ES2352725T3 - 2-PHENYL-INDOLES AS ANTAGONISTS OF PROSTAGLANDIN RECEPTOR D2. - Google Patents

Abstract

A compound of formula (A) ** (See formula) ** where: R is R1CH2SO2-, R2CH2SO2NH- or R3NHSO2-; R1 is phenyl optionally substituted by halo, R2 is phenyl substituted by halo, R3 is 2,6-dichloro-benzyl, 3,5-dichloro-benzyl, 2,4-dichloro-phenylethyl, 2-methoxyphenylethyl, 3-methoxy-phenylethyl , 4-methoxy-phenylethyl, 2-trifluoromethyl-phenylethyl, 10 phenylethyl or 3-phenyl-n-propyl, R4 is hydrogen, R5 is chlorine, R6 is hydrogen and R8 is hydroxy; or R is cyclohexylaminosulfonyl, R4 is 4-chloro, 4-fluoro, 4-methyl or 7-chloro, R5 is chloro or ethyl, R6 is hydrogen or methyl, and R8 is hydroxy; or R is cyclohexylaminosulfonyl, R4 is hydrogen, R5 is chlorine, R6 is hydrogen, R8 is -NHR7, and R7 is methyl, methylsulfonyl, ethylsulfonyl, haloalkylsulfonyl or tetrazolyl; or one of its pharmaceutically acceptable salts, hydrates or solvates, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate.

Description

The present invention relates to 2-phenyl-indole compounds, their preparation, pharmaceutical compositions containing these compounds and their pharmaceutical use in the treatment of diseases that can be modulated by the inhibition of the prostaglandin D2 receptor.

BACKGROUND OF THE INVENTION

It has been shown that local exposure to allergens in patients with allergic rhinitis, bronchial asthma, allergic conjunctivitis and atopic dermatitis results in rapid elevation of prostaglandin D2 levels "(PGD2)" in nasal and bronchial lavage fluids, tears and fluids. of skin chambers. PGD2 has many inflammatory actions, such as increasing vascular permeability in the conjunctiva and skin, increasing resistance of the nasal airways, narrowing of the airways and infiltration of eosinophils in the conjunctiva and trachea.

PGD2 is the main product of the cyclooxygenase of arachidonic acid produced from mast cells with immune challenge [Lewis, RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ II, prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE, J. Immunol. 129, 1627-1631, 1982]. Activated mast cells, an important source of PGD2, are one of the key participants in creating the allergic response in conditions such as asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis and other diseases [Brightling CE, Bradding P, Pavord ID Wardlaw AJ, New Insights into the role of the mast cell in asthma, Clin Exp Allergy, 33, 550-556, 2003].

Many of the actions of PGD2 are mediated through its action on the prostaglandin type D ("DP") receptor, a G protein-coupled receptor expressed in the epithelium and smooth muscle.

In asthma, it has long been recognized that the respiratory epithelium is a key source of inflammatory cytokines and chemokines that direct disease progression [Holgate S, Lackie P, Wilson S, Roche W, Davies D, Bronchial Epithelium as a Key Regulator of Airway Allergen Sensitization and Remodeling in Asthma, Am J Respir Crit Care Med. 162, 113-117, 2000]. In an experimental murine model of asthma, the DP receptor is spectacularly over-regulated in the airway epithelium after exposure to antigens [Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya S, prostaglandin D2 as a mediator of allergic asthma, Science 287, 20132017, 2000]. In "knockout" mice that lack the DP receptor, there is a marked reduction in airway hyperactivity and chronic inflammation [Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya S, Prostaglandin D2 as a mediator of allergic asthma, Science, 287, 2013-2017, 2000 ]; two of the cardinal characteristics of human asthma.

It is also believed that the DP receptor is involved in human allergic rhinitis, a common allergic disease characterized by the symptoms of sneezing, itching, rhinorrhea and nasal congestion. Local administration of PGD2 in the nose produces a dose-dependent increase in nasal congestion [Doyle WJ, Bochm S, Skoner DP, Physiologic responses to intranasal dose-response challenges with histamine, methacholine, bradykinin and prostaglandin in adult volunteers with and without nasal allergy, J. Allergy Clin. Immunol., 86 (6 Pt 1), 924-935, 1990].

DP receptor antagonists have been shown to reduce airway inflammation in an experimental model of asthma in guinea pigs [Arimura A, Yasui K, Kishino J, Asanuma F, Hasegawa H, Kakudo S, Ohtani M, Arita H (2001 ), Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S5751, J Pharmacol Exp Ther. 298 (2), 411-9, 2001]. Therefore, PGD2 seems to act on the DP receptor and plays an important role in the appearance of certain key features of allergic asthma.

DP antagonists have been shown to be effective in relieving allergic rhinitis symptoms in multiple species and, more specifically, have been shown to inhibit antigen-induced nasal congestion, the most obvious symptom of allergic rhinitis [Jones, TR , Savoie, C., Robichaud, A., Sturino, C., Scheigetz, J. Lachance, N., Roy, B., Boyd, M., Abraham, W., Studies with a DP receptor antagonist in sheep and guinea pig models of allergic rhinitis, Am. J. Resp. Crit. Care Med. 167, A218, 2003; and Arimura A, Yasui K, Kishino J, Asanuma F, Hasegawa H, Kakudo S, Ohtani M, Arita H, Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751. J Pharmacol Exp Ther. 298 (2), 411-9, 2001].

DP antagonists are also effective in experimental models of allergic conjunctivitis and allergic dermatitis [Arimura A, Yasui K, Kishino J, Asanuma F, Hasegawa H, Kakudo S, Ohtani M, Arita H, Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751. J Pharmacol Exp Ther. 298 (2), 411-9, 2001; and Torisu K, Kobayashi K, Iwahashi M, Nakai Y, Onoda T, Nagase T, Sugimoto I, Okada Y, Matsumoto R, Nanbu F, Ohuchida S, Nakai H, Toda M, Discovery of a new class of potent, selective and orally active prostaglandin D2 receptor antagonists,

5 Bioorg. & Med. Chem., 12, 5361-5378, 2004]. Patent document wO2006 / 081343 describes 2-phenyl indole derivatives, their preparation, pharmaceutical compositions containing these compounds and their pharmaceutical use in the treatment of pathologies capable of being modulated by inhibiting the prostaglandin D2 receptor.

10 SUMMARY OF THE INVENTION

The present invention relates to a compound of formula (A),

image 1

where:

R is

R1CH2SO2-, R2CH2SO2NH-, or R3NHSO2-, R1

is phenyl optionally substituted with halo,

R2 is

halo substituted phenyl,

R 3 is 2,6-dichloro-benzyl, 3,5-dichloro-benzyl, 2,4-dichloro-phenylethyl, 2-methoxyphenylethyl, 3-methoxy-phenylethyl, 4-methoxy-phenylethyl, 2-trifluoromethyl-phenylethyl, phenylethyl or 3-phenyl-n-propyl,

R4 is

25 hydrogen,

R5 is

chlorine,

R6 is

hydrogen and R8 is

hydroxy; or R is cyclohexylaminosulfonyl, R4 is 4-chloro, 4-fluoro, 4-methyl or 7-chloro, R5 is chloro or ethyl, R6 is hydrogen or methyl, and R8 is hydroxy; or R is cyclohexylaminosulfonyl, R4 is hydrogen, R5 is chlorine, R6 is hydrogen, R8 is -NHR7, and R7 is methyl, methylsulfonyl, ethylsulfonyl, haloalkylsulfonyl or tetrazolyl;

or one of its pharmaceutically acceptable salts, hydrates or solvates, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate.

Another aspect of the present invention is a pharmaceutical composition comprising a pharmaceutically effective amount of one or more compounds of the invention, or one of its pharmaceutically acceptable hydrate salts or solvates, one of its pharmaceutically acceptable ester prodrugs or a salt, hydrate or pharmaceutically acceptable ester prodrug solvate, mixed with a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

Definition of Terms

As used above and used throughout the description of the invention, it will be understood that the following terms, unless otherwise indicated, have the following meanings:

The term "compounds of the present invention", and equivalent expressions, are intended to include compounds of Formulas (A), (I), (II) or (III) as described hereinbefore, where said expression includes prodrugs, pharmaceutically acceptable salts and

10 solvates, for example, hydrates, when the context allows. Similarly, the reference to intermediates, whether claimed or not themselves, is intended to cover their salts, and solvates, when the context allows.

The term "haloalkyl" refers to alkyl substituted with one to three halo groups. Particular haloalkyls are lower alkyl substituted with one to three

15 halogens The most particular haloalkyls are lower alkyl substituted with a halogen.

The term "haloalkylsulfonyl" refers to haloalkyl-SO2-. An example includes CF3-SO2-.

"Patient" includes humans and other mammals.

The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention that are, within the scope of medical judgment, suitable for use in contact with the tissues of patients with undue toxicity. , irritation, allergic response in proportion to a benefit / risk ratio

Reasonable and effective for the desired use of the compounds of the invention. The term "prodrug" means a compound that is transformed in vivo to give a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation can take place by different mechanisms, such as through hydrolysis in the

30 blood Compounds that have metabolically cleavable groups have the advantage that they may have a better bioavailability as a result of a better solubility and / or absorption rate granted by the parent compound by virtue of the presence of the metabolically cleavable group, and thus, such Compounds act as prodrugs. A thorough analysis is provided in Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology; K. Widder et al., Ed., Academic Press, 42, 309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bandgaard, ed., Chapter 5; "Design and Applications of Prodrugs" 113-191 (1991); Advanced Drug Delivery Reviews, H. Bundgaard, 8, 1-38, (1992); J. Pharm. Sci., 77, 285 (1988); Chem. Pharm. Bull., N. Nakeya et al, 32, 692 (1984); Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, 14

A.C.S.

Symposium Series, and Bioreversible Carriers in Drug Design, E.B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987;

J.

Med. Chem., Vol. 47, No. 10, 1-12 (2004), which are incorporated herein by reference.

Prodrugs of a compound of the invention are ester prodrugs. The term "ester prodrug" refers to a compound that can be converted in vivo by metabolic means (eg, by hydrolysis) into a compound of the invention. For example, an ester prodrug of a compound of the invention containing a carboxy group can be converted by in vivo hydrolysis into the corresponding compound of the invention, such as the methyl ester prodrug, ethyl ester prodrug or ester prodrug 2- dimethylamino-ethyl.

"Pharmaceutically acceptable salts" refers to the addition salts of organic and inorganic acids and the non-toxic base addition salts of the compounds of the present invention. These salts can be prepared in situ during the isolation and final purification of the compounds.

The term "therapeutically effective amount" refers to an effective amount of compound or compounds according to the present invention that produces the desired therapeutic effect described herein, such as an allergy relief effect, or a relief effect of the inflammation.

"Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association includes hydrogen bonds. In certain cases, the solvate may be isolated, for example, when one or more of the solvent molecules are incorporated into the crystalline network of the crystalline solid. The term "solvate" includes both insulated solvates and solvates in solution phase. Representative solvates include hydrates, ethanolates and methanolates.

Some of the compounds of the present invention are of a basic nature, and compounds of this type are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt.

Acid addition salts are a more convenient use; and in practice, the use of the salt form intrinsically amounts to the use of the free base form. Acids that can be used to prepare acid addition salts preferably include those that produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in the pharmaceutical doses of the salts. , so that the beneficial inhibitory effects inherent in the free base are not invalidated by side effects attributable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form, even if the particular salt, per se, is desired only as an intermediate , such as, for example, when the salt is formed for purification and identification purposes only, or when it is used as an intermediate product for the preparation of a pharmaceutically acceptable salt by ion exchange processes. In particular, acid addition salts can be prepared by reacting separately the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt formed in this way. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids. Exemplary acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, quinatos, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulfamates, malonates, salicylates, propionates, methylene-bis-ß-hydroxynaphthoates, gentisates, isethionates, di-para-toluoyltartrates, ethanesulfonates sulphonaphosphonate sulfonates See, for example S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66, 1-19 (1977), which is incorporated herein by reference.

When the compound of the invention is substituted with an acidic moiety, salts may be formed by the addition of bases and are simply a more convenient use; and in practice, the use of the salt form intrinsically amounts to the free acid form. The bases that can be used to prepare the base addition salts preferably include those that produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in the pharmaceutical doses of the salts. , so that the inhibitory effects inherent in the free base are not invalidated by side effects attributable to cations. The base addition salts can also be prepared by reacting separately the purified compound in its acid form with a suitable inorganic or organic base obtained from alkali metal and alkaline earth metal salts and isolating the salt formed in this way. Base addition salts include metal salts and pharmaceutically acceptable amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum salts. Particular salts are sodium and potassium salts. Suitable inorganic base addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like. Suitable amine base addition salts are prepared from amines that have sufficient basicity to form a stable salt and preferably include the amines that are frequently used in medical chemistry because of their low toxicity and acceptability for medical use. Ammonium, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) -aminomethane, tetramethylamine hydroxide , dibenzylamine, ephenamine, dehydroabyethylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, for example, lysine and arginine and dicyclohexylamine.

In addition to being useful by themselves as active compounds, the salts of the compounds of the invention are useful for the purposes of purification of the compounds, for example by exploiting the differences in solubility between the salts and the parent compounds, by-products and / or starting materials by techniques well known to those skilled in the art.

It will be appreciated that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may be independently in the R or S configuration. It will be obvious to those skilled in the art that certain compounds of the invention may also show geometric isomerism. It should be appreciated that the present invention includes individual geometric isomers, stereoisomers and mixtures thereof, including racemic mixtures, of the compounds of the invention. Such isomers can be separated from their mixtures by the application or adaptation of known methods, for example, chromatographic techniques and recrystallization techniques, or are prepared separately from the appropriate isomers of their intermediate compounds. In addition, in situations where tautomers of the compounds of the invention are possible, the present invention is intended to include all tautomeric forms of the compounds.

A particular embodiment of the present invention is a compound of formula (I),

image 1

Where: R is R1CH2SO2-, R2CH2SO2NH-, or R3NHSO2-; R1

it is phenyl optionally substituted with halo; R2 is halo substituted phenyl; and R3 is 2,6-dichloro-benzyl, 3,5-dichloro-benzyl, 2,4-dichloro-phenylethyl, 2-methoxyphenylethyl, 3-methoxy-phenylethyl, 4-methoxy-phenylethyl, 2-trifluoromethyl- phenylethyl, phenylethyl or 3-phenyl-n-propyl;

or one of its pharmaceutically acceptable salts, hydrates or solvates, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate.

Another preferred embodiment of the present invention is a compound of the formula (I) in which R is R3NHSO2-, or a pharmaceutically active salt, hydrate or solvate.

acceptable, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate. Another particular embodiment of the present invention is a compound of formula (II),

image 1

5 where:

R4 is

4-chloro, 4-fluoro, 4-methyl or 7-chloro;

R5 is

chlorine or ethyl; Y

10 R6es

hydrogen or methyl;

or one of its pharmaceutically acceptable salts, hydrates or solvates, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate.

Another particular embodiment of the present invention is a compound of formula (II), wherein R5 is chlorine and R6 is hydrogen, or a pharmaceutically acceptable salt, hydrate or solvate, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate.

Another particular embodiment of the present invention is a compound of formula (III), wherein R 7 is methyl, methylsulfonyl, ethylsulfonyl, haloalkylsulfonyl or tetrazolyl or one of its pharmaceutically acceptable salts, hydrates or solvates, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate.

image 1

Another particular embodiment of the present invention is a selected compound between {2- [4-Chloro-3- (2,6-dichloro-benzyl sulfamoyl) -phenyl] -1H-indole-3-yl} -acetic acid, {2- [4-Chloro-3- (3,5-dichloro-benzyl sulfamoyl) -phenyl] -1H-indole-3-yl} -acetic acid, (2- {4-Chloro-3- [2- (2,4-dichloro-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid, (2- {4-Chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid, (2- {4-Chloro-3- [2- (3-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid, (2- {4-Chloro-3- [2- (4-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid, (2- {4-Chloro-3- [2- (2-trifluoromethoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid, [2- (4-Chloro-3-phenethylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid, {2- [4-Chloro-3- (3-phenyl-propylsulfamoyl) -phenyl] -1H-indole-3-yl} -acetic acid, 2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -N-methyl-acetamide, [4-Chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid, [4-Chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl]-potassium acetate, [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -4-fluoro-1H-indole-3-yl] -acetic acid, [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -4-methyl-1H-indole-3-yl] -acetic acid,

[7-Chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid, 2-Chloro-N-cyclohexyl-5- [3- (2-methanesulfonylamino-2-oxo-ethyl) -1H-indole-2-yl] benzenesulfonamide,

2-Chloro-N-cyclohexyl-5- [3- (2-ethanesulfonylamino-2-oxo-ethyl) -1H-indole-2-yl]

benzenesulfonamide, 2-Chloro-N-cyclohexyl-5- [3- (2-oxo-2-trifluoromethanesulfonylamino-ethyl) -1H-indole-2-yl] benzenesulfonamide,

2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -N- (1H-tetrazol-5-yl) -acetamide, [2- (3-Cyclohexylsulfamoyl-4-ethyl-phenyl) -1H-indole-3-yl] -acetic acid,

2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -propionic acid, {2- [4-chloro-3- (3-chloro-phenylomethanesulfonyl) -phenyl] -1H -indole-3-yl} -acetic acid, or {2- [4-chloro3- (3-chloro-phenylomethanesulfonylamino) -phenyl] -1H-indole-3-yl} -acetic acid,

or one of its pharmaceutically acceptable salts, hydrates or solvates, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate.

The compounds of the invention show prostaglandin D2 receptor antagonist activity and are useful as agents of pharmacological action. Therefore, they are incorporated into pharmaceutical compositions and are used in the treatment of patients suffering from certain medical disorders.

Compounds within the scope of the present invention are prostaglandin D2 receptor antagonists in accordance with assays described in the literature and described in the pharmacological assay section presented below, and it is believed that the results of these assays correlate with activity. Pharmacological in humans and other mammals. Thus, in a further embodiment, the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from or prone to conditions that can be improved by the administration of a PGD2 antagonist. Thus, for example, the compounds of the present invention may be useful in the treatment of a variety of disorders mediated by PGD2 including, but not limited to, allergic disease (such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma and allergy food), systemic mastocytosis, disorders accompanied by activation of systemic mast cells, anaphylactic shock, bronchoconstriction, bronchitis, urticaria, eczema, diseases accompanied by itching (such as atopic dermatitis and urticaria), diseases (such as cataracts, retinal detachment, inflammation, infection and sleep disorders) that are generated secondarily as a result of the behavior that accompanies itching (such as scratching and bumping), inflammation, chronic obstructive pulmonary disease, ischemia-reperfusion injury, stroke, chronic rheumatoid arthritis, pleurisy, ulcerative colitis and the like.

In addition, the compounds of the present invention are useful in treatments that involve a combination therapy with:

(i)

antihistamines, such as fexofenadine, loratadine and citirizine, for the treatment of allergic rhinitis;

(ii)

Leukotriene antagonists, such as montelukast and zafirulast, for the treatment of allergic rhinitis, COPD, allergic dermatitis, allergic conjunctivitis, etc. (see specifically the claims of WO 01/78697 A2);

(iii) beta agonists, such as albuterol, salbuterol and terbutaline, for the treatment of asthma, COPD, allergic dermatitis, allergic conjunctivitis, etc;

(iv)

antihistamines, such as fexofenadine, loratadine, desloratadine and cetirizine, for the treatment of asthma, COPD, allergic dermatitis, allergic conjunctivitis, etc;

(v)

PDE4 (phosphodiesterase 4) inhibitors, such as roflumilast and cilomilast, for the treatment of asthma, COPD, allergic dermatitis, allergic conjunctivitis, etc; or

(saw)

with antagonists of TP (thromboxane A2 receptor) or CrTh2 (molecule homologous to the chemoattractant receptor expressed in Th2 cells), such as Ramatrobran (BAY-u3405), for the treatment of COPD, allergic dermatitis, allergic conjunctivitis, etc.

A special embodiment of the therapeutic methods of the present invention is the treatment of allergic rhinitis.

Another special embodiment of the therapeutic methods of the present invention is the treatment of bronchial asthma.

It should be understood that references herein to a treatment include prophylactic therapy, as well as the treatment of established conditions.

The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention mixed with a pharmaceutically acceptable carrier.

In practice, the compound of the present invention can be administered in a pharmaceutically acceptable dosage form to humans and other animals by topical or systemic administration, including oral, inhalation, rectal, nasal, buccal, sublingual, vaginal, colonic administration. , parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. It will be appreciated that the preferred route may vary, for example, depending on the condition of the recipient.

"Pharmaceutically acceptable dosage forms" refers to dosage forms of the compound of the invention and include, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants, tablets, pills, emulsions, solutions, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations. The techniques and formulations can be found, in general, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition.

A particular aspect of the invention provides a compound according to the present invention to be administered in the form of a pharmaceutical composition. The pharmaceutical compositions according to the present invention comprise compounds of the present invention and pharmaceutically acceptable carriers.

Pharmaceutically acceptable carriers include at least one component selected from the group consisting of pharmaceutically acceptable carriers, diluents, coatings, adjuvants, excipients or vehicles, such as preservatives, fillers, disintegrating agents, wetting agents, emulsifying agents, stabilizing agents. emulsion, suspending agents, isotonic agents, sweetening agents, flavoring agents, perfume agents, coloring agents, antibacterial agents, antifungal agents, other therapeutic agents, lubricating agents, agents for delaying or promoting adsorption and administration agents, depending on the nature of the mode of administration and dosage forms.

Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.

Examples of antibacterial and antifungal agents for the prevention of the action of microorganisms include parabens, chlorobutanol, phenol, sorbic acid and the like.

Exemplary isotonic agents include sugars, sodium chloride and the like.

Examples of agents that delay adsorption to prolong absorption include aluminum monostearate and gelatin.

Examples of agents that promote adsorption to improve absorption include dimethyl sulfoxide and related analogs.

Examples of diluents, solvents, vehicles, solubilizing agents, emulsifiers and emulsion stabilizers include water, chloroform, sucrose, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl benzoate, polyols, propylene glycol , 1,3butylene glycol, glycerol, polyethylene glycols, dimethylformamide, Tween® 60, Span® 60, ketostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate, sorbitan fatty acid esters, vegetable oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil) and injectable organic esters such as ethyl oleate and the like, or suitable mixtures of these substances.

Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate and dicalcium phosphate.

Examples of disintegrating agents include starch, alginic acids and certain complex silicates.

Examples of lubricants include magnesium stearate, sodium lauryl sulfate, talc, as well as high molecular weight polyethylene glycols.

In general, the choice of the acceptable pharmaceutical carrier is determined according to the chemical properties of the active compound such as solubility, the particular mode of administration and the conditions to be taken into account in pharmaceutical practice.

The pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as a solid dosage form, such as capsules, wafers or tablets each containing a predetermined amount of the active ingredient or as a powder or granulate; as a liquid dosage form such as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, or as a liquid emulsion of water in oil or oil in water. The active substance can also be presented as a bolus, electuary or paste.

"Solid dosage form" means that the dosage form of the compound of the invention is a solid form, for example, capsules, tablets, pills, powders, dragees or granules. In such solid dosage forms, the compound of the invention is mixed with at least one usual inert excipient (or vehicle) such as sodium citrate or dicalcium phosphate or (a) fillers or diluents, such as, for example, starches, lactose, sucrose , glucose, mannitol and silicic acid, (b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, (c) humectants, such as, for example, glycerol, (d) disintegrating agents such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some complex silicates and Na2CO3, (e) agents for retarders, such as, for example, paraffin, (f) absorption accelerators , such as, for example, quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate. (h) adsorbents, such as, for example, kaolin and bentonite, (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, (j) opacifying agents, (k ) buffering agents and agents that release the compound or compounds of the invention in a certain part of the intestinal tract in a delayed manner.

A tablet can be prepared by compression or by molding, optionally with one or more auxiliary ingredients. Compression tablets may be prepared by compression in a suitable machine of the active substance in fluid form such as in the form of powder or granules, optionally mixed with a binding agent, lubricant, inert diluent, preservative, surfactant or dispersion. Excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used. The molding tablets can be obtained by molding in a suitable machine a mixture of the powdered compounds moistened with an inert liquid diluent. The tablets may optionally be coated or grooved to provide a slow or controlled release of the active ingredient present therein.

The solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

If desired and in order to achieve a more efficient distribution, the compounds can be microencapsulated or associated with slow release or directed release systems such as biocompatible and biodegradable polymer matrices (eg, poly (d, co-glycolidel-lactide)), liposomes and microspheres, and injected subcutaneously or intramuscularly by a technique called subcutaneous or intramuscular deposition to provide continuous slow release of the compound or compounds for a period of 2 weeks or more. The compounds can be sterilized, for example, by filtration through a bacterial retention filter or by the incorporation of sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use.

"Liquid dosage form" means that the dose of active compound to be administered to the patient is in liquid form, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as solvents, solubilizing agents and emulsifiers.

When aqueous suspensions are used, they may contain emulsifying agents or agents that facilitate suspension.

Pharmaceutical compositions suitable for topical administration refer to formulations that are in a form suitable for topically administered to a patient. The formulation may be presented as a topical ointment, ointment, powders, sprays and inhalants, gels (based on water or alcohol), creams, as is generally known in the art, or incorporated into a matrix base for application in a patch, which would allow controlled release of the compound through the transdermal barrier. When formulated in an ointment, the active ingredients can be used with a paraffinic base or with a water-miscible ointment base. Alternatively, the active ingredients can be formulated in a cream with an oil-in-water cream base. Formulations suitable for topical administration in the eye include ophthalmic drops in which the active ingredient is dissolved or suspended in a suitable vehicle, especially an aqueous solvent for the active ingredient. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and gum arabic or tragacanth; pills comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes comprising the active ingredient in a suitable liquid vehicle.

The oil phase of the emulsion pharmaceutical composition may be constituted from known ingredients in a known manner. Although the phase may simply comprise an emulsifier (otherwise known as an emulsifier), it conveniently comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. In a particular embodiment, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Together, the emulsifier (s) with or without stabilizer (s) constitute the emulsifying wax, and the wax together with the oil and grease constitute the base of emulsifying ointment that constitutes the dispersed oil phase of the cream formulations.

If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of a polyhydric alcohol, that is, an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. Topically formulations, desirably, may include a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected areas.

The choice of suitable oils or fats for a composition is based on obtaining the desired properties. In this way, a cream should preferably be a non-greasy, non-staining and washable product, with a consistency suitable to prevent leakage from the tubes or other containers. Mono- or dibasic straight or branched chain alkyl esters such as diisopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixture of branched chain esters known as Crodamol CAP can be used. These can be used alone or in combination depending on the required properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

Pharmaceutical compositions suitable for rectal or vaginal administration refer to formulations that are in a form suitable for rectal or vaginal administration to a patient and that contain at least one compound of the invention.

Suppositories are a particular form for such formulations that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at the usual temperatures but liquid at the temperature body and, therefore, fuse in the rectum or vaginal cavity and release the active component.

The pharmaceutical compositions administered by injection may be administered by transmuscular, intravenous, intraperitoneal and / or subcutaneous injection. The compositions of the present invention are formulated in liquid solutions, in particular in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the compositions can be formulated in solid form and redissolved or suspended immediately before use. Lyophilized forms are also included. The formulations are sterile and include aqueous or non-aqueous emulsions, suspensions or injection solutions, which may contain suspending agents and thickening and antioxidant agents, buffers, bacteriostats and solutes that make the formulations isotonic and have a conveniently adjusted pH, with the blood of the desired recipient.

A pharmaceutical composition of the present invention suitable for nasal or inhalation administration refers to compositions that are in a form suitable for nasal administration or inhalation to a patient. The composition may contain a vehicle, in powder form, having a particle size, for example, in the range of 1 to 500 micrometers (including particle sizes in a range between 20 and 500 micrometers in increments of 5 micrometers such such as 30 micrometers, 35 micrometers, etc.). Suitable compositions in which the vehicle is a liquid, for administration, for example, as a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Compositions suitable for aerosol administration can be prepared according to conventional methods, and can be administered with other therapeutic agents. Dose meter inhalers are useful for administering the compositions according to the invention for inhalation therapy.

Actual dosage levels of the active ingredient (s) in the compositions of the invention can be varied to obtain an amount of the active ingredient (s) that is effective (n). effective) to obtain a desired therapeutic response for a specific composition and method of administration to the patient. A dosage level selected for any particular patient, therefore, depends on a variety of factors, including the desired therapeutic effect, the route of administration, the desired duration of treatment, the etiology and severity of the disease, the condition, weight , sex, diet and age of the patient, the type and potency of each active ingredient, absorption rates, metabolism and / or excretion and other factors.

The total daily dose of the compounds of this invention administered to a patient in a single dose or in divided doses may be in amounts, for example, from about 0.001 to about 100 mg / kg body weight per day and preferably 0.01 at 10 mg / kg / day. For example, in an adult, the doses are generally from about 0.01 to about 100, preferably from about 0.01 to about 10 mg / kg of body weight per day by inhalation, from about 0.01 to about 100, preferably from 0.1 to 70, more especially from 0.5 to 10 mg / kg of body weight per day by oral administration, and from about 0.01 to about 50, preferably from 0.01 to 10 mg / kg of body weight daily by intravenous administration. The percentage of active ingredient in a composition can be varied, although it should constitute a proportion so that an adequate dosage is obtained. The unit dosage compositions may contain such amounts of such submultiples thereof as may be used to constitute the daily dose. Obviously, unit dosage forms can be administered at approximately the same time. A dose can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to a higher or lower dose and may find a much weaker maintenance dose adequate. For other patients, it may be necessary to provide long-term treatments in the proportion of 1 to 4 doses per day, according to the physiological requirements of each particular patient. It is understood that, for other patients, it will be necessary to prescribe no more than one or two daily doses.

The formulations can be prepared in unit dosage form by any method known in the pharmaceutical art. Such methods include the step of associating the active ingredient with the vehicle that constitutes one or more additional ingredients. In general, the formulations are prepared by uniformly and intimately associating the active ingredient with liquid vehicles or finely divided solid vehicles, or both, and then, if necessary, shaping the product.

The formulations can be presented in single-dose or multi-dose containers, for example, ampoules and vials sealed with elastomeric stoppers, and can be preserved in a freeze-dried (lyophilized) state that only requires the addition of the sterile liquid vehicle, for example , water for injection, immediately before use. Solutions and suspensions for improvised injection can be prepared from sterile powders, granules and tablets of the type described previously.

The compounds of the invention can be prepared by applying or adapting known methods, and this means the methods used to date or described in the literature, for example, those described by R.C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

Ester prodrugs of the compounds of the invention can be prepared by coupling compounds of the invention having a carboxy group, with an alcohol of Formula YOH (wherein Y is alkyl or alkyl substituted with amino, alkylamino or dialkylamino), to give an ester link using conventional coupling procedures. Examples include coupling in the presence of HBTU and optionally in the presence of DIEA, in DCM at room temperature.

According to another aspect of the invention, the acid addition salts of the compounds of this invention can be prepared by reacting the free base with the appropriate acid, by applying or adapting known methods. For example, acid addition salts of the compounds of this invention can be prepared by dissolving the free base in water or in an aqueous solution of alcohol or other suitable solvents containing the appropriate acid, and isolating the salt by evaporating the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt is separated directly or can be obtained by concentrating the solution.

The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, the original compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, eg an aqueous solution of sodium bicarbonate or an aqueous solution of ammonia.

The compounds of this invention can be regenerated from their base addition salts by applying or adapting known methods. For example, parental compounds of the invention can be regenerated from their salts by the addition of bases by treatment with an acid, for example hydrochloric acid.

The compounds of the present invention can be conveniently prepared or formed during the process of the invention in the form of solvates (eg, hydrates). The hydrates of the compounds of the present invention can be conveniently prepared by recrystallization in an aqueous / organic solvent mixture, using organic solvents such as dioxane, tetrahydrofuran or methanol.

In accordance with another aspect of the invention, base addition salts of the compounds of this invention can be prepared by reacting the free acid with the appropriate base by applying or adapting known methods. For example, base addition salts of the compounds of this invention can be prepared by dissolving the free acid in water or in an aqueous solution of alcohol or other suitable solvents containing the appropriate base, and isolating the salt by evaporating the solution, or by reacting the free acid and the base in an organic solvent, in which case the salt is separated directly or can be obtained by concentrating the solution.

The starting and intermediate materials can be prepared by the methods described herein or by adaptation of known methods.

The compounds of the invention, their methods or preparation and their biological activity will appear more clearly from the examination of the following examples.

The compounds of the invention are identified, for example, by the following analytical methods.

High Pressure Liquid Chromatography-Mass Spectrometry (LCMS) experiments to determine retention times (TR) and associated mass ions are performed using one of the following methods.

Mass spectra (MS) are recorded using a Micromass LCT mass spectrometer. The method is positive electrospray ionization, scanning mass m / z from 100 to 1000. Liquid chromatography is performed on a binary pump and degasser of the Hewlett Packard 1100 series; stationary phase: Phenomenex Synergi 2µ Hydro-RP 20 x 4.0 mm column, mobile phase: A = 0.1% formic acid (FA) in water, B = 0.1% FA in acetonitrile. Injection volume of 5 µl by CTC Analytical PAL System. The flow rate is 1 ml / minute. The gradient is 10% B to 90% B in 3 minutes and 90% B to 100% B in 2 minutes. The auxiliary detectors are: UV detector Hewlett Packard 1100 Series, wavelength = 220 nm and the temperature of the Sedere SEDEX 75 Evaporative Light Scattering (ELS) detector = 46 ° C, nitrogen pressure = 4 bar.

1 H at 300 MHz nuclear magnetic resonance (NMR) spectra are recorded at room temperature using a Varian Mercury spectrometer (300 MHz) with a 5 mm ASW probe. In NMR, chemical shifts (�) are indicated in parts per million (ppm) with respect to tetramethylsilane (TMS) as an internal standard.

As used in the examples and preparations shown below, as well as in the rest of the application, the terms used will have the indicated meanings: "kg" refers to kilograms, "g" refers to grams, "mg" refers to milligrams, "µg" refers to micrograms, "mol" refers to moles, "mmol" refers to millimoles, "M" refers to molar, "mM" refers to millimolar, "µM" refers to micromolar, "nM" refers to nanomolar, "L" refers to liters, "mL" or "ml" refers to milliliters, "µL" refers to microliters, "" C "refers to degrees Celsius," mp "or" mp "refers to melting point," bp "or" bp "refers to boiling point," mm Hg "refers to pressure in millimeters of mercury," cm "refers to centimeters," nm "refers to nanometers," abs. "refers to absolute," conc. "refers to concentrate," c "refers to concentration in g / mL," rt "refers to room temperature," TLC "refers refers to layer chromatography fine, "HPLC" refers to high performance liquid chromatography, "i.p." refers to intraperitoneally, "i.v." refers to intravenous, "s" = singlet, "d" = doublet. "t" = triplet; "C" = quadruplet; "M" = multiplet, "dd" = doublet of doublets; "br" = width, "LC" '= liquid chromatograph, "MS" = mass spectrograph, "ESI / MS" = electrospray ionization / mass spectrograph, "RT" = retention time, "M" = molecular ion , "PSI" = pounds per square inch, "DMSO" = dimethyl sulfoxide, "DMF" = N, N-dimethylformamide. "CDI" = 1,1'-carbonyldiimidazole, "DCM" or "CH2Cl2" = dichloromethane. "HCl" = hydrochloric acid, "SPA" = Scintillation Proximity Test, "ATTC" = American Tipon Crop Collection, "FBS" = Fetal Bovine Serum, "MEM" = Minimum Essential Medium, "CPM" = Minute Accounts , "EtOAc" = ethyl acetate, "PBS" = Phosphate Buffered Saline, "TMD" = transmembrane domain, "IBMX" = 3-isobutyl-1-methylxanthine, "cAMP" = cyclic adenosine monophosphate, "IUPAC" = Union Interconal of Pure and Applied Chemistry, "MHz" = megahertz, "PEG" = polyethylene glycol, "MeOH" = methanol, "N" = normal, "THF" = tetrahydrofuran, "h" = hours, "min" = minute (s ), "MeNH2" = methylamine, "N2" = nitrogen gas, "iPrOH" =

isopropyl alcohol, "O.D." = external diameter, "MeCN" or "CH3CN" = acetonitrile,

"Et2O" = ethyl ether, "TFA" = TFA, "Prep LC" = "ultrafast" liquid chromatography

preparatory, "SPE" = solid phase extraction, "LAH" = lithium aluminum hydride,

5 "pmol" = picomolar, "heptane" = n-heptane, resin "HMBA-AM" = aminomethyl resin

of 4-hydroxymethylbenzoic acid, "PdCl2 (dppf) 2" = DCM complex and dichloride

1,1'-bis (diphenylphosphino) ferrocene-palladium (II), "HBTU" = 2- (1H hexafluorophosphate)

benzotriazol-1il) -1,1,3,3-tetramethyluronium, "DIEA" = diisopropylethylamine, "CsF" = fluoride

of cesium, "LiOH" = lithium hydroxide, "�" = approximately, "IC50" = the concentration of the compound that produces 50% inhibition in the SPA cAMP test in cells

human LS 174 T.

EXAMPLES

Example 1:

(a) {2- [4-Chloro-3- (2,4-dichloro-benzyl sulfulfyl) -phenyl] -1H-indole-3-yl} -acetic acid

image 1

15 Stage 1. Cooling nitric acid (1.5 L) is cooled to approximately -5 ° C in an ice / salt bath. Over a period of 30 minutes, 4- (4-chlorophenyl) -4-oxo-butyric acid (150 g, 0.706 mol) is added portionwise to the mechanically stirred solution and the reaction mixture is stirred at a temperature between approximately

20 5 ° C and approximately -7 ° C for 3.5 hours. The reaction mixture is poured onto crushed ice / water (3 liters) and stirred overnight at room temperature. The solid material is filtered, washed with water until the washings are neutral, air dried and finally dried in a vacuum oven at approximately 85 ° C to obtain 4- (4-chloro-3-nitro-phenyl) acid -4-oxo-butyric in the form of a solid (159.1 g).

Step 2. A mechanically stirred suspension of 4- (4-chloro-3-nitro-phenyl) -4oxo-butyric acid (150 g, 0.582 mol) in water (900 ml) and concentrated HCl (12 ml) add a solution of sodium bisulfite (393 g, 2.07 mol, in 800 ml of water) for a period of 40 minutes at 100-105 ° C. After the addition, the mixture is heated at reflux for 1 hour. The pH value is adjusted to ~ 2 by the addition of 4N HCl (100 ml). The mixture is heated at reflux for an additional 30 minutes, cooled to room temperature and filtered to obtain 4- (3-amino-4-chloro-phenyl) -4-oxobutyric acid as a solid (79.3 g ). LCMS: RT = 2.39 minutes, MS: 228 (M + H); 1H NMR (300 MHz, DMSO-D6) � 2.51 (t, J = 6 Hz, 2H) 3.11 (t, J = 6 Hz, 2H) 5.58 (s, 2H), 7.1 ( dd, J = 6.2 Hz, J = 2 Hz, 1H) 7.29 (d, J = 8 Hz, 1H) 7.36 (d, J = 2 Hz, 1H) 12.08 (wide s, 1H ).

Step 3: 4- (3-Amino-4-chloro-phenyl) -4-oxo-butyric acid (16.2 g, 71.16 mmol) in DMF (20 ml) is added to a mixture of concentrated HCl (35 ml) and ice (150 g). A solution of sodium nitrite (5.25 g, 76.1 mmol) in water (18 ml) is added by pipette below the surface of the solution for 5 minutes at a temperature between -5 ° C and -10 ° C. The reaction mixture is heated to 0 ° C and stirred for 15 min. This solution is slowly added at room temperature to a mixture of copper chloride dihydrate (5.58 g, 32.7 mmol) in glacial acetic acid (175 ml) that has been saturated with sulfur dioxide gas. The resulting solution is stirred for 45 minutes at room temperature, water (500 ml) is added and the solution is stirred for 1 hour. The flask is cooled to 10 ° C and the solid is filtered and washed with water to produce 4- (4-chloro-3-chlorosulfonyl-phenyl) -4-oxo-butyric acid as a solid (12.94 g,) . LCMS: RT = 2.68 minutes, MS: 310 (M + H); 1H NMR (300 MHz, DMSO-D6) � ppm 2.56 (t, J = 6 Hz, 2H) 3.19 (t, J = 6 Hz, 2H) 7.51 (d, J = 8 Hz, 1H ) 7.87 (dd, J = 6 Hz, J = 2 Hz, 1H) 8.39 (d, J = 2 Hz, 1H) 12.66 (width s, IH).

Step 4: 4- (4-Chloro-3-chlorosulfonyl-phenyl) -4-oxo-butyric acid (2 g, 6.43 mmol) is added to a stirred solution of 2,4-dichlorobenzylamine (2.82 g, 16 mmol) in a mixture of DCM: MeOH mixture (1: 1, 50 mL) at 0 ° C. The reaction mixture is heated to room temperature and stirred for 20 hours. The reaction mixture is acidified with 2N aqueous HCl (pH ~ 2) and extracted twice with DCM. The combined organic layer is washed with water and brine, dried over sodium sulfate and evaporated in vacuo to produce 4- [4-chloro-3- (2,4-dichloro-benzylsulfamoyl) -phenyl] -4-oxo- butyric in the form of a semi-solid (2.1 g). LCMS: RT = 2.38 minutes, MS: 448 (M-H).

Step 5: To a mixture of 4- [4-Chloro-3- (2,4-dichloro-benzylsulfamoyl) -phenyl] -4-oxobutyric acid (800 mg, 1.78 mmol), p-toluenesulfonic acid monohydrate (520 mg, 2.7 mmol) and zinc chloride (370 mg, 2.7 mmol) in glacial acetic acid (15 ml) in a microwave container is added phenylhydrazine (300 mg, 2.78 mmol). He

Capped vessel is heated in a microwave at 180 ° C for 40 minutes. The reaction mixture is diluted with EtOAc, transferred to a conical flask and 2N aqueous HCl (~ 50 ml) is added. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layer is washed with water, dried over sodium sulfate and concentrated. The residue is purified by separation by preparative HPLC (mobile phase: acetonitrile-water with 0.1% TFA; 10-100% gradient for 10 minutes) to produce {2- [4-chloro-3- (2, 4-dichloro-benzyl sulfamoyl) -phenyl] -1H-indole-3-yl} acetic as a solid (145 mg). LCMS: TR = 2.78 minutes, MS: 523 (M + H). 1H NMR (300 MHz, DMSO-D6) � 3.74 (s, 2H) 4.23 (d, J = 6 Hz, 2H) 7.06 (t, J = 7 Hz, 1H)

10 7.17 (t, J = 7 Hz, 1H) 7.3-7.48 (m, 4H), 7.56 (d, J = 8 Hz, 1H) 7.75 (d, J = 8, 3 Hz, 1H) 7.87 (d, J = 8 Hz, 1H) 8.22 (d, J = 2 Hz, 1H) 8.64 (t, J = 6.9 Hz, 1H) 11.52 ( s, 1H), 12.4 (wide s, 1H). IC50 = 4 nM

(b) {2- [4-Chloro-3- (2,6-dichloro-benzyl sulfulfyl) -phenyl] -1H-indole-3-yl} -acetic acid

image 1

Step 1: By proceeding in a manner similar to Example 1 (a), step 4, but substituting 2,4-dichlorobenzylamine for 2,6-dichlorobenzylamine (2.82 g), 4- [4-chloro-3 acid] is prepared - (2,6-Dichloro-benzylsulfamoyl) -phenyl] -4-oxo-butyric acid as a powder (2.12 g). LCMS: TR = 2.1 minutes, MS: 448 (M-H).

Stage 2: Proceeding in a manner similar to Example 1 (a), stage 5, but

20 replacing 4- [4-Chloro-3- (2,4-dichloro-benzyl sulfulfyl) -phenyl] -4-oxo-butyric acid with 4- [4-chloro-3- (2,6-dichloro-benzyl sulfulfyl) acid -phenyl] -4-oxo-butyric acid (0.8 g), {2- [4-chloro-3- (2,4-dichloro-benzylsulfamoyl) -phenyl] -1H-indole-3-yl} acid is prepared -acetic acid in the form of a solid (80 mg). LCMS: TR = 2.72 minutes, MS: 523 (M + H); 1H NMR (300 MHz, DMSO-D6) � 3.75 (s, 2H) 4.36 (d, 2H, J = 5.2 Hz), 7.06 (t, J = 7 Hz, 1H) 7, 1-7.45 (m,

25 5H) 7.73 (d, J = 8.5Hz, 1H) 7.57 (d, J = 8Hz, 1H) 7.88 (dd, J = 6Hz, J = 2.2Hz, 1H) 8.25 (d, J = 2 Hz, 1H) 8.33 (t, J = 5 Hz, 1H) 11.5 (s, 1H), 12.4 (wide s, 1H). IC50 = 3 nM

(c) {2- [4-Chloro-3- (3,5-dichloro-benzyl sulfulfyl) -phenyl] -1H-indole-3-yl} -acetic acid

image 1

Step 1: By proceeding in a manner similar to Example 1 (a), step 4, but substituting 2,4-dichlorobenzylamine with 3,5-dichlorobenzylamine (2.82 g), 4- 4- [4-chloro-3 acid is prepared. - (3,5-Dichloro-benzylsulfamoyl) -phenyl] -4-oxo-butyric acid as a solid (2.12 g). LCMS: TR = 2.42 minutes, MS: 450 (M + H).

Step 2: Proceeding in a manner similar to Example 1 (a) method A, step 5, but substituting 4- [4-chloro-3- (2,4-dichloro-benzyl sulfulfyl) -phenyl] -4-oxo-butyric acid by 4- [4-Chloro-3- (3,5-dichloro-benzyl sulfamoyl) -phenyl] -4-oxo-butyric acid (0.8 g), {2- [4-chloro-3- acid] is prepared (3,5-Dichloro-benzyl sulfamoyl) -phenyl] -1H-indole-3-yl} -acetic acid as a solid (160 mg). LCMS: TR = 2.78 minutes, MS: 523 (M + H). 1H NMR (300 MHz, DMSO-D6) � 3.72 (s, 2H) 4.19 (d, J = 6.2 Hz, 2H), 7.06 (t, J = 7 Hz, 1H) 7, 1-7.45 (m, 5H) 7.57 (d, J = 8 Hz, 1H) 7.71 (d, J = 8.2 Hz, 1H) 7.85 (dd, J = 6.2 Hz , J = 2.2 Hz, 1H) 8.19 (d, J = 2.2 Hz, 1H) 8.65 (t, J = 6.4 Hz, 1H) 11.5 (s, 1H), 12 , 4 (s wide, 1H). IC50 =

15 12nM

(d) (2- {4-Chloro-3- [2- (2,4-dichloro-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) acetic acid

image 1

Stage 1: Proceeding in a manner similar to Example 1 (a), stage 4, but

By replacing 2,4-dichlorobenzylamine with 2,4-dichlorophenethylamine (3.04 g), 4- {4-chloro-3- [2- (2,4-dichloro-phenyl) -ethylsulfamoyl] -phenyl} acid is prepared -4-oxo-butyric in the form of a solid (2.3 g). LCMS: TR = 2.52 minutes, MS: 464 (M + H).

Step 2: Proceeding in a manner similar to Example 1 (a) method A, step 5, but substituting 4- [4-chloro-3- (2,4-dichloro-benzyl sulfulfyl) -phenyl] -4-oxo-butyric acid by 4- {4-chloro-3- [2- (2,4-dichloro-phenyl) -ethylsulfamoyl] -phenyl} -4-oxo-butyric acid (0.83 g), acid (2- {4 -chloro-3- [2- (2,4-dichloro-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) acetic acid (150 mg). LCMS: TR = 2.64 minutes, MS: 537 (M + H). 1H NMR (300 MHz, DMSO-D6) � 2.81 (t, J = 7 Hz, 2H) 3.2 (m, 2H) 3.75 (s, 2H), 7.06 (t, J = 7 , 2 Hz, 1H) 7.16 (t, J = 7.3 Hz, 1H) 7.29 (s, 2H) 7.43 (m, 2H) 7.56 (d, J = 7.7 Hz, 1H) 7.74 (d, J = 8.2 Hz, 1H) 7.9 (dd, J = 6.3 Hz, J = 2.2 Hz, 1H) 8.13 (t, J = 5.7 Hz, 1H) 8.23 (d, J = 2.2 Hz, 1H) 11.52 (s, 1H), 12.4 (wide s, 1H). IC50 = 2 nM

Example 2:

(a) (2- {4-Chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid

image 1

Step 1. A mixture of 2-chloronitrobenzene (53 g, 0.34 mol), iron (1.5 g) and bromine (23 ml, 0.45 mol) is stirred at reflux temperature in an atmosphere of N2 for 20 hours The reaction is concentrated and the residue is purified by flash chromatography on silica gel eluting with 10% EtOAc -heptane. The appropriate fractions are

They are concentrated, filtered, washed with ethanol and dried. The solid is recrystallized from ethanol to obtain 5-bromo-2-chloronitrobenzene (37.9 g). After storage of the mother liquor at 0 ° C overnight, a second product culture is isolated and dried to obtain more 5-bromo-2-chloronitrobenzene (7 g). MS: 235 (M + H); P. f. 65-67 ° C. Step 2. A solution of 5-bromo-2-chloronitrobenzene (10.3 g,

43.6 mmol) in EtOAc (200 ml) is hydrogenated on Raney nickel (6 g of a 50% solution in H2O) at 379.21 kPa (55 psi) of H2 for 5 hours. The mixture is filtered through a bed of Celite and rinsed with EtOAc. The filtrate is treated with ether HCl (60 ml, 1 M solution in Et2O) under an N2 atmosphere. The resulting suspension is stirred for 1 hour and Et2O (100-200 ml) is added. The mixture is filtered to obtain

5-Bromo-2-chloroaniline hydrochloride (4.85 g) as a solid. MS: 205 (M + H);

P. f. 152-155 ° C.

Step 3. A suspension of 5-bromo-2-chloroaniline hydrochloride (41.4 g, 0.17 mol) in CH3CN (380 ml) is cooled to 5 ° C and concentrated HCl (277 ml) is added for 10 minutes. The suspension is cooled to -5 ° C and a solution of NaNO2 (14.2 g, 0.21 mol) in H2O (40 ml) is added dropwise over 10-15 minutes. The mixture is stirred for a further 5 minutes and 30% SO2 (w / w) in HOAc (435 ml) is added at 0 ° C, followed by the addition of a solution of copper (II) chloride dihydrate (15.3 g, 0.09 mol) in H2O (40 ml). The reaction is stirred at room temperature for 1.5 hours. The reaction mixture is filtered and the solid is dried to obtain 5-bromo-2-chlorobenzenesulfonyl chloride (18.4 g). The filtrate is maintained at 0 ° C for 18 hours. The precipitate is collected and dried to obtain more 5-bromo-2-chlorobenzenesulfonyl chloride (9.6 g). MS: 288 (M + H).

Step 4. 5-Bromo-2-chlorobenzenesulfonyl chloride (2 g, 6.9 mmol) is slowly added to a solution of 2- (2-methoxy-phenyl) -ethylamine (1.6 g, 10.74 mmol) and DIEA (2.3 g, 17.8 mmol) in DCM: MeOH mixture (1: 1, 50 mL) at 0 ° C. The resulting mixture is heated to room temperature and stirred for 20 hours. The reaction mixture is acidified with 2N aqueous HCl (~ 25 ml) and extracted twice with DCM (~ 50 ml). The organic layer is washed with water and brine, dried over sodium sulfate and evaporated in vacuo to yield 5-bromo-2-chloro-N- [2- (2-methoxy-phenyl) -ethyl] -benzenesulfonamide (2, 23g) in the form of a white powder. LCMS: RT = 2.78 minutes, MS: 403 (M + H).

Step 5. To a solution of 1- (tert-butoxycarbonyl) -5-methoxy-1H-indole-2-ylboronic acid (2.2 g, 7.5 mmol), 5-bromo-2-chloro-N- [ 2- (2-Methoxy-phenyl) -ethyl] -benzenesulfonamide (2 g, 5 mmol) and CsF (1.14 g, 7.5 mmol) in dioxane-H2O (100 mL, 9: 1) PdCl2 is added (dppf) 2 (400 mg) at room temperature in an N2 atmosphere. The reaction is heated to 80 ° C and stirred for 2 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc and filtered through a short column of silica. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography on silica gel eluting with 3% to 30% EtOAc in heptane to give 2- {4-chloro-3- [2- (tert-butyl ester) 2-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -indole-1-carboxylic acid (1.9 g). LCMS: TR = 3.4 minutes, MS: 541 (M + H).

Step 6. A mixture of 2- {4-chloro-3- [2- (2-methoxy-phenyl) ethylsulfamoyl] -phenyl} -indole-1-carboxylic acid tert-butyl ester (1.2 g, 2, 2 mmol) and TFA: DCM (1: 1, 20 ml) is stirred at room temperature for 3 hours and concentrated in vacuo. The residue is dissolved in EtOAc and washed with saturated aqueous NaHCO3, water and brine. The organic layer is separated, dried over Na2SO4 and concentrated. The residue is purified by flash chromatography on silica gel eluting with 5% to 40% EtOAc in heptane to yield 2-chloro-5- (1H-indole-2-yl) -N- [2- (2-methoxy- phenyl) -ethyl] benzenesulfonamide in the form of a powder (980 mg). LCMS: TR = 3 minutes, MS: 441 (M + H).

Step 7. Oxalyl chloride (2M in DCM, 2 ml) is slowly added to a solution of 2-chloro-5- (1H-indole-2-yl) -N- [2- (2-methoxy-phenyl) -ethyl] -benzenesulfonamide (600 mg, 1.36 mmol) in DCM (15 ml) at 0 ° C. The reaction mixture is allowed to warm to room temperature. After stirring for 3 hours, MeOH (5 mL) is added and stirred for another 10 minutes. The mixture is concentrated. The residue is purified by flash chromatography on silica gel eluting with 10% to 50% EtOAc in heptane to produce (2- {4-chloro-3- [2- (2-methoxy-phenyl) ethyl sulfulfyl] methyl ester] -phenyl} -1H-indole-3-yl) -oxo-acetic acid in the form of a semi-solid (540 mg). LCMS: TR = 2.72 minutes, MS: 527 (M + H).

Step 8. Triethylsilane (0.5 ml) is slowly added to a solution of methyl ester of the acid (2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H- indole-3-yl) -oxo-acetic acid (500 mg; 0.95 mmol) in TFA (5 ml) at room temperature. After stirring for 16 h, the reaction mixture is concentrated in vacuo. The residue is purified by flash chromatography on silica gel eluting with 10% to 40% EtOAc in heptane to yield (2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl acid methyl ester] ] -phenyl} -1Hindole-3-yl) -acetic acid in the form of a semi-solid (440 mg). LCMS: TR = 2.88 minutes, MS: 513 (M + H); 1H NMR (300 MHz, CDCl3) � 2.81 (t, J = 6.8 Hz, 2H), 3.23 (q, J = 12.6 Hz, J = 6.6 Hz, 2H), 3, 72 (s, 3H), 3.73 (s, 3H), 3.81 (s, 2H), 5.24 (t, J = 5.7 Hz, 1H), 6.82 (m, 2H), 7.02 (d, J = 7.3 Hz, 1H), 7.2 (m, 3H), 7.4 (d, J = 7.9 Hz, 1H), 7.5 3 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.86 (dd, J = 6.1 Hz, 2.2 Hz, 1H), 8.3 (d , J = 2.2 Hz, 1H), 8.5 (s, 1H).

Step 9. To a mixture of (2- {4-chloro-3- [2- (2-methoxy-phenyl) ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid methyl ester (400 mg , 0.8 mmol) in MeOH / H2O (2: 1, 20 ml), lithium hydroxide monohydrate (200 mg, 4.8 mmol) is added. The reaction mixture is stirred at 80 ° C for 3 h and concentrated. The residue is acidified with 2N aqueous HCl (pH ~ 2) and extracted twice with ethyl acetate. The combined organic layer is washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue is purified by flash chromatography on silica gel eluting with 20% to 60% EtOAc in heptane to yield (2- {4-chloro-3- [2- (2-methoxy-phenyl) ethyl sulfulfyl] -phenyl} -1H-indole-3-yl) -acetic acid in the form of a powder (310 mg). LCMS: TR = 2.57 minutes, MS: 497 (M-H); 1H NMR (300 MHz, DMSO-D6) � 2.67 (t, J = 8 Hz, 2H), 3.1 (m, 2H), 3.62 (s, 3H), 3.75 (s, 2H ), 6.82 (m, 2H), 7.02-7.2 (m, 4H), 7.41 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 7, 9 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.91 (dd, J = 6.3 Hz, 2.2 Hz, 1H), 8.01 (t, J = 5.7 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 11.55 (s, 1H), 12.42 (s, 1H). IC50 = 3.8 nM

(b) (2- {4-Chloro-3- [2- (3-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) acetic acid

image 1

Step 1. By proceeding in a manner similar to Example 2 (a), step 4, but substituting 2- (3-methoxy-phenyl) -ethylamine for 2- (3-methoxy-phenyl) -ethylamine, 5-bromo-2- is prepared chloro-N- [2- (3-methoxy-phenyl) -ethyl] -benzenesulfonamide in the form of a solid

10 (2.2 g). LCMS: TR = 2.71 minutes, MS: 402 (M-H).

Step 2: Proceeding in a manner similar to Example 2 (a), step 5, but substituting 5-bromo-2-chloro-N- [2- (2-methoxy-phenyl) -ethyl] -benzenesulfonamide with 5-bromo-2- Chloro-N- [2- (3-methoxy-phenyl) -ethyl] -benzenesulfonamide, 2- {4-chloro-3- [2- (3-methoxy-phenyl) -ethylsulfamoyl] -phenyl acid tert-butyl ester is prepared } -indole-1-carboxylic

15 in the form of an oil (1.69 g). LCMS: TR = 3.34 minutes, MS: 541 (M + H).

Step 3: Proceeding in a manner similar to Example 2 (a), step 6, but substituting 2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} tert-butyl ester -indole-1-carboxylic acid by 2- {4-chloro-3- [2- (3-methoxy-phenyl) ethylsulfamoyl] -phenyl} -indole-1-carboxylic acid tert-butyl ester, 2-chloro- 5- (1H-indole-2-yl) -N- [2- (3

Methoxy-phenyl) -ethyl] -benzenesulfonamide in the form of a solid (960 mg). LCMS: TR = 2.92 minutes, MS: 441 (M + H).

Step 4: Proceeding in a manner similar to Example 2 (a), step 7, but substituting 2-chloro-5- (1H-indole-2-yl) -N- [2- (2-methoxy-phenyl) -ethyl ] -Benzenesulfonamide by 2-Chloro-5- (1H-indole-2-yl) -N- [2- (3-methoxy-phenyl) -ethyl] -benzenesulfonamide, is prepared

25 (2- {4-Chloro-3- [2- (3-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3yl) -oxo-acetic acid methyl ester in the form of a semi-solid ( 551 mg). LCMS: TR = 2.66 minutes, MS: 527 (M + H).

Step 5: Proceeding in a manner similar to Example 2 (a), step 8, but substituting (2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} - methyl ester) - 1H-indole-3-yl) -oxo-acetic acid methyl ester (2- {4-chloro-3- [2- (3-methoxyphenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -oxo-acetic acid (2- {4-chloro-3- [2- (3-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid methyl ester is prepared (450 mg) LCMS: TR = 2.82 minutes, MS: 513 (M + H). 1 H NMR (300 MHz, CDCl 3) � 2.78 (t, J = 6.8

5 Hz, 2H), 3.27 (c, J = 13 Hz, J = 6.6 Hz, 2H), 3.73 (s, 3H), 3.75 (s, 3H), 3.81 (s , 2H), 5.07 (t, J = 6 Hz, 1H), 6.7 (m, 3H), 7.2 (m, 3H), 7.4 (d, J = 8.1 Hz, 1H ), 7.55 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 6.1 Hz, 2.2 Hz, 1H), 8.3 (d, J = 2.2 Hz, 1H), 8.47 (s, 1H).

Stage 6: Proceeding in a manner similar to Example 2 (a), stage 9, but

10 substituting (2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} -1H-indole-3-yl) -acetic acid by methyl ester of the acid (2- {4-Chloro-3- [2- (3-methoxy-phenyl) ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid (2- {4-chloro-3- [2- (3-Methoxyphenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid as a solid (320 mg). LCMS: TR = 2.5 minutes, MS: 497 (M-H). 1 H NMR (300 MHz, DMSO-D6) � 2.69 (t, J = 7.2 Hz,

15 2H), 3.18 (m, 2H), 3.67 (s, 3H), 3.75 (s, 2H), 6.7 (t, J = 6.5 Hz, 3H), 7.12 (m, 3H), 7.41 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 8.2 Hz , 1H), 7.9 (dd, J = 6.2 Hz, 2.1 Hz, 1H), 8.04 (wide t, 1H), 8.25 (d, J = 2.1 Hz, 1H) , 11.55 (s, 1H), 12.45 (wide s, 1H). IC50 = 3.3 nM

(c) (2- {4-Chloro-3- [2- (4-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid

image 1

Step 1. By proceeding in a manner similar to Example 2 (a), step 4, but substituting 2- (4-methoxy-phenyl) -ethylamine for 2- (4-methoxy-phenyl) -ethylamine, 5-bromo-2 is prepared -chloro-N- [2- (4-methoxy-phenyl) -ethyl] -benzenesulfonamide in the form of a semi-solid (2.3 g). LCMS: TR = 2.71 minutes, MS: 402 (M-H).

Step 2: Proceeding in a manner similar to Example 2 (a), step 5, but substituting 5-bromo-2-chloro-N- [2- (2-methoxy-phenyl) -ethyl] -benzenesulfonamide with 5-bromo-2 -chloro-N- [2- (4-methoxy-phenyl) -ethyl] -benzenesulfonamide, 2- {4-chloro-3- [2- (4-methoxy-phenyl) -ethylsulfamoyl] - tert-butyl ester is prepared phenyl} -indole-1-carboxylic acid in the form of an oil (1.87 g). LCMS: TR = 3.33 minutes, MS: 541 (M + H).

Step 3: Proceeding in a manner similar to Example 2 (a), step 6, but substituting 2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} tert-butyl ester -indole-1-carboxylic acid by 2- {4-chloro-3- [2- (4-methoxy-phenyl) ethylsulfamoyl] -phenyl} -indole-1-carboxylic acid tert-butyl ester, 2-chloro- 5- (1H-indole-2-yl) -N- [2- (4-methoxy-phenyl) -ethyl] -benzenesulfonamide as a solid (950 mg). LCMS: TR = 2.91 minutes, MS: 441 (M + H).

Step 4: Proceeding in a manner similar to Example 2 (a), step 7, but substituting 2-chloro-5- (1H-indole-2-yl) -N- [2- (2-methoxy-phenyl) -ethyl ] -benzenesulfonamide by 2-chloro-5- (1H-indol-2-yl) -N- [2- (4-methoxy-phenyl) -ethyl] -benzenesulfonamide, methyl ester of the acid (2- {4- Chloro-3- [2- (4-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3yl) -oxo-acetic acid in the form of a semi-solid (552 mg). LCMS: TR = 2.66 minutes, MS: 527 (M + H).

Step 5: Proceeding in a manner similar to Example 2 (a), step 8, but substituting (2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} - methyl ester) - 1H-indole-3-yl) -oxo-acetic acid methyl ester of (2- {4-chloro-3- [2- (4-methoxyphenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -oxo-acetic acid (2- {4-chloro-3- [2- (4-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid methyl ester (445 mg) LCMS: TR = 2.81 minutes, MS: 513 (M + H); 1H NMR (300 MHz, CDCl3) � 2.76 (t, J = 6.6 Hz, 2H), 3.23 (m, 2H), 3.73 (s, 2H), 3.77 (s, 3H ), 3.82 (s, 2H), 5 (t, J = 6.1 Hz, 1H), 6.78 (dd, J = 5 Hz, 2 Hz, 2H), 7.02 (dd, J = 6.6 Hz, 2 Hz, 2H), 7.26 (m, 3H), 7.41 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H ), 7.69 (d, J = 7.9 Hz, 1H), 7.88 (dd, J = 6.0 Hz, 2.2 Hz, 1H), 8.3 (d, J = 2.2 Hz, 1H), 8.33 (s, 1H).

Step 6: Proceeding in a manner similar to Example 2 (a), step 9, but substituting (2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} - methyl ester) - 1H-indole-3-yl) -acetic acid (2- {4-chloro-3- [2- (4-methoxy-phenyl) ethylsulfamoyl] -phenyl} -1H-indole-3-yl) - acetic acid (2- {4-chloro-3- [2- (4-methoxyphenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid is prepared as a solid (295 mg). LCMS: TR = 2.51 minutes, MS: 497 (M-H). 1H NMR (300 MHz, DMSO-D6) � 2.64 (t, J = 7.4 Hz, 2H), 3.11 (m, 2H), 3.67 (s, 3H), 3.75 (s , 2H), 6.75 (d, J = 8.6 Hz, 2H), 7.05 (m, 3H), 7.17 (t, J = 7.3 Hz, 1H), 7.41 (d , J = 8.1 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.9 (dd, J = 6.3 Hz, 2 Hz, 1H), 8.01 (wide s, 1H), 8.23 (d, J = 2 Hz, 1H), 11.54 (s, 1H), 12.42 (s wide, 1H). IC50 = 3 nM

(d) (2- {4-Chloro-3- [2- (2-trifluoromethoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3yl) -acetic acid

image 1

Step 1. Proceeding in a manner similar to Example 2 (a), step 4, but substituting 2- (2-methoxy-phenyl) -ethylamine for 2- (2-trifluoromethoxy-phenyl) -ethylamine (2.2 g), 5-Bromo-2-chloro-N- [2- (2-trifluoromethoxy-phenyl) -ethyl] -benzenesulfonamide is prepared as a solid (2.4 g). LCMS: RT = 2.96 minutes, MS: 455.9 (M-H).

Step 2: Proceeding in a manner similar to Example 2 (a), step 5, but substituting 5-bromo-2-chloro-N- [2- (2-methoxy-phenyl) -ethyl] -benzenesulfonamide with 5-bromo-2- chloro-N- [2- (2-trifluoromethoxy-phenyl) -ethyl] -benzenesulfonamide (2.3 g), 2- {4-chloro-3- [2- (2-trifluoromethoxy acid) tert-butyl ester is prepared -phenyl) ethylsulfamoyl] -phenyl} -indole-1-carboxylic acid in the form of a solid (2.05 g). LCMS: TR = 3.49 minutes, MS: 595 (M + H).

Step 3: Proceeding in a manner similar to Example 2 (a), step 6, but substituting 2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} tert-butyl ester -indole-1-carboxylic acid by 2- {4-chloro-3- [2- (2-trifluoromethoxy-phenyl) -ethylsulfamoyl] -phenyl} -indole-1-carboxylic acid tert-butyl ester, 2-chloro-5 is prepared - (1 Hindol-2-yl) -N- [2- (2-trifluoromethoxy-phenyl) -ethyl] -benzenesulfonamide in the form of a powder (985 mg). LCMS: TR = 3.1 minutes, MS: 493 (M-H).

Step 4: Proceeding in a manner similar to Example 2 (a), step 7, but substituting 2-chloro-5- (1H-indole-2-yl) -N- [2- (2-methoxy-phenyl) -ethyl ] -Benzenesulfonamide by 2-Chloro-5- (1H-indole-2-yl) -N- [2- (2-trifluoromethoxy-phenyl) -ethyl] -benzenesulfonamide, methyl ester of the acid (2- {4- Chloro-3- [2- (2-trifluoromethoxy-phenyl) -ethylsulfamoyl] phenyl} -1H-indole-3-yl) -oxo-acetic acid as a solid (575 mg). LCMS: TR = 2.84 minutes, MS: 581 (M + H).

Step 5: Proceeding in a manner similar to Example 2 (a), step 8, but substituting (2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} - methyl ester) - 1H-indole-3-yl) -oxo-acetic acid methyl ester (2- {4-chloro-3- [2- (2-trifluoromethoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -oxo-acetic acid (2- {4-chloro-3- [2- (2-trifluoromethoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3yl) -acetic acid methyl ester is prepared in the form of a powder (470 mg). LCMS: TR = 3 minutes, MS: 567 (M + H). 1H NMR (300 MHz, CDCl3) � 2.91 (t, J = 7 Hz, 2H), 3.27 (c, J = 13.4 Hz, J = 6.8 Hz, 2H), 3.73 ( s, 3H), 3.81 (s, 2H), 5.07 (t, J = 6 Hz, 1H), 7.25 (m, 6H), 7.41 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.7 (d, J = 7.59 Hz, 1H), 7.91 (dd, J = 6.1, 2.2 Hz, 1H), 8.28 (s, 1H), 8.33 (d, J = 2.2 Hz, 1H).

Stage 6: Proceeding in a manner similar to Example 2 (a), stage 9, but

5 substituting (2- {4-Chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} -1H-indole-3-yl) -acetic acid by methyl ester of the acid (2- {4-Chloro-3- [2- (2trifluoromethoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid (2- {4-chloro-3- [2- (2- trifluoromethoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid in the form of a powder (340 mg). LCMS: TR = 2.69 minutes, MS: 551 (M-H). 1 H NMR (300 MHz,

10 DMSO-D6) � 2.8 (t, J = 7 Hz, 2H), 3.17 (c, J = 13.4 Hz, J = 6.4 Hz, 2H), 3.74 (s, 2H ), 7.06 (t, J = 7.5 Hz, 1H), 7.17-7.35 (m, 5H), 7.41 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2.1 Hz, 1H), 7.91 (dd, J = 6.2 Hz, 2.1 Hz, 1H), 8.17 (t, J = 5.6 Hz, 1H), 8.24 (d, J = 2 Hz, 1H), 11.57 (s, 1H), 12.42 (wide s , 1 HOUR). IC50 = 20 nM

(e) [2- (4-Chloro-3-phenethylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid

image 1

Step 1. By proceeding in a manner similar to Example 2 (a), step 4, but substituting 2- (2-methoxy-phenyl) -ethylamine for phenethylamine (1.3 g), 5-bromo2-chloro-N is prepared -phenethyl benzenesulfonamide (2.1 g) as a solid. LCMS: TR = 2.71 minutes, MS: 402 (M-H).

Step 2: Proceeding in a manner similar to Example 2 (a), step 5, but substituting 5-bromo-2-chloro-N- [2- (2-methoxy-phenyl) -ethyl] -benzenesulfonamide with 5-bromo-2 -chloro-N-phenethyl-benzenesulfonamide (1.9 g), 2- (4-chloro-3-phenethylsulfamoyl-phenyl) -indole-1-carboxylic acid tert-butyl ester (1.69 g) is prepared. LCMS: TR = 3.38 minutes, MS: 511 (M + H).

Step 3: Proceeding in a manner similar to Example 2 (a), step 6, but substituting 2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl tert-butyl ester } -indole-1-carboxylic acid by 2- (4-chloro-3-phenethylsulfamoylphenyl) -indole-1-carboxylic acid tert-butyl ester, 2-chloro-5- (1H-indole-2-yl) is prepared - N-phenethylbenzenesulfonamide in the form of a solid (900 mg). LCMS: TR = 2.96 minutes, MS: 411 (M + H).

Step 4: Proceeding in a manner similar to Example 2 (a), step 7, but substituting 2-chloro-5- (1H-indole-2-yl) -N- [2- (2-methoxy-phenyl) -ethyl ] -benzenesulfonamide by

5 2-Chloro-5- (1H-indole-2-yl) -N-phenethyl-benzenesulfonamide, [2- (4-chloro-3-phenethylsulfamoyl-phenyl) -1H-indole-3- methyl ester is prepared il] -oxo-acetic in the form of a semi-solid (542 mg). LCMS: TR = 2.68 minutes, MS: 497 (M + H).

Step 5: Proceeding in a manner similar to Example 2 (a), step 8, but substituting (2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] 10-phenyl} methyl ester -1H-indole-3-yl) -oxo-acetic acid methyl ester of [2- (4-chloro-3-phenethylsulfamoyl-phenyl) -1H-indole-3-yl] -oxo-acetic acid methyl ester of the acid is prepared [2 (4-Chloro-3-phenethylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid as a solid (410 mg). LCMS: TR = 2.84 minutes, MS: 483 (M + H); 1H NMR (300 MHz, DMSO-D6) � 2.72 (t, J = 7.5 Hz, 2H), 3.15 (q, J = 13.4 Hz, J = 6.5 Hz, 2H), 3.61 (s, 3H), 3.86 (s, 2H), 7.18 (m,

15 7H), 7.41 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H ), 7.87 (dd, J = 6.2 Hz, 2 Hz, 1H), 8.08 (t, 5.5 Hz, 1H), 8.2 (d, J = 2 Hz, 1H), 11 .6 (1H, s).

Step 6: Proceeding in a manner similar to Example 2 (a), step 9, but substituting (2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} - methyl ester) - 1H-indole-3-yl) -acetic acid by [2- (4-chloro-3-phenethylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid methyl ester, [2- (4-chloro] acid is prepared -3-phenethylsulfamoyl-phenyl) -1 Hindol-3-yl] -acetic acid (280 mg). LCMS: TR = 2.53 minutes, MS: 467 (M-H); 1H NMR (300 MHz, DMSO-D6) � 2.72 (t, J = 7.4 Hz, 2H), 3.15 (m, 2H), 3.75 (s, 2H), 7.15 (m , 7H), 7.41 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H ), 7.89 (dd, J = 6.3 Hz, 2 Hz, 1H), 8.06 (t, 5.7 Hz, 1H), 8.24 (d, J = 2 Hz, 1H), 11 , 55 (s, 1H), 12.45 (s

25 wide, 1H).

(f) {2- [4-Chloro-3- (3-phenyl-propylsulfamoyl) -phenyl] -1H-indole-3-yl} -acetic acid

image 1

Step 1. By proceeding in a manner similar to Example 1, step 4, but substituting 2- (2-methoxy-phenyl) -ethylamine for 3-phenyl-propylamine (1.4 g), 5-bromo-2-chloro is prepared

N- (3-phenyl-propyl) -benzenesulfonamide (2 g) in the form of a semi-solid. LCMS: TR = 2.86 minutes, MS: 386 (M-H).

Step 2: Proceeding in a manner similar to Example 2 (a), step 5, but substituting 5-bromo-2-chloro-N- [2- (2-methoxy-phenyl) -ethyl] -benzenesulfonamide with bromo-2- Chloro-N- (3-phenyl-propyl) -benzenesulfonamide (1.9 g), 2- [4-chloro-3- (3-phenyl-propylsulfamoyl) -phenyl] -indole-1- tert-butyl ester is prepared carboxylic in the form of a solid (1.73 g). LCMS: TR = 3.43 minutes, MS: 525 (M + H).

Step 3: Proceeding in a manner similar to Example 2 (a), step 6, but substituting 2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} tert-butyl ester -indole-1-carboxylic acid by 2- [4-chloro-3- (3-phenylpropylsulfamoyl) -phenyl] -indole-1-carboxylic acid tert-butyl ester, 2-chloro-5- (1H-indole) is prepared 2-yl) -N- (3-phenylpropyl) -benzenesulfonamide in the form of a powder (950 mg). LCMS: TR = 3.03 minutes, MS: 425 (M + H).

Step 4: Proceeding in a manner similar to Example 2 (a), step 7, but substituting 2-chloro-5- (1H-indole-2-yl) -N- [2- (2-methoxy-phenyl) -ethyl ] -benzenesulfonamide by 2-chloro-5- (1H-indol-2-yl) -N- (3-phenyl-propyl) -benzenesulfonamide, {2- [4-chloro-3- (3-methyl acid ester) is prepared -phenyl-propylsulfamoyl) -phenyl] -1H-indole-3-yl} -oxo-acetic acid in the form of a semi-solid (540 mg). LCMS: TR = 2.76 minutes, MS: 511 (M + H).

Step 5: Proceeding in a manner similar to Example 2 (a), step 8, but substituting (2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} - methyl ester) - 1H-indole-3-yl) -oxo-acetic acid by {2- [4-chloro-3- (3-phenylpropylsulfamoyl) -phenyl] -1H-indole-3-yl} -oxo-acetic acid methyl ester, se Prepare {2 [4-chloro-3- (3-phenyl-propylsulfamoyl) -phenyl] -1H-indole-3-yl} -acetic acid methyl ester (430 mg). LCMS: RT = 2.92 minutes, MS: 497 (M + H); 1H NMR (300 MHz, CDCl3) � 1.82 (m, 2H), 2.62 (t, J = 7.5 Hz, 2H), 3 (m, 2H), 3.72 (s, 3H), 3.8 (s, 2H), 5.13 (t, J = 6 Hz, 1H), 7.07 - 7.28 (m, 7H), 7.39 (d, J = 8.1 Hz, 1H ), 7.6 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.89 (dd, J = 6.1 Hz, 2.2 Hz, 1H), 8.08 (t, 5.5 Hz, 1H), 8.31 (d, J = 2 Hz, 1H).

Step 6: Proceeding in a manner similar to Example 2 (a), step 9, but substituting (2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] phenyl} - methyl ester) - 1H-indole-3-yl) -acetic acid by {2- [4-chloro-3- (3-phenylpropylsulfamoyl) -phenyl] -1H-indole-3-yl} -acetic acid methyl ester is prepared {2 - [4-Chloro-3- (3-phenylpropylsulfamoyl) -phenyl] -1H-indole-3-yl} -acetic acid in the form of a powder (300 mg). LCMS: TR = 2.61 minutes, MS: 481 (M-H); 1H NMR (300 MHz, DMSO-D6) � 1.67 (m, 2H), 2.5 (m, 2H, located under DMSO peak), 2.93 (m, 2H), 3.73 (s, 2H), 7 - 7.3 (m, 7H), 7.41 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.83 ( d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 8.04 (apparent s, 1H), 8.26 (s, 1H), 11.6 (s, 1H), 12.45 (wide s, 1H). IC50 = 7 nM

Example 3: 2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -N-methyl-acetamide

image 1

Step 1. 5-Bromo-2-chlorobenzenesulfonyl chloride (4 g, 13.8 mmol) is slowly added to a solution of cyclohexylamine (3.5 g, 35 mmol) in DCM: MeOH mixture (1: 1, 100 mL) at 0 ° C. The resulting mixture is heated to room temperature and stirred for 20 hours. The reaction mixture is acidified with 2N aqueous HCl (~ 100 ml) and extracted twice with DCM (~ 150 ml). The organic layer is washed with water (~ 100 ml) and brine (~ 50 ml), dried over sodium sulfate and evaporated in vacuo to yield 5-bromo-2-chloro-N-cyclohexyl-benzenesulfonamide (4.2 g ). LCMS: TR = 3 minutes, MS: 351 (M-H).

Step 2. To a solution of 1- (tert-butoxycarbonyl) -1H-indole-2-ylboronic acid (2.2 g),

5-Bromo-2-chloro-N-cyclohexyl-benzenesulfonamide (1.8 g) and CsF (1.4 g) in 1,4-dioxane H2O (60 ml, 10: 1) PdCl2 (dppf) 2 is added (375 mg) at room temperature in a nitrogen atmosphere. The reaction is heated to 80 ° C and stirred for 3 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc and filtered through a short column of silica. The filtrate is concentrated in vacuo and purified by

Flash column chromatography on silica gel eluting with 5% to 50% EtOAc in heptane to produce 2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -indole-1-carboxylic acid tert-butyl ester (1.9 g ). LCMS: TR = 3.31 minutes, MS: 489 (M + H).

Step 3. A mixture of trifluoacetic acid (10 ml) and dichloromethane (10 ml) is added to

2- 2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -indole-1-carboxylic acid tert-butyl ester (1.9 g). The reaction mixture is stirred at room temperature for 2 hours. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc and washed with saturated aqueous NaHCO3, water and brine. The organic layer is separated, dried over sodium sulfate and concentrated to produce 2-chloro-N-cyclohexyl-5- (5-methoxy-1H-indole-2-yl) benzenesulfonamide (1.4 g). LCMS: TR = 3.17 minutes, MS: 389 (M + H).

Step 4: Oxalyl chloride (1.7 ml of a 2M solution in dichloromethane) is slowly added to a solution of 2-chloro-N-cyclohexyl-5- (1H-indole-2-yl) benzenesulfonamide (300 mg, 0.77 mmol) in DCM (6 ml) at 0 ° C. The reaction mixture is allowed to warm to room temperature and stirred for 3 h. Methylamine in THF (7 ml of a 2M solution) is added and stirred for 15 minutes. The mixture is concentrated and the residue is chromatographed on silica gel eluting with 30-70% EtOAc / heptane to yield 2- [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1Hindole-3-yl] -N -methyl-2-oxo-acetamide in the form of a powder (285 mg). LCMS: TR = 2.22 minutes, MS: 474 (M + H); 1H NMR (300 MHz, DMSO-D6) � 0.9 - 1.7 (m series, 10 H), 2.36 (d, J = 4.7 Hz, 3H), 3.02 (m, 1H ), 7.3 (m, 2H), 7.52 (d, J = 8 Hz, 1H), 7.76 (m, 2H), 7.99 (d, J = 8 Hz, 1H), 8, 06 (dd, J = 5 Hz, J = 1.8 Hz, 1H), 8.15 (d, J = 1.8 Hz, 1H), 8.49 (d, J = 4.8 Hz, 1H) , 12.65 (s, 1 H).

Step 5. Triethylsilane (1 ml) is slowly added to a solution of 2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -N-methyl-2-oxo-acetamide (150 mg; 0.32 mmol) in TFA (4 ml) at room temperature. After stirring for � 72 h, the reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc and washed with saturated aqueous NaHCO3 and water, dried over Na2SO4 and concentrated. The residue is purified by separation by preparative HPLC (mobile phase: acetonitrile-water with 0.1% TFA; 10-100% gradient for 10 minutes) to produce 2- [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -N-methyl-acetamide in the form of a semi-solid (110 mg). LCMS: TR = 2.6 minutes, MS: 460 (M + H); 1H NMR (300 MHz, DMSO-D6) � 0.9-1.7 (m, 10 H), 2.6 (d, J = 4.6 Hz, 3H), 3.04 (m, 1H), 3.6 (s, 2H), 7.03 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.4 (d, J = 8 Hz, 1H), 7.6 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 4.6 Hz, 1H), 8.14 (dd, J = 6 Hz, J = 2.2 Hz, 1H), 8.33 (d, J = 2 Hz , 1H), 11.5 (s, 1H). IC50 = 509 nM

Example 4: [4-Chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid

image 1

Method A:

Step 1. Di-tert-butyl dicarbonate (39.6 g) is added to a solution of 4-chloroindole (25 g) and 4- (dimethylamino) pyridine (2 g) in DCM (800 ml). The reaction is stirred at room temperature for 18 h. The reaction mixture is washed with 1 N HCl (150 ml) and 1 N NaHCO3 (150 ml). The organic layer is separated, dried over MgSO4 and concentrated. The crude product is recrystallized from heptane / ether to obtain the ester.

10-Chloro-indole-1-carboxylic acid tert-butyl (41.9 g). LCMS: TR = 3.34 minutes, MS: 251 (M + H).

Step 2. To a solution of 4-chloro-indole-1-carboxylic acid tert-butyl ester (10 g) in dry THF (50 ml) is added triisopropyl borate (13.7 ml) under an N2 atmosphere . The mixture is cooled to 0 ° C in an ice bath. Diisopropylamine of

15 lithium (33.8 ml, 2 M) for one hour at 0 ° C. The reaction is stirred at 0 ° C for 30 minutes. 2N HCl (80 ml) is added. The resulting mixture is extracted with EtOAc. The organic layer is dried, filtered and concentrated. The residue is recrystallized from acetonitrile / H2O to produce 1- (tert-butoxycarbonyl) -4-chloro-1H-indole-2-boronic acid as a solid (4.5 g).

Step 3. To a solution of 1- (tert-butoxycarbonyl) -4-chloro-1H-indole-2-ylboronic acid (4.27g, 14.45 mmol), 5-bromo-2-chloro-N-cyclohexyl -benzenesulfonamide (3 g, 8.5 mmol) and CsF (2.58 g, 17 mmol) in dioxane-H2O (85 mL, 10: 1) PdCl2 (dppf) 2 (694 mg, 0.85 mmol) is added ) at room temperature in an atmosphere of N2. The reaction is heated to 80 ° C and stirred for 2 hours. The reaction mixture is concentrated at

25 empty. The residue is dissolved in EtOAc and filtered through a short column of silica. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography on silica gel eluting with 5% to 50% EtOAc in heptane to yield 4-chloro-2- (4-chloro-3- acid tert-butyl ester). cyclohexylsulfamoyl-phenyl) -indole-carboxylic acid in the form of a solid (3.42 g). LCMS: TR = 3.5 minutes, MS: 523 (M + H).

Step 4. TFA (20 ml) is added to a solution of 4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -indole-1-carboxylic acid tert-butyl ester (3.42 g, 6.53 mmol) in DCM (40 ml). The reaction mixture is stirred at room temperature overnight. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated to yield 2-chloro-5- (4-chloro-1H-indole-2-yl) -N -cyclohexyl-benzenesulfonamide in the form of a solid (2.8 g). LCMS: TR = 3.04 minutes, MS: 423 (M + H).

Step 5: Ethylxalyl chloride (2.42 g, 17.8 mmol) is slowly added to a suspension of 2-chloro-N-cyclohexyl-5- (1H-indole-2-yl) -benzenesulfonamide (1.5 g , 3.54 mmol) in dichloroethane (150 ml) followed by AlCl3 (2.36 g, 17.8 mmol) at 0 ° C. The resulting dark brown solution is allowed to warm to room temperature and stirred for 16 h. MeOH (5 ml) is added to the reaction mixture at 0 ° C and diluted with DCM. The organic layer is washed with water and brine, dried over Na2SO4 and concentrated to produce [4-chloro-2- (4-chloro-3-cyclohexylsulfamoylphenyl) -1H-indole-3-yl] -oxo acid ethyl ester -acetic acid in the form of a solid (1.8 g). LCMS: TR = 2.87 minutes, MS: 523 (M + H). 1H NMR (300 MHz, DMSO-D6) � 0.8 - 1.7 (m series, 13H) 3.04 (m, 1H), 4.07 (c, J = 14.3 Hz, J = 7 , 2 Hz, 2H), 7.3 (m, 2H), 7.54 (dd, J = 4.2 Hz, 2.4 Hz, 1H), 7.83 (m, 2H), 8.04 ( d, J = 8.1 Hz, 1H), 8.17 (d, J = 2 Hz, 1H), 12.95 (s, 1H).

Step 6. [4-Chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) 1H-indole-3-yl] -oxo-acetic acid (1.8 g, 3.45 mmol) is stirred with triethylsilane (6 ml) and TFA (24 ml) at room temperature. After stirring for � 72 h, the reaction mixture is concentrated in vacuo. The residue is dissolved in DCM (~ 150 ml) and washed twice with water (~ 100 ml) and brine (~ 50 ml), dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography on silica gel eluting with 5% to 50% EtOAc in heptane to yield [4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3 ethyl ester -yl] -acetic acid in the form of a powder (1.45 g). LCMS: TR = 3.14 minutes, MS: 509 (M + H). 1H NMR (300 MHz, DMSO-D6) � 0.8 - 1.7 (m series, 13H) 3.03 (m, 1H) 3.96 (s, 2H), 4.14 (c, J = 14.2 Hz, J = 7.2 Hz, 2H), 7.07 (d, J = 7.5 Hz, 1H) 7.14 (t, J = 7.8 Hz, 1H) 7.4 (d , J = 8 Hz, 1H) 7.8 (m, 2H), 7.98 (d, J = 8.1 Hz, 1H) 8.14 (d, J = 2 Hz, 1H) 11.95 (s , 1 HOUR).

Step 7: A mixture of ethyl ester of [4-chloro-2- (4-chloro-3-cyclohexylsulfamoylphenyl) -1H-indole-3-yl] -acetic acid (1.45 g, 2.85 mmol) and hydroxide Lithium monohydrate (600 mg, 14.3 mmol) in MeOH / H2O (2: 1, 100 ml) is stirred at 80 ° C for 4 h. KOH (800 mg; 14.3 mmol) is added to the mixture and stirring is maintained at 80 ° C for 16 h. The reaction mixture is concentrated in vacuo. The residue is acidified with 2N aqueous HCl (pH ~ 2). The resulting white solids are collected by filtration, washed with Et2O and heptane and dried under vacuum for ~ 72 h to produce [4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3- il] -acetic acid in the form of a crystalline solid (1.1 g). LCMS: TR = 2.64 minutes, MS: 481 (M + H); 1H NMR (300 MHz, DMSO-D6) � 0.9 - 1.7 (m series, 10H), 3.05 (m, 1H), 3.88 (s, 2H), 7.06 (d, J = 7.4 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.8 (m, 2H) , 7.97 (d, J = 8.1 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 11.92 (s, 1H), 12.45 (wide s, 1H ). IC50 = 0.2 nM

Method B:

Step 1. Di-tert-butyl dicarbonate (39.6 g) is added to a solution of 4-chloroindole (25 g) and 4- (dimethylamino) pyridine (2 g) in DCM (800 ml). The reaction is stirred at room temperature for 18 h. The reaction mixture is washed with 1 N HCl (150 ml) and 1 N NaHCO3 (150 ml). The organic layer is separated, dried over MgSO4 and concentrated. The crude product is recrystallized from heptane / ether to obtain the 4-chloro-indole-1-carboxylic acid tert-butyl ester (41.9 g).

Step 2. To a solution of 4-chloro-indole-1-carboxylic acid tert-butyl ester (10 g) in dry THF (50 ml) is added triisopropyl borate (13.7 ml) under an N2 atmosphere . The mixture is cooled to 0 ° C in an ice bath. Lithium diisopropylamine (33.8 ml, 2 M) is added for one hour at 0 ° C. The reaction is stirred at 0 ° C for 30 minutes. 2N HCl (80 ml) is added. The resulting mixture is extracted with EtOAc. The organic layer is dried, filtered and concentrated. The residue is recrystallized from acetonitrile / H2O to produce 1- (tert-butoxycarbonyl) -4-chloro-1H-indole-2-boronic acid as a solid (4.5 g).

Step 3. To a solution of 1- (tert-butoxycarbonyl) -4-chloro-1H-indole-2-ylboronic acid (1.04 g), 5-bromo-2-chloro-N-cyclohexyl-benzenesulfonamide (1 g ) and CsF (864 mg) in dioxane-H2O (29 ml, 10: 1) PdCl2 (dppf) 2 (232 mg) is added at room temperature under a nitrogen atmosphere. The reaction is heated to 80 ° C and stirred overnight. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc and filtered through a short column of silica. The filtrate is concentrated in vacuo and purified by flash column chromatography on silica gel eluting with 10% to 50% EtOAc in heptane to yield 4-chloro-2 (4-chloro-3-cyclohexylsulfamoyl acid tert-butyl ester). -phenyl) -indole-1-carboxylic acid in the form of a solid (1.04 g).

Step 4. Trifluoacetic acid (5 ml) is added to a solution of 4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -indole-1-carboxylic acid tert-butyl ester (1.04 g) in DCM (10 ml). The reaction mixture is stirred at room temperature for 4 h. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated to yield 2-chloro-5- (4-chloro-1H-indole-2-yl) -N -cyclohexyl-benzenesulfonamide in the form of a solid (860 mg). LCMS: TR = 3.06 minutes, MS: 423 (M + H).

Step 5. Oxalyl chloride (0.26 ml) is slowly added to a solution of 2-chloro-5 (4-chloro-1H-indole-2-yl) -N-cyclohexyl-benzenesulfonamide (860 mg) in dichloromethane ( 20 ml) at room temperature. After stirring for 2 h, MeOH (5 ml) is added and the mixture is stirred for 15 minutes. The mixture is concentrated. The residue is purified by flash column chromatography on silica gel eluting with 0% to 50% EtOAc in heptane to yield [4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole methyl ester -3-yl] -oxo-acetic acid in the form of a solid (140 mg).

Step 6. Triethylsilane (0.086 ml) is slowly added to a solution of [4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -oxoacetic acid methyl ester (140 mg) in trifluoacetic acid (1.4 ml) at room temperature. After stirring overnight, the volatile material is removed in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated. The residue is purified by flash column chromatography on silica gel eluting with 10% to 50% EtOAc in heptane to yield [4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H methyl ester -indole-3-yl] -acetic acid in the form of a solid (93 mg).

Step 7. To a solution of [4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid methyl ester (92 mg) in MeOH / H2O (1: 1 , 3.6 ml) lithium hydroxide monohydrate (16 mg) is added. The reaction mixture is stirred at 80 ° C for 18 h. EtOAc (10 ml) is added and the solution is washed with 1 N HCl (5 ml). The organic layer is separated, dried over MgSO4 and concentrated to produce [4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid as a solid (67 mg) LCMS: TR = 2.52 minutes, MS: 481 (M + H); 1H NMR (300 MHz, CD3OD) � 1.09-1.35 (m, 5H), 1.51-1.74 (m, 5H), 3.11 (m, 1H), 3.81 (sa, 2H), 7.05 (m, 2H), 7.39 (m, 1H), 7.65 (m, 2H), 8.32 (m, 1H), 11.17 (sa, 1H).

Example 5: [4-Chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl]-potassium acetate

image 1

A mixture of [4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl]

Acetic acid (537 mg, 1,115 mmol) and 200 ml of ethanol is stirred at ~ 40 ° C for 10 minutes. The resulting solution is allowed to cool to room temperature and potassium hydroxide (62 mg, 1.1 mmol) is added. Stirring is continued at room temperature until the KOH dissolves. The solution is concentrated in vacuo at 40 ° C. The resulting white solids are dried under vacuum for ~ 20 h to produce [4-chloro-2- (4-chloro

10 3-Cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl]-potassium acetate in the form of a crystalline solid (575 mg). LCMS: TR = 2.64 minutes, MS: 481 (M + H of the parental acid). 1 H NMR (300 MHz, DMSO-D6) � 0.9 -1.7 (m series, 10H), 3.06 (m, 1H), 3.66 (s, 2H), 6.93 (d, J = 7.2 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 8.3, 1H), 8.1 (dd, J = 6.4 Hz, 2 Hz, 2H), 8.32 (d, J = 2 Hz, 1H), 11.75 (s, 1H).

15 Example 6:

[2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -4-fluoro-1H-indole-3-yl] -acetic acid

image 1

Step 1. Di-tert-butyl dicarbonate (8.88 g) is added to a solution of 4-fluoroindole (5 g) and 4- (dimethylamino) pyridine (0.45 g) in dichloromethane (185 ml). The reaction is stirred at room temperature for 4 h. The reaction mixture is washed with 1 N HCl (100 ml) and 1 N NHCO3 (100 ml). The organic layer is separated, dried over MgSO4 and dried.

concentrated to produce 4-fluoro-indole-1-carboxylic acid tert-butyl ester in the form of an oil (8.32 g). LCMS: RT = 3.34 minutes, MS: 236.09 (M + H).

Step 2. To a solution of 4-fluoro-indole-1-carboxylic acid tert-butyl ester (3 g) in dry THF (16 ml) is added triisopropyl borate (3.6 ml) in a nitrogen atmosphere . The mixture is cooled to 0 ° C in an ice bath. Lithium diisopropylamine (12.8 ml, 2 M) is added for one hour at 0 ° C. The reaction is stirred at 0 ° C for 30 minutes. 2N HCl (10 ml) is added to interrupt the reaction. The resulting mixture is extracted with EtOAc. The residue is purified by flash column chromatography on silica gel eluting with 5% to 50% EtOAc in heptane to yield 1- (tert-butoxycarbonyl) -4-fluoro-1H-indole-2-ylboronic acid as a solid (1.65 g).

Step 3. To a solution of 1- (tert-butoxycarbonyl) -4-fluoro-1H-indole-2-ylboronic acid (1.19 g), 5-bromo-2-chloro-N-cyclohexyl-benzenesulfonamide (1 g ) and CsF (863 mg) in dioxane-H2O (27.5 ml, 10: 1) PdCl2 (dppf) 2 (231 mg) is added at room temperature under a nitrogen atmosphere. The reaction is heated to 80 ° C and stirred for 2 days. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc and filtered through a short column of silica. The filtrate is concentrated in vacuo and purified by flash column chromatography on silica gel eluting with 5% to 30% EtOAc in heptane to yield 2-chloro-5- (4-fluoro-1Hindole-2-yl) -N -cyclohexyl-benzenesulfonamide in the form of a solid (516 mg). LCMS: RT = 4.46 minutes, MS: 407 (M + H).

Step 4. Oxalyl chloride (0.16 ml) is slowly added to a solution of 2-chloro-5 (4-fluoro-1H-indole-2-yl) -N-cyclohexyl-benzenesulfonamide (496 mg) in dichloromethane ( 12 ml) at room temperature. After stirring for 3 h, MeOH (4 ml) is added and the mixture is stirred for 15 minutes. The mixture is concentrated. The residue is purified by flash column chromatography on silica gel eluting with 5% to 50% EtOAc in heptane to yield [4-fluoro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole methyl ester -3-yl] -oxo-acetic acid in the form of a solid (470 mg).

Step 5. Triethylsilane (0.3 ml) is slowly added to a solution of [4-fluoro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -oxo acid methyl ester -acetic acid (570 mg) in trifluoacetic acid (5 ml) at room temperature. After stirring overnight, the volatile material is removed in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated. The residue is purified by flash column chromatography on silica gel eluting with 10% to 50% EtOAc in heptane to yield [4-fluoro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H methyl ester -indole-3-yl] -acetic acid in the form of a white solid (350 mg). LCMS: RT = 3.18 minutes, MS: 479.1 (M + H).

Step 6. To a solution of methyl ester of [4-fluoro-2- (4-chloro-3 acid

Cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -acetic acid (250 mg) in MeOH / H2O (1: 1, 7 ml) is added lithium hydroxide monohydrate (44 mg). The reaction mixture is stirred at 80 ° C overnight. EtOAc (15 ml) is added and the solution is washed with 1 N HCl (10 ml). The organic layer is separated, dried over MgSO4 and concentrated to produce [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -4-fluoro-1H-indole-3-yl] -acetic acid as a

10 solid (2.19 mg). LCMS: TR = 2.83 minutes, MS: 465 (M + H); 1 H NMR (300 MHz, DMSO) � 1.09-1.24 (m, 5H), 1.49-1.61 (m, 5H), 3.07 (m, 1H), 3.81 (s, 2H), 6.8 (m, 1H), 7.15 (m, 1H), 7.26 (m, 1H), 7.84 (m, 2H), 7.98 (m, 1H), 8, 23 (m, 1H), 11.86 (sa, 1H). IC50 = 0.7 nM

Example 7:

[2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -4-methyl-1H-indole-3-yl] -acetic acid

image 1

Step 1. Di-tert-butyl dicarbonate (9.15 g) is added to a solution of 4-methylindole (5 g) and 4- (dimethylamino) pyridine (0.46 g) in dichloromethane (190 ml). The reaction is stirred at room temperature for 4 h. The reaction mixture is washed with 1 N HCl (100

20 ml) and 1 N NHCO3 (100 ml). The organic layer is separated, dried over MgSO4 and concentrated to produce 4-methyl-indole-1-carboxylic acid tert-butyl ester as an oil (8.75 g).

Step 2. To a solution of 4-methyl-indole-1-carboxylic acid tert-butyl ester (3 g) in dry THF (16 ml) is added triisopropyl borate (4.45 ml) in an atmosphere of

25 nitrogen The mixture is cooled to 0 ° C in an ice bath. Lithium diisopropylamine (11.6 ml, 2 M) is added for one hour at 0 ° C. The reaction is stirred at 0 ° C for 30 minutes. 2N HCl (10 ml) is added to interrupt the reaction. The resulting mixture is extracted with EtOAc. The residue is recrystallized from CH3CN / H2O to produce 1 (tert-butoxycarbonyl) -4-methyl-1H-indole-2-ylboronic acid as a solid (1.53 g).

Step 3. To a solution of 1- (tert-butoxycarbonyl) -4-methyl-1H-indole-2-ylboronic acid (1.41 g), 5-bromo-2-chloro-N-cyclohexyl-benzenesulfonamide (1 g ) and CsF (863 mg) in dioxane-H2O (27.5 ml, 10: 1) PdCl2 (dppf) 2 (232 mg) is added at room temperature under a nitrogen atmosphere. The reaction is heated to 80 ° C and stirred overnight. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc and filtered through a short column of silica. The filtrate is concentrated in vacuo and purified by flash column chromatography on silica gel eluting with 0% to 50% EtOAc in heptane to yield 2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) tert-butyl ester. -4-methyl-indole-1-carboxylic acid in the form of a solid (845 mg).

Step 4. Trifluoacetic acid (5 ml) is added to a solution of 2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -4-methyl-indole-1-carboxylic acid tert-butyl ester (845 mg) in dichloromethane (10 ml). The reaction mixture is stirred at room temperature overnight. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated to yield 2-chloro-5- (4-methyl-1H-indole-2-yl) -N -cyclohexyl-benzenesulfonamide in the form of a solid (652 mg). LCMS: TR = 3.11 minutes, MS: 403 (M + H).

Step 5. Oxalyl chloride (0.21 ml) is slowly added to a solution of 2-chloro-5 (4-methyl-1H-indole-2-yl) -N-cyclohexyl-benzenesulfonamide (650 mg) in dichloromethane ( 16 ml) at room temperature. After stirring overnight, MeOH (5 ml) is added and stirred for 15 minutes. The mixture is concentrated. The residue is purified by flash column chromatography on silica gel eluting with 0% to 50% EtOAc in heptane to produce [2- (4-chloro-3-cyclohexylsulfamoylphenyl) -4-methyl-1H-indole methyl ester -3-yl] -oxo-acetic acid in the form of a yellow solid (588 mg). LCMS: TR = 2.8 minutes, MS: 489 (M + H).

Step 6. Triethylsilane (0.38 ml) is slowly added to a solution of [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -4-methyl-1H-indole-3-yl] -oxo acid methyl ester -acetic acid (588 mg) in trifluoacetic acid (2 ml) at room temperature. After stirring overnight, the volatile material is removed in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated. The residue is purified by flash column chromatography on silica gel eluting with 0% to 40% EtOAc in heptane to yield [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -4-methyl-1H methyl ester -indole-3-yl] -acetic acid in the form of a solid (338 mg). LCMS: TR = 2.95 minutes, MS: 475 (M + H).

Step 7. To a solution of [2- (4-chloro-3-cyclohexylsulfamoylphenyl) -4-methyl-1H-indole-3-yl] -acetic acid methyl ester (330 mg) in MeOH / H2O (1: 1 , 7 ml) lithium hydroxide monohydrate (58 mg) is added. The reaction mixture is stirred at 80 ° C for 18 h. EtOAc (15 ml) is added and the solution is washed with 1 N HCl (10 ml). The organic layer 5 is separated, dried over MgSO4 and concentrated to produce [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -4-methyl-1H-indole-3-yl] -acetic acid as a white solid (210 mg). LCMS: RT = 2.60 minutes, MS: 461.12 (M + H); 1 H NMR (300 MHz, DMSO) � 1.02-1.28 (m, 5H), 1.46-1.64 (m, 5H), 3.07 (m, 1H), 2.63 (s, 3H), 3.95 (s, 2H), 6.79 (d, J = 6.9 Hz, 1H), 7.05 (t, J = 8.1 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.80 (m, 2H),

10 7.96 (d, J = 8.1 Hz, 1H), 8.21 (s, 1H), 11.53 (s, 1H), 12.54 (s at, 1H). IC50 = 1.5 nM

Example 8:

[7-Chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid

image 1

Step 1. Di-tert-butyl dicarbonate (7.92 g) is added to a 7-chloroindole solution

15 (5 g) and 4- (dimethylamino) pyridine (0.4 g) in DCM (165 ml). The reaction is stirred at room temperature for 18 h. The reaction mixture is washed with 1 N HCl (100 ml) and 1 N NHCO3 (100 ml). The organic layer is separated, dried over MgSO4 and concentrated to produce 7-chloro-indole-1-carboxylic acid tert-butyl ester as an oil (8.22 g).

Step 2. To a solution of 7-chloro-indole-1-carboxylic acid tert-butyl ester (3 g) in dry THF (15 ml) is added triisopropyl borate (4.11 ml) in an atmosphere of nitrogen. The mixture is cooled to 0 ° C in an ice bath. Lithium diisopropylamine (8.94 ml, 2 M) is added for one hour at 0 ° C. The reaction is stirred at 0 ° C for 30 minutes. 2N HCl (10 ml) is added to interrupt the reaction. The resulting mixture

25 is extracted with EtOAc. The residue is purified by flash column chromatography on silica gel eluting with 10% to 50% EtOAc in heptane to yield 1- (tert-butoxycarbonyl) -7-chloro-1H-indole-2-ylboronic acid as a solid (0.86 g).

Step 3. To a solution of 1- (tert-butoxycarbonyl) -7-chloro-1H-indole-2-ylboronic acid (860 mg), 5-bromo-2-chloro-N-cyclohexyl-benzenesulfonamide (733 mg) and CsF (632 mg) in dioxane-H2O (22 ml, 10: 1) is added PdCl2 (dppf) 2 (163 mg) at room temperature under a nitrogen atmosphere. The reaction is heated to 80 ° C and stirred overnight. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc and filtered through a short column of silica. The filtrate is concentrated in vacuo and purified by flash column chromatography on silica gel eluting with 10% to 50% EtOAc in heptane to yield 7-chloro-2- (4-chloro-3- acid tert-butyl ester). cyclohexylsulfamoyl-phenyl) -indole-1-carboxylic acid in the form of a solid (630 mg).

Step 4. Trifluoacetic acid (3 ml) is added to a solution of 7-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -indole-1-carboxylic acid tert-butyl ester (630 mg) in dichloromethane (7 ml). The reaction mixture is stirred at room temperature overnight. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated in vacuo. The crude product is purified by flash column chromatography on silica gel eluting with 10% to 40% EtOAc in heptane to yield 2-chloro-5 (7-chloro-1H-indole-2-yl) -N-cyclohexyl- benzenesulfonamide in the form of a solid (386 mg).

Step 5. Oxalyl chloride (0.12 ml) is slowly added to a solution of 2-chloro-5 (7-chloro-1H-indole-2-yl) -N-cyclohexyl-benzenesulfonamide (386 mg) in dichloromethane ( 9 ml) at room temperature. After stirring for 18 h, MeOH (3 ml) is added and stirred for 15 minutes. The mixture is concentrated. The residue is purified by flash column chromatography on silica gel eluting with 5% to 45% EtOAc in heptane to yield [7-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole methyl ester -3-yl] -oxo-acetic acid in the form of a solid (239 mg).

Step 6. Triethylsilane (0.15 ml) is slowly added to a solution of [7-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -oxo acid methyl ester -acetic acid (239 mg) in trifluoacetic acid (2.4 ml) at room temperature. After stirring overnight, the volatile material is removed in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated. The residue is purified by flash column chromatography on silica gel eluting with 10% to 50% EtOAc in heptane to yield [7-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H methyl ester -indole-3-yl] -acetic acid in the form of a solid (93 mg). LCMS: TR = 4.5 minutes, MS: 495 (M + H).

Step 7. To a solution of [7-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid methyl ester (93 mg) in MeOH / H2O (1: 1 , 4 ml) lithium hydroxide monohydrate (16 mg) is added. The reaction mixture is stirred at 80 ° C for 18 h. EtOAc (10 ml) is added and the solution is washed with 1 N HCl (5 ml). The organic layer is separated, dried over MgSO4 and concentrated to produce [7-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid as a solid (85 mg) LCMS: TR = 2.6 minutes, MS: 481 (M + H); 1H NMR (300 MHz, DMSO) � 1.09

10 1.35 (m, 5H), 1.59-1.73 (m, 5H), 3.19 (m; 1H), 3.84 (brs, 2H), 7.21 (m, 1H), 7.38 (m, 1H), 7.67 (m, 1H), 7.95 (m, 1H), 8.02-8.05 (m, 2H), 8.40 (brs, 1H), 11 , 9 (brs, 1H). IC50 = 3.7 nM

Example 9:

2-Chloro-N-cyclohexyl-5- [3- (2-methanesulfonylamino-2-oxo-ethyl) -1H-indole-2-yl] 15 benzenesulfonamide

image 1

Step 1. To a solution of 1- (tert-butoxycarbonyl) -1H-indole-2-ylboronic acid (10 g), 5-bromo-2-chloro-N-cyclohexyl-benzenesulfonamide (6.8 g) and CsF (5, 8 g) in dioxane-H2O (220 ml, 10: 1) PdCl2 (dppf) 2 (1.57 g) is added at room temperature under a nitrogen atmosphere. The reaction is heated to 80 ° C and stirred for 6 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc and filtered through a short column of silica. The filtrate is concentrated in vacuo and purified by flash column chromatography on silica gel eluting with 10% to 50% EtOAc in heptane to yield 2- (4-chloro-3 tert-butyl ester

Cyclohexylsulfamoyl-phenyl) -indole-1-carboxylic acid in the form of a solid (8.2 g).

Step 2. Trifluoacetic acid (65 ml) is added to a solution of 2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -indole-1-carboxylic acid tert-butyl ester (13 g) in dichloromethane (150 ml) . The reaction mixture is stirred at room temperature for 2 h. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated to yield 2-chloro-5- (1H-indole-2-yl) -N-cyclohexyl-benzenesulfonamide. in the form of a solid (9.7 g). LCMS: TR = 3.17 minutes, MS: 389 (M + H).

Step 3. Oxalyl chloride (0.33 ml) is slowly added to a solution of 2-chloro-5 (1H-indole-2-yl) -N-cyclohexyl-benzenesulfonamide (1 g) in dichloromethane (25 ml) to room temperature. After stirring for 1.8 h, MeOH (5 ml) is added and the mixture is stirred for 15 minutes. The mixture is concentrated. The residue is purified by flash column chromatography on silica gel eluting with 10% to 45% EtOAc in heptane to yield [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl methyl ester] ] -oxo-acetic in the form of a solid (1.2 g).

Step 4. Triethylsilane (0.59 ml) is slowly added to a solution of [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -oxo-acetic acid methyl ester (1 , 2 g) in trifluoacetic acid (12 ml) at room temperature. After stirring overnight, the volatile material is removed in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated. The residue is purified by flash column chromatography on silica gel eluting with 10% to 50% EtOAc in heptane to produce [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3 methyl ester] -il] -acetic acid in the form of a solid (818 mg).

Step 5. To a solution of [2- (4-chloro-3-cyclohexylsulfamoylphenyl) -1H-indol-3-yl] -acetic acid methyl ester (818 mg) in MeOH / H2O (1: 1, 18 ml) Lithium hydroxide monohydrate (149 mg) is added. The reaction mixture is stirred at 80 ° C for 18 h. EtOAc (15 ml) is added and the solution is washed with 1 N HCl (10 ml). The organic layer is separated, dried over MgSO4 and concentrated to produce [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid as a solid (740 mg).

Step 6. To a solution of [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] acetic acid (185 mg), N- (3-dimethylaminopropyl) -N'- hydrochloride Ethylcarbodiimide (82 mg) and dimethylaminopyridine (50 mg) in dichloromethane (4 ml) methanesulfonamide (41 mg) is added at 0 ° C. The reaction mixture is allowed to warm to room temperature and stirred overnight. The resulting solution is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 1 N HCl. The organic layer is separated, dried over MgSO4 and concentrated in vacuo. The crude material is triturated with dichloromethane and filtered to produce 2-chloro-N-cyclohexyl-5- [3- (2-methanesulfonylamino-2-oxo-ethyl) -1H-indole-2-yl] benzenesulfonamide as a solid (115 mg). LCMS: RT = 2.39 minutes, MS: 524 (M + H); 1H NMR (300 MHz, DMSO) � 1.10-1.28 (m, 5H), 1.61-1.64 (m, 5H), 3.07 (m, 1H), 3.26 (s, 3H), 3.88 (s, 2H), 7.10 (m, 1H), 7.21 (m, 1H), 7.44 (m, 1H), 7.61 (m, 1H), 7, 82 (m, 1H), 7.98 (m, 2H), 8.25 (s, 1H), 11.65 (s, 1H), 12.12 (s, 1H). IC50 = 2 nM

Example 10:

2-Chloro-N-cyclohexyl-5- [3- (2-ethanesulfonylamino-2-oxo-ethyl) -1H-indole-2-yl] benzenesulfonamide

image 1

Step 1. To a solution of [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl]

Acetic (200 mg), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (90 mg) and dimethylaminopyridine (55 mg) in dichloromethane (4.5 ml) ethanesulfonamide (51 mg) is added at 0 ° C. The reaction mixture is allowed to warm to room temperature and stirred overnight. The resulting solution is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 1 N HCl. The organic layer is separated, dried over

15 MgSO4 and concentrated in vacuo. The crude material is triturated with dichloromethane and filtered to produce 2-chloro-N-cyclohexyl-5- [3- (2-ethanesulfonylamino-2-oxo-ethyl) -1H-indole-2-yl] benzenesulfonamide as a solid (174 mg). LCMS: RT = 2.44 minutes, MS: 538 (M + H); 1H NMR (300 MHz, DMSO) � 1.07-1.33 (m, 8H), 1.51-1.69 (m, 5H), 3.13 (m, 1H), 3.34 (m, 2H), 3.94 (s, 2H), 7.14 (t, J = 7.2 Hz, 1H), 7.26 (t, J = 7.2 Hz, 1H),

20 7.50 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 7.2 Hz, 1H), 8 , 00 (m, 1H), 8.34 (m, 1H), 11.70 (s, 1H), 12.06 (5, 1H). IC50 = 2.7 nM

Example 11:

2-Chloro-N-cyclohexyl-5- [3- (2-oxo-2-trifluoromethanesulfonylamino-ethyl) -1H-indole-2yl] -benzenesulfonamide

image 1

Step 1. To a solution of [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] acetic acid (150 mg), N- (3-dimethylaminopropyl) -N 'hydrochloride -ethylcarbodiimide (68 mg) and dimethylaminopyridine (40 mg) in dichloromethane (4 ml) trifluoromethanesulfonamide (52 mg) is added at 0 ° C. The reaction mixture is allowed to warm to room temperature and stirred overnight. The resulting solution is

10 concentrate in vacuo. The residue is dissolved in EtOAc and washed with 1 N HCl. The organic layer is separated, dried over MgSO4 and concentrated in vacuo to yield 2-chloro-N-cyclohexyl-5- [3- (2-trifluoromethanesulfonylamino-2-oxo -ethyl) -1H-indole-2-yl] benzenesulfonamide in the form of a solid (206 mg). LCMS: TR = 2.58 minutes, MS: 576 (M + H); 1H NMR (300 MHz, CD3OD) � 1.17-1.27 (m, 5H), 1.55-1.75 (m, 5H), 3.12

15 (m, 1H), 4.01 (s, 2H), 7.11 (m, 1H), 7.42 (m, 1H), 7.50 (m, IH), 7.68 (m, 1H ), 7.80 (m, 1H), 8.3 (m, IH). IC50 = 14 nM

Example 12:

2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -N- (1H-tetrazol-5-yl)

acetamide

image 1

Step 1. To a solution of [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] acetic acid (200 mg), N- (3-dimethylaminopropyl) -N'- hydrochloride Ethylcarbodiimide (90 mg) and dimethylaminopyridine (55 mg) in dichloromethane (4.5 ml) is added 1H-tetrazol-5-amine (48 mg) at 0 ° C. The reaction mixture is allowed to warm to room temperature and stirred for 2 days. The resulting solution is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 1 N HCl. The organic layer is separated, dried over MgSO4 and concentrated in vacuo. The crude material is triturated with dichloromethane and filtered.

5 to produce 2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -N- (1H-tetrazol-5-yl) acetamide as a solid (50 mg) . LCMS: TR = 2.26 minutes, MS: 514 (M + H); 1H NMR (300 MHz, DMSO) � 1.14-1.3 (m, 5H), 1.51-1.65 (m, 5H), 3.1 (m, 1H), 4.1 (s, 2H), 7.11 (m, 1H), 7.23 (m, 1H), 7.48 (m, 1H), 7.7 (m, 1H), 7.84 (m, 1H), 8, 06 (m, 2H), 8.34 (s, 1H), 11.69 (sa, 1H), 12.46 (sa, 1H). IC50 = 15 nM

10 Example 13:

[2- (3-Cyclohexylsulfamoyl-4-ethyl-phenyl) -1H-indole-3-yl] -acetic acid

image 1

Step 1. 1-Bromo-4-ethyl-benzene (3 g) is dissolved in 30 ml of DCM and the mixture is

cool to 0 ° C in an ice bath. Chlorosulfonic acid (11.3 g) is added dropwise over the course of 20 minutes and the solution is stirred at 0 ° C for 4 hours. The

reaction mixture is carefully poured onto ice and allowed to warm to

room temperature. The mixture is transferred to a separatory funnel and the

layers are separated. The aqueous layer is washed with more DCM. Layers

organic are combined, dried (MgSO4), filtered and evaporated to yield 5-bromo-2-ethyl-benzenesulfonyl chloride (1.78 g) as an oil that is used

without further purification in stage 2.

Step 2. Cyclohexylamine (0.9 g) and diisopropylethylamine (1.5 g) are dissolved in 20 ml of

DCM and the solution is cooled to 0 ° C. To this is added in portions chloride of 5

Bromo-2-ethyl-benzenesulfonyl (1.7 g in 20 ml of DCM) for 5 minutes. The mixture 25 is stirred at 0 ° C for 30 minutes and at room temperature for 1 hour. He

solvent is removed under reduced pressure and 10% aqueous HCl is added to the residue and

DCM The layers are separated and the aqueous layer is washed with more DCM. The

Combined layers of DCM are dried (MgSO4), filtered and evaporated. The resulting solid is recrystallized from DCM / heptane to produce 5-bromo-N-cyclohexyl-2-ethylbenzenesulfonamide (1.36 g). LCMS: TR = 2.96 minutes, MS: 346 (M + H).

Step 3. 5-Bromo-N-cyclohexyl-2-ethyl-benzenesulfonamide (1.3 g), 1Boc-indole-2-boronic acid (1.48 g) and cesium fluoride (0.86 g) are mixed with 10: 1 dioxane: H2O (44 ml). The solution is degassed with nitrogen and PdCl2 (dppf) 2 (0.31 g) is added. The mixture is heated at 80 ° C for 2.5 hours. The reaction mixture is poured into H2O. EtOAc is added and the layers are separated. The EtOAc layer is concentrated. Heptane is added to produce a precipitate that is filtered off. The EtOAc filtrate is passed through a bed of silica, evaporated on silica and purified on an 80 g silica gel column using an ISCO Companion purification system (EtOAc / heptane gradient) to produce tertiary ester. 2- (3-Cyclohexylsulfamoyl-4-ethyl-phenyl) -indole-1-carboxylic acid butyl (1.19 g). LCMS: TR = 3.54 minutes, MS: 483 (M + H).

Step 4. 2- (3-Cyclohexylsulfamoyl-4-ethyl-phenyl) -indole-1-carboxylic acid tert-butyl ester (1.18 g) is treated with 10 ml of TFA for 30 minutes at room temperature. The TFA is removed under reduced pressure. The residue is partitioned between EtOAc and 10% aqueous NaHCO3 and the layers are separated. The organic layer is washed with more 10% aqueous NaHCO3, water and brine. The organic layer is dried (MgSO4), filtered, evaporated on silica and purified on a 40 g silica gel column using an ISCO Companion purification system (EtOAc / heptane gradient) to produce N-cyclohexyl-2 -ethyl-5- (1H-indole-2-yl) -benzenesulfonamide (0.65 g). LCMS: TR = 3.07 minutes, MS: 383 (M + H).

Step 5. N-Cyclohexyl-2-ethyl-5- (1 H -indole-2-yl) -benzenesulfonamide (0.64 g) is suspended in 30 ml of diethyl ether. Oxalyl chloride (0.32 g) is added dropwise at room temperature and the mixture is stirred for 6 hours. Methanol (2 ml) is added, the solution is stirred for 10 minutes and the solvent is removed under reduced pressure. The crude material is purified on an 80 g silica gel column using an ISCO Companion purification system (gradient of EtOAc / heptane) to produce methyl ester of [2- (3-cyclohexylsulfamoyl-4-ethyl-phenyl) - 4H-indole-3-yl] oxo-acetic acid (0.66 g). LCMS: TR = 2.75 minutes, MS: 469 (M + H).

Step 6. [2- (3-Cyclohexylsulfamoyl-4-ethyl-phenyl) -1Hindole-3-yl] oxo-acetic acid methyl ester (0.63 g) is dissolved in 10 ml of TFA. Triethylsilane (0.31 g) is added dropwise at room temperature and the solution is stirred for 18 hours. The reaction mixture is concentrated under reduced pressure. EtOAc and saturated NaHCO3 are added to the residue and the layers are separated. The EtOAc layer is evaporated on silica gel and purified on a 40 g silica gel column using an ISCO Companion purification system (EtOAc / heptane gradient) to produce methyl ester of [2- (3-cyclohexylsulfamoyl acid] -4-ethyl-phenyl) -1H-indole-3-yl] -acetic acid (0.53 g).

5 LCMS: TR = 2.95 minutes, MS: 455 (M + H); 1H NMR (300 MHz, CDCl3) � 1H NMR (300 MHz, CDCl3) � 1.05-1.29 (m, 5H), 1.37 (t, J = 7.5 Hz, 3H), 1.50 -1.79 (m, 5H), 3.14 (c, J = 7.5 Hz, 2H), 3.22 (m, 1H), 3.73 (s, 3H), 3.84 (s, 2H), 4.55 (d, J = 7.9 Hz, 1H), 7.167.28 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.83 (dd, J = 7.9, 1.8 Hz, 1H), 8.28 ( d, J = 1.9 Hz, 1H), 8.32 (s, 1H).

10 Step 7. [2- (3-Cyclohexylsulfamoyl-4-ethyl-phenyl) -1Hindole-3-yl] -acetic acid methyl ester (0.33 g) is dissolved in 6 ml of MeOH 3: 3: 1 : THF: H2O. LiOH monohydrate (2 equiv.) Is added and the solution is heated at 80 ° C overnight. The solvent is evaporated under reduced pressure. EtOAc and HCl aq are added. at 10% and the layers are separated. The EtOAc layer is washed with more amount of ac HCl. at 10%,

15 water and brine. The organic layer is dried (MgSO4), filtered and evaporated and the residue is recrystallized from DCM / heptane to produce [2- (3-cyclohexylsulfamoyl-4-ethylphenyl) -1H-indole-3-yl] -acetic acid in form of a solid (193 mg). LCMS: TR = 2.6 minutes, MS: 441 (M + H); 1 H NMR (300 MHz, DMSO-D6) � 1.0-1.24 (m, 5H), 1.31 (t, J = 7.5 Hz, 3H), 1.45-1.62 (m, 5H), 3.05 (m, 1H), 3.08 (c, J = 7.4 Hz, 2H), 3.75 (s, 2H), 7.07 (t, J =

20 7.8 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 7.42 (d, J = 8 Hz, 1H), 7.59 (m, 2H), 7, 76 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 8.18 (s, 1H), 11.46 (s, 1H), 12, 37 (s, 1 H). IC50 = 0.5 nM

Example 14:

2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -propionic acid

image 1

Step 1. To a solution of 1- (tert-butoxycarbonyl) -indole-2-ylboronic acid (5.5 g), 5-bromo-2-chloro-N-cyclohexyl-benzenesulfonamide (5 g) and CsF (4.3 g ) in dioxane-H2O (143 ml, 10: 1) PdCl2 (dppf) 2 (1.16 g) is added at room temperature under a nitrogen atmosphere. The reaction is heated to 80 ° C and stirred for 18 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc and filtered through a short column of silica. The filtrate is concentrated in vacuo and purified by flash column chromatography on silica gel eluting with 5% to 30% EtOAc in heptane to yield 2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -indole tert-butyl ester. -1-carboxylic in the form of a solid (6.2 g). LCMS: TR = 5.03 minutes, MS: 511 (M + Na).

Step 2. Trifluoacetic acid (10 ml) is added to a solution of 2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -indole-1-carboxylic acid tert-butyl ester (6.2 mg) in dichloromethane (20 mg) ml) The reaction mixture is stirred at room temperature overnight. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated to yield 2-chloro-N-cyclohexyl-5- (1H-indole-2-yl) -benzenesulfonamide. in the form of a solid (5.3 g).

Step 3. Oxalyl chloride (1.59 ml) is slowly added to a solution of 2-chloro-Ncyclohexyl-5- (1H-indol-2-yl) -benzenesulfonamide (4.8 mg) in dichloromethane (120 ml) at room temperature. After stirring for 3 h, MeOH (10 ml) is added and the mixture is stirred for 15 minutes. The mixture is concentrated. The residue is purified by flash column chromatography on silica gel eluting with 5% to 50% EtOAc in heptane to yield [2- (4-chloro-3-cyclohexylsulfamoylphenyl) -1H-indole-3-yl methyl ester ] -oxo-acetic in the form of a solid (2.5 g).

Step 4. Triethylsilane (1.7 ml) is slowly added to a solution of [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -oxo-acetic acid methyl ester (2 , 5 g) in trifluoacetic acid (25 ml) at room temperature. After stirring overnight, the volatile material is removed in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated. The residue is purified by flash column chromatography on silica gel eluting with 10% to 50% EtOAc in heptane to produce [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3 methyl ester] -yl] -acetic acid in the form of a solid (1.84 g). LCMS: RT = 4.14 minutes, MS: 461 (M + H).

Step 5. Di-tert-butyl dicarbonate (807 mg) is added to a solution of [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -acetic acid methyl ester ( 775 mg), triethylamine (0.52 ml) and 4- (dimethylamino) pyridine (42 mg) in DCM (17 ml). The reaction is stirred at room temperature for 2 days. The reaction mixture is washed with 1 N HCl (10 ml) and 1 N NHCO3 (10 ml). The organic layer is separated, dried over MgSO4 and concentrated to produce 2- [4-chloro-3- (N-tert-butoxycarbonyl) -cyclohexylsulfamoyl-phenyl] -3-methoxycarbonylmethyl-indole-1-carboxylic acid tert-butyl ester (1.03 g).

Step 6. To a solution of 2- [4-chloro-3- (N-tert-butoxycarbonyl) -cyclohexylsulfamoyl-phenyl] -3-methoxycarbonylmethyl-indole-1-carboxylic acid tert-butyl ester (864 mg) in DMF (13 ml) is added in a NaH portion (157 mg) at 0 ° C. The resulting mixture is stirred at 0 ° C for 15 minutes and MeI (0.82 ml) is added at 0 ° C. The reaction mixture is allowed to warm to room temperature and stirred for 3 h. The reaction is interrupted by the addition of saturated NH4Cl (10 ml). The mixture is extracted with EtOAc (20 ml). The organic layer is washed 3 times with water (10 ml), separated, dried over MgSO4 and concentrated. The residue is purified by flash column chromatography on silica gel eluting with 10% to 45% EtOAc in heptane to yield 2- [4-chloro-3- (N-tert-butyloxycarbonyl) cyclohexylsulfamoyl- tert-butyl ester phenyl] -3- (1-methoxycarbonyl-ethyl) -indole-1-carboxylic acid in the form of a white solid (400 mg). LCMS: RT = 4.3 minutes, MS: 675 (M + H).

Step 7. Trifluoacetic acid (2 ml) is added to a solution of 2- [4-chloro-3- (N-tert-butyloxycarbonyl) -cyclohexylsulfamoyl-phenyl] -3- (1-methoxycarbonylethyl) tert-butyl ester -indole-1-carboxylic acid (165 mg) in dichloromethane (4 ml). The reaction mixture is stirred at room temperature for 4 hours. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 1 N NaHCO3. The organic layer is separated, dried over MgSO4 and concentrated. The residue is purified by flash column chromatography on silica gel eluting with 10% to 50% EtOAc in heptane to yield 2- [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) 1H-indole-methyl ester. 3-yl] -propionic in the form of a white solid (94 mg). LCMS: TR = 3.2 minutes, MS: 475 (M + H).

Step 8. To a solution of 2- [2- (4-Chloro-3-cyclohexylsulfamoylphenyl) -1H-indol-3-yl] -propionic acid methyl ester (94 mg) in MeOH / H2O (1: 1, 2 ml) lithium hydroxide monohydrate (17 mg) is added. The reaction mixture is stirred at 80 ° C for 2 h. EtOAc (10 ml) is added and the solution is washed with 1 N HCl (5 ml). The organic layer is separated, dried over MgSO4 and concentrated to produce 2- [2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -propionic acid as a solid (90 mg) . LCMS: RT = 2.88 minutes, MS: 461 (M + H); 1 H NMR (300 MHz, DMSO) � 1.15-1.37 (m, 5H), 1.51-1.71 (m, 8H), 3.13 (m, 1H), 4.06 (m, 1H), 7.02 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 6.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H) , 7.67 (m, 2H), 7.84 (d, J = 8.1 Hz, 1H), 8.37 (s, 1H). IC50 = 5.3 nM

Example 15: {2- [4-Chloro-3- (3-Chloro-phenylmethanesulfonyl) -phenyl] -1H-indole-3-yl} -acetic acid

image 1

Step 1. Sodium sulphite (1.7 g) and dibasic sodium phosphate (0.98 g) are dissolved in 20 ml of water and the mixture is heated at 30 ° C until everything dissolves. 5-Bromo-2-chloro-benzenesulfonyl chloride (2 g) is added and the reaction mixture is heated at 60 ° C overnight. The reaction mixture is cooled and 110 bromomethyl-3-chlorobenzene (1.4 g) is added dropwise as a solution in 20 ml of acetone. The mixture is heated at 60 ° C for 2 hours and cooled to room temperature. The reaction mixture is partitioned between EtOAc and water and the layers are separated. The aqueous layer is washed with more EtOAc. The combined organic layers are washed with water and brine. The organic layer is dried (MgSO4), filtered and evaporated. The crude material is recrystallized from EtOAc / heptane to produce 4-bromo-1-chloro-2- (3-chloro-phenylmethanesulfonyl) -benzene (1.47 g). LCMS: RT = 2.8 minutes, MS: 379 (M + Na), 1H NMR (300 MHz, CDCl3) � 4.37 (s, 2H), 6.70 (sa, 1H), 7.15-7 , 35 (m, 6H), 7.73 (d, J = 2 Hz, 1H).

Step 2. To a solution of 4-bromo-1-chloro-2- (3-chloro-phenylmethanesulfonyl) -benzene (1

20 g), 1- (tert-butoxycarbonyl) -indole-2-ylboronic acid (1 g) and cesium fluoride (0.6 g) in 22 ml of 10: 1 dioxane: water is added PdCl2 (dppf) 2 (0.216 g) at room temperature in a nitrogen atmosphere. The reaction mixture is heated at 80 ° C overnight. After cooling, the reaction mixture is poured into water and extracted with EtOAc. The organic layer is concentrated and heptane is added to

25 produce a precipitate that is filtered. The filtrate is passed through a bed of silica and then evaporated on silica gel. The crude material is purified by flash chromatography on silica gel (EtOAc / heptane) to produce 2- [4-chloro-3- (3-chloro-phenylmethanesulfonyl) -phenyl] -indole-1-carboxylic acid tert-butyl ester (0.84 g). LCMS: TR = 3.42 minutes, MS: 516 (M + Na).

Step 3. Trifluoroacetic acid (10 ml) is added to 2- [4-chloro-3- (3-chloro-phenylmethanesulfonyl) -phenyl] -indole-1-carboxylic acid tert-butyl ester (0.79 g) and the solution The resulting mixture is mixed for 35 minutes at room temperature. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 10% NaHCO3. The organic layer is dried (MgSO4), filtered, evaporated on silica gel and purified by flash chromatography on silica gel (EtOAc / heptane) to yield 2- [4-chloro-3- (3-chloro-phenylmethanesulfonyl) - phenyl] -1H-indole (0.49 g). LCMS: TR = 3 minutes, MS: 416 (M + Na).

Step 4. To a suspension of 2- [4-chloro-3- (3-chloro-phenylmethanesulfonyl) -phenyl] -1H-indole (0.48 g) in 25 ml of Et2O is added dropwise oxalyl chloride (0.22 g) at room temperature. After 7 hours, more oxalyl chloride (0.22 g) is added and the mixture is stirred overnight. Methanol (2 ml) is added dropwise and the mixture is stirred for 10 minutes. The reaction mixture is poured into water and extracted with EtOAc. The organic layer is washed with aqueous NaHCO3 and brine. The organic layer is dried (Na2SO4), filtered and evaporated on silica gel. The crude material is purified by flash chromatography on silica gel (EtOAc / heptane) to produce {2- [4-chloro-3- (3-chlorophenylmethanesulfonyl) -phenyl] -1H-indole-3-yl} methyl ester -oxo-acetic (0.43 g). LCMS: TR = 2.73 minutes, MS: 502 (M + Na).

Step 5. Triethylsilane (0.23 g) is added dropwise to a solution of {2- [4-chloro-3- (3-chloro-phenylmethanesulfonyl) -phenyl] -1H-indole-3- methyl ester il} -oxo-acetic acid (0.5 g) in 10 ml of trifluoroacetic acid. After stirring for 5 hours, the reaction mixture is concentrated under reduced pressure. The residue is partitioned between EtOAc and sat. NaHCO3. The organic layer is evaporated on silica gel and purified by flash chromatography on silica gel (EtOAc / heptane) to produce {2- [4-chloro-3- (3-chloro-phenylmethanesulfonyl) -phenyl] methyl ester. -1H-indole-3-yl} -acetic acid (0.34 g). LCMS: TR = 2.86 minutes, MS: 488 (M + Na).

Step 6. To a solution of {2- [4-chloro-3- (3-chlorophenylmethanesulfonyl) -phenyl] -1H-indole-3-yl} -acetic acid methyl ester (0.3 g) in 14 ml of 3: 3: 1 THF: MeOH: H2O is added lithium hydroxide (0.077 g). The solution is stirred at 80 ° C overnight. The solvent is removed under reduced pressure and 10% aqueous HCl is added to the residue. The aqueous layer is extracted twice with EtOAc. The combined organic layers are dried (MgSO4), filtered and evaporated to produce {2- [4-chloro-3- (3-chloro-phenylmethanesulfonyl) -phenyl] -1H-indole-3-yl} -acetic acid ( 210 mg) LCMS: TR = 2.43 minutes, MS: 474.1 (M + Na). 1H NMR (300 MHz, DMSO) � 3.61 (s, 2H), 4.97 (s, 2H), 7.08 (t, J = 7.2 Hz, 1H), 7.21 (m, 2H ), 7.34-7.44 (m, 4H), 7.57 (d, J = 7.9 Hz, 1H), 7.95-8.05 (m, 2H), 8.37 (d, J = 2 Hz, 1H), 11.58 (s, 1H), 12.43 (s, 1H). IC50 = 106 nM

Example 16:

{2- [4-Chloro-3- (3-Chloro-phenylmethanesulfonylamino) -phenyl] -1H-indole-3-yl} acetic acid

image 1

Step 1. To the salt of 5-bromo-2-chloro-phenylamine hydrochloride (0.81 g) in 20 ml of DCM is added Et3N (0.85 g) and the solution is cooled to 0 ° C. 3-Chlorophenylmethanesulfonyl chloride (0.75 g) is added portionwise as a solution in 5 ml of DCM. The mixture is allowed to warm to room temperature and stirred overnight. The solvent is removed under reduced pressure and the residue is dissolved again in EtOAc. The EtOAc is extracted with 10% aqueous HCl, saturated Na2CO3 and brine. The organic layer is dried (MgSO4), filtered, evaporated on silica gel and purified by flash chromatography on silica gel (EtOAc / heptane) to yield N- (5-bromo-2-chloro-phenyl) -C- ( 3-Chloro-phenyl) -methanesulfonamide (1.56 g). LCMS: TR = 2.77 20 minutes, MS: 394 (M + Na).

Step 2. To a solution of N- (5-bromo-2-chloro-phenyl) -C- (3-chloro-phenyl) methanesulfonamide (0.6 g), 1- (tert-butoxycarbonyl) -indole-2 acid -lboronic (0.6 g) and cesium fluoride (0.35 g) in 10: 1 1 of dioxane: water (11 ml) is added PdCl2 (dppf) 2 (0.125 g) in a nitrogen atmosphere. The mixture is heated at 80 ° C for 3 hours. After cooling, the reaction mixture is poured into water and extracted with EtOAc. The organic layer is concentrated and heptane is added to produce a precipitate that is filtered. The filtrate is passed through a bed of silica and evaporated on silica gel. The crude material is purified by flash chromatography on gel.

of silica (EtOAc / heptane) to produce 2- [4-chloro-3- (3-chloro-phenylmethanesulfonylamino) -phenyl] -indole-1-carboxylic acid tert-butyl ester (0.73 g). LCMS: TR = 3.36 minutes, MS: 531 (M + Na).

Step 3. Trifluoroacetic acid (10 ml) is added to 2- [4-chloro-3- (3-chloro-phenylmethanesulfonylamino) -phenyl] -indole-1-carboxylic acid tert-butyl ester (0.70 g) and the solution resulting is stirred at room temperature for 1 hour. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc and washed with 10% NaHCO3. The organic layer is dried (MgSO4), evaporated on silica gel and purified by flash chromatography on silica gel (EtOAc / heptane) to yield N- [2-chloro-5- (1H-indole-2-yl) -phenyl ] -C- (3-Chloro-phenyl) -methanesulfonamide (0.56 g). LCMS: TR = 2.93 minutes, MS: 431 (M + Na).

Step 4. To a suspension of N- [2-chloro-5- (1 H -indole-2-yl) -phenyl] -C- (3-chloro-phenyl) methanesulfonamide (0.51 g) in 30 ml of DCM Oxalyl chloride (0.23 g) is added dropwise at room temperature. After stirring for 2 hours, methanol (2 ml) is added dropwise and the mixture is stirred for 10 minutes. Then, the reaction mixture is evaporated on silica gel and purified by flash chromatography on silica gel (EtOAc / heptane) to produce {2- [4-chloro-3- (3-chloro-phenylmethanesulfonylamino) acid methyl ester. -phenyl] -1H-indole-3-yl} -oxo-acetic acid (0.46 g). LCMS: TR = 2.67 minutes, MS: 517 (M + Na).

Step 5. Triethylsilane (0.19 g) is added dropwise to a solution of {2- [4-chloro-3- (3-chloro-phenylmethanesulfonylamino) -phenyl] -1H-indole-3- methyl ester il} -oxo-acetic acid (0.42 g) in 10 ml of trifluoroacetic acid. The mixture is stirred for 6 hours. More triethylsilane (0.1 g) is added and the solution is stirred overnight at room temperature. Then, the mixture is concentrated under reduced pressure and the residue is partitioned between EtOAc and sat. NaHCO3. The organic layer is evaporated on silica gel and purified by flash chromatography on silica gel (EtOAc / heptane) to produce {2- [4-chloro-3- (3-chlorophenylmethane-sulfonylamino) -phenyl] methyl ester. -1H-indole-3-yl} -acetic acid (0.3 g). LCMS: TR = 2.86 minutes, MS: 503 (M + Na).

Step 6. To a solution of {2- [4-chloro-3- (3-chlorophenylmethanesulfonylamino) -phenyl] -1H-indole-3-yl} -acetic acid methyl ester (0.24 g) in 3: 3 : 1 THF: MeOH: H2O (14 ml) lithium hydroxide (0.041 g) is added. The solution is stirred at 80 ° C overnight. 2 more equivalents of lithium hydroxide are added and heating is continued for 6 h until the reaction is complete. The solvent is removed under reduced pressure and 10% aqueous HCl is added to the residue. The mixture is extracted twice with EtOAc. The combined organic layers are dried (MgSO4), filtered, evaporated on silica gel and purified by flash chromatography on silica gel (EtOAc / heptane) to produce acid {2- [4-chloro-3- (3- chlorophenylmethanesulfonylamino) -phenyl] -1H-indole-3-yl} -acetic acid (186 mg). LCMS: TR = 2.53 minutes, MS: 489 (M + Na). 1H NMR (300 MHz, DMSO) � 3.78 (s, 2H), 4.67 (s, 2H), 7.07 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H), 7.40-7.46 (m, 4H), 7.51 (s, 1H), 7.57 (m, 2H), 7.70 (d, J = 8, 2 Hz, 1H), 7.83 (s, 1H), 9.75 (s, 1H), 11.44 (s, 1H), 12.44 (s, 1H). IC50 = 12 nM

PHARMACOLOGICAL TESTS

The inhibitory effects of the compounds according to the invention are evaluated in a functional human DP assay. A cAMP assay is used using the human cell line LS174T, which expresses the endogenous DP receptor. The protocol is similar to that described previously (Wright DH, Ford-Hutchinson AW, Chadee K, Metters KM, The human prostanoid DP receptor stimulates mucin secretion in LS174T cells, Br J Pharmacol., 131 (8): 1537-1545 (2000) ).

Protocol for cAMP assay by SPA in human LS174T cells

materials

•

PGD2 (Cayman Chemical N °at 12010)

•

IBMX (Sigma N °at 5879)

•

CAMP direct scan test system by SPA (Amersham Code RPA 559)

•

96-well cell plates (Wallac N °at 1450-516)

•

Counter of scintillation Wallac 1450 Microplate Trilux (PerkinElmer)

•

Plate sealants

•

Eppendorf tubes

•

Dulbecco phosphate buffered saline (PBS) (Invitrogen N °at. 14040-133)

•

Distilled water

•

Vortex

•

Magnetic stirrer and stir bars

Reagent Preparation:

All reagents should be allowed to equilibrate at room temperature before reconstitution.

1 x test buffer

Transfer the contents of the bottle to a 500 ml graduated test tube by repeated washing with distilled water. Adjust the final volume to 500 ml with distilled water and mix thoroughly.

Lysis reagents 1 and 2

Dissolve each of the lysis reagents 1 and 2 in 200 ml of assay buffer respectively. Leave at room temperature for 20 minutes to dissolve.

SPA anti-rabbit beads

Add 30 ml of lysis buffer 2 to the bottle. Shake the bottle gently for 5 minutes.

Antiserum

Add 15 ml of lysis buffer 2 to each vial and mix gently until the content has completely dissolved.

Marker (I125-AMPc)

Add 14 ml of lysis buffer 2 to each vial and mix gently until the content has completely dissolved.

Immunoreactive Preparation

1) Add equal volumes of indicator, antiserum and reagent of SPA anti-rabbit to a bottle, ensuring that a sufficient volume of this mixture is prepared for the desired number of wells (150 µl / well).

2) Mix thoroughly.

3) This immunoreactive solution should be prepared recently before each test and not reused.

Pattern

1) Add 1 ml of lysis buffer 1 and mix gently until the contents have completely dissolved.

2) The final solution contains cAMP at a concentration of 512 pmol / ml.

3) Label 7 polypropylene or polystyrene tubes, 0.2 pmol, 0.4 pmol, 0.8 pmol, 1.6 pmol, 3.2 pmol, 6.4 pmol and 12.8 pmol.

4) Insert with a pipette 500 µL of lysis buffer 1 in all tubes.

10 5) In the 12.8 pmol tube, introduce 500 µl of stock solution standard (512 pmol / ml) with a pipette and mix thoroughly. Transfer 500 µl of the 12.8 pmol tube to the 6.4 pmol tube and mix thoroughly. Repeat this dilution in half successively with the other tubes.

6) 50 µl aliquots per duplicate of each serial dilution and standard

15 of stock solution will produce 8 standard levels of cAMP varying from 0.2-25.6 pmol of standard.

Compound dilution buffer

Add 50 µl of 1 mM IBMX in 100 ml of PBS to achieve a final concentration of 100 µM and sonicate at 30 ° C for 20 minutes.

20 Preparation of PGD2

Dissolve 1 mg of PGD2 (FW, 352.5) in 284 µl of DMSO to prepare a 10 mM stock solution and store at 20 ° C. It is prepared recently before each trial. Add 3 µl of 10 mM stock solution to 20 ml of DMSO, mix thoroughly and transfer 10 ml to 40 ml of PBS.

25 Dilution of Compound

The dilution of the compound is performed in Biomex 2000 (Beckman) using the 11 points of Method 1_AMPc DP.

5 µl of each compound is transferred from the 10 mM compound stock solution plates to the wells of a 96-well plate respectively as indicated below.

 image 1

one 2 3 4 5 6 7 8 9 10 eleven 12

TO

one image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1

B

2 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1

C

3 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1

D

4 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1

AND

5 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1

F

6 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1

G

7 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1

H

reference image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1

Fill the plate with 45 µl of DMSO except column 7, which is filled with 28 µl of DMSO. Pipette column 1 thoroughly and transfer 12 µl to parallel column 7. Perform serial dilutions 1:10 from column 1 to column 6 and from column 7 to column 11 by transferring 5 µl to 45 µl of DMSO to obtain the following concentrations:

First plate

Final concentration

Column 12

0

Column 11

0.03 µM

Column 10

0.3 µM

Column 9

3 µM

Column 8

0.03 mM

First plate

Final concentration

Column 7

0.3 mM

Column 6

0.01 µM

Column 5

0.1 µM

Column 4

1 µM

Column 3

0.01 mM

Column 2

0.1 mM

Column 1

1 mM

Fill a new 96-well plate with 247.5 µl of compound dilution buffer. Transfer 2.5 µl of serially diluted compounds from the previous plate to the new plate (1: 100 dilution) as follows:

First plate

Second plate Final concentration

Column 12

Column 1 0

Column 6

Column 2 0.1 nM

Column 11

Column 3 0.3 nM

Column 5

Column 4 1 nM

Column 10

Column 5 3 nM

Column 4

Column 6 0.01 µM

Column 9

Column 7 0.03 µM

Column 3

Column 8 0.1 µM

Column 8

Column 9 0.3 µM

First plate

Second plate Final concentration

Column 2

Column 10 1 µM

Column 7

Column 11 3 µM

Column 1

Column 12 10 µM

Cell growth

1. LS174 T cells are always grown in MEM (ATCC Cat. No. 30-2003), 10% FBS (ATCC Cat. No. 30-2020) and additional 2 mM L-glutamine, at 37 ° C and 5% CO2.

5 2. Heat 0.05% trypsin and Versine (Invitrogen Cat. No. 25300-054) in a 37 ° C water bath.

3. Remove the growth medium from the cells. The cells in the T165 flask are washed twice with 4 ml of trypsin followed by incubation at 37 ° C and 5% CO2 for 3 minutes.

10 4. Add 10 ml of medium and pipette thoroughly to separate the cells and count them.

5. Bring the cell density to 2.25 x 105 cells / ml and sow 200 µl of cells / well (45,000 cells / well) in 96-well plates 1 day before the assay.

15 Test Procedure

Day 1

Sow 45,000 cells / well in 200 µl of medium in 96-well plates. Incubate the cell plate at 37 ° C, 5% CO2 and 95% humidity overnight.

20 Day2

1. Perform the dilution of the compound.

2. Prepare assay buffer, lysis buffer 1 and 2, PGD2 and standard.

3. Aspirate the medium from the cells and add 100 µl of compound solution using the Zymark ScicloneALH / FD DP cAMP protocol.

5

4. Incubate the cells at 37 ° C, 5% CO2 and 95% humidity for 15 minutes.

10

5. Add 5 µl of 300 nM PGD2 (20 x 15 nM final concentration) in each well using the Zymark PGD2 DP cAMP protocol and incubate the cells at 37 ° C, 5% CO2 and 95% humidity for an additional 15 minutes.

6. Aspirate the medium from the cells and add 50 µl of lysis buffer 1 using the Zymark DP cAMP lysis protocol and incubate at room temperature with stirring for 30 minutes.

fifteen

7. Add 150 µl of immunoreactive to all wells (a total volume of 200 µl / well).

8. Close the plates tightly and shake for 2 minutes, put them in the chamber of the scintillation counter µ of Wallac microtiter plates for 16 hours.

Day 3

twenty

Count the amount of [125I] cAMP for 2 minutes Trilux 1450 scintillation. in a accountant of

Data Processing

Preparation of the cAMP standard curve versus CPM Table 1. Typical test data for the standard

CAMP (pmol / ml)

CPM image 1 CPM Media

0.2

5725 5769 5530

0.4

5367 5259 6317

0.8

4695 4796 6507

1.6

4251 4178 6581

3.2

3434 3429 6601

6.4

2758 2716 6711

12.8

2094 2054 6680

25.6

1531 1573 6653

CAMP concentrations (pmol / ml) of unknown samples are calculated from a cAMP standard curve versus CPM. The% inhibition is calculated using the following formula:

image 1

The present invention can be carried out in other specific forms.

Claims (15)

1. A compound of formula (A) image 1 where: R is R1CH2SO2-, R2CH2SO2NH- or R3NHSO2-; R1 is phenyl optionally substituted with halo, R2 is halo substituted phenyl, R3 is 2,6-dichloro-benzyl, 3,5-dichloro-benzyl, 2,4-dichloro-phenylethyl, 2-methoxy phenylethyl, 3-methoxy-phenylethyl, 4-methoxy-phenylethyl, 2-trifluoromethyl-phenylethyl, phenylethyl or 3-phenyl-n-propyl, R4 is hydrogen, R5 is chlorine, R6 is hydrogen and R8 is hydroxy; or 15 R is cyclohexylaminosulfonyl, R4 is 4-chloro, 4-fluoro, 4-methyl or 7-chloro, R5 is chlorine or ethyl, R6 is hydrogen or methyl, and R8 is hydroxy; or R is cyclohexylaminosulfonyl, R4 is hydrogen, R5 is chlorine, R6 is hydrogen, 5 R8 is -NHR7, and R7 is methyl, methylsulfonyl, ethylsulfonyl, haloalkylsulfonyl or tetrazolyl; or one of its pharmaceutically acceptable salts, hydrates or solvates, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate. The compound according to claim 1, which is a compound of formula (I): image 1 where: R is R1CH2SO2-, R2CH2SO2NH- or R3NHSO2-; R1 is phenyl optionally substituted with halo; R2 is halo substituted phenyl; Y R3 is 2,6-dichloro-benzyl, 3,5-dichloro-benzyl, 2,4-dichloro-phenylethyl, 2-methoxyphenylethyl, 3-methoxy-phenylethyl, 4-methoxy-phenylethyl, 2-trifluoromethyl-phenylethyl, phenylethyl or 3-phenyl-n-propyl; 20 or one of its pharmaceutically acceptable salts, hydrates or solvates, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate.

3.

The compound according to claim 2, wherein R is R3NHSO2-, or a pharmaceutically acceptable salt, hydrate or solvate thereof, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate .

Four.

The compound according to claim 1, which is a compound of formula (II):

image 1 where: R4 is 4-chloro, 4-fluoro, 4-methyl or 7-chloro; R5 is chlorine or ethyl; Y R6 is hydrogen or methyl; or one of its pharmaceutically acceptable salts, hydrates or solvates, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate. The compound according to claim 4, wherein R5 is chlorine and R6 is hydrogen, or a pharmaceutically acceptable salt, hydrate or solvate, one of its pharmaceutically acceptable ester prodrugs or a salt, hydrate or solvate. of the pharmaceutically acceptable ester prodrug. 6. The compound according to claim 1, which is a compound of formula 20 (III): image 1 where: R7 is methyl, methylsulfonyl, ethylsulfonyl, haloalkylsulfonyl or tetrazolyl, or one of its pharmaceutically acceptable salts, hydrates or solvates, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate. 7. The compound according to claim 1, which is selected from {2- [4-chloro-3- (2,6-dichloro-benzylsulfamoyl) -phenyl] -1H-indole-3-yl} -acetic acid, {2- [4-Chloro-3- (3,5-dichloro-benzylsulfamoyl) -phenyl] -1H-indole-3-yl} -acetic acid, (2- {4-chloro-3- [2- ( 2,4-dichloro-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid, 10 (2- {4-Chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid, (2- {4-chloro-3 - [2- (3-Methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid (2- {4-chloro-3- [2- (4-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indole-3-yl) -acetic acid (2- {4-chloro-3- [2- (2-trifluoromethoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid, [2- (4-chloro-3-phenethylsulfamoyl acid -phenyl) -1H-indole-3-yl] -acetic acid, 15 {2- [4-Chloro-3- (3-phenyl-propylsulfamoyl) -phenyl] -1H-indole-3-yl} -acetic acid, {2- [4-chloro-3- (3-chloro- phenylmethanesulfonylamino) -phenyl] -1H-indol-3-yl} -acetic acid {2- [4-chloro-3- (3-chloro-phenylmethanesulfonylamino) -phenyl] -1H-indole-3-yl} -acetic acid, [4-Chloro-2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -acetic acid, [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -4-fluoro -1H-indole-3-yl] -acetic acid, 20 [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -4-methyl-1H-indole-3-yl] -acetic acid, [7-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) ) -1H-indole-3-yl] -acetic acid [2- (3-cyclohexylsulfamoyl-4-ethyl-phenyl) -1H-indole-3-yl] -acetic acid, 2- [2- (4-Chlorine) -3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -propionic, 2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl] -N-methyl-acetamide , 2-Chloro-N-cyclohexyl-5- [3- (2-methanesulfonylamino-2-oxo-ethyl) -1H-indol-2-yl] benzenesulfonamide, 2-Chloro-N-cyclohexyl-5- [3- ( 2-ethanesulfonylamino-2-oxo-ethyl) -1H-indol-2-yl] benzenesulfonamide, 2-Chloro-N-cyclohexyl-5- [3- (2-oxo-2-trifluoromethanesulfonylamino-ethyl) -1H-indole-2-yl] benzenesulfonamide, or 2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -N- (1H-tetrazol-5-yl) -acetamide, or one of its pharmaceutically acceptable salts, hydrates or solvates, one of its pharmaceutically acceptable ester prodrugs or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate.

8.

The pharmaceutically acceptable salt of the compound according to claim 1 is [4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indole-3-yl]-potassium acetate.

9.

A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, one of its pharmaceutically acceptable ester prodrugs or a salt, hydrate or solvate of the ester prodrug, mixed with a pharmaceutically acceptable vehicle.

10.

Use of the compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, one of its pharmaceutically acceptable ester prodrugs or a salt, hydrate or solvate of the ester prodrug for the manufacture of a medicament for treating an allergic disease , systemic mastocytosis, a disorder accompanied by systemic mast cell activation, anaphylactic shock, bronchoconstriction, bronchitis, eczema, a disease accompanied by itching, a disease that is generated secondarily as a result of a behavior that accompanies itching, chronic obstructive pulmonary diseases , ischemia-reperfusion injury, stroke, chronic rheumatoid arthritis, pleurisy or ulcerative colitis.

eleven.

Use according to claim 10, wherein the behavior accompanying the itching is scratching or hitting.

12.

Use according to claim 10, wherein the disease that is generated secondarily as a result of the behavior that accompanies the itching are cataracts, retinal detachment, inflammation, infection or sleep disorder.

13.

Use according to claim 10, wherein the allergic disease is allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma or food allergy.

14.

Use according to claim 10, wherein the diseases accompanied by itching are atopic dermatitis or urticaria.

fifteen.

A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1, a compound selected from the group consisting of an antihistamine, a leukotriene antagonist, a beta agonist, a PDE4 inhibitor, a TP antagonist and a CrTh2 antagonist, in admixture with a pharmaceutically acceptable carrier.

16.

The pharmaceutical composition according to claim 15, wherein the antihistamine is fexofenadine, loratadine, desloratadine or citirizine, the leukotriene antagonist is montelukast or zafirlukast, the beta agonist is albuterol, salbuterol or terbutaline, the PDE4 inhibitor is roflumilast cilomilast, the TP antagonist is Ramatroban and the CrTh2 antagonist is Ramatroban.

17.

A compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, one of its pharmaceutically acceptable ester prodrugs, or a pharmaceutically acceptable ester prodrug salt, hydrate or solvate for use in the treatment of a allergic disease, in particular allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma or food allergy, systemic mastocytosis, a disorder accompanied by systemic mast cell activation, anaphylactic shock, bronchoconstriction, bronchitis, eczema, a disease accompanied by itching selected from atopic dermatitis or urticaria, a disease that is generated secondarily as a result of a behavior that accompanies the itching, in particular cataracts, retinal detachment, inflammation, infection or sleep disorders, in which the behavior that accompanies the itching is scratching or hitting obstructive pulmonary diseases cr Nicas, ischemia-reperfusion injury, cerebrovascular accident, chronic rheumatoid arthritis, pleurisy or ulcerative colitis.