NZ753053B2

NZ753053B2 - Phenyl propionic acid derivatives and uses thereof

Info

Publication number: NZ753053B2
Application number: NZ753053A
Authority: NZ
Inventors: Kyungmi An; Shuolin Cui; Changhee Hong; Jaehoon Kang; Hyunjung Kwak; Hongsub Lee; Hyojung Song; Kyung Mi An; shuo lin Cui; Chang Hee Hong; Jae Hoon Kang; Hyun Jung Kwak; Hong Sub Lee; Hyo Jung Song
Original assignee: Il Dong Pharmaceutical Co Ltd
Priority date: 2016-12-15
Filing date: 2017-12-14
Publication date: 2021-04-30

Abstract

The present invention relates to the compounds according to Formula (I), the racemates, enantiomers, diastereomers thereof or pharmaceutical acceptable salts thereof, or pharmaceutical compositions comprising these, for the treatment or prevention of metabolic disorders. The compounds according to Formula (I) are, as GPR40 agonists, available for oral administration with glucose-dependent insulin secretion mechanism, which exhibit excellent glucose lowering efficacy without the risk of hypoglycemia. Thus, the compounds and/or pharmaceutical compositions comprising the compounds as effective components are useful in treating and/or preventing symptoms of type 2 diabetes through adequate control of blood glucose. ormula (I) are, as GPR40 agonists, available for oral administration with glucose-dependent insulin secretion mechanism, which exhibit excellent glucose lowering efficacy without the risk of hypoglycemia. Thus, the compounds and/or pharmaceutical compositions comprising the compounds as effective components are useful in treating and/or preventing symptoms of type 2 diabetes through adequate control of blood glucose.

Description

Description Title of Invention: PHENYL NIC ACID DERIVATIVES AND USES THEREOF Technical Field The present invention relates to phenyl propionic acid derivatives, isomers, and phar— maceutically permissible salts thereof, and on its medicinal uses.

Background Art Diabetes mellitus (DM) is mainly divided into Type 1 and Type 2 diabetes. Type 1 diabetes mellitus (TlDM) is a condition terized by the genetically posed destruction of pancreatic B—cells that are responsible for the production of insulin, which results in the body's inability to produce sufficient insulin for the control of blood glucose level. Type 2 diabetes us (T2DM), covering up to 95% of the total diabetic patients, is an acquired disease in which environmental factors cause somatic cells to become insulin—resistant, which in terms disables effective absorption of blood glucose. Chronic rise in blood glucose level caused by insulin abnormality leads to s complications, including obesity, neuralgia, diabetic retinopathy, nephropathy, cardiovascular diseases and dyslipidemia.

Early symptoms of onset of the disease include hyperuresis and unidentified weight loss, and the disease itself can be ly diagnosed through precise examinations of HbAlc level, fasting and postprandial glucose level, and glucose tolerance test. T2DM patients generally y HbAlc level of over 6.5%, fasting plasma glucose (FPG after 8 hrs) level of over 126 mg/dL, and the postprandial level (2 hrs—Plasma Glucose) of over 200 mg/dL. According to data from the International Diabetes Federation (IDF), the number of T2DM patients around the globe increased from 30 million in 1985 to 415 million in 2015, and is expected to rise by 7 million annually to 642 million adult patients by 2040, which marks over 10% of the global population. In addition, approximately 50% of the patients also suffer from related cations with 5 million resulting , making them responsible for 14.5% of the global death count Increasing number of patients has resulted in subsequent growth of the global market for the ent of T2DM. The market value increased significantly from 28.8 n dollars in 2009 to 63.6 billion dollars in 2014 and is expected to reach 163.2 billion dollars by 2020. Dietary habits, lack of exercise and irregular lifestyle have been d out as the ct causes of such increase in the occurrence of es mellitus. Therefore, patients are prescribed a variety of nal treatments along with balanced diet, regular exercise and maintenance of y weight, but there still are unmet needs for discovery of novel medications for the full ry of the disease.

Currently being actively prescribed medications for T2DM can be categorized based on their mechanisms of action. However, each type has shortcomings which cannot be overcome. For e, Metformin of ide type, the primary treatment for T2DM, places patients at risk of diarrhea, abdominalgia, dyspepsia, and lack of durability in long—term use. Sulfonylureas (SUs), independent from blood glucose level, stimulate pancreatic B—cells and thus place patients at risk of hypoglycemia.

Liver safety concerns, CV risk, weight gain and risk of bladder cancer have been reported with thiazolidinediones, so the drug has been awn from the market.

Sodium—glucose co—transporter—2 2) inhibitors make patients become vulnerable to urinary tract and genital infections, and a—glucosidase inhibitors may induce side—effects including dyspepsia and diarrhea. Furthermore, Dipeptidyl peptidase—4 (DPP—IV) inhibitors are d to patients without any renal conditions.

Therefore, there is a need for discovery of novel medications for T2DM which is able to overcome such limitations, and accordingly, GPR40 (G—protein—coupled or 40) agonists have recently been gaining attention.

G—protein coupled receptor 40 (GPR40), a seven—transmembrane protein, is a type of GPCR of the rhodopsin family, and is primarily sed in B—cells of pancreatic islets. Since its y ligands are medium—to—long change fatty acids, the receptor is also known as Free fatty acid receptor 1 (FFARl).

The mechanism of pancreatic B—cell's insulin secretion through GPR40 is mainly de— termined by either ligands or GPR40 agonists that bind to the receptor. When binding activates the receptor, primary signaling pathway for n secretion is promoted through Gaqm, which is a type of subunits of GPCR. Then, the pathway hydrolyzes cell membrane phospholipids through Phospholipase C (PLC) to produce Dia— eral (DAG) and Inositol osphate (1P3), which subsequently activate Protein Kinase Dl (PKD l) to induce F—actin protein modification, and Calcium ion ion to ultimately induce insulin secretion.

The mechanism that GPR40 activation induces insulin secretion with blood glucose— dependent manner was proven through experiments using rodent models. (Diabetes, 2007, 56, 1087-1094; es, 2009, 58, 1067—1076). Such blood glucose—dependent mechanism of insulin secretion has no risk of hypothermia, which makes GPR40 an at— tractive target for novel drug development. In addition, GPR40 is involved in maintaining pancreatic B—cell survival through regulation of PIX—l and BCL2, which also results in sustaining of efficacy even in a long—term ent (BMC Cell Biol., 2014, 15, 24). Furthermore, since the distribution of GPR40 expression is relatively limited, there is low risk of adverse effects in other organs, and improving blood— glucose tasis h GPR40 tion is potentially involved in other metabolic disorders including obesity and hypertension.

Based on such ages, for the past few years, industrial efforts have made in— vestments in the development of GPR40 agonists, but no drug has been released to the market. Among the discoveries, Fasiglifam of Takeda, the first GPR40 agonist to enter al trials, has been shown its glucose—lowering efficacy in patients with T2DM in phase II trials. r, despite its efficacy, the compound was discontinued in phase III trial due to liver safety concerns (Diabetes obes metab., 2015, 17, 675—681).

It is definitive that discovery of novel GPR40 agonists which bear mechanism of glucose—dependent insulin secretion is in necessity of modern society, where the number of patients suffering from metabolic disorders including T2DM is still drastically sing, to provide effective means of treating such metabolic diseases.

Disclosure of Invention Technical Problem The objective of the present invention relies on providing agonists acting on GPR40; particularly novel phenyl propionic acid derivatives, s, and pharmaceutically available salts thereof.

In addition, the object of the present invention is to provide medicinal use for ent of GPR40—mediated disorders. r, the technical object to be achieved in the present invention is not limited to those aforementioned above, and other s may be clearly understood by those skilled in the art from the following description.

Solution to Problem Compounds represented by Formula (I); a racemate, an enantiomer, or a diastereomer thereof, or a pharmaceutically acceptable salt thereof: [Formula (1)] R1 is hydrogen, or C14 linear or branched alkyl; R2 is hydrogen, cyano, hydroxyl, CM linear or branched alkyl, or C14 linear or ed alkoxy; R3 and R4 are each ndently hydrogen, n, cyano, C14 linear or branched alkoxy, or 0R8; wherein R8 is hydrogen; C340 heterocycloalkyl comprising l—4 hetero atoms selected from the group consisting of N, O, and S; or substituted alkyl with C340 heterocy— cloalkyl comprising l—4 hetero atoms selected from the group consisting of N, O, and R5 and R6 are each independently hydrogen, halogen, cyano, halomethyl, hydroxyl, C 1,4 linear or branched alkyl, or C1,4linear or branched alkoxy; Y is NH or O; 21, Z2 and W are each independently CR7 or N; wherein R7 is en, halogen, cyano, hydroxyl, C14 linear or branched alkyl, or C 1,4 linear or ed alkoxy.

This invention is provided to the compounds according to Formula (I), as racemates, enantiomers, diastereomers thereof; or pharmaceutical acceptable salts, for the treatment of disorders; wherein responsive to agonism of the GPR40.

This invention is provide to the process of nds according to Formula (I), as racemates, enantiomers, romers thereof; or pharmaceutical acceptable salts.

Advantageous Effects of Invention The compounds of the present invention, as GPR40 agonists, are orally available and are ely effective in lowering blood glucose level to normal state without any risk of inducing hypoglycemia via glucose—dependent insulin secretion. Therefore, compounds and/or eutically effective pharmaceutical composition sing the compounds of the present invention are useful in the treatment, ng, and/or re— gression of symptoms of type 2 diabetes. In addition, compounds of the present invention modulate glucose excursion via GPR40 activation; the therapeutic effect can also be potentially available in obesity and ension.

In addition, since the compounds of the present invention have shown improved and/ or enhanced therapeutic effects of alleviating and/or treating symptoms of type 2 diabetes compared to isting medications when evaluated of e—lowering effects of the compounds on animal models and/or human—organ derived materials, the compounds can be evaluated as being highly useful to potential beneficiaries of the present invention.

Mode for the Invention Compounds represented by Formula (I); a racemate, an enantiomer, or a diastereomer thereof, or a pharmaceutically acceptable salt thereof: [Formula (1)] R1 is en, or C14 linear or branched alkyl; R2 is hydrogen, cyano, hydroxyl, CM linear or branched alkyl, or C14 linear or 2017/014757 branched alkoxy; R3 and R4 are each independently hydrogen, halogen, cyano, C14 linear or branched alkoxy, or 0R8; wherein R8 is hydrogen; C340 heterocycloalkyl comprising l—4 hetero atoms selected from the group consisting of N, O, and S; or substituted alkyl with C340 heterocy— cloalkyl comprising l—4 hetero atoms selected from the group consisting of N, O, and R5 and R6 are each independently hydrogen, halogen, cyano, halomethyl, hydroxyl, C 1,4 linear or branched alkyl, or C1,4linear or branched alkoxy; Y is NH or O; 21, Z2 and W are each independently CR7 or N; n R7 is hydrogen, halogen, cyano, hydroxyl, C14 linear or branched alkyl, or C 1,4 linear or branched alkoxy. es of preferred compounds according to the a (I) in present invention are ing: (S)—3—(4—(((R)—4—(6—(( l , l—dioxidotetrahydro—2H—thiopyran—4—yl)oxy)pyridin—3—yl)—7—ﬂ uoro—2,3—dihydro— lH—inden— l—yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—ﬂuoro—4—(6—((3—methyloxetan—3—yl)methoxy)pyridin—3—yl)—2,3—dihydr o— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—4—(6—(2—( l , l—dioxidothiomorpholino)ethoxy)pyridin—3—yl)—7—fluoro—2,3 —dihydro— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—ﬂuoro—4—(6—(oxetan—3—yloxy)pyridin—3—yl)—2,3—dihydro— lH—inden— l—y l)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydr o— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—ﬂuoro—4—(6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—2,3—dihydr o— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (4—(((R)—7—ﬂuoro—4—(6—(((S)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro — lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—ﬂuoro—4—(4—methyl—6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2 ,3—dihydro— lH—inden— l—yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—ﬂuoro—4—(2—methyl—6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2 ydro— lH—inden— l—yl)oxy)phenyl)hex—4—ynoic acid; (4—(((R)—4—(5—chloro—6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—7—ﬂuoro—2, 3—dihydro— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—ﬂuoro—4—(5—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—2—yl)—2,3—dihydr o— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—fluoro—4—(4—methyl—6—((3—methyloxetan—3—yl)methoxy)pyridin—3—yl)— 2017/014757 2,3—dihydro— lH—inden— l—yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—fluoro—4—(2—methyl—6—((3—methyloxetan—3—yl)methoxy)pyridin—3—yl)— 2,3—dihydro— en— l—yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—ﬂuoro—4—(5—((3—methyloxetan—3—yl)methoxy)pyridin—2—yl)—2,3—dihydr o— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—ﬂuoro—4—(5—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydr o— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—7—ﬂuoro—4—(5—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—2,3—dihydr o— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—4—(5—chloro—6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—7—ﬂuoro—2 ,3—dihydro— lH—inden— l—yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—4—(5—cyano—6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—7—ﬂuoro—2, 3—dihydro— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—4—(5—cyano—6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—7—ﬂuoro—2 ,3—dihydro— lH—inden— l—yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—5—cyano—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro — lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—5—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydr o— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—5—methoxy—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihy dro— lH—inden— l—yl)oxy)phenyl)hex—4—ynoic acid; (4—(((R)—5—cyano—4—(6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—2,3—dihydr o— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (4—(((R)—5—ﬂuoro—4—(6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—2,3—dihydr o— lH—inden— l —yl)oxy)phenyl)hex—4—ynoic acid; (S)—3—(4—(((R)—5—methoxy—4—(6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—2,3—dih ydro— lH—inden— l—yl)oxy)phenyl)hex—4—ynoic acid; (4—(((R)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydr o— lH—inden— l —yl)amino)phenyl)hex—4—ynoic acid; 3—(6—(((R)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro—l H—inden— l—yl)oxy)pyridin—3—yl)hex—4—ynoic acid.

In the present invention, "heterocycloalkyl" refers to cycloalkyl groups containing hetero atoms. Exemplary cycloalkyl groups include, but not limited to, oxetane, tetrahydrofuran, pyran, azetidine, pyrrolidinyl, piperazinyl, morpholine or thiomorpholine.

In the present ion, "C14 alkyl" is a saturated hydroxylcarbonyl group with linear or branched chains of l to 4 carbon atoms. Exemplary alkyl groups include, but WO 11012 not limited to, methyl, ethyl, propyl, buthyl, l—methylethyl, l or dimethyl.

In the present invention, "C14 alkoxy" is an OR group with l to 4 carbon atoms and R as defined above. Exemplary alkoxy groups include, but not limited to, methoxy, ethoxy, propoxy, butoxy, l—methylethoxy or 1, l—dimethylethoxy.

In the present ion, "Cm alkyl" is a saturated hydroxylcarbonyl group with linear or ed chains of l to 2 carbon atoms. Exemplary alkyl groups include, but not limited to, methyl or ethyl.

In the t invention, "Cm alkoxy" is an OR group with l to 2 carbon atoms and R as defined above. Exemplary alkoxy groups include, but not limited to, methoxy or ethoxy.

In the present ion, "halo" is defined as bromine, fluorine, or chlorine atom.

Herein, the term "pharmaceutically acceptable" refers to a usable component or com— position, within the medical criteria, that does not incorporate irrational risk of toxicity.

The nds of the invention contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. A stereoisomer is referred to as an omer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic—mixture or a racemate.

In the present invention, "diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Di— astereomers have different al properties, such as melting , boiling points, spectral properties, and reactivity. Mixtures of diastereomers may become separated under high resolution analytical procedures such as electrophoresis and chro— matography.

In the present invention, "enantiomers" refer to two stereoisomers of a compound which are non—superimposable mirror images of one another.

The phrase "pharmaceutically acceptable salt" as used herein, refers to pharma— ally acceptable organic or inorganic salts of a compound of the invention.

Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, e, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, te, gluconate, glucuronate, saccharate, e, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p—toluenesulfonate, and pamoate (i.e., l,l'—methylene—bis—(2—hydroxy—3—naphthoate)) salts. A ceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other r ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. rmore, a ceutically acceptable salt may have more than one d atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple r ions. Hence, a pharma— ceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any le method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hy— drobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, c acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha y acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p—toluenesulfonic acid or methanesulfonic acid, or the like.

If the compound of the invention is an acid, the desired pharmaceutically able salt may be prepared by any suitable , for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and nic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, ium and lithium.

In another aspect, the present invention provides a method of preparing the compounds represented by Formula (I) or pharmaceutically approved salts thereof.

[Reaction I] WO 11012 HO R?— {“j/ + R3/R4-‘LG z ' 1‘22. X \STEP1a 1a 23 fix/\[f, R STEP 1b KKLA RS/R4—0H + : 2:22 \X ZQZB 1b 2b 3 R6 R R5 R5 STEP 2 ---- Y B Y 0’38 I’ . O 6 Unless otherwise stated, the groups, residues, and substituent, particularly R6, Y, W, 21, and Z2 are defined as above and hereinafter. 2017/014757 R1 is hydrogen, or C14 linear or ed alkyl; R2 is hydrogen, cyano, hydroxyl, CM linear or branched alkyl, or C14 linear or branched alkoxy; R3 and R4 are each independently hydrogen, halogen, cyanide, C14 linear or branched , or 0R8; wherein R8 is hydrogen; C340 cycloalkyl comprising l—4 hetero atoms selected from the group consisting of N, O, and S; or substituted alkyl with C340 heterocy— cloalkyl comprising l—4 hetero atoms selected from the group consisting of N, O, and R5 and R6 are each independently hydrogen, halogen, cyano, halomethyl, hydroxyl, C [,4 linear or branched alkyl, or CH linear or branched ; Y is NH or O; 21, Z2 and W are each independently CR7 or N; n R7 is hydrogen, halogen, cyano, hydroxy, C14 linear or branched alkyl, or C [,4 linear or branched alkoxy. ically, the process of preparing the compounds of Formula (1) includes; The step of preparing compound 3 through substitution reaction of compound 1 and compound 2 (Step 1); The step of preparing a compound that is represented either by compound 4 or compound 6 through boronylation reaction of compound 4 and compound 6 (Step 2); The step of preparing compound 7 through Suzuki coupling reactions of compound 3 and compound 5 or compound 4 and compound 6 (Step 3); The step of preparing compound 9 h Mitsunobu sation of compound 7 and compound 8 (Step 4); or The step of preparing compounds of Formula (I) through hydrolysis reaction of compound 9 (Step 5).

The preparing processes of Formula (I) can be bed in more detail for each step as s; i) In Step 1, compound 3 can be prepared through substitution of leaving group of compound 2 with compound 1. In addition, solvents available for the reaction include methylformamide, acetonitrile, dimethylsulfoxide or toluene, and bases used in the reaction include cesium ate, potassium carbonate or sodium hydride. To be specific, the step bes preparation of compound 3 through substitution reaction of compound 1 and compound 2 with adequate solvents and bases, for example, N,N—dimethylformamide and potassium carbonate. ii) The Step 2 describes the process of preparing compound 4 or compound 6 through boronylation reaction of compound 3 or compound 5 with equivalent or excessive use of boronylation reagents and metal catalysts. Metal catalysts, more specifically palladium catalysts, e [1,1'—Bis(diphenylphosphino)ferrocene]dichloro Palladium (II), dicholoromethane (Pd(dppf)Clz ° DCM) or Palladium tetrakis(triphenylphosphine) (Pd(PPh3)4). In addition, solvents involved in the reaction include dichloromethane, acetonitrile, 1, 4—dioxane or toluene. The boronic—reagent can be selected from either Bis(pinacolato)diboron or Bis(neopentylglycolato)diboron. To be more specific, the process of preparing compound 4 can be bed in the following on; A reaction of a solution of compound 3 and adequate catalysts, boronic—reagents, base and solvents, for example, 1,4—dioxane with Pd(dppf)Clz, potassium e and Bis(pinacolato)diboron. iii) The Step 3 bes the process of preparing compounds that are represented by compound 7 from Suzuki coupling reaction of compound 4 or compound 6 obtained from Step 2 and compound 3 or compound 5. The coupling reaction can be processed with adequate combinations of palladium catalysts and bases, and the sts available for the reaction include Tetrakis(triphenylphosphine) (Pd(PPh3)4), Bis(triphenylphosphine)Palladium (II) dichloride (PdClz(PPh3)2), Palladium dichloride (PdClz) or Palladium acetate (Pd(OCOCH3)2). In addition, solvents used for the reaction include ydrofuran, lether, diphenylether, diisopropylether, N,N—dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, chlorobenzene, toluene, benzene or water ormixture of these solvents. To be more specific, the Step describes the s of preparing compound 7 through Suzuki coupling reaction of nd 3 and compound 4 with the combination of adequate solvents, catalyst, ligand and base, for example, mixture of toluene and water with sz (dba)3, biphenyl—dicyclohexyl—phosphine, and potassium phosphate tribasic. iv) The Step 4 describes the process of preparing compound 9 through obu reaction of compound 7 and compound 8. To be more specific, compound 9 can be prepared from Mitsunobu reaction of the mixture solution of compound 7 and compound 8 with triphenylphosphine and azodicarbonyl)dipiperidine (ADDP) under 0 . v) The Step 5 describes the process of preparing compounds of Formula (I) through hydrolysis reaction of nd 9 under basic condition. In particular, nds of a (I) can be prepared through compound 9 reacting with adequate base under room temperature, resulting the reduction of ester to carboxylic acid. Bases available for the on include potassium hydroxide, sodium hydroxide or lithium hydroxide.

To be more specific, compounds of Formula (I) can be prepared from the reaction of compound 9 with adequate base, for example, lithium hydroxide.

The present invention provides a ceutical ition for the treatment of metabolic disorders, which comprises the compounds of a (I), racemate, enantiomer, diastereoisomer thereof, or pharmaceutically able salts thereof.

Compounds of the invention intended for pharmaceutical use comprise compounds of Formula (1), their pharmaceutically acceptable salts, solution, and hydrates. .

The term "prevention", as used herein, covers any inhibition or regression of diseases that are induced by the compounds of the present invention.

The term "treatment", as used herein, covers any treatment of es in a mammal, particularly a human, and includes inhibiting the diseases, i.e., arresting the de— velopment; or relieving the diseases, i.e. inducing regression of the diseases and/or their symptoms or conditions and slowing disease progression.

The term "metabolic disorder", as used herein, refers to any disorders caused by metabolic abnormality in lipids or glucose, and includes, but not limited to, obesity, type 2 diabetes, disturbed glucose tolerance, insulin resistance, hyperglycemia, hyper— lipidemia, hypertriglyceridemia, hypercholesteremia, and dyslipidemia.

The t invention provides a method of ng metabolic disorders in a subject in need thereof, comprising administration of effective amounts of the pharmaceutical composition to the subject. The dosage of pharmaceutical composition of the present invention may vary depending on the t's weight, age, gender, physical condition, diet, time and mode of administration, excretion rates, and severity of illness, but is readily apparent to those skilled in the art. Mammals, ably humans, are ble for the individuals without limit.

The term "therapeutically effective amount" refers to an amount of a compound of the present invention that ameliorates, attenuates or eliminates a particular disease or condition or prevents or delays the onset of a particular disease or ion. In the case of es mellitus, the therapeutically effective amount of the drug may reduce postprandial blood glucose level; reduce HbAlc level; treat or inhibit diabetic pathy or nephropathy; inhibit (slow to some extent and preferably stop) progress of diabetes; weight loss; ameliorate or enhance atic B—cell function; and/or relieve to some extent one or more of the symptoms associated with diabetes. To the extent the drug may modulate blood glucose level to normal state.

The "pharmaceutical composition" as used herein may contain effective component and ceutically able formulation, and the pharmaceutical compositions suitable for the delivery of compounds of the present invention and s for their preparation can be readily nt to those skilled in the art.

The pharmaceutical composition as used herein can be administered either orally or parenterally through diverse formulations, and the ive dose of administration may vary depending on physical condition, body weight and ty of the illness of the t, formulation, and administration time and route, but can be readily determined by those skilled in the art. ations suitable for oral administration include tablets, pills, soft capsules, liquid, suspension, emulsifier, syrups, granules, and elixir, and typically comprise ts (i.e. e, dextrose, e mannitol, solbitol, cellulose, and/or glycine) and lubricant (i.e. silica, talc, stearic acid and its magnesium or calcium salt and/or polyethylene glycol). Tablets of the formulation also comprise binders including magnesium aluminium silicate, starch paste, gelatin, methyl cellulose, sodium carboxy methyl cellulose, and/or poly—venyl pyrrolidine, and depending on cir— nces, tablets may comprise disintegrants including , agar, alginic acid or its sodium salt, or boiling mixture, absorbent, coloring agent, ﬂavoring agents, or sweeteners.

The pharmaceutical composition as used herein is administered with pharma— ceutically effective amounts. The term "pharmaceutically effective amount" refers to sufficient amount of a compound in the present invention that can treat disease with rational and te t/risk ratio, and the effective amount can be readily de— termined depending on the types of subject's illness, severity, activity of the compound, sensitivity of the subject to the compound, administration time, route and excretion ratio, ent interval, factors including inistered drugs and other well—known medical factors. Compounds of the present invention can be combined or co—administered with other types of drugs as a combination therapy or monotherapy, and can be administered with add—on therapy to the pre—existing treatment with single or multiple administration. Aforementioned factors must be all considered adequately to determine within the bounds of goal achieving maximum therapeutic effect with minimum s of the compound without harmful or serious adverse effects, and this process can be y determined by those skilled in the art.

In particular, the therapeutically effective amount of the compound in the present invention can vary depending on the subject's age, gender, and body weight, and typically ranges from 0.001 to 150 mg per 1 kilogram of body weight, desirably from 0.01 to 100 mg/kg/day or 0.01 to 100 mg/kg/48 hrs with Q.D., B.I.D. or T.I.D.

The t invention ns, but not limited to, in detail through the following examples and experimental examples.

[Intermediates] <Intermediate 1> 13S114-Hydroxy—phenyl1—hex—4—ynoic acid methyl ester WO 11012 0 U C><O 0 0i W H A? _ -—» 13*?O m» ”(3Q \\ % -—' \ 1 s HO HO / {JLOH 2L0“, Step 1: 5—(4—Hydroxy—benzylidene)—2,2—dimethyl—[1,3]dioxane—4,6—dione 4—Hydroxybenzaldehyde (1.0 eq.) was dissolved in water (0.9 M) at 75°C. Sub— sequently, a solution of meldrum's acid (1.1 eq.) in water (1.2 M) was added to the reaction mixture. The mixture was stirred at 75 °C for 2 h, and then added with a solution of meldrum's acid (0.5 eq.) in water (1.2 M). The mixture was d at 75°C for r 2 h. The mixture was allowed to reach room temperature,filtered with iced— water. The wet solid was dried in an oven (50°C) to afford —(4—hydroxy—benzylidene)—2,2—dimethyl—[1,3]dioxane—4,6—dione.

Step 2: (+/-)[1-(4-Hydroxy—phenyl)—but—2—ynyl]—2,2—dimethyl — [1,3]dioxane—4,6—dione 1—Propynylmagnesium bromide in tetrahydrofuran (0.5 N, 3.0 eq.) was added dropwise to a solution of —(4—hydroxy—benzylidene)—2,2—dimethyl—1,3—dioxane—4,6—dione (1.0 eq.) in y— an anhydrous (0.4 M) at 4°C under N2 atmosphere. The reaction mixture was stirred at room temperature for 30 min. The mixture was quenched with saturated aqueous ammonium chloride solution and washed with hexane. After the aqueous layer was ted, the mixture was acidified with 1.0 M aqueous hydrochloric acid solution and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resultant residue was purified by ﬂash column chromatography on silica gel eluting to afford —[1—(4—hydroxy—phenyl)—but—2—ynyl]—2,2—dimethyl—[1,3]dioxane—4,6—dione. [138 [139 Step 3: (+/-)(4-Hydroxy—phenyl)—hex—4—ynoic acid [140 [141I—JI—JI—JI—J (+/—)—5—[1—(4—Hydroxy—phenyl)—but—2—ynyl]—2,2—dimethyl—[ 1 ,3]dioxane—4,6—dione (1.0 eq.) was dissolved in the mixture of 3—pentanone (0.8 M) and water (1.6 M) and stirred at 100°C for 48 h. The mixture was allowed to reach room temperature, and basified with 3.0 M aqueous potassium hydroxide solution. The aqueous layer was collected, acidified with concentrated hydrochloric acid, and d with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and con— centrated. No further purification was needed to afford (+/—)—3—(4—hydroxy—phenyl)—hex—4—ynoic acid.

Step 4: (3S)(4-Hydroxy—phenyl)—hex—4—ynoic acid A solution of (lS,2R)—l—amino—2—indanol (0.6 eq.) in acetonitrile anhydrous (0.8 M) was added to a solution of (+/—)—3—(4—hydroxy—phenyl)—hex—4—ynoic acid (1.0 eq.) in acetonitrile anhydrous (0.8 M) at 70 °C and stirred for 4 h. The mixture was allowed to reach room temperature, the salt was filtered. The salt was added in mixture of ace— ile (0.4 M) and water (4.3 M) at 70°C and stirred for 4 h. The reaction mixture was allowed to reach room temperature, and the salt was filtered. After two runs in the same manner, the salt was added in the mixture of ethyl acetate and water at room tem— perature. 2.0 M aqueous hydrochloric acid solution was added and the mixture was stirred usly at room temperature. After two clear layers were obtained, the layers were separated and diluted with ethyl acetate. The c layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. No further purification was needed to afford (3S)—3—(4—hydroxy—phenyl)—hex—4—ynoic acid.

Step 5: (3S)(4-Hydroxy—phenyl)—hex—4—ynoic acid methyl ester Concentrated sulfuric acid (5 drops) was added to the mixture of —(4—hydroxy—phenyl)—hex—4—ynoic acid (1.0 eq.) in ol (0.5 M) at room temperature. The mixture was stirred at 90 °C for 18 h. The mixture was allowed to reach room temperature, and basified with saturated aqueous sodium onate solution and extracted with ethyl e. The organic layer was washed with water and brine, dried over magnesium sulfate, ed and concentrated. No further purification was needed to afford (3S)—3—(4—hydroxy—phenyl)—hex—4—ynoic acid methyl ester. 2017/014757 <Intermediate 2> S - 4-Bromo—7—fluoro—2 3—dih dro—lH—inden — 1— l ox tert—but l dimeth lsilane F F 9 0H F oras Br Br Br Step 1: (S)Bromo—7—ﬂuoro—2,3—dihydro— lH—inden— 1—01 Formic acid (3.5 eq.) was added to a solution of triethylamine (3.0 eq.) in dichloromethane (1.5 M) at 4°C. o—7—ﬂuoro—2,3—dihydro—lH—inden—l—one (1.0 eq.) was added and then purged with N2 for 5 min.

Chloro{ [( l S,ZS)—(—)—2—amino— l ,2—diphenylethyl](4—toluenesulfonyl)amido } —(mesitylen e)ruthenium(II) (0.02 eq.) was added and then stirred at room temperature for 18 h.

The mixture was diluted with dichloromethane and washed with water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated.

The resultant residue was ed by ﬂash column chromatography on silica gel to afford bromo—7—ﬂuoro—2,3—dihydro—lH—inden—l—ol. Enantiomeric excess was confirmed by <Chiral UPCC analysis method I>.

Step 2: (S)-((4-Bromo—7—fluoro—2,3—dihydro—lH—inden—l—yl)oxy)(tert — butyl)dimethylsilane Imidazole (3.0 eq.) was added to a solution of (S)—4—bromo—7—ﬂuoro—2,3—dihydro—lH—inden—l—ol (1.0 eq.) in dichloromethane (1.5 M) at 4°C. The reaction mixture was stirred at room temperature for 15 min. tert— WO 11012 2017/014757 Butyldimethylsillyl de (2.0 eq.) was added and then the mixture was allowed to reach room temperature, stirred for 1 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine and dried over magnesium sulfate, filtered and concentrated. The resultant residue was purified by flash column chromatography on silica gel to afford (S)—((4—bromo—7—ﬂuoro—2,3—dihydro—1H—inden—1—yl)oxy)(tert—butyl)dimethylsilane. <Intermediate 3> S Bromo—1— tert—but ldimeth lsil l ox —2 3—dih dro—1H—indene—5—carbonitrile Step 1 : 4—Bromo—5—methoxy—2,3—dihydro— 1H—inden— 1 —one N—Bromosuccinimide (1.0 eq.) was added to a solution of —methoxy—2,3—dihydro—1H—inden—1—one (1.0 eq.) in water (0.1 M) and the reaction mixture was heated to 60°C. 40% aqueous sulfuric acid solution (2.0 eq.) was added and d at 60°C for 6 h. The crude product was extracted with tert—butyl methyl ether and dried over magnesium sulfate, filtered and concentrated. Then, the mixture was additionally ed bycrystallization using ethanol to give pure 4—bromo—5—methoxy—2,3—dihydro— 1H—inden— 1 —one.

Step 2: 4—Bromo—5—hydroxy—2,3—dihydro— 1H—inden— l—one Sodium thiomethoxide (4.4 eq.) was added to a solution of 2017/014757 4—bromo—5—methoxy—2,3—dihydro—lH—inden—l—one (1.0 eq.) in N,N—dimethylformamide (1.7 M). The reaction mixture was stirred at 120°C for 3h. The mixture was allowed to reach room ature, neutralized with 1.0M hydrochloride solution and d with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resultant residue was purified by flash column chromatography on silica gel to afford 4—bromo—5—hydroxy—2,3—dihydro— lH—inden— 1 —one. [170 [1711—11—11_11_1 Step 3: 4—Bromo— l—oxo—2,3—dihydro— lH—inden—5—yl triﬂuoromethanesulfonate [172 [173 Triﬂuoromethanesulfonic anhydride (1.1 eq.) was added dropwise to a solution of 2,6—lutidine (2.5 eq.) and 4—bromo—5—hydroxy—2,3—dihydro—lH—inden—l—one(l.0 eq.) in dichloromethane (3.5 M) at 4 OC. The reaction mixture was allowed to reach room tem— perature, and stirred for 3 h. The mixture was diluted with dichloromethane and washed with saturated aqueous ammonium de solution. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated.

The resultant residue was purified by ﬂash column chromatography on silica gel to afford 4—bromo— l—oxo—2,3—dihydro— lH—inden—5—yl trifluoromethanesulfonate. [174 [175 Step 4: 4—Bromo— l—oxo—2,3—dihydro— lH—indene—5—carbonitrile [176 [1771—11—11_11_1 Zinc cyanide (0.3 eq.), tris(dibbenzylideneacetone)dipalladium(0) (0.05 eq.) and 1,l—bis(diphenylphosphino)ferrocene (0.1 eq.) were added to a solution of o—l—oxo—2,3—dihydro—lH—inden—5—yl romethanesulfonate (1.0 eq.) in methylformamide (0.6 M). The reaction mixture was stirred at 70 °C for 1 h.

The mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The resultant residue was purified by ﬂash column chromatography on silica gel to afford 4—bromo— 1—oxo—2,3—dihydro—1H—indene—5—carbonitrile. [178 [179 Step 5: (S)Bromo— 1 —hydroxy—2,3—dihydro— lH—indene—5—carbonitrile [180 [1811—11—11_11_1 Formic acid (3.5 eq.) was added to a solution of ylamine (3.0 eq.) in dichloromethane (0.2 M) at 4 OC. 4—Bromo—l—oxo—2,3—dihydro—lH—indene—5—carbonitrile (1.0 eq.) was added and then purged with N2 for 5 min.

Chloro{ [(1S,2S)—(—)—2—amino—1,2—diphenylethyl](4—toluenesulfonyl)amido}—(mesitylen e)ruthenium(II) (0.02 eq.) was added and stirred at room temperature for 18 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The resultant residue was purified by ﬂash column chromatography on silica gel to afford (S)—4—bromo—1—hydroxy—2,3—dihydro—1H—indene—5—carbonitrile. Enantiomeric excess was confirmed by <Chiral UPCC analysis method I>.

Step 6: Bromo—1—((tert—butyldimethylsilyl)oxy)—2,3—dihydro — ene—5—carbonitrile Imidazole (5.0 eq.) was added to a solution of (S)—4—bromo—1—hydroxy—2,3—dihydro—1H—indene—5—carbonitrile (1.0 eq.) in romethane (0.1 M) at 4 OC. The reaction mixture was stirred at room temperature for 15 min. tert—Butyldimethylsillyl chloride (5 .0 eq.) was added and then the reaction mixture was allowed to reach room temperature and stirred for 1 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine and dried over magnesium e, filtered and concentrated. The resultant residue was purified by flash column chromatography on silica gel to afford (S)—4—bromo—1—((tert—butyldimethylsilyl) oxy)—2,3—dihydro—1H—indene—5—carbonitrile. <Intermediate 4> S - 4-Bromo—5—fluoro—2 3—dih dro—lH—inden — 1— lox tert—but ldimeth lsilane O OH OTBS —»~ —+~ 00 F F F Br Br Br Step 1: Bromo—5—ﬂuoro—2,3—dihydro— 1H—inden— 1—ol WO 11012 Formic acid (3.5 eq.) was added to a solution of triethylamine (3.0 eq.) in dichloromethane (0.2 M) at 4 OC. o—5—ﬂuoro—2,3—dihydro—1H—inden—1—one (1.0 eq.) was added and then purged with N2 for 5 min.

Chloro{ [(1S,2S)—(—)—2—amino—1,2—diphenylethyl](4—toluenesulfonyl)amido}—(mesitylen e)ruthenium(II) (0.02 eq.) was added and stirred at room temperature for 18 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was washed with brine and dried over magnesium sulfate, filtered and concentrated.

The resultant e was purified by ﬂash column chromatography on silica gel to afford (S)—4—bromo—5—ﬂuoro—2,3—dihydro—1H—inden—1—ol. Enantiomeric excess was confirmed by l UPCC analysis method I>.

Step 2: (S)-((4-Bromo—5—fluoro—2,3—dihydro— 1H—inden— 1—yl)oxy)(tert — butyl)dimethylsilane Imidazole (3.0 eq.) was added to a on of (S)—4—bromo—5—ﬂuoro—2,3—dihydro—1H—inden—1—ol (1.0 eq.) in dichloromethane (1.5 M) at 4 OC. The reaction mixture was stirred at room temperature for 15 min. tert— Butyldimethylsillyl chloride (2.0 eq.) was added and then the reaction mixture was allowed to reach room temperature, stirred for 18 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine and dried over magnesium sulfate, ed and concentrated. The resultant residue was purified by flash column chromatography on silica gel to afford (S)—((4—bromo—5—ﬂuoro—2,3—dihydro—1H—inden—1—yl)oxy)(tert—butyl)dimethylsilane. <Intermediate 5> S - o—5—methox —2 3—dih dro—1H—inden — 1— lox tert—but ldimeth lsilane /O(a.\\\ /O /O /O --» g. -~—» 1% —-+ 1% 0 Br 0 Br OH Br OTBS L_,_1 v.1 Step 1: 4—Bromo—5—methoxy—2,3—dihydro— 1H—inden— 1 —one N—Bromosuccinimide (1.0 eq.) was added to a solution of —methoxy—2,3—dihydro—1H—inden—1—one (1.0 eq.) in water (0.1 M) and the reaction mixture was heated to 60 0C. 40% aqueous sulfuric acid solution (2.0 eq.) was added and stirred for 6 h. The crude product was extracted with tert—butyl methyl ether and dried over magnesium sulfate, filtered and concentrated. Then the mixture was addi— tionally purified by crystallization using ethanol to afford pure 4—bromo—5—methoxy—2,3—dihydro— 1H—inden— 1 —one.

Step 2: (S)Bromo—5—methoxy—2,3—dihydro— 1H—inden— 1—ol Formic acid (3.5 eq.) was added to a solution of ylamine (3.0 eq.) in dichloromethane (0.2 M) at 4 OC. 4—Bromo—5—methoxy—2,3—dihydro—1H—inden—1—one (1.0 eq.) was added and then the mixture was purged with N2 for 5 min. { [(1S,2S)—(—)—2—amino—1,2—diphenylethyl](4—toluenesulfonyl)amido}—(mesitylen e)ruthenium(II) (0.02 eq.) was added and d at room temperature for 18 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was washed with brine and dried over magnesium sulfate, filtered and concentrated.

The resultant residue was purified by ﬂash column chromatography on silica gel to afford (S)—4—bromo—5—methoxy—2,3—dihydro—1H—inden—1—ol. Enantiomeric excess was confirmed by l UPCC analysis method I>.

Step 3: (S)-((4-Bromo—5—methoxy—2,3—dihydro— 1H—inden— 1—yl)oxy)(tert — butyl)dimethylsilane Imidazole (5.0 eq.) was added to a solution of (S)—4—bromo—5—methoxy—2,3—dihydro—1H—inden—1—ol (1.0 eq.) in dichloromethane (0.1 M) at 4 OC. The reaction e was stirred at room temperature for 15 min. tert— Butyldimethylsillyl chloride (5 .0 eq.) was added and then the reaction mixture was allowed to reach room temperature, d for 1 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine and dried over magnesium sulfate, filtered and concentrated. The resultant residue was purified by flash column chromatography on silica gel to afford (S)—((4—bromo—5—methoxy—2,3—dihydro—1H—inden—1—yl)oxy)(tert—butyl)dimethylsilane. <Intermediate 6> 1 S )] 1-1 B utyldimethylsilyl )oxy 1—5—methoxy — 2 3—dih dro—1H—inden—4— l—2— tetrah dro—2H— ran—4— lox ridine ,1“ 1'0\ /\\ s/Tfar ——D 03k T]? —> x : /\\ 2) K —P* C1} I“? \ O 0/ \l /‘\ CVAV \O/K‘N//_ ]/ /l\ \lA/’ AQTBS [ ]1 k 5 Step 1: 5—Bromo—2—((tetrahydro—2H—pyran—4—yl)oxy)pyridine Sodium e (1.3 eq.) was slowly added to a on of tetrahydro—2H—pyran—4—ol (1.0 eq.) and 5—bromo—2—chloropyridine (1.2 eq.) in N,N—dimethylformamide (0.8 M) and the reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was allowed to reach room ature, quenched with water. The mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine and dried over magnesium sulfate, filtered and concentrated. The resultant e was purified by flash column chromatography on silica gel to afford —bromo—2—((tetrahydro—2H—pyran—4—yl)oxy)pyridine.

Step 2: 2—((Tetrahydro—2H—pyran—4—yl)oxy)—5—(4,4,5,5—tetramethyl — 1,3 ,2—dioxaborolan—2—yl)pyridine Potassium acetate (2.0 eq.) was added to a solution of —bromo—2—((tetrahydro—2H—pyran—4—yl) oxy) pyridine (1.0 eq.) and bis(pinacolato)diboron (1.2 eq.) in oxane (0.1 M) and then purged with N2 for 10 min. The reaction mixture was stirred at 110 °C for 18 h. The reaction mixture was allowed to reach room temperature, diluted with ethyl acetate and washed with water.

The organic layer was washed with brine and dried over magnesium sulfate, filtered and concentrated. The resultant residue was purified by flash column tography on silica gel to afford 2—((tetrahydro—2H—pyran—4—yl)oxy)—5—(4,4,5 ,5—tetramethyl— 1 ,3 ,2—dioxaborolan—2—yl)pyri dine.

Step 3: (S)(1-((tert—Butyldimethylsilyl)oxy)—5—methoxy—2,3—dihydro — 1H—inden—4—yl)—2—((tetrahydro—2H—pyran—4—yl)oxy)pyridine ibenzylideneacetone)dipalladium(0) (0.05 eq.) was added to a solution of (S)—((4—bromo—5—methoxy—2,3—dihydro—1H—inden—1—yl)oxy)(tert—butyl)dimethylsilane (1.0 eq.), 2—((tetrahydro—2H—pyran—4—yl)oxy)—5—(4,4,5 ,5—tetramethyl— 1 ,3 ,2—dioxaborolan—2—yl)pyri dine (1.2 eq.), 2—dicyclohexylphosphino—2',6'—dimethoxybiphenyl (0.1 eq.), and potassium phosphate tribasic (3.0 eq.) in toluene (0.1 M) and water (1.0 M) and then purged with N2 for 10 min. The reaction mixture was stirred at 120 °C for 18 h under N 2 atmosphere. The reaction mixture was allowed to reach room temperature, filtered through Celite. The filtrate was diluted with ethyl acetate and washed with water. The c layer was washed with brine and dried over magnesium sulfate, filtered and concentrated. The resultant residue was purified by ﬂash column chromatography on silica gel to afford (S)—5—(l—((tert—butyldimethylsilyl)oxy)—5—methoxy—2,3—dihydro— lH—inden—4—yl)—2—((tetr ahydro—2H—pyran—4—yl)oxy)pyridine. <Intermediate 7> 3- 6-H drox ridin—3— l hex—4— noic acid eth lester (ffK'G \:>,\(') 0 l? [AOH 004‘ “‘0 cwJ x (WET/go '\ .........» m \ ____, m. A \ x x \\ Li a; E 0 N \ I] §‘\\ N j/ x0 N” \OﬂNr /A\L ﬁLOJ ‘\\ WWW). l. 7r\\x ———b \\ 2 [Y\ “0 N HO’ \N ’ Step 1: 5—((6—Methoxypyridin—3—yl)methylene)—2,2—dimethyl—l,3—dioxane—4,6—dione 6—Methoxypyridine—3—carbaldehyde (1.0 eq.) was dissolved in water (0.9 M) at 75 OC.

Subsequently, a solution of meldrum's acid (1.1 eq.) in water (1.2 M) was added to the mixture. The mixture was stirred at 75 °C for 2 h, and then added with a solution of meldrum's acid (0.5 eq.) in water (1.2 M). The on mixture was stirred at 75 °C for 2 h. The e was allowed to reach room temperature, ed with iced—water. The wet solid resultant was dried in an oven (50 0C) to afford 5—((6—methoxypyridin—3—yl) methylene)—2,2—dimethyl— l , 3—dioxane—4,6—dione. [23 l] Step 2: 5—(l—(6—Methoxypyridin—3—yl)but—2—ynyl)—2,2—dimethyl — l,3—dioxane—4,6—dione A on of —((6—methoxypyridin—3—yl)methylene)—2,2—dimethyl—l,3—dioxane—4,6—dione (1.0 eq.) in tetrahydrofuran anhydrous (0.4 M) was added dropwise to l—propynylmagnesium bromide in tetrahydrofuran (0.5 N, 1.5 eq.) at 4 °C under N2 here. The mixture was stirred at room temperature for 30 min. The mixture was ed with saturated aqueous ammonium chloride solution and extracted with hexane. After the aqueous layer was collected, the e was acidified with 1.0 M aqueous hydrochloric acid solution and d with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resultant residue was ed by ﬂash column chromatography on silica gel eluting to afford —(1—(6—methoxypyridin—3—yl)but—2—ynyl)—2,2—dimethyl—1,3—dioxane—4,6—dione.

Step 3: ethoxypyridin—3—yl)hex—4—ynoic acid —(1—(6—Methoxypyridin—3—yl)but—2—ynyl)—2,2—dimethyl— 1,3—dioxane—4,6—dione (1.0 eq.) was dissolved in the mixture of methylformamide (0.2 M) and water (2.0 M) at 100 °C and stirred for 18 h. The reaction mixture was allowed to reach room ature, quenched with saturated aqueous ammonium chloride solution and the extracted with ethyl acetate. The organic layer was washed with brine, dried over ium sulfate, ed and concentrated. No further purification was needed to afford 3—(6—methoxypyridin—3—yl)hex—4—ynoic acid.

Stpe 4: 3—(6—Hydroxypyridin—3—yl) hex—4—ynoic acid Concentrated hydrochloric acid solution (8.0 M) was added to the mixture of 3—(6—methoxypyridin—3—yl)hex—4—ynoic acid (1.0 eq.) in 1,4—dioxane (2.0 M) and water (2.0 M) at room temperature. The mixture was stirred at 100 °C for 18 h under N2 at— mosphere. The reaction mixture was allowed to reach room temperature, basified with saturated aqueous sodium bicarbonate solution and extracted with ethyl e. The organic layer was washed with brine, dried over magnesium sulfate, filtered and con— centrated. No r purification was needed to afford 3—(6—hydroxypyridin—3—yl) hex— 4—ynoic acid.

Step 5: 3—(6-Hydroxypyridin—3—yl) hex—4—ynoic acid ethyl ester Concentrated sulfuric acid (5 drops) was added to the mixture of 3—(6—hydroxypyridin—3—yl) hex—4—ynoic acid (1.0 eq.) in ethanol (0.9 M) at room tem— perature. The mixture was stirred at 90 °C for 18 h. The reaction mixture was allowed to reach room temperature, basified with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. No further purification was needed to afford ydroxypyridin—3—yl) hex—4—ynoic acid ethyl ester. <Intermediate 8> [\J O/\" (3| \ Br O/‘ e; O O E‘x/l x \ /\ Br ] * 38/ * ‘ : L 1 3’ ’ J (”89 m ”>60“? ‘2 OMS \ HO N ‘x ‘O N (”x /))E’O_ ‘ H0\ A ﬂ. .F l- ] H‘x’x’ix/‘ C] “Y fOH + 1,O\ ..........,. \cl \ lqﬁ/ ‘WOTBS W... Dm \‘i,/‘\ my .. ,z Le o N”2 K, QAN/ ll] 1:1]:,F/ /\ Ci zirﬁrygi\ .0. v” 0’ ‘N’ y «Km/Ox Step 1: Tetrahydro—2H—pyran—4—yl methanesulfonate [25 l] Methanesulfonyl chloride (1.2 eq.) was added to a solution of tetrahydro— 2H—pyran—4—ol (1.0 eq.) and triethylamine (3.0 eq.) in dichloromethane (0.3 M) at 4 OC.

The reaction mixture was stirred at room ature for l h. The mixture was diluted with dichloromethane and washed with water. The organic layer was washed with brine, ted aqueous ammonium chloride, and dried over ium sulfate, filtered and concentrated. The resultant residue was purified by flash column chro— matography on silica gel to afford tetrahydro—2H—pyran—4—yl methanesulfonate.

Step 2: 5—Bromo—3—chloro—2—((tetrahydro—2H—pyran—4—yl)oxy)pyridine Potassium carbonate (2.0 eq.) was added to a solution of tetrahydro—2H—pyran—4—yl methanesulfonate (l.2 eq.) and 5—bromo—3—chloropyridine—l—ol (l.0 eq.) in N,N—dimethylformamide (0.2 M). The reaction mixture was stirred at 100 °C for 18 h.

The reaction mixture was allowed to reach room temperature, d with ethyl acetate and washed with water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The ant residue was purified by ﬂash column chromatography on silica gel to afford —bromo—3—chloro—2—((tetrahydro—2H—pyran—4—yl) oxy) pyridine.

Step 3: (S)(1-((tert—Butyldimethylsilyl)oxy)—7—fluoro—2,3—dihydro — lH—inden—4—yl)—3—chloro—2—((tetrahydro—2H—pyran—4—yl)oxy)pyridine Tris(dibenzylideneacetone)dipalladium(0) (0.05 eq.) was added to a solution of —bromo—3—chloro—2—((tetrahydro—2H—pyran—4—yl)oxy)pyridine (1.0 eq.), rt—butyl((7—ﬂuoro—4—(4,4,5 ,5—tetramethyl— l ,3,2—dioxaborolan—2—yl)—2,3—dihydro— l H—inden—l—yl)oxy)dimethylsilane (l.2 eq.), 2—dicyclohexylphosphino—2',6'—dimethoxybiphenyl (0.1 eq.), and potassium phosphate tribasic (3.0 eq.) in toluene (0.1 M) and water (1.0 M) and then purged with N2 at— re for 10 min. The reaction mixture was stirred at 120 °C for 18 h under N2 at— mosphere. The reaction mixture was allowed to reach room temperature, filtered through Celite. The filtrate was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and con— centrated. The resultant residue was ed by ﬂash column chromatography on silica gel to afford (S)—5—(l—((tert—butyldimethylsilyl)oxy)—7—ﬂuoro—2,3—dihydro—lH—inden—4—yl)—3—chloro—2 —((tetrahydro—2H—pyran—4—yl)oxy)pyridine. [26 l] Step 4: (S)(S-Chloro—6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl )—7—fluoro—2,3—dihydro— lH—inden— 1 —ol 1.0 M Tetra—n—butyl ammonium fluoride (2.0 eq.) was added dropwise to a solution (S)—5—(l—((tert—butyldimethylsilyl)oxy)—7—ﬂuoro—2,3—dihydro—lH—inden—4—yl)—3—chloro—2 —((tetrahydro—2H—pyran—4—yl)oxy)pyridine (1.0 eq.) in tetrahydrofuran (0.1 M) at 4 OC.

The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine and dried over ium e, filtered and trated. The resultant e was purified by flash column chromatography on silica gel to afford (S)—4—(5—chloro—6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—7—ﬂuoro—2,3—dihydro—l H—inden— l—ol.

Step 5: (S)(4-(((R)(5-Chloro—6—((tetrahydro—2H—pyran — 4—yl)oxy)pyridin—3—yl)—7—fluoro—2, 3—dihydro— lH—inden— l—yl)oxy)phenyl)hex—4—ynoate methyl ester l,l'—(Azodicarbonyl)dipiperidine (1.5 eq.) was added nwise over 10 min to a solution of (S)—4—(5—chloro—6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—7—ﬂuoro—2,3—dihydro—l H—inden—l—ol (1.0 eq.), —(4—hydroxy—phenyl)—hex—4—ynoic acid methyl ester (1.0 eq.), and butylphosphine (1.5 eq.) in toluene (0.1 M) at 4 OC. The mixture was stirred at room ature for 18 h. After addition of hexane (0.05 M) to reaction mixture, the resulting white solid was removed by filtration. The filtrate was con— centrated and then purified by flash column chromatography on silica gel to afford (S)—3—(4—(((R)—4—(5—chloro—6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—7—fluoro—2, 3—dihydro—lH—inden—l—yl)oxy)phenyl)hex—4—ynoate methyl ester. <Intermediate 9> Chiral UPCC analysis method I Flow rate: 2 mL/min.

Mobile phase: Isocratic COz/Ethanol ) Stationary phase: CHIRALPAK—IA 250*4.6 mm ID.

Temperature: 25 OC Absorbance Wavelength: 220 nm [Examples] <Example 1> ﬂu0r0-2 3-dih dro-lH-inden-l- 10X hen lheX noic acid F .F [\Q‘ﬁo. TN ‘ \ \ t /3~j‘.\\\0 /b. :E / Q / OH 0% /\‘ \ 4) E 0% /\‘ \ /> 3 01.3 \ ‘N o 033 f ‘N li2 o \\ O 11' ‘k 0 2.0 M aqueous lithium hydroxide solution (5.0 eq.) was added to a solution of (S)—3—(4—(((R)—4—(6—(( l , l—dioxidotetrahydro—2H—thiopyran—4—yl)oxy)pyridin—3—yl)—7—flu oro—2,3—dihydro—lH—inden—l—yl)oxy)phenyl)hex—4—ynoic acid methyl ester (1.0 eq.) in tetrahydrofuran(l.0 M) and methanol (4.0 M) at 4 OC. The mixture was stirred atroom temperature for 18 h. The mixture was neutralized with saturated aqueous ammonium chloride on and diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The resultant residue was ed by ﬂash column chromatography on silica gel to afford (S)—3—(4—(((R)—4—(6—((1,1—dioxidotetrahydro—2H—thiopyran—4—yl)oxy)pyridin—3—yl)—7—flu oro—2,3—dihydro—1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid. MS ESI (positive) m/z: 564.15 (M+H). 1H NMR (400 MHz, CDCl3) a 8.18 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.29-7.25 (m, 1H), 7.04 (t, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 5.93 (s, 1H), 5.45 (s, 1H), .07 (m, 1H), 3.44-3.37 (m, 2H), .23 (m, 1H), 3.03—2.98 (m, 2H), 2.90-2.80 (m, 2H), 2.76-2.71 (m, 1H), 2.57-2.54 (m, 2H), 2.48-2.32 (m, 4H), 1.84 (d, J = 2.4 Hz, 3H). <Example 2> 18114-111R1Fluoro—4—16—113—methyloxetan — 3— lmethox ridin—3— l—2 3—dih dro—1H—inden—1— lox hen lhex—4— noic acid The title compound was synthesized from (S)—3—(4—(((R)—7—ﬂuoro—4—(6—((3—methyloxetan—3—yl)methoxy)pyridin—3—yl)—2,3—dihydro den—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester h the same procedure as used in Example 1. MS ESI (positive) m/z: 516.15 (M+H). 1H NMR (400 MHz, CDCl3) a 8.21 (d, J = 2.4 Hz, 1H), 7.67-7.65 (m, 1H), 7.33-7.28 (m, 3H), 7.03 (t, J = 8.6 Hz, 1H), 6.97—6.95 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), .93—5.91 (m, 1H), 4.68 (d, J = 5.6 Hz, 2H), 4.47 (d, J = 5.6 Hz, 2H), 4.42 (s, 2H), 4.09—4.08 (m, 1H), 3.28—3.26 (m, 1H), 2.92—2.85 (m, 1H), 2.81—2.65 (m, 2H), 2.39—2.36 (m, 2H), 1.84 (d, J = 2.4 Hz, 3H). <Example 3> 3-dih dro-lH-inden-l- 1 0X hen l heX noic acid The title nd was synthesized from (S)—3—(4—(((R)—4—(6—(2—(1,1—dioxidothiomorpholino)ethoxy)pyridin—3—yl)—7—ﬂuoro—2,3—d ihydro—1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 593.08 (M+H). 1H NMR (400 MHz, CDCl3) a 8.16 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.6, 2.4 Hz, 1H), 7.35-7.26 (m, 3H), 7.08—7.00 (m, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.8 Hz, 1H), 5.92 (t, J = 2.6 Hz, 1H), 4.49 (t, J = 5.4 Hz, 2H), 4.11-4.02 (m, 1H), 3.29-3.15 (m, 5H), 3.15—2.99 (m, 6H), 2.90—2.70 (m, 3H), 2.42-2.35 (m, 2H), 1.84 (d, J = 2.4 Hz, 3H). <Exam le 4> S 4- R Fluoro—4— 6— oxetan—3— lox ridin—3— l 1—2,3—dihydro—1H—inden—1—ylloxy[phenyllhex—4—ynoic acid The title compound was synthesized from (S)—3—(4—(((R)—7—ﬂuoro—4—(6—(oxetan—3—yloxy)pyridin—3—yl)—2,3—dihydro—1H—inden—1—yl) oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in e 1. MS ESI (positive) m/z: 488.12 (M+H). 1H NMR (400 MHz, CDCl3) a 8.12 (s, 1H), 7.67 (d, J = 4.4 Hz, 1H), 7.33-7.24 (m, 3H), 7.01 (t, J = 2.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 4.8 Hz, 1H), 5.92 (t, J = 2.6 Hz, 1H), 5.67 (t, J = 5.4 Hz, 1H), 5.04-5.01 (m, 2H), 4.79-4.76 (m, 2H), 4.09—4.06 (m, 1H), 3.29—3.25 (m, 1H), 2.81-2.79 (m, 1H), 2.78-2.75 (m, 1H), 2.74-2.70 (m, 1H), 2.39-2.35 (m, 2H), 1.84 (s, 3H). <Example 5> 14-111R1Fluoro—4—16—111R1—tetrahydrofuran — 3— l ox ridin—3— l —2 3—dih dro—1H—inden—1— l ox hen l hex—4— noic acid The title nd was synthesized from (S)—3—(4—(((R)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro— 1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 502.24 (M+H). 1H NMR (400 MHz, CDCl3) a 8.15 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 8.6, 2.6 Hz, 1H), 7.38—7.26 (m, 3H), 7.03 (t, J = 8.6 Hz, 1H), 6.98—6.93 (m, 2H), 6.81 (dd, J = 8.4, 0.4 Hz, 1H), 5.95—5.91 (m, 1H), .58 (m, 1H), 4.11—3.89 (m, 5H), 3.29—3.19 (m, 1H), 2.91-2.71 (m, 3H), 2.42-2.15 (m, 4H), 1.84 (d, J = 2.4 Hz, 3H). 4— lox ridin—3— l—2 3—dih dro—1H—inden—1— lox hen lhex—4— noic acid The title compound was synthesized from (S)—3—(4—(((R)—7—ﬂuoro—4—(6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—2,3—dihydro —1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 516.06 (M+H). 1H NMR (400 MHz, CDCl3) a 8.15 (d, J = 2.4 Hz, 1H), 7.63 (dd, J = 8.6, 2.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.29-7.26 (m, 1H), 7.02 (t, J = 8.6 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 1H), 5.92-5.90 (m, 1H), 5.26—5.25 (m, 1H), .02 (m, 1H), 4.00—3.98 (m, 2H), 3.65—3.60 (m, 2H), 3.25—3.21 (m, 1H), 2.86-2.80 (m, 2H), 2.75-2.70 (m, 1H), 2.37-2.34 (m, 2H), .07 (m, 2H), 1.85-1.80 (m, 5H). <Example 7> 1S114-111R1Fluoro—4—16—111S1—tetrahydrofuran — 3— l ox ridin—3— l —2 3—dih dro—1H—inden—1— l ox hen l hex—4— noic acid The title compound was synthesized from (S)—3—(4—(((R)—7—ﬂuoro—4—(6—(((S)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro— 1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure 2017/014757 as used in Example 1. MS ESI (positive) m/z: 502.15 (M+H). 1H NMR (400 MHz, CDCl3) a 8.15 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 8.6, 2.6 Hz, 1H), 7.38—7.26 (m, 3H), 7.03 (t, J = 8.6 Hz, 1H), 6.98—6.93 (m, 2H), 6.81 (dd, J = 8.4, 0.4 Hz, 1H), 5.95—5.91 (m, 1H), 5.61—5.58 (m, 1H), 4.11—3.89 (m, 5H), 3.29—3.19 (m, 1H), 2.91-2.71 (m, 3H), 2.42-2.15 (m, 4H), 1.84 (d, J = 2.4 Hz, 3H). <Example 8> S 4- R Flu0r0 4-meth 1 R -tetrah drofuran 1 0X ridin l -2 3-dih dro-lH-inden-l- 1 0X hen l hex n0ic acid The title compound was sized from (S)—3—(4—(((R)—7—ﬂuoro—4—(4—methyl—6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3 —dihydro—lH—inden—l—yl)oxy)phenyl)hex—4—ynoic acid methyl ester h the same procedure as used in Example 1. MS ESI (positive) m/z: 516.19 (M+H). 1H NMR (400 MHz, CDCl3) a 7.78 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.16-7.12 (m, 1H), 7.01 (t, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H), 5.95 (d, J = 5.6 Hz, 1H), 5.58—5.52 (m, 1H), 4.10—3.84 (m, 5H), 2.88-2.71 (m, 3H), 2.65-2.47 (m, 1H), 2.44-2.22 (m, 3H), 2.20-2.11 (m, 1H), 2.11 (s, 3H), 1.84 (d, J = 2.4 Hz, 3H). <Example 9> S 4- R Flu0r0 2-meth 1 R -tetrah drofuran 1 0X ridin l -2 3-dih dro-lH-inden-l- 1 0X hen l hex n0ic acid The title nd was synthesized from (S)—3—(4—(((R)—7—ﬂuoro—4—(2—methyl—6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3 —dihydro—lH—inden—l—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI ive) m/z: 516.11 (M+H). 1H NMR (400 MHz, CDCl3) a 7.38-7.31 (m, 3H), 7.16-7.10 (m, 1H), .95 (m, 3H), 6.60 (d, J = 8.4 Hz, 1H), 5.94 (d, J = 4.8 Hz, 1H), 5.63—5.58 (m, 1H), 4.16—3.87 (m, 5H), 3.02—2.92 (m, 1H), 2.88-2.69 (m, 2H), 2.65-2.55 (m, 1H), 2.48-2.37 (m, 1H), 2.35—2.13 (m, 6H), 1.84 (d, J = 2.4 Hz, 3H). le 10> S 4- R S-Chlor0 R -tetrah drofuran 1 0X ridin l flu0r0 -2 3-dih dro-lH-inden-l- 1 0X hen l hex n0ic acid The title compound was synthesized from (S)—3—(4—(((R)—4—(5—chloro—6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—7—ﬂuoro—2,3— dihydro—lH—inden— l—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 536.15 (M+H). 1H NMR (400 MHz, CDCl3) a 7.97 (s, 1H), 7.61 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), WO 11012 7.21 (t, J = 8.4 Hz, 1H), 6.93 (t, J = 8.4 Hz, 1H), 6.83 (t, J = 8.4 Hz, 2H), 5.79 (t, J = 4.6 Hz, 1H), .52 (m, 1H), 4.04—3.97 (m, 5H), 3.21—3.16 (m, 1H), 2.88—2.67 (m, 3H), 2.28—2.17 (m, 4H), 1.74 (s, 3H). <Example 11> 1S114-111R1Fluoro—4—15—111R1—tetrahydrofuran — 3— l ox ridin—2— l —2 3—dih dro—1H—inden—1— l ox hen l hex—4— noic acid The title nd was synthesized from (S)—3—(4—(((R)—7—ﬂuoro—4—(5—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—2—yl)—2,3—dihydro— 1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 502.20 (M+H). 1H NMR (400 MHz, CDCl3) o 8.36 (s, 1H), 7.66 (dd, J = 8.6, 2.6 Hz, 1H), 7.46 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 2.0 Hz, 2H), 7.25-7.23 (m, 1H), 7.03 (t, J = 8.6 Hz, 1H), 6.96 (t, J = 2.6 Hz, 2H), 5.92—5.90 (m, 1H), 5.01—4.99 (m, 1H), 4.06—3.93 (m, 5H), 3.61—3.57 (m, 1H), 3.38—3.19 (m, 1H), 2.80-2.77 (m, 1H), .74 (m, 1H), 2.65-2.39 (m, 4H), 1.54 (s, 3H). <Example 12> 1S114-111R1Fluoro—4—14—methyl—6—113—methyloxetan — 3— lmethox ridin—3— l—2 3—dih dro—1H—inden—1— lox hen lhex—4— noic acid The title nd was synthesized from (S)—3—(4—(((R)—7—ﬂuoro—4—(4—methyl—6—((3—methyloxetan—3—yl)methoxy)pyridin—3—yl)—2, 3—dihydro—1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 530.17 (M+H). 1H NMR (400 MHz, CDCl3) o 7.91 (s, 1H), 7.32-7.30 (m, 2H), 7.15-7.12 (m, 1H), 7.02—7.00 (m, 1H), 6.98—6.94 (m, 2H), 6.77 (s, 1H), 5.95—5.93 (m, 1H), 4.68 (d, J = 5.6 Hz, 2H), 4.46 (d, J = 5.6 Hz, 2H), 4.38 (s, 2H), 4.09—4.08 (m, 1H), 3.03—2.90 (m, 1H), 2.78-2.65 (m, 3H), 2.43-2.37 (m, 1H), 2.32-2.27 (m, 1H), 2.10 (s, 3H), 1.83 (d, J = 2.4 Hz, 3H). <Example 13> 1S114-111R1Fluoro—4—12—methyl—6—113—methyloxetan — 3— lmethox ridin—3— l—2 3—dih dro—1H—inden—1— lox hen — noic acid The title compound was synthesized from (S)—3—(4—(((R)—7—ﬂuoro—4—(2—methyl—6—((3—methyloxetan—3—yl)methoxy)pyridin—3—yl)—2, 3—dihydro—1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 530.16 (M+H). 1H NMR (400 MHz, CDCl3) o 7.38-7.29 (m, 3H), 7.16—7.08 (m, 1H), .90 (m, 3H), 6.64 (d, J = 8.4 Hz, 1H), 5.91 (d, J = 5.2 Hz, 1H), 4.69 (d, J = 5.8 Hz, 2H), 4.46 (d, J = 5.8 Hz, 2H), 4.40 (s, 2H), 4.12-4.05 (m, 1H), 2.99-2.88 (m, 1H), 2.85-2.64 (m, 2H), 2.62-2.54 (m, 1H), 2.48-2.31 (m, 1H), 2.29-2.20 (m, 4H), 1.81 (d, J = 2.4 Hz, WO 11012 3H). <Example 14> 18114-111R1Fluoro—4—15—113—methyloxetan — 3— lmethox ridin—2— l—2 3—dih dro—1H—inden—1— lox hen — noic acid The title compound was synthesized from (S)—3—(4—(((R)—7—ﬂuoro—4—(5—((3—methyloxetan—3—yl)methoxy)pyridin—2—yl)—2,3—dihydro —1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 516.13 (M+H). 1H NMR (400 MHz, CDCl3) a 8.45 (d, J = 2.8 Hz, 1H), .60 (m, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.4, 2.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.05 (t, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 5.93-5.90 (m, 1H), 4.58 (dd, J = 58.2, 6.2 Hz, 4H), 4.15 (s, 3H), 4.11-4.02 (m, 1H), 3.37-3.28 (m, 1H), 3.12—3.02 (m, 1H), 2.86—2.69 (m, 2H), 2.44-2.35 (m, 2H), .82 (m, 3H), 1.48 (s, 3H). <Example 15> 1S114-111R1Fluoro—4—15—111R1—tetrahydrofuran — 3— l ox ridin—3— l —2 3—dih dro—1H—inden—1— l ox hen l hex—4— noic acid The title compound was synthesized from (S)—3—(4—(((R)—7—ﬂuoro—4—(5—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro— 1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 502.19 (M+H). 1H NMR (400 MHz, CDCl3) a 8.38-8.15 (br S, 2H), 7.37-7.30 (m, 4H), 7.07 (t, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 5.92 (t, J = 4.0 Hz, 1H), 5.08—4.99 (m, 1H), 4.14—3.98 (m, 4H), 3.97—3.91 (m, 1H), 3.22-3.13 (m, 1H), 2.90-2.71 (m, 3H), .37 (m, 2H), 2.34-2.23 (m, 1H), 2.21-2.15 (m, 1H), 1.84 (d, J = 2.4 Hz, 3H). 4— lox ridin—3— l—2 3—dih dro—1H—inden—1— lox hen lhex—4— noic acid The title compound was sized from (S)—3—(4—(((R)—7—ﬂuoro—4—(5—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—2,3—dihydro —1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 516.16 (M+H). 1H NMR (400 MHz, CDCl3) a 8.30 (d, J = 2.4 Hz, 1H), 8.24 (s, 1H), 7.35-7.30 (m, 3H), 7.05 (t, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 5.92—5.90 (m, 1H), 4.59—4.55 (m, 1H), 4.11-4.06 (m, 1H), 4.02-3.97 (m, 2H), 3.63-3.57 (m, 2H), 3.27—3.19 (m, 1H), 2.89-2.81 (m, 2H), 2.76-2.70 (m, 1H), 2.39-2.34 (m, 2H), 2.08-2.01 (m, 2H), 1.87-1.80 (m, 5H). <Example 17> 0-2 3-dih dro-lH-inden-l- 1 0X hen l heX noic acid The title compound was sized from (S)—3—(4—(((R)—4—(5—chloro—6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—7—fluoro—2, 3—dihydro—1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 550.06 (M+H). 1H NMR (400 MHz, CDCl3) a 8.05 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 4.8 Hz, 2H), 7.30-7.26 (m, 1H), 7.03 (t, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 5.93—5.89 (m, 1H), 5.40—5.32 (m, 1H), 4.10—4.00 (m, 3H), 3.70—3.63 (m, 2H), 3.31-3.20 (m, 1H), 2.91-2.70 (m, 3H), 2.45-2.32 (m, 2H), 2.15—2.06 (m, 2H), .80 (m, 5H). <Example 18> 2 3-dih dro-lH-inden-l- 1 0X hen l hex noic acid The title compound was synthesized from (4—(((R)—4—(5—cyano—6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—7—ﬂuoro—2,3— o—lH—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 527.04 (M+H). 1H NMR (400 MHz, CDCl3) a 8.37 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.30-7.26 (m, 1H), 7.06 (t, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 5.93—5.90 (m, 1H), 5.67—5.63 (m, 1H), 4.17—3.92 (m, 5H), 3.31-3.20 (m, 1H), 2.90-2.71 (m, 3H), 2.45-2.25 (m, 4H), 1.84 (d, J = 2.4 Hz, 3H). <Example 19> -2 3-dih dro-lH-inden-l- 1 0X hen l heX noic acid The title compound was synthesized from (S)—3—(4—(((R)—4—(5—cyano—6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—7—fluoro—2,3 —dihydro—1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 540.93 (M+H). 1H NMR (400 MHz, CDCl3) a 8.36 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), .26 (m, 1H), 7.06 (t, J = 8.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 5.93—5.91 (m, 1H), 5.41—5.39 (m, 1H), 4.08—4.01 (m, 3H), .62 (m, 2H), 3.29-3.21 (m, 1H), 2.88-2.80 (m, 2H), 2.76-2.71 (m, 1H), 2.40-2.37 (m, 2H), 3.13-2.09 (m, 2H), 1.93-1.89 (m, 2H), 1.85 (d, J = 2.4 Hz, 3H). <Example 20> 18114-111R1Cyano—4—16—111R1—tetrahydrofuran — 3— lox ridin—3— l—2 3—dih dro—1H—inden—1— lox hen lhex—4— noic acid The title compound was synthesized from (S)—3—(4—(((R)—5—cyano—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro— 1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 509.12 (M+H). 1H NMR (400 MHz, CDCl3) a 8.19 (d, J = 2.4 Hz, 1H), 7.89-7.64 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 5.79 (t, J = 5.8 Hz, 1H), .60 (m, 1H), 4.10—3.90 (m, 5H), 3.05—2.97 (m, 1H), 2.90—2.53 (m, 4H), 2.35—2.22 (m, 3H), 1.83 (d, J = 2.0 Hz, 3H). <Example 21> 1S114-111R1Fluoro—4—16—111R1—tetrahydrofuran — 3— l ox ridin—3— l —2 3—dih —inden—1— l ox hen l hex—4— noic acid The title compound was synthesized from (S)—3—(4—(((R)—5—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro— 1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 502.22 (M+H). 1H NMR (400 MHz, CDCl3) a 8.14 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.08 (t, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 4.4 Hz, 1H), 5.79 (t, J = 5.8 Hz, 1H), 5.65—5.60 (m, 1H), 4.10—3.90 (m, 5H), 3.05—2.97 (m, 1H), 2.87—2.72 (m, 3H), 2.56-2.53 (m, 1H), 2.35-2.22 (m, 3H), 1.84 (d, J = 2.0 Hz, 3H). <Example 22> 18114-111R1Methoxy—4—16—111R1—tetrahydrofuran — 3— l ox 3— l —2 3—dih dro—1H—inden—1— l ox hen l hex—4— noic acid The title compound was sized from (4—(((R)—5—methoxy—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydr o—1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 514.16 (M+H). 1H NMR (400 MHz, CDCl3) a 8.11 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.4, 2.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.75—5.69 (m, 1H), .57 (m, 1H), 4.12—3.96 (m, 4H), 3.95—3.88 (m, 1H), 3.77 (s, 3H), 3.02-2.92 (m, 1H), 2.85-2.67 (m, 3H), 2.51-2.42 (m, 1H), 2.35-2.24 (m, 1H), 2.20-2.15 (m, 2H), 1.84 (d, J = 2.4 Hz, 3H). 4— lox ridin—3— l—2 3—dih dro—1H—inden—1— lox hen lhex—4— noic acid The title compound was synthesized from (S)—3—(4—(((R)—5—cyano—4—(6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—2,3—dihydro —1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 523.09 (M+H). 1H NMR (400 MHz, CDCl3) a 8.16 (d, J = 2 Hz, 1H), .65 (m, 2H), 7.02 (t, J = 8.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.6 Hz, 1H), .77 (m, 1H), 5.33—5.26 (m, 1H), 4.10—4.06 (m, 1H), 4.03—3.98 (m, 2H), .60 (m, 2H), 3.02—2.95 (m, 1H), 2.88—2.81 (m, 2H), 2.76-2.70 (m. 1H), 2.62-2.54 (m, 1H), 2.23-2.15 (m, 1H), 2.12-2.08 (m, 2H), 1.88—1.79 (m, 5H). 4— lox ridin—3— l—2 3—dih —inden—1— lox hen lhex—4— noic acid The title compound was synthesized from (S)—3—(4—(((R)—5—ﬂuoro—4—(6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—2,3—dihydro —1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 516.17 (M+H). 1H NMR (400 MHz, CDCl3) a 8.12 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.06 (t, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 4.4 Hz, 1H), 5.68 (t, J = 5.8 Hz, 1H), 5.33—5.26 (m, 1H), 4.08—3.96 (m, 3H), 3.65—3.60 (m, 2H), 3.02—2.95 (m, 1H), 2.86-2.79 (m, 2H), 2.74-2.69 (m. 1H), 2.59-2.53 (m, 1H), 2.21-2.16 (m, 1H), 2.11-2.06 (m, 2H), 1.84-1.75 (m, 5H). 4— lox ridin—3— l—2 3—dih dro—1H—inden—1— lox hen — noic acid The title compound was synthesized from (S)—3—(4—(((R)—5—methoxy—4—(6—((tetrahydro—2H—pyran—4—yl)oxy)pyridin—3—yl)—2,3—dihyd ro—1H—inden—1—yl)oxy)phenyl)hex—4—ynoic acid methyl ester through the same procedure as used in Example 1. MS ESI (positive) m/z: 528.16 (M+H). 1H NMR (400 MHz, CDCl3) a 8.10 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 8.4, 2.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 5.75—5.59 (m, 1H), .20 (m, 1H), 4.11—3.98 (m, 3H), 3.76 (s, 3H), 3.68—3.61 (m, 2H), 3.11-2.92 (m, 1H), 2.79-2.62 (m, 3H), 2.50-2.40 (m, 1H), 2.23-2.11 (m, 3H), 1.88-1.78 (m, 5H). <Example 26> 1S114-111R1Fluoro—4—16—111R1—tetrahydrofuran — 3— lox ridin—3— l—2 3—dih dro—1H—inden—1— lamino hen lhex—4— noic acid ~40 no \_ \ l i / O\ / ‘ o 731/O\ if If? of F A / F >40H ————-—b- I\ <“""'<3J:N’/~11 ]\ Os x ——-—> \ —-—-¢> \ ”N3 0‘ x NHQ {Q‘b | L] 1 N5 Q U o N’ Step 1: (S)(4-(((Triﬂuoromethyl)sulfonyl)oxy)phenyl)hex—4—ynoate methyl ester Triﬂuoromethanesulfonic anhydride (1.2 eq.) was added to a solution of tri— mine (3.0 eq.) and (3S)—3—(4—Hydroxy—phenyl)—hex—4—ynoic acid methyl ester (1.0 eq.) in romethane (3.5 M). The on mixture was stirred at room tem— perature for 18 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over magnesium e, filtered and concentrated. The resultant residue was purified by flash column chromatography on silica gel to afford (4—(((triﬂuoromethyl)sulfonyl)oxy)phenyl)hex—4—ynoate methyl ester.

Step 2: 5—((R)— l —Azido—7—fluoro—2,3—dihydro— lH—inden—4—yl )—2—(((R)—tetrahydrofuran—3—yl)oxy)pyridine ylphosphoryl azide (l.l eq.) was added to a solution of (S)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro— lH—inden—l —01 (1.0 eq.) and l,8—diazabicyclo(5.4.0)undec—7—ene (1.6 eq.) in toluene (0.2 M) at 4 OC. The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over magnesium sulfate, filtered and concentrated. The resultant residue was purified by flash column chro— matography on silica gel to afford —((R)— l—azido—7—ﬂuoro—2,3—dihydro— lH—inden—4—yl)—2—(((R)—tetrahydrofuran—3—yl)oxy) pyridine.

Step 3: (R)Fluoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl )—2,3—dihydro— lH—inden— l—amine 5—((R)— l —Azido—7—fluoro—2,3—dihydro— lH—inden—4—yl)—2—(((R)—tetrahydrofuran—3—yl)ox y)pyridine (1.0 eq.) was added to a suspension of 10% palladium / charcoal (0.6 eq.) in l (0.1 M). The mixture was stirred at room temperature for 2 h under H2 at— mosphere. The on mixture is filtered through Celite and concentrated. No further purification was needed to afford (R)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro—lH—inden— l — amine.

Step 4: (S)(4-(((R)Fluoro—4—(6—(((R)—tetrahydrofuran — 3—yl)oxy)pyridin—3—yl)—2,3—dihydro— lH—inden— l—yl)amino)phenyl)hex—4—ynoic acid methyl ester Tris(dibenzylideneacetone)dipalladium(0)(0.05 eq.) was added to a solution of (R)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro—lH—inden— l—amine (l.0 eq.), (S)—3—(4—(((triﬂuoromethyl)sulfonyl)oxy)phenyl)hex—4—ynoate methyl ester (12 eq.), 2—dicyclohexylphosphino—2',4",6'—triisopropylbiphenyl (0.2 eq.), and sodium utoxide (2.5 eq.) in l,4—dioxane (0.1 M). The on e was stirred at room temperature for 18 h. Then the mixture was reacted under microwave irradiation for l h. The reaction mixture was diluted with ethyl acetate and washed with water. The c layer was washed with brine and dried over magnesium sulfate, filtered and concentrated. The resultant residue was purified by flash column chromatography on silica gel to afford (S)—3—(4—(((R)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro— lH—inden— l—yl)amino)phenyl)hex—4—ynoic acid methyl ester.

Step 5: (S)(4-(((R)Fluoro—4—(6—(((R)—tetrahydrofuran — xy)pyridin—3—yl)—2,3—dihydro— lH—inden— l—yl)amino)phenyl)hex—4—ynoic acid 2.0 M aqueous lithium hydroxide solution (5.0 eq.) was added to a solution of (S)—3—(4—(((R)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro— lH—inden—l—yl)amino)phenyl)hex—4—ynoic acid methyl ester (10 eq.) in tetrahydrofuran (1.0 M) and methanol (4.0 M) at 4 OC. The reaction mixture was stirred at room tem— perature for 18 h. The mixture was neutralized with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The organic layer was washed with brine, dried over ium sulfate, filtered, and concentrated. The ant residue was purified by ﬂash column chromatography on silica gel to afford (S)—3—(4—(((R)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro— 1H—inden—1—yl)amino)phenyl)hex—4—ynoic acid. MS ESI (postive) m/z: 501.15 (M+H). 1H NMR (400 MHz, MeOD) a 8.21 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.8, 2.4 Hz, 1H), 7.34-7.28 (m, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.04 (t, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.4 Hz, 2H), 5.61-5.57 (m, 1H), 5.21-5.18 (m, 1H), 4.64 (br s, 1H), 4.09—3.89 (m, 5H), 3.29—3.20 (m, 1H), 2.91-2.82 (m, 1H), 2.67-2.60 (m, 2H), 2.40-2.28 (m, 2H), 2.22-2.12 (m, 2H), 1.83 (d, J = 2.4 Hz, 3H). <Exam le 27> 3- 6- R Fluoro—4— 6— R —tetrah drofuran — 3— l ox ridin—3— l —2 3—dih dro—1H—inden—1— l ox ridin—3— l hex—4— noic acid Step 1: 3—(6-(((R)—7—Fluoro—4—(6—(((R)—tetrahydrofuran — 3—yl)oxy)pyridin—3—yl)—2,3—dihydro—1H—inden—1—yl)oxy)pyridin—3—yl)hex—4—ynoic acid ethyl ester Azodicarbonyl)dipiperidine (1.5 eq.) was added portionwise over 10 min to a solution of (S)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro— en— 1 —ol (1.0 eq.), 3—(6—hydroxypyridin—3—yl)hex—4—ynoic acid ethyl ester (1.0 eq.), and tri— n—butylphosphine (1.5 eq.) in toluene (0.1 M) at 4 OC. The reaction e was d at room temperature for 18 h. After addition of hexane (0.05 M) to the reaction mixture, the resulted white solid was removed by filtration. The filtrate was con— centrated and then purified by flash column chromatography on silica gel to afford 3—(6—(((R)—7—fluoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro— 1H—i nden—1—yl)oxy)pyridin—3—yl)hex—4—ynoic acid methyl ester.

Step 2: 3—(6—(((R)—7—Fluoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin — 2,3—dihydro—1H—inden—1—yl)oxy)pyridin—3—yl)hex—4—ynoic acid 2.0 M aqueous lithium hydroxide solution (5.0 eq.) was added to a solution of 3—(6—(((R)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro—1H—i nden—1—yl)oxy)pyridin—3—yl)hex—4—ynoic acid methyl ester (1.0 eq.) in tetrahydrofuran (1.0 M) and methanol (4.0 M) at 4 OC. The reaction mixture was stirred at room tem— perature for 18 h. The mixture was neutralized with saturated aqueous ammonium chloride on and diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The ant residue was purified by ﬂash column chromatography on silica gel to afford 3—(6—(((R)—7—ﬂuoro—4—(6—(((R)—tetrahydrofuran—3—yl)oxy)pyridin—3—yl)—2,3—dihydro—1H—i nden—1—yl)oxy)pyridin—3—yl)hex—4—ynoic acid. MS ESI (postive) m/z: 503.94 (M+H). 1H NMR (400 MHz, CDCl3) a 8.16 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.6 Hz, 1H), 7.57-7.54 (m, 2H), 7.27-7.25 (m, 1H), 6.94 (t, J = 8.6 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 6.63 (d, J = 2.4, 0.4 Hz, 1H), 6.58—6.54 (m, 1H), 5.52—5.51 (m, 1H), 4.06—3.85 (m, 5H), 3.29—3.19 (m, 1H), 2.79-2.71 (m, 2H), 2.68-2.65( m, 1H), 2.42-2.32 (m, 1H), 2.29—2.08 (m, 3H), 1.97 (d, J = 2.4 Hz, 3H). <C0mparative Example 1> -2 3-dih dro-l-benzofuran l acetic acid N.“CR.

O//\\O [(3S)—6—{(2',6'—Dimethyl—4'—[3—(methylsulfonyl)propoxy]—[1,1'—biphenyl]—3—yl)}metho xy)—2,3—dihydro—1—benzofuran—3—yl]acetic acid was sized based on the reference patent application No.2008—00193 l. [in vitro Evaluation] <in vitm Assay l> Cell—based Aequorin Assay Recombinant cells grown 18 h prior to the test in media without antibiotics were detached by gentle ﬂushing with PBS—EDTA (5 mM EDTA), recovered by cen— trifugation and resuspended in "assay buffer" (DMEM/HAM's Fl2 with HEPES + 0.1% BSA fatty—acid free). Cells were incubated at room ature for at least 4 h with Coelenterazine (Molecular Probes). Dose response curves with the reference compounds were performed before testing the nds.

For agonistic activity testing, 50 ul of cell sion was injected on 96—well plates with plated 50 ul of test compounds or reference agonist. The ing emission of light was recorded using the Hamamatsu onal Drug Screening System 6000 (FDSS 6000).

To standardize the emission of recorded light mination of the " 100% signal") across plates and across different experiments, some of the wells contained the reference agonist at its ECIOO obtained during the test validation. Agonistic activities of test compounds were expressed as a percentage of the activity of the reference agonist at its ECIOO concentration.

[Table 1] Example No. Agonistic activity(%, 1 uM) Comparative Example 1 Agonistic activities of compounds in the present invention are shown in Table 1. (+++ : over 70, ++ : 40 — 70, + : under 40) As shown in Table 1, the example compounds of the present invention were med to be excellent in activating GRP40 at 1 uM concentration. In particular, majority of the compounds exhibited more ed ties compared to the 'Com— parative Example 1' which has been known to promote insulin secretion through the tion of GPR40.

Industrial Applicability The compounds of the present invention, as GPR40 agonists, are orally available and are extremely ive in lowering blood glucose level to normal state without any risk of inducing ycemia via glucose—dependent insulin secretion. ore, compounds and/or therapeutically effective pharmaceutical composition comprising the compounds of the present invention are useful in the treatment, delaying, and/or re— gression of symptoms of type 2 diabetes.

In addition, compounds of the present invention modulate glucose excursion via GPR40 activation; the therapeutic effect can also be potentially available in obesity and hypertension.

In addition, since the compounds of the present ion have shown ed and/ or enhanced therapeutic s of alleviating and/or treating symptoms of type 2 diabetes compared to pre—existing medications when evaluated of glucose—lowering effects of the compounds on animal models and/or human—organ derived materials, the compounds can be evaluated as being highly useful to potential beneficiaries of the present invention. 【

Claims

CLAIMS 】【Claim 1】 A compound represented by: (S)(4-(((R)fluoro(6-(((R)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)fluoro(6-((tetrahydro-2H-pyranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)fluoro(6-(((S)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)(5-chloro((tetrahydro-2H-pyranyl)oxy)pyridinyl)fluoro- hydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)(5-cyano(((R)-tetrahydrofuranyl)oxy)pyridinyl)fluoro- 2,3-dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)(5-cyano((tetrahydro-2H-pyranyl)oxy)pyridinyl)fluoro- 2,3-dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)cyano(6-(((R)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)fluoro(6-(((R)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; or (S)(4-(((R)fluoro(6-((tetrahydro-2H-pyranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid, or a racemate of the compound, an enantiomer of the compound, a diastereomer of the compound, or a pharmaceutically acceptable salt of the nd, the racemate, the enantiomer, or the diastereomer. 【Claim 2】 A pharmaceutical composition for the tion or treatment of metabolic disorder, comprising the compound, the racemate, the enantiomer, the reomer, or the pharmaceutically acceptable salt according to claim 1. 【Claim 3】 The pharmaceutical ition according to claim 2, further comprising a pharmaceutically acceptable excipient. 【Claim 4】 The ceutical composition according to claim 2, wherein the metabolic disorder is selected from the group consisting of obesity, type 2 diabetes, incompatible glucose tolerance, insulin resistance, hyperglycemia, ipidemia, hypertriglyceridemia and hypercholesterolemia. 【Claim 5】 A method for prevention or treatment of metabolic disorder, comprising: stering to a non-human subject a pharmaceutical composition comprising a compound represented by: (4-(((R)fluoro(6-(((R)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)fluoro(6-((tetrahydro-2H-pyranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)fluoro(6-(((S)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)(5-chloro((tetrahydro-2H-pyranyl)oxy)pyridinyl)fluoro- 2,3-dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)(5-cyano(((R)-tetrahydrofuranyl)oxy)pyridinyl)fluoro- 2,3-dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)(5-cyano((tetrahydro-2H-pyranyl)oxy)pyridinyl)fluoro- 2,3-dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)cyano(6-(((R)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)fluoro(6-(((R)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; or (4-(((R)fluoro(6-((tetrahydro-2H-pyranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid, or a racemate of the compound, an enantiomer of the compound, a diastereomer of the compound, or a pharmaceutically acceptable salt of the compound, the racemate, the omer, or the diastereomer. 【Claim 6】 Use of a compound represented by: (S)(4-(((R)fluoro(6-(((R)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)fluoro(6-((tetrahydro-2H-pyranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)fluoro(6-(((S)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)(5-chloro((tetrahydro-2H-pyranyl)oxy)pyridinyl)fluoro- 2,3-dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)(5-cyano(((R)-tetrahydrofuranyl)oxy)pyridinyl)fluoro- 2,3-dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)(5-cyano((tetrahydro-2H-pyranyl)oxy)pyridinyl)fluoro- 2,3-dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)cyano(6-(((R)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- o-1H-indenyl)oxy)phenyl)hexynoic acid; (S)(4-(((R)fluoro(6-(((R)-tetrahydrofuranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid; or (S)(4-(((R)fluoro(6-((tetrahydro-2H-pyranyl)oxy)pyridinyl)-2,3- dihydro-1H-indenyl)oxy)phenyl)hexynoic acid, or a racemate of the compound, an enantiomer of the compound, a diastereomer of the compound, or a pharmaceutically acceptable salt of the compound, the racemate, the enantiomer, or the diastereomer for the manufacture of a medicament for the prevention or ent of metabolic disorder.