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Title:
TETRALINE SULFONAMIDE DERIVATIVES FOR USE IN THE TREATMENT OF PROLIFERATIVE DISORDERS
Document Type and Number:
WIPO Patent Application WO/2012/175654
Kind Code:
A1
Abstract:
Tetraline sulfonamides derivatives highly specific towards CA IX and/or CA XII human carbonic anhydrase for targeting solid tumors.

Inventors:
MASEREEL BERNARD (BE)
FREDERICK RAPHAEL (BE)
SUPURAN CLAUDIU T (IT)
Application Number:
PCT/EP2012/062052
Publication Date:
December 27, 2012
Filing Date:
June 22, 2012
Export Citation:
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Assignee:
UNIV NOTRE DAME DE LA PAIX (BE)
MASEREEL BERNARD (BE)
FREDERICK RAPHAEL (BE)
SUPURAN CLAUDIU T (IT)
International Classes:
C07C311/46; A61K31/18; A61K31/415; A61K31/433; A61P35/00; C07D231/16; C07D285/06
Domestic Patent References:
WO2004048544A22004-06-10
WO2006137092A12006-12-28
WO2008071421A12008-06-19
WO2009089383A22009-07-16
WO2004048544A22004-06-10
Foreign References:
US7829065B22010-11-09
US20080138291A12008-06-12
Other References:
PASTOREKOVA ET AL.: "Drug Design of Zinc-Enzyme Inhibitors", 2009, JOHN WILEY & SONS, INC., pages: 193 - 222
POULSEN, S.-A., EXPERT OPIN. THER. PATENTS, vol. 20, no. 6, 2010, pages 795 - 806
GULER ET AL., CURR. MED. CHEM., vol. 17, 2010, pages 1516 - 1526
POTTER CPS; HARRIS AL, BRIT. J. CANCER, vol. 89, 2003, pages 2 - 7
WINUM ET AL., J. MED. CHEM., vol. 46, 2003, pages 2197 - 2204
Attorney, Agent or Firm:
PRONOVEM - OFFICE VAN MALDEREN (Brussels, BE)
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Claims:
CLAIMS

1. A compound of having the general formula (I) or a pharmaceutically acceptable salt thereof

wherein

X is oxygen or sulfur;

R is an alkyl or an aryl group;

Y is NH or 0;

n is equal to 0 or 1.

2. The compound of claim 1, having the general formula (II) or (III)

(ID (in) wherein

X is oxygen or sulfur;

R is an alkyl or an aryl group;

Y is NH or 0;

n is equal to 0 or 1

3. The compound of claim 1 or 2, wherein X is oxygen.

4. The compound according to any of the preceding claims , wherein n is equal to 0.

5. The compound according to any of the preceding claims, wherein the group R is an alkyl group, preferably a Cl-Cll alkyl group.

6. The compound of claim 5 wherein the Cl- Cll alkyl group is linear.

7. The compound of claim 5 wherein the Cl- Cll alkyl group is branched.

8. The compound of claim 5 wherein the alkyl group is C3-C10 cyclic alkyl group.

9. The compound according to any of the preceding claims, wherein R is an alkyl group that does not comprise any halogen residues and/or no divalent metal and preferably consist of C and H residues.

10. The compound according to any of the preceding claims, wherein the group R is an aryl group, preferably an hetero aryl group, more preferably a 5- membered heteroaryl group.

11. The compound according to any of the preceding claims being in the R-configuration .

12. The compound according to any of the preceding claims 1 to 11 being in the S-configuration .

13. The compound according to any of the preceding claims being selected from the compounds of tables I and I I .

14. The compound of claim 13 being selected from the group consisting of MC5, MC6, MC8, MC9, MCIO, MC13, MC17, MC21, R-MC22 , S-MC24 , MC31, MC32, MC34, MC37, MC38, MC39, MC40, MC62, CV38-2, CV42-2 and CV46, preferably selected from the group consisting of MC5, MC6, MC8, MC9, MC17, R-MC22, MC32, MC38, MC39, MC62, CV38-2, CV42-2 and CV46 and more preferably from the group consisting of MC5, MC6, MC8, MC9, MC17, R-MC22, MC38, MC39, and CV46, and still more being MC6, MC8 or MC17.The compound according to any of the preceding claims being labeled and/or linked to a radioactive element.

15. The (non therapeutic) use of the compound according to any of the preceding claims for the diagnostic and/or monitoring of an proliferative disorder such as cancer, preferably of a cancer made of solid tumors.

16. A pharmaceutical composition comprising the compound according to any of the preceding claims 1 to 14.

17. The compound according to any of the preceding claims 1 to 14 for use in the treatment of or in the prevention of a proliferative disorder, such as cancer, preferably a cancer selected from the group consisting of breast, uterine cervix, ovarian, kidney, lung, esophagus, colorectal, endometrial, bladder, prostate, brain, head and neck cancers .

18. A process for a production of the compound according to any of the preceding claims 1 to 14 and comprising the step of submitting an 1-amino, 6 sulfonamide te t rahydronapha t alene (according to formula (IV)) to an acylation on the amine group;

(IV)

or of

- submitting an 1-amino tetrahydronaphatalene

(according to formula (V)) to:

(V)

an acylation on the amine group and

the addition of one sulfonamide group at position 5, 6, 7 or 8.

19. The process of claim 18, wherein the amino group is at position 1 or 2 in the formulae IV or V.

20. The process of claims 18 or 19 wherein the acylation step is followed by the addition of a sulfonamide group.

21. The process of claims 18 or 19 wherein the addition of the sulfonamide group is followed by an acylation step.

22. The process according to any of the preceding claims 18 to 21, wherein the acylation step is performed using R-(C=0)-C1, R- (C=0) -0- (C=0) -R, or R-N=C=X compounds, wherein X is 0 or S.

Description:
TETRALINE SULFONAMIDE DERIVATIVES FOR USE IN THE TREATMENT

OF PROLIFERATIVE DISORDERS

Field of the invention

[0001] The present invention is in the fields of chemistry, biochemical engineering, and oncology. More specifically, it relates to organic and inorganic compounds, preferably aromatic and heterocyclic sulfonamides, and their use to treat proliferative disorders, such as cancer (i.e. preneoplastic and/or neoplastic diseases) by specifically inhibiting the carbonic anhydrase activity of proteins known alternatively as the MN proteins, the MN/CA IX and MN/CA XII isoenzyme, or MN/CA IX or MN/CA XII or CA IX or CA XII. The present invention also relates to methods of treating such proliferative disorder (preneoplastic and/or neoplastic diseases) characterized by CA IX and/or CA XII overexpression, by administering inhibitors of CA IX and/or CA XII, preferably derivatives of aromatic and heterocyclic sulfonamides .

[0002] The invention further concerns diagnostic

/prognostic methods including imaging methods, for this proliferative disorder (preneoplastic /neoplastic diseases), using the disclosed potent CA IX and/or CA XII- specific inhibitors. Background of the invention and state of the art

[0003] Carbonic anhydrases (CA, EC 4.2.1.1) are ubiquitous zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide (CO 2 ) to generate bicarbonate anion (HC03 ~ ) and a proton (H + ) . CA can either produce or consume bicarbonate and thereby participate in biosynthesis reactions, ion transport across the membranes, and acid- base balance via this activity (Pastorekova et al . 2009, Drug Design of Zinc-Enzyme Inhibitors, C.T. Supuran and J.- Y. Winum Eds., John Wiley & Sons, Inc. p. 193-222).

[0004] The substrates of the CA-catalyzed reaction are known to regulate a broad range of physiological functions that involve the production and transport of CO 2 , protons and bicarbonate. This equilibrium underpins, e.g., respiration and transport of CO 2 and HC03 ~ between metabolizing tissues and lungs, pH homeostasis, bone development and function, electrolyte secretion, and biosynthesis where HC03 ~ is a substrate. The hydration of CO 2 under physiological conditions, although spontaneous, does not proceed fast enough in the absence of CA to support these biological processes (Poulsen, S.-A. 2010, Expert Opin. Ther. Patents 20 ( 6) : 795-806) .

[0005] Cancer represents a pathologic situation characterized by numerous aberrant features at molecular, cellular, and tissue levels. Two membrane-bound CA isozymes (CA IX and CA XII) are predominantly associated with and ove rexpr e s s ed in many tumors, contrasting with their restricted expression in normal tissues, and are connected in critical processes associated with cancer progression and response to therapy (Guler et al. 2010 Curr. Med. Chem. 17:1516-1526). The tumour-associated isoenzymes, CA IX and CA XII, are expressed in a wide variety of malignancies and appear to be tightly regulated by mi cr oenvi r onmen t a 1 hypoxia. CA IX expression is linked to poor prognosis in a number of human tumours, and may be a marker of aggressive malignant phenotype and a mechanism of progression (Potter CPS and Harris AL . 2003 Brit. J. Cancer 89, 2-7) .

[0006] Activity of carbonic anhydrases (including that of CA IX and XII, but also CA I, II,...) can be efficiently blocked by sulphonamide/sulfamate/sulfamide inhibitors. That fact has been therapeutically exploited in diseases caused by excessive activities of certain CA isoforms (e.g. CA II in glaucoma) . However, the sulfonamides available so far indiscriminately inhibit various CA isoenzymes (14 are presently known in humans) that are localized in different subcellular compartments and play diverse biological roles. This lack of selectivity compromises the clinical utilization of these compounds due to undesired side effects caused by concurrent inhibition of many CA isoforms and represents a main drawback also for the sulfonamide application against CA IX and/or XII in anticancer therapy.

[0007] In WO2008/071421 , n i t r o de r i v a t i ve s of carbonic anhydrase inhibitors are described as potential inhibitors of several carbonic anhydrase isoforms, including isoforms IX and XII. However, none of these compounds are tetraline sulphonamide derivatives and none are highly selective for CA IX and/or CA XII.

[0008] In US7829065, WO2009089383, WO2004048544, and

US2008138291, CA IX-specific inhibitors are described and, again, none of these compounds are tetraline sulphonamide derivatives and none are highly selective for CA IX and CA XII. Summary of the invention

[0009] A first aspect of the present invention is a method for a screening and/or for an identification of a specific inhibitor of one or more tumor-associated isoform(s) of the carbonic anhydrase enzyme, said method comprising the steps of:

putting into contact variable concentrations of an isolated chemical compound (suspected to interact with one or with several isoforms of the carbonic anhydrase) with at least one tumor-associated isoform(s) of the said enzyme (such as isoforms IX and/or XII);

measuring the inhibition constant (Ki; nM) of the said compound towards the said tumor-associated enzyme isoform ( s ) ;

- putting variable concentrations of the said compound into contact with at least another isoform (e.g. isoform I and/or II and/or III and/or IV and/or V and/or VI and/or VII and/or VIII and/or X and/or XI and/or XIII and/or XIV) of the carbonic anhydrase enzyme, such as isoform I and/or II of the carbonic anhydrase;

measuring the inhibition constant (Ki; nM) of the compound towards this another isoform (I and/or II) of the carbonic anhydrase and

deducing whether this compound is specific towards the said tumor-associated enzyme isoform(s).

[0010] Preferably, in this method, the inhibition constant (Ki; nM) of the specific (isolated) chemical compound towards tumor-associated isoform (s) (such as isoforms IX and/or XII) of the (human) carbonic anhydrase is at least about 5-fold lower than the inhibition constant (Ki; nM) of this specific (isolated) chemical compound towards the other isoform(s) of the carbonic anhydrase, preferably at least 10-fold lower, more preferably at least 100-fold lower. [0011] Advantageously, in this method, the tumor associated isoform is (are) isoforms IX and/or XII, and/or the other isoform is/are isoforms I and/or II, preferably the tumor associated isoform are both isoforms IX and XII and the other isoform is/are isoforms I and/or II.

[0012] Preferably, in this method, the inhibitor is a tetrahydronaphatalene (tetraline) and/or a sulfonamide, more preferably a tetrahydronaphatalene (tetraline) sulfonamide .

[0013] A related aspect of the present invention is the inhibitor obtainable by this method.

[0014] Still a related aspect of the present invention is a tumor-associated specific carbonic anhydrase inhibitor, wherein this inhibitor is specific for isoform IX and/or isoform XII of the carbonic anhydrase.

[0015] A preferred specific inhibitor of isoform IX and/or isoform XII of the carbonic anhydrase is a tetrahydronaphatalene (tetraline) and/or sulfonamide, more preferably a tetrahydronaphatalene (tetraline) sulfonamide.

[0016] Most preferably, the inhibition constant (Ki; nM) of this specific inhibitor towards the isoform IX and/or the isoform XII is at least about 5-fold lower than the inhibition constant (Ki; nM) towards isoform I and/or isoform II, preferably at least about 10-fold lower, more preferably at least 100-fold lower and/or the inhibition constant (Ki; nM) towards the isoform IX and/or the isoform XII is at least about 5-fold lower than the inhibition constant (Ki; nM) towards isoform I, preferably at least about 10-fold lower, more preferably at least 100-fold lower and/or the inhibition constant (Ki; nM) towards isoform IX and/or isoform XII is at least about 5-fold lower than the inhibition constant (Ki; nM) towards isoform II, preferably at least about 10-fold lower, more preferably at least 100-fold lower. [0017] Another related aspect of the present invention is a pharmaceutical composition comprising an adequate pharmaceutical carrier or diluents and the (specific) inhibitor of the present invention.

[0018] Another related aspect of the present invention is this (specific) inhibitor for use in the treatment of or in the prevention of a hyper-proliferative disorder, such as cancer, preferably a cancer selected from the group consisting of breast, uterine cervix, ovarian, kidney, lung, esophagus, colorectal, endometrial, bladder, prostate, brain, head and neck cancers and more preferably for use in breast or colorectal cancer.

[0019] Another related aspect of the present invention is a compound (preferably the specific inhibitor of the present invention) having the general formula (I) or a pharmaceutically acceptable salt thereof

wherein

X is oxygen or sulfur;

R is preferably an alkyl or an aryl group;

Y is NH or 0 (oxygen) ;

n is equal to 0 or 1.

[0020] Another related aspect of the present invention is a pharmaceutical composition comprising the compound (preferably the specific inhibitor of the present invention) having the general formula (I) , or a pharmaceutically acceptable salt thereof

wherein

X is oxygen or sulfur;

R preferably is an alkyl or an aryl group;

Y is NH or 0 (oxygen) ;

n is equal to 0 or 1.

[0021] Another related aspect of the present invention is a compound (preferably the specific inhibitor of the present invention) having the general formula (I), or a pharmaceutically acceptable salt thereof

wherein

X is oxygen or sulfur;

R is preferably an alkyl or an aryl group;

Y is NH or 0 (oxygen) ;

n is equal to 0 or 1 for use in the treatment or in the prevention of a hyper- proliferative disorder such as cancer, preferably a cancer selected from the group consisting of breast, uterine cervix, ovarian, kidney, lung, esophagus, colorectal, endometrial, bladder, prostate, brain, head and neck cancers and more preferably for use in breast or colorectal cancer .

[0022] Preferably, this compound (more preferably the specific inhibitor of the present invention) and/or this compound for use as a medicament and/or this compound for use in the treatment of cancer has the general formula (II) or (III)

X is oxygen or sulfur;

R is preferably an alkyl or an aryl group;

Y is NH or 0 (oxygen) ;

n is equal to 0 or 1

[0023] Preferably, in this compound (specific inhibitor and/or medicament) X (derivative) is oxygen.

[0024] Preferably, in this compound (specific inhibitor and/or medicament) n is equal to 0.

[0025] Preferably, in this compound (specific inhibitor and/or medicament) the group R is an alkyl group, preferably a Cl-Cll alkyl group, being possibly linear or branched or cyclic (C3-C10 or C3-C8).

[0026] Possibly, in this compound (specific inhibitor and/or medicament) the group R is an alkyl group that does not comprise any halogen residues and/or no divalent metal and preferably consist of C and H residues.

[0027] Preferably (alternatively) , in this compound

(specific inhibitor and/or medicament) the group R is an aryl group, preferably an hetero aryl group, more preferably a 5-membered heteroaryl group.

[0028] Preferably, this compound (specific inhibitor and/or medicament) is in the R-configuration .

[0029] Alternatively, this compound (specific inhibitor and/or medicament) is in the S-configuration .

[0030] More preferably this compound (specific inhibitor and/or medicament) is (are) selected from the compounds (formulae) of tables I and II.

[0031] Advantageously this compound (specific inhibitor and/or medicament) is (are) selected from the group consisting of MC5, MC6, MC8, MC9, MCIO, MC13, MC17, MC21, R-MC22, S-MC24, MC31, MC32, MC34, MC37, MC38, MC39, MC40, MC62, CV38-2, CV42-2 and CV46, preferably selected from the group consisting of MC5, MC6, MC8, MC9, MC17, R- MC22, MC32, MC38, MC39, MC62, CV38-2, CV42-2 and CV46 and more preferably from the group consisting of MC5, MC6, MC8, MC9, MC17, R-MC22, MC38, MC39, and CV46, and still more being MC6, MC8 or MC17.

[0032] Another aspect of the present invention is related to this specific inhibitor and/or medicament for use in the prevention of metastasis and/or as anti- metastatic agent.

[0033] Advantageously, this compound (specific inhibitor and/or medicament) is labeled and/or linked to a radioactive element. [0034] Another aspect of the present invention is the (non therapeutic) use of this compound (specific inhibitor and/or medicament) for the diagnostic and/or monitoring of an hyper-proliferative disorder such as cancer, preferably of a cancer made of solid tumors.

[0035] Another aspect of the present invention is a process for a production of this compound (specific inhibitor and/or medicament) and comprising the step of submitting an 1-amino, 6 sulfonamide tetrahydronaphatalene (according to formula (IV) ) to an acylation on the amine group;

(IV)

or of

- submitting an 1-amino tetrahydronaphatalene

(according to formula (V)) to:

(V) an acylation on the amine group and

- the addition of a (one) sulfonamide group at position 5, 6, 7 or 8 (preferably at position 6) .

[0036] Preferably, in this process, the amino group is at position 1 or 2 in the formulae IV or V. [0037] Possibly, in this process, the acylation step is followed by the addition of a sulfonamide group.

[0038] Alternatively, in this process, the addition of the sulfonamide group is followed by the acylation step.

[0039] Advantageously, in this process, the acylation step is performed using R-(C=0)-C1, R- (C=0) -O- (C=0) -R, or R-N=C=X compounds, wherein X is 0 or S.

Detailed description of the invention

[0040] The identification of CA IX and/or CA XII- specific inhibitors opens an new field in cancer treatment, allowing to specifically target (to specifically visualize, to specifically weaken and even to specifically kill) cancerous cells over expressing these enzymes.

[0041] The inventors have identified compounds having inhibitory constants (Ki) towards CA IX and/or CA XII isoforms within the low nanomolar range (i.e. 1-10 nM) .

[0042] The inventors have found that some inhibitors are very active towards CA IX and/or CA XII-isoforms, but are also very active towards the other CA isoforms such as isoforms I and/or II.

[0043] The inventors have further refined their analysis and advantageously identified compounds having a stronger inhibition of CA IX and/or of CA XII isoforms than of the other CA isoforms such as isoforms I and/or II. For instance, these compounds have inhibition constant in the low nanomolar range (i.e. about 1 to about 10 nM) for isoforms IX and/or XII, and in the micromolar range (i.e. about 100 nM to 10 μΜ, preferably 1 μΜ to 10 μΜ) for the other CA isoforms, such as isoform I and/or for isoform II.

[0044] The inventors have deduced the corresponding ratios of inhibition and identified compounds having ratios of inhibition higher than about 5, other compounds having inhibition ratios higher than about 10, even higher than about 100 and even some compounds having inhibition ratios higher than about 1000, meaning a wide possibility to selectively inhibit CA IX and/or CA XII isoforms without affecting the other isoforms. These compounds represent preferred specific inhibitors towards CA IX and/or CA XII isoforms .

[0045] The CA IX and/or CA XII-specific inhibitors of this invention can be used d i a g n o s t i c a 11 y and prognostically for pre-cancer and cancer, and to determine the status of a patient, and therapeutically, individually or in different combinations with conventional therapeutic regimens to treat pre-cancers and/or cancer.

[0046] It has been found that the tetraline sulfonamide derivative compounds described herein have anti-tumour and anti-cancer activity and are useful in the treatment, diagnosis and/or prognosis of proliferative disorders in subjects.

[0047] The molecules of the present invention are useful, for example, as diagnostic tool for screening populations for the presence of cancerous or pre-cancerous disease, determining the risk of developing cancerous disease, diagnosing the presence of cancerous and/or pre- cancerous disease, monitoring the disease status of patients with cancerous disease, and/or determining the prognosis for the course of cancerous disease.

[0048] Particularly, the CA IX and/or CA XII- specific inhibitors of this invention can be used diagnostically/prognostically to detect precancerous and/or cancerous cells by the selective binding to CA IX and/or CA XII, preferably to CA IX and/or CA XII activated by hypoxic conditions, wherein said CA IX and/or CA XII-specific inhibitors are coupled to a label or to some visualizing means. Such detection of CA IX and/or CA XII over- expression and/or of hypoxic conditions can be helpful in determining effective treatment options, and in predicting treatment outcome and the prognosis of disease development. Further the CA IX and/or CA XII -specific inhibitors when labelled or linked to an appropriate visualizing means can be used for imaging tumours and/or metastases that express CA IX and/or CA XII .

[0049] In another aspect, the CA IX and/or CA XII- specific inhibitors of this invention are used to hinder cancer expansion and/or progression by blocking CA IX and/or CA XII activity.

[0050] Advantageously, the CA IX and/or CA XII- specific inhibitors are conjugated to radioisotopes for radiotherapy.

[0051] Possibly, the CA IX and/or CA XII-specific inhibitors for use in cancer treatment are combined with a variety of conventional (cancer) therapeutic drugs and/or different inhibitors of cancer-related pathways (such as chemotherapy, endocrine therapy, immune therapy, preferably based upon administration of (anti Her2) antibodies) and/or radiotherapy, wherein advantageously different combinations of treatment regimens with the CA IX and/or CA XII-specific inhibitors of this invention increases overall treatment efficacy.

[0052] For instance, the CA IX and/or CA XII- specific inhibitors of this invention are advantageously combined with a (one or several) compound (s) selected from the group consisting of doxorubicine, temozolomide, vincristine, vinorelbine, procarbazine, carmustine, lomustine, taxol, taxotere, tamoxifen, retinoic acid, 5- fluorouracil , cyclophosphamide and thalidomide. [0053] Figure 1 shows the general procedure followed in the synthesis of the tetraline sulphonamide derivative according to the present invention.

Figure 2 shows molecules according to the invention.

[0054] In the present invention, the term

"proliferative disorders" includes neoplasm and cancers, dysplasia, premalignant or precancerous lesions, abnormal cell growths, benign tumours, malignant tumours, or metastasis, and preferably refers to cancer.

[0055] The cancer is advantageously selected from the group consisting of leukaemia, non-small cell lung cancer, small cell lung cancer, CNS cancer (brain) , melanoma, ovarian cancer, uterine cervix, endometrial, kidney cancer, prostate cancer, breast cancer, glioma, colon cancer, bladder cancer, sarcoma, pancreatic cancer, colorectal cancer, head and neck cancer, liver cancer, bone cancer, bone marrow cancer, stomach cancer, duodenum cancer, oesophageal cancer (cancer of the oesophagus) , thyroid cancer, haematological cancer and/or lymphoma.

[0056] Preferably, the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, CNS cancer (brain) , melanoma, ovarian cancer, uterine cervix, endometrial, kidney cancer, prostate cancer, breast cancer, glioma, colon cancer, bladder cancer, sarcoma, pancreatic cancer, colorectal cancer, head and neck cancer, liver cancer, stomach cancer, duodenum cancer, oesophageal cancer, and thyroid cancer and/or is a solid tumour.

[0057] Of most particular interest are solid tumours in which vasculature is poor and limits the blood supply to the tumour mass; this in turn reduces the delivery of oxygen to tumour cells. Examples of such tumours are breast, brain (e.g., glioblastoma), clear cell renal, colorectal, head and neck, bladder and NSCLCs .

[0058] More preferably, the cancers contain cancer cells in hypoxic conditions.

[0059] The terms "treat" or "treatment" refers to both therapeutic treatment and prophylactic or preventative measures and administration, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of the proliferative disease (cancer) . Beneficial or desired clinical results include alleviation of symptoms, diminishment of extent of disease, stabilised (i.e., not worsening) state of disease, delay or slowing of disease progression, reduction or prevention of cancerous cell migration and colonisation of new tissues (i.e., anti- migratory effect), amelioration or palliation of the disease state, remission (whether partial or total) , whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Particularly intended herein are therapeutic or curative treatments of proliferative disorders such as tumours or cancer.

[0060] The term "substituted" denotes that one or more hydrogen (s) on one or more other (s) atom(s) (typically C, N, 0 or S atom(s), usually C atom(s)) of a group indicated by the modifier "substituted" is replaced with a selection from the recited group, provided that the normal valency of the atoms of the indicated group is not exceeded, and that the substitution results in a chemically stable compound, ompound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an useful agent . [0061] The term "halo" or "halogen" as a group or part of a group is generic for fluoro, chloro, bromo and iodo, and may particularly preferably refer to fluoro, chloro or bromo, even more preferably to fluoro.

[0062] Alkyl groups consist on hydrocarbon radical and may be linear, branched or cyclic.

[0063] The term alkyl (group) refers to radicals made of carbon and hydrogen atoms (linear, branched or cyclic) . Alkyls groups may be, less preferably, (partially) unsaturated and/or substituted and/or comprise an heteroatom ( s ) (such as an halogen, an oxygen, sulfur or nitrogen) or polar group (such as aldehyde and/or cetone and/or hydroxyl and/or amine and/or carboxylic) at one or two (or more) positions.

[0064] The terms "Cl-Cll alkyl", as a group or part of a group refer to a (linear or branched) hydrocarbyl radicals of Formula CnH2n+l wherein n is a number ranging from 1 to 11. Generally, alkyl groups as intended herein comprise from 1 to 11 carbon atoms. Less preferably, Cl-Cll alkyl comprise an (one or two or even more) heteroatom and/or is substituted.

[0065] The term "cycloalkyl" as a group or part of a group refers to a saturated or, less preferably, partially unsaturated hydrocarbyl radical having 1, 2 or more cyclic structures.

[0066] Cycloalkyl groups may comprise 3 or more carbon atoms in a ring and preferably comprise from 3 to 10 carbon atoms, and possibly from 3 to 8 carbon atoms with possible addition of one or more heteroatom ( s ) .

[0067] Specifically, the term "C3-C8 cycloalkyl" as a group or part of a group refers to monocyclic or bicyclic cycloalkyl groups, preferably to monocyclic cycloalkyl groups, comprising independently from 3 to 8 carbon atoms in each ring. [0068] The term "aryl" as a group or part of a group refers to a polyunsaturated, aromatic hydrocarbyl group comprising a single aromatic ring (e.g., phenyl) or (less preferably) multiple (e.g., two, three or four) aromatic rings fused together (e.g., naphthyl) or linked covalently (e.g., biphenyl), typically containing 5 to 12 carbon atoms, preferably 5, 6 or 10 carbon atoms in a ring. Less preferably one or more hydrogen of the aryl groups are substituted by 1, 2, 3, 4, 5, 6 or even more heteroatom ( s ) (such as an halogen, an oxygen, sulfur or nitrogen) and/or polar group (such as aldehyde and/or cetone and/or hydroxyl and/or amine and/or carboxylic) and/or alkyl group (linear, branched, cyclic, or substituted) as described above.

[0069] Where a carbon atom in an aryl group is replaced with a (1, 2 or 3) heteroatom ( s ) (such as one or two N and/or one S atom or even with one 0 atom), the resultant ring is referred to herein as a heteroaryl ring.

[0070] The compounds described herein and their pharmaceutically acceptable addition salts contain one or more centers of chirality and exists as stereoisomeric forms .

[0071] The term "stereoisomeric forms" refers to all the possible isomeric forms that the compounds described herein may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible s tereochemically isomeric forms, said mixtures containing all dias tereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S- configuration. Examples

Preferred examples of compounds of the general Formula I, the stereoisomeric forms thereof or the pharmaceutically acceptable addition salts, hydrates or solvates thereof, as prepared and disclosed herein include those listed in Table 1.

Table 1

F F

F F

RF197 RF194

2- (2,3,4,5, 6-pentafluorobenzamido) - 1- (2, 3, 4, 5, 6- 1,2,3, 4-tetrahydronaphtalene pentafluorobenzamido ) -1,2,3,4- tetrahydronaphtalene

NH

\\

O

MCI MC2

1-acetamido-l , 2,3,4-

1-valproylamino-l , 2,3,4- tetrahydronaphtalene

tetrahydronaphtalene MC3 MC4-cyclohexanecarboxamido-l ,2,3,4- 1 -adamantanecarboxamido- tetrah dronaphtalene 1,2,3 4-tetrahydronaphtalene

MC7 MCll-cyclopentanecarboxamido-l, 2,3,4-

1- (2-ethyl-butyrylamino) - tetrahydronaphtalene

1,2,3, 4-tetrah dronaphtalene

MC12 MC15

1-isobutyrylamino-l , 2,3,4- 1-pivaloylamino-l , 2,3,4- tetrahydronaphtalene tetrahydronaphtalene

R-l- (2,3,4,5,6- 5-1- (2,3,4,5,6- pentafluorobenzamido ) -1,2,3,4- pentafluorobenzamido ) -1,2,3,4- tetrahydronaphtalene tetrahydronaphtalene

F,C

MC36 MC47

1- (2,2, 2-trifluoroacetamido) -- (2,3,5, 6-tetrafluorobenzamido)

1,2,3, 4-tetrahydronaphtalene 1,2,3, 4-tetrahydronaphtalene

MC54 CV38-1

1- (3-chloro-propionylamino) - 1-undecanoylamino-l , 2,3,4- 1,2,3, 4-tetrahydronaphtalene tetrahydronaphtalene

CV42-1 CV44-1/.R-MC2

1-nonanoylamino-l , 2,3,4- Λ-1-valproylamino-l , 2,3,4- tetrahydronaphtalene tetrahydronaphtalene 0 O

CV45-1/5-MC2 MC53

S-l-valproylamino-l , 2,3,4- 1-butanoylamino-l , 2,3,4- tetrahydronaphtalene tetrahydronaphtalene

O

MC57

1- (dodecanoylamino ) -1,2,3,4- tetrahydronaphtalene

Further preferred albeit non-limiting examples of compounds of the general Formula I, the stereoisomeric forms thereof or the pharmaceutically acceptable addition salts, hydrates or solvates thereof, as prepared and disclosed herein include those listed in Table 2.

Table 2

[0072] The present invention also encompasses processes for the preparation of compounds of Formula I and subgroups thereof.

[0073] In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice.

[0074] Functional groups, which are desirable to protect, include hydroxy, amino, carboxylic acid, ketones and aldehydes. Suitable protecting groups for hydroxy include trialkylsilyl groups (such as for example tert- butyldimethylsilyl , tert-butyldiphenylsilyl or trimethylsilyl) , benzyl and tetrahydro-ipyranyl . Suitable protecting groups for amino include tert-butyloxycarbonyl , ben z y 1 o x yca rb on y 1 , e thoxycarbony 1 , benzyl. Suitable protecting groups for ketones and aldehydes include methoxy, ethoxy, or one bivalent protecting group such as, for example, 2, 2-dimethylpropane-l, 3-diolate . Suitable protecting groups for carboxylic acid include Cl-6 alkyl or benzyl esters.

[0075] The compounds of Formula I and the subgroups thereof can be prepared by a succession of steps as described hereunder.

Synthesis of the compounds according to the invention

General techniques

[0076] Melting points were measured with a Tottoli- Buchi Melting point B540 apparatus in open capillary tubes, and are uncorrected. Elemental analyses (C, H, N, S) were performed on a Thermo Finnigan Flash EA 112 elemental analyzer. NMR spectra were recorded on a Jeol spectrometer (JNM ECX 400) . The 1 H-NMR, 13 C-NMR and 19 F-NMR spectra were recorded at 400, 100 and 376 MHz, respecti ely. The chemical shifts were reported in parts per million (ppm) relative to the singlet at 7.26 ppm for chloroform in CDCI3, the singlet at 2.50 ppm from dimethyl sulfoxyde in (CD3) 2 SO, the singlet at 3.31 ppm for methanol in CD3OD, and the coupling constants are in Hz. The following abbreviations are used for spin multiplicity: s, singlet; d, doublet; t, triplet; q, quadruplet, qt, quintuplet; m, multiplet; b, broad. Routine thin layer chromatography (TLC) was performed on silica gel plates (Silicagel GF254 ® from VWR) . Column chromatography was performed on BiotageSPl 25+M column (flow = 25 mL/min) (spherical particle size 60-200 ym from MP Biomedicals) equipped with a UV-spectrophotometer as detector (wavelengths = 254 and 320 nm) . Solvents from Aldrich and VWR were used without further purification. The optical rotations were determined at the sodium D line (589 nm) at a temperature of 20°C using a Perkin Elmer polarimeter 343 (1 dm cell) .

Scheme 1

[0077] The individual steps of Figure 1 are set out below in additional detail.

Example 1

General procedure for Ni-acylation of 1-amino-l, 2, 3, 4- tetrahydronaphtalene or N 2 -acylation of 2-amino-l, 2, 3, 4- tetrahydronaphtalene (Reaction b. of Scheme 1)

[0078] According to reaction b. of Scheme 1, 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.40 mmol) or 2-amino-l, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.40 mmol) is dissolved in chloroform (10 mL) , one equivalent of pyridine and 1.2 equivalent of acyl chloride Ri-CO-Cl are added, and the mixture is stirred for two hours under argon atmosphere. The reaction is monitored by TLC with a mixture of cyclohexane/ethyl acetate (8/2, v/v) as eluant. The reaction mixture is diluted with chloroform (30 mL) . This organic medium is washed twice with HC1 2 N (2 x 30 mL) , once with brine solution (30 mL) , and dried with MgSC^ which is collected by filtration. The organic solvent was finally evaporated under reduced pressure to give the crude product which is used in the reaction c. Scheme 1.

Synthesis of compound RF197 (see Table 1) : 2- (2, 3, 4, 5, 6- pentafluorobenzamido) -1,2,3, 4-tetrahydronaphtalene

[0079] The title compound was synthesized from 2- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of 2 , 3 , 4 , 5 , 6-pentafluorobenzoyl chloride (0.94 g, 4.075 mmol) as described here above.

White powder; Yield = 42%; Rf = 0.66; Molecular formula =

Ci 7 H 12 NOF 5 ; Mass spectra : [M + 1] = 342.2 m/z

Synthesis of compound RF194 (see Table 1) : 1- (2, 3, 4, 5, 6- pentafluorobenzamido) -1,2,3, 4-tetrahydronaphtalene

[0080] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of 2 , 3 , 4 , 5 , 6-pentafluorobenzoyl chloride (0.94 g, 4.075 mmol) as described here above.

White powder; Yield = 32%; Rf = 0.66; Molecular formula = Ci 7 H 12 NOF 5 ; Mass spectra : [M + 1] = 342.1 m/z

Synthesis of compound MC2 (see Table 1) : 1-valproylamino- 1,2,3, 4-tetrahydronaphtalene

[0081] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of valproyl chloride (0.663 g, 4,075 mmol) as described here above. White powder; Yield = 37%; Rf = 0.78; Molecular formula =

Ci 8 H 27 NO; Mass spectra : [M + 1] = 274.2 m/z

Synthesis of compound MC3 (see Table 1 ) : 1- cyclohexanecarboxamido-1 , 2, 3, 4-tetrahydronaphtalene

[0082] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of cyclohexanecarbonyl chloride (0.573 g, 4.075 mmol) as described here above.

White powder; Yield = 34%; Rf = 0.65; Molecular formula = Ci 7 H 23 NO; Mass spectra : [M + 1] = 258.2 m/z

Synthesis of compound MC4 (see Table 1 ) : 1- adamantanecarboxamido-1 , 2, 3, 4-tetrahydronaphtalene

[0083] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of adamantanecarbonyl chloride (0.810 g, 4.075 mmol) as described here above.

White powder; Yield = 43%; Rf = 0.26; Molecular formula =

C 21 H 27 NO; Mass spectra : [M + 1] = 310.3 m/z

Synthesis of compound MC7 (see Table 1 ) : l^ cyclopentanecarboxamido-1, 2, 3, 4-tetrahydronaphtalene

[0084] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of cyclopentanecarbonyl chloride (0.540 g, 4.075 mmol) as described here above.

White powder; Yield = 75%; Rf = 0.71; Molecular formula =

Ci 6 H 2 iNO; Mass spectra : [M + 1] = 244.1 m/z

Synthesis of compound MCll (see Table 1) : 1- (2-ethyl- butyrylamino) -1,2,3, 4-tetrahydronaphtalene

[0085] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of 2-ethyl-butyryl chloride (0.548 g, 4.075 mmol) as described here above.

White powder; Yield = 35%; Rf = 0.71; Molecular formula =

Ci 6 H 23 NO; Mass spectra : [M + 1] = 246.2 m/z

Synthesis of compound MC12 (see Table 1 ) : 1- isobutyrylamino-1 , 2, 3, 4-tetrahydronaphtalene

[0086] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of isobutyryl chloride (0.434 g, 4.075 mmol) as described here above.

White powder; Yield = 56%; Rf = 0.71; Molecular formula =

Ci 4 H 19 NO; Mass spectra : [M + 1] = 218.1 m/z

Synthesis of compound MC15 (see Table 1) : 1-pivaloylamino- 1,2,3, 4-tetrahydronaphtalene

[0087] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of pivaloyl chloride (0.491 g, 4.075 mmol) as described here above.

White powder; Yield = 52%; Rf = 0.51; Molecular formula = C 15 H 21 NO; Mass spectra : [M + 1] = 232.1 m/z

Synthesis of compound i-MC19 (see Table 1) : R-l- (2, 3, 4, 5, 6- pentafluorobenzamido) -1,2,3, 4-tetrahydronaphtalene

[0088] The title compound was synthesized from R-l- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of 2 , 3 , 4 , 5 , 6-pentafluorobenzoyl chloride (0.939 g, 4.075 mmol) as described here above.

White powder; Yield = 42%; Rf = 0.73; Molecular formula =

Ci 7 H 12 NOF 5 ; Mass spectra : [M + 1] = 342.1 m/z Synthesis of compound S-MC20 (see Table 1) : S-l- (2, 3, 4, 5, 6- pentafluorobenzamido) -1,2,3, 4-tetrahydronaphtalene

[0089] The title compound was synthesized from 5-1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of 2 , 3 , 4 , 5 , 6-pentafluorobenzoyl chloride (0.939 g, 4.075 mmol) as described here above.

White powder; Yield = 75%; Rf =0.81; Molecular formula =

Ci 7 H 12 NOF 5 ; Mass spectra : [M + 1] = 342.1 m/z

Synthesis of compound MC25 (see Table 1) : 1-propionylamino- 1,2,3, 4-tetrahydronaphtalene

[0090] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of propionyl chloride (0.377 g, 4.075 mmol) as described here above.

White powder; Yield = 64%; Rf = 0.32; Molecular formula =

Ci 3 H 17 NO; Mass spectra : [M + 1] = 204.1 m/z

Synthesis of compound MC28 (see Table 1 ) : 1- cylcopropanecarboxamido-1 , 2, 3, 4-tetrahydronaphtalene

[0091] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of cyclopropanecarbonyl chloride (0.426 g, 4.075 mmol) as described here above.

White powder; Yield = 61%; Rf = 0.49; Molecular formula =

Ci 4 H 17 NO; Mass spectra : [M + 1] = 216.1 m/z

Synthesis of compound MC29 (see Table 1) : 1-decanoylamino- 1,2,3, 4-tetrahydronaphtalene

[0092] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of decanoyl chloride (0.777 g, 4.075 mmol) as described here above. White powder; Yield = 74%; Rf =0.60; Molecular formula =

C 20 H 31 NO; Mass spectra : [M + 1] = 302.2 m/z

Synthesis of compound MC30 (see Table 1 ) : 1- cylcobutanecarboxamido-1 , 2, 3, 4-tetrahydronaphtalene

[0093] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of cyclobut anecarbonyl chloride (0.483 g, 4.075 mmol) as described here above.

White powder; Yield = 45%; Rf = 0.84; Molecular formula = Ci 5 H 19 NO; Mass spectra : [M + 1] = 230.1 m/z

Synthesis of compound MC33 (see Table 1) : 1- (4-bromo-2- ethyl-5-methyl-2H-pyrazole-3-carboxamido) -1,2,3,4- tetrahydronaphtalene

[0094] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of 4-bromo-2-ethyl-5-methyl-2H-pyrazole-3-carbonyl chloride (1.025 g, 4.075 mmol) as described here above.

White powder; Yield = 44%; Rf = 0.53; Molecular formula =

Ci 7 H 2 oN 3 OBr; Mass spectra : [M + 1] = 364.0 m/z Synthesis of compound MC35 (see Table 1) : 1- (4-methyl- [1,2,3] thiadiazole-5-carboxamido) -1,2,3,4- tetrahydronaphtalene

[0095] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of 4 -methyl- [ 1 , 2 , 3 ] thiadiazole-5-carbonyl chloride (0.663 g, 4.075 mmol) as described here above.

White powder; Yield = 43%; Rf = 0.64; Molecular formula =

Ci 4 H 15 N 3 OS; Mass spectra : [M + l] = 274.0 m/z Synthesis of compound MC36 (see Table 1) : 1- (2, 3,5,6- tetrafluorobenzamido) -1,2,3, 4-tetrahydronaphtalene

[0096] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of 2 , 3 , 5 , 6-tetrafluorobenzoyl chloride (0.866 g, 4.075 mmol) as described here above.

White powder; Yield = 80%; Rf = 0.76; Molecular formula =

Ci 7 H 13 NOF 4 ; Mass spectra : [M + 1] = 324.0 m/z

Synthesis of compound MC53 (see Table 1) : 1-butyrylamino- 1,2,3, 4-tetrahydronaphtalene

[0097] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of butanoyl chloride (0.377 g, 4.075 mmol) as described here above.

White powder; Yield = 67%; Rf = 0.22; Molecular formula =

Ci 4 H 19 NO; Mass spectra : [M + 1] = 218.0 m/z

Synthesis of compound MC54 (see Table 1) : 1- (3-chloro- propionylamino) -1,2,3, 4-tetrahydronaphtalene

[0098] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of 3-chloro-propiony1 chloride (0.517 g, 4.075 mmol) as described here above.

White powder; Yield = 71%; Rf = 0.08; Molecular formula =

Ci 3 H 16 ClNO; Mass spectra : [M + 1] = 238.0 m/z

Synthesis of compound MC57 (see Table 1 ) : 1- dodecanoylamino-1 , 2, 3, 4-tetrahydronaphtalene

[0099] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of dodecanoyl chloride (0.891 g, 4.075 mmol) as described here above. White powder; Yield = 79%; Rf = 0.29; Molecular formula =

C 22 H 35 NO; Mass spectra : [M + 1] = 330.2 m/z

Synthesis of compound CV38-1 (see Table 1) : 1- undecanoylamino-1 , 2, 3, 4-tetrahydronaphtalene

[0100] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of undecanoyl chloride (0.834 g, 4.075 mmol) as described here above.

White powder; Yield = 92%; Rf = 0.38; Molecular formula = C 21 H 33 NO; Mass spectra : [M + 1] = 316.1 m/z

Synthesis of compound CV42-1 (see Table 1) : 1- nonanoylamino-1 , 2, 3, 4-tetrahydronaphtalene

[0101] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of nonanoyl chloride (0.720 g, 4.075 mmol) as described here above.

White powder; Yield = 107,2%; Rf = 0.46; Molecular formula

= C 19 H 29 NO; Mass spectra : [M + 1] = 288.1 m/z

Synthesis of compound i -CV44-l (see Table 1) : . -l- valproylamino-1, 2, 3, 4-tetrahydronaphtalene

[0102] The title compound was synthesized from R-l- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of valproyl chloride (0.663 g, 4.075 mmol) as described here above.

Brown powder; Yield = 43%; Rf = 0.56; Molecular formula =

Ci 8 H 27 NO; Mass spectra : [M + 1] = 274, 1 m/z

Synthesis of compound S-CV45-1 (see Table 1) : S-l- valproylamino-1 , 2, 3, 4-tetrahydronaphtalene

[0103] The title compound was synthesized from 5-1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of valproyl chloride (0.663 g, 4.075 mmol) as described here above.

Brown powder; Yield = 50%; Rf = 0.44; Molecular formula =

Ci 8 H 27 NO; Mass spectra : [M + 1] = 274, 1 m/z

Example 2

General procedure for Ni-acylation of 1-amino-l, 2, 3, 4- tetrahydronaphtalene or N2-acylation of 2-amino-l, 2, 3, 4- tetrahydronaphtalene (Reaction i. of Scheme 1)

[0104] According to reaction i. of Scheme 1, 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.40 mmol) is dissolved in dichloromethane (20 mL) under argon atmsphere and freezed to -20°C. Three equivalents of triethylamine and six equivalents of acetic anhydride Ri-CO-O-CO-Ri are added, and the mixture is stirred for two hours under argon atmosphere at room temperature. The reaction is monitored by TLC with a mixture of cyclohexane /ethyl acetate (8/2, v/v) as eluant. The reaction mixture is diluted with dichloromethane (30 mL) . This organic medium is washed twice with ¾0 (2 x 30 mL) , once with brine solution (30 mL) , and dried with MgSC^ which is collected by filtration. The organic solvent was finally evaporated under reduced pressure to give the crude product which is used in the reaction c. of Scheme 1.

Synthesis of compound MCI (see Table 1) : 1-acetamido- 1,2,3, 4-tetrahydronaphtalene

[0105] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of triethylamine (2.062 g, 20.376 mmol) and acetic anhydride (5,11 g, 4.075 mmol) as described here above. White powder; Yield = 64%; Rf = 0.14; Molecular formula = Ci 2 H 15 NO; Melting point = 140.2-140.7 °C; Mass spectra : [M +

1] = 190.1 m/z

Synthesis of compound MC47 (see Table 1) : l-(2,2,2- trifluoro) acetamido-1, 2, 3, 4-tetrahydronaphtalene

[0106] The title compound was synthesized from 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.396 mmol) in presence of t r i e t hy 1 ami ne (2.062 g, 20.376 mmol) and trifluoroacetic anhydride (0.856 g, 4.075 mmol) as described here above.

Orange powder; Yield = 50%; Rf = 0.34; Molecular formula =

Ci 2 H 12 F 3 NO; Mass spectra : [M - 1] = 242.2 m/z

Example 3 General procedure for the synthesis of Ni-substituted, 1- amino-1, 2, 3, 4-tetrahydronaphtalene-6-sulfonamides and N 2 - s ub s t i tu t e d , 2-amino-l, 2, 3, 4-tetrahydronaphtalene-6- sulfonamides (Reaction c. of Scheme 1)

[0107] Eighteen equivalents of chlorosulfonic acid (3.0 mL) are added in a two necks flask previously dried with argon and freezed to -70°C. One equivalent of Ni- substituted, 1-amino-l, 2, 3, 4-tetrahydronaphtalene or N 2 - substituted, 2-amino-l, 2, 3, 4-tetrahydronaphtalene is added portionwise. The mixture is stirred for three hours at room temperature under argon atmosphere, then poured into a mixture of ice and ethyl acetate (20 mL) . The organic layer is dried with MgS0 4 which is collected by filtration, evaporated under reduced pressure to give the crude product which is dissolved in tetrahydrofurane (2 mL) under argon atmosphere. This solution is added dropwise to 21 equivalent of aqueous NH 4 OH (2.0 mL) , and stirred for 12 hours. The reaction is monitored by TLC with a mixture of cyclohexane/ethyl acetate (1/1, v/v) as eluant. The formed precipitate is dissolved in 10 mL of a mixture of water/ethyl acetate (1/1) . The organic layer is washed once with a brine solution (10 mL) and dried with MgSC^ which is collected by filtration. After solvent evaporation under reduced pressure, the residue is purified by column chromatography as described in the general section. The eluant is a gradient of ethyl acetate (0-70 ~6 ) in cyclohexane .

Synthesis of compound RF195 (see Table 2): 1- (2, 3,5,6- pentafluorobenzamido) -1,2,3, 4-tetrahydronaphtalene-6- sulfonamide

[0108] The title compound was synthesized from RF194

(228 mg, 0.86 mmol) in presence of chlorosulfonic acid (15.48 mmol, 1.03 mL) and aquous NH 4 OH (18.06 mmol, 0.71 mL) as described here above.

White powder; Yield = 54%; Rf = 0.53; Molecular formula = C 17 H 13 F 5 N2O 3 S ; Melting point = 146.0-146.6 °C; Mass spectra :

[M + 1] = 421.1 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : δ 1, 72-1, 95 (m, 4H) , 2, 67-2, 72 (m, 2H) , 5,09-5,13 (m, 1H) , 7, 02-7, 50 (m, 3H) , 7,71-7,77 (m, 2H) , 9, 34-9, 36 (d, 2H)

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : δ 20,03 ; 29,02 ; 30,02 ; 48,12 ; 125,03 ; 125,90 ; 135,56 ; 135,56 ; 138,13 ; 146,70 ; 156,47

Synthesis of compound MC5 (see Table 2) : 1-acetamido- 1,2,3, 4-tetrahydronaphtalene-6-sulfonamide

[0109] The title compound was synthesized from MCI

(757 mg, 4.00 mmol) in presence of chlorosulfonic acid (72.0 mmol, 4.79 mL) and aqueous NH 4 OH (84.0 mmol, 3.31 mL) as described here above. White powder; Yield = 46%; Rf = 0.11; Molecular formula = Ci 2 H 16 2 0 3 S; Melting point = 211.0-213.0°C; Mass spectra : [M

+ 1] = 269.1 m/z

MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1.63-1.70 (m, 2H) , 1.85-1.92 (m, 4H) , 2.69-2.80 (m, 2H) , 4.96-4.99 (m, 1H) , 7.23-7.41 (m, 3H) , 7.51-7.77 (m, 2H) , 8.35 (d, 2H, J = 8,7 Hz) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 20.11 ; 23.28 ; 29.29 ; 30.21 ; 46.57 ; 124.35 ; 125.98 ; 129.87 ; 138.97 ; 141.81 ; 142.36 ; 169.11.

Synthesis of compound MC6 (see Table 2) : 1-valproylamino- 1,2,3, 4-tetrahydronaphtalene-6-sulfonamide

[0110] The title compound was synthesized from MC2

(1.781 g, 6.52 mmol) in presence of chlorosulfonic acid (117.5 mmol, 7.85 mL) and aqueous NH 4 OH (136.9 mmol, 5.39 mL) as described here above.

White powder; Yield = 45%; Rf = 0.36; Molecular formula = C18H28 2O3 S ; Melting point = 186.4-188.3°C; Mass spectra : [M

+ 1] = 353.1 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 0 , 82-0 , 83 (m, 6H) , 1,18-1,84 (m, 12H) , 2,14-2,18 (m, 1H) , 2, 74-2, 79 (m, 2H) , 4, 98-5, 02 (m, 1H) , 7, 24-7, 30 (m, 3H) , 7, 54-7, 59 (m, 2H) , 8,27 (d, J = 9,16 Hz, 1H) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 14, 54, 14, 61, 20, 22, 20,78, 29,33, 30,43, 35,54, 45,68, 46,52, 124,37, 126,05, 129,90, 138,89, 141,84, 142,34, 174,97.

Synthesis of compound MC8 (see Table 2 ) : 1- cyclohexanecarboxamido-1 , 2, 3, 4-tetrahydronaphtalene-6- sulfonamide

[0111] The title compound was synthesized from MC3

(375 mg, 1.45 mmol) in presence of chlorosulfonic acid (26.1 mmol, 1.74 mL) and aqueous NH 4 OH (30.5 mmol, 1.26 mL) as described here above. White powder; Yield = 62%; Rf = 0.10; Molecular formula = C17H24 2O3 S ; Melting point = 184.7-187.2°C; Mass spectra : [M

+ 1] = 337.2 m/z

MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1.14-1.96 (m, 14H), 2.10-2.13 (m, 1H) , 2.73 (s, 2H) , 4.95-5.00 (s, 1H) , 7.01- 7.80 (m, 5H) , 8.12-8.14 (m, 1H) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 20.37 ; 25.81 ; 25.86 ; 26.02 ; 29.30 ; 29.67 ; 29.86 ; 30.17 ; 44.51 ; 46.32 ; 124.28 ; 125.68 ; 129.84 ; 139.18 ; 141.77 ; 142.31 ; 175.31.

Synthesis of compound MC9 (see Table 2 ) : 1- adamantanecarboxamido-1 , 2, 3, 4-tetrahydronaphtalene - 6- sulfonamide

[0112] The title compound was synthesized from MC4 (447 mg, 1.44 mmol) in presence of chlorosulfonic acid (25.9 mmol, 1.73 mL) and aqueous NH 4 OH (30.2 mmol, 0.40 mL) as described here above.

White powder; Yield = 36%; Rf = 0.24; Molecular formula = C21H28 2O3 S ; Melting point = 238.4-241.5°C; Mass spectra : [M + 1] = 389;3 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1.63-1.95 (m, 19H), 2.74 (s, 2H) , 4.98-5.01 (m, 1H) , 7.21-7.24 (m, 3H) , 7.50 (s, 2H) , 7.72 (d, 1H, J = 8,5 Hz).

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 20.92 ; 28.26 ; 29.42 ; 30.02 ; 36.69 ; 39.12 ; 46.74 ; 124.13 ; 125.31 ; 129.72 ; 139.54 ; 141.85 ; 142.28 ; 177.18.

Synthesis of compound MCIO (see Table 2 ) : 1- cyclopentanecarboxamido-1 , 2, 3, 4-tetrahydronaphtalene-6- sulfonamide

[0113] The title compound was synthesized from MC7

(386 mg, 2.40 mmol) in presence of chlorosulfonic acid (43.2 mmol, 2.89 mL) and aqueous NH 4 OH (50.4 mmol, 2.00 mL) as described here above. White powder; Yield = 9%; Rf = 0.37; Molecular formula = C16H22 2O3 S ; Melting point = 181.0-182.0 °C; Mass spectra : [M

+ 1] = 323.2 m/z

MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1,46-1,83 (m, 12H), 2, 54-2, 56 (m, 1H) , 2,73 (s, 2H) , 4,97 (s, 1H) , 7.24-7.30 (m, 3H) , 7.53-7, 56 (m, 2H) , 8,19 (d, 1H, J = 8.9 Hz).

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 20.35 ; 26.29 ; 30.70 ; 44.68 ; 46.55 ; 124.31 ; 125.77 ; 129.87 ; 139.16 ; 141.78 ; 142.32 ; 175.43.

Synthesis of compound MC13 (see Table 2): 1- (2-ethyl- butyrylamino) -1,2,3, 4-tetrahydronaphtalene-6-sulfonamide

[0114] The title compound was synthesized from MCll

(326 mg, 1.33 mmol) in presence of chlorosulfonic acid (23.9 mmol, 1.60 mL) and aqueous NH 4 OH (27.9 mmol, 1.10 mL) as described here above.

White powder; Yield = 53%; Rf = 0.12; Molecular formula = C16H24 2O3 S ; Melting point = 190.7-193.3 °C; Mass spectra : [M + 1] = 325.2 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 0.78-0.83 (m, 6H) , 1.32-1.95 (m, 9H) , 2.73 (s, 2H) , 5.01-5.07 (m, 1H) , 7.22- 7.25 (m, 3H) , 7.54-7.60 (m, 2H) , 8.28 (d, 1H, J = 8.7 Hz). NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 12.37 ; 12.61 ; 20.20 ; 26.04 ; 29.33 ; 30.45 ; 46.49 ; 49.62 ; 124.37 ; 126.06 ; 129.91 ; 138.92 ; 141.80 ; 142.34 ; 174.68.

Synthesis of compound MC17 (see Table 2 ) : 1- isobutyrylamino-1 , 2, 3, 4-tetrahydronaphtalene-6-sulfonamide

[0115] The title compound was synthesized from MC12

(248 mg, 1.14 mmol) in presence of chlorosulfonic acid (20.5 mmol, 1.37 mL) and aqueous NH 4 OH (24.8 mmol, 0.98 mL) as described here above.

White powder; Yield = 58%; Rf = 0.07; Molecular formula = C14H20N2O3 S ; Melting point = 174.7-177.5°C; Mass spectra : [M + 1] = 297.1 m/z MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1.00 (s, 6H) , 1.62-1.64 (m, 2H) , 1.83-1.87 (m, 2H) , 2.35-2.40 (m, 1H) , 2.70-2.81 (m, 2H) , 4.95-4.98 (m, 1H) , 7.24-7.30 (m, 3H) , 7.54-7.56 (m, 2H) , 8.16 (d, 1H, J = 8.7 Hz).

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 20.04 ; 20.23 ; 20.36 ; 29.32 ; 30.16 ; 34.48 ; 46.42 ; 124.32 ; 125.73 ; 129.86 ; 139.14 ; 141.79 ; 142.35 ; 176.22.

Synthesis of compound MC21 (see Table 2) : 1-pivaloylamino- 1,2,3, 4-tetrahydronaphtalene-6-sulfonamide

[0116] The title compound was synthesized from MC15

(0.439 mg, 1.90 mmol) in presence of chlorosulfonic acid (34.2 mmol, 2.28 mL) and aqueous NH 4 OH (39.9 mmol, 1.57 mL) as described here above.

White powder; Yield = 38%; Rf = 0.17; Molecular formula = C 15 H22 2O 3 S ; Melting point = 167.3-168.2 °C; Mass spectra : [M

+ 1] = 311.0 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1.09-1.14 (m, 9H) , 1.68-1.95 (m, 4H) , 2.75 (s, 2H) , 4.98-5.02 (m, 1H) , 7.22- 7.24 (m, 3H) , 7.52-7.54 (m, 2H) , 7.79 (d, 1H, J = 8.9 Hz). NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 21.03 ; 27.91 ; 29.42 ; 29.99 ; 38.61 ; 47.05 ; 124.13 ; 125.24 ; 129.77 ; 139.57 ; 141.85 ; 142.30 ; 177.71.

Synthesis of compound i-MC22 (see Table 2): R-l- (2, 3, 4, 5, 6- pentafluorobenzamido) -1,2,3, 4-tetrahydronaphtalene-6- sulfonamide

[0117] The title compound was synthesized from J?-

MC19 (433 mg, 1.27 mmol) in presence of chlorosulfonic acid (22.9 mmol, 1.53 mL) and aqueous NH 4 OH (26.7 mmol, 1.05 mL) as described here above.

White powder; Yield = 51%; Rf = 0.27; Molecular formula = C 1 7H 1 3 F5N2O3 S ; Melting point = 223.0-228.2 °C; Mass spectra :

[M - 1] = 418.8 m/z MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1, 78-1, 95 (m, 4H) , 2,77 (s, 2H) , 5,16-5,20 (m, 1H) , 7, 26-7, 42 (m, 3H) , 7.59-7.78 (m, 2H) , 9,39 (d, 1H, J = 8.5 Hz).

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 19.81 ; 29.11 ; 29.86 ; 47.96 ; 124.90 ; 125.94 ; 130.16 ; 136.14 ; 137.17 ; 142.02 ; 142.57 ; 156.66.

Synthesis of compound S-MC24 (see Table 2): S-l- (2, 3, 4, 5, 6- pentafluorobenzamido) -1,2,3, 4-tetrahydronaphtalene-6- sulfonamide

[0118] The title compound was synthesized from S-

MC20 (762 mg, 2.23 mmol) in presence of chlorosulfonic acid (40.1 mmol, 2.68 mL) and aqueous NH 4 OH (46.8 mmol, 1.84 mL) as described here above.

White powder; Yield = 42%; Rf = 0.33; Molecular formula = C 1 7H 1 3 F5N2O3 S ; Melting point = 222.3-227.7 °C; Mass spectra :

[M + 1] = 420.9 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1.78-1.81 (m, 4H) , 2.77 (s, 2H) , 5.16-5.23 (m, 1H) , 7.27-7.30 (m, 3H) , 7.59-7.70 (m, 2H) , 9.41 (d, 1H, J = 8.5 Hz).

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 19.81 ; 29.11 ; 29.86 ; 47.95 ; 124.89 ; 125.94 ; 130.16 ; 137.17 ; 142.02 ; 142.57, 156.55.

Synthesis of compound MC31 (see Table 2) : 1-propionylamino- 1,2,3, 4-tetrahydronaphtalene-6-sulfonamide

[0119] The title compound was synthesized from MC25

(550 mg, 2.7 mmol) in presence of chlorosulfonic acid (48.6 mmol, 3.25 mL) and aqueous NH 4 OH (56.7 mmol, 2.23 mL) as described here above.

White powder; Yield = 78%; Rf = 0.05; Molecular formula = Ci 3 H 18 2 03S; Melting point = 159.2-160.7 °C; Mass spectra : [M

+ 1] = 283.0 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 0.98-1.03 (m, 3H) , 1.62-1.70 (m, 4H) , 1.82-1.85 (m, 2H) , 2.08-2.12 (m, 2H), 4.95-4.98 (m, 1H) , 7.23-7.36 (m, 3H) , 7.57-7.73 (m, 2H) , 8.20 (d, 1H, J = 8.7 Hz) .

MR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 10.85 ; 20.47 ; 29.31 ; 29.36 ; 30.47 ; 46.75 ; 124.57 ; 126.12 ; 130.11 ; 139.33 ; 142.05 ; 142.61 ; 173.20.

Synthesis of compound MC32 (see Table 2) : 1-decanoylamino- 1,2,3, 4-tetrahydronaphtalene-6-sulfonamide

[0120] The title compound was synthesized from MC29

(944 mg, 3.13 mmol) in presence of chlorosulf onic acid (56.3 mmol, 3.76 mL) and aqueous NH 4 OH (65.7 mmol, 2.59 mL) as described here above.

White powder; Yield = 25%; Rf = 0.26; Molecular formula = C20H32N2O3 S ; Melting point = 145.2-148.5°C; Mass spectra : [M

+ 1] = 381.1 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 0.80-0.82 (m, 3H) , 1.21 (s, 12H) , 1.50-1.82 (m, 6H) , ,2.06-2.10 (m, 2H) , 2.73-2.75 (m, 2H) , 4.97-5.02 (m, 1H) , 7.23-7.24 (m, 3H) , 7.54-7.57 (m, 2H) , 8.21 (d, 1H, J = 8.7 Hz) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 14.50 ; 20.16 ; 22.64 ; 25.93 ; 29.19 ; 29.23 ; 29.30 ; 29.35 ; 29.42 ; 30.24 ; 31.81 ; 35.99 ; 46.51 ; 124.33 ; 125.95 ; 129.84 ; 139.01 ; 141.79 ; 142.37.

Synthesis of compound MC34 (see Table 2 ) : 1- cylcopropanecarboxamido-1 , 2, 3, 4-tetrahydronaphtalene-6- sulfonamide

[0121] The title compound was synthesized from MC28

(538 mg, 2.5 mmol) in presence of chlorosulfonic acid (45.0 mmol, 3.00 mL) and aqueous NH 4 OH (52.5 mmol, 2.07 mL) as described here above.

White powder; Yield = 30%; Rf = 0.08; Molecular formula = Ci 4 H 18 2 0 3 S; Melting point = 204.3-205.9°C; Mass spectra : [M + 1] = 295.0 m/z MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 0.63-0.66 (m, 4H) , 1.13 (t, 1H, J = 7.1 Hz), 1.56-1.67 (m, 2H) , 1.83-1.85 (m, 2H) , 2.70-2.82 (m, 2H) , 4.99 (s, 1H) , 7.24-7.37 (m, 3H) , 7.55- 7.59 (m, 2H) , 8.51 (d, 1H, J = 8.7 Hz) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 6.98 ; 14.08 ; 20.03 ; 29.31 ; 30.28 ; 47.52 ; 124.43 ; 126.03 ; 129.92 ; 138.90 ; 141.86 ; 142.36 ; 172.59.

Synthesis of compound MC37 (see Table 2 ) : 1- cylcobutanecarboxamido-1 , 2, 3, 4-tetrahydronaphtalene-6- sulfonamide

[0122] The title compound was synthesized from MC30

(337 mg, 1.47 mmol) in presence of chlorosulf onic acid (26.5 mmol, 1.77 mL) and aqueous NH 4 OH (30.9 mmol, 1.22 mL) as described here above.

White powder; Yield = 74%; Rf = 0.31; Molecular formula = C15H20 2O3 S ; Melting point = 182.2-186.7 °C; Mass spectra : [M + 1] = 309.0 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1.51-2.16 (m, 10H) , 2.73 (s, 1H) , 3.01 (s, 2H) , 4.96-4.99 (m, 1H) , 7.23-7.35 (m, 3H) , 7.53-7.55 (m, 2H) , 8.06 (d, 1H, J = 8.7 Hz) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 18.36 ; 20.29 ; 25.09 ; 25.21 ; 29.31 ; 30.17 ; 46.97 ; 124.31 ; 125.79 ; 129.84 ; 139.12 ; 141.79 ; 142.34 ; 174.01.

Synthesis of compound MC38 (see Table 2) : 1- (4-bromo-2- ethyl-5-methyl-2H-pyrazole-3-carboxamido) -1,2,3,4- tetrahydronaphtalene- 6- sulfonamide

[0123] The title compound was synthesized from MC33

(509 mg, 1.86 mmol) in presence of chlorosulf onic acid (33.5 mmol, 2.24 mL) and aqueous NH 4 OH (39.1 mmol, 1.54 mL) as described here above.

White powder; Yield = 15%; Rf = 0.26; Molecular formula = Ci 7 H 2 iBr 4 0 3 S; Melting point = 214.4-216.2°C; Mass spectra :

[M + 1] = 442.9 m/z MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1,25 (t, 3H, J = 7.1

Hz), 1,78-1,89 (m, 2H) , 2,09-2,10 (m, 4H) , 2,77 (s, 2H) , 4,12-4,16 (m, 2H) , 5,15-5,20 (m, 1H) , 7, 22-7, 28 (m, 3H), 7.57-7.81 (m, 2H) , 8.98 (d, 1H, J = 8.7 Hz).

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 12,27 ; 16,17 ; 20, 34 ; 29, 22 ; 29, 89 ; 46, 44 ; 47, 70 ; 93,41 ; 124, 60 ; 125,91 ; 129,99 ; 136,67 ; 137,82 ; 141,93 ; 142,40 ; 145,50 ; 159, 35.

Synthesis of compound MC39 (see Table 2) : 1- (4-methyl- [1,2,3] thiadiazole-5-carboxamido) -1,2,3,4- tetrahydronaphtalene- 6-sulfonamide

[0124] The title compound was synthesized from MC35

(403 mg, 1.47 mmol) in presence of chlorosulfonic acid (26.5 mmol, 1.77 mL) and aqueous NH 4 OH (30.9 mmol, 1.22 mL) as described here above.

White powder; Yield = 31%; Rf = 0.06; Molecular formula = Ci 4 H 16 4 03S2; Melting point = 171.9-174.3 °C; Mass spectra :

[M + 1] = 353.0 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1 , 78-1 , 95 (m, 4H) , 2, 75-2, 77 (m, 5H) , 5,20-5,21 (m, 1H) , 7, 28-7, 29 (m, 3H), 7.57-7.70 (m, 2H) , 9,27 (d, 1H, J = 8.5 Hz).

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 13,79 ; 20, 27 ; 29, 24 ;

29,82 ; 48,12 ; 124,58 ; 125,80 ; 130,04 ; 137,79 ; 142,05 ; 142,53 ; 144,66 ; 158,98 ; 159,37.

Synthesis of compound MC40 (see Table 2): 1- (2, 3,5,6- tetrafluorobenzamido) -1,2,3, 4-tetrahydronaphtalene-6- sulfonamide

[0125] The title compound was synthesized from MC36

(924 mg, 2.86 mmol) in presence of chlorosulfonic acid (51.5 mmol, 3.44 mL) and aqueous NH 4 OH (60.1 mmol, 2.37 mL) as described here above. White powder; Yield = 57%; Rf = 0.18; Molecular formula = Ci 7 H 14 F 4 2 0 3 S; Melting point = 196.3-198.8 °C; Mass spectra :

[M + 1] = 402.9 m/z

MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1 , 78-1 , 95 (m, 4H) , 2, 77-2, 78 (m, 2H) , 5,17-5,21 (m, 1H) , 7, 26-7, 40 (m, 4H), 7.59-7.71 (m, 2H) , 9,38 (d, 1H, J = 8.5 Hz).

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 19,82 ; 29,11 ; 29, 89 ; 47,95 ; 108,22 ; 118, 30 ; 124,88 ; 125,95 ; 130,13 ; 137,27 ; 142,00 ; 142,56 ; 157,48.

Synthesis of compound MC48 (see Table 2): l-(2,2,2- trifluoroacetamide) -1,2,3, 4-tetrahydronaphtalene-6- sulfonamide

[0126] The title compound was synthesized from MC47

(1.065 g, 4.37 mmol) in presence of chlorosulfonic acid (78.7 mmol, 5.26 mL) and aqueous NH 4 OH (117.99 mmol, 4.65 mL) as described here above.

White powder; Yield = 7%; Rf = 0.47; Molecular formula = Ci 2 H 13 F 3 2 0 3 S; Melting point = 196 , 7-201 , 2 °C; Mass spectra :

[M + 1] = 323, 0 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1, 75-1, 93 (m, 4H) , 2, 72-2, 77 (m, 2H) , 5,07 (s, 1H) , 7, 29-7, 34 (m, 3H) , 7,54- 7, 61 (m, 2H) , 9, 93 (s, 1H) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 20, 07, 29, 17, 29, 37,

48,07, 115,11, 124,86, 125,43, 130,18, 136,70, 142,25, 142,54, 156,81.

NMR 1 F (376 MHz, DMSO-d 6 ) δ (ppm) : -73, 84 (s) .

Synthesis of compound MC62 (see Table 2): 1- (3-chloro- propionylamino) -1,2,3, 4-tetrahydronaphtalene-6-sulfonamide

[0127] The title compound was synthesized from MC54 (507 mg, 2.14 mmol) in presence of chlorosulfonic acid

(38.52 mmol, 2.57 mL) and aqueous NH 4 OH (44.94 mmol, 1.77 mL) as described here above. White powder; Yield = 27%; Rf = 0.11; Molecular formula = Ci 3 H 17 ClN 2 0 3 S; Melting point = 130.3-130.5°C; Mass spectra :

[M + 1] = 317.0 m/z

MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 1 , 82-1 , 86 (m, 4H) , 2, 46-2, 47 (m, 2H) , 2, 58-2, 60 (m, 2H) , 3, 80-3, 82 (m, 2H) , 5,01-5,04 (m, 1H) , 7, 24-7, 29 (m, 3H) , 7,56-7,61 (m, 2H) , 8,47 (d, 1H, J = 8.9 Hz) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 20, 02, 29, 26, 30, 22,

38,85, 41,56, 46,80, 124,47, 126,05, 129, 92, 138,55, 141,88, 142,41, 168,93.

Synthesis of compound CV38-2 (see Table 2) : 1- undecanoylamino-1 , 2, 3, 4-tetrahydronaphtalene-6-sulfonamide

[0128] The title compound was synthesized from CV38-

1 (759 mg, 2.41 mmol) in presence of chlorosulfonic acid (43.38 mmol, 2.90 mL) and aqueous NH 4 OH (50.61 mmol, 1.99 mL) as described here above.

White powder; Yield = 26%; Rf = 0.29; Molecular formula = C2 1 H 34 N2O 3 S ; Melting point = 140.7-141.9°C; Mass spectra : [M

+ 1] = 395.1 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 0,81-0,84 (m, 3H) , 1,21 (s, 14H), 1,49-1,51 (m, 2H) , 1, 58-1, 72 (m, 2H) , 1,82-1,84 (m, 2H) , 2,05-2,10 (m, 2H) , 2, 69-2, 80 (m, 2H) , 4,98-5,00 (m, 1H) , 7, 23-7, 37 (m, 3H) , 7,51-7,57 (m, 2H) , 8,21-8,25 (m, 1H) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 14, 50, 20, 17, 22, 65,

25,93, 29,24-29,55 30,24, 31, 85, 35, 99, 46,51, 55,45, 124,33, 125,95, 129,85, 139,02, 141,79, 142,36, 172,20.

Synthesis of compound CV42-2 (see Table 2) : 1- nonanoylamino-1 , 2, 3, 4-tetrahydronaphtalene-6-sulfonamide

[0129] The title compound was synthesized from CV42-

1 (883 mg, 3.07 mmol) in presence of chlorosulfonic acid (55.26 mmol, 3.69 mL) and aqueous NH 4 OH (64.47 mmol, 2.54 mL) as described here above. White powder; Yield = 22%; Rf = 0.32; Molecular formula = C19H30N2O3 S ; Melting point = 142.7-144.6 °C; Mass spectra : [M

+ 1] = 367.0 m/z

MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 0,81-0,84 (m, 3H) , 1,22 (s, 10H), 1,49-1,51 (m, 2H) , 1, 58-1, 74 (m, 2H) , 1,82-1,84 (m, 2H) , 2,04-2,11 (m, 2H) , 2, 69-2, 80 (m, 2H), 4,89 (s, 1H) , 7,23-7,33 (m, 3H) , 7,54-7,61 (m, 2H) , 8,23 (d, 1H, J = 8,70 Hz, ) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 14, 51, 20, 17, 22, 63, 25,93, 29,12-29,32, 30,24, 35,99, 46,50, 124,33, 125,94, 129,86, 139,00, 141,80, 142,35, 172,20.

Synthesis of compound CV44-2/i-MC6 (see Table 2) : R-l- valproylamino-1 , 2, 3, 4-tetrahydronaphtalene-6-sulfonamide

[0130] The title compound was synthesized from CV44- 1 (328 mg, 1.20 mmol) in presence of chlorosulfonic acid

(21.60 mmol, 1.44 mL) and aqueous NH 4 OH (25.20 mmol, 0.99 mL) as described here above.

White powder; Yield = 25%; Rf = 0.53; Molecular formula = C18H28 2O3 S ; Melting point = 231.5-232.9 °C; Mass spectra : [M + 1] = 353.0 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 0 , 80-0 , 85 (m, 6H) ,

1,14-1,32 (m, 6H) , 1, 38-1, 54 (m, 2H) , 1, 59-1, 74 (m, 2H), 1, 82-1, 85 (m, 2H) , 2,15-2,20 (m, 1H) , 2, 64-2, 80 (m, 2H) , 5,00 (s, 1H) , 7, 20-7, 30 (m, 3H) , 7, 55-7, 60 (m, 2H) , 8,27 (d, 1H, J = 8, 70 Hz) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 14, 54, 14, 62, 20, 22, 20,69, 20,88, 29,34, 30,44, 35,46, 35,63, 45,67, 46,50, 124,37, 126,07, 129,89, 138,91, 141,81, 142,37, 174,90.

Synthesis of compound CV45-2/S-MC6 (see Table 2) : S-l- valproylamino-1, 2, 3, 4-tetrahydronaphtalene-6-sulfonamide

[0131] The title compound was synthesized from CV45-

1 (385 mg, 1,41 mmol) in presence of chlorosulfonic acid (25.38 mmol, 1,69 mL) and aqueous NH 4 OH (29.61 mmol, 1.17 mL) as described here above.

White powder; Yield = 25%; Rf = 0.51; Molecular formula = C18H28 2O3 S ; Melting point = 233.1-233.9 °C; Mass spectra : [M + 1] = 353.0 m/z

MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 0 , 80-0 , 85 (m, 6H) ,

1,16-1,27 (m, 6H) , 1, 44-1, 54 (m, 2H) , 1, 62-1, 74 (m, 2H), 1, 82-1, 85 (m, 2H) , 2,16-2,18 (m, 1H) , 2, 68-2, 80 (m, 2H) , 5,00 (s, 1H) , 7, 20-7, 30 (m, 3H) , 7, 54-7, 60 (m, 2H) , 8,27 (d, 1H, J = 8, 70 Hz) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 14, 54, 14, 62, 20, 22, 20,69, 20,87, 29,34, 30,44, 35,46, 35,63, 45,67, 46,50, 124,37, 126,07, 129,89, 138,92, 141,82, 142,37, 174,90.

Synthesis of compound CV46 (see Table 2) : 1-butyrylamino- 1,2,3, 4-tetrahydronaphtalene-6-sulfonamide

[0132] The title compound was synthesized from MC57

(553 mg, 2.55 mmol) in presence of chlorosulfonic acid

(45.90 mmol, 3.07 mL) and aquous NH 4 OH (53.55 mmol, 2.11 mL) as described here above.

White powder; Yield = 24%; Rf = 0.07; Molecular formula =

C14H20 2O3 S ; Melting point = 152.6-155.0 °C; Mass spectra : [M

+ 1] = 297.0 m/z

NMR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 0 , 82-0 , 89 (m, 3H) , 1,49-1,71 (m, 4H) , 1,81-1,86 (m, 2H) , 2,02-2,11 (m, 2H), 2, 68-2, 81 (m, 2H) , 4,99 (s, 1H) , 7, 25-7, 34 (m, 3H) , 7,54- 7,61 (m, 2H) , 8,24 (d, 1H, J = 8,70 Hz).

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 14, 14, 19, 35, 20, 21,

29, 31, 30, 27, 37, 91, 46, 52, 124, 33, 125, 92, 129, 86, 139, 03, 141,80, 142,35, 172,05.

Synthesis of compound CV48 (see Table 2 ) : 1- dodecanoylamino-1 , 2, 3, 4-tetrahydronaphtalene-6-sulfonamide

[0133] The title compound was synthesized from MC57

(718 mg, 2.18 mmol) in presence of chlorosulfonic acid (39.24 mmol, 2.62 mL) and aquous NH 4 OH (45.78 mmol, 1.80 mL) as described here above.

White powder; Yield = 43%; Rf = 0.47; Molecular formula = C22H36 2O3 S ; Melting point = 144.7-146.7°C; Mass spectra : [M + 1] = 409.2 m/z

MR Χ Η (400 MHz, DMSO-d 6 ) δ (ppm) : 0, 80-0, 84 (m, 3H) , 1,21 (s, 16H), 1,49-1,51 (m, 2H) , 1, 58-1, 74 (m, 2H) , 1,82-1,84 (m, 2H) , 2,05-2,10 (m, 2H) , 2,67-2,81 (m, 2H), 4,98 (s, 1H) , 7, 23-7, 35 (m, 3H) , 7,52-7,61 (m, 2H) , 8,21-8,25 (m, 1H) .

NMR 13 C (100 MHz, DMSO-d 6 ) δ (ppm) : 14, 51, 20, 17, 22, 65,

25,93, 29,19-29,55, 30,24, 31,85, 35,98, 46,50, 124,33, 125,95, 129,85, 139,00, 141,79, 142,36, 172,20.

Example 4

General procedure for synthesis of 1-ureido-, 2-ureido, 1- thioureido-, or 2-thioureido-l, 2, 3, 4-tetrahydronaphtalene (Reaction d. of Scheme 1)

[0134] According to reaction d. of Scheme 1, 1- amino-1, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.40 mmol) or 2-amino-l, 2, 3, 4-tetrahydronaphtalene (500 mg, 3.40 mmol) is dissolved in 10 mL of an organic solvent (chloroform,...), 1.2 equivalent of isocyanate (Ri-N=C=0) or isothiocyanate (Ri-N=C=S) is added, and the mixture is stirred for several hours (0.5-12h) . At the end of the reaction, the reaction mixture is diluted with the same solvent (30 mL) . This organic medium is washed twice with water (2 x 30 mL) , once with brine solution (30 mL) , and dried with MgSC^ which is collected by filtration. The organic solvent was finally evaporated under reduced pressure to give the crude product which is purified by column chromatography as described in the general section. Example 5

General procedure for synthesis 1-ureido-, 2-ureido, 1- thioureido-, or 2-thioureido-l, 2, 3, 4-tetrahydronaphtalene- 6-sulfonamide (Reaction e. of Scheme 1)

[0135] According to reaction e. of Scheme 1, an excess of chlorosul fonic acid (3.0 mL) are added in a two necks flask previously dried with argon and freezed to - 70°C. One equivalent of 1-ureido-, 2-ureido, 1-thioureido-, or 2-thioureido-l, 2, 3, 4-tetrahydronaphtalene is added portionwise. The mixture is stirred at room temperature under argon atmosphere, then poured into a mixture of ice and ethyl acetate (20 mL) . The organic layer is dried with MgSC which is collected by filtration, evaporated under reduced pressure to give the crude product which is dissolved in tetrahydrofurane (2 mL) under argon atmosphere. This solution is added dropwise to a large excess of aqueous NH 4 OH (2.0 mL) , and stirred for several hours. The formed precipitate is dissolved in 10 mL of a mixture of water/ethyl acetate (1/1) . The organic layer is washed once with a brine solutin (10 mL) and dried with MgSC which is collected by filtration. After solvent evaporation under reduced pressure, the residue is purified by column chromatography as described in the general section to give the title compound.

Example 6

General procedure for synthesis 1-nitro- or 2-nitro- 1, 2, 3, 4-tetrahydronaphtalene-6-sulfonamide (Reaction f. of Scheme 1)

[0136] According to reaction f . of Scheme 1, an excess of chlorosul fonic acid (3.0 mL) are added in a two necks flask previously dried with argon and freezed to - 70°C. One equivalent of 1-nitro or 2-nitro -1,2,3,4- tetrahydronaphtalene is added portionwise. The mixture is sirred at room temperature under argon atmosphere, and then poured into a mixture of ice and ethyl acetate (20 mL) . The organic layer is dried with MgSC^ which is collected by filtration, evaporated under reduced pressure to give the crude product which is dissolved in tetrahydrofurane (2 mL) under argon atmosphere. This solution is added dropwise to a large excess of aquous NH 4 OH (2.0 mL) , and stirred for several hours. The formed precipitate is dissolved in 10 mL of a mixture of water/ethyl acetate (1/1) . The organic layer is washed once with a brine solutin (10 mL) and dried with MgSC which is collected by filtration. After solvent evaporation under reduced pressure, the residue is purified by column chromatography as described in the general section to give the title compound.

Example 7

General procedure for synthesis 1-amino- or 2-amino- 1, 2, 3, 4-tetrahydronaphtalene-6-sulfonamide (Reaction g. of Scheme 1)

[0137] According to reaction g. of Scheme 1, 1- nitro- or 2-nitro-l, 2, 3, 4-tetrahydronaphtalene-6- sulfonamide are dissolved in an organic solvent and reduced to their corresponding amino derivatives by catalytic hydrogenation using, for instance, Zn/HCl or ¾ and Pd/C. The catalyzer is removed by filtration, the solvent is removed under reduced pressure, and the crude residue is purified by column chromatography to give the title compound. Example 8

General procedure for Ni-acylation of 1-amino-l, 2, 3, 4- tetrahydronaphtalene- 6-sulfonamide or N2-acylation of 2- amino-1, 2, 3, 4-tetrahydronaphtalene-6-sulfonamide (Reaction h. of Scheme 1)

[0138] According to reaction h. of Scheme 1, 1- amino-1, 2, 3, 4-tetrahydronaphtalene-6-sulfonamide (500 mg) or 2-amino-l, 2, 3, 4-tetrahydronaphtalene-6-sulfonamide (500 mg) is dissolved in chloroform (10 mL) , one equivalent of pyridine and 1.2 equivalent of acyl chloride Ri-CO-Cl are added, and the mixture is stirred for two hours under argon atmosphere. The reaction is monitored by TLC with a mixture of cyclohexane/ethyl acetate (8/2, v/v) as eluant. The reaction mixture is diluted with chloroform (30 mL) . This organic medium is washed twice with HC1 2 N (2 x 30 mL) , once with brine solution (30 mL), and dried with MgSC>4 which is collected by filtration. The organic solvent was finally evaporated under reduced pressure to give the title compound .

Example 9: Separation of the enantiomers of Ni- substituted, 1-amino-l ,2,3 , 4-tetrahydronaphtalene-6- sulfonamides or N 2 -substituted, 2-amino-l ,2,3,4- tetrahydronaphtalene-6-sulfonamides

[0139] The R/S Ni-substituted, 1-amino-l, 2, 3, 4- tetrahydronaphtalene-6-sulfonamides or ^-substituted, 2- amino-1, 2,3, 4-tetrahydronaphtalene-6-s ulfonamides are separated by liquid chromatography. The compound is dissolved at 0.5 mM in ethanol and injected on a column (ChiralcelOD-H, length = 25 cm; diameter = 4.6 mm, particle diameter = 5 ym) and eluted (0.8 mL.min "1 ) with a mobile phase containing hexane-ethanol (75-25 v/v) . Peaks are detected at 254 nm.

Separation of enantiomers of compound (see table 2) : . , S-

RF195 1- (2, 3, 5, 6-tetratafluorobenzamido) -1,2,3,4- tetrahydronaphtalene- 6-sulfonamide

[0140] The title compound is dissolved in ethanol

(0.5 mM) injected and eluted as described here above. The retention time of .R-RF195 and S-RF195 are 5.97 and 14.74 minutes respectively.

Example 10: In vitro characterization of the biological effects of the compounds according to the invention

A/ Inhibition of carbonic anhydrase (CA)

[0141] Enzymatic tests were performed in order to rapidly measure the effect of the present compounds on the activity of recombinant human carbonic anhydrases type I, II, IX, and XII. CA I and CA II were supplied by Sigma- Aldrich. The recombinant hCA XII and hCA IX were obtained as reported (Winum et al . , 2003, J. Med. Chem. 46:2197- 2204) .

[0142] The CA catalyzed CO 2 hydration activity was followed by an SX.18MV-R Applied Photophysics stopped-flow instrument (Oxford, UK) stopped-flow instrument. Phenol red (at a concentration of 0.2 mM) was used as indicator, working at the absorbance maximum of 557 nm, with 10 mM Hepes (pH 7.5) as buffer, 0.1 M a 2 S0 4 (for maintaining constant the ionic strength) , following tha CA-catalyzed CO 2 hydration reaction for a period of 10-100 seconds. Saturated CO 2 solution in water at 25 °C was used as substrate. Stock solutions of inhibitor were prepared at a concentration of 10 mM in a mixture of DMSO : water ( 1 : 1 v/v), and dilutions up to 0.01 nM done with the assay buffer mentioned above. At least seven different inhibitor concentrations were used for measuring the inhibition constant .

[0143] Inhibitor and enzyme solutions were pre- incubated together for 10 min at 25°C prior assay, in order to allow for the formation of the E-I complex. Enzyme concentrations were 1.0 μΜ for hCA I and hCA II, and 0.1 μΜ for CA IX and CA XII. Triplicate experiments were done for each inhibitor concentration and the values reported are the mean of such results.

[0144] Kis were obtained from Lineweaver-Burk plots.

Results are presented in Table 3 herein below.

Table 3: Inhibitory potency against hCA I, hCA II, hCA IX and hCA XII expressed as the K ± value (nM) . The isozyme selectivity towards CA IX and CA XII is expressed as the Ki ratio

Table 3 :

B/ Selectivity of carbonic anhydrase (CA) towards CA IX and CA XII

[0145] The selectivity of the inhibitory potency of tetralines towards hCA IX and hCA XII is given by the ratio of Ki values. For instance, the CA IX selectivity is given by the ratios hCAI/IX and hCA II/IX (see table 2) whereas the CA XII selectivity is given by the hCAI/XII and hCA II/XII (see table 2) . C/ Effect on the extra- and intracellular ph values of cultured cells overexpressing CA IX and/or CA XII

[0146] Stable transgenic cells able to overexpress the membrane bound CA IX and/or CA XII are cultured in buffered solution in normoxic or hypoxic conditions. The intracellular (pHi) and extracellular (pHe) pH variations are measured by using the technique of distribution of the weak acid (ie [ 14 C]benzoic acid or by using a pH-sensitive fluorescent dye such as BCECF-AM. The effect of tetraline on pH values is measured by adding these derivatives at a concentration ranging from 1 mM to 0.1 nM.

D/ In vivo antitumoral activity of carbonic anhydrase inhibitors

[0147] Cancer cells overexpressing CA IX and CA XII are injected (sc or iv) in mice or rats. Animals are treated with tetralines for several days (1-100 mg.kg-1) and the tumour volume is monitored and quantified using bioluminescent imaging. Tetralines can be associated to several known anti-cancer agents (ie doxorubicine) .