INDANYLOXYDIHYDROBENZOFURANYLACETIC ACIDS

The present invention relates to compounds of general formula I, wherein the groups (Het)Ar and R1 are defined as in claim 1, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.

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Description
FIELD OF THE INVENTION

The present invention relates to novel indanyloxydihydrobenzofuranylacetic acids, that are agonists of the G-protein coupled receptor 40 (GPR40, also known as free fatty acid receptor FFAR 1), to processes for their preparation, to pharmaceutical compositions containing these compounds and to their medical use for the prophylaxis and/or treatment of diseases which can be influenced by the modulation of the function of GPR40. Particularly, the pharmaceutical compositions of the invention are suitable for the prophylaxis and/or therapy of metabolic diseases, such as diabetes, more specifically type 2 diabetes mellitus, and conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease and dyslipidemia.

BACKGROUND OF THE INVENTION

Metabolic diseases are diseases caused by an abnormal metabolic process and may either be congenital due to an inherited enzyme abnormality or acquired due to a disease of an endocrine organ or failure of a metabolically important organ such as the liver or the pancreas.

Diabetes mellitus is a disease state or process derived from multiple causative factors and is defined as a chronic hyperglycemia associated with resulting damages to organs and dysfunctions of metabolic processes. Depending on its etiology, one differentiates between several forms of diabetes, which are either due to an absolute (lacking or decreased insulin secretion) or to a relative lack of insulin. Diabetes mellitus Type I (IDDM, insulin-dependent diabetes mellitus) generally occurs in adolescents under 20 years of age. It is assumed to be of auto-immune etiology, leading to an insulitis with the subsequent destruction of the beta cells of the islets of Langerhans which are responsible for the insulin synthesis. In addition, in latent autoimmune diabetes in adults (LADA; Diabetes Care. 8: 1460-1467, 2001) beta cells are being destroyed due to autoimmune attack. The amount of insulin produced by the remaining pancreatic islet cells is too low, resulting in elevated blood glucose levels (hyperglycemia). Diabetes mellitus Type II generally occurs at an older age. It is above all associated with a resistance to insulin in the liver and the skeletal muscles, but also with a defect of the islets of Langerhans. High blood glucose levels (and also high blood lipid levels) in turn lead to an impairment of beta cell function and to an increase in beta cell apoptosis.

Persistent or inadequately controlled hyperglycemia is associated with a wide range of pathologies. Diabetes is a very disabling disease, because today's common anti-diabetic drugs do not control blood sugar levels well enough to completely prevent the occurrence of high and low blood sugar levels. Out of range blood sugar levels are toxic and cause long-term complications for example retinopathy, renopathy, neuropathy and peripheral vascular disease. There is also a host of related conditions, such as obesity, hypertension, stroke, heart disease and hyperlipidemia, for which persons with diabetes are substantially at risk.

Obesity is associated with an increased risk of follow-up diseases such as cardiovascular diseases, hypertension, diabetes, hyperlipidemia and an increased mortality. Diabetes (insulin resistance) and obesity are part of the “metabolic syndrome” which is defined as the linkage between several diseases (also referred to as syndrome X, insulin-resistance syndrome, or deadly quartet). These often occur in the same patients and are major risk factors for development of diabetes type II and cardiovascular disease. It has been suggested that the control of lipid levels and glucose levels is required to treat diabetes type II, heart disease, and other occurrences of metabolic syndrome (see e.g., Diabetes 48: 1836-1841, 1999; JAMA 288: 2209-2716, 2002).

The free fatty acid receptor GPR40 (also referred to as either FFAR, FFAR1, or FFA1) is a cell-surface receptor and a member of the gene superfamily of G-protein coupled receptors, which was first identified as a so-called orphan receptor, i.e. a receptor without a known ligand, based on the predicted prescence of seven putative transmembrane regions in the corresponding protein (Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun. 239: 543-547). GPR40 is found to be highly expressed in several particular cell types: the pancreatic β cells and insulin-secreting cell lines, as well as in enteroendocrine cells, taste cells, and is reported to be expressed in immune cells, splenocytes, and in the human and monkey brain. Meanwhile, fatty acids of varying chain lengths are thought to represent the endogenous ligands for GPR40, activation of which is linked primarily to the modulation of the Gq family of intra-cellular signaling G proteins and concomitant induction of elevated calcium levels, although activation of Gs- and G1-proteins to modulate intracellular levels of cAMP have also been reported. GPR40 is activated especially by long-chain FFA, particularly oleate, as well as the PPAR-gamma agonist rosiglitazone.

It has been recognized that the fatty acids that serve as activators for GPR40 augment the elevated plasma glucose-induced secretion of insulin through GPR40 receptors that are expressed in the 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 initial controversy, the use of GPR40 agonist appears to be the appropriate for increasing insulin release for the treatment of diabetes (see e.g. Diabetes 2008, 57, 2211; J. Med. Chem. 2007, 50, 2807). Typically, long term diabetes therapy leads to the gradual diminution of islet activity, so that after extended periods of treatment Type 2 diabetic patients need treatment with daily insulin injections instead. GPR40 agonists may have the potential to restore or preserve islet function, therefore, GPR40 agonists may be beneficial also in that that they may delay or prevent the diminution and loss of islet function in a Type 2 diabetic patient.

It is well established that the incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide; also known as gastric inhibitory peptide) stimulate insulin secretion and are rapidly inactivated in vivo by DPP-4. These peptidyl hormones are secreted by endocrine cells that are located in the epithelium 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 the trigger for incretin release. Incretins are carried through the circulation to beta cells in the pancreas and cause the beta cells to secrete more insulin in anticipation of an increase of blood glucose resulting from the digesting meal. Further studies indicating that the GPR40 modulatory role on the release of incretins from the enteroendocrine cells, including CCK, GLP-1, GIP, PYY, and possibly others, suggest that GPR40 modulators may contribute to enhanced insulin release from the pancreatic beta cells also indirectly by e.g. a synergistic effect of GLP-1 and possibly GIP on the insulin release, and the other release incretins may also contribute to an overall beneficial contribution of GPR40 modulation on metabolic diseases. The indirect contributions of GPR40 modulation on insulin release through the elevation of plasma levels of incretins may be further augmented by the coadministration of inhibitors of the enzymes responsible for the incretin degradation, such as inhibitors of DPP-4.

Insulin imbalances lead to conditions such as type II diabetes mellitus, a serious metabolic disease. The modulation of the function of GPR40 in modulating insulin secretion indicates the therapeutic agents capable of modulating GPR40 function could be useful for the treatment of disorders such as diabetes and conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease and dyslipidemia.

OBJECT OF THE PRESENT INVENTION

The object of the present invention is to provide new compounds, hereinafter described as compounds of formula I, in particular new indanyloxy-2,3-dihydrobenzofuranylacetic acids, which are active with regard to the G-protein-coupled receptor GPR40, notably are agonists of the G-protein-coupled receptor GPR40.

A further object of the present invention is to provide new compounds, in particular new indanyloxydihydrobenzofuranylacetic acids, which have an activating effect on the G-protein-coupled receptor GPR40 in vitro and/or in vivo and possess suitable pharmacological and pharmacokinetic properties to use them as medicaments.

A further object of the present invention is to provide effective GPR40 agonists, in particular for the treatment of metabolic disorders, for example diabetes, dyslipidemia and/or obesity.

A further object of the present invention is to provide methods for treating a disease or condition mediated by the activation the G-protein-coupled receptor GPR40 in a patient.

A further object of the present invention is to provide a pharmaceutical composition comprising at least one compound according to the invention.

A further object of the present invention is to provide a combination of at least one compound according to the invention with one or more additional therapeutic agents.

Further objects of the present invention become apparent to the one skilled in the art by the description hereinbefore and in the following and by the examples. GPR40 modulators are known in the art, for example, the compounds disclosed in WO 2004041266 (EP 1559422), WO 2007033002, WO 2009157418 and WO 2012072691. The indanyloxydihydrobenzofuranylacetic acids of the present invention may provide several advantages, such as enhanced potency, high metabolic and/or chemical stability, high selectivity and tolerability, enhanced solubility, and the possibility to form stable salts.

SUMMARY OF THE INVENTION

In a first aspect the invention relates to compounds of formula I

wherein

  • (Het)Ar is linked via a carbon atom and is selected from the group (Het)Ar-G1 consisting of
    • phenyl, naphthyl and a mono- or bicyclic heteroaromatic group having 5 to 10 ring member atoms of which 2 to 9 ring members are carbon atoms and either
    • one ring member is an unsubstituted or substituted heteroatom selected from N, NH, NRN, O, S, S(═O) and S(═O)2, or
    • one ring member is N and a second ring member is selected from N, NH, NRN, O, S, S(═O) and S(═O)2, or
    • two ring members are N and a third ring member is selected from N, NH, NRN, O, S, S(═O) and S(═O)2,
      • wherein in naphthyl the ring not attached to the indanyl-O atom of formula I optionally is partially saturated,
      • wherein in bicyclic heteroaromatic groups the ring not attached to the indanyl-O atom of formula I optionally is partially saturated, while the aromatic ring includes at least one heteroatom, and optionally
        • one ring member in the partially or fully saturated bridge is replaced by N, NH, NRN, O, S, S(═O) or S(═O)2, or
        • one ring member in the partially or fully saturated bridge is replaced by N, NH or NRN and a second ring member is replaced by NH, NRN, O, S, C(═O), S(═O) or S(═O)2, or
        • two not vicinal ring members in a fully saturated bridge are replaced by O atoms,
    • wherein any of these groups is substituted with 1 group R2 or 1 NH group is replaced by an NR2 group; and
    • wherein any of these groups is optionally and independently substituted with 1 to 4 R3 groups;
  • or (Het)Ar-G1 is selected from the group consisting of 2,3-dihydroindole, 2,3-dihydroisoindole, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, benzo[1,3]dioxole, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, chroman, isochroman and 2,3-dihydrobenzo[1,4]dioxine,
    • wherein any of these groups is linked via an aromatic carbon atom to the indanyloxy group in formula (I), and wherein in each of these bicyclic groups 1 CH2 group is optionally replaced by C(═O) and each of these bicyclic groups is optionally substituted with 1 R2 group and optionally and independently substituted with 1 to 4 R3 groups;
  • R1 is selected from the group R1-G1 consisting of H, F, Cl, F3C—, NC—, F3C—O— and H3C—S(═O)2—;
  • R2 is selected from the group R2-G1 consisting of
    • C1-6-alkyl, C2-6-alkenyl, C2-6-alkinyl, C3-6-cycloalkyl-, C1-4-alkyl-NH—, (C1-4-alkyl)2N—, C1-6-alkyl-O—, C3-6-cycloalkyl-O—, C1-4-alkyl-S—, C1-4-alkyl-S(═O)—, and C1-4-alkyl-S(═O)2,
      • wherein each alkyl and cycloalkyl group is substituted with 1 to 3 groups independently selected from R4 and optionally substituted with 1 or more F atoms;
    • and of C1-4-alkyl-C(═O)—, heterocyclyl-C(═O)—, HNRN—C(═O)—, C1-4-alkyl-NRN—C(═O)—, C3-6-cycloalkyl-NRN—C(═O)—, heterocyclyl-NRN—C(═O)—, phenyl-NRN—C(═O)—, heteroaryl-NRN—C(═O)—, HO2C—, C1-4-alkyl-O—C(═O)—, C3-6-cycloalkyl-O—C(═O)—, heterocyclyl-O—C(═O)—, —NHRN, C1-4-alkyl-C(═O)NRN—, C3-6-cycloalkyl-C(═O)NRN—, heterocyclyl-C(═O)NRN—, phenyl-C(═O)NRN—, heteroaryl-C(═O)NRN—, C1-4-alkyl-S(═O)2NRN—, C3-6-cycloalkyl-S(═O)2NRN—, heterocyclyl-S(═O)2NRN—, phenyl-S(═O)2NRN—, heteroaryl-S(═O)2NRN—, heterocyclyl-O—, phenyl-O—, heteroaryl-O—, C3-6-cycloalkyl-S—, heterocyclyl-S—, phenyl-S—, heteroaryl-S—, C3-6-cycloalkyl-S(═O)—, heterocyclyl-S(═O)—, phenyl-S(═O)—, heteroaryl-S(═O)—, C3-6-cycloalkyl-S(═O)2—, heterocyclyl-S(═O)2—, phenyl-S(═O)2—, heteroaryl-S(═O)2—, HNRN—S(═O)2—, C1-4-alkyl-NRN—S(═O)2—, heterocyclyl, phenyl, and heteroaryl,
      • wherein each alkyl, cycloalkyl and heterocyclyl group is optionally substituted with 1 to 3 groups independently selected from R4 and optionally substituted with 1 or more F atoms;
      • wherein each phenyl and heteroaryl group is optionally substituted with 1 to 5 substituents independently selected from R5;
      • wherein heterocyclyl is selected from
        • a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by NRN, NR4, O, S, S(═O) or S(═O)2 and/or 1>CH— group is replaced by N, or
        • wherein 1 CH2 group is replaced by NRN, NR4, O or S, and/or 1>CH—group is replaced by N, and 1 additional CH2 group is replaced by C(═O) or S(═O)2; and
      • wherein heteroaryl is selected from
        • tetrazolyl, pyridinonyl,
        • a 5-membered heteroaromatic ring containing 1 ring member selected from NRN, NR5, N, O and S, or
        • containing 1 N and 1 ring member selected from NRN, NR5, N, O and S, or
        • containing 1 NRN, NR5, N, O or S and 2 N, and
        • a 6-membered heteroaromatic ring which contains 1 to 3 N atoms,
    • with the proviso that R2 in total must not be C1-4-alkyl-, C1-4-alkyl-O—C1-4-alkyl, HO—C1-4-alkyl, C2-4-alkenyl, C2-4-alkinyl, NH2, C1-4-alkyl-NH—, (C1-4-alkyl)2N—, C1-4-alkyl-O—, C1-4-alkyl-S—, C1-4-alkyl-S(═O)—, and C1-4-alkyl-S(═O)2;
  • R3 is selected from the group R3-G1 consisting of F, Cl, Br, I, CN, OH, C1-4-alkyl, C3-6-cycloalkyl, HO—C1-4-alkyl, C1-4-alkyl-O—C1-4-alkyl, —NRNH, C1-4-alkyl-NRN—, C1-4-alkyl-O—, C3-6-cycloalkyl-O—, C1-4-alkyl-O—C1-4-alkyl-O—, C1-4-alkyl-S—, C1-4-alkyl-S(═O)—, and C1-4-alkyl-S(═O)2—,
    • wherein any alkyl and cycloalkyl group is optionally substituted with 1 or more F atoms;
  • R4 is selected from the group R4-G1 consisting of Cl, Br, I, C1-4-alkyl, CN, C3-6-cycloalkyl, C1-4-alkyl-C(═O)—, heterocyclyl-C(═O)—, H2N—C(═O)—, C1-4-alkyl-NRN—C(═O)—, C3-6-cycloalkyl-NRN—C(═O)—, heterocyclyl-NRN—C(═O)—, phenyl-NRN—C(═O)—, heteroaryl-NRN—C(═O)—, HO—C(═O)—, C1-4-alkyl-O—C(═O)—, —NHRN, C1-4-alkyl-NRN—, C1-4-alkyl-C(═O)NRN—, C3-6-cycloalkyl-C(═O)NRN—, heterocyclyl-C(═O)NRN—, phenyl-C(═O)NRN—, heteroaryl-C(═O)NRN—, C1-4-alkyl-S(═O)2NRN—, C3-6-cycloalkyl-S(═O)2NRN—, heterocyclyl-S(═O)2NRN—, phenyl-S(═O)2NRN—, heteroaryl-S(═O)2NRN—, —OH, C1-4-alkyl-O—, C1-4-alkyl-O—C1-4-alkyl-O—, C3-6-cycloalkyl-O—, heterocyclyl-O—, phenyl-O—, heteroaryl-O—, C1-4-alkyl-S—, C3-6-cycloalkyl-S—, heterocyclyl-S—, phenyl-S—, heteroaryl-S—, C1-4-alkyl-S(═O)—, C3-6-cycloalkyl-S(═O)—, heterocyclyl-S(═O)—, phenyl-S(═O)—, heteroaryl-S(═O)—, C1-4-alkyl-S(═O)2—, C3-6-cycloalkyl-S(═O)2—, heterocyclyl-S(═O)2—, phenyl-S(═O)2—, heteroaryl-S(═O)2—, H2N—S(═O)2—, C1-4-alkyl-NRN—S(═O)2—, heterocyclyl, phenyl and heteroaryl,
    • wherein any alkyl, cycloalkyl and heterocyclyl group is optionally substituted with 1 or more F atoms and optionally substituted with 1 or 2 groups independently selected from H3C—, HO—, H3C—O— and —CN;
    • wherein heterocyclyl is selected from
      • a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by NRN, O, S, S(═O) or S(═O)2 and/or 1>CH— group is replaced by N, or wherein 1 CH2 group is replaced by NRN, O or S, and/or 1>CH— group is replaced by N, and 1 additional CH2 group is replaced by C(═O) or S(═O)2; and
    • wherein heteroaryl is selected from
      • tetrazolyl, pyridinonyl,
      • a 5-membered heteroaromatic ring containing 1 ring member selected from NRN, O and S, or
      • containing 1 N and 1 ring member selected from NRN, O and S, or containing 1 NRN, O or S and 2 N, and
      • a 6-membered heteroaromatic ring which contains 1 to 3 N atoms, and each heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from F, Cl, —CH3, —CN and —O—CH3;
  • R5 is selected from the group R5-G1 consisting of F, Cl, Br, CN, C1-4-alkyl, cyclopropyl, F3C—, HO—C1-4-alkyl-, C1-4-alkyl-O—C1-4-alkyl-, C1-4-alkyl-O—, F3C—O—, —S(═O)—C1-4-alkyl and S(═O)2—C1-4-alkyl; and
  • RN is selected from the group RN-G1 consisting of H, C1-4-alkyl, C1-4-alkyl-C(═O)—, C1-4-alkyl-NH—C(═O)—, C1-4-alkyl-N(C1-4-alkyl)-C(═O)—, C1-4-alkyl-O—C(═O)— and C1-4-alkyl-S(═O)2—;
    wherein in any definition mentioned hereinbefore and if not specified otherwise, any alkyl group or sub-group may be straight-chained or branched,
    the isoforms, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, or the combinations thereof.

The expression “optionally substituted with 1 or more F atoms” means that none or one up to successively all H atoms bound to carbon atoms of the respective group or submoiety may be replaced by F atoms, preferably 1 to 5 H atoms or, more preferred, 1 to 3 H atoms may be replaced by F atoms.

The extension -Gn used within the definitions is meant to identify genus n of the respective substituent. For example, R1-G1 defines genus 1 of the substituent R1.

In a further aspect this invention relates to a pharmaceutical composition, comprising one or more compounds of general formula I or one or more pharmaceutically acceptable salts thereof according to the invention, optionally together with one or more inert carriers and/or diluents.

In a further aspect this invention relates to a method for treating diseases or conditions which are mediated by activating the G-protein-coupled receptor GPR40 in a patient in need thereof characterized in that a compound of general formula I or a pharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a method for treating a metabolic disease or disorder, such as diabetes, dyslipidemia and/or obesity, in a patient in need thereof characterized in that a therapeutically effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided the use of a compound of the general formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for a therapeutic method as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided a compound of the general formula I or a pharmaceutically acceptable salt thereof for use in a therapeutic method as described hereinbefore and hereinafter.

In a further aspect this invention relates to a method for treating a disease or condition mediated by the activation of the G-protein-coupled receptor GPR40 in a patient that includes the step of administering to the patient in need of such treatment a therapeutically effective amount of a compound of the general formula I or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents.

In a further aspect this invention relates to the use of a compound of the general formula I or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents for the treatment of diseases or conditions which are mediated by the activation of the G-protein-coupled receptor GPR40.

In a further aspect this invention relates to a pharmaceutical composition which comprises a compound according to general formula I or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents.

Other aspects of the invention become apparent to the one skilled in the art from the specification and the experimental part as described hereinbefore and hereinafter.

DETAILED DESCRIPTION

Unless otherwise stated, the groups, residues, and substituents, particularly (Het)Ar, R1, R2, R3, R4, R5 and RN are defined as above and hereinafter. If residues, substituents, or groups occur several times in a compound, they may have the same or different meanings. Some preferred meanings of individual groups and substituents of the compounds according to the invention will be given hereinafter. Any and each of these definitions may be combined with each other.

(Het)Ar: (Het)Ar-G1:

The group (Het)Ar is preferably selected from the group (Het)Ar-G1 as defined hereinbefore.

(Het)Ar-G2:

According to one embodiment the group (Het)Ar is selected from the group (Het)Ar-G2 consisting of phenyl, naphthyl, and a heteroaromatic group linked via a carbon atom having 5 to 10 ring member atoms of which 2 to 9 atoms are carbon atoms and either

    • one ring member is an unsubstituted or substituted heteroatom selected from N, NH, NRN, O, S, S(═O) and S(═O)2, or
    • one ring member is N and a second ring member is selected from N, NH, NRN, O, S, S(═O) and S(═O)2, or
    • two ring members are N and a third ring member is selected from N, NH, NRN, O, S, S(═O) and S(═O)2,
      • wherein in naphthyl the ring not attached to the indanyl-O atom of formula I optionally is partially saturated,
      • wherein in bicyclic heteroaromatic groups the ring not attached to the indanyl-O atom of formula I optionally is partially saturated, while the aromatic ring includes at least one heteroatom,
        wherein each of these groups is substituted with 1 group R2 or 1 NH group is replaced by an NR2 group; and
        wherein any of these groups is optionally substituted with 1 to 3 groups independently selected from R3;
        or (Het)Ar-G2 denotes 2,3-dihydrobenzofuran, benzo[1,3]dioxole, 2,3-dihydro-benzo[1,4]dioxine or 3,4-dihydro-1H-quinolin-2-one, which are optionally substituted with 1 or 2 groups independently selected from R3.

(Het)Ar-G3:

According to one embodiment the group (Het)Ar is selected from the group (Het)Ar-G3 consisting of

phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, indolinyl, benzoimidazolyl, indazolyl, benzoxazolyl and benzothiazolyl,
wherein each of these groups is substituted with one group R2 and optionally substituted with 1 to 3 groups independently selected from R3;
or (Het)Ar-G3 denotes 2,3-dihydrobenzofuran, benzo[1,3]dioxole, 2,3-dihydro-benzo[1,4]dioxine or 3,4-dihydro-1H-quinolin-2-one, which are optionally substituted with 1 or 2 groups independently selected from R3.

(Het)Ar-G4:

According to one embodiment the group (Het)Ar is selected from the group (Het)Ar-G4 consisting of

phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, indolinyl, benzoimidazolyl, indazolyl, benzoxazolyl and benzothiazolyl, wherein each of these groups is substituted with one group R2 and optionally substituted with 1 to 3 groups independently selected from R3;
or (Het)Ar-G4 denotes 2,3-dihydrobenzofuran, benzo[1,3]dioxole, 2,3-dihydro-benzo[1,4]dioxine or 3,4-dihydro-1H-quinolin-2-one, which are optionally substituted with 1 group R3.

(Het)Ar-G5:

In another embodiment the group (Het)Ar is selected from the group (Het)Ar-G5 consisting of

wherein each of these groups is substituted with one group R2 and optionally substituted with 1 to 3 groups independently selected from R3.

(Het)Ar-G5a:

In another embodiment the group (Het)Ar is selected from the group (Het)Ar-G5a consisting of

which is substituted with one group R2 and optionally substituted with 1 to 3 groups independently selected from R3.

(Het)Ar-G5b:

In another embodiment the group (Het)Ar is selected from the group (Het)Ar-G5b consisting of

wherein each of these groups is substituted with one group R2 and optionally substituted with 1 or 2 groups independently selected from R3.

(Het)Ar-G5c:

In another embodiment the group (Het)Ar is selected from the group (Het)Ar-G5c consisting of

wherein each of these groups is substituted with one group R2 and optionally substituted with 1 to 3 groups independently selected from R3.

(Het)Ar-G6:

In another embodiment the group (Het)Ar is selected from the group (Het)Ar-G6 consisting of

wherein each of the phenyl subgroups is optionally additionally substituted with 1 or 2 F atoms or 1 CN group.

(Het)Ar-G6a:

In another embodiment the group (Het)Ar is selected from the group (Het)Ar-G6a consisting of

R1: R1-G1:

The group R1 is preferably selected from the group R1-G1 as defined hereinbefore.

R1-G2:

In another embodiment the group R1 is selected from the group R1-G2 consisting of H, F, Cl, F3C— and NC—.

R1-G3:

In another embodiment the group R1 is H.

R2: R2-G1:

The group R2 is preferably selected from the group R2-G1 as defined hereinbefore.

R2-G2:

In another embodiment the group R2 is selected from the group R2-G2 consisting of C1-4-alkyl, C3-6-cycloalkyl-, C1-4-alkyl-O—, C3-6-cycloalkyl-O—, C1-4-alkyl-S(═O)—, and C1-4-alkyl-S(═O)2—,

    • wherein each alkyl and cycloalkyl group is substituted with 1 or 2 groups independently selected from R4 and optionally substituted with 1 C1-3-alkyl and/or 1 to 3 F atoms;
      and of heterocyclyl-C(═O)—, H2N—C(═O)—, C1-4-alkyl-NRN—C(═O)—, C3-6-cycloalkyl-NRN—C(═O)—, heterocyclyl-NRN—C(═O)—, heteroaryl-NRN—C(═O)—, C1-4-alkyl-C(═O)NRN—, C3-6-cycloalkyl-C(═O)NRN—, heterocyclyl-C(═O)NRN—, phenyl-C(═O)NRN—, heteroaryl-C(═O)NRN—, C1-4-alkyl-S(═O)2NRN—, C3-6-cycloalkyl-S(═O)2NRN—, heterocyclyl-S(═O)2NRN—, heteroaryl-S(═O)2NRN—, heterocyclyl-O—, phenyl-O—, heteroaryl-O—, C3-6-cycloalkyl-S(═O)—, heterocyclyl-S(═O)—, phenyl-S(═O)—, heteroaryl-S(═O)—, C3-6-cycloalkyl-S(═O)2—, heterocyclyl-S(═O)2—, phenyl-S(═O)2—, heteroaryl-S(═O)2—, HNRN—S(═O)2—, C1-4-alkyl-NRN—S(═O)2—, heterocyclyl, phenyl, and heteroaryl,
    • wherein each alkyl, cycloalkyl, and heterocyclyl group is optionally substituted with 1 group selected from R4 and optionally substituted with 1 or 2 C1-3-alkyl and/or 1 to 3 F atoms;
    • wherein each phenyl and heteroaryl group is optionally substituted with 1 to 3 groups independently selected from R5;
    • wherein heterocyclyl is selected from
      • a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by NRN or O, and/or 1>CH— group is replaced by N, and 1 additional CH2 group is optionally replaced by C(═O) or S(═O)2;
    • wherein heteroaryl is selected from
      • tetrazolyl, pyridin-2-onyl,
      • a 5-membered heteroaromatic ring containing 1 ring member selected from NRN, NR5, N, O and S, or
      • containing 1 N and 1 ring member selected from NRN, NR5, N, O and S, or containing 1 NRN, NR5, N, O or S and 2 N, and
      • a 6-membered heteroaromatic ring which contains 1 or 2 N atoms,
        with the proviso that R2 in total must not be C1-4-alkyl-, C1-4-alkyl-O—C1-4-alkyl, HO—C1-4-alkyl, C1-4-alkyl-O—, C1-4-alkyl-S(═O)—, and C1-4-alkyl-S(═O)2.

R2-G3:

In another embodiment the group R2 is selected from the group R2-G3 consisting of C1-4-alkyl, C3-6-cycloalkyl-, C1-4-alkyl-O— and C3-6-cycloalkyl-O—,

    • wherein each alkyl and cycloalkyl group is substituted with 1 group selected from R4 and optionally substituted with 1 or 2 C1-3-alkyl and/or 1 to 3 F atoms;
      and of heterocyclyl-C(═O)—, H2N—C(═O)—, C1-3-alkyl-NRN—C(═O)—, C1-4-alkyl-C(═O)NRN—C3-6-cycloalkyl-C(═O)NRN—, heterocyclyl-C(═O)NRN—, C1-4-alkyl-S(═O)2NRN—, heterocyclyl-O—, heteroaryl-O—, heterocyclyl-S(═O)2—, H2N—S(═O)2—, heterocyclyl, phenyl, and heteroaryl,
    • wherein each alkyl, cycloalkyl and heterocyclyl group is optionally substituted with 1 group selected from R4 and optionally substituted with 1 or 2-CH3 groups and/or 1 to 3 F atoms;
    • wherein each phenyl and heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from R5;
    • wherein heterocyclyl is selected from
    • a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by NRN or O and/or 1>CH— group is replaced by N, and 1 additional CH2 group is optionally replaced by C(═O);
    • wherein heteroaryl is selected from
    • tetrazolyl, or
    • a 5-membered heteroaromatic ring containing 1 ring member selected from NRN, NR5, N, O and S, or
    • containing 1 N and 1 ring member selected from NRN, NR5, N, O and S, or containing 1 NRN, NR5, N, O or S and 2 N, and
    • a 6-membered heteroaromatic ring which contains 1 to 2 N atoms,
      with the proviso that R2 in total must not be C1-4-alkyl-, C1-4-alkyl-O—C1-4-alkyl, HO—C1-4-alkyl, and C1-4-alkyl-O—.

R2-G4:

In another embodiment the group R2 is selected from the group R2-G4 consisting of C1-4-alkyl, C3-6-cycloalkyl-, C1-4-alkyl-O— and C3-6-cycloalkyl-O—,

    • wherein each alkyl and cycloalkyl group is substituted with 1 group selected from R4 and optionally substituted with 1 or 2 H3C— group;
      and of heterocyclyl-C(═O)—, H2N—C(═O)—, C1-2-alkyl-NH—C(═O)—, (C1-2-alkyl)2N—C(═O)—, C1-3-alkyl-C(═O)—NH—, heterocyclyl-O—, heteroaryl-O—, heterocyclyl and heteroaryl,
    • wherein each heterocyclyl group is optionally substituted with 1 group selected from R4 and optionally substituted with 1 additional H3C— group;
    • wherein each heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from R5;
    • wherein heterocyclyl is selected from a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by O and/or 1>CH— group is replaced by N, and 1 additional CH2 group is optionally replaced by C(═O); and
    • wherein heteroaryl is selected from pyridinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl and tetrazolyl;
      with the proviso that R2 in total must not be C1-4-alkyl-, C1-4-alkyl-O—C1-4-alkyl, HO—C1-4-alkyl, and C1-4-alkyl-O—.

R2-G5:

According to another embodiment the group R2 is selected from the group R2-G5 consisting of

NC—C1-2-alkyl-, HO—C5-6-alkyl-, tetrahydropyranyl-CH2—, pyrrolidin-1-yl-CH2—, piperidin-1-yl-CH2—, morpholin-4-yl-CH2—, H3C—C(═O)—NH—CH2—, C1-2-alkyl-NH—C(═O)—, (C1-2-alkyl)2N—C(═O)—, pyrrolidin-1-yl-C(═O)—, morpholin-4-yl-C(═O)—, H3C—C(═O)—NH—, pyrrolidin-2-on-1-yl, HO—C2-5-alkyl-O—, H3C—O—C2-4-alkyl-O—, H3C—S(═O)2—C1-3-alkyl-O—, tetrahydrofuranyl-O—, tetrahydropyranyl-O—, tetrahydropyranyl, and tetrahydropyranyl-CH2—O— optionally substituted with one HO— group, and pyridinyl, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl and tetrazolyl, wherein each of these heteroaryl groups is optionally substituted with 1 or 2 H3C— groups or 1 HO—C(CH3)2—CH2— group.

R2-G6:

According to another embodiment the group R2 is selected from the group R2-G6 consisting of

R2-G6a:

According to another embodiment the group R2 is selected from the group R2-G6a consisting of

R3 R3-G1:

The group R3 is preferably selected from the group R3-G1 as defined hereinbefore.

R3-G2:

In another embodiment the group R3 is selected from the group R3-G2 consisting of F, Cl, CN, C1-3-alkyl, C3-4-cycloalkyl-, C1-3-alkyl-O— and H3C—S(═O)2—, wherein any alkyl and cycloalkyl group is optionally substituted with 1 or more F atoms.

R3-G3:

In another embodiment the group R3 is selected from the group R3-G3 consisting of F, —CH3 and CN.

R3-G4:

In another embodiment the group R3 is F.

R4 R4-G1:

The group R4 is preferably selected from the group R4-G1 as defined hereinbefore.

R4-G2:

In one embodiment the group R4 is selected from the group R4-G2 consisting of C1-4-alkyl-, —CN, C3-6-cycloalkyl-, heterocyclyl-C(═O)—, H2N—C(═O)—, C1-4-alkyl-NRN—C(═O)—, C3-6-cycloalkyl-NRN—C(═O)—, heterocyclyl-NRN—C(═O)—, heteroaryl-NRN—C(═O)—, —NH2, C1-4-alkyl-NRN—, C1-4-alkyl-C(═O)NRN—, C3-6-cycloalkyl-C(═O)NRN—, heterocyclyl-C(═O)NRN—, heteroaryl-C(═O)NRN—, C1-4-alkyl-S(═O)2NRN—, —OH, C1-4-alkyl-O—, C1-4-alkyl-O—C1-4-alkyl-O—, C3-6-cycloalkyl-O—, heterocyclyl-O—, phenyl-O—, heteroaryl-O—, C1-4-alkyl-S(═O)—, C3-6-cycloalkyl-S(═O)—, C1-4-alkyl-S(═O)2—, C3-6-cycloalkyl-S(═O)2—, heterocyclyl and heteroaryl,

    • wherein any alkyl, cycloalkyl, and heterocyclyl group is optionally substituted with 1 or more F atoms and optionally substituted with 1 or 2 groups independently selected from H3C—, HO—, H3C—O—, and —CN;
    • wherein heterocyclyl is selected from
    • a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by NRN or O and/or 1>CH— group is replaced by N, and 1 additional CH2 group is optionally replaced by C(═O);
    • and wherein heteroaryl is selected from
    • imidazolyl, pyrazolyl, oxazolyl, triazolyl, tetrazolyl, pyridinyl and pyrimidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from —CH3 and —O—CH3.

R4-G3:

In another embodiment the group R4 is selected from the group R4-G3 consisting of C1-4-alkyl-, —CN, C3-6-cycloalkyl-, heterocyclyl-C(═O)—, H2N—C(═O)—, —C(═O)NHCH3, —C(═O)N(CH3)2, —N(CH3)2, C1-3-alkyl-C(═O)NRN—, C1-3-alkyl-S(═O)2NRN—, —OH, C1-4-alkyl-O—, C3-6-cycloalkyl-O—, heterocyclyl-O—, C1-3-alkyl-S(═O)—, C1-3-alkyl-S(═O)2—, heterocyclyl and heteroaryl,

    • wherein any alkyl, cycloalkyl and heterocyclyl group is optionally substituted with 1 or more F atoms and optionally substituted with 1 or 2 groups independently selected from H3C—, HO—, H3C—O— and —CN,
    • wherein heterocyclyl is selected from
    • a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by NRN or O and/or 1>CH— group is replaced by N, and 1 additional CH2 group is optionally replaced by C(═O);
      and wherein heteroaryl is selected from
    • imidazolyl, pyrazolyl, oxazolyl, triazolyl, pyridinyl and pyrimidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from —CH3 and —O—CH3.

R4-G4:

In another embodiment the group R4 is selected from the group R4-G4 consisting of C1-2-alkyl-, —CN, H2N—C(═O)—, —C(═O)NHCH3, —C(═O)N(CH3)2, —N(CH3)2, H3C—C(═O)NH—, H3C—S(═O)2NH—, —OH, C1-3-alkyl-O—, heterocyclyl-O—, H3C—S(═O)—, H3C—S(═O)2—, heterocyclyl, and heteroaryl,

    • wherein heterocyclyl is selected from
    • oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, and morpholin-4-yl, wherein each of these rings is optionally substituted with 1 CH3 or 1 OH group;
    • and wherein heteroaryl is selected from
    • imidazolyl, pyrazolyl, oxazolyl and triazolyl, each of which is optionally substituted with 1 or 2-CH3 groups.

R4-G5:

According to another embodiment the group R4 is selected from the group R4-G5 consisting of

—CH3, H3C—C(═O)NH—, —OH, H3C—O—, H3C—S(═O)2—, tetrahydropyranyl, 4-hydroxy-tetrahydropyran-4-yl and morpholin-4-yl.

R4-G5a:

According to another embodiment the group R4 is selected from the group R4-G5a consisting of

—CH3, —CN, H3C—C(═O)NH—, —OH, H3C—O—, H3C—S(═O)2—, pyrrolidin-1-yl, piperidin-1-yl, tetrahydropyran-4-yl, 4-hydroxy-tetrahydropyran-4-yl and morpholin-4-yl.

R4-G6:

According to another embodiment the group R4 is selected from the group R4-G6 consisting of

—CH3, —OH, H3C—O— and H3C—S(═O)2—. Rs R5-G1:

The group R5 is preferably selected from the group R5-G1 as defined hereinbefore.

R5-G2:

In one embodiment the group R5 is selected from the group R5-G2 consisting of F, Cl, C1-3-alkyl, HO—C1-4-alkyl-, —CF3, —CN, C1-3-alkyl-O—, F3C—O—, —S(═O)CH3 and —S(═O)2—CH3.

R5-G3:

In another embodiment the group R5 is selected from the group R5-G3 consisting of F, —CH3, HO—C(CH3)2—CH2—, —CF3, —CN and —OCH3.

R5-G4:

In another embodiment the group R5 is selected from the group R5-G4 consisting of —CH3 and HO—C(CH3)2—CH2—.

RN RN-G1:

The group RN is preferably selected from the group RN-G1 as defined hereinbefore.

RN-G2:

In another embodiment the group RN is selected from the group RN-G2 consisting of H, C1-3-alkyl, H3C—C(═O)—, and C1-3-alkyl-S(═O)2—.

RN-G3:

In another embodiment the group RN is selected from the group RN-G3 consisting of H, H3C—, H3C—C(═O)—, and C1-3-alkyl-S(═O)2—.

Examples of preferred subgeneric embodiments (E) according to the present invention are set forth in the following table, wherein each substituent group of each embodiment is defined according to the definitions set forth hereinbefore and wherein all other substituents of the formula I are defined according to the definitions set forth hereinbefore:

E (Het)Ar- R1- R2- R3- R4- R5- RN- E-1 (Het)Ar-G1 R1-G1 R2-G1 R3-G1 R4-G1 R5-G1 RN-G1 E-2 (Het)Ar-G2 R1-G2 R2-G2 R3-G2 R4-G2 R5-G2 RN-G2 E-3 (Het)Ar-G3 R1-G2 R2-G3 R3-G3 R4-G3 R5-G3 RN-G3 E-4 (Het)Ar-G4 R1-G2 R2-G4 R3-G3 R4-G4 R5-G3 — E-5 (Het)Ar-G4 R1-G3 R2-G3 R3-G2 R4-G3 R5-G2 RN-G3 E-6 (Het)Ar-G4 R1-G3 R2-G3 R3-G3 R4-G4 R5-G3 RN-G3 E-7 (Het)Ar-G5a R1-G2 R2-G2 R3-G2 R4-G2 R5-G2 RN-G3 E-8 (Het)Ar-G5a R1-G2 R2-G3 R3-G3 R4-G3 R5-G2 RN-G3 E-9 (Het)Ar-G5a R1-G2 R2-G4 R3-G3 R4-G4 R5-G3 — E-10 (Het)Ar-G5b R1-G2 R2-G2 R3-G2 R4-G2 R5-G2 RN-G3 E-11 (Het)Ar-G5b R1-G2 R2-G3 R3-G3 R4-G3 R5-G2 RN-G3 E-12 (Het)Ar-G5b R1-G2 R2-G4 R3-G3 R4-G4 R5-G3 — E-13 (Het)Ar-G5c R1-G2 R2-G2 R3-G2 R4-G2 R5-G2 RN-G3 E-14 (Het)Ar-G5c R1-G2 R2-G3 R3-G3 R4-G3 R5-G2 RN-G3 E-15 (Het)Ar-G5c R1-G2 R2-G4 R3-G3 R4-G4 R5-G3 — E-16 (Het)Ar-G4 R1-G3 R2-G4 R3-G3 R4-G4 R5-G3 — E-17 (Het)Ar-G4 R1-G3 R2-G4 R3-G3 R4-G5 R5-G3 — E-18 (Het)Ar-G4 R1-G3 R2-G4 R3-G3 R4-G5a R5-G3 — E-19 (Het)Ar-G4 R1-G3 R2-G4 R3-G3 R4-G6 R5-G4 — E-20 (Het)Ar-G4 R1-G3 R2-G5 R3-G4 — — — E-21 (Het)Ar-G5 R1-G3 R2-G4 R3-G3 R4-G4 R5-G3 — E-22 (Het)Ar-G5a R1-G3 R2-G4 R3-G3 R4-G4 R5-G3 — E-23 (Het)Ar-G5a R1-G3 R2-G4 R3-G3 R4-G5 R5-G3 — E-24 (Het)Ar-G5b R1-G3 R2-G4 R3-G3 R4-G4 R5-G3 — E-25 (Het)Ar-G5b R1-G3 R2-G4 R3-G3 R4-G5 R5-G3 — E-26 (Het)Ar-G5c R1-G3 R2-G4 R3-G3 R4-G4 R5-G3 — E-27 (Het)Ar-G5c R1-G3 R2-G4 R3-G3 R4-G5 R5-G3 — E-28 (Het)Ar-G4 R1-G3 R2-G4 R3-G3 R4-G5a R5-G3 — E-29 (Het)Ar-G5a R1-G3 R2-G4 R3-G3 R4-G6 R5-G4 — E-30 (Het)Ar-G5b R1-G3 R2-G4 R3-G3 R4-G6 R5-G4 — E-31 (Het)Ar-G5c R1-G3 R2-G4 R3-G3 R4-G6 R5-G4 — E-32 (Het)Ar-G5a R1-G3 R2-G5 R3-G4 — — — E-33 (Het)Ar-G5b R1-G3 R2-G5 R3-G4 — — — E-34 (Het)Ar-G5c R1-G3 R2-G5 R3-G4 — — — E-35 (Het)Ar-G5a R1-G3 R2-G6 R3-G4 — — — E-36 (Het)Ar-G5b R1-G3 R2-G6 R3-G4 — — — E-37 (Het)Ar-G5c R1-G3 R2-G6 R3-G4 — — — E-38 (Het)Ar-G5a R1-G3 R2-G6a R3-G4 — — — E-39 (Het)Ar-G5b R1-G3 R2-G6a R3-G4 — — — E-40 (Het)Ar-G5c R1-G3 R2-G6a R3-G4 — — — E-41 (Het)Ar-G6 R1-G3 — — — — — E-42 (Het)Ar-G6a R1-G3 — — — — —

Preferred are those compounds of formula I, wherein

  • (Het)Ar is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, indolinyl, benzoimidazolyl, indazolyl, benzoxazolyl or benzothiazolyl, wherein each of these groups is substituted with 1 group R2 and optionally substituted with 1 to 3 groups independently selected from R3; or
  • (Het)Ar is 2,3-dihydrobenzofuran, benzo[1,3]dioxole, 2,3-dihydro-benzo[1,4]dioxine or 3,4-dihydro-1H-quinolin-2-one, which are optionally substituted with 1 group R3;
  • R1 is H;
  • R2 is C1-4-alkyl, C3-6-cycloalkyl-, C1-4-alkyl-O— or C3-6-cycloalkyl-O—,
    • wherein each alkyl and cycloalkyl group is substituted with 1 group R4 and optionally substituted with 1 or 2 H3C— group; or
  • R2 is heterocyclyl-C(═O)—, H2N—C(═O)—, C1-2-alkyl-NH—C(═O)—, (C1-2-alkyl)2N—C(═O)—, C1-3-alkyl-C(═O)—NH—, heterocyclyl-O—, heteroaryl-O—, heterocyclyl or heteroaryl,
    • wherein each heterocyclyl group is optionally substituted with 1 group selected from R4 and optionally substituted with 1 additional H3C— group;
    • wherein each heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from R5;
    • wherein heterocyclyl is a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by O and/or 1>CH— group is replaced by N, and 1 additional CH2 group is optionally replaced by C(═O);
    • wherein heteroaryl is pyridinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl or tetrazolyl;
      with the proviso that R2 in total must not be C1-4-alkyl-, C1-4-alkyl-O—C1-4-alkyl, HO—C1-4-alkyl, and C1-4-alkyl-O—;
  • R3 is F, —CH3 or CN;
  • R4 is C1-2-alkyl-, —CN, H2N—C(═O)—, —C(═O)NHCH3, —C(═O)N(CH3)2, —N(CH3)2, H3C—C(═O)NH—, H3C—S(═O)2NH—, —OH, C1-3-alkyl-O—, heterocyclyl-O—, H3C—S(═O)—, H3C—S(═O)2—, heterocyclyl, and heteroaryl,
    • wherein heterocyclyl is oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl or morpholin-4-yl, each of which is optionally substituted with 1 CH3 or 1 OH group;
    • wherein heteroaryl is imidazolyl, pyrazolyl, oxazolyl or triazolyl, each of which is optionally substituted with 1 or 2-CH3 groups;
  • R5 is F, —CH3, HO—C(CH3)2—CH2—, —CF3, —CN or —OCH3;
  • and the pharmaceutically acceptable salts thereof.

More preferred are those compounds of formula I, wherein

  • (Het)Ar is phenyl, which is substituted with 1 group R2 and optionally substituted with 1 to 3 groups independently selected from R3;
  • R1 is H;
  • R2 is C1-4-alkyl, C3-6-cycloalkyl-, C1-4-alkyl-O— or C3-6-cycloalkyl-O—,
    • wherein each alkyl and cycloalkyl group is substituted with 1 group R4 and optionally substituted with 1 or 2 H3C— group; or
  • R2 is heterocyclyl-C(═O)—, H2N—C(═O)—, C1-2-alkyl-NH—C(═O)—, (C1-2-alkyl)2N—C(═O)—, C1-3-alkyl-C(═O)—NH—, heterocyclyl-O—, heteroaryl-O—, heterocyclyl or heteroaryl,
    • wherein each heterocyclyl group is optionally substituted with 1 group selected from R4 and optionally substituted with 1 additional H3C— group;
    • wherein each heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from R5;
    • wherein heterocyclyl is a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by O and/or 1>CH— group is replaced by N, and 1 additional CH2 group is optionally replaced by C(═O);
    • wherein heteroaryl is pyridinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl or tetrazolyl;
      with the proviso that R2 in total must not be C1-4-alkyl-, C1-4-alkyl-O—C1-4-alkyl, HO—C1-4-alkyl, and C1-4-alkyl-O—;
  • R3 is F, —CH3 or CN;
  • R4 is C1-2-alkyl-, —CN, H2N—C(═O)—, —C(═O)NHCH3, —C(═O)N(CH3)2, —N(CH3)2, H3C—C(═O)NH—, H3C—S(═O)2NH—, —OH, C1-3-alkyl-O—, heterocyclyl-O—, H3C—S(═O)—, H3C—S(═O)2—, heterocyclyl, and heteroaryl,
    • wherein heterocyclyl is oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl or morpholin-4-yl, each of which is optionally substituted with 1 CH3 or 1 OH group;
    • wherein heteroaryl is imidazolyl, pyrazolyl, oxazolyl or triazolyl, each of which is optionally substituted with 1 or 2-CH3 groups;
  • R5 is F, —CH3, HO—C(CH3)2—CH2—, —CF3, —CN or —OCH3;
    and the pharmaceutically acceptable salts thereof.

Particularly preferred compounds, including their tautomers and stereoisomers, the salts thereof, or any solvates or hydrates thereof, are described in the experimental section hereinafter.

The compounds according to the invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably the compounds are obtained analogously to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section. In some cases the sequence adopted in carrying out the reaction schemes may be varied. Variants of these reactions that are known to the skilled man but are not described in detail here may also be used. The general processes for preparing the compounds according to the invention will become apparent to the skilled man on studying the schemes that follow. Starting compounds are commercially available or may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner. Before the reaction is carried out any corresponding functional groups in the compounds may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the skilled man.

The compounds of the invention I are preferably accessed from a precursor 1 that bears the carboxylic acid protected as ester (Scheme 1); (Het)Ar and R1 have the meanings as defined hereinbefore and hereinafter. The ester group may be hydrolysed in the presence of an acid, such as hydrochloric acid or sulfuric acid, or an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, to yield the carboxylic acid. The hydrolysis is preferably conducted in aqueous solvents, such as water combined with tetrahydrofuran, 1,4-dioxane, alcohol, e.g. methanol, ethanol and isopropanol, or dimethyl sulfoxide, at 0 to 120° C. A tert-butyl ester is preferably cleaved under acidic conditions, e.g. trifluoroacetic acid or hydrochloric acid, in a solvent, such as dichloromethane, 1,4-dioxane, isopropanol or ethyl acetate. A benzyl ester is advantageously cleaved using hydrogen in the presence of a transition metal, preferably palladium on carbon. Benzyl esters bearing electron donating groups on the phenyl ring, such as methoxy, may also be removed under oxidative conditions; ceric ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyanoquinone (DDQ) are reagents commonly used for this

Compound I may be assembled using building blocks 2, 3 and 4 (Scheme 2); (Het)Ar and R1 have the meanings as defined hereinbefore and hereinafter.

Building blocks 3 and 4 may be combined in a stereoselective fashion employing the conditions of the Mitsunobu reaction or variations thereof (Scheme 3); (Het)Ar and R1 have the meanings as defined hereinbefore and hereinafter. The reaction is usually conducted with a phosphine and an azodicarboxylic ester or amide in tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, benzene, dichloromethane, or mixtures thereof, at −30 to 100° C. Phosphines often used are triphenylphosphine and tributylphosphine, which are commonly combined with dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-(4-chlorobenzyl) azodicarboxylate, dibenzyl azodicarboxylate, di-tert-butyl azodicarboxylate, azodicarboxylic acid bis-(dimethylamide), azodicarboxylic acid dipiperidide, or azodicarboxylic acid dimorpholide.

The group (Het)Ar may be attached to the indane moiety via an oxygen starting from various precursors (Scheme 4); (Het)Ar and R1 have the meanings as defined hereinbefore and hereinafter. The two parts may be linked using one of them decorated with a hydroxy group (X or Z denotes OH) and the other one with a boronic acid group (X or Z denotes B(OH)2). The two building blocks accordingly equipped may be coupled employing copper(II) acetate in the presence of a base, e.g. pyridine or triethylamine, molecular sieves, optionally a co-oxidant, e.g. oxygen, in a solvent, e.g. dichloromethane, at 0 to 60° C. Alternatively, the linkage between (Het)Ar and indane via oxygen is formed upon coupling the indane moiety, bearing an OH group (Z═OH), and (Het)Ar, bearing a leaving group (X=e.g., F, Br, Cl, I). The O of the OH group replaces the leaving group by nucleophilic substitution or a transition metal catalyzed reaction. The former proceeding is particularly suited for electron deficient (Het)Ar groups which are coupled with the hydroxylated indane in the presence of a base, e.g. Cs2CO3, K2CO3, KOH, triethylamine or NaH, preferably in a solvent, e.g. toluene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, alcohol, water or mixtures thereof, at 0 to 220° C. The transition metal catalyzed coupling is used for (Het)Ar groups bearing Cl, Br or I as leaving group. Suitable transition metal catalysts are commonly derived from palladium or copper. The active catalyst may be an elemental form of the transition metal or formed from a salt of the transition metal, such as fluoride, chloride, bromide, iodide, acetate, triflate or trifluoroacetate, which are optionally combined with ligands, such as phosphines, e.g. tri-tert-butylphosphine, tricyclohexylphosphine, optionally substituted biphenyl-dicyclohexyl-phosphines, optionally substituted biphenyl-di-tert-butyl-phosphines, 1,1′-bis(diphenylphosphino)-ferrocene, triphenylphosphine, tritolylphosphine, or trifurylphosphine, phosphites, 1,3-disubstituted imidazole carbenes, 1,3-disubstituted imidazolidine carbenes, pyridines or phenanthrolines. The reaction is usually carried out in the presence of a base, e.g. NaOH, KOH, Na2CO3, K2CO3, Cs2CO3, triethylamine or ethyldiisopropylamine, in toluene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, alcohol, water, or mixtures thereof, preferably at 10 to 180° C.

Intermediate 3 or derivatives thereof, as 3″, may be obtained from indanone 7, which, in turn, may be prepared from phenylpropionic acid derivative 6 (Scheme 5); R1 has the meaning as defined hereinbefore and hereinafter. For the intramolecular acylation (Friedel-Crafts acylation), 6→7, a considerable number of approaches has been reported. The reaction may be performed starting with a carboxylic acid, carboxylic ester, carboxylic anhydride, carboxylic chloride or fluoride, or a nitrile using a Lewis acid as catalyst. The following Lewis acids are some of the more often used ones: hydrobromic acid, hydroiodic acid, hydrochloric acid, sulfuric acid, phosphoric acid, P4O10, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, ClSO3H, Sc(OSO2CF3)3, Tb(OSO2CF3)3, SnCl4, FeCl3, AlBr3, AlCl3, SbCl5, BCl3, BF3, ZnCl2, montmorillonites, POCl3, and PCl5. The reaction may be conducted, e.g., in dichloromethane, 1,2-dichloroethane, nitrobenzene, chlorobenzene, carbon disulfide, mixtures thereof, or without an additional solvent in an excess of the Lewis acid, at 0 to 180° C. Carboxylic acids are preferably reacted in polyphosphoric acid at 0 to 120° C., while carboxylic chlorides are preferably reacted with AlCl3 in dichloromethane or 1,2-dichloroethane at 0 to 80° C.

The subsequent reduction of the keto group in compound 7 providing the alcohol 3″ in enantiomerically enriched or pure form may be accomplished using hydrogen or a hydrogen source, such as formate or silane, and a transition metal catalyst derived from, e.g., Ir, Rh, Ru or Fe and a chiral auxiliary. For instance, a ruthenium complex, such as chloro{[(1S,2S)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)-amido}-(mesitylene)ruthenium(II), may deliver the hydroxy compound 3″ with high enantiomeric excess using, e.g., formic acid in the presence of a base, e.g. triethylamine, in dichloromethane, at −20 to 60° C. Alternatively, boranes combined with an enantiomerically pure [1,3,2]oxazaborol may be used as reducing agent (Corey-Bakshi-Shibata reaction or Corey-Itsuno reaction). Typical reaction conditions for this approach are borane (complexed with, e.g., dimethyl sulfide) and (R)- or (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol in, e.g., dichloromethane, toluene, methanol, tetrahydrofuran, or mixtures thereof, at 0 to 60° C.

The synthetic routes presented may rely on the use of protecting groups. For example, potentially reactive groups present, such as hydroxy, carbonyl, carboxy, amino, alkylamino, or imino, may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction. Suitable protecting groups for the respective functionalities and their removal are well known to the one skilled in the art and are described in the literature of organic synthesis.

The compounds of general formula I may be resolved into their enantiomers and/or diastereomers as mentioned below. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers and racemic compounds may be separated into their enantiomers.

The cis/trans mixtures may be resolved, for example, by chromatography into the cis and trans isomers thereof. The compounds of general formula I which occur as racemates may be separated by methods known per se into their optical antipodes and diastereomeric mixtures of compounds of general formula I may be resolved into their diastereomers by taking advantage of their different physico-chemical properties using methods known per se, e.g. chromatography and/or fractional crystallization; if the compounds obtained thereafter are racemates, they may be resolved into the enantiomers as mentioned below.

The racemates are preferably resolved by column chromatography on chiral phases or by crystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as esters or amides with the racemic compound. Salts may be formed with enantiomerically pure acids for basic compounds and with enantiomerically pure bases for acidic compounds. Diastereomeric derivatives are formed with enantiomerically pure auxiliary compounds, e.g. acids, their activated derivatives, or alcohols. Separation of the diastereomeric mixture of salts or derivatives thus obtained may be achieved by taking advantage of their different physico-chemical properties, e.g. differences in solubility; the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids commonly used for such a purpose as well as optically active alcohols applicable as auxiliary residues are known to those skilled in the art.

As mentioned above, the compounds of formula I may be converted into salts, particularly for pharmaceutical use into the pharmaceutically acceptable salts. As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.

The compounds according to the invention are advantageously also obtainable using the methods described in the examples that follow, which may also be combined for this purpose with methods known to the skilled man from the literature.

TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) of formula (I)”, “compound(s) of the invention” and the like denote the compounds of the formula (I) according to the present invention including their tautomers, stereoisomers and mixtures thereof and the salts thereof, in particular the pharmaceutically acceptable salts thereof, and the solvates and hydrates of such compounds, including the solvates and hydrates of such tautomers, stereoisomers and salts thereof.

The terms “treatment” and “treating” embrace both preventative, i.e. prophylactic, or therapeutic, i.e. curative and/or palliative, treatment. Thus the terms “treatment” and “treating” comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy. In addition the terms “treatment” and “treating” comprise prophylactic treatment, i.e. a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk.

When this invention refers to patients requiring treatment, it relates primarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein.

The terms “modulated” or “modulating”, or “modulate(s)”, as used herein, unless otherwise indicated, refer to the activation of the G-protein-coupled receptor GPR40 with one or more compounds of the present invention.

The terms “mediated” or “mediating” or “mediate”, as used herein, unless otherwise indicated, refer to the (i) treatment, including prevention of the particular disease or condition, (ii) attenuation, amelioration, or elimination of one or more symptoms of the particular disease or condition, or (iii) prevention or delay of the onset of one or more symptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or more hydrogens on the designated atom, radical or moiety is replaced with a selection from the indicated group, provided that the atom's normal valence is not exceeded, and that the substitution results in an acceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent “aryl-C1-3-alkyl-” means an aryl group which is bound to a C1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.

In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail.

An asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached.

For example, the term “3-carboxypropyl-group” represents the following substituent:

wherein the carboxy group is attached to the third carbon atom of the propyl group.

The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or “cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group is optionally substituted with” and the like denotes that each group X, each group Y and each group Z either each as a separate group or each as part of a composed group may be substituted as defined. For example a definition “Rex denotes H, C1-3-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl or C1-3-alkyl-O—, wherein each alkyl group is optionally substituted with one or more Lex.” or the like means that in each of the beforementioned groups which comprise the term alkyl, i.e. in each of the groups C1-3-alkyl, C3-6-cycloalkyl-C1-3-alkyl and C1-3-alkyl-O—, the alkyl moiety may be substituted with Lex as defined.

Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine and iodine.

The term “Cl1-n-alkyl”, wherein n is an integer from 1 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-5-alkyl embraces the radicals H3C—, H3C—CH2—, H3C—CH2—CH2—, H3C—CH(CH3)—, H3C—CH2—CH2—CH2—, H3C—CH2—CH(CH3)—, H3C—CH(CH3)—CH2—, H3C—C(CH3)2—, H3C—CH2—CH2—CH2—CH2—, H3C—CH2—CH2—CH(CH3)—, H3C—CH2—CH(CH3)—CH2—, H3C—CH(CH3)—CH2—CH2—, H3C—CH2—C(CH3)2—, H3C—C(CH3)2—CH2—, H3C—CH(CH3)—CH(CH3)— and H3C—CH2—CH(CH2CH3)—.

The term “C1-n-alkylene” wherein n is an integer 1 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term C1-4-alkylene includes —(CH2)—, —(CH2—CH2)—, —(CH(CH3))—, —(CH2—CH2—CH2)—, —(C(CH3)2)—, —(CH(CH2CH3))—, —(CH(CH3)—CH2)—, —(CH2—CH(CH3))—, —(CH2—CH2—CH2—CH2)—, —(CH2—CH2—CH(CH3))—, —(CH(CH3)—CH2—CH2)—, —(CH2—CH(CH3)—CH2)—, —(CH2—C(CH3)2)—, —(C (CH3)2—CH2)—, —(CH(CH3)—CH(CH3))—, —(CH2—CH(CH2CH3))—, —(CH(CH2CH3)—CH2)—, —(CH(CH2CH2CH3))—, —(CHCH(CH3)2)— and —C(CH3)(CH2CH3)—.

The term “C2-n-alkenyl”, is used for a group as defined in the definition for “C1-n-alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond. For example the term C2-3-alkenyl includes —CH═CH2, —CH═CH—CH3, —CH2—CH═CH2.

The term “C2-n-alkynyl”, is used for a group as defined in the definition for “C1-n-alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond. For example the term C2-3-alkynyl includes —C≡CH, —C≡C≡CH3, —CH2—C≡CH.

The term “C3-n-carbocyclyl” as used either alone or in combination with another radical, denotes a monocyclic, bicyclic or tricyclic, saturated or unsaturated hydrocarbon radical with 3 to n C atoms. The hydrocarbon radical is preferably nonaromatic. Preferably the 3 to n C atoms form one or two rings. In case of a bicyclic or tricyclic ring system the rings may be attached to each other via a single bond or may be fused or may form a spirocyclic or bridged ring system. For example the term C3-10-carbocyclyl includes C3-10-cylcoalkyl, C3-10-cycloalkenyl, octahydropentalenyl, octahydroindenyl, decahydronaphthyl, indanyl, tetrahydronaphthyl. Most preferably the term C3-n-carbocyclyl denotes C3-n-cylcoalkyl, in particular C3-7-cycloalkyl.

The term “C3-n-cycloalkyl”, wherein n is an integer 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. The cyclic group may be mono-, bi-, tri- or spirocyclic, most preferably monocyclic. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term “heteroaryl” or heteroaromatic group, unless specified otherwise, means a mono- or polycyclic, preferably mono- or bicyclic-ring system containing one or more heteroatoms selected from N, NH, NRN, O or S(O)r with r=0, 1 or 2 wherein at least one of the heteroatoms is part of an aromatic ring, RN preferably is a C1-3-alkyl group, and wherein said ring system may have a carbonyl group. More preferably the term “heteroaryl” as used herein, either alone or in combination with another radical, means a mono- or bicyclic-ring system containing 1, 2, 3 or 4 heteroatoms selected from N, NH, NRN, O or S(O)r with r=0, 1 or 2 wherein at least one of the heteroatoms is part of an aromatic ring, RN preferably is a methyl group, and wherein said ring system may have a carbonyl group. The term “heteroaryl” is intended to include all the possible isomeric forms.

Thus, the term “heteroaryl” or heteroaromatic group includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:

Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.

Chemical Stability

Degradation kinetics is used to simulate chemical stability of compounds in the acidic part of the gastro intestinal tract. The compounds of the invention show significantly superior chemical stability in acidic aqueous media (pH value ca. 1.2) compared to related compounds bearing electron neutral or releasing groups on the benzo part of the indane moiety.

The chemical stability of the compounds of the invention at pH value of ca. 1.2 is determined as follows:

Compound is dissolved in an HPLC vial either in a mixture of acetonitrile/0.1 M aqueous HCl (2:3; pH ca. 1.2) or in a mixture of acetonitrile/Mcllvaine buffer pH 7.4 (2:3) to get a concentration of approximately 0.25 mg/ml. The vial was then transferred into an HPLC autosampler system and maintained at a temperature of 37° C. A first sample is taken and injected immediately into a standard HPLC system with a UV DAD detector. Further samples are injected after 2, 4, 6, 8 and 10 hours. Degradation of the compound is measured by determining the recovery rate of compound [%] for each injection using an HPLC standard gradient method. Therefore the peak area of the main peak for the first injection (AUt0) is determined and set as 100%. Peak area of the main peak is determined also for the further injections (AUtn, n=2, 4, 6, 8, 10) and expressed as fraction of (AUt0)/(AUtn, n=2, 4, 6, 8, 10) [%].

The recovery rate of the compounds according to the invention after 2 h at pH value of ca. 1.2 determined as described above is typically above 90%, preferably above 95%.

The following table compares the recovery rate after 2 h at pH value of ca. 1.2 of examples described in the experimental part with the results obtained with two examples XX and XXI disclosed in WO2012072691. The number of the compound in the table corresponds to the number of the Example in the experimental section.

Example XX Example XXI Recovery rate Example after 2 h  1  97.5%  2  >98%  3  97.5%  6  >98%  9  >99% 11  96.5% 12  >99% XX  <5% XXI  <5%

Pharmacological Activity

The activity of the compounds of the invention may be demonstrated using the following assay:

IP1 accumulation measurements using the IPOne assay system—1321 N1 cells stably expressing human GPR40 receptor (Euroscreen, Belgium) are seeded 24 h before the assay in white 384-well plates in culture medium containing 10% FCS, 1% Na-Pyruvate and 400 μg/mL G418. IP1 is assayed according to the manufacturer's description (Cisbio Bioassays, France). In brief, the assay is started by substitution of the culture medium by stimulation buffer (Hepes 10 mM, CaCl2 1 mM, MgCl2 0.5 mM, KCl 4.2 mM, NaCl 146 mM, glucose 5.5 mM and LiCl 50 mM, pH 7.4). Cells are stimulated for 1 h at 37° C., 5% CO2 by addition of the compounds that are diluted in stimulation buffer containing LiCl. Assays are stopped by adding HTRF-conjugates (IP1-d2 and Anti-IP1 cryptate Tb) and lysis buffer, provided by the manufacturer. After an incubation time of 1 h at room temperature plates are measured using an EnVision™, Perkin Elmer. The obtained fluorescence ratios at 665/615 nM are then used to calculate the pEC50 values using Assay Explorer 3.3 Software (Accelrys, Inc.) by interpolation using an IP1 reference curve and subsequent sigmoidal curve fitting allowing for a variable hill slope.

The compounds according to the invention typically have EC50 values in the range from about 1 nM to about 10 μM, preferably less than 1 μM, more preferably less than 100 nM.

EC50 values for compounds according to the invention are shown in the following Table. The number of the compound corresponds to the number of the Example in the experimental section.

Exam- EC50 Exam- EC50 Exam- EC50 Exam- EC50 ple [nM] ple [nM] ple [nM] ple [nM] 1 7 2 5 3 13 4 15 5 25 6 8 7 55 8 34 9 18 10 11 11 6 12 18 13 282 14 23 15 3 16 9 17 23 18 31 19 12 20 7 21 6 22 5 23 84 24 10 25 6 26 6 27 9 28 20 29 12 30 13 31 58 32 13 33 45 34 6 35 5 36 8 37 8 38 41 39 23 40 733 41 85 42 120 43 18 44 7 45 29 46 62 47 8 48 9 49 17 50 4 51 29 52 31 53 7 54 9 55 6 56 38 57 4 58 18 59 216 60 20 61 13 62 12 63 22 64 27 70 44

In view of their ability to modulate the activity of the G-protein-coupled receptor GPR40, in particular an agonistic activity, the compounds of general formula I according to the invention, including the corresponding salts thereof, are theoretically suitable for the treatment of all those diseases or conditions which may be affected or which are mediated by the activation of the G-protein-coupled receptor GPR40.

Accordingly, the present invention relates to a compound of general formula I as a medicament.

Furthermore, the present invention relates to the use of a compound of general formula I or a pharmaceutical composition according to this invention for the treatment and/or prevention of diseases or conditions which are mediated by the activation of the G-protein-coupled receptor GPR40 in a patient, preferably in a human.

In yet another aspect the present invention relates to a method for treating a disease or condition mediated by the activation of the G-protein-coupled receptor GPR40 in a mammal that includes the step of administering to a patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.

Diseases and conditions mediated by agonists of the G-protein-coupled receptor GPR40 embrace metabolic diseases or conditions. According to one aspect the compounds and pharmaceutical compositions of the present invention are particularly suitable for treating diabetes mellitus, in particular Type 2 diabetes, Type 1 diabetes, complications of diabetes (such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot, ulcers or macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuricaemia.

The compounds and pharmaceutical compositions of the present invention are also suitable for preventing beta-cell degeneration such as e.g. apoptosis or necrosis of pancreatic beta cells. The compounds and pharmaceutical compositions of the present invention are also suitable for improving or restoring the functionality of pancreatic cells, and also for increasing the number and size of pancreatic beta cells.

Therefore according to another aspect the invention relates to compounds of formula I and pharmaceutical compositions according to the invention for use in preventing, delaying, slowing the progression of and/or treating metabolic diseases, particularly in improving the glycaemic control and/or beta cell function in the patient.

In another aspect the invention relates to compounds of formula I and pharmaceutical compositions according to the invention for use in preventing, delaying, slowing the progression of and/or treating type 2 diabetes, overweight, obesity, complications of diabetes and associated pathological conditions.

In addition the compounds and pharmaceutical compositions according to the invention are suitable for use in one or more of the following therapeutic processes:

    • for preventing, delaying, slowing the progression of or treating metabolic diseases, such as for example type 1 diabetes, type 2 diabetes, insufficient glucose tolerance, insulin resistance, hyperglycaemia, hyperlipidaemia, hypercholesterolaemia, dyslipidaemia, syndrome X, metabolic syndrome, obesity, high blood pressure, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction or bone-related diseases (such as osteoporosis, rheumatoid arthritis or osteoarthritis);
    • for improving glycaemic control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or the glycosylated haemoglobin HbA1c;
    • for preventing, delaying, slowing or reversing the progression of disrupted glucose tolerance, insulin resistance and/or metabolic syndrome to type 2 diabetes;
    • for preventing, delaying, slowing the progression of or treating a condition or a disease selected from among the complications of diabetes, such as for example retinopathy, nephropathy or neuropathies, diabetic foot, ulcers or macroangiopathies;
    • for reducing weight or preventing weight gain or assisting weight loss;
    • for preventing or treating the degradation of pancreatic beta cells and/or improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion;
    • for maintaining and/or improving insulin sensitivity and/or preventing or treating hyperinsulinaemia and/or insulin resistance.

In particular, the compounds and pharmaceutical compositions according to the invention are suitable for the treatment of obesity, diabetes (comprising type 1 and type 2 diabetes, preferably type 2 diabetes mellitus) and/or complications of diabetes (such as for example retinopathy, nephropathy or neuropathies, diabetic foot, ulcers or macroangiopathies).

The compounds according to the invention are most particularly suitable for treating type 2 diabetes mellitus.

The dose range of the compounds of general formula I applicable per day is usually from 0.001 to 10 mg per kg body weight, for example from 0.01 to 8 mg per kg body weight of the patient. Each dosage unit may conveniently contain from 0.1 to 1000 mg, for example 0.5 to 500 mg.

The actual therapeutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the compound or composition will be administered at dosages and in a manner which allows a therapeutically effective amount to be delivered based upon patient's unique condition.

The compounds, compositions, including any combinations with one or more additional therapeutic agents, according to the invention may be administered by oral, transdermal, inhalative, parenteral or sublingual route. Of the possible methods of administration, oral or intravenous administration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula I, optionally in combination with one or more further therapeutic agents, will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc. Oral formulations, particularly solid forms such as e.g. tablets or capsules are preferred. The content of the pharmaceutically active compound(s) is advantageously in the range from 0.1 to 90 wt.-%, for example from 1 to 70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. The tablets may also consist of several layers. The particular excipients, carriers and/or diluents that are suitable for the desired preparations will be familiar to the skilled man on the basis of his specialist knowledge. The preferred ones are those that are suitable for the particular formulation and method of administration that are desired. The preparations or formulations according to the invention may be prepared using methods known per se that are familiar to the skilled man, such as for example by mixing or combining at least one compound of formula I according to the invention, or a pharmaceutically acceptable salt of such a compound, and one or more excipients, carriers and/or diluents.

Combination Therapy

The compounds of the invention may further be combined with one or more, preferably one additional therapeutic agent. According to one embodiment the additional therapeutic agent is selected from the group of therapeutic agents useful in the treatment of diseases or conditions described hereinbefore, in particular associated with metabolic diseases or conditions such as for example diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia. Additional therapeutic agents which are suitable for such combinations include in particular those which for example potentiate the therapeutic effect of one or more active substances with respect to one of the indications mentioned and/or which allow the dosage of one or more active substances to be reduced.

Therefore a compound of the invention may be combined with one or more additional therapeutic agents selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and/or obesity and agents for the treatment of high blood pressure, heart failure and/or atherosclerosis.

Antidiabetic agents are for example metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-(alpha, gamma or alpha/gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIV inhibitors, SGLT2-inhibitors, insulin and insulin analogues, GLP-1 and GLP-1 analogues or amylin and amylin analogues, cycloset, 11β-HSD inhibitors. Other suitable combination partners are inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, alpha2-antagonists, CCR-2 antagonists or glucokinase activators. One or more lipid lowering agents are also suitable as combination partners, such as for example HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and the derivatives thereof, PPAR-(alpha, gamma or alpha/gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors or cholesterol absorption inhibitors such as, bile acid-binding substances such as, inhibitors of ileac bile acid transport, MTP inhibitors, or HDL-raising compounds such as CETP inhibitors or ABC1 regulators.

Therapeutic agents for the treatment of overweight and/or obesity are for example antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, β3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor.

Therapeutic agents for the treatment of high blood pressure, chronic heart failure and/or atherosclerosis are for example A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.

The dosage for the combination partners mentioned above is usually 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.

Preferably, compounds of the present invention and/or pharmaceutical compositions comprising a compound of the present invention optionally in combination with one or more additional therapeutic agents are administered in conjunction with exercise and/or a diet.

Therefore, in another aspect, this invention relates to the use of a compound according to the invention in combination with one or more additional therapeutic agents described hereinbefore and hereinafter for the treatment of diseases or conditions which may be affected or which are mediated by the activation of the G-protein-coupled receptor GPR40, in particular diseases or conditions as described hereinbefore and hereinafter.

In yet another aspect the present invention relates a method for treating a disease or condition mediated by the activation of the G-protein-coupled receptor GPR40 in a patient that includes the step of administering to the patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of one or more additional therapeutic agents described in hereinbefore and hereinafter,

The use of the compound according to the invention in combination with the additional therapeutic agent may take place simultaneously or at staggered times.

The compound according to the invention and the one or more additional therapeutic agents may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so-called kit-of-parts.

Consequently, in another aspect, this invention relates to a pharmaceutical composition which comprises a compound according to the invention and one or more additional therapeutic agents described hereinbefore and hereinafter, optionally together with one or more inert carriers and/or diluents.

Other features and advantages of the present invention will become apparent from the following more detailed Examples which illustrate, by way of example, the principles of the invention.

EXAMPLES

The Examples that follow are intended to illustrate the present invention without restricting it.

Preliminary Remarks:

As a rule, 1H-NMR and/or mass spectra have been obtained for the compounds prepared. The Rf values are determined using Merck silica gel 60 F254 plates and UV light at 254 nm.

The terms “ambient temperature” and “room temperature” are used interchangeably and designate a temperature of about 20° C.

Analytical HPLC parameters employed for characterization of products (TFA denotes trifluoroacetic acid and FA denotes formic acid):

Method: 1 Device: Agilent 1200 with DA and MS detector Column: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ Temper- Solvent % Solvent % Solvent Flow ature Time [min] [H2O, 0.1% TFA] [Methanol] [mL/min] [° C.] 0.0 95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 100 2.2 60 1.80 0 100 2.2 60

Method: 2 Device: Agilent 1200 with DA and MS detector Column: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% FA] nitrile] [mL/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 3 Device: Agilent 1200 with DA and MS detector Column: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% TFA] nitrile] [mL/min] [° C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 4 Device: Agilent 1200 with DA and MS detector Column: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% TFA] nitrile] [mL/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 5 Device: Agilent 1200 with DA and MS detector Column: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% NH3] nitrile] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 6 Device: Waters Acquity with 3100 MS Column: XBridge BEH C18, 3.0 × 30 mm, 1.7 μm Column supplier: Waters Gradient/ % Solvent % Solvent Temper- Solvent [H2O, [Aceto- Flow ature Time [min] 0.1% NH4OH] nitrile] [ml/min] [° C.] 0.0 95.0 5.0 1.5 60.0 0.80 0.1 99.9 1.5 60.0 0.90 0.1 99.9 1.5 60.0

Method: 7 Device: ThermoFinnigan HPLC Surveyor DAD, MSQ single quadrupole Column: Synergi Hydro RP100A, 3 × 50 mm, 2.5 μm Column Supplier: Phenomenex Gradient/ % Solvent % Solvent Temper- Solvent [H2O/CH3CN 9:1, + [CH3CN/ Flow ature Time [min] (NH4COOH 5 mM)] H2O 9:1] [mL/min] [° C.] 0.0 100 0 1.2 25 4.00 0 100 1.2 25 5.30 0 100 1.2 25 5.50 100 0 1.2 25 6.00 100 0 1.2 25

Method: 8 Device: ThermoFinnigan HPLC Surveyor DAD, MSQ single quadrupole Column: Synergi Hydro RP100A, 3 × 50 mm, 2.5 μm Column Supplier: Phenomenex Gradient/ % Solvent % Solvent Temper- Solvent [H2O/CH3CN 9:1, + [CH3CN/ Flow ature Time [min] (NH4COOH 5 mM)] H2O 9:1] [mL/min] [° C.] 0.0 100 0 1.2 25 1.50 100 0 1.2 25 9.00 0 100 1.2 25 10.50 0 100 1.2 25 11.00 100 0 1.2 25 12.00 100 0 1.2 25

Method: 9 Device: Agilent 1200 with DA- and MS-Detector Column: Sunfire C18, 3.0 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% TFA] nitrile] [mL/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 10 Device: Agilent 1200 with DA- and MS-Detector Column: Sunfire C18, 3.0 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% HCOOH] nitrile] [mL/min] [° C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 11 Device: Agilent 1100 with DA, Waters Autosampler and MS-Detector Column: SunFire C18, 4.6 × 30 mm, 3.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% TFA] nitrile] [mL/min] [° C.] 0.00 98 2 2.5 60 1.50 0 100 2.5 60 1.80 0 100 2.5 60

Method: 12 Device: Agilent 1200 with DA- and MS-Detector Column: Sunfire C18, 3.0 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% TFA] nitrile] [mL/min] [° C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 13 Device: Agilent 1200 with DA- and MS-Detector Column: Sunfire C18, 3.0 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% FA] nitrile] [mL/min] [° C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 14 Device: LC/MS Waters Alliance 2695 HPLC System DAD, Quattro Micro Triple Column: Xbridge Phenyl, 3.5 μm, 3 × 30 mm Column Supplier: Waters Gradient/ % Solvent % Solvent Temper- Solvent [H2O, 10% CH3CN [Acetonitrile, Flow ature Time [min] NH4HCO3 5 mM] 10% H2O] [mL/min] [° C.] 0.0 100 0 1.3 35 4.50 0 100 1.3 35 5.80 0 100 1.3 35 6.00 100 0 1.3 35

Method: 15 Device: LC/MS ThermoFinnigan HPLC Surveyor DAD, LCQFleet Ion Trap Column: Xselect CSH, 2.5 μm, 4.6 × 50 mm Column Supplier: Waters % Solvent % Solvent Gradient/ [H2O, [H3CCN, Temper- Solvent 10% H3CCN, 10% H2O, Flow ature Time [min] 0.1% FA] 0.1% FA] [mL/min] [° C.] 0.0 100 0 1.4 25 4.00 0 100 1.4 25 5.30 0 100 1.4 25 5.50 100 0 1.4 25 6.00 100 0 1.2 25

Method: 16 Device: Agilent 1200 with DA- and MS- Detector Column: Sunfire C18, 3.0 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% FA] nitrile] [mL/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 17 Device: Agilent 1200 with DA and MS detector Column: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% NH3] nitrile] [ml/min] [° C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method: 18 Device: Agilent 1100 with DA, Gilson Autosampler and MS-Detector Column: SunFire C18, 3.0 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% TFA] nitrile] [mL/min] [° C.] 0.00 99 1 2.0 60 0.90 0 100 2.0 60 1.10 0 100 2.0 60

Method: 19 Device: Agilent 1100 with DA, Waters Autosampler and MS-Detector Column: SunFire C18, 3.0 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent [Aceto- Flow ature Time [min] [H2O, 0.1% TFA] nitrile] [mL/min] [° C.] 0.00 98 2 2.0 60 1.20 0 100 2.0 60 1.40 0 100 2.0 60

Intermediate 1 [(S)-6-Hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

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) is stirred at reflux temperature for 4 h. After cooling to room temperature, the mixture is concentrated. Ethyl acetate is added to the residue, and the resulting mixture is washed with water, saturated aqueous NaHCO3 solution and brine and dried (MgSO4). The solvent is evaporated, and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 2:1→1:2) to give the title compound. 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) is shaken under hydrogen atmosphere (3 bar) at room temperature for 3 h. The catalyst is separated by filtration and the filtrate is concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) to give the racemic title compound. Mass spectrum (ESI+): m/z=209 [M+H]+.

The enantiomers may be separated by SFC on chiral phase (column: Daicel ADH, 5 μm, 250 mm×20 mm; eluent: scCO2/(isopropanol+0.2% diethylamine) 80:20, 70 mL/min):

(S)-(6-Hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester: tR=2.33 min.

(R)-(6-Hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester: tR=2.75 min.

Alternatively, the pure enantiomer may be obtained as described in WO 2008001931.

Intermediate 2 (S)-4-Bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol

Formic acid (8.1 mL) is added to a solution of triethylamine (25.6 mL) in dichloromethane (50 mL) chilled in an ice bath. 4-Bromo-7-fluoro-2,3-dihydro-1H-inden-1-one (14.0 g) is added, the solution is warmed to room temperature, and the flask is purged with argon for 5 min. Chloro{[(1S,2S)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}-(mesitylene)ruthenium(II) (0.85 g; alternatively, the catalyst is formed in situ from dichloro(p-cymene)-ruthenium(II) dimer and N-[(1S,2S)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide) is added, and the mixture is stirred at room temperature for 16 h. Water is added and the resulting mixture is extracted with dichloromethane. The combined extract is washed with saturated aqueous NaHCO3 solution and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10-50:50) to give the title compound.

LC (method 1): tR=1.04 min; Mass spectrum (ESI+): m/z=213/215 (Br) [M+H−H2O]+.

Intermediate 3 {(S)-6-[(R)-4-Bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

A solution of di-tert-butyl azodicarboxylate (18.0 g) in tetrahydrofuran (80 mL) is added dropwise over 45 min to a solution of [(S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester (11.0 g), (S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol (12.0 g) and tributylphosphine (19.3 mL) in tetrahydrofuran (320 mL) at −10° C. The resulting solution is stirred for 30 min and then poured into saturated aqueous NaHCO3 solution. The mixture is extracted with dichloromethane, and the combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10-70:30) to give the title compound. LC (method 1): tR=1.41 min; Mass spectrum (ESI+): m/z=421 [M+H]+.

Intermediate 4 {(S)-6-[(R)-7-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

A microwave vial charged with a stir bar, {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (7.0 g), bis-(pinacolato)-diboron (5.6 g), potassium acetate (4.2 g) and 1,4-dioxane (100 mL) is purged with argon for 10 min. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (0.60 g) is added, the vial is sealed, and the mixture is stirred at 100° C. for 4 h. After cooling to room temperature, saturated aqueous NH4Cl solution is added and the resulting mixture is extracted with diethyl ether. The combined extracts are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1-70:30) to give the title compound. LC (method 1): tR=1.48 min; Mass spectrum (ESI+): m/z=469 [M+H]+.

Intermediate 5 {(S)-6-[(R)-7-Fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Aqueous hydrogen peroxide solution (35%, 3.7 mL) is added dropwise to a solution of {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (5.0 g) in acetic acid (30 mL) chilled in an ice bath. The solution is stirred with cooling for 0.5 h and at room temperature for another 2 h. Ice-cold water (50 mL) and 2 N aqueous NaOH solution (20 mL) are added, and the mixture is stirred at room temperature overnight. The mixture is extracted with ethyl acetate, and the combined extracts are washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20-60:40) to give the title compound. LC (method 2): tR=1.01 min; Mass spectrum (ESI+): m/z=359 [M+H]+.

Intermediate 6 [(S)-6-{(R)-4-[4-(Benzyloxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]acetic acid methyl ester

Triethylamine (726 mg) is added to a mixture of {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (400 mg), 4-(benzyloxy)phenylboronic acid (509 mg), freshly activated molecular sieves 4A (6.0 g), copper(II) acetate (204 mg) and dichloromethane (19.5 mL) at room temperature. The flask is purged with O2 and sealed. The reaction mixture is stirred under an O2 atmosphere (1 bar) at room temperature over night. The mixture is diluted with dichloromethane, filtered and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10-80:20) to give the title compound. LC (method 3): tR=0.96 min; Mass spectrum (ESI+): m/z=541 [M+H]+.

Intermediate 7 {(S)-6-[(R)-7-Fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

A mixture of [(S)-6-{(R)-4-[4-(benzyloxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]acetic acid methyl ester (410 mg), 10% palladium on carbon (50 mg), and tetrahydrofuran (20 mL) is shaken under a hydrogen atmosphere (3.5 bar) at room temperature for 2 h. The catalyst is filtered off and the filtrate is concentrated in vacuo to give the title compound. LC (method 3): tR=0.41 min; Mass spectrum (ESI+): m/z=451 [M+H]+.

Intermediate 8 [(S)-6-{(R)-7-Fluoro-4-[4-(2-methoxy-ethoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

A mixture of {(S)-6-[(R)-7-fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (60 mg), toluene-4-sulfonic acid 2-methoxy-ethyl ester (34 mg), and cesium carbonate (60 mg) in N,N-dimethylformamide (2 mL) is stirred for 1.5 h at 60° C. After cooling to room temperature, the mixture is diluted with water an extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4), and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) to give the title compound. LC (method 3): tR=0.70 min; Mass spectrum (ESI+): m/z=509 [M+H]+.

Intermediate 9 [(S)-6-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a procedure analogous to that described for Intermediate 8. LC (method 3): tR=0.70 min; Mass spectrum (ESI+): m/z=537 [M+H]+.

Intermediate 10 [(S)-6-{(R)-7-Fluoro-4-[4-(2-hydroxy-2-methyl-propoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,2-dimethyl-oxirane following a procedure analogous to that described for Intermediate 8. LC (method 3): tR=0.66 min; Mass spectrum (ESI+): m/z=545 [M+Na]+.

Intermediate 11 [(S)-6-{(R)-7-Fluoro-4-[4-(3-methanesulfonyl-propoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester following a procedure analogous to that described for Intermediate 8. LC (method 3): tR=0.52 min; Mass spectrum (ESI+): m/z=571 [M+H]+.

Intermediate 12 {(S)-6-[(R)-7-Fluoro-4-(4-morpholin-4-ylmethyl-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-morpholinylmethyl)phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=0.95 min; Mass spectrum (ESI+): m/z=534 [M+H]+.

Intermediate 13 {(S)-6-[(R)-4-(3-Acetylamino-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-acetamidophenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.11 min; Mass spectrum (ESI−): m/z=490 [M−H]−.

Intermediate 14 [(S)-6-{(R)-4-[3-(Acetylamino-methyl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(acetamidomethyl)-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.07 min; Mass spectrum (ESI+): m/z=506 [M+H]+.

Intermediate 15 {(S)-6-[(R)-4-(4-Acetylamino-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-acetamidophenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.09 min; Mass spectrum (ESI+): m/z=492 [M+H]+

Intermediate 16 [(S)-6-{(R)-7-Fluoro-4-[4-(pyrrolidine-1-carbonyl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(pyrrolidine-1-carbonyl)phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.15 min

Intermediate 17 {(S)-6-[(R)-7-Fluoro-4-(4-imidazol-1-yl-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(1H-imidazol-1-yl)phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=0.96 min; Mass spectrum (ESI+): m/z=501 [M+H]+

Intermediate 18 {(S)-6-[(R)-4-(2,3-Dihydro-benzofuran-5-yloxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,3-dihydrobenzofuran-5-ylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.22 min; Mass spectrum (ESI+): m/z=477 [M+H]+

Intermediate 19 {(S)-6-[(R)-4-(4-Ethylcarbamoyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(ethylcarbamoyl)phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.11 min; Mass spectrum (ESI+): m/z=506 [M+H]+

Intermediate 20 {(S)-6-[(R)-4-(4-Cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

A mixture of {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (100 mg), 4-fluoro-benzonitrile (34 mg), and cesium carbonate (91 mg) in N,N-dimethylformamide (2 mL) is heated to 130° C. for 30 min in a microwave oven. The reaction mixture is concentrated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. LC (method 2): tR=1.18 min; Mass spectrum (ESI+): m/z=460 [M+H]+.

Intermediate 21 [(S)-6-{(R)-7-Fluoro-4-[4-(1H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

A mixture of {(S)-6-[(R)-4-(4-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (150 mg), sodium azide (83 mg), and ammonium chloride (79 mg) in N,N-dimethylformamide (5 mL) is stirred at 110° C. over night. More sodium azide (83 mg) and ammonium chloride (79 mg) are added and the mixture is stirred at 110° C. for another 8 h. The reaction mixture is cooled to room temperature, diluted with water, and sodium nitrite (122 mg) is added. The pH is adjusted to 1-2 with 4M HCl and the mixture is stirred for 1 h at room temperature. The mixture is extracted with ethyl acetate and the combined extracts are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10-0:100) to give the title compound. LC (method 4): tR=1.09 min; Mass spectrum (ESI−): m/z=501 [M−H]−.

Intermediate 22 and 23 [(S)-6-{(R)-7-Fluoro-4-[4-(1-methyl-1H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester and [(S)-6-{(R)-7-Fluoro-4-[4-(2-methyl-2H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

The title compounds are prepared by treatment of [(S)-6-{(R)-7-fluoro-4-[4-(1H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester with methyl iodide in the presence of potassium carbonate in N,N-dimethylformamide at room temperature. Product ratio Intermediate 22: 23=2:8.

Intermediate 22: LC (method 4): tR=1.12 min; Mass spectrum (ESI+−): m/z=517 [M+H]+.

Intermediate 23: LC (method 4): tR=1.19 min; Mass spectrum (ESI+−): m/z=517 [M+H]+.

Intermediate 24 {(S)-6-[(R)-4-(2-bromopyridin-4-yloxy)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy]-2,3-dihydrobenzofuran-3-yl}acetic acid methyl ester

A mixture of {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (300 mg), 2-bromo-4-fluoro-pyridine (155 mg), and cesium carbonate (273 mg) in N,N-dimethylformamide (2 mL) is heated to 80° C. for 16 h. The reaction mixture diluted with water and extracted with ethyl acetate. The combined extracts are dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. LC (method 2): tR=1.18 min; Mass spectrum (ESI+): m/z=514, 516 [M+H]+.

Intermediate 25 {(S)-6-[(R)-7-fluoro-4-{2-[(S)-tetrahydro-furan-3-yloxy]-pyridin-4-yloxy}-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

A mixture of {(S)-6-[(R)-4-(2-bromopyridin-4-yloxy)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy]-2,3-dihydrobenzofuran-3-yl}acetic acid methyl ester (70 mg), (S)-tetrahydro-furan-3-ol (23 μL), cesium carbonate (67 mg), copper(I) iodide (1.3 mg), and 3,4,7,8-tetramethyl-1,10-phenanthroline (3.2 mg) in toluene (2 mL) is heated to 120° C. for 24 h. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and washed with water. The organic phase is concentrated in vacuo and used for the next reaction step without further purification.

Intermediate 26 4-(6-Fluoro-pyridin-3-yloxy)-2-methyl-butan-2-ol

A mixture of 6-fluoro-pyridin-3-ol (280 mg), toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester (721 mg), and cesium carbonate (807 mg) in N,N-dimethylformamide (10 mL) is heated to 50° C. for 2 h. The reaction mixture diluted with water and extracted with ethyl acetate. The combined extracts are dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30) to give the title compound. LC (method 5): tR=0.81 min; Mass spectrum (ESI+): m/z=200 [M+H]+.

Intermediate 27 [(S)-6-{(R)-7-Fluoro-4-[5-(3-hydroxy-3-methyl-butoxy)-pyridin-2-yloxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(6-fluoro-pyridin-3-yloxy)-2-methyl-butan-2-ol in N-methyl-2-pyrrolidinon following a procedure analogous to that described for Intermediate 20. The crude product is used for the next reaction step without further purification.

Intermediate 28 {(S)-6-[(R)-7-Fluoro-4-(5-iodo-pyridin-2-yloxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-5-iodo-pyridine following a procedure analogous to that described for Intermediate 24. LC (method 4): tR=1.24 min; Mass spectrum (ESI+): m/z=562 [M+H]+.

Intermediate 29 {(S)-6-[(R)-7-Fluoro-4-{5-[(S)-tetrahydro-furan-3-yloxy}-pyridin-2-yloxy}-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(5-iodo-pyridin-2-yloxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (S)-tetrahydro-furan-3-ol following a procedure analogous to that described for Intermediate 25. The crude product is used for the next reaction step without further purification.

Intermediate 30 5-Bromo-1,3-difluoro-2-(3-methanesulfonyl-propoxy)-benzene

A mixture of 4-bromo-2,6-difluoro-phenol (500 mg), methanesulfonic acid 3-methanesulfonyl-propyl ester (517 mg), and cesium carbonate (1.56 g) in N,N-dimethylacetamide (10 mL) is heated to 80° C. for 3 h. The reaction mixture diluted with water and extracted with ethyl acetate. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→80:20) to give the title compound.

Intermediate 31 2-(3,5-Difluoro-4-(3-(methylsulfonyl)propoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound is prepared from 5-bromo-1,3-difluoro-2-(3-methanesulfonyl-propoxy)-benzene and bis-(pinacolato)-diboron following a procedure analogous to that described for Intermediate 4. Mass spectrum (EI+): m/z=376 [M]+

Intermediate 32 3,5-Difluoro-4-(3-(methylsulfonyl)propoxy)phenylboronic acid

A mixture of 2-(3,5-difluoro-4-(3-(methylsulfonyl)propoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (800 mg), sodium metaperiodate (1.77 g), and ammonium acetate (557 mg) in acetone (5 mL) and water (10 mL) is stirred at room temperature for 2 h. Solids are filtered off and the filtrate is concentrated in vacuo, diluted with water and extracted with ethyl acetate. The combined extracts are concentrated in vacuo and the residue is triturated with cyclohexane, filtered off and dried to give the title compound, which is used without further purification for the next reaction step.

Intermediate 33 [(S)-6-{(R)-4-[3,5-Difluoro-4-(3-methanesulfonyl-propoxy)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3,5-difluoro-4-[3-(methylsulfonyl)propoxy]phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 7): tR=3.50 min; Mass spectrum (ESI+): m/z=607 [M+H]+

Intermediate 34 2-Methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g), cesium carbonate (336 mg), and 2,2-dimethyl-oxirane (5 mL) is heated in a microwave oven to 120° C. for 30 min. The reaction mixture is diluted with ethyl acetate and filtered. The filtrate is concentrated in vacuo to give the title compound, which is used for the next reaction step without further purification.

Intermediate 35 3,5-Difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol

A mixture of 4-bromo-2,3-difluorophenol (707 mg), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (900 mg), potassium carbonate (1.40 g), 2,6-di-tert-butyl-4-methylphenol (373 mg), tricyclohexylphosphine (76 mg), and tris(dibenzylideneacetone)dipalladium(0) (124 mg) in 1,4-dioxane (4 mL) and water (1.5 mg) is heated in a microwave oven under a nitrogen atmosphere to 100° C. for 1 h. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined extracts are concentrated in vacuo and the residue chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→60:40) to give the title compound. Mass spectrum (EI+): m/z=268 [M]+.

Intermediate 36 3,5-Difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)phenyl trifluoromethanesulfonate

The title compound is prepared from 3,5-difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol and trifluoromethanesulfonic anhydride in the presence of triethylamine in dichloromethane. Mass spectrum (EI+): m/z=400 [M]+.

Intermediate 37 1-{4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrazol-1-yl}-2-methyl-propan-2-ol

The title compound is prepared from 3,5-difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)phenyl trifluoromethanesulfonate following a procedure analogous to that described for Intermediate 4. Mass spectrum (EI+): m/z=378 [M]+.

Intermediate 38 3,5-Difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenylboronic acid

The title compound is prepared from 1-{4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrazol-1-yl}-2-methyl-propan-2-ol following a procedure analogous to that described for Intermediate 32. LC (method 8): tR=4.34 min; Mass spectrum (ESI+): m/z=297 [M+H]+

Intermediate 39 {(S)-6-[(R)-4-{3,5-Difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenoxy}-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3,5-difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 7): tR=4.02 min; Mass spectrum (ESI+): m/z=609 [M+H]+

Intermediate 40 {(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-bromophenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.28 min; Mass spectrum (ESI+): m/z=514, 516 [M+H]+

Intermediate 41 {(S)-6-[(R)-7-Fluoro-4-(4-thiazol-2-yl-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

A mixture of {(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (75 mg), 2-thiazolylzinc bromide (584 μL), tetrakis(triphenylphosphine) palladium(0) (17 mg), and tetrahydrofuran (2 mL) under an argon atmosphere is heated to 100° C. for 2 h in a microwave oven. After cooling to room temperature, the reaction mixture is diluted with methanol and filtered. The filtrate is concentrated in vacuo and purified by HPLC on reversed phase using acetonitrile, water and TFA as eluents. LC (method 4): tR=1.24 min; Mass spectrum (ESI+): m/z=518 [M+H]+.

Intermediate 42 [(S)-6-{(R)-7-Fluoro-4-[4-(2-methyl-thiazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

A 2 M aqueous Na2CO3 solution (72 μL) is added to a mixture of {(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (37 mg), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (19 mg), and [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (3.5 mg), in 1,4-dioxane (2 mL). The reaction mixture is heated to 100° C. over night under an argon atmosphere. After cooling to room temperature, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is used for the next reaction step without further purification. LC (method 4): tR=1.22 min; Mass spectrum (ESI+): m/z=532 [M+H]+.

Intermediate 43 [(S)-6-{(R)-7-Fluoro-4-[5-(4-hydroxy-4-methyl-pent-1-enyl)-pyridin-2-yloxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

A mixture of {(S)-6-[(R)-7-fluoro-4-(5-iodo-pyridin-2-yloxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (200 mg), tetrabutylammonium chloride (101 mg), 2-methyl-pent-4-en-2-ol (107 mg), and N,N-diisopropylethylamine (123 mg) in N,N-dimethylformamide (5 mL) is purged with argon for several minutes. Palladium(II) acetate (10 mg) is added and the reaction mixture is heated to 90° C. over night. After cooling to room temperature, the reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in acetonitrile and purified by preparative HPLC. LC (method 2): tR=1.15 min; Mass spectrum (ESI+): m/z=534 [M+H]+.

Intermediate 44 [(S)-6-{(R)-7-Fluoro-4-[5-(4-hydroxy-4-methyl-pentyl)-pyridin-2-yloxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester

The title compound is prepared from [(S)-6-{(R)-7-fluoro-4-[5-(4-hydroxy-4-methyl-pent-1-enyl)-pyridin-2-yloxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester by hydrogenation in the presence of 10% palladium on carbon in methanol at room temperature. The crude product is used for the next reaction step without further purification.

Intermediate 45 (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy]-2,3-dihydro-1H-inden-4-ylboronic acid

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Intermediate 32. LC (method 10): tR=0.52 min; Mass spectrum (ESI+): m/z=387 [M+H]+

Intermediate 46 {(S)-6-[(R)-7-Fluoro-4-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yloxy)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 7-hydroxy-3,4-dihydro-1H-quinoline-2-one following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=1.15 min; Mass spectrum (ESI+): m/z=504 [M+H]+

Intermediate 47 {(S)-6-[(R)-4-(Benzo[d][1,3]dioxol-5-yloxy)-7-fluoro-indan-1-yloxly]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and benzo[1,3]dioxol-5-ol following a procedure analogous to that described for Intermediate 6. LC (method 9): tR=1.23 min; Mass spectrum (ESI+): m/z=479 [M+H]+

Intermediate 48 {(S)-6-[(R)-4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yloxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 2,3-dihydro-benzo[1,4]dioxin-6-ol following a procedure analogous to that described for Intermediate 6. LC (method 9): tR=1.24 min; Mass spectrum (ESI+): m/z=493 [M+H]+

Intermediate 49 ((S)-6-{(R)-4-[4-(3,6-Dihydro-2H-pyran-4-yl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

Step 1: ((S)-6-{(R)-4-[4-(3,6-Dihydro-2H-pyran-4-yl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

A mixture of {(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (22 mg), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (50 mg), K3PO4 (10 mg), and water (10 μL) in tetrahydrofuran (2 mL) is purged with argon. [1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (PEPPSI-IPr, 5 mg) is added and the mixture is heated to 80° C. over night under an argon atmosphere. After cooling to room temperature, the reaction mixture is diluted with diethyl ether, washed with aqueous NH4Cl solution, dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel using petrol ether and ethyl acetate as eluents. LC (method 12): tR=0.93 min; Mass spectrum (ESI+): m/z=539 [M+Na]+.

Step 2: ((S)-6-{(R)-7-Fluoro-4-[4-(tetrahydro-2H-pyran-4-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from ((S)-6-{(R)-4-[4-(3,6-dihydro-2H-pyran-4-yl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester by hydrogenation in the presence of triethylamine and 10% palladium on carbon in tetrahydrofuran at room temperature. LC (method 12): tR=0.93 min; Mass spectrum (ESI+): m/z=541 [M+Na]+

Intermediate 50 ((S)-6-{(R)-7-Fluoro-4-[4-(4-hydroxy-4-methyl pentyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

Step 1: 5-(9-Bora-bicyclo[3.3.1]non-9-yl)-2-methyl-pentan-2-ol

A mixture of 2-methyl-pent-4-en-2-ol (50 mg) and 9-bora-bicyclo[3.3.1]nonane (0.5 M solution in tetrahydrofuran, 1 mL) is stirred for 6 h at room temperature. The solution is used directly for the next step.

Step 2: ((S)-6-{(R)-7-Fluoro-4-[4-(4-hydroxy-4-methylpentyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 5-(9-bora-bicyclo[3.3.1]non-9-yl)-2-methyl-pentan-2-ol (0.45 M solution in tetrahydrofuran) following a procedure analogous to that described for Intermediate 49, Step 1. LC (method 12): tR=0.91 min; Mass spectrum (ESI+): m/z=557 [M+Na]+

Intermediate 51 2,5-Difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol

The title compound is prepared from 4-bromo-2,5-difluorophenol and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol following a procedure analogous to that described for Intermediate 35. Mass spectrum (EI+): m/z=268 [M]+.

Intermediate 52 [(S)-6-((R)-4-{2,5-Difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 2,5-difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol following a procedure analogous to that described for Intermediate 6. Mass spectrum (ESI+): m/z=609 [M+H]+

Intermediate 53 1-(3-Hydroxy-3-methyl-butyl)-1H-indazol-5-ol

Step 1: 4-(5-Benzyloxy-indazol-1-yl)-2-methyl-butan-2-ol

A mixture of 5-benzyloxy-1H-indazole (400 mg) and toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester (507 mg), and potassium carbonate (740 mg) in N,N-dimethylformamide (8 mL) is stirred for 2 days at 60° C. After cooling to room temperature, the mixture is diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→20:80) to give the title compound. LC (method 4): tR=1.04 min; Mass spectrum (ESI+): m/z=311 [M+H]+.

Step 2: 1-(3-Hydroxy-3-methyl-butyl)-1H-indazol-5-ol

The title compound is prepared from 4-(5-benzyloxy-indazol-1-yl)-2-methyl-butan-2-ol by hydrogenation in the presence 10% palladium on carbon in methanol at room temperature. LC (method 4): tR=0.71 min; Mass spectrum (ESI+): m/z=221 [M+H]+

Intermediate 54 ((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yloxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 1-(3-hydroxy-3-methyl-butyl)-1H-indazol-5-ol following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.59 min; Mass spectrum (ESI+): m/z=561 [M+H]+

Intermediate 55 2,6-Difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol

The title compound is prepared from 4-bromo-2,6-difluorophenol and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol following a procedure analogous to that described for Intermediate 35. Mass spectrum (EI+): m/z=268 [M]+.

Intermediate 56 [(S)-6-((R)-4-{2,6-Difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 2,6-difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol following a procedure analogous to that described for Intermediate 6. LC (method 15): tR=4.24 min; Mass spectrum (ESI+): m/z=609 [M+H]+

Intermediate 57 ((S)-6-{(R)-7-Fluoro-4-[4-(2-methylthiazol-4-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 4-(2-methyl-thiazol-4-yl)-phenol following a procedure analogous to that described for Intermediate 6. The crude product is used for the next reaction step without further purification.

Intermediate 58 1-(3-Hydroxy-3-methyl-butyl)-1H-indol-5-ol

Step 1: 4-(5-Benzyloxy-indol-1-yl)-2-methyl-butan-2-ol

The title compound is prepared by treatment of 5-benzyloxy-1H-indole with sodium hydride followed by toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester in N,N-dimethylformamide at 50° C. LC (method 10): tR=0.68 min; Mass spectrum (ESI+): m/z=310 [M+H]+.

Step 2: 1-(3-Hydroxy-3-methyl-butyl)-1H-indol-5-ol

The title compound is prepared from 4-(5-benzyloxy-indol-1-yl)-2-methyl-butan-2-ol by hydrogenation in the presence of triethylamine and 10% palladium on carbon in methanol at room temperature. LC (method 10): tR=0.82 min; Mass spectrum (ESI+): m/z=220 [M+H]+

Intermediate 59 ((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indol-5-yloxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 1-(3-hydroxy-3-methyl-butyl)-1H-indol-5-ol following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.88 min; Mass spectrum (ESI+): m/z=560 [M+H]+

Intermediate 60 2,5-Difluoro-4-(3-hydroxy-3-methyl-butoxy)-phenol

Step 1: 4-(4-Bromo-2,5-difluoro-phenoxy)-2-methyl-butan-2-ol

The title compound is prepared from 4-bromo-2,5-difluoro-phenol and toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a procedure analogous to that described for Intermediate 26. Mass spectrum (EI+): m/z=294 [M]+.

Step 2: 4-[2,5-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methyl-butan-2-ol

The title compound is prepared from 4-(4-bromo-2,5-difluoro-phenoxy)-2-methyl-butan-2-ol and bis-(pinacolato)-diboron following a procedure analogous to that described for Intermediate 4. Mass spectrum (EI+): m/z=342 [M]+

Step 3: 2,5-Difluoro-4-(3-hydroxy-3-methyl-butoxy)-phenol

The title compound is prepared from 4-[2,5-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methyl-butan-2-ol following a procedure analogous to that described for Intermediate 5. Mass spectrum (EI+): m/z=232 [M]+

Intermediate 61 ((S)-6-{(R)-4-[2,5-Difluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 2,5-difluoro-4-(3-hydroxy-3-methyl-butoxy)-phenol following a procedure analogous to that described for Intermediate 6. LC (method 7): tR=4.08 min; Mass spectrum (ESI+): m/z=573 [M+H]+

Intermediate 62 [(S)-6-((R)-7-Fluoro-4-{4-[(tetrahydro-2H-pyran-4-yl)methyl]phenoxy}-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester

Step 1: 4-(9-Bora-bicyclo[3.3.1]non-9-ylmethyl)-tetrahydropyran

A mixture of 4-methylene-tetrahydropyran (50 mg) and 9-bora-bicyclo[3.3.1]nonane (0.5 M solution in tetrahydrofuran, 1 mL) is stirred for 6 h at room temperature. The solution is used directly for the next step.

Step 2: [(S)-6-((R)-7-Fluoro-4-{4-[(tetrahydro-2H-pyran-4-yl)methyl]phenoxy}-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(9-bora-bicyclo[3.3.1]non-9-ylmethyl)-tetrahydropyran (0.45 M solution in tetrahydrofuran) following a procedure analogous to that described for Intermediate 49, Step 1. LC (method 12): tR=0.99 min; Mass spectrum (ESI+): m/z=533 [M+H]+

Intermediate 63 1-(3-Hydroxy-3-methyl-butyl)-1H-indazol-5-ol

Step 1: 4-(6-Benzyloxy-indazol-1-yl)-2-methyl-butan-2-ol

The title compound is prepared from 1H-indazol-6-ol and toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a procedure analogous to that described for Intermediate 53, Step 1. LC (method 4): tR=1.04 min; Mass spectrum (ESI+): m/z=311 [M+H]+.

Step 2: 1-(3-Hydroxy-3-methyl-butyl)-1H-indazol-6-ol

The title compound is prepared from 4-(6-benzyloxy-indazol-1-yl)-2-methyl-butan-2-ol by hydrogenation in the presence 10% palladium on carbon in methanol at room temperature. LC (method 4): tR=0.74 min; Mass spectrum (ESI+): m/z=221 [M+H]+

Intermediate 64 ((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-6-yloxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 1-(3-hydroxy-3-methyl-butyl)-1H-indazol-6-ol following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.65 min; Mass spectrum (ESI+): m/z=561 [M+H]+

Intermediate 65 {(S)-6-[(R)-7-Fluoro-4-(3-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Step 1: {(S)-6-[(R)-4-(4-Benzyloxy-3-fluoro-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 4-benzyloxy-3-fluoro-phenol following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=1.30 min; Mass spectrum (ESI+): m/z=559 [M+H]+

Step 2: {(S)-6-[(R)-7-Fluoro-4-(3-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(4-benzyloxy-3-fluoro-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester by hydrogenation in the presence 10% palladium on carbon in methanol at room temperature. LC (method 4): tR=1.13 min; Mass spectrum (ESI+): m/z=469 [M+H]+

Intermediate 66 [(S)-6-((R)-7-Fluoro-4-{3-fluoro-4-[(4-hydroxytetrahydro-2H-pyran-4-yl)methoxy]-phenoxy}-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester

A mixture of {(S)-6-[(R)-7-fluoro-4-(3-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (32 mg), 1,6-dioxa-spiro[2.5]octane (8 mg), and cesium carbonate (24 mg) in N,N-dimethylformamide (2 mL) is heated to 80° C. over night. The reaction mixture is cooled to room temperature and used directly for the next step. LC (method 4): tR=1.15 min; Mass spectrum (ESI+): m/z=583 [M+H]+

Intermediate 67 ((S)-6-{(R)-7-Fluoro-4-[4-(1-methyl-1H-imidazol-2-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 4-(1-methyl-1H-imidazol-2-yl)-phenol following a procedure analogous to that described for Intermediate 6. The crude product is used for the next reaction step without further purification.

Intermediate 68 2,5-Difluoro-4-(3-methanesulfonyl-propoxy)-phenol

Step 1: 1-Bromo-2,5-difluoro-4-(3-methylsulfanyl-propoxy)-benzene

A solution of 4-bromo-2,5-difluoro-phenol (2.00 g) in tetrahydrofuran is cooled in an ice bath. Di-tert-butyl azodicarboxylate (2.42 g), triphenylphosphine (2.76 g), and 3-methylthiopropanol (0.99 mL) are added and the resulting solution is stirred for 30 min at 0° C. The solvent is removed in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→80:20) to give the title compound. Mass spectrum (EI+): m/z=296 [M]+.

Step 2: 1-Bromo-2,5-difluoro-4-(3-methanesulfonyl-propoxy)-benzene

The title compound is prepared from 1-bromo-2,5-difluoro-4-(3-methylsulfanyl-propoxy)-benzene by oxidation with potassium peroxomonosulfate in a mixture of water and tetrahydrofuran at room temperature. Mass spectrum (EI+): m/z=328 [M]+.

Step 3: 2-[2,5-Difluoro-4-(3-methanesulfonyl-propoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

The title compound is prepared from 1-bromo-2,5-difluoro-4-(3-methanesulfonyl-propoxy)-benzene and bis-(pinacolato)-diboron following a procedure analogous to that described for Intermediate 4. Mass spectrum (EI+): m/z=376 [M]+.

Step 4: 2,5-Difluoro-4-(3-methanesulfonyl-propoxy)-phenol

The title compound is prepared from 2-[2,5-difluoro-4-(3-methanesulfonyl-propoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane following a procedure analogous to that described for Intermediate 5. LC (method 7): tR=1.94 min; Mass spectrum (ESI−): m/z=265 [M−H]−.

Intermediate 69 [(S)-6-((R)-4-{2,5-Difluoro-4-[3-(methlsulfonyl)propoxl]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 2,5-difluoro-4-(3-methanesulfonyl-propoxy)-phenol following a procedure analogous to that described for Intermediate 6. LC (method 7): tR=3.82 min; Mass spectrum (ESI+): m/z=607 [M+H]+

Intermediate 70 ((S)-6-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and [4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.87 min; Mass spectrum (ESI+): m/z=587 [M+Na]+.

Intermediate 71 ((S)-6-{(R)-4-[2-Cyano-5-(4-hydroxy-4-methyl pentyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

Step 1: {(S)-6-[(R)-4-(5-Bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-bromo-2-fluoro-benzonitrile following a procedure analogous to that described for Intermediate 24. LC (method 12): tR=0.87 min; Mass spectrum (ESI+): m/z=538, 540 [M+H]+.

Step 2: ((S)-6-{(R)-4-[2-Cyano-5-(4-hydroxy-4-methylpentyl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(5-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester and 2-methyl-pent-4-en-2-ol following a procedure analogous to that described for Intermediate 62 (Step 1 and 2). LC (method 12): tR=0.77 min.

Intermediate 72 {(S)-6-[(R)-4-(2-Cyano-5-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester

Step 1: ((S)-6-{(R)-4-[2-Cyano-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(5-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester and bis-(pinacolato)-diboron following a procedure analogous to that described for Intermediate 4. LC (method 12): tR=0.43 min; Mass spectrum (ESI+): m/z=586 [M+H]+.

Step 2: {(S)-6-[(R)-4-(2-Cyano-5-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Intermediate 5. LC (method 12): tR=0.50 min; Mass spectrum (ESI+): m/z=476 [M+H]+.

Intermediate 73 ((S)-6-{(R)-4-[2-Cyano-5-(3-hydroxy-3-methylbutoxy)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(2-cyano-5-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester and toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a procedure analogous to that described for Intermediate 8. LC (method 12): tR=0.71 min; Mass spectrum (ESI+): m/z=562 [M+H]+.

Intermediate 74 {(S)-6-[(R)-4-(3-Cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester

Step 1: 4-(tert-Butyl-dimethyl-silanyloxy)-3-cyano-phenyl-boronic acid

Triisopropyl borate (1.77 mL) is added to a solution of 5-bromo-2-(tert-butyl-dimethyl-silanyloxy)-benzonitrile (800 mg) in tetrahydrofuran (12 mL) and the mixture is cooled to −78° C. n-Butyllithium (15% in hexane; 1.92 mL) is added and the reaction mixture is stirred at −78° C. for 3 h. More n-butyllithium (15% in hexane; 0.2 mL) is added and the mixture is allowed to warm to −50° C., and stirred at this temperature for 1.5 h. Hydrochloric acid (1M, 4.9 mL) is added and the mixture is allowed to warm to room temperature. After 1 h the reaction mixture is diluted with brine and extracted with diethyl ether. The combined extracts are concentrated in vacuo, diluted with hexane, stirred for 30 min, and left standing over night at room temperature. The white precipitate is filtered off, washed with hexane, and dried in vacuo to give the title compound. LC (method 4): tR=1.08 min; Mass spectrum (ESI+): m/z=278 [M+H]+

Step 2: ((S)-6-{(R)-4-[4-(tert-Butyl-dimethyl-silanyloxy)-3-cyano-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(tert-butyl-dimethyl-silanyloxy)-3-cyano-phenyl-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 9): tR=1.35 min; Mass spectrum (ESI+): m/z=590 [M+H]+.

Step 3: {(S)-6-[(R)-4-(3-Cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from ((S)-6-{(R)-4-[4-(tert-butyl-dimethyl-silanyloxy)-3-cyano-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester by treatment with tetrabutylammonium fluoride in tetrahydrofuran at room temperature. LC (method 9): tR=1.14 min; Mass spectrum (ESI+): m/z=476 [M+H]+.

Intermediate 75 ((S)-6-{(R)-4-[3-Cyano-4-((R)-tetrahydrofuran-3-yloxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(3-cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester and toluene-4-sulfonic acid (S)-tetrahydro-furan-3-yl ester following a procedure analogous to that described for Intermediate 8. LC (method 9): tR=1.20 min; Mass spectrum (ESI+): m/z=546 [M+H]+.

Intermediate 76 ((S)-6-{(R)-4-[3-Cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(3-cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester and toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a procedure analogous to that described for Intermediate 8. LC (method 9): tR=1.20 min; Mass spectrum (ESI+): m/z=562 [M+H]+.

Intermediate 77 {(S)-6-[(R)-7-Fluoro-4-(2-fluoro-5-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Step 1: {(S)-6-[(R)-7-Fluoro-4-(5-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 5-bromo-202-fluoro-phenol following a procedure analogous to that described for Intermediate 6. LC (method 12): tR=0.99 min; Mass spectrum (ESI+): m/z=531, 533 [M+H]+

Step 2: ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(5-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and bis-(pinacolato)-diboron following a procedure analogous to that described for Intermediate 4. LC (method 10): tR=1.13 min; Mass spectrum (ESI+): m/z=579 [M+H]+.

Step 3: {(S)-6-[(R)-7-Fluoro-4-(2-fluoro-5-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Intermediate 5. LC (method 10): tR=0.67 min; Mass spectrum (ESI+): m/z=469 [M+H]+.

Intermediate 78 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-5-(3-hydroxy-3-methylbutoxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(2-fluoro-5-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a procedure analogous to that described for Intermediate 8. LC (method 10): tR=0.84 min; Mass spectrum (ESI+): m/z=555 [M+H]+.

Intermediate 79 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-5-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(2-fluoro-5-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and tetrahydro-pyran-4-ol following a procedure analogous to that described for Intermediate 3. LC (method 10): tR=0.92 min; Mass spectrum (ESI+): m/z=575 [M+Na]+.

Intermediate 80 {(S)-6-[(R)-4-(2-Cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Step 1: {(S)-6-[(R)-4-(4-Benzyloxy-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 5-benzyloxy-2-hydroxy-benzonitrile following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.99 min; Mass spectrum (ESI+): m/z=566 [M+H]+

Step 2: {(S)-6-[(R)-4-(2-Cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(4-benzyloxy-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester by hydrogenation in the presence 10% palladium on carbon in methanol at room temperature. LC (method 10): tR=0.61 min; Mass spectrum (ESI+): m/z=476 [M+H]+

Intermediate 81 ((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(2-cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a procedure analogous to that described for Intermediate 8. LC (method 10): tR=0.77 min; Mass spectrum (ESI+): m/z=562 [M+H]+.

Intermediate 82 {(S)-6-[(R)-4-(4-Bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 5-bromo-2-fluoro-benzonitrile following a procedure analogous to that described for Intermediate 24. LC (method 12): tR=0.88 min; Mass spectrum (ESI+): m/z=538, 540 [M+H]+.

Intermediate 83 ((S)-6-{(R)-4-[2-Cyano-4-(1-methyl-1H-pyrazol-5-yl)phenoxy-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester

A mixture of {(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (80 mg), 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (62 mg), K3PO4 (95 mg), toluene (2 mL), and water (200 μL) is purged with argon for 10 min. Palladium(II) acetate (3 mg) and dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane (SPhos; 10 mg) are added and the reaction mixture is stirred at 90° C. under an argon atmosphere for two days. After cooling to room temperature, the reaction mixture is diluted with aqueous NH4Cl solution and extracted with diethyl ether. The combined extracts are dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 85:15→50:50) to give the title compound. LC (method 10): tR=0.70 min; Mass spectrum (ESI+): m/z=540 [M+H]+.

Intermediate 84 ((S)-6-{(R)-4-[2-Cyano-4-(3,5-dimethylisoxazol-4-yl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3,5-dimethylisoxazole-4-boronic acid following a procedure analogous to that described for Intermediate 83. LC (method 10): tR=0.81 min; Mass spectrum (ESI+): m/z=555 [M+H]+.

Intermediate 85 {(S)-6-[(R)-7-Fluoro-4-(2-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Step 1: {(S)-6-[(R)-7-Fluoro-4-(4-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 4-bromo-2-fluoro-phenol following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=1.05 min; Mass spectrum (ESI+): m/z=531, 533 [M+H]+

Step 2: ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and bis-(pinacolato)-diboron following a procedure analogous to that described for Intermediate 4. LC (method 10): tR=1.14 min; Mass spectrum (ESI+): m/z=579 [M+H]+.

Step 3: {(S)-6-[(R)-7-Fluoro-4-(2-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Intermediate 5. LC (method 10): tR=0.67 min; Mass spectrum (ESI+): m/z=469 [M+H]+.

Intermediate 86 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(2-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and tetrahydro-pyran-4-ol following a procedure analogous to that described for Intermediate 3. LC (method 13): tR=0.81 min; Mass spectrum (ESI+): m/z=575 [M+Na]+.

Intermediate 87 ((S)-6-{(R)-4-[4-Cyano-3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(4-cyano-3-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-bromo-tetrahydropyran following a procedure analogous to that described for Intermediate 8. The crude product is used for the next reaction step without further purification.

Intermediate 88 ((S)-6-{(R)-4-[4-Cyano-3-(2-hydroxy-2-methylpropoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(4-cyano-3-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and isobutylene oxide in N,N-dimethylformamide in the presence of Cs2CO3 at 80° C. The crude product is used for the next reaction step without further purification.

Intermediate 89 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(2-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a procedure analogous to that described for Intermediate 8. LC (method 13): tR=0.74 min; Mass spectrum (ESI+): m/z=577 [M+Na]+.

Intermediate 90 ((S)-6-{(R)-4-[4-(3,5-Dimethylisoxazol-4-yl)-2-fluorophenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3,5-dimethylisoxazole-4-boronic acid following a procedure analogous to that described for Intermediate 83. LC (method 13): tR=0.82 min; Mass spectrum (ESI+): m/z=548 [M+H]+.

Intermediate 91 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole following a procedure analogous to that described for Intermediate 83. LC (method 13): tR=0.70 min; Mass spectrum (ESI+): m/z=533 [M+H]+.

Intermediate 92 ((S)-6-{(R)-4-[2-Cyano-4-(4-hydroxy-4-methyl pentyl)phenoxy-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-pent-4-en-2-ol following a procedure analogous to that described for Intermediate 62 (Step 1 and 2). LC (method 12): tR=0.78 min. Mass spectrum (ESI+): m/z=560 [M+H]+.

Intermediate 93 ((S)-6-{(R)-7-Fluoro-4-[3-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 1-(3-hydroxy-phenyl)-pyrrolidin-2-one following a procedure analogous to that described for Intermediate 6. LC (method 9): tR=1.18 min; Mass spectrum (ESI+): m/z=518 [M+H]+.

Intermediate 94 ((S)-6-{(R)-7-Fluoro-4-[4-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 1-(4-hydroxy-phenyl)-pyrrolidin-2-one following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=1.14 min; Mass spectrum (ESI+): m/z=518 [M+H]+.

Intermediate 95 ((S)-6-{(R)-7-Fluoro-4-[4-(pyrrolidin-1-ylmethyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 4-pyrrolidin-1-ylmethyl-phenol following a procedure analogous to that described for Intermediate 6. LC (method 9): tR=0.95 min; Mass spectrum (ESI+): m/z=518 [M+H]+.

Intermediate 96 ((S)-6-{(R)-4-[4-(Cyanomethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 4-hydroxybenzyl cyanide following a procedure analogous to that described for Intermediate 6. LC (method 9): tR=1.19 min; Mass spectrum (ESI+): m/z=474 [M+H]+.

Intermediate 97 ((S)-6-{(R)-4-[4-(2-Cyanoethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from (R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy}-2,3-dihydro-1H-inden-4-ylboronic acid and 3-(4-hydroxy-phenyl)-propionitrile following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=1.18 min; Mass spectrum (ESI+): m/z=488 [M+H]+.

Intermediate 98 ((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methylbutyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

Step 1: ((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methyl-but-1-enyl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

A mixture of {(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (5 mg), 2-methyl-but-3-en-2-ol (30 mg), and triethylamine (50 μL) in N,N-dimethylformamide (0.5 mL) is purged with argon for 10 min. Palladium(II) acetylacetonate (5 mg) is added and the reaction mixture is stirred over night at 90° C. under an argon atmosphere. After cooling to room temperature, the reaction mixture is diluted with diethyl ether and washed with aqueous NH4Cl solution. The organic phase is dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (petrol ether/ethyl acetate) to give the title compound. LC (method 12): tR=0.68 min; Mass spectrum (ESI+): m/z=544 [M+H]+

Step 2: ((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methylbutyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(3-hydroxy-3-methyl-but-1-enyl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester by hydrogenation in the presence of triethylamine and 10% palladium on carbon in tetrahydrofuran at room temperature. LC (method 12): tR=0.71 min; Mass spectrum (ESI+): m/z=546 [M+H]+

Intermediate 99 4-[(R)-7-Fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofuran-6-yloxy)-indan-4-yloxy]1-benzoic acid

Step 1: 4-[(R)-7-Fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofuran-6-yloxy)-indan-4-yloxy]-benzoic acid benzyl ester

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(benzyloxycarbonyl)-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 9): tR=1.30 min; Mass spectrum (ESI+): m/z=569 [M+H]+.

Step 2: 4-[(R)-7-Fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofuran-6-yloxy)-indan-4-yloxy]-benzoic acid

The title compound is prepared from 4-[(R)-7-fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofuran-6-yloxy)-indan-4-yloxy]-benzoic acid benzyl ester by hydrogenation in the presence of 10% palladium on carbon in ethyl acetate at room temperature. LC (method 9): tR=1.13 min; Mass spectrum (ESI+): m/z=479 [M+H]+.

Intermediate 100 ((S)-6-{(R)-4-[4-(Dimethylcarbamoyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (58 mg) is added to a mixture of 4-[(R)-7-fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofuran-6-yloxy)-indan-4-yloxy]-benzoic acid (78 mg) and ethyldiisopropylamine (85 μL) in N,N-dimethylformamide (2 mL). The resulting mixture is stirred at room temperature for 30 min. Dimethylamine (2 M in tetrahydrofuran; 85 μL) is added and the reaction mixture is stirred at room temperature for 2 h. The crude product is used without further purification for the next reaction step. LC (method 9): tR=1.14 min; Mass spectrum (ESI+): m/z=506 [M+H]+.

Intermediate 101 ((S)-6-{(R)-7-Fluoro-4-[4-(morpholine-4-carbonyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from 4-[(R)-7-fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofuran-6-yloxy)-indan-4-yloxy]-benzoic acid and morpholine following a procedure analogous to that described for Intermediate 100. LC (method 9): tR=1.13 min; Mass spectrum (ESI+): m/z=548 [M+H]+.

Intermediate 102 ((S)-6-{(R)-4-[2-Cyano-4-(2,6-dimethylpyridin-4-yl)phenoxy)]-7-fluoro-indan-1-yloxy)}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

Step 1: ((S)-6-{(R)-4-[2-Cyano-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and bis-(pinacolato)-diboron following a procedure analogous to that described for Intermediate 4. LC (method 10): tR=1.06 min.

Step 2: ((S)-6-{(R)-4-[2-Cyano-4-(2,6-dimethylpyridin-4-yl)phenoxy)]-7-fluoro-indan-1-yloxy)}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester and 4-bromo-2,6-dimethyl-pyridine following a procedure analogous to that described for Intermediate 83, using [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) as catalyst. LC (method 17): tR=0.70 min; Mass spectrum (ESI+): m/z=565 [M+H]+.

Intermediate 103 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(6-methylpyridin-2-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester and 2-bromo-6-methyl-pyridine following a procedure analogous to that described for Intermediate 83, using [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) as catalyst. LC (method 10): tR=0.97 min; Mass spectrum (ESI+): m/z=544 [M+H]+.

Intermediate 104 ((S)-6-{(R)-4-[4-(2,6-Dimethylpyridin-4-yl)-2-fluorophenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester and 4-bromo-2,6-dimethyl-pyridine following a procedure analogous to that described for Intermediate 83, using [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) as catalyst. LC (method 17): tR=0.82 min; Mass spectrum (ESI+): m/z=558 [M+H]+.

Intermediate 105 ((S)-6-{(R)-4-[2-Cyano-4-(6-methylpyridin-2-yl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester and 2-bromo-6-methyl-pyridine following a procedure analogous to that described for Intermediate 83, using [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) as catalyst. LC (method 10): tR=0.90 min; Mass spectrum (ESI+): m/z=551 [M+H]+.

Intermediate 106 {(S)-6-[(R)-4-(2-Cyano-4-formyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

Step 1: {6-[4-(2-Cyano-4-vinyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

A mixture of {(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (320 mg), potassium vinyltrifluoroborate (200 mg), Cs2CO3 (600 mg), and water (100 μL) in toluene (5 mL) is purged with argon. 1,1′-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) (30 mg) is added and the reaction mixture is heated over night to 100° C. under an argon atmosphere in an autoclave. After cooling to room temperature, the reaction mixture is diluted with diethyl ether, washed with aqueous NH4Cl solution, dried over MgSO4, and concentrated in vacuo. The residue is purified by silica gel chromatography (petrol ether/ethyl acetate) to give the title compound. LC (method 12): tR=0.86 min; Mass spectrum (ESI+): m/z=486 [M+H]+.

Step 2: {(S)-6-[(R)-4-(2-Cyano-4-formyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester

A mixture of {6-[4-(2-cyano-4-vinyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (165 mg), osmium tetroxide (4% in water; 100 μL), and water (0.5 mL) in 1,4-dioxane (5 mL) is stirred at room temperature for 30 min. Sodium (meta)periodate (400 mg) is added and the mixture is stirred at room temperature for 4 h. The mixture is diluted with diethyl ether, washed with aqueous sodium thiosulfate solution, dried over MgSO4, and concentrated in vacuo. The crude product is used for the next reaction step without further purification. LC (method 12): tR=0.67 min; Mass spectrum (ESI+): m/z=488 [M+H]+.

Intermediate 107 {(S)-6-[(R)-4-(2-Cyano-4-(piperidin-1-ylmethyl)phenoxy]-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester

A mixture of {(S)-6-[(R)-4-(2-cyano-4-formyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (50 mg) and piperidine (60 mg) in 1,2-dichloroethane (2 mL) is stirred for 1 h at room temperature. Sodium triacetoxyborohydride (50 mg) is added and the reaction mixture is stirred over night at room temperature. The mixture is diluted with diethyl ether, washed with aqueous NaHCO3 solution, dried over MgSO4, and concentrated in vacuo. The residue is purified by MPLC to give the title compound. LC (method 4): tR=1.00 min; Mass spectrum (ESI+): m/z=557 [M+H]+.

Intermediate 108 ((S)-6-{(R)-4-[2-Cyano-4-(morpholin-4-ylmethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester

The title compound is prepared from {(S)-6-[(R)-4-(2-cyano-4-formyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and morpholine following a procedure analogous to that described for Intermediate 107. LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=559 [M+H]+.

Example 1 [(S)-6-{(R)-7-Fluoro-4-[4-(2-methoxy-ethoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

1 M aqueous NaOH solution (0.7 mL) is added to a solution of [(S)-6-{(R)-7-fluoro-4-[4-(2-methoxy-ethoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester (62 mg) in methanol (2 mL) and tetrahydrofuran (2 mL) at room temperature. The mixture is stirred at room temperature for 6 h. The organic solvent is evaporated, water is added, and the resulting mixture is neutralized with 1 M aqueous HCl solution (0.7 mL). The solution is stirred at room temperature for 0.5 h.

The precipitate is separated by filtration, washed with water and dried to give the title compound. LC (method 3): tR=0.39 min; Mass spectrum (ESI−): m/z=493 [M−H]−.

Example 2 [(S)-6-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-{(R)-7-fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 3): tR=0.41 min; Mass spectrum (ESI−): m/z=521 [M−H]−.

Example 3 [(S)-6-{(R)-7-Fluoro-4-[4-(2-hydroxy-2-methyl-propoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-{(R)-7-fluoro-4-[4-(2-hydroxy-2-methyl-propoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 3): tR=0.35 min; Mass spectrum (ESI+): m/z=531 [M+Na]+.

Example 4 [(S)-6-{(R)-7-Fluoro-4-[4-(3-methanesulfonyl-propoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid

The title compound is prepared from [(S)-6-{(R)-7-fluoro-4-[4-(3-methanesulfonyl-propoxy)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 3): tR=0.22 min; Mass spectrum (ESI+): m/z=557 [M+H]+.

Example 5 {(S)-6-[(R)-7-Fluoro-4-(4-morpholin-4-ylmethyl-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4-morpholin-4-ylmethyl-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=0.87 min; Mass spectrum (ESI−): m/z=518 [M−H]−.

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

The title compound is prepared {(S)-6-[(R)-4-(3-acetylamino-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=1.01 min; Mass spectrum (ESI−): m/z=476 [M−H]−.

Example 7 [(S)-6-{(R)-4-[3-(Acetylamino-methyl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

The title compound is prepared [(S)-6-{(R)-4-[3-(acetylamino-methyl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=0.99 min; Mass spectrum (ESI−): m/z=490 [M−H]−.

Example 8 {(S)-6-[(R)-4-(4-Acetylamino-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

The title compound is prepared {(S)-6-[(R)-4-(4-acetylamino-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=1.00 min; Mass spectrum (ESI−): m/z=476 [M−H]−.

Example 9 [(S)-6-{(R)-7-Fluoro-4-[4-(pyrrolidine-1-carbonyl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

The title compound is prepared [(S)-6-{(R)-7-fluoro-4-[4-(pyrrolidine-1-carbonyl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=1.06 min; Mass spectrum (ESI+): m/z=518 [M+H]+.

Example 10 {(S)-6-[(R)-7-Fluoro-4-(4-imidazol-1-yl-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

The title compound is prepared {(S)-6-[(R)-7-fluoro-4-(4-imidazol-1-yl-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=0.89 min; Mass spectrum (ESI+): m/z=487 [M+H]+.

Example 11 {(S)-6-[(R)-4-(2,3-Dihydro-benzofuran-5-yloxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

The title compound is prepared from {(S)-6-[(R)-4-(2,3-dihydro-benzofuran-5-yloxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=1.13 min; Mass spectrum (ESI+): m/z=463 [M+H]+.

Example 12 {(S)-6-[(R)-4-(4-Ethylcarbamoyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

The title compound is prepared from {(S)-6-[(R)-4-(4-ethylcarbamoyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=1.01 min; Mass spectrum (ESI−): m/z=490 [M−H]−.

Example 13 [(S)-6-{(R)-7-Fluoro-4-[4-(1H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-{(R)-7-fluoro-4-[4-(1H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=0.99 min; Mass spectrum (ESI−): m/z=487 [M−H]−.

Example 14 [(S)-6-{(R)-7-Fluoro-4-[4-(1-methyl-1H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-{(R)-7-fluoro-4-[4-(1-methyl-1H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=1.04 min; Mass spectrum (ESI−): m/z=501 [M−H]−.

Example 15 [(S)-6-{(R)-7-Fluoro-4-[4-(2-methyl-2H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-{(R)-7-fluoro-4-[4-(2-methyl-2H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=1.10 min; Mass spectrum (ESI−): m/z=501 [M−H]−.

Example 16 {(S)-6-[(R)-7-fluoro-4-{2-[(S)-tetrahydro-furan-3-yloxy]-pyridin-4-yloxy}-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-{2-[(S)-tetrahydro-furan-3-yloxy]-pyridin-4-yloxy}-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=1.09 min; Mass spectrum (ESI−): m/z=506 [M−H]−.

Example 17 [(S)-6-{(R)-7-Fluoro-4-[5-(3-hydroxy-3-methyl-butoxy)-pyridin-2-yloxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-{(R)-7-fluoro-4-[5-(3-hydroxy-3-methyl-butoxy)-pyridin-2-yloxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. Mass spectrum (ESI−): m/z=522 [M−H]−.

Example 18 {(S)-6-[(R)-7-Fluoro-4-{5-[(S)-tetrahydro-furan-3-yloxy}pyridin-2-yloxy}-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-{5-[(S)-tetrahydro-furan-3-yloxy}-pyridin-2-yloxy}-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=1.05 min; Mass spectrum (ESI−): m/z=506 [M−H]−.

Example 19 [(S)-6-{(R)-4-[3,5-Difluoro-4-(3-methanesulfonyl-propoxy)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-{(R)-4-[3,5-difluoro-4-(3-methanesulfonyl-propoxy)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 7): tR=2.76 min; Mass spectrum (ESI+): m/z=593 [M+H]+.

Example 20 {(S)-6-[(R)-4-{3,5-Difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenoxy}-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

The title compound is prepared from {(S)-6-[(R)-4-{3,5-difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenoxy}-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 7): tR=2.89 min; Mass spectrum (ESI+): m/z=595 [M+H]+.

Example 21 {(S)-6-[(R)-7-Fluoro-4-(4-thiazol-2-yl-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4-thiazol-2-yl-phenoxy)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=1.15 min; Mass spectrum (ESI+): m/z=504 [M+H]+.

Example 22 [(S)-6-{(R)-7-Fluoro-4-[4-(2-methyl-thiazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-{(R)-7-fluoro-4-[4-(2-methyl-thiazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=1.13 min; Mass spectrum (ESI+): m/z=518 [M+H]+.

Example 23 [(S)-6-{(R)-7-Fluoro-4-[5-(4-hydroxy-4-methyl-pentyl)-pyridin-2-yloxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-{(R)-7-fluoro-4-[5-(4-hydroxy-4-methyl-pentyl)-pyridin-2-yloxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 6): tR=0.39 min; Mass spectrum (ESI+): m/z=522 [M+H]+.

Example 24 {(S)-6-[(R)-7-Fluoro-4-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yloxy)-indan-1-yloxly]-2,3-dihydrobenzofuran-3-yl}-acetic acid

The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yloxy)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.05 min; Mass spectrum (ESI+): m/z=490 [M+H]+.

Example 25 {(S)-6-[(R)-4-(Benzo[d][1,3]dioxol-5-yloxy)-7-fluoro-indan-1-yloxly]-2,3-dihydrobenzofuran-3-yl}-acetic acid

The title compound is prepared from {(S)-6-[(R)-4-(benzo[d][1,3]dioxol-5-yloxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.15 min; Mass spectrum (ESI+): m/z=465 [M+H]+.

Example 26 {(S)-6-[(R)-4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yloxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid

The title compound is prepared from {(S)-6-[(R)-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yloxy)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.14 min; Mass spectrum (ESI+): m/z=479 [M+H]+.

Example 27 ((S)-6-{(R)-7-Fluoro-4-[4-(tetrahydro-2H-pyran-4-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[4-(tetrahydro-2H-pyran-4-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 11): tR=1.37 min; Mass spectrum (ESI−): m/z=503 [M−H]−.

Example 28 ((S)-6-{(R)-7-Fluoro-4-[4-(4-hydroxy-4-methyl pentyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[4-(4-hydroxy-4-methylpentyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 12): tR=0.69 min; Mass spectrum (ESI+): m/z=521 [M+H]+.

Example 29 [(S)-6-((R)-4-{2,5-Difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-((R)-4-{2,5-difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 7): tR=3.06 min; Mass spectrum (ESI+): m/z=595 [M+H]+.

Example 30 ((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yloxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yloxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=1.07 min; Mass spectrum (ESI+): m/z=547 [M+H]+.

Example 31 [(S)-6-((R)-4-{2,6-Difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenoxy}-157-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-((R)-4-{2,6-difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 7): tR=3.03 min; Mass spectrum (ESI+): m/z=595 [M+H]+.

Example 32 ((S)-6-{(R)-7-Fluoro-4-[4-(2-methylthiazol-4-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[4-(2-methylthiazol-4-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=0.94 min; Mass spectrum (ESI+): m/z=518 [M+H]+.

Example 33 ((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indol-5-yloxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indol-5-yloxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 10): tR=0.73 min; Mass spectrum (ESI+): m/z=546 [M+H]+.

Example 34 ((S)-6-{(R)-4-[2,5-Difluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[2,5-difluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 7): tR=3.11 min; Mass spectrum (ESI+): m/z=559 [M+H]+.

Example 35 [(S)-6-((R)-7-Fluoro-4-{4-[(tetrahydro-2H-pyran-4-yl)methyl]phenoxy}-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-((R)-7-Fluoro-4-{4-[(tetrahydro-2H-pyran-4-yl)methyl]phenoxy}-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 12): tR=0.79 min; Mass spectrum (ESI+): m/z=519 [M+H]+.

Example 36 ((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-6-yloxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-6-yloxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=1.08 min; Mass spectrum (ESI+): m/z=547 [M+H]+.

Example 37 [(S)-6-((R)-7-Fluoro-4-{3-fluoro-4-[(4-hydroxytetrahydro-2H-pyran-4-yl)-methoxy]phenoxy}-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-((R)-7-fluoro-4-{3-fluoro-4-[(4-hydroxytetrahydro-2H-pyran-4-yl)methoxy]phenoxy}-indan-1-yloxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.08 min; Mass spectrum (ESI+): m/z=569 [M+H]+.

Example 38 ((S)-6-{(R)-7-Fluoro-4-[4-(1-methyl-1H-imidazol-2-yl)phenoxy]1-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[4-(1-methyl-1H-imidazol-2-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 13): tR=0.34 min; Mass spectrum (ESI+): m/z=501 [M+H]+.

Example 39 [(S)-6-((R)-4-{2,5-Difluoro-4-[3-(methlsulfonyl)propoxl]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid

The title compound is prepared from [(S)-6-((R)-4-{2,5-difluoro-4-[3-(methylsulfonyl)-propoxy]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 14): tR=2.42 min; Mass spectrum (ESI−): m/z=591 [M−H]−.

Example 40 ((S)-6-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methylbutoxy)-2,6-dimethyl phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 3): tR=0.61 min; Mass spectrum (ESI+): m/z=551 [M+H]+.

Example 41 ((S)-6-{(R)-4-[2-Cyano-5-(4-hydroxy-4-methyl pentyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-5-(4-hydroxy-4-methylpentyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 12): tR=0.50 min; Mass spectrum (ESI+): m/z=546 [M+H]+.

Example 42 ((S)-6-{(R)-4-[2-Cyano-5-(3-hydroxy-3-methylbutoxy)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-5-(3-hydroxy-3-methylbutoxy)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 12): tR=0.41 min; Mass spectrum (ESI+): m/z=548 [M+H]+.

Example 43 ((S)-6-{(R)-4-[3-Cyano-4-((R)-tetrahydrofuran-3-yloxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[3-cyano-4-((R)-tetrahydrofuran-3-yloxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.11 min; Mass spectrum (ESI+): m/z=532 [M+H]+.

Example 44 ((S)-6-{(R)-4-[3-Cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[3-cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.11 min; Mass spectrum (ESI+): m/z=548 [M+H]+.

Example 45 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-5-(3-hydroxy-3-methylbutoxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[2-fluoro-5-(3-hydroxy-3-methylbutoxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 10): tR=0.60 min; Mass spectrum (ESI+): m/z=541 [M+H]+.

Example 46 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-5-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[2-fluoro-5-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 10): tR=0.68 min; Mass spectrum (ESI+): m/z=539 [M+H]+.

Example 47 ((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 10): tR=0.52 min; Mass spectrum (ESI+): m/z=548 [M+H]+.

Example 48 ((S)-6-{(R)-4-[2-Cyano-4-(1-methyl-1H-pyrazol-5-yl)phenoxy]-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(1-methyl-1H-pyrazol-5-yl)phenoxy]-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 13): tR=0.26 min; Mass spectrum (ESI+): m/z=526 [M+H]+.

Example 49 ((S)-6-{(R)-4-[2-Cyano-4-(3,5-dimethylisoxazol-4-yl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(3,5-dimethylisoxazol-4-yl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 13): tR=0.47 min; Mass spectrum (ESI+): m/z=541 [M+H]+.

Example 50 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 13): tR=0.59 min; Mass spectrum (ESI+): m/z=539 [M+H]+.

Example 51 ((S)-6-{(R)-4-[4-Cyano-3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[4-cyano-3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.13 min; Mass spectrum (ESI+): m/z=546 [M+H]+.

Example 52 ((S)-6-{(R)-4-[4-Cyano-3-(2-hydroxy-2-methylpropoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[4-cyano-3-(2-hydroxy-2-methylpropoxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.09 min; Mass spectrum (ESI+): m/z=534 [M+H]+.

Example 53 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 13): tR=0.47 min; Mass spectrum (ESI+): m/z=541 [M+H]+.

Example 54 ((S)-6-{(R)-4-[4-(3,5-Dimethylisoxazol-4-yl)-2-fluorophenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[4-(3,5-dimethylisoxazol-4-yl)-2-fluorophenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 10): tR=0.71 min; Mass spectrum (ESI+): m/z=534 [M+H]+.

Example 55 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 10): tR=0.54 min; Mass spectrum (ESI+): m/z=519 [M+H]+.

Example 56 ((S)-6-{(R)-4-[2-Cyano-4-(4-hydroxy-4-methyl pentyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(4-hydroxy-4-methylpentyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 12): tR=0.52 min; Mass spectrum (ESI−): m/z=544 [M−H]−.

Example 57 ((S)-6-{(R)-7-Fluoro-4-[3-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[3-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.09 min; Mass spectrum (ESI+): m/z=504 [M+H]+.

Example 58 ((S)-6-{(R)-7-Fluoro-4-[4-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[4-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=1.05 min; Mass spectrum (ESI+): m/z=504 [M+H]+.

Example 59 ((S)-6-{(R)-7-Fluoro-4-[4-(pyrrolidin-1-ylmethyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[4-(pyrrolidin-1-ylmethyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=0.89 min; Mass spectrum (ESI+): m/z=504 [M+H]+.

Example 60 ((S)-6-{(R)-4-[4-(Cyanomethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[4-(cyanomethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.10 min; Mass spectrum (ESI+): m/z=460 [M+H]+.

Example 61 ((S)-6-{(R)-4-[4-(2-Cyanoethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[4-(2-cyanoethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=1.09 min; Mass spectrum (ESI+): m/z=474 [M+H]+.

Example 62 ((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methylbutyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(3-hydroxy-3-methylbutyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 12): tR=0.41 min; Mass spectrum (ESI+): m/z=532 [M+H]+.

Example 63 ((S)-6-{(R)-4-[4-(Dimethylcarbamoyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[4-(dimethylcarbamoyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.04 min; Mass spectrum (ESI+): m/z=492 [M+H]+.

Example 64 ((S)-6-{(R)-7-Fluoro-4-[4-(morpholine-4-carbonyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[4-(morpholine-4-carbonyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1. LC (method 9): tR=1.03 min; Mass spectrum (ESI+): m/z=534 [M+H]+.

Example 65 ((S)-6-{(R)-4-[2-Cyano-4-(2,6-dimethylpyridin-4-yl)phenoxy)]-7-fluoro-indan-1-yloxy)}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(2,6-dimethylpyridin-4-yl)phenoxy)]-7-fluoro-indan-1-yloxy)}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 16): tR=0.85 min; Mass spectrum (ESI+): m/z=551 [M+H]+.

Example 66 ((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(6-methylpyridin-2-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(6-methylpyridin-2-yl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 10): tR=0.74 min; Mass spectrum (ESI+): m/z=530 [M+H]+.

Example 67 ((S)-6-{(R)-4-[4-(2,6-Dimethylpyridin-4-yl)-2-fluorophenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[4-(2,6-dimethylpyridin-4-yl)-2-fluorophenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 16): tR=0.87 min; Mass spectrum (ESI+): m/z=544 [M+H]+.

Example 68 ((S)-6-{(R)-4-[2-Cyano-4-(6-methylpyridin-2-yl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(6-methylpyridin-2-yl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 10): tR=0.67 min; Mass spectrum (ESI+): m/z=537 [M+H]+.

Example 69 {(S)-6-[(R)-4-(2-Cyano-4-(piperidin-1-ylmethyl)phenoxy]-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid

The title compound is prepared from {(S)-6-[(R)-4-(2-cyano-4-(piperidin-1-ylmethyl)phenoxy]-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 18): tR=0.58 min; Mass spectrum (ESI+): m/z=543 [M+H]+.

Example 70 ((S)-6-{(R)-4-[2-Cyano-4-(morpholin-4-ylmethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid

The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(morpholin-4-ylmethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a procedure analogous to that described for Example 1, using KOH as base and ethanol as solvent. LC (method 19): tR=0.62 min; Mass spectrum (ESI+): m/z=545 [M+H+.

The following compounds are obtained from the respective methyl ester employing the procedure described for Example 1. The methyl esters of the following compounds are prepared from either {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and the corresponding phenyl or heteroaryl boronic acid following a procedure analogous to that described for Intermediate 6, or {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and the corresponding fluoro-benzene or heteroaryl fluoride following a procedure analogous to that described for Intermediate 20. The individual (Het)Ar groups used in the coupling reaction, bearing either a boronic acid group or fluorine atom, are prepared using the procedures described above or other methods known to the skilled man and described in the literature. Alternatively, the residue attached to the (Het)Ar group, already linked to the rest of the molecule via the O in compounds I, is elaborated from an appropriate precursor group, e.g., iodine, bromine or chlorine atom or hydroxy group, using routinely employed proceedings described in the literature of organic chemistry and in the experimental part above.

Claims

1. A compound of formula (I)

wherein:
(Het)Ar is linked via a carbon atom and is selected from the group consisting of: phenyl, naphthyl, and a mono- or bicyclic heteroaromatic group having 5 to 10 ring member atoms of which 2 to 9 ring members are carbon atoms and either (i) one ring member is an unsubstituted or substituted heteroatom selected from N, NH, NRN, O, S, S(═O), and S(═O)2, (ii) one ring member is N and a second ring member is selected from N, NH, NRN, O, S, S(═O), and S(═O)2, or (iii) two ring members are N and a third ring member is selected from N, NH, NRN, O, S, S(═O), and S(═O)2, wherein in the naphthyl, the ring not attached to the indanyl-O atom of formula (I) optionally is partially saturated, and in the bicyclic heteroaromatic group, the ring not attached to the indanyl-O atom of formula (I) optionally is partially saturated, while the aromatic ring includes at least one heteroatom, and optionally (i) one ring member in the partially or fully saturated bridge is replaced by N, NH, NRN, O, S, S(═O), or S(═O)2, (ii) one ring member in the partially or fully saturated bridge is replaced by N, NH, or NRN and a second ring member is replaced by NH, NRN, O, S, C(═O), S(═O), or S(═O)2, or (iii) two not vicinal ring members in a fully saturated bridge are replaced by O atoms, wherein any of these groups is substituted with 1 group R2 or 1 NH group is replaced by an NR2 group and any of these groups is optionally and independently substituted with 1 to 4 R3 groups; or
(Het)Ar is selected from the group consisting of 2,3-dihydroindole, 2,3-dihydroisoindole, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, benzo[1,3]dioxole, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, chroman, isochroman, and 2,3-dihydrobenzo[1,4]dioxine, wherein any of these groups is linked via an aromatic carbon atom to the indanyloxy group in formula (I), and wherein in each of these bicyclic groups, 1 CH2 group is optionally replaced by C(═O) and each of these bicyclic groups is optionally substituted with 1 R2 group and optionally independently substituted with 1 to 4 R3 groups;
R1 is H, F, Cl, F3C—, NC—, F3C—O—, or H3C—S(═O)2—;
R2 is C1-6-alkyl, C2-6-alkenyl, C2-6-alkinyl, C3-6-cycloalkyl-, C1-4-alkyl-NH—, (C1-4-alkyl)2N—, C1-6-alkyl-O—, C3-6-cycloalkyl-O—, C1-4-alkyl-S—, C1-4-alkyl-S(═O)—, or C1-4-alkyl-S(═O)2, wherein each alkyl and cycloalkyl group is substituted with 1 to 3 groups independently selected from R4 and optionally substituted with 1 or more F atoms; or
R2 is C1-4-alkyl-C(═O)—, heterocyclyl-C(═O)—, HNRN—C(═O)—, C1-4-alkyl-NRN—C(═O)—, C3-6-cycloalkyl-NRN—C(═O)—, heterocyclyl-NRN—C(═O)—, phenyl-NRN—C(═O)—, heteroaryl-NRN—C(═O)—, HO2C—, C1-4-alkyl-O—C(═O)—, C3-6-cycloalkyl-O—C(═O)—, heterocyclyl-O—C(═O)—, —NHRN, C1-4-alkyl-C(═O)NRN—, C3-6-cycloalkyl-C(═O)NRN—, heterocyclyl-C(═O)NRN—, phenyl-C(═O)NRN—, heteroaryl-C(═O)NRN—, C1-4-alkyl-S(═O)2NRN—, C3-6-cycloalkyl-S(═O)2NRN—, heterocyclyl-S(═O)2NRN—, phenyl-S(═O)2NRN—, heteroaryl-S(═O)2NRN—, heterocyclyl-O—, phenyl-O—, heteroaryl-O—, C3-6-cycloalkyl-S—, heterocyclyl-S—, phenyl-S—, heteroaryl-S—, C3-6-cycloalkyl-S(═O)—, heterocyclyl-S(═O)—, phenyl-S(═O)—, heteroaryl-S(═O)—, C3-6-cycloalkyl-S(═O)2—, heterocyclyl-S(═O)2—, phenyl-S(═O)2—, heteroaryl-S(═O)2—, HNRN—S(═O)2—, C1-4-alkyl-NRN—S(═O)2—, heterocyclyl, phenyl, or heteroaryl, wherein each alkyl, cycloalkyl, and heterocyclyl group is optionally substituted with 1 to 3 groups independently selected from R4 and optionally substituted with 1 or more F atoms, each phenyl and heteroaryl group is optionally substituted with 1 to substituents independently selected from R5, heterocyclyl is (i) a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by NRN, NR4, O, S, S(═O), or S(═O)2 and/or 1>CH— group is replaced by N, or (ii) 1 CH2 group is replaced by NRN, NR4, O— or S, and/or 1>CH— group is replaced by N, and 1 additional CH2 group is replaced by C(═O) or S(═O)2, and heteroaryl is (i) tetrazolyl, (ii) pyridinonyl, (iii) a 5-membered heteroaromatic ring containing 1 ring member selected from NRN, NR5, N, O, and S, or containing 1 N and 1 ring member selected from NRN, NR5, N, O, and S, or containing 1 NRN, NR5, N, O, or S and 2 N, or (iv) a 6-membered heteroaromatic ring which contains 1 to 3 N atoms, with the proviso that R2 is not C1-4-alkyl-, C1-4-alkyl-O—C1-4-alkyl, HO—C1-4-alkyl, C2-4-alkenyl, C2-4-alkinyl, NH2, C1-4-alkyl-NH—, (C1-4-alkyl)2N—, C1-4-alkyl-O—, C1-4-alkyl-S—, C1-4-alkyl-S(═O)—, or C1-4-alkyl-S(═O)2;
R3 is F, Cl, Br, I, CN, OH, C1-4-alkyl, C3-6-cycloalkyl, HO—C1-4-alkyl, C1-4-alkyl-O—C1-4-alkyl, —NRNH, C1-4-alkyl-NRN—, C1-4-alkyl-O—, C3-6-cycloalkyl-O—, C1-4-alkyl-O—C1-4-alkyl-O—, C1-4-alkyl-S—, C1-4-alkyl-S(═O)—, or C1-4-alkyl-S(═O)2—, wherein any alkyl and cycloalkyl group is optionally substituted with 1 or more F atoms;
R4 is Cl, Br, I, C1-4-alkyl, CN, C3-6-cycloalkyl, C1-4-alkyl-C(═O)—, heterocyclyl-C(═O)—, H2N—C(═O)—, C1-4-alkyl-NRN—C(═O)—, C3-6-cycloalkyl-NRN—C(═O)—, heterocyclyl-NRN—C(═O)—, phenyl-NRN—C(═O)—, heteroaryl-NRN—C(═O)—, HO—C(═O)—, C1-4-alkyl-O—C(═O)—, —NHRN, C1-4-alkyl-NRN—, C1-4-alkyl-C(═O)NRN—, C3-6-cycloalkyl-C(═O)NRN—, heterocyclyl-C(═O)NRN—, phenyl-C(═O)NRN—, heteroaryl-C(═O)NRN—, C1-4-alkyl-S(═O)2NRN—, C3-6-cycloalkyl-S(═O)2NRN—, heterocyclyl-S(═O)2NRN—, phenyl-S(═O)2NRN—, heteroaryl-S(═O)2NRN—, —OH, C1-4-alkyl-O—, C1-4-alkyl-O—C1-4-alkyl-O—, C3-6-cycloalkyl-O—, heterocyclyl-O—, phenyl-O—, heteroaryl-O—, C1-4-alkyl-S—, C3-6-cycloalkyl-S—, heterocyclyl-S—, phenyl-S—, heteroaryl-S—, C1-4-alkyl-S(═O)—, C3-6-cycloalkyl-S(═O)—, heterocyclyl-S(═O)—, phenyl-S(═O)—, heteroaryl-S(═O)—, C1-4-alkyl-S(═O)2—, C3-6-cycloalkyl-S(═O)2—, heterocyclyl-S(═O)2—, phenyl-S(═O)2—, heteroaryl-S(═O)2—, H2N—S(═O)2—, C1-4-alkyl-NRN—S(═O)2—, heterocyclyl, phenyl, or heteroaryl, wherein any alkyl, cycloalkyl, and heterocyclyl group is optionally substituted with 1 or more F atoms and optionally substituted with 1 or 2 groups independently selected from H3C—, HO—, H3C—O—, and —CN, heterocyclyl is a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by NRN, O, S, S(═O), or S(═O)2 and/or 1>CH— group is replaced by N, or 1 CH2 group is replaced by NRN, O, or S, and/or 1>CH— group is replaced by N, and 1 additional CH2 group is replaced by C(═O) or S(═O)2, and heteroaryl is (i) tetrazolyl, (ii) pyridinonyl, (iii) a 5-membered heteroaromatic ring containing 1 ring member selected from NRN, O, and S, or containing 1 N and 1 ring member selected from NRN, O, and S, or containing 1 NRN, O or S and 2 N, and (iv) a 6-membered heteroaromatic ring which contains 1 to 3 N atoms, and each heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from F, Cl, —CH3, —CN, and —O—CH3;
R5 is F, Cl, Br, CN, C1-4-alkyl, cyclopropyl, F3C—, HO—C1-4-alkyl-, C1-4-alkyl-O—C1-4-alkyl-, C1-4-alkyl-O—, F3C—O—, —S(═O)—C1-4-alkyl, or S(═O)2—C1-4-alkyl; and
RN is H, C1-4-alkyl, C1-4-alkyl-C(═O)—, C1-4-alkyl-NH—C(═O)—, C1-4-alkyl-N(C1-4-alkyl)-C(═O)—, C1-4-alkyl-O—C(═O)—, or C1-4-alkyl-S(═O)2—,
wherein any alkyl group or sub-group is straight-chained or branched, unless specified otherwise,
or a salt thereof.

2. The compound according to claim 1, wherein R1 is H, or a salt thereof.

3. The compound according to claim 1, wherein (Het)Ar is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, indolinyl, benzoimidazolyl, indazolyl, benzoxazolyl, or benzothiazolyl, each substituted with one group R2 and optionally substituted with 1 to 3 groups independently selected from R3, or (Het)Ar is 2,3-dihydrobenzofuran, benzo[1,3]dioxole, 2,3-dihydro-benzo[1,4]dioxine, or 3,4-dihydro-1H-quinoline-2-one, each optionally substituted with 1 group R3, or a salt thereof.

4. The compound according to claim 1, wherein (Het)Ar is phenyl substituted with one group R2 and optionally substituted with 1 to 3 groups independently selected from R3, or a salt thereof.

5. The compound according to claim 1, wherein R3 is F, —CH3, or CN, or a salt thereof.

6. The compound according to claim 1, wherein:

R2 is C1-4-alkyl, C3-6-cycloalkyl-, C1-4-alkyl-O—, or C3-6-cycloalkyl-O—, wherein each alkyl and cycloalkyl group is substituted with 1 group selected from R4 and optionally substituted with 1 or 2 C1-3-alkyl and/or 1 to 3 F atoms;
R2 is heterocyclyl-C(═O)—, H2N—C(═O)—, C1-3-alkyl-NRN—C(═O)—, C1-4-alkyl-C(═O)NRN—, C3-6-cycloalkyl-C(═O)NRN—, heterocyclyl-C(═O)NRN—, C1-4-alkyl-S(═O)2NRN—, heterocyclyl-O—, heteroaryl-O—, heterocyclyl-S(═O)2—, H2N—S(═O)2—, heterocyclyl, phenyl, or heteroaryl, wherein each alkyl, cycloalkyl, and heterocyclyl group is optionally substituted with 1 group selected from R4 and optionally substituted with 1 or 2-CH3 groups and/or 1 to 3 F atoms, each phenyl and heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from R5, heterocyclyl is selected from a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by NRN or O and/or 1>CH— group is replaced by N, and 1 additional CH2 group is optionally replaced by C(═O), heteroaryl is selected from tetrazolyl, a 5-membered heteroaromatic ring containing 1 ring member selected from NRN, NR5, O, and S, or containing 1 N and 1 ring member selected from NRN, NR5, O, and S, or containing 1 NRN, NR5, O, or S and 2 N, and a 6-membered heteroaromatic ring which contains 1 to 2 N atoms, with the proviso that R2 is not C1-4-alkyl-, C1-4-alkyl-O—C1-4-alkyl, HO—C1-4-alkyl, or C1-4-alkyl-O—,
or a salt thereof.

7. The compound according to claim 1, wherein:

R2 is selected from the group consisting of NC—C1-2-alkyl-, HO—C5-6-alkyl-, tetrahydropyranyl-CH2—, pyrrolidin-1-yl-CH2—, piperidin-1-yl-CH2—, morpholin-4-yl-CH2—, H3C—C(═O)—NH—CH2—, C1-2-alkyl-NH—C(═O)—, (C1-2-alkyl)2N—C(═O)—, pyrrolidin-1-yl-C(═O)—, morpholin-4-yl-C(═O)—, H3C—C(═O)—NH—, pyrrolidin-2-on-1-yl, HO—C2-5-alkyl-O—, H3C—O—C2-4-alkyl-O—, H3C—S(═O)2—C1-3-alkyl-O—, tetrahydrofuranyl-O—, tetrahydropyranyl-O—, tetrahydropyranyl, and tetrahydropyranyl-CH2—O— optionally substituted with one HO— group, and pyridinyl, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, and tetrazolyl, wherein each heteroaryl group is optionally substituted with 1 or 2 H3C— groups or 1 HO—C(CH3)2—CH2— group,
or a salt thereof.

8. The compound according to claim 1, wherein:

(Het)Ar is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, indolinyl, benzoimidazolyl, indazolyl, benzoxazolyl, or benzothiazolyl, each substituted with one group R2 and optionally substituted with 1 to 3 groups independently selected from R3; or
(Het)Ar is 2,3-dihydrobenzofuran, benzo[1,3]dioxole, 2,3-dihydro-benzo[1,4]dioxine, or 3,4-dihydro-1H-quinoline-2-one, each optionally substituted with 1 group R3;
R1 is H;
R2 is C1-4-alkyl, C3-6-cycloalkyl-, C1-4-alkyl-O—, or C3-6-cycloalkyl-O—, wherein each alkyl and cycloalkyl group is substituted with 1 group selected from R4 and optionally substituted with 1 or 2 H3C— group;
R2 is heterocyclyl-C(═O)—, H2N—C(═O)—, C1-2-alkyl-NH—C(═O)—, (C1-2-alkyl)2N—C(═O)—, C1-3-alkyl-C(═O)—NH—, heterocyclyl-O—, heteroaryl-O—, heterocyclyl, or heteroaryl, wherein each heterocyclyl group is optionally substituted with 1 group selected from R4 and optionally substituted with 1 additional H3C— group, each heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from R5, heterocyclyl is selected from a C4-6-cycloalkyl group wherein 1 CH2 group is replaced by O and/or 1>CH— group is replaced by N, and 1 additional CH2 group is optionally replaced by C(═O), and heteroaryl is pyridinyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or tetrazolyl; with the proviso that R2 is not C1-4-alkyl-, C1-4-alkyl-O—C1-4-alkyl, HO—C1-4-alkyl, or C1-4-alkyl-O—;
R3 is F, —CH3, or CN;
R4 is C1-2-alkyl-, —CN, H2N—C(═O)—, —C(═O)NHCH3, —C(═O)N(CH3)2, —N(CH3)2, H3C—C(═O)NH—, H3C—S(═O)2NH—, —OH, C1-3-alkyl-O—, heterocyclyl-O—, H3C—S(═O)—, H3C—S(═O)2—, heterocyclyl, or heteroaryl, wherein heterocyclyl is oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, or morpholin-4-yl, wherein each of these rings is optionally substituted with 1 CH3 or 1 OH group, and heteroaryl is selected from imidazolyl, pyrazolyl, oxazolyl, or triazolyl, each optionally substituted with 1 or 2-CH3 groups; and
R5 is F, —CH3, HO—C(CH3)2—CH2—, —CF3, —CN, or —OCH3;
or a salt thereof.

9. The compound according to claim 8, wherein (Het)Ar is phenyl substituted with one group R2 and optionally substituted with 1 to 3 groups independently selected from R3, or a salt thereof.

10. A pharmaceutically acceptable salt of the compound according to claim 1.

11. A pharmaceutical composition comprising a compounds according to claim 1 or a pharmaceutically acceptable salt thereof, and an inert carrier or diluent.

12. A method for treating diseases or conditions which can be influenced by the modulation of the function of GPR40 in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. (canceled)

14. A method of treating metabolic diseases and conditions associated with the disease in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to claim 11, further comprising an additional therapeutic agents.

16. The pharmaceutical composition according to claim 15, wherein the additional therapeutic agents is selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and/or obesity, and agents for the treatment of high blood pressure, heart failure, and/or atherosclerosis.

Patent History
Publication number: 20140163025
Type: Application
Filed: Dec 2, 2013
Publication Date: Jun 12, 2014
Applicant: BOEHRINGER INGELHEIM INTERNATIONAL GMBH (Ingelheim am Rhein)
Inventors: Matthias ECKHARDT (Biberach an der Riss), Sara FRATTINI (Castelleone), Elke LANGKOPF (Biberach an der Riss), Holger WAGNER (Mettenberg)
Application Number: 14/093,583