Dual compounds inhibiting cycloxygenase-antagonists of the thromboxane receptor and their use

Abstract

The invention relates to compounds of general formula (I) which are cyclooxygenase inhibitors and thromboxane receptor antagonists. Said compounds are useful as medicaments, preferably in the prevention and / or treatment of diseases and / or disorders related to pathologies on an inflammatory basis.

Description

[0001] DUAL COMPOUNDS INHIBITING CYCLOXYGENASE-ANTAGONISTS OF THE THROMeOXANE RECEPTOR AND THEIR USE

[0002] Technical field of the invention

[0003] The invention relates to dual-activity compounds that act as antagonists of the thromboxane receptor (TP) and inhibitors of cyclooxygenase 1 and / or 2 (COX-1, COX-2, or COX-1 and COX-2), i.e. COX-1 / TP, COX-2 / TP or COX-1 and COX-2 / TP (also known as COXTRANs). These compounds are particularly useful in the prevention and / or treatment of diseases and / or disorders related to inflammation.

[0004] State of the art

[0005] Chronic inflammation is a major global health problem that affects millions of people worldwide. Inflammation is part of the innate response to offensive stimuli and is necessary to maintain the integrity of the body. However, unresolved tissue inflammation leads to chronic inflammation associated with the development of many different pathological conditions. According to a recent Global Burden of Disease (GBD) report, chronic inflammatory diseases have been recognised as the most significant cause of death, with over 50% of all deaths attributable to inflammation-related disorders such as ischaemic heart disease, stroke, cancer, diabetes, non-alcoholic fatty liver disease, and autoimmune and neurodegenerative conditions.

[0006] The management of chronic inflammation associated with various chronic diseases is a complex problem, as it is usually complicated by a lack of knowledge about the exact nature of the inflammatory stimulus.

[0007] Different pharmacological approaches can be used to act on different signalling pathways.

[0008] Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed and consumed drugs and represent the first and most common option for the symptomatic treatment of mild to moderate inflammatory pain and for the management of chronic inflammatory diseases such as osteoarthritis, rheumatoid arthritis and musculoskeletal injuries.

[0009] NSAIDs exert their anti-inflammatory, analgesic and antipyretic action by inhibiting the biosynthesis of prostanoids generated from arachidonic acid (AA) through the activity of cyclooxygenase (COX)-l and COX-2. COX-1 and COX-2 generate the same prostanoids, but their expression is regulated differently, thus contributing to different temporal and tissue functions in vivo. Prostanoids act in an autocrine / paracrine manner on their molecular targets through interaction with G protein-coupled receptors (GPCRs).COX-1 is a constitutive enzyme expressed in most tissues and generates prostanoids involved primarily in physiological functions, such as gastric cytoprotection and haemostatic integrity.

[0010] However, platelet COX-1, through the production of thromboxane (TX)A2, contributes to atherothrombosis due to its ability to activate the receptor (called the TP receptor) expressed in platelets and vascular cells involved in platelet activation and vasoconstriction.

[0011] New implications of TXA2 in inflammation / fibrosis / tumourigenesis have emerged due to its ability to activate stromal cells such as fibroblasts, inducing morphological and functional changes and the induction of COX-2 and its main product, prostaglandin (PG)E2.

[0012] Although COX-2 is constitutively expressed in some cells (such as vascular cells), it is highly regulated and its expression can be induced in response to inflammatory and mitogenic stimuli.

[0013] However, post-transcriptional regulation of COX-2 expression is also involved in controlling protein levels in inflammation and cancer. Increased COX-2-dependent PGE2 in the tumour microenvironment promotes tumour growth and metastatic spread by inhibiting immune surveillance and inducing angiogenesis. Furthermore, PGE2 can activate tumour epithelial cells, causing proliferation, survival, migration / invasion and epigenetic changes. However, COX-2, expressed constitutively in vascular cells, exerts protective effects on the cardiovascular system by generating PGI2 (prostacyclin) and activating its IP receptor. Prostacyclin acts by limiting endogenous stimuli, including TXA2 derived from platelet COX-1, platelet activation, proliferation and vascular remodelling, hypertension, atherogenesis and cardiac function.

[0014] NSAIDs comprise a chemically heterogeneous family of compounds that are classified into two groups based on their impact on COX-1: traditional (t)NSAIDs (also called non-selective NSAIDs), which act on both COX-1 and COX-2 activity, and selective COX-2 inhibitors (called coxibs). Coxibs and (t) NSAIDs share the same clinical efficacy (analgesic and anti-inflammatory effects) due to COX-2 inhibition, but they differ in their effects on the gastrointestinal system.

[0015] Coxibs have a safer gastrointestinal profile due to their lower inhibition of C0X-1-dependent PGE2 and PGI2 biosynthesis, which have cytoprotective effects on the gastrointestinal system. In some clinical studies, coxibs are associated with a lower incidence of serious gastrointestinal side effects than (t)NSAIDs, such as upper gastrointestinal bleeding (UGIB). Traditional NSAIDs, but not coxibs, inhibit COX- 1 -dependent prostanoids in the gastrointestinal mucosa in many individuals and are associated with profound but transientinhibition of COX-1 activity in platelets, thereby altering haemostasis in a small number of individuals.

[0016] However, both coxibs and (t)NSAIDs are associated with an increased risk of cardiovascular toxicity, including hypertension, oedema, heart failure and thrombotic events.

[0017] These effects depend on the inhibition of COX-2 in the kidneys and vascular cells. It should be noted that (t)NSAIDs, except for low-dose aspirin, do not protect the cardiovascular system due to their transient and incomplete inhibition of COX- 1 -dependent platelet TXA2. This pathway must be almost completely inhibited throughout the drug's dosage range to determine an antiplatelet effect; a low concentration of TXA2 can induce complete platelet activation induced by subthreshold concentrations of other platelet agonists. Similarly, coxibs do not affect platelet function because platelets do not express COX-2. Experimental evidence suggests a role for COX- 1 -dependent TXA2 in the increase in blood pressure (BP) and in overload-induced cardiac fibrosis and intestinal inflammation. TXA2 produced in platelets induces profibrotic genes, including TGF-β1, and the expression of COX -2, a proinflammatory pathway, in myofibroblasts. In a salt-sensitive hypertension mouse model [high-salt diet in mice with deletion of the prostacyclin (PGI2) IP receptor (IPKO)], aspirin prevents the accumulation of cardiac myofibroblasts, platelet extravasation into the heart, and cardiac fibrosis when TXA2 is not restricted. These findings suggest that inhibition of platelet-derived TXA2 by low-dose aspirin may attenuate the hypertensive and profibrotic effects of COX-1 inhibition.

[0018] It has recently been demonstrated that non-platelet TXA2 generation is an independent risk factor for long-term all-cause mortality and cardiovascular mortality in an unselected cohort of elderly individuals. Therefore, it has been suggested that blocking non-platelet TXA2 generation or its biological effects could improve survival in patients with cardiovascular disease and potentially other conditions. TP receptor antagonists can potentially suppress the effects of platelet-derived and non-platelet-derived TXA2 without affecting vascular prostacyclin levels.

[0019] The current use of (t)NSAIDs or coxibs is associated with several side effects, such as gastrointestinal, renal and cardiovascular effects.

[0020] Over the years, the development of new drugs has been proposed as a strategy to mitigate the side effects of NSAIDs, particularly gastrointestinal and vascular ones. The first approach consisted of developing NSAID prodrugs, designed primarily to mitigate gastrointestinal side effects; these prodrugs were obtained by conjugating the acid function of a selected NSAID with phosphoric acid derivatives (Phospho-NSAIDs), natural antioxidants or carbohydrate derivatives via an ester bond. Using the polypharmacology design approach,pharmaceutical chemists have developed several classes of modified multi-target NSAIDs. Multitarget NSAIDs were designed by combining a COX inhibitor (COXi) with another molecule with appropriate vasodilatory and gastroprotective properties. Among others, COXi / NO donors (NO-NSAIDs, NO-COXIBs) and COXi / H2S donors (HS-NSAIDs) have been obtained.

[0021] Finally, a two-pronged approach was applied for multi-target action at different levels of the arachidonic acid (AA) cascade. Examples of this approach include the generation of dual COXi / 5-LOXi, COXi / LTA4Hi, COXi / sEHi and COXi / FAAHi compounds.

[0022] An alternative two-pronged strategy involves inhibiting the enzyme and downstream receptors in the AA cascade, such as sEH / PPARy or COX-2 / TP receptors. As reported above, the TP receptor is a target of particular interest in the vascular system and platelets. Although TXA2is the most potent ligand for the TP receptor, other prostaglandins can activate this G protein-coupled receptor with varying potency. For example, PGE2 has been shown to act through TP activation, causing a vasoconstrictive response in rats, and isoprostanes, non-enzymatic products of AA metabolism that are therefore not blocked by aspirin or NSAIDs, have been shown to contract the aorta of rats through TP receptor activation. Paradoxically, even PGI2, a vasodilator prostanoid, can activate the TP receptor, causing vasoconstriction through TP receptor activation. Finally, a TP receptor antagonist, terutroban, has been shown to inhibit atherogenesis in Apoe- / -mice and, in a phase III clinical trial, has been shown to be as effective as aspirin in preventing ischaemic stroke in the general population and superior in preventing recurrent events in patients with a history of ischaemic stroke.

[0023] Etodolac is a well-known NSAID approved by the FDA, which has a structural core of 2-(1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid, used for the treatment of mild to moderate pain, osteoarthritis and rheumatoid arthritis. It has preferential inhibition of COX -2 over COX-1, being 8-10 times more potent on COX-2. Etodolac was developed in the 1980s and its structure-activity relationship for anti-inflammatory activity was studied in vivo using an adjuvant chronic arthritis model in rats.

[0024] In light of the above, there is still a need for new drugs that act through a dual mechanism, for example as thromboxane receptor antagonists and cyclooxygenase inhibitors, i.e. COXTRANs, which are useful in the prevention and / or treatment of inflammation-related diseases and / or disorders, particularly with an improved safety profile, for example in terms of the cardiovascular, renal and gastrointestinal systems.Brief Description of Figures

[0025] Figures 1 A and B show the antagonism of human platelet aggregation induced by U-46619, a TP receptor agonist, of the compounds indicated. Concentration-inhibition curves of platelet aggregation of the compounds indicated in washed platelets obtained from human blood. The values shown represent platelet aggregation (mean ± SE) expressed as % of maximum aggregation induced by U-46619 (0.1 mM). Experiments were performed at least three times in duplicate. All curves shown were generated by computer using GraphPad Prism v.5.

[0026] Figure 2 shows the inhibition of COX-1 and COX-2 activity by the compounds indicated. COX-1 activity was assessed in terms of inhibition of calcium ionophore-induced TXB2 production in washed human platelets; COX-2 activity was assessed in terms of inhibition of lipopolysaccharide (LPS)-induced PGE2 production in isolated human monocytes. Data are expressed as a percentage inhibition of TXB2 or PGE2 release relative to untreated controls. Error bars represent the mean ± SE of at least three independent experiments, each performed in duplicate. All curves shown were generated by computer using GraphPad Prism v.5.

[0027] Figure 3. (A): Evaluation of TP receptor antagonism in isolated rat aortic rings pretreated with 10 pM indomethacin and contracted with U-46619 (1.0 nM - 3.0 pM) in the presence of compounds CXT30 (10 pM, A), CXT15 (10 pM, ■), CXT29 (10 pM, o) or vehicle alone (control, •). (B): Evaluation of TP receptor antagonism in isolated rat aortic rings pretreated with 10 pM indomethacin and contracted with U-46619 (1.0 nM - 3.0 pM) in the presence of compounds CXT20 (1 pM, □), CXT21 (1 pM, dashed line, o), MK-0524 (0.1 pM, dashed line, A) or vehicle alone (control, •). Error bars represent the mean ± SEM of at least three independent experiments. The curves were generated by computer from the simultaneous analysis of independent experiments using GraphPad Prism version 7.0. The pA2 values were calculated using the Gaddum equation: pA2 = log[CR-l]-log[B], where CR = ratio of EC50 with and without antagonist; [B] = concentration of antagonist.

[0028] Figure 4. (A) and (B) Concentration-response curves for COX-1 and COX-2 inhibition by compounds CXT15 and CXT29 in human whole blood. For the COX-2 inhibition assay, PGE2 production was measured in the presence or absence of the compound after 24-hour incubation with LPS on heparinised blood samples. For the COX-1 assay, TXB2 production was measured during whole blood coagulation. Different concentrations of compounds or DMSO vehicle were incubated. (C) Anti-aggregating activity of compounds MK-0524 (•), CXT15 (■) and CXT29 (dashed line, o) on human PRP (platelet-rich plasma). Plateletaggregation was induced by U-46619 in PRP samples pre-incubated with test compounds or vehicle alone (control samples). The anti-aggregating activity of the compounds was evaluated as % inhibition of platelet aggregation relative to control samples.

[0029] Figure 5. Ex vivo concentration-response curve for U-46619-induced platelet aggregation after oral administration of compounds CXT15 and CXT29 in mice. U-46619 (1 pM - 30 pM) was administered alone in the vehicle (control, ■) or in the presence of the reported concentration of compound CXT15 (A and B, •) or CXT29 (C, •). A pool of animals was used, so each data point represents the average of six different animals. Data were analysed using the four-parameter logistic model. All curves are computer-generated.

[0030] Figure 6. Antinociceptive effects of CXT29 in the CFA (complete Freund's adjuvant-induced inflammatory pain model in mice. The mechanical sensitivity of a hind paw was determined using a dynamic plantar aesthesiometer. Twenty-four hours after CFA injection into a hind paw, mice were treated orally with CXT29 (50 mg / kg, A), diclofenac (50 mg / kg, ▼), or vehicle (3% Methocel in PBS, ■). Note that paw withdrawal latencies increased significantly 1 hour (h) and 2 h after CXT29 administration and 1 h after diclofenac administration (n = 8-9 mice per group). Results are presented as mean ± SEM. Data were analysed using two-way repeated measures ANOVA with Dunnett's post hoc test; ** p < 0.005 compared to 24 h post-CFA.

[0031] Summary of the invention

[0032] The present invention relates to compounds of formula (I):

[0033]

[0034] wherein X, A and Y are as defined below,

[0035] and their enantiomers, diastereoisomers, rotamers, tautomers, isotopes and mixtures thereof; and the pharmaceutically acceptable salts, hydrates or solvates thereof.

[0036] The invention also relates to compositions containing at least one compound of general formula (I) as defined below and at least one pharmaceutically acceptable excipient and / or vehicle.

[0037] A further object of the invention is a compound of general formula (I) for use as a medicament, particularly useful in the prevention and / or treatment of inflammation-related diseases and / or disorders.Detailed description of the invention

[0038] The invention relates to compounds of formula (I):

[0039]

[0040] their enantiomers, diastereoisomers, rotamers, tautomers and mixtures thereof; and the pharmaceutically acceptable salts, hydrates or solvates thereof,

[0041] wherein:

[0042] X is selected from H, halogen or C1-C4 alkyl, linear or branched; preferably is H, F or CH3; more preferably is F;

[0043] A is selected from H or halogen; preferably H or F; more preferably it is H;

[0044] Y is selected from halogen, preferably Cl or I, provided that when X=H, A=H, Y is F, Br or I, or Y is different from Cl; or

[0045] (C3-C6) linear or branched, saturated or unsaturated, unsubstituted alkyl, such as -CH2CH(CH3)CH3 or -CH2CH2CH=CH2; or substituted with halogen, such as -CH2CH2CH2CF3; wherein, when X = H and A = H, Y is a linear or branched (Cs-Ce) alkyl, saturated or unsaturated, unsubstituted or substituted with halogen; or

[0046] S, S(O) or SO2 each substituted with a linear or branched, saturated or unsaturated (Ci-Ce) alkyl chain, or saturated or unsaturated (C3-C6) cycloalkyl; preferably selected from -S-CH3, -SO2CH3, -SO2-cyclopropyl or -SCh-cyclohexyl; or

[0047] (C3-C6)-cycloalkyl, saturated or unsaturated, unsubstituted or substituted with (C1-C4)- alkyl; wherein, when X = H and A = H, Y is cyclobutyl, or an unsubstituted or (Ci-C4)-alkyl-substituted unsaturated (C3-C6) cycloalkyl; preferably 1 -cyclohexenyl; or

[0048] -CH2-(C3-Ce) saturated cycloalkyl, unsubstituted or substituted, preferably -CFb-cyclopentyl; or

[0049] phenyl unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, (Ci-C4)-C(O)-, (C1-C4) O-, (CI-C4)-CONH-, -CONH2, SO2-, (Ci-C4)-SO2-, preferably selected from phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,5-diCl-phenyl, 3,5-diCl-phenyl, 2-OH-phenyl, 3-OH-phenyl, 3-(HO-CH2)-phenyl, 4-(HO-CH2)-phenyl, 3-(CH3CO)-phenyl, 3-(CH3O)-phenyl; 3-(CH3CONH)-phenyl, 3-(H2NCO)-phenyl, 3-(CH3SO2)-phenyl; orbenzyl substituted or unsubstituted with one or more substituents selected from halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, hydroxyl, nitrile, nitro group, preferably benzyl, 2-Cl-benzyl, 3-chloro-benzyl, 4-chloro-benzyl, 2-fluoro-benzyl, 3 -fluoro-benzyl, 4-fluoro-benzyl, 2-CHs-benzyl, 3- CHs-benzyl, 4- CHs-benzyl, 3, 4-chloro, fluoro-benzyl, 3,2-Cl, F-benzyl, 3,5-Cl, F-benzyl, 3,5-diF-benzyl, 2,6-Cl, F-benzyl, 4,2-F, Cl-benzyl, 2,4-diF-benzyl, 4,2-Cl, F-benzyl, 3,4-CHs, F-benzyl, 2,3-F, CHs-benzyl, 3-CFs-benzyl, 3-(CHsO)-benzyl, 4-(CHsO)-benzyl, 3,5-F, CHsO-benzyl, 3-CN-benzyl, 3-NO2-benzyl; or

[0050] a 5- or 6-membered heterocycle having one or two heteroatoms selected from N and / or O, unsubstituted or substituted with one or more substituents selected from (Ci-C3)-alkyl, preferably selected from 3-pyridyl, 5-pyrimidyl, 3-pyrazolyl, 2-CH3-3-pyrazolyl, 4-isoxazolyl,

[0051] -CH2-morpholinyl; or

[0052]

[0053] r

[0054] wherein:

[0055] - if Y is

[0056]

[0057] Rs

[0058] W is selected from (CFDn where n is an integer between 2 and 3, SO2, S and S(O); preferably it is CH=CH, more preferably with Z or E configuration, CH2CH2, C=C, CH2-CH=CH, CH2CH2CH2;

[0059] Ri, R2, R3, R4 and R5 are independently selected from H, halogen; preferably H or F, more preferably Ri is F.

[0060] The invention further concerns compounds of formula (la):

[0061]

[0062] (la)

[0063] wherein:

[0064] Y is benzyl substituted with one or more substituents, which may be the same or different, selected from hydrogen; halogens, preferably Cl or F; more preferably hydrogen; or

[0065] (Ci-C4)-alkyl, linear or branched, preferably CFE; or

[0066] (Ci-C4)-alkoxy, preferably CH3O; or

[0067] nitro group;wherein benzyl is substituted with at least one of the following substituents or at least one of the following combinations of substituents: 4-C1, 3,5-Cl, F, 3,5-diF, 2,6-Cl, F, 4-CFh, 4-(CH3O)-, 3,5-diF, CH3O- or 3-NO2, proved to be effective as COX-1 inhibitors and thromboxane receptor antagonists (COX-1 and TP).

[0068] The invention further relates to compounds of formula (lb):

[0069]

[0070] wherein

[0071] X is selected from H; halogen, preferably F; or C1-C4 alkyl, linear or branched, preferably CH3; X is preferably CH3 or F; more preferably F;

[0072] when X is CH3, Y is halogen, preferably Cl;

[0073] - when X is H, Y is SO2CH3;

[0074] when X is F; Y is halogen, preferably Cl or I, or

[0075] -S-(Ci-C4) linear or branched alkyl, preferably -S- CH3; or

[0076] CF3-(CI-C4)- linear or branched alkyl, preferably CH2CH2CH2CF3; SO2-(C5-Ce)- saturated cycloalkyl, unsubstituted or substituted, preferably SO2-cyclohexyl; or SO2-phenyl, wherein phenyl is substituted or unsubstituted, preferably unsubstituted;

[0077] 5- or 6-membered heterocycle having one or two heteroatoms selected from N and / or O, unsubstituted or substituted with one or more substituents selected from (Ci-C3)-alkyl, linear or branched; preferably pyridyl, pyrimidyl, pyrazolyl, 2-CH3-3-pyrazolyl, isoxazolyl, morpholinyl, more preferably selected from 3-pyridyl, 5-pyrimidyl, 3-pyrazolyl, 2-CH3-3-pyrazolyl, 4-isoxazolyl;

[0078] benzyl unsubstituted or substituted with one or more substituents, the same or different from each other, selected from hydrogen, halogens, preferably Cl; or

[0079] (Ci-C4)-alkyl, linear or branched, preferably CH3; or

[0080] cyano group;

[0081] wherein benzyl is at least substituted with 3- CH3, 3-C1, or 3-CN;

[0082] phenyl substituted with one or more substituents, the same or different from each other, selected from halogen, preferably Cl or F; hydroxyl; ((CI-C4)-OH)-; H2NCO-; -CONH-(CI-C4); -CON(CI-C4)2; or ((Ci-C4)-SO2)-; wherein phenyl is substituted with at least one of the following substituents or at least one of the following combinations of substituents 2,5-diCl, 3,5-diCl, 2-OH, 3-(OH-CH2)-, 4-(OH-CH2)-, 3(H2NCO)-, or -3-(CH3SO2)-; orR2

[0083] RI- zR,

[0084] . W11 R,^,

[0085]

[0086] Rf', wherein when W is CH2CH2, Ri is F or H, R2, R3, R4 and R5 are H,

[0087] they proved to be effective as COX-2 inhibitors and thromboxane receptor antagonists (COX-2 and TP).

[0088] A preferred aspect of the present invention is the compounds of formula (Ic):

[0089]

[0090] wherein

[0091] X is halogen, preferably F, or H when A is F;

[0092] A is H or F, preferably H;

[0093] Y is

[0094] -SO2-(Ci-C4) linear or branched alkyl, preferably -SO2CH3; or

[0095] unsubstituted phenyl; or

[0096] phenyl substituted with one or more substituents, the same or different from each other, selected from halogen, preferably Cl; (Ci-C CONH-; hydroxyl; - SO2-(C3-C4)-saturated cycloalkyl, unsubstituted or substituted, preferably - SO2 CH3; (Ci-C4)-C(O)-, preferably (CH3CO)-; (Ci-C4)-alkoxy, preferably CH3O-;

[0097] wherein phenyl is substituted with at least one of the following substituents or at least one of the following combinations of substituents 2-C1, 3-C1, 4-C1, 3-(CH3CONH)-; 3-OH; -SO2-cyclopropyl; 3-(CH3CO)-; 3-(CH3O)-; or

[0098] (C3-C6)-cycloalkyl, unsaturated, unsubstituted or substituted,

[0099] wherein, when X = H and A = H, Y is cyclobutyl, or an unsubstituted or (Ci-C4)-alkyl-substituted unsaturated (C3-C6) cycloalkyl, preferably cyclohexenyl, more preferably 1-cyclohexenyl; or

[0100] -CH2-(C3-C6)-cycloalkyl, saturated, unsubstituted or substituted, preferably CH2-cyclopentyl; or

[0101] benzyl substituted or unsubstituted with one or more substituents, the same or different from each other, selected from halogen, preferably Cl or F; (Ci-C4)-alkyl, preferably CH3; (C1-C4)-alkoxy, preferably (CH3O)-; or CF3;wherein benzyl is substituted with at least one of the following substituents or at least one of the following combinations of substituents: 2-C1, 2-F, 3-F, 4-F, 3,4-Cl, F, 3,2-Cl, F, 2,4-Cl, F, 4,2-Cl, F, 2,4-diF or 3-CF3; 2, 3-F, CH3- or 3,4- CH3, F-; 2- CH3-; 3-(CH3O)-; or

[0102] R2

[0103] w £ Y 1 R4

[0104]

[0105] Rs, wherein

[0106] when W is CH=CH, preferably with E configuration, R1 is H or F, R2, R3, R4 and R5 are H, and when W is C≡C, R1, R2, R3, R4 and R5 are H, and

[0107] when W is CH2CH=CH, R1, R2, R3, R4 and R5 are H, preferably with E configuration, the compounds of formula Ic proved to be effective as COX-1 and COX-2 inhibitors and thromboxane receptor antagonists (C0X1, C0X2 and TP).

[0108] According to the present invention, ‘C7-C4 alkyl' refers to an alkyl chain containing 1 to 4 carbon atoms, linear or branched, saturated, for example methyl, ethyl, propyl, isopropyl, butyl, sec -butyl, tert-butyl, or unsaturated, e.g. vinyl, 1 -propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butenyl, 2-butenyl, 3-butenyl, preferably ethynyl, 1-propynyl, 2-propynyl, 1-butenyl, 2-butenyl, 3-butenyl, in the case of the chain establishing the double bond, it can assume an E or Z configuration.

[0109] The " Ci-C4 alkyl’ group may be substituted by a halogen (Cl, F, Br, I), OH, cyano group, nitro group, amino group, or Ci-C4alkylamino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 allyl, C1-C4 haloalkyl, C1-C4 haloalkoxy.

[0110] ‘C3-C6 cycloalkyV indicates a saturated or partially saturated hydrocarbon ring containing 3 to 6 carbon atoms, monocyclic, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0111] The group ‘C3-C6 cycloalkyV may be substituted by halogen (Cl, F, Br, I), OH, cyano group, nitro group, amino group, or C1-C4 alkylamino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 allyl, C1-C4 haloalkyl, C1-C4 haloalkoxy.

[0112] ‘Aryl’ indicates an aromatic ring containing 6 carbon atoms, monocyclic, preferably phenyl or benzyl.

[0113] ‘5- or 6-membered, heterocycle’’ refers to a saturated or partially saturated, monocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen or sulphur, preferably the heterocycle contains at least one nitrogen or oxygen atom.

[0114] The term "halogen’ refers to fluorine, chlorine, bromine and iodine.The compounds of the invention that have one or more stereogenic (asymmetric) carbon atoms may exist as stereoisomers (optical isomers), i.e. as enantiomers or as diastereoisomers or mixtures thereof.

[0115] According to the present invention, the compounds may be in the form of optically pure enantiomers; pure diastereoisomers; mixtures of enantiomers; mixtures of diastereoisomers; racemic mixtures, racemates, or racemic mixtures of enantiomers. Furthermore, according to the present invention, the compounds may exist as conformational isomers or rotamers, tautomers, tautomeric mixtures, or, when present, isotopes.

[0116] According to the present invention, a "protective group’’ may be selected from those listed in Peter G. M. Wuts, Theodora W. Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, 2007 John Wiley & Sons Inc. on pages 533-646 and pages 696-926, and in Isidro-Llobet A., Alvarez M. Albericio F.’s “Amino Acid-Protecting Groups” Chem. Soc. Rev.

[0117] 2009, 109, 2455–2504. Examples of protective groups for the amino group are tertbutoxycarbonyl (Boc), acetyl, and examples of protective groups for the terminal carboxylic acid are methyl, ethyl, tert-butyl, benzyl.

[0118] The compounds according to the present invention can be converted into the corresponding pharmaceutically acceptable salts by reaction with acids, organic or inorganic, or bases, organic or inorganic, or with amino acids, such as lysine or arginine.

[0119] Examples of pharmaceutically acceptable inorganic acids or bases are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sodium hydroxide, potassium hydroxide, and calcium hydroxide.

[0120] Examples of pharmaceutically acceptable organic acids or bases are oxalic acid, tartaric acid, maleic acid, succinic acid, citric acid, fumaric acid, acetic acid, methane sulfonic acid, benzoic acid, carbonic acid, pamoic acid, tris-(2-hydroxymethyl)-aminomethane (tromethamine), sodium methylate.

[0121] The compounds of formula (I), (la), (lb) and (Ic) are preferably selected from those indicated in Table 1.Table 1

[0122] Compound X A W Y Structure X O

[0123] O

[0124] .0 FZA 0O-'' CXT 1 F H Cl ZX-N^V'COOH ■ H 1 Cl

[0125] P CXT9 H H SO2-CH3 'COOH i H1O2S^

[0126] CXT10 F H SO2-CH3 MXT COOH1H < O2S^

[0127] CXT11 F H S-CH3

[0128] F. / ^ -Z^O CXT12 F H I T V-4-\ W > COOH iH 1CXT14 CH3H Cl Z I V-A \AN ) COOH 1 H i Cl

[0129] O

[0130] 1: 1

[0131] COOH CXT15 F H SCh-phenyl! H

[0132] OaS.-:'x

[0133]

[0134] \

[0135] Fv P!1 P X.

[0136] CXT20 F H phenyl X ■■?>''' N > 'COOH; H

[0137] Fx. / 0 < T V4-\ CXT21 F H 3-Cl-phenyl '> COOH: H

[0138] 3- K p!1 P X.

[0139] CXT22 F H (CH3CONH)- X ■■?>''' Nx. 'COOH; H

[0140] 0 phenyl

[0141] H

[0142] Fx. / 0 3(HO-CH2)- i; y V4-\ CXT23 S OOOH F H: H phenyl

[0143] ks X..-" Jk. OH

[0144] F-. - / AO y T' V-v\ 3-(H2NCO)-; COOH CXT24 F H; H phenyl

[0145] k^Av-NH2O

[0146] W k

[0147] > COOH CXT26 F H 3-OH-phenyl: H

[0148]

[0149] Fx,.<x

[0150] lj T v ■■ - 4(HO-CH2)-; COO 6K CXT27; H

[0151] F H 8 / phenyl

[0152] VOH

[0153] { _ (.

[0154] Q u. X Fx J 0 If T

[0155] COOH CXT29 F H benzyl; H

[0156] F'x " P S02- COOH CXT30 F H • H

[0157] o cl pro ylas ci o px

[0158] X /

[0159] 1 — X Fx.-x, J 0 If T X-J— COOK CXT31 F H 2-OH-phenyl: H

[0160] HO.

[0161] CXT32 F H 2-Cl-phenyl

[0162] ..—x Fx xXx J 0 li 7 V-i--\; COOH CXT33 F H 4-Cl-phenyl; H

[0163] Cl

[0164]

[0165] 3-(CH3CO)- 6 CXT35 F H 8 phenyl

[0166] £..- i >• £ j (> }>.

[0167] /

[0168] Fx..-x, / 0 If T

[0169] 3-(CH3SO2)- COOH CXT36 F H; H phenyl

[0170] k..ls. CHs Oa

[0171] F'x "p 3-(CH3O)- COOH CXT37 F H: H phenyl

[0172] Z-A

[0173] ) 4 '(} <). 7. X, / 0 If T X-J— 'COOH CXT38 F H 3 -pyridyl; H

[0174] r is /

[0175] 8 o

[0176] CXT39 F H 5-pyrimidyl

[0177] 7— X Fx J 0

[0178] ; COOH CXT40 F H 3-pyrazolyl; H

[0179] N<;'>

[0180] HN-'-'

[0181]

[0182] 2-CH3-3- 6 CXT41 F H

[0183] pyraz lyl / 8 o

[0184] , z..~

[0185] / LZAJ

[0186] ?— X Fx J 0 If T

[0187] COOH CXT42 F H 1 -cyclohexenyl; H

[0188] F'x. '•'-Xx-'Z 'P SO2- COOH CXT43 F H • H cyclohexyl 0:0 x.--, XSj

[0189] 1 — X Fx.-x, J 0 If T X-J— 2,5-diCl- COOH CXT44 F H: H phenyl Ok. K

[0190] F'x 'P 3,5-diCl- \ COOH CXT45 F H: H phenyl

[0191] $s s? 5' CXT46 F H 4-isoxazolyl

[0192] x

[0193]

[0194] ^X \ COOH 4-(CH3O)- H / CXT62 F H

[0195] benzyl

[0196] '^0.

[0197] . >! >— V" X •X- JM > COOH H / CXT64 F H 4-Cl-benzyl

[0198] ^"'Cl

[0199] vCX

[0200] \ COOH H / CXT65 F H 4-F-benzyl

[0201] X^xp

[0202] CH2- Xj^VcOOH CXT68 F H H /

[0203] cyclopentyl

[0204] M. >! >. VX > COOH H / CXT72 F H 2-CH3-benzyl

[0205] Y< X

[0206] \ COOH H / CXT73 F H 3 -CH3-benzyl

[0207]

[0208] CO 3OH CXT74 F H 4-CH3-benzyl T H!

[0209] / 8

[0210] - > J.. / :::= \ °

[0211] Q.

[0212] / zr~

[0213] S COOH

[0214] ; H / CXT75 F H 2-Cl-benzyl

[0215] CI '-'X::''

[0216] 4- CXT77 F H LANZ) COOH f H / trifluorobutyl

[0217] ^CF3

[0218] CXT78 F H 3-Cl-benzyl

[0219] f-.,'kx - / A0 I; '[ V-yx 'N'; COOH; H CXT79 F H 3-F-benzyl X

[0220] F

[0221] FY •'VVYX'NCX > COOH: H CXT80 F H 2-F-benzyl V, - Ss

[0222]

[0223] S 'COOH 3-(OCH3)-; H / CXT81 F H

[0224] benzyl

[0225] MeO

[0226] |!. V h" X > COOH 3-C1-4-F- T H / CXT82 F H

[0227] benzyl

[0228] ci

[0229] ... / "o < / \ COOH 3-C1-2-F- i H / CXT83 F H

[0230] benzyl X-;'‘

[0231] f '

[0232] c

[0233] i i >.. V K" X ■ JM > COOH T H / CXT84 F H 3-CF3-benzyl

[0234] CF3fx 2 ~ o I; 'T'"x4-F-3-CH3- X^" N'X; 'COOH; H / CXT85 F H

[0235] benzyl

[0236] (. > V. v\ \j ■> COOH 2-F-3-CH3- H CXT86 F H

[0237] benzyl

[0238]

[0239] S 'COOH; H / CXT87 F H 3-CN-benzyl

[0240] NC

[0241] |!. V K" X > COOH T H / CXT88 F H 3-NO2-benzyl

[0242] \,-.-'xx.s

[0243] 02N

[0244] ~ O S 'COOH 3-F-5-OCH3-; H / CXT90 F H

[0245] benzyl

[0246] MeO

[0247] W i! >.. V >" X

[0248] ■ JM > COOH 3-C1-5-F- T H / CXT91 F H

[0249] benzyl

[0250] ci

[0251] F\

[0252] X^" N'X; 'COOH; H / CXT92 F H 3,5-diF-benzyl

[0253] r

[0254] (Z) \ COOH CXT93 F H Phenyl f / r.; H

[0255] CH=CH

[0256]

[0257] X X X § 8 O CXT94 F H CH2CH2 Phenyl..7,8 CX"'" zi^( 'zx (x / S

[0258] Z / k — / 7 / '

[0259] \ \......70 / 0

[0260] / / \. /

[0261] U- IL u. /

[0262] 2-C1-6-F- CXT95 F H

[0263] benzyl

[0264] jj s

[0265] -N\ COOH CXT96 H F benzyl

[0266] V7

[0267] '0 7 GQOH; H / CXT97 F H C=C Phenyl

[0268] 2-C1-4-F- CXT98 F H

[0269] benzyl

[0270]

[0271] CXT99 F H 2,4-diF-benzyl I

[0272] ZX

[0273] \. / 77

[0274] . / 0 j; 'f

[0275] y* N > COOH CH2CH=C: H / CXT100 F H phenyl X,_

[0276] H

[0277] (E)

[0278] CXT101 F H phenyl

[0279] CH=CH

[0280] o,.,

[0281] / \ ■

[0282] ■ / ^0 1 T v-e\ 4-C1-2-F- >COOHs H CXT102 F H 8 o benzylx'■''X

[0283] r J x-,'.- 4Cj

[0284] F\ / . A^ _ / 'p h i

[0285] (E) < -X'-N) COOH CXT103 F H 2-F-phenyl

[0286] CH=CH

[0287] ^

[0288]

[0289] "fi Xv.2—xXCOOH CXT105 F H CH2CH2 2-F-phenyl 1 H

[0290]

[0291] According to a preferred aspect, the compounds of the invention are selected from those indicated in Table la.

[0292] Table la

[0293] Compound X A W Y Structure

[0294] P

[0295] ) COOH 4-(CH3O)-: H CXT62 F H

[0296] benzyl

[0297] .

[0298] U" N' S 'COOH; H CXT64 F H 4-Cl-benzyl

[0299] Cl

[0300] 0 COOH CXT74 F H 4-CH3-benzyl T H /

[0301]

[0302] F,. A J '0

[0303] jj Y V-A'-x T 'sA " N > OOO: H 8H CXT88 F H 3-NO2-benzyl

[0304] O2YN \zx u.x-P^'

[0305] \.70

[0306] X i / — \

[0307] S 'COOH 3-F-5-OCH3-; H CXT90 F H x. p benzyl

[0308] MeO

[0309] 3-C1-5-F- CXT91 F H

[0310] benzyl

[0311] 7 _

[0312] \ / \!. O

[0313] \ 'COOH; H CXT92 F H 3,5-diF-benzyl P •” T c

[0314] 0 X F

[0315] 2-C1-6-F- CXT95 F H

[0316] benzyl

[0317]

[0318] According to a preferred aspect, the compounds of the invention are selected from those indicated in Table lb.Table lb

[0319] X

[0320] Compound X A Y Structure 0

[0321] W 0 i l y zi^"" ’0CXT 1 F H Cl COCH 0 C»- IH 1u.

[0322] CXT9 H H SO2-CH3 COQH o2svH

[0323] CXT11 F H S-CH3

[0324] R 0 CXT12 F H I

[0325] iH 7

[0326] CXT14 CH3 H Cl XX0yCooH i H! Cl

[0327] r~'\

[0328] 9 — x COOH CXT15 F H SCh-phenyl I H /

[0329] r — \F' v-'":X..- ' < P 3(HO-CH2)- S COOH CXT23 F H: H phenyl

[0330] kx X-- Jkx.-’ OH

[0331]

[0332] 3-(H2NCO)- S 'COOH i H CXT24 F H

[0333] phenyl

[0334] 0

[0335] 9 4(HO-CH2)- S COOH: H CXT27 F H

[0336] phenyl

[0337] xOH

[0338] r“”\ Vvv?->.

[0339] COOH CXT29 F H benzyl: H

[0340] P

[0341] ii | p-\ > COQH CXT31 F H 2-OH-phenyl • H

[0342] 3-(CH3SO2)- \ COOH CXT36 F H; l-f phenyl

[0343] Ou

[0344] F\ p - \XCOOH CXT38 F H 3 -pyridyl; H

[0345] r is

[0346]

[0347] CXT39 F H 5-pyrimidyl

[0348] H | V— v\ > COQH CXT40 F H 3-pyrazolyl; H HN~"

[0349] r“”\ 2-CH3-3- Vvv?->.

[0350] COOH CXT41 F H: l-f pyrazolyl

[0351] •n

[0352] 4.

[0353] SO2- \ > COOH CXT43 F H • H cyclohexyl OaS^- ^

[0354] 'x 8 X

[0355] r-.-\ 2,5-diCl- Vvv?->.

[0356] COOH CXT44 F H: l-f phenyl

[0357] F\ b 3,5-diCl- "XCOOH CXT45 F H i H phenyl

[0358] Cr'^'-'''xCi

[0359]

[0360] T O CXT46 F H 4-isoxazolyl

[0361] z8 / 0. '

[0362] CXT73 F H 3 -CH3 -benzyl

[0363] 4- iPCp^pCOOH CXT77 F H T H /

[0364] trifluorobutyl

[0365] kCF3

[0366] T 4 z.

[0367] CXT78 F H 3-Cl-benzyl

[0368] <> zz. /

[0369] (< ■ y \ —

[0370] "' o 8 p T 'COOK; H CXT87 F H 3-CN-benzyl

[0371] NO

[0372] Fx T) 'p " Y VY~\ T COOH CXT94 F H CH2CH2 phenyl § H /

[0373]

[0374] "fi Xv. X-xXCOOH CXT105 F H CH2CH2 2-F-phenyl 1 H

[0375]

[0376] According to a preferred aspect, the compounds of the invention are selected from those indicated in Table 1c.

[0377] Table 1c

[0378] Compound X A W Y Structure

[0379] CXT10 F H SO2-CH3 TTVb

[0380] > COOH i H1

[0381] CXT20 F H phenyl: H /

[0382] K0A'".

[0383] CXT21 F H 3-Cl-phenyl COOH; H / x'"' Ci

[0384] 3- VYCX CXT22 F H (CH3CONH)- > OOO-f: H phenyl 9

[0385] A-'"

[0386] H

[0387]

[0388] S 'COOH CXT26 F H 3-OH-phenyl i H

[0389] P

[0390] H | V— v\ S02- > COOH CXT30 F H

[0391] cyclopropyl

[0392] w

[0393] r“”\ Vvv?->. COOH CXT32 F H 2-Cl-phenyl: l-f

[0394] P

[0395] ii | -p-\ CXT33 F H 4-Cl-phenyl; H

[0396] 61

[0397] 3-(CH3CO)- Vvv?->. COOH CXT35 F H; l-f phenyl

[0398] 0

[0399] F\ p 3-(CH3O)- - \XCOOH CXT37 F H i H phenyl

[0400] k. AoXH3

[0401]

[0402] V"\

[0403] X COOH CXT42 F H 1 -cyclohexenyl: H

[0404] P

[0405] 'L-Vf / S 'COOH; H CXT65 F H 4-F-benzyl

[0406] —xCH2- CXT68 F H VN / COOH cyclopentyl [ H /

[0407] " O

[0408] F, zss. / 0 jj Y V V V " N > COOH: H CXT72 F H 2-CH3-benzyl

[0409] F-v-er--^ P ‘L. Vf / \ 'COOH; H CXT75 F H 2-Cl-benzyl

[0410] ci -e;"

[0411] F. -. / 0 ij Y V V V " N > COOH: H CXT79 F H 3-F-benzyl

[0412] F

[0413]

[0414] J 'o xx " N > OOOH H CXT80 F H 2-F-benzyl

[0415] F

[0416] z — \ A

[0417] N \ COOH 3-(OCH3)- H CXT81 F H

[0418] benzyl X

[0419] M sO

[0420] .. / 0 VX\ -N > OOOH 3-C1-4-F- H CXT82 F H

[0421] benzyl x.

[0422] ''X'F ci

[0423] z-~\ A

[0424] -V \ 'COOH 3-C1-2-F- H CXT83 F H

[0425] benzyl \

[0426] X"'

[0427] ci

[0428] Fx / ^.. / xo XXx -N > OOOH H CXT84 F H 3-CF3-benzyl

[0429] X.

[0430] CF,

[0431] / — \ A 5--4 °--V \ COOH 4-F-3-CH3- H CXT85 F H

[0432] benzylv\ 'S's

[0433] 'X'F

[0434]

[0435] F,..,x J '0

[0436] jj Y V-x-x " N > OOOH 2-F-3-CH3-: H CXT86 F H

[0437] benzyl

[0438] F.. " O (Z) I T \7" N;■ COOH CXT93 F H phenyl X';.; H /

[0439] CH=CH

[0440] ,.,x -'ZP ij Y V-'-ex < N > OOOH ': H / CXT96 H F Benzyl

[0441] TJ /

[0442] \ / Q _

[0443] ^x- C T i7 C" N^ \ 'COOH; H

[0444] X 97 F H C=C Phenyl

[0445] 4Jo x

[0446] zo 8 X

[0447] 2-C1-4-F- CXT98 F H

[0448] benzyl

[0449] FX^.^,,, Y b \XCOOH CXT99 F H 2,4-diF-benzyl! H /

[0450] ::

[0451]

[0452] F, J 0

[0453] CH2CH=CH

[0454] : H o CXT100 F H Phenyl / o

[0455] H

[0456] s:...'J'

[0457] Y F-'

[0458] / tL

[0459] X!

[0460] VCOOH

[0461] (E) i H

[0462] CXT101 F H phenyl "'“'x

[0463] CH=CH

[0464] COOH

[0465] 4-C1-2-F- i M

[0466] CXT102 F H

[0467] benzyl

[0468] p - A A sC(

[0469] (E)

[0470] CXT103 F H 2-F-phenyl

[0471] CH=CH

[0472]

[0473] According to a further preferred aspect, the compounds of the invention are selected from CXT15, CXT21, CXT26, CXT29, CXT32, CXT33, CXT37, CXT41, CXT42, CXT44, CXT45, CXT62, CXT64, CXT65, CXT72, CXT75, CXT78, CXT80, CXT82, CXT83, CXT86, CXT87, CXT88, CXT93, CXT95, CXT97, CXT98, CXT98, CXT99, CXT101, CXT103, CXT105, more preferably between CXT21, CXT29, CXT33, CXT42, CXT45, CXT62, CXT64, CXT65, CXT75, CXT78, CXT82, CXT97, CXT98, CXT99, even more preferably, the compound is CXT29.

[0474] It was surprisingly found that compounds of formula (I), (la), (lb) and (Ic), having a 2-(1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid structure, exhibit thromboxane (TP)receptor antagonism and cyclooxygenase 1 and / or 2 (COX-1, COX-2, or COX-1 and COX-2) or COX-l / TP, COX-2 / TP or COX-1 and COX-2 / TP (also known as COXTRANs), and are therefore capable of reducing or suppressing thromboxane A2 (TXA2)-dependent platelet aggregation and inflammatory pain in mice after oral administration.

[0475] As shown in the Examples, experiments have shown that the compounds of the invention have dual activity as COX-1 and / or COX-2 inhibitors and TP receptor antagonists.

[0476] A further subject of the invention are compounds of general formula (I), (la), (lb) or (Ic) for use as a medicament, in particular as COX-1 and / or COX-2 inhibitors and thromboxane (TP) receptor antagonists (also known as COXTRANs, i.e. COX inhibitors and thromboxane receptor antagonists).

[0477] According to a further aspect, the invention relates to compounds of general formula (I), (la), (lb) or (Ic) for use in the prevention and / or treatment of diseases and / or disorders related to inflammatory pathologies, in particular those involving (hyper)activation of COX-1 and COX-2, and / or activation of the thromboxane receptor, such as mild or moderate inflammatory pain; musculoskeletal injuries such as osteoarthritis, rheumatoid arthritis, atherosclerosis and arthrosis; autoimmune diseases; neurodegenerative diseases, such as Alzheimer's disease; heart diseases, such as cardiac ischaemia; cancer, particularly metastatic cancer, such as hepatocellular carcinoma, colorectal cancer, breast cancer and melanoma; non-alcoholic fatty liver disease; diseases related to endothelial function, such as cardiac and pulmonary fibrosis; stroke.

[0478] The compounds of the invention, in fact, have a combined effect:

[0479] - inhibition of platelet activation, and / or

[0480] - blocking of the proatherogenic activities of TXA2 and its effects on the integrity of the blood-brain barrier, which plays a role in the progression of neurodegenerative diseases, and / or - inhibiting the effects of TXA2, whether of platelet origin or not, on the proliferation of tumour cells and their invasiveness, and / or

[0481] - inhibiting the formation of PGE2 derived from COX-2, modulating its pro-inflammatory effects and effects on tumour progression.

[0482] The compounds of the invention of formula (I), (la), (lb) or (Ic) can be used in combination with other therapeutic agents, such as anti-inflammatories, non-steroidal antiinflammatory drugs (NSAIDs), antidiabetics, anti-Alzheimer's drugs, anti-Parkinson's drugs, anti-sclerosis drugs, and anticancer drugs, to achieve greater therapeutic efficacy, a reduction in the amount of drug to be administered to the patient, and consequently also a lower incidence of associated adverse effects.The invention also relates to compositions containing at least one compound of general formula (I), (la), (lb) or (Ic) and at least one pharmaceutically acceptable excipient or vehicle.

[0483] The daily dose of active ingredient to be administered may be a single dose or an effective amount divided into multiple doses to be administered, for example, throughout the day. The dosage regimen and frequency of administration for the treatment of the above-mentioned diseases with the compound of the invention and / or with the pharmaceutical compositions of the present invention will be selected based on various factors, including, for example, the patient's age, body weight, gender and medical condition, as well as the severity of the disease, the route of administration, pharmacological considerations and any concomitant therapy with other drugs. In some cases, lower or higher dosage levels than the above-mentioned range and / or more frequent dosages may be used, at the discretion of the physician, based on the status of the disease.

[0484] The compounds of the invention may be administered orally, parenterally, topically, by injection, for example, by intra-articular injection.

[0485] All the features described in the present invention should be considered combinable with each other, unless explicitly stated otherwise.

[0486] The compounds of the invention can be obtained by conventional synthetic routes, in particular according to the schemes provided below. For example, the compounds were synthesised according to the synthetic route shown in Scheme 1.

[0487] The compounds of general formula (I) can be synthesised according to Schemes 1-11 shown below.Scheme 1

[0488] OH

[0489] 1-6 7-14 15-22 1 (X=F, A=H, R6=I) 7 (X=F, A=H, R6=I) 15 (X=F, A=H, R6=I) 2 (X=F, A=H, Rg=Br) 8 (X=F, A=H, R6=Br) 16 (X=F, A=H, Rg=Br) 3 (X=CH3, A=H, R6=I) 9 (X=CH3, A=H, R6=l) 17 (X=CH3, A=H, R6=I) 4 (X=H, A=F, R6=Br) 10 (X=H, A=F, R6=Br) 18 (X=H, A=F, R6=Br) 5 (X=F, A=H, R6=SMe) 11 (X=F, A=H, R6=SMe) 19 (X=F, A=H, R6=SMe) 6 (X=H, A=H, R6=SMe) 12 (X=H, A=H, R6=SMe) 20 (X=H, A=H, R6=SMe)

[0490] 13 (X=F, A=H, R6=CI) 21 (X=F, A=H, R6=Cl)

[0491]

[0492] 14 (X=CH3, A=H, R6=Cl) 22 (X=CH3, A=H, R6=Cl)

[0493] The reaction to obtain compounds of formula 7-12 can be carried out using a suitably substituted aniline (1-6) which is reacted according to a nitrosation-reduction reaction. In step (i), a compound of formula 1-6 is first reacted with an aqueous solution of NaNO2in the presence of 37% HC1 at a temperature between -20 °C and +5 °C for a period of between a few minutes and a few hours, then with a reducing agent, such as SnCl2·2H2O in 37 % HC1 or sodium sulfite, at a temperature between -20°C and +25 °C for a period of between a few minutes and a few hours, as shown in Scheme 1, to obtain the intermediates of formula 7-12.

[0494] The compounds of formula 7-14 obtained from the previous reaction (7-12) or commercially available (13-14) are converted, through step (ii), into the indole compounds of formula 15-22 by treatment with 2,3-dihydrofuran, with or without zinc chloride. The reaction is carried out in a solvent such as dichloromethane, THF, 1,4-dioxane or ethylene glycol, in the presence of water (1-20%) at a temperature between +40 and +170 °C for a time between 3 and 24 hours.Scheme 2

[0495] OH

[0496] x.^,.^. / 'p

[0497] . X-A N 'SXCOOMe

[0498] Ai H /

[0499] 15-23, 35, 94-95 24-32, 35, 96-97

[0500] 15 (X=F, A=H, R6=I) 24 (X=F, A=H, R6=I)

[0501] 16 (X=F, A=H, R6=Br) 25 (X=F, A=H, R6=Br)

[0502] 17 (X=CH3, A=H, R6=I) 26 (X=CH3, A=H, R6=I)

[0503] 18 (X=H, A=F, R6=Br) 27 (X=H, A=F, R6=Br)

[0504] 19 (X=F, A=H, R6=SMe) 28 (X=F, A=H, R6=SMe)

[0505] 20 (X=H, A=H, R6=SMe) 29 (X=H, A=H, R6=SMe)

[0506] 21 (X=F, A=H, R6=Cl) 30 (X=F, A=H, R6=Cl)

[0507] 22 (X=CH3, A=H, R6=Cl) 31 (X=CH3, A=H, R6=Cl) 23 (X=F, A=H, R6=H) 32 (X=F, A=H, R6=H)

[0508] 35 (X=F, A=H, R6=SO2phenyl) 36 (X=F, A=H, R6=SO2phenyl)

[0509] 94 (X-F, A-H. Re-CH?-cyc»penly?) 96 (X=F, A=H, R6=CH2-cyclopentyl) 9

[0510]

[0511] 95 (X=F, A=H, R6=CH2CH2CH2CF3) 97 (X=F, A=H, R6=CH2CH2CH2CF3)

[0512] Compounds 15-23, 35 and 94-95 are converted, as shown in Scheme 2, into ester derivatives 24-32, 36 and 96-97 by treatment with BFs- OEt in the presence of methyl-3-oxopentanoate or methyl 3-methoxypentenoate, in a suitable anhydrous solvent, such as DCM, THF and 1,4-dioxane. The reaction is carried out at temperatures between -10 and +35°C for a period of between a few minutes and 24 hours.

[0513] Scheme 3

[0514] xvy o ¥ V X\ _ 4--\ * N" COOMeA\ COOMe 1 H / ? H /

[0515]

[0516] -s O2S,X

[0517] 28 (X=F, A=H) 33 (X=F, A=H)

[0518] 29 (X=H, A=H) 34 (X=H, A=H)

[0519] The oxidation reaction shown in Scheme 3 is carried out starting from thioether derivatives 28-29 by treatment with an oxidising agent such as metachloroperoxybenzoic acid, tert-butyl hydroperoxide or hydrogen peroxide to obtain sulfonic derivatives with a structure similar to 33-34. The reaction is carried out in a suitable solvent such as dichloromethane, acetonitrile or methanol, at a temperature between 0 and +50°C and for a time between 1 and 24 hours.Scheme 4

[0520]

[0521] 15 (X=F, A=H) 35 (X=F, A=H)

[0522] Sulfonyl compounds with a type 35 structure were obtained by reacting an iodinated derivative with a type 15 structure in the presence of a sulfonyl acid such as benzenesulfonic acid, in the presence of a copper(II) salt such as Cu(OAc)2, CuCO3or CuCl2and an excess of base such as NaOH, KOH or LiOH. The reaction is allowed to proceed at a temperature between +50 and +200°C in a solvent such as dimethyl sulfoxide or dimethylformamide for a period of between 1 and 12 hours, as shown in Scheme 4.

[0523] Scheme 5

[0524] ■\ - >. p 'cOOMe ) CQOMe HO,. OH B' R724-25 or 37-61

[0525] 37 (X=F, A=H, R7=phenyl) 24 (X=F, A=H, R6=I) xLo 38 (X=F, A=H, R7=3-chlorophenyl) 25 (X=F, A=H, R6=Br) ( B-R7

[0526] / t'O 39 (X=F, A=H, R7=3-acetamidophenyl)

[0527]

[0528] 40 (X=F, A=H, R7=3-(hydroxymethyl)phenyl)

[0529] 41 (X=F, A=H, R7=3-carbamoylphenyl) 42 (X=F, A=H, R7=3-hydroxyphenyl) 43 (X-F, A-H. Ry-4-hydroxyphenyi) 44 (X=F, A=H, R7=2-hydroxyphenyl) 45 (X=F, A=H, R7=2-chlorophenyl)

[0530] 46 (X=F, A=H, R7=4-chlorophenyl)

[0531] 47 (X=F, A=H, R7=3-acetylphenyl)

[0532] 48 (X=F, A=H, R7=3-(methylsulfonyl)phenyl) 49 (X=F, A=H, R7=3-methoxyphenyl) 50 (X=F, A=H, R7=3,5-dichlorophenyl) 51 (X=F, A=H, R7=2,5-dichlorophenyl) 52 (X=F, A-H. R7- pyridin-3-y!}

[0533] 53 (X=F, A=H, R7=pyrimidin-5-yl)

[0534] 54 (X=F, A=H, R7=1H-pyrazol-3-yl)

[0535] 55 (X=F, A=H, R7=1-methyl-1H-pyrazol-5-yl) 56 (X=F, A=H, R7=1-cyclohexenyl)

[0536] 57 (X=F, A=H, R7=isoxazol-4-yl)

[0537] 58 (X=F, A=H, R7=benzyl)

[0538] 59 (X=F, A=H, R7=4-methoxybenzyl)

[0539] 60 (X=F, A=H, R7=4-chlorobenzyl)

[0540] 61 (X=F, A=H, R7=4-fluorobenzyl)The compounds of formula 37-61 can be obtained, as described in Scheme 5, by reacting the intermediate of formula 24 or 25 with an organoboron compound suitably substituted in R? according to a Suzuki-Miyaura reaction. A palladium-based catalyst is used, such as Pd(dba)2, Pd(PPh3)2Cl2, Pd(PPh3)4, Pd(PPh3)2(OAc)2, Pd(dppf)Cl2in the presence of a base such as K2CO3, Na2CO3, K3PO4in a suitable solvent such as DME, THF or 1,4-dioxane and suitably mixed with water (1-50 % v / v) at a temperature between 0 and +100 °C for a time between a few minutes and 24 hours.

[0541] Scheme 6

[0542] 'p x„. / b si i \ \ ROOM©X©::: X- N X COOMe.. x X COOMe I H / ‘ i H / B, Br-o O' OHs R8

[0543] 25, 27 62-63 58, 64-86, 88-85 23 (X-F A=H, 62 {X=+, A-H} 27 (X=H, A=F, R8=Br) 63 (X«H. A-F} 58 (X=F, A=H, Ra=+enzvi)

[0544] 64 (X=H, A=F, R^benzy!) 65 (X=F. A«H, Rg=2-methylbenzyl) 66 (X=F, A=H. Ra=2-tluorobenzyl) 67 (X=F. A=H, R^-flBorobenzyl) 68 (X«F. A«H, Rs^-meihylbenzyl) 69 (X-F, A-H. Ra=3-chtorobenzyl) 70 (X=F, A=H, Rs=3-flBorobenzyl) 71 (X=+. A-H R8=3-meihoxybenzyl) 72 (X-F, A-H. Ra~3-(ttiflBoromethyObenzyf) 73 (X=F, A=H, Rg^-nitrobenzyt) 74 (X-F. A-H, R8=3-cianobenzy!) 75 (X-F, A-H, Ra-4-metnylbenzyl) 76 (X=R A=H, Ra-3'Ch!oiO'2-fiuorobenzyl) 77 (X=+. A=H, R8=2-fluora-3-methylbenzyO 78 (X-F, A-. H. Ra-1-chioro-6-f;iiorc'bBnzyf > 79 (X=+, A»H, Ra-2,4-dif!©orober)zyl) 80 (X=F. A-H, R8=2-fluoro-4-chiorobenzy!) 81 (X-F, A-H, Ra=2-chtoro-44iuorobenzyt) 82 (X~F, A~H, Ra-3,5-difk.'Orobenzyl} S3 (X-F, A-H R8=3-chloro-5~tiuorobenzy!) 84 (X-F A-H, R8=3-fluoro-5-inethoxyberizy!) 85 (X=F, A-H, Ra=3-chioro-4-fluorobenzyf) 88 (X-F, A-H, R8=4-flBoro-3-methytbenzyi) 88 (X=F, A-H, R8=(12>2-pheny(sthenyl)

[0545]

[0546] 89 (X=F, A~H. Ra=cinnamyl}

[0547] Compounds 58, 64-86, 88-89 can be obtained through a Suzuki-Miyaura-type reaction by reacting intermediate 62 or 63 with a suitably substituted bromide of formula Br-R8 in the presence of a palladium-based catalyst such as Pd(dba)2, Pd(PPh3)2Cl2, Pd(PPh3)4, Pd(PPh3)2(OAc)2, Pd(dppf)Cl2, Pd(PPh3)2C12, a base such as K2CO3, Na2CO3, K3PO4in a suitable solvent such as DME, THF or 1,4-dioxane and suitably mixed with water (1-50% v / v) for a time ranging from a few minutes to 24 hours, as illustrated in Scheme 6 (step ii). The reaction is carried out at a temperature ranging from -20 to +180 °C. To obtain intermediates 62 and 63, compounds 25 and 27 are treated with an organoborane such as, for example, pinacolborane or bis(pinacolato)diborane, in the presence of a palladium-based catalyst, suchas, for example, Pd(dba)2, or an iridium-based catalyst, such as, for example, [Ir(cod)OMe]2, in the presence of ligands such as tricyclohexylphosphine or 4,4'-di-tert-butyl-2,2'-bipyridine and a base such as K2CO3, Na2COs, K3PO4 (Scheme 6, step i). The reaction is carried out in a suitable solvent such as DME, THF or 1,4-dioxane, at a temperature between -20°C and +180°C for a time between 30 minutes and 24 hours.

[0548] Scheme 7

[0549] ,.,kx / b

[0550] \ COOMeA[ H /

[0551]

[0552] Rs24 (X-F A»H) 87 (X~F< A~H. R^phenyi)

[0553] Compounds with a structure similar to 87, functionalised with a triple bond, can be synthesised using the Sonogashira reaction, starting from iodides with a structure similar to 24, using variously substituted terminal alkynes HC≡C-R9, such as ethinylbenzene, in the presence of a palladium-based catalyst, such as Pd(PPh3)2C12, Pd(PPh3)4, Pd(PhCN)2C12, and a copper(I)-based catalyst, such as Cui, as shown in Scheme 7. The reaction is carried out in the presence of a suitable base, such as pyridine, triethylamine, n-butanolamine, in a suitable solvent, such as THF, 1,4-dioxane or benzene. The reaction temperature is between -20°C and +150°C and the time required for completion is between 30 minutes and 8 hours.

[0554] Scheme 8

[0555] \ p A-A-AV S COOMe \ " COOMe; H /

[0556] Rin 25 90-91 92-93 25 (X=F. A=H, Rs=Br) 90 (X=F, A=H, R10=phenyl) 92 (X=F, A=H. Ri0=phenyi}

[0557]

[0558] 91 (X-F< A-H. R.o:;2-f!uofophe-;iy!) 93 (X=F, A=H, R10=2-fluorophenyl)

[0559] Compounds 90-91 are obtained by reacting the brominated derivative with formula of type 25 in a Heck reaction with a suitably substituted olefinic derivative H2C=CH-RIO, as shown in Scheme 8, step i. A palladium-based catalyst is used, such as Pd(dppf)Cl2, Pd(OAc)2 orPd(PPh3)2Cl2, a base such as NaOAc, Et3N, pyridine and a suitably substituted terminal olefin. The reaction is carried out at a temperature between +50°C and +200°C, in a solvent such as DMF or THF, for a period of between 2 and 16 hours. The compounds of formula 92-93 were obtained by hydrogenation of compounds with a structure of type 90-91 using hydrogen gas and 10% palladium on carbon as a catalyst. The reaction was carried out in a solvent such as THF or 1,4-dioxane, at a temperature between -20 and +50 °C for a period of between 10 minutes and 5 hours.

[0560] Scheme 9

[0561]

[0562] 15, 18 94-95

[0563] 15 (X=F, A=H) 94 (X=F, A=H, R11=CH2-cyclopentyl)

[0564] 18 (X=H, A=F) 95 (X=F, A=H, R11=CH2CH2CH2CF3)

[0565] The reaction shown in Scheme 9 allows a different type of aliphatic chain to be inserted into derivatives with structures 16 and 18, starting from the respective alkyl bromides with formula Br-Rn, through a cross-coupling mechanism. The reaction is carried out using a nickel-based catalyst (such as NiI2, NiCl2) or palladium (such as PdCl2) catalyst, in the presence of zinc or magnesium powder, sodium iodide or potassium iodide and finally a ligand such as PPh3, 4,4'-diterbutyl-2,2'-bipyridine or chiraphos. The reaction is carried out in a suitable solvent, such as DMA, 1,4-dioxane, THF, at a temperature between 0°C and +120°C, for a period of between 2 and 36 hours.Scheme 10

[0566]

[0567] 28, 30-31, 33-34. CXT1, CXT9-13, CXT14-15,

[0568] 36-61, 64-93 CXT20-24, CXT26-27, CXT29,

[0569] CXT31-33, CXT35-42, CXT44-46,

[0570] 28, 30 (X-F, A-H, R12= R6) CXT62, CXT64-65, CXT68,

[0571] 31 (X=CH3, A=H, R12= R6) CXT72-75, CXT77-88, CXT90-103

[0572] 33 (X=F. A-H, R12= SO2CH3) e CXT105

[0573] 34 (X=H, A=H, R12= SO2CH3)

[0574] 36 (X-F, A-H, R12= SO2Ph)

[0575] 37-61 (X=F, A=H. R12=R7)

[0576] 65-86, 88-89 (X=F, A= H. R12=R8)

[0577] 64 (X~H, A~F. RI2=R8)

[0578] 87 (X=F, A=H, R12= CCPh)

[0579] 90 (X-F, A-H, R!2=stiryl)

[0580] 91 (X=F, A=H, R12=2-fluorostirile)

[0581] 92 (X=F, A=H, R j2=fenetyl)

[0582] 93 (X=F, A=H, R12=2-fluoroophenethyl)

[0583] The hydrolysis illustrated in Scheme 10 can be carried out by treating an ester compound of the formula shown with a base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in a suitable solvent such as THF, 1,4-dioxane, water or mixtures thereof (percentage between 20 and 70%), at temperatures between -20 and +100 °C and for a time varying from a few minutes to 72 hours.

[0584] Scheme 11

[0585]

[0586] CXT12 (X=F, A=H) CXT30 (X=F, A=H, Y=SO2-cyclopentyl)

[0587] CXT43 (X=F, A=H, Y=SO2-cycloesyl) Sulfonyl compounds with CXT30 and CXT43 structures were obtained by reacting an iodinated derivative with a CXT12 structure in the presence of a suitably substituted sulfonic acid with the formula R13SO2H, in the form of free acid or salted as sodium or potassium salt, in the presence of a copper(II) salt, such as Cu(OAc)2, CuCO3or CuCl2, and an excess of base,such as NaOH, KOH, LiOH. The reaction is allowed to proceed at a temperature between +50 and +200°C, in a solvent such as dimethyl sulfoxide or dimethylformamide, for a period of time between 1 and 12 hours, as shown in Scheme 11.

[0588] The following examples further illustrate the invention.

[0589] Experimental part

[0590] The following abbreviations are used in the present invention:

[0591] NSAIDs: nonsteroidal anti-inflammatory drugs; COX, cyclooxygenase; GPCR, G protein-coupled receptors; TX, thromboxane; TP, thromboxane receptor; PG, prostaglandin; UGIB, upper gastrointestinal bleeding; AA, arachidonic acid; COXTRAN, COX inhibitors, thromboxane antagonists; PRP, platelet-rich plasma; DMSO, dimethyl sulfoxide; HBSS, Hank's balanced salt solution; PK, pharmacokinetics; CFA, Freund's complete adjuvant; LPS, lipopolysaccharide; CMC, carboxymethylcellulose; KRB, Krebs-bicarbonate buffer; PBS, phosphate-saline buffer.

[0592] Materials and methods

[0593] All reactions were monitored by thin layer chromatography (TLC) on Merck 60 F254 plates (0.25mm), which were revealed with UV light and / or by spraying a solution of KMnO4 (0.5 g in 100 mL of 0.1 N NaOH), Bromocresol Green (0.04 g in 100 mL of EtOH, then treated with IN NaOH). Purifications by flash chromatography were performed using Merck silica gel with 60 mesh particles. Commercially available reagents and solvents were used without further purification.

[0594] The 'H and13C spectra were recorded on a Jeol ECZ 600 M30, at 600 and 150 MHz, respectively. The coupling constants (J) are expressed in Hertz (Hz) and the chemical shifts (5) values are given in ppm with respect to the deuterated solvent used as an internal standard.

[0595] The abbreviations used to describe multiplicity are: s=singlet, d=doublet, m=multiplet dd= doublet of doublets; while for abbreviations to identify protons ArH=aromatic protons, PipH=piperidine protons. Low-resolution ESI mass spectra were recorded on a MicromassQuattro Micro TP API (Waters Corporation, Milford, MA, USA) equipped with an ESI source.

[0596] The purity of the final products was determined through reversed-phase HPLC (RP-HPLC). Analyses were performed with an HP1100 chromatographic system (Agilent Technologies, Palo Alto, CA, USA) equipped with a quaternary pump (G1311A), a membrane degasser (G1379A), a diode array (DAD) detector (G1315B) integrated into the HP1100 system. The analysis data were processed using the HP ChemStation system (Agilent Technologies). The analytical column employed is a LiChrosper 100 C18-e (250x4.6 mm, 5pm)(Merck KGaA, 64271 Darmstadt, Germany) using as eluent that indicated for each compound. All compounds were solubilized in the mobile phase at a concentration of approximately 0.1 mg / mL and injected through a 20 pL loop. Retention times (tR) were obtained at a flow rate of 1.0 mL / min, and the effluent was monitored at two wavelengths (226 and 254 nm) and calibrated to the 800 nm reference. The purity of the compounds was derived as the percentage ratio of the main peak airways to those of any impurities at the two wavelengths, also using DAD purity analysis of the chromatographic peak. For each compound, the actual purity value and the eluent used for elution are reported in the characterization phase. Melting points (mp) were determined in glass capillary using a Biichi 540 melting point measuring apparatus.

[0597] Further abbreviations used are: petroleum ether 40-70 °C (PE), ethyl acetate (EtOAc), diethyl ether (Et2O), methanol (MeOH), tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethoxyethane (DME), dimethylamide (DMA), trifluoroacetic acid (TFA), retention factor (Rf), retention time (tR), Mass spectrometry (MS), nuclear magnetic resonance (NMR), acetic anhydride (Ac2O), hour (h), minute (min), room temperature (RT or rt), thin layer chromatography (TLC), flash column chromatography (FC), room temperature (rt).

[0598] Example 1. General procedure for the synthesis of intermediates 15-22

[0599] pH

[0600] Xx b oc

[0601] Rs

[0602] 1 (X»F, A«H, Rg-i) 7 (X=F. A=H, Re=0 15 (X«F. A-H. Rs-B

[0603] 2 (X«F, A«H, Rg-Br) 8 (X-F. A-H, R8»Br) 16 (X-F, A=H. Rs=Br) 3 (X=CH3, A=H, R6=I) 9 (X=CH3, A=H, R6=I) 17 (X=CH3, A=H, R6=I)

[0604] 4 (X=H. A=F. R<5=Br) 10 (X=H, A=F, Rg^Brj 18 {X-H, A-F. Rs-8r)

[0605] 5 (X-F. A-H, Re-SMe) 11 (X«F. A-H. Rs~SMe) 19 (X=F, A=H, R6=SMe)

[0606] 6 (X-H. A-H, Rg^SMa) 12 (X»H, A-H, RgaSMe) 20 (X=H, A-H, Rg^SMej

[0607] 13 (X=F, A=H, R6=Cl) 21 (X=F, A=H,

[0608]

[0609] 14 (X=CH3, A=H, R6=Cl) 22 (X=CH3, A=H, R6=Cl)

[0610] Reagents and conditions: a) i) NaNO2sol, HCl 37%, 0°C, 30 min; ii) SnCh ^lhO, HCl 37%, 0°C, 2h. b) 2,3 -dihydrofuran, l,4-dioxane / H2O (15:1), 95°C, 4h. c) 2,3-dihydrofuran, tartaric acid / DMU 4:6, 70°C, 16 h.GENERAL PROCEDURE A

[0611] In a one-necked flask, the appropriate aniline (4-fluoro-2-iodoaniline 1, 3g, 1 eq; 4-fluoro-2-bromoaniline 2, 8 g, 1 eq; 2-iodo-4-methyleneylin 3, 3 g, 1 eq, 2-bromo-3-fluoroaniline4, 4 g, 1 eq, 4-fluoro-2-(methylthio)aniline 5, 2 g, 1 eq, 2-(methylthio) aniline 6, 1 g, 1 eq) was suspended in 37 % HC1 (27 mL) and allowed to stir for 30 min at 0 °C. Subsequently, an aqueous NaNOi solution (2 eq) was added dropwise to the reaction mixture and left to stir for 30 minutes at 0 °C. After 30 minutes, this mixture was added to a suspension of SnCh-2 H2O (3 eq) in 37% HC1 (14 mL) and left to mechanically stir for 2h. At the end of the reaction, the mixture was filtered under vacuum on biichner and the obtained solid was treated with a 4M NaOH solution and extracted with DCM and H2O. The organic phases were dried over anhydrous Na2SO4 and the desired hydrazine was precipitated as hydrazine hydrochloride by the addition of a 6 M HC1 solution in 1,4-dioxane. The solvent was removed by evaporation under reduced pressure and the solid obtained consisting of the products 4-fluoro-2-iodophenylhydrazine hydrochloride (7), 2-Bromo-4-fluorophenyl hydrazine hydrochloride (8), 2-iodo-4-methylphenyl hydrazine hydrochloride (9), 2-bromo-3 -fluorohydrazine hydrochloride (10), 4-Fluoro-2-(methylthio) hydrazine hydrochloride (11) and 2-(methylthio) hydrazine hydrochloride (12) were dried over P2O5 overnight and used directly in the next step, without further purification.

[0612] GENERAL PROCEDURE B

[0613] Hydrazine hydrochloride (7-10, 1 eq) was dissolved in a flask in l,4-Dioxane / H2O (45 mL / 3 mL) and following addition of 2,3 -dihydrofuran (1.5 eq), the mixture was left stirring under N2 at 95 °C for 4 h. At the end of the reaction, the mixture was brought to room temperature (RT), vacuum filtered and concentrated by evaporation of the solvent under reduced pressure. The product was extracted with EtOAc (3 x 25 mL) and H2O (30 mL) and the organic phases were dried over anhydrous Na2SO4. Once the solvent was removed by vacuum evaporation, the crude product was purified by flash chromatography and dried over P2O5 overnight, thus obtaining the desired pure 15-18 indole derivative.

[0614] GENERAL PROCEDURE C

[0615] In a two-necked flask a mixture of tartaric acid and dimethylurea (DMU) 40:60 was heated at 70°C until melted. Hydrazines hydrochloride 11-14 (1 eq) and 2,3-dihydrofuran (2 eq) were added to the mixture and the reaction was allowed to proceed under stirring for 16 h under a nitrogen atmosphere at 70°C. The still hot mixture is then treated with 10% NaOH, extracted with DCM (3 x 25 mL), the combined organic phases are dried over Na2SO4, and evaporated. The crude product was then suitably purified by flash chromatography, as indicated, to afford the desired indole 19-22.Example 2. Synthesis of 2-(5-fluoro-7-iodo-lH-indol-3-yl)ethanol (15). Compound 15 was obtained by reacting intermediate 7 (3.63 g, 12.6 mmol) with 2, 3 -dihydrofuran (1.42 mL, 18.8 mmol) in 1,4-dioxane / H2O (40 mL / 3 mL) according to the general procedure described in Example 1, Method B. The crude product was purified by flash chromatography, using an 8:2 PE / Acetone mixture as eluent. The pure product 15 is obtained as a yellow coloured solid (yield: 30%).JH NMR (600 MHz, CDCh) 68,12 (s, 1H, NH), 7,33 (dd, J = 8,5, 2,2 Hz, 1H, ArH6), 7,28 - 7,22 (m, 1H, ArH4), 7,17 (d, J = 1,9 Hz, 1H, ArH2), 3,87 (t, J = 6,4 Hz, 2H, C2CH2OH), 2,93 (t, J = 6,3 Hz, 2H, CH2C2OH), 1,66 (s, 1H, OH).13C NMR (151 MHz, CDCh) 6 157,24 (d, JC-F = 239,4 Hz), 135,31, 127,07, 124,75, 119,17, 114,49, 104,34, 75,49, 62,55, 28,95. MS-ESI [M]': m / z 304.

[0616] Example 3. Synthesis of 2-(7-Bromo-5-fluoro-lH-indol-3-yl)ethanol (16).

[0617] Compound 16 was obtained by reacting intermediate 8 (8.51 g, 35.2 mmol) with 2,3-dihydrofuran (3.98 mL, 52.9 mmol) in 1,4-dioxane / H2O (45 mL / 3 mL) according to the general procedure described in Example 1, Method B. The product was purified by flash chromatography, using an 8:2 PE / Acetone mixture as eluent. The pure product 16 is obtained as a yellow solid (yield: 39%).1H NMR (600 MHz, CDCh) 8 8,30 (s, 1H, NH), 7,23 (dd, J = 9,10, 2,22 Hz, 1H, ArH6), 7,16 (dd, J = 8,64, 2,27 Hz, 2H, two signals: ArH4, ArH2), 3,88 (t, J = 6,38 Hz, 2H, C2CH2OH), 2,95 (t, J = 6,35 Hz, 1H, CH2C2OH), 1,79 (s, 1H, OH).13C NMR (151 MHz, CDCh) 6 157,32 (d, JC-F= 238,7 Hz), 132,06, 128,25, 124,90, 114,26, 113,54, 104,36, 103,60, 62,61, 28,86. MS [M-H]': m / z = 256 / 258.

[0618] Example 4. Synthesis of 2-(7-iodo-5-methyl-lH-indol-3-yl)ethanol (17). Compound 17 was obtained by reacting intermediate 9 (3.66 g, 12.8 mmol) with 2, 3 -dihydrofuran (1.45 mL, 19.2 mmol) in 1,4-dioxane / H2O (20 mL / 1.5 mL) according to the general procedure described in Example 1, Method B. The crude product was purified by flash chromatography using DCM / EtOAc 98:2 as eluent to give a yellow solid (yield: 38%). %).1H NMR (600 MHz, CDCh) 6 8,07 (s, 2H, NH), 7,42 (d, J = 0,76 Hz, 1H, H4), 7,37 (d, J = 0,77 Hz, 1H, H6), 7,09 (d, J = 2,38 Hz, 1H, H2), 3,89 (t, J = 6,39 Hz, 2H), 2,97 (td, J = 6,39, 0,87 Hz, 2H, C2CH2OH).

[0619] 2,43 (s, 3H, CH2CH3). 1,63 (s, 1H, OH).13C NMR (151 MHz, CDCh) 6 136,83, 132,25, 130,89, 127,71, 123,09, 118,91, 113,49, 76,47, 67,19, 62,71, 29,07. MS [M-H]': m / z = 300.

[0620] Example 5. Synthesis of 2-(7-Bromo-6-fluoro-lH-indol-3-yl)ethanol 18. Compound 18 was obtained by reacting intermediate 10 (4.23 g, 17.5 mmol) with 2,3-dihydrofuran (1.98 mL, 26.3 mmol) in 1,4-dioxane / H2O (47 mL / 8 mL) according to the general procedure described in Example 1, Method B. The crude product was purified by flash chromatography using DCM / acetone 95:5 as eluent (yield 4.6%). 'H NMR (600 MHz, CDCh) 6 8,25 (s, 1H,NH), 7,46 (ddt, J = 8,61, 4,65, 0,98 Hz, 1H, H4), 7,16 - 7,09 (m, 1H, H2), 6,99 - 6,90 (m, 1H, H5), 3,89 (td, J = 6,36, 0,95 Hz, 2H, C2CH2OH), 2,98 (td, J= 6,35, 0,94 Hz, 2H, CH2C772OH), 1,61 (s, 1H, OH).13C NMR (151 MHz, CDCh) 8 156,23 (d, J = 239,91 Hz), 135,70 (d, J = 5,13 Hz), 124,81, 123,26 (d, J = 3,60 Hz), 118,68 (d, J = 9,29 Hz), 114,11, 109,11 (d, J = 24,72 Hz), 91,24 (d, J = 26,02 Hz), 62,74, 28,83. MS [M-H]’: m / z = 256 / 258.

[0621] Example 6. Synthesis of 2-(5-fluoro-7-(methylthio)-lH-indol-3-yl)ethan-l-ol (19).

[0622] The reaction was carried out with compound 11 (2.67 g, 12.8 mmol), 2, 3 -dihydrofuran (1.94 mL, 25.6 mmol), tartaric acid / DMU 40:60 (24 g) according to the procedure described in Example 1, Method C. The crude product was purified by flash chromatography using a mixture of 98:2 DCM / MeOH as eluent, yielding pure product 19 as a red solid (yield 49%).1H NMR (600 MHz, CDCh) 6 8,31 (s, 1H, NH), 7,16 - 7,10 (m, 2H, ArH6.2), 6,97 (dd, J = 9,5, 2,2 Hz, 1H, ArH4), 3,87 (t, J = 6,4 Hz, 2H, CH2OH), 2,96 (t, J = 6,3 Hz, 2H, CH2), 2,51 (s, 3H, SCH3), 1,96 (s, 1H, OH).13C NMR (151 MHz, CDCh) 6 157,95 (d, JC-F= 236,8 Hz), 132,66, 127,27 (d, JC-F= 10,0 Hz), 124,25, 120,73 (d, JC-F= 9,9 HZ), 113,44 (d, JC-F= 5,0 HZ), 111,11 (d, JC-F = 27,8 Hz), 102,57 (d, JC-F= 23,5 Hz), 62,61, 28,80, 17,30. MS [M-H]’: m / z = 224.

[0623] Example 7. Synthesis of 2-(7-(methylthio)-lH-indol-3-yl)ethan-l-ol (20). The reaction was carried out with compound 12 (0.4 g, 2.1 mmol), 2,3-dihydrofuran (0.32 mL, 4.2 mmol), tartaric acid / DMU 40:60 (4 g) according to the procedure described in Example 1, Method C. The crude product was purified by flash chromatography using a mixture of 98:2 DCM / MeOH as eluent, yielding pure product 20 as a red solid (yield 20%). 'H NMR (600 MHz, CDCh) 68,61 (s, 1H, NH), 7,55 (d, J = 7,9 Hz, 1H, ArH4), 7,29 (d, J = 7,3 Hz, 1H, ArH6), 7,14 (t, J = 7,6 Hz, 1H, ArH5), 7,03 (d, J = 1,7 Hz, 1H, ArH2), 3,91 (t, J = 6,5 Hz, 2H, CH2OH), 3,03 (t, J = 6,5 Hz, 2H, CH2), 2,55 - 2,47 (m, 3H, CH3), 2,22 (s, 1H, OH).13C NMR (151 MHz, CDCh) 6 136,60, 127,48, 124,06, 122,92, 120,23, 119,24, 118,05, 113,16, 62,75, 28,93, 17,91. MS [M-H]’: m / z = 206.

[0624] Example 8. Synthesis of 2-(7-chloro-5-fluoro-lH-indol-3-yl)ethan-l-ol (21). The reaction was carried out with commercial 2-chloro-4-fluorophenyl hydrazine hydrochloride 13 (1.0 g, 5.1 mmol), 2,3-dihydrofuran (0.77 mL, 10.2 mmol), tartaric acid / DMU 40:60 (9.7 g) according to the procedure described in Example 1, Method C. The crude product was purified by flash chromatography using a mixture of PE / EtOAc / MeOH 8: 1.5:0.5 as eluent, yielding pure product 21 as an orange solid (yield 21%). 'H NMR (300 MHz, CDCh) 6 8,50 (s, 1H, NH), 7,08 (dd, J = 15,1, 5,9 Hz, 1H, ArH4), 7,04 (s, 1H, ArH6), 6,91 (dd, J = 9,0, 2,1 Hz, 1H, ArH2), 3,78 (t, J = 6,4 Hz, 2H, CH2OH), 2,86 (t, J = 6,4 Hz, 2H, CH2), 2,31 (d, J = 14,1 Hz, 1H, OH).

[0625] 13C NMR (75 MHz, CDCh) 6 157,46 (d, JC-F = 235 Hz), 130,83, 128,78 (d, JC-F = 10,5 Hz),125,29, 116,95 (d, JC-F = 12,8 Hz), 114,14 (d, JC-F = 2 Hz), 110,79 (d, JC-F= 30 Hz); 103,14 (d, JC-F=2,3 Hz), 62,85, 28,96. MS [M-H]+: m / z = 214 / 216.

[0626] Example 9. 2-(7-chloro-5-methyl-lH-indol-3-yl)ethan-l-ol (22). The reaction was carried out with commercial 2-chloro-4-methylphenyl hydrazine hydrochloride 14 (1.5 g, 7.8 mmol), 2,3-dihydrofuran (1.18 mL, 15.6 mmol), tartaric acid / DMU 40:60 (14.8 g) according to the procedure described in Example 1, Method C. The crude product was purified by flash chromatography using a mixture of 98:2 DCM / MeOH as eluent to give pure product 22 as a yellow solid (yield 23%). 'H NMR (300 MHz, CDC13) 88,55 (s, 1H, NH), 7,08 (dd, J = 15,1, 5,9 Hz, 1H, ArH4), 7,04 (s, 1H, ArH6), 6,91 (dd, J = 9,0, 2,1 Hz, 1H, ArH2), 3,78 (t, J = 6,4 Hz, 2H, CH2OH), 2,86 (t, J = 6,4 Hz, 2H, CH2), 2,31 (d, J = 14,1 Hz, 1H, OH).13C NMR (75 MHz, CDCh) 6 157,46 (d, JC-F = 235 Hz), 130,83, 128,78 (d, JC-F= 10,5 Hz), 125,29, 116,95 (d, JC-F = 12,8 Hz), 114,14 (d, JC-F = 2 Hz), 110,79 (d, JC-F= 30 Hz), 103,14 (d, JC-F= 2,3 Hz), 62,85, 28,96. MS [M-H]’: m / z = 210 / 212.

[0627] Example 10. General procedure for the synthesis of intermediates 24-32

[0628] OH

[0629] xx^.-^...^a XV^r'\ J5.

[0630] — - AA^Z^^

[0631] R6h

[0632] 15 (X=F, A=H, R6=I) 24 (X=F, A=H,

[0633] 16 (X=F, A«H. R6=8<i 25 iX=F, A=H, Rs=Bf}

[0634] 17 (X=CH3, A=H, R6=I) 26 (X=CH3, A=H, R6=I)

[0635] 18 (X=H, A=F, R6=Br) 27 (X=H, A=F, R6=Br)

[0636] 19 (X=F, A=H, R6=SMe) 28 (X=F, A=H, R6=SMe)

[0637] 20 (X=H, A=H, R6=SMe) 29 (X=H, A=H, R6=SMe)

[0638] 21 (X=F, A=H, R6=Cl) 30 (X=F, A=H, R6=Cl)

[0639] 22 (X=CH3, A=H, R6=Cl) 31 (X=CH3, A=H, R6=Cl)

[0640]

[0641] 23 (X=F, A=H, R6=H) 32 (X=F, A=H, R6=H)

[0642] Reagents and conditions: a) methyl 3-oxopentanoate, BF3·OEt2, anhydrous DCM, 0 °C to 25 °C, 5h.

[0643] In a two-necked flask, in which an anhydrous and inert environment was created, a solution of indole (15-23, 1 eq) in anhydrous DCM was added by means of a gas-tight syringe. After the addition of methyl 3-oxopentanoate (1.5 eq), thanks to the use of a gas-tight syringe, the mixture was stirred at 0 °C. After 10 minutes, BF3·OEt2(1.3 eq) was added dropwise with a gas-tight syringe. Subsequently, the mixture was brought to room temperature and left to stir under N2for 5h. The reaction was treated with saturated NaHCOs solution and extracted with DCM. The organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4and concentrated by evaporation of the solvent under vacuum. The crude product was purified by flash chromatography to give the pure products 24-32.Example 11. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-iodo-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (24). Product 24 was obtained by reacting 15 (1.24 g, 4.06 mmol) with methyl 3-oxopentanoate (0.61 mL, 4.87 mmol), BF3·OEt2(0.41 mL, 3.25 mmol) in anhydrous DCM (31 mL) according to the general procedure described in Example 10. The crude product was purified by flash chromatography using a mixture of PE / EtOAc 9.5:0.5 as eluent. Pure product 23 was obtained as a white coloured solid (yield: 65%).JH NMR (600 MHz, CDCh) 89,22 (s, 1H, NH), 7,29 (dd, J = 8,6, 2,2 Hz, 1H, H7), 7,13 (dd, J = 9,1, 2,2 Hz, 1H, H5), 4,03-3,92 (m, 2H, H3), 3,76 (s, 3H, COOCH3), 3,00-2,93 (dd, J = 45,6, 16,6 Hz, 2H, CH2COOCH3), 2,76-2,69 (m, J = 15,2, 4,7 Hz, 2H, H4), 2,15-2,01 (m, J = 14,7, 7,3 Hz, 2H, CH2CH3), 0,84 (t, 3H, CH2C3).13C NMR (151 MHz, CDCh) 6 173,05, 157,20 (d, JC-F = 238,7 Hz), 139,06, 134,84, 126,02 (d, JC-F = 10,0 Hz), 118,43 (d, JC-F = 23,3 Hz), 109,85, 103,67 (d, JC-F = 26,2 Hz), 75,37 (d, JC-F = 8,7 Hz), 74,63, 60,4, 52,31, 42,76, 30,64, 22,47, 7,64. MS [M-H]’: m / z = 416.

[0644] Example 12. Synthesis of Methyl 2-(8-bromo-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (25). Product 25 was obtained by reacting 16 (3.0 g, 11.6 mmol) with methyl 3-oxopentanoate (2.2 mL, 11.7 mmol), BF3·OEt2(1.9 mL, 15.1 mmol) in anhydrous DCM (50 mL) according to the general procedure described in Example 10. The crude product was purified by flash chromatography, using a mixture of PE / EtOAc 95:5 as eluent. Pure product 25 was obtained as a white coloured solid (yield: 58%). 'H NMR (600 MHz, CDCh) 69,29 (s, 1H, NH), 7,13 - 7,09 (m, 2H, H57), 4,07-4,02 e 3,94-3,75 (m, 2H, H4), 3,75 (s, 3H, COOCH3), 3,04 - 2,90 (m, 2H, CH2COOCH3), 2,80-2,76 e 2,71-2,67 (m, 2H, H3), 2,17-2,11 e 2,04-1,98 (m, 2H, CH2CH3), 0,84 (t, J = 7,37 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCh) 6 173,11, 157,31 (d, JC-F = 238,16 Hz), 139,22, 131,48, 127,19 (d, JC-F = 10,07 Hz), 112,77 (d, JC-F = 29,09 Hz), 109,65 (d, JC-F = 4,85 Hz), 104,24 (d, J = 12,30 Hz), 102,89 (d, JC-F = 23,25 Hz), 74,69, 60,52, 52,33, 42,69, 30,57, 22,48, 7,63. MS [M-H]’: m / z = 368 / 370.

[0645] Example 13. Synthesis of Methyl 2-(l-ethyl-8-iodo-6-methyl-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (26). Product 26 was obtained by reacting 17 (1.48 g, 4.92 mmol) with methyl 3-oxopentanoate (0.74 mL, 5.9 mmol), BF3·OEt2(0.49 mL, 3.93 mmol) in anhydrous DCM (26 mL) according to the general procedure described in Example 10. The crude product was purified by flash chromatography using PE / AcOEt 95:5 as eluent yielding 26 as a white solid (66% yield).1H NMR (600 MHz, CDCh) 69,00 (s, 1H, NH), 7,37 (d, J = 0,70 Hz, 1H, ), 7,25 (s, OH), 4,08 - 3,87 (m, 2H), 3,75 (s, 3H), 3,04 - 2,89 (m, 2H), 2,83 - 2,67 (m, 2H), 2,41 (s, 1H), 2,09 (ddq, J = 81,38, 14,59, 7,34 Hz, 2H), 0,83 (t, J = 7,36 Hz,3H).13C NMR (151 MHz, CDCh ) 8 172,95, 137,07, 136,33, 131,72, 130,70, 126,74, 118,29, 109,18, 76,45, 74,78, 60,59, 52,28, 42,86, 30,70, 22,62, 21,14, 7,67. MS [M-H]': m / z = 412.

[0646] Example 14. Synthesis of Methyl 2-(8-bromo-l-ethyl-7-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (27). Product 27 was obtained by reacting 18 (0.571 g, 2.21 mmol) with methyl 3-oxopentanoate (0.167 mL, 1.33 mmol), BF3·OEt2(0.116 mL, 0.88 mmol) in anhydrous DCM (13 mL) according to the general procedure described in Example 6. The crude product was purified by flash chromatography using PE / AcOEt 98:2 as eluent yielding product 27 as a white solid (49% yield).1H NMR (600 MHz, CDCh) 89,33 (s, 1H, NH), 7,33 (ddd, J = 8,52, 4,70, 0,67 Hz, 1H, H5), 6,91 (dd, J = 9,38, 8,51 Hz, 1H, H6), 4,08 - 3,89 (m, 2H, H4), 3,75 (d, J = 4,82 Hz, 3H, COOCH3), 3,04 - 2,88 (m, 2H, C2COOCH3), 2,82 - 2,70 (m, 2H, H3), 2,18 - 1,96 (m, 2H, C2CH3), 0,83 (t, J = 7,38 Hz, 3H, CH2C3).13C NMR (151 MHz, CDCh) 6 173,16, 155,91 (d, 7= 238,83 Hz), 137,46 (d, 7 = 3,65 Hz), 135,12 (d, 7 = 5,09 Hz), 123,84, 117,80 (d, 7 = 9,31 Hz), 109,38, 108,66 (d, 7 = 24,68 Hz), 91, 40 (d, 7 = 25,97 Hz), 74,68, 60,53, 52,31, 42,80, 30,59, 22,44, 7,64. MS [M-H]': m / z = 368 / 370.

[0647] Example 15. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(methylthio)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (28). The reaction was carried out with compound 19 (0.5 g, 2.22 mmol), methyl 3-oxopentanoate (0.33 mL, 2.66 mmol), BF3·OEt2(0.21 mL, 1.77 mmol) in anhydrous DCM (20 mL). The crude product was purified by flash chromatography using a 9: 1 PE / EtOAc mixture as eluent, to give pure product 28 (90% yield).

[0648] 1H NMR (600 MHz, CDCh) 69,24 (s, 1H, NH), 7,01 (dd, J = 9,2, 2,2 Hz, 1H, ArH7), 6,92 (dd, J = 9,6, 2,3 Hz, 1H, ArH5), 4,07 - 3,88 (m, 2H, OCH2-), 3,73 (s, 3H, COOCH3), 2,95 (dd, J = 49,4, 16,5 Hz, 2H, CH2COO-), 2,80 - 2,63 (m, 2H, CH2), 2,57 - 2,50 (m, 3H, SCH3), 2,06 (ddq, J = 80,5, 14,6, 7,4 Hz, 2H, C2CH3), 0,82 (t, J = 7,4 Hz, 3H, CH3).13C NMR (151 MHz, CDCh) 5 172,98, 157,91 (d, JC-F= 235,9 Hz), 138,33, 131,80, 126,17 (d, JC-F= 10,1 Hz), 120,54, 110,24 (d, JC-F = 27,5 Hz), 109,00 (d, JC-F = 4,7 Hz), 101,91 (d, JC-F = 23,3 Hz), 74,68, 60,55, 52,22, 42,73, 30,63, 22,38, 17,06, 7,63. MS [M-H]': m / z = 336.

[0649] Example 16. Synthesis of Methyl 2-(l-ethyl-8-(methylthio)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (29). The reaction was carried out with compound 20 (0.46 g, 2.23 mmol), methyl 3-oxopentanoate (0.34 mL, 2.68 mmol), BF3·OEt2(0.22 mL, 1.78 mmol) in DCM (20 mL). The crude product was purified by flash chromatography using a 9: 1 PE / EtOAc mixture as eluent, to give pure product 29 (90% yield). MS [MH]-: m / z = 318.

[0650] Example 17. Synthesis of Methyl 2-(8-chloro-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (30). The reaction was carried out with compound 21 (0.2 g, 0.94 mmol), methyl 3-oxopentanoate (0.14 mL, 1.13 mmol), BF3OEt2(0.09 mL,0.75 mmol) in anhydrous DCM (10 mL). The crude product was purified by flash chromatography using a 9: 1 PE / EtOAc mixture as eluent, to give pure product 30 (yield 99%).JH NMR (300 MHz, CDCh) 89,32 (s, 1H, NH), 7,07 (dd, J = 9,0, 2,2 Hz, 1H, ArH7), 6,97 (dd, J = 9,1, 2,2 Hz, 1H, ArH5), 4,09 - 3,86 (m, 2H, OCH2-), 3,75 (s, 3H, COOCH3), 2,97 (q, J = 16,6 Hz, 2H, CH2COO-), 2,83 - 2,63 (m, 2H, CH2), 2,08 (ddd, J = 44,0, 14,5, 7,3 Hz, 2H, C2CH3), 0,83 (t, J = 7,4 Hz, 3H, CH3).13C NMR (75 MHz, CDCh) 6 173,37, 157,50 (d, JC-F= 235,5 Hz), 139,38, 130,15, 127,72 (d, JC-F= 9,75 Hz), 116,88 (d, JC-F= 12,8 Hz), 110, 28 (d, Jc-F= 29,25 Hz), 109,77 (d, JC-F= 4,5 Hz), 102,61 (d, JC-F= 23,25 Hz), 74,95, 60,79, 52,58, 42,93, 30,84, 22,69, 7,90. MS [M-H]+: m / z = 328 / 326.

[0651] Example 18. Synthesis of Methyl 2-(8-chloro-l-ethyl-6-methyl-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (31). The reaction was carried out with compound 22 (0.38 g, 1.81 mmol), methyl 3-oxopentanoate (0.27 mL, 2.13 mmol), BF3-OEt2(0.18 mL, 1.45 mmol) in anhydrous DCM (10 mL). The crude product was purified by flash chromatography using a 9: 1 PE / EtOAc mixture as eluent, to give pure product 31 (yield 70%). 'H NMR (600 MHz, CDCh) 6 9,10 (s, 1H, NH), 7,18 (d, J = 0,5 Hz, 1H, ArH7), 7,01 (d, J = 0,7 Hz, 1H, ArH5), 4,08 - 3,88 (m, 2H, OCH2-), 3,73 (d, J = 2,0 Hz, 3H, COOCH3), 2,96 (dd, J = 51,9, 16,4 Hz, 2H, CH2COO-), 2,75 (ddd, J = 19,7, 11,5, 7,8 Hz, 2H, CH2), 2,43 (s, 3H, ArCH3), 2,08 (ddd, J = 81,8, 14,5, 7,3 Hz, 2H, C2CH3), 0,88 - 0,79 (m, 3H, CH3).13C NMR (151 MHz, CDCh) 8 172,91, 137,26, 131,37, 129,88, 128,17, 122,61, 116,71, 116,28, 108,79, 74,76, 60,59, 52,17, 42,81, 30,70, 22,48, 21,35, 7,64. MS (ESI positive) [M-H]+: m / z = 322 / 324.

[0652] Example 19. Synthesis of Methyl 2-(l-ethyl-6-fluoro-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (32). In a two-necked flask, in which an anhydrous and inert environment was created, a solution of commercial 2-(5-fluoro-lH-indol-3-yl)ethan-l-ol 23 (1 g, 5.58 mmol), methyl 3-oxopentanoate (1.2 eq, 0.84 mL, 6.70 mmol), BF3-OEt2(0.8 eq, 0.56 mL, was added 4.46 mmol) in anhydrous DCM (10.0 mL). The crude product was purified by reverse phase flash-chromatography (column AQ C18 spheres 20-35 pm 100 A 20g), using as eluent a mixture of CH3CN / H2O + 0.1% TFA with gradient from 30% to 60% CH3CN obtaining product 32 as a pale yellow oil (yield: 88%). Product 32 was dried over P2Os overnight.1H NMR (600 MHz, CDCh) δ 9,07 (s, 1H, NH), 7,28 - 7,24 (m, 1H, H8), 7,13 (dd, J = 9,5, 2,4 Hz, H7), 6,93 - 6,88 (m, 1H, H5), 4,06 - 3,91 (m, 2H, H3), 3,73 (s, 3H, COOCH3), 2,96 (dd, J = 60,5, 16,7 Hz, 2H, H13), 2,83 - 2,67 (m, 2H, H4), 2,18 - 1,93 (m, 2H, CH2CH3), 0,82 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCh) 6 173,25 (COOCH3), 157,85 (d, JC-F = 234,6 Hz, CF), 138,32 (C9), 132,20 (C12), 126,91 (Cn), 111,79 (C8), 109,96 (d, JC-F = 26,2 Hz, C5),108,33 (Cw), 103,29 (d, JC-F = 23,3 Hz, C7), 74,61 (Ci), 60,57 (C3), 52,09 (COOCH3), 42,66 (C13), 30,63 (CH2CH3), 22,31 (C4), 7,59 (CH2CH3). MS [M-H]’: m / z = 290.

[0653] Example 20. General procedure for the synthesis of compounds 33 and 34

[0654] :i: J3\

[0655] \ COOMesCOOMe

[0656] : H

[0657] OgS,

[0658] 28 (X=F) 33 (X=F)

[0659]

[0660] 29 (X=H} 34 (X=H)

[0661] Reagents and conditions: a) m-chloroperoxybenzoic acid, DCM, rt, 18 h.

[0662] To a solution of the appropriate ester 28-29 (leq) in DCM cooled to 0°C, metachloroperoxybenzoic acid (mCPBA, 3 eq) is added. The reaction is allowed to proceed with stirring at room temperature for 16h. The mixture is then washed 3 times with 10% NaOH, the organic phase dried over Na2SO4 and evaporated. The crude Product was then purified by flash chromatography to give pure compounds 33-34.

[0663] Example 21. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(methylsulfonyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (33). The reaction was carried out with compound 28 (0.215 g, 0.64 mmol), mCPBA (0.33 g, 1.9 mmol), DCM (9.0 mL), according to the procedure given in Example 20. The crude product was purified by flash chromatography using a mixture of 98:2 DCM / MeOH as eluent to give pure compound 33 as a white solid (yield 31%). MS (ESI negative) [MH]-: m / z = 370.

[0664] Example 22. Synthesis of Methyl 2-(l-ethyl -8-(methylsulfonyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (34). The reaction was carried out with compound 29 (0.64 g, 2.0 mmol), mCPBA (1.04 g, 6.0 mmol), DCM (27.0 mL) according to the procedure given in Example 20. The crude product was purified by flash chromatography using a mixture of 98:2 DCM / MeOH as eluent to give pure compound 34 as a white solid (yield 33%). MS [MH]-: m / z = 352.Example 23. Synthesis of 2-(5-fluoro-7-(phenylsulfonyl)-lH-indol-3-yl)ethan-l-ol (35)

[0665]

[0666] Reagents and conditions: (a) sodium benzenesulfinate, Cu(OAc)2, NaOH 5M, DMSO, 120 °C, 4 h.

[0667] To a solution of compound 15 (0.500 g, 1.64 mmol, 1 eq) in DMSO (10 mL), Cu(OAc)2•H2O (1.30 g, 6.56 mmol, 4 eq), sodium benzenesulfinate (1.07 g, 6.56 mmol, 4 eq) and a 5 M aqueous NaOH solution (0.38 mL) were added and the mixture was heated to 120 °C and stirred under a nitrogen atmosphere for 4 hours. The mixture was then cooled to room temperature and filtered over a pad of Celite. The suspension was diluted with H2O and extracted with diethyl ether (3 x 10 mL). The organic extracts were washed with 0.25 M EDTA solution (10 mL), saturated NaCl solution (10 mL) and then dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel, PE / EtOAc / MeOH 8:1.5:0.5) to give 35 as a yellow solid (293 mg, 56% yield). 'H NMR (600 MHz, CDCh) 89,63 (s, 1H, NH), 7,98 (dd, J = 8,4, 1,1 Hz, 2H, ArH2.6’), 7,58 - 7,54 (m, 1H, ArH4), 7,50 - 7,46 (m, 3H, ArH3’-4’-5’), 7,43 (dd, J = 8,4, 2,3 Hz, 1H, ArH6), 7,27 (d, J = 2,0 Hz, 1H, ArH2), 3,87 (t, J = 6,3 Hz, 2H, CH2OH), 2,95 (t, J = 6,3 Hz, 2H, C772CH2OH).13C NMR (151 MHz, CDCh) 6 156,52 (d, JC-F = 239,6 Hz), 141,61, 133,75, 130,76, 129,52, 129,37, 127,08, 126,44, 123,22, 113,52, 110,88, 110,68, 62,60, 28,38. MS (ESI negative) [M-H]’: m / z = 320.

[0668] Example 24. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(phenylsulfonyl)-, 3,4,9-tetrahydropyran [3,4-b] indol- 1-yl) acetate (36).

[0669]

[0670] Reagents and conditions: (a) methyl 3-oxopentanoate, BF3*OEt2, anhydrous DCM, rt, 5 h.

[0671] A solution of 35 (0.290 g, 0.91 mmol, 1 eq) in anhydrous DCM (14 mL) was added by syringe to a two-necked flask, maintained under an N2 atmosphere. Methyl 3-oxopentanoate (0.137 mL, 1.09 mmol, 1.2 eq) was added by a syringe and the mixture was cooled to 0 °C with stirring. BF3*OEt2 (0.090 mL, 0.73 mmol, 0.8 eq) was added dropwise using a syringe; then, the reaction was stirred at room temperature for 5 hours. The reaction was treated with saturated aqueous NaHCO3solution (25 mL) and extracted with DCM (3 x 30 mL). The pooled organic phases were washed with saturated NaCl solution (25 mL), dried over Na2SO4and evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel, PE / EtOAc 9:1) to provide 36 as a light yellow solid (220 mg, yield 56%). MS [MH]-: m / z = 430.

[0672] Example 25. General procedure for the synthesis of compounds 37-51

[0673] a, b or c - \ COQMe B

[0674] 24 37-51

[0675]

[0676] Table 2 shows the reagents used. Method A: K2CO3, Pd(dba)2, DME / H2O 1:1, 90 °C, 30 min. Method B: Pd(PPh3)4, K2CO3, 1, 4- dioxane / H2O 9:1, 90 °C, 3 h. Method C: Pd(PPh3)2(OAc)2, K3PO4, 1,4-dioxane / H2O 9:1, 90 °C, 2-3 h.

[0677] Table 2

[0678] Ri R2 R3R4

[0679] 37 H H H H

[0680] 38 H Cl H H

[0681] 39 H NHCOCH3 H H

[0682] 40 H CH2OH H H

[0683]

[0684] 41 H CONH2 H H

[0685] 42 H OH H H

[0686] 43 H H CH2OH H

[0687] 44 OH H H H

[0688] 45 Cl H H H

[0689] 46 H H Cl H

[0690] 47 H COCH3 H H

[0691] 48 H SO2CH3 H H

[0692] 49 H OCH3 H H

[0693] 50 Cl H H Cl

[0694] 51 H Cl H Cl

[0695]

[0696] GENERAL PROCEDURE METHOD A

[0697] To a solution of 24 (1 eq) in a 1:1 mixture of DME / H2O and Pd(dba)2(0.1 eq), the appropriate boronic acid (1 eq), K2CO3 (2 eq) were added and the mixture was heated to 90 °C with stirring under N2 atmosphere until complete consumption of the starting material. The mixture was cooled to RT and filtered. The filtrate was extracted with EtOAc (3 x 20 mL) or, when necessary, acidified by treatment with 2M HC1 (10 mL) and then extracted with EtOAc (3 x 20 mL). The pooled organic phases were washed with saturated NaCl solution (20 mL), dried over Na2SO4, and evaporated to dry. The crude product was purified by flash chromatography to give the corresponding methyl ester as indicated.

[0698] GENERAL PROCEDURE METHOD B

[0699] To a stirred solution of 24 (1 eq) in 1,4-dioxane are added Pd(PPh3)4(0.1 eq), an aqueous solution of K2CO3 (2 eq, in 0.5 mL of H2O) and the appropriate boronic acid (1 eq). The mixture was heated to 90 °C and stirred in a nitrogen atmosphere for 3 h. The mixture was then cooled to room temperature, filtered, extracted with DCM (3 x 20 mL), and the organic phases were washed with saturated NaCl solution (20 mL), dried over Na2SO4, and evaporated to dry conditions. The crude product was purified by flash chromatography as indicated.

[0700] GENERAL PROCEDURE METHOD C

[0701] To a solution of compound 24 (1 eq) in 1,4-dioxane was added Pd(PPh3)2(OAc)2 (0.1 eq) and the mixture was stirred vigorously for 10 minutes under N2 atmosphere. Subsequently, a solution of K3PO4 (2 eq) in H2O was added and the reaction mixture was heated to 90 °C. The appropriate boronic acid (1 eq), dissolved in a 9:1 1,4-dioxane / H2O mixture, was addeddropwise and the reaction was stirred for 3-15 h at 90 °C. The reaction was monitored by TLC and, if not complete, 0.7 eq of the appropriate boronic acid was added to the mixture. After 1 hour, the reaction was cooled to RT and filtered. The filtrate was extracted with EtOAc (3 x 20 mL), the organic phases were washed with saturated NaCl solution, dried over Na2SO4and evaporated under reduced pressure. The crude product was purified by flash chromatography as indicated.

[0702] Example 26. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-phenyl-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (37). Product 37 was obtained by reacting 24 (0.080 g, 0.19 mmol) with phenylboronic acid (0.024 mg, 0.19 mmol), K2CO3 (0.053 g, 0.38 mmol), Pd(dba)2(0.011 g, 0.019 mmol) in DME / H2O (4 mL) following the general procedure of Example 25, Method A. Reaction time: 2 h. The crude product was purified by flash chromatography using a 6:4 PE / DCM mixture as eluent. Product 37 was obtained as a white solid (95% yield). MS [MH]-: m / z = 366.

[0703] Example 27. Synthesis of Methyl 2-(8-(3-chlorophenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (38). Product 38 was obtained by reacting 24 (0.200 g, 0.48 mmol) with (3 -chlorophenyl) boronic acid (0.075 mg, 0.48 mmol), K2CO3 (0.133 g, 0.96 mmol), Pd(dba)2(0.028 g, 0.048 mmol) in DME / H2O (8 mL) following the general procedure of Example 25, Method A. Reaction time: 10 min. The crude product was purified by flash chromatography using a 1: 1 PE / DCM mixture as eluent. Product 38 was obtained as a yellow oil (yield 57%). MS (ESI negative) [MH]-: m / z = 400 / 402.

[0704] Example 28. Synthesis of Methyl 2-(8-(3-acetamidophenyl)-l-ethyl-6-fluoro-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (39). Product 39 was obtained by reacting 24 (0.200 g, 0.48 mmol) with (3-acetamidophenyl)boronic acid (0.086 mg, 0.48 mmol), K2CO3 (0.133 g, 0.96 mmol), Pd(dba)2(0.028 g, 0.048 mmol) in DME / H2O (8 mL) following the general procedure of Example 25, Method A. Reaction time: 15 min. The crude product was purified by flash chromatography using a mixture of PE / EtOAc / MeOH 7:2:1 as eluent. Product 39 was obtained as an orange solid (yield 94%). MS [MH]-: m / z = 423.

[0705] Example 29. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-(hydroxymethyl)phenyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (40). Product 40 was obtained by reacting 24 (0.200 g, 0.48 mmol) with (3- (hydroxy methyl)phenyl)boronic acid (0.073 g, 0.48 mmol), K2CO3 (0.133 g, 0.96 mmol), Pd(dba)2(0.028 g, 0.048 mmol) in DME / H2O (8 mL) following the general procedure of Example 25, Method A. Reaction time: 20 min. The crude product was purified by flash chromatography using a mixture of PE / EtOAc / MeOH 8: 1.5:0.5 as eluent Product 40 was obtained as a white solid (yield 99%). MS (ESI negative) [MH]-: m / z = 396.Example 30. Synthesis of Methyl 2-[8-(3-carbamoylphenyl)-l-ethyl-6-fluoro-4,9-dihydro-3 H-pyran[3,4-b]indol-l-yl]acetate (41). Product 41 was obtained by reacting 24 (0.150 g, 0.36 mmol) with (3 -carbamoylphenyl) boronic acid (0.059 g, 0.36 mmol), K2CO3 (0.100 g, 0.72 mmol), Pd(dba)2(0.021 g, 0.036 mmol) in DME / H2O (8 mL) following the general procedure of Example 25, Method A. Reaction time: 15 min. The crude product was purified by flash chromatography using a 98:2 DCM / MeOH mixture as eluent. Product 41 was obtained as a yellow solid (81% yield). MS [MH]-: m / z = 409.

[0706] Example 31. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-hydroxyphenyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (42). Product 42 was obtained by reacting 24 (0.150 g, 0.36 mmol) with (3 -hydroxyphenyl) boronic acid (0.050 g, 0.36 mmol), K2CO3 (0.100 g, 0.72 mmol), Pd(dba)2(0.021 g, 0.036 mmol), DME / H2O (7 mL) following the general procedure of Example 25, Method A. The reaction mixture was treated with 2M HC1 after filtration and before extraction with EtOAc. Reaction time: 20 min. The crude product was purified by flash chromatography using a mixture of PE / EtOAc / MeOH 7:2:1 as eluent. Product 42 was obtained as a yellow oil (99% yield). MS [MH]-: m / z = 382.

[0707] Example 32. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(4-(hydroxymethyl) phenyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (43). Product 43 was obtained by reacting 24 (0.180 g, 0.43 mmol) with (4-(hydroxymethyl)phenyl)boronic acid (0.066 g, 0.43 mmol), K2CO3 (0.119 g, 0.86 mmol), Pd(dba)2(0.025 g, 0.043 mmol) in DME / H2O (7 mL) following the general procedure of Example 25, Method A. Reaction time: 15 min. The crude product was purified by flash chromatography using a mixture of PE / EtOAc / MeOH 8:1.5:0.5 as eluent. Product 43 was obtained as a brown solid (yield 72%). MS [MH]-: m / z = 396.

[0708] Example 33. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(2-hydroxyphenyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (44). Product 44 was obtained by reacting 24 (0.150 g, 0.36 mmol), with (2-hydroxyphenyl) boronic acid (0.050 g, 0.36 mmol), K2CO3 (0.100 g, 0.72 mmol), Pd(dba)2(0.021 g, 0.036 mmol), DME / H2O (7 mL) following the general procedure of Example 25, Method A. The reaction mixture was treated with 2M HC1 after filtration and before extraction with EtOAc. Reaction time: 20 min. The crude product was purified by flash chromatography using a mixture of PE / EtOAc / MeOH 7:2:1 as eluent. Product 44 was obtained as a white solid (94% yield). MS [MH]-: m / z = 382.

[0709] Example 34. Synthesis of Methyl 2-(8-(2-chlorophenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (45). Product 45 was obtained by reacting 24 (0.150 g, 0.36 mmol) with (2-chlorophenyl) boronic acid (0.056 g, 0.36 mmol), K2CO3 (0.100 g, 0.72 mmol), Pd(dba)2(0.021 g, 0.036 mmol) in DME / H2O (7 mL) following the generalprocedure of Example 25, Method A. Reaction time: 30 min. The crude product was purified by flash chromatography using a 9:1 PE / EtOAc mixture as eluent. Product 45 was obtained as a white solid (yield 41%). MS [MH]-: m / z = 400 / 402.

[0710] Example 35. Synthesis of Methyl 2-(8-(4-chlorophenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (46). Product 46 was obtained by reacting 24 (0.150 g, 0.36 mmol) with (4-chlorophenyl) boronic acid (0.056 g, 0.36 mmol), K2CO3 (0.100 g, 0.72 mmol), Pd(dba)2(0.021 g, 0.036 mmol) in DME / H2O (7 mL) following the general procedure of Example 25, Method A. Reaction time: 30 min. The crude product was purified by flash chromatography using pure DCM as eluent. Product 46 was obtained as a white solid (81% yield). MS (ESI negative) [MH]-: m / z = 400 / 402.

[0711] Example 36. Synthesis of Methyl 2-(8-(3-acetylphenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (47). Product 47 was obtained by reacting 24 (0.100 g, 0.24 mmol) with 1’ (3 -acetylphenyl) boronic acid (0.039 g, 0.24 mmol), K2CO3 (0.066 g, 0.48 mmol), Pd(dba)2(0.014 g, 0.024 mmol) in DME / H2O (4.7 mL) following the general procedure of Example 25, Method A. Reaction time: 30 min. The crude product was purified by flash chromatography using a mixture of PE / EtOAc / MeOH 8.25:1.5:0.25 as eluent. Product 47 was obtained as a yellow solid (yield 48%). MS [MH]-: m / z = 408.

[0712] Example 37. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-(methylsulfonyl) phenyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (48). The synthesis of compound 48 was performed following the procedure of Example 25, method B. To a stirred solution of 24 (0.100 g, 0.24 mmol, 1 eq) in 1,4-dioxane (5 mL), Pd(PPh3)4(0.028 g, 0.024 mmol, 0.1 eq), an aqueous solution of K2CO3 (0.066 g, 0.48 mmol, are added 2.48 mmol) in 0.5 mL of H2O and (3-(sulfonyl) phenyl) boronic acid (0.048 g, 0.24 mmol). The mixture is heated to 90 °C and stirred in a nitrogen atmosphere for 3 h. The mixture was then cooled to room temperature, filtered, and extracted with DCM (3 x 20 mL). The organic phases are washed with saturated NaCl solution, dried over Na2SO4and evaporated under reduced pressure. The crude product was purified by flash chromatography using a mixture of PE / EtOAc 6.5:3.5 as eluent. Product 48 was obtained as a white solid (95% yield). MS [MH]-: m / z = 444.

[0713] Example 38. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-methoxyphenyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (49). Product 49 was obtained by reacting 24 (0.150 g, 0.36 mmol) with (3 -methoxyphenyl) boronic acid (0.055 g, 0.36 mmol), K3PO4 (0.153 g, 0.72 mmol), Pd(PPh3)2(OAc)2 (0.027 g, 0.036 mmol) in l,4-dioxane / H2O (22 mL) following the general procedure of Example 25, Method C. The crude product was purified by flashchromatography using a 9:1 PE / EtOAc mixture as eluent. Product 49 was obtained as a white solid (yield 76%). MS [MH]-: m / z = 396.

[0714] Example 39. Synthesis of Methyl 2-(8-(3,5-dichlorophenyl)-l-ethyl-6-fluoro-l,3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetate (50). Product 50 was obtained by reacting 24 (0.150 g, 0.36 mmol) with (3,5-dichlorophenyl) boronic acid (0.069 g, 0.36 mmol), K3PO4 (0.153 g, 0.72 mmol), Pd(PPh3)2(OAc)2(0.027 g, 0.036 mmol) in 1,4-dioxane / H2O (25 mL) following the general procedure of Example 25, Method C. The crude product was purified by flash chromatography using a mixture of PE / EtOAc 9.5:0.5 as eluent. Product 50 was obtained as a yellow oil (yield 78%). MS (ESI negative) [MH]-: m / z = 434 / 436 / 438.

[0715] Example 40. Synthesis of Methyl 2-(8-(2,5-dichlorophenyl)-l-ethyl-6-fluoro-l,3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetate (51). Product 51 was obtained by reacting 24 (0.150 g, 0.36 mmol) with (2,5-dichlorophenyl) boronic acid (0.069 g, 0.36 mmol), K3PO4 (0.153 g, 0.72 mmol), Pd(PPh3)2(OAc)2(0.027 g, 0.036 mmol) in 1,4-dioxane / H2O (25 mL) following the general procedure of Example 25, Method C. The crude product was purified by flash chromatography using a mixture of PE / EtOAc 9.5:0.5 as eluent. Product 51 was obtained as a yellow oil (yield 75%). MS [MH]-: m / z = 434 / 436 / 438.

[0716] Example 41. General procedure for the synthesis of compounds 52-56.

[0717] Z a or b T YWA - - | T V-4-A < NZCOOMe jH zHO._, OH 1 H / I B R7

[0718] RT

[0719]

[0720] 24 S2-57 Table 3 shows the reagents used. Conditions: (a) K2CO3, Pd(dba)2, 1,4-dioxane / H2O 9:1, 90 °C, 2h; (b) Pd(PPh3)2(OAc)2, K3PO4, 1,4-dioxane / H2O 9:1, 90 °C, 2-3h.Table 3

[0721] Compound R7

[0722] 53iTS

[0723] 54

[0724] -NH

[0725] 55

[0726] MM

[0727]

[0728] XZT- 0 1.

[0729] 56

[0730]

[0731] METHOD A

[0732] To a solution of 24 (1 eq) in 1,4-dioxane, Pd(dba)2(0.1 eq) was added with stirring under nitrogen. Subsequently, an aqueous solution of O.88M K2CO3 (2 eq) and the appropriately substituted boronic acid were added. The mixture was heated to 90°C and kept under stirring. After the reaction was concluded, the mixture was cooled and extracted under reduced pressure with EtOAc (3 x 20 mL) and the collected organic phases evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide the corresponding product 53. The products were characterized by MS (ESI) and used directly in the next step.

[0733] METHOD B

[0734] To a solution of 24 (1 eq) in 1,4-dioxane, Pd(PPh3)2(OAc)2 (0.1 eq) was added and the mixture was stirred vigorously for 10 minutes under a nitrogen atmosphere. Then a solution of K3PO4 (2 eq) in water (1.5 mL) was added and the reaction mixture was heated to 90 °C. Theappropriate boronic acid (1 eq), dissolved in a 9:1 1,4-dioxane / H2O mixture (3.5 mL), was added dropwise and the reaction was stirred for 3-5 hours at 90 °C. The reaction was monitored by TLC and 0.7 eq of the appropriate boronic acid was added to the mixture. After 2 hours, the reaction was cooled to room temperature and filtered. The filtrate was extracted with EtOAc (3 x 20 mL), the organic extracts were washed with saturated NaCl solution, dried over Na2SO4and evaporated to dryness. The crude product was purified by flash column chromatography to provide the corresponding product 52, 54-56. The products were characterized by MS (ESI) and used directly in the next step.

[0735] Example 42. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(pyridin-3-yl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (52). The reaction was carried out with 24 (0.100 g, 0.24 mmol), 3-pyridylboronic acid (0.030 g, 0.24 mmol), K3PO4 (0.102 g, 0.48 mmol), Pd(PPh3)2(OAc)2 (0.018 g, 0.024 mmol) in, 1,4-dioxane / H2O (17 mL) according to the procedure given in Example 41, Method B. After purification by flash column chromatography (silica gel, DCM / EtOAc 9:1) product 52 was obtained as a pale yellow solid (81 mg, yield 92%). MS [MH]-: m / z = 367.

[0736] Example 43. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(pyrimidin-5-yl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (53). To a solution of 24 (0.150 g, 0.36 mmol, 1 eq) in 1,4-dioxane were added Pd(dba)2(0.021 g, 0.036 mmol, 0.1 eq), an aqueous solution of K2CO3 (0.88 M, 0.80 mL, 2 eq) and 5-pyrimidinylboronic acid (0.045 g, 0.36 mmol, 1 eq) according to the procedure given in Example 41, Method A. The reaction mixture was heated to 90 °C and stirred under N2 atmosphere for 2 h. The mixture was cooled to room temperature, filtered and extracted with EtOAc (3 x 20 mL). The organic phases were washed with saturated NaCl solution, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel, DCM / EtOAc 7.5:2.5) to provide 53 as a yellow solid (41 mg, yield 31%). MS [MH]-: m / z = 368.

[0737] Example 44. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(l H-pyrazol-3-yl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (54). The reaction was carried out with 24 (0.150 g, 0.36 mmol), (1 H-pyrazol-3-yl) boronic acid (0.040 g, 0.36 mmol), K3PO4 (0.153 g, 0.72 mmol), Pd(PPh3)2(OAc)2(0.027 g, 0.036 mmol) in 1,4-dioxane / H2O (22 mL) according to the procedure given in Example 41, Method B. After purification by flash column chromatography (silica gel, DCM / EtOAc 9:1) product 54 was obtained as a white solid (112 mg, yield 87%). MS [MH]-: m / z = 356.Example 45. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(l-methyl-lH-pyrazol-5-yl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (55). The reaction was carried out with 24 (0.150 g, 0.36 mmol), (l-methyl-lH-pyrazol-5-yl) boronic acid (0.077 g, 0.61 mmol), K3PO4 (0.153 g, 0.72 mmol), Pd(PPh3)2(OAc)2(0.027 g, 0.036 mmol) in 1,4-dioxane / H2O (22 mL) according to the procedure given in Example 41, Method B. After purification by flash column chromatography (silica gel, DCM / EtOAc 9: 1) product 55 was obtained as a white solid (49 mg, yield 37%). MS [MH]-: m / z = 370.

[0738] Example 46. Synthesis of Methyl 2-(8-(cyclohex-l-en-l-yl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (56). The reaction was carried out with 24 (0.150 g, 0.36 mmol), cyclohex- 1-en-l-ylboronic acid (0.045 g, 0.36 mmol), K3PO4 (0.153 g, 0.72 mmol), Pd(PPh3)2(OAC)2(0.027 g, 0.036 mmol) in 1,4-dioxane / H2O (22 mL) according to the procedure given in Example 41, Method B. After purification by flash column chromatography (silica gel, DCM / EtOAc 9:1) product 56 was obtained as a light yellow solid (103 mg, yield 77%). MS [MH]-: m / z = 370.

[0739] Example 47. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(isoxazol-4-yl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (57).

[0740] y b a p

[0741] """) COOMe ~ COOMe

[0742] I K / -A f-: H /

[0743] !6...0, A\

[0744] B \':i

[0745]

[0746] 24 J.. 57

[0747] b~N

[0748] Reagents and conditions: a) K3PO4, Pd(PPh3)2(OAc)2, dioxane / H2O 9:1, 90 °C; b) LiOH 3M, 1,4-dioxane, RT, 16h.

[0749] The reaction was carried out with 24 (0.100 g, 0.24 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) isoxazole (0.047 g, 0.24 mmol), K3PO4(0.102 g, 0.48 mmol), Pd(PPh3)2(OAc)2(0.018 g, 0.024 mmol) in l,4-dioxane / H2O (17 mL). After purification by flash column chromatography (silica gel, PE / EtOAc 9:1) product 57 was obtained as a pale yellow oil (71 mg, yield 83%). MS [MH]-: m / z = 357.Example 48 - General procedure for the synthesis of compounds 58-61

[0750] 24 & 58 (Rf=H)

[0751] „ A ^ OH 59 (RI=OCH3) ' 60 (R,=C1)

[0752]

[0753] 61 (R,=F)

[0754] Reagents and conditions: Pd(dppf)Cl2, K2CO3, dioxane / H2O, 90 °C, 16 h.

[0755] To a solution of the ester (24, 1 eq) in 1,4-dioxane (2.5 mL), kept in an N2 atmosphere, were added Pd(dppf)Cl2(0.15 eq), a solution of K2CO3 (3 eq) in water (0.6 mL) and the appropriate 2-benzyl-4,4,5,5-tetramethyl-l,3,2-dioxoborolane (2 eq) or, where specified, the appropriate benzylboronic acid (2 eq). The reaction mixture was heated to 90 °C for 16 h. The reaction was then cooled to room temperature and vacuum filtered. The filtrate was extracted with Et20 (3 x 20 mL), the organic phases washed with saturated NaCl solution (30 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by flash chromatography as indicated. The final product was dried in a desiccator over P2O5 for 18 h to give the desired ester.

[0756] Example 49. Synthesis of Methyl 2-(8-benzyl-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (58)- METHOD A. The reaction was carried out with compound 24 (0.480 g, 1.15 mmol), benzylboronic acid (0.053 g, 2.3 mmol), K2CO3 (0.477 g, 3.45 mmol) in 1,4-dioxane (9 mL) and H2O (2 mL) following the procedure described in Example 48. The crude product was purified by flash chromatography using 95:5 PE / EtOAc as eluent to give 58 (yield 56%).1H NMR (600 MHz, CDCh) 6 8,93 (s, 1H, NH), 7,30 - 7,28 (m, 5H, H2’,3’,4’,5’,6’), 7,02 (dd, J = 9,5, 2,6 Hz, 1H, H7), 6,75 (dd, J = 10,0, 2,4 Hz, 1H, H5), 4,16 (s, 2H, H17), 4,04 - 3,87 (m, 2H, H3), 3,65 (s, 3H, COOC / L), 2,95 - 2,83 (m, 2H, H13), 2,79 -2,65 (m, 2H, H4), 2,10 - 1,88 (m, 2H, CW2CH3). 0,76 (t, J = 7,4 Hz, 3H, C 2CH3).13C NMR (151 MHz, CDCh) 5 172,97, 157,90 (d, JC-F = 234,6 Hz), 139,09, 137,96, 131,16, 128,96, 128,72, 126,67, 126,51, 124,94 (d, J = 8,7 Hz), 110,60 (d, JC-F = 26,2 Hz), 108,54, 101,51 (d, JC-F=23,3 Hz), 74,57, 60,51, 52,04, 42,47, 37,95, 30,56, 22,35, 7,57. MS [M-H]’: m / z = 380.Example 50. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(4-methoxybenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (59). The reaction was carried out with compound 24 (0.400 g, 0.359 mmol), 2-(4-methoxybenzyl)-4,4,5,5-tetramethyl-l,3,2-dioxoborolane (0.466 mL, 0.718 mmol), K2CO3 (0.398 g, 1.08 mmol) in 1,4-dioxane (3.5 mL) and H2O (1 mL) following the procedure described in Example 48. The crude product was purified by flash chromatography using 95:5 PE / EtOAc as eluent to give 59 (yield 68%).JH NMR (600 MHz, CDCh): 88,91 (s, 1H, NH), 7,20 (d, J = 8,8 Hz, 2H, H2,6’), 7,01 (dd, J = 9,2, 2,4 Hz, 1H, H7), 6.84 (d, J = 8,8 Hz, 2H, H3’,5’), 6,73 (dd, J = 10,0, 2,4 Hz, 1H, H5), 4,11 (s, 2H, CH2Ph), 4,03 -3,99 e 3,93 - 3,88 (m, 2H, H3), 3,78 (s, 3H, OCH3), 3,66 (s, 3H, COOCH3), 2,95 - 2,92 e 2,87 - 2.84 (m, 2H, C772COOCH3), 2,79-2,74 e 2,70 - 2,65 (m, 2H, H4), 2,09 - 2,03 e 1,98 - 1,90 (m, 2H, OCT). 0,77 (t, J = 7,4 Hz, 3H, CH2m).13C NMR (151 MHz, CDCh): 6 173,00, 158,37, 158,12 (d, JC-F = 234,6 Hz), 137,98, 131,20, 129,98, 126,69 (d, JC-F= 10,0 HZ), 125,45 (d, JC-F= 8,7 Hz), 114,18, 110,50 (d, JC-F= 26,2 HZ), 108,61, 101,45 (d, JC-F= 23,3 Hz), 74,64, 60,56, 55,38, 52,02, 42,54, 37,10, 30,64, 22,40, 7,62. MS [M-H]': m / z = 411.

[0757] Example 51. Synthesis of Methyl 2-(8-(4-chlorobenzyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (60). The reaction was carried out with compound 24 (0.200 g, 0.478 mmol), 2-(4-chlorobenzyl)-4,4,5,5-tetramethyl-l,3,2-dioxoborolane (0.053 g, 0.022 mmol), K2CO3 (0.199 g, 1.43 mmol) in 1,4-dioxane (2.5 mL) and H2O (0.5 mL) following the procedure described in Example 48. The crude product was purified by flash chromatography using 95:5 PE / EtOAc as eluent to give 60 (60% yield). 'H NMR (600 MHz, CDCh) 69,00 (s, 1H, NH), 7,31 - 7,23 (m, 2H, H2,6’), 7,24 - 7,20 (m, 2H, H3’,5’), 7,05 (dd, J = 9,2, 2,4 Hz, 1H, H7), 6,75 (dd, J = 9,9, 2,4 Hz, 1H, H5), 4,19 - 4,10 (m, 2H, CH2Ph), 4,05 -3,88 (m, 2H, H3), 3,67 (s, 3H, COOCH3), 2,98 - 2,84 (m, 2H, C772COOCH3), 2,81 - 2,66 (m, 2H, H4), 2,12 - 1,88 (m, 2H, CW2CH3), 0,79 (t, J = 7,4 Hz, 3H, CH2C / L).13C NMR (151 MHz, CDCh) 8 173,20, 157,92 (d, JC-F= 234,7 Hz), 138,27, 137,66, 132,35, 131,12, 130,32, 128,88, 126,87 (d, JC-F = 10,0 Hz), 124,31 (d, JC-F= 8,9 Hz), 110,68 (d, JC-F= 26,3 Hz), 108,68, 101,85 (d, JC-F = 23,2 Hz), 74,55, 60,54, 52,08, 42,48, 37,42, 30,60, 22,40, 7,59. MS [M-H]': m / z = 416 / 414.

[0758] Example 52. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(4-fluorobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (61). The reaction was carried out with compound 24 (0.200 g, 0.478 mmol), 2-(4-fluorobenzyl)-4,4,5,5-tetramethyl-l,3,2-dioxoborolane (0.053 g, 0.0718 mmol), K2CO3 (0.199 g, 1.43 mmol) in 1,4-dioxane (2.5 mL) and H2O (0.5 mL)following the procedure described in Example 48. The crude product was purified by flash chromatography using 95:5 PE / EtOAc as eluent, to give 61 (60% yield).JH NMR (600 MHz, CDCh) 8 8,99 (s, 1H, NH), 7,27 - 7,23 (m, 2H, H2,6), 7,05 (dd, J = 9,22, 2,39 Hz, 1H, H7), 7,01 - 6,97 (m, 2H, H3, 5 ), 6,75 (dd, J = 9,99, 2,57 Hz, 1H, H5), 4,15 (d, J = 4,55 Hz, 2H, CH2Ph), 4,04-4,00 e 3,93-3,89 (m, 2H, H3), 3,67 (s, 3H, COOCH3), 2,99-2,94 e 2,88-2,82 (m, 2H, C / ACOOMc), 2,80-2,75 e 2,71-2,67 (m, 2H, H4), 2,11-2,04 e 1,96-1,89 (m, 2H, CH2CH3), 0,79 (t, J = 7,33 Hz, 3H, CH2CH;).13C NMR (151 MHz, CDC13) 6 173,16, 161,76 (d, JC-F = 244,25 Hz), 157,94 (d, JC-F= 234,59 Hz), 138,21, 134,82 (d, JC-F= 2,95 Hz), 131,12, 130,41 (d, JC-F = 7,88 Hz), 126,83 (d, JC-F = 9,98 Hz), 124,72 (d, JC-F = 8,87 Hz), 115,53 (d, JC-F = 21,32 Hz), 110,61 (d, JC-F= 26,20 Hz), 108,67, 101,74 (d, JC-F= 23,20 Hz), 74,56, 60,54, 52,04, 42,48, 37,25, 30,58, 22,39, 7,58. MS [M-H]’: m / z= 398.

[0759] Example 53 - General procedure for the synthesis of intermediates 62-63.

[0760] i — \

[0761] X. J O n TW a orb - > COOMe 'COOMe

[0762] Ai H /

[0763] 26 (X~R A-H, R8=Br) 62 (X=E A=H)

[0764] 27 (X~H, A~F, R6~Br) 63 (X~H, A=F)

[0765]

[0766] 32 (X-F, A-H, R6=H)

[0767] Reagents and conditions: a) Pd2(dba)2, KO Ac, bis(pinacolate)diborane, tricyclohexylphosphine, 1,4-dioxane, 100 °C, 16h; b) [Ir(cod)OMe]2, 4,4’- di-tert-butyl-2,2’ -bipyridine, HBpin, anhydrous THF, 60 °C, 4h.

[0768] METHOD A

[0769] In a two-necked flask, after creating an anhydrous and inert environment, the appropriate ester (25 or 27, 1 eq) was dissolved in 1,4-dioxane. Anhydrous potassium acetate (4 eq) and bis (pinacolate) diborane (2 eq) are then added and the reaction was left to stir for 10 minutes at room temperature. Pd2(dba)2(0.015 eq) and PCy3(0.07 eq) are added to the mixture and three vacuum / nitrogen cycles were performed to recreate an anhydrous and inert environment. Thereaction was allowed to stir at 100 °C, under N2 flow, for 16h. At the end of the reaction, the mixture was filtered over Celite and brought to dryness by vacuum evaporation.

[0770] Example 54. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(4,4,5,5-tetramethyl-l,3,2-dioxoborolan-2-yl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (62). The reaction was carried out by dissolving derivative 25 (330 mg, 0.89 mmol) in 1,4-dioxane (10 mL) and then adding KOAc (350 mg, 3.57 mmol), bis(pinacolate)diborane (452 mg, 1.78 mmol), Pd2(dba)2 (12.3 mg, 0.0134 mmol) and PCy3(17.5 mg, 0.0624 mmol) according to the procedure given in Example 53, Method A. The crude product was purified by flash chromatography using 98:2 PE / Acetone as eluent and dried under vacuum on P2O5 for 18h. Thus, 62 is obtained as a white solid in yields of 85%.JH NMR (600 MHz, CDCh) 89,76 (s, 1H, NH), 7,28 (dd, J = 9,4, 2,6 Hz, 1H, H7), 7,23 - 7,21 (dd, J = 10,2, 2,4 Hz, 1H, H5), 4,04 - 3,88 (m, 2H, C H2O), 3,70 (s, 3H, COOCH3), 2,93 (dd, J = 35,4, 16,4 Hz, 2H, H13), 2,80 - 2,66 (m, 2H, C TOj. 2,17 -2,06 (m, 2H, C / 72CH3). 1,40 (d, J = 8,1 Hz, 12H, H6’_ T,8\ 9 ), 0,84 (t, J = 7,4 Hz, 3H, CH2CH3).

[0771] 13C NMR (151 MHz, CDCh) 6 172,36, 157,60 (d, JC-F = 234,3 Hz), 138,35, 137,61, 126,23, 126,17, 115,80, 106,95 (d, JC-F = 26,3 Hz), 84,20, 83,64, 74,88, 60,59, 51,78, 42,52, 31,06, 25,16, 22,36, 7,75. MS [M-H]’: m / z = 420.

[0772] Example 55. Synthesis of Methyl 2-(l-ethyl-7-fluoro-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (63). The reaction was carried out by dissolving derivative 27 (170 mg, 0.459 mmol) in 1,4-dioxane (6 mL) and then adding anhydrous potassium acetate (180 mg, 1.84 mmol), bis(pinacolate)diborane (233 mg, 0.92 mmol), Pd2(dba)2(6.3 mg, 0.0069 mmol) and PCy3 (9.0 mg, 0.0321 mmol), according to the procedure given in example 53, method A. The crude product was purified by flash chromatography using 98:2 PE / Acetone as eluent and vacuum dried over P2O5 for 18 h. Thus, 63 is obtained as a white solid in yields of 47%. 'H NMR (600 MHz, CDCh) 6 9,98 (s, 1H, NH), 7,50 (ddd, J= 8,50, 5,35, 0,63 Hz, 1H, H5), 6,81 (dd, J= 10,04, 8,52 Hz, 1H, H6), 4,06 -3,89 (m, 2H, H4), 3,71 (s, 3H, COOCH3), 3,01 - 2,88 (m, 2H, C772COOCH3), 2,84 - 2,67 (m, 2H, H3), 2, 19 - 2,05 (m, 2H, C772CH3), 1,44 (d, J = 7,00 Hz, 12H, (CH3)4), 0,85 (t, J = 7,38 Hz, 3H, CH2m). MS [M-H]’: m / z = 416.Example 56. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(4,4,5,5-tetramethyl-l,3,2-dioxoborolan-2-yl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (62).

[0773] METHOD B

[0774] In a two-necked flask, after creating an inert, anhydrous atmosphere, catalyst [Ir (cod) OMe] 2 (0.05 eq, 73.8 mg, 0.111 mmol) weighed under inert atmosphere (N2) was inserted. The flask is quickly connected to a condenser equipped with three routes and 3 vacuum / nitrogen cycles are performed to ensure an inert atmosphere. Using a gas-tight syringe, 4,4’-di-tert-butyl-2,2’-bipyridine (0.145 eq, 84.2 mg, 0.319 mmol) and methyl 2-(l-ethyl-6-fluoro-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate 32 (1 eq, 640 mg, 2.20 mmol) dissolved in 25 mL of anhydrous THF. Finally, pinacolborane (10 eq, 3.19 mL, 21.97 mmol) is added dropwise, using a gas-tight syringe to obtain a red solution. The reaction was allowed to stir at 60 °C for 4 hours under an inert atmosphere (N2). At the end of the reaction the mixture is brought to dry by evaporation of the solvent under reduced pressure and purified by flash chromatography with 98:2 PE / Acetone eluent, obtaining product 62 as a white solid in yields of 71%. The characterization of this compound is identical to that of the product obtained by method A.

[0775] Example 57. General procedure for the synthesis of compounds 58, 64-75

[0776] \ COOMeA1 H /

[0777] Y Y

[0778]

[0779] 62 (X»F, A~H}

[0780] 63(X«H, A«F)

[0781] Table 4 shows the reagents, the conditions used are: a) PdCl2(PPh3)2, Na2COs, THF / H2O 1:1, 40 °C, 16 h.Table 4

[0782] X A Ri R2 R3

[0783] 58 F H H H H

[0784] 64 H F H H H

[0785] 65 F H CH3H H

[0786] 66 F H Cl H H

[0787] 67 F H F H H

[0788] 68 F H H CH3H

[0789] 69 F H H Cl H

[0790] 70 F H H F H

[0791] 71 F H H OCH3H

[0792] 72 F H H CF3H

[0793] 73 F H H NO2H

[0794] 74 F H H CN H

[0795] 75 F H H H CH3

[0796]

[0797] Compound 62 or 63 (1 eq) was reacted with the properly substituted benzylbromide (1 eq), PdCl2(PPh3)2 (0.1 eq) and Na2CO3(2.5 eq) in a 1:1 THF / H2O mixture at 40 °C, under N2 flow, for 16 h. The reaction mixture was vacuum filtered and extracted with DCM (3 x 20 mL). The organic phases were dried over Na2SO4and brought to dryness by vacuum evaporation. Pure compounds 58, 64-75 were obtained following flash silica gel chromatography using the indicated eluent, vacuum dried over P2O5 for 18 h, and characterized by MS(ESI),1H, and13C NMR.

[0798] Example 58. Synthesis of Methyl 2-(8-benzyl-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (58)- METHOD B. The reaction was carried out with compound 62 (0.72 mmol, 300 mg), benzylbromide (0.72 mmol, 0.085 mL), (PPh3)2PdCl2(0.036 mmol, 25.2 mg), Na2CO3(1.8 mmol, 190.0 mg) in THF / H2O (7.0 mL / 7.0 mL) for 16 h according to the procedure described in Example 57. The crude product was purified by flash chromatography, using a 9: 1 PE / EtOAc mixture as eluent, yielding pure product 58 as a white solid (yield: 80%). 'H NMR (600 MHz, CDC13) 5: 8,93 (s, 1H, NH), 7,32 - 7,19 (m, 5H,H2’,3’,4’,5’,6’), 7,02 (dd, J = 9,51, 2,60 Hz, 1H, ArH7), 6,75 (dd, J = 9,51, 2,60 Hz ArH5), 4,17 (s, 2H, CH2Ph), 4,03 - 3,99 e 3,92-3,88 (m, 2H, H3a, H3b, 3,65 (s, 3H, COOCH3), 2,96 - 2,82 (m, 2H, CH2COOMe), 2,79-2,74 e 2,70-2,66 (m, 2H, H4a, H4b), 2,05-2,03 e 1,95-1,88 (m, 2H, C2aCH3, C2bCH3), 0,76 (t, J = 7,38 Hz, 3H, CH2C3).13C NMR (151 MHz, CDC13) 5: 173,03, 157,96 (d, JC-F = 234 Hz), 139,15, 138,02, 131,22, 129,02, 128,78, 126,70 (d, JC-F = 9,9 Hz), 126,57, 124,99 (d, JC-F = 9,1 Hz), 110,66 (d, JC-F = 26,2 Hz), 108,61 (d, JC-F = 4,7 Hz), 101,56 (d, JC-F = 23,2 Hz), 74,63, 60,57, 52,09, 42,52, 38,00, 30,61, 22,40, 7,62. MS [M-H]': m / z = 380.

[0799] Example 59. Synthesis of Methyl 2-(8-benzyl-l-ethyl-7-fluoro-l,3,4,9 tetrahydropyran[3,4-b]indol-l-yl)acetate (64). The reaction was carried out with compound 63 (0.192 mmol, 80 mg), benzylbromide (0.018 ml, 0.154 mmol), (PPh3)2PdCl2(7.0 mg, 0.0096 mmol), Na2CO3(50.8 mg, 0.48 mmol) in THF / H2O (7.0 mL / 7.0 mL) for 16 h according to the procedure described in Example 57. The reaction mixture was vacuum filtered and extracted with DCM (3 x 15 mL). The organic phases were dried over Na2SO4and brought to dryness by vacuum evaporation. Pure compound 63 was obtained following flash silica gel chromatography using Pe / AcOEt 95:5 as eluent, dried over P20s overnight (30% yield). 'H NMR (600 MHz, CDC13) 5 8,92 (s, 1H, NH), 7,37 - 7,29 (m, 2H, H2,6), 7,29 (ddd, J = 8,57, 5,02, 0,67 Hz, 1H, H5), 7,28 -7,25 (m, 2H, H3,5), 7,22 -7,13 (m, 1H, H4), 6,91 (dd, J = 10,29, 8,57 Hz, 1H, H6), 4,32 - 4,15 (m, 2H, CH2Ph), 4,05 - 3,85 (m, 1H, H3), 3,64 (s, 3H, COOCH3), 2,94 - 2,82 (m, 2H, CH2COOCH3), 2,81 - 2,65 (m, 2H, H4), 2,10 - 1,87 (m, 2H, C2CH3), 0,75 (t, J = 7,36 Hz, 3H, CH2C3).13C NMR (151 MHz, CDC13) 5 173,00, 157,41 (d, JC-F = 236,07 Hz), 139,50, 136,61 (d, JC-F = 3,38 Hz), 135,26 (d, JC-F = 8,63 Hz), 128,71, 126,36, 123,15, 117,03 (d, Jc-F= 10,38 Hz), 110,23 (d, JC-F = 20,84 Hz), 108,48, 108,14 (d, JC-F = 25,84 Hz), 74,59, 60,54, 52,03, 42,57, 30,63, 22,34, 7,61. MS [M-H]': m / z = 381.

[0800] Example 60. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(2-methylbenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (65). The reaction was carried out with compound 62 (0.48 mmol, 200 mg), 2-methylbenzylbromide (0.48 mmol, 0.064 mL), (PPh3)2PdCl2(0.048 mmol, 33.6 mg), Na2CO3(1.2 mmol, 127 mg) in THF / H2O (2.2 mL / 2.2 mL) for 16 h according to the procedure described in Example 57. The crude product was purified by flash chromatography, using a 95:5 PE / EtOAc mixture as eluent to give pure compound 65 (yield: 58%). 'H NMR (600 MHz, CDC13) 58,88 (s, 1H, NH), 7,22 -7,16 (m, 4H, H3’,4’,5’.6’), 7,02 (dd, J = 9,2, 2,4 Hz, 1H, H7), 6,56 (dd, J = 10,2, 2,4 Hz, 1H, H5), 4,16 (s, 2H, Hi7), 4,06 - 3,90 (m,2H, H3), 3,68 (s, 3H, COOC / L), 2,91 (dd, J = 47,6, 16,5 Hz, 2H, Hi3), 2,82 - 2,67 (m, 2H, H4), 2.28 (s, 3H, C CH32,09 - 1,90 (m, 2H, C2CH3), 0,78 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCh) 5 172,90, 158,10 (d, JC-F = 234,3 Hz), 137,87, 137,10, 136,93, 130,62, 130,60, 129,93, 126,99, 126,62 (d, J= 10,0 Hz), 126,39, 124,30 (d, J = 5,1 Hz), 110,32 (d, JC-F = 26,3 Hz), 108,60, 101,36 (d, JC-F = 23,3 Hz), 74,71, 60,60, 52,08, 42,64, 35,43, 30,70, 22,40, 19,79, 7,65. MS [M-H]': m / z = 394.

[0801] Example 61. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(2-chlorobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (66). The reaction was carried out with compound 62 (0.575 mmol, 240 mg), 2-chlorobenzylbromide (0.575 mmol, 0.075 mL), (PPh3)2PdCh (0.0575 mmol, 40.4 mg), Na2CO3(1.44 mmol, 152.6 mg) in THF / H2O (2.8 mL / 2.8 mL) for 16 h according to the procedure described in Example 57. The crude product was purified by flash chromatography, using a 9:1 PE / EtOAc mixture as eluent to give pure compound 66 (yield: 71%). 'H NMR (600 MHz, CDCh) 58,99 (s, 1H, NH), 7,42 - 7,40 (m, 1H, H6), 7,21 -7,15 (m, 3H, H3’,4’,5’), 7,03 (dd, J = 9,2, 2,4 Hz, 1H, H7), 6,66 (dd, J = 10,1, 2,4 Hz, 1H, H5), 4,28 (d, J = 1,6 Hz, 2H, H17), 4,05 - 3,90 (m, 2H, H3), 3,66 (s, 3H, COOCH3), 2,92 (dd, J = 48,8, 16,5 Hz, 2H, Hi3), 2,81 - 2,66 (m, 2H, H4), 2,12 - 1,92 (m, 2H, CH2CH3). 0,79 (t, J = 7,4 Hz, 3H, CH2C3).13C NMR (151 MHz, CDCh) 8 172,93, 158,01 (d, J = 234,9 Hz), 138,10, 136,75, 134,40, 131,24, 131,06, 129,80, 128,91, 128,15, 126,82 (d, J = 10,0 Hz), 123,42 (d, J = 8,7 Hz), 110,65 (d, JC-F = 26,3 Hz), 108,78, 101,75 (d, JC-F = 23,3 Hz), 74,73, 60,59, 52,09, 42,66, 34,95, 30,76, 22,42, 7,66. MS [M-H]': m / z = 414 / 416.

[0802] Example 62. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(2-fluorobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (67). The reaction was carried out with compound 62 (0.719 mmol, 300 mg), 2-fluorobenzylbromide (0.719 mmol, 0.09 mL), (PPh3)2PdCh (0.0719 mmol, 50 mg), Na2CO3(1.8 mmol, 190 mg) in THF / H2O (3.4 mL / 3.4 mL) for 16 h according to the procedure described in Example 57. The crude product was purified by flash chromatography, using a 9:1 PE / EtOAc mixture as eluent to give pure compound 67 (yield: 73%). 'H NMR (600 MHz, CDCh) δ 9,05 (s, 1H, NH), 7,24 - 7,18 (m, 2H, H4,6’), 7,09 - 7,03 (m, 2H, H3’,5’), 7,02 (dd, J = 9,2, 2,4 Hz, 1H, H7), 6,75 (dd, J = 10,0, 2,4, 0,4 Hz, 1H, H5), 4,17 (s, 2H, H17), 4,04 - 3,89 (m, 2H, H3), 3,68 (d, J = 2,1 Hz, 3H, COOCH3), 3,00 - 2,85 (m, 2H, Hi3), 2,73 (m, 2H, H4), 2,15 - 1,91 (m, 2H, CH2CH3). 0,79 (t, J = 7,4 Hz, 3H, CH2C3).13C NMR (151 MHz, CDCl3) δ 172,99, 161,08 (d, J = 246,2 Hz), 157,98 (d, J = 234,7 Hz), 138,13, 131,16, 128,46, 128,41, 126,85, 126,21, 124,42, 123,69 (d, J = 8,7 Hz), 115,60 (d, J = 22,3 Hz),110,50 (d, JC-F = 26,3 Hz), 108,79, 101,74 (d, JC-F = 23,3 Hz), 74,70, 60,58, 52,09, 42,62, 37,35, 30,71, 22,42, 7,65. MS [M-H]': m / z = 398.

[0803] Example 63. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-methylbenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (68). The reaction was carried out with compound 62 (0.48 mmol, 200 mg), 3 -methylbenzylbromide (0.48 mmol, 0.064 mL), (PPh3)2PdCl2(0.048 mmol, 33.6 mg), Na2CO3(1.2 mmol, 127 mg) in THF / H2O (2.2 mL / 2.2 mL) for 16 h according to the procedure described in Example 57. The crude product was purified by flash chromatography, using a 95:5 PE / EtOAc mixture as eluent to give pure compound 68 (yield: 79%). 'H NMR (600 MHz, CDCh) δ 8,95 (s, 1H, NH), 7,22 (t, J = 7,5 Hz, 1H, H5), 7,15 (s, 1H, H2), 7,12 (d, J = 7,6 Hz, 1H, H6), 7,05 (dd, J = 9,1, 2,2 Hz, 2H, H7,4), 6,79 (dd, J = 10,0, 2,4 Hz, 1H, H5), 4,15 (s, 2H, H17), 4,06 - 3,91 (m, 2H, H3), 3,69 (s, 3H, COOCH3), 2,99 - 2,86 (m, 2H, H13), 2,82 - 2,67 (m, 2H, H4), 2,35 (s, 3H, C3·CH3), 2,12 - 1,91 (m, 2H, C2CH3). 0,79 (t, J = 7,4 Hz, 3H, CH2C3).13C NMR (151 MHz, CDCh) 6 172,93, 157,95 (d, JC-F = 237,8 Hz), 139,06, 138,37, 137,96, 131,27, 129,78, 128,65, 127,30, 126,05, 125,19, 124,30 (d, J C-F = 5,1 Hz), 110,61 (d, JC-F = 26,1 Hz), 108,60, 101,47 (d, JC-F = 23,2 Hz), 74,64, 60,55, 52,00, 42,57, 38,02, 30,66, 22,39, 21,49, 7,60. MS [M-H]': m / z = 394.

[0804] Example 64. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-chlorobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (69). The reaction was carried out with compound 62 (0.719 mmol, 300 mg), 3 -chlorobenzylbromide (0.719 mmol, 0.09 mL), (PPh3)2PdCl2(0.0719 mmol, 50 mg), Na2CO3(1.8 mmol, 190 mg) in THF / H2O (3.4 mL / 3.4 mL) for 16 h according to the procedure described in Example 57. The crude product was purified by flash chromatography, using a 95:5 PE / EtOAc mixture as eluent to give pure compound 69 (yield: 68%). 'H NMR (600 MHz, CDCh) δ 9,07 (s, 1H, NH), 7,29 - 7,28 (m, 1H, H2), 7,23 - 7,18 (m, 1H, H5), 7,19 (m, 1H, H4), 7,17 (m, 1H, H6), 7,05 - 7,03 (dd, J = 9,1, 2,4 Hz, 1H, H7), 6,77 - 6,73 (dd, J = 10,0, 2,4 Hz, 1H, H5), 4,13 (d, J = 2,5 Hz, 2H, Hi7), 4,03 - 3,87 (m, 2H, H3), 3,67 (s, 3H, COOC3), 2,90 (dd, J = 51,4, 16,9 Hz, 2H, H13), 2,73 (m, 2H, H4), 2,10 - 1,88 (m, 2H, C2CH3), 0,77 (t, J = 7,4 Hz, 3H, CH2C3).13C NMR (151 MHz, CDCh) 6 173,25, 159,43 (d, J = 234,9 Hz), 139,37, 138,33, 134,59, 131,14, 129,98, 129,09, 128,50, 127,18, 126,81, 123,61 (d, J = 8,7 Hz), 110,71 (d, JC-F = 26,3 Hz), 108,73, 101,93 (d, JC-F = 23,3 Hz), 74,58, 60,59, 52,16, 42,55, 37,71, 30,59, 22,42, 7,61. MS [M-H]': m / z = 414 / 416.

[0805] Example 65. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-fluorobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (70). The reaction was carried out with compound62 (0.719 mmol, 300 mg), 3 -fluorobenzylbromide (0.719 mmol, 0.09 mL), (PPh3)2PdCl2(0.0719 mmol, 50 mg), Na2CO3(1.8 mmol, 190 mg) in THF / H2O (3.4 mL / 3.4 mL) for 16 h according to the procedure described in Example 57. The crude product was purified by flash chromatography, using a 95:5 PE / EtOAc mixture as eluent to give pure compound 70 (yield: 59%).1H NMR (600 MHz, CDCl3) δ 9,05 (s, 1H, NH), 7,27 - 7,22 (m, 1H, H5), 7,08 - 7,06 (m, 1H, H6), 7,04 (dd, J = 9,2, 2,4 Hz, 1H, H7), 7,00 - 6,97 (m, 1H, H2), 6,92 - 6,87 (m, 1H, H4), 6,76 (dd, J = 9,9, 2,4 Hz, 1H, H5), 4,19 - 4,12 (m, 2H, H17), 4,03 - 3,88 (m, 2H, H3), 3,67 (d, J = 1,8 Hz, 3H, COOCH3), 2,96 - 2,83 (m, 2H, H13), 2,79 - 2,64 (m, 2H, H4), 2,11 - 1,87 (m, 2H, C2CH3), 0,77 (t, J = 7,4 Hz, 3H, CH2C3).13C NMR (151 MHz, CDCl3) δ 173,22, 163,18 (d, J = 246,2 Hz), 157,93 (d, J = 234,7 Hz), 141,8, 138,28, 131,15, 130,20, 126,89, 124,65 (d, J = 8,7 Hz), 124,18, 115,95 (d, J = 21,4 Hz), 113,48 (d, J = 21,1 Hz) 110,68 (d, JC-F = 26,3 Hz), 108,73, 101,89 (d, JC-F = 23,3 Hz), 74,59, 60,57, 52,09, 42,51, 37,80, 30,59, 22,41, 7,60. MS [M-H]': m / z = 398.

[0806] Example 66. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-methoxybenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (71). The reaction was carried out with compound 62 (0.829 mmol, 340 mg), 3-methoxybenzyl bromide (0.829 mmol, 0.12 mL), (PPh3)2PdCl2(0.0829 mmol, 58 mg), Na2CO3(2.07 mmol, 219 mg) in THF / H2O (4 mL / 4 mL) for 16 h according to the procedure described in Example 57. The crude product was purified by flash chromatography, using a 9:1 PE / EtOAc mixture as eluent to give pure compound 71 (yield: 67%). 'H NMR (600 MHz, CDCh) δ 8,94 (s, 1H, NH), 7,23 - 7,18 (m, 1H, H5), 7,02 (dd, J = 9,3, 2,4 Hz, 1H, H7), 6,87 (dd, J = 4,1, 3,5 Hz, 1H, H2), 6,85 - 6,83 (m, 1H, H6), 6,75 (m, 2H, H4',5), 4,14 - 4,09 (m, 2H, Hi7), 4,02 - 3,88 (m, 2H, H3), 3,77 (s, J = 5,1 Hz, 3H, OCH3), 3,66 (s, 3H, COOCH3), 2,95 - 2,81 (m, 2H, H13), 2,79 - 2,64 (m, 2H, H4), 1,99 (m, 2H, C2CH3).

[0807] 0,76 (t, J = 7,4 Hz, 3H, CH2C3).13C NMR (151 MHz, CDCl3) δ 173,0, 160,01, 158,75 (d, J = 234,7 Hz), 140,76, 138,03, 129,76, 126,79, 126,72, 124,87 (d, J = 8,7 Hz), 121,42, 114,62, 112,17, 110,64 (d, JC-F = 26,3 Hz), 108,63, 101,52 (d, JC-F = 23,3 Hz), 74,66, 60,58, 55,26, 52,04, 42,57, 38,14, 30,67, 22,42, 7,62. MS [M-H]': m / z =410.

[0808] Example 67. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-(trifluoromethyl) benzyl)- 1,3, 4, 9-tetrahydropyran[3,4-b]indol-l-yl)acetate (72). The reaction was carried out with compound 62 (0.359 mmol, 150 mg), 1-bromomethy 1-3 -trifluoromethylbenzene (0.359 mmol, 0.055 mL), (PPh3)2PdCl2(0.0359 mmol, 25 mg), Na2CO3(0.898 mmol, 95 mg) in THF / H2O (1.7 mL / 1.7 mL) for 16 h according to the procedure described in Example 57. The crudeproduct was purified by flash chromatography, using a 95:5 PE / EtOAc mixture as eluent to give pure compound 71 (yield: 50%).1H NMR (600 MHz, CDCl3) δ 9,16 (s, 1H, NH), 7,59 (s, 1H, H2), 7,49 - 7,37 (m, 1H, H4,5’,6’), 7,05 (dd, J = 9,2, 2,4 Hz, 1H, H7), 6,78 - 6,73 (dd, J = 9,9, 2,4 Hz, 1H, H5), 4,26 - 4,17 (m, 2H, H17), 4,04 - 3,86 (m, 2H, H3), 3,65 (s, 3H, COOCH3), 2,90 (m, 2H, H13), 2,79 - 2,66 (m, 2H, H4), 2,07 - 1,84 (m, 2H, C / 72CH3), 0,76 (t, J = 7,4 Hz, CH2C3).13C NMR (151 MHz, CDCl3) δ 173,28, 157,79 (d, J = 234,7 Hz), 138,39, 136,17, 132,27, 130,95, 130,86, 128,53, 126,90, 123,76, 123,37 (d, J = 8,7 Hz), 121,11, 116,74, 110,61 (d, JC-F = 26,3 Hz), 108,37, 101,85 (d, JC-F = 23,3 Hz), 74,45, 60,50, 52,08, 42,44, 37,08, 30,47, 22,33, 7,52. MS [M-H]': m / z =448.

[0809] Example 68. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-nitrobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (73). The reaction was carried out with compound 62 (0.359 mmol, 150 mg), 1 -bromomethyl- 3 -nitrobenzene (0.359 mmol, 0.047 mL), (PPh3)2PdCl2(0.0359 mmol, 25 mg), Na2CO3(0.898 mmol, 95 mg) in THF / H2O (1.7 mL / 1.7 mL) for 16 h according to the procedure described in Example 57. The crude product was purified by flash chromatography, using a 95:5 PE / EtOAc mixture as eluent to give pure compound 73 (yield: 72%). 'H NMR (600 MHz, CDC13) δ 9,20 (s, 1H, NH), 8,22 (s, J = 1,9 Hz, 1H, H2), 8,08 (m, 1H, H4), 7,60 (d, J = 7,2 Hz, 1H, H6), 7,45 (t, J = 7,9 Hz, 1H, H5), 7,06 (dd, J = 9,2, 2,4 Hz, H7), 6,77 (dd, J = 9,8, 2,4 Hz, H5), 4,27 (m, 2H, Hi7), 4,05 - 3,86 (m, 2H, H3), 3,64 (s, J = 3,2 Hz, 3H, COOCH3), 2,89 (m, 2H, Hi3), 2,79 - 2,64 (m, 2H, H4), 2,05 - 1,82 (m, 2H, C / 72CH3), 0,77 (t, J = 7,4 Hz, 3H, CH2C3).13C NMR (151 MHz, CDCl3) δ 173,48, 157,87 (d, J = 234,7 Hz), 148,66, 141,38, 138,67, 135,16, 131,01, 129,65, 127,16, 123,93, 123,21 (d, J = 8,7 Hz), 121,82, 110,71 (d, JC-F = 26,3 Hz), 108,77, 102,34 (d, JC-F = 23,3 Hz), 74,47, 60,57, 52,15, 42,55, 37,79, 30,45, 22,38, 7,55. MS [M-H]': m / z =425.

[0810] Example 69. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-cyanobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (74). The reaction was carried out with compound 62 (0.359 mmol, 150 mg), l-bromomethyl-3 -cyanobenzene (0.359 mmol, 0.047 mL), (PPh3)2PdCl2(0.0359 mmol, 25 mg), Na2CO3(0.898 mmol, 95 mg) in THF / H2O (1.7 mL / 1.7 mL) for 16 h according to the procedure described in Example 57. The crude product was purified by flash chromatography, using a 95:5 PE / EtOAc mixture as eluent to give pure compound 74 (yield: 69%). 'H NMR (600 MHz, CDC13) 5 9,25 - 9,13 (m, 1H, NH), 7,62 (s, 1H, H6), 7,53 - 7,51 (m, 1H, H4), 7,51 - 7,49 (m, 1H, H2), 7,38 (dd, J = 9,6, 5,9 Hz, 1H, H3), 7,06 (dd, J = 9,2, 2,4 Hz, 1H, ArH7), 6,79 - 6,73 (m, 1H, H5), 4,22 - 4,10 (m, 2H, Hi7), 4,03 -3,86 (m, 2H, H3), 3,74 - 3,66 (m, 3H, COOCH3), 2,96 - 2,84 (m, 2H, H13), 2,78 - 2,66 (m, 2H, H4), 2,04 - 1,84 (m, 2H, C2CH3). 0,77 (t, J = 7,4 Hz, 3H, CH2C3).13C NMR (151 MHz, CDCl3) δ 173,45, 157,02, 140,75, 138,55, 133,44, 132,39, 130,94, 130,37, 129,48, 127,07, 123,17, 118,94, 112,78, 110,54, 108,74, 102,14,74,42, 60,51, 52,27,42,50, 37,63, 30,43,22,32, 7,51. MS [M-H]’: m / z =405.

[0811] Example 70. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(4-methylbenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (75). The reaction was carried out with compound 62 (0.24 mmol, 100 mg), 4-methylbenzylbromide (0.24 mmol, 0.032 mL), (PPha PdCh (0.012 mmol, 8.8 mg), Na2CO3(0.599 mmol, 63.5 mg) in THF / H2O (1.1 mL / 1.1 mL) for 16 h according to the procedure described in Example 57. The crude product was purified by flash chromatography, using a 95:5 PE / EtOAc mixture as eluent to give pure compound 75 (yield: 63%). 'H NMR (600 MHz, CDCh) δ 8,90 (s, 1H, NH), 7,19 - 7,09 (m, 4H, H2’,3’.5’,6’), 7,02 -7,00 (m, 1H, H7), 6,75 - 6,71 (m, 1H, H5), 4,12 (s, J = 7,9 Hz, 2H, H17), 4,03 - 3,88 (m, 2H, H3), 3,66 (s, J = 5,3 Hz, 3H, COOCH3), 2,95 - 2,83 (m, 2H, H13), 2,79 - 2,64 (m, 2H, H4), 2,31 (s, J = 6,9 Hz, 3H, C4·CH3), 2,09 - 1,89 (m, 2H, C2CH3). 0,76 (t, J = 7,4 Hz, 3H, CH2C3).

[0812] 13C NMR (151 MHz, CDCl3) δ 172,99, 158,78 (d, J = 235,0 Hz), 137,9, 136,08, 136,05, 131,25, 129,45, 128,91, 126,65 (d, J = 10,0 Hz), 125,29 (d, J = 8,7 Hz), 110,55 (d, JC-F = 26,3 Hz), 108,53, 101,46 (d, JC-F = 23,3 Hz), 74,65, 60,59, 52,02, 42,57, 37,57, 30,67, 22,35, 21,14, 7,63. MS [M-H]’: m / z =394.

[0813] Example 71. General procedure for the synthesis of compounds 76-86.

[0814] "sGOOMe - AH Z

[0815] o' 0 ^2 V'V' 'Bf. \'A# P:;

[0816]

[0817] Table 5 shows the reagents, the conditions used are: PdCl2(PPh3)2, Na2CO3, THF / H2O 1:1, 40 °C, 16 h.Table 5

[0818] Ri R2 R3R4Rs

[0819] 76 F Cl H H H

[0820] 77 F CH3H H H

[0821] 78 F H H H Cl

[0822] 79 F H F H H

[0823] 80 F H Cl H H

[0824] 81 Cl H F H H

[0825] 82 H F H F H

[0826] 83 H F H Cl H

[0827] 84 H OCH3H F H

[0828] 85 H Cl F H H

[0829] 86 H CH3F H H

[0830]

[0831] Compound 62 (1 eq) was reacted with properly di-substituted benzylbromide (1 eq), PdCl2(PPh3)2 (0.05-0.1 eq) and Na2CO3(2.5 eq) in a 1:1 THF / H2O mixture at 40 °C, under N2 flow, for 4-16 h. The reaction mixture was vacuum filtered and extracted with DCM (3 x 20 mL). The organic phases were dried over Na2SO4and brought to dryness by vacuum evaporation. Pure compounds 76-86 were obtained following flash silica gel chromatography using the indicated eluent, vacuum dried over P2O5 for 18 h, and characterized by MS(ESI),1H, and13C NMR.

[0832] Example 72. Synthesis of Methyl 2-(8-(3-chloro-2-fluorobenzyl)-l-ethyl-6-fluoro-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (76). The reaction was carried out with compound 62 (0.359 mmol, 150 mg), l-(bromomethyl)-3-chloro-2-fluorobenzene (0.359 mmol, 0.048 mL), (PPh3)2PdCl2(0.0359 mmol, 25 mg), Na2CO3(0.898 mmol, 95 mg) in THF / H2O (1.7 mL / 1.7 mL) for 16 h according to the procedure described in Example 71. The crude product was purified by direct phase flash chromatography, using a 9: 1 PE / EtOAc mixture as eluent to give pure compound 76 (yield: 32%).1H NMR (600 MHz, CDC13) δ 9,14 (s, 1H, NH), 7,28 - 7,24 (m, 1H, H4'), 7,12 - 7,09 (m, 1H, H2), 7,04 (dd, J = 9,2, 2,3 Hz, 1H, H7), 6,98 (td, J = 7,9, 1,1 Hz, 1H, H3), 6,75 (dd, J = 9,9, 2,3 Hz, 1H, H5), 4,25 - 4,14 (m, 2H, H17), 4,04 -3,88 (m, 2H, H3), 3,70 (s, 3H, COOCH3), 2,91 (dt, J = 41,3, 11,8 Hz, 2H, Hi3), 2,79 - 2,65 (m,2H, H4), 2,14 - 1,92 (m, 2H, C772CH3), 0,79 (t, J = 7,4 Hz, 3H, CH2C3).13C NMR (151 MHz, CDCl3) δ 173,10, 158,62, 157,06, 155,61, 138,30, 130,95, 129,27, 129,01, 127,99, 126,85, 124,67, 110,44, 108,72, 102,04, 74,57, 60,50, 52,11, 42,50, 36,04, 30,56, 22,33, 7,57. MS [M-H]’: m / z =432 / 434.

[0833] Example 73. Synthesis of Methyl 2-(8-(2-fluoro-3-methylbenzyl)-l-ethyl-6-fluoro-8-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (77). The reaction was carried out with compound 62 (0.359 mmol, 150 mg), l-(bromomethyl)-2-fluoro-3-methylbenzene (0.359 mmol, 0.05 mL), (PPh3)2PdCl2(0.0359 mmol, 25 mg), Na2CO3(0.898 mmol, 95 mg) in THF / H2O (1.7 mL / 1.7 mL) for 16 h according to the procedure described in Example 71. The crude product was purified by flash chromatography, using a 9:1 PE / EtOAc mixture as eluent to give pure compound 77 (yield: 47%).1H NMR (600 MHz, CDCh) δ 9,01 (s, 1H, NH), 7,07 - 7,05 (m, 1H, H2), 7,03 (d, J = 3,1 Hz, 1H, H4), 7,02 - 7,00 (m, 1H, H7), 6,95 - 6,91 (m, 1H, H3), 6,76 (dd, J = 10,1, 2,4 Hz, 1H, H5), 4,15 (s, 2H, H17), 4,04 - 3,90 (m, 2H, H3), 3,68 (s, 3H, COOCH3), 2,98 - 2,86 (m, 2H, H13), 2,79 - 2,65 (m, 2H, H4), 2,28 (dd, J = 4,8, 2,2 Hz, 3H, C5·CH3), 2,12 - 1,94 (m, 2H, C2CH3), 0,82 - 0,77 (m, 3H, CH2C3).13C NMR (151 MHz, CDCl3) δ 172,86, 160,36, 158,69, 157,13, 137,95, 131,07, 129,91, 128,47, 126,74, 125,75, 124,99, 123,83, 110,53, 108,66, 101,65, 74,66, 60,52, 53,50, 51,99, 42,58, 30,68, 22,34, 7,58. MS [M-H]’: m / z =412.

[0834] Example 74. Synthesis of Methyl 2-(8-(l-chloro-6-fluorobenzyl)-l-ethyl-6-fluoro-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (78). The reaction was carried out with compound 62 (0.478 mmol, 200 mg), 2-chloro-6-fluorobenzyl bromide (0.479 mmol, 0.065 mL), (PPh3)2PdCl2(0.024 mmol, 16.8 mg), Na2CO3(1.20 mmol, 127 mg) in THF / H2O (2.5 mL / 2.5 mL) for 4 h according to the procedure described in Example 71. The crude product was purified by flash chromatography using 9:1 PE / EtOAc as eluent mixture yielding pure compound 78 (yield: 36%). 'H NMR (600 MHz, CDCh) δ 9,21 (s, 1H, NH), 7,24 - 7,21 (m, 1H, H3), 7,19 (td, J = 8,1, 5,8 Hz, 1H, H5'), 7,04 (ddd, 7= 9,4, 8,1, 1,4 Hz, 1H, H4), 7,00 (dd, 7 = 9,1, 2,0 Hz, 1H, H7), 6,66 (dd, 7 = 10,3, 1,6 Hz, 1H, H5), 4,35 - 4,27 (m, 2H, Hi7a, Hi7b), 4,05 - 3,92 (m, 2H, H3), 3,72 (s, 3H, COOC / L), 2,97 (dd, 7= 56,1 Hz, 16,5 Hz, 2H, CH2COOMe), 2,80 - 2,66 (m, 2H, H4a, H4b), 2,17 - 2,00 (m, 2H, C2CH3). 0,83 (t, 7 = 7,4 Hz, 3H, CH2C3).

[0835] 13C NMR (151 MHz, CDCl3) δ 173,02, 161,73 (d, JC-F=247,3 Hz), 153,48 (d, JC-F=244,5 Hz), 138,05, 135,78 (d, 7C-F = 5,8 Hz), 131,05, 128,67 (d, 7C-F= 9,6 Hz), 125,73 (d, 7C-F= 3,5 Hz), 126,79 (d, 7C-F= 9,8 Hz), 125,28 (d, 7C-F = 19,0 Hz), 122,32 (d, 7C-F= 8,00 Hz), 114,38 (d, JC-F= 23,2 Hz), 110,07 (d, JC-F= 27,3 Hz), 108,81 (d, JC-F= 4,7 Hz), 101,75 (d, JC-F= 23,3 Hz), 74,78, 60,60, 52,14, 42,70, 30,81, 27,78, 22,40, 7,70. MS [M-H]’: m / z =432 / 434.

[0836] Example 75. Synthesis of Methyl 2-(8-(2-fluoro-4-fluorobenzyl)-l-ethyl-6-fluoro-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (79). The reaction was carried out with compound 62 (0.359 mmol, 150 mg), 2-fluoro-4-fluorobenzyl bromide (0.359 mmol, 0.046 mL), (PPh3)2PdCl2(0.018 mmol, 12.6 mg), Na2CO3(0.898 mmol, 95 mg) in THF / H2O (2 mL / 2 mL) for 4 h according to the procedure described in Example 71. The crude product was purified by flash chromatography using 9:1 PE / Acetone as eluent mixture yielding pure compound 79 (yield: 69%). MS (ESI negative) [MH]-: m / z =416.

[0837] Example 76. Synthesis of Methyl 2-(8-(2-fluoro-4-chlorobenzyl)-l-ethyl-6-fluoro-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (80). The reaction was carried out with compound 62 (0.431 mmol, 180 mg), 2-fluoro-4-chlorobenzyl bromide (0.431 mmol, 0.043 mL), (PPh3)2PdCl2(0.0215 mmol, 15 mg), Na2CO3(1.08 mmol, 114 mg) in THF / H2O (2 mL / 2 mL) for 4 h according to the procedure described in Example 71. The crude product was purified by flash chromatography using 9:1 PE / Acetone as eluent mixture yielding pure compound 80 (yield: 60%). 'H NMR (600 MHz, CDC13) δ 9,13 (s, 1H, NH), 7,14 (t, J = 8,2 Hz, 1H, H5), 7,13 (dd, J = 9,6, 2,1 Hz, 1H, H7), 7,06-7,03 (m, 2H, H2'e H3'), 6,75 (dd, J = 9,9, 2,8 Hz, 1H, H5), 4,15 (q, J= 15,7 Hz, 2H, Hi7), 4,05 - 3,90 (m, 2H, H3), 3,70 (s, 3H, COOC / L), 2,94 (dd, J = 50,6, 16,9 Hz, 2H, CH2COOMe), 2,81 - 2,66 (m, 2H, H4), 2,15 - 1,93 (m, 2H, C2CH3), 0,82 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDC13) δ 173,17, 160,79 (d, JC-F= 248,8 Hz), 157,90 (d, JC-F= 234,8 Hz), 138,33, 133,17 (d, Jc-i = 10,4 Hz), 131,74 (d, Jc-F= 5,2 Hz), 130,98, 126,93 (d, JC-F= 9,9 Hz), 124,88 (d, Jc-i = 15,9 Hz), 124,77 (d, Jc-i = 3,6 Hz), 122,93 (d, JC-F= 9,0 Hz), 116,40 (d, Jc-i = 25,7 Hz), 110,51 (d, Jc-i = 26,4 Hz), 108,81 (d, JC-F= 4,6 Hz), 101,99 (d, Jc-i = 23,2 Hz), 74,59, 60,53, 52,10, 42,52, 30,62, 30,17, 22,39, 7,62. MS [M-H]’: m / z =432 / 434.

[0838] Example 77. Synthesis of Methyl 2-(8-(2-chloro-4-fluoro-benzyl)-l-ethyl-6-fluoro-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (81). The reaction was carried out with compound 62 (0.431 mmol, 180 mg), 2-chloro-4-fluorobenzyl bromide (0.431 mmol, 96 mg), (PPh3)2PdCl2(0.0215 mmol, 15 mg), Na2CO3(1.08 mmol, 114 mg) in THF / H2O (2 mL / 2 mL) for 6 h according to the procedure described in Example 71. The crude product was purified by flash chromatography using 9:1 PE / Acetone as eluent mixture yielding pure compound 81 (yield: 75%). 'H NMR (600 MHz, CDC13) δ 9,03 (s, 1H, NH), 7,18 (dd, J= 8,5, 2,6 Hz, H2),7,15 (dd, J= 8,5, 6,1 Hz, H5), 7,04 (dd, J = 9,1, 2,2 Hz, 1H, H7), 6,90 (tt, JC-F= 8,5, 4,2 Hz, H3), 6,65 (dd, J = 10,0, 2,2 Hz, 1H, H5), 4,24 (q, J = 16,1 Hz, 2H, Hi7), 4,07 - 3,89 (m, 2H, H3), 3,67 (s, 3H, COOC3), 2,92 (dd, J = 52,2, 16,7 Hz, 2H, CH2COOMe), 2,81 - 2,66 (m, 2H, H4), 2,13 - 1,90 (m, 2H, C2CH3), 0,79 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCl3) δ 173,10, 161,46 (d, JC-F=248,4 Hz), 157,96 (d, JC-F=234,4 Hz), 138,25, 134,88 (d, Jc-F= 10,3 Hz), 132,63 (d, Jc-i = 3,6 Hz), 131,81 (d, Jc-i = 8,6 Hz), 131,11, 126,86 (d, Jc-i = 10,0 Hz), 123,12 (d, JC-F= 9,0 Hz), 117,06 (d, Jc-i = 24,6 Hz), 114,35 (d, Jc-i = 21,0 Hz), 110,60 (d, JC-F= 26,5 Hz), 108,80 (d, Jc-i = 4,6 Hz), 101,90 (d, Jc-i = 23,2 Hz), 74,63, 60,56, 52,09, 42,57, 34,33, 30,67, 22,41, 7,64. MS [M-H]’: m / z =432 / 434.

[0839] Example 78. Synthesis of Methyl 2-(8-(3,5-difluorobenzyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (82). The reaction was carried out with compound 62 (0.359 mmol, 150 mg), l’l-(bromomethyl)-3,5-difluorobenzene (0.359 mmol, 0.046 mL), (PPh3)2PdCl2(0.0359 mmol, 25 mg), Na2CO3(0.898 mmol, 95 mg) in THF / H2O (1.7 mL / 1.7 mL) for 16 h according to the procedure described in Example 71. The crude product was purified by flash chromatography using a 9:1 PE / EtOAc mixture as eluent to give pure compound 82 (yield: 47%). 'H NMR (600 MHz, CDCh) δ 9,15 (s, 1H, NH), 7,06 (dd, J = 9,2, 2,4 Hz, 1H, H7), 6,83 - 6,81 (m, 2H, H2,6), 6,77 (dd, J = 9,8, 2,4 Hz, 1H, H5), 6,64 (tt, J = 9,0, 2,3 Hz, 1H, H4), 4,17 - 4,09 (m, 2H, Hi7), 4,03 - 3,87 (m, 2H, H3), 3,68 (s, 3H, COOCH3), 2,98 - 2,83 (m, 2H, Hi3), 2,79 - 2,64 (m 2H, H4), 1,99 (ddp, J = 29,1, 21,8, 7,4 Hz, 2H, C / 72CH3), 0,78 (t, J = 7,4 Hz, 3H, CH2C3).13C NMR (151 MHz, CDCl3) δ 173,32, 164,08, 162,44, 158,57, 157,01, 143,14, 138,42, 130,98, 126,93, 123,19, 111,87, 111,71, 110,55, 108,73, 102,22, 102,07, 101,85, 74,45, 60,50, 52,04, 42,41, 37,81, 30,47, 22,33, 7,52. MS) [M-H]’: m / z =416.

[0840] Example 79. Synthesis of Methyl 2-(8-(3-chloro-5-fluorobenzyl)-l-ethyl-6-fluoro-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (83). The reaction was carried out with compound 62 (0.359 mmol, 150 mg), l-(bromomethyl)-3-chloro-5-fluorobenzene (0.359 mmol, 86.3 mg), (PPh3)2PdCl2(0.0359 mmol, 25 mg), Na2CO3(0.898 mmol, 95 mg) in THF / H2O (1.7 mL / 1.7 mL) for 16 h according to the procedure described in Example 71. The crude product was purified by flash chromatography using a 9: 1 PE / EtOAc mixture as eluent to give pure compound 83 (yield: 43%).1H NMR (600 MHz, CDCh) δ 9,24 (s, 1H, NH), 7,10 (d, J = 1,2 Hz, 1H, H4), 7,06 (dd, J = 9,2, 2,4 Hz, 1H, H7), 6,93 (dt, J = 8,4, 2,1 Hz, 1H, H6), 6,92 -6,89 (m, 1H, H2), 6,77 (dd, J= 9,8, 2,4 Hz, 1H, H5), 4,14 - 4,09 (m, 2H, Hi7), 4,03 - 3,87 (m,2H, H3), 3,69 (s, 3H, COOCH3), 2,91 (dd, J = 54,0, 17,0 Hz, 2H, H13), 2,79 – 2,65 (m, 2H, H4), 2,11 – 1,87 (m, 2H, CH2CH3). 0,78 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCh) 5 173,34, 162,04, 158,56, 142,95, 138,46, 135,11, 130,96, 127,02, 124,93, 123,08, 114,50, 110,57, 108,73, 102,26, 74,46, 60,51, 52,12, 42,45, 37,63, 30,48, 22,33, 7,53. MS) [M-H]': m / z =432 / 434.

[0841] Example 80. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-fluoro-5-methoxybenzyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (84). The reaction was carried out with compound 62 (0.359 mmol, 150 mg), 1- (bromomethyl)-3-fluoro-5-methoxybenzene (0.359 mmol, 78.7 mg), (PPha PdCh (0.0359 mmol, 25 mg), Na2CO3(0.898 mmol, 95 mg) in THF / H2O (1.7 mL / 1.7 mL) for 16 h according to the procedure described in Example 71. The crude product was purified by flash chromatography using a 9:1 PE / EtOAc mixture as eluent to give pure compound 84 (yield: 42%).1H NMR (600 MHz, CDCh) 89,06 (s, 1H, NH), 7,03 (dd, J = 9,2, 2,3 Hz, 1H, H7), 6,76 (dd, 7= 9,9, 2,4 Hz, 1H, H5), 6,65 - 6,63 (m, 1H, H2), 6,59 (ddd, J = 9,2, 2,2, 1,5 Hz, 1H, H6), 6,46 (dt, J = 10,6, 2,3 Hz, 1H, H4), 4,13 - 4,06 (m, 2H, H17), 4,03 - 3,87 (m, 2H, H3), 3,76 (s, 3H, OCH3), 3,67 (s, 3H, COOCH3), 2,90 (dd, J = 54,9, 17,0 Hz, 2H, H13), 2,79 – 2,64 (m, 2H, H4), 2,11 – 1,88 (m, 2H, CH2CH3). 0,77 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCh) 6 173,15, 164,62, 163,00, 161,12, 158,60, 142,24, 138,17, 131,08, 126,77, 123,97, 110,67, 110,38, 108,61, 108,29, 101,74, 99,78, 74,52, 60,50, 55,53, 52,00, 42,44, 38,07, 30,53, 22,34, 7,55. MS) [M-H]': m / z =428.

[0842] Example 81. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(3-chloro-4-fluorobenzyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (85). The reaction was carried out with compound 62 (0.359 mmol, 150 mg), 4-(bromomethyl)-2-chloro-l-fluorobenzene (0.359 mmol, 0.048 mL), (PPha PdCh (0.0359 mmol, 25 mg), Na2CO3(0.898 mmol, 95 mg) in THF / H2O (1.7 mL / 1.7 mL) for 16 h according to the procedure described in Example 71. The crude product was purified by flash chromatography, using a 95:5 PE / EtOAc mixture as eluent to give pure compound 85 (yield: 83%).1H NMR (600 MHz, CDCh) 69,09 (s, 1H, NH), 7,34 -7,31 (m, 1H, H2), 7,15 - 7,11 (m, 1H, H6), 7,07 - 7,03 (m, 2H, H7,5), 6,74 (dd, J = 10,0, 2,4, 0,4 Hz, 1H, H5), 4,16 - 4,06 (m, 2H, Hi7), 4,04 - 3,87 (m, 2H, H3), 3,67 (s, 3H, COOC / h), 2,90 (m, 2H, H13), 2,79 - 2,65 (m, 2H, H4), 2,11 – 1,84 (m, 2H, CH2CH3). 0,78 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCh) 6 173,28 (COOCH3), 157,79 (d, J = 234,7 Hz), 152,16 (d, J = 234,7 Hz), 138,39, 136,17, 132,27, 130,95, 128,53, 126,90, 123,37 (d, J = 8,7 Hz),121,17, 116,67 (d, J = 21,0 Hz), 110,61 (d, JC-F = 26,3 Hz), 108,42, 101,92 (d, JC-F = 23,3 Hz), 74,45, 60,50, 52,08, 42,44, 37,08, 30,47, 22,33, 7,52. MS) [M-H]': m / z =432 / 434.

[0843] Example 82. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(4-fluoro-3-methylbenzyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (86). The reaction was carried out with compound 62 (0.359 mmol, 150 mg), 4-(bromomethyl)-l-fluoro-2-methylbenzene (0.359 mmol, 0.05 mL), (PPh3)2PdCl2(0.0359 mmol, 25 mg), Na2CO3(0.898 mmol, 95 mg) in THF / H2O (1.7 mL / 1.7 mL) for 16 h according to the procedure described in Example 71. The crude product was purified by flash chromatography using a 9: 1 PE / EtOAc mixture as eluent to give pure compound 86 (yield: 47%).1H NMR (600 MHz, CDCh) 89,06 - 8,79 (m, 1H, NH), 7,35 - 7,17 (m, 1H, H6), 7,12 - 7,08 (m, 1H, H2), 7,06 - 7,01 (m, 1H, H7), 6,93 - 6,89 (m, 1H, H3), 6,74 (dt, J = 10,0, 2,1 Hz, 1H, H5), 4,09 (s, 2H, H17), 4,02 - 3,88 (m, 2H, H3), 3,71 - 3,56 (m, 3H, COOCH3), 2,95 - 2,83 (m, 2H, Hi3), 2,78 - 2,65 (m, 2H, H4), 2,23 - 2,17 (m, 3H, C5CH3), 2,08 - 1,87 (m, 2H, C2CH3), 0,81 - 0,66 (m, 3H, CH2CH3).13C NMR (151 MHz, CDCh) 6 173,04, 159,43, 157,10, 138,07, 134,41, 131,09, 127,57, 124,91, 115,00, 110,60, 108,54, 101,64, 74,53, 60,50, 53,49, 51,94, 42,48, 37,29, 30,55, 7,52. MS) [M-H]': m / z =412.

[0844] Example 83. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(phenylethynyl)-l, 3,4,9-tetrahydropyran [3,4-b] indol- 1-yl) acetate (87).

[0845]

[0846] Reagents and conditions: (a) PdCl2(PPh3)2, CuI, anhydrous 1,4-dioxane, ethynyl benzene, Et3N, 40 °C, 1h.

[0847] (PPh3)2PdCl2(5 mg, 0.0072 mmol, 0.02 eq), Cui (2.7 mg, 0.0144 mmol, 0.04 eq) and by means of a syringe a solution of intermediate 24 (150 mg, 0.360 mmol, 1 eq) in 1.5 mL of anhydrous 1,4-dioxane are inserted into an anhydrous two-necked flask under N2atmosphere. Finally, ethynylbenzene (0.079 mL, 0.72 mmol, 2 eq) and Et3N (0.11 mL, 0.79 mmol, 2.2 eq)are added. The reaction is allowed to proceed for 1 h at 40 °C under an atmosphere of N2. The mixture was vacuum filtered over Buchner and the filtrate extracted with DCM (3 x 15 mL). The organic phases were dried over Na2SO4and evaporated under reduced pressure. The crude product was purified by flash chromatography (95:5 PE / Acetone eluent) to give 87 as a yellow solid (85% yield).

[0848] Example 84. General procedure for the synthesis of compounds 88-89

[0849] 88 R8=(Z)-styryl 89 R8=cinnamyl

[0850]

[0851] Reagents and conditions: (a) Pd(PPh3)2Cl2, Na2CO3, THF / H2O 1:1, THF; (2-bromovinyl)benzene or (E)-(3-bromopropen-1-yl)benzene, 40 °C, 3 h.

[0852] Pd(PPh3)2Cl2(0.05 eq) and Na2CO3(2.5 eq) THF / H2O 1:1 are inserted into an anhydrous two-necked flask in an N2 atmosphere. They are then added to the suspension obtained using a gas-tight syringe a solution of 62 (1 eq) in THF and the (2-bromovinyl) benzene or (E) -(3 -bromopropen- 1-yl) benzene (1 eq). The reaction is allowed to proceed at 40 °C with stirring for 3 h under an atmosphere of N2. The mixture was extracted with DCM (3 x 15 mF), the organic phases were dried over Na2SO4and evaporated under reduced pressure.

[0853] Example 85. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-[(l Z)-2-phenylethenyl)] -l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (88). The reaction was carried out with compound 62 (600.0 mg, 1.74 mmol), Pd(PPh3)2Cl2(50.47 mg, 0.0719 mmol), Na2CO3(380.67 mg, 3.60 mmol), 2-bromovinyl benzene (0.187 mL, 1.438 mmol) in 1:1 THF / H2O (6.5 mL, 6.5 mL). The crude product was purified by flash chromatography using 9:1 PE / Acetone as eluent mixture yielding compound 88 as a colorless oil (yield: 38%). 'H NMR (600 MHz, CDC13) 58,33 (s, 1H, NH), 7,19 - 7,16 (m, 2H, ArH3,5), 7,15 - 7,12 (m, 3H, ArH2,4’, 6’), 7,05(dd, J = 9,1, 2,4 Hz, ArH7), 6,88 (ddd, J = 10,1, 2,4, 0,8 Hz, ArH5), 6,78 (dd, J = 36,7, 12,2 Hz, 2H, CH=CH), 4,00 - 3,83 (m, 2H, H3a, H3b), 3,63 (s, 3H, COOCW,), 2,76 – 2,61 (m, 2H, CH2COOMe), 1,72 – 1,64 (m, 2H, 2H, H4a, H4b), 0,88 – 0,83 (m, 2H, CH2CH3), 0,59 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDC13) 171,66, 157,07 (d, JC-F= 234,1 Hz), 137,25, 136,21, 131,42, 128,61, 128,14, 127,76, 127,15, 126,35 (d, JC-F= 10,1 Hz), 125,03, 121,21 (d, JC-F= 9,2 Hz), 109,43 (d, JC-F= 26,1 Hz), 107,70 (d, JC-F= 4,9 Hz), 102,21 (d, JC-F= 23,4 Hz), 74,05, 59,99, 51,35, 42,09, 29,91, 21,65, 7,12. MS (ESI negative) [M-H]’: m / z = 392.

[0854] Example 86. Synthesis of Methyl 2-(8-cinnamyl-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (89). The reaction was carried out with compound 62 (150 mg, 0.359 mmol), Pd(PPh3)2Cl2(12.61 mg, 0.018 mmol), Na2CO3(95 mg, 0.90 mmol), (3 -bromopropen- 1-yl) benzene (0.052 mL, 0.359 mmol) in 1:1 THF / H2O (6 mL, 6 mL). The crude product was purified by flash chromatography (9:1 PE / Acetone eluent) to give pure compound 89 (25% yield). 'H NMR (600 MHz, CDC13) 59,39 (s, 1H, NH), 7,31 - 7,22 (m, 2H, H3, 5 ), 7,23 - 7,13 (m, 2H, H2’, 6’), 7,14 - 7,06 (m, 1H, H4), 6,93 (dd, J = 9,24, 2,51 Hz, 1H, H5), 6,70 (dd, J = 10,03, 2,59 Hz, 1H, H7), 6,53 (d, J = 15,69 Hz, 1H, CH2CH=CHPh), 6,30 (dt, J= 15,79, 6,82 Hz, 1H, CH2C77=CHPh), 3,97 - 3,80 (m, 2H, H3), 3,67 (qd, J= 15,65, 6,89 Hz, 2H, C / 72CH=C / 7Ph), 3,43 (s, 1H, COOCH3), 2,91 - 2,76 (m, 2H, CftCOOMe), 2,73 -2,56 (m, 2H, H4), 2,04 - 1,82 (m, 2H, C772CH3), 0,68 (t, J= 7,29 Hz, 3H, CH2m). [M-H]’: m / z = 406.

[0855] Example 87. General procedure for the synthesis of compounds 90-93

[0856] \ p " > COOMe H /

[0857]

[0858] Table 6 shows the reagents, the conditions used are: a) Pd(dppf)Cl, styrene, NaOAc, DMF, 140°C, 16 h; b) Pd / C 10%, anhydrous THF, H2, 20° C, 4 h.Table 6

[0859] Ri

[0860] 90 — > 92 H

[0861] 91 — > 93 F

[0862]

[0863] STEP A

[0864] To a solution of derivative 25 (1 eq) in DMF in a double-necked flask under anhydrous atmosphere, NaOAc (2 eq) and the dichloro [ 1, l'-bis (diphenylphosphino) ferrocene] palladium (II) catalyst (0.3 eq) are added. After performing 2 vacuum / nitrogen cycles the properly substituted styrene (2.5 eq) is added by means of a gas-tight syringe. The reaction is allowed to proceed at 140 °C, under nitrogen flow for 16 h. At the end, the mixture is filtered, the DMF is evaporated under vacuum, and the resulting residue is extracted with DCM / H2O. The organic phases are collected, dried over Na2SO4and the solvent evaporated. The crude products were purified by flash chromatography to obtain compounds 90 and 91, characterized by MS(ESI),JH and13C NMR.

[0865] STEP B

[0866] To obtain compounds 92 and 93, the appropriate vinylbenzene derivative (90 or 91, 1 eq) was hydrogenated, dissolving it in anhydrous THF in a two-necked flask. The Pd / C catalyst 10% (0.1 eq) was added to the mixture and subsequently the equipment was connected to a flask filled with H2. The reaction was allowed to proceed with stirring for 4 h at room temperature. Upon completion, the mixture was filtered over celite and concentrated. The crude was purified by flash direct phase chromatography and final compounds 92 and 93 were dried over P2O5 and characterized by MS (ESI),JH and13C NMR.

[0867] Example 88. Synthesis of Methyl (E)-2-(l-ethyl-6-fluoro-8-styryl-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (90). Compound 90 was obtained with intermediate 25 (300.0 mg, 0.810 mmol), NaOAc (132.89 mg, 1.62 mmol), dichloro [1, l'-bis (diphenylphosphino) ferrocene] palladium (177.80 mg, 0.243 mmol), styrene (0.233 mL, 2.025 mmol) in DMF (20 mL) according to the procedure described in Example 87, step A. The crude product was purified by flash chromatography using a 9:1 Pe / Acetone mixture as eluent, yielding compound 90 as a yellow oil (yield 33%).Example 89. Synthesis of Methyl (E)-2-(l-ethyl-6-fluoro-8-(2-fluorostyryl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (91). Compound 91 was obtained with intermediate 25 (450.0 mg, 1.215 mmol) in DMF (25.0 mL), NaOAc (199.3 mg, 2.43 mmol), dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(II) (266.71 mg, 0.365 mmol), l-(2-bromo vinyl) -2-fluorobenzene (0.362 mL, 3.04 mmol) according to the procedure described in Example 87, step A. The crude product was purified by flash direct phase chromatography using as eluent mixture PE / DCM / MeOH 8:1.8:0.2 (187 mg, yield: 34%).

[0868] Example 90. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-phenethyl-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (92). The reaction was carried out on derivative 90 (50.0 mg, 1.271 mmol) in THF (4 mL), Pd / C 10% (13.5 mg, 0.0127 mmol) according to the procedure described in Example 87, step B. The crude product was purified by direct phase flash chromatography using a 9:1 PE / EtOAc mixture yielding pure compound 92 (99% yield).

[0869] Example 91. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-[2-fluoro-phenylethyl)] -l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (93). The reaction was carried out on derivative 91 (146.0 mg, 0.356 mmol) in THF (15.0 ml), Pd / C 10% (37.8 mg, 0.0356 mmol) according to the procedure described in Example 87, step B. The crude product was purified by flash chromatography, using as eluent a 9: 1 PE / Acetone mixture yielding pure compound 93 (yield: 90%).

[0870] Example 92. General procedure for the synthesis of compounds 94-97

[0871] 16Qr94-95

[0872] 8% ' CF3

[0873] Reagents and conditions: a): bromomethylcyclopentane, or l-bromo-4,4,4-t

[0874]

[0875] rifluorobutane, Nih, 4,4’ -diterbutyl-2, 2’ -bipyridine, Zn°, Nal, pyridine, DMA, 70 °C, 16 h; b) methyl- 3 -oxopentanoate, BF3 OEt2, anhydrous D CM, RT, 5 h.Table 7

[0876] R6

[0877] 94 — > 96 cyclopropylmethyl

[0878] 95 — > 97 4,4, 4-trifluorobuty 1

[0879]

[0880] STE] P A

[0881] To a solution of 16 in DMA, the appropriate bromide (2 eq), Nil2(0.1 eq), 4,4’-diterbutyl-2, 2’ -bipyridine (0.1 eq), pyridine (0.1 eq), Nal (0.25 eq) and powdered zinc (3 eq) were added and the reaction was allowed to proceed for 16 h at 70 °C. The mixture is then treated with 1 M aqueous NaHSO4, filtered and washed with DCM and then extracted with DCM / H2O. The collected organic phases were dried over Na2SO4and evaporated. The obtained crude was purified by flash chromatography to obtain the pure 94-95 products, which were characterized by MS (ESI),JH and13C NMR.

[0882] STEP B

[0883] The synthesis was performed according to the procedure given in Example 10 starting from intermediates 94-95.

[0884] Example 93. Synthesis of 2-(7-(Cyclopentylmethyl)-5-fluoro-lH-indol-3-yl)ethan-l-ol (94). The reaction was carried out with compound 16 (100.0 mg, 0.388 mmol), bromomethylcyclopentane (0.1 mL, 0.775 mmol), Nil2(12.2 mg, 0.0388 mmol), 4,4’-diterbutyl-2, 2’ -bipyridine (10.4 mg, 0.0388 mmol), pyridine (3.0 pL, 0.0388 mmol), Nal (14.5 mg, 0.097 mmol), zinc powder (76.0 mg, 1.16 mmol), DMA (1.0 mL) according to the procedure described in Example 92, Step A. The crude was purified by flash chromatography using an 8:2 PE / Acetone mixture as eluent yielding product 94 as a yellow oil (yield 32%).JH NMR (600 MHz, CDC13) 58,01 (s, 1H, NH), 7,12 (d, J = 2,48 Hz, 1H, H2), 7,10 (dd, J = 9,36, 2,43 Hz, 1H, H6), 6,80 (dd, J = 10,11, 2,45 Hz, 1H, H4), 3,89 (t, J = 6,33 Hz, 2H, CH2CH2OH), 2,98 (td, J = 6,33, 0,85 Hz, 2H, C772CH2OH), 2,78 (d, J = 7,48 Hz, 2H, CH2Cyp), 2,25 (m, 1H, Hl’), 1,80 - 1,72 (m, 2H, H2’a, H5’a), 1,72 - 1,63 (m, 2H, H2’b, H5’b), 1,59 - 1,49 (m, 2H, H3’a, H4’a), 1,30 - 1,21 (m, 2H, H3’b, H4’b),13C NMR (151 MHz, CDC13) 5 158,04 (d, JC-F = 234,62 Hz), 132,24, 127,49 (d, JC-F = 9,95 Hz), 126,43 (d, JC-F = 8,66 Hz), 123,71, 113,03 (d, J = 4,86 Hz), 110,78 (d, JC-F = 25,95 Hz), 101,39 (d, JC-F = 23,39 Hz), 62,61, 40,29, 37,40, 33,00, 28,93, 25,06. MS (ESI-MS) [M-H]’: m / z 260.Example 94. Synthesis of 2-(5-Fluoro-7-(4,4,4-trifluorobutyl)-lH-indol-3-yl)ethan-l-ol (95). The reaction was carried out with compound 16 (100.0 mg, 0.388 mmol), 1-bromo-4,4,4-trifluorobutane (0.24 mL, 1.94 mmol), Nih (12.2 mg, 0.0388 mmol), 4,4’-diterbutyl-2,2’-bipyridine (10.4 mg, 0.0388 mmol), pyridine (3.0 pL, 0.0388 mmol), Nal (14.5 mg, 0.097 mmol), zinc powder (76.0 mg, 1.16 mmol), DMA (1.0 mL) according to the procedure described in Example 92, Step A. The crude was purified by flash chromatography using an 8:2 PE / Acetone mixture as eluent, yielding product 95 as a pink oil (yield 28%).JH NMR (600 MHz, CDC13) 58,09 (s, 1H, NH), 7,13 (dd, J = 9,30, 2,41 Hz, 1H, H6), 7,09 (s, 1H, H2), 6,78 (dd, J = 9,92, 2,41 Hz, 1H, H4), 3,88 (t, J = 6,36 Hz, 2H, CH2C772OH), 2,96 (td, J = 6,36, 0,84 Hz, 2H, CH2CH2C772CF3), 2,86 (t, J = 7,64 Hz, 2H, C772CH2OH), 2,20 - 2,11 (m, 2H, C772CH2CH2CF3), 2,03 - 1,97 (m, 2H, CH2C772CH2CF3).13C NMR (151 MHz, CDC13) 5 158,00 (d, JC-F = 235,14 Hz), 131,90, 127,91 (d, JC-F = 9,79 Hz), 127,21 (q, JC-F = 276,07 Hz), 124,57 (d, JC-F = 8,80 Hz), 113,25 (d, JC-F = 4,91 Hz), 110,20 (d, JC-F = 26,21 Hz), 102,09 (d, JC-F = 23,28 Hz), 62,59, 33,26 (q, JC-F = 28,43 Hz), 29,72, 28,77, 21,82. MS (ESIMS) [M-H]’: m / z 288.

[0885] Example 95. Synthesis of Methyl 2-(8-(cyclopentylmethyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (96). The reaction was carried out using intermediate 94 (0.48 mg, 0.18 mmol), methyl-3-oxopentanoate (0.046 mL, 0.37 mmol), BF3·OEt2(0.046 mL, 0.37 mmol), anhydrous 1,4-dioxane (4.0 mL) according to the procedure described in Example 92, Step B. The product was purified by flash chromatography using as eluent DCM, to obtain compound 96 as a yellow oil (80% yield).1H NMR (600 MHz, CDC13) 5 9,08 (s, 1H, NH), 6,98 (dd, J = 9,26, 2,43 Hz, 1H, ArH7), 6,75 (dd, J = 10,19, 2,43 Hz, 1H, ArH5), 4,06-4,02 and 3,95-3,90 (m, 2H, H3a, H3b), 3,72 (s, 3H, COOCH3), 3,03-3,01 e 2,93-2,91 (m, 2H, CffiaCOOMe, CH2bCOOMe), 2,85-2,80 e 2,72-2,68(m, 2H, H4a, H4b), 2,79-2,75 (m, 2H, H17), 2,28-2,21 e 2,19-2,13 (m, 2H, CH2aCH3, CH2bCH3), 2,00 (m, 1H, Hl’), 1,82 - 1,73 (m, 2H, H2’a, H5’a), 1,71 - 1,65 (m, 2H, H2’b, H5’b), 1,60 - 1,49 (m, 2H, H3’a, H4’a), 1,32 - 1,23 (m, 2H, H3’b, H4’b), 0,83 (t, J = 7,37 Hz, 3H, CH2C773).13C NMR (151 MHz, CDC13) 5 173,38, 158,01 (d, JC-F = 233,93 Hz), 137,74, 131,46, 126,38, 126,32 (d, JC-F = 9,40 Hz), 110,11 (d, JC-F = 25,75 Hz), 108,57 (d, JC-F = 4,76 Hz), 100,80 (d, JC-F = 23,36 Hz), 74,67, 60,66, 52,13, 42,73, 40,61, 37,36, 32,96, 32,91, 30,73, 25,08, 25,05, 22,45, 7,68. MS (ESI-MS) [M-H]’: m / z 372.Example 96. Synthesis of Methyl 2-(l-ethyl-6-fluoro-8-(4,4,4-trifluorobutyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate (97). The reaction was carried out using intermediate 95 (0.80 mg, 0.28 mmol), methyl-3-oxopentanoate (0.052 mL, 0.41 mmol), BFs’OEti (0.052 mL, 0.41 mmol), anhydrous DCM (2.0 mL) according to the procedure described in Example 92, Step B. The product was purified by flash chromatography using as eluent DCM, to obtain compound 97 as a white solid (yield 45%).JH NMR (600 MHz, CDC13) 5 9,25 (s, 1H, NH), 7,03 (dd, J = 9,23, 2,41 Hz, 1H, H7), 6,75 (dd, J = 9,93, 2,37 Hz, 1H, H5), 4,06-4,03 e 3,96-3,92 (m, 2H, H3a, H3b), 3,74 (s, 3H, COOCH3), 3,08 - 2,85 (m, 4H, two signals: CffiCOOMe, C772CH2CH2CF3), 2,81-2,77 e 2,73-2,68 (m, 2H, H4a, H4b), 2,21-1,96 (m, 6H, three signals: CH2C772CH2CF3, CH2CH2C772CF3, C772CH3), 0,84 (t, J = 7,38 Hz, 3H, CH2C773).13C NMR (151 MHz, CDC13) 5 173,65, 158,00 (d, JC-F = 234,65 Hz), 138,22, 131,15, 127,26 (q, JC-F = 276,25 Hz), 126,82 (d, JC-F = 10,04 Hz), 124,39 (d, JC-F = 8,81 Hz), 109,68 (d, JC-F = 26,00 Hz), 108,82 (d, JC-F = 4,68 Hz), 101,61 (d, JC-F = 23,25 Hz), 74,60, 60,64, 52,17, 42,71, 33,36 (q, JC-F = 28,60 Hz), 30,67, 30,10, 22,41, 21,84, 7,63. MS (ESI-MS) [M-H]’: m / z 401.

[0886] Example 97. Synthesis of compounds CXT1, CXT9-15, CXT20-24, CXT26-27, CXT29, CXT31-33, CXT35-42, CXT44-46, CXT62, CXT64-65, CXT68, CXT72-75, CXT77-88, CXT90-103 and CXT105

[0887]

[0888] Reagents and conditions: a): LiOH 3M, 1,4-dioxane, 20 °C, 16 h; b) LiOH 0.1M, THF, 16 h, 20 °C.Table 8

[0889] Name Rs X A Name Rs X A 30 -> CXT1 Cl F H 96 → CXT68 cyclopentylmethyl F H 34 -> CXT9 methylsulfonyl CH’, H 65 → CXT72 2-methylbenzyl F H 33 > CXT10 methylsulfonyl F H 68 → CXT73 3-methylbenzyl F H 28 -> CXT11 SMe F H 75— > CXT74 4-methylbenzyl F H 15 -> CXT12 I F H 66 -> CXT75 2-chlorobenzyl F H 31 -> CXT14 Cl CH’, H 97 -> CXT77 4,4,4- trifluorobutyl F H 36 -> CXT15 phenylsulfonyl F H 69 -> CXT78 3-chlorobenzyl F H 37 -> CXT20 phenyl F H 70 -> CXT79 3-fluorobenzyl F H 38 -> CXT21 3 -chlorophenyl F H 67 -> CXT80 2-fluorobenzyl F H 39 -> CXT22 3- acetamidophenyl F H 71 -> CXT81 3 -methoxybenzyl F H 40 -> CXT23 3-(hydroxymethyl)phenyl F H 85 -> CXT82 3-chloro-4-fluorobenzyl F H 41 -> CXT24 3- carbamoylphenyl F H 76 -> CXT83 3-chloro-2-fluorobenzyl F H 3- 42 -> CXT26 3- hydroxymethyl F H 72 → CXT84 F H (trifluoromethyl)benzyl 4-fluoro-3- 43 -> CXT27 4-(hydroxymethyl)phenyl F H 86 -> CXT85 F H methylbenzyl

[0890] 2-fluoro-3- 58 -> CXT29 benzyl F H 77 -> CXT86 F H methylbenzyl

[0891] 44 -> CXT31 2- hydroxyphenyl F H 74 -> CXT87 3-cianobenzyl F H 45 -> CXT32 2-chlorophenyl F H 73 -> CXT88 3- nitrobenzyl F H 3-fluoro-5- 46 -> CXT33 4-chlorophenyl F H 84 -> CXT90 F H methoxybenzyl

[0892] 47 -> CXT35 3- acetylphenyl F H 83 -> CXT91 3-chloro-5-fluorobenzyl F H 48 -> CXT36 3-(methylsulfonyl) phenyl F H 82 -> CXT92 3, 5-difluorobenzyl F H 49 -> CXT37 3- methoxyphenyl F H 88 -> CXT93 (Z)-phenylethenyl F H 52 -> CXT38 3- pyridinyl F H 92 -> CXT94 phenethyl F H 53 -> CXT39 5- pyrimidinyl F H 78 -> CXT95 2-chloro-6-fluorobenzyl F H 54 -> CXT40 1H-3- pyrazolyl F H 64 -> CXT96 benzyl H F 55 -> CXT41 1 -methyl- 1 H-5 -pyrazolyl F H 87 -> CXT97 phenylethenyl F H 56 -> CXT42 1- Cyclohexenyl F H 81 -> CXT98 2-chloro-4-fluorobenzyl F H 50 -> CXT44 2,5-dichlorophenyl F H 79 -> CXT99 2,4-difluorobenzyl F H 51 → CXT45 3,5-dichlorophenyl F H 89 → CXT100 (E)- 3-phenylallyl F H 57 -> CXT46 4- isoxazolyl F H 90 -> CXT101 (E)-phenylethenyl F H 59 -> CXT62 4-methoxybenzyl F H 80 -> CXT102 2-fluoro-4-chlorobenzyl F H (E)-2-fluoro

[0893] 60 -> CXT64 4-chlorobenzyl F H 91 -> CXT103 F H phenylethenyl

[0894] 61 -> CXT65 4-fluorobenzyl F H 93 -> CXT105 2-fluoro phenylethenyl F H

[0895]

[0896] PROCEDURE METHOD A

[0897] To a solution of the appropriate ester 15, 28, 30-31, 33-34, 36-57, 59-61, 65-77, 82-86, 96-97 (1 eq) in 1,4-dioxane was added a solution of 3 M LiOH in water (5 eq) and the mixture was stirred at room temperature for 16 h. 2M HC1 (20 mL) or, where specified, phosphate buffer pH 7.4 (20 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (3 x 20 mL). The organic phases were washed with saturated NaCl solution (30 mL), dried over Na2SO4and evaporated in vacuo. The crude product was purified by flash chromatography using DCM / MeOH as the eluent phase or by reversed-phase pressure chromatography using a 20-35 pm 100 A AQ C18 bead column, as indicated. The final compounds were vacuum dried over P2O5 and characterized by MS(ESI),1H and13C NMR.

[0898] METHOD B PROCEDURE

[0899] To a solution of the appropriate ester 64, 78-81, 87-93 (1 eq) dissolved in THF and an aqueous solution of 0.1 M LiOH (3 eq) was added. The reaction was carried out for 16 h at room temperature. At the end of the reaction the mixture was treated with 2N HC1 solution (10 mL). The mixture was extracted with DCM (3 x 20 mL) and the organic phases were dried over Na2SO4. Once the solvent was evaporated under vacuum, the crude product was purified by flash chromatography using DCM / MeOH as the eluent phase or by reverse phase pressure chromatography, as indicated. The final compounds were vacuum dried over P2O5 and characterized by MS(ESI),1H and13C NMR.

[0900] Example 98. Synthesis of 2-(8-chloro-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT1). The reaction was carried out with compound 30 (0.20 g, 0.61 mmol), 3M LiOH (1.02 mL, 3.07 mmol), 1,4-dioxane (20 mL) according to the procedure given in Example 97, Method A. The crude product was purified by flash chromatography using a 9:1 DCM / MeOH mixture as eluent, yielding the pure CXT1 product as a white solid (100% yield).1H NMR (300 MHz, CDCh) 68,93 (s, 1H, NH), 7,08 (d, J = 8,9 Hz, 1H, ArH7), 6,99 (d, J = 2,1 Hz, 1H, ArH5), 4,06 (dd, J = 14,6, 8,5 Hz, 2H, OCH2-), 3,07 (s, 2H, CH2COO-), 2,78 (d, J = 3,3 Hz, 2H, CH2), 2,23 - 2,00 (m, 2H, C772CH3), 0,88 (t, J = 7,3 Hz, 3H, CH3).13C NMR (75 MHz, CDCh) 5176,13, 157,5 (d, JC-F = 236,25 Hz), 138,25, 130,25, 127,71 (d, JC-F= 10,4 Hz), 116,78 (d, JC-F= 2,25 Hz), 110,64 (d, JC-F= 28,5 Hz), 110,00 (d, JC-F= 5,25 Hz), 102,79 (d, JC-F= 23,25 Hz), 75,32, 61,00, 42,78, 31,14, 22,53, 8,00. MS) [M-H]’: m / z= 310 / 312.Example 99. Synthesis of 2-(-l-ethyl -8-(methylsulfonyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT9). The reaction was carried out with compound 34 (0.23 g, 0.66 mmol), 3M LiOH (1.1 mL, 3.3 mmol), 1,4-dioxane (20 mL) according to the procedure given in Example 97, Method A. The crude product was purified by flash chromatography using a 95:5 DCM / MeOH mixture as eluent, yielding the pure CXT9 compound as a white solid (yield 87%).JH NMR (600 MHz, CD3Cl) 59,97 (s, 1H, NH), 7,75 (d, J = 7,7 Hz, 1H, ArH7), 7,63 (d, J = 7,6 Hz, 1H, ArH5), 7,22 (dd, J = 17,3, 9,6 Hz, 1H, ArH6), 4,04 (d, J = 44,8 Hz, 2H, OCH2-), 3,08 (d, J = 10,9 Hz, 3H, SO2CH3), 3,06 - 2,96 (m, 2H, CH2COO-), 2,83 (d, J = 15,5 Hz, 2H, CH2), 2,19 - 2,04 (m, 2H, C / / 2CH3), 0,86 (t, J = 7,4 Hz, 3H, CH3).13C NMR (151 MHz, CD3Cl) 5 174,74, 138,08, 132,02, 128,90, 124,62, 122,15, 121,97, 119,37, 109,08, 74,97, 60,53, 44,85, 42,39, 30,76, 22,08, 7,69. MS) [M-H]': m / z = 336.

[0901] Example 100. Synthesis of 2-(-l-ethyl-6-fluoro-8-(methylsulfonyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT10). The reaction was carried out with compound 33 (0.075 g, 0.20 mmol), 3 M LiOH (0.33 mL, 1.0 mmol), 1,4-dioxane (7.0 mL) according to the procedure given in Example 97, Method A. The crude product was purified by flash chromatography using a 95:5 DCM / MeOH mixture as eluent, yielding pure CXT10 compound as a white solid (yield 90%). 'H NMR (600 MHz, CD3OD) 57,51 (dd, J = 9,0, 2,4 Hz, 1H, ArH7), 7,38 (dd, J = 8,6, 2,4 Hz, 1H, ArH5), 4,06 - 3,92 (m, 2H, OCH2-), 3,17 (s, 3H, SCH3), 2,97 (dt, J = 33,8, 9,2 Hz, 2H, CH2COO-), 2,78 - 2,68 (m, 2H, CH2), 2,20 - 1,98 (m, 2H, C772CH3), 0,79 (t, J = 7,4 Hz, 3H, CH3).13C NMR (75 MHz, CD3OD) 5 173,01, 156,09 (d, JC-F= 235,5 Hz), 142,22, 130,18 (d, JC-F= 9,1 HZ), 128,53, 123,73 (d, JC-F= 8,1 HZ), 110,39 (d, JC-F= 23,1 Hz), 109,45 (d, JC-F= 4,6 Hz), 109,37 (d, JC-F = 28,5 Hz), 75,77, 60,30, 44,03, 42,84, 30,89, 22,44, 8,45. MS) [M-H]': m / z = 355.

[0902] Example 101. Synthesis of 2-(l-ethyl-6-fluoro-8-(methylthio)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT11). The reaction was carried out with compound 28 (0.15 g, 0.46 mmol), 3 M LiOH (0.76 mL, 2.28 mmol), 1,4-dioxane (14 mL) according to the procedure given in Example 97, Method A. The crude product was purified by flash chromatography using a 95:5 DCM / MeOH mixture as eluent, yielding the pure CXT11 product as a yellow solid (yield 77%).1H NMR (600 MHz, CD3OD) 5 8,89 (s, 1H, NH), 7,01 (dd, J = 9,1, 2,2 Hz, 1H, ArH7), 6,95 - 6,88 (m, 1H, ArH5), 4,07 (dd, J = 11,0, 5,6 Hz, 1H, OCH2-), 3,04 (q, J = 16,4 Hz, 2H, CH2COO-), 2,81 - 2,71 (m, 2H, CH2), 2,47 (d, J = 4,8 Hz, 3H, SCH3), 2,14 (dd, J = 14,6, 7,4 Hz, 2H, C772CH3), 0,86 (t, J = 7,4 Hz, 3H, CH3).13C NMR(151 MHz, CD3OD) 5 175,70, 158,00 (d, JC-F = 236,5 Hz), 137,32, 131,95, 126,20 (d, JC-F = 10,1 Hz), 120,60 (d, JC-F= 9,8 Hz), 110,58 (d, JC-F= 27,5 Hz), 109,22 (d, JC-F = 5,0 Hz), 102,05 (d, JC-F= 23,8 Hz), 75,09, 60,74, 42,62, 30,91, 22,23, 17,08, 7,72. MS [M-H]': m / z = 322.

[0903] Example 102. Synthesis of 2-(l-ethyl-6-fluoro-8-iodo-l,3,4,9-tetrahydropyran[3,4-b[indol-l-yl)acetic acid (CXT12). The reaction was carried out with compound 15 (0.35 g, 0.84 mmol), 3 M LiOH (1.40 mL, 4.19 mmol), 1,4-dioxane (10 mL) according to the procedure given in Example 97, Method A. The crude product was purified by flash chromatography using a mixture of 95:5 DCM / MeOH as eluent, yielding the pure CXT12 product as a white solid (yield 96%). 'H NMR (600 MHz, CD3OD) 57,23 (dd, J = 8,7, 2,3 Hz, 1H, ArH7), 7,11 (dd, J = 9,2, 2,3 Hz, 1H, ArH5), 4,03 - 3,92 (m, 2H, OCH2-), 2,94 (dd, J = 44,7, 14,9 Hz, 2H, CH2COO-), 2,65 (m, 2H, CH2), 2,08 (dd, J = 19,5, 7,3 Hz, 2H, C2CH3). 0,74 (t, J = 7,4 Hz, 3H, CH3).13C NMR (151 MHz, CD3OD) 5 175,07, 158,62 (d, JC-F= 237,7 Hz), 140,91, 136,94, 128,04 (d, JC-F= 9,9 Hz), 119,56 (d, JC-F= 28,6 Hz), 111,14, 104,39 (d, JC-F = 23,2 Hz), 77,03, 75,62 (d, JC-F= 11,1 Hz), 61,84, 43,79, 32,13, 23,52, 8,32. MS [M-H]': m / z = 402.

[0904] Example 103. Synthesis of 2-(8-chloro-l-ethyl-6-methyl-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT14). The reaction was carried out with compound 31 (0.33 g, 1.02 mmol), 3 M LiOH (1.71 mL, 5.13 mmol), 1,4-dioxane (15 mL) according to the procedure given in Example 97, Method A. The crude product was purified by flash chromatography using a 95:5 DCM / MeOH mixture as eluent, yielding the pure CXT14 product as a yellow solid (yield 91%). 'H NMR (600 MHz, CD3OD) 5 10,24 (s, 1H, NH), 7,11 (s, 1H, ArH7), 6,90 (d, J = 0,7 Hz, 1H, ArH5), 4,04 - 3,92 (m, 2H, OCH2-), 2,90 (dd, J = 83,5, 14,4 Hz, 2H, CH2COO-), 2,77 - 2,58 (m, 2H, CH2), 2,35 (s, 3H, ArCH3), 2,12 – 2,01 (m, 2H, C2CH3), 0,71 (t, J = 7,4 Hz, 3H, CH3).13C NMR (151 MHz, CD3OD) 5 173,18, 137,17, 131,60, 129,10, 128,48, 121,84, 116,17, 115,66, 108,26, 75,63, 60,41, 42,41, 30,75, 21,86, 19,97, 6,76. MS [M-H]': m / z = 306 / 308.

[0905] Example 104. Synthesis of 2-(l-ethyl-6-fluoro-8-(phenylsulfonyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT15). To a stirred solution of 36 (0.220 g, 0.51 mmol, 1 eq) in 1,4-dioxane (5 mL), was added an aqueous solution of 3 M LiOH (0.85 mL, 2.55 mmol) according to the procedure given in Example 97, Method A. The crude product was purified by flash column chromatography (silica gel, DCM / MeOH 95:5) to provide CXT15 as a white solid (179 mg, yield 84%).1H NMR (600 MHz, CDC13) 5 10,16 (s, 1H, NH), 7,98 -7,93 (m, 2H, ArH2-6’), 7,48 (t, J = 7,4 Hz, 1H, ArH4), 7,43 (t, J = 7,6 Hz, 2H, ArH3’.5), 7,39(dd, J = 8,4, 2,3 Hz, 1H, ArH7), 7,32 (dd, J = 8,7, 2,3 Hz, 1H, ArH5), 4,08 - 3,92 (m, 2H, CH2O-), 3,05 (dd, J = 34,9, 16,7 Hz, 2H, CH2COO-), 2,74 (dd, J = 12,6, 10,6 Hz, 2H, CH2), 2,22 -2,03 (m, 2H, C772CH3), 0,83 (t, J = 7,4 Hz, 3H, CH3).13C NMR (151 MHz, CDC13) 5 176,20, 156,58 (d, JC-F = 239,0 Hz), 141,56, 140,04, 133,60, 129,50, 129,42 (d, JC-F = 7,3 Hz), 128,75, 127,07, 123,13 (d, JC-F = 8,1 Hz), 110,03 (d, JC-F = 25,4 Hz), 109,04 (d, JC-F = 4,5 Hz), 74,76, 60,38, 42,32, 30,65, 21,99, 7,59. MS [M-H]': m / z = 416.

[0906] Example 105. Synthesis of 2-(l-ethyl-6-fluoro-8-phenyl-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT20). The reaction was carried out with compound 37 (0.068 g, 0.19 mmol) and 3 M LiOH (0.317 mL, 0.95 mmol) in 1,4-dioxane (1.5 mL) according to the procedure described in Example 97, Method A. After purification by flash chromatography (silica gel, DCM / MeOH 95:5) the CXT20 product was obtained as a white solid (62 mg, yield 92%).1H NMR (300 MHz, (CD3)2CO) 5 10,02 (s, 1H, NH), 7,62 (d, J= 7,0 Hz, 2H, ArH2’-6’), 7,48 (t, J = 7,4 Hz, 2H, ArH3.5’), 7,38 (d, J = 6,6 Hz, 1H, ArH4), 7,14 (d, J = 8,9 Hz, 1H, ArH7), 6,91 (d, J = 10,0 Hz, 1H, ArH5), 3,99 (d, J= 4,3 Hz, 2H, OCH2-), 2,93 (q, J = 15,6 Hz, 2H, CH2COO-), 2,77 - 2,66 (m, 2H, CH2), 1,16 - 1,10 (m, 2H, C772CH3), 0,73 (t, J = 6,9 Hz, 3H, CH3).13C NMR (75 MHz, (CD3)2CO) 5 209,27, 158,69 (d, JC-F =232,5 Hz), 138,30, 139,12, 138,301, 130,13, 129,17, 128,24, 127,78, 126,33, 108,99 (d, JC-F = 26,4 Hz), 108,43, 102,06 (d, JC-F = 23,3 Hz), 68,49, 60,14, 42,42, 29,61, 22,05, 7,04. MS [M-H]': m / z = 352.

[0907] Example 106. Synthesis of 2-(8-(3-chlorophenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT21). The reaction was carried out with compound 38 (0.107 g, 0.27 mmol) and 3 M LiOH (0.450 mL, 1.35 mmol) in 1,4-dioxane (2 mL) according to the procedure described in Example 97, Method A. After flash chromatography purification (silica gel, PE / EtOAc / MeOH 8:1.5:0.5) CXT21 was obtained as a yellow solid (104 mg, 99% yield).1H NMR (300 MHz, DMSO-d6) 8 10,73 (s, 1H, NH), 7,57 - 7,28 (m, 4H, ArH2.4’-5 -6’), 7,08 (d, J = 8,0 Hz, 1H, ArH7), 6,81 (d, J = 9,2 Hz, 1H, ArH5), 3,77 (d, J = 17,7 Hz, 2H, OCH2-), 2,67 (dd, J = 70,4, 13,4 Hz, 2H, CH2COO-), 2,35 (s, 2H, CH2), 2,02 - 1,77 (m, 2H, C772CH3), 0,52 (t, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 172,97, 157,26 (d, JC-F =232,0 Hz), 140,85, 140,33, 134,16, 131,28, 130,04, 128,69, 128,12, 127,60, 124,87, 124,81, 109,43 (d, JC-F =26,8 Hz), 108,23, 103,10 (d, JC-F = 22,8 Hz), 75,66, 60,17, 43,53, 30,80, 22,32, 8,28. MS [M-H]': m / z = 388 / 386.Example 107. Synthesis of 2-(8-(3-acetamidophenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT22). The reaction was carried out with compound 39 (0.192 g, 0.45 mmol) and 3 M LiOH (0.750 mL, 2.25 mmol) in 1,4-dioxane (3 mL) according to the procedure described in Example 97, Method A. After purification by flash chromatography (silica gel, DCM / MeOH 95:5) the CXT22 product was obtained as a light brown solid (161 mg, yield 87%).JH NMR (600 MHz, DMSO-d6) 8 12,20 (s, 1H, COOH), 10.47 (s, 1H, NH), 10,04 (s, 1H, N77-CO), 7,76 (s, 1H, ArH2), 7,71 -7,66 (m, 1H, ArH4), 7,41 (t, J=7,9 Hz, 1H, ArH5), 7,23 (d, J=7,7 Hz, 1H, ArH6), 7,16 (dd, J = 9,3, 2,4 Hz, 1H, ArH7), 6,81 (dd, J=10,2, 2,5 Hz, 1H, ArH5), 3,95 - 3,82 (m, 2H, OCH2-), 2,83 (dd, J = 66,3, 14,1 Hz, 2H, CH2COO-), 2,71 - 2,53 (m, 2H, CH2), 2,10 – 2,00 (m, 3H, NHCOC3), 1,95 (dq, J = 14,8, 7,2 Hz, 2H, CH2CH3), 0,62 (t, J = 7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 171,85, 168,48, 156,96 (d, JC-F = 232,2 Hz), 139,91, 139,72, 138,14, 129,71, 129,26, 127,33, 126,03, 123,03, 118,95, 118,25, 108,62 (d, JC-F = 25,7 Hz), 107,90, 101,97 (d, JC-F = 22,8 Hz), 75,24, 66,38, 59,73, 42,38, 30,33, 24,15, 21,82, 7,80. MS [M-H]’: m / z = 409.

[0908] Example 108. Synthesis of 2-(l-ethyl-6-fluoro-8-(3-(hydroxymethyl) phenyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT23). The reaction was carried out with compound 40 (0.200 g, 0.50 mmol) and 3 M LiOH (0.835 mL, 2.50 mmol) in 1,4-dioxane (3 mL) according to the procedure described in Example 97, method A. After purification by flash chromatography (silica gel, PE / EtOAc / MeOH 7:2: 1) the CXT23 product was obtained as a pale brown solid (180 mg, yield 94%).1H NMR (600 MHz, DMSO-d6) 6 10,44 (s, 1H, NH), 7.47 (dt, J = 8,8, 8,4 Hz, 3H, ArH4’.5’-6’), 7,38 (dd, J = 7,3, 4,5 Hz, 1H, ArH2), 7,16 (dd, J = 9,3, 2,4 Hz, 1H, ArH7), 6,85 (dt, J = 16,1, 8,0 Hz, 1H, ArH5), 4,58 (s, 2H, CH2OH), 4,00 - 3,83 (m, 2H, OCH2-), 2,84 (dd, J = 67,6, 14,2 Hz, 2H, CH2COO-), 2,70 - 2,52 (m, 2H, CH2), 2,08 - 1,85 (m, 2H, C772CH3), 0,62 (t, J = 7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 8 171,91, 157,04 (d, J = 231,9 Hz), 143,32, 139,62, 137,46, 129,72, 128,74, 127,41, 126,65, 126,23, 125,77, 108,75 (d, J = 26,1 Hz), 107,89, 101,88 (d, J = 22,4 Hz), 75,21, 66,38, 62,90, 59,74, 42,40, 30,38, 21,82, 7,77. MS (ESI) [M-]: m / z 383.

[0909] Example 109. Synthesis of 2-(8-(3-carbamoylphenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT24). The reaction was carried out with compound 41 (0.060 g, 0.15 mmol) and 3 M LiOH (0.250 mL, 0.75 mmol) in 1,4-dioxane (2 mL) according to the procedure described in Example 97, Method A. After purification by flash chromatography (silica gel, 9: 1 DCM / MeOH) the CXT24 product was obtained as a white solid(58 mg, 98% yield).JH NMR (600 MHz, DMSO-d6) 6 11,82 (s, 1H, COOH), 8,56 (s, 1H, NH), 8,06 (s, 1H, ArH2), 7,85 (d, J = 7,8 Hz, 1H, ArH4), 7,75 (d, J = 7,7 Hz, 1H, ArH6), 7,58 (t, J = 7,7 Hz, 1H, ArH5), 7,32 (s, 2H, CONH2), 7,18 (dd, J = 9,4, 2,3 Hz, 1H, ArH7), 7,00 (dd, J = 10,4, 2,4 Hz, 1H, ArH5), 3,94 – 3,82 (m, 2H, OCH2-), 2,78 – 2,58 (m, 4H, CH2and CH2COO-), 2,05 - 1,84 (m, 2H, C772CH3), 0,68 (t, J =7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 5 168,77, 157,60 (d, JC-F =231,2 Hz), 141,94, 138,13, 135,98, 131,43, 129,92, 129,68, 127,58, 127,25, 125,39, 108,08 (d, JC-F= 27,4 Hz), 107,32, 102,82 (d, JC-F =22,5 Hz), 75,36, 60,08, 40,0, 30,53, 21,79, 8,32. MS [M-H]': m / z = 395.

[0910] Example 110. Synthesis of 2-(l-ethyl-6-fluoro-8-(3-hydroxyphenyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT26). The reaction was carried out with compound 42 (0.145 g, 0.38 mmol) and 3 M LiOH (0.635 mL, 1.9 mmol) in 1,4-dioxane (2.5 mL) according to the procedure described in Example 97, Method A. After purification by flash chromatography (silica gel, PE / EtOAc / MeOH 7:2:1) the CXT26 product was obtained as a white solid (128 mg, yield 91%). 'H NMR (600 MHz, DMSO-d6) 8 10,76 (s, 1H, NH), 7,27 (t, J = 7,8 Hz, 1H, ArH2'), 7,13 (dd, J= 9,3, 2,4 Hz, 1H, ArH4), 7,04-6,93 (m, 2H, ArH5-6’), 6,80 (ddd, J = 9,7, 6,3, 2,1 Hz, 2H, ArH5-7), 3,87 (m, 2H, OCH2-), 2,79 (dd, J= 41,7, 14,4 Hz, 2H, CH2COO-), 2,67 - 2,54 (m, 2H, CH2), 2,07 - 1,89 (m, 2H, CH2CH3), 0,63 (t, J= 7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 172,00, 158,32, 157,45 (d, JC-F = 232,1 Hz), 140,66, 139,54, 130,49, 130,04, 127,82, 126,70, 119,43, 115,68, 115,27, 108,91 (d, JC-F = 26,2 Hz), 107,99, 102,27 (d, JC-F = 23,1 Hz), 75,20, 60,13, 42,05, 30,69, 22,36, 8,30. MS [M-H]': m / z = 368.

[0911] Example 111. Synthesis of 2-(l-ethyl-6-fluoro-8-(4 - (hydroxymethyl) phenyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT27). The reaction was carried out with compound 43 (0.125 g, 0.31 mmol) and 3 M LiOH (0.517 mL, 1.55 mmol) in 1,4-dioxane (2 mL) according to the procedure described in Example 97, Method A. After purification by flash chromatography (silica gel, PE / EtOAc / MeOH 7:2: 1) the CXT27 product was obtained as a yellow solid (99 mg, yield 83%).1H NMR (600 MHz, DMSO-d6) 6 10,95 (s, 1H, NH), 7,55 (d, J = 8,1 Hz, 2H, ArH2’-6’), 7,43 (d, J = 8,1 Hz, 2H, ArH3’.5), 7,14 (dd, J = 9,3, 2,4 Hz, 1H, ArH7), 6,87 (dd, J = 10,3, 2,4 Hz, 1H, ArH5), 5,32 (s, 1H, OH), 4,54 (s, 2H, CH2OH), 3,92 -3,80 (m, 2H, OCH2-), 2,77 (dd, J = 37,6, 14,5 Hz, 2H, CH2COO-), 2,68 - 2,55 (m, 2H, CH2), 2,04 - 1,89 (m, 2H, CH2CH3), 0,64 (t, J = 7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 172,61, 157,04 (d, J = 232,1 Hz), 142,04, 140,46, 136,11, 129,57, 128,00, 127,39, 127,07,125,92, 108,43 (d, J = 26,7 Hz), 107,36, 101,75 (d, J = 23,0 Hz), 75,04, 64,95, 62,68, 59,61, 43,41, 30,14, 21,88, 15,19, 7,79. MS [M-H]': m / z = 382.

[0912] Example 112. Synthesis of 2-(8-benzyl-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT29). The reaction was carried out with 58 (0.653 g, 1.71 mmol), an aqueous solution of 3 M LiOH (2.9 mL, 5 eq) in 1,4-dioxane (11 mL) following the procedure given in Example 97, Method A. The crude product was purified by flash chromatography (silica gel, DCM / MeOH 9:1) to afford CXT29 as a pale yellow solid (471 mg, yield 75%). 'H NMR (600 MHz, CDCh) 8 8,29 (s, 1H, NH), 7,29 - 7,24 (m, 2H, ArH2’-6’), 7,23 - 7,17 (m, 3H, ArH3’-4’-5’), 7,04 (dd, J = 9,15, 2,43 Hz, 1H, ArH7), 6,76 (dd, J = 9,97, 2,41 Hz, 1H, ArH5), 4,11 (s, 2H, CH2Ph), 4,09-3,97 (m, 2H, CH2O-), 2,98 - 2,88 (m, 2H, CH2COOH), 2,82 - 2,70 (m, 2H, CH2), 2,00 - 1,87 (m, 2H, C772CH3), 0,76 (t, J = 7,35 Hz, 3H, CH3).13C NMR (151 MHz, CDC13) 6175,40, 158,07 (d, JC-F = 235,10 Hz), 139,09, 136,72, 131,42, 128,92, 128,87, 126,79 (d, JC-F= 10,07 Hz), 126,72, 124,93 (d, JC-F= 8,82 Hz), 111,15 (d, JC-F= 26,15 Hz), 108,76 (d, JC-F= 4,56 Hz), 101,76 (d, JC-F= 23,36 Hz), 75,08, 60,83, 42,49, 38,00, 30,88, 22,20, 7,69. MS [M-H]': m / z = 366.

[0913] Example 113. Synthesis of 2-(l-ethyl-6-fluoro-8-(2-hydroxyphenyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT31). The reaction was carried out with compound 44 (0.130 g, 0.34 mmol) and 3 M LiOH (0.567 mL, 1.7 mmol) in 1,4-dioxane (2 mL) according to the procedure described in Example 97, Method A. After purification by flash chromatography (silica gel, PE / EtOAc / MeOH 7:2:1) the CXT31 product was obtained as a white solid (94 mg, yield 75%).1H NMR (600 MHz, DMSO-d6) 6 12,06 (s, 1H, COOH), 10,08 (s, 1H, NH), 9,61 (s, 1H, OH), 7,31-7,18 (m, 2H, ArH2.3), 7,11 (d, J=9,3, Hz, 1H, ArH4), 6,98 (d, J=8,l Hz, 1H, ArH5), 6,88 (t, J = 7,4 Hz, 2H, ArH7), 6,78 (d, J=10,3 Hz, 2H, ArH5), 4,00-3,83 (m, 2H, OCH2-), 2,80 (dd, J = 57,2, 14,2 Hz, 2H, C2COOH), 2,70 - 2,54 (m, 2H, CH2), 2,10 - 1,86 (m, 2H, C772CH3), 0,60 (t, J= 7,2 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 172,38, 157,06 (d, JC-F = 231,2 Hz), 155,39, 139,41, 131,50, 131,07, 129,40, 126,98, 125,08, 124,29, 119,70, 116,56, 110,40 (d, JC-F =25,7 Hz), 107,64, 101,85 (d, JC-F =22,4 Hz), 75,70, 60,27, 42,87, 30,80, 22,38, 8,31. MS [M-H]': m / z = 368.

[0914] Example 114. Synthesis of 2-(8-(2-chlorophenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT32). The reaction was carried out with compound 45 (0.058 g, 0.14 mmol) and 3 M LiOH (0.235 mL, 0.7 mmol) in 1,4-dioxane (1 mL) according to the procedure described in Example 97, method A. After purification by flashchromatography (silica gel, PE / EtOAc / MeOH 8:1.5:0.5) the CXT32 product was obtained as a white solid (54 mg, 100% yield).JH NMR (600 MHz, DMSO-d6) 8 12,01 (s, 1H, COOH), 10,41 (s, 1H, NH), 7,62 (d, 7,2 Hz, 1H, ArH6), 7,45 (m, 3H, ArH3’-4’-5’), 7,21 (d, J = 9,2 Hz, 1H, ArH7), 6,76 (d, J = 9,2 Hz, 1H, ArH5), 3,92-3,86 (m, 2H, OCH2-), 2,87-2,63 (m, 2H, CH2COO-), 2,69 (m, 2H, CH2), 1,97 (m, 2H, C2CH3), 0,61 (t, J = 6,8 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 171,53, 156,30 (d, JC-F= 231,3 Hz), 139,61, 136,45, 132,75, 131,93, 130,30, 129,81, 129,66, 127,43, 126,80, 123,40, 109,76 (d, JC-F = 29,7 HZ), 107,53, 102,56 (d, JC-F = 22,5 Hz), 75,27, 59,77, 42,45, 30,38, 21,81, 7,77. MS [M-H]': m / z = 386 / 388.

[0915] Example 115. Synthesis of 2-(8-(4-chlorophenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT33). The reaction was carried out with compound 46 (0.117 g, 0.29 mmol) and 3 M LiOH (0.485 mL, 1.45 mmol) in 1,4-dioxane (2 mL) according to the procedure described in Example 97, Method A. After purification by flash chromatography (silica gel, PE / EtOAc / MeOH 8:1.5:0.5) the CXT33 product was obtained as a white solid (102 mg, yield 91%). 'H NMR (600 MHz, DMSO-d6) 6 12,02 (s, 1H, COOH), 10,63 (s, 1H, NH), 7,62 (m, 2H, ArH2.6’), 7,58 (m, 2H, ArH3.5’), 7,22 (d, J = 9,7 Hz, 1H, ArH7), 6,92 (d, J = 9,7 Hz, 1H, ArH5), 3,99 - 3,86 (m, 2H, OCH2-), 2,90-2,77 (m, 2H, CH2COO-), 2,66 (m, 2H, CH2), 2,02 (m, 2H, C772CH3), 0,65 (t, J = 7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 5 171,80, 156,98 (d, JC-F = 232,4 Hz), 139,92, 136,52, 132,46, 130,30, 129,67, 128,93, 127,41, 124,66, 108,80 (d, JC-F = 26,2 Hz), 107,93, 102,33 (d, JC-F = 22,8 Hz), 75,24, 59,73, 42,59, 30,37, 21,80, 7,79. MS [M-H]': m / z = 386 / 388.

[0916] Example 116. Synthesis of 2-(8-(3-acetylphenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT35). The reaction was carried out with compound 47 (0.077 g, 0.19 mmol) and 3 M LiOH (0.315 mL, 0.95 mmol) in 1,4-dioxane (1 mL) according to the procedure described in Example 97, Method A. After purification by flash chromatography (silica gel, DCM / MeOH 98:2) the CXT35 product was obtained as a pale yellow solid (46 mg, yield 61%). 'H NMR (600 MHz, CD3CN) 59,28 (s, 1H, NH), 8,10 (s, 1H, ArH2), 7,92 (m, 1H, ArH4), 7,76 (m, 1H, ArH6), 7,55 (m, 1H, ArH5), 7,11 (d, J = 9,8 Hz, 1H, ArH7), 6,92 (d, J = 9,8 Hz, 1H, ArH5), 3,98 - 3,84 (m, 2H, OCH2-), 2,86 - 2,74 (m, 2H, CH2COO-), 2,65 (m, 2H, CH2), 2,54 (s, 3H, COCH3), 1,84 (m, 2H, C772CH3), 0,65 (t, J = 7,3 Hz, 3H, CH3).13C NMR (151 MHz, CD3CN) 5 199,09, 172,98, 158,72 (d, JC-F = 232,6 Hz), 139,93, 139,24, 138,86, 133,83, 130,99, 130,50, 129,26, 128,53, 128,22, 126,37, 110,28 (d, Jc-F = 27,0 Hz), 109,62, 103,53 (d, JC-F = 23,3 Hz), 75,94, 61,11, 42,98, 31,34, 27,18, 22,60, 7,84. MS [M-H]': m / z = 394.

[0917] Example 117. Synthesis of 2-(l-ethyl-6-fluoro-8-(3-(methylsulfonyl) phenyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT36). The reaction was carried out with compound 48 (0.102 g, 0.23 mmol) and 3 M LiOH (0.385 mL, 1.15 mmol) in 1,4-dioxane (2 mL) according to the procedure described in Example 97, Method A. After purification by flash chromatography (silica gel, PE / EtOAc / MeOH 8:1.5:0.5) the CXT36 product was obtained as a white solid (71 mg, yield 72%). 'H NMR (600 MHz, DMSO-d6) 8 12,09 (s, 1H, COOH), 10,69 (s, 1H, NH), 8,09 (d, J = 1,4 Hz, 1H, ArH2), 7,98 (m, 2H, ArH4.6’), 7,83 (m, 1H, ArH5), 7,28 (d, J = 9,7 Hz, 1H, ArH7), 7,08 (d, J = 9,7 Hz, 1H, ArH5), 3,97 - 3,89 (m, 2H, OCH2-), 3,32 (s, 3H, SO2CH3), 2,90 - 2,75 (m, 2H, CH2COO-), 2,67 (m, 2H, CH2), 2,01 (m, 2H, C2CH3), 0,67 (t, J = 7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 171,67, 157,03 (d, JC-F=232,3 Hz), 141,59, 140,04, 138,83, 133,45, 130,11, 129,73, 127,72, 126,98, 126,01, 124,21, 109,27 (d, JC-F = 26,5 Hz), 108,09, 102,90 (d, JC-F = 22,6 Hz), 75,24, 59,74, 43,53, 42,50, 30,48, 21,79, 7,81. MS [M-H]’: m / z = 430.

[0918] Example 118. Synthesis of 2-(l-ethyl-6-fluoro-8-(3-methoxyphenyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT37). The reaction was carried out with compound 49 (0.108 g, 0.27 mmol) and 3 M LiOH (0.450 mL, 1.35 mmol) in 1,4-dioxane (2 mL) according to the procedure described in Example 97, method A. After purification by flash chromatography (silica gel, PE / EtOAc / MeOH 8:1.5:0.5) the CXT37 product was obtained as a white solid (55 mg, yield 53%).1H NMR (600 MHz, CD3CN) 69,27 (s, 1H, NH), 7,33 (t, J = 7,9 Hz, 1H, ArH5), 7,10 (m, 1H, ArH6), 7,08 - 7,05 (d, J = 9,7 Hz, 2H, ArH7-5), 6,93 - 6,85 (m, 2H, ArH2’-4’), 3,96 - 3,84 (m, 2H, OCH2-), 3,76 (s, 3H, OCH3), 2,86 - 2,76 (m, 2H, CH2COO-), 2,68 (m, 2H, CH2), 1,84 (m, 2H, C772CH3), 0,65 (t, J = 7,4 Hz, 3H, CH3).13C NMR (151 MHz, CD3CN) 6 173,04, 161,08, 158,68 (d, JC-F = 232,2 Hz), 140,23, 139,71, 131,21, 130,90, 128,42, 127,17, 121,46, 114,73, 114,22, 110,08 (d, JC-F = 27,0 Hz), 109,46, 103,11 (d, JC-F = 23,5 Hz), 75,89, 61,09, 55,88, 42,88, 31,27, 22,60, 7,84. MS [M-H]': m / z = 382.

[0919] Example 119. Synthesis of 2-(l-ethyl-6-fluoro-8-(pyridin-3-yl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT38). The reaction was carried out with 52 (0.081 g, 0.22 mmol) and 3 M LiOH (0.366 mL, 1.10 mmol) in 1,4-dioxane (1.3 mL) according to the procedure given in Example 97, Method A. After purification by flash column chromatography (silica gel, 9:1 DCM / MeOH) the CXT38 product was obtained as a paleyellow solid (62 mg, 80% yield).JH NMR (600 MHz, DMSO-d6) 8 11,09 (s, 1H, NH), 8,84 (s, 1H, ArH2), 8,63 (d, J = 3,9 Hz, 1H, ArH4), 8,02 (d, J = 7,9 Hz, 1H, ArH6), 7,55 (dd, J = 7,7 Hz, 1H, ArH5), 7,26 (d, J = 9,7 Hz, 1H, ArH7), 7,00 (d, J = 9,7 Hz, 1H, ArH5), 3,95 - 3,81 (m, 2H, OCH2-), 2,85 - 2,68 (m, 2H, CH2COO-), 2,66 (m, 2H, CH2), 2,02 (m, 2H, C772CH3), 0,66 (t, J = 7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 171,40, 157,03 (d, JC-F= 232,4 Hz), 148,98, 148,69, 140,65, 135,94, 133,52, 129,76, 127,62, 124,07, 122,44, 109,04 (d, JC-F = 26,1 Hz), 107,70, 102,77 (d, JC-F = 22,9 Hz), 75,19, 59,67, 43,30, 30,26, 21,87, 7,84. MS [M-H]’: m / z = 353.

[0920] Example 120. Synthesis of 2-(l-ethyl-6-fluoro-8-(pyrimidin-5-yl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT39). The reaction was carried out with 53 (0.086 g, 0.23 mmol) and 3 M LiOH (0.388 mL, 1.16 mmol) in 1,4-dioxane (1.4 mL) according to the procedure given in Example 97, method A. After purification by flash column chromatography (silica gel, DCM / MeOH 95:5) the CXT39 product was obtained as a pale yellow solid (39 mg, yield 48%).1H NMR (600 MHz, DMSO-d6) 6 12,10 (s, 1H, COOH), 10,98 (s, 1H, NH), 9,22 (s, 1H, ArH3), 8,99 (s, 2H, ArH2’-4’), 7,26 (d, J = 9,0 Hz, 1H, ArH7), 7,05 (d, J = 9,0 Hz, 1H, ArH5), 4,01 - 3,76 (m, 2H, OCH2-), 2,75 (m, 2H, CH2COO-), 2,61 (m, 2H, CH2), 1,96 (m,2H, C772CH3), 0,59 (t, J = 6,4 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 171,64, 157,46,156,98 (d, JC-F = 232,2 Hz), 156,30, 140,41, 131,51, 129,96, 127,76, 118,91, 109,40 (d, JC-F = 26,7 Hz), 108,06, 103,53 (d, JC-F = 23,1 Hz), 75,29, 59,73, 42,82, 30,43, 21,78, 7,82. MS [M-H]’: m / z = 354.

[0921] Example 121. Synthesis of 2-(l-ethyl-6-fluoro-8-(lH-pyrazol-3-yl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT40). The reaction was carried out with 54 (0.112 g, 0.31 mmol) and 3 M LiOH (0.522 mL, 1.57 mmol) in 1,4-dioxane (1.8 mL) according to the procedure given in Example 97, Method A. After purification by flash column chromatography (silica gel, PE / EtOAc / MeOH 7:2:1) the CXT40 product was obtained as a white solid (93 mg, yield 87%).1H NMR (600 MHz, DMSO-d6) 8 13,12 (s, 1H, COOH), 10,70 (s, 1H, NH), 7,87 (d, J = 1,9 Hz, 1H, ArH2), 7,39 (d, J = 9,9 Hz, 1H, ArH7), 7,17 (d, J = 9,9 Hz, 1H, ArH5), 6,94 (d, J = 2,3 Hz, 1H, ArH3), 4,00 - 3,87 (m, 2H, OCH2-), 2,90 (m, 2H, CH2COO-), 2,68 (m, 2H, CH2), 2,08 (m, 2H, C772CH3), 0,72 (t, J = 7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 173,15, 157,45 (d, JC-F = 231,0 Hz), 139,39, 134,69, 130,22, 128,98, 127,61, 108,00, 106,84 (d, JC-F = 27,3 Hz), 103,11, 102,62 (d, JC-F = 23,3 Hz), 75,01, 60,21, 43,07, 30,86, 22,37, 8,32. MS [M-H]': m / z = 342.Example 122. Synthesis of 2-(l-ethyl-6-fluoro-8-(l-methyl-lH-pyrazol-5-yl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT41). The reaction was carried out with 55 (0.049 g, 0.13 mmol) and 3 M LiOH (0.220 mL, 0.66 mmol) in 1,4-dioxane (0.8 mL) according to the procedure given in Example 97, Method A. After purification by flash column chromatography (silica gel, DCM / MeOH 95:5) the CXT41 product was obtained as a white solid (45 mg, 96% yield).JH NMR (600 MHz, DMSO-d6) 8 12,04 (s, 1H, COOH), 10,62 (s, 1H, NH), 7,59 (d, J = 1,8 Hz, 1H, ArH2), 7,31 (d, J = 9,6 Hz, 1H, ArH7), 6,93 (d, J = 9,6 Hz, 1H, ArH5), 6,44 (d, J = 1,9 Hz, 1H, ArH3), 4,00 - 3,88 (m, 2H, OCH2-), 3,70 (s, 3H, NCH3), 2,95 - 2,72 (m, 2H, CH2COO-), 2,67 (m, 2H, CH2), 2,00 (m, 2H, C772CH3), 0,63 (t, J = 7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 171,60, 156,30 (d, JC-F = 232,5 Hz), 139,98, 138,95, 138,20, 130,43, 127,24, 114,51, 109,97 (d, JC-F = 26,5 Hz), 107,99, 106,86, 103,61 (d, JC-F = 23,0 Hz), 75,26, 59,77, 42,46, 37,09, 30,51, 21,76, 7,72. MS (ESI) [M-]’: m / z 356.

[0922] Example 123. Synthesis of 2-(8-(cyclohex-l-en-l-yl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT42). The reaction was carried out with 56 (0.101 g, 0.27 mmol) and 3 M LiOH (0.453 mL, 1.36 mmol) in 1,4-dioxane (1.6 mL) according to the procedure given in Example 97, Method A. After purification by flash column chromatography (silica gel, DCM / MeOH 95:5) the CXT42 product was obtained as a pale yellow solid (95 mg, yield 98%).1H NMR (600 MHz, DMSO-d6) 6 12,20 (s, 1H, COOH), 10,15 (s, 1H, NH), 7,03 (d, J = 9,9 Hz, 1H, ArH7), 6,74 (d, J = 9,9 Hz, 1H, ArH5), 6,04 (s, 1H, ArH2), 3,97 - 3,85 (m, 2H, OCH2-), 2,95 - 2,83 (m, 2H, CH2COO-), 2,61 (m, 2H, CH2), 2,47 - 2,31 (m, 2H, CyH3’-6’), 2,24 (m, 2H, CyH6-3), 2,04 (m, 2H, C772CH3), 1,84 - 1,74 (m, 2H, CyH4-5), 1,72 - 1,64 (m, 2H, CyH5-4’), 0,64 (t, J = 7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 172,05, 156,86 (d, JC-F = 231,4 Hz), 138,85, 134,14, 129,23, 128,56, 127,19, 126,91, 107,61, 106,68 (d, JC-F = 25,8 Hz), 100,95 (d, JC-F = 22,8 Hz), 75,12, 59,72, 42,44, 30,32, 27,95, 25,20, 22,62, 21,79, 21,69, 7,80. MS [M-H]’: m / z = 356.

[0923] Example 124. Synthesis of 2-(8-(2,5-dichlorophenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT44). The reaction was carried out with compound 50 (0.117 g, 0.27 mmol) and 3 M LiOH (0.450 mL, 1.35 mmol) in 1,4-dioxane (2 mL) according to the procedure described in Example 97, Method A. After purification by flash chromatography (silica gel, DCM / MeOH 98:2) the CXT44 product was obtained as a white solid (106 mg, yield 93%). 'H NMR (600 MHz, DMSO-d6) 6 12,09 (s, 1H, COOH), 10,50 (s, 1H, NH), 7,61 (d, J = 8,6 Hz, 1H, ArH6), 7,52 (dd, J = 8,6, 2,0 Hz, 1H, ArH3), 7,49 (d, J = 1,9Hz, 1H, ArH7), 7,26 - 7,19 (m, 1H, ArH4), 6,79 (dd, J = 9,7, 1,7 Hz, 1H, ArH5), 3,97 - 3,83 (m, 2H, OCH2-), 3,28 - 2,79 (m, 2H, CH2COO-), 2,70 - 2,43 (m, 2H, CH2), 1,93 (d, J = 7,2 Hz, 2H, CH2CH3), 0,57 (t, J = 7,1 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 8 171,59, 156,26 (d, JC-F = 232,3 Hz), 139,85, 138,27, 131,77, 131,77, 131,42, 131,37, 130,12, 129,50, 126,84, 122,07, 109,67 (d, JC-F = 27,7 Hz), 107,58, 103,09 (d, JC-F = 22,8 Hz), 75,27, 59,77, 42,66, 30,49, 21,81, 7,78. MS [M-H]': m / z = 422 / 421 / 420.

[0924] Example 125. Synthesis of 2-(8-(3,5-dichlorophenyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT45). The reaction was carried out with compound 51 (0.123 g, 0.28 mmol) and 3 M LiOH (0.470 mL, 1.41 mmol) in 1,4-dioxane (2 mL) according to the procedure described in Example 97, method A. After purification by flash chromatography (silica gel, PE / EtOAc / MeOH 8:1.5:0.5) the CXT45 product was obtained as a white solid (49 mg, yield 41%). 'H NMR (600 MHz, DMSO-d6) 6 11,98 (s, 1H, COOH), 10,63 (s, 1H, NH), 7,67 (s, 1H, ArH4), 7,57 (d, J = 1,5 Hz, 2H, ArH2-6’), 7,24 (dd, J = 9,2, 2,0 Hz, 1H, ArH7), 6,96 (dd, J = 10,0, 2,1 Hz, 1H, ArH5), 3,95 - 3,85 (m, 2H, OCH2-), 2,82 (m, 2H, CH2COO-), 2,69 - 2,58 (m, 2H, CH2), 2,05 - 1,92 (m, 2H, C772CH3), 0,63 (t, J = 7,3 Hz, 3H, CH3).13C NMR (151 MHz, DMSO-d6) 6 171,26, 156,57 (d, JC-F = 232,7 Hz), 140,86, 139,71, 134,23, 129,31, 127,35, 127,11, 127,01, 122,74, 109,05 (d, JC-F = 26,4 Hz), 107,88, 102,91 (d, JC-F = 22,8 Hz), 75,02, 59,47, 42,16, 30,22, 21,48, 7,49. MS [M-H]': m / z =422 / 421 / 420.

[0925] Example 126. Synthesis of 2-(l-ethyl-6-fluoro-8-(isoxazol-4-yl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT46). The reaction was carried out with 57 (0.071 g, 0.20 mmol) and 3 M LiOH (0.330 mL, 0.99 mmol) in 1,4-dioxane (1.1 mL) according to the procedure given in Example 97, Method A. After purification by flash column chromatography (silica gel, 9: 1 DCM / MeOH) the CXT46 product was obtained as a white solid (62 mg, 90% yield). 'H NMR (600 MHz, DMSO-d6) 6 11,25 (s, 1H, COOH), 10,58 (s, 1H, NH),7,80 (s, 1H, ArH2), 7,60 (s, 1H, ArH3), 6,93 (d, 8,5 Hz, 1H, ArH7), 6,62 (d, 8,5 Hz, 1H, ArH5), 3,83 - 3,74 (m, 2H, OCH2-), 2,89 - 2,63 (m, 2H, CH2COO-), 2,48 (dd, J = 16,0, 11,9 Hz, 2H, CH2), 1,93 - 1,82 (m, 2H, C772CH3), 0,54 - 0,51 (m, 3H, CH3).13C NMR (151 MHz, DMSO-d6) δ 171,55, 161,79, 156,69 (d, JC-F = 231,8 Hz), 139,59, 138,02, 129,88, 127,46, 126,67, 117,08, 108,09 (d, JC-F = 23,5 Hz), 106,96, 102,04 (d, JC-F = 24,1 Hz), 75,22, 59,80, 42,54, 30,70, 21,76, 7,83. MS [M-H]’: m / z = 343.Example 127. Synthesis of 2-(l-ethyl-6-fluoro-8-(4-methoxybenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT62). The reaction was carried out with 59 (0.100 g, 0.243 mmol), an aqueous solution of 3 M LiOH (1.62 mL, 4.86 mmol, 20 eq) in 1,4-dioxane (3 mL) following the procedure given in Example 97, Method A. The crude product was purified by reverse phase with CH3CN / H2O 0.1% TFA 4:6 as eluent to afford CXT62 (yield 72%).JH NMR (600 MHz, CD3OD3): 57,14 - 7,09 (m, 2H, H2,6’), 6,92 (d, J = 9,0 Hz, 1H, H7), 6,83 - 6,75 (m, 2H, H3’,5’), 6,51 (d, J = 10,3 Hz, 1H, H5), 4,08 (s, 2H, CH2Ph), 4,03 -3,92 (m, 2H, CH2O), 3,70 (s, 3H, OCH3), 2,97-2,95 e 2,84-2,82 (m, 2H, CftCOOH), 2,77-2,69 e 2,62-2,56 (m, 2H, CW2CH2O), 2,05 (q, J = 7,6 Hz, 2H, C / LCH,). 0,72 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CD3OD3): 5 174,52, 159,59, 159,12 (d, JC-F = 232,5 Hz), 138,97, 133,04, 132,90, 130,84, 128,06 (d, JC-F = 10,1 Hz), 127,11 (d, JC-F = 8,7 Hz), 114,86, 110,48 (d, JC-F= 26,3 Hz), 109,49, 101,55 (d, JC-F= 23,3 Hz), 76,87, 61,71, 55,61, 43,77, 36,84, 32,09, 23,07, 8,07. MS [M-H]': m / z = 414.

[0926] Example 128. Synthesis of 2-(8-(4-chlorobenzyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT64). The reaction was carried out with 60 (0.125 g, 0.30 mmol), an aqueous solution of 3 M LiOH (2.0 mL, 4.86 mmol, 20 eq) in 1,4-dioxane (3 mL) following the procedure given in Example 97, Method A. The crude product was purified by reverse phase with 4:6 CH3CN / H2O +0.1% TFA as eluent to afford CXT64 (yield 58%). 'H NMR (600 MHz, CD3OD) 57,06 (d, J = 8,59 Hz, 2H, H2,6), 7,01 (d, J = 6,90 Hz, 2H, H3, 5 ), 6,79 (d, J = 9,27 Hz, 1H, H7), 6,39 (d, J = 10,48 Hz, 1H, H5), 3,99 (s, 2H, CH2Ph), 3,87 - 3,79 (m, 2H, CH2O), 2,82-2,79 e 2,68-2,65 (m, 2H, CftCOOH), 2,58-2,54 e 2,50-2,45 (m, 2H, CW2CH2O), 1,89 (q, J = 7,20 Hz, 2H, C / LCH,). 0,56 (t, J = 7,02 Hz, 3H, CH2CH3).13C NMR (151 MHz, CD3OD) 5 174,48, 159,09 (d, JC-F = 232,87 Hz), 140,01, 139,20, 132,98, 132,94, 131,35, 129,45, 128,27 (d, JC-F = 10,05 Hz), 125,92 (d, JC-F = 8,83 Hz), 110,64 (d, JC-F = 26,44 Hz), 109,62 (d, JC-F = 4,59 Hz), 101,93 (d, JC-F = 23,40 Hz), 76,89, 61,73, 43,80, 36,97, 32,14, 23,07, 8,06. MS [M-H]': m / z = 402 / 404.

[0927] Example 129. Synthesis of 2-(l-ethyl-6-fluoro-8-(4-fluorobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT65). The reaction was carried out with 61 (0.080 g, 0.20 mmol), an aqueous solution of 3 M LiOH (1.3 mL) in 1,4-dioxane (2 mL) following the procedure given in Example 97, Method A. The crude product was purified by reverse phase with CH3CN / H2O 0.1% TFA 4:6 as eluent to afford CXT65 (yield 95%). 'H NMR (600 MHz, CD3OD) 57,25 - 7,17 (m, 1H, H2,6), 7,00 - 6,91 (m, 3H, two signals: H7,H3’,5’), 6,54 (dd, J = 10,28, 2,43 Hz, 1H, H5), 4,16 (s, 2H, Hi7), 4,06 - 3,95 (m, 2H, CH2O), 2,98-2,96 e 2,84-2,82 (dd, J = 82,37, 14,45 Hz, 2H, CftCOOH), 2,78-2,71 e 2,67-2,61 (m, 2H, C / Z2CH2O), 2,06 (q, J = 7,39 Hz, 2H, C772CH3), 0,73 (t, J = 7,35 Hz, 3H, CH2CH;).13C NMR (151 MHz, CD3OD) 5 174,59, 162,90 (d, JC-F = 242,63 Hz), 159,12 (d, JC-F = 232,77 Hz), 139,22, 137,14 (d, JC-F = 3,32 Hz), 132,92, 131,46 (d, JC-F = 7,89 Hz), 128,25 (d, JC-F = 10,07 Hz), 126,39 (d, JC-F = 8,94 Hz), 116,00 (d, JC-F = 21,41 Hz), 110,55 (d, JC-F = 26,45 Hz), 109,57, 101,80 (d, JC-F = 23,39 Hz), 76,91, 61,74, 43,89, 36,84, 32,15, 23,10, 8,07. MS [M-H]': m / z = 384.

[0928] Example 130. 2-(8-(cyclopentylmethyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT68). The reaction was carried out using intermediate 96 (0.075 mg, 0.20 mmol), 3 M LiOH (0.34 mL, 1.0 mmol), 1,4-dioxane (3.0 mL) according to the procedure given in Example 97, Method A. The crude was purified by reverse phase chromatography using a 0.1% TFA 6:4 ACN7 H2O mixture as eluent to afford the pure CXT68 product (yield 46%). 'H NMR (600 MHz, CDC13) 5 8,79 (s, 1H, NH), 6,99 (dd, J = 9,21, 2,44 Hz, 1H, ArH7), 6,73 (dd, J = 10,22, 2,44 Hz, 1H, ArH5), 4,13-4,09 and 4,07-4,03 (m, 2H, H3a, H3b), 3,10 (d, Jgem = 2,53 Hz, 2H, CffiaCOOMe, C772Z? COOMe), 2,85 - 2,74 (m, 2H, H4), 2,65 (d, J = 7,47 Hz, 2H, H17), 2,20 - 2,12 (m, 1H, Hl’), 2,20-2,12 e 2,07-2,01 (m, 2H, Cf£2aCH3, C7726CH3), 1,77 - 1,69 (m, 2H, H2’a, H5’a), 1,68 - 1,60 (m, 2H, H2’b, H5’b), 1,55 - 1,47 (m, 2H, H3’a, H4’a), 1,22 - 1,17 (m, 2H, H3’b, H4’b), 0,89 (t, J = 7,36 Hz, 3H, CH2C773).13C NMR (151 MHz, CDC13) 5 176,13, 158,08 (d, JC-F = 234,34 Hz), 136,40, 131,61, 126,46 (d, JC-F = 8,84 Hz), 126,29 (d, JC-F = 10,10 Hz), 110,47 (d, JC-F = 25,72 Hz), 108,67 (d, JC-F = 4,66 Hz), 100,85 (d, JC-F = 23,42 Hz), 75,27, 60,93, 42,65, 40,27, 37,25, 32,89, 32,77, 30,95, 25,02, 25,01, 22,25, 7,74. MS (ESI-MS) [M-H]': m / z 358.

[0929] Example 131. Synthesis of 2-(l-ethyl-6-fluoro-8-(2-methylbenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT72). The reaction was carried out with compound 65 (0.100 g, 0.25 mmol) and 3 M LiOH (0.43 mL, 1.26 mmol) in 1,4-dioxane (1.5 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 44%). 'H NMR (600 MHz, CDC13) 58,29 (s, 1H, NH), 7,19 (dd, J = 5,0, 1,2 Hz, 1H, H3), 7,15 (m, J = 8,8, 4,7, 2,5 Hz, 1H, H5), 7,11 (d, J = 7,1 Hz, 1H, H6), 7,01 (d, J = 9,1 Hz, 1H, H7), 6,60 (d, J = 10,1 Hz, 1H, H5), 4,16 - 3,99 (m, 4H, Hi7, H3), 2,91 (m, 2H, Hi3), 2,77 (m, J = 25,6, 15,4, 5,0 Hz, 2H, H4), 2,21 (s, J = 5,0 Hz, 3H, C2CW,', 1,99 - 1,90 (m, 2H,CH2CH3), 0,77 (t, J = 7,4 Hz, 3H, CH2CW;).13C NMR (151 MHz, CDCh) 6 174,91, 158,19 (d, JC-F = 235,1 Hz), 137,29, 136,96, 131,52, 130,70, 129,73, 127,15, 126,70, 126,39 (d, J = 10,0 Hz), 124,20 (d, J = 5,1 Hz), 110,76 (d, JC-F = 26,5 Hz), 108,68, 101,53 (d, JC-F = 23,4 Hz), 75,24, 60,88, 42,52, 35,71, 30,98, 22,17, 19,71, 7,73. MS [M-H]’: m / z =380.

[0930] Example 132. Synthesis of 2-(l-ethyl-6-fluoro-8-(3-methylbenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT73). The reaction was carried out with compound 68 (0.150 g, 0.38 mmol) and 3 M LiOH (0.63 mL, 1.9 mmol) in 1,4-dioxane (2.3 mL) according to the procedure set forth in Example 97, Method A. The crude product was purified by reverse phase chromatography using a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 50%) as eluent. 'H NMR (600 MHz, CDCh) 8 8,38 (s, 1H, NH), 7,19 - 7,14 (m, 1H, H5), 7,06 - 7,00 (m, 4H, H7, H2,4’,6’), 6,76 (dd, J = 10,0, 2,4 Hz, 1H, H5), 4,08 (s, 2H, H17), 4,11 - 3,98 (m, 2H, H3), 2,98 - 2,91 (m, 2H, H13), 2,83 - 2,71 (m, 2H, H4), 2,28 (s, 3H, C3 CH3), 2,01 - 1,90 (m, 2H, CW2CH3). 0,77 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCh) 6 175,50, 158,07 (d, J = 235,0 Hz), 139,00, 138,56, 136,66, 131,47, 129,67, 128,71, 127,45, 126,78 (d, J = 10,0 Hz), 125,95, 125,13 (d, J = 8,7 Hz), 111,02 (d, JC-F = 26,3 Hz), 108,73, 101,64 (d, JC-F = 23,3 Hz), 75,18, 60,83, 42,55, 37,86, 30,94, 22,19, 21,44, 7,68. MS [M-H]’: m / z =380.

[0931] Example 133. Synthesis of 2-(l-ethyl-6-fluoro-8-(4-methylbenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT74). The reaction was carried out with compound 75 (0.104 g, 0.26 mmol) and 3 M LiOH (0.44 mL, 1.31 mmol) in 1,4-dioxane (1.6 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of 1:1 CH3CN / H2O + 0.1% TFA (yield: 70%). 'H NMR (600 MHz, CDCh) 6 8,22 (s, 1H, NH), 7,10 (dt, J = 14,9, 5,1 Hz, 4H, H2’,3’,5’.6’), 7,04 - 7,00 (m, 1H, H7), 6,75 (dd, J = 10,0, 2,4 Hz, 1H, H5), 4,08 (d, J = 3,8 Hz, 2H, H17), 4,07 - 3,97 (m, 2H, H3), 2,92 - 2,89 (m, 2H, H13), 2,81 - 2,71 (m, 2H, H4), 2,30 (s, 3H, C4Cft), 1,99 - 1,87 (m, 2H, CW2CH3). 0,76 (t, J = 7,4 Hz, 3H, CH2CW;).13C NMR (151 MHz, CDCh) 6 174,39, 158,10 (d, J = 234,9 Hz), 136,56, 136,34, 136,00, 131,47, 129,55, 128,85, 126,76 (d, J = 10,0 Hz), 125,27 (d, J = 8,7 Hz), 111,06 (d, JC-F = 26,3 Hz), 108,72, 101,65 (d, JC-F = 23,3 Hz), 75,18, 60,88, 42,43, 37,59, 30,94, 22,19, 21,12, 7,70. MS [M-H]’: m / z =380.

[0932] Example 134. Synthesis of 2-(l-ethyl-6-fluoro-8-(2-chlorobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT75). The reaction was carried out withcompound 66 (0.132 g, 0.32 mmol) and 3 M LiOH (0.53 mL, 1.59 mmol) in 1,4-dioxane (2.1 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 82%).JH NMR (600 MHz, CDCh) 8 8,45 (s, 1H, NH), 7,42 - 7,38 (m, 1H, H3), 7,20 - 7,14 (m, 3H, H4,5’,6’), 7,04 (dd, J = 9,1, 2,4 Hz, 1H, H7), 6,71 (dd, J = 10,0, 2,4 Hz, 1H, H5), 4,28 - 4,20 (m, 2H, H17), 4,10 - 3,98 (m, 2H, H3), 2,98 - 2,90 (m, 2H, H13), 2,83 -2,73 (m, 2H, H4), 2,06 - 1,93 (m, 2H, C LCH,). 0,81 (t, J = 7,4 Hz, 3H, CHiCft).13C NMR (151 MHz, CDCh) 6 177,41, 158,91 (d, J = 234,9 Hz), 137,92, 136,63, 134,13, 132,57, 130,97, 129,79, 128,30, 127,31, 123,57 (d, J = 8,7 Hz), 111,19 (d, JC-F = 26,3 Hz), 108,91, 102,05 (d, JC-F = 23,3 Hz), 75,21, 60,88, 42,35, 34,95, 31,02, 22,20, 7,76. MS [M-H]': m / z =400 / 402.

[0933] Example 135. 2-(l-ethyl-6-fluoro-8-(4,4,4-trifluorobutyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT77). The reaction was carried out using intermediate 97 (0.050 mg, 0.13 mmol), 3 M LiOH (0.22 mL, 0.66 mmol), 1,4-dioxane (3.0 mL) according to the procedure given in Example 97, Method A. The crude was purified by reverse phase chromatography using a 0.1% TFA 1:1 ACN / H2O mixture as eluent to afford the pure CXT77 product (yield 54%).1H NMR (600 MHz, CDC13) 6 8,88 (s, 1H, NH), 7,00 (dd, J = 9,09, 2,40 Hz, 1H, H7), 6,64 (dd, J = 10,04, 2,41 Hz, 1H, H5), 4,15 -4,05 (m, 2H, H3a, H3b), 3,16 - 3,07 (m, 2H, C772COOH), 2,80 (td, J = 5,48, 1,07 Hz, 2H, C772CH2CH2CF3), 2,67 - 2,45 (m, 2H, H4a, H4b), 2,20 - 1,96 (m, 4H, two signals: CH2C / 72CH2CF3, CH2CH2C772CF3), 1,87 (m, 2H, C772CH3), 0,90 (t, J = 7,36 Hz, 3H, CH2C773).13C NMR (151 MHz, CDC13) 6 174,53, 158,12 (d, JC-F = 235,07 Hz), 136,52, 131,32, 129,23 (q, JC-F = 273,84 Hz), 126,56 (d, JC-F = 9,78 Hz), 124,78 (d, J = 8,71 Hz), 109,95 (d, J = 26,14 Hz), 108,66 (d, J = 4,55 Hz), 101,52 (d, J = 23,50 Hz), 75,52, 60,98, 42,40, 33,26 (q, J = 28,32 Hz), 30,95, 29,62, 22,17, 21,59, 7,73. MS (ESLMS) [M-H]': m / z 386.

[0934] Example 136. Synthesis of 2-(l-ethyl-6-fluoro-8-(3-chlorobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT78). The reaction was carried out with compound 69 (0.190 g, 0.46 mmol) and 3 M LiOH (0.76 mL, 2.28 mmol) in 1,4-dioxane (3.0 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 +0.1% TFA (yield: 71%).1H NMR (600 MHz, CDCh) 88,58 (s, 1H, NH), 7,21 - 7,16 (m, 3H, H2 +5 ), 7,08 (m, 1H, H6), 7,05 (dd, J = 9,1, 2,4 Hz, 1H, H7), 6,72 (dd, J = 9,9, 2,4 Hz, 1H, H5), 4,06 -4,03 (m, 2H, Hi7), 4,10 - 3,97 (m, 2H, H3), 3,01 - 2,91 (m, 2H, H13), 2,82 - 2,71 (m, 2H, H4),2,07 - 1,89 (m, 2H, C / LCH,). 0,80 (t, J = 7,4 Hz, 3H, CH2C / L.13C NMR (151 MHz, CDCh) 5 174,70, 158,02 (d, J = 234,9 Hz), 141,15, 137,09, 134,57, 131,28, 130,03, 128,98, 127,07, 126,89, 124,00, 123,94 (d, J = 8,7 Hz), 111,07 (d, JC-F = 26,3 Hz), 108,87, 102,05 (d, JC-F = 23,3 Hz), 75,07, 60,80, 42,30, 37,40, 30,83, 22,22, 7,69. MS [M-H]': m / z =400 / 402.

[0935] Example 137. Synthesis of 2-(l-ethyl-6-fluoro-8-(3-fluorobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT79). The reaction was carried out with compound 70 (0.170 g, 0.43 mmol) and 3 M LiOH (0.71 mL, 2.13 mmol) in 1,4-dioxane (2.7 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 73%). 'H NMR (600 MHz, CDCh) 8 8,50 (s, 1H, NH), 7,25 - 7,20 (m, 1H, H5), 7,05 (dd, J = 9,1, 2,4 Hz, 1H, H7), 6,99 (dd, J = 7,6, 0,5 Hz, 1H, H6), 6,92 - 6,86 (m, 2H, H2’,4’), 6,74 (dd, J = 9,9, 2,4 Hz, 1H, H5), 4,09 (s, 2H, H17), 4,10 - 3,96 (m, 2H, H3), 2,99 - 2,91 (m, 2H, H13), 2,81 - 2,72 (m, 2H, H4), 2,05 - 1,88 (m, 2H, C / LCH,). 0,79 (t, J = 7,4 Hz, 3H, CH2CW3).13C NMR (151 MHz, CDCh) 6 174,61, 163,18 (d, J = 246,2 Hz), 158,03 (d, J = 234,7 Hz), 141,68, 137,08, 131,30, 130,28, 126,93, 124,52 (d, J = 8,7 Hz), 124,10, 115,83 (d, J = 21,4 Hz), 113,60 (d, J = 21,1 Hz), 111,11 (d, JC-F = 26,3 Hz), 108,87, 102,04 (d, JC-F = 23,3 Hz), 75,02, 60,79, 42,27, 37,58, 30,81, 22,22, 7,66. MS [M-H]': m / z =384.

[0936] Example 138. Synthesis of 2-(l-ethyl-6-fluoro-8-(2-fluorobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT80). The reaction was carried out with compound 67 (0.194 g, 0.49 mmol) and 3 M LiOH (0.80 mL, 1.46 mmol) in 1,4-dioxane (3.1 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 80%). 'H NMR (600 MHz, CDCh) 6 8,57 (s, 1H, NH), 7,21 - 7,14 (m, 2H, H4’.6’), 7,07 - 7,00 (m, 3H, H7,3’.5’), 6,77 (dd, J = 10,0, 2,4, 0,4 Hz, 1H, H5), 4,17 - 4,09 (m, 2H, H17), 4,08 - 3,98 (m, 2H, H3), 3,02 - 2,92 (m, 2H, H13), 2,82 - 2,70 (m, 2H, H4), 2,09 -1,93 (m, 2H, C772CH3). 0,82 (t, J = 7,4 Hz, 3H, CH2C / L.13C NMR (151 MHz, CDCh) 6 174,16, 161,69 (d, J = 246,2 Hz), 157,29 (d, J = 234,7 Hz), 136,93, 131,21, 131,10, 131,08, 128,60, 128,55, 126,89, 126,82, 126,09, 125,98, 124,59 (d, J = 8,7 Hz), 115,56 (d, J = 22,3 Hz), 110,85 (d, JC-F = 26,3 Hz), 108,94, 101,94 (d, JC-F = 23,3 Hz), 75,13, 60,83, 42,41, 37,99, 30,94, 22,22, 7,73. MS [M-H]': m / z =384.

[0937] Example 139. Synthesis of 2-(l-ethyl-6-fluoro-8-(3-methoxybenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT81). The reaction was carried out withcompound 71 (0.110 g, 0.27 mmol) and 3 M LiOH (0.45 mL, 1.34 mmol) in 1,4-dioxane (1.5 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 71%).JH NMR (600 MHz, CDCh) 8 8,37 (s, 1H, NH), 7,19 (t, J = 7,9 Hz, 1H, H5), 7,02 (dd, J = 9,2, 2,4 Hz, 1H, H7), 6,77 (m, 4H, H5,2’,4’,6’), 4,07 - 3,95 (m, 4H, H3,i7), 3,75 (s, 3H, OCH3), 2,91 (m, 2H, H13), 2,76 (m, 2H, H4), 2,04 - 1,90 (m, 2H, CW2CH3), 0,77 (t, J = 7,4 Hz, 3H, CH2C773).13C NMR (151 MHz, CDCh) 6 174,11, 159,78, 157,97 (d, J = 234,7 Hz), 140,68, 136,67, 131,26, 129,84,126,71, 124,69 (d, J = 8,7 Hz), 121,45, 114,92, 111,87, 110,94 (d, JC-F = 26,3 Hz), 108,68, 101,72 (d, JC-F = 23,3 Hz), 75,12, 60,73, 55,37, 42,21, 38,05, 30,89, 22,15, 7,66. MS [M-H]': m / z =396.

[0938] Example 140. Synthesis of 2-(l-ethyl-6-fluoro-8-(3-chloro-4-fluorobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT82). The reaction was carried out with compound 85 (0.117 g, 0.27 mmol) and 3 M LiOH (0.45 mL, 1.35 mmol) in 1,4-dioxane (1.5 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 95%). 'H NMR (600 MHz, CDCh) 6 8,57 (s, 1H, NH), 7,26 - 7,24 (m, 1H, H2), 7,10 - 7,01 (m, 3H, H7,5’.6’), 6,74 - 6,68 (m, 1H, H5), 4,11 - 3,97 (m, 4H, H3, i7), 3,04 -2,92 (m, 2H, H13), 2,82 - 2,73 (m, 2H, H4), 2,09 - 1,87 (m, 2H, CH2CH3), 0,81 (t, J = 7,4 Hz, 3H, CH2Oh).13C NMR (151 MHz, CDCh) 6 172,57, 156,69 (d, J = 234,7 Hz), 151,19 (d, J = 234,7 Hz), 139,22, 138,45, 132,05, 131,10, 128,44, 125,20, 123,97 (d, J = 8,7 Hz), 121,17, 116,72 (d, J = 21,0 Hz), 110,99 (d, JC-F = 26,3 Hz), 108,88, 102,14 (d, JC-F = 23,3 Hz), 74,95, 60,72, 41,99, 36,69, 30,71, 22,15, 7,60. MS [M-H]': m / z =418 / 420.

[0939] Example 141. Synthesis of 2-(8-(3-chloro-2-fluorobenzyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT83). The reaction was carried out with compound 76 (0.040 g, 0.092 mmol) and 3 M LiOH (0.15 mL, 0.46 mmol) in 1,4-dioxane (0.5 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 82%).1H NMR (600 MHz, CDCh) 88,67 (s, 1H, NH), 7,24 (td, J = 8,0, 1,7 Hz, 1H, H4), 7,06 - 7,03 (m, 1H, H2), 7,04 - 7,01 (m, 1H, ArH7), 6,96 (td, J = 7,9, 0,9 Hz, 1H, H3), 6,74 (dd, J = 9,9, 2,4 Hz, 1H, ArH5), 4,15 - 4,09 (m, 2H, Hi7), 4,08 - 3,99 (m, 2H, H3), 3,04 - 2,95 (m, 2H, Hi3), 2,77 (dt, J = 10,6, 5,3 Hz, 2H, H4), 2,10 - 1,96 (m, 2H, H15), 0,83 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCh) 6 174,43, 157,17, 155,44, 137,07,131,08, 129,13, 129,10, 127,86, 126,87, 124,80, 122,80, 110,93, 108,93, 102,22, 75,07, 60,74, 42,26, 30,83, 22,15, 7,65. MS [M-H]': m / z =418 / 420.

[0940] Example 142. Synthesis of 2-(l-ethyl-6-fluoro-8-(3-(trifluoromethyl) benzyl)-l,3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT84). The reaction was carried out with compound 72 (0.080 g, 0.18 mmol) and 3 M LiOH (0.30 mL, 0.89 mmol) in 1,4-dioxane (1.0 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 67%).JH NMR (600 MHz, CDCh) 8 8,63 (s, 1H, NH), 7,54 - 7,49 (m, 1H, H2), 7,49 - 7,44 (m, 1H, H6), 7,39 (d, J = 5,8 Hz, 2H, H4,5’), 7,05 (dd, J = 9,1, 2,4 Hz, 2H, H7), 6,71 (dd, J = 9,9, 2,4 Hz,2H, H5), 4,17 - 4,09 (m, 2H, H17), 4,08 - 3,97 (m, 2H, H3), 3,01 -2,91 (m, 2H, H13), 2,82 - 2,72 (m, 2H, H4), 2,05 - 1,88 (m, 2H, CW2CH3. 0,79 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCl3) δ 174,09, 158,74 (d, J = 234,7 Hz), 139,98, 137,11, 132,24, 131,15, 131,08, 129,21, 126,89, 125,50, 125,08 (d, J = 8,7 Hz), 123,75, 123,53, 110,95 (d, JC-F = 26,3 Hz), 108,83, 102,09 (d, JC-F = 23,3 Hz), 74,95, 60,74, 42,09, 37,47, 30,70, 22,15, 7,57. MS [M-H]’: m / z =434.

[0941] Example 143. Synthesis of 2-(l-ethyl-6-fluoro-8-(4-fluoro-3-methylbenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT85). The reaction was carried out with compound 86 (0.058 g, 0.14 mmol) and 3 M LiOH (0.23 mL, 0.70 mmol) in 1,4-dioxane (0.7 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 75%). 'H NMR (600 MHz, CDCh) 68,43 (d, J = 16,2 Hz, 1H, NH), 7,05 -7,01 (m, 1H, ArH7), 7,02 - 6,99 (m, 1H, H2), 6,98 (dt, J = 4,5, 2,0 Hz, 1H, H6), 6,92 - 6,87 (m, 1H, H3), 6,73 - 6,69 (m, 1H, ArH5), 4,08 - 4,03 (m, 2H, Hi7), 4,03 - 3,97 (m, 2H, H3), 2,99 - 2,91 (m, 2H, H13), 2,81 - 2,72 (m, 2H, H4), 2,20 (dd, J = 8,5, 1,8 Hz 3H, C5 CH3), 2,02 - 1,89 (m, 2H, H15), 0,78 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCh) 6 159,44, 157,22, 136,79, 134,29, 131,77, 131,26, 127,50, 126,77, 125,21, 115,02, 110,84, 108,71, 101,81, 74,99, 60,75, 42,30, 37,01, 30,80, 22,15, 7,61. MS [M-H]': m / z =398.

[0942] Example 144. Synthesis of 2-(l-ethyl-6-fluoro-8-(2-fluoro-3-methylbenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT86). The reaction was carried out with compound 77 (0.060 g, 0.15 mmol) and 3 M LiOH (0.24 mL, 0.73 mmol) in 1,4-dioxane (0.7 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1%TFA (yield: 79%).JH NMR (600 MHz, CDCh) 68,56 (s, 1H, NH), 7,05 - 7,03 (m, 1H, ArH7), 7,02 (t, J = 2,1 Hz, 1H, H2), 7,01 (d, J = 2,6 Hz, 1H, H4), 6,92 (dd, J = 9,7, 5,3 Hz, 1H, H3), 6,77 (dd, J = 10,0, 2,4 Hz, 1H, ArH5), 4,15 - 4,07 (m, 2H, H17), 4,07 - 3,99 (m, 2H, H3), 3,01 - 2,94 (m, 2H, Hi3), 2,81 - 2,72 (m, 2H, H4), 2,26 (d, J = 2,0 Hz, 3H, C5CH3), 2,08 - 1,96 (m, 2H, H15), 0,81 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDCh) 5 174,50, 160,20, 158,59, 136,72, 131,17, 130,05, 128,38, 126,69, 125,55, 125,01, 123,96, 110,65, 108,82, 101,84, 75,11, 60,78, 42,43, 30,95, 22,15, 7,68. MS [M-H]': m / z =398.

[0943] Example 145. Synthesis of 2-(8-(3-cyanobenzyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT87). The reaction was carried out with compound 74 (0.050 g, 0.12 mmol) and 3 M LiOH (0.21 mL, 0.62 mmol) in 1,4-dioxane (0.6 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 47.42%). 'H NMR (600 MHz, (CD3)2CO) 5 9,98 (s, 1H, NH), 7,67 - 7,65 (m, 1H, H6), 7,61 - 7,58 (m, 1H, H4), 7,58 - 7,55 (m, 1H, H3), 7,48 - 7,44 (m, 1H, H2), 7,04 - 7,01 (m, 1H, ArH7), 6,73 - 6,69 (m, 1H, ArH5), 4,27 (s, 2H, Hi7), 4,01 - 3,96 (m, 2H, H3), 2,95 - 2,82 (m, 2H, Hi3), 2,73 - 2,61 (m, 2H, H4), 2,05 (d, J = 0,9 Hz, 2H, H15), 0,68 (dd, J = 1,8, 6,9 Hz, 3H, CH2CH3).13C NMR (151 MHz, (CD3)2CO) 5 171,70, 156,97, 141,78, 138,77, 133,52, 132,16, 129,65, 127,36, 124,24, 118,57, 112,34, 109,72, 108,75, 101,47, 75,16, 60,22, 42,42, 36,08, 30,82, 21,98, 7,21. MS [M-H]': m / z =391.

[0944] Example 146. Synthesis of 2-(l-ethyl-6-fluoro-8-(3-nitrobenzyl)-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetate acid (CXT88). The reaction was carried out with compound 73 (0.110 g, 0.26 mmol) and 3 M LiOH (0.43 mL, 1.29 mmol) in 1,4-dioxane (1.4 mL) according to the procedure given in Example 97, Method A. The crude product was purified by reverse phase chromatography using as eluent a mixture of CH3CN / H2O 6:4 + 0.1% TFA (yield: 88%). 'H NMR (600 MHz, CDCh) 8 8,70 (s, 1H, NH), 8,12 (t, J = 1,8 Hz, 1H, H2), 8,05 (m, 1H, H4), 7,53 - 7,49 (m, 1H, H6), 7,43 (dd, J = 9,4, 6,5 Hz, H5), 7,07 (dd, J = 9,1, 2,4 Hz, H7), 6,73 (J = 9,8, 2,4 Hz, H5), 4,21 - 4,13 (m, 2H, Hi7), 4,11 - 4,01 (m, 2H, H3), 3,00 (d, J = 1,1 Hz, 2H, Hi3), 2,79 (t, J = 5,5 Hz, 2H, H4), 2,07 - 1,87 (m, 2H, CH2CH3), 0,83 (t, J = 7,4 Hz, 3H, CH2CH / ).13C NMR (151 MHz, CDCh) 6 175,14, 157,95 (d, J = 234,7 Hz), 148,56, 141,20, 136,88, 134,98, 131,15, 129,65, 127,05, 123,67, 123,18 (d, J = 8,7 Hz), 121,81, 111,18 (d, JC-F = 26,3 Hz), 108,94, 102,42 (d, JC-F = 23,3 Hz), 75,39, 60,80, 42,07, 37,18, 30,75, 22,07, 7,58. MS [M-H]': m / z =411.Example 147. Synthesis of 2-(1-ethyl-6-fluoro-8-(3-fluoro-5-methoxybenzyl)-1,3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT90). The reaction was carried out with compound 84 (0.065 g, 0.15 mmol) and 3 M LiOH (0.25 mL, 0.75 mmol) in 1,4-dioxane (2.0 mL) according to the procedure given in Example 97, Method A. The crude product was purified by flash direct phase chromatography, using as eluent a mixture of DCM / MeOH 98:2 (yield: 75%). H NMR (600 MHz, CDCh) 8 8,43 (d, J = 11,8 Hz, 1H, NH), 7,04 (dd, J = 9,2, 2,3 Hz, 1H, ArH7), 6,78 (dd, J = 9,8, 2,4 Hz, 1H, ArH5), 6,63 (s, 1H, H4), 6,57 - 6,53 (m, 1H, H2), 6,50 - 6,47 (m, 1H, H6), 4,08 (t, J = 2,9 Hz, 2H, Hi7), 4,06 - 3,94 (m, 2H, H3), 3,77 (s, 3H, OCH3), 2,96 - 2,86 (m, 2H, Hi3), 2,81 - 2,69 (m, 2H, H4), 2,10 - 1,91 (m, 2H, His), 0,80 (t, 7 = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDC13) δ 173,96, 163,90 (d, J = 245,45 Hz), 161,06 (d, J = 11,21 Hz), 158,01 (d, 7 = 235,20 Hz), 142,18 (d, 7 = 9,34 Hz), 137,05, 131,26, 126,88 (d, 7= 9,94 Hz), 123,97 (d, 7= 9,06 Hz), 111,02 (d, 7 = 26,41 Hz), 110,78 (d, 7= 2,43 Hz), 108,89 (d, 7= 4,73 Hz), 108,25 (d, 7= 21,76 Hz), 102,05 (d, 7 = 23,15 Hz), 99,79 (d, 7 = 25,28 Hz), 75,04, 60,76, 55,72, 42,12, 37,91, 30,87, 22,23, 7,69. MS [M-H]': m / z =414.

[0945] Example 148. Synthesis of 2-(8-(3-chloro-5-fluorobenzyl)-1-ethyl-6-fluoro-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT91). The reaction was carried out with compound 83 (0.065 g, 0.15 mmol) and 3 M LiOH (0.25 mL, 0.75 mmol) in 1,4-dioxane (2.0 mL) according to the procedure given in Example 97, Method A. The crude product was purified by flash direct phase chromatography, using as eluent a mixture of DCM / MeOH 98:2 (yield: 63.24%).1H NMR (600 MHz, CDC13) 6 8,69 (d, 7 = 24,0 Hz, 1H, NH), 7,07 (dd, 7 = 9,1, 2,3 Hz, 1H, ArH7), 7,04 (dd, 7 = 2,2, 1,0 Hz, 1H, H4), 6,95 - 6,92 (m, 1H, H2), 6,86 - 6,82 (m, 1H, H6), 6,74 (dd, 7 = 9,8, 2,4 Hz, 1H, ArH5), 4,08 - 3,96 (m, 4H, Hi7,3), 2,97 (q, 7 = 17,0 Hz, 2H, Hi3), 2,81 - 2,72 (m, 2H, H4), 2,10 - 1,91 (m, 2H, His), 0,82 (t, 7 = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDC13) δ 173,73, 162,94 (d, 7 = 250,04 Hz), 157,98 (d, 7 = 235,47 Hz), 142,88 (d, 7 = 7,95 Hz), 141,48 (d, 7 = 16,27 Hz), 137,26 (d,7= 18,89 Hz), 131,14, 126,98, 124,89 (d, 7 = 2,94 Hz), 123,12 (d, 7= 8,97 Hz), 114,59 (d, 7 = 24,87 Hz), 114,41 (d, 7 = 21,40 Hz), 111,10 (d, 7 = 26,28 Hz), 109,00 (d, 7 = 4,91 Hz), 102,38 (d, 7 = 23,25 Hz), 74,94, 60,78, 41,96, 37,34, 30,75, 22,24, 7,67. MS [M-H]': m / z = 418 / 420.

[0946] Example 149. Synthesis of 2-(8-(3,5-difluorobenzyl)-1-ethyl-6-fluoro-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT92). The reaction was carried out with compound 82 (0.070 g, 0.17 mmol) and 3 M LiOH (0.28 mL, 0.84 mmol) in 1,4-dioxane (2.0 mL) according to the procedure given in Example 97, Method A. The crude product waspurified by flash direct phase chromatography, using as eluent a mixture of DCM / MeOH 98:2 (yield: 54.26%).JH NMR (600 MHz, CDCh) 8 8,72 (s, 1H, NH), 7,11 - 7,04 (m, 1H, ArH7), 6,72 (t, J = 2,5 Hz, 2H, H2,6’), 6,71 - 6,70 (m, 1H, ArH5), 6,60 (tt, J = 9,0, 2,3 Hz, 1H, H4), 4,10 - 4,01 (m, 2H, Hi7), 3,98 (dd, J = 14,5, 9,9 Hz, 2H, H3), 3,06 - 2,95 (m, 2H, Hi3), 2,85 -2,74 (m, 2H, H4), 2,13 - 1,90 (m, 2H, His), 0,82 (d, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDC13) δ 175,38, 164,04, 162,39, 158,68, 143,03, 137,17, 131,13, 126,87, 123,10, 111,71, 111,54, 111,16, 110,99, 108,85, 102,31, 102,22, 102,16, 102,05, 101,89, 75,02, 60,74, 42,23, 37,24, 30,69, 22,16, 7,59. MS [M-H]’: m / z = 402.

[0947] Example 150. Synthesis of 2-(1-ethyl-6-fluoro-8-[(1Z)-2-phenylethenyl)]-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT93). To obtain compound CXT93, ester derivative 88 (163 mg, 0.414 mmol) was dissolved in THF and 0.1 M aqueous LiOH solution (12.43 mL, 1.243 mmol) was added. The reaction was carried out for 16 hours at RT according to the procedure given in Example 97, Method B. The crude product was purified by flash chromatography using a 98:2 DCM / MeOH mixture (yield: 98%) as eluent.1H NMR (600 MHz, CDC13) δ 7,98 (s, 1H, NH), 7,30 - 7,23 (m, 4H, H2’,3’,4’,5’.6’), 7,21 (dd, J = 9,0, 2,4 Hz, 1H, ArH7), 7,05 (dd, J = 10,1, 2,3 Hz, 1H, ArH5), 6,85 (q, J = 12,2 Hz, 2H, CH2=CH2), 4,18 -4,01 (m, 2H, H3a, H3b), 2,90 (dd, J = 36,2, 16,2 Hz, 2H, C / LCOOH), 2,93 - 2,74 (m, 2H, H4a, H4b), 1,87 - 1,70 (m, 2H, C LCH3), 0,75 (t, J = 7,3 Hz, 3H, CH2C L).13C NMR (151 MHz, CDC13) δ 176,5, 157,77 (d, Jc-i = 234,9 Hz), 136,92, 136,78, 131,70, 128,90, 128,65, 128,50, 127,93, 127,03 (d, JC-F= 10,1 Hz), 126,02, 121,86 (d, Jc-i = 9,3 Hz), 110,59 (d, Jc-i = 26,0 Hz), 108,48 (d, JC-F= 4,8 Hz), 103,07 (d, Jc-i = 23,6 Hz), 74,84, 60,78, 42,65, 30,61, 22,12, 7,86. MS [M-H]’: m / z = 378.

[0948] Example 151. Synthesis of 2-(1-ethyl-6-fluoro-8-phenethyl-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT94). The reaction was carried out with compound 92 (0.051 g, 0.1290 mmol) and 0.1 N LiOH (3.22 mL, 0.322 mmol) in THF (3.22 mL) according to the procedure given in Example 97, Method B. The crude product was purified by flash direct phase chromatography, using as eluent a mixture of DCM / MeOH 98:2 (yield: 72%). 'H NMR (600 MHz, CDC13) δ 8,44 (s, 1H, NH), 7,27 - 7,15 (m, 5H, H2’,3’,4’,5’.6’), 7,00 (dt, J = 6,2, 3,5 Hz, 1H, ArH7), 6,80 - 6,74 (m, 1H, ArH5), 4,12 - 3,94 (m, 2H, H3), 3,01 - 2,93 (m, 6H, HI3, I7, I8), 2,82 - 2,68 (m, 2H, His), 2,04 - 1,92 (m, 2H, H4), 0,82 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDC13) δ 175,47, 158,86, 141,58, 136,51, 131,45, 128,57,126,49, 126,29, 125,78, 110,11, 108,76, 101,31,75,15, 60,86,42,56, 36,04, 33,30, 30,86,22,14, 7,77. MS (ESI-MS) [M-H]': m / z 381.

[0949] Example 152. Synthesis of 2-(1-ethyl-6-fluoro-8-(2-chloro-6-fluoro-benzyl)-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT95). The reaction was carried out with compound 78 (75 mg, 0.173 mmol) in a mixture of THF / 0.1 M LiOH solution (4.29 mL, 0.429 mmol) in a 1:1 ratio according to the procedure given in Example 97, Method B. The crude product was purified by reverse phase chromatography using a mixture of CH3CN / H2O 1:1 + 0.1% TFA (yield 63%) as eluent.JH NMR (600 MHz, CDC13) δ 8,82 (s, 1H, NH), 7,20 (dd, J = 8,1, 2,0 Hz, 1H, ArH7), 7,16 (td, J = 8,1, 5,9 Hz, 1H, H4), 7,02 - 6,98 (m, 2H, H3e H5), 6,75 (dd, J = 10,2, 3,0 Hz, 1H, ArH5), 4,25 (ddd, 7= 41,1, 15,1, 1,9 Hz, 2H, Hi7a, Hi7b), 4,10 - 3,99 (m, 2H, H3a, H3b), 3,03 (q, 7= 16,3 Hz, 3H, C LCOOMc), 2,81 - 2,71 (m, 2H, H4a, H4b), 2,08 (dtd, 7= 18,6, 14,6, 7,3 Hz, 2H, C LCH3), 0,85 (t, 7= 7,4 Hz, 3H, CH2CH3 ).13C NMR (151 MHz, CDC13) δ 175,14, 161,62 (d, 7C-F= 247,0 Hz), 157,98 (d, 7C-F= 234,9 Hz), 136,87, 135,55 (d, 7C-F= 5,8 Hz), 131,20, 128,77 (d, 7C-F= 9,8 Hz), 126,83 (d, 7C-F= 10,0 Hz), 125,82 (d, 7C-F= 3,4 Hz), 125,21 (d, 7C-F= 18,7 Hz), 122,31 (d, 7C-F= 8,9 Hz), 114,37 (d, 7C-F= 23,3 Hz), 110,84 (d, 7C-F= 27,6 Hz), 108,99 (d, 7 = 4,6 Hz), 101,97 (d, 7 = 23,5 Hz), 75,18, 60,83, 42,65, 31,07, 27,85, 22,21, 7,78. MS [M-H]’: m / z = 418 / 420.

[0950] Example 153. Synthesis of 2-(8-benzyl-1-ethyl-7-fluoro-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT96). To a solution of ester 64 (50.0 mg, 0.131 mmol) in THF (5 mL) was added a solution of 0.1 M LiOH in water (4 mL, 0.393 mmol) according to the procedure given in Example 97, Method B. The crude product was purified by direct phase flash chromatography with 98:2 DCM / MeOH as eluent to afford compound CXT96 (yield 42%).1H NMR (600 MHz, CDC13) δ 8,24 (s, 1H, NH), 7,30 (dd, 7 = 8,63, 4,94 Hz, 1H, H5), 7,26 - 7,22 (m, 4H, H2’,3’,5’, 6’), 7,16 (ddt, 7 = 7,44, 6,14, 1,91 Hz, 1H, H4), 6,93 (dd, 7= 10,23, 8,57 Hz, 1H, H6), 4,26 - 4,12 (m, 2H, CH2Ph), 4,09 - 3,94 (m, 2H, H3), 2,87 (s, 2H, CH2COOH), 2,83 - 2,72 (m, 2H, H4), 1,90 (ddt, 7= 18,36, 14,54, 7,33 Hz, 2H, CH2CH3).

[0951] 0,74 (t, 7 = 7,36 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDC13) δ 159,79, 157,60 (d, 7C-F = 236,74 Hz), 139,34, 135,47 (d, 7C-F = 8,66 Hz), 135,34 (d, 7C-F = 2,87 Hz), 128,84, 128,67, 126,55, 123,17, 117,21 (d, 7C-F = 10,37 Hz), 110,10 (d, 7C-F = 20,72 Hz), 108,55, 108,37, 75,04, 60,81, 42,40, 30,84, 30,55 (d, 7C-F = 3,73 Hz), 22,13, 7,70. MS [M-H]': m / z = 367.

[0952] Example 154. Synthesis of 2-(1-ethyl-6-fluoro-8-(phenylethynyl)-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT97). The reaction was carried out with 87(0.080 g, 0.204 mmol), an aqueous solution of 3 M LiOH (6.13 mL, 0.613 mmol) in THF (6 mL) following the procedure given in Example 97, Method B. The crude product was purified by flash silica gel chromatography with 98:2 DCM / MeOH as eluent to afford CXT97 (yield 91%).JH NMR (600 MHz, CDC13) δ 9,04 (s, 1H, NH), 7,64 - 7,54 (m, 2H, H2,6’), 7,38 - 7,32 (m, 3H, H3’,4’,5’), 7,15 (ddd, J = 9,05, 2,39, 0,60 Hz, 1H, H5), 7,10 (dd, J = 9,64, 2,38 Hz, 1H, H7), 4,12 - 3,92 (m, 2H, H3), 3,08 - 2,93 (m, 2H, CH2COOH), 2,85 - 2,67 (m, 2H, H4), 2,09 (ddd, J = 57,34, 14,64, 7,34 Hz, 2H, C / / 2CH3), 0,86 (t, J = 7,37 Hz, 1H, CH2C / / ,').13C NMR (151 MHz, CDC13) δ 175,65, 157,38 (d, JC-F = 234,97 Hz), 137,62, 133,37, 131,87, 128,72, 128,51, 126,48 (d, JC-F = 10,21 Hz), 122,90, 112,99 (d, JC-F = 27,48 Hz), 109,23 (d, JC-F = 4,79 Hz), 106,82 (d, JC-F = 11,62 Hz), 104,87 (d, JC-F = 23,82 Hz), 94,22, 84,60 (d, JC-F = 3,06 Hz), 74,88, 60,73, 42,40, 30,71, 22,25, 7,73. MS [M-H]’: m / z = 376.

[0953] Example 155. Synthesis of 2-(1-ethyl-6-fluoro-8-(2-chloro-4-fluoro-benzyl)-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT98). The reaction was carried out with compound 81 (113 mg, 0.260 mmol) in a mixture of THF / 0.1 M LiOH solution (7.80 mL, 0.780 mmol) in a 1:1 ratio according to the procedure given in Example 97, Method B. The crude product was purified by flash direct phase chromatography, using a mixture of DCM / MeOH 99:1 (yield 82%) as eluent. 'H NMR (600 MHz, CDC13) δ 8,68 (s, 1H, NH), 7,14 (dd, J= 8,5, 2,6 Hz, 1H, ArH7), 7,08 - 7,02 (m, 2H, H2e H3), 6,89 - 6,85 (m, 1H, H5), 6,64 (dd, J = 10,0, 2,4 Hz, 1H, ArH5), 4,14 (dd, J = 42,3, 17,8 Hz, 2H, Hi7a, Hi7b), 4,06 (dt, J = 41,3, 11,5 Hz, 2H, H3a, H3b), 3,05 - 2,97 (m, 3H, CW2COOH), 2,79 (dtt, J = 25,7, 15,3, 5,0 Hz, 2H, H4a, H4b), 2,12 - 1,92 (m, 2H, C7 / 2CH3), 0,83 (t, J = 7,4 Hz, 3H, C 2CH3).13C NMR (151 MHz, CDC13) δ 176,00, 161,42 (d, Jc-i = 248,6 Hz), 158,05 (d, Jc-i = 235,2 Hz), 137,00, 134,55 (d, Jc-i = 10,2 Hz), 132,52 (d, J C-F= 3,5 Hz), 131,60 (d, Jc-i = 8,6 Hz), 131,29, 126,86 (d, Jc-i = 10,0 Hz), 123,14 (d, JC-F= 9,0 Hz), 116,95 (d, Jc-i = 24,6 Hz), 114,36 (d, Jc-i = 20,9 Hz), 110,88 (d, Jc-i = 26,5 Hz), 109,00 (d, Jc-i = 4,8 Hz), 102,06 (d, J = 23,3 Hz), 75,16, 60,78, 42,61, 34,03, 30,93, 22,18, 7,70. MS [M-H]’: m / z = 418 / 420.

[0954] Example 156. Synthesis of 2-(1-ethyl-6-fluoro-8-(2,4-difluorobenzyl)-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT99). The reaction was carried out with compound 79 (104 mg, 0.250 mmol) in a mixture of THF / 0.1 M LiOH solution (7.47 mL, 0.747 mmol) in a 1:1 ratio according to the procedure given in Example 97, Method B. The crude product was purified by flash direct phase chromatography, using as eluent a mixture of DCM / MeOH 98:2 (yield 57%).1H NMR (600 MHz, CDC13) δ 8,63 (s, 1H, NH), 7,10 (tt, J =9,8, 4,9 Hz, 1H, H5), 7,03 (dd, J = 9,1, 2,4 Hz, 1H, ArH7), 6,84 - 6,75 (m, 2H, H2e H3), 6,73 (dd, 7 = 9,9, 2,4 Hz, 1H, ArH5), 4,05 (dd, 7= 36,9, 18,2 Hz, 2H, Hi7a, Hi7b),4,01 (ddd,7= 11,4, 10,4, 7,2 Hz, 2H, H3a, H3b), 3,00 (q, 7 = 16,6 Hz, 3H, C7LCOOH), 2,81 - 2,72 (m, 2H, H4a, H4b), 2,10 - 1,95 (m, 2H, C772CH3), 0,83 (t, 7 = 7,4 Hz, 3H, CH2C77,' -13C NMR (151 MHz, CDC13) δ 174,68, 160,76 (d, 7C-F= 246,8 Hz), 158,03 (d, 7C-F= 235,4 Hz), 155,41 (d, 7C-F=270,9 Hz), 137,10, 131,62, 131,56 (dd, 7= 9,5, 5,9 Hz), 131,08, 126,91 (d, 7= 10,0 Hz), 123,38 (d, 7 = 8,1 Hz), 121,88 (dd, 7 = 15,9, 3,7 Hz), 111,65 (dd, 7= 21,3, 3,6 Hz), 110,78 (d, 7C-F= 26,6 Hz), 109,01 (d, 7 = 4,8 Hz), 104,04 (d, 7 = 26,0 Hz), 103,87 (d, 7 = 25,8 Hz), 102,08 (d, 7C-F= 23,5 Hz), 75,04, 60,79, 42,37, 30,86, 29,85, 22,22, 7,71. MS [M-H]': m / z =402.

[0955] Example 157. Synthesis of (E)-2-(1-ethyl-6-fluoro-8-(3-phenylallyl)-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT100). To obtain compound CXT100, ester derivative 89 (52.0 mg, 0.132 mmol, 1 eq) was dissolved in THF (4.0 mL) and 0.1 M aqueous LiOH solution (3.96 mL, 0.396 mmol, 3 eq) was added according to the procedure given in Example 97, Method B. The crude product was by reverse phase chromatography using as eluent a mixture of CH3CN / H2O + 0.1% TFA 6:4 (yield: 38%).1H NMR (600 MHz, CDC13) δ 8,77 (s, 1H, NH), 7,32 (dd, 7= 8,37, 1,21 Hz, 2H, H3,5), 7,30 -7,20 (m, 2H, H2,6), 7,21 -7,12 (m, 1H, H4), 7,05 (dd, 7 = 9,14, 2,42 Hz, 1H, H5), 6,80 (dd, 7 = 9,94, 2,42 Hz, 1H, H7), 6,54 (dt, 7 = 15,88, 1,62 Hz, 1H, CH2CH=CHPh), 6,32 (dt, 7 = 15,79, 6,72 Hz, 1H, CH2C / 7=CHPh), 4,11 - 3,96 (m, 2H, H3), 3,65 (dt, 7 = 6,74, 1,90 Hz, 2H, C772CH=CHPh), 3,05 - 2,92 (m, 2H, CH2COOMe), 2,84 - 2,72 (m, 2H, H4), 2,14- 1,91 (m, 2H, C772CH3), 0,82 (t, 7 = 7,34 Hz, 3H, CH2Cfh).13C NMR (151 MHz, CDC13) δ 175,16, 158,08 (d, JC-F= 235,10 Hz), 137,23, 136,86, 131,97, 131,51, 128,64, 127,51, 127,31, 126,68 (d, JC-F = 10,02 Hz), 126,31, 123,88 (d, JC-F = 8,76 Hz), 110,54 (d, JC-F = 26,12 Hz), 108,76 (d, JC-F = 4,71 Hz), 101,71 (d, JC-F = 23,42 Hz), 75,12, 60,81, 42,32, 35,28, 30,86, 22,23, 7,73. MS [M-H]': m / z = 392.

[0956] Example 158. Synthesis of (E)-2-(1-ethyl-6-fluoro-8-styryl-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT101). To obtain compound CXT101, derivative 90 (101.0 mg, 0.257 mmol, 1 eq) was dissolved in THF and an aqueous solution of 0.1 M LiOH (7.71 mL, 0.771 mmol, 3 eq) was added, according to the procedure given in Example 97, Method B. The crude product was purified by direct phase flash chromatography using a DCM / MeOH 99 mixture as eluent: 1 (yield: 99%).1H NMR (600 MHz, CDC13) δ 12,09 (s, 1H, NH), 10,84 (s, 1H, OH), 7,72 (dd, 7= 16,3, 1,6 Hz, 1H, C77=CH-Ph), 7,69 (dd, 7= 8,1, 1,3 Hz, 2H, H2’,6’), 7,43 (t, 7 = 7,8 Hz, 2H, H3,5), 7,39 (d, 7= 16,2 Hz, 1H, CH=C77-Ph), 7,35(dd, J = 10,9, 2,4 Hz, 1H, ArH7), 7,33 - 7,30 (m, 1H, H4), 7,12 (dd, J = 9,2, 2,4 Hz, 1H, ArH5), 3,95 (dddd, J = 12,9, 11,3, 7,0, 3,8 Hz, 2H, H3a, H3b), 2,84 (dd, J = 136,8, 13,6 Hz, 2H, C / LCOOH), 2,70 - 2,58 (m, 2H, H4a, H4b), 2,10 - 2,02 (m, 2H, C 72CH3), 0,66 (t, J = 7,3 Hz, 3H, CH2C L).13C NMR (151 MHz, CDC13) δ 171,67, 157,82 (d, Jc-i = 231,1 Hz), 139,34, 137,66, 131,49, 130,10, 129,20, 128,35, 127,76 (d, Jc-i = 10,6 Hz), 127,17, 123,28, 122,13 (d, JC-F= 9,5 Hz), 108,31 (d, Jc-i = 4,6 Hz), 104,27 (d, Jc-i = 26,1 Hz), 102,85 (d, Jc-i = 23,7 Hz), 75,73, 60,38, 43,38, 31,39, 22,22, 8,34. MS [M-H]': m / z = 378.

[0957] Example 159. Synthesis of 2-(1-ethyl-6-fluoro-8-(2-fluoro-4-chloro-benzyl)-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT102). The reaction was carried out with compound 80 (112 mg, 0.258 mmol) in a mixture of THF / 0.1 M LiOH solution (7.74 mL, 0.774 mmol) in a 1:1 ratio according to the procedure given in Example 97, Method B. The crude product was purified by flash direct phase chromatography, using as eluent a mixture of DCM / MeOH 99:1 (yield 65%). 'H NMR (600 MHz, CDC13) δ 8,70 (s, 1H, NH), 7,08 (dd, J = 9,7, 2,0 Hz, 1H, ArH7), 7,09-7,00 (m, 2H, H2e H3e 1H, H5), 6,72 (dd, J = 9,9, 2,4 Hz, 1H, ArH5), 4,09-3,98 (m, 2H, H3a, H3be 2H, Hi7a, Hi7b), 3,05 - 2,96 (m, 3H, C LCOOH), 2,81 -2,71 (m, 2H, H4a, H4b), 2,09 - 1,94 (m, 2H, C 72CH3), 0,83 (t, J = 7,4 Hz, 3H, CH2C L).13C NMR (151 MHz, CDC13) δ 175,51, 160,58 (d, Jc-i = 247,9 Hz), 158,00 (d, Jc-i = 235,2 Hz), 137,18, 133,30 (d, Jc-i = 10,4 Hz), 131,65 (d, Jc-i = 5,2 Hz), 131,09, 126,94 (d, Jc-i = 9,8 Hz), 124,89 (d, JC-F= 3,4 Hz), 124,77 (d, Jc-i = 16,0 Hz), 123,03 (d, Jc-i = 8,9 Hz), 116,31 (d, Jc-i = 25,9 Hz), 110,80 (d, Jc-i = 26,3 Hz), 109,02 (d, Jc-i = 4,8 Hz), 102,15 (d, Jc-i = 23,3 Hz), 75,05, 60,78, 42,48, 30,85, 29,90, 22,22, 7,71. MS [M-H]': m / z =418 / 420.

[0958] Example 160. Synthesis of (E)-2-(1-ethyl-6-fluoro-8-(2-fluorostyryl)-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT103). To obtain compound CXT103, derivative 91 (47.0 mg, 0.114 mmol, 1 eq) was dissolved in THF and an aqueous solution of 0.1 M LiOH (3.43 mL, 3.43 mmol, 3 eq) was added, according to the procedure given in Example 97, Method B. The crude product was purified by direct phase flash chromatography using a DCM / MeOH 98 mixture as eluent:2 (99% yield). 'H NMR (600 MHz, DMSO-D6) δ 12,07 (s, 1H, COOH), 10,87 (s, 1H, NH), 7,90 (td, J = 7,79, 1,77 Hz, 1H, H5), 7,77 (dd, J = 16,32, 1,63 Hz, 1H, CH=C77-Ph), 7,41 (d, J = 16,32 Hz, 1H, C77=CH-Ph), 7,42 - 7,34 (m, 1H, H2), 7,36 (dd, J = 10,88, 2,40 Hz, 1H, H7), 7,32-7,25 (m, 2H, H3,4), 7,16 (dd, J = 9,22, 2,41 Hz, 1H, H5), 4,01 - 3,87 (m, 2H, H4), 2,95 (d, J = 13,62 Hz, 1H, CH22COOH), 2,72 (d, J = 13,60 Hz, 1H, CH2bCOOH), 2,70 - 2,59 (m, 2H, H3), 2,12 - 2,00 (m, 2H, C 72CH3), 0,66 (t, J= 7,32 Hz, 3H, CH2C77;).13C NMR (151 MHz, DMSO-D6) δ 171,16, 159,64 (d, J = 247,90 Hz), 157,23 (d, J = 226,37 Hz), 139,00, 131,06, 129,61 (d, J = 7,25 Hz), 127,34 (d, J = 11,20 Hz), 125,58, 124,74, 124,65, 122,60 (d, J = 5,71 Hz, C=C-Ph), 122,47(C=C-Ph), 122,53 (d, J = 15,98 Hz), 121,30 (d, J = 10,71 Hz), 121,07 (d, J = 19,49 Hz), 115,85 (d, J = 21,92 Hz), 107,84 (d, J = 4,45 Hz), 104,09 (d, J = 24,02 Hz), 102,86 (d, J = 23,57 Hz), 75,22, 59,87, 42,85, 30,86, 21,7, 7,82. MS [M-H]’: m / z = 396.

[0959] Example 161. Synthesis of (E)-2-(1-ethyl-6-fluoro-8-(2-fluorophenethyl)-1, 3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetic acid (CXT105). The reaction was carried out with compound 93 (0.133 g, 0.322 mmol) and 0.1 N LiOH (9.7 mL, 0.965 mmol) in THF (9.7 mL), according to the procedure given in Example 97, Method B. The crude product was purified by direct phase flash chromatography using 99:1 DCM / MeOH as the eluting phase (yield 82%). 'H NMR (600 MHz, DMSO) δ 8,58 (s, 1H, NH), 7,17 (ddd, J = 13,5, 7,6, 1,7 Hz, 1H3), 7,13 (td, J = 7,7, 1,7 Hz, 1H, H2), 7,04 - 7,02 (m, 2H, H4, H5), 7,00 (dd, J = 9,0, 2,6 Hz, ArH7), 6,78 (dd, J = 10,0, 2,4 Hz, ArH5), 4,11 - 3,97 (m, 2H, H3a, H3b), 3,03 - 2,95 (m, 2H, Hi7a, Hi7b, Hi8a, Hisb), 3,00 (dd, J = 12,6, 5,3 Hz, 2H, CTLCOOH), 2,82 - 2,71 (m, 2H, H4a, H4b), 2,11 -1,96 (m, 2H, C772CH3), 0,84 (t, J = 7,4 Hz, 3H, CH2CH3).13C NMR (151 MHz, CDC13) δ 167,67, 161,36 (d, 7 = 244,2 Hz), 158,10 (d, J = 234,8 Hz), 136,75, 131,37, 130,86 (d, 7= 5,0 Hz), 128,34 (d, 7 = 15,7 Hz), 128,17 (d, 7= 8,1 Hz), 126,60 (d, 7 = 10,0 Hz), 125,49 (d, 7 = 9,l Hz), 124,29 (d, 7 = 3,5 Hz), 115,42 (d, 7 = 22,0 Hz ), 110,10 (d, 7 = 25,9 Hz), 108,91 (d, 7 = 4,7 Hz), 101,47 (d, 7 = 23,5 Hz), 75,11, 60,88, 42,53, 32,20, 30,95, 29,81, 22,25, 7,81. MS (ESIMS) [M-H]’: m / z 396.

[0960] Example 162. Synthesis of compounds CXT30 and CXT43

[0961] F. J 0

[0962] COOH 5 COOH

[0963] 0 0 i H /

[0964] 's'

[0965]

[0966] R / 'OH

[0967] CXT12 CXT30 R-j-cicta ropy'

[0968] CXT43 R,=ciclohesy)

[0969] Reagents and conditions: a): Cu(OAc)2, NaOH 5M, DMSO, 120 °C, 3-4 h.GENERAL PROCEDURE

[0970] To a solution of compound CXT12 (1 eq) in DMSO (5 mL) were added Cu(OAc)2 (4 eq), suitably substituted sulfinic acid (4 eq) and an excess of 5M NaOH. The reaction mixture was heated to 120 °C and stirred under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature, diluted with 2 M HC1 and filtered over Celite. The filtrate was extracted with EtOAc (3 x 20 mL), the extracts washed with saturated NaCl solution, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by semi-preparative HPLC chromatography or by flash direct phase chromatography.

[0971] Example 163. Synthesis of 2-(8-(cyclopropylsulfonyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT30). The reaction was carried out with compound CXT12 (0.100 g, 0.25 mmol) in DMSO (5 mL) to which Cu(OAc)2 (0.198 g, 0.99 mmol), cyclopropanesulfinic acid (0.127 g, 0.99 mmol) and an excess of 5M NaOH (57 pL) were added. The crude product was purified by semi-preparative HPLC chromatography on LiChrosper C18e column using as eluent a 60:40 CH3CN / H2O mixture + 0.1% TFA, IR: 11 min), to provide CXT30 as a white solid (74 mg, yield 78%).1H NMR (600 MHz, DMSO-de) 5 11,01 (s, 1H, NH), 7,63 (t, J= 8,1 Hz, 1H, ArH7), 7,39-7,18 (m, 1H, ArH5), 3,98-3,79 (m, 2H, OCH2-), 2,91-2,85 (m, 2H, CH2COO-), 2,66 (m, 1H, SO2CH-), 2,17-1,89 (s, 2H, CH2CH2O-), 1,28-1,11 (m, 2H, CH2CH3), 1,04-0,87 (m, 4H, -CH2CH2-), 0,74 (m, 3H, CH3).13C NMR (151 MHz, DMSO-d6) δ 173,11, 155,46 (d, JC-F= 235,8 Hz), 142,19, 129,83, 128,47, 123,12, 109,97 (d, JC-F= 23,2 Hz), 109,15 (d, JC-F= 28,6 Hz), 108,86, 75,33, 59,90, 42,88, 32,75, 30,44, 22,15, 8,10, 5,54, 4,45. MS [M-H]’: m / z = 380.

[0972] Example 164. Synthesis of 2-(8-(cyclohexylsulfonyl)-l-ethyl-6-fluoro-l, 3,4,9-tetrahydropyran[3,4-b]indol-l-yl)acetic acid (CXT43). The reaction was carried out with compound CXT12 (0.100 g, 0.25 mmol) in DMSO (5 mL) Cu(OAc)2 (0.198 g, 0.99 mmol), cyclohexanesulfinic acid (0.127 g, 0.99 mmol) and an excess of 5 M NaOH (57 pL) were added. The crude product was purified twice by flash direct phase chromatography using a mixture of PE / EtOAc / MeOH 80:15:5 as eluent to provide CXT43 as a pale yellow solid (16 mg, yield 15%).1H NMR (600 MHz, CD3OD) δ 10,67 (s, 1H, COOH), 8,09 (s, 1H, NH), 7,54 (d, J = 8,8 Hz, 1H, ArH7), 7,29 (d, J = 8,8 Hz, 1H, ArH5), 4,07 - 3,95 (m, 2H, OCH2-), 3,12 (m, 1H, SO2CH-), 2,94 (m, 2H, CH2COO-), 2,76 (m, 2H, CH2), 2,13 (m, 2H, CH2CH3), 2,05 - 1,97 (m, 2H, -CH2CHSO2-), 1,81 (m, 2H, -CH2CHSO2-), 1,64 (m, 1H, -CH2CH2CHSO2-), 1,48 - 1,33(m, 2H, -CH2CH2CHSO2-), 1,32 - 1,20 (m, 2H, -CH2CH2CHSO2-), 1,19 - 1,07 (m, 1H, -CH2’CH2CHSO2-), 0,80 (t, J = 7,4 Hz, 3H, CH3). MS [M-H]’: m / z = 422.

[0973] Pharmacological Tests - Materials and Methods

[0974] Example 165. Isolation of human platelets and analysis of platelet aggregation

[0975] The platelets were obtained from human buffy coat (blood bank of Niguarda Hospital, donors of both sexes, aged between 18 and 60 years - the donors gave their free and informed consent to the use of the blood samples in the laboratory setting, as provided for by the State Regions agreement no. 225 / CSR / 2018 and pursuant to art. 170 bis, paragraph 4 of the Industrial Property Code.), 40 mL of buffy coat was diluted with Hank's saline solution (HBSS 1:1, KC1 0.40 g / L; KH2PO40.06 g / L; NaCl 8.00 g / L; NaHCO30.35 g / L; Na2HPO40.048 g / L; D-glucose 1.00 g / L) and centrifuged at 280 g for 15 min at room temperature to obtain platelet-rich plasma (PRP), which was further centrifuged at 650 g for 10 min at room temperature. Sedimented platelets were suspended in 10-15 mL of wash buffer ( mM composition: citric acid monohydrate 39, glucose monohydrate 5, KC15, CaCh 2, MgCh-6 H2O 1, NaCl 103, pH 6.5), centrifuged again at 650 g for 15 min at room temperature, and finally resuspended in HBSS solution supplemented with CaC12-2H2O (0.185 g / L), MgC12-6H2O (0.10 g / L), MgSO4-7H2O (0.10 g / L). Platelet concentration was adjusted to approximately 2x108 cells mL’1and aggregation assessed by the Bom turbidimetric assay (Pap-8 aggregometer, Bio / Data Corporation, Sentinel Diagnostics, Milan, Italy), at 37 °C in a 0.5 mL sample. After incubation with the drug, or vehicle as a control (dimethyl sulfoxide -DMSO- maximum 0.2%, v / v), for 5 min at 37 °C, platelet aggregation was induced by U46619 (0.1 pM), with continuous shaking, and monitored for 6-8 min. The experiments were repeated at least in triplicate using platelets from different subjects. Due to the inter-subject variability of the platelet response stimulated with the agonist, the activity of each compound was expressed as percent inhibition relative to the corresponding control aggregation.

[0976] Example 166. COX-1 inhibitory activity (human platelets)

[0977] Human platelet samples (0.5 ml) were treated with an increasing concentration of the tested compounds or with vehicle alone (DMSO), incubated at 37 °C in a Dubnoff bath for 30 min and stimulated with 2 pM calcium ionophore A23187 for 15 min at 37 °C. The reaction was stopped by centrifugation at 1500 g (4 °C) for 5 minutes. The production of TXB2 (TXA2metabolite) was evaluated in the supernatant by mass spectrometry. The activity of each compound was expressed as percent inhibition relative to the corresponding control assay.

[0978] Example 167. COX-2 inhibitory activity (lymphomonocytes)

[0979] The study of COX-2 activity was carried out in a suspension of lymphomonocytes isolated from buffy coat (diluted in HBSS 1:1). The PRP-deprived buffy coat was carefully stratified over the same volume of Ficoll-Paque for density gradient centrifugation (400 g for 30 min at 10 °C); the enriched cell ring was collected and washed twice with HBSS and centrifuged (280 g for 15 min at 10 °C) to remove the remaining suspended platelets. Immediately thereafter, a lysis buffer (NaCl 0.2% weight / volume, w / v) was added to remove the remaining erythrocytes, immediately balanced with an equal volume of equilibrating solution (NaCl 1.6% + sucrose 0.2%, w / v). Lymphomonocytes were finally resuspended in HBSS supplemented with CaCl2-2 H2O (0.185 g / L), MgCl2-6 H2O (0.10 g / L), MgSO4-7 H2O (0.10 g / L). Samples of 0.5 ml (cell concentration adjusted to approximately 2-4 xl06 cells mL-1) were pretreated (30 min, 37 °C) with an increasing concentration of the tested compound, or vehicle as a control, and then treated with LPS (10 pg / ml, 24 h, 37 °C). COX-2 activity was assessed by quantifying PGE2production. The activity of each compound was expressed as percent inhibition of PGE2production compared to the corresponding control over 24 hours. PGE2determination was performed by mass spectrometry.

[0980] Example 168. Mass spectrometry determination of eicosanoids

[0981] Quantitative determinations of TXB2and PGE2were evaluated by LC-MS / MS; for each eicosanoid, 2 different transitions were selected: TXB2m / z 369>169 and m / z 369>195; PGE2m / z 351 >271 and m / z 351 >195, the most abundant being used as a quantifier and the second as a qualifier. Quantification was performed using isotope dilution of the deuterated internal standards d4- TXB2and d4-PGE2, monitoring the m / z 373> 173 and m / z 355>275 transitions, respectively. MRM (multiple reaction monitoring) analyses were performed using an LC-(ESI)-MS / MS triple quadrupole spectrometer (ABSciex API 4000) operating in negative ion mode. Chromatographic separation was achieved using a reversed-phase column (EVO Kinetex C18, 2.1 x 150 mm x 5 microns, Phenomenex), with a flow rate of 0.4 mL / min and a gradient from 70% solvent A (H2O + 0.05 mL / L acetic acid pH=5.7) to 100% solvent B (65% ACN + 35% methanol) over 3.5 minutes.Example 169. Inhibition of COX-1 and COX-2 activities in human whole blood

[0982] Blood samples were taken from healthy volunteers who had not taken any antiinflammatory drugs in the two weeks preceding the study. The volunteers, treated according to the Helsinki Protocol for biomedical experimentation, gave their free and informed consent to the use of the blood samples for research purposes pursuant to Article 170 bis, paragraph 4 of the Industrial Property Code. The collected blood was divided into two aliquots to test the inhibition of COX-1 and COX-2 (Patrignani, P.; Panara, MR; Greco, A.; Fusco, O.; Natoli, C.; lacobelli, S.; Cipollone, F.; Ganci, A.; Creminon, C.; Maclouf, J. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J. Pharmacol. Exp. Ther. 1994, 271(3), 1705-1712.). The aliquot intended for the study of COX-2 was treated with sodium heparin (10 lU / mL) and acetylsalicylic acid (10 pg / mL) to suppress prostanoid production from COX-1; the aliquot intended for the study of COX-1 was not treated.

[0983] Solutions of the compounds, tested at different concentrations, were prepared in DMSO (0.05-50 mM) and 2 pL aliquots of the solutions were distributed into incubation tubes. Heparinized blood (1.0 mL) was added to each tube to test for COX-2 inhibition or untreated blood (1.0 mL) to test for COX-1 inhibition. Samples for the study of COX-1 activity were incubated in glass tubes for 1 hour at 37 °C and centrifuged at 2000 g for 10 minutes; serum was stored at -20 °C until TXB2 dosing

[0984] Samples for determination of COX-2 activity were incubated with lipopolysaccharide from E. coli (LPS, 10 pg / mL) in polyethylene tubes for 24 hours at 37 °C to allow COX-2 expression in monocytes and maximal PGE2 production. The samples were centrifuged at 2000 g for 10 min, and the plasma was stored at -20 °C until PGE2 dosing. Baseline PGE2 production in blood not treated with LPS was subtracted from all samples. Prostanoid production (TXB2 and PGE2) was assessed by enzyme immunoassay (Cayman Chemical). The percent inhibition of TXB2 (COX-1) and PGE2 (COX-2) production in samples treated with the compound was calculated by comparing control samples treated with DMSO alone. For the active compounds IC50 values were calculated by nonlinear regression analysis. For the low active compounds the results were expressed as percent inhibition at the maximum concentration tested. At least 3 experiments were performed for each compound.Example 170. Ex vivo inhibition of platelet aggregation

[0985] Male C57B16 mice (12-13 weeks old) provided by Charles River, housed in a temperature-controlled environment, 12-hour light / dark cycle with ad libitum access to water and fed a standard pellet diet, were randomized into several groups. The compounds were dissolved in 1% carboxymethylcellulose (CMC) at concentrations of 5 mg / ml for CXT29 and 20 mg / ml and 40 mg / ml for CXT15 and vortexed to give complete suspension. Mice were immediately treated orally by gavage with CXT29 (50 mg / kg), CXT15 (200 mg / kg and 100 mg / kg), or vehicle (CMC). After 2 hours, mice were anesthetized with ketamine hydrochloride (75 mg / kg; Intervet) and medetomidine (1 mg / kg; Virbac) and blood was collected in the presence of 3.8% sodium citrate (1: 10 v / v) by cardiac venipuncture, by pooling blood obtained from mice belonging to the same experimental group into a single sample in order to obtain a volume sufficient for the assessment of platelet aggregation in response to increasing concentrations of thromboxane receptor agonist. The samples thus obtained were immediately centrifuged at 350 g for 15 minutes at room temperature to obtain platelet-rich plasma. All experiments were approved by the National Committee of the Ministry of Health-University of Milan and the DGSA.

[0986] Example 171. TP receptor antagonism in rat aorta

[0987] Male Wistar rats were anesthetized with isoflurane and sacrificed by cervical dislocation. The aorta was immediately removed, stripped of fat and connective tissue, and cut into rings approximately 3-4 mm wide. The rings were mounted in organ baths containing 30 mL of Krebs buffer (KRB) with the following composition (mM): NaCl 111.2, KC15.0, CaCh 2.5, MgSC 1.2, KH2PO4 1.0, NaHCOs 12.0, glucose 11.1, maintained at 37 °C and in the presence of 95% 02-5% CO2 (pH 7.4). Aortic rings were mounted on organ hooks and connected to isometric transducers, applying a voltage of 1.0 g. Vascular smooth muscle contractions and relaxations were recorded and visualized by a computerized data acquisition system connected to a bridge amplifier “Power MacLab”. The rings were allowed to equilibrate for 60 minutes and the integrity of the endothelium was assessed with 10 pM acetylcholine (ACh) in precontracted 1 pM phenylephrine rings. A relaxation >75% of the tone induced by phenylephrine was considered a sign of functional endothelium. The aortic rings were then washed and equilibrated for another period of 60 minutes. After a 20-minute pretreatment with 10 pM indomethacin, the rings were incubated for an additional 20 minutes with the study inhibitors or with solvent alone (DMSO) in the case of the control. Cumulative additions of U-46619 were made at the end of the incubation period to obtain the agonist concentrationresponse curve. All responses were expressed as a percentage of the maximum contraction induced by 50 mM KC1 and IC50 values were calculated by nonlinear regression analysis. For each inhibitor, the pA2 value was calculated with Gaddum's equation: pAi = log[CR-l]-log[B], where CR = ratio of EC50 with and without antagonist; [B] = antagonist concentration. At least three experiments were performed for each compound.

[0988] Example 172. TP receptor antagonism in platelet-rich plasma (PRP)

[0989] Venous blood samples were obtained from healthy volunteers who had not taken any platelet inhibitory drug for at least one week. Volunteers were treated according to the Helsinki protocol for biomedical experimentation and gave informed consent to the use of blood samples for research purposes. To study antagonism at the thromboxane (TP) receptor, human blood was anticoagulated with a citrate solution and treated with acetylsalicylic acid (10 pg / mL). Platelet-rich plasma (PRP) was prepared by centrifugation at 200 g for 20 min. Aliquots (500 pL) of PRP were added to the aggregometer cuvettes (Chrono-log 4902D), and aggregation was recorded as increased light transmission under continuous shaking (1000 rpm) at 37°C for 10 min after stimulus addition. The study compounds were incubated with PRP 10 min before the addition of the agonist U-46619 (0.5-2.5 pM). Vehicle alone (0.5% DMSO) was added to PRP to verify platelet function in control samples. At least three experiments were performed for each compound. The antiplatelet activity of the tested compounds was evaluated as the percentage inhibition of platelet aggregation compared to control samples. IC50 values were calculated by nonlinear regression analysis.

[0990] In vivo pharmacology

[0991] Animals

[0992] Experiments were performed on 6-12 week old male and female C57BL / 6N mice (Charles River, Sulzfeld, Germany). The animals were housed on a 12-hour light / dark cycle with access to food and water ad libitum. The studies were performed by a blinded animal treatment observer. All experiments adhered to the International Association for the Study of Pain guidelines and the ARRIVE (Animals in Research: Reporting In Vivo Experiments) guidelines and were approved by our local Ethics Committee for Animal Research (Regierung sprasidium Darmstadt, Germany). DRUGS: Compound CXT29 and diclofenac(Sigma-Aldrich, Darmstadt, Germany) were suspended at a concentration of 50 mg / mL in phosphate-buffered saline (PBS) containing 3% methylcellulose (Methocel A15LV, Sigma-Aldrich, Darmstadt, Germany). To make the suspension homogeneous, the mixtures were vortexed for 5 minutes immediately before administration.

[0993] Example 173. Inflammatory pain induced by Freund's complete adjuvant (CFA).

[0994] The mechanical sensitivity of a hind leg was assessed using a dynamic plantar esthesiometer (Ugo Basile, Comerio, VA, Italy). The animals were placed on a wire mesh grid and accustomed to the apparatus chamber for 1 hour. A thin probe (0.5 mm in diameter) was applied against the plantar surface of the paw from below with an increasing force of 0 to 5g within 10s and a constant force of 5g for a further 10s until a strong retreat occurred (Schmidtko, A.; Gao, W.; Sausbier, M.; Rauhmeier, I.; Sausbier, U.; Niederberger, E.; Scholich, K.; Huber, A.; Neuhuber, W.; Allescher, H. D.; Hofmann, F.; Tegeder, I.; Ruth, P.; Geisslinger, G. Cysteine -rich protein 2, a novel downstream effector of cGMP / cGMP-dependent protein kinase I-mediated persistent inflammatory pain. J. Neurosci. 2008, 28(6), 1320-1330). Paw withdrawal latency was automatically recorded and averaged over 6-8 measurements. After baseline measurements, 20 pL of Freund's complete adjuvant (CFA, containing 1 mg / mE heat-killed Mycobacterium tuberculosis in 85% paraffin oil and 15% mannide monooleate; Sigma- Aldrich, Darmstadt, Germany) was injected into the plantar surface of the hind paw (Ferreira, J.; Campos, M. M.; Pesquero, J. B.; Araujo, R. C.; Bader, M.; Calixto, J. B. Evidence for the participation of kinins in Freund's adjuvant-induced inflammatory and nociceptive responses in kinin Bl and B2 receptor knockout mice. Neuropharmacology. 2001, 41(8), 1006-1012). Mechanical sensitivity was again determined 24 hours after CFA injection. Immediately thereafter, the drugs or vehicle were administered by oral probe and mechanical sensitivity was determined over 2 hours.

[0995] Statistical analysis.

[0996] Statistical analysis was performed using Prism 9 (GraphPad). Data were analyzed using two-way repeated ANOVA measures followed by Dunnetfs post hoc test for multiple comparisons. Concentration-response curves were analyzed using the four-parameter logistic model. The parameter errors are all expressed in percentage coefficient of variation (% CV). Data are presented as mean ± standard error of mean (SEM) and a probability value p < 0.05 was considered statistically significant.Example 174. Evaluation of TP receptor antagonism and inhibition of cyclooxygenases according to the first procedure.

[0997] The synthesized compounds were evaluated for their ability to act as TP receptor antagonists on platelets washed from healthy human volunteers, in which the TPa isoform is widely expressed. Washed platelet samples were stimulated with U-46619 (0.1 pM), a stable TXA2 analogue, to induce platelet aggregation as previously reported. Compounds (1 nM-100 pM) or vehicle (DMSO max 0.2% v / v) were incubated for 5 min before addition of U-46619. The antiplatelet activity of the compounds, reported as IC50 ± CV%, is collected in Table 9. The ability of the synthesized compounds to inhibit COX- 1 and COX -2 activity was measured in platelet and lymphomonocyte suspensions, respectively. To measure COX-1 inhibition, human platelets were isolated from PRP by centrifugation and incubated with increasing concentration of test compounds (1 nM-100 pM) or vehicle for 30 min. COX-2-dependent PGE2 production was then triggered with LPS (10 pg / mL; 24h). PGE2 production was quantified by liquid chromatography tandem mass spectrometry using [d4] PGE2 as an internal standard. The results obtained, expressed as IC50 values for COX-1 and COX-2 inhibition, are collected in Table 9, which also reports the selectivity towards COX-2 (SI), calculated as the ratio of IC50 for COX-1 to COX-2.

[0998] Table 9

[0999] Compound Thromboxane (TP) iiiiliiiliiiii IIIII(OBBIBIIIII) iiiii llliilll!

[1000] receptor antagonism - Inhibition Inhibition iliiiliil Inhibition of platelet balance'' aggregation

[1001] lllliiilllll

[1002] etodolac 1

[1003] Reference 18.4 + 10% 2.59 ± 13% 0.037 + 17% 70 497 compound

[1004] MK-0524

[1005] (laropiprant)

[1006] 0.003 + 24% 9.14 + 52% 2.84 + 23% 2.7 0.00106 Reference

[1007] compound

[1008] CXT1 1.79 + 14% 5.19 + 13% 0.020 + 30% 250 90

[1009]

[1010] CXT9 6.12 + 17% 20.4 + 18% 0.679 + 14% 30 9.01 CXT 10 3.36 + 15% 7.93 + 68% 1.11 + 13% 7.1 3.02 CXT 11 1.35 + 19% 2.77 + 17% 0.023 + 29% 120 58.7 CXT12 0.57 + 24% 0.51 +9.7% 0.011 + 15% 46 51.8 CXT14 2.00 + 31% 7.30 + 18% 0.039 + 40% 187 51.3 CXT15 0.15 + 13% 18.7 + 16% 0.19 +14% 98 0.79 CXT20 0.086 + 34% 0.055 + 9.2% 0.070 + 45% 0.78 1.23 CXT21 0.034 + 44% 0.088 +4.8% 0.047 + 17% 1.9 0.72 CXT22 0.026 + 44% 19.5 + 6.7% 7.13 + 14% 2.7 0.0036 CXT23 0.085 + 19% 12.2 + 14% 0.783 + 17% 16 0.11 CXT24 0.180 + 30% 27.6 + 12% 0.649 + 16% 42.5 0.28 CXT26 0.12 + 26% 0.86 + 9% 0.41 + 17% 2.1 0.29 CXT27 0.31 + 21% 209 + 36% 1.41 + 30% 148 0.22 CXT29 0.096 + 14% 0.722 + 15% 0.013 + 12% 56 7.38 CXT31 0.22 + 38% 6.31 +25% 1.58 + 13% 3.99 0.14 CXT32 0.38 + 19% 0.097 + 42% 0.18 + 12% 0.54 2.1 CXT33 0.15 + 32% 0.118 + 22% 0.086 + 34% 1.4 1.70 CXT35 0.072 + 18% 0.58 + 10% 0.61 + 26% 0.95 0.12 CXT36 0.239 + 12% 16.2 +28% 1.25 + 23% 12.9 0.19 CXT37 0.189 + 20% 0.46 + 19% 0.29 + 17% 1.6 0.65 CXT38 0.358 + 6% 3.13 +43% 0.45 + 51% 6.9 0.79 CXT39 1.48 + 11% 9.47 + 30% 0.36 + 95% 26 4.11 CXT40 2.58 + 38% 59.2 + 51% 0.39 + 28% 151 6.61 CXT41 0.410 + 11% 6.76 + 69% 0.21 + 40% 32 1.95 CXT42 0.119 + 8.0% 0.089 + 17% 0.072 + 12% 1.2 1.65 CXT43 0.11 + 18% 81.0 + 57% 0.44 + 14% 184 0.25 CXT44 0.034 + 17% 2.55 + 13% 0.282 + 31% 9.0 0.12 CXT45 0.016 + 12% 1.37 +25% 0.132 + 48% 10 0.12 CXT46 2.16 + 94% 39.6 + 18% 0.075 + 32% 528 28.8

[1011]

[1012] Example 175. Evaluation of TP receptor antagonism and cyclooxygenase inhibition according to the second procedure.

[1013] The synthesized compounds were evaluated for their ability to act as TP receptor antagonists on rat thoracic aorta rings by measuring their ability to inhibit contraction induced by compound U-46619, a stable TXA2 analogue (Example 227). The results are reported as pA2 calculated by applying the Gaddum equation and are collected in Table 10. For selected compounds the ability to act as antagonists to the thromboxane receptor was also evaluated on human platelet-enriched plasma by measuring the ability of the compounds to inhibit platelet aggregation induced by the addition of U-46619 (example 228). The antiplatelet activity of the compounds, reported as IC50 (95% CI), is collected in Table 10. The ability of the synthesized compounds to inhibit the activity of COX-1 and COX-2 was measured in whole human blood by measuring the production of TXB2 or PGE2. The results obtained, expressed as IC50 or as percent inhibition, are shown in Table 10. Unlike the first procedure used, the second allows the compounds to be studied in the presence of plasma proteins, therefore in an experimental environment more similar to the physiological one.

[1014] Table 10

[1015] IC50 pM (CI 95%) inhibition of platelet TP antagonism

[1016] aggregation COX-1 COX-2 pA2±SE

[1017] IC50 pM (CI 95%) etodolac 1

[1018] 11.8 (9.4- Reference 1.5 (1.2-1.8) Not measurable

[1019] 15.7)

[1020] compound

[1021] ketorolac

[1022] 0.17 (0.11- 0.15 (0.09- Reference

[1023] 0.26) 0.26)

[1024] compound

[1025] MK-0524 0.72 (0.62- 7.75 + 0.12

[1026] (laropiprant) 0.83)

[1027]

[1028] Reference

[1029] compound

[1030] CXT20 67 (47-101) 22 (12-42) 6.62 + 0.02

[1031] CXT29 22 (12-43) 4.6 (2.9-7.1) 6.60 + 0.08 21 (17-27)

[1032] CXT30 26 (13-58) 21 (14-31) 5.93 + 0.09 45 (35-58)

[1033] 352 (224- CXT62 27 (21-35) 7.93 + 0.05 7.1 (6.2-8.2)

[1034] 546)

[1035] CXT64 18 (9.4-34) 93 (63-130) 8.09 + 0.02 1.1 (0.6-1.9) CXT65 9.6 (4.2-22) 14 (10-18) 7.80 + 0.06 6.6 (5.2-8.5)

[1036] CXT68 22 (14-33) 14 (11-18) 6.54 + 0.02

[1037] CXT72 44 (25-79) 24 (13-44) 7.48 + 0.03

[1038] 16 % + 12

[1039] CXT73 inhib. at 54 (26-148) 7.08 + 0.05

[1040] lOOpM

[1041] 51 % ± 6

[1042] CXT74 49 (37-64) inhib. at 7.45 + 0.06

[1043] lOOpM

[1044] CXT75 34 (24-46) 10 (6.6-16) 7.13 + 0.02

[1045] 0.46 (0.20- CXT77 13 (6.8-26) 6.22 + 0.13

[1046] 0.90)

[1047] 60 + 8.7%

[1048] CXT78 inhib. at 14 (6.4-31) 7.01 + 0.04

[1049] lOOpM

[1050] CXT79 26 (18-38) 9.1 (3.5-20) 6.92 + 0.17

[1051] CXT80 11 (7-18) 5.4 (3.6-7.8) 7.04 + 0.08

[1052]

[1053] CXT81 38 (n=2) 28 (13-75) 7.03 + 0.04

[1054] CXT82 24 (17-33) 12 (8.8-16) 8.00 + 0.06

[1055] CXT83 16 (11-25) 16 (8-33) 7.09 + 0.08

[1056] CXT84 35 (21-64) 36 (23-60) 6.82 + 0.14

[1057] CXT85 34 (30-40) 24 (12-46) 8.17 + 0.04

[1058] CXT86 26 (19-36) 30 (18-49) 7.36 + 0.06

[1059] CXT87 72 (34-111) 19 (10-34) 6.98 + 0.16

[1060] CXT88 17 (5.9-54) 52 (29-109) 7.21 + 0.15

[1061] 40 ± 5 %

[1062] CXT90 61 (15-115) inhib. at 7.16 + 0.04

[1063] 100p. M

[1064] 30 ± 2 %

[1065] CXT91 42 (26-67) inhib. at 6.94 + 0.16

[1066] 100p. M)

[1067] 59 ± 8 %

[1068] CXT92 86 (n=l) inhib. at 6.72 + 0.06

[1069] 100p. M

[1070] CXT93 35 (14-118) 11 (6.8-18) 6.45 + 0.16

[1071] CXT94 12 (5.9-21) 1.6 (1.0-2.5) 6.82 + 0.07 72 (71-73)

[1072] 51+ 2%

[1073] CXT95 31 (9.2-130) inhib. at 6.27 + 0.02

[1074] 100|JM

[1075] CXT96 22 (7.7-59) 12 (7.9-20) 6.73 + 0.15

[1076] CXT97 22 (14-36) 12 (7.6-21) 7.74 + 0.11

[1077] CXT98 14 (6.1-34) 20 (11-35) 7.98 + 0.07 3.4 (2.8-4.4)

[1078]

[1079] CXT99 13 (5.6-27) 13 (6.5-25) 7.69 + 0.21 CXT100 14 (7.2-27) 38 (22-70) 6.69 + 0.24 CXT101 13 (4.6-46) 7.1 (2.7-15) 7.03 + 0.12 CXT102 39 (26-56) 24 (13-44) 8.39 + 0.04 CXT103 28 (8.6-90) 18 (9.6-37) 7.02 + 0.02 CXT105 7.7 (4.5-13) 1.9 (1.4-2.6) 6.65 + 0.18

[1080]

Claims

CLAIMS1. Compounds of formula (I):enantiomers, diastereoisomers, rotamers, tautomers, isotopes and mixtures thereof; and the pharmaceutically acceptable salts, hydrates or solvates thereof,wherein:X is selected from H, halogen or (C1-C4) alkyl, linear or branched; preferably it is H, F or CH3; more preferably it is F;A is selected from H or halogen; preferably H or F; more preferably it is H;Y is selected from halogen, preferably Cl or I, provided that when X=H, A=H, Y is I, Br or F; or(C3-C6) alkyl, linear or branched, saturated or unsaturated, unsubstituted, such as -CH2CH(CH3)CH3 or -CFhCFhCF^CFh; or substituted with halogen such as -CH2CH2CH2CF3; wherein, when X=H and A=H, Y is (Cs-Ce) alkyl linear or branched, saturated or unsaturated, unsubstituted or substituted with halogen; orS, S(O) or SO2 each substituted with (C1-C6) alkyl linear or branched, saturated or unsaturated; or (C3-C6) cycloalkyl saturated or unsaturated; preferably selected from -S-CH3, -SO2CH3, -SO2-cyclopropyl or -SO2-cyclohexyl; or(C3-C6)-cycloalkyl, saturated or unsaturated, unsubstituted or substituted with (Ci-C^-alkyl, preferably 1 -cyclohexenyl; wherein, when X=H, A=H, Y is cyclo-butyl or (C3-C6) unsaturated cycloalkyl, unsubstituted or substituted with (C1-C4) alkyl; or-CH2-(C3-C6) cycloalkyl, saturated, unsubstituted or substituted, preferably -CH2-cyclopentyl; orphenyl unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, (Ci-C4)-C(O)-, (Ci-C4)O-, (CI-C4)-CONH-, -CONH2, (Ci-C4)-SO2-, preferably selected from phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,5-diCl-phenyl, 3,5-diCl-phenyl, 2-OH-phenyl, 3-OH-phenyl, 3-(HO-CH2)-phenyl, 4-(HO-CH2-phenyl, 3-(CH3CO)-phenyl, 3-(CH3O)-phenyl; 3-(CH3CONH)-phenyl, 3-(H2NCO)-phenyl, 3 -(CH3SO2) -phenyl; or benzyl substituted or unsubstituted with one or more substituents selected from halogen, (Ci-C4)-alkyl, (Ci-C4)-alkoxyl, hydroxyl, nitrile, nitro group, preferably benzyl, 2-Cl-benzyl, 3-C1-benzyl, 4-Cl-benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 2-CH3-benzyl, 3-CH3-benzyl, 4-CH3-benzyl, 3,4-Cl, F-benzyl, 3,2-Cl, F-benzyl, 3,5-Cl, F-benzyl, 3,5-diF-benzyl, 2,6-Cl, F-benzyl, 4,2-F, Cl-benzyl, 2,4-diF-benzyl, 4,2-Cl, F-benzyl, 3,4-CH3, F-benzyl, 2,3-F, CH3-benzyl, 3-CF3-benzyl, 3-(CH3O)-benzyl, 4-(CH3O)-benzyl, 3,5-F, CH3O-benzyl, 3-CN-benzyl, 3-NO2-benzyl; or5- or 6-membered heterocycle, having one or two heteroatoms selected from N and / or O, unsubstituted or substituted with one or more substituents selected from (Ci-C3)-alkyl, preferably selected from 3-pyridyl, 5-pyrimidyl, 3-pyrazolyl, 2-CH3-3-pyrazolyl,R24-isoxazolyl, -CFh-morpholinyl; orR';;wherein:- ifYisW is selected from (CH2)n where n is an integer between 2 or 3, SO2, S and S(O), preferably it is CH=CH, more preferably with Z or E configuration, CH2CH2, C≡C, CH2-CH=CH, CH2CH2 CH2;RI, R2, R3, R4and R5 are independently of each other selected from H, halogen; preferably H or F, more preferably Ri is F.

2. Compounds of formula (la):wherein:Y is benzyl substituted with one or more substituents, equal or different from each other, selected from hydrogen, halogen, preferably Cl or F; or(Ci-C4)-alkyl, linear or branched, preferably CH3; or(Ci-C4)-alkoxyl, preferably -CH3O-;nitro group;wherein benzyl is substituted with at least one of the following substituents or at least one ofthe following combinations of substituents 4-C1, 3,5-Cl, F, 3,5-diF, 2,6-Cl, F, 4-CH3, 4-(CH3O), CH3O- or 3-NO2.

3. Compounds of formula (lb):wherein:X is selected from H; halogen, preferably F; C1-C4 alkyl, linear or branched, preferably CH3; preferably it is CH3 or F; more preferably F;- when X is CH3, Y is halogen, preferably Cl;- when X is H, Y is SO2CH3;- when X is F; Y is selected from halogen, preferably Cl or I; or-S-(Ci-C4) alkyl linear or branched, preferably -S-CH3; orCF3-(Ci-C4)-alkyl linear or branched, preferably CH2CH2CH2CF3; orSO2-(C5-C6) cycloalkyl saturated, unsubstituted or substituted, preferably SO2-cyclohexyl; or SO2-phenyl, wherein phenyl is substituted or unsubstituted, preferably unsubstituted; or5- or 6-membered heterocycle, having one or two heteroatoms selected from N and / or O, unsubstituted or substituted with one or more substituents selected from (Ci-C3)-alkyl, linear or branched; preferably pyridyl, pyrimidyl, pyrazolyl, isoxazolyl, morpholinyl, more preferably selected from 3-pyridyl, 5-pyrimidyl, 3-pyrazolyl, 2-CH3-3-pyrazolyl, 4-isoxazolyl; or benzyl unsubstituted or substituted with one or more substituents, equal or different from each other, selected from hydrogen, halogen, preferably Cl, (Ci-C4)-alkyl, linear or branched, preferably -CH3, or cyano group; more preferably hydrogen; wherein benzyl is at least substituted with 3-CH3, 3-C1, or 3-CN; orphenyl substituted with one or more substituents, equal or different from each other, selected from halogen, preferably Cl or F, hydroxyl, ((C1-C4)-OH)-, H2NCO-, -CONH-(C1-C4), -CON(C1-C4)2, or ((C1-C4)-SO2)-, wherein phenyl is substituted with at least one of the following substituents or at least one of the following combinations of substituents 2,5-diCl, 3,5-diCl, 2-OH, 3-(OH-CH2)-,4-(OH-CH2)-, 3(H2NCO)-, or -3-(CH3SO2)-; orR2RI- zR,. W11R5R,^,wherein when W is CH2CH2, Ri is F or H, R2, R3, R4 and R5 are H.

4. Compounds of formula (Ic):whereinX is halogen, preferably F;A is H or F, preferably H, when X is H, A is F;Y is -SO2-(C1-C4) alkyl linear or branched, preferably -SO2CH3;unsubstituted phenyl;phenyl substituted with one or more substituents, equal or different from each other, selected from halogen, preferably Cl, (C1-C4)-CONH-, hydroxyl, -SO2-(C3-C4)-cycloalkyl saturated, unsubstituted or substituted, preferably -SO2-CH3, (C1-C4)-C(O)-, preferably (CH3CO)-, (C1-C4)-alkoxyl, more preferably CH3O-, wherein phenyl is substituted with at least one of the following substituents or at least one of the following combinations of substituents 2-Cl, 3-Cl, 4-Cl, 3-(CH3CONH)-, 3-OH, -SO2-cyclopropyl, 3-(CH3CO)-, 3-(CH3O)-; or(C3-C6)-cycloalkyl, unsaturated, unsubstituted or substituted, wherein, when X=H, A=H, Y is cyclo-butyl or (C3-C6)cycloalkyl unsaturated, unsubstituted or substituted with (Ci-C4)-alkyl, preferably Y is cyclohexenyl, more preferably 1 -cyclohexenyl;-CH2-(C3-C6)-cycloalkyl saturated, unsubstituted or substituted, preferably -CFh-cyclopentyl; orbenzyl substituted or unsubstituted with one or more substituents, equal or different from each other, selected from halogen, preferably Cl or F, (Ci-C4)-alkyl, preferably CH3, (Ci-C4)-alkoxyl, preferably (CH3O)-, or CF3, wherein benzyl is substituted with at least one of the following substituents or at least one of the following combinations of substituents 2-C1, 2-F, 3-F, 4-F, 3,4-Cl, F, 3,2-Cl, F, 2,4-Cl, F, 4,2-Cl, F, 2,4-diF or 3-CF3; 2,3-F, CH3- or 3,4-CH3, F-; 2-CH3-; 3-(CH3O)-; orR2whereinwhen W is CH=CH, preferably with E configuration, Ri is H or F, R2, R3, R4 and R5 are H, and when W is C= C, Ri, R2, R3, R4 and R5 are H, andwhen W is CH2CH=CH, Ri, R2, R3, R4 and R5 are H, preferably with configuration E.

5. Compounds of formula (I), (la), (lb) or (Ic), according to any one of claims 1-4, selected from the group comprising:Compound X A W Y Structure0CXT1 F H Cl LAN ) COOH aH 1CXT9 H H SO2-CH3O2S,HCXT10 F H SO2-CH3 AAN )AOOH • H 'O2S^0CXT11 F H S-CH3 L-XN A COOH AH!CXT12 F H ILAN ) COOH iH 1Compound X A W Y StructureCXT14 CH3H ClI H / Cl>0h 'i V~> COOH CXT15 F H SCh-phenyl! HOxS.,sx<'r'CXT20 \ COOH F H phenyl: l-ip CXT21 'COOK F H 3-Cl-phenyl iH''3- 'PCXT22 \ \'OOH F H (CH3CONH)-: l-ip phenylH0 3(HO-CH2)- CXT23 F H 'L-AN' COOH; H / phenylL. A OHCompound X A W Y Structureo ll T3-(H2NCO)-; COOH CXT24 F H i H phenylO!!> COOH CXT26 F H 3-OH-phenyl: H / • / o ll T V-<-\ 4(HO-CH2)-; COOH CXT27 F H i H phenyl^5Zv0H) IZ: / ' a CXT29 F H benzyl§SO2- > 'COOH CXT30 F H • H cyclopropyl o?sX / X^x^" NZS 'COOK CXT31 F H 2-OH-phenyl i HHOXx5rKCompound X A W Y Structure.. / p ) COOH CXT32 F H 2-Cl-phenyl • HK J. O T P GOOH CXT33 F H 4-Cl-phenyl; H / Cl3-(CH3CO)- CXT35 F Hphenyl‘ ‘ / / .r..r.J JJJ K K..( O ■■ ZZ■■■.K K 11 I 1 S S.V Oli T O' '- / 3-(CH3SO2)- \ 'COCH CXT36 F H; H / 8 8 o o phenylk- A CH, Os3-(CH3O)- CXT37 F HphenylXX^" NZSXcooHCXT38 F H 3 -pyridyl; HK ilCompound X A W Y StructureO / 8 ) COOH CXT39 F H 5-pyrimidyl: H \ •'' HN.x X.**. N\. / / K J. O 7i T VV P GOOH CXT40 F H 3-pyrazolyl i HHN-"2-CH3-3- CXT41 F HpyrazolylK J.I! T 'V-I-- 'GOOH CXT42 F H 1 -cyclohexenyl i HSO2- > 'COOH CXT43 F H • H cyclohexyl O, SXV’ x-x xX2,5-diCl- X^" NZS 'COOK CXT44 F H i HphenylCompound X A W Y Structure 6 / 8 3,5-diCl- CXT45 F H \ •phenyl a 2^crj (3 C.? \sX CXT46 F H 4-isoxazolylXP''CQOH 4-(CH3O)- i H / CXT62 F HbenzylX;'-5> xo.■■■'■vC-i-x \XCO0H: H CXT64 F H 4-Cl-benzylxx- " ClXP'cOOH i H / CXT65 F H 4-F-benzylx xpFxCH2- CXT68 F H cyclopentyl COOHCompound X A W Y Structure..,7 p 6 S / .8 'COOH; H,^Lo. / .--xCXT72 F H 2-CH3-benzyl\ \: a / \ / . / / / F.x,< fl T"^.0> COOH: H / CXT73 F H 3-CH3-benzylCOOH CXT74 F H 4-CH3-benzyl T n / Z— XS 'COOK i H CXT75 F H 2-Cl-benzyl4- COOH CXT77 F H H / trifluorobutyl^■CF3CXT78 F H 3-Cl-benzylCompound X A W Y Structure..,7 YS 'COOH; H / CXT79 F H 3-F-benzylFF.x,<0fl T"^.: H / CXT80 F H 2-F-benzylY'YF'^FvY (. AN S 'COOH 3-(OCH3)-; H / CXT81 F HbenzylMeOF.x,<0fl Y S.3-C1-4-F- > C°: H / OHCXT82 F HbenzylciS ''COOH 3-C1-2-F-; H / CXT83 F HbenzylF><Y ciS IP’X!? V~\ ) COOH: H CXT84 F H 3-CF3-benzylCF3Compound X A W Y Structure- / YS 'COOH 4-F-3-CH3-; H / CXT85 F HbenzylY F,<0fl T "^.2-F-3-CH3-: H ' CXT86 F Hbenzyl YYY’YY'' S 'COOH; H / CXT87 F H 3-CN-benzylNC,<0fl Y S.> C°OH: H / CXT88 F H 3-NO2-benzylYYx,y YS C'OQH 3-F-5-OCH3-; H / CXT90 F HbenzylMeOI! V~\ ) COOH 3-C1-5-F-: H CXT91 F Hbenzyl:: YciCompound X A W Y Structurez 8 S 'COOH; H C 2 V < / XT9 °" 'F H 3,5-diF-benzyl\.7 U FF,..7 '0 1i T x... J • (Z) \ 'COOK CXT93 F H phenylCH=CHR. / a lj '" T> COOH CXT94 F H CH2CH2 phenyl J H2-C1-6-F- CXT95 F Hbenzyl\XCOOH CXT96 H F benzylCompound X A W Y Structure S t'QQH; H / CXT97 F H c=c phenyl2-C1-4-F- CXT98 F Hbenzyl'p > COOH CXT99 F H 2,4-diF-benzyl 1 H / 7? / \ Q / _ Vi A" G- ■-- FXv^ pS COOH CH2CH=C; H / CXT100 F H phenylHi:! V~‘\-\ X, x-'-1'' fs| > COCH (E) | H / CXT101 F H phenylCH=CHCompound X A W Y Structure-Q,--N" > COOH 4-C1-2-F- HCXT102 F HbenzylOF"X^'C)'0(E) \ \oOH CXT103 F H 2-F-phenyl HCH=CH44.\ COOH CXT105 F H CH2CH2 2-F-phenyl H6. Compounds of formula (I) or (la) according to any one of claims 1, 2 and 5 selected from the group comprising:Compound X A W Y Structurefl IN ) COOH 4-(CH3O)-: HCXT62 F Hbenzyl.7: 'T x. <->'COOH; HCXT64 F H 4-Cl-benzylxC!X 0 U'N Y C T 4 H - H - e z l, O CX F C b y 8OH 7 4 3 n T H '^4 / .-; { y ™ / X / / — ' X <44 'COOH i H CXT88 F H 3-NO2-benzylO2N / ”* \ fx C fiXT Nx>—<— 'J \ COOH 3-F-5-OCH3-: H CXT90 F HbenzylMeO / *•*• ’X 4 'COOH 3-C1-5-F- i H CXT91 F Hbenzyl V-'Vv-YCi / ”* \ C 0 'T Y-Y \-\ COOH: H CXT92 F H 3,5-diF-benzylF2-C1-6-F- CXT95 F Hbenzyl7. Compounds of formula (I) or (lb) according to any one of claims 1, 3 and 5 selected from the group comprising:Compound X A W Y StructureCXT 1 F H Cl COOH ciH 7[i Yw-x CXT 9 H H SO2-CH3 LAhl ) COOH o2sxHCXT11 F H S-CH3 COOH YH 1CXT12 F H ICOOH iH 7CXT14 CH3H Cl ) COOH 1 H 'ClF\ J '0i; '■r'LA| / COOH CXT15 F H SO2-phenyl! HOjSx -lxr J\3(HO-CH2)- S COOH CXT23 F H i H / phenyl3-(H2NCO)- ■> COOH CXT24 F H: H phenyl64(HO-CH2)- S COOH CXT27 F H i Hxsphenyl'OHii | -p-\ CXT29 F H benzyl; HSX Xx-'‘Vvv?->.COOH CXT31 F H 2-OH-phenyl: l-fF\ p 3-(CH3SO2)- - \XCOOH CXT36 F H; H phenyl^-A.O, CH b3Oar""\X COOH CXT38 F H 3-pyridyl: Hz8 f' ii i. / -O-'''(<>?••••_ xz'.> COOH CXT39 F H 5-pyrimidyl: HIsr“”\ COOH CXT40 F H 3-pyrazolyl: l-fHN"-2-CH3-3- CXT41 F HpyrazolylSO2- X COOH CXT43 F H: l-f cyclohexyl O2sz..,.-V>F\ 0 2,5-diCl- " COOH CXT44 F H i H phenyl Oky>- ” '"' Clr""\3,5-diCl- M'-s / X COOH CXT45 F H: H phenylCf / \.. X.- -x CXT46 F H 4-isoxazolyl,.< Xvv'C-K \ COOH: H / CXT73 F H 3-CH3-benzyl4- CXT77 F H M' N > COOH [ H / trifluorobutyl^CF3P 'COOH; H CXT78 F H 3-Cl-benzylci>. v\ N } COOH: H / CXT87 F H 3-CN-benzyl 'X..-- sX XXNOX 0 0 CXT94F H CH2CH2 phenyli «■ / V, V, / / "".!x- 'COOH CXT105 F H CH2CH2 2-F-phenyl i H / 8. Compounds of formula (I) or (Ic) according to any one of claims 1, 4 and 5 selected from the group comprising:Compound X A W Y StructureCXT10 F H SO2-CH3 TIQ \- COOH i H / O2S.xZ-— X CXT20 F H phenyl ’L-Af / 'COOHi HVrCX CXT21 F H 3-Cl-phenyl N ) COOH: H3- CXT22 F H (CH3CONH)- phenyl9 COOH CXT26 F H 3-OH-phenyl: Hr""\ Vvv?->. SO2- COOH CXT30 F H: l-f cyclopropyl OaS..\ / / ">.ii | A xz xs: b— <~-x> COOH CXT32 F H 2-Cl-phenyl • HCixb 0 X\ COOH CXT33 F H 4-Cl-phenyl i HOfF\ b 3-(CH3CO)- " \XCOOH CXT35 F H i H phenyl^. JX.., CH36r""\3-(CH3O)- •• X COOH CXT37 F H: H phenylH | V— v\ > COOH CXT42 F H 1 -cyclohexenyl; HF,. A. / 0 jj Y ex 'sF- " N > OOOH: H CXT65 F H 4-F-benzylX,, XCH2- CXT68 F H COOH T H / cyclopentylp-v-er--(vP\ 'COOH; H CXT72 F H 2-CH3-benzylF.. A. / 0 jj Y %... p-x " N > <>3OH: H CXT75 F H 2-Cl-benzylci -"'xe:F,,.,x J 0jj Y" N > OOOH: H o CXT79 F H 3-F-benzylV,.o.F - / \ ° z — \ ’L-AJ?' S 'COOH; H CXT80 F H 2-F-benzylF v*'F.. A. / 0 jj Y" N > OOOH 3-(OCH3)-: H CXT81 F HbenzylMedF-v'^r-'Y, 'pS 'COOH 3-C1-4-F-; H CXT82 F HbenzylC!3-C1-2-F- CXT83 F Hbenzyl / — \ PH i V--v--v '•x^N > COOH: l-i CXT84 F H 3-CF3-benzylCF3F, J '0jj Y V-x-x " N > OOO XH 4-F-3-CH3-: H CXT85 F H 8,u benzyl( > (.2-F-3-CH3- CXT86 F HbenzylW s ■ V—) V’\ (Z) \ COOH CXT93 F H phenyl I H CH=CH > 4. z-'p \ 'COOH ’ i H / CXT96 H F benzylF.. / 0 jj Y'sF- " N > <>3OH: H CXT97 F H C=C phenylX*s*x'z’**'2-C1-4-F- > COOH CXT98 F H! HbenzylCXT99 F H 2,4-diF-benzylF.. „ / 0Y; V-4-x> COOH CH2CH=C T HCXT100 F H phenylH\ _) GOOH (E) i HCXT101 F H phenylCH=CH*75 / OH iV. \ COOH 4-C1-2-F- § H / / c CXT102 F H 8benzyl XF,x'b(E) \SCOOH CXT103 F H 2-F-phenyl i HCH=CH9. Compounds of formula (I), (la), (lb) or (Ic) according to any one of claims 1-8, selected from CXT15, CXT21, CXT26, CXT29, CXT32, CXT33, CXT37, CXT41, CXT42, CXT44, CXT45, CXT62, CXT64, CXT65, CXT72, CXT75, CXT78, CXT80, CXT82, CXT83, CXT86, CXT87,CXT88, CXT93, CXT95, CXT97, CXT98, CXT99, CXT101, CXT103, CXT105, preferably selected from CXT21, CXT29, CXT33, CXT42, CXT45, CXT62, CXT64, CXT65, CXT75, CXT78, CXT82, CXT97, CXT98, CXT99; preferably selected from CXT29, CXT62, CXT65, CXT78, CXT99; more preferably the compound is CXT29.

10. Compounds of formula (I), (la), (lb) or (Ic) according to any one of claims 1-9, for use as a medicament.

11. Compounds of formula (I), (la), (lb) or (Ic) according to any one of claims 1-9, for use as COXi and / or COX2 inhibitors and thromboxane (TP) receptor antagonists.

12. Compounds of formula (I), (la), (lb), or (Ic) according to any one of claims 1-9, for use in the prevention and / or treatment of diseases and / or disorders related to inflammatory-based diseases, particularly involving COX-1 and COX-2 (hyper)activation, and / or thromboxane receptor activation, comprising mild to moderate inflammatory pain; musculoskeletal injuries, preferably osteoarthritis, rheumatoid arthritis, atherosclerosis and arthrosis; autoimmune diseases; neurodegenerative diseases, preferably Alzheimer's disease; heart diseases, preferably cardiac ischemia; cancer diseases, preferably metastatic, more preferably hepatocellular carcinoma, colorectal cancer, breast cancer, and melanoma; non-alcoholic hepatic steatosis; endothelial function-related diseases, preferably cardiac and pulmonary fibrosis; stroke.

13. Compositions comprising at least one compound of formula (I), (la), (lb) or (Ic) according to any one of claims 1-9, and at least one pharmaceutically acceptable excipient or vehicle.

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