New phosphoglicerate dehydrogenase inhibitors for the treatment of fibrosis

Abstract

The present invention generally relates to compounds of general formula (I) inhibiting 3- phosphoglycerate dehydrogenase (hereinafter PHGDH) receptor; the invention relates to compounds, including pharmaceutically acceptable salts thereof, and their use for the prevention and / or treatment of fibrosis, in particular idiopathic pulmonary fibrosis (IPF), as sole agent or in combinations with other active ingredients, as well as to the use of pharmaceutical compositions and combinations comprising said compounds.

Description

NEW PHOSPHOGLICERATE DEHYDROGENASE INHIBITORS FOR THE TREATMENT OF FIBROSIS FIELD OF INVENTION The present invention generally relates to compounds of general formula (I) inhibiting 3- phosphoglycerate dehydrogenase (hereinafter PHGDH) receptor; the invention relates to compounds, including pharmaceutically acceptable salts thereof, and their use for the prevention and / or treatment of fibrosis, in particular idiopathic pulmonary fibrosis (IPF), as sole agent or in combinations with other active ingredients, as well as to the use of pharmaceutical compositions and combinations comprising said compounds. BACKGROUND OF THE INVENTION 3-phosphoglycerate dehydrogenase (PHGDH) is the enzyme that catalyzes the first rate- limiting step in the de novo biosynthesis of L-serine starting from glucose, which is the conversion of 3-phosphoglycerate into 3-phosphohydroxypyruvate with a reduction of nicotinamide adenine dinucleotide (NAD+) to NADH, and it is considered as a major enzyme in the diversion of glycolysis towards serine synthesis. Serine, a critical amino acid for protein and nucleic acid biosynthesis, in turn is metabolized and incorporated into a variety of biomolecules including glycine (see Yang M., Vousden, K H., Nature Reviews Cancer 2016,16, 650–662). PHGDH is required to promote collagen protein synthesis. Indeed, glycine accounts for one- third of all amino acids within the collagen molecule, and the high content of glycine is critical for the stabilization of collagen helix. Collagen is the main structural protein in the extracellular space, and it is produced in excess in IPF patients during fibroblasts into myofibroblasts differentiation that accumulates within the fibrotic tissue and leads to loss of organ architecture and function. Moreover, PHGDH and the serine / glycine synthesis pathway is part of a wider network which links glycolysis with one-carbon metabolism and nucleotide synthesis contributing to cell proliferation in pathologies such as inflammation and fibrosis. Therefore, the PHGDH inhibition has the potential to reduce the aberrant production and release of collagen such as inhibit cell proliferation (see Selvarajah et al., Science Signaling, 2019;12(582):eaav 3048). Various compounds have been described in the literature as potent PHGDH inhibitors. Raze Therapeutics disclosed in various patent applications (for example WO2017156179) compounds which are effective as orthosteric PHGDH inhibitors, and their use in the treatment of many PHGDH-mediated disorders, in particular melanoma, breast, or lung cancer.Examples of PHGDH inhibitors useful for treating proliferative diseases, benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases are disclosed in WO2016115463 (Whitehead Institute For Biomedical Research; Dana-Farber Cancer Institute, Inc). Fibrosis is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodeling and the formation of permanent scar tissue (see Wynn, Thomas A., 2004 Nature Reviews 4 (8): 583–594). Fibrosis can occur in many tissues within the body, typically as a result of inflammation or damage, and examples include liver, lungs, kidney, brain and heart. Idiopathic pulmonary fibrosis (IPF) is a rare, progressive illness of the respiratory system, characterized by the thickening and stiffening of lung tissue, associated with the formation of scar tissue. It is a type of chronic scarring lung disease characterized by a progressive and irreversible decline in lung function. (see HR, Egan JJ, et al. American Journal of Respiratory and Critical Care Medicine, 2011, 183 (6): 788–824). Despite the above prior art, there remains a potential for developing novel medicaments comprising a PHGDH inhibitor suitable for oral administration, useful for the prevention and / or treatment of fibrosis, in particular IPF. The underlying problem of the present invention therefore lies in the provision of a medicament comprising a compound of formula (I) as herein disclosed, for the prevention and / or treatment of fibrosis, in particular IPF, and at the same time a good oral profile, obtainable with a suitable BSEP (Bile Salt Export Pump inhibition) profile and good permeability. In this respect, the state of the art does not describe or suggest derivatives of general formula (I) of the present invention having inhibitory activity on PHGDH which demonstrate good results in assays for the prevention and / or treatment of fibrosis, in particular IPF, and at the same time a suitable BSEP profile and a good permeability, which represent a solution to the aforementioned need. SUMMARY OF THE INVENTION In a first aspect the(I)wherein R2is H or absent; R1is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)alkyl- OR7, heteroaryl and -(C3-C7)heterocycloalkyl or when R2is absent, R1is fused to the C* to form a spiro -(C3-C7)cycloalkyl or -(C3- C7)heterocycloalkyl; R3is halogen or -(C1-C6)alkyl; R4is H or F; R5is H or selected from the group consisting of halogen, -OR7and -(C1-C6)alkyl, wherein said -(C1-C6)alkyl is optionally substituted by -(C3-C7)heterocycloalkyl; R6and R7are independently H or -(C1-C6)alkyl, wherein said -(C1-C6)alkyl is optionally substituted by -(C3-C7)heterocycloalkyl; R8is H or -(C1-C6)alkyl; and pharmaceutically acceptable salts thereof. In a second aspect, the invention refers to a pharmaceutical composition comprising a compound of formula (I) in a mixture with one or more pharmaceutically acceptable carrier or excipient. In a third aspect, the invention refers to a compound of formula (I) for use as medicament. In a further aspect, the invention refers to a compound of formula (I) for use in the prevention and / or treatment of fibrosis and / or diseases, disorders, or conditions that involve fibrosis. In a further aspect, the invention refers to a compound of formula (I) for use in the prevention and / or treatment idiopathic pulmonary fibrosis (IPF). DETAILED DESCRIPTION OF THE INVENTION Unless otherwise provided, the term “compound of formula (I)” comprises in its meaning solvates, stereoisomers, tautomers, deuterated and pharmaceutically acceptable salts or solvates thereof. The term “pharmaceutically acceptable salts”, as used herein, refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or basic group, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable. Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic basic addition salts of acid residues such as carboxylic groups. Cations of inorganic bases which can be suitably used to prepare salts comprise ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.Those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric acid, hydrobromic acid, iodic acid, formic acid, benzoic acid, sulfuric acid, nitric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, nitric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, p-toluenesulfonic acid, trifluoroacetic acid, 2-naphthoic acid, tartaric acid, 1-hydroxy-2- naphthoic acid, naphthalene-2,7-disulfonic acid and citric acid. The term "solvate" means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate might be isolated by crystallization, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvate may comprise either a stoichiometric or non-stoichiometric amount of the solvent molecules. The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable. The term "diastereomer " refers to stereoisomers that are not mirror images. The term "racemate" or "racemic mixture" refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity. When one of the compounds of this invention is defined as a specific enantiomer or diastereoisomer, the number reported in the name of this specific enantiomer or diastereoisomer is intended to define the order of elution of the compound during any process of chiral separation. For example, a compound defined as “Diastereoisomer 1” is intended to be the first eluted compound in the above-described chiral separation process. In case of separation of 4 diastereoisomers by two different chromatographic methods, a compound defined as “Diastereoisomer 1” is intended to be the first eluted compound in the first chiral separation mentioned, while a compound defined as “Diastereoisomer 3” is intended to be the first eluted compound in the second chiral separation mentioned. The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom(s) and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)). The term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchanged by migration of an atom or group within the molecule. The term “H” refers to hydrogen.The term "deuterium" refers to the isotopic deuterium of hydrogen (H). The term "deuterated" refers to the case where the hydrogen atoms on an alkyl, cycloalkyl, aryl, heteroaryl group are substituted by at least one isotopic deuterium, with the upper limit of the number of deuterium substituents being equal to the sum of the number of hydrogen atoms that can be substituted. Unless otherwise indicated, the number of deuterium substituents is any integer between 1 and said upper limit, preferably substitution by 1 to 20 deuterium atoms, more preferably 1 to 10 deuterium atoms, more preferably 1 to 6 deuterium atoms, and further preferably 1 to 3 deuterium atoms. The term “halogen” or “halogen atoms” or “halo” as used herein includes fluorine, chlorine, bromine and iodine atom. The term “F” refers to fluorine. The term "(Cx-Cy)alkyl" wherein x and y are integers, refers to a straight or branched chain alkyl group having from x to y carbon atoms. Thus, when x is 1 and y is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n- hexyl. The term “(Cx-Cy)haloalkyl” wherein x and y are integers, refers to the above defined “(Cx- Cy)alkyl” groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which can be the same or different. Examples of said “(Cx-Cy)haloalkyl” groups may thus include halogenated, poly-halogenated and fully halogenated alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, e.g. trifluoromethyl. The term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined. The term “(Cx-Cy)cycloalkyl” wherein x and y are integers, refers to saturated or partially unsatured mono- or poly-cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The term “(Cx-Cy)heterocycloalkyl” wherein x and y are integers, refers to saturated or partially unsaturated monocyclic or polycyclic groups containing the indicated number of ring carbon atoms in which at least one ring carbon atom is replaced by at least one heteroatom or hetero-group (e.g. N, NH, S or O) or may bear an oxo (=O) substituent group. The said heterocycloalkyl (i.e. heterocyclic radical or group) might be further optionally substituted on the available positions in the ring, namely on a carbon atom, or on a heteroatom or hetero-group available for substitution. Substitution on a carbon atom includes spiro di-substitution as well as substitution on two adjacent carbon atoms, in both cases thus forming an additional condensed 5- to 6-membered heterocyclic ring. Non limiting examples of “(Cx-Cy)heterocycloalkyl” arerepresented by morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, thiomorpholinyl, pyrrolinyl, dihydro- or tetrahydro-thiazolyl, oxetanyl, tetrahydropyranyl, pyranyl, dihydro- or tetrahydro-furanyl. The term “aryl” refers to mono- or bi-cyclic carbon ring systems wherein the ring is aromatic. Examples of suitable aryl ring systems include, for instance, phenyl or naphthyl. The term “heteroaryl” refers to mono- or bi- or tri-cyclic ring systems with 5 to 20, preferably from 5 to 15 ring atoms, in which at least one ring is aromatic and in which at least one ring atom is a heteroatom (e.g. N, NH, S or O). Examples of “heteroaryl” include thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, dihydrobenzofuranyl, triazinyl. A group may be optionally substituted, wherein the term “optionally substituted” refers to being substituted or unsubstituted. When the term "one or more " refers to any atoms or groups as substituents of the groups of the compound of formula (I), it is intended that from 1 to 3, preferably 1 to 2, more preferably 1 of such substituents may replace hydrogens on such variables. A bond pointing to a wavy or squiggly line, such asused in structural formulas herein, depicts the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. The term "bond" used to define a substituent refers to the situation where the two functional groups which the substituent is connected to are directly linked to each other with no additional atoms in between. The carbonyl group is herein preferably represented as -(CO)- as an alternative to the other common representations such as -CO-, C=O, -C(O)- or -C(=O)-. A dashis not between two letters or symbols is meant to represent the point of attachment for a substituent. Whenever basic amino or quaternary ammonium groups are present in the compounds of formula (I), pharmaceutically acceptable anions may be present, selected among chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate, emipamoate, xinafoate and naphthalene disulfonate. Likewise, in the presence of acidic groups, such as for instance COOH groups, corresponding pharmaceutically acceptable cations may be present, for instance including alkaline or alkaline earth metal ions, including sodium, potassium, calcium and the like. The term “IC50” refers to the half maximal inhibitory concentration as a measure of the potency of a substance in inhibiting a specific biological or biochemical function.The term “pIC50” refers to the negative logarithm of the IC50 value expressed as molar concentration. The term “PHGDH” or “phosphoglycerate dehydrogenase”, is alternatively referred to as 3- PGDH, 3PGDHm HEL-S-113, NLS, PDG, PGAD, PGD, PGDH, PHGDHD, or SERA. The term “PHGDH” encompasses mutants, variants, homologs, fragments, and synthetically modified phosphoglycerate dehydrogenases. The term “treating”, or “treatment” of a disease state includes: (i) inhibiting the disease state, i.e. arresting the development of the disease state or its clinical symptoms, or (ii) relieving the disease state, i.e. causing temporary or permanent regression of the disease state or its clinical symptoms. The term “preventing”, or “prevention” of a disease state includes causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state but does not yet experience or display symptoms of the disease state. For example, treating or preventing a respiratory disease or disorder includes treating or preventing the symptoms the disorder such as cough and / or urge to cough associated with a respiratory disease. The term “therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to affect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route, and form of administration. The terms "fibrosis" or "fibrotic disorder," as used herein, refers to conditions that are associated with the abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract. As above indicated, the present invention relates to compounds of formula (I) which are inhibitors of the PHGDH receptor and demonstrate desirable characteristics in vitro and in vivo that make them suitable for the prevention and / or treatment of fibrosis, preferably idiopathic pulmonary fibrosis (IPF). In particular, the present invention relates to PHGDH inhibitors of general formula (I), or pharmaceutically acceptable salts thereof, to be used for the prevention and / or treatment of fibrosis or fibrotic conditions. As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits PHGDH with measurable affinity. In certain embodiments, an inhibitor has an IC50 and / or binding constant of less than about 100 μΜ, less than about 50 μΜ, less than about 1 μΜ, less than about500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. In other embodiments, an inhibitor has a pIC50on phenotypic assays of 5.5, or between 5.5 and 6.5, or higher than 6.5. The compounds of formula (I) of the present invention are able to act as inhibitors of PHGDH receptor in a substantive and effective way, particularly appreciated by the skilled person when looking at a suitable and efficacious compound useful for the treatment of many disorders associated with fibrosis, and in particular the treatment of idiopathic pulmonary fibrosis (IPF). As indicated in the Experimental part, the antifibrotic activity of the compounds of formula (I) has been monitored measuring the expression of fibrotic mediators, such as for example alpha smooth muscle actin (α-SMA). As can be appreciated in Table 20 of the experimental part, the compounds of formula (I) are able not only to reduce the fibroblast to myofibroblast transition (FMT) induced by TGF-β, but also to inhibit the release of α-SMA in NHLF treated with TGF-β (10ng / ml). In this respect, all the tested compounds, dose-dependently, reduce the expression of α-SMA, after 72 hours of incubation. The antifibrotic activity of compounds of formula (I) has been demonstrated also measuring the expression of collagen I (Col-I), known fibrotic mediator, in Fibroblast to myofibroblast transition (FMT) in in vitro assay. Collagen is a downstream effector of the PHGDH pathway, and its inhibition underlines the key role of this marker in fibrosis processes. As reported in the Table 20, the tested compounds dose-dependently inhibit the collagen I deposition, after 72h of treatment. These findings suggest that de novo synthesis of serine and glycine is required for pulmonary fibrosis; the inhibition of myofibroblast differentiation and collagen deposition is strongly correlated and necessary for the antifibrotic activity of the compounds. As further advantage, the compounds of the present invention may result efficacious also in the Bleomycin-induced pulmonary fibrosis in mice. Bleomycin-induced pulmonary fibrosis in mice is the most commonly applied in vivo experimental model to induce lung fibrosis. Instillation of Bleomycin in the trachea induces a multiphasic response that starts with an acute and severe inflammation followed by a diffuse matrix and collagen deposition that led to histological changes, with evident fibrosis accumulation and loss of functional parenchymal tissue, replicating certain pathological features consistent with those observed in the lungs of IPF patients. Indeed, the bleomycin animal model is widely used in the assessment of potential antifibrotic agents. More advantageously, beyond the inhibitory property versus PHGDH, the compounds of the present invention are also endowed with a suitable BSEP inhibition profile, that is relevant for the progression of any oral drug candidate.Liver toxicity is a relatively frequent finding during preclinical safety testing in animals and is an important cause of compound attrition prior to clinical trials (Waring, M.J. et al. Nat. Rev. Drug Discov.14, 475–486 (2015)). Bile salt export pump (BSEP) inhibition has emerged as an important mechanism that may contribute to the initiation of human drug-induced liver injury (DILI), and it should be considered alongside other mechanisms when evaluating possible DILI risk because is essential for normal bile flow and healthy liver function. Proactive evaluation and understanding of BSEP inhibition is recommended in drug discovery and development to aid internal decision making on potential human DILI risk. (J. G. Kenna, CLINICAL PHARMACOLOGY & THERAPEUTICS, 104, 5, 916-932 (2018)) The bile salt export pump (BSEP) is an efflux transporter located on the canalicular membrane of hepatic cells and is the primary transporter of bile acids from the hepatocyte to the biliary system. Together with other hepatic transporters of uptake and efflux, it is involved in the homeostasis of bile salts. In the last decade, BSEP inhibition has emerged as an important mechanism that may contribute to the initiation of human drug‐induced liver injury and therefore it is important to consider BSEP inhibition alongside when considering the risk of possible acute drug‐induced liver failure. Of note, the compounds of formula (I) of the present invention are characterized by an in vitro BSEP inhibition at 100 µM < 50 % that can be considered suitable and acceptable from a safety point of view, as shown in Table 21 of the experimental part. Even more advantageously, the compounds of formula (I) of the present invention are also endowed with a good permeability profile that, in its turn, can ensure a suitable bioavailability for an oral administration. The permeability was assessed in human Caco-2 cell line, an in vitro model that mimic human gastrointestinal barrier and so useful to predict oral absorption. A passive permeability value ≥ 15 nm / sec is considered suitable for an oral administration, as shown in Table 22 of the experimental part. In compounds of formula (I) of the invention, an Hydrogen or a Fluorine at position 5 on the indole group, in combination with the presence of a substituent in position alpha to the carboxylic group, leads unexpectedly to a series of compounds that is active for IPF in the phenotypic assay, endowed with a very good BSEP inhibition and permeability profile, that are thus suitable for treatment of fibrosis, with a very promising bioavailability profile for oral administration. As indicated in the experimental part, in Comparative Examples Results Section, conversely to Comparative Example A, characterized by the presence of a methyl at position 5 on the indolegroup, and conversely to Comparative Example B, characterized by the presence of OMe at position 5 on the indole group, the presence of a hydrogen or a fluorine at position 5 on the indole group in combination with the presence of a substituent in position alpha to the carboxylic group, leads unexpectedly to a series of compounds of formula (I) that is active for IPF in the phenotypic assay, endowed with a very good BSEP inhibition and permeability profile, thus suitable for treatment of fibrosis with a very promising bioavailability profile for oral administration. The state of the art does not describe or suggest derivatives of general formula (I) of the present invention having inhibitory activity on PHGDH which demonstrate good results in assays for the prevention and / or treatment of fibrosis, in particular IPF, and at the same time a suitable BSEP profile and a good permeability. Accordingly, the compounds of formula (I) can be used in the oral treatment of fibrosis, and in particular treatment of idiopathic pulmonary fibrosis, whenever PHGDH receptors are involved. Thus, in one aspect the present invention refers to a compound of formula (I):wherein R2is H or absent; R1is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)alkyl- OR7, heteroaryl and -(C3-C7)heterocycloalkyl or when R2is absent, R1is fused to the C* to form a spiro -(C3-C7)cycloalkyl or -(C3- C7)heterocycloalkyl; R3is halogen or -(C1-C6)alkyl; R4is H or F; R5is H or selected from the group consisting of halogen, -OR7and -(C1-C6)alkyl, wherein said -(C1-C6)alkyl is optionally substituted by -(C3-C7)heterocycloalkyl; R6and R7are independently H or -(C1-C6)alkyl, wherein said -(C1-C6)alkyl is optionally substituted by -(C3-C7)heterocycloalkyl; R8is H or -(C1-C6)alkyl; and pharmaceutically acceptable salts thereof.All the listed groups for each of the variable moieties R1, R2, R3, R4, R5,R6, R7and R8of the compounds of the invention have to be intended as alternatives and may be combined with each other in embodiments which are included in the scope of the invention. In one embodiment, R2is H or absent. In a preferred embodiment, R2is H. In another preferred embodiment, R2is absent. In one embodiment, R1is selected from the group consisting of -(C1-C6)alkyl, -(C1- C6)haloalkyl, -(C1-C6)alkyl-OR7, heteroaryl and -(C3-C7)heterocycloalkyl, or when R2is absent, R1is fused to the C* to form a spiro -(C3-C7)cycloalkyl or -(C3-C7)heterocycloalkyl. In one preferred embodiment, R1is selected from the group consisting of -(C1-C4)alkyl, - (C1-C4)haloalkyl, -(C1-C4)alkyl-OR7, heteroaryl and -(C3-C7)heterocycloalkyl. In a more preferred embodiment, R1is selected from the group consisting of -(C1-C4)alkyl, -(C1-C4)haloalkyl and - (C1-C4)alkyl-OR7. In a more preferred embodiment, R1is selected from the group consisting of methyl, ethyl, hydroxyethyl, ethyl methyl ether and trifluoroethyl. In a more preferred embodiment, R1is selected from methyl or ethyl. In another preferred embodiment, R1is selected from the group consisting of heteroaryl or -(C3-C7)heterocycloalkyl. In a more preferred embodiment, R1is selected from the group consisting of heteroaryl or -(C3-C6)heterocycloalkyl. In a more preferred embodiment, R1is selected from pyridine or tetrahydropyran. In another embodiment, when R2is absent, R1is fused to the C* to form a spiro -(C3- C7)cycloalkyl or -(C3-C7)heterocycloalkyl. In a preferred embodiment, when R2is absent R1is fused to the C* to form a spiro -(C3-C6)cycloalkyl or -(C3-C6)heterocycloalkyl. In a more preferred embodiment, when R2is absent R1is fused to the C* to form a spiro -(C3-C4)cycloalkyl or -(C3- C6)heterocycloalkyl. In an even more preferred embodiment, when R2is absent R1is fused to the C* to form a spiro cyclobutane or tetrahydropyran. In one embodiment, R3is halogen or -(C1-C6)alkyl. In a preferred embodiment, R3is halogen or -(C1-C4)alkyl. In one embodiment, R3is halogen. In a preferred embodiment, R3is halogen selected from the group consisting of chloride, bromide, fluorine and iodide. In a more preferred embodiment, R3is selected from chloride or fluorine. In another embodiment, R3is -(C1-C6)alkyl. In a preferred embodiment, R3is -(C1-C4)alkyl. In a more preferred embodiment, R3is methyl or ethyl. In a even more preferred embodiment, R3is methyl. In one embodiment, R4is H or F. In a preferred embodiment, R4is H. In another preferred embodiment, R4is F. In another preferred embodiment, R4is fluorine. In one embodiment, R5is H or selected from the group consisting of halogen, -OR7and -(C1- C6)alkyl, wherein said -(C1-C6)alkyl is optionally substituted by -(C3-C7)heterocycloalkyl. In a preferred embodiment, R5is H or selected from the group consisting of halogen, -OR7 and -(C1- C4)alkyl, wherein said -(C1-C4)alkyl is optionally substituted by -(C3-C7)heterocycloalkyl.In one preferred embodiment, R5is H. In another preferred embodiment, R5is halogen. In a more preferred embodiment, R5is halogen selected from chloride, bromide, fluorine, iodide. In a more preferred embodiment, R5is selected from chloride or fluorine. In an even more preferred embodiment, R5is fluorine. In another preferred embodiment, R5is bromide. In another embodiment, R5is -OR7. In a preferred embodiment, R5is methoxy. In another embodiment, R5is -(C1-C6)alkyl, wherein said -(C1-C6)alkyl is optionally substituted by -(C3-C7)heterocycloalkyl. In a preferred embodiment, R5is -(C1-C4)alkyl, wherein said -(C1-C4)alkyl is optionally substituted by -(C3-C6)heterocycloalkyl. In a more preferred embodiment, R5is methyl or ethyl, optionally substituted by -(C3-C6)heterocycloalkyl. In another preferred embodiment, R5is morpholino-ethyl or morpholino-methyl. In one embodiment, R6and R7are independently H or -(C1-C6)alkyl, wherein said -(C1- C6)alkyl is optionally substituted by -(C3-C7)heterocycloalkyl. In a preferred embodiment, R6and R7are independently H or -(C1-C4)alkyl, wherein said -(C1-C4)alkyl is optionally substituted by - (C3-C7)heterocycloalkyl. In a more preferred embodiment, R6and R7are independently H or -(C1- C4)alkyl, wherein said -(C1-C4)alkyl is optionally substituted by -(C3-C6)heterocycloalkyl. In one preferred embodiment, R6and R7are H. In another embodiment, R6and R7are -(C1- C6)alkyl, wherein said -(C1-C6)alkyl is optionally substituted by -(C3-C7)heterocycloalkyl. In a preferred embodiment, R6and R7are independently methyl or ethyl, wherein said ethyl is optionally substituted by -(C3-C7)heterocycloalkyl. In a more preferred embodiment, R6and R7are independently methyl, wherein said methyl is optionally substituted by morpholine. In one embodiment, R8is H or -(C1-C6)alkyl. In a preferred embodiment, R8is H. In another preferred embodiment, R8is -(C1-C6)alkyl. In a more preferred embodiment, R8is H or -(C1- C4)alkyl. In a more preferred embodiment, R8is H or methyl. All the listed groups for each of the variable moieties R1, R2, R3, R4, R5,R6,R7and R8of the compounds of the invention have to be intended as alternatives and may be combined with each other in embodiments which are included in the scope of the invention. In a preferred embodiment, the present invention refers to a compound of formula (I) represented in the formula :(Ia)wherein R1, R2, R3, R4, R5,R6, R7and R8are defined as above. In a preferred embodiment, the present invention refers to a compound of formula (I) wherein R8is H, represented in the formula (Ib): HOwherein R1, R2, R3, R4, R5,R6and R7are defined as above. In a preferred embodiment, the present invention refers to a compound of formula (Ia) wherein R8is H, represented in the formula (Ic):wherein R1, R2, R3, R4, R5,R6and R7are defined as above. In a preferred embodiment, the present invention refers to a compound of formula (I) or a compound of formula (Ia) or a compound of formula (Ib) or a compound of formula (Ic), wherein: R2is H or absent; R1is selected from the group consisting of -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C1-C4)alkyl- OR7, heteroaryl and -(C3-C6)heterocycloalkyl or when R2is absent, R1is fused to the C* to form a spiro -(C3-C4)cycloalkyl or -(C3- C6)heterocycloalkyl; R3is halogen or -(C1-C4)alkyl; R4is H or F; R5is H or selected from the group consisting of halogen, -OR7and -(C1-C4)alkyl, wherein said -(C1-C4)alkyl is optionally substituted by -(C3-C4)heterocycloalkyl;R6and R7are independently H or -(C1-C4)alkyl, wherein said -(C1-C4)alkyl is optionally substituted by -(C3-C6)heterocycloalkyl; and pharmaceutically acceptable salts thereof. In a preferred embodiment, the present invention refers to a compound of formula (I) or a compound of formula (Ia) or a compound of formula (Ib) or a compound of formula (Ic), wherein: R2is H or absent; R1is selected from the group consisting of methyl, ethyl, trifluoropropyl, -(C1-C2)alkyl-OR7, pyridine and tetrahydropyran or when R2is absent, R1is fused to the C* to form a spiro cyclobutane or tetrahydropyran; R3is selected from chloride, fluorine, methyl; R4is H or F; R5is H or selected from the group consisting of fluorine, methoxy, methyl, ethyl, wherein said methyl or ethyl are optionally substituted by morpholine; R6and R7are independently H or methyl, wherein said methyl is optionally substituted morpholine; R8is H or methyl; and pharmaceutically acceptable salts thereof. In a preferred embodiment, the present invention refers to a compound of formula (I) or a compound of formula (Ia) or a compound of formula (Ib) or a compound of formula (Ic), wherein: R3is selected from chloride, fluorine, methyl; R5is H or selected from the group consisting of fluorine, methoxy, methyl, ethyl, wherein said methyl or ethyl are optionally substituted by morpholine. In a more preferred embodiment, the present invention refers to a compound of formula (I) or a compound of formula (Ia) or a compound of formula (Ib) or a compound of formula (Ic), wherein: R2is H; R1is selected from the group consisting of methyl, ethyl, trifluoropropyl, -(C1-C2)alkyl-OR7, pyridine and tetrahydropyran. In another more preferred embodiment, the present invention refers to a compound of formula (I) or a compound of formula (Ia) or a compound of formula (Ib) or a compound of formula (Ic), wherein: R2is absent, R1is fused to the C* to form a spiro cyclobutane or tetrahydropyran;In an even more preferred embodiment, the present invention refers to a compound of formula (I) or (Ia), wherein R5is methyl and R6and R7are hydrogen, represented in the formula (Id): HO 8wherein R2is H or absent; R1is selected from ethyl or methyl, or when R2is absent, R1is fused to the C* to form a tetrahydropyrane; R3is chloride or fluorine; R4is H or F; R8is H or -(C1-C6)alkyl; and pharmaceutically acceptable salts thereof. All the preferred groups listed above for each of the variable moieties R1, R2, R3, R4, R5, R6, R7and R8of the compounds of the invention may be combined with each other in embodiments which are included in the scope of the invention. In a more preferred embodiment, the invention refers to at least one of the compounds listed in Table 1 below and pharmaceutically acceptable salts thereof. Table 1 - List of preferred compounds Example N° Structure IUPAC NAME HO 2-(4-((S)-1-(4-chloro-1-methyl- HN O 1H-indole-2-carboxamido)-2- 1 Cl OOHhydroxyethyl)phenyl)butanoic N acid CH3CH3HO 2-(4-((S)-1-(4-chloro-1,6- HN O dimethyl-1H-indole-2- Cl OOHcarboxamido)-2- N hydroxyethyl)phenyl)butanoic CH3CH3acidH3CHO Diastereoisomer 1 of HN O 2-(4-((S)-1-(4-chloro-1,6- Cl OOHdimethyl-1H-indole-2- N carboxamido)-2- CH3CH3hydroxyethyl)phenyl)butanoic H3C acid HO Diastereoisomer 2 of HN O 2-(4-((S)-1-(4-chloro-1,6- Cl OOHdimethyl-1H-indole-2- N carboxamido)-2- CH3CH3hydroxyethyl)phenyl)butanoic H3C acid HO 2-(4-((S)-1-(4-chloro-5-fluoro-1- HN O methyl-1H-indole-2- Cl carboxamido)-2- OOHhydroxyethyl)phenyl)butanoic F N acid CH3CH3HO Diastereoisomer 1 of HN O 2-(4-((S)-1-(4-chloro-5-fluoro-1- Cl methyl-1H-indole-2- OOHcarboxamido)-2-FN C hydroxyethyl)phenyl)butanoic CH3 H3acid HO Diastereoisomer 2 of HN O 2-(4-((S)-1-(4-chloro-5-fluoro-1- Cl methyl-1H-indole-2- OOHcarboxamido)-2- F N CH3 CH3hydroxyethyl)phenyl)butanoic acidHO HN O 2-(4-((S)-1-(4-chloro-1-methyl-7- Cl (morpholinomethyl)-1H-indole-2- OOHcarboxamido)-2- N hydroxyethyl)phenyl)butanoic CH3CH3acid NOHO 2-(4-((S)-1-(4-chloro-1-methyl-6- HN O Cl (morpholinomethyl)-1H-indole-2- OOHcarboxamido)-2- N CH3CH3hydroxyethyl)phenyl)butanoicO N acid HO 2-(4-((S)-1-(4-chloro-1,6- HN O dimethyl-1H-indole-2- Cl OOHcarboxamido)-2- N hydroxyethyl)phenyl)-4- CH3methoxybutanoic acid O H3C HO 2-(4-((S)-1-(4-chloro-5-fluoro-1- HN O methyl-1H-indole-2- Cl OOHcarboxamido)-2- N hydroxyethyl)phenyl)-4- F CH3methoxybutanoic acid O HO 2-(4-((S)-1-(4-chloro-1,6- HN O dimethyl-1H-indole-2- Cl carboxamido)-2- OOHhydroxyethyl)phenyl)-2- N CH3(tetrahydro-2H-pyran-4-yl)acetic acidH3C OHO HN O 2-(4-((S)-1-(4-chloro-5-fluoro-1- Cl methyl-1H-indole-2- OOHcarboxamido)-2- F N hydroxyethyl)phenyl)-5,5,5- CH3trifluoropentanoic acid F F FHO (S)-1-(4-(1-(4-chloro-5-fluoro-1- HN O methyl-1H-indole-2- Cl carboxamido)-2- OOHhydroxyethyl)phenyl)cyclobutane F N -1-carboxylic acid CH3HO (S)-1-(4-(1-(4-chloro-1,6- HN O dimethyl-1H-indole-2- Cl OOHcarboxamido)-2- N hydroxyethyl)phenyl)cyclobutane CH3-1-carboxylic acidH3CHO 2-(4-((S)-1-(4-chloro-5-fluoro-1- HN O methyl-1H-indole-2- Cl carboxamido)-2- OOHhydroxyethyl)phenyl)-2- F N CH (tetrahydro-2H-pyran-4-yl)acetic 3 acid O HO HN O 2-(4-((S)-1-(4-chloro-1,6- Cl dimethyl-1H-indole-2- OOHcarboxamido)-2- N hydroxyethyl)phenyl)-5,5,5- CH3trifluoropentanoic acidH3C F FFHO (S)-4-(4-(1-(4-chloro-5-fluoro-1- HN O methyl-1H-indole-2- Cl carboxamido)-2- OOHhydroxyethyl)phenyl)tetrahydro- F N 2H-pyran-4-carboxylic acid CH3O HO (S)-4-(4-(1-(4-chloro-1,6- HN O dimethyl-1H-indole-2- Cl OOHcarboxamido)-2- N hydroxyethyl)phenyl)tetrahydro- CH3O 2H-pyran-4-carboxylic acid H3CHO 2-(4-((S)-1-(4-chloro-1-methyl-6- HN O (2-morpholinoethyl)-1H-indole-2- Cl OOHcarboxamido)-2- O N hydroxye N H3CHthyl)phenyl)butanoic C 3 acid HO (S)-4-(4-(1-(4-chloro-5,6- HN O difluoro-1-methyl-1H-indole-2- Cl OOHcarboxamido)-2- F N hydroxyethyl)phenyl)tetrahydro- CH3O 2H-pyran-4-carboxylic acid F HO (S)-4-(4-(1-(4-chloro-5-fluoro- HN O 1,6-dimethyl-1H-indole-2- Cl OOHcarboxamido)-2- F N hydroxyethyl)phenyl)tetrahydro- CH3O 2H-pyran-4-carboxylic acid H3C HO 2-(4-((S)-1-(4-chloro-5-fluoro- HN O 1,6-dimethyl-1H-indole-2- Cl OOHcarboxamido)-2-FN hydroxyethyl)phenyl)butanoic CH3 CH3acidH3CHO 2-(4-((S)-1-(4-chloro-1,6- HN O dimethyl-1H-indole-2- Cl OOHcarboxamido)-2- N CH hydroxyethyl)phenyl)propanoic CH33acid H3C HO Diastereoisomer 1 of HN O 2-(4-((S)-1-(4-chloro-1,6- Cl OOHdimethyl-1H-indole-2- N CH3carboxamido)-2- CH3hydroxyethyl)phenyl)propanoic H3C acidHO Diastereoisomer 2 of HN O 2-(4-((S)-1-(4-chloro-1,6- Cl OOHdimethyl-1H-indole-2- N CH carboxamido)-2- CH33hydroxyethyl)phenyl)propanoic H3C acid HO (S)-4-(4-(1-(4-chloro-5-fluoro-6- HN O methoxy-1-methyl-1H-indole-2- Cl OOHcarboxamido)-2- F N hydroxyethyl)phenyl)tetrahydro- CH3O 2H-pyran-4-carboxylic acid O HO 2-(4-((S)-1-(4,5-difluoro-1,6- HN O dimethyl-1H-indole-2- F OOHcarboxamido)-2-FN hydroxyethyl)phenyl)butanoic CH3 CH3acid H3C HO Diastereoisomer 1 of HN O 2-(4-((S)-1-(4,5-difluoro-1,6- F OOHdimethyl-1H-indole-2-FN carboxamido)-2- CH3 CH3hydroxyethyl)phenyl)butanoic H3C acid HO Diastereoisomer 2 of HN O 2-(4-((S)-1-(4,5-difluoro-1,6- F OOHdimethyl-1H-indole-2-FN carboxamido)-2- CH3 CH3hydroxyethyl)phenyl)butanoic H3C acid HO 2-(4-((S)-1-(4-chloro-5-fluoro-6- HN O methoxy-1-methyl-1H-indole-2- Cl OOHcarboxamido)-2-FN hydroxyethyl)phenyl)butanoic CH3 CH3acid OHO HN O 2-(4-((S)-2-hydroxy-1-(1,4,6- H3C trimethyl-1H-indole-2- OOHcarboxamido)ethyl)phenyl)butano N CH3CH3ic acid H3C HO 2-(4-((S)-1-(4-chloro-1,6- HN O dimethyl-1H-indole-2- Cl OOHcarboxamido)-2- N hydroxyethyl)phenyl)-2-(pyridin- CH33-yl)acetic acid N H3C HO 2-(4-((S)-1-(4,5-difluoro-1,6- HN O dimethyl-1H-indole-2- F OOHcarboxamido)-2-FNCH3hydroxyethyl)phenyl)propanoic CH3acid H3C HO Diastereoisomer 1 of HN O 2-(4-((S)-1-(4,5-difluoro-1,6- F OOHdimethyl-1H-indole-2-FNCH3carboxamido)-2- CH3hydroxyethyl)phenyl)propanoicH3Cacid HO Diastereoisomer 2 of HN O 2-(4-((S)-1-(4,5-difluoro-1,6- F OOHdimethyl-1H-indole-2-FNCH3carboxamido)-2- CH3hydroxyethyl)phenyl)propanoic H3C acid HO 2-(4-((S)-1-(4-chloro-5,6- HN O difluoro-1-methyl-1H-indole-2- Cl OOHcarboxamido)-2-FN hydroxyethyl)phenyl)butanoic CH3 CH3acid FHO 2-(4-((S)-1-(4-fluoro-1,6- HN O dimethyl-1H-indole-2- F OOHcarboxamido)-2- N hydroxyethyl)phenyl)butanoic CH3CH3acid H3C HO Diastereoisomer 1 of HN O 2-(4-((S)-1-(4-fluoro-1,6- F OOHdimethyl-1H-indole-2- N carboxamido)-2- CH3CH3hydroxyethyl)phenyl)butanoic H3C acid HO Diastereoisomer 2 of HN O 2-(4-((S)-1-(4-fluoro-1,6- F OOHdimethyl-1H-indole-2- N carboxamido)-2- CH3CH3hydroxyethyl)phenyl)butanoic H3C acid HO 2-(4-((S)-1-(4-chloro-5-fluoro- HN O 1,6-dimethyl-1H-indole-2- Cl OOHcarboxamido)-2- F NCHhydroxyethyl)phenyl)propanoic CH33acid H3C HO Diastereoisomer 1 of HN O 2-(4-((S)-1-(4-chloro-5-fluoro- Cl OOH1,6-dimethyl-1H-indole-2-FNCH3carboxamido)-2- CH3hydroxyethyl)phenyl)propanoic H3C acid HO Diastereoisomer 2 of HN O 2-(4-((S)-1-(4-chloro-5-fluoro- Cl OOH1,6-dimethyl-1H-indole-2-FNCH3carboxamido)-2- CH3hydroxyethyl)phenyl)propanoicH3CacidHO (S)-1-(4-(1-(4,5-difluoro-1,6- HN O dimethyl-1H-indole-2- 44 F OOHcarboxamido)-2- F N hydroxyethyl)phenyl)cyclobutane CH3-1-carboxylic acid H3C HO (S)-1-(4-(1-(4-chloro-5-fluoro-6- HN O methoxy-1-methyl-1H-indole-2- 45 Cl OOHcarboxamido)-2- F N hydroxyethyl)phenyl)cyclobutane CH3-1-carboxylic acid O It is to be understood that all the single deuterates, enantiomers, diastereoisomers and mixtures thereof, in any proportion, or pharmaceutically acceptable salts and solvates of the compounds of formula (I) are encompassed within the scope of the present invention. In a preferred embodiment, the present invention refers to a compound of formula (I) or a compound of formula (Ia), wherein R1and R2are fused together in a -(C3-C4)cycloalkyl or -(C3- C6)heterocycloalkyl. In another embodiment, the invention refers to a compound of formula (I) as PHGDH inhibitor suitable for oral administration useful for the prevention and / or treatment of fibrosis, in particular IPF. In this respect, it has been found that the compounds of formula (I) of the present invention have antifibrotic activity, monitored measuring the expression of α-SMA in Phenotypic assay, expressed as pIC50, equal or higher than 5.5. Preferably, the compounds of the present invention have a pIC50on α-SMA in phenotypic assay between 5.5 and 6.5. More preferably, the compounds of the present invention have a pIC50on α-SMA in phenotypic assay higher than 6.5. The compounds of the present invention are also characterized by an in vitro BSEP inhibition at 100 µM ≤ 50 %, that can be considered suitable and acceptable from a safety point of view, and by a passive permeability value ≥ 15 nm / sec, which is considered suitable for an oral administration. Preferably, compounds showed BSEP inhibition values between 50 and 25%. More preferably, compounds showed BSEP inhibition values between 25 and 13%; most preferably, compounds showed BSEP inhibition at 100 µM below 13%. The present invention also refers to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in admixture with at least one or more pharmaceutically acceptable carrier and / or excipient.As used herein, "effective amount" in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects and it can nevertheless be routinely determined by the skilled artisan. The compounds of formula (I) may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the route of administration chosen. In one embodiment, the invention refers to a pharmaceutical composition of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carrier or excipient, for example those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A. In therapeutic use, the compound of formula (I) may be administered by any convenient, suitable, or effective route. Administration of the compounds of the invention and their pharmaceutical compositions may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) and by inhalation. Preferably, the compounds of the present invention are administered orally or by inhalation. In a more preferred embodiment, the compounds of the present invention or their pharmaceutical compositions are administered orally. In another preferred embodiment, the compounds of the present invention or their pharmaceutical compositions are administered by inhalation. In one preferred embodiment, the pharmaceutical composition comprising the compound of formula (I) is a solid oral dosage form such as tablets, gel caps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. In a further embodiment, the pharmaceutical composition comprising a compound of formula (I) is a liquid oral dosage form such as aqueous and non-aqueous solution, emulsion, suspension, syrup. Such liquid dosage form can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and / or suspending the compounds of the invention.In a further embodiment, the pharmaceutical composition comprising the compound of formula (I) is an inhalable preparation such as inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations. Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations and may be administered through a suitable inhalation device which may be respectively selected from dry powder inhaler, pressurized metered dosed inhaler, or a nebulizer. In another embodiment the invention is also directed to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention, or a pharmaceutically acceptable salt thereof, obtained as described above according to the invention, in form of a single- or multi-dose dry powder inhaler or a metered dose inhaler. For administration as a dry powder, single- or multi-dose inhalers known from the prior art may be utilized. In that case the powder may be filled in gelatine, plastic or other capsules, cartridges, or blister packs or in a reservoir. A diluent or carrier, chemically inert to the compounds of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction, may be added to the powdered compounds of the invention. Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form. The propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers, and optionally other excipients. The propellant-free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers. The compounds of the invention can be administered as the sole active agent or in combination with other pharmaceutical active ingredients. The dosages of the compounds of the invention depend upon a variety of factors including among others the particular disease to be treated, the severity of the symptoms, the route of administration and the like. In a further aspect, the invention refers to the use of the compounds of formula (I) for the preparation of a medicament. In another aspect, the present invention refers to a compound of formula (I) for use as a medicament. Thus, the invention refers to a compound of formula (I) in the preparation of a medicament, preferably for use in the treatment of disorders associated with 3-phosphoglycerate dehydrogenase (PHGDH) receptors mechanism.In a further embodiment, the present invention refers to a compound of formula (I) for use in the prevention and / or treatment of diseases, disorders or conditions associated with dysregulation of PHGDH. In one aspect, the invention also refers to a method for the prevention and / or treatment of disorders associated with PHGDH receptors mechanisms, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I). In one embodiment, the present invention refers to a compound of formula (I) useful for the prevention and / or treatment of fibrosis and / or diseases, disorders, or conditions that involve fibrosis. In a preferred embodiment, the present invention is directed to the compounds of formula (I) for use for the prevention and / or treatment of a fibrotic disease. In another embodiment, the present invention provides a method for preventing and / or treating fibrotic diseases, the method comprising administering a compound of formula (I). In another embodiment, the present invention provides a method for preventing and / or treating fibrotic diseases, the method comprising administering a pharmaceutical composition comprising the compounds of formula (I). In another aspect, the present invention is directed to a pharmaceutical composition comprising the compounds of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients, for use for the prevention and / or treatment of fibrotic diseases. In a further aspect, the fibrotic diseases mentioned above are selected from pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. Preferably, the compounds of formula (I) of the present invention are useful for the treatment and / or prevention of fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. In another embodiment, the invention refers to the use of the compound of formula (I) or its pharmaceutical composition for the preparation of a medicament for the treatment and / or prevention of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.In another embodiment, the invention refers to a compound of formula (I) or a pharmaceutical composition for use in the prevention and / or treatment of fibrotic disease, wherein the fibrotic disease is selected from: pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. In another embodiment, the invention refers to a method for the treatment and / or prevention of fibrotic diseases selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis, the method comprising administering a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients. More preferably, the compounds of formula (I) of the present invention are useful for the treatment of idiopathic pulmonary fibrosis (IPF). In a more preferred embodiment, the fibrotic disease mentioned above is IPF. In another preferred embodiment, the invention refers to a compound of formula (I) or its pharmaceutical composition for use in the prevention and / or treatment of IPF. In another preferred embodiment, the invention refers to the use of the compounds of formula (I) or its pharmaceutical composition for the preparation of a medicament for the treatment and / or prevention of IPF. In another preferred embodiment, the invention refers to a method for the treatment and / or prevention of IPF, the method comprising administering a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients. Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of the compound of formula (I). The magnitude of prophylactic or therapeutic dose of the compound of formula (I) will, of course, vary with the nature of the severity of the condition to be treated and with its route of administration, and will generally be determined by clinical trial as required in the pharmaceutical art. It will also vary according to the age, weight and response of the individual patient. All preferred groups or embodiments described above for compounds of formula (I) may be combined with each other and apply as well mutatis mutandis.PREPARATIONS OF INTERMEDIATES AND EXAMPLES Chemical Names of the compounds were generated with Structure To Name Enterprise 10.0 Cambridge Software or are common chemical names. All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art. In the procedures that follow, some of the starting materials are identified through an “Intermediate” or “Example” number with indications on step number. This is provided merely for assistance to the skilled chemist. When reference is made to the use of a “similar” or “analogous” procedure, as it will be appreciated by those skilled in the art, such a procedure may involve minor variations, for example reaction temperature, reagent / solvent amount, reaction time, work-up conditions or chromatographic purification conditions, that will be appreciated by those skilled in the art. List of Abbreviations 1H-NMR: Proton nuclear magnetic resonance; 2-MeTHF: 2-methyltetrahydrofuran; AA powder: (L-Asp acid; L-Asparagin; L-Glutamic acid; Hydroxy L-Proline; L-Proline); ab.: antibody; ACN: acetonitrile; ACN-d3: deuterated acetonitrile; AcOH: Acetic acid; AIBN: azobisisobutyronitrile; AUC: area under the curve; Bn: benzyl; Boc: tert-butyloxycarbonyl; Boc2O: Di-tert-butyl dicarbonate; BSA: Bovine Serum Albumin; c.a.: commercially available; CDCl3: deuterated chloroform; ClBil: biliary clearance; CV: Column Volumes; dba: dibenzylideneacetone; DCE: 1,2-dichloroethane; DCM: Dichloromethane; de: diastereomeric excess; DIAD: diisopropyl azodicarboxylate; DIBAL-H: Diisobutylaluminium hydride; DIPEA: N,N-Diisopropylethylamine; DMA: dimethylacetamide; DMAP: 4-dimethylaminopyridine; DMEM: Dulbecco's Modified Eagle Medium; DMF: N,N-Dimethylformamide; DMSO: Dimethylsulfoxide; DMSO-d6: deuterated dimethyl sulfoxide; DavePhos: 2- Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl; ee: enantiomeric excess; eq.: equivalents; EtOAc: Ethyl acetate; FBS: Fetal Bovine Serum; FCC: Flash column chromatography; h: hour / s; Hal: halogen; HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); HPLC: high pressure liquid chromatography; HPLC-MS / MS: high pressure liquid chromatography-mass spectrometry / mass spectrometry; LCMS: Liquid chromatography-mass spectrometry; LDA: lithium diisopropylamide; LG: leaving group; LiHMDS: Lithium bis(trimethylsilyl)amide; MEM: Minimal Essential Medium; MeOH: methyl alcohol; min: minute / s; MPLC: medium-pressure liquid chromatography; Ms: mesyl (MsCl: mesylchloride); NaHMDS: sodium bis(trimethylsilyl)amide; NCE: new chemical entity; NHLF: Normal Human Lung Fibroblast; NMR: nuclear magnetic resonance; on: overnight; P / S: Penicillin-Streptomycin; PBS: PhosphateBuffered Saline;Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0); pen / strep: Penicillin- streptomycin; PGn: protecting group; PgP: P -glycoprotein; PTS: p-toluenesulfonic acid; r.t.: Retention time; RT: Room temperature; sat aq: saturated aqueous; SCX: strong cation exchange; SDS: Sodium Dodecyl Sulfate; SFC: supercritical fluid chromatography; SFC-MS: supercritical fluid chromatography-mass spectrometry; SN: nucleophilic substitution; TBME: tert-Butyl methyl ether; TBS: TRIS-buffered saline; TEA: Triethylamine; TFA: Trifluoroacetic acid; TGFβ: Transforming Growth Factor-B; TGX-gel : Tris-Glycine eXtended- Gels; THF: Tetrahydrofuran; TLC: Thin-layer chromatography; TsOH: p-toluenesulfonic acid; UPLC®: Ultra Performance Liquid Chromatography; XPhos: Dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2- yl]phosphane; α-SMA: alpha-smooth muscle actin; General Synthetic Schemes The compounds of the present invention can be prepared in a number of ways known to the one skilled in the art of organic synthesis. It will be understood that the functionality / s present on the molecule should be consistent with the transformation proposed. This will sometimes require a modification of the order of synthetic steps in order to obtain a desired compound of the invention. While the optimal reaction conditions may vary depending on the reactants or solvent used, such conditions can be readily determined by those skilled in the art by routine optimization procedures. Thus, processes described below should not be viewed as limiting the scope of the synthetic methods available for the preparation of the compounds of the invention. In some cases, generally known protective groups (PG) may be employed when needed to mask or protect sensitive or reactive moieties, in accordance with general principles of chemistry (Protective groups in organic syntheses, 3rd ed. T. W. Greene, P. G. M. Wuts). In other cases, also leaving group (LG) can be used. The term "leaving group" is well known and understood in the art and one of skill in the art would know a variety of leaving groups that would be suitable for use in this embodiment as well as reaction conditions suitable for their use. Examples of suitable leaving groups include sulfonates, halides, phosphates, thiolates, carboxylates, phenoxides and others. The compounds of formula (I), including all the compounds here above listed, can be generally prepared according to the procedures outlined in Schemes shown below, wherein at least one non-limiting synthetic route is provided for the preparation of the exemplified compounds (i.e. the Examples). Properly substituted 1-methyl1H-indole-2-carboxylic acids of general formula (VI) can be prepared according to Scheme 1, through multi-step synthetic sequences starting from corresponding suitably substituted benzaldehydes of general formula (II). Such benzaldehydes can be converted into 2-azido-3-phenylacrylates of general formula (III) by means of condensation reactions employing 2-azidoacetates, such as for example methyl 2-azidoacetates, ethyl 2-azidoacetates or others, in the presence of a base, such as for example metal alkoxides like sodium methoxide, lithium methoxide, potassium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide or others, in a suitable solvent, such as for example methanol or ethanol or others. 2-azido-3-phenylacrylates (III) can be cyclised to yield indoles of formula (IV), for example by heating at high temperatures in suitable solvents, such as for example xylene or others. Indoles (IV) can then be N-alkylated to corresponding N-Me indoles of general formula (V) in the presence of methylating agents such as for example methyl halides, like methyl iodide or others, and of a base, such as for example a metal carbonate like potassium or sodium carbonate or others, in a suitable solvent, such as DMF, DMA, 1,4-dioxane or others or mixtures thereof. 1-methyl- 1H-indole-2-carboxylates (V) can be converted into corresponding 1-methyl-1H-indole-2- carboxylic acids of general formula (VI) by ester function cleavage, for example by means of basic cleavage in the presence of metal hydroxides such as for example lithium, sodium, potassium or other hydroxides, in a suitable solvent or mixture of solvents, such as for example THF, methanol, ethanol, water or others or mixtures thereof. In some instances, Intermediates (IV) can be directly converted into Intermediates (VI) by two-step procedures in which crude Intermediates (V) are not purified nor fully characterised. Reagents to be used in such two-step procedures can be the same reagents employed in stepwise approach previously described. Scheme 1(V) (VI)Wherein R3, R4, R5, R6are defined as above. Intermediates (IVc) can be prepared according to route (a) or route (b) in Scheme 2, starting from suitable Intermediates (IVa) and (IVb) respectively. Indole nitrogen of intermediates (IVa)and (IVb) is first protected by a suitable protecting group PG2 that can be removed selectively with respect to PG1. Such PG2can be for example a carbamate, such as for example Boc group, and can be inserted by reaction with suitable PG2Cl or (PG2)2O in the presence of bases and / or acyl-trasfer reagents, such as for example TEA, DMAP or others, in suitable solvents, such as for example THF or others. Protected Intermediates (VIIa) and (VIIb) can be halogenated (LG = halogen, for example bromide) on methyl substituents of indole scaffold to yield Intermediates (VIIIa) and (VIIIb) respectively, for example by the use of N-halosuccinimides, such for example N- bromosuccinimide, in the presence of a radical reaction initiator, such as for example AIBN or others, in suitable solvents, such as for example PhCF3, DCE or others. Intermediates (VIIIa) and (VIIIb) can then be reacted with suitable heterocycles to give corresponding Intermediates (IXa), which are then converted into corresponding intermediates (IVc) by selective removal of PG2, for example by acidic treatment if PG2is a Boc group. Such acidic treatment can involve for example the use of suitable acids, for example TFA or HCl, in a suitable solvent, such as DCM, or 1,4- dioxane or alcohols or others, or mixtures of them thereof. Scheme 2 a) PG1O b)Wherein R3, R4, R5, R6are defined as above. Intermediates (Vb) can be obtained according to Scheme 3 starting from suitable Intermediates (Va). Intermediates (Va) can be subject to metal-catalysed cross-coupling reactions, such as for example Pd-catalysed Suzuki cross-couplings, employing boron derivatives, such asfor example alkyltrifluoroborates or others, and a base, such as for example a carbonate, like cesium carbonate or others, to give Intermediates (X), characterised by a alcohol group protected with PG3. Protecting group PG3 on such alcohol is selected in a manner to allow selective removal in the presence of PG1, and can be for example a silyl group, a cyclic acetal, a Bn group or other protective groups that are labile in acidic or hydrogenolytic conditions. PG3removal from Intermediates (X), for example in acidic conditions in the case of cyclic acetals, such as employing PTS in an alcohol, like for example methanol or others, yields Intermediates (XI) bearing a free - OH group. Such hydroxyl group can be converted into a suitable leaving group LG, such as an halide, a mesylate or others, yielding Intermediates (XII). Mesylation reaction can be performed for example by using MsCl in the presence of a base, such as for example TEA or others, in a suitable solvent, such as for example DCM or others. Intermediates (Vb) can be obtained from Intermediates (XII) for example by means of SNreactions in the presence of desired heterocycles in suitable solvents, such as for example acetonitrile, THF or others. Scheme 3 R4Wherein R3, R4, R5, R6are defined as above. Intermediate (XIV) can be prepared according to Scheme 4, from corresponding Intermediate (XIII) or its hydrochloride, by reaction with Boc2O with or without the presence of a suitable base, such as for example TEA or others, in a suitable solvent or solvent mixture, such as for example DCM, alcohols or mixtures thereof. Intermediate (XV) can be obtained by treatment of Intermediate (XIV) with 2,2-dimethoxypropane in acidic conditions, such as for example in the presence of TsOH or other acids, in a suitable solvent, such as for example acetone or others.Intermediate (XV) can be converted into corresponding intermediate (XVI) by suitable Pd- catalysed cross-coupling reactions, such as for example Suzuki cross-couplings or others, reacting Intermediates (XV) with suitable alkylboronic acids or alkyl boronates or alkyl trifluoroborates or others, using a suitable Pd source, such for example Pd2(dba)3 or others, and an appropriate Pd ligand, such as for example XPhos or others. Alternatively, Negishi cross-couplings can yield Intermediates (XVI) by reacting Intermediates (XV) with suitable alkyl-zinc reagents and using a suitable Pd source, such for example Pd2(dba)3 or others, and an appropriate Pd ligand, such as for example XPhos or others. Alkyl-zinc reagents can be prepared in a number of methods well known to those skilled in the art, starting for example from corresponding alkyl halides, such as for example alkyl bromides or others, bearing a carboxylic acid group suitably protected for example as an ester, such as for example a methyl ester, an ethyl ester or a tert-butyl ester or others. Intermediates (XVI) can then be transformed into Intermediates (XVII) by alpha-alkylation to ester group. Such alkylation reactions can be promoted by a base, such as for example metal hydrides, like NaH or others, or metal amides, such as for example LDA, LiHMDS, NaHMDS or others. Alkylating agents can be selected from suitably substituted mono-haloalkyls, such as for example alkylbromides or alkyliodides or others, giving rise to Intermediates (XVII). In one embodiment suitably substituted di-haloalkyls, such as for example 1,n-dibromides or 1,n-diiodides (n=3-7) or others, can be used, thus giving rise to Intermediates (XVII). In another embodiment other leaving groups instead of halides can be considered in such alkylation or double alkylation reaction, such as for example mesylates or others. Suitable solvents for the reaction converting Intermediates (XVI) into Intermediates (XVII) can be selected for example from DMF, DMA, DMSO, THF, 1,4-dioxane or others, or mixtures thereof. It should be noted that Intermediates (XVII) and subsequent intermediates can be obtained as single enantiomers, or as mixtures of diastereoisomers, depending on the nature of selected substituents. Intermediates (XVIII) can then be obtained by acidic treatment of Intermediates (XVII), for example by the use of HCl, or TFA or other acids in solvents such as DCM, 1,4-dioxane, alcohols, or others, or mixtures thereof. Intermediates (XVIII) can be isolated as HCl or TFA salts and used as is in next steps or can be isolated and used as free amines. Alternatively, Intermediates of formula (XV) may be converted in compounds of formula (XVII) by cross-coupling reactions in the presence of a palladium catalyst such as Palladium(II) acetate and DavePhos or another palladium source / phosphine-based ligand at high temperature (around 80 °C) for a few hours, in an organic solvent such as toluene with an appropriate base, such as LDA, and suitable arylacetates.Scheme 4 HO HO O R8Wherein R1, R2, R8are defined as above. Accordingly, the present invention provides an intermediate compound (XVIII)wherein R2is H or absent; R1is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)alkyl- OR7, heteroaryl and -(C3-C7)heterocycloalkyl or when R2is absent, R1is fused to the C* to form a spiro -(C3-C7)cycloalkyl or -(C3- C7)heterocycloalkyl; R8is H or -(C1-C6)alkyl; or the pharmaceutically acceptable salts thereof, for the preparation of the compound of formula (I). In one preferred embodiment, the present invention provides an intermediate compound (XVIII)(XVIII)wherein R2is H or absent;R1is selected from the group consisting of trifluoropropyl, -(C1-C2)alkyl-OR7, pyridine and tetrahydropyran or when R2is absent, R1is fused to the C* to form a spiro cyclobutane or tetrahydropyran; R7is H or -(C1-C6)alkyl; R8is H or -(C1-C6)alkyl; or the pharmaceutically acceptable salts thereof, for the preparation of the compound of formula (I). The invention further provides the use of the intermediate compound XVIII as defined above in the preparation of a compound of formula (I), or pharmaceutically acceptable salts thereof. Alternatively, Intermediate (XXI) can be prepared according to Scheme 4a, starting from commercially available Intermediates (XIX) through Ellman’s addition reactions to enantiopure sulfinamides, such as (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2- sulfinamide, in a presence of a base, such as for example butyllithium, in a suitable solvent, such as for example THF, to give Intermediates (XX). Intermediates (XXI) can be obtained by esterification of Intermediate (XX) such as for example by reactions with alkyl halides, such as for example iodomethane, in the presence of a base, such as potassium carbonate, in a suitable solvent, such as DMF. O R8Wherein R1, R2, R8are defined as above. According to Scheme 5, properly substituted 1H-indole-2-carboxylic acids of general formula (VI) can be condensed to Intermediates (XVIII), as free amine or salts, through in situ activation of carboxylic acid function, for example as acylchloride or by the use of coupling agents, such as for example HATU or others, and subsequent nucleophilic acyl substitution reaction in the presence of a base, such as for example DIPEA or TEA or others, in a suitable solvent, such as DMF, DMA, THF, DCM or others or mixtures thereof. Such condensation reaction yields compounds of formula (I). Compounds of general formula (Ib) can finally be obtained fromcompounds of formula (I) by ester function cleavage, in acidic conditions such as for example in the presence of HCl or TFA or other acids, or in basic conditions, such as for example in the presence of metal hydroxides (non-limiting example are Li+, Na+, K+or other hydroxides), in suitable solvents such as THF, 1,4-dioxane, alcohols, water or mixtures thereof. Additionally, in cases where a compound of formula (Ib) is isolated as a mixtures of stereoisomers, further compounds of formula (Ib) can be obtained from these by means of chiral separations techniques well known from the skilled person, such as chiral column chromatography or others. Scheme 5 HO OH R4Wherein R1, R2, R3, R4, R5, R6, R8are defined as above. Exemplified preparation processes are given in the following experimental part. General Experimental details Purifications Purification by “chromatography”, “flash chromatography” or “flash column chromatography (FCC)” refers to purification using a Biotage, or Interchim puriFlash purification system, or equivalent MPLC system using a pre-packed polypropylene column containing stationary phase (cartridge). Where products were purified using an Si cartridge, this refers to an Interchim pre-packed polypropylene column (or equivalent) containing unbounded activated silica with spherical particles with average size of 15 μm or Isolute® pre-packed polypropylene column (or equivalent) containing unbounded activated silica with irregular particles with average size of 50 μm. Fractions containing the required product (identified by TLC and / or LCMS analysis) were pooled and concentrated in vacuo. Where an SCX cartridge was used, ‘SCX cartridge’ refers to a Bond Elut® pre-packed polypropylene column (or equivalent) containing a non-end-capped propylsulphonic acid functionalised silica strong cation exchange sorbent. NMR MethodsNMR spectra were obtained on a Bruker Avance III 600 (5 mm RT inverse probe head), Bruker DRX 500, Bruker Avance AV 400 (5 mm RT direct probehead) or Bruker DPX 300 spectrometers using standard Bruker pulse sequences. DMSO-d6, MeOD-d4 or CDCl3 were used as solvents. Chemical shifts are given relative to internal standard tetramethylsilane or solvent residual peak. All experiments were recorded at 298 K, unless stated differently. Chemical shifts are reported as δ values in ppm relative to tetramethylsilane. Coupling constants (J values) are given in hertz (Hz) and multiplicities are reported using the following abbreviation: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, nd=not determined. LC-MS Methods Method 1 Method 1 was performed on a Acquity UPLC® coupled with SQD mass spectrometer; Column: Acquity BEH C18 (50mm x 2.1mm i.d., 1.7μm), mobile phase A: 0.1% (v / v) formic acid in water, mobile phase B: 0.1% (v / v) formic acid in acetonitrile; see Table 2 for the experimental conditions. Table 2 - Method 1 conditions Gradient – Time Flow (mL / min) A % B% 0.00 0.9 97 3 1.50 0.9 3 97 1.90 0.9 3 97 1.91 0.9 97 3 2.00 0.9 97 3 Column temperature: 40 °C; UV detection: from 210 nm to 400 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-), Scan Range: 100 to 1500 AMU. Method 2 Method 2 was performed on a Acquity H class UPLC® coupled with QDA mass spectrometer; Column: Acquity BEH C18 (100mm x 2.1mm i.d., 1.7μm), mobile phase A: 0.1% (v / v) formic acid in water, mobile phase B: 0.1% (v / v) formic acid in acetonitrile; see Table 3 for the experimental conditions. Table 3 - Method 2 conditions Gradient – Time Flow (mL / min) A % B% 0.00 0.6 97 3 1.00 0.6 97 3 11.00 0.6 3 97 11.50 0.6 3 97 11.60 0.6 97 3 12.00 0.6 97 3Column temperature: 40 °C; UV detection: from 210 nm to 400 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-), Scan Range: 100 to 1250 AMU. Chiral separation protocols The diastereomeric separation of compounds was achieved by Supercritical Fluid Chromatography (SFC) using any of the following instruments: Novasep SUPERSEP 400, Sepiatec preparative SFC system (Prep100), Multigram 2 Preparative SFC system, ABsys2 Preparative SFC system or by Liquid Chromatography (LC) using Gilson Preparative LC system, Agilent 1260 LC System coupled with SFC and G6540B UHD Accurate. Appropriate isocratic methods were selected based on methanol or ethanol solvent systems under basic conditions. The fractions that contained the desired product were evaporated to near dryness using a rotary evaporator. The resultant solids were then transferred into final vessels with MeOH or EtOH, which was removed on a Biotage V10 at 35°C before being freeze dried. Analysis of two enantiomers was performed from reconstituted final samples on a Waters Acquity UPC2 system (SFC, SFC-MS) or an Agilent 1100 HPLC system (LC). Preparative chiral separations Method Chiral-Prep-1: SFC was performed using a Lux A2 (21.2mm x 250mm, 5µm) column with an isocratic run (50:50 EtOH:CO2(0.2% v / v NH3)), Flow Rate 50 mL / min, BPR 100 BarG, Detector Wavelength 225 nm, Injection Volume 0.5 mL (3 mg), 40°C column temperature. Method Chiral-Prep-2: SFC was performed using a Lux A2 (21.2mm x 250mm, 5µm) column with an isocratic run (30:70 MeOH:CO2 (0.2% v / v NH3)), Flow Rate 50 mL / min, BPR 100 BarG, Detector Wavelength 225 nm, Injection Volume 0.5 mL (15 mg), 40°C column temperature. Method Chiral-Prep-3: Chiral separation was performed using a Chiralcel OJ-H (21mm x 250mm, 5um) Column in Isocratic Conditions 25:75 MeOH:CO2 (0.2% v / v NH3), Flow Rate 50 mL / min, BPR 100 BarG, Detector Wavelength 224 nm, Injection Volume 1200 uL (7 mg), Temperature 40°C Method Chiral-Prep-4: Chiral separation was performed using a Chiralpak IG (21mm x 250 mm, 5um) Column with Isocratic Conditions (20:80 MeOH:CO2(0.2% v / v NH3), Flow Rate 50 mL / min, BPR 100 BarG, Detector Wavelength 218 nm, Injection Volume 300 uL (7.8 mg), Temperature 40°C. Method Chiral-Prep-5:Chiral separation was performed using a Chiralcel OJ-H (21mm x 250mm, 5um) Column in Isocratic Conditions 30:70 MeOH:CO2(0.2% v / v NH3), Flow Rate 50 mL / min, BPR 125 BarG ,Detector Wavelength 218 nm, Injection Volume 600 uL (3.1 mg), Temperature 40°C Method Chiral-Prep-6: (II purification) Chiral separation was performed using a Lux A1 (21.2mm x 250mm, 5um) Column in Isocratic Conditions 25:75 MeOH:CO2(0.2% v / v NH3), Flow Rate 50 mL / min, BPR 100 BarG, Detector Wavelength 218 nm, Injection Volume 500 uL, Temperature 40°C. Method Chiral-Prep-7: Chiral separation was performed using a Chiralpak IG (21mm x 250 mm, 5um) Column in Isocratic Conditions 25:75 MeOH:CO2 (0.2% v / v NH3), Flow Rate 50 mL / min, BPR 100 BarG, Detector Wavelength 234 nm, Injection Volume 300 uL (6 mg), Temperature 40°. Method Chiral-Prep-8: Chiral separation was performed using a Chiralcel OJ-H (21mm x 250mm, 5um) Column in Isocratic Conditions 25:75 MeOH:CO2 (0.2% v / v NH3), Flow Rate 50 mL / min, BPR 100 BarG, Detector Wavelength 218 nm, Injection Volume 500 uL (3.5 mg), Temperature 40°C. Chiral analytical methods Method Chiral-QC-1 SFC-MS was performed using a Lux A2 (4.6mm x 250mm, 5µm) column with an isocratic run (50:50 EtOH:CO2(0.1% v / v NH3)), Flow Rate 3 mL / min, BPR 125 BarG, Detector Wavelength 210-400 nm, Injection Volume 1.0 µL, 40 °C column temperature. Method Chiral-QC-2 SFC-MS was performed using a Lux A2 (4.6mm x 250mm, 5µm) column with an isocratic run (30:70 MeOH:CO2 (0.1% v / v NH3)), Flow Rate 3 mL / min, BPR 125 BarG, Detector Wavelength 210-400 nm, Injection Volume 1.0 µL, 40 °C column temperature. Method Chiral-QC-3: Chiral Purity Analysis Conditions: Chiralpak IG (4.6mm x 250mm, 5um) Column in Isocratic Conditions 25:75 MeOH:CO2 (0.1% v / v NH3), Flow Rate 3 mL / min, Detector Wavelength 210-400nm, Injection Volume 1.0 uL, BPR 125 BarG, Temperature 40°C. Method Chiral-QC-4: SFC-MS was performed using a Chiralpak IJ (4.6mm x 250mm, 5um) Column in Isocratic Conditions 20:80 MeOH:CO2(0.1% v / v NH3), Flow Rate 3 mL / min, Detector Wavelength 210- 400nm, Injection Volume 1.0 uL, BPR 125 BarG, Temperature 40°C. Method Chiral-QC-5:SFC-MS was performed using Chiralpak IG (4.6mm x 250mm, 5um) Column in Isocratic Conditions 30:70 MeOH:CO2(0.1% v / v NH3), Flow Rate 3 mL / min, Detector Wavelength 210- 400nm, Injection Volume 1.0 uL, BPR 125 BarG, Temperature 40°C. PREPARATION OF INTERMEDIATES: Intermediates (III) Intermediate (III-2): methyl (Z)-2-azido-3-(2-chloro-4-methylphenyl)acrylate O(III-2) To a solution of 2-chloro-4-methyl-benzaldehyde (5.00 g, 31.4 mmol) and methyl 2- azidoacetate (7.64 mL, 78.4 mmol) in methanol (50 mL) was added sodium methoxide, 5M solution in methanol (18.82 mL, 94.1 mmol) under Argon at maintaining the temperature between -10 and 5 °C over 10 min. The reaction mixture was left in an ice bath to gradually warm to RT and stirred for 4 h. The mixture was poured into ice-water. The obtained precipitate was collected by filtration, washed with water and dried in vacuo to yield the title compound as light yellow solid (5.40 g, 21.5 mmol, yield: 68 % ). LC-MS Method 1: r.t.1.43 min. 1H NMR (500 MHz, DMSO-d6): δ 8.11 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.12 (s, 1H), 3.87 (s, 3H), 2.33 (s, 3H). The same synthetic procedure, or adaptations thereof, was applied to the synthesis of intermediates (III) in table 4 below, starting from proper intermediates. m / z was not observed. Table 4 - Intermediates (III) Structure IUPAC NameReagentsIntermediate Analytical data O -+N N O N Commerciall (III-21) y available Cl F F methyl (E)-2-azido-3-(2-chloro-3,4-difluoro-phenyl)prop-2-enoate LC-MS Method 1: r.t.1.38 minO -+N N O N Commerciall (III-22) y available Cl F methyl (E)-2-azido-3-(2-chloro-3-fluoro-4-methyl-phenyl)prop-2-enoate LC-MS Method 1: r.t.1.44 min O -+N N O N Commerciall (III-27) y available Cl O F methyl (E)-2-azido-3-(2-chloro-3-fluoro-4-methoxy-phenyl)prop-2-enoate LC-MS Method 1: r.t.1.33 min O - N+N O N Commerciall (III-28) y available F F methyl (E)-2-azido-3-(2,3-difluoro-4-methyl-phenyl)prop-2-enoate LC-MS Method 1: r.t.1.38 min O - N+N O N Commerciall (III-38) y available F LC-MS Method 1: r.t.1.38 min Intermediates (IV) Intermediate (IV-2): methyl 4-chloro-6- 1H-indole-2-carboxylateMethyl (Z)-2-azido-3-(2-chloro-4-methylphenyl)acrylate (III-2) (5.40 g, 21.5 mmol) was added to xylene (216 mL) in one portion at 130 °C. The solution was stirred at reflux for 1.5 h. Reaction mixture was cooled to RT and evaporated to a small volume. To the residue was added n-heptane and the resulting mixture was stirred with cooling in an ice bath for 2 h. The obtainedsolid was filtered, washed with n-heptane and dried in vacuo to yield the title compound as light yellow solid (3.34 g, 14.3 mmol, yield: 70 %). LC-MS Method 1: r.t.1.22 min, MS ESI (+) m / z = 224.02 [M+H]+. The same synthetic procedure, or adaptations thereof, was applied to the synthesis of intermediates (IV) in Table 5 below, starting from proper intermediates (III): Table 5 - Intermediates (IV) Structure IUPAC NamReagentsIntermediateeAnalytical data Cl F O (III-21) (IV-21)FN HOmethyl 4-chloro-5,6-difluoro-1H-indole-2-carboxylate LC-MS Method 1: r.t.1.19 min, MS ESI (+) m / z = 244.29 [M-H]- Cl F O (III-22) (IV-22) N H O methyl 4-chloro-5-fluoro-6-methyl-1H-indole-2-carboxylate LC-MS Method 1: r.t.1.22 min, MS ESI (+) m / z = 240.32 [M-H]- Cl F O (III-27) (IV-27)ONOHmethyl 4-chloro-5-fluoro-6-methoxy-1H-indole-2-carboxylate LC-MS Method 1: r.t.1.14 min, MS ESI (+) m / z = 257.95 [M+H]+F F O (III-28) (IV-28) N O H methyl 4,5-difluoro-6-methyl-1H-indole-2-carboxylate LC-MS Method 1: r.t.1.14 min, MS ESI (+) m / z = 226.02 [M+H]+Intermediate (IV-9): methyl 4-chloro-6-(morpholinomethyl)-1H-indole-2-carboxylate Omethyl 4-chloro-6-methyl-1H-indole-2-carboxylate (93.0 mg, 0.416 mmol) was dissolved in THF (3 mL) Boc2O (99.8 mg, 0.457 mmol) was added followed by N,N-dimethylpyridin-4-amine (5.08 mg, 0.0416 mmol). RM was stirred at rt overnight. Reaction mixture was diluted with DCM and washed with sat NaHCO3. Organic layer was concentrated and the residue was purified by FCC (EtOAc in cyclohexane 0-30%) to give the title compound (104, 0.3 mmol, yield 73 %). LC-MS Method 1: r.t.1.57 min, MS ESI (+) m / z = 268 [M-56+H]+To a solution of 1-(tert-butyl) 2-methyl 4-chloro-6-methyl-1H-indole-1,2-dicarboxylate (104 mg, 0.321 mmol) in DCE (4.0 mL), N-Bromosuccinimide (57.2 mg, 0.321 mmol) was added followed by AIBN (10.5 mg, 0.0642 mmol) and the mixture was stirred at 75°C for 2h, then it was concentrated and purified by FCC (EtOAc in cyclohexane 1 / 9) to obtain title compound (62 mg, 0.14 mmol, yield 44 %). =1-(tert-butyl) 2-methyl 6-(bromomethyl)-4-chloro-1H-indole-1,2-dicarboxylate (62.0 mg, 0.154 mmol) was dissolved in THF (3 mL), morpholine (0.0404 mL, 0.462 mmol) was added and the mixture was stirred at rt for 3 hours. The mixture was concentrated and purified by FCC (EtOAc in cyclohexane 0-50%) to obtain title compound (49 mg, 0.12 mmol, yield 84%). LC-MS Method 1: r.t.0.85 min, MS ESI (+) m / z = 409 [M+H]+. Step 4: methyl 4-chloro-6-(morpholinomethyl)-1H-indole-2-carboxylate IV-9 1-(tert-butyl) 2-methyl 4-chloro-6-(morpholinomethyl)-1H-indole-1,2-dicarboxylate (37.0 mg, 0.09 mmol) was dissolved in DCM (2 mL), 2,2,2-trifluoroacetic acid (0.202 mL, 2.7 mmol) was added and the mixture was stirred at rt overnight. Then it was concentrated, redissolved in DCM / sat NaHCO3. Organic layer was separated and dried to give the title compound (28 mg, 0.09 mmol, yield 98 % ), which was used in the next step as it is. LC-MS Method 1: r.t.0.65 min, MS ESI (+) m / z = 309 [M+H]+. The same synthetic sequence, or adaptations thereof, was applied to the synthesis of intermediate (IV-8) in table 6 below, starting from proper commercially available intermediate, following the four steps: Table 6 - Intermediates (IV) Structure Reagents Intermediate IUPAC Name Analytical data Cl commercially O available ethyl 4- chloro-6-methyl- N O 1H-indole-2- H carboxylate, (IV-8) N following the four O synthetic step of (IV-9) ethyl 4-chloro-7-(morpholinomethyl)-1H-indole-2-carboxylate LC-MS Method 1: r.t.0.78 min, MS ESI (+) m / z = 323 [M+H]+Intermediates (V) Intermediate (V-2): methyl 4- 1H-indole-2-carboxylate(V-2)To a solution of methyl 4-chloro-6-methyl-1H-indole-2-carboxylate (3.34 g, 14.9 mmol) in dry DMF (45 mL) was added potassium carbonate (6.19 g, 44.8 mmol), followed by MeI (6.36 g, 2.79 mL, 44.8 mmol). The resulting mixture was heated to 60°C and stirred for 4 h. The reaction mixture was cooled down to RT and quenched with water. Formed precipitate was filtered, washed with water and dried. The sample was triturated with methanol. The obtained solid was filtered, washed with methanol and dried in vacuum to yield the title compound as white solid (2.47 g, 10.4 mmol, 70 % yield). LC-MS Method 1: r.t.1.40 min, MS ESI (+) m / z = 238.04 [M+H]+. The same synthetic procedure, or adaptations thereof, was applied to the synthesis of intermediates (V) in table 7 below, starting from proper intermediates (IV): Table 7 - Intermediates (V) Structure IUPAC NReagentsIntermediateameAnalytical data O Cl O Commerciall (V-5) F N y available CH3methyl 4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxylate LC-MS Method 1: r.t.1.29 min, MS ESI (+) m / z = 241.88 [M+H]+Cl O N O (IV-8) (V-8) N O ethyl 4-chloro-1-methyl-7-(morpholinomethyl)-1H-indole-2-carboxylate LC-MS Method 1: r.t.0.93 min, MS ESI (+) m / z = 337 [M+H]+O Cl O N CH (IV-9) (V-9)3O N methyl 4-chloro-1-methyl-6-(morpholinomethyl)-1H-indole-2-carboxylate LC-MS Method 1: r.t.0.70 min, MS ESI (+) m / z = 323 [M+H]+Cl F O (IV-21) (V-21)FNOmethyl 4-chloro-5,6-difluoro-1-methyl-indole-2-carboxylate LC-MS Method 1: r.t.1.36 min, MS ESI (+) m / z = 259.97 [M+H]+Cl F O (IV-22) (V-22) N O methyl 4-chloro-5-fluoro-1,6-dimethyl-indole-2-carboxylate LC-MS Method 1: r.t.1.40 min, MS ESI (+) m / z = 255.96 [M+H]+Cl F O (IV-27) (V-27)ONOmethyl 4-chloro-5-fluoro-6-methoxy-1-methyl-indole-2-carboxylate LC-MS Method 1: r.t.1.29 min, MS ESI (+) m / z = 271.89 [M+H]+F F O (IV-28) (V-28) N O methyl 4,5-difluoro-1,6-dimethyl-indole-2-carboxylate LC-MS Method 1: r.t.1.33 min, MS ESI (+) m / z = 240.05 [M+H]+O Commerciall(V-32)NOy available methyl 1,4,6-trimethylindole-2-carboxylate LC-MS Method 1: r.t.1.35 min, MS ESI (+) m / z = 218.09 [M+H]+F O Commerciall (V-38) N O y available methyl 4-fluoro-1,6-dimethyl-indole-2-carboxylate LC-MS Method 1: r.t.1.30 min, MS ESI (+) m / z = 222.07 [M+H]+Intermediate (V-20): methyl 4-chloro-1-methyl-6-(2-morpholinoethyl)indole-2- carboxylate Cl Step 1: methyl 4-chloro-1-indole-2-carboxylate (X-20) Clmethyl 6-bromo-4-chloro-1-methyl-indole-2-carboxylate (WO2018167019, 200 mg, 0.66 mmol) was added to a vial followed by potassium;trifluoro(2-tetrahydropyran-2- yloxyethyl)boranuide (0.234 g, 0.99 mmol), toluene (4 mL), dicesium;carbonate (0.646 g, 1.98 mmol) and water (1.2 mL). Argon was bubbled into the mixture and Pd(Amphos)Cl2 (0.047 g, 0.066 mmol) was added. The tube was sealed, evacuated, backfilled with argon and heated at 100°C for 4 hours. The mixture was diluted with EtOAc and water, layers were separated, organic layer was washed with water, dried and concentrated to get a crude which was purified by FCC (EtOAc in cyclohexane 0-50%) to obtain title compound (136 mg, 0.34 mmol, 51 % yield). LC-MS Method 1: r.t.1.47 min, MS ESI (+) m / z = 352 [M+H]+methyl 4-chloro-1-methyl-6-(2-tetrahydropyran-2-yloxyethyl)indole-2-carboxylate (136 mg, 0.387 mmol) was dissolved in MeOH (2 mL), 4-methylbenzenesulfonic acid (0.0133 g, 0.077 mmol) was added and the mixture was stirred at rt for 2 hours. The reaction mixture was diluted with DCM and washed with sat NaHCO3. Organic layer was dried and concentrated to get a crude which was purified by FCC (EtOAc in cyclohexane 0-60%) to give title compound (90 mg, 0.32 mmol, 82 % yield). LC-MS Method 1: r.t.1.05 min, MS ESI (+) m / z = 268 [M+H]+Step 3: methyl 4-chloro-1-methyl-6-(2-methylsulfonyloxyethyl)indole-2-carboxylate (XII- 20)Cl methyl 4-chloro-6-(2-(50 mg, 0.19 mmol) was dissolved in DCM (2 mL). The mixture was cooled down to 0°C then Mesyl chloride (28.9 µL, 0.37 mmol) was added followed by N,N-diethylethanamine (52.1 µL, 0.37 mmol). The resulting mixture was stirred at rt for 1 h. Reaction was quenched with sat NH4Cl and extracted with DCM. Organic phase was separated, dried and concentrated to get title compound which was used in next step as it is (65 mg, 0.17 mmol, 94 % yield). LC-MS Method 1: r.t.1.19 min, MS ESI (+) m / z = 346 [M+H]+Step 4: methyl 4-chloro-1-methyl-6-(2-morpholinoethyl)indole-2-carboxylate (V-20) methyl 4-chloro-1-methyl-6-(2-methylsulfonyloxyethyl)indole-2-carboxylate (45.0 mg, 0.13 mmol) was dissolved in MeCN (2 mL), morpholine (22.5 µL, 0.26 mmol) was added and the mixture was heated at 75°C overnight. The reaction mixture was concentrated and purified by FCC (from 0 to 10% MeOH in DCM) to give title compound (30 mg, 0.085, 65 % yield). LC-MS Method 1: r.t.0.74 min, MS ESI (+) m / z = 337.26 [M+H]+Intermediates (VI) Intermediate (VI-2): 4-chloro-1,6-dimethyl-1H-indole-2-carboxylic acidTo a solution of methyl 4-chloro-1,6-dimethyl-1H-indole-2-carboxylate (2.47 g, 10.4 mmol) in a solvent mixture of THF (50 mL) and H2O (50 mL) was added LiOH (747 mg, 31.2 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated, diluted with water and acidified with aqueous 1M HCl solution until pH=1.5. The formed precipitate was collected by filtration, washed with water and dried to yield the title compound as white solid (2.29 g, 10.2 mmol, yield 99 %). LC-MS Method 1: r.t.1.14 min, MS ESI (+) m / z = 224.02 [M+H]+. The same synthetic procedure, or adaptations thereof, was applied to the synthesis of intermediates (VI) in table 8 below, starting from proper intermediates (V):Table 8 - Intermediates (VI) Structure Reagents Intermediate IUPAC Name Analytical data OH Cl O N (V-5) (VI-5) F CH34-chloro-5-fluoro-1-methyl-1H-indole-2-carboxylic acid LC-MS Method 1: r.t.1.05 min, MS ESI (+) m / z = 227.97 [M+H]+Cl O N OH (V-8) (VI-8) N O 4-chloro-1-methyl-7-(morpholinomethyl)-1H-indole-2-carboxylic acid LC-MS Method 1: r.t.0.63 min, MS ESI (+) m / z = 309 [M+H]+OH Cl O N ( 9) C V-9) (VI- H3O N 4-chloro-1-methyl-6-(morpholinomethyl)-1H-indole-2-carboxylic acid LC-MS Method 1: r.t.0.63 min, MS ESI (+) m / z = 309 [M+H]+Cl O N N OH (V-20) (VI-20) O 4-chloro-1-methyl-6-(2-morpholinoethyl)indole-2-carboxylic acid LC-MS Method 1: r.t.0.57 min, MS ESI (+) m / z = 323.21 [M+H]+Cl F O (V-21) (VI-21)FNOH4-chloro-5,6-difluoro-1-methyl-indole-2-carboxylic acid LC-MS Method 1: r.t.1.11 min, MS ESI (+) m / z = 245.89 [M+H]+Cl F O (V-22) (VI-22) N OH 4-chloro-5-fluoro-1,6-dimethyl-indole-2-carboxylic acid LC-MS Method 1: r.t.1.15 min, MS ESI (+) m / z = 239.96 [M-H]- Cl F O (V-27) (VI-27)ONOH4-chloro-5-fluoro-6-methoxy-1-methyl-indole-2-carboxylic acid LC-MS Method 1: r.t.1.04 min, MS ESI (+) m / z = 257.95 [M+H]+F F O (V-28) (VI-28) N OH 4,5-difluoro-1,6-dimethyl-indole-2-carboxylic acid LC-MS Method 1: r.t.1.09 min, MS ESI (+) m / z = 224.01 [M-H]- O (V-32) (VI-32) N OH 1,4,6-trimethylindole-2-carboxylic acid LC-MS Method 1: r.t.1.10 min, MS ESI (+) m / z = 204.09 [M-H]- F O (V-38) (VI-38) N OH 4-fluoro-1,6-dimethyl-indole-2-carboxylic acid LC-MS Method 1: r.t.1.06 min, MS ESI (+) m / z = 208.06 [M+H]+Intermediate (XIV): tert-butyl - -2-hydroxyethyl)carbamate(XIV) To a solution of commercially available (S)-2-amino-2-(4-bromophenyl)ethan-1-ol (commercially available, eNovation Chemicals LLC) (10.0 g, 46.3 mmol) in dry DCM (70 mL)and EtOH (5 mL), triethylamine (12.9 mL, 92.6 mmol) was added. The reaction mixture was cooled to 0 °C and solution of Boc2O (11.11 g, 50.91 mmol) in dry DCM (30 ml) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h, then allowed to reach RT and stirred for additional 3 h. The reaction mixture was diluted with DCM (100 ml) and organic layer was washed with saturated aqueous NaHCO3(2x70 mL) and brine (2x70 mL), then dried over anhydrous Na2SO4and evaporated to give the title compound as white solid (14.723 g, 44.2 mmol, yield 96 %). LC-MS Method 1: r.t.1.05 min, MS ESI (+) m / z = 260.03 / 262.01 [M-56+H]+. Intermediate (XV): tert-butyl (S)-4-(4-bromophenyl)-2,2-dimethyloxazolidine-3- carboxylate O(XV) To the solution of tert-butyl N-[(1S)-1-(4-bromophenyl)-2-hydroxy-ethyl]carbamate (17.7 g, 56.0 mmol) in acetone (300 mL), p-toluenesulfonic acid monohydrate (1065 mg, 5.6 mmol) and 2,2-dimethoxy propane (68.59 mL, 279.9 mmol) were added. The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to a smaller volume, then 250 mL of EtOAc was added and resulting mixture washed with saturated aqueous NaHCO3 (2x50 mL) and brine (3x50 mL), then dried over anhydrous Na2SO4and evaporated to give the title compound as yellow solid (19.76 g, 55.5 mmol, yield 99 %). LC-MS Method 1: r.t.1.42 min, MS ESI (+) m / z = 299.93 / 301.93 [M-56+H]+. Intermediate (XVI): tert-butyl (S)-4-(4-(2-ethoxy-2-oxoethyl)phenyl)-2,2- dimethyloxazolidine-3-carboxylateStep 1: Synthesis of Reformatsky reagent / bromo-(2-ethoxy-2-oxo-ethyl)zinc: A mixture of the zinc granular, 30-100 mesh (20.0 g, 306.0 mmol) in anhydrous 2-MeTHF (125 mL), under N2, was warmed to 30 °C. At that temperature ethyl 2-bromoacetate (1.25 g, 0.83 mL, 7.5 mmol), followed by DIBAL-H, 1M in toluene (2.99 mL, 3.0 mmol) were added to the reaction mixture. The suspension was heated to 40 °C and then ethyl 2-bromoacetate (25 g, 16.6 mL, 150.0 mmol) was added dropwise over 1.5 h, maintaining the temperature between 45 °C and 50 °C. During that period color of the reaction mixture became orange. After the addition of 2-bromoacetate was completed, the reaction mixture was stirred for 40 minutes, during which time the temperature of the reaction mixture gradually decreased to RT. The resulting mixture was used in the next reaction step as is, calculating concentration as 1.05 mol / L. Step 2: Negishi coupling. A solution of tert-butyl (4S)-4-(4-bromophenyl)-2,2-dimethyl-oxazolidine-3-carboxylate (13.6 g, 38.2 mmol) in 2-MeTHF (100 mL) was purged with N2for 20 min. The purging of the reaction with N2 was continued and then XPhos (3.64 g, 7.6 mmol), followed by Pd2(dba)3 (3.50 g, 3.8 mmol) were added. The reaction mixture was heated to 60 °C and then freshly prepared solution of bromo-(2-ethoxy-2-oxo-ethyl)zinc, 1.05 M in 2-MeTHF (90.9 mL, 95.4 mmol) was added dropwise at 60°C over 2 h. The reaction mixture was stirred at 60°C for additional 30 min, then cooled to RT. To the reaction mixture saturated aqueous NH4Cl (100 ml) was added, stirred for 30 min and filtered over a pad of Celite. The residue was washed with 200 mL of EtOAc. The layers were separated, and the organic layer was washed with brine (2 x 100 mL) and concentrated in vacuo to give the crude product (20.62 g) as purple oily residue. The crude product was purified by flash chromatography on a Si cartridge (gradient elution 0-8 % EtOAc in cyclohexane). Fractions with pure product were combined and evaporated under reduced pressure to yield the title compound as brown oil (8.16 g, 22.2 mmol, yield 58 %). LC-MS Method 1: r.t.1.33 min, MS ESI (+) m / z = 308.15 [M-56+H]+. Intermediates (XVII) Intermediate (XVII-1): tert-butyl (4S)-4-(4-(1-ethoxy-1-oxobutan-2-yl)phenyl)-2,2- dimethyloxazolidine-3-carboxylate(XVII-1) To a solution of tert-butyl (4S)-4-[4-(2-ethoxy-2-oxo-ethyl)phenyl]-2,2-dimethyl- oxazolidine-3-carboxylate (2.0 g, 5.50 mmol) in THF (45.0 mL), LiHMDS (1.3 M in THF, 4.66 mL, 6.1 mmol) was added dropwise at 0°C under Argon. The reaction mixture was stirred at 0 °C for 1 h, then iodoethane (858 mg, 5.5 mmol) dissolved in THF (10 ml) was added dropwise into the solution at -10-0 °C and stirring was continued at -10-0°C for 2 h. The reaction mixture was poured into cold saturated aqueous ammonium chloride solution (55 ml) and extracted with EtOAc (3 x 55 ml). The organic layers were combined, dried and evaporated. The obtained crude product was purified by flash chromatography on a Si cartridge (gradient elution 0-10 % EtOAc in cyclohexane) to give the title compound (1.75 g, 4.34 mmol, yield 79 %).LC-MS Method 1: r.t.1.46 min, MS ESI (+) m / z = 336.12 [M-56+H]+. The same synthetic procedure, or adaptations thereof, was applied to the synthesis of intermediates (XVII) in table 9 below, starting from proper intermediates: Table 9 - Intermediates (XVII) Structure teIUPAC NReagentsIntermediaameAnalytical data O O O O (XVI) (XVII-10) O N O tert-butyl (4S)-4-[4-(1-ethoxycarbonyl-3-methoxy-propyl)phenyl]-2,2- dimethyl-oxazolidine-3-carboxylate LC-MS Method 1: r.t.1.35 min, MS ESI (+) m / z = 366.10 [M+H-56]+O O N O (XVI) (XVII-12) O O O tert-butyl (4S)-4-(4-(2-ethoxy-2-oxo-1-(tetrahydro-2H-pyran-4- yl)ethyl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate LC-MS Method 1: r.t.1.37 min, MS ESI (+) m / z = 392.22 [M+H-56]+O N O O (XVI) (XVII-13) F O F F O tert-butyl (4S)-4-[4-(1-ethoxycarbonyl-4,4,4-trifluoro-butyl)phenyl]-2,2- dimethyl-oxazolidine-3-carboxylate LC-MS Method 1: r.t.1.48 min, MS ESI (+) m / z = 404.18 [M+H-56]+O N O O O (XVI) (XVII-24) O tert-butyl (4S)-4-[4-(2-ethoxy-1-methyl-2-oxo-ethyl)phenyl]-2,2- dimethyl-oxazolidine-3-carboxylate LC-MS Method 1: r.t.1.38 min, MS ESI (+) m / z = 378.09 [M+H]+Intermediate (XXI-14): methyl 1-(4-((1S)-2-((tert-butyldimethylsilyl)oxy)-1-((tert- butylsulfinyl)amino)ethyl)phenyl)cyclobutane-1-carboxylate(S)-2-methylpropane-2-sulfinamide (3.00 g, 240.3 mmol) and 2-[tert- butyl(dimethyl)silyl]oxyacetaldehyde (3.00 g, 16.3 mmol) were dissolved in THF (45 mL) under argon. Tetraethoxytitanium (7.77 g, 32.7 mmol) was added dropwise and reaction mixture was stirred at 50°C for 1 hour then at rt for additional 2 hours. Reaction mixture was quenched with brine and the precipitate was filtered off over Celite and washed with ethyl acetate. The organic layer was separated by separatory funnel and washed with brine, dried over Na2SO4and concentrated in vacuo to provide crude that was purified by FCC (EtOAc in cyclohexane 0-20%) to obtain title compound (2.75 g, 9.9 mmol, yield 61 %). TLC(EtOAc / cyclohexane=8 / 2) showed formation of desired imine and no more starting aldehyde. 2: 1- -2- (dimethyl)silyl]oxy-1-(tert-HTo a solution of 1-(4-bromophenyl)cyclobutanecarboxylic acid (500 mg, 2.05 mmol) in THF (20 mL) at - 78°C under argon, butyllithium (2500 mmol / L, 3.14 mL, 7.84 mmol) was added dropwise. Reaction mixture was stirred at that temperature for 30 minutes and then solution of (E)- N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (684 mg, 2.46 mmol) in THF (5 mL) was added dropwise. Reaction mixture was stirred at that temperature for 30 minutes. Reaction mixture was quenched with water and warmed up to rt. Diethylether was added to the mixture, aq layer was separated and cooled to 5°C then acidified with 1M HCl to pH 4, product was extracted with ethyl acetate. Combined organics were dried over Na2SO4and concentrated in vacuo to provide title compound which was used as it is in the next step (475 mg, 0.29 mmol, yield 15 %). LC-MS Method 1: r.t.1.44 min, MS ESI (+) m / z = 454.31 [M+H]+Step 3: methyl 1-(4-((1S)-2-((tert-butyldimethylsilyl)oxy)-1-((tert- butylsulfinyl)amino)ethyl)phenyl)cyclobutane-1-carboxylate (XXI-14) To a solution of 1-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(tert- butylsulfinylamino)ethyl]phenyl]cyclobutanecarboxylic acid (475 mg, 1.05 mmol) in DMF (5 mL) potassium carbonate (0.434 g, 3.14 mmol) was added followed by iodomethane (0.135 mL, 2.09 mmol). Reaction mixture was stirred at rt for 1h, then it was diluted with EtOAc and washed with water. Organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide a crude product that was purified by FCC (EtOAc in cyclohexane 0-50%) to give title compound (91 mg, 0.19 mmol, 19 %). LC-MS Method 1: r.t.1.60 min, MS ESI (+) m / z = 468.34 [M+H-56]+Intermediate (XVII-18): tert-butyl (S)-4-(4-(4-(ethoxycarbonyl)tetrahydro-2H-pyran- 4-yl)phenyl)-2,2-dimethyloxazolidine-3-carboxylateO To a solution of tert-butyl (4S)-4-[4-(2-ethoxy-2-oxo-ethyl)phenyl]-2,2-dimethyl- oxazolidine-3-carboxylate (0.500 g, 1.38 mmol) in anhydrous DMF (2.5 mL), sodium hydride (60.0 %, 110.0 mg, 2.75 mmol) was added at 0°C and the reaction was stirred at 0°C for 30 min. Then 1-bromo-2-(2-bromoethoxy)ethane (182 µL, 1.44 mmol) was added into the solution dropwise at 0°C. The reaction mixture was left stirring at rt for 1 h.The mixture was quenched with NH4Cl sat. solution and extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4, filtered off and evaporated in vacuo to obtain a crude which was purified by FCC (from 100 % of Cyclohexane to 75% / 15% Cyclohexane / EtOAc) to give title compound (212 mg, 0.49 mmol, yield 36 %). LC-MS Method 1: r.t.1.34 min, MS ESI (+) m / z = 378.18 [M+H-56]+Intermediate (XVII-33): tert-butyl (4S)-4-(4-(2-ethoxy-2-oxo-1-(pyridin-3- yl)ethyl)phenyl)-2,2-dimethyloxazolidine-3-carboxylatePalladium(II) acetate (37.1 mg, 0.165 mmol) and DavePhos (130 mg, 0.330 mmol) were dissolved in toluene (4 mL), sonicated and degassed by bubbling argon for 15 minutes. Reaction mixture was chilled to -10 °C. To the reaction mixture LDA (1.30 mmol / L, 414 mg, 2.48 mmol) was added dropwise and reaction mixture was stirred for 15 minutes at - 10 °C. Then ethyl 2-(3- pyridyl)acetate (273 mg, 1.65 mmol) was dissolved in toluene (2 mL) and the mixture was added dropwise to the reaction mixture. Reaction mixture was stirred for 15 minutes at - 10 °C. Then Intermediate XV, tert-butyl (4S)-4-(4-bromophenyl)-2,2-dimethyl-oxazolidine-3-carboxylate (300 mg, 0.825 mmol) was dissolved in toluene (4 mL) and added dropwise to the reaction mixture that was heated at 80 °C and stirred for 1.5 hours. Reaction mixture was partitioned between ethyl acetate and water. Organic phase was washed with brine, dried over Na2SO4and concentrated in vacuo to provide a crude which was purified by FCC (from 100 % cyclohexane to 70 / 30 cyclohexane / ethyl acetate) to obtain title compound (288 mg, 0.621 mmol, 75 %). LC-MS Method 1: r.t.1.07 min, MS ESI (+) m / z = 441.27 [M+H]+Intermediates (XVIII) Intermediate (XVIII-1): ethyl 2-(4-((S)-1-amino-2-hydroxyethyl)phenyl)butanoate hydrochlorideCH3(XVIII-1) tert-Butyl (4S)-4-[4-(1-ethoxycarbonylpropyl)phenyl]-2,2-dimethyl-oxazolidine-3- carboxylate (1.75 g, 4.5 mmol) was dissolved in 4M HCl in dioxane (7.50 g, 51.4 ml, 205.6 mmol). The reaction mixture was stirred at RT overnight, then concentrated in vacuo to give crude title product as colorless oil (hydrochloride; 1.37 g, quantitative yield). LC-MS Method 1: r.t.0.62 min, MS ESI (+) m / z = 252.11 [M+H]+. The same synthetic procedure, or adaptations thereof, was applied to the synthesis of intermediates (XVIII) in table 10 below, starting from proper intermediates: Table 10 - Intermediates XVIII Structure teIUPReagentsIntermediaAC NameAnalytical data OH H2N tert-butyl (4S)- 4-[4-(2-ethoxy- 2-oxo- ethyl)phenyl]- (XVIII-10) 2,2-dimethyl- O O oxazolidine-3- O carboxylate tert-butyl (4S)-4-[4-(1-ethoxycarbonyl-3-methoxy-propyl)phenyl]-2,2- (XVII-10) dimethyl-oxazolidine-3-carboxylate LC-MS Method 1: r.t.0.73 min, MS ESI (+) m / z = 282.10 [M+H]+NH2HO O O (XVII-12) (XVIII-12) O ethyl 2-(4-((S)-1-amino-2-hydroxyethyl)phenyl)-2-(tetrahydro-2H-pyran- 4-yl)acetate LC-MS Method 1: r.t.0.56 min, MS ESI (+) m / z = 308.14 [M+H]+OH NH2(XVII-13) (XVIII-13) F O F F O ethyl 2-(4-((S)-1-amino-2-hydroxyethyl)phenyl)-5,5,5-trifluoropentanoate LC-MS Method 1: r.t.0.93 min, MS ESI (+) m / z = 320.11 [M+H]+NH2HO (XXI-14) (XVIII-14) O O methyl 1-[4-(1-amino-2-hydroxy-ethyl)phenyl]cyclobutanecarboxylate LC-MS Method 1: r.t.0.78 min, MS ESI (+) m / z = 250.10 [M+H]+HONH2 O (XVII-18) (XVIII-18) O O ethyl 4-[4-[(1S)-1-amino-2-hydroxy-ethyl]phenyl]tetrahydropyran-4- carboxylate LC-MS Method 1: r.t.0.52 min, MS ESI (+) m / z = 294.11 [M+H]+NH2HO O (XVII-24) (XVIII-24) O ethyl 2-[4-[(1S)-1-amino-2-hydroxy-ethyl]phenyl]propanoate LC-MS Method 1: r.t.0.54 min, MS ESI (+) m / z = 238.11 [M+H]+NH2HO O O (XVII-33) (XVIII-33) N ethyl 2-[4-[(1S)-1-amino-2-hydroxy-ethyl]phenyl]-2-(3-pyridyl)acetate LC-MS Method 1: r.t.0.69 min, MS ESI (+) m / z = 301.09 [M+H]+PREPARATION OF EXAMPLES: Example (I-2): ethyl 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoate HO(I-2) To a solution of 4-chloro-1,6-dimethyl-indole-2-carboxylic acid (1.00 g, 4.5 mmol) in dry DMF (50 mL), HATU (2.04 g, 5.37 mmol) and DIPEA (2.34 mL, 13.41 mmol) were added. After stirring at RT for 15 min, ethyl 2-[4-[(1S)-1-amino-2-hydroxy-ethyl]phenyl]butanoate hydrochloride (1.42 g, 4.9 mmol) was added and stirring was continued at RT for 2 h. Reaction was quenched with saturated aqueous NaHCO3solution and resulting mixture extracted with EtOAc (3x). The organic layers were combined, washed with saturated aqueous NaHCO3 solution and brine, then dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. Obtained crude product was purified by flash chromatography on a Si cartridge (gradient elution 0-50 % EtOAc in cyclohexane) to yield the title compound as brownish solid (1.34 g, 2.9 mmol, yield 66 %). LC-MS Method 1: r.t.1.33 min, MS ESI (+) m / z = 457.20 [M+H]+. The same synthetic procedure, or adaptations therof, was applied to the synthesis of Examples (I) in table 11 below, starting from proper Intermediates: Table 11 - Examples (I) Structure ExampleIUPAC NameReagentsAnalytical data HO HN O Cl Commercially OOavailable, (I-1) N (XVIII-1) CH3CH3ethyl 2-(4-((S)-1-(4-chloro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoate LC-MS Method 1: r.t.1.27 min, MS ESI (+) m / z = 443.14 [M+H]+.HO HN O Cl OO(VI-5), N (XVIII-1) (I-5) F CH3CH3ethyl 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)butanoate LC-MS Method 1: r.t.1.28 min, MS ESI (+) m / z = 461.15 [M+H]+ HO HN O Cl OO(VI-8), N (XVIII-1) (I-8) CH3N Oethyl 2-(4-((S)-1-(4-chloro-1-methyl-7-(morpholinomethyl)-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoate LC-MS Method 1: r.t.0.91 min, MS ESI (+) m / z = 542.24 [M+H]+ HO HN O Cl OO(VI-9), N (XVIII-1) (I-9) CH3CH3O N ethyl 2-(4-((S)-1-(4-chloro-1-methyl-6-(morpholinomethyl)-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoate LC-MS Method 1: r.t.0.83 min, MS ESI (+) m / z = 542.32 [M+H]+ HO HN O Cl OO(VI-2), N (I-10) (XVIII-10) CH3O H3C ethyl 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)-4-methoxybutanoate LC-MS Method 1: r.t.1.26 min, MS ESI (+) m / z = 487.18 [M+H]+HO HN O Cl OO(VI-5), (I-11) F N (XVIII-10) CH3O ethyl 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)-4-methoxybutanoate LC-MS Method 1: r.t.1.19 min, MS ESI (+) m / z = 491.21 [M+H]+ HO HN O Cl OO(VI-2), N (I-12) CH (XVIII-12) 3H3C Oethyl 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetate LC-MS Method 1: r.t.1.26 min, MS ESI (+) m / z = 513.18 / 515.18 [M+H]+ HO HN O Cl OO(VI-5), F N (I-13) CH3(XVIII-13) F F F ethyl 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)-5,5,5-trifluoropentanoate LC-MS Method 1: r.t.1.26 min, MS ESI (+) m / z = 513.18 / 515.18 [M+H]+ HO HN O Cl OO(VI-5), (I-14) (XVIII-14) F N CH3methyl (S)-1-(4-(1-(4-chloro-5-fluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)cyclobutane-1-carboxylate LC-MS Method 1: r.t.1.24 min, MS ESI (+) m / z = 459.12 [M+H]+HO HN O Cl OO(VI-2), N (I-15) CH3(XVIII-14) H3Cmethyl (S)-1-(4-(1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)cyclobutane-1-carboxylate LC-MS Method 1: r.t.1.29 min, MS ESI (+) m / z = 455.12 [M+H]+HO HN O Cl OO(VI-5), (I-16) F N CH3(XVIII-12) O ethyl 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetate LC-MS Method 1: r.t.1.19 min, MS ESI (+) m / z = 517.17 / 519.12 [M+H]+HO HN O Cl OO(VI-2), N (I-17) CH3(XVIII-13) H3C F FFethyl 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)-5,5,5-trifluoropentanoate LC-MS Method 1: r.t.1.37 min, MS ESI (+) m / z = 525.15 [M+H]+HO HN O Cl OO(VI-5), (I-18) (XVIII-18) F N CH3O ethyl (S)-4-(4-(1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)tetrahydro-2H-pyran-4-carboxylate LC-MS Method 1: r.t.1.17 min, MS ESI (+) m / z = 503.07 [M+H]+HO HN O Cl OO(VI-2), N (I-19) (XVIII-18) CH3O H3Cethyl (S)-4-(4-(1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)tetrahydro-2H-pyran-4-carboxylate LC-MS Method 1: r.t.1.24 min, MS ESI (+) m / z = 499.16 [M+H]+HO HN O Cl OO O(VI-20), (I-20) N (XVIII-1) N CH3CH3ethyl 2-(4-((S)-1-(4-chloro-1-methyl-6-(2-morpholinoethyl)-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoate LC-MS Method 1: r.t.0.84 min, MS ESI (+) m / z = 556.35 [M+H]+HO HN O Cl OO(VI-21), (I-21) F N CH (XVIII-18) 3 O F ethyl (S)-4-(4-(1-(4-chloro-5,6-difluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)tetrahydro-2H-pyran-4-carboxylate LC-MS Method 1: r.t.1.21 min, MS ESI (+) m / z = 521.19 [M+H]+HO HN O Cl OO(VI-22), F N (I-22) CH3(XVIII-18) O H3C ethyl (S)-4-(4-(1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)tetrahydro-2H-pyran-4-carboxylate LC-MS Method 1: r.t.1.24 min, MS ESI (+) m / z = 517.23 [M+H]+HO HN O Cl OO(VI-22), (I-23)FN CH3 CH3(XVIII-1) H3Cethyl 2-(4-((S)-1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoate LC-MS Method 1: r.t.1.33 min, MS ESI (+) m / z = 475.38 [M+H]+HO HN O Cl OO(VI-2), N CH (I-24) CH33(XVIII-24) H3C ethyl 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoate LC-MS Method 1: r.t.1.27 min, MS ESI (+) m / z = 443.15 [M+H]+HO HN O Cl OO(VI-27), (I-27) F N CH (XVIII-18) 3 O O ethyl (S)-4-(4-(1-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)tetrahydro-2H-pyran-4-carboxylate LC-MS Method 1: r.t.1.15 min, MS ESI (+) m / z = 533.24 [M+H]+HO HN O F OO(VI-28), (I-28)FN CH3 CH3(XVIII-1) H3Cethyl 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoate LC-MS Method 1: r.t.1.29 min, MS ESI (+) m / z = 459.23 [M+H]+HO HN O Cl OO(VI-27), (I-31)FN CH (XVII 3CH3I-1) O ethyl 2-(4-((S)-1-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoate LC-MS Method 1: r.t.1.25 min, MS ESI (+) m / z = 491.20 [M+H]+HO HN O H3C OO(VI-32), N (I-32) CH3CH3(XVIII-1) H3C ethyl 2-(4-((S)-2-hydroxy-1-(1,4,6-trimethyl-1H-indole-2- carboxamido)ethyl)phenyl)butanoate LC-MS Method 1: r.t.1.31 min, MS ESI (+) m / z = 437.27 [M+H]+HO HN O Cl OO(VI-2), N (I-33) CH3(XVIII-33) N H3C ethyl 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)-2-(pyridin-3-yl)acetate LC-MS Method 1: r.t.1.02 min, MS ESI (+) m / z = 506.23 [M+H]+HO HN O F OO(VI-28), (I-34)FNCHCH33(XVIII-24) H3Cethyl 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoate LC-MS Method 1: r.t.1.23 min, MS ESI (+) m / z = 445.22 [M+H]+HO HN O Cl OO(VI-21), (I-37)FN CH (XVII 3CH3I-1) F ethyl 2-(4-((S)-1-(4-chloro-5,6-difluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoate LC-MS Method 1: r.t.1.31 min, MS ESI (+) m / z = 479.18 [M+H]+HO HN O F OO(VI-38), N (I-38) CH3CH3(XVIII-1) H3C ethyl 2-(4-((S)-1-(4-fluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoate LC-MS Method 1: r.t.1.28 min, MS ESI (+) m / z = 441.22 [M+H]+HO HN O Cl OO(VI-22), (I-41)FNCHCH33(XVIII-24) H3C ethyl 2-(4-((S)-1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoate LC-MS Method 1: r.t.1.28 min, MS ESI (+) m / z = 461.16 [M+H]+HO HN O F OO(VI-28), F N (I-44) CH3(XVIII-14) H3C ethyl (S)-1-(4-(1-(4,5-difluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)cyclobutane-1-carboxylate LC-MS Method 1: r.t.1.26 min, MS ESI (+) m / z = 457.23 [M+H]+HO HN O Cl OO(VI-27) F N (I-45) CH (XVIII-14) 3 O methyl (S)-1-(4-(1-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)cyclobutane-1-carboxylate LC-MS Method 1: r.t.1.22 min, MS ESI (+) m / z = 489.18 [M+H]+Example 2: 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acidEthyl 2-[4-[ - 2-carbonyl)amino]-2-hydroxy- ethyl]phenyl]butanoate (1.34 g, 2.9 mmol) was dissolved in THF (20.5 mL) / MeOH (20.5 mL) / water (20.5 mL) solvent mixture, then lithium hydroxide (562 mg, 23.5 mmol) was added. The reaction mixture was left stirring at RT overnight. On completion, the reaction mixture was evaporated in vacuo. The residue was diluted with water and solution was acidified with aqueous 1M HCl to pH 1.5. Formed precipitate was collected by filtration, washed with water and dried in vacuum oven to yield the title compound as white solid (1.24 g, 2.8 mmol, yield 96 %). LC-MS Method 2: r.t.6.80 min, MS ESI (+) m / z = 429.37 [M+H]+. 1H NMR (500 MHz, MeOD-d4): δ 7.39 – 7.29 (m, 4H), 7.19 (s, 2H), 6.98 (s, 1H), 5.15 (t, J = 6.7 Hz, 1H), 3.92 (s, 3H), 3.82 (d, J = 6.7 Hz, 2H), 3.34 – 3.30 (m, 1H), 2.45 (s, 3H), 2.08 – 1.97 (m, 1H), 1.73 – 1.62 (m, 1H), 0.89 (t, J = 7.3 Hz, 3H). The same synthetic procedure, or adaptations thereof, was applied to the synthesis of Examples and Intermediate in table 12 below, starting from corresponding reagent (I):Table 12 - Examples Structure Yield and Reagents Example IUPAC Name Amount Analytical data HO HN O Cl OOH27 mg; yield: (I-1) N 42% CH3CH3 1 2-(4-((S)-1-(4-chloro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid LC-MS Method 2: r.t.6.02 min, MS ESI (+) m / z = 415.19 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.31 - 12.22 (br s, 1 H), 8.89 (d, J=8.2 Hz, 1 H), 7.54 (d, J=8.2 Hz, 1 H), 7.40-7.32 (m, 3 H), 7.28 - 7.23 (m, 3 H), 7.19 (d, J=7.6 Hz, 1 H), 5.08 - 5.02 (m, 1 H), 4.96 (t, J=5.8 Hz, 1 H), 3.97 (s, 3 H), 3.75 - 3.68 (m, 1 H), 3.68 - 3.62 (m, 1 H), 3.38 (t, J=7.6 Hz, 1 H), 1.99 - 1.90 (m, 1 H), 1.68 - 1.59 (m, 1 H), 0.82 (t, J=7.2 Hz, 3 H). HO HN O Cl OOH71 mg; (I-5) N yield: 95% F CH3CH32-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2- 5 carboxamido)-2-hydroxyethyl)phenyl)butanoic acid LC-MS Method 2: r.t.6.06 min, MS ESI (+) m / z = 433.16 [M+H]+1H NMR (DMSO-d6 , 600 MHz): δ 9.38 (1H, br s), 9.19 (1H, br d, J = 8.3 Hz), 7.57 (2H, dddd, J = 9.1 Hz, J = 3.8 Hz, J = 1.9 Hz, J = 0.8 Hz), 7.50 (1H, s), 7.44 (1H, d, J = 0.6 Hz), 7.30 (2H, ddd, J = 9.9 Hz, J = 9.0 Hz, J = 2.6 Hz), 7.21 - 7.27 (8H, m), 5.30 (2H, br s), 4.93 - 5.02 (2H, m), 3.97 (3H, s), 3.97 (3H, s), 3.48 - 3.65 (4H, m), 3.14 - 3.20 (2H, m), 1.88 - 1.99 (2H, m), 1.53 (2H, dtd, J = 13.5 Hz, J = 6.9 Hz, J = 3.7 Hz), 0.80 (3H, t, J = 7.3 Hz), 0.79 (3H, t, J = 7.3 Hz) (mixture of two diastereoisomers). HO HN O Cl OOH7 mg; yield: 8 N (I-8) CH345% NO2-(4-((S)-1-(4-chloro-1-methyl-7-(morpholinomethyl)-1H- indole-2-carboxamido)-2-hydroxyethyl)phenyl)butanoic acidLC-MS Method 2: r.t.4.69 min, MS ESI (+) m / z = 514.35 [M+H]+.1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 7.40 (d, J = 7.4 Hz, 2H), 7.33 (d, J = 7.4 Hz, 2H), 7.26 (s, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 5.19 (t, J = 6.6 Hz, 1H), 4.41 (br s, 2H), 4.23 (s, 3H), 3.85 (d, J = 6.9 Hz, 2H), 3.70-3.82 (m, 4H), 3.45 (t, J = 7.6 Hz, 1H), 2.79-3.09 (bs, 4H), 2.02-2.13 (m, 1H), 1.70-1.81 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H) HO HN O Cl OOH17 mg; N (I-9) CH3CH3yield: 63% O N 2-(4-((S)-1-(4-chloro-1-methyl-6-(morpholinomethyl)-1H- indole-2-carboxamido)-2-hydroxyethyl)phenyl)butanoic acid LC-MS Method 2: r.t.4.36 min, MS ESI (+) m / z = 514.29 [M+H]+1H NMR (METHANOL-d4, 500 MHz): δ (ppm) 7.53 (s, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.30 (s, 1H), 7.28 (s, 1H), 5.19 (t, J = 6.6 Hz, 1H), 4.12 (br s, 2H), 4.00 (s, 3H), 3.86 (d, J = 6.7 Hz, 2H), 3.80 (br s, 4H), 3.44 (t, J = 7.6 Hz, 1H), 2.97 (br s, 4H), 2.00- 2.11 (m, 1H), 1.69-1.80 (m, 1H), 0.90 (t, J = 7.3 Hz, 3H). HO HN O Cl OOH27 mg; yield: N (I-10) CH 71% 3 H O 3C2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)-4-methoxybutanoic acid LC-MS Method 2: r.t.6.16 min, MS ESI (+) m / z = 459.18 [M+H]+1H NMR (400 MHz, DMSO-d6): δ 12.32 (br s, 1H), 8.82 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.31 (s, 1H), 7.30 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H), 5.06 - 4.99 (m, 1H), 4.94 (t, J = 5.8 Hz, 1H), 3.92 (s, 3H), 3.73 - 3.53 (m, 3H), 3.27 - 3.18 (m, 2H), 3.18 - 3.15 (m, 3H), 2.42 (s, 3H), 2.23 - 2.12 (m, 1H), 1.85 - 1.72 (m, 1H).HO HN O Cl OOH25 mg; yield: (I-11) F N 62% CH3O 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)-4-methoxybutanoic acid LC-MS Method 2: r.t.6.21 min, MS ESI (+) m / z = 463.22 [M+H]+1H NMR (600 MHz, DMSO-d6): δ 12.33 (1H, bs), 8.94 (1H, d, J = 8.2 Hz), 7.57 - 7.61 (1H, m), 7.39 (1H, s), 7.37 (2H, d, J = 8.1 Hz), 7.32 (1H, t, J = 9.6 Hz), 7.24 (2H, d, J = 8.2 Hz), 5.03 - 5.08 (1H, m), 4.98 (1H, bs), 3.98 (3H, s), 3.69 - 3.74 (1H, m), 3.62 - 3.67 (1H, m), 3.59 (1H, t, J = 7.4 Hz), 3.20 - 3.27 (2H, m), 3.18 (3H, d, J = 1.8 Hz), 2.16 - 2.22 (1H, m), 1.78 - 1.85 (1H, m). HO HN O Cl OOH15 mg; yield: N (I-12) CH348% H3C O2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetic acid LC-MS Method 2: r.t.6.03 min, MS ESI (+) m / z = 485.18 [M+H]+1H NMR (400 MHz, DMSO-d6): δ 12.36 (br s, 1 H), 8.81 (d, J=8.1 Hz, 1 H), 7.35 (d, J=8.2 Hz, 2 H), 7.32 (s, 1 H), 7.30 (s, 1 H), 7.26 (d, J=8.3 Hz, 2 H), 7.04 (s, 1 H), 5.00 - 5.06 (m, 1 H), 4.94 (t, J=5.8 Hz, 1 H), 3.92 (s, 3 H), 3.81 - 3.86 (m, 1 H), 3.67 - 3.73 (m, 2 H), 3.59 - 3.66 (m, 1 H), 3.23 - 3.29 (m, 1 H), 3.20 (d, J=10.4 Hz, 1 H), 3.11 - 3.17 (m, 1 H), 2.43 (s, 3 H), 2.05 - 2.15 (m, 1 H), 1.63 - 1.69 (m, 1 H), 1.22 - 1.33 (m, 1 H), 0.97 - 1.05 (m, 2 H). HO HN O Cl OOHF N 44 mg; yield: CH3(I-13) 81% F F F 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)-5,5,5-trifluoropentanoic acidLC-MS Method 2: r.t.6.41 min, MS ESI (+) m / z = 501.09 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.55 (br s, 1H), 8.94 (d, J = 8.6 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.41 - 7.37 (m, 3H), 7.32 (t, J = 9.4 Hz, 1H), 7.25 (d, J = 3.9 Hz, 2H), 5.09 - 5.02 (m, 1H), 4.98 (t, J = 5.8 Hz, 1H), 3.97 (s, 3H), 3.75 - 3.68 (m, 1H), 3.68 - 3.63 (m, 1H), 3.61 (t, J = 7.4 Hz, 1H), 2.29 - 2.01 (m, 3H), 1.88 - 1.76 (m, 1H). HO HN O Cl OOH35 mg; yield: (I-14) F N 40% CH3(S)-1-(4-(1-(4-chloro-5-fluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)cyclobutane-1-carboxylic acid LC-MS Method 2: r.t.6.18 min, MS ESI (+) m / z = 445.10 [M+H]+1H NMR (400 MHz, DMSO-d6): δ 12.28 (br s, 1H), 8.93 (d, J = 7.9 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.39 - 7.34 (m, 3H), 7.30 (t, J = 9.3 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 5.09 - 4.99 (m, 1H), 4.96 (t, J = 5.9 Hz, 1H), 3.96 (s, 3H), 3.75 - 3.59 (m, 2H), 2.73 - 2.62 (m, 2H), 2.42 - 2.30 (m, 2H), 1.96 - 1.83 (m, 1H), 1.82 - 1.70 (m, 1H). HO HN O Cl OOH38 mg; yield: N (I-15) CH 46% 3H3C(S)-1-(4-(1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)cyclobutane-1-carboxylic acid LC-MS Method 2: r.t.6.50 min, MS ESI (+) m / z = 441.13 [M+H]+1H NMR (400 MHz, DMSO-d6): δ 12.28 (br s, 1H), 8.83 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.32 - 7.30 (m, 1H), 7.30 - 7.28 (m, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.04 - 7.02 (m, 1H), 5.06 - 4.98 (m, 1H), 4.94 (t, J = 5.7 Hz, 1H), 3.92 (s, 3H), 3.75 - 3.59 (m, 2H), 2.72 - 2.63 (m, 2H), 2.42 (s, 3H), 2.40 - 2.32 (m, 2H), 1.95 - 1.83 (m, 1H), 1.81 - 1.70 (m, 1H).HO HN O Cl OOH25 mg; yie F N ld: (I-16) CH357% O 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)-2-(tetrahydro-2H-pyran- 4-yl)acetic acid LC-MS Method 2: r.t.5.71 min, MS ESI (+) m / z = 489.15 [M+H]+1H NMR (400 MHz, DMSO-d6): δ 12.37 (br s, 1 H), 8.92 (d, J=8.4 Hz, 1 H), 7.58 (dd, J=8.9, 3.7 Hz, 1 H), 7.38 (s, 1 H), 7.36 (d, J=8.2 Hz, 2 H), 7.31 (t, J=9.7 Hz, 1 H), 7.26 (d, J=8.3 Hz, 2 H), 5.01 - 5.07 (m, 1 H), 4.96 (t, J=5.9 Hz, 1 H), 3.96 (s, 3 H), 3.80 - 3.86 (m, 1 H), 3.68 - 3.73 (m, 2 H), 3.60 - 3.68 (m, 1 H), 3.24 - 3.28 (m, 1 H), 3.20 (d, J=10.5 Hz, 1 H), 3.11 - 3.18 (m, 1 H), 2.04 - 2.15 (m, 1 H), 1.62 - 1.67 (m, 1 H), 1.21 - 1.34 (m, 1 H), 0.97 - 1.04 (m, 2 H). HO HN O Cl OOH18 mg; yield: N (I-17) CH339% H3C FF F2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)-5,5,5-trifluoropentanoic acid LC-MS Method 2: r.t.6.74 min, MS ESI (+) m / z = 497.11 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.53 (br s, 1H), 8.84 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.34 - 7.30 (m, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.04 (s, 1H), 5.08 - 5.01 (m, 1H), 4.97 (br s, 1H), 3.93 (s, 3H), 3.75 - 3.68 (m, 1H), 3.68 - 3.62 (m, 1H), 3.60 (t, J = 7.5 Hz, 1H), 2.43 (s, 3H), 2.31 - 2.00 (m, 3H), 1.87 - 1.77 (m, 1H). HO HN O Cl OOH9 mg; yield: (I-18) F N 32% CH3O (S)-4-(4-(1-(4-chloro-5-fluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)tetrahydro-2H-pyran-4- carboxylic acidLC-MS Method 2: r.t.5.66 min, MS ESI (+) m / z = 475.14 [M+H]+1H NMR (500 MHz, DMSO-d6): δ12.59 (br s, 1 H), 8.95 (d, J=8.2 Hz, 1 H), 7.59 (dd, J=9.2, 3.7 Hz, 1 H), 7.28 - 7.43 (m, 6 H), 5.02 - 5.07 (m, 1 H), 4.99 (br s, 1 H), 3.97 (s, 3 H), 3.81 (br d, J=10.4 Hz, 2 H), 3.68 - 3.75 (m, 1 H), 3.62 - 3.68 (m, 1 H), 3.44 (t, J=11.0 Hz, 2 H), 2.36 (br d, J=12.8 Hz, 2 H), 1.75 - 1.83 (m, 2 H). HO HN O Cl OOH17 mg; yield: N (I-19) CH 35% 3 O H3C (S)-4-(4-(1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid LC-MgS Method 2: r.t.5.97 min, MS ESI (+) m / z = 471.17 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.64 (br s, 1 H), 8.85 (d, J=7.9 Hz, 1 H), 7.39 (d, J = 8.6 Hz, 2 H), 7.35 (d, J = 8.5 Hz, 2 H), 7.33 (s, 1 H), 7.31 (s, 1 H), 7.05 (s, 1 H), 5.00 - 5.07 (m, 1 H), 4.97 (t, J=5.6 Hz, 1 H), 3.93 (s, 3 H), 3.81 (br d, J=9.5 Hz, 2 H), 3.67 - 3.74 (m, 1 H), 3.61 - 3.67 (m, 1 H), 3.44 (t, J=10.8 Hz, 2 H, overlapping with the signal of H2O), 2.44 (s, 3 H), 2.33 - 2.39 (m, 2 H), 1.75 - 1.83 (m, 2 H). HO HN O Cl OO OH15 mg; yield: (I-20) N 58 N3CH% CH 3 2-(4-((S)-1-(4-chloro-1-methyl-6-(2-morpholinoethyl)-1H- indole-2-carboxamido)-2-hydroxyethyl)phenyl)butanoic acid LC-MS Method 2: r.t.4.28 min, MS ESI (+) m / z = 528.35 [M+H]+1H NMR (METHANOL-d4, 500 MHz): δ (ppm) 7.38 (d, J =8.1 Hz, 2H), 7.30-7.34 (m, 3H), 7.23 (s, 1H), 7.08 (s, 1H), 5.14-5.20 (m, 1H), 3.94 (s, 3H), 3.81-3.86 (m, 6H), 3.40-3.45 (m, 1H), 3.00-3.13 (m, 8H), 2.01-2.10 (m, 1H), 1.70-1.79 (m, 1H), 0.89 (t, J = 7.5 Hz, 3H). HO HN O Cl OOH16 mg; yield: F N (I-21) CH332% O F (S)-4-(4-(1-(4-chloro-5,6-difluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)tetrahydro-2H-pyran-4- carboxylic acidLC-MS Method 2: r.t.6.43 min, MS ESI (+) m / z = 493.33 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.52 (1H, bs), 8.94 (1H, d, J = 8.1 Hz), 7.83 - 7.77 (1H, m), 7.42 (1H, s), 7.39 (2H, d, J = 8.6 Hz), 7.35 (2H, d, J = 8.5 Hz), 5.07 - 5.01 (1H, m), 4.99 (1H, bs), 3.94 (3H, s), 3.84 - 3.78 (2H, m), 3.74 - 3.68 (1H, m), 3.67 - 3.61 (1H, m), 3.44 (2H, t, J = 11.1 Hz), 2.39 - 2.33 (2H, m), 1.83 - 1.75 (2H, m). HO HN O Cl OOH23 mg; yield: F N (I-22) CH3O 38% H3C (S)-4-(4-(1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)tetrahydro-2H-pyran-4- carboxylic acid LC-MS Method 2: r.t.6.60 min, MS ESI (+) m / z = 489.39 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.59 (1H, bs), 8.89 (1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 5.6 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.37 - 7.33 (3H, m), 5.07 - 5.01 (1H, m), 4.98 (1H, bs), 3.94 (3H, s), 3.84 - 3.78 (2H, m), 3.74 - 3.68 (1H, m), 3.67 - 3.61 (1H, m), 3.44 (2H, t, J = 11.1 Hz), 2.41 - 2.39 (3H, m), 2.39 - 2.33 (2H, m), 1.83 - 1.75 (2H, m). HO HN O Cl OOH43 mg; yield: F N (I-23) CH 90% 3CH3H3C 2-(4-((S)-1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoic acid LC-MS Method 2: r.t.6.88 min, MS ESI (+) m / z = 447.37 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 9.43 (1H, bs), 9.22 - 9.15 (1H, m), 7.49 (1H, s), 7.47 - 7.43 (2H, m), 7.41 (1H, s), 7.26 - 7.18 (8H, m), 5.43 (2H, bs), 5.01 - 4.89 (2H, m), 3.93 (3H, s), 3.93 (3H, s), 3.62 - 3.42 (4H, m), 3.17 - 3.07 (2H, m), 2.40 (3H, s), 2.39 (3H, s), 2.00 - 1.86 (2H, m), 1.56 - 1.46 (2H, m), 0.83 - 0.76 (6H, m).HO HN O Cl OOH46 mg; yield: N CH3(I-24) 96% CH3H3C 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)propanoic acid LC-MS Method 2: r.t.6.56 min, MS ESI (+) m / z = 415.31 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 9.09 – 8.94 (m, 1H), 7.37 – 7.29 (m, 2H), 7.25 – 7.17 (m, 4H), 7.03 (s, 1H), 5.35 – 5.06 (m, 1H), 5.01- 4.91 (m, 1H), 3.92 (s, 3H), 3.66 – 3.58 (m, 1H), 3.58 – 3.50 (m, 1H), 3.30 (1H,), 2.43 (s, 3H), 1.29 – 1.16 (m, 3H). HO HN O Cl OOH9.8 mg; F N (I-27) CH3yield: 28% O O (S)-4-(4-(1-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole- -carboxamido)-2-hydroxyethyl)phenyl)tetrahydro-2H-pyran-4- carboxylic acid LC-MS Method 2: r.t.6.12 min, MS ESI (+) m / z = 505.39 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.59 (1H, bs), 8.81 (1H, d, J = 8.1 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.37 - 7.33 (3H, m), 7.28 (1H, d, J = 6.6 Hz), 5.06 - 5.00 (1H, m), 4.97 (1H, bs), 3.96 (3H, s), 3.94 (3H, s), 3.83 - 3.77 (2H, m), 3.73 - 3.67 (1H, m), 3.66 - 3.61 (1H, m), 3.44 (2H, t, J = 11.1 Hz), 2.39 - 2.33 (2H, m), 1.83 - 1.75 (2H, m). HO HN O F OOH41 mg; yield: F N (I-28) CHCH76% 33H3C2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoic acid LC-MS Method 2: r.t.6.57 min, MS ESI (+) m / z = 431.37 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.32 (1H, bs), 8.81 (1H, d, J = 8.0 Hz), 7.37 (1H, s), 7.35 (2H, d, J = 8.1 Hz), 7.29 (1H, d, J = 4.9 Hz), 7.24 (2H, d, J = 8.1 Hz), 5.06 - 5.00 (1H, m), 4.97 (1H, bs), 3.92 (3H, s), 3.72 - 3.67 (1H, m), 3.66 - 3.61 (1H, m), 3.41 - 3.38 (1H, m), 2.41 - 2.40 (3H, m), 2.00 - 1.89 (1H, m), 1.68 - 1.57 (1H, m), 0.82 (3H, t, J = 7.4 Hz).HO HN O Cl OOH10 mg; yield: F N (I-31) CH28% CH3 3O -(4-((S)-1-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole- 2-carboxamido)-2-hydroxyethyl)phenyl)butanoic acid LC-MS Method 2: r.t.6.16 min, MS ESI (+) m / z = 463.15 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 8.78 (d, J = 8.1 Hz, 1H), 7.36 – 7.32 (m, 3H), 7.27 (d, J = 6.7 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 5.05 – 4.99 (m, 1H), 4.99 – 4.93 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.74 – 3.66 (m, 1H), 3.66 – 3.60 (m, 1H), 1.99 – 1.89 (m, 1H), 1.66 – 1.57 (m, 1H), 0.81 (t, J = 7.4 Hz, 3H). HO HN O H3CO OH43 mg; yield: N (I-32) CH 82% 3 CH3H3C 2-(4-((S)-2-hydroxy-1-(1,4,6-trimethyl-1H-indole-2- carboxamido)ethyl)phenyl)butanoic acid LC-MS Method 2: r.t.6.28 min, MS ESI (+) m / z = 409.25 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.27 (1H, bs), 8.64 (1H, d, J = 8.0 Hz), 7.35 (2H, d, J = 8.0 Hz), 7.28 (1H, s), 7.24 (2H, d, J = 8.0 Hz), 7.10 (1H, s), 6.74 (1H, s), 5.07 - 5.00 (1H, m), 4.96 (1H, bs), 3.90 (3H, s), 3.73 - 3.62 (2H, m), 3.36 (1H, t, J = 7.6 Hz), 2.48 (3H, s), 2.39 (3H, s), 2.00 - 1.89 (1H, m), 1.67 - 1.57 (1H, m), 0.82 (3H, t, J = 7.3 Hz). HO HN O Cl OOH13 mg; yield: N (I-33) CH 64% 3 N H3C -(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)-2-(pyridin-3-yl)acetic acid LC-MS Method 2: r.t.5.09 min, MS ESI (+) m / z = 478.40 [M+H]+H NMR (600 MHz, DMSO-d6): δ 8.84 - 8.86 (m, 1 H), 8.51 (s, 1 H), 8.35 (br d, J=4.40 Hz, 1 H), 7.74 - 7.78 (m, 1 H), 7.28 - 7.32 (m, 6 H), 7.25 - 7.28 (m, 1 H), 7.04 (s, 1 H) 4.96 - 5.03 (m, 2 H), 4.82 (br s, 1 H), 3.92 (s, 3 H), 3.63 - 3.73 (m, 1 H), 3.58 - 3.64 (m, 1 H), 2.43 (s, 3 H).HO HN O F OOH38 mg; yield: F NCHCH3(I-34) 72% 3 H3C 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acid LC-MS Method 2: r.t.6.25 min, MS ESI (+) m / z = 417.36 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.13 (bs, 1H), 8.83 (d, J = 8.1 Hz, 1H), 7.39 - 7.32 (m, H), 7.29 (d, J = 5.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 5.06 - 4.99 (m, 1H), 4.98 (bs, 1H), 3.92 (s, 3H), 3.72 - 3.67 (m, 1H), 3.65 - 3.59 (m, 2H), 2.40 (s, 3H), 1.33 (d, J = 7.1 Hz, 3H). HO HN O Cl OOH36 mg; yield: (I-37) F N 90% CH3 CH3F 2-(4-((S)-1-(4-chloro-5,6-difluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoic acid LC-MS Method 2: r.t.6.67 min, MS ESI (+) m / z = 451.36 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 9.56 (1H, bs), 9.28 (1H, d, J = 7.8 Hz), 7.81 - 7.74 (2H, m), 7.58 (1H, s), 7.49 (1H, s), 7.27 - 7.17 (8H, m), 5.42 (2H, bs), 5.00 - 4.89 (2H, m), 3.94 (3H, s), 3.94 (3H, s), 3.62 - 3.41 (4H, m), 3.19 - 3.11 (2H, m), 2.00 - 1.87 (2H, m), 1.57 - 1.46 (2H, m), 0.83 - 0.76 (6H, m). HO HN O F OOH34 mg; yield: N (I-38) CH3CH375% H3C2-(4-((S)-1-(4-fluoro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)butanoic acid LC-MS Method 2: r.t.6.46 min, MS ESI (+) m / z = 413.42 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.37 (1H, bs), 8.75 (1H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.32 (1H, s), 7.24 (2H, d, J = 8.1 Hz), 7.18 (1H, s), 6.75 (1H, d, J = 11.2 Hz), 5.06 - 5.00 (1H, m), 4.96 (1H, bs), 3.92 (3H, s), 3.73 - 3.67 (1H, m), 3.66 - 3.61 (1H, m), 3.37 (1H, t, J = 7.6 Hz), 2.43 (3H, s), 1.99 - 1.90 (1H, m), 1.68 - 1.58 (1H, m), 0.82 (3H, t, J = 7.3 Hz).HO HN O Cl OOH42 mg; yield: F NCHCH3(I-41) 88% 3 H3C2-(4-((S)-1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acid LC-MS Method 2: r.t.6.51 min, MS ESI (+) m / z = 433.31 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 9.30 (1H, d, J = 7.8 Hz), 9.22 (1H, d, J = 7.8 Hz), 7.46 (1H, s), 7.45 (1H, s), 7.43 (1H, s), 7.40 (1H, s), 7.24 - 7.19 (8H, m), 5.51 (2H, bs), 4.98 - 4.91 (2H, m), 3.93 (6H, s), 3.64 - 3.47 (4H, m), 3.37 - 3.29 (2H, m), 2.41 - 2.38 (6H, m), 1.28 - 1.23 (6H, m). HO HN O F OOHF N 48 mg; yield: (I-44) CH384% H3C (S)-1-(4-(1-(4,5-difluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)cyclobutane-1-carboxylic acid LC-MS Method 2: r.t.6.73 min, MS ESI (+) m / z = 443.38 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 12.29 (bs, 1H), 8.81 (d, J = 8.1 Hz, 1H), 7.39 - 7.34 (m, 3H), 7.29 (d, J = 4.9 Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 5.06 - 4.99 (m, 1H), 4.99 - 4.92 (m, 1H), 3.92 (s, 3H), 3.73 - 3.66 (m, 1H), 3.66 - 3.60 (m, 1H), 2.73 - 2.65 (m, 2H), 2.49 - 2.39 (m, 3H), 2.40 - 2.33 (m, 2H), 1.95 - 1.84 (m, 1H), 1.81 - 1.71 (m, 1H). HO HN O Cl OOH43 mg; F N (I-45) CH3yield: 49% O (S)-1-(4-(1-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole- 2-carboxamido)-2-hydroxyethyl)phenyl)cyclobutane-1- carboxylic acid LC-MS Method 2: r.t.6.63 min, MS ESI (+) m / z = 474.44 [M+H]+1H NMR (500 MHz, DMSO-d6): δ 11.71 (bs, 1H), 8.81 (d, J = 8.1 Hz, 1H), 7.38 - 7.34 (m, 3H), 7.28 (d, J = 6.6 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 5.06 - 5.00 (m, 1H), 4.98 (bs, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.74 - 3.68 (m, 1H), 3.66 - 3.61 (m, 1H), 2.73 - 2.65 (m, 2H), 2.40 - 2.33 (m, 2H), 1.95 - 1.85 (m, 1H), 1.81 - 1.71 (m, 1H).Examples from chiral separations Examples 3 and 4: 1steluted diastereoisomer and 2ndeluted diastereoisomer of 2-(4- ((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2-hydroxyethyl)phenyl)butanoic acid (Example 2) HO A mixture of twommol), was dissolved to 14 mg / mL in MeOH and was separated using Method Chiral-Prep-1 to give the desired products, Example 3 and 4, as off-white solids. 1steluted single diastereoisomer (Example 3): 163 mg, yield 33%. 2ndeluted single diastereoisomer (Example 4): 199 mg, yield 40 %. Analytical data for examples 3 and 4 are reported in Table 13 Table 13- Analytical data for Example 3 and 4 Structure Mixture Example IUPAC Name Analytical Data HO HN O Cl OOHExample 2 N Method Chiral-Pre 3 C p-1 CH H3H3C3 diastereoisomer 1 of 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H- indole-2-carboxamido)-2-hydroxyethyl)phenyl)butanoic acid Method Chiral-QC-1: r.t. = 3.26 min, de 99 % LC-MS (ESI, m / z): method 2, r.t. = 6.80 min, m / z (M+1) = 429.37 1H NMR (500 MHz, DMSO-d6): δ 12.04 (bs, 1H), 8.85 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.32 (s, 1H), 7.31 (s, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.04 (s, 1H), 5.06 – 5.00 (m, 1H), 4.98 (bs, 1H), 3.93 (s, 3H), 3.73 – 3.67 (m, 1H), 3.66 – 3.61 (m, 1H), 3.37 – 3.33 (m, 1H), 2.43 (s, 3H), 1.99 – 1.89 (m, 1H), 1.67 – 1.57 (m, 1H), 0.82 (t, J = 7.3 Hz, 3H).HO HN O Cl OOHExample 2 N CH Method Chiral- 3 CH3Prep-1 H3C4 diastereoisomer 2 of 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H- indole-2-carboxamido)-2-hydroxyethyl)phenyl)butanoic acid Method Chiral-QC-1: r.t. = 6.91 min, de 97 % LC-MS (ESI, m / z): method 2, r.t. = 6.79 min, m / z (M+1) = 429.37 1H NMR (500 MHz, DMSO-d6): δ 12.04 (bs, 1H), 8.84 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.32 (s, 1H), 7.31 (s, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.05 (s, 1H), 5.06 - 5.00 (m, 1H), 4.98 (bs, 1H), 3.93 (s, 3H), 3.73 - 3.67 (m, 1H), 3.66 - 3.61 (m, 1H), 3.38 - 3.34 (m, 1H), 2.43 (s, 3H), 1.99 - 1.89 (m, 1H), 1.67 - 1.57 (m, 1H), 0.82 (t, J = 7.3 Hz, 3H). Examples 6 and 7: 1steluted diastereoisomer and 2ndeluted diastereoisomer of 2-(4- ((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid (Example 5)A mixture of two diastereoisomers (Example 5, 500 mg, 1.13 mmol), was dissolved to 7 mg / mL in MeOH and was separated using Method Chiral-Prep-2 to give the desired products, Example 6 and 7, as off-white solids. 1steluted single diastereoisomer (Example 6): 166.8 mg, yield 34 %. 2ndeluted single diastereoisomer (Example 7): 158.1 mg, yield 32 %. Analytical data for examples 6 and 7 are reported in Table 14Table 14 - Analytical data for Example 6 and 7 Structure ExampleIUPAC NameMixtureAnalytical Data HO HN O Cl OOHExample 5 F N Method Chiral-Prep-2 CH3CH3diastereoisomer 1 of 2-(4-((S)-1-(4-chloro-5-fluoro-1- 6 methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid Method Chiral-QC-2: r.t. = 4.85 min, de 95.4 % LC-MS (ESI, m / z): method 2, r.t. = 6.06 min, m / z (M+1) = 433.14 1H NMR (500 MHz, DMSO): δ 8.99 (1H, d, J = 8.2 Hz), 7.58 (1H, dd, J = 9.1 Hz, J = 3.8 Hz), 7.40 (1H, s), 7.29 - 7.35 (3H, m), 7.24 (2H, d, J = 8.2 Hz), 4.88 - 5.26 (2H, m), 3.97 (3H, s), 3.67 - 3.73 (1H, m), 3.61 - 3.65 (1H, m), 3.32 (1H, t, J = 7.5 Hz), 1.88 - 1.99 (1H, m), 1.54 - 1.64 (1H, m), 0.81 (3H, t, J = 7.3 Hz). HO HN O Cl OOHN Example 5 CH3CH3Method Chiral-Prep-2 H3C7 diastereoisomer 2 of 2-(4-((S)-1-(4-chloro-5-fluoro-1- methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid Method Chiral-QC-2: r.t. = 6.38 min, de 97 % LC-MS (ESI, m / z): method 2, r.t. = 6.06 min, m / z (M+1) = 433.12 1H NMR (500 MHz, DMSO): δ 9.02 (1H, d, J = 8.1 Hz), 7.58 (1H, dd, J = 9.1 Hz, J = 3.8 Hz), 7.40 (1H, s), 7.29 - 7.35 (3H, m), 7.24 (2H, d, J = 8.3 Hz), 4.88 - 5.30 (2H, m), 3.97 (3H, s), 3.66 - 3.72 (1H, m), 3.60 - 3.64 (1H, m), 3.32 (1H, t, J = 7.5 Hz), 1.88 - 1.99 (1H, m), 1.54 - 1.64 (1H, m), 0.81 (3H, t, J = 7.3 Hz). Examples 25 and 26: 1steluted diastereoisomer and 2ndeluted diastereoisomer of 2-(4- ((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoic acid (Example 24)HO A mixture of twommol) was dissolved to 6 mg / mL in MeOH (0.2% NH3) and separated using Method Chiral-Prep-3 to give the desired products, Example 25 and 26, as off-white solids. 1steluted single diastereoisomer (Example 25): 403.4 mg, yield 42 %. 2ndeluted single diastereoisomer (Example 26): 371.3 mg, yield 38 %. Analytical data for examples 25 and 26 are reported in Table 15 Table 15 - Analytical data for Example 25 and 26 Structure ExampleIUPAC NameMixtureAnalytical Data HO HN O Cl OOHExample 24 N CH3Method Chiral-Prep-3 CH3H3C 25 Diastereoisomer 1 of 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acid Method Chiral-QC-4: r.t. = 5.45 min, de 98.8 % LC-MS (ESI, m / z): method 2, r.t. = 6.69 min, m / z (M+1) = 415.36 1H NMR (500 MHz, DMSO): δ 8.90 (d, J = 8.1 Hz, 1H), 7.33 - 7.29 (m, 4H), 7.23 (d, J = 8.1 Hz, 2H), 7.04 (s, 1H), 5.05 (bs, 1H), 5.04 - 4.97 (m, 1H), 3.93 (s, 3H), 3.72 - 3.66 (m, 1H), 3.64 - 3.59 (m, 1H), 3.56 - 3.50 (m, 1H), 2.43 (s, 3H), 1.30 (d, J = 7.1 Hz, 3H). HO HN O Cl OOHExample 24 26 N CH3CH3Method Chiral-Prep-3 H3CDiastereoisomer 2 of 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acidMethod Chiral-QC-4: r.t. = 6.03 min, de 99.6 % LC-MS (ESI, m / z): method 2, r.t. = 6.71 min, m / z (M+1) = 415.36 1H NMR (500 MHz, DMSO): δ 8.88 (d, J = 8.1 Hz, 1H), 7.33 - 7.29 (m, 4H), 7.23 (d, J = 8.1 Hz, 2H), 7.04 (s, 1H), 5.06 (bs, 1H), 5.04 - 4.98 (m, 1H), 3.93 (s, 3H), 3.73 - 3.67 (m, 1H), 3.65 - 3.60 (m, 1H), 3.57 - 3.51 (m, 1H), 2.43 (s, 3H), 1.31 (d, J = 7.1 Hz, 3H). Examples 29 and 30: 1steluted diastereoisomer and 2ndeluted diastereoisomer of 2-(4- ((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid (Example 28) HOA mixture of two diastereoisomers (Example 28, 750 mg, 1.72 mmol) was dissolved to 26 mg / mL in methanol and was then purified by SFC to give the desired products, Example 29 and 30, as off-white solids. 1steluted single diastereoisomer (Example 29): 223 mg, yield 30 %. 2ndeluted single diastereoisomer (Example 30): 276 mg, yield 37 %. Analytical data for examples 29 and 30 are reported in Table 16 Table 16 - Analytical data for Example 29 and 30 Structure ExampleIUPAC NameMixtureAnalytical Data HO HN O F OOHExample 28 F N Method Chiral-Prep-4 CH3 CH3Followed by Method Chiral-Prep-6 H3C 29 Diastereoisomer 1 of of 2-(4-((S)-1-(4,5-difluoro-1,6- dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid Method Chiral-QC-3: r.t. = 4.83 min, de 99.4 % LC-MS (ESI, m / z): method 2, r.t. = 6.25 min, m / z (M+1) = 431.18 1H NMR (500 MHz, DMSO): δ 8.86 (d, J = 8.0 Hz, 1H), 7.37 - 7.35 (m, 1H), 7.32 - 7.25 (m, 3H), 7.21 (d, J = 8.2 Hz, 2H), 5.25 - 4.77 (m, 2H), 3.90 (s, 3H), 3.71 - 3.56 (m, 2H), 3.30 - 3.25 (m, 1H), 2.41 - 2.36 (m, 3H), 1.99 - 1.85 (m, 1H), 1.63 - 1.51 (m, 1H),0.79 (t, J = 7.2 Hz, 3H).HO HN O F OOHFN Example 28 CH3 CH3Method Chiral-Prep-4 H3C 30 Diastereoisomer 2 of 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl- 1H-indole-2-carboxamido)-2-hydroxyethyl)phenyl)butanoic acid Method Chiral-QC-3: r.t. = 5.79 min, de 98.4 % LC-MS (ESI, m / z): method 2, r.t. = 6.25 min, m / z (M+1) = 431.18 1H NMR (500 MHz, DMSO): δ 8.88 (d, J = 8.1 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.33 - 7.25 (m, 3H), 7.21 (d, J = 8.2 Hz, 2H), 5.25 - 4.82 (m, 2H), 3.90 (s, 3H), 3.69 - 3.56 (m, 2H), 3.31 - 3.24 (m, 1H), 2.41 - 2.37 (m, 3H), 1.99 - 1.86 (m, 1H), 1.63 - 1.50 (m, 1H), 0.79 (t, J = 7.4 Hz, 3H). Examples 35 and 36: 1steluted diastereoisomer and 2ndeluted diastereoisomer of 2-(4- ((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acid (Example 34)A mixture of two diastereoisomers (Example 34, 700 mg, 1.67 mmol) was dissolved to 5.2 mg / mL in methanol and was then purified by SFC to give the desired products, Example 35 and 36, as off-white solids. 1steluted single diastereoisomer (Example 35): 305 mg, yield 44 %. 2ndeluted single diastereoisomer (Example 36): 334 mg, yield 48 %. Analytical data for examples 35 and 36 are reported in Table 17Table 17 - Analytical data for Example 35 and 36 Structure ExampleIUPAC NameMixtureAnalytical Data HO HN O F OOHExample 34 F NCH3Method Chiral-Prep-5 CH3H3C 35 Diastereoisomer 1 of 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl- 1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acid Method Chiral-QC-4: r.t. = 4.71 min, de 98.8 % LC-MS (ESI, m / z): method 2, r.t. = 5.98 min, m / z (M+1) = 417.17 1H NMR (500 MHz, DMSO): δ 8.87 (d, J = 8.1 Hz, 1H), 7.38 – 7.35 (m, 1H), 7.32 – 7.25 (m, 3H), 7.21 (d, J = 8.1 Hz, 2H), 5.29 – 4.75 (m, 2H), 3.90 (s, 3H), 3.70 – 3.55 (m, 2H), 3.50 (1H,), 2.41 – 2.36 (m, 3H), 1.28 (d, J = 7.0 Hz, 3H). HO HN O F OOHFNCH3Example 34 CH3Method Chiral-Prep-5 H3C 36 Diastereoisomer 2 of 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl- 1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acid Method Chiral-QC-4: r.t. = 5.76 min, de 98.0 % LC-MS (ESI, m / z): method 2, r.t. = 5.98 min, m / z (M+1) = 417.17 1H NMR (500 MHz, DMSO): δ 9.15 (d, J = 8.0 Hz, 1H), 7.43 - 7.40 (m, 1H), 7.28 - 7.24 (m, 1H), 7.20 - 7.11 (m, 4H), 5.42 - 5.30 (m, 1H), 4.95 - 4.86 (m, 1H), 3.89 (s, 3H), 3.54 - 3.43 (m, 2H), 3.25 - 3.17 (m, 1H), 2.41 - 2.37 (m, 3H), 1.20 (d, J = 7.1 Hz, 3H). Examples 39 and 40: 1steluted diastereoisomer and 2ndeluted diastereoisomer of 2-(4- ((S)-1-(4-fluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2-hydroxyethyl)phenyl)butanoic acid (Example 38)HOA mixture of two mmol) was dissolved was dissolved to 20 mg / mL in MeOH and then purified by SFC to give the desired products, Example 39 and 40, as off-white solids. 1steluted single diastereoisomer (Example 39): 304 mg, yield 40 %. 2ndeluted single diastereoisomer (Example 40): 281 mg, yield 38 %. Analytical data for examples 39 and 40 are reported in Table 18 Table 18 - Analytical data for Example 39 and 40 Structure ExampleIUPAC NameMixtureAnalytical Data HO HN O F OOHExample 38 N Method Chiral-Prep-7 CH3CH3H3C 39 Diastereoisomer 1 of 2-(4-((S)-1-(4-fluoro-1,6-dimethyl-1H- indole-2-carboxamido)-2-hydroxyethyl)phenyl)butanoic acid Method Chiral-QC-5: r.t. = 3.88 min, de 99.6 % LC-MS (ESI, m / z): method 2, r.t. = 6.40 min, m / z (M+1) = 413.17 1H NMR (500 MHz, DMSO): δ 8.78 (d, J = 8.1 Hz, 1H), 7.34 - 7.29 (m, 3H), 7.22 (d, J = 8.1 Hz, 2H), 7.17 (s, 1H), 6.74 (d, J = 11.0 Hz, 1H), 5.17 - 4.84 (m, 2H), 3.92 (s, 3H), 3.73 - 3.65 (m, 1H), 3.64 - 3.59 (m, 1H), 3.33 - 3.28 (m, 1H), 2.43 (s, 3H), 1.98 - 1.87 (m, 1H), 1.65 - 1.53 (m, 1H), 0.80 (t, J = 7.3 Hz, 3H). HO HN O F OOHExample 38 40 N CH Method Chiral-Prep 3 CH3-7 H3C Diastereoisomer 2 of 2-(4-((S)-1-(4-fluoro-1,6-dimethyl-1H- indole-2-carboxamido)-2-hydroxyethyl)phenyl)butanoic acidMethod Chiral-QC-5: r.t. = 4.73 min, de 98.2 % LC-MS (ESI, m / z): method 2, r.t. = 6.39 min, m / z (M+1) = 413.45 1H NMR (500 MHz, DMSO): δ 8.82 (d, J = 8.1 Hz, 1H), 7.35 - 7.28 (m, 3H), 7.22 (d, J = 8.1 Hz, 2H), 7.17 (s, 1H), 6.74 (d, J = 11.1 Hz, 1H), 5.29 - 4.77 (m, 2H), 3.92 (s, 3H), 3.70 - 3.64 (m, 1H), 3.64 - 3.58 (m, 1H), 3.32 - 3.27 (m, 1H), 2.43 (s, 3H), 1.98 - 1.87 (m, 1H), 1.64 - 1.53 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H). Examples 42 and Example 43: 1steluted diastereoisomer and 2ndeluted diastereoisomer of 2-(4-((S)-1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acid (Example 41) HOA mixture of two diastereoisomers (Example 41, 700 mg, 1.61 mmol) was dissolved was dissolved to 7 mg / mL in MeOH (0.2% v / v NH3) and then purified by SFC to give the desired products, Example 42 and 43, as off-white solids. 1steluted single diastereoisomer (Example 42): 86 mg, yield 12 %. 2ndeluted single diastereoisomer (Example 43): 253 mg, yield 36 %. Analytical data for examples 42 and 43 are reported in Table 19 Table 19 - Analytical data for Example 42 and 43 Structure ExampleIUPAC NameMixtureAnalytical Data HO HN O Cl OOHNCHExample 41 42F 3CH3Method Chiral-Prep-8 H3C Diastereoisomer 1 of 2-(4-((S)-1-(4-chloro-5-fluoro-1,6- dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acidMethod Chiral-QC-4: r.t. = 5.98 min, de 96.8 % LC-MS (ESI, m / z): method 2, r.t. = 6.54 min, m / z (M+1) = 433.34 1H NMR (500 MHz, DMSO): δ 8.97 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 5.6 Hz, 1H), 7.34 (s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 5.28 - 5.04 (m, 1H), 5.04 - 4.95 (m, 1H), 3.93 (s, 3H), 3.71 - 3.65 (m, 1H), 3.63 - 3.56 (m, 1H), 3.53 - 3.45 (m, 1H), 2.42 - 2.37 (m, 3H), 1.29 (d, J = 7.0 Hz, 3H). HO HN O Cl OOHFNCH3Example 41 CH3Method Chiral-Prep-8 H3C 43 Diastereoisomer 2 of 2-(4-((S)-1-(4-chloro-5-fluoro-1,6- dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acid Method Chiral-QC-4: r.t. = 7.46 min, de 98.8 % LC-MS (ESI, m / z): method 2, r.t. = 6.55 min, m / z (M+1) = 433.39 1H NMR (500 MHz, DMSO): δ 8.89 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 5.6 Hz, 1H), 7.37 - 7.31 (m, 3H), 7.23 (d, J = 8.1 Hz, 2H), 5.10 - 4.85 (m, 2H), 3.93 (s, 3H), 3.74 - 3.67 (m, 1H), 3.66 - 3.56 (m, 2H), 2.42 - 2.37 (m, 3H), 1.32 (d, J = 7.0 Hz, 3H). COMPARATIVE EXAMPLES Comparative newly synthesized A and B were prepared as described below. Comparative Example A is characterized by the substitution of a methyl at position 5 on the indole group instead of H or F of the compounds of formula (I) of the invention. Comparative Example B is characterized by the substitution of OMe at position 5 on the indole group instead of H or F, as compounds of formula (I) of this invention. Comparative Example A: 2-(4-((S)-1-(4-chloro-6-fluoro-1,5-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acidF Step III-46: methyl (E)-2-azido-3-(2-chloro-4-fluoro-3-methyl-phenyl)prop-2-enoateO Following the preparation offrom commercially available 2- chloro-4-fluoro-3-methyl-benzaldehyde, the title compound was obtained (638 mg, 2.37 mmol, 82 % yield). LC-MS (ESI, m / z): method 1, r.t. = 1.46 min IV- 4- 1H- 2-Following the preparation of IV-2, starting from Intermediate III-46, the title compound was obtained (237 mg, 0.98 mmol, 42 % yield). LC-MS (ESI, m / z): method 1, r.t. = 1.28 min, m / z (M-1) = 240.0Following the preparation of V-2, starting from Intermediate IV-46, the title compound was obtained (232 mg, 0.9 mmol, 97 %). LC-MS (ESI, m / z): method 1, r.t. = 1.45 min, m / z (M+1) = 255.98 Step VI-46: 4-chloro-6-fluoro-1,5-dimethyl-1H-indole-2-carboxylic acidFollowing the preparation of VI-2, starting from Intermediate V-46, the title compound was obtained (213 mg, 0.81 mmol, 98 % yield). LC-MS (ESI, m / z): method 1, r.t. = 1.18 min, m / z (M+1) = 241.99 Step 1: ethyl 2-(4-((S)-1-(4-chloro-6-fluoro-1,5-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoateCl OH Following the preparation of46, the title compound was obtained (43 mg, 0.09 mmol, 75 % yield). LC-MS (ESI, m / z): method 1, r.t. = 1.30 min, m / z (M+1) = 461.17 Step 2: 2-(4-((S)-1-(4-chloro-6-fluoro-1,5-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acid Following the preparation of Example 2, starting from corresponding ethyl 2-(4-((S)-1-(4- chloro-6-fluoro-1,5-dimethyl-1H-indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoate, the title compound was obtained (35 mg, 0.08 mmol, 87 % yield). LC-MS (ESI, m / z): method 2, r.t. = 6.63 min, m / z (M+1) = 433.36 1H NMR (500 MHz, DMSO-d6): δ 9.22 (1H, d, J = 7.8 Hz), 9.16 (1H, d, J = 7.8 Hz), 7.47 (1H, s), 7.45 (1H, s), 7.40 (1H, s), 7.38 (1H, s), 7.24 - 7.20 (8H, m), 5.36 (2H, bs), 4.98 - 4.92 (2H, m), 3.91 (6H, s), 3.67 - 3.58 (2H, m), 3.57 - 3.50 (2H, m), 3.40 - 3.33 (2H, m), 2.35 - 2.32 (6H, m), 1.28 - 1.24 (6H, m). Comparative Example B: 2-(4-((S)-1-(4-chloro-5-methoxy-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acidStep V-47 : methyl 4-chloro-5-methoxy-1-methyl-1H-indole-2-carboxylateFollowing the preparation of V-2, starting from commercially available 4-chloro-5- methoxy-1H-indole-2-carboxylic acid, the title compound was obtained (3.24 g, 12.8 mmol, 96 % yield). LC-MS (ESI, m / z): method 1, r.t. = 1.24 min, m / z (M+1) = 254.15Step VI-47 : 4-chloro-5-methoxy-1-methyl-indole-2-carboxylic acid Cl Following the preparation of VI-2,title compound was obtained (3.0 g, 12.6 mmol, 99 % yield). LC-MS (ESI, m / z): method 1, r.t. = 0.96 min, m / z (M+1) = 240.02 Step 1: ethyl 2-(4-((S)-1-(4-chloro-5-methoxy-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoateFollowing the preparation of I-2, starting from XVIII-24 and VI-47, the title compound was obtained (47 mg, 0.1 mmol, 70 % yield). LC-MS (ESI, m / z): method 1, r.t. = 1.14 min, m / z (M+1) = 459.18 Step 2: 2-(4-((S)-1-(4-chloro-5-methoxy-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acid Following the preparation of Example 2, starting from corresponding ethyl 2-(4-((S)-1-(4- chloro-5-methoxy-1-methyl-1H-indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoate, the title compound was obtained (41 mg, 0.09 mmol, 95 % yield). LC-MS (ESI, m / z): method 2, r.t. = 5.73 min, m / z (M+1) = 431.37 1H NMR (500 MHz, DMSO-d6): δ 12.27 (br s, 1H), 8.86 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.28 – 7.18 (m, 4H), 5.06 – 4.99 (m, 1H), 4.95 (t, J = 5.9 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.74 – 3.67 (m, 1H), 3.67 – 3.60 (m, 2H), 1.33 (d, J = 7.2 Hz, 3H). PHARMACOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION Phenotypic assay – High Content Screening optimization of α-SMA staining in NHLF cells Method NHLF cells (Lonza #CC2512) were seeded as 2000 cells / well in 384-well plates in MEM medium w / o serine and glycine (Sigma #M2279) + 1% pen / strep + 5 mM L-glutamine + 10% FBS and incubated overnight at 37°C, 5% CO2.The next day, cells were washed with PBS and starvation MEM medium w / o serine and glycine (0% FBS) was added and cells were incubated overnight at 37°C, 5% CO2. The day after, cells were pre-incubated with compounds or vehicle (0.3% DMSO) for 1 h. Compounds were tested at 9 consecutive 3-fold dilutions starting from 30 µM. Each compound was tested in duplicate. Cells were further incubated for 72 h at 37°C, 5% CO2, 95% humidity. After 72h of incubation, α-SMA expression was quantified using immunostaining: - Fixation in 4% paraformaldehyde, - Blocking with 3% BSA, 2% FBS, 0.2% Triton-X in PBS, - Primary ab. anti-α-SMA (AbCam #ab7817) diluted 500x in blocking buffer - Anti-mouse secondary ab. AF488 (ThermoFisher #A11029) …. % of α-SMA positive cells was determined by High Content Imaging (Molecular Device), data analysis was performed using MetaXpress software (Molecular Devices) and % of α-SMA positive was further used to calculate % of inhibition for tested compounds. Total cell number was determined by Hoechst staining and % of viability over TGFβ stimulated controls was calculated. Fibroblast to myofibroblast transition (FMT) in vitro assay: Collagen I detection Method NHLF cells were seeded as 80000 cells / well in 12-well plates in MEM medium w / o serine and glycine (Sigma #M2279) + 1% pen / strep + 5 mM L-glutamine + 10% FBS and incubated overnight at 37°C, 5% CO2. To examine the expression of Collagen I, cells were treated with different concentrations of compounds, in MEM medium for 1h followed by stimulation with TGF-β for 72h at 37°C, 5% CO2. Following cell treatments, medium was removed and whole cell extracts were prepared by directly adding to the well the 1X loading buffer (125mM Tris-HCl pH 6.8, 4% SDS, 0.2% Orange G, 50% glycerol, 2.5% β-mercaptoethanol, Li-cor Biosciences), boiled for 5 min and then electrophoresed on Mini protean TGX gel 4-12% (Biorad). After electrophoresis, proteins were transferred to a nitrocellulose membrane. Immunodetection of Col- I, and glyceraldeide 3-phosphate dehydrogenase (GAPDH) were obtained by using mouse anti- Col1A1 (Santa Cruz) and rabbit anti-GAPDH (Cell Signaling Technology) all diluted at 1:1000 in TBS-tween 0.1%. Secondary antibodies were goat anti rabbit and goat anti mouse IgG conjugated with IRDye800 and IRDye680 probes (Li-cor) respectively, both diluted at 1:15,000 in TBS-tween 0.1% containing 1% of skim milk. Detection and quantification were performed with Odyssey imaging system (Li-cor) using GAPDH as loading control. Results were expressed as IC50value, given in nM for each NCE or pIC50(negative logarithm of IC50). The results for individual compounds are provided below in Table 20.Table 20 - pIC50 values in in vitro assays Example No. α-SMA Collagen I 3 5.6 4 6.4 7.1 18 5.6 19 6.1 24 5.5 25 6.1 28 5.8 38 6.0 41 5.7 44 6.7 45 6.0 As reported in the Table 20, all tested compounds, dose-dependently, reduce the expression of α-SMA, after 72 hours of incubation. It has been found that the compounds of formula (I) of the present invention have antifibrotic activity, monitored measuring the expression of α-SMA in Phenotypic assay, expressed as pIC50, equal or higher than 5.5. Preferably, the compounds of the present invention have a pIC50 on α-SMA in phenotypic assay between 5.5 and 6.5. More preferably, the compounds of the present invention have a pIC50on α-SMA in phenotypic assay higher than 6.5. Furthermore, tested compound dose-dependently inhibits the collagen I deposition, after 72h of treatment. These findings suggest that de novo synthesis of serine and glycine is required for pulmonary fibrosis; the inhibition of myofibroblast differentiation and collagen deposition is strongly correlated and necessary for the antifibrotic activity of the compounds. BSEP inhibition Method BSEP inhibition was evaluated using cryopreserved human hepatocytes (Plateable Cryopreserved Human Hepatocytes, BIOIVT) cultured for 5 day between two layer of collagen (sandwich configuration). In this culture condition, hepatocytes express relevant transporters including BSEP and retain the bile canalicular structure. On day 5 of culture, hepatic cells are ready for the assay and the biliary clearance of Taurocolic Acid (TCA), a known BSEP substrate, can be estimated in presence and in absence of compound of interest. The sample solution was prepared dissolving test compound and TCA in DMSO and then diluted in the Assay Buffer: Hank’s Balance Salt Solution (HBSS+) warmed at 37°C before use, to give the 10 µM TCA working solution with and without 100 µM of test compound. Hepatocytes were incubated for 10 minutes with these working solutions allowing TCA to be excreted into bile.At the end of incubation, the working solution was aspirated, and the content of the bile was collected through the addition of HBSS Modified without Ca2+ / Mg2+ (HBSS-). The presence of Ca2+ in the buffer is required to maintain the integrity of the tight junctions, the diffusional barrier between the canalicular lumen and extracellular space. Instead, incubation of cells in Ca2+ -free buffer disrupts the tight junctions and opens the bile canalicular structures, allowing the bile content to be released and collect for HPLC-MS / MS analysis. The in vitro biliary clearance of TCA incubated with and without test compounds is calculated according to the following formula: ^^^^^^^^^^^^. ^^^^^^^^^^^^^^^^ ClBil(µL / min / mg protein) = ^^^^^^^^^^^^ where Acc. Bile = (TCA amount in HBSS (-) buffer samples (pmol / mg protein) * Volume of each samples (mL)) / Protein content per well (mg) AUC = Incubation time (min) * T0 Concentration. T0 concentration is the initial TCA concentration in the medium. The inhibition of BSEP was calculated as percentage of inhibition of TCA biliary clearance in presence of compound of interest, according to the following formula: (TCA ^^^^^^^^^^ ^^^^^^^^ℎ^^^^^^^^^^^^^^^^^^^^^^^^^^^^% = 100 − ^^^^^^^^^^^ with test^^^^^^^^^^^^^^ ^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ℎ^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^The results for individual compounds are provided below in Table 21. Table 21: BSEP inhibition for exemplified compounds Example No. BSEP Inhibition at 100 µM 1, 4, 10, 12, 16, 21, 24, 31, 32, 33, 34 + 22, 23, 25 ++ 18, 19 +++ +: 50-25% BSEP inhibition @ 100 uM Example concentration ++: 25-13% BSEP inhibition @ 100 uM Example concentration +++: <13% BSEP inhibition @ 100 uM Example concentration Compounds according to this invention are characterized by an in vitro BSEP inhibition at 100 µM < 50 %, that can be considered suitable and acceptable from a safety point of view. Preferably, compounds showed BSEP inhibition values between 50 and 25%. More preferably, compounds showed BSEP inhibition values between 25 and 13%; most preferably, compounds showed BSEP inhibition at 100 µM below 13%. Permeability MethodThe permeability of the compounds of the present invention was evaluated performing the assay on Caco-2 cells monolayers (human colon adenocarcinoma immortalized cell) by measuring the transport of compound (absorption and secretion) in both directions: apical to basolateral direction (A>B) and basolateral to apical (B>A) with and without PgP inhibitor (Elacridar). The cells, purched from ReadyCell in 96 well format (Cod. KRECE-CCR50), were cultured by the supplier for 21 day on transwell supports in DMEM 1g / L glucose culture medium supplemented with Fetal Bovin Sierum (10%), Glutamine 200mM (1%) and Penicillin 10000 U / ml- 10 mg / ml Streptomycin (1%). On day 21 of colture, cell monolayers integrity was verified by measuring the trans-epithelial electric resistance (TEER) using the EVOM equipment (Endohm, WPI, Germany) and studying the apparent permeability (Papp) of reference compounds (Sulpiride and Metoprolol). Furthermore, as a control, the Talinolol 10uM (Pgp efflux substrate) with and without Elacridar in both directions was used. The sample solution was prepared dissolving test compound in DMSO at the concentration of 10 mM and then diluted in the Assay Buffer (Hank’s Balance Salt Solution) warmed at 37°C before use, to give the 10 µM Compound working solution with and without 10µM Elacridar. These working solutions were added to donor compartment (apical for A>B direction and basolateral for B>A direction) and Assay Buffer (Hank’s Balance Salt Solution) to the receiver compartment (basolateral for A>B direction and apical for B>A direction).The plate was incubated at 37°C for 120 min, all incubation were conducted in triplicates. At the end of incubation, samples from donor and receiver compartments were collected for HPLC-MS / MS analyses. The permeability coefficients (Papp) in both directions: apical to basolateral (A>B) and basolateral to apical (B>A) with and without PgP inhibitor (Elacridar) was calculated in nm / sec, using the following equation: Papp = Cr ⋅ Vr⋅ 10000nm t⋅ A ⋅ C0 000�� sec where: Cr = measured concentration in the receiver well at the time t (expressed as IS ratio) Vr = volume of the receiver well (ml) t = time (sec) A = membrane surface area (cm2) C0 =initial donor concentration Passive Papp is considered Papp A>B with PgP inhibitor Elacridar. The results for individual compounds are provided below in Table 22.Table 22-passive permeability for exemplified compounds Example No. Passive Permeability nm / sec 1, 2, 3, 4, 5, 6, 7, 14, 15, 23, 24, 25, 26, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 41, 42, 44≥15As showed in Table 22, all the compound of the present invention demonstrated a passive permeability value ≥ 15 nm / sec, which is considered suitable for an oral administration. Comparative Examples Results Comparative Example A: 2-(4-((S)-1-(4-chloro-6-fluoro-1,5-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acid Comparative Example A is characterized by the substitution of a methyl at position 5 on the indole group instead of H or F as compound of formula (I), and has been tested as described above along with the BSEP and permeability assays. Differently from the compounds of formula (I) of the present invention, the compound of comparative Example A shows a BSEP inhibition at 100 µM of 54%. Said inhibition cannot be considered acceptable for an oral drug candidate. Comparative Example B: 2-(4-((S)-1-(4-chloro-5-methoxy-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acid Comparative Example B is characterized by the substitution of a methoxy at position 5 on the indole group instead of H or F, as compounds of formula (I), and has been tested as described above along with the BSEP and permeability assays. Differently from the compounds of formula (I) of the present invention, the compound of comparative Example B shows a passive permeability of 13.6 nm / s and thus not suitable for an oral administration. All the above results demonstrate that in the compounds of formula (I) of the present invention, the presence of a H or a F at position 5 on the indole group, in combination with the presence of a substituent in position alpha to the carboxylic group, leads unexpectedly to a series of compounds that is active for IPF in the phenotypic assay, endowed with a very good BSEP inhibition and permeability profile, thus suitable for treatment of fibrosis with a very promising bioavailability profile for oral administration.

Claims

CLAIMS 1. A compound of formula (I): HO 8wherein R2is H or absent; R1is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1- C6)alkyl-OR7, heteroaryl, -(C3-C7)heterocycloalkyl or when R2is absent, R1is fused to the C* to form a spiro -(C3-C7)cycloalkyl or -(C3- C7)heterocycloalkyl; R3is halogen or -(C1-C6)alkyl; R4is H or F; R5is H or selected from the group consisting of halogen, -OR7, -(C1-C6)alkyl, wherein said -(C1-C6)alkyl is optionally substituted by -(C3-C7)heterocycloalkyl; R6and R7are independently H or -(C1-C6)alkyl, wherein said -(C1-C6)alkyl is optionally substituted by -(C3-C7)heterocycloalkyl; R8is H or -(C1-C6)alkyl; and pharmaceutically acceptable salts thereof.

2. A compound of formula (Ia): 8(Ia)wherein R1, R2, R3, R4, R5,R6,R7and R8are defined as in claim 1; and pharmaceutically acceptable salts thereof.

3. A compound of formula (I) according to claim 1 or 2, wherein R8is H, represented by the formula (Ic): HOwherein R1, R2, R3, R4, R5,R6and R7are defined as in claim 1; and pharmaceutically acceptable salts thereof.

4. The compound of formula (I) according to claim 1-3, wherein: R3is selected from chloride, fluorine, methyl; R5is H or selected from the group consisting of fluorine, methoxy, methyl, ethyl, wherein said methyl or ethyl are optionally substituted by morpholine; R6and R7are independently H or methyl, wherein said methyl is optionally substituted morpholine; and pharmaceutically acceptable salts thereof.

5. The compound of formula (I) according to claim 1-4, wherein: R2is H; R1is selected from the group consisting of methyl, ethyl, trifluoropropyl, -(C1- C2)alkyl-OR7, pyridine, tetrahydropyran; and pharmaceutically acceptable salts thereof.

6. The compound of formula (I) according to claim 1-4, wherein: R2is absent; R1is fused to the C* to form a spiro cyclobutane or tetrahydropyran; and pharmaceutically acceptable salts thereof.

7. The compound according to any one of claims 1 to 6, selected from at least one of: 2-(4-((S)-1-(4-chloro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid;2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid; Diastereoisomer 1 of 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)butanoic acid; Diastereoisomer 2 of 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)butanoic acid; 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid; Diastereoisomer 1 of 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoic acid; Diastereoisomer 2 of 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoic acid; 2-(4-((S)-1-(4-chloro-1-methyl-7-(morpholinomethyl)-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid; 2-(4-((S)-1-(4-chloro-1-methyl-6-(morpholinomethyl)-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid; 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)-4-methoxybutanoic acid; 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)-4-methoxybutanoic acid; 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetic acid; 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)-5,5,5-trifluoropentanoic acid; (S)-1-(4-(1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)cyclobutane-1-carboxylic acid; (S)-1-(4-(1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)cyclobutane-1-carboxylic acid; 2-(4-((S)-1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetic acid; 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)-5,5,5-trifluoropentanoic acid; (S)-4-(4-(1-(4-chloro-5-fluoro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid;(S)-4-(4-(1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid; 2-(4-((S)-1-(4-chloro-1-methyl-6-(2-morpholinoethyl)-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid; (S)-4-(4-(1-(4-chloro-5,6-difluoro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid; (S)-4-(4-(1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid; 2-(4-((S)-1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid; 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acid; Diastereoisomer 1 of 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)propanoic acid; Diastereoisomer 2 of 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)propanoic acid; (S)-4-(4-(1-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid; 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid; Diastereoisomer 1 or 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoic acid; Diastereoisomer 2 or 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)butanoic acid; 2-(4-((S)-1-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid; 2-(4-((S)-2-hydroxy-1-(1,4,6-trimethyl-1H-indole-2- carboxamido)ethyl)phenyl)butanoic acid; 2-(4-((S)-1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)-2-(pyridin-3-yl)acetic acid; 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acid; Diastereoisomer 1 of 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acid;Diastereoisomer 2 of 2-(4-((S)-1-(4,5-difluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acid; 2-(4-((S)-1-(4-chloro-5,6-difluoro-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid; 2-(4-((S)-1-(4-fluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)butanoic acid; Diastereoisomer 1 of 2-(4-((S)-1-(4-fluoro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)butanoic acid; Diastereoisomer 2 of 2-(4-((S)-1-(4-fluoro-1,6-dimethyl-1H-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)butanoic acid; 2-(4-((S)-1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acid; Diastereoisomer 1 of 2-(4-((S)-1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acid; Diastereoisomer 2 of 2-(4-((S)-1-(4-chloro-5-fluoro-1,6-dimethyl-1H-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoic acid; (S)-1-(4-(1-(4,5-difluoro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)cyclobutane-1-carboxylic acid; (S)-1-(4-(1-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl)cyclobutane-1-carboxylic acid; as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts and solvates thereof.

8. Intermediate Compound (XVIII) or the pharmaceutically acceptable salts thereof, for the preparation of the compound of formula (I) as defined in claim 1, having formula:(XVIII) wherein R1, R2, R7, R8are as defined in claims 1 to 6.

9. The intermediate Compound (XVIII) according to claim 8 wherein R2is absent;R1is fused to the C* to form a spiro -(C3-C7)cycloalkyl or -(C3-C7)heterocycloalkyl.

10. The intermediate Compound (XVIII) according to claim 8 wherein R2is H or absent; R1is selected from the group consisting of trifluoropropyl, -(C1-C2)alkyl-OR7, pyridine and tetrahydropyran or when R2is absent, R1is fused to the C* to form a spiro cyclobutane or tetrahydropyran; or the pharmaceutically acceptable salts thereof, for the preparation of the compound of formula (I).

11. Use of an intermediate compound (XVIII) for the preparation of the compound of formula (I) according to any one of claims 1 to 7 8(XVIII) wherein R1, R2, R8are as defined in claims 1 to 6.

12. The Use of an intermediate compound (XVIII) according to claim 11 wherein R1, R2are as defined in claims 10.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, in admixture with one or more pharmaceutically acceptable carrier or excipient.

14. A compound of formula (I) according to any one of claims 1-7 or a pharmaceutical composition according to claims 13 for use as a medicament.

15. A compound of formula (I) according to claims 1 to 7 or a pharmaceutical composition according to claims 11 for use according to claim 13 in the prevention and / or treatment of fibrosis and / or diseases, disorders, or conditions that involve fibrosis.

16. A compound of formula (I) or a pharmaceutical composition for use according to claim 15 in the prevention and / or treatment of fibrosis including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

17. A compound of formula (I) or a pharmaceutical composition for use according to claim 16 in the prevention and / or treatment idiopathic pulmonary fibrosis (IPF).

18. The pharmaceutical composition for use according to claim 14-17 for oral administration.

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