Phosphoglycerate dehydrogenase inhibitors for treating fibrosis

Abstract

Phosphoglycerate dehydrogenase inhibitors for treating fibrosis The present invention relates to a novel therapeutic use of compounds of general formula (I) PHGDH inhibitors for the prevention and / or treatment of fibrosis, particularly idiopathic pulmonary fibrosis (IPF). The present invention also relates to the use of pharmaceutical compositions and combinations comprising said compounds for the prevention and / or treatment of fibrosis, particularly IPF.

Description

[Technical Field]

[0001] The present invention relates to the use of compounds of general formula (I) as single agents or in combination with other active ingredients, as well as pharmaceutical compositions and combinations comprising said compounds, for the prevention and / or treatment of fibrosis, in particular idiopathic pulmonary fibrosis (IPF). [Background technology]

[0002] Fibrosis is a pathological wound healing process in which connective tissue replaces normal parenchymal tissue to an unchecked extent, resulting in significant tissue remodeling and the formation of permanent scar tissue (see Wynn, Thomas A., 2004 Nature Reviews 4 (8): 583-594).

[0003] Fibrosis can occur in many tissues in the body, typically as a result of inflammation or injury, examples include the liver, lungs, kidneys, brain and heart.

[0004] Idiopathic pulmonary fibrosis (IPF) is a rare, progressive respiratory disease characterized by thickening and hardening of lung tissue accompanied by the formation of scar tissue. It is a 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.)

[0005] Approximately 3 million people worldwide are affected, and the incidence appears to be increasing each year. The incidence is predicted to double by 2030 (see Fernandex Perez ER, et al, Chest, 2020; 137:129-137). Mortality is similar to that of lung cancer, with a median survival time of 2-3 years after diagnosis, and respiratory failure is the most common cause of death.

[0006] Nintedanib and pirfenidone, two FDA-approved medications currently on the market, slow disease progression and extend life expectancy in patients with IPF. However, treated patients continue to experience loss of lung function and premature death, and adverse events with both nintedanib and pirfenidone have a significant impact on patients' quality of life.

[0007] Therefore, IPF represents a high unmet medical need, and in recent years, many efforts have been made to develop alternative treatments.

[0008] 3-Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first rate-limiting step in the de novo biosynthesis of serine from glucose and is considered a key enzyme in the conversion of glycolysis to serine synthesis. Serine, an amino acid important for protein and nucleic acid biosynthesis, is in turn metabolized and incorporated into various biomolecules, including glycine. (See Yang M., Vousden, K H., Nature Reviews Cancer 2016,16, 650-662)

[0009] PHGDH is required for promoting collagen protein synthesis. In fact, glycine accounts for one-third of all amino acids in the collagen molecule, and a high glycine content is important for stabilizing the collagen helix.

[0010] Collagen is the major structural protein in the extracellular space, and in patients with IPF, it is produced in excess when fibroblasts differentiate into myofibroblasts, accumulating in fibrous tissue and leading to loss of organ structure and function.

[0011] Furthermore, PHGDH and the serine / glycine synthesis pathway are part of a broader network that links glycolysis with single-carbon metabolism and nucleotide synthesis to contribute to cell proliferation in pathologies such as inflammation and fibrosis.

[0012] Therefore, PHGDH inhibition may reduce the abnormal production and release of collagen, which inhibits cell proliferation (see Selvarajah et al., Science Signaling, 2019;12(582):eaav3048).

[0013] A variety of compounds have been described in the literature as PHGDH inhibitors.

[0014] WO 2017156165 (Raze Therapeutics) discloses compounds of general formula (I) that are effective as PHGDH inhibitors and their use in the treatment of a number of PHGDH-mediated disorders, in particular melanoma, breast cancer or lung cancer.

[0015] Alternative PHGDH inhibitors that show promise for the prevention and / or treatment of fibrosis have been described as non-competitive or allosteric inhibitors of the PHGDH enzyme (see Pacold et al, Nat Chem Biol. 2016; 12: 452-458).

[0016] Examples of said PHGDH inhibitors useful for treating fibrotic diseases are disclosed in WO2016115463 (Whitehead Institute For Biomedical Research; Dana-Farber Cancer Institute, Inc.).

[0017] In particular, one compound, identified as NCT-503, was tested in a bleomycin-induced pulmonary fibrosis model (see Hamanaka et al., Am J Respir Cell Mol Biol. 2018 May; 58(5):585-593) and showed preliminary efficacy in attenuating pulmonary fibrosis in mice treated 7 days after intratracheal instillation of leomycin.

[0018] Despite the above prior art, there remains a possibility to develop medicaments comprising PHGDH inhibitors useful for the prevention and / or treatment of fibrosis, particularly IPF, which have an improved efficacy profile and at the same time feature lower brain exposure to reduce potential adverse neurological events.

[0019] Therefore, the problem underlying the present invention is to provide a medicament comprising a compound of formula (I) for the prevention and / or treatment of fibrosis, in particular IPF.

[0020] In a first aspect, the present invention provides a compound of formula (I): [ka] [In the formula, R 1 is hydrogen or C 1-4 is alkyl; R 2 and R 3 are each independently a halogen, —OR, —CN, C optionally substituted with 1, 2 or 3 halogens; 1-6 Aliphatic, or -LR 8 or R 2 and R 3 may optionally be joined together with the carbon atom to which they are attached and any intervening atoms to form a 5-8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L is independently C 1-6 a divalent straight or branched hydrocarbon chain, wherein 1-4 methylene units of said chain are independently optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -C(O)N(R)-, -(R)NC(O)-, -N(R)-, -N(R)C(O)N(R)-, -S-, -SO-, or -SO2-; Each R is independently hydrogen or C 1-6an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 8 is hydrogen, C 1-6 an aliphatic or optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 4 is hydrogen, halogen, -OR 5 , —CN, C optionally substituted by 1, 2 or 3 halogens 1-6 Aliphatic, or -LR 8 and; R 5 is hydrogen, -(CH2) n -phenyl, -(CH2) n -Cy ’ or C optionally substituted by 1, 2 or 3 halogens 1-6 is alkyl; each -Cy'- is a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 6 is hydrogen or C 1-4 is alkyl; R 7 is hydrogen, -CO2R, optionally substituted C 1-6 aliphatic, -Cy-, or a divalent 3- to 7-membered ring; L 1 is a covalent bond or, C 1-8a divalent straight or branched hydrocarbon chain, wherein 1-5 methylene units of the chain are optionally and independently replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O), -OC(O)N(R), -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R), or -Cy-; -Cy- is each independently a divalent 6-membered arylene ring containing 0 to 2 nitrogen atoms, or a divalent 5-membered heteroarylene ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a divalent partially unsaturated 8 to 10-membered bicyclic heterocycloene ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein -Cy- is C 1-4 optionally substituted with 1 or 2 substituents independently selected from alkyl or -OR; X is O, S or -N(R 10 )-and; R 10 is C optionally substituted by 1, 2 or 3 halogens 1-6 Aliphatic, -C(O)CH3 or -SO2-N(R 1 )(R 11 ) and; R 11 -C(O)CH3, -C(O)NHR 1 or pyrazinyl; n is independently 0, 1, 2, 3, 4, or 5; m is independently 0, 1, or 2; and Y 1 and Y 2 are each independently =N- or =C(R 4 )-is] or a pharmaceutically acceptable salt thereof.

[0021] In a second aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of IPF.

[0022] In a third aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable carriers or excipients for use in the prevention and / or treatment of fibrosis.

[0023] In a fourth aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable carriers or excipients for use in the prevention and / or treatment of IPF. [Brief explanation of the drawings]

[0024] [Figure 1] Figure 1: Inhibition of collagen expression [Figure 2] Figure 2: Inhibition of α-SMA expression [Figure 3] Figure 3: Inhibition of cell proliferation [Figure 4] Figure 4: Plasma and tissue concentrations of compound 19 [Figure 5] Figure 5: Inhibition of 13C-labeled serine synthesis in plasma by compound 19 [Figure 6] Figure 6: Inhibition of 13C-labeled serine synthesis in the lung by compound 19 [Figure 7] Figure 7: Inhibition of 13C-labeled serine synthesis in the brain by compound 19 [Figure 8] Figure 8: Inhibition of 13C-labeled serine synthesis in plasma by compound 19a [Figure 9] Figure 9: Inhibition of 13C-labeled serine synthesis in the lung by compound 19a [Figure 10] Figure 10: Inhibition of 13C-labeled serine synthesis in the brain by compound 19a [Figure 11] Figure 11: Ashcroft score analysis for compound 19 [Figure 12]Figure 12: Automated histological analysis for compound 19 (artificial intelligence APP - fibrosis area) [Figure 13] Figure 13: Automated histological analysis for compound 19 (artificial intelligence APP - collagen APP) [Figure 14] Figure 14: Markers in lung homogenate by compound 19 [Figure 15] Figure 15: Plasma serine levels with compound 19 [Figure 16] Figure 16: Plasma levels of Compound 19 after final dose [Figure 17] Figure 17: FVC-lowering effect of compound 19a compared to the saline group [Figure 18] Figure 18: Biomarkers in BALF (A and B) and plasma (C) by compound 19a [Figure 19] Figure 19: Ashcroft score analysis and automated analysis of fibrosis for compound 19a [Figure 20] Figure 20: Ashcroft score analysis for NCT-503 [Figure 21] Figure 21: Markers in lung homogenates by NCT-503 [Figure 22] Figure 22: Plasma serine levels with NCT-503 [Figure 23] Figure 23: Plasma and brain levels of NCT-503 after final dose

[0025] definition The terms "aliphatic" or "aliphatic group," as used herein, refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon chain (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation but is not aromatic, and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon chain that is fully saturated or contains one or more units of unsaturation but is not aromatic and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0026] The term "lower alkyl" refers to C 1-4 It means a straight-chain or branched alkyl group. Exemplary lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0027] The term "lower haloalkyl" refers to a C alkyl group substituted by one or more halogen atoms. 1-4 It means a straight or branched chain alkyl group.

[0028] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (such as N-substituted pyrrolidinyl)).

[0029] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0030] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated straight or branched hydrocarbon chain" means divalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0031] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0032] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0033] As used herein, the term "cyclopropylenyl" means [ka] It means a divalent cyclopropyl group having the structure:

[0034] The term "halogen" means F, Cl, Br or I.

[0035] The term "aryl," used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as used herein, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0036] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, with 6, 10, or 14 pi electrons shared within the cyclic array, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently may be optionally substituted.

[0037] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and that, in addition to carbon atoms, has one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It can be NR (as in N-substituted pyrrolidinyl).

[0038] Heterocyclic ring can be bonded to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom can be optionally substituted.Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl and quinuclidinyl.The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" means an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently may be optionally substituted.

[0039] As used herein, the term "partially unsaturated" means a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0040] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced with a suitable substituent.

[0041] Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with one or more substituents selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.

[0042] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, geometric (or conformational)) forms of the structure, e.g., R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise specified, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.

[0043] The term "pharmaceutically acceptable salts," as used herein, refers to derivatives of compounds where the parent compound is suitably modified by converting any of the free acid or basic groups, if any, into the corresponding addition salts with any base or acid that is conventionally intended to be pharmaceutically acceptable.

[0044] The term "fibrotic condition," "fibrotic disease," or "fibrosis" means a condition associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment, including, but not limited to, pulmonary fibrosis, familial pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (CHP), liver fibrosis, renal or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, sarcoidosis, and systemic sclerosis, liver fibrosis, or cirrhosis.

[0045] The term "PHGDH" or "phosphoglycerate dehydrogenase" is also 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.

[0046] The terms "treating" or "treatment" of a disease state include (i) inhibiting the disease state, i.e., arresting the progression of the disease state or its clinical symptoms, or (ii) alleviating the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

[0047] The term "preventing" or "prevention" of a disease state includes preventing the development of clinical symptoms of the disease state in a subject who is exposed to or predisposed to the disease state but who has not yet experienced or exhibited symptoms of the disease state. For example, treating or preventing a respiratory disease or disorder includes treating or preventing symptoms of the disorder, such as coughing and / or the urge to cough, associated with a respiratory disease.

[0048] The term "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease state, is sufficient to affect treatment for that disease state. A "therapeutically effective amount" will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, and the route and form of administration.

[0049] The present invention relates to compounds of general formula (I) as defined herein for use in the prevention and / or treatment of fibrotic diseases.

[0050] Unlike other PHGDH inhibitors of the prior art, such as NCT-503, the compounds of formula (I) are surprisingly effective in a substantial and effective manner in the treatment of fibrosis, particularly IPF, and will be particularly appreciated by those skilled in the art when considering improved treatments for fibrosis.

[0051] As shown in the experimental section, compounds of formula (I) exhibit improved in vitro profiles and demonstrated antifibrotic activity in in vitro and in vivo models.

[0052] The antifibrotic activity of preferred compounds of formula (I) was monitored by measuring the expression of the fibrotic mediators, collagen I (Col-I) and alpha-smooth muscle actin (alpha-SMA).

[0053] As seen in Example 1 of Table 2, compound 19 can reduce TGF-β-induced fibroblast-to-myofibroblast transition (FMT) and inhibit the release of α-SMA in NHLFs treated with TGF-β (10 ng / ml) for 48 hours, and unlike compound NCT-503, compound 19 can also reduce cell proliferation induced by serum treatment (72 hours) in NHLFs.

[0054] The antifibrotic activity of compounds of Formula (I) has also been demonstrated by measuring the expression of collagen I (Col-I), a known fibrotic mediator during fibroblast-to-myofibroblast transition (FMT), in an in vitro assay. Furthermore, collagen is a downstream effector of the PHGDH pathway, and its inhibition emphasizes the important role of this marker in the fibrotic process. These findings suggest that de novo synthesis of serine and glycine is required for pulmonary fibrosis; inhibition of myofibroblast differentiation and collagen deposition is strongly linked and necessary for the antifibrotic activity of the compounds.

[0055] As reported in Table 3 of Example 2, all other test compounds dose-dependently reduced aSMA expression after 72 hours of incubation, except for NCT-503, which only partially reduced aSMA expression. Furthermore, the test compounds dose-dependently inhibited collagen I deposition after 72 hours of treatment.

[0056] More advantageously, the compound of formula (I) exhibits surprisingly lower CNS (central nervous system) exposure than previous compounds, in the compound NCT-503. As reported in Example 3, due to the lower brain exposure, the risk of potential neurological adverse effects already known for other PHGDH inhibitors is significantly reduced.

[0057] As an added advantage, the compounds of the present invention have been found to be particularly effective in bleomycin-induced pulmonary fibrosis in mice, which is the most widely used in vivo model.Bleomycin-induced pulmonary fibrosis in mice is the most commonly used in vivo experimental model for inducing pulmonary fibrosis.Injection of bleomycin into the trachea induces a multiphasic reaction, beginning with acute and severe inflammation, followed by diffuse matrix and collagen deposition, resulting in histological changes with obvious fibrosis accumulation and loss of functional parenchymal tissue, reproducing the specific pathological features observed in the lungs of IPF patients.

[0058] Indeed, the bleomycin animal model is widely used to evaluate potential antifibrotic agents.

[0059] As observed in Example 5 and shown in Figures 11A, 11B, 12 and 13, compound 19 significantly reduced the pathological features of induced fibrosis as measured by Ashcroft score and automated histological analysis; conversely, as reported in Figure 20, compound NCT-503 did not reduce bleomycin-induced pulmonary fibrosis or the severity of fibrosis.

[0060] Furthermore, as further evidence of improved efficacy, compounds of the present invention can reduce the levels of fibrosis markers typically induced by bleomycin treatment, such as collagen accumulation (pro-collagen I) and matrix deposition (WISP-1), as seen in Figures 14A, 14B, and 14C. In stark contrast, treatment with NCT-503 has no effect on the levels of all of the same markers, as shown in Comparative Example 7 and Figures 21A and 21B.

[0061] As observed in Example 6 and shown in Figure 19A, Compound 19a, a diastereoisomer of Compound 19, showed a significant increase in fibrosis in the Ashcroft score in the bleomycin model, which was significantly reduced after treatment with Compound 19a. As shown in Figure 19B, Compound 19a was able to reduce fibrotic tissue in a dose-dependent manner, with a clear effect.

[0062] Bleomycin infusion significantly increased the intrapulmonary levels of collagen I and MMP-7 assessed in BALF (Figures 18A and 18B) and improved the decline in forced vital capacity (FVC) by 77% at a dose of 100 mg / kg. Compound 19a significantly reduced the levels of these biomarkers in a dose-dependent manner, with the maximum effect observed at a dose even lower than that of compound 19.

[0063] Thus, the compounds of formula (I) have shown efficacy in the treatment of fibrosis, in particular idiopathic pulmonary fibrosis, whenever the PHGDH receptor is involved.

[0064] In one embodiment, the present invention provides a compound of formula (I): [ka] [In the formula, R 1 is hydrogen or C 1-4 is alkyl; R 2 and R 3 are each independently a halogen, —OR, —CN, C optionally substituted with 1, 2 or 3 halogens; 1-6 Aliphatic, or -LR 8 or R 2 and R 3 may optionally be joined together with the carbon atom to which they are attached and any intervening atoms to form a 5-8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L is independently C 1-6 a divalent straight or branched hydrocarbon chain, wherein 1-4 methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -C(O)N(R)-, -(R)NC(O)-, -N(R)-, -N(R)C(O)N(R)-, -S-, -SO-, or -SO2-; Each R is independently hydrogen or C 1-6an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 8 is hydrogen, C 1-6 an aliphatic or optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 4 is hydrogen, halogen, -OR 5 , —CN, C optionally substituted by 1, 2 or 3 halogens 1-6 Aliphatic, or -LR 8 and; R 5 is hydrogen, -(CH2) n -phenyl, -(CH2) n -Cy ’ or C optionally substituted by 1, 2 or 3 halogens 1-6 is alkyl; each -Cy'- is a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 6 is hydrogen or C 1-4 is alkyl; R 7 is hydrogen, -CO2R, optionally substituted C 1-6 aliphatic, -Cy- or a divalent 3- to 7-membered ring; L 1 is a covalent bond or C 1-8a divalent straight or branched hydrocarbon chain, wherein 1-5 methylene units of the chain are optionally and independently replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O), -OC(O)N(R), -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R), or -Cy-; -Cy- is each independently a divalent 6-membered arylene ring containing 0 to 2 nitrogen atoms, or a divalent 5-membered heteroarylene ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a divalent partially unsaturated 8 to 10-membered bicyclic heterocycloene ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein -Cy- is C 1-4 optionally substituted with 1 or 2 substituents independently selected from alkyl or -OR; X is O, S or -N(R 10 )-and; R 10 is C optionally substituted by 1, 2 or 3 halogens 1-6 Aliphatic, -C(O)CH3 or -SO2-N(R 1 )(R 11 ) and; R 11 -C(O)CH3, -C(O)NHR 1 or pyrazinyl; n is independently 0, 1, 2, 3, 4, or 5; m is independently 0, 1, or 2; and Y 1 and Y 2 are each independently =N- or =C(R 4 )-is] or a pharmaceutically acceptable salt thereof.

[0065] The variables R, R of the compounds of the invention1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , L, L 1 , R 10 , R 11 ,X,n,m,Cy,Cy',Y 1 and Y 2 All groups listed for each of the groups are intended as alternatives and may be combined with each other in embodiments within the scope of the present invention.

[0066] In one embodiment, R 1 is hydrogen or C 1-4 In one preferred embodiment, R 1 is methyl or ethyl. In a more preferred embodiment, R 1 is methyl.

[0067] In one embodiment, R 2 and R 3 are each independently a halogen, —OR, —CN, C optionally substituted with 1, 2 or 3 halogens; 1-6 Aliphatic, or -LR 8 or R 2 and R 3 may optionally be joined together with the carbon atoms to which they are attached and intervening atoms to form a 5-8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0068] In one embodiment, R 2 is halogen, -OR, -LR 8 , [ka] is selected from the group consisting of:

[0069] In one preferred embodiment, R 2is F, Cl, -CF3, -OCF3, -OCHF2, -OCH2Ph, -OCH3, -CN, -CH3, [ka] is selected from the group consisting of:

[0070] In a more preferred embodiment, R 2 is selected from the group consisting of F, Cl, —OCH3 and —CH3.

[0071] In one embodiment, R 3 is halogen, OR, [ka] is selected from the group consisting of:

[0072] In one preferred embodiment, R 3 is selected from the group consisting of F, Cl, —OCH3 and —CH3. In a further preferred embodiment, R 3 is -CH3.

[0073] In one embodiment, R 4 is hydrogen, halogen, -OR 5 , —CN, C optionally substituted by 1, 2 or 3 halogens 1-6 Aliphatic, or -LR 8 In a preferred embodiment, R 4 is H, halogen, -OR, [ka] is selected from the group consisting of:

[0074] In one preferred embodiment, R 4 is selected from the group consisting of hydrogen, F, Cl, —OCH3 and —CH3. In a further preferred embodiment, R 4 is hydrogen.

[0075] In one embodiment, R5 is hydrogen, -(CH2) n -phenyl, -(CH2) n -Cy ’ or C optionally substituted by 1, 2 or 3 halogens 1-6 In a preferred embodiment, R 5 is hydrogen or C optionally substituted by 1, 2 or 3 halogens 1-6 It is alkyl.

[0076] In one embodiment, R 6 is hydrogen or C 1-4 In a preferred embodiment, R 6 is hydrogen or methyl.

[0077] In one embodiment, R 8 are independently hydrogen, C 1-6 It is an aliphatic or optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In a preferred embodiment, R 8 are independently hydrogen or C 1-6 It is aliphatic.

[0078] In one embodiment, R is hydrogen or C 1-6 In a preferred embodiment, R is selected from the group containing an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In a preferred embodiment, R is hydrogen.

[0079] In one embodiment, R 6is hydrogen or C 1-4 In a preferred embodiment, R 6 is hydrogen or methyl.

[0080] In one embodiment, L 1 is a covalent bond or C 1-8 and a divalent linear or branched hydrocarbon chain, wherein 1-5 methylene units of the chain are optionally independently replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O), -OC(O)N(R), -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO-, -SON(R)-, -(R)NSO-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R), or -Cy-. 1 is C 1-8 a divalent straight or branched hydrocarbon chain, wherein 1 to 5 methylene units of the chain are optionally and independently replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O), -OC(O)N(R), -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R), or -Cy-.

[0081] In a preferred embodiment, L 1 is SO2NH-, [ka] is selected from the group consisting of:

[0082] In a more preferred embodiment, L 1 teeth, [ka] is selected from the group consisting of:

[0083] In one embodiment, R 7 is hydrogen, -CO2R, optionally substituted C 1-6 In one preferred embodiment, R 7 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, tetrazolyl, and —COH.

[0084] In one embodiment, -Cy- is each independently a divalent 6-membered arylene ring containing 0-2 nitrogen atoms, or a divalent 5-membered heteroarylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a divalent partially unsaturated 8- to 10-membered bicyclic heterocycloene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein -Cy- is C 1-4 It may be optionally substituted with one or two substituents independently selected from alkyl or -OR.

[0085] In one embodiment, R 10 is C optionally substituted by 1, 2 or 3 halogens 1-6 Aliphatic, -C(O)CH3, or -SO2-N(R 1 )(R 11 In a preferred embodiment, R 10 is C optionally substituted by 1, 2 or 3 halogens 1-6 It is aliphatic, or -C(O)CH3.

[0086] In one embodiment, X is O, S or —N(R 10 )-. In one preferred embodiment, X is O.

[0087] In one embodiment, Y 1 and Y 2 are each independently =N- or =C(R 4In a preferred embodiment, Y 1 and Y 2 is -CH.

[0088] The variables R, R of the compounds of the invention 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , L, L 1 , R 10 , R 11 ,X,n,m,Cy,Cy',Y 1 and Y 2 All groups listed for each of the groups are intended as alternatives and may be combined with each other in embodiments within the scope of the present invention.

[0089] In another embodiment, the invention relates to a compound of formula (I) as defined above for use in the prevention and / or treatment of a fibrosis selected from the group consisting of pulmonary fibrosis, familial pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (CHP), liver fibrosis, renal fibrosis or kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, sarcoidosis and systemic sclerosis, liver fibrosis and cirrhosis.

[0090] In one preferred embodiment, the invention relates to compounds of formula (I) as defined above for use in the prevention and / or treatment of IPF.

[0091] In an equally preferred embodiment, the invention relates to compounds of formula (I) as defined above for use in the prevention and / or treatment of renal fibrosis.

[0092] In some embodiments, the present invention provides a compound of formula II-a, II-b, II-c, II-d or II-e: [ka] [In the formula, R1 , R 2 , R 3 , R 4 , R 6 , R 7 , L 1 , Y 1 and Y 2 are each as defined above and as described in the embodiments herein. or a pharmaceutically acceptable salt thereof.

[0093] In one preferred embodiment, the present invention relates to a compound selected from formula II-a, II-b, II-c, II-d or II-e as defined above for use in the prevention and / or treatment of a fibrosis selected from the group consisting of pulmonary fibrosis, familial pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (CHP), liver fibrosis, renal fibrosis or kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, sarcoidosis and systemic sclerosis, liver fibrosis and cirrhosis.

[0094] In a further preferred embodiment, the present invention relates to a compound selected from formula II-a, II-b, II-c, II-d or II-e for use in the prevention and / or treatment of IPF.

[0095] In an equally preferred embodiment, the present invention relates to a compound selected from formula II-a, II-b, II-c, II-d or II-e as defined above for use in the prevention and / or treatment of renal fibrosis.

[0096] In one embodiment, the present invention provides a method for the prevention and / or treatment of fibrosis, comprising: Formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or III-i: [ka] [ka] [In the formula, R1 , R 2 , R 3 , R 4 , R 6 , R 7 , L 1 , Y 1 and Y 2 are each as defined above and as described in the embodiments herein. or a pharmaceutically acceptable salt thereof.

[0097] In one preferred embodiment, the present invention provides a compound selected from formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or III-i as defined above for use in the prevention and / or treatment of a fibrosis selected from the group consisting of pulmonary fibrosis, familial pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (CHP), liver fibrosis, renal fibrosis or kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, sarcoidosis and systemic sclerosis, liver fibrosis and cirrhosis.

[0098] In one preferred embodiment, the present invention provides a compound selected from formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or III-i as defined above for use in the prevention and / or treatment of IPF.

[0099] In an equally preferred embodiment, the present invention provides a compound selected from formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or III-i as defined above for use in the prevention and / or treatment of renal fibrosis.

[0100] According to a preferred embodiment, the present invention relates to at least one compound selected from the compounds shown in Table 1 below, for use in the prevention and / or treatment of fibrosis. [Table 1] Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34

[0101] It is to be understood that all single deuterated forms, enantiomers, diastereoisomers and mixtures thereof in any proportion, or pharmaceutically acceptable salts and solvates of compounds of formula (I) are encompassed within the scope of the present invention.

[0102] In one preferred embodiment, the present invention relates to at least one compound selected from the compounds listed in Table 1 above for use in the prevention and / or treatment of a fibrosis selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (CHP), liver fibrosis, renal fibrosis or kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, sarcoidosis and systemic sclerosis, liver fibrosis and cirrhosis.

[0103] In a more preferred embodiment, the present invention relates to at least one compound selected from the compounds listed in Table 1 above, for use in the prevention and / or treatment of IPF.

[0104] In an equally more preferred embodiment, the present invention relates to at least one compound selected from the compounds listed in Table 1 above, for use in the prevention and / or treatment of renal fibrosis.

[0105] The preparation and synthesis intermediates of the compounds listed in Table 1, along with PHGDH activity inhibition data, have already been described in WO2017156165 (Raze Therapeutics).

[0106] In one embodiment, the present invention provides compound 19: [ka] compound 19 Regarding.

[0107] In one preferred embodiment, the present invention relates to compound 19 for use in the prevention and / or treatment of fibrosis selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (CHP), liver fibrosis, renal fibrosis or kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, sarcoidosis and systemic sclerosis, liver fibrosis and cirrhosis.

[0108] In a more preferred embodiment, the present invention relates to compound 19 for use in the prevention and / or treatment of IPF.

[0109] In another embodiment, the present invention provides compound 19a, diastereoisomer 2 of (±)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydro-furan-3-yl)phenyl)-3-methylbutanoic acid, for use in the prevention and / or treatment of fibrosis: [ka] compound 19a Regarding.

[0110] In one preferred embodiment, the present invention relates to compound 19a for use in the prevention and / or treatment of fibrosis selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (CHP), liver fibrosis, renal fibrosis or kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, sarcoidosis and systemic sclerosis, liver fibrosis and cirrhosis.

[0111] In a more preferred embodiment, the present invention relates to compound 19a for use in the prevention and / or treatment of IPF.

[0112] In an equally preferred embodiment, the present invention relates to compound 19a for use in the prevention and / or treatment of renal fibrosis.

[0113] The compounds of formula (I) are typically administered one or more times, for example twice daily, optionally in combination with a dosing regimen in which several doses are administered at various time intervals for a given period of time, according to the knowledge of the skilled artisan.

[0114] The dosage of the compounds of the present invention can depend on a variety of factors, including the particular disease being treated, the severity of the condition, the route of administration, and the like, among others.

[0115] In another embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of fibrosis, whereby said compound is administered for days, weeks, months or years, including indefinitely.

[0116] In one aspect, the present invention also relates 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 carriers for use in the prevention and / or treatment of fibrosis.

[0117] In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable carriers or excipients, e.g. as described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA, for use in the prevention and / or treatment of fibrosis. Administration of the compounds of the present invention and pharmaceutical compositions thereof can be achieved, for example, orally, intranasally, parenterally (subcutaneously, intravenously, intramuscularly, intradermally and by infusion), and by inhalation, depending on the needs of the patient.

[0118] Preferably, the compounds of the invention for use in the prevention and / or treatment of fibrosis are administered orally or by inhalation.

[0119] In one preferred embodiment, the pharmaceutical composition comprising a compound of formula (I) is a solid oral dosage form such as a tablet, gelcap, capsule, caplet, granule, lozenge, and bulk powder.

[0120] The compounds of the present invention may be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (sucrose, mannitol, lactose, starch, etc.) and known excipients, including suspending agents, solubilizing agents, buffers, binders, disintegrating agents, preservatives, coloring agents, flavoring agents, lubricants, etc.

[0121] In a further embodiment, pharmaceutical compositions comprising a compound of formula (I) for use in the prevention and / or treatment of fibrosis are liquid oral dosage forms such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups, etc. Such liquid dosage forms may also contain suitable known inert diluents, such as water, and suitable known excipients, such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the compounds of the present invention.

[0122] In a further embodiment, the pharmaceutical composition comprising a compound of formula (I) for use in the prevention and / or treatment of fibrosis is an inhalable formulation, such as an inhalable powder, a propellant-containing metered aerosol or a propellant-free inhalable formulation.

[0123] For administration as a dry powder, single or multi-dose inhalers known from the prior art can be used, in which case the powder can be filled into gelatin, plastic or other capsules, cartridges, or blister packs or reservoirs.

[0124] Diluents or carriers that are chemically inert to the compounds of the invention, such as lactose or any other additive suitable for improving the respirable fraction, may be added to the powdered compounds of the invention.

[0125] Inhalation aerosols containing a propellant gas such as hydrofluoroalkanes can contain the compounds of the present invention in solution or dispersion form. Propellant-driven formulations can also contain other ingredients such as cosolvents, stabilizers, and other excipients as needed.

[0126] Propellant-free inhalable formulations containing the compounds of the invention may be in the form of a solution or suspension in an aqueous, alcoholic, or hydroalcoholic vehicle and may be delivered by jet or ultrasonic nebulizers, or soft mist nebulizers, as known in the art.

[0127] In one aspect, the present invention relates to a device comprising a pharmaceutical composition comprising a compound of formula (I) for use in the prevention and / or treatment of fibrosis according to the present invention in the form of a single or multi-dose dry powder inhaler or a metered dose inhaler.

[0128] The compounds of the present invention for use in the prevention and / or treatment of fibrosis may be administered as the sole active agent or in combination with other pharmaceutically active ingredients.

[0129] In a further aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of fibrosis.

[0130] In one embodiment, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of fibrosis selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (CHP), liver fibrosis, renal fibrosis or kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, sarcoidosis and systemic sclerosis, liver fibrosis and cirrhosis.

[0131] In one preferred embodiment, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of IPF.

[0132] In one preferred embodiment, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of renal fibrosis.

[0133] In a more preferred embodiment, the present invention relates to the use of compound 19 for the prevention and / or treatment of IPF.

[0134] In another preferred embodiment, the present invention relates to the use of compound 19a for the prevention and / or treatment of IPF.

[0135] In a further aspect, the present invention relates to a method for preventing and / or treating fibrosis, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0136] In one embodiment, the present invention relates to a method for preventing and / or treating a fibrosis selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (CHP), liver fibrosis, renal fibrosis or kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, sarcoidosis and systemic sclerosis, liver fibrosis and cirrhosis, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0137] In one preferred embodiment, the present invention relates to a method for preventing and / or treating IPF, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0138] In an equally preferred embodiment, the present invention relates to a method for preventing and / or treating renal fibrosis, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0139] In a more preferred embodiment, the present invention relates to a method for preventing and / or treating IPF, comprising administering compound 19 or a pharmaceutically acceptable salt thereof.

[0140] In another preferred embodiment, the present invention relates to a method for preventing and / or treating IPF, comprising administering compound 19a or a pharmaceutically acceptable salt thereof.

[0141] All preferred groups or embodiments described above for compounds of formula (I) for use in the prevention and / or treatment of fibrosis may be combined with each other and may be applied mutatis mutandis.

[0142] The various aspects of the invention described in this application are illustrated by, but not limited to, the following compounds.

[0143] Preparation of compounds All compounds of the present invention are synthesized by the method described in WO2017156165, but compounds 19a, 19b, 19c, and 19d can be obtained from compound 19 by the following method.

[0144] Chemical names of compounds were generated using Structure To Name Enterprise 10.0 Cambridge Software or are common chemical names. All reagents for which no synthesis is described in the experimental section are commercially available, known compounds, or can be synthesized from known compounds by known methods by one skilled in the art.

[0145] In the following procedures, some starting materials are designated by "intermediate" or "compound" number and step number, which is provided solely as an aid to the skilled chemist.

[0146] Abbreviation SFC = supercritical fluid chromatography; R = retention time; iPrNH2 = isopropylamine; TMS = tetramethylsilane NMR characterization: 1H NMR spectra were recorded on a Varian MR-400 spectrometer operating at 400 MHz (proton frequency) equipped with a 5 mm 1H / nX broadband probehead with a self-shielded Z gradient coil for inverse detection, a deuterium digital lock channel unit, and a quadrature digital detection unit with transmitter offset frequency shift.

[0147] Alternatively, NMR spectra were performed on a Bruker AVANCE III HD 600 spectrometer operating at 600 MHz (proton frequency) equipped with a TCI INVERSE TRIPLE RESONACE CRYOPROBE HC / ND-0.5-Z ATMA. The probe is equipped with an active shielded uniaxial Z-gradient. 13 C and 15 Simultaneous decoupling of multiple X nuclei, such as N, is possible, and automatic tuning and matching are possible. The standard sample temperature range is 0°C to 80°C.

[0148] Chemical shifts are given in δ values ​​(ppm) relative to tetramethylsilane (TMS) as an internal standard. Coupling constants (J values) are given in Hertz (Hz), and multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, quin = quintet, m = multiplet, br = broad.

[0149] In some cases, the NH signal of the amide bond or the OH signal of the acid bond (exchangeable proton) may not be observed, and in some cases may be hidden under the signal of water or under the signal of DMSO or other residual solvents.

[0150] LC / UV / MS analysis method LC / MS retention times are estimated to be subject to an experimental error of ±0.5 min.

[0151] Method 1: Acquity CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 40 °C; Mobile phase: Eluent B (ACN / water 95:5 + 0.05% HCOOH) in Eluent A (water / ACN 95:5 + 0.05% HCOOH) from 1% to 99.9% within 1.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0152] Chiral Supercritical Fluid Chromatography (SFC) Separation Protocol Diastereomeric separation of the compounds was achieved by supercritical fluid chromatography (SFC) using a Waters Prep SFC200 system (P200 CO2 pump, 2545 modifier pump, 2489 UV / VIS detector). Analysis of the two enantiomers was performed on the reconstituted final sample.

[0153] A Waters 7937 liquid handler served as the fraction collector. The appropriate isocratic method was selected based on the methanol solvent system under base conditions. The standard SFC method used the following modifiers: CO2, 100 mL / min, 100 Bar back pressure, and 40 °C column temperature. Under base conditions, isopropylamine (0.5% V / V) was used as a modifier. The sample solution was filtered through a GHP 0.45 μm filter. The collected fractions were analyzed using an Agilent SFC (Agilent 1260). The collected fractions containing the desired product were concentrated by vacuum centrifugation.

[0154] Method 1: SFC-MS was performed on a Waters Thar Prep 100 preparative SFC system using a Chiralcel OD-H (30 mm x 250 mm, 5 μm) column with a constant flow (15:85 MeOH + 0.5% iPrNH:CO), a flow rate of 100 mL / min, BPR 100 Bar, a detector wavelength of 220 nm, an injection volume of 150 mL, a stacking interval of 28 min, an elution time of 60 min, and a column temperature of 40 °C.

[0155] Method 2: SFC-MS was performed on a Waters Thar Prep100 preparative SFC system using a Chiralpak IC OD-H (30 mm x 250 mm, 5 μm) column with isocratic run (30:70 MeOH + 0.5% iPrNH:CO), flow rate 100 mL / min, BPR 100 BarG, detector wavelength 220 nm, injection volume 25 mL, stacking interval 4.38 min, elution time 12 min, and 40°C column temperature.

[0156] Supercritical fluid chromatography (SFC)-mass spectrometry (MS) analysis conditions Method 3: SFC-MS was performed on an SFC Agilent system using a Chiralcel OD (4.6 mm x 250 mm, 5 um) column with isocratic run (20:80 MeOH + 0.5% iPrNH:CO), flow rate 2.4 mL / min, BPR 104 BarG, detector wavelength 210 nm, injection volume 50 μL (1 mg / mL in MeOH), and 40 °C column temperature.

[0157] A single diastereoisomer of compound 19 was obtained by two successive purifications by preparative chiral SFC. [ka]

[0158] Compound 19b and Compound 19d: the first-eluting and fourth-eluting diastereoisomers of 2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydro-furan-3-yl)phenyl)-3-methylbutanoic acid.

[0159] The racemic mixture of compound 19 (2.5 g, 5.11 mmol) was dissolved in 150 mL of MeOH+0.5% iPrNH2 and separated by preparative SFC using Method 1 to give the desired product as the iPrNH2 salt. 1The iPrNH2:acid stoichiometry observed in the 1H NMR spectra varied from 1:1 to 0.5:1.

[0160] First eluted diastereoisomer (compound 19b): 491 mg, 19.6%.

[0161] Fourth eluting diastereoisomer (compound 19d): 466 mg, 18.6%.

[0162] Mixture of second and third eluting diastereoisomers: 1.07 g, 42.8%.

[0163] Compound 19a and Compound 19c: the second-eluting diastereoisomer and the third-eluting diastereoisomer of 2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydro-furan-3-yl)phenyl)-3-methylbutanoic acid.

[0164] The mixture of the second and third eluting isomers (1.07 g) was dissolved in 25 mL of MeOH+0.5% iPrNH2 and separated by preparative SFC using Method 2 to give the desired product as the iPrNH2 salt.

[0165] Second eluting diastereoisomer (compound 19a): 374 mg, 35%.

[0166] Third eluting diastereoisomer (compound 19c): 459 mg, 42.9%. [Table 35]

[0167] Pharmacological activity of the compounds of the present invention In vitro assays TGFb-induced release of profibrotic markers and serum-induced proliferation The antifibrotic activity of compounds of the invention was monitored by measuring the expression of the fibrotic mediators collagen I (Col-I) and alpha-smooth muscle actin (α-SMA) after treating lung cells with TGF-β and compared to nintedanib (see Frank Hilberg et al, Cancer Res 2008 Jun 15;68(12):4774-82) and the allosteric inhibitor NCT-503 (see Hamanaka et al., Am J Respir Cell Mol Biol. 2018 May;58(5):585-593).

[0168] method Human normal lung fibroblasts (NHLF) were purchased from Lonza (Basel, Switzerland). NHLF were cultured at 37°C in an atmosphere of 95% air and 5% CO2 in Eagle's minimum essential medium (EMEM) without serine and glycine, supplemented with 10% fetal bovine serum (FBS), antibiotics (50 U / ml penicillin and 0.05 mg / ml streptomycin), and 2 mM L-glutamine. NHLF cultures were used from passages 1 to 9. Prior to all experiments, cells were cultured overnight in serum-free medium.

[0169] NHLFs were seeded into 12-well plates and cultured until 70% confluent. To examine the expression of fibrotic markers, cells were treated with different concentrations of compounds and NCT-503 in EMEM medium for 1 hour, followed by stimulation with TGF-β for 48 hours at 37°C and 5% CO2. After cell treatment, the medium was removed, and whole-cell extracts were prepared by adding 1X loading buffer (125 mM Tris-HCl pH 6.8, 4% SDS, 0.2% Orange G, 50% glycerol, 2.5% β-mercaptoethanol, Li-cor Biosciences) directly to the wells. After boiling for 5 minutes, the extracts were electrophoresed on a Mini Protean TGX gel 4-12% (Biorad). After electrophoresis, proteins were transferred to a nitrocellulose membrane. Immunodetection of Col-I, α-SMA, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was performed using mouse anti-Col1A1 antibody (Santacruz), mouse anti-α-SMA antibody (Sigma), and rabbit anti-GAPDH antibody (Cell Signaling Technology), all diluted 1:1000 in TBS-Tween 0.1%. Secondary antibodies were goat anti-rabbit IgG and goat anti-mouse IgG conjugated with IRDye800 and IRDye680 probes (Li-cor), respectively, both diluted 1:15,000 in TBS-Tween 0.1% containing 1% skim milk. Detection and quantification were performed using the Odyssey Imaging System (Li-cor), with GAPDH used as a loading control.

[0170] Example 1: Compound 19 in an in vitro assay The antiproliferative activity of the compounds of the present invention was monitored by measuring the incorporation of bromodeoxyuridine (BrdU), a thymidine analog, into newly synthesized DNA after treatment of lung cells. Briefly, NHLFs were seeded into 96-well plates and treated with different concentrations of compound 19 and NCT-503 in EMEM medium for 1 hour, followed by stimulation with fetal bovine serum (FBS) for 72 hours at 37°C and 5% CO2. After cell treatment, 10 μl / well of BrdU labeling solution was added and allowed to incorporate into proliferating cells for 2 hours at 37°C and 5% CO2. The medium was removed, the cells were fixed, and DNA was denatured by adding FixDenat. Subsequently, the cells were incubated with 100 μl / well of anti-BrdU-POD for detection. The reaction products were quantified by measuring absorbance at each wavelength using a scanning multiwell spectrophotometer (ELISA reader).

[0171] The efficacy of compound 19 and NCT-503 is shown in Table 2.

[0172] The activity of the compound is expressed as pIC 50 (I C 50 The values ​​are expressed as the logarithm of the concentration of the compound that inhibits 50% of the expression of fibrotic markers or FBS-induced cell proliferation.

[0173] [Table 36]

[0174] As can be seen in Figure 1, compound 19 inhibits TGF-β-induced fibroblast-to-myofibroblast transition (FMT), as indicated by a decrease in collagen protein expression (A).

[0175] As shown in Figure 2, compound 19 (50 μM) can inhibit the release of α-SMA in NHLFs treated with TGF-β (10 ng / mL) for 48 h more effectively than NCT-503 (50 μM) and even more effectively than nintedanib (1 μM).

[0176] Unlike NCT-503, compound 19 can also reduce cell proliferation of NHLFs induced by serum treatment (72 h), as shown in Figure 3 .

[0177] Phenotypic assay - High content screening optimization of αSMA staining in NHLF cells method NHLF cells (Lonza #CC2512) were seeded at 2000 cells per well in a 384-well plate and incubated overnight at 37°C, 5% CO2 in serine- and glycine-free MEM medium (Sigma #M2279) + 1% pen / strep + 5 mM L-glutamine + 10% FBS.

[0178] The next day, cells were washed with PBS, supplemented with serine- and glycine-free starvation MEM medium (0% FBS), and incubated overnight at 37°C, 5% CO2. The following day, cells were pretreated with compound or vehicle (0.3% DMSO) for 1 hour. Compounds were tested in nine serial 3-fold dilutions starting from 30 μM. Each compound was tested in duplicate. Cells were further incubated for 72 hours at 37°C, 5% CO2, and 95% humidity. After 72 hours of incubation, αSMA expression was quantified using immunostaining: Fixation in 4% paraformaldehyde Blocking with 3% BSA, 2% FBS, 0.2% Triton-X in PBS Primary antibody: anti-αSMA antibody (AbCam #ab7817) diluted 500x in blocking buffer · Anti-mouse secondary antibody AF488 (ThermoFisher #A11029). The percentage of αSMA-positive cells was measured by high-content imaging (Molecular Devices), and data analysis was performed using MetaXpress software (Molecular Devices). The percentage of αSMA-positive cells was further used to calculate the inhibition rate of the tested compounds. Total cell number was measured by Hoechst staining, and the percentage of viability relative to the TGFβ-stimulated control was also calculated.

[0179] Fibroblast-to-myofibroblast transition (FMT) in vitro assay: Collagen I detection method NHLF cells were seeded at 80,000 cells per well in 12-well plates and incubated overnight at 37°C, 5% CO in serine- and glycine-free MEM medium (Sigma #M2279) + 1% pen / strep + 5 mM L-glutamine + 10% FBS. Assays were performed as previously reported.

[0180] Example 2: Other compounds in phenotypic assays (detection of aSMA and collagen) The potency of the compounds of the present invention and NCT-503 is shown in Table 3. The activity of the compounds is expressed as pIC50 (logarithm of IC50, the concentration of the compound that results in 50% inhibition of the expression of fibrotic markers).

[0181] [Table 37]

[0182] result As shown in Table 3, all test compounds dose-dependently reduced aSMA expression after 72 hours of incubation. In contrast, NCT-503 only partially reduced aSMA expression. Furthermore, the test compounds dose-dependently inhibited collagen I deposition after 72 hours of treatment. These results suggest that de novo serine and glycine synthesis is required for pulmonary fibrosis, and that myofibroblast differentiation and inhibition of collagen deposition are strongly correlated and necessary for the antifibrotic activity of the compounds.

[0183] In vivo assay Effect of compounds on inhibition of serine biosynthesis PK / PD model: In vivo [ 13 C6] glucose tracing PHGDH catalyzes the rate-limiting step in glucose-derived serine synthesis, 13 After oral administration of C6-glucose 13 Pharmacokinetic / pharmacodynamic (PK / PD) studies evaluating C3-serine synthesis inhibition were performed in male mice (C57BL / 6J).

[0184] Example 3: Compound 19 in a PK / PD model method Animals were fasted overnight before treatment. Compound 19 was administered at a dose of 300 mg / kg, or vehicle (0.5% Tween 80, 0.5% methylcellulose in HO) was administered 0.5 hours after which 13C6-glucose (2 g / kg, Merck Life Sciences Srl) was administered by oral gavage. Blood, lung, and brain samples were collected at 1, 6.5, and 24.5 hours after administration of compound 19 or vehicle. At each time point, animals were terminally anesthetized with an intraperitoneal injection of thiopental (200 mg / kg / 10 mL; MSD Animal Health Srl). All tissues were removed within 5 minutes to preserve metabolic status and immediately frozen in liquid nitrogen. Blood was collected by cardiac puncture and collected in heparin tubes. Blood was centrifuged at 10,000 g for 10 minutes to obtain plasma.

[0185] 13 Tissue concentrations of C3-serine were measured by liquid chromatography-tandem mass spectrometry (LC / MS / MS). Graphs were generated and statistically analyzed using GraphPad Prism (version 8.1.2). Plasma or tissue homogenate samples (tissues homogenized in a 50 / 50 mixture of water and acetonitrile) were extracted with three volumes of acetonitrile. The supernatant was injected into an HPLC system (Agilent 1260 Quaternary Pump with Agilent 1200 High-Performance Autosampler SL; Agilent). Compound 19 was analyzed using a Kinetex EVO C18 analytical column (100A, 50x2.1mm, 2.6µm; Phenomenex). 13 For the analysis of C3-serine, an InfinityLab Poroshell 120 Hilic-Z (50x2.1mm 2.7μm; Agilent) was used. The mobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B). Chromatographic separation was performed using a gradient elution method (see conditions below): Compound 19 (0.0–0.5 min, 10% B; 0.5–3.0 min, gradient to 90% B; 3.0–5.0 min, 90% B; 5.0–6.0 min, gradient to 10% B; 6.0–10.0 min, 10% B—flow rate: 0.4 mL / min). · 13 C3-Serine (0.0–0.5 min, 95% B; 0.5–4.0 min, gradient to 60% B; 4.0–5.0 min, 60% B; 5.0–6.0 min, gradient to 95% B; 6.0–10.0 min, 95% B—flow rate: 0.4 mL / min).

[0186] Mass spectrometry was performed using a linear ion trap triple quadrupole mass spectrometer (4000 Q TRAP; AB SCIEX) equipped with a turbospray ion source. The mass spectrometer was operated in positive ion mode, and quantification was performed using multiple reaction molecular weight monitor (MRM) mode. Peak integration was performed using Analyst (version 1.6.2). Graphs and statistical analysis were performed using GraphPad Prism (version 8.1.2).

[0187] result Plasma and tissue exposure of compound 19 was measured at three time points and is shown in Figure 4. Consistent with the presence of a carboxylic acid moiety, plasma and tissue concentrations of compound 19 showed limited distribution to the lung (mean lung / plasma ratio: 0.4) and very low CNS exposure (mean brain / plasma ratio: 0.01).

[0188] As shown in Figures 5 and 6, the observed concentrations were able to result in significant inhibition (70-85%) of labeled serine in plasma and lung at 1 and 6.5 hours. As shown in Figure 7, although labeled serine levels in the brain were significantly higher than those in plasma and lung, no significant inhibition was observed at any time point, as expected given the low brain concentrations observed for compound 19 (unpaired t-test at each time point, comparing treated and control groups).

[0189] Example 4: Comparison of Compound 19 and Compound 19a in a PK / PD model method Mice were treated with compound 19a (3 mg / kg, 10 mg / kg, 30 mg / kg, 100 mg / kg, and 300 mg / kg orally), compound 19 (300 mg / kg orally), or vehicle (0.5% Tween 80, 0.5% methylcellulose in HO) 0.5 hours after administration. 13C6-glucose (2 g / kg, Merck Life Science Srl) was administered by oral gavage. At the designated time points (1 h after compound or vehicle administration), animals were terminally anesthetized by intraperitoneal injection of thiopental (200 mg / kg / 10 mL; MSD Animal Health Srl). All tissues were harvested within 5 min to preserve metabolic status and immediately frozen in liquid nitrogen. Blood was collected by cardiac puncture and collected in heparin tubes. Blood was centrifuged at 10,000 g for 10 min to obtain plasma.

[0190] result As shown in Figures 8 and 9, both compound 19 and compound 19a caused significant inhibition of labeled serine in plasma and lung, demonstrating dose-response curves. Compound 19a, in particular, significantly reduced labeled serine levels at all doses tested, demonstrating dose-dependent inhibition of 37%–95% in plasma (Figure 8) and 16%–97% in lung tissue (Figure 9). The ED80 in both tissues was estimated to be approximately 30 mg / kg. Compound 19 produced 87% (***p ≤ 0.001) and 85% (***p ≤ 0.001) inhibition in plasma and lung, respectively. Brain serine concentrations were slightly reduced by high doses of compound 19a (12% at 100 mg / kg and 30% at 300 mg / kg), but, similar to reference compound 19, did not reach statistical significance (Figure 10).

[0191] Example 5: Effect of Compound 19 on the development of bleomycin-induced pulmonary fibrosis in male mice The effects of compound 19 were evaluated in a mouse model in which fibrosis was induced by oral and pharyngeal double injection with bleomycin. C57BL / 6J mice were chosen for evaluating the effects of test compounds because they are more susceptible to bleomycin-induced fibrosis than other mouse strains. Compound 19 was administered under the treatment regimen after the peak of the acute inflammatory phase of the lung injury response (day 7 after the first bleomycin injection) to ensure better evaluation of the anti-fibrotic effect separately from the anti-inflammatory effect.

[0192] method Male C57BL6 / J mice (7–8 weeks old) were purchased from Envigo RMS (San Pietro al Natisone, UD, Italy). All mice were maintained under pathogen-free conditions and provided with food and water ad libitum.

[0193] Lung injury was induced by double oropharyngeal injections of bleomycin hydrochloride (BLM, BAXTER) at a dose of 0.02 U / mouse in 50 μl of saline solution (0.9%) on days 0 and 4. Control animals received double oropharyngeal injections of 50 μl of saline solution.

[0194] Compound 19 was administered orally at 10 ml / kg twice daily at two doses, 400 mg / kg / day and 600 mg / kg / day, in 0.5% Tween 80, 0.5% methylcellulose in HO, starting 7 days after the first oropharyngeal administration of bleomycin. Treatment continued for two weeks.

[0195] Animals were administered nintedanib esylate at a dose of 60 mg / kg / day, 10 mL / kg, once daily for comparison with FDA-approved medications for the treatment of IPF patients. Control mice received vehicle alone for the same time interval. All animals were weighed twice weekly from day 0 to day 21.

[0196] On day 21, mice were anesthetized by intraperitoneal injection of thiopental (200 mg / kg / 10 mL; pentothal sodium, MSD Animal Health Srl). Blood was collected by cardiac puncture and collected in heparin tubes. Plasma was obtained by centrifugation at 10,000 g for 10 minutes. Lungs were washed with saline solution through the heart, fixed in formalin, embedded in paraffin, and stained with Masson's trichrome to assess the extent and severity of fibrosis and collagen deposition.

[0197] Scoring was performed on Masson's trichrome-stained slides using a method based on the Ashcroft scale (grades 0 to 8) as described by Ashcroft et al. (See Ashcroft T, Simpson JM, Timbrell V, J Clin Pathol 1988; 41(4):467-70). Corrected by Hubner et al. (see Hubner RH, Gitter W, Eddine El Mokhtari N, et al., Biotechniques. 2008;44(4):507-517).

[0198] Masson's trichrome-stained slides were scanned using a NanoZoomer S60 (Hamamatsu Photonics KK, Shizuoka, Japan) and imported into the Visiopharm Integrator System (VIS; version 2017.2.4.3387). Quantification of pulmonary fibrosis was performed by automated analysis using the VIS Analysis Protocol Package (APP), which is designed to identify and quantify fibrotic tissue by detecting altered connective tissue accumulation, excessive collagen deposition, and cellular density.

[0199] To quantify lung protein content and the levels of specific proteins as markers of fibrosis and collagen deposition, lungs from a subgroup of animals were weighed, homogenized in phosphate buffered saline (PBS), and the proteins of interest were quantified by immunoassay or colorimetric assay. Hydroxyproline content was measured using a hydroxyproline colorimetric assay kit (Sigma MAK008, USA) according to the manufacturer's protocol. WISP-1, collagen I, procollagen I, and elastin were measured using ELISA kits. Protein quantification was performed using the DC protein assay (Bio-Rad Laboratories, Italy). Plasma serine levels were measured using a DL-serine assay kit (Abcam, Cambridge, MA).

[0200] The experimental design used to test the effect of compound 19 on the development of bleomycin-induced pulmonary fibrosis in mice included five groups of 20 animals, as shown in Table 4.

[0201] [Table 38]

[0202] In a bleomycin-induced pulmonary fibrosis model in mice, body weight was lost during the first 7 days after the first oropharyngeal injection of bleomycin, followed by slow recovery until day 21.

[0203] Mice treated with Compound 19 or nintedanib showed no additional weight loss during the two weeks of treatment compared to the BLM / vehicle-treated group.

[0204] No significant differences in survival rates were observed among all animal groups, with only one animal dying during treatment with compound 19 at the highest dose tested, compared to two animals dying in the BLM / vehicle group.

[0205] The lung / body weight of bleomycin-treated mice was significantly increased compared to the control group, indicating increased lung inflammation, fluid accumulation, matrix deposition, and ultimately fibrosis.

[0206] Compound 19 showed a non-significant trend in lung / body weight reduction (-31% at the highest dose), slightly better than that achieved by nintedanib (-21%).

[0207] At the histological level, bleomycin-treated animals developed the expected lesions consistent with pulmonary fibrosis at 21 days, with collagen deposition in the lung and partial obliteration of lung architecture.

[0208] As shown in Figure 11A, Ashcroft scores showed increased fibrosis in mice treated with bleomycin compared to control mice, but treatment with compound 19 reduced the fibrosis score similarly to nintedanib. Furthermore, as shown in Figure 11B, compound 19 specifically reduced the frequency of the most severe fibrosis scores and tended to increase milder scores.

[0209] Quantification of fibrotic tissue by automated analysis showed a significant increase in bleomycin-induced pulmonary fibrosis in treated animals on day 21, which correlated with the results of the Ashcroft score analysis.

[0210] As shown in Figure 12, compound 19 significantly reduced the severity of fibrosis, reducing the tissue area occupied by fibrotic lesions by ≈25%.

[0211] Finally, automated collagen deposition quantification revealed a decrease in collagen content with all treatments, reaching a statistically significant decrease at the highest dose of compound 19, as shown in Figure 13 .

[0212] Bleomycin significantly increased the lung levels of several proteins that are markers of collagen accumulation (hydroxyproline, HYP; collagen I) and matrix deposition (WISP-1). As shown in Figures 14A, 14B, and 14C, the content of these proteins was significantly reduced after treatment with compound 19, and the effect was greater than that of nintedanib.

[0213] The inhibition of de novo serine synthesis induced by PHGDH inhibition was confirmed by detecting circulating serine levels in the plasma of animals treated with compound 19. As shown in Figure 15, a significant decrease was observed at both doses of test compound 19.

[0214] Plasma bioanalysis of compound 19 was carried out under the same experimental conditions as reported in Example 3.

[0215] Plasma exposure of Compound 19 was measured at three time points (0.5, 2, and 7 hours) after the last oral dose. PK data are shown in Figure 16 and demonstrate good oral exposure.

[0216] Example 6: Effect of Compound 19a on the development of bleomycin-induced pulmonary fibrosis in male mice The effects of compound 19a were evaluated in a mouse model (C57BL / 6J mouse strain) in which fibrosis was induced by double oropharyngeal (OA) injection of bleomycin. Compound 19a was administered according to a 14-day treatment regimen from day 7 after the first OA injection of bleomycin until day 21, which was considered the endpoint of this model.

[0217] method Male C57BL6 / J mice (7–8 weeks old) were purchased from Envigo RMS (San Pietro al Natisone, UD, Italy). All mice were maintained under pathogen-free conditions and provided with food and water ad libitum.

[0218] Lung injury was induced by double OA injection of 0.03 U / mouse of bleomycin hydrochloride (BLM, BAXTER, Deerfield, IL, USA) in 50 μL of saline solution (NaCl 0.9%) on days 0 and 4. The control group received double OA injection of 50 μL of saline solution.

[0219] Compound 19a was administered orally twice daily at three doses: 3 mg / kg, 30 mg / kg, and 100 mg / kg 10 mL / kg using 0.5% Tween 80, 0.5% methylcellulose as a vehicle for dissolution in HO.

[0220] The experimental group was treated with nintedanib esylate at a dose of 50 mg / kg 10 ml / kg twice daily to compare the efficacy of the test compound with FDA-approved drugs in IPF-treated patients. Control mice received vehicle only at the same time intervals.

[0221] On day 21, respiratory mechanics were measured using the FlexiVent system (SCIREQ Inc., Montreal Qc, Canada) (Vanoirbeek et al., 2010).

[0222] Briefly, mice were anesthetized by intraperitoneal injection of ketamine (Anesketin®, Dechra Inc., Handelsweg, NL) and xylazine (Xilagesic®, Calier Inc., Barcelona, ​​ES) solutions (100 mg / kg and 10 mg / kg, respectively). After achieving anesthesia, for forced vital capacity (FVC) analysis, anesthetized mice were tracheotomized using an 18-gauge metal cannula, connected to a FlexiVent via an endotracheal cannula, and ventilated at a respiratory rate of 150 breaths / min and a tidal volume of 10 mL / kg against a positive end-expiratory pressure of 3 cm H2O until mean lung volumes reached values ​​similar to those observed during spontaneous breathing. To prevent spontaneous breathing, mice were also given 1 mg / kg pancuronium bromide intraperitoneally. FlexiVent software version 8.1 was used to perform perturbations.

[0223] Plasma and bronchoalveolar lavage fluid (BALF) samples were collected immediately after in vivo evaluation.

[0224] First, blood was collected by cardiac puncture and centrifuged at 2000×g at 4° C. for 10 minutes to collect plasma.

[0225] The lungs were then gently lavaged three times with 0.6 mL of clear BAL fluid using a tracheal cannula. The resulting BALF was centrifuged at 1000 x g for 10 minutes at 4°C. The cell-free supernatant was used for quantitative measurement of biomarkers.

[0226] The following biomarkers were measured in BALF and plasma samples using commercially available ELISA kits: collagen I (assessed in BALF), an indicator of collagen accumulation; matrix metallopeptidase 7 (MMP-7, assessed in BALF), an indicator of abnormal fibrogenesis and ECM remodeling; and pulmonary surfactant protein D (SP-D, assessed in plasma), a marker of alveolar epithelial cell damage and dysfunction.

[0227] Finally, whole lungs were excised, fixed in formalin, and embedded in paraffin. Sections were stained with Masson's trichrome stain to assess the grade and severity of fibrosis and collagen deposition.

[0228] Scoring was performed on Masson's trichrome-stained slides using the Ashcroft scale (grades 0-8) (see Hubner RH, Gitter W, Eddine El Mokhtari N, et al., Biotechniques. 2008;44(4):507-517).

[0229] Slides were scanned using a NanoZoomer S60 (Hamamatsu Photonics KK, Shizuoka, Japan) and imported into the Visiopharm Integrator System (VIS; version 2017.2.4.3387). Quantification of pulmonary fibrosis was performed using automated analysis with the support of the VIS Analysis Protocol Package (APP), which is designed to identify and quantify fibrotic tissue by detecting altered connective tissue accumulation, excessive collagen deposition, and cellular density.

[0230] The experimental design used to test the effect of compound 19a on the development of bleomycin-induced pulmonary fibrosis in mice included six groups (N = 7–14), as reported in Table 5 . [Table 39]

[0231] result Compared to the saline group, bleomycin administration induced a consistent 0.27 mL decline in FVC. Compound 19a significantly improved the FVC decline by 77% at a dose of 100 mg / kg compared to BLM / vehicle (**p≦0.01) (FIG. 17).

[0232] Bleomycin infusion induced a significant increase in lung levels of collagen I and MMP-7 assessed in BALF (Figures 18A and 18B). Compound 19a significantly reduced the content of these biomarkers in a dose-dependent manner, with a maximum effect at 100 mg / kg, comparable to nintedanib for collagen I (52% reduction with compound 19a, *p≦0.05 vs. 56% reduction with nintedanib, *p≦0.05) but superior for MMP-7 (>100% reduction with compound 19a, ***p≦0.001 vs. 86% reduction with nintedanib, *p≦0.05).

[0233] Plasma samples showed a significant (**p≦0.01) increase in SP-D levels in injured animals. In animals treated with compound 19a, a dose-dependent decrease in SP-D levels was observed at 100 mg / kg, with a significant decrease in SP-D levels (74% decrease, *p≦0.05), slightly less than that observed with nintedanib (87% decrease, **p≦0.01) (Figure 18C).

[0234] At the histological level, bleomycin-treated animals developed lesions consistent with pulmonary fibrosis, with collagen deposition in the lungs and partial alterations in lung architecture.

[0235] Ashcroft scores showed a significant (***p≦0.001) increase in fibrosis in the BLM / vehicle group compared to control mice, which was significantly reduced by 56% (*p≦0.05) by compound 19a treatment (FIG. 19A).

[0236] Automated analysis of fibrotic tissue revealed a significant increase in lung fibrosis, represented by severe and moderate pulmonary fibrosis, in bleomycin-induced mice. Compound 19a reduced fibrosis in a dose-dependent manner, demonstrating efficacy comparable to that of nintedanib at a dose of 100 mg / kg (Figure 19B).

[0237] Comparative Example 7 Effect of NCT-503 on the development of bleomycin-induced pulmonary fibrosis in male mice The allosteric inhibitor NCT-503 was evaluated in the same mouse model as compound 19. Comparative Example 7 was carried out under the same experimental conditions as Example 5.

[0238] The experimental design used to test the effect of the allosteric compound NCT-503 on the development of bleomycin-induced pulmonary fibrosis in mice included five groups of 20 animals, as shown in Table 6. [Table 40]

[0239] NCT-503 was administered orally at initial doses of 200 mg / kg / day and 600 mg / kg / day, 10 ml / kg, dissolved in 1% Tween 80, 0.5% methylcellulose in H2O, twice daily with the same treatment protocol.

[0240] The animals could not tolerate the highest dose of NCT-503, and a significant reduction in bleomycin-induced weight loss (approximately 20% compared to day 0) was observed. NCT-503 was administered at 600 mg / kg / day for 4 days, and then discontinued on day 10. After a 2-day washout period, treatment was resumed at the final dose of 300 mg / kg / day once daily. Although animals in this group recovered weight by the end of the experiment, some animals died during the experiment, and the survival rate dropped to 40%. This experimental group was not included in the final analysis.

[0241] Although animals receiving NCT-503 at a dose of 200 mg / kg / day did not show significant weight loss, we chose to administer the drug once daily until the end of the study, with the final dose being 100 mg / kg / day.

[0242] Bleomycin administration resulted in a significant increase in lung weight compared to the control group, whereas treatment with NCT-503 and nintedanib did not result in a decrease in lung / body weight.

[0243] Mice treated with NCT-503 did not result in a reduction in bleomycin-induced pulmonary fibrosis as measured by Ashcroft score analysis compared to vehicle-treated mice, as shown in Figure 20A. Furthermore, NCT-503 did not show a significant tendency to reduce the severity of fibrosis (Figure 20B).

[0244] The levels of several markers of collagen accumulation (pro-collagen I) and matrix deposition (WISP-1) were unaffected by treatment with NCT-503, as shown in Figures 21A and 21B.

[0245] NCT-503 did not induce inhibition of de novo serine synthesis as measured by circulating serine levels in NCT-503-treated animals, as shown in FIG.

[0246] Plasma and tissue exposure to NCT-503 was measured as described in Example 2. Plasma and brain concentrations of NCT-503 were measured by liquid chromatography-tandem mass spectrometry (LC / MS / MS) assay. Plasma or tissue homogenate samples (tissues were homogenized in a 50 / 50 mixture of water and acetonitrile) were extracted with three volumes of acetonitrile. The supernatant was injected into an HPLC system (Agilent 1260 Quaternary Pump with Agilent 1200 High-Performance Autosampler SL; Agilent) using a Kinetex EVO C18 analytical column (100A, 50x2.1mm, 2.6μm; Phenomenex). The mobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B). Chromatographic separation was performed using gradient elution (0.0–0.5 min, 5% B; 0.5–4.0 min, gradient to 90% B; 4.0–5.5 min, 90% B; 5.5–7.0 min, gradient to 5% B; 7.0–11.0 min, 5% B—flow rate: 0.3 mL / min).

[0247] Mass spectrometry was performed using a linear ion trap triple quadrupole mass spectrometer (4000 Q TRAP; AB SCIEX) equipped with a turbospray ion source. The mass spectrometer was operated in positive ion mode, and quantification was performed in multiple reaction monitoring (MRM) mode. Peak integration was performed using Analyst (version 1.6.2). Graphs were generated using GraphPad Prism (version 8.1.2).

[0248] Plasma and brain exposure of NCT-503 was measured at three time points (0.5, 2, and 7 hours) after the final oral dose. PK data are shown in Figure 23.

[0249] NCT-503 exhibited significantly higher central nervous system (CNS) exposure compared to compound 19 and compound 19a, as evidenced by a primary brain / plasma ratio of 2.4.

Claims

1. 1. A compound of formula (I): 【Chemistry 1】 [In the formula, R 1 is hydrogen or C 1-4 is alkyl; R 2 and R 3 are each independently a halogen, —OR, —CN, C optionally substituted with 1, 2 or 3 halogens; 1-6 Aliphatic, or -LR 8 or R 2 and R 3 may optionally be joined together with the carbon atom to which they are attached and any intervening atoms to form a 5-8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L is independently C 1-6 a divalent straight or branched hydrocarbon chain, wherein 1-4 methylene units of said chain are independently optionally -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -C(O)N(R)-, -(R)NC(O)-, -N(R)-, -N(R)C(O)N(R)-, -S-, -SO-, or -SO 2 - may be replaced by; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 8 is hydrogen, C 1-6 an aliphatic or optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 4 is hydrogen, halogen, -OR 5 , —CN, C optionally substituted by 1, 2 or 3 halogens 1-6 Aliphatic, or -LR 8 and R 5 is hydrogen, -(CH 2 ) n -phenyl, -(CH 2 ) n -Cy' or C optionally substituted by 1, 2 or 3 halogens 1-6 is alkyl; each -Cy' is a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 6 is hydrogen or C 1-4 is alkyl; R 7 is hydrogen, -CO 2 R, optionally substituted C 1-6 aliphatic, -Cy- or a divalent 3- to 7-membered ring; L 1 is a covalent bond or C 1-8 a divalent linear or branched hydrocarbon chain, wherein 1-5 methylene units of said chain are independently optionally selected from -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O), -OC(O)N(R), -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 may be replaced by -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R) or -Cy-; -Cy- is each independently a divalent 6-membered arylene ring containing 0 to 2 nitrogen atoms, or a divalent 5-membered heteroarylene ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a divalent partially unsaturated 8 to 10-membered bicyclic heterocycloene ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein -Cy- is C 1-4 optionally substituted with 1 or 2 substituents independently selected from alkyl or -OR; X is O, S or -N(R 10 )-and; R 10 is C optionally substituted by 1, 2 or 3 halogens 1-6 Aliphatic, -C(O)CH 3 or -SO 2 -N(R 1 )(R 11 ) and R 11 is -C(O)CH 3 , -C(O)NHR 1 or pyrazinyl; n is independently 0, 1, 2, 3, 4, or 5; m is independently 0, 1, or 2; and Y 1 and Y 2 are each independently =N- or =C(R 4 )-is] or a pharmaceutically acceptable salt thereof.

2. R 1 2. The compound of formula (I) for use according to claim 1, wherein is methyl.

3. R 2 が、F、Cl、-CF 3 、-OCF 3 ,-OCHF 2 ,-AND 2 Ph、-OH 3 、-CN、-CH 3 、 【Chemistry 2】 A compound of formula (I) for use according to claims 1 to 2, selected from the group consisting of:

4. R 2 F, Cl, -OCH 3 and -CH 3 A compound of formula (I) for use according to claims 1 to 3, selected from the group consisting of:

5. R 3 F, Cl, -OCH 3 and -CH 3 A compound of formula (I) for use according to claims 1 to 4, selected from the group consisting of:

6. R 4 A compound of formula (I) for use according to claims 1 to 5, wherein is hydrogen.

7. R 6 A compound of formula (I) for use according to claims 1 to 6, wherein is hydrogen or methyl.

8. L 1 But SO 2 NH-, 【Transformation 3】 8. A compound of formula (I) for use according to claims 1 to 7, wherein:

9. R 7 is hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, tetrazolyl and -CO 2 A compound of formula (I) for use according to claims 1 to 8, selected from the group consisting of H.

10. X is O; Y 1 and Y 2 A compound of formula (I) for use according to claims 1 to 9, wherein is CH.

11. The compound has the formula II-a, II-b, II-c, II-d or II-e: 【Chemistry 4】 [In the formula, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , L 1 , Y 1 and Y 2 are as defined in claims 1 to 10, respectively.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 10, selected from:

12. The compound has formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, or III-i: 【Transformation 5】 [In the formula, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , L 1 , Y 1 and Y 2 are as defined in claims 1 to 10, respectively.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 10, selected from:

13. Compounds of formula (I) for the use according to claims 1 to 12, The compound is, as its single deuterated form, enantiomer, diastereoisomer or mixture thereof in any proportion, or as a pharmaceutically acceptable salt and solvate thereof, N-(3-(4-(N-acetylsulfamoyl)phenyl)oxetan-3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide; (±)-3-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}oxolane-3-carboxylic acid; (±)-3-cyclopropyl-2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}propanoic acid; (±)-3-cyclopropyl-2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}propanoic acid; 2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-acetic acid; (2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-acetic acid; (±)-2-Cyclobutyl-2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}acetic acid; (±)-2-Cyclobutyl-2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}acetic acid; (±)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)phenyl)-4-methylpentanoic acid; (±)-2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}-4-methylpentanoic acid; 2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}-5-hydroxypentanoic acid; (±)-2-Cyclobutyl-2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxolan-3-yl]phenyl}acetic acid; (±)-2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}-2-cyclobutylacetic acid; (±)-2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}butanoic acid; (±)-2-Cyclopropyl-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxy-amido)tetrahydrofuran-3-yl)phenyl)acetic acid; (±)-2-Cyclopentyl-2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxolan-3-yl]phenyl}acetic acid; (±)-2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]phenyl}pentanoic acid; (±)-2-{4-[3-(4,5-dichloro-1-methyl-1H-indole-2-amido)oxolan-3-yl]phenyl}pentanoic acid; (±)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydro-furan-3-yl)phenyl)-3-methylbutanoic acid; (±)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydro-furan-3-yl)phenyl)-3-methylbutanoic acid diastereoisomer 1; Diastereoisomer 2 of (±)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydro-furan-3-yl)phenyl)-3-methylbutanoic acid; (±)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydro-furan-3-yl)phenyl)-3-methylbutanoic acid diastereoisomer 3; (±)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydro-furan-3-yl)phenyl)-3-methylbutanoic acid diastereoisomer 4; (±)-2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]phenyl}-3-methylbutanoic acid; (±)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]-oxetan-3-yl]phenyl]-3-methyl-butanoic acid; (±)-2-Cyclopentyl-2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}acetic acid; (±)-2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]phenyl}butanoic acid; (±)-2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}pentanoic acid; (±)-2-Cyclopentyl-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]acetic acid; (±)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]-oxetan-3-yl]phenyl]-2-cyclopentyl-acetic acid; 2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}-2-methylpropanoic acid; 1-{4-[3-(4,5-dichloro-1-methyl-1H-indole-2-amido)oxetan-3-yl]phenyl}cyclopropane-1-carboxylic acid; (±)-2-[4-[3-[(4,5-dichloro-6-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoic acid; (±)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoic acid; (±)-2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}pentanoic acid; 2-{3-chloro-4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}acetic acid; 2-{3-chloro-4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}propanoic acid; (R)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl ]phenyl]propanoic acid; (S)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl ]phenyl]propanoic acid; 2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)phenyl)-2-methylpropanoic acid; 2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]-3-fluorophenyl}-2-methylpropanoic acid; (±)-2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}pentanoic acid; (±)-2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]-3-fluorophenyl}-2-methylpropanoic acid; (±)-2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]-3-fluorophenyl}propanoic acid; 5-Dichloro-1-methyl-N-[3-[4-(1H-tetrazol-5-ylmethyl)phenyl]oxetan-3-yl]indole-2-carboxamide; (±)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)phenyl)butanoic acid; (±)-2-(4-(3-(4-chloro-5-methoxy-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)phenyl)butanoic acid; 3-chloro-4-[3-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]benzoic acid; 4-[3-(4-chloro-6-methoxy-1,5-dimethyl-1H-indole-2-amido)oxetan-3-yl]-3-methylbenzoic acid; 3-chloro-4-[3-(4-chloro-6-methoxy-1,5-dimethyl-1H-indol-2-amido)oxetan-3-yl]benzoic acid; 4-[3-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]-3-methylbenzoic acid; 2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}propanoic acid; (±)-2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]-3-fluorophenyl}propanoic acid; 4-[3-(4-chloro-6-methoxy-1,5-dimethyl-1H-indole-2-amido)oxetan-3-yl]-3-fluorobenzoic acid; 4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]-3-methylbenzoic acid; (±)-N-(3-(4-(1-(1H-tetrazol-5-yl)ethyl)phenyl)tetrahydrofuran-3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide; (±)-2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]-3-fluorophenyl}-2-methylpropanoic acid; (±)-2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxolan-3-yl]-3-fluorophenyl}-2-methylpropanoic acid; (±)-2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]-3-fluorophenyl}propanoic acid; 4-[3-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]-3-fluorobenzoic acid; (±)-2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxolan-3-yl]-3-fluorophenyl}propanoic acid; (±)-1-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indole-2-amido)oxolan-3-yl]phenyl}cyclopropane-1-carboxylic acid; (±)-1-{4-[3-(4,5-dichloro-1-methyl-1H-indole-2-amido)oxolan-3-yl]phenyl}cyclopropane-1-carboxylic acid; 4-[3-(4-chloro-5-methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]-3-methylbenzoic acid; 2-{4-[3-(4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]-3-fluorophenyl}acetic acid; 2-{4-[3-(4-chloro-6-methoxy-1,5-dimethyl-1H-indol-2-amido)oxetan-3-yl]-3-fluorophenyl}acetic acid; 2-{4-[3-(4-chloro-1,5-dimethyl-1H-indol-2-amido)oxetan-3-yl]-3-fluorophenyl}acetic acid; (±)-2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]phenyl}propanoic acid; 3-chloro-4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]benzoic acid; 3-chloro-4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]benzoic acid; (±)-2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}propanoic acid; (±)-2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}propanoic acid; 2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]-3-methoxyphenyl}acetic acid; 2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]-3-fluorophenyl}propanoic acid; (±)-2-[3-cyano-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydro-furan-3-yl]phenyl]acetic acid; (±)-2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxolan-3-yl]phenyl}butanoic acid; (±)-5-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxolan-3-yl]pyridine-2-carboxylic acid; (±)-6-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxolan-3-yl]pyridine-3-carboxylic acid; 4-[3-(4-chloro-5-methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]-3-fluorobenzoic acid; 4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]-3-fluorobenzoic acid; (±)-2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]phenyl}-2-methylpropanoic acid; (±)-2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]phenyl}acetic acid; 4-[3-(4,5-dichloro-1-methyl-1H-indole-2-amido)oxetan-3-yl]-3-fluorobenzoic acid; (±)-4-{3-[4,5-dichloro-1-methyl-6-(oxetan-3-ylmethoxy)-1H-indol-2-amido]oxolan-3-yl}benzoic acid; (±)-4-(3-(6-((1H-imidazol-2-yl)methoxy)-4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoic acid; 2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]-3-methylphenyl}acetic acid; 4-[3-(4,5-dichloro-1-methyl-1H-indole-2-amido)oxetan-3-yl]-3-methylbenzoic acid; 2-{3-chloro-4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}acetic acid; 3-chloro-4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]benzoic acid; 2-{4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]-3-fluorophenyl}acetic acid; (±)-2-{4-[3-(4,5-dichloro-1-methyl-1H-indole-2-amido)oxolan-3-yl]phenyl}-2-methylpropanoic acid; (±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydro-furan-3-yl]-2-ethyl-benzoic acid; (±)-4-(3-(6-(3-amino-2-hydroxypropoxy)-4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoic acid; 2-{4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxetan-3-yl]-3-fluorophenyl}acetic acid; (±)-4,5-dichloro-N-(3-(4-(cyanomethyl)phenyl)tetrahydrofuran-3-yl)-1-methyl-1H-indole-2-carboxamide; (±)-4-{3-[4,5-dichloro-1-methyl-6-(oxolan-3-ylmethoxy)-1H-indole-2-amido]oxolan-3-yl}benzoic acid; (±)-4-[3-[[4,5-dichloro-1-methyl-6-[(3-methyl-2-oxo-oxazolidin-5-yl)methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoic acid; (±)-4-{3-[4,5-dichloro-1-methyl-6-(oxolan-2-ylmethoxy)-1H-indole-2-amido]oxolan-3-yl}benzoic acid; (±)-4-(3-{4-chloro-1-methyl-6-[(2-oxo-1,3-oxazolidin-5-yl)methoxy]-1H-indol-2-amido}oxolan-3-yl)benzoic acid; (±)-4-[3-(4-chloro-5-cyclopropyl-1-methyl-1H-indol-2-amido)oxolan-3-yl]benzoic acid; (±)-4-(3-{4,5-dichloro-6-[2-(dimethylamino)ethoxy]-1-methyl-1H-indole-2-amido}oxolan-3-yl)benzoic acid; (±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydro-furan-3-yl]-2-methyl-benzoic acid; (±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydro-furan-3-yl]-3-methyl-benzoic acid; (±)-4-{3-[4,5-dichloro-6-(2-methoxyethoxy)-1-methyl-1H-indol-2-amido]oxolan-3-yl}benzoic acid; (±)-2-Cyclopropyl-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoic acid; (±)-4-(3-{4,5-dichloro-1-methyl-6-[(1-methyl-5-oxopyrrolidin-3-yl)methoxy]-1H-indole-2-amido}oxolan-3-yl)benzoic acid; 2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}acetic acid; (±)-4-[3-(4,5-dichloro-6-ethoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]benzoic acid; (±)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl ]phenyl]propanoic acid; (±)-4-[3-(4-chloro-5-fluoro-1-methyl-1H-indol-2-amido)oxolan-3-yl]benzoic acid; (±)-3-chloro-4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxolan-3-yl]benzoic acid; (R)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)phenyl)acetic acid; (S)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)-tetrahydrofuran-3-yl)phenyl)acetic acid; (±)-4-[1-acetyl-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]pyrrolidin-3-yl]benzoic acid; (±)-4-[3-[[4,5-dichloro-1-methyl-6-[(2-oxooxazolidin-5-yl)methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoic acid; 2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)-phenyl)acetic acid; (±)-4-(3-{9-chloro-6-methyl-2H,3H,6H-[1,4]dioxino[2,3-f]indole-7-amido}oxolan-3-yl)benzoic acid; (±)-4-[3-(4-chloro-6-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]benzoic acid; (±)-4-[3-(4,5-dichloro-6-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]benzoic acid; (±)-4-[3-(4-chloro-1,5-dimethyl-1H-indol-2-amido)oxolan-3-yl]benzoic acid; (±)-4-[3-(4-chloro-1-methyl-1H-indol-2-amido)oxolan-3-yl]benzoic acid; (±)-4-[3-(4,5-dichloro-1-methyl-1H-indole-2-amido)oxolan-3-yl]-3-fluorobenzoic acid; (±)-2-[3-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]acetic acid; (±)-2-cyano-4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoic acid; (±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-phenyl-pyrrolidin-3-yl]benzoic acid; (±)-4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxolan-3-yl]benzoic acid; (±)-4-[3-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxan-3-yl]benzoic acid; 4-[4-(4,5-dichloro-1-methyl-1H-indol-2-amido)oxan-4-yl]benzoic acid; (±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]benzoic acid; (±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-ethyl-pyrrolidin-3-yl]benzoic acid; (±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-oxetan-3-yl]benzoic acid; (±)-4,5-Dichloro-1-methyl-N-[3-[4-(1H-tetrazol-5-yl)phenyl]tetrahydro-furan-3-yl]indole-2-carboxamide; (±)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]acetic acid; (±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-methyl-pyrrolidin-3-yl]benzoic acid; (±)-N-[3-(4-carbamoylphenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide; (R)-4-[(3)-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)-amino]-tetrahydrofuran-3-yl]benzoic acid; (S)-4-[(3)-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoic acid; (±)-4,5-Dichloro-N-[3-(4-cyanophenyl)tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide; (±)-N-[3-(4-bromophenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide; (±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoic acid; (±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoic acid; (±)-4,5-Dichloro-N-[3-[3-(hydroxymethyl)phenyl]-1-(methylcarbamoyl-sulfamoyl)-3-piperidyl]-1-methyl-indole-2-carboxamide; (±)-3-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-(methylcarbamoylsulfamoyl)-3-piperidyl]benzoic acid; (±)-4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)-1-(N-(methylcarbamoyl)sulfamoyl)piperidin-3-yl)benzoic acid; (±)-N-[3-(3-carbamoylphenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide; (±)-4,5-Dichloro-N-[3-(3-cyanophenyl)-1-(methylcarbamoylsulfamoyl)-3-piperidyl]-1-methyl-indole-2-carboxamide; (±)-Dichloro-N-[3-(3-cyanophenyl)tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide; 4-[1-(acetylsulfamoyl)-4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-4-piperidyl]benzoic acid; N-(1-(N-acetylsulfamoyl)-4-(3-aminophenyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide; (±)-4,5-Dichloro-1-methyl-N-[1-(methylcarbamoylsulfamoyl)-3-phenyl-3-piperidyl]indole-2-carboxamide; (±)-4,5-Dichloro-N-[3-(3-cyanophenyl)-1-(methylcarbamoylsulfamoyl)-3-piperidyl]-1-methyl-indole-2-carboxamide; N-(1-(N-acetylsulfamoyl)-3-phenylazetidin-3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide; N-(1-(N-acetylsulfamoyl)-4-(3-(hydroxymethyl)phenyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide; N-(4-(3-acetamidophenyl)-1-acetylpiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide; 3-(1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)piperidin-4-yl)benzoic acid; 4,5-Dichloro-1-methyl-N-[4-phenyl-1-(pyrazin-2-ylsulfamoyl)-4-piperidyl]indole-2-carboxamide; N-(4-(3-acetamidophenyl)-1-(N-acetylsulfamoyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide; N-(1-(N-acetylsulfamoyl)-4-(3-cyanophenyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide; N-(1-(N-acetylsulfamoyl)-4-phenylpiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide; (±)-Ethoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]phenyl}-2-cyclohexylacetic acid; 2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoic acid; (2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoic acid; (±)-2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}-2-(piperidin-4-yl)acetic acid; (±)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-(4-hydroxycyclohexyl)acetic acid; 4-chloro-5-methoxy-1-methyl-N-(3-(4-(N-propionylsulfamoyl)phenyl)-oxetan-3-yl)-1H-indole-2-carboxamide; 4-chloro-5-methoxy-1-methyl-N-(3-(4-((methylsulfonyl)carbamoyl)-phenyl)oxetan-3-yl)-1H-indole-2-carboxamide; (±)-2-Cyclopropyl-2-(4-(3-(4,5-dichloro-6-methoxy-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)phenyl)acetic acid; 4-chloro-N-{3-[4-(acetamidosulfonyl)phenyl]oxetan-3-yl}-5-methoxy-1-methyl-1H-indole-2-carboxamide; (±)-2-{4-[3-(4-chloro-5-methoxy-1-methyl-1H-indol-2-amido)oxetan-3-yl]phenyl}-2-(oxan-4-yl)acetic acid A compound selected from at least one of:

14. The compound is 【Transformation 6】 compound 19 14. The compound for use according to claim 13, which is: or a pharmaceutically acceptable salt thereof.

15. 14. The compound for use according to claim 13, wherein the compound is diastereoisomer 2 of (±)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydro-furan-3-yl)phenyl)-3-methylbutanoic acid or a pharmaceutically acceptable salt thereof.

16. 16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claims 1 to 15 for use in the prevention and / or treatment of fibrosis selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (CHP), liver fibrosis, renal fibrosis or kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, sarcoidosis and systemic sclerosis, liver fibrosis and cirrhosis.

17. 17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 16 for use in the prevention and / or treatment of IPF.

18. A pharmaceutical composition comprising a compound of formula (I) as defined in claims 1 to 15 or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable carriers or excipients for use in the prevention and / or treatment of fibrosis.

19. 19. A pharmaceutical composition comprising a compound of formula (I) for use according to claim 18, wherein the fibrosis is selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (CHP), liver fibrosis, renal fibrosis or kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, sarcoidosis and systemic sclerosis, liver fibrosis and cirrhosis.

20. 20. A pharmaceutical composition comprising a compound of formula (I) according to claim 19 for use in the prevention and / or treatment of IPF.

21. The pharmaceutical composition according to claims 19 to 20, for oral administration.

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