RS204A - 1-PHENYLSULFONYL-1,3-DIHYDRO-2H-INDOL-2-ONE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION IN THERAPY - Google Patents

Abstract

The invention concerns compounds of formula (I), as well as their addition salts with acids or organic salts, their solvates and/or hydrate(s), exhibiting affinity and selectivity for arginine-vasopressin V1b receptors and/or for ocytocin receptors, and further, for certain compounds an affinity for V1a receptors. The invention also concerns the method for preparing them, intermediate compounds of formula (IV) useful for their preparation, pharmaceutical compositions containing them and their use for preparing medicines.

Description

DERIVATIVES

1-PHENYLSULFONYL-1,3-DIHYDRO-2H-INDOL-2-ONE,

THEIR OBTAINING AND THEIR APPLICATION IN THERAPY

This invention relates to 1,3-dihydro-2H-indol-2-one derivatives, their preparation and their use in therapy.

The compounds according to the present invention show affinity for arginine-vasopressin (AVP) V1bi receptors and/or oxytocin (OT) receptors, and in addition, some of them show affinity for AVP V1a receptors.

AVP is a hormone known for its antidiuretic effect and its effect in the regulation of blood pressure. It stimulates several types of receptors: Vi(Via, Vit>), V2. These receptors are located especially in the liver, blood vessels (coronary, renal and hepatic), platelets, kidneys, uterus, adrenal gland, pancreas, central nervous system and pituitary gland. Therefore, AVP shows cardiovascular, hepatic, pancreatic, antidiuretic and effects on platelet aggregation, as well as effects on the central and peripheral nervous system, and on the uterus.

OT is a neurohypophyseal hormone of cyclic nonapeptide structure, similar to AVP. OT receptors are found mainly on the smooth muscles of the uterus and on the myoepithelial cells of the mammary glands. OT plays an important role in the birth of a child, because it is involved in the contraction of the muscles of the uterus and in lactation. In addition, OT receptors are also located on other peripheral tissues and in the central nervous system; OT can therefore have effects in the cardiovascular, renal, endocrine or behavioral fields.

The localization of various receptors is described in: S. Jard et al., "Vasopressin and oxytocin receptors: an overview", in Progress in Endocrinology, editors H. Imura and K. Shizume, Experta Medica, Amsterdam, 1988, 1183-1188, and in the following articles: J. Lab. Clin. Med. 1989, 114(6), 617-632 and Pharmacol. Rev. 1991, 43(1), 73-108.

More specifically, AVP Via receptors are located in many peripheral organs and in the brain. They have been cloned especially in rats and humans and regulate most of the known effects of AVP: platelet aggregation, uterine contractions, blood vessel contraction, aldosterone secretion, cortisol, CRF (corticotropin-releasing factor) and ACTH (adrenocorticotrophic hormone), hepatic glycogenolysis, cell proliferation and the main central effects of AVP (hypothermia, memory, etc.).

Vibsu receptors were originally identified in the adenohypophysis of various animal species (rat, pig, marten, sheep, etc.), including humans (S. Jard et al., Mol. Pharmacol. 1986, 30, 171-177; Y. Arsenijevic et al., J. Endocrinol. 1994, 141. 383-391; J. Schwartz et al., Endocrinology 1991, 129(2). 1107-1109; Y. De Kevser et al., FEBS Letters 1994, 356, 215-220) where they stimulate the release of adenocorticotrophic hormone via AVP and enhance the effects of CRF on the release of ACTH (G.E. Gillies et al., 1982, 299. 355). In the hypothalamus, V1 receptors also cause the direct release of CRF (Neuruendocrinology 1994, 60, 503-508), so, in these various aspects, they are involved in stressful situations.

These V1b receptors have been cloned in rat, human and mouse (Y. De Kevser, FEBS Letters 1994, 356, 215-220; T. Sugimoto et al., J. Biol. Chem. 1994, 269(43). 27088-27092; N. Saito et al., Biochem. Biophys. Rec. Comm. 1995, 212(3). 751-757; S. J. Lolait, 1996, 92, 6783-6787; M. A. Ventura, 1999, 22, 251-260), and various studies, in situ hybridization, PCR (polymerase chain reaction, etc.) central tissues (especially the brain, hypothalamus and adenohypophysis) and in peripheral tissues (kidneys, pancreas, adrenal glands, heart, lungs, intestine, stomach, liver, mesentery, bladder, thymus, spleen, uterus, retina, thyroid, etc.) and in some tumors (pituitary, pulmonary, etc. tumors), indicating a wide biological and/or pathological role of these receptors and potential involvement in various diseases.

For example, studies in rats have shown that AVP regulates the endocrine pancreas, via the receptor Vib) by stimulating the secretion of insulin and glucagon (B. Lee et al., Am. J. Physiol. 1995, 269( Endocrinol. Metab. 32): E1095-E1100), or the production of catecholamines in the adrenal medulla, which is the site of local synthesis of AVP (E. Grazzini et al. al., Endocrinology 1996, 137(a), 3906-3914). Thus, in the adrenal medulla tissue, it is considered that AVP through these receptors plays an important role in some types of adrenal pheochromocytoma AVP secretion, thereby inducing restrained catecholamine production, which is the cause of hypertensive states that are resistant to angiosin II receptor antagonists and to enzyme conversion inhibitors. The adrenal cortex is also rich in Via receptors, which are involved in the production of glucocorticoids and mineralocorticoids (aldosterone and cortisol). Through these receptors, AVP (in the bloodstream or locally synthesized) can induce the formation of aldosterone with an efficiency comparable to the same angiotensin II (G. Guillon et al., Endocrinology 1995, 136(3). 1285, 1295). Cortisol is a powerful regulator of the production of ACTH, the stress hormone.

Recent studies have also shown that the adrenal glands are able to directly release CRF and/or ACTH, through the activation of Vibi/or Via receptors, generated in medullary cells (G. Mavocchi et al., Peptides 1997, 18(2), 191-195; E. Grazzini etal., J. Clin. Endocrinol. Metab. 1999, 84(6), 2195-2203).

Vibs receptors are also considered tumor markers. ACTH-secreting tumors, such as some pituitary tumors, some bronchial carcinomas (SCLC (small cell lung cancers)), pancreatic, adrenal and thyroid carcinomas, which in some cases induce Cushing's syndrome (J. Bertherat et al., Eur. J. Endocrinol. 1996, 135, 173; G A. Vlttert et al., Lancet 1990, 335, 991-994; G. Dickstein. J. Metab. 1996, 2934-2941. Regarding Via receptors, these are a more specific marker for small cell lung cancers (SCLS) (P.J. Woll et al., Biochem. Biphys. Res. Commun. 1989, 164(1), 66-73). Thus, the compounds according to the present invention are obvious diagnostic agents and offer a new therapeutic approach in the proliferation and detection of these tumors, even at an early stage (radiolabeling; SPECT (Single Photon Emission Computed Tomography); PET scanning (Scanned Positron Emission Tomography)).

The abundant presence of V receptor messengers in the stomach and intestine suggests the involvement of AVP, via this receptor, in the release of gastrointestinal hormones, such as cholecystokinin, gastrin or secretin (T. Sugimoto et al., "Molecular Cloning and Functional Expression of VibReceptor Gene, in Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research", editors T. Saito, K. Kurokavva and S. Yoshida, Elsevier Science, 1995, pp. 409-413).

It has been found in some patent applications that 1,3-dihydro-2H-indol-2-one derivatives are ligands of the arginine-vasopressin receptor and/or the oxytocin receptor: patent applications WO 93/15051, EP 636608, EP 636609, WO 95/18105, WO 97/15556 and WO 97/15556 can be mentioned. 98/25901.

It has now been found that new 1,3-dihydro-2H-indol-2-one derivatives exhibit affinity selectivity for arginine-vasopressin receptors Vb1/or oxytocin receptors, and in addition, some of them exhibit affinity for V1a receptors. These derivatives show no affinity for AVP V2 receptors.

Thus, in accordance with one aspect of the present invention, one subject of the present invention are compounds of the formula:

where are they

n is 1 or 2;

X represents the group -CH2-, -O-, -NH-, -O-CH2-, -NH-CH2-, -NH-CH2CH2-; Rrepresents a halogen atom, (Ci-C4)alkyl, (Ci-C4)alkoxy;

R2 represents a hydrogen atom, a halogen atom, (CrC4)alkyl, (d-C4)alkoxy,

trifluoromethyl radical;

R3 represents a halogen atom, (Ci-C3) alkyl, (Ci-C3) alkoxy, trifluoromethyl

radical, trifluoromethoxy radical;

R 4 represents a hydrogen atom, a halogen atom, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkyl; Rs represents a radical chosen from:

R 6 represents (C 1 -C 4 ) alkoxy;

R7 represents (C1-C4 alkoxy;

and also their salts with mineral or organic acids, their solvates and/or their hydrates.

Compounds of formula (I) may contain one or more asymmetric carbon atoms. Therefore, they can exist in the form of enantiomers or diastereomers. These enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures, form part of the present invention.

The compounds of formula (I) can exist in the form of bases or addition salts with acids. These addition salts are part of the present invention.

It is convenient that these salts are obtained with pharmaceutically acceptable acids, but salts of other acids are also useful, for the purpose of purification or isolation of compounds of formula (I), also forming part of this invention.

Compounds of formula (I) can also exist in the form of hydrates or solvates, i.e. in the form of associates or combinations with one or more molecules of water or solvent. These hydrates and solvates are also part of the present invention.

The term "halogen" means an atom of chlorine, bromine, fluorine or iodine.

The term "alkyl" means a linear or branched alkyl radical, having one to three carbon atoms or one to four carbon atoms, such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radical.

The term "Alkoxy" means a linear or branched alkoxy radical, having one to three carbon atoms or one to four carbon atoms, such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy radical.

Suitably, the present invention relates to compounds of formula (I) in which R 5 represents a radical selected from: -O.-O-O-D-O-O

In accordance with the present invention, those compounds of formula (I) in which R 1 represents a chlorine atom or a methyl radical are preferred.

In accordance with the present invention, those compounds of formula (I) are preferred in which R 2 represents a hydrogen atom, a chlorine atom, a methyl radical, a methoxy radical or a trifluoromethyl radical.

In accordance with the present invention, those compounds of formula (I) are preferred in which R 3 represents a chlorine atom, a fluorine atom, a methoxy radical, an ethoxy radical, an isopropoxy radical, a trifluoromethoxy radical or a trifluoromethyl radical.

In accordance with the present invention, those compounds of formula (I) are preferred in which R 4 represents a hydrogen atom or a methoxy radical.

According to the present invention, those compounds of formula (I) are preferred in which R 5 represents 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or 1,3-thiazol-2-yl.

In accordance with the present invention, those compounds of formula (I) are preferred in which R 6 in position 2 is phenyl and is a methoxy radical.

In accordance with the present invention, those compounds of formula (I) are preferred in which R 7 represents a methoxy radical.

Particularly preferred are those compounds of formula (I) in which:

n and X are defined for the compound of formula (I);

It represents a chlorine atom or a methyl radical;

R2 represents a hydrogen atom, or is in position 4 or 6 of indol-2-one, and represents

chlorine atom, methyl radical, methoxy radical or trifluoromethyl radical;

R3 represents a chlorine atom, a fluorine atom, a methoxy radical, an ethoxy radical,

isopropoxy radical, trifluoromethyl radical or trifluoromethoxy radical;

R4 represents a hydrogen atom or a methoxy radical;

R5 represents 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or

2,3-thiazol-2-yl;

R6 is in position 2 of phenyl, and represents the methoxy radical;

R7 is a methoxy radical;

and also their salts with mineral or organic acids and their solvates and/or hydrates.

More specifically, preferred are those compounds of formula (I) in which:

n is 1 or 2;

X represents the group -CH2-, -O-, -NH-;

R1 represents a chlorine atom;

R2 represents a hydrogen atom;

R3 represents a methoxy radical, an ethoxy radical or an isopropoxy radical;

R4 represents a hydrogen atom;

R5 represents a radical chosen from:

R6 is in position 2 of phenyl, and represents the methoxy radical;

R7 is a methoxy radical;

and also their salts with mineral or organic acids and their solvates and/or hydrates.

More particularly, preferred compounds of formula (I) are also those in which:

n is 1;

X represents the group -CH2-, -O-, -NH-;

R-i represents a chlorine atom or a methyl radical;

R2 represents a hydrogen atom, or is in position 4 or 6 of indol-2-one, and represents

chlorine atom, methyl radical, methoxy radical;

R3 represents a chlorine atom, a fluorine atom or a methoxy radical;

R4 represents a hydrogen atom;

R5 represents a radical chosen from:

R6 is in position 2 of phenyl, and represents the methoxy radical;

R7 is a methoxy radical;

and also their salts with mineral or organic acids and their solvates and/or hydrates.

Finally, more specifically, preferred are those compounds of formula (I) in which:

n is 1; X represents the group -O-, -NH, -NH-CH2CH2-; R1 represents a chlorine atom; R2 represents a hydrogen atom; R3 represents a chlorine atom or a methoxy radical; R4 represents a hydrogen atom; R5 represents a radical

R6 is in position 2 of phenyl, and represents the methoxy radical;

R7 is a methoxy radical;

and also their salts with mineral or organic acids and their solvates and/or hydrates.

The following compounds are most preferred:

5-chloro-3-(2-ethoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-[2-oxo-2-[4- (4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-3-(2-isopropoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-[2-oxo-2-[4- (4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5-Chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3,1H-indol-3-yl 4-(2-pyridyl)-1-piperazinecarboxylate;

5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1α-indoph-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate;

N-[5-chloro-1-[(2,4-dimethoxyphenyl)-sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(3-pyridyl)-homopiperazine-1-carboxamide; N-[5-chloro-1-[(2,4-dimethoxyphenyl)-sulfonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-pyridyl)-piperazine-1-carboxamide; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-3-[[3-oxo-3-[4-(2-pyridyl)-1-piperazinyl]propyl]amino]-1,3-dihydro-2H-indol-2-one; 5,6-dichloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-6-methyl-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1N-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-6-methoxy-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate; N-[5-chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-2-oxo-2,3-

dihydro-1 H -indol-3-yl]-4-(2-pyridyl)piperazine-1-carboxamide; N-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-pyridyl)piperazine-1-carboxamide; N-[6-chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-5-methyl-2-oxo-2,3-dihydro-1 H -indol-3-yl]-4-(4-pyridyl)piperazine-1-carboxamide; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorophenyl)-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5,6-dichloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorophenyl)-3-[2-oxo-2-[4-(4-

pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2 H -indol-2-one;

5-chloro-3-(2,3-dimethoxyphenyl)-1-[(2,4-dimethoxy^

pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2 H -indol-2-one;

5-chloro-1-[(214-dimethoxyphenyl)sulfonyl]-3-(2-ethoxyphenyl)-3-[2-oxo-2-[4-(3-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2/-/-indol-2-one;

5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-isopropoxyphenyl)-3-[2-oxo-2-[4-(3-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one;

5-chloro-1-[(2,4<imethoxyphenyl)sulfonyl]-3-(2-isopropoxyphenyl)-3-[2-oxo-2-[4-(4-pyridyl)-1-homopiperazine]ethyl]-1,3-dihydro-2/-/-indol-2-one; 5-chloro-1-[(2,4<limethoxyphenyl)sulfonyl]-3-(2-isopropoxyphenyl)-3-[2-oxo-2-[4-(1,3-thiazol-2-yl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-etho[1H-indol-3-yl 4-(3-pyridyl)-1-piperazinecarboxylate;

5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-

1 H -indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate;

in the form of optically pure isomers or in the form of a mixture, and also their salts with mineral or organic acids, and their solvates and/or hydrates.

In accordance with the following aspect, the subject of this invention is a process for obtaining compounds of formula (I), characterized by

that the compound of the formula:

where R 1 , R 2 , R 3 , R 4 and X are as defined for the compound of formula (I), and Y represents a hydroxyl group or a chlorine atom, when X represents a group

-CH2-, -OCH2-, -NH-CH2-, -NH-CH2-CH2-; or

Y represents phenoxy, when X represents the group -0-; -NH-;

W represents a hydrogen atom when X represents the group -CH2-; -OCH2-; or

W represents a group

wherein R 6 and R 7 are as defined for the compound of formula (I), when X represents the group -O-; -NH-; -NH-CH2-; -NH-CH2-CH2-; reacts with a compound of formula: where n and R 5 are defined for a compound of formula (I); when W represents a group

giving the expected compound of formula (I); or when

W represents a hydrogen atom, the compound that is then obtained has the formula: which reacts, in the presence of a base, with a sulfonyl halide of the formula:

where R 6 and R 7 are defined for the compound of formula (I) and Hal represents a halogen atom.

Optionally, the compound of formula (I) is converted into its salt with a mineral or organic acid.

When Y represents a hydroxyl group, the reaction of the compound of formula (II) with the compound of formula (III) is carried out in the presence of a coupling agent, used in the herniation of the peptide, such as benzotriazol-1-yloxythyr(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yloxythyr-pyrrolidinophosphonium hexafluorophosphate, in the presence of a base, such as triethylamine or N,N-diisopropylethylamine, in a solvent such as dichloromethane or N,N-dimethylformamide, at a temperature between 0°C and room temperature.

When Y represents a chlorine atom, the reaction of compound (II) with compound (III) is carried out in the absence or presence of a base, such as triethylamine or N,N-diisopropylethylamine, in a solvent, such as dichloromethane or chloroform, and at a temperature between -60°C and room temperature. In the absence of a base, an excess of compound (III) is used.

When Y represents phenoxy, the reaction of compound (II) with compound (III) is carried out in a solvent, such as dichloromethane, chloroform or tetrahydrofuran, or a mixture of these solvents, at a temperature between room temperature and the reflux temperature of the solvent.

In this way, either the compound of formula (I) or the compound of formula (IV) is obtained directly. The reaction of a compound of formula (IV) with a sulfonyl halide (V) is carried out in the presence of a strong base, for example, a metal hydride, such as sodium hydride or an alkali metal alkoxide, such as potassium tert-butoxide, in a solvent, such as N,N-dimethylformamide or tetrahydrofuran, at a temperature between ~70°C and room temperature. Preferably, this reaction is carried out using a compound of formula (V), where Hal represents a chlorine atom.

The thus obtained compounds of formula (I) can subsequently be separated from the reaction medium and purified by standard methods, for example by crystallization or chromatography.

The thus obtained compounds of formula (I) can be isolated as the free base or as a salt according to standard techniques. Compounds of formula (II) are obtained by various operational methods. Compounds of formula (I), where X represents a -CH 2 - group, Y represents hydroxyl, and W represents hydrogen, are obtained according to Scheme 1 below, where R 1 , R 2 , R 3 and R 4 are as defined for the compound of formula (I) and Alk is (C 1 -C 2 )alkyl.

In step a1 of Scheme 1, the compound of formula (VIII) is obtained by dehydroxylation of the corresponding compound of formula (VI), under the action of triethylsilane, in accordance with the procedure from Bioorganic and Medicinal Chemistry Letters 1997, 7(10), 1255-1260.

The compound of formula (VIII) can also be obtained by the cyclization reaction (step b1) of the compound of formula (VII) in a strongly acidic medium, for example in sulfuric acid or polyphosphoric acid, according to the procedure described in WO 95/18105, or uJ. Org. Chem. 1968, 33, 1640-1643.

In step c1, a compound of formula (VIII) is reacted with a compound of formula Hal-CHaCOOAlk, where Hal represents a halogen atom, preferably bromine or chlorine, and Alk represents (C-i-C2)alkyl, in the presence of a base, such as an alkali metal carbonate (for example, potassium carbonate) and an alkali metal iodide (for example, potassium iodide) or in the presence of a strong base, such as an alkali metal hydride (for example, sodium hydride), or an alkali metal alkoxide (eg, sodium ethoxide), giving a compound of formula (IX). The reaction is carried out in a solvent such as acetone or N,N-dimethylformamide, at a temperature between 0°C and the reflux temperature of the solvent.

In step d1, the expected compound of formula (II) is obtained by hydrolysis of the compound of formula (IX) in an alkaline medium using an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in a solvent such as water, methanol, ethanol, tetrahydrofuran or dioxane, or a mixture of these solvents, at a temperature between 0°C and the reflux temperature of the solvent.

The compounds of formula (VI) are known and are prepared according to known procedures, such as those described in WO 95/18105.

For example, the compound of the formula (VI) is obtained by the reaction of the 1/-/-indole-2,3-dione derivative of the formula:

where R 1 R 2 are defined for the compound of formula (I),

with an organo-magnesium derivative of the formula:

wherein R 3 and R 4 are as defined for compounds of formula (I) and Hal represents a halogen atom, preferably bromine or iodine, in a solvent, such as tetrahydrofuran or diethyl ether, at a temperature between 0°C and the reflux temperature of the solvent.

A compound of formula (VI), in which R3 is as defined for a compound of formula (I), and R4, which is different from hydrogen, is in the 3- or 6-position of phenyl, can also be obtained by reacting compounds of the formula:

where R 3 is as defined for a compound of formula (I) and R 4 is in the 2 or 5 position of phenyl, with a lithium derivative, such as n-butyllithium, and the resulting lithiated intermediate is then reacted with a compound of formula (X). This reaction is carried out in a solvent, such as diethylether, tetrahydrofuran, hexane or a mixture of these solvents, at a temperature between -70°C and room temperature.

Derivatives of 1/7-indole-2,3-dione (X) are commercially available or obtained according to procedures described in Tetrahedron Letters 1998, 39, 7679-7682; Tetrahedron Letters 1994, 35, 7303-7306; J. Org. Chem. 1977, 42(8), 1344-1348; J. Org. Chem. 1952, 17, 149-156; J. Am. Chem. Soc. 1946, 68, 2697-2703; Organic Syntheses 1925, V, 71-74 and in Advances in Heterocyclic Chemistr/, ed. A.R. Katritzkv and A.J. Bolton, Academic Press, New York, 1975, 18, 2-58.

Organo-magnesium (XI) derivatives are obtained according to standard procedures, which are well known to those skilled in the art.

In particular, compounds of formula (VI), in which R3= (C1-C2) alkoxy and R4= H, or R3= R4= (C1-C2) alkoxy, with R4 in position 3 or 6 of phenyl, and R2 is different from a halogen atom, while R1 is defined for the compound of formula (I), can be obtained by the procedure described in Scheme 2.

In step a2 of Scheme 2, a compound of formula (XII) is first reacted with a lithium derivative, such as n-butyllithium, in the absence or presence of a base, such as N,N,N',N'-tetramethylethylenediamine, and the resulting lithiated intermediate is then reacted with diethyl oxalate to give a compound of formula (XIII). This reaction is carried out in a solvent, such as diethylether, tetrahydrofuran, hexane, or a mixture of these solvents, at a temperature between -70°C and room temperature.

In step b2, the compound of formula (XIV) is first reacted with two equivalents of a lithium derivative, such as tert-butyllithium, and the resulting lithiated intermediate is then reacted with the compound of formula (XIII), giving the expected compound of formula (VI). This reaction is carried out in a solvent, such as diethylether, tetrahydrofuran, pentane or a mixture of these solvents, at a temperature between -70°C and room temperature.

Compounds of formula (XII) are commercially available, or are synthesized in a conventional manner.

Compounds of formula (XIV) are obtained by reacting the corresponding aniline derivatives with di-tert-butyl dicarbonate, according to conventional procedures.

Compounds of formula (VII) are known and are obtained according to procedures such as those described in WO 95/18105, or in J. Org. Chem. 1968, 33, 1640-1643.

Compounds of formula (II), where X = -CH2-, Y represents a chlorine atom, and W = H, are obtained from the corresponding compounds of formula (II) in which Y = OH, by reaction with thionyl chloride, in a solvent, such as toluene, at a temperature between 0°C and the reflux temperature of the solvent.

Compounds of formula (II), where -X- represents the -0- group, Y represents phenoxy, and W

is

are obtained according to Scheme 3 below, where R1, R2, R3,

R 4 , R 6 and R 7 are as defined for the compound of formula (I).

In step a3 of Scheme 3, the hydroxyl in the compound of formula (VI) is selectively protected, using, for example, hexamethyldisilazane, according to the procedure described in Synthetic Communications 1993, 23(12), 1633-1641.

The thus obtained compound of formula (XV) reacts, in step b3, with the sulfonyl halide of formula (V), in the presence of a strong base, under the conditions described above.

In step c3, deprotection of the trimethylsilyl group in the obtained compound of formula (XVI) gives the compound of formula (XVIII). This reaction is carried out by the action of a strong acid, such as hydrochloric acid or trifluoroacetic acid, in a solvent such as dichloromethane, acetone, tetrahydrofuran or water, or in a mixture of these solvents, at a temperature between room temperature and the reflux temperature of the solvent.

The compound of formula (XVIII) can also be obtained by reaction in step d3, from the compound of formula (X) with the sulfonyl halide of formula (V), in accordance with the conditions described above, followed by the reaction of the thus obtained compound of formula (XVII) with the organo-magnesium derivative of formula (XI), in accordance with the conditions previously described.

In step f3, the thus obtained compound of formula (XVIII) is reacted with phenylchloroformate, in the presence of a base, such as pyridine, in a solvent, such as dichloromethane, or without solvent, at a temperature between 0°C and 100°C, giving the expected compound of formula (II).

The compound of formula (VI) is obtained according to the procedures described earlier. A compound of formula (VI) can also be obtained by oxidation in air of a compound of formula (VIII) in the presence of a base, such as sodium hydride, in the presence of dimethyldisulfide.

The compound of the formula (VI) can also be obtained by hydrolysis of the halide of the formula:

where R 1 , R 2 , R 3 and R 4 are defined for the compound of formula (I), and Hal represents a halogen atom, preferably bromine or chlorine. This reaction is carried out in a solvent such as tetrahydrofuran at a temperature between room temperature and the reflux temperature of the solvent.

Compounds of formula (XIX) are known and are obtained according to known procedures, such as those described in VVO 95/18105.

Compounds of formula (II), where -X- represents the -NH- group, Y represents phenoxy, a

W represents a group

are obtained in accordance with the procedures that are

described in WVO 95/18105.

Compounds of formula (II), where -X- represents an -O-CH2- group, Y represents hydroxyl and W represents hydrogen, are prepared according to Scheme 4 below, where R 1 R 2 , R 3 and R 4 are as defined for the compound of formula (I).

In step a4 of Scheme 4, a compound of formula (XIX) is reacted with methyl glycolate in the presence of a strong base, such as sodium hydride, in a solvent, such as tetrahydrofuran or dichloromethane, at a temperature between 0°C and the reflux temperature of the solvent.

The thus obtained compound of formula (XX) is hydrolyzed in step b4, in an alkaline medium by the procedures previously described in step d1 of Scheme 1, giving the expected compound of formula (II).

Compounds of formula (II), where X = -0-CH 2 -, Y represents a chlorine atom, and W = H, are obtained from the corresponding compounds of formula (II) where Y = OH, by reaction with thionyl chloride, according to the procedure previously described.

Compounds of formula (II) where -X- represents the -NH-CH2- group, Y represents

hydroxyl, and VV represents the group

are obtained according to Scheme 5 below, where R 1 (R 2 , R 3 , R 4 , R e and R 7 are as defined for a compound of formula (I).

In step a5 of Scheme 5, a compound of formula (XIX) is reacted with glycine tert-butyl ether in the presence of a base, such as triethylamine or N,N-diisopropylethylamine, in a solvent, such as dichloromethane, chloroform or tetrahydrofuran, or a mixture of these solvents, at a temperature between 0°C and room temperature.

The thus obtained compound of formula (XXI) is reacted in step b5 with the sulfonyl halide of formula (V), in the presence of a strong base, according to the conditions previously described.

In step c5, the thus obtained compound of formula (XXII) is hydrolyzed in an acidic medium, using a strong acid, such as hydrochloric acid or trifluoroacetic acid, in a solvent, such as dichloromethane, tetrahydrofuran, acetone or water, or a mixture of these solvents, or without a solvent, at a temperature between 0°C and room temperature. Thus, the expected compound of formula (II) is obtained.

Compounds of formula (II), where X = -NH-CH2, Y represents a chlorine atom, and W is

are obtained from the corresponding compounds of formula (II) in which

Y = OH, according to the procedures previously described.

Compounds of formula (I), where -X- represents the -NH-CH2-CH2- group, Y represents

hydroxyl, and W represents a group

are obtained according to Scheme 6 below, where R 1 , R 2 , R 3 , R 4 , R 6 and R 7 are as defined for the compound of formula (I).

In step a6 of Scheme 6, the compound of formula (XIX) is reacted with p-alanine-butyl ester, in the presence of a base, such as triethylamine or N,N-diisopropylethylamine, in a solvent, such as dichloromethane, chloroform or tetrahydrofuran, or in a mixture of these solvents, at a temperature between 0°C and room temperature.

The thus obtained compound of formula (XXIII) is reacted in step b6 with the sulfonyl halide of formula (V), in the presence of a strong base, according to the conditions previously described.

In step c6, the thus obtained compound of formula (XXIV) is hydrolyzed in an acidic medium according to the conditions described earlier in step c5 of Scheme 5. Thus, the expected compound of formula (II) is obtained.

Compounds of formula (II), where -X- = -NH-CH2-CH2, Y represents a chlorine atom, and W are obtained from the corresponding compounds of formula (II), where Y =

OH, according to the procedures described earlier.

Compounds of formula (III) are commercially available or are obtained according to known methods described in J. Org. Chem. 1953, 18, 1484-1488, in J. Med. Chem. 1978, 21(6), 536-542, in Chem. Pharm. Bulli 1991, 39(9), 2288-2300, in Tetrahedron Letters 1998, 39, 617-620, or in WO 97/28129.

For example, a compound of formula (III) is obtained by reacting a compound of formula: where n is defined for a compound of formula (I) and Z represents hydrogen or an N-protected group, with a compound of formula: organic bases, such as diisopropylethylamine, or between alkali metal carbonates, such as sodium carbonate or potassium carbonate. In the absence of a base, the reaction is carried out using an excess of a compound of formula (XXV). This reaction can also be carried out without a solvent by heating a mixture of compounds (XXV) and (XXVI) to temperatures between 140°C and 180°C.

Where appropriate, when Z represents an N-protecting group, it is removed according to standard procedures to give the expected compounds of formula (III). Compounds of formula (XXV) or formula (XXVI) are known and are obtained by known procedures.

Compounds of formula (V) are known, or are obtained by known processes, such as those described in EP-0469984 B and in VVO 95/18105. For example, compounds of formula (V) can be obtained by halogenation of the corresponding benzenesulfonic acids or their salts, for example their sodium or potassium salts. This reaction is carried out in the presence of a halogenating agent, such as phosphorus oxochloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide, or phosphorus pentachloride, without a solvent, or in an inert solvent, such as a halogenated hydrocarbon or N.N-dimethylformamide, at a temperature between -10°C and 200°C.

The compound 2,4-dimethoxybenzenesulfonyl chloride is obtained according to the procedure of J. Am. Chem. Soc. 1952, 74, 2008. The compound 3,4-dimethoxybenzenesulfonyl chloride is commercially available, or is obtained by the process of J. Med. Chem. 1977, 20(10), 1235-1239.

In order to obtain the compound of formula (I) in the form of an optically pure isomer, standard separation methods can be used: for example, fractional crystallization of a salt formed from a racemic base with an optically active acid, the principle of which is well known, or standard techniques of chromatography on a chiral phase.

Optically pure compounds of formula (I) can also be obtained from optically pure intermediate compounds useful for obtaining compounds of formula (I).

Therefore, if it is desired to obtain an optically pure compound of formula (I), where -X- = -CH2-, the optical separation of the compound of formula (II), where -X- = -CH2-, Y = OH, and W = H, is carried out in accordance with the procedure described in J. Am. Chem. Soc, 1989, 111, 7650-7651, using (R)-pantolactone as the chiral agent, or using a chiral amine, such as (+)-cinchonine.

An optically pure compound of formula (I), where -X- = -0-, can be obtained according to the procedure described in Scheme 7 below, where R 1 , R 2 , R 3 , R 4 , n and R 5 are defined for the compound of formula (I) and R represents phenyl or isobutyl.

In step a7 of Scheme 7, a compound of formula (VI) is reacted with phenylchloroformate, in the presence of a base, such as pyridine, in a solvent, such as dichloromethane, or without solvent, at a temperature between 0°C and 100°C.

The thus obtained compound of formula (XXVII) reacts, in step b7, with the compound of formula (III); in a solvent, such as dichloromethane, chloroform or tetrahydrofuran, or in a mixture of these solvents, at a temperature between room temperature and the reflux temperature of the solvent, to give a compound of formula (XXVIII).

Reaction of a compound of formula (XXVII) with L-lucinol (R = isobutyl) or D-lucinol, or with (R)-(-)-(a)-phenylglycinol (R = phenyl), or with (S)-(+)-(a)-phenylglycinol, in step c7, gives a mixture of diastereomers of compound of formula (XXIX) which can be separated, for example, by chromatography or crystallization.

By reacting one of the diastereomers of compound (XXIX), in step d7, with a strong base, such as sodium methoxide, in a solvent such as methanol or tetrahydrofuran, or a mixture of these solvents, at a temperature between 0°C and the reflux temperature of the solvent, an optically pure compound of formula (XXX) is obtained.

The reaction of compound (XXX) with a sulfonyl halide of formula (V), in accordance with the procedures previously described, gives an optically pure compound of formula (I), where X = -0-.

If one wants to obtain an optically pure compound of formula (I), in which -X- = -NH-,

compound of formula (II), in which -X- = -NH-, Y = phenoxy, a

is obtained optically pure by the procedure described in Scheme 8 below, where R 1 , R 2 , R 3 , R 4 , R 6 and R 7 are defined for the compound of formula (I), and Hal represents a halogen atom, preferably chlorine or bromine.

In step a8 of Scheme 8, the compound of formula (XIX) is reacted with (S)-(+)-(a)-phenylglycinol or with (R)-(-)-(a)-phenylglycinol, giving a mixture of diastereoisomers of the compound of formula (XXXI), which can be separated by chromatography or crystallization.

In step b8, an optically pure compound of the formula (XXXII) is obtained by oxidation with lead tetraacetate, and by hydrolysis in an acidic medium, one of the diastereomers of the compound is obtained

(XXXI).

In step c8, the reaction of the thus obtained compound (XXXII) with the sulfonyl halide of formula (V), followed by the reaction of the thus obtained compound (XXXIII) with phenyl chloroformniate (step d8), in accordance with the procedures described in WO 95/18105, gives the expected optically pure compound (II).

During one of the steps of obtaining compounds of formula (I) or intermediate compounds of formula (II), (III) or (IV), it may be necessary and/or desirable to protect reactive or sensitive functional groups, such as amine, hydroxyl or carboxyl groups, present in any of the observed molecules. This protection can be accomplished using conventional protecting groups, such as those described in "Protective Groups in Organic Chemistry", edited by J.F.VV. McOmie, Plenum Press, 1973, or in "Protective Groups in Organic Synthesis" edited by T.W. Greene and P.G.M. Vutts, John Wiley and Sons, 1991, or in "Protective Groups" by P.J. Kociensky-og, 1994, Georg Thieme Verlag. Removal of protecting groups can be performed in a convenient subsequent step, using procedures known to those skilled in the art, which do not affect the rest of the molecule under consideration.

N-protecting groups which may be used are standard N-protecting groups, which are well known to those skilled in the art, such as, for example, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, benzyl, benzhydrylidene or benzyloxycarbonyl groups.

The compounds of formula (V) are novel and form part of the present invention.

Thus, in accordance with the following aspect, the present invention relates to compounds of the formula:

where are:

n is 1 or 2;

X represents the group -CH2-, -O-, -O-CH2;

R represents a halogen atom, (Ci-C4)alkyl, (Ci-C4) alkoxy;

R2 represents a hydrogen atom, a halogen atom, (C1-C4)alkr1, (C1-C4)alkoxy,

trifluoromethyl radical;

R3 represents a halogen atom, (d-C3)alkyl, (CrC3)alkoxy, trifluoromethyl

radical, trifluoromethoxy radical;

R 4 represents a hydrogen atom, a halogen atom, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkyl; R5 represents a radical chosen from:

and also their salts with mineral or organic acids, in the form of optically pure isomers or in the form of a mixture.

Compounds of formula (I) above also include those in which one or more hydrogen atoms or carbon atoms have been replaced by their radioactive isotope, for example tritium or carbon-14. Such labeled compounds are useful in research, metabolic or pharmacokinetic studies and in biochemical tests, as receptor ligands.

In the Preparations and Examples that follow, this invention is illustrated, but not limited to.

The following abbreviations are used in the Preparations and Examples:

ether: diethyl ether

isoethane diisopropyl ether

DMF: N,N-dimethylformamide

THF: tetrahydrofuran

DCM: dichloromethane

EtOAc: ethyl acetate

TMEDA: N,N,N'.N'-tetramethylethylenediamine

DIPEA: diisopropylethylamine

TFA: trifluoroacetic acid

HMDS: hexamethyldisilazane

BOP: benzotriazol-1-yloxytri(dimethylamino)phosphonium

hexafluorophosphate

PyBOP: benzotriazol-1-yloxytyrpyrrolidine-phosphonium hexafluorophosphate DCC: 1,3-dicyclohexylcarbodiimide

HOBT: 1-hydroxybenzotriazole hydrate

Hydrochloric ether: a saturated solution of hydrogen chloride in diethyl ether

Temp. warmer melting temperature

RT: room temperature

Temp. the key. Boiling point

HPLC: high performance liquid chromatography

Proton magnetic resonance (<1>H NMR) spectra were recorded at 200 MHz in de-DMSO, using the de-DMSO peak as reference. Chemical shifts 8 are reported in parts per million (ppm). The observed signals are expressed as: s (singlet), bs (broad singlet), d (doublet), dd (double doublet), t (triplet), dt (double triplet), q (quartet), up (unresolved peak), mt (multiplicity).

NMR spectra confirm the structures of these compounds.

PREPARATIONS

Preparations of compounds of formula (II).

Preparation 1. 1.

2- r5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl1acetic acid

(II): R 1 =Cl; R2=H; R3 = OCH3; R4=H; X = -CH2-; Y=OH; W = H

A) 5-chloro-3-hydroxy-3-(2-methoxyphenyl)-1,3<lih

This compound is obtained in accordance with the procedure from VVO 95/18105. A solution of 2-methoxyphenylmagnesium bromide is obtained from 16 g of magnesium in 35 mL of ether and a solution of 124 g of 1-bromo-2-methoxybenzene in 175 mL of ether. This solution is added dropwise, under argon, to a mixture of 30 g of 5-chloro-1H-indole-2,3-dione in 250 ml of THF, previously cooled in an ice bath, and then this mixture is allowed to stir until the temperature returns to RT. After stirring for 1 h at RT, the reaction mixture was gently poured into saturated NH4Cl solution, and the THF was evaporated under vacuum. The resulting precipitate is separated by filtration under reduced pressure, then washed with isoether. 42 g of the expected compound is obtained, which is used in the next step without further purification.

B) 5-chloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 5.8 g of the compound obtained in the previous step, 25 ml of TFA and 10 ml of triethylsilane was concentrated under vacuum at 100°C, and the residue was dissolved in 30 ml of isoether and left to stand for 15 h at 20°C. The resulting precipitate is separated by filtration under reduced pressure, then washed with isoether and then with heptane. 4.3 g of the expected product is obtained.

C) ethyl 2-15-chloro-3-(2-methoxyphenyl)-2<)xo-2,3<iiihydro-

Mix 2.85 g of the compound obtained in the previous step, 2.05 g of ethyl bromoacetate, 2.05 g of Cl and 3.1 g of K2CO3 in 15 mL of acetone, and reflux for 20 h. Mineral salts are separated by filtration, and the filtrate is concentrated under vacuum. The residue was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is triturated with isoether, and the resulting precipitate is filtered off under reduced pressure. The precipitate is chromatographed on silica gel, eluting with DCM and then with EtOAc. 1.55 g of the expected product is obtained, after recrystallization from isoether, temp. warmer 184-187°C.

D) 2-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic

acid

A solution of 0.5 g of NaOH pellets in 10 mL of water was added, at RT, to a mixture of 1.5 g of the compound obtained in the previous step, in 30 mL of MeOH, and this mixture was stirred for 20 h at 20°C. The reaction mixture was concentrated under vacuum, and the residue was dissolved in 20 mL of water, the aqueous phase was washed with EtOAc and acidified to pH 1 by adding concentrated HCl, and the resulting precipitate was filtered off under reduced pressure. 1.15 g of the expected product is obtained, temp. warmer 135-139°C.

Preparation 1. 2,

2- f5- chloro- 3-( 2- ethoxyphenyl)- 2- oxo- 2. 3- dihydro- 1/-/- indol- 3- ylacetic acid

(II): Ri = CI; R2=H; R3 = -OCH2CH3; R4=H; X = -CH 2 ; Y = OH; W=H

A) 1-bromo-2-ethoxybenzene

Mix 17.5 g of 2-bromophenol, 66 mL of diethyl sulfate and 170 mL of 10% NaOH solution, reflux for 2 h. After cooling the reaction mixture to RT, it is extracted with EtOAc, the organic phase is washed with 2M NaOH solution, dried over Na2SO4 and the solvent is evaporated under vacuum. 19.6 g of the expected compound are obtained.

B) 5-chloro-3-(2-ethoxyphenyl)-3-hydroxy1,3-dihydro-2H-indol-2-one

A solution of 2-ethoxyphenylmagnesium bromide is prepared from 2.2 g of magnesium in 10 mL of ether and from a solution of 16.5 g of the compound obtained in the previous step, in 40 mL of ether. This solution is added dropwise, under a nitrogen atmosphere, to a mixture of 5 g of 5-chloro-1H-indole-2,3-dione in 20 mL of THF, while maintaining the temperature of the reaction medium below 35°C. After stirring at RT for 2 h, the reaction mixture was poured into 200 mL of 2M HCl, extracted with EtOAc, the organic phase dried over Na 2 SO 4 and the solvents evaporated under vacuum. The residue is stirred in isoter and left to crystallize. The resulting crystalline product is separated by filtration under reduced pressure, washed with isoether and dried. 5.7 g of the expected product is obtained, temp. warmer 251 °C.

C) 5-chloro-3-(2-ethoxyphenyl)-1,3-dihydro-2H-indol-2-one

This compound is obtained according to the procedure described in step B of Preparation 1.1, starting from 4 g of the compound obtained in the previous step, 15 mL of TFA and 5.6 mL of triethylsilane. 3.6 g of the expected product is obtained.

D) ethyl 2-[5-chloro-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetate

This compound is obtained according to the procedure described in step C of Preparation 1.1, starting from 3.5 g of the compound obtained in the previous step, 2.2 g of ethyl bromoacetate, 2.2 g of Kl and 3.5 K2CO3 in 20 mL of acetone. 1.7 g of the expected compound is obtained, after precipitation from isoether, temp. warmer 181°C.

E) 2-[5-chloroD-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic

acid

Mix 1.65 g of the compound obtained in the previous step and 2 mL of 30% NaOH solution in 50 mL of water and 20 mL of THF, stir for 24 h at RT. The mixture is concentrated under vacuum, and the residue is dissolved in 100 mL of water, then the aqueous phase is washed with EtOAc, acidified to pH 1 by adding concentrated HCl, extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated under vacuum. 1.2 g of the expected product is obtained, after crystallization from isoether, temp. warmer 212°C.

Preparation 1. 3

2- f5- chloro- 3-( 2- isopropoxyphenyl)- 2- oxo- 2, 3- dihydro- 1H- indole- 3- inacetic acid,

dextrorotatory isomer

(II): Ri = Cl; R 2 = H; R 3 = OCH(CH 3 ) 2 ; R 4 = H; X = -CH2-; Y = OH; W = H

A) 1- bromo- 2- isopropoxybenzene

A sodium ethoxide solution is prepared from 280 mL of EtOH and 7.3 g of sodium, then 50 g of 2-bromophenone is added and the mixture is stirred at RT for 30 min. Then 43 g of isopropyl bromide was added, and the mixture was refluxed for 15 h. The reaction mixture is concentrated under vacuum, the residue is dissolved in 1M NaOH solution, extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The resulting oil is distilled under reduced pressure, yielding 49.3 g of the expected product as a colorless liquid, temp. the key. 113-115°C at 3366 Pa.

B) 5-chloro-3-hydroxy-3-(2-isopropoxyphenyl)-1^

A solution of 2-isopropoxyphenylmagnesium bromide is obtained from 6.3 g of magnesium in 20 mL of ether and 49.3 g of the compound obtained in the previous step. This solution was added over 3 min to a mixture of 13.3 g of 5-chloro-1H-indole-2,3-dione in 30 mL of THF, followed by 90 min of refluxing. After cooling to RT, the reaction mixture was poured into an ice/conc. HCl mixture, extracted with EtOAc, the organic phase washed with 1 M NaOH solution and water, dried over Na 2 SO 4 , and the solvent evaporated under vacuum. The residue is stirred in hot isoether, and the resulting precipitate is filtered off under reduced pressure, but after trituration. 17.4 g of the expected product is obtained.

C) 5-chloro-3-(2-isopropoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 3.5 g of the compound obtained in the previous step, 15 mL of TFA and 5.5 mL of triethylsilane was refluxed for 8 h. This mixture was concentrated in vacuo and the residue chromatographed on silica gel, eluting with isoether and then with DCM. 2.2 g of the expected product is obtained, after crystallization from heptane, temp. warmer 154°C.

D) ethyl 2-[5-chloro-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indole-3-

yl acetate

This compound is obtained according to the procedure described in step C of Preparation 1.1, starting from 2.55 g of the compound obtained in the previous step, 1.67 g of ethyl bromoacetate, 1.66 g of Cl and 2.52 g of K 2 CO 3 in 12 mL of acetone. The obtained product is chromatographed on aluminum oxide, eluting with DCM and then acetone. 1.6 g of the expected product is obtained, after crystallization from isoether, temp. warmer 193°C.

E) 2-[5-chloro-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indole-3-

acetic acid

A solution of 1 g of NaOH pellets in 10 mL of water was added, at 40°C, to a solution of 1.6 g of the compound obtained in the previous step, in 10 mL of EtOH, and this mixture was stirred for 20 h at 20°C. The resulting mixture is concentrated under vacuum, and the residue is dissolved in 30 mL of water, heated to 40°C, and the insoluble material is separated by filtration. The filtrate was acidified to pH 1 by addition of concentrated HCl, and the resulting precipitate was filtered off under reduced pressure and dried. 1.15 g of the expected product is obtained, temp. warmer 146-148°C.

F) (3R)-4,4-dimethyl-2oxotetrahydro-3-furanyl 2-[5-chloro-3-(2-isopmoxyphenyl)-2<>xo-2,3<lihydro-1H-indol-3-yl]acetate, more polar

isomer

A mixture of 2 g of the compound obtained in the previous step and 10 mL of thionyl chloride was stirred for 20 h at 20°C. This mixture was concentrated in vacuo, the residue was taken up in DCM, and the solvent was concentrated in vacuo at RT to give 2 g of the acid chloride. This acid chloride is dissolved in 20 mL of DCM, and this solution is added to a mixture of 0.8 g of (R)-pantolactone and 1 g of N-methylpyrrolidine in 10 mL of DCM, previously cooled to 10°C, and the resulting mixture is stirred for 2 h at RT. The reaction mixture was concentrated under vacuum, the residue was stirred in water, extracted with EtOAc, the organic phase was washed with water and dried over Na 2 SO 4 , and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel H, eluting with DCM. The diastereomers are separated, and the more polar compound is collected. 0.6 g of the expected product is obtained.

G)2-[5-chloro-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indole-3-

il] acetic acid, right-handed isomer

A solution of 0.8 g of lithium hydroxide monohydrate in 10 mL of water was added to the mixture of 0.8 g of the compound obtained in the previous step, in 30 mL of MeOH, and the mixture was stirred for 20 h at 20°C. The reaction mixture was concentrated under vacuum, and the residue was extracted with water, the aqueous phase was washed with ether, acidified to pH 1 by adding concentrated HCl and extracted with DCM, and the organic phase was dried over Na2SO4, and the solvent was evaporated under vacuum. 0.5 g of the expected product is obtained.

a<20>D= +84° (c = 0.25; chloroform).

Preparation 1. 4

2-[ 3-( 2- chlorophenin- 5- methyl- 2- oxo- 2. 3- dihydro- 1H- indol- 3- yl1acetic acid

(II): R 1 = CH 3 ; R 2 = H; R 3 =Cl; R4=H; X = -CH2-; Y=OH; W=H

A) 3-(2-chlorophenyl)-5-methyl-1,3-dihydro-2H-indol-2one

This compound is obtained according to the procedure described in VVO 95/18105, in steps A and B of Preparation 65.

B) methyl 2-[3-(2-chlorothenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]acetate

A mixture of 5 g of the compound obtained in the previous step in 10 mL of DMF is cooled to a temperature below 10°C, then 0.87 g of 60% sodium hydride in oil is added in portions, and the mixture is stirred for 30 min. Then 3.15 mL of methylbromoacetate was added, and the mixture was stirred at RT for 4 h, then another 1 mL of methylbromoacetate was added, and the mixture was stirred at RT for 16 h. The reaction mixture was poured into water, extracted with EtOAc, the organic phase was washed with water and dried over Na 2 SO 4 , and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM and then with a mixture of DCM/EtOAc (95/5; V/V). 0.57 g of the expected product is obtained.

C) 2-[3-(2-chlorophenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic

acid

A solution of 0.16 g of NaOH pellets in 40 mL of water was added to a mixture of 0.57 g of the compound obtained in the previous step in 10 mL of dioxane, and the resulting mixture was stirred for 24 h at RT. 50 mL of water is added to the reaction mixture, the aqueous phase is washed with EtOAc, acidified to pH 1 by adding 1M HCl and extracted with EtOAc, then the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/EtOAc (95/5, V/V). 0.27 g of the expected product is obtained.

Preparation 1. 5

2- f5. 6<lichloro- 3- f2- methoxyphenin- 2<>xo- 2. 3<lihydro- 1H- indole- 3- inacetic acid

(II): R 1 =Cl; R 2 = 6-Cl; R3 = OCH3; R4=H; X = -CH 2 ; Y = OH; W = H

A) 5, 6-dichloro-1H-indole-2, 3-dione

This compound is obtained according to the procedure described in J. Am. Chem. Soc. 1946, 68, 2697-2703, or in accordance with the procedure described in J. Org. Chem. 1952, 17, 149-156.

B) 5, 6- dichloro- 3- hydroxy- 3-( 2- methoxyphenyl)- 1, 3- dihydm- 2M

7.5 g of 1-bromo-2-methoxybenzene is added dropwise to a suspension of 1.1 g of magnesium in 20 mL of ether, which contains several crystals of iodine, and reflux is maintained from the very beginning. At the end of the addition, the mixture is heated under reflux for 2 h. A suspension of 4.3 g of 5,6-dichloro-1H-indole-2,3-dione in 20 mL of THF was then added, and the resulting mixture was refluxed for 30 min. After cooling to RT, the reaction mixture was filtered and the water/ice/concd.HCl mixture was extracted with EtOAc, the organic phase was dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is triturated in hot isoether, and the resulting precipitate is filtered off under reduced pressure and washed with ether. 5.2 g of the expected product is obtained, temp. warmer 245-246°C.

C) 5,6-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2one

A mixture of 5.1 g of the compound obtained in the previous step, 25 mL of TFA and 10 mL of triethylsilane was refluxed for 15 h. The mixture is concentrated under vacuum, the residue is triturated in heptane, and the resulting precipitate is filtered off under reduced pressure. 4.8 g of the expected product is obtained, after crystallization from isoether, temp. warmer 195-197°C.

D) ethyl 2-[5,6-dichloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indole-3-HJacetate

A mixture of 4.8 g of the compound obtained in the previous step, 2.7 g of ethyl bromoacetate, 2.7 g of Cl and 4.4 g of K2CO3 in 25 mL of acetone was refluxed for 16 h. Mineral salts are separated by filtration, and the filtrate is concentrated under vacuum. The residue was chromatographed on silica gel, eluting with DCM and then with EtOAc. 2.6 g of the expected product is obtained, after crystallization from isoether, temp. warmer 214-219.

E) 2- 15, 6- dichloro- 3-( 2- methoxyphenyl)- 2- oxo- 2, 3- dihydro- 1H- indole- 3-

acetic acid

3.2 mL of 2M NaOH solution was added to a mixture of 2.5 g of the compound rejected in the previous step in 50 mL of MeOH, and the mixture was stirred for 48 h at 20°C. The resulting mixture is concentrated under vacuum, the residue is dissolved in 30 mL of water, the insoluble material is separated by filtration, and the filtrate is acidified to pH 1 by adding concentrated HCl, then extracted with EtOAc, the organic phase is washed with water, dried over Na2SO4 and the solvent is evaporated under vacuum. 2 g of the expected product is obtained, after crystallization from isoether, temp. warmer 222-224°C.

Preparation 1. 6

2- r5- chloro- 3-(2- methoxyphenyl)- 6- methyl- 2- oxo- 2. 3- dihydro- 1H- indol- 3- ylacetic

acid

(II): R 1 = Cl; R 2 = 6-CH 3 ; R 3 = OCH 3 ; R 4 = H; X = -CH2-; Y = OH; W = H

A) ethyl-2-(2-methoxyphenyl)-2-oxoacetate

A solution of 27 g of 1-bromo-2-methoxybenzene in 270 mL of ether is cooled to -70°C in an argon atmosphere, then 90 mL of a 1.6 M solution of n-butyllithium in pentane is added dropwise, and the mixture is then stirred for 45 min. 78 mL of diethyl oxalate was added rapidly and the mixture was stirred, allowing the temperature to return to RT. After stirring for 1 h at RT, saturated NH4Cl is added to the reaction mixture, the phases are separated after standing, the aqueous phase is extracted with ether, the combined organic phases are washed with water and saturated NaCl solution, dried over Na2SO4 and the solvents are evaporated under vacuum. Excess diethyloxalate is removed by distillation under vacuum (temp. key. = 87°C at 2000 Pa). The obtained product is chromatographed on silica gel, eluting with a mixture of DCM/hexane (50/50, VA/) and then with DCM. The obtained product is purified by distillation under vacuum. 13 g of the expected product is obtained, temp. the key. = 110°C at 3 Pa.

B) 5-chloro-3-hydroxy-3-(2-methoxyphenyl)-6-m^

a) tert-butyl 4-chloro-3-methylphenylcarbamate

A mixture of 10 g of 4-chloro-3-methylaniline and 15.26 g of di-tert-butyldicarbonate in 50 mL

of dioxane is stirred for 24 h at RT. The reaction mixture is concentrated under vacuum, and the residue is chromatographed on silica gel, eluting with a DCM/hexane mixture with a gradient from (50/50; V/V) to (70/30; V/V). 5.6 g of the expected product is obtained, which is used without further purification.

b) a solution of 5 g of tert>butyl-4-chloro-3-methylphenylcarbamate in 45 mL of ether is cooled to -70°C, in an argon atmosphere, 30 mL of 1.5 solution is added dropwise

of tert-butyllithium in pentane, and the mixture was stirred for 1 h, allowing the temperature to rise to -10°C, and then stirred at -10°C for 1 h and 45 min. The reaction mixture was cooled to -70°C, a solution of 5 g of the compound obtained in step A in 25 mL of THF was added dropwise, the mixture was stirred for 1 h and allowed to warm to -30°C, then stirred overnight, allowing the temperature to return to RT. Saturated NH4Cl solution is added to the reaction mixture, THF is evaporated, and the remaining aqueous phase is extracted three times with EtOAc, the organic phase is washed with water and saturated NaCl solution, dried over Na2SO4, the solvent is partially evaporated, and the crystalline product is separated by filtration using reduced pressure. 2.6 g of the expected product is obtained, temp. warmer 254-256°C.

C) S- chloro- S^- methoxypheniO- S- methyl- l^ ihydro^ H- indol^- one

A mixture of 3 g of the compound obtained in the previous step, 15 mL of TFA and 6 mL of triethylsilane was refluxed for 15 h. The mixture was concentrated under vacuum and the residue triturated in pentane to give 2.85 g of the expected product, temp. warmer 193°C.

D) ethyl 2-[5- chloro-3-(2-methoxythenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indole-3-

yl] acetate

A mixture of 2.8 g of the compound obtained in the previous step, 1.7 g of ethyl bromoacetate, 1.7 g of Cl and 2.7 g of K2CO3 in 15 mL of acetone was refluxed for 16 h. Mineral salts are separated by filtration, and the filtrate is concentrated under vacuum. 2.35 g of the expected product is obtained, after crystallization from isoether, temp. warmer 170°C.

E) 2-[5-chloro-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indole-3-H-acetic acid

Mix 2.3 g of the compound obtained in the previous step and 3.5 g of a 12M solution of NaOH in 100 mL of MeOH and 5 mL of water, mix for 20 h at 20°C. This mixture was concentrated under vacuum and the residue was taken up in 30 mL of water, acidified to pH 1 by adding concentrated HCl, extracted with EtOAc, the organic phase washed with water and dried over Na2SO4 and the solvent evaporated under vacuum. 1.3 g of the expected product is obtained, after crystallization from isoether, temp. warmer 214-216°C.

Preparation 1. 7

2- r5- chloro- 3-( 2- isopropoxyphenine- 6- methyl- 2- oxo- 2. 3<lihydro- 1H- indol- 3- ylacetic

acid

(II): R 1 =Cl; R2 = 6-CH3; R3 = OCH(CH3)2; R4 = H; X = -CH2-; Y=OH; W = H

A) ethyl 2-[ 2-[( tert- butoxycarbonyl) amino]- 5- chloro- 4- m

A solution of 5.9 g of tert-butyl 4-chloro-3-methylphenylcarbamate in 60 mL of ether is cooled to -50°C in a nitrogen atmosphere, then 42 mL of tert-butyllithium solution in pentane is added dropwise, and the mixture is stirred for 2 h, allowing the temperature to rise to -20°C. The reaction mixture was cooled to -70°C, then a solution of 4.5 g of diethyloxalate in 30 mL of THF was added dropwise, and the resulting mixture was stirred for 1 h, allowing the temperature to return to 20°C. The reaction mixture is poured into saturated NH4Cl solution, the phases are separated after standing, the aqueous phase is extracted with EtOAc, the combined organic phases are washed with 1M HCl, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of isoether/pentane (50/50; V/V). 8 g of the expected product are obtained in the form of an oil that crystallizes, temp. warmer 111°C.

B) 5-chloro-6-methyl-1H-indole-2,3-dione

A mixture of 8 g of the compound obtained in the previous step and 60 mL of 2M HCl in THF was refluxed for 2 h. The reaction mixture was concentrated under vacuum and the residue was taken up in EtOH and the solvent was concentrated again under vacuum. The residue was taken up in EtOH, the resulting precipitate was filtered under reduced pressure and washed with isoether. 1.9 g of the expected product is obtained.

C) 5-chloro-3-hydroxy-3-(2-isopropoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

3.2 g of 1-bromo-2-isopropoxybenzene is added dropwise to a suspension of 0.36 g of magnesium in 10 mL of ether, and reflux is maintained from the very beginning. After the addition is complete, the mixture is heated under reflux for 2 h. Then, a solution of 1.8 g of the compound obtained in the previous step in 30 mL of THF was added in one portion, and the mixture was refluxed for 30 min. After cooling to RT, the reaction mixture was poured into ice/conc. HCl, extracted with EtOAc, the organic phase dried over Na 2 SO 4 and the solvent evaporated under vacuum. The residue is triturated in hot isoether, the resulting precipitate is filtered off under reduced pressure and washed with hot EtOAc. 1.8 g of the expected product is obtained, which is used without further purification.

D) 5-chloroiv-3-(2-isopropoxyphenyl)-6-methyl-1,3-dihydiv-2H-yn^

A mixture of 2.3 g of the compound obtained in the previous step, 15 mL of TFA and 3.8 mL of triethylsilane was refluxed for 10 h. The resulting mixture is concentrated under vacuum (13 Pa), the residue is triturated in pentane, and the resulting precipitate is filtered off under reduced pressure. The precipitate is chromatographed on silica gel, eluting with DCM. 0.85 g of the expected product is obtained, temp. warmer 145-146°C.

E) ethyl 2-[5-chloro-3-(2-isopropoxyphenite)-6-methyl-2-oxo-213-dihydro-1H-indol-3-yl]acetate

A mixture of 0.8 g of the compound obtained in the previous step, 0.53 g of ethyl bromoacetate, 0.53 g of Cl and 0.8 g of K2CO3 in 6 mL of acetone was refluxed for 15 h. Mineral salts are separated by filtration, and the filtrate is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water, and the insoluble material is separated by filtration. The filtrate is chromatographed on silica gel, eluting with DCM and then with a mixture of DCM/EtOAc (70/30; V/V). 0.55 g of the expected product is obtained, temp. warmer 152-154°C.

F) 2-[5-chloro-3-(2-isopropoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indole-3-

acetic acid

Mix 0.53 g of the compound obtained in the previous step and 0.25 g of NaOH pellets in 20 mL of MeOH and 5 mL of water, stir for 20 h at 25°C. The mixture is concentrated under vacuum, and the residue is dissolved in 20 mL of water, then acidified to pH 1 by adding concentrated HCl. The resulting precipitate is separated by filtration under reduced pressure. 0.45 g of the expected product is obtained, after crystallization from a mixture of isoether/pentane (50/50; VA/), temp. warmer 148-150°C.

Preparation 1. 8

5- chloro- 1- f<, 2, 4- dimethoxyphenyl) sulfonyl 1- 3-( 2- methoxyphenyl)- 2- oxo- 2. 3- dihydro- 1H-

indol-3-yl phenylcarbonate

(II): R 1 =Cl; R2=H; R3 = OCH3; R4=H; X=-0-;

A) 5-chloro-3-(2-methoxyphenyl)-3-[(thmethylsilyl)oxy]-1,3-dihydro-2H-indol-2-one

A mixture of 2.9 g of the compound obtained in step A of Preparation 1.1 and 0.16 g of anhydrous zinc chloride in 40 mL of acetonitrile is heated under reflux, then 1.7 g of HMDS is added, and the mixture is refluxed for 1 h. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water and dried over Na 2 SO 4 , and the solvent was evaporated under vacuum. 2.4 g of the expected product is obtained, after crystallization from isoether, temp. warmer 185-187°C.

B) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-3-[(trimethylsilyl)oxy]-1,3-dihydro-2H-indol-2-one

0.17 g of 60% sodium hydride in oil was added to a mixture of 2.4 g of the compound obtained in the previous step, in 30 mL of THF, and this mixture was stirred at RT for 20 min. Then 1.7 g of 2,4-dimethoxybenzenesulfonyl chloride was added, and the mixture was stirred at RT for 1 h. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water and dried over Na 2 SO 4 , and the solvent was evaporated under vacuum. 2.65 g of the expected product is obtained, after crystallization from isoether, temp. warmer 157-158°C.

C) 5- chloro-1-[(2, 4- dimethoxyphenyl) sulfonyl]-3- hydroxy-3-@^ 1, 3-

dihydro-2H-indol-2-one

A mixture of 2.4 g of the compound obtained in the previous step and 10 mL of TFA in 20 mL of DCM was stirred for 4 h at 20°C. This mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with 10% Na 2 CO 3 solution, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. 1.75 g of the expected product is obtained, after crystallization from isoether, temp. warmer 153-160°C.

D) 5- chloro-1-[(2, 4<Methoxyphenyl) sulfonyl]- 3-( 2- methoxyphenyl)- 2- oxo- 2, 3-

dihydro-1H-indol-3-yl phenylcarbonate

A mixture of 1.6 g of the compound obtained in the previous step and 1 g of phenylchloroformate in 20 mL of pyridine was stirred for 3 days at 20°C. The mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with 10% AcOH solution and dried over Na 2 SO 4 , and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with ether. 1.05 g of the expected compound is obtained, after crystallization from isoether, temp. warmer 212-213°C.

Preparation 1. 9

5-Chloro-1-r(2,4-dimethoxyphenyl)sulfonyl-3-(2-isopropoxyphenyl)-2-oxo-2.3-dihydro-1H-indol-3-yl phenylcarbonate

(II): Ri=Cl; R 2 = H; R 3 = OCH(CH 3 ) 2 ; R 4 = H; X = -0-;

A) 5-chloro-1-[(2A<limethoxyphenyl) sulfonyl]- 1M

0.5 g of 60% sodium hydride in oil was added to a mixture of 3.6 g of 5-chloro-1H-indole-2,3-dione in 20 mL of DMF, and the mixture was stirred for 30 min at 20°C. Then 4.8 g of 2,4-dimethoxybenzenesulfonyl chloride was added, and the mixture was stirred for 1 h at 20°C. The resulting mixture was concentrated under vacuum (1.3 Pa), the residue was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is triturated in isoether, and the resulting precipitate is filtered off under reduced pressure. 2.9 g of the expected compound are obtained, after crystallization from hot EtOAc, temp. warmer 194.5°C.

B) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-hydroxy-3-(2-isopropoxyphenyl)-1,3-dihydro-2H-indol-2-one

Prepare a solution of 2-isopropoxyphenylmagnesium from 0.5 g of magnesium in 20 mL of THF and 4 g of 1-bromo-2-isopropoxybenzene. This solution was added dropwise, at RT, to a mixture of 4.8 g of the compound obtained in the previous step in 50 mL of THF, followed by 1 h of refluxing. After cooling to RT, the reaction mixture was poured into an ice/6M HCl mixture, extracted with EtOAc, the organic phase washed with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH (99/1; V/V). 3.8 g of the expected product are obtained.

C) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl phenylcarbonate

A mixture of 1 g of the compound obtained in the previous step and 1.4 g of phenylchloroformate in 10 mL of pyridine was stirred for 48 h at RT. The mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water, 1M HCl solution, water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. 0.86 g of the expected product is obtained, after crystallization from isoether, temp. warmer 197°C.

Preparation 1. 10

phenyl 5- chloro- 3- r( 2- isopropoxyphenyl)- 2- oxo- 3- f( phenoxycarbonyl) oxyl- 1-

indolinecarboxylate

(XXVII): Ri = CI; R 2 = H; R3 = OCH(CH3)2; R4 = H

A mixture of 6.34 g of the compound obtained in step B of Preparation 1.3, in 60 mL of pyridine, is heated to 70°C, then 7 g of phenylchloroformate is added dropwise, and the mixture is then stirred for 3 h at 70°C, then overnight at RT. The reaction mixture is poured into water, extracted with DCM, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM. The product is obtained by trituration in isoether, and the resulting precipitate is separated by filtration under reduced pressure. 8 g of the expected compound are obtained.

Preparation 1. 11

5-chloro-3-(2-chlorophenyl)-1-[(2,4- dimethoxyphenyl)

inHnl-^-il ftanil karhnnat

(II): R 1 =Cl; R2=H; R3 = CI; R4=H; X=-0-;

A) 5-chloro-3-(2-chlorophenyl)-1-[(2,4<Ximethoxyrenyl)sulfonyl]-3-h

dihydro-2H-indol-2-one

A solution of 2-chlorophenylmagnesium bromide is prepared from 0.4 g of magnesium, 0.01 g of iodine, 20 mL of ether and 2.9 g of 1-bromo-2-chlorobenzene. A mixture of 2.8 g of the compound obtained in step A of Preparation 1.9, in 30 mL of THF, is added to this solution under reflux for 1 min, and the resulting mixture is kept under reflux for another 20 min. After cooling to RT, the reaction mixture was poured into an ice/conc. HCl mixture, extracted with EtOAc, the organic phase washed with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. The residue is chromatographed on silica gel, eluting with isoether and then with DCM. 1.55 g of the expected product is obtained in the form of a foam, which is used without further purification.

B) 5-chloro-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl phenylcarbonate

A mixture of 0.65 g of the compound obtained in the previous step and 0.3 g of phenylchloroformate in 5 mL of pyridine was stirred for 10 h at 20°C. The mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with 1M HCl solution, with 1M NaOH solution and water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. 0.6 g of the expected product is obtained, after crystallization from isoether, temp. warmer 222-223°C.

Preparation 1. 12

5- chloro- 1- r( 2. 4- dimethoxyphenyl) sulfonine- 3-( 2- fluorophenyl)- 2- oxo- 2. 3- dihydro- 1H-

indol-3-yl phenyl carbonate

(II): Ri = CI; R2=H; R3=F; R4=H; X=-0-;

A) D, L- 2-fluoromandeic acid

This compound is obtained according to the procedure described in J. Org. Chem. 1968, 33, 2565-2566. This compound can also be obtained by the following procedure, given below. A mixture of 17.4 g of 2-fluorobenzaldehyde and 9.6 g of potassium cyanide in 30 mL of ether is cooled to a temperature below 10°C, 15 mL of concentrated HCl is added over 30 min, and the resulting mixture is stirred for 2 h at RT. After standing, the phases are separated, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The thus obtained crude product is dissolved in 20 mL of concentrated HCl, then refluxed for 5 h. After cooling to RT, the reaction mixture is extracted with ether, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. 17.5 g of the expected product is obtained after crystallization from isoether.

B) N-p-chlorothenyl-DL-2-fluoromandelamide

A mixture of 17.5 g of the compound obtained in the previous step and 13 g of p-chloroaniline in 100 mL of 1,2-dichlorobenzene was refluxed for 3 h, removing the resulting water using a Dean-Stark apparatus. After cooling to RT, the mixture is allowed to crystallize. The resulting precipitate was filtered off under reduced pressure and dissolved in EtOAc, the organic phase was washed twice with 4M HCl, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. 16.2 g of the expected product is obtained after crystallization from isoether.

C) 5-chloro-3-(2-fluorophenyl)-1,3-dihydro-2H-indol-2-one

16.1 g of the compound obtained in the previous step was added at RT to a mixture of 64 mL of concentrated (95%) H2SO4 and 16 mL of fuming sulfuric acid (30% oleum), and the mixture was then stirred for 8 h. The reaction mixture was poured into ice/water, extracted with EtOAc, the organic phase washed twice with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 12.2 g of the expected product are obtained after crystallization from isoether.

D) 3-bromo-5-chloroD-3-(2-fluorophenyl)-1,3-dihydro-2H-indol-2-one

A solution of 0.78 ml of bromine in 20 ml of chloroform is slowly added, at RT, to a solution of 4 g of the compound obtained in the previous step in 100 ml of chloroform. The reaction mixture was concentrated under vacuum to give 4 g of the expected product after crystallization from isoether.

E) 5-chloro-3-(2-fluorophenyl)-5-hydroxy-1,3-dihydro-2H-indol-2-one

A mixture of 2 g of the compound obtained in the previous step in 5 mL of water and 20 mL of THF was refluxed for 20 h. The mixture was concentrated under vacuum, the residue was triturated in 10% Na 2 CO 3 solution, and the resulting precipitate was filtered off under reduced pressure. 1.45 g of the expected product is obtained, after crystallization from isoether, temp. warmer 265°C (decomposition).

F) 5-chloro-3-(2-fluorophenyl)-3-[(thmethylsilyl)ox^1,3-dihydro-2H-indol-2-one

A mixture of 1.4 g of the compound obtained in the previous step and 0.12 g of zinc chloride in 32 mL of acetonitrile is heated under reflux, 6 mL of HMDS is added, and the mixture is refluxed for 8 h. The resulting mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. 1.35 g of the expected product is obtained, after crystallization from heptane, temp. warmer 125-127°C.

G) 5-chloro-1-[(2,4<Jimethoxythenyl)sulfonyl]-3-(2-fluorophenyl)-3-[(trimethylsilyl)oxy]-1,3-dihydro-2H-indol-2-one

This compound is obtained according to the procedure described in step B of Preparation 1.8, starting from 1.3 g of the compound obtained in the previous step, 0.1 g of 60% sodium hydride in oil, 15 mL of THF and 1 g of 2,4-dimethoxybenzenesulfonyl chloride. 1.75 g of the expected product is obtained, after crystallization from isoether, temp. warmer 184-186°C.

H) 5-chloro-1-[(2A^ imethoxyphenyl) sulfonyl]- 3-( 2-^

dihydro-2H-indol-2-one

A mixture of 1.7 g of the compound obtained in the previous step, 2 mL of 12M HCl and 2 mL of water in 30 mL of acetone was stirred for 4 h. The mixture was concentrated under vacuum, the residue was dissolved in MeOH and concentrated under vacuum. The residue is triturated in isoether, and the precipitate is filtered off under reduced pressure. 1.3 g of the expected product is obtained, temp. warmer 144-146°C.

I) 5- chloro-1-[(2, 4<imithoxyphenyl) sulfonyl]- 3-( 2- fluorophenyl)- 2- oxo- 2, 3-

dihydro-1H-indol-3-yl phenylcarbonate

0.7 g of phenylchloroformate was added at RT to a mixture of 1 g of the compound obtained in the previous step and 0.5 mL of pyridine in 20 mL of DCM, and the mixture was stirred for 48 h. The reaction mixture was washed twice with water, the organic phase was dried over Na 2 SO 4 , and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH (99.5/0.5; V/V). 0.93 g of the expected product is obtained.

Preparation 1. 13

5- chloro- 1- f( 2, 4- dimethoxyphenyl) sulfonine- 3-( 2- trifluoromethylphenine- 2- oxo- 2. 3- dihydro-

1H-indol-3-yl phenylcarbonate

(II): Ri = CI; R 2 = H; R 3 = CF 3 ; R4 = H; X=-0-;

A) 5-Chloro-3-Hydroxy-3-(2-Tyrfluoromethylphenyl)-1,3<liM^

A mixture of 2.3 g of magnesium and 0.001 g of iodine in 20 mL of ether is heated under reflux, then a solution of 26 g of 1-bromo-2-trifluoromethylbenzene in 20 mL of ether is added dropwise, and the resulting mixture is refluxed for 60 min. Then a solution of 9 g of 5-chloro-1H-indole-2,3-dione in 40 mL of THF was added, and refluxing was continued for another 30 min. After cooling to RT, the reaction mixture was poured into an ice/conc. HCl mixture, extracted with ether, the organic phase washed with 1M NaOH solution and water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 5.3 g of the expected product is obtained, after crystallization from heptane, temp. warmer 205-208°C.

B) 5-chloro-3-(2-trifluoromethylthenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 3 g of the compound obtained in the previous step and 0.1 g of zinc chloride in 20 mL of acetonitrile is heated for 1 h under reflux. The mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and dried over Na 2 SO 4 , and the solvent is evaporated under vacuum. 3.9 g of the expected product is obtained in the form of an oil, which crystallizes, temp. warmer 175-176°C.

C) 5-Chloro-1-[(2,4<jimethoxyphenyl)sulfonyl]-3-(2-thfluoromethylthenyl)-3-[(trimethylsilyl)oxy]-1,3-dihydro-2H-indol-2-one

This compound is obtained according to the procedure described in step B of Preparation 1.8, starting from 3.8 g of the compound obtained in the previous step, 0.45 g of 60% sodium hydride in oil, 30 mL of THF and 2.5 g of 2,4-dimethoxybenzenesulfonyl chloride. 5 g of the expected product is obtained, after crystallization from heptane, temp. warmer 144-145°C.

D) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-hydroxy-3-(2-trifluoromethylphenyl)-1,3-dihydro-2H-indol-2-one

Mix 4.9 g of the compound obtained in the previous step, 3 mL of 12M HCl and 5 mL of water in 50 mL of THF, and stir for 15 h at 20°C. The resulting mixture was concentrated under vacuum at a temperature below 40°C, and the residue was dissolved in 30 mL of 10% NaHCO3 solution, extracted with EtOAc, these extracts were dried over Na2SO4, and the solvent was evaporated under vacuum. 3.8 g of the expected product is obtained, after crystallization from a mixture of isoether/heptane (80/20; VA/}, temp. heat. 143°C.

E) 5-chloro-1-{(2,4-dimethoxyphenyl)sulfonyl]-3-(2-tritluomm)

2, 3-dihydro-1H-indol-3-yl phenylcarbonate

2 g of phenylchloroformate is added dropwise, at 20°C, to a mixture of 1.7 g of the compound obtained in the previous step in 20 mL of pyridine, and this mixture is stirred for 7 h at 20°C. The resulting mixture is concentrated under vacuum, the residue is dissolved in 30 mL of 10% AcOH solution, extracted with ether, the organic phase is washed with 10% NaHCO3 solution and water, dried over Na2SO4 and the solvent is evaporated under vacuum. 1.8 g of the expected product is obtained, after crystallization from heptane, temp. warmer 191°C.

Preparation 1. 14

5-chloro-1-f(2,4-dimethoxyphenyl)sulfonyl1-3-(2-trifluoromethoxyphenyl)-2-oxo-2,3-

dihydro-1H-indol-3-yl phenylcarbonate

(II): Ri = CI; R2=H; R3 = OCF3; R4 = H; X = -0-;

A) 5-chloro-3-hydroxy-3-(2-trifluoromethoxyphen).

A solution of 25 g of 1-bromo-2-trifluoromethoxybenzene in 130 mL of ether is added dropwise to a mixture of 2.8 g of magnesium in 20 mL of ether, and the reflux is maintained from the very beginning. After the addition is complete, the mixture is heated under reflux for 1 h. A mixture of 7.5 g of 5-chloro-1/-indole-2,3-dione in 100 mL of THF was then added at a temperature below 40°C, followed by 1 h of refluxing. After cooling to RT, the reaction mixture was poured into an ice/conc. HCl mixture, extracted with EtOAc, the organic phase washed with water and 1M NaOH solution, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 6.5 g of the expected product is obtained, after crystallization from a mixture of DCM/isoether (20/80; VA/), temp. warmer 214°C.

B) 5-chloro-3-(2-thluoromethoxypheni)-3-1(tri^

indol-2-one

A mixture of 2 g of the compound obtained in the previous step, 0.05 g of zinc chloride and 1.4 g of HMDS in 100 mL of acetonitrile was refluxed for 2 h. This mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. 2.5 g of the expected product is obtained, which is used without further purification.

C) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-trifluoromethoxyphenyl)-3-[(trimethylsilyl)oxy]-1,3-dihydro-2H-indol-2-one

This compound is obtained according to the procedure described in step B of Example 1.8, starting from 2.5 g of the compound obtained in the previous step, 0.3 g of 60% sodium hydride in oil, 50 mL of THF and 1.7 g of 2,4-dimethoxybenzenesulfonyl chloride. 2.7 g of the expected product is obtained, after crystallization from isoether, temp. warmer 181°C.

D) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-hydroxy-3-(2-trifluoromethoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 2.7 g of the compound obtained in the previous step and 1 mL of concentrated HCl in 50 mL of acetone was stirred for 1 h at a temperature below 40°C. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. 1.66 g of the expected product is obtained, after crystallization from isoether, temp. warmer 81 °C.

E) 5-chloro-1-1(2,4-dimethoxyphenyl)sulfonyl]-3-(2-trifluoromethoxyphenyl)-2-

oxo-2,3-dihydro-1H-indol-3-yl phenylcarbonate

1.15 g of phenylchloroformate was added, at RT, to a mixture of 1.6 g of the compound obtained in the previous step and 0.8 mL of pyridine in 20 mL of DCM, and the mixture was stirred for 1 h at RT. The reaction mixture was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. 1.34 g of the expected product is obtained, after crystallization from isoether, temp. warmer 203-204°C.

Preparation 1. 15

5- chloro- 1- r( 2. 4- <jimethoxyphenyl) sulfonine- 3-( 2- methoxyphenyl)- 6- methyl- 2- oxo- 2, 3-

dihydro-1/-/- indol-3-yl phenylcarbonate

(II): R 1 = Cl; R 2 = 6-CH 3 ; R 3 = OCH 3 ; R 4 = H; X = -0-;

A) 5-chloro-3-(2-methoxyphenyl)-6-methyl-3-[(trim^

indol-2-one

A mixture of 0.65 g of the compound obtained in step B of Preparation 1.6 and 0.05 g of zinc chloride in 10 mL of acetonitrile is heated under reflux, then 2.1 mL of HMDS is added, and refluxing is maintained for 1 h. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. 0.7 g of the expected product is obtained, after crystallization from heptane, temp. warmer 227°C.

B) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-6-methyl-3-[(trimethylsyl)oxy]-1,3-dihydro-2H-indol-2-one

This compound is obtained according to the procedure described in step B of Preparation 1.8, starting with 0.85 g of the compound obtained in the previous step, 0.06 g of 60% sodium hydride in oil, 20 mL of THF and 0.6 g of 2,4-dimethoxybenesulfonyl chloride. 0.95 g of the expected product is obtained, after crystallization from isoether, temp. warmer 190-191°C.

C) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-hydroxy-3-(2-methoxyphenyl)

methyl-1,3-dihydro-2H-indol-2-one

0.5 mL of 12M HCl solution was added to a solution of 0.85 g of the compound obtained in the previous step in 20 mL of acetone, and the mixture was stirred for 4 h at 20°C. The resulting mixture was concentrated under vacuum, the residue was dissolved in 50 mL of DCM, and the solvent was concentrated again under vacuum. 0.75 g of the expected product is obtained, after crystallization from isoether, temp. warmer 207-208°C.

D) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-6-methyl-2-

oxo-2,3-dihydro-1H-indol-3-yl phenylcarbonate

1 g of phenylchloroformate was added to a solution of 0.7 g of the compound obtained in the previous step in 10 mL of pyridine, and the mixture was stirred for 48 h at 20°C. The resulting mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with 1M HCl solution, water, with 1M NaOH solution and water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. 0.75 g of the expected product is obtained, after crystallization from isoether, temp. warmer 196°C (dec.).

Preparation 1. 16

5- chloro- 3-( 2- chlorophenyl)- 1- f( 2. 4- dimethoxyphenyl) sulfonyl- 6- methoxy- 2- oxo- 2, 3-

dihydro-1H-indol-3-yl phenylcarbonate

(II): Ri=Cl; R 2 = 6-OCH 3 ; R 3 = Cl; R 4 = H; X = -0-;

A) 4-chloro-3-methoxyaniline

A mixture of 36 g of 2-chloro-5-nitroanisole and Raney nickel in 150 mL of MeOH and 200 mL of THF is hydrogenated for 4 h in a Parr apparatus at 35°C and under a pressure of 1.3 bar. The catalyst is separated by filtration through Celite<®>, and the filtrate is concentrated under vacuum. 28 g of the expected product is obtained, which is used without further purification.

B) N-(4-chloro-3-methoxythenyl)-D,L-2-chloromandelamide

A mixture of 28 g of the compound obtained in the previous step and 33.13 g of D,L-chloromandelic acid in 128 mL of 1,2-dichlorobenzene is heated for 4 h at 230°C, removing the formed water using a Dean-Stark apparatus. The reaction mixture was partially concentrated under vacuum and allowed to crystallize. The resulting crystalline product is separated by filtration under reduced pressure and washed with isoether. 40 g of the expected product is obtained.

C) 5-chloro-3-(2-chloromrenyl)-6-methoxy-1,3<iihidm-2W

40 g of the compound obtained in the previous step was quickly added to 550 g of polyphosphoric acid, and the mixture was heated to 60°C for 8 h and allowed to stir overnight, allowing the temperature to return to RT. Ice-cooled water is added to the reaction mixture, and the resulting precipitate is filtered off under reduced pressure and washed with water. This precipitate was dissolved in EtOAc, and the white product obtained after trituration was filtered off under reduced pressure and washed with isoether. 17.2 g of the expected product is obtained, temp. warmer 243-247°C.

D) 5-chloro-3-(2-chlorophenyl)-3-hydroxy-6-methoxy-1,3-dihydro-2H-indol-2-one

Add, at RT and under an argon atmosphere, 2.56 g of 60% sodium hydride in oil to a solution of 17.2 g of the compound obtained in the previous step, in 220 mL of THF. After gas evolution stops, 6.85 g of dimethylsulfide is added, air is blown through the reaction mixture, and the mixture is stirred at RT for 72 h. Water was added to the reaction mixture, THF was evaporated under vacuum, the remaining aqueous phase was extracted with EtOAc, the organic phase was washed with water and saturated NaCl solution, dried over Na2SO4 and the solvent was evaporated under vacuum. The obtained product is dissolved in DCM, the solvent is partially evaporated, the mixture is allowed to crystallize, and the resulting crystalline product is separated by filtration under reduced pressure. 6 g of the expected product is obtained, temp. warmer 237-240°C.

E) 5-chloro-3-(2-chlororenyl)-6-methoxy-3-[(trim^1,3-dihydro-2H-indol-2-one

A mixture of 1 g of the compound obtained in the previous step and 0.07 g of zinc chloride in 10 mL of acetonitrile is heated under reflux, then 3 mL of HMDS is added, and refluxing is continued for another 1 h. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water and dried over Na 2 SO 4 , and the solvent was evaporated under vacuum. 1.25 g of the expected product is obtained, after crystallization from heptane, temp. warmer 211 -212°C.

F) 5-chlorophenyl)-3-(2-chlorophenyl)-1-[(2A<limethoxyphenyl)su^

[(trimethylsilyl)oxy}-1,3-dihydro-2H-indol-2-one

This compound is obtained according to the procedure described in step B of Preparation 1.8, starting from 1.2 g of the compound obtained in the previous step, 0.08 g of 60% sodium hydride in oil, 15 mL of THF and 0.8 g of 2,4-dimethoxybenzenesulfonyl chloride. 1.6 g of the expected compound is obtained, after crystallization from isoether, temp. warmer 217-219°C.

G) 5- chloro- 3-( 2- chlorophenyl)- 1- 1( 2, 4- dimethoxyphenyl) sulfonyl]- 3- hydroxy- 6-

methoxy-1,3-dihydro-2H-indol-2-one

A mixture of 1.55 g of the compound obtained in the previous step and 2 mL of 12M HCl in 30 mL of acetone was stirred for 4 h at 20°C. The resulting mixture was concentrated under vacuum, the residue was dissolved in acetone and concentrated again under vacuum. The residue was taken up in DCM and concentrated under vacuum. The residue is triturated in isoether, and the resulting precipitate is filtered off under reduced pressure. 1.3 g of the expected product is obtained, temp. warmer 233-235°C.

H) 5- chloro- 3-( 2- chlorophenyl)- 1-[( 2, 4- dimethoxyphenyl) sulfonyl]- 6- methoxy- 2-

oxo-2,3-dihydro-1H-indol-3-yl phenylcarbonate

A mixture of 1.3 g of the compound obtained in the previous step in 10 mL of pyridine was cooled to 10°C, 0.8 g of phenylchloroformate was added, and the mixture was stirred for 20 h at 20°C. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with 1M HCl solution, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM. 0.7 g of the expected product is obtained, after crystallization from a mixture of pentane/isoether, temp. warmer 162-163°C.

Preparation 1. 17

5- chloro- 1- f( 2- 4- dimethoxyphenyl) sulfonyl- 3-( 2. 5- dimethoxyphenyl)- 2- oxo- 2. 3- dihydro-

1 //-/- indol-3-yl phenylcarbonate

(II): R 1 =Cl; R2=H; R3=OCH3; R4 = 5-OCH3; X=-0-;

A) 5-chloro-3-hydroxy-3-(2,5-dimethoxythenyl)-1,3-dihydroxy-2H-indol-2-one

A solution of 2,5-dimethoxyphenylmagnesium bromide is obtained from 2.2 g of magnesium, 18 g of 1-bromo-2,5-dimethoxybenzene and 50 mL of ether. This solution is added dropwise to a mixture of 5 g of 5-chloro-1H-indole-2,3-dione in 50 mL of THF, at a temperature below 30°C, and then refluxed for 3 h. After cooling to RT, the reaction mixture was poured into 1M HCl solution, extracted with EtOAc, the organic phase washed with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 1.7 g of the expected product is obtained after crystallization from hot isoether.

B) 5-chloro-3-(2,5<limethoxypheneU)-3-[(thm^

2- he

A mixture of 4 g of the compound obtained in the previous experiment and 0.085 g of zinc chloride in 45 mL of atonitrile is heated under reflux, then 2.8 mL of HMDS is added, and refluxing is continued for another 1 h. The resulting mixture is concentrated under vacuum, the residue is stirred in water, extracted with ether, the organic phase is washed with water, dried over Na2SO4 and the solvent is evaporated under vacuum. 5 g of the expected product is obtained after crystallization from isoether.

C) 5-chloro-3-(2,5-dimethoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-[(trimethylsilyl)oxy]-1,3-dihydro-2H-indol-2-one

This compound is obtained according to the procedure described in step B of Preparation 1.8, starting from 2 g of the compound obtained in the previous step, 0.135 g of 60% sodium hydride in oil, 40 mL of THF and 1.3 g of 2,4-dimethoxybenzenesulfonyl chloride. 2.2 g of the expected product is obtained after crystallization from isoether.

Dl 5-chloro-3-(2,5-dimethoxyphenyl)-1-[(2,4<Dimethoxyphenyl)sulfonyl]-3-hydroxy-1,3-dihydro-2H-indol-2-one

A mixture of 1 g of the compound obtained in the previous step and 0.5 mL of 2M HCl in 20 mL of acetone was stirred for 4 h at 20°C. This mixture was concentrated under vacuum, and the residue was slurried in DCM and concentrated again under vacuum. The residue is triturated in isoether, and the resulting precipitate is filtered off under reduced pressure. 0.84 g of the expected product is obtained.

E) 5-chloro-1-[(2,4<limethoxyphenyl)sulfonyl]-3-(2^

2, 3-dihydro-1H-indol-3-yl phenylcarbonate

A mixture of 0.8 g of the compound obtained in the previous step and 0.4 mL of phenylchloroformate in 5 mL of pyridine was stirred overnight at RT. Water is added to

reaction mixture, and the resulting mixture extracted with DCM, the organic phase washed with 2M HCl solution, dried over Na 2 SO 4 and the solvent evaporated under vacuum. 0.84 g of the expected product is obtained after crystallization from isoether.

Preparation 1. 18

5- chloro- 1- f( 2. 4- dimethoxypheninesulfonyl- 3-( 2- methoxyphenyl)- 2- oxo- 2. 3- dihydro- 1H-

indol-3-yl phenylcarbamate

(II): Ri = CI; R2=H; R3 = OCH3; R4=H; X = -NH-;

A) 3-amino-5-chloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

This compound is obtained in accordance with the procedure described in VVO 95/18105, in Preparation 7.

B) 3-amino-5-chloro-1-[(2A^irnetoxyphenyl)sulfonyl]-3-(2- methoxyphen^

dihydro-1H-indol-2-one

A solution of 1.64 g of the compound obtained in the previous step in 20 mL of DMF was cooled to 4°C, 0.25 g of 50% sodium hydride in oil was added, and the mixture was stirred for 30 min at 4°C. Then 1.34 g of 2,4-dimethoxybenzenesulfonyl chloride was added, and the mixture was stirred at RT for 4 h. 50 mL of water was added to the reaction mixture, the obtained mixture was extracted with EtOAc, the organic phase was washed with saturated NaCl solution, dried over Na2SO4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM/EtOAc (97/3; V/V). 2 g of the expected compound are obtained, after crystallization from the DCM/isoether mixture.

C) 5- chloro- 1-[( 2, 4- dimethoxyphenyl) sulfonyl]- 3-( 2- methoxyphenyl)- 2- oxo- 2, 3-

dihydro-1H-indol-3-yl phenylcarbamate

A solution of 2 g of the compound obtained in the previous step and 10 mL of pyridine in 10 mL of DCM was cooled to 4°C, 0.77 mL of phenylchloroformate was added, and the mixture was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with saturated NaCl solution, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/EtOAc (96/4; VA/). 2.6 g of the expected product are obtained, after crystallization from a mixture of DCM/isoether, temp. warmer 191°C.

Preparation 1. 19

5- chloro- 1- r( 2. 4- dimethoxyphenyl) sulfonine- 3-( 2- methoxyphenyl)- 2- oxo- 2. 3- dihydro- 1H-

indol-3-yl phenylcarbamate, one isomer

(II): Ri=Cl; R 2 = H; R 3 = OCH 3 ; R 4 = H; X = -NH-;

A) 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 9 g of the compound obtained in step A of Preparation 1.1 and 3.74 mL of pyridine in 100 mL of DCM is cooled to 0°C, a solution of 3.45 mL of thionyl chloride in 3 mL of DCM is added dropwise over 3 min, and the mixture is stirred for 30 min. Water was added to the reaction mixture, and the DCM was evaporated under vacuum. The resulting precipitate is separated by filtration under reduced pressure, washed four times with water, then with cold isoether and dried. 8.8 g of the expected product is obtained.

B) 5-chloro-3-[[(1S)-2-hydroxy-1-phenylethyl]amino]-3-(2-m^

dihydro-2H-indol-2one, isomers A and B

A mixture of 7 g of the compound obtained in the previous step and 7.65 g of (S)-(+)-ct-phenylglycinol in 100 mL of chloroform was stirred for 2 h at RT. Then 2.9 g of DIPEA was added, and the mixture was stirred at RT for 48 h. The resulting precipitate is separated by filtration under reduced pressure, and isomer A is collected. The filtrates are washed with 5% K2CO3 solution, the organic phase is dried over Na2SO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/EtOAc (70/30; VA/). Two diastereomers are separated: - less polar isomer, isomer A: 4.55 g were obtained (from precipitation and chromatography); a<20>D= +193° (c = 0.16; chloroform);

- more polar isomer, isomer B.

C) 3-amino-5-chloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one,

dextrorotatory isomer

Mix 4.55 g of the compound obtained in the previous step (isomer A) and 5.5 g of lead tetraacetate in 75 mL of DCM and 35 mL of MeOH, stir for 1 h and 30 min at RT. This mixture was concentrated under vacuum, the residue was triturated in saturated NaHCO 3 solution, extracted with EtOAc, the organic phase was washed with water and saturated NaCl solution, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The resulting oil was dissolved in 100 mL of 3M HCl solution, 10 mL of MeOH was added, and the mixture was stirred at RT for 2 h. The organic solvents were concentrated under vacuum, the aqueous phase washed twice with ether, made basic by addition of pellets of KOH, extracted with EtOAc, the organic phase washed with water and saturated NaCl solution, dried over Na2SO4 and the solvent evaporated under vacuum. 1.178 g of the expected product is obtained, after crystallization from a mixture of DCM/THF, temp. = 202°C.

a<20>D= +83.3° (c = 0.16; chloroform).

C) 3-amino-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-1,3-

dihydro- 2H- indol- 2one, dextrorotatory isomer

A solution of 1.178 g of the compound obtained in the previous step in 10 mL of DMF was cooled to 0°C, 0.188 g of 60% sodium hydride in oil was added under an argon atmosphere, and the mixture was stirred until the evolution of gas stopped. Then 1.02 g of 2,4-dimethoxybenzenesulfonyl chloride was added, and the mixture was stirred at RT for 3 h. The reaction mixture was poured into 5% K2CO3 solution, extracted with EtOAc, the organic phase was washed with water, 5% K2CO3 solution and saturated NaCl solution, dried over Na2SO4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/EtOAc (95/5; VA/). 1.254 g of the expected product are obtained, after crystallization from a mixture of DCM/isoether, temp. warmer 172-173°C.

a<20>D= +113° (c = 0.18; chloroform).

D) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-oxyphenyl)-1-oxo-2,3-dihydro-1H-indol-3-yl phenylcarbamate, one isomer

A solution of 1.1 g of the compound obtained in the previous step in 10 mL of DCM was cooled in an ice bath, 1.8 mL of pyridine was added, and then 0.37 mL of phenylchloroformate was added dropwise, and the mixture was still kept cold overnight. The reaction mixture was diluted with DCM, the organic phase was washed three times with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue was chromatographed on silica gel eluting with a mixture of DCM/EtOAc (98/2; VA/). 1.136 g of the expected product was obtained.

Preparation 1. 20

5- chloro- 1-[( 2, 4- dimethoxyphenyl) sulfonyl]- 3-( 2- isopropoxyphenyl)- 2- oxo- 2, 3- dihydro-

1/-/- Indole-3-yl phenylcarbamate, one isomer

(II): Ri=Cl; R 2 = H; R 3 = OCH(CH 3 ) 2 ; R 4 = H; X = -NH-;

A) 3,5-dichloro-3-(2-isopropoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 12 g of the compound obtained in step B of Preparation 1.3 and 8.35 mL of pyridine in 165 mL of DCM is cooled to 0°C, 7.62 mL of thionyl chloride is added dropwise, and the mixture is stirred for 15 min. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/EtOAc (90/10; V/V). 15.22 g of the expected product are obtained.

B) 5-chloro-3-[[(1S)-2-hydroxy-1-phenylethyl]amino]-3-(2-isop

dihydro-2H-inol-2-one, isomer A and isomer B

A mixture of 8.17 g of the compound obtained in the previous step and 3.66 g of (S)-(+)-α-phenylglycinol in 265 mL of chloroform was stirred for 1 h at RT. Then 4.66 mL of DIPEA was added, the mixture was stirred at RT for 3 h, and then heated at 50°C for 18 h. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with 5% K2CO3 solution and water, dried over Na2SO4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/EtOAc (90/10; VA/), so that the following separation occurs: - less polar isomer, isomer A: 4.98 g, obtained after crystallization from isoether, temp. warmer 212.7°C. A = +212.4° (c = 0.2, chloroform).

Chromatography was continued, eluting with a mixture of DCM/EtOAc (70/30; VA/), and the following separation was carried out: - the lower isomer, isomer B: 3.49 g, obtained after crystallization from isoether, temp. warmer 241.3'C. <x20D = -6.6° (c = 0.2; chloroform).C) 3-amino-5-chloro-3-(2-isopropoxyphenyl)-1,3-dihydro-2H-indol-2-one,

dextrorotatory isomer

A solution of 3.9 g of the compound obtained in the previous step (isomer A) in 75 mL of DCM and 37 mL of MeOH was cooled to 0°C, 4.35 g of lead tetraacetate was added, and the mixture was stirred for 2 h. 3 drops of 5% NaHC03 solution are added to the mixture, the mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with water and saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated under vacuum. The resulting product was dissolved in 120 mL of concentrated HCl and washed with ether, the aqueous phase made basic by addition of K2CO3, extracted with EtOAc and allowed to crystallize. The resulting crystals are separated by filtration under reduced pressure and dried. The liquids from the filtration are concentrated under vacuum, and the residue is chromatographed on silica gel, eluting with a mixture of DCM/EtOAc (65/35; VA/), and the obtained product crystallizes from isoether. A total of 2.03 g of the expected compound is obtained, temp. warmer 193°C. a<20>D= +44° (c =0.18; chloroform).

D) 3-amino-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2- isopropoxyphenyl)-1,3-dihydro-2H-indol-2-one, dihedral isomer

This compound was obtained according to the procedure described in step D of Preparation 1.19, starting from 1.86 g of the compound obtained in the previous step, 0.282 g of 60% sodium hydride in oil, 20 mL of DMF and 1.395 g of 2,4-dimethoxybenzenesulfonyl chloride. 2.68 g of the expected product are obtained after crystallization from hexane. a<20>D= +79° (c = 0.2; chloroform).

E) 5-chloro-1-[(2,4-dimethoxythenyl)sulfonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl phenylcarbamate, one isomer

A mixture of 2.68 g of the compound obtained in the previous step and 4.5 mL of pyridine in 25 mL of DCM was cooled to 0°C, 1.06 g of phenylchloroformate was added over 30 s, and the mixture was kept under these cold conditions for 18 h. The reaction mixture is directly chromatographed on silica gel, prepared in a mixture of DCM/hexane (80/20; VA/), then eluted with a mixture of DCM/EtOAc (95/5; VA/). 2.88 g of the expected product is obtained, which is used without further purification.

Preparation 1. 21

5- chloro- 1-^ 2. 4- dimethoxyphenyl) sulfonyl- 3-( 2- isopropoxyphenyl)- 2- oxo- 2. 3- dihydro-

1 H-indol-3-yl phenylcarbamate, one isomer

(II): R 1 =Cl; R2=H; R3 = OCH(CH3)2; R4=H; X = -NH-; A) 3-amino-5-chloro-3-(2-isopropoxyphenyl)-1,3-dihydro-2H-indol-2-one,

levorotatory isomer

A solution of 3.4 g of the compound obtained in step B of Preparation 1.20 (isomer B) in 65 mL of DCM and 32.4 mL of MeOH was cooled to 0°C, 3.8 g of lead tetraacetate was added, and the mixture was stirred for 40 min. 3 drops of 5% NaHCO 3 solution are added, the mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with water and saturated NaCl solution, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The resulting product was dissolved in 120 mL of 0.5 M HCl and washed with ether, the aqueous phase was made basic with K 2 CO 3 , and the resulting precipitate was filtered off under reduced pressure. 1.9 g of the expected product is obtained, after crystallization from isoether, temp. warmer 192°C. a<20>D= - 42° (c = 0.2; chloroform).

B) 3-amino-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-isopropyl)

1, 3-dihydro-2H-indol-2-one, levorotatory isomer

This compound was obtained according to the procedure described in step D of Preparation 1.19, starting from 1.67 g of the compound obtained in the previous step, 0.253 g of 60% sodium hydride in oil, 20 mL of DMF and 1.249 g of 2,4-dimethoxybenzenesulfonyl chloride. 2.453 g of the expected compound are obtained after crystallization from hexane.

a<20>D= -79.8° (c = 0.2; chloroform).

C) 5-chloro-1-[(2,4-dimethoxythenyl)sulfonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl phencarbamate, one isomer

A mixture of 2.103 g of the compound obtained in the previous step and 3.5 mL of pyridine in 20 mL of DCM was cooled to 0°C, 0.665 mL of phenylchloroformate was added, and the mixture was allowed to cool for another 36 h. The resulting mixture was concentrated under vacuum, the residue was stirred in 5% K2CO3 solution, extracted with EtOAc, the organic phase was washed with water and saturated NaCl solution, dried over Na2SO4, and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/hexane (80/20; V/V). 1.88 g of the expected product is obtained, which is used without further purification.

Preparation 1. 22

5- chloro- 1- r( 2. 4- dimethoxyphenyl) sulfonine- 3-( 2. 5- dimethoxyphenych- 2- oxo- 2. 3- dihydro-

1 H-indol-3-yl phenylcarbamate

(II): Ri = Cl; R 2 = H; R 3 = OCH 3 ; R 4 = 5-OCH 3 ; X = -NH-;

A) 3,5-dichloro-3-(2,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 3 g of the compound obtained in step A of Preparation 1.17 and 1.2 mL of pyridine in 50 mL of DCM was cooled to a temperature below 20°C, 0.8 mL of thionyl chloride was added, and the mixture was stirred for 1 h. The reaction mixture is washed with water, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM. 1.9 g of the expected product is obtained, which is used without further purification.

B) 3-amino-5-chloro-3-(2,5-dimethoxythenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 1.25 g of the compound obtained in the previous step in 7 mL of THF was cooled to 0°C, then gaseous ammonia was blown through the solution for 6 h, 4 times for 10 min, and then the mixture was stirred for 24 h at RT. The resulting mixture was concentrated under vacuum, the residue was slurried in DCM, and the solvent was evaporated under vacuum. The residue was chromatographed on silica gel, eluting with DCM and then with DCM/EtOAc (60/40; VA/). 0.808 g of the expected product was obtained, which was used without further purification.

C) 3-amino-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

This compound was obtained according to the procedure described in step D of Preparation 1.19, starting from 0.749 g of the compound obtained in the previous step, 0.113 g of 60% sodium hydride in oil, 7 mL of DMF and 0.612 g of 2,4-dimethoxybenzenesulfonyl chloride. 0.9 g of the expected product is obtained, after crystallization from a mixture of DCM/isoether, temp. warmer 191°C.

D) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2,5-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl phenylcarbamate

A mixture of 0.52 g of the compound obtained in the previous step and 1 mL of pyridine in 5 mL of DCM was cooled to 0°C, 0.16 mL of phenylchloroformate was added, and the mixture was stirred for 16 h. Water was added to the reaction mixture, DCM was evaporated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water and saturated NaCl solution, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM. 0.46 g of the expected product is obtained, which is used without further purification.

Preparation 1. 23

5- chloro- 3-( 2- chlorophenine- 1- r( 2. 4- dimethoxypheninesulfonine- 2- oxo- 2. 3- dihydro- 1H-

indol-3-yl phenylcarbamate

(II): Ri = Cl; R 2 = H; R3 = Cl; R4 = H; X = -NH-;

A) 3- amino- 5- chloro- 3-( 2- chlorophenyl)- 1 - 1( 2, 4- dimethoxyphenyl) sulfonyl]- 1, 3-

dihydro-2H-indol-2-one

This compound is obtained according to the procedure described in VVO 95/18105, in Example 3.

B) 5- chloro- 3-( 2- chlorophenyl)- 1- 1( 2, 4- dimethoxyphenyl) sulfonyl]- 2- oxo- 2, 3-

dihydro-1H-indol-3-yl phenylcarbamate

A solution of 3 g of the compound obtained in the previous step in 25 mL of pyridine is cooled to 0°C, a solution of 1.25 g of phenylchloroformate in 2 mL of DCM is added dropwise, and the mixture is stirred for 3 h at 0°C and then overnight at RT. The mixture was cooled again to 0°C, 0.96 g of phenylchloroformate was added, and the mixture was left to cool for 18 h. The resulting mixture was concentrated under vacuum, the residue was slurried in 5% K 2 CO 3 solution, extracted with EtOAc, the organic phase was dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/EtOAc (95/5; VAA. 2.88 g of the expected product are obtained.

Preparation 1. 24

5- chloro- 1-[( 2, 4<limethoxyphenyl) sulfonyl- 3-( 2- methoxyphenyl)- 6- nethyl- 2- oxo- 2. 3-

dihydro-1H-indol-3-yl phenylcarbamate

(II): Ri = CI; R2 = 6-CH3; R3 = OCH3, R4 = H; X = -NH-;

A) 3,5-dichloro-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

A mixture of 2.0 g of the compound obtained in step B of Preparation 1.6 in 45 mL of DCM was cooled to 0°C, 0.77 mL of pyridine was added, followed by the addition of 1.17 g of thionyl chloride, and the mixture was stirred for 2 h, after allowing the temperature to return to RT. Water and DCM are added to the reaction mixture, and after standing, the phases are separated, the organic phase is washed four times with water, dried over Na2SO4 and the solvent is evaporated under vacuum. The expected product is obtained, which is used without further purification.

B) 3-amino-5-chloro-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

Gaseous ammonia is blown for 30 min, at RT, through a mixture of 3.4 g of the compound obtained in the previous step in 25 mL of DCM, and the obtained mixture is stirred for 18 h. This mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with saturated NaCl solution, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH (95/5; VA/). 2 g of the expected product are obtained.

C) 3-amino-5-chloro-1-[(2,4<limethoxyphenyl)sulchnyl]-3-(2-methoxyphenyl)-6-

methyl-1,3-dihydro-2H-indol-2-one

This compound is obtained according to the procedure described in step B of Preparation 1.18, starting from 2 g of the compound obtained in step five, 0.29 g of 60% sodium hydride in oil, 15 mL of DMF and 1.54 g of 2,4-dimethoxybenzenesulfonyl chloride. 3.2 g of the expected product is obtained.

D) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-6-methyl-2-

oxo-2,3-dihydro-1H-indol-3-yl phenylcarbamate

A solution of 3.2 g of the compound obtained in the previous step and 10 mL of pyridine in 30 mL of DCM was cooled to 4°C, 1.2 mL of phenylchloroformate was added dropwise, and the mixture was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with 5% KHSO 4 solution, with 5% Na 2 CO 3 solution, water and saturated NaCl solution, dried over Na 2 SO 4 , and the solvent was evaporated under vacuum. 2.3 g of the expected compound are obtained after crystallization from a mixture of DCM/isoether.

Preparation 1. 25

5- chloro- 1- r( 2, 4- dimethoxyphenyl) sulfonine- 3-( 2- methoxyphenyl)- 6- trifluoromethyl- 2- oxo-

2. 3-Dihydro-1H-indol-3-yl phenylcarbamate, one isomer

(II): R 1 Cl , R 2 = 6-CF 3 ; R3 = OCH3; R4=H; X = -NH-;

A) 5-chloro-3-hydroxy-(2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydro-2H-indol-2-one

a) tert-butyl 4-chloro-3-trifluoromethyl phenylcarbamate

This compound is obtained according to the procedure described in step B a)

Preparation 1.6, starting from 4-chloro-3-trifluoromethylaniline and di-tert-butyldicarbonate in dioxane. The expected product is obtained in the form of oil, which solidifies, temp. warmer 90°C. t

b) A solution of 4 g of tert-butyl 4-chloro-3-trifluoromethylphenylcarbamate in 30 mL of ether is cooled to -70°C, in an argon atmosphere, and 22 mL of 1.6

of tert-butyllithium solution in pentane, and the mixture was stirred for 1 h, allowing the temperature to rise to -10°C, then stirred at -10°C for 2 h and 30 min. The reaction mixture is cooled to -70°C, a solution of 3.05 g of the compound obtained in step A of Preparation 1.6 in 15 mL of THF is added dropwise, and the mixture is stirred for 1 h, allowing the temperature to rise to -30°C, and then stirred for 16 h, allowing it to

temperature back to ST. A saturated solution of NH4CI is added to the reaction mixture, and the ether and THF are evaporated, and the obtained aqueous phase is extracted with EtOAc, the organic phase is washed with water and saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM and then with a DCM/EtOAc mixture (90/10; VA/). 1.48 g of the expected product is obtained, after crystallization from an ether/hexane mixture, temp. warmer 230-231 °C.

B) 3,5-dichloro-3-(2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydro-2H-indol-2-one

A suspension of 1.3 g of the compound obtained in step A, in 8 mL of DCM, was cooled to 0°C, 0.43 mL of pyridine was added, and then 0.4 mL of thionyl chloride, and this mixture was stirred for 15 min. The reaction mixture is washed three times with water, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. 1.2 g of the expected product is obtained, which is used without further purification.

C) 5-chloro-3-II(1S)-2-hydroxy-1-phenyleth

trifluoromethyl-1,3-dihydro-2H-indol-2-one, isomer A and isomer B

A mixture of 1.29 g of the compound obtained in the previous step and 0.47 g of (S)-(+)-(a)-phenyl-glycinol in 35 mL of chloroform was stirred for 4 h at RT. Then 0.6 mL of DIPEA was added, the solvent was concentrated to half, and the mixture was stirred at RT for 22 h. The reaction mixture is concentrated under vacuum, and the residue is chromatographed on silica gel, eluting with a mixture of DCM/EtOAc (85/15; V/V). One diastereomer was isolated: - less polar isomer, isomer A: 0.712 g obtained by crystallization from a mixture of DCM/isoether, temp. warmer 205°C. a<20>D= +164° (c = 0.16; chloroform).

Continue with chromatography, eluting with a mixture of DCM/EtOAc (70/30V/V), and the second diastereomer is isolated:

-half of the isomer, isomer B: 0.45 g is obtained, temp. warmer 242°C.

a<20>D= -55° (c = 0.15; chloroform).

D) 3-amino-5-chloro-3-(2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydro-2H-indol-2-one, one isomer

A solution of 0.7 g of the compound obtained in the previous step (isomer A) in 15 mL of DCM and 7 mL of MeOH was cooled to 0°C, lead tetraacetate was added, and the mixture was stirred for 40 min. a few drops of 5% NaHCO 3 solution are added, and the mixture is concentrated under vacuum. The residue was taken up in water and extracted 3* with EtOAc, the organic phase was washed with water and saturated NaCl solution, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The obtained product is dissolved in 30 mL of water, 30 mL of 5M HCl solution is added dropwise, and then THF, until the dissolution is complete, and the mixture is stirred for 1 hour. The reaction mixture is diluted with 50 mL of water, the aqueous phase is washed with 150 mL of ether, then with concentrated NaOH solution, then extracted with EtOAc, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM/MeOH (92/8; V/V). 0.19 g of the expected product is obtained.

E) 3-amino-5-chloro-1-[(2,4-dimethoxyphenyl)-sulfonyl]-3-(2-methoxyphenyl)-6-

thfluoromethyl- 1, 3- dihydro- 2H- indol- 2- one, one isomer

This compound was obtained according to the procedure described in step B of Preparation 1.18, starting from 0.19 g of the compound obtained in the previous step, 0.023 g of 60% sodium hydride in oil, 2 mL of DMF and 0.138 g of 2,4-dimethoxybenzenesulfonyl chloride. 0.22 g of the expected compound is obtained.

F) 5-chloro-1-1(2,4-dimethoxyrenyl)sulfonyl]-3-(2-methoxyphenyl)-6-thfluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl phenylcarbamate, one

isomer

This compound was obtained according to the procedure described in Step C of Preparation 1.18, starting from 0.215 g of the compound obtained in the previous step, 0.31 mL of pyridine, 5 mL of DCM, and 0.079 g of phenylchloroformate. 0.208 g of the expected product is obtained.

Preparation 1. 26

6- chloro- 3-( 2- chlorophenyl)- 1- r( 2. 4- dimethoxyphenysulfonin- 5- methyl- 2- oxo- 2. 3- dihydro-

1 //-/- indol-3-yl phenylcarbamate

(II): R 1 = CH 3 ; R 2 = 6-Cl; R3 = CI; R4=H; X = -NH-;

A) N-(3-chloro-4-methylphenyl)-DL-2-chloro-mandelamide

A mixture of 52.72 g of DL-2-chloromandelic acid and 40 g of 3-chloro-4-methylaniline in 400 mL of 1,2-dichlorobenzene was refluxed for 6 h, removing the resulting water using a Dean-Stark apparatus. After cooling to RT, the mixture is allowed to crystallize, and the resulting precipitate is filtered off under reduced pressure. The expected product is obtained, after recrystallization from a mixture of DCM/isoether, temp. warmer 164°C.

B) 6-chloro-3-(2-chlorophenyl)-5-methyl-1,3-dihydroindol-2-one

Cool 125 mL of concentrated (95%) H2SO4 to 5°C, then add 23 mL of fuming sulfuric acid (30% oleum) dropwise. Then, 25 g of the compound obtained in the previous step is added in portions, at a temperature below 5°C, and the mixture is stirred for 48 h at RT. The reaction mixture is poured into an ice/water mixture, the resulting precipitate is filtered off under reduced pressure, and washed with water to pH 7. This precipitate is dissolved in EtOAc, the organic phase is washed with saturated NaCl solution, dried over Na2SO4, the solvent is evaporated under vacuum, and the resulting precipitate is filtered off under reduced pressure. The expected product is obtained, temp. warmer 186°C.

C) 3-bromo-6-chloro-3-(2-chlorophenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

A solution of 2.6 mL of bromine in 10 mL of DCM is slowly added, at RT, to a suspension of 16.36 g of the compound obtained in the previous step, in 200 mL of DCM. The following addition of a solution of 0.26 mL of bromine in 5 mL of DCM was made, and then the reaction mixture was concentrated under vacuum. The residue was dissolved twice in DCM, and the solvent was evaporated each time under vacuum. The residue was dissolved in EtOAc, the organic phase was washed with saturated NaCl solution, dried over MgSO 4 , and the solvent was evaporated under vacuum. The expected compound is obtained.

D) 3- amino- 6- chloro- 3-( 2- chlorophenyl)- 5- methyl- 1, 3- dihydro- 2H- indol- 2-one

30 mL of a concentrated solution of ammonia in water was added to a solution of 4.25 g of the compound obtained in the previous step in 30 mL of THF, and the mixture was stirred at RT for 24 h. Another 10 mL of concentrated ammonia solution in water is added, and the mixture is stirred overnight at RT. The resulting mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. 3.02 g of the expected product is obtained, after crystallization from DCM, temp. topj. = 233°C.

E) 3-amino-6-chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-5-methyl-1,3-dihydro-2H-indol-2-ol

This compound was obtained according to the procedure described in step B of Preparation 1.18, starting from 0.54 g of the compound obtained in the previous step, 0.077 g of 60% sodium hydride in oil, 5 mL of DMF and 0.435 g of 2,4-dimethoxybenzenesulfonyl chloride. 0.592 g of the expected product is obtained after crystallization from a DMSO/isoether mixture.

F) 6- chloro- 3-( 2- chlorophenyl)- 1-[( 2, 4- dimethoxyphenyl) sulfonyl]- 5- methyl- 2- oxo-2, 3- dihydro- 1 H- indol- 3- yl phenylcarbamate

This compound is obtained according to the procedure described in step C of Preparation 1.18, starting from 0.592 g of the compound obtained in the previous step, 1 mL of pyridine, 6 mL of DCM and 0.19 mL of phenylchloroformate. 0.690 g of the expected product is obtained, which is used without further purification.

Preparation 1. 27

2-rr5-chloro-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl1oxy]acetic,

acid

(II): Ri = CI; R2=H; R 3 =-OCH(CH 3 ) 2 ; R4=H; X = -O-CH2-; Y = OH; W=H

A) methyl 2-[[5-chloro-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indole-3-Hoxy]acetate

0.29 g of 60% sodium hydride in oil was added to a solution of 1.05 g of methyl glycolate in 20 mL of THF, and the mixture was stirred at RT for 10 min. Then a solution of 1.88 g of the compound obtained in step A of Preparation 1.20 is added dropwise, and the mixture is stirred for 10 min at RT. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water and 1M HCl solution, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue was chromatographed on silica gel, eluting with DCM and then with EtOAc. 0.8 g of the expected product is obtained, after crystallization from isoether, temp. warmer 210-213°C.

B) 2-[[ 5- chloro-3-( 2- isopmoxyphenyl)- 2- oxo

yl]oxy]acetic acid

A solution of 0.24 g of NaOH pellets in 5 mL of water, at 20°C, was added to a solution of 0.8 g of the compound obtained in the previous step in 40 mL of MeOH, and the mixture was stirred at RT for 15 h. The resulting mixture is concentrated under vacuum, the residue is dissolved in 25 mL of water, acidified by dropping 1 mL of 12M HCI, and the resulting precipitate is separated by filtration under reduced pressure. 0.8 g of the expected product is obtained, temp. warmer 225-228°C.

Preparation 1. 28

2- f5- chloro- 1-[( 2. 4- dimethoxyphenyl)- sulfonyl1- 3-( 2- methoxyphenyl)- 2- oxo- 2, 3- dihydro-

1 //-/- indole-3-yl| amino] acetic acid

(II): Ri=Cl; R 2 = H; R 3 = -OCH 3 ; R 4 = H; X = -NH-CH2; Y = OH;

A) tert-butyl 2-[[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3<lM^

[ammonium] acetate

A solution of 2.4 g of glycine t/u-butyl ester hydrochloride in 50 mL of chloroform and 50 mL of THF was cooled in an ice bath, 2.3 g of triethylamine was added, and then 3.5 g of the compound obtained in step A of Preparation 1.19, and the mixture was stirred overnight at RT. The resulting mixture was concentrated under vacuum, the residue was slurried in water, extracted with DCM, the organic phase was dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is triturated in isoether, and the resulting precipitate is filtered off under reduced pressure. 2.2 g of the expected product is obtained.

B) tert-butyl 2-[[5-chloro-1-1(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-

oxo-2,3-dihydro-1H-indol-3-yl]amino]acetate

0.225 g of 60% sodium hydride in oil was added to a mixture of 2.1 g of the compound obtained in the previous step in 10 mL of DMF, and the mixture was stirred for 30 min. Then 1.2 g of 2,4-dimethoxybenzenesulfonyl chloride was added, and the mixture was stirred at RT for 18 h. The reaction mixture was poured into water, extracted with EtOAc, the organic phase was dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM. 2.5 g of the expected product is obtained after crystallization from isoether.

C) 2-[[5-chloro-1-[(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indole-3-

yl]amino]acetic acid

Mix 2.5 g of the compound obtained in the previous step and 10 mL of TFA and stir for 3 h. This mixture was concentrated under vacuum, the residue was taken up in hexane, and the resulting precipitate was filtered off under reduced pressure. 2 g of the expected product is obtained.

Preparation 1. 29

3- rr5- chloro- 1- f( 2. 4- dimethoxypheninesulfonine- 3-( 2- methoxyphenines- 2- oxo- 2. 3- dihydro-

1 //-/- Indole-3-inaminolpropionic acid

(II): Ri=Cl; R 2 = H; R 3 = -OCH 3 ; R 4 = H; X = -NH-CH2-CH2-; X = OH;

A) tert-butyl 3-[[ 5- chloroD- 3-( 2- methoxyphenyl)- 2- oxo- 2, 3- dihydrogen

yl] amino] propionate

2.15 g of triethylamine was added to the mixture of 3 g of the compound obtained in step A of Preparation 1.19 and 2.1 g of p-alanine tert-butyl ester hydrochloride in 50 mL of DCM and 50 mL of THF, and the mixture was stirred at RT for 18 h. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/EtOAc (80/20; V/V). 3.2 g of the expected product are obtained, after crystallization from a mixture of DCM/isoether, temp. warmer 170°C.

B) tert-butyl 3-[[ 5- chloro- 1-[( 2, 4- dimethoxyphenyl) sulfonyl]- 3-( 2- methoxyphenyl)- 2-

oxo-2,3-dihydro-1H-indol-3-yl]amino]propionate

This compound was obtained according to the procedure described in step B of Preparation 1.18, starting from 2.16 g of the compound obtained in the previous step, 0.225 g of 60% sodium hydride in oil, 15 mL of DMF and 1.21 g of 2,4-dimethoxybenzenesulfonyl chloride. 2.4 g of the expected product is obtained, after crystallization from a mixture of heptane/EtOAc, temp. warmer 175°C.

C) 3-[[ 5- chloro- 1-[( 2, 4<imethoxythenyl) sulfonyl]- 3-( 2- methoxyphenyl)- 2- oxo- 2, 3-

dihydro-1H-indol-3-yl] amino] propionic acid

A mixture of 2.4 g of the compound obtained in the previous step and 15 mL of TFA in 5 mL of DCM was stirred for 18 h. This mixture is concentrated under vacuum, the residue is dissolved in ether, and the resulting precipitate is filtered off under reduced pressure. 2.2 g of the expected product is obtained, temp. warmer >250°C.

Preparation 1. 30

2- r5-chloro-3-(2-fluorophenyl)-2-oxo-2.3-dihydro-1/-/-indol-3-yl1acetic acid.

dextrorotatory isomer

(II): Ri = Cl; R 2 = H; R3= -F; R 4 = H; X = -CH2-; Y = OH; W = H

A) ethyl 2-[5-chloro-3-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetate

A mixture of 2.6 g of the compound obtained in step C of Preparation 1.12, 1.84 g of ethyl bromoacetate, 1.66 g of Cl and 2 g of K2CO3 in 10 mL of acetone is refluxed for 20 h. Mineral salts are separated by filtration, and the filtrate is concentrated under vacuum. The residue was chromatographed on silica gel, eluting with DCM and then with EtOAc. 2.1 g of the expected product is obtained after precipitation from isoether.

B) 2-[5-chloro-3-(2-fluomefnyl)-2<)xo-2,3-dihydm-1HH

acid

Mix 2 g of the compound obtained in the previous step and 2 mL of 30% NaOH solution in 1 mL of water and 50 mL of EtOH, stir for 20 h at RT. This mixture is concentrated under vacuum, the residue is dissolved in 40 mL of water, acidified to pH 1 by adding concentrated HCl, and the resulting precipitate is filtered off under reduced pressure and washed with water. 1.9 g of the expected product is obtained.

C) 2-[5-chloro-3-(2-fluorophenyl)-2-oxo-2,3-dihydiv^^

acid, dextrorotatory isomer

A mixture of 0.97 g of the compound obtained in the previous step and 0.89 g of (+)-cinchonine (ct^D= +225°; c = 0.5; EtOH) in 31.5 mL of MeOH is heated to 40° C. and then heated under reflux. The resulting precipitate was filtered off under reduced pressure while still hot and washed with hot MeOH and then ether to give 0.485 g of the (+)-cinchonine salt. Dissolve 0.485 g of the thus obtained salt in a water/EtOAc mixture, acidify to pH 0 by adding 3M HCl, stir, extract with EtOAc, wash the organic phase with water, dry over Na2SO4 and evaporate the solvent under vacuum. 0.22 g of the expected product is obtained in the form of the dextrorotatory isomer. a<20>D= +61.3° (c =0.15; chloroform).

Preparation 1. 31

2-[5.6-dichloro-3-(2-fluorophenyl)-2-oxo-2.3-dihydro-1H-indol-3-ylacetic acid

(II): R 1 =Cl; R 2 = 6-Cl; R3=F; R4 = H; X = -CH2-; Y = OH; W = H.

A) N-(3, 4-dichlorophenyl)-DL-2-fluoromandelamide

A mixture of 7.5 g of the compound obtained in step A of Preparation 1.12 and 7.5 g of 3,4-dichloroaniline in 40 mL of 1,2-dichlorobenzene is refluxed for 3 h, removing the resulting water using a Dean-Stark apparatus. This mixture was concentrated under vacuum, the residue was triturated in isoether, and the resulting precipitate was filtered off under reduced pressure. 9 g of the expected product is obtained.

B) 5, 6-dichloro-3-(2-fluorophenyl)-1,3-dihydro-2H-indol-2-one

Add 8.9 g of the compound obtained in the previous step, at RT, to a mixture of 35 mL of concentrated (95%) H2SO4 and 9 mL of fuming sulfuric acid (30% oleum), and the mixture is stirred for 8 h. The reaction mixture is poured into an ice/water mixture, and the resulting precipitate is filtered off under reduced pressure and washed with water. The precipitate is chromatographed on silica gel, eluting with DCM and then with isoether. Two isomers are separated: - the less polar compound from step B yields 3.7 g, temp. warmer 204-205°C; -polaminium compound, 4,5-dichloro-3-(2-fluorophenyl)-1,3-dihydro-2H-indol-2-one, gives 1.5 g, temp. warmer 244-247°C

C) ethyl 2-[5, 6- dichloro-3-(2- fluorophenyl)-2- oxo-2, 3- dihydro-1H- indole-3-

yl acetate

A mixture of 3 g of the compound obtained in the previous step, 1.7 g of ethyl bromoacetate, 1.8 g of Kl and 1.4 g of K2CO3 in 20 mL of acetone was refluxed for 10 h. This mixture is concentrated under vacuum, the residue is taken up in water, extracted with EtOAc, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with isoether. 2.1 g of the expected compound is obtained, after trituration in pentane and then in isoether, temp. warmer 152-158°C.

D) 2-[5,6-dichloro-3-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]synacetate

acid

A mixture of 2 g of the compound obtained in the previous step and 3 mL of a 30% NaOH solution in 5 mL of water and 40 mL of EtOH was stirred for 20 h at RT. This mixture was concentrated under vacuum, the residue was triturated in water, the aqueous phase was washed with ether, acidified to pH 1 by adding concentrated HCl, extracted with EtOAc, the organic phase was dried over Na 2 SO 4 and the solvent was evaporated under vacuum. 1.5 g of the expected product is obtained, after trituration in isoether, temp. warmer 245°C.

Preparation 1. 32

2- r5- chloro- 3-( 2, 3- dimethoxyphenyl)- 2- oxo- 2. 3- diN acid

(II): Ri = CI; R 2 = H; R3 = OCH3; R4 = 3-OCH3; X = -CH2-; Y=OH; W=H

A) ethyl-2-(2,3-dimethoxyphenyl)-2-oxoacetate

A mixture of 27.6 g of 1,2-dimethoxybenzene in 160 mL of ether is cooled to -40°C, 250 mL of a 1.6M solution of n-butyllithium in hexane is added dropwise, and the mixture is then stirred for 24 h, allowing the temperature to return to RT. The reaction mixture was cooled to -20°C, 136 mL of diethyl oxalate was quickly added, and the mixture was stirred allowing the temperature to return to RT. After stirring for 30 min at RT, the reaction mixture was poured into a saturated solution of NH4CI, after resting the phases were separated, the aqueous phase was extracted with ether, the combined organic phases were washed with 2* water, dried over Na2SO4 and the solvents were evaporated under vacuum. Excess diethyloxalate is removed by distillation under vacuum (temp. key. = 90°C at 2400 Pa). The crude product obtained is chromatographed on silica gel, eluting with a mixture of heptane/isoether (90/10; V/V). 25 g of the expected product is obtained, which is used without further purification in the next step.

B) 5-chloro-3-hydroxy-3-(2,3-dimethoxyphenyl)-1,3-dihydm-2H-indol-2one

a) tert-butyl 4-chlorophenylcarbamate

Mix 12.7 g of 4-chloroaniline and 22 g of di-tert-butyldicarbonate in 60 mL of dioxane

stirred for 24 h at RT. This reaction mixture was concentrated under vacuum, the residue was taken up in pentane, and the resulting precipitate was filtered off under reduced pressure and dried. 22.5 g of the expected product is obtained.

b) A mixture of 11.4 g of tert-butyl 4-chlorophenylcarbamate in 100 mL of ether is cooled to -40°C, in an atmosphere of dry nitrogen, and 80 mL of 1.5 M is added dropwise to it

of tert-butyllithium solution in pentane, and the mixture was stirred for 3 h at -20°C. The reaction mixture was cooled to -40°C, and a solution of 14 g of the compound obtained in step A in 50 mL of THF was added during 1 h, and the mixture was stirred at RT for 4 days. The reaction mixture is poured into a saturated solution of NH4Cl, and the resulting precipitate is separated

by filtration under reduced pressure and dried. 10.2 g of the expected compound is obtained, which is used without further purification in the next step.

C) 5-chloro-3-(2,3-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 8.5 g of the compound obtained in the previous step, 40 mL of TFA and 11.5 mL of triethylsilane was refluxed for 5 h. The mixture was concentrated under vacuum, the residue was taken up in water, extracted with EtOAc, the resulting precipitate was filtered off under reduced pressure, washed with EtOAc and then with isoether to give 5.1 g of the expected product. The filtrates were separated after standing, the organic phase was dried over Na 2 SO 4 and the solvent was evaporated under vacuum. Another 1.4 g of the expected product is obtained, after crystallization from EtOAc, temp. warmer 193°C.

D) ethyl 2-[5-chloro-1H-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indole-3-HJacetate

A mixture of 6.2 g of the compound obtained in the previous step, 3.6 g of ethyl bromoacetate, 3.5 g of Cl and 6.2 g of K 2 CO 3 in 20 mL of DMF is heated for 8 h at 60°C. The mixture was concentrated under vacuum, the residue was taken up in water and extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH (99/1; V/V). 3 g of the expected product are obtained, temp. warmer 155°C.

E) 2-[5-chloro-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indole-3-

acetic acid

A mixture of 3 g of the compound obtained in the previous step and 0.5 g of NaOH pellets in 40 mL of water and 10 mL of dioxane was stirred for 24 h at RT. 150 mL of water is added, the aqueous phase is washed with EtOAc, acidified to pH 1 by adding concentrated HCl, and the resulting precipitate is filtered off under reduced pressure, washed with water and dried. 2.5 g of the expected product is obtained, temp. warmer 235°C.

Preparation 1. 33

2- r5-chloro-3-(2-ethoxyphenyl)-6-methyl

acid

(II): R 1 =Cl; R2 = 6-CH3; R3 = OCH2CH3; R 4 - H; X = -CH2-; Y=OH; W=H

A) 5-chloro-3-(2-ethoxyphenyl)-3-hydroxy-6-methyl-1^

This compound is obtained according to the procedure described in step C of Preparation 1.7, starting from the compound obtained in step A of Preparation 1.2 and the compound obtained in step B of Preparation 1.7. 1.05 g of the expected product is obtained, temp. warmer 253°C.

B) 5-chloro-3-(2-ethoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

A mixture of 1.05 g of the compound obtained in the previous step, 5.5 mL of TFA and 2.2 mL of triethylsilane was refluxed for 5 h. This mixture is concentrated under vacuum, and the residue is chromatographed on silica gel, eluting with DCM and then with a mixture of DCM/MeOH (99.5/0.5; VA/). 0.5 g of the expected product is obtained, temp. warmer 228°C.

C) ethyl 2-[5-chloro-3-(2-ethoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-racefar

This compound is obtained according to the procedure described in step C of Preparation 1.1, starting from 5.5 g of the compound obtained in the previous step, 0.29 g of ethyl bromoacetate, 0.29 g of Cl and 0.46 g of K 2 CO 3 in 5 mL of acetone. 0.25 g of the expected compound is obtained.

D) 2-[5-chloro-3-(2-ethoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indole-3-

acetic acid

This compound is obtained according to the procedure described in step E of Preparation 1.2, starting from 0.25 g of the compound obtained in the previous step, 0.3 mL of a 30% solution of NaOH in 2.8 mL of water and 7 mL of THF. 0.2 g of the expected product is obtained.

Preparation 1. 34

5-chloro-1-r(2.4<limethoxyphenyl)sulfonyl1-3-(2-ethoxyphenyl)-2-oxo-2.3-dihydro-1H-

indol-3-yl phenylcarbonate

(II): R₂Cl; R2=H; R3 = OCH2CH3; R4 = H; X = -0-;

A) 5-chloro-3-(2-ethoxyphenyl)-3-[(thmethylsilyl)oxy]-1,3-dihydro-2H-indole-2-

he

This compound is obtained according to the procedure described in step A of Preparation 1.8, starting from 2 g of the compound from step B of Preparation 1.2, 0.1 g of zinc chloride, 6.6 mL of HMDS and 30 mL of acetonitrile. After trituration in heptane, 1.5 g of the expected compound is obtained.

B) 5-chloro-1-[(2,4-dimethoxythenyl)sulfonyl]-3-(2-ethoxyphenyl)-3-[(trimethylsilyl)oxy]-1,3- dihydroz~ 2H-indol-2-one

This compound is obtained according to the procedure described in step B of Preparation 1.8, starting from 1.45 g of the compound obtained in the previous step, 20 mL of THF, 0.05 g of 60% sodium hydride in oil and 1 g of 2,4-dimethoxybenzenesulfonyl chloride. 1.6 g of the expected product is obtained after trituration in isoether.

C) 5-chloro-1-1(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

A mixture of 1.55 g of the compound obtained in the previous step and 3 mL of 12 M HCl in 100 mL of acetone was stirred for 3 h at RT. This mixture was concentrated under vacuum and the residue was chromatographed on silk gel, eluting with DCM. After trituration in isoether, 1.4 g of the expected product is obtained.

D) 5-chloro-1-[(2,4<XimethoxyTenyl)sulfonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-

dihydro-1H-indol-3-yl phenylcarbonate

A mixture of 1.35 g of the compound obtained in the previous step in 20 mL of pyridine was cooled to 10°C, phenylchloroformate was added, and the mixture was stirred for 20 h, allowing the temperature to return to RT. The resulting mixture was concentrated under vacuum, the residue was dissolved in 1M HCl solution, extracted with isoether, and the resulting precipitate was filtered off under reduced pressure and washed with isoether. 1.8 g of the expected product is obtained, temp. warmer 210-211°C (dec.).

Refutation of compounds of formula (III).

Preparation 2. 1

1-(2-pyrazinyl)piperazine

(III): n = 1;

A mixture of 3 g of piperazine, 1.04 mL of 2-chloropyrazine and 1.85 g of K2CO3 in 100 mL of EtOH was refluxed for 48 h. The reaction mixture is concentrated under vacuum, the residue is stirred in water, then made basic to pH 10 by adding 10% NaOH solution, extracted with chloroform, the organic phase is washed with water, dried over Na2SO4 and the solvent is evaporated under vacuum. 1.8 g of the expected product is obtained after crystallization from hexane.

Preparation 2. 2

1-(3-pyridyl)piperazine

(III): n = 1;

This compound was obtained according to the procedure described in Tetrahedron Letters, 1998, 39, 617-620.

Preparation 2. 3

1 - (2- pyridyl) homopiperazine

(III): n = 2;

A mixture of 2-bromopyridine and 12 g of homopiperazine is heated for 6 h at 100°C. 50 mL of water was added to the reaction mixture, and the obtained mixture was extracted with EtOAc, the organic phase was washed with saturated NaCl solution, dried over Na2SO4 and the solvent was evaporated under vacuum. 1.28 g of the expected product is obtained.

Preparation 2. 4

1-(4-pyridyl)homopiperazine

(III): n = 2;

A mixture of 2 g of 4-bromopyridine and 10 g of homopiperazine is heated at 100°C for 4 hours. 100 mL of water is added to the reaction mixture, and the resulting mixture is made basic to pH 10 by adding 10% NaOH solution, and extracted three times with 100 mL of chloroform, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. 0.9 g of the expected product is obtained.

Preparation 2. 5

1-(3-pyridazinyl)piperazine trihydrochloride

(III), 3HCl: n= 1;

A) tert-butyl 4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate

A mixture of 13.52 g of tert-butyl 1-piperazinecarboxylate, 10.81 g of 3,6-dichloropyridazine and 20 mL of triethylamine in 100 mL of n-butanol was refluxed for 5 h. This mixture was concentrated under vacuum, and the residue was chromatographed on silica gel, eluting with DCM/EtOAc (90/10; VA/). 14 g of the expected product was obtained, which was used without further purification.

B) tert-butyl 4-(3-pyridazinyl)-1-piperazinecarboxylate

A mixture of 10.5 g of the compound obtained in the previous step and 2.5 g of 10% palladium on activated carbon in 30 mL of DMF and 250 mL of EtOH is hydrogenated overnight at RT and atmospheric pressure. The catalyst is separated by filtration, and the filtrate is concentrated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH from (97/3; V/V) to (90/10; V/V). 9.1 g of the expected product is obtained, which is used without further purification.

C) 1-(3-pindazinyl) piperazine trihydrochloride

A mixture of 3.8 g of the compound obtained in the previous step, 50 mL of a 2M solution of HCl in ether, and 20 mL of MeOH was stirred overnight at RT. The mixture is concentrated under vacuum, the residue is triturated in ether, and the resulting precipitate is filtered off under reduced pressure. 3 g of the expected product is obtained.

Preparation 2. 6

1-(1.3-thiazol-2-piperazine dihydrochloride

(III), 2HCl: n= 1;

A) tert-butyl 4-(1,3-thiazol-2-yl)-1-piperazinecarboxylate

A mixture of 5 g tert-butyl 1-piperazinecarboxylate, 4.4 g 2-bromo-1,3-thiazole and 7.4 g K2CO3 in 50 mL EtOH was refluxed for 4 days. Water was added to the reaction mixture, EtOH was evaporated under vacuum, the obtained aqueous phase was extracted with EtOAc, the organic phase was washed with saturated K2CO3 solution and saturated NaCl solution, dried over Na2SO4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture (98/2; V/V). 5 g of the expected product is obtained, after precipitation from a cold DCM/hexane mixture and filtration using reduced pressure, temp. warmer 114-116°C.

B) 1-(1,3-thiazol-2-yl)piperazine dihydrochloride

A mixture of 2.8 g of the compound obtained in the previous step and 50 mL of a 2M solution of HCl in ether, to which a minimal amount of DCM was previously added, then MeOH until the reaction mixture was dissolved, was stirred for 7 h at RT. The resulting mixture was concentrated under vacuum to give 2.35 g of the expected product.

Example 1

5- chloro- 1- f( 2, 4<limethoxypheninesulfonyl- 3-( 2- methoxyphenyne- 3- f 2- oxo- 2- r 4-( 4- pyridyl)-

1 - piperazinilletin-1.3-dihydro-2H-indol-2-one (I): Ri=CI; R 2 = H; R3=OCH3; R4 = H; X = -CH2-; n=1; R6 = 2-OCH3; R7 = OCH3.

A) 5-chloro-3-(2-methoxyphenyl)-3-[2-oxo-2-[4-(4^

1, 3-dihydro-2H-indol-2-one

1.7 g of BOP, 2.5 mL of DIPEA and then 0.6 g of 1-(4-pyridyl)piperazine are added, at 20°C, to a mixture of 1.1 g of the compound obtained in Preparation 1.1 in 20 mL of DCM, and the mixture is stirred for 2 h at 20°C. Then 30 mL of 2M NaOH was added, and the mixture was stirred for 15 min. The reaction mixture was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvents were evaporated under vacuum. The residue is triturated in isoether, and the resulting precipitate is filtered off under reduced pressure. The precipitate is chromatographed on silica gel, eluting with DCM and then with acetone. 1.4 g of the expected product is obtained, after crystallization from isoether, temp. warmer 111°C

B) 5-chloro-1-[(2A<1methoxyphenyl)sulfonyl]-3-^

(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one

0.08 g of 60% sodium hydride in oil, at 20°C, was added to a mixture of 0.7 g of the compound obtained in the previous step, in 15 mL of THF, and this mixture was stirred for 20 min. Then 0.44 g of 2,4-dimethoxybenzenesulfonyl chloride was added, and the mixture was stirred for 1 hour and 30 minutes. The reaction mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue was chromatographed on silica gel, eluting with DCM, then with EtOAc and acetone. 0.7 g of the expected product is obtained, after crystallization from isoether, temp. warmer 136-141 °C (dec.).

Example 2

5- chloro- 3-( 2- ethoxyphenyl)- 1- R2, 4- dimethoxypheninesulfonine- 3- f2- oxo- 2- f4-( 4- pyridine-

1 - piperazinillethin- 1. 3- dihydro- 2tr- indol- 2-one

(I): R:=Cl; R 2 = H; R 3 = OCH 2 CH 3 ; R 4 = H; X = -CH2-; n = 1;

R6 = 2-OCH3; R7 = OCH3

A) 5- chloro- 3-( 2- ethoxyphenyl)- 3-[ 2- oxo- 2-[ 4-( 4- pyridyl)- 1- piperazinyl] ethyl]- 1, 3-

dihydro-2H-indol-2-one

A mixture of 1.1 g of the compound obtained in Preparation 1.2, 1.52 g of BOP, 2 mL of DIPEA and 0.6 g of 1-(4-pyridyl)piperazine in 20 mL of DCM was stirred for 24 h at RT. The resulting crystalline product was filtered off under reduced pressure and dried to give 0.81 g of the expected product. The liquids from the filtration are extracted with a solution of concentrated HCl, after standing the phases are separated, ice is added to the acidic phase, and the acidic phase is made basic by adding 10M NaOH, extracted with EtOAc, the organic phase is washed with water, dried over Na2SO4 and the solvent is evaporated under vacuum. Another 0.09 g of the expected product is obtained, temp. warmer 185°C.

B) 5- chloro- 3-( 2- ethoxyphenyl)- 1-[( 2, 4- dimethoxyphenyl) sulfonyl]- 3-[ 2- oxo- 2-[ 4-( 4- pyridyl)- 1- piperazinyl] ethyl]- 1, 3- dihydro- 2H- indol- 2-one

0.085 g of 60% sodium hydride in oil was added to the mixture of 0.9 g of the compound obtained in the previous step in 20 mL of the THF/DMF mixture (90/10; VA/), and this mixture was stirred for 15 min at RT. Then 0.45 g of 2,4-dimethoxybenzenesulfonyl chloride was added, and the mixture was stirred for 30 min at RT. The reaction mixture was poured into water, extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH (96/4; V/V). 0.42 g of the expected product is obtained, after crystallization from isoether, temp. warmer 226°C.

Example 3

5- chloro- 3-( 2- isoproDoxyphenyl)- 1- f( 2. 4- dimethoxyphenyl) surfonyl- 3- f2- oxo- 2- f4-( 4-

pyridyl)-1-piperazinethyl-1,3-dihydro-2H-indol-2-one, levogyric isomer

(I): Ri = CI; R 2 = H; R3 = OCH(OCH3)2: R4 = H; X = -CH2-; n = 1; R6 = 2-OCH3; R7 = OCH3

A) 5-chloro-3-(2-isopropoxyphenyl)-3-[2<)xo-2-[4-(4-pyridyl)-^

1, 3- dihydro- 2H- indol- 2-one, dextrorotary isomer

A mixture of 0.43 g of the compound obtained in Preparation 1.3, 0.6 g of BOP, 0.75 g of DIPEA and 0.2 g of 1-(4-pyridyl)piperazine in 15 mL of DCM was stirred for 2 h at 20°C. Then 25 mL of 2M NaOH was added, and the mixture was stirred for 20 min at 20°C. The reaction mixture was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM and then acetone. 0.33 g of the expected product is obtained.

a<20>D= +37° (c = 0.25; chloroform).

B) 5-chloro-3-(2-isopropoxyphenyl)-1-[(2,4<iimethoxyphenyl)su^2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one, levogiri

isomer

0.025 g of 60% sodium hydride in oil was added to a mixture of 0.3 g of the compound obtained in the previous step in 10 mL of THF, and this mixture was stirred for 15 min at 20°C. Then 0.19 g of 2,4-dimethoxybenzenesulfonyl chloride was added, and the mixture was stirred for 2 h at 20°C. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted with EtOAc, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM and then with acetone. 0.1 g of the expected product is obtained. a<20>D= -21.3° (c = 0.1;

DCM)

<1>H NMR (DMSO-de) δ (ppm): 0.6 (d, 3H), 1.2 (d, 3H), 3.0-4.0 (m+2s, 16H), 4.6 (mt, 1H), 6.4-7.2 (mt, 9H), 7.4 (bd, 1H), 7.7 (dd, 2H), 8.1 (d, 2H).

Example 4

3-(2-chlorophenyl)-1-f(2.4-dimethoxyphenyl)-surphonyl-5-methyl-3-r2-oxo-2-r4-(4-pyridyl)-1-

piperazinillethin- 1. 3- dihydro- 2/-/- indol- 2- one

(I): R 1 = CH 3 ; R 2 = H; R 3 =Cl; R4=H; X = -CH2-; n=1; R6 = 2-OH3; R7 = OCH3

A) 3-(2-chlorophenyl)-5-methyl-3-[2-oxo-2-[4-(2-pyridyl)-1-pipem

dihydro-2H-indol-2-one

A mixture of 0.26 g of the compound obtained in Preparation 1.4 and 0.2 mL of thionyl chloride in 10 mL of toluene was refluxed for 2 h, and then the reaction mixture was concentrated under vacuum. The thus obtained acid chloride is dissolved in 10 mL of DCM, and this solution is added to a mixture of 0.3 g of 1-(2-pyridyl)piperazine in 20 mL of DCM, and this mixture is stirred at RT for 2 h. The reaction mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH (98/2; V/V). 0.32 g of the expected product is obtained.

B) 3-(2-chlorophenyl)-1-[2(2A<limethoxyphenyl)sulfonyl]-^

(2-pyridyl)-1-piperazinyl]ethyl]-1,3<lihd

Add 0.0335 g of 60% sodium hydride in oil, at RT, to a mixture of 0.3 g of the compound obtained in the previous step in 10 mL of THF, and this mixture is stirred for 30 min. Then 0.2 g of 2,4-dimethoxybenzenesulfonyl chloride was added, and the mixture was stirred at RT for 1 h. 50 mL of water was added to the reaction mixture, and the resulting mixture was extracted with EtOAc, the organic phase was dried over Na2SO4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH (98/2; V/V). 0.32 g of the expected product is obtained, after crystallization from isoether, temp. warmer 239°C.

Example 5

5- chloro- 1- F( 2. 4- dimethoxyphenyl) sulfonyl- 3-( 2- methoxyphenyl)- 2- oxo- 2. 3- dihydro- 1H-

indol-3-yl 4-(2-pyridyl)-1-piperazinecarboxylate

(I): Ri = CI; R2=H; R3 = OCH3; R4=H; X=-0-; n = 1;

R6 = 2-OCH3; R7 = OCH3.

A mixture of 0.5 g of the compound obtained in Preparation 1.8 and 0.3 g of 1-(2-pyridyl)piperazine in 10 mL of DCM was stirred for 20 h at 20°C. The reaction mixture was chromatographed on silica gel, eluting with DCM and then with EtOAc. 0.2 g of the expected product is obtained, after crystallization from isoether, temp. warmer 210-215°C.

Example 6

5-chloro-1-r(2.4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2<)xo-2.3-dihydro-1H-

indol-3-yl 4-(4-pyridyl>-1-piperazinecarboxylate).

(I): Ri = CI; R 2 = H; R3 = OCH3; R4 = H; X = -0-; n=1;

R6 = 2-OCH3; R7 = OCH3.

A mixture of 0.32 g of the compound obtained in Preparation 1.8 and 0.32 g of 1-(4-pyridyl)piperazine in 15 mL of DCM was stirred for 20 h at 20°C. The mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with 2M NaOH solution, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM, then with EtOAc and finally with acetone. 0.25 g of the expected product is obtained, after crystallization from isoether, temp. warmer 194-198°C.

Example 7

5-chloro-1-r(2,4-dimethoxyphenyl)sulfonyl1-3-(2- isopropoxyrphenyl)-2-oxo-213-dihydro-

1 //-/- indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate

(I): Ri = CI; R 2 = H; R3 = OCH(CH3)2; R4=H; X = -0-; n=1; R6 = 2-OCH3; R7 = OCH3.

A mixture of 0.66 g of the compound obtained in Preparation 1.9 and 0.45 g of 1-(4-pyridyl)piperazine in 20 mL of DCM was stirred for 24 h at RT. The reaction mixture is washed with water, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH (99/1; V/V). 0.41 g of the expected product is obtained, after crystallization from EtOAc, temp. warmer 253°C.

Example 8

5- chloro- 1-[( 2. 4- dimethoxypheninesulfonyl 1- 3-( 2- isopropoxyrphenyl)- 2- oxo- 2. 3- dihydro- 1/-/- indol- 3- yl 4-( 4- pyridyl)- 1 - piperazinecarboxylate 1. 5- fumarate f

(I), 1.5 C 2 H 2 O 4 : Ri = Cl; R 2 = H; R 3 = OCH(CH 3 ) 2 ; R 4 = H; X = -0-; n = 1;

R6 = 2-OCH3; R7 = OCH3.

A mixture of 0.3 g of the compound obtained in Example 7 and 0.056 g of fumaric acid in 15 mL of acetonitrile is refluxed for 3 h. The resulting precipitate is filtered off under reduced pressure while still hot, washed with ether and dried. 0.24 g of the expected product is obtained, temp. warmer 235°C.

Example 9

5- chloro- 1-[( 2, 4- dimethoxyphenyl) sulfonyl 1- 3-( 2- isopropoxyphenine- 2- oxo- 2, 3- dihydro-

1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate, levogyric isomer

(I): Ri = CI; R 2 = H; R3 = OCH(CH3)2; R4 = H; X = -0-; n = 1; R6=2-OCH3; R7 = OCH3.

A) phenyl 5-chloro-3-(2-isopropoxyphenyl)-2-oxo-3-[[[4-(4-pyridyl)-1-

piperazinyl] carbonyl] oxy]- 1- indolinecarboxylate

A mixture of 6 g of the compound obtained in Preparation 1.10 and 1.8 g of 1-(4-pyridyl)piperazine in 60 mL of DCM was stirred for 24 h at RT. The solvent is partially concentrated under vacuum, and the resulting solution is chromatographed directly on silica gel, eluting with a mixture of EtOAc/MeOH (95/5; VA/). 4.0 g of the expected product is obtained.

B) 5-chloro-1-[[[(1S)-1-(hydroxymethyl)-3-methylbutyl]amino^isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate, less polar and more polar isomer

A mixture of 3.8 g of the compound obtained in the previous step and 2.16 g of L-leucionol in 50 mL of chloroform was stirred for 48 h. This mixture is concentrated under vacuum, the residue is stirred in DCM, and the resulting suspension is chromatographed on aluminum oxide, eluting with a mixture of DCM/MeOH (99/1; VA/). The product is chromatographed again on silica gel, eluting with a mixture of DCM/MeOH (98.5/1.5; VA/). The diastereomers are separated: - less polar isomer: obtained 0.53 Mr. a<m>D= -19.3° (c = 0.34; chloroform) - the more polar isomer, which crystallizes from a mixture of DCM/isoether, giving 0.548 g, temp. warmer 199-202°C. a<20>D= -8.8° (c = 0.11; chloroform).

C) 5-chloro-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-

pyridyl)-1-piperazinecarboxylate, levorotatory isomer

A mixture of 0.5 g of the compound obtained in the previous step (more polar isomer) and 0.042 g of sodium methoxide in 5 mL of MeOH and 5 mL of THF was stirred for 18 h at RT. Water is added to the reaction mixture, the solvents are concentrated under vacuum, and the aqueous phase is extracted 4* with DCM, the extracts are dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH (92/8; V/V). 0.225 g of the expected product is obtained, after crystallization from a mixture of DCM/isoether, temp. warmer 195-205°C.

a<25>D= -18.8° (c = 0.266; chloroform).

D)5chloro-1-1(2,4-dimethoxyphenyl)sulfonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-

dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazine-carboxylate, levogyric isomer

0.02 g of 60% sodium hydride in oil was added, under an argon atmosphere, to a mixture of 0.213 g of the compound obtained in the previous step and 3 mL of DMF, and then, after gas evolution stopped, 0.119 g of 2,4-dimethoxybenzenesulfonyl chloride was added, and the mixture was stirred at RT for 3 h. The reaction mixture was poured into 5% K2CO3 solution, extracted with EtOAc, the organic phase dried over Na2SO4 and the solvent evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH, from (95/5; V/V) to 93/7; V/V). 0.161 g of the expected product is obtained, after crystallization from a mixture of DCM/hexane/iii isoether, temp. warmer 160-164°C. a20D =-71.8° (c= 0.18; chloroform).

Example 10

5- chloro- 1-[( 2. 4- dimethoxyphenyl) sulfonine- 3-( 2- isopropoxyphenyl)- 2- oxo- 2, 3- dihydro-

1/-/- Indole-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate. dextro isomer

(I): Ri = CI; R 2 = H; R3 = OCH(CH3)2; R4=H; X = -0-; n = 1; Re = 2-OCH3; R7 = OCH3

A) 5-chloro-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-

pyridyl)-1- piperazinecarboxylate, dextrorotatory isomer

This compound was prepared according to the procedure described in step C of Example 9, starting from 0.529 g of the compound obtained in step B of Example 9 (the less polar isomer) and 0.043 g of sodium methoxide in 5 mL of MeOH and 5 mL of THF. 0.198 g of the expected product is obtained, after crystallization from a mixture of DCM/isoether, temp. warmer 196-198°C. a<25>D= +20.7° (c = 0.32; chloroform).

B) 5-chloro-1-[(2,4-dimethoxyphenyl)sultonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate, denosyl

isomer

This compound was obtained according to the procedure described in step D of Example 9, starting from 0.328 g of the compound obtained in the previous step, 0.03 g of 60% sodium hydride in oil, 4 mL of DMF and 0.18 g of 2,4-dimethoxybenzenesulfonyl chloride, temp. warmer 161-167°C. a<20>D= +72.5° (c = 0.14; chloroform).

Example 11

5-chloro-1-f(2.4-dimethoxyphenyl)sulfonyl1-3-(2.5-dimethoxyphenin-2-oxo-2.3-dihydro-

1 H-indol-3-yl 4-(2-pyridyl)-1-piperazinecarboxylate

(I): Ri = Cl; R 2 = H; R 3 = OCH 3 ; R 4 = 5-OCH 3 ; X = -0-; n = 1; R6 = 2-OCH3; R7 = OCH3

A mixture of 0.4 g of the compound obtained in preparation 1.17 and 0.4 g of 1-(2-pyridyl)piperazine in 5 mL of DCM was stirred for 72 h at 20°C. This mixture was concentrated under vacuum, the residue was dissolved in 30 mL of water, and the resulting precipitate was filtered off under reduced pressure. 0.4 g of the expected product is obtained, after crystallization from MeOH, temp. warmer 254°C.

Example 12

5-chloro-1-rf2. 4- dimethoxyphenyl) sulfonyl- 3-( 2. 5- dimethoxyphenyl)- 3- oxo- 2. 3- dihydro-

1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate

(I): Ri = CI; R 2 = H; R3 = OCH3; R4 = 5-OCH3; X = -0-;n=1; R6 = 2-OCH3; R7 = OCH3

A mixture of 0.4 g of the compound obtained in Preparation 1.17 and 0.4 g of 1-(4-pyridyl)piperazine in 5 mL of DCM was stirred for 72 h at 20°C. The mixture is concentrated under vacuum, the residue is dissolved in 20 mL of water, and the resulting precipitate is filtered off under reduced pressure. This residue was slurried in acetone and the solvent was concentrated under vacuum. The residue was chromatographed on silica gel, eluting with DCM, then with EtOAc and finally with acetone. 0.4 g of the expected product is obtained, after crystallization from isoether, temp. warmer 247-249°C.

Example 13

N- r5- chloro- 1- f( 2. 4- dimethoxyphenyl)- sulfonine- 3-( 2- methoxyphenine- 2- oxo- 2. 3- dihydro-

1H-indole-3-iH-4-(4-pyridyl)piperazine-1-carboxamide • 0.25H?O

(I): Ri = CI; R 2 = H; R3 = OCH3; R4 = 5-OCH3; X = -NH-; n=1; R6 = 2-OCH3; R7 = OCH3

A mixture of 0.5 g of the compound obtained in Preparation 1.18 and 0.268 g of 1-(4-pyridyl)piperazine in 5 mL of chloroform was refluxed for 4 h. This mixture is concentrated under vacuum, and the residue is chromatographed on silica gel, eluting with DCM and then with a gradient mixture of DCM/EtOAc up to (85/15; V/V). 0.281 g of the expected product is obtained, after crystallization from a mixture of DCM/isoether/hexane.

Example 14

N- r5- chloro- 1- r( 2. 4- dimethoxyphenyl) surfonin- 3-( 2- methoxyphenin- 2- oxo- 2. 3- dihydro-1/ 7- indol- 3- yl- 4-( 4- pyridyl) piperazine- 1- carboxamide 0. 75H?O. levogyri isomer (I): Ri = CI; R2 = H; R3 = OCH3; R4 = H; X = -NH-; n = 1;

R6 = 2-OCH3, R7 = OCH3

Mix 1.136 g of the compound obtained in Preparation 1.19 and 0.608 g of 1-(4-pyridyl)piperazine in 10 mL of chloroform, stir for 48 h at RT, and then reflux for 1 h. After cooling to ST, the reaction mixture is directly chromatographed on silica gel, eluting with a DCM/MeOH mixture from (95/5; V/V) to (92/8; V/V). The obtained product crystallizes from the DCM/isoether mixture, and then the obtained product is dissolved in a minimum volume of MeOH, and then precipitated by adding isoether. 0.65 g of the expected product is obtained. a<20>D= -43° (c = 0.16; chloroform).

Example 15

N- f5- chloro- 1- r( 2, 4- dimethoxyphenyl) sulfonyl- 3-( 2- methoxyphenin- 2- oxo- 2, 3- dihydro-

1 H-indol-3-yl-4-(2-pyridyl)homopiperazine-1-carboxamide

(I): Ri = Cl; R 2 = H; R 3 = OCH 3 ; R 4 = H; X = -NH-; n = 2; R6 = 2-OCH3; R7 = OCH3

A mixture of 0.4 g of the compound obtained in Preparation 1.18 and 1.3 g of the compound obtained in Preparation 2.3 in 20 mL of DCM was stirred for 18 h at RT. The mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with saturated NaCl solution, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH (94/6; V/V). 0.22 g of the expected product is obtained, after crystallization from a mixture of DCM/isoether, temp. warmer 152°C.

Example 16

N- r5- chloro- 1- f( 2. 4- dimethoxyphenyl) surfonyl 1- 3-( 2- methoxyphenyl)- 2- oxo- 2. 3- dihydro-

1Windol-3-ylM-(4-pyridinehomopiperazine-1-carboxamide • 0.8H?O

(I): Ri = CI; R 2 = H; R3 = OCH3; R4=H; X=-NH-; n = 2; R6 = 2-OCH3; R7 = OCH3

A mixture of 0.5 g of the compound obtained in Preparation 1.18 and 0.375 g of the compound obtained in Preparation 2.4 in 20 mL of DCM was refluxed for 18 h. The mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with 5% Na2CO3 solution, water and saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of DCM/MeOH (94/6; V/V). 0.386 g of the expected product is obtained, after crystallization from a mixture of DCM/isoether, temp. warmer 168°C.

Example 17

N- f5- chloro- 1- f( 2, 4- dimetho

dihydro-1H-indol-3-yl-4-(3-pyridipiperazine-1-carboxamide, dextrorotatory isomer

(I): Ri = Cl; R 2 = H; R3 = OCH(CH3)2; R4=H; X = -NH-; n = 1; R6 = 2-OCH3; R7 = OCH3

A mixture of 0.639 g of the compound obtained in Preparation 1.20 and 0.325 g of the compound obtained in Preparation 2.2 in 10 mL of chloroform and 5 mL of THF was refluxed for 36 h. The reaction mixture is directly chromatographed on silica gel, eluting with a mixture of DCM/MeOH (96/4; V/V). 0.215 g of the expected product is obtained, after crystallization from a mixture of DCM/isoether, temp. warmer 148°C.

a<20>D= +25.6° (c =0.15; chloroform).

<1>H NMR (DMSO-de) δ (ppm): 1.10 (d, 3H), 1.2 (d, 3H), 3.0 (mt, 4H), 3.4 (mt, 4H), 3.5 (s, 3H), 3.9 (s, 3H), 4.7 (mt, 1H), 6.6 (mt, 2H), 6.9 (t, 1H). 7.1 (d, 1H), 7.2-7.4 (m, 6H), 7.6 (s, 1H), 7.8 (dd, 1H), 7.9 (d, 1H), 8.0 (d, 1H), 8.3 (bs, 1H).

Example 18

N-[5-chloro-1-f(2,4-dimethoxyphenyl)surfonin-3-(2-isopropoxyphenyl)-2-oxo-2,3-

dihydro-1H-indole-3-yn-4-phopyridyl)piperazine-1-carboxamide, levogyric isomer

(I): Ri = CI; R 2 = H; R3 = OCH(CH3)2; R4=H; X = -NH-; n = 1; R6 = 2-OCH3; R7 = OCH3

This compound is obtained according to the procedure described in Example 17, starting from 0.5 g of the compound obtained in Preparation 1.21 and 0.26 g of the compound obtained in Preparation 2.2 in 10 mL of chloroform and 5 mL of THF.

a<20>D= -33° (c = 0.15; chloroform).

Example 19

N-r5-chloro-1-[f2. 4- dimethoxyphenine sulfonyl- 3-( 2- isopropoxyphenych- 2- oxo- 2, 3-

dihydro-1/-/-indol-3-yl]-4-(4-pyridipiperazine-1-carboxamide, dextro isomer

(I): Ri = CI; R 2 = H; R3 = OCH(CH3)2; R4=H; X = -NH-; n = 1;

R6 = 2-OCH3; R7 = OCH3

A mixture of 0.5 g of the compound obtained in Preparation 1.21 and 0.26 g of 1-(4-pyridyl)piperazine in 5 mL of chloroform was refluxed for 18 h. The reaction mixture is directly chromatographed on silica gel, eluting with a mixture of DCM/MeOH from (95/5; V/V) to (92/8; V/V). The product is obtained by evaporation in the cold, after crystallization from a mixture of DCM/hexane/isoether. 0.46 g of the expected product is obtained

a<20>D= +7.9° (c = 0.175; chloroform).

Example 20

N- f5- chloro- 1- f( 2. 4- dimethoxyphenine sulfonyl- 3-( 2- isopropoxyphenine- 2- oxo- 2. 3-

dihydro-1H-indol-3-yl1-4-(4-pyridyl)piperazine-1-carboxamide, levogyric isomer

(I): Ri = CI; R 2 = H; R3 = OCH(CH3)2; R4=H; X = -NH-; n = 1; R6 = 2-OCH3; R7 = OCH3

A mixture of 0.9 g of the compound obtained in Preparation 1.20 and 0.463 g of 1-(4-pyridyl)piperazine in 10 mL of chloroform was stirred for 48 h at RT. The reaction mixture is directly chromatographed on silica gel, eluting with a mixture of DCM/MeOH (95/5;

V/V).The expected product is obtained by evaporation in the cold, after crystallization from a mixture of DCM/hexane/isoether. 0.789 g of the expected product is obtained

a<20>D= -10.3° (c = 0.17; chloroform).

<1>H NMR (DMSO-de) δ (ppm): 1.0 (d, 6H), 3.2-3.7 (m+s, 11H), 3.8 (s, 3H), 4.6 (mt, 1H), 6.6 (s+mt, 2H), 6.8 (t, 1H), 6.9 (d, 1H), 7.2 (d, 2H), 7.3 (mt, 4H), 7.6 (s, 1H), 7.7 (d, 1H), 7.8 (d, 1H), 8.2 (d, 2H).

Example 21

N-f5-chloro-1-r(2.4-dimethoxyphenyl)sulfonyl-3-(2-dimethoxyphenyl)-2-oxo-2,3-dihydro-

1 H-indole-3-yn-4-(2-pyridi0piperazine-1-carboxamide)

(I): Ri = Cl; R 2 = H; R 3 = OCH 3 ; R 4 = 5-OCH 3 ; X = -NH-; n = 1;

R6 = 2-OCH3; R7 = OCH3

This compound is obtained according to the procedure described in Example 13, starting from 0.46 g of the compound obtained in Preparation 1.22 and 0.21 mL of 1-(2-pyridyl)piperazine in 5 mL of chloroform. 0.382 g of the expected product is obtained after crystallization from a mixture of DCM/isoether/hexane.

<1>H NMR (DMSO-ds) δ (ppm): 3.4-3.8 (m+3s, 17H), 4.0 (s, 3H), 6.8 (mt, 2H), 7.0 (mt, 4H), 7.4 (mt, 3H), 7.8 (d, 1H), 7.9 (d, 1H), 8.2 (mt, 2H).

Example 22

N- r5- chloro- 1- f( 2, 4- dimethoxyphenyl) sulfonyl- 3-( 2- methoxyphenych- 6- trifluoromethyl- 2-

oxo- 2, 3- dihydro- 1/-/- indol- 3- yn- 4-( 4- pyridyl) piperazine- 1- carboxamide, one

enantiomer

(I): Ri = CI; R2 = 6-CF3; R3=OCH3; R4 = H; X = -NH-; n = 1; R6 = 2-OCH3; R7 = OCH3

This compound is obtained according to the procedure described in Example 15, starting from 0.203 g of the compound obtained in Preparation 1.25 and 0.098 g of 1-(4-pyridyl)piperazine in 3 mL of chloroform and 3 mL of THF. 0.098 g of the expected product is obtained, after crystallization from a mixture of DCM/isoether, temp. warmer 174°C.

Example 23

5- chloro- 1- f( 2. 4- dimethoxyphenyl) sulfonyl1- 3- r2- isopropoxyphenine- 3- F2- oxo- 2- f4-( 4-

pyridiD-1-piperazinylethoxy-l. 3-dihydro-2H-indol-2-one

(I): Ri = CI; R 2 = H; R3 = OCH(CH3)2; R4=H; X = -O-CH2-; n = 1; R6 = 2-OCH3; R7 = OCH3

A) 5-chloro-3-(2- isopmoxyphenyl)-3-[2<>xo-2-[4-(4-pi^

piperazinyl] ethoxy]- 1, 3<iihydro- 2H- indole- 2<>n

Add 1.2 g of BOP, 2 mL of DIPEA, and then 0.48 g of 1-(4-pyridyl)piperazine, at 20°C, to a mixture of 1 g of the compound obtained in Preparation 1.27 in 20 mL of DCM, and this mixture is stirred at RT for 1 h. Then 20 mL of 2M NaOH was added, the mixture was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvents were evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM, then with EtOAc and finally with acetone. 0.55 g of the expected product is obtained, after crystallization from ether, temp. warmer 115-120°C.

B) 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2- isopiopoxyphenyl)-3-[^^

2-[4-(4-pyridyl)-1-piperazinyl]ethoxy]-1,3-dihydro-2H-indol-2-one

This compound is obtained according to the procedure described in step B of Example 1, starting from 0.5 g of the compound obtained in the previous step, 0.04 g of 60% sodium hydride in oil, 10 mL of THF and 0.3 g of 2,4-dimethoxybenzenesulfonyl chloride. 0.55 g of the expected product is obtained, after crystallization from isoether, temp. warmer 201-203°C.

Example 24

5- chloro- 1- r( 2. 4- dimethoxyphenyl) sulfonyl- 3-( 2- methoxyphenin- 3- rr2- oxo- 2-[ 4-( 2- pyridyl)-

1-piperazininethamino1-1,3-dihydro-2H-indol-2-one

(I): Ri = CI; R 2 = H; R3 = OCH3; R4=H; X = -NH-CH2-; n=1; R6 = 2-OCH3; R7 = OCH3

0.329 g of PyBOP was added to a solution of 0.33 g of the compound obtained in Preparation 1.28, 0.11 g of 1-(2-pyridyl)piperazine and 0.121 g of triethylamine in 5 mL of DCM, and this mixture was stirred at RT for 3 h. The resulting mixture was concentrated under vacuum, the residue was extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM/EtOAc (90/10; V/V). 0.29 g of the expected product is obtained, after crystallization from isoether, temp. warmer 155°C.

Example 25

5- chloro- 1- r( 2. 4- dimethoxypheninesulfonyl- 3-( 2- methoxyphenych- 3- fr3- oxo- 3- f4-( 2- pyridyl)-

1- piperazininopropyllaminol- 1. 3- dihydro- 2/-/- indol- 2-one

(I): Ri = CI; R 2 = H; R3 = OCH3; R4=H; X = -NH-CH2-CH2-; n=1; R6 = 2-OCH3; R7 = OCH3

0.37 g of PyBOP was added to a solution of 0.4 g of the compound obtained in Preparation 1.29, 0.127 g of 1-(2-pyridyl)piperazine and 0.143 g of triethylamine in 10 mL of DCM, and this mixture was stirred at RT for 2 h. The reaction mixture was diluted with DCM, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM/EtOAc (90/10; V/V). 0.36 g of the expected product is obtained, after crystallization from isoether, temp. warmer 214°C.

<1>H NMR (DMSO-de) 6 ): 2.0-2.5 (2mt, 4H), 3.1-3.6 (m+s, 11H), 3.7 (s, 3H), 3.9 (s, 3H), 6.6-7.0 (m, 6H), 7.1 (t, 1H), 7.3 (t, 1H), 7.5 (dd, 1H), 7.6 (mt, 1H), 7.7-8.0 (mt, 4H), 8.2 (dd, 1H).

Example 26

N- r5- chloro- 1- r( 2, 4- dimethoxyphenyl) sulfonyl 1- 3-( 2- isopropoxyphenyl)- 2- oxo- 2, 3-

Dihydro-1H-indol-3-yl]-4-(3-pyridazinyl)piperazine-1-carboxamide, one enantiomer

(I): Ri = CI; R 2 = H; R3 = OCH(CH3)2; R4=H; X = -NH-; n = 1; R6 = 2-OCH3; R7 = OCH3

A solution of 0.07 g of the compound obtained in Preparation 1.20 was added to a solution of 0.054 g of 1-(3-pyridazinyl)piperazine in 2 mL of chloroform, and the mixture was heated to 60°C for 24 h. The reaction mixture is directly chromatographed on silica gel, eluting with a mixture of DCM/MeOH (95/5; V/V). The expected product is obtained. Purity by HPLC: 100%.

Example 27

N- r5- chloro- 1- r( 2, 4- dimethoxyphenyl) surfonin- 3-( 2- isopropoxyphenyl)- 2- oxo- 2. 3-

dihydro-1H-indol-3-yl-4-(2-pyrimidinyl)piperazine-1-carboxamide, one enantiomer

(I): Ri = CI; R 2 = H; R3 = OCH(CH3)2; R4=H; X = -NH-; n = 1; R6 = 2-OCH3; R7 = OCH3

This compound is obtained according to the procedure described in Example 26, starting from 0.054 g of 1-(2-pyrimidinyl)piperazine in 2 mL of chloroform and 0.07 g of the compound obtained in Preparation 1.20. The expected product is obtained. Purity by HPLC: 99%.

Working in accordance with the procedures described in the above examples, starting from compounds of formula (II) where W = H and compounds of formula (V), compounds of formula (IV) listed in Table I below are obtained.

(a) The compound obtained according to the procedure described in step A of Example 1, starting from the compound from Preparation 1.1 and the compound from Preparation 2.1 (b) The compound obtained according to the procedure described in step A of Example 1, starting from the compound from Preparation 1.5 and 1-(4-pyridyl)piperazine. (c) The compound obtained according to the procedure described in step A of Example 1, starting from the compound from Preparation 1.5 and the compound from Preparation 2.2. (d) Compound obtained according to the procedure described in step A of Example 3, starting from the compound of Preparation 1.6 and 1-(4-pyridyl)piperazine. (e) The compound obtained according to the procedure described in step A of Example 3, starting from the compound from Preparation 1.6 and the compound from Preparation 2.2. (f) Compound obtained according to the procedure described in step A of Example 3, starting from the compound of Preparation 1.7 and 1-(4-pyridyl)piperazine. (g) Compound obtained according to the procedure described in step A of Example 1, starting from the compound obtained in step B of Preparation 1.30 and 1-(4-pyridyl)piperazine. (h) Compound obtained according to the procedure described in step A of Example 1, starting from the compound of Preparation 1.31 and 1-(4-pyridyl)piperazine. (i) Compound obtained according to the procedure described in step A of Example 1, starting from the compound of Preparation 1.32 and 1-(4-pyridyl)piperazine. G) Compound obtained according to the procedure described in step A of Example 1, starting from compounds from Preparations 1.2 and 2.2. (k) The compound obtained according to the procedure described in step A of Example 1, starting from the compound of Preparation 1.33 and 1-(4-pyridyl)piperazine. (I) The compound obtained according to the procedure described in step A of Example 1, starting from the compound from step E of Preparation 1.3 and the compound from Preparation 2.2. (m) The compound obtained according to the procedure described in step A of Example 1, starting from the compound from step E of Preparation 1.3 and the compound from Preparation 2.4. (n) The compound obtained according to the procedure described in step A of Example 1, starting from the compound of step E of Preparation 1.3 and 1-(2-pyrimidinyl)piperazine. (o) The compound obtained according to the procedure described in step A of Example 1, starting from the compound of step E of Preparation 1.3 and 1-(3-pyridazinyl)piperazine. (p) The compound obtained according to the procedure described in step A of Example 1, starting from the compound of step E of Preparation 1.3 and 1-(1,3-thiazol-2-yl)piperazine. (q) The compound obtained according to the procedure described in step A of Example 1, starting from the compounds of Preparations 1.7 and 2.2. (r) Compound obtained according to the procedure described in step A of Example 1, starting from the compound of Preparation 1.30 and 1-(4-pyridyl)piperazine. (s) The compound obtained according to the procedure described in step A of Example 1, starting from the compound of step E of Preparation 1.3 and 1-(4-pyridyl)piperazine. Working in accordance with the procedure described in the above examples, starting from compounds of formula (II) in which and compounds of formula (III), or starting from compounds of formula (IV) and 2,4-dimethoxybenzenesulfonyl chloride, compounds according to the present invention are obtained, which are listed in Table II below. (a) The compound is prepared according to the procedure described in step B of Example 1, starting from compound IV. 1. (b) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV.2. (c) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV.3. (d) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV.4. (e) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV.5. (f) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV.6. (g) The compound is obtained according to the procedure described in Example 5, starting from the compound of Preparation 1.11 and 1-(2-pyridyl)piperazine. (h) The compound is obtained according to the procedure described in Example 5, starting from the compound of Preparation 1.11 and 1-(4-pyridyl)piperazine. (i) The compound is obtained according to the procedure described in Example 6, starting from the compound of Preparation 1.12 and 1-(4-pyridyl)piperazine. (j) The compound is obtained according to the procedure described in Example 6, starting from the compound of Preparation 1.13 and 1-(4-pyridyl)piperazine. (k) The compound is obtained according to the procedure described in Example 7, starting from the compound of Preparation 1.14 and 1-(4-pyridyl)piperazine. (I) The compound is obtained according to the procedure described in Example 5, starting from the compound of Preparation 1.15 and 1-(4-pyridyl)piperazine. (m) The compound is obtained according to the procedure described in Example 5, starting from the compound of Preparation 1.16 and 1-(4-pyridyl)piperazine. (n) The compound is obtained according to the procedure described in Example 13, starting from the compound of Preparation 1.18 and 1-(2-pyridyl)piperazine. (o) The compound is obtained according to the procedure described in Example 13, starting from the compound of Preparation 1.23 and 1-(2-pyridyl)piperazine. (p) The compound is obtained according to the procedure described in Example 13, starting from the compound of Preparation 1.23 and 1-(4-pyridyl)piperazine. (q) The compound is obtained according to the procedure described in Example 13, starting from the compound of Preparation 1.23 and 1-(2-pyrimidinyl)piperazine. (r) The compound is obtained according to the procedure described in Example 15, starting from the compound of Preparation 1.24 and 1-(4-pyridyl)piperazine. (s) The compound was obtained according to the procedure described in Example 13, starting from the compound of Preparation 1.26 and 1-(4-pyridyl)piperazine. (t) The compound is obtained according to the procedure described in Example 25, starting from the compound of Preparation 1.29 and 1-(4-pyridyl)piperazine. (u) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV.7. (v) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV.8.

(w) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV.9.

(x) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV. 10.

(y) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV.11.

(z) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV. 12.

(aa) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV. 13.

(ab) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV. 14.

(ac) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV. 15.

(ad) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV. 16.

(ae) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV. 17.

(af) A mixture of 0.3 g of the compound obtained in Preparation 1.34, 0.3 g of the compound from Preparation 2.2 and 2 g of DIPEA in 15 mL of DMF was stirred for 4 days at RT. This mixture was concentrated under vacuum, the residue was taken up in water, extracted with EtOAc, the organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM and then with acetone. After trituration in isoether, 0.27 g of the expected product is obtained.

(ag) A mixture of 0.4 g of the compound obtained in Preparation 1.34 and 0.6 g of 1-(4-pyridyl)piperazine in 0.6 mL of THF was stirred for 5 days at RT. This mixture was concentrated under vacuum, the residue was dissolved in 20 mL of water and 20 mL of EtOAc and stirred, and the resulting precipitate was filtered off under reduced pressure and washed with isoether. 0.4 g of the expected product is obtained.

(ah) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV. 18.

(ai) The compound is obtained according to the procedure described in step B of Example 1, starting from compound IV. 19.

(aj) A 2M solution of HCl was added to a solution of 0.2 g of the compound from Example 3 in 20 mL of EtOH, and the resulting mixture was concentrated under vacuum. The residue is dissolved in 2-propanol, the resulting precipitate is filtered under reduced pressure, washed with ether and dried. 0.12 g of the hydrochloride is obtained.

(ak) A mixture of 0.3 g of the compound from Example 3 and 0.059 g of fumic acid in 20 mL of acetonitrile is refluxed for 10 min. After cooling, the resulting precipitate was filtered off under reduced pressure to give 0.24 g of fumarate.

(al) mix 0.3 g of the compound from Example 3 and 0.51 g of 85% H3PO4 in 20 mL of EtOH and heat for 10 min at 60°C. After cooling, the resulting precipitate was filtered off under reduced pressure, yielding 0.3 g of the expected product.

Example 46

<1>H NMR (DMSO-de) 6 (ppm): 2.3 (s, 3H), 3.2-3.8 (m+s, 1H), 3.9 (s, 3H), 6.7 (mt, 2H), 6.9 (d, 2H), 7.2-7.4 (m, 5H), 7.8 (s, 1H), 7.9 (d, 1H). 8.2 (d, 2H).

The compounds of the present invention were subjected to biochemical tests.

The affinity of the compounds of formula (I) according to the present invention for arginine-vasopressin V1 receptors was determined in vitro using the procedure described by Y. De Kevser et al. FEBS Letters, 1994, 356, 215-220. This procedure consists in testing in vitro displacement of tritiated arginine-vasopressin ([<3>H]-AVP) on receptors V1b, present on the adenohypophyseal membrane of cell preparations, which carry rat or human receptors Vib. For the compounds of the present invention the 50% inhibitory concentration (IC50) for tritiated arginine-vasopressin binding is low and varies from 10"6 to 10"<9>M.

The affinity of the compounds of formula (I) according to the present invention for arginine-vasopressin V1 receptors was determined in vitro, using the method given by Thibonnier et al., in J. Biol. Chem. 1994, 269, 3304-3310. This procedure consists in examining in vitro displacement of tritiated arginine-vasopressin ([<3>H]-AVP) on Via receptors, present on the membrane of cell preparations bearing rat or human V1a receptors. Compounds of formula (I) show affinity for Via arginine-vasopressin receptors with IC50 values varying from 10"6 to 10"<9>M.

The affinity of the compounds of formula (I) according to the present invention to vasopressin V2 receptors was also tested (the procedure was described by M. Bimbaumer et al., Nature, 1992, 357, 333-335). Tested compounds have little or no affinity for V2 receptors, with IC50 values typically greater than 10"6 M.

The affinity of compounds of the present invention for oxytocin receptors was determined in an in vitro binding assay using the procedure described by J. Elands et al. in Eur. J. Pharmacol. 1987, 147, 197-207. This procedure consists in testing in vitro displacement of oxytocin analogues with radioactive iodine towards oxytocin receptors in a cell membrane preparation transfected with human uterine oxytocin receptor. IC50 values (concentrations that inhibit 50% binding of the radioiodine analogue of oxytocin to its receptors) are low and vary from 10"6 to 10"<9>M, in this assay.

The compounds of the present invention are particularly active as an ingredient in pharmaceutical preparations, the toxicity of which is compatible with their use as medicinal products.

In accordance with the following of its aspects, this invention relates to the use of a compound of formula (I), or one of its salts, solvates and/or hydrates, which are pharmaceutically acceptable for obtaining medical products intended for any pathology in which arginine-vasopressin and/or its Vibreceptors and/or Via receptors and/or oxytocin and/or its receptors participate.

Thus, the compounds according to the present invention can be used, in humans or animals, for the treatment or prevention of various vasopressin-dependent conditions, such as cardiovascular conditions, for example, hypertension, pulmonary hypertension, heart failure, myocardial infarction or coronary vasospasm, especially in smokers, Raynaud's disease, unstable angina pectoris and PTCA (percutaneous transluminal coronary angioplasty), cardiac ischemia or disorder of hemostasis; conditions of the central nervous system, such as, for example, migraine, cerebral vasospasm, cerebral hemorrhage, cerebral edema, depression, anxiety, stress, emotional disorders, obsessive-compulsive disorder, panic attacks, psychotic states or memory disorders; conditions of the renal system, such as renal vasospasm, necrosis of the renal cortex, nephrogenic diabetes insipidus; conditions of the gastric system, such as gastric vasospasm, cirrhosis of the liver, ulcers or pathological vomiting, for example, nausea, including nausea due to chemotherapy or seasickness; or diabetic nephropathy.

The compounds of the present invention may also be used for the treatment of sexual behavior disorders; in women, the compounds of the present invention can be used to treat dysmenorrhea or premature labor. The compounds of the present invention may also be used for the treatment of small cell lung cancer; hyponatremic encephalopathy; pulmonary syndrome; Meniere's disease; glaucoma; cataracts; obesity; Type I and Type II diabetes; atherosclerosis; Cushing's syndrome; insulin resistance; or hypertriglyceridemia; or in post-operative treatments, especially after abdominal surgery.

The compounds according to the present invention can also be used for the treatment or prevention of any pathology resulting from stress, such as fatigue and its syndromes, ACTH-dependent disorders, cardiac disorders, pain, modifications in gastric emptying, in faecal excretion (colitis, irritable bowel syndrome or Crohn's disease) or in acid secretion, hyperglycemia, immunosuppression, inflammatory processes (rheumatoid arthritis and osteoarthritis), multiple infection, cancer, asthma, psoriasis, allergies and various neuropsychiatric disorders, such as anorexia nervosa, bulimia, mood disorders, depression, anxiety, sleep disorders, panic states, phobias, obsessions, disorders in pain perception (fibromyalgia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease or Huntington's disease), drug addiction, drug withdrawal, hemorrhagic stress, muscle spasms or hypoglycemia. The compounds of the present invention may also be used for the treatment or prevention of chronic stress conditions, such as immunosuppression, fertility disorders, or hypothalamic-pituitary-adrenal axis dysfunction.

The compounds of the present invention can also be used as psychostimulants, which lead to an increase in alertness or emotional reactivity to the environment, making adaptation easier.

Compounds according to the present invention with affinity for oxytocin receptors are particularly suitable for the prevention and/or treatment of oxytocin-dependent disorders. Compounds according to this invention have advantages in cicatrization, in analgesia, in anxiolysis, in the prevention of pain, in the prevention of anxiety, depression, schizophrenia, autism, obsessive-compulsive disorder, in motherhood (facilitating recognition and acceptance of the mother by the child) and in social behavior, and in memory; regulation of food and drink intake, drug addiction, drug withdrawal and sexual motivation; they can also be conveniently used in urogenital disorders, especially in obstetrics and gynecology, and in particular as uterine relaxants or obstetric agents, or to control uterine contractions before the final term of pregnancy, to control premature birth or to control preparatory actions for cesarean delivery, to solve problems of sterility or fertility, birth control (especially in veterinary use), to control sexual inflammation, stopping lactation, weaning from sucking and transfer and implantation of embryos, during fertilization in vitro; for the treatment of endometriosis, dysmenorrhea, and also for stress urinary incontinence or urgent incontinence, benign prostatic hypertrophy and erectile dysfunction, hypertension, hyponatremia, heart failure, atherosclerosis, angiogenesis, tumor proliferation, Kaposi's syndrome and for the regulation of fat accumulation by means of adipocytes.

In addition to oxytocin playing a role in controlling luteinizing hormone (J.J. Evans, J. Endocrin. 1996, 151, 169-174), the compounds of this invention can be used to induce contraception.

Furthermore, the compounds according to the present invention can be used due to their antitumor effects, in secreting oxytocin tumors, especially in breast cancer and prostate cancer.

The use of the compounds according to the present invention for the prevention and/or treatment of the diseases mentioned above, and also for obtaining medicinal products for the treatment of those diseases, forms an integral part of the present invention.

The above compounds of formula (I), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof can be used in mammals to be treated in daily doses of 0.01 to 100 mg per kg of body weight, preferably in daily doses of 0.1 to 50 mg/kg. In humans, this dose preferably varies from 0.1 to 4,000 mg per day, more specifically from 0.5 to 1,000 mg per day, depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.

For use in the form of medicinal products, the compounds of formula (I) are usually prescribed in unit doses. Said unit doses are preferably formulated into pharmaceutical preparations in which the active ingredient is mixed with one or more pharmaceutical additives.

Thus, according to the following of its aspects, this invention relates to pharmaceutical preparations containing, as an active ingredient, a compound of formula (I), or its pharmaceutically acceptable salt, solvate and/or hydrate, and also one or more pharmaceutically acceptable additives.

In the pharmaceutical preparations of the present invention, for administration by oral sublingual, inhalation, subcutaneous, intramuscular, intravenous, transdermal, local or rectal route, the active ingredient can be administered to an animal or human being in the form of a single dose, as a mixture with a conventional pharmaceutical carrier. Suitable single-dose administration forms include oral forms such as tablets, gelatin capsules, powders, granules, and oral solutions or suspensions, sublingual or buccal administration forms, aerosols, topical administration forms, implants, subcutaneous, intramuscular, intravenous, intranasal, or intraocular administration forms, and rectal administration forms.

The active ingredient of formula (I) is present in each unit dose in the amount adjusted for the intended daily dose. Usually, each unit dosage form is conveniently adjusted according to the dosage in the type of administration, for example tablets, gelatin capsules and the like, sachets, blisters, syrups and the like, or drops, so that the unit dosage contains from 0.1 to 1,000 mg of active ingredient, preferably from 0.5 to 250 mg, which is prescribed one to four times a day.

Although these doses are only examples for average situations, there may be specific cases where higher or lower doses are appropriate; such doses also form part of this

invention. In accordance with the usual practice, the doses suitable for each patient are determined by the doctor, in accordance with the prescribing procedure and the age, weight and response of the said patient.

According to another of its aspects, the present invention also relates to a method for treating the pathologies indicated above, which consists in prescribing to the patient an effective dose of a compound according to the present invention, or a pharmaceutically acceptable salt thereof.

Claims (8)

1. Compound of the formula: indicated by: n is 1 or 2; X represents the group -CH2-, -O-, -NH-, -O-CH2-, -NH-CH2-, -NH-CH2CH2-; R represents a halogen atom, (Ci-C4)alkyl, (CrC4) alkoxy; R2 represents a hydrogen atom, a halogen atom, (Ci-C4) alkyl, (CrC4) alkoxy, trifluoromethyl radical; R3 represents a halogen atom, (CrC3)alkyl, (Ci-C3) alkoxy, trifluoromethyl radical, trifluoromethoxy radical; R 4 represents a hydrogen atom, a halogen atom, (C 1 -C 3 )alkyl, (C 1 -C 3 )Alkoxy; R5 represents a radical chosen from: R 6 represents (C 1 -C 4 ) alkoxy; R 7 represents (C 1 -C 4 )Alkoxy; and also their salts with mineral or organic acids, their solvates and/or their hydrates. 2. A compound according to Claim 1, characterized in that: n and X are defined for the compound of formula (I) in Claim 1; It represents a chlorine atom or a methyl radical; R2 represents a hydrogen atom, or is in position 6 of indol-2-one and represents a chlorine atom, a methyl radical, a methoxy radical or a trifluoromethyl radical; R3 represents a chlorine atom, a fluorine atom, a methoxy radical, an ethoxy radical, an isopropoxy radical, a trifluoromethyl radical or a trifluoromethoxy radical; R4 represents a hydrogen atom or a methoxy radical; R is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl or 1,3-thiazol-2-yl; R6 is in position 2 of phenyl, and represents the methoxy radical; R7 is a methoxy radical; and also their salts with mineral or organic acids, their solvates and/or their hydrates. 3. A compound selected from: 5-chloro-3-(2-ethoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-[2-oxo-2-[4- (4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2 H -indol-2-one; 5-chloro-3-(2-isopropoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-[2-oxo-2-[4- (4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2 H -indol-2-one; 5-Chloro-1-[(2,4Hymethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-[1t]-indol-3-yl 4-(2-pyridyl)-1-piperazinecarboxylate; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate; N-[5-chloro-1-[(2,4-dimethoxyphenyl)-sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(3-pyridyl)-homopiperazine-1-carboxamide; N-[5-chloro-1-[(2,4-dimethoxyphenyl)-sulfonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3- dihydro-1H-indol-3-yl]-4-(4-pyridyl)-piperazine-1-carboxamide; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-3-[[3-oxo-3- [4-(2-pyridyl)-1-piperazinyl]propyl]amino]-1,3-dihydro-2 H -indol-2-one; 5,6-dichloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-3-[2-oxo-2- [4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-6-methyl-3-[2-oxo-2- [4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3- dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-6-methoxy-3-(2-methoxyphenyl)-2-oxo-2,3- dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate; N-[5-chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-2-oxo-2,3- dihydro-1 H -indol-3-yl]-4-(2-pyridyl)piperazine-1-carboxamide; N-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3- dihydro-1 H -indol-3-yl]-4-(4-pyridyl)piperazine-1-carboxamide; N-[6-chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-5-methyl-2-oxo-2,3- dihydro-1H-indol-3-yl]-4-(4-pyridyl)piperazine-1-carboxamide; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorophenyl)-3-[2-oxo-2-[4-(4- pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5,6-dichloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorophenyl)-3-[2-oxo-2-[4-(4- pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-3-(2,3-dimethoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-[2-oxo-2-[4-(4- pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2 H -indol-2-one; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxyphenyl)-3-[2-oxo-2-[4-(3- pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-1-[(2,4<limethoxyphenyl)sulfonyl]-3-(2-isopropoxyphenyl)-3-[2K)xo-2-[4-(3^ pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-isopropoxyphenyl)-3-[2-oxo-2-^ pyridyl)-1-homopiperazine]ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-isopropoxyphenyl)-3-[2-oxo-2-[4-(1,3- thiazol-2-yl)-1-piperazinyl]ethyl]-1,3-dihydro-2 H -indol-2-one; 5-chloro-1-[(2,4<limethoxyphenyl)sulfonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(3-pyridyl)-1-piperazinecarboxylate; 5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazinecarboxylate; in the form of optically pure isomers or in the form of a mixture, and also their salts with mineral or organic acids, and their solvates and/or hydrates. 4. Process for obtaining compounds of formula (I) according to Claim 1, characterized in that compound of the formula: where are: where R-i, R2, R3, R4 and X are defined for the compound of formula (I) in Claim 1, and Y represents a hydroxyl group or a chlorine atom, when X represents the group -CH2-, -OCH2-, -NH-CH2-, -NH-CH2-CH2-; or Y represents phenoxy, when X represents the group -0-; -NH-; W represents a hydrogen atom when X represents the group -CH2-; -OCH2-; or W represents a group wherein F?6 and R7 are defined for the compound of formula (I) in Claim 1, when X represents the group -0-; -NH-; -NH-CH2-; -NH-CH2-CH2-; reacts with a compound of the formula: where n and R 5 are as defined for the compound of formula (I) in Claim 1; when W represents a group giving the expected compound of formula (I); or when W represents a hydrogen atom, the resulting compound has the formula: which reacts, in the presence of a base, with a sulfonyl halide of the formula: where R 6 and R 7 are as defined for the compound of formula (I) in Claim 1, and Hal represents a halogen atom. 5. Compound of the formula: indicated by: n is 1 or 2; X represents the group -CH2-; -O-CH2; R-i represents a halogen atom, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy; R2 represents a hydrogen atom, a halogen atom, (Ci-C4) alkyl, (d-C4) alkoxy trifluoromethyl radical; R3 represents a halogen atom, (C-i-C3)alkyl, (Ci-C3)alkoxy, trifluoromethyl radical, trifluoromethoxy radical; R 4 represents a hydrogen atom, a halogen atom, (C-1-C3)alkyl, (d-C3)alkoxy; Rs represents a radical chosen from: and also their salts with mineral or organic acids, in the form of optically pure isomers or in the form of a mixture. 6. Medical product, characterized in that it contains a compound according to any one of Claims 1 to 3, or its pharmaceutically acceptable salt with a mineral or organic acid and its pharmaceutically acceptable solvate and/or hydrate. 7. Pharmaceutical preparation, characterized by the fact that as an active ingredient it contains a compound according to any of Claims 1 to 3, or its pharmaceutically acceptable salt with a mineral or organic acid and its pharmaceutically acceptable solvate and/or hydrate, and also one or more pharmaceutically acceptable additives. 8. Use of a compound according to any of Claims 1 to 3 or its pharmaceutically acceptable salts with mineral or organic acids and its pharmaceutically acceptable solvates and/or hydrates, for obtaining medical products for the treatment of cardiovascular conditions, stress, anxiety, depression, obsessive-compulsive disorder, panic attacks, renal system complaints, gastrointestinal complaints, small cell lung cancer, obesity, Type II diabetes, insulin resistance, hypertriglyceridemia, atherosclerosis, Cushing's syndrome, dysmenorrhea and premature birth.