-yl)propanoate (587) (0.510 g, 93.7%). Step C: An intermediate 3 - (4 · hydroxy - 5, 6, 7 &gt; tetrahydroindenyl) ethyl propionate (588) (0.243 g, 50.3%) was obtained as an oil residue. Intermediate 29 149105-sp-20100806.doc -140- 201200505 3-(2-Ethyl-5-fluoro-4-hydroxyphenyl)propanoic acid ethyl ester (594)

A similar reaction route for the synthesis of (S85) was used to synthesize the intermediate 3-(2-ethyl-5-fluoro-4-hydroxyphenyl)propanoic acid ethyl ester (594). Step A: 1-Fluoro-2-oxo-vinylbenzene (589) (15 g, 30.3%) was provided as a colorless oil. Step Β: 4-Ethylfluoro-2-bromobenzene (59 〇) (u, 717%) was obtained as a colorless oil. Step C - 2-Ethyl-5-fluoro-4-tetramethoxybenzaldehyde (591) (〇 98 g, 76.1%) was obtained as a colorless oil. Step D: Ethyl (E)-3-(2-ethyl-5-fluoro-4-methoxyphenyl)acrylate (592) (1.3 g, 96.5%). Step E. Ethyl 3-(2-ethyl-5-fluoro-4-methoxyphenyl)propanoate (593) (1.3 g, -96.2%). Step F. Provided the intermediate 3·(2-ethyl-5-fluoro-hydrophenylphenyl)propanoic acid ethyl ester (594) (0.617 g, 51.4%) as a colorless oil. Intermediate 30 3-(3-Fluoro-4-hydroxy-2-propylphenyl)propanoic acid ethyl ester (6〇〇)

S 149105-sp-20100806.doc -141 - 201200505

A similar reaction route for the (585) synthesis was used to synthesize the intermediate 3-(3-fluoro-4-hydroxy-2-propylphenyl)propanoic acid ethyl ester (6 〇〇). Step A. Provided (E)-2-yl-1-methoxy-3-(prop-1-enyl)benzene (595) (1.4 _ g '32.5%) was a colorless oil. Step B. Provided 2_fluoro-based decyloxy-3-propylbenzene (596) (1.2 g, 83.0%) as a colorless oil. Step C. 3-Fluoromethoxy-2-propylbenzyl route (597) (丨〇克, 73.4 ° /.) is provided as a colorless oil. Step 4 D. Provided (6) _3_(3_Fluoro- 4 methoxy-2-propylphenyl) propyl acrylate (598) (1.2 g, 86.8%) as a colorless oil. Step E: Providing ethyl 3-(3-fluoropiperidinyloxy-2-propylphenyl)propanoate (599) (1. 2 g, 95.9%) as a colorless oil. Step F: Providing the intermediate 3·(3-fluorophenyl hydroxy-whenyl phenyl) propionate ethyl ester (600) (1.1 g, 98.2%) as a colorless oil. Intermediate 31 H3-Fluoro-4-hydroxy-2-pentylphenyl)propionic acid ethyl ester (6〇6) H9I05-sp-20100806.doc •142- 201200505

A similar reaction scheme used for the synthesis of (585) was used to synthesize the intermediate 3-(3-1--4--4-yl-2-pentylphenyl)propionic acid ethyl acetate (6〇6). Step A: Providing (Ε)·2_fluoro-1-methoxy-3-(pent-1-enyl) stupid (601) (3.5 g, 69.3%) as a colorless oil. Step B: 2-Fluoro-1-methoxy-3-pentyl stupid (6〇2) (3.1 g, 88.2%). Step C: 3-fluoro-4-methoxy-2-pentylbenzene (6 〇 3) (2.4 g, 67.9%) was provided as a colorless oil. Step D: (E)-3-(3-Fluoro-4-methoxy-2-inpentyl)ethyl acrylate (604) (2.9 g, 89.7%). Step Ε: Ethyl 3-(3-fluoro-4-methoxy-2-pentylphenyl)propanoate (605) (2.7 g, 94.4%). Step F. An intermediate of ethyl 3-(3-fluoroyl hydroxyhydroxy-2-pentylphenyl)propanoate (606) (2.5 g, 98.7%) was obtained as a colourless oil. Intermediate 32 3-(2-ethyl-3-fluoropiperidinyl)_2-methylpropionic acid ethyl ester (6〇9) 149105-SP-20100806.doc -143· 1^' 201200505

Step A: Synthesis of (E)-3-(2-ethyl-3-fluoro-4-indolyloxyphenyl)-2-mercaptopropionic acid B in a similar manner as described for the synthesis of (515) g (607) (1.3 g, 89.4%) as a white solid. Step B: Synthesis of ethyl 3-(2-ethyl-3-octyl-4-methoxyphenyl)-2-methylpropanoate (6〇8) using a similar manner as described for the synthesis of (513) (1.3 g, 98.5%), a colorless oil. Step C: A similar procedure as described for the synthesis of (514) was used to synthesize the intermediate 3-(2-ethyl-3-fluoropiperidinyl)-2-propionic acid ethyl ester (609) (1.2 g , 98.2%), as a colorless oil. r interferment μ j 3-(3-Fluoro-4-hydroxy-2-isoamylphenyl)propionic acid ethyl ester (615)

61〇 en 612

614 Magic 5 uses a similar reaction pathway for the synthesis of (585) to synthesize intermediate 149105-sp-20100806.doc (S) -144· 201200505 3-(3-fluoro-4-hydroxy-2-isoprene Ethyl phenyl) ethyl propionate (615). Step 2 provides (E &gt; 2 - fluoro + decyloxy - 3 - (3 - decylbutenyl) benzene (61 〇) (3.5 g '88.5%) as a colorless oil. Step B: provide 2-fluoro -1 -Isoamyl_3_methoxybenzene (611) (32 g, 89.7%) 'as colorless oil. Step C: provides 3-fluoro-2-isopentyl-4-methoxybenzene Formaldehyde (612) (2.8 g, 73.2%) as a colorless oil. Step D: provided (E)ethyl 3-(3-fluoroyl-2.isopentyl-4-indoleoxyphenyl) acrylate (613) (1.3 g, 89.4%) as a white solid. Step E: provided ethyl 3-(3fluoro-2-isopentyl-4-indoleoxyphenyl)propanoate (614) (1.3 g, 98.5 %), as a colorless oil. Step F: provided the intermediate ethyl 3-(3-fluoro-4-hydroxy-2-isopentylphenyl)propanoate (615) (1.2 g, 98.2%) as colorless oil.

Intermediate 34 3-(2-butyl-3-fluoro-4-phenyl)propionic acid ethyl acetate (621)

619 620 621 A similar reaction scheme used for the synthesis of (585) was used to synthesize the intermediate 3-(2-butyl-3-fluoro-4-hydroxyphenyl)propanoic acid ethyl ester (621). 149105-sp-20100806.doc - 145 - 201200505 Step A: Provided (E&gt;1_(丁巧·稀基) Qianki 3Methoxybenzene) (4 $ 克 ' 96.1%) as a colorless oil. Step B. provides μ butyl 2 -fluoro 3 - methoxybenzene (10) 7) ^ 2 g, % ?%), which is a colorless oil. Step C. 2-Butyl-3-F-fluoro-4-yloxybenzaldehyde (618) (34 g, 69.2%) was obtained as a colorless oil. Step D. Providing (Ε)_3_(2_butyl_3_fluorosulfonyloxyphenyl)ethyl acrylate (619) (1.0 g, 76.60 /.)' as a white solid. Step E· Provided ethyl 3-(2-butyl-3-fluoro-tolyloxyphenyl)propanoate (62 〇) (1.0 g, 97_4 ° /.) as a colorless oil. Step F. Provided the intermediate 3_(2_butyl_3_fluoro-m-hydroxyphenyl) ethyl propionate (621) (0.937 g, 97.7%) as a colourless oil. Intermediate 35 3_(3_Fluoro-4 hydroxybenzene | hydrazine, 2,3,3-tetrahydropropionic acid ethyl ester (625)

Step Α: in a mixture of 3-fluoro-4-methoxybenzobenzaldehyde (0.589 g, 3 〇 mmol), potassium carbonate (1.8 g '13.0 mmol) in methanol (65 mL) Dimethyl 1-diazo 2-carboxyketopropylphosphonate (14 g, 7.2 mmol) was slowly added at room temperature. The resulting mixture was stirred at room temperature for 2 hours to sat. Sodium hydride quenched the reaction and extracted with ethyl acetate. The organic phase was washed with br. br. </RTI> &lt;RTI ID=0.0&gt;&gt; The residue was purified by flash chromatography (10% EtOAc in hexanes) to afford 4-ethynyl-2-fluoro-1-methoxybenzene (622). , 76 9%), as a colorless oil. Step B: Slowly add a solution of n-butyl chain (1.17 ml) in a mixture of diisopropylamine (0.262 ml, 87.87 mmol) in tetrahydrofuran (5 ml) under _78^ and nitrogen. , 1.87 millimolar, 丨·6Μ, in hexane). After stirring for 30 minutes, a solution of 4-ethynyl-2-fluoro-1-indolylbenzene (622) (〇18〇Φ g, 0·94 mmol) in tetrahydrofuran (1 mL) was slow. Slowly added to the reaction mixture. The mixture was brought to 〇 ° C, and 丨 , , , , , 氯 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Quenched and extracted with a shout. The organic phase was washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography on EtOAc (5 EtOAc / EtOAc EtOAc). (0.070 g, 6,3%), a colorless oil. _ step C: using the similar method described in (513) for synthesis (except for the use of gas cylinders) 'to synthesize the normalized 3-(3-fluoro-4-indolyl)-propionic acid Gw) (0.050 g, 68.9%), as a colorless oil. Step D: using a similar manner as described for the synthesis of (514), to synthesize an intermediate of triethyl 3-(3-fluoro-4-hydroxyphenyl)propanoate (625) (〇〇43 g, 92.1%) is a colorless oil. Intermediate 36 3-(3-Fluoro-4-alkyl-2-propylphenyl)-2,2,3,3-tetrahydropropionic acid B from (629) g I49105-sp-20100806. Doc -147- 201200505

Step A: In a solution of diisopropylamine (〇 841 mL, 6 mmol) in tetrahydrofuran (15 mL), _78. Under a nitrogen atmosphere, a solution of n-butyllithium (3·75 ml, 6.0 mmol, 1.6 M in hexane) was slowly added. After stirring for 3 minutes, a solution of TMS-diazoxane (3. mM, 6.0 mmol, 2 Torr in hexane) was slowly added to the reaction mixture. The mixture was stirred for 3 minutes, then a solution of 3-fluoro-fluoro-p-methoxy-whenyl-benzaldehyde ( 597 ) ( 585 g, 3.0 mM) in tetrahydrofuran (3 mL). The resulting mixture was stirred at room temperature for 12 hours, then quenched with saturated aqueous ammonia and extracted with diethyl ether. The organic phase was washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAc) It is a colorless oil. Step B: Synthesis of ethyl 3-(3-fluoro-4-methoxy-2-propylphenyl)propynoate (627) (〇14 g, using a similar manner as described for the synthesis of (623). 56.6%), is a colorless oil. Step C: Using a similar manner as described for the synthesis of (513) (but using a 〇2 gas cylinder) to synthesize the deuterated 3-(3-fluoro-4-methoxy-2-propylphenyl) Ethyl propionate (628) (0.085 g, 58.9 °/.) is a colorless oil. Step D: using a similar method described in (514) for synthesis to synthesize intermediate 3-49105-sp-20I00806.doc -148- 201200505 3-(3-fluoro-based 4-hydroxy-2-propyl) Phenyl)ethyl propionate (629) (〇.〇78 g '96.6%) as a colorless oil. Intermediate 37-(2-Ethyl-3-fluoro- 4-hydroxyphenyl)_2,2,3,3_tetradecanoic acid ethyl ester (633)

A similar reaction route for the (625) synthesis was used to synthesize the intermediate (633). Step A: Using a similar manner as described for the synthesis of (622) to synthesize 2-ethyl-1-ethynyl-3-fluoro-4-methoxybenzene (630) (〇.39〇克, 72 9 %) as colorless oil 0 Step B: Providing ethyl 3-(2-ethyl-3-fluoro-4-methoxyphenyl)propynoate (631) (0.100 g, 18.3%) as a colorless oil . Step C: Ethyl 3-(2-ethyl-3-fluoro-4-tetrahydrophenyl)propanoate (632) (0.080 g, 77.5%). Step D: An ethyl ester (633) (EtOAc, EtOAc (EtOAc) Intermediate 38 ethyl 3-(3-fluoro-4-hydroxy-2-mercaptophenyl)propanoate (637) 149105-sp-20100806.doc .149- 201200505

Step A: Using a similar manner as described for the synthesis in (545) to synthesize 3-fluoro-4-pyridyl-2-methylbenzaldehyde (634) (0.910 g, 73.1 〇/〇) as white powder. Step B: Using a similar manner as described for the synthesis of (537), to synthesize (E)_3_(3·Fluoro-4-methoxy-2-methylphenyl)acrylate (635) ^ 2 g, 9〇8%), as a white powder. Step C: using a similar manner as described for the synthesis of (513) to synthesize ethyl 3-(3-fluoro-4-methoxy-2-indolyl)propanoate (636) (1.2 g, 97.5%) is a colorless oil. Step D: using an analogous procedure as described for the synthesis of (514) to synthesize the intermediate 3-(3-fluoro-4-hydroxy-2-methylphenyl)propanoic acid ethyl ester (637) (1 gram, 95.1%), a colorless oil. Intermediate 39 3-(3-ethyl-4-phenyl)propionic acid ethyl acetate (641)

«40 641 Step A: A similar reaction scheme used for the synthesis of (545) was used to synthesize 3-ethyl-4-methoxybenzaldehyde (638) (0.690 g, 89.4%) as a yellow oil. 149105-sp-20100806.doc -150· 201200505 Step B: Synthesis of (E)-3-(3-ethyl-4-methoxyphenyl)acrylic acid B using a similar reaction scheme used for the synthesis of (537) Ester (639) (0.440 g, 100%) as a colorless oil. Step C: Using a similar reaction route for the synthesis of (513) to synthesize 3-(3-ethyl-4-methoxyphenyl)propanoic acid B (640) (0.360 g, 91.1%) as Colorless oil. Step D: Using the similar reaction scheme used for the synthesis of (514) to synthesize the intermediate ethyl 3-(3-ethyl-4-hydroxyphenyl)propanoate (641) (0.316 g, 93.6%) as Colorless oil. Intermediate 40

638 3-(3-Ethyl-4-hydroxyphenyl)-2-mercaptopropionic acid ethyl ester (644)

Step A: Using a similar reaction route for the synthesis of (51S) to synthesize (Ε)·3-(3-ethyl-4-indoleoxyphenyl methacrylate (642) (0.460 g '99.0%) '' is a white powder. Step Β: using a similar reaction route for the synthesis of (513) to synthesize ethyl 3-(3-ethyl-4-methoxyphenyl)-2-methylpropanoate (643) (0.400 g, 86.3%) 'is a colorless oil. Step c: Using a similar reaction route for the synthesis of (514) to synthesize the intermediate 3-(3-ethyl-4-hydroxyphenyl)_2_ Ethyl methacrylate (644) (0.343 g,

S 149105-sp-20100806.doc 151 201200505 90·7%), is a colorless oil. Intermediate 41 3-(4-Aminophenyl)-2-methylpropanoic acid B (646)

645 Step A: 4-nitrobenzaldehyde (2 g, 13.2 mmol) and (1-ethoxycarbonylethylidene) triphenyl charged (4.80 g, 13.2 mmol) in tetrahydroquinone The solution in (13 ml) was refluxed for 24 hours. The reaction was concentrated in vacuo and purified by flash chromatography eluting with EtOAc eluting with EtOAc (EtOAc) Ester (645). Step B. A solution of ethyl (E)-2-mercapto-3-(4-decylphenyl)acrylate (645) (2.49 g ' 10.6 mmol) in ethanol (1 mL) Inside, add pd/c (25 mg, 10% Degussa type). A hydrogen cylinder was added and the reaction was evacuated and backfilled three times with hydrogen. The reaction was stirred at room temperature overnight and then dried over Celite &lt;&quot;&quot;&quot;&&&&&&&&&&&&&&&&& Intermediate 42 4-(2-fluorenyl-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)ethyl)phenol (65〇)

Ρρηλ

149105-sp-20l00806.doc • 152· 201200505 Step A: 7-(Chloromethyl)-5-fluoro-2,2-dimethyl-2,3_ two gas stupid and bitten (647) (1 g, 4.66 mmol), triphenylphosphine (1.22 g, 466 mmol) and toluene (46 mL) were heated under reflux for 48 hours. The reaction was filtered and the solid was washed with diethyl ether to afford chlorobenzene ((5-fluoro-2,2-dimercapto-2,3-dibenzophenanthene-7-yl)methyl)triphenyl Base scale (648). Step B: chlorination ((5-fluoro 2-, 2-dimethyl-2,3-dihydrobenzofuran)methyl)triphenyl scale (6 &lt; 48) (500 mg, 1.09 In a solution of anhydrous tetrahydrofuran (ίο ml), n-butyllithium (〇67 ml, 1.31 mmol, 2 M in hexane) was added at room temperature for 1 min. Thereafter, 4 (benzyloxy) benzofural (231 mg, 1.09 mmol) was added, and stirred for additional 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel eluting with EtOAc (EtOAc) _Dimethyl-2,3-dihydrobenzofuran, a cis/trans mixture (649). Step C: 7-(4-(decyloxy) stupid vinyl)-5-fluoro-2,2-diindenyl 2,3-dihydrobenzofuran (649) (207.7 mg, 0.583 m In a solution of ethanol (6 ml), Pd/C (2 mg, 10% Degussa type) was added. A hydrogen cylinder was added and the reaction was evacuated and backfilled three times with hydrogen. The reaction was stirred at room temperature and filtered through a pad of diatomaceous earth and concentrated in vacuo to give a fluoro-2,2-methyl-2,3-dihydrobenzofuran. ) Ethyl)phenol (65〇). Intermediate 43 3 (5 pen base-[ι,ι _biphenyl]_2-yl) propionic acid ethyl vinegar (653)

S 149105-sp-20I00806.doc -153· 201200505

Η2 ι Pd/C Step c

Step A: 2-bromo-4-hydroxybenzaldehyde (350 mg, 1.74 mmol), phenyldihydroxyborane (233.5 mg, 1.92 mmol), Pd(PPh3)4 (60 mg, A mixture of 0.052 mmol, saturated sodium bicarbonate (6 mL), methanol (15 mL) and toluene (6.0 mL) was then warmed overnight at 12 ° C in a pressure tube. Ethyl acetate and water were added, and the liquid layer was separated. The aqueous phase was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered, and evaporated. The crude compound was purified by flash column chromatography eluting EtOAc EtOAc (30%) Step B: 5-hydroxy-[1,1,-biphenyl]_2-carboxaldehyde (651) (292 mg, 1.47 mmol) and (carboxymethylene)-triphenylphosphane (564) · 5 mg, 1.62 mmoles. The solution in Aben (15 liters) was refluxed for 24 hours, and the reaction was concentrated in vacuo 'by flash column chromatography on ruthenium with hexane and Et. Ac (3〇0/.) was purified to give (E)-3-(5-carbamic-[1,1,-biphenyl]-2-yl)ethyl acrylate (652). Step C. Ethyl (E)-3-(5-carbyl-[1, fluorenyl-biphenylyl)-propyl acetoate (652) (420 mg, 1.57 mmol) in ethanol (6 mL) In the solution, pd/c (42 mg, 10% Degussa type) was added. A hydrogen cylinder was added and the reaction was evacuated and backfilled three times with hydrogen. The reaction was stirred at room temperature overnight, filtered through a pad of Celite </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> And M5-hydroxy-[ΐ,ι·-biphenyl]_2_

Intermediate 44 5-Alkyl-7-(methyl-methyl)_2,2-dimethyl-depleted hydrazine I T-based furan-3(2H)-one (657)

Cl 654 S0CI2 step c

CuS04· 5H20 Step A

Cl Cl 657

Step 丨 BH3 · THF 〇

Cl 656 Step A: 5-Phenyl 2,2-dimethyl is dihydrobenzo benzoic acid (IV) (2.39 g '10.5 mmol), potassium persulfate (8 % g, 31 6 mmol) A solution of copper sulfate pentahydrate (2.62 g, 10.5 mmol) and acetonitrile/water (1.1) (9 mL) was heated under reflux for 1 hour. Ethyl acetate and water were added, and the liquid layer was separated. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo to afford &lt;RTI ID=0.0&gt; 3-Dihydro benzofuran-7-carboxylic acid (655) as a yellow solid. Step B: 5-Chloro-2,2-dimercapto-3-one-2,3-dihydrobenzofuran-7-carboxylic acid (655) (2.67 g, 1 U mmol) in tetrahydrofuran In a solution (56 ml), BH3·tetrahydrofuran (1 U mL, iu mmol) was added dropwise and stirred overnight. The reaction was quenched with ice and methanol then extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate then dried over sodium sulfate, filtered and evaporated. The crude compound was purified by flash column chromatography eluting with EtOAc (50%) eluting with EtOAc (50%) to afford 5- chloro _7_ (by 149105-sp-20100806.doc-155-201200505 -2,2-Dimercaptofuran-furan-3(2H).one (656) (278 mg). The saturated sodium bicarbonate layer was acidified to recover the starting acid (655) (1.68 g). Step C: 5·V-7-(hydroxymethyl)-2,2-dimethylbenzofuran_3(2H)-one (656) (278 mg, 丨.23 mmol) The solvent-free solution of thionylene dichloride (5 ml) was stirred at room temperature for 48 hours. The reaction was concentrated to give 5-carbaz-7-(chloromethyl)-2,2-dimethylbenzofuran-3(2H)-one (657) as a brown/yellow solid. Intermediate 45 7-deodorant methyl)-5-sayyl-2,2-dimethylbenzofuran_3 (2 ketone (660)

Step A: 4-yl-2-indole (10 g '79.28 mmol), 2-methylisobutyric acid ethyl ester (23.2 ml, 158.6 mmol), potassium carbonate (21 9 g, A solution of 158 6 mmoles and DMSO (80 mL) was stirred at room temperature for 72 hours. Water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (3 mL EtOAc) and the combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was purified by flash chromatography on EtOAc (EtOAc) eluting ester. Ethyl 2-(4-fluoroyl-2-mercaptophenoxy)-2-methylpropanoate (13.3 g, 55.44 mmol) in tetrahydrofuran (4 mL) with decyl alcohol I49105-sp-20100806 .doc • 156· 201200505 (10 ml), add ν &amp; η (6 66 g, 166.32 mmol) in water (14 ml) and stir overnight. The volatiles were removed in vacuo and acidified using concentrated HCl. The milky white solution was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo to give 2-(4-diyl-2-methylphenoxy)-2-methylpropanoic acid (658) ), as a yellow solid. Step B··In the solution of 2_(4-fluorophenylnonylphenoxy)_2-mercaptopropionic acid (658) (5 g, 23.6 mmol) in tetrahydrofuran (5 mL), Catalyzed DMF with chlorinated grass mash (25 ml, 28 3 mmol). The reaction was allowed to warm to room temperature, stirred for 1 hour and concentrated in vacuo. This oil was dissolved in dichloromethane (50 mL), cooled to &lt;RTI ID=0.0&gt;&gt; The reaction was allowed to warm to room temperature overnight. Ice water was added and the dichloromethane was removed in vacuo. The aqueous phase was extracted with ethyl acetate (3 mL EtOAc)EtOAc. The crude compound was purified by flash chromatography on silica gel eluting with EtOAc (20%) to afford 5-fluorophenyl-2,2,7 trimethylbenzofuran-3(2H). (659). • Step C: The 5-fluoro-2,2,7-trimethylbenzopyrano- 3 ketone (659) (1 〇〇 mg, 0.515 mmol), N-bromo-amber A solution of hydrazine imine (1 〇〇 8 g, 0.567 mmol), gasified benzamidine (12 mg, 〇〇〇 5 mmol) and carbon tetrachloride (2 ml) was heated under reflux overnight. . Saturated sodium bicarbonate was added, and extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash chromatography on silica gel eluting with hexanes EtOAc (5%) to give 7-(bromomethyl)-5-formyl-2,2-dimethylbenzofuran -3(2Η)-ketone (660).

S 149105^sp-20100806.doc •157· 201200505 Intermediate 46 3-(5-Fluoro-4-hydroxy-2-propylphenyl)propanoic acid ethyl ester (666)

Step A-F: Compound (666) was prepared in a similar manner as described for the synthesis of (585). Intermediate 47 5-Bromo-7-(methylmethyl)-2,2-dimethyl-2,3-dihydrobenzofuran (670)

Step A: Add bromine (0.8 mL, 15.6 mmol) in acetic acid (6 mL) to 2,2-dimethyl-2,3-dihydrobenzene using a dropping funnel at 0 °C. Furan-7-carboxylic acid (1 g, 5.20 mmol) in a solution in acetic acid. The reaction was allowed to warm to rt and stirred overnight. Add 2M sodium sulfite solution until all red color disappears. The volatiles were removed in vacuo and dioxane was added and the layers were separated. The organic phase is washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-bromo-2,2-dimethyl-2,3-I49105-sp-20100806.doc - 158- 201200505 Dihydro benzofuran-7-carboxylic acid (667). Step B: Slowly add sulfinium dichloride (〇·6 ml, 812 mmol) to 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran_7_ Carboxylic acid (667) (u gram, 4·06 mmol) in methanol (41 mL). After refluxing for 3 hours, the solvent was removed in vacuo to give methyl 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (668). Step C: methyl 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (668) (466 mg, 1.63 mmol) in tetrahydrofuran (16 mL) Solution in solution • Add LAH (1 ml, 1.96 mmol) at 0 °C. The reaction was stirred at 0 C for 1 hour and quenched with 0.2 mL water, EtOAc EtOAc (EtOAc) The reaction was allowed to warm to rt and diluted with ether. Add a sulfuric acid lock, filter the solution, wash with a riddle, and remove the solvent in vacuo to provide (5-actino-2,2-dimethyl-2,3-dihydrobenzobenzoate-7 -yl)methanol (669).

Step D: (5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methanol (669) (390 g, 1.51 house Moule) in the second gas In a solution of Hyun (15 ml), sulfite (二56 ml, 7.58 mmol) was added. The reaction was stirred at room temperature for 2 hours and then concentrated to give &lt;RTI ID=0.0&gt;&gt; 〇). Intermediate 48 3 (3-((-Methylamino)indolyl)-4-hydroxyphenyl)_2-mercaptopropionic acid ethyl ester (673) Η〇·&quot;

Ph;i? lT〇Et

671 ‘〇 Hz· Pd/C Step B H0

672 149105-sp-20100806.doc -159· 201200505

K2co3 甲笨 HO

Step A: Compound (671) was prepared in a similar manner as described for the synthesis of (515). Step B: Compound (672) was prepared in a similar manner as described for the synthesis of (513). Step C · 3-(4-Phenyl)-2-methylpropanoic acid ethyl acetate (672) (150 mg, 〇72 mmol), potassium carbonate (149.3 mg, 1.08 mmol) in toluene ( N,N-dimethylmethylene ammonium iodide (173.2 mg, 〇94 mmol) was added to the solution in 7 ml) and stirred for 72 hours. Water was added and the reaction was extracted with ethyl acetate. EtOAc was combined and evaporated. The crude compound was purified by flash chromatography on silica gel eluting with EtOAc (50%) to give 3-(3-((diamino)methyl)- 4 phenyl) - ethyl methacrylate (673). Intermediate 49

149105-sp-20100806.doc -160- 201200505 Step A: in 2,2-dimethyl-2,3·dihydrobenzopyrene _7-butyric acid vinegar (ι克, 4.54 mmol) The solution in trifluoroacetic acid (7 ml) was intrinsic. Underarm ’ Slowly add nitric acid (1.36 ml). The reaction was stirred for one hour and then at room temperature for 30 minutes. The reaction was added to ice, and the solid formed was collected by filtration and washed with water to afford 2,2-di-n-yl-5-nitro-2,3-dihydrobenzofuran-7-carboxylic acid Ethyl ester (674), a yellow solid 〇〇 2 g, 83%). Step B: 2,2-Dimethyl-5-ylidyl-2,3-dihydroindolofuran_7_Resinic acid (674) (1 _02 g '3,84 mmol) in ethanol (4 〇 ml) in the solution, add

Pd/C (l〇() mg, 1G% Deg position). A hydrogen cylinder was added and the reaction was evacuated and backfilled three times with hydrogen. The reaction was stirred at room temperature overnight, filtered through a pad of Celite, and concentrated in vacuo to give &lt;RTI ID=0.0&gt; Ester (675) (899 mg, 99%). Step C · 5-Amino-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid ethyl ester (675) (300 mg, 1.28 mmol), ortho-decanoic acid A solution of ethyl ester (42 ml, 2 55 mmol), sodium azide (124.8 mg, 1_92 mmol) and acetic acid (12 mL) was heated at 100 t for 2 h. And add water. The aqueous phase was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) 2,3-Dihydrobenzofuran_7-carboxylic acid ethyl ester (676) (184 mg, 50%). Step D ··2,2-dimercaptotetrazole+yl)_2,3_2 Ethyl benzofuran _7_carboxylate (676) (182 mg, 0.631 mmol), lithium hydroxide (1 〇 6 mg, 2.53 mmol), methanol (1 mL), tetrahydrofuran (1 mL) The solution of water (4 ml) 149105_sp-20100806.doc -161 - 201200505 was heated at 50 ° C for 1 hour. In the true Yun Shu _ remove volatiles and add 2nhC1. The white solid was collected by hydrazine and washed with water to provide η dimethyl·5 two-membered yl) _2,3•dihydrobenzohydo acid _ (say milligrams, 83°/.). Step Ε: 2,2-Dimethyl_5_(1Η_四哇+基)_2,3 2-gas benzophenone. A solution of _7 acid (677) 035 mg '0.519 mmol), Ν•methylmorpholine (57 μl, 0.519 mmol) and tetrahydrofuran (〇 〇 ml) is in 〇. Isobutyl chloroformate (68 μL, 0.519 mmol) was added under the arm and stirred for 2 hours. Add sodium borohydride (58. 9 mg, 丨 brother mM) in water (3 ml) and stir for 1 hour at room temperature! hour. The reaction was concentrated in vacuo and water was added. The aqueous phase was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered, and evaporated. The crude compound was purified by flash column chromatography on silica gel eluting with hexane and Et EtOAc (6 〇%) to give (2,2-dimethyl-5·(1Η•tetrazole small) _2 , 3 dihydrobenzofuran _7-yl)methanol (v)^ (77.8 mg, 61%). Intermediate 50 Ester (681) 3-(3,5-Difluoro-4-hydroxyphenyl)_2-ethoxypropionic acid B α PPha

BnO

Step A - 〇Y^OE 丨 cr 679

Step B

PPh3 DBU· THF BnO

0E1 680 O H2, Pd/c F, ~- Step C Ϊ

OEt 681 Step A: Ethyl 2-chloro-2-ethoxyacetate (10 g, 6 〇 mmol) at I49l05-sp-2〇l〇〇8〇6,d〇c -I62· 201200505 To the solution in chloroform (303⁄4: liter), triphenylphosphine (i57 g, 卯mole) was added and allowed to mix overnight to /. The solvent was removed in vacuo and the B domain was added. The solvent was again removed and dried under high vacuum to give diethoxy-2-ethylideneethyl)triphenyl chloride (21 g, (yield) yield) (679) as a foamy solid. . Step B: Add DBU (0.67 ml) to a solution of (1,2-diethoxy-2-ketoethyl)triphenyl scale (1.61 g, 3.76 mmol) in tetrahydrofuran (56 mL). , 4.51 mmol, and the reaction was stirred at room temperature for _ 10 minutes. 4_(Benzyloxy)-3,5-difluorobenzaldehyde (1·4 g, 5.64 mmol) was added in one portion, and the mixture was stirred at room temperature for 18 hr. The / granules were removed in vacuo, acetonitrile was added and the solid was filtered. The filtrate was concentrated in vacuo, and the residual oil was purified by flash column chromatography ( </ </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -3,5-Difluorophenyl)-2-ethoxyethyl acrylate (68 〇). Step C · · (Z)-3-(4-(decyloxy)-3,5-difluorophenyl)-2-ethoxyethyl acrylate (680) (1.3 g, 3.59 mmol) In a solution of ethanol (25 ml), Pd/C (140 mg, 10% Degussa type) was added. A hydrogen cylinder was added and the reaction was evacuated and backfilled three times with hydrogen. The reaction was stirred overnight at room temperature, filtered through a pad of celite, and concentrated in vacuo to give 3-(3,5-difluoro-4-hydroxyphenyl)-2-ethoxypropanoate Ester (0.81 g) (681). Intermediate 51 2-(4-Hydroxy-3-indolylphenoxy)acetic acid ethyl ester (682)

K2C〇3 ACN. 80°C . -Λ, 682 2-methyl-1,4-diol (5 g, 40.2 mmol), 2-bromoacetate (ll 149105-sp-20100806.doc • 163-201200505 Equivalent) and a mixture of acetonitrile (2 equivalents) in acetonitrile (50 mL) at 8 Torr. Heat under 18 for 18 hours. The reaction was allowed to cool to room temperature and the acetonitrile was removed in vacuo. Water was added and the crude residue was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAc (EtOAc EtOAc) Intermediate 52 2-(4-Hydroxy-2-indolylphenoxy)acetic acid ethyl ester (685)

Step 685: A. 1-(4-Phenyl-3-methylphenyl)ethanone (5 g, 33.3 mmol), 2-bromoacetic acid ethyl ester (1.1 eq.) and carbonic acid planer (2 equivalents) The mixture in acetonitrile (2 mL) was stirred at room temperature overnight. The acetonitrile was removed in vacuo and the crude oil was dissolved in ethyl acetate (50 mL) and washed with &lt;RTIgt;1&lt;/RTI&gt; The organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo to afford ethyl <RTIgt; Step Β 2-(4-Ethyl-2-methylphenoxy)acetic acid ethyl ester (6 milk) (8 78 g, 37 mmol), mCPBA (2 equivalents) and p_Ts0H monohydrate (〇 15 equivalents) The solution in dioxane (10 ml) was heated under thieves overnight. The reaction was cooled to room temperature and 1 MKI (2×200 mL), 5% NaHSQ3 (2×15 () U9105-sp-20100806.doc -164 - 201200505 ml) and water (200 ml) for washing. The organic layer was dehydrated and dried over sodium sulfate and concentrated in vacuo. Purification of crude material by Shixi gum chromatography (9)

EtOAc in hexanes 6 to provide 2-(4-ethoxylated hydroxy-m-methyl phenoxy succinate (684) (72%). Step C. 2-(4-Ethyloxy-2 _Methylphenoxy)acetate ethyl ester (caffe) (6 79 g, 27 mmol) added sodium methoxide (U equivalent) in a solution of anhydrous methanol (15 mL), and the reaction was in the room Stir gently for 3 hours. Quench the reaction with im HC1 and remove volatiles in vacuo. Dissolve the oil in ethyl acetate _ml) with water (2X_ml) and brine (10) ML) wash. The organic layer was dried with sodium sulfate, filtered and evaporated tolulululululululululululululululu Intermediate 53 2-(4-Hydroxyphenoxy)acetic acid ethyl ester (688)

686

NaOMe Step C

s 〇 Et mCPBA TsOH Step B γ 〇ΛΓ 688 Step A-C: Compound (688) was prepared in a similar manner as described for the synthesis of (685). Intermediate 54 5-Chloro-7-(methylmethyl)-2,3,3-tridecyl-2,3-dihydrobenzindole. South (693) 149105-sp-20100806.doc •165- 201200505

Step A-E: Compound (693) was prepared in a similar manner as described for the synthesis of (5). Intermediate 55

, iT 3-(4-hydroxyphenyl)-4-indolyl valerate (695)

»2丨 Pd/C Step IB

Step A-B: Compound (695) was produced in a similar manner as described for the synthesis of (11). Intermediate 56 5-hydroxy-2,3-dihydro-1H-indole-2-carboxylic acid decyl ester (697), 〇

H2 hcic^

Step A: Methyl 5-methoxy-1-keto-2,3-dihydro-1H-indole-2-carboxylate (5.5 g, 25 mmol) in acetic acid (0.64M) and perchlor. The mixture in acid (14.9 M) was suspended in a pressure vessel and shaken under a hydrogen atmosphere (30 psi) for 4 hours. The mixture was filtered through a pad of celite and washed with a gas. The organic phase was washed with water (5X) until the pH was neutral and then washed with brine. The organic layer 149105-sp-20100806.doc •166- 201200505 was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by ruthenium chromatography to give 5: methoxy- 2,3-dihydro-lh-indole-2-carboxylate (696) (46%).

Step Β. 5-methoxy-2,3-dihydro-1h-indole-2-carboxylic acid decyl ester (696) (2.35 g, 11_4 mmol) in anhydrous di-methane (4 mL) It is cooled to _78. Add three evolutionary boron (15 equivalents) in the solution. The reaction was stirred at _78 &lt;&gt;c for 30 minutes, at 0 C for 2 hours, and at room temperature overnight. The reaction mixture was allowed to cool to 〇 c and the reaction was quenched slowly with methanol. After stirring for 15 minutes, a saturated sodium hydrogencarbonate solution was slowly added to the mixture and placed in a mash. . Stir for 30 minutes. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-hydroxy-2,3-dihydro-l-indole-2-carboxylic acid Ester (697). Intermediate 57

Ethyl 3-(4-3⁄4-yl-2-isopropoxyphenyl)propanoate (7〇〇)

700 Step A: 4_(Benzyloxy)-2-hydroxybenzaldehyde (1 g, 4.38 mol), 2_propidium iodide (1.2 eq.) and potassium carbonate (25 eq.) in acetone (4 mL) The mixture was refluxed overnight. The reaction was cooled to room temperature and filtered through a pad of Celite pad and concentrated to dryness. The crude material was subjected to flash column chromatography, and purified with ethyl acetate and hexane to provide 4-(hydroxy)-2-isopropylidene 9 benzophenone 149105-sp-20100806.doc-167-201200505 aldehyde ( 698) 〇Step Β · 4-(decyloxy)_2_isopropoxy oxo (Liu) (gamma, 1.776 mmol) with (ethoxycarbonylmethylene)triphenylphosphorane (V) The solution in the benzene was heated at 100 ° C overnight. The reaction was allowed to cool to room temperature and concentrated in vacuo. The crude material was purified by silica gel chromatography (〇_5〇% Et 〇Ac in hexane) to give (Ε)-3·(4-(benzyloxy)_2_isopropoxyphenyl)acrylic acid Ester (699). Step C: Add pd to Ethyl (3_(o-oxy)_2_isopropoxyphenyl)acrylate (699) (530 mg, L56 mmol) in ethanol (12 mL) /c (0'5 eq., 10% DegUSSa type). Add a hydrogen gas bottle and fill the reaction with pomelo gas and fill it back three times with hydrogen. The reaction was stirred at room temperature overnight, filtered through a pad of Shiyoshi, and Concentration in vacuo gave ethyl 3-(4-hydroxy-2isopropoxyphenyl)propanoate (700).

CI Intermediate 58 5-Alkyl-7-(Chloromethyl)-2-mercaptobenzopyrene South (705)

Step Α-Ε: Compound (705) was prepared in a similar manner as described for the synthesis of (5). 149105-sp-20100806.doc -168- 201200505

Intermediate 59 3-(4-Phenyl-based) ethyl propionate (7〇8)¥ 丫丨

706 H2

Pd/C Step B \〇

707

Step A

708 Step A-C. Compound (708) was prepared in a similar manner as described for the synthesis of (542). Intermediate 60 H2-((Dimethylamino)indolyl) 4-hydroxyphenyl)propanoic acid ethyl ester (711)

^Br BnBr

KjC〇3 Step A

Br ^Y〇Et〇r〇~ shouting base) 3 7〇9 Et3N, DMF step B

710

IN 71 Step A: 4-Bromo-3-((dimethylamino)methyl)phenol (4 g, 17.4 mmol), evolution hydrazine (2 eq.) and potassium carbonate (3 eq.) in DMF ( The mixture in 100 ml) was stirred at 80 ° C overnight. The reaction mixture was allowed to cool to room temperature and then quenched with water &lt The combined organic layers were washed with brine <RTI ID=0.0> The crude material was purified by chromatography (0-50%EtOAcEtOAcEtOAc) elute (98%). Step B: Compound (71〇) is a similar formula as described for (1〇) synthesis

S I49l05-sp-20l00806.doc -169- 201200505 Manufactured. Step C: Compound (711) was prepared in a similar manner as described for the synthesis of (11). Ethyl 3-(4-hydroxy-2-mercaptobenzofuran-7-yl)propanoate (716)

K2C〇3 Intermediate 61

Step A hco2h Step C

Step E 716 Step A-C: Compound (714) was prepared in a similar manner as described for the synthesis of (3). Step D: Compound (715) was prepared in a similar manner as described for the synthesis of (537). Step E: Compound (716) was prepared in a similar manner as described for the synthesis of (513). Intermediate 62 5-Alkyl-7-(gas sulfhydryl)-3,3-dimethyl-2,3-dihydrobenzofuran (725)

149105-sp-20100806.doc -170- 201200505 Step A: a solution of 4-chloro (12.6 g, 〇 1 mol) and 3_gas-based 2-methyl-propene (10.8 g, 0.12 mol) Concentrated sulfuric acid (5 g, 〇〇5 mol) was added and stirred at 〇C for 1 hour. The mixture was diluted with cold water and extracted with ether. The ether-containing extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography on silica gel to afford 4-[pi]-2-(1-chloro-2-methylpropan-2-yl) (721). Step B: Add 4-chloro-2-(1-carbyl-2-mercaptopropyl-2) to a suspension of NaH (1.44 g, 36 mmol) in anhydrous tetrahydrofuran at 0 °C - 基) 纷(721) # (6.6g, 30.0 millimoles). The reaction mixture was stirred at 0 ° C for 1 hour. The reaction was quenched with decyl alcohol' diluted with water and extracted with ether. The hydrazine-containing extract was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give &lt;RTI ID=0.0&gt;&gt;&gt; Step C 'Compound (723) is prepared in a similar manner as described for the synthesis of (545). Step D: Compound (724) is prepared in a similar manner as described for the synthesis of (546). Step Ε: Compound (725) was prepared in a similar manner as described for the synthesis of (511). Intermediate 63 3,3-di-deuterated-5-chloro-7-(chloromethyl)-2,2-dimercapto-2,3-dihydro accompaniment d South 149105-sp-20! 00806.doc -171 - (730) 201200505

Ci ci 726 727

728 72d 730 Step A: Compound (726) was prepared in a similar manner as described for the synthesis of (655). Step B: Lithium aluminum oxide (0.21 g, 5.0 mmol) in dry ether (10 mL) was stirred under nitrogen for 15 min and slowly added with aq. 0_7 grams, 5.5 millimoles). Five minutes after the addition, 5-chloro 2,2-dimercaptobenzofuran-3(2H)-one (726) (1 g '5 mmol) with aluminum sulfide (〇7 g '5.5 A mixture of millimolar in anhydrous ether (20 mL) was added to a solution of the mixed metal hydride. The reaction mixture was stirred vigorously <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; The reaction mixture was further diluted with water (25 liters) and the aqueous layer was extracted with four portions (4 X mL). The combined organic layers were washed with water, 1% by weight sodium hydrogen carbonate solution and water, and dried over sodium sulfate. The solvent is removed in a vacuum, and the residue is purified by flash chromatography on a silica gel to give 3,3-dihydrocarbyl-2,2-indolyl-2,3-dihydrobenzene. And hehe. South (727). Step C: Compound (728) was prepared in a similar manner as described for the synthesis of (545). Step D: Compound (729) was prepared in a similar manner as described for the synthesis of (546). 149105-sp-20100806.doc -172· 201200505 Step E: Compound (730) was prepared in a similar manner as described for the synthesis of (511). Intermediate 64 7-(Chloromethyl)-5,6-difluoro-2,2-dimethyl-2,3-dihydrobenzofuran (737)

Step E 733

~KzCOa DMF Step C

735 734

Step A: 3,4-difluorophenol (2 g, 15.37 mmol), 3-oxo-2-mercaptopropene (1.66 ml, 16.91 mmol) and potassium carbonate (3.2 g, 23_06 mmol) The mixture in DMF (10 ml) was stirred at 85 for 6 hours. The mixture was passed through and the filtrate was evaporated to dryness. The residue was purified by flash column chromatography eluting with hexane-EtOAc (2:1) to afford 1,2-difluoro benzene (2- (y) 78 grams '63%). WNMRGOOMHaCDCIJ (5 7.05 (q, J = 9.5 Hz, 1H), 6.76-6.71 (m, 1H), 6.63-6.60 (m, 1H), 5,07 (s, 1H), 5.00 (s 1 Η) 4.38 ( s, 2H), 1.82 (s, 3H) Step B: In a solution of the second-butyllithium in cyclohexane (6.7 ml) and anhydrous tetrahydrotetramine (15 ml), in - At 75 ° C, 1,2_di-milo-4_(2-methylallyloxy)benzene (731) (1.6 g, 8.68 mmol) was added. The resulting mixture was 149105-sp-20100806.doc - 173· 201200505 The mixture was stirred at -75 ° C for 2.5 hours, then transferred to a round bottom flask containing dry ice. The resulting mixture was shaken for 5 minutes, and water ((7) ml) was added dropwise. The mixture was acidified using concentrated hydrochloric acid. To pH1, and extracted with Et 〇Ac (8 mL χ3). The organic phase was washed with brine (60 mL Χ2), water (6 mL) and dried over anhydrous sodium sulfate and solvent An oil of 2,3-difluoro-6-(2-methallylhydrazino)benzoic acid (732) (1 9 g) was obtained, which was used directly in the next step without further purification. Step C · 2,3-Difluoro-6-(2-decallyloxy)benzene Citrate (732) 0 45 g, 6.35 mmol, 3-chloro-2-methylpropene (0.77 ml, 7 62 mmol) and potassium carbonate (1.76 g, 12.7 mmol) in anhydrous DMF The mixture was stirred overnight (yield: EtOAc). The mixture was filtered and evaporated to dryness. The residue was purified by flash chromatography, eluting with hexanes EtOAc (4:1). To provide 2,3-difluoro-6-(2-methylallyloxy)benzoic acid 2-tolyl (733) (1.55 g, 87%). iHNMR (400 MHz, CDCl3) 714 714 (q J = 9 5Hz lH), .6.63-6.60 (m, 1H), 5.09 (s, 1H), 5.06 (s, 1H), 4.98 (s, 2H), 4.78 (s, 2H), 4.45 (s, 2H ), 1.81 (s, 3H), 1.79 (s, 3H). Step D · 2,3-Difluoro-6-(2-methylallyloxy)benzoic acid 2-tolyl (733) (L53 g, 5.42 mol) in _ (35 ml), heated in a microwave at 200 C for hrs. The solvent was removed in vacuo to provide 2,3-difluoro-6 2-Hydroxy-5·(2-decenyl)benzoic acid 2- decyl propyl ester (734) (1 53 g) which was used directly in the next step without further purification. Step Ε: 2,3-difluoro-6-hydroxy-5-(2-methylallyl)benzoic acid 2·methylallyl ester (734) was refluxed in 96% formic acid (15 ml) solution for 22 hours. . The solvent was removed in vacuo, and the residue was purified by flash column chromatography eluting with hexanes EtOAc s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s 6-Difluoro-2,2-dimercapto-3H-benzofuran-7-rebel (735) (0.76 g, 61 〇/〇). 1 H NMR (400 MHz, DMSO-d6) 6 7.43 (t,J = 9_2 Hz, 1H), 2.98 (s, 2H), 1.41 (s, 6H). Step F: Addition of 1.0 M side-burning tetrahydrogen to 5,6-difluoro-2,2-dimercapto-3H-benzofuran-7-carboxylic acid (735) (0.75 g, 3.29 mmol) The complex solution (12 ml) was stirred and the mixture was stirred at room temperature overnight. The reaction was cooled to 〇 ° C, acidified to pH 1 with 5N HCl, and then neutralized to pH 8 with 5N NaOH. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The product was purified by preparative HPLC to give (5,6-difluoro-2,2-dimercapto-3H-benzofuran-7-yl)methanol (736) (0.4 g, 57%). 1 H NMR (400 MHZ, DMSO-d6) δ 7.18 (t, J = 9.0 Hz, 1H), 4.38 (s, 2H), 2.97 (s, 2H), 1.40 (s, 6H). Step G: (5,6-Difluoro-2,2-dimethyl-3H-benzofuran-7-yl)methanol (736) (0.18 g, 0.84 mmol) in anhydrous dichloromethane (5 In the solution in ML), SOC12 was added dropwise under 〇C. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was taken in EtOAc EtOAc. The &gt; trough solution was washed with water (30 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to give a solid W chloromethyl &lt;5,6 difluoro-2,2-dimethyl 2,3-Dihydrobenzopyran (737) (0.194 g, 99%). Intermediate 65 3_(7-Pyryl-2,3-dihydro-1H-indole-4-yl)propionic acid ethyl ester (74 〇) I49105-sp-20100806.doc -175- 201200505 /〇丫Cl

740 Step A: Compound (738) was prepared in a similar manner as described for the synthesis of (545). Step B: Compound (739) was prepared in a similar manner as described for the synthesis of (537). Step C: Compound (740) was prepared in a similar manner as described for the synthesis of (513). Intermediate 66 0 741 742 Step A: Compound (741) was prepared in a similar manner as described for the synthesis of (537). Step B: Compound (742) was prepared in a similar manner as described for the synthesis of (513). Intermediate 67 ethyl 3-(2-bromo-4-hydroxy-5-methoxyphenyl)propanoate (742)

p&gt;^〇E, Ph Ο

Step A

OEt H2, Pd/C

Step JWB

2-(5-Hydroxy-2,3-dihydro-1H-indol-1-yl)acetic acid (23) ο

149105-sp-20100806.doc -176- 201200505 The intermediate is formed by combining the intermediate 68 2_(5-hydroxy-2,3-dihydro-1H by the method disclosed in WO 2〇〇4/〇ιΐ445 -茚-1-yl)acetic acid (24)

OEt 24 The above intermediate is synthesized by the method as disclosed in EP 234872.

25 methyl-nitrogen-benzidine-4-hydroxy-acid methyl vinegar (25) intermediates are synthesized by the method as disclosed in WO 2007/030061. Intermediates 70 and 71 The following intermediates are purchased from commercial sources. And used to synthesize one or more representative compounds of the invention.

26

27 intermediate 72 (2-methylbenzo[d]carbazol-7-yl)methanol (744), 0H Me

OEt

OEt

Et〇-|-〇Et V-O 〇 V-o

LAH, nh2 ptsa

Step A ^ Step B 743 744 Proacetic acid Step A: 3-amino-2-hydroxybenzoic acid, 6 5; 3 mmol;

S 149105-sp-20100806.doc -177· 201200505 A solution of triethyl vinegar (4 ml) and p-toluenesulfonic acid (4 mg) was heated at 1 ° C for 18 hours. The reaction was concentrated in vacuo, and the crude material was purified by flash column chromatography eluting with EtOAc EtOAc (EtOAc) p-Sodium-7-carboxylate (743) (1-27 g, 95%). Step B: In a solution of ethyl 2-methylbenzoxazole-7-carboxylate (743) (1.27 g, 6.19 mmol) in tetrahydrofuran (61 mL). Under the armpits, lithium aluminum hydride (7.43 ml '7.43 mmol, 1 M in tetrahydrofuran) was added. The reaction was stirred at 0&lt;0&gt;C for 1 hour and then EtOAc (EtOAc)反应H and 1.8 ml of water quenched the reaction. The reaction was allowed to warm to rt and diluted with ether. Magnesium sulfate was added, and the solution was filtered, washed with diethyl ether and solvent was evaporated in vacuo to afford (2-methylbenzo-carbazol-7-yl)methanol (744) ( 〇 687 g, 68%). Intermediate 73 2-(6-Methoxybenzofuran-3-yl)acetate (745) OMe ΗΟ-^^-Ο 745 Step A · 2-(6-decyloxybenzopyrene) To a solution of acetic acid (6 g, 2 9 mmol) in anhydrous dichloromethane (2 mL) was added boron tribromide (1.5 eq. The reaction was stirred at _78t for 3 hrs for 2 h at EtOAc then EtOAc (EtOAc) EtOAc. After stirring for 15 minutes A, a saturated sodium hydride solution of sodium hydride was slowly added to the mixture, and it was stirred under a mash for a minute. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with ethyl acetate, EtOAc (EtOAc), EtOAc (EtOAc) The combined organic layers were dried over sodium sulfate and concentrated to give &lt;RTI ID=0.0&gt;

(R)-4-benzyl _3_((r)_3_(4_Phenyl)-2-methylpropenyl)tetrahydrol U-butan-2-one (748)

Ph 748

747 Ph Step A. In a solution of (4-(decyloxy)phenyl)methanol (214 g, _mole) in diethyl ether (: 03⁄4 liter). . Phosphorus tribromide (g, 4 〇 millimolar) was added and mixed at (TC for 3 Torr, and at room temperature for 3 hours. The reaction was quenched with water and the layers were separated. Layer with water (2x400 ml),

Wash with saturated sodium bicarbonate (2 x 400 mL) and brine. The ether layer was dehydrated with sodium sulfate to dry the '(4)' and concentrated in vacuo to give a (n-oxy(tetra)yrosyl)benzene (746). Step B. In a solution of (r)_4_mercapto_3_propenyltetrahydropyrene 2_嗣 (17 g, 72 8 mol) in tetrahydrofuran (2 ml) Under _78t: sodium bis(trimethyl decyl)alkylamine (8 mM, 79.4 mmol) was added and stirred for 1 hour. A solution of 1-(thyloxy)_4_(indolyl)benzene (hydrazine) (2 g, η 2 mmol) in tetrahydrofuran (50 ml) was slowly added to _78 〇c. The oxazolidinone/mixture was allowed to warm to room temperature overnight. Remove the solvent in a vacuum,

S 149105-sp-20100806.doc -179- 201200505 and the residue was dissolved in ethyl acetate. The organic layer was washed with water, brine, dehydrated and dried with sulfuric acid steel, and condensed in a vacuum. The crude person was subjected to flash column chromatography on Shishijiao, and purified by &amp; burning and Et〇Ac (2〇%) to obtain (R)«yl-3-((R&gt;H4_(Oxygen) Phenyl)phenyl)propenyl)tetrahydrooxazol-2-one (747). Step C: Compound (748) is prepared in a similar manner as described for the synthesis of (513) &quot; intermediate 75(S)-4-mercapto-3-((S)-3-(4-hydroxyl) Phenyl)_2_methylpropanyl)tetrahydrocarbazole winter _ (7s^

, OH PBr3, Br ΒπΟ〆 749

NaHMPS Step B

BnO

Step A BnCT H2 Pd/C Step C

Step A · The synthesis of the intermediate (749) was previously described in the intermediate. Step B: Compound (750) is prepared in a similar manner as described for the synthesis of (747). 'Step C: Compound (751) was prepared in a similar manner as described for the synthesis of (513). Intermediate 76 and intermediate 77 gas 唾 唾 唾 丙 ( (R)-4-罕基-3-((S)-3-(3,5-difluoro-4-hydroxyphenyl)_2·A Benzyl hydrazino)tetra-2-one (754) and (8) hydrazino-3-((R)-3-(3,5-difluoro-4-hydroxyphenyl)_2-methyl) tetrahydrogen Sit-2-one (755) 149105-sp-20100806.doc •180- 201200505

Step A. Ethyl 3-(3,5-difluoro-4-hydroxyphenyl)_2-methylpropanoate (9) (930 mg, 3.81 Torr) with potassium carbonate (1. 〇 5 g Benzyl chloride (〇53 ml, 4 57 mmol) was added to a mixture of DMp (8 mL) and stirred at 50 ° C overnight. The reaction was diluted with water and extracted with ethyl acetate (3 EtOAc). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc EtOAc EtOAc EtOAc ). Step B · Ethyl 3-(4-(octyloxy)_3,5-difluorophenyl)-2-methylpropanoate (752) φ (1·09 g, 3.26 mmol) in tetrahydrofuran (10 ml Lithium hydroxide (547 mg, 13 〇 4 mmol) was added to a mixture of water (10 ml) and methanol (20 ml), and the solution was stirred overnight at 8 〇t. The reaction was concentrated, acidified with 1N HCI andEtOAcEtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford &lt;RTI ID=0.0&gt;&gt; Step C is 3-(4-(decyloxy)-3,5-difluorophenyl)-2-methylpropanoic acid (753) (〇 99 g, 3.23 mmol) in tetrahydrofuran (2.5 mL) In the solution, under 〇&lt;t 149105-SP-20100806.doc -181 . 201200505, add triethylamine (0.50 ml, 3 57 mmol) and gasified trimethylacetamidine (〇·44 ml, 3.57) Millions) and the reaction was stirred for 3 minutes. In another burning, '(R)-4-mercaptotetrahydro P No. _2_嗣 (0.48 g, 2.69 mmol) was dissolved in tetrahydrofuran (4 ml) and cooled to _78〇c . n-Butyllithium (L77 mL, 2.69 mmol, 1.52 M in hexanes) was added and the mixture was stirred for 30 min. Add a solution of 3-(4-(,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The mixture was stirred for 3 hours' and at room temperature for 30 minutes. The reaction was quenched with saturated ammonium sulphate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane and EtOAc to give two diastereomers (8) _ _ _ _ _ _ _ 3 _ (s) _ 3 _

I (4-(+oxy)-3,5-monofluorophenyl)_2-methylpropanyl)tetrahydropurine. Sitting _2_ketone with (R)-4-pyringyl-3-((R)-3-(4-(indicyl)_3,5-difluorophenyl)_2-methylpropanyl) Hydrocarbazol-2-one. The sulfhydryl group is removed as Pd/C under hydrogen atmosphere as described above for the synthesis of compound (9) to provide (R)_4_fluorenyl winter (3,5•difluoro-4-hydroxyphenyl)-2 -Methylpropenyl)tetrahydrocarbazole-2-ketone (754) and (R)_4 fluorenyl-3-((r)_3_(3,5·-fluoropiperidinyl)-2-methylpropane Stuffed base) tetrahydro p-salt 2-phenone (755). Intermediate 78 and intermediate 79 (R)-4-mercapto-3-((S)-3-(3-fluoro-4-hydroxyphenyl)_2-methylpropanyl)tetrahydrocarbazole- 2-嗣(759) and (R)-4-yopyl-3-((R)-3-(3-fluoro-4-hydroxyphenyl)-2-methylpropanyl)tetrahydrocarbazole -2-ketone (760) 149105-sp-20100806.doc •182· 201200505

3) h2, Pd/C Step c Step A: Compound (757) was prepared in a similar manner as described for the synthesis of (752). Step B: Compound (758) was prepared in a similar manner as described for the synthesis of (753). Step C: Compounds (759) and (760) are prepared in a similar manner as described for the synthesis of (754) and (755). Intermediate 80 and intermediate 81 (R)-4-mercapto-3-( (S)-3-(4-Hydroxy-3-(trifluoromethyl)phenyl)-2-mercaptopropyl)tetrahydrocarbazole-2-ketone (764) and (R)-4-芊3-(R)-3-(4-hydroxy-3-(trifluoromethyl)benzene

3) H2, Pd/C Step C 149105-sp-20100806.doc -183- 201200505 Step A: Compound (762) was prepared in a similar manner as described for the synthesis of (752). Step B: Compound (763) was prepared in a similar manner as described for the synthesis of (753). Step C. Compounds (764) and (765) were prepared in a manner similar to that described for the synthesis of (754) and (755). Intermediate 82 (7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-4-yl)methanol (779)

厶 Step B

Step A: Compound (776) was prepared in a similar manner as described for the synthesis of (1). Step B: Compound (777) was produced in a similar manner as described for the synthesis of (2). Step C: Compound (778) was prepared in a similar manner as described for the synthesis of (3). Step D: Compound (779) was produced in a similar manner as described for the synthesis of (4). Intermediate 83 (6-Fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-4-yl)methanol (783) 149105-sp-20100806.doc -184 * 201200505

F 782

K2C〇3 DMF Step A

1) HC02H 2) SOCI2, ΜβΟΗ Step C Step A: Compound (780) was produced in a similar manner as described for the synthesis of (1).

Step B: Compound (781) was prepared in a similar manner as described for the synthesis of (2). Two regioisomers were obtained during single bond transfer rearrangement and separated by flash column chromatography. Step C: Compound (782) was produced in a similar manner as described for the synthesis of (3). The acid obtained after the cyclization is esterified by adding 20 equivalents of liquefied sulfoxide to the solution of the acid in decyl alcohol. Step D: Compound (783) was produced in a similar manner as described for the synthesis of (4). Intermediate 84

(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-4-yl) decyl alcohol (787)

784 785

149105-sp-20100806.doc -185 201200505 Step A: Compound (784) was prepared in a similar manner as described for the synthesis of (1). Step B: Compound C785) was prepared in a similar manner as described for the synthesis of (2). Two regioisomers were obtained during single bond transfer rearrangement and separated by flash column chromatography. Step C: Compound (786) was produced in a similar manner as described for the synthesis of (3). The acid obtained after the cyclization is esterified by adding 20 equivalents of liquefied sulfoxide to the solution of the acid in methanol. Step D: Compound (787) was prepared in a similar manner as described for the synthesis of (4). Intermediate 85 (5-Alkyl-2,2-dimethyl-2,3-dihydroindolofuran-4-yl)nonanol (791)

Step A: Compound (788) was prepared in a similar manner as described for the synthesis of (1). Step B: Compound (789) was produced in a similar manner as described for the synthesis of (2). Two regioisomers were obtained during single bond transfer rearrangement and separated by flash column chromatography. Step C: Compound (790) was prepared in a similar manner as described for the synthesis of (3) 149105-sp-20100806.doc -186-201200505. The acid obtained after the cyclization is esterified by adding 20 equivalents of thionium dichloride to the solution of the acid in methanol. Step D: Compound (791) was produced in a similar manner as described for the synthesis of (4). Intermediate 86

Di-deuterated (5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methanol (792)

792 Step A: Compound (792) was prepared in a similar manner as described for the (510) synthesis. Intermediate 87 2,3-Diindole-3-(4-hydroxyphenyl)propionic acid ethyl ester (794)

Step A: Compound (793) is in a similar manner as described for the synthesis of (537)

production. Step B: Compound (794) was prepared in a similar manner as described for the synthesis of (513) (but using a D2 cylinder). Intermediate 88 deuterated (5-carbyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) decyl alcohol (796)

149105-sp-20100806.doc -187- 201200505 Step A. Under dry air, cool (3) the solution in hydrazine to _78 c and add diisobutylaluminum hydride. The solution was maintained at _78 &lt;&gt;c, then saturated sodium bisulfite was added. The solution was allowed to warm to room temperature and the layers were separated. The terpene benzene layer was extracted with several portions of acidic sulfite, combined with an aqueous layer, basified to pH 8-9 with 2M sodium hydroxide (with cooling), and extracted with ether. The ether was washed with water, dried and dried, and evaporated to give (795). Step B: Compound (796) was prepared in a similar manner as described for the synthesis of (4). (3-氘化_5_气基-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methanol (10)〇)

_r\ Vj I

Step A: Compound (797) was prepared in a similar manner as described for the synthesis of (4). Step B: in a solution of 3-deuterated-5-chloro, 2,2-dimercapto-2,3-dihydrobenzofuran-3, (797), diethyl decane and dichloromethane Boron trifluoride etherate was added thereto and stirred at room temperature. The reaction was quenched with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give &lt;RTI ID=0.0&gt;&gt;&gt; 149105-sp-20100806.doc -188- 201200505 Step C: Compound (799) was prepared in a similar manner as described for the synthesis of (545). Step D: Compound (800) was prepared in a similar manner as described for the synthesis of (546). Intermediate 90

7-(Chloromethyl)-5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran ΟΗ Ο O OH O OH Ο

801 802A ...a i [,... K2C03l DMF i! 1 1 ----- 1 u 70 0C, 22 hours I:

Step iA

HCQ2H (90%) reflux, 22 hours Step C

F 803

Bh3/thf οπ to room temperature 16 hours Step D

F 804 SOCI2

〇弋 to room temperature Step E

Cl F 647 Step A: Compound (801) was prepared in a similar manner as described for the synthesis of (1). Step B: Compounds (802A) and (802B) were prepared in a manner similar to that described for the synthesis of (2). The two compounds are continued in the mixture to the next step. Step C: Compound (803) was produced in a similar manner as described for the synthesis of (3). Step D: Compound (804) was prepared in a similar manner as described for the synthesis of (510). Step E: Compound (647) was produced in a similar manner as described for the synthesis of (5). Intermediate 91 149105-sp-20100806.doc -189- 201200505 7 (Iso-indenyl)-5-ethyl-2,2-dimercapto-2,3-dihydrobenzaff. South (gig)

Step A: Compound (811) was produced in a similar manner as described for the synthesis of (S43). Step B: Compound (812) was prepared in a similar manner as described for the synthesis of (S44) except that no solvent was used in the rearrangement. Step C: 4-ethyl-2-(2-methallyl)phenol (812) (4 g, 22.7 mmol), p-indole acid monohydrate (400 mg, 2.10 mmol) And a solution of gas (120 ml) was stirred at room temperature overnight. The reaction was concentrated in vacuo and purified by flash chromatography on silica gel eluting with hexane and acetonide to give 5-ethyl-2,2-dimethyl-2,3- Dihydrobenzofuran (813). Step D: Compound (814) was prepared in a similar manner as described for the synthesis of (545). Step E: Compound (815) was prepared in a similar manner as described for the synthesis of (546). Step F: Compound (816) was prepared in a similar manner as described for the synthesis of (511). Intermediate 92 7-(Chloromethyl)-2,2,5-trimethyl-2,3-dihydrobenzofuran (822) 149105-sp-20100806.doc -190- 201200505

820 821 822 Step A: Compound (817) was prepared in a similar manner as described for the synthesis of (543).

Step B: Compound (818) was prepared in a similar manner as described for the synthesis of (544), except that solvent was not used in the rearrangement. Step C: Compound (819) was prepared in a similar manner as described for the (813) synthesis. Step D: Compound (820) was prepared in a similar manner as described for the synthesis of (545). Step E: Compound (821) was prepared in a similar manner as described for the synthesis of (546). Step F: Compound (822) was prepared in a similar manner as described for the synthesis of (511). Intermediate 93 7-(Chloromethyl)-5-isopropyl-2,2-dimercapto-2,3-dihydrobenzofuran (828)

S 149I05-sp-20I00806.doc • 191 - 201200505

Step A: Compound (823) was prepared in a similar manner as described for the synthesis of (543). Step B: Compound (824) was prepared in a similar manner as described for the synthesis of (544), except that no solvent was used in the rearrangement. Step C: Compound (825) was prepared in a similar manner as described for the synthesis of (813). Step D: Compound (826) was prepared in a similar manner as described for the synthesis of (545). Step E: Compound (827) was prepared in a similar manner as described for the synthesis of (546). Step F: Compound (828) was prepared in a similar manner as described for the synthesis of (511). Intermediate 94 (2,2-Dimethyl-5-(indolylsulfonyl)-2,3-dihydrobenzofuran-7-yl) decyl alcohol (831)

S02Me 830

S〇2Me 831 Step A: a solution of ethyl 2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (2.03 g, 9.22 mmol) in methanol (40 mL) Inside, add iodine (2.57 149105-sp-20100806.doc -192- 201200505 11.06 millimolar). Will react

Step B: Add sodium hydroxide (11.5 mg, to 10.14 mmol) with silver sulfate (3 45 g at room temperature for 3 hours, and pass 矽0.288 mmol) to l-catch# A solution of the amine (33 J mg, 0.288 mmol) in EtOAc (3 mL) was stirred for 30 min. In this solution, ethyl 5-bromo-2,2-didecyldihydrobenzofuran-7-carboxylate (829) (5 〇〇 mg, 144 mmol) was added, and methane sulphate was added. Salt (176.6 mg, 1.73 mmol) and copper iodide (1) (27 4 mg, 144 MW), and the reaction was stirred at 8 (rc) for 18 hours. Water (2 mL) was added. And extracted with ethyl acetate (3×30 ml). The combined organic layer was dried with sodium sulfate, filtered, evaporated and evaporated Dissolution) to provide ethyl 2,2·didecyl-5-(methylsulfonylsulfonyl)-2,3-dihydrobenzofuran-7-carboxylate (830) (186.9 mg, 44%). Step C: Compound (831) was prepared in a similar manner as described for the synthesis of (4). Intermediate 95 7-(Chloromethyl)-5-mercapto-2,2-dimercapto-2,3- Dihydrobenzofuran (835)

£149105-sp-20100806.doc -193 - 201200505

Step A: Compound (832) was prepared in a similar manner as described for the synthesis of (829). Step B: Compound (833) was prepared in a similar manner as described for the synthesis of (545). Step C: Compound (834) was prepared in a similar manner as described for the synthesis of (546). Step D: Compound (835) was prepared in a similar manner as described for the synthesis of (511). Intermediate 96

7-(Chloroindenyl)-2,2-diethyl-5-fluoro-2,3-dihydrobenzofuran (843) OH

836 837 838

Step A: pentan-3-one (10.5 g, 100.0 mmol) with Amberlyst-15 I49105-sp-20100806.doc -194- 201200505 Resin (75.0 g) in Duan Qi Yao (1. In the mixture, N-methyl-succinimide (35.6 g, 2 〇〇. 〇 millimol) was added at room temperature. The resulting mixture was mixed for 12 hours at 5 °t. The reaction was allowed to cool to rt. EtOAc (EtOAc)EtOAc. The organic layers were combined and washed with water (2 EtOAc, EtOAc) Hexane was added to the reaction mixture to suddenly precipitate the by-product hydroxy-succinimide. The collected filtrate was purified by flash chromatography (1% EtOAc in hexanes) to afford the desired product 2-bromopentane 3- ketone (836) (10.7 g, 65.0 %) is a colorless oil. Step Β: To a solution of 4-fluorophenol (8.0 g, 71.4 mmol) in dimercaptoamine (130.0 ml), add potassium carbonate (13 5 g, 97 4 mmol) and 2 -Bromopentane-3-one (836) (10.7 g, 64.9 mmol). The suspension was heated at 70 C for 18 h, cooled to room temperature and diluted with water (5 mL) and Extraction with ethyl acetate (2 x 25 ml). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography ( EtOAc EtOAc (EtOAc) elute %) is a colorless oil. Step C · Using a similar manner as described for the synthesis of (517) to synthesize fluoro--4-((3-methylenepentan-2-yl)oxy) stupid (838) (4.4 g, 85.5 %) is a colorless oil. Step D: using a similar manner as described for the synthesis of (518) to synthesize (E)-2-(2-ethylbut-2-en-1-yl)-4-fluoro group (839) (4_4) Gram, 1% by weight), is a colorless oil. 149105-sp-20100806.doc -195 - 201200505 Step E. A similar manner as described for the synthesis of (519) was used to synthesize 2,2-ethyl-5-1-yl-2,3-dihydrobenzofuran. South _) (23 g, 53 8%), is a colorless step F. Using a similar manner as described for the synthesis of (545) to synthesize 2,2_diethyl-5-fluoro-2,3-dihydro Benzofuran_7-carboxaldehyde (841) (15 g, 56.0%) ^ is a yellow oil. Step G: Synthesis of (2,2·ethylethyl-5-fluoro-2,3-dihydrobenzofuran-7-yl) decyl alcohol (842) using a similar manner as described for the synthesis of (546) (1 5 g, 56.0%) 'Yellow oil. Step Η. Using a similar manner as described for the synthesis of (511) to synthesize 7-(carbomethyl)-2,2-diethyl-5-fluoro-2,3-dihydrobenzifuran (843) (1 4 g, 96.6%), a colorless oil. Intermediate 97 7-(gas-based fluorenyl)-5-fluoro-2,2-dipropyl-2,3-dihydrobenzopyran (851) ΟΗ

149l05-sp-20100806.doc -196- 201200505 A similar reaction route for the synthesis of (843) was used to synthesize the intermediate 7_(methylmethyl)_5-murol-propyl-2,3-dihydrophenylhydrazine p Fu (851). Step A: 3-Bromoheptan-4-one (844) (17.0 g, 88.1%). Step B. 3-(4-Phenylphenoxy)heptan-4-one (845) (5.1 g, 28.5%). Step C: 1-Fluoro-4_((4-ylideneheptan-3-yl)oxy)benzene (846) (2.4 g, 47.1%). Step D · Provide (E)-4-fluoro-2-(2-propylpent-2-ylidene-1-yl)-brew (847) (2,3 g, 100%), yellow oil. Step E: Providing 5-fluoro-2,2-dipropyl-2,3-dihydrobenzofuran (848) (1.5 g, 65.2%) as a colorless oil. Step F: Providing 5-fluoro- 2,2-Dipropyl-2,3-dihydrobenzofuran-7-carboxaldehyde (849) (1.2 g, 71.1%) as a yellow oil. Step G: Provided (5-fluoro-2,2-dipropyl-2,3-dihydrobenzofuran-7-yl)nonanol (850) (0-93 g, 76.9%) as a yellow oil. Step Η: Providing the intermediate 7-(methylmethyl)-5-d-yl-2,2-dipropyl-2,3-dihydrobenzofuran (851) (0.954 g, 95.6%) as an oil residue Things. Intermediate 98 7-(Gasinyl)-5-fluoro-2-(decyloxymethyl)-2,3-dihydrobenzopyrene (858)

S 149105-sp-20100806.doc •197· 201200505

Step A: In a solution of 4-fluorophenol (22.4 g, 200 mmol) in DCM (2 mL), add 50 ° / 〇 NaOH (aq) (1 mL), 3_ Bromopropene (26.0 ml '300.0 mmol) and tetra-n-butylammonium bromide (19 g, 6 〇 millimolar). The suspension was stirred at room temperature for 24 hours. The layers were separated and washed with water (2.times.100 mL), brine (1 mL) and dried and evaporated. The residue was purified by chromatography ( EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc . Step B - A similar manner as described for the synthesis of (518) was used to synthesize 2-alkol-4-fluorophenol (853) (6.0 g, 1%) as a colorless oil. Step C: Slowly add 77% 3_gas peroxygen in an ice-cold solution of 2-allyl-4-fluorophenol (853) (6.0 g, 36.2 mmol) in CHCWISO. A suspension of benzoic acid (8.1 g, 36.2 mmol) in CHC 3 (36 2 mL). The resulting mixture was stirred at EtOAc (2 mL), EtOAc (EtOAc)EtOAc. And concentrated in a vacuum. The residue was purified by flash chromatography (30·40 EtOAc / EtOAc in hexane) to afford the desired product (5-fluoro-2,3-dihydrobenzofuran-2-yl) Methanol (854) (3.88 g, 57 7%) as a yellow oil. Step D. (5-Fluoro-2,3-dihydrobenzopyran-2-yl)cohol (854) gram, 6.0 mmoles in dimethylformamide (13 〇) In the solution in 〇ml), add I49105-sp-20100806.doc -198· 201200505 plus 60% NaH (0.480 g, 12.0 mmol) and Mel (1.12 ml, 18. 〇 millimolar) in the mineral oil. . The suspension was stirred at room temperature for 24 hours and diluted with water (50 mL) and extracted with ethyl acetate (2.times.25 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10%EtOAcEtOAcEtOAc) elute South (855) (0.650 g, 59.5%), colorless oil.

Step E: Using a similar manner as described for the synthesis of (545), to synthesize fluorenyl-2-(methoxylated) 2,3-dihydrobenzopyran·7-pass boiled (four) (〇175 g ' 23,3%), yellow oil. Step F: using a similar butterfly-like method as described for the synthesis of (546) to synthesize (5-fluoro-hydroxyoxymethyl)-2,3-dihydrophenylpyranyl-7-yl)methanol _ _ gram , 62.3%), as yellow oil. Step G: using the formula (511) to synthesize the above-mentioned ancient Ku's formula to provide the intermediate 7-(gas-based fluorenyl)-5-fluoro-2,(曱methoxyindenyl)·2λ _ 〃 Soil; a stupid and furan ( _ gram, 25.1%), is an oil residue. Open chewing 'intermediate 99 7-(gas-based mercapto)-5-fluoro-2-(nonyloxydecylmethyl-3-hydrogenbenzone)

OH

F

J^c\ J^c〇3, DMF Step A

85Θ (865)

860

Step D

NaH

s 149105-sp-20100806.doc -199, 201200505

1. The reaction is carried out by using the synthetic intermediate 7-(chloromethyl)_2-methyl-2,3-dihydrobenzo-furan with respect to the methyl group of the (858) synthesis)-5-fluoro group- 2-(Methoxy (865). Step A·· Using a similar manner as described for the synthesis of (1) to synthesize p-based icy ((2-methylallyl)oxy)benzene (tetra) (129 g, 38 7 %), as a colorless oil. Step B: Provide 4 · Fluoro-based exo-propyl) age _ &amp; 〇 克 ', off, for yellow oil. Step C: k provides (5-fluoro-2-indenyl 2,3-dihydrobenzo benzo (861) (3.8 g, 57.8%) as a yellow oil. m. 5-Fluoro- 2 -(methoxymethyl &gt; 2 methyl 2,3-diazabenzoin (862) (1.1 g, 92.6%) was provided as a colorless oil. Step E: provided 5- Fluoryl-2-(methoxymethyl)&gt;2-methyl-23 dihydrobenzofuran-7-carboxaldehyde (863) (0.460 g, 36.9%) as a colorless oil. Step F: provided (5 -Fluoro-2-(methoxymethyl).2-fluorenyl-2,3·dihydrobenzofuran-7-yl)methanol (864) (0.460 g, 99.1%) as a yellow oil. G. Providing the intermediate 7-(gas-based fluorenyl)_5-fluoro-2-(2-methoxymethyl)_2-methyl-2,3-dihydrobenzofuran (865) (0.376 g, 75.6%) ), as an oil residue. Intermediate 100 (7-(Chloroindenyl)-5-1yl-2,3-dihydrobenzopyran-2-yl)acetate (869) 149105-sp- 20100806.doc •200· 201200505

Step A: (5·Fluoro-2/methyl-2,3-dihydrobenzofuran-2-yl)methanol (854) (0.530 g, 3.15 mmol) in DCM (3.2 mL) Diethylamine (0.878 ml, 6.3 mmol), DMAp (〇〇77 g, 〇63 mmol) and acetic acid (222 ml, 2.4 mmol) were added to the ice-cold solution. The solution was dropped for 2 hours under 〇t. The layers were separated and washed with EtOAc EtOAc m. The residue is purified by chromatography (〇_丨〇% 〇&amp; in hexane) to give the desired (5-fluoro-2,3-dihydrobenzopyran-2-yl)acetate _ _ (〇. Buick, 80.0%) 'Be a colorless oil. Step B: using a similar method as described for (10) synthesis to synthesize (5-fluoro-7-methyl-branched-2,3-dihydrobenzopyranyl)acetate A__ 克克' 50.3%), It is a yellow solid. Step C: Let the similar method described in _synthesis be quasi-quinone-like: hydrogen benzopyran-2-yl) acetic acid"_

Gram, 38.5%), is yellow oil. Step V: Use a similar method as described in (iv) Synthesis to provide medium 149105-sp-20100806.doc 201-201200505 (7-(chloromethyl)-5-carbyl-2,3-dihexane Benzofuranyl)acetic acid methyl vinegar (869) (0.094 g, 74.7%) as an oil residue. Intermediate 101 (7-(Chloromethyl)-5-yl-2-mercapto-2,3-dihydroindolefuran:yl)acetate

ON

(873A)

F 661

A similar reaction scheme for the synthesis of (869) was used to synthesize the intermediate (chloroguanidino)-5-fluoro-2-indolyl-2,3-dihydrobenzofuranylacetic acid methyl vinegar (873A). Step A. Provided (5-fluoro-2-methyl-2,3-dihydrobenzopyran-2-yl)acetic acid methyl ester (870) (0.630 g, 89.2%) as a colourless oil. Step B: Providing methyl (5-fluoro-7-carbamido-2-methyl-2,3-dihydrobenzofuran-2-yl)acetate (871) (0.448 g, 63.3%) as Yellow solid. Step C: Providing (5-fluoro-7-(hydroxyindenyl)-2-methyl-2,3-dihydrobenzofuran) methyl acetate (872) (0.240 g, 53.1%) as Yellow oil. Step D: Providing the intermediate (7-(methyl-methyl)-5-fluoro-2-indolyl 2,3-dihydrobenzofuran-2-yl)acetate (873A) (0.240 g, 93.1%), which is an oil residue. I49105-sp-20100806.doc -202 - 201200505 Intermediate l〇2 7-(Chloromethyl)-5-cyclopentyl-2,2-dimethyl-2,3_di+benzofuran (876 ), 丨I ^ *7^0 r\

〇&gt;

Pd(OAc)2 Step A

829

&amp;74 Step A: Add ethyl 5-mercapto-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate in a 20 ml microwave-tube under N2 (0.692)克, 2.0 mol), cyclopentene (0.882 ml, 1 〇. 〇mol), TBAF (0.644 g, 2.0 mol), K2 C03 (0.691 g, 5.0 mol), DMF (8.0 ml), acetic acid Palladium (π) (o.oii gram '0.05 mmol) and tri-o-tolylphosphine (0,030 g, 〇1 〇 millimolar). The mixture was sealed in a glass tube at 11 Torr. Stir underarm overnight (21 hours). The reaction was cooled to rt and EtOAc (1 mL) was evaporated. The mixture was stirred for 30 min, filtered over EtOAc (EtOAc)EtOAc. The organic layer was washed with water (2×10 mL), brine (10 mL) and dried over sodium sulfate. The residue was purified by chromatography (0-10%EtOAcEtOAcEtOAc) elute _7_Carboxylic acid ethyl ester (873B) (〇38 g, 66.4 ° /.), a yellow oil. Step B•• Use the method described in (9) Synthetic to synthesize 5-5| soil, f-group·2,3_monohydrobenzo ketone_7-edge mannine ethyl vinegar ((4) (0.310 Clip 149105-sp-20100806.doc -203 - 201200505 81.0%), as a colorless solid. Step C: using a similar manner as described in (4) synthesis to synthesize (5-cyclopentyl-2,2-- Methyl-2,3-dihydrobenzo-bate _7-yl)methanol (μ) (〇270 g, 100%) as a colorless oil. Step D: using a similar method as described for the synthesis of (511) To provide the intermediate 7-(azepine)-5-cyclopentyl-2,2-dimethyl-2,3-dihydrobenzofuran (876) (0-232 g '80.1./〇), It is an oil residue. Intermediate 103 3-(4-((5-ethoxy-2,2-dimethyl-2,3-dihydroindolyl)7-yl)methoxy)_2, 3_ Dimethylphenyl)propionic acid (881)

Step A: Reducing compound (2) (4·51 g '20 mmol) with Hg(OAc) 2 (6 37 I49105-sp-20100806.doc -204-201200505 g, 20 mmol) while Stir in THF (4 mL) for 3 hours. The reaction mixture was cooled to 〇t and a solution of sodium borohydride (76 mg, EtOAc) When the addition was completed, the reaction was stirred at room temperature for 2 hours. The reaction mixture was treated with saturated Na.sub.2Cl.sub.3 and the layers were separated. The organic layer was treated with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by EtOAc (EtOAc) elute Step B·· Compound (883) was prepared in a similar manner as described in the synthesis of (4).

Step C: Compound (884) was produced in a similar manner as described for the synthesis of (5). X intermediate 105 7-(Chloromethyl-2,2-dimethyl_5_(trimethoxymethoxy dihydrobenzopyran)

(890)

0, CF3 step card step secret C 886 88$

1) S0C12 OH

Step D

83⁄4 890 A similar manner as described in (1) Synthesis f3ct0 f3c-° 887 Bft Step A: Compound (88S) was prepared. Step B. The chemical (886) was made in a similar manner as described for the synthesis of (7). However, no solvent was used in the rearrangement. ^ 149105-sp-20100806.doc 201200505 The step CU complex (887H is prepared in a similar manner as described in (3) Synthetic Households. Step D: Compound (888) is as described in relation to (668) synthesis Prepared in a similar manner.Step E: Compound (889) was prepared in a similar manner as described for the synthesis of (4). Step F: Compound (890) was prepared in a similar manner as described for the synthesis of (5) &gt; 106 7-(Chloroindenyl)-5-fluoro-2,2-dimercaptoindoline + carboxylic acid oxime ester (6) nh2 ~

BF3.〇Et2 an NH

NH

F 891 〇.Λ Step A Step 5B 丫 Pd(OAc)2 PCyaHBF^ Δ Step WC 892

Step A: 2-bromo-4,fluoropropanol (4 g, millimolar), Bp; ο% (2 9 ml, 1.1 eq.) and 2,2,2-triephthyl imidic acid The third butyl ester (96 ml, 2.5 eq.) was stirred at room temperature in cyclohexane (30 mL). The reaction was quenched with saturated NaHC(R)3 and washed with ethyl acetate. The organic layer was collected, washed with brine, dried over sodium sulfate and filtered. The organic phase is concentrated in the air. The residue was purified by EtOAc (0-50%EtOAcEtOAcEtOAc) Step B: A solution of the compound (891) (0.5 g, 2.04 mmol) in chloroformic acid succinic acid 149105-sp-20I00806.doc - 206 - 201200505 ( ίο s) was refluxed for 5 hours. The reaction was allowed to cool to room temperature; water was added and extracted with chloroform. The organic layer was separated, dried over sodium sulfate, dried and evaporated. The residue was purified by EtOAc (EtOAc EtOAc) Step C ·· Compound (892) (0.620 g, 2.04 mmol), pd(〇Ac) 2 (13.8 mg, 0.03 equivalent), PCy3.HBF4 (45 mg, 0.06 equivalent), Cs2C03 (931 pg, 1.4, a mixture of t-BuC02H (62.5 mg, 〇·3 equivalents) in diphenylbenzene (2 mL), heated at 14 °C under &amp; atmosphere for 3 hours. Allow the reaction to cool to room The temperature was passed through a column packed with celite and concentrated in vacuo. The residue was purified by chromatography (0-50% EtOAc in hexane) to afford compound (893). (893) (1.47 g, 6.6 mmol) in THF (30 mL) EtOAc (EtOAc: EtOAc (EtOAc) Stir at -78 ° C for 30 min. Add DMF (10 mL, EtOAc) &lt;RTI ID=0.0&gt;&gt; Extracted with ethyl acetate (2 χ). The combined organic layers were washed with brine, dried over sodium sulfate, dried and evaporated and evaporated. (〇_3〇% EtOAc in hexanes) to provide compound (894). Step E: Compound (894) (1·0 g of &lt; Sodium borohydride (0.452 g, 3 eq.) was slowly added to the reaction mixture at room temperature. The reaction was stirred overnight, then quenched with water and slowly stirred. The residue was dissolved in EtOAc. EtOAc (EtOAc m. (0-30% EtOAc in hexanes) to provide compound (895). Step F: Compound (896) was obtained in a similar manner as described for the synthesis of (5). Intermediate 107

F

Oxyl 3-(2,3-difluoro-4-hydroxyphenyl)propionate (898)

Step A: Compound (897) was prepared in a similar manner as described for the synthesis of (10). Step B · Compound (898) was prepared in a similar manner as described for the synthesis of (11). Intermediate 108

F

Ethyl 3-(2,5-difluoro-4-hydroxyphenyl)propanoate (899)

Step A·· Compound (899) was prepared in a similar manner as described for the synthesis of (10). Step B: Compound (900) was prepared in a similar manner as described for the synthesis of (11). Intermediate 109 ethyl 3-(2,3-dichloro-4-hydroxyphenyl)propanoate (904) 149105-sp-20100806.doc - 208 - 201200505

H2. Rh/AJ Step C

OEt Step A: Compound (901) was prepared in a similar manner as described for the synthesis of (545). Step B: Compound (902) is in a similar manner as described for the synthesis of (537)

production. Step C: Compound (903) was prepared in a similar manner as described for the synthesis of (513) except that 5% hydrazine on alumina was used instead of palladium/carbon. Step D: Compound (904) was prepared in a similar manner as described for the synthesis of (514). Intermediate 110

Ethyl 3-(3-chloro-4-hydroxy-2-indolylphenyl)propanoate (908)

H2i Pd/C Step C

OEt Step A: Compound (905) was prepared in a similar manner as described for the synthesis of (545). Step B: Compound (906) was prepared in a similar manner as described for the synthesis of (537). 149105-sp-20100806.doc -209- 201200505 Step C: Compound (907) was prepared in a similar manner as described for the synthesis of (513) except that 5% hydrazine on alumina was used instead of palladium/carbon. Step D: Compound (908) was prepared in a similar manner as described for the synthesis of (514). Preparation of GPR120 agonist Example 1 2-(5-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzoxan.South-7-yl)decyloxy)~6- Gas-based-2,3-diindole-1H-indol-1-yl)acetic acid (29)

Step A: To a solution of intermediate (5) (0.100 g, 0.43 mmol) in acetonitrile (3 mL), Intermediate 22 (0.103 g, 0.43 m Millions of ears). The resulting suspension was mixed for $ hours at 75 °C. The reaction was allowed to cool to room temperature and was passed through a pad of celite. The mixture was concentrated in vacuo and the residue was purified by chromatography eluting with EtOAc (EtOAc EtOAc EtOAc) Step B: A solution of lithium hydroxide (1.0 mL, 1.0 mL) was added to a solution of EtOAc (EtOAc) (EtOAc) The reaction was stirred at room temperature for 4 hours. The mixture was acidified with EtOAc and diluted with ethyl acetate (5 mL). The organic layer was washed with br. 149 </RTI> &lt;RTI ID=0.0&gt;&gt; The filtrate was concentrated in vacuo and the residue was purified eluting elut elut elut elut WNMRGOOMHaCDCIs) 5 : 7.05 (s, 1H), 6.94-6.90 (m, 3H), 5.03 (s, 2H), 3.54-3.51 (m, 1H), 3.00 (s, 2H), 2.86-2.72 (m, 3H ), 2.50-2.40 (m, 2H), 1.80-1.75 (m, 1H), 1.48 (s, 6H).

Example 2 3-(4-((2,2-Dimethylindol-8-yl)methoxy)-3,5-difluorophenyl)-2-mercaptopropionic acid (31)

UOH THF/MeOH Step B

Step A: In a solution of intermediate (16) (0.140 g, 0.73 mmol) in tetrahydrofuran (3 mL), Intermediate 9 (0.178 g, 0.73 m. Triphenylphosphine (3 mM/g, 0.36 g, 1.1 mmol) and isopropylbis-dibenzoate (0.214 mL '1.1 mmol). The resulting suspension was stirred for 18 hours. The reaction was diluted with ethyl acetate and filtered through a pad. The filtrate was concentrated in vacuo and the residue was purified eluting elut elut elut elut Step B: To a solution of the intermediate (30) (0.100 g, 0.256 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL), EtOAc (1.0M, 1.0 mL) . The reaction was stirred at room temperature for 4 hours. The mixture was acidified with 1 M.sub.1 and diluted with ethyl acetate (5 mL). The organic layer was washed with brine (5 EtOAc EtOAc EtOAc &lt;RTI ID=0.0&gt; The filtrate was concentrated in vacuo and the residue was purified eluting elut elut elut elut elut 1 H NMR (400 MHz, CDC13) 5 : 7.28 (d, 1H), 7.03 (d, 1H), 6.82 (t, 1H), 6.71 (d, 2H), 5.15 (s, 2H), 3.00-2.95 ( m, 1H), 2.77 (t, 2H), 2.73-2.70 (m, 1H), 2.62-2.57 (m, 1H), 1.77 (t, 2H), 1.19 (d, 3H), 0.89 (s, 6H) . Representative compounds of the present invention are made by the procedures described in the above Examples, using suitable starting materials which are apparent to those skilled in the art, and are shown below. Example 3 3-(4-((2,3-Dihydrobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)-2-mercaptopropionic acid (32)

1 H NMR (400 MHz, CDC13) δ : 7.21-7.16 (m, 2Η), 6.83 (t, 1H), 6.70 (d, 2H), 5.13 (s, 2H), 4.57 (t, 2H), 3.21 ( t, 2H), 2.99-2.94 (m, 1H), 2.74-2.69 (m, 1H), 2.62-2.56 (m, 1H), U9 (d, 3H). Example 4 2-Methyl-3-(4-((2,2,5·trimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)propionic acid (33)

H NMR (400 MHz, CDC13) &lt;5: 7.09-7.05 (m, 3H), 6.95-6.90 (m, 3H), 149105-sp-20100806.doc -212- 201200505 4.98 (s, 2H), 3.03- 2.99 (m, 1H), 2.98 (2H, s), 2.78-2.51 (m, 1H), 2.63-2.58 (m, 1H), 2.27 (s, 3H), 1.47 (s, 6H), 1.16 (d, 3H). Example 5 3-(3,5-Difluoro-4-((2,2,5-trimethyl-2,3-dihydro benzopyrano-7-yl)decyloxy)phenyl)-2 - mercaptopropionic acid (34)

1 H NMR (400 MHz, CDC13) δ : 7.03 (s, 1Η), 6.90 (s, 1H), 6.69 (d, 2H),

5.10 (s, 2H), 2.99-2.96 (m, 1H), 2.94 (s, 2H), 2.74-2.69 (m, 1H), 2.61-2.56 (m, 1H), 2.26 (s, 3H), 1, 40 (s, 6H), 1.18 (d, 3H). Example 6 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzopyran-7-yl)methoxy)_3_曱 η

Phenyl)-2-methylpropionic acid (35)

1 H NMR (400 MHz, CDC13) δ : 7.00-6.78 (m, 5H), 4.98 (s, 2H), 3.00 (s, 2H), 2.96-3.00 (m, 1H), 2.76-2.70 (m, 1H ), 2.61-2.55 (m, 1H), 2.26 (s, 3H), 1.48 (s, 6H), 1.18 (d, J = 7.2 Hz, 3H). LC-MS ESI m/z: found: 371.2 [MH]···············曱oxy)_3_曱-oxyphenyl)-2-mercaptopropionic acid (36) 149105-sp-20100806.doc -213- 201200505

1 H NMR (400 MHz, CDC13 ) δ : 7.02-6.99 (dd, J = 10.0 Hz, 2.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.78-6.75 (dd, J = 5.2 Hz , 2.4 Hz, 1H), 6.71 (s, 1H), 6.66-6.64 (m, 1H), 5.06 (s, 2H), 3.87 (s, 3H), 3.02-2.97 (m, 3H), 2.76-2.70 ( m, 1H), 2.62-2.57 (m, 1H), 1.48 (s, 6H), 1.16 (d, J = 7.2 Hz, 3H). Example 8 3-(3-Fluoro-4-((5-fluoro-2,2-dimercapto-2,3-dihydroindenoindol-7-yl)decyloxy)phenyl) -2-mercaptopropionic acid (37)

1 H NMR (400 MHz, CDC13) &lt;5: 6.90-6.70 (m, 3H), 6.79-6.83 (m, 2H), 5.04 (s, 2H)} 2.99 (s, 2H), 2.95-2.99 (m , 1H), 2.68-2.74 (m, 1H), 2.57-2.62 (m, 1H), 1.47 (s, 0H), U7 (d, J = 7.2 Hz, 3H). LC-MS ESI m/z : measured Value 375.1 [MH]' Example 9 3-(4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)_3_(trifluoro Methyl)phenyl)-2-methylpropionic acid (38)

1 H NMR (400 MHz, CDC13) 5 : 7.39 (s, 1H), 7.26 (m, 2H), 7.05 (s, 1H), 149105-sp-20100806.doc -214- 201200505 7.01 (d, J = 9.2 Hz, 1H), 5.06 (s, 2H), 3.00 (s, 2H), 3.04-2.99 (m, 1H), 2.77-2.72 (m, 1H), 2.69-2.64 (m, 1H), 1.48 (s, 6H), 1.19 (d, J = 6.8 Hz, 3H). LC-MS ESI m/z: found 441.1 [MH] - Example 10 3-(4-((5- Base-2,3-dihydrobenzofuran_7-yl)decyloxy)_3_敦

Phenyl)-2-mercaptopropionic acid (39)

1H NMR (400 MHz, CDC13) &lt;5: 7.25 (s, 1H), 7.04 (s, 1H), 6.97-6.91 (m, 2H), 6.84-6.82 (m, 1H), 5.03 (s, 2H) , 3.00 (s, 2H), 2.99-2.95 (m, 1H), 2.75-2.70 (m, 1H), 2.63-2.58 (m, 1H), 1.48 (s, 6H), 1.18 (d, J = 6.4 Hz , 3H). LC-MS ESI m/z: found 390.1 Example 11 3-(4-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzofuran) ) 曱oxy)_3_曱

Base-based)-2-mercaptopropionic acid (40)

1 H NMR (400 MHz, CDC13) δ : 7.25 (s, 1H), 7.04 (s, 1H), 6.97-6.93 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 4.96 (s, 2H), 3.00 (s, 2H), 2.99-2.96 (m, 1H), 2.76-2.70 (m, 1H), 2.63-2.58 (m^ 1H), 2.26 (s, 3H), 1.48 (s, 6H) , 1.18 (d, J = 7.2Hz, 3H). Example 12 149 K) 5-sp-20100806.doc 215· 201200505 M3-Chloro-4-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) )methoxy)phenyl)-2-methylpropionic acid (41)

1 H NMR (400 MHz, CDC13) δ : 7.30 (s, 1 Η), 7.21 (d, J = 2.0 Hz, 1H), 7.05 (s, 1H), 6.98 (dd, J = 8.4, 2.0 Hz, 1H) , 6.92 (d, J = 8.4 Hz, 1H), 5.04 (s, 2H), 3.00 (s, 2H), 2.98-2.94 (m, 1H), 2.74-2.70 (m, 1H), 2.63-2.58 (m , 1H), 1.48 (s, 6H), 1.18 (d, J = 6.4 Hz, 3H). LC-MS ESI m/z : found 407.0 [M-Η]' Example 13 3-(3,5-II Gas-4-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoic acid (42)

1H NMR (400 MHz, CDC13) δ ·* 7.24 (s, 1H), 7.09 (d, J = 8.8 Hz, 2H), 7.04 (s, 1H), 6.91 (d, J = 8.8 Hz, 2H), 4.96 (s, 2H), 3.00 (s, 2H), 3.03-2.98 (m, 1H), 2.76-2.73 (m, 1H), 2.65-2.60 (m, 1H), 1.48 (s, 6H), 1.18 (d , J = 6.8 Hz, 3H). LC-MS ESI m/z: found 373.2 [MH] </ s s s s s s s s s s s s s s s s s s Mercapto-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-mercaptopropionic acid (43) 149105-sp-20100806.doc • 216 - 201200505 Ο

1Η NMR (400 MHz, CDC13) δ 7.38 (s, 1Η), 7.13 (s, 2H), 7.07 (s, 1H), 4.98 (s, 2H), 2.99 (s, 2H), 3.02-2.96 (m, 1H), 2.77-2.73 (m, 1H), 2.63-2.60 (m,1H), 1.44 (s,6H), 1.21 (d, J = 6.8 Hz, 3H). LC-MS ESI m/z : measured value 441.0, 443.3, 445.3 [MH]* Example 15 3-(4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)- 3-methoxyphenyl)-2-methylpropionic acid (44)

1H NMR (400 MHz, CDC13) δ: 7.27 (s, 1H), 7.02 (s, 1H)S 6.84 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 6.64 ( Dd, J = 8.4, 1.6 Hz, 1H), 5.04 (s, 2H), 3.87 (s, 3H), 2.99 (s, 2H), 3.01-2.97 (m, 1H), 2.76-2.71 (m, 1H) , 2.63- 2.58 (m, 1H), 1_48 (s, 6H), 1.18 (d, J = 6·8 Hz, 3H), LC-MS ESI m/z: found 403.0 [MH] - Example 16 3- (4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-mercaptopropionic acid (45)

1 H NMR (400 MHz, CDC13) ά : 7.09 (d, J = 8.6 Hz, 2H), 6.97 (d, J = 149105-spk20100806.doc •217- 201200505 10.0 Hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 3.00 (s, 2H), 3.03-2.98 (m, 1H), 2.76-2.71 (m, 1H), 2.65-2.59 (m, 1H), 1.48 (s,6H), 1.17 (d,J = 7.2 Hz, 3H). LC-MS ESI m/z : found 357.1 [MH] - Example 17 3-(4- ((2,2-Dimethyl-2,3-dihydrobenzofuran-4-yl)decyloxy)phenyl)-2-methylpropionic acid (46)

1 H NMR (400 MHz, CDC13) &lt;5: 7.15-7.10 (m, 3H), 6.90-6.88 (m, 3H), 6.72 (d, J = 8.4 Hz, 1H), 4.95 (s, 2H), 3.04 (s, 2H), 3.03-2.98 (m, 1H), 2.75- 2.72 (m, 1H), 2.67-2.62 (m, 1H), 1.48 (s, 6H), 1.18 (d, J = 6.8 Hz, 3H) » Example 18 3-(3,5-Difluoro-4-((5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy) Stupid)-2-methylpropionic acid (47)

1 H NMR (400 MHz, CDC13) δ : 6.97 (dd, J = 9.2, 2.4 Hz, 1H), 6.8 (dd, J = 9.2, 2.4 Hz, 1H), 6.71 (d, J = 8.8 Hz, 2H) , 5.08 (s, 2H), 2.96 (s, 2H), 2.99-2.94 (m, 1H), 2.74-2.66 (m, 1H), 2.59 (dd, J = 13.6, 6.8 Hz, 1H), 1.41 (s , 6H), 1.18 (d, J = 6.8 Hz, 3H) » Example 19 2-(3,5-Difluoro-4-((5-fluoro-2,2-dimethyl-2,3-di) Hydrobenzo-3-p-pyran-7-yl)methoxy)phenyl)cyclopropanecarboxylic acid (48) 149105-sp-20100806.doc -218- 201200505

1 H NMR (400 MHz, CDC13) δ : 6.96 (dd, J = 9.6, 2.4 Hz, 1H), 6.8 (dd, J = 9.6, 2.4 Hz, 1H), 6.62 (d, J = 8.4 Hz, 2H) , 5.08 (s, 2H), 2.96 (s, 2H), 2.54-2.46 (m, 1H), 1.84-1.8 (m, 1H), 1.68-1.62 (m, 1H), 1.41 (s, 6H), 1.38 -1.30 (m,1H) 〇Example 20

3-(3,5-Difluoro-4-((2-indolyl 2,3-dihydrobenzop-am-7-yl)decyloxy)phenyl)-2-methylpropanoic acid ( 49)

^NMRC^OMH^CDC^) δ : 7.21 (d, J = 7.6 Hz, 1Η), 7.11 (d, J = 7.2 Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.8 Hz, 2H), 5.15 (d, J = 11.4 Hz, 1H), 5.12 (d, J = 11.4 Hz, 1H), 4.95-4.88 (m, 1H), 3.30 (dd, J = 15.2, 7.6 Hz, 1H), 2.86 (t, J = 7.6 Hz, 2H), 2.79 (dd, J = 15.2, 7.6 Hz, 1H), 2.64 (t, J = 7.6 Hz, 2H), 1.41 (d, J = 6.4 Hz, 3H). Example 21 3-(4-((2,2-Dimercapto-2,3-dihydrobenzofuran-4-yl)methoxy)-3,5-difluorophenyl)-2-indenyl Propionic acid (50) 0

1H NMR (400 MHz, CDC13) (5: 7.08 (t, J = 8·0 Hz, 1H), 6.84 (d, J = 8.0 149105-sp-20100806.doc -219- 201200505

Hz, 1H), 6.76-6.68 (m, 3H), 5.04 (s, 2H), 3.11 (s, 2H), 2.96 (dd, J = 13.6, 7.4 Hz, 1H), 2.74-2.66 (m, 1H) , 2.59 (dd, J = 13.6, 7.4 Hz, 1H), 1.48 (s, 6H), 1.18 (d, J = 6.8Hz, 3H). Example 22 2-(4-((2,2-Dimercapto-2,3-dihydrobenzofuranyl)decyloxy)-3,5-difluorophenyl)cyclopropanecarboxylic acid (51)

1H NMR (400 MHz, CDC13) δ : 7.08 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 6.63 (d, J = 8.8 Hz, 2H), 5.04 (s, 2H), 3.11 (s, 2H), 2.52-2.46 (m, 1H), 1.88-1.8 (m, 1H), 1.68-1.62 (m, 1H), 1.48 (s, 6H), 1.34-1.3 (m, 1H). Example 23 3-(4-((2,2-Dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)-2-indenyl Propionic acid (52)

'H NMR (400 MHz, CDC13) δ 7.21 (d, J = 7.6 Hz, 1H), 7.06 (dd, J = 7.2, 1.2 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.70 ( m, 2H), 5.14 (s, 2H), 2.98 (s, 2H). 2.97-2.93 (m, 1H), 2.72-2.68 (m, 1H), 2.60-2.55 (m, 1H), 1.42 (s, 6H), 1.19 (d, J = 6.8 Hz, 3H). Example 24 2-(4-((2,2-Dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)-3,5-difluorobenzene 149105-sp-20I00806.doc •220· 201200505 base) cyclopropanecarboxylic acid (53)

1 H NMR (400 MHz, CDC13) 5 7.21 (d, J = 7.6 Hz, 1H), 7.08 (dd, J = 7.2, 1.2 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.61 ( m, 2H), 5.13 (s} 2H), 2.98 (s, 2H), 2.49-2.45 (m, 1H), 1.84-1.80 (m, 1H), 1.66-1.61 (m, 1H), 1.41 (s, 6H), 1.33-1.28 (m, 1H). Example 25

3-(4-((2,2-Amercapto-2,3-a) benzoyl-7-yl) decyloxy)-3,5-diphenyl)propionic acid (54)

lHNMR (400MHz, DMSO-d6) δ 12.14(s, 1H)} 7.14-7.09 (m, 2H), 6.96 (s, 1H), 6.93 (br s, 1H), 6.76 (t, J = 7.5 Hz, 1H ), 5.00 (s, 2H), 2.95 (s, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.49 (m, 2H), 1.31 (s, 6H). Example 26

3-(2-Chloro-4-((5-chloro-2,2-dimethyl-2,3-dihydro benzofuran-7-yl)methoxy)phenyl)-2-indole Propionic acid (55)

1 H NMR (400 MHz, DMSO-d6) 5 12.18 (s, 1H), 7.22-7.17 (m, 3H), 7.07 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 8.5, 2.5 Hz , 1H), 4.93 (s, 2H), 3.03 (s, 2H), 2.96-2.89 (m, 1H), 2.66-2.60 (m, 2H), 1.43 (s, 6H), 1.03 (d, J = 6.3 Hz, 3H). 149105-sp-20100806.doc -221 - 201200505 LC-MS ESI m/z : found 407.1 [MH] - Example 27 2-(3,5-difluoro-4-((4-fluoro) Base-2,2-dimethyl-2,3-dihydro benzofuran-7-yl)methoxy)phenyl)cyclopropanecarboxylic acid (56)

^ NMR (400 MHz, DMSO-d6) 5 12.34 (s, 1H), 7.16-7.12 (m, 1H), 6.95-6.91 (m, 2H), 6.63-6.59 (m, 1H), 4.96 (s, 2H ), 2.99 (s, 2H), 2.37-2.32 (m, 1H), 1.81-1.77 (m5 1H), 1.41-1.28 (m, 8H). LC-MS ESI m/z: found 390.9 [M-Η ]* Example 28 3-(1 2,3 4-Difluoro·4-((4-Gas-5-yl-2,6-didecyl-2,3-dihydrobenzofuran-7-yl)methoxy Base) styryl)-2-mercaptopropionic acid (57)

149105-sp-20100806.doc •222- 1 12.9, 6.6,1H), 2.63-2.51 (m, 2H), 1.34 (s, 6H), 1.00 (d, J = 6.7 Hz, 3H). 2

LC-MS ESI m/z: found: 392.8 [M-HT 3 </RTI> <RTI ID=0.0></RTI> Benzopyran-7-yl)methoxy 5 H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), δ 7.16-7.12 (m, 1H), 6 6.93-6.90 (m, 2H), 6.63-6.58 (m, 1H), 4.98 (s, 2H), 3.00 (s, 2H), 2.80 (dd, J = 7 yl) phenyl)-2-methylpropionic acid (58) 201200505 ο Ο ιΗ NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1Η), 7.24-7.21 (m, 1Η), 7.14-7.10 (m, 1H), 7.03-7.01 (m, 1H), 6.91-6.89 (m, 1H) ), 6.66 (t, J = 8.6 Hz, 1H), 4.95 (s, 2H), 3.06 (s, 2H), 2.80 (m, 1H), 2.59-2.53 (m, 2H), 1.42 (s, 6H) , 1.00 (d, J = 6.5 Hz, 3H). LC-MS ESI m/z: found: 375.0 [MH] - Example 30 3-(4-((4-fluoro)-2,2-dimethyl- 2,3-dihydrobenzopyranoyl-7-yl)methoxy)benzene

Base)-2-mercaptopropionic acid (59)

1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.23-7.20 (m, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H) , 6.65 (t, J = 8.6 Hz, 1H), 4.87 (s, 2H), 3.06 (s, 2H), 2.81-2.78 (m, 1H), 2.56-2.51 (m, 2H), 1.45 (s, 6H) ), 1.00 (d, J = 6.5 Hz, 3H). LC-MS ESI m/z : found 357.2 [Μ-ΗΓ

Example 31 2-(4-((2,2-Dimercapto-4-(trifluoromethyl)-2,3-dihydrobenzop-pentan-7-yl)methoxy)-3,5 -difluorophenyl)cyclopropanecarboxylic acid (60)

1 H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.97-6.95 (m, 2H ), 5.06 (s, 2H), 3.12 (s, 2H), 2.38-2.32 (m, 1H), 1.81-1.79 (m, 1H), 1.42-1.30 (m, 8H). LC-MS ESI m/z : U9105-sp-20100806.doc -223 - 201200505 Found 441.3 [MH]· Example 32 3-(4-((2,2-Dimethyl-4-(trifluoromethyl)-2,3- Hydrobenzofuran-7-yl)decyloxy)-3,5-(p-carbyl)-2-mercaptopropionic acid (61)

!H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1 Η), 7.36 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.96-6.94 (m, 2H ), 5.07 (s, 2H), 3.13 (s, 2H), 2.81 (dd, J = 12.8, 6.6 Hz, 1H), 2.68-2.48 (m, 2H), 1.37 (s, 6H), 1.00 (d, J = 6.7 Hz, 3H)· LC-MS ESI m/z: found: 443.2 [MH] - Example 33 3-(4-((2,2-dimethyl-4-(trifluoromethyl)) ,3-dihydrobenzopyranyl-7-yl)methoxy)-3-ylphenyl)-2-methylpropionic acid (62)

lU NMR (400 MHz, DMSO-d6) (5 12.13 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.16-7.03 (m, 3H), 6.91 (d, J = 8.3 Hz, 1H ), 5.06 (s, 2H), 3.18 (s, 2H), 2.81-2.79 (m, 1H), 2.62-2.51 (m, 2H), 1.46 (s, 6H), 1.00 (d, J = 6.6 Hz, 3H). LC-MS ESI m/z: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; And furan _7-yl) decyloxy) phenyl)-2-methylpropionic acid (63) 149 l05-sp*20100806.doc -224- 201200505

]H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.12-7.07 (m, 3H), 6.89 (d, J = 8.5 Hz, 2H ), 4.99 (s, 2H), 3.18 (s} 2H), 2.81-2.78 (m, 1H), 2.58-2.51 (m, 2H), 1.46 (s, 6H), 1.00 (d, J = 6.5 Hz, 3H). LC-MS ESI m/z : found 407.1

Examples 35A and 35B 2-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzindole)-South-7-yl)methoxy)-3,5-di Fluorophenyl)cyclopropanecarboxylic acid (64)

149105-sp-20100806.doc •225 - 201200505 (64B) : 1 H NMR (400 MHz, CDC13) 5 7.21 (s, 1H), 7.05 (s, 1H), 6.62 (d, J = 7.8 Hz, 2H) , 5.05 (s, 2H), 2.95 (s, 2H), 2.54-2.40 (m, 1H), 1.86-1.80 (m, 1H), 1.66-1.60 (m, 1H), 1.40 (s, 6H), 1.35 - 1.27 (m, 1H). LC-MS ESI m. Example 36 2-(5-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzotriac-7-yl)decyloxy)-2,3-dihydro-1H - although -1-yl) acetic acid (still)

NMR NMR (400 MHz, CDC13) 5 7.24 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 7.04 (s, 1H), 6.87 (s, 1H), 6.81 (d, J = 8.3 Hz , 1H), 4.96 (s, 2H), 3.61-3.45 (m, 1H), 3.00 (s, 2H), 2.95-2.77 (m, 3H), 2.50-2.38 (m, 2H), 1.82-1.75 (m , 1H), 1.48 (s, 6H). Example 37 2-(5-((5-Arsyl-2,2-dimercapto-2,3-dihydrobenzop-Fenonyl-7-yl)methoxy)_2,3_di-argon- 1H-Ink-1-yl)gf acid (66)

1H NMR (400 MHz, CDC13) δ 7.08 (m, 1H), 7.02-6.93 (m, 1H), 6.87 (s, 1H), 6.80 (m, 2H), 4.97 (s, 2H), 3.61-3.45 ( m, 1H), 2.99 (s, 2H), 2.92-2.74 (m, 3H), 2.50-2.35 (m, 2H), 1.77 (m, 1H), 1.48 (s, 6H). Example 38 149105-sp-20100806.doc -226 - 201200505 3-(4-((5-Alkyl-2,2-dimethyl-2,3-dibenzobenzopyran-7-yl)methoxy) Base-3,5-difluorophenyl)-2-methylpropionic acid (67)

NMR (400 MHz, CDC13) δ 7.22 (s, 1Η), 7.04 (s, 1H), 6.72 (s, 1H), 6.70 (s, 1H), 5.07 (s, 2H), 3.03-2.91 (m, 3H) ), 2.72 (m, 1H), 2.59 (m, 1H), 1.42 (s, 6H), 1.19 (d, J = 7.0 Hz, 3H). Example 39

3-(4-((5-Alkyl-2,2-dimercapto-2,3-dihydrobenzop-ranyl-7-yl)decyloxy)_2-anthraceneoxyphenyl)-2- Methyl propionic acid (68)

1 H NMR (400 MHz, CDC13) δ 7.05-6.99 (m, 3 Η), 6.52-6.48 (m, 2H), 4.96 (s, 2H), 3.79 (s, 3H), 3.00 (s, 2H), 2.98 -2.94 (m, 1H), 2.84-2.80 (m, 1H), 2.66-2.61 (m, 1H), 1.48 (s, 6H), 1.15 (d, J = 7.0 Hz, 3H)=

Example 40 3-(4-((2,3-Amidino-2,3-monohydrobenzopyrano-7-yl)decyloxy)-3,5-difluorophenyl)-2-indole Propionic acid (69)

LC-MS ESI m/z: found: 375.1,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -7-yl)decyloxy)_3,5-I49105-sp-20100806.doc -227- 201200505 difluorophenyl)cyclopropyl)acetic acid (70)

1H NMR (400 MHz, CDC13) δ 7.23 (s, 1 Η), 7.04 (s, 1H), 6.61 (d, J = 8.9

Hz, 2H), 5.04 (s, 2H), 2.95 (s, 2H), 2.50-2.38 (m, 2H), 1.74-1.65 (m, 1H), 1.40 (s, 6H), U0-1.25 (m, 1H), 0.98-0.88 (m, 2H). Example 42 3-(4-((5,6-Difluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3,5-difluorobenzene Benzyl-2-methylpropionic acid (71)

1H NMR (400 MHz, DMSO-d6) δ 7.27 (t, J = 9.2 Hz, 1H), 6.91 (d, J = 9.2 Hz, 2H), 5.04 (s, 2H), 2.91 (s, 2H), 2.82 -2.77 (m, 1H), 2.61-2.51 (m, 2H), 1.25 (s, 6H), 0.98 (d, J = 6.4 Hz, 3H). LC-MS ESI m/z : found 41N [MH] -. Example 43 3-(4-((5,6-Difluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl: K2-mercaptopropyl Acid (72)

1H NMR (400 MHz, DMSO-d6) δ 7.31 (t, J = 9.0 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.93 (s , 2H), 3.00 (s, 2H), 2.79 (m, 1H), 2.54 (m, 2H), 1.31 (s, 6H), 0.99 (d, J = 6.4 Hz, 3H). LC-MS ESI m/ z : measured 149l05-sp-20100806.doc 201200505 value 375.1 [M-Η]·. Example 44 3-(4-((2,2-Dimethyl-2,3-dihydro benzofuran-7-yl)oxy)indolyl)-3-fluorophenyl)-2-methyl Propionic acid (73)

H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1 Η), 7.41-7.37 (m, 1H), 7.08-7.02 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 7.2 Hz, 1H), 6.71-6.67 (m, 1H), 5.03 (s, 2H), 2.96 (s, 2H), 2.89-2.85 (m, 1H)} 2.64-2.60 (m, 2H) ), 1.37 (s, 6H), 1.02 (d, J = 6.0 Hz, 3H). LC-MS ESI m/z: Example 45 3-(4-((6-Fluoro-4H-benzo[d][l,3]dioxordecen-8-yl)decyloxy)phenyl)-2-

Methyl propionic acid (74)

149105-sp-20100806.doc -229· 201200505

NMR NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.01-6.99 (m, 2H), 6.95-6.92 (m, 1H), 6.76 (s, 1H), 6.71-6.69 (m, 1H ), 4.86 (s, 2H), 3.01 (s, 2H), 2.70 (t, J = 7.6 Hz, 2H), 2.40 (t, J = 7.6 Hz, 2H), 2.20 (s, 3H), 1.41 (s , 6H). LC-MS ESI m. Example 47 3-(2-Vinyl-4-((5-fluoro-2,2-dimethyl-2,3-dioxabenzopyran-7-yl)methoxy)phenyl)propanoic acid (76)

NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 7.23-7.20 (m, 1H), 7.05-7.01 (m, 2H), 6.97-6.95 (m, 1H), 6.90-6.88 (m, 1H), 4.92 (s, 2H), 3.01 (s, 2H), 2.84-2.79 (m, 2H), 2.48-2.43 (m, 2H), 1.41 (s, 6H). LC-MS ESI m/z : Found 377.1. Example 48 3-(2-Fluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)propanoic acid (77)

1H NMR (400 MHz, DMSO-d6) 5 12.15 (s, 1H), 7.16 (t, J = 8.6 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 10.0 Hz , 1H), 6.81 (d, J = 12.0 Hz, 1H), 149105-sp-20100806.doc -230- 201200505 6.73 (d, J = 8.4 Hz, 1H), 4.90 (s, 2H), 3.01 (s, 2H), 2.72 (t, J = 7.6 Hz, 2H), 2.44 (t, J = 7·6 Hz, 2H), 1.40 (s, 6H). LC-MS ESI m/z : found 361.4 [MH] · 〇 Example 49 3-(2,6-Difluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzo-yt-7-yl)methoxy) Phenyl)propionic acid (78)

NMR NMR (400 MHz, DMSO-d6) S 12.20 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 9.6 Hz, 1H), 6.75 (d, J = 9.2 Hz , 1H), 4.91 (s, 2H), 3.01 (s, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.39 (t, J = 7.4 Hz, 2H), 1.40 (s, 6H). LC - MS ESI m/z : found 379.1 [MH]-. Example 50 3-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)methoxy)-2-indole

Oxyphenyl) propionic acid (79)

1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1 Η), 7.02-6.95 (m, 3H), 6.56 (s, 1H), 6.47 (d, J = 8.0 Hz, 1H), 4.89 (s, 2H), 3.73 (s, 3H), 3.01 (s, 2H), 2.66 (t, J = 7.6 Hz, 2H), 2.37 (t, J = 7.4 Hz, 2H), 1.40 (s, 6H). LC- MS ESI m/z: calcd. 373.4 [MH]-. Example 51 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)decyloxy)·2-A 149105-sp-20100806 .doc -231 - 201200505 Phenylphenyl)propionic acid (80)

1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.17 (d, J = 10.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 6.71 (d, J = 8.4 Hz, 1H), 4.86 (s, 2H), 3.01 (s, 2H), 2.70 (t, J = 7.6 Hz, 2H), 2.40 (t, J = 7.8 Hz, 2H), 2.20 (s, 3H), 1.41 (s, 6H). LC-MS ESI m/z: Found 373·2 [MH]. Example 52 3-(2-Alkyl-4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzop-pentan-7-yl)methoxy)phenyl) -propionic acid (81)

1 H NMR (400 MHz, DMSO-d6) ά 12.18 (s, lH), 7.23-7.18 (m, 3H), 7.05 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.92 (s , 2H), 3.01 (s, 2H), 2.81 (t, J = 7.6 Hz, 2H), 2.45 (t, J = 8.0 Hz, 2H), 1.41 (s, 6H). LC-MS ESI m/z : Found 398.3 [MH]-. Example 53 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzoheptin-7-yl)methoxy)-2-fluorophenyl)-propane Acid (82)

1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 7.20-7.14 (m, 3H), 6.82 149105-sp-20100806.doc • 232- 201200505 (d, J = 11.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 4.90 (s, 2H), 3.02 (s, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.44 (t, J = 7.6 Hz, 2H), 1 · 41 (s, 6H). LC-MS ESI m. Example 54 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzopyran-7-yl)methoxy)_2,6-difluorophenyl) Propionic acid (83)

]H NMR (400 MHz, DMSO-d6) δ 12.19 (br, 1 Η), 7.27-7.20 (m, 2H), 6.75 (d, J = 9.2 Hz, 2H), 4.92 (s, 2H), 3.02 (s , 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.40 (t, J = 7.6 Hz, 2H), 1.41 (s, 6H). LC-MS ESI m/z : found 395.1 [MH]· . Example 55 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzop-Unan-7-yl)methoxy)_2_indolylphenyl) Propionic acid (84)

H NMR (400 MHz, DMSO-d6) δ 12.03 (br, 1H), 7.21-7.17 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.56 (s, 1H), 6.47 (d , J = 8.0 Hz, 1H), 4.89 (s, 2H), 3.74 (s, 3H), 3.02 (s, 2H), 2.66 (t, J = 7.6 Hz, 2H), 2.38 (t, J - 7.8 Hz , </ RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> <RTIgt; Example 56 3-(2-Bromo-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzopyrene. South_7-yl)methoxy-149105-sp-20100806 .doc -233 - 201200505 base)-5-methoxyphenyl)propionic acid (85)

^NMRC^OMH^DMSO-^) δ 12.20 (br, 1Η), 7.14 (s, 1Η), 7.03-6.92 (m, 3H), 4.90 (s, 2H), 3.72 (s, 3H), 3.01 (s , 2H), 2.80 (m, 2H), 2.47 (m, 2H), 1.40 (s, 6H). LC-MS ESI m/z: Example 57 3-(2-Bromo-4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-5-methoxy Phenyl)propionic acid (86)

]H NMR (400 MHz, DMSO-d6) δ 12.21 (br, 1 Η), 7.20-7.14 (m, 3H), 6.96 (s, 1H)S 4.90 (s, 2H), 3.71 (s, 3H), 3.01 (s, 2H), 2.80 (m, 2H), 2.47 (m, 2H), 1.41 (s, 6H). LC-MS ESI m/z: Example 58 2-((4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)thio)-acetic acid ( 87)

1H NMR (400 MHz, DMSO-d6) δ 12.58 (br, 1H), 7.30 (d, J = 7.2 Hz, 2H), 7.02-6.94 (m, 4H), 4.90 (s, 2H), 3.61 (s, 2H), 3.00 (s, 2H), 1.40 (s, 6H). LC-MS ESI m/z: Found: 361.2 [MH]. 149105-sp-20100806.doc -234 - 201200505 Example 59 2-((4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran-7)-yloxy) Phenyl) thio)-acetic acid (88)

1 H NMR (400 MHz, DMSO-d6) δ 12.60 (br, 1 Η), 7.30 (d, J = 7.2 Hz, 2H), 7.23-7.18 (m, 2H), 6.95 (d, J = 8.0 Hz, 2H ), 4.90 (s, 2H), 3.61 (s, 2H),

</ RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Example 60 (E)-3-(2-Ethyl-4-((5-fluoro-2,2-dimercapto-2,3-dihydro-p-pyranyl-7)-methoxy) )phenyl)acrylic acid (89)

'Η NMR (400 MHz, DMSO-d6) δ 12.27 (br, 1H), 7.77-7.73 (m, 1H), 7.68-7.62 (m, 1H), 7.04-7.00 (m, 1H), 6.99-6.96 ( m, 1H), 6.87-6.84 (m, 2H), 6.29 (d, J = 15.6 Hz, 1H), 4.95 (s, 2H), 3.01 (s, 2H), 2.69-2.67 (m, 2H), 1.41 (s, 6H), 1.10-1.08 (m, 3H). LC-MS ESI m/z: Found: 369.2 [M-Η]. Example 61 3-(4-((5-Gasyl-2,2-dimercapto-2,3-diindole benzene p-pyran-7-yl)methoxy)_2_(trimethyl)benzene Propionate (90) 0^ 149105-sp-20100806.doc 235· 201200505

NMR (400 MHz, DMSO-d6) δ 12.22 (br, 1H), 7.39-7.37 (m, 1H), 7.23-7.20 (m, 2H), 7.03-6.97 (m, 2H), 4.98 (s5 2H), 3.00 (s, 2H), 2.89-2.86 (m, 2H), 2.49-2.44 (m, 2H), 1.40 (s, 6H). LC-MS ESI m/z: Found 41. Example 62 3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)_2-(trifluoromethyl)phenyl Propionic acid (91)

NMR (400 MHz, DMSO-d6) &lt;5 12.22 (br, 1H), 7.40-7.38 (m, 1H), 7.23-7.19 (m, 4H), 4.98 (s, 2H), 3.01 (s, 2H) , 2.89-2.86 (m, 2H), 2.49-2.45 (m, 2H), 1.40 (s, 6H). LC-MS ESI m/z: found: 427.4 [MH]. Example 63 3-(7-((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzopyranyl-7)ylmercapto)_2,3_dihydro-1Η-茚-4-yl)propionic acid (92)

NMR (400 MHz, CDC13) &lt;5 6.99-6.96 (m, 1H), 6.94-6.90 (m, 1H), 6.79-6.77 (m, 1H), 6.72-6.68 (m, 1H), 5.00 (s, 2H), 3.00 (s, 2H), 2.98-2.85 149105-sp-20100806.doc 236- 201200505 (m, 6H), 2.62 (t, J = 8.0 Hz, 2H), 2.12-2.06 (m, 2H), </ RTI> </ RTI> </ RTI> <RTIgt; Example 64 3-(7-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)-2,3-dihydro-1H-indole _4·基)propionic acid (W)

4 NMR (400 MHz, CDC13) 5 7.26-7.24 (m, 1H), 7.05-7.02 (m, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H) , 4.98 (s, 2H), 3.00 (s, 2H), 2.97-2.83 (m, 6H), 2.62 (t, J = 7.8 Hz, 2H), 2.10 (t, J = 7.8 Hz, 2H), 1.48 ( s, 6H)· LC-MS ESI m/z: found 399.3 [MH]. Example 65 (R)-3-(4-((5-Arsyl-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2- Mercaptopropionic acid (94)

To a solution of lithium hydroxide (65 mg, 1.55 mmol) in water (2 ml), 30% hydrogen peroxide (. 4 mL, 3.88 mmol) was added and stirred for 30 min. Allow the solution to cool to hydrazine. (:, and added to (S)-5-knotyl-l-((R)-3-(4-((5-fluoro-2,2-dimethyl-2,3) at 〇 °C -Dihydrobenzofuran-7-yl)decyloxy)phenyl)_2·methylpropenyl)tetrahydropyrrole-2-one (805) (500 mg, 0.97 mmol) at 4:1 In a solution of hydrogen puffol/water (5 ml), the reaction was stirred under 〇. 〇 149105-sp-20100806.doc • 237 · 201200505 hours, and sodium sulfite in water (3 ml) ( 489 mg, 3 88 mmol. The reaction was quenched. The solvent was removed in vacuo at room temperature. The solution was cooled to 0 ° C and acidified with 6 NCI. Sodium dehydration and drying 'filtration' and concentration in vacuo. The crude compound was purified by flash column chromatography eluting with hexane and Et0Ac (2%) to obtain (R)-3-(4) -((5-Fluoro-2,2-monomethyl-2,3-dihydrobenzopyrene. Nan-7-yl)decyloxy)phenyl)-2-methylpropanoic acid (94). 1H NMR (400 MHz, CDC13) 5 : 7.09 (d, J = 8 5

Hz, 2H), 6.97 (d, J — 9.7 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H), 6.79 (d J = 7 6 Hz, 1H), 4.97 (s, 2H), 3.05- 2.95 (m, 3H), 2.75-2.58 (m, 2H), 1.48 (s, 6H), 1.16 (d,J = 4.0 Hz, 3H). LC-MS ESI m/z: found 357.0 [MH]- . Example 66 (S)-3-(4-((5-|L-based-2,2-dif-yl-2,3-dihydrobenzop-e-N-)-yloxy)benzene

Base)-2-methylpropionic acid (95)

806 95 Compound (95) was prepared in a similar manner as described for the synthesis of (94). ! h NMR (400 MHz, CDC13) δ : 7.09 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 9.7 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H), 6.79 (d , J = 7.6 Hz, 1H), 4.97 (s, 2H), 3.05-2.95 (m, 3H), 2.75-2.58 (m, 2H), 1.48 (s, 6H), 1.16 (d, J = 4.0 Hz, </RTI> </RTI> <RTI ID=0.0></RTI> Example 67 3-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl)amino)phenyl)-2-yl Propionate (96) 149105-sp-20100806.doc 238 · 8 201200505 ο

OH !Η NMR (400 MHz, DMSO-d6) ¢5 6.93-6.77 (m, 4H), 6.49 (d, J = 7.8 Hz, 2H), 4.05 (s, 2H), 2.98 (s, 2H), 2.70 -2.66 (m, 1H), 2.47-2.39 (m, 2H), 1.40 (s, 6H), 0.95 (d, J = 8.0 Hz, 3H). LC-MS ESI m/z : 356. -. Example 68 3-(4-(5-ranyl-2,2-indanyl-2,3-diazabenzidine. South-7-sodium sulphate)phenyl)-2_ decyl-propyl Acid (97) Ο

5-Fluoro-2,2-dimercapto-2,3-dihydro benzofuran-7-carboxylic acid (803) (compound made in a similar manner as described for the synthesis of (735)) 1〇13 mg, 0.482 mmoles, dissolved in dioxane (4 ml), and added 3_(4-aminophenylphenethyl propyl propionate (646) (100 mg, 0.482 mmol) ), triethylamine (〇, 4 ml ' 2.89 mmol) and 1 - propane phosphonic acid cyclic anhydride (〇 · 34 ml, 〇 · 58 mmol, 50% in ethyl acetate), and in the room After stirring overnight, the reaction was concentrated in vacuo and purified by flash chromatography eluting with EtOAc EtOAc EtOAc Methyl-2,3-dihydrobenzofuran_7·carboxycarboxamido)phenyl)-2-mercaptopropionic acid ethyl ester. This ester was dissolved in tetrahydrofuran (1 mL), decyl alcohol (1.0 ml) And water (3 ml). Add lithium hydroxide and stir the reaction at room temperature for 4 hours. Acidify the mixture with 1 ΜΗα, and 149105-sp-20100806.doc

S-239- 201200505 was diluted with EtOAc (3 mL). The organic layer was washed with brine (3 ml), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give 3-(4-(5-fluoro-2,2-monomethyl-2,3-dihydrobenzopyrene-N--7-treaminyl)phenyl) 2-mercaptopropionic acid (97). 1 H NMR (400 MHz, CDC13) (5 9.53 (br, 1H), 7.66 (dd, J = 9.9, 2.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.02 (dd, J = 9.9, 2.6 Hz, 1H), 3.13-3.00 (m, 3H), 2.72 (m, 2H), 1.60 (s, 6H), 1.19 (d, J = 8.0 Hz, 3H). Example 69 3-(3,5-Difluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)) Oxy)phenyl)-2-ethoxypropionic acid (98)

1 H NMR (400 MHz, CDC13) δ 6.94 (d, J = 9.4 Hz, 1H), 6.77 (m, 3H), 5.09 (s, 2H), 4.03 (m, 1H), 3.62 (m, 1H), 3.44 (m, 1H), 3.09-2.82 (m, 4H), 1.42 (s, 6H), 1_19 (t, J = 7.0 Hz, 3H). LC-MS ESI m/z: found 423.4 [MH]' = Example 70 2-(4-(2-(5-Fluoro-2,2-dimercaptodihydrobenzofuran-7-yl)ethyl)phenoxy)acetic acid (99)

4-(2-(5-Fluoro-2,2-dimethyl-2 3 -dihydrobenzofuran-7-yl)ethyl)phenol (65〇) (!64.1 mg ' 0·573 毫Mohr), ethyl bromoacetate (9S 7 mg, 〇573 149105-sp-20100806.doc •240· 201200505 millimolar), carbonated planer (265 mg, 0,688 mmol) and acetonitrile (5 ml) At 50. (The mixture was heated for 18 hours. The reaction was concentrated in vacuo then purified by flash chromatography eluting with EtOAc EtOAc (30%). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3 ml) Wash 'dehydrated with sodium sulfate and filtered. Concentrate the filtrate in vacuo to give 2-(4-(2-(5-fluoro-2,2-dimethyl-2,3-) Hydrogen benzofuran·7·yl)ethyl)phenoxy)acetic acid (99). iHNMRHOOMHACDClJ^y.lUcU = 7.8 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 4.65 (s, 2H), 2.96 (s, 2H), 2.88-2.73 (m, 4H), 1.43 (s, 6H). LC - MS ESI m/z : found 343.4 [MH]. Example 71 3-(5-((5-Aneso-2,2-dimethyl-2,3-dihydrobenzop-yt-7-yl)methoxy)

Biphenyl]-2-yl)propionic acid (100)

1H NMR (400 MHz, DMSO-d6) δ 7.48-7.12 (m, 8 Η), 6.92 (s, 1H)S 6 73 (s, 1H), 4.92 (s, 2H), 2.99 (s, 2H), 2.66 (m, 2H), 2.26 (m, 2H), 1.33 (Sj 6H). Example 72 3-(5-((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzopyran-7-yl)decyloxy)_p j,biphenyl]-2 -yl)propionic acid (101) 149105-sp-20100806.doc -241 - 201200505

Ln NMR (400 MHz, DMSO-d6) δ 12.00 (br, 1H), 7.48-7.13 (m, 6H), 6.95-6.90 (m, 3H), 6.73 (s, 1H), 4.91 (s, 2H), 2.98 (s, 2H)} 2.66 (m, 2H), 2.26 (m, 2H), 1.33 (s, 6H), LC-MS ESI m/z: Found: 419.3 [MH]-. Example 73 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzoindole)-N-7-yl)nonyloxy)-5-fluoro-2- Propyl phenyl) propionic acid (102)

^NMRC^OMH^DMSO-ds) δ 12.15 (br, 1Η), 7.18 (m, 2Η), 6.96 (m, 2H), 4.96 (s, 2H), 3.01 (s, 2H), 2.70 (m, 2H) ), 2.42 (m, 4H), 1.47 (m, 2H), 1.40 (s, 6H), 0.87 (t, J = 8_0 Hz, 3H). LC-MS ESI m/z : found 419.4 [M-Η ]. Example 74 3-(5-Fluoro-4-((5-fluoro-2,2-dimethyl-2,3-diargonbenzoindol-7-yl)methoxy)-2-propane Phenyl phenyl) propionic acid (103)

1H NMR (400 MHz, DMSO-d6) δ 12.14 (br, 1H), 6.99 (m, 2H), 6.96 (m, 2H), 4.95 (s, 2H), 3.00 (s, 2H), 2.70 (m, 2H)} 2.45 (m, 4H), 1.46 (m, 2H), 1.39 (s, 6H), 0.87 (d, J = 7·2 Hz, 3H). LC-MS ESI m/z: found 403.4 [ MH]-. 149105-sp-20100806.doc -242 - 201200505 Example 75 3-(4-((5-Chloro-2,2-dimethyl-3-keto-2,3-dihydrobenzofuran-7-) Methoxy)-2-ethyl-3-phenylphenyl)propionic acid (104)

1 H NMR (400 MHz, DMSO-d6) δ 12.16 (br, 1 Η), 7.85 (s, 1H), 7.70 (s, 1H), 7.03 (m, 1H), 6.92 (m, 1H), 5.14 (s , 2H), 2.76 (m, 2H), 2.58 (m, 2H), 1.38 (s, 6H), 1.06 (m, 3H). LC-MS ESI m/z: found: 419.3 [MH]. Example 76 3-(4-((5-Gasyl-2,2-dimethyl-3-indolyl-2,3-dioxabenzopyran-7-yl)methoxy)-2- Propyl phenyl) propionic acid (105)

0

149105-sp-20100806.doc -243 - 201200505 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (br, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.20-7.16 (m, 1H), 7.04 (d, J = 12.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 5.16 (s, 2H), 2.78 (m, 1H), 2.56 (m, 2H), 1.39 ( s, 6H), 1.00 (d, J = 4.0 Hz, 3H). LC-MS ESI m/z: Found: 405.3 [MH]. Example 78 3-(3-Alkyl-4-((5-fluoro-2,2-dimercapto-3-indolyl-2,3-diazabenzotrimium-7-yl) methoxy Phenyl)-2-methylpropionic acid (107)

1 H NMR (400 MHz, DMSO-d6) &lt;5 12.14 (br, 1H), 7.73 (dd, J = 8.0, 4.0 Hz, 1H), 7.48 (dd, J = 8.0, 4.0 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 12.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 5.16 (s, 2H), 2.79-2.75 (m, 1H) , 2.56-2.51 (m, 2H), 1.39 (s, 6H), 1.00 (d, J = 6.3 Hz, 3H). LC-MS ESI m/z: Found: 389.1 [MH]-. Example 79 3-(4-((5-Chloro-2,2-dimercapto-3-one-2,3-dihydrobenzofuran-7-yl)decyloxy)-3-(III Fluorinyl)phenyl)-2-mercaptopropionic acid (108)

lH NMR (400 MHz, CDC13) δ 7.77 (s, 1Η), 7.58 (s, 1H), 7.43 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz , 1H), 5.19 (s, 2H), 3.09-2.97 (m, 1H), 2.76-2.68 (m, 2H), 1.48 (s, 6H), 1.20 (d, J = 6.7 Hz, 3H). LC- MS ESI m/z: found 455.0 [MH]. 149105-sp.20100806.doc •244- 201200505 Example 80 3-(4-((5-Alkyl-3-hydroxy-2,2-dimethyl-2,3-dihydrobenzopyranyl)) Oxy)-3-fluorophenyl)-2-methylpropionic acid (1〇9)

3-(4-((5-Chloro-2,2-dimethyl-3-keto-2,3-dihydrobenzoc-yl)-methoxy)-3-fluorobenzene Addyl borohydride (15 mg ' 0.393 mmol) in a solution of tetrahydrofuran / decyl alcohol (2:1, 2 ml) in a solution of 2-mercaptopropionic acid (106) (80 mg, 0.197 mmol) ear). After the reaction was stirred at room temperature for 15 hours, water was added and the solution was extracted with ethyl acetate, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 3-(4-((5-carbyl-3-yl)- 2,2-dimethyl-2,3-dihydrobenzoindan-7-yl) Oxy)-3-fluorophenyl)_2-methylpropionic acid (109). 1H NMR (400 MHz, CDC13) (5 7.40 (s, 1H), 7, 31 (s, 1H), 6.92

(m, 2H), 6.82 (d, J = 12.0 Hz, 1H), 5.04 (s, 2H), 4.75 (s, 1H), 2.93 (m, 1H), 2.71 (m, 1H), 2.64 (m, 1H), 1.49 (s, 3H), 1.34 (s, 3H), 1.18 (d, J = 6.9 Hz, 3H). LC-MS ESI m/z: found: 407.3 [MH]-. Example 81 3-(4-((5-Molyl-2,2-dimercapto-2,3·dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoic acid (110)

1 H NMR (400 MHz, CDC13) δ 731 (s, 1 Η), 7.11 (s, 1H), 7.02 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.2 Hz, 2H), 4.89 ( s, 2H)} 2.95-2.91 (m, 3H), 2.73-2.47 149105-sp-20100806.doc • 245 - 201200505 (m, 2H), 1.41 (s, 6H), 1·10 (d, J = 6 · 8 Hz, 3H). LC-MS ESI m/z: found 418.0 [M-Η]. Example 82 3-(4-((5-(4-Chlorophenyl)-2,2-dimethyl-2,3-dihydrobenzoindole-7-yl)methoxy)

Phenyl)-2-mercaptopropionic acid (ill)

3-(4-((5-Amino-2,2-dimethyl-2,3-dihydrobenzo-benzoic acid) methoxy)phenyl)-2-methylpropanoic acid Ester (110) (80 mg, 0.179 mmol), 4-phenylphenyl dihydroxyborane (30.8 mg, 0.197 mmol), Pd(PPh3)4 (7 mg, 00.006 mmol), saturated carbonic acid A solution of sodium hydrogen (0.64 mL), methanol (1.5 mL) and toluene (0.64 mL) was taken in a microwave reactor at 11 Torr. Heat it under your arm for 4 minutes. Water and ethyl acetate were added to this solution, and the two liquid layers were separated. The crude compound was subjected to flash column chromatography on silica gel, and purified with hexane and Et EtOAc (3 〇%;) to give 3-(4·((5·(4- phenyl)) 2, 2 _ Dimercapto·2,3_: Hydrogen benzofuranyl-7-yl)decyloxy)phenyl)-2-mercaptopropionic acid ethyl ester. This ester was dissolved in tetrahydrofuran (1.0 ml), methanol (1.0 ml) and water (3 ml). A citric acid was added and the mixture was stirred at rt EtOAc (EtOAc) (EtOAc) The organic layer was washed with brine (3 mL) dried over sodium sulfate sulfate The filtrate was concentrated in vacuo to give 3-(4·((5-(4-phenylphenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) methoxy Phenyl)-2-methylpropionic acid (ill). 4 NMR (400 MHz, CDC13) &lt;5 •246 - 149l05-sp-20l00806.doc 3 201200505 7.43-7.39 (m, 3H), 7.34 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.3 Hz, 2H), 5.05 (s, 2H), 3.07 (s, 2H), 3.00 (dd, J = 13.4, 6.4 Hz, 1H), 2.73-2.67 (m, 1H), 2.62-2.58 (m, 1H), 1.51 (s, 6H), 1.17 (d, J = 6.8 Hz, 3H). LC-MS ESI m /z : measured value 449.1 [M-Η]·. Example 83 3-(4-((5-(4-Fluorophenyl)-2,2-dimethyl-2,3-dihydrobenzoin-7-yl)methoxy)

Phenyl)-2-methylpropionic acid (112)

Compound (112) was prepared in a similar manner as described for the (111) synthesis. 1 H NMR (400 MHz, CDC13) δ 7.44-7.38 (m, 4 Η), 7.16-7.02 (m, 4H), 6.95 (d, J = 8.3 Hz, 2H), 5.05 (s, 2H), 3.07 (s , 2H), 3.03 (dd, J = 13.4, 6.4 Hz, 1H), 2.80-2.68 (m, 1H), 2.67-2.56 (m, 1H), 1.51 (s, 6H), 1.17 (d, J = 6.8 Hz, 3H). LC-MS ESI m.

Example 84 3-(4-((5-(3-Phenylphenyl)-2,2-diindenyl-2,3-dihydroindolyl-7-yl)methoxy)

Phenyl)-2-methylpropionic acid (113)

Compound (113) was prepared in a similar manner as described for (in) synthesis. 1 H NMR (400 MHz, CDC13) δ 7.49-7.46 (m, 2H), 7.38 (d5 J = 7.8 Hz, 1H), 149105-sp-20100806.doc • 247- 201200505 7.34-7.17 (m, 3H), 7.09 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 5.05 (s, 2H), 3.07 (s, 2H), 3.02-2.97 (m, 1H), 2.75-2.71 (m, 1H), 2.64-2.59 (m, 1H), 1.52 (s, 6H), 1.17 (d, J = 6.9 Hz, 3H). LC-MS ESI m/z: found 449.0 [M-Η] - ° Example 85 3-(4-((5-(2-Chlorophenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl) -2-methylpropionic acid (114)

Compound (114) was prepared in a similar manner as described for the (111) synthesis. !H NMR (400 MHz, CDC13) δ 7.47-7.38 (m, 1Η), 7.35-7.27 (m, 3H), 7.24-7.19 (m, 2H), 7.08 (d, J = 6·9 Hz, 2H) , 6.93 (d, J = 6.6 Hz, 2H), 5.05 (s, 2H), 3.08 (s, 2H), 3.04-2.93 (m, 1H), 2.74-2.71 (m5 1H), 2.65-2.60 (m, 1H), 1.52 (s, 6H), 1_15 (d, J = 8.0 Hz, 3H). LC-MS ESI m/z: found 449.2 [M-Η]. Example 86

3-(4-((5-(3-oxaoxyphenyl)-2,2-dimercapto-2,3-dihydrobenzobenzophenan-7-yl)methylindolyl) - mercaptopropionic acid (115)

Compound (115) was prepared in a similar manner as described for the (111) synthesis. 149105-sp-20100806.doc •248 ·

201200505 NMR (400 MHz, CDC13) δ 7.46 (s, 1H), 7.30-7.28 (m, 2H), 7.15-7.08 (m, 3H), 7.02 (s, 1H), 6.94 (d, J = 7.7 Hz, 2H), 6.82 (d, J = 8.0 Hz, 1H), 5.06 (s, 2H), 3.84 (s, 3H), 3.07 (s, 2H), 3.01-2.96 (m, 1H), 2.79-2.53 (m , 2H), 1.51 (s, 6H), U7 (d, J = 6.7 Hz, 3H). LC-MS ESI m/z: found: 445.2 [MH]. Example 87

3-(4-((2,2-Dimethyl-5-(3-(trifluoromethyl)phenyl)-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl )-2-f-propionic acid (116)

Compound (116) was prepared in a similar manner as described for the (111) synthesis. ]H NMR (400 MHz, CDC13) δ 7.74 (s, 1Η), 7.68 (d, J = 8.0 Hz, 1H), 7.51-7.49 (m, 3H), 7.32 (s, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 5.06 (s, 2H), 3.09 (s, 2H), 3.03-2.98 (m, 1H), 2.76-2.59 (m, 2H) , 1.52 (s, 6H), 1.17 (d, J = 6.9 Hz, 3H). LC-MS ESI m/z: found 483_1 [MH]. Example 88 3-(4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)-3-((dimethylamino) Mercapto)phenyl)-2-mercaptopropionic acid (117)

1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 7.30 (s, 1H), 7.24-7.23 (m, 3H), 7.11 (d, J = 8.8 Hz, 1H), 5.00 (s , 2H), 4.20 (d, J = 4.7 Hz, 2H), 3.03 (s, 2H), 2.89-2.76 (m, 1H), 2.70 (s, 6H), 2.57-2.48 (m, 2H), 1.42 ( s, 6H), 1.02 149105-sp-20100806.doc • 249· 201200505 (d, J = 6.4 Hz, 3H). LC-MS ESI m/z: found 431 ·7 [M-Η]. Example 89 3-(4-((5-(Diethylamino)-2,2-dimethyl-2,3-dihydrobenzo-[beta]-N-7-yl)methoxy)phenyl)- 2-methylpropionic acid (118)

3-(4_((5-)-2,2-dimercapto-2,3-dihydrobenzo- -7-yl)methoxy)luphenyl)-2-methylpropanoic acid Ethyl ester (11 〇) (78 mg, 0.17 mmol), diethylamine (0.08 ml '〇·78 mmol), [1,1,-biphenyl]_2·yl 2 _3· Phosphine (16 mg, 0.052 mmol), ginseng (diphenylmethyleneacetone) dipalladium (476 mg, 0.052 mmol) and sodium tris-butoxide (25 mg, 0.26 mmol) in A The mixture was stirred in EtOAc (2 mL). And concentrated in a vacuum. The crude compound was purified by flash column chromatography eluting with hexane and Et EtOAc (5 〇%) to give 3-(4-((5-(diethylamine)) Ethyl)-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)-2-ethylpropanoate. Dissolve this ester in tetrahydroanthracene .South GO ml), methanol (1.0 ml) and water (3 ml). The hydroxide chain was added and the reaction was stirred at room temperature for 24 hours. The mixture was acidified with (10) and diluted with Ε· (3 ml). The organic layer was washed with brine (3 ml), dehydrated with sulfuric acid steel, and filtered. The filtrate was concentrated in vacuo to give 3_(4_((5-(diethylamino)-2,2·didecyl-2,3-dihydrobenzofuran-7) decyloxy)phenyl ) 2曱149105-sp-20100806.doc 8 -250 - 201200505 Propionic acid (118). 1 H NMR (400 MHz, CDC13) (5 7.38 (s, 1 Η), 7.18 (s, 1H), 7.09 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H) , 5.04 (s, 2H), 3.84-3.47 (m, 2H), 3.34-3.09 (m, 2H), 3.06 (s, 2H), 3.01-2.89 (m, 1H), 2.78-2.57 (m, 2H) , 1.51 (s, 6H), 1.18 (d, J = 6.7 Hz, 3H), 1.07 (t, J = 6.9 Hz, 6H). LC-MS ESI m/z: found 410.4 [MH]. 3-(4-((2,2-Dimethyl-5-(1 H-tetras(ytyl-1-yl)-2,3-dihydrobenzop-amyl-7-yl) decyloxy) Phenyl)-2-methylpropionic acid (119)

1 H NMR (400 MHz, CDC13) δ 8.86 (s, 1 Η), 7.52 (s, 1H), 7.41 (s, 1H), 7.11 (d, J = 7.8 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 5.06 (s, 2H), 3.12 (s, 2H), 3.02-2.98 (m, 1H), 2.77-2.62 (m, 2H), 1.55 (s, 6H), 1.18 (d, J = </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 91 3-(4-((7-Fluoro-2,2-dimethyl-2,3-dihydrobenzopyran-4-yl)methoxy)phenyl)-2-indenylpropyl Acid (120)

149105-sp-20100806.doc •251 · 1 H NMR (400 MHz, CDC13) 7.10 (d, 2H), 6.92 (m, 1H), 6.87 (d, 2H), 6.79 (m, 1H), 4.89 (s , 2H), 3.07 (S&gt; 2H), 3.00 (m, 1H), 2.76-2.61 (m, 3H), 1.51 (s, 6H), 1.17 (d, 3H). Example 92 201200505 3-(3,5-Fluoro-4-((7-fluoro-2,2-dimethyl-2,3-dihydrobenzopyran-4-yl)methoxy)benzene Base)-2-mercaptopropionic acid (121)

1H NMR (400 MHz, CDC13) δ 6.86 (t, 1 Η), 6.76-6.70 (m, 3H), 4.99 (s, 2H), 3.16 (s, 2H), 2.95 (m, 1H), 2.71 (m, 1H), 2.59 (m, 1H), 1.52 (s, 6H), 1.18 (d, 3H). Example 93 2-(3,5-Difluoro-4-((7-acetyl-2,2-dimethyl-2,3-dihydrobenzofuran-4-yl)decyloxy)phenyl) Cyclopropanecarboxylic acid (122)

1 H NMR (400 MHz, CDC13) δ 6.86 (t, 1H), 6.75-6.72 (m5 1H), 6.62 (d, 2H), 4.99 (s, 2H), 3.15 (s, 2H), 2.49 (m, 1H), 1.83 (m, 1H), 1.64 (m, 1H), 1.52 (s, 6H), 1.31 (m, lH). Example 94 2-(5-((7-Fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-4-yl)methoxy)-2,3-dihydro-1H -茚-1-yl)acetic acid (123)

1H NMR (400 MHz, CDC13) (5 7.11 (d, 1H), 6.92 (t, 1H), 6.83-6.76 (m, 3H), 4.89 (s, 2H), 3.54 (m, 1H), 3.08 (s , 2H), 2.92-2.77 (m, 3H), 2.51-2.41 (m, 2H), 1.83-1.74 (m, 1H), 1.52 (s, 6H). Example 95 149105-sp-20100806.doc -252 - 201200505 3-(3,5-Difluoro-4-((5-fluoro)2,2-dimethyl-2,3-dihydrobenzofuranyl)methoxy)phenyl)-2- Mercaptopropionic acid (124)

H NMR (400 MHz, CDC13) δ 6.80-6.70 (m, 3Η), 6.63-6.60 (m, 1H), 5.10 (s, 2H), 3.12 (s, 2H), 2.96 (m, 1H), 2.72 ( m, 1H), 2.60 (m, 1H), 1.46 (s, 6H), 1.19 (d, 3H). Example 96

3-(4-((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-4-yl)decyloxy)phenyl)-2-methylpropanoic acid (125 )

1H NMR (400 MHz, CDC13) d 7.10 (d, 2H), 6, 89 (d, 2H), 6.82 (t, 1H), 6.62 (dd, 1H), 5.03 (s, 2H), 3.07 (s, 2H), 3.04-2.98 (m, 1H), 2.76-2.71 (m, 1H), 2.66-2.60 (m, 1H), 1.45 (s, 6H), 1.18 (d, 3H). Example 97

(R)-3-(3,5-difluoro-4-((5-1-yl-2,2-dimethyl-2,3-dihydrobenzofuran-4-yl)methoxy)benzene Base)-2-mercaptopropionic acid (126)

Compound (126) was prepared in a similar manner as described for the synthesis of (94). NMR NMR (400 MHz, CDCI3) δ 6.80-6.70 (m, 3H), 6.63-6.60 (m, 1H), 5.10 (s, 2H), 3.12 (s, 2H), 2.99-2.94 (m, 1H) , 2.75-2.70 (m, 1H), 2.63-2.57 (m, 1H),

S 149105-sp-20100806.doc •253 - 201200505 1.46 (s,6H), 1.18 (d,3H). Example 98 3-(4-((5-Chloro-2,2-dimethyl-2,3-dioxabenzoin-7-yl)decyloxy)-2-methoxyphenyl)- 2-mercaptopropionic acid (127)

1 H NMR (400 MHz, CDC13) δ 7.05-6.99 (m, 3 Η), 6.52-6.48 (m, 2H), 4.96 (s, 2H), 3.79 (s, 3H), 3.00 (s, 2H), 2.98 -2.94 (m, 1H), 2.84-2.80 (m, 1H), 2.66-2.61 (m, 1H), 1.46 (s, 6H), 1.15 (d, 3H) 〇Example 99 2-(3,5-II Deficient 4-((5-1-yl-2,2-dimethyl-2,3-dihydrobenzop-butan-4-yl)methoxy)phenyl)cyclopropanecarboxylic acid (128)

*Η NMR (400 MHz, CDCI3) δ 6.81-6.76 (m, 1Η), 6.66-6.61 (m, 3H), 5.10 (s, 2H), 3.11 (s, 2H), 2.52-2.47 (m, 1H) , 1.87-1.82 (m, 1H), 1.68-1.63 (m, 1H), 1.46 (s, 6H), 1.35-1.30 (m, 1H). Example 100 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzop-butan-4-yl)methoxy)-3,5-difluorobenzene Base)-2-mercaptopropionic acid (129)

1H NMR (400 MHz, CDC13) δ 7.11 (d, 1Η), 6.74 (d, 2H), 6.64 (d, 1H), 5.17 (s, 2H), 3.14 (s, 2H), 3.00-2.95 (m, 1H), 2.75-2.70 (m, 1H), 2.63-2.58 149105-sp-20100806.doc -254 - 201200505 (m,1H), 1.46 (s,6H), 1.19 (d,3H). Example 101 3-(3,5-Difluoro-4-((6-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-4-yl)methoxy)phenyl )-2-methylpropionic acid (130)

1 H NMR (400 MHz, CDC13) δ 6.73 (d, 2Η), 6.59 (d, 1H), 6.42 (d, 1H),

4.98 (s, 2H), 3.03 (s, 2H), 2.98-2.93 (m, 1H), 2.73-2.70 (m, 1H), 2.63-2.58 (m, 1H), 1.47 (s, 6H), 1.19 ( d, 3H). Example 102 3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzopyran-4-yl)decyloxy)phenyl)-2-methylpropane Acid (131) 〇

1 H NMR (400 MHz, CDC13) δ 7.15-7.10 (m, 3H), 6.89 (d, 2H), 6.64 (d,

1H), 5.10 (s, 2H), 3.09 (s, 2H), 3.03-2.98 (m, 1H), 2.74-2.71 (m, 1H), 2.66-2·61 (m, 1H), 1.44 (s, 6H), 1.17 (d, 3H). Example 103 2-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzoindole-7-yl)methoxy)_3_methylphenoxy)acetic acid (132)

^NMRC^OMHz, CDC13) (5: 10.07 (br, 1H), 7.25 (d, 1H), 7.04 (s, 149l05-sp-20I00806.doc -255 - 201200505 1H), 6.76-6.66 (m, 3H) , 4.94 (s, 2H), 4.63 (s, 2H), 3.00 (s, 2H), 2.12 (s, 3H), 1.49 (s, 6H)· LC-MS ESI m/z : found 375.0 [MH] - Example 104 2-(4-((4-Alkyl-2,2-dimethyl-2,3-dihydro-p-anthene--7-yl)-decyloxy)-2-phenylphenoxy Acetate (133)

1H NMR (400 MHz, CDC13) ά : 7.24 (s, 1Η), 7.04 (s, 1H), 6.85 (d, 1H), 6.76-6.73 (m, 1H), 6.67 (s, 1H), 4.93 (s , 2H), 4.64 (s, 2H), 3.00 (s, 2H), 2.27 (s, 3H), 1.49 (s, 6H). LC-MS ESI m/z: found 375.0 [MH]-. Example 105 2-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydro-p-benzoe-N-7-yl)decyloxy)phenoxy)acetic acid (134) )

1H NMR (400 MHz, CDC13) &lt;5: 7.20 (s, 1H), 7.01 (s, 1H), 6.90 (d, 2H), 6.84 (d, 2H), 4.91 (s, 2H), 4.54 (s , 2H), 2.97 (s, 2H), 1.45 (s, 6H). LC-MS ESI m/z: Found: 363.1 [MH]. Example 106 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzop-pentan-7-yl)decyloxy)_3,5-difluorophenyl ) Butyric acid (135)

149105-sp-20100806.doc -256 - 201200505 1H NMR (400 MHz, CDC13) δ : 7.20 (s, 1H), 7.01 (s, 1H), 6.75-6.69 (m, 2H), 5.03 (s, 2H) , 2.93 (s, 2H), 2.56-2.44 (m, 3H), 1.37 (s, 6H), 1.23 (d, 3H). LC-MS ESI m/z: found: 409.2 [MH]. Example 107 3-(3,5-Difluoro-4-((5-decyloxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl )-2-methylpropionic acid (136)

'HNMRC^OMH^CDC^) δ : 6.81 (s, 1H), 6.71-6.69 (m, 3H), 5.11 (s, 2H), 3.74 (s, 3H), 2.98-2.94 (m, 3H), 2.70 (m, 1H), 2.60-2.55 (m, 1H), 1.40 (s, 6H), 1.17 (d, 3H). LC-MS ESI m/z: found: 405.1 [MH]. Example 108 3-(4-((5-Methoxy-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)-2-mercaptopropyl Acid (137)

1 H NMR (400 MHz, CDC13) (5: 7.08 (d, 2H), 6.93 (d, 2H), 6.81 (s, 1H), 6.69 (s, 1H), 4.99 (s, 2H), 3.74 (s , 3H), 3.02-2.99 (m, 3H), 2.71 (m, 1H), 2.63-2.59 (m,1H), 1.47 (s,6H), 1.16 (d,3H). LC-MS ESI m/z Found: 369.3 [MH]. Example 109 3-(4-((5-Chloro-2,3,3-trimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy )_3,5_difluorophenyl)-2-methylpropionic acid (138) 149105-sp-20100806.doc -257 · 201200505

1 H NMR (400 MHz, CDC13) δ : 7.23 (s, 1H), 6.97 (s, 1H)} 6.70 (d, 2H), 5.08-5.04 (m, 2H), 4.35 (m, 1H), 2.99- 2.94 (m, 1H), 2.71-2.56 (m, 2H), 1.30 (d, 3H), 1.27 (s, 3H), 1.19 (d, 3H), 1.05 (s, 3H). LC-MS ESI m/ z : Found 423.4 [M-Η]-. Example 110 3-(4-((5-Ethoxy-2,2-dimethyl-2,3-dihydrobenzoxanth-7-yl)methoxy)-3,5-difluoro Phenyl)-2-methylpropionic acid (139)

1 H NMR (400 MHz, CDC13) δ : 6.78 (s, 1H), 6.68 (m, 3H), 5.09 (s, 2H), 3.97-3.92 (m, 2H), 2.96-2.91 (m, 3H), 2.70 (m, 1H), 2.60-2.57 (m, 1H), 1.39-1.34 (m, 9H), 1.17 (d, 3H). LC-MS ESI m/z: Found: 419.3 [MH]. Example 111 3-(4-((5-(Benzyloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3,5-difluoro Phenyl)-2-methylpropionic acid (140)

1H NMR (400 MHz, CDC13) δ: 7.43-7.31 (m, 5H), 6.92 (s, 1H), 6.76 (s, 1H), 6.69 (d, 2H), 5.11 (s, 2H), 4.98 (s , 2H), 2.97-2.93 (m, 3H), 2.76-2.66 (m, I49105-sp-20100806.doc -258 · 201200505 2H), 2.60-2.56 (m,1Η),1·39 (s, 6H) </ RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Example 112 5-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-diaza-1H-indole-2 -carboxylic acid (141)

1H NMR (400 MHz, CDC13) ^ : 7.25 (s, 1H), 7.09 (d, 1H)S 7.03 (s, 1H), 6.86 (s, 1H), 6.80 (d, 1H), 4.95 (s, 2H ), 3.40-3.36 (m, 1H), 3.28-3.15 (m, 4H), 2.99 (s, 2H), 1·47 (s, 6H)· LC-MS ESI m/z : found 371.0 [MH] ·. Example 113 5-((5-Fluoro-2,2-dimethyl-2,3-dihydrophenylhydraphthyl)-yloxy)-2,3-dihydro-1H-indole- 2-carboxylic acid (142) ^r°

F

1 H NMR (400 MHz, CDC13) 5 : 7.08 (d, 1H), 6.97 (d, 1H), 6.85 (s, 1H), 6.81-6.77 (m, 2H), 4.97 (s, 2H), 3.98- 3.34 (m, 1H), 3.28-3.14 (m, 4H), 2.99 (s, 2H), 1.48 (s, 6H). LC-MS ESI m/z: found 355.2 [MH]. Example 114 6-((5-Fluoro-2,2-dimethyl-2,3-di-nosed and bitten D-N-7-yl)methoxy)_2-indoleic acid (143)

149105-sp-20100806.doc • 259- 201200505 1H NMR (400 MHz, DMSO-d6) δ: 12.88 (br, 1H), 8.50 (s, 1H), 8.00 (d, 1H), 7.91-7.83 (m, (H, 2H) /z : measured value 365.0 [MH]-. Example 115 3-(4-((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)-2-isopropylindolylphenyl) Propionic acid (144)

1 H NMR (400 MHz, CDC13) (5: 7.02 (d, 1H), 6.96 (d, 1H), 6.78 (d, 1H), 6.50-6.46 (m, 2H), 4.95 (s, 2H), 4.51 (m, 1H), 2.99 (s, 2H), 2.83 (m, 2H), 2.62 (m, 2H), 1.47 (s, 6H), 1.32 (d, 6H). LC-MS ESI m/z : measured Value 401.8 [MH]. Example 116 3-(4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)_2-iso Propoxyphenyl)propionic acid (145) Ο

1H NMR (400 MHz, CDC13) δ: 7.24 (d, 1H), 7.02 (s, 2H), 6.48 (m, 2H), 4.94 (s, 2H), 4.51 (m, 1H), 2.99 (s, 2H) ), 2.83 (m, 2H), 2.62 (m, 2H), 1.47 (s, 6H), 1_32 (d, 6H). LC-MS ESI m/z: found 417.0 [MH]. Example 117 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)methoxy)_2-ethoxyphenyl)propanoic acid (146) 149105-sp-20100806.doc -260· 201200505

1H NMR (400 MHz, CDC13) δ: 7.24 (s, 1H), 7.02 (s, 2H), 6.48 (s, 2H), 4.94 (s, 2H), 3.99 (m, 2H), 2.99 (s, 2H ), 2.87 (m, 2H), 2.63 (m, 2H), 1.47 (s, 6H), 1.40 (t, 3H). LC-MS ESI m/z: found: 403.3 [M-Η]. Example 118 3-(2-Ethoxy-4-((5-decyloxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)indole

Oxy)phenyl)propionic acid (147)

1 H NMR (400 MHz, CDC13) δ : 7.01 (m, 1H), 6.80 (s, 1H), 6.68 (s, 1H), 6.50 (s, 2H), 4.97 (s, 2H)} 4.00 (m, 2H), 3.73 (s, 3H), 2.98 (s, 2H), 2.85 (m, 2H), 2.63 (m, 2H), 1.45 (s, 6H), 1.38 (m, 3H). LC-MS ESI m /z : measured value 399.2 [MH]·.

Example 119 3-(4-((5-Oxo-2-methyl benzofuran-7-yl)methoxy)_2-ethylphenyl)propionic acid (148)

1 H NMR (400 MHz, CDC13) δ : 7.38 (s, 1H), 7.32 (s, 1H), 7.09 (d, 1H)} 6.88 (s, 1H), 6.80 (d, 1H), 6.35 (s, 1H), 5.28 (s, 2H), 2.93 (m, 2H), 2.67-2.60 (m, 4H), 2_46 (s, 3H), 1.23 (m, 3H). LC-MS ESI m/z : measured value 370.9 149105-sp-20100806.doc -261 - 201200505 [M-Η]- ° Example 120 3-(4-((5-Chloro-2-methyl benzofuran-7-yl)methoxy)_3 _Fluorophenyl)-2-mercaptopropionic acid (149)

WNMRGOO MHz, CDC13) &lt;5: 7.38 (s, 1H), 7.31 (s, 1H), 6.99-6.93 (m, 2H), 6.85 (d, 1H), 6.34 (s, 1H), 5.34 (s, 2H), 3.02-2.96 (m, 1H), 2.73-2.71 (m, 1H), 2, 65-2.59 (m, 1H), 2.45 (s, 3H), 1.18 (m, 3H). LC-MS ESI m/z : found 375.2 [M-Η]-. Example 121 3-(4-((5-Fluoro-2,2-dimercapto-2,3-dihydro acne. Nan-7-yl)methoxy)tea-1-yl)propanoic acid (150)

1H NMR (400 MHz, DMSO-d6) δ: 8.41 (d, 1 Η), 7.95 (d, 1H), 7.58-7.49 (m, 2H), 7.25 (m, 1H), 7.09 (d, 1H), 6.86 -6.81 (m, 2H), 5.17 (s, 2H), 3.36 (m, 2H), 3.02 (s, 2H), 2.79 (m, 2H), 1.48 (s, 6H). LC-MS ESI m/z : Measured value 393.4 [M-Η]·. Example 122 3-(2-((Dimethylamino)methyl)-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)) Oxy)phenyl)propionic acid (151) 149I05-sp-20100806.doc -262 - 201200505

1 H NMR (400 MHz, DMSO-d6) δ : 7.21 (d, 1H), 7.03 (d, 1H), 6.93 (s, 2H), 6.80 (d, 1H), 4.92 (s, 2H), 4.26 ( s, 2H), 3.00 (s, 2H), 2.89 (m, 2H), 2.83 (s, 6H), 2·78 (m, 2H), 1.47 (s, 6H). LC-MS ESI m/z: Found 400.4 [M-Η]·. Example 123 3-(4-((5-Ethylamino-2,2-dimercapto-2,3-dihydroindolofuran-7-yl)decyloxy)

Phenyl)-2-methylpropionic acid (152)

1 H NMR (400 MHz, DMSO-d6) δ: 7.44 (s, 1H), 7.31 (br, 1H), 7.06 (d, 2H), 6.99 (s, 1H), 6.87 (d, dH), 4.97 ( s, 2H), 3.02-2.92 (m, 3H), 2.74-2.61 (m, 2H), 2.11 (s, 3H), 1.47 (s, 6H), 1.17 (d, 3H). LC-MS ESI m/ z: measured value 396.5

Example 124 3-(4-((2,2-Dimethyl-5-(trifluoromethoxy)-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2 -methylpropionic acid (153)

*H NMR (400 MHz, DMSO-d6) δ: 7.14-7.08 (m, 3Η), 6.95-6.91 (m, 3H), 4.98 (s, 2H), 3.05-2.95 (m, 3H), 2.74-2.69 (m, 1H), 2.64-2.59 (m, 1H), 149105-sp-20100806.doc -263 · 201200505 1_49 (s,6H), 1.16 (d,3H). LC-MS ESI m/z : measured value 423.4 [M-Η]·. Example 125 3-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2-mercaptobenzofuran-7 _ base) propionic acid (154)

NMR (400 MHz, DMSO-d6) δ: 7.07-6.99 (m, 3 Η), 6.82 (d, 1H), 6.51 (s, 1H), 5.13 (s, 2H), 3.03-3.00 (m, 4H), 2.66-2.63 (m, 2H), 2.42 (s5 3H), 1.45 (s, 6H). LC-MS ESI m/z: found: 397.3 [MH]. Example 126 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzop-y-7-yl)decyloxy)-3-(trifluoromethyl) ) phenyl)-2-methylpropionic acid 2-ethylamidoethyl ester (155) ο Η

3-(4-((5-Gasyl-2,2-diindenyl-2,3-dihydrobenzofuran-7-yl)decyloxy)-3-(trifluoromethyl)phenyl )-2-mercaptopropionic acid (38) (50 mg, 0.113 mmol), tetrafluoroboric acid 0-(benzotriazole small)_N,N,N,,N,-tetramethylguanidine (54.3 mg , 0.169 mmol, and a solution of diisopropylethylamine (39.3 μl, 0.225 mmol) in DMF (1.5 mL), stirred at room temperature for 3 min, then N-acetamidoethanolamine ( The reaction mixture was stirred at room temperature overnight. After evaporating the solvent in vacuo, the residue was purified by preparative HPLC, 149105-sp-20100806.doc -264 · 201200505 4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)-3-(trifluoromethyl)phenyl)-2- 2-ethylaminoethyl methacrylate (155) (45 mg, 7.00 (m} 2H), 5.47 (br, 1H), 5.06 (s, 2H), 4.10 (m, 2H), 3.44-3.37 (m, 2H), 3.05 (s, 2H), 2.96-2.91 (m, 1H), 2.76-2.66 (m, 2H), 1.93 (s, 3H), 1.49 (s, 6H), 1.19 (d, J = 6.8 Hz, 3H). LC-MS ESI m/z: found 528.0 [M - Η]. Example 127 3-(4-(((( Chloro-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)methyl)amino)benzene φ-)propionic acid (156)

1 H NMR (400 MHz, CDC13) 5 7.27 (bs, 1H), 7.08 (s, 1H), 7.01 (d, J = 8.2 Hz, 2H), 7.00 (s, 1H), 6.60 (d, J = 8.2 Hz, 2H), 4.21 (s, 2H), 2.98 (s, 2H), 2.84 (t, J = 7.8 Hz, 2H), 2.62 (t, J = 7.8 Hz, 2H), 1.48 (s, 6H) » Example 128 3-(4-(((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzop-Sulenyl-7-yl)indolyl)amino)phenyl)propyl Acid (157)

1H NMR (400 MHz, CDC13) δ 7.00 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 8.5

Hz, 1H)S 6.73 (d, J = 8.5 Hz, 1H), 6.59 (d, J = 7.8 Hz, 2H), 4.22 (s, 2H), 2.98 (s, 2H), 2,83 (t, J = 7.7 Hz, 2H), 2.61 (t, J = 7.7 Hz, 2H), 1.47 (s, 6H) » Example 129 s 149105-sp-20100806.doc -265 - 201200505 3-(4-((5-气气Benzyl-2,2-dimethyl-3-keto-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-mercaptopropionic acid (158)

1 H NMR (400 MHz, CDC13) 5 7.76 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 5.10 (s, 2H), 3.01 (dd, J = 13.4, 6.5 Hz, 1H), 2.76-2.60 (m, 2H), 1.48 (s, 6H), 1.18 (d, J = 6.9 Hz, 3H) 〇 Example 130 3-(4-((5-Alkyl-3-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy) Phenyl)-2-mercaptopropionic acid (159)

Compound (159) was prepared in a similar manner as described for the 109 synthesis. NMR NMR (400 MHz, CDC13) δ 7.38 (d, J = 1.8 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 4.96 (s, 2H), 4.74 (s, 1H), 2.97 (dd, J = 13.4, 6.6 Hz, 1H), 2.75-2.58 (m, 2H), 1.48 (s, 3H) ), 1.34 (s, 3H), 1.16 (d, J = 6.8 Hz, 3H).

Examples 131A and 131B 2_(4_((5·乳基_2,2-didecyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)cyclopropanecarboxylic acid (160) 149105-sp-20100806.doc -266· 201200505 ο

1Η NMR (400 MHz, CDC13) δ 7.02 (d, J = 8.6 Hz, 2H), 6.93 (m, 3H), 6.79 (d, J = 7.9 Hz, 1H), 4.98 (s, 2H), 3.00 (s , 2H), 2.61-2.45 (m, 1H), 1.88-1.76 (m, 1H), 1.64-1.56 (m, 1H), 1.48 (s, 6H), 1.38-1.30 (m, 1H).

(160) for palm separation, using preparative Regis Pack, 5/100, 250 x 21, 1 mm, flow rate 30 ml/min, solvent system 2.5:97.5 1 isopropyl alcohol: hexane: acetic acid, provided (160A) (RT = 12-15 minutes) and (160B) (RT = 20-23 minutes). (160A) : 1H NMR (400 MHz, CDC13) δ 7.02 (d, J = 7.9 Hz, 2H), 6.92 (dd, J = 18.5, 9.6 Hz, 3H), 6.78 (d, J = 6.9 Hz, 1H) , 4.97 (s, 2H), 2.99 (s, 2H), 2.62-2.44 (m, 1H), 1.86-1.77 (m, 1H), 1.65-1.56 (m, 1H), 1.47 (s, 6H), 1.39 </ RTI> </ RTI> </ RTI> <RTIgt; (160) for palm separation, using preparative Regis Pack, 5/100, 250 x 21.1 mm, flow rate 30 ml/min, solvent system 2.5:97.5:0.1 isopropanol: hexane: acetic acid, supplied (160A ) (RT = 12-15 minutes) and (160B) (RT = 20-23 minutes). (160B) : 1H NMR (400 MHz, CDC13) δ 7.02 (d, J = 8.5 Hz, 2H), 6.98-6.85 (m, 3H), 6.78 (d, J = 7.5 Hz, 1H), 4.97 (s, 2H), 2.99 (s, 2H), 2.61-2.49 (m, 1H), 1.85-1.76 (m, 1H), 1.64-1.58 (m, 1H), 1.47 (s, 6H), 1.38-1.30 (s, 1H). LC-MS ESI m/z: Found: 355.3 (MH), Example 132 3-(4-((5-fluoro-2,2-didecyl-2,3-dihydrobenzofuran) 7-yl)nonyloxy)phenyl)propionic acid (161)

S 149105-sp-20100806.doc -267- 201200505

1H NMR (400 MHz, CDC13) (5 7.11 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 9.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H), 2.99 (s, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.64 (t, J = 7.7 Hz, 2H), 1.48 (s, 6H). Example 133 2-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzoindol-7-yl)methoxy)phenyl)acetic acid (162 )

OH 1H NMR (400 MHz, CDC13) δ 7.17 (d, J = 7.7 Hz, 2H), 6.94 (m, 3H), 6.79 (d, J = 7.8 Hz, 1H), 4.98 (s, 2H), 3.57 ( s, 2H), 2.99 (s, 2H), 1.47 (s, 6H). Example 134 3-(2-Ethyl-4-((5-fluoro-2,2·dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)propanoic acid (163)

1 H NMR (400 MHz, CDC13) d 7.05 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 9.9

Hz, 1H), 6.80 (m, 3H), 4.97 (s, 2H), 2.99 (s, 2H), 2.90 (t, J = 7.7 Hz, 2H), 2.67-2.59 (m, 4H), 1.47 (s , 6H), 1.21 (t, J = 7.4 Hz, 3H). Example 135 3-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)methoxy)_2-iso-268- I49105-sp -20100806.doc 8 201200505 Propyl phenyl) propionic acid (164)

1 H NMR (400 MHz, CDC13) δ 7.05 (d, J = 8.0 Hz, 1H), 6.98 (d, J - 9.3 Hz, 1H), 6.89 (s, 1H), 6.83-6.70 (m, 2H), 4.97 (s, 2H), 3.14-3.04 (m, 1H), 2.99 (s, 2H), 2.93 (t, J = 7.8 Hz, 2H), 2.59 (t, J = 7.8 Hz, 2H), 1.47 (s , 6H), 1.22 (d, J = 6.6 Hz, 6H). Example 136

3-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzoin-7-yl)methoxy)_2-(trifluoromethoxy)benzene Propionate (165)

1 H NMR (400 MHz, CDC13) (5 7.16 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 9.9

Hz, 1H), 6.87-6.77 (m, 3H), 4.97 (s, 2H), 3.00 (s, 2H), 2.91 (d, J = 7.4 HZj 2H), 2.62 (t, J = 7.3 Hz, 2H) , 1.47 (s, 6H) 〇

Example 137 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)decyloxy)_2·•isopropylphenyl) Propionic acid (166)

]H NMR (400 MHz, CDC13) 5 7.25 (s, 1H), 7.1-7.0 (m, 2H), 6.89 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.95 (s, 2H) ), 3.15-3.05 (m, 1H), 2.99 (s, 2H) 2.94 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 1.47 (s, 6H), 1.22 ( d, J = 6.5 149105-sp-20100806.doc -269- 201200505

Hz, 6H). Example 138 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)_2-ethylphenyl)propanoic acid ( 167)

1H NMR (400 MHz, CDC13) δ 7.25 (s, 1 Η), 7.08-7.02 (m, 2H), 6.83 (s5 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.95 (s, 2H), 2.99 (s, 2H), 2.91 (t, J = 7.9 Hz, 2H), 2.66-2.56 (m, 4H), 1.47 (s, 6H), 1_22 (t, J = 7·5 Hz, 3H). Example 139 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)-2-(trifluoromethoxy) Phenyl) propionic acid (168)

*H NMR (400 MHz, CDC13) δ 7.20 (s, 1Η), 7.16 (d, J = 8.1 Hz, 1H), 7.05 (s, 1H), 6.90-6.82 (m, 2H), 4.95 (s, 2H ), 3.00 (s, 2H), 2.92 (d, J = 7.9 Hz, 2H), 2.63 (d, J = 7.6 Hz, 2H), 1.47 (s, 6H). Example 140 3-(4-((2,2-Dimethyl-2,3-dihydrobenzofuran-4-yl)methoxy)-2-ethylphenyl)propanoic acid (169)

H NMR (400 MHz, CDC13) δ 7.17-7.16 (m, 2H), 6.90 (d, J = 7.1 Hz, 149105-sp-20100806.doc -270· 8 201200505 1H), 6.83 (s, 1H), 6.79 -6.70 (m, 2H), 4.95 (s, 2H), 3.06 (s, 2H), 2.93 (t, J = 6.1 Hz, 2H), 2.7-2.58 (m, 4H), 1.49 (s, 6H), 1.23 (t, J = 6.1 Hz, 3H). Example 141 (R)-3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzop-pentan-7-yl)decyloxy)_3_fluorophenyl )-2-mercaptopropionic acid (170)

807 UOH, H2〇2

Compound (170) was prepared in a similar manner as described for the synthesis of (94). !h NMR (400 MHz, CDC13) δ 7.24 (s, 1Η), 7.03 (s, 1H), 6.98-6.87 (m, 2H), 6.82 (d, J = 7.8 Hz, 1H), 5.02 (s, 2H) ), 3.02-2.92 (m, 3H), 2.75-2.65 (m, 1H), 2.58 (dd, J = 12.8, 8.0 Hz, 1H), 1.46 (s, 6H), 1.16 (d, J = 6.2 Hz, 3H). Example 142 (S)-3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydroindolfuran-7-yl)methoxy)-3-

Fluorophenyl)-2-mercaptopropionic acid (171)

Compound (171) was prepared in a similar manner as described for the synthesis of (94). 1H NMR (400 MHz, CDC13) δ 7.24 (s, 1H), 7.03 (s, 1H), 6.98-6.88 (m, 2H), 6.83 (s, 1H), 5.02 (s, 2H), 3.02-2.92 ( m, 3H), 2.75-2.65 (m, 1H), 2.64-2.54 (m, 1H), 1.46 (s, 6H), 1.16 (d, J = 6.0 Hz, 3H). Example 143 (11)-3-(4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)

S I49105-sp-20100806.doc -271 - 201200505 Benzyl-3-(trifluoromethyl)phenyl)_2-mercaptopropionic acid (172)

CI 809 Compound (172) was prepared in a similar manner as described for the synthesis of (94) NMR (400 MHz, CDC13) 5 7.38 (s, 1H), 7.27-7.23 (m, 2H), 7.11-6.89 (m , 2H), 5.06 (s, 2H), 3.11-2.90 (m, 3H), 2.76-2.60 (m, 2H), 1.48 (s, 6H), 1.18 (d, J = 6.7 Hz, 3H). Example 144 (S)-3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzop-pentan-7-yl)decyloxy)-3-( Trifluoromethyl)phenyl)·2·methylpropionic acid (Π3)

Compound (173) was prepared in a similar manner as described for the synthesis of (94). 1 Η NMR (400 MHz, CDC13) δ 7.38 (s, 1H), 7.27-7.23 (m, 2H), 7.10-6.93 (m, 2H), 5.06 (s5 2H), 3.08-2.90 (m, 3H), 2.75-2.60 (m, 2H), 1.48 (s, 6H), 1.17 (d, J = 6.7 Hz, 3H). Example 145 3-(4-((3,3-Didecyl-5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl) )-2-methylpropionic acid (174) Ο

I49l05-sp-20J00806.doc •272 · 201200505 1H NMR (400 MHz, CDC13) δ 7.09 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 9

Hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 9 Hz, 1H), 4.97 (s, 2H), 3.13-2.93 (m, 1H), 2.81-2.55 (m , 2H), 1.47 (s, 6H), U7 (d, J = 6.9 Hz, 3H). Example 146 3-(4-((3,3-Diindole-5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3 -fluorophenyl)-2-methylpropionic acid (175)

1 H NMR (400 MHz, CDC13) δ 7.26 (s, 1H), 7.04 (s, 1H), 6.98-6.88 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 5.03 (s, 2H) ), 2.98 (dd, J = 13.6, 6.6 Hz, 1H), 2.76-2.65 (m, 1H), 2.60 (dd, J = 13.5, 7.7 Hz, 1H), 1.47 (s, 6H), 1.17 (d, J = 6_9Hz, 3H). Example 147 3-(4-((3,3-Diindole-5-yl-2,2-diindenyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3 -(trifluoromethyl)phenyl)-2-methylpropionic acid (176)

1 H NMR (400 MHz, CDC13) δ 7.40 (s, 1H), 7.3-7.24 (m, 2H), 7.10-6.97 (m, 2H), 5.08 (s, 2H), 3.03 (dd, J = 13.4, 6.3 Hz, 1H), 2.8-2.62 (m, 2H), 1.49 (s, 6H), 1 _20 (d, J = 6.7 Hz, 3H). Example 148 3-(4-((5-Chloro-3,3-dimercapto-2,3-dihydrobenzop-am-7-yl)methoxy)phenyl)-2-methyl Propionic acid (177)

S 149105-sp-20100806.doc •273 - 201200505

1 H NMR (400 MHz, CDC13) δ 7.26 (s, 1H), 7.10 (d, J = 7.3 Hz, 2H), 7.00 (s, 1H), 6.91 (d, J = 8.2 Hz, 2H), 4.97 ( s, 2H), 4.28 (s, 2H), 3.01 (dd, J = 13.4, 6.3 Hz, 1H), 2.76-2.57 (m, 2H), 1.34 (s, 6H), 1.17 (d, J = 6.8 Hz , 3H). Example 149 3-(4-((5-Gasyl-3,3-dimethyl-2,3-dihydrobenzop-pentan-7-yl)methoxy)-3-fluorophenyl)- 2-methylpropionic acid (178)

1 H NMR (400 MHz, CDC13) 5 7.26 (s, 1H), 7.00 (s, 1H), 6.97-6.90 (m, 2H), 6.84 (d, J = 7.7 Hz, 1H), 5.04 (s, 2H) ), 4.28 (s, 2H), 2.98 (dd, J = 13.4, 6.6 Hz, 1H), 2.76-2.65 (m, 1H), 2.61 (dd, J = 13.5, 7.8 Hz, 1H), 1.33 (s, 6H), 1.18 (d, J = 6.8 Hz, 3H). Example 150 3-(4-((2,2-Dimethyl-2,3-dihydrobenzofuran-4-yl)methoxy)-2,3-dimethylphenyl)propanoic acid (179 )

1H NMR (400 MHz, CDC13) ά 7.13 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.75-6.70 (m , 2H), 4.93 (s, 2H), 3.03 (s, 2H), 2.94 (t, J = 8.0 Hz, 2H), 2.60 (t, J = 8.0 Hz, 2H), 2.24 (s, 3H), 2.20 (s, 3H), 1.48 (s, 6H). 149105-sp-20100806.doc -274- 201200505 Example 151 3-(3,5-Difluoro-4-((2-mercaptobenzo[b]nonyl-7-yl)decyloxy)phenyl) -2-mercaptopropionic acid (180)

1H NMR (400 MHz, CDC13) δ 7.63 (d, J = 7.6 Hz, 1H), 7.37-7.28 (m, 2H), 7.01 (s, 1H), 6.74 (d, J = 8.7 Hz, 2H), 5.33 (s, 2H), 3.01-2.93 (m, 1H), 2.75-2.69 (m, 1H), 2.64-2.56 (m, 4H), 1.19 (d, J = 6.9 Hz, 3H). LC-MS ESI m /z : measured value 375.0 [MH]_. Example 152 2-(5-((2-Methylbenzo[b]nonin-7-yl)methoxy)-2,3-dihydro-1H-indol-1-yl)acetic acid (181)

1 H NMR (400 MHz, CDC13) δ 7.67-7.58 (m, 1 Η), 7.32 (d, J = 4.8 Hz, 2H), 7.11 (d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 6.92 (s, 1H), 6.86 (d} J = 8.2 Hz, 1H), 5.25 (s, 2H), 3.62-3.47 (m, 1H), 2.96-2.77 (m, 3H), 2.60 (s, 3H) , 2.51-2.38 (m, 2H), 1.84-1.72 (m, 1H). Example 153 2-(6-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzifuryl-7-yl)methoxytetrahydroindol-1-yl)acetic acid (182 ) £ 149105-sp-20100806.doc •275· 201200505

1H NMR (400 MHz, CDC13) &lt;5 7.08 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 9.9 Hz, 1H), 6.79 (d, J = 8.3 Hz, 2H), 6.70 (s , 1H), 4.96 (s, 2H), 3.37-3.23 (m, 1H), 3.00 (s, 2H), 2.79-2.67 (m, 3H), 2.59-2.50 (m, 1H), 1.98-1.64 (m , 4H), 1.48 (s, 6H). LC-MS ESI m/z: found: 385.1 (M+H) + -2,3-dihydrobenzopyran-7-yl)decyloxy)-1,2,3,4-tetrahydroindol-1-yl)acetic acid (183)

1 H NMR (400 MHz, CDC13) δ 7.24 (s, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.04 (s, 1H), 6.79 (dd, J = 8.6, 2.6 Hz, 1H), 6.70 (d, J = 2.5 Hz, 1H), 4.95 (s, 2H), 3.40-3.23 (m, 1H), 3.00 (s, 2H), 2.81-2.69 (m, 3H), 2.61-2.50 (m, 1H), 2.01-1.64 (m, 4H), 1.48 (s, 6H). LC-MS ESI m/z: Example 155 3-(3-Chloro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)-2 - mercaptopropionic acid (184)

1H NMR (400 MHz, CDC13) δ 7.21 (s, 1H), 7.08-6.90 (m, 3H), 6.80 (d, 149105-sp-20100806.doc -276- 201200505 J = 7.2 Hz, 1H), 5.06 ( s, 2H), 3.04-2.91 (m, 3H), 2.76-2.66 (m, 1H), 2.63-2.54 (m, 1H), 1.48 (s, 6H), 1.17 (d, J = 6.9 Hz, 3H) LC-MS: 393.0 (M+H+). Example 156 3-(4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-3-methylbutanoic acid (185)

1H NMR (400 MHz, CDC13) δ 7.32-7.20 (m, 3Η), 7.04 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 4.96 (s, 2H), 3.00 (s, 2H) , 2.63 (s, 2H), 1.47 (s, 6H), 1.44 (s, 6H). Example 157 3-(4-((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzop-am-7-yl)decyloxy)phenyl)-3-methyl Butyric acid (186)

1H NMR (400 MHz, CDC13) δ 7.27 (d, J = 9.6 Hz, 2H), 6.97 (d, J = 7.1

Hz, 1H), 6.93 (d, J = 9.6 Hz, 2H), 6.79 (d, J = 7.1 Hz, 1H), 4.97 (s, 2H), 3.00 (s, 2H), 2.62 (s, 2H), 1.48 (s, 6H), 1.44 (s, 6H). Example 158 3-methyl-3-(4-((2,2,5-trimethyl-2,3-dihydrobenzopyran-7-yl)methoxy)phenyl)butyric acid (187 ) 149I05-sp-20100806.doc •277- 201200505

NMR NMR (400 MHz, CDC13)) § 7.27 (d, J = 8.8 Hz, 2H), 7.05 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.90 (s, 1H), 4.98 ( s, 2H), 2.98 (s, 2H), 2.63 (s, 2H), 2.26 (s, 3H), 1_46 (s, 6H), 1.44 (s, 6H). LC-MS ESI m/z : measured value 369.0 (M+H)+ 〇Example 159 3-(4-((5-Gasyl-3H-spiro[benzofuran-2, oxime-cyclopentan]-7-yl) decyloxy)phenyl) -2-mercaptopropionic acid (188)

NMR (400 MHz, CDC13) δ 7.22 (s, 1 Η), 7.09 (d, J = 8.3 Hz, 2H), 7.04 (s, 1H), 6.91 (d, J = 8.3 Hz, 2H), 4.94 (s, 2H), 3.15 (s, 2H), 3.10-2.90 (m, 1H), 2.77-2.66 (m, 1H), 2.65-2.53 (m, 1H), 2.11-2.04 (m, 2H), 1.94-1.82 ( m, 2H), 1.80-1.62 (m, 4H), 1.16 (d,J = 6.9 s, 3H). LC-MS ESI m/z: found 399.3 (M-Η). Example 160 4-(4-((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)butyric acid (189)

1H NMR (400 MHz, CDC13) δ 7.08 (d, J = 8.1, 2H), 6.97 (d, 1H), 6.90 (d, J = 8.1 Hz, 2H), 6.79 (d, 1H), 4.97 (s, 2H), 2.99 (s, 2H), 2.60 (t, J = 7.5 149105-sp-20100806.doc -278- 201200505

Hz, 2H), 2.36 (t, J = 7.4 Hz, 2H), 1.98-1.83 (m, 2H), 1.48 (s, 6H). LC-MS ESI m/z : found 357.3 (M-Η)· . Example 161 4-(3,5-Difluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl) Butyric acid (190)

1 H NMR (400 MHz, CDC13) δ 6.98 (d, 1 Η), 6.80 (d, 1H), 6.69 (d, 2H), 5.07 (s, 2H), 2.96 (s, 2H), 2.58 (t, J = 7.6 Hz, 2H), 2.36 (t, J = 7.3 Hz, 2H), 1.98-1.82 (m, 2H), 1.41 (s, 6H)· LC-MS ESI m/z : found 393.1 (MH)· . Example 162 3-(4-((5-Fluoro-3H-spiro[benzofuran-2,1·-cyclopentan]-7-yl)methoxy)phenyl)-2-mercaptopropionic acid (191)

1 H NMR (400 MHz, CDC13) 5 7.08 (d, J = 8.3, 2H), 6.98-6.87 (m, 3H), 6.79 (d, J = 7.7 Hz, 1H), 4.96 (s, 2H), 3.15 (s, 2H), 3.10-2.90 (m, 1H), 2.78-2.66 (m, 1H), 2.66-2.53 (m, 1H), 2.13-2.01 (m, 2H), 1.95-1.84 (m, 2H) , 1.80-1.65 (m, 4H), 1.16 (d, J = 6.8 Hz, 3H). LC-MS ESI m/z : found 383.2 (MH) - 〇 Example 163 2-(5-((5-fluoro) -3H-spiro[benzofuran·2,ΐ'_cyclopentane]-7-yl)methoxy)_2,3-dihydro-1H-indol-1-yl)acetic acid (192)

S 149105-sp-20100806.doc •279· 201200505

*H NMR (400 MHz, DMSO) δ 12.16 (s, 1H), 7.06 (d, J = 8.3 Hz, 1H), 7.00 (d, 1H), 6.92 (d, 1H), 6.82 (s, 1H), 6.72 (d, J = 8.2 Hz, 1H), 4.88 (s, 2H), 3.31-3.23 (m, 1H), 3.17 (s, 2H), 2.84-2.57 (m, 3H), 2.30-2.15 (m, 2H), 1.94 (s, 2H), 1.83-1.51 (m, 7H) _ LC-MS ESI m/z: found 395.3 (M-Η). Example 164 3-(4-((5-Fluoro-3H-spiro[benzofuran-2, fluorenyl-cyclopentanyl]-7-yl) decyloxy)phenyl)propionic acid (193)

1 H NMR (400 MHz, CDC13) δ 7.11 (d, J = 8.1 Hz, 2H), 6.98-6.86 (m, 3H), 6.79 (d, J = 7.5 Hz, 1H), 4.96 (s, 2H), 3.15 (s, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.64 (t, J = 7.8 Hz, 2H), 2.14-2.01 (m, 2H), 1.96-1.80 (m, 2H), 1.81 -1.63 (m, 4H). LC-MS ESI m. Example 165 2-(4-((5-Fluoro-3H-spiro[benzofuran-2, fluorenyl-cyclopentanyl]-7-yl) decyloxy)phenyl)cyclopropanecarboxylic acid (194)

1H NMR (400 MHz, CDC13) δ 7.02 (d, J = 8.3 Hz, 2H), 6.96-6.87 (m, 3H), 6.79 (d, J = 8.5 Hz, 1H), 4.96 (s, 2H), 3.15 (s, 2H), 2.62-2.48 (m, 1H), 149105-sp-20100806.doc •280 - 201200505 2.12-2.02 (m, 2H), 1.93-1.56 (m, 8H), 1.39-1.29 (m, 1H). LC-MS ESI m. Example 166 3-(4-((5-Gasyl-3H-spiro[benzofuran-2, fluorenyl-cyclopentanyl]-7-yl)methoxy)phenyl)propanoic acid (195)

lH NMR (400 MHz, CDC13) &lt;5 7.22 (s, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.04 (s, 1H), 6.91 (d, J = 8.2 Hz, 2H), 4.94 (s, 2H), 3.15 (s, 2H), 2.89 (t, J = 7.3 Hz, 2H), 2.64 (t, J = 7.9 Hz, 2H), 2.15-2.00 (m, 2H), 1.96-1.84 ( m, 2H), </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 167 4-(4-((2,2,5-tridecyl-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)butanoic acid (196)

*H NMR (400 MHz, CDC13) δ 7.10-7.00 (m, 3H), 6.96-6.87 (m, 3H), 4.97 (s, 2H), 2.97 (s, 2H), 2.60 (t, J = 7.3 Hz , 2H), 2.35 (t, J = 7.3 Hz, 2H), 2.26 (s, 3H), 1.98-1.85 (m, 2H), 1.46 (s, 6H). LC-MS ESI m/z : found 353.1 (MH)- 〇 Example 168 4-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzopyrene e-nan-7-yl)methoxy)phenyl) Butyric acid (197) 149105-sp-20100806.doc -281 - 201200505

Γ 1 Η NMR (400 MHz, CDC13) δ 7.24 (s, 1Η), 7.10-7.01 (m, 3H), 6.91 (d, J = 7.9 Hz, 2H), 4.95 (s, 2H), 2.99 (s, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.36 (t, J = 7.4 Hz, 2H), 1.95-1.85 (m, 2H), 1·47 (s, 6H). LC-MS ESI m /z : Found 373.4 (MH)-. Example 169 4-(3,5-Difluoro-4-((2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)butanoic acid ( 198)

1H NMR (400 MHz, CDC13) δ 7.03 (s, 1H), 6.90 (s, 1H), 6.67 (d, J = 8.6

Hz, 2H), 5.08 (s, 2H), 2.93 (s, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.36 (t, J = 7.3 Hz, 2H), 2.25 (s, 3H), 1.98-1.81 (m, 2H), 1.39 (s, 6H). Example 170 4-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)-3,5-difluorophenyl) Butyric acid (199)

1 H NMR (400 MHz, CDC13) δ 7.22 (s, 1H), 7.04 (s, 1H), 6.69 (d, J = 8.5

Hz, 2H), 5.05 (s, 2H), 2.96 (s, 2H), 2.58 (t, J = 7.6 Hz, 2H), 2.36 (t, J = 7.3 Hz, 2H), 1.95-1.83 (m, 2H) ), 1.41 (s, 6H)· LC-MS ESI m/z : found 409.1 (MH) '° i49105-sp-20100806.doc -282- 201200505 Example 171 4-(4-((5-fluoro) 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylbutyric acid (200)

1H NMR (400 MHz, CDC13) δ 7.08 (d, J = 8.5 Hz, 2H), 6.97 (d, 1H), 6.90 (d, J = 8.5 Hz, 2H), 6.78 (d, 1H), 4.97 (s , 2H), 2.99 (s, 2H), 2.59 (t, J = 7.9 Hz, 2H), 2.55-2.44 (m, 1H), 2.08-1.94 (m, 1H), 1.76-1.61 (m, 1H), 1.47

(s, 6H), 1.22 (d, J = 7.0 Hz, 3H). LC-MS ESI m/z: found 371.1 (M-H). Example 172 4-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzop-ran-7-yl)decyloxy)phenyl)-2-indenyl Butyric acid (201)

!H NMR (400 MHz, CDC13) d 7.24 (s, 1H), 7.09 (d, J = 7.7 Hz, 2H), 7.03 (s, 1H), 6.90 (d, J = 7.7 Hz, 2H), 4.95 ( s, 2H), 2.99 (s, 2H), 2.60 (t, J = 7.9 Hz, 2H), 2.55-2.43 (m, 1H), 2.08-1.93 (m, 1H), 1.79-1.63 (m, 1H) , 1.47 (s, 6H), 1.22 (d, J = 6.9 Hz, 3H)·LC-MSESI m/z: found. 387.5 (MH)-t&gt; Example 173 3-(4-((5-fluoro)- 2,2-Dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)_3_indolylphenyl)propionic acid (202)

I49I05-sp-20I00806.doc •283 - 201200505 ^ NMR (400 MHz, CDC13) δ 6.99 (d, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.80-6.75 (m, 2H), 6.66 ( d, J = 8.3 Hz, 1H), 5.06 (s, 2H), 3.87 (s, 3H), 2.98 (s, 2H), 2.88 (t, J = 7.8 Hz, 2H), 2.65 (t, J = 7.7 Hz, 2H), 1.47 (s, 6H). LC-MS ESI m. Example 174 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)-3-methoxyphenyl)propanoic acid (203)

1 H NMR (400 MHz, CDC13) δ 7.26 (s, 1H), 7.01 (s, 1H), 6.84 (d, J = 8.1

Hz, 1H), 6.73 (s, 1H), 6.66 (d, J = 8.1 Hz, 1H), 5.04 (s, 2H), 3.87 (s, 3H), 2.98 (s, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H), 1.47 (s, 6H). LC-MS ESI m/z: found 389.2 (MH) - » Example 175 (S)-2- (5-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dihydro-1H- although -1 Acetate (204)

1 H NMR (400 MHz, CDC13) (5 7.08 (d, J = 8·0 Hz, 1H), 6.97 (d, J = 9.6 Hz, 1H), 6.87 (s, 1H), 6.83-6.77 (m, 2H), 4.97 (s, 2H), 3.63-3.41 (m, 1H), 2.99 (s, 2H), 2.97-2.72 (m, 3H), 2.51-2.34 (m, 2H), 1.83-1.71 (m, 1H), 1.48 (s, 6H). LC-MS ESI m/z: found: 369.2 (MH)-. Example 176 I49105-sp-20100806.doc -284 - 8 201200505 (S)-2-(5-( (5-Alkyl-2,2-dimethyl-2,3-dihydrobenzopyranyl-7-yl)decyloxy)_1 2,3-dihydro-1H-indol-1-yl)acetic acid (2〇5)

1 H NMR (400 MHz, CDC13) &lt;5 7.24 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.03 (s, 1H), 6.87 (s, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.95 (s, 2H), 3.63-3.41 (m, 1H), 3.00 (s, 2H), 2.95-2,73 (m, 3H), 2.54-2.33 (m, 2H), </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 177 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzopipepto-7-yl)methoxy)phenyl)propanoic acid (206)

149105_sp-20100806.doc , 285 - 1 H NMR (400 MHz, CDC13) δ 7.24 (s, 1H), 7.11 (d, J = 7.7 Hz, 2H), 7.04 (s, 1H), 6.91 (d, J = 7.7 Hz, 2H), 4.96 (s, 2H), 2.99 (s, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2_64 (t, J = 7.8 Hz, 2H), 1.47 (s, 6H) LC-MS ESI m/z: found: 359.1 (MH). Example 178 2 (Fantasy-^^-milk-gas-based-^-dimethyl-synthesis dihydrobenzobenzone---yloxy)-2,3-dihydro-1H-indole-1 -Base)Acetic acid (207) 201200505 1 H NMR (400 MHz, CDC13) &lt;5 7.08 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 9.9 Hz, 1H), 6.87 (s, 1H) , 7.80-7.75 (m, 2H), 4.97 (s, 2H), 3.63-3.41 (m, 1H), 3.00 (s, 2H), 2.95-2.73 (m, 3H), 2.53-2.34 (m, 2H) , </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 179 (11)-2-(5-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzopyran-7-yl)methoxy)-2,3- Dihydro-1H-indol-1-yl)acetic acid (1 2 3 4 5〇8)

1 H NMR (400 MHz, CDC13) &lt;5 7.25 (s, 1H), 7.09 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.87 (s, 1H), 6.81 (d, J = 8.2, 1H), 4.96 (s, 2H), 3.60-3.42 (m, 1H), 3.00 (s, 2H), 2.95-2.74 (m, 3H), 2.54-2.32 (m, 2H), 1.86-1.71 (m, 1H), 1.48 (s, 6H). LC-MS ESI m/z: found: 384.9 (MH), Example 180 2-(3-fluoroyl-4-((5-fluoro)-2 -dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)cyclopropanecarboxylic acid (209) _

149105-sp-20100806.doc • 286 *

1 H NMR (400 MHz, CDC13) δ 7.00-6.88 (m, 2H), 6.85-6.71 (m, 3H), 2 5,04 (s, 2H), 2.99 (s, 2H), 2.59-2.43 (m , 1H), 1.86-1.74 (m, 1H), 1.69-1.54 3 (m, 1H), 1.47 (s, 6H), 1.38-1.27 (s, 1H). LC-MS ESI m/z : found 373.1 4 (MH)' 〇5 Example 181 201200505 2-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3 -fluorophenyl)cyclopropanecarboxylic acid (210) 〇

1H NMR (400 MHz, CDC13) δ 7.23 (s, 1 Η), 7.04 (s, 1H), 6.94 (t, J = 8.6 Hz, 1H), 6.80 (t, J = 11.7 Hz, 2H), 5.03 (s , 2H), 2.99 (s, 2H), 2.57-2.42 (m, 1H), 1.86-1.72 (m, 1H), 1.68-1.54 (m, 1H), 1.47 (s, 6H), 1.36-1.27 (m , 1H). LC-MS ESI m/z: Found: 389, 2 (MH). Example 182 4-(4-((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzopyran-7-yl)decyloxy)phenyl)-3-methylbutyl Acid (211)

1H NMR (400 MHz, CDC13) δ 7.05 (d, J = 7.7 Hz, 2H), 6.97 (d, J = 9.5

Hz, 1H), 6.90 (d, J = 7.4 Hz, 2H), 6.79 (d, J = 7.9 Hz, 1H), 4.97 (s, 2H), 2.99 (s, 2H), 2.61-2.51 (m, 1H) ), 2.50-2.30 (m, 2H), 2.27-2.09 (m, 2H), 1.47 (s, 6H), 0,96 (d, J = 6.2 Hz, 3H). LC-MS ESI m/z : measured The value is 371.2 (MH)·. Example 183 4-(4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzopyran-7-yl)methoxy)phenyl)-3-methylbutyl Acid (212)

1H NMR (400 MHz, CDC13) δ 7.25 (s, 1H), 7.06 (d, J = 8.6 Hz, 3H), 149105-sp-20100806.doc 287 · 201200505 6.90 (d, J = 7.9 Hz, 2H), 4.96 (s, 2H), 2.99 (s, 2H), 2.63-2.30 (m, 3H), 2.29-2.08 (m, 2H), 1.48 (s, 6H), 0.96 (d, J = 6.2 Hz, 3H) LC-MS ESI m/z Found: 387.3 (MH).

Examples 184A and 184B 2-(3,5-Difluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy) Base) cyclopropanecarboxylic acid (2 working 3)

1 H NMR (400 MHz, CDC13) δ 6.97 (d, J = 9.5 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 6.60 (d, J = 8.9 Hz, 2H), 5.05 (s, 2H), 2.95 (s, 2H), 2.43 (t, J = 6.9 Hz, 2H), 1.75-1.63 (m, 1H), 1.39 (s, 6H), 1.35-1.25 (m, 1H), 1.01-0.82 (m, 2H). LC-MS ESI m. (213) For palm separation, use preparative Pirkle Covalent (R,R) Whelk-O® 2, 10/100, 250 x 21.1 mm, flow rate 30 ml/min, solvent system 2:98:0.1 isopropyl Alcohol: Hexane: Acetic acid, supplied (213A) (RT = 12.0 min) and (213B) (RT = 14.0 min). (213A): 1 H NMR (400 MHz, CDC13) 5 6.97 (d, J = 9.6 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 9.0 Hz, 2H), 5.05 (s, 2H), 2.95 (s, 2H), 2.43 (t, J = 7.7 Hz, 2H), 1.75-1.63 (m, 1H), 1.39 (s, 6H), 1.35-1.25 (m, lri) , 0.98-0.83 (m, 2H). (213) For palm separation, use preparative Pirkle Covalent (R,R) Whelk-O® 2, 10/100, 250 x 21.1 mm, flow rate 30 ml/min, solvent system 2:98:0.1 isopropyl Alcohol: Hexane: Acetic acid, supplied (213A) (RT = 12.0 min) and (213B) (RT = 14.0 min). (213B): 1 H NMR (400 MHz, CDC13) 5 6.97 (d, J = 9.9 Hz, 1H), 6.79 (d, J = 7.1 Hz, 1H), 6.60 (d, J = 8.5 Hz, 2H), 5.05 (s, 2H), 2.95 (s, 149105-sp-20100806.doc -288 - 201200505 2H), 2.51-2.30 (m, 2H), 1.75-1.64 (m, 1H), 1.39 (s, 6H), 1.35-1.26 (m, 1H), 0.91 (ddd, J = 11.9, 6.7, 2.0 Hz, 2H). Example 185 2-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzoindole. N-7-yl)decyloxy)-3,5-difluoroanthracene Cyclopropanecarboxylic acid (214)

1H NMR (400 MHz, CDC13) δ 7.23 (s, 1 Η), 7.04 (s, 1H), 6.60 (d, J = 9.0 Hz, 2H), 5.03 (s, 2H), 2.95 (s, 2H), 2.43 (t, J = 7.5 Hz, 2H), 1.74-1.66 (m, 1H), 1.40 (s, 6H), 1.36-1.26 (s, 1H), 1.00-0.84 (m, 2H). LC-MS ESI m /z : Found 421.3 (MH)_. Example 186 3-(4-((2,2-Dimethyl-5-phenyl-2,3-dihydrobenzop-am-7-yl)decyloxy)phenyl)propanoic acid (215)

1 H NMR (400 MHz, CDC13) δ 7.55-7.46 (m, 3H), 7.38 (t, J = 7.5 Hz, 2H), 7.33-7.26 (m, 2H), 7.11 (d, J = 8.2 Hz, 2H ), 6.95 (d, J = 8.4 Hz, 2H), 5.06 (s, 2H), 3.08 (s, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.64 (t, J = 7.7 Hz, 2H ), 1.51 (s, 6H) _ LC-MS ESI m/z: Found: 401.2 (M - Η). Example 187 2-(5-((2,2-Dimethyl-5-phenyl-2,3-dihydro benzopyran- 7-yl)decyloxy)-2,3-dihydro-1H -茚-1-yl)acetic acid (216)

S 149105-sp-20100806.doc -289- 201200505

'H NMR (400 MHz, CDC13) δ 7.54-7.47 (m, 3H), 7.39 (t, J = 7.3 Hz, 2H), 7.33-7.26 (m, 2H), 7.08 (d, J = 8.2 Hz, 1H ), 6.92 (s, 1H), 6.84 (d, J = 8.6 Hz, 1H), 5.06 (s, 2H), 3.62-3.44 (m, 1H), 3.08 (s, 2H), 2.96-2.76 (m, 3H), 2.51-2.35 (m, 2H), 1.85-1.70 (m, 1H), 1.52 (s, 6H). LC-MS ESI m/z: found: 427.2 (MH). Example 188 (R)-2-(5-((6-Denyl-2,2-dimethyl-2,3-dihydrobenzopyran-4-yl)methoxy)-2,3-di Hydrogen-1H-indol-1-yl)acetic acid (217)

!H NMR (400 MHz, CDC13) &lt;5 7.11 (d, J = 7.7 Hz, 1H), 6.83 (s, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 9.7 Hz, 1H), 6.42 (d, J = 9.0 Hz, 1H), 4.92 (s5 2H), 3.65-3.44 (m, 1H), 2.97 (s, 2H), 2.93-2.74 (m, 3H), 2.54- 2.36 (m, 2H), 1.87-1.71 (m, 1H), 1.48 (d, J = 5_9 Hz, 6H). LC-MS ESI m/z: found 369.0 (M-Η). Example 189 3-(2-Fluoro-4-((5-fluoro-3H-spiro[benzofuran_21·_cyclopentane p7-yl)methoxy)phenyl)propanoic acid (218) U9105 -sp-20100806.doc .290, 201200505

1H NMR (400 MHz, CDC13) δ 7.08 (t, J = 8.4 Hz, 1H), 6.92 (d, J = 9.3

Hz, 1H), 6.80 (d, J - 7.3 Hz, 1H), 6.69 (d, J = 9.7 Hz, 2H), 4.95 (s, 2H), 3.15 (s, 2H), 2.89 (t, J = 7A Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.16-2.01 (m, 2H), 1.95-1.85 (m, 2H), 1.78-1.65 (m, 4H). (M-H+). LC-MS ESI m/z: Found: 387.2 (MH). Example 190

3-(4-((5-Fluoro-3H-spiro[benzo]furan-2,1'-cyclopentan]-7-yl)methoxy)-2-indole

Phenyl) propionic acid (219)

1 H NMR (400 MHz, CDC13) δ 7.02 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 9.4

Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.49 (d, J = 9.2 Hz, 2H), 4.96 (s, 2H), 3.78 (s, 3H)} 3.15 (s, 2H), 2.86 (t, J = 7.7 Hz, 2H), 2.62 (t, J = 7.7 Hz, 2H), 2.17-2.00 (m, 2H), 1.97-1.84 (m, 2H), 1.80-1.62 (m, 4H) LC-MS ESI m/z: Found 399.3 (M-?). Example 191 2-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzindazin-7-yl)methoxy)henyl)cyclopropanecarboxylic acid (220)

1 H NMR (400 MHz, CDC13) ^ 7.10 (d, J = 7.7 Hz, 2H), 6.97 (d, J = 9.9 149105-sp-20I00806.doc -291 - 201200505

Hz, 1H), 6.91 (d, J = 7.3 Hz, 2H), 6.78 (d, J = 7.7 Hz, 1H), 4.97 (s, 2H), 2.99 (s, 2H), 2.75-2.46 (m, 2H) ), 1.80-1.61 (m, 1H), 1.47 (s, 6H), 1.34-1.18 (m, 2H), 0.98-0.80 (m, 1H). LC-MS ESI m/z: found 369.1 (MH) -. Example 192 2-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)decyloxy) benzyl) cyclopropanecarboxylic acid (221 )

NMR NMR (400 MHz, CDC13) (5 7.25 (s, 1H), 7.10 (d, J = 7.4 Hz, 2H), 7.03 (s, 1H), 6.92 (d, J = 7.1 Hz, 2H), 4.96 ( s, 2H), 2.99 (s, 2H), 2.75-2.46 (m, 2H), 1.78-1.65 (m, 1H), 1.47 (s, 6H), 1.34-1.20 (m, 2H), 0.94-0.82 ( m, 1H). LC-MS ESI m/z: found: 385.0 (M - Η). </RTI> Example 193 3-(4-((5- s yl) Cyclopentane]-7-yl)methoxy&gt;2-fluorophenyl)propionic acid (222)

1H NMR (400 MHz, CDC13) (5 7.19 (s, 1H), 7.13-7.02 (m, 2H), 6.69 (d, J = 10.0 Hz, 2H), 4.93 (s, 2H), 3.15 (s, 2H ), 2.90 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 2.14 - 2.02 (m, 2H), 1.98-1.64 (m, 6H). LC-MS ESI m/ z: found 403.4 (MH)· 〇 Example 194 3-(4-((5-Alkyl-3H-spiro[benzofuran-2,1'-cyclopentane]-7-yl)methoxy) _2_methoxy 149105-sp-20100806.doc •292- 201200505 Phenyl)propionic acid (223)

1H NMR (400 MHz, CDC13) δ 7.23 (s, 1H), 7.03 (d, J = 9.4 Hz, 2H), 6.50 (d, J = 10.3 Hz, 2H), 4.94 (s, 2H), 3.79 (s , 3H), 3.15 (s, 2H), 2.87 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H), 2.13-2.00 (m, 2H), 1.98-1.60 (m, 6H). LC-MS ESI m/z: Found: 415.0 (M - Η).

Example 195 3-(2-Alkyl-4-((5-fluoro-3H-spiro[benzopyran-2, fluorene-cyclopentan]-7-yl)methoxy)phenyl)propanoic acid (224)

NMR NMR (400 MHz, CDC13) δ 7.13 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J = 9.6 Hz, 1H), 6.81 (t, J = 7.4 Hz, 2H ), 4.95 (s, 2H), 3.15 (s, 2H), 2.98 (t, J = 7.7 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 2.19-2.04 (m, 2H), 1.99 </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> Example 196 3-(2-Chloro-4-((5-chloro-3H-spiro[benzopyran-2, fluorene-cyclopenta]-7-yl)methoxy)phenyl)propanoic acid (225)

!H NMR (400 MHz, CDC13) δ 7.19 (s, 1Η), 7.13 (d, J = 8.2 Hz, 1H), 7.05 (s, 1H), 7.00 (s, 1H), 6.82 (d, J = 8.1 Hz, 1H), 4.93 (s, 2H), 3.15 (s, 2H),

S 149l05-sp-20100806.doc -293 - 201200505 2.98 (t, J = 7.1 Hz, 2H), 2.66 (t, J = 7.3 Hz, 2H), 2.21-1.95 (m, 2H), 1.95-1.82 (m </ RTI> </ RTI> </ RTI> <RTI ID=0.0></RTI> Example 197 3-(2,6-Dichloro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl) Propionic acid (226)

1H NMR (400 MHz, CDC13) δ 6.95 (s, 2Η), 6.90 (d, J = 9.1 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 4.95 (s, 2H), 3.26-3.12 (m, 2H), 3.01 (s, 2H), 2.65-2.51 (m, 2H), 1.50 (s, 6H), LC-MS ESI m/z: Example 198 3-(2,6-dioxa-4-((5-carbyl-2,2-diindenyl-2,3-dihydrobenzopyran-7-yl)methoxy)phenyl Propionic acid (227)

NMR (400 MHz, CDC13) (5 7.18 (s, 1H), 7.06 (s, 1H), 6.95 (s, 2H), φ 4.94 (s, 2H), 3.26-3.09 (m, 2H), 3.01 (s , 2H), 2.66-2.50 (m, 2H), 1.50 (s, 6H). LC-MS ESI m/z: found 430.8 (M-Η)*. Example 199 2-(2-(4-(( 5-Alkyl-2,2-monomethyl-2,3-dihydrobenzop-indolyl-7-yl)methoxy)phenyl)cyclopropyl)acetic acid (228)

-294 · I49105-sp-20100806.doc

201200505 1 H NMR (400 MHz, CDC13) δ 6.98 (dd, J = 21.4, 8.8 Hz, 3H), 6.88 (d, J = 7.1 Hz, 2H), 6.78 (d, J = 7.1 Hz, 1H), 4.96 (s, 2H), 2.99 (s, 2H), 2.43 (d, J = 6.9 Hz, 2H), 1.77-1.69 (m, 1H), 1.47 (s, 6H), 1.36-1.22 (m, 1H), 0.99-0.90 (m, 1H), 0.85-0.77 (m, 1H). LOMS ESI m/z: found 368.9 (M-Η). Example 200 2-(2-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)benzene)

Base) propyl)acetic acid (229)

!H NMR (400 MHz, CDC13) 5 7.23 (s, 1H), 7.01 (d, J = 8.6 Hz, 3H), 6.88 (d, J = 6.9 Hz, 2H), 4.94 (s, 2H), 2.99 ( s, 2H), 2.43 (d, J = 6.2 Hz, 2H), 1.81-1.68 (m, 1H), 1.47 (s, 6H), 1.38-1.26 (m, 1H), 1.01-0.89 (m, 1H) , LC-MS ESI m/z: found: 384.8 (MH). Example 201 2-(2-(4-((5-Fluoro-3H-spiro[benzofuran-2, fluorenyl-cyclopentan]-7-yl) decyloxy)benzene

Base) propyl)acetic acid (230)

1 H NMR (400 MHz, CDC13) &lt;5 7.01 (d, J = 6.8 Hz, 2H), 6.94 (d, J = 10.3 Hz, 1H), 6.88 (d, J = 7.0 Hz, 2H), 6.78 ( d, J = 7.6 Hz, 1H), 4.95 (s, 2H), 3.14 (s, 2H), 2.43 (d, J = 5.5 Hz, 2H), 2.16-2.02 (m, 2H), 1.97-1.83 (m , 2H), 1.80-1.62 (s, 5H), 1.37-1.22 (m, 1H), 0.99-0.89 (m, 1H), 0.86-0.75 (m, 1H). LC-MS ESI m/z : measured value 395.2 (M-Η)· 〇

S 149105-sp-20100806.doc -295 - 201200505 Example 202 2-(2-(4-((5-Gasyl-3H-spiro[benzofuran-2J••cyclopentane]-7-yl)methoxy) Phenyl)cyclopropyl)acetic acid (231)

1 H NMR (400 MHz, CDC13) δ 6.82 (s, 1 Η), 6.62 (d, J = 9.4 Hz, 3H), 6.49 (d, J = 7.3 Hz, 2H), 4.54 (s, 2H), 2.75 ( s, 2H), 2.17-1.95 (m, 2H), 1.79-1.62 (m, 2H), 1.57-1.42 (m, 2H), 1.40-1.24 (m, 5H), 0.99-0.87 (m, 1H), </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 5-fluoro-3H-spiro[benzopyran-1,2'-cyclopentan]-7-yl)nonyloxy)phenyl)propionic acid (232)

149t05-sp-20l00806.doc -296- 1 H NMR (400 MHz, CDC13) δ 7.05 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 9.7 Hz, 1H), 6.84-6.73 (m, 3H), 4.96 (s, 2H), 3.15 (s, 2H), 2.91 (t, J = 7.8 Hz, 2H), 2.71-2.50 (m, 4H), 2.15-2.00 (m, 2H), 1.98-1.82 (m, 2H), 1.81-1.61 (m, 4H), 1.21. (t, J = 7.3 Hz, 3H). LC-MS ESI m/z: Example 204 2 3-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)_2,6-dimethylphenyl Propionic acid (233) 201200505

1H NMR (400 MHz, CDC13) δ 6.97 (d, J = 9.7 Hz, 1H), 6.79 (s, 1H), 6.67 (s, 2H), 4.95 (s, 2H), 3.00 (s, 2H), 2.92 (s, 2H), 2.47 (d, J = 8.4 Hz, 2H), 2.30 (s, 6H), 1.48 (s, 6H). LC-MS ESI m/z: found 371.3. Example 205 3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzo-bit.N--7-yl)methoxy)-2,6-dimethyl Phenyl) propionic acid (234)

1 H NMR (400 MHz, CDC13) (5 7.03 (s, 1H), 6.67 (s, 2H), 4.93 (s, 2H), 3.00 (s, 2H), 2.92 (s, 2H), 2.47 (s, 2H), 2.30 (s, 6H), 1.48 (s, 6H). LC-MS ESI m/z: found: 387.3 (MH) s. Example 206 3-(4-((5-)- -Dimethyl-2,3-dihydrobenzopyrene 11 Nan-7-yl)methoxy)-2,5-dimethylphenyl)propionic acid (235)

*H NMR (400 MHz, CDC13) 5 7.00 (d, J = 8.5 Hz, 1H), 6.92 (s, 1H), 6.79 (s, 1H), 6.72 (s, 1H), 4.97 (s, 2H), 3.00 (s, 2H), 2.90-2.81 (m, 2H), 2.63-2.53 (m, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 1.48 (s, 6H). LC-MS ESI m/z : found 371.0 (M-Η). Example 207

S 149105-sp-20100806.doc -297- 201200505 3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzopyrene.South-7-yl)methoxy) Base)-2,5-dimercapto) propionic acid (236)

1 H NMR (400 MHz, CDC13) δ 7.26 (s, 1 Η), 7.04 (s, 1H), 6.92 (s, 1H), 6.71 (s, 1H), 4.95 (s, 2H), 3.00 (s, 2H ), 2.86 (s, 2H)} 2.60 (d, J = 6.6 Hz, 2H), 2.27 (s, 3H), 2_22 (s, 3H), 1.48 (s, 6H). LC-MS ESI m/z : Found 387.3 (MH)- 〇 Example 208 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzoindole-7-yl)methoxy)- 2,3-dimercaptophenyl)propionic acid (237)

1H NMR (400 MHz, CDC13) δ 6.99-6.95 (m, 2H), 6.75 (d, J = 9.8 Hz, 2H), 4.97 (s, 2H), 2.99 (s, 2H), 2.93 (s, 2H) , 2.59 (d, J = 7.5 Hz, 2H), 2.23 (s, 6H), 1.47 (s, 6H). LC-MS ESI m/z: found 371.3 (MH)-. Example 209 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzo-p-Enan_7-yl)decyloxy)_2,3-dimethylbenzene Propionate (238)

1H NMR (400 MHz, CDC13) δ 7.25 (s, 1H), 7.04 (s, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 4.95 (s , 2H), 2.99 (s, 2H), 2.94 (d, J = 4.5 I49105-sp-20100806.doc -298- 201200505

Hz, 2H), 2.59 (s, 2H), 2.23 (s, 6H), 1.47 (s, 6H). LC-MS ESI m/z: Found: 387.3 (M-H)-. Example 210 2-(2-(2-Fluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl) Cyclopropyl)acetic acid (239)

1H NMR (400 MHz, CDC13) δ 6.97-6.74 (m, 3Η), 6.66 (s, 2H), 4.94 (s,

2H), 2.99 (s, 2H), 2.61-2.32 (m, 2H), 1.90-1.76 (m, 1H), 1.48 (s, 6H), 1.40-1.28 (m, 1H), 1.01-0.90 (m, 1H), 0.90-0.79 (m, 1H). LC-MS ESI m. Example 211 2-(2-(4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzoheptin-7-yl)methoxy)-2-fluorophenyl) )cyclopropyl)acetic acid (240)

!H NMR (400 MHz, CDC13) 5 7.20 (s, 1H), 7.04 (s, 1H), 6.91-6.79 (m, 1H), 6.67 (s, 2H), 4.93 (s, 2H), 2.99 (s , 2H), 2.61-2.30 (m, 2H), 1.90-1.73 (m, 1H), 1.48 (s, 6H), 1.4M.28 (m, 1H), 1.01-0.90 (m, 1H), 0.90- 0.77 (m, 1H). LC-MS ESI m/z: found: 403.1 (MH) - 〇 Hydrobenzofuran-7-yl)methoxy)_2-propylphenyl)propionic acid (241) 149105-sp-20100806.doc •299- 201200505

1 H NMR (400 MHz, CDC13) δ 7.05 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 9.5 Hz, 1H), 6.79 (s, 3H), 4.96 (s, 2H), 2.99 ( s, 2H), 2.95-2.83 (m, 2H), 2.66-2.50 (m, 4H), 1.67-1.53 (m, 2H), 1.47 (s, 6H), 1.02-0.89 (m, 3H). LC- MS ESI m/z Found: 385.0 (MH). Example 213 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2-propylphenyl)propanoic acid (242)

*H NMR (400 MHz, CDC13) &lt;5 7.25 (s, 1H), 7.16-6.96 (m, 2H), 6.90-6.68 (m, 2H), 4.94 (s, 2H), 2.99 (s, 2H) , 2.94-2.84 (m, 2H), 2.68-2.43 (m, 4H), 1.75-1.55 (m, 2H), 1.47 (s, 6H), 1.04-0.91 (m, 3H). LC-MS ESI m/ z : Found 401.2 (MH) _. Example 214 3-(5-Fluoro-4-((5-Denyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2.methylbenzene Propionate (243)

1H NMR (400 MHz, CDC13) δ 6.99 (d, J = 9.3 Hz, 1H), 6.90-6.73 (m, 3H), 5.03 (s, 2H), 2.99 (s, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.59 (t, J = 7.5 Hz, 149105-sp-20100806.doc •300· 201200505 2H), 2.23 (s, 3H), 1.48 (s, 6H). LC-MS ESI m/z : Actual value 375.0 (M-Η)·. Example 215 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzop-am-7-yl)methoxy)-5-fluoro-2- Nonylphenyl)propionic acid (244)

1H NMR (400 MHz, CDC13) δ 7.26 (s, 1 Η), 7.04 (s, 1H), 6.87-6.84 (m, 2H), 5.01 (s, 2H), 2.99 (s, 2H), 2.84 (t, J = 7.8 Hz, 2H), 2.59 (t, J = 7.7 Hz, 2H), 2.23 (s, 3H), 1.48 (s, 6H). LC-MS ESI m/z : found 391,3 (M- Η)·. Example 216 3-(2-Ethyl-1,3-yl-4-((5-fluoro-2,2-dimercapto-2,3-dihydrobenzop-am-7-yl) anthracene Phenyl)propionic acid (245)

1 H NMR (400 MHz, CDC13) δ 7.00 (d, J = 9.5 Hz, 1H), 6.86-6.71 (m, 3H), 5.03 (s, 2H), 2.99 (s, 2H), 2.90 (t, J = 6.7 Hz, 2H), 2.73-2.56 (m, 4H), 1.47 (s, 6H), 1.18 (t, J = 6.6 Hz, 3H). LC_MS ESI m/z : found 389.4 (M-Η)· 〇Example 217 3-(4-((5-Gasyl-2,2-monomethyl-2,3-dihydrobenzopyran-7-yl)decyloxy)_2-ethyl-3-fluoro Phenyl) propionic acid (246)

S 149105-sp-20100806.doc •301- 201200505 ο

OH 1 Η NMR (400 MHz, CDC13) δ 7.26 (s, 1H), 7.03 (s, 1H), 6.81 (s, 2H), 5.01 (s, 2H), 2.99 (s, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.76-2.53 (m, 4H), 1.47 (d, J = 1.3 Hz, 6H), 1.18 (t, J = 6.9 Hz, 3H). LC-MS ESI m/z : measured Value 405.3 (M-Η)· 〇Example 218

3-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzo-b--7-yl)decyloxy)-5,6,7,8-tetra-argon Naphthalen-1-yl)propionic acid (247)

1 H NMR (400 MHz, DMSO) δ 12.11 (s, 1H), 7.09-6.65 (m, 4H), 4.87 (s, 2H), 3.00 (s, 2H), 2.81-2.26 (m} 9H), 2.17 (s3 1H), 1.66 (s, 2H), 1.39 (s, 6H). LC-MS ESI m/z: found 397.3 (MH) · 〇 Example 219 3-(4-((5-) ,2-Dimethyl-2,3-dihydrobenzoxov0N-7-yl)decyloxy)-5,6,7,8-Lutetrahydronaphthalenyl-diylpropionic acid (248) 〇

1H NMR (400 MHz, DMSO) &lt;5 12.08 (s, 1H), 7.17 (s, 2H), 7.05-6.64 (m, 2H), 4.88 (s, 2H), 3.01 (s, 2H), 2.81- 2.30 (m, 9H), 2.22-2.08 (m, 1H), 1.65 (s, 2H), 1.40 (s, 6H). LC-MS ESI m/z: Example 220 • 302· 149105-sp-20100806.doc 8 201200505 3-(2-Ethyl-5-f-yl-4-((5-fluoro-2,2-dimercapto-2,3-dihydro) Stupid and puff mouth South _7-base) 曱oxy)phenyl)propionic acid (249)

1 H NMR (400 MHz, CDC13) δ 7.00 (d, J = 9.6 Hz, 1H), 6.93-6.71 (m, 3H), 5.04 (s, 2H), 2.99 (s, 2H), 2.87 (t, J = 7.8 Hz, 2H), 2.68-2.45 (m, 4H), 1.47 (s, 6H), 1.16 (dd, J = 8.4, 6.6 Hz, 3H). LC-MS ESI m/z : found 389.4 (M -Η)·〇Example 221 3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzoindole-7-yl)methoxy)_2-hexyl- 5-fluorophenyl)propionic acid (250)

1H NMR (400 MHz, CDC13) 5 7.25 (s, 1H), 7.04 (s, 1H), 6.85 (dd, J =

18.8 Hz, 10.4, 2H), 5.03 (s, 2H), 2·99 (s, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.67-2, 45 (m, 4H), 1.47 (s , 6H), 1.17 (t, J = 7.5 Hz, 3H). LC-MS ESI m/z: Found: 405.4 (MH). Example 222 3-(3-Fluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzopyrano-7-yl)methoxy)·2-propane Phenyl phenyl) propionic acid (251)

S 149105-sp-20100806.doc -303 - 201200505 1 H NMR (400 MHz, CDC13) δ 6.99 (d, J = 9.7 Hz, 1H), 6.87-6.73 (m, 3H), 5.03 (s, 2H), 2.99 (s, 2H), 2.89 (t, J = 7.2 Hz, 2H), 2.67-2.53 (m, 4H), 1.57 (dd, J = 15.1, 8.1 Hz, 2H), 1.47 (d, J = 1.6 Hz , 6H), 0.98 (t, J = 7.0 Hz, 3H) _ LC-MS ESI m/z : found 403.0 (M-Η) · 〇 Example 223 3-(4-((5-)- 2-Dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-fluoro-2-propylphenyl)propionic acid (252)

JH NMR (400 MHz, CDC13) δ 7.25 (d, J = 2.2 Hz, 1H), 7.03 (s, 1H), 6.81 (s, 2H), 5.01 (s, 2H), 2.98 (s, 2H), 2.89 (t, J = 7.0 Hz, 2H), 2.82-2.36 (m, 4H), 1.57 (d, J = 6.7 Hz, 2H), 1.47 (s, 6H), 0.98 (t, J = 7.2 Hz, 3H) LC-MS ESI m/z: Found 41. Example 224 3-(3-Fluoro-4-((5-|l-yl-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)-2-pentyl Phenyl) propionic acid (253) #

1H NMR (400 MHz, CDC13) δ 6.99 (d, J = 9.7 Hz, 1H), 6.85-6.70 (m, 3H), 5.02 (s, 2H), 2.98 (s, 2H), 2.90-2.85 (m, 2H), 2.68-2.53 (m, 4H), 1.64-1.42 (m, 8H), 1.35 (s, 4H), 0.89 (s, 3H). LC-MS ESI m/z: found 431.1 (MH)· 〇149105-sp-20l00806.doc -304- 201200505 Example 225 3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy) Benzyl-3-yl-1-pentylphenyl)propionic acid (254)

1 H NMR (400 MHz, CDC13) δ 7.26 (s, 1 Η), 7.03 (s, 1H), 6.83-6.80 (m, 2H), 5.01 (s, 2H), 2.98 (s, 2H), 2.89 (t , J = 7.7 Hz, 2H), 2.67-2.51 (m, 4H), 1.65-1.42 (m, 8H), 1.36 (s, 4H), 0.89 (s, 3H). LC-MS ESI m/z : measured The value is 447.1 (MH)-. Example 226 3-(2-Ethyl-3-fluoro-4-((5-carbyl-2,2-dimethyl-2,3-dibenzobenzoin-7-yl) decyloxy Phenyl)-2-mercaptopropionic acid (255)

1 H NMR (400 MHz, CDC13) 5 7.00 (d, J = 8.2 Hz, 1H), 6.88-6.71 (m, 3H), 5.03 (s, 2H), 3.10-2.95 (m, 3H), 2.78-2.52 (m, 4H), 1.47 (s, 6H), 1.17 (t, J = 7·2 Hz, 6H). LC-MS ESI m/z: found: 403.4 (M-Η). Example 227 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)-2-ethyl-3-fluorobenzene Base)-2-methylpropionic acid (256)

S 149105-sp-20100806.doc - 305 - 201200505

1 H NMR (400 MHz, CDC13) δ 7.26 (s, 1H), 7.04 (s, 1H), 6.83-6.78 (m, 2H), 5.01 (s, 2H), 3.12-2.88 (m, 3H), 2.82 -2.48 (m, 4H), 1.47 (s, 6H), 1.17 (t, J = 7_3 Hz, 6H). LC-MS ESI Wz: found 419.4 (MH). Example 228 3-(4-(Di-(5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)-3-fluoro-2 -ethylphenyl)propionic acid (257)

OH !H NMR (400 MHz, CDC13) δ 7.00 (d, J = 9.6 Hz, 1H), 6.88-6.73 (m, 3H), 2.99 (s, 2H)} 2.90 (t, J = 7.9 Hz, 2H) , 2.75-2.55 (m, 4H), 1.47 (s, 6H), 1.18 (t, J = 7.5 Hz, 3H). LC-MS ESI m/z: found 391.3 (MH). Example 229

3-(4-(di-deuterated (5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-fluoro-2-propanyl Propionate (258)

*H NMR (400 MHz, CDC13) δ 6.99 (d, J = 9.5 Hz, 1H), 6.87-6.73 (m, 3H), 2.99 (s, 2H), 2.89 (t, J = 8.0 Hz, 2H), 2.70-2.52 (m, 4H), 1.57 (dd, J = 15.1, 7.4 Hz, 2H), 1.47 (s, 6H), 0.99 (t, J = 7.3 Hz, 3H). LC-MS ESI m/z : t measured 405.4 (MH)·. 149105-sp-20100806.doc -306 - 201200505 Example 230 3-(4-(Di-deuterated (5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)) Methoxy)-3-fluorophenyl)-2-methylpropionic acid (259)

1 H NMR (400 MHz, CDC13) δ 7.04-6.88 (m, 3 Η), 6.80 (t, J = 8.7 Hz, 2H), 3.05-2.91 (m, 3H), 2.70 (dd, J = 14.0, 7.0 Hz , 1H), 2.61-2.57 (m, 1H), 1.47 (s, 6H), 1.16 (d, J = 6.9 Hz, 3H). LC-MS ESI m/z : found 377.2 (M-Η)· 〇 Example 231 3-(4-(Di-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)-3-(trifluoromethyl) Base) phenyl)_2_methylpropionic acid (260)

1 H NMR (400 MHz, CDC13) δ 7.38 (s, 1H), 7.25 (d, J = 6.3 Hz, 1H), 7.06-6.95 (m, 2H), 6.79 (d, J = 7.8 Hz, 1H), 3.10-2.93 (m, 3H), 2.68 (d, J = 7.3 Hz, 2H), 1.48 (s, 6H), U8 (d, J = 6_8 Hz, 3H). LC-MS ESI m/z : measured value 427.1 (1^1 parent. Example 232 3-(3-Fluoro-4-((5-carbyl-2,2-dimercapto-2,3-dihydrobenzopyran-7-yl)) Oxy)-2-isopentylphenyl)propionic acid (261)

S I49105-sp-20100806.doc -307- 201200505

OH !H NMR (400 MHz, CDC13) δ 7.00 (d, J = 9.5 Hz, 1H), 6.87-6.72 (m, 3H), 5.03 (s, 2H), 2.99 (s, 2H), 2.89 (t, J = 7.9 Hz, 2H), 2.65-2.58 (m, 4H), 1.74-1.57 (m, 1H), 1.47 (s, 6H), 1.44-1.34 (m, 2H), 0.96 (d, J = 6.6 Hz , 6H). LC-MS ESI m/z: Found: 431.3 (M - Η). Example 233 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-yl-2-pyran Phenyl phenyl) propionic acid (262)

1H NMR (400 MHz, CDC13) δ 7.26 (s, 1Η), 7.03 (s, 1H), 6.81 (s, 2H), 5.01 (s, 2H), 2.99 (s, 2H), 2.89 (t, J = 7.9 Hz, 2H), 2.64-2.59 (m, 4H), 1.68-1.62 (m, 1H), 1.47 (s, 6H), 1.44-1.33 (m, 2H), 0.96 (d, J = 6.6 Hz, 6H LC-MS ESI m/z : found 447.1 (Μ·Η)· 〇 Example 234 3-(4-(dimerized (5-carbyl-2,2-dimethyl-2,3-di) Hydrobenzofuran-7-yl)methoxy)-3-fluoro-2-ethylphenyl)propionic acid (263)

1H NMR (400 MHz, CDC13) S 7.26 (s, 1H), 7.04 (s, 1H), 6.81 (s, 2H), 149105-sp-20100806.doc -308 - 201200505 2.99 (s, 2H), 2.90 ( t, J = 7.9 Hz, 2H), 2.75-2.54 (m, 4H), 1.47 (s, 6H), 1.18 (t, J = 7.5 Hz, 3H). LC-MS ESI m/z : found 407.2 ( MH)·. Example 235 3-(4-(Di-(5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)-3-yl-2 -propylphenyl)propionic acid (264)

1 H NMR (400 MHz, CDC13) δ 7.26 (s, 1 Η), 7.04 (s, 1H), 6.86-6.77 (m, 2H), 2.99 (s, 2H), 2.90 (t, J = 7.9 Hz, 2H ), 2.69-2.53 (m, 4H), 1.57 (dd, J = 15.4, 7.8 Hz, 2H), 1.47 (s, 6H), 0.99 (t, J = 7.3 Hz, 3H). LC-MS ESI m/ z: measured value 421.4 (MH)·. Example 236 3-(4-(Di-(5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7)methoxy)-3-fluorophenyl) -2-mercaptopropionic acid (265)

1H NMR (400 MHz, CDC13)) δ 7.24 (s, 1H), 7.04 (s, 1H), 6.97-6.87 (m, 2H), 6.82 (d, J = 7.9 Hz, 1H), 3.04-2.92 (m , 3H), 2.79-2.50 (m, 2H), 1.47 (s, 6H), 1.17 (d, J = 6.9 Hz, 3H) _ LC-MS ESI m/z : found 393.2 (M_H). Example 237 3-(4-(-jfL (5-carbyl-2,2-dimethyl-2,3-dihydro acyl p-pyranyl-7-yl) decyloxy)-3-(three Fluoromethyl)phenyl)-2•methylpropionic acid (266)

S 149105^sp-20100806.doc -309- 201200505

!H NMR (400 MHz, CDC13) δ 7.38 (s, 1H), 7.25-7.21 (m, 2H), 7.07-6.97 (m, 2H), 3.06-2.93 (m, 3H), 2.68 (d, J = 7.5 Hz, 2H), 1.48 (s, 6H), 1.18 (d, J = 6.6 Hz, 3H) _ LC-MS ESI m/z: 443 1 (mH)-. Example 238 3-(2-Butyl-3-fluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)methoxy) )phenyl)propionic acid C267)

1 H NMR (400 MHz, CDC13) δ 7.00 (d, J = 9.7 Hz, 1H), 6.89-6.74 (m, 3H), 5.03 (s, 2H), 2.99 (s, 2H), 2.96-2.84 (m , 2H), 2.71-2.54 (m, 4H), 1.61-1_33 (m, 10H), 0.94 (t, J = 7.2 Hz, 3H). LC-MS ESI m/z: found 417.3 (MH). Example 239 3-(2-butyl-4-((5-carbyl-2,2-dimercapto-2,3-di-argonbenzopyran-7-yl)methoxy)-3-fluoro Phenyl)propionic acid (268)

1 H NMR (400 MHz, CDC13) δ 7.26 (s, 1 Η), 7.03 (s, 1H), 6.86-6.77 (m, 2H), 5.01 (s, 2H), 2.99 (s, 2H), 2.90 (t , J = 8.0 Hz, 2H), 2.72-2.54 (m, 4H), 1.61-1.31 (m, 10H), 0.94 (t, J = 7.2 Hz, 3H)· LC-MS ESI m/z: found 433.3 149105-sp-20100806.doc -310- 201200505 (M-Η)-. Example 240 3-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)_3_(trifluoromethyl)phenyl) -2-mercaptopropionic acid (269)

1H NMR (400 MHz, CDC13) δ 7.38 (s, 1 Η), 7.24 (s, 1H), 7.01 (d, J = 7.8 Hz, 2H), 6.79 (d, J = 8.1 Hz, 1H), 5.08 (s , 2H), 3.04-2.91 (m, 3H), 2.80-2.55 (m, 2H), 1.48 (s, 6H), 1.18 (d, J = 6.8 Hz, 3H). LC-MS ESI m/z : measured The value is 425.0 (MH)_. Example 241 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)methoxy)-3-fluorophenyl)-2 ,2,3,3-tetrahydropropionic acid (270)

CI 1H NMR (400 MHz, CDC13) 5 7.24 (s, 1H), 7.04 (s, 1H), 6.99-6.78 (m, 3H), 5.03 (s, 2H), 2.99 (s, 2H), 1.47 (s , LC-MS: 399.3 (M-H+). Example 242 3-(3-Fluoro-4((5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)-2-propylbenzene Base)-2,2,3,3-tetrahydropropionic acid (271) 149105-sp-20100806.doc • 311 - 201200505

1 H NMR (400 MHz, CDC13) δ 6.99 (d, J = 10.0 Hz, 1H), 6.87-6.71 (m, 3H), 5.03 (s, 2H), 2.99 (s, 2H), 2.62 (t, J = 7.3 Hz, 2H), 1.59-1.53 (m, 2H), 1.47 (s, 6H), 0.99 (t, J = 7.3 Hz, 3H). LC-MS ESI m/z: found 407.4 (MH)- . Example 243 3-(2-Ethyl-3-ylyl-4-((5-carbyl-2,2-dimercapto-2,3-diazabenzone. South-7-yl) methoxy Phenyl) 2,3,3,3-tetrahydropropionic acid (272)

1 H NMR (400 MHz, CDC13) δ 7.00 (d, J = 10.3 Hz, 1H), 6.87-6.73 (m, 3H)} 5.03 (s, 2H), 2.99 (s, 2H), 2.75-2.61 (m , 2H), 1.47 (s, 6H), 1.18 (t, J = 7_5 Hz, 3H). LC-MS ESI m/z: found 393.3 (MH)*. Example 244 3-(3-Fluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)-2-methyl Phenyl) propionic acid (273)

!H NMR (400 MHz, CDC13) δ 6.98 (d, J = 9.6 Hz, 1H), 6.85-6.71 (m, 3H), 5.04 (s, 2H)} 2.99 (s, 2H), 2.88 (t, J = 7.9 Hz, 2H), 2.58 (t, J = 7.8 Hz, 2H), 2.23 (s, 3H), 1.47 (s, 6H)_ LC-MS ESI m/z : found 375.3 (MH). 149I05-sp.20100806.doc •312- 201200505 Example 245 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy) )-3-fluoro-2-methylphenyl)propionic acid (274)

]H NMR (400 MHz, CDC13) δ 7.25 (s, 1Η), 7.03 (s, 1H), 6.80 (s, 2H), 5.02 (s, 2H), 2.99 (s, 2H), 2.88 (t, J = 7.8 Hz, 2H), 2.59 (t, J = 7.8 Hz, 2H), 2.23 (s, 3H), 1.47 (s, 6H). LC-MS ESI m/z: found 391.4.

Example 246 3-(3-Ethyl-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzop-pentan-7-yl)methoxy)phenyl) Propionic acid (275)

1 H NMR (400 MHz, CDC13) (5 7.00-6.90 (m, 3H), 6.83 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 6.9 Hz, 1H), 4.96 (s, 2H) , 2.98 (s, 2H), 2.87 (t, J = 7.9 Hz, 2H), 2.72-2.55 (m, 4H), 1.46 (s, 6H), 1.20 (t, J = 7.5 Hz, 3H). LC- MS ESI 〇^: found 371.2 (1^-11)-. Example 247 3-(4-((5-)- 2,2- dimethyl-2,3-dihydrobenzophene 7-yl)methoxy)-3-ethylphenyl)propionic acid (276)

1H NMR (400 MHz, CDC13) δ 7.17 (s, 1H), 6.97-6.89 (m, 3H), 6.78 (d,

S 149105-sp-20100806.doc -313 - 201200505 J = 8.2 Hz, 1H), 4.89 (s, 2H), 2.93 (s, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.67-2.51 ( m, 4H), 1_41 (s, 6H), 1.14 (t,J = 7·5 Hz, 3H). LC-MS ESI m/z: found: 387.2 (MH). Example 248 3-(3-Ethyl-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)methoxy)phenyl)- 2-methylpropionic acid (277)

1 H NMR (400 MHz, CDC13) ¢5 6.98-6.93 (m, 3H), 6.82-6.79 (m, 2H), 4.96 (s, 2H), 3.05-2.89 (m, 3H), 2.79-2.49 (m , 4H), 1.46 (s, 6H), 1.25-1.08 (m, 6H). LC-MS ESI m/z: Found: 385.3 (MH). Example 249 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)_3_ethylphenyl)-2- Methyl propionic acid (278)

1H NMR (400 MHz, CDC13) (5 7.17 (s, 1H), 6.97 (s, 1H), 6.92-6.84 (m, 2H), 6.77 (d, J = 8.2 Hz, 1H), 4.89 (s, 2H ), 3.00-2.84 (m, 3H), 2.74-2.43 (m, 4H), 1.40 (s, 6H), 1.17-0.99 (m, 6H), LC-MS ESI m/z: found 4 〇 1.2 ( M-Η)·〇Example 250 3-(2-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzop-pentan-7-yl)decyloxy)phenyl Propionic acid (279) 149105-sp-20100806.doc -314- 201200505 ο

Ci Ή NMR (400 MHz, CDC13) δ 7.22 (s, 1H), 7.18 (t, J = 6.6 Hz, 2H), 7.06 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.89 ( t, J = 7.4 Hz, 1H), 4.99 (s, 2H), 3.05-2.93 (m, 4H), 2.70 (t, J = 7.7 Hz, 2H), 1.48 (s, 6H). Example 251 3-(3-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzop-am-7-yl)decyloxy)phenyl)-2-indenyl Propionic acid (280)

〇Cl 1 H NMR (400 MHz, CDC13) δ 7.25-7.22 (m, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.04 (s, 1H), 6.88-6.75 (m, 3H), 4.97 (s, 2H), 3.05 (dd, J = 13.5, 6.1 Hz, 1H), 3.00 (s, 2H), 2.81-2.77 (m, 1H), 2.66-2.63 (m, 1H), 1.48 (s, 6H) ), 1.18 (d, J = 6,9Hz, 3H). Example 252 3-(4-((2,2-Dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)propanoic acid hydrazine (400 (281)

ζ, CDC13) δ 7.28-7.20 (m, 1Η), 7.09 (t, J = 8.4 Hz, 3H), 6.93 (d, J = 8.6 Hz, 2H), 6.82 (t, J = 7.5 Hz, 1H), </ RTI> <RTIgt; </ RTI> <RTIgt; Example 253 3_(4-((2,2-Dimercapto-2,3-dimurphenyl)p-oxa-7-yl)decyloxy)phenyl)-2-indenyl 149105-sp-20100806. Doc •315· 201200505 Propionic acid (282)

1 H NMR (400 MHz, CDC13) &lt;5 7.25 (d, J = 11.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 3H), 6.93 (d5 J = 8.5 Hz, 2H), 6.83 (t , J = 7.5 Hz, 1H), 5.02 (s, 2H), 3.06-2.94 (m, 3H), 2.75-2.69 (m, 1H), 2.63-2.58 (m, 1H), 1.48 (s, 6H), 1.16 (d, J = 6.9Hz, 3H). Example 254 3-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)-2,3,5-trimethyl Phenyl)propionic acid (M3)

1H NMR (400 MHz, CDC13) δ 7.06 (d, J = 9.7 Hz, 1H)5 6.89-6.75 (m, 2H), 4.66 (s, 2H), 3.00 (s, 2H), 2.97-2.87 (m, 2H), 2.60 (t, J = 8.0 Hz, 2H), 2.27 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.45 (s, 6H). LC-MS ESI m/z : Found 385.0 (MH)-. Example 255 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzo-p-α-N-)-yloxy)-2,3,5_ triterpene Phenyl phenyl) propionic acid (284)

1H NMR (400 MHz, CDC13) occupies 7.32 (s, 1H), 7.07 (s, 1H), 6.85 (s, 1H), 149105-sp-20100806.doc • 316_ 201200505 4.64 (s, 2H), 3.00 (s , 2H), 2.98-2.84 (m, 2H), 2.66-2.53 (m, 2H), 2.27 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.45 (s, 6H). LC-MS ESI m/z: found 401.3 (M - Η) · 〇 Example 256 3-(4-((5-fluoro-3H-spiro[benzofuran-2, oximecyclopentene]-7- Methoxy)-2,3-dimercaptophenyl)propionic acid (285)

1 H NMR (400 MHz, CDC13) δ 7.05-6.90 (m, 2 Η), 6.79-6.75 (m, 2H), 4.96 (s, 2H), 3.15 (s, 2H), 2.98-2.87 (m, 2H) , 2.64-2.53 (m, 2H), 2.23 (s, 6H), 2.12-2.04 (m, 2H), 1.96-1.84 (m, 2H), 1.81-1.63 (m, 4H). LC-MS ESI m/ z : Found: 397.4 (MH)·. Example 257 2-(5-((5-Vinyl-2-isopropoxybenzyl)oxy)fluoro)-2,3-dihydro-1H-indol-1-yl)acetic acid (286)

!H NMR (400 MHz, CDC13) δ 7.48 (s, 1H), 7.22-7.19 (m, 1H), 6.97-6.94 (m, 1H), 6.88-6.86 (m, 1H), 6.83-6.81 (m, 1H), 5.08 (s, 2H), 4.59-4.53 (m, 1H), 3.58-3.51 (m, 1H), 2.92-2.74 (m, 3H), 2.52-2.39 (m, 2H), 1.84-1.75 ( m, 1H), 1.34 (d, 6H). Example 258 2-(5-((5-Alkyl-2-isopropoxybenzyl)oxy)_2,3-dihydro_1H_茚 small 149105-sp-20100806.doc -317· 201200505 base) Acetic acid (287)

^ NMR (400 MHz, CDC13) δ 7.45 (s, 1H), 7.20-7.18 (m, 1H), 7.11-7.09 (m, 1H), 6.87-6.79 (m, 3H), 5.02 (s, 2H), 4.59-4.53 (m, 1H), 3.56-3.53 (m, 1H), 2.93-2.79 (m, 3H), 2.51-2.41 (m, 2H), 1.81-1.74 (m, 1H), 1.34 (d, 6H) ). Example 259 2-(5-((2-Isopropoxypyridin-3-yl)methoxy)-2,3-dihydro-1H-indol-1-yl)acetic acid (288)

1 H NMR (400 MHz, DMSO-d6) δ: 12.18 (br, 1H), 8.10 (d, J = 4.4 Hz, 1H), 7.73 (d, J = 6.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.97-6.94 (m, 1H), 6.85 (s, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.32-5.29 (m, 1H), 4.96 (s, 2H), 2.82-2.79 (m, 1H), 2.76-2.62 (m} 3H), 2.30-2.24 (m, 2H), 1.66-1.61 (m, 1H), ® 1.28 (d, J = 7.1 Hz, 6H). LC - MS ESI m/z : found 340.2 (M-Η). Example 260 3-(4-((lH- Oroxazol-7-yl)decyloxy)-3,5-difluorophenyl)-2-mercaptopropionic acid (289)

1H NMR (400 MHz, CDC13) δ: 8.14 (s, 1Η), 7.76 (d, 1H), 7.31 (d, 1H), 7.26 (s, 1H), 7.15 (m, 1H), 6.82-6.78 (m , 1H), 5.45 (s, 2H), 2.98-2.93 (m, 149l05-sp-20100806.doc -318- 8 201200505 1H), 2.78-2.73 (m, 1H), 2.67-2.63 (m, 1H), 1.22 (d,3H). LC-MS ESI m. Example 261 3-(3,5-Difluoro-4-((2-methylbenzo[d]indot-7-yl)methoxy)phenyl)-2-methylpropanoic acid (290)

1 H NMR (400 MHz, CDC13) ¢5 7.62 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 6.72 (d , J = 9.2 Hz, 2H), 5.41 (s, 2H), 2.99-2.93 (m, 1H), 2.73-2.71 (m, 1H), 2.65 (s, 3H), 2.63-2.58 (m, 1H), </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 262 2-(6-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy) stupid

Furan-3-yl)acetic acid (291)

1H NMR (400 MHz, DMSO-d6) δ: 12.46 (br, 1H), 7.76 (s, 1H), 7.45 (d, 1H), 7.24 (s, 1H), 7.04-7.00 (m, 2H), 6.93 (d, 1H), 4.99 (s, 2H), 3.63 (s, 2H), 3.04 (s, 2H), 2, 50 (s, 3H), 1.45 (s, 6H). LC-MS ESI m/z : Measured value 369.0 [M-Η]' 〇 Example 263 2-(7-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzopyranyl-7)-yloxy) Base ketone-2H-nonene-4_yl)acetic acid (292)

S 149105-sp-20100806.doc -319- 201200505

1 H NMR (400 MHz, CDC13) δ : 6.93 (d, 3H), 6.82 (m, 1H), 6.64 (m, 1H), 6.34 (s, 1H), 5.06 (d, 2H), 3.15 (m, 1H), 3.08-3.01 (m, 2H), 2.95 (m, 2H), 1.51-1.44 (m, 6H). LC-MS ESI m/z ·········· Example 264 3-(4-((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-N-hydroxy-2- Methyl acrylamide (293)

1 H NMR (400 MHz, CDC13) δ 7.03 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 10.4 Hz, 1H), 6.89 (d, J - 8.1 Hz, 2H), 6.79 (d, J = 7.8 Hz, 1H), 4.96 (s, 2H), 2.99 (s, 2H), 2.91-2.84 (m, 1H), 2.79 (s, 1H), 2.67-2.58 (m, 1H), 2.41-2.29 (m, 1H), 1.47 (s, 6H), U9 (d, J = 6.7 Hz, 3H). LC-MS ESI m/z: found 372.4 (MH) · ° Example 265 3-(4-(( 5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)-N-hydroxypropionamide (294)

!H NMR (400 MHz, CDC13) δ 7.07 (d, J = 7.8 Hz, 2H), 6.98-6.88 (m, 3H), 6.79 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 2.99 (s, 2H), 2.91 (t, J = 7.5 Hz, 149105-sp-20100806.doc • 320· 201200505 2H), 2.80 (s, 1H), 2.41 (t, J = 10.4 Hz, 2H), 1.47 (s, 6H). LC-MS ESI m. Example 266 3-(4-((5-Gasyl-2,2-dimercapto-2,3-dihydrobenzoindole)-South-7-yl)nonyloxy)phenyl)-4-methyl Valeric acid (295)

1H NMR (400 MHz, CDCl3) δ 725 (s, 1 Η), 7.06-7.03 (m, 3H), 6.90 (d, J = 8.0 Hz, 2H), 4.95 (s, 2H), 2.99 (s, 2H) , 2.89-2.70 (m, 2H), 2.59-2.54 (m, 1H), 1.88-1.74 (m,1H), 0.91 (d, J = 6.6 Hz, 3H), 0,74 (d, J = 6.6 Hz , 3H). Example 267 3-(4-((6-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-4-yl)methoxy)-2,3-didecylphenyl Propionic acid (296)

1H NMR (400 MHz, CDC13) δ 6.97 (d, J = 8.1 Hz, 1H), 6.92 (s, 1H), 6.70-6.66 (m5 2H), 4.87 (s, 2H), 2.99-2.88 (m, 4H ), 2.60 (t, J = 8.4 Hz, 2H), 2.23 (s, 3H), 2.20 (s, 3H), 1.47 (s, 6H). Example 268 3-(2-Ethoxy-4-((5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)propene Acid (297) 149l05-sp-20100806.doc -321 - 201200505

!H NMR (400 MHz, DMSO-d6) δ : 12.00 (br, s), 7.01-6.94 (m, 3H), 6.53 (s, 1H), 6.45-6.43 (m, 1H), 4.87 (s, 2H ), 3.98-3.96 (m, 2H), 3.00 (s, 2H), 2.68-2.66 (m, 2H), 2.37-2.35 (m, 2H), 1.40 (s, 6H), 1.28-1.26 (m, 3H) LC-MS ESI m/z: found 387.3 [MH]. Example 269 3-(4-((2,2-Dimercapto-5-(indolylsulfonyl)-2,3-dihydrobenzofuran-7-yl)decyloxy)-2,3- Dimethylphenyl)propionic acid (298)

1H NMR (400 MHz, CDC13) δ 7.90 (s, 1Η), 7.66 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.00 (s , 2H), 3.09 (s, 2H), 3.03 (s, 3H), 2.98-2.89 (m, 2H), 2.64-2.54 (m, 2H), 2.23 (s, 3H), 2.22 (s, 3H), </ RTI> </ RTI> <RTIgt; Example 270 3-(4-((5-Gasyl-2,2-dimercapto-3-keto-2,3-di-argonbenzo-p- 11-11--7-yl) decyloxy)-2, 3-dimethylphenyl)propionic acid (299)

1H NMR (400 MHz, CDC13) δ 7.57 (dd, J = 9.2, 2.7 Hz, 1H), 7.26-7.22 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 149105-sp-20100806.doc - 322 - 201200505 3.00-2.90 (m, 2H), 2.66-2.56 (m, 2H), 2.25 (s, 6H), 1.48 (s, 6H). LC-MS ESI m/z: Found. Example 271 3-(4-((5-Fluoro-3-hydroxy-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-di Nonylphenyl)propionic acid (300)

1H NMR (400 MHz, CDC13) (5 7.16 (dd, J = 9.6, 2.8 Hz, 1H), 7.04 (dd, J = 9.6, 2.8 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 5.02 (s, 2H), 4.76 (s, 1H), 2.98-2.89 (m, 2H), 2.64-2.53 (m, 2H), 2.23 (s, 6H) , 1.51 (s, 3H), 1.36 (s, 3H). LC-MS ESI m/z: s. 2,5-trimethyl-2,3-dihydroindolofuran-7-yl)nonyloxy)

Phenyl) propionic acid (301)

1H NMR (400 MHz, CDC13) δ 7.07 (s, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.90 (s, 1H), 6.80 (d, J = 8.3 Hz, 1H), 4.97 (s , 2H), 2.98 (s, 2H), 2.96-2.88 (m, 2H), 2.63-2.53 (m, 2H), 2.27 (s, 3H), 2.23 (s, 6H), 1.46 (s, 6H). LC-MS ESI m/z: Found: 367.1 [MH]. Example 273 3-(4-((5-Ethyl-2,2-dimercapto-2,3-dihydrobenzop-β-N-7-yl)methoxy)_2,3-dimethyl Phenyl) propionic acid (302)

S I49105-sp-20100806.doc - 323 - 201200505 ο

1 Η NMR (400 MHz, CDC13) &lt;5 7.10 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.93 (s5 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 2.99 (s, 2H), 2.97-2.89 (m, 2H), 2.64-2.53 (m, 4H), 2.23 (s, 6H), 1.47 (s, 6H), 1.20 (t, J = 7.6 Hz, 3H). LC-MS ESI m/z: found 381.1 pVl-H]- 274 274 3-(2-ethyl-4-((5-ethyl-2,2-didecyl) -2,3-dihydrobenzofuran-7-yl)methoxy)-3-fluorophenyl)propionic acid (303)

1H NMR (400 MHz, CDC13) &lt;5 7.03 (s, 1H), 6.85-6.72 (m, 2H), 6.74 (d, J = 8.5 Hz, 1H), 4.98 (s, 2H), 2.92 (s, 2H), 2.86-2.78 (m, 2H), 2.63-2.60 (m, 2H), 2.55-2.46 (m, 4H), 1.40 (s, 6H), 1.13-1.09 (m, 6H). LC-MS ESI m/z: found 399.2 [Μ-ΗΓ. Example 275 3-(4-((5-Moth-2,2-dimethyl-2,3-dihydrobenzop-pentan-7-yl)methoxy)-2,3-didecyl Phenyl) propionic acid (304)

1 H NMR (400 MHz, CDC13 ) δ 7.57 (s, 1H), 7.37 (s, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 4.93 ( s, 2H), 3.00 (s, 2H), 2.96-2.88 (m, 149105-sp-20100806.doc - 324 · 201200505 2H), 2.64-2.55 (m, 2H), 2.23 (s, 3H), 2.22 ( s, 3H), 1.47 (s, 6H). LC-MS ESI m/z: Found: 479.1 [MH]. Example 276 3-(4-((5-Ethoxy-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)_2,3-dimercaptophenyl Propionic acid (305)

!H NMR (400 MHz, CDC13) δ 6.94 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.67 (s, 1H), 4.97 ( s, 2H), 3.98-3.93 (m, 2H), 2.98 (s, 2H), 2.94-2.90 (m, 2H), 2.60-2.56 (m, 2H), 2.22 (s, 6H), 1.46 (s, <RTI ID=0.0></RTI> </RTI> <RTIgt; Example 277 3-(4-((5-Gas-2-methyl-2,3-dihydrobenzocypin-7-yl)methoxy)_2,3-dimethyl

Phenyl phenyl) propionic acid (306)

1 H NMR (400 MHz, CDC13) δ 7.25 (s, 1H), 7.06 (s, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 5.01- 4.95 (m, 2H), 3.34-3.28 (m, 1H), 2.95-2.91 (m, 2H), 2.84-2.78 (m, 1H), 2.61-2.57 (m, 2H), 2.23 (s, 6H), 1.47 (d, J = 6.4 Hz, 3H). LC-MS ESI m/z: Example 278 3-(2-Ethoxy-4-((5-ethoxy-2,2-dimethyl-2,3-dihydrobenzop-pentan-7-yl)methoxy)benzene Propionate (307) £ 149105-sp-20100806.doc - 325 - 201200505

!H NMR (400 MHz, CDC13) δ 7.02 (d, J = 8.8 Hz, 1H), 6.80 (s, 1H), 6.68 (s, 1H), 6.51-6.49 (m, 2H), 4.96 (s, 2H ), 4.02-3.93 (m, 4H), 2.97 (s, 2H)} 2.88-2.85 (m, 2H), 2.64-2.61 (m, 2H), 1.46 (s·, 6H), 1.41-1.34 (m, 6H). LC-MS ESI m/z: Found 41. Example 279 3-(4-((2,2-Dimercapto-5-(tridecyloxy)-2,3-dihydro-p-p-pyran-7-yl)methoxy)2,3- Dimercaptophenyl)propionic acid (308)

1H NMR (400 MHz, CDC13) &lt;5 7.17 (s, 1H), 6.97-6.94 (m, 2H), 6.76 (d, J = 8.4 Hz, 1H), 4.97 (s, 2H), 3.03 (s, 2H), 2.95-2.91 (m, 2H), 2.61-2.57 (m, 2H), 2.23 (s, 6H), 1.49 (s, 6H). LC-MS ESI m/z: found 437.3 (MH)· . Example 280 3-(4-((5-Denyl-1-(carbaryl)-2,2-dimethylindan-7-yl)methoxy)-2,3-dimethyl Phenyl)propionic acid (309)

1H NMR (400 MHz, CDC13) &lt;5 6.99 (d, J = 8.6 Hz, 1H), 6.93-6.89 (m, 2H), 6.80 (d, J = 8.6 Hz, 1H), 5.01 (s, 2H) } 3.85 (s, 3H), 3.07 (s, 2H), 149105-sp-20100806.doc - 326 - 201200505 2.96-2.94 (m, 2H), 2.62-2.58 (m, 2H), 2.22 (s, 3H) , 2.14 (s, 3H), 1.54 (s, 6H). LC-MS ESI m/z: Found: 428.5 (M - Η). Example 281 3-(4-((5-Fluoro-2,2-dimercaptoindan-7-yl)decyloxy)-2,3-dimercaptophenyl)propanoic acid (310)

Compound (909) (120 mg, 0.28 mmol) in MeOH (5 mL) & 2N

NaOH (1 ml) was heated at 80 ° C for 5 hours. The volatile material 'Add water' was removed in vacuo and the reaction was acidified to pH 3 with IN HCl. The aqueous layer was extracted with ethyl acetate (3.times.20 mL) and the combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give compound (310). 1H NMR (400 MHZ, CDC13) (5 7.32 (dd, J = 8.8, 4.8 Hz, 1H), 7.06-7.02 (m, 1H), 6.95-6.92 (m, 1H), 6.67 (d, J = 8.8 Hz , 1H), 5.06 (s, 2H), 3.87 (s, 1H), 3.13 (s, 2H), 2.92-2.89 (m, 2H), 2.59-2.55 (m, 2H), 2.19 (s, 3H), 2.12 (s, 3H), 1.58 (s, 6H). LC-MS ESI m/z: found: 370.0 (M - Η). Example 282 3-(4·((5_Fluoro-1,2, 2-trimercaptodihydroindenyl)decyloxy)_2,3-diphenylphenyl)propionic acid (311)

S 149105-sp-20100806.doc -327 - 201200505 Add sodium hydride (4.3 mg, 2 eq.) to a solution of (310) (20 mg, 0.05 mmol) in dMF (3 mL) The mixture was stirred at 4 (TC for 1 hour. The solution was allowed to warm to room temperature, excess methane iodide was added and the mixture was sealed and warmed to 40 ° C overnight. The reaction was quenched with water and The ester (2 x 20 mL) was extracted. The combined organic layers were dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTI ID=0.0> MHz, CDC13) (5 6.97 (d, J = 8.2 Hz, 1H), 6.93-6.91 (m, 2H), 6.78 (d, J = 8.2 Hz, 1H), 4.99 (s, 2H), 3.83 (s, 2H), 3.68 (s, 3H), 2.94-2.90 (m, 2H), 2.56-2.52 (m, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 1.54 (s, 6H). LC - MS ESI m/z: found 384.5 (M - Η).. Example 283 3-(4-((5-fluoro)-2,2-dipropyl-2,3-dihydrobenzofuran-7 -yl)nonyloxy)-2,3-dimercaptophenyl)propionic acid (312)

!H NMR (400 MHz, CDC13) δ 7.02-6.91 (m, 2Η), 6.78-6.74 (m, 2H), 4.96 (s, 2H), 2.99 (s, 2H), 2.96-2.89 (m, 2H) , 2.65-2.55 (m, 2H), 2.23 (s, 6H), 1.73-1.60 (m, 4H), 1.45-1.30 (m, 4H), 0.93 (t, J = 7.3 Hz, 6H). LC-MS ESI m/z : found 427.4 (M-Η). Example 284 3-(4-((2,2-Diethyl-5-f-yl-2,3-dihydrobenzoquinone)-N--7-yl)methoxy)_2,3-dimethylbenzene Propionate (313) 149105-sp-20100806.doc -328 - 201200505

*H NMR (400 MHz, CDC13) δ 7.02-6.91 (m, 2H), 6.78-6.74 (m, 2H), 4.98 (s, 2H), 2.98 (s, 2H), 2.96-2.90 (m, 2H) , 2.63-2.55 (m, 2H), 2.24 (s, 6H), 1.74 (q, J = 7.4 Hz, 4H), 0.92 (t, J = 7·4 Hz, 6H). LC-MS ESI m/z : Found 399.2 (MH)·. Example 285

3-(4-((5-Fluoro-2-(decyloxymethyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3- Dimethylphenyl)propionic acid (314)

1H NMR (400 MHz, CDC13) δ 7.02-6.98 (m, 1 Η), 6.95 (d, J = 8.4 Hz, 1H), 6.81-6.77 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H) , 4.98 (s, 2H), 3.46 (s, 2H), 3.41 (s, 3H), 3.25 (d, J = 15.8 Hz, 1H), 2.97-2.82 (m, 3H), 2.64-2.53 (m, 2H ), 2.23 (s, 6H), 1 46 (s, 3H). LC-MS ESI m/z: Example 286 3-(4-((5-Fluoro-2-(methoxymethyl)-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-didecyl Phenyl) propionic acid (315)

1H NMR (400 MHz, CDC13) 5 7.03-6.99 (m, 1H), 6.95 (d, J = 8.4 Hz, s 149105-sp-20100806.doc -329- 201200505 1H), 6.84-6.80 (m, 1H) , 6.73 (d, J = 8.4 Hz, 1H), 5.03-5.01 (m, 3H), 3.69-3.53 (m, 2H), 3.44 (s, 3H), 3.32-3.18 (m, 1H), 3.09-2.99 (m, 1H), 2.97-2.87 (m, 2H), 2.65-2.54 (m, 2H), 2.23 (s, 6H). LC-MS ESI m/z: found: 387.2 (MH). Example 287 3-(4-((5-Fluoro-2-(hydroxymethyl)-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl Propionic acid (316)

1H NMR (400 MHz, CD3 OD) δ 6.96-6.84 (m, 3H), 6.74 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 3.80-3.63 (m, 2H), 3.29-3.21 (m, 2H), 3.11-3.00 (m, 1H), 2.93-2.82 (m, 2H), 2.54-2.42 (m, 2H), 2.22 (s, 3H), 2.19 (s, 3H). LC-MS ESI m/z : found 373.0 (MH). Example 288 3-(4-((5-Fluoro-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)decyloxy)-2,3- Dimethylphenyl)propionic acid (317)

1 H NMR (400 MHz, CD3 OD) δ 6.96-6.81 (m, 3H), 6.74 (d, J = 8.4 Hz, 1H), 4.96 (s, 2H), 3.63-3.54 (m, 2H), 3.30- 3.22 (m, 1H), 2.94-2.82 (m, 3H), 2.52-2.44 (m, 2H), 2.22 (s, 3H), 2.19 (s, 3H), 1.42 (s, 3H). LC-MS ESI m/z : found 387.0 (Μ-Η)·. 149105-sp-20100806.doc ·33〇_ 8 201200505 Example 289 3-(4-((5-isopropyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)) Methoxy)-2,3-dimethylphenyl)propionic acid (318)

1 H NMR (400 MHz, CDC13) 5 7.14 (s} 1H), 7.00-6.92 (m, 2H), 6.83 (d, J = 8.5 Hz, 1H), 4.98 (s, 2H), 3.00 (s, 2H ), 2.97-2.91 (m, 2H), 2, 90-2.79 (m,

1H), 2.65-2.55 (m, 2H), 2.23 (s, 6H), 1.47 (s, 6H), 1.23 (d, J = 6.8 Hz, 6H). LC-MS ESI m/z : found 395.4 ( MH)·. Example 290 3-(4-((5-Cyclopentyl-2,2-dimethyl-1 2,3-dihydrobenzopyran-7-yl)methoxy)-2,3-

Dimercaptophenyl)propionic acid (319)

149105-sp-20100806.doc -331 · 1 H NMR (400 MHz, CDC13) (5 7.15 (s, 1H), 7.00-6.92 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 3.00 (s, 2H), 2.97-2.85 (m, 3H), 2.64-2.55 (m, 2H), 2.23 (s, 6H), 2.10-1.95 (m, 2H), 1.83-1.49 (m, 6H), 1.47 (s, 6H). LC-MS ESI m/z: Found: 421.3 (MH)-. Example 291 2 3-(4-((5-ethoxy-2,2~2) Methyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2-ethyl-3-fluorophenyl)propionic acid (320) 201200505

1 H NMR (400 MHz, CDC13) &lt;5 6.94-6.73 (m, 3H), 6.68 (s, 1H), 5.05 (s, 2H), 3.95 (q, J = 7.0 Hz, 2H), 2.97 (s , 2H), 2.91-2.87 (m, 2H), 2.74-2.64 (m, 2H), 2.63-2.55 (m, 2H), 1.46 (s, 6H), 1.35 (t, J = 7.0 Hz, 3H), 1.17 (t, J = 7.5 Hz, 3H). LC-MS ESI m. Example 292 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzoindene B-7-yl)methoxy)-2,3-difluorobenzene Propionate (321)

NMR (400 MHz, DMSO-d6) ^ 12.10 (br, 1H), 7.23-7.22 (m, 2H), 7.01-7.00 (m, 2H), 5.01 (s, 2H), 3.02 (s, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.50-2.48 (m, 2H), 1·40 (s, 6H). LC-MS ESI m/z: 395. Example 293 3-(2,3-Difluoro-4-((5-1-yl-2,2-dimethyl-2,3-dihydrobenzo-)N-7-yl)methoxy)benzene Propionate (322)

*H NMR (400 MHz, DMSO-d6) ^ 12.10 (br, 1H)S 7.05-6.97 (m, 4H), 5.00 (s, 2H), 3.01 (s, 2H), 2.77 (t, J = 7.6 Hz , 2H), 2.49-2.46 (m, 2H), 1.39 (s, 149105-sp-20100806.doc -332 - 201200505 6H)· LC-MS ESI m/z : Measured value 379,1 [M-Η]· . Example 294 3-(2,5-Difluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl) Propionic acid (323)

NMR NMR (400 MHz, DMSO-d6) δ 12.22 (br, 1 Η), 7.20-7.11 (m, 2H), 7.05 (dd, J = 8.0, 2.8 Hz, 1H), 6.9B (dd, J = 9.8, 2.6 Hz, 1H), 4.97 (s, 2H), 3.02 (s, 2H), 2.71 (t, J = 7.6 Hz, 2H), 2.49-2.44 (m, 2H), 1.40 (s, 6H). LC- MS ESI m/z: found 379.1 [M-Η]. Example 295 3-(4-((5-Gasyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)-2,5-difluorophenyl) Propionic acid (324)

NMR NMR (400 MHz, DMSO-d6) δ 12.21 (br, 1H), 7.23-7.11 (m, 4H), 4.98 (s, 2H), 3.02 (s, 2H), 2.71 (t, J = 7.6 Hz, 2H), 2.48-2.45 (m, 2H), 1.40 (s, 6H). LC-MS ESI m/z: Found: 395.1 [MH]. Example 296 3-(2,3-dioxa-4-((5-fluoro-2,2-dimercapto-2,3-dihydroindolyl-7-yl)decyloxy)phenyl Propionic acid (325)

149105-sp-20100806.doc - 333 - 201200505 1 H NMR (400 MHz, CDC13) δ 7.07 (d, J - 8.6 Hz, 1H), 7.02 (dd, J = 9.6, 2.3 Hz, 1H), 6.88 (d , J = 8.6 Hz, 1H), 6.82-6.77 (m, 1H), 5.07 (s, 2H) 3.05-2.95 (m, 4H), 2.67 (t, J = 7_7 Hz, 2H), 1.48 (s, 6H) ). Example 297 3-(3-Chloro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)-2-indenyl) Phenyl)propionic acid (326)

1H NMR (400 MHz, CDC13) δ 7.06 (d, J = 9.7 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.82-6.74 (m, 2H), 5.06 (s, 2H), 3.00 (s, 2H), 2.93 (t, J = 8 Hz, 2H), 2.58 (t, J = 8 Hz, 2H), 2.38 (s, 3H), 1.48 (s, 6H) Example 298 3-(4- ((6-Fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-4-yl)decyloxy)-2,3-dimethylphenyl)propionic acid (327)

1 H NMR (400 MHz, CDC13) 5 6.97 (d, J = 8.5 Hz, 1H), 6.69-6.64 (m, 2H), 6.42 (dd, J = 9.3, 2.2 Hz, 1H), 4.88 (s, 2H ), 2.98-2.92 (m, 4H), 2.60 (t, J = 8.0 Hz, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.48 (s, 6H). Example 299 (R)-3-(4-((2,2-Dimercapto-5-(trifluoromethoxy)-2,3-dihydrobenzofuran-7-yl)methoxy)benzene Benzyl-2-methylpropionic acid (328) 149105-sp-20100806.doc - 334 - 201200505

Compound (328) was prepared in a similar manner as described for the synthesis of (94). 'H NMR (400 MHz, CDC13) 5 7.14 (s, 1H), 7.09 (d, J = 8 &gt; 7 ^) 6.94 (s, 1H), 6.91 (d, J = 8.7 Hz, 2H), 4.97 ( s, 2H), 3.04-2.97 (m, 3H) 2.73-2.67 (m, 1H), 2.61 (dd, J = 13.4, 8.0 Hz, 1H), 1.49 (s, 6H), 1.16 (dj 6.9Hz, 3H ).

Example 300 (S)-3-(4-((2,2-Dimercapto-5-(trifluoromethoxy)-2,3-dihydrobenzofuran _7-yl)methoxy) Phenyl)-2-mercaptopropionic acid (329)

Compound (329) was prepared in a similar manner as described for the synthesis of (94). 1H NMR (400 MHz, CDC13) 7.14 (s, 1H), 7.09 (d, J = 8.7 Hz, 2H)

6.95 (s, 1H), 6.91 (d, J = 8.7 Hz, 2H), 4.98 (s, 2H), 3.02-2.98 (m, 33⁄4) 2.75-2.71 (m,1H), 2.61 (dd, J = 13.4 , 8.0 Hz, 1H), 1.49 (s, 6H), 1.16 (d, j = 6.9Hz, 3H). Example 301 3-(2,3-Dimercapto-4-((2-methyl-2,3-dihydrobenzopyran-7-yl)methoxy)phenyl)propanoic acid (330)

1H NMR (400 MHz, CDC13) δ 7.27 (d, J = 7.5 Hz, 1H), 7.11 (d, J = 7.5

S 149l05-sp-20100806.doc -335 - 201200505

Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.84 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 5.02 (s, 2H), 4.99- 4.90 (m, 1H), 3.34 (dd, J = 15.3, 8.9 Hz, 1H), 2.94 (t, J = 7.7 Hz, 2H), 2.83 (dd, J = 15.3, 7.6 Hz, 1H), 2.59 (t , J = 7'7 Hz, 2H), 2.23 (s, 6H), 1.47 (d, J = 6·2 Hz, 3H). Biological Examples Biological Example 1 GPR120 Stable Cell Line The human GPR120 stable cell line was purchased from Multispan (26219 Eden Landing Road, Hayward, CA 94545). This GPR120 cell line was produced in HEK293 cells co-expressing Gqi5. In this cell line, the Flag epitope tag (DYKDDDDK) is fused to the amino terminus of the human GPR120 protein. The concentration of intracellular Ca2+ was measured as measured as described below. Human GPR120 cells were plated at 70,000 cells per well and covered in 96 well plates (poly-D-lysine coated black/transparent plate, Greiner Bio-One)' and at 37 ° C and 5 ° / 〇 Incubate overnight in the conditions of C〇2. The Ca2+ detection dye stock solution was prepared by adding 10 ml of detection buffer (HBSS/20 mM HEPES, pH 7.4) to the FLIPR Calcium 4 test monolithic kit (Molecular Device Company). One milliliter of Ca2+ detection dye solution was prepared by further diluting 〇·5 ml of Ca2+ detection dye stock solution with 10 ml of detection buffer. The medium in which the cells were removed&apos; and the microliters of the Ca2+ detection dye solution was immediately dispensed to each well, followed by incubation at 37 ° C and 5% CO 2 for 50 minutes to allow the Ca 2+ dye to be incorporated into the cells. Then, the cell plates were placed in a Flexstation (Molecular Devices Inc.) for 20 minutes at 37 °C. The compound 149105-sp-20100806.doc - 336 - 201200505 was dissolved in 100 ° /. The cells were diluted in DMSO to the desired concentration in DMSO and placed in the Flexstation and cell plates simultaneously for 20 minutes before incubation at 37 °C. Fluorescence intensity was measured immediately after compound addition (25 μL/well) on the Flexstation at an excitation wavelength of 485 nm and an emission wavelength of 525 (with an automatic cutoff of 515 nm). The increase in fluorescence intensity corresponds to an increase in intracellular Ca2+ content. Determination of Compound Activity The compound was dissolved in 1% DMSO to a concentration of 20 mM to provide a stock solution. To determine the activity against human GPR120, the compound is added to the human GPR120 (described above) in a stable cell, at eight concentrations ranging from 0.00001 to 20 //M, in a 96 well plate, and The fluorescence intensity is measured over 90 seconds with a 2-second interval. The EC5Q value (the concentration of the GPR120 agonist, wherein 50% of the highest activity of the agonist was found) was calculated using the change in fluorescence intensity (maximum-minimum value). For the determination of the percentage activity of the tested compound, the fluorescence intensity value obtained at a specific concentration is related to the reference compound GW9508 (4-[[(3-phenoxyphenyl)indenyl]amino]phenylpropene) The maximum fluorescence intensity values obtained for the acid; British Pharmacological Journal 2006 148, 619-628) or the compound of Example 25 were compared. When GW9508 is used as a reference compound, the highest activity of GW9508 at 6.7 //M is called 100% activity. When the compound of Example 25 was used as a reference compound, the highest activity of the compound of Example 25 at 2.5 was referred to as 100% activity. Typically, the GW9508 activity reaches a maximum at a concentration of about 6.7 /zM, and typically the compound of Example 25 achieves maximum activity at about 2.5 //M. The activity of the tested compounds according to this method 149105-sp-20100806.doc -337 - 201200505 was shown in Table 1 below. Table 1 shows the activity expressed as % activity at 5, the highest activity at 6.7 //M compared to GW9508, or the % activity at 2.5, compared to the highest activity of the reference compound of Example 25. Table 1 Example % Activity (GW9508 Reference Compound) Example % Activity (Example 25 Reference Compound) Example % Activity (Example 25 Reference Compound) Example % Activity (Example 25 Reference Compound) 2 134.6745 41 116.46 115 151.78 184 97.04 3 123.7995 42 140.94 116 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 208 147.47 10 106.7955 54 138.97 127 152.93 209 142.22 11 124.2119 56 108.51 130 103.85 214 143.21 12 116.1354 59 117.58 131A 103.75 216 144.23 13 119.0442 63 95.03 131B 105.8 218 114.48 14 84.491935 65 141.04 133 103.4 220 115.86 15 109.19585 67 141.82 134 151.44 228 119.11 16 110.8294 68 69.03 136 140.51 230 86.25 17 72.210235 69 78.46 140 146.18 231 101.01 18 130.0714 70 117.72 141 143.3 241 159.62 ^ 19 125.53 955 71 133.8 143 90.56 243 155.23 20 138.03915 73 114.85 143 90.56 250 10.23 21 112.58335 77 109.62 145 143.69 251 . 61.14 22 126.02425 79 3.85 146 140.72 254 146.14 23 112.7429 80 86.25 147 138.65 257 124.62 24 100.346555 82 24 148 113.89 258 139.95 25 101.766095 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 176.57625 94 98.45 160 172.13 264 110.24 31 149.52665 96 124.82 162 154.48 266 42.73 32 143.07365 99 101.53 165 158.08 267 140.82 33 142.9517 103 98.96 171 98.97 34 117.88768 106 154.51 173 159.06 35 60.108775 108 143.85 175 152.44 36 122.91405 109 72.36 176 138.42 37 124.67965 111 51.55 178 106 38 83.43202 112 115.42 179 105.44 40 95.33438 114 123.58 182 98.43

Examples 1-29, 35-39, 70-79, 81, 84-85, 92-110, 112-116, 118-121, 124, 127-129, 131-132, 134-163, 165-170 have been found The compounds of 172, 174-182, 184-249 and 252-266 have an EC5 〇 lower than or equal to 1 "M. Examples 30-33, 42, 44, 46-67, 80, 82, 86-91 have been found, Compounds 111,123, 125-126, 130, 133, 171, 173, 183 and 251 have an EC5 〇 greater than 1 /ζΜ and less than or equal to 10//Μ. Examples 34, 40-41, 43, 45 have been found. , compounds of 68-69 and 250 have EC5 〇 greater than 10 _ 〇 biological example 2

Glucose uptake in 3T3-L1 adipocytes Covers 3T3-L1 fibroblasts into growth medium (DMEM supplemented with 10% FBS, 1% penicillin-streptomycin) and grows to confluence for 7 days, with Replace the medium every 2 to 3 days. Differentiation into adipocyte lines was induced by culturing the cells in DMEM supplemented with 10% FBS, 1% penicillin-streptomycin, 698 nM bovine insulin, 518 // Μ IBMX and 248 nM dexamethasone. Glucose uptake activity was measured by measuring the absorption of 2-deoxy-D-[3H]glucose. Briefly, 3T3-L1 adipocytes were washed twice with PBS to adipose cell buffer (FCB: 125 mM NaCl, 5 mM KC1, 1.8 mM CaCl2, 2.6 mM s 149105-sp-20100806.doc • 339-201200505)

MgS04, 25 mM Hepes, 2 mM pyruvate and 2% BSA, 0.2 by sterilizing filtration) were incubated once with GPR120 agonist in FCB and at 37 ° C for 30 minutes. Insulin was prepared in FCB at the indicated concentrations, added to the cells, and incubated at 37 °C for 20 minutes. Glucose uptake was initiated by the addition of 2-deoxy-D-[3H]glucose (0.083 yCi/ml and 1.1 mM 2-deoxy-D-glucose in FCB) and incubation at 37 °C for 10 minutes. Glucose uptake was terminated by removing the contents of the well and washing the cells three times with cold PBS. The cells were lysed in scintillation fluid and the 2-deoxy-D-[3H]glucose (MicroBeta TriLux 1450 - Perkin Elmer) retained by the cells was counted. Cell viability was independently assessed using the CellTitre-Glo Luminescent Cell Viability Assay Kit (Promega) according to the manufacturer's instructions. Glucose uptake is quantified by normalizing the glucose uptake metric for each compound treatment to its corresponding cell viability value. The fold induction of glucose uptake is calculated by normalizing all values against the average of the base values (taken 1-fold). Biological Example 3 Insulin Secretion (Immune Islet Fusion) To determine the effect of a GPR120 agonist on insulin secretion from islets, the islet is obtained from Sprague Dawley rats and is in vitro, Culture with GPR120 agonist in the presence of low and high glucose. The 200-250 gram Spoogdori mouse was obtained from the Charles River laboratory and kept under regular food (Purina 5001). Prior to this procedure, the rats were anesthetized with a pentobarbital intraperitoneal injection at 200 mg/kg. Place the bile duct where it enters the duodenum and place the 149105-sp-20100806.doc • 340 · 201200505 catheter in the bile duct between the liver and the pancreas. The pancreas was perfused through a catheter with a solution of 0.75 mg/ml collagenase P (Roche) supplemented with 0.1% glucose and 0.02% BSA in HBSS buffer (Biowhitaker). Next, the pancreas was excised from the rats and placed in 5 ml of collagenase P solution in a 37 ° C water bath for 8 minutes. After 8 minutes, the digested pancreas was vigorously shaken by hand for 30 seconds. The resulting digest was washed four times in HBSS buffer and then applied to a discontinuous polysucrose gradient. To make the gradient, the digest was resuspended in 7.5 ml of Ficoll DL400 solution (Sigma) at a density of 1.108 in a 15 ml tube. Next, three 2 ml layers of reduced density (1.096, 1.069, 1.037) of polysucrose solution were added to the tube to create a density gradient. The gradient was centrifuged at 1500 rpm for 15 minutes, and then islets were selected from the upper two layers. The islets were washed four times in HBSS buffer and then cultured in RPMI 1640 medium (Gibco) supplemented with 1% fetal bovine serum. On the next day, 25 size-matched islets were placed in the surrounding fusion chamber and exposed to Krebs Ringer buffer (KRB; 119 mM NaCl) using a Cellex Acu-Sys S surrounding fusion culture system at a rate of 1 ml/min. 4.7 mM KC1, 25 mM NaHC03, 2.5 mM CaCl2, 1.2 mM MgS〇4, 1.2 mM KH2 P04). The islets were exposed to KRB containing 2 mM glucose in the presence of 0.1-100 GPR120 agonist or vehicle (DMSO) for 30 minutes, followed by a buffer containing 16 mM glucose for 30 minutes and then returned to 2 mM. Glucose, after another 30 minutes. Peripheral fusions were collected at 1 minute intervals using a detached collector and insulin was detected using an ELISA kit (Mercodia Supersensitive Mouse Insulin ELISA Kit, ALPCO). The rate of insulin secretion in response to glucose was plotted against time and the AUC of the curve was determined to quantify the insulin secretion response to 16 mM glucose during the fusion around 30 I49105-sp-20100806.doc -341 - 201200505 minutes. The statistical significance of the difference in AUC between treated and untreated islets was determined by paired Student's t test. Biological Example 4 Oral Glucose Tolerance Male 8-10 week old C57BL/6J mice (Harlan) were maintained under a regular food diet from Harlan (2018 Teklad Global). On the day of the experiment, the mice were fasted for 6 hours and then randomly divided into arrays (n=10-15) to receive the tested GPR.120 agonist or vehicle (1% CMC, at a dose of 100 mg/kg, 2% TWEEN 80). The compound was orally delivered at 10 ml/kg via a feeding method. The blood glucose level was measured by a glucose meter (Ascensia Elite XL, Bayer) at time -30 minutes before the compound was administered. After 30 minutes (at time 0), the blood glucose was measured again, and then the mice were orally administered with 3 g/kg of glucose at 10 ml/kg. The blood glucose metric was obtained by glucose meter (Ascensia Elite XL, Bayer) at 20, 40, 60, 90 and 120 minutes after glucose administration. The glucose content was plotted against time and the area of increase (AUC) below the glucose drift curve was determined from time 0 using Graphpad Prism 5.01. Outliers were excluded using the Tukey's block diagram and the statistical significance of the difference in the AUC of the vehicle treatment was determined by the non-parametric Krnskal-Wallis test and the Dunn's post test. Tables 2 and 3 below show the average percent inhibition of glucose drift for the fifteen animals tested in each cohort. These compounds were tested at mg/kg and the blood glucose levels were determined in the presence and absence of the test compound at 149105-sp-20100806.doc • 342 - 201200505. Report the percentage of glucose reduction. The tested compounds are selected from the exemplified compounds in a poor form. These results confirm that GPRi2〇 agonist hypoglycemia in response to oral glucose challenge. Table 2 Compounds ----------- % reduction at 100 mg / kg AUC glucose shift Sitagliptin (1 mg / kg) ------- 〆 58.6 Example 10 --------- 58.1 ___ Example 13 ----~___〆61.9 ---------〆 Table 3 The compound at 100 mg/kg reduces the AUC glucose shift S. Sitagliptin (1 mg/kg) 48.6 Example 35 (racemic) --------17.7 Example 36 33.6 Example 16 ---____, 52.4 Biological Example 5 Incretin and enteroendocrine hormone Measured in C57BL/6J mice, GPR120 agonists for insulin, glucagon-like peptides such as glucagon peptide-1 (GLP-1), glucose-dependent insulin peptide (GIP), cholecystokinin (CCK), and peptide YY (PYY) The effect of secretion was determined as follows. Male 8-10 week old C57BL/6J mice (Harlan) were maintained under regular food diet from Harlan (2018 Teklad Global). On the day of the experiment, the rats were fasted for 6 hours and then randomly divided into treatment groups (n=15p, all groups were treated with the DPPIV inhibitor sitagliptin at 1 mg/kg to prevent active GLP-1 Degradation. GPR120 agonist compound is in the range of 3-100 mg / kg, in 1% CMC, 2% TWEEN 80, by 149105-sp-20100806.doc - 343 - 201200505 by oral feeding or peritoneal Intracavitary injection (ip), taken at -30 minutes. Sitagliptin was administered in the same dosage solution. Oral glucose was administered at 3 g/kg at 0 min. After glucose administration 3 Minutes, animals were anesthetized with pentobarbital (40 mg/ml in 10% ethanol) and blood was collected by heart puncture in 4 minutes and collected in a microfilter tube (BD) with potassium EDTA. For the glucose-independent incretin study, the same procedure was used, but in the absence of oral glucose administration. The administration and blood collection of the GPR120 agonist compound were as described above. For the GLP-1 assay, the collection tube also contained the GLP-1 assay kit. Provided in DPP-IV Inhibitors Insulin is measured according to the manufacturer's instructions using the Mercodia Mouse Insulin ELISA Kit (ALPCO). Bioactive GLP-1 is based on the manufacturer's instructions using a glucagon peptide-1 (active) ELISA Test kit (Linco) metric. Total GIP (biological activity plus inactivity) is measured using the rat/mouse total GIP ELISA assay kit (Linco) according to the manufacturer's instructions. CCK (non-sulfated cholecystokinin octapeptide, 26 -33) Measured according to the manufacturer's instructions using the human, rat, and mouse CCK ELISA test kit (Phoenix medicine). PYY is based on the manufacturer's instructions, using the canine, mouse, pig, and rat PYY ELISA test kit. (Peninsula Laboratories) Measure. Biological Example 6 Gastric Emptying In order to evaluate the effect of GPR120 agonist on gastric emptying, 8-10 weeks old male C57BL/6J mice (Harlan) were fasted for 16-18 hours, then GPR120 agonist (1-100 mg/kg) or vehicle (1% CMC, 2% TWEEN 80) was administered orally or by intraperitoneal injection 30 minutes before the study of gastric emptying. 149105-sp-20100806.doc • 344- 201200505

deal with. Redness (嶋PR in deionized water) is administered in a cut or glucose _ _% in 20% glucose. Immediately after the red (four) cast _ minutes, the control animals were sacrificed by cervical dislocation, and the average amount of phenol red recovered was measured as dirty red. After the red drug was administered, the rest of the animals from each group were sacrificed at the time of (4). The gastric system f is clamped between the pylorus and the end of the heart and then separated. The clamped month was transferred to a 5 inch conical tube containing 5 ml of deionized water. The missing piece was removed, and each stomach was cut into fine pieces by scissors, and the contents were extracted by centrifugation at 3 〇〇〇 for 10 minutes, and the supernatant was filtered to remove the particles. .丨ml 1NNA〇H was added to each 2 ml of the filtered supernatant to provide color development. The phenol concentration reading was measured by measuring the absorbance of the extracted material at a wavelength of 558 nm and then converting it to a concentration using the extinction coefficient of phenol red in the aqueous solution. Gastric emptying is calculated by the following formula: % gastric emptying = ((Α-Β) / Α) χ 100, where A is the average amount (absorbance) of phenol red recovered after ingestion (1〇〇 % retained group), and B is the amount of phenol red (absorbance) left in the stomach at a specific time after ingestion. Biology Example 7 Improvement of Diabetes Parameters in Animal Models of Diabetes Female ZDF rats (Charles River Laboratory) were obtained at 6 weeks of age and were placed on a high-fat diet (RD 13004, study) Before the meal), let it adapt to the environment for 1 week. The GPR120 compound was administered to rats in 1% CMC, 2% TWEEN 80 at a concentration ranging from 0.3 to 300 mg/kg by means of a per-feeding method. Weight and food intake are monitored every time. After 14 days of dosing 149105-sp-20100806.doc -345 - 201200505, blood samples were taken from overnight fasting animals to measure glucose and insulin. The glucose system uses a glucose meter (Ascensia Elite XL, Bayer) metric, while the insulin system uses a rat insulin ELISA kit (ALPCO) metric. The insulin and glucose levels were compared to vehicle treated animals to determine efficacy. Male high-fat hunger-eatered rat (Jackson), which was placed on a high-fat diet D12492 (study diet, 60 kcal% fat) at 4 weeks of age, obtained at 10 weeks of age and It adapts to the environment for 1 week. The GPR120 compound was administered in 1% CMC, 2% TWEEN 80 at a concentration ranging from 0.3 to 300 mg/kg by daily feeding. Body weight and food intake are monitored daily. After 14 days of dosing, blood samples were taken from overnight fasting animals to measure glucose and insulin. Glucose was measured using a glucose meter (Ascensia Elite XL, Bayer) and insulin was measured using the Mouse Insulin ELISA Kit (ALPCO). The insulin and glucose levels were compared to vehicle treated animals to determine efficacy. The ob/ob mouse (Jackson) was obtained at 6 weeks of age and allowed to acclimate to the environment for 1-2 weeks. The GPR120 compound was administered in 1% CMC, 2% TWEEN 80 at a concentration ranging from 0.3 to 300 mg/kg by daily feeding. Body weight and food intake are monitored daily. After 14 days of dosing, blood samples were taken from overnight fasting animals to measure glucose and insulin. Glucose was measured using a glucometer (Ascensia Elite XL, Bayer) and insulin was measured using the mouse lysin ELISA kit (ALPCO). Insulin and glucose levels were compared to vehicle treated animals to determine efficacy. Biology Example 8 149105-sp-20100806.doc -346 - 201200505 Intraperitoneal Glucose Tolerance Test Male 8-10 week old C57BL/6J mice (Harlan) were maintained in regular food from Harlan (2018 Teklad Global) Under the meal. On the day before the experiment, the rats were fasted overnight and then randomly divided into arrays (n=10-15) to receive the tested GPR120 agonist or vehicle at a dose of 100 mg/kg (1% CMC, 2%). TWEEN 80). The compound was delivered orally at 10 ml/kg via a feeding method. The blood glucose level was measured by a glucose meter (Ascensia Elite XL, Bayer) at time -30 minutes before the compound was administered. After 30 minutes (under time), the blood glucose was measured again, and then the mice were administered intraperitoneally at 2 ml/kg glucose at 10 ml/kg. The blood glucose metric was obtained by glucose meter (Ascensia Elite XL, Bayer) at 20, 40, 60, 90 and 120 minutes after glucose administration. The glucose content was plotted against time and the area of increase (AUC) below the glucose drift curve was determined from time 0 using Graphpad Prism 5.01. Outliers were excluded using the Tukey's block diagram and the statistical significance of the difference in AUC of the compound treatment was determined by the nonparametric Kruskal-Wallis test and the Dunn's post test. Table 4 below shows the average percent inhibition of glucose drift for the ten tested animals in each cohort. The compound was tested at 30 mg/kg and the blood glucose level was determined in the presence and absence of the test compound. Report the percentage of glucose reduction. The compounds tested are selected from the examples by way of example. These results confirm that GPR120 agonists lower blood glucose in response to IP glucose challenge. 149105-sp-20100806.doc -347 - 201200505 Table 4 Example of IPGTT reduction at 30 mg/kg Example 10 30.7 Example 142 36.2 Example 141 30.55 Example 65 22.2 Example 16 19.4 Example 132 6.5 Example 134 30.2 Example 208 41.7 Example 77 10.4 Example 13 31 Example 209 43.6 Example 268 23 Example 64 24.9 Example 131 (racemic) 23.1 Example 178 16.3 Example 9 19.8 Example 50 26.2 All patents, patent applications, publications and publications cited herein are hereby incorporated by reference in their entirety. Incorporated for reference. Any conflict between any of the references cited herein and the statements in this patent specification is intended to be resolved in a manner that is beneficial to the latter. Similarly, any conflict between the definition of a word or wording and the definition of a word or wording as provided in this patent specification is intended to be resolved in a manner that is beneficial to the latter. 149105-sp-20100806.doc •348 ·

Claims (1)

201200505 VII, the scope of application for patent: L a compound of formula (A) Or a pharmaceutically acceptable salt thereof, wherein: the group J is absent or selected from the group consisting of νβ W1 w w1 The ring Q is selected from the group consisting of aryl 'micro ¢ 0: , τ2 &gt; and T4 〇xc where Q is replaced by (R6)k as appropriate; A1, A2, A3 and A4 are independently selected from the group consisting of n and c, with the condition 'A', A2, A3 and A4 are only 〇, 1 or 2 are N; 丨, T2, T3 and T4 are independently selected from the group consisting of n, 〇, CR丨 and CRl2, with the condition that ^, ^, The protection and protection are only from 丨 or: the series is selected from N and Ο; W1, W2, W3 and W4 are independently selected from the group consisting of N, CRi, CR1R2, 〇, s, s(〇) and s (〇) 2, with the proviso that the ring is not 1,3-dioxobic; E1, E2 and E3 are independently selected from the group consisting of c and N; one of X and γ is a bond, _CH _CHD_ or _CD 2 and x and γ are another - 149105-sp-20100806.doc S 201200505 is selected from the following group: _, _, _C ((^, c(0)NRa, - (four)... 〇-, -s-' ·δ(0)_ and ·δ(0)2_; L is -(CR4R5)q-, where depending on the situation—a _(cr4r5) is _Ν_, _〇_, _S- , -CR4=CR5_ or - stupid-substitution; G is selected from the group consisting of -C(0)0Z and -(:(0)ΝΖ2; each tether is independently selected from the group consisting of: η, alkyl Substituted alkyl; each R1 and R2 are independently selected from the group consisting of hydrazine, hydrazine, halo, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, keto, alkoxy, substituted morphoxy, CN, -OH, -NRaRb, -C(〇)Ra,, C(0)0Ra -C(0)NRaRb, 视%(9)Rb, _SRa, __把和啊#, and depending on the case, Ri and R2 may be cyclized to form a C37 heterocyclic group, a substituted C3.7 hetero-amino group, and a spiro C3. 7 heterocyclic group, substituted spiro c3 7 heterocyclyl, C3 7 cycloalkyl, substituted (: 3-7 cycloalkyl, spiro C3_7 cycloalkyl or spiro substituted c3_7 cycloalkyl; each R3 is independent a group selected from the group consisting of hydrazine, dentate, alkyl, substituted alkyl, alkoxy, substituted alkoxy, _c(0)NRaRb, -NRac(0)Rb'-NRaRb, _s (〇) 2Ra, cycloalkyl, substituted cycloalkylaryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy and _CN; R and R5 are independently selected from the group consisting of H, hydrazine, fluoro, alkyl, and Substituted alkyl, alkoxy and substituted alkanoyl, and optionally R4 and R5 may be cyclized to form (:3-7 heterocyclyl, substituted 149105-sp-20100806.doc 201200505 heterocyclyl, Spiro C3·7 heterocyclic group, substituted spiro C3-7 heterocyclic group, c37 alkylene group, substituted (: 3_7 ring-based base, snail (^巧环院基或螺替的C3 _ 7环院) Each R6 is independently selected from the group consisting of H, lyophilyl, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyclized Substituted, substituted cycloalkyl, bake, substituted alkynyl substituted alkynyl, CN, _〇Ra, _C(0)〇Ra, _C(〇)NRaRb, 视 妒, goods ,···^ and -S(0)2Ra; each R and Rb are independently selected from the group consisting of H, _c_Ra, thiol substituted thiol, ring-based, heterocyclic, substituted a cyclic group, a dilute group: an alkynyl group, an aryl group, a substituted aryl group, a heteroaryl group, and a heterocyclic group via (4); the subscript k is 0, 1, 2 or 3; the subscript m is 〇, ι, 2 Or 3; and the subscript q is 0, 1, 2, 3 or 4. 2. A compound of the formula 1, which has the formula (B): R1\/ c, , W G 149105-sp-20100806.doc 201200505 The group consisting of. a compound of the formula 3, which has the formula (c R2 4. 5. 6. The compound of claim 4, where E!, E2 and E3 are all c. The compound of claim 5, wherein the lanthanide is selected from the group consisting of -CH2-, -CHD-, and -CD2-, and γ is 〇. 7. The compound of claim 6 wherein 'in L' the subscript q is 2 or 3. 8. The compound of claim 7 wherein the subscript 9 is 2. 9. The compound of claim 8, wherein G is _c(〇)〇z. The compound of claim 9, wherein Z is η. 11. The compound according to claim 10, wherein the subscript m is i or 2, and each R3 is independently selected from the group consisting of a halogen group, an alkyl group, a substituted alkyl group, an alkyl fluorenyl group and a substituted group. Alkoxy group. 12. The compound of claim u wherein each R3 is independently selected from the group consisting of: F, a, -CH3, -CH2ch3, -CH(CH3)2, -cf3'-och3-〇ch2ch3 and -OCF3 〇13. The compound of claim 12 wherein the uldent 1 and R2 are independently selected from the group consisting of Ci3 alkyl and -CF3. 14. The compound of claim 13 wherein R1 and R2 are both -CH3. 15. The compound of claim 14 wherein the subscript k is 〇, 1 or 2 » «*4 149105_sp-20l00806.doc 201200505 16. If the compound of item 15 is selected, each of the lines is independently selected from the group consisting of Group · Fluoro, Chloro, -CH3, -c2 h5, cargo, _〇CH2 Ch3 and %. π·A compound of claim i, wherein ring q is /. 18. The compound of claim 17, wherein ring w is absent, and each r3 is independently selected from the group consisting of alkoxy groups, substituted alkoxy groups, and functional groups. 19. A compound according to the claim, or a pharmaceutically acceptable salt thereof, selected from the group consisting of * 2-(5-((5-Gasyl_2,2-dimethyl|2,3-dihydrobenzobenzoin.7-yl)methoxy).6_风•基·2,3· Diazo-1Η·indol-1-yl)acetic acid (29); 3-(4-((2,2-dimethylinden-8-yl)methoxy)&gt;3,5-difluorophenyl) _2_Methylpropionic acid (31); 3-(4-((2,3-dihydrobenzofuran-7-yl)methoxy)&gt;3,5-difluorophenyl)_2-methylpropane Acid (32); 2-methyl-3-(4.((2,2,5-trimethyl)dihydrobenzopyrano-~yl)methoxy)phenyl)propionic acid (33); 3 like difluoro-4_((2,2,5-trimethyl-2,3-dihydrobenzoxanthole-7) phantomoxy)phenyl)-2-methylpropionic acid (34); 3-(4-((5-Fluoro-2,2-dimethyl-2,3·dihydrobenzofuran; yl)methoxy)methylphenyl)-2-methylpropanoic acid (35 ) ^ ^-Fluoro- 2,2-dif-based 2'3-dihydrobenzofuran. South_7_yl)methoxy a methoxyphenyl)-2-methylpropionic acid (36) 3-(3-fluoro-4-((5-fluoro)-2,2-dimethyl-2,3-dihydrobenzofuranyloxy)phenyl)-2-methylpropanoic acid (37) ; ^ «η 149105-sp-20100806.doc 201200505 3-(4-((5-Chloro-2,2-dimercapto-2,3-dihydroindolofuran-7-yl)) Oxy))_3_(dioxamethyl)benzyl)-2-indole Propionic acid (38); 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)_3_fluorophenyl)- 2-methylpropionic acid (39); 3 (4-((5-carbyl-2,2-monomethyl-2,3-dihydrobenzopyran-7-yl)decyloxy)_3_ 曱Phenyl)-2-mercaptopropionic acid (40); 3-(3-carbyl-4-((5-carbyl-2,2-dimercapto-2,3-dihydrobenzofuran) (曱)oxy)benyl)-2-methylpropionic acid (41); 3-(3,5-diox-4-((5-carbyl-2,2-dimercapto-2,3) -dihydrobenzofuran, 7-yl)decyloxy)phenyl)-2.methylpropionic acid (42); 3-(3,5-diox-4-((5-carbyl-2) ,2-dimercapto-2,3-dihydro benzofuranyl) methoxy)phenyl)-2-methylpropionic acid (43); 3-(4-((5-carbyl-2) ,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxymethoxyphenyl)-2-methylpropionic acid (44); 3-(4-((5- defeat) 2,2·monomethyl-2,3-dihydrobenzopyrene-7-yl)decyloxy)phenyl)-2-mercaptopropionic acid (45); 3-(4-(( 2,2-Dimethyl-2,3-dihydrobenzofuran-4-yl)methoxy)phenyl)_2_r-decylpropionic acid (46); 3-(3,5-difluoro- 4-((5-Fluoro.2,2^methyl-2,3-dihydrobenzofuran-7-yl) methoxy Phenyl)-2-methylpropionic acid (47); 2-(3,5-difluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzene) And furfuryl-7-yl) methoxy)phenyl)cyclopropanecarboxylic acid (48); 3-(3,5-difluoro-4·((2-methyl-2,3-dihydrobenzo) Furan·7-yl)methoxy)phenyl)-2-methylpropionic acid (49); 149105-sp-20100806.doc 201200505 3-(4-((2,2-Dimethyl-2,3-dihydrobenzo-c-I))decyloxydiphenyl)-2-mercaptopropionic acid (50); ' 2- ( 4-((2,2-dimethyl-2,3-dihydrobenzopyranyl)yloxy)_3&gt; phenyl)cyclopropanecarboxylic acid (51); 3- (4-((2) ,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxydiphenyl)-2-methylpropionic acid (52); ' 2-(4-((2,2) · dimethyl 2,3-dihydrobenzo-bite _7_yl)f-oxy-diphenyl) Cyclopropanecarboxylic acid (53); 3 pu ((2,2-dimethyl) 2,3_dihydrobenzobenzopyran _7_yl)methoxy)2) propionic acid (54); '-3 chlorinated bucket ((5-carbyl-2,2 dimethyl) Handle Nitrogen and bite _ oxy)phenyl)-2-mercaptopropionic acid (55); 2- (3,5-difluoro fluoro ((4-fluoro-2,2-dimethyl) 2,3_dioxin and furan-7-yl) decyloxy)phenyl)cyclopropanecarboxylic acid (56); 3-(3,5-one-rat-4-((4-hexyl-2, 2-dimercapto-2,3-,methoxy)phenyl)-2-methylpropionic acid (57); hydrogen benzofuran fluorinated fluorofluoro-7-yl) 3-(3-Fluoro-4-((4-fluoro)-2,2-dimercapto-2,3-di"po, 丄-虱-open-furan-7-yl)methoxy) 2-mercaptopropionic acid (58); 3-(4-((4-fluoro)-2,2-dimethyl-2,3-dihydroindolyl)methoxy) Phenyl)-2-methylpropionic acid (59); ^ 2-(4-((2,2-dimethyl-m-(trifluoromethyl-like: hydrogen stupid). methoxy) -3,5·difluorophenyl)cyclopropanecarboxylic acid (6〇); 3-(4-((2,2-dimercapto-4-(trifluoromethyl)-2,3-dihydrobenzene) And furan-7-methyl)-3,5-difluorophenyl)_2-methylpropionic acid (61); 149105-sp-20100806.doc 201200505 Hydrogen benzofuran-7-yl) methyl hydrogen And furan-7-yl) 曱3-(4-((2,2-diindolyl (trifluoromethyl)-2,3-dioxy)-3-fluorophenyl), 2·fluorenyl Propionic acid (62); 3-(4-((2,2-dimercapto-4-(trifluoromethyl)-2,3-dilacyl)phenyl)-2-mercaptopropionic acid (63 -7-yl)methoxy)-yl)nonyloxy)--7-yl)methoxy)-2-(4-((5-ylyl-2,2-dimethyl-2) , 3-dihydro benzopyran 3,5-difluorophenyl)cyclopropanecarboxylic acid (¢4); 2-(5-((5-(yl)-)-2,2-di-f--2,3 -dihydrobenzopyran 2.3-dihydrogen -1沁茚-1-yl)acetic acid (65); 2-(5-((5-fluoro-2,2-difyl-2,3-dihydro benzo, s. south 2.3- dihydrogen) -1H-indol-1-yl)acetic acid (66); 3-(4_((5-carbyl-2,2-dimethyl-2,3-dihydrobenzopyrene 7 poetry Tiannan-7 -yl)methoxy)- 3,5-difluorophenyl)-2-methylpropionic acid (67); 3-(4-((5-carbyl-2,2-dimethyl-2, 3_dihydrobenzofurazan 7g, kaitiannan-7-yl)methoxy)_2_methoxyphenyl)-2.methylpropionic acid (68); 3-(4-((2,3) -dimercapto-2,3_dihydrobenzobenzoate _7_yl) methoxy-like difluorophenyl)-2-methylpropionic acid (69); 2- (2-(4-(( 5-Alkyl 2,2-dimethyl-2,3-dihydrobenzofuran-7(yl)methoxy)-3,5-difluorophenyl)cyclopropyl)acetic acid (7 〇) ; 3-(4-((5,6-Difluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)decyloxy)-3,5-difluorophenyl ··2-mercaptopropionic acid (71); 3-(4·((5,6-difluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) anthracene Phenyl)-2-methylpropionic acid (72); 3-(4-((2,2-dimethyl-2,3-dihydrobenzopyran-7-yl)oxy) Mercapto)_3-fluorophenyl)-2-methylpropionic acid (73); 149105-sp-20100806.doc 201200 505 3-(4-((6-Fluoro- 4 Η benzo[d][l,3]dioxolene _8-yl) decyloxy) phenyl)-2-mercaptopropionic acid ( 74); 3-(4_((5-Fluoro-2,2-methyl-2,3-dihydrobenzofuranyl)methoxy)-2-methylphenyl)propanoic acid (75) 3-(2-Alkyl-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)propanoic acid ( 76); 3-(2-Fluoro-4-((5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)propane Acid (77); 3-(2,6-Difluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) decyloxy)phenyl)propanoic acid (78); 3-(4-((5-Fluoro-2,2-dimercapto-2,3-dihydro benzofuran-7) methoxymethoxyphenyl)propanoic acid (79) 3_(Chloro-chloride-2,2-dimethyl-2,3-dihydro benzopyranyl-7-yl)methoxymethoxyphenyl)propionic acid (80); 3-(2 -Chloro-conductive gas group -2,2-dimethyl dimethyl dibenzophenone _7-yl) methoxy) phenyl)-propionic acid (81); 3 ke 5 · chloro-2, 2-Dimethyl-2,3_dihydro benzoate bite domain _7_yl) methoxy fluorenyl fluorophenyl)-propionic acid (82); 3-(4-((5-chloro)-2, 2-Dimethyl-2,3-dihydropurine ugly itw lactofuran-7-yl)methoxy)-2,6-difluorophenyl)propionic acid (83); 3-(4-( (5-Chloro-2,2-dimethyl-2,3-dihydroindole t + methoxyphenyl)propionic acid (IV); 虱本开咳--(4)methoxy K- yl. _2,2-dimethyl di-benzobenzopyran-7-yl)methoxy)-5-methoxyphenyl)propionic acid (85); 149105-sp-20100806.doc 201200505 3-(2 - Molyl-4-((5-chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)-5-methoxyphenyl)propionic acid (86 2-((4-((5-Alkyl-2,2-dimercapto-2,3-dihydrobenzop-amyl-7-yl)methoxy) phenyl)thio)- Acetic acid (87); 2-((4-((5-chloro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)) )-acetic acid (88); (E)-3-(2-ethyl-4-((5-fluoro-2,2-dimethyl-2,3-dihydro benzofuran) _7 base Methoxy)phenyl)acrylic acid (89); 3-(4-((5-a)-2,2-diindenyl-2,3-di-p-benzoindole. N-methyl)methoxy) -2-(Trifluoromethyl)phenyl)propanoic acid (90); 3 (4-((5-carbyl-2,2-methyl-2,3-carbazinium. South-7) -yl)methoxy)___(trifluoromethyl)phenyl)propionic acid (91); M7-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzo) Furyl)methoxy)_2'3-*mononitro-1H-indol-4-yl)propionic acid (92); 3-(7-((5-carbyl-2,2-dimethyl-) 2,3-Dihydrobenzopyranyl-7-yl)methoxy)_ 2,3--rat-1H-ind-4-yl)propionic acid (93); (R) -M4-((5) -Fluoro- 2,2-dimethyl-2,3-dihydrobenzofuranyl)methoxy)phenyl)-2-methylpropionic acid (94); (S) 3-(4- ((5-Fluoro-2,2-indolyl-2,3-dihydrobenzoin- _7-yl)methoxy)benzene 2-methylpropionic acid (95); 3-(4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl) Amino)phenyl)-2-methylpropionic acid (96); 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate) Amidino)phenyl)-2-methylpropionic acid (97); 149105-sp, 20100806.doc -10· 201200505 3-(3,5-difluoro winter ((5-fluoro-2,2- Dimethyl-2,3-dihydrobenzofuran-7-yl) decyloxy) benzyl)-2-ethoxypropionic acid (98); 2-(4-(2-(5-fluoro) _2,2-dimercapto-2,3-dihydrobenzofuranylethyl)ethyl)aloxy)acetic acid (99); 3-(5-((5-carbyl-2,2-diindole) Benzyl-2,3-dihydrobenzofuran-7-yl)methoxy)_[U'-biphenyl]-2-yl)propionic acid (1〇〇); 3-(5-((5) -fluoro- 2,2-dimethyl-2,3-dihydrobenzop-pentan-7-yl)methoxy)-[1, fluorenyl-phenyl]-2-yl)propionic acid 1〇1); 3 (4 ((5-Alkyl-2,2-indolyl-2,3-dihydrobenzoin-7-yl)decyloxy)_5_fluoro-2-propyl Phenyl)propionic acid (102); 3-(5-fluoro-4-((5-fluoro)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy Base)-2-propylphenyl)propionic acid (1〇3); 3-(4-((5-carbyl-2,2) -Dimethyl-3-keto-2,3-dihydrobenzofuran-7-yl)methyllacyl)-2-ethyl-3-fluorophenyl)propionic acid (1〇4); 3- (4_((5-Chloro-2,2-dimethyl-3-keto-2,3-dihydrobenzofuran-7-yl) oxime)-2-propylphenyl)propanoic acid (1〇5); H4-((5-Chloro-2,2-dimercapto-3-keto-2,3-dihydrobenzofuran-7-yl)methyllacyl)-3_fluoro Phenyl)-2-mercaptopropionic acid (1〇6); 3-(3-fluoro-4-((5-fluoro-2,2-dimethyl-3-keto-2,3-) Dihydrobenzopyran-7-yl)methoxy)phenyl)_2-methylpropionic acid (107); 3-(4-((5-chloro-2,2-dimethyl-3-) Keto-2,3-dihydrobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)_2-methylpropionic acid (1〇8); 3-(4- ((5-Chloro-3-hydroxy-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)·3-fluorophenyl)-2-methylpropane Acid (109); I49105-sp-20I00806.doc 201200505 3_(4_((5_漠基-2,2_dimethyldihydrobenzofuran)methoxy)phenyl)-2-A Propionate (110); • fluorenyl 2,3-di• &gt; Hydrogen benzofuran-7-yl) oxime-methyl-2,3-di&gt; Hydrogen t-p-pentan-7- Methoxy -2,3-di 9 argon and fluorenyl-7-yl)methoxy-indolyl-2,3-dihydroindolofuran-7-yl)methoxy 3-(4-((5-(4) - gas phenyl)-2,2-diyl)phenyl)-2-methylpropionic acid (111) 3-(4-((5-(4-fluorophenyl)-2,2-diyl) Phenyl)-2-mercaptopropionic acid (112) 3-(4-((5-(3-phenylphenyl)-2,2-diyl)phenyl)-2-methylpropanoic acid (113) 3-(4-((5-(2-chlorophenyl)-2,2-diyl)phenyl)-2-methylpropanoic acid (114) 3-(4-((5-(3-曱) Oxyphenyl)-2,2-dimercapto-2,3-dihydrobenzofuran _7-yl)carboxamido)phenyl)-2-mercaptopropionic acid (115); 3-(4- ((2,2-Dimethyl-5-(3-(trifluoromethyl)phenyl)_2,3-dihydrobenzofuran). Nan-7-yl)nonyloxy)phenyl)-2-mercaptopropionic acid (116); 3-(4-((5-a)-2,2-dimethyl-2,3-dihydro Benzofuran-7-yl)methoxy)_3_((dimethylamino)methyl)phenyl)-2-methylpropionic acid (117); 3-(4-((5-(diethylamine)) -2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)nonyloxy)phenyl)-2-methylpropionic acid (118); 3-(4-(( 2,2-Dimethyl-5-(1Η-tetrazol-1-yl)-2,3-dihydrobenzofuranyl)methoxy)phenyl)-2-methylpropanoic acid (119); 3-(4-((7-Fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-4-yl)methoxy)phenyl)-2-methylpropanoic acid (120 3-(3,5-difluoro-4-((7-fluoro-2,2-dimercapto-2,3-dihydrobenzofuranyl)methoxy)phenyl)-2 -methylpropionic acid (121); 149l05-sp-20100806.doc -12- 201200505 2-(3,5-difluoro-4-((7-denyl-2,2-dimethyl-2,3- Dihydro cumin and cough tongs) methoxy)phenyl)cyclopropanecarboxylic acid (122); ^ 2-(5-fluoro-2,2-methyl-2,3-di Nitrobenzo-p-"Gan, 叮-嗝-4-yl)carbenyl)-2,3-dihydro-1Η~Ά-1-yl)acetic acid (123); 3- (3,5-di I -4-((5-Denji-2,2-two Benzyl-2,3-dihydroindolizine mercapto) methoxy)phenyl)-2-mercaptopropionic acid (124); ^ 3-(4_((5·glycol-2,2-dimethyl) Base-2,3-dihydrobenzocytosium alpha (n) methoxyl) phenyl)-2-mercaptopropionic acid (125); (R)-3-(3,5-difluoro-4-((5-fluoro)-2,2-dimethyl)decyloxy)phenyl)-2-mercaptopropionic acid (126); _2,3-diqibenzofuran 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzo-bita.)-methoxymethoxy) Phenyl)-2-mercaptopropionic acid (127); ^, dec, π π唧_4-thinoxy) phenyl)cyclopropanecarboxylic acid (128); Η4-((5-chloro-2) , dimethyl-2,3-dihydrobenzopyrene"*, +cafu carbyl)methoxy, 3,5-difluorophenyl)-2-mercaptopropionic acid (129); 3-(3,5-, one gas-4-((6-ranyl-2,2-dimercapto-2,3--ft-depleted 4_, fluorenyl-furan-4-ylmethoxy) Phenyl)-2-mercaptopropionic acid (130); 3-(4-((5-chloro-2,2-dimercapto-2,3-dihydroindolfuran-4-yl)methoxy) 2-methyl 4-propionic acid (131); 2-(4-((5-carbyl-2,2-dimethyl-2,3-dihydro acnefuran; yl) methoxy Base)_3_nonylphenoxy)acetic acid (132); 2-(4-((4-chloro-2,2-dimethyl-2,3-dihydroindolyl)-7-yl) Oxy)·2_methylphenoxy)acetic acid (133); 149105-sp-20100806.doc -13- 201200505 2- (4-((5-)- 2,2-didecyl-2,3 -dihydrobenzoindol-7-yl)methoxy)phenoxy)acetic acid (134); 3-(4-((5-carbyl-2,2-dimethyl-2,3-di) Hydrobenzofuran-7-yl) methoxy) 3,5-difluorophenyl)butyric acid (135); 3-(3,5-difluoro-4-((5-decyloxy-2) ,2-dimercapto-2,3-dihydrobenzopyranyl-7-yl)decyloxy)phenyl)-2-methylpropionic acid (136); 3-(4-((5-methoxy) Benzyl-2,2-dimethyl-2,3-dihydrobenzofuran-7(yl)decyloxy)phenyl)-2-mercaptopropionic acid (137); 3-(4_((5- Chloro-2,3,3-trimethyl-2,3-dihydro And 吱.South_7_yl)methoxy)_3,5-one gas base)-2-methylpropionic acid (138); 3-(4-((5-ethoxy-2,2-) Mercapto-2,3-dihydrobenzobenzoin-7-yl)methoxy)-3,5-difluorophenyl)-2-methylpropionic acid (139); 3-(4-(( 5-(loweroxy)-2,2-dimethyl-2,3-dihydrobenzopyranoyl-7-yl)methoxy)-3,5-fluorobenzyl)-2-methyl Propionic acid (140); 5-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzofuranyl)methoxy)_2,3·一氲-1Η-印- 2-dibasic acid (141); 5-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran; yl)methoxy)_2 虱-1Η-印-2 - tempering acid (142); 6-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)_2-teacarboxylic acid (143); · 3-(4-((5-Chalc-2,2-dimethyl-2,3-dihydrobenzopyranyl-7-yl)methoxy) from isopropoxyphenyl)propanoic acid ( 144); 3-(4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzifuryl-7-yl)methoxy)_2_isopropoxyphenyl)propane Acid (145); 149105-SP-20100806.doc 14 201200505 Oxy)-2- 3-(4-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzofuran) 7-base) methyl ethoxyphenyl Propionic acid (146); yl-2,3-dihydrobenzofuran_7_3-(2-ethoxy-4-((5-methoxy-2-,2-dimethyl)methoxy) Phenyl)propionic acid (147); 3-(4-((5-chloro-2-methylbenzopyranyl-7-yl)methoxy)_2-ethylphenyl)propanoic acid (148) 3-(4-((5-Chloro-2-methylbenzofuran-7-yl)decyloxy)_3_fluorophenyl)_2-methylpropionic acid (149); 3-(4-((5-fluoro-2,2-dimercapto-2,3-dihydrobenzifuryl-7-yl)decyloxy)tea-1-yl)propanoic acid (150); 3-(2-((-methylamino)methyl)-4-((5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy) Phenyl)propionic acid (151); 3-(4-((5-ethylamino)-2,2-dimethyl-2,3-dihydrobenzopyranyl-7-yl)methoxy Phenyl)-2-methylpropionic acid (152); 3-(4-((2,2- fluorenyl-5-(trifluoromethoxy)-2,3-dihydrobenzopyran) -7-yl) methoxy)phenyl)-2-methylpropionic acid (153); 3-(4-((5-fluoro-2,2-dimethyl-2,3-dihydro] And pf. South-7-yl)methoxy)-2-mercaptofuran-7-yl)propionic acid (154); 3-(4-((5-chloro-2,2-) Methyl-2,3-dihydrobenzofuranyl)methoxy)-3-(trifluoromethyl)phenyl)mercaptopropionic acid 2-acetamidoethyl ester (155); 3-(4 -(((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl)amino)phenyl)propanoic acid (156); 3-(4 -(((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)indolyl)amino)phenyl)propanoic acid (157); S 149l05-sp -20100806.doc -15- 201200505 3-(4-((5-Gas-2) ,2-dimethyl-3-keto-2,3-dihydrobenzofuran _7-yl)methoxy)phenyl)-2-methylpropionic acid (158); 3-(4- ((5-Chloro-3-diyl-2,2-dimercapto-2,3-dihydrobenzofuran _7-yl)methoxy)phenyl)-2-mercaptopropionic acid ( 159) ; ^ 2-(4-((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)cyclopropanecarboxylic acid (160 3-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)propanoic acid (161); - (4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuranyl)methoxy)phenyl)acetic acid (162); 3- (2-ethyl- 4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)propionic acid (163); 3-(4-(( 5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxyisopropylphenyl)propionic acid (164); 3-(4-((5) -fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2-(tri-Imethoxy)pyridyl)propionic acid (165); -(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzifuryl-7)methoxypropylphenyl)propanoic acid (166); 3-( 4-((5-Chloro-2,2-dimercapto-2,3-di) Stupid and furan; methoxy)phenyl)propionic acid (167); 3-(4-((5-carbyl-2,2-dimercapto-2,3·dihydro benzofuran) 7-yl)methoxy)_2·(trifluoromethoxy)phenyl)propionic acid (168); 3-(4-((2,2-dimethyl-2,3-dihydrobenzofuran) ·4·yl)methoxyethylphenyl)propionic acid (169); ! 49105-sp^20100806.doc •16· 201200505 (R) -3-(4-((5-lacyl-2,2) -dimercapto-2,3-dihydro acne pf n _7-yl)methoxy)-3-fluorophenyl)-2-methylpropionic acid (170); (S) -3- (4-((5-Gasyl-2,2-dimethyl-2,3-dihydroindolfuran-7-yl)methoxy)-3-phenylphenyl)-2-methylpropanoic acid (171); (R)-3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-( Trifluoromethyl)phenyl)_2-methylpropionic acid (172) (S)-3-(4-((5-carbyl-2,2-dimethyl-2,3-dihydrobenzop)喃 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; -2,2-dimercapto-2,3-dihydrobenzopyranyl-7-yl)decyloxy)phenyl)-2-methylpropionic acid (174); 3-(4-((3, 3-dioxin-5-chloro-2,2-dimethyl-2,3-dihydrogen Benzobenzoin_7_yl)methoxy)-3-fluorophenyl)-2-methylpropionic acid (175); 3-(4-((3,3-dicarbo-5-chloro)- 2,2-Dimercapto-2,3-dihydroindole. South; hydrazino)-3-(trifluoromethyl)phenyl)-2-mercaptopropionic acid (176); 3-(4-((5-chloro-3,3-dimethyl) -2,3-dihydro acylamino-7-yl)methoxy)phenyl)-2-methylpropionic acid (177); 3-(4-((5-chloro-3,3-) Dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)_3_fluorophenyl)-2-methylpropionic acid (178); 3-(4-((2,2-) Mercapto-2,3-dihydrobenzofuran-4-yl)decyloxy)-2,3-dimethylphenyl)propionic acid (179); 3-(3,5-difluoro-4- ((2-Methylbenzo[b]sulfon-7-yl)methoxy)phenyl)-2-methylpropionic acid C180); 2-(5-((2-mercaptobenzo[b][b ] sulfeno-7-yl) decyloxy)-2,3-dihydro-1H-indol-1-yl)acetic acid (181); 149l05-sp-20100806.doc -17· 201200505 2-(6-( (5-fluoro-2,2-dimercapto-2,3-dihydrobenzopyrene °-7-yl)decyloxy)_ 1,2,3,4-tetrahydroanthracene-i-yl Acetic acid (182); 2-(6-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)_ 1,2,3 , 4-tetrahydronaphthalene_ι_yl)acetic acid (183); 3-(3-carbyl-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran) _7_yl)decyloxy)phenyl)-2-methylpropionic acid (184); 3 (4 ((5-gas) Base-2,2-__mercapto-2,3-diazabenzop-pentan-7-yl)methoxy)phenyl)·3-methylbutyric acid (185); 3-(4- ((5-1-based-2,2-monomethyl-2,3-dihydrobenzofolf-7-yl)methoxy)phenyl)-3-methylbutyric acid (186); Mercapto-3-(4-((2,2,5-dimercapto-2,3-diazabenzop-am-7-yl)decyloxy)phenyl)butyric acid (187); 3 - (4-((5-Alkyl-3H-spiro[benzofuran-polycyclopentane]-7-yl)methoxy)phenyl) 4-mercaptopropionic acid (188); 4- (4- ((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)butyric acid (189); 4-(3,5-di Fluoro-4-((5-fluoro- 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) decyloxy)phenyl)butyric acid (190); M4-(( 5-fluoro-3H-spiro [benzofuran-21, _cyclopentane]; yl) methoxy) phenyl)-2-mercaptopropionic acid (191); 2- (5-((5- Fluoro-3H-spiro[benzofuran_2,i,.cyclopentane]-7-yl)methoxy)-2,3-diox-1H-indol-1-yl)hydrous acid (192); 3-(4-((5-Fluoro-3H-spiro[benzofuran-2, fluorene, _cyclopentane]-7-yl) decyloxy)phenyl)propanoic acid (193); 149105-sp- 20100806.doc -18- 201200505 2- ( 4-((5-Fluoro-3H-spiro[benzopyrene η南_2, Γ-cyclopentan]-7-yl)methoxy)phenyl)cyclopropanecarboxylic acid (194); 3- ( 4-((5-Gas-3H-spiro[benzofuran-2, fluorenyl-cyclopentan]-7-yl) decyloxy)phenyl)propanoic acid (195); 4- (4-(( 2,2,5-tridecyl-2,3-dihydrobenzoyran-7-yl)decyloxy)phenyl)butyric acid (196); 4-(4-((5-chloro)- 2,2-Dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)butyric acid (197); _ 4-(3&gt;difluoro-4-((2, 2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)butyric acid (198); 4-(4-((5-chloro-2,2) -dimercapto-2,3-dihydrobenzopyran-7-yl)decyloxy)_3,5-difluorophenyl)butyric acid (199); 4-(4-((5_气) Base-2,2-monomethyl-2,3-dioxaquinone p-amyl-7-yl)decyloxy)phenyl)-2-methylbutyric acid (200); 4-(4-( (5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)-2-methylbutyric acid (201); 3-(4 -((5-^-yl-2,2-monomethyl-2,3-diazabenzoin-7-yl)methoxy)_3_methoxyphenyl)propionic acid (202); chloro- 2,2-Dimethyl-2,3-dihydrobenzofuran-7-yl)nonyloxy )_3_methoxyphenyl)propionic acid (203); (S)-2-(5-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) ) methoxy)-2,3-dihydro-1H-indol-1-yl)acetic acid (204); (S)-2-(5-((5-carbyl-2,2-dimethyl-) 2,3-Dihydrobenzofuran-7-yl)methoxy)-2,3-dihydro-1H-indol-1-yl)acetic acid (205); 149105-sp-20l00806.doc 19 201200505 3- (4-((5-Chloro-2,2-dimethyl-2,3-dihydro benzofuran-7) methoxy oxime) phenyl)propionic acid (206); ^ (R)- 2-(5-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7)methoxy)-2,3-diindole-1H-indole-1- Acetate (207); (R)-2-(5-((5-Chloro-2,2-dimethyl-2,3-dihydrofurfuranyl)methoxy)-2, 3-dihydro-1H-Is-1-yl)acetic acid (208); 2-(3-ylidene-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzene) And hehe. South _7_US) methoxy)phenyl)cyclopropanecarboxylic acid (209); 2-(4-((5-chloro-2,2-dimethyl-2,3-dihydroindrene) _7_yl) decyloxy)·3 · fluorophenyl)cyclopropanecarboxylic acid (210); 4-(4-((5-fluoro-2,2-dimercapto-2,3-di) Hydrogenbenzofuran-7-yl)methoxy)phenyl)-3-indolylbutyric acid (211); 4-(4-((5-carbyl-2,2-dimethyl-2,3) -dihydrobenzofuran-7-yl)decyloxy)phenyl)-3-indolylbutyric acid (212); 2-(3,5-difluoro-4-((5-fluoro)-2, 2-Dimercapto-2,3-dihydrobenzofuran-7(yl)methoxy)indolyl)cyclopropanecarboxylic acid (213); 2-(4-((5-carbyl-2,2-) Dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)-ru3,5-difluoroindolyl)cyclopropanecarboxylic acid (214); 3·(4-((2,2) - Dimercapto-5-phenyl-2,3-dihydrobenzifuryl-7-yl)methoxy)phenyl)propionic acid (215); 2-(5-((2,2-dimethyl) (5-phenyl-2,3-dihydrobenzifuryl-7-yl)nonyloxy)-2,3-dihydro-1Η-indol-1-yl)acetic acid (216); (R)-2 -(5-((6-Fluoro-2,2-dimethyl-2,3-dihydrofurfuranyl)methoxy)-2,3-dihydro-1Η-indol-1-yl )Acetic acid (217); 149105-sp-20100806.doc •20- 201200 505 3-(2-Alkyl-4-((5-alkyl, 3 Α田H' spiro[benzofuran-2, Γ-cyclopentan]-7-yl)methoxy)phenyl) Propionic acid (218); 3-(4-((5-fluoro)-3Η-spiro[[(())))曱Phenylphenyl)propionic acid (219); 2-(4-((5-alkyl·2,2-dimethyl- 1 Τ 2,3-dihydrobenzofuran-7-yl) oxime Cyclo)propanecarboxylic acid (220); 2-(4-((5-chloro-2,2-methyl, 2,3-dihydrobenzofuran-7)methoxy) Base group) cyclopropanecarboxylic acid (221); 3-(4-((5-Alkyl-3Η- snail [stupid and sputum _2, r_cyclopentan]), methoxy)_2_fluorophenyl)propionic acid (222); 3-( 4-((5-Alkyl-3H-spiro[benzofuran_21, cyclopentane]-7-yl) decyloxy oxyphenyl) propionic acid (223); 3-(2-carbyl-4 -((5-Fluoro-3H-spiro[benzofuran-2, fluorene,-cyclopentane]-7())methoxy)phenyl)propanoic acid (224); 3-(2-chloro- 4-((5-Chloro-3H-spiro[benzofuran-2,1L cyclopentane]-7-yl)methoxy)phenyl)propanoic acid (225); 3-(2,6-dichloro- 4-((5-Fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl) decyloxy)phenyl)propionic acid (226); 3-(2,6 -dichloro-4-((5-carbyl-2,2-dimercapto-2,3-dihydrobenzofuranyl)methoxy)phenyl)propionic acid (227); 2-(2- (4-((5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)cyclopropyl)acetic acid (228); 2- (2-(4-((5-Chloro-2,2-didecyl) 2,3-dihydrobenzofuranyl)methoxy)phenyl)cyclopropyl)acetic acid (229); 149105 -sp-20100806.doc -21 201200505 2-(2-(4-(5-Fluoro-3H-spiro[p-oxafurancyclopentane;|_7-yl)decyloxy)phenyl)cyclopropyl )vinegar Acid (230); 2-(2-(4-((5-Chloro-3H-spiro[benzofuran-2, wide cyclopentane]-7-yl)methoxy)phenyl)cyclopropyl) Acetic acid (231); 3-(2-ethyl-4-((5-carbyl-3H. succinyl]] methoxy)phenyl)propionic acid (232); -(4-((5-ytyl-2,2-dimethyl-2,3-diethyl, + fluorenylfuran-7-yl) decyloxy)_2.6-didecylphenyl Propionic acid (233); 3-(4-((5-chloro-2,2-diindenyl 2,3-dif + ^ fluorenyl)-) - Dimethylphenyl)propionic acid (234); Hydrogen benzofuran-7-yl)methoxy)-hydrobenzofuran-7-yl)nonyloxy)_hydrobenzofuran-7-yl) Methoxy)_ 3-(4-((5-fluoro-2,2-dimercapto-2,3.2.5-didecylphenyl)propionic acid (235); 3-(4-(( 5-Chloro-2,2-dimercapto-2,3·2.5-dimercaptophenyl)propionic acid (236); 3-(4-((5-fluoro-2,2-didecyl) -2,3-2.3- Dimercaptophenyl)propionic acid (237); 3-(4-((5-gaso-based dimethyl-2,3-dihydro cumin screaming 7 base)) Oxy)_2.3-dimethylphenyl)propionic acid (238); 2-(2-(2-fluoro-based ice ((5-gas-based dimethyl dihydrobenzopyranyl)) A Oxy)phenyl)cyclopropyl)acetic acid (239); hydrogen benzofuran-7-yl) oxime 2-(2-(4-((5-)-yl-2,2-dimethyl-2) , 3_yl)-2-fluorophenyl)cyclopropyl)acetic acid (240); 3-(4-((5-Denyl 2'2. dimethyl-2,3-dihydro benzofuranyl) ) methoxy-propylphenyl)propionic acid (241); ^ 149105-sp-20100806.doc •22· 201200505 3-(4-((5-)- 2,2-didecyl-2,3 -dihydrobenzoc-amyl-7-yl)decyloxy)_2-propylphenyl)propionic acid (242); 3-(5-fluoro-based winter ((5-Denyl-2,2-dimethyl) 2,3-dihydrobenzofuran-7-yl)methoxy&gt;2-methylphenyl)propionic acid (243); 3-(4-((5-carbyl-2,2-dimethyl) Base-2,3-dihydrobenzop-amyl-7-yl)nonyloxy-2-ylphenyl)propionic acid (244); 3-(2-ethyl-3-fluoro- 4-((5Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)propanoic acid (245); ^ 3-(4-( (5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)_2_ethyl-3-fluorophenyl)propionic acid (246); 3- (4-((5-Fluoro-2,2-dimercapto-2,3·dihydrobenzofuran-7-yl)methoxy) 5.6.7.8-tetrahydronaphthalen-1-yl)propanoic acid ( 247); 3-(4-((5- Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)_5.6.7.8-tetrazolan-1-yl)propionic acid (248); 3- (2-Ethyl-5-fluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydroindolofuran-7-yl)methoxy)phenyl)propane Acid (249); Lu 3-(4-((5-Chloro-2,2-dimercapto-2,3-dihydrobenzopyrano-7)methoxy)·2_ethyl- 5-fluorophenyl)propionic acid (250); 3-(3-fluoro-4-((5-fluoro)2,2-indolyl-2,3-dihydrobenzindene πNan_7 _yl)methoxy)-2-propylphenyl)propionic acid (251); 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran) _7_yl)methoxy)_3_fluoro-2-propylphenyl)propionic acid (252); 3-(3-fluoro-4-((5-fluoro)-2,2-didecyl) -2,3·dihydrobenzofuran-7-yl)methoxy)-2-pentylphenyl)propionic acid (253); S 149105-sp-20100806.doc •23- 201200505 3-(4- ((5-Alkyl-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy)_3_fluoro-2-pentylphenyl)propanoic acid (254); 3-(2-Ethyl-3-fluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzo-dozenan)-methoxy) Phenyl)-2-methylpropionic acid (255); chloro-2,2-di Benzyl-2,3-dihydrobenzofuran-7-yl)methoxy)2-ethyl-3-fluorophenyl)-2-mercaptopropionic acid (2S6); 3-(4-(1 ill) (5-Fluoro-2,2-dimethyl-2,3-dihydro benzopyranyl-7-yl)methoxy)-3-fluoro-2-ethylphenyl)propanoic acid ( 257); 3-(4-(5-carbyl-2,2-dimethyl-2,3-dihydro benzopyranyl-7-yl)methoxy)-3-fluoro -2-propylphenyl)propionic acid (258); 3-(4-(dimerized (5-fluoro-2,2-dimethyl-2,3-dihydrobenzindole_7_) Methoxy)-3-fluorophenyl)-2-methylpropionic acid (259); 3-(4-(5-ranyl-2,2-dimethyl-2,3- Dihydrobenzoate bites. _7_yl)methoxy)-3-(trifluoromethyl)phenyl)-2-mercaptopropionic acid (260); 3-(3-fluoro-4-((5-fluoro)- 2,2-dimercapto-2,3-dihydrobenzopyrene. South _7-yl)methoxy)-2-isopentylphenyl)propionic acid (261); 3-(4-(( 5-Alkyl-2,2-dimercapto-2,3-dihydrobenzoxanthine &gt;7-yl)nonyloxy)_3_fluoro-2-isopentylphenyl)propionic acid (262 3-(4-(one-money (5-carbyl-2,2-dimercapto-2,3-dibenzobenzoin.) methoxy)-3-fluoro-2- Ethyl strepto)propionic acid (263); 3-(4-(dimerized (5-carbyl-2,2-dimercapto-2,3-dihydrobenzofurazan-7-yl)-) Oxy)-3-fluoro-2-propylphenyl)propionic acid (264); 3-(4-(dihydro-(5-carbyl-2,2-dimethyl-2,3-di) Hydrobenzopyrene. Nan_7_yl)methoxy)-3-fluorophenyl)-2-methylpropionic acid (265); 149105-sp-20l00806.doc •24·201200505 3-(4-( Di-deuterated (5-chloro-2,2-dimethyl-2,3-dihydro benzopyranyl)methyllactyl)-3-(triponyl)phenyl)-2-indenyl Propionic acid (266); 3-(2-butyl-3-fluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzophthalazin-7-yl)曱oxy)phenyl)propionic acid (267); 3-(2-butyl-4-((5) -Chloro-2,2-dimercapto-2,3-dihydrobenzifuryl-7-yl)methoxy)-3-fluorophenyl)propionic acid (268); 3-(4-(( 5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy(trifluoromethyl)phenyl)-2-mercaptopropionic acid (269); 3-(4-((5-Chloro-2'2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxyfluorophenyl)-2,2,3,3- Tetrahydropropionic acid (270); 3-(3-fluoro-4-((5-fluoro-2,2-dimercapto-2,3-dihydrobenzofuran-7-yl)methoxy) 2-(2-phenylphenyl)-2,2,3,3-tetrahydropropionic acid (271); 3-(2-ethyl-3-fluoro-4-((5-fluoro) 2,2·Dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)benyl)-2,2,3,3-tetrahydropropionic acid (272); 3-( 3-fluoro-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7())methoxy)-2-methylphenyl)propanoic acid (273); 3-(4-((5-Chloro-2,2-dimethyl-2,3-dioxabenzofuran-7-yl)methoxy)-fluoro-2-methylphenyl Propionic acid (274); 3-(3 ethyl winter ((5-fluoro 2- 2,2-dimethyl) dibenzophenanthyl-7)methoxy)phenyl)propionic acid (275 3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzifuryl-7-yl)methoxy)ethylethyl)propanoic acid (276) 3-(3ethyl winter ((5-fluoro 2-, 2-dimethyl) diazolobenzoyl-7-yl)methoxy)phenyl)-2-methylpropionic acid (277 ); m· 149105-sp-20100806.doc -25- 201200505 3-(4-((5-气基·2,2- Methyl-2,3·dihydro benzofuran j-yl)methoxyethylphenyl)-2-methylpropionic acid 078); 3-(2-((5-chloro-2,2-) Methyl-2,3-dihydrobenzifuryl-7-yl)methoxy)phenyl)propionic acid (279); gas-based 2,2-diindolyl-; 2,3-dihydrobenzoyl Furan, yl)methoxy)phenyl)-2-methylpropionic acid (280); 3-(4-((2,2-dimethyl-2,3-dihydrobenzofuran) ) foxy)phenyl)propionic acid (281); 3-(4-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl) _2_ mercaptopropionic acid (282); 3-(4-((5-fluoro-2,2-dimercapto-2,3-dihydroindolofuran-7-yl)methoxy)_ 2.3. 5-trimethylphenyl)propionic acid (283); 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydroindolfuran-7-yl)methoxy) Base)_ 2.3.5-trimethylphenyl)propionic acid (284); 3-(4-((5-fluoro-3H-spiro[benzofuran-2,1'-cyclopenta]-7-yl) Methoxy)_2 3 -didecylphenyl)propionic acid (285); 2-(5-((5-ylyl-2-isopropoxybenzyl)oxy)_6-fluoroyl-2, 3 dihydro_1H_^ -1-yl)acetic acid (286); 2-(5-((5-yl-2-isopropoxydecyl)oxy)_2,3_dihydro·m_茚Small base) acetic acid (287); 2-(5-((2-isopropoxypyridine-3-yl)decyloxy)_2,3-dihydro-1H•indole small) Acetic acid (288); 3- (4- ((1Η-+坐-7-yl) decyloxy). 3,5-difluorophenyl)_2-methylpropionic acid (289); 3_(3,5-difluoro-4-((2_)曱 笨 并 阶 阶 阶 阶 ) ) 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 ,2-dimethyl-2,3-dihydrobenzofuran; yl)methoxy)benzofuran-3-yl)acetic acid (291); 2-(7-((5-fluoro-2) 2-Dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy ketone-2H-nonen-4-yl)acetic acid (292); 3- (4-((5-fluoro) Base-2,2-dimethyl-2,3·dihydrobenzofuranyl)methoxy)phenyl)-N-hydroxy-2-mercaptopropanamide (293); 3-(4-((5-Fluoro-2,2-dimethyl-2,3-dihydro benzofuran-7-yl)methoxy)phenyl)-N-hydroxypropanamide (294 3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydroindolyl)methoxy)phenyl)-4-methylpentanoic acid (295) ; ^ 3-(4-((6-Alkyl-2,2-dimercapto-2,3-dihydrobenzofuran-4-yl)methoxy)_ 2,3-didecylphenyl) Propionic acid (296); 3-(2-ethoxy-4-((5-1-yl-2,2-dimethyl-2,3-dihydroindolyl)methoxy)benzene Propionate (297); 3-(4-((2,2-dimethyl-5-(methyl)-bromo) 2,3-dimethoxy)-2,3-dimethylphenyl)propanoic acid (298); Hydrogen exemplified p-pyrano- 7-yl) hydrogen benzofuran _7-yl) methyl 3-(4-((5-fluoro-2,2-didecyl-3-)yl-2,3 -oxy)-2,3-dimethylphenyl)propionic acid (299); 3-(4-((5-fluoro-3-hydroxy-2,2-didecyl-2,3-di) Hydrobenzofuran-7-yl)methoxy)-2,3-dimercaptophenyl)propionic acid (300); 3-(2,3-dimethyl-4-((2,2,5) -trimethyl-2,3-dihydrobenzofuran-7-yl)decyloxy)phenyl)propionic acid (301); 3-(4-((5-ethyl-2,2-dimethyl) Base-2,3-dihydro benzopyran-7-yl)methoxy)_149105-sp-20100806.doc -27- 201200505 2.3-dimethylphenyl)propionic acid (302); 3-( 2-ethyl-4-((5-ethyl-2,2-dimethyl-2,3-dihydro | ugly ♦ furan-7-yl)methoxy)-3-fluorophenyl)propyl Acid (303); 3-(4-((5-iodo-2,2-dimethyl-2,3-dihydrobenzofura, &amp; 2-7') methoxy)-2.3 - dimethylphenyl)propionic acid (304); 3-(4·((5-ethoxy-2,2-dimethyl-2,3-dihydrobenzopyrene + U-smell-- 7-yl)methoxy)-2,3-dimethylphenyl)propionic acid (305); 3- (4-((5-Chloro-2-methyl-2,3-dihydrobenzop-pentan-7-yl) anthracene) 2 3 monomethylphenyl)propanoic acid (306); ^ ' 3-(2-Ethoxy-4-((5-ethoxy-2,2-dimethyl-2,3-dioxabenzofuran-7-yl)methoxy)phenyl)propanoic acid (307); 3-(4-((2,2-Dimethyl-5-(trifluoromethoxy) 2,3-dihydro benzofuran) methoxy) 2,3- Dimethylphenyl)propionic acid (308); 3-(4·((5·Denyl·b (methoxy)[,2,2-dimethyldihydro)]methoxy)-2 ,3-dimethylphenyl)propionic acid (309); 3-(4-((5-fluoro)-2,2-dimethylindoline-7-yl)methoxydimethylphenyl Propionic acid (310); 3-(4_((5-fluoro-I,2,2-tridecyldihydroindolyl)carbenyl)_2,3-diphenylphenyl)propionic acid (311) ; ^ ' 3-(4·((5 gas-based 2,2-dipropyl-2,3-dihydro benzofuran; yl)methoxy)-2,3-dimercaptobenzene Propionate (3U); 3-(4-((2,2-diethyl-5-formyl-2,3-dihydrobenzo-L-open-furan-7-yl)methoxy) - 2.3- Dimercaptophenyl)propionic acid (313); 3-(4-((5-fluoro-2-(decyloxyfluorenyl))-2-yl); T丞2,3·dihexane Stupid furan-7- 149l05-sp-201 00806.doc • 28- 201200505 methoxy)-2,3-dimethylphenyl)propionic acid (314); 3-(4-((5-fluoro-2-(nonyloxy) fluorenyl) )-2,3-dihydrobenzofuranyl)methoxy)·2,3-dimercaptophenyl)propionic acid (315); 3-(4-((5-fluoro-2-) Hydroxymethyl)-2,3-dihydrobenzifuryl)methoxy 2,3-dimercapto)propionic acid (316); 3-(4-((5-fluoro-2-) Hydroxymercapto)-2-methyl-2,3-dihydro benzofuran; yl)methoxy) 2,3-dimethylphenyl)propionic acid (317); 3-(M(5-isopropyl-2,2-dimercapto-2,3-di-arsinofuranyl)methoxy)-2,3-dimethylphenyl)propionic acid (318); 3-(4-((5-cyclopentyl-2,2-dimercapto-2,3-dihydrofurfuryl)methoxy)-2,3-dimercaptophenyl)propanoic acid ( 319); ethoxydimercapto-2,3-dihydrobenzifuryl)methoxy)-2-ethyl-3-fluorophenyl)propionic acid (320); 3-(4-(( 5-Alkyl-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)mercapto)-2,3-difluorophenyl)propionic acid (321); 3-( 2,3-difluoro fluoro ((5-fluoro-2,2-dimethyl-2,3-dihydrobenzifuryl) methoxy)phenyl)propionic acid (322); 3-(2 '5_Difluoro-ice ((5-fluoro 2-, 2-dimethyl-2,3-dihydrobenzofuran) methoxy)phenyl)propionic acid (323); 3-(4 -((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran; yl)methoxy)-2,5-difluorophenyl)propionic acid (324); 3- (2,3-dioxa-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) methoxy)phenyl)propanoic acid (325 3·(3-Alkyl-4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuranyl)- 149105-sp-20100806.doc -29- 201200505 Oxy)-2-methylphenyl) Acid (326); 3-(4-((6-fluoro)-2,2-monomethyl-2,3-diindole 吱0~4_yl) methoxy) 2,3-di Methylphenyl)propionic acid (327); (R)-3-(4-((2,2-dimercapto-5-(trifluoromethoxy)) 2,3-dihydrobenzofuran·7_ Methoxy)phenyl)-2-methylpropionic acid (328); (s)-M4-((2,2-dimethyl-5-(trifluoromethoxy)-2,3 dihydrobenzene And furan·7·yl)methoxy)phenyl)-2-methylpropionic acid (329); and M2′3-dimethyl-4 is methyl-2,3-dihydrobenzofuran Base) foxy)phenyl)propionic acid (330). 20. A composition comprising a compound of any one of claims n9, and a pharmaceutically acceptable carrier. 21. - such as: seeking items ..." the use of any of the compounds in the manufacture of pharmaceuticals, the agent for the treatment of diseases or symptoms, selected from the group consisting of: (4) urinary disease, U-type Diabetes and metabolic syndrome. 22. The use of claim 21, wherein the disease is type H diabetes. 23. The use of a compound of claim 1 $ _ for the manufacture of a medicament. Lowering blood sugar. 24 kinds::: The compound of the item (10) is used in the manufacture of the drug, and the agent is used to modulate the GpRm activity in the cell. 149105-sp-20100806.doc 201200505 IV. Designated representative figure : (1) The representative representative of the case is: (none) (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 149l05-sp-20100806.doc 8