RU2461556C2 - Substituted oxydol derivatives and use thereof as vasopressin receptor ligands - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I)

, where R1 denotes an ethoxy group; R2 denotes hydrogen; R3 denotes a cyano group; R4 denotes hydrogen; R5 denotes hydrogen, a methoxy group or an ethoxy group; R6 denotes hydrogen or a methoxy group; R7 denotes hydrogen, methyl, ethyl, n-propyl or isopropyl; X1 denotes -NH-; X2 denotes N or CH; X3 denotes N or CH; where X2 and X3 do not denote N at the same time; and pharmaceutically acceptable salts and tautomeric forms thereof. The invention also relates to a medicinal agent for treating and/or preventing a vasopressin-dependent disease, which contains the compound given in claim 1, use of the compound of formula I to prevent and/or treat vasopressin-dependent diseases, as well as a method of treating and/or preventing said diseases.

EFFECT: novel compounds which can be useful in treating vasopressing-dependent diseases are described.

22 cl, 90 ex, 4 tbl

Description

Description

The present invention relates to new substituted derivatives of oxindole, to medicines containing them, and to their use for the treatment of diseases.

Vasopressin is an endogenous hormone that exhibits a wide variety of effects on organs and tissues. The vasopressin system is believed to be related to various pathological conditions, such as, for example, heart failure and high blood pressure. To date, three receptors are known (V1a, V1b or V3 and V2) by which vasopressin mediates its many effects. Therefore, antagonists of these receptors are being investigated as new possible therapeutic approaches to the treatment of diseases (M. Thibonnier, Exp. Opin. Invest. Drugs 1998, 7 (5), 729-740).

In the present description, new substituted oxindoles having an arylsulfonyl group at position 1 are described. Previously, 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones have been described as vasopressin receptor ligands. WO9315051, WO9518105, WO9825901, WO0155130, WO0155134, WO0164668 and WO0198295 describe derivatives derived from an oxindole backbone and bearing arylsulfonyl groups at position 1. These compounds differ essentially by substitution at position 3.

In particular, WO9315051 and WO9825901 describe 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones, where the oxindole structure is substituted at position 3 with two alkyl radicals that can also form together a cycloalkyl radical (spiro bond) as ligands vasopressin receptors. Alternatively, the spiro ring may contain heteroatoms such as oxygen and nitrogen (optionally with substituents).

WO9518105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones carrying a nitrogen atom at position 3 as vasopressin receptor ligands. In addition, at position 3, radicals are attached which are selected from the group consisting of alkyl, cycloalkyl, phenyl and benzyl (optionally with substituents in each case).

WO03008407 describes 1-phenylsulfonyloxyindoles, wherein pyridylpiperazines are attached to the oxindole at position 3 via an oxycarbonyl group.

WO2005030755 describes, by way of example 108, a carbamate compound, 5-cyano-1- (2,4-dimethoxyphenylsulfonyl) -3- (2-methoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole 4- (1-Methylpiperidin-4-yl) piperazine-1-carboxylic acid 3-yl ester (according to IUPAC nomenclature: 5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-methoxypyridine -3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl-4- (1-methylpiperidin-4-yl) piperazine-1-carboxylate).

WO06005609 describes 2-ethoxyphenylurea compounds, N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxyphenyl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide (as an example 119) and N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-Ethoxyphenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (4-methylpiperazin-1-yl) piperidine-1-carboxamide (as an example 128).

In addition to the affinity of binding to the vasopressin V1b receptor, additional properties may be useful for the treatment and / or prevention of vasopressin-dependent disorders, such as, for example:

1) selectivity for the vasopressin V1b receptor compared to the vasopressin V1a receptor, i.e. the ratio of the binding affinity of the V1a receptor (Ki (V1a) (defined in the "nanomolar (nM)" units) and the binding affinity of the V1b receptor (Ki (V1b)) (defined in the "nanomolar (nM)" unit). The greater the ratio of Ki (V1a) / Ki (V1b), the higher the V1b selectivity;

2) selectivity for the vasopressin V1b receptor compared to the vasopressin V2 receptor, i.e. the ratio of the binding affinity of the V2 receptor (Ki (V2) (defined in the "nanomolar (nM)" units) and the binding affinity of the V1b receptor (Ki (V1b)) (defined in the "nanomolar (nM)" unit). The greater the ratio of Ki (V2) / Ki (V1b), the higher the V1b selectivity;

3) selectivity for the vasopressin V1b receptor compared to the oxytocin OT receptor, i.e. the ratio of the binding affinity of the OT receptor (Ki (OT) (defined in "nanomolar (nM)" units) and the binding affinity of the receptor V1b (Ki (V1b)) (defined in "nanomolar (nM)" units). The larger the ratio of Ki (OT) / Ki (V1b), the higher the V1b selectivity;

4) metabolic stability, determined, for example, using the half-life determined in vitro in liver microsomes of various species (for example, rat or human);

5) only a slight, if any, inhibition of the enzymes of cytochrome P450 (CYP): cytochrome P450 (CYP) is the name for the superfamily of heme-containing proteins with enzymatic activity (oxidases). They are also especially important for the decomposition (metabolism) of foreign substances, such as pharmaceuticals or xenobiotics, in mammals. The most important representatives of the types and subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. With the simultaneous administration of CYP 3A4 inhibitors (for example, grapefruit juice, cimetidine, erythromycin) and drugs that decompose under the influence of this enzymatic system, and which thus compete for the same binding site on the enzyme, their decomposition can slow down, and the actions and side effects of the administered drug may be amplified in an undesirable manner;

6) suitable solubility in water (in mg / ml);

7) suitable pharmacokinetics (time profile of the concentration of the compounds according to this invention in plasma or in tissues, for example, in the brain). The pharmacokinetics can be described by the following parameters: elimination half-life, volume of distribution, plasma clearance, AUC ("area under the curve", area under the concentration-time curve), bioavailability when administered orally, the ratio of the concentration of the substance in the brain / plasma;

8) a certain proportion of the active substance is present in a state bound to plasma proteins (drug / plasma protein binding ratio (PPB));

9) only slight blocking of the hERG channel or no blocking at all: compounds that block the hERG channel can increase the QT interval, which therefore leads to serious pulse disturbances (for example, “pirouette ventricular tachycardia”). Using the substitution assay described in the literature with radioactively labeled dofetilide (G.J. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199), the ability of compounds to block potassium channels of hERG can be determined. The lower the IC50 according to the results of the “Dophetylid analysis”, the more likely a strong hERG block is. In addition, the degree of blocking of the hERG channel can be assessed by electrophysical experiments, using cells transfected with the hERG channel, using the method of “fixing the potential of the whole cell” (GJ Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187- 199).

The aim of the present invention is the provision of compounds with high and selective activity, preferably, in particular, in relation to the receptor of vasopressin V1b, for the treatment or prevention of various vasopressin-dependent diseases. In addition, the substance in accordance with the invention must have one or more of the above advantages 1) -9), in particular, the corresponding selectivity for the receptor V1b compared to the receptor V1a.

This goal is achieved by compounds of General formula (I)

Where

R1 represents an ethoxy group;

R2 is hydrogen;

R3 represents a cyano group;

R4 is hydrogen;

R5 represents hydrogen, a methoxy group or an ethoxy group;

R6 represents hydrogen or a methoxy group;

R7 represents hydrogen, methyl, ethyl, n-propyl or isopropyl;

X1 represents —NH—;

X2 represents N or CH;

X3 represents N or CH;

where X2 and X3 are not simultaneously N (in other words, a nitrogen atom); and their pharmaceutically acceptable salts, tautomeric forms and prodrugs.

Accordingly, the present invention relates to compounds of general formula (I) (also “compounds (I)” below), including their tautomeric forms and pharmaceutically acceptable salts of compounds (I), and prodrugs of compounds (I).

A preferred object of this invention are compounds of General formula (I), where

R1 represents an ethoxy group;

R2 is hydrogen;

R3 represents a cyano group;

R4 is hydrogen;

R5 represents hydrogen or a methoxy group, especially a methoxy group;

R6 represents hydrogen or a methoxy group, especially a methoxy group;

R7 represents hydrogen, methyl, ethyl, n-propyl or isopropyl;

X1 represents —NH—;

X2 represents N or CH;

X3 represents N or CH;

where X2 and X3 are not simultaneously a nitrogen atom; and their pharmaceutically acceptable salts, tautomeric forms and prodrugs.

A particularly preferred object of this invention are compounds of General formula (I), where

R1 represents an ethoxy group;

R2 is hydrogen;

R3 represents a cyano group;

R4 is hydrogen;

R5 represents hydrogen or a methoxy group, especially a methoxy group;

R6 represents hydrogen or a methoxy group, especially a methoxy group, in particular methyl or ethyl;

R7 represents hydrogen, methyl or ethyl;

X1 represents —NH—;

X2 represents N;

X3 represents CH;

and their pharmaceutically acceptable salts, tautomeric forms and prodrugs.

An additional particularly preferred object of this invention are compounds of General formula (I), where

R1 represents an ethoxy group;

R2 is hydrogen;

R3 represents a cyano group;

R4 is hydrogen;

R5 represents hydrogen or a methoxy group, especially a methoxy group;

R6 represents hydrogen or a methoxy group, especially a methoxy group;

R7 represents hydrogen, methyl or ethyl, especially methyl or ethyl;

X1 represents —NH—;

X2 represents CH;

X3 represents N;

and their pharmaceutically acceptable salts, tautomeric forms and prodrugs.

An additional particularly preferred object of this invention are compounds of General formula (I), where

R1 represents an ethoxy group;

R2 is hydrogen;

R3 represents a cyano group;

R4 is hydrogen;

R5 represents hydrogen or a methoxy group, especially a methoxy group;

R6 represents hydrogen or a methoxy group, especially a methoxy group;

R7 represents hydrogen, methyl or ethyl, especially methyl or ethyl;

X1 represents —NH—;

X2 represents CH;

X3 represents CH;

and their pharmaceutically acceptable salts, tautomeric forms and prodrugs.

An additional particularly preferred object of this invention are compounds of General formula (I), where

R1 represents an ethoxy group;

R2 is hydrogen;

R3 represents a cyano group;

R4 is hydrogen;

R5 represents a methoxy group;

R6 represents a methoxy group;

R7 is methyl or ethyl;

X1 represents —NH—;

X2 represents CH, and X3 represents N; or

X2 is N and X3 is CH;

and their pharmaceutically acceptable salts, tautomeric forms and prodrugs.

Examples of preferred embodiments of the present invention are compounds in accordance with General formula (I) and their pharmaceutically acceptable salts, tautomeric forms and prodrugs, where

R1 represents an ethoxy group,

R2 is hydrogen,

R3 represents a cyano group,

R4 is hydrogen,

X1 is NH,

and where the radicals X2, X3, R5, R6 and R7 in each case have the meanings listed in one of the series of table 1 below.

Table 1 Example No. X2 X3 R5 R6 R7 one N CH methoxy group methoxy group methyl 2 N CH methoxy group H methyl 3 N CH ethoxy group H methyl four N CH H H methyl 5 N CH H methoxy group methyl 6 N CH ethoxy group methoxy group methyl 7 N CH methoxy group methoxy group ethyl 8 N CH methoxy group H ethyl 9 N CH ethoxy group H ethyl 10 N CH H H ethyl eleven N CH H methoxy group ethyl 12 N CH ethoxy group methoxy group ethyl 13 N CH methoxy group methoxy group n-propyl fourteen N CH methoxy group H n-propyl fifteen N CH ethoxy group H n-propyl 16 N CH H H n-propyl 17 N CH H methoxy group n-propyl eighteen N CH ethoxy group methoxy group n-propyl 19 N CH methoxy group methoxy group isopropyl twenty N CH methoxy group H isopropyl 21 N CH ethoxy group H isopropyl 22 N CH H H isopropyl 23 N CH H methoxy group isopropyl 24 N CH ethoxy group methoxy group isopropyl 25 N CH methoxy group methoxy group H 26 N CH methoxy group H H 27 N CH ethoxy group H H 28 N CH H H H 29th N CH H methoxy group H thirty N CH ethoxy group methoxy group H 31 CH N methoxy group methoxy group methyl 32 CH N methoxy group H methyl 33 CH N ethoxy group H methyl 34 CH N H H methyl 35 CH N H methoxy group methyl 36 CH N ethoxy group methoxy group methyl 37 CH N methoxy group methoxy group ethyl 38 CH N methoxy group H ethyl 39 CH N ethoxy group H ethyl 40 CH N H H ethyl 41 CH N H methoxy group ethyl 42 CH N ethoxy group methoxy group ethyl 43 CH N methoxy group methoxy group n-propyl 44 CH N methoxy group H n-propyl 45 CH N ethoxy group H n-propyl 46 CH N H H n-propyl 47 CH N H methoxy group n-propyl 48 CH N ethoxy group methoxy group n-propyl 49 CH N methoxy group methoxy group isopropyl fifty CH N methoxy group H isopropyl 51 CH N ethoxy group H isopropyl 52 CH N H H isopropyl 53 CH N H methoxy group isopropyl 54 CH N ethoxy group methoxy group isopropyl 55 CH N methoxy group methoxy group H 56 CH N methoxy group H H 57 CH N ethoxy group H H 58 CH N H H H 59 CH N H methoxy group H 60 CH N ethoxy group methoxy group H 61 CH CH methoxy group methoxy group methyl 62 CH CH methoxy group H methyl 63 CH CH ethoxy group H methyl 64 CH CH H H methyl 65 CH CH H methoxy group methyl 66 CH CH ethoxy group methoxy group methyl 67 CH CH methoxy group methoxy group ethyl 68 CH CH methoxy group H ethyl 69 CH CH ethoxy group H ethyl 70 CH CH H H ethyl 71 CH CH H methoxy group ethyl 72 CH CH ethoxy group methoxy group ethyl 73 CH CH methoxy group methoxy group n-propyl 74 CH CH methoxy group H n-propyl 75 CH CH ethoxy group H n-propyl 76 CH CH H H n-propyl 77 CH CH H methoxy group n-propyl 78 CH CH ethoxy group methoxy group n-propyl

79 CH CH methoxy group methoxy group isopropyl 80 CH CH methoxy group H isopropyl 81 CH CH ethoxy group H isopropyl 82 CH CH H H isopropyl 83 CH CH H methoxy group isopropyl 84 CH CH ethoxy group methoxy group isopropyl 85 CH CH methoxy group methoxy group H 86 CH CH methoxy group H H 87 CH CH ethoxy group H H 88 CH CH H H H 89 CH CH H methoxy group H 90 CH CH ethoxy group methoxy group H

In particular, the present invention relates to the following compound of formula Ia (which corresponds to the compound of Example 1 of Table 1)

as well as pharmaceutically acceptable salts, tautomeric forms and prodrugs of Ia.

In particular, the present invention also relates to the compound of Example 7 of Table 1, as well as its pharmaceutically acceptable salts, tautomeric forms and prodrugs.

In particular, the present invention also relates to the compound of Example 31 of Table 1, as well as its pharmaceutically acceptable salts, tautomeric forms and prodrugs.

In particular, the present invention also relates to the compound of Example 37 of Table 1, as well as its pharmaceutically acceptable salts, tautomeric forms and prodrugs.

Compounds (I) or (Ia) of the present invention have a chiral center at position 3 of the 2-oxindole ring. According to this invention, the compounds of general formula (I) or (Ia) may therefore be a 1: 1 mixture of enantiomers (racemate) or a non-racemic mixture of enantiomers in which one of the two enantiomers, i.e. either the (left-handed) enantiomer that rotates the plane of polarization of linearly polarized light to the left ((-) is the enantiomer below), or the (right-handed) enantiomer that rotates the plane of polarization of linearly polarized light to the right ((+) is the enantiomer below) is enriched, or essentially enantiomerically pure compounds (enantiomeric excess ee> 90%), i.e. essentially enantiomerically pure (-) - enantiomer or (+) - enantiomer. Preferably, the compounds are essentially enantiomerically pure compounds. Particular preference is given to compounds which are essentially enantiomerically pure (ee> 90%).

The present invention therefore provides pure enantiomers as well as mixtures thereof, for example mixtures in which one enantiomer is present in enriched form, as well as racemates. The invention also provides pharmaceutically acceptable salts, tautomers and prodrugs of the pure enantiomers (I) or (Ia), and enantiomeric mixtures in the form of pharmaceutically acceptable salts, tautomers and prodrugs of the compound (I) or (Ia).

Preferred embodiments of the invention are compounds of general formula (I) or (Ia) as defined above, which are characterized in that they are in optically active form and, in each case, are an enantiomer that rotates the plane of polarization of polarized light to the left , (i.e., the levorotatory enantiomer) of the compound of general formula (I) in question, in the form of a free base, or a pharmaceutically acceptable salt, tautomeric form or prodrug thereof. The levorotatory enantiomers of compounds (I) or (Ia) are also referred to below as (-) - enantiomers.

Preferred embodiments of the present invention are those compounds of general formula (I) or (Ia), as defined above, which are characterized in that they are in optically active form, wherein the absolute configuration of the chiral carbon atom of the C-3 ring of such compounds corresponds to the absolute configuration when C-3 (-) - enantiomer of the compound of formula (Ia) as a free base. Such a configuration is also referred to as a “preferred configuration” below. X-ray diffraction analyzes showed that the (-) - enantiomer of the compounds of formula (Ia) has an S configuration with respect to the center of asymmetry at the carbon atom of position 3 of the oxindole ring.

In accordance with this invention, preference is given to compounds of the general formula (I) or (Ia), their tautomers, their pharmaceutically acceptable salts and their prodrugs, as defined above, in which the corresponding (-) - enantiomer is present at optical purity (enantiomeric excess, ee ) more than 50%.

In accordance with this invention, preference is given to compounds of the general formula (I) or (Ia), their tautomers, their pharmaceutically acceptable salts and their prodrugs, as defined above, in which an enantiomer having a preferred absolute configuration at the carbon atom of the C-3 ring is shown at optical purity (enantiomeric excess, ee) of more than 50%.

In accordance with this invention, preference is given to compounds of the general formula (I) or (Ia), their tautomers, their pharmaceutically acceptable salts and their prodrugs, as defined above, in which the corresponding (-) - enantiomer is present at optical purity (enantiomeric excess, ee ) more than 90%.

In accordance with this invention, preference is given to compounds of the general formula (I) or (Ia), their tautomers, their pharmaceutically acceptable salts and their prodrugs, as defined above, in which an enantiomer having a preferred absolute configuration at the carbon atom of the C-3 ring is provided with optical purity (enantiomeric excess, ee) of more than 90%.

Similarly, preferred embodiments of the present invention are compounds of general formula (I) or (Ia), as defined above, which are characterized in that they are in optically inactive form, in other words, as a racemate, or as a pharmaceutically acceptable salt, tautomeric forms or prodrugs of the racemate.

An additional object of the present invention relates to medicines containing at least one compound of General formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug, as defined above.

An additional object of the present invention relates to compounds of General formula (I) or (Ia) and / or their pharmaceutically acceptable salt or their prodrug, as defined above, for use as a medicine.

An additional object of the present invention relates to compounds of the general formula (I) or (Ia) and / or their pharmaceutically acceptable salt or their prodrug, as defined above, for use in the treatment or prevention of a disease, in particular a vasopressin-dependent disease or the disease described in context of this description.

An additional object of the present invention relates to the use of at least one compound of general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug thereof, as defined above, for the treatment and / or prevention of at least one vasopressin-dependent disease and / or for the manufacture of a medicament for the treatment and / or prophylaxis of at least one vasopressin-dependent disease. Vasopressin-dependent diseases are those diseases in which the development of the disease depends at least in part on vasopressin, i.e. diseases in which the level of vasopressin, which can directly or indirectly affect the picture of the disease, rises.

The present invention also relates to the use of compounds (I) or (Ia) in accordance with this invention and / or their pharmaceutically acceptable salt or prodrug for the treatment and / or prevention of a disease, in which the development of the disease depends at least in part on vasopressin, i.e. e. diseases in which the level of vasopressin, which can directly or indirectly affect the picture of the disease, rises. The present invention also relates to the use of compounds (I) or (Ia) in accordance with the invention and / or their pharmaceutically acceptable salt or prodrug for the manufacture of a medicament for the treatment and / or prevention of such a disease.

The present invention relates in particular to the use of at least one compound of general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof, as defined above, for the treatment and / or prevention of at least one disorder selected from the group consisting of diabetes, in particular diabetes insipidus, insulin resistance, nighttime urinary incontinence, incontinence, diseases that cause blood clotting disorders, and / or delayed urination and their use for the manufacture of drugs A medication for the treatment and / or prophylaxis of at least one of the above diseases.

The present invention relates in particular to the use of at least one compound of general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof, as defined above, for the treatment and / or prevention of at least one disorder selected from the group consisting of hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (PTCA, percutaneous transluminal coronary angioplasty), coronary heart disease, renal impairment topics, edema, renal vasospasm, renal cortical necrosis, hyponatremia, hypokalemia, Schwarz-Barter syndrome, gastrointestinal disorders, gastritis vasospasm, cirrhosis, stomach and intestinal ulcers, vomiting, vomiting that occurs during chemotherapy, and vomiting motion sickness, and their use for the manufacture of a medicament for the treatment and / or prevention of at least one of the above diseases.

The compounds (I) or (Ia) of the present invention, their salts, their tautomers and their prodrugs can also be used to treat various vasopressin-dependent diseases, which are manifested by central nervous factors or disorders in the HPA axis (hypothalamic-pituitary-adrenal axis), for example, for affective disorders such as depressive disorders and bipolar disorders. These include, for example, dysthymic disorders, phobia, post-traumatic stress disorders, generalized anxiety syndromes, panic disorders, seasonal depression and sleep disturbances.

The compounds (I) or (Ia) of the present invention, their salts, their tautomers and their prodrugs can likewise be used to treat cases of anxiety disorders and stress-dependent anxiety disorders, such as, for example, generalized anxiety disorders, phobia, post-traumatic anxiety disorders, panic anxiety disorders, obsessive-compulsive anxiety disorders, acute stress-dependent anxiety disorders and social phobia. The compounds of this invention can also be used to treat memory disorders, Alzheimer's disease, psychosis, psychotic disorders, sleep disorders and / or Cushing's syndrome, and all stress-dependent diseases.

An additional object of this invention relates to the use of at least one compound of general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug, as defined above, for the treatment of affective disorders and / or for the manufacture of a medicament for the treatment of affective disorders .

An additional object of the present invention relates to the use of at least one compound of general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof, as defined above, for the treatment of anxiety disorders and / or stress-dependent anxiety disorders and / or for the production of a medicament for the treatment of anxiety disorders and / or stress-dependent anxiety disorders.

An additional object of the present invention relates to the use of at least one compound of the general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug, as defined above, for the treatment of memory disorders and / or Alzheimer's disease and / or for the manufacture of a medicinal product agents for treating memory impairment and / or Alzheimer's disease.

An additional object of the present invention relates to the use of at least one compound of the general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof, as defined above, for the treatment of psychoses and / or psychotic disorders and / or for the manufacture of a medicament for the treatment of psychoses and / or psychotic disorders.

An additional object of the present invention relates to the use of at least one compound of the general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug, as defined above, for the treatment of Cushing's syndrome or other stress-related diseases and / or for the manufacture of a medicament for the treatment of Cushing's syndrome or other stress-related diseases.

An additional object of the present invention relates to the use of at least one compound of general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug, as defined above, for the treatment of sleep disorders and / or for the manufacture of a medicament for the treatment of sleep disorders .

An additional object of the present invention relates to the use of at least one compound of general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug, as defined above, for the treatment of depressive disorders and / or for the manufacture of a medicament for the treatment of depressive disorders .

An additional object of the present invention relates to the use of at least one compound of the general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug, as defined above, for the treatment of childhood mood disorders and / or for the manufacture of a medicament for treating mood disorders that begin in childhood. It is understood that the term “mood disorders beginning in childhood” means mood disorders and depression that begin to manifest as early as childhood.

An additional object of this invention relates to the use of at least one compound of general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug, as defined above, for the treatment of vasomotor symptoms and / or thermoregulatory dysfunctions, such as, for example, symptom of a rush of blood.

An additional object of the present invention relates to the use of at least one compound of the general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug, as defined above, for the treatment and / or prevention of drug addiction, drug addiction and / or addiction mediated by other factors for the treatment and / or prevention of stress caused by the removal of one or more factors mediating addiction, and / or for the treatment and / or prevention of stress-related relapses of narcotic The dependence, drug dependency and / or dependency mediated by other factors.

An additional object of the present invention relates to the use of at least one compound of general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug, as defined above, for the treatment and / or prevention of schizophrenia and / or psychosis.

An additional object of this invention relates to a method for treating and / or preventing at least one disorder selected from the group consisting of diabetes, in particular diabetes insipidus, insulin resistance, bedwetting, incontinence, diseases in which blood coagulation disorders occur, and for delayed urination in a patient, characterized in that the patient is administered an effective amount of at least one compound of general formula (I) or (Ia) and / or its pharmaceutically acceptable salts or prodrugs.

An additional object of this invention relates to a method for the treatment and / or prevention of at least one disorder selected from the group consisting of hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemic heart disease, renal system disorders, edema, renal vasospasm, renal cortical necrosis, hyponatremia, hypokalemia, Schwarz-Barter syndrome, stomach disorders gastrointestinal tract, gastritis vasospasm, cirrhosis, stomach and intestinal ulcers, vomiting, vomiting that occurs during chemotherapy, and vomiting during motion sickness in a patient, characterized in that the patient is administered an effective amount of at least one compound of the general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof.

An additional object of the present invention relates to a method for treating and / or preventing affective disorders in a patient, characterized in that the patient is administered an effective amount of at least one compound of general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof.

An additional object of the present invention relates to a method for treating anxiety disorders and / or stress-dependent anxiety disorders in a patient, characterized in that the patient is administered an effective amount of at least one compound of general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug .

An additional object of the present invention relates to a method for treating memory disorders and / or Alzheimer's disease in a patient, characterized in that the patient is administered an effective amount of at least one compound of general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug.

An additional object of the present invention relates to a method for treating psychoses and / or psychotic disorders in a patient, characterized in that the patient is administered an effective amount of at least one compound of general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof.

An additional object of the present invention relates to a method for treating Cushing's syndrome in a patient, characterized in that the patient is administered an effective amount of at least one compound of general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof.

An additional object of this invention relates to a method for treating sleep disorders in a patient, characterized in that the patient is administered an effective amount of at least one compound of general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrug.

An additional object of the present invention relates to a method for treating depressive disorders in a patient, characterized in that the patient is administered an effective amount of at least one compound of general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof.

An additional object of this invention relates to a method for the treatment and / or prevention of vasomotor symptoms and / or dysfunctions of thermoregulation, such as, for example, a symptom of a rush of blood, in a patient, characterized in that the patient is administered an effective amount of at least one compound of the general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof.

An additional object of this invention relates to a method for the treatment and / or prevention of drug addiction, drug addiction and / or addiction mediated by other factors, treatment and / or prophylaxis of stress caused by the removal of one or more factors mediating addiction, and / or treatment and / or prophylaxis of stress-induced relapses of drug addiction, drug addiction and / or addiction mediated by other factors in a patient, characterized in that the patient is administered e an effective amount of at least one compound of general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof.

An additional object of this invention relates to a method for the treatment and / or prevention of schizophrenia and / or psychosis in a patient, characterized in that the patient is administered an effective amount of at least one compound of general formula (I) or (Ia) and / or its pharmaceutically acceptable salt or prodrugs.

An additional object of the present invention relates to a method as defined above, which is characterized in that the patient is a mammal, preferably a human or a mammal, or a transgenic non-human mammal.

Compounds of the general formula (I) or (Ia), their pharmaceutically acceptable salts and prodrugs, as defined above, can be prepared by a person skilled in the art of the present invention, when and / or when the process steps are carried out in a manner known per se.

A further preferred embodiment relates to compounds of general formula (I) or (Ia), their tautomers, their prodrugs and their pharmaceutically acceptable salts, as described above, which are characterized in that they are selective for the vasopressin receptor subtype V1b compared to at least one of closely related subtypes of the vasopressin / oxytocin receptor (e.g., vasopressin V1a, vasopressin V2 and / or oxytocin).

A further preferred embodiment relates to compounds of the general formula (I) or (Ia), their tautomers, their prodrugs and their pharmaceutically acceptable salts, as described above, which are characterized in that they have improved metabolic stability.

The metabolic stability of a compound can be determined, for example, by incubating a solution of the compound with liver microsomes from certain species (e.g., rat, dog or human) and determining the half-life of the compound under these conditions (RS Obach, Curr Opin Drug Discov Devel. 2001, 4, 36-44). From the observed longer half-life, we can conclude that the metabolic stability of this compound improves. Stability in the presence of human liver microsomes is of particular interest, since it makes it possible to predict the metabolic decomposition of this compound in the human liver. Consequently, compounds with increased metabolic stability (determined from a liver microsome test) may also decompose more slowly in the liver. Slower metabolic degradation in the liver can lead to higher and / or long-acting concentrations (effective levels) of the compound in the body so that the half-life of the compounds of this invention is extended. Increased and / or long-acting effective levels can lead to higher efficacy of this compound in the treatment or prevention of various vasopressin-dependent diseases. Improved metabolic stability may also lead to increased oral bioavailability, since the compound, when absorbed in the intestine, is less metabolically degraded in the liver (the so-called first-pass effect). Increased oral bioavailability may, since the concentration (effective level) of the compound is increased, lead to higher efficacy of this compound when administered orally.

A further preferred embodiment relates to compounds of the general formula (I) as described above, characterized in that in patients or corresponding animal models capable of predicting therapeutic use, they have improved pharmacological activity compared to the oxindole compounds known in the foregoing prior art.

Each of the claimed preferred substituent values may be combined with any other substituent values.

This invention relates in particular to compounds of the general formula (I), which are selected from the group consisting of the compounds of the examples listed below, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 and 90, as well as their tautomeric forms, their prodrugs and especially their physiologically acceptable salts, and their non-salt forms, such as hydrates and / or solvates. Particular preference is given to providing the above compounds in the form of a free base or in the form of acid addition salts.

This invention, in particular, also relates to the (-) - enantiomers of the compounds of examples 1-90 in accordance with the general formula (I) selected from the compounds of the examples listed below, 1B, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B, 32B, 33B, 34B, 35B, 36B, 37B, 38B, 39B, 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 51B, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, 77B, 78B, 79B, 80B, 81B, 82B, 83B, 84B, 85B, 86B, 87B, 88B, 89B and 90B, as well as tautomeric forms, prodrugs and especially physiologically acceptable salts, and non-salt forms such as hydra s and / or solvates of compounds of formula (I). Particular preference is given to providing the above compounds in the form of a free base or in the form of acid addition salts.

The term "prodrugs" is intended to mean those compounds that are metabolized in vivo to the compounds of this invention. Specific examples of prodrugs are described in CG Wermeth (Ed.): The Practice of Medicinal Chemistry, Academic Press, San Diego, 1996, pages 671-715. These include, for example, phosphates, carbamates or amino acids, esters, and others. In the present invention, suitable prodrugs of compounds of formula I are compounds of formula I, wherein the nitrogen atom that carries R7 is part of an amide / peptide group, i.e. nitrogen carries an acyl group, such as a C1-C4 alkylcarbonyl group, for example, acetyl, propionyl, n-butyryl (n-propylcarbonyl), isobutyryl, n-butylcarbonyl or tert-butylcarbonyl (pivaloyl), benzoyl, CO linked radical derived from an amino acid such as a CO linked radical derived from glycine, alanine, serine, phenylalanine, etc. Suitable prodrugs also include alkylcarbonyloxyalkylcarbamate, wherein R7 in formula I is a functional group of the formula —C (═O) —O — CHR ^a —OC (═O) —R ^b , where R ^a and R ^b are independently of one another, selected from C ₁ -C ₄ alkyl groups. Similar carbamates have been widely described by J. Alexander, R. Cargill, SR Michelson, H. Schwam, J. Medicinal Chem. 1988, 31 (2), 318-322. These groups are cleaved under metabolic conditions to give a compound of formula I, wherein R7 is hydrogen.

The invention further relates to pharmaceutically acceptable salts of the compounds of formula I, which are also called physiologically acceptable salts. These salts are mainly obtained by reacting the free base of compounds (I) in accordance with this invention with a suitable acid. Suitable acids are listed, for example, in "Fortschritte der Arzneimittelforschung" [Advances in Drug Research], 1966, Birkhäuser Verlag, Vol. 10, pp. 224-285. These include, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid and fumaric acid.

The compounds of this invention are effective when administered in various ways. Administration, for example, can be carried out intravenously, intramuscularly, subcutaneously, topically, intratracheally, intranasally, transdermally, vaginally, rectally, sublingually, buccally or orally, and often it is administered intravenously, intramuscularly or especially orally.

The present invention also relates to pharmaceutical compositions that contain the compound (I) of the present invention and / or its tautomer, and / or its pharmaceutically acceptable salt, and / or its prodrug and suitable pharmaceutical carriers (drug carriers). The amount of compound I in the pharmaceutical composition may depend on the type of formulation of the composition and may lie, for example, in the range from 0.0001 mg / g to 1 g / g, in particular from 0.001 mg / g to 0.5 g / g of the composition.

Such drug carriers are selected in accordance with the form of the pharmaceutical agent and the desired type of administration.

The compounds of this invention of general formula (I) or, if appropriate, suitable salts of these compounds can be used in the manufacture of pharmaceutical compositions for oral, sublingual, buccal, subcutaneous, intramuscular, intravenous, local, intratracheal, intranasal, transdermal, vaginal or rectal administration, and can be administered to animals or humans in unit dosage forms mixed with conventional pharmaceutical carriers for the prophylaxis or treatment of the above on disruption or disease.

Suitable unit dosage forms (unit dosage forms) include oral forms, such as tablets, gelatine capsules, powders, granules, oral solutions or suspensions, sublingual, buccal, intratracheal or intranasal forms, aerosols, implants, forms for subcutaneous, intramuscular or intravenous administration and a form for rectal administration.

The compounds of this invention can be used in the form of creams, ointments or lotions for topical administration.

To achieve the desired prophylactic or therapeutic effect, the dose of the active compound may vary from 0.01 to 50 mg per kg of body weight per day.

Each unit dose may contain from 0.05 to 5000 mg, preferably from 1 to 1000 mg, of the active compound in combination with a pharmaceutical carrier. Such a single dose can be administered from 1 to 5 times a day, so that a daily dose of from 0.5 to 25,000 mg, preferably from 1 to 5,000 mg, is administered.

When a solid tablet composition is obtained, the active compound is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets may be coated with sucrose, a cellulose derivative or other suitable substance, or may be treated in another way in order to exhibit prolonged or delayed activity and release a predetermined amount of the active compound continuously.

A gelatin capsule preparation is prepared by mixing the active compound with an excipient and placing the resulting mixture in soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration in the form of drops may contain the active compounds together with a sweetener, which is preferably non-caloric, methylparaben or propylparaben as antiseptics, flavoring and a suitable coloring agent.

Water-dispersible powders or granules may contain the active compounds in admixture with dispersants, wetting agents or suspending agents, such as polyvinylpyrrolidones, and sweeteners or flavor enhancers.

Rectal or vaginal administration is achieved by the use of suppositories, which are prepared with binders that melt at rectal temperature, such as cocoa butter or polyethylene glycols. Parenteral administration is via the use of aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically suitable dispersing agents and / or wetting agents, for example propylene glycol or polyethylene glycol.

The active compound can also be formulated as microcapsules or centrosomes, if necessary, with one or more carriers or additives.

In addition to the compounds of general formula (I) or their pharmaceutically acceptable salts or prodrugs, the compositions of this invention may contain additional active compounds that may be useful in treating lesions or disorders defined above.

In addition, the present invention, therefore, relates to pharmaceutical compositions that contain many active compounds, where at least one of them is a compound (I) in accordance with this invention, its tautomer, salt or prodrug.

Obtaining compounds of this invention

Examples of synthetic approaches for preparing the oxindole derivatives of the present invention are described below.

The preparation of oxindoles in accordance with this invention can be carried out in various ways, as shown in synthesis schemes 1 and 2. In these synthesis schemes, substituents have the meanings as defined in general formula (I).

3-Hydroxy-1,3-dihydroindol-2-ones IV can be obtained by adding metallated heterocycles III to the 3-keto group of isatines II. Metallized heterocycles, such as, for example, the corresponding Grignard reagent (Mg) or organolithium compound, can be obtained in a standard way from halogen or hydrocarbon compounds. Specific techniques can be found in Houben-Weyl, Methoden der Organischen Chemie [Methods of organic chemistry], Vol. 13, 1-2, Chap. Mg and Li compounds. Isatins II were either commercially available or were obtained by analogy with the methods described in the literature (Advances in Heterocyclic Chemistry, AR Katritzky and AJ Boulton, Academic Press, New York, 1975, 18, 2-58; J. Brazil. Chem. Soc. 12, 273-324, 2001).

Using KCN or Zn (CN) ₂ with Pd (0) catalysis in solvents such as dimethylformamide or tetrahydrofuran, if necessary, also with the addition of bases such as K ₂ CO ₃ or other carbonates and amines, 3- can be converted at elevated temperatures hydroxyoxindoles IV, which in the 6-membered aromatic ring contain, for example, R ³ or R ⁴ as radicals, an iodine substituent, in similar cyano-containing 3-hydroxyindoles IV. Suitable for use as salts of Pd (0) are, for example, transition metal complexes obtained in situ from PdCl ₂ or PdOAc ₂ by the addition of phosphines such as tris (ortotolyl) phosphine. You can also use commercial complexes of palladium, such as, for example, a catalyst tetrakis (triphenylphosphine) palladium (0) and / or additional phosphine ligands.

The 3-hydroxyoxindoles IV can be converted to compounds V which carry the leaving group LG 'at position 3, the leaving group LG' being a regular leaving group, such as, for example, a halide, mesylate or tosylate. Intermediate V, where, for example, LG 'means chlorine, can be obtained by treating alcohol IV with thionyl chloride in the presence of a base such as, for example, pyridine. Alternatively, alcohols IV can be prepared by conversion to mesylate using methanesulfonyl chloride in the presence of a base such as, for example, triethylamine. Compounds V are then reacted with amines, such as, for example, ammonia, which gives similar amines VI as a result of substitution reactions. Then, after deprotonation with a strong base, such as, for example, potassium tert-butoxide or sodium hydride, in DMF, compounds such as compound VI can be converted to product VIII by treatment with sulfonyl chlorides VII. The sulfonyl chlorides VII used are either commercially available or they can be prepared by a method analogous to known methods (see, for example, J. Med. Chem. 40, 1149 (1997)).

Compounds VIII are converted to compounds IX by reaction with reagents to obtain amino groups such as, for example, chloroformates, isocyanates or carbamoyl chlorides, mainly using standard methods (see J. March, Advanced Organic Chemistry, 1992, 4th edition., Wiley, New York, pages 417-421; 499; 903). For example, LG as the leaving group may be O-phenyl in compound IX, which is prepared by reacting compound VIII with phenyl chloroformate in the presence of a base such as, for example, pyridine.

Subsequent reaction with amines X, if necessary at elevated temperature and with the addition of auxiliary bases, such as, for example, triethylamine or diisopropylethylamine, gives the compounds of this invention of general formula (I). Amines X are either commercially available, or they can be obtained by methods known in the literature.

Another alternative method for preparing amine X is by reacting amines with aldehydes or ketones in the presence of reducing agents, such as, for example, sodium cyanoborohydride or sodium acetoxyborohydride, by the reductive amination mechanism (J. March, Advanced Organic Chemistry, 1992, 4th edition., Wiley, New York, pages 411; 898).

Synthesis Scheme 1

The synthesis steps for preparing compounds I in accordance with this invention can be rearranged in a different order, as described in Synthesis Scheme 2, similarly to Synthesis Scheme 1 above. Thus, the amino group in compound VI is first prepared using, for example, phenylchloroformate, whereby compounds XIa and / or XIb are obtained. With an excess of amine X, or even with the aid of an auxiliary base, urea XII derivatives are obtained which can be converted during the subsequent reaction under other standard conditions by deprotonation of compounds XII using a strong base such as, for example, sodium hydride or potassium tert-butoxide, and subsequent treatment with sulfonyl chlorides VII in DMF, in compound I in accordance with this invention.

Synthesis Scheme 2

Below the invention is illustrated in more detail with examples, it is understood that the examples do not limit the invention.

Compounds in accordance with this invention can be obtained using various synthetic approaches. The above methods are described respectively in synthesis schemes 1 and 2, are described in more detail only as an example based on the above examples, while they are not limited solely to synthetic approaches 1 or 2 or similar to the above methods.

EXPERIMENTAL PART

Example 1:

N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide

1a) 3- (2-Ethoxypyridin-3-yl) -3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one

While cooling in an ice bath, 20.86 g (76.40 mmol) of 5-iodoisatin was stirred in 400 ml of anhydrous tetrahydrofuran (THF) and 3.22 g (80.50 mmol, 60% w / w) sodium hydride were added in small portions, while the temperature was maintained between 0-10 ° C. While cooling in an ice bath, the suspension was stirred for one hour, resulting in a Grignard pyridine reagent. At room temperature, 20 g (80.30 mmol) of 2-ethoxy-3-iodopyridine were dissolved in 400 ml of anhydrous THF, and 95.6 ml (1M solution in THF, 95.60 mmol) was added to this solution over 5-10 minutes. ethylmagnesium bromide upon cooling, at a temperature of 22 to 15 ° C. This solution was stirred for 20 minutes, during which time the color changed from colorless to slightly yellowish.

Then, the resulting Grignard pyridine reagent solution was added over 5-10 minutes to a solution of 5-iodoisatin sodium salt cooled in an ice bath, while the temperature ranged from 5 to 18 ° C. After completion of the Grignard reagent addition, the ice bath was removed and the reaction mixture was stirred at room temperature for another 2 hours. An excessively saturated solution of ammonium chloride was added, then ethyl acetate, and the resulting mixture was stirred for another 5 minutes. The aqueous phase was separated and extracted with ethyl acetate (2 ×). The combined organic phases were washed with water (2 ×) and the solvent was removed under reduced pressure. At first, unreacted 5-iodoisatin precipitated from a bottoms diluted solution, it was removed, and after an additional concentration, the product also crystallized out of solution. The suspension was kept in a refrigerator at 5 ° C for two hours, then a slightly yellowish solid was filtered off and washed with a small amount of ethyl acetate. After drying at 40 ° C., the desired 3- (2-ethoxypyridin-3-yl) -3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one (17.1 g, 43.16) was isolated mmol, 57%).

ESI-MS [M + H ⁺ ] = 397.05, calculated for C ₁₅ H ₁₃ IN ₂ O ₃ = 396.19.

1b) 5-Cyano-3-hydroxy-3- (2-ethoxypyridin-3-yl) -1,3-dihydroindol-2-one

7.1 g (17.92 mmol) of 3- (2-ethoxypyridin-3-yl) -3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one was stirred under nitrogen in 100 ml anhydrous THF at room temperature. 2.1 g (17.92 mmol) of zinc cyanide was added and then 0.51 g (0.45 mmol) of tetrakis (triphenylphosphine) palladium (0). The reaction mixture was transferred directly to a preheated oil bath at a temperature of 100 ° C. This mixture was stirred at 100 ° C (oil bath temperature) and after 30 minutes another 0.51 g (0.45 mmol) of catalyst was added. In total, the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and excess water was added. This mixture was extracted with ethyl acetate (3 ×), and the combined organic phases were washed with water (3 ×). The solvent was evaporated to dryness under reduced pressure, and the residue was suspended in small volumes of ethyl acetate. A slightly yellowish solid was separated by filtration, washed with ethyl acetate and dried in a vacuum oven. 3.7 g (12.44 mmol, 69.4%) of the desired product 5-cyano-3-hydroxy-3- (2-ethoxypyridin-3-yl) -1,3-dihydroindol-2-one could be isolated.

ESI-MS [M + H ⁺ ] = 296.05, calculated for C ₁₆ H ₁₃ N ₃ O ₃ = 295.30.

1c) 3-Chloro-3- (2-ethoxypyridin-3-yl) -2-oxoindolin-5-carbonitrile

6.00 g (20.32 mmol) of 5-cyano-3-hydroxy-3- (2-ethoxypyridin-3-yl) -1,3-dihydroindol-2-one was suspended under nitrogen in 60 ml of anhydrous dichloromethane (dried using molecular sieves). Then, 2.30 ml (28.45 mmol) of pyridine was added. The reaction mixture was cooled to 0 ° C. and then 2.06 ml (28.45 mmol) of pure thionyl chloride (exothermic reaction) was added dropwise. This mixture was stirred at room temperature for one hour. The formation of a yellow suspension was observed. The progress of the reaction was monitored by thin layer chromatography (TLC) (silica gel, dichloromethane / methanol in a ratio of 95: 5). The reaction mixture was carefully poured into ice water. After 15 minutes of stirring, the organic phase was separated. The aqueous phase was extracted with dichloromethane (2 ×). All organic phases were combined, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The product gave 5.70 g (18.17 mmol, 89%) of 3-chloro-3- (2-ethoxypyridin-3-yl) -2-oxoindolin-5-carbonitrile as an amorphous solid, which was used for the subsequent reaction without additional cleaning.

ESI-MS [M + H ⁺ ] = 314.1, calculated for C ₁₆ H ₁₂ ClN ₃ O ₂ = 313.75.

1d) 3-amino-3- (2-ethoxypyridin-3-yl) -2-oxoindolin-5-carbonitrile

5.70 g (18.17 mmol) of 3-chloro-3- (2-ethoxypyridin-3-yl) -2-oxoindolin-5-carbonitrile was dissolved in 50 ml of dichloromethane. To the cooled reaction solution, 14 ml (98.11 mmol) of 7 N were slowly added dropwise under a nitrogen atmosphere. methanol ammonia solution. The color of the solution changed to light yellow, and this solution was stirred at room temperature overnight, during which time the product slowly crystallized from the solution. The progress of the reaction was monitored by thin layer chromatography TLC (silica gel, dichloromethane / methanol in a ratio of 9: 1). The solvent was removed under reduced pressure, the residue was again collected and dissolved in dichloromethane. Then the mixture was extracted with water. The phases were separated and the fatty phase that formed between the phases was added to the aqueous phase. The aqueous phase was extracted with ethyl acetate until the fatty phase passed into solution. All organic phases obtained were combined and the solvent was removed under reduced pressure. The residue was triturated with diethyl ether, which led to the formation of a solid, which was filtered and dried in a vacuum oven at a moderate temperature (35 ° C). This gave 4.54 g (15.43 mmol, 85%) of 3-amino-3- (2-ethoxypyridin-3-yl) -2-oxoindolin-5-carbonitrile as a solid.

ESI-MS [M + H ⁺ ] = 295.3, calculated for C ₁₆ H ₁₄ N ₄ O ₂ = 294.32.

1e) 3-amino-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxoindolin-5-carbonitrile

3.54 g (12.03 mmol) of 3-amino-3- (2-ethoxypyridin-3-yl) -2-oxoindolin-5-carbonitrile was dissolved in 80 ml of anhydrous dimethylformamide (dried using molecular sieves). Under a nitrogen atmosphere and upon cooling, using an ice bath, 1.49 g (13.23 mmol) of potassium tert-butoxide was added in small portions. The color of the reaction mixture changed, and the brown solution was stirred at 0 ° C for another hour, so that deprotonation was completed. At a reduced temperature, 3.16 g (13.23 mmol) of 2,4-dimethoxybenzenesulfonyl chloride was added and this mixture was stirred at 0 ° C for another two hours. The progress of the reaction was monitored by thin layer chromatography TLC (silica gel, dichloromethane / methanol in a ratio of 9: 1). The reaction mixture was poured into ice water and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and the solvent was evaporated. The residue was suspended in diethyl ether and stirred until the product precipitated as a solid and it became possible to separate by filtration. After removing the solvent, the mother liquor was again treated with diethyl ether (2 ×), until finally, after drying, 4.67 g (9.44 mmol, 79%) of the desired 3-amino-1 - [(2,4- dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxoindolin-5-carbonitrile as a solid.

ESI-MS [M + H ⁺ ] = 495.15, calculated for C ₂₄ H ₂₂ N ₄ O ₆ S = 494.53.

1f) Phenyl [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl ] carbamate

4.67 g (9.44 mmol) of 3-amino-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxoindolin-5-carbonitrile was dissolved in 120 ml pyridine and cooled to 0 ° C using an ice bath. 1.30 ml (10.39 mmol) of pure phenylchloroformate was added and the reaction mixture was stirred at 0 ° C for 2 hours. The progress of the reaction was monitored by thin layer chromatography TLC (silica gel, dichloromethane / methanol in a ratio of 95: 5). The solvent and especially pyridine was removed under reduced pressure, the residue was diluted with water and extracted with ethyl acetate (3 ×). The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. Traces of pyridine were removed by repeated addition of toluene and rotary evaporation. Diethyl ether was added to the separated residue, and the solid crystallized overnight to obtain 5.62 g (9.14 mmol, 97%) of the desired product phenyl [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl ] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] carbamate.

ESI-MS [M + H ⁺ ] = 615.15, calculated for C ₃₁ H ₂₆ N ₄ O ₈ S = 614.64.

1g) N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole-3- yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide

1.00 g (1.63 mmol) of phenyl [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3- were mixed dihydro-1H-indol-3-yl] carbamate, 596 mg (3.25 mmol) of 1- (1-methylpiperidin-4-yl) piperazine and 8 ml of dried THF, and the mixture was stirred at room temperature for 24 hours. The end of the reaction was detected by analytical HPLC (RP, acetonitrile / water eluents, 0.01% TFA). The solvent was removed and the residue was purified by preparative HPLC using dichloromethane and 6% methanol as eluents on a Chromolith column (direct phase, Merck). After repeated column chromatography, it became possible to isolate 230 mg (0.33 mmol, 21%) of N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) - 2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide.

Alternatively, treatment and purification after completion of the reaction can be carried out as follows: the solvent was removed. The crude material was dissolved in ethyl acetate and extracted with 1N. HCl. Impurities were detected in the organic phase, while the product was in an acidic aqueous phase. Accordingly, the aqueous phase was neutralized with a 2N solution. NaOH and extracted with ethyl acetate. After drying over magnesium sulfate, filtration and removal of ethyl acetate under reduced pressure, the product could crystallize with diethyl ether. N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide was obtained in> 50% yield.

ESI-MS [M + H ⁺ ] = 704.2, calculated for C ₃₅ H ₄₁ N ₇ O ₇ S = 703.82.

¹ H-NMR ([D6] -DMSO, 400 MHz) δ [ppm] = 8.12 (d, 1H, J = 4.8 Hz), 7.88 (d, 1H, J = 8, 8 Hz), 7.87 (d, 1H, J = 8.7 Hz), 7.81 (d, 1H, J = 8.5 Hz), 7.72 (d, 1H, J = 7.6 Hz ), 7.67 (s, 1H), 7.64 (s, 1H), 7.02 (dd, 1H, J = 5.0 Hz, J = 7.5 Hz), 6.69 (d, 1H , J = 8.9 Hz), 6.65 (s, 1H), 4.15 (m, 2H), 3.85 (s, 3H), 3.44 (s, 3H), 3.20 (m , 4H), 2.76 (m, 2H, J = 11.1 Hz), 2.34 (m, 4H), 2.11 (m, 4H), 1.81 (m, 2H, J = 11, 3 Hz), 1.64 (m, 2H, J = 10.7 Hz), 1.37 (m, 2H), 1.06 (t, 1H, J = 7.0 Hz).

Example 5 :

N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3-yl} -4 - (1-methylpiperidin-4-yl) piperazin-1-carboxamide

5a) Phenyl-5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-3 - [(phenoxycarbonyl) amino] indoline-2-carboxylate

2.78 g (9.43 mmol) of 3-amino-3- (2-ethoxypyridin-3-yl) -2-oxoindolin-5-carbonitrile (obtained according to example 1, stage 1a) -1c)) were suspended in 25 ml dichloromethane and cooled in an ice bath to 0 ° C. 7.63 ml (94.34 mmol) of pyridine was added, and then 2.37 ml (18.87 mmol) of phenyl chloroformate was slowly added dropwise so that the temperature did not exceed 5-10 ° C. After the ice bath melted, the reaction mixture was stirred at room temperature overnight, and a weakly colored solid precipitated from the solution. The reaction mixture was diluted with dichloromethane, and after adding water, the solid returned to the solution. The phases were separated and the aqueous phase was extracted again with dichloromethane (1 ×). The combined organic phases were washed first with water (3 ×) and then with a saturated solution of sodium chloride (1 ×). After drying over magnesium sulfate, filtration and evaporation of the solvent under reduced pressure, the residue was again dissolved in diethyl ether, 10 times more pentane was added. A white precipitate formed and was filtered off with suction, washed with pentane and dried in a vacuum oven at 40 ° C. After fractional crystallization, a total of 4.46 g (8.35 mmol, 89%) of phenyl-5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-3 - [(phenyloxycarbonyl) amino] indoline was isolated -1-carboxylate.

ESI-MS [M + H ⁺ ] = 535.15, calculated for C ₃₀ H ₂₂ N ₄ O ₆ = 534.53.

5b) N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidin-4-yl ) piperazine-1-carboxamide

First, 760 mg (1.42 mmol) of phenyl-5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-3 - [(phenoxycarbonyl) amino] indoline-1-carboxylate was poured into 5 ml of THF and 1.42 g (5.69 mmol) of 1- (1-methylpiperidin-4-yl) piperazine insoluble at room temperature were added. The reaction mixture was stirred overnight and the reaction was monitored by TLC (silica gel, dichloromethane / methanol 15: 5) to determine the extent of the reaction. The reaction was diluted with ethyl acetate and washed with water (1 ×) and saturated sodium chloride solution (1 ×). The organic phase was dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dissolved in a small amount of diethyl ether and 6 times more cyclohexane was added. A colorless solid precipitated containing 615 mg (1.22 mmol, 86%) of pure N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H -indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide.

ESI-MS [M + H ⁺ ] = 504.25, calculated for C ₂₇ H ₃₃ N ₇ O ₃ = 503.61.

5c) N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide

80.0 mg (0.16 mmol) N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (1-Methylpiperidin-4-yl) piperazin-1-carboxamide was dissolved in dimethylformamide and 7.63 mg (0.19 mmol, 60% w / w) sodium hydride was added at 0 ° C. During deprotonation of the 1,3-dihydro-2H-indol-2-one derivative, the mixture was stirred for 10 minutes and then 39.4 mg (0.19 mmol) of 4-methoxybenzenesulfonyl chloride was added. Then the mixture was warmed to room temperature and stirred for 30 minutes. The extent of the reaction was monitored by TLC (silica gel, dichloromethane / methanol 1: 1). Saturated sodium bicarbonate and ethyl acetate were added to the reaction mixture, and then the phases were separated. The aqueous phase was re-extracted with ethyl acetate (1 ×). The combined organic phase was washed with water (1 ×) and saturated sodium chloride (1 ×), dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (HPLC) (ISCO Companion, 4 g NP cartridge) using dichloromethane / methanol (5-20%) as mobile phases. 27.3 mg (0.04 mmol, 23% yield, 90% purity) N- [5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2 were isolated -oxo-2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide.

ESI-MS [M + H ⁺ ] = 674.2, calculated for C ₃₄ H ₃₉ N ₇ O ₆ S = 673.80.

Alternative purification methods prior to crystallization of the crude mixtures include conventional direct phase column chromatography (NP-SiO ₂ cartridge, Chromabond) using dichloromethane / methanol as mobile phases and preparative HPLC (RP, mobile phase acetonitrile / water, 0.01% TFA or 0.01% acetic acid).

Examples 2-4 and 6-30:

Compounds in accordance with examples 2-4 and 6-30 can be obtained by a method analogous to the production methods according to example 1 and / or example 5 using suitable starting materials.

Example 2 :

N- {5-Cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3-yl} -4 - (1-methylpiperidin-4-yl) piperazin-1-carboxamide

ESI-MS [M + H ⁺ ] = 674.05, calculated for C ₃₄ H ₃₉ N ₇ O ₆ S = 673.80.

Example 3 :

Trifluoroacetate N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] - 4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide

ESI-MS [M + H ⁺ ] = 688.3, calculated for C ₃₅ H ₄₁ N ₇ O ₆ S = 687.82.

Example 4 :

N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidine -4-yl) piperazin-1-carboxamide

ESI-MS [M + H ⁺ ] = 644.2, calculated for C ₃₃ H ₃₇ N ₇ O ₅ S = 643.77.

Example 31:

N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide

First, 100 mg (0.16 mmol) phenyl [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro- 1H-indol-3-yl] carbamate (prepared according to Example 1, step 1a) -1f)) was poured into 8 ml of anhydrous tetrahydrofuran (dried using molecular sieves) and 44.7 mg (0.24 mmol) of 1-methyl -4- (piperidin-4-yl) piperazine. The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (silica gel, dichloromethane / methanol in a 9: 1 ratio) and LCMS (RP, acetonitrile / water as eluents and 0.01% TFA). The solvent was removed under reduced pressure, the residue was taken up in dichloromethane and extracted with a 2N solution. sodium hydroxide (1 ×). The combined organic phases were dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The crude mixture was purified twice by column chromatography (5 g Chromabond NP-SiO ₂ cartridge) using a dichloromethane / methanol mixture in a ratio of 99: 1 to 80:20 as an eluent. 53.8 mg (0.08 mmol, 47%) of pure N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo were isolated -2,3-dihydro-1H-indol-3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide.

ESI-MS [M + H ⁺ ] = 704.25, calculated for C ₃₅ H ₄₁ N ₇ O ₇ S = 703.82.

¹ H-NMR ([D6] -DMSO, 400 MHz) δ [ppm] = 8.13 (dd, 1H, J = 1.4 Hz, J = 4.8 Hz), 7.88 (d , 1H, J = 8.5 Hz), 7.87 (d, 1H, J = 8.8 Hz), 7.81 (dd, 1H, J = 1.6 Hz, J = 8.6 Hz), 7.71 (dd, 1H, J = 1.4 Hz, J = 7.6 Hz), 7.68 (d, 1H, J = 1.3 Hz), 7.65 (s, 1H), 7, 02 (dd, 1H, J = 4.9 Hz, J = 7.6 Hz), 6.68 (d, 1H, J = 8.9 Hz), 6.65 (s, 1H), 4.17 ( m, 2H), 3.85 (s, 3H), 3.80 (m, 2H), 3.44 (s, 3H), 2.62 (m, 2H), 2.41-2.12 (m 9H), 2.12 (s, 3H), 1.61 (m, 2H), 1.16 (m, 2H), 1.09 (t, 3H, J = 7.0 Hz).

Examples 32-36:

Compounds in accordance with examples 32-36 can be obtained by a method similar to the methods of obtaining according to example 1, 5 and / or 31 using suitable starting materials.

Example 32 :

N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3-yl] -4 - (4-methylpiperazin-1-yl) piperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 674.8 calculated for C ₃₄ H ₃₉ N ₇ O ₆ S = 673.80.

Example 33 :

Trifluoroacetate N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] - 4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 688.2, calculated for C ₃₅ H ₄₁ N ₇ O ₆ S = 687.82.

Example 34 :

N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-methylpiperazine -1-yl) piperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 644.7, calculated for C ₃₃ H ₃₇ N ₇ O ₅ S = 643.77.

Example 35 :

Trifluoroacetate N- [5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3-yl] - 4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 674.2, calculated for C ₃₄ H ₃₉ N ₇ O ₆ S = 673.80.

Example 37:

N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide

First, 100 mg (0.16 mmol) of phenyl [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro was charged -1H-indol-3-yl] carbamate (prepared according to Example 1, step 1a) -1f)) dissolved in 8 ml of anhydrous tetrahydrofuran (dried using molecular sieves). Then, 74.9 mg (0.24 mmol) of 1-ethyl-4-piperidin-4-yl-piperazine and 0.07 ml of triethylamine were added to this reaction mixture, which was then stirred at room temperature overnight. To speed up the reaction and achieve complete conversion, the mixture was again heated to 50 ° C. The progress of the reaction was monitored by TLC (silica gel, dichloromethane / methanol in a 9: 1 ratio) and LCMS (RP, acetonitrile / water as eluents and 0.01% TFA). The solvent was removed under reduced pressure, the residue was taken up in dichloromethane and extracted with a 2N solution. sodium hydroxide (1 ×). The combined organic phases were dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The crude mixture was first purified by silica gel column chromatography (20 × 200 mm column) using dichloromethane and 2% methanol as eluents. The pooled, slightly contaminated product fractions were again purified by preparative HPLC on a Chromolith column (direct phase, from Merck) using dichloromethane and methanol (gradient 0-10% by volume of methanol over 15 minutes) as eluents. This gave 20 mg (0.03 mmol, 17%) of the desired N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo- 2,3-dihydro-1H-indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide.

ESI-MS [M + H ⁺ ] = 718.25, calculated for C ₃₆ H ₄₃ N ₇ O ₇ S = 717.85.

¹ H-NMR ([D6] -DMSO, 400 MHz) δ [ppm] = 8.13 (dd, 1H, J = 1.2 Hz, J = 4.6 Hz), 7.88 (d , 1H, J = 8.2 Hz), 7.87 (d, 1H, J = 8.7 Hz), 7.81 (dd, 1H, J = 1.4 Hz, J = 8.6 Hz), 7.72 (dd, 1H, J = 1.3 Hz, J = 7.6 Hz), 7.68 (d, 1H, J = 1.1 Hz), 7.66 (s, 1H), 7, 02 (dd, 1H, J = 4.9 Hz, J = 7.6 Hz), 6.68 (dd, 1H, J = 2.0 Hz, J = 8.8 Hz), 6.65 (d, 1H, J = 2.2 Hz), 4.17 (m, 2H), 3.85 (s, 3H), 3.81 (m, 2H), 3.44 (s, 3H), 2.62 ( m, 2H), 2.43-2.29 (m, 11H), 1.61 (m, 2H), 1.15 (m, 2H), 1.09 (t, 3H, J = 7.0 Hz ), 0.97 (t, 3H, J = 7.1 Hz).

Examples 38-90:

Compounds in accordance with examples 38-90 can be obtained by a method similar to the production methods according to examples 1, 5, 31, 37, 55, 61 and / or 67 using suitable starting materials.

Example 40 :

N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-ethylpiperazine -1-yl) piperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 658.25, calculated for C ₃₄ H ₃₉ N ₇ O ₅ S = 657.79.

Example 43 :

N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 732.3 calculated for C ₃₇ H ₄₅ N ₇ O ₇ S = 731.88.

Example 55 :

N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4-piperazin-1-ylpiperidin-1-carboxamide

55a) tert-Butyl-4- [1 - ({[[5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3 -dihydro-1H-indol-3-yl] amino} carbonyl) piperidin-4-yl] piperazine-1-carboxylate

First, 100 mg (0.16 mmol) phenyl [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) 2-oxo-2,3-dihydro-1H -indol-3-yl] carbamate (obtained according to example 1, stage 1a) -1f)) was loaded into 8 ml of anhydrous tetrahydrofuran (dried using molecular sieves) and 65.8 mg (0.24 mmol) of tert-butyl- 4-piperidin-4-ylpiperazin-1-carboxylate. The mixture was then stirred at room temperature overnight. The extent of the reaction was monitored by TLC (silica gel, CH ₂ Cl ₂ / MeOH 9: 1) and LCMS (RP, mobile phases acetonitrile / water and 0.01% TFA). The solvent was removed under reduced pressure, the residue was taken up in dichloromethane and extracted with a 2N solution. sodium hydroxide (1 ×). The combined organic phases were dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The crude mixture was purified by column chromatography (5 g Chromabond NP-SiO ₂ cartridge) using a 98: 2 dichloromethane / methanol mixture as the mobile phase. This gave 55.3 mg (0.07 mmol, 43%) of the desired product, which was directly used in the next reaction step for removing the Boc protecting group.

ESI-MS [M + H ⁺ ] = 790.30, calculated for C ₃₉ H ₄₇ N ₇ O ₉ S = 789.91.

55b) N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4-piperazin-1-ylpiperidin-1-carboxamide

First, 55.3 mg (0.07 mmol) of tert-butyl-4- [1 - ({[5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl ) -2-oxo-2,3, -dihydro-1H-indol-3-yl] amino} carbonyl) piperidin-4-yl] piperazin-1-carboxylate was loaded into 4 ml of methanol and 1.0 ml of 5-6M was added hydrochloric acid in isopropanol. The mixture was stirred at room temperature. The extent of the reaction was monitored by TLC (silica gel, CH ₂ Cl ₂ / MeOH 9: 1). After complete conversion, the residual alcohol solvent was removed, the residue was placed in dichloromethane and, using 1 N. the aqueous sodium hydroxide solution was adjusted by extraction to pH 9. The organic phase was separated from the aqueous phase and the aqueous phase was re-extracted with dichloromethane (2 ×). The combined organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was crystallized from diethyl ether. Alternatively, the residue can also be purified either by conventional direct phase column chromatography (NP-SiO ₂ cartridge, Chromabond) using a dichloromethane / methanol mixture as mobile phases or preparative HPLC (RP, mobile phases acetonitrile / water, 0.01% TFA ) After crystallization, 15.9 mg (0.023 mmol, 33%) of N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo- was isolated 2,3-dihydro-1H-indol-3-yl] -4-piperazin-1-ylpiperidin-1-carboxamide.

ESI-MS [M + H ⁺ ] = 690.45 calculated for C ₃₄ H ₃₉ N ₇ O ₇ S = 689.80.

Examples 25-30, 56-60 and 85-90 :

Compounds in accordance with examples 25-30, 56-60 and 85-90 can also be obtained by a method similar to the production methods according to examples 1, 5, 31, 37 and / or 55 using suitable starting materials.

Example 25 :

Bis (trifluoroacetate) N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4-piperidin-4-ylpiperazin-1-carboxamide

ESI-MS [M + H ⁺ ] = 690.15, calculated for C ₃₄ H ₃₉ N ₇ O ₇ S = 689.80.

Example 85 :

Bis (trifluoroacetate) N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4,4'-bipiperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 689.25, calculated for C ₃₅ H ₄₀ N ₆ O ₇ S = 688.81.

In compounds (I) in accordance with this invention, R7, according to synthesis scheme 1 or 2, can also be introduced sequentially by reductive amination, which will be illustrated by examples 61 and 67.

Example 61 :

N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide

First, 100 mg (0.138 mmol) of 4- [1 - ({[5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2 , 3-dihydro-1H-indol-3-yl] amino} carbonyl) piperidin-4-yl] piperidinium chloride (corresponding to the chloride salt of the compound of example 85) (obtained according to example 1, step 1a) -1f) and example 55, step 55a ) -55b)) in 10 ml of dichloromethane. 20 μl (0.207 mmol) of an aqueous solution of formaldehyde (37% strength) was added and the reaction mixture was stirred for 5 minutes. The solution became a little cloudy. 98 mg (0.69 mmol) of sodium sulfate and 20 μl (0.279 mmol) of glacial acetic acid were added and the mixture was stirred for 1.5 hours. 48.7 mg (0.207 mmol) of sodium acetoxyborohydride hydrogenation reagent were added in small portions, after 15 minutes the reaction mixture became clear and then soon cloudy again. The mixture was stirred at room temperature overnight and heated to 40 ° C for another hour. First, the reaction mixture was diluted with 30 ml of dichloromethane and then was extracted with saturated sodium bicarbonate solution (3 ×). The combined organic phases were dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. 75 mg of crude product was isolated, which was purified by preparative HPLC on a Chromolith column (PH-18e, from Merck, mobile phases acetonitrile / water, 0.01% acetic acid). 5 mg (0.007 mmol, 5%) of the desired N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3 were isolated -dihydro-1H-indol-3-yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide (proportionally present as an acetate salt).

ESI-MS [M + H ⁺ ] = 703.2, calculated for C ₃₆ H ₄₂ N ₆ O ₇ S = 702.83.

Example 67 :

N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl trifluoroacetate ] -1'-ethyl-4,4'-bipiperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 717.30, calculated for C ₃₇ H ₄₄ N ₆ O ₇ S = 716.86.

The separation of the racemate of racemic compounds in accordance with examples 1-90:

As an example, using the compound of Example 1, the separation of racemates into their enantiomers (Example 1A and 1B) is shown by separation on a preparative chiral column:

A.) Separation of the racemate of the racemic compounds of Example 1:

100 mg (0.14 mmol) of racemic N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro -1H-indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide (Example 1) was separated on a chiral preparative column (Chiralcell OD, flow rate 55 ml / min) using a mixture of heptane / ethanol (700: 300) as eluent. The enantiomer that elutes first, having a positive optical rotation (Example 1A), can be isolated in 19 mg (0.03 mmol, 19%), and the enantiomer that follows, having a negative optical rotation (Example 1B), can be isolated with 8 mg yield (0.01 mmol, 8%).

Example 1A:

(+) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide

ESI-MS [M + H ⁺ ] = 704.25, calculated for C ₃₅ H ₄₁ N ₇ O ₇ S = 703.82.

HPLC (Chiralcell OD 0.46 cm × 25 cm; n-heptane / ethanol 7: 3) R _f = 9.04 min.

Optical rotation α (22 ° C, 589 nm, CHCl ₃ , 1 mg / ml) = dextrorotatory.

¹ H-NMR ([D6] -DMSO, 500 MHz) δ [ppm] = 8.13 (dd, 1H, J = 1.6 Hz, J = 4.9 Hz), 7.89 (d , 1H, J = 8.9 Hz), 7.88 (d, 1H, J = 8.6 Hz), 7.82 (dd, 1H, J = 1.7 Hz, J = 8.6 Hz), 7.72 (dd, 1H, J = 1.5 Hz, J = 7.7 Hz), 7.68 (d, 1H, J = 1.6 Hz), 7.65 (s, 1H), 7, 02 (dd, 1H, J = 4.9 Hz, J = 7.6 Hz), 6.69 (dd, 1H, J = 2.2 Hz, J = 8.9 Hz), 6.66 (d, 1H, J = 2.1 Hz), 4.17 (m, 2H), 3.86 (s, 3H), 3.45 (s, 3H), 3.21 (m, 4H), 2.77 ( m, 2H, J = 11.0 Hz), 2.34 (m, 4H), 2.12 (m, 4H), 1.82 (m, 2H, J = 10.9 Hz), 1.64 ( m, 2H, J = 10.8 Hz), 1.37 (m, 2H), 1.08 (t, 3H, J = 7.0 Hz).

Example 1B:

(-) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide

ESI-MS [M + H ⁺ ] = 704.25, calculated for C ₃₅ H ₄₁ N ₇ O ₇ S = 703.82.

HPLC (Chiralcell OD 0.46 cm × 25 cm; n-heptane / ethanol 7: 3) R _f = 25.73 min.

Optical rotation α (22 ° C, 589 nm, CHCl ₃ , 1 mg / ml) = levorotatory.

¹ H-NMR ([D6] -DMSO, 500 MHz) δ [ppm] = 8.13 (dd, 1H, J = 1.2 Hz, J = 4.7 Hz), 7.88 (d , 1H, J = 8.9 Hz), 7.87 (d, 1H, J = 8.5 Hz), 7.81 (dd, 1H, J = 1.5 Hz, J = 8.5 Hz), 7.72 (dd, 1H, J = 1.1 Hz, J = 7.6 Hz), 7.68 (s, 1H), 7.64 (s, 1H), 7.01 (dd, 1H, J = 4.9 Hz, J = 7.6 Hz), 6.69 (dd, 1H, J = 1.9 Hz, J = 9.0 Hz), 6.66 (d, 1H, J = 1.9 Hz), 4.16 (m, 2H), 3.85 (s, 3H), 3.45 (s, 3H), 3.20 (m, 4H), 2.77 (m, 2H, J = 11 5 Hz), 2.34 (m, 4H), 2.12 (m, 4H), 1.82 (m, 2H, J = 11.3 Hz), 1.64 (m, 2H, J = 11 5 Hz), 1.37 (m, 2H), 1.07 (t, 3H, J = 7.0 Hz).

B.) Separation of the racemate of the racemic compound according to Example 31:

N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide (Example 31) was separated on a chiral preparative column (Chiralcell OD, flow rate 55 ml / min) using n-heptane / ethanol (700: 300) as eluent. The enantiomer that elutes first has a positive optical rotation (Example 31A), and the enantiomer that follows has a negative optical rotation (Example 31B).

Example 31A:

(+) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 704.80, calculated for C ₃₅ H ₄₁ N ₇ O ₇ S = 703.82.

HPLC (Chiralcell OD 0.46 cm × 25 cm; n-heptane / ethanol 7: 3) R _f = 9.60 min.

Optical rotation α (22 ° C, 589 nm, CHCl ₃ , 1 mg / ml) = dextrorotatory.

¹ H-NMR ([D6] -DMSO, 500 MHz) δ [ppm] = 8.12 (dd, 1H, J = 1.6 Hz, J = 4.8 Hz), 7.87 (d , 1H, J = 8.5 Hz), 7.86 (d, 1H, J = 8.8 Hz), 7.81 (dd, 1H, J = 1.7 Hz, J = 8.6 Hz), 7.73 (dd, 1H, J = 1.5 Hz, J = 7.7 Hz), 7.69 (s, 1H), 7.67 (d, 1H, J = 1.5 Hz), 7, 02 (dd, 1H, J = 4.9 Hz, J = 7.6 Hz), 6.67 (dd, 1H, J = 2.2 Hz, J = 8.9 Hz), 6.65 (d, 1H, J = 2.1 Hz), 4.14 (m, 2H), 3.83 (s, 3H), 3.80 (m, 2H), 3.42 (s, 3H), 2.60 ( m, 2H), 2.39-2.10 (m, 9H), 2.10 (s, 3H), 1.60 (m, 2H), 1.12 (m, 2H), 1.06 (t , 3H, J = 7.0 Hz).

Example 31B:

(-) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 704.80, calculated for C ₃₅ H ₄₁ N ₇ O ₇ S = 703.82.

HPLC (Chiralcell OD 0.46 cm × 25 cm; n-heptane / ethanol 7: 3) R _f = 34.31 min.

Optical rotation α (22 ° C, 589 nm, CHCl ₃ , 1 mg / ml) = levorotatory.

¹ H-NMR ([D6] -DMSO, 500 MHz) δ [ppm] = 8.12 (dd, 1H, J = 1.6 Hz, J = 4.9 Hz), 7.86 (d , 1H, J = 8.7 Hz), 7.85 (d, 1H, J = 8.8 Hz), 7.81 (dd, 1H, J = 1.6 Hz, J = 8.6 Hz), 7.72 (dd, 1H, J = 1.4 Hz, J = 7.6 Hz), 7.69 (s, 1H), 7.67 (d, 1H, J = 1.6 Hz), 7, 02 (dd, 1H, J = 4.9 Hz, J = 7.6 Hz), 6.67 (dd, 1H, J = 2.2 Hz, J = 8.9 Hz), 6.64 (d, 1H, J = 2.0 Hz), 4.13 (m, 2H), 3.83 (s, 3H), 3.80 (m, 2H), 3.42 (s, 3H), 2.60 ( m, 2H), 2.42-2.10 (m, 9H), 2.10 (s, 3H), 1.60 (m, 2H), 1.12 (m, 2H), 1.06 (t , 3H, J = 7.0 Hz).

C.) Separation of the racemate of the racemic compound according to Example 37:

N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide (Example 37) was separated on a chiral preparative column (Chiralcell OD, flow rate 55 ml / min) using a mixture of n-heptane / ethanol (700: 300) as eluent. The enantiomer that elutes first has a positive optical rotation (Example 37A), and the enantiomer that follows has a negative optical rotation (Example 37B).

Example 37A:

(+) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 718.30, calculated for C ₃₆ H ₄₃ F ₃ N ₇ O ₇ S = 717.85.

HPLC (Chiralcell OD 0.46 cm × 25 cm; n-heptane / ethanol 7: 3) R _f = 7.29 min.

Optical rotation α (22 ° C, 589 nm, CHCl ₃ , 1 mg / ml) = dextrorotatory.

¹ H-NMR ([D6] -DMSO, 500 MHz) δ [ppm] = 8.13 (dd, 1H, J = 1.7 Hz, J = 4.9 Hz), 7.89 (d , 1H, J = 8.6 Hz), 7.88 (d, 1H, J = 8.8 Hz), 7.82 (dd, 1H, J = 1.8 Hz, J = 8.6 Hz), 7.72 (dd, 1H, J = 1.7 Hz, J = 7.7 Hz), 7.69 (d, 1H, J = 1.7 Hz), 7.67 (s, 1H), 7, 02 (dd, 1H, J = 4.9 Hz, J = 7.7 Hz), 6.69 (dd, 1H, J = 2.2 Hz, J = 8.9 Hz), 6.66 (d, 1H, J = 2.2 Hz), 4.18 (m, 2H), 3.85 (s, 3H), 3.81 (m, 2H), 3.44 (s, 3H), 2.62 ( m, 2H), 2.42-2.24 (m, 11H), 1.62 (m, 2H), 1.15 (m, 2H), 1.09 (t, 3H, J = 7.1 Hz ), 0.96 (t, 3H, J = 7.2 Hz).

Example 37B:

(-) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 718.25, calculated for C ₃₆ H ₄₃ F ₃ N ₇ O ₇ S = 717.85.

HPLC (Chiralcell OD 0.46 cm × 25 cm; n-heptane / ethanol 7: 3) R _f = 12.41 min.

Optical rotation α (22 ° C, 589 nm, CHCl ₃ , 1 mg / ml) = levorotatory.

¹ H-NMR ([D6] -DMSO, 500 MHz) δ [ppm] = 8.12 (dd, 1H, J = 1.6 Hz, J = 4.9 Hz), 7.88 (d , 1H, J = 8.5 Hz), 7.87 (d, 1H, J = 8.8 Hz), 7.80 (dd, 1H, J = 1.7 Hz, J = 8.6 Hz), 7.71 (dd, 1H, J = 1.5 Hz, J = 7.7 Hz), 7.68 (d, 1H, J = 1.5 Hz), 7.66 (s, 1H), 7, 00 (dd, 1H, J = 4.9 Hz, J = 7.6 Hz), 6.67 (dd, 1H, J = 2.2 Hz, J = 8.9 Hz), 6.65 (d, 1H, J = 2.1 Hz), 4.16 (m, 2H), 3.84 (s, 3H), 3.80 (m, 2H), 3.44 (s, 3H), 2.61 ( m, 2H), 2.41-2.23 (m, 11H), 1.60 (m, 2H), 1.14 (m, 2H), 1.08 (t, 3H, J = 7.1 Hz ), 0.95 (t, 3H, J = 7.2 Hz).

D.) Separation of the racemate of racemic compounds 2-30, 21-36 and 38-90:

In a manner analogous to the separation of racemates of racemic compounds 1, 31 and 37, it is possible to separate the racemates 2-30, 32-36 and 38-90, thereby obtaining the corresponding (+) - enantiomers 2A, 3A, 4A, 5A, 6A, 7A, 8A , 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A and 32A, 33A, 34A , 35A and 38A, 39A, 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A , 62A, 63A, 64A, 65A, 66A, 67A, 68A, 69A, 70A, 71A, 72A, 73A, 74A, 75A, 76A, 77A, 78A, 79A, 80A, 81A, 82A, 83A, 84A, 85A, 86A , 87A, 88A, 89A and 90A

and corresponding (-) - enantiomers 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B 24B, 25B, 26B, 27B, 28B, 29B, 30B and 32B, 33B, 34B, 35B and 38B, 39B, 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 51B , 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B , 77B, 78B, 79B, 80B, 81B, 82B, 83B, 84B, 85B, 86B, 87B, 88B, 89B and 90B.

Enantiomers A and B can also be obtained using enantiomerically pure precursors and intermediates, for example, similar to synthesis schemes 1 or 2, preferably according to synthesis scheme 1. Separation of the racemic mixture into (+) - enantiomers and (-) - enantiomers can be carried out by chiral preparative chromatography, preferably through the corresponding amine structural element VI.

Example 7B :

Trifluoroacetate (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole -3-yl] -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide

ESI-MS [M + H ⁺ ] = 718.25, calculated for C ₃₆ H ₄₃ N ₇ O ₇ S = 717.85.

Example 40B :

(-) - N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 658.25, calculated for C ₃₄ H ₃₉ N ₇ O ₅ S = 657.79.

Example 61B :

Trifluoroacetate (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl) -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole -3-yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 703.30, calculated for C ₃₆ H ₄₂ N ₆ O ₇ S = 702.83.

¹ H-NMR ([D6] -DMSO, 500 MHz) δ [ppm] = 9.26 (1H, protonation of TFA), 8.12 (dd, 1H, J = 1.7 Hz, J = 4 , 9 Hz), 7.87 (dd, 2H, J = 1.3 Hz, J = 8.7 Hz), 7.80 (dd, 1H, J = 1.8 Hz, J = 8.5 Hz) , 7.80 (m, 2H), 7.66 (s, 1H), 7.00 (dd, 1H, J = 4.9 Hz, J = 7.6 Hz), 6.68 (dd, 1H, J = 2.2 Hz, J = 8.9 Hz), 6.65 (d, 1H, J = 2.1 Hz), 4.16 (m, 2H), 3.85 (s, 6H), 3 44-3.41 (m, 5H), 2.85 (m, 2H), 2.73 (m, 2H), 2.57 (m, 2H), 1.81 (m, 2H), 1, 55 (m, 2H), 1.34-1.22 (m, 4H), 1.08 (t, 3H, J = 7.0 Hz), 0.92 (m, 2H).

Example 67B :

Trifluoroacetate (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole -3-yl] -1'-ethyl-4,4'-bipiperidin-1-carboxamide

ESI-MS [M + H ⁺ ] = 717.35; calculated for C ₃₇ H ₄₄ N ₆ O ₇ S = 716.86.

Amines of general formula X can be prepared according to synthesis scheme 1 or 2 by a reductive amination reaction. Below in the context of this description shows the use of obtaining the amine compound 1-ethyl-4-piperidin-4-ylpiperazine as an example:

Example 91: 1-Ethyl-4-piperidin-4-ylpiperazine

91a) tert-butyl-4- (4-ethylpiperazin-1-yl) piperidine-1-carboxylate

First, 29.2 g (256 mmol) of N-ethylpiperazine and 50.0 g (256 mmol) of tert-butyl-4-oxopiperidine-1-carboxylate (corresponding to 1-Boc-4-piperidone) were charged in 800 ml of ethanol under ice cooling and 15.4 g (256 mmol) of glacial acetic acid were added. Then, to the cooled reaction mixture, 16.1 g (256 mmol) of sodium acetoxyborohydride were added in small portions. At first, slight gas formation was observed and, after adding 2/3 of the reducing agent, foaming. The reaction mixture was stirred at room temperature overnight. Upon isolation of the reaction product, 200 ml of 2N was added to the reaction solution with cooling. aqueous sodium hydroxide solution, the ethanol solvent was distilled off, and the remaining reaction mixture was diluted with water. The mixture was extracted with diethyl ether (2 ×) and washed with saturated sodium chloride solution (1 ×), the combined organic phases were dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The desired product was obtained as a yellow oil, which was then chromatographed on a 4 L Nutsche filter filled with silica gel using dichloromethane and 10% methanol as eluents. This gave a total of 40 g (135 mmol, 53%) of tert-butyl 4- (4-ethylpiperazin-1-yl) piperidine-1-carboxylate.

91 b) 1-Ethyl-4-piperidin-4-ylpiperazine as the chloride salt:

First, to remove the protective group, 40 g (135 mmol) of tert-butyl 4- (4-ethylpiperazin-1-yl) piperidin-1-carboxylate was loaded into 200 ml of methanol and 1.8 L of dichloromethane and 100 ml of 5- were added 6M solution of HCl in isopropanol. The solution became a suspension, and slight gas formation could be observed. The reaction mixture was stirred at 40 ° C (water bath temperature) for one hour and at room temperature over the weekend. To complete the removal of the protective group to obtain the desired product, another 50 ml of a 5-6M solution of HCl in isopropanol was added and the mixture was stirred at 40 ° C. Dichloromethane was distilled off on a rotary evaporator and another 200 ml of methanol and 30 ml of a 5-6M solution of HCl in isopropanol were added. After one hour of stirring at the boiling temperature under reflux, a white suspension was formed with strong gas evolution. Subsequently, a suspension with a low viscosity was formed, which was cooled to room temperature. The precipitate was filtered off with suction and washed with methanol and diethyl ether. After drying, 36 g (117 mmol, 87%) of 1-ethyl-4-piperidin-4-ylpiperazine were isolated as the chloride salt.

¹ H-NMR (D ₂ O, 400 MHz) δ [ppm] = 3.74-3.47 (m, 11H), 3.28 (q, 2H, J = 7.3 Hz), 3.06 (dt, 2H, J = 2.2 Hz, J = 13.2 Hz), 2.38 (m, 2H, J = 13.6 Hz), 1.89 (dq, 2H, J = 4.1 Hz, J = 13.3 Hz), 1.30 (t, 3H, J = 7.3 Hz).

The chemical structures of the compounds according to examples 1-90 (racemate) and the corresponding dextrorotatory (+) - enantiomers (examples 1-90 with the added letter "A", such as, for example, 1A, 2A, etc.) and the corresponding levorotatory ( -) - enantiomers (examples 1-90 with the letter "B" added, such as, for example, 1B, 2B, etc.) are shown in table 2 below:

Соединения общей формулы (Ib), где радикалы R5, R6, R7, X2 и X3 имеют значения, указанные ниже (в ряду для каждого случая): table 2

The compounds of general formula (Ib), where the radicals R5, R6, R7, X2 and X3 have the meanings indicated below (in a row for each case): Note No. X2 X3 R5 R6 R7 IUPAC Name
(according to ACD-Lab version 8.00 new product version 8.05) one N CH methoxy methoxy methyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide 1A N CH methoxy methoxy methyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide 1B N CH methoxy methoxy methyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide 2 N CH methoxy H methyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide

2A N CH methoxy H methyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide 2B N CH methoxy H methyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide 3 N CH ethoxy H methyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide 3A N CH ethoxy H methyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide 3B N CH ethoxy H methyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide four N CH H H methyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide 4A N CH H H methyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide 4B N CH H H methyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide 5 N CH H methoxy methyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide 5A N CH H methoxy methyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide 5B N CH H methoxy methyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide

6 N CH ethoxy methoxy methyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide 6A N CH ethoxy methoxy methyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide 6B N CH ethoxy methoxy methyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide 7 N CH methoxy methoxy ethyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 7A N CH methoxy methoxy ethyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 7B N CH methoxy methoxy ethyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 8 N CH methoxy H ethyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 8A N CH methoxy H ethyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 8B N CH methoxy H ethyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 9 N CH ethoxy H ethyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 9A N CH ethoxy H ethyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide

9B N CH ethoxy H ethyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 10 N CH H H ethyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-ethylpiperidin-4-yl) piperazin-1-carboxamide 10A N CH H H ethyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-ethylpiperidin-4-yl) piperazin-1-carboxamide 10B N CH H H ethyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-ethylpiperidin-4-yl) piperazin-1-carboxamide eleven N CH H methoxy ethyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 11A N CH H methoxy ethyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 11B N CH H methoxy ethyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 12 N CH ethoxy methoxy ethyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 12A N CH ethoxy methoxy ethyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 12B N CH ethoxy methoxy ethyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide 13 N CH methoxy methoxy n-propyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide

13A N CH methoxy methoxy n-propyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide 13B N CH methoxy methoxy n-propyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide fourteen N CH methoxy H n-propyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide 14A N CH methoxy H n-propyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide 14B N CH methoxy H n-propyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide fifteen N CH ethoxy H n-propyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide 15A N CH ethoxy H n-propyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide 15B N CH ethoxy H n-propyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide 16 N CH H H n-propyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-propylpiperidin-4-yl) piperazin-1-carboxamide 16A N CH H H n-propyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-propylpiperidin-4-yl) piperazin-1-carboxamide 16B N CH H H n-propyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-propylpiperidin-4-yl) piperazin-1-carboxamide

17 N CH H methoxy n-propyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide 17A N CH H methoxy n-propyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide 17B N CH H methoxy n-propyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide eighteen N CH ethoxy methoxy n-propyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide 18A N CH ethoxy methoxy n-propyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide 18B N CH ethoxy methoxy n-propyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-propylpiperidin-4-yl) piperazine-1-carboxamide 19 N CH methoxy methoxy isopropyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 19A N CH methoxy methoxy isopropyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 19B N CH methoxy methoxy isopropyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide twenty N CH methoxy H isopropyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 20A N CH methoxy H isopropyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide

20B N CH methoxy H isopropyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 21 N CH ethoxy H isopropyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 21A N CH ethoxy H isopropyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 21B N CH ethoxy H isopropyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 22 N CH H H isopropyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-Isopropylpiperidin-4-yl) piperazin-1-carboxamide 22A N CH H H isopropyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-Isopropylpiperidin-4-yl) piperazin-1-carboxamide 22B N CH H H isopropyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-Isopropylpiperidin-4-yl) piperazin-1-carboxamide 23 N CH H methoxy isopropyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 23A N CH H methoxy isopropyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 23B N CH H methoxy isopropyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 24 N CH ethoxy methoxy isopropyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide

24A N CH ethoxy methoxy isopropyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 24B N CH ethoxy methoxy isopropyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (1-isopropylpiperidin-4-yl) piperazine-1-carboxamide 25 N CH methoxy methoxy H (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4-piperidin-4-ylpiperazin-1-carboxamide 25A N CH methoxy methoxy H (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4-piperidin-4-ylpiperazin-1-carboxamide 25B N CH methoxy methoxy H (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4-piperidin-4-ylpiperazin-1-carboxamide 26 N CH methoxy H H (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperidin-4-ylpiperazin-1-carboxamide 26A N CH methoxy H H (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperidin-4-ylpiperazin-1-carboxamide 26B N CH methoxy H H (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperidin-4-ylpiperazin-1-carboxamide 27 N CH ethoxy H H (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4-piperidin-4-ylpiperazin-1-carboxamide 27A N CH ethoxy H H (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4-piperidin-4-ylpiperazin-1-carboxamide 27B N CH ethoxy H H (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4-piperidin-4-ylpiperazin-1-carboxamide

28 N CH H H H (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- piperidin-4-ylpiperazin-1-carboxamide 28A N CH H H H (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- piperidin-4-ylpiperazin-1-carboxamide 28B N CH H H H (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- piperidin-4-ylpiperazin-1-carboxamide 29th N CH H methoxy H (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperidin-4-ylpiperazin-1-carboxamide 29A N CH H methoxy H (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperidin-4-ylpiperazin-1-carboxamide 29B N CH H methoxy H (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperidin-4-ylpiperazin-1-carboxamide thirty N CH ethoxy methoxy H (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4-piperidin-4-ylpiperazin-1-carboxamide 30A N CH ethoxy methoxy H (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4-piperidin-4-ylpiperazin-1-carboxamide 30B N CH ethoxy methoxy H (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4-piperidin-4-ylpiperazin-1-carboxamide 31 CH N methoxy methoxy methyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 31A CH N methoxy methoxy methyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide

31B CH N methoxy methoxy methyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 32 CH N methoxy H methyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 32A CH N methoxy H methyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 32B CH N methoxy H methyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 33 CH N ethoxy H methyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 33A CH N ethoxy H methyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 33B CH N ethoxy H methyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 34 CH N H H methyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 34A CH N H H methyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 34B CH N H H methyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 35 CH N H methoxy methyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 35A CH N H methoxy methyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide

35B CH N H methoxy methyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 36 CH N ethoxy methoxy methyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 36A CH N ethoxy methoxy methyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 36B CH N ethoxy methoxy methyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide 37 CH N methoxy methoxy ethyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 37A CH N methoxy methoxy ethyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 37B CH N methoxy methoxy ethyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 38 CH N methoxy H ethyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 38A CH N methoxy H ethyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 38B CH N methoxy H ethyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide

39 CH N ethoxy H ethyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 39A CH N ethoxy H ethyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 39B CH N ethoxy H ethyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 40 CH N H H ethyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 40A CH N H H ethyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 40B CH N H H ethyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 41 CH N H methoxy ethyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 41A CH N H methoxy ethyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 41B CH N H methoxy ethyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 42 CH N ethoxy methoxy ethyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 42A CH N ethoxy methoxy ethyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide

42B CH N ethoxy methoxy ethyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide 43 CH N methoxy methoxy n-propyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 43A CH N methoxy methoxy n-propyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 43B CH N methoxy methoxy n-propyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 44 CH N methoxy H n-propyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 44A CH N methoxy H n-propyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 44B CH N methoxy H n-propyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 45 CH N ethoxy H n-propyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 45A CH N ethoxy H n-propyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 45B CH N ethoxy H n-propyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 46 CH N H H n-propyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide

46A CH N H H n-propyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 46B CH N H H n-propyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 47 CH N H methoxy n-propyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3- yl} -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 47A CH N H methoxy n-propyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3- yl} -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 47B CH N H methoxy n-propyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3- yl} -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 48 CH N ethoxy methoxy n-propyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 48A CH N ethoxy methoxy n-propyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 48B CH N ethoxy methoxy n-propyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide 49 CH N methoxy methoxy isopropyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole 3-yl] -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 49A CH N methoxy methoxy isopropyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole 3-yl] -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 49B CH N methoxy methoxy isopropyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole 3-yl] -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide

fifty CH N methoxy H isopropyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3- yl} -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 50A CH N methoxy H isopropyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3- yl} -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 50B CH N methoxy H isopropyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3- yl} -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 51 CH N ethoxy H isopropyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 51A CH N ethoxy H isopropyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 51B CH N ethoxy H isopropyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 52 CH N H H isopropyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-Isopropylpiperazin-1-yl) piperidin-1-carboxamide 52A CH N H H isopropyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-Isopropylpiperazin-1-yl) piperidin-1-carboxamide 52B CH N H H isopropyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-Isopropylpiperazin-1-yl) piperidin-1-carboxamide 53 CH N H methoxy isopropyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 53A CH N H methoxy isopropyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide

53B CH N H methoxy isopropyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 54 CH N ethoxy methoxy isopropyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 54A CH N ethoxy methoxy isopropyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 54B CH N ethoxy methoxy isopropyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4- (4-isopropylpiperazin-1-yl) piperidin-1-carboxamide 55 CH N methoxy methoxy H (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4-piperazin-1-ylpiperidin-1-carboxamide 55A CH N methoxy methoxy H (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4-piperazin-1-ylpiperidin-1-carboxamide 55B CH N methoxy methoxy H (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4-piperazin-1-ylpiperidin-1-carboxamide 56 CH N methoxy H H (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperazin-1-ylpiperidin-1-carboxamide 56A CH N methoxy H H (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperazin-1-ylpiperidin-1-carboxamide 56B CH N methoxy H H (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperazin-1-ylpiperidin-1-carboxamide 57 CH N ethoxy H H (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4-piperazin-1-ylpiperidin-1-carboxamide

57A CH N ethoxy H H (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4-piperazin-1-ylpiperidin-1-carboxamide 57B CH N ethoxy H H (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4-piperazin-1-ylpiperidin-1-carboxamide 58 CH N H H H (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- piperazin-1-ylpiperidin-1-carboxamide 58A CH N H H H (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- piperazin-1-ylpiperidin-1-carboxamide 58B CH N H H H (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- piperazin-1-ylpiperidin-1-carboxamide 59 CH N H methoxy H (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperazin-1-ylpiperidin-1-carboxamide 59A CH N H methoxy H (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperazin-1-ylpiperidin-1-carboxamide 59B CH N H methoxy H (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- yl} -4-piperazin-1-ylpiperidin-1-carboxamide 60 CH N ethoxy methoxy H (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4-piperazin-1-ylpiperidin-1-carboxamide 60A CH N ethoxy methoxy H (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4-piperazin-1-ylpiperidin-1-carboxamide 60B CH N ethoxy methoxy H (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4-piperazin-1-ylpiperidin-1-carboxamide

61 CH CH methoxy methoxy methyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide 61A CH CH methoxy methoxy methyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide 61B CH CH methoxy methoxy methyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide 62 CH CH methoxy H methyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-methyl-4,4'-bipiperidin-1-carboxamide 62A CH CH methoxy H methyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-methyl-4,4'-bipiperidin-1-carboxamide 62B CH CH methoxy H methyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-methyl-4,4'-bipiperidin-1-carboxamide 63 CH CH ethoxy H methyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide 63A CH CH ethoxy H methyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide 63B CH CH ethoxy H methyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide 64 CH CH H H methyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' methyl-4,4'-bipiperidin-1-carboxamide 64A CH CH H H methyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' methyl-4,4'-bipiperidin-1-carboxamide

64B CH CH H H methyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' methyl-4,4'-bipiperidin-1-carboxamide 65 CH CH H methoxy methyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-methyl-4,4'-bipiperidin-1-carboxamide 65A CH CH H methoxy methyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-methyl-4,4'-bipiperidin-1-carboxamide 65B CH CH H methoxy methyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-methyl-4,4'-bipiperidin-1-carboxamide 66 CH CH ethoxy methoxy methyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide 66A CH CH ethoxy methoxy methyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide 66B CH CH ethoxy methoxy methyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-methyl-4,4'-bipiperidin-1-carboxamide 67 CH CH methoxy methoxy ethyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-ethyl-4,4'-bipiperidin-1-carboxamide 67A CH CH methoxy methoxy ethyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-ethyl-4,4'-bipiperidin-1-carboxamide 67B CH CH methoxy methoxy ethyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-ethyl-4,4'-bipiperidin-1-carboxamide 68 CH CH methoxy H ethyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-ethyl-4,4'-bipiperidin-1-carboxamide

68A CH CH methoxy H ethyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-ethyl-4,4'-bipiperidin-1-carboxamide 68B CH CH methoxy H ethyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-ethyl-4,4'-bipiperidin-1-carboxamide 69 CH CH ethoxy H ethyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-ethyl-4,4'-bipiperidin-1-carboxamide 69A CH CH ethoxy H ethyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-ethyl-4,4'-bipiperidin-1-carboxamide 69B CH CH ethoxy H ethyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-ethyl-4,4'-bipiperidin-1-carboxamide 70 CH CH H H ethyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' ethyl-4,4'-bipiperidin-1-carboxamide 70A CH CH H H ethyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' ethyl-4,4'-bipiperidin-1-carboxamide 70B CH CH H H ethyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' ethyl-4,4'-bipiperidin-1-carboxamide 71 CH CH H methoxy ethyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-ethyl-4,4'-bipiperidin-1-carboxamide 71A CH CH H methoxy ethyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-ethyl-4,4'-bipiperidin-1-carboxamide 71B CH CH H methoxy ethyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-ethyl-4,4'-bipiperidin-1-carboxamide

72 CH CH ethoxy methoxy ethyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-ethyl-4,4'-bipiperidin-1-carboxamide 72A CH CH ethoxy methoxy ethyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-ethyl-4,4'-bipiperidin-1-carboxamide 72B CH CH ethoxy methoxy ethyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-ethyl-4,4'-bipiperidin-1-carboxamide 73 CH CH methoxy methoxy n-propyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-propyl-4,4'-bipiperidin-1-carboxamide 73A CH CH methoxy methoxy n-propyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-propyl-4,4'-bipiperidin-1-carboxamide 73B CH CH methoxy methoxy n-propyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-propyl-4,4'-bipiperidin-1-carboxamide 74 CH CH methoxy H n-propyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-propyl-4,4'-bipiperidin-1-carboxamide 74A CH CH methoxy H n-propyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-propyl-4,4'-bipiperidin-1-carboxamide 74B CH CH methoxy H n-propyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-propyl-4,4'-bipiperidin-1-carboxamide 75 CH CH ethoxy H n-propyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-propyl-4,4'-bipiperidin-1-carboxamide 75A CH CH ethoxy H n-propyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-propyl-4,4'-bipiperidin-1-carboxamide 75B CH CH ethoxy H n-propyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-propyl-4,4'-bipiperidin-1-carboxamide 76 CH CH H H n-propyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' propyl-4,4'-bipiperidin-1-carboxamide 76A CH CH H H n-propyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' propyl-4,4'-bipiperidin-1-carboxamide 76B CH CH H H n-propyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' propyl-4,4'-bipiperidin-1-carboxamide 77 CH CH H methoxy n-propyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-propyl-4,4'-bipiperidin-1-carboxamide 77A CH CH H methoxy n-propyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-propyl-4,4'-bipiperidin-1-carboxamide 77B CH CH H methoxy n-propyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-propyl-4,4'-bipiperidin-1-carboxamide 78 CH CH ethoxy methoxy n-propyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-propyl-4,4'-bipiperidin-1-carboxamide 78A CH CH ethoxy methoxy n-propyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-propyl-4,4'-bipiperidin-1-carboxamide 78B CH CH ethoxy methoxy n-propyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-propyl-4,4'-bipiperidin-1-carboxamide 79 CH CH methoxy methoxy isopropyl (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-isopropyl-4,4'-bipiperidin-1-carboxamide

79A CH CH methoxy methoxy isopropyl (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 79B CH CH methoxy methoxy isopropyl (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 80 CH CH methoxy H isopropyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 80A CH CH methoxy H isopropyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 80B CH CH methoxy H isopropyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 81 CH CH ethoxy H isopropyl (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 81A CH CH ethoxy H isopropyl (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 81B CH CH ethoxy H isopropyl (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 82 CH CH H H isopropyl (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' -isopropyl-4,4'-bipiperidin-1-carboxamide 82A CH CH H H isopropyl (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' -isopropyl-4,4'-bipiperidin-1-carboxamide 82B CH CH H H isopropyl (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -1 ' -isopropyl-4,4'-bipiperidin-1-carboxamide

83 CH CH H methoxy isopropyl (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 83A CH CH H methoxy isopropyl (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 83B CH CH H methoxy isopropyl (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 84 CH CH ethoxy methoxy isopropyl (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 84A CH CH ethoxy methoxy isopropyl (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 84B CH CH ethoxy methoxy isopropyl (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -1'-isopropyl-4,4'-bipiperidin-1-carboxamide 85 CH CH methoxy methoxy H (±) -N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4,4'-bipiperidin-1-carboxamide 85A CH CH methoxy methoxy H (+) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4,4'-bipiperidin-1-carboxamide 85B CH CH methoxy methoxy H (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4,4'-bipiperidin-1-carboxamide 86 CH CH methoxy H H (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -4,4'-bipiperidin-1-carboxamide 86A CH CH methoxy H H (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -4,4'-bipiperidin-1-carboxamide

86B CH CH methoxy H H (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -4,4'-bipiperidin-1-carboxamide 87 CH CH ethoxy H H (±) -N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4,4'-bipiperidin-1-carboxamide 87A CH CH ethoxy H H (+) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4,4'-bipiperidin-1-carboxamide 87B CH CH ethoxy H H (-) - N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3- yl] -4,4'-bipiperidin-1-carboxamide 88 CH CH H H H (±) -N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4, 4'-bipiperidin-1-carboxamide 88A CH CH H H H (+) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4, 4'-bipiperidin-1-carboxamide 88B CH CH H H H (-) - N- [5-cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4, 4'-bipiperidin-1-carboxamide 89 CH CH H methoxy H (±) -N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -4,4'-bipiperidin-1-carboxamide 89A CH CH H methoxy H (+) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -4,4'-bipiperidin-1-carboxamide 89B CH CH H methoxy H (-) - N- {5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indole-3- silt} -4,4'-bipiperidin-1-carboxamide 90 CH CH ethoxy methoxy H (±) -N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4,4'-bipiperidin-1-carboxamide

90A CH CH ethoxy methoxy H (+) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4,4'-bipiperidin-1-carboxamide 90B CH CH ethoxy methoxy H (-) - N- [5-cyano-1 - [(2-ethoxy-4-methoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H- indol-3-yl] -4,4'-bipiperidin-1-carboxamide

METHODS FOR DETERMINING BIOLOGICAL ACTIVITY

Vasopressin V1b receptor binding assay:

Substances:

The test substances were dissolved at a concentration of 10 ^-2 M in DMSO and then diluted from 5 × 10 ^-4 M to 5 × 10 ^-9 M in DMSO. This series of preliminary dilutions in DMSO was diluted with a buffer solution for analysis 1:10. The concentration of the substance in the mixture for analysis was again diluted 1: 5 (2% DMSO in the mixture).

Membrane preparation:

CHO-K1 cells with a stably expressed human vasopressin V1b receptor (clone 3H2) were harvested from culture and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini # 1836170) using a Polytron homogenizer in culture medium for 2 × 10 seconds and then centrifuged at 40,000 × g for 1 h. The membrane pellet was again homogenized and centrifuged as described above, and then placed in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at -190 ° C.

Binding Assay:

The binding assay was performed by a method based on the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)). The incubation buffer solution was: 50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4.

In a mixture for analysis (250 μl), membranes (50 μg / ml protein in the incubation buffer) from CHO-K1 cells with stably expressed human V1b receptors (hV1b_3H2_CHO cell line) were incubated with 1.5 nM ³ H-AVP (8- Arg-vasopressin, PerkinElmer # 18479) in an incubation buffer solution (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4) (total binding) or additionally with increased concentrations of the analyte (substitution experiment). Nonspecific binding was determined using 1 μM AVP (Bachem # H1780). All determinations were performed in triplicate. After incubation (60 minutes at room temperature), the free radioligand was removed by vacuum filtration (Skatron 7000 cell collector) through layers of a Wathman GF / B glass fiber filter, and the filters were transferred to scintillation vials. Liquid scintillation measurement was performed on a Tricarb 2000 or 2200CA model (Packard) instrument. Conversion of measured pulses per minute (cpm) to decays per minute (dpm) was performed using standard blanking experiments.

Evaluation of the results of the analysis :

Binding parameters were calculated by non-linear regression using the SAS program. The algorithms of this program function by analogy with the LIGAND analysis program (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). Kd ³ H-AVP for recombinant human V1b receptors is 0.4 nM and was used to determine the Ki value.

The study shows that the compounds of the present invention as a whole have high affinity for the V1b receptor, which, expressed as K _i (h-V1b) values, is usually below 150 nM, in particular not more than 50 nM and especially not more than 10 nM. The results are shown in table 3

Vasopressin V1a receptor binding assay:

Substances:

The test substances were dissolved at a concentration of 10 ^-2 M in DMSO. These DMSO solutions were further diluted in an incubation buffer solution (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4).

Membrane preparation:

CHO-K1 cells with a stably expressed human vasopressin V1a receptor (clone 5) were harvested from culture and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini # 1836170) using a Polytron homogenizer in culture medium for 2 × 10 seconds and then centrifuged at 40,000 × g for 1 h. The membrane pellet was again homogenized and centrifuged as described above, and then placed in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at -190 ° C.

Binding Assay:

The binding assay was performed by a method based on the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer solution was: 50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4.

In a mixture for analysis (250 μl), membranes (20 μg / ml protein in incubation buffer) from CHO-K1 cells with stably expressed human V1a receptors (hV1a_5_CHO cell line) were incubated with 0.04 nM ¹²⁵ I-AVP (8- Arg-vasopressin, NEX 128) in an incubation buffer solution (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4) (total binding) or additionally with increased concentrations of the analyte (substitution experiment). Nonspecific binding was determined with 1 μM AVP (Bachem # H1780). The determinations were performed in triplicate. After incubation (60 minutes at room temperature), the free radioligand was removed by vacuum filtration (Skatron 7000 cell collector) through layers of a Wathman GF / B glass fiber filter, and the filters were transferred to scintillation vials.

Liquid scintillation measurement was performed on a Tricarb 2000 or 2200CA model (Packard) instrument. Conversion of measured pulses per minute (cpm) to decays per minute (dpm) was performed using standard blanking experiments.

Evaluation of the results of the analysis :

Binding parameters were calculated by non-linear regression using the SAS program. The algorithms of this program function by analogy with the LIGAND analysis program (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). Kd ¹²⁵ I-AVP for recombinant hV1a receptors was determined during saturation experiments. Kd 1.33 nM was used to determine the Ki value.

The study shows that the compounds of the present invention as a whole have selectivity for the V1b receptor compared to the V1a receptor, which, expressed as K _i (h-V1a) / K _i (h-V1b) values, usually exceeds 10 and often is over at least 15, in particular at least 50 and especially at least 100. The results are shown in table 3.

Vasopressin V2 Receptor Binding Assay:

Substances:

The test substances were dissolved at a concentration of 10 ^-2 M in DMSO. These DMSO solutions were further diluted in an incubation buffer solution (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4).

Membrane preparation:

CHO-K1 cells with a stably expressed human vasopressin V2 receptor (clone 23) were harvested from culture and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini # 1836170) using a Polytron homogenizer in culture medium for 2 × 10 seconds and then centrifuged at 40,000 × g for 1 h. The membrane pellet was again homogenized and centrifuged as described above, and then placed in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at -190 ° C.

Binding Assay:

The binding assay was performed by a method based on the method of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer solution was: 50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4.

In a mixture for analysis (250 μl), membranes (50 μg / ml protein in the incubation buffer) from CHO-K1 cells with stably expressed human V2 receptors (hV2_23_CHO cell line) were incubated with 1-2 nM ³ H-AVP (8- Arg-vasopressin, PerkinElmer # 18479) in an incubation buffer solution (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4) (total binding) or additionally with increased concentrations of the analyte (substitution experiment). Nonspecific binding was determined with 1 μM AVP (Bachem # H1780). The determinations were performed in triplicate.

After incubation (60 minutes at room temperature), the free radioligand was removed by vacuum filtration (Skatron 7000 cell collector) through layers of a Wathman GF / B glass fiber filter, and the filters were transferred to scintillation vials.

Liquid scintillation measurement was performed on a Tricarb 2000 or 2200CA model (Packard) instrument. Conversion of measured pulses per minute (cpm) to decays per minute (dpm) was performed using standard blanking experiments.

Evaluation of the results of the analysis:

Binding parameters were calculated by non-linear regression using the SAS program. The algorithms of this program function by analogy with the LIGAND analysis program (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). Kd ³ H-AVP for recombinant hV2 receptors is 2.4 nM and was used to determine the Ki value.

The study shows that the compounds of the present invention as a whole have selectivity for the V1b receptor compared to the V2 receptor, which, expressed as K _i (h-V2) / K _i (h-V1b), usually exceeds 10 and often is over at least 15, in particular at least 50.

Oxytocin Receptor Binding Assay

Substances:

The substances were dissolved at a concentration of 10 ^-2 M in DMSO and diluted in incubation buffer solution (50 mM Tris, 10 mM MgCl ₂ , 0.1% BSA, pH 7.4).

Cellular preparation:

Confluent HEK-293 cells with temporarily expressed recombinant human oxytocin receptors were centrifuged at 750 × g and at room temperature for 5 minutes. The residue was placed in ice lysis buffer (50 mM Tris-HCl, 10% glycerol, pH 7.4 and Roche Complete Protease Inhibitor) and subjected to osmotic shock at 4 ° C for 20 minutes. The lysed cells were then centrifuged at 750 × g and at 4 ° C for 20 minutes, the residue was placed in an incubation buffer solution and 10 ⁷ cells / ml aliquots were prepared. Aliquots were frozen at -80 ° C until use.

Binding Assay:

On the day of the experiment, the cells were thawed, diluted with incubation buffer and homogenized using Multipette Combitip (Eppendorf, Hamburg). A 0.250 ml reaction mixture was mixed from 2 to 5 × 10 ⁴ recombinant cells, 3-4 nM ³ H-oxytocin (PerkinElmer, NET 858) in the presence of the analyte (inhibition dependence) or only incubation buffer solution (total binding). Nonspecific binding was determined using 10 ^-6 M oxytocin (Bachem AG, H2510). The determinations were performed in triplicate. Bound and free radioligand were separated by vacuum filtration through Wathman GF / B glass filters using a Skatron 7000 cell collector. Bound radioactivity was determined by liquid scintillation measurement on a Tricarb 2000 or 2200CA beta particle counter (Packard).

Evaluation of the results of the analysis:

Binding parameters were calculated by nonlinear regression analysis (SAS) by analogy with the LIGAND Munson and Rodbard program (Analytical Biochem. 107, 220-239 (1980)). The Kd ³ H-oxytocin for recombinant hOT receptors is 7.6 nm and was used to determine the Ki value.

The study shows that the compounds of the present invention as a whole have selectivity for the V1b receptor compared to the oxytocin receptor, which, expressed as K _i (h-OT) / K _i (h-V1b), usually exceeds 10 and often is over at least 15, in particular at least 25, and especially at least 50. The results are shown in table 3.

Table 3 Example K _i (h-V1b) * [nM] K _i (h-V1a) / K _i (h-V1b) * K _i (h-OT) / K _i (h-V1b) * one +++ +++ +++ 1B +++ +++ +++ 2 ++ +++ +++ 3 ++ +++ +++ four ++ ++ ++ 7B +++ +++ +++ 25 +++ +++ ++ 31 +++ +++ +++ 31B +++ +++ +++ 32 ++ + +++

35 +++ + ++ 37 +++ +++ +++ 37B +++ +++ +++ 40 +++ ++ +++ 40B +++ + +++ 43 +++ +++ +++ 55 +++ +++ ++ 61 +++ +++ +++ 61B +++ +++ +++ 67 +++ +++ +++ 67B +++ +++ +++ 85 +++ +++ ++ K _i (h-V1b) K _i (h-V1a) / K _i (h-V1b) K _i (h-OT) / K _i (h-V1b) + > 50-150 nM 15-50 15-25 ++ 10-50 nM > 50-100 > 25-50 +++ <10 nM > 100 > 50

Determination of microsomal half-life:

The metabolic stability of the compounds of this invention was determined by the following analysis.

Test substances are incubated at a concentration of 0.5 μM, as follows:

0.5 μM of the test substance is preincubated with various types of liver microsomes (rat, human, or other species) (0.25 mg microsomal protein / ml) in a 0.05 M potassium phosphate buffer pH 7.4 in microtiter plates at 37 ° C for 5 minutes The reaction begins with the addition of NADPH (1 mg / ml). 50 μl aliquots were taken after 0, 5, 10, 15, 20 and 30 minutes, the reaction was immediately stopped with the same volume of acetonitrile and cooled. Samples are frozen until analysis. Using MSMS, the remaining concentration of undecomposed test substance is determined. The half-life (T1 / 2) is determined by increasing the signal / time unit of the analyte, and the half-life of the analyte can be calculated using first-order kinetics to reduce the concentration of the compound with time. Microsomal clearance (mCl) is calculated using the formula mCl = ln2 / T1 / 2 / (microsomal protein content in mg / ml) × 1000 [ml / min / mg] (modified in accordance with the literature: Di, The Society for Biomoleculaur Screening, 2003, 453-462; Obach, DMD, 1999 vol 27. N 11, 1350-1359).

The study shows that the compounds of the present invention as a whole have high metabolic stability, which results in a value of human microsomal clearance of generally not more than 220 μl min ^-1 mg ^-1 , often 120 μl min ^-1 mg ^-1 and, in particular, not more than 60 μl min ^-1 mg ^-1 . The results are shown in table 4.

Table 4 Example Human microsomal clearance [μl min. ^-one  mg ^-one ] one +++ 1B +++ four +++ 5 +++ 7B +++ 25 +++ 31 ++ 31B +++ 34 +++ 35 ++ 37 ++ 37B +++ 40 ++ 40B ++ 55 ++ 61B +++ 85 ++ Human microsomal clearance + > 120-220 μl min ^-1 mg ^-1 ++ 60-120 μl min ^-1 mg ^-1 +++ <60 μl min ^-1 mg ^-1

Determination of plasma protein binding (PPB) by equilibrium dialysis:

150 μl of rat or human plasma with 1 or 10 μM of the test substance is pipetted on one side of the wells of a 96-well dialysis plate, 150 μl of PPS buffer solution is pipetted on the other side. Wells are separated by a dialysis membrane, which passes substances with a molecular weight of up to 6-8000 daltons.

The wells of the 96-well dialysis plate are closed and gently shaken overnight.

The next morning, 10 μl of plasma is separated and 90 μl of PPS buffer solution is diluted and the protein is precipitated using 200 μl of acetonitrile. The precipitated protein is separated by centrifugation and used for MSMS analysis of 100 μl of the supernatant. 100 μl was separated from the buffer side for MSMS analysis. See also the following literature link: Banker, Journal of Pharmaceutical Sciences Vol. 92, 5, 967-974, 2003.

Methods for determining in vitro inhibition of cytochrome P450 (CYP)

Luminescent substrates for 2C9 and 3A4:

0.4 mg / ml human liver microsomes were preincubated for 10 minutes with test substances to be tested (0-20 μM), CYP specific substrates, in a 0.05 M potassium phosphate buffer pH 7.4 at 37 ° C . The cyp-specific substrate for CYP 2C9 is luciferin H, the substrate for CYP 3A4 is luciferin BE. The reaction begins when NADPH is added. After 30 minutes of incubation at room temperature, a luciferin reagent is added and the resulting luminescence signal is measured (modified in accordance with literature reference: Promega, Technical Bulletin P450-GLO ^TM Assays).

Inhibition of CYP 3A by midazolam over time

The study consists of 2 parts. In the first part, the test substance is preincubated with liver microsomes (with NADPH), i.e. pre-incubation, followed by the addition of substrate; in the second part, the substrate and the test substance are simultaneously added, i.e. coincubation.

Pre-incubation:

0.05 mg / ml microsomal protein (human liver microsomes) is pre-incubated with 0-10 μM (or 50 μM) of the test substance in a 50 mM potassium phosphate buffer solution for 5 minutes. The reaction begins with the use of NADPH. After 30 minutes, 4 μM midazolam (final concentration) was added and the mixture was incubated for another 10 minutes. After 10 min, 75 μl of the reaction solution was separated and quenched with 150 μl of acetonitrile solution.

Coincubation:

0.05 mg / ml microsomal protein (human liver microsomes), 4 μM midazolam (final concentration) and 0-10 μM (or 50 μM) of the test substance are preincubated in 50 mM potassium phosphate buffer for 5 minutes. The reaction begins with the use of NADPH. After 10 min, 75 μl of the reaction solution was separated and quenched with 150 μl of acetonitrile solution. Samples are frozen until MSMS analysis (modified according to published literature: Obdach, Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1, 336-348, 2006; Walsky, Drug Metabolism and Disposition Vol 32, 6, 647-660, 2004 )

The method for determining solubility in water (in mg / ml)

The water solubility of the compounds of this invention can be determined, for example, in accordance with the so-called “flask shaking” method (in accordance with ASTM International: E 1148-02, Standard test methods for measurement of aqueous solubility, Book of Standards Volume 11.05.). In the context of this description, an excess of solid compound is added to a buffer solution having a certain pH (for example, phosphate buffered saline pH 7.4) and the resulting mixture is shaken or stirred until it reaches a stationary state (usually 24 or 48 hours, sometimes even up to 7 days). The insoluble solid is then removed by filtration or centrifugation, and the concentration of the dissolved compound is determined by UV spectroscopy or high performance liquid chromatography (HPLC) using a suitable calibration curve.

Claims (22)

1. Compounds of General Formula (I)

where R1 represents an ethoxy group;
R2 is hydrogen;
R3 represents a cyano group;
R4 is hydrogen;
R5 represents hydrogen, a methoxy group or an ethoxy group;
R6 represents hydrogen or a methoxy group;
R7 represents hydrogen, methyl, ethyl, n-propyl or isopropyl;
X1 represents —NH—;
X2 represents N or CH;
X3 represents N or CH;
where X2 and X3 are not simultaneously N;
and their pharmaceutically acceptable salts and tautomeric forms. 2. The compound according to claim 1, where R5 represents hydrogen or a methoxy group. 3. The compound according to claim 1, where R7 represents hydrogen, methyl or ethyl. 4. Compounds according to any one of claims 1 to 3, where
R5 represents hydrogen or a methoxy group;
R7 represents hydrogen, methyl or ethyl;
X1 represents —NH—;
X2 represents N, and
X3 is CH. 5. Compounds according to any one of claims 1 to 3, where
R5 represents hydrogen or a methoxy group;
R7 represents hydrogen, methyl or ethyl;
X1 represents —NH—;
X2 represents CH, and
X3 represents N. 6. Compounds according to any one of claims 1 to 3, where
R5 represents a methoxy group;
R6 represents a methoxy group;
R7 is methyl or ethyl;
X1 represents —NH—;
X2 represents CH, and X3 represents N, or
X2 represents N, and X3 represents CH. 7. Compounds according to any one of claims 1 to 3, where
R5 represents a methoxy group;
R6 represents a methoxy group;
R7 is methyl;
X1 represents —NH—;
X2 represents N, and
X3 is CH. 8. Compounds according to any one of claims 1 to 3, where
R5 represents a methoxy group;
R6 represents a methoxy group;
R7 is methyl;
X1 represents —NH—;
X2 represents CH, and
X3 represents N. 9. Compounds according to any one of claims 1 to 3, where
R5 represents a methoxy group;
R6 represents a methoxy group;
R7 is ethyl;
X1 represents —NH—;
X2 represents CH, and
X3 represents N. 10. Compounds of general formula (I) according to any one of claims 1 to 9, characterized in that they are present in an optically active form and are (levorotatory) (-) - enantiomer that rotates the plane of polarization of linearly polarized light to the left, specified the compounds of general formula (I), in the form of a free base, and their pharmaceutically acceptable salts and / or tautomeric forms. 11. Compounds of general formula (I) according to any one of claims 1 to 9, characterized in that they are present in an optically active form in which the absolute configuration of the chiral C-3 carbon atom of the ring corresponds to the absolute configuration at C-3 (levorotatory) ( -) - the enantiomer that rotates the plane of polarization of linearly polarized light to the left, the compounds of formula (Ia) in the form of a free base

and their pharmaceutically acceptable salts and tautomeric forms. 12. The compounds of general formula (I) of claim 10 in an optically active form, characterized in that the corresponding levorotatory (-) - enantiomer is present with an optical purity (enantiomeric excess, its) of more than 50%, and their pharmaceutically acceptable salts and tautomeric forms . 13. The compounds of general formula (I) according to claim 11 in an optically active form, characterized in that the enantiomer having a preferred absolute configuration at the C-3 carbon atom of the ring is present with an optical purity (enantiomeric excess, its) of more than 50%, and their pharmaceutically acceptable salts and tautomeric forms. 14. The compounds of general formula (I) of claim 10 in an optically active form, characterized in that the corresponding levorotatory (-) - enantiomer is present with an optical purity (enantiomeric excess, its) of more than 90%, and their pharmaceutically acceptable salts and tautomeric forms . 15. The compounds of general formula (I) according to claim 11 in an optically active form, characterized in that the enantiomer having a preferred absolute configuration at the C-3 carbon atom of the ring is present with an optical purity (enantiomeric excess, its) of more than 90%, and their pharmaceutically acceptable salts and tautomeric forms. 16. The compounds of general formula (I) according to any one of claims 1 to 9 in the form of a racemate and pharmaceutically acceptable salts and tautomeric forms of the racemate of the compounds of general formula (I). 17. Compounds according to any one of the preceding paragraphs, selected from the group including
N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidin-4-yl) piperazine-1-carboxamide;
(+) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide;
(-) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide;
N- {5-Cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3-yl} -4 - (1-methylpiperidin-4-yl) piperazin-1-carboxamide;
N- {5-Cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3-yl} -4 - (1-methylpiperidin-4-yl) piperazin-1-carboxamide;
N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl trifluoroacetate] - 4- (1-methylpiperidin-4-yl) piperazin-1-carboxamide;
N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (1-methylpiperidine -4-yl) piperazin-1-carboxamide;
N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide;
(+) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide;
(-) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide;
N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3-yl] -4 - (4-methylpiperazin-1-yl) piperidin-1-carboxamide;
N- [5-cyano-1 - [(2-ethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl trifluoroacetate] - 4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide;
N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-methylpiperazine -1-yl) piperidin-1-carboxamide;
Trifluoroacetate N- [5-cyano-3- (2-ethoxypyridin-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-1H-indol-3-yl] - 4- (4-methylpiperazin-1-yl) piperidin-1-carboxamide;
N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide;
(+) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide;
(-) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide;
N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-ethylpiperazine -1-yl) piperidin-1-carboxamide;
(-) - N- [5-Cyano-3- (2-ethoxypyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -2,3-dihydro-1H-indol-3-yl] -4- (4-ethylpiperazin-1-yl) piperidin-1-carboxamide;
N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4- (4-propylpiperazin-1-yl) piperidin-1-carboxamide;
N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -4-piperazin-1-ylpiperidin-1-carboxamide;
Bis (trifluoroacetate) N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4-piperidin-4-yl-piperazin-1-carboxamide;
Bis (trifluoroacetate) N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole- 3-yl] -4,4′-bipiperidin-1-carboxamide;
N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -1′-methyl-4,4′-bipiperidin-1-carboxamide;
Trifluoroacetate (-) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole -3-yl] -1′-methyl-4,4′-bipiperidin-1-carboxamide;
N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indol-3-yl trifluoroacetate ] -1′-ethyl-4,4′-bipiperidin-1-carboxamide;
Trifluoroacetate (-) - N- [5-cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole -3-yl] -1′-ethyl-4,4′-bipiperidin-1-carboxamide;
Trifluoroacetate (-) - N- [5-Cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxypyridin-3-yl) -2-oxo-2,3-dihydro-1H-indole -3-yl] -4- (1-ethylpiperidin-4-yl) piperazine-1-carboxamide;
or at least one pharmaceutically acceptable salt or one tautomeric form thereof. 18. A medicament for the treatment and / or prophylaxis of at least one vasopressin-dependent disease, comprising at least one compound of the general formula (I) according to any one of claims 1-17, or at least one pharmaceutically acceptable salt thereof or one thereof tautomeric form. 19. At least one compound of general formula (I) according to any one of claims 1-17, or at least one pharmaceutically acceptable salt thereof or one tautomeric form thereof for use as a medicine for the treatment and / or prevention of at least one vasopressin-dependent disease. 20. The use of at least one compound of general formula (I) according to any one of claims 1-17, or at least one pharmaceutically acceptable salt thereof or one of its tautomeric forms for the treatment and / or prevention of at least one vasopressin-dependent disease. 21. The use of at least one compound of general formula (I) according to any one of claims 1-17, or at least one pharmaceutically acceptable salt thereof or one of its tautomeric forms for the treatment and / or prevention of at least one disorder selected from the group consisting of
diabetes, insulin resistance, bedwetting, incontinence, diseases in which blood clotting disorders occur;
hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), coronary heart disease, disorders of the renal system, edema, renal vasospasm, necrosis of the cortex, kidney disease, hyponea, hypona Barter, gastrointestinal tract disorders, gastritis vasospasm, liver cirrhosis, stomach and intestinal ulcers, vomiting, vomiting that occurs during chemotherapy, vomiting during motion sickness;
affective disorders;
anxiety
memory impairment and / or Alzheimer's disease;
psychoses and / or psychotic disorders;
Cushing's syndrome or other stress-related diseases;
sleep disturbances;
depressive disorders such as childhood mood disorders;
vasomotor symptoms and / or dysfunctions of thermoregulation, such as, for example, a symptom of a rush of blood;
drug dependencies, drug dependencies and / or dependencies mediated by other factors for treating and / or preventing stress caused by the removal of one or more factors mediating the addiction, and / or for treating and / or preventing stress-induced relapses of drug addiction, drug dependencies and / or dependencies mediated by other factors;
schizophrenia and / or psychosis
and / or delayed urination. 22. A method of treating and / or preventing at least one disorder selected from the group consisting of
diabetes, insulin resistance, bedwetting, incontinence, diseases in which blood clotting disorders occur;
hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), coronary heart disease, disorders of the renal system, edema, renal vasospasm, necrosis of the cortex, kidney disease, hyponea, hypona Barter, gastrointestinal tract disorders, gastritis vasospaem, liver cirrhosis, stomach and intestinal ulcers, vomiting, vomiting that occurs during chemotherapy, and vomiting during motion sickness ;
affective disorders;
anxiety disorders and / or stress-dependent anxiety disorders; memory impairment and / or Alzheimer's disease;
psychoses and / or psychotic disorders;
Cushing's syndrome;
sleep disturbances;
depressive disorders such as childhood mood disorders;
vasomotor symptoms and / or dysfunctions of thermoregulation, such as, for example, a symptom of a rush of blood;
drug dependencies, drug dependencies and / or dependencies mediated by other factors, treating and / or preventing stress caused by the removal of one or more factors mediating the addiction, and / or treating and / or preventing stress-induced relapses of drug addiction, drug dependencies and / or dependencies mediated by other factors;
schizophrenia and / or psychosis;
and delayed urination in a patient, characterized in that the patient is administered an effective amount of at least one compound of general formula (I) according to any one of claims 1 to 17 or at least one pharmaceutically acceptable salt thereof or one of its tautomeric forms.