TW201307312A - Indanyloxydihydrobenzofuranylacetic acids - Google Patents

Abstract

The present invention relates to compounds defined by formula (I) wherein the variables R1, R2, R3, m, and n are defined as in claim 1, possessing valuable pharmacological activity. Particularly, the compounds are activators of the receptor GPR40 and thus are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.

Description

Dihydrofurfuryloxydihydrobenzofuranacetic acid

The present invention relates to novel indanyloxy dihydrobenzofuran acetic acid, which is an agonist of G protein coupled receptor 40 (GPR40, also known as free fatty acid receptor FFAR 1); a preparation method thereof; Pharmaceutical compositions of such compounds; and their use for the prevention and/or treatment of diseases which may be affected by the function of GPR40. In particular, the pharmaceutical compositions of the present invention are useful for the prevention and/or treatment of metabolic diseases such as diabetes, more specifically type 2 diabetes, and conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease. And dyslipidemia.

A metabolic disease is a disease caused by an abnormal metabolic process and may be a congenital disease caused by an abnormality of an inherited enzyme or a disease caused by a disease of an endocrine organ or an important metabolic organ such as liver or pancreas.

Diabetes is a disease condition or process that is derived from multiple etiological factors and is defined as chronic hyperglycemia associated with organ damage and dysfunction of metabolic processes. Several forms of diabetes due to absolute insulin deficiency (lack or reduction of insulin secretion) or relative deficiency can be distinguished based on the etiology of diabetes. Type 1 diabetes (IDDM, insulin-dependent diabetes) usually occurs in adolescents under the age of 20. It is assumed to have autoimmune etiology, leading to insulitis and subsequent destruction of beta cells of the islets of Langerhans responsible for insulin synthesis. In addition, in occult autoimmune diabetes in adults (LADA; Diabetes Care. 8: 1460-1467, 2001), beta cells are destroyed by autoimmune attack. Residual islet cells The amount of insulin produced is too low, causing an increase in blood sugar levels (hyperglycemia). Type II diabetes usually occurs at an older age. It is particularly associated with insulin resistance in the liver and skeletal muscle and is also associated with Langerhans island defects. Hyperglycemia (and high blood lipid levels) in turn leads to beta cell dysfunction and increased apoptosis of beta cells.

Persistent or inappropriately controlled hyperglycemia is associated with multiple pathologies. Diabetes is a disease that can cause disability, because today's common anti-diabetic drugs do not adequately control blood sugar levels to completely prevent high and low blood sugar levels. Out-of-range blood glucose levels are toxic and can cause long-term complications such as retinopathy, nephropathy, neuropathy, and peripheral vascular disease. Individuals with diabetes also have a substantial risk of multiple related conditions such as obesity, hypertension, stroke, heart disease and hyperlipidemia.

Obesity is associated with increased risk and increased mortality from secondary diseases such as cardiovascular disease, hypertension, diabetes, hyperlipidemia. Diabetes (insulin resistance) and obesity are part of the "metabolic syndrome", and metabolic syndrome is defined as the association between several diseases (also known as syndrome X, insulin resistance syndrome or deadly quartet). These diseases often occur in the same patient and are a major risk factor for the development of type 2 diabetes and cardiovascular disease. It has been shown that it is desirable to control lipid content and glucose content for the treatment of type 2 diabetes, heart disease and other metabolic syndromes that occur (see, for example, Diabetes 48: 1836-1841, 1999; JAMA 288: 2209-2716, 2002).

The free fatty acid receptor GPR40 (also known as FFAR, FFAR1 or FFA1) is a member of the gene superfamily of cell surface receptors and G protein coupled receptors. Based on the presumptive presence of seven putative transmembrane regions in the corresponding proteins, they are first identified as so-called orphan receptors, ie, receptors without known ligands (Sawzdargo et al., (1997) Biochem. Biophys. Res. Commun. 239: 543-547). GPR40 was found to be highly expressed in several specific cell types: pancreatic beta cells and secretory insulin cell lines as well as enteroendocrine cells, taste cells, and it has been reported to be expressed in immune cells, spleen cells, and human and monkey brains. At the same time, it is believed that the fatty acids with different chain lengths represent the endogenous ligands of GPR40, and their activation is mainly related to the regulation of the Gq family of intracellular signaling G proteins and the accompanying induction of increased calcium content, but it has also been reported that activated Gs And Gi protein can regulate the intracellular content of cAMP. GPR40 is especially activated by long chain FFA, in particular oleate, and the PPAR-gamma agonist rosiglitazone.

It is understood that fatty acids, which are activators of GPR40, enhance insulin secretion induced by high plasma glucose via the GPR40 receptor expressed in insulin-secreting cells (Itoh et al., (2003) Nature 422: 173-176; Briscoe et al. (2003) J. Biol. Chem. 278: 11303-11311; Kotarsky et al. (2003) Biochem. Biophys. Res. Commun. 301: 406-410). Despite the initial debate, the use of GPR40 agonists appears to be suitable for increasing insulin release to treat diabetes (see, eg, Diabetes 2008, 57, 2211; J. Med. Chem. 2007, 50, 2807). In general, long-term diabetes treatment leads to a gradual decrease in islet activity, so after long-term treatment, patients with type 2 diabetes need to switch to insulin injections every day. The GPR40 agonist has the potential to restore or preserve islet function, so the GPR40 agonist is also beneficial in that it can delay or prevent 2 Decreased and lost islet function in patients with type 2 diabetes.

It has been well established that incretin GLP-1 (glycin-like peptide-1) and GIP (glucose-dependent insulinotropic peptide; also known as gastric inhibitory peptide) stimulate insulin secretion and are DPP-4 in vivo. Quickly inactivated. These peptidyl hormones are secreted by endocrine cells located in epithelial cells of the small intestine. When these endocrine cells sense an increase in the concentration of glucose in the lumen of the digestive tract, they act as triggers for incretin release. Incretin is delivered to the beta cells of the pancreas via circulation and causes the beta cells to secrete more insulin before the digestive diet causes an increase in blood glucose. Other studies suggesting that GPR40 regulates the release of incretins (including CCK, GLP-1, GIP, PYY, and other cells that may be present) by enteroendocrine cells suggest that GPR40 modulators may also indirectly enhance insulin release from pancreatic beta cells. For example, the synergistic effect of GLP-1 and possibly GIP on insulin release, and other release of incretin may also contribute to the overall beneficial effects of GPR40 modulation on metabolic diseases. The synergistic effect of GPR40 modulation on insulin release via plasma incretin levels can be further enhanced by co-administration of an enzyme inhibitor that causes incretin degradation, such as an inhibitor of DPP-4.

Insulin imbalance leads to conditions such as type 2 diabetes, a severe metabolic disease. Modulation of GPR40 function in regulating insulin secretion A therapeutic agent capable of modulating GPR40 function is useful for treating conditions such as diabetes and conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease, and dyslipidemia.

Purpose of the invention

Based on the problem of the present invention to provide an effective and selective GPR40 agonist (Described below as a compound of formula (I)) for the prevention and/or treatment of metabolic diseases such as diabetes, more specifically type 2 diabetes, and conditions associated with the disease, including insulin resistance, obesity Disease, cardiovascular disease and dyslipidemia, and its continuous complications and conditions.

GPR40 modulators are known in the art, for example, the compounds disclosed in WO 2004041266 (EP 1559422), WO 2007033002 and WO 2009157418. The dihydrofurfuryloxydihydrobenzofuran acetic acid of the present invention provides several advantages such as potency, high metabolism and/or chemical stability, high selectivity and tolerance, strong solubility, and formation of stable salts. .

In one aspect, the invention provides a compound of formula (I) as defined below: Its isoforms, tautomers, stereoisomers, solvates, hydrates and salts, in particular, physiologically acceptable salts thereof with inorganic or organic acids or bases, or combinations thereof.

The invention further provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

The invention further provides a method of treating and/or preventing a disease responsive to modulation of GPR40 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

The invention further provides a treatment and/or prevention adapted from the following Disease: a disease associated with the regulation of metabolic disorders, such as carbohydrate metabolism and its continuous complications or lipid metabolism (ie, lipid disorders) and its continuous complications, the method comprising administering to a patient in need of treatment a therapeutically effective amount a compound of formula (I).

The invention further provides a method for treating and/or preventing an indication selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension , hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X3 cardiovascular disease, atherosclerosis, nephropathy, ketoacidosis, thrombotic disorder, nephropathy, diabetes Neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, hypoglycemia, cancer or edema, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

In some embodiments, a compound of formula I is administered in combination with other therapeutic agents. In some such embodiments, the other therapeutic agent is metformin and/or is a PPAR agonist (ie, a thiazolidinedione such as pioglitazone), and/or is glinide, And/or a DPP-IV inhibitor (ie, linagliptin), and/or a SGLT2-inhibitor, and/or a GLP-1 receptor agonist (ie, a GLP-1 analog) Or a mimetic (ie, glutide), and/or an insulin or insulin analog, and/or an 11β-HSD1 inhibitor, and/or a glucokinase activator, and/or GPR119 An agonist. Other therapeutic agents can be administered prior to administration of the compound of formula I, Cast during or after.

The invention further provides a compound of formula (I) as described herein for use in a therapeutic method for treating a human or animal body.

The invention further provides a compound of formula (I) for use in the treatment and/or prevention of a disease responsive to modulation of GPR40.

The invention further provides a compound of formula (I) for use in therapy and/or prevention selected from the group consisting of modulating metabolic disorders, such as carbohydrate metabolism and its continuous complications or lipid metabolism (ie, lipid disorders) and its associated complications. Indications for the disease.

The invention further provides a compound of formula (I) for use in the treatment and/or prevention of an indication selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, Hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X3 cardiovascular disease, atherosclerosis, nephropathy, ketoacidosis, thrombosis Sexual disorders, kidney disease, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, hypoglycemia, cancer or edema.

The invention further provides the use of a compound of formula (I) for the preparation of a pharmaceutical composition for the treatment and/or prevention of a disease responsive to GPR40 modulation.

The invention further provides the use of a compound of formula (I) for the preparation and/or prevention of a selected and modulated metabolic disorder, such as carbohydrate metabolism and its continuous complications or lipid metabolism (ie, lipid imbalance) and A pharmaceutical composition for indications of diseases associated with continuous complications.

The invention further provides the use of a compound of formula (I) for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of an indication selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, Insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X3 cardiovascular disease, atherosclerosis Hardening, kidney disease, ketoacidosis, thrombotic disorder, kidney disease, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, hypoglycemia, cancer or edema.

In another aspect, the invention provides a therapeutic composition comprising a compound of formula (I) and (a) another therapeutic agent, such as a therapeutic agent described herein, such as metformin and/or thiazolidinedione / or glinide and / or DPP-IV inhibitors (such as linagliptin) and / or SGLT2-inhibitors (such as dapagliflozin or 1-chloro-4- (β-D-glucopyranose - 1-yl)-2-{4-[( S )-tetrahydrofuran-3-yloxy]-benzyl}-benzene) and/or PPAR agonist (eg pioglitazone) and/or GLP-1 receptor An agent (ie, a GLP-1 analog or mimetic (eg, glute)) and/or an insulin or insulin analog and/or an 11β-HSD1 inhibitor and/or a glucokinase activator and/or a GPR119 agonist The composition is in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by GPR40. In some such embodiments, the disease or condition is type II diabetes. In some embodiments, the compound of formula (I) and the second therapeutic agent are provided as a single composition, while in other embodiments, they are provided separately as a dispensing portion of the kit.

The invention provides in its broadest/first embodiment E-0 compounds of formula (I): Wherein: R ¹ is selected from the group consisting of H, F, Cl, Br, I, C _1-8 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl , C _3-12 cycloalkyl-C _1-4 alkyl, C _5-12 bicycloalkyl-, C _5-12 bicycloalkyl-C _1-6 alkyl-, C _5-6 cycloalkenyl, C _{5-6cycloalkenyl} -C _1-4 alkyl, C _1-8 alkoxy, C _3-6 cycloalkyl-oxy and C _3-6 cycloalkyl-C _1-4 alkoxy, wherein Any such group is optionally substituted with 1 to 3 fluorine atoms and/or 1 to 3 R ⁴ groups, C _3-12 heterocyclic group, C _3-12 heterocyclic group-C _{1- 4-} alkyl, bicyclic heterocyclyl-, bicyclic heterocyclyl-C _1-6 alkyl-, heterocyclyl-C _1-4 alkyl-oxy and C _3-12 heterocyclyloxy, any of These groups are optionally substituted with 1 to 3 R ⁴ groups, aryl, aryl-C _1-4 alkyl, aryl-C _1-4 alkyl-oxy, aryloxy, Heteroaryl, heteroaryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl-oxy and heteroaryloxy, any of which groups optionally, from 1 to 5 Substituted R ⁵ groups, C _1-4 alkyl-thio, C _1-4 alkyl-sulfinyl and C _1-4 alkyl-sulfonyl, any of which may optionally be 1 to 3 Atom, and cyano, nitro, amino, C _1-4 alkylamino and two (C _1-4 alkyl) - group; wherein the heterocyclic group and the sub-portion may be partially unsaturated and containing 1 Up to 3 heteroatoms or groups selected from N, NR ^N , O and S, with the proviso that at most two of the heteroatoms are O and S, and no OO, SS and SO bonds are formed, but are bonded to the hetero The methylene group of the atom may be replaced by a carbonyl group, and the heterocyclic groups are bonded to the respective residues via a carbon or nitrogen atom; R ^N represents H, C _1-4 alkyl-, C _1-4 alkyl-C ( O)- or C _1-4 alkyl-OC(O)-, wherein the aforementioned bicyclic heterocyclic group and sub-portion are partially unsaturated and comprise 6 to 12 ring members and 1 to 3 are selected from N, NR ^N , The heteroatoms or groups of O and S are limited such that at most two of the heteroatoms are O and S and no OO, SS and SO bonds are formed, and the methylene group bonded to the hetero atom can be replaced by a carbonyl group. The heterocyclic group is bonded to each residue via a carbon or nitrogen atom; R ^N represents H, C _1-4 alkyl-, C _1-4 alkyl-C(O)- or C _1-4 alkyl-OC (O)-, wherein the aforementioned bicycloalkyl and bicyclic heterocyclic groups and sub-portions comprise a fused, bridged and spiro ring system, wherein the aforementioned aryl group and The moiety comprises 6 to 10 carbon atoms, wherein in the bicyclic aromatic group, the ring which is not attached to the respective residue may be partially saturated, and wherein the aforementioned heteroaryl group and the sub-portion are composed of 5 to 14 atoms, and 1 to 1 3 heteroatoms selected from N, O or S(O) _r , wherein r=0, 1 or 2, wherein in the polycyclic heteroaromatic group, the ring not attached to the respective residue may be partially or completely Saturated, and at least one aromatic ring comprises one or more heteroatoms, and R ² is selected from the group consisting of F, Cl, Br, I, cyano, C _1-4 alkyl, C _3-6 cycloalkyl And a C _1-4 alkoxy group, wherein any alkyl group and cycloalkyl group or sub-portion are optionally substituted with 1 to 3 fluorine atoms, and R ³ is selected from the group consisting of F, Cl, Br, I, C _1-4 alkyl and C _1-4 alkoxy, wherein any alkyl or sub-portion is optionally substituted with 1 to 3 fluorine atoms, and R ⁴ is selected from the group consisting of F, Cl, Br, I, cyano, C _1-4 alkyl, hydroxy, hydroxy-C _1-4 alkyl, C _1-4 alkyl-oxy, C _1-4 alkoxy-C _1-4 alkyl, C _{1 -4} alkyl - thio, C _1-4 alkyl - sulfinyl group, C _1-4 alkyl - acyl sulfo, C _3-6 cycloalkyl -, C _3-6 cycloalkyl - oxo -, wherein any of the alkyl and cycloalkyl groups or portions optionally sub to 3 fluorine atoms substituted with 1, and R ⁵ selected from the group consisting of lines consisting of the group: F, Cl, Br, I , cyano, nitro, Amino, C _1-4 alkyl-amino, di(C _1-4 alkyl)-amino, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 -alkynyl, hydroxy, Hydroxy-C _1-4 alkyl, C _1-4 alkyl-oxy, C _1-4 alkoxy-C _1-4 alkyl, C _1-4 alkyl-thio, C _1-4 alkyl - sulfinyl, C _1-4 alkyl-sulfonyl, C _3-6 cycloalkyl-, C _3-6 cycloalkyl-oxy, any alkyl and cycloalkyl or sub-portion The case is substituted with 1 to 5 fluorine atoms, preferably 1 to 3 fluorine atoms, and m is selected from the numbers 0, 1, 2 and 3, preferably selected from the numbers 0, 1 and 2, or more preferably selected from the number 0. And 1, however, the number 0 is optimal, and n is selected from the numbers 0, 1, 2, and 3, preferably selected from the numbers 0 and 1, but the number 0 is optimal, wherein in any of the definitions mentioned above and Unless otherwise specified, any alkyl moiety referred to in this application may be a straight or branched alkyl group, isoforms, tautomers, stereoisomers, metabolites, prodrugs, Solvate, hydrate The physiologically formed thereon with an inorganic or organic acid or base salts acceptable salt thereof, certain words, or combinations thereof.

Terms and definitions

Terms not specifically defined herein should be given to those skilled in the art in light of the present invention and context. However, as used in this specification, the following terms have the meanings specified and the following conventions will be followed unless stated to the contrary.

In the group, radical or moiety defined below, the number of carbon atoms is usually indicated before the group, for example, C _1-6 alkyl means an alkyl group having 1 to 6 carbon atoms (alkyl) Group) or alkyl radical. In general, for a group containing two or more subgroups, the last named subgroup is a group attachment point, for example the substituent "aryl-C _1-3 alkyl-" means aryl linkage. To a C _1-3 alkyl group, the C _1-3 alkyl group is bonded to the core or group of the linking substituent.

In general, unless otherwise indicated, the point of attachment of a specified residue to another group should be variable, ie any atom having a hydrogen that can be displaced within the residue can be the point of attachment to the group. .

Unless otherwise specified, the specified chemical formula or name shall cover all conceivable structural isomers throughout the specification and accompanying claims. And stereoisomers, including tautomers, enantiomers, diastereomers, cis/trans isomers, E/Z isomers, and the like, and mixtures thereof, such as enantiomers a 1:1 mixture of constructs (referred to as a racemate), a mixture of individual enantiomers in different ratios, a mixture of diastereomers or a mixture of any of the above, wherein such The constructs and salts, including pharmaceutically acceptable salts thereof and solvates thereof (such as hydrates), include solvates of the free compounds or solvates of the salts of the compounds.

The phrase "pharmaceutically acceptable" is used herein to mean that it is suitable for contact with human and animal tissues without reasonable toxicity, irritation, allergic reactions or other problems or complications within reasonable medical judgment. The compounds/substances, compositions and/or dosage forms that match the benefit/risk ratio.

The term "partially unsaturated" as used herein means that there are 1, 2 or more, preferably 1 or 2 double bonds in a given group or moiety. As used herein, the term "partially unsaturated" preferably does not encompass fully unsaturated groups or moieties.

The term halogen means an atom selected from the group consisting of F, Cl, Br and I.

The term C _1-nalkyl denotes a saturated or unbranched chain hydrocarbon group having 1 to n C atoms, wherein n has a value of 1 to 18. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, The third amyl group, n-hexyl group, isohexyl group and the like.

The term "C1 _- nalkylene", alone or in combination with another group, denotes an acyclic straight or branched chain divalent alkyl group containing from 1 to n carbon atoms, wherein n is an integer from 1 to n. For example, the term C _1-4 alkylene includes -(CH ₂ )-, -(CH ₂ -CH ₂ )-, -(CH(CH ₃ ))-, -(CH ₂ -CH ₂ -CH ₂ )-, -(C(CH ₃ ) ₂ )-, -(CH(CH ₂ CH ₃ ))-, -(CH(CH ₃ )-CH ₂ )-, -(CH ₂ -CH(CH ₃ )) -, -(CH ₂ -CH ₂ -CH ₂ -CH ₂ )-, -(CH ₂ -CH ₂ -CH(CH ₃ ))-, -(CH(CH ₃ )-CH ₂ -CH ₂ )-, -(CH ₂ -CH(CH ₃ )-CH ₂ )-, -(CH ₂ -C(CH ₃ ) ₂ )-, -(C(CH ₃ ) ₂ -CH ₂ )-, -(CH(CH _{3 )} )-CH(CH ₃ ))-, -(CH ₂ -CH(CH ₂ CH ₃ ))-, -(CH(CH ₂ CH ₃ )-CH ₂ )-, -(CH(CH ₂ CH ₂ CH ₃ )) -, -(CHCH(CH ₃ ) ₂ )- and -C(CH ₃ )(CH ₂ CH ₃ )-.

The term C2 _- nalkenyl denotes a branched or unbranched chain hydrocarbon group having 2 to n C atoms and a C=C double bond, wherein n has a value of 3 to 10. Examples of such groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like.

The term alkynyl refers to a branched or unbranched chain hydrocarbon group having 2 to n C atoms and a C≡C-parameter bond, wherein n has a value of 3 to 10. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentyne A group, a 3-pentynyl group, a 4-pentynyl group, a 1-hexynyl group, a 2-hexynyl group, a 3-hexynyl group, a 4-hexynyl group, a 5-hexynyl group, and the like.

The term C _1-n alkoxy denotes a C _1- nalkyl-O group wherein C _1-n alkyl is as defined above. Examples of such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, tert-butoxy, n-pentyloxy Base, isopentyloxy, neopentyloxy, third pentyloxy, n-hexyloxy, isohexyloxy and the like.

The term C1 _- nalkylcarbonyl denotes a C1 _-nalkyl -C(=O) group, wherein C1 _- nalkyl is as defined above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, t-butylcarbonyl, tert-butylcarbonyl, n-pentyl A carbonyl group, an isopentylcarbonyl group, a neopentylcarbonyl group, a third pentylcarbonyl group, a n-hexylcarbonyl group, an isohexylcarbonyl group or the like.

The term C _{3-ncycloalkyl} denotes a saturated mono-, di-, tri- or spirocarbocyclyl radical having from 3 to n carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, bicyclo[3.2.1]octyl, spiro [4.5] 癸 base, 蒎 蒎 base, drop Base, thiol group, adamantyl group, etc. The term C _3-7 cycloalkyl preferably denotes a saturated monocyclic group.

The term C _5-n represents a cycloalkenyl group as hereinbefore defined and additionally has at least one C = C C double bond _{5-n-cycloalkyl.}

The term C _3-n cycloalkylcarbonyl denotes a C _{3 -n} cycloalkyl-C(=O) group, wherein C _{3 -n} -cycloalkyl is as defined above.

The term C _3- nhecycloalkyl denotes a saturated mono, di, tri or spiro carbocyclic group as defined above having from 3 to m of C atoms, wherein m carbon atoms are independently selected from N via m , hetero atom substitution of NR ^N , O, S, SO and SO ₂ . Examples of such groups include aziridine, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, Tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, thiomorpholinyl, azepanyl , oxetanyl, thiaheptanyl, 1-aza-bicyclo[2.2.2]octane, 1,4-diaza-bicyclo[2.2.2]octane, and the like. The term heterocycloalkyl preferably denotes a saturated monocyclic C _5-6 cycloalkyl group in which one or two carbon atoms are replaced by N and/or O.

If the C _3- nhecycloalkyl group is an optionally unsaturated heterocycloalkyl group, the designated group has 1, 2 or more, preferably 1 or 2 double bonds, but does not form a heteroaryl group. Family system. In the case of an optionally unsaturated C3 _-n heterocyclic group, the methylene group immediately adjacent to the hetero atom may be substituted by a carbonyl group to form a tautomeric unsaturated endoamine having a heteroaryl group substituted with a hydroxy group. And included in the definition; examples are 1H-pyridin-2-one and 1H-pyrimidin-2-one.

The term tri(C _1-4 alkyl)nonanyl includes decyl groups having the same or 2 or 3 different alkyl groups.

The term di(C _1-3 alkyl)amine contains an amine group having two identical or different alkyl groups.

If the group or residue is optionally substituted, this applies to any form of group or residue. For example, if the alkyl group is mono- or poly-fluorinated as appropriate, the alkyl group also includes an alkyl group as part of a larger group (eg, alkoxy, alkylcarbonyl, alkoxyalkyl, etc.) a residue, or if a (hetero)aryl group is optionally mono- or polysubstituted by a substituent or a group of substituents, the (hetero)aryl group also includes as part of a larger group (eg, (hetero) aryl -C _1-n-alkyl group, (hetero) aryloxy, (hetero) aryloxy -C _1-n alkyl, (hetero) aryl -C _1-n alkoxy etc.) (hetero) aryl base. Thus, for example, where R ¹ has, for example, the meaning of (hetero)aryloxy, while (hetero)aryl is optionally fluorinated or polyfluorinated and (hetero)aryl, especially phenyl, Di-, tri-, tetra- and pentafluorophenoxy. The same applies to groups or residues in which one of the groups or residues is replaced by another group, for example the CH ₂ group is optionally replaced by O, S, NR ^N , CO or SO ₂ . By way of example, especially a residue having the meaning of hydroxy-C _1-3 alkyl, wherein the CH ₂ group is optionally replaced by CO (=carbonyl), which group also contains a carboxyl group, a carboxymethyl group, a hydroxymethylcarbonyl group, 1-hydroxy-2-oxo-ethyl, carboxyethyl, 2-carboxyethyl, 1-carboxyethyl, hydroxymethylcarbonylmethyl, 1-hydroxy-2-oxo-propyl, hydroxy Ethylcarbonyl, (2-hydroxyethyl)carbonyl, hydroxy-3-oxo-propyl, 1-hydroxy-3-o-oxy-propyl, 2-hydroxy-3-o-oxy-propyl, (1-hydroxyethyl)-carbonyl, 2-hydroxy-1-o-oxy-propan-2-yl, hydroxy-2-p-oxy-propan-2-yl and 3-hydroxy-1-yloxy- Prop-2-yl. Similarly, such as one or more CH ₂ groups optionally substituted by, for example, a carbonyl group and optionally substituted by, for example, the definition of the hydroxyl or amine group of C _1-n also includes no explicit CH and / or CH ₂ groups of Residues such as a carboxyl group and an aminocarbonyl group.

All of the atoms/elements described herein (including atoms that are part of a group) contain all stable isotopic forms of the individual elements. For example, whenever hydrogen is specifically or partially mentioned as a group such as a methyl group, the hydrogen includes hydrogen and deuterium in the form of stable isotopes of elemental hydrogen.

As used herein, the term "aryl", alone or in combination with another substituent (for example as a sub-portion), unless otherwise specified, means an aromatic monocyclic or aromatic polycyclic system containing a carbon atom, such as phenyl. Or naphthyl. Any of the above-mentioned aryl groups, if not otherwise specified, are substituted as appropriate.

As used herein, the term "heteroaryl", alone or in combination with another substituent (eg, as a sub-portion), unless otherwise specified, means that one, two, or three are selected from the group consisting of O, S, S=O, A five or six member heterocyclic aromatic group or an 8- to 10-membered bicyclic heteroaryl ring of a hetero atom in S(=O) ₂ and N. The ring may be attached to the remainder of the molecule via a carbon atom or, if present, via a nitrogen atom. Any of the above-mentioned heteroaryl groups, if not otherwise specified, are optionally substituted, including at the carbon and nitrogen atoms. The following are examples of 5- or 6-membered heterocyclic aromatic groups:

Examples of 8- to 10-membered bicyclic heteroaryl rings include pyridyl , hydrazine, pyridazine, isoindole, oxazole, hydrazine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzisothiazole, pyridopyrimidine, Acridine, pyrimidine and pyrimidine.

As used herein, the term "(hetero)aryl", alone or in combination with another substituent (for example, as a sub-portion), unless otherwise specified, means aryl and heteroaryl, wherein aryl and heteroaryl are as defined above The text is defined.

As used herein, the term "substituted" means that any one or more hydrogens on a given atom are replaced by a group selected from a specified group, with the proviso of not exceeding the viable valence of the specified atom, and the substitution yielding a stable compound. . More specifically, as used herein, the expression "substituted" or "optionally substituted" means, unless otherwise specified, substituted by a group selected from a specified substituent or, if not otherwise specified, 2 or 3 substituents selected from a group consisting of a halogen atom (fluorine, chlorine, bromine or iodine atom), a C _1-6 alkyl group, a C _2-6 alkenyl group, a ring C _{3 -8} alkyl, cyclo C _3-7 alkenyl, cyano, hydroxy, hydroxy-C _1-6 alkyl, hydroxy-C _3-6 alkenyl, C _1-6 alkoxy, C _1-6 -alkane Oxy-C _1-6 alkyl, tetrahydrofuranyl, tetrahydropentanyl, pyrrolidinyl, piperidinyl, thiol, C _1-6 alkylthio, amine, C _1-6 alkyl-amino , C _3-6 alkenyl-amino, di(C _1-6 alkyl)-amino, amino-C _1-6 alkyl, C _1-3 alkyl-amino-C _1-6 alkyl , bis(C _1-3 alkyl)-amino-C _1-6 alkyl, hydroxycarbonyl, phenyl, phenyl-C _1-3 alkyl, phenoxy, phenyl-C _1-3 alkoxy , phenoxy-C _1-3 alkyl, phenylcarbonyl, pyridyl, thiazolyl, pyridinecarbonyl, C _1-6 alkyl-carbonyl, C _1-6 -alkoxy-carbonyl, C _3-6 -alkenyloxy-carbonyl, aminocarbonyl, C _1-6 alkyl -aminocarbonyl, bis(C _1-6 alkyl)-aminocarbonyl, bis(C _3-6 alkenyl)-aminocarbonyl, C _1-6 alkyl-carbonylamino, C _1-6 alkyl -sulfonyl, C _1-6 alkyl-sulfinyl, C _1-6 alkyl-sulfonylamino, aminosulfonyl, C _1-6 alkylaminosulfonyl and di(C) _1-6 alkyl)-aminosulfonyl, and the substituents may be the same or different, and any alkyl or alkyl moiety thereof may be partially or fully fluorinated as appropriate, such as CH ₃ substitution of the substituents referred to herein. Or a methyl moiety is meant to include the corresponding fluoro analogs, such as CFH ₂ -, CF ₂ H- and CF ₃ - groups, and wherein any phenyl, pyridyl and thiazolyl or phenyl moiety, pyridyl moiety The thiazolyl moiety is optionally substituted with one or two substituents independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-3 alkyl, C _1-3 alkoxy, amine, C _{1 -3} alkyl-amino group, di(C _1-3 alkyl)-amino group, C _1-3 alkylcarbonyl-amino group, C _1-3 alkylcarbonyl-C _1-3 alkyl-amino group, cyano or hydroxy, and is connected via the composition selected from the group to the nitrogen atom of substituent: C _1-6 alkyl, C _3-6 alkenyl group, a cycloalkyl C _3-7 alkyl , -C _1-6 cycloalkyl C _3-7 alkyl group, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl group, a cyano group, a hydroxyl group, a hydroxy -C _1-6 alkyl , C _1-6 -alkoxy-C _1-6 alkyl, amino-C _1-6 alkyl, C _1-3 alkyl-amino-C _1-6 alkyl, di (C _1-3 Alkyl)-amino-C _1-6 alkyl, phenyl, phenyl-C _1-6 alkyl, phenylcarbonyl, pyridyl, pyridinecarbonyl, C _1-6 alkyl-carbonyl, C _1-6 - alkoxy-carbonyl, aminocarbonyl, C _1-6 alkyl-aminocarbonyl, di(C _1-6 alkyl)-aminocarbonyl, C _1-6 alkyl-sulfonyl, C _{1- a 6-} alkylsulfinyl group, an aminosulfonyl group, a C _1-6 alkylaminosulfonyl group, and a di(C _1-6 alkyl)-aminosulfonyl group, and the substituents may be the same or different And wherein any alkyl or alkyl moiety thereof is partially or fully fluorinated as appropriate, for example, a CH ₃ substituent or a methyl moiety of a substituent as referred to herein is meant to include the corresponding fluorine analog, such as CFH ₂ -, CF ₂ H- and CF ₃ - groups, and any of the di(C _1-3 alkyl)-amino or di(C _1-6 alkyl)-amino moiety may optionally form a 4 to 8 membered ring with the nitrogen atom. And any of the phenyl and pyridyl or benzene Sub-portion sub-portion and pyridyl are optionally substituted with 1 or 2 substituents each independently selected from fluoro, chloro, bromo, iodo, C _1-3 alkyl, C _1-3 alkoxy, amino, C _1-3 alkoxy Substituted by a substituent of a benzyl-amino group, a C _1-3 alkylcarbonyl-amino group, a cyano group or a hydroxy group.

It should be understood that the expressions "prevention", "prophylaxis", "prophylactic treatment" or "preventive treatment" as used herein are synonymous and mean to reduce the occurrence of the above conditions in patients. The risk, in particular the increased risk of the condition mentioned above or having a corresponding medical history, such as a patient suffering from a metabolic disorder such as diabetes or obesity or an increased risk of another condition mentioned herein. Thus, as used herein, the expression "preventing a disease" means treating and caring for an individual at risk of developing the disease prior to the clinical onset of the disease. The purpose of prevention is to combat the onset of a disease, condition or condition, and includes administration of the active compound to prevent or delay the onset of symptoms or complications and to prevent or delay the associated disease, condition or disease. Symptoms occur. The success of this prophylactic treatment is reflected statistically, based on the reduction in the incidence of the condition in a population of patients at risk for this condition compared to a population of patients who are not prophylactically treated.

The expression "treatment" or "therapy" means the therapeutic treatment of a patient who has developed one or more of these conditions in a dominant, acute or chronic form, depending on the condition and its severity. Symptomatic treatment to alleviate the symptoms or etiological treatment of a particular indication to reverse or partially reverse the condition or delay the progression of the indication until a reversal or partial reversal of the condition may occur. Thus, as used herein, the expression "disease treatment" means treating and caring for a patient who develops a disease, condition or disorder. The purpose of treatment is to combat the disease, condition or condition. Treatment includes administering an active compound to eliminate or control a disease, condition or disorder and to alleviate symptoms or complications associated with the disease, condition or disorder.

As used herein, the term "metabolite" refers to (i) a metabolite, including intermediates and products; (ii) any substance involved in metabolism (as a metabolite, or necessary for metabolism); or (iii) during metabolism. Any substance produced or used. In particular, it refers to the final product remaining after metabolism.

As used herein, the term "prodrug" means (i) an inactive form of a drug that exerts its effect upon conversion to a suitable or active form by metabolic processes in the body; or (ii) produces a pharmacologically active metabolite but does not Active substance (ie, inactive precursor).

The term "prodrug" or "prodrug derivative" means a covalently bonded derivative, carrier or precursor of a parent compound or active drug substance which exhibits its pharmacological effects upon undergoing at least some biological transformation. Such prodrugs have a group that is metabolically cleavable or otherwise convertible, and is rapidly converted in vivo to produce a parent compound, for example, by hydrolysis in blood or by activation via oxidation, such as in the case of a thioether group. . The most common prodrugs include esters of parent compounds and guanamine analogs. Prodrugs are formulated to achieve improved chemical stability, improved patient acceptance and compliance, improved bioavailability, extended duration of action, improved organ selectivity, improved formulation (eg, increased water solubility), and/or side effects (eg, toxicity) Reduce the purpose. In general, prodrugs are themselves weakly or biologically inactive and stable under normal conditions. Prodrugs can be readily prepared from parent compounds using methods known in the art, such as those described in the following literature: A Textbook of Drug Design and Development , Krogsgaard-Larsen and H. Bundgaard (ed.), Gordon & Breach, 1991, especially Chapter 5; "Design and Applications of Prodrugs"; Design of Prodrugs , H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery. KBSloan (ed.), Marcel Dekker, 1998; Methods in Enzymology , K. Widder et al, (eds.), Vol. 42, Academic Press, 1985, especially pages 309-396; Burger's Medicinal Chemistry and Drug Discovery , 5th edition, M. Wolff (ed.), John Wiley & Sons, 1995, especially Volume 1 and pages 172-178 and pages 949-982; Pro-Drugs as Novel Delivery Systems , T. Higuchi and V. Stella (ed.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design , EB Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in its entirety.

As used herein, the term "pharmaceutically acceptable prodrug" means that the prodrug of the compound of the present invention is suitable for use in contact with humans and tissues of lower animals in the context of sound medical judgment without undue toxicity, irritation, allergic reaction and It has a similar effect, is commensurate with the reasonable benefit/risk ratio, and is effective for the intended use and, if possible, in the form of zwitterions.

Preferred embodiment of the invention

Other preferred embodiments of the invention are characterized by the following definitions:

a) as an alternative embodiment (a ¹ ) to (a ⁵ ) , the definition of R ¹ (a ⁱ ) :

(a ¹ ): According to the first preferred embodiment, R ¹ is as defined above in accordance with the most extensive/first embodiment E-0 of the present invention.

(a ² ): According to the second preferred embodiment, R ¹ is selected from the group consisting of H, F, Cl, Br, I, C _1-6 alkyl, C _5-6 alkenyl, C _3-10 Cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _5-6 cycloalkenyl, C _1-6 alkoxy, C _3-6 cycloalkyl-oxy and C _3-6 Cycloalkyl-C _1-4 alkoxy, any of which is optionally substituted with 1 to 3 fluorine atoms and/or 1 to 3 R ⁴ groups, C _5-10 heterocycle , C _5-10 heterocyclyl-C _1-4 alkyl, bicyclic heterocyclyl-, bicyclic heterocyclyl-C _1-4 alkyl-, C _5-10 heterocyclyl-C _1-4 alkyl -oxy and C _5-10 heterocyclyloxy, any of which is optionally substituted with 1 to 3 R ⁴ groups, phenyl, phenyl-C _1-4 alkyl, Phenyl-C _1-4 alkyl-oxy, phenoxy, heteroaryl, heteroaryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl-oxy and heteroaryloxy And any such group is optionally substituted with 1 to 3 R ⁵ groups, C _1-2 alkyl-thio, optionally substituted with 1 to 3 fluorine atoms, and cyano, wherein the heterocyclic group and sub-portions may be partially unsaturated and containing 1 to 3 heteroatoms selected from N, heteroaryl NR ^N, O and S atoms or the group , the restriction is that at most two of the heteroatoms are O and S, and no OO, SS and SO bonds are formed, and the methylene group bonded to the hetero atom may be replaced by a carbonyl group, and the heterocyclic groups are via carbon or The nitrogen atom is bonded to a respective residue; R ^N represents H, C _1-4 alkyl-, C _1-4 alkyl-C(O)- or C _1-4 alkyl-OC(O)-, wherein the aforementioned The bicyclic heterocyclic group and the sub-portion may be partially unsaturated and comprise from 6 to 10 ring members and from 1 to 3 heteroatoms or groups selected from N, NR ^N , O and S, with the proviso that at most only Two are O and S and do not form OO, SS and SO bonds, and the methylene group bonded to the hetero atom may be replaced by a carbonyl group, and the heterocyclic group is bonded to each residue via a carbon or nitrogen atom; R ^N represents H, C _1-4 alkyl-, C _1-4 alkyl-C(O)- or C _1-4 alkyl-OC(O)-, wherein the aforementioned bicycloalkyl and bicyclic heterocyclic groups and sub-portions comprise a fused and bridged ring system wherein the aforementioned heteroaryl and sub-portions are composed of 5 to 10 atoms and contain 1 to 3 heteroatoms selected from N, O or S(O) _r , wherein r = 0, 1 or 2, wherein in the polycyclic heteroaromatic group, the ring not attached to the respective residue may be partially or fully saturated, and at least Aromatic ring comprising one or more hetero atoms.

(a ³ ): According to a third preferred embodiment, R ¹ is selected from the group consisting of H, F, Cl, Br, C _1-6 alkyl, C _5-6 alkenyl, C _3-6 naphthenic a C _3-6 cycloalkyl-C _1-4 alkyl group, a C _5-6 cycloalkenyl group, a tetrahydropyranyl-C _1-2 alkyl group, and a C _1-6 alkoxy group, any of which The group is optionally substituted with 1 to 3 fluorine atoms and/or 1 to 3 R ⁴ groups, oxetanyl, tetrahydrofuranyl, dihydropiperidyl, tetrahydropyranyl, Morpholinyl, tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, 8-oxa-spiro[4.5]decenyl, 3- Oxan-spiro[5.5]undecenyl, 2-oxa-bicyclo[3.1.1]heptyl, 2-oxa-bicyclo[2.2.1]heptyl, 2-oxa-bicyclo[3.1. 1]hept-4-yloxy, 2-oxa-bicyclo[3.1.1]hept-5-yloxy, 2-oxa-bicyclo[3.1.1]hept-6-yloxy, 2- Oxa-bicyclo[2.2.1]hept-4-yloxy, 2-oxa-bicyclo[2.2.1]hept-5-yloxy and 2-oxa-bicyclo[2.2.1]hept-6 a -oxy group, any of which is optionally substituted with 1 to 3 R ⁴ groups, 2-sided oxy-1,2-dihydro-pyridyl, optionally 1 to 3 two R ⁴ groups Generation, phenyl and heteroaryl, wherein any of these groups is independently and optionally substituted with 1 to 3 R ⁵ groups, trifluoromethyl and cyano group, wherein the aryl and heteroaryl subportion A 5- and 6-membered monocyclic ring system containing 1 or 2 heteroatoms selected from the group consisting of N, NR ^N and O, wherein R ^N represents H and C _1-4 alkyl.

(a ⁴ ): According to the fourth preferred embodiment, R ¹ is selected from the group consisting of F, Cl, Br, CN, C _1-6 alkyl, C ₅ alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkyl, C _5-6 cycloalkenyl, tetrahydropiperidyl-C _1-2 alkyl and C _1-6 alkoxy, any of these groups The group is optionally substituted with 1 to 3 fluorine atoms and/or 1 to 3 R ⁴ groups, oxetanyl, tetrahydrofuranyl, dihydropiperidyl, tetrahydropyranyl, morpholine , 8-oxa-spiro[4.5]dec-1-enyl, 3-oxa-spiro[5.5]undec-7-alkenyl and 2-oxa-bicyclo[3.1.1]heptyl, Any of these groups is optionally substituted with 1 to 3 R ⁴ groups, pyrazolyl, imidazolyl, isoxazolyl, phenyl, naphthyl, pyridyl, 2-sided oxy- 1,2-Dihydro-pyridyl, pyrimidinyl, pyrazinyl and isoquinolyl, optionally substituted with from 1 to 3 R ⁵ groups.

(a ⁵ ): According to the fifth preferred embodiment, R ¹ is selected from the group consisting of F, Cl, Br, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl -C _1-4 alkyl, cyclopentenyl and C _1-6 alkoxy, any of which groups optionally, if appropriate, 1 to 3 fluorine atoms and/or 1 or 2 R ⁴ groups Substituted, dihydropiperidyl and tetrahydropyranyl.

(a ⁶ ): According to the sixth preferred embodiment, R ¹ is selected from the group consisting of F, Cl, Br, CN, C _1-6 alkyl, pentafluoroethyl, C ₅ alkenyl, C _{3- 6} cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkyl, C _5-6 cycloalkenyl, tetrahydropiperidyl-C _1-2 alkyl and C _1-6 alkoxy, wherein Any such groups are optionally substituted with from 1 to 3 fluorine atoms and/or from 1 to 3 groups independently selected from the group consisting of methyl, cyano, methoxy and hydroxy, phenyl, optionally Substituted by 1 to 3 groups independently selected from the group consisting of Cl, C _1-3 alkyl, trifluoromethyl, pentafluoroethyl, methoxy and hydroxy, pyridyl, optionally 1 to 3 independently a group selected from the group consisting of F, methyl, trifluoromethyl, cyano and methoxy, pyrazolyl, imidazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, 2-oxo-oxyl-1, 2-Dihydro-pyridyl, naphthyl and isoquinolyl, each optionally substituted with 1 to 3 methyl groups, dihydropiperidyl, morpholinyl, oxetanyl and tetrahydropyranyl Each is optionally substituted with 1 to 3 methyl groups, 8-oxa-spiro[4.5]dec-1-enyl and 3-oxa-spiro[5.5]undec-7-alkenyl.

b) as an alternative embodiment (b ¹ ) to (b ⁴ ) , the definition of R ² (b ⁱ ) :

(b ¹ ): According to the first preferred embodiment, R ² is as defined above in accordance with the most extensive/first embodiment E-0 of the present invention.

(b ² ): According to a second preferred embodiment, R ² is selected from the group consisting of F, Cl, Br, methyl, difluoromethyl, trifluoromethyl, cyclopropyl, methoxy, Difluoromethoxy and trifluoromethoxy.

(b ³ ): According to a third preferred embodiment, R ² is selected from the group consisting of F, Cl, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy and Trifluoromethoxy.

(b ⁴ ): According to a fourth preferred embodiment, R ² is selected from the group consisting of F, Cl, methyl and methoxy.

c) as an alternative embodiment (c ¹ ) to (c ³ ) , the definition of R ³ (c ⁱ ) :

(c ¹ ): According to the first preferred embodiment, R ³ is as defined in the broadest text of the invention above, or as mentioned under the first embodiment E-0 .

(c ² ): According to a second preferred embodiment, R ³ is selected from the group consisting of F, Cl, Br, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy And trifluoromethoxy.

(c ³ ): According to a third preferred embodiment, R ³ is selected from the group consisting of F, methyl and methoxy.

d) as an alternative embodiment (d ¹ ) to (d ⁴ ) , the definition of R ⁴ (d ⁱ ) :

(d ¹ ): According to the first preferred embodiment, R ⁴ is defined as mentioned above in the broadest text of the invention or in the first embodiment E-0 .

(d ² ): According to the second preferred embodiment, R ⁴ is selected from the group consisting of F, Cl, cyano, C _1-4 alkyl, hydroxy, hydroxy-C _1-4 alkyl, C _{1- 4-} alkyl-oxy, C _1-4 alkoxy-C _1-4 alkyl, C _3-6 cycloalkyl-, C _3-6 cycloalkyl-oxy-, any of these aliphatic and The cycloaliphatic group or sub-portion is optionally substituted with 1 to 3 fluorine atoms.

(d ³ ): According to the third preferred embodiment, R ⁴ is selected from the group consisting of F, cyano, hydroxy, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy And trifluoromethoxy.

(d ⁴ ): According to the fourth preferred embodiment, R ⁴ is selected from the group consisting of F, cyano, methyl, hydroxy and methoxy.

e) as an alternative embodiment (e ¹ ) to (e ³ ) , the definition of R ⁵ e ⁱ ) :

(e ¹ ): According to the first preferred embodiment, R ⁵ is as defined above in accordance with the most extensive/first embodiment E-0 of the present invention.

(e ² ): According to a second preferred embodiment, R ⁵ is selected from the group consisting of F, Cl, cyano, C _1-3 alkyl (preferably methyl), difluoromethyl, trifluoro Methyl, pentafluoroethyl, hydroxy, methoxy, difluoromethoxy and trifluoromethoxy.

(e ³ ): According to a third preferred embodiment, R ⁵ is selected from the group consisting of F, Cl, cyano, C _1-3 alkyl (preferably methyl), trifluoromethyl, pentafluoro Ethyl, hydroxy and methoxy.

Each of a ¹ , b ¹ , c ¹ , d ¹ , and e ¹ represents a characterization of the corresponding substituent as described above. Thus, in view of the above definitions, preferred individual embodiments of the first aspect of the invention are sufficiently characterized by the term ( a ¹ b ¹ c ¹ d ¹ e ¹ ), provided that individual letters i in this term are assigned individual numbers. The indices i are different from each other independently. The present invention should include all of the individual embodiments described in the brackets in the entire arrangement of the index i (see above definition).

Table 1 below shows these Examples E-1 to E-20 of the present invention which are considered to be particularly preferred:

It includes tautomers, stereoisomers, mixtures and salts thereof, especially pharmaceutically acceptable salts thereof.

The following preferred examples of the compounds of formula (I) are described using the general formulae (I.1) to (I.8), including any tautomers and stereoisomers thereof (if otherwise specified), solvates , hydrates and salts, especially pharmaceutically acceptable salts thereof.

Wherein in each of the above formulas (I.1) to (I.8), the groups R ¹ , R ² , R ³ , m and n are as defined above. Any of the preferred embodiments E-1 to E-1 as disclosed in Table 1 are applicable to any of the general formulae (I.1) to (I.8).

Particularly preferred embodiments of the invention are described in the examples.

The compounds of the invention can be obtained using synthetic methods generally known. The compound is preferably obtained by the following method of the invention as described in more detail below.

The compound (I) of the present invention is preferably obtained from the precursor 1 having a carboxylic acid functional group in a protected or masked form, as outlined in Scheme 1; R ¹ , R ² , R ³ , m and n The meaning is as defined above and below. Suitable precursors for the carboxylic acid can be, for example, carboxylates, carboguanamines, cyano, alkenes, oxazoles or thiazoles. All such groups have been converted to carboxylic acid functional groups by various means as described in the organic chemistry literature and known to those skilled in the art. Preferred precursor groups are the carboxylic acid esters C _1-4 alkyl esters or benzyl carboxylates, each of which may be additionally mono- or polysubstituted by fluorine, methyl and/or methoxy. These ester groups may be hydrolyzed by an acid such as hydrochloric acid or sulfuric acid or an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide to produce a carboxylic acid functional group; the hydrolysis is preferably at 0 ° C to 120 ° C in water. The solvent (such as water) and tetrahydrofuran, 1,4-dioxane, alcohol (such as methanol, ethanol and isopropanol) or dimethyl hydrazine are carried out. The third butyl ester is preferably cleaved in a solvent such as dichloromethane, 1,4-dioxane, isopropanol or ethyl acetate under acidic conditions such as trifluoroacetic acid or hydrochloric acid. The benzyl ester is preferably cleaved with hydrogen in the presence of a transition metal, preferably palladium/carbon. The benzyl ester with an electron-donating group such as a methoxy group on the aromatic ring can also be removed under oxidizing conditions; ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyanoguanidine (DDQ) There are two reagents commonly used in this method.

Compound 1 can in turn be obtained from indoline 2 with a leaving group and indanol 3 modified with a carboxylic acid precursor group (Scheme 2); R ¹ , R ² , R ³ , m in Scheme 2 and The meaning of n is as defined above and below. The leaving group LG 2 is substituted in the 3 O through via nucleophilic substitution; LG may be adapted Cl, Br, I, methyl group sulfonylureas, sulfonylureas phenyl, p-toluenesulfonyloxy group and three sulfonylureas Fluoromethylsulfonyloxy. The reaction is usually carried out in, for example, triethylamine, ethyldiisopropylamine, 1,8-diazabicyclo[5.4.0]undecene, carbonate (for example, Li ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ And Cs ₂ CO ₃ ), hydroxides (such as LiOH, NaOH and KOH), alkoxides (such as NaOMe, NaOEt and KOtBu), hydrides (such as NaH and KH), guanamines (such as NaNH ₂ , KN (SiMe _{3 ) 2} and LiN(iPr) ₂ ) and an oxide (for example, CaO and Ag ₂ O) are present in the presence of a base. Such as silver salts (such as AgNO ₃ , AgOSO ₂ CF ₃ and Ag ₂ CO ₃ ), crown ethers (such as 12-crown-4, 15-crown-5 and 18-crown-6), tris(dimethylamino)phosphine Additives of (HMPT) and 1,3-dimethyl-3,4,5,6-dihydro-2-pyrimidinone (DMPU) may be beneficial or even necessary for the reaction to be carried out. Preferred solvents are dimethyl hydrazine, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone, 1,4-dioxane. Tetrahydrofuran, an alcohol (such as ethanol or isopropanol), water or a mixture thereof, and not all solvents may be combined with the various additives and bases mentioned above. Suitable reaction temperatures range from -20 ° C to 140 ° C.

The alternative reaction of the combination of building blocks 2 and 3 is a Mitsunobu reaction or a change thereof (Scheme 3); the meanings of R ¹ , R ² , R ³ , m and n in Scheme 3 are as described above and below. definition. The reaction is preferably carried out from phosphine and azodicarboxylate or decylamine in tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, benzene, dichloromethane or a mixture thereof at -30 ° C to 100 ° C. The phosphines usually used are triphenylphosphine and tributylphosphine, which are usually combined with dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate and azodicarboxylic acid. -Chlorobenzyl ester), dibenzyl dihydrogen dicarboxylate, di-t-butyl azodicarboxylate, bis(dimethyl decylamine) dihydrodicarboxylate, dioxetidine azodicarboxylate or azodicarboxylic acid Diterpene morpholine combination.

Intermediate 2/2 'should be obtained from the 4-indanone, 4-indanone in turn prepared from the acid derivative 5 (Scheme 4); the process 4 R ^1, R ² and m are the meanings described above based And as defined below. For the intramolecular deuteration reaction (Friedel-Crafts acylation) 5 → 4 , many methods have been reported. The reaction can be carried out using a carboxylic acid, a carboxylic acid ester, a carboxylic acid anhydride, a carboxy ruthenium chloride or a carboxy fluorene fluoride or a nitrile as a starting material, using a Lewis acid as a catalyst. The following Lewis acids are some of the more commonly used Lewis acids: hydrobromic acid, hydroiodic acid, hydrochloric acid, sulfuric acid, phosphoric acid, P ₄ O ₁₀ , trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, ClSO ₃ H , Sc(OSO ₂ CF ₃ ) ₃ , Tb(OSO ₂ CF ₃ ) ₃ , SnCl ₄ , FeCl ₃ , AlBr ₃ , AlCl ₃ , SbCl ₅ , BCl ₃ , BF ₃ , ZnCl ₂ , montmorillonite, POCl ₃ and PCl ₅ . The reaction can be carried out, for example, at 0 ° C to 180 ° C in dichloromethane, 1,2-dichloroethane, nitrobenzene, chlorobenzene, carbon disulfide, mixtures thereof or in the absence of another solvent in excess Lewis acid. get on. The carboxylic acid is preferably reacted in polyphosphoric acid at 0 ° C to 120 ° C, and the carboxy ruthenium chloride is preferably reacted with AlCl ₃ in dichloromethane or 1,2-dichloroethane at 0 ° C to 80 ° C.

The ketone group is subsequently reduced to the standard conversion in organic synthesis in Scheme 4, primarily by lithium borohydride, sodium borohydride, lithium aluminum hydride, and diisobutylaluminum hydride. Sodium borohydride is used in the form of an aqueous solution or an alcohol solution at 0 ° C to 60 ° C, and the other reducing agents mentioned are in an inert solvent such as tetrahydrofuran, diethyl ether, dichloromethane and toluene at -80 ° C to Use at 60 ° C. The reduction of the ketone group can also be carried out in a stereoselective manner to give an alcohol in enantiomerically enriched or pure form. Preferably, the palm reducing agent is a borane in combination with pure enantiomeric [1,3,2]oxazoborole in the presence of a pure enantiomeric transition metal catalyst (Curry-Barker) A Corey-Bakshi-Shibata reaction or a Corey-Itsuno reaction or formic acid, formate, hydrogen or decane. Typical reaction conditions for the former process are borane (combined with, for example, methyl sulfide) and ( R )-3,3 in, for example, dichloromethane, toluene, methanol, tetrahydrofuran or mixtures thereof at 0 ° C to 60 ° C. -diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazolane or ( S )-3,3-diphenyl -1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazoborole. Use of a palmitic transition metal catalyst, such as a ruthenium complex (eg, chloro{[(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl) - guanylamino}-(mesitylene) ruthenium (II)) can be obtained by reducing the ketone with, for example, formic acid in the presence of a base such as triethylamine in the presence of a base such as triethylamine at -20 ° C to 60 ° C. A highly hydroxy compound with a high degree of conformation.

Alternatively, the indanone 4 can be synthesized as described in Scheme 5; the meanings of R ¹ , R ² and m are as defined above and below. From benzene 6 and 3-halo-propionic acid or derivatives thereof or acrylic acid or a derivative thereof as a starting material, a one-pot reaction can be carried out via a combination of Friedel-Crafts alkylation and deuteration reaction or The desired indanone 4 (Reaction formula 1.)) is obtained in two separate reactions. These reactions are catalyzed by a Lewis acid such as trifluoromethanesulfonic acid, sulfuric acid, phosphoric acid, AlCl ₃ , ZnCl ₂ and phosphorus pentoxide, and preferably at 0 ° C to 140 ° C in the absence of another solvent. It is carried out in an excess of Lewis acid or dichloromethane, 1,2-dichloroethane, cyclohexane or carbon disulfide. A preferred combination comprises compound 6 , 3-chloro-propionyl chloride and AlCl ₃ in dichloromethane or 1,2-dichloroethane at 20 ° C to 80 ° C.

From acetylene benzene 7 as a starting material, indanone 4 can be obtained by a transition metal catalyzed reaction with carbon monoxide (Reaction formula 2.)).铑 is a preferred catalyst substrate which is combined with a phosphine such as triphenylphosphine and a base such as triethylamine and used in a solvent at a high carbon monoxide pressure, preferably 50 to 150 bar, at 150 ° C to 200 ° C. Preferably, it is in tetrahydrofuran (see, for example, J. Org. Chem. 1993 , 58 , 5386-92).

The combination of styrene 8 and carbon monoxide, which is substituted with a 2-halo or pseudohalogen group in the presence of a transition metal, also allows the preparation of indanone 4 (reaction formula 3.)). The palladium catalyst is preferably used as a source of carbon monoxide together with carbon monoxide or molybdenum hexacarbonyl. Preferred solvents are N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and 1,4-dioxane, preferably at 20 ° C to 150 ° C. It is used by conventional heating or microwave irradiation at °C. Preferred additives for the conversion of pyridine and tetrabutylammonium chloride (see, for example, J. Am. Chem. Soc. 2003 , 125 , 4804-7 and J. Org. Chem. 2005 , 70 , 346-9).

A common synthetic route to construct block 3 is outlined in Scheme 6; the meaning of R ³ and n is as defined above and below. 2-iodoether or 2-bromoether 9 can be converted to a second by addition of a carbon anion or group generated in situ to a double bond and subsequent capture of the cyclic anion by a proton and capture of the cyclic group by a hydrogen-based source Hydroquinone 3 (reaction formula 1.)). nBuLi, iPrMgCl, iPrMgCl ^* LiCl, Mg, Mg ^* LiCl, Zn and Zn ^* LiCl is a CM bond (M=Li, Mgl, Znl, etc.) which converts CI or C-Br bond into a nucleophilic enough to be added with a double bond. Preferred reagent. The reaction with the lithium and magnesium reagents is preferably carried out at -100 ° C to 60 ° C in hexane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, toluene or a mixture thereof. Zn is preferably used in tetrahydrofuran, dimethyl hydrazine, N-methylpyrrolidone or a mixture thereof at 0 ° C to 100 ° C. Typical reaction conditions for the group route are, for example, benzene containing hydrogenated tributyltin and azobisisobutyronitrile at 60 ° C to 100 ° C (see, for example, J. Org. Chem. 1987, 52, 4072-8) and at 20 ℃ to 120 ℃ UV radiation of NaCNBH ₃ containing N, N- dimethylformamide (see, e.g. Synlett 2005, 2248-50).

In the reaction formula 2.), allyl ether 10 is combined with carbon monoxide to obtain indoline 3 . Such a reaction is preferably carried out by a palladium catalyst in the presence of carbon monoxide or molybdenum hexacarbonyl as a source of carbon monoxide (for example, Tetrahedron Lett. 2010 , 51 , 2102-5).

Starting from benzofuran 11 or dihydrobenzofuran 12 , dihydroindole 3 is produced after reduction of the double bond. Hydrogen is a preferred reducing agent which is used primarily in combination with transition metal catalysts such as palladium on carbon, Raney nickel and PtO ₂ . N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, alcohol (such as methanol and ethanol), acetic acid, water or a mixture thereof at a hydrogen pressure of from 1 to 100 bar and a temperature of from 20 ° C to 120 ° C Good as a solvent. This reaction can also be carried out in a stereoselective manner to give compound 3 in enantiomerically enriched or pure form.

The starting compounds in Scheme 6 contain standard procedures used in organic synthesis. Intermediate 11 can be prepared, for example, as described in Scheme 7; R ³ and n are as defined above and below. Compound 11 Compound 13 thus obtained may, in turn obtained from Compound 13 15 14 Phenol and ester compositions. Conversion to compound 13 can be carried out in toluene at 0 ° C to 120 ° C in the presence of a Lewis acid such as sulfuric acid, ZrCl ₄ , InCl ₃ , methanesulfonic acid, p-toluenesulfonic acid, HI or amberlyst. This is achieved in dichloromethane, acetic acid, ethanol, water or in the absence of solvent in an excess of Lewis acid. Conversion of compound 13 to intermediate 11 is preferably effected from sodium hydroxide in aqueous solution at 0 ° C to 100 ° C under basic conditions.

The synthetic route presented can depend on the use of the protecting group. For example, a possible reactive group (such as a hydroxyl group, a carbonyl group, a carboxyl group, an amine group, an alkylamino group or an imido group) may be protected by a conventional protecting group during the reaction, and the protecting groups are again after the reaction. Lysis. Protecting groups suitable for the respective functional groups and their removal are well known to those skilled in the art and are described in the organic synthesis literature.

The compounds of formula I can be resolved into their enantiomers and/or diastereomers as mentioned above. Thus, for example, a cis/trans mixture can be resolved to its cis and trans isomers, and the racemic compound can be separated into its enantiomers.

The cis/trans mixture can be resolved into its cis form by, for example, chromatography. Trans isomer. Compounds of formula I in the form of racemates can be separated into their optical enantiomers by methods known per se (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), and Diastereomeric mixtures of the compounds of the formula I can be resolved into their diastereomers by methods known per se (for example by chromatography and/or fractional crystallization) using their different physicochemical properties; The compound is a racemate, which can also be resolved as an enantiomer as mentioned above.

The racemate is preferably formed into a salt or a derivative (such as an ester or an anthracene) with a racemic compound by palmar column chromatography or by crystallization from an optically active solvent or by reaction with an optically active substance. Amine) to resolve. Salts can be formed from pure enantiomeric acids (for basic compounds) and from pure enantiomeric bases (for acidic compounds). Diastereomeric derivatives can be formed from pure enantiomeric auxiliary compounds such as acids, activated derivatives thereof or alcohols. The diastereomeric mixture of the salt or derivative thus obtained can be separated by its different physicochemical properties (for example, solubility difference); the free pair can be released from the pure diastereomeric salt or derivative by the action of a suitable reagent. A reflection. Optically active acids commonly used for this purpose are, for example, D- and L-forms of tartaric acid, benzhydryl tartaric acid, xylyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid. Or quinic acid. The optically active alcohol suitable as the auxiliary residue may be, for example, (+) or (-)-menthol, and the optically active thiol group in the guanamine may be, for example, (+)- or (-)-menthyloxycarbonyl.

As stated above, the compounds of formula I can be converted into salts, especially into pharmaceutically acceptable salts for pharmaceutical use. "Pharmaceutically acceptable salt" as used herein refers to a derivative of the disclosed compound wherein the parent compound is modified by making it an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts such as basic residues of amines, alkali metal or organic salts such as acidic residues of carboxylic acids, and the like. For example, such salts include acetate, ascorbate, benzenesulfonate (besylate), benzoate, bicarbonate, hydrogen tartrate, bromide/hydrobromic acid Salt, calcium edetate/ethylenediaminetetraacetate, camphorsulfonate, carbonate, chloride/hydrochloride, citrate, ethanedisulfonate (ethanedisulfonate), relying on Estolate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, beta-acetamide, hexyl benzene Diphenolate, sea amide, hydroxy maleate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, almond Acid salt, methane sulfonate, mucic acid salt, naphthalene sulfonate, nitrate, oxalate, pamoate, pantothenate, phenylacetate, phosphate/diphosphate, polygalactosaldehyde Acid salts, propionates, salicylates, stearates, acetates, succinates, sulfonamides, sulfates, tannates, tartrates, tea chlorates Oclate), toluenesulfonate (tosylate), triethiodide, ammonium salt, benzathine, chloroprocaine, choline, Diethanolamine, ethylenediamine, meglumine and procaine. Other pharmaceutically acceptable salts can be formed from cations of metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like (see also Pharmaceutical salts, Birge, SM et al, J. Pharm. Sci. , (1977), 66 , 1-19). Some of the salts mentioned above may also be suitable for the purification or isolation of the compounds of the invention.

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods. In general, the free acid or free base form of such compounds can be combined with sufficient base or acid in water or an organic diluent such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile or mixtures thereof. The reaction is carried out to prepare the salts.

Salts other than those mentioned above which are suitable, for example, for purifying or isolating the compounds of the invention, such as trifluoroacetate, also form part of the invention.

The compounds of the invention are also suitably obtained by the methods described in the Examples below, which may also be combined for this purpose with literature methods known to those skilled in the art.

As already mentioned, the compounds of the formula I according to the invention and their physiologically acceptable salts have valuable pharmacological properties, in particular the activation of the receptor GPR 40.

Biological example

The effective stimulatory effects of the compounds of the invention can be determined by in vitro analysis as follows:

(A) Intracellular calcium measurement using the FLIPR system - 1321N1 cells (Euroscreen, Belgium) stably expressing the human GPR40 receptor 24 hours prior to analysis in 10% FCS, 1% sodium pyruvate and 400 μg/ml G418 The medium was inoculated into a black transparent bottom 384-well plate coated with collagen. On the day of analysis, each well was washed twice with 100 μL of Krebs Ringer Buffer (KRB) containing 15 mM sodium bicarbonate and 30 mM Hepes, leaving a remaining volume of 20 μl per well. Prior to stimulation, the cells were Ca ²⁺ sensitive with Calcium 4 Assay kit ^{TM in} the presence of 4 mM of probenicid in the dark according to the manufacturer's instructions (MDS Analytical technologies, Ismaning, Germany) at room temperature. The light dye was loaded for 80 minutes. Changes in intracellular Ca ²⁺ concentration when compounds were added were monitored using a FLIPR Tetra device (Fluorescence Imaging Plate Reader; MDS Analytical technologies). Then the peak height obtained using the fluorescent signal of using GraphPad Prism 5 (Graphpad Software Inc, USA), using an S-shaped curve fitting program considering variable Hill slope (hill slope) values calculated ₅₀ EC.

The EC _{50 of the} compounds of the formula (I) of the invention analyzed as described above is, for example, less than 10,000 nM, specifically less than 1000 nM, and most preferably less than 100 nM.

(B) Analysis system using IP ₁ IPOne accumulated measurement - 24 hour 1321N1 cells stably expressing the GPR40 human receptor (Euroscreen, Belgium) prior to analysis containing 10% FCS, 1% sodium pyruvate and 400 μg / mL The medium of G418 was inoculated into a black transparent bottom 384-well plate coated with collagen. IP _{1 was} analyzed according to the manufacturer's instructions (Cisbio Bioassays, France). Briefly, the analysis was started by replacing the medium with LiCl-free stimulation buffer (Hepes 10 mM, CaCl ₂ 1 mM, MgCl ₂ 0.5 mM, KCl 4.2 mM, NaCl 146 mM, and glucose 5.5 mM, pH 7.4). The cells were stimulated by adding a compound diluted with a stimulation buffer containing LiCl (resulting in a final LiCl concentration of 50 mM) at 37 ° C, 10% CO ₂ for 1 hour. The assay was terminated by the addition of the manufacturer's HTRF conjugate (IP1-d2 and anti-IP1 cryptate Tb) and lysis buffer. After incubation at room temperature for one hour, using EnVision ^TM, Perkin Elmer measurement culture dish. The pEC obtained at 665/615 nM was then used to calculate the pEC using the GraphPad Prism 5 (Graphpad Software Inc, USA) by interpolation using the IP ₁ reference curve followed by the S-curve fit to consider the variable Hill slope. ₅₀ value.

The EC _{50 of the} compounds of the formula (I) of the invention analyzed as described above is, for example, less than 10,000 nM, specifically less than 1000 nM, and most preferably less than 100 nM.

The pharmaceutical composition of the present invention may further comprise another therapeutic agent. Particularly preferred are compositions wherein the other therapeutic agent is selected from the group consisting of antidiabetic agents such as insulin, long acting and short acting insulin analogs, sulfonylurea, biguanide, DPP-IV inhibitor, SGLT2 inhibitor, 11β- HSD inhibitor, glucokinase activator, AMPK activator, Glp-1 receptor agonist, GIP receptor agonist, DGAT inhibitor, PPAR gamma agonist, PPAR delta agonist and derived from thiazolidinedione Other antidiabetic agents; lipid lowering agents, such as statine, fiber esters, nicotinic acid derivatives or HMG coenzyme A reductase inhibitors; cardiovascular therapeutics such as nitrates; antihypertensive agents such as beta Blockers, ACE inhibitors, Ca channel blockers, angiotensin II a receptor antagonist, a diuretic, a platelet aggregation inhibitor; or an anti-neoplastic agent such as an alkaloid, an alkylating agent, an antibiotic or an antimetabolite; or an anti-obesity agent.

Particularly preferred are compounds such as human NPH insulin, human long-acting or ultra-long-acting insulin, insulin Lispro, insulin Aspart, insulin Glulisine, insulin detemir. ) or insulin Glargine, metformin, phenformin, acarbose, miglitol, voglibose, pioglitazone, roggliin Ketone (rosiglizatone), rivoglitazone, aleglitazar, alogliptin, saxagliptin, sitagliptin, vildagliptin ( Vildagliptin), linagliptin, dapagliflozin, remogliflozin etabonate, sergliflozin, canagliflozin, exenatide (exenatide), liraglutide (sitagliptin), albiglutide, pramlintide, carbutamide, chlorpropamide, glibenclamide (glibenclamide) (glyburide) Gliclazide, glimepiride, glipizide, gliquidone, simvastatine, bezafibrate, fenofibine Fenofibrate, gemfibrozil, clofibrate, etofibrate, fluvastatine, lovastatine, pravastatin, Colestyramide, acipimox and niacin.

One of ordinary skill in the art will appreciate that the compounds of the present invention and another therapeutic agent can be formulated as a single dosage form, or can be present in separate dosage forms and can be administered concomitantly (i.e., simultaneously) or sequentially.

The pharmaceutical composition of the present invention may be in any form suitable for the intended administration method.

The compound of the present invention may optionally contain a dosage unit formulation of a conventional pharmaceutically acceptable excipient, orally, parenterally, such as transbronchial, subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, Dermal, transmucosal, subdural, topical or topical via iontophoresis, sublingual, by inhalation spray, aerosol or transrectal and the like.

The excipients which can be used in the formulation of the pharmaceutical composition of the present invention comprise a carrier; a vehicle; a diluent; a solvent such as a monohydric alcohol such as ethanol, isopropanol, and a polyhydric alcohol such as ethylene glycol, and edible. Oils, such as soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, oil esters, such as ethyl oleate, isopropyl myristate; binders, adjuvants, solubilizers, thickeners, stable Agent, disintegrant, slip agent, lubricant, buffer, emulsifier, wetting agent, suspending agent, sweetener, coloring agent, flavoring agent, coating agent, preservative, antioxidant, processing agent, drug delivery regulation And enhancers such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-beta - cyclodextrin, polyvinylpyrrolidone, low melting wax, ion exchange resin.

Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, 15th ed., Mack Publishing Co., New Jersey (1991).

Dosage forms for oral administration include tablets, capsules, buccal tablets, pills, wafers, granules, oral liquids such as syrups, suspensions, solutions, emulsions, and restorative powders.

Formulations for parenteral administration include aqueous or oily solutions or emulsions for infusion, aqueous or oily solutions for injection, suspensions or emulsions, syringes for prefilled injections and/or reconstituted powders.

Topical/surface administration dosage forms include insufflators, aerosols, metered aerosols, transdermal therapeutic systems, medicated patches, rectal suppositories, and/or ovate suppositories.

The amount of a compound of the invention which may be combined with excipients to formulate a single dosage form will vary depending upon the host treated and the particular mode of administration.

The pharmaceutical compositions of the present invention can be prepared in a manner known to those skilled in the art, as described, for example, in Remington's Pharmaceutical Sciences, 15th Edition, Mack Publishing Co., New Jersey (1991).

For the purposes of the present invention, a therapeutically effective dose will generally be from about 1 mg to 2000 mg per day, preferably from about 10 mg to about 1000 mg per day, and optimally from about 10 mg to about 500 mg per day, which may be administered in one or more doses. Good by means of oral administration.

However, it will be appreciated that the particular dosage of a compound of the invention for any particular patient will depend on a number of factors, such as age, sex, weight, general health, diet, individual response of the patient to be treated, time of administration, severity of disease to be treated Degree, activity of specific compounds used, dosage form, mode of administration And accompanying drug therapy. The therapeutically effective amount for a particular situation will be readily determined by routine experimentation and within the skill and judgment of the general clinician or physician.

In another aspect, the invention relates to the use of a compound of the invention or a physiologically acceptable salt of the compound in combination with at least one of the active substances described above as a combination partner for the preparation of a suitable A pharmaceutical composition for treating or preventing a disease or condition which affects the effect of the receptor GPR40. Such diseases or conditions are preferably metabolic diseases, in particular one of the diseases or conditions listed above, most specifically diabetes or diabetic complications.

The use of a compound of the invention or a physiologically acceptable salt thereof in combination with another active substance can be carried out simultaneously or at interleaved times, but in particular in short time intervals. If administered simultaneously, the two active substances are administered to the patient together; and if used at the staggered time, the two active substances are administered to the patient for a period of less than or equal to 12 hours, but specifically less than or equal to 6 hours. .

Accordingly, in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention or a physiologically acceptable salt of the compound and at least one active substance as a combination partner as described above, In the case of one or more inert carriers and/or diluents.

The compound of the present invention or a physiologically acceptable salt thereof and another active substance to be combined therewith may be present in a formulation such as a troche or capsule, or separately in two identical or different formulations, for example It is in the form of a so-called package part.

The following examples are intended to illustrate the invention and not to limit it: The terms "ambient temperature" and "room temperature" are used interchangeably and indicate a temperature of about 20 °C.

Usually, ¹ H-NMR and/or mass spectrum of the prepared compound is obtained. The r _f value was determined using a Merck silicone 60 _{F 254} plate and UV light at 254 nm or stained with a suitable reagent such as molybdenum phosphate.

Analytical HPLC parameters used to characterize the product:

Intermediate 1 Methyl [6-(4-trifluoromethyl-indan-1-yloxy)-2,3-dihydro-benzofuran-3-yl]-acetate

Step 1 : (6-Hydroxy-benzofuran-3-yl)-acetic acid methyl ester

A mixture of (6-hydroxy-benzofuran-3-yl)-acetic acid (for preparation see WO 2008001931; 14.0 g), concentrated sulfuric acid (5 mL) and methanol (250 mL) was stirred at reflux temperature for 4 hours. After cooling to room temperature, the mixture was concentrated. Ethyl acetate was added to the residue, and the resulting mixture was washed with water, washed with saturated NaHCO ₃ solution and brine, and dried (MgSO _4). The solvent was evaporated and the residue was purified elut elut elut elut elut Yield: 9.0 g (60% of theory); mass spectrum (ESI ⁺ ): m/z = 207[M+H] ⁺ .

Step 2 : (6-Hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

a mixture of (6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester (5.00 g), 10% palladium on carbon (0.50 g) and methanol (50 mL) under a hydrogen atmosphere (3 bar) at room temperature Under the shock for 3 hours. The catalyst was separated by filtration and the filtrate was concentrated. The residue was crystallized from EtOAc (EtOAc:EtOAc:EtOAc Yield: 2.60 g (51% of theory); mass spectrum (ESI ⁺ ): m/z = 209 [M+H] ⁺ .

The enantiomer can be passed through the palm phase SFC (column: Daicel ADH, 5 μm, 250 mm × 20 mm; eluent: scCO ₂ / (isopropyl alcohol + 0.2% diethylamine) 80: 20, 70 mL / min) separation :( S) - (6- hydroxy-2,3-dihydro - benzofuran-3-yl) - acetic acid methyl ester: t _R = 2.33 min.

(R) - (6- hydroxy-2,3-dihydro - benzofuran-3-yl) - acetic acid methyl ester: t _R = 2.75 min. Alternatively, the pure enantiomer can be obtained as described in WO 2008001931.

Step 3 : [6-(4-Trifluoromethyl-indan-1-yloxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

Add diethyl azodicarboxylate (40% toluene solution, 1.13 mL; or use diisopropyl azodicarboxylate or di-t-butyl azodicarboxylate) to (6-hydroxy-2) at room temperature , 3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (0.52 g), 4-trifluoromethyl-indan-1-ol (for preparation see WO 2009157418; 0.50 g) and triphenyl A solution of phosphine (0.65 g) in tetrahydrofuran (20 mL). The resulting solution was stirred at room temperature for 3 hours and then concentrated. The title compound was obtained as a mixture of four stereoisomers. Yield: 0.51 g (53% of theory); mass spectrum (ESI ⁺ ): m/z = 393 [M+H] ⁺ .

Intermediate 2 Methyl {6-[( R )-4-bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Following a procedure similar to that described in Step 3 of Intermediate 1, from (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester and ( S )-4-bromo-di Hydroquinone-1-ol (for preparation see WO 2009157418 and Agricultural and Biological Chemistry (1982), 46(10), 2579-85) The title compound was prepared. Yield: 56% of theory; LC (method 1): t _R = 1.43 min; mass spectrum (ESI ⁺ ): m/z = 403 / 405 (Br) [M+H] ⁺ . Non-pure enantiomeric compounds by chromatographic separation of the title compound or by using [( S )-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetate in the above procedure Ester is obtained.

Intermediate 3 {6-[( R )-4-(1-methyl-1H-pyrazol-4-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Methyl acetate

Stirring bar, {6-[( R )-4-bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (100 mg) ), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron a flask of 2-yl)-1H-pyrazole (52 mg), 2 M Na ₂ CO ₃ (0.31 mL) and N,N-dimethylformamide (1 mL) at room temperature with argon Spray for 5 minutes. [1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium dichloromethane complex (20 mg) was added and the mixture was heated to 90 °C. After stirring at 90 ° C for 3 hours, the mixture was cooled to ambient temperature and diluted with water. And the mixture was dried (MgSO ₄₎ of the combined extracts was extracted with ethyl acetate. The solvent was evaporated and the residue was purified eluted elut elut elut elut Yield: 50 mg (50% of theory); LC (method 1): t _R = 1.25 min; mass spectrum (ESI ⁺ ): m/z = 405 [M+H] ⁺ .

Intermediate 4 {6-[(R)-4-(3,6-Dihydro-2H-pyran-4-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-methyl}-methyl acetate

Following a procedure similar to that described in Intermediate 3 from {6-[( R )-4-bromo-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -methyl acetate and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxon The title compound was prepared from 2-yl)-3,6-dihydro-2H-pyran. Yield: 41% of theory; LC (method 1): t _R = 1.55 min; mass spectrum (ESI ⁺ ): m/z = 407 [M+H] ⁺ .

Intermediate 5 {6-[( R )-4-(1-methyl-2-oxooxy-1,2-dihydro-pyridin-4-yl)-indan-1-yloxy]-2,3 -dihydro-benzofuran-3-yl}-acetic acid methyl ester

Following a procedure similar to that described in Intermediate 3 from {6-[( R )-4-bromo-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -methyl acetate and 1-methyl-2-oxooxy-1,2-dihydro-pyridine-4- The title compound was prepared by acid. Yield: 62% of theory; LC (method 1): t _R = 1.20 min; mass spectrum (ESI ⁺ ): m/z = 432 [M+H] ⁺ .

Intermediate 6 {6-[( R )-4-(4-methoxy-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid A ester

Following a procedure similar to that described in Intermediate 3 from {6-[( R )-4-bromo-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -methyl acetate and 4-methoxy-phenyl The title compound was prepared by acid. Yield: 62% of theory; LC (method 1): t _R = 1.46 min; mass spectrum (ESI ⁺ ): m/z = 431 [M+H] ⁺ .

Intermediate 7 {6-[4-(2,2-Difluoro-1-methoxy-ethyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -methyl acetate

Step 1 : (4-Bromo-indoline-1-yloxy)-tert-butyl-dimethyl-decane

Tributyl dimethyl decane chloride (6.60 g) was added in three aliquots to 4-bromo-indoline-1-ol cooled to about 10 ° C (for preparation see J. Org. Chem. 1984 , 49). , 4226-37 and WO 2006/065809; 6.22 g) and imidazole (4.97 g) in a solution of N,N-dimethylformamide (40 mL). The cooling bath was removed and the solution was stirred at room temperature for 6 hours. Water (100 mL) was added and the resulting mixture was stirred for 30 min. The mixture was acidified using 1 M aqueous HCl (pH ~ 5) and extracted with ethyl acetate. Dried (MgSO ₄₎ of the combined extracts and the solvent was evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc Yield: 6.3 g (66% of theory).

Step 2 : 1-[1-(Third butyl-dimethyl-decyloxy)-indan-4-yl]-2,2-difluoro-ethanol

Add n-butyllithium (1.6 mol/L hexane solution, 0.96 mL) to (4-bromo-indo-1-yloxy)-tert-butyl-dimethyl-decane at -78 °C (0.50 g) in a solution in tetrahydrofuran (5 mL). The resulting solution was stirred at -78 °C for 20 min, then ethyl difluoroacetate (0.16 mL) dissolved in THF (1 mL). Solution was stirred at -78 deg.] C for 1 h and then quenched by addition of saturated NH ₄ Cl aq. The aqueous mixture was extracted with EtOAc and EtOAc (EtOAc) And the solution was cooled in an ice bath was added NaBH ₄ (58 mg). The cooling bath was removed and the resulting mixture was stirred at room temperature overnight. A saturated aqueous solution of NaHCO _{3 was} added, and the resulting mixture was stirred for 1 hour. The mixture was extracted tert-butyl methyl ether and dried with (MgSO ₄₎ of the combined extracts and concentrated. The title compound was obtained as a colorless oil. Yield: 0.20 g (40% of theory); mass spectrum (ESI ^- ): m/z = 327 [MH] ^- .

Step 3 : Tert-butyl-[4-(2,2-difluoro-1-methoxy-ethyl)-indan-1-yloxy]-dimethyl-decane

Sodium hydride (60% mineral oil solution; 22 mg) was added to 1-[1-(t-butyl-dimethyl-decyloxy)-indan-4-yl]-2 at room temperature , a solution of 2-difluoro-ethanol (0.18 g) in tetrahydrofuran (1 mL). The mixture was stirred for 30 minutes, after which time methyl iodide (2 mol/L of butyl dimethyl ether solution; 0.41 mL) was added. The mixture was stirred overnight at room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. Dried (MgSO _4), and the combined extracts were concentrated to the give the title compound as an oil. Yield: 0.19 g (crude material); LC (Method 1): t _R = 1.52 min.

Step 4 : 4-(2,2-Difluoro-1-methoxy-ethyl)-indan-1-ol

Add tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution; 1.6 mL) to the third butyl-[4-(2,2-difluoro-1-methoxy-ethyl) cooled in an ice bath a solution of dihydroindol-1-yloxy]-dimethyl-decane (0.18 g) in tetrahydrofuran (1 mL). The solution was stirred for 3 hours under cooling and then quenched by the addition of water. And the mixture was dried (MgSO ₄₎ of the combined extracts was extracted with ethyl acetate. The solvent was evaporated and the residue was purified eluted elut elut elut elut elut Yield: 80 mg (67% of theory); LC (method 2): t _R =1.14 / 1.15 min; mass spectrum (ESI ⁺ ): m/z = 211 [M+HH ₂ O] ⁺ .

Step 5 : {6-[4-(2,2-Difluoro-1-methoxy-ethyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -yl}-methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from 4-(2,2-difluoro-1-methoxy-ethyl)-indan-1-ol and (6-hydroxy-2, The title compound was prepared from methyl 3-dihydro-benzofuran-3-yl)-acetate. Yield: 68% of theory; LC (method 1): t _R = 1.31 min; mass spectrum (ESI ⁺ ): m/z = 419 [M+H] ⁺ .

Intermediate 8 {6-[( R )-4-(tetrahydro-pyran-4-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid Methyl ester

{6-[( R )-4-(3,6-Dihydro-2H-furan-4-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 A mixture of methyl acetate-methyl acetate (70 mg), PtO ₂ (20 mg) and ethyl acetate (5 mL) was shaken at room temperature under a hydrogen atmosphere (3 bar). The catalyst was isolated by filtration, and the filtrate was evaporated to purified crystals crystals Yield: 70 mg (quantitative); mass spectrum (ESI ⁺ ): m/z = 409 [M+H] ⁺ .

Intermediate 9 {6-[4-(1-Methoxy-2,2-dimethyl-propyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl }-methyl acetate

Step 1 : 1-[1-(Third butyl-dimethyl-decyloxy)-indan-4-yl]-2,2-dimethyl-propan-1-ol

The title compound was prepared from (4-bromo-dihydroinden-1-yloxy)-tert-butyl-dimethyl-decane and pivalaldehyde using a procedure similar to that described in Step 2 of Intermediate 7. Obtained as a mixture of two diastereomers; since pivalaldehyde is used as an electrophile, subsequent reduction as described in Intermediate 7, Step 2 is omitted. Yield: 35% of theory; LC (method 1): t _R = 1.54 / 1.56 min; mass spectrum (ESI ⁺ ): m/z = 352 [M+NH ₄ ] ⁺ .

Step 2 : Tert-butyl-[4-(1-methoxy-2,2-dimethyl-propyl)-indan-1-yloxy]-dimethyl-decane

Follow the procedure shown in Step 3 similar to Intermediate 7 from 1-[1-(t-butyl-dimethyl-decyloxy)-indan-4-yl]-2,2-di Methyl-propan-1- The title compound was prepared as the alcohol and was obtained as a mixture of two diastereomers. Yield: Quantitative (crude product).

Step 3 : 4-(1-Methoxy-2,2-dimethyl-propyl)-indan-1-ol

Follow the procedure shown in Step 4 similar to Intermediate 7 from Tributyl-[4-(1-methoxy-2,2-dimethyl-propyl)-indan-1-yloxy The title compound was prepared as a dimethyl-decane and was obtained as a mixture of two diastereomers. Yield: 50% of theory; mass spectrum (ESI ⁺ ): m/z = 217 [M+HH ₂ O] ⁺ .

Step 4 : {6-[4-(1-Methoxy-2,2-dimethyl-propyl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-methyl}-methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from 4-(1-methoxy-2,2-dimethyl-propyl)-indan-1-ol and (6-hydroxy-2) The title compound is prepared as methyl 3-hydro-benzofuran-3-yl)-acetate; the product is obtained as a mixture of diastereomers. Yield: 46% of theory; mass spectrum (ESI ⁺ ): m/z = 425 [M+H] ⁺ .

Intermediate 10 {( S )-6-[4-(Cyclobutyl-methoxy-methyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Methyl acetate

Step 1 : [1-(Third butyl-dimethyl-decyloxy)-indan-4-yl]-cyclobutyl-ketone

Add n-butyllithium (1.6 mol/L hexane solution, 0.96 mL) to (4-bromo-indo-1-yloxy)-tert-butyl-dimethyl-decane at -78 °C (0.50 g) in a solution in tetrahydrofuran (5 mL). The resulting solution was stirred at -78 °C for 20 minutes, then methoxy-methyl-decylamine (0.22 g) of cyclobutanecarboxylate dissolved in tetrahydrofuran (1 mL). The solution was stirred at -78 °C for 1 hour and then warmed to room temperature overnight in a cooling bath. Saturated aqueous NH ₄ Cl was added and the mixture was extracted with ethyl acetate. The combined extracts were concentrated and purified eluted elut elut elut elut elut Yield: 0.38 g (75% of theory); LC (method 1): t _R = 1.58 min; mass spectrum (ESI ⁺ ): m/z = 331 [M+H] ⁺ .

Step 2 : [1-(Third butyl-dimethyl-decyloxy)-indan-4-yl]-cyclobutyl-methanol

Stir [1-(T-butyl-dimethyl-decyloxy)-dihydroindol-4-yl]-cyclobutyl-methanone (0.38 g), NaBH ₄ (40 mg) at room temperature Mix with ethanol (2 mL) overnight. A saturated aqueous solution of NaHCO _{3 was} added, and the resulting mixture was stirred for 1 hour. The mixture was extracted tert-butyl methyl ether and dried with (MgSO ₄₎ of the combined extracts and concentrated. The residue was chromatographed eluted EtOAc (EtOAc:EtOAc Yield: 0.11 g (29% of theory); Mass spectrum ^{(ESI +): m / z} = 350 [M + NH 4] +.

Step 3 : Tert-butyl-[4-(cyclobutyl-methoxy-methyl)-indan-1-yloxy]-dimethyl-decane

The title was prepared from [1-(t-butyl-dimethyl-decyloxy)-indan-4-yl]-cyclobutyl-methanol following a procedure similar to that described in Step 3 of Intermediate 7. Compound. Yield: 96% of theory (crude product).

Step 4 : 4-(cyclobutyl-methoxy-methyl)-indan-1-ol

Follow the procedure shown in Step 4 similar to Intermediate 7 from tert-butyl-[4-(cyclobutyl-methoxy-methyl)-indan-1-yloxy]-dimethyl - decane to prepare the title compound. Yield: 75% of the theoretical value; the LC (Method _{1): t R = 1.56 min} ; Mass spectrum ^{(ESI +): m / z} = 215 [M + HH 2 O] +.

Step 5 : {( S )-6-[4-(Cyclobutyl-methoxy-methyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from 4-(cyclobutyl-methoxy-methyl)-indan-1-ol and ( S )-(6-hydroxy-2,3 -Dihydro-benzofuran-3-yl)-acetic acid methyl ester The title compound was obtained. Yield: 63% of theory; LC (method 3): t _R = 1.89 min; mass spectrum (ESI ⁺ ): m/z = 423 [M+H] ⁺ .

Intermediate 11 2-(5,5-Dimethyl-cyclopent-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaboron

Step 1 : 5,5-Dimethyl-cyclopent-1-enyl trifluoromethanesulfonate

n-Butyllithium (1.6 mol/l, 18.4 mL) was added to a solution of diisopropylamine (4.2 mL) cooled to -78 °C in tetrahydrofuran (50 mL). The solution was stirred at -78 °C for 20 minutes and then at 0 °C for a further 20 minutes. The solution was cooled to -78 ° C and 2,2-dimethyl-cyclopentanone (3.00 g) was added. The solution was stirred at -78 °C for 3 hours, then N-phenylbis(trifluoromethanesulfonimide) (10.00 g) dissolved in tetrahydrofuran (50 mL) was added dropwise. The solution was warmed to room temperature overnight in a cooling bath. The solution was diluted with heptane (100 mL) and saturated Na ₂ CO ₃ aq. The organic phase was separated and washed with saturated Na ₂ CO ₃ solution, water and brine. Dried (MgSO ₄₎ the organic phase and the solvent was evaporated. The residue was crystallized from EtOAc (EtOAc:EtOAc: Yield: 1.80 g (28% of theory).

Step 2 : 2-(5,5-Dimethyl-cyclopent-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaboron

Containing 5,5-dimethyl-cyclopent-1-enyl trifluoromethanesulfonate (1.70 g), bis(pinacolyl)diboron (1.80 g), Pd(PPh ₃ ) ₂ Cl ₂ (0.15 g), PPh ₃ (0.17 g) and sodium phenolate (1.21 g) were purged with argon for 10 minutes. Toluene (20 mL) was then added, and the resulting mixture was stirred at 50 ° C for 2 hr. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate. Dried (MgSO ₄₎ of the combined extracts and concentrated. The residue was chromatographed eluted EtOAc (EtOAc:EtOAc Yield: 1.25 g (81% of theory).

Intermediate 12 {6-[( R )-4-(5,5-Dimethyl-cyclopent-1-enyl)-indan-1-yloxy]-2,3- Methyl dihydro-benzofuran-3-yl}-acetate

Stirring bar, {6-[( R )-4-bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.23 g) , 3-(5,5-dimethyl-cyclopent-1-enyl)-1,5-dimethyl-2,4-dioxa-3-boron-bicyclo[3.1.0] Alkane (0.18 g), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (45 mg), K ₃ PO ₄ (0.30 g), water (0.15 mL) A flask of N,N-dimethylformamide (3 mL) was sparged with argon at room temperature for 5 minutes. Palladium(II) acetate (12 mg) was added and the mixture was heated to 75 °C. After stirring at 75 ° C overnight, the mixture was cooled to ambient temperature and diluted with water. And the mixture was dried (MgSO ₄₎ of the combined extracts was extracted with ethyl acetate. The solvent was evaporated and the residue was crystalljjjjjjjjjj Yield: 0.12 g (50% of theory); LC (method 1): t _R = 1.56 min; mass spectrum (ESI ⁺ ): m/z = 419 [M+H] ⁺ .

Intermediate 13 Methyl {( S )-6-[( R )-4-difluoromethoxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : 4-Difluoromethoxy-indoline-1-one

4-hydroxy-indoline-1-one (0.50 g), ethyl 1-bromo-1,1-difluoroacetate (0.65 mL), K ₂ CO ₃ (1.00 g) and N,N-dimethyl A mixture of formamide (5 mL) was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate and the organic phase was washed with 1 M aqueous hydrochloric acid and brine. Dried (MgSO ₄₎ organic phase was concentrated. The residue was obtained by chromatography on silica gel (hexanes / ethyl acetate: 20:1: 7:3) to give difluoro-(1-o-oxy-dihydroindol-4-yloxy)-ethyl acetate (0.21 g) , dissolved in methanol (3 mL). A 4 M aqueous NaOH solution (0.25 mL) was added and the mixture was stirred at room temperature for 1 hour. 4 M aqueous hydrochloric acid (0.3 mL) was added and the solution was stirred at room temperature for 1 hour. The solution was extracted with ethyl acetate and dried (MgSO _4), and the combined extracts were concentrated to the give the title compound as an oil. Yield: 0.18 g (26% of theory).

Step 2 : ( S )-4-Difluoromethoxy-indan-1-ol

Formic acid (0.12 mL) was added to a solution of triethylamine (0.39 mL). 4-Difluoromethoxy-indoline-1-one (0.18 g) was added and the flask was purged with argon. Adding chlorine {[(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)nonylamino}-(mesitylene) ruthenium(II) (30 mg; or the catalyst consists of N-[(1S,2S)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide and dichloro(p-methyl-isopropyl) The phenyl)-ruthenium (II) dimer was formed in situ) and the mixture was stirred at room temperature for 16 hours. Water was added and the resulting mixture was extracted with dichloromethane. Washed with saturated aqueous NaHCO ₃ and the combined extracts were dried of (MgSO _4). The solvent was evaporated and the residue was crystalljjjjjjjjjj Yield: 70 mg (39% of theory); LC (method 1): t _R = 0.93 min; Mass (ESI ⁺ ): m/z = 183 [M+HH ₂ O] ⁺ .

Step 3 : {( S )-6-[( R )-4-Difluoromethoxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-difluoromethoxy-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro- The title compound was prepared from methyl benzofuran-3-yl)-acetate. Yield: 52% of the theoretical value; the LC (Method _{3): t R = 1.36 min} ; Mass spectrum ^{(ESI +): m / z} = 391 [M + H] +.

Intermediate 14 {( S )-6-[( R )-4-(1-methoxy-cyclobutyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Methyl acetate

Step 1 : 1-[( S )-1-(Tertiary-butyl-dimethyl-decyloxy)-indan-4-yl]-cyclobutanol

Follow the procedure described in Step 2 similar to Intermediate 7 from [( S )-4-bromo-indan-1-yloxy]-tert-butyl-dimethyl-decane (similar to Intermediate 7) /Step 1 compound, prepared from ( S )-4-bromo-indan-1-ol, ( S )-4-bromo-indan-1-ol as obtained in WO 2009157418 or WO 8908096) The title compound was prepared from cyclobutanone; since the ketone was used as an electrophile, the subsequent reduction as described in Intermediate 7, Step 2 was omitted. TLC: r _f = 0.30 (silica gel, cyclohexane / ethyl acetate 4: 1); Mass spectrum ^{(ESI +): m / z} = 336 [M + NH 4] +.

Step 2 : ( S )-Tertibutyl-[4-(1-methoxy-cyclobutyl)-indan-1-yloxy]-dimethyl-decane

Following the procedure described in Step 3 analogous to Intermediate 7, 1-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-cyclo The title compound was prepared from butanol. TLC: r _f = 0.85 (gel, hexane/ethyl acetate 4:1).

Step 3 : ( S )-4-(1-methoxy-cyclobutyl)-indan-1-ol

Follow the procedure described in Step 4 similar to Intermediate 7 from ( S )-Tertibutyl-[4-(1-methoxy-cyclobutyl)-indan-1-yloxy]- The title compound was prepared from dimethyl-decane. Yield: 75% of the theoretical value; the LC (Method _{3): t R = 1.07 min} ; Mass spectrum ^{(ESI +): m / z} = 201 [M + HH 2 O] +.

Step 4 : {( S )-6-[( R )-4-(1-methoxy-cyclobutyl)-indan-1-yloxy]-2,3-dihydro-benzofuran Methyl-3-methyl}-acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-(1-methoxy-cyclobutyl)-indan-1-ol and ( S )-(6-hydroxy- The title compound was prepared from 2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester. LC (Method _{1): t R = 1.42 min} ; Mass spectrum ^{(ESI +): m / z} = 431 [M + Na] +.

Intermediate 15 {( S )-6-[( R )-6-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzo Methyl furan-3-yl}-acetate

Step 1 : ( S )-6-Trifluoromethyl-indan-1-ol

The title compound was prepared from 6-trifluoromethyl-indan-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 92% of the theoretical value; the LC (Method _{4): t R = 1.72 min} ; Mass spectrum ^{(ESI +): m / z} = 185 [M-OH] +.

Step 2 : {( S )-6-[( R )-6-Trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid Methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-6-trifluoromethyl-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro- The title compound was prepared from methyl benzofuran-3-yl)-acetate. Yield: 52% of the theoretical value; the LC (Method _{4): t R = 2.12 min} ; Mass spectrum ^{(ESI -): m / z} = 391 [MH] -.

Intermediate 16 Methyl {( S )-6-[( R )-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-5-Trifluoromethyl-indan-1-ol

The title compound was prepared from 5-trifluoromethyl-indoline-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 84% of theory; LC (method 4): t _R = 1.76 min; mass spectrum (ESI ⁺ ): m/z = 185 [M-OH] ⁺ .

Step 2 : {( S )-6-[( R )-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid Methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-5-trifluoromethyl-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro- The title compound was prepared from methyl benzofuran-3-yl)-acetate. Yield: 52% of the theoretical value; the LC (Method _{4): t R = 2.14 min} ; Mass spectrum ^{(ESI -): m / z} = 391 [MH] -.

Intermediate 17 Methyl {( S )-6-[( R )-5-chloro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-5-Chloro-indan-1-ol

The title compound was prepared from 5-chloro-indoline-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 87% of theory; LC (method 4): t _R = 1.64 min; mass spectrum (ESI ⁺ ): m/z = 151 / 153 (CI) [M-OH] ⁺ .

Step 2 : {( S )-6-[( R )-5-Chloro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-5-chloro-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro-benzofuran The title compound was prepared from -3-yl)-methyl acetate. Yield: 45% of the theoretical value; the LC (Method _{4): t R = 2.11 min} ; Mass spectrum ^{(ESI -): m / z} = 357/359 (Cl) [MH] -.

Intermediate 18 Methyl {( S )-6-[( R )-4-chloro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-4-Chloro-indan-1-ol

The title compound was prepared from 4-chloro-indoline-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 82% of theory; LC (method 4): t _R = 1.64 min; mass spectrum (ESI ⁺ ): m/z = 151 / 153 (CI) [M-OH] ⁺ .

Step 2 : {( S )-6-[( R )-4-Chloro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-chloro-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro-benzofuran The title compound was prepared from -3-yl)-methyl acetate. Yield: 48% of the theoretical value; the LC (Method _{4): t R = 2.13 min} ; Mass spectrum ^{(ESI -): m / z} = 357/359 (Cl) [MH] -.

Intermediate 19 Methyl {( S )-6-[( R )-7-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-7-Trifluoromethyl-indan-1-ol

The title compound was prepared from 7-trifluoromethyl-indan-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 72% of the theoretical value; the LC (Method _{4): t R = 1.69 min} ; Mass spectrum ^{(ESI +): m / z} = 185 [M-OH] +.

Step 2 : {( S )-6-[( R )-7-Trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid Methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-7-trifluoromethyl-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro- The title compound was prepared from methyl benzofuran-3-yl)-acetate. Yield: 48% of theory; LC (method 4): t _R = 2.08 min; mass spectrum (ESI ⁺ ): m/z = 393 [M+H] ⁺ .

Intermediate 20 {( S )-6-[( R )-7-fluoro-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Methyl acetate

Step 1 : ( S )-7-Fluoro-4-trifluoromethyl-indan-1-ol

The title compound was prepared from 7-fluoro-4-trifluoromethyl-indan-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 70% of the theoretical value; the LC (Method _{4): t R = 1.73 min} ; Mass spectrum ^{(ESI +): m / z} = 203 [M-OH] +.

Step 2 : {( S )-6-[( R )-7-Fluoro-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-7-fluoro-4-trifluoromethyl-indan-1-ol and ( S )-(6-hydroxy-2,3 -Dihydro-benzofuran-3-yl)-acetic acid methyl ester The title compound was obtained. Yield: 69% of theory; LC (method 4): t _R = 2.10 min; mass spectrum (ESI ⁺ ): m/z = 411 [M+H] ⁺ .

Intermediate 21 Methyl {( S )-6-[( R )-4-trifluoromethoxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-4-Trifluoromethoxy-indan-1-ol

The title compound was prepared from 4-trifluoromethoxy-indoline-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 82% of the theoretical value; the LC (Method _{4): t R = 1.76 min} ; Mass spectrum ^{(ESI +): m / z} = 201 [M-OH] +.

Step 2 : {( S )-6-[( R )-4-Trifluoromethoxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-trifluoromethoxy-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydrogen The title compound was prepared from -benzofuran-3-yl)-acetic acid methyl ester. Yield: 49% of theory; LC (method 4): t _R = 2.14 min; mass spectrum (ESI ⁺ ): m/z = 409 [M+H] ⁺ .

Intermediate 22 {( S )-6-[( R )-6-methyl-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -methyl acetate

Step 1 : ( S )-6-Methyl-4-trifluoromethyl-indan-1-ol

The title compound was prepared from 6-methyl-4-trifluoromethyl-indan-1-one following the procedure described in Step 2 to Intermediate 13.

Step 2 : {( S )-6-[( R )-6-Methyl-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -yl}-methyl acetate

Follow the procedure described in Step 3 of Intermediate 1 from ( S )-6-methyl-4-trifluoromethyl-indan-1-ol and ( S )-(6-hydroxy-2,3- The title compound was prepared from dihydro-benzofuran-3-yl)-acetic acid methyl ester. Yield: 39% of the theoretical value; the LC (Method _{4): t R = 2.17 min} ; Mass spectrum ^{(ESI +): m / z} = 429 [M + Na] +.

Intermediate 23 {( S )-6-[( R )-4-(1-methoxy-2,2-dimethyl-propyl)-indan-1-yloxy]-2,3-dihydro -benzofuran-3-yl}-acetic acid methyl ester (a mixture of two diastereomers)

Step 1 : ( S )-1-[1-(Third butyl-dimethyl-decyloxy)-indan-4-yl]-2,2-dimethyl-propan-1-ol (a mixture of two diastereomers)

Follow the procedure described in Step 2 similar to Intermediate 7 from [( S )-4-bromo-indan-1-yloxy]-tert-butyl-dimethyl-decane (similar to Intermediate 7) /Step 1 compound, prepared from ( S )-4-bromo-indan-1-ol, ( S )-4-bromo-indan-1-ol as obtained in WO 2009157418 or WO 8908096) The title compound was prepared from pivalaldehyde; since the aldehyde was used as an electrophile, the subsequent reduction as described in Intermediate 7, Step 2 was omitted. Yield: 89% of theory; LC (method 1): t _R = 1.54 / 1.56 min; mass spectrum (ESI ⁺ ): m/z = 357 [M+Na] ⁺ .

Step 2 : Tert-butyl-[4-(1-methoxy-2,2-dimethyl-propyl)-indan-1-yloxy]-dimethyl-decane (2 non- a mixture of enantiomers)

Follow the procedure described in Step 3 similar to Intermediate 7 from ( S )-1-[1-(t-butyl-dimethyl-decyloxy)-indan-4-yl]-2 , 2-Dimethyl-propan-1-ol (a mixture of two diastereomers) gave the title compound. Yield: Quantitative (crude product). LC (Method _{1): t R = 1.65 min} .

Step 3 : ( S )-4-(1-Methoxy-2,2-dimethyl-propyl)-indan-1-ol (mixture of two diastereomers)

Follow the procedure described in Step 4 similar to Intermediate 7 from tert-butyl-[( S )-4-(1-methoxy-2,2-dimethyl-propyl)-indoline- 1-Thekoxy]-dimethyl-decane (a mixture of two diastereomers) gave the title compound. Yield: 61% of theory; LC (method 1): t _R = 1.24 / 1.26 min; mass spectrum (ESI ⁺ ): m/z = 217 [M+HH ₂ O] ⁺ .

Step 4 : {( S )-6-[( R )-4-(1-methoxy-2,2-dimethyl-propyl)-indan-1-yloxy]-2,3 -Dihydro-benzofuran-3-yl}-acetic acid methyl ester (mixture of two diastereomers)

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-(1-methoxy-2,2-dimethyl-propyl)-indan-1-ol and ( S The title compound was prepared as the methyl ester of (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetate. Yield: 39% of theory; LC (method 1): t _R = 1.50 min; mass spectrum (ESI ^- ): m/z = 425 [M+H] ⁺ .

Intermediate 24 {( S )-6-[( R )-7-Methyl-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -methyl acetate

Step 1 : ( S )-7-Methyl-4-trifluoromethyl-indan-1-ol

The title compound was prepared from 7-methyl-4-trifluoromethyl-indan-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 73% of theory; LC (method 4): t _R = 1.79 min; mass spectrum (ESI ⁺ ): m/z = 199 [M-OH] ⁺ .

Step 2 : {( S )-6-[( R )-7-Methyl-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -yl}-methyl acetate

Following the procedure described in Step 3 of Intermediate 1, ( S )-7-Methyl-4-trifluoromethyl-indan-1-ol and ( S )-(6-hydroxy-2,3- The title compound was prepared from dihydro-benzofuran-3-yl)-acetic acid methyl ester. Yield: 39% of theory; LC (method 4): t _R = 2.13 min; mass spectrum (ESI ^- ): m/z = 405 [MH] ^- .

Intermediate 25 Methyl {( S )-6-[( R )-4-cyclopropyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-Third butyl-(4-cyclopropyl-indan-1-yloxy)-dimethyl-decane

The cyclopropyl zinc bromide (0.5 mol/L tetrahydrofuran solution; 12 mL) was slowly added to the [( S )-4-bromo-indoline-1-yloxy group] cooled in an ice bath under an argon atmosphere. -T-butyl-dimethyl-decane (1.00 g), palladium(II) acetate (69 mg), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'- A mixture of biphenyl (0.25 g) and tetrahydrofuran (50 mL). The cooling bath was removed and the resulting mixture was stirred at room temperature overnight. Then, cyclopropyl zinc bromide (0.5 mol/L tetrahydrofuran solution; 2 mL) was further added and the same amount was added after stirring for another day. After stirring for an additional hour, water was added and the resulting mixture was extracted with ethyl acetate. Washed with water and brine and the organic layers were combined, dried (Na ₂ SO ₄₎ and concentrated. The title compound was obtained as an oil. Yield: 0.72 g (73% of theory); the LC (Method _{4): t R = 2.46 min} .

Step 2 : ( S )-4-cyclopropyl-indan-1-ol

Preparation of the title compound from ( S )-t-butyl-(4-cyclopropyl-dihydroindol-1-yloxy)-dimethyl-decane following a procedure similar to that described in Step 4 of Intermediate 7 . Yield: 70% of theory; LC (method 4): t _R = 1.71 min; mass spectrum (ESI ⁺ ): m/z = 157 [M+HH ₂ O] ⁺ .

Step 3 : {( S )-6-[( R )-4-cyclopropyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid A ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-cyclopropyl-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro-benzene The title compound was prepared from furan-3-yl)-acetic acid methyl ester. Yield: 37% of the theoretical value; the LC (Method _{4): t R = 2.12 min} ; Mass spectrum ^{(ESI +): m / z} = 387 [M + Na] +.

Intermediate 26 Methyl {( S )-6-[( R )-4-isopropyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-4-Isopropenyl-indan-1-ol

Trit(triphenylphosphine)palladium(0) (0.27 g) was added to ( S )-4-bromo-indoline-1-ol (1.00 g; for preparation see WO 2009157418 and WO 8908096) under a hydrogen atmosphere. ,4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaboron (1.58 g), a mixture of K ₃ PO ₄ (2.99 g), 1,2-dimethoxyethane (10 mL) and water (5 mL). The mixture was stirred at 90 ° C for 4 hours in a microwave oven. Water was added and the resulting mixture was extracted with ethyl acetate. Washed with water and brine and the organic layers were combined, dried (Na ₂ SO ₄₎ and concentrated. The residue was chromatographed (heptane / ethyl acetate). Yield: 0.96 g (quantitative); LC (method 4): t _R = 1.73 min; mass spectrum (ESI ⁺ ): m/z = 157 [M+HH ₂ O] ⁺ .

Step 2 : ( S )-4-Isopropyl-indan-1-ol

Platinum oxide (0.11 g) was added to ( S )-4-isopropenyl-indan-1-ol (0.81 g) dissolved in ethyl acetate (40 mL). Hydrogen gas (balloon pressure) was applied and the resulting mixture was stirred at room temperature for 1 hour. The mixture was filtered through celite and the filtrate was concentrated. The title compound was obtained as a colorless oil. Yield: 0.82 g (87% of theory); LC (method 4): t _R = 1.77 min; mass spectrum (ESI ⁺ ): m/z = 159 [M+HH ₂ O] ⁺ .

Step 3 : {( S )-6-[( R )-4-Isopropyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-isopropyl-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro-benzene The title compound was prepared from furan-3-yl)-acetic acid methyl ester. Yield: 33% of the theoretical value; the LC (Method _{4): t R = 2.17 min} ; Mass spectrum ^{(ESI -): m / z} = 365 [MH] -.

Intermediate 27 {( S )-6-[( R )-4-(2,6-Dimethyl-phenyl)-indan-1-yloxy]-2,3-di Hydrogen-benzofuran-3-yl}-acetic acid methyl ester

Step 1 : ( S )-4-(2,6-Dimethyl-phenyl)-indan-1-ol

Trit(triphenylphosphine)palladium(0) (0.14 g) was added to the (S)-4-bromo-2,3-dihydro-1H-indol-1-ol (0.50 g) under Ar atmosphere. , K ₂ CO ₃ (0.97 g), 2,6-dimethylphenyl In a microwave vial of acid (0.70 g), 1,2-dimethoxyethane (10 mL) and water (2.5 mL). The vial was sealed and the mixture was stirred at 100 ° C for 3 hours in a microwave oven. The mixture was diluted with water and extracted with ethyl acetate. Washed with brine the combined organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The residue was crystallized from EtOAc (EtOAc) elute Yield: 0.15 g (27% of theory); LC (method 4): t _R = 1.93 min; mass spectrum (ESI ⁺ ): m/z = 221 [M+HH ₂ O] ⁺ .

Step 2 : {( S )-6-[( R )-4-(2,6-Dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzo Methyl furan-3-yl}-acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-(2,6-dimethyl-phenyl)-indan-1-ol and ( S )-(6-hydroxyl) The title compound was prepared from methyl-2,3-dihydro-benzofuran-3-yl)-acetate. Yield: 32% of theory; LC (method 4): t _R = 2.23 min; mass spectrum (ESI ⁺ ): m/z = 451 [M+Na] ⁺ .

Intermediate 28 {( S )-6-[( R )-4-(2,2-dimethyl-propyl)-indan-1-yloxy]-2,3-di Hydrogen-benzofuran-3-yl}-acetic acid methyl ester

Step 1 : ( S )-Tertibutyl-[4-(2,2-dimethyl-propyl)-indan-1-yloxy]-dimethyl-decane

The neopentyl bromide (0.5 mol/L, 12 mL) was slowly added to the [( S )-4-bromo-indoline-1-yloxy]-cooled in an ice bath under an argon atmosphere. Tributyl-dimethyl-decane (1.00 g), palladium(II) acetate (0.07 g), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (0.25 g) in a mixture with tetrahydrofuran (50 mL). The cooling bath was removed and the resulting mixture was stirred at room temperature for 2 hours. Water was added and the resulting mixture was extracted with ethyl acetate. Washed with water and brine and the organic layers were combined, dried (Na ₂ SO ₄₎ and concentrated. The title compound was obtained as a colorless oil. Yield: 0.88 g (86% of theory); LC (method 4): t _R = 2.70 min; mass spectrum (ESI ⁺ ): m/z = 187 [M-OSiMe ₂ tBu] ⁺ .

Step 2 : ( S )-4-(2,2-Dimethyl-propyl)-indan-1-ol

Follow the procedure described in Step 4 similar to Intermediate 7 from ( S )-t-butyl-[4-(2,2-dimethyl-propyl)-indan-1-yloxy] The title compound was prepared from dimethyl-decane. Yield: 87% of theory; LC (Method 4): t _R = 1.94 min; Mass (ESI ⁺ ): m/z = 187 [M+HH ₂ O] ⁺ .

Step 3 : {( S )-6-[( R )-4-(2,6-Dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzo Methyl furan-3-yl}-acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-(2,2-dimethyl-propyl)-indan-1-ol and ( S )-(6-hydroxyl The title compound was prepared from methyl-2,3-dihydro-benzofuran-3-yl)-acetate. Yield: 32% of theory; LC (method 4): t _R = 2.26 min; mass spectrum (ESI ⁺ ): m/z = 417 [M+Na] ⁺ .

Intermediate 29 {( S )-6-[( R )-4-(2-isopropyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl }-methyl acetate

Step 1 : ( S )-4-(2-Isopropyl-phenyl)-indan-1-ol

Follow the procedure described in Step 1 similar to Intermediate 27 from ( S )-4-bromo-indan-1-ol and (2-isopropylphenyl) The title compound was prepared by acid. Yield: 97% of theory; LC (method 4): t _R = 1.96 min; mass spectrum (ESI ⁺ ): m/z = 235 [M-OH] ⁺ .

Step 2 : {( S )-6-[( R )-4-(2-isopropyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-methyl}-methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-(2-isopropyl-phenyl)-indan-1-ol and ( S )-(6-hydroxy-2) The title compound was prepared from methyl 3-hydro-benzofuran-3-yl)-acetate. Yield: 54% of theory; LC (method 4): t _R = 2.24 min; mass spectrum (ESI ⁺ ): m/z = 465 [M+Na] ⁺ .

Intermediate 30 {( S )-6-[( R )-5-Methyl-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -methyl acetate

Step 1 : 3-(3-Methyl-2-trifluoromethyl-phenyl)-propionic acid ethyl ester

1-Bromo-3-methyl-2-(trifluoromethyl)benzene (0.17 mL), N,N-diisopropylethylamine (0.36 mL) and acrolein (0.48) under Ar atmosphere mL) was added to a flask equipped with a stir bar, tetrabutylammonium chloride (0.29 g) and anhydrous N,N-dimethylformamide (5 mL). The mixture was purged with Ar for 5 minutes, after which palladium(II) acetate (2.4 mg) was added. The flask was placed in a preheated (90 ° C) oil bath and the mixture was stirred for 10 minutes. After cooling to room temperature, the mixture was poured into 2 N aqueous hydrochloric acid (30 mL) and the resulting mixture was ₂ O and extracted with Et. The combined washed with water and brine and the organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The title compound was obtained from EtOAc (EtOAc) Yield: 0.11 g (39% of theory).

Step 2 : 3-(3-Methyl-2-trifluoromethyl-phenyl)-propionic acid

The title compound was prepared from 3-(3-methyl-2-trifluoromethyl-phenyl)-propionic acid ethyl ester. Yield: 94% of the theoretical value.

Step 3 : 5-Methyl-4-trifluoromethyl-indan-1-one

3-[3-Methyl-2-(trifluoromethyl)phenyl]propanoic acid (0.61 g) dissolved in trifluoromethanesulfonic acid (5.8 ml) was stirred at 60 ° C for 2 hours. After cooling to room temperature, the mixture was poured into water (500 mL) and the mixture was extracted with diethyl ether. The combined organic extracts were washed with brine and concentrated. The title compound was obtained as a colorless solid. Yield: 0.31 g (56% of theory).

Step 4 : ( S )-5-Methyl-4-trifluoromethyl-indan-1-ol

The title compound was prepared from 5-methyl-4-trifluoromethyl-indan-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 70% of theory; LC (method 4): t _R = 1.80 min; mass spectrum (ESI ⁺ ): m/z = 199 [M-OH] ⁺ .

Step 5 : {( S )-6-[( R )-5-Methyl-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -yl}-methyl acetate

Follow the procedure described in Step 3 of Intermediate 1 from ( S )-5-methyl-4-trifluoromethyl-indan-1-ol and ( S )-(6-hydroxy-2,3- The title compound was prepared from dihydro-benzofuran-3-yl)-acetic acid methyl ester. Yield: 54% of theory; LC (method 4): t _R = 2.14 min; mass spectrum (ESI ^- ): m/z = 405 [MH] ^- .

Intermediate 31 Methyl {( S )-6-[( R )-4,5-difluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-4,5-Difluoro-indan-1-ol

The title compound was prepared from 4,5-difluoro-indoline-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 87% of theory; LC (method 4): t _R = 1.62 min; mass spectrum (ESI ⁺ ): m/z = 153 [M-OH] ⁺ .

Step 2 : {( S )-6-[( R )-4,5-Difluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid Methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4,5-difluoro-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro- The title compound was prepared from methyl benzofuran-3-yl)-acetate. Yield: 60% of theory; the LC (Method _{4): t R = 2.01 min} ; Mass spectrum ^{(ESI -): m / z} = 359 [MH] -.

Intermediate 32 and intermediate 33 ( S )-4-[( R )-2,2,2-trifluoro-1-methoxy-ethyl]-indan-1-ol and ( S )-4-[( S )-2 , 2,2-trifluoro-1-methoxy-ethyl]-indan-1-ol

Step 1 : 1-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-2,2,2-trifluoro-ethanone

Add n-butyllithium (2.5 mol/L hexane solution, 0.92 mL) slowly to [( S )-4-bromo-indan-1-yloxy]-t-butyl group cooled to -78 °C a solution of dimethyl-nonane (0.50 g) in tetrahydrofuran (25 mL). The solution was stirred for 30 minutes, then ethyl trifluoroacetate (0.55 mL) dissolved in tetrahydrofuran (5 ml). The mixture was stirred at -78 °C for 30 minutes and then warmed to room temperature by removing the cooling bath. Water was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na ₂ SO ₄₎ and concentrated. The residue was used in the next step without further purification. Yield: 0.52 g (99% of theory); LC (method 4): t _R = 2.64 min; mass spectrum (ESI ^- ): m/z = 343 [MH] ^- .

Step 2 : 1-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-2,2,2-trifluoro-ethanol (2 species a mixture of diastereomers)

Add NaBH ₄ (57 mg) to 1-[( S )-1-(t-butyl-dimethyl-decyloxy)-indan-4-yl]-2, cooled to 0 °C. A solution of 2,2-trifluoro-ethanone (0.52 g) in ethanol (8 mL). The mixture was stirred at 0 °C for 5 minutes and then the cooling bath was removed. After the mixture was stirred at room temperature for 1 hour, water was added and the resulting mixture was extracted with ethyl acetate. Washed with brine the combined organic layers were dried (Na ₂ SO ₄₎ and concentrated. The title compound was obtained from EtOAc (EtOAc) Yield: 0.39 g (75% of theory). LC (Method _{4): t R = 2.45 min} .

Step 3 : Tert-butyl-dimethyl-[( S )-4-(2,2,2-trifluoro-1-methoxy-ethyl)-indan-1-yloxy]- Hydrane (a mixture of two diastereomers)

Following the procedure described in Step 3 analogous to Intermediate 7, 1-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-2 , 2,2-Trifluoro-ethanol (mixture of 2 diastereomers) gave the title compound. Yield: 94% of the theoretical value. LC (Method 4): t _R = 2.73 min; Mass (ESI ^- ): m/z = 229 [M-OSiMe ₂ tBu] ⁺ .

Step 4 : ( S )-4-[( R )-2,2,2-trifluoro-1-methoxy-ethyl]-indan-1-ol and ( S )-4-[( S )-2,2,2-trifluoro-1-methoxy-ethyl]-indan-1-ol

Follow the procedure described in Step 4 similar to Intermediate 7 from tert-butyl-dimethyl-[( S )-4-(2,2,2-trifluoro-1-methoxy-ethyl) -Indoline-1-yloxy]-decane (a mixture of two diastereomers) gave the title compound. The two obtained diastereomers were separated by silica gel chromatography (heptane / ethyl acetate).

( S )-4-[( R ) ^* -2,2,2-trifluoro-1-methoxy-ethyl]-indan-1-ol (arbitrarily designated stereoisomeric center ( ^* ) Configuration): LC (method 4): t _R = 1.73 min; mass spectrum (ESI ⁺ ): m/z = 229 [M-OH] ⁺ ; ( S )-4-[( S ) ^* -2,2 , 2-trifluoro-1-methoxy-ethyl]-indan-1-ol (arrangement of any given stereogenic center ( ^* ) specified): LC (method 4): t _R = 1.73 Min; mass spectroscopy (ESI ⁺ ): m/z = 229[M-OH] ⁺ .

Intermediate 34 {( S )-6-[( R )-4-(( R ) ^* -2,2,2-trifluoro-1-methoxy-ethyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (Optionally specify the stereogenic center shown ( ^* ) configuration)

Following the procedure described in Step 3 similar to Intermediate 1, ( S )-4-[( R ) ^*- 2,2,2-trifluoro-1-methoxy-ethyl]-indoline- Preparation of 1-alcohol (arbitrary designation of the indicated stereoisomeric center ( ^* )) and ( S )-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester Compound. Yield: 31% of theory; LC (method 4): t _R = 2.05 min; mass spectrum (ESI ^- ): m/z = 435 [MH] ^- .

Intermediate 35 {( S )-6-[( R )-4-(( S ) ^* -2,2,2-trifluoro-1-methoxy-ethyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (Optionally specify the stereogenic center shown ( ^* ) configuration)

Following the procedure described in Step 3 similar to Intermediate 1, ( S )-4-[( S ) ^*- 2,2,2-trifluoro-1-methoxy-ethyl]-indoline- Preparation of 1-alcohol (arbitrary designation of the indicated stereoisomeric center ( ^* )) and ( S )-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester Compound. Yield: 63% of theory; LC (method 4): t _R = 2.04 min; mass spectrum (ESI ^- ): m/z = 435 [MH] ^- .

Intermediate 36 ( S )-4-(3,3,4-Trimethyl-oxetan-2-yl)-indan-1-ol (2 dissolving fractions containing different diastereomers)

Step 1 : ( S )-1-(Third butyl-dimethyl-decyloxy)-indoline-4-carbaldehyde

Add n-butyllithium (15% hexane solution, 1.15 mL) to ( S )-4-bromo-indoline-1-yloxy)-tert-butyl-dimethyl group cooled to -78 °C a solution of decane (0.40 g) in tetrahydrofuran (10 mL). The resulting solution was stirred at -50 °C for 1 hour, after which N,N-dimethylformamide (1 mL) was added. Solution was stirred at -78 deg.] C for 1 h and then quenched by addition of saturated NH ₄ Cl aq. The aqueous mixture was extracted with diethyl ether, washed with water and the combined extracts were washed, and dried (Na ₂ SO _4). Evaporation of the solvent gave the crude title compound. Yield: 0.33 g (96% of theory); LC (method 6): t _R = 1.64 min; mass spectrum (ESI ⁺ ): m/z=277[M+H] ⁺ .

Step 2 : ( S )-1-[1-(Third butyl-dimethyl-decyloxy)-indan-4-yl]-but-3-en-1-ol

1-Bromo-3-methyl-but-2-ene (0.40 mL), NaI (0.52 g) and In powder (0.27 g) were added to ( S )-1- (third) in the indicated order at room temperature A solution of butyl-dimethyl-decyloxy)-indoline-4-carbaldehyde (0.32 g) in N,N-dimethylformamide (5 mL). The resulting solution was stirred at room temperature for 4 hours. Add diethyl ether and washed with water and Na ₂ S ₂ O ₃ aqueous mixture was washed and dried (Na ₂ SO _4). Evaporation of the solvent gave the crude title compound. Yield: 0.39 g (97% of theory); LC (method 6): t _R = 1.78 / 1.82 min (mixture of diastereomers); mass spectrum (ESI ⁺ ): m/z = 369 [M+ Na] ⁺ .

Step 3 : ( S )-Tertibutyl-[4-(4-iodomethyl-3,3-dimethyl-oxetan-2-yl)-indan-1-yloxy ]-dimethyl-decane

Adding Li ₂ CO ₃ (0.56 g) and iodine (0.56 g) to ( S )-1-[1-(t-butyl-dimethyl-decyloxy)-indoline at room temperature A solution of 4-yl]-but-3-en-1-ol (0.38 g) in acetonitrile (3 mL). The resulting mixture was stirred at room temperature for 72 hours. Ether was added and the resulting mixture was Na ₂ S ₂ O ₃ solution and with brine and dried (Na ₂ SO _4). Evaporation of the solvent and EtOAc (EtOAc/EtOAc) Yield: 0.20 g (39% of theory).

Step 4 : ( S )-Tertibutyl-dimethyl-[4-(3,3,4-trimethyl-oxetan-2-yl)-indan-1-yloxy ]-decane

( S )-Tertibutyl-[4-(4-iodomethyl-3,3-dimethyl-oxetan-2-yl)-dihydroindol-1-yloxy]-di A mixture of methyl-decane (0.19 g), 10% palladium on carbon (30 mg), triethylamine (0.15 mL) and methanol (10 mL) was shaken under a hydrogen atmosphere (3 bar) at room temperature for 6 hours. The catalyst was separated by filtration and the filtrate was concentrated. The title compound was obtained from EtOAc (EtOAc/EtOAc) Yield: 0.08 g (57% of theory); LC (method 6): t _R = 1.84 min; mass spectrum (ESI ⁺ ): m/z = 369 [M+Na] ⁺ .

Step 5 : ( S )-4-(3,3,4-Trimethyl-oxetan-2-yl)-indan-1-ol (2 containing different diastereomers) Dissolved)

Follow the procedure described in Step 4 similar to Intermediate 7 from ( S )-T-butyl-dimethyl-[4-(3,3,4-trimethyl-oxetan-2- The title compound was prepared as the hydrazin-1-yloxy]-decane. Two dissolving fractions with different diastereomers were obtained after silica gel chromatography (petroleum ether/ethyl acetate).

( S )-4-(3,3,4-Trimethyl-oxetan-2-yl)-indan-1-ol (dissolved fraction 1): LC (Method 6): t _R = 0.48 min.

( S )-4-(3,3,4-Trimethyl-oxetan-2-yl)-indan-1-ol (dissolved fraction 2): LC (Method 6): t _R = 0.62 min.

Intermediate 37 and intermediate 38 {( S )-6-[( R )-4-(3,3,4-Trimethyl-oxetan-2-yl)-indan-1-yloxy]-2,3 -Dihydro-benzofuran-3-yl}-acetic acid methyl ester (two soluble fractions containing different diastereomers)

Following the procedure described in Step 3 similar to Intermediate 1, ( S )-4-(3,3,4-trimethyl-oxetan-2-yl)-indan-1-ol (Intermediate 36, Step 5, Dissolved Part 1; or Intermediate 36, Step 5, Dissolved Part 2) and ( S )-(6-Hydroxy-2,3-dihydro-benzofuran-3-yl)- The title compound was prepared from methyl acetate.

Intermediate 37: {( S )-6-[( R )-4-(3,3,4-trimethyl-oxetan-2-yl)-dihydroanthracene from Fraction 1 oxy-1-yl] -2,3-dihydro - benzofuran-3-yl} - acetic acid methyl ester: LC (method _{6): t R = 1.45 min} ; mass spectrum ^{(ESI +): m / z} = 445 [M+Na] ⁺ .

Intermediate 38: {( S )-6-[( R )-4-(3,3,4-trimethyl-oxetan-2-yl)-indoline - derived from Dissolved 2 oxy-1-yl] -2,3-dihydro - benzofuran-3-yl} - acetic acid methyl ester: LC (method _{6): t R = 1.43 min} ; mass spectrum ^{(ESI +): m / z} = 445 [M+Na] ⁺ .

Intermediate 39 [( S )-(indoline-1-yloxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 by indoline-1-ol and ( S )-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetate The ester was prepared as the title compound.

Intermediate 40 Methyl {( S )-6-[( R )-4-chloro-5-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-4-Chloro-5-fluoro-indan-1-ol

The title compound was prepared from 4-chloro-5-fluoro-indan-1-one following the procedure described in Step 2 to Intermediate 13.

Step 2 : {( S )-6-[( R )-4-chloro-5-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-chloro-5-fluoro-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydrogen The title compound was prepared from -benzofuran-3-yl)-acetic acid methyl ester. Yield: 53% of the theoretical value; the LC (Method _{4): t R = 2.28 min} ; Mass spectrum ^{(ESI -): m / z} = 375/377 (Cl) [MH] -.

Intermediate 41 Methyl {( S )-6-[( R )-4-cyano-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-1-(Tertiary-butyl-dimethyl-decyloxy)-indoline-4-carbonitrile

[( S )-4-Bromo-indan-1-yloxy]-tert-butyl-dimethyl-decane (0.20 g), copper (I) cyanide (0.08 g) and N-methyl A mixture of pyrrolidone (1 mL) was stirred at 170 ° C for 1 hour under microwave irradiation. The mixture was diluted with ether and the resulting mixture was washed with aqueous 5% NaHCO ₃ and dried (Na ₂ SO _4). Evaporation of the solvent gave the crude title compound. Yield: 0.16 g (93% of theory).

Step 2 : ( S )-4-cyano-indan-1-ol

The title compound was prepared from ( S )-1-(t-butyl-dimethyl-decyloxy)-indoline-4-carbonitrile following a procedure similar to that described in Step 4 of Intermediate 7.

Step 3 : {( S )-6-[( R )-4-Cyano-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-cyano-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro-benzo The title compound was prepared from furan-3-yl)-acetic acid methyl ester. Yield: 85% of the theoretical value; the LC (Method _{9); t R = 8.43 min} ; Mass spectrum ^{(ESI +): m / z} = 350 [M + Na] +.

Intermediate 42 {( S )-6-[( R )-4-(3-cyano-pyridin-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -yl}-methyl acetate

Step 1 : {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Methyl-2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Stirring rod, {(S)-6-[(R)-4-bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid A flask of ester (0.85 g), bis(pinacolyl)diboron (0.54 g), potassium acetate (0.56 g) and 1,4-dioxane (10 mL) was purged with argon for 10 minutes. 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium dichloromethane adduct (0.08 g) was added and the mixture was stirred at 100 ° C for 1.5 hours. After cooling to room temperature, the mixture was concentrated and the residue was dissolved in methanol. The resulting mixture was filtered and the filtrate was concentrated. Reverse phase chromatography (methanol / water) residue gave the title compound. Yield: 0.15 g (27% of theory); LC (method 1): t _R = 1.50 min; mass spectrum (ESI ⁺ ): m/z=473[M+Na] ⁺ .

Step 2 : {( S )-6-[( R )-4-(3-cyano-pyridin-2-yl)-indan-1-yloxy]-2,3-dihydro-benzo Methyl furan-3-yl}-acetate

Follow the procedure described in Step 1 similar to Intermediate 27 by {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2] Oxyboron Preparation of the title compound from methyl 2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and 2-chloro-3-cyano-pyridine . Yield: 45% of theory; LC (method 1): t _R = 1.24 min; mass spectrum (ESI ⁺ ): m/z = 427 [M+H] ⁺ .

Intermediate 43 Trifluoro-methanesulfonic acid 8-oxa-spiro[4.5]dec-1-en-1-yl ester

Step 1 : 4-(3-Chloro-propyl)-tetrahydro-furan-4-carboxylic acid methyl ester

Lithium bis(trimethyldecane)amine (1 mol/l in toluene, 7.5 mL) was added dropwise to tetrahydrofuran-4-carboxylic acid methyl ester (1.0 mL) cooled to -78 ° C in tetrahydrofuran ( In a solution of 10 mL). The solution was stirred at -78 °C for 1 hour, after which 1-chloro-3-iodo-propane (0.8 mL) was added. The solution was allowed to warm to room temperature overnight and then diluted with ether. The resulting mixture was washed with aqueous Na ₂ S ₂ O ₃ and aqueous NaHCO ₃ and dried (Na ₂ SO ₄ ). Evaporation of the solvent gave the crude title compound. Yield: 1.49 g (91% of theory).

Step 2 : Methyl 4-(3-iodo-propyl)-tetrahydro-pyran-4-carboxylate

A mixture of methyl 4-(3-chloro-propyl)-tetrahydropyran-4-carboxylate (1.49 g), sodium iodide (1.43 g) and acetone (5 mL) was stirred overnight. After cooling to room temperature, diethyl ether was added and the resulting mixture was washed with aqueous Na ₂ S ₂ O ₃ . The organic phase was dried and concentrated to give the title compound. Yield: 1.79 g (85% of theory); mass spectrum (ESI ⁺ ): m/z = 313 [M+H] ⁺ .

Step 3 : 8-oxa-spiro[4.5]nonan-1-one

Addition of tert-butyllithium (1.7 mol/l pentane solution, 4.9 mL) to methyl 4-(3-iodo-propyl)-tetrahydropyran-4-carboxylate cooled to -78 °C (1.29 g) in a solution in tetrahydrofuran (13 mL). Solution was stirred at -78 deg.] C for 1 hour and then by adding quenched with aqueous NH ₄ Cl. And the mixture was dried (Na ₂ SO ₄₎ of the combined extracts was extracted with diethyl ether. The solvent was evaporated and the residue was crystalljjjjjjjjjj Yield: 0.37 g (58% of theory); mass spectrum (ESI ⁺ ): m/z = 155 [M+H] ⁺ .

Step 4 : Trifluoro-methanesulfonic acid 8-oxa-spiro[4.5]dec-1-en-1-yl ester

Add bis(trimethyldecane)amino potassium (0.5 mol/l toluene solution, 2.7 mL) to 8-oxa-spiro[4.5]indole-1-one (0.17 g) cooled to -78 ° C in tetrahydrofuran In a solution (5 mL). The solution was stirred at -78 °C for 30 minutes, then a solution of N,N-bis(trifluoromethanesulfonyl)aniline (0.41 g) in tetrahydrofuran (2 mL) was slowly added. The solution was allowed to warm to room temperature over a one hour period. Ether was added and the resulting mixture was washed with 1 M aqueous HCl and dried (Na ₂ SO _4). The solvent was evaporated and the residue was crystalljjjjjjjjjj Yield: 0.23 g (73% of theory); mass spectrum (ESI ⁺ ): m/z = 287 [M+H] ⁺ .

Intermediate 44 {( S )-6-[( R )-4-(8-oxa-spiro[4.5]dec-1-en-1-yl)-dihydroindol-1-yloxy]-2,3- Methyl dihydro-benzofuran-3-yl}-acetate

Stirring rod, {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxon 2-yl)-indoline-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.15 g), trifluoro-methanesulfonic acid 8-oxo hetero - spiro [4.5] dec-1-en-1-yl ester _{(0.08 g), K 3 PO} 4 (0.12 g) and tetrahydrofuran (4 mL) the flask was purged with argon for 10 minutes. 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium dichloromethane adduct (0.08 mg) was added and the mixture was stirred at 100 ° C for 5 hours. After cooling to room temperature, the mixture was diluted with ether, washed with aqueous NH ₄ Cl and dried (Na ₂ SO _4). The solvent was evaporated and the residue was purified elut elut elut Yield: 0.09 g (75% of theory); LC (method 1): t _R = 1.46 min; mass spectrum (ESI ⁺ ): m/z = 483 [M+Na] ⁺ .

Intermediate 45 {( S )-6-[( R )-4-(2,6,6-trimethyl-cyclohex-1-enyl)-indan-1-yloxy]-2,3-di Hydrogen-benzofuran-3-yl}-acetic acid methyl ester

Step 1 : 2,6,6-trimethyl-cyclohex-1-enyl trifluoromethanesulfonate

The title compound was prepared from 2,2,6-trimethyl-cyclohexanone following a procedure similar to that described in Step 4 of Intermediate 43. Yield: 27% of the theoretical value.

Step 2 : {( S )-6-[( R )-4-(2,6,6-trimethyl-cyclohex-1-enyl)-indan-1-yloxy]-2, 3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Following the procedure described in Intermediate 44, {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron 2-yl)-indoline-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and trifluoro-methanesulfonic acid 2,6,6-three Methyl-cyclohex-1-enyl ester The title compound was prepared. Yield: 73% of theory; LC (method 6): t _R = 1.89 min; mass spectrum (ESI ⁺ ): m/z = 469 [M+Na] ⁺ .

Intermediate 46 {( S )-6-[( R )-4-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-indan-1-yloxy]-2,3- Methyl dihydro-benzofuran-3-yl}-acetate

Follow the procedure described in Step 1 similar to Intermediate 27 from [( S )-6-(( R )-4-bromo-indan-1-yloxy)-2,3-dihydro-benzene Methyl furan-3-yl]-acetate and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron The title compound was prepared from 2-yl)-1H-pyrazole.

Intermediate 47 {( S )-6-[( S )-6-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran Methyl-3-methyl}-acetate

Step 1 : ( R )-6-Trifluoromethyl-indan-1-ol

The title compound was prepared from 6-trifluoromethyl-indoline-1-one following the procedure described in Step 2, similar to Intermediate 13; chloro{[(1R,2R)-(-)-2-amino -1,2-Diphenylethyl](4-toluenesulfonyl)nonylamino}(mesitylene)ruthenium (II) was used as a catalyst. Yield: 92% of theory; LC (method 1): t _R = 1.08 min; mass spectrum (ESI ^- ): m/z = 201 [MH] ^- .

Step 2 : {( S )-6-[( S )-6-Trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid Methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( R )-6-trifluoromethyl-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro- The title compound was prepared from methyl benzofuran-3-yl)-acetate. Yield: 45% of theory; LC (method 1): t _R = 1.41 min; mass spectrum (ESI ⁺ ): m/z = 393 [M+H] ⁺ .

Intermediate 48 {( S )-6-[( R )-4-(2-Sideoxy-2H-pyridin-1-yl)-indan-1-yloxy]-2,3-dihydro-benzo Methyl furan-3-yl}-acetate

Step 1: (S)-Third butyl-(4-iodo-indan-1-yloxy)-dimethyl-decane

Add NaI (2.06 g), CuI (0.16 g) and N,N'-dimethylethylidene-1,2-diamine (0.18 mL) to ( S )-t-butyl-(4-bromo) - Dihydroindol-1-yloxy)-dimethyl-decane (0.90 g) in a degassed solution of 1,4-dioxane (15 ml). The resulting mixture was stirred at 110 ° C until the starting material was completely converted. Water was added and the mixture was extracted with ethyl acetate. The combined washed with brine and the extracts were dried (Na ₂ SO _4). The solvent was evaporated and EtOAc (EtOAc) Yield: 0.78 g (92% of theory); the LC (Method _{4): t R = 2.73 min} .

Step 2 : 1-[( S )-1-(Tertiary-butyl-dimethyl-decyloxy)-indan-4-yl]-1H-pyridin-2-one

Add a hot solution of ( S )-t-butyl-(4-iodo-indan-1-yloxy)-dimethyl-decane (1.81 g) in dimethyl hydrazine (50 mL) to Containing K ₂ CO ₃ (1.34 g), cuprous iodide (0.09 g), 2-hydroxy-pyridine (0.55 g) and 4,7-dimethoxy-1,10-morpholine (0.17 g) In the autoclave. The autoclave was purged with argon and then heated at 130 ° C overnight. After cooling to room temperature, water was added and the aqueous mixture was extracted with ethyl acetate. Washed with brine the combined organic extracts were dried (Na ₂ SO ₄₎ and concentrated. The title compound was obtained from EtOAc (EtOAc) Yield: 0.54 g (33% of theory); LC (method 4): t _R = 2.31 min; mass spectrum (ESI ⁺ ): m/z=342[M+H] ⁺ .

Step 3 : ( S )-1-(1-Hydroxy-dihydroindol-4-yl)-1H-pyridin-2-one

Follow the procedure described in Step 4 similar to Intermediate 7 from 1-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-1H - Pyridin-2-one The title compound was prepared. 54% of theory; LC (method 4): t _R = 1.46 min; mass spectrum (ESI ⁺ ): m/z = 288 [M+H] ⁺ .

Step 4 : {( S )-6-[( R )-4-(2-Sideoxy-2H-pyridin-1-yl)-indan-1-yloxy]-2,3-dihydro -benzofuran-3-yl}-acetic acid methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-1-(1-hydroxy-dihydroindol-4-yl)-1H-pyridin-2-one and ( S )-(6- The title compound was prepared from methyl hydroxy-2,3-dihydro-benzofuran-3-yl)-acetate. Yield: 47% of the theoretical value.

Intermediate 49 {( S )-6-[( R )-5-(2,6-Dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -yl}-methyl acetate

Step 1 : ( S )-5-Bromo-indan-1-ol

The title compound was prepared from 5-bromo-indoline-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 79% of theory; LC (method 1): t _R = 1.04 min; mass spectrum (ESI ⁺ ): m/z = 195/197 (Br) [M-OH] ⁺ .

Step 2 : ( S )-5-(2,6-Dimethyl-phenyl)-indan-1-ol

Follow the procedure described in Step 1 similar to Intermediate 27 from ( S )-5-bromo-indan-1-ol and 2,6-dimethylphenyl The title compound was prepared by acid. Yield: 36% of theory; LC (method 1): t _R = 1.31 min; mass spectrum (ESI ⁺ ): m/z = 221 [M-OH] ⁺ .

Step 3 : {( S )-6-[( R )-5-(2,6-Dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzo Methyl furan-3-yl}-acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-5-(2,6-dimethyl-phenyl)-indan-1-ol and ( S )-(6-hydroxyl The title compound was prepared from methyl-2,3-dihydro-benzofuran-3-yl)-acetate. Yield: 42% of theory; LC (method 1): t _R = 1.52 min; mass spectrum (ESI ⁺ ): m/z = 451 [M+Na] ⁺ .

Intermediate 50 Methyl {( S )-6-[( S )-6-bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( R )-6-Bromo-indan-1-ol

The title compound was prepared from 6-bromo-indoline-1-one following the procedure described in Step 2 to Intermediate 13; chloro{[(1R,2R)-(-)-2-amino-1, 2-Diphenylethyl](4-toluenesulfonyl)nonylamino}(mesitylene)ruthenium (II) was used as a catalyst. Yield: 99% of theory; LC (method 1): t _R = 1.03 min; mass spectrum (ESI ⁺ ): m/z = 195 [M-OH] ⁺ .

Step 2 : {( S )-6-[( S )-6-Bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( R )-6-bromo-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro-benzofuran The title compound was prepared from -3-yl)-methyl acetate. Yield: 53% of theory; LC (method 1): t _R = 1.43 min; mass spectrum (ESI ⁺ ): m/z = 403 / 405 (Br) [M+H] ⁺ .

Intermediate 51 {( S )-6-[( R )-5-(2-isopropyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl }-methyl acetate

Step 1 : ( S )-5-(2-isopropyl-phenyl)-indan-1-ol

Follow the procedure described in Step 1 similar to Intermediate 27 from ( S )-5-bromo-indan-1-ol and 2-isopropylphenyl The title compound was prepared by acid. Yield: 93% of theory; LC (method 1): t _R = 1.34 min; mass spectrum (ESI ⁺ ): m/z = 235 [M-OH] ⁺ .

Step 2 : {( S )-6-[( R )-5-(2-isopropyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-methyl}-methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-5-(2-isopropyl-phenyl)-indan-1-ol and ( S )-(6-hydroxy-2) The title compound was prepared from methyl 3-hydro-benzofuran-3-yl)-acetate. Yield: 41% of theory; LC (method 1): t _R = 1.55 min; mass spectrum (ESI ⁺ ): m/z = 465 [M+Na] ⁺ .

Intermediate 52 {( S )-6-[( R )-4-(3-oxa-spiro[5.5]undec-7-en-7-yl)-indan-1-yloxy]-2, 3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound was obtained following the synthetic procedures described above and the corresponding procedures described for Intermediate 43 and Intermediate 44. LC (Method _{1): t R = 1.49 min} ; Mass spectrum ^{(ESI +): m / z} = 497 [M + Na] +.

Intermediate 53 {( S )-6-[( R )-4-(1-methyl-1H-imidazol-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran Methyl-3-methyl}-acetate

Following the procedure similar to that described in Example 53, {(S)-6-[(R)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Preparation of the title compound from methyl 2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and 2-iodo-1-methyl-imidazole The toluene was replaced with 1,4-dioxane and reacted in a microwave oven at 120 ° C for 0.5 hours.

Intermediate 54 {( S )-6-[( R )-4-(3-methyl-pyridin-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -yl}-methyl acetate

Following the procedure similar to that described in Example 53, {(S)-6-[(R)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Preparation of the title compound from methyl 2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and 2-bromo-3-methyl-pyridine . LC (Method _{1): t R = 1.06 min} ; Mass spectrum ^{(ESI +): m / z} = 416 [M + H] +.

Intermediate 55 {( S )-6-[( R )-4-(4-methoxy-2,6-dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro -benzofuran-3-yl}-acetic acid methyl ester

Step 1 : (( S )-6-{( R )-4-[4-(Tertiary Butyl-Dimethyl-decyloxy)-2,6-dimethyl-phenyl]-dihydro Methyl 茚-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetate

Following the procedure similar to that described in Example 53, {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Methyl-2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and (4-bromo-3,5-dimethyl- The title compound was prepared from phenoxy)-tert-butyl-dimethyl-decane; tetrabutylammonium bromide was added to the reaction mixture and the reaction was carried out in a microwave oven at 120 °C. Yield: 69% of theory; LC (method 1): t _R = 1.65 min; mass spectrum (ESI ⁺ ): m/z = 559 [M+H] ⁺ .

Step 2 : {( S )-6-[( R )-4-(4-hydroxy-2,6-dimethyl-phenyl)-indan-1-yloxy]-2,3-di Hydrogen-benzofuran-3-yl}-acetic acid methyl ester

Following the procedure described in Step 4 similar to Intermediate 7, (( S )-6-{( R )-4-[4-( T -butyl-dimethyl-decyloxy)-2, The title compound was prepared from methyl 6-dimethyl-phenyl]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetate. 81% of theory; LC (method 1): t _R = 1.36 min: mass spectrum (ESI ⁺ ): m/z = 445 [M+H] ⁺ .

Step 3 : {( S )-6-[( R )-4-(4-methoxy-2,6-dimethyl-phenyl)-indan-1-yloxy]-2,3 -dihydro-benzofuran-3-yl}-acetic acid methyl ester

Add methyl iodide (9 μL) to {( S )-6-[( R )-4-(4-hydroxy-2,6-dimethyl-phenyl)-indoline-1- at room temperature Methyloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (40 mg), K ₂ CO ₃ (25 mg) and N,N-dimethylformamide (2 In a mixture of mL). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The mixture was washed with water and brine and dried (MgSO _4). Evaporation of the solvent gave the title compound. Yield: 31 mg (75% of theory); the LC (Method _{1): t R = 1.50 min} ; Mass spectrum ^{(ESI +): m / z} = 459 [M + H] +.

Intermediate 56 4-bromo-2-methoxy-3,5-dimethyl-pyridine

Step 1 : 4-Bromo-3,5-dimethyl-pyridine 1-oxide

Bromine (1.1 mL) was added dropwise to a mixture of lead tetraacetate (13.01 g), 3,5-dimethyl-pyridine-N-oxide (2.46 g) and acetic acid (20 mL) stirred at 70 °C. in. After stirring the mixture overnight at 70 ° C, another portion of bromine (0.56 mL) was added and stirring was continued for 24 hours. After cooling to room temperature, the mixture was neutralized using NaOH. The precipitate was separated by filtration and the filtrate was concentrated. The residue was dissolved in water / methanol and the resulting mixture was filtered. The filtrate was concentrated and purified with EtOAcqqqqq Yield: 2.60 g (64% of theory); LC (method 1): t _R =0.69 min; mass spectrum (ESI ⁺ ): m/z=202/204 (Br) [M+H] ⁺ .

Step 2 : 4-Bromo-3,5-dimethyl-pyridin-2-ol

Add trifluoroacetic anhydride (0.87 mL) to 4-bromo-3,5-dimethyl-pyridine 1-oxide (1.01 g) and triethylamine (3.5 mL) in tetrahydrofuran (50 mL). In the solution. Remove the cooling bath and stir the solution at room temperature 2.5 hour. Water was added and the solution was concentrated. Reverse phase chromatography (acetonitrile / water) residue gave the title compound. Yield: 0.29 g (29% of theory).

Step 3 : 4-Bromo-2-methoxy-3,5-dimethyl-pyridine

Methyl iodide (0.15 mL) was added to 4-bromo-3,5-dimethyl-pyridin-2-ol (0.10 g), Ag ₂ CO ₃ (0.21 g) and chloroform (6 mL) at room temperature In the mixture. The mixture was stirred at reflux temperature overnight. After cooling to room temperature, water and dichloromethane were added and the resulting mixture was filtered. The filtrate was extracted with dichloromethane. Dried (MgSO _4), and the combined extracts were concentrated to the give the title compound. Yield: 0.08 g (71% of theory); the LC (Method _{1): t R = 1.29 min} .

Intermediate 57 {( S )-6-[( R )-4-(2-methoxy-3,5-dimethyl-pyridin-4-yl)-indan-1-yloxy]-2,3 -dihydro-benzofuran-3-yl}-acetic acid methyl ester

Containing {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxyboron 2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.11 g), 4-bromo-3,5-di A vial of methyl-2-methoxy-pyridine (0.06 g) and 1,4-dioxane (4 mL) was purified with Ar for 10 min. Add bis(dibenzylideneacetone)palladium(0) (14 mg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (21 mg) and Ba(OH) in the specified order. ₂ (0.13 g) and the resulting mixture was stirred at 80 ° C overnight. After cooling to room temperature, the mixture was filtered and the filtrate was crystallised <RTI ID=0.0> Yield: 0.07 g (57% of theory).

Intermediate 58 {( S )-6-[( R )-4-(1,3,5-trimethyl-2-oxooxy-1,2-dihydro-pyridin-4-yl)-indoline-1 -methyloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Step 1 : 4-Bromo-1,3,5-trimethyl-1H-pyridin-2-one

A mixture of 4-bromo-3,5-dimethyl-pyridin-2-ol (0.10 g), dimethyl carbonate (0.42 mL) and K ₂ CO ₃ (0.10 g) was stirred at 120 ° C overnight. After cooling to room temperature, water was added and the mixture was extracted with dichloromethane. Dried (Na ₂ SO _4), and the combined extracts were concentrated to the give the crude title compound. Yield: 0.11 g (quantitative); the LC (Method _{1): t R = 0.95 min} .

Step 2 : {( S )-6-[( R )-4-(1,3,5-trimethyl-2-oxo-1,2-dihydro-pyridin-4-yl)-dihydro Methyl-1-enyloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Follow the procedure described in Intermediate 57 by {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Methyl-2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and 4-bromo-1,3,5-trimethyl -1H-pyridin-2-one The title compound was prepared. Yield: 36% of the theoretical value.

Intermediate 59 {( S )-6-[( R )-4-o-tolyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Following the procedure similar to that described in Example 53, {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron The title compound is prepared from methyl-2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and 2-bromo-toluene; Butylammonium was added to the reaction mixture and the reaction was carried out in a microwave oven at 120 °C. Yield: 67% of theory; LC (method 1): t _R = 1.50 min; mass spectrum (ESI ⁺ ): m/z = 437 [M+Na] ⁺ .

Intermediate 60 {( S )-6-[( R )-4-(1,2,4-Trimethyl-6-o-oxy-1,6-dihydro-pyridin-3-yl)-indoline-1 -methyloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Step 1 : 5-Bromo-4,6-dimethyl-pyridin-2-ol

A solution of 5-bromo-4,6-dimethyl-pyridin-2-ylamine (2.01 g) in water (120 mL) and 32% aqueous hydrochloric acid (40 mL) was evaporated to reflux. NaNO ₂ (2.00 g) dissolved in water (40 mL) was added to the hot filtrate under vigorous stirring. The resulting mixture was stirred overnight at room temperature. The mixture was allowed to cool in an ice bath and the precipitate was separated by filtration. The precipitate was washed with water and dried to give the title compound. Yield: 1.17 g (58% of theory); LC (method 1): t _R = 0.82 min; mass spectrum (ESI ⁺ ): m/z=202/204 (Br) [M+H] ⁺ .

Step 2 : 5-Bromo-1,4,6-trimethyl-1H-pyridin-2-one

The title compound was prepared from 5-bromo-4,6-dimethyl-pyridin-2-ol following the procedure described in Step 1 to Intermediate 58. Yield: 65% of the theoretical value; the LC (Method _{1): t R = 0.87 min} ; Mass spectrum ^{(ESI +): m / z} = 216/218 (Br) [M + H] +.

Step 3 : {( S )-6-[( R )-4-(1,2,4-Trimethyl-6-o-oxy-1,6-dihydro-pyridin-3-yl)-dihydro Methyl-1-enyloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Follow the procedure described in Intermediate 57 by {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Methyl-2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and 5-bromo-1,4,6-trimethyl -1H-pyridin-2-one The title compound was prepared. Yield: 33% of the theoretical value.

Intermediate 61 {( S )-6-[( R )-4-(6-Methoxy-2,4-dimethyl-pyridin-3-yl)-indan-1-yloxy]-2,3 -dihydro-benzofuran-3-yl}-acetic acid methyl ester

Step 1 : 3-Bromo-6-methoxy-2,4-dimethyl-pyridine

The title compound was prepared from 5-bromo-4,6-dimethyl-pyridin-2-ol and iodomethane following the procedure described in Step 3 to Intermediate. Yield: 60% of theory; LC (method 1): t _R = 1.21 min; mass spectrum (ESI ⁺ ): m/z = 216/218 (Br) [M+H] ⁺ .

Step 2 : {( S )-6-[( R )-4-(6-Methoxy-2,4-dimethyl-pyridin-3-yl)-indan-1-yloxy]- Methyl 2,3-dihydro-benzofuran-3-yl}-acetate

Follow the procedure described in Intermediate 57 by {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Methyl-2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and 3-bromo-6-methoxy-2,4 The title compound was prepared from dimethyl-pyridine. Yield: 36% of the theoretical value.

Intermediate 62 {( S )-6-[( R )-4-morpholin-4-yl-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid ester

Step 1 : 4-[( S )-1-(Tertiary-butyl-dimethyl-decyloxy)-indan-4-yl]-morpholine

Equipped with a stir bar, (( S )-4-bromo-indan-1-yloxy)-tert-butyl-dimethyl-decane (0.10 g), morpholine (37 μL), third Microwave vials of sodium alkoxide (42 mg) and 1,4-dioxane (1 mL) were purged with Ar for 10 minutes. Adding chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II)- The tributyl ether adduct (2.5 mg) was stirred and the mixture was stirred at 100 ° C for 10 minutes in a microwave oven. After cooling to room temperature, washed with ethyl acetate and the mixture was washed with water and brine and dried (Na ₂ SO _4). The solvent was evaporated and the residue was purified elut elut elut

Step 2 : ( S )-4-morpholin-4-yl-indan-1-ol

Follow the procedure described in Step 4 similar to Intermediate 7 from ( S )-4-[1-(t-butyl-dimethyl-decyloxy)-indan-4-yl]-? The title compound was prepared from the porphyrin. Yield: 94% of theory; LC (method 1): t _R = 0.59 min; mass spectrum (ESI ⁺ ): m/z = 220 [M+H] ⁺ .

Step 3 : {( S )-6-[( R )-4-morpholin-4-yl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -methyl acetate

Following the procedure described in Step 3 of Intermediate 1, ( S )-4-morpholin-4-yl-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro- The title compound was prepared from methyl benzofuran-3-yl)-acetate. Yield: 23% of theory; LC (method 1): t _R = 1.28 min; mass spectrum (ESI ⁺ ): m/z = 410 [M+H] ⁺ .

Intermediate 63 and intermediate 64 ( S )-4-[( R )-3,3-dimethyl-tetrahydro-piperidin-2-yl]-indan-1-ol and ( S )-4-[( S )-3 ,3-dimethyl-tetrahydro-piperidin-2-yl]-dihydroindole-1-ol

Step 1 : 1-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-2,2-dimethyl-pent-4-ene -1-ol (a mixture of two diastereomers)

Follow the procedure described in Step 1 similar to Intermediate 36 from [( S )-4-bromo-indoline-1-yloxy]-tert-butyl-dimethyl-decane and 2,2- The title compound was prepared from dimethyl-pent-4-enal. Yield: 58% of the theoretical value; the LC (Method _{6): t R = 1.83 /} 1.87 min (2 diastereomers thereof Species).

Step 2 : 1-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-2,2-dimethyl-pentyl-1,5 -diol (a mixture of two diastereomers)

Add borane tetrahydrofuran complex (1 mol/L, 3.6 mL) to 1-[( S )-1-(t-butyl-dimethyl-decyloxy)-indoline cooled in an ice bath A solution of 4-yl]-2,2-dimethyl-pent-4-en-1-ol (0.43 g) in tetrahydrofuran (6 mL). The solution was stirred for 1 hour, after which an aqueous NaOH solution (4 mol/L, 1.8 mL) and aqueous hydrogen peroxide (35%, 1.8 mL) were added. The mixture was stirred for 1 hour and then a half-saturated NaCl solution was added. And the mixture was dried (Na ₂ SO ₄₎ of the combined extracts were extracted with ether and concentrated to give the crude product. Yield: 0.45 g (quantitative). LC (method 6): t _R = 1.62 / 1.66 min; Mass (ESI ⁺ ): m/z = 401 [M+Na] ⁺ .

Step 3 : Tert-butyl-[( S )-4-(3,3-dimethyl-tetrahydropyran-2-yl)-indan-1-yloxy]-dimethyl-decane (a mixture of two diastereomers)

Add triethylamine (0.5 mL), 4-methyl-benzenesulfonyl chloride (0.25 g) and 4-dimethylaminopyridine (catalytic amount) to 1-[( S )-1 in the indicated order at room temperature. -(t-butyl-dimethyl-decyloxy)-indan-4-yl]-2,2-dimethyl-pentan-1,5-diol (0.45 g) in dichloromethane In a solution (6 mL). The solution was stirred at room temperature for 72 hours and then heated to 60 ° C in a microwave oven. After stirring at 60 ° C for 2 hours, the solution was cooled to room temperature and diluted with diethyl ether. Water, 1 M NaOH aq NH ₄ Cl and the resulting mixture was washed with an aqueous solution and dried (Na ₂ SO _4). The solvent was evaporated and the residue was purified elut elut elut Yield: 0.20 g (46% of theory); LC (method 1): t _R = 1.94 min; mass spectrum (ESI ⁺ ): m/z = 378 [M+NH ₄ ] ⁺ .

Step 4 : ( S )-4-[( S )-3,3-dimethyl-tetrahydro-piperidin-2-yl]-indan-1-ol and ( S )-4-[( R )-3,3-dimethyl-tetrahydro-piperidin-2-yl]-dihydroindole-1-ol

Follow the procedure described in Step 4 similar to Intermediate 7 from tert-butyl-[( S )-4-(3,3-dimethyl-tetrahydropyran-2-yl)-indoline- The title compound was prepared from 1-yloxy]-dimethyl-decane. The two diastereomers were separated by silica gel chromatography (petroleum ether / ethyl acetate). Arbitrarily specify the configuration of the stereoisomeric center ( ^* ) shown.

Intermediate 63: LC (Method 6): t _R = 0.85 min; Mass (ESI ⁺ ): m/z = 229 [M-OH] ⁺ .

Intermediate 64: LC (Method _{6): t R = 0.98 min} ; Mass spectrum ^{(ESI +): m / z} = 229 [M-OH] +.

Intermediate 65 {( S )-6-[( R )-4-(( S )-3,3-dimethyl-tetrahydro-pyran-2-yl)-indan-1-yloxy]-2 , 3-dihydro-benzofuran-3-yl}-acetic acid methyl ester, an isomer, optionally designated as a stereogenic center ( ^* Configuration

Following the procedure described in Step 3 similar to Intermediate 1, ( S )-4-[( S )-3,3-dimethyl-tetrahydro-pyran-2-yl]-indoline-1 The title compound is prepared from the alcohol (pure isomer, intermediate 63) and ( S )-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-methyl acetate. Yield: 64% of theory; LC (method 6): t _R = 1.61 min; mass spectrum (ESI ⁺ ): m/z = 437 [M+H] ⁺ .

Intermediate 66 {( S )-6-[( R )-4-(( R )-3,3-dimethyl-tetrahydro-pyran-2-yl)-indan-1-yloxy]-2 , 3-dihydro-benzofuran-3-yl}-acetic acid methyl ester, an isomer, optionally designated as a stereogenic center ( ^* Configuration

Following the procedure described in Step 3 similar to Intermediate 1, ( S )-4-[( R )-3,3-dimethyl-tetrahydro-pyran-2-yl]-indoline-1 - The title compound is prepared from the alcohol (pure isomer, intermediate 64) and ( S )-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-methyl acetate. Yield: 54% of theory; LC (method 6): t _R = 1.59 min; mass spectrum (ESI ⁺ ): m/z = 437 [M+H] ⁺ .

Intermediate 67 {( S )-6-[( R )-4-(5-fluoro-2-methoxy-pyridin-4-yl)-indan-1-yloxy]-2,3-dihydro- Benzofuran-3-yl}-acetic acid methyl ester

Following the procedure described in Intermediate 44, {( S )-6-[( R )-4-bromo-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-yl}-methyl acetate and 5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron The title compound was prepared from 2-yl)-pyridine. Yield: 73% of theory; LC (method 6): t _R = 1.53 min; mass spectrum (ESI ⁺ ): m/z = 450 [M+H] ⁺ .

Intermediate 68 {( S )-6-[( R )-4-(2-Trifluoromethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Methyl acetate

Following the procedure similar to that described in Example 53, {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Preparation of methyl-2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and 1-iodo-2-trifluoromethyl-benzene The title compound; tetrabutylammonium bromide was added to the reaction mixture and the reaction was carried out in a microwave oven at 120 °C. Yield: 76% of theory; LC (method 1): t _R = 1.47 min; mass spectrum (ESI ⁺ ): m/z = 491 [M+Na] ⁺ .

Intermediate 69 {( S )-6-[( R )-4-(6,6-Dimethyl-cyclohex-1-enyl)-indan-1-yloxy]-2,3-dihydro- Benzofuran-3-yl}-acetic acid methyl ester

Step 1 : Tris-methanesulfonic acid 6,6-dimethyl-cyclohex-1-enyl ester

The title compound was prepared from 2,2-dimethyl-cyclohexanone following the procedure described in Step 4 to Intermediate 43. Yield: 34% of the theoretical value.

Step 2 : {( S )-6-[( R )-4-(6,6-Dimethyl-cyclohex-1-enyl)-indan-1-yloxy]-2,3- Methyl dihydro-benzofuran-3-yl}-acetate

Following the procedure described in Intermediate 44, 6,6-dimethyl-cyclohex-1-enyl trifluoromethanesulfonate and {( S )-6-[( R )-4-(4) ,4,5,5-tetramethyl-[1,3,2]diboron The title compound was prepared from methyl-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. Yield: 74% of theory; LC (method 6): t _R = 1.85 min; mass spectrum (ESI ⁺ ): m/z = 455 [M+Na] ⁺ .

Intermediate 70 {( S )-6-[( R )-4-(5-methoxy-2-methyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzo Methyl furan-3-yl}-acetate

Step 1 : 2-Bromo-4-methoxy-1-methyl-benzene

The title compound was prepared from 3-bromo-4-methyl-phenol following a procedure similar to that described in Step 3 of Intermediate 56. Yield: 76% of theory; LC (Method 1): tR = 1.26 min.

Step 2 : {( S )-6-[( R )-4-(5-Methoxy-2-methyl-phenyl)-indan-1-yloxy]-2,3-dihydro -benzofuran-3-yl}-acetic acid methyl ester

Follow the procedure similar to that described in Example 53 from {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron 2-yl)-indoline-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-bromo-4-methoxy-1-methyl The title compound was prepared from the base-benzene; tetrabutylammonium bromide was added to a solution of the reaction mixture in toluene and water and the reaction was carried out in a microwave oven at 120 °C. Yield: 73% of theory; LC (method 1): t _R = 1.48 min; mass spectrum (ESI ⁺ ): m/z = 467 [M+Na] ⁺ .

Intermediate 71 {( S )-6-[( R )-4-(5-Hydroxy-2-methyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-methyl}-methyl acetate

Step 1 : (3-Bromo-4-methyl-phenoxy)-tert-butyl-dimethyl-decane

Addition of tert-butyldimethyl decane chloride (0.18 g) to 3-bromo-4-methyl-phenol (0.20 g) and triethylamine (0.23 mL) in dichloromethane (3) In the solution in mL). 4-Dimethylaminopyridine (13 mg) was added and the solution was stirred at room temperature overnight. Dichloromethane and added with 1 M hydrochloric acid, NaHCO ₃ aqueous solution and brine, and dried (MgSO _4). The solvent was evaporated and the residue was purified elut elut elut Yield: 0.25 g (78% of theory); the LC (Method _{1): t R = 1.59 min} .

Step 2 : (( S )-6-{( R )-4-[5-(Tertiary-butyl-dimethyl-decyloxy)-2-methyl-phenyl]-indoline-1 -methyloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

Following the procedure similar to that described in Example 53, {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Methyl-2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and (3-bromo-4-methyl-phenoxy) The title compound was prepared as the tert-butyl-dimethyl-decane; tetrabutylammonium bromide was added to a solution of the reaction mixture in toluene and water and the reaction was carried out in a microwave oven at dimethyl 120 °C. Yield: 33% of the theoretical value; the LC (Method _{1): t R = 1.64 min} .

Step 2 : {( S )-6-[( R )-4-(5-Hydroxy-2-methyl-phenyl)-indoline-1-yloxy]-2,3-dihydro-benzene Methyl furan-3-yl}-acetate

Following the procedure described in Step 4 similar to Intermediate 7, (( S )-6-{( R )-4-[5-( T -butyl-dimethyl-decyloxy)-2- The title compound was prepared from methyl-phenyl]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid. LC (Method _{1): t R = 1.36 min} ; Mass spectrum ^{(ESI +): m / z} = 453 [M + Na] +.

Intermediate 72 {( S )-6-[( R )-4-isoquinolin-1-yl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid Methyl ester

Following a procedure similar to that described in Intermediate 44, 1-bromo-isoquinoline and {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1, 3,2]diboron The title compound was prepared from methyl-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. Yield: 46% of theory; LC (method 6): t _R = 1.15 min; mass spectrum (ESI ⁺ ): m/z = 452 [M+H] ⁺ .

Intermediate 73 {( S )-6-[( R )-4-(1-methoxy-1,2,2-trimethyl-propyl)-indan-1-yloxy]-2,3- Methyl dihydro-benzofuran-3-yl}-acetate

Step 1 : 1-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-2,2-dimethyl-propan-1-one

Add 1,1-dihydro-1,1,1-triethoxycarbonyl-1,2-benziodooxacyclo-3(1H)-one (15% dichloromethane solution, 1.4 mL) As for the 1-[( S )-1-(t-butyl-dimethyl-decyloxy)-dihydroindol-4-yl]-2,2-dimethyl-propyl-cooled in an ice bath 1-Alcohol (0.19 g) in dichloromethane (5 mL). The solution was stirred at room temperature for 1 hour and then concentrated. The residue was chromatographed (EtOAc/EtOAc) Yield: 0.16 g (85% of theory); LC (method 1): t _R = 1.56 min; mass spectrum (ESI ⁺ ): m/z=355[M+Na] ⁺ .

Step 2 : 2-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-3,3-dimethyl-butan-2-ol

Methylmagnesium bromide (1.4 mol/l tetrahydrofuran/toluene solution; 3 mL) was added to 1-[( S )-1-(t-butyl-dimethyl-decyloxy)- at room temperature A solution of dihydroindol-4-yl]-2,2-dimethyl-propan-1-one (0.14 g) in toluene (15 mL). The solution was stirred at 45 ° C for 1 hour. The solution was poured into ice water and dichloromethane was added to the mixture. The mixture was acidified with 1 M hydrochloric acid and stirred for 15 min. The organic layer was separated, dried (Na ₂ SO ₄₎ and concentrated to give the crude title compound. Yield: 0.16 g (quantitative); the LC (Method _{1): t R = 1.58 min} .

Step 3 : Tert-butyl-[( S )-4-(1-methoxy-1,2,2-trimethyl-propyl)-indan-1-yloxy]-dimethyl -decane

2-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-3 dissolved in tetrahydrofuran (2 mL) at room temperature, 3-Dimethyl-butan-2-ol (0.17 g) was added to a flask equipped with a stir bar and potassium hydride (30% oil, 0.19 g). The mixture was stirred at room temperature for 20 minutes, after which time methyl iodide (2 mol/L of butyl dimethyl ether solution, 0.36 mL) was added. The mixture was stirred for 1 hour and then cooled in an ice bath. Aqueous NH ₄ Cl solution was slowly added and the resulting mixture was extracted with diethyl ether. Dried (Na ₂ SO ₄₎ of the combined extracts and concentrated. The residue was chromatographed (EtOAc/EtOAc) Yield: 0.11 g (64% of theory); the LC (Method _{1): t R = 1.67 min} .

Step 4 : ( S )-4-(1-Methoxy-1,2,2-trimethyl-propyl)-indan-1-ol

Follow the procedure described in Step 4 similar to Intermediate 7 from tert-butyl-[( S )-4-(1-methoxy-1,2,2-trimethyl-propyl)-dihydro The title compound was prepared from 茚-1-yloxy]-dimethyl-decane. Yield: 80% of theory; LC (method 1): t _R = 1.31 min; mass spectrum (ESI ⁺ ): m/z = 471 [M+Na] ⁺ .

Step 5 : {( S )-6-[( R )-4-(1-methoxy-1,2,2-trimethyl-propyl)-indan-1-yloxy]-2 ,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Following the procedure described in Step 3 similar to Intermediate 1, ( S )-4-(1-methoxy-1,2,2-trimethyl-propyl)-indan-1-ol and The title compound was prepared from ( S )-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester. Yield: 47% of theory; LC (method 1): t _R = 1.54 min; mass spectrum (ESI ⁺ ): m/z = 461 [M+Na] ⁺ .

Intermediate 74 {( S )-6-[( R )-4-(1,1-Difluoro-2-methoxy-ethyl)-indan-1-yloxy]-2,3-dihydro- Benzofuran-3-yl}-acetic acid methyl ester

Step 1 : [( S )-1-(Tertiary-butyl-dimethyl-decyloxy)-indan-4-yl]-difluoro-ethyl acetate

Third butyl-[( S )-4-iodo-indan-1-yloxy]-dimethyl-decane (2.43 g), bromine-difluoro-acetic acid ethyl acetate (1.1 mL), copper powder A mixture of (1.65 g) and dimethyl hydrazine (25 mL) was stirred at 60 ° C for 6 hours under an Ar atmosphere. Ethyl acetate and aqueous NH ₄ Cl and the mixture was extracted with ethyl acetate. The combined washed with water and the extracts were dried (Na ₂ SO _4). The solvent was evaporated and the residue was purified elut elut elut Yield: 2.13 g (89% of theory); mass spectrum (ESI ⁺ ): m/z = 388 [M+NH ₄ ] ⁺ .

Step 2 : 2-[( S )-1-(Terbutyl-dimethyl-decyloxy)-indan-4-yl]-2,2-difluoro-ethanol

Sodium borohydride (0.20 g) was added to [( S )-1-(t-butyl-dimethyl-decyloxy)-indan-4-yl]-difluoro- cooled in an ice bath Ethyl acetate (0.37 g) in MeOH (25 mL). The mixture was stirred in a cooling bath while warming to room temperature overnight. Brine was added and the methanol was evaporated. The residue was extracted with ethyl acetate and dried (Na ₂ SO _4), and the combined extracts were concentrated to the give the crude title compound.

Step 3 : Tert-butyl-[( S )-4-(1,1-difluoro-2-methoxy-ethyl)-indan-1-yloxy]-dimethyl-decane

Add NaH (about 60% mineral oil solution; 22 mg) to 2-[( S )-1-(t-butyl-dimethyl-decyloxy)-indoline-4- at room temperature A solution of 2,2-difluoro-ethanol (0.17 g) in tetrahydrofuran (4 mL). The mixture was stirred at room temperature for 20 minutes, after which time methyl iodide (17 μL) was added. The mixture was stirred overnight and then water was added. And the mixture was dried (Na ₂ SO ₄₎ of the combined extracts was extracted with ethyl acetate and concentrated to give the crude title compound.

Step 4 : ( S )-4-(1,1-Difluoro-2-methoxy-ethyl)-indan-1-ol

Follow the procedure described in Step 4 similar to Intermediate 7 from tert-butyl-[( S )-4-(1,1-difluoro-2-methoxy-ethyl)-indoline-1 -Kyloxy]-dimethyl-decane The title compound was prepared.

Step 5 : {( S )-6-[( R )-4-(1,1-Difluoro-2-methoxy-ethyl)-indan-1-yloxy]-2,3- Methyl dihydro-benzofuran-3-yl}-acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-(1,1-difluoro-2-methoxy-ethyl)-indan-1-ol and ( S ) The title compound was prepared from -(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester.

Intermediate 75 {( S )-6-[( R )-4-(2-methyl-naphthalen-1-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -yl}-methyl acetate

Follow the procedure described in Intermediate 44 for 1-bromo-2-methyl-naphthalene and {( S )-6-[( R )-4-(4,4,5,5-tetramethyl- [1,3,2]diboron The title compound was prepared from methyl-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. Yield: 77% of the theoretical value; the LC (Method _{6): t R = 1.77 min} ; Mass spectrum ^{(ESI +): m / z} = 487 [M + Na] +.

Intermediate 76 {( S )-6-[( R )-4-(tetrahydro-pyran-4-carbonyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Base}-acetic acid

Step 1 : [( S )-1-(Tertiary-butyl-dimethyl-decyloxy)-indan-4-yl]-(tetrahydro-pyran-4-yl)-methanone

Add n-butyllithium (1.6 mol/L hexane solution, 1.0 mL) to [( S )-4-bromo-indoline-1-yloxy]-tert-butyl group cooled to -78 °C. A solution of dimethyl-nonane (0.49 g) in tetrahydrofuran (10 mL). The resulting solution was stirred at -78 ° C for 1 hour, after which tetrahydro-pyran-4-carboxylate methoxy-methyl-decylamine (0.30 g) was added. The solution was stirred at -78 °C for 1 hour and then warmed to room temperature overnight in a cooling bath. Aqueous NaHCO _{3 was} added and the mixture was extracted with ethyl acetate. Dried (Na ₂ SO _4), and the combined extracts were concentrated to the give the crude title compound. Yield: 0.52 g (97% of theory).

Step 2 : [( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-(tetrahydro-pyran-4-yl)-methanone

Follow the procedure described in Step 4 similar to Intermediate 7 from tert-butyl-[( S )-4-(1,1-difluoro-2-methoxy-ethyl)-indoline-1 -Kyloxy]-dimethyl-decane The title compound was prepared. Yield: 36% of theory; mass spectrum (ESI ⁺ ): m/z = 247 [M+H] ⁺ .

Step 3 : {( S )-6-[( R )-4-(tetrahydro-pyran-4-carbonyl)-indan-1-yloxy]-2,3-dihydro-benzofuran Methyl-3-methyl}-acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from [( S )-1-hydroxy-indan-4-yl]-(tetrahydro-pyran-4-yl)-methanone and ( S The title compound was prepared as the methyl ester of (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetate. Yield: 49% of theory; mass spectrum (ESI ⁺ ): m/z = 437[M+H] ⁺ .

Step 4 : {( S )-6-[( R )-4-(tetrahydro-pyran-4-carbonyl)-indan-1-yloxy]-2,3-dihydro-benzofuran -3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(tetrahydro-pyran-4-carbonyl)-indan-1-yloxy]-2, The title compound was prepared from methyl 3-dihydro-benzofuran-3-yl}-acetate. Yield: 74% of theory; mass spectrum (ESI ^- ): m/z = 421 [MH] ^- .

Intermediate 77 {( S )-6-[( R )-4-pent-4-enylindol-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

The title compound was obtained following the synthetic procedure described above and the corresponding procedure described in Intermediate 76. Pent-4-enoate methoxy-methyl-decylamine was used as the electrophile in step 1. Mass Spectrum (ESI ⁺ ): m/z = 393 [M+H] ⁺ .

Intermediate 78 {( S )-6-[( R )-4-(2-Tetrahydro-piperazin-4-yl-ethenyl)-indan-1-yloxy]-2,3-dihydro- Benzofuran-3-yl}-acetic acid

The title compound was obtained following the synthetic procedure described above and the corresponding procedure described in Intermediate 76. N-Methoxy-N-methyl-2-(tetrahydro-piperidin-4-yl)-acetamide was used as the electrophile in Step 1. Mass spectrum ^{(ESI -): m / z} = 435 [MH] -.

Intermediate 79 {( S )-6-[( R )-4-(1,1-Difluoro-2-methoxy-2-methyl-propyl)-indan-1-yloxy]-2, 3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Step 1 : 1-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-1,1-difluoro-2-methyl-prop -2-ol

Add methylmagnesium bromide (1.4 mol/l tetrahydrofuran/toluene solution; 3.6 mL) to [( S )-1-(t-butyl-dimethyl-decyloxy)-cooled in an ice bath A solution of dihydroindol-4-yl]-difluoro-acetic acid ethyl ester (0.37 g) in tetrahydrofuran (10 mL). The solution was allowed to warm to room temperature overnight in a cooling bath. Aqueous NH ₄ Cl solution was slowly added and the resulting mixture was extracted with ethyl acetate. Dried (Na ₂ SO _4), and the combined extracts were concentrated to the give the crude title compound.

Step 2 : Tert-butyl-[( S )-4-(1,1-difluoro-2-methoxy-2-methyl-propyl)-indan-1-yloxy]-di Methyl-decane

Following the procedure described in Step 3 analogous to Intermediate 74, 1-[( S )-1-( T -butyl-dimethyl-decyloxy)-indan-4-yl]-1 , 1-Difluoro-2-methyl-propan-2-ol The title compound was prepared.

Step 3 : ( S )-4-(1,1-Difluoro-2-methoxy-2-methyl-propyl)-indan-1-ol

Follow the procedure described in Step 4 similar to Intermediate 7 from tert-butyl-[( S )-4-(1,1-difluoro-2-methoxy-2-methyl-propyl)- The title compound was prepared from dihydroinden-1-yloxy]-dimethyl-decane.

Step 4 : {( S )-6-[( R )-4-(1,1-Difluoro-2-methoxy-2-methyl-propyl)-indan-1-yloxy] -2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-(1,1-difluoro-2-methoxy-2-methyl-propyl)-indan-1- The title compound was prepared from the alcohol and ( S )-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester.

Intermediate 80 {( S )-6-[( R )-4-(1,1-difluoro-2-hydroxy-2-methyl-propyl)-indan-1-yl Methyl oxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-4-(1,1-Difluoro-2-hydroxy-2-methyl-propyl)-indan-1-ol

Follow the procedure described in Step 4 similar to Intermediate 7 from tert-butyl-[( S )-4-(1,1-difluoro-2-hydroxy-2-methyl-propyl)-dihydro The title compound was prepared from 茚-1-yloxy]-dimethyl-decane.

Step 2 : {( S )-6-[( R )-4-(1,1-Difluoro-2-hydroxy-2-methyl-propyl)-indan-1-yloxy]-2 ,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Following the procedure described in Step 3 similar to Intermediate 1, ( S )-4-(1,1-difluoro-2-hydroxy-2-methyl-propyl)-indan-1-ol and The title compound was prepared from ( S )-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester.

Intermediate 81 {( S )-6-[( R )-4-(4,6-Dimethyl-pyrimidin-5-yl)-indan-1-yloxy]-2,3-dihydro-benzo Methyl furan-3-yl}-acetate

Follow the procedure described in Intermediate 44 for 5-bromo-4,6-dimethyl-pyrimidine and {( S )-6-[( R )-4-(4,4,5,5-four Methyl-[1,3,2]diboron The title compound was prepared from methyl-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. Yield: 47% of theory; LC (method 6): t _R = 1.14 min; mass spectrum (ESI ⁺ ): m/z = 431 [M+H] ⁺ .

Intermediate 82 {( S )-6-[4-(1-Methyl-cyclopropyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid ester

Step 1 : 4-Isopropenyl-indoline-1-one

The title compound was prepared from 4-bromo-indoline-1-one and isopropenyl trifluoroborate following a procedure similar to that described in Intermediate 44. Yield: 67% of the theoretical value; the LC (Method _{6): t R = 0.67 min} ; Mass spectrum ^{(ESI +): m / z} = 173 [M + H] +.

Step 2 : 4-(1-Methyl-cyclopropyl)-indan-1-one

A solution of trifluoroacetic acid (0.20 mL) in dichloromethane (4 mL) EtOAc. The solution was stirred for 20 minutes then a solution of diiodomethane (0.29 mL) in dichloromethane (4 mL). The solution was stirred for a further 20 minutes and then a solution of 4-isopropenyl-indan-1-one (0.21 g) in dichloromethane (4 mL). The solution was stirred overnight at room temperature. The solution was diluted with dichloromethane and washed ₄ Cl aqueous NH. Dried (MgSO _4), and the solution was concentrated. The residue was purified by reverse phase chromatography (MeOH/EtOAc/EtOAc) Yield: 0.07 g (32% of theory); LC (method 6): t _R = 0.84 min; mass spectrum (ESI ⁺ ): m/z = 187 [M+H] ⁺ .

Step 3 : 4-(1-Methyl-cyclopropyl)-indan-1-ol

The title compound was prepared from 4-(1-methyl-cyclopropyl)-indan-1-one following the procedure described in Step 2 to Intermediate. Yield: 84% of theory; LC (method 6): t _R = 0.93 min; mass spectrum (ESI ⁺ ): m/z = 171 [M+H] ⁺ .

Step 4 : {( S )-6-[4-(1-Methyl-cyclopropyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from 4-(1-methyl-cyclopropyl)-indan-1-ol and ( S )-(6-hydroxy-2,3-di The title compound was prepared from hydrogen-benzofuran-3-yl)-acetic acid methyl ester. Yield: 74% of the theoretical value; the LC (Method _{6): t R = 1.63 min} ; Mass spectrum ^{(ESI +): m / z} = 401 [M + Na] +.

Intermediate 83 {( S )-6-[( R )-4-(2,6-Dichloro-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Methyl acetate

Follow the procedure described in Intermediate 53 for 1,3-dichloro-2-iodo-benzene and {( S )-6-[( R )-4-(4,4,5,5-tetramethyl) Base-[1,3,2]diboron Preparation of the title compound from methyl-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate; 1,4-dioxin at 85 ° C The alkane is used as a solvent.

Intermediate 84 {( S )-6-[( R )-4-(2,2,2-Trifluoro-ethenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran -3-yl}-acetic acid

Add n-butyllithium (1.6 mol/L hexane solution, 0.25 mL) to {( S )-6-[( R )-4-bromo-indoline-1-yloxy group cooled to -78 °C a solution of -2,3-dihydro-benzofuran-3-yl}-acetic acid (50 mg) in tetrahydrofuran (5 mL). The solution was stirred at -78 °C for 0.5 h then a solution of ethyl trifluoroacetate (0.10 mL) in THF (1 mL). The solution was stirred at -78 °C for 1 hour and then warmed to room temperature overnight in a cooling bath. Ether was added and the solution was washed with aqueous NH Cl _4. The (Na ₂ SO ₄ ) solution was dried and concentrated to give the title compound. Yield: 51 mg (98% of theory); LC (method 6): t _R = 1.06 min; mass spectrum (ESI ^- ): m/z = 405 [MH] ^- .

Intermediate 85 {( S )-6-[( R )-4-(2-chloro-6-methyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-methyl}-methyl acetate

Follow the procedure described in Intermediate 53 for 1-chloro-2-iodo-3-methyl-benzene and {( S )-6-[( R )-4-(4,4,5,5- Tetramethyl-[1,3,2]diboron Preparation of the title compound from methyl-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate; 1,4-dioxin at 85 ° C The alkane is used as a solvent.

Intermediate 86 {( S )-6-[( R )-4-(6-methoxy-3-trifluoromethyl-pyridin-2-yl)-indan-1-yloxy]-2,3- Methyl dihydro-benzofuran-3-yl}-acetate

Following the procedure similar to that described in Intermediate 44, 2-iodo-6-methoxy-3-trifluoromethyl-pyridine and {( S )-6-[( R )-4-(4,4, 5,5-tetramethyl-[1,3,2]diboron The title compound was prepared from methyl-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. Yield: 67% of theory; LC (method 1): t _R = 1.44 min; mass spectrum (ESI ⁺ ): m/z = 500 [M+H] ⁺ .

Intermediate 87 {( S )-6-[( R )-4-(8-Methyl-naphthalen-1-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -yl}-methyl acetate

Following a procedure similar to that described in Intermediate 44, 1-bromo-8-methyl-naphthalene and {( S )-6-[( R )-4-(4,4,5,5-tetramethyl- [1,3,2]diboron The title compound was prepared from methyl-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. Yield: 90% of theory; LC (method 1): t _R = 1.55 min; mass spectrum (ESI ⁺ ): m/z = 487 [M+Na] ⁺ .

Intermediate 88 {( S )-6-[( R )-4-(2,4-dimethyl-pyridin-3-yl)-indan-1-yloxy]-2,3-dihydro-benzo Methyl furan-3-yl}-acetate

Follow the procedure described in Intermediate 44 for 3-bromo-2,4-dimethyl-pyridine and {( S )-6-[( R )-4-(4,4,5,5-four Methyl-[1,3,2]diboron The title compound was prepared from methyl-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. Yield: 47% of theory; LC (method 1): t _R = 1.06 min; mass spectrum (ESI ⁺ ): m/z = 430 [M+H] ⁺ .

Intermediate 89 {( S )-6-[( R )-4-(2-pentafluoroethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Methyl acetate

Step 1 : 1-Bromo-2-pentafluoroethyl-benzene

Trimethyl-pentafluoroethyl-decane (1.0 mL) was added to 1-bromo-2-iodo-benzene (0.50 mL), KF (0.27 g), CuI (0.89 mg) at room temperature. In a mixture with N,N-dimethylformamide (1 mL). The reaction vessel was sealed and the mixture was stirred at 80 ° C overnight. After cooling to room temperature, diethyl ether was added and the mixture was washed with NH ₄ Cl solution. Dried (MgSO ₄₎ organic phase was concentrated to give the crude title compound. Yield: 1.05 g (98% of theory); the LC (Method _{7): t R = 1.77 min} .

Step 2 : {( S )-6-[( R )-4-(2-pentafluoroethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran Methyl-3-methyl}-acetate

Following the procedure described in Intermediate 44, 1-bromo-2-pentafluoroethyl-benzene and {( S )-6-[( R )-4-(4,4,5,5-tetramethyl) Base-[1,3,2]diboron The title compound was prepared from methyl-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. Yield: 68% of theory; LC (method 1): t _R = 1.69 min; mass spectrum (ESI ⁺ ): m/z = 541 [M+Na] ⁺ .

Intermediate 90 Methyl {( S )-6-[( R )-5-t-butyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : ( S )-5-Ter Butyl-Dihydrofurfuryl Alcohol

The title compound was prepared from 5-t-butyl-indoline-1-one following a procedure similar to that described in Step 2 of Intermediate 13. Yield: 84% of theory; LC (method 4): t _R = 2.07 min; mass spectrum (ESI ⁺ ): m/z = 173 [M-OH] ⁺ .

Step 2 : {( S )-6-[( R )-5-Terbutyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid Methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-5-tert-butyl-dihydrofurfuryl alcohol and ( S )-(6-hydroxy-2,3-dihydro-benzofuran The title compound was prepared from -3-yl)-methyl acetate. Yield: 46% of theory; LC (method 1): t _R = 1.51 min; mass spectrum (ESI ⁺ ): m/z = 403 [M+Na] ⁺ .

Intermediate 91 {( S )-6-[( R )-4-(Cyano-dimethyl-methyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Methyl acetate

Step 1 : ( S )-[1-(Third butyl-dimethyl-decyloxy)-indan-4-yl]-acetonitrile

The bis(diphenylphosphino)ferrocene-dichloropalladium dichloromethane adduct (0.47 g) was added to a stir bar, ( S )-(4-bromo-2) at room temperature under an Ar atmosphere. ,3-dihydro-1H-indol-1-yloxy)-tert-butyl-dimethyldecane (2.10 g), 4-(4,4,5,5-tetramethyl-1,3, 2-diboron -2-yl)isoxazole (1.50 g), CS ₂ CO ₃ (6.27 g), N,N-dimethylformamide (50 mL) and water (10 mL). The mixture was stirred at 90 ° C overnight. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The combined washed with water and brine and the organic extracts were dried (Na ₂ SO _4). The solvent was evaporated and EtOAc (EtOAc) Yield: 1.84 g (37% of theory); the LC (Method _{4): t R = 2.37 min} .

Step 2 : ( S )-2-[1-(Third butyl-dimethyl-decyloxy)-indan-4-yl]-2-methyl-propanenitrile

Add bis(trimethyldecane)amino potassium (0.5 mol/L toluene solution; 2.1 mL) to ( S )-[1-(t-butyl-dimethyl-decyloxy) cooled to -60 °C A solution of hydrazin-4-yl]-acetonitrile (0.30 g) in tetrahydrofuran (10 mL). The solution was stirred at -60 °C for 20 minutes, after which time methyl iodide (65 μL) was added. The solution was stirred at -60 ° C for an additional 30 minutes, after which a portion of bis(trimethyldecane)amine potassium (0.5 mol/L in toluene; 2.1 mL) was added, and after stirring for another 20 minutes, a portion of methyl iodide was added. 65 μL). The solution was further stirred for 2 hours, after which bis(trimethyldecane)amino potassium (0.5 mol/L toluene solution; 2.1 mL) was added, and after another 5 minutes, methyl iodide (65 μL) was added. The solution was stirred at -50 °C for 1 hour and then diluted with diethyl ether. With 1 M aqueous hydrochloric acid solution and washed with Na ₂ S ₂ O ₃ aqueous solution, and dried (Na ₂ SO _4). The solvent was evaporated and the residue was purified elut elut elut Yield: 0.24 g (72% of theory); LC (method 1): t _R = 1.51 min; mass spectrum (ESI ⁺ ): m/z = 338 [M+Na] ⁺ .

Step 3 : ( S )-2-(1-Hydroxy-dihydroindol-4-yl)-2-methyl-propanenitrile

Follow the procedure described in Step 4 similar to Intermediate 7 from ( S )-2-[1-(t-butyl-dimethyl-decyloxy)-indan-4-yl]-2 -Methyl-propionitrile The title compound was prepared. Yield: 76% of theory; LC (method 1): t _R = 0.91 min; mass spectrum (ESI ⁺ ): m/z = 184 [M-OH] ⁺ .

Step 4 : {( S )-6-[4-(Cyano-dimethyl-methyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl }-methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-2-(1-hydroxy-dihydroindol-4-yl)-2-methyl-propionitrile and ( S )-(6- The title compound was prepared from methyl hydroxy-2,3-dihydro-benzofuran-3-yl)-acetate. Yield: 65% of the theoretical value; the LC (Method _{1): t R = 1.30 min} ; Mass spectrum ^{(ESI +): m / z} = 414 [M + Na] +.

Intermediate 92 {( S )-6-[( R )-4-chloro-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Methyl acetate

Step 1 : ( S )-4-Chloro-5-trifluoromethyl-indanol

The title compound was prepared from 4-chloro-5-trifluoromethyl-indan-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 55% of theory; mass spectrum (ESI ^- ): m/z = 235 / 237 (CI) [MH] ^- .

Step 2 : {( S )-6-[( R )-4-chloro-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Methyl acetate

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-chloro-5-trifluoromethyl-indanol and ( S )-(6-hydroxy-2,3-dihydrogen The title compound was prepared from -benzofuran-3-yl)-acetic acid methyl ester. Yield: 70% of theory; LC (method 6): t _R = 1.60 min; mass spectrum (ESI ⁺ ): m/z = 427 / 429 (CI) [M+H] ⁺ .

Intermediate 93 {( S )-6-[( R )-4-(3-methyl-pyrazin-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-methyl}-methyl acetate

Following the procedure similar to that described in Example 53, {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Preparation of 2--2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-chloro-3-methyl-pyrazine Compound; the reaction was carried out in tetrahydrofuran at 100 °C. LC (Method _{7): t R = 1.68 min} ; Mass spectrum ^{(ESI +): m / z} = 417 [M + H] +.

Intermediate 94 {( S )-6-[( R )-4-(3-methoxy-2,6-dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro -benzofuran-3-yl}-acetic acid methyl ester

Step 1 : 3-Methoxy-2,6-dimethyl-phenol

The title compound was prepared from 2,4-dimethyl-benzene-1,3-diol and methyl iodide following procedures similar to those described in Step 3 of Intermediate 55. Yield: 55% of theory; LC (method 7): t _R = 1.28 min; mass spectrum (ESI ⁺ ): m/z = 153 [M+H] ⁺ .

Step 2 : Trimethoxy-methanesulfonic acid 3-methoxy-2,6-dimethyl-phenyl ester

Trifluoromethanesulfonic anhydride (0.10 mL) was added to a solution of 3-methoxy-2,6-dimethyl-phenol (65 mg) and dimethylpyridine (0.10 mL) In a solution of 2 mL). The cooling bath was removed and the solution was stirred at room temperature overnight. Dichloromethane was added and the solution was washed with 1 M aqueous hydrochloric acid. Dried (Na ₂ SO ₄₎ organic phase was concentrated. The title compound was obtained from EtOAc (EtOAc/EtOAc) Yield: 80 mg (75% of theory); the LC (Method _{7): t R = 1.79 min} .

Step 3 : {( S )-6-[( R )-4-(3-methoxy-2,6-dimethyl-phenyl)-indan-1-yloxy]-2,3 -dihydro-benzofuran-3-yl}-acetic acid methyl ester

Following the procedure described in Intermediate 44, trimethoxy-methanesulfonic acid 3-methoxy-2,6-dimethyl-phenyl ester and {( S )-6-[( R )-4-( 4,4,5,5-tetramethyl-[1,3,2]diboron Preparation of the title compound; methyl admixture of tetrahydrofuran and toluene at 100 ° C; methyl-2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-methyl acetate The reaction takes place. Yield: 40% of theory; the LC (Method _{6): t R = 1.64 min} ; Mass spectrum ^{(ESI +): m / z} = 481 [M + Na] +.

Intermediate 95 {( S )-6-[( R )-4-pentafluoroethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Step 1 : 1-Bromo-2-pentafluoroethyl-benzene

The title compound was prepared as described in Step 1 of Intermediate 89.

Step 2 : Methyl 3-(2-pentafluoroethyl-phenyl)-propionate

The title compound was prepared from 1-bromo-2-pentafluoroethyl-benzene and 3,3-dimethoxy-propene following the procedure described in Step 1 to Intermediate 30. Yield: 26% of the theoretical value; the LC (Method _{6): t R = 1.16 min} .

Step 3 : 3-(2-pentafluoroethyl-phenyl)-propionic acid

The title compound was prepared from methyl 3-(2-pentafluoroethyl-phenyl)-propanoate following a procedure similar to that described in Example 1. Yield: 87% of theory; LC (method 6): t _R = 0.93 min; mass spectrum (ESI ^- ): m/z = 267 [MH] ^- .

Step 4 : 4-pentafluoroethyl-indoline-1-one

The title compound was prepared from 3-(2-pentafluoroethyl-phenyl)-propionic acid following the procedure described in Step 3 to Intermediate 30; Yield: 69% of theory; LC (Method 6): t _R = 0.98 min; Mass (ESI ⁺ ): m/z = 251 [M+H] ⁺ .

Step 5 : ( S )-4-pentafluoroethyl-indan-1-ol

The title compound was prepared from 4-pentafluoroethyl-indan-1-one following the procedure described in Step 2 to Intermediate 13. Yield: 80% of theory; the LC (Method _{6): t R = 0.97 min} ; Mass spectrum ^{(ESI +): m / z} = 235 [M-OH] +.

Step 6 : {( S )-6-[( R )-4-pentafluoroethyl-indoline-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid Methyl ester

Follow the procedure described in Step 3 similar to Intermediate 1 from ( S )-4-pentafluoroethyl-indan-1-ol and ( S )-(6-hydroxy-2,3-dihydro- The title compound was prepared from methyl benzofuran-3-yl)-acetate. Yield: 68% of theory; LC (method 6): t _R = 1.60 min; mass spectrum (ESI ⁺ ): m/z = 443 [M+H] ⁺ .

Intermediate 96 {( S )-6-[( R )-6-fluoro-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Methyl acetate

The title compound was obtained following the synthetic procedure described above and the corresponding procedures described for Intermediate 30 and Intermediate 95. LC (Method _{7): t R = 1.92 min} ; Mass spectrum ^{(ESI +): m / z} = 411 [M + H] +.

Intermediate 97 {( S )-6-[( R )-4-(2-methoxy-4-trifluoromethyl-pyridin-3-yl)-indan-1-yloxy]-2,3- Methyl dihydro-benzofuran-3-yl}-acetate

Step 1 : 3-iodo-2-methoxy-4-trifluoromethyl-pyridine

Add sodium (18 mg) dissolved in methanol (0.5 mL) to a solution of 2-chloro-3-iodo-4-trifluoromethyl-pyridine (0.20 g) in methanol (1.5 mL) in. The solution was stirred overnight at 60 °C. After cooling to room temperature, diethyl ether was added and the solution was washed with water and brine. Dried (Na ₂ SO ₄₎ organic phase was concentrated. The residue was chromatographed (dichloromethane) to give the title compound. Yield: 0.06 g (30% of theory); LC (method 1): t _R = 1.25 min; mass spectrum (ESI ⁺ ): m/z=304[M+H] ⁺ .

Step 3 : {( S )-6-[( R )-4-(2-methoxy-4-trifluoromethyl-pyridin-3-yl)-indan-1-yloxy]-2 ,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Following the procedure described in Intermediate 44, 3-iodo-2-methoxy-4-trifluoromethyl-pyridine and {( S )-6-[( R )-4-(4,4, 5,5-tetramethyl-[1,3,2]diboron The title compound was prepared from methyl-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. Yield: 61% of theory; LC (method 1): t _R = 1.44 min; mass spectrum (ESI ⁺ ): m/z = 500 [M+H] ⁺ .

Intermediate 98 {( S )-6-[( R )-4-(3-methoxy-2-methyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzo Methyl furan-3-yl}-acetate

Following the procedure similar to that described in Example 44 from {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron 2-yl)-indoline-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1-bromo-3-methoxy-2-methyl The title compound was prepared from the base-benzene. LC (Method _{7): t R = 1.66 min} ; Mass spectrum ^{(ESI +): m / z} = 445 [M + H] +.

Intermediate 98 Methyl {7-methyl-6-[(R)-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : 4-Chloromethyl-7-hydroxy-8-methyl- En-2-one

Ethyl 4-chloroacetic acid ethyl acetate (6.63 g) was slowly added to concentrated sulfuric acid (17 mL) with stirring at 0 °C. 2-Methyl resorcinol (5.0 g) was added portionwise, after which the mixture was stirred at room temperature for 3 hours. The mixture was slowly poured into a mixture of ice and water and the precipitated product was collected by filtration, washed with water and dried in vacuo to give the title compound. Yield: 8.29 g (91% of theory); mass spectrum (ESI ⁺ ): m/z = 225/227 (CI) [M+H] ⁺ .

Step 2 : (6-Hydroxy-7-methyl-benzofuran-3-yl)-acetic acid

4-chloromethyl-7-hydroxy-8-methyl- The alken-2-one (8.29 g) was suspended in 250 mL of 1 M aqueous NaOH and heated under reflux for 3 h. The mixture was cooled to 0 ° C, acidified with concentrated sulfuric acid and then extracted with ethyl acetate. The organic extract was dried with MgSO4, filtered Yield: 7.35 g (96% of theory); Mass spectrum ^{(ESI -): m / z} 205 [MH] -.

Step 3 : (6-Hydroxy-7-methyl-benzofuran-3-yl)-acetic acid methyl ester

(6-Hydroxy-7-methyl-benzofuran-3-yl)-acetic acid (7.35 g) was dissolved in MeOH (EtOAc) (EtOAc) The mixture was cooled to rt. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by EtOAcqqq elut elut Yield: 2.93 g (38% of theory); Mass spectrum ^{(ESI -): m / z} 219 [MH] -.

Step 4 : (6-Hydroxy-7-methyl-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

(6-Hydroxy-7-methyl-benzofuran-3-yl)-acetic acid methyl ester (1.0 g) was suspended in methanol (100 mL) and 10% palladium/activated carbon was used at a pressure of 5 bar ( 100 mg) was hydrogenated as a catalyst for 4 days. The mixture was filtered through dicalite to remove the catalyst, followed by vacuum removal of the solvent. The residue was purified by EtOAcqqq elut elut Yield: 467 mg (46% of theory); Mass spectrum ^{(ESI +): m / z} 223 [M + H] +.

Step 5 : {7-Methyl-6-[(R)-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Methyl acetate

Dissolve (6-hydroxy-7-methyl-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (200 mg) in dry tetrahydrofuran (5 mL) and add ( S )-4 Trifluoromethyl-indan-1-ol (181 mg) followed by triphenylphosphine (236 mg). The mixture was cooled to 0 ° C and dibutyl azodicarboxylate (207 mg) was added. The mixture was stirred at 0 °C for 4 hours, then the solvent was removed in vacuo. The residue was purified by EtOAcqqq elut elut Yield: 190 mg (52% of theory); mass spectrum (ESI ⁺ ): m/z 407 [M+H] ⁺ .

Intermediate 99 Methyl 4-methyl-6-[(R)-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate

Step 1 : 4-Chloromethyl-7-hydroxy-5-methyl- En-2-one

Ethyl 4-chloroacetic acid ethyl acetate (3.98 g) was slowly added to concentrated sulfuric acid (10 mL) with stirring at 0 °C. Orcinol (3.0 g) was added portionwise, after which the mixture was stirred at room temperature for 3 hours. The mixture was slowly poured into a mixture of ice and water and the precipitated product was collected by filtration, washed with water and dried in vacuo to give the title compound. Yield: 5.13 g (94% of theory); mass spectrum (ESI ⁺ ): m/z = 225/227 (CI) [M+H] ⁺ .

Step 2 : (6-Hydroxy-4-methyl-benzofuran-3-yl)-acetic acid

4-chloromethyl-7-hydroxy-5-methyl- The alken-2-one (5.13 g) was suspended in 125 mL of 1 M aqueous NaOH and heated under reflux for 3 h. The mixture was cooled to 0 ° C, acidified with cone. The organic extract was dried with MgSO4, filtered Yield: 4.27 g (90% of theory); Mass spectrum ^{(ESI -): m / z} 205 [MH] -.

Step 3 : (6-Hydroxy-4-methyl-benzofuran-3-yl)-acetic acid methyl ester

(6-Hydroxy-4-methyl-benzofuran-3-yl)-acetic acid (4.27 g) was dissolved in methanol (50 mL). The mixture was cooled to rt. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by EtOAcqqq elut elut Yield: 3.70 g (81% of theory); Mass spectrum ^{(ESI -): m / z} 219 [MH] -.

Step 4 : (6-Hydroxy-4-methyl-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

(6-Hydroxy-4-methyl-benzofuran-3-yl)-acetic acid methyl ester (1.0 g) was suspended in methanol (150 mL) and 10% palladium/activated carbon was used at a pressure of 5 bar ( 100 mg) was hydrogenated as a catalyst for 3 days. The mixture was filtered through celite to remove the catalyst, then the solvent was removed in vacuo. The residue was purified by EtOAcqqq elut elut Yield: 470 mg (47% of theory); mass spectrum (ESI ⁺ ): m/z 223[M+H] ⁺ .

Step 5 : {4-Methyl-6-[(R)-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Methyl acetate

Dissolve (6-hydroxy-4-methyl-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (200 mg) in dry tetrahydrofuran (5 mL) and add ( S )-4 Trifluoromethyl-indan-1-ol (181 mg) followed by triphenylphosphine (236 mg). The mixture was cooled to 0 ° C and di-tert-butyl azodicarboxylate (207 mg) was added and the mixture was stirred at 0 ° C for 4 hours, then solvent was evaporated in vacuo. The residue was purified by EtOAcqqq elut elut Yield: 114 mg (31% of theory); Mass spectrum ^{(ESI +): m / z} 407 [M + H] +.

Intermediate 100 {5-Methyl-6-[(R)-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Step 1 : 4-Chloromethyl-7-hydroxy-6-methyl- En-2-one

Ethyl 4-chloroacetic acid ethyl acetate (1.33 g) was slowly added to concentrated sulfuric acid (3.5 mL) with stirring at 0 °C. 4-Methyl resorcinol (1.0 g) was added portionwise, after which the mixture was stirred at room temperature overnight. The mixture was slowly poured into a mixture of ice and water and the precipitated product was collected by filtration, washed with water and dried in vacuo to give the title compound. Yield: 1.80 g (99% of theory); mass spectrum (ESI ⁺ ): m/z = 225/227 (CI) [M+H] ⁺ .

Step 2 : (6-Hydroxy-5-methyl-benzofuran-3-yl)-acetic acid

4-chloromethyl-7-hydroxy-6-methyl- The alken-2-one (1.80 g) was suspended in 58 mL of 1 M aqueous NaOH and heated under reflux for 3 h. The mixture was cooled to 0 ° C, acidified with cone. The organic extract was dried with MgSO4, filtered Yield: 1.53 g (90% of theory); Mass spectrum ^{(ESI -): m / z} 205 [MH] -.

Step 3 : (6-Hydroxy-5-methyl-benzofuran-3-yl)-acetic acid methyl ester

(6-Hydroxy-5-methyl-benzofuran-3-yl)-acetic acid (1.80 g) was dissolved in MeOH (EtOAc) (EtOAc) The mixture was cooled to rt. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by EtOAcqqqq elut elut Yield: 1.18 g (61% of theory); mass spectrum (ESI ⁺ ): m/z 221 [M+H] ⁺ .

Step 4 : (6-Hydroxy-5-methyl-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

(6-Hydroxy-5-methyl-benzofuran-3-yl)-acetic acid methyl ester (1.16 g) was suspended in methanol (50 mL) and 10% palladium/activated carbon was used at a pressure of 5 bar ( 100 mg) was hydrogenated as a catalyst for 3 hours. The mixture was filtered through celite to remove the catalyst, then the solvent was removed in vacuo. The residue was purified by EtOAcqqq elut elut Yield: 1.02 mg (87% of theory); Mass spectrum ^{(ESI +): m / z} 223 [M + H] +.

Step 5 : [5-Methyl-6-((R)-4-trifluoromethyl-indan-1-yloxy)-2,3-dihydro-benzofuran-3-yl]- Methyl acetate

Dissolve (6-hydroxy-5-methyl-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (200 mg) in dry tetrahydrofuran (5 mL) and add ( S )-4 Trifluoromethyl-indan-1-ol (181 mg) followed by triphenylphosphine (236 mg). The mixture was cooled to 0 ° C and dibutyl azodicarboxylate (207 mg) was added. The mixture was stirred at 0 °C for 4 hours, then the solvent was removed in vacuo. The residue was purified by EtOAcqqq elut elut elut Yield: 175 mg (48% of theory); mass spectrum (ESI ⁺ ): m/z 407 [M+H] ⁺ .

Example 1 [6-(4-Trifluoromethyl-indan-1-yloxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid

Add 4 M NaOH aqueous solution (0.48 mL) to [6-(4-trifluoromethyl-indan-1-yloxy)-2,3-dihydro-benzofuran-3- at room temperature Methyl acetate (0.25 g) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and acidified using 1 M aqueous hydrochloric acid. The resulting mixture was extracted with ethyl acetate, washed with brine and the extracts were combined and dried (MgSO _4). Evaporation of the solvent gave the title compound as a mixture of four stereoisomers. Yield: 0.24 g (quantitative); mass spectrum (ESI ⁺ ): m/z = 379 [M+H] ⁺ .

Example 2, Example 3, Example 4, and Example 5 Stereoisomer of [6-(4-trifluoromethyl-indan-1-yloxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid

Separation example by palm phase phase SFC (column: Daicel IC, 250 mm × 4.6 mm, 5 μm, 40 ° C; dissolving agent: CO ₂ / 10% ethanol containing 0.2% diethylamine, 4 mL/min) A mixture of stereoisomers obtained in 1. Obtaining two stereoisomers in pure form and obtaining two other stereoisomers in a 1:1 mixture with each other; configuration of any given stereogenic center (for palm phase SFC (conditions as described above) Retention time for the example: Example 2: t _R = 4.18 min; Example 3 and Example 4: t _R = 4.73 min; Example 5: t _R = 5.74 min).

Example 6 {6-[( R )-4-bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {6-[( R )-4-bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- The title compound was prepared from methyl acetate. LC (Method _{1): t R = 1.36 min} ; Mass spectrum ^{(ESI +): m / z} = 389/391 (Br) [M + H] +.

Pure enantiomeric compound {( S )-6-[( R )-4-bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Acetic acid is obtained by chromatography of the diastereomer mixture Example 6, or by using the pure enantiomeric starting material {( S )-6-[( R )-4-bromo-indoline-1 Methyl-oxy]-2,3-dihydro-benzofuran-3-yl}-acetate is obtained by saponification.

Example 7 {6-[( R )-4-(1-methyl-1H-pyrazol-4-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Base}-acetic acid

Following the procedure similar to that described in Example 1, {6-[( R )-4-(1-methyl-1H-pyrazol-4-yl)-indan-1-yloxy]-2, The title compound was prepared from methyl 3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.16 min} ; Mass spectrum ^{(ESI +): m / z} = 391 [M + H] +.

Example 8 {6-[( R )-4-(3,6-Dihydro-2H-pyran-4-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-based}-acetic acid

Following the procedure similar to that described in Example 1, {6-[( R )-4-(3,6-dihydro-2H-pyran-4-yl)-indan-1-yloxy]- The title compound was prepared from 2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{1): t R = 1.26 min} ; Mass spectrum ^{(ESI +): m / z} = 393 [M + H] +.

Example 9 {6-[( R )-4-(1-methyl-2-oxooxy-1,2-dihydro-pyridin-4-yl)-indan-1-yloxy]-2,3 -dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {6-[( R )-4-(1-methyl-2-oxo-l,2-dihydro-pyridin-4-yl)-indoline The title compound was prepared from methyl-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{2): t R = 1.34 min} ; Mass spectrum ^{(ESI +): m / z} = 418 [M + H] +.

Example 10 {6-[( R )-4-(4-methoxy-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {6-[( R )-4-(4-methoxy-phenyl)-indan-1-yloxy]-2,3-dihydro- The title compound was prepared from benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{2): t R = 1.61 min} ; Mass spectrum ^{(ESI +): m / z} = 417 [M + H] +.

Example 11 {6-[4-(2,2-Difluoro-1-methoxy-ethyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -acetic acid

Following the procedure similar to that described in Example 1, {6-[4-(2,2-difluoro-1-methoxy-ethyl)-indan-1-yloxy]-2,3- The title compound was prepared from dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{1): t R = 1.23 min} ; Mass spectrum ^{(ESI +): m / z} = 405 [M + H] +.

Example 12 {6-[( R )-4-(tetrahydro-pyran-4-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {6-[( R )-4-(tetrahydro-pyran-4-yl)-indan-1-yloxy]-2,3-dihydro The title compound was prepared from benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{1): t R = 1.27 min} ; Mass spectrum ^{(ESI +): m / z} = 395 [M + H] +.

Example 13 {6-[4-(1-Methoxy-2,2-dimethyl-propyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl }-acetic acid

Following the procedure similar to that described in Example 1, {6-[4-(1-methoxy-2,2-dimethyl-propyl)-indan-1-yloxy]-2,3 -Dihydro-benzofuran-3-yl}-acetic acid methyl ester The title compound was obtained. LC (Method _{3): t R = 1.45 min} ; Mass spectrum ^{(ESI +): m / z} = 411 [M + H] +.

Example 14 {( S )-6-[4-(Cyclobutyl-methoxy-methyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[4-(cyclobutyl-methoxy-methyl)-indan-1-yloxy]-2,3-di The title compound was prepared from hydrogen-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{1): t R = 1.39 min} ; Mass spectrum ^{(ESI +): m / z} = 409 [M + H] +.

Example 15 {6-[( R )-4-(5,5-Dimethyl-cyclopent-1-enyl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-based}-acetic acid

Following the procedure similar to that described in Example 1, {6-[( R )-4-(5,5-dimethyl-cyclopent-1-enyl)-indan-1-yloxy]- The title compound was prepared from 2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (method 1): t _R = 1.51 min; Mass (ESI ⁺ ): m/z = 405[M+H] ⁺ .

Example 16 {6-[( R )-4-(2,2-dimethyl-cyclopentyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -acetic acid

{6-[( R )-4-(5,5-Dimethyl-cyclopent-1-enyl)-indan-1-yloxy]-2,3-dihydro-benzofuran- A mixture of 3-yl}-acetic acid (40 mg), PtO ₂ (20 mg) and ethyl acetate (3 mL) was shaken under a hydrogen atmosphere (3 bar) at room temperature for 4 hours. The catalyst was isolated by filtration and the filtrate was concentrated to give the title compound. Yield: 40 mg (quantitative); LC (method 1): t _R = 1.52 min; mass spectrum (ESI ⁺ ): m/z = 407 [M+H] ⁺ .

Example 17 {( S )-6-[(R)-4-Difluoromethoxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-difluoromethoxy-indoline-1-yloxy]-2,3-dihydro-benzene The title compound was prepared from furan-3-yl}-acetic acid methyl ester. LC (Method _{2): t R = 1.31 min} ; Mass spectrum ^{(ESI +): m / z} = 377 [M + H] +.

Example 18 {( S )-6-[( R )-4-(1-methoxy-cyclobutyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Base}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(1-methoxy-cyclobutyl)-indan-1-yloxy]-2, The title compound was prepared from methyl 3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.35 min} ; Mass spectrum ^{(ESI +): m / z} = 395 [M + H] +.

Example 19 {( S )-6-[( R )-6-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-6-trifluoromethyl-indoline-1-yloxy]-2,3-dihydro-benzo The title compound was prepared from furan-3-yl}-acetic acid methyl ester. LC (Method _{4): t R = 1.98 min} ; Mass spectrum ^{(ESI -): m / z} = 377 [MH] -.

Example 20 {( S )-6-[( R )-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-5-trifluoromethyl-indoline-1-yloxy]-2,3-dihydro-benzo The title compound was prepared from furan-3-yl}-acetic acid methyl ester. LC (Method _{4): t R = 2.00 min} ; Mass spectrum ^{(ESI -): m / z} = 377 [MH] -.

Example 21 {( S )-6-[( R )-5-chloro-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Base}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-5-chloro-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -Base}-methyl acetate to prepare the title compound. LC (Method _{5): t R = 3.41 min} ; Mass spectrum ^{(ESI -): m / z} = 343/345 (Cl) [MH] -.

Example 22 {( S )-6-[( R )-4-chloro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-chloro-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -Base}-methyl acetate to prepare the title compound. LC (Method 4): t _R = 1.99 min; Mass (ESI ^- ): m/z = 343/345 (CI) [MH] ^- .

Example 23 {( S )-6-[( R )-7-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following a procedure similar to that described in Example 1, {( S )-6-[( R )-7-trifluoromethyl-indoline-1-yloxy]-2,3-dihydro-benzo The title compound was prepared from furan-3-yl}-acetic acid methyl ester. LC (Method _{5): t R = 3.33 min} ; Mass spectrum ^{(ESI -): m / z} = 377 [MH] -.

Example 24 {( S )-6-[( R )-7-fluoro-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-7-fluoro-4-trifluoromethyl-indoline-1-yloxy]-2,3-di The title compound was prepared from hydrogen-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{4): t R = 1.98 min} ; Mass spectrum ^{(ESI -): m / z} = 395 [MH] -.

Example 25 {( S )-6-[( R )-4-trifluoromethoxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-trifluoromethoxy-indoline-1-yloxy]-2,3-dihydro-benzene The title compound was prepared from furan-3-yl}-acetic acid methyl ester. LC (Method _{4): t R = 2.02 min} ; Mass spectrum ^{(ESI -): m / z} = 393 [MH] -.

Example 26 {( S )-6-[( R )-6-methyl-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-6-methyl-4-trifluoromethyl-indoline-1-yloxy]-2,3- The title compound was prepared from dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{4): t R = 2.05 min} ; Mass spectrum ^{(ESI -): m / z} = 391 [MH] -.

Example 27 {( S )-6-[( R )-4-(1-methoxy-2,2-dimethyl-propyl)-indan-1-yloxy]-2,3-dihydro -benzofuran-3-yl}-acetic acid (a mixture of two diastereomers)

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(1-methoxy-2,2-dimethyl-propyl)-indoline-1 Methyloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (mixture of two diastereomers) gave the title compound. LC (Method _{1): t R = 1.43 /} 1.45 min ( diastereomeric mixture); Mass spectrum ^{(ESI -): m / z} = 409 [MH] -.

Example 28 and Example 29 {( S )-6-[( R )-4-(( R ) ^* 1-methoxy-2,2-dimethyl-propyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid (Example 28 ) and {( S )-6-[( R )-4-(( S ) ^* 1-methoxy-2,2-dimethyl-propyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid (Example 29 )

The mixture of diastereomers of Example 27 was subjected to a palmitic phase SFC (column: Daicel ADH, 250 x 4.6 mm; mobile phase: methanol containing 0.2% diethylamine/supercritical carbon dioxide 25:75; flow rate: At 4 mL/min), the title compound was obtained in separate fractions. Arbitrarily specify the configuration of the stereoisomeric center ( ^* ) shown.

Example 28: LC (Method 1): t _R = 1.43 min; Mass Spectrum (ESI ^- ): m/z = 409 [MH] ^- .

Example 29: LC (Method 1): t _R = 1.45 min; Mass (ESI ^- ): m/z = 409 [MH] ^- .

Example 30 {( S )-6-[( R )-7-Methyl-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-7-methyl-4-trifluoromethyl-indan-1-yloxy]-2,3- The title compound was prepared from dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{4): t R = 2.01 min} ; Mass spectrum ^{(ESI -): m / z} = 391 [MH] -.

Example 31 {( S )-6-[( R )-4-cyclopropyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-cyclopropyl-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran The title compound was prepared from -3-yl}-methyl acetate. LC (Method _{4): t R = 2.00 min} ; Mass spectrum ^{(ESI -): m / z} = 349 [MH] -.

Example 32 {( S )-6-[( R )-4-Isopropyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-isopropyl-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran The title compound was prepared from -3-yl}-methyl acetate. LC (Method _{4): t R = 2.04 min} ; Mass spectrum ^{(ESI -): m / z} = 351 [MH] -.

Example 33 {( S )-6-[( R )-4-(2,6-Dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -based}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2,6-dimethyl-phenyl)-indan-1-yloxy]-2 The title compound was prepared from methyl 3-hydro-benzofuran-3-yl}-acetate. LC (Method _{5): t R = 3.74 min} ; Mass spectrum ^{(ESI -): m / z} = 413 [MH] -.

Example 34 {( S )-6-[( R )-4-(2,2-dimethyl-propyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -based}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2,2-dimethyl-propyl)-indan-1-yloxy]-2 The title compound was prepared from methyl 3-hydro-benzofuran-3-yl}-acetate. LC (Method _{5): t R = 3.79 min} ; Mass spectrum ^{(ESI -): m / z} = 379 [MH] -.

Example 35 {( S )-6-[( R )-4-(2-isopropyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl }-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2-isopropyl-phenyl)-indan-1-yloxy]-2,3 -Dihydro-benzofuran-3-yl}-acetic acid methyl ester The title compound was obtained. LC (Method _{5): t R = 3.76 min} ; Mass spectrum ^{(ESI -): m / z} = 427 [MH] -.

Example 36 {( S )-6-[( R )-5-Methyl-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} -acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-5-methyl-4-trifluoromethyl-indan-1-yloxy]-2,3- The title compound was prepared from dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{5): t R = 3.52 min} ; Mass spectrum ^{(ESI -): m / z} = 391 [MH] -.

Example 37 {( S )-6-[( R )-4,5-Difluoro-indan-1-yloxy]-2,3-dihydro-benzofuran 喃-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4,5-difluoro-indan-1-yloxy]-2,3-dihydro-benzo The title compound was prepared from furan-3-yl}-acetic acid methyl ester. LC (Method _{5): t R = 3.25 min} ; Mass spectrum ^{(ESI -): m / z} = 345 [MH] -.

Example 38 {( S )-6-[( R )-4-(( R ) ^* -2,2,2-trifluoro-1-methoxy-ethyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid (optional Specify the stereogenic center shown ( ^* ) configuration)

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(( R ) ^*- 2,2,2-trifluoro-1-methoxy-ethyl)- Preparation of the title compound from dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester; arbitrarily assigned configuration of the indicated stereoisomeric center ( ^* ), examples a diastereomer of 39. LC (Method _{5): t R = 3.30 min} ; Mass spectrum ^{(ESI -): m / z} = 421 [MH] -.

Example 39 {( S )-6-[( R )-4-(( S ) ^* -2,2,2-trifluoro-1-methoxy-ethyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid (optional Specify the stereo Heterogeneous center ^* ) configuration)

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(( S ) ^*- 2,2,2-trifluoro-1-methoxy-ethyl)- Preparation of the title compound from dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester; arbitrarily assigned configuration of the indicated stereoisomeric center ( ^* ), examples a diastereomer of 38. LC (Method _{5): t R = 3.30 min} ; Mass spectrum ^{(ESI -): m / z} = 421 [MH] -.

Example 40 {( S )-6-[( R )-4-(5,5-Dimethyl-cyclopent-1-enyl)-indan-1-yloxy]-2,3-dihydro- Benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(5,5-dimethyl-cyclopent-1-enyl)-indan-1-yl The title compound was prepared from oxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. {( S )-6-[( R )-4-(5,5-Dimethyl-cyclopent-1-enyl)-indan-1-yloxy]-2,3-dihydro- The benzofuran-3-yl}-acetic acid methyl ester is further composed of {( S )-6-[( R )-4-bromo-indoline-1-yloxy]-2 as described in Intermediate 12. 3-Dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(5,5-dimethyl-cyclopent-1-enyl)-1,5-dimethyl-2,4- Dioxa-3-boron-bicyclo[3.1.0]hexane was obtained. LC (Method _{4): t R = 2.35 min} ; Mass spectrum ^{(ESI +): m / z} = 427 [M + Na] +.

Alternatively, the title compound is obtained by chromatography of diastereomer mixture Example 15.

Example 41 {( S )-6-[( R )-4-(3,3,4-Trimethyl-oxetan-2-yl)-indan-1-yloxy]-2,3 -Dihydro-benzofuran-3-yl}-acetic acid, the stereogenic center shown ( ^* Configuration is uncertain, diastereomer of Example 42

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(3,3,4-trimethyl-oxetan-2-yl)-indoline Preparation of the title compound from -1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (Intermediate 37); configuration of the indicated stereoisomers ( ^* ) is undefined , the diastereomer of Example 42. LC (Method _{6): t R = 1.31 min} ; Mass spectrum ^{(ESI -): m / z} = 407 [MH] -.

Example 42 {( S )-6-[( R )-4-(3,3,4-Trimethyl-oxetan-2-yl)-indan-1-yloxy]-2,3 -Dihydro-benzofuran-3-yl}-acetic acid, the stereogenic center shown ( ^* The configuration is uncertain, the diastereomer of Example 41

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(3,3,4-trimethyl-oxetan-2-yl)-indoline Preparation of the title compound from -1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (Intermediate 38); configuration of the indicated stereoisomer center ( ^* ) is undefined , the diastereomer of Example 41. LC (Method _{6): t R = 1.26 min} ; Mass spectrum ^{(ESI -): m / z} = 407 [MH] -.

Example 43 {( S )-[6-(dihydroinden-1-yloxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid

Prepared from [( S )-6-(indoline-1-yloxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester by a procedure similar to that described in Example 1. Title compound. LC (Method _{8): t R = 5.87 min} ; Mass spectrum ^{(ESI -): m / z} = 309 [MH] -.

Example 44 {( S )-6-[( R )-4-chloro-5-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-chloro-5-fluoro-dihydroindol-1-yloxy]-2,3-dihydro-benzene The title compound was prepared from furan-3-yl}-acetic acid methyl ester. LC (Method _{5): t R = 3.65 min} ; Mass spectrum ^{(ESI -): m / z} = 361/363 (Cl) [MH] -.

Example 45 {( S )-[( R )-6-(4-cyano-dihydroindol-1-yloxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid

Following the procedure similar to that described in Example 1, {( S )-[( R )-6-(4-cyano-dihydroindol-1-yloxy)-2,3-dihydro-benzofuran The title compound was prepared from -3-yl]-methyl acetate. LC (Method _{9); t R = 7.24 min} ; Mass spectrum ^{(ESI +): m / z} = 336 [M + H] +.

Example 46 {( S )-6-[( R )-4-(3-cyano-pyridin-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -based}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(3-cyano-pyridin-2-yl)-indan-1-yloxy]-2 The title compound was prepared from methyl 3-hydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.13 min} ; Mass spectrum ^{(ESI -): m / z} = 411 [MH] -.

Example 47 {( S )-6-[( R )-4-(8-oxa-spiro[4.5]dec-1-en-1-yl)-dihydroindol-1-yloxy]-2,3- Dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(8-oxa-spiro[4.5]dec-1-en-1-yl)-indoline- The title compound was prepared from methyl 1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): r R = 1.40 min} ; Mass spectrum ^{(ESI +): m / z} = 447 [M + H] +.

Example 48 {( S )-6-[( R )-4-(2,6,6-trimethyl-cyclohex-1-enyl)-indan-1-yloxy]-2,3-di Hydrogen-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2,6,6-trimethyl-cyclohex-1-enyl)-indoline-1 The title compound was prepared as the methyloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{6): t R = 1.81 min} ; Mass spectrum ^{(ESI -): m / z} = 431 [MH] -.

Example 49 {( S )-6-[( R )-4-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-indan-1-yloxy]-2,3- Dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indoline- The title compound was prepared from methyl 1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.19 min} ; Mass spectrum ^{(ESI -): m / z} = 417 [MH] -.

Example 50 {( S )-6-[( S )-6-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl]-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( S )-6-trifluoromethyl-indoline-1-yloxy]-2,3-dihydro-benzo The title compound was prepared from furan-3-yl]-acetic acid methyl ester. LC (Method _{1): t R = 1.34 min} ; Mass spectrum ^{(ESI -): m / z} = 377 [MH] -.

Example 51 {( S )-6-[( R )-4-(2-Sideoxy-2H-pyridin-1-yl)-indan-1-yloxy]-2,3-dihydro-benzo Furan-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2-o-oxy-2H-pyridin-1-yl)-indan-1-yloxy The title compound was prepared as the methyl-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{5): t R = 2.96 min} ; Mass spectrum ^{(ESI -): m / z} = 402 [MH] -.

Example 52 {( S )-6-[( R )-5-(2,6-Dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -based}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-5-(2,6-dimethyl-phenyl)-indan-1-yloxy]-2 The title compound was prepared from methyl 3-hydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.47 min} ; Mass spectrum ^{(ESI -): m / z} = 413 [MH] -.

Example 53 {( S )-6-[( S )-6-(2,6-Dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -based}-acetic acid

Purification with Ar, stirring rod, {(S)-6-[(S)-6-bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl} - methyl acetate (0.20 g), 1 M Na ₂ CO ₃ aqueous solution (1.5 mL), 2,6-dimethylphenyl A vial of acid (0.08 g), ethanol (1 mL) and toluene (3 mL). Trit(triphenylphosphine)palladium(0) (26 mg) was added and the mixture was stirred at 100 ° C overnight. After cooling to room temperature, diethyl ether was added and the mixture was extracted with ethyl acetate. Washed with NH ₄ Cl solution and brine was combined with the organic extracts and dried (Na ₂ SO _4). Evaporation of the solvent and EtOAc (EtOAc/EtOAc/EtOAc) Yield: 0.10 g (49% of theory); LC (method 1): t _R = 1.47 min; mass spectrum (ESI ^- ): m/z = 413 [MH] ^- .

Example 54 {( S )-6-[( R )-5-(2-isopropyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl }-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-5-(2-isopropyl-phenyl)-indan-1-yloxy]-2,3 -Dihydro-benzofuran-3-yl}-acetic acid methyl ester The title compound was obtained. LC (Method 1): t _R = 1.50 min; Mass (ESI ^- ): m/Z = 427 [MH] ^- .

Example 55 {( S )-6-[( S )-6-Bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( S )-6-bromo-indoline-1-yloxy]-2,3-dihydro-benzofuran-3 -Base}-methyl acetate to prepare the title compound. LC (Method 1): t _R = 1.34 min; Mass (ESI ^- ): m/z = 387 / 389 (Br) [MH] ^- .

Example 56 {( S )-6-[( R )-4-(3-oxa-spiro[5.5]undec-7-en-7-yl)-indan-1-yloxy]-2, 3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(3-oxa-spiro[5.5]undec-7-ene-7-yl)-dihydro The title compound was prepared from methyl dec-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.43 min} ; Mass spectrum ^{(ESI -): m / z} = 459 [MH] -.

Example 57 {( S )-6-[( R )-4-(1-methyl-1H-imidazol-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran -3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(1-methyl-1H-imidazol-2-yl)-indan-1-yloxy] The title compound was prepared from -2,3-dihydro-benzofuran-3-yl}-methyl acetate. LC (Method _{1): t R = 0.85 min} ; Mass spectrum ^{(ESI -): m / z} = 389 [MH] -.

Example 58 {( S )-6-[( R )-4-(3-methyl-pyridin-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -based}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(3-methyl-pyridin-2-yl)-indan-1-yloxy]-2 The title compound was prepared from methyl 3-hydro-benzofuran-3-yl}-acetate. LC (Method 1): t _R = 0.95 min; Mass (ESI ^- ): m/z = 400 [MH] ^- .

Example 59 {( S )-6-[( R )-4-(4-methoxy-2,6-dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro -benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(4-methoxy-2,6-dimethyl-phenyl)-indan-1- The title compound was prepared from methyloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{1): t R = 1.44 min} ; Mass spectrum ^{(ESI -): m / z} = 443 [MH] -.

Example 60 {( S )-6-[( R )-4-(2-methoxy-3,5-dimethyl-pyridin-4-yl)-indan-1-yloxy]-2,3 -dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2-methoxy-3,5-dimethyl-pyridin-4-yl)-indoline The title compound was prepared from methyl-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.39 min} ; Mass spectrum ^{(ESI -): m / z} = 444 [MH] -.

Example 61 {( S )-6-[( R )-4-(1,3,5-trimethyl-2-oxooxy-1,2-dihydro-pyridin-4-yl)-indoline-1 -yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(1,3,5-trimethyl-2-oxo-1,2-dihydro-pyridine The title compound was prepared from methyl 4--4-)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.20 min} ; Mass spectrum ^{(ESI -): m / z} = 444 [MH] -.

Example 62 {( S )-6-[( R )-4-o-tolyl-indan-1-yloxy]-2,3-dihydro-benzo Furan-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-o-tolyl-indan-1-yloxy]-2,3-dihydro-benzofuran The title compound was prepared from -3-yl}-methyl acetate. LC (Method _{1): t R = 1.44 min} ; Mass spectrum ^{(ESI -): m / z} = 399 [MH] -.

Example 63 {( S )-6-[( R )-4-(1,2,4-Trimethyl-6-o-oxy-1,6-dihydro-pyridin-3-yl)-indoline-1 -yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(1,2,4-trimethyl-6-o-oxy-1,6-dihydro-pyridine The title compound was prepared from methyl 3-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.18 min} ; Mass spectrum ^{(ESI -): m / z} = 444 [MH] -.

Example 64 {( S )-6-[( R )-4-(6-Methoxy-2,4-dimethyl-pyridin-3-yl)-indan-1-yloxy]-2,3 -dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(6-methoxy-2,4-dimethyl-pyridin-3-yl)-indoline The title compound was prepared from methyl-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.16 min} ; Mass spectrum ^{(ESI -): m / z} = 444 [MH] -.

Example 65 {( S )-6-[( R )-4-morpholin-4-yl-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following a procedure similar to that described in Example 1, {( S )-6-[( R )-4-morpholin-4-yl-dihydroindol-1-yloxy]-2,3-dihydro- The title compound was prepared from benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{1): t R = 1.18 min} ; Mass spectrum ^{(ESI -): m / z} = 394 [MH] -.

Example 66 {( S )-6-[( R )-4-(( S )-3,3-dimethyl-tetrahydro-pyran-2-yl)-indan-1-yloxy]-2 , 3-dihydro-benzofuran-3-yl}-acetic acid, pure isomer, optionally designated stereogenic center ( ^* ) Configuration.

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(( S )-3,3-dimethyl-tetrahydropyran-2-yl)-dihydro The title compound was prepared as the indole-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (p. LC (Method _{6): t R = 1.48 min} ; Mass spectrum ^{(ESI -): m / z} = 421 [MH] -.

Example 67 {( S )-6-[( R )-4-(( R )-3,3-dimethyl-tetrahydro-pyran-2-yl)-indan-1-yloxy]-2 , 3-dihydro-benzofuran-3-yl}-acetic acid, pure isomer, optionally designated stereogenic center ( ^* Configuration

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(( R )-3,3-dimethyl-tetrahydropyran-2-yl)-dihydro The title compound was prepared as the indole-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (p. LC (Method _{6): t R = 1.44 min} ; Mass spectrum ^{(ESI -): m / z} = 421 [MH] -.

Example 68 {( S )-6-[( R )-4-(5-fluoro-2-methoxy-pyridin-4-yl)-indan-1-yloxy]-2,3-dihydro- Benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(5-fluoro-2-methoxy-pyridin-4-yl)-indan-1-yl The title compound was prepared from oxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{6): t R = 1.36 min} ; Mass spectrum ^{(ESI -): m / z} = 434 [MH] -.

Example 69 {( S )-6-[( R )-4-(2-Trifluoromethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Base}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2-trifluoromethyl-phenyl)-indan-1-yloxy]-2, The title compound was prepared from methyl 3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{6): t R = 1.41 min} ; Mass spectrum ^{(ESI -): m / z} = 453 [MH] -.

Example 70 {( S )-6-[( R )-4-(6,6-Dimethyl-cyclohex-1-enyl)-indan-1-yloxy]-2,3-dihydro- Benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(6,6-dimethyl-cyclohex-1-enyl)-indan-1-yl The title compound was prepared from oxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{6): t R = 1.75 min} ; Mass spectrum ^{(ESI -): m / z} = 417 [MH] -.

Example 71 {( S )-6-[( R )-4-(5-methoxy-2-methyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzo Furan-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(5-methoxy-2-methyl-phenyl)-indan-1-yloxy The title compound was prepared as the methyl-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.41 min} ; Mass spectrum ^{(ESI -): m / z} = 429 [MH] -.

Example 72 {( S )-6-[( R )-4-(5-Hydroxy-2-methyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-based}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(5-hydroxy-2-methyl-phenyl)-indan-1-yloxy]- The title compound was prepared from 2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{1): t R = 1.28 min} ; Mass spectrum ^{(ESI -): m / z} = 415 [MH] -.

Example 73 {( S )-6-[( R )-4-(2-trifluoromethyl-pyridin-3-yl)-indan-1-yloxy]- 2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 53, {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Preparation of methyl-2-yl)-indoline-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and 3-bromo-2-trifluoromethyl-pyridine The title compound; the ester is saponified under the reaction conditions. LC (Method _{7): t R = 1.71 min} ; Mass spectrum ^{(ESI -): m / z} = 454 [MH] -.

Example 74 {( S )-6-[( R )-4-(3,5-Dimethyl-isoxazol-4-yl)-indan-1-yloxy]-2,3-dihydro- Benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 53, {( S )-6-[( R )-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Methyl-2-yl)-dihydroindol-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate and 4-iodo-3,5-dimethyl-iso The title compound is prepared from oxazole; the ester is saponified under the reaction conditions. LC (Method _{1): t R = 1.70 min} ; Mass spectrum ^{(ESI -): m / z} = 404 [MH] -.

Example 75 and Example 76 {( S )-6-[( R )-4-(( S )-2,2-dimethyl-cyclopentyl)-indan-1-yloxy]-2,3-dihydro- Benzofuran-3-yl}-acetic acid and {( S )-6-[( R )-4-(( R )-2,2-di Methyl-cyclopentyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid, pure isomer, optionally designated stereoisomers ( ^* Configuration

{( S )-6-[( R )-(5,5-Dimethyl-cyclopent-1-enyl)-indan-1-yloxy]-2,3-dihydro-benzo A mixture of furan-3-yl}-acetic acid (0.32 g), platinum (IV) oxide (36 mg) and ethyl acetate (18 mL) was stirred at room temperature under a hydrogen atmosphere (1 bar) for 1 hour. The mixture was filtered and the filtrate was concentrated. Separation of the mixture of diastereomers by reverse phase HPLC (heptane / isopropyl alcohol / trifluoroacetic acid) afforded the title compound. Arbitrarily specify the configuration of the stereoisomeric center ( ^* ) shown.

Example 75: LC (Method 5): t _R = 4.20 min; Mass Spectrum (ESI ^- ): m/z = 405 [MH] ^- .

Example 76: LC (Method _{5): t R = 4.23 min} ; Mass spectrum ^{(ESI -): m / z} = 405 [MH] -.

Example 77 {( S )-6-[( R )-4-isoquinolin-1-yl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-isoquinolin-1-yl-dihydroindol-1-yloxy]-2,3-dihydro The title compound was prepared from benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{6): t R = 0.86 min} ; Mass spectrum ^{(ESI -): m / z} = 436 [MH] -.

Example 78 {( S )-6-[( R )-4-(1-methoxy-1,2,2-trimethyl-propyl)-indan-1-yloxy]-2,3- Dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(1-methoxy-1,2,2-trimethyl-propyl)-indoline- The title compound was prepared from methyl 1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.48 min} ; Mass spectrum ^{(ESI -): m / z} = 423 [MH] -.

Example 79 {( S )-6-[( R )-4-(1,1-Difluoro-2-methoxy-ethyl)-indan-1-yloxy]-2,3-dihydro- Benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(1,1-difluoro-2-methoxy-ethyl)-indan-1-yl The title compound was prepared from oxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{7): t R = 1.69 min} ; Mass spectrum ^{(ESI -): m / z} = 403 [MH] -.

Example 80 {( S )-6-[( R )-4-(2-methyl-naphthalen-1-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -based}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2-methyl-naphthalen-1-yl)-indan-1-yloxy]-2 The title compound was prepared from methyl 3-hydro-benzofuran-3-yl}-acetate. LC (Method _{6): t R = 1.68 min} ; Mass spectrum ^{(ESI -): m / z} = 449 [MH] -.

Example 81 (( S )-6-{( R )-4-[1-hydroxy-1-(tetrahydro-pyran-4-yl)-ethyl]-indan-1-yloxy}-2, 3-dihydro-benzofuran-3-yl)-acetic acid

Follow the procedure described in Step 2 analogous to Intermediate 73 from {( S )-6-[( R )-4-(tetrahydro-pyran-4-yl)-indan-1-yloxy The title compound was prepared using -2,3-dihydro-benzofuran-3-yl}-acetic acid; excess methyl magnesium bromide was used. LC (Method _{7): t R = 1.59 min} ; Mass spectrum ^{(ESI -): m / z} = 437 [MH] -.

Example 82 {( S )-6-[( R )-4-(1-hydroxy-1-methyl-pent-4-enyl)-indan-1-yloxy]-2,3-dihydro- Benzofuran-3-yl}-acetic acid

Following the procedure described in Step 2, similar to Intermediate 73, from {( S )-6-[( R )-4-pent-4-enylindol-dihydroindol-1-yloxy]-2, The title compound was prepared from 3-dihydro-benzofuran-3-yl}-acetic acid; excess methyl magnesium bromide was used. LC (Method _{7): t R = 1.72 min} ; Mass spectrum ^{(ESI -): m / z} = 407 [MH] -.

Example 83 (( S )-6-{( R )-4-[1-hydroxy-1-methyl-2-(tetrahydro-pyran-4-yl)-ethyl]-indan-1-yloxy }}-2,3-dihydro-benzofuran-3-yl)-acetic acid

Follow the procedure described in Step 2 similar to Intermediate 73 from {( S )-6-[( R )-4-(2-tetrahydro-piperazin-4-yl-ethenyl)-indoline The title compound was prepared from 1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid; excess methyl magnesium bromide was used. LC (Method _{7): t R = 1.61 min} ; Mass spectrum ^{(ESI -): m / z} = 451 [MH] -.

Example 84 {( S )-6-[( R )-4-(1,1-Difluoro-2-methoxy-2-methyl-propyl)-indan-1-yloxy]-2, 3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(1,1-difluoro-2-methoxy-2-methyl-propyl)-dihydro The title compound was prepared from methyl dec-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{7): t R = 1.80 min} ; Mass spectrum ^{(ESI -): m / z} = 431 [MH] -.

Example 85 {( S )-6-[( R )-4-(1,1-difluoro-2-hydroxy-2-methyl-propyl)-indan-1-yloxy]-2,3- Dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(1,1-difluoro-2-hydroxy-2-methyl-propyl)-indoline- The title compound was prepared from methyl 1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{7): t R = 1.66 min} ; Mass spectrum ^{(ESI -): m / z} = 417 [MH] -.

Example 86 {( S )-6-[( R )-4-(4,6-Dimethyl-pyrimidin-5-yl)-indan-1-yloxy]-2,3-dihydro-benzo Furan-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(4,6-dimethyl-pyrimidin-5-yl)-indan-1-yloxy The title compound was prepared as the methyl-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{6): t R = 0.95 min} ; Mass spectrum ^{(ESI -): m / z} = 415 [MH] -.

Example 87 {( S )-6-[( R )-4-(1-methyl-cyclopropyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl }-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(1-methyl-cyclopropyl)-indan-1-yloxy]-2,3 -Dihydro-benzofuran-3-yl}-acetic acid methyl ester The title compound was obtained. LC (Method _{6): t R = 1.51 min} ; Mass spectrum ^{(ESI -): m / z} = 363 [MH] -.

Example 88 {( S )-6-[( R )-4-(2,6-Dichloro-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Base}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2,6-dichloro-phenyl)-indan-1-yloxy]-2, The title compound was prepared from methyl 3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{7): t R = 1.89 min} ; Mass spectrum ^{(ESI -): m / z} = 453/455/457 (2 Cl) [MH] -.

Example 89 {( S )-6-[( R )-4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-dihydroindole-1- 氧基oxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Follow the procedure described in Step 2 similar to Intermediate 73 from {( S )-6-[( R )-4-(2,2,2-trifluoro-ethinyl)-indoline-1- The title compound was prepared from oxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid; excess methyl magnesium bromide was used. LC (Method _{6): t R = 1.03 min} ; Mass spectrum ^{(ESI -): m / z} = 421 [MH] -.

Example 90 {( S )-6-[( R )-4-(2-chloro-6-methyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-based}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2-chloro-6-methyl-phenyl)-indan-1-yloxy]- The title compound was prepared from 2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{7): t R = 1.92 min} ; Mass spectrum ^{(ESI -): m / z} = 433/435 (Cl) [MH] -.

Example 91 {( S )-6-[( R )-4-(6-methoxy-3-trifluoromethyl-pyridin-2-yl)-indan-1-yloxy]-2,3- Dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(6-methoxy-3-trifluoromethyl-pyridin-2-yl)-indoline- The title compound was prepared from methyl 1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.39 min} ; Mass spectrum ^{(ESI -): m / z} = 484 [MH] -.

Example 92 {( S )-6-[( R )-4-(8-Methyl-naphthalen-1-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3 -based}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(8-methyl-naphthalen-1-yl)-indan-1-yloxy]-2 The title compound was prepared from methyl 3-hydro-benzofuran-3-yl}-acetate. LC (Method _{7): t R = 1.51 min} ; Mass spectrum ^{(ESI -): m / z} = 449 [MH] -.

Example 93 {( S )-6-[( R )-4-(2,4-dimethyl-pyridin-3-yl)-indan-1-yloxy]-2,3-dihydro-benzo Furan-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2,4-dimethyl-pyridin-3-yl)-indan-1-yloxy The title compound was prepared as the methyl-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 0.98 min} ; Mass spectrum ^{(ESI -): m / z} = 414 [MH] -.

Example 94 {( S )-6-[( R )-4-(2-pentafluoroethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Base}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2-pentafluoroethyl-phenyl)-indan-1-yloxy]-2, The title compound was prepared from methyl 3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{6): t R = 1.57 min} ; Mass spectrum ^{(ESI -): m / z} = 503 [MH] -.

Example 95 {( S )-6-[( R )-5-Terbutyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-5-t-butyl-dihydroindol-1-yloxy]-2,3-dihydro-benzo The title compound was prepared from furan-3-yl}-acetic acid methyl ester. LC (Method _{1): t R = 1.45 min} ; Mass spectrum ^{(ESI -): m / z} = 365 [MH] -.

Example 96 {( S )-6-[( R )-4-Ter Butyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Purification of NiCl ₂ ^* 1.5H ₂ O with Ar (for preparation see J. Am. Chem. Soc. 2011 , 133 , 8478-81; 6 mg), 1,3-dicyclohexyl-imidazolium tetrafluoroborate (12 mg And {( S )-6-[( R )-4-bromo-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid (0.15 g) A solution in tetrahydrofuran (3 mL). The solution was cooled in an ice/sodium chloride bath and butyl bromochloride (1 mol/L tetrahydrofuran solution; 1.2 mL) was added over a period of 5 min. The solution was stirred in a cooling bath for 1.5 hours while warming to 0 °C. The solution was poured into a stirred mixture of ethyl acetate and aqueous NH ₄ Cl and the mixture was stirred for 5 min. The organic phase was separated and washed with brine and dried (Na ₂ SO _4). Evaporation of the solvent and EtOAc EtOAc (EtOAc) LC (Method _{6): t R = 1.54 min} ; Mass spectrum ^{(ESI -): m / z} = 365 [MH] -.

Example 97 {( S )-6-[( R )-4-(Cyano-dimethyl-methyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3- Base}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(cyano-dimethyl-methyl)-indan-1-yloxy]-2, The title compound was prepared from methyl 3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.22 min} ; Mass spectrum ^{(ESI -): m / z} = 376 [MH] -.

Example 98 {( S )-6-[( R )-4-chloro-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-chloro-5-trifluoromethyl-indoline-1-yloxy]-2,3-di The title compound was prepared from hydrogen-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{6): t R = 1.48 min} ; Mass spectrum ^{(ESI -): m / z} = 411/413 (Cl) [MH] -.

Example 99 {( S )-6-[( R )-4-(3-methyl-pyrazin-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran- 3-based}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(3-methyl-pyrazin-2-yl)-indan-1-yloxy]- The title compound was prepared from 2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method 7): t _R = 1.57 min; Mass (ESI ^- ): m/z = 401 [MH] ^- .

Example 100 {( S )-6-[( R )-4-(3-methoxy-2,6-dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro -benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(3-methoxy-2,6-dimethyl-phenyl)-indan-1- The title compound was prepared from methyloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{6): t R = 1.55 min} ; Mass spectrum ^{(ESI -): m / z} = 443 [MH] -.

Example 101 {( S )-6-[( R )-4-pentafluoroethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-pentafluoroethyl-indoline-1-yloxy]-2,3-dihydro-benzo The title compound was prepared from furan-3-yl}-acetic acid methyl ester. LC (Method _{6): t R = 1.51 min} ; Mass spectrum ^{(ESI -): m / z} = 427 [MH] -.

Example 102 {( S )-6-[( R )-6-fluoro-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}- Acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-6-fluoro-4-trifluoromethyl-indan-1-yloxy]-2,3-di The title compound was prepared from hydrogen-benzofuran-3-yl}-acetic acid methyl ester. LC (Method _{7): t R = 1.84 min} ; Mass spectrum ^{(ESI -): m / z} = 395 [MH] -.

Example 103 {( S )-6-[( R )-4-(2-methoxy-4-trifluoromethyl-pyridin-3-yl)-indan-1-yloxy]-2,3- Dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(2-methoxy-4-trifluoromethyl-pyridin-3-yl)-indoline- The title compound was prepared from methyl 1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{1): t R = 1.37 /} 1.38 min ( mixture of 2 revolutions slow isomer); Mass spectrum ^{(ESI -): m / z} = 484 [MH] -.

Example 104 {( S )-6-[( R )-4-(3-methoxy-2-methyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzo Furan-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {( S )-6-[( R )-4-(3-methoxy-2-methyl-phenyl)-indan-1-yloxy The title compound was prepared as the methyl-2,3-dihydro-benzofuran-3-yl}-acetate. LC (Method _{7): t R = 1.55 min} ; Mass spectrum ^{(ESI -): m / z} = 429 [MH] -.

Example 105 {7-Methyl-6-[(R)-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following a procedure similar to that described in Example 1, {7-methyl-6-[(R)-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzene The title compound was prepared from furan-3-yl}-acetic acid methyl ester. The compound was purified by semi-preparative HPLC to give the title compound as a mixture of two diastereomers. LC (Method _{8): t R = 7.32 min} ; Mass spectrum ^{(ESI -): m / z} 391 [MH] -.

Example 106 {4-Methyl-6-[(R)-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following the procedure similar to that described in Example 1, {4-methyl-6-[(R)-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzene The title compound was prepared from furan-3-yl}-acetic acid methyl ester. The compound was purified by semi-preparative HPLC to give the title compound as a mixture of two diastereomers. LC (Method _{8): t R = 7.30 min} ; Mass spectrum ^{(ESI -): m / z} 391 [MH] -.

Example 107 {5-Methyl-6-[(R)-4-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

Following a procedure similar to that described in Example 1, {5-methyl-6-[(R)-4-trifluoromethyl-dihydroindol-1-yloxy]-2,3-dihydro-benzene The title compound was prepared from furan-3-yl}-acetic acid methyl ester. The compound was purified by semi-preparative HPLC to give the title compound as a mixture of two diastereomers. HPLC-MS (Method _{9); t R = 9.14 min} ; Mass spectrum ^{(ESI +): m / z} 393 [M + H] +.

Follow the procedure described in Step 3 similar to Intermediate 1 for methyl ( S )-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetate and the respective indoline-2 - Alcohol The following compounds were prepared; the resulting carboxylic acid ester was cleaved as described in Example 1 to give the carboxylic acid. Individual indoline-1-ols are prepared analogously to the examples mentioned above and other methods known in the literature.

Claims (12)

a compound of formula (I), Wherein: R ¹ is selected from the group consisting of H, F, Cl, Br, I, C _1-8 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl , C _3-12 cycloalkyl-C _1-4 alkyl, C _5-12 bicycloalkyl-, C _5-12 bicycloalkyl-C _1-6 alkyl-, C _5-6 cycloalkenyl, C _{5-6cycloalkenyl} -C _1-4 alkyl, C _1-8 alkoxy, C _3-6 cycloalkyl-oxy and C _3-6 cycloalkyl-C _1-4 alkoxy, wherein Any such group is optionally substituted with 1 to 3 fluorine atoms and/or 1 to 3 R ⁴ groups, C _3-12 heterocyclic group, C _3-12 heterocyclic group-C _{1- 4-} alkyl, bicyclic heterocyclyl-, bicyclic heterocyclyl-C _1-6 alkyl-, heterocyclyl-C _1-4 alkyl-oxy and C _3-12 heterocyclyloxy, any of These groups are optionally substituted with 1 to 3 R ⁴ groups, aryl, aryl-C _1-4 alkyl, aryl-C _1-4 alkyl-oxy, aryloxy, Heteroaryl, heteroaryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl-oxy and heteroaryloxy, any of which groups optionally, from 1 to 5 Substituted R ⁵ groups, C _1-4 alkyl-thio, C _1-4 alkyl-sulfinyl and C _1-4 alkyl-sulfonyl, any of which may optionally be 1 to 3 Atom, and cyano, nitro, amino, C _1-4 alkylamino and two (C _1-4 alkyl) - group; those wherein the heterocyclic group and the sub-portion may be partially unsaturated and Containing 1 to 3 heteroatoms or groups selected from N, NR ^N , O and S, with the proviso that at most two of the heteroatoms are O and S, and no OO, SS and SO bonds are formed, The methylene group bonded to the hetero atom may be replaced by a carbonyl group, and the heterocyclic groups are bonded to the respective residues via a carbon or nitrogen atom; R ^N represents H, C _1-4 alkyl-, C _1-4 alkane a base-C(O)- or C _1-4 alkyl-OC(O)-, wherein the aforementioned bicyclic heterocyclic groups and sub-portions are partially unsaturated and comprise from 6 to 12 ring members and from 1 to 3 From the heteroatoms or groups of N, NR ^N , O and S, the limitation is that at most two of the heteroatoms are O and S and do not form OO, SS and SO bonds, but are bonded to the heteroatoms. The methyl group may be substituted by a carbonyl group, and the heterocyclic groups are bonded to the respective residues via a carbon or nitrogen atom; R ^N represents H, C _1-4 alkyl-, C _1-4 alkyl-C(O)- C _1-4 alkyl or -OC (O) -, those wherein the alkyl group and a bicyclic heterocyclic group and bicyclic sub-portion comprises a fused bridged and a ring system wherein the aforementioned aryl and sub-portions comprise from 6 to 10 carbon atoms, wherein in the bicyclic aromatic group, the ring not attached to the respective residue is partially saturated, and wherein the aforementioned heteroaryl group and The subportion is composed of 5 to 14 atoms and contains 1 to 3 hetero atoms selected from N, O or S(O) _r , wherein r = 0, 1 or 2, wherein in the polycyclic heteroaromatic group, Rings not linked to respective residues may be partially or fully saturated, while at least one aromatic ring includes one or more heteroatoms, and R ² is selected from the group consisting of F, Cl, Br, I, cyano, C _{a 1-4} alkyl group, a C _3-6 cycloalkyl group and a C _1-4 alkoxy group, wherein any alkyl group and cycloalkyl group or sub-portion are optionally substituted by 1 to 3 fluorine atoms, and R ³ is selected from a group consisting of F, Cl, Br, I, C _1-4 alkyl and C _1-4 alkoxy, wherein any alkyl or sub-portion is optionally substituted with 1 to 3 fluorine atoms, R ⁴ is Selected from the following groups: F, Cl, Br, I, cyano, C _1-4 alkyl, hydroxy, hydroxy-C _1-4 alkyl, C _1-4 alkyl-oxy, C _1-4 alkoxy -C _1-4 alkyl, C _1-4 alkyl - alkylthio, C _1-4 alkyl - sulfinyl group, C _1-4 alkyl - sulfonamide Group, C _3-6 cycloalkyl -, C _3-6 cycloalkyl - group -, and wherein any of the alkyl or cycloalkyl optionally substituted with sub-portions 1-3 fluorine atoms, and R ⁵ lines Selected from the following groups: F, Cl, Br, I, cyano, nitro, amine, C _1-4 alkyl-amino, di(C _1-4 alkyl)-amine, C _{1- 4-} alkyl, C _2-4 alkenyl, C _2-4 -alkynyl, hydroxy, hydroxy-C _1-4 alkyl, C _1-4 alkyl-oxy, C _1-4 alkoxy-C _{1 -4} alkyl, C ₁ - ₄ alkyl - alkylthio, C _1-4 alkyl - sulfinyl group, C _1-4 alkyl - acyl sulfo, C _3-6 cycloalkyl -, C _{3- 6} cycloalkyl-oxy-, wherein any alkyl and cycloalkyl or sub-portion is optionally substituted with from 1 to 5 fluorine atoms, and m is selected from the numbers 0, 1, 2 and 3, preferably selected from the number 0, 1 and 2, or better selected from the numbers 0 and 1, but the number 0 is optimal, and n is selected from the numbers 0, 1, 2 and 3, preferably selected from the numbers 0 and 1, but the number 0 is optimal. And wherein any of the alkyl moieties mentioned in the present application may be a linear or branched alkyl group, or a salt thereof, in any of the above-mentioned definitions and unless otherwise specified. The compound of claim 1, wherein: R ¹ is selected from the group consisting of H, F, Cl, Br, C _1-6 alkyl, C _5-6 alkenyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _5-6 cycloalkenyl, C _1-6 alkoxy, C _3-6 cycloalkyl-oxy and C _3-6 cycloalkyl-C _{a 1-4} alkoxy group, wherein any such groups are optionally substituted with 1 to 3 fluorine atoms and/or 1 to 3 R ⁴ groups, C _5-10 heterocyclic group, C _{5 - 10} heterocyclyl -C _1-4 alkyl, bicyclic heterocyclyl -, bicyclic heterocyclyl -C _1-4 alkyl -, C _{at 5-10} heterocyclyl -C _1-4 alkyl - alkoxy and C _{5-10heterocyclyloxy} , any of which is optionally substituted with 1 to 3 R ⁴ groups, phenyl, phenyl-C _1-4 alkyl, phenyl-C _{1 a 4-} alkyl-oxy group, a phenoxy group, a heteroaryl group, a heteroaryl-C _1-4 alkyl group, a heteroaryl-C _1-4 alkyl-oxy group, and a heteroaryloxy group, any of which And the like is optionally substituted with 1 to 3 R ⁵ groups, C _1-2 alkyl-thio, optionally substituted with 1 to 3 fluorine atoms, and cyano, wherein the aforementioned heterocyclic ring group and sub-portion may be partially unsaturated and containing 1 to 3 heteroatoms selected from N, heteroaryl NR ^N, O and S atoms or the group , wherein the restriction is that at most two of the heteroatoms are O and S, and no OO, SS and SO bonds are formed, and the methylene group bonded to the hetero atom may be replaced by a carbonyl group, and the heterocyclic groups are via a carbon or nitrogen atom is bonded to a respective residue; R ^N represents H, C _1-4 alkyl-, C _1-4 alkyl-C(O)- or C _1-4 alkyl-OC(O)-, Wherein the aforementioned bicyclic heterocyclic group and sub-portion may be partially unsaturated and comprise 6 to 10 ring members and 1 to 3 hetero atoms or groups selected from N, NR ^N , O and S, with the limitation that At most two of the heteroatoms are O and S and do not form OO, SS and SO bonds, and the methylene group bonded to the hetero atom may be replaced by a carbonyl group, and the heterocyclic groups are bonded to each via a carbon or nitrogen atom. a further residue; R ^N represents H, C _1-4 alkyl-, C _1-4 alkyl-C(O)- or C _1-4 alkyl-OC(O)-, wherein the aforementioned bicycloalkyl And the bicyclic heterocyclic group and the sub-portion comprise a fused and bridged ring system, wherein the aforementioned heteroaryl and sub-portions are composed of 5 to 10 atoms, and 1 to 3 are selected from N, O or S(O) _r a hetero atom, wherein r = 0, 1 or 2, wherein in the polycyclic heteroaromatic group, not attached to the respective residue or The rings may be partially or fully saturated, while the at least one aromatic ring includes one or more heteroatoms, or a salt thereof. The compound of claim 1, wherein: R ¹ is selected from the group consisting of H, F, Cl, Br, C _1-6 alkyl, C _5-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkyl, C _5-6 cycloalkenyl, tetrahydropiperidyl-C _1-2 alkyl and C _1-6 alkoxy, any of these groups Optionally, independently substituted with 1 to 3 fluorine atoms and/or 1 to 3 R ⁴ groups, oxetanyl, tetrahydrofuranyl, dihydropiperidyl, tetrahydropyranyl, morpholinyl , tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, 8-oxa-spiro[4.5]decenyl, 3-oxa- Spiro[5.5]undecenyl, 2-oxa-bicyclo[3.1.1]heptyl, 2-oxa-bicyclo[2.2.1]heptyl, 2-oxa-bicyclo[3.1.1]g 4-yloxy, 2-oxa-bicyclo[3.1.1]hept-5-yloxy, 2-oxa-bicyclo[3.1.1]hept-6-yloxy, 2-oxa- Bicyclo[2.2.1]hept-4-yloxy, 2-oxa-bicyclo[2.2.1]hept-5-yloxy and 2-oxa-bicyclo[2.2.1]hept-6-yloxy Any one of these groups optionally substituted with 1 to 3 R ⁴ groups, 2-sided oxy-1,2-dihydro-pyridyl, optionally 1 to 3 R ⁴ Group Substituted, phenyl and heteroaryl, any of which is optionally substituted with 1 to 3 R ⁵ groups, trifluoromethylthio and cyano, wherein the aforementioned heteroaryl and The subportion comprises a 5- and 6-membered monocyclic ring system containing 1 or 2 heteroatoms selected from N, NR ^N and O, wherein R ^N represents H and C _1-4 alkyl, and m and n both represent the number 1 , or its salt. The compound of claim 1, wherein: R ¹ is selected from the group consisting of H, F, Cl, Br, C _1-6 alkyl, C _5-6 alkenyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _5-6 cycloalkenyl, C _1-6 alkoxy, C _3-6 cycloalkyl-oxy and C _3-6 cycloalkyl-C _{a 1-4} alkoxy group, wherein any of these groups is optionally substituted with 1 to 3 fluorine atoms and/or 1 to 3 R ⁴ groups, C _5-10 heterocyclic group, C _{5 - 10} heterocyclyl -C _1-4 alkyl, bicyclic heterocyclyl -, bicyclic heterocyclyl -C _1-4 alkyl -, C _{at 5-10} heterocyclyl -C _1-4 alkyl - alkoxy and C _{5-10heterocyclyloxy} , any of which is optionally substituted with 1 to 3 R ⁴ groups, phenyl, phenyl-C _1-4 alkyl, phenyl-C _{1 a 4-} alkyl-oxy group, a phenoxy group, a heteroaryl group, a heteroaryl-C _1-4 alkyl group, a heteroaryl-C _1-4 alkyl-oxy group, and a heteroaryloxy group, any of which And the like is optionally substituted with 1 to 3 R ⁵ groups, C _1-2 alkyl-thio, optionally substituted with 1 to 3 fluorine atoms, and cyano, wherein the aforementioned heterocyclic ring group and sub-portion may be partially unsaturated and containing 1 to 3 heteroatoms selected from N, heteroaryl NR ^N, O and S atoms or the a group having the restriction that at most two of the heteroatoms are O and S, and no OO, SS and SO bonds are formed, and the methylene group bonded to the hetero atom may be replaced by a carbonyl group, and the heterocyclic groups Binding to a respective residue via a carbon or nitrogen atom; R ^N represents H, C _1-4 alkyl-, C _1-4 alkyl-C(O)- or C _1-4 alkyl-OC(O)- Wherein the aforementioned bicyclic heterocyclic group and sub-portion are partially unsaturated and comprise from 6 to 10 ring members and from 1 to 3 heteroatoms or groups selected from N, NR ^N , O and S, with the limitation that At most two of the heteroatoms are O and S and do not form OO, SS and SO bonds, and the methylene group bonded to the hetero atom may be replaced by a carbonyl group, and the heterocyclic groups are bonded via a carbon or nitrogen atom to Respective residues; R ^N represents H, C _1-4 alkyl-, C _1-4 alkyl-C(O)- or C _1-4 alkyl-OC(O)-, wherein the aforementioned bicycloalkanes And bicyclic heterocyclic groups and sub-portions comprising fused and bridged ring systems, wherein the aforementioned heteroaryl and sub-portions are composed of 5 to 10 atoms, and 1 to 3 are selected from N, O or S(O) _{r is} a heteroatom, wherein r = 0,1 or 2, wherein the polycyclic aromatic heteroaryl groups, are not connected to the respective residues of Such rings may be partially or fully saturated, aromatic ring and at least one comprises one or more hetero atoms, R ² selected from the group consisting of the group consisting of: F, Cl, Br, methyl, difluoromethyl, trifluoromethyl , cyclopropyl, methoxy, difluoromethoxy and trifluoromethoxy, R ³ is selected from the group consisting of F, Cl, Br, methyl, difluoromethyl, trifluoromethyl, Methoxy, difluoromethoxy and trifluoromethoxy, R ⁴ is selected from the group consisting of F, cyano, hydroxy, methyl, difluoromethyl, trifluoromethyl, methoxy, Difluoromethoxy and trifluoromethoxy, R ⁵ is selected from the group consisting of F, Cl, cyano, C _1-3 alkyl (preferably methyl), difluoromethyl, trifluoromethyl The group, pentafluoroethyl, hydroxy, methoxy, difluoromethoxy and trifluoromethoxy, and m and n each independently represent the number 0 or 1, or a salt thereof. The compound of claim 1, wherein: R ¹ is selected from the group consisting of H, F, Cl, Br, C _1-6 alkyl, C _5-6 alkenyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _5-6 cycloalkenyl, C _1-6 alkoxy, C _3-6 cycloalkyl-oxy and C _3-6 cycloalkyl-C _{a 1-4} alkoxy group, wherein any of these groups is optionally substituted with 1 to 3 fluorine atoms and/or 1 to 3 R ⁴ groups, C _5-10 heterocyclic group, C _{5 - 10} heterocyclyl -C _1-4 alkyl, bicyclic heterocyclyl -, bicyclic heterocyclyl -C _1-4 alkyl -, C _{at 5-10} heterocyclyl -C _1-4 alkyl - alkoxy and C _{5-10heterocyclyloxy} , any of which is optionally substituted with 1 to 3 R ⁴ groups, phenyl, phenyl-C _1-4 alkyl, phenyl-C _{1 a 4-} alkyl-oxy group, a phenoxy group, a heteroaryl group, a heteroaryl-C _1-4 alkyl group, a heteroaryl-C _1-4 alkyl-oxy group, and a heteroaryloxy group, any of which And the like is optionally substituted with 1 to 3 R ⁵ groups, C _1-2 alkyl-thio, optionally substituted with 1 to 3 fluorine atoms, and cyano, wherein the aforementioned heterocyclic ring The base and subportion may be partially unsaturated and comprise from 1 to 3 heteroatoms or groups selected from N, NR ^N , O and S a group having the restriction that at most two of the heteroatoms are O and S, and no OO, SS and SO bonds are formed, and the methylene group bonded to the hetero atom may be replaced by a carbonyl group, and the heterocyclic groups are via a carbon or nitrogen atom is bonded to a respective residue; R ^N represents H, C _1-4 alkyl-, C _1-4 alkyl-C(O)- or C _1-4 alkyl-OC(O)-, Wherein the aforementioned bicyclic heterocyclic group and sub-portion may be partially unsaturated and comprise 6 to 10 ring members and 1 to 3 hetero atoms or groups selected from N, NR ^N , O and S, with the limitation that At most two of the heteroatoms are O and S and do not form OO, SS and SO bonds, and the methylene group bonded to the hetero atom may be replaced by a carbonyl group, and the heterocyclic groups are bonded to each via a carbon or nitrogen atom. a further residue; R ^N represents H, C _1-4 alkyl-, C _1-4 alkyl-C(O)- or C _1-4 alkyl-OC(O)-, wherein the aforementioned bicycloalkyl And the bicyclic heterocyclic group and the sub-portion comprise a fused and bridged ring system, wherein the aforementioned heteroaryl and sub-portions are composed of 5 to 10 atoms, and 1 to 3 are selected from N, O or S(O) _r a hetero atom, wherein r = 0, 1 or 2, wherein in the polycyclic heteroaromatic group, not attached to the respective residue or Other groups may be partially or fully saturated ring, aromatic ring and at least one comprises one or more hetero atoms, R ² selected from the group consisting of: F, Cl, Br, methyl, difluoromethyl, trifluoromethyl, Cyclopropyl, methoxy, difluoromethoxy and trifluoromethoxy, R ³ is selected from the group consisting of F, Cl, Br, methyl, difluoromethyl, trifluoromethyl, A Oxy, difluoromethoxy and trifluoromethoxy, R ⁴ is selected from the group consisting of F, cyano, hydroxy, methyl, difluoromethyl, trifluoromethyl, methoxy, Fluoromethoxy and trifluoromethoxy, R ⁵ is selected from the group consisting of F, Cl, cyano, C _1-3 alkyl (preferably methyl), difluoromethyl, trifluoromethyl , pentafluoroethyl, hydroxy, methoxy, difluoromethoxy and trifluoromethoxy, m represents 0 and n represents 0, or a salt thereof. The compound of claim 1, wherein: R ¹ is selected from the group consisting of H, F, Cl, Br, C _1-6 alkyl, C _5-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkyl, C _5-6 cycloalkenyl, tetrahydropiperidyl-C _1-2 alkyl and C _1-6 alkoxy, any of these groups Optionally, independently substituted with 1 to 3 fluorine atoms and/or 1 to 3 R ⁴ groups, oxetanyl, tetrahydrofuranyl, dihydropiperidyl, tetrahydropyranyl, morpholinyl , tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, 8-oxa-spiro[4.5]decenyl, 3-oxa- Spiro[5.5]undecenyl, 2-oxa-bicyclo[3.1.1]heptyl, 2-oxa-bicyclo[2.2.1]heptyl, 2-oxa-bicyclo[3.1.1]g 4-yloxy, 2-oxa-bicyclo[3.1.1]hept-5-yloxy, 2-oxa-bicyclo[3.1.1]hept-6-yloxy, 2-oxa- Bicyclo[2.2.1]hept-4-yloxy, 2-oxa-bicyclo[2.2.1]hept-5-yloxy and 2-oxa-bicyclo[2.2.1]hept-6-yloxy Any one of these groups optionally substituted with 1 to 3 R ⁴ groups, 2-sided oxy-1,2-dihydro-pyridyl, optionally 1 to 3 R ⁴ Group Substituted, phenyl and heteroaryl, any of which is optionally substituted with 1 to 3 R ⁵ groups, trifluoromethylthio and cyano, wherein the aforementioned heteroaryl and The subportion comprises a 5- and 6-membered monocyclic ring system containing 1 or 2 heteroatoms selected from N, NR ^N and O, wherein R ^N represents H and C _1-4 alkyl, R ² , R ³ , R ⁴ And R ⁵ , m and n are as defined in the claim 5, m represents 0 and n represents 0, or a salt thereof. A pharmaceutically acceptable salt of a compound according to any one of claims 1 to 6. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 6 or one or more pharmaceutically acceptable salts thereof, optionally with one or more inert carriers and/or diluents. A use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or condition which can be influenced by the function of GPR40, For the needy patients to prevent and / or treat the following metabolic diseases, such as: diabetes, more specifically type 2 diabetes, and the conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease and dyslipidemia . A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use as a medicament. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition which can be affected by modulation of GPR40 function, in particular for the prevention and/or treatment of metabolic diseases Such as: diabetes, more specifically type 2 diabetes, and the conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease and dyslipidemia. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 6 or one or more pharmaceutically acceptable salts thereof and one or more other therapeutic agents, optionally with one or more inert carriers And/or diluent.