Indoles as 5-ht6 modulators

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

 

The scope of the invention

The present invention relates to new compounds, to pharmaceutical compositions comprising these compounds, to processes for their preparation and to the use of these compounds to obtain drugs against associated with 5-HT6receptor disorders.

Background of the invention

Obesity is a condition characterized by increased body fat mass, which leads to excessive weight, exceeding accepted standards. In the Western world, obesity is one of the most common disorders associated with malnutrition, and represents a serious health problem in many industrialized countries. This disorder can lead to increased mortality due to the large number of cases of diseases such as cardiovascular diseases, diseases of the digestive system, respiratory diseases, cancer and type 2 diabetes. The search for compounds that reduce body weight, was carried out over many decades. One area of research involves the activation of serotonergic systems, either by direct activation of subtypes of serotonin receptor, or by inhibiting re-uptake of serotonin. However, the exact desired profile receptor subtype is unknown.

Serotonin (5-hydroxytryptamine or 5-HT) is a key transmitter of the peripheral and Central nervous system, and it is believed that it modulates a wide range of physiological and pathological functions, including, for example, anxiety, regulation of sleep, aggression, power, and depression. There were reports about the identification and cloning of several subtypes of the serotonin receptor. In 1993, several groups reported the cloning of 5-HT6the receptor. See, for example, (Ruat, M. et al. (1993) Biochem. Biophys. Res. Commun. 193: 268-276; Sebben, M. et al. (1994) NeuroReport 5: 2553-2557). Believe that this receptor is positively associated with adenylylcyclase, and it was shown that it demonstrates an affinity for the antipsychotic tools such as clozapine. Recently it was reported about the effect of the antagonist of 5-HT6and 5-HT6antisense oligonucleotides to reduce food intake in rats. See, for example, (Bentley, J. C. et al. (1999) Br J Pharmacol. Suppl. 126, P66; Bentley, J. C. et al. (1997) J. Psychopharmacol. Suppl. A64, 255; Woolley, M. L. et al. (2001) Neuropharmacology 41: 210-219).

Were identified compounds with increased affinity and selectivity for 5-HT6receptor, for example, in WO 00/34242 and Isaac, M. et al. (2000) described 6-bicyclopentyl-1-arylsulfonyl and 6-bicycloheptadiene-1-arylsulfonyl derivatives as new, strong and selective antagonists of 5-HT6the receptor. Bioorganic & Mediinal Chemistry Letters 10: 1719-1721 (2000), Bioorganic & Medicinal Chemistry Letters 13: 3355-3359 (2003), Expert Opinion Therapeutic Patents 12(4) 513-527 (2002).

Disclosure of invention

The present invention mainly relates to certain indole and indolinone compounds which exhibit affinity for 5-HT6the receptor.

Surprisingly, it was found that some indole and indoline compounds show affinity for 5-HT6receptor at nanomolar level. Generally, the preferred compounds described in this application are characterized in that they contain functional benzyl-amino group at the 4-position of the indole or indoline, preferably, the functional benzyl-amino group at the 4-position of the indole. This class of amines has improved in vivo properties and, as expected, is not metabolized in unwanted metabolites. In some embodiments, embodiments of the invention, the compounds described in this application (for example, indole compounds and their pharmaceutically acceptable salts can have antagonistic activity against 5-HT6the receptor. In some embodiments, embodiments of the invention, the compounds described in this application (for example, indole compounds, and their pharmaceutically acceptable salts can have the activity of agonists and partial agonists of 5-HT6the receptor. The preferred compounds may include compounds which have antagonistic activity. As such, the compounds described in this application are deemed to be useful for one of the following: treatment or prevention of obesity and type 2 diabetes, weight loss and weight gain, as well as for treatment or prophylaxis of disorders of the Central nervous system such as anxiety, depression, panic attacks, memory disorders, disorders of cognition, epilepsy, sleep disorders, migraine, anorexia, bulimia, disorders associated with overeating, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea and/or schizophrenia, panic attacks, disorder attention deficit/hyperactivity disorder (ADHD), withdrawal of drugs with abuse (e.g., dependence on amphetamine, cocaine and/or nicotine), neurodegenerative diseases characterized by impaired growth of nerve cells, and pain. In some embodiments, embodiments of the invention, the reduction of body weight and weight gain (for example, treatment of disorders associated with disturbance of body weight) is achieved, inter alia, by reducing food intake. As used in this application, the term "disorder associated with impaired body weight" refers to disorders caused by an imbalance between energy consumption the GII and energy consumption, which leads to abnormal (e.g., excessive) body weight. Such disorders associated with disturbance of body weight, include obesity.

In one aspect, the present invention relates to the compound of formula (I)

where:

represents a simple bond or double bond;

m is 0, 1 or 2 (for example, 2);

n is 0, 1, 2 or 3 (for example, 3);

in variants of the embodiment of the invention, when the value of m is 1, then one of C2and C3(see the formula (I-A) indole/indolinone ring system substituted with hydrogen, and the other of C2and C3indole/indolinone ring system is substituted by either hydrogen, or one of the non-hydrogen of options specified in the definition of R0;

in variants of the embodiment of the invention, when the value of m is equal to 0, then each of C2and C3indole/indolinone ring system substituted with hydrogen;

in variants of the embodiment of the invention, when the value n is equal to 2, then one of C5C6and C7(see the formula (I-A) indole/indolinone ring system represents hydrogen and the other two from the C5C6and C7indole/indolinone ring systems are each, independently, substituted with hydrogen or one of the non-hydrogen of options specified in the definition of R2;

in variants of the embodiment of the invention, when the value of n is 1, then two of C5C6and C7indole/indolinone ring system represent hydrogen, the remainder of C5C6and C7indole/indolinone ring system is substituted by either hydrogen, or one of the non-hydrogen of options specified in the definition of R2;

in variants of the embodiment of the invention, when the value of n is 0, then each of C5C6and C7indole/indolinone ring system substituted with hydrogen;

each R0, independently, selected from the following:

(a) hydrogen,

(b) halogen, preferably chlorine,

(c) C1-6-alkyl,

(d) C3-7-cycloalkyl,

(e) hydroxy-C1-4-alkyl,

(f) -COOR6,

(g) -CONR5R5,

(h) -CO-R8,

(i) -CN,

(j) aryl, and

(k) heteroaryl,

where in the case when R0represents or includes heteroaryl or aryl residue, each heteroaryl or aryl residue, optionally, may be substituted in one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) the provisions Deputy independently selected from the following:

(a) halogen,

(b) C1-4-alkyl,

(c) C1-4-alkylthio,

(d) C1-4-alkoxy,

(e) -CF3,

(f) -CN, and

(g) hydroxymethyl;

R1represents a group selected from CL is blowing:

(a) C1-6-alkyl,

(b) C3-7-cycloalkyl,

(c) C3-6-alkenyl,

(d) aryl,

(e) aryl-C2-6alkenyl,

(f) aryl-C1-6-alkyl,

(g) heteroaryl,

(h) heteroaryl-C2-6alkenyl, and

(i) heteroaryl-C1-6-alkyl, where in the case when R1constitutes or includes any heteroaryl or aryl residue, alone or as part of another group, this heteroaryl or aryl residue, optionally, independently substituted in one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) the provisions Deputy independently selected from the following:

(a) halogen,

(b) C1-6-alkyl,

(c) a fluorine-C1-6-alkyl,

(d) C3-7-cycloalkyl,

(e) C2-6alkenyl,

(f) a fluorine-C2-6alkenyl,

(g) ethinyl,

(h) hydroxy-C1-4-alkyl,

(i) hydroxy,

(j) C1-6-alkoxy,

(k) a fluorine-C1-6-alkoxy,

(1) -SCF3,

(m) -SCF2H,

(n) -SO2NR5R5,

(o) -S(O)eR8where e is 0, 1, 2 or 3,

(p) -CN

(q) -NR5R5,

(r) -NHSO2R8,

(s) -NR6COR8,

(on) -NO2,

(u) -CONR5R5,

(v) -C(=O)R8,

(w) -COOH,

(x) C1-6-alkoxycarbonyl,

(y) C3-7-cycloalkane,

(z) phenyl, optionally substituted by one or more substituents, such as halogen, C1-4-alkyl, C1-4-Ala is LTI, C1-4-alkoxy, cyano, or trifluoromethyl,

(aa) phenoxy, optionally substituted by one or more substituents, such as halogen, C1-4-alkyl, C1-4-alkylthio, C1-4-alkoxy, cyano or trifluoromethyl,

(ab) benzyloxy, optionally substituted by one or more substituents, such as halogen, C1-4-alkyl, C1-4-alkylthio, C1-4-alkoxy, cyano or trifluoromethyl,

(ac) benzoyl, optionally substituted by one or more substituents, such as halogen, C1-4-alkyl, C1-4-alkylthio, C1-4-alkoxy, cyano or trifluoromethyl, and

(ad) heteroaryl, optionally substituted by trifluoromethyl and stands;

each R2independently selected from the following:

(a) hydrogen

(b) halogen,

(c) C1-6-alkyl,

(d) a fluorine-C1-6-alkyl,

(e) C3-7-cycloalkyl,

(f) C2-6alkenyl,

(g) a fluorine-C2-6alkenyl,

(h) ethinyl,

(i) hydroxy-C1-4-alkyl,

(j) hydroxy,

(k) C1-6-alkoxy,

(1) fluorine-C1-6-alkoxy,

(m) C3-7-cycloalkane,

(n) a fluorine-C3-7-cycloalkane,

(o) -SCF3,

(p) SCF2H,

(q) -SO2NR5R5,

(r) -S(O)eR8where e is 0, 1, 2 or 3,

(s) -CN

(t) -NR5R5,

(u) -NHSO2R8,

(v) -NR6COR8,

(w) -NO2,

(x) -CONR5R5,

(y) -OCONR5R5,

(z) -C(=O)R8,

(aa) -COOH,

(ab) C1-6-alkoxycarbonyl, and

(ac) -OR11;

R3represents a group selected from the following:

where

X is selected from O or-NR6;

z has a value of 2; and

(i) both R4represent hydrogen; or

(ii) one of R4represents hydrogen and the other represents a

(a) C1-4-alkyl,

(b) a fluorine-C1-4-alkyl,

(c) hydroxy-C1-4-alkyl, and

(d) cyano; or

(iii) both R4represent methyl;

R5each independently selected from the following:

(a) hydrogen,

(b) C1-6-alkyl,

(c) a fluorine-C1-6-alkyl,

(d) heteroaryl-C1-2-alkyl

(e) C3-7-cycloalkyl, or

two groups of R5together with the nitrogen atom to which they are linked, form a heterocyclic ring;

R6each independently selected from the following:

(a) hydrogen,

(b) C1-4-alkyl,

(c) a fluorine-C2-4-alkyl, and

(d) hydroxy-C1-3-alkyl;

R7selected from the following:

(a) hydrogen,

(b) C1-4-alkyl,

(c) a fluorine-C2-4-alkyl,

(d) 2-cyanoethyl,

(e) hydroxy-C2-4-alkyl,

(f) C3-4alkenyl,

(g) C3-4-quinil,

(h) C3-7-cycloalkyl,

(i) C3-4-cycloalkyl-C1-4-alkyl and

(j) C1-4-alkoxy-C2-4-alkyl;

p> R8each independently selected from the following:

(a) C1-6-alkyl,

(b) a fluorine-C1-6-alkyl,

(c) C3-7-cycloalkyl,

(d) aryl, and

(e) heteroaryl,

where in the case when R8is a heteroaryl or aryl residue, each heteroaryl or aryl residue, optionally, independently substituted in one or more (e.g., 1-5, 1-4, 1-3, 1-2 or 1) the provisions Deputy independently selected from the following:

(a) halogen, (b) C1-4-alkyl,

(c) C1-4-alkylthio,

(d) C1-4-alkoxy,

(e) -CF3,

(f) -OCF3,

(g) -CN, and

(h) hydroxymethyl;

R9selected from the following:

(a) hydrogen,

(b) fluorine, provided that the fluorine is not linked to the carbon atom adjacent to a ring nitrogen atom,

(c) C1-4-alkyl,

(d) -NR6R6provided that the group-NR6R6not linked to a carbon atom adjacent to a ring nitrogen atom,

(e) hydroxy, provided that the hydroxy-group is not linked to a carbon atom adjacent to a ring nitrogen atom, and

(f) hydroxy-C1-4-alkyl;

R10each independently selected from the following:

(a) hydrogen,

(b) hydroxy, C2-4-alkyl,

(c) C1-3-alkoxy-C2-4-alkyl,

(d) cyclopropyl;

(e) cyclobutyl,

(f) benzyl, and

(g) C1-4-alkyl, provided that when R 10represent ethyl, thenrepresents a double bond;

R11selected from the

(a)- (CH2CN

(b) benzyl;

R12each independently selected from the following:

(a) hydrogen,

(b) C1-4-alkyl,

(c) a fluorine-C1-4-alkyl,

(d) hydroxy-C1-3-alkyl and

(e) C1-6-alkoxycarbonyl;

and their pharmaceutically acceptable salts, hydrates, solvate, geometric isomers, tautomers, optical isomers and metabolites (e.g., pharmaceutically acceptable salts), particularly N-oxides of tertiary amines, demetilirovanny amines and N-oxidized heteroaromatic rings.

In some embodiments, embodiments of the invention, provided that the compound of formula (I) may represent an N-methyl-1-(phenylsulfonyl)-1H-indol-4-methanamine.

In another aspect, the present invention relates to the compound of formula (I), where:

represents a simple bond or double bond;

m has a value of 1;

n has a value of 1;

R0represents a group selected from the following:

(a) hydrogen,

(b) C1-6-alkyl,

(c) C3-7-cycloalkyl,

(d) hydroxy-C1-4-alkyl,

(e) -COOR6,

(f) -CONR5R5,

(g) -CO-R8,

(h) -CN,

(i) aryl, and

(j) heteroaryl,

where in the case when R0 represents or includes heteroaryl or aryl residue, each heteroaryl or aryl residue, optionally, may be substituted in one or more (e.g., 1-5, 1-4, 1-3, 1-2 or 1) the provisions Deputy independently selected from the following:

(a) halogen,

(b) C1-4-alkyl,

(c) C1-4-alkylthio,

(d) C1-4-alkoxy,

(e) -CF3,

(f) -CN, and

g) hydroxymethyl;

R3represents a group selected from the following:

and

X, R1, R2, R4, R6, R7, R9, R10, R11and R12have the meanings given for formula (I).

Preferably, when in the formula (I), X represents-NR6. More preferably, X represents-NR6where R6represents N.

Also preferably, when in the formula (I):

represents a double bond;

R0represents a group selected from the following:

(a) hydrogen,

(b) C1-6-alkyl,

(c) C3-7-cycloalkyl,

(d) hydroxy-C1-4-alkyl,

(e) -CO-R8,

(f) -CN,

(g) aryl, and

(h) heteroaryl,

where any heteroaryl or aryl residue, optionally, independently substituted or several positions Deputy, selected from the following:

(a) halogen,

(b) C1-4 -alkyl,

(c) C1-4-alkylthio,

(d) C1-4-alkoxy,

(e) -CF3,

(f) -CN, and

(g) hydroxymethyl;

R1represents a group selected from the following:

(a) aryl,

(b) heteroaryl,

where any heteroaryl or aryl residue, optionally, independently substituted at one or several positions Deputy, selected from the following:

(a) halogen,

(b) C1-6-alkyl,

(c) a fluorine-C1-6-alkyl,

(d) C3-7-cycloalkyl,

(e) C2-6alkenyl,

(f) a fluorine-C2-6alkenyl,

(g) ethinyl,

(h) hydroxy-C1-4-alkyl,

(i) hydroxy,

(j) C1-6-alkoxy,

(k) a fluorine-C1-6-alkoxy,

(l) -SCF3,

(m) -SCF2H,

(n) -SO2NR5R5,

(o) -S(O)eR8where e is 0, 1 or 2,

(p) -CN

(q) -NR5R5,

(r) -NHSO2R8,

(s) -NR6COR8,

(on) -NO2,

(u) -CONR5R5and

(v) -C(=O)R8;

R2represents a group selected from the following:

(a) hydrogen,

(b) halogen,

(c) C1-6-alkyl,

(d) C3-7-cycloalkyl,

(e) hydroxy-C1-4-alkyl,

(f) hydroxy,

(g) C1-6-alkoxy,

(h) -SCF3,

(i) SCF2H,

(j) -SO2NR5R5,

(k) -S(O)eR8where e is 0, 1, 2 or 3,

(l) -CN,

(m) -NR5R5,

(n) -NHSO2R8,

(o) -NR6COR8,

(P) -CONR5R5,

(q) -OCONR5R5,

(r) -C(=O)R8and

(s) -OR11;

R3represents a group selected from the following:

R4represents a group selected from the following:

(a) hydrogen,

(b) C1-4-alkyl and

(C) hydroxy-C1-4-alkyl;

R5each independently selected from the following:

(a) hydrogen and

(b) C1-3-alkyl,

or two groups R5together with the nitrogen atom to which they are linked, form a heterocyclic ring;

R6each independently selected from the following:

(a) hydrogen,

(b) methyl, and

(c) ethyl;

R7selected from the following:

(a) hydrogen,

(b) C1-4-alkyl,

(c) 2-cyanoethyl,

(d) 2-hydroxyethyl,

(e) C3-4alkenyl,

(f) C3-7-cycloalkyl,

(h) C3-4-cycloalkyl-C1-4-alkyl and

(i) C1-4-alkoxy-C2-4-alkyl;

R8each independently selected from the following:

(a) C1-3-alkyl,

(b) C3-7-cycloalkyl,

(c) aryl and

(d) heteroaryl,

where any heteroaryl or aryl residue, optionally, independently substituted at one or several positions Deputy, selected from the following:

(a) fluorine,

(b) chlorine

(c) bromine,

(d) C1-4-alkyl,

(e) C1-4-alkylthio,

(f) C1-4-alkoxy,

(g) -CF3

(h) -CN, and

(i) hydroxymethyl;

R9selected from the following:

(a) hydrogen,

(b) C1-4-alkyl,

(c) -NR6R6provided that the group-NR6R6not linked to a carbon atom adjacent to a ring nitrogen atom,

(d) hydroxy, provided that the hydroxy-group is not linked to a carbon atom adjacent to a ring nitrogen atom, and

(e) hydroxymethyl;

R10each independently selected from the following:

(a) hydrogen,

(b) hydroxy, C2-4-alkyl,

(c) C1-3-alkoxy-C2-4-alkyl,

(d) C1-4-alkyl

(e) cyclopropyl and

(f) cyclobutyl;

R11selected from the following:

(a)- (CH2CN

(b) benzyl;

R12each independently selected from the following:

(a) hydrogen,

(b) C1-2-alkyl and

(c) hydroxy-C1-2-alkyl.

In addition, preferably, when in the formula (I):

represents a double bond;

R0represents a group selected from the following:

(a) hydrogen,

(b) methyl, and

(c) hydroxymethyl;

R1represents a group selected from the following:

(a) aryl, and

(b) heteroaryl;

where any heteroaryl or aryl residue, optionally, independently substituted at one or several positions Deputy, selected from the following:

(a) halogen,

(b) methyl,

(c) Tr is vermeil,

(d) methoxy,

(e) tert-butyl and

(f) -CN;

R2represents a group selected from the following:

(a) hydrogen,

(b) fluorine,

(c) chlorine,

(d) bromine,

(e) hydroxy,

(f) methoxy,

(g) ethoxy,

(h) isopropoxy,

(i) -OCON(Me)2and

(j) -OR11;

R3represents a group selected from the following:

R4represents hydrogen;

R7selected from the following:

(a) hydrogen,

(b) methyl,

(c) n-propyl,

(d) isopropyl and

(e) 2-methoxyethyl;

R9selected from the following:

(a) hydrogen,

(b) methyl,

(c) -NH2provided that the group-NH2not linked to a carbon atom adjacent to a ring nitrogen atom,

(d) hydroxy, provided that the hydroxy-group is not linked to a carbon atom adjacent to a ring nitrogen atom, and

(e) hydroxymethyl;

R10each independently selected from the following:

(a) hydrogen,

(b) methyl,

(c) ethyl,

(d) isopropyl,

(e) 2-hydroxyethyl,

(f) 2-methoxyethyl

(g) cyclopropyl and

(h) cyclobutyl;

R11selected from the following:

(a)- (CH2CN,

(b) benzyl;

R12each independently selected from the following:

(a) hydrogen,

(b) methyl, and

(c) hydroxymethyl.

In a more preferred compounds of formula (I):

represents the t of a double bond;

R0represents a group selected from the following:

(a) hydrogen,

(b) methyl, and

(c) hydroxymethyl;

R1represents a group selected from the following:

(a) phenyl,

(b) pyridyl and

(c) 2-thienyl,

where any heteroaryl or aryl residue, optionally, independently substituted at one or several positions Deputy, selected from the following:

(a) chlorine,

(b) fluorine,

(c) methyl,

(d) trifluoromethyl,

(e) methoxy and

(f) -CN;

R2represents a group selected from the following:

(a) hydrogen,

(b) fluorine,

(c) hydroxy,

(d) methoxy,

(e) ethoxy,

(f) isopropoxy,

(g) -OCON(Me)2and

(h) -OR11;

R3represents a group selected from the following:

R4represents hydrogen;

R7selected from the following:

(a) hydrogen,

(b) methyl,

(c) n-propyl,

(d) isopropyl and

(e) 2-methoxyethyl;

R9selected from the following:

(a) hydrogen,

(b) methyl,

(c) -NH2provided that the group-NH2not linked to a carbon atom adjacent to a ring nitrogen atom,

(d) hydroxy, provided that the hydroxy-group is not linked to a carbon atom adjacent to a ring nitrogen atom, and

(e) hydroxymethyl;

R10each independently selected from the following:

a) hydrogen,

(b) methyl,

(c) ethyl,

(d) isopropyl,

(e) 2-hydroxyethyl,

(f) 2-methoxyethyl; and

R11selected from the following:

(a)- (CH2CN,

(b) benzyl;

R12each independently selected from the following:

(a) hydrogen,

(b) methyl, and

(c) hydroxymethyl.

Other preferred compounds of formula (I) are those in which R1selected from the group consisting of the following

(a) chloroimidazo[2,1-b][1,3]thiazolyl, preferably 6 chloroimidazo[2,1-b][1,3]thiazol-5-yl,

(b) 3,4-dihydro-2H-1,5-benzodioxepine, preferably 3,4-dihydro-2H-1,5-benzodioxepin-7-yl,

(c) 2,1,3-benzothiadiazole, preferably 2,1,3-benzothiadiazole-4-yl,

(d) trifloromethyl, preferably 4-trifloromethyl,

(e) methyl-1-benzothieno, preferably 5-methyl-1-benzothieno-2-yl,

(f) dimethyl-1H-imidazolyl, preferably 1,2-dimethyl-1H-imidazol-4-yl,

(g) chinoline, preferably quinoline-8-yl,

(h) [methyl(trifluoromethyl)-1H-pyrazolyl]thienyl, preferably 5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-thienyl,

(i) 1-naphthyl,

(j) 2-naphthyl, and

(k) methyl; and each of R0and R2-R12independently from each other, can have the values defined above or below in this application.

Also preferred are the compounds of formula (I), where:

R3represents a group selected from the following:

where z, R4, R9and R10have the meanings given for formula (I).

Also preferred are the compounds of formula (I), where

R3represents a group selected from the following:

R4represents hydrogen or methyl;

R9represents hydrogen,

R10each independently selected from the following:

(a) hydrogen and

(b) methyl.

Preferably, R3representsin the compounds of formula (I), R4represents hydrogen or methyl; and

R10each independently selected from the following:

(a) hydrogen and

(b) methyl.

One preferred subclass of the compounds represented by the compounds of formula (Ib):

where:

R0represents a group selected from the following:

(a) hydrogen,

(b) methyl, and

(c) hydroxymethyl;

R1represents a group selected from the following:

(a) phenyl,

(b) 2-naphthyl,

(c) 2-thienyl and

(d) 6 chloroimidazo[2,1-b][1,3]thiazol-5-yl,

where any heteroaryl or aryl residue, optionally, independently substituted at one or several positions Deputy, selected from the following:

(a) chlorine,

(b) fluorine,

(c) bromine,

(d) methyl,

(e) trifluoromethyl,

(f) methoxy and

(g) -CN;

2represents a group selected from the following:

(a) hydrogen,

(b) fluorine,

(c) hydroxy,

(d) methoxy,

(e) ethoxy,

(f) isopropoxy,

(g) -OCON(Me)2and

(h) -OR11.

In another aspect, the present invention relates to compounds of formula (I), where:

represents a simple bond;

R1represents a group selected from the following:

(a) phenyl,

(b) pyridyl and

(c) 2-thienyl,

where any heteroaryl or aryl residue, optionally, independently substituted at one or several positions Deputy, selected from the following:

(a) chlorine,

(b) fluorine,

(c) methyl,

(d) trifluoromethyl,

(e) methoxy, and

(f) -CN;

R2represents a group selected from the following:

(a) hydrogen,

(b) fluorine,

(c) hydroxy,

(d) methoxy,

(e) ethoxy,

(f) isopropoxy,

(g) -OCON(Me)2and

(h) -OR11; and

R11selected from the following:

(a)- (CH2CN and

(b) benzyl.

Preferred compounds include:

1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,

4-(1,4-Diazepan-1-ylmethyl)-1-(phenylsulfonyl)-1H-indole,

1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}pyrrolidin-3-amine,

1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}pyrrolidin-3-amine,

1-[(4-Were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole,

1-[(4-Were)su is hanil]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole,

4-(1,4-Diazepan-1-ylmethyl)-1-[(4-were)sulfonyl]-1H-indole,

4-[(4-Methyl-1,4-diazepan-1-yl)methyl]-1-[(4-were)sulfonyl]-1H-indole,

1-[(4-Were)sulfonyl]-4-[(4-methylpiperazin-1-yl)methyl]-1H-indole,

4-[(4-Isopropylpiperazine-1-yl)methyl]-1-[(4-were)sulfonyl]-1H-indole,

1-[(4-Were)sulfonyl]-4-[(4-propylpiperazine-1-yl)methyl]-1H-indole,

1-[(4-Were)sulfonyl]-4-(pyrrolidin-1-ylmethyl)-1H-indole,

1-[(2-Methoxy-5-were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole,

1-[(2-Methoxy-5-were)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole,

N-({1-[(2-Methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)piperidine-4-amine,

1-Isopropyl-N-({1-[(2-methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)piperidine-4-amine,

1-[(2-Methoxy-5-were)sulfonyl]-4-[(2-methylpyrrolidine-1-yl)methyl]-1H-indole,

1-[(2-Methoxy-5-were)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]indoline,

1-[(2-Methoxy-5-were)sulfonyl]-4-[(4-methylpiperazin-1-yl)methyl]indoline,

1-[(2-Methoxy-5-were)sulfonyl]-4-(pyrrolidin-1-ylmethyl)indolin,

({1-[(2-Methoxy-5-were)sulfonyl]-2,3-dihydro-1H-indol-4-yl}methyl)dimethylamine,

1-[(4-Forfinal)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole,

4-(1,4-Diazepan-1-ylmethyl)-1-[(4-forfinal)sulfonyl]-1H-indole,

1-[(4-Forfinal)sulfonyl]-4-(pyrrolidin-1-ylmethyl)-1H-indole,

({1-[(4-Forfinal)Sul is of IMT]-1H-indol-4-yl}methyl)dimethylamine,

1-[(4-Forfinal)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole,

1-[(2-Were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole,

1-[(2-Were)sulfonyl]-4-[(4-methylpiperazin-1-yl)methyl]-1H-indole,

1-({1-[(2-Were)sulfonyl]-1H-indol-4-yl}methyl)pyrrolidin-3-ol,

1-[(2-Were)sulfonyl]-4-(pyrrolidin-1-ylmethyl)-1H-indole,

2-[Methyl({1-[(2-were)sulfonyl]-1H-indol-4-yl}methyl)amino]ethanol,

N,N-Dimethyl-1-{1-[(2-were)sulfonyl]-1H-indol-4-yl}methanamine,

4-(Piperazine-1-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl|-1H-indole,

((2R)-1-[(1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]pyrrolidin-2-yl}methanol,

4-(Pyrrolidin-1-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole,

2-{Methyl[(1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]amino}ethanol

N,N-Dimethyl-1-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methanamine,

4-(Piperazine-1-ylmethyl)-1-(2-thienylmethyl)-1H-indole,

N-Ethyl-N-{[1-(2-thienylmethyl)-1H-indol-4-yl]methyl}ethanamine,

4-(Pyrrolidin-1-ylmethyl)-1-(2-thienylmethyl)-1H-indole,

4-[(4-Propylpiperazine-1-yl)methyl]-1-(2-thienylmethyl)-1H-indole,

N,N-Dimethyl-1-[1-(2-thienylmethyl)-1H-indol-4-yl]methanamine,

4-(Piperazine-1-ylmethyl)-1-(pyridine-3-ylsulphonyl)-1H-indole,

N,N-Dimethyl-1-[1-(pyridine-3-ylsulphonyl)-1H-indol-4-yl]methanamine,

1-(Pyridine-3-ylsulphonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,

1(Phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,

N,N-Dimethyl-1-[1-(phenylsulfonyl)-1H-indol-4-yl]methanamine,

3-Methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,

3-Methyl-4-[(4-methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole,

3-Methyl-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,

N,N-Dimethyl-1-[3-methyl-1-(phenylsulfonyl)-1H-indol-4-yl]methanamine,

6-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,

{[6-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine,

6-Methoxy-4-{[(3R)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole,

6-Methoxy-4-{[(3S)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole,

6-Methoxy-4-[(4-methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole,

4-(1,4-Diazepan-1-ylmethyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole,

6-Methoxy-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,

2-[{[6-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}(methyl)amino]ethanol,

6-Fluoro-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,

4-(1,4-Diazepan-1-ylmethyl)-6-fluoro-1-(phenylsulfonyl)-1H-indole,

6-Fluoro-4-{[(3S)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole,

6-Fluoro-4-{[(3R)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole,

6-Fluoro-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,

2-[{[6-Fluoro-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}(methyl)amino]ethanol,

{[6-Fluoro-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine,

6-Fluoro-4-[(methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole,

1-(Phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indol-6-yl dimethylcarbamate,

4-(1,4-Diazepan-1-ylmethyl)-1-(phenylsulfonyl)-1H-indol-6-ol,

1-[(4-Forfinal)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole,

6-Methoxy-4-(piperazine-1-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole,

1-[(2-Chlorophenyl)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole,

1-[(3-Chloro-2-were)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole,

1-[(2,5-Acid)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole,

2-{[6-Methoxy-4-(piperazine-1-ylmethyl)-1H-indol-1-yl]sulfonyl}benzonitrile,

({1-[(4-Forfinal)sulfonyl]-1H-indol-4-yl}methyl)amine,

N-({1-[(4-Forfinal)sulfonyl]-1H-indol-4-yl}methyl)ethanamine,

7-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,

2-Methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,

Methyl 4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-2-carboxylate,

(4-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-2-yl)methanol,

(2-Methoxyethyl){[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}amine,

N-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}propan-2-amine,

4-{[4-(2-Methoxyethyl)piperazine-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole,

((2R)-1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}pyrrolidin-2-yl)methanol,

4-(Azetidin-1-ylmethyl)-1-(phenylsulfonyl)-1H-indole,

Ethyl 5-methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ileti is)-1H-indole-2-carboxylate,

5-Methoxy-N-methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole-2-carboxamide,

N-Ethyl-5-methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole-2-carboxamide,

5-Ethoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-N-(2-thienylmethyl)-1H-indole-2-carboxamide,

4-(Azetidin-1-ylmethyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole,

1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indol-5-ol,

1-(Phenylsulfonyl)-4-piperazine-2-yl-1H-indole,

4-(1,4-Dimethylpiperazine-2-yl)-1-(phenylsulfonyl)-1H-indole,

[7-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]piperazine-1-yl)acetonitrile,

4-(Azetidin-1-ylmethyl)-7-methoxy-1-(phenylsulfonyl)-1H-indole,

{[1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indol-5-yl]oxy}acetonitrile,

5-Isopropoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,

5-(Benzyloxy)-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,

4-{[(2-Hydroxyethyl)(methyl)amino]methyl}-1-(phenylsulfonyl)-1H-indol-5-ol,

4-[(3-Hydroxypyrrolidine-1-yl)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol,

[1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-6-(trifluoromethyl)-1H-indol-2-yl]methanol,

5-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,

5-Ethoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,

1-Phenyl-N-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methanamine,

N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}cyclopropanation,

{[5-Methoxy-1-(f is ylsulphonyl)-1H-indol-4-yl]methyl}dimethylamine,

N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}CYCLOBUTANE,

N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}-N-methylcyclobutane,

1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}azetidin-3-ol,

4-(Azetidin-1-ylmethyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole,

4-{[4-(Azetidin-1-ylmethyl)-1H-indol-1-yl]sulfonyl}benzonitrile,

2-((2S)-1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}azetidin-2-yl)propan-2-ol,

4-(Azetidin-1-ylmethyl)-2-methyl-1-(phenylsulfonyl)-1H-indole,

4-(Azetidin-1-ylmethyl)-1-[(2-chlorophenyl)sulfonyl]-1H-indole,

4-(Azetidin-1-ylmethyl)-1-[(5-chloro-2-thienyl)sulfonyl]-1H-indole,

4-(Azetidin-1-ylmethyl)-1-(2-naphthylmethyl)-1H-indole,

4-(Azetidin-1-ylmethyl)-1-[(2-methoxy-5-were)sulfonyl]-1H-indole,

4-(Azetidin-1-ylmethyl)-1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-indole,

4-(Azetidin-1-ylmethyl)-1-[(4-tert-butylphenyl)sulfonyl]-1H-indole,

4-(Azetidin-1-ylmethyl)-1-[(2,6-differenl)sulfonyl]-1H-indole,

4-(Azetidin-1-ylmethyl)-1-{[2-(trifluoromethyl)phenyl]-sulfonyl}-1H-indole,

3-{[4-(Azetidin-1-ylmethyl)-1H-indol-1-yl]sulfonyl}-benzonitrile,

4-(Azetidin-1-ylmethyl)-1-{[4-bromo-2-(trifluoromethyl)phenyl]-sulfonyl}-1H-indole,

4-(Azetidin-1-ylmethyl)-1-(2-thienylmethyl)-1H-indole,

4-(Azetidin-1-ylmethyl)-1-[(2,5-differenl)sulfonyl]-1H-indole,

[(5-Methoxy-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]dimethylamine,

4-(AZ is tidin-1-ylmethyl)-7-(benzyloxy)-1-(methylsulphonyl)-1H-indole,

({1-[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-5-methoxy-1H-indol-4-yl}methyl)dimethylamine,

4-[(Dimethylamino)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol,

{[5-Ethoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine,

({5-Ethoxy-1-[(2-methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine,

{[5-Ethoxy-1-(1-naphthylmethyl)-1H-indol-4-yl]methyl}dimethylamine,

{[5-Ethoxy-1-(2-naphthylmethyl)-1H-indol-4-yl]methyl}dimethylamine,

({1-[(2-Chlorophenyl)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine,

({1-[(3-Chloro-2-were)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine,

({5-Methoxy-1-[(2-methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine,

({1-[(2,3-Dichlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}methyl)dimethylamine,

{[5-Ethoxy-1-(quinoline-8-ylsulphonyl)-1H-indol-4-yl]methyl}dimethylamine,

{[5-Ethoxy-1-({5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-thienyl}sulfonyl)-1H-indol-4-yl]methyl}dimethylamine,

({1-[(2,5-Dichlorophenyl)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine,

({5-Ethoxy-1-[(2,4,6-trichlorophenyl)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine,

1-[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N-methylmethanamine,

({1-[(2-Methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)methylamine,

4-[(Dimethylamino)methyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol,

1-[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N,N-dimethylethanamine,

p> 6-Fluoro-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indol-5-ol,

6-Fluoro-5-methoxy-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,

4-(Azetidin-1-ylmethyl)-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol,

4-(Azetidin-1-ylmethyl)-6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indole,

4-{[Ethyl(methyl)amino]methyl}-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol,

N-{[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}-N-methylethanamine,

6-Fluoro-4-[(methylamino)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol,

{[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylamine,

1-{5-Methoxy-1-[(4-methoxyphenyl)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine,

1-{1-[(3-Chlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,

1-{1-[(2,5-Differenl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,

1-(1-{[4-Fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine,

1-[5-Methoxy-1-(quinoline-8-ylsulphonyl)-1H-indol-4-yl]-N,N-dimethylethanamine,

1-{1-[(2-Chlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,

1-{1-[(2-Chloro-6-were)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,

1-{1-[(3-Chloro-4-forfinal)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,

1-{5-Methoxy-1-[(2-were)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine,

2-({4-[(Dimethylamino)methyl]-5-methoxy-1H-indol-1-yl}sulfonyl)benzonitrile,

1-{1-[(2,6-Dif is arvanil)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,

1-{1-[(1,2-Dimethyl-1H-imidazol-4-yl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,

1-{5-Methoxy-1-[(5-methyl-1-benzothieno-2-yl)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine,

1-{5-Methoxy-1-[(2-methoxy-4-were)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine,

1-{1-[(2,4-Dichlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,

1-{1-[(5-Bromo-2-methoxyphenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,

1-[1-(2,1,3-Benzothiadiazole-4-ylsulphonyl)-5-methoxy-1H-indol-4-yl]-N,N-dimethylethanamine,

1-[1-(3,4-Dihydro-2H-1,5-benzodioxepin-7-ylsulphonyl)-5-methoxy-1H-indol-4-yl]-N,N-dimethylethanamine,

1-{1-[(2,5-Acid)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,

1-(5-Methoxy-1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)-N,N-dimethylethanamine,

1-(5-Methoxy-1-{[4-(triptoreline)phenyl]sulfonyl}-1H-indol-4-yl)-N,N-dimethylethanamine,

3-({4-[(Dimethylamino)methyl]-5-methoxy-1H-indol-1-yl}sulfonyl)benzonitrile,

1-[5-Methoxy-1-(pyridine-3-ylsulphonyl)-1H-indol-4-yl]-N,N-dimethylethanamine,

Methyl {1-[1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine,

{1-[1-(Phenylsulfonyl)-1H-indol-4-yl]ethyl}amine,

Dimethyl {1-[1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine,

4-(Azetidin-1-ylmethyl)-2,3-dichloro-5-methoxy-1-(phenylsulfonyl)-1H-indole,

{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}amine,

4-[(dimethylamino)methyl]-6-methoxy-1-(phenylsulfonyl)1H-indol-5-ol,

1-[5,6-dimethoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N,N-dimethylethanamine,

{[3-chloro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine,

{[3-chloro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylamine,

{[5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}amine,

6-fluoro-4-[1-(methylamino)ethyl]-1-(phenylsulfonyl)-1H-indol-5-ol,

4-[1-(dimethylamino)ethyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol,

{1-[6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}methylamine and

{1-[6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}dimethylamine

and their pharmaceutically acceptable salts.

In another aspect, the present invention relates to a method for obtaining compounds of formula (I) according to the present invention, which includes:

a) interaction of 4-methyl-1-R1-substituted sulfonyl-1H-indole with N-bromosuccinimide;

b) interaction of the product from step a) with groups selected from the following:

where the group R1, R7, R9, R10, R12and X have the meanings defined for formula (I)or a salt or protected derivative;

and, optional, then the formation of pharmaceutically acceptable salts of the compounds of formula (I).

In the following aspect, the present invention relates to a method for obtaining compounds of formula (I), whereis mabogoane communication, which includes:

aa) the interaction of 4-bromoindole derivative of the formula (III)

where m, n, R0and R2have the meanings defined above, with sulphonylchloride formula R1SO2Cl, where R1has the values defined above, to obtain compounds of formula (IV)

where R0, R1and R2have the meanings defined above;

bb) the interaction of the compounds of formula (IV) with tributyl(vinyl)stannane in the presence of a palladium complex such as bis(triphenylphosphine)palladium(II) diacetate[Pd(PPh3)2OAc2], as a catalyst, to obtain the compounds of formula (V)

where m, n, R0, R1and R2have the meanings defined above;

cc) the interaction of the compounds of formula (V) osmium tetroxide (OsO4and periodates sodium obtaining aldehyde derivative of formula (VI)

where m, n, R0, R1and R2have the meanings defined above;

dd) the interaction of the compounds of formula (VI) with a suitable amine, selected from the following:

where X represents NR6and R6, R7, R9, R10and R12have the meanings defined above, or its salt or protected product is effective, in the presence of a suitable reducing agent such as NaBH4, NaBH3CN or triacetoxyborohydride sodium [NaB(OAc)3)H], to obtain the compounds of formula (I), whererepresents a double bond; and, optionally, then the formation of pharmaceutically acceptable salts of the compounds of formula (I).

In one aspect, the present invention relates to a method for obtaining compounds of formula (I), whererepresents a simple bond, which includes:

aaa) the interaction of the compounds of formula (IV) with a reducing agent such as NaBH3CN, triperoxonane acid (TFA) to obtain the compounds of formula (VII)

where R0, R1and R2have the meanings defined above;

bbb) the interaction of the compounds of formula (VII) in accordance with the stages of the bb-dd), described above, to obtain compounds of formula (I), whererepresents a simple bond; and, optionally, then the formation of pharmaceutically acceptable salts of the compounds of formula (I).

The reaction used in the methods described above can be carried out using traditional methods and reagents known to specialists in this field and/or illustrated in this application. The necessary starting materials for obtaining the connection of the clusters described in this application or known from the prior art or can be obtained analogously to getting known compounds, and/or can be obtained, as described in this application.

In the reaction stage (aa) reaction can be performed in the presence of a base such as a hydroxide of an alkali metal, such as, for example, an aqueous solution of sodium hydroxide, and a catalyst phase transfer, such as tetrabutylammonium hydrosulfate, in a solvent such as dichloromethane. See, for example: Liebigs Ann. Chem. 1986, 2065-2080.

In the reaction stage bb) palladium-catalyzed reaction of cross-linking (linking method Stille) can be performed in a solvent such as toluene or acetonitrile. The reaction, optionally, can be performed under microwave exposure.

In the reaction stage cc) oxidative cleavage of the alkene to the aldehyde functional group can be accomplished using conditions described in Org. Lett. 2004. 6, 3217-3219. Alkene is treated with osmium tetroxide/periodates sodium in a mixture of polar solvents, such as dioxane and water, in the presence of a base, such as 2,6-lutidine.

In the reaction stage dd) the reaction may be carried out using standard methods for reductive amination. See, for example: J Med. Chem. 2005, 48, 1745-1758 (connection 68, icanoe in this document) and J Org. Chem. 1996. 61, 3849-3862. In addition, the reaction, optionally, can be performed under microwave exposure.

The reaction stage aaa) can be performed as described, for example, in Tetrahedron Lett. 1989, 30, 6833-6836.

When interacting amine corresponding to the group selected from the

at the stage b) or (dd), does not contain an additional nitrogen atom of a primary or secondary amine, a suitable protective group such as tert-butoxycarbonyl (t-BOC), may be introduced prior to the interaction, in order to prevent unwanted interactions such azocam primary or secondary amine. Examples of N-protected amines containing more than one reactive nitrogen atom include N-tert-butoxycarbonylmethyl and tert-butyl 4-aminopiperidine-1-carboxylate. Specified protective group can be split when it is no longer necessary to obtain the compounds of formula (I). The reaction conditions for the deletion of such protective groups depend on the choice and characteristics of this group. So, for example, tert-butoxycarbonyl can be removed by treatment with a suitable acid. Methods of use of protective groups (insertion and removal of protection) are known from the prior art and described, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons (1999).

Receiving the amount of compound of formula (I) can be converted into another compound of formula (I) ways, well known from the prior art. For example, the compound of formula (I), where R2selected from C1-4-alkoxy can be converted into another compound of formula (I), where R represents hydroxy, standard, known from the literature methods for the cleavage of ethers. The reaction conditions may be such as described in Example 70.

Another example involves the conversion of compounds of formula (I), where R2selected from hydroxy, into another compound of formula (I), where R2selected from-OCONR5R5where R5has the values defined above, by reacting with a suitable carbamylcholine derived formulas ClCONR5R5. The reaction conditions may be such as described in Example 69.

Moreover, the compound of formula (I), where R1represents an optionally substituted aryl, can be converted into another compound of formula (I), where R1represents another optionally substituted aryl. The reaction conditions may be such as described in Intermediate connection 40 and Example 73.

The compounds of formula (III) are commercially available, can be obtained using the procedures described in this application, or similar methods, or in accordance with known methods.

In another aspect, the present invention relative to the Xia to the use of compounds of Formula (I) and Formula (Ib), described in this application in therapy, for example, for use in treatment or prevention associated with 5-HT6receptor disorders or to achieve reduction of body weight and/or weight gain.

In the following aspect, the present invention relates to a pharmaceutical composition which comprises a compound as defined above as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier, for example, for use in the treatment or prevention associated with 5-HT6receptor disorders or to achieve reduction of body weight and/or weight gain.

In one aspect, the present invention relates to a method of treatment of a human or animal suffering from associated with 5-HT6receptor disorders or to achieve reduction of body weight and/or weight gain in humans or animal. The method may include the introduction of a subject (e.g. human or animal, dog, cat, horse, cow)in need, an effective amount of one or more compounds of any of Formula (I) or Formula (Ib)described in this application, their salts or compositions containing such compounds or salts.

In another aspect, the present invention relates to a method of treatment of a human or animal suffering from associated with 5HT 6receptor disorders, which includes an introduction to a subject (e.g. human or animal, dog, cat, horse, cow)in need, an effective amount of one or more compounds of any of Formula (I) or Formula (Ib)described in this application, their salts or compositions containing such compounds or salts.

In the following aspect, the present invention relates to a method of reducing body weight and/or reduce weight gain in humans or animals which comprises the administration to a subject (e.g. human or animal, dog, cat, horse, cow)in need, an effective amount of one or more compounds of any of Formula (I) or Formula (Ib)described in this application, their salts or compositions containing such compounds or salts. The subject can be a suffering from overweight or obesity of the subject. In some embodiments, embodiments of the invention, the subject can have a body mass index (BMI) from about 18.5 kg/m2to about 39.9 kg/m2(for example, from about 18.5 kg/m2to about 24,9 kg/m2; from about 25.0 kg/m2to about 29,9 kg/m2; from about 30.0 kg/m2to about to 34.9 kg/m2; from about 35,0 kg/m2to about 39.9 kg/m2). In some embodiments, embodiments of the invention, the subject may have a BMI equal to or greater than Cenacolo 40 kg/m 2. In some embodiments, embodiments of the invention, the subject can have a waist circumference equal to or greater than about 35 inches (88.9 cm) (for example, waist circumference equal to or greater than about 40 inches (101.6 cm)). In some embodiments, embodiments of the invention, the subject may be a subject female with waist circumference equal to or greater than about 35 inches (88.9 cm). In some embodiments, embodiments of the invention, the subject may be a subject is a male having a waist circumference equal to or greater than about 40 inches (101.6 cm). In some embodiments, embodiments of the invention, the subject can have any combination of BMI and waist circumference, as described in this application (for example, and without limitation, a subject can have a BMI of from about 18.5 kg/m2to about 24,9 kg/m2and waist circumference equal to or greater than about 35 inches (88.9 cm) (for example, waist circumference equal to or greater than about 40 inches (101.6 cm)). Measuring BMI and waist circumference can be implemented in accordance with the methods described, for example, in Aronne, L.J. Obesity Research 2002, 10, 105 S (Arrone). Identification with overweight or obese subjects can also be implemented using other indicators, such as described in Arrone.

In one aspect, the present invention relates to a method of treating type II diabetes in cheloveka animal, in need thereof which comprises the administration to a subject (e.g. human or animal, dog, cat, horse, cow)in need, an effective amount of one or more compounds of any of Formula (I) or Formula (Ib)described in this application, their salts or compositions containing such compounds or salts.

In another aspect, the present invention relates to a method of treatment of disorders of the Central nervous system of a human or animal in need thereof which comprises the administration to a subject (e.g. human or animal, dog, cat, horse, cow)in need, an effective amount of one or more compounds of any of Formula (I) or Formula (Ib)described in this application, their salts or compositions containing such compounds or salts. Disorder of the Central nervous system may represent, for example, anxiety, depression, panic attacks, memory disorders, disorders of cognition, epilepsy, sleep disorders, migraine, anorexia, bulimia, disorders associated with overeating, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, horey's chorea, schizophrenia, disorder attention deficit/hyperactivity disorder or syndrome medicines when zloupotrebljeni and them.

In the following aspect, the present invention relates to a method of treating pain in a human or animal in need thereof which comprises the administration to a subject (e.g. human or animal, dog, cat, horse, cow)in need, an effective amount of one or more compounds of any of Formula (I) or Formula (Ib)described in this application, their salts or compositions containing such compounds or salts.

In one aspect, the present invention relates to a method of treatment of neurodegenerative disorders in human or animal in need thereof which comprises the administration to a subject (e.g. human or animal, dog, cat, horse, cow)in need, an effective amount of one or more compounds of any of Formula (I) or Formula (Ib)described in this application, their salts or compositions containing such compounds or salts. Neurodegenerative disorder may represent, for example, Alzheimer's disease, Parkinson's disease or horey Huntington.

In another aspect, the present invention relates to a method of improving the appearance of a mammal (in need thereof, which comprises oral administration of a given mammal one or more compounds of any of Formula (I) or Formula (Ib)described in this the soup of the application their salts or compositions containing such compounds or salts, in a dose effective to reduce appetite. The method may include repeated administration of doses up to achieve a cosmetically favorable loss of body weight. The methods described in this application can also include a stage of determining that the subject in need of treatment associated with 5-HT6receptor disorder, or what is necessary to achieve weight reduction and/or weight gain. Identification of a subject in need of such treatment depends on an assessment of the subject or specialist in the field of health and can be subjective (e.g. opinion) or objective (for example, measurement by means of test or diagnostic method).

The next object of the present invention is a method of preventing associated with 5-HT6receptor disorders or achieve reduction of body weight and/or weight gain, which includes an introduction to the subject in need of such treatment, an effective amount of the compounds specified above.

In one aspect, the present invention relates to a method of modulating the activity of 5-HT6the receptor. Such methods may include contacting a 5-HT6receptor with one or more compounds of any of Formula (I) or Formula (Ib)described in this application, their salts Il the compositions, containing such compounds or salts (for example, the introduction to the subject in need of such treatment, an effective amount of the compounds specified above).

In the following aspect, the present invention relates to the use of compounds of any of Formula (I) or Formula (Ib)described in this application, to obtain drugs for use for the prevention or treatment associated with 5-HT6receptor disorders or to achieve weight reduction and/or weight gain.

Compounds listed above may be agonists, partial agonists or antagonists of 5-HT6the receptor. Preferably, the compounds act as partial agonists or antagonists at 5-HT6the receptor. More preferably, the compounds act as antagonists at 5-HT6the receptor. Examples associated with 5-HT6receptor disorders include obesity; type II diabetes; disorders of the Central nervous system such as anxiety, depression, panic attacks, memory disorders, disorders of cognition, epilepsy, sleep disorders, migraine, anorexia, bulimia, disorders associated with overeating, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, disorder deficit attention to the project/hyperactivity disorder (ADHD), withdrawal of drugs with abuse (e.g., dependence on cocaine, amphetamine and/or nicotine), neurodegenerative diseases characterized by impaired growth of nerve cells, and pain.

Compounds and compositions are useful for treating diseases or to achieve reduction of body weight and/or weight gain. Such diseases include obesity; type II diabetes; disorders of the Central nervous system such as anxiety, depression, panic attacks, memory disorders, disorders of cognition, epilepsy, sleep disorders, migraine, anorexia, bulimia, disorders associated with overeating, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, disorder attention deficit/hyperactivity disorder (ADHD), withdrawal of drugs with abuse (e.g., dependence on cocaine, amphetamine and/or nicotine), neurodegenerative disease characterized by the violation of growth of nerve cells, and pain.

In one aspect, the present invention relates to the cosmetic use of compounds of formula (I)described in the present application, for example, to cause weight loss and cosmetic compositions containing these compounds as the active ingredient, in combination with a cosmetically acceptable diluent or carrier. The invention also provides a non-therapeutic method for improving the appearance of healthy, non-obese mammals, including humans, which comprises oral administration of a given mammal the compounds of formula I, described in this application, or its pharmaceutically effective salts, at a dose effective to reduce appetite, (and the repetition of the specified injection until cosmetically favorable weight loss or weight gain).

Definition

The following definitions are applicable throughout the text description and the attached claims.

If not approved, or not specified otherwise, the term "C1-6-alkyl" means a linear or branched alkyl group containing from 1 to 6 carbon atoms. Examples of the specified C1-6the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and also pentyl and hexyl from linear and branched chain. As a group, which is part of the range covered "C1-6-alkyl"includes all subgroups within these limits, such as C1-5-alkyl, C1-4-alkyl, C1-3-alkyl, C1-2-alkyl, C2-6-alkyl, C2-5-alkyl, C2-4-alkyl, C2-3-alkyl, C3-6-alkyl, C-5 -alkyl, etc. in a Similar way, "aryl-C1-6-alkyl" means C1-6is an alkyl group substituted by one or more aryl groups. Unless otherwise stated, "fluorine-C1-6-alkyl" means C1-6is an alkyl group substituted by one or more fluorine atoms. Examples of the specified fluorine-C1-6-alkyl include 2-foretel, vermeil, trifluoromethyl and 2,2,2-triptorelin.

If not approved, or not specified otherwise, the term "hydroxy-C1-4-alkyl" means a linear or branched alkyl group in which a hydrogen atom is substituted by an OH group. Examples of the specified hydroxy-C1-4-alkyl include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 2-hydroxy-2-methylpropyl.

If not approved, or not specified otherwise, the term "C1-6-alkoxy" means a linear or branched alkoxygroup containing from 1 to 6 carbon atoms. Examples of the specified C1-6-alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and pentox, hexose with linear and branched chain. As a group, which is part of the range covered "C1-6-alkoxy" provide for all subgroups within these limits, such as C1-5-alkoxy, C1-4-alkoxy, C1-3-alkoxy, C1-2-alkoxy, C2-6-alkoxy, C2-5-alkoxy, C2-4-alcox is, C2-3-alkoxy, C3-6-alkoxy, C4-5-alkoxy, etc.

If not approved, or not specified, the fluorine-C1-6-alkoxy" means C1-6-alkoxygroup substituted by one or more fluorine atoms. Examples of the specified fluorine-C1-6-alkoxy include triptoreline, deformedarse, monitorless, 2-floratone, 2,2,2-triptoreline, and 1,1,2,2-tetrafluoroethoxy.

If not approved, or not specified otherwise, the term "C1-4-alkoxy-C2-4-alkyl" means linear or branched alkoxygroup containing from 1 to 4 carbon atoms associated with the alkyl group containing from 1 to 4 carbon atoms. Examples of the specified C1-4-alkoxy-C2-4-alkyl include methoxymethyl, ethoxymethyl, isopropoxide, n-butoxymethyl and tert-butoxymethyl. As a group, which is part of the range covered "C1-4-alkoxy-C2-4-alkyl"includes all subgroups within these limits, such as C1-3-alkoxy-C2-4-alkyl, C1-4-alkoxy-C2-3-alkyl, C1-2-alkoxy-C2-3-alkyl, C2-4-alkoxy-C2-4-alkyl, C2-3-alkoxy-C2-4-alkyl, C2-4-alkoxy-C2-3-alkyl, etc.

If not approved, or not specified otherwise, the term "C2-6alkenyl" means a linear or branched alkenylphenol group containing from 2 to 6 carbon atoms. Examples specify the CSO C 2-6-alkenyl include vinyl, allyl, 2,3-dimethylallyl, 1-butenyl, 1-pentenyl and 1-hexenyl. As a group, which is part of the range covered "C2-6-alkenyl", provide for all subgroups within these limits, such as C2-5alkenyl, C2-4alkenyl, C2-3alkenyl, C3-6alkenyl, C4-5alkenyl etc. in a Similar way, "aryl-C2-6alkenyl" means C2-6-alkenylphenol group, substituted by one or more aryl groups. Examples of the aforementioned aryl-C2-6-alkenyl include styryl and cinnamyl.

If not approved, or not specified otherwise, the term "fluorine-C2-6alkenyl" means a linear or branched alkenylphenol group containing from 2 to 6 carbon atoms, substituted by one or more fluorine atoms. Examples of the specified fluorine-C2-6-alkenyl include 1-torvinen, 1,2-defermined, triforine, and 2-forproper.

If not approved, or not specified otherwise, the term "C3-4-quinil" means a linear or branched alkylamino group containing from 3 to 4 carbon atoms. Examples of the specified C3-4-quinil include 1-PROPYNYL, 2-PROPYNYL, 1-butynyl and 2-butynyl.

If not approved, or not specified otherwise, the term “C3-7-cycloalkyl” means a cyclic alkyl group with a ring size of 3 to 7 carbon atoms. Examples of the specified cycloalkyl is and include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, and cycloheptyl. As a group, which is part of the range covered "C3-7-cycloalkyl", provide for all subgroups within these limits, such as C3-6-cycloalkyl, C3-5-cycloalkyl, C3-4-cycloalkyl, C4-7-cycloalkyl, C4-6-cycloalkyl, C4-5-cycloalkyl, C5-7-cycloalkyl, C6-7-cycloalkyl etc.

If not approved, or not specified otherwise, the term "aryl" refers to a hydrocarbon ring system consisting of one, two or three rings containing at least one aromatic ring and containing from 6-14 carbon atoms. Examples of arilou are phenyl, pentalene, indenyl, indanyl, 1,2,3,4-tetrahydronaphthyl, 1-naphthyl, 2-naphthyl, fluorenyl and antril. Aryl ring optionally can be substituted. Similarly, phenoxy refers to a phenyl group linked to the oxygen atom.

The aryl group can be linked with the rest of the molecule through any available ring carbon atom, regardless of whether such a ring carbon in the aromatic ring or a partially saturated ring.

The term "heteroaryl" refers to mono - or bicyclic aromatic ring system, thus it is necessary that only one ring was aromatic, and the said heteroaryl g is the SCP may be associated with the rest of the molecule through a carbon atom or nitrogen in any ring, containing from 5 to 10 ring atoms (mono - or bicyclic), in which one or more ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium. Examples of such heteroaryl rings include follow, pyrrolidinyl, thienyl, oxazolidinyl, isoxazolyl, imidazolidinyl, thiazolidine, isothiazolinone, pyridinoline, pyrimidinyl, personilnya, imidazothiazole, romanello, chinazolinei, indolenine, isoindolyl, indolinyl, isoindolyl, indazolinone, pyrazolidine, pyridazinyl, hyalinella, athinodorou, benzofuranyl, dihydrobenzofuranyl, benzodioxolyl, benzodioxolyl, benzothiazoline, benzimidazolyl, benzothiazolyl, benzothiadiazole, benzotriazolyl group, imidazo[2,1-b][1,3]thiazolyl and 3,4-dihydro-2H-l,5-benzodioxepin. If bicyclic heteroaryl ring is substituted, it may be substituted at any ring.

If not approved, or not specified otherwise, the term "heterocyclic" refers to non-aromatic (i.e. partially or fully saturated) mono - or bicyclic ring system containing from 4 to 10 ring atoms with at least one heteroatom such as O, N or S and the remaining ring atoms are carbon atoms. Examples of heterocyclic gr the PP include piperidino, tetrahydropyranyloxy, tetrahydrofuranyl, sepanlou, azetidinone, pyrrolidinyloxy, morpholinyl, imidazolidinyl, thiomorpholine, pyranyloxy, dioxinlike and piperazinilnom group. When the sulfur atom present in the heterocyclic groups, it optionally may be in oxidized form (i.e. S=O or O=S=O).

If not approved, or not specified otherwise, the term "halogen" means fluorine, chlorine, bromine or iodine.

The term-S(O)eR8where e is 0, 1, 2 or 3 is set, illustrated by formulas (VIII)to(XI):

"Optional" or "optionally" means that the described event or circumstance may but not necessarily, take place, and that the description includes instances when such an event or circumstance occurs and instances in which it does not.

"Pharmaceutically acceptable" means useful for obtaining a pharmaceutical composition, which, basically, is a safe, non-toxic and not junk either biological or from any other point of view, and includes the value “useful for veterinary use, as well as for pharmaceutical applications to humans.”

"Treatment"as used in this application includes the prevention of a specified disorder or condition or blogchina or troubleshoot disorders, if it was installed.

"Effective amount" refers to the number of connections, which provides a therapeutic effect in the subject, which is treated. therapeutic effect may be objective (i.e. measurable with the help of some test or marker) or subjective (i.e., the subject gives evidence of its presence or feels this effect).

The term "Proletarskoye form" means a pharmacologically acceptable derivative such as ester or amide, while the body is the biotransformation of this derivative with the formation of the active drug substance. As a reference, see Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8th ed., Mc-Graw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13-15; and "The Organic Chemistry of Drug Design and Drug Action" by Richard B. Silverman. Chapter 8, p 352. (Academic Press, Inc. 1992. ISBN 0-12-643730-0).

In the text the following abbreviations are used:

CV denotes coefficient of variation

DCM means dichloromethane,

DMSO means dimethylsulfoxide,

EDTA means ethylenediaminetetraacetic acid,

EGTA means ethylenebis(oxyethylenenitrilo)tetraoxane acid,

ESI ionization means electrospray,

HEPES means 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid,

HPLC means high performance liquid chromatography,

'lah means sociallyengaged,

LSD means lysergic KIS the GTC, diethylamid,

MeCN means acetonitrile,

SPA scintillation means the approximate analysis,

TFU means triperoxonane acid,

THF means tetrahydrofuran,

UV means ultraviolet

aq. mean water

us. means rich

CT. or K.T. means room temperature

deg means degrees Celsius

MeOH means methanol

TLC means thin layer chromatography

EQ. means equivalents.

All possible isomeric forms (pure enantiomers, diastereomers, tautomers, racemic mixtures and unequal mixtures of two enantiomers) described for compounds included in the scope of the present invention. Such compounds can also prisutstvovati in the form of CIS - or TRANS-, E - or Z-isomers on double bond. There are all isomeric forms.

The compounds of formula (I) can be used as such or, if it is appropriate, in the form of their pharmacologically acceptable salts (acid or basic additive salts). It is assumed that pharmacologically acceptable additive salts referred to above include therapeutically active non-toxic form acidic - and basic-additive salts, which can form compounds. Compounds with ό properties, can be converted into their pharmaceutically acceptable acid additive salts of p and processing forms the Foundation of a suitable acid. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, modesty hydrogen, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyestra acid, lactic acid, peruvemba acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzolsulfonat acid, toluensulfonate acid, methanesulfonate acid, triperoxonane acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, n-aminosalicylic acid, pamula acid, benzoic acid, ascorbic acid and the like, examples of the basic additive salt forms include salts of sodium, potassium, calcium and salts with pharmaceutically acceptable amines such as ammonia, alkylamines followed, benzathine, and amino acids, such as arginine and lysine. The additive term salt as used in this application also includes a solvate, which can form compounds and their salts, such as, for example, hydrates, alcoholate, etc.

For clinical use, the compounds of the present invention can be formulated in pharmaceutical compositions for oral, rectal, parenteral or other methods introduced who I am. Pharmaceutical compositions are typically prepared by mixing the active substance or its pharmaceutically acceptable salts with conventional pharmaceutical excipients. Examples of excipients are water, gelatin, Arabic gum, lactose, microcrystalline cellulose, starch, matrikamantra, acid calcium phosphate, magnesium stearate, talc, colloidal silicon dioxide and the like, Such compositions can also contain other pharmacologically active agents and conventional additives such as stabilizers, wetting agents, emulsifiers, fragrances, buffers, etc. are Usually a number of active compounds is 0.1-95% by weight of the preparation, preferably 0.2 to 20%, based on the weight of the drug for parenteral administration and, more preferably 1-50%, the calculation of the mass of the drug for oral administration.

The dose and frequency of dosing of specific compounds vary depending on various factors, including the activity of the specific compound, the metabolic stability and length of action of this compound, the patient's age, body weight, General health, sex, diet, route and time of administration, rate of excretion, combination of drugs, the severity of the condition to be treated, and pale is the undergoing treatment. It is expected that useful compounds should have a beneficial effect when administered in the range from about 0.001 mg/kg/day to about 200 mg/kg/day (for example, from about 0.01 mg/kg/day to about 200 mg/kg/day, from about 0.1 mg/kg/day to about 200 mg/kg/day; from about 1 mg/kg/day to about 200 mg/kg/day; or from about 5 mg/kg/day to about 200 mg/kg/day; from about 0.001 mg/kg/day to about 100 mg/kg/day; from about 0.01 mg/kg/day to about 100 mg/kg/day, from about 0.1 mg/kg/day to about 100 mg/kg/day; from about 1 mg/kg/day to about 100 mg/kg/day; or from about 5 mg/kg/day to about 100 mg/kg/day; from about 0.001 mg/kg/day to about 50 mg/kg/day; from about 0.01 mg/kg/day to about 50 mg/kg/day, from about 0.1 mg/kg/day to about 50 mg/kg/day; from about 1 mg/kg/day to about 50 mg/kg/day; or from about 5 mg/kg/day to about 50 mg/kg/day). In some embodiments, embodiments of the invention, the daily dose may, for example, be in the range of from about 0.001 mg to about 100 mg per kilogram of body weight, with the introduction of a single dose or in several doses, for example, from about 0.01 mg to about 25 mg each. Typically, such a dose is administered orally, but may also be selected and parenteral administration.

The composition can then be obtained by known methods, such as granulation, extrusion, microencapsulation, coating using a spray, and so what. The composition can be obtained by conventional methods in the pharmaceutical form, which are tablets, capsules, granules, powders, syrups, suspensions, suppositories or the courthouse square for injection. Liquid compositions can be obtained by dissolution or suspension of the active substance in water or other suitable media. Tablets and granules may have a coating applied in the traditional way.

In the following aspect, the present invention relates to methods for producing compounds of any of formulas described in this application, including the interaction of any one or more compounds of the formulas described in this application, including any of the methods described in this application. The compounds of formula (I)shown above can be obtained traditional or equivalent methods.

The methods described above can be performed to obtain the compounds of the present invention in free base form or in the form of an acid additive salt. Pharmaceutically acceptable acid additive salt can be obtained by dissolving the free base in a suitable organic solvent and treatment of the acid solution, in accordance with conventional procedures to obtain an acid additive salts of ό compounds. Examples of forming a salt additive to the slot specified above.

The compounds of formula (I) may contain one or more chiral carbon atoms, and therefore they can be received in the form of optical isomers, e.g. in the form of a pure enantiomer or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. Separation of mixtures of optical isomers of obtaining pure enantiomers is well known in the prior art and, for example, this can be done by fractionated crystallization of the salt with an optically active (chiral) acids, or by chromatographic separation on chiral columns. Chemicals used in the synthesis methods described in this application, may include, for example, solvents, reagents, catalysts and reagents for the introduction and removal of protection. The methods described above may also additionally include stage, either before or after stages, specifically described in this application, for the introduction or removal of suitable protective groups to ensure that, as a result, the possibility of the synthesis of compounds.

In addition, the various stages of the synthesis can be performed in alternate sequence or order to obtain the desired compounds. Methods of synthesis for chemical transformations that can be used for the synthesis of related compounds known from the prior art and cluzaud, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser''s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995)and subsequent editions.

The necessary starting materials for preparing compounds of formula (I) are either known or can be obtained analogously to receive the known compounds.

Hereinafter the invention will be illustrated with the help of below does not limit the invention to the Examples. Below, specific examples should be considered as purely illustrative and in no way limiting the rest of this disclosure. It is believed that a person skilled in the art, without additional effort on the basis provided in this application descriptions will be able to use the present invention in its most full. All publications mentioned in this application, is incorporated into the present application by reference in its entirety.

Ways

Data1H nuclear magnetic resonance (NMR) and13C NMR were obtained using a spectrometer Bruker Advance DPX 400 when 400,1 and to 100.6 MHz, respectively, or, alternatively, the spectrometer Varian Inova 400 at 400 and 100.5 MHz, respectively, or, alternatively, on a spectrometer Bruker NMR 500 when 500,1 MHz and 125,1 MHz, respectively, is whether alternative, spectrometer JEOL eclipse 270 when, 270.0 MHz and 67.5 MHz, respectively. All spectral data were obtained using residual solvent as the internal standard.

Analysis preparative HPLC/MS was carried out using Waters/Micromass Platform ZQ, equipped with a System A: column ACE 5 C8 (19×50 mm), eluent: MilliQ water, MeCN and MilliQ/MeCN/0.1% of TFU, and System B: column Xterra MS C18, 5 μm, 19×50 mm), eluent: MilliQ water, MeCN and NH4HCO3(50 mm), and System C: column Gilson/YMC AQ C18; 150×30 mm Mass spectrometry using electrospray (MS) was performed using a liquid chromatograph Agilent 1100 Series/mass selective detector (MSD) or, alternatively, the mass spectrometer Perkin-Elmer API 150EX, obtaining a pseudo-molecular [M+H]+ion target molecules. Preparative HPLC/UV was performed on a Gilson system equipped with a System A: YMC ODS-AQ (150×30 mm) with a time gradient of 8.5 min, or System B: column ACE 5 C8 (5 μm, 30×100 mm), or System C: YMC ODS-AQ (50×20 mm) with a time gradient 5 min, using as eluent: water/0.1% of TFU and CH3CN. Analytical HPLC was carried out on the system Agilent 1100 equipped with a System A: ACE 3 (C8, 50×3.0 mm) or System B: YMC ODS-AQ, (33×3.0 mm) using the eluent system: water/0.1% of TFU and CH3CN, 1 ml/min, with a time gradient of 3 minutes LC-MS analysis was performed using a gas chromatograph Hewlett Packard 5890 with to onceu HP-5MS 15 m x 0.25 mm*0,mm, connected with 5971 MS detector. Preparative flash chromatography was performed on silica gel 60 (230-400 mesh mesh) Merck. For the names of the compounds used ACD Name of 6.0. Reactions under microwave heating was carried out using a Personal Chemistry Smith Creator with the use of 0.5-2 ml or 2.5 ml vials Smith Process Vials, equipped with aluminum caps and septa.

Table 1
ExampleChemical nameStructure
11-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, hydrochloride
24-(1,4-Diazepan-1-ylmethyl)-1-(phenylsulfonyl)-1H-indole, hydrochloride

31-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}pyrrolidin-3-amine
41-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}pyrrolidin-3-amine, triptorelin
51-[(4-Were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)
61-[(4-Were)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole, bis(triptorelin)
74-(1,4-Diazepan-1-ylmethyl)-1-[(4-were)sulfonyl]-1H-indole, bis(triptorelin)
84-[(4-Methyl-1,4-diazepan-1-yl)methyl]-1-[(4-were)sulfonyl]-1H-indole, bis(triptorelin)
91-[(4-Were)sulfonyl]-4-[(4-methylpiperazin-1-yl)methyl]-1H-indole, bis(triptorelin)
104-[(4-Isopropylpiperazine-1-yl)methyl]-1-[(4-were)sulfonyl]-1H-indole, bis(triptorelin)
111-[(4-Were)sulfonyl]-4-[(4-propylpiperazine-1-yl)methyl]-1H-indole, bis(thrift ratatat)
121-[(4-Were)sulfonyl]-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin
131-[(2-Methoxy-5-were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)
141-[(2-Methoxy-5-were)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole, bis(triptorelin)
15N-({1-[(2-Methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)piperidine-4-amine, bis(triptorelin)
161-Isopropyl-N-({1-[(2-methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)piperidine-4-amine, bis(triptorelin)

171-[(2-Methoxy-5-were)sulfonyl]-4-[(2-methylpyrrolidine-1-yl)methyl]-1H-indole, triptorelin
181-[(2-Methoxy-5-were)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]indoline, bis(triptorelin)
191-[(2-Methoxy-5-were)sulfonyl]-4-[(4-methylpiperazin-1-yl)methyl]indoline, bis(triptorelin)
201-[(2-Methoxy-5-were)sulfonyl]-4-(pyrrolidin-1-ylmethyl)indolin, triptorelin
21({1-[(2-Methoxy-5-were)sulfonyl]-2,3-dihydro-1H-indol-4-yl}methyl)dimethylamine, triptorelin
221-[(4-Forfinal)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole, bis(triptorelin)
234-(1,4-Diazepan-1-ylmethyl)-1-[(4-forfinal)sulfonyl]-1H-indole, bis(triptorelin)
241-[(4-Forfinal)sulfonyl]-4-(pyrrolidin-1-ylmethyl)-1 is-indole, triptorelin
25({1-[(4-Forfinal)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine, triptorelin
261-[(4-Forfinal)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)
271-[(2-Were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)
281-[(2-Were)sulfonyl]-4-[(4-methylpiperazin-1-yl)methyl]-1H-indole, bis(triptorelin)
291-({1-[(2-Were)sulfonyl]-1H-indol-4-yl}methyl)pyrrolidin-3-ol, triptorelin
301-[(2-Were)sulfonyl]-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin
312-[Methyl({1-[(2-were)sulfonyl]-1H-Indo) - Rev.-4-yl}methyl)amino]ethanol, triptorelin

32N,N-Dimethyl-1-{1-[(2-were)sulfonyl]-1H-indol-4-yl}methanamine, triptorelin
334-(Piperazine-1-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole, bis(triptorelin)
34{(2R)-1-[(1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]pyrrolidin-2-yl}methanol, triptorelin
354-(Pyrrolidin-1-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole, triptorelin
362-{Methyl[(1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]amino}ethanol, triptorelin
37N,N-Dimethyl-1-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methanamine, triptorelin
384-(Piperazine-1-ylmethyl)-1-(2-thienylmethyl)-1H-indole, bis(triptorelin)
39N-Ethyl-N-{[1-(2-thienylmethyl)-1H-indol-4-yl]methyl}ethanamine, triptorelin
404-(Pyrrolidin-1-ylmethyl)-1-(2-thienylmethyl)-1H-indole, triptorelin
414-[(4-Propylpiperazine-1-yl)methyl]-1-(2-thienylmethyl)-1H-indole, bis(triptorelin)
42N,N-Dimethyl-1-[1-(2-thienylmethyl)-1H-indol-4-yl]methanamine, triptorelin
434-(Piperazine-1-ylmethyl)-1-(pyridine-3-ylsulphonyl)-1H-indole, Tris(triptorelin)
44N,N-Dimethyl-1-[1-(pyridine-3-ylsulphonyl)-1H-indol-4-yl]methanamine, bis(triptorelin)
451-(Pyridine-3-ylsulphonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole, bis(triptorelin)
461-(Phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin

47N,N-Dimethyl-1-[1-(phenylsulfonyl)-1H-indol-4-yl]methanamine, triptorelin
48Comparative Example:
4-{[(1-Methylpyrrolidine-3-yl)oxy]methyl}-1-(phenylsulfonyl)-1H-indole, triptorelin
493-Methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)
503-Methyl-4-[(4-methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)
513-Methyl-1-(phenylsulfonyl)-4-(pyrrolidin-1 ileti is)-1H-indole, triptorelin
52N,N-Dimethyl-1-[3-methyl-1-(phenylsulfonyl)-1H-indol-4-yl]methanamine, triptorelin
536-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)
54{[6-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin
556-Methoxy-4-{[(3R)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)
566-Methoxy-4-{[(3S)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)
576-Methoxy-4-[(4-methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)
584-(1,4-Dia is even-1-ylmethyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)
596-Methoxy-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin
602-[{[6-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}(methyl)amino]ethanol, triptorelin

616-Fluoro-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)
624-(1,4-Diazepan-1-ylmethyl)-6-fluoro-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)
636-Fluoro-4-{[(3S)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)
646-Fluoro-4-{[(3R)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)
656-Fluoro-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin
662-[{[6-Fluoro-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}(methyl)amino]ethanol, triptorelin
67{[6-Fluoro-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin
686-Fluoro-4-[(4-methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)
691-(Phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indol-6-yl, dimethylcarbamate triptorelin
704-(1,4-Diazepan-1-ylmethyl)-1-(phenylsulfonyl)-1H-indol-6-ol
711-[(4-Forfinal)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole acetate
726-Methoxy-4-(piperazine-1-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole, bis(triptorelin)
731-[(2-Chlorophenyl)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)
741-[(3-Chloro-2-were)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

751-[(2,5-Acid)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole bis(triptorelin)
762-{[6-Methoxy-4-(piperazine-1-ylmethyl)-1H-indol-1-yl]sulfonyl}benzonitrile, bis(triptorelin)
77({1-[(4-Forfinal)sulfonyl]-1H-indol-4-yl}methyl)amine, triptorelin
78N-({1-[(4-Forfinal)sulfonyl]-1H-indole--yl}methyl)ethanamine, triptorelin
797-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)
802-Methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, hydrochloride
81Methyl 4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-2-carboxylate, bis(triptorelin)
82(4-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-2-yl)methanol, bis(triptorelin)
83(2-Methoxyethyl) {[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}amine, triptorelin
84N-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}propan-2-amine, triptorelin
854-{[4-(2-Methoxyethyl)piperazine-1-yl]methyl}-1-(anysurfer)-1H-indole, bis(triptorelin)
86((2R)-1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}pyrrolidin-2-yl)methanol, triptorelin
874 Azetidin-1-ylmethyl)-1-(phenylsulfonyl)-1H-indole, triptorelin
88Ethyl 5-methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole-2-carboxylate
895-Methoxy-N-methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole-2-carboxamide, triptorelin

90N-Ethyl-5-methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole-2-carboxamide, triptorelin
915-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-N-(2-thienylmethyl)-1H-indole-2-carboxamide, triptorelin
924-(Azetidin-1-ylmethyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole, triptorelin
931-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indol-5-ol, triptorelin
941-(Phenylsulfonyl)-4-piperazine-2-yl-1H-indole, bis(triptorelin)
954-(1,4-Dimethylpiperazine-2-yl)-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)
96[7-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]piperazine-1-yl)acetonitrile, triptorelin
974-(Azetidin-1-ylmethyl)-7-methoxy-1-(phenylsulfonyl)-1H-indole, triptorelin
98{[1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indol-5-yl]oxy}acetonitrile
995-Isopropoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole
1005-(Benzyloxy)-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole
1014-{[(2-Hydroxyethyl)(methyl)amino]methyl}-1-(phenylsulfonyl)-1H-indol-5-ol
1024-[(3-Hydroxypyrrolidine-1-yl)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol

103[1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-6-(trifluoromethyl)-1H-indol-2-yl]methanol, bis(triptorelin)
1045-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)
1055-Ethoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, triptorelin
1061-Phenyl-N-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methanamine, triptorelin
107N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}cyclopropanation, triptorelin
108{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine, hydrochloride
109N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}CYCLOBUTANE, triptorelin
110N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}-N-methylcyclobutane, triptorelin
1111-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}azetidin-3-ol, triptorelin
1124-(Azetidin-1-ylmethyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole, triptorelin
1134-{[4-(Azetidin-1-ylmethyl)-1H-indol-1-yl]sulfonyl}benzonitrile, triptorelin
1142-((2S)-1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}azetidin-2-yl)propan-2-ol, triptorelin
1154-(Azetidin-1-ylmethyl)-2-methyl-1-(phenylsulfonyl)-1H-indole, triptorelin
1164-(Azetidin-1-ylmethyl)-1-[(2-chlorophenyl)sulfonyl]-1H-indole, triptorelin
1174-(Azetidin-1-ylmethyl)-1-[(5-chloro-2-thienyl)sulfonyl]-1H-indole, triptorelin

1184-(Azetidin-1-ylmethyl)-1-(2-naphthylmethyl)-1H-indole, triptorelin
1194-(Azetidin-1-ylmethyl)-1-[(2-methoxy-5-were)sulfonyl]-1H-indole, trifurcata the
1204-(Azetidin-1-ylmethyl)-1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-indole, triptorelin
1214-(Azetidin-1-ylmethyl)-1-[(4-tert-butylphenyl)sulfonyl]-1H-indole, triptorelin
1224-(Azetidin-1-ylmethyl)-1-[(2,6-differenl)sulfonyl]-1H-indole, triptorelin
1234-(Azetidin-1-ylmethyl)-1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-indole, triptorelin
1243-{[4-(Azetidin-1-ylmethyl)-1H-indol-1-yl]sulfonyl}benzonitrile, triptorelin
1254-(Azetidin-1-ylmethyl)-1-{[4-bromo-2-(trifluoromethyl)phenyl]sulfonyl}-1H-indole, triptorelin
1264-(Azetidin-1-ylmethyl)-1-(2-tieneral is of IMT-1H-indole, triptorelin
1274-(Azetidin-1-ylmethyl)-1-[(2,5-differenl)sulfonyl]-1H-indole, triptorelin
128[(5-Methoxy-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]dimethylamine, triptorelin
1294-(Azetidin-1-ylmethyl)-7-(benzyloxy)-1-(methylsulphonyl)-1H-indole, triptorelin
130({1-[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-5-methoxy-1H-indol-yl}methyl)dimethylamine, triptorelin
1314-[(Dimethylamino)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol, triptorelin
132{[5-Ethoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin

133({5-Ethoxy-1-[(2-methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine, triptorelin
134{[5-Ethoxy-1-(1-naphthylmethyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin
135{[5-Ethoxy-1-(2-naphthylmethyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin
136({1-[(2-Chlorophenyl)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine, triptorelin
137({1-[(3-Chloro-2-were)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine, triptorelin
138({5-Methoxy-1-[(2-methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine, triptorelin
139({1-[(2,3-Dichlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}methyl)dimethylamine, triptorelin
140{[5-Ethoxy-1-(quinoline-8-ylsulphonyl)-1H-indol-4-yl]methyl}dimethylamine, bis(triptorelin)
141{[5-Ethoxy-1-({5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-thienyl}sulfonyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin
142({1-[(2,5-Dichlorophenyl)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine, triptorelin
143({5-Ethoxy-1-[(2,4,6-trichlorophenyl)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine, triptorelin
1441-[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N-methylmethanamine, triptorelin
145({1-[(2-Methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)methylamine, triptorelin
1464-[(Dimethyl what Mino)methyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol, triptorelin
1471-[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N,N-dimethylethanamine

1486-Fluoro-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indol-5-ol
1496-Fluoro-5-methoxy-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin
1504-(Azetidin-1-ylmethyl)-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol, triptorelin
1514-(Azetidin-1-ylmethyl)-6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indole, triptorelin
1524-{[Ethyl(methyl)amino]methyl}-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol
153N-{[6-Fluoro-5-methoxy-1-(f is ylsulphonyl)-1H-indol-4-yl]methyl}-N-methylethanamine, triptorelin
1546-Fluoro-4-[(methylamino)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol, triptorelin
155{[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylamine, triptorelin
1561-{5-Methoxy-1-[(4-methoxyphenyl)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine
1571-{1-[(3-Chlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine
1581-{1-[(2,5-Differenl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine
1591-(1-{[4-Fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine
1601-[5-Methoxy-1-(quinoline-8-ylsulphonyl)-1H-indol-4-the l]-N,N-dimethylethanamine
1611-{1-[(2-Chlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine
1621-{1-[(2-Chloro-6-were)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine

1631-{1-[(3-Chloro-4-forfinal)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine
1641-{5-Methoxy-1-[(2-were)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine
1652-({4-[(Dimethylamino)methyl]-5-methoxy-1H-indol-1-yl}sulfonyl)benzonitrile
1661-{1-[(2,6-Differenl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine
1671-{1-[(1,2-Dimethyl-1H-imidazol-4-the l)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine
1681-{5-Methoxy-1-[(5-methyl-1-benzothieno-2-yl)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine
1691-{5-Methoxy-1-[(2-methoxy-4-were)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine
1701-{1-[(2,4-Dichlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine
1711-{1-[(5-Bromo-2-methoxyphenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine
1721-[1-(2,1,3-Benzothiadiazole-4-ylsulphonyl)-5-methoxy-1H-indol-4-yl]-N,N-dimethylethanamine
1731-[1-(3,4-Dihydro-2H-1,5-benzodioxepin-7-ylsulphonyl)-5-methoxy-1H-indol-4-yl]-N,N-dimethylethanamine
1741-{1-[(2,5-Acid), sulfone the]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine
1751-(5-Methoxy-1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)-N,N-dimethylethanamine
1761-(5-Methoxy-1-{[4-(triptoreline)phenyl]sulfonyl}-1H-indol-4-yl)-N,N-dimethylethanamine
1773-({4-[(Dimethylamino)methyl]-5-methoxy-1H-indol-1-yl}sulfonyl)benzonitrile

1781-[5-Methoxy-1-(pyridine-3-ylsulphonyl)-1H-indol-4-yl]-N,N-dimethylethanamine
179Methyl{1-[1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine
180{1-[1-(Phenylsulfonyl)-1H-indol-4-yl]ethyl}amine
181Dimethyl{1-[1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine
1824-(Azetidin-1-ylmethyl)-2,3-dichloro-5-methoxy-1-(phenylsulfonyl)-1H-indole
183{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}amine
1844-[(Dimethylamino)methyl]-6-methoxy-1-(phenylsulfonyl)-1H-indol-5-ol
1851-[5,6-Dimethoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N,N-dimethylethanamine
186{[3-Chloro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin
187{[3-Chloro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylamine, triptorelin
188{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}amine, triptorelin
1896-Fluoro-4-[1-(methylamino)ethyl]-1-(phenylsulfonyl)-1H-indol-5-ol, triptorelin
1904-[1-(Dimethylamino)ethyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol
191{1-[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}methylamine, triptorelin
192{1-[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}dimethylamine, triptorelin

The intermediate connection 1

4-Methyl-1-(phenylsulfonyl)-1H-indole

Specified substance was obtained in accordance with the method described in the literature (Chemical & Pharmaceutical Bulletin (1994), 42(10), 2150-3, Tetrahedron Letters (1993), 34(3), 489-92). MS (ESI+) for C15H13NO2S m/z 272 (M+H)+.

Intermediate compound 2

4-(methyl bromide)-1-(phenylsulfonyl)-1H-indole

The specified connection was obtained using N-bromosuccinimide (1.2 equiv.) as an agent, synthesized, and benzoyl peroxide (0.25 equiv.) as an initiator, in CCl4. The final product was purified the lash-chromatography system (eluent chloroform-hexane 1:1) Yield of 61.6%, 3.5 g). MS (ESI+) for C15H12BrNO2S m/z 351 (M+H)+(Mentioned in the title compound was previously described in WO 9602502 Al 19960201)

Example 1

1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, hydrochloride

4-(methyl bromide)-1-(phenylsulfonyl)-1H-indole - Intermediate compound 2 (1,025 g), NaHCO3(1.5 EQ.) and N-BOC-piperazine (1.5 EQ.) was subjected to boiling under reflux in ethanol for 40 minutes. The reaction was monitored using TLC (eluent system CHCl3-EtOH 20:1). Final processing of the crude product extraction and further purification of column chromatography (eluent-CHCl3gave the final product in the form of oil. This substance was processed using 5M HCl in i-D with obtaining salt of the final product (300 mg, 24%). The path of synthesis, which is followed to obtain Example 1, shown in the following diagram

Output (HCl-salt) 300 mg (24%); MS (ESI+) for C19H21N3O2S*HCl m/z 356 M+H)+

Example 2

4-(1,4-Diazepan-1-ylmethyl)-1-(phenylsulfonyl)-1H-indole, hydrochloride

4-(methyl bromide)-1-(phenylsulfonyl)-1H-indole - Intermediate compound 2, NaHCO3and 1-BOC-homopiperazine was dissolved in ethanol and subjected to boiling under reflux at 85°C during the night. The solvent is evaporated and the residue was purified using preparative HPLC/MS (System A), 20-50%, with getting to 25.3 mg (19%) protection is built product. The protected product was dissolved in anhydrous DCM and the solution was added 2M HCl in diethyl ether. After 6 hours of stirring, the solvent is evaporated from the receipt of 16.5 mg (83%) of product as HCl salt.1H NMR (400 MHz, MeOD) δ ppm 2,18 (s, 2H) 3,30-3,51 (m, 4H) 3,64 (approx., d, 4H) br4.61 (s, 2H) 7,07 (s, 1H) 7,34-to 7.50 (m, 4H) 7,51-7,58 (m, 1H) 7,79 (d, J=3,51 Hz, 1H) of 7.90 (d, J=7,53 Hz, 2H) 8,07 (d, J=8,28 Hz, 1H).

Example 3

1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}pyrrolidin-3-amine

Followed the experimental procedure described for Example 2 using tert-butyl pyrrolidin-3-ylcarbamate. Output: 821 mg (84%). (ESI+) for C19H21N3O2S m/z 356 (M+H)+.

Example 4

1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}pyrrolidin-3-amine, triptorelin

Followed the experimental procedure described for Example 2 using tert-butyl 3-aminopyrrolidine-1-carboxylate. Yield: 163 mg (99%). (ESI+) for C19H21N3O2S m/z 356 (M+H)+.

Intermediate compound 3

4-Bromo-1-[(4-were)sulfonyl]-1H-indole

4-Bromoindole (1.24 g, 6.3 mmol), p-toluensulfonate (1,32 g, 6,9 mmol) and tetrabutylammonium bisulfate (42 mg, 0.1 mmol) was dissolved in DCM (50 ml). Was added an aqueous solution of 2.5 M NaOH (6 ml, 15 mmol) and the mixture was intensively stirred for 1 hour. Was diluted with water and DCM, collected DCM phase was washed twice with water, dried and concentrated to half the rising product as a white crystalline substance (2,07 g, 5.9 mmol). Yield 94%. MS (ESI+) for C15H12BrNO2S m/z 352 (M+H)+.

Intermediate compound 4

1-[(4-Were)sulfonyl]-4-vinyl-1H-indole

4-bromo-1-[(4-were)sulfonyl]-1H-indole (600 mg, 1,71 mmol; Intermediate compound 3), tributyl(vinyl)stannane (0,550 ml, 1.88 mmol) and Pd(PPh3)2OAc2(32 mg, 0,043 mmol) were mixed in anhydrous toluene (8 ml) and was stirred for 24 hours at 110°C using STEM block, then at room temperature for 40 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified flash chromatography (20% DCM in hexane to 50% DCM in hexane). This gave specified in the header connection 390 mg, 77% in the form of a colorless viscous oil. MS (ESI+) for C17H15NO2S m/z 298 (M+H)+.

The intermediate compound 5; part 1

1-[(4-Were)sulfonyl]-1H-indole-4-carbaldehyde

OsO4(6 mg, is 0.023 mmol) was added to a stirred mixture of 1-[(4-were)sulfonyl]-4-vinyl-1H-indole (68 mg, 0.23 mmol; Intermediate compound 4) and 2,6-lutidine (54 μl, 0.46 mmol) in dioxane (6 ml). Colorless mixture became black for 1 minute. Solution was added periodate sodium (0,197 g to 0.92 mmol) in water (1.5 ml, heated to dissolve). Immediately there was a formation of a grey precipitate. The mixture was stirred for 20 minutes and distributed is between the aqueous solution of 2M HCl (25 ml) and DCM (25 ml). The organic layer was dried, filtered and combined with part 2 Intermediate compound 5.

The intermediate compound 5; part 2

1-[(4-Were)sulfonyl]-1H-indole-4-carbaldehyde

Followed the experimental procedure described for intermediate 5 part 1, using OsO4(27 mg, 0.11 mmol), 1-[(4-were)sulfonyl]-4-vinyl-1H-indole (0,321 g at 1.08 mmol; Intermediate compound 4), 2,6-lutidine (0,251 ml, 0.23 mmol), dioxane (12 ml), periodate sodium (0,924 g, 4,32 mmol) and water (4 ml). The mixture was stirred for 20 minutes and was distributed between the aqueous solution of 2M HCl (25 ml) and DCM (25 ml). The organic layer was dried, filtered, combined with the party 1 Intermediate compounds 5 and concentrated to obtain the total yield 390 mg, 99%, black solid. MS (ESI+) for C16H13NO3S m/z 300 (M+H)+.

Example 5

1-[(4-Were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

To anhydrous THF (4 ml) was added, in order, 1-[(4-were)sulfonyl]-1H-indole-4-carbaldehyde (40 mg, 0.13 mmol; Intermediate compound 5), 1-BOC-piperazine (27 mg, 0.15 mmol), acetic acid (76 μl, of 1.33 mmol) and NaB(OAc)3H (57 mg, 0.27 mmol). The mixture was subjected to microwave irradiation for 600 seconds at 130°C. was Added an additional amount of 1-BOC-piperazine (27 mg, 0.15 mmol) and NaB(OAc)3H(57 mg, 0.27 mmol) and the mixture was subjected to irradiation at 130°C for 300 sec. This gave 100% conversion to the product. The reaction mixture was filtered and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, 25-47% MeCN, 0.1% of TFU). Specified in the title compound (29 mg, 36%) was obtained as a light brown solid. MS (ESI+) for C20H23N3O2S m/z 370 (M+H)+.

Example 6

1-[(4-Were)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole, bis(triptorelin)

Followed the experimental procedure described for Example 5, using 2-methylpiperazine (15 mg, 0.15 mmol), except for the stage of removal of protection. Purification was performed using preparative HPLC/UV (System A, 22-44% MeCN, 0.1% of TFU). Specified in the title compound (32 mg, 39%) was obtained as a brown solid. MS (ESI+) for C21H25N3O2S m/z 384 (M+H)+.

Example 7

4-(1,4-Diazepan-1-ylmethyl)-1-[(4-were)sulfonyl]-1H-indole, bis(triptorelin)

To anhydrous THF (4 ml) was added, in order, 1-[(4-were)sulfonyl]-1H-indole-4-carbaldehyde (30 mg, 0.10 mmol; Intermediate compound 5), 1-BOC-homopiperazine (30 mg, 0.15 mmol), acetic is islote (57 μl, 1.00 mmol) and NaB(OAc)3H (51 mg, 0.24 mmol). The mixture was subjected to microwave irradiation for 420 seconds at 130°C. the Reaction mixture was filtered and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, 21-43% MeCN, 0.1% of TFU). Specified in the title compound (24 mg, 39%) was obtained as a brown solid. MS (ESI+) for C21H25N3O2S m/z 384 (M+H)+.

Example 8

4-[(4-Methyl-1,4-diazepan-1-yl)methyl]-1-[(4-were)sulfonyl]-1H-indole, bis(triptorelin)

Followed the procedure of Example 7, except for the stage of removing protection, using N-methylhomopiperazine (17 mg, 0.15 mmol). Preparative HPLC/UV (System A, 23-44% MeCN, 0.1% of TFU). Specified in the title compound (35 mg, 56%) was obtained as a brown solid. MS (ESI+) for C22H27N3O2S m/z 398 (M+H)+.

Example 9

1-[(4-Were)sulfonyl]-4-[(4-methylpiperazin-1-yl)methyl]-1H-indole, bis(triptorelin)

Followed the procedure of Example 7, except for the stage of removing protection, using N-methylpiperazine (15 mg, 0.15 mmol). Preparative HPLC/UV (System A, 25-48% MeCN, 0.1% of TFU). Specified in the title compound (24 mg, 40%) was obtained as a gray solid substances is STV. MS (ESI+) for C21H25N3O2S m/z 384 (M+H)+.

Example 10

4-[(4-Isopropylpiperazine-1-yl)methyl]-1-[(4-were)sulfonyl]-1H-indole, bis(triptorelin)

Followed the procedure of Example 7, except for the stage of removing protection, using 1-isopropylpiperazine (19 mg, 0.15 mmol). Preparative HPLC/UV (System A, 28-50% MeCN, 0.1% of TFU). Specified in the title compound (21 mg, 32%) was obtained as a brown solid. MS (ESI+) for C23H29N3O2S m/z 412 (M+H)+.

Example 11

1-[(4-Were)sulfonyl]-4-[(4-propylpiperazine-1-yl)methyl]-1H-indole, bis(triptorelin)

Followed the procedure of Example 7, except for the stage of removing protection, dihydrobromide N-propylpiperazine (44 mg, 0.15 mmol). More dihydrobromide N-propylpiperazine (15 mg, 0.05 mmol) and NaB(OAc)3H (20 mg, 0.09 mmol) and irradiation at 130°C for 300 sec gave complete conversion. Preparative HPLC/UV (System A, 28-51% MeCN, 0.1% of TFU). Specified in the title compound (19 mg, 29%) was obtained as a gray solid. MS (ESI+) for C23H29N3O2S m/z 412 (M+H)+.

Example 12

1-[(4-Were)sulfonyl]-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin

Followed the procedure of Example 7, except for the stage of removing protection, using pyrrolidine (13 µl, 0,mol). Preparative HPLC/UV (System A, 30-53% MeCN, 0.1% of TFU). Specified in the title compound (20 mg, 44%) was obtained as a brown solid. MS (ESI+) for C20H22N2O2S m/z 355 (M+H)+.

The intermediate compound 6

4-Bromo-1-[(2-methoxy-5-were)sulfonyl]-1H-indole

Followed the procedure described for Intermediate 3 using (2-methoxy-5-were)sulphonylchloride. Yield 1.4 g (72%). MS (ESI+) for C16H14BrNO3S m/z 382 (M+H)+.

Intermediate compound 7

1-[(2-Methoxy-5-were)sulfonyl]-4-vinyl-1H-indole

4-Bromo-1-[(2-methoxy-5-were)sulfonyl]-1H-indole (518 mg, of 1.36 mmol; Intermediate compound 6), tributyl(vinyl)stannane (0,438 ml, 1.50 mmol) and Pd(PPh3)2OAc2(51 mg, 0,068 mmol) were mixed in anhydrous toluene (8 ml) and was stirred for 17 hours at 110°C using STEM block. The mixture was filtered and added an additional amount of tributyl(vinyl)stannane (0,200 ml of 0.68 mmol) and Pd(PPh3)2OAc2(30 mg, 0.040 mmol) with constant stirring for 23 hours. This procedure was repeated again (added additional reagents) with constant stirring for 24 hours, which gave complete conversion. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash-chromate what graphy (DCM/hexane 2:3). This gave the desired product (2,62 g, 59%) as not quite white solid. MS (ESI+) for C18H17NO3S m/z 328 (M+H)+.

Intermediate compound 8

1-[(2-Methoxy-5-were)sulfonyl]-1H-indole-4-carbaldehyde

OsO4(10 mg, 0.05 mmol) was added to a stirred mixture of 1-[(2-methoxy-5-were)sulfonyl]-4-vinyl-1H-indole (262 mg, 0.80 mmol; Intermediate compound 7) and 2,6-2,6-lutidine (186 μl, 0.46 mmol) in dioxane (9 ml). Colorless mixture became black for 1 minute. Solution was added periodate sodium (0,684 g, 3.2 mmol) in water (3 ml), heated to dissolve). Immediately formed a grey precipitate. The mixture was stirred for 30 minutes and was distributed between the aqueous solution of 2M HCl (25 ml) and DCM (25 ml). The organic layer was dried, filtered and concentrated to obtain specified in the title compound (290 mg, 110%, there still remained a number of dioxane in accordance with the data NAMR) as a black solid. MS (ESI+) for C17H15NO4S m/z 330 (M+H)+.

Example 13

1-[(2-Methoxy-5-were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

1-[(2-Methoxy-5-were)sulfonyl]-1H-indole-4-carbaldehyde (27 mg, 0,082 mmol; Intermediate compound 8), 1-BOC-piperazine (23 mg, 0.12 mmol), acetic acid (47 μl, 0.82 mmol) and NaB(OAc)3H (42 mg, 0.20 mmol), specified in the order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 420 seconds at 130°C. was Added an additional amount of 1-BOC-piperazine (23 mg, 0.12 mmol), acetic acid (23 μl, 0.41 mmol) and NaB(OAc)3H (42 mg, 0.20 mmol) and the reaction mixture was subjected to irradiation again at 130°C for 600 seconds. The mixture was filtered and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, 23-44% MeCN, 0.1% of TFU). Specified in the title compound (22 mg, 45%) was obtained as a light brown solid. MS (ESI+) for C21H25N3O3S m/z 400 (M+H)+.

Example 14

1-[(2-Methoxy-5-were)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole, bis(triptorelin)

1-[(2-Methoxy-5-were)sulfonyl]-1H-indole-4-carbaldehyde (27 mg, 0,082 mmol; Intermediate compound 8), 2-methylpiperazine (12 mg, 0.12 mmol), acetic acid (47 μl, 0.82 mmol) and NaB(OAc)3H (42 mg, 0.20 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 420 seconds at 130°C. the Reaction mixture was filtered and concentrated. Purification was performed using preparative HPLC/UV (System A, 25-47% MeCN, 0.1% of TFU). Specified in the header connect the tion (18 mg, 34%) was obtained as a light brown solid. MS (ESI+) for C22H27N3O3S m/z 414 (M+H)+.

Example 15

N-({1-[(2-Methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)piperidine-4-amine, bis(triptorelin)

1-[(2-Methoxy-5-were)sulfonyl]-1H-indole-4-carbaldehyde (27 mg, 0,082 mmol; Intermediate compound 8), tert-butyl 4-aminopiperidine-1-carboxylate (25 mg, 0.12 mmol), acetic acid (47 μl, 0.82 mmol) and NaB(OAc)3H (42 mg, 0.20 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 420 seconds at 130°C. was Added an additional amount of tert-butyl 4-aminopiperidine-1-carboxylate (25 mg, 0.12 mmol), acetic acid (23 μl, 0.41 mmol) and NaB(OAc)3H (42 mg, 0.20 mmol) and the reaction mixture was subjected to irradiation again at 130°C for 600 seconds. Was still about 30% of the original substance. The mixture was filtered and distributed between DCM (15 ml) and saturated aqueous NaHCO3(15 ml). The organic layer was concentrated. Purification using evaporative column (FlashTube™ fran Trikonex; elution with 10% MeOH in DCM) gave 50 mg of this substance (25 mg) was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. Purification using preparative HPLC/UV (System A, 23-44% MeCN, 0.1% of TFU). Specified the title compound (7 mg, 27%) was obtained as a light brown solid. MS (ESI+) for C22H27N3O3S m/z 414 (M+H)+.

Example 16

1-Isopropyl-N-({1-[(2-methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)piperidine-4-amine, bis(triptorelin)

1-[(2-Methoxy-5-were)sulfonyl]-1H-indole-4-carbaldehyde (27 mg, 0,082 mmol; Intermediate compound 8), 1-isopropylpiperazine-4-amine (17 mg, 0.12 mmol), acetic acid (47 μl, 0.82 mmol) and NaB(OAc)3H (42 mg, 0.20 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 420 seconds at 130°C. was Added an additional amount of 1-isopropylpiperazine-4-amine (17 mg, 0.12 mmol), acetic acid (23 μl, 0.41 mmol) and NaB(OAc)3H (42 mg, 0.20 mmol) and the reaction mixture was subjected to irradiation again at 130°C for 60 minutes. Was still about 45% of the original substance. The mixture was filtered and concentrated. Purification was performed using preparative HPLC/UV (System A, 24-46% MeCN, 0.1% of TFU). Specified in the title compound (16 mg, 29%) was obtained as a light brown solid. MS (ESI+) for C25H33N3O3S m/z 456 (M+H)+.

Example 17

1-[(2-Methoxy-5-were)sulfonyl]-4-[(2-methylpyrrolidine-1-yl)methyl]-1H-indole, triptorelin

Followed the procedure of Example 16 using 2-methylpyrrolidine (13 μl, 0.12 mm is eh). Preparative HPLC/UV (System A, 32-55% MeCN, 0.1% of TFU). Specified in the title compound (16 mg, 36%) was obtained as a light brown solid. MS (ESI+) for C22H26N2O3S m/z 399 (M+H)+.

Intermediate compound 9

4-Bromo-1-[(2-methoxy-5-were)sulfonyl]indolin

NaBH3CN (480 mg, 7,63 mmol) was added in portions, in an atmosphere of N2to ice TFU (15 ml). The mixture was stirred for 15 minutes and was added in portions with 4-bromo-1-[(2-methoxy-5-were)sulfonyl]-1H-indole (645 mg, 1.70 mmol; Intermediate compound 6). The mixture was allowed to warm to room temperature and was stirred for 1.5 hours. Added additional amount of NaBH3CN (480 mg, 7,63 mmol) with constant stirring for 1 hour. The reaction mixture was extinguished with water (30 ml) and was extragonadal twice using DCM. DCM layers were combined and were extragonadal aqueous solution of Na2CO3(~pH 10). The organic layer was dried, filtered and concentrated to obtain specified in the title compound (525 mg, 80%) as a yellow viscous oil. MS (ESI+) for C16H16BrNO3S m/z 382 (M+H)+.

Intermediate compound 10

1-[(2-Methoxy-5-were)sulfonyl]-4-viniendose

4-Bromo-1-[(2-methoxy-5-were)sulfonyl]indolin (a total of 721 mg, 1,89 mmol; Intermediate compound 9), tributyl(vinyl)stannane (is this 1,10 ml, of 3.78 mmol) and Pd(PPh3)2OAc2(142 mg, 0,19 mmol) in anhydrous toluene (12 ml) were divided into 3 test tubes and stirred at 110°C using STEM block during the weekend (68 hours). Was still about 30% of the original substance. The reaction mixture was combined, filtered and concentrated. Again dissolved in anhydrous MeCN (8 ml), was divided into 2 tubes for microwave heating, and then adding tributyl(vinyl)stannane (300 μl, of 1.03 mmol) and Pd(PPh3)2OAc2(30 mg, 0.04 mmol) in each tube. The mixture was subjected to microwave irradiation at 180°C for 600 seconds. Filtration and concentration followed by purification using flash chromatography (30% hexane in DCM) gave specified in the title compound (300 mg, 48%) as a colourless viscous oil. MS (ESI+) for C18H19NO3S m/z 330 (M+H)+.

Intermediate compound 11

1-[(2-Methoxy-5-were)sulfonyl]indolin-4-carbaldehyde

OsO4(9 mg, 0.05 mmol) was added to a stirred mixture of 1-[(2-methoxy-5-were)sulfonyl]-4-vinlandia (240 mg, 0.73 mmol; Intermediate compound 10) and 2,6-lutidine (170 μl, of 1.46 mmol) in dioxane (12 ml). Colorless mixture became black for 1 minute. Solution was added periodate sodium (0.625 g, of 2.92 mmol) in water (4 ml, heated to dissolve). Once formed grey sieges is K. The mixture was stirred for 25 minutes, combined with previously obtained by the party of this intermediate compound (following the procedure of this experiment and from the Intermediate 10; 60 mg, 18 mmol), and distributed between the aqueous solution of 2M HCl (25 ml) and DCM (25 ml). The organic layer was dried, filtered and concentrated to obtain specified in the title compound (360 mg, there still remained a number of dioxane in accordance with the data NAMR) in the form of a black viscous oil. MS (ESI+) for C17H17NO4S m/z 332 (M+H)+.

Example 18

1-[(2-Methoxy-5-were)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]indoline, bis(triptorelin)

1-[(2-Methoxy-5-were)sulfonyl]indolin-4-carbaldehyde (30 mg, 0,091 mmol; Intermediate compound 11), 2-methylpiperazin (18 mg, 0.18 mmol), acetic acid (52 μl, of 0.91 mmol) and NaB(OAc)3H (58 mg, 0.27 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 660 seconds at 130°C, filtered, concentrated and purified using preparative HPLC/UV (System A, MeCN/H2O, 0.1% OF TFU). Specified in the title compound (13 mg, 22%) was obtained as a light brown solid. MS (ESI+) for C22H29N3O3S m/z 416 (M+H)+.

Example 19

1-[(2-Methoxy-5-were)sulfonyl]-4-[(4-methylpiperid the Zin-1-yl)methyl]indoline, bis(triptorelin)

Followed the experimental procedure described for Example 18, using 1-methylpiperazine (18 mg, 0.18 mmol). Specified in the title compound (21 mg, 36%) was obtained as colorless solid. MS (ESI+) for C22H29N3O3S m/z 416 (M+H)+.

Example 20

1-[(2-Methoxy-5-were)sulfonyl]-4-(pyrrolidin-1-ylmethyl)indolin, triptorelin

Followed the experimental procedure described for Example 18, using pyrrolidine (15 μl, 0.18 mmol). Specified in the title compound (15 mg, 33%) was obtained as a light brown solid. MS (ESI+) for C21H26N2O3S m/z 387 (M+H)+.

Example 21

({1-[(2-Methoxy-5-were)sulfonyl]-2,3-dihydro-1H-indol-4-yl}methyl)dimethylamine, triptorelin

Followed the experimental procedure described for Example 18, using dimethylamine hydrochloride (15 mg, 0.18 mmol). Specified in the title compound (13 mg, 30%) was obtained as a light brown solid. MS (ESI+) for C19H24N2O3S m/z 361 (M+H)+.

Intermediate compound 12

1-[(4-Forfinal)sulfonyl]-4-vinyl-1H-indole

Followed the experimental procedure described for intermediate 7. Flash chromatography (30% DCM in hexane) to give 347 mg, 75% white solid. MS (ESI+) d the I C 16H12FNO2S m/z 302 (M+H)+.

Intermediate compound 13

1-[(4-Forfinal)sulfonyl]-1H-indole-4-carbaldehyde

Followed the procedure described for Intermediate 8, using OsO4(15 mg, 0,058 mmol), 1-[(4-forfinal)sulfonyl]-4-vinyl-1H-indole (347 mg, 1.15 mmol; Intermediate compound 12), 2,6-lutidine (268 μl, 2.3 mmol), dioxane (15 ml), periodate sodium (0,984 g, 4.6 mmol) and water (5 ml). Specified in the title compound (360 mg, 103%, there still remained a number of dioxane in accordance with the data NAMR) received in the form of a black viscous oil. MS (ESI+) for C15H10FNO3S m/z 304 (M+H)+.

Example 22

1-[(4-Forfinal)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole, bis(triptorelin)

1-[(4-Forfinal)sulfonyl]-1H-indole-4-carbaldehyde (30 mg, 0,099 mmol; Intermediate compound 13), 2-methylpiperazine (20 mg, 0.20 mmol), acetic acid (57 μl, 0,99 mmol) and NaB(OAc)3H (63 mg, 0.30 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 900 seconds at 130°C. the Mixture was filtered and concentrated. Purification was performed using preparative HPLC/UV (System A, MeCN, 0.1% of TFU). Specified in the title compound (26 mg, 43%) was obtained as a light brown solid. MS (ESI+) for C20H22FN3O2S m/z 388 (M+H) +.

Example 23

4-(1,4-Diazepan-1-ylmethyl)-1-[(4-forfinal)sulfonyl]-1H-indole, bis(triptorelin)

1-[(4-Forfinal)sulfonyl]-1H-indole-4-carbaldehyde (30 mg, 0,099 mmol; Intermediate compound 13), 1-BOC-homopiperazine (39 μl, 0.20 mmol), acetic acid (57 μl, 0,99 mmol) and NaB(OAc)3H (63 mg, 0.30 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 900 seconds at 130°C. the Mixture was filtered and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, MeCN, 0.1% of TFU). Specified in the title compound (24 mg, 39%) was obtained as colorless solid. MS (ESI+) for C20H22FN3O2S m/z 388 (M+H)+.

Example 24

1-[(4-Forfinal)sulfonyl]-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin

Followed the experimental procedure described for Example 22, using pyrrolidine (16 μl, 0.20 mmol). Specified in the title compound (21 mg, 45%) was obtained as a light brown solid. MS (ESI+) for C19H19FN2O2S m/z 359 (M+H)+.

Example 25

({1-[(4-Forfinal)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine, triptorelin

Followed experimental% the fool, described for Example 22, using dimethylamine hydrochloride (16 mg, 0.20 mmol). Specified in the title compound (13 mg, 29%) was obtained as a light brown solid. MS (ESI+) for C17H17FN2O2S m/z 333 (M+H)+.

Example 26

1-[(4-Forfinal)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

1-[(4-Forfinal)sulfonyl]-1H-indole-4-carbaldehyde (75 mg, 0.25 mmol; Intermediate compound 13), 1-BOC-piperazine (92 mg, 0.50 mmol), acetic acid (0,141 ml, 2,47 mmol) and NaB(OAc)3H (157 mg, of 0.74 mmol), in that order, added to anhydrous THF (5 ml). The mixture was subjected to microwave irradiation for 900 seconds at 130°C. the Mixture was filtered and concentrated. The residue was dissolved in MeOH (3 ml) and concentrated HCl (1.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. MeOH is evaporated and the resulting suspension was distributed between DCM and saturated aqueous Na2CO3. The organic layer was dried, filtered and concentrated. Half the quantity of the crude product was purified preparative HPLC/UV (System A, MeCN, 0.1% of TFU). Specified in the title compound (26 mg, 17%) was obtained as a light brown solid. MS (ESI+) for C19H20FN3O2S m/z 374 (M+H)+.

Intermediate compound 14

4-Bromo-1-[(2-were)sulfonyl]-1H-indole

Aq is th solution of 2.5 M NaOH (5 ml) was added to a stirred mixture of 4-bromo-1H-indole (1000 mg, 5.3 mmol), 2-methylbenzenesulfonamide (1100 mg, 5.6 mmol) and tetrabutylammonium bisulfate (173 mg, 0.5 mmol) in DCM (10 ml). The reaction mixture was stirred at ambient temperature overnight. The mixture was diluted with DCM and water and the layers were separated. DCM was washed with water 2 times, dried (MgSO2) and concentrated to obtain 1.6 g of the crude substance, which was purified using flash chromatography (SiO2, eluent EtOAc:hexane 9:1) to obtain specified in the header of the product (1 g, 54%). MS (ESI+) for C15H12BrNO2S m/z 350 (M+H)+.

Intermediate compound 15

1-[(2-Were)sulfonyl]-4-vinyl-1H-indole

4-Bromo-1-[(2-were)sulfonyl]-1H-indole (500 mg, 1,43 mmol; Intermediate compound 14) was dissolved in anhydrous MeCN (8 ml) and was divided in two vial for microwave heating. Tributyl(vinyl)stannane (0,417 ml of 1.43 mmol) and Pd(PPh3)2OAc2(27 mg, being 0.036 mmol) was added to each vial. The reaction mixture was subjected to microwave irradiation at 180°C for 720 seconds. The mixtures were combined, filtered and concentrated. Purification was performed by flash chromatography (30% hexane in DCM). This gave the product (300 mg, 71%) as a yellow viscous oil. MS (ESI+) for C17H15NO2S m/z 298 (M+H)+.

The intermediate connection 16

1-[(2-Were)sulfonyl]-1H-indole-4-carbaldehyde

OsO4(15 m is, 0.06 mmol) was added to a stirred mixture of 1-[(2-were)sulfonyl]-4-vinyl-1H-indole (300 mg, 1.01 mmol; Intermediate compound 15) and 2,6-lutidine (235 μl, 2.02 mmol) in dioxane (24 ml). Colorless mixture became black for 3 minutes. Added periodate sodium (0,865 g, 4.04 mmol) in water (8 ml, heated to dissolve). Immediately formed a grey precipitate. The mixture was stirred for 1,40 hours and extragonadal aqueous solution of 2M HCl (25 ml) and DCM (2×25 ml). The organic layers were combined, dried, filtered and concentrated to obtain specified in the title compound (358 mg, 118%, there still remained a number of dioxane in accordance with the data NAMR) in the form of a black resin. MS (ESI+) for C16H13NO3S m/z 300 (M+H)+.

Example 27

1-[(2-Were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

1-[(2-were)sulfonyl]-1H-indole-4-carbaldehyde (50 mg, 0,17 mmol; Intermediate compound 16), 1-BOC-piperazine (62 mg, 0.33 mmol), acetic acid (95 μl, 1,67 mmol) and NaB(OAc)3H (106 mg, 0.50 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 720 seconds at 130°C. the Mixture was filtered and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and the sight of the Ali using preparative HPLC/UV (System A, 19 to 42% MeCN, 0.1% of TFU). Specified in the title compound (7 mg, 7%) was obtained as a light brown solid. MS (ESI+) for C20H23N3O2S m/z 370 (M+H)+.

Example 28

1-[(2-Were)sulfonyl]-4-[(4-methylpiperazin-1-yl)methyl]-1H-indole, bis(triptorelin)

1-[(2-Were)sulfonyl]-1H-indole-4-carbaldehyde (50 mg, 0,17 mmol; Intermediate compound 16), 1-methylpiperazine (34 μl, 0.33 mmol), acetic acid (95 μl, 1,67 mmol) and NaB(OAc)3H (106 mg, 0.50 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 720 seconds at 130°C, filtered, concentrated and purified using preparative HPLC/UV (System A, 23-50% MeCN, 0.1% of TFU). Specified in the title compound (17 mg, 16%) was obtained in the form of not-quite-white solid. MS (ESI+) for C21H25N3O2S m/z 384 (M+H)+.

Example 29

1-({1-[(2-Were)sulfonyl]-1H-indol-4-yl}methyl)pyrrolidin-3-ol triptorelin

Followed the experimental procedure described for Example 28, using pyrrolidin-3-ol (28 μl, 0.33 mmol). HPLC/UV (System A, 22-49% MeCN, 0.1% of TFU). Specified in the title compound (17 mg, 20%) was obtained as a light brown solid. MS (ESI+) for C20H22N2O3S m/z 371 (M+H)+.

Example 30

1-[(2-Were)sulfonyl]-4-(feast of alidin-1-ylmethyl)-1H-indole, triptorelin

Followed the experimental procedure described for Example 28, using pyrrolidine (28 μl, 0.33 mmol). HPLC/UV (System A, 28-53% MeCN, 0.1% of TFU). Specified in the title compound (12 mg, 17%) was obtained as a light brown solid. MS (ESI+) for C20H22N2O2S m/z 355 (M+H)+.

Example 31

2-[Methyl({1-[(2-were)sulfonyl]-1H-indol-4-yl}methyl)amino]ethanol, triptorelin

Followed the experimental procedure described for Example 28 using 2-(methylamino)ethanol (27 μl, 0.33 mmol). HPLC/UV (System A, 22-49% MeCN, 0.1% of TFU). Specified in the title compound (16 mg, 21%) was obtained as a light brown solid. MS (ESI+) for C19H22N2O3S m/z 359 (M+H)+.

Example 32

N,N-Dimethyl-1-{1-[(2-were)sulfonyl]-1H-indol-4-yl}methanamine, triptorelin

Followed the experimental procedure described for Example 28, using dimethylamine hydrochloride (27 mg, 0.33 mmol). HPLC/UV (System A, 23-50% MeCN, 0.1% of TFU). Specified in the title compound (11 mg, 15%) was obtained as a light brown solid. MS (ESI+) for C18H20N2O2S m/z 329 (M+H)+.

Intermediate compound 17

4-Bromo-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole

An aqueous solution of 2,5M NaOH (5 ml) was added to a stirred mixture of 4-br the m-1H-indole (1000 mg, 5.3 mmol), 3-(trifluoromethyl)benzosulfimide (1300 mg, 5.6 mmol) and tetrabutylammonium bisulfate (173 mg, 0.5 mmol) in DCM (10 ml). The reaction mixture was stirred at ambient temperature overnight. The mixture was diluted with DCM and water and the layers were separated. DCM was washed with water 2 times, dried (MgSO2) and concentrated to obtain 1.6 g of the crude substance, which was purified using flash chromatography (SiO2, eluent EtOAc:hexane 9:1) to obtain specified in the header of the product (0,91 g, 44%). MS (ESI+) for C15H9BrF3NO2S m/z 404,2 (M+H)+.

Intermediate compound 18

1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-4-vinyl-1H-indole

Followed the experimental procedure described for intermediate 15 using 4-bromo-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole (500 mg, 1,24 mmol; Intermediate compound 17), tributyl(vinyl)stannane (just 0,723 ml of 2.86 mmol) and Pd(PPh3)2OAc2(a total of 46 mg, holding 0.062 mmol). Specified in the title compound (348 mg, 80%) was obtained as a yellow viscous oil. MS (ESI+) for C17H12F3NO2S m/z 352 (M+H)+.

Intermediate compound 19

1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-1H-indole-4-carbaldehyde

Followed the experimental procedure described for intermediate 16, using 1-{[3-(trifluoromethyl)phenyl]Sul is the IMT}-4-vinyl-1H-indole (348 mg, 0,99 mmol; Intermediate compound 18), OSCM (13 mg, 0.05 mmol), 2,6-lutidine (230 μl, 2.0 mmol) and periodate sodium (0,848 g of 3.96 mmol). Specified in the title compound was obtained (368 mg, 105%, there still remained a number of dioxane in accordance with the data NAMR) in the form of a black resin. MS (ESI+) for C16H10F3NO3S m/z 354 (M+H)+.

Example 33

4-(Piperazine-1-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole, bis(triptorelin)

1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-1H-indole-4-carbaldehyde (58 mg, 0.16 mmol; Intermediate compound 19), 1-BOC-piperazine (61 mg, 0.33 mmol), acetic acid (94 μl, of 1.64 mmol) and NaB(OAc)3H (104 mg, 0.49 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 720 seconds at 130°C. the Mixture was filtered and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, 20-45% MeCN, 0.1% of TFU). Specified in the title compound (57 mg, 53%) was obtained as a light brown solid. MS (ESI+) for C20H20F3N3O2S m/z 424 (M+H)+.

Example 34

{(2R)-1-[(1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]pyrrolidin-2-yl}methanol, triptorelin

1-{[3-(Thrift rmutil)phenyl]sulfonyl}-1H-indole-4-carbaldehyde (58 mg, 0.16 mmol; Intermediate compound 19), (2R)-pyrrolidin-2-ylmethanol (32 μl, 0.33 mmol), acetic acid (94 μl, of 1.64 mmol) and NaB(OAc)3H (104 mg, 0.49 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 720 seconds at 130°C, filtered, concentrated and purified using preparative HPLC/UV (System A, 27-49% MeCN, 0.1% of TFU). Specified in the title compound (40 mg, 44%) was obtained as a light brown solid. MS (ESI+) for C21H21F3N2O3S m/z 439 (M+H)+.

Example 35

4-(Pyrrolidin-1-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole, triptorelin

Followed the experimental procedure described for Example 34, using pyrrolidine (27 μl, 0.33 mmol). Preparative HPLC/UV (System A, 29-51% MeCN, 0.1% of TFU). Specified in the title compound (32 mg, 38%) was obtained as a light brown solid. MS (ESI+) for C20H19F3N2O2S m/z 409 (M+H)+.

Example 36

2-{Methyl[(1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]amino}ethanol, triptorelin

Followed the experimental procedure described for Example 34 using 2-(methylamino)ethanol (26 μl, 0.33 mmol). Preparative HPLC/UV (System A, 27-49% MeCN, 0.1% of TFU). Specified in the title compound (33 mg, 38%) was obtained in the form of a Saint is to brown solid. MS (ESI+) for C19H19F3N2O3S m/z 413 (M+H)+.

Example 37

N,N-Dimethyl-1-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methanamine, triptorelin

Followed the experimental procedure described for Example 34, using dimethylamine hydrochloride (27 mg, 0.33 mmol). Preparative HPLC/UV (System A, 27-49% MeCN, 0.1% of TFU). Specified in the title compound (33 mg, 38%) was obtained as a light brown solid. MS (ESI+) for C18H17F3N2O2S m/z 383 (M+H)+.

Intermediate compound 20

4-Bromo-1-(2-thienylmethyl)-1H-indole

An aqueous solution of 2,5M NaOH (3 ml) was added to a stirred mixture of 2-thiophenesulfonyl (1,03 g, 5,61 mmol), 4-bromoindole (1,00 g, 5,10 mmol) and tetrabutylammonium bisulfate (87 mg, 0.05 mmol). The reaction mixture was stirred overnight (22 hours). Added additional amount of 2-thiophenesulfonyl (50 mg, 0.27 mmol) with constant stirring for 3 hours. The layers were left to separate. The organic layer was washed twice with water, dried and concentrated to obtain specified in the connection header (1,67 g, 96%) as a gray solid. MS (ESI+) for C12H8BrNO2S2m/z 342 (M+H)+.

The intermediate connection 21

1-(2-Thienylmethyl)-4-vinyl-1H-indole

Followed the experimental the th procedure described for intermediate 15 using 4-bromo-1-(2-thienylmethyl)-1H-indole (500 mg, of 1.46 mmol; Intermediate compound 20), tributyl(vinyl)stannane (just 0,864 ml of 2.92 mmol) and Pd(PPh3)2OAc2(55 mg, 0,073 mmol). Specified in the title compound (333 mg, 79%) was obtained as colorless solid. MS (ESI+) for C14H11NO2S2m/z 290 (M+H)+.

Intermediate compound 22

1-(2-Thienylmethyl)-1H-indole-4-carbaldehyde

Followed the experimental procedure described for intermediate 16, using 1-(2-thienylmethyl)-4-vinyl-1H-indole (333 mg, 1.15 mmol; Intermediate compound 21), OsO4(15 mg, 0.06 mmol), 2,6-lutidine (268 μl, 2,30 mmol) and periodate sodium (0,984 g, 4,60 mmol). Specified in the title compound was obtained (306 mg, 91%, there still remained a number of dioxane in accordance with the data NAMR) in the form of a black resin. MS (ESI+) for C13H9NO3S2m/z 292 (M+H)+.

Example 38

4-(Piperazine-1-ylmethyl)-1-(2-thienylmethyl)-1H-indole, bis(triptorelin)

1-(2-Thienylmethyl)-1H-indole-4-carbaldehyde (51 mg, 0.18 mmol; Intermediate compound 22), 1-BOC-piperazine (65 mg, 0.35 mmol), acetic acid (l00 µl of 1.75 mmol) and NaB(OAc)3H (111 mg, of 0.53 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to mikrovolnovaya irradiation for 720 seconds at 130°C. The mixture was filtered and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, 18-44% MeCN, 0.1% of TFU). Specified in the title compound (32 mg, 31%) was obtained as a brown solid. MS (ESI+) for C17H19N3O2S2m/z 362 (M+H)+.

Example 39

N-Ethyl-N-{[1-(2-thienylmethyl)-1H-indol-4-yl]methyl}ethanamine, triptorelin

1-(2-Thienylmethyl)-1H-indole-4-carbaldehyde (51 mg, 0.18 mmol; Intermediate compound 22), N-tiletamine (36 μl, 0.35 mmol), acetic acid (l00 µl of 1.75 mmol) and NaB(OAc)3H (111 mg, of 0.53 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 720 seconds at 130°C, filtered, concentrated and purified using preparative HPLC/UV (System A, 23-50% MeCN, 0.1% of TFU). Specified in the title compound (7 mg, 9%) was obtained as a brown solid. MS (ESI+) for C17H20N2O2S2m/z 349 (M+H)+.

Example 40

4-(Pyrrolidin-1-ylmethyl)-1-(2-thienylmethyl)-1H-indole, triptorelin

Followed the experimental procedure described for Example 39, using pyrrolidine (29 μl, 0.35 mmol). Preparative HPLC/UV (System A, 1-48% MeCN, 0,1% TFU). Specified in the title compound (34 mg, 43%) was obtained as a brown solid. MS (ESI+) for C17H18N2O2S2m/z 347 (M+H)+.

Example 41

4-[(4-Propylpiperazine-1-yl)methyl]-1-(2-thienylmethyl)-1H-indole, bis(triptorelin)

Followed the experimental procedure described for Example 39, using dihydrobromide 1-propylpiperazine (102 mg, 0.35 mmol). Preparative HPLC/UV (System A, 19-45% MeCN, 0.1% of TFU). Specified in the title compound (24 mg, 45%) was obtained as a gray solid. MS (ESI+) for C20H25N3O2S2m/z 404 (M+H)+.

Example 42

N,N-Dimethyl-1-[1-(2-thienylmethyl)-1H-indol-4-yl]methanamine, triptorelin

Followed the experimental procedure described for Example 39, using dimethylamine hydrochloride (29 mg, 0.35 mmol). Preparative HPLC/UV (System A, 20-45% MeCN, 0.1% of TFU). Specified in the title compound (20 mg, 26%) was obtained as a brown solid. MS (ESI+) for C15H16N2O2S2m/z 321 (M+H)+.

Intermediate compound 23

Pyridine-3-sulphonylchloride, hydrochloride

Pyridine-3-sulfonic acid (3.00 g, 18,8 mmol), and PCl5(4,79 g, 23,0 mmol) were mixed in POCl3(6 ml). The reaction mixture was stirred and subjected to boiling under reflux at 120°C during the night (15 hours). Was cooled to room temperature, diluted using CHCl3(20 ml) and saturated using HCl (gas). This made the selection of a white precipitate, which was filtered, washed using CHCl3and dried under reduced pressure to obtain specified in the connection header (3,36 g, 83%) as a white powder.

Intermediate compound 24

4-Bromo-1-(pyridine-3-ylsulphonyl)-1H-indole

An aqueous solution of 2M NaOH (1 ml) was added to stir the mixture hydrochloride pyridine-3-sulphonylchloride (240 mg, 1.12 mmol; Intermediate compound 23), 4-bromoindole (200 mg, of 1.02 mmol) and tetrabutylammonium bisulfate (35 mg, 0.10 mmol). The reaction mixture was stirred for 45 minutes and the layers were left to separate. The organic layer was washed two times diluted aqueous solution of NaOH, dried and concentrated to obtain specified in the title compound (325 mg, 95%) as not quite white solid. MS (ESI+) for C13H9BrN2O2S m/z 337 (M+H)+.

Intermediate compound 25

1-(Pyridine-3-ylsulphonyl)-4-vinyl-1H-indole

Followed the experimental procedure described for intermediate 15 using 4-bromo-1-(pyridine-3-ylsulphonyl)-1H-indole (285 mg, 0.85 mmol; Intermediate compound 24) in anhydrous MeCN (5 ml, one bottle), tributyl(vinyl)stannane (0,494 ml, was 1.69 mmol) and Pd(PPh3) 2OAc2(32 mg, 0,042 mmol). Flash chromatography (1% MeOH in DCM) gave specified in the title compound (208 mg, 80%) as a yellow viscous oil. MS (ESI+) for C15H12N2O2S m/z 285 (M+H)+.

The intermediate connection 26

1-(Pyridine-3-ylsulphonyl)-1H-indole-4-carbaldehyde

Followed the experimental procedure described for intermediate 16, using 1-(pyridine-3-ylsulphonyl)-4-vinyl-1H-indole (208 mg, 0.73 mmol; Intermediate compound 25), OsO4(9 mg, 0.04 mmol), 2,6-lutidine (170 μl, of 1.46 mmol) and periodate sodium (0.625 g, of 2.92 mmol). After a single purification with flash chromatography, some of the material remained insoluble in DCM/MeOH and filtered. Specified in the title compound (123 mg, 59%, were still a number of dioxane in accordance with the data NAMR) received in the form of a black resin. MS (ESI+) for C14H10N2O3S m/z 287 (M+H)+.

Example 43

4-(Piperazine-1-ylmethyl)-1-(pyridine-3-ylsulphonyl)-1H-indole, Tris(triptorelin)

1-(Pyridine-3-ylsulphonyl)-1H-indole-4-carbaldehyde (41 mg, 0.14 mmol; Intermediate compound 26), 1-BOC-piperazine (53 mg, 0.29 mmol), acetic acid (82 μl, of 1.43 mmol) and NaB(OAc)3H (91 mg, 0.43 mmol), in that order, added to anhydrous THF (4 ml). Added an additional amount of 1-BOC-piperazine (27 mg, 0.14 mmol), UKS is red acid (41 μl, to 0.72 mmol) and NaB(OAc)3H (45 mg, 0.21 mmol). The mixture was subjected to microwave irradiation for 900 seconds at 130°C. the Mixture was filtered and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, 13 to 33% MeCN, 0.1% of TFU). Specified in the title compound (9 mg, 9%) was obtained as a brown solid. MS (ESI+) for C18H20N4O2S m/z 357 (M+H)+.

Example 44

N,N-Dimethyl-1-[1-(pyridine-3-ylsulphonyl)-1H-indol-4-yl]methanamine, bis(triptorelin)

1-(Pyridine-3-ylsulphonyl)-1H-indole-4-carbaldehyde (41 mg, 0.14 mmol; Intermediate compound 26), dimethylamine hydrochloride (23 mg, 0.29 mmol), acetic acid (82 μl, of 1.43 mmol) and NaB(OAc)3H (91 mg, 0.43 mmol), in that order, added to anhydrous THF (4 ml). Added additional amount of dimethylamine hydrochloride (12 mg, 0.14 mmol), acetic acid (41 μl, to 0.72 mmol) and NaB(OAc)3H (45 mg, 0.21 mmol) and the Mixture was subjected to microwave irradiation for 900 seconds at 130°C, filtered, concentrated and purified preparative HPLC/UV (System A, 18-45% MeCN, 0.1% of TFU). Specified in the title compound (5 mg, 7%) was obtained as a brown solid. MS (ESI+) for C16H17N3O2S m/z 316 (M+H)+.

Example 45

1-(Pyridine-3-ylsulphonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole, bis(triptorelin)

Followed the experimental procedure described for Example 44, using pyrrolidine (24 μl, 0.29 mmol). Preparative HPLC/UV (System A, 22-48% MeCN, 0.1% of TFU). Specified in the title compound (12 mg, 15%) was obtained as a brown solid. MS (ESI+) for C18H19N3O2S m/z 342 (M+H)+.

Example 46

1-(Phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin

K2CO3(59 mg, 0.43 mmol) and pyrrolidine (35 μl, 0.43 mmol) was added to 4-(methyl bromide)-1-(phenylsulfonyl)-1H-indole (30 mg, 0,086 mmol; Intermediate compound 2) in anhydrous MeCN (4 ml). The mixture was subjected to microwave irradiation at 150°C for 600 seconds. The reaction mixture was filtered, concentrated and purified preparative HPLC/UV (System A, 25-52% MeCN, 0.1% of TFU). Specified in the title compound (23 mg, 60%) was obtained as colorless solid. MS (ESI+) for C19H20N2O2S m/z 341 (M+H)+.

Example 47

N,N-Dimethyl-1-[1-(phenylsulfonyl)-1H-indol-4-yl]methanamine, triptorelin

Followed the experimental procedure described for Example 46, using dimethylamine hydrochloride (35 mg, 0.43 mmol) and K2CO3(118 mg, 0.86 mmol). Preparative HPLC/UV (System A, 20-46% MeCN, 0.1% of TFU). Specified the title compound (20 mg, 55%) was obtained as colorless solid. MS (ESI+) for C17H18N2O2S m/z 315 (M+H)+.

Comparative example 48

4-{[(1-Methylpyrrolidine-3-yl)oxy]methyl}-1-(phenylsulfonyl)-1H-indole, triptorelin

1 Methylpyrrolidine-3-ol (3.2 mg, 0,030 mmol) was dissolved in anhydrous THF (1 ml) was added potassium carbonate (7.9 mg, to 0.060 mmol) and the mixture was heated in a STEM block at 75°C. After 20 minutes, was added 4-(methyl bromide)-1-(phenylsulfonyl)-1H-indole (0.01 g, 0.03 mmol; Intermediate compound 2) and the mixture was heated for 1 hour. Was added water (2 ml) and ethyl acetate (2 ml) and the mixture was separated. The organic layer was extragonadal saturated saline (2 ml) and the solvent evaporated. The residue was purified preparative HPLC/UV (System A 10-40% MeCN in 0.1% TFU) with the receipt of 2.9 mg (14%) indicated in the title compound as a pale yellow resin. MS (ESI+) for C20H22N2O3S m/z 371 (M+H)+.

Intermediate compound 27

4-Bromo-1H-indole-3-carbaldehyde

POCl3(1,02 g, 6,63 mmol) was added dropwise to ice DMF (3 ml) and was stirred for 15 minutes. Was slowly added 4-bromoindole (1,00 g, 5,10 mmol) in DMF (1 ml). The mixture was heated to 35°C with constant stirring for 1.20 hours (formed yellow precipitate). The reaction mixture was cooled on ice and treated with ice and 20% mass/mass aqueous solution of NaOH on the pH 14 (bright pink). Heating at the boiling point under reflux for 15 minutes gave a yellow transparent solution, which was the selection of a white precipitate when it was left to reach room temperature. The precipitate was filtered, washed with ice water and dried under reduced pressure over a weekend with obtaining specified in the connection header (1,14 g, 65%) as not quite white solid. MS (ESI+) for C9H6BrNO m/z 224 (M+H)+.

The intermediate connection 28

4-Bromo-3-methyl-1H-indol

LAH (1,0M in THF, of 5.75 ml of 5.75 mmol) was added dropwise subjected to boiling under reflux 4-bromo-1H-indole-3-carbaldehyde (644 mg, 2,87 mmol; Intermediate compound 27) in anhydrous THF (20 ml). The mixture was boiled under reflux for 1 hour, allowed to reach room temperature and extinguished with water (220 ml), masses/mass 15% aqueous NaOH solution (220 ml) and water (650 ml). The precipitate was filtered off, the filtrate was concentrated and the residue was extragonadal aqueous solution of NaOH (10 ml) and DCM (2×10 ml). The organic layers were combined with the merged layers obtained earlier batch of this intermediate compound (following the procedure of this experiment and on the basis of 4-bromo-1H-indole-3-carbaldehyde, 100 mg, 0.45 mmol; Intermediate compound 27), dried and concentrated to obtain specified in the agolove compound (556 mg, 80%) as a light brown oil. MS (ESI+) for C9H8BrN m/z 210 (M+H)+.

Intermediate compound 29

4-Bromo-3-methyl-1-(phenylsulfonyl)-1H-indole

An aqueous solution of 4M NaOH (3 ml) was added to a stirred mixture of 4-bromo-3-methyl-1H-indole (456 mg, 2,17 mmol; Intermediate compound 28), benzosulfimide (306 μl g, 2,39 mmol) and tetrabutylammonium bisulfate (74 mg, 0.22 mmol) in DCM (30 ml). The reaction mixture was stirred for 1 hour, combined with previously obtained by the party of this intermediate compound (following the procedure of this experiment and on the basis of 4-bromo-3-methyl-1H-indole (100 mg, 0.48 mmol; Intermediate compound 28), washed twice with water, dried and concentrated. The crude product was purified column flash chromatography (DCM/hexane 1:3). The product (650 mg, 70%) was obtained as a white solid. MS (ESI+) for C15H12BrNO2S m/z 350 (Monoisotope+H)+.

The intermediate connection 30

3-Methyl-1-(phenylsulfonyl)-4-vinyl-1H-indole

Tributyl(vinyl)stannane (0,400 ml, 1.37 mmol) and Pd(PPh3)2OAc2(51 mg, 0,069 mmol) was added to 4-bromo-3-methyl-1-(phenylsulfonyl)-1H-indole (240 mg, 0.69 mmol; Intermediate compound 29) in anhydrous MeCN (4 ml). The reaction mixture was subjected to microwave irradiation at 180°C for 720 seconds. The mixture was combined with previously received shipments promezhutochnogo the connection (following the procedure of this experiment and on the basis of 4-bromo-3-methyl-1-(phenylsulfonyl)-1H-indole, 50 and 310 mg; Intermediate compound 29), filtered and concentrated. Purification was performed by flash chromatography (30% hexane in DCM). This gave the product (420 mg, 82%) as a white solid. MS (ESI+) for C17H15NO2S m/z 298 (M+H)+.

The intermediate connection 31

3-Methyl-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde

OsO4(29 mg, 0.12 mmol) was added to a stirred mixture of 3-methyl-1-(phenylsulfonyl)-4-vinyl-1H-indole (342 mg, 1.15 mmol; Intermediate compound 30) and 2,6-lutidine (268 μl, 2.3 mmol) in dioxane (15 ml). Colorless mixture became black for 1 minute. Solution was added periodate sodium (0,984 g, 4.6 mmol) in water (5 ml), heated to dissolve). Immediately formed a grey precipitate. The mixture was stirred for 50 minutes, combined with previously obtained by the party of this intermediate compound (following the procedure of this experiment and based on 3-methyl-1-(phenylsulfonyl)-4-vinyl-1H-indole, 70 mg; Intermediate compound 30)was extragonadal water (30 ml) and DCM (2×30 ml). The organic layers were combined, dried, filtered and concentrated to obtain specified in the title compound (463 mg, 89%) as a black solid. MS (ESI+) for C16H13NO3S m/z 300 (M+H)+.

Example 49

3-Methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

3-Methyl-1-(Peninsula who yl)-1H-indole-4-carbaldehyde (40 mg, 0.13 mmol; Intermediate compound 31), 1-BOC-piperazine (50 mg, 0.27 mmol), acetic acid (76 μl, of 1.34 mmol) and NaB(OAc)3H (85 mg, 0.40 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 720 seconds at 130°C, filtered and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, 20-45% MeCN, 0.1% of TFU). Specified in the title compound (32 mg, 40%) was obtained as a light brown solid. MS (ESI+) for C20H23N3O2S m/z 370 (M+H)+.

Example 50

3-Methyl-4-[(4-methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)

3-Methyl-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (40 mg, 0.13 mmol; Intermediate compound 31), 1-methylpiperazine (27 mg, 0.27 mmol), acetic acid (76 μl, of 1.34 mmol) and NaB(OAc)3H (85 mg, 0.40 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 720 seconds at 130°C, filtered, concentrated and purified using preparative HPLC/UV (System A, 23-50% MeCN, 0.1% of TFU). Specified in the title compound (31 mg, 38%) was obtained as a light brown solid. MS (ESI+) for C21H25N3Osub> 2S m/z 384 (M+H)+.

Example 51

3-Methyl-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin

Followed the experimental procedure described for Example 50, using pyrrolidine (22 μl, 0.27 mmol). Preparative HPLC/UV (System A, 28-53% MeCN, 0.1% of TFU). Specified in the title compound (20 mg, 32%) was obtained as a light brown solid. MS (ESI+) for C20H22N2O2S m/z 355 (M+H)+

Example 52

N,N-Dimethyl-1-[3-methyl-1-(phenylsulfonyl)-1H-indol-4-yl]methanamine, triptorelin

Followed the experimental procedure described for Example 50, using dimethylamine hydrochloride (22 mg, 0.27 mmol). Preparative HPLC/UV (System A, 23-50% MeCN, 0.1% of TFU). Specified in the title compound (12 mg, 20%) was obtained as colorless solid. MS (ESI+) for C18H20N2O2S m/z 329 (M+H)+.

The intermediate connection 32

4-Bromo-6-methoxy-1-(phenylsulfonyl)-1H-indole

4-Bromo-6-methoxyindole (0.07 g, 0.3 mmol) was dissolved in anhydrous dichloromethane (4 ml) was added benzosulphochloride (0.06 g, 0.3 mmol), tetrabutylammonium bisulfate (0.01 g, 0.01 mmol) and 4 n NaOH solution (0.5 ml) and the mixture was stirred at room temperature for 50 minutes. The mixture was extragonadal water (2×4 ml), dried (Na2SO4) and was evaporated. The crude product was combined with recip is authorized previously by the party of this intermediate compound (following the procedure of this experiment and on the basis of 4-bromo-6-methoxyindole (0.35 g, 1.5 mmol). MS (ESI+) for C15H12BrNO3S m/z 366 (M+H)+.

The intermediate connection 33

6-Methoxy-1-(phenylsulfonyl)-4-vinyl-1H-indole

4-Bromo-6-methoxy-1-(phenylsulfonyl)-1H-indole (0.33 g, 0.9 mmol; Intermediate compound 32) was dissolved in anhydrous toluene (4 ml) was added tributyl(vinyl)stannane (of 0.53 ml, 1.8 mmol) and acetate bis(triphenylphosphine)palladium(II) (0.03 g, 0.05 mmol). The mixture was stirred STEM block at 110°C for 16 hours. The crude product was combined with that obtained previously by the party of this intermediate compound was filtered and the solvent evaporated. The residue was purified flash chromatography using a mixture of isohexane:dichloromethane 1:1 as eluent to obtain 0,30 g (89%) specified in the connection header. MS (ESI+) for C17H15NO3S m/z 314 (M+H)+.

The intermediate connection 34

6-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde

6-Methoxy-1-(phenylsulfonyl)-4-vinyl-1H-indole (0.27 g, 0.9 mmol; Intermediate compound 33) was dissolved in dioxane (24 ml) was added 2,6-lutidine (0.2 ml, 1.7 mmol). Added osmium tetroxide (0,011 g, 0.04 mmol) and after 15 minutes of mixing the color of the mixture changed to black. Added periodate sodium (0.74 g, 3.4 mmol)dissolved in water (8 ml, heated to dissolve), and began the formation of a precipitate. After 1 hour stirring at room temperature the E. the mixture was distributed between 2 N. the HC1 solution and dichloromethane. The organic layer was dried (Na2SO4) and concentrated to obtain 0,41 g of the crude product. MS (ESI+) for C16H13NO4S m/z 316 (M+H)+.

Example 53

6-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

6-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (0.03 g, 0.1 mmol; Intermediate compound 34) was dissolved in anhydrous THF (2 ml) was added tert-butylpiperazine-1-carboxylate (0.035 g, 0.2 mmol), acetic acid (0.05 ml, 1.0 mmol) and triacetoxyborohydride sodium (0,061 g, 0.3 mmol). The mixture was subjected to microwave irradiation at 130°C for 600 seconds. The mixture was filtered and the solvent evaporated. The residue was dissolved in 1.5 ml of methanol and added a few drops of concentrated HCl and the mixture was processed in the STEM block to remove the BOC-protection at 50°C for 1 hour. The mixture was purified preparative HPLC/UV (System A 20-50% MeCN in 0.1% TFU) to obtain 15 mg (25%) of product as a brown resin. MS (ESI+) for C20H23N3O3S m/z 386 (M+H)+.

Example 54

{[6-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin

Was obtained using the procedure described for Example 53, using dimethylamine hydrochloride (0,021 g, 0.3 mmol). Yield: 16 mg (38%) of a brown resin after cleaning preparative HPLC/UV (System A20-50% MeCN in 0.1% TFU). MS (ESI+) for C18H20N2O3S m/z 345 (M+H)+.

Example 55

6-Methoxy-4-{[(3R)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)

Was obtained using the procedure described for Example 53, using (2R)-2-methylpiperazine (0.025 g, 0.30 mmol). Yield: 22 mg (37%) of a brown resin after cleaning preparative HPLC/UV (System A 20-50% MeCN in 0.1% TFU). MS (ESI+) for C21H25N3O3S m/z 400 (M+H)+.

Example 56

6-Methoxy-4-{[(3S)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)

Was obtained using the procedure described for Example 53, using (2S)-2-methylpiperazine (0.025 g, 0.3 mmol). Yield: 26 mg (44%) of a brown resin after cleaning preparative HPLC/UV (System A 20-50% MeCN in 0.1% TFU). MS (ESI+) for C21H25N3O3S m/z 400 (M+H)+.

Example 57

6-Methoxy-4-[(4-methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)

Was obtained using the procedure described for Example 53, using 1-methylpiperazine one (0.03 ml, 0.3 mmol). Yield: 40 mg (67%) grey resin after cleaning preparative HPLC/UV (System A 20-50% MeCN in 0.1% TFU). MS (ESI+) for C21H25N3O3S m/z 400 (M+H)+.

Example 58

4-(1,4-Diazepan-1-ylmethyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)

Poluchalis using procedures described for Example 53, using BOC-homopiperazine (0,051 g, 0.3 mmol). Yield: 41 mg (69%) of a light brown resin after cleaning preparative HPLC/UV (System A 20-50% MeCN in 0.1% TFU). MS (ESI+) for C21H25N3O3S m/z 400 (M+H)+.

Example 59

6-Methoxy-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin

Was obtained using the procedure described for Example 53, using pyrrolidine (0,02 ml, 0.2 mmol). Yield: 27 mg (59%) of a brown resin after cleaning preparative HPLC/UV (System A 20-50% MeCN in 0.1% TFU). MS (ESI+) for C20H22N2O3S m/z 371 (M+H)+.

Example 60

2-[{[6-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}(methyl)amino]ethanol, triptorelin

Was obtained using the procedure described for Example 53, using 2-(methylamino)ethanol (0,02 ml, 0.1 mmol). Yield: 11 mg (30%) brown resin after cleaning preparative HPLC/UV (System A 20-50% MeCN in 0.1% TFU). MS (ESI+) for C19H22N2O4S m/z 375 (M+H)+.

The intermediate connection 35

4-Bromo-6-fluoro-1H-indol

1-Bromo-5-fluoro-2-methyl-3-nitrobenzene (2.00 g, 8,55 mmol) and (dimethoxymethyl)dimethylamine (5,66 ml, and 42.7 mmol) in anhydrous DMF (20 ml) was subjected to boiling under reflux in an atmosphere of N2within 8 hours, then at room temperature overnight. The mixture was diluted with p the power of DCM and extragonadal 5 times with water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was dissolved in AcOH (10 ml) and added dropwise to a boiling mixture of Fe(s, a fine powder) in AcOH (10 ml). The mixture was subjected to boiling under reflux for 40 minutes, divided between DCM and saturated aqueous Na2CO3/saturated salt solution (the mixture was filtered through celite to phase separation). The aqueous layer was extragonadal again using DCM. The organic layers were combined, dried and concentrated. Purification was performed by column flash chromatography (DCM/hexane 1:3) to obtain the specified title compound (660 mg, 39%) as a yellow oil. MS (ESI+) for C8H5BrFN m/z 214 (M+H)+.

Intermediate compound 36

4-Bromo-6-fluoro-1-(phenylsulfonyl)-1H-indole

An aqueous solution of 4 M NaOH (5 ml) was added to a stirred mixture of 4-bromo-6-fluoro-1H-indole (500 mg, 2.34 mmol; Intermediate compound 35), benzosulfimide (329 μl g, 2.57 mmol) and tetrabutylammonium bisulfate (78 mg, 0.23 mmol) in DCM (30 ml). The reaction mixture was stirred for 1 hour, combined with previously obtained by the party of this intermediate compound (following the procedure of this experiment and on the basis of 4-bromo-6-fluoro-1H-indole, 152 mg, 0.71 mmol; Intermediate compound 35), washed twice with water, dried and concentrated. The product of the (1.08 g, 100%) was obtained as a beige solid. MS (ESI+) for C14H9BrFNO2S m/z 354 (M+H)+.

The intermediate connection 37

6-Fluoro-1-(phenylsulfonyl)-4-vinyl-1H-indole

Tributyl(vinyl)stannane (0,413 ml of 1.41 mmol) and Pd(PPh3)2OAc2(53 mg, 0,071 mmol) was added in 2 vial for microwave heating, containing 4-bromo-6-fluoro-1-(phenylsulfonyl)-1H-indole (250 mg, 0.71 mmol; Intermediate compound 36) in anhydrous MeCN (4 ml) each. The reaction mixture was subjected to microwave irradiation at 180°C for 720 seconds. The mixture was combined with previously obtained by the party of this intermediate compound (following the procedure of this experiment and on the basis of 4-bromo-6-fluoro-1-(phenylsulfonyl)-1H-indole, 50 mg; Intermediate compound 36), filtered and concentrated. Purification was performed by flash chromatography (hexane/DCM 2:1). This gave the product (316 mg, 68%) as a white solid. MS (ESI+) for C16H12FNO2S m/z 302 (M+H)+.

Intermediate compound 38

6-Fluoro-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde

OsO4(26 mg, 0.1 mmol) was added to a stirred mixture of 6-fluoro-1-(phenylsulfonyl)-4-vinyl-1H-indole (309 mg, 1,03 mmol; Intermediate compound 37) and 2,6-lutidine (239 μl, 2.05 mmol) in dioxane (18 ml). Colorless mixture became black for 1 minute. Solution was added periodate sodium (0,877 g, 4.1 mmol who) in water (6 ml, heated to dissolve). Immediately formed a grey precipitate. The mixture was stirred for 15 minutes, was extragonadal water (30 ml) and DCM (2×30 ml). The organic layers were combined, dried, filtered and concentrated to obtain specified in the title compound (326 mg, 105%) as a black solid. MS (ESI+) for C15H10FNO3S m/z 304 (M+H)+.

Example 61

6-Fluoro-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

6-Fluoro-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (38 mg, 0.13 mmol; Intermediate compound 38), 1-BOC-piperazine (47 mg, 0.25 mmol), acetic acid (72 μl, 1.25 mmol) and NaB(OAc)3H (80 mg, 0.38 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 720 seconds at 130°C, filtered and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, 20-50% MeCN, 0.1% of TFU). Specified in the title compound (35 mg, 47%) was obtained in the form of not-quite-white solid. MS (ESI+) for C19H20FN3O2S m/z 374 (M+H)+.

Example 62

4-(1,4-Diazepan-1-ylmethyl)-6-fluoro-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)

Followed the experimental procedure described on the I of Example 61, using 1-BOC-homopiperazine (50 mg, 0.25 mmol). Preparative HPLC/UV (System A, 20-50% MeCN, 0.1% of TFU). Specified in the title compound (35 mg, 45%) was obtained as a light brown solid. MS (ESI+) for C20H22FN3O2S m/z 388 (M+H)+.

Example 63

6-Fluoro-4-{[(3S)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)

6-Fluoro-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (38 mg, 0.13 mmol; Intermediate compound 38), (2S)-2-methylpiperazine (25 mg, 0.25 mmol), acetic acid (72 μl, 1.25 mmol) and NaB(OAc)3H (80 mg, 0.38 mmol), in that order, added to anhydrous THF (4 ml). The mixture was subjected to microwave irradiation for 720 seconds at 130°C, filtered, concentrated and purified using preparative HPLC/UV (System A, 25-55% MeCN, 0.1% of TFU). Specified in the title compound (13 mg, 17%) was obtained as a light brown solid. MS (ESI+) for C20H22FN3O2S m/z 388 (M+H)+.

Example 64

6-Fluoro-4-{[(3R)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)

Followed the experimental procedure described for Example 63, using (2R)-2-methylpiperazine (25 mg, 0.25 mmol). Preparative HPLC/UV (System A, 23-50% MeCN, 0.1% of TFU). Specified in the title compound (16 mg, 20%) was obtained as a light brown solid substances the. MS (ESI+) for C20H22FN3O2S m/z 388 (M+H)+.

Example 65

6-Fluoro-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin

Followed the experimental procedure described for Example 63, using pyrrolidine (21 μl, 0.25 mmol). Preparative HPLC/UV (System A, 25-55% MeCN, 0.1% of TFU). Specified in the title compound (22 mg, 37%) was obtained as colorless solid. MS (ESI+) for C19H19FN2O2S m/z 359 (M+H)+.

Example 66

2-[{[6-Fluoro-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}(methyl)amino]ethanol, triptorelin

Followed the experimental procedure described for Example 63, using 2-(methylamino)ethanol (20 μl, 0.25 mmol). Preparative HPLC/UV (System A, 20-50% MeCN, 0.1% of TFU). Specified in the title compound (25 mg, 42%) was obtained as colorless solid. MS (ESI+) for C18H19FN2O3S m/z 363 (M+H)+.

Example 67

{[6-Fluoro-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin

Followed the experimental procedure described for Example 63, using dimethylamine hydrochloride (20 mg, 0.25 mmol). Preparative HPLC/UV (System A, 22-52% MeCN, 0.1% of TFU). Specified in the title compound (15 mg, 27%) was obtained as colorless solid. MS (ESI+) for C17H17FN2O2S m/z 333 (M+H)+

Example 68

6-Fluoro-4-[(4-methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)

Followed the experimental procedure described for Example 63, using 1-methylpiperazine (28 μl, 0.25 mmol). Preparative HPLC/UV (System A, 22-52% MeCN, 0.1% of TFU). Specified in the title compound (15 mg, 27%) was obtained as a brown solid. MS (ESI+) for C20H22FN3O2S m/z 388 (M+H)+.

The intermediate connection 39

1-(Phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indol-6-ol

Was obtained using the procedure described for Example 70, using 6-methoxy-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole (0,018 g, 0.05 mmol; Example 59). Yield: 12 mg (71%) of a brownish-red solid. MS (ESI+) for C19H20N2O3S m/z 357 (M+H)+.

Example 69

1-(Phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indol-6-yl dimethylcarbamate, triptorelin

1-(Phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indol-6-ol (12,2 mg; 0,034 mmol; Intermediate compound 39) was dissolved in 1 ml of pyridine was added dimethylcarbamoyl (18,0 mg; 0,171 mmol). The reaction mixture was left for stirring at room temperature for 1 hour. From the reaction mixture kept off the solvent and the crude substance was purified preparative HPLC. Output: 4,9 mg (25%). MS (ESI+) for C22H 25N3O4S m/z 428 (M+H)+.

Example 70

4-(1,4-Diazepan-1-ylmethyl)-1-(phenylsulfonyl)-1H-indol-6-ol

To 4-(1,4-diazepan-1-ylmethyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole (0.12 g, 0.03 mmol; Example 58) was added 33% HBr in acetic acid (2 ml) and the mixture was subjected to boiling under reflux in a STEM block at 125°C for 20 hours, which gave 70% conversion to the product. Added additional amount of HBr in acetic acid (1 ml) and the mixture was subjected to boiling under reflux for a further 20 hours, which gave 90% conversion to the product. Added additional amount of HBr in acetic acid (1 ml) and the mixture was subjected to boiling under reflux for 21 hours. The mixture was cooled to room temperature and was added a saturated solution of NaHCO3(foaming) until neutral pH. The mixture was extragonadal 3*EtOAc/ethanol (10:1). The organic layers were dried (Na2SO4), filtered and the solvent evaporated to obtain 9.5 mg (82%) of a brownish-red solid. MS (ESI+) for C20H23N3O3S m/z 386 (M+H)+.

The intermediate connection 40

tert-Butyl 4-[(6-methoxy-1H-indol-4-yl)methyl]piperazine-1-carboxylate

40% mass/mass aqueous solution of NaOH (1 ml) was added to tert-butyl 4-({1-[(4-forfinal)sulfonyl]-6-methoxy-1H-indol-4-yl}methyl)piperazine-1-carboxylate (62 mg, 1.12 mmol) in EtOH (10 ml). The reaction mixture was subjected to boiling under reflux for 1.5 hours, allowed to reach room temperature and was extragonadal DCM (2×50 ml) and water (40 ml). The organic layers were combined, dried and concentrated to obtain 450 mg of the crude product. Purification was performed using preparative HPLC/UV (System A, 30-65% MeCN, 0.1% of NH4OAc). The residue was extragonadal DCM and water and the organic layer was dried, filtered and concentrated to obtain specified in the title compound (130 mg, 32%based on 1-[(4-forfinal)sulfonyl]-6-methoxy-4-vinyl-1H-indole, obtained in accordance with the method of obtaining an Intermediate compound 33) as a light brown solid. MS (ESI+) for C19H27N3O3m/z 346 (M+H)+.

Example 71

1-[(4-Forfinal)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole acetate

NaH (6 mg, 0.14 mmol, 60% in mineral oil) was added to tert-butyl 4-[(6-methoxy-1H-indol-4-yl)methyl]piperazine-1-carboxylate (10 mg, 0,029 mmol; Intermediate compound 40) in anhydrous THF (1 ml). The reaction mixture was stirred for 5 minutes, was added 4-forbindelsesfaneblad (8 mg, 0,044 mmol) in anhydrous THF (0.5 ml) and the mixture was stirred over night. The reaction mixture was cooled on ice and extinguished with the help of ice and THF evaporated. The residue was dissolved in MeOH (3 ml) and EXT is ulali concentrated HCl (0.5 ml). The mixture was subjected to microwave irradiation at 100°C for 300 sec, concentrated to reduce the volume to ~1.5 ml, followed by filtration and purification using preparative HPLC/UV (System A, 25-55% MeCN, 0.1% of NH4OAc). Specified in the title compound (5 mg, 39%) was obtained as a white solid. MS (ESI+) for C20H22FN3O3S m/z 404 (M+H)+.

Example 72

6-Methoxy-4-(piperazine-1-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole, bis(triptorelin)

NaH (8 mg, 0.20 mmol, 60% in mineral oil) was added to tert-butyl 4-[(6-methoxy-1H-indol-4-yl)methyl]piperazine-1-carboxylate (23 mg, 0,067 mmol; Intermediate compound 40) in anhydrous THF (1.5 ml). The reaction mixture was stirred for 45 minutes, was added 3-(trifluoromethyl)benzosulphochloride (16 μl, 0,099 mmol) in anhydrous THF (2 ml) and the mixture was stirred over night. Added additional amount of NaH (1 EQ.) and 3-(trifluoromethyl)benzosulfimide (1.5 EQ.) with constant stirring for 1 hour 30 minutes. Added additional amount of NaH (3 EQ.) with constant stirring for 1 hour. The mixture was cooled on ice, put a few drops of water and acidified with concentrated HCl (0.5 ml). THF is evaporated and added MeOH (1.5 ml). The mixture was subjected to microwave irradiation at 100°C for 300 sec, the placenta is brilliant filtration and purification using preparative HPLC/UV (System A, 33-63% MeCN, 0.1% of TFU). Specified in the title compound (10 mg, 21%) was obtained as colorless solid. MS (ESI+) for C21H22F3N3O3S m/z 454 (M+H)+.

Example 73

1-[(2-Chlorophenyl)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

NaH (18 mg, 0.47 mmol, 60% in mineral oil) was added to tert-butyl 4-[(6-methoxy-1H-indol-4-yl)methyl]piperazine-1-carboxylate (23 mg, 0,067 mmol; Intermediate compound 40) in anhydrous THF (1.5 ml). The reaction mixture was stirred for 30 minutes, and the color changed from orange to green. Was added 2-chlorobenzenesulfonamide (36 μl, 0.27 mmol) in anhydrous THF (0.5 ml) and the mixture was stirred over night. Added additional amount of NaH (3 EQ.) with constant stirring 1.40 hours. Added additional amount of NaH (3 equiv.) was stirred for 15 minutes, followed by adding 2-chlorobenzenesulfonamide (1 EQ.) with constant stirring for 2 hours. This gave ~90% conversion to the product. The mixture was cooled on ice, put a few drops of water and extragonadal DCM (×2) and saturated saline solution. The organic layers were combined, dried and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified is using preparative HPLC/UV (System A, 20-50% MeCN, 0.1% of TFU). Specified in the title compound (10 mg, 24%) was obtained as a blue solid. MS (ESI+) for C20H22ClN3O3S m/z 420 (M+H)+.

Example 74

1-[(3-Chloro-2-were)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

NaH (18 mg, 0.47 mmol, 60% in mineral oil) was added to tert-butyl 4-[(6-methoxy-1H-indol-4-yl)methyl]piperazine-1-carboxylate (23 mg, 0,067 mmol; Intermediate compound 40) in anhydrous THF (1.5 ml). The reaction mixture was stirred for 30 minutes, and the color changed from orange to green. Was added 3-chloro-2-methylbenzenesulfonamide (60 mg, 0.27 mmol) in anhydrous THF (0.5 ml) and the mixture was stirred over night. Added additional amount of NaH (equ.) with constant stirring for 1.40 hours. Added additional amount of NaH (3 equiv.) was stirred for 15 minutes, followed by addition of 3-chloro-2-methylbenzenesulfonamide (equ.) with constant stirring for 2 hours. Added additional amount of NaH (3 EQ.) and 3-chloro-2-methylbenzenesulfonamide (1 EQ.) with constant stirring over night. This gave ~80% conversion to the product. The mixture was cooled on ice, put a few drops of water and extragonadal DCM (×2) and saturated saline solution. The organic layers were combined, dried and koncentrira the Lee. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, 20-50% MeCN, 0.1% of TFU). Specified in the title compound (14 mg, 32%) was obtained as a blue solid. MS (ESI+) for C21H24ClN3O3S m/z 434 (M+H)+.

Example 75

1-[(2,5-Acid)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

NaH (18 mg, 0.47 mmol, 60% in mineral oil) was added to tert-butyl 4-[(6-methoxy-1H-indol-4-yl)methyl]piperazine-1-carboxylate (23 mg, 0,067 mmol; Intermediate compound 40) in anhydrous THF (1.5 ml). The reaction mixture was stirred for 30 minutes, and the color changed from orange to green. Added 2,5-dimethoxybenzenesulfonamide (63 mg, 0.27 mmol) in anhydrous THF (0.5 ml) and the mixture was stirred over night. Added additional amount of NaH (3 EQ.) with constant stirring for 1.40 hours. Added additional amount of NaH (3 equiv.) was stirred for 15 minutes, followed by the addition of 2,5-dimethoxybenzenesulfonamide (2 EQ.) with constant stirring for 2 hours. The mixture was cooled on ice, put a few drops of water and extragonadal DCM (×2) and saturated saline solution. The organic layers joint is issued, was dried and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, 20-50% MeCN, 0.1% of TFU). Specified in the title compound (14 mg, 31%) was obtained as a blue solid. MS (ESI+) for C22H27N3O5S m/z 446 (M+H)+.

Example 76

2-{[6-Methoxy-4-(piperazine-1-ylmethyl)-1H-indol-1-yl]sulfonyl}benzonitrile, bis(triptorelin)

NaH (18 mg, 0.47 mmol, 60% in mineral oil) was added to tert-butyl 4-[(6-methoxy-1H-indol-4-yl)methyl]piperazine-1-carboxylate (23 mg, 0,067 mmol; Intermediate compound 40) in anhydrous THF (1.5 ml). The reaction mixture was stirred for 30 minutes, and the color changed from orange to green. Was added 2-cyanobenzenesulfonyl (54 mg, 0.27 mmol) in anhydrous THF (0.5 ml) and the mixture was stirred over night. Added additional amount of NaH (2 EQ.) and 2-cyanobenzenesulfonyl (equ.) with constant stirring 1.40 hours. Added additional amount of NaH (3 equiv.) was stirred for 15 minutes, followed by adding 2-cyanobenzenesulfonyl (1 EQ.) with constant stirring for 2 hours. This gave ~70% conversion to the product. The mixture was cooled on ice, put a few drops of water and uh what was tragically DCM (×2) and saturated saline solution. The organic layers were combined, dried and concentrated. The residue was dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec. The mixture was filtered and purified using preparative HPLC/UV (System A, 16-47% MeCN, 0.1% of TFU). Specified in the title compound (13 mg, 31%) was obtained as a blue solid. MS (ESI+) for C21H22N4O3S m/z 411 (M+H)+.

Example 77

({1-[(4-Forfinal)sulfonyl]-1H-indol-4-yl}methyl)amine, triptorelin

To 1-[(4-Forfinal)sulfonyl]-1H-indole-4-carbaldehyde (30 mg, 0.10 mmol; Intermediate compound 13) in anhydrous MeOH (2 ml) was added ammonium acetate (76 mg, 1.0 mmol) and NaBH3CN (19 mg, 0.30 mmol). The mixture was subjected to microwave irradiation for 10 minutes at 130°C followed by filtration and purification using preparative HPLC/UV (System A, 20-50% MeCN, 0.1% of TFU). This gave specified in the title compound (5 mg, 12%) as a colourless solid. MS (ESI+) for C15H13FN2O2S m/z 288 [M-NH2]+.

Example 78

N-({1-[(4-Forfinal)sulfonyl]-1H-indol-4-yl}methyl)ethanamine, triptorelin

Ethylamine (2M in THF, of 0.20 ml, 0.40 mmol) was added to 1-[(4-forfinal)sulfonyl]-1H-indole-4-carbaldehyde (30 mg, 0.10 mmol; Intermediate compound 13) in anhydrous THF (3 ml). The mixture was stirred for 20 minutes, with the further addition of acetic acid (57 μl, 0,99 mmol) and NaBH3(OAc)3(105 mg, 0.50 mmol). The reaction mixture was subjected to microwave irradiation for 30 minutes at 130°C, filtered and concentrated. Purification was performed by preparative HPLC/UV (System A, 20-50% MeCN, 0.1% of TFU). This gave specified in the title compound (4 mg, 10%) as a colourless solid. MS (ESI+) for C17H17FN2O2S m/z 333 (M+H)+.

The intermediate connection 41

4-Bromo-3-methyl-2-NITROPHENOL

2-Nitro-3-METHYLPHENOL (10 g, 65 mmol) was dissolved in CHCl3(10 ml) and cooled on ice. Br2(3.2 ml, 62 mmol) was dissolved in kontsentrirovannoy acetic acid (7.5 ml) and added dropwise to the solution. The reaction mixture was stirred at 0°C for 2 hours. Added ice and the layers were separated. The aqueous layer was extragonadal using CHCl3combined organic layers were washed H2O and saturated saline solution, dried over Na2SO4, was filtered and was concentrated to obtain 4-bromo-3-methyl-2-NITROPHENOL, 15 g (99%).

The intermediate connection 42

4-Bromo-3-methyl-2-nitrophenylpyruvic ether

4-Bromo-3-methyl-2-NITROPHENOL (7,17 g, 31 mmol, Intermediate connection 41) was dissolved in acetone (50 ml). Added K2CO3(8.65 g, 62 mmol), followed by addition of MeI (3.9 ml, 62 mmol)and the reaction mixture was stirred at ambient temperature in ECENA 18 hours. The crude mixture was concentrated, added an H2O and the mixture was extragonadal using CH2Cl2, dried over Na2SO4, was filtered and was evaporated to obtain 4-bromo-3-methyl-2-nitrophenylamino ether, 7 g (92%).

The intermediate connection 43

4-Bromo-7-methoxy-1-(phenylsulfonyl)-1H-indole

4-Bromo-3-methyl-2-nitrophenylpyruvic ester (6.8 g, 27.6 mmol, Intermediate compound 42) was dissolved in DMF (20 ml). Added dimethylformamidine (6 ml) and pyrrolidine (2.3 ml, 28 mmol) and the reaction mixture was heated at 90°C for 18 hours. The reaction mixture was allowed to cool to ambient temperature, was added CH2Cl2and the mixture was extragonadal using H2O, the organic layer was dried over Na2SO4, filtered and concentrated.

The crude substance was dissolved in acetic acid and added dropwise to a solution of Fe (4.5 g, 82 mmol) in boiling acetic acid (40 ml). The reaction mixture was heated at the boiling point under reflux for 30 minutes and then allowed to cool to ambient temperature. Added H2O and the mixture was neutralized with the help of Na2CO3was extragonadal using CH2Cl2, dried over Na2SO4, filtered and concentrated. The crude substance was purified column chromatography dioxide to amnia (ethyl acetate/heptane 1:1) to obtain 4-bromo-7-methoxyindole in the form of a dark oil. This substance is directly used in the next stage.

4-Bromo-7-methoxyindole (2 g, 8,8 mmol) was dissolved in CH2Cl2(300 ml). Added PhSO2Cl (2.4 g, 9.4 mmol), followed by the addition of tetrabutylammonium bisulfate (0.34 g, 0.88 mmol) and aqueous solution of 4M NaOH (17 ml), in the specified order. The reaction mixture was stirred at ambient temperature for 3 hours. The layers were separated and the aqueous layer was extragonadal using CH2Cl2, washed using H2O, dried over Na2SO4, filtered and concentrated. The crude substance was recrystallized from ethanol to obtain 4-bromo-7-methoxy-1-(phenylsulfonyl)-1H-indole, 0,9,

Example 79

7-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

4-Bromo-7-methoxy-1-(phenylsulfonyl)-1H-indole (200 mg, 0.55 mmol, Intermediate compound 43), tributyltinhydride (348 mg, 1.1 mmol) and bis(acetate)bis(triphenylphosphine)palladium(II) (46 mg, 0.06 mmol) were mixed in anhydrous acetonitrile (2 ml) and subjected to microwave heating at 180°C for 10 minutes. The reaction mixture was filtered through celite and concentrated. The crude product was purified column chromatography on silica (CHCl3/hexane 7:3) to obtain 4-vinyl-7-methoxy-1-(phenylsulfonyl)-1H-indole, 0,19 g, which is directly ispolzovaniya the next stage.

This substance (0,19 g, 0.61 mmol) was dissolved in dioxane (7 ml)was added 2,6-lutidine (0,13 g, 1,22 mmol) and OsO4(23 mg, 0.09 mmol) and the mixture was stirred at ambient temperature for minutes and added NaIO4(0.51 g, 2.4 mmol) in H2O (about 1 ml). The mixture was stirred at ambient temperature for 30 minutes. Added CHCl3and the mixture was extragonadal aqueous solution of 2M HCl, dried over Na2SO4, was filtered and was concentrated to obtain 4-carbaldehyde-7-methoxy-1-(phenylsulfonyl)-1H-indole. The crude aldehyde was used in the next stage without additional purification. 4-Carbaldehyde-7-methoxy-1-(phenylsulfonyl)-1H-indole (0.25 g, 0.8 mmol) was dissolved in methanol (10 ml)was added boc-piperazine (0.3 g, 1.6 mmol) and NaCNBH3(64 mg, 0.96 mmol), followed by the addition of acetic acid (until pH=5). The reaction mixture was stirred at ambient temperature for 18 hours.

The reaction mixture was concentrated and the crude substance was purified column chromatography on silica (ethyl acetate/heptane 2:1) to obtain tert-butyl 4-{[7-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate, 0,38 g, which is directly used in the next stage. tert-Butyl 4-{[7-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (0,38 g, 0.78 mmol who) was dissolved in methanol (1 ml), was added a mixture of methanol/concentrated HCl 4:1 (1 ml) and the reaction mixture was subjected to microwave heating at 100°C for 3 minutes. Added H2O and the mixture was extragonadal using CHCl3, the aqueous phase was podslushivaet using Na2CO3and extragonadal with ethyl acetate, dried over Na2SO4, filtered and concentrated to obtain the crude product, which was purified by reversed-phase preparative HPLC using a column ACE Prep UV C8 150×30 mm, flow rate of 38 ml/min, the time gradient of 8.5 minutes, using the eluent system: water/0.1%of TFU and CH3CN (15-45% MeCN), fractions collected based on UV-signal (254 nm). The most pure fractions were combined and the acetonitrile evaporated. Yield: 12 mg (2.5%). Light brown resin. MS (electrospray; [M+H]+) m/z 386.

The intermediate connection 44

4-Bromo-1-(phenylsulfonyl)-1H-indole

Sodium hydride (2.8 g, 60%, of 70.4 mmol) was washed with heptane to remove mineralnavo oil to the reaction. This sodium hydride was mixed with THF (250 ml) and cooled in an ice bath before addition of 4-bromoindole (4.6 g, 23.5 mmol). The reaction mixture was stirred for 15 minutes and then added benzosulphochloride (6,22 g of 35.2 mmol). The reaction mixture was stirred at room temperature overnight. Added ice and water, followed by addition of EtOAc. The phases were separated and the aq is the phase was extragonadal using EtOAc twice. The combined organic phases were dried (MgSO4before evaporation of the solvent. The crude product was sufficiently pure for use in the next stage. Got charged 8.52 g of oil which was aterials during maturation, yield 100%. MS (ESI+) for C14H10BrNO2S m/z 336 (M+H)+.

The intermediate connection 45

1-(Phenylsulfonyl)-4-vinyl-1H-indole

4-Bromo-1-(phenylsulfonyl)-1H-indole (charged 8.52 g, to 25.3 mmol, Intermediate compound 44) was dissolved in anhydrous toluene (20 ml) in an atmosphere of N2(gas), and then added ministunned (16,07 g of 50.7 mmol) and acetate bis[triphenylphosphine)palladium(II) (0.95 g, 1.3 mmol). The reaction mixture was heated to 110°C for 16 hours, cooled to room temperature, filtered through a layer of celite and the solvent evaporated. The resulting oil was dissolved in acetonitrile and hexane, the phases were separated. The combined acetonitrile phase was evaporated and the crude product was purified flash chromatography using 30% DCM in hexane. Allocated 4.4 g of the desired product as a white solid, yield 62%. MS (ESI+) for C16H13NO2S m/z 284 (M+H)+.

The intermediate connection 46

2-Methyl-1-(phenylsulfonyl)-4-vinyl-1H-indole

1-(Phenylsulfonyl)-4-vinyl-1H-indole (190 mg, 0.7 mmol, Intermediate compound 45) was weighed in a pre-dried reaction flask and was purged with gaseous nitrogen for 1 hour. Added anhydrous THF (50 ml) and the reaction flask was cooled to -78°C before the addition of LDA (0.35 ml, 0.7 mmol, 2M). The reaction mixture was stirred for 15 minutes before adding iodomethane (for 95.2 mg, 0.7 mmol). The reaction mixture gave to slowly reach room temperature over night. Added 1 ml of MeOH and the reaction mixture was evaporated on the silicon dioxide. Was purified using flash chromatography using 20% DCM in hexane. Received 61 mg of a white solid, yield 30%. MS (ESI+) for C17H15NO2S m/z 298 (M+H)+.

The intermediate connection 47

2-Methyl-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde

2-Methyl-1-(phenylsulfonyl)-4-vinyl-1H-indol-4 (61 mg, 0.2 mmol, Intermediate connection 46) was dissolved in dioxane (50 ml) before the addition of 2,6-lutidine (44 mg, 0.4 mmol). Added osmium tetroxide (2,61 mg, 0.01 mmol) as a solid. To the solution in dioxane was added periodate sodium (175 mg, 0.8 mmol)dissolved in water (6 ml) (heated to dissolve). The reaction mixture was stirred for 2 hours at room temperature. Added water and DCM, the phases were separated. The aqueous phase was extragonadal using DCM 5 times. The combined organic phases were dried (MgSO4) and the solvent evaporated. The crude product was purified flash chromatography using a 15% solution of DCM in hexane as eluent. Come and 50 mg of the product as a purple oil, yield 83%. MS (ESI+) for C16H13NO3S m/z 300 (M+H)+.

The intermediate connection 48

tert-Butyl 4-{[2-methyl-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate

2-Methyl-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (94 mg, 0.3 mmol, Intermediate compound 47) was dissolved in THF (betwedn.) (4 ml) before adding boc-piperazine (87,7 mg, 0.5 mmol)and then acetic acid (188 mg, 3.1 mmol) was added triacetoxyborohydride sodium (199 mg, 0.9 mmol). The reaction mixture was subjected to microwave heating for 720 seconds at 130°C. the Solvent is evaporated, added water and DCM. The phases were separated and the aqueous phase was extragonadal using DCM twice. The combined organic phases were dried (MgSO4) and the solvent evaporated. The crude product was purified preparative HPLC (30-60). Allocated 110 mg in the form of oil, yield 80%. MS (ESI+) for C25H31N3O4S m/z 470 (M+H)+.

Example 80

2-Methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, hydrochloride

tert-Butyl 4-{[2-methyl-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (110 mg, 0.23 mmol, Intermediate compound 48) was dissolved in MeOH (4 ml) and 1 ml of concentrated HCl and heated to 100°C for 3 minutes in a microwave device. The solvent is evaporated, received 86 mg of a white solid, yield 100%. MS (ESI+) for C20H23N3 O2S m/z 370 (M+H)+.

The intermediate connection 49

1-(Phenylsulfonyl)-1H-indole-4-carbaldehyde

1H-Indole-4-carbaldehyde (0,300 g, a 2.01 mmol), benzosulphochloride (0,47 g, to 2.67 mmol) and tetrabutylammonium bisulfate (0,070 g, 0.21 mmol) was dissolved in dichloromethane (10 ml) was added NaOH solution (413 mg, 10,33 mmol) in water (3 ml). The mixture was stirred over night, diluted with water and was extragonadal dichloromethane (×1). The combined organic layers were dried (MgSO4) and the crude product was purified through a plug of silica using 1% MeOH in dichloromethane as eluent. Output: 541 mg (95%). White solid. MS (electrospray; [M+H]+) m/z 286,3.

The intermediate connection 50

1-tert-Butyl 2-methyl 4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1,2 -, in primary forms

1-tert-Butyl 2-methyl piperazine-1,2 -, in primary forms (0,205 g, 0.64 mmol), 1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (0,160 g of 0.56 mmol, Intermediate compound 49) and acetic acid (0,100 g, by 1.68 mmol) was dissolved in MeOH (5 ml) and was stirred for 3 minutes before adding cyanoborohydride sodium (to 0.060 g, 0.95 mmol). The mixture was stirred at room temperature for 15 minutes, the mixture was evaporated and distributed between water and dichloromethane. The organic phase was dried (MgSO4) and was evaporated. The crude product was purified flash chromatography using 1%MeOH to 2.5% MeOH in dichloromethane. A colorless oil. This intermediate compound was used directly in the next stage to obtain the Intermediate compound 51. MS (electrospray; [M+H]+) m/z 514,6.

The intermediate connection 51

1-(tert-Butoxycarbonyl)-4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-2-carboxylic acid

1-tert-Butyl 2-methyl 4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1,2 -, in primary forms (all the number of Intermediate compound 50) was dissolved in 1M KOH (3 ml) in MeOH (3 ml) and THF (3 ml) and stirred over night. The mixture was evaporated and diluted with dichloromethane and water. the pH was brought to 4 with a solution of 1 N. HCl (2.5 ml) and a saturated solution of dihydrophosphate. The organic phase was evaporated and purified flash chromatography using a 2.5% MeOH to 5% MeOH in dichloromethane. Yield: 85 mg (30%, calculated on the basis of 1-(phenylsulfonyl)-1H-indole-4-carbaldehyde). White solid. MS (electrospray; [M+H]+) m/z 500,4.

Example 81

Methyl 4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-2-carboxylate, bis(triptorelin)

1-tert-Butyl 2-methyl 4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1,2 -, in primary forms (0,013 g of 0.025 mmol, Intermediate compound 50) was dissolved in dichloromethane (1 ml) and added TFU (0.5 ml). The mixture was stirred for 1 hour and evaporated. Yield: 16 mg (100%). A colorless oil. MS (electrospray; [M+H]+) m/z 414,6.

Example 82

<> (4-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-2-yl)methanol, bis(triptorelin)

1M BH3in THF (0.2 ml, 0.2 mmol) was added dropwise to a solution of 1-(tert-butoxycarbonyl)-4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-2-carboxylic acid (0,010 g, at 0.020 mmol, Intermediate compound 51) in THF (0.5 ml) and the mixture was stirred for 2 days at room temperature. Added TFU (1 ml) and water (0.5 ml) and the mixture was stirred over night. The mixture was evaporated and dissolved in MeOH, filtered and purified by reversed-phase preparative HPLC using a column ACE Prep UV C8 150×30 mm, flow rate of 38 ml/min, the time gradient of 8.5 minutes, using the system for elution: water/0.1%of TFU and CH3CN (31-62% MeCN), fractions collected based on UV-signal (254 nm). The most pure fractions were combined and the acetonitrile evaporated. Output: 2.7 mg (22%). A colorless oil. MS (electrospray; [M+H]+) m/z 386,4.

General procedure for reductive amination used in the Examples 83-87:

1-(Phenylsulfonyl)-1H-indole-4-carbaldehyde (0.015 g, 0,053 mmol, Intermediate compound 49), the required amine (0.16 mmol) and acetic acid (0,031 g of 0.53 mmol) was dissolved in THF (1 ml) was added triacetoxyborohydride sodium (0,033 g, 0.16 mmol). The mixture was stirred at 40°C for 3 hours, evaporated and purified as described below:

Example 83

(2-Methoxyethyl) {[1-(panels hanil)-1H-indol-4-yl]methyl}amine, triptorelin

Amin: 2-Methoxyethylamine (0,012 g, 0.16 mmol)

Was purified using reverse-phase preparative HPLC using a column ACE Prep UV C8 21×50 mm, flow rate 25 ml/min, the time gradient of 11 minutes using the system for elution: water/0.1% of TFU and CH3CN (11-41% MeCN), fractions collected based on UV-signal (254 nm). The most pure fractions were combined and the acetonitrile evaporated. Output: to 22.3 mg of a Colorless resin. MS (electrospray; [M+H]+) m/z 345,4.

Example 84

N-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}propan-2-amine, triptorelin

Amin: Isopropylamine (0,0093 g, 0.16 mmol)

Was purified using reverse-phase preparative HPLC using a column ACE Prep UV C8 21×50 mm, flow rate 25 ml/min, the time gradient of 11 minutes using the system for elution: water/0.1% of TFU and CH3CN (12-42% MeCN), fractions collected based on UV-signal (254 nm). The most pure fractions were combined and the acetonitrile evaporated. Output: 6,2 mg of White solid. MS (electrospray; [M+H]+) m/z 329,4.

Example 85

4-{[4-(2-Methoxyethyl)piperazine-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)

Amine: 1-(2-Methoxyethyl)piperazine (0.015 g, 0.11 mmol)

Was purified using reverse-phase preparative HPLC using a column ACE Prep UV C8 21×50 mm, flow rate 25 ml/min, the time gradient of 11 minutes using the system for e is lirovaniya: water/0.1%of TF A and CH 3CN (9-39% MeCN), fractions collected based on UV-signal (254 nm). The most pure fractions were combined and the acetonitrile evaporated. Output: 24,1 mg (86%). Colorless resin. MS (electrospray; [M+H]+) m/z 414,5.

Example 86

((2R)-1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}pyrrolidin-2-yl)methanol, triptorelin

Amin: D-Prolinol (to 0.011 g, 0.11 mmol)

Was purified using reverse-phase preparative HPLC using a column ACE Prep UV C8 21×50 mm, flow rate 25 ml/min, the time gradient of 11 minutes using the system for elution: water/0.1%of TFU and CH3CN (11-41% MeCN), fractions collected based on UV-signal (254 nm). The most pure fractions were combined and the acetonitrile evaporated.

Output: 23,0 mg (86%). Colorless resin. MS (electrospray; [M+H]+) m/z 371,4.

Example 87

4 Azetidin-1-ylmethyl)-1-(phenylsulfonyl)-1H-indole, triptorelin

Amin: Azetidinone (0,010 g, 0.11 mmol)

Was purified using reverse-phase preparative HPLC using a column ACE Prep UV C8 21×50 mm, flow rate 25 ml/min, the time gradient of 11 minutes using the system for elution: water/0.1%of TFU and CH3CN (11-41% MeCN), fractions collected based on UV-signal (254 nm). The most pure fractions were combined and the acetonitrile evaporated. Output: 14,9 mg (64%). Colorless resin. MS (electrospray; [M+H]+) m/z 327,4.

The intermediate connection 52

Ethyl 4-bromo-5-methoxy-1H-indole-2-rboxylic

The target molecule was obtained in accordance with the method described in the literature (Kruse, L.I., Meyer, M. D. Ergoline synthons. 2. Synthesis of 1,5-Dihydrobenz[cd]indole-4(3H)-ones and 1,3,4,5-Tetrahydrobenz[cd]indole-4-amines. J Org. Chem. 1984, 49, 4761-4768). MS (ESI+) for C12H12BrNO3m/z 298/300 (M+H)+.

The intermediate connection 53

Ethyl 4-bromo-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate

Procedure: as described for Intermediate connection 44.

Ethyl 4-bromo-5-methoxy-1H-indole-2-carboxylate (1.5 g, 5.0 mmol, Intermediate compound 52) gave 0.96 g of a white powder, yield 44%. MS (ESI+) for C18H16BrNO5S m/z 438 (M+H)+.

The intermediate connection 54

Ethyl 5-methoxy-1-(phenylsulfonyl)-4-vinyl-1H-indole-2-carboxylate

Procedure: as described for Intermediate 45. Ethyl 4-bromo-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate (0.96 g, 2.2 mmol, Intermediate compound 53) gave a quantitative yield in the form of not-quite-white solid. MS (ESI+) for C20H19NO5S m/z 386 (M+H)+.

The intermediate connection 55

Ethyl 4-formyl-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate

The procedure as described for Intermediate 47.

Ethyl 5-methoxy-1-(phenylsulfonyl)-4-vinyl-1H-indole-2-carboxylate (860 mg, 2.2 mmol, Intermediate compound 54) to give 440 mg of the product as not quite white solids, o is d 51%. MS (ESI+) for C19H17NO6S m/z 388 (M+H)+.

The intermediate connection 56

Ethyl 4-{[4-(tert-butoxycarbonyl)piperazine-1-yl]methyl}-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate

The procedure as described for Intermediate connection 48.

Ethyl 4-formyl-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate (440 mg, 1.2 mmol, Intermediate compound 55) to give 330 mg of the desired product as a colourless solid, yield 52%. MS (ESI+) for C28H35N3O7S m/z 558 (M+H)+.

Example 88

Ethyl 5-methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole-2-carboxylate

The procedure as described for Example 80.

Ethyl 4-{[4-(tert-butoxycarbonyl)piperazine-1-yl]methyl}-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate (32 mg, 0,057 mmol, Intermediate compound 56) was given to 15.9 mg, yield 61% after preparative purification in neutral conditions. MS (ESI+) for C23H27N3O5S m/z 458 (M+H)+.

The intermediate connection 57

Lithium 4-{[4-(tert-butoxycarbonyl)piperazine-1-yl]methyl}-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate

Ethyl 4-{[4-(tert-butoxycarbonyl)piperazine-1-yl]methyl}-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate (330 mg, 0.6 mmol, Intermediate compound 56) was dissolved in THF (10 ml) before the addition of lithium hydroxide (17 mg, 0.7 mmol), followed by an Addendum is receiving 4 ml of water. The reaction mixture was heated to 70°C for 24 hours, after Cho reaction was completed. The reaction mixture was evaporated. This gave 3 g of white solid, which was washed with several portions of hot DCM, and then hot THF. United flushing phase was evaporated. This gave 270 mg of a slightly brownish solid. Yield 83%. MS (ESI+) for C26H30N3O7SLi m/z 530 (M+H)+.

The intermediate connection 58

tert-Butyl 4-{[5-methoxy-2-[(methylamino)carbonyl]-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate

4-{[4-(tert-Butoxycarbonyl)piperazine-1-yl]methyl}-5-methoxy-1H-indole-2-carboxylic acid (14 mg, 0,0274 mmol, Intermediate compound 57) was dissolved in DCM (5 ml) before the addition of triethylamine (11 mg, 109 mmol), followed by methylamine hydrochloride (4 mg, by 0.055 mmol). To the reaction mixture were added hydrochloride dimethylaminopropyl)carbodiimide (11 mg, by 0.055 mmol) and 1-hydroxybenzotriazole (10 mg, by 0.055 mmol). The reaction mixture was stirred at 40°C for 24 hours. Added water and the phases were separated. The organic phase was evaporated and the crude product was purified using preparative HPLC. This gave 3.4 mg of product as a white solid, yield 23%. MS (ESI+) for C27H34N4O6S m/z 543 (M+H)+.

The intermediate connection 59

tert-Butyl 4-{[2-[(ethylaminomethyl]-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate

The procedure as described for Intermediate connection 58.

Using 4-{[4-(tert-Butoxycarbonyl)piperazine-1-yl]methyl}-5-methoxy-1H-indole-2-carboxylic acid (14 mg, 0,0274 mmol, Intermediate compound 57), and hydrochloride of methanamine (3,709 mg, 0,0549 mmol) as starting compounds gave 6,3 mg of product as a white solid, yield 42%. MS (ESI+) for C28H36N4O6S m/z 557 (M+H)+.

The intermediate connection 60

tert-Butyl 4-[(5-methoxy-1-(phenylsulfonyl)-2-{[(2-thienylmethyl)amino]carbonyl}-1H-indol-4-yl)methyl]piperazine-1-carboxylate

The procedure as described for Intermediate connection 58.

Using 4-{[4-(tert-Butoxycarbonyl)piperazine-1-yl]methyl}-5-methoxy-1H-indole-2-carboxylic acid (14 mg, 0,0274 mmol, Intermediate compound 57) and 1-(2-thienyl)methanamine (6,21 mg, 0,0549 mmol) as starting compounds give 2.8 mg of product as a white solid, yield 16%. MS (ESI+) for C31H36N4O6S2m/z 625 (M+H)+.

Example 89

5-Methoxy-N-methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole-2-carboxamide, triptorelin

tert-Butyl 4-{[5-methoxy-2-[(methylamino)carbonyl]-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (3.4 mg, 0,063 mmol, Intermediate compound 58) was dissolved in DCM (2 ml) before adding TFU (1 ml). The reaction mixture was paramesh the Wali for 2 hours at room temperature, after the reaction was completed. The solvent is evaporated and the oil obtained was dissolved in methanol and the solvent evaporated. The obtained brown solid was stored under vacuum for 24 hours. Received quantitative yield. MS (ESI+) for C22H26N4O4S m/z 443 (M+H)+.

Example 90

N-Ethyl-5-methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole-2-carboxamide, triptorelin

Procedure: as described for Example 89.

tert-Butyl 4-{[2-[(ethylamino)carbonyl]-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (6.3 mg, 0,113 mmol, Intermediate compound 59) gave a quantitative yield of product was obtained as a brown solid. MS (ESI+) for C23H28N4O4S C2HF3O2m/z 457 (M+H)+.

Example 91

5-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-N-(2-thienylmethyl)-1H-indole-2-carboxamide, triptorelin

Procedure: as described for Example 89.

tert-Butyl 4-[(5-methoxy-1-(phenylsulfonyl)-2-{[(2-thienylmethyl)amino]carbonyl}-1H-indol-4-yl)methyl]piperazine-1-carboxylate (2.8 mg, 0,0045 mmol, Intermediate compound 60) gave a quantitative yield of product was obtained as a brown solid. MS (ESI+) for C26H28N4O4S2C2HF3O2m/z 525 (M+H)+.

Example 92

4-(Azetidin-1-ylmethyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole, triptorelin

6-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (Intermediate compound 34, 0,020 g 0,063 mmol), hydrochloride of azetidine (0,071 g, from 0.76 mmol) and acetic acid (0,019 g, 0.32 mmol) was dissolved in MeOH (2 ml) was added triacetoxyborohydride sodium (0,67 g, 0.32 mmol). The mixture was stirred for 1 hour before adding 5 drops of 1 n HCl solution and the mixture was filtered and purified by reversed-phase preparative HPLC using a column ACE Prep UV C8 150×30 mm, flow rate of 38 ml/min, the time gradient of 8.5 minutes using the system for elution: water/0.1%of TFU and CH3CN (25-51% MeCN), fractions collected based on UV-signal (254 nm). The most pure fractions were combined and the acetonitrile evaporated. Yield: 15 mg (51%). White solid. MS (electrospray; [M+H]+) m/z 357,4.

The intermediate connection 61

4-Bromo-5-(benzyloxy)-1-(phenylsulfonyl)-1H-indole

Using the same procedure as described for Intermediate 44, starting from 5-(benzyloxy)-4-bromo-1H-indole of 3.85 g (12.7 mmol) received 5,71 g (101%) dark green crystallizing oil. MS (ESI+) for C21H16BrNO3S m/z 442/444 (M+H)+.

The intermediate connection 62

5-(Benzyloxy)-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde

The reaction was performed using takoyzhe procedures as described for Intermediate 75, with an Intermediate connection 61, 4,74 g (10,7 mmol) as the starting material. The crude product was purified using chromatography on a column of silica using as eluent a mixture of petroleum ether/EtOAc, starting with 90/10 then 80/20, to obtain 5-(benzyloxy)-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde, 2,44 g (58%) as a yellow solid. MS (ESI+) for C22H17NO4S m/z 392 (M+H)+.

The intermediate connection 63

tert-Butyl 4-{[5-(benzyloxy)-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate

To 5-(benzyloxy)-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde, the Intermediate connection 62 205 mg (0.52 mmol) in dichloroethane [DCE](10 ml) was added BOC-piperazine, 137 mg (0,74 mmol), NaBH(OAc)3, 333 mg (1.6 mmol) and HOAc, 45 mg (0.8 mmol) and the mixture was stirred at room temperature in a sealed tube overnight. Added water, the phases were separated and dried (MgSO4), the organic phase was evaporated under reduced pressure and the black residue was purified using chromatography on a column of silica, using CHCl3100% as eluent, to obtain 260 mg (88%) of a dark oil. MS (ESI+) for C31H35N3O5S m/z 562 (M+H)+.

The intermediate connection 64

tert-Butyl 4-{[5-hydroxy-1-(phenylsulfonyl)-1 is-indol-4-yl]methyl}piperazine-1-carboxylate

To a solution of 5-(benzyloxy)-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, Intermediate connection 63, 1.20 g (2.1 mmol), in MeOH was added 10% Pd/C, 200 mg, and the suspension was washed several times a spurt of N2. The stirring was stopped and Pd/C gave a precipitate, was added ammonium formate, again made of N2-the atmosphere and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a layer of celite, the solvent was removed under reduced pressure and the pale yellow oil was purified using chromatography on a column of silica, using CHCl3(100%), with a target molecule in the form of a colorless foamy substance of 0.59 g (59%). MS (ESI+) for C24H29N3O5S m/z 472 (M+H)+.

Example 93

1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indol-5-ol, triptorelin

tert-Butyl 4-{[5-hydroxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (10 mg, 0.018 mmol, Intermediate compound 64) was dissolved in DCM/TFU 50/50 (1 ml) and left at room temperature for 4 hours, after which the solvent was removed under reduced pressure and the residue was purified using preparative HPLC, Method A, with the receipt of 5.5 mg (53%) of target compound as a colorless oil. MS (ESI+) for C19H21N3O3S m/z 372 (M+H)+.

The ex is offered by the connection 65

4-Pyrazin-2-yl-1H-indole

4-Bromoindole (0.1 g, 0.51 mmol), bis(pinacolato)LIBOR (0.172 g, 0.77 mmol), potassium acetate (0.075 g, 0,765 mmol) and PdCl2(0,022 g 0,031 mmol) was dissolved in DME (3 ml) and heated in a device for microwave heating for 900 seconds at 125°C. the Reaction mixture was cooled and was added NaHCO3(0,129 g, 1.53 mmol), 2-chloropyrazine (0,087 g, 0.77 mmol) tetrakis(triphenylphosphine)palladium (0,0295 g, was 0.026 mmol), H2O (1 ml) and DME (1 ml) and the mixture was stirred device for microwave heating for 900 seconds at 120°C. the Mixture was diluted with dichloromethane and filtered. The filtrate was washed with water (2×), dried (MgSO4) and was evaporated. The crude product was purified flash chromatography using 2.5% to 5% CH3OH in dichloromethane. Received the crude product was purified flash chromatography using mixtures of hexane/EtOAc 7:3 to 1:1 as eluent. Yield: 93 mg (47%). White solid. MS (electrospray; [M+H]+) m/z 196,3.

Intermediate compound 66

1-(Phenylsulfonyl)-4-pyrazin-2-yl-1H-indole

4-Pyrazin-2-yl-1H-indole (to 0.060 g, 0,307 mmol, Intermediate compound 65), benzosulphochloride (0,071 g, 0.40 mmol) and tetrabutylammonium bisulfate (0,010 g 0,031 mmol) was dissolved in dichloromethane (3 ml) was added NaOH solution (0,061 g, 1.5 mmol) in water (1 ml). The mixture was stirred at room temperature overnight, diluted dichloromethane and water and extragonadal dichloromethane (2×). The organic phase was dried (MgSO4) and was evaporated. The crude product was purified flash chromatography using CH2Cl2up to 1% MeOH in CH2Cl2as eluent. Yield: 81 mg (79%). White solid. MS (electrospray; [M+H]+) m/z 336,4.

Example 94

1-(Phenylsulfonyl)-4-piperazine-2-yl-1H-indole, bis(triptorelin)

1-(phenylsulfonyl)-4-pyrazin-2-yl-1H-indole (of 0.081 g, 0,242 mmol, Intermediate, compound 66) and Pd(OAc)2(0,020 g 0,089 mmol) was dissolved in acetic acid (20 ml) was shaken in an atmosphere of H2(55 psi (3,867 kg/cm2)). After 2.5 hours, the reaction mixture was evaporated and was distributed between dichloromethane and 1 N. a solution of Na2CO3. The organic phase was dried (MgSO4) and was evaporated. The crude product was purified by reversed-phase preparative HPLC using a column ACE Prep UV C8 150×30 mm, flow rate of 38 ml/min, the time gradient of 8.5 minutes using the system for elution: water/0.1%of TFU and CH3CN (10-35% MeCN), fractions collected based on UV-signal (254 nm). The most pure fractions were combined and the acetonitrile evaporated. Was isolated as a salt TFU. Yield: 30 mg (22%). White solid. MS (electrospray; [M+H]+) m/z 342,4.

Example 95

4-(1,4-Dimethylpiperazine-2-yl)-1-(phenylsulfonyl)-1H-indole, bis(triptorelin)

1-(phenylsulfonyl)-4-piperazine-2-yl-1H-indole bis(triptorelin) (0.015 g, 0,044 mm is l, Example 94) and 30% solution of formaldehyde in water storage capacity (0.044 g, 0.44 mmol) was dissolved in MeOH (2 ml) was added triacetoxyborohydride sodium (0,046 g, 0.22 mmol). The mixture was stirred for 2 hours at room temperature and was added 3 drops of 1 n HCl solution. The reaction mixture was filtered and purified using reverse-phase preparative HPLC using a column ACE Prep UV C8 150×30 mm, flow rate of 38 ml/min, the time gradient of 8.5 minutes using the system for elution: water/0.1%of TFU and CH3CN (19-46% MeCN), fractions collected based on UV-signal (254 nm). Output: 4.0 mg (15%). White solid. MS (electrospray; [M+H]+) m/z 370,4.

Example 96

[7-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]piperazine-1-yl)acetonitrile, triptorelin

1-Benzazolyl-7-methoxy-1H-indole-4-carbaldehyde (50 mg, 0.2 mmol, obtained as in Example 79), piperazine (28 mg, 0.3 mmol) and methanol (0.5 ml) was loaded into a test tube suitable for microwave irradiation. The mixture was heated at 100° for 1 minute in a microwave oven. Added trimethylsilylacetamide (21 μl, 0.2 mmol) and heat treated at 100° for 1 minute, repeated. IHMS analysis showed the formation of the expected product. The crude product was purified using prep LC on a column of YMC (24-52% MeCN over 16 minutes). Got to 26.2 mg (40%). MS ESI+ for C16H13NO4S, m/z 325 (M-piperazine)+m/z 384 (M-nitrile)+, m/z 411 (M+H)+.

u> Example 97

4-(Azetidin-1-ylmethyl)-7-methoxy-1-(phenylsulfonyl)-1H-indole, triptorelin

1-Benzazolyl-7-methoxy-1H-indole-4-carbaldehyde (20 mg, 0.06 mmol, obtained as in Example 79), hydrochloride of azetidine (30 mg, 0.32 mmol) and sodium acetate (26 mg, 0.32 mmol) were mixed in 1,2-dichloroethane (1 ml) and stirred at 40° for 1 hour, cooled to room temperature, followed by the addition of triacetoxyborohydride sodium (22 mg, 0.1 mmol). The mixture was stirred over night. Analysis IHMS showed the absence of any residual source materials. The mixture was evaporated, dissolved in DMF, filtered and purified via prep HPLC YMC, 40 ml/min 22-50 ml MeCN for 16 minutes. Got to 9.8 mg (43%). MS ESI+for C19H20N2O3S m/z 357 (M+H)+.

Example 98

{[1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indol-5-yl]oxy}acetonitrile

To a solution of tert-butyl 4-{[5-hydroxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (45 mg, 0.10 mmol; Intermediate compound 64) in anhydrous DCM (2 ml) was added bromoacetonitrile, 57 mg (0.48 mmol), tetrabutylammonium bisulfate, 8 mg (0.02 mmol), 2M NaOH (1 ml) and dvuhrazovoe system was intensively stirred at room temperature overnight. The organic phase was separated and the aqueous phase was washed once with water. The solvent of the combined organic phases was removed when ponie nom pressure and the residue was purified using preparative HPLC, method B, with the receipt of 2.9 mg (7%) of target compound as a pale brown oil. MS (ESI+) for C21H22N4O3S m/z 411 (M+H)+.

Example 99

5-Isopropoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole

Using the same procedure as described for Example 105, using isopropanol as the alcohol got to 4.6 mg (31%) of target compound. MS (ESI+) for C22H27N3O3S m/z 414 (M+H)+.

Example 100

5-(Benzyloxy)-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole

tert-Butyl 4-{[5-(benzyloxy)-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (30 mg, 0.05 mmol, Intermediate compound 63) was mixed with a 50/50 mixture of TFU/dichloromethane (3 ml) at room temperature for four hours. The solvent was removed under reduced pressure and the crude product was purified using preparative HPLC, method B, with the receipt of 9.5 mg (40%) of colorless oil. MS (ESI+) for C26H27N3O3S m/z 462 (M+H)+.

Example 101

4-{[(2-Hydroxyethyl)(methyl)amino]methyl}-1-(phenylsulfonyl)-1H-indol-5-ol

To a solution of 5-(Benzyloxy)-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (50 mg, 0.12 mmol, Intermediate compound 62) in DCE (3 ml) was added 22 mg (0.26 mmol) of N-methylethanolamine and 80 mg (0.38 mmol) of triacetoxyborohydride sodium and the mixture was heated in hermit is a rule a sealed tube at 40°C during the night. The solvent was removed under reduced pressure and the residue was dissolved in MeOH (2 ml), was added 20 mg of 10% Pd/C and the mixture is washed with a strong jet of N2added NH4+HCOO-(50 mg, 0.8 mmol), the reaction mixture was again washed in a strong stream of N2and stirred at 40°C during the night. The solvent was removed under reduced pressure, semi-solid substance was distributed to absorb between CHCl3/H2O, washed with H2O (×1), saturated brine (×1), dried (MgSO4) and the solvent was removed under reduced pressure. Took the sample and purified using preparative HPLC, method B, with the receipt of 6.3 mg of colorless oil. MS (ESI+) for C18H20N2O4S m/z 361 (M+H)+.

Example 102

4-[(3-Hydroxypyrrolidine-1-yl)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol

Using the same procedure as described for Example 101, using 3-hydroxypyrrolidine, synthesized of 6.7 mg of the target compound. MS (ESI+) for C19H20N2O4S m/z 373 (M+H)+.

Intermediate compound 66

[3-Bromo-4-(trifluoromethyl)phenyl]hydrazine, hydrochloride

A solution of NaNO2(949 mg, of 13.75 mmol) in water (4 ml) was added dropwise to ice a mixture of [3-bromo-5-(trifluoromethyl)phenyl]amine (3.00 g, 12.5 mmol) in concentrated HCl/water (8 ml, 1:1). The reaction mixture was stirred at 0°C in techenie hours. Added two additional solution NaNO2(431 mg, of 6.25 mmol) in water (2 ml) with constant stirring for 1 hour after each addition. Was slowly added SnCl2(8,46 g, 37.5 mmol) in concentrated HCl (8 ml) (milk suspension); immediately formed brown precipitate. The mixture was diluted with water, podslushivaet 50% mass/mass aqueous solution of NaOH and extragonadal using DCM (×2), together with saturated salt solution. The aqueous layer was again extragonadal simple ether and left for phase separation during the weekend. The organic layers were combined, dried, filtered and concentrated. The crude product was purified column flash chromatography (DCM → 2% MeOH in DCM). Solution was added 2M HCl in simple ether to obtain specified in the title compound (1.13 g, 31%) as not quite white solid. MS (ESI+) for C7H6BrF3N2m/z 255 (M+H)+.

The intermediate connection 67

Ethyl 4-bromo-6-(trifluoromethyl)-1H-indole-2-carboxylate and ethyl 6-bromo-4-(trifluoromethyl)-1H-indole-2-carboxylate

Hydrochloride [3-bromo-4-(trifluoromethyl)phenyl]hydrazine, Intermediate, compound 66 (554 mg, 1,90 mmol), etherpiraat (211 μl, 1,90 mmol) and monohydrate p-toluensulfonate acid (11 mg, 0.06 mmol) in anhydrous toluene (15 ml) was subjected to boiling under reflux for 2 hours using a equipped with a radio be the Dean-stark. This mixture was added to the boiling mixture (2 hours, the trap Dean-stark) p-monohydrate toluensulfonate acid in anhydrous toluene (15 ml). Boiling under reflux was continued overnight. The reaction mixture was allowed to cool and was extragonadal DCM and saturated aqueous NaHCO3. The organic layer was dried, filtered and concentrated. The crude products were purified column flash chromatography (DCM/hexane) to obtain specified in the title compound (285 mg, 45%), not divided, as not quite white solid. Analysis GHMS for C12H9BrF3NO2m/z 335 (Monoisotopic)+showed two peaks with the same mass.

The intermediate connection 68

Ethyl 4-bromo-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-2-carboxylate and ethyl 6-bromo-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indole-2-carboxylate

An aqueous solution of 4M NaOH (1.5 ml) was added to a stirred mixture of ethyl 4-bromo-6-(trifluoromethyl)-1H-indole-2-carboxylate and ethyl 6-bromo-4-(trifluoromethyl)-1H-indole-2-carboxylate, Intermediate compound 67 (283 mg, 0.84 mmol), benzosulfimide (164 mg, of 0.93 mmol) and tetrabutylammonium bisulfate (17 mg, 0,084 mmol) in DCM (10 ml). The reaction mixture was stirred for 5 hours and added more benzosulfimide (11 μl, 0,084 mmol) with constant stirring for 2 hours. P is a promotional mixture was kept in the refrigerator over night. The mixture was diluted using DCM and washed twice with water. The organic layer was dried, filtered and concentrated with getting listed in the title compound (369 mg, 92%) as a red viscous oil. Analysis GHMS for C18H13BrF3NO4S m/z 477 (Monoisotopic)+showed two peaks with the same mass.

The intermediate connection 69

[4-Bromo-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indol-2-yl]methanol and [6-bromo-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indol-2-yl]methanol

LAH (32 mg, 0.85 mmol) was added in portions during 10 minutes to a cooled with ice to a solution of ethyl 4-bromo-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-2-carboxylate and ethyl 6-bromo-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indole-2-carboxylate, Intermediate compound 68 (290 mg, 0.61 mmol)in anhydrous THF:simple ether (2:1, 6 ml). The mixture was stirred for 10 minutes at 0°C was added ice water. The precipitate was filtered off, washed using THF and the eluate was concentrated. The residue was extragonadal DCM (×2) and water, the organic layer was dried, filtered, concentrated and combined with the previous batch of [4-bromo-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indol-2-yl]methanol and [6-bromo-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indol-2-yl]methanol (following the same procedure as described above using 78 mg of the original substance). Cleanup with p the power column flash chromatography (DCM/hexane 3:1) gave the product (100 mg, 30%) as a white solid. Analysis GHMS for C16H11BrF3NO3S m/z 433 (Monoisotopic)+showed two peaks with the same mass.

The intermediate connection 70

[1-(Phenylsulfonyl)-6-(trifluoromethyl)-4-vinyl-1H-indol-2-yl]methanol and [1-(phenylsulfonyl)-4-(trifluoromethyl)-6-vinyl-1H-indol-2-yl]methanol

Tributyl(vinyl)stannane (0,114 ml to 0.39 mmol) and Pd(PPh3)2OAc2(15 mg, at 0.020 mmol) was added [4-bromo-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indol-2-yl]methanol and [6-bromo-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indol-2-yl]methanol, the Intermediate compound 69 (85 mg, 0.20 mmol)in anhydrous MeCN (2 ml) each. The reaction mixture was subjected to microwave irradiation at 180°C for 720 seconds. The mixture was combined with the previous party specified in the title compounds (followed the same experimental procedure as described above, on the basis of 13 mg), filtered and concentrated. Purification was performed by flash chromatography (hexane/DCM 1:3). This gave the product (85 mg, 99%) as a colourless viscous oil.

The intermediate connection 71

2-(Hydroxymethyl)-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-4-carbaldehyde and 2-(Hydroxymethyl)-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indole-6-carbaldehyde

OSO4(5 mg, 0.02 mmol) was added to a stirred mixture of [1-(phenylsulfonyl)-6-(trifluoromethyl)-4-vinyl-1H-indol-2-yl]methane is a and [1-(phenylsulfonyl)-4-(trifluoromethyl)-6-vinyl-1H-indol-2-yl]methanol Intermediate compound 70 (82 mg, 0.22 mmol), and 2,6-lutidine (50 μl, 0.43 mmol) in dioxane (6 ml). Colorless mixture became black for 1 minute. Solution was added periodate sodium (0,184 g, 0.86 mmol) in water (2 ml), heated to dissolve). Immediately formed a grey precipitate. The mixture was stirred for 30 minutes, was extragonadal water (20 ml) and DCM (2×20 ml). The organic layers were combined, dried, filtered and concentrated with getting listed in the title compound (94 mg, 114%) in the form of a black resin. MS (ESI+) for C17H12F3NO4S m/z 384 (M+H)+.

Example 103

[1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-6-(trifluoromethyl)-1H-indol-2-yl]methanol, bis(triptorelin)

2-(Hydroxymethyl)-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-4-carbaldehyde and 2-(Hydroxymethyl)-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indole-6-carbaldehyde (Intermediate compound 71) in anhydrous THF (8 ml) was distributed in two vial for microwave heating (47 mg, 0.12 mmol each), and then in each vial was added 1-BOC-piperazine (46 mg, 0.25 mmol), acetic acid (70 μl, of 1.23 mmol) and NaB(OAc)3H (78 mg, and 0.37 mmol). The mixture was subjected to microwave irradiation for 720 seconds at 130°C, filtered and concentrated. The residues were dissolved in MeOH (1.5 ml) and concentrated HCl (0.5 ml) and subjected to microwave irradiation at 100°C for 300 sec, filters the if and purified using preparative HPLC/UV (System A, 20-50% MeCN, 0.1% of TFU). Concentration of fractions containing the compound with the lowest retention time gave 38 mg of [1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-6-(trifluoromethyl)-1H-indol-2-yl]methanol. Purification was performed using preparative HPLC/UV (System A, 20-50% MeCN, 0.1% of NH4OAc). After concentration was carried out by extraction using DCM (×2) and water solution of Na2CO3/saturated salt solution. The organic layers were combined, dried, filtered and concentrated to obtain 7 mg, 6% light yellow solid. HPLC purity 98% RT= 1.59 minutes (System A, 10-97% MeCN over 3 min), 98% RT= 1.35 min (System B, 10-97% MeCN over 3 min).1H NMR (500 MHz, CHLOROFORM-D) δ ppm is 2.37 (s, 4H) is 2.88 (t, J=4,71 Hz, 4H) of 3.60 (s, 2H) 4,95 (s, 2H) PC 6.82 (s, 1H) 7,45 (t, J=a 7.85 Hz, 2H) 7,49 (s, 1H) 7,56 (t, J=rate of 7.54 Hz, 1H) a 7.85 (d, J=8,48 Hz, 2H) 8,19 (s, 1H).13C NMR (126 MHz, CHLOROFORM-D) δ ppm 45,97 (s, 2C) 54,23 (s, 2C) 58,43 (s, 1C) 63,31 (s, 1C) 109,04 (s, 1C) 117,93 (s, 1C) 121,88-127,09 (m, 1C) 122,09 (s, 1C) 124,91 (s, 2C) 126,55 (s, 2C) 129,49 (s, 2C) 134,32 (s, 1C) 135,61 (s, 1C) 137,53 (s, 1C) 138,15 (s, 1C) 141,98 (s, 1C). Also implemented COSY, HSQC and HMBC to confirm the structure. MS (ESI+) for C21H22F3N3O3S m/z 454 (M+H)+.

The intermediate connection 72

2-Bromo-3-methyl-4-nitro-phenol

Bromination of 3-methyl-4-NITROPHENOL was carried out as described in the literature (Muntwyler, R., Widmer, J., Keller-Schierlein, W. Synthese des 5-Chlor-6-methyl-salicylsäure-methyläthers a Abbauproduktes des Chlorothricins. Helv Chim Acta 1970, 53, 1544-1547). This gave a 2:1 mixture of 2-bromo-3-methyl-4-NITROPHENOL and 2-bromo-5-methyl-4-NITROPHENOL. 2-Bromo-5-methyl-4-NITROPHENOL,1H NMR (400 MHz, CHLOROFORM-D) δ ppm of 2.58 (s, 3H) 5,98 (s, 1H) 6,94 (s, 1H) 8,29 (s, 1H), 2-Bromo-3-methyl-4-NITROPHENOL,1H NMR (400 MHz, CHLOROFORM-D) δ ppm to 2.67 (s, 3H) 6,16 (s, 1H) 6,98 (d, J=9,03 Hz, 1H) 7,88 (d, J=9,03 Hz, 1H), MS (ESI+) for C7H6BrNO3m/z 232/234 (M+H)+.

The intermediate connection 73

4-Bromo-5-methoxy-1H-indol

2-Bromo-3-methyl-4-NITROPHENOL, (100 g, 0.43 mol, Intermediate compound 72) was dissolved in acetone (500 ml), was added powdered K2CO3119 g (0.86 mol), and methyliodide 83 g (0.59 mol)and the reaction mixture was heated at the boiling point under reflux for one hour. The suspension was filtered and the solvent was removed under reduced pressure to obtain brown spontaneously crystallizing oil, which was used directly in the next stage of the synthesis. Quantitative output. The crude detoxify 106 g (0.43 mol) was dissolved in anhydrous DMF (350 ml), was added dimethylformamidine [DMFDMA] 103 g (0.87 mol) and the reaction mixture was heated and stirred at 90°C for two days. Over the next three days, each day was added portion DMFDMA 20 g (to 0.17 mol), the mixture continued to heat up. The solvent was removed under reduced pressure and the black/red oil is a simple residue was dissolved in HOAc (300 ml). A viscous solution was carefully added to a stirring suspension of iron powder 72 g (1.3 mol) in warm HOAc (700 ml) at such a speed that there is an exothermic reaction. The viscous reaction mixture was heated at the boiling point under reflux for one hour, the solids were filtered off and the solvent was removed under reduced pressure. The black residue was dissolved in warm CHCl3(700 ml), was added heptane (600 ml) and 50 g of silica gel, the mixture was filtered through a layer of silica, washed with a mixture of 50/50 CHCl3/heptane and the solvent was again removed under reduced pressure. The black residue was purified using chromatography on a column of silica using petroleum ether/EtOAc 90/10 as eluent, to obtain 14.9 g (15%) of target compound in the form of an olive-green solid. MS (ESI+) for C9H8BrNO m/z 226/228 (M+H)+.

The intermediate connection 74

4-Bromo-5-methoxy-1-(phenylsulfonyl)-1H-indole

To a solution of 4-bromo-5-methoxy-1H-indole 2,59 g (11.5 mmol, Intermediate compound 73) in DCM (20 ml) was added benzosulphochloride 2,12 g (12,0 mmol), tetrabutylammonium bisulfate 0,23 g (0.7 mmol) and 2M NaOH (20 ml) and the biphasic mixture was intensively stirred at room temperature for 30 minutes. The organic phase is washed once with water and once with saturated SOLEV the m solution, dried (MgSO4) and the solvent was removed under reduced pressure to get sulfonamida in the form spontaneously crystallizing oil 4,20 g (98%).

The intermediate connection 75

5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde

To the warm solution of 4-bromo-5-methoxy-1-(phenylsulfonyl)-1H-indole (3,91 g of 10.7 mmol, Intermediate compound 74) in toluene (7 ml) was added tributyltinhydride 5,08 g (16.0 mmol) and Pd(PPh3)2Cl20,37 g (0.5 mmol). The solution was heated at the boiling point under reflux during the night, added a teaspoon of silicon dioxide and the mixture was filtered through a layer of silicon dioxide. The solvent was removed under reduced pressure and the oil obtained was ground into powder with petroleum ether to obtain semi-crystalline mass, which was used directly in the next stage. The above crude substance was dissolved in dioxane (110 ml)was added 2,6-lutidine, to 2.29 g (21,3 mmol) and OSO4, 0.27 g (1.1 mmol) and the mixture was stirred at room temperature for five minutes. The dark solution was added a warm solution of periodate sodium 6.85 g (32,0 mmol) in water (35 ml) and the resulting suspension was stirred over night. Again was added dioxane (40 ml), the solids were filtered off and the solvent from the filtrate evaporated under reduced pressure to get tons is a lot of red oil, which was recrystallized from EtOH to obtain 1.55 g (46%), two-stage, light-brown solid. MS (ESI+) for C16H13NO4S m/z 316 (M+H)+.

The intermediate connection 76

tert-Butyl 4-{[5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate

5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (0.10 g, MX 0.317 mmol, Intermediate compound 75), boc-piperazine (amount of 0.118 g, 0,634 mmol) and acetic acid (0,095 g, was 1.58 mmol) was dissolved in THF (5 ml) was added triacetoxyborohydride sodium (0,134 g to 0.63 mmol). The mixture was stirred for 2 hours and was diluted with dichloromethane and 1 N. a solution of Na2CO3. The mixture was extragonadal dichloromethane (2×) and the combined organic layers were dried (MgSO4) and was evaporated. The crude product was passed through a plug of silica gel, elwira 5% MeOH in dichloromethane. Yield 100 mg (65%). White solid. MS (ESI+) for C25H31N3O5S m/z 486,4 (M+H)+.

Example 104

5-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, bis(triptorelin)

tert-Butyl 4-{[5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (0,050 g is 0.102 mmol, Intermediate compound 76) was dissolved in dichloromethane (4 ml) was added TFU (1 ml). The mixture was stirred at room temperature for 2 hours and evaporated. The crude product was purified is Briseno-phase preparative HPLC using a column ACE Prep UV C8 150×30 mm, the flow rate of 38 ml/min, the time gradient of 8.5 minutes using the system for elution: water/0.1% of TFU and CH3CN (20-40% MeCN), fractions collected based on UV-signal (254 nm). The most pure fractions were combined and the acetonitrile evaporated. Yield: 29 mg (46%). Brown liquid after 1 hour of not quite white solid. Was isolated as a salt TFU. MS (ESI+) for C20H23N3O3S m/z 386,4 (M+H)+.

Example 105

5-Ethoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole, triptorelin

To a solution of tert-butyl 4-{[5-hydroxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate, 60 mg (0.13 mmol), Intermediate compound 64 in anhydrous DCM (4 ml) was added triphenylphosphine, 43 mg (0.16 mmol), TMAD, 33 mg (0,19 mmol) and EtOH, 9 mg (0,19 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the oily residue was dissolved in a 50/50 mixture TFU/dichloromethane and stirred for 4 hours. From the crude product, which was removed BOC group, the solvent was removed under reduced pressure and the residue was purified using preparative HPLC, method B, with the receipt of 8.3 mg (12%) of target compound as a colorless oil. MS (ESI+) for C21H25N3O3S m/z 400 (M+H)+.

Example 106

1-Phenyl-N-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}IU anamin, triptorelin

To a solution of Intermediate 49 300 mg (1.1 mmol) in DCE (15 ml) was added benzylamine (135 mg, 1.3 mmol) and NaBH(OAc)3, (443 mg, 2.1 mmol) and the mixture was stirred at 40°C for five hours. Added water and the reaction mixture was stirred for 15 minutes, the phases were separated and the organic phase is washed once with water. Took a small sample for analysis was purified using preparative HPLC, column ACE C8, using 0.1%of TFU/ACN as eluent, to obtain 6.2 mg of the target compound. MS (ESI+) for C22H20N2O2S m/z 377 (M+H)+.

Example 107

N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}cyclopropanation, triptorelin

5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (50 mg, 0.16 mmol; Intermediate compound 75) was dissolved in anhydrous THF (4 ml) before adding cyclopropylamine (57 mg, 0.24 mmol) and then acetic acid (95 mg, of 1.59 mmol) and triacetoxyborohydride sodium (101 mg, 0.48 mmol). The reaction mixture was subjected to microwave heating for 720 seconds at 130°C. the Solvent was removed and the crude product was purified using preparative HPLC/UV (System A, 30-60% MeCN, 0.1% of TFU). Specified in the header connection (to 39.4 mg, 69%) was obtained as a white solid. MS (ESI+) for C19H20N2O3S C2HF3O2m/z 357 (M+H)+.

Example 108

{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine, hydrochloride

5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (0.5 g, 1.6 mmol; Intermediate compound 75), 5.5 M dimethylamine in EtOH (5 ml, 27.5 mmol) and acetic acid (2 ml, and 31.7 mmol) was dissolved in MeOH (50 ml) and was heated to 50°C for 20 minutes before adding cyanoborohydride sodium (0.5 g, 7.9 mmol) in one portion. The mixture was stirred for 30 minutes and was evaporated to half its volume. The mixture was added dropwise to a chilled 0.1 G. of NaOH solution and was extragonadal dichloromethane (2×). The combined organic layers were washed with saturated salt solution, dried (MgSO4) and was evaporated. The crude product was purified flash chromatography using a 2.5% MeOH in dichloromethane to 5% MeOH in dichloromethane with 1% NEt3to obtain 440 mg (63%) of final product as a colourless oil. The oil was dissolved in diethyl ether and was added 1 n solution of HCl in diethyl ether (1.5 ml, 1.5 mmol) dropwise with stirring. The mixture was evaporated and the white crystals were dried in vacuo. MS (ESI+) for C18H20N2O3S m/z 345 (M+H)+.

Example 109

N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}CYCLOBUTANE, triptorelin

5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (50 mg, 0.16 mmol; Intermediate compound 75) was dissolved in anhydrous THF (4 ml) before adding the cyclobutylamine (71 mg, 0.24 mmol)and then acetic acid (95 mg, of 1.59 mmol) and triacetoxyborohydride sodium (101 mg, 0.48 mmol). The reaction mixture was subjected to microwave heating for 720 seconds at 130°C. the Solvent was removed and the crude product was purified using preparative HPLC/UV (System A, 30-60% MeCN, 0.1% of TFU). Specified in the title compound (10 mg, 17%) was obtained as a white solid. MS (ESI+) for C20H22N2O3S C2HF3O2m/z 371 (M+H)+.

Example 110

N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}-N-methylcyclobutane, triptorelin

5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (50 mg, 0.16 mmol, Intermediate compound 75) was dissolved in anhydrous THF (4 ml) before adding cyclobutylamine (71 mg, 0.24 mmol)and then acetic acid (95 mg, of 1.59 mmol) and triacetoxyborohydride sodium (101 mg, 0.48 mmol). The reaction mixture was subjected to microwave heating for 720 seconds at 130°C. was Added acetic acid (95 mg, of 1.59 mmol) and triacetoxyborohydride sodium (101 mg, 0.48 mmol) and formalin (1 ml) and the reaction mixture was again subjected to microwave heating for 720 seconds at 130°C. the Solvent was removed and the crude product was purified using preparative HPLC/UV (System A, 30-60% MeCN, 0.1% of TFU). Specified in the title compound (24.5 mg, 40%) was obtained as a white solid washes the VA. MS (ESI+) for C21H24N2O3S C2HF3O2m/z 385 (M+H)+.

Example 111

1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}azetidin-3-ol, triptorelin

Azetidin-3-ol in the form of cleaners containing hydrochloride salt (27 mg, 0.27 mmol) and NaOAc (30 mg, 0.36 mmol) suspended in DMSO (2 ml) and treated with ultrasound for about 2 minutes. Added intermediate compound 49 (35 mg, 0.12 mmol) and NaBH(OAc)3, (62 mg, 0.29 mmol) and the reaction mixture was stirred at 40° for 30 minutes. Was added water (10 ml) and the reaction mixture was extragonadal 3 times using DCM, the combined organic phases are washed once with water and the organic phase was evaporated. The oil obtained was purified using preparative LC System B, with getting to 19.9 mg (35%) of target compound as a colorless oil. MS (ESI+) for C18H18N2O3S m/z 343 (M+H)+.

Example 112

4-(Azetidin-1-ylmethyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole, triptorelin

5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (50 mg, 0.16 mmol; Intermediate compound 75) was dissolved in anhydrous THF (4 ml) before adding azetidine (13 mg, 0.24 mmol)and then acetic acid (95 mg, of 1.59 mmol) and triacetoxyborohydride sodium (101 mg, 0.48 mmol). The reaction mixture was subjected to microwave heating for 720 seconds at 130°C. the Solvent was removed and the crude product is purified using preparative HPLC/UV (System A, 30-60% MeCN, 0.1% of TFU). Specified in the header of the connection (of 22.3 mg, 40%) was obtained as a white solid. MS (ESI+) for C19H20N2O3S C2HF3O2m/z 357 (M+H)+.

The intermediate connection 77

4-(Azetidin-1-ylmethyl)-1H-indole

Triacetoxyborohydride sodium (1,46 g, 6,9 mmol) was added to a solution of 1H-indole-4-carbaldehyde (0.5 g, 3.4 mmol) and azetidine (0.39 g, 6,87 mmol) in THF (15 ml). The mixture was stirred for 1 hour and was diluted with dichloromethane and NaHCO3(aq.). The organic phase is washed with saturated salt solution (1×), dried (MgSO4) and was evaporated. The crude product was dissolved in dichloromethane and was added hexane (1:1). No white powder was filtered and washed with a mixture of dichloromethane:hexane (1:1). Yield: 400 mg (52%). Not quite white solid. MS (ESI+) for C12H14N2m/z 187 (M+H)+.

Example 113

4-{[4-(Azetidin-1-ylmethyl)-1H-indol-1-yl]sulfonyl}benzonitrile, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (4.3 mg, 0.1 mmol) at room temperature. The mixture was stirred for 20 minutes before addition of 4-cyanobenzenesulfonyl (21,7 mg, 0.11 mmol). The mixture was left to stir for 30 minutes and was added 2 drops of 1 n HCl solution. The mixture was filtered and was purified and the use of preparative HPLC with column ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 6.0 mg (24%). Light brown oil. MS (ESI+) for C19H13N3O2S m/z 352 (M+H)+.

The intermediate connection 78

Methyl (2S)-1-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}azetidin-2-carboxylate, triptorelin

The target compound was obtained using the same procedure as described for Example 111 using the intermediate 49, 124 mg (0.43 mmol)and methyl (2S)-azetidin-2-carboxylate, in the form of cleaners containing hydrochloride salt (100 mg, 0.66 mmol). Received the crude product was purified using preparative HPLC on a column of ACE C8 using 0.1% of TFU/ACN as eluent, to obtain 72 mg (33%) of target compound as a colorless oil. MS (ESI+) for C20H20N2O4S m/z 385 (M+H)+. Although, as was shown by LC methods, the product was completely clean, the spectra of 1-NMR showed the presence of some aromatic impurities with an intensity of about 10 mol%.

Example 114

2-((2S)-1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}azetidin-2-yl)propan-2-ol, triptorelin

Intermediate compound 78 (25 mg, 0,065 mmol) was distributed between ice 0,1M NaOH/CHCl3, the aqueous phase was extragonadal once using CHCl3joint organization of the definition phase was dried (Na 2SO4) and the solvent was removed under reduced pressure. The obtained colorless oil was dissolved in anhydrous THF (5 ml), the atmosphere of N2solution was added 1,2M MeLi in THF, 0.5 ml (0.6 mmol) and the yellow solution was left for 20 minutes at room temperature. Added MeOH, the solvent is evaporated under reduced pressure and the residue was purified using preparative HPLC System B, with the receipt of 4.8 mg (15%) of colorless oil. MS (ESI+) for C21H24N2O3S m/z 385 (M+H)+.

Example 115

4-(Azetidin-1-ylmethyl)-2-methyl-1-(phenylsulfonyl)-1H-indole, triptorelin

2-Methyl-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (32 mg, 0.11 mmol; Intermediate compound 47) was dissolved in anhydrous THF (4 ml) before adding azetidine (9,2 mg, 0.16 mmol)and then acetic acid (64 mg, 1.07 mmol) and triacetoxyborohydride sodium (68 mg, 0.32 mmol). The reaction mixture was subjected to microwave heating for 720 seconds at 130°C. the Solvent was removed and the crude product was purified using preparative HPLC/UV (System A, 30-60% MeCN, 0.1% of TFU). Specified in the title compound (2.3 mg, 6%) was obtained as a transparent oil. MS (ESI+) for C19H20N2O2S C2HF3O2m/z 341 (M+H)+.

Example 116

4-(Azetidin-1-ylmethyl)-1-[(2-chlorophenyl)sulfonyl]-1H-indole, triptorelin

DMF (1 ml) was added in F. the law, containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5.4 mg, 0.13 mmol)at room temperature. The mixture was stirred for 20 minutes before adding 2-chlorobenzenesulfonamide (22.7 mg, 0.11 mmol). The mixture was left to stir for 1 hour and added 2 drops of 1 n HCl solution. The mixture was diluted using MeOH, filtered and purified using preparative HPLC with column ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 12.0 mg (47%). White solid. MS (ESI+) for C18H17ClN2O2S m/z 361 (M+H)+.

Example 117

4-(Azetidin-1-ylmethyl)-1-[(5-chloro-2-thienyl)sulfonyl]-1H-indole, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5.4 mg, 0.13 mmol) at room temperature. The mixture was stirred for 20 minutes before adding 5-chlorothiophene-2-sulphonylchloride (23,3 mg, 0.11 mmol). The mixture was left to stir for 1 hour and added 2 drops of 1 n HCl solution. The mixture was diluted using MeOH, filtered and purified using preparative HPLC with column ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile was used as the e mobile phases, at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 12.0 mg (46%). White solid. MS (ESI+) for C16H15ClN2O2S2m/z 367 (M+H)+.

Example 118

4-(Azetidin-1-ylmethyl)-1-(2-naphthylmethyl)-1H-indole, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5.4 mg, 0.13 mmol)at room temperature. The mixture was stirred for 20 minutes before adding 2-attilalongoria (24.3 mg, 0.11 mmol). The mixture was left to stir for 1 hour and added 2 drops of 1 n HCl solution. The mixture was diluted using MeOH, filtered and purified using preparative HPLC with column ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 7.5 mg (28%). Light red solid. MS (ESI+) for C22H20N2O2S m/z 377 (M+H)+.

Example 119

4-(Azetidin-1-ylmethyl)-1-[(2-methoxy-5-were)sulfonyl]-1H-indole, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5.4 mg, 0.13 mmol)at room temperature. The mixture was stirred for 20 minutes before adding 6-methoxy-m-t is lolslipperyslope (22.7 mg, 0.11 mmol). The mixture was left to stir for 1 hour and added 2 drops of 1 n HCl solution. The mixture was diluted using MeOH, filtered and purified using preparative HPLC with column ACE C8 5 m (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 13.3 mg (50%). White solid. MS (ESI+) for C20H22N2O3S m/z 371 (M+H)+.

Example 120

4-(Azetidin-1-ylmethyl)-1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-indole, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5.4 mg, 0.13 mmol)at room temperature. The mixture was stirred for 20 minutes before adding 6-chloroimidazo[2,1-b]thiazole-5-sulphonylchloride (23,7 mg, 0.11 mmol). The mixture was left to stir for 1 hour and added 2 drops of 1 n HCl solution. The mixture was diluted using MeOH, filtered and purified using preparative HPLC with column ACE C8 5 m (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 8,9 mg (32%). White solid. MS (ESI+) for C17H15ClN4O2S2m/z 407 (M+H)+.

Note the R 121

4-(Azetidin-1-ylmethyl)-1-[(4-tert-butylphenyl)sulfonyl]-1H-indole, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5.4 mg, 0.13 mmol)at room temperature. The mixture was stirred for 20 minutes before addition of 4-tert-butylbenzenesulfonamide (27,6 mg, 0.11 mmol). The mixture was left to stir for 1 hour and added 2 drops of 1 n HCl solution. The mixture was diluted using MeOH, filtered and purified using preparative HPLC with column ACE C8 5 m (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 4.3 mg (16%). Colorless liquid. MS (ESI+) for C22H26N2O2S m/z 383 (M+H)+.

Example 122

4-(Azetidin-1-ylmethyl)-1-[(2,6-differenl)sulfonyl]-1H-indole, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5.4 mg, 0.13 mmol)at room temperature. The mixture was stirred for 20 minutes before adding 2,6-differentialthreshold (20.5 mg, 0.11 mmol). The mixture was left to stir for 1 hour and added 2 drops of 1 n HCl solution. The mixture was diluted using MeOH, filtered and purified using the-W preparative HPLC with column ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 8.0 mg (31%). Light brown solid. MS (ESI+) for C18H16F2N2O2S m/z 363 (M+H)+.

Example 123

4-(Azetidin-1-ylmethyl)-1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-indole, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5.4 mg, 0.13 mmol)at room temperature. The mixture was stirred for 20 minutes before adding 2-triftormetilfullerenov (of 22.8 mg, 0.11 mmol). The mixture was left to stir for 1 hour and added 2 drops of 1 n HCl solution. The mixture was diluted using MeOH, filtered and purified using preparative HPLC with column ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 13,7 mg (50%). Light brown liquid. MS (ESI+) for C19H17F3N2O2S m/z 395 (M+H)+.

Example 124

3-{[4-(Azetidin-1-ylmethyl)-1H-indol-1-yl]sulfonyl}benzonitrile, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5,mg, 0.13 mmol)at room temperature. The mixture was stirred for 20 minutes before adding 3-cyanobenzenesulfonyl (26,3 mg, 0.11 mmol). The mixture was left to stir for 1 hour and added 2 drops of 1 n HCl solution. The mixture was diluted using MeOH, filtered and purified using preparative HPLC with column ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 2.4 mg (10%). Colorless liquid. MS (ESI+) for C19H17N3O2S m/z 352 (M+H)+.

Example 125

4-(Azetidin-1-ylmethyl)-1-{[4-bromo-2-(trifluoromethyl)phenyl]sulfonyl}-1H-indole, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5.4 mg, 0.13 mmol)at room temperature. The mixture was stirred for 20 minutes before addition of 4-bromo-2-(trifluoromethyl)benzosulfimide (or 24.2 mg, 0.11 mmol). The mixture was left to stir for 1 hour and added 2 drops of 1 n HCl solution. The mixture was diluted using MeOH, filtered and purified using preparative HPLC with column ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of the and 11.5 minutes. Yield: 11 mg (35%). Light brown liquid. MS (ESI+) for C19H16BrF3N2O2S m/z 475 (M+H)+.

Example 126

4-(Azetidin-1-ylmethyl)-1-(2-thienylmethyl)-1H-indole, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5.4 mg, 0.13 mmol)at room temperature. The mixture was stirred for 20 minutes before adding 2-thiophenesulfonyl (26,4 mg, 0.11 mmol). The mixture was left to stir for 1 hour and added 2 drops of 1 n HCl solution. The mixture was diluted using MeOH, filtered and purified using preparative HPLC with column ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Yield: 12 mg (50%). Colorless liquid. MS (ESI+) for C16H16N2O2S2m/z 333 (M+H)+.

Example 127

4-(Azetidin-1-ylmethyl)-1-[(2,5-differenl)sulfonyl]-1H-indole, triptorelin

DMF (1 ml) was added to a vial containing 4-(azetidin-1-ylmethyl)-1H-indole (10 mg, 0,054 mmol; Intermediate compound 77) and 60% NaH (5.4 mg, 0.13 mmol)at room temperature. The mixture was stirred for 20 minutes before adding 2,5-differentialthreshold (19.6 mg, 0.11 mmol). The mixture was left for paramasivan what I'm in for 1 hour and added 2 drops of 1 N. HCl solution. The mixture was diluted using MeOH, filtered and purified using preparative HPLC with column ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 4.5 mg (18%). Colorless liquid. MS (ESI+) for C18H16F2N2O2S m/z 363 (M+H)+.

The intermediate connection 79

(5-Methoxy-1H-indol-4-ylmethyl)dimethylamine

5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (366 mg, of 1.16 mmol; Intermediate compound 75) was dissolved in DCE, has consistently added dimethylamine (3,48 mmol in the form of a 2M solution in MeOH) and triacetoxyborohydride sodium (738 mg, of 3.48 mmol). The reaction mixture was allowed to mix at room temperature for 23 hours, diluted with the help of DCM, was added NaOH (2M, aqueous solution) until then, until reaching pH = 10. The organic phase was separated and the aqueous phase was extragonadal once using DCM. The combined organic phases were dried over Na2SO4and was purified preparative HPLC. Yield: 57 mg of the residue mauve color.

Example 128

[(5-Methoxy-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]dimethylamine, triptorelin

(5-Methoxy-1H-indol-4-ylmethyl)-dimethylamine (23,5 mg, 0,115 mmol; Intermediate compound 79) distributed two porci the mi in DMF, added NaH (60%) and the mixture was stirred for 30 minutes before adding 3-triftormetilfullerenov (56,3 mg, 0,230 mmol). The reaction mixture was diluted with water and was extragonadal using DCM, dried and concentrated. The obtained residue was purified using preparative HPLC. Yield: 7 mg MS (ESI+) for C19H19F3N2O3S m/z 413 (M+H)+.

The intermediate connection 80

4-Bromo-3-methyl-2-NITROPHENOL

3-Methyl-2-NITROPHENOL (11.4 g, 74,4 mmol) was dissolved in chloroform (11 ml) and cooled in a bath of ice-water. To stir the cooled solution was added dropwise bromine (3.8 ml of 74.4 mmol) in HOAc (9 ml). The solution was stirred at 0° for 2 hours. To the reaction mixture were added ice. The organic phase was separated and the aqueous phase was extragonadal chloroform. The combined organic phase was washed with saturated saline solution and water. In the evaporation was received 17,2, MS (ESI+) for C7H6BrNO3m/z 232, 234 (M+H)+.

The intermediate connection 81

Benzyl 4-bromo-3-methyl-2-nitrophenyloctyl ether

Intermediate compound 80 (17,2 g, 74,1 mmol) was dissolved in acetone (150 ml). Added K2CO3(of 15.4 g of 111.2 mmol, 1.5 EQ.). The solution was stirred for 5 minutes and then added benzylbromide (10 ml, 81.2 mmol, 1.1 EQ.). The solution was subjected to boiling under reflux for 90 m the chickpeas. The potassium carbonate was filtered and the solution was evaporated. The residue was recrystallized from ethanol. Received 20,2,

The intermediate connection 82

1-{(E)-2-[3-(Benzyloxy)-6-bromo-2-nitrophenyl]vinyl}pyrrolidin

1-Benzyloxy-4-bromo-3-methyl-2-nitrobenzene (20 g, was 62.1 mmol; Intermediate compound 81) was dissolved in DMF. Added DMFDMA (to 9.93 ml of 74.5 mmol) and pyrrolidine (6.22 per ml, of 74.5 mmol). The solution was heated at 110° in a nitrogen atmosphere. The TLC analysis (EtOAc/Hexane 1/3) showed that starting material was consumed after 2 hours. The heating was off. The reaction mixture was allowed to reach room temperature and left to stand over night. The solution was evaporated and the residue was utverjdala when aged in the refrigerator. Added 50 ml of methanol and the mixture was heated. The solid was partially dissolved. The mixture was allowed to reach room temperature and then filtered. The solid is washed with methanol and dried. Received 17 year

The intermediate connection 83

7-(Benzyloxy)-4-bromo-1H-indole

1-[-2-(3-Benzyloxy-6-bromo-2-nitro-phenyl)vinyl]pyrrolidine (10 g, of 24.8 mmol; Intermediate compound 82), suspended in HOAc (25 ml)was added to a boiling mixture of iron (4.15 g, 74,4 mmol) in HOAc. After 2 hours of boiling the TLC analysis showed the absence of any of the original substance. The reaction mixture was filtered while it was still warm. The residue was evaporated is dissolved in toluene. Toluene suspension was applied on a column with silica and suirable a mixture of toluene/hexane 1/1. Received 3,1, MS (ESI+) for C15H12BrNO m/z 302, 304 (M+H)+.

The intermediate connection 84

7-(Benzyloxy)-4-bromo-1-(methylsulphonyl)-1H-indole

Sodium hydride (suspension of 60% in oil) (0,48 g, to 19.9 mmol) was washed with hexane and dried in vacuum. Added indole derivative (2.0 g, 5.6 mmol; Intermediate compound 83)dissolved in DMF (12 ml). The suspension was stirred for 10 minutes and then added methanesulfonamide (1,54 ml, to 19.9 mmol). The mixture was stirred for 2 hours at room temperature. Added water and the reaction mixture was extragonadal using DCM. In the evaporation was received solid, which was washed with methanol. Got a 1.6, MS (ESI+) for C16H14BrNO3S m/z 380, 382 (M+H)+.

The intermediate connection 85

7-(Benzyloxy)-1-(methylsulphonyl)-1H-indole-4-carbaldehyde

To a solution of 7-benzyloxy-1-methanesulfonyl-4-vinyl-1H-indole (1.3 g, 3.9 mmol; Intermediate compound 84) in dioxane (25 ml) was added lutidine (900 ml, 7.9 mmol), metaperiodate sodium (3,37 g, 15.8 mmol) in water (10 ml)and osmium tetroxide (100 mg, 0.1 mmol) (in that order). Almost immediately formed precipitate, and the mixture was stirred for 1 hour at room temperature. Added water. The precipitate of otfiltrovana washed with water. The solid was extragonadal acetonitrile. The combined acetonitrile solution was evaporated. The product was purified using chromatography with direct phase using flash chromatograph Biotage and 5-40% EtOAc in petroleum ether 40-60°C. was Obtained 0,40 mg MS (ESI+) for C17H15NO4S m/z 330 (M+H)+.

Example 129

4-(Azetidin-1-ylmethyl)-7-(benzyloxy)-1-(methylsulphonyl)-1H-indole, triptorelin

Azetidinone (17 mg, 0.18 mmol) and 7-benzyloxy-1-methanesulfonyl-1H-indole-4-carbaldehyde (30 mg, 0.09 mmol) was dissolved in 2 ml of 1,2-dichloroethane. Added acetoxyvalerenic sodium (58 mg, 0.27 mmol) and the mixture was stirred over night at room temperature. The product was purified using reversed-phase preparative HPLC (YMC C8, 0.1% of TFU/CH3CN) obtaining triptoreline salt specified in the connection header of 7.8 mg MS ESI+ m/z 371 (M+H)+.

Example 130

({1-[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-5-methoxy-1H-indol-4-yl}methyl)dimethylamine, triptorelin

5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (296 mg, 0,939 mmol; Intermediate compound 75) was dissolved in DCE was added dimethylamine (2.82 mmol in the form of a 2M solution in MeOH) and triacetoxyborohydride sodium (597 mg, 2.82 mmol)in that order. The reaction mixture was left for stirring at room temperature for 4 hours. Added water dissolve the NaOH for alkalizing and the mixture was extragonadal using DCM, was dried and concentrated.

Then added 10 ml of EtOH and 2 ml of NaOH (6M aq.) and the reaction mixture was heated to boiling point under reflux for 2 hours and left at room temperature over night. Intermediate desulfonylation product was purified using preparative HPLC. This product (46 mg, 0.23 mmol) was dissolved in 1 ml DMF was added NaH (60%) (10,8 mg, 0.45 mmol) and the mixture was stirred for 30 minutes before adding 6-chloro-imidazo[2,1-b]thiazole-5-sulphonylchloride (115 mg, 0.45 mmol). Added TFU to neutralize the excess base and the crude product was purified preparative HPLC. Yield: 6 mg MS (ESI+) for C17H17ClN4O3S2m/z 425 (M+H)+.

The intermediate connection 86

5-(Benzyloxy)-1-(phenylsulfonyl)-1H-indole

DCM (200 ml) was added to 5-benzyloxyindole (15 g, 67 mmol), benzylmalonate acid (17.8 g, 101 mmol) and tetrabutylammonium sulfate (6,84 g, 20 mmol), followed by adding a solution of 5 M NaOH (40 ml). The reaction mixture was stirred at room temperature for 3 hours. The aqueous layer was washed using DCM (2×30 ml) and the organic layers were combined and washed with saturated saline solution (30 ml). After drying (MgSO4) and concentration in vacuo was carried out by crystallization of their MeOH to obtain a product with the release of 83% (20,3 g).

Intermediate compounds is their 87

1-(Phenylsulfonyl)-1H-indol-5-ol

To a solution of 5-(benzyloxy)-1-(phenylsulfonyl)-1H-indole (0.50 g, 1.37 mmol; Intermediate compound 86) in EtOH (3 ml) was added Pd/C (30 wt%, 0.15 g), cyclohexene (1 ml) and HCl (1 ml). The reaction mixture was heated to 150°C for 1 hour using microwave heating. Pd/C was filtered and the solvent was removed under reduced pressure. The product (purity 95%) was used without further purification.

Example 131

4-[(Dimethylamino)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol, triptorelin

Paraformaldehyde (65 mg, of 2.20 mmol) and a solution of 2 M dimethylamine in EtOH (1.1 ml, of 2.20 mmol) was heated up to obtain a clear solution. The solution was added to 1-(phenylsulfonyl)-1H-indol-5-Olu (500 mg, 1.82 mmol; Intermediate compound 87) in EtOH (10 ml) and the mixture was stirred at ambient temperature for 3 days. The solvent is evaporated. Output: 528 mg (87%); white solid. LC-MS: purity of 88%. A small portion (28 mg) was purified using a Gilson HPLC system, using 15-50% MeCN in 0.1% TFU. Yield: 18 mg; brown resin. MS (ESI+) for C17H18N2O3S m/z 331 (M+H)+.

Example 132

{[5-Ethoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin

NaH (95%) (101 mg, to 4.23 mmol) was added to a solution of 4-[(dimethylamino)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol (700 mg, 2,11 mmol; Example 31) in DMF (20 ml) at ambient temperature. The mixture was stirred for 15 minutes before adding iodata (0,203 ml, 2.54 mmol). After 1 hour was added water and the mixture was extragonadal using Et2O. a Small portion was purified using a Gilson HPLC system, using 20-50% MeCN in 0.1% TFU. Yield: 65 mg; colorless oil. MS (ESI+) for C19H22N2O3S m/z 359 (M+H)+.

The intermediate connection 88

1-(5-Ethoxy-1H-indol-4-yl)-N,N-dimethylethanamine

{[5-Ethoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine (655 mg, 1,831 mmol; Example 133) was added to EtOH (5 ml) and 2 M NaOH (5 ml) and heated at 70°C for 5 hours. Was added water, and precipitation of white matter. The mixture was extragonadal using DCM. The organic phase was extragonadal using 1 M HCl (3×20 ml). The aqueous phase was podlachian (pH 9) using 2 M NaOH and extragonadal using DCM (3×50 ml). The combined organic layers were dried (MgSO4) and was evaporated. Output: 293 mg (74%); brown oil. MS (ESI+) for C13H18N2O m/z 219 (M+H)+.

Example 133

({5-Ethoxy-1-[(2-methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine, triptorelin

NaH (7 mg, 0.29 mmol) was added to a solution of 1-(5-ethoxy-1H-indol-4-yl)-N,N-dimethylethanamine (28 mg, 0,128 mmol; Intermediate connection 88) in DMF (1 ml) and the mixture was stirred at room temperature for 10 minutes before adding 6-methoxy-3-matilal is melhorada (42 mg, 0,192 mmol). The mixture was stirred at room temperature for 1 hour and then the mixture was distributed between water (2 ml) and DCM (10 ml). The aqueous phase was extragonadal using DCM (5 ml) and the combined organic layers were concentrated. The residue was purified using a Gilson HPLC system, using 30-60% MeCN in 0.1% TFU as eluent. Yield: 15.8 mg (24%); brown oil. MS (ESI+) for C21H26N2O4S m/z 403 (M+H)+.

Example 134

{[5-Ethoxy-1-(1-naphthylmethyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin

NaH (7 mg, 0.29 mmol) was added to a solution of 1-(5-ethoxy-1H-indol-4-yl)-N,N-dimethylethanamine (28 mg, 0,128 mmol; Intermediate connection 88) in DMF (1 ml) and the mixture was stirred at room temperature for 10 minutes before adding 1-naphthalenesulfonate (44 mg, 0,192 mmol). The mixture was stirred at room temperature for 1 hour and then the mixture was distributed between water (2 ml) and DCM (10 ml). The aqueous phase was extragonadal using DCM (5 ml) and the combined organic layers were concentrated. The residue was purified using a Gilson HPLC system, using 30-60% MeCN in 0.1% TFU as eluent. Output: to 25.3 mg (38%); brown oil. MS (ESI+) for C23H24N2O3S m/z 409 (M+H)+.

Example 135

{[5-Ethoxy-1-(2-naphthylmethyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin

NaH (7 mg, 0.29 mmol) was added the solution of 1-(5-ethoxy-1H-indol-4-yl)-N,N-dimethylethanamine (28 mg, 0,128 mmol; Intermediate connection 88) in DMF (1 ml) and the mixture was stirred at room temperature for 10 minutes before adding 2-naphthalenesulfonate (44 mg, 0,192 mmol). The mixture was stirred at room temperature for 1 hour and then the mixture was distributed between water (2 ml) and DCM (10 ml). The aqueous phase was extragonadal using DCM (5 ml) and the combined organic layers were concentrated. The residue was purified using a Gilson HPLC system, using 30-60% MeCN in 0.1% TFU as eluent. Output: 13.8V mg (21%); brown oil. MS (ESI+) for C23H24N2O3S m/z 409 (M+H)+.

Example 136

({1-[(2-Chlorophenyl)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine, triptorelin

NaH (7 mg, 0.29 mmol) was added to a solution of 1-(5-ethoxy-1H-indol-4-yl)-N,N-dimethylethanamine (28 mg, 0,128 mmol; Intermediate connection 88) in DMF (1 ml) and the mixture was stirred at room temperature for 10 minutes before adding 2-chlorobenzene-1-sulphonylchloride (41 mg, 0,192 mmol). The mixture was stirred at room temperature for 1 hour and then the mixture was distributed between water (2 ml) and DCM (10 ml). The aqueous phase was extragonadal using DCM (5 ml) and the combined organic layers were concentrated. The residue was purified using a Gilson HPLC system, using 30-60% MeCN in 0.1% TFU as eluent. Output: 28.5 mg (44%); brown oil. MS (ESI+) for C19H 21ClN2O3S m/z 393 (M+H)+.

Example 137

({1-[(3-Chloro-2-were)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine, triptorelin

NaH (7 mg, 0.29 mmol) was added to a solution of 1-(5-ethoxy-1H-indol-4-yl)-N,N-dimethylethanamine (28 mg, 0,128 mmol; Intermediate connection 88) in DMF (1 ml) and the mixture was stirred at room temperature for 10 minutes before adding 3-chloro-2-methylbenzenesulfonamide (43 mg, 0,192 mmol). The mixture was stirred at room temperature for 1 hour and then the mixture was distributed between water (2 ml) and DCM (10 ml). The aqueous phase was extragonadal using DCM (5 ml) and the combined organic layers were concentrated. The residue was purified using a Gilson HPLC system, using 30-60% MeCN in 0.1% TFU as eluent. Output: 17,8 mg (27%); brown oil. MS (ESI+) for C20H23ClN2O3S m/z 407 (M+H)+.

The intermediate connection 89

[(5-Methoxy-1H-indol-4-yl)methyl]dimethylamine, triptorelin

{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine triptorelin (127 mg, 0,278 mmol) was subjected to boiling under reflux in EtOH (2 ml) and 1 M NaOH (2 ml) for 3 hours. The mixture was extragonadal using DCM. The product was purified using a Gilson HPLC system, using 20-40% MeCN in 0.1% TFU. Output: 54,6 mg (62%); colourless oil.

Example 138

({5-Methoxy-1-[(2-methoxy-5-were)su is hanil]-1H-indol-4-yl}methyl)dimethylamine, triptorelin

NaH (4 mg, 0,160 mmol, 95%) was added to a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (17 mg, 0,053 mmol, TFU-salt; an Intermediate connection 89) in DMF (1 ml) and the mixture was stirred for 10 minutes before adding 2-methoxy-5-methylbenzenesulfonamide (18 mg, 0,080 mmol). After 1 hour the reaction mixture was suppressed by adding a few drops of TFU, was diluted using MeOH and filtered. The mixture was purified using HPLC system Waters using 15-60% MeCN in 0.1% TFU. Output: 2.4 mg (9%); brown oil. MS (ESI+) for C20H24N2O4S m/z 389 (M+H)+.

Example 139

({1-[(2,3-Dichlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}methyl)dimethylamine, triptorelin

NaH (4 mg, 0,160 mmol, 95%) was added to a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (17 mg, 0,053 mmol, TFU-salt; Intermediate compound 77) in DMF (1 ml) and the mixture was stirred for 10 minutes before adding 2,3-dichlorobenzenesulfonyl (20 mg, 0,080 mmol). After 1 hour the reaction mixture was suppressed by adding a few drops of TFU and diluted using MeOH and filtered. The mixture was purified using HPLC system Waters using 15-60% MeCN in 0.1% TFU. Output: 7.7 mg (28%); brown oil. MS (ESI+) for C18H18Cl2N2O3S m/z 413 (M+H)+.

Example 140

{[5-Ethoxy-1-(quinoline-8-ylsulphonyl)-1H-indol-4-yl]methyl}dimethylamine, bis(trif orsett)

NaH (5 mg, 0.21 mmol) was added to a solution of 1-(5-ethoxy-1H-indol-4-yl)-N,N-dimethylethanamine (14 mg, 0,064 mmol; Intermediate connection 88) in DMF (0.5 ml) and the mixture was stirred at room temperature for 10 minutes before adding the 8-chinaincorporated (22 mg, 0,096 mmol). The mixture was stirred at room temperature for 1 hour and then the mixture was distributed between water (2 ml) and DCM (10 ml). The aqueous phase was extragonadal using DCM (5 ml) and the combined organic layers were concentrated. The residue was purified using a Gilson HPLC system, using 30-60% MeCN in 0.1% TFU as eluent. Output: 5,7 mg (17%); brown oil. MS (ESI+) for C22H23N3O3S m/z 410 (M+H)+.

Example 141

{[5-Ethoxy-1-({5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-thienyl}sulfonyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin

NaH (5 mg, 0.21 mmol) was added to a solution of 1-(5-ethoxy-1H-indol-4-yl)-N,N-dimethylethanamine (14 mg, 0,064 mmol; Intermediate connection 88) in DMF (0.5 ml) and the mixture was stirred at room temperature for 10 minutes. Was added 5-(1-methyl-3-vermeil)-1H-pyrazole-5-yl)thiophene-2-sulphonylchloride (32 mg, 0,096 mmol). The mixture was stirred at room temperature for 1 hour and then the mixture was distributed between water (2 ml) and DCM (10 ml). The aqueous phase was extragonadal using DCM (5 ml) and the combined organic layers were concentrated. the STATCOM was purified using HPLC system Waters, using 15-60% MeCN in 0.1% TFU as eluent. Output: 4.4 mg (11%); brown oil. MS (ESI+) for C22H23F3N4O3S2m/z 513 (M+H)+.

Example 142

({1-[(2,5-Dichlorophenyl)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine, triptorelin

NaH (5 mg, 0.21 mmol) was added to a solution of 1-(5-ethoxy-1H-indol-4-yl)-N,N-dimethylethanamine (14 mg, 0,064 mmol; Intermediate connection 88) in DMF (0.5 ml) and the mixture was stirred at room temperature for 10 minutes before adding 2,5-dichlorobenzenesulfonate (23,5 mg, 0,096 mmol). The mixture was stirred at room temperature for 20 minutes and then the mixture was suppressed by adding a few drops of TFU, was diluted using MeOH and filtered. The mixture was purified using HPLC system Waters using 15-60% MeCN in 0.1% TFU in the water. Output: 11,3 mg (33%); brown oil. MS (ESI+) for C19H20Cl2N2O3S m/z 427 (M+H)+.

Example 143

({5-Ethoxy-1-[(2,4,6-trichlorophenyl)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine, triptorelin

NaH (5 mg, 0.21 mmol) was added to a solution of 1-(5-ethoxy-1H-indol-4-yl)-N,N-dimethylethanamine (14 mg, 0,064 mmol; Intermediate connection 88) in DMF (0.5 ml) and the mixture was stirred at room temperature for 10 minutes before adding 2,4,6-trichlorobenzaldehyde (26.9 mg, 0,096 mmol). The mixture was stirred at room temperature in ECENA 20 minutes and then the mixture was suppressed by adding a few drops of TFU, was diluted using MeOH and filtered. The mixture was purified using HPLC system Waters using 15-60% MeCN in 0.1% TFU in the water. Output: 8.4V mg (23%); brown oil. MS (ESI+) for C19H19Cl3N2O3S m/z 461 (M+H)+.

Example 144

1-[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N-methylmethanamine, triptorelin

2M Methylamine in MeOH (0.1 ml, 0.2 mmol) was added to a solution of 5-methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (10 mg, to 0.032 mmol; Intermediate compound 75) in THF (1 ml) and was stirred for 10 minutes at room temperature before adding triacetoxyborohydride sodium (10 mg, 0,048 mmol). The mixture was stirred overnight and was added NaBH4(2 mg, 0,053 mmol). The mixture was stirred for 40 minutes, was added 1 drop of water and the mixture was purified preparative HPLC using a column ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 5.1 mg (36%). A colorless oil. MS (ESI+) for C17H18N2O3S m/z 331 (M+H)+.

The intermediate connection 90

1-[(2-Methoxy-5-were)sulfonyl]-1H-indole-4-carbaldehyde

To a suspension of sodium hydride(165 mg, 6,9 mmol) in DMF(5 ml) was added indole-4-carboxaldehyde (500 mg, 3.4 mm is eh). The mixture was stirred for 15 minutes, then was added 2-methoxy-5-methyl-benzosulphochloride (1140 mg, 5.2 mmol) and the mixture was stirred for 1 hour at room temperature. Added water and the reaction mixture was extragonadal using EtOAc. In the evaporation was obtained 1,2, MS (ESI+) for C17H15NO4S m/z 330 (M+H)+.

Example 145

({1-[(2-Methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)methylamine, triptorelin

The intermediate compound 90 (50 mg, 0.2 mmol) was dissolved in DCE (2 ml) was added 2M solution of methylamine in THF (152 μl, 0.3 mmol). The solution was stirred for 10 minutes and then added triacetoxyborohydride (64 mg, 0.3 mmol). After 3 hours was left with no source of substance, was formed the desired product, as well as dimer m/z 659. The reaction mixture was evaporated. Added water and the reaction mixture was extragonadal using EtOAc. The EtOAc phase contained a dimer and only a small amount of monomer. The aqueous phase was podslushivaet using 1M NaOH and extragonadal using EtOAc. The EtOAc phase was evaporated and purified using reverse-phase preparative HPLC. Got to 11.6 mg MS (ESI+) m/z 345 (M+H)+

The intermediate connection 91

5-Hydroxy-4-fluoro-2-nitrotoluene

25 g (198,2 mmol, 1 EQ.) 2-fluoro-5-METHYLPHENOL was dissolved in a mixture of 53.5 ml of acetic acid and 7.9 ml of concentrated sulfuric acid and paramesh the Wali at 0°C. To this mixture was added a solution of 13.7 g (198,2 mmol, 1 EQ.) NaNO2in 40 ml of water within 2 hours. The brown suspension was stirred for 1 hour and poured into a large quantity of ice water. Nitrosoguanidine was filtered and partially dried. Then it was added in portions to a stirred solution of 17.8 ml of 70% nitric acid and 53.5 ml of water and kept at 40-50°C until gas evolution stops, and the color of the suspension changed to light yellow. The suspension was poured into a large quantity of ice water, a yellowish precipitate was filtered and dried in vacuum. The compound was purified on a column of silica gel using 1% MeOH/CH2Cl2as the eluent, to obtain the 24,0 g (140,2 mmol) 5-hydroxy-4-fluoro-2-nitrotoluene in the form of a yellowish solid (yield 71%). The compound may be further purified through recrystallization from CH2Cl2/isohexane or toluene. MS (ESI-) for C7H6FNO3m/z 170 (M-H)-.

The intermediate compound 92

5-Benzyloxy-4-fluoro-2-nitrotoluene

22,0 g (of 128.6 mmol, 1 EQ.) The intermediate was dissolved in 250 ml of anhydrous acetonitrile and to the solution was added 35.5 g (257,2 mmol, 2 EQ.) K2CO3. To the resulting suspension was added dropwise to 16.8 ml (141,4 mmol, 1.1 EQ.) benzylbromide and the reaction mixture was heated at 60°C over night. The solution is tel evaporated and the residue was dissolved in CH 2Cl2/water. The phases were separated, the organic phase was dried over MgSO4, was filtered and was evaporated to obtain the crude product as a brownish-yellow solid. This substance was recrystallized their hot diethyl ether to obtain 29.5 g (112,9 mmol) of light-yellow crystals (yield 88%).

The intermediate connection 93

5-Benzyloxy-6-Florinda

Suspension 10,55 g (40,4 mmol, 1 EQ.) Intermediate 92 13.5 ml (64,6 mmol, 1.6 EQ.) bis-dimethylamino-tert-butoxysilane was stirred at 90°C during the night. The obtained red-orange solid was dried under vacuum and was again dissolved in 250 ml of 1/10 of a mixture of ethanol/dioxane was added about 1 g of Raney Nickel. The connection was first made using gaseous hydrogen at room temperature for 5 hours. The catalyst was filtered over telicom and the solvent evaporated to obtain the crude indole in the form of a dark brown oil. The crude product was purified using chromatography on silica gel using CH2Cl2as the eluent, to obtain 2.2 g (9.1 mmol) as a yellow solid (yield 23%). The connection can be further purified by recrystallization from CH2Cl2/isohexane. MS (ESI+) for C15H12FNO m/z 242 (M+H)+.

The intermediate connection 94

<> N-Benzazolyl-5-benzyloxy-6-Florinda

To a stirred solution of 2.0 g (8,29 mmol, 1 EQ.) Intermediate compound 93 in 30 ml of anhydrous DMF was added 0.35 g (to 8.70 mmol, of 1.05 equiv.) NaH (60% in mineral oil) at 0°C and the solution was stirred for 30 minutes at room temperature. After the reaction mixture was again cooled to 0°C and added dropwise at 1.17 ml (9,12 mmol, 1.1 EQ.) benzosulfimide. The reaction mixture is kept at 4°C overnight, then added a drop of methanol and the solvent was removed in vacuum. The crude indole was dissolved in CH2Cl2and was poured into a saturated solution of NaHCO3. The phases were separated, the organic layer was dried over MgSO4, was filtered and was evaporated to obtain Intermediate compound 94 in the form of a yellow oil. The compound was purified by chromatography on silica gel using CH2Cl2as eluent to obtain 2,88 g (7,54 mmol) of light yellow oil, which was hardened during maturation (yield 91%). MS (ESI+) for C21H16FNO3S m/z 382 (M+H)+.

The intermediate connection 95

6-Fluoro-1-(phenylsulfonyl)-1H-indol-5-ol

To a solution of 2.5 g (6,55 mmol) Intermediate compound 94 in 100 ml of ethanol was added 0.25 g of 10% Pd/C. the Suspension was first made at room temperature for 2 hours. The catalyst was filtered over telicom and the solvents were removed. accidenly product was purified on a column of silica gel using a 0.5% MeOH/CH 2Cl2as eluent to obtain 1,79 g book (6.16 mmol) of final product as a white solid (yield 94%). MS (ESI+) for C14H10FNO3S m/z 292 (M+H)+.

Example 146

4-[(Dimethylamino)methyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol, triptorelin

Paraformaldehyde (of 48.7 mg, 1,620 mmol) and a solution of 2 M dimethylamine in MeOH (0,85 ml, 1.70 mmol) was heated up to obtain a clear solution. This solution was added to a suspension of 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (236 mg, 0,810 mmol; Intermediate compound 95) in EtOH (4 ml) and the mixture was heated in a microwave oven at 90°C for 10 minutes. The solvent is evaporated. Output: 277 mg, white solid. 25 mg of this substance was purified using HPLC system Waters using 20-60% MeCN in 0.1% TFU. Output: 28.4 mg (73%, two-stage); colorless oil. MS (ESI+) for C17H17FN2O3S m/z 349 (M+H)+.

Example 147

1-[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N,N-dimethylethanamine

N,N-dimethylformamidine (0,964 ml, 7,233 mmol) was added to a solution of 4-[(dimethylamino)methyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (252 mg, 0,723 mmol; Example 146) in DMF (8 ml) and the mixture was divided into two test tubes and heated in a microwave oven at 180°C for 180 sec. The solvent is evaporated and the residue was purified using a Gilson HPLC system, using 30-70% MeCN in 50 n is ambanigujarat buffer as eluent (Xterra). Output: 101,7 mg (39%); white solid. MS (ESI+) for C18H19FN2O3S m/z 363 (M+H)+.

Example 148

6-Fluoro-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indol-5-ol

Paraformaldehyde (20.6 mg, China 0,686 mmol) and pyrrolidine (0,057 ml, China 0,686 mmol) in EtOH (1 ml) was heated up to obtain a clear solution. The solution was added 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-Olu (100 mg, 0,343 mmol; Intermediate compound 95) in EtOH (1 ml) and the mixture was heated at 90°C for 10 minutes. The solvent is evaporated. Yield: 137 mg, and about 20% of the substance was purified using a Gilson HPLC system, using 15-45% MeCN in 50 nm ambanigujarat buffer. Yield: 21 mg (82%); white solid. MS (ESI+) for C19H19FN2O3S m/z 375 (M+H)+.

Example 149

6-Fluoro-5-methoxy-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole, triptorelin

Paraformaldehyde (20.6 mg, China 0,686 mmol) and pyrrolidine (0,057 ml, China 0,686 mmol) in EtOH (1 ml) was heated up to obtain a clear solution. The solution was added 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-Olu (100 mg, 0,343 mmol; Intermediate compound 95) in EtOH (1 ml) and the mixture was heated at 90°C for 10 minutes. The solvent is evaporated. Yield: 137 mg, and about 20% of the substance was purified using a Gilson HPLC system, using 15-45% MeCN in 50 nm ambanigujarat buffer. Yield: 21 mg (82%); white solid vases is in. To DMF (2.5 ml) and DMF-DMA (500 ml) was added 80% of the crude substance obtained as described above, and the mixture was heated at 180°C in a microwave oven for 180 sec. LC-MS: starting material:product 1:2. The solvent is evaporated and the residue was purified using HPLC system Waters using 15-60% MeCN in 0.1% TFU. Yield: 28 mg (26%); brown oil. MS (ESI+) for C20H21FN2O3S m/z 389 (M+H)+.

Example 150

4-(Azetidin-1-ylmethyl)-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol, triptorelin

Paraformaldehyde (20.6 mg, China 0,686 mmol) and azetidin level (0.041 ml, China 0,686 mmol) in EtOH (1 ml) was heated up to obtain a clear solution. The solution was added 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-Olu (100 mg, 0,343 mmol; Intermediate compound 95) in EtOH (1 ml) and the mixture was heated in a microwave oven at 90°C for 10 minutes. The solvent is evaporated and 20% substance was purified using HPLC system Waters using 20-60% MeCN in 0.1%). Output: 16.5 mg (51%); brown oil. MS (ESI+) for C18H17FN2O3S m/z 361 (M+H)+.

Example 151

4-(Azetidin-1-ylmethyl)-6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indole, triptorelin

Paraformaldehyde (20.6 mg, China 0,686 mmol) and azetidin level (0.041 ml, China 0,686 mmol) in EtOH (1 ml) was heated up to obtain a clear solution. The solution was added 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-Olu (100 mg, 0,343 mmol, Intermediate joint is 95) in EtOH (1 ml) and the mixture was heated in a microwave oven at 90°C for 10 minutes. The solvent is evaporated and 20% substance was purified using HPLC system Waters using 20-60% MeCN in 0.1% TFU. Output: 16.5 mg (51%); brown oil. 80% of the crude substance obtained as described above was dissolved in DMF (2.5 ml) was added DMF-DMA (500 ml). The mixture was heated at 180°C for 180 sec. The solvent is evaporated and the residue was purified using HPLC system Waters using 20-60% MeCN in 0.1% TFU. Output: 21,1 mg; brown oil. MS (ESI+) for C19H19FN2O3S m/z 375 (M+H)+.

Example 152

4-{[Ethyl(methyl)amino]methyl}-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol

Paraformaldehyde (20.6 mg, China 0,686 mmol) and N-ethylmethylamine (0,059 ml, China 0,686 mmol) in EtOH (1 ml) was heated up to obtain a clear solution. The solution was added 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-Olu (100 mg, 0,343 mmol; Intermediate compound 95) in EtOH (1 ml) and the mixture was heated in a microwave oven at 90°C for 10 minutes. The solvent is evaporated and 20% substance was purified using a Gilson HPLC system, using 15-45% MeCN in 50 nm ambanigujarat buffer. Yield: 13 mg; white solid. MS (ESI+) for C18H19FN2O3S m/z 363 (M+H)+.

Example 153

N-{[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}-N-methylethanamine, triptorelin

Paraformaldehyde (20.6 mg, China 0,686 mmol) and N-ethylmethylamine (0,059 ml, China 0,686 mmol) in EtOH (1 ml) was heated in Loti to obtain a clear solution. The solution was added 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-Olu (100 mg, 0,343 mmol; Intermediate compound 95) in EtOH (1 ml) and the mixture was heated in a microwave oven at 90°C for 10 minutes. The solvent is evaporated and 20% substance was purified using a Gilson HPLC system, using 15-45% MeCN in 50 nm ambanigujarat buffer. Yield: 13 mg; white solid.

80% of the crude substance obtained as described above was dissolved in DMF (2.5 ml) and DMF-DMA (500 μl) and the mixture was heated at 180°C for 180 sec. The solvent is evaporated and the residue was purified using HPLC system Waters using 20-60% MeCN in 0.1% TFU, twice. Output: 2.8 mg; brown oil. MS (ESI+) for C19H21FN2O3S m/z 377 (M+H)+.

N-{[6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}-N-methylethanamine, triptorelin

The intermediate connection 96

6-Fluoro-5-hydroxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde

A solution of 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (200 mg, 687 mmol; Intermediate compound 95) in MeOH (2,14 ml) was treated with 2M NaOH (860 ml) and formaldehyde (2 ml 37% of the mass in H2O, 26.8 mmol) and was heated in an Emrys optimizer microwave at 120°C for 5 minutes. The solvent was removed in vacuo, the residue was taken for absorption in the H2O and 1M HCl (pH 1)was extragonadal using EtOAc (3×), washed with saturated solution of NaHCO3, nasiman the m salt solution, dried (Na2SO4) and the solvent was removed in vacuum to obtain a brownish syrup (265 mg), which is directly used at the stage of oxidation. A solution of the crude 6-fluoro-4-(hydroxymethyl)-1-(phenylsulfonyl)-1H-indol-5-ol (858 mmol) in CH2Cl2/MeOH (4,5+0,1 ml) were processed using MnO2(1.12 g, 12.9 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was filtered through a plug of SiO2and washed using CH2Cl2(40 ml) to obtain the specified title compound as a yellow solid (72 mg). This substance is directly used in the subsequent stages.

Example 154

6-Fluoro-4-[(methylamino)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol, triptorelin

The crude 6-fluoro-5-hydroxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (25 mg, to 78.3 mmol; Intermediate compound 96), methylamine (49 μl of a solution of 8M in EtOH, 392 μmol) and triacetoxyborohydride sodium (66,4 mg, 313 μmol) were mixed in 1,2-dichloroethane (3 ml) and stirred at room temperature for 4 hours. The solvent was removed in vacuo, the residue was taken for absorption in MeOH and purified using preparative HPLC/UV (System A, 5-35% MeCN, 0.1% of TFU) obtaining specified in the title compound as a brown glassy substance (4.3 mg, 12%). MS (ESI+) for C16H16FN2 3S m/z 335 (M+H)+.

Example 155

{[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylamine, triptorelin

The crude 6-fluoro-5-hydroxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (40,1 mg, 126 μmol; Intermediate compound 96) suspended in acetone (3.5 ml), was treated using the K2CO3(34.7 mg, 251 mmol) and MeI (the 15.6 μl, 251 μmol) and stirred in a sealed tube at 65°C for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature and diluted with the help of CH2Cl2, washed using H2O, dried (Na2SO4) and the solvent was removed in vacuum to obtain a glassy solid intensely yellow (41,4 mg), which was directly used in the recovery aminating. The crude 6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (41,4 mg, 124 μmol), methylamine (78,6 μl of a solution of 8M in EtOH, 629 μmol) and triacetoxyborohydride sodium to 66.5 mg, 314 μmol) were mixed in 1,2-dichloroethane (4 ml) and stirred at room temperature for a period of 18.5 hours. The solvent was removed in vacuo, the residue was taken for absorption in MeOH and purified using preparative HPLC/UV (System A, 9-39% MeCN, 0.1% of TFU) obtaining specified in the connection header in the form of not-quite-white solid (26.1 mg, 45%). MS (ESI+) for C17H18FN2/sub> O3S m/z 349 (M+H)+.

The intermediate connection 97

1-(5-Methoxy-1H-indol-4-yl)-N,N-dimethylethanamine

To 5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine (1.50 g, 4,36 mmol)dissolved in EtOH (100 ml)was added 2M NaOH (40 ml) and the reaction mixture was heated to 70°C for 7 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed using DCM. The organic layer was collected, dried (MgSO4), filtered and evaporated. Specified in the title compound (830 mg, 93%) was obtained as a brown solid. MS (ESI+) for C12H16N2O m/z 205 (M+H)+.

Example 156

1-{5-Methoxy-1-[(4-methoxyphenyl)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 4-methoxybenzoyl-1-sulphonylchloride (23 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (2 mg, 6%) as a white solid. MS (ESI+) for C19H22N2O4S /z 375 (M+H) +.

Example 157

1-{1-[(3-Chlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 3-chlorobenzene-1-sulphonylchloride (23 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (3 mg, 10%) as a white solid. MS (ESI+) for C18H19ClN2O3S m/z 379 (M+H)+.

Example 158

1-{1-[(2,5-Differenl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 2,5-differentialalgebraic (23 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System is mA B) give specified in the header of the product (3 mg, 10%) as a white solid. MS (ESI+) for C18H18F2N2O3S m/z 381 (M+H)+.

Example 159

1-(1-{[4-Fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 4-fluoro-3-(trifluoromethyl)benzosulphochloride (29 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (3 mg, 8%) as a white solid. MS (ESI+) for C19H18F4N2O3S m/z 431 (M+H)+.

Example 160

1-[5-Methoxy-1-(quinoline-8-ylsulphonyl)-1H-indol-4-yl]-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 8-chinaincorporated (25 mg, 0.11 mmol). The reaction mixture was left for stirring at room is the temperature during the night. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (3 mg, 11%) as a white solid. MS (ESI+) for C21H21N3O3S m/z 396 (M+H)+.

Example 161

1-{1-[(2-Chlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 2-chlorobenzene-1-sulphonylchloride (23 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (5 mg, 17%) as a brown solid. MS (ESI+) for C18H19ClN2O3S m/z 379 (M+H)+.

Example 162

1-{1-[(2-Chloro-6-were)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and obavljale 2-chloro-5-methylbenzol-1-sulphonylchloride (25 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (7 mg, 24%) as a white solid. MS (ESI+) for C19H21ClN2O3S m/z 394 (M+H)+.

Example 163

1-{1-[(3-Chloro-4-forfinal)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 3-chloro-4-torbenson-1-sulphonylchloride (25 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (4 mg, 14%) as a white solid. MS (ESI+) for C18H18ClFN2O3S m/z 397 (M+H)+.

Example 164

1-{5-Methoxy-1-[(2-were)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) in anatoy temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 2-methylbenzol-1-sulphonylchloride (21 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (7 mg, 28%) as a white solid. MS (ESI+) for C19H22N2O3S m/z 359 (M+H)+.

Example 165

2-({4-[(Dimethylamino)methyl]-5-methoxy-1H-indol-1-yl}sulfonyl)benzonitrile

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 2-cyanobenzenesulfonyl (22 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (6 mg, 22%) as a white solid. MS (ESI+) for C19H19N3O3S m/z 370 (M+H)+.

Example 166

1-{1-[(2,6-Differenl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H and the Dol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 2,6-differentialalgebraic (23 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (6 mg, 24%) as a white solid. MS (ESI+) for C18H18F2N2O3S m/z 381 (M+H)+.

Example 167

1-{1-[(1,2-Dimethyl-1H-imidazol-4-yl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 1,2-dimethyl-1H-imidazol-4-sulphonylchloride (21 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (4 mg, 14%) as a brown solid. MS (ESI+) for C17H22N4O3S m/z386 (M+H) +.

Example 168

1-{5-Methoxy-1-[(5-methyl-1-benzothieno-2-yl)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 5-methyl-1-benzothiophen-2-sulphonylchloride (27 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (8 mg, 27%) as a white solid. MS (ESI+) for C21H22N2O3S2m/z 415 (M+H)+.

Example 169

1-{5-Methoxy-1-[(2-methoxy-4-were)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 2-methoxy-4-methylbenzenesulfonamide (24 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Cleaning with COI is whether the preparative HPLC/UV (System B) give specified in the header of the product (5 mg, 17%) as a white solid. MS (ESI+) for C20H24N2O4S m/z 389 (M+H)+.

Example 170

1-{1-[(2,4-Dichlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 2,4-dichlorobenzenesulfonyl (27 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (5 mg, 17%) as a white solid. MS (ESI+) for C18H18Cl2N2O3S m/z 414 (M+H)+.

Example 171

1-{1-[(5-Bromo-2-methoxyphenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 5-bromo-2-methoxybenzenesulfonamide (31 mg, 0.11 mmol). The reaction mixture was left for stirring at room temperature the e during the night. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (9 mg, 27%) as a white solid. MS (ESI+) for C19H21BrN2O4S m/z 454 (M+H)+.

Example 172

1-[1-(2,1,3-Benzothiadiazole-4-ylsulphonyl)-5-methoxy-1H-indol-4-yl]-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine(15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and added 2,1,3-benzothiadiazole-4-sulphonylchloride (26 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (3 mg, 11%) as a yellow solid. MS (ESI+) for C18H18N4O3S2m/z 403 (M+H)+.

Example 173

1-[1-(3,4-Dihydro-2H-1,5-benzodioxepin-7-ylsulphonyl)-5-methoxy-1H-indol-4-yl]-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine(15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room is temperature for 15 minutes and was added 3,4-dihydro-2H-1,5-benzodioxepin-7-sulphonylchloride (27 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (5 mg, 17%) as a yellow solid. MS (ESI+) for C21H24N2O5S m/z 417 (M+H)+.

Example 174

1-{1-[(2,5-Acid)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine(15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 2,5-dimethoxybenzenesulfonamide (26 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (5 mg, 17%) as a beige solid. MS (ESI+) for C20H24N2O5S m/z 405 (M+H)+.

Example 175

1-(5-Methoxy-1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine(15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mm is l) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 2-(trifluoromethyl)benzosulphochloride (27 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (5 mg, 17%) as a colourless solid. MS (ESI+) for C19H19F3N2O3S m/z 413 (M+H)+.

Example 176

1-(5-Methoxy-1-{[4-(triptoreline)phenyl]sulfonyl}-1H-indol-4-yl)-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 4-(triptoreline)benzosulphochloride (29 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (6 mg, 21%) as a white solid. MS (ESI+) for C19H19F3N2O4S m/z 429 (M+H)+.

Example 177

3-({4-[(Dimethylamino)methyl]-5-methoxy-1H-indol-1-yl}Sul who were radioactive)benzonitrile

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (15 mg, 0.07 mmol; Intermediate compound 97) in DMF (1 ml) was added NaH (4 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and was added 3-cyanobenzenesulfonyl (22 mg, 0.11 mmol). The reaction mixture was left to stir at room temperature overnight. The reaction mixture was suppressed by the addition of water. Purification using preparative HPLC/UV (System B) give specified in the header of the product (4 mg, 13%) as a white solid. MS (ESI+) for C19H19N3O3S m/z 370 (M+H)+.

Example 178

1-[5-Methoxy-1-(pyridine-3-ylsulphonyl)-1H-indol-4-yl]-N,N-dimethylethanamine

To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine (30 mg, 0.15 mmol; Intermediate compound 97) hydrochloride and pyridine-3-sulphonylchloride (43 mg, 0.20 mmol) in DCM (1 ml) was added 5 M NaOH (2 ml). The reaction mixture was stirred at room temperature overnight. The organic phase was collected and the solvent was removed under reduced pressure. Purification using preparative HPLC/UV (System B) give specified in the header of the product (2 mg, 4%) as a white solid. MS (ESI+) for C17H19N3O3S m/z 346 (M+H)+.

The intermediate connection 98

1-[1-(Peninsul is of IMT-1H-indol-4-yl]ethanol

A solution of indole-4-carboxaldehyde (1,00 g, 6,89 mmol) in DMF (60 ml) in an atmosphere of N2were processed using NaH (95%; 20,7 mmol, 496 mg) at room temperature for 15 minutes. Added benzosulphochloride (972 μl, 7,58 mmol) and stirring was continued for 1 minute. The mixture was cooled to 0°C and extinguished using H2O. the Reaction mixture was extragonadal using EtOAc (3×), the combined organic phases are washed with H2O (3×), saturated salt solution and dried (Na2SO4). Concentration in vacuo gave an orange sticky substance (1,79 g), which was directly used in the reactions proceed according to the method of the Grignard reagent. A solution of the crude 1-(phenylsulfonyl)-1H-indole-4-carbaldehyde in THF (60 ml) were processed using MeMgBr (9,84 ml, 1.4 M in toluene/THF, 13,78 mmol) at room temperature for 20 minutes, after which was added 9,84 ml (2 EQ.) the Grignard reagent and stirring continued for another 5 minutes.

The reaction was suppressed by addition of a saturated solution of NH4Cl was extragonadal using EtOAc (3×), the combined organic phases were washed with saturated salt solution, dried (Na2SO4) and the solvent was removed in vacuum to obtain a yellowish-brown sticky substance (of 2.21 g). The crude product was subjected to flash chromatography (SiO2CH2Cl2:MeOH = 1001) obtaining specified in the title compound as a yellow/orange foamy substance (1,687 g, 81% of 2 stages). MS (ESI+) for C16H15NO3S m/z 284 (M-OH)+.

The intermediate connection 99

4-(1-Iodate)-1-(phenylsulfonyl)-1H-indole

To a solution of PPh3(457 mg, of 1.74 mmol) in CH2Cl2(7.5 ml) at room temperature was added I2(442 mg, of 1.74 mmol; Intermediate compound 99) and the mixture was stirred for 5 minutes, after which was added a solution of 1-[1-(phenylsulfonyl)-1H-indol-4-yl]ethanol (500 mg, of 1.66 mmol; Intermediate compound 98) in CH2Cl2(7.5 ml) and stirring continued for 3.5 hours at room temperature. The reaction mixture is washed with the help of Na2S2O3(to remove excess I2), dried (Na2SO4), the solvent was removed in vacuum and the obtained residue was purified column chromatography (SiO2CH2Cl2= 100%) to give a yellow/brown solid (235,5 mg), which was directly used in the subsequent stages.

Example 179

Methyl{1-[1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine

A solution of 4-(1-Iodate)-1-(phenylsulfonyl)-1H-indole (50 mg, 122 μmol; Intermediate compound 99) in CH2Cl2(1.5 ml) were processed using MeNH2(153 μl solution of 8 M in EtOH, to 1.22 mmol) at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, the resulting residue was taken for my absorption the Oia in MeOH/THF and purified using preparative HPLC (System B, 22-52% MeCN, 50 mm NH4HCO3) obtaining specified in the title compound as a white waxy solid (13.2 mg, 12% two steps). MS (ESI+) for C17H18N2O2S m/z 284 (M-NHMe)+, 315 (M+H)+.

Example 180

{1-[1-(Phenylsulfonyl)-1H-indol-4-yl]ethyl}amitriptylin

A solution of 4-(1-Iodate)-1-(phenylsulfonyl)-1H-indole (50 mg, 122 μmol; Intermediate compound 99) in DMF (1.5 ml) was treated with the salt of phthalimide potassium (113 mg, 610 μmol) at room temperature for 6 hours. Added hydrazinoacetate (296 μl, 6,10 mmol), the reaction mixture was heated to 75°C and stirring was continued for 1 hour. The crude mixture was taken for absorption in the H2O, extragonadal using EtOAc (3×), the combined organic phases were washed with saturated salt solution, dried (Na2SO4) and the solvent was removed in vacuum. The resulting residue was taken for absorption in THF and purified using preparative HPLC (System A, 5-35% MeCN, 0.1% of TFU) obtaining specified in the connection header in the form of not-quite-white solid (15.1 mg, 10% for two steps). MS (ESI+) for C16H16N2O2S m/z 284 (M-NH2)+.

Example 181

Dimethyl{1-[1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine

A solution of 4-(1-Iodate)-1-(phenylsulfonyl)-1H-indole (40 mg, 97,3 mmol; Intermediate compound 99) in CH2 Cl2(1.5 ml) were processed using Me2NH (174 μl of a solution of 5.6 M in EtOH, 973 mmol) at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, the resulting residue was taken for absorption in MeOH/THF and purified using preparative HPLC (System B, 30-60% MeCN, 50 mm NH4HCO3) obtaining specified in the title compound as a white waxy solid (10,6 mg, 11% two steps). MS (ESI+) for C18H20N2O2S m/z 329 (M+H)+.

Example 182

4-(Azetidin-1-ylmethyl)-2,3-dichloro-5-methoxy-1-(phenylsulfonyl)-1H-indole, triptorelin

Hydrochloride 4-(azetidin-1-ylmethyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole (250 mg, 0.64 mmol; Example 112) was converted to its free base by extraction between CHCl3/1M NaOH. The obtained free base was dissolved in anhydrous THF (4 ml)was added NCS 425 mg (3.2 mmol) and the clear solution was stirred at 40°C for 30 minutes. The solvent is evaporated under reduced pressure and the resulting oil was distributed for absorption between 0.1 M NaOH/CHCl3. The dried (MgSO4) organic phase was evaporated under reduced pressure and the resulting brown oil was purified preparative HPLC (ACE C8 5 mm, water containing 0.1% TFU-CH3CN) to obtain 33 mg (9.6 per cent) indicated in the title compound as a pale yellow solid which substances together with 64 mg (20%) 3-chlorinated product. MS (ESI+) for C19H18Cl2N2O3SMS m/z 425 (M+H)+.

Example 183

{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}amine

{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}amine, hydrochloride

4-(methyl bromide)-1-(phenylsulfonyl)-1H-indole (30 mg, 0.09 mmol; Intermediate compound 2) was dissolved in DMF (2 ml) was added phthalimide potassium (5 EQ.). The mixture was stirred at room temperature overnight. Added water and the reaction mixture was extragonadal using EtOAc. The EtOAc phase was evaporated. To the residue was added ethanol (3 ml) and hydrazinehydrate (235 μl). The mixture was stirred at 78° for 30 minutes. Added water and the suspension was extragonadal using EtOAc. An ethyl acetate phase was evaporated and added 100 μl of HCl (1M in diethyl ether. Received solid. Diethyl ether is evaporated from this solid and the solid is washed with the aid of EtOAc. Got to 19.3 mg of product as the HCl salt. MS (ESI+) m/z 270 (M+H-NH3)+

The intermediate connection 100

5-(Benzyloxy)-6-methoxy-1-(phenylsulfonyl)-1H-indole

5-benzyloxy-6-methoxyindole (5.0 g, 20 mmol), benzosulfimide (5.2 g, 30 mmol) and tetrabutylammonium bisulfate (2,0, 6 mmol) was added DCM (200 ml) and 4M NaOH (50 ml). The reaction mixture was left to stir at room temperature overnight. The organic layer was collected and the aqueous phase was washed with SIP the soup DCM (2×30 ml). The combined organic layers were then washed with saturated brine (2×50 ml). After drying (MgSO4), filtration and evaporation was obtained brown oil. The product was precipitated by adding diethyl ether. Recrystallization from MeOH gave specified in the title compound with yield of 84% (6,55 g) as light yellow crystals. MS (ESI+) for C22H19NO4S m/z 394 (M+H)+.

The intermediate connection 101

6-Methoxy-1-(phenylsulfonyl)-1H-indol-5-ol

To 5-(benzyloxy)-6-methoxy-1-(phenylsulfonyl)-1H-indole (6.6 g, 17 mmol; Intermediate compound 100) and Pd/C (2 g, 30 wt%) was added EtOH (30 ml), cyclohexene (9 ml) and HCl (9 ml). The reaction mixture was heated to 150°C for 5 minutes using microwave heating.

Pd/C was filtered and the solvent was removed under reduced pressure to obtain specified in the connection header with a quantitative yield (5 g) in the form of a black resin. The product was used in the next stage without any further purification. MS (ESI+) for C15H13NO4S m/z 304 (M+H)+.

Example 184

4-[(Dimethylamino)methyl]-6-methoxy-1-(phenylsulfonyl)-1H-indol-5-ol

Paraformaldehyde (28 mg, 0,932 mmol) and a solution of 2 M Me2NH in MeOH (of 0.47 ml, 0,932 mmol) was heated up to obtain a clear solution. The solution was added to 6-methoxy-1-(phenylsulfonyl)-1H-indol-5-Olu (61 mg, 0.21 mmol; Intermediate compound 101) in EtOH (1.5 ml) and the mixture was heated in a microwave oven at 80°C for 10 minutes. A small portion was purified using a Gilson HPLC system, using 25-55% MeCN in 50 nm ammonium bicarbonate as eluent. Output: 3.8 mg; white solid. MS (ESI+) for C18H20N2O4S m/z 361 (M+H)+.

Example 185

1-[5,6-Dimethoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N,N-dimethylethanamine

4-[(Dimethylamino)methyl]-6-methoxy-1-(phenylsulfonyl)-1H-indol-5-ol (60 mg, 0,166 mmol; Example 184) was dissolved in DMF (2 ml) was added DMF-DMA (300 ml). The mixture was heated in a microwave oven at 180°C for 180 sec. The solvent is evaporated and the residue was purified using a Gilson HPLC system, using 30-60% MeCN in 50 nm ambanigujarat buffer as eluent. Yield: 13.2 mg (21%); brown oil. MS (ESI+) for C19H22N2O4S m/z 375 (M+H)+.

Example 186

{[3-Chloro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine, triptorelin

{[5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine (80.0 mg, 0.23 mmol; Example 108) was dissolved in anhydrous THF (4 ml) was added NCS (for 93.4 mg, 0.7 mmol). The mixture was stirred for 3 hours and evaporated. The crude product was purified using flash chromatography using a 2.5% MeOH in dichloromethane → 5% MeOH in dichloromethane with 1% NEt3as ale the NTA, and then preparative HPLC on a column of ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes, obtaining specified in the connection header. Yield: 7 mg (6%). Light yellow oil. MS (ESI+) for C18H19ClN2O3S m/z 379 (M+H)+.

The intermediate connection 102

tert-Butyl {[5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylcarbamate

{[5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylamine (0,627 g, 1.9 mmol; Example 144) was dissolved in dichloromethane (25 ml) was added boc-anhydride (of 0.62 g, 2.8 mmol). The mixture was stirred for 2 hours, washed with saturated salt solution, dried (MgSO4) and was evaporated. The crude product was purified through a plug of silica using 5% MeOH in dichloromethane as eluent. Output 0,628 g (78%). White solid. MS (ESI+) for C22H26N2O5S m/z 375 (M+H)+.

Example 187

{[3-Chloro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylamine, triptorelin

Tert-butyl [(5-methoxy-1H-indol-4-yl)methyl]methylcarbamate (30.0 mg, 0,103 mmol; Intermediate compound 102) was dissolved in THF (2 ml) was added NCS (25.0 mg, 0,19 mmol). The mixture was stirred for 3 hours and diluted with dichloromethane. The organic phase is washed with water, dried (MgSO4 ) and was evaporated. This chlorinated crude intermediate compound (33,0 mg, 0.10 mmol) was dissolved in DMF (2 ml) was added NaH (10.1 mg, 0.25 mmol). The mixture was stirred for 10 minutes before adding benzosulfimide (35,9 mg, 0.20 mmol). The mixture was stirred for 20 minutes and was diluted with dichloromethane and water. The organic phase was separated, dried (MgSO4) and was evaporated. The residue was dissolved in dichloromethane (2 ml) and added triperoxonane acid (0.5 ml). The mixture was stirred for 1 hour and evaporated. The crude product was purified using preparative HPLC on a column of ACE C8 5 μm (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes. Output: 1.2 mg (2.5%). Dark resin. MS (ESI+) for C17H17ClN2O3S 364,0648 m/z 365 (M+H)+.

Example 188

{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}amine, triptorelin

Ammonium acetate (0,146 g, 1,90 mmol) was added to a solution of 5-methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (30 mg, 0,095 mmol; Intermediate compound 75) in MeOH (3 ml) and was stirred for 20 minutes at 50°C before adding NaCNBH3(6 mg, 0,095 mmol). The mixture was stirred for 1 hour, put 3 drops of water and evaporated. The crude product was purified using flash chromatography with used the eat 1% MeOH to 2.5% MeOH in dichloromethane with 1% NEt 3as eluent and then purified using preparative HPLC on a column of ACE C8 5 m (a 21.2×100 mm). Water containing 0.1% TFU, and acetonitrile were used as mobile phases at a flow rate of 20 ml/minute, with a time gradient of 11.5 minutes, obtaining specified in the connection header. Output: 4,6 mg (15%). White solid. HPLC purity of 99%. MS (ESI+) for C16H16N2O3S 316,0882 (M-16)+m/z 300.

The intermediate connection 103

6-Fluoro-4-(1-hydroxyethyl)-1-(phenylsulfonyl)-1H-indol-5-ol

A solution of the crude 6-fluoro-5-hydroxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (86,4 mg, 271 μmol; Intermediate compound 96) in THF (3 ml) were processed using MeMgBr (774 μl of a solution of 1.4 M in toluene/THF, 4 EQ.) at room temperature and was stirred for 30 minutes. After 30 minutes, was added 2 EQ., and after 45 minutes 4 EQ. the Grignard solution and stirring was continued for 15 minutes. The reaction mixture was suppressed by addition of a saturated solution of NH4Cl was extragonadal using EtOAc (3×), the combined organic phases were washed with saturated salt solution, dried and the solvent was removed in vacuum to obtain a yellow-brown solid (95,6 mg). This substance was purified using preparative HPLC (15-45% MeCN/50 mm NH4HCO3) obtaining specified in the connection header is as yellowish solid (31.8 mg, 11% from 3 stages). MS (ESI+) for C16H14FNO4S m/z 318 (M-OH)+, 358 (M+Na)+.

The intermediate connection 104

6-Fluoro-4-(1-Iodate)-1-(phenylsulfonyl)-1H-indol-5-ol

To a solution of PPh3(24.6 mg, for 93.9 mmol) in CH2Cl2(1 ml) at room temperature was added I2(23,8 mg, for 93.9 mmol) and the mixture was stirred for 5 minutes, after which the solution was added 6-fluoro-4-(1-hydroxy-ethyl)-1-(phenylsulfonyl)-1H-indol-5-ol (30.0 mg, and 89.5 mmol; Intermediate compound 103) in CH2Cl2(1 ml) and stirring was continued for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the resulting crude product is directly used for the next stages amination.

Example 189

6-Fluoro-4-[1-(methylamino)ethyl]-1-(phenylsulfonyl)-1H-indol-5-ol, triptorelin

A solution of the crude 6-fluoro-4-(1-Iodate)-1-(phenylsulfonyl)-1H-indol-5-ol (about to 44.5 mmol; Intermediate compound 104) in CH2Cl2(1 ml) were processed using MeNH2(111 μl solution of 8 M in EtOH, 888 mmol) at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, the resulting residue was taken for absorption in MeOH and purified using preparative HPLC (6-36% MeCN, 0.1% of TFU) obtaining specified in the title compounds as a white, waxy solid substances is a (7,1 mg, 34% of the two stages). MS (ESI+) for C17H17FN2O3S m/z 349 (M+H)+.

Example 190

4-[1-(Dimethylamino)ethyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol

A solution of the crude 6-fluoro-4-(1-Iodate)-1-(phenylsulfonyl)-1H-indol-5-ol (about to 44.5 mmol; Intermediate compound 104) in CH2Cl2(1 ml) were processed using Me2NH (159 μl of a solution of 5.6 M in EtOH, 890 mmol) at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, the resulting residue was taken for absorption in MeOH and purified using preparative HPLC (25-55% MeCN, 50 mm NH4HCO3) obtaining specified in the connection header in the form of not-quite-white solid (10.0 mg, 62% of the two stages). MS (ESI+) for C18H19FN2O3S m/z 363 (M+H)+.

The intermediate connection 105

1-[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethanol

The crude 6-fluoro-5-hydroxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (85 mg, 266 μmol; Intermediate compound 96) suspended in acetone (5 ml) and treated with the help of K2CO3(73,6 mg, 532 mmol) and MeI (49,7 μl, 798 mmol) and was stirred in a sealed tube at 65°C for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature and diluted with the help of CH2Cl2, washed using H2O, dried (Na2 4) and the solvent was removed in vacuo to obtain 6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde in the form of vitreous solids intense yellow color (72,3 mg), the purity of 65% according to LC/MS, which is directly used in the subsequent reactions proceed by the method of the Grignard reagent.

A solution of the crude 6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (72,3 mg, 217 μmol) in THF (2 ml) were processed using MeMgBr (310 μl of a solution of 1.4 M in toluene/THF, equ.) at room temperature and was stirred for 20 minutes (50% conversion). After 20 minutes was added 2 EQ. the Grignard solution and stirring was continued for 15 minutes. The reaction mixture was suppressed by addition of a saturated solution of NH4Cl was extragonadal using EtOAc (3×), the combined organic phases were washed with saturated salt solution, dried and the solvent was removed in vacuum to obtain a yellow-brown foamy substance (81,9 mg) with a purity of 56% according to LC/MS. This substance was purified using preparative HPLC (25-55% MeCN/50 mm NH4HCO3) obtaining specified in the connection header in the form of not-quite-white solid (26.5 mg, 9% from 4 stages). MS (ESI+) for C17H16FNO4S m/z 332 (M-OH)+.

The intermediate connection 106

6-Fluoro-4-(1-Iodate)-5-methoxy-1-(phenylsulfonyl)-1H-ind the l

To a solution of PPh3(to 20.9 mg of 79.6 mmol) in CH2Cl2(0.5 ml) at room temperature was added I2(20.2 mg, of 79.6 mmol) and the mixture was stirred for 5 minutes, after which the solution was added 1-[6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethanol (26.5 mg, to 75.8 mmol; Intermediate compound 105) in CH2Cl2(1 ml) and stirring was continued for 4.5 hours at room temperature. The reaction mixture was concentrated in vacuo and the resulting crude product is directly used for the next stages amination.

Example 191

{1-[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}methylamine, triptorelin

A solution of the crude 6-fluoro-4-(1-Iodate)-5-methoxy-1-(phenylsulfonyl)-1H-indole (about to 37.9 mmol; Intermediate compound 106) in CH2Cl2(1 ml) were processed using MeNH2(95 μl solution of 8 M in EtOH, 758 mmol) at room temperature for 3 hours. The reaction mixture was concentrated in vacuo, the resulting residue was taken for absorption in MeOH and purified using preparative HPLC (13-43% MeCN, 0.1% of TFU) obtaining specified in the title compound as a yellow-brown solid (9.4 mg, 52% of the two stages). MS (ESI+) for C18H19FN2O3S m/z 363 (M+H)+.

Example 192

{1-[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}is imacillin, triptorelin

A solution of the crude 6-fluoro-4-(1-Iodate)-5-methoxy-1-(phenylsulfonyl)-1H-indole (about to 37.9 mmol; Intermediate compound 106) in CH2Cl2(1 ml) were processed using Me2NH (135 μl of a solution of 5.6 M in EtOH, 758 mmol) at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, the resulting residue was taken for absorption in MeOH and purified using preparative HPLC (12-42% MeCN, 0.1% of TFU) obtaining specified in the title compound as a white waxy solid (9.5 mg, 51% of the two stages). MS (ESI+) for C19H21FN2O3S m/z 377 (M+H)+.

Biological tests

The ability of the compounds of the present invention to contact with 5-HT6receptor and to be pharmaceutically useful can be determined using in vivo and in vitro assays known in the prior art.

(a) analysis of the binding of 5-HT6receptor

The measurement of the affinity binding against 5-HT6receptor human was performed in HEK293 cells, transfected with the 5-HT6receptor, using [3H]-LSD as a labeled ligand, in accordance with the General method described Boess F. G et al. Neuropharmacology 36(4/5) 713-720, 1997.

Materials

Cell culture

The cell line HEK-293, transtitional 5-HT6the receptor is m man cultured in the modified Dulbecco environment Needle containing 5% detalizirovannoi bovine serum (Gibco BRL 10106-169), 0.5 mm sodium pyruvate and 400 μg/ml of geneticin (G-418) (Gibco BRL 10131-019). Was carried out by re-seeding of the cells 1:10 twice a week.

Chemicals

Radioligand [3H]LSD 60-240 CI/mmol, from company Amersham Pharmacia Biotech (Buckinghamshire, England), was obtained in ethanol, and stored at -20°C. Compounds were dissolved in 100% DMSO and diluted with buffer to bind.

Used materials and equipment

Compounds were diluted in 96-well V-bottom polypropylene tablets Costar (Corning Inc. Costar, NY, USA). Samples were incubated Packard Optiplate (Packard Instruments B. V., Groningen, The Netherlands). The total number of added radioligand was measured in 24-hole Barex tablets Packard (Packard Instruments B. V., Groningen, The Netherlands) in the presence of scintillation fluid Microscint™ 20 (Packard Bioscience, Meriden, CT, USA).

Buffer

Buffer for binding consisted of 20 mm HEPES, 150 mm NaCl, 10 mm MgCl2and 1 mm EDTA, pH 7,4.

Methods

Membrane drug

Cells were grown to approximately 90% of confluently 24.5×24,5 mm cups for cultivation. Wednesday aspirated and after washing the ice PBS the cells were scraped off using 25 ml of Tris buffer (50 mm Tris-HCl, 1 mm EDTA, 1 mm EGTA, pH 7,4) and window scraper. The cells were then broken using a homogenizer transmitter station and ostavi the Xia particles were removed using a low-speed centrifugation, 1000×g for 5 minutes. Finally, membranes were collected using high-speed centrifugation (20000×g), suspended in buffer for binding and froze in aliquot at -70°C.

Linking radioligand

Frozen cell membranes were thawed once again homogenized using a homogenizer transmitter station and combined with balls agglutinin from wheat germ SPA (Amersham Life Sciences, Cardiff, England) for 30 minutes with continuous shaking of the tubes. After joining, the beads were centrifuged for 10 minutes at 1000 g and then suspended in 20 ml of buffer for binding 96-well plate. Then initiated the binding reaction by adding radioligand and test compounds to a suspension of beads or membranes. After incubation at room temperature analytical tablets were analyzed using a scintillation counter.

Followed the original SPA method, except that membranes were obtained from HEK293 cells expressing the receptor 5-HT6man, instead of HeLa cells (Dinh DM, Zaworski PG, Gill GS, Schlachter SK, Lawson CF, Smith MW. Validation of human 5-HT6receptors expressed in HeLa cell membranes: saturation binding studies, pharmacological profiles of standard CNS agents and SPA development. The decision Upjohn Company Technical Report 7295-95-064 1995;27 December). Specific binding of [3H]-LSD was saturable, whereas the nonspecific binding increased the ü linearly with the concentration of added radioligand. [3H]-LSD was associated with high affinity to 5-HT6the receptors. The value of Kdwas identified as 2,6±0,2 nm on the basis of four independent experiments.

The total binding of 3 nm [3H]-LSD concentration radioligand used in competitive assays, typically amounted to 6000 dpm(disintegrations per minute), and specific binding of more than 70%. 5-HT evoked dependent on the concentration of the inhibition of binding of [3H]-LSD, with an overall mean value of Ki 236 nm when tested against two different membrane preparations. The discrepancy between the analyses for the three experiments was CV = 10% with an average value of Ki 173 nm (SD 30) and Hill coefficient of 0.94 (SD 0,09). The difference in the range of the analysis was 3% (n=4). All its ligands displace the specific binding of [3H]-LSD dependent on koncentrirali way, albeit with a different activity. Affinity for 5-HT6receptor comparative connections: methiothepin (Ki 2 nm) >mianserin (190 nm) ~ 5-HT (236 nm) >methysergide (482 nm) > mesulergine (1970 nm).

Determination of protein

The protein concentration was determined using BioRad protein analysis (Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 1976;72:248-54). As the standard used bovine serum albumin.

Scintillation account

Radioactivity was determined by the using a scintillation counter Packard TopCount™ (Packard Instruments, Meriden, CT, USA), efficiency accounts for about 20%. The efficiency of accounts was determined in a separate series of experiments.

Experiments saturation

In saturation experiments have used at least 6 concentrations radioligand (0.1 to 20 nm [3H]-LSD) in two repetitions. Specific binding was calculated as the difference between total binding and nonspecific binding, which was defined as the binding of radioligand in the presence of 5 μm of lisuride. Bmaxand the dissociation constant Kdwas determined using analysis of nonlinear regression using equation 1. Lurepresents the concentration of unbound radioligand, y is the associated number of radioligand.

Competitive analysis

Total and nonspecific binding radioligand was determined in eight repetitions for each. Samples containing the test compound was tested twice at 11 concentrations. Incubation was carried out at room temperature for 3 hours. Value IR50, i.e. the concentration of test compound, which provided 50% inhibition of specific binding of radioligand was determined using analysis of nonlinear regression and the value of Kiwas calculated using equation 2 [Cheng Y. C. Biochem. Pharmacol. 22, 3099-3108, 1973].

L = concentration of radioligand

p> Kd= the affinity of radioligand

(b) Analysis of the characteristic activity of 5-HT6

Antagonists of the receptor 5-HT6people were characterized by measuring the inhibition of 5-HT-induced increase of cAMP in HEK 293 cells expressing the receptor 5-HT6person (see Boess et al. (1997) Neuropharmacology 36: 713-720). Briefly, HEK293 cells/5-HT6were sown in 96-well tablets polylysine plated at a density of 25,000/well and were grown in DMEM (modified Dulbecco environment Needle) (without phenol red)containing 5% cialisbuynow fetal bovine serum for 48 hours at 37°C in 5% CO2the incubator. The medium is then aspirated and replaced with 0.1 ml of medium for the quantitative determination of (balanced salt solution Hank, containing 20 mm HEPES, 1.5 mm isobutylmethylxanthine and 1 mg/ml bovine serum albumin). After addition of the test substances, 50 μl, dissolved in the medium for quantification, cells were incubated for 10 minutes at 37°C in 5% CO2the incubator. Wednesday again aspirated and the cAMP content was determined using the kit for determination of radioactivity cAMP (Amersham Pharmacia Biotech, BIOTRAK RPA559). Quantitative determination of the activity of the antagonists was carried out by determining the concentration that caused 50% inhibition of 5-HT ([5-HT]= 8× EC50)-inducido the data increase cAMP, using the formula IR50,corr=IR50/(1+[5HT]/EC50).

Compounds of the present invention have a selective affinity for the receptors 5-HT6man, with values of Kiand IR50,corrin the range between 0.5 nm and 5 μm, or demonstrate the % inhibition of [3H]-LSD ≥ 20% at 50 nm, and are antagonists, agonists or partial agonists of the receptor 5-HT6man. The compounds show good selectivity for receptors 5-HT1a, 5-HT1b, 5-HT2a, 5-HT2band 5-HT2cperson.

Table 2
Affinity binding (Ki) on the receptor h5-HT6
ExampleKi(nm)
11,8
473,3
870,9

Table 3
Antagonistic activity on the receptor h5-HT6
ExampleKi(nm)
16
15 403
2196
4259
48436
6996
7766
8217
870,6
9163
95106
96216
10319

(c) In vivo analysis of the reduction in food intake

Information related to serotonin and consumption of food, see Blundell, J. E and Halford, J. C. G. (1998) Serotonin and Appetite Regulation. Implications for the Pharmacological Treatment of Obesity. CNS Drugs 9:473-495.

Suffering obese mouse (ob/ob) was selected as the primary animal model for screening, since this mutant mouse consumes a large amount of food that gives a high signal-to-noise ratio. For a more complete study and comparison of data efficiency, the effect of compounds on food intake also investigated in wild-type mice (C57BL/6J). Recorded the amount of food consumed in ECENA 15 hours infusion connections.

All experiments used male mice (obese C57BL/6JBom-Lepoband wild-type with normal body weight C57BL/6JBom; Bomholtsgaard, Denmark) aged 8-9 weeks, with an average body weight of 50 g (obese) and 25 g (with normal body weight). Animals were placed in individual cages at a temperature of 23±1°C, humidity 40-60%, and they had free access to water and standard laboratory food. Established a 12/12-hour light / dark cycle with the light is switched off at 17-00. The animals were allowed to habituate to the environment for at least one week before the study.

Test compounds were dissolved in the solvents that are suitable for each specific compounds such as cyclodextrin, cyclodextrin/methansulfonate acid, polyethylene glycol/methansulfonate acid, saline. For each test was preparing fresh solutions. Used doses of 30, 50 and 100 mg kg-1day-1. Test compounds were of analytical purity.

Animals were weighed at the beginning of the study and were randomly selected on the basis of body weight. Used osmotic Minnesota Alzet Model 200 1D; infusion rate 8 ml/hour) and carried the load, essentially as recommended in the instructions Alzet (Alza Scientific Products, 1997; Theeuwes, F and Yam, S. I. Ann. Biomed. Eng. 4(4). 343-353, 1976). Used nepreryvno the subcutaneous infusion of 24 hours. To fill minnasota used or different concentrations of the test compounds dissolved in the carrier or solution medium, and maintained in medium preheated to 37°C (about 1 hour). Minnesota implanted subcutaneously in the neck/back under short-term anesthesia (metapan/enflurane). This surgical procedure lasted approximately 5 minutes.

The weight of the pelleted diets were measured at 17 : 00 and at 20 : 00 for two days before (baseline) and one day after implantation of the osmotic minnasota. The using was carried out using computer scales Mettler Toledo PR 5002. Accidental loss have been adjusted. At the end of the study the animals were killed by displacement of the neck and the blood was collected from the trunk for later analysis concentrations in plasma drug.

Proteins from plasma samples precipitated with methanol, centrifuged and the supernatant was transferred into vials for HPLC and injectively in the system liquid chromatography/mass spectrometry. The mass spectrometer was set in positive mode ionization electrospray and parallel control reactions (Multiple Reaction Monitoring). To calculate the concentrations of unknown samples were used linear regression analysis standards, passed through the source.

Consumption of food within 15 hours of the ISM is reli three days in a row and calculate the percentage of the baseline values for each animal from the day before treatment and after treatment. Values were expressed as mean values ± SD(standard deviation) and ± SEM(mean standard error) from eight animals per group dosing. Statistical evaluation was performed using one-way ANOVA analysis method Well-Wallis using interest underlying values. If the received statistical significance at the level p<0,05 was used U-test Mann-Whitney statistical comparison of groups of control and processing.

1. The compound of formula (I)

whererepresents a simple bond or double bond;
n is 1, 2 or 3;
m is 1 or 2;
each R0independently selected from the following:
(a) hydrogen,
(b) halogen,
(c)1-6alkyl,
(e) hydroxy-C1-4-alkyl,
(f) -COOR6,
(g) -CONR5R5;
R1represents a group selected from the following:
(a)1-6-alkyl,
(d)6-14-aryl,
(g) mono - or bicyclic heteroaryl ring system, containing 5-10 ring carbon atoms, 1-3 of which are replaced by nitrogen or sulfur, or represents 1,5-benzodioxepin where any heteroaryl or aryl residue separately or as part of another group optionally independently substituted in one or several positions by the Deputy, is independently selected from the following:
(a)halogen,
() C 1-6-alkyl,
(c) a fluorine-C1-6-alkyl,
(h) hydroxy-C1-4-alkyl,
(i) hydroxy,
(J) C1-6-alkoxy,
(k) a fluorine-C1-6-alkoxy,
(R) -CN,
(ad) a 5-membered heteroaryl containing two nitrogen atom, optionally substituted by trifluoromethyl and stands;
each R2independently selected from the following:
(a) hydrogen,
(b) halogen,
(c)1-6-alkyl,
(d) a fluorine-C1-6-alkyl,
(i) hydroxy-C1-4-alkyl,
(j) hydroxy,
(k)1-6-alkoxy,
(1) fluorine-C1-6-alkoxy,
(u) -NR5R5,
(ab)1-6-alkoxycarbonyl and
(ac) OR11,
R3represents a group selected from the following:



where X is selected from O or-NR6;
z has a value of 2; and
(i) both R4represent hydrogen; or
(ii) one of R4represents hydrogen and the other is the
(a) C1-4-alkyl,
(d)cyano; or
(iii) both R4represent methyl;
R5each independently selected from the following:
(a) hydrogen,
(b) (C1-6-alkyl,
(c) a fluorine-C1-6-alkyl,
(d) a 5-membered heteroaryl-C1-2is alkyl containing Odie is a sulfur atom;
R6each independently selected from the following:
(a) hydrogen,
(b) (C1-4-alkyl and
(c) hydroxy-C1-3-alkyl;
R7selected from the following:
(a) hydrogen,
(b) (C1-4-alkyl,
R9selected from the following:
(a) hydrogen,
(c)1-4-alkyl,
(d) -NR6R6provided that the group-NR6R6not linked to a carbon atom adjacent to a ring nitrogen atom,
(e) hydroxy, provided that the hydroxy-group is not linked to a carbon atom adjacent to a ring nitrogen atom, and
(f) hydroxy-C1-4-alkyl;
R10each independently selected from the following:
(a) hydrogen,
(b) hydroxy-C2-4-alkyl,
(c)1-3-alkoxy-C2-4-alkyl,
(d) cyclopropyl,
(e) cyclobutyl,
(f) benzyl, and
(g)1-4-alkyl,
R11selected from the following:
(a)- (CH2CN,
(b) benzyl;
R12each independently selected from the following:
(a) hydrogen,
(b) (C1-4-alkyl,
(c) a fluorine-C1-3-alkyl,
(d) hydroxy-C1-3-alkyl and
(e)1-6-alkoxycarbonyl;
and its pharmaceutically acceptable salts, provided that the compound of formula (I) may represent an N-methyl-1-(phenylsulfonyl)-1H-indol-4-methanamine.

2. The compound according to claim 1, where
represents a simple bond or double bond;
n has a value of 1;
m has a value of 1;
R0predstavljaet a group, selected from the following:
(a) hydrogen,
(b) (C1-6-alkyl,
(d) hydroxy-C1-4-alkyl,
(e) -COOR6and
(f) -CONR5R5;
R3represents a group selected from


3. The compound according to claim 1, where X represents a-NR6.

4. The compound according to claim 1, where
represents a simple bond or double bond;
each R0independently selected from the following:
(a) hydrogen,
(b) (C1-6-alkyl,
(d) hydroxy-C1-4-alkyl;
R0represents a group selected from the following:
(a)6-14-aryl,
(b) mono - or bicyclic heteroaryl ring system,
containing 5-10 ring carbon atoms, 1-3 of which are replaced by nitrogen or sulfur, or represents 1,5-benzodioxepin,
where any heteroaryl or aryl residue separately or as part of another group optionally independently substituted in one or several positions by the Deputy, is independently selected from the following:
(a) halogen,
(b) (C1-6-alkyl,
(c) a fluorine-C1-6-alkyl,
(h) hydroxy-C1-4-alkyl,
(1) hydroc and,
(j) C1-6-alkoxy,
(k) a fluorine-C1-6-alkoxy;
R2selected from the following:
(a) hydrogen,
(b)halogen,
(c)1-6-alkyl,
(e) hydroxy-C1-4-alkyl,
(f) hydroxy,
(g)1-6-alkoxy,
(q) -OCONR5R5,
(s)-OR11;
R3represents a group selected from the following:

;
R4selected from the following:
(a) hydrogen,
(b) C1-4-alkyl; and
R5each independently selected from the following:
(a) hydrogen,
(b) C1-3-alkyl;
R6each independently selected from the following:
(a) hydrogen,
(b) methyl, and
(c) ethyl;
R7selected from the following:
(a) hydrogen,
(b) (C1-4-alkyl;
R9selected from the following:
(a) hydrogen,
(b) (C1-4-alkyl,
(c) -NR6R6provided that the group-NR6R6not linked to a carbon atom adjacent to a ring nitrogen atom,
(d) hydroxy, provided that the hydroxy-group is not linked to a carbon atom adjacent to a ring nitrogen atom, and
(e) hydroxymethyl;
R10each independently selected from the following:
(a) hydrogen,
(b) hydroxy-C2-4-alkyl,
(c)1-3-alkoxy-C2-4-alkyl,
(d)1-4-alkyl,
(e) cyclopropyl and
(f) cyclobutyl;
R11 is selected from the following:
(a)- (CH2CN,
(b) benzyl;
R12each independently selected from the following:
(a) hydrogen,
(b) (C1-2-alkyl and
(c) hydroxy-C1-2-alkyl.

5. The compound according to claim 4, where
R0represents a group selected from the following:
(a) hydrogen,
(b) methyl, and
(c) hydroxymethyl;
R1represents a group selected from the following:
(a)6-14-aryl, and
(b) mono - or bicyclic heteroaryl ring system, containing 5-10 ring carbon atoms, 1-3 of which are replaced by nitrogen or sulfur, or represents 1,5-benzodioxepin where any heteroaryl or aryl residue optionally independently substituted in one or several positions Deputy, selected from the following:
(a) halogen,
(b) methyl,
(c) trifluoromethyl,
(d) methoxy,
(e) tert-butyl and
(f) -CN;
R2represents a group selected from the following:
(a) hydrogen,
(b) fluorine,
(c) chlorine,
(d) bromine,
(e) hydroxy,
(f) methoxy,
(g) ethoxy,
(h) isopropoxy,
(i) -OCON(Me)2and
(j) -OR11;
R4represents hydrogen;
R7selected from the following:
(a) hydrogen,
(b) methyl,
(c) n-propyl,
(d) isopropyl;
R9selected from the following:
(a) hydrogen,
(b) methyl,
(c) -NH2provided that the group-NH2not linked to a carbon atom adjacent to a ring nitrogen atom,
(d) hydro is C provided that said hydroxy-group is not linked to a carbon atom adjacent to a ring nitrogen atom, and
(e) hydroxymethyl;
R10each independently selected from the following:
(a) hydrogen,
(b) methyl,
(c) ethyl,
(d) isopropyl,
(e) 2-hydroxyethyl,
(f) 2-methoxyethyl,
(g) cyclopropyl and (h) cyclobutyl;
R11selected from the following:
(a)- (CH2CN,
(b) benzyl;
R12each independently selected from the following:
(a) hydrogen,
(b) methyl, and
(c) hydroxymethyl.

6. The compound according to claim 5,
where R1represents a group selected from the following:
(a) phenyl,
(b) pyridyl and
(c) 2-thienyl,
where any heteroaryl or aryl residue optionally independently substituted in one or several positions Deputy, selected from the following:
(a) chlorine,
(b) fluorine,
(c) methyl,
(d) trifluoromethyl,
(e) methoxy and
(f) -CN;
R2represents a group selected from the following:
(a) hydrogen,
(b) fluorine,
(c) hydroxy,
(d) methoxy,
(e) ethoxy,
(f) isopropoxy,
(g) -OCON(Me)2and
(h) -OR11;
R11selected from the following:
(a)- (CH2CN,
(b) benzyl.

7. The compound according to claim 1, where
R3represents a group selected from the following:

R4represents hydrogen or methyl;
R9represents hydrogen;
R10each independently selected from the trail who were:
(a) hydrogen,
(b) methyl.

8. The compound according to claim 1, where R3represents a

R4represents H or methyl;
R10each independently selected from the following:
(a) hydrogen and
(b) methyl.

9. The compound according to claim 1 of formula (Ib)

where
R0represents a group selected from the following:
(a) hydrogen,
(b) methyl, and
(c) hydroxymethyl;
R1represents a group selected from the following:
(a) phenyl,
(b) 2-naphthyl,
(c) 2-thienyl and
(d) 6 chloroimidazo[2,1-b][1,3]thiazole-5-Il,
where any heteroaryl or aryl residue optionally independently substituted in one, two or three positions Deputy, selected from the following:
(a) chlorine,
(b) fluorine,
(c) bromine,
(d) methyl,
(e) trifluoromethyl,
(f) methoxy and
(g) -CN;
R2represents a group selected from the following:
(a) hydrogen,
(b) fluorine,
(c) hydroxy,
(d) methoxy,
(e) ethoxy,
(f) isopropoxy,
(g) -OCON(Me)2and
(h) -OR11;
R11selected from the following:
(a)- (CH2CN and
(b) benzyl.

10. The compound according to claim 1, where
represents a simple bond;
R1represents a group selected from the following:
(a) phenyl,
(b) pyridyl and
(c) 2-thienyl,
where any heteroaryl or aryl residue optionally independently Thames is N. in one or more positions Deputy selected from the following:
(a) chlorine,
(b) fluorine,
(c) methyl,
(d) trifluoromethyl,
(e) methoxy and
(f) -CN;
R2represents a group selected from the following:
(a) hydrogen,
(b) fluorine,
(c) hydroxy,
(d) methoxy,
(e) ethoxy,
(f) isopropoxy,
(g) -OCON(Me)2and
(h) -OR11;
R11selected from the following:
(a)- (CH2CN,
(b) benzyl.

11. The compound according to claim 1, which represents the following link:
1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,
4-(1,4-Diazepan-1-ylmethyl)-1-(phenylsulfonyl)-1H-indole,
1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}pyrrolidin-3-amine,
1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}pyrrolidin-3-amine,
1-[(4-Were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole,
1-[(4-Were)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole,
4-(1,4-Diazepan-1-ylmethyl)-1-[(4-were)sulfonyl]-1H-indole,
4-[(4-Methyl-1,4-diazepan-1-yl)methyl]-1-[(4-were)sulfonyl]-1H-indole,
1-[(4-Were)sulfonyl]-4-[(4-methylpiperazin-1-yl)methyl]-1H-indole,
4-[(4-Isopropylpiperazine-1-yl)methyl]-1-[(4-were)sulfonyl]-1H-indole,
1-[(4-Were)sulfonyl]-4-[(4-propylpiperazine-1-yl)methyl]-1H-indole,
1-[(4-Were)sulfonyl]-4-(pyrrolidin-1-ylmethyl)-1H-indole,
1-[(2-Methoxy-5-were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole,
1-[(2-Methoxy-5-were)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole,
N-({1-[(2-IU the hydroxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)piperidine-4-amine,
1-Isopropyl-N-({1-[(2-Methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)piperidine-4-amine,
1-[(2-Methoxy-5-were)sulfonyl]-4-[(2-methylpyrrolidine-1-yl)methyl]-1H-indole,
1-[(2-Methoxy-5-were)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]indoline,
1-[(2-Methoxy-5-were)sulfonyl]-4-[(4-methylpiperazin-1-yl)methyl]indoline,
1-[(2-Methoxy-5-were)sulfonyl]-4-(pyrrolidin-1-ylmethyl)indolin,
({1-[(2-Methoxy-5-were)sulfonyl]-2,3-dihydro-1H-indol-4-yl}methyl)dimethylamine,
1-[(4-Forfinal)sulfonyl]-4-[(3-methylpiperazin-1-yl)methyl]-1H-indole,
4-(1,4-Diazepan-1-ylmethyl)-1-[(4-forfinal)sulfonyl]-1H-indole,
1-[(4-Forfinal)sulfonyl]-4-(pyrrolidin-1-ylmethyl)-1H-indole,
({1-[(4-Forfinal)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine,
1-[(4-Forfinal)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole,
1-[(2-Were)sulfonyl]-4-(piperazine-1-ylmethyl)-1H-indole,
1-[(2-Were)sulfonyl]-4-[(4-methylpiperazin-1-yl)methyl]-1H-indole,
1-({1-[(2-Were)sulfonyl]-1H-indol-4-yl}methyl)pyrrolidin-3-ol,
1-[(2-Were)sulfonyl]-4-(pyrrolidin-1-ylmethyl)-1H-indole,
2-[Methyl({1-[(2-were)sulfonyl]-1H-indol-4-yl}methyl)amino]ethanol,
N,N-Dimethyl-1-{1-[(2-were)sulfonyl]-1H-indol-4-yl}methanamine,
4-(Piperazine-1-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl-1H-indole,
((2R)-1-[(1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]pyrrolidin-2-yl} methanol,
4-(Pyrrolidin-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole,
2-{Methyl[(1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]amino}ethanol,
N,N-Dimethyl-1-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methanamine,
4-(Piperazine-1-ylmethyl)-1-(2-thienylmethyl)-1H-indole,
N-Ethyl-N-{[1-(2-thienylmethyl)-1H-indol-4-yl]methyl}ethanamine,
4-(Pyrrolidin-1-ylmethyl)-1-(2-thienylmethyl)-1H-indole,
4-[(4-Propylpiperazine-1-yl)methyl]-1-(2-thienylmethyl)-1H-indole,
N,N-Dimethyl-1-[1-(2-thienylmethyl)-1H-indol-4-yl]methanamine,
4-(Piperazine-1-ylmethyl)-1-(pyridine-3-ylsulphonyl)-1H-indole,
N,N-Dimethyl-1-[1-(pyridine-3-ylsulphonyl)-1H-indol-4-yl]methanamine,
1-(Pyridine-3-ylsulphonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,
1-(Phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,
N,N-Dimethyl-1-[1-(phenylsulfonyl)-1H-indol-4-yl]methanamine,
3-Methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,
3-Methyl-4-[(4-methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole,
3-Methyl-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,
N,N-Dimethyl-1-[3-methyl-1-(phenylsulfonyl)-1H-indol-4-yl]methanamine,
6-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,
{[6-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine,
6-Methoxy-4-{[(3R)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole,
6-Methoxy-4-{[(3S)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole,
6-Methoxy-4-[(4-methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole,
4-(1,4-Diaz is pan-1-ylmethyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole,
6-Methoxy-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,
2-[{[6-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}(methyl)amino]ethanol,
6-Fluoro-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,
4-(1,4-Diazepan-1-ylmethyl)-6-fluoro-1-(phenylsulfonyl)-1H-indole,
6-Fluoro-4-{[(3S)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole,
6-Fluoro-4-{[(3R)-3-methylpiperazin-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole,
6-Fluoro-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,
2-[{[6-Fluoro-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}(methyl)amino]ethanol,
{[6-Fluoro-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine,
6-Fluoro-4-[(4-methylpiperazin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indole,
1-(Phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indol-6-yl dimethylcarbamate,
4-(1,4-Diazepan-1-ylmethyl)-1-(phenylsulfonyl)-1H-indol-6-ol,
1-[(4-Forfinal)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole,
6-Methoxy-4-(piperazine-1-ylmethyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole,
1-[(2-Chlorophenyl)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole,
1-[(3-Chloro-2-were)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole,
1-[(2,5-Acid)sulfonyl]-6-methoxy-4-(piperazine-1-ylmethyl)-1H-indole,
2-{[6-Methoxy-4-(piperazine-1-ylmethyl)-1H-indol-1-yl]sulfonyl}benzonitrile,
({1-[(4-Forfinal)sulfonyl]-1H-indol-4-yl}methyl)amine,
N-({1-[(4-Forfinal)sulfonyl]-1H-indol-4-yl}methyl)ethanamine,
7-Labels and-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,
2-Methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,
Methyl 4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-2-carboxylate,
(4-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-2-yl)methanol,
(2-Methoxyethyl){[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}amine,
N-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}propan-2-amine,
4-{[4-(2-Methoxyethyl)piperazine-1-yl]methyl}-1-(phenylsulfonyl)-1H-indole,
((2R)-1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl} pyrrolidin-2-yl)methanol,
4-(Azetidin-1-ylmethyl)-1-(phenylsulfonyl)-1H-indole,
Ethyl 5-methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole-2-carboxylate,
5-Methoxy-N-methyl-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole-2-carboxamide,
N-Ethyl-5-methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole-2-carboxamide,
5-Ethoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-N-(2-thienylmethyl)-1H-indole-2-carboxamide,
4-(Azetidin-1-ylmethyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole,
1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indol-5-ol,
1-(Phenylsulfonyl)-4-piperazine-2-yl-1H-indole,
4-(1,4-Dimethylpiperazine-2-yl)-1-(phenylsulfonyl)-1H-indole,
[7-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]piperazine-1-yl)acetonitrile,
4-(Azetidin-1-ylmethyl)-7-methoxy-1-(phenylsulfonyl)-1H-indole,
{[1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indol-5-yl]oxy}acetonitrile,
5-Isopropoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,
5-Benzyloxy)-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,
4-{[(2-Hydroxyethyl)(methyl)amino]methyl}-1-(phenylsulfonyl)-1H-indol-5-ol,
4-[(3-Hydroxypyrrolidine-1-yl)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol,
[1-(Phenylsulfonyl)-4-(piperazine-1-ylmethyl)-6-(trifluoromethyl)-1H-indol-2-yl]methanol,
5-Methoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,
5-Ethoxy-1-(phenylsulfonyl)-4-(piperazine-1-ylmethyl)-1H-indole,
1-Phenyl-N-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methanamine,
N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}cyclopropanation,
{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine,
N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}CYCLOBUTANE,
N-{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}-N-methylcyclobutane,
1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}azetidin-3-ol,
4-(Azetidin-1-ylmethyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole,
4-{[4-(Azetidin-1-ylmethyl)-1H-indol-1-yl]sulfonyl}benzonitrile,
2-((2S)-1-{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl} azetidin-2-yl)propan-2-ol,
4-(Azetidin-1-ylmethyl)-2-methyl-1-(phenylsulfonyl)-1H-indole,
4-(Azetidin-1-ylmethyl)-1-[(2-chlorophenyl)sulfonyl]-1H-indole,
4-(Azetidin-1-ylmethyl)-1-[(5-chloro-2-thienyl)sulfonyl]-1H-indole,
4-(Azetidin-1-ylmethyl)-1-(2-naphthylmethyl)-1H-indole,
4-(Azetidin-1-ylmethyl)-1-[(2-methoxy-5-were)sulfonyl]-1H-indole,
4-(Azetidin-1-ylmethyl)-1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-indole,
4-(Azetidin-1-ylmethyl)-1-[(4-tert-is utility)sulfonyl]-1H-indole,
4-(Azetidin-1-ylmethyl)-1-[(2,6-differenl)sulfonyl]-1
N-indole,
4-(Azetidin-1-ylmethyl)-1-{[2-(trifluoromethyl)phenyl]-sulfonyl}-1H-indole,
3-{[4-(Azetidin-1-ylmethyl)-1H-indol-1-yl]sulfonyl}-benzonitrile,
4-(Azetidin-1-ylmethyl)-1-{[4-bromo-2-(trifluoromethyl)phenyl]-sulfonyl}-1H-indole,
4-(Azetidin-1-ylmethyl)-1-(2-thienylmethyl)-1H-indole,
4-(Azetidin-1-ylmethyl)-1-[(2,5-differenl)sulfonyl]-1H-indole,
[(5-Methoxy-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)methyl]dimethylamine,
4-(Azetidin-1-ylmethyl)-7-(benzyloxy)-1 -(methylsulphonyl)-1 H-indole,
({1-[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-5-methoxy-1H-indol-4-yl}methyl)dimethylamine,
4-[(Dimethylamino)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol,
{[5-Ethoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine,
({5-Ethoxy-1-[(2-methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine,
{[5-Ethoxy-1-(1-naphthylmethyl)-ZINAIDA-indol-4-yl]methyl}dimethylamine,
{[5-Ethoxy-1-(2-naphthylmethyl)-1H-indol-4-yl]methyl}dimethylamine,
({1-[(2-Chlorophenyl)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine,
({1-[(3-Chloro-2-were)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine,
({5-Methoxy-1-[(2-methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine,
({1-[(2,3-Dichlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}methyl)dimethylamine,
{[5-Ethoxy-1-(quinoline-8-ylsulphonyl)-1H-indol-4-yl]methyl}dimethylamine,
{[5-Ethoxy-1-({5-[1-IU the Il-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-thienyl}sulfonyl)-1H-indol-4-yl]methyl}dimethylamine,
({1-[(2,5-Dichlorophenyl)sulfonyl]-5-ethoxy-1H-indol-4-yl}methyl)dimethylamine,
({5-Ethoxy-1-[(2,4,6-trichlorophenyl)sulfonyl]-1H-indol-4-yl}methyl)dimethylamine,
1-[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N-methylmethanamine,
({1-[(2-Methoxy-5-were)sulfonyl]-1H-indol-4-yl}methyl)methylamine,
4-[(Dimethylamino)methyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol,
1-[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N,N-dimethylethanamine,
6-Fluoro-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indol-5-ol,
6-Fluoro-5-methoxy-1-(phenylsulfonyl)-4-(pyrrolidin-1-ylmethyl)-1H-indole,
4-(Azetidin-1-ylmethyl)-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol,
4-(Azetidin-1-ylmethyl)-6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indole,
4-{[Ethyl(methyl)amino]methyl}-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol,
N-{[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}-N-methylethanamine,
6-Fluoro-4-[(methylamino)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol,
{[6-Fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylamine,
1-{5-Methoxy-1-[(4-methoxyphenyl)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine,
1-{1-[(3-Chlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,
1-{1-[(2,5-Differenl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,
1-(1-{[4-Fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-5-methoxy-1H-indol-4-yl)-N,N-dimethylethanamine,
1-[5-Methoxy-1-(quinoline-8-ylsulphonyl)-1H-indol-4-yl]-N,N-dimethylethanamine,
1-{1-[(2-what lorgeril)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,
1-{1-[(2-Chloro-6-were)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,
1-{1-[(3-Chloro-4-forfinal)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,
1-{5-Methoxy-1-[(2-were)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine,
2-({4-[(Dimethylamino)methyl]-5-methoxy-1H-indol-1-yl}sulfonyl)benzonitrile,
1-{1-[(2,6-Differenl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,
1-{1-[(1,2-Dimethyl-1H-imidazol-4-yl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,
1-{5-Methoxy-1-[(5-methyl-1-benzothieno-2-yl)sulfonyl]-1H-indol-4-yl}-N,N-dimethylethanamine,
1-{5-Methoxy-1-[(2-methoxy-4-were)sulfonyl]-1H-indol-4-yl} - N,N-dimethylethanamine,
1-{1-[(2,4-Dichlorophenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,
1-{1-[(5-Bromo-2-methoxyphenyl)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,
1-[1-(2,1,3-Benzothiadiazole-4-ylsulphonyl)-5-methoxy-1H-indol-4-yl]-N,N-dimethylethanamine,
1-[1-(3,4-Dihydro-2H-1,5-benzodioxepin-7-ylsulphonyl)-5-methoxy-1H-indol-4-yl]-N,N-dimethylethanamine,
1-{1-[(2,5-Acid)sulfonyl]-5-methoxy-1H-indol-4-yl}-N,N-dimethylethanamine,
1-(5-Methoxy-1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-4-yl)-N,N-dimethylethanamine,
1-(5-Methoxy-1-{[4-(triptoreline)phenyl]sulfonyl}-1H-indol-4-yl)-N,N-dimethylethanamine,
3-({4-[(Dimethylamino)methyl]-5-methoxy-1H-indol-1-yl}sulfonyl)benzonitrile,
1-[5-Methoxy-1-(pyridine-3-ylsulphonyl)-1H-and the Dol-4-yl]-N,N-dimethylethanamine,
Methyl {1-[1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine,
{1-[1-(Phenylsulfonyl)-1H-indol-4-yl]ethyl}amine,
Dimethyl {1-[1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine,
4-(Azetidin-1-ylmethyl)-2,3-dichloro-5-methoxy-1-(phenylsulfonyl)-1H-indole,
{[1-(Phenylsulfonyl)-1H-indol-4-yl]methyl}amine,
4-[(Dimethylamino)methyl]-6-methoxy-1-(phenylsulfonyl)-1H-indol-5-ol,
1-[5,6-dimethoxy-1-(phenylsulfonyl)-1H-indol-4-yl]-N,N-dimethylethanamine,
{[3-chloro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine,
{[3-chloro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylamine,
{[5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}amine,
6-fluoro-4-[1-(methylamine)ethyl]-1-(phenylsulfonyl)-1H-indol-5-ol,
4-[1-(dimethylamino)ethyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol,
{1-[6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}methylamine
and
{1-[6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethyl}dimethylamine,
or its pharmaceutically acceptable salt.

12. Pharmaceutical composition having antagonistic activity against T6receptor containing the compound according to claim 1 in combination with a pharmaceutically acceptable diluent or carrier.

13. The use of compounds according to any one of claims 1 to 11 to obtain drugs for weight loss or decreased weight gain.

14. The use of compounds according to any one of claims 1 to 11 for receiving Leka the only means for the treatment of type II diabetes.

15. The use of compounds according to any one of claims 1 to 9 to obtain drugs for the treatment of disorders of the Central nervous system.

16. The application indicated in paragraph 15, where the disorder of the Central nervous system selected from the following: anxiety, depression, panic attacks, memory disorders, disorders of cognition, epilepsy, sleep disorders, migraine, anorexia, bulimia, disorders associated with overeating, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, disorder attention deficit/hyperactivity disorder and withdrawal syndrome drugs with abuse.

17. The use of compounds according to any one of claims 1 to 11 to obtain drugs for the treatment of pain.

18. The use of compounds according to any one of claims 1 to 11 to obtain drugs for the treatment of neurodegenerative disorders.

19. The use of compounds according to any one of claims 1 to 11 for obtaining a medicinal product, which has antagonistic activity against 5-HT6the receptor.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel agents for controlling plant fungal diseases, specifically 3,7-dithia-1,5-diazabicyclo[3,3,0]octane as an agent against Bipolaris sorokiniana, Aspergillus fumigates, Aspergillus niger, synthesis of which takes place in a single step using readily available reactants in contrast to multi-step synthesis of existing agents used for controlling fungal diseases of plants and materials.

EFFECT: obtaining novel agents for controlling plant fungal diseases.

1 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (R)-N-(3-amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide substantially free from (S)-N-(3-amino-propyl)-N[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methypropyl]-4-methyl-benzamide, or its pharmaceutically acceptable salt which shows the properties of Eg5 inhibitor.

EFFECT: invention also refers to a pharmaceutical composition containing said compound and its pharmaceutically acceptable salt.

4 cl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

,

where R1 represents CH3; R2 represents halogeno or CN; R3 represents H or CH3; R4 represents H or CH3; n represents 0, 1 or 2; and to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition and to application of the compounds of formula (I) in preparing a drug exhibiting antagonist activity in relation to CX3CR1 receptor.

EFFECT: provided the compounds of formula (I) as CX3CR1 receptor antagonists.

20 cl, 1 tbl, 3 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) where the bond b represents a double bond; X represents -S-; each Z1 and Z3 independently represents a direct bond, -N(R5) - or - (CH2)q; Z2 represent -C(O)- or -C(S)-; m represents an integer equal to 1; n represents an integer equal to 1; each of q independently represents an integer varying within 1 to 4; R0 represents hydrogen, halogen, hydroxy, unsubstituted C1-C3alkyl or unsubstituted C1-C3alkoxy; R1 is independently selected from a group consisting of halogen, optionally substituted C1-C3alkyl, -R6OR7, -R6N(R7)2, -R6C(O)R7, -R6C(O)OR7, -R6C(O)N(R7)R9N(R7)2, -R6OC(O)R8, -R6C(O)N(R7)2 or -R6OR9N(R7)2; R2 represents hydrogen; R4 is selected from a group consisting of morpholine, isoxazolyl, thiazolyl, oxazolyl, benzisoxazolyl, benzothiazolyl, dioxynyl, dioxolyl, and optionally substituted phenyl. Also, the invention refers to pharmaceutically acceptable salts of the compounds of formula (I) and to a pharmaceutical composition exhibiting antiproliferative activity and containing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) exhibiting antiproliferative activity.

21 cl, 11 dwg, 5 tbl, 19 ex

Antiviral compound // 2441010

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1 denotes CH3; R2 denotes halogen or CN; R3 denotes H or CH3; R4 denotes H or CH3; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition and use of compounds of formula (I) in preparing a medicinal agent, having CX3CR1 receptor antagonist activity.

EFFECT: compounds can be used as CX3CR1 receptor antagonists.

13 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula in which Q together with carbon and nitrogen atoms whereto attached forms a 9-10-member bicyclic heterocycle, and R1 and R2, R3, R4, R5 and R6 are as specified in cl.1 of the patent claim, or to its enantiomers, or a mixture of its enantiomers, or to its pharmaceutically acceptable salt. Also, an invention refers to a method for activation of glucokinase activity in mammals, by introduction of the compound described above, to a method of treating the pathological conditions associated with glucokinase activity and impaired glucose tolerance by means of introduction of the compound of formula I, to a pharmaceutical composition on the basis of the presented compounds, and also to application of the compounds of formula I for preparing the pharmaceutical composition.

EFFECT: there are produced and described new compounds which are activators of glucokinase activity and can be used as therapeutic agents for preventing and treating impaired glucose tolerance, insulin-independent diabetes and obesity.

14 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I), which can be used as a medicinal agent having PI3-kinase inhibiting properties. In general formula (I)

,

A denotes N, Ra denotes C1-C8alkyl, phenyl substituted with 1-2 residues selected from a group comprising halogen and C1-C6halogenalkyl, Rb denotes hydrogen, R1 denotes hydrogen or C1-C8alkyl, R2 denotes hydrogen or a substitute selected from a group comprising: C1-C8alkyl, substituted with one substitute selected from C1-C6alkoxy group, -(CO)-O-C1-C6alkyl, N(C1-C6alkyl)2; 6-member heterocycloalkyl containing a nitrogen atom as a heteroatom, substituted with 1-2 substitutes selected from an oxo group and phenyl; (5-6-member heterocycloalkyl containing 1-2 heteroatoms selected from nitrogen and oxygen)-C1-C4alkyl, optionally substituted with 1-2 substitutes independently selected from -(CO)-O-C1-C6alkyl, C1-C6alkyl, -(CO)-O-benzyl, oxo group, benzyl substituted with C1-C6alkyl, 6-member heteroaryl containing 2 nitrogen atoms as heteroatoms; phenyl which is optionally substituted with 1 substitute selected from a 6-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, optionally substituted with -(CO)-O-C1-C6alkyl, (5-6-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with C1-C6alkyl)-C1-C4alkyl, optionally substituted with an oxo group, -(C1-C4alkyl)-NR7-(CO)O-C1-C6alkyl; phenyl-C1-C5alkyl, optionally substituted with 1-2 substitutes selected from NH2, N(C1-C6alkyl)2, C1-C6alkyl, N(C1-C6alkyl)2-C1-C6alkyl, OR7, OCF3, haloC1-C6alkyl, CN, SO2R7, NR7COR8, CONH2, NR7-(CO)O-C,-C6alkyl; -(C1-C4alkyl)-NR7-(CO)O-C1-C6alkyl, 5-member heteroaryl containing 2 nitrogen atoms as heteroatoms, (5-6-member heterocycloalkyl containing 1-2 heteroatoms independently selected from nitrogen and oxygen), optionally substituted with an oxo group, (5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms substituted with 1-3 substitutes independently selected from oxo group, C1-C6alkyl)-C1-C4alkyl, -C(O)-NH-(C3-C8cycloalkyl), -C(O)-NH-(C1-C6alkyl), -C(O)-N(C1-C6alkyl)2, COR7, NR7(CO)NR8R9; (5-6-member heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, sulphur and oxygen)-C1-C6alkyl, optionally substituted with 1-2 substitutes selected from C1-C6alkyl, C3-C8cycloalkyl, CN and OH; (9-member heteroaryl containing a nitrogen atom as a heteroatom)-C1-C4alkyl; C3-C8cycloalkyl, optionally substituted with a 5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with an oxo group; C3-C8cycloalkyl-C1-C4alkyl, optionally substituted with 1 substitute selected from C1-C4alkyl-(CO)OR8, NR (CO)OR8; 1,3-benzodioxole-C1-C4alkyl; 1,4-benzodioxane-C1-C4alkyl; isoindoline-C1-C4alkyl substituted with 1 CO-NH2 substitute; or R1 and R2 together form a 5- or 6-member saturated ring which optionally contains an additional heteroatom selected from oxygen and nitrogen, and optionally substituted with 1-3 substitutes independently selected from OH, C1-C6alkyl, (CO)OR8, (C1-C4alkyl)-(CO)OR8, NR7(CO)OR8, -(C1-C4alkyl)-NR7(CO)OR8, NR7COR8, -(C1-C4alkyl)-NR7COR8, -NH-C(O)CF3, -CH(OH)-phenyl, NR7(CO)NR8R9, NR7(CO)CH2NR8R8, -NR7(SO2)R8, phenyl, optionally substituted C1-C6alkoxy, OH, 9-10-member bicyclic heteroaryl containing 1-2 nitrogen atoms as heteroatoms, optionally substituted with a phenyl oxo group, substituted with a hydroxy group, -CH2-isoquinoline, substituted with an oxo group, 5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with an oxo group, -CH2-O-(phenyl, substituted with 3 substitutes independently selected from halogen and amino); or R1 and R2 together form a saturated 9-11-member spirocyclic system with 1-2 additional nitrogen heteroatoms, substituted with 1-2 substitutes independently selected from -C1-C6alkyl, OH, oxo group and phenyl; or R2 denotes a residue selected from a group of residues of general formulae:

, , , , , and , where X denotes C1-C7alkylene, Q denotes C1-C7alkylene, R3, R4 have identical or different values and denote hydrogen or a substitute selected from a group comprising C1-C8alkyl, 9-member bicyclic heteroaryl containing 2 nitrogen atoms as heteroatoms, substituted with C1-C6alkyl, phenyl substituted with C1-C4alkyl, 6-member heteroaryl containing 2 nitrogen atoms as heteroatoms, 5-member heterocyclyl containing 1 nitrogen atom as a heteroatom, (C3-C8cycloalkyl)-C1-C4alkyl-, or R3, R4 together form a 6-member saturated ring containing an oxygen atom as an additional heteroatom, R7, R8, R9 have identical or different values and denote hydrogen or a substitute selected from a group comprising C1-C8alkyl, 5-6-member heterocycloalkyl containing 1-2 heteroatoms independently selected from nitrogen and oxygen, C3-C8cycloalkyl, C1-C6haloalkyl, C3-C8cycloalkyl- C1-C4alkyl-, C1-C4alkoxy-C1-C4alkyl-.

EFFECT: high efficiency of using the disclosed compounds in preparing a medicinal agent.

10 cl, 1 tbl, 299 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where R1 denotes a lower alkyl; R2 denotes phenyl or a 5- or 6-member heteroaryl containing 1-2 N atoms or 1 N atom and 1 S atom as heteroatoms, which may be unsubstituted or substituted with a substitute selected from halogen or lower alkyl; R3 denotes hydrogen, phenyl or a 5-6-member heteroaryl containing 1-2 N atoms and 1 O atom as heteroatoms, which can be unsubstituted or substituted with a substitute selected from 1-2 halogen atoms, lower alkyl or a S(O)2-lower alkyl group; as well as pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, having metabotropic glutamate receptor mGluR5 antagonist properties, which contains the compound of formula (I) as active component and pharmaceutically acceptable excipients.

EFFECT: possibility of using said derivatives as mGluR5 receptor antagonists.

25 cl, 2 dwg, 1 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

FIELD: chemistry.

SUBSTANCE: described are novel 7-member heterocyclic compounds of general formula (values of radicals are given in the claim) or salts thereof or solvates thereof having chymase inhibiting activity and suitable for preventing or treating different diseases in which chymase is involved, a method of producing said compounds, intermediate compounds and a pharmaceutical composition for preventing or treating diseases in which chymase is involved, including compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

EFFECT: improved properties of the compound.

23 cl, 12 tbl, 308 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where each radical R-R5 and Y assume values given in the description, or salts thereof, which have GPR40 receptor modulating action.

EFFECT: intensification of secretion of insulin or an agent for preventing or treating diabetes, and a pharmaceutical composition based on said compounds.

17 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula I in which R1 is chosen from the group including: H; alkyl; alkylenearyl and pyridin; R2 is chosen from the group including: cycloalkyl; aryl; CO-NH-cycloalkyl; CO-NH-aryl either unsubstituted or substituted with the help of halogen, CF3; SO2-aryl either unsubstituted or substituted with the help of alkyl; or in which R1 and R2 together form a 5- or 6-membered ring that does not need to contain 1 additional nitrogen heteroatom and that may also be substituted with the help of aryl; and that may also contain a carbonyl group; and that may also be condensed with aryl; R3 and R4 denote H; and acid additions to their physiologically acceptable salts. Invention also refers to a pharmaceutical composition, to the way of production of the formula I compound, to application of the formula I compound, and to the way of treatment or prevention of fatty degeneration, type II diabetes, metabolic syndrome and associated and/or secondary diseases or pathologic conditions endured by mammals.

EFFECT: production of new bioactive compounds that inhibit the isoenzyme of hydroxy citric acid II (hCA II).

11 cl, 11 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel clathrate complex of β-cyclodextrin with 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine of formula : with molar ratio 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine: β-cyclodextrin from 1:1 to 1:10, synthesis method and use thereof as an antiviral agent for treating influenza. The disclosed method involves mixing solutions of β-cyclodextrin and 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine in molar ratio from 1:1 to 1:10 while stirring and heating to temperature not higher than 70°C and then maintaining said conditions until a homogeneous solution is obtained and extraction of the obtained complex.

EFFECT: clathrate complex is a novel effective anti-influenza virus agent which is obtained using a novel efficient method.

13 cl, 2 ex, 3 tbl, 11 dwg

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