Thienopyrazoles

FIELD: chemistry.

SUBSTANCE: description is given of thienopyrazol of formula I its pharmaceutically acceptable salts or esters, in which X represents N or C-R7; X1 represents N or C-R1; R1, R2, R3, R4, R5 and R6 are independently chosen from a group which contains hydrogen, possibly substituted acyl, alkyl, alkoxy group, acylaminogroup, alkoxyalkyl, (Y1)(Y2)NC(=O)-, alkoxycarbonyl, aryl, halogen, carboxy group; or R5 and R6 together with two carbon atoms with a double bond, with they are bonded, form a benzene ring; R7 is a hydrogen atom, halogen or alkyl; and Y1 and Y2 are independently a hydrogen atom, alkyl, aryl or heteroaryl, or Y1 and Y2 together with a nitrogen atom, with which they are bonded, form a heteroaryl group or heterocycloalkyl group. The invention also relates to pharmaceutical compositions, containing these compounds. Thienopyrazoles can be used for treating diseases, which can be affected by protein kinase inhibition, particularly, interleukin-2-induced tyrosine kinase.

EFFECT: wider field of application of the compounds.

14 cl, 1 tbl, 98 ex

 

The present invention relates to theoperation General formula I, their reception, pharmacological drugs, which include such compounds, and their use in the treatment of painful conditions that can be corrected by the inhibition of protein kinases, in particular, interleukin-2 inducible tyrosine kinase (ITK).

Protein kinase is a family of enzymes involved in signaling processes that control the activation, growth and differentiation of cells in response to signals transmitted extracellular mediators, as well as to changes in the environment. In General, these kinases can be classified into several groups; those that selectively catalyze the phosphorylation of hydroxyl groups of serine and/or treoninove residues, and those that selectively catalyze the phosphorylation of hydroxy groups tyrosine residues [S.K.Hanks and T.Hunter, FASEB. J., 1995, 9, pp. 576-596]. Such reactions phosphorylation can cause serious changes in the function of proteins; therefore, protein kinases play an important role in regulating a variety of cellular processes, including, in particular, metabolism, reproduction, differentiation and survival of cells.

The unusually high activity of protein kinases was observed in the clinical pictures of many diseases caused by disorders of cellular functions. Right or to the public it could be called, for example, a violation of the relevant control mechanism kinase related, for example, by mutation, overexpression or impaired activation of the enzyme, either excessive or insufficient production of cytokines or growth factors are also involved in the transduction of signals before or after the action of kinases. In all these cases, you can expect a positive effect of selective inhibition of the action of the kinase.

ITC is a specific for T-cells to tyrosinekinase family of TES necessary for the normal functioning of Th2. Asthma refers to diseases characterized by increased production of the Th2 cytokine, including IL-4. Therefore, the inhibitor of ITC in case of asthma should have an impact on the development of the disease by inhibiting production of Th2 cytokine.

We found a new group of theoperation possessing useful pharmacological properties, in particular the ability to inhibit protein kinases, more specifically to inhibit the protein kinase ITK.

Brief description of the invention

Thus, in one aspect the invention relates to compounds of General formula I,

The formula I

where:

X represents N or C-R7;

X1denotes N or C-R1;

R1, R2, R3, R4, R5and R6denote, independently of the t other hydrogen, possibly substituted acyl, possibly substituted alkyl, possibly substituted alkoxygroup, possibly substituted allmenalp, possibly substituted alkenylphenol group, possibly substituted alkoxyalkyl group,

(Y1)(Y2)NC(=O)-, (Y1)(Y2)N-, possibly substituted alkoxycarbonyl group, possibly substituted alkylsulfonyl group, possibly substituted alkylsulfonyl group, possibly substituted alkylsulfonyl group, possibly substituted alkylthiols, possibly substituted alkylamino group, possibly substituted arilou group, possibly substituted aryl, possibly substituted aroylamino, possibly substituted arylalkyl, possibly substituted arielalexisxrp, possibly substituted allakariallak, possibly substituted allamoxicillinpills group, possibly substituted aryloxyalkyl, possibly substituted arylalkylamine, possibly substituted alloctype, possibly substituted aryloxyalkyl group, possibly substituted arylsulfonyl group, possibly substituted arylsulfonyl group, possibly substituted arylcarbamoyl group, possibly substituted killigrew may substituted cycloalkenyl group, possibly substituted cycloalkenyl group, possibly substituted cycloalkyl the second group, possibly substituted cycloalkylcarbonyl group, possibly substituted cycloalkanes, possibly substituted heteroaryl group, possibly substituted heteroaromatic, possibly substituted heteroallyl group, possibly substituted heteroarylboronic, possibly substituted heteroatomcontaining group, possibly substituted heteroepitaxy, possibly substituted heteroepitaxial group, possibly substituted geterotsyklicescoe group, possibly substituted heteroarylboronic group, possibly substituted geterotsiklicheskikh group, possibly substituted geterotsiklicheskikh, possibly substituted geterotsiklicheskikh group, a halide group, a hydroxy-group, trifluoromethyl, a nitro-group, possibly substituted hydroxyalkyl group, carboxypropyl or cyano;

R5and R6together with the two carbons with a double bond between them, can also form a possibly substituted benzene ring;

R7denotes hydrogen, a halide group or a possibly substituted alkyl group; and

Y1and Y2denote, independently of one another, hydrogen, possibly substituted alkyl, possibly substituted aryl, possibly substituted heteroaryl or Y1and Y2together with the neighbouring atomo is nitrogen, can form a possibly substituted heteroaryl group, or a possibly substituted geterotsyklicescoe group, or a prodrug, acid bioisostere, pharmaceutically acceptable salt or MES of such compound or prodrug, or acid bioisostere such a salt or MES.

Preferred compounds of the present invention are compounds corresponding to the formula I, where X is N.

Also preferred compounds of the present invention are compounds corresponding to the formula I, where X is C-R7in particular C-H or C-halogen.

Also preferred compounds of formula I, where X1denotes n

Also preferred compounds of formula I, in which X1represents C-R1in particular, C-H.

Are also preferred compounds of formula I in which one of R2and R3is hydrogen and the other is a hydrogen, possibly substituted acyl, possibly substituted alkoxygroup, possibly substituted alkoxycarbonyl group, possibly substituted alkyl, halide group, or (Y1)(Y2)NC(=O)-.

Also preferred compounds of formula I, where R4denotes hydrogen.

Also preferred compounds of formula I, where R5denotes hydrogen, possibly substituted alkoxycarbonyl group may Zam is placed alkyl, possibly substituted aryl, carboxypropyl or (Y1)(Y2)NC(=O)-.

Also preferred compounds of formula I in which R6is hydrogen.

Also preferred compounds of formula I in which R5and R6together with two adjacent carbon atoms with a double bond between them, form a possibly substituted benzene ring.

It should be understood that this invention covers all relevant combinations listed here the particular and preferred groups.

A special group of compounds of the present invention to form a compound of formula (Ia)

Formula (Ia)

where X, R1, R2, R3, R4, R5and R6denote the above group, or a prodrug, acid bioisostere, pharmaceutically acceptable salt or MES of such compounds; or a prodrug or sour bioisostere such a salt or MES.

Preferred compounds of formula (Ia)in which X represents:

(i) N;

(ii) C-Br;

(iii) C-H.

Also preferred compounds of formula I(a), in which R1denotes hydrogen.

Also preferred compounds of formula I(a), in which one of R2and R3denotes H, and the second means:

(i) hydrogen

(ii) possibly substituted acyl [e.g.,and ];

(iii) possibly substituted alkoxygroup [for example,,,,,,,,,,and];

(iv) possibly substituted alkoxycarbonyl group [for example,]; or

(v) possibly substituted alkyl [e.g.,,,,,,,,,,,,,,,,,,,,,,,,,,and];

(vi) halide group [for example, braugruppe]; or

(vii) (Y1)(Y2)NC(=O)- [for example,,,,,,and].

Preferred are the compounds of formula I(a), in which R4denotes hydrogen.

Also preferred are the compounds of formula I(a), in which R5means:

(i) hydrogen;

(ii) possibly substituted alkoxycarbonyl group [for example,];

(ii) possibly substituted alkyl [e.g.,,,,,,,,,and];

(iii) possibly substituted aryl [e.g.,];

(iv) carboxypropyl or

(iv) (Y1)(Y2)NC(=O)- [for example,,,and].

Also preferred are the compounds of formula I(a), in which R6denotes hydrogen.

Another special group of compounds of this invention are the compounds is of formula (Ib)

(Ib)

where R2, R3, R4, R5and R6denote the above specified group.

The item:

The compounds of formula I and the intermediate and raw materials, used in cooking, are named in accordance with IUPAC nomenclature, in accordance with which the characteristic groups have the following descending sequence of priorities in the designation of the main groups: acids, esters, amides, etc. In an alternative embodiment, compounds called program AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, the compound of formula I, in which X1indicates C-H, X is C-H, R2denotes hydrogen, R3refers to 3-(4-hydroxypiperidine-1-yl)propyloxy

(), R4denotes hydrogen, R5denotes dimethylaminomethyl

(and R6denotes hydrogen; that is, the compound has the following structure:

gets the name 1-{3-[2-(5-dimethylaminoethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}piperidine-4-ol.

The specific implementation of the present invention include the following compounds of formula I:

2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-benzimidazole, example 1;

6-methoxy-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-benzimida the ol, example 2;

3-(6-methoxy-1H-benzimidazole-2-yl)-1H-benzo[4,5]thieno[3,2-c]pyrazole, example 3;

6-(3-piperidine-1-ylpropionic)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-benzimidazole, example 4;

5-(3-piperidine-1-yl-propoxy)-2-(1H-thieno[3,2c]pyrazole-3-yl)-indole, example 5;

1-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-4-ol, example 6;

6-(3-piperidine-1-yl-propoxy)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole, example 7;

1-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}piperidine-3-ol, example 8;

(1-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}piperidine-3-yl)methanol, example 9;

6-[3-(4-ethylpiperazin-1-yl)-propoxy]-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole, example 10;

dimethyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-amine, example 11;

diethyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-amine, example 12;

diallyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-amine, example 13;

1-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-pyrrolidin-3-ol, example 14;

2-(methyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-amino)-ethanol, example 15;

1-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yloxy]-propyl}-piperidine-4-ol, example 16;

1-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yloxy]-propyl}-piperidine-3-ol, example 17;

(1-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yloxy]-propyl}-piperidine-3-yl)-methanol, example 18;

1-{3-[2-(1H-thieno[3,2-c]PI is the azole-3-yl)-1H-indol-5-yloxy]-propyl}-pyrrolidin-3-ol, example 19;

3-(5-(3-piperidine-1-yl-propoxy)-1H-benzoimidazol-2-yl)-1H-benzo[4,5]thieno[3,2-c]pyrazole, example 20;

(2-thiophene-2-yl-ethyl)-amide 2-{1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-5-carboxylic acid, example 21;

1-{3-[2-(5-dimethylaminoethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1h-indole-6-yloxy]-propyl}-piperidine-4-ol, example 22;

tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid;

tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid;

tert-butyl ester 2-(1-tert-butoxycarbonyl-5-dimethylaminomethyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid;

tert-butyl ester 2-(1-tert-butoxycarbonyl-5-dimethylaminomethyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-hydroxyindole-1-carboxylic acid;

[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]methanol, example 23;

phenyl-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-methanol, example 24;

phenyl-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-methanon, example 25;

1-phenyl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-ethanol, example 26;

(S)-1-phenyl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-ethanol, example 27;

1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-propane-1-it, example 28;

1-cyclohexyl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol, example 29;

p> 1-cyclohexyl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol, enantiomer 1, example 30;

1-pyridin-2-yl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol, example 31;

2-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol, example 32;

(R)-2-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol, example 33A;

(S)-2-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol, example 33B;

1-(2-pyrrolidin-1-ylmethylene)-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol, example 34;

1-tert-butyl-5-methyl ether 3-(5-acetyl-1-tert-butoxycarbonyl-1H-indol-2-yl)thieno[3,2-c]pyrazole-1,5-dicarboxylic acid, example 35;

methyl ester 3-(5-acetyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid, example 36;

3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid, example 37;

[4-(4-forfinal)-piperazine-1-yl]-[3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-yl]-methanon, example 38;

(3 ethoxy-propyl)-amide 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid, example 39;

methyl ester 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid, example 40;

(pyridine-2-ylmethyl)-amide 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid, example 41;

5-bromo-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole, example 42;

methyl ester of 2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-carboxylic acid, example 43;

dicyclopropyl-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-methanol, example 44;

(4-benzo[1,3]dioxol-5-iletileri-1-yl)-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]metano, example 45;

[4-(2-cyclohexylethyl)-piperazine-1-yl]-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]metano, example 46;

(2-hydroxy-2-phenylethyl)-amide 2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-carboxylic acid, example 47;

(2-cyclohex-1-teletel)-amide 2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-carboxylic acid, example 48;

(2-thiophene-2-retil)-amide 2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-carboxylic acid, example 49;

(4-pyridine-2-reparation-1-yl)-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-methanon, example 50;

(2-pricin-3-retil)-amide 2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-carboxylic acid, example 51;

cyclohexylmethyl-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-ylmethyl]-amine, example 52;

5-[4-(4-Chlorobenzyl)-piperazine-1-ylmethyl]-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole, example 53;

[2-(4-phenoxyphenyl)-ethyl]-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-ylmethyl]-amine, example 54;

3-[6-(3-piperidine-1-ylpropionic)-1H-benzoimidazol-2-yl]-1H-benzo[4,5]thieno[3,2-c]pyrazole, example 55;

1-{3-[2-(5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-3-ol, example 56;

1-{3-[2-(5-Phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-4-ol, example 57;

2-(5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(3-piperidine-1-ylpropionic)-1H-ind the l, example 58;

1-(3-{2-[5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole-3-yl]-1H-indole-6-yloxy}-propyl)-piperidine-4-ol, example 59;

5-methoxy-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-pyrrol[3,2-b]pyridine, example 60;

3-bromo-6-(3-piperidine-1-ylpropionic)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole, example 61;

{3-[6-(3-piperidine-1-ylpropionic)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-yl}-methanol, example 62;

1-{3-[6-(3-piperidine-1-ylpropionic)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-ylmethyl}piperidine-4-ol, example 63;

2-{5-[4-(4-forfinal)piperazine-1-ylmethyl]-1H-thieno[3,2-c]pyrazole-3-yl}-6-(3-piperidine-1-ylpropionic)-1H-indole, example 64;

methyl-{3-[6-(3-piperidine-1-ylpropionic)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-ylmethyl}-pyridine-2-ylamine, example 65;

benzyl-{3-[6-(3-piperidine-1-ylpropionic)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-ylmethyl}-amine, example 66;

6-(3-piperidine-1-ylpropionic)-2-[5-(4-triftormetilfosfinov-1-ylmethyl)-1H-thieno[3,2-c]pyrazole-3-yl]-1H-indole, example 67;

[2-(5-piperidine-1-ylmethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-methanol, example 68;

1-{3-[2-(5-benzoyloxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-4-ol, example 69;

3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, example 70;

3-[2-(5-benzoyloxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, example 71;

[2-(5-benzoyloxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-piperidin-2-ylmethanol, example 72;

1-{3-[6-(1-ethyl-1-hydroxypropyl)-1H-shall ndol-2-yl]-1H-thieno[3,2-c]pyrazole-5-ylmethyl}-piperidine-4-ol, example 73;

3-[2-(5-dimethylaminomethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, example 74;

3-(2-{5-[4-(pyridine-4-yloxy)-piperidine-1-ylmethyl]-1H-thieno[3,2-c]pyrazole-3-yl}-1H-indol-6-yl)-pentane-3-ol, example 75;

3-[2-(5-piperazine-1-ylmethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, example 76;

3-[2-(5-piperazine-1-yl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, example 77;

3-{2-[5-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-1H-thieno[3,2-c]pyrazole-3-yl]-1H-indol-6-yl}-pentane-3-ol, example 78;

3-[2-(5-pyridin-4-yl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, example 79;

bis-(1-methylpiperidin-4-yl)-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-methanol, example 80;

3-[2-(5-deformity-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, example 81;

4-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-piperidine-4-ol, example 82;

6-(4-foreperiod-4-yl)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole, example 83;

2-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-butane-2-ol, example 84;

1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-Etalon, example 85;

3-[3-piperidine-4-yl-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, example 86;

3-[3-pyridin-4-yl-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, example 87;

3-[3-(4-methyl-piperazine-1-yl)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, example 88;

3-[3-morpholine-4-ylmethyl-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, example 89;

4-[2-(1H-thieno[3,2-c]Piras the l-3-yl)-1H-indol-6-yl]-tetrahydropyran-4-ol, example 90;

3-{2-[5-(1-hydroxy-1-methylethyl)-1H-thieno[3,2-c]pyrazole-3-yl]-1H-indol-6-yl}-pentane-3-ol, example 91;

3-[2-(5-methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-3-pyridin-4-yl-1H-indol-6-yl]-pentane-3-ol, example 92;

4-[2-(5-methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-tetrahydropyran-4-ol, example 93;

3-[2-(5-methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-3-piperazine-1-yl-1H-indol-6-yl]-pentane-3-ol, example 94;

3-[2-(5-methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-3-morpholine-4-ylmethyl-1H-indol-6-yl]-pentane-3-ol, example 95;

2-{3-[6-(1-ethyl-1-hydroxypropyl)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-yl}-tetrahydrofuran-3-carbonitrile, example 96;

3-[2-(5-methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-3-methyl-1H-indol-6-yl]-pentane-3-ol, example 97 and

3-[2-(5-methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-3-piperidine-4-yl-1H-indol-6-yl]-pentane-3-ol, example 98;

and prodrugs, sour bioisostere, pharmaceutically acceptable salt or solvate of such compounds or prodrugs and sour bioisostere such salt or solvate. Data properties specific compounds are summarized in Table 1 below.

Brief description of drawings

The drawing shows a schematic of the chemical synthesis of describing the process of getting this or the other compounds of the present invention.

A full description of preferred implementations of the present invention

In the present description assumes that the term “connection is by means of invention”, and equivalent expressions comprise the compounds of formula I, as described above, the expression of which includes the prodrugs, pharmaceutically acceptable salt and solvate such as a hydrate, when the context. Similarly, it is understood that references to an intermediate connection, regardless of whether they are included in the claims or not, include their salts and solvate in cases when the context. For clarity, specific proper context examples sometimes are illustrated in the text, however, are purely for illustration and without intending to exclude other suitable context examples.

In accordance with their use above and throughout the description, the following terms, unless otherwise indicated, shall mean the following values.

“Patient” includes both humans and other mammals.

“Pharmaceutically effective amount” is intended to describe the amount of a compound, composition, drug or other active ingredient that is effective to obtain the desired therapeutic effect.

“Sour bioisostere” refers to a group having similar chemical and physical characteristics, and who are in General similar to carboxypropyl biological properties (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, page 283 "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993, 33, pp. 576-579 "Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 195, pages 34-38 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem, 1995, 343, pages 105-109 "Theoretical Studies Applied To Drug Design: ab initio Electronic Distributions In Bioisosteres"). Examples of suitable acidic bioisostere include-C(=O)-NHOH, -C(=O)-CH2OH, -C(=O)-CH2SH, -C(=O)-NH-CN, alphagroup, phosphonopropyl, alkylsulphonyl group, tetrazolyl group, arylcarbamoyl group, heteroarylboronic group, N-methoxycarbonyl group, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidine or heterocyclic phenols such as 3-hydroxyisoquinoline and 3-hydroxy-1-methylpyrazole.

“Acyl” means an H-CO - or alkyl-CO-group, an alkyl group which is described here. Typical acyl groups includeand. “Maybe substituted acyl” denotes an acyl group which may be substituted in the alkyl portion one or more Deputy alkyl groups. Typical substituted acyl groups include.

“Alluminare” it acyl-NH - group, acyl group which are described here. “Maybe substituted alluminare” means allmenalp, which can be substituted in the alkyl portion one or more Deputy alkyl groups.

“Alkenyl” means an aliphatic hydrocarbon group containing one Il is more than the double bond carbon-carbon and which may be linear or branched, having from about 2 to 15 carbon atoms in the chain. Preferred alkeneamine groups have from about 2 to 12 carbon atoms in the chain, and more preferably from 2 to about 4 carbon atoms in the chain. “Branched”, when used here and throughout the text, means that one or more alkyl groups such as methyl, ethyl or propyl, are attached to a linear chain; in this case, the linear alkenylphenol chain. “Alkenyl lower order” means about 2 to 4 carbon atoms in the chain, which may be linear or branched. Typical alkeneamine groups include ethynyl, propenyl, n-butenyl, Isobutanol, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylmethanol and decenyl. “Maybe substituted alkenyl” means alkenylphenol group which may be substituted by one or more Deputy alkyl groups.

“Alkoxygroup” refers to the group alkyl-O-, an alkyl group which is described here. Typical alkoxygroup include metaxylene, amoxilina, n-propoxyimino, isopropoxide, n-butoxyphenol and epoxypropyl. “Maybe substituted alkoxygroup” means alkoxygroup, which can be substituted in the alkyl portion one or more Deputy alkyl groups. Typical substituted alkoxygroup include, ,,,,,,,and.

“Alkoxyalkyl group” refers to the group alkyl-O-alkyl-, alkyl group which is described here. Typical alkoxymethyl group include methoxymethyl and ethoxymethyl. “Maybe substituted alkoxyalkyl group” means alkoxyalkyl group which may be substituted in the alkyl portion one or more Deputy alkyl groups.

“Alkoxycarbonyl group” refers to the group alkyl-O-CO-, an alkyl group which is described here. Typical alkoxycarbonyl groups include methoxy and ethoxycarbonyl group. “Maybe substituted alkoxycarbonyl group” means alkoxycarbonyl group which may be substituted in the alkyl portion one or more Deputy alkyl groups.

“Alkyl” means, except as provided herein, aliphatic hydrocarbon group which may be linear or branched and have from about 1 to 15 carbon atoms in the chain. Specific alkyl groups have from 1 to about 6 carbon atoms. Typical alkyl groups include C1-6alkyl groups such as methyl, ethyl, n-ropel, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. “Maybe substituted alkyl” denotes an alkyl group which may be substituted by one or more alkyl Deputy, where the substituents are alkyl groups” include, for example, acyl, allmenalp, alkoxygroup, alkoxycarbonyl group, alkylenedioxy, alkylsulfonyl group, alkylsulfonyl group, allylthiourea, possibly substituted arilou group, possibly substituted aroylamino, possibly substituted aryl, possibly substituted arylalkyl, possibly substituted arylalkylamine, possibly substituted arylalkylamines group, possibly substituted arylalkylamine, possibly substituted alloctype, possibly substituted aryloxyalkyl group, possibly substituted arylsulfonyl group, possibly substituted arylsulfonyl group, possibly substituted killigrew carboxypropyl, cyano, cycloalkenyl group, a halide group, possibly substituted heteroaryl group, possibly substituted heteroaryl group, possibly substituted heteroallyl group, possibly substituted heteroaromatics, possibly substituted heteroaromatic, possibly substituted heteroepitaxy, possibly substituted geterotsyklicescoe group, hydroxyl the PPU, the nitrogroup, oxoprop, trifluoromethyl, Y7Y8N, Y7Y8NCO-, Y7Y8NSO2-where Y7and Y8denote, independently of one another, hydrogen, alkyl, aryl, arylalkyl, heteroaryl or heteroaromatic. Typical substituted alkyl groups include,,,,,,,,,,,,,,,,,,,,,,,,,,,,,and.

“Alkylene” denotes a linear or branched bivalent hydrocarbon chain having from 1 to about 15 carbon atoms. Special alkionovymi groups ablauts the lower alkylene group, having from 1 to about 6 carbon atoms. Typical groups include methylene and ethylene.

“Alkylsulfonyl group” refers to the group alkyl-SO-, alkyl group discussed above. Preferred groups are those in which the alkyl group is C1-6alkyl. “Maybe substituted alkylsulfonyl group” means alkylsulfonyl group which may be substituted in the alkyl portion one or more Deputy alkyl groups.

“Alkylsulfonyl group” refers to the group alkyl-SO2-, an alkyl group discussed above. Preferred groups are those in which the alkyl group is C1-6alkyl. “Maybe substituted alkylsulfonyl group” means alkylsulfonyl group which may be substituted in the alkyl portion one or more Deputy alkyl groups.

“Alkylsulfonyl group” refers to the group alkyl-SO2-NH-C(=O)-, alkyl group discussed above. Preferred alkylsulfonyl groups are those in which the alkyl group is C1-6alkyl. “Maybe substituted alkylsulfonyl group” means alkylsulfonyl group which may be substituted in the alkyl portion one or more Deputy alkiline the group.

“Allylthiourea” refers to the group alkyl-S-, alkyl group discussed above. Typical ancilliary include metalcorp, ethylthiourea, isopropylthio and reptiliomorpha. “Maybe substituted allylthiourea” means allylthiourea, which can be substituted in the alkyl portion one or more Deputy alkyl groups.

“Quinil” means an aliphatic hydrocarbon group containing a triple bond of carbon-carbon and which may be linear or branched and have from about 2 to 15 carbon atoms in the chain. Preferred alkyline groups have from 2 to about 12 carbon atoms in the chain, and more preferably from about 2 to 6 carbon atoms in the chain. Typical alkyline group include ethinyl, PROPYNYL, n-butynyl, Isobutanol, 3-methylbut-2-inyl and n-pentenyl. “Maybe substituted quinil” means alkylamino group which may be substituted by one or more Deputy alkyl groups.

“Arolina group” refers to the group aryl -, aryl group which is described below. Typical groups include benzoyl and 1 - and 2-naphtol. “Maybe substituted arolina group” means arilou group, the aryl part of which may be substituted by one or more Deputy aryl group, as described here.

“Aroylamino” this grupperar-NH-, arolina of which is described above. “Maybe substituted aroylamino” means aroylamino, which can be substituted in the aryl part by one or more Deputy aryl group.

“Aryl” as a group or part of a group denotes: (i) monocyclic or multicyclonic aromatic carbocyclic portion containing from about 6 to 14 carbon atoms, such as phenyl or naphthyl; or (ii) partially saturated multicyclonic aromatic carbocyclic portion, in which aryl and cycloalkyl or cycloalkenyl group condensed, forming a cyclic structure, such as tetrahydronaphthyl, ingenernoe or indanamine ring. “Maybe substituted aryl group” may be substituted by one or more aryl Deputy, which may be the same or different, where “Deputy aryl group” includes, for example, acyl, allmenalp, alkoxygroup, alkoxycarbonyl group, alkyl, alkylenedioxy, alkylsulfonyl group, alkylsulfonyl group, allylthiourea, arilou group, aroylamino, aryl, arylalkyl, arielalexisxrp, arylalkylamines group, arylalkylamine, alloctype, aryloxyalkyl group, arylsulfenyl group, arylsulfonyl group, killigrew, carboxypropyl, cyan is the group halide group, heteroaryl group, heteroaryl group, heteroallyl group, heteroarylboronic, heteroaromatic, heterokaryosis, geterotsiklicheskikh group, a hydroxy-group, a nitrogroup, trifluoromethyl, Y5Y6N, Y5Y6NCO-, Y5Y6NSO2-where Y5and Y6denote, independently of one another, hydrogen, alkyl, aryl, arylalkyl, heteroaryl and heteroallyl, or Y5and Y6together with the adjacent nitrogen atom, form a nitrogen-containing saturated alicyclic ring containing from 3 to 7 members.

“Maybe substituted benzene ring” denotes a benzene ring which may be substituted by one or more Deputy aryl group.

“Arylalkyl” means an aryl-alkyl group, the aryl and the alkyl part of which is described above. Preferred arylalkyl groups contain C1-6alkyl part. Typical arylalkyl groups include benzyl, 2-phenethyl and naphthalenethiol. “Maybe substituted arylalkyl” means arylalkyl group which may be substituted in the aryl part by one or more Deputy aryl group and may be substituted in the alkyl portion one or more Deputy alkyl groups. Typical substituted arylalkyl groups include and.

“Arylalkylamine” denotes the group arylalkyl, arylalkyl group described above. Typical arialcategory include benzyloxyphenol and 1 - or 2-naphthalenyloxy. “Maybe substituted arylalkylamine” means arylalkylamine, which can be substituted in the aryl part by one or more Deputy aryl group and the alkyl part is one or more Deputy alkyl groups.

“Arylalkylamine group” means a group arylalkyl-O-alkyl, arylalkyl and alkyl groups as discussed above. Typical arylalkylamine group include benzyloxyethyl and 1 - or 2-naphthaleneacetic. “Maybe substituted arylalkylamine group” means arylalkylamine group which may be substituted in the aryl part by one or more Deputy aryl group and the alkyl part is one or more Deputy alkyl groups.

“Arylalkylamine group” means a group arylalkyl-O-CO-, arylalkyl group described above. Typical arylalkylamines group is benzyloxycarbonyl. “Maybe substituted arylalkylamine group” means arylalkylamines group which may be substituted in the aryl part by one or more the Deputy aryl group and the alkyl part is one or more Deputy alkyl groups.

“Aryloxyalkyl group” refers to the group aryl-O-alkyl. Typical aryloxyalkyl is phenoxymethyl. “Maybe substituted aryloxyalkyl group denotes aryloxyalkyl group which may be substituted in the aryl part by one or more Deputy aryl group and the alkyl part is one or more Deputy alkyl groups.

“Arylalkylamine” denotes the group arylalkyl-S-, arylalkyl of which is described above. Typical arylalkylamine is menzilcioglu. “Maybe substituted arylalkylamine” is arylalkylamine, which can be substituted in the aryl part by one or more Deputy aryl group and the alkyl part is one or more Deputy alkyl groups.

“Alloctype” refers to the group aryl-O-, aryl part of which is described above. Typical alloctype may include substituted phenoxyl and naftochimgroup. “Maybe substituted alloctype” means alloctype, which can be substituted in the aryl part by one or more Deputy aryl group.

“Aryloxyalkyl group” refers to the group aryl-O -, aryl part of which is described above. Typical aryloxyalkyl groups include phenoxycarbonyl and Naftok carbonyloxy group. “Maybe substituted aryloxyalkyl group” means aryloxyalkyl group which may be substituted in the aryl part by one or more Deputy aryl group.

“Arylsulfonyl group” refers to the group aryl-SO-, aryl group described above. “Maybe substituted arylsulfonyl group” means arylsulfonyl group which may be substituted in the aryl part by one or more Deputy aryl group.

“Arylsulfonyl group” refers to the group aryl-SO2-, aryl group described above. “Maybe substituted arylsulfonyl group” means arylsulfonyl group which may be substituted in the aryl part by one or more Deputy aryl group.

“Arylcarbamoyl group” refers to the group aryl-SO2-NH-C(=O)-, aryl group described above. “Maybe substituted arylcarbamoyl group” means arylcarbamoyl group which may be substituted in the aryl part by one or more Deputy aryl group.

“Aristocrata” refers to the group aryl-S-, aryl group described above. Typical aristocraty include phenylthiourea and naphthylthiourea. “Maybe substituted aristocrata” means killigrew, which can bytesmessage in the aryl part by one or more Deputy aryl group.

“Cycloalkenyl group” denotes a non-aromatic monocyclic or multicyclonic ring system containing at least one double bond in the carbon-carbon bonds and having from about 5 to 10 carbon atoms. Typical monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl. Typical multicylinder cycloalkenyl ring is norbornanyl. “Maybe substituted cycloalkenyl group” means cycloalkenyl group which may be substituted by one or more Deputy alkyl groups.

“Cycloalkylcarbonyl group” means a group cycloalkyl-O-alkyl, cycloalkyl group which are described below. Typical cycloalkenyl group include cyclopropylmethyl and cyclopentylacetyl. “Maybe substituted cycloalkylcarbonyl group” means cycloalkenyl group which may be substituted by one or more Deputy alkyl groups.

“Cycloalkyl group” denotes a non-aromatic monocyclic or multicyclonic ring system containing from about 3 to about 10 carbon atoms. Typical monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. Typical multicyclone cycloalkyl ring include n likeafter, adamant-(1 or 2)-yl and norbornyl and spirocycles group, for example, Spiro[4,4]non-2-yl. “Maybe substituted cycloalkyl group” means cycloalkyl group which may be substituted by alkyl or by one or more Deputy alkyl groups.

“Cycloalkylcarbonyl group” means a group cycloalkenyl, cycloalkyl and alkyl parts of which are described above. Typical monocycline cycloalkenyl group include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. “Maybe substituted cycloalkylcarbonyl group” means cycloalkylcarbonyl group which may be substituted by alkyl or by one or more Deputy alkyl groups.

“Cycloalkylation” denotes the group cycloalkyl, cycloalkyl group described above. Typical cycloalkylcarbonyl include cyclopropylamino, cyclopentyloxy, cyclohexyloxy and cycloheptylamine. “Maybe substituted cycloalkanones” means cycloalkylation, which can be substituted in the alkyl portion one or more Deputy alkyl groups.

“Halide group” or “halogen” denotes fluorine, chlorine, bromine or iodine.

“Heteroaryl group” means a group heteroaryl-CO-, heteroaryl part of which described the WMD here. Typical groups include pyridylcarbonyl. “Maybe substituted heteroaryl group” means heteroaryl group which may be substituted by one or more Deputy aryl group.

“Heteroaromatic” denotes the group heteroaryl-NH-, heteroaryl of which is described above. “Maybe substituted heteroaromatic” means heteroaromatics, which may be substituted by one or more Deputy aryl group.

“Heteroaryl group” as a group or part of a group denotes an aromatic monocyclic or multicyclonic organic portion containing from about 5 to 14 ring members, in which one or more members is not carbon, for example nitrogen, oxygen or sulfur. Examples of suitable heteroaryl groups include benzimidazolyl, follow, imidazolidinyl, isoxazolidine, athinodorou, isothiazolinone, oxadiazolidine, personilnya, pyridazinyl, pyrazolidine, pyridyloxy, pyrimidinyl, pyrrolidinyl, chinazolinei, hyalinella, 1,3,4-thiadiazolyl, thiazolidine, thienyl and triazolyl group. “Maybe substituted heteroaryl group” denotes a heteroaryl group which may be substituted by one or more Deputy aryl group.

p> “Heteroallyl group” means a group heteroallyl, heteroaryl and alkyl parts of which are as described above. Preferred heteroallyl groups contain C1-4alkyl part. Typical heteroallyl group include pyridylmethyl. “Maybe substituted heteroaromatic” means heteroallyl group which may be substituted in the heteroaryl part with one or more Deputy aryl group and the alkyl part is one or more Deputy alkyl groups.

“Heteroarylboronic” denotes the group heteroallyl, heteroallyl group which corresponds described above. Typical heteroarylboronic include pyridyloxy. “Maybe substituted heteroarylboronic” means heteroarylboronic, which can be substituted in the heteroaryl part with one or more Deputy aryl group, and which may be substituted in the alkyl portion one or more Deputy alkyl groups.

“Heteroepitaxial group” means a group heteroallyl-O-alkyl, heteroallyl and alkyl parts of which are as described above. Typical heteroepitaxial groups include 4-pyridylmethylamine and 3 - or 4-chinainternational the ing group. “Maybe substituted heteroepitaxial group” means heteroepitaxial group which may be substituted in the heteroaryl part with one or more Deputy aryl group, and the alkyl part is one or more Deputy alkyl groups.

“Heteroanalogues” denotes the group heteroaryl-O-, heteroaryl group which corresponds described above. Typical heterokaryosis include pyridyloxy. “Maybe substituted heteroanalogues” means heteroepitaxy, which can be substituted in the heteroaryl part with one or more Deputy aryl group.

“Heteroepitaxial group” means a group heteroaryl-O-alkyl, heteroaryl and alkyl parts of which are the same as described above. “Maybe substituted heteroepitaxial group” means heteroepitaxial group which may be substituted in the heteroaryl part with one or more Deputy aryl group and the alkyl part is one or more Deputy alkyl groups.

“Heteroarylboronic group” means a group heteroaryl-SO2-NH-C(=O)-, heteroaryl group which coincides with the above. “Maybe substituted heteroarylboronic group” means heteroaryl ylcarbonyl group, which may be substituted by one or more Deputy aryl group.

“Heterocytolysine group” denotes a non-aromatic or partially aromatic monocyclic or multicyclonic organic part having from 5 to about 14 members in the ring which contains one or more heteroatoms such as O, S or NY9where Y9denotes hydrogen, possibly substituted alkyl, possibly substituted aryl, possibly substituted arylalkyl group, cycloalkyl group, possibly substituted heteroaryl group or a possibly substituted heteroallyl group. Typical heterocytolysine groups include morpholine, piperidine, piperazine, pyrrolidine, tetrahydrofuran and perpetrators. “Maybe substituted heterocytolysine group” means geterotsyklicescoe group which may be substituted by alkyl or by one or more Deputy alkyl groups.

“Geterotsiklicheskikh group” means a group geterotsiklicheskikh-, heterocytolysine and alkyl parts of which are as described above. “Maybe substituted geterotsiklicheskikh group” means geterotsiklicheskikh group which may be substituted by alkyl or by one or more Deputy alkyl groups.

“Geterotsiklicheskikh” means g is uppy kind heteroseksualci-O-, heterocytolysine of which is described above. “Maybe substituted geterotsiklicheskikh” means geterotsiklicheskikh, which can be substituted in geterotsiklicheskikh part by alkyl or by one or more Deputy alkyl groups.

“Heterocyclisation group” means a group heteroseksualci-O-alkyl, heterocytolysine of which is described above. “Maybe substituted heterocyclisation group” means geterotsiklicheskikh group which may be substituted in geterotsiklicheskikh or the alkyl portion one or more Deputy alkyl groups.

“Hydroxyalkyl group” refers to a group BUT-alkyl-, an alkyl group which corresponds described above. Preferred hydroxyalkyl groups include C1-4alkyl. Typical hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. “Maybe substituted hydroxyalkyl group” means a hydroxyalkyl group which may be substituted in the alkyl portion one or more Deputy alkyl groups.

"Y7Y8N-" means a substituted or an unsubstituted amino group, where Y7and Y8meet the above groups. Typical groups include amino group is (H 2N-), methylaminopropyl, ethylamino, dimethylaminopropyl, and diethylaminopropyl.

"Y7Y8NCO-" denotes a substituted or unsubstituted karbamoilnuyu group, where Y7and Y8meet the above groups. Typical groups are carbarnoyl (H2NCO-) and dimethylcarbamoyl (Me2NCO-).

"Y7Y8NSO2-" denotes a substituted or unsubstituted sulfamoyl group, where Y7and Y8meet the above groups. Typical groups are sulfamoyl (H2NSO2-and dimethylsulphamoyl (Me2NSO2-).

“Prodrug” means a compound which is converted in vivo metabolic means (e.g. by hydrolysis) to a compound of formula I, including its N-oxides. For example, ester compounds of the formula I containing a hydroxy-group, can be converted by hydrolysis in vivo to the original molecule. Similarly, ester compounds of the formula I containing carboxypropyl, can be converted by hydrolysis in vivo to the original molecule.

“MES” means a physical Association of a compound of this invention with one or more solvent molecules. This physical Association involves a hydrogen bond. In certain cases, the MES can be selected, for example, when one or more solvent molecules included in to istoricheskoe lattice solid crystalline body. “MES” means both the solution phase and the selected solvate. Typical representatives of the solvate includes hydrates, ethanolate, methanolate etc.

Suitable esters of compounds of formula I containing a hydroxy-group, are for example acetates, citrates, lactates, tartratami, malonate, oxalates, salicylates, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthoate, gentisate, isethionate, di-p-toluoyltartaric, methansulfonate, econsultancy, bansilalpet, p-toluensulfonate, cyclohexylsulfamate and hinata.

Suitable esters of compounds of formula I containing carboxypropyl are, for example, the esters described in F.J.Leinweber, Drug Metab. Res., 1987, 18, page 379.

A particularly useful class of esters of compounds of formula I containing a hydroxy-group, can be formed from acids selected from described by Bundgaard et. al., J. Med. Chem., 1989, 32, p. 2503-2507 and including substituted (aminomethyl)benzoate, such as dialkylaminomethyl, in which the two alkyl groups may be combined together and/or separated by an oxygen atom or a possibly substituted by a nitrogen atom, for example alkilirovanny a nitrogen atom, more precisely (morpholinomethyl)benzoate, for example 3 - or 4-(morpholinomethyl)benzoate, and (4-alkylpiperazine-1-yl)benzoate, for example 3 - or 4-(4-alkylpiperazine-1-yl)benzoate.

Some compounds is altoadige invention are alkaline, such compounds are useful in the form of free base or pharmaceutically acceptable acid additive salts of such compounds.

An acid additive salt is more convenient for use; and in practice the use of salt inevitably leads to the use of free base. Acids which can be used to prepare the acid additive salts preferably include those which when reacted with the free base form of pharmaceutically acceptable salts, i.e. salts, the anions of which are not toxic to the patient in pharmaceutical doses of the salts, and a positive inhibitory effect produced by a freelance basis, not destroyed side effects caused by the anions. Although pharmaceutically acceptable salts of these alkaline compounds are preferred, all acid additive salts are useful as sources of the free bases, even if the particular salt, per se, is required only as an intermediate product as, for example, when the salt is formed only for purposes of purification and identification, or when it is used as intermediate compounds in the preparation of pharmaceutically acceptable salts by ionoobmennyh processes. Pharmaceutically acceptable salt, covered by the invention include the salts obtained the mineral and organic acids, and include hydrogenogenic, such as hydrochloride and hydrobromide, sulfates, phosphates, nitrates, sulfamate, acetates, citrates, lactates, tartratami, malonate, oxalates, salicylates, propionate, succinate, fumarate, maleate, methylene-bis-b-hydroxynaphthoate, gentisate, isethionate, di-p-toluoyltartaric, methane-sulfonates, econsultancy, bansilalpet, p-toluensulfonate, cyclohexylsulfamate and hinata.

When the compound of the invention is substituted acid fragment can form alkali-additive salts, which are more convenient to use the form; and in practice the use of salt forms inevitably results in a free acid form. The Foundation, which can be used in the preparation of these alkali-additive salts include preferably those which when reacted with the free acid form pharmaceutically acceptable salts, i.e. salts, the cations of which are not toxic to the patient in pharmaceutical doses of the salts, and a positive inhibitory effect of free reason not weakened side effects caused by the cations. Pharmaceutically acceptable salts, including salts, salts derived from alkali and alkaline earth metals, in the scope of this invention include salts derived from the following bases: sodium hydride, sodium hydroxide, hydroc the ID of potassium, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, Ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenziletilendiaminom, chloroprocaine, diethanolamine, procaine, N-benzylpenicillin, diethylamine, piperazine, Tris(hydroxymethyl)aminomethan, the hydroxide of Tetramethylammonium, etc.

In addition to the use as active compounds, salts of the compounds of the invention can be used for purification of the compounds, for example, based on the difference in solubilities between the salts and the parent compounds, by-products and/or starting materials by methods well known to specialists in this field.

Compounds of the invention are inhibitors of ITK and, therefore, have useful pharmacological properties. Accordingly, they are entered into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. Thus, the present invention provides, in accordance with a further aspect, the compounds of the invention and compositions containing compounds of the invention for use in therapy.

Compounds covered by the present invention are inhibitors of the ITC in accordance with the tests described in the literature, and the tests described below, the results of which is in the modern view correlate to pharmacological activity in humans and other mammals. Thus, in the further implementation of the present invention provides compounds of the invention and compositions containing compounds of the invention, for use in the treatment of a patient suffering from or susceptible to painful conditions that can be improved by the appointment of ITK inhibitor. For example, the compounds of the present invention are useful in the treatment of asthma.

Links to treatment in this text is meant as a preventative therapy and treatment of diagnosed conditions.

The present invention also encompasses pharmaceutical compositions containing at least one compound of the invention, in combination with a pharmaceutically acceptable carrier or binder.

Compounds of the invention may be administered in any suitable way. In practice, the compounds of the present invention can be administered parenterally, topically, rectally, orally, or by inhalation, especially oral route.

Compositions in accordance with the invention, can be prepared by conventional methods, using one or more pharmaceutically acceptable components, auxiliary or binders. Excipients include, among other things, diluents, sterile aqueous medium and various non-toxic organic Rast is oriali. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and may contain one or more agents from the group comprising sweeteners, flavorings, colorants, or stabilizers, to obtain pharmaceutically acceptable preparations. The choice of carrier and active ingredient content in the media in General is determined in accordance with the solubility and chemical properties of the active compounds, the specific manner of appointment and the conditions that must be observed in medical practice. Such binders as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and loosening agents, such as starch, alginic acid and certain complex silicates in combination with sliding agents such as magnesium stearate, sodium lauryl sulphate and talc, can be used for preparing tablets. For the preparation of capsules is advantageous to use lactose and polyethylene glycol having a high molecular weight. When using aqueous suspensions can contain emulsifying agents, or agents that promote the formation of a suspension. You can also use diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerin and the chloroform or the mixture.

For parenteral purpose use emulsions, suspensions or solutions of the products in accordance with the invention in a vegetable oil such as sesame, peanut, or olive oil, or aqueous-organic solutions, such as water and propylene glycol, organic esters for injection applications, such as etiloleat, as well as sterile aqueous solutions of pharmaceutically acceptable salts. Solutions of salts of products in accordance with the invention is particularly useful when assigning intramuscular or subcutaneous injection. Aqueous solutions, including solutions of salts in pure distilled water can be used for intravenous injection, provided that their pH is adjusted accordingly, they are placed in the appropriate buffer solution and brought to the isotonic condition sufficient amount of glucose or sodium chloride, and that they are sterilized by heating, irradiation or by microfiltration.

The local application can be used gels (water or alcohol), creams or ointments containing compounds of the invention. Compounds of the invention can also be administered in a gel or matrix base for application in the form of a patch that will allow the controlled introduction connections via transdermal barrier.

When used in inhalation the compounds from which Britania can be dissolved or prepared in the form of a suspension in a suitable carrier for use in spray or aerosol spray can, or may be absorbed or adsorbed on a suitable solid media for use in a dry powder inhaler.

Solid compositions for rectal applications include candles, which have been prepared in accordance with known methods and containing at least one of the compounds of this invention.

The percentage of active ingredient in the compositions of the invention may vary subject to the necessary proportions to provide the desired dose. Obviously, some of the dosage forms can be used at the same time. The required dose will be determined by the physician and depends on the desired therapeutic effect, the route of administration and duration of treatment and the patient's condition. For adults doses ranging from 0.001 to 50, preferably from 0.001 to 5 mg/kg of body weight per day by inhalation, from 0.01 to 100, preferably from 0.1 to 70, more specifically from 0.5 to 10 mg/kg body weight / day orally and from 0.001 to 10, preferably from 0.01 to 1 mg/kg of body weight per day intravenously. In each case, the dose will be determined in accordance with individual patient factors such as age, weight, General health status, and other characteristics that may affect the efficacy of the drug product.

Compounds in accordance with the invention can be administered as often as needed to achieve the desired terapevticheskoj the effect. Some patients react quickly to a more or less high doses, and a much smaller maintenance doses may be adequate. For other patients may need long-term treatment in an amount of from 1 to 4 doses per day, depending on the physiological needs of each individual patient. In General, the active product can be used orally 1 to 4 times a day. Of course, for some patients it will be enough to take one or two doses per day.

Compounds of the invention can be prepared by application or adaptation of known methods, previously used or described in the literature.

In the reactions described below, it may be necessary to protect reactive functional groups, e.g. hydroxy groups, amine groups, aminogroup, tigroup or carboxypropyl, in cases where these groups are required in the final product, to avoid their participation in the reactions. Traditional protective groups may be used in accordance with standard practice, see, for example, T.W.Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

You should take into account the fact that the compounds of the present invention may contain asymmetric centers. Data asymmetric centers may have, independently from each other, both R and S configuration is the situation. Specialists in this field will be obvious that certain compounds of the invention can exhibit geometrical isomerism. It is implied that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures of compounds of formula I, described above. Such isomers can be separated from mixtures with the use or adaptation of known methods, for example methods of chromatography and recrystallization, or prepared separately from the appropriate isomers of their intermediates. In addition, when possible existence of tautomers of the compounds of formula I, it is understood that the present invention includes all tautomeric forms of the compounds.

In accordance with another feature of the invention, the acid additive salts of the compounds of this invention can be prepared by the interaction of the free base with the appropriate acid, by application or adaptation of known methods. For example, the acid additive salts of the compounds of this invention can be prepared either by dissolving the free base in water or water-alcohol solution or other suitable solvent containing the appropriate acid and the release of salt by evaporating the solution, or by conducting the reaction between the free base and to what slotow in an organic solvent, such as tetrahydrofuran, in this case salt is produced directly or can be isolated by concentration of the solution.

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

In accordance with another feature of the invention, the alkali-additive salts of the compounds of this invention can be obtained by the reaction between the free acid and the corresponding base with the application or adaptation of known methods. For example, alkali-additive salts of the compounds of this invention can be prepared either by dissolving the free acid in water or water-alcohol solution or other suitable solvent containing the appropriate base, and excretion of salt by evaporating the solution, or by conducting the reaction between the free acid and a base in an organic solvent in the latter case, the salt is produced directly or can be obtained by concentration of the solution.

The compounds of this invention can be regenerated from their salts accession reason the application or adaptation of known methods. For example, the parent compound of this invention can be regenerated from their alkali-additive salts by reaction of the latter with an acid, for example hydrochloric acid.

Compounds of the present invention can be easily obtained, or they may be formed in the process of the proposed invention in the form of a solvate (e.g. hydrate). Hydrates of the compounds of the present invention can be easily prepared by recrystallization from water.

Raw materials and intermediate compounds that are not in the sale, can be prepared by application or adaptation of known methods, for example methods described in the examples or their obvious chemical equivalents.

The present invention is illustrated, but not limited to the following illustrative examples.

2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-benzimidazole of the present invention in General receive in accordance with scheme I.

Scheme I

3-(1H-benzimidazole-2-yl) 1H-[benzo[4,5]thieno[3,2-c]pyrazoles of the present invention in General receive in accordance with scheme II.

Scheme II

2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indoles of the present invention in General receive in accordance with scheme III.

Scheme III

In schemes I, II, III, V, VI, VII and VIII R1/sup> ', R2', R3', R4', R5', R6' and R7' denote R1, R2, R3, R4, R5, R6and R7accordingly, as defined herein, or represent protected forms thereof, or intermediate groups such.

In particular, aminoethoxy-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indoles of the present compounds receive in accordance with scheme IV.

Scheme IV

In scheme IV, HN(Y3)(Y4) denotes a possibly substituted heteroseksualci-N, where heteroseksualci-N denotes hydrogen at a saturated nitrogen inside geteroseksualbnogo ring, or Y3and Y4denote Y7and Y8respectively, or a protected derivative thereof, or an intermediate group.

2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indoles of the present invention of formula (Ia)in which one of R1, R2, R3and R4indicates a possibly substituted alkyl group of the formula[where Radenotes alkyl, cycloalkyl group, possibly substituted aryl or heteroaryl group], and the others represent hydrogen, generally receive in accordance with the scheme V.

Scheme V

Examplesinclude, and

2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indoles of the present invention of formula (Ia)in which one of R1, R2, R3and R4indicates a possibly substituted alkyl group of the formula[where Raand Rbdenote possibly substituted alkyl, possibly substituted cycloalkyl group, possibly substituted aryl or possibly substituted heteroaryl group], and the others represent hydrogen, generally receive according to scheme VI.

Scheme VI

Examplesinclude,,,,,,,,,and

2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indoles of the present invention of formula (Ia)in which one of R1, R2, R3and R4indicates a possibly substituted alkyl group of the formula[where Raindicates a possibly substituted alkyl, possibly substituted cycloalkyl group, possibly substituted aryl or possibly substituted heteroaryl group], and the other describes the indicate hydrogen, in General receive according to scheme VII.

Scheme VII

Examplesin scheme VII include,and

2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indoles of the present invention of formula (Ia)in which one of R1, R2, R3and R4denotes hydrogen, the other denotes a possibly substituted acyl group, possibly substituted arilou group or perhaps substituted heteroaryl group and the others represent hydrogen, generally receive according to scheme VIII.

Scheme VIII

2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indoles of the present invention of formula (Ia)in which one of R1, R2, R3and R4denotes (Y1)(Y2)NC(=O)-, and the others represent hydrogen, generally receive in accordance with the scheme IX.

Scheme IX

Examples Y1)(Y2)NC(=O)- in scheme IX include,,,,,and

2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indoles of the present invention of formula (Ia)in which one of R1, R , R3and R4denotes a methyl group substituted Y7Y8N- (where Y7and Y8denote, independently of one another, hydrogen, alkyl, aryl, arylalkyl group, heteroaryl group, or heteroallyl group)and the others represent hydrogen, generally receive in accordance with the scheme X.

Scheme X

Examples are a methyl group, substituted Y7Y8N - scheme X include,,and

The compounds of this invention can also be prepared by vzaimoprevrascheny other compounds of this invention.

For example, the compounds of formula (I)containing carboxypropyl, can be prepared by hydrolysis of the corresponding esters. The hydrolysis can be easily carried out by alkaline hydrolysis using a base such as an alkali metal hydroxide such as lithium hydroxide, or carbonate of an alkali metal, for example potassium carbonate, in the presence of water-organic solvent mixture, using organic solvents, such as dioxane, tetrahydrofuran or methanol, at temperatures from room temperature up to the boiling point. Hydrolysis of the ester can also be carried out by acid hydrolysis and the use of inorganic acids, such as hydrochloric acid, in the presence of a mixture of water and inert organic solvents, with the use of such organic solvents, such as dioxane or tetrahydrofuran, at temperatures from 50°C to 80°C.

As another example, the compounds of formula (I)containing carboxypropyl, can be prepared by acid catalyzed cleavage of tert-butilkoi group corresponding tert-butyl esters using standard reaction conditions, for example reaction with triperoxonane acid at room temperature.

As another example, compounds of formula (I)containing carboxypropyl, can be prepared by hydrogenation of the corresponding benzyl esters. The reaction may be conducted in the presence of ammonium formate and a suitable metal catalyst, for example palladium deposited on an inert carrier such as carbon, preferably in such a solution as methanol or ethanol, and at a temperature of about the boiling point. The reaction can also be carried out in the presence of a suitable metal catalyst, such as platinum or palladium, possibly deposited on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.

As another example of the interconversion process connection Faure the uly (I), containing the Y1Y2N-C(=O)- group, can be prepared by reaction of compounds of formula (I)containing carboxypropyl, with an amine of the formula Y1Y2NH with the formation of the amide bond using standard methods of binding peptides. Examples include (i) binding in the presence of O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium of hexaflurophosphate and triethylamine (or diisopropylethylamine) in tetrahydrofuran (or dimethylformamide) at room temperature, (ii) binding in the presence of a carbodiimide, such as dicyclohexylcarbodiimide in the presence of triethylamine, (iii) reaction with 1-hydroxybenzotriazole and a carbodiimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in an inert solvent, such as dimethylformamide, and at room temperature. So, for example, 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid (example 37) can react with 1-(4-forefeel)piperazine in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole, with the formation of [4-(4-forfinal)-piperazine-1-yl]-[3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-yl]metano (example 38).

Except for specially marked cases, the following conditions apply to the procedures used in the examples below.

Chiral separation are carried out on the Olonka ChiralPak AD 20 μm (250×20 mm EXT. dia.) using isocratic elution conditions and 80:20:0.1 mixture of heptane/ethanol/diethylamine, the total analysis time is 30 minutes with a speed of elution of 1.0 ml/min, and detection at 254 nm.

Chiral separation and fractional analysis is performed using column ChiralPak AD 10 μm (250×4.6 mm EXT. dia.), using isocratic elution conditions and 70:30:0.2 of a mixture of heptane/ethanol/dimethylamine, the total analysis time is 30 minutes with a speed of elution of 1.0 ml/min, and detection at 254 nm.

LC/MS analyses are performed using the following method: Agilent 1100 Series HPLC with YMC CombiScreen Pro C18 5,5 μm 4.6 mm 33 mm column (reversed phase, using gradient elution and a mixture of (A) acetonitrile/0.1% of triperoxonane acid and (B) water/0.1% of triperoxonane acid (5%A:95%B to 95%A:5%B over 5.1 minutes) at a speed of elution of 1.2 ml/min; tablet device Agilent 1100 Series automatic input samples input equal to 2 μl; detector diode line Agilent 1100 Series with detection wave length at 215, 254 and 320 nm; Hewlett Packard 1100 Series mass spectrometer with elektrorazpredelenie and positive ionization.

The spectra of nuclear magnetic resonance (NMR) 1H were recorded on a spectrometer (300 MHz Varian Mercury. In the spectra of nuclear magnetic resonance (NMR) chemical shifts (δ) expressed the tsya in ppm relative to tetramethylsilane. Abbreviations indicate the following: s=singlet, d=doublet, t=triplet, m=multiplet,=Quartet, DD=doublet of doublets, DDD=doublet of double doublets.

Determination of the melting point was carried out on the device Buchi 535, and the obtained values are given in degrees Celsius.

Determine Rf performed with the use of ready-made TLC plates with silica gel 60 F254.

Example 1

2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-benzimidazole

Example 1A

Oxalyl chloride (0,601 ml of 6.99 mmol, 1.2 EQ.) add to a mixture of 3-bromothiophene-2-carboxylic acid (1.20 g, 5,80 mmol), N,N-dimethylformamide (few drops, catalytic amount) and anhydrous dichloromethane (25 ml) at room temperature under nitrogen atmosphere for 20 minutes. The reaction mixture is stirred for 17 hours, rinsed with nitrogen and concentrated under reduced pressure to obtain a solid yellow-brown substance. Crude 3-bromothiophene-2-carbonylchloride dissolved in dichloromethane (25 ml) and added dropwise over 10 minutes a solution of N,O-dimethylhydroxylamine at 0°C (843 mg, 8,64 mmol), diisopropylethylamine (2,50 ml of 14.3 mmol) and dichloromethane (25 ml). Over night the reaction mixture was gradually heated to room temperature. The mixture is washed with water, dried in the presence of magnesium sulfate and concentrate when s is low pressure. The crude product is purified by chromatography on silica, elwira 1:1 mixture of ethyl acetate/heptane, with the formation of methoxyethylamine 3-bromo-thiophene-2-carboxylic acid, in the form of a white solid: TLC Rf of 0.33 (silica, 1:1 ethyl acetate/heptane); LC/MS: (M+H 249,94, RT=2,18 min);1H NMR [(CD3)2SO), 300 MHz]: δ a 7.85 (d, 1H, J=5.3 Hz), 7,17 (d, 1H, 5.3 Hz), 3,62 (s, 3H), 3,24 (s, 3H).

Example 1B

A mixture of benzimidazole (10.0 g, and 84.6 mmol), benzylchloride ester simple (to 5.9 ml, 42 mmol) and acetonitrile is heated under reflux for 6 hours. The solvent is removed under reduced pressure, the resulting suspension is mixed with dichloromethane and washed with water. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The crude product chromatographic on silica, elwira 9:1 mixture of ethyl acetate/dichloromethane, with the formation of an orange solid. The product is secondary chromatographic on silica, elwira 8:2 mixture of ethyl acetate/dichloromethane, to obtain an orange solid. When crushed powder with ether to obtain 1-benzoyloxymethyl-1H-benzimidazole in the form of a beige solid.

Example 1C

In a solution of 1-benzoyloxymethyl-1H-benzimidazole (648 mg, of 2.72 mmol, example 1B) in tetrahydrofuran (15 ml) at -78o C in nitrogen atmosphere with stirring n-utility (1,30 ml of 2.5 M solution in hexane, 3.25 mmol) over 5 minutes and the resulting yellow solution was stirred at -78oC. After 25 minutes, add a solution of methoxyethylamine 3-bromo-thiophene-2 carboxylic acid (680 mg, of 2.72 mmol, example 1A) in tetrahydrofuran (10 ml) for 15 minutes and the reaction mixture stirred at -78oC. After 1 hour the reaction mixture is heated to room temperature and stirred for another 2 hours. The reaction is quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed in turn with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a yellow oily liquid. The crude product chromatographic on silica, elwira 40%mixture of ethyl acetate and heptane to obtain the product. Rubbing with ether/heptane gives (1-benzoyloxymethyl-1H-benzimidazole-2-yl)-(3-bromothiophene-2-yl)methanon in the form of a whitish powder; TLC Rf value of 0.52 (silica, 1:1 mixture of ethyl acetate/heptane); LC/MS: (M+H 427,0, RT=3,84 min);1H NMR [(CD3)2SO), 300 MHz]: δ 8,18 (d, 1H, 5,2 Hz), of 7.90-of 7.82 (m, 2H), 7,55 is 7.50 (m, 1H), 7,45-7,38 (m, 2H), 7,25-7,17 (m, 5H), 6,13 (s, 2H), 4,58 (s, 2H).

Example 1D

A mixture of (1-benzoyloxymethyl-1H-benzimidazole-2-yl)-(3-bromothiophene-2-yl)methanone (500 mg, 1.06 mmol, example 1C), the Hydra is she benzophenone (276 mg, of 1.41 mmol), palladium (II) acetate (13,4 mg, 0.06 mmol), 1,1'-bis(diphenylphosphino)ferrocene (of 57.5 mg, 0.104 g), cesium carbonate (570 mg, about 1.75 mmol) and toluene (10 ml) under nitrogen atmosphere was stirred at 90oC for 15 hours. The dark reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered and undissolved particles washed with ethyl acetate. The combined filtrates and washings are washed in turn with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to condition yellow oily liquid. The crude product chromatografic on the elute silica and 80% with a mixture of dichloromethane/heptane, to obtain [3-(N'-benzhydrylidene-hydrazino)-thiophene-2-yl]-(1-benzyloxyethyl-1H-benzoimidazol-2-yl)methanon in the form of a yellow-orange powder: TLC Rf of 0.30 (silica, 80% dichloromethane/heptane); LC/MS: (M+H 543,1, RT=4,68 min);1H NMR [(CD3)2SO), 300 MHz]: δ 11,64 (s, 1H), 8,08 (d, 1H, 5.5 Hz), 7,84-7,13 (m, 20 H)to 6.00 (s, 2H), 4,46 (s, 2H).

A mixture of [3-(N'-benzhydrylpiperazine)thiophene-2-yl]-(1-benzyloxyethyl-1H-benzoimidazol-2-yl)methanone (300 mg, 0,553 mmol, example 1D), conc. hydrochloric acid (4 ml) and ethanol (12 ml) is heated at 75oC for 260 minutes. The reaction mixture is cooled to room temperature, diluted with water (40 ml) and alkalinized by addition of 5%of the CSOs aqueous solution of calcium carbonate. The mixture is extracted with ethyl acetate and the combined filtrates and washings are washed in turn with water and brine. The organic layer is dried over potassium carbonate and concentrated under reduced pressure before formation of a brown solid substance. Solid chromatographic on the silica. Step gradient elution with 70%ethyl acetate/heptane, 80%ethyl acetate/heptane and 90%ethyl acetate/heptane gives an orange solid. Rubbing with ethyl acetate/heptane gives 2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-benzoimidazol in the form of a beige powder: TLC Rf 0.28 in (silica, 75% ethyl acetate/heptane); LC/MS: (M+H 241,0, RT=2,15 min);1H NMR [(CD3)2SO), 300 MHz]: δ 13.56MHz (s, 1H), 12,94 (2, 1H), 7,78 (d, 1H, 5.3 Hz), 7,69 (d, 1H, 7,3 Hz), of 7.48 (d, 1H, 7.0 Hz), 7,22-to 7.15 (m, 3H).

Example 2

6-Methoxy-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-benzoimidazol

Example 2A

To a solution of 5-methoxybenzimidazole (6,18 g, and 41.7 mmol) in dimethylformamide (60 ml) in an atmosphere of nitrogen was added sodium hydride (1.84 g of 60% dispersion in oil, to 46.0 mmol) in two portions and the reaction mixture was stirred at room temperature. After 0.5 hours add solution benzylchloride ether (7,83 g, 50 mmol) in dimethylformamide (40 ml) dropwise over 15 minutes and the reaction mixture was stirred over night at room temperature. Re Klenow mixture was poured into water (500 ml) and extracted three times with ethyl acetate (150 ml). The combined extracts are washed successively with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a yellow oily liquid. Oily liquid chromatographic on the silica. Step gradient elution with ethyl acetate, 5%methanol in ethyl acetate and 10%methanol in ethyl acetate gives to 3.02 g (27%) 1-benzoyloxymethyl-6-methoxy-1H-benzoimidazole in the form of a waxy solid: TLC Rf 0,23 main (silica, ethyl acetate); LC/MS: (M+H 269,1, RT=2,49 min) and a 3.83 g (34%) 1-benzoyloxymethyl-5-methoxy-1H-benzoimidazole in the form of an oily liquid: TLC Rf of 0.15 main (silica, ethyl acetate); LC/MS: (M+H 269,1 RT=2,34 min).

Example 2B

With stirring to a solution of 1-benzoyloxymethyl-6-methoxy-1H-benzoimidazole (1,00 g, 3.72 mmol, example 2A) in anhydrous tetrahydrofuran (15 ml) at -78oC in an atmosphere of nitrogen was added n-utility (1,80 ml of 2.5 M solution in hexane, 4.5 mmol) in 8 minutes and the resulting yellow solution was stirred at -78oC. After 25 minutes, a solution of methoxyethylamine 3-bromothiophene-2-carboxylic acid (1,03 g of 4.12 mmol) in tetrahydrofuran (10 ml) added dropwise within 20 minutes to the reaction mixture at

-78oC. the Reaction mixture was gradually heated to room temperature during the night is. The reaction mixture was poured into 10%aqueous solution of ammonium chloride (75 ml) and the mixture is extracted twice with ethyl acetate (50 ml). The organic layer is successively washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a yellow oily liquid. The crude product chromatografic on the elute silica and 30%ethyl acetate/heptane and then 40%ethyl acetate/heptane, to obtain a waxy substance. Rubbing with 25%ethyl acetate/heptane gives 546 mg (32%) (1-benzoyloxymethyl-6-methoxy-1H-benzoimidazol-2-yl)-(3-bromothiophene-2-yl)methanone powder: TLC Rf of 0.43 (silica, 40% ethyl acetate/heptane); LC/MS: (M+H 457, RT=3.85 minutes);1H NMR [(CD3)2SO), 300 MHz]: δ 8,14 (d, 5.2 Hz, 1H), 7,76 (d, 9.0 Hz, 1H), was 7.36 (d, 5.0 Hz, 1H), 7,29-7,20 (m, 6H),? 7.04 baby mortality (DD, 2.5 and 9.0 Hz, 1H), 6,13 (s, 2H), 4,59 (s, 2H), a 3.87 (s, 3H).

Example 2C

A mixture of (1-benzoyloxymethyl-6-methoxy-1H-benzoimidazol-2-yl)-(3-bromothiophene-2-yl)methanone (680 mg, 1,49 mmol, example 2B), benzophenone hydrazone (408 mg, of 2.08 mmol), palladium (II) acetate (17,0 mg, 0.05 mmol), 1,1'-bis(diphenylphosphino)-ferrocene (82,0 mg, 0,148 mmol), cesium carbonate (775 mg, of 2.38 mmol) and toluene (15 ml) under nitrogen atmosphere was stirred at 90oC for 20 hours. The dark reaction mixture was cooled to room temperature, diluted with ethyl acetate (25 ml), filter the comfort and undissolved particles washed with ethyl acetate (25 ml). The filtrate is successively washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a black viscous substance. The crude product chromatographic on silica, elute with dichloromethane, giving 605 mg (70%) [3-(N'-benzhydrylpiperazine)-thiophene-2-yl]-(1-benzoyloxymethyl-6-methoxy-1H-benzoimidazol-2-yl)methanon as fragile red foam: TLC Rf of 0.27 (silica, dichloromethane); LC/MS: M+H 573,2, RT=4,62 minutes.

A mixture of [3-(N'-benzhydrylpiperazine)-thiophene-2-yl]-(1-benzoyloxymethyl-6-methoxy-1H-benzoimidazol-2-yl)methanone (300 mg, 0,553 mmol, example 2C), conc. hydrochloric acid (4 ml) and ethanol (12 ml) is heated at 75oC under stirring for 260 minutes. The reaction mixture is cooled to room temperature, diluted with water (40 ml) and alkalinized by addition of 5%aqueous potassium carbonate solution. The mixture is extracted with ethyl acetate and the combined extracts washed sequentially with water and brine. The organic layer is dried in the presence of potassium carbonate and concentrated under reduced pressure, resulting in a get a brown solid. Powder chromatographic on the silica. Step gradient elution with 70%ethyl acetate in heptane, 80%ethyl acetate in heptane and 90%ethylacetate heptane gives an orange solid. Rubbing with ethyl acetate in heptane gives 6-methoxy-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-benzoimidazol in the form of a beige powder: TLC Rf 0.28 in (silica, 75% ethyl acetate in heptane); LC/MS: M+H 241,0, RT=2,15 min;1H NMR [(CD3)2SO), 300 MHz]: there are two substances (60:40), presumably slowly exchanging the imidazole tautomers with the chemical shifts of allowed lines: main (additional); δ 13,48 (13,51) wide. (1H; NH benzimidazole), 12,79 Shire. (1H; NH of pyrazole), to 7.77 (1H, J=5 Hz; H-α thiophene), EUR 7.57 (7,35) d (1H, J=8,5 Hz; H-7 benzimidazole), 7,20 d (1H, J=5 Hz; H-β thiophene), of 6.96 (7,25) d (1H, J=2 Hz; H-4 of benzimidazole), 6,82 m (1H; H-6 benzimidazole), 3,80 (3,32) with (3H; methoxy). Chemical shifts are determined relative to the internal standard, DMSO-D5(δ 2,50).

Example 3

3-(6-Methoxy-1H-benzimidazole-2-yl)-1H-benzo[4,5]thieno[3,2-c]pyrazole

This compound (LC/MS: M+H 321,07, RT=2,47 min) obtained using methods similar to those described in example 2, using methoxyethylamine 3-bromo-benzothiophen-2-carboxylic acid

instead of methoxyethylamine 3-bromo-thiophene-2-carboxylic acid in stage combinations in example 2B.

Example 4

6-(3-piperidine-1-ylpropionic)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-benzimidazole

This compound (LC/MS: M+H 382,1, RT=2,0 min) obtained using methods similar to that described in example 2, using 6-(3-piperidine-1-ylpropionic)-1H-benzimidazole

instead of 5-methoxybenzimidazole in example 2A.

Example 5

5-(3-piperidine-1-ylpropionic)-2-(1H-thieno[3,2-c]pyrazole-3-yl)indole

Stage 1. Example 5A

To a solution of 1H-thieno[3,2-c]pyrazole (160 mg, 1,29 mmol) and iodine (490 mg, 1.94 mmol) in dimethylformamide (5 ml) add potassium hydroxide (220 mg, a 3.87 mmol). The mixture is stirred at room temperature for 30 minutes. Then add a solution of sodium bisulfite (200 mg) in water (2 ml). The mixture is twice extracted with diethyl ether. The combined organic layers are dried over magnesium sulfate and concentrated. The remainder chromatographic (n-heptane-ethyl acetate, 90:100)to obtain 195 mg (60%) 3-iodo-1H-thieno[3,2-c]pyrazole in the form of a beige powder. LC/MS: RT= 2,50 min, 250,90 m/e (M+1).

Stage 2. Example 5B

To a suspension of 3-iodine-1H-thieno[3,2-c]pyrazole (195 mg, 0.78 mmol, example 5A) in dichloromethane (5 ml), add triethylamine (110 ml, 0.86 mmol) and then added di-tert-BUTYLCARBAMATE (205 mg, of 0.94 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol). The solution was stirred at room temperature for 30 minutes. Then it is diluted with dichloromethane and successively washed with water and brine. The organic layer is dried over sulfate MAGN which I concentrate. The remainder chromatographic on silica gel (n-heptane-ethyl acetate, 90:10 as eluent)to obtain 220 mg (81%) of tert-butyl methyl ether 3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid as a yellow powder. LC/MS: RT=3,45 min, 372,94 m/e (M+Na).

Stage 3. Example 5C

To a solution of tert-butyl methyl ether 3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid (200 mg, or 0.57 mmol, example 5B) and bis-(diphenylphosphinomethyl)dichloropalladium (complex with dichloromethane 1:1, 21 mg, 0.03 mmol) in 1,4-dioxane (5 ml) is added 5-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (335 mg, 0.86 mmol), prepared as described in examples 4-6 from the publication of international patent application no WO 02/32861, then add a solution of cesium carbonate (741 mg, 2.28 mmol) in water (2 ml). The mixture was stirred under reflux for 15 minutes. Then it is diluted with ethyl acetate and washed with water and brine. The organic layer is dried over magnesium sulfate and concentrated. The remainder chromatographic on silica gel (n-heptane-ethyl acetate, 95:05 as eluent)to obtain 200 mg (61%) of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid as a white foam. LC/MS: RT=4,29 min, 570,1 m/E.

Stage 4. Example 5D

To restorated-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid (320 mg, 0,56 mmol, Example 5C) in tetrahydrofuran (5 ml) at 0°C add tetrabutylammonium fluoride (a 1.0 M in tetrahydrofuran, of 0.67 ml, 0.67 mmol). The solution was stirred at 0°C for 30 minutes. Then remove the solvent and the residue chromatographic on silica gel (dichloromethane-ethyl acetate, 95:05 90:10 as eluent)to obtain 205 mg (80%) of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-hydroxyindole-1-carboxylic acid as an orange foam. LC/MS: RT=3,74 min, 456,0 m/E.

Stage 5. Example 5E

To a solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-hydroxyindole-1-carboxylic acid (195 mg, 0.43 mmol, example 5D) 1.3-dibromopropane (2 ml) is added cesium carbonate (350 mg, at 1.08 mmol). The resulting suspension is heated to 100°C for 30 minutes. Then it is filtered and concentrated. The remainder chromatographic on silica gel (ethyl acetate-n-heptane, from 05:95 to 20:80 as eluent)to obtain 103 mg (42%) of tert-butyl ester 5-(3-bromopropane)-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid as a yellow glassy mass. LC/MS: RT=to 4.38 minutes, 576,11 m/E.

Stage 6. 5-(3-piperidine-1-ylpropionic)-2-(1H-thieno[3,2-c]pyrazole-3-yl)indole

To a solution of tert-butyl ester 5-(3-bromopropane)-2-(1-tert-BU is oxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid (100 mg, 0,17 mmol, example 5E) in acetonitrile (4 ml) is added piperidine (33 μl, 0.34 mmol) and DIEA on the polymer (diisopropylethylamine, 3,86 mmol/g, 45 mg, 0.34 mmol). The mixture is heated to 70°C for 2 hours. DIA on the polymer is passed through a filter, and the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane (DHM) (1 ml). Added anisole (0.4 ml), then add triperoxonane acid (TFU) (0.5 ml). The bright orange solution was stirred at 50°C for 1 hour and then transferred directly into ionoobmennye cartridge (VARIAN mega bond elut SCX, 5 g), washed with methanol and elute 1.0 M ammonia in methanol. The desired fractions are collected and concentrated. The remainder chromatographic (n-heptane-ethyl acetate, 95:05 90:10 as eluent)to obtain 44 mg of the crude product. Rubbing beige mass in dichloromethane gives 5-(3-piperidine-1-ylpropionic)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-indole [12 mg, 18%, example 5] in the form of a white powder. LC/MS: RT=min 2,20, 381,18 m/E.1H NMR [(CD3)2SO), 300 MHz]: δ 13,25 (wide s, 1H) and is 11.39 (wide s, 1H) [NH protons of the indole and pyrazole], 7,74 (d, J=5 Hz, 1H) and 7,19 (d, J=5 Hz, 1H) [protons of thiophene], 7,29 (width d, J=8.5 Hz, 1H) [H-7 indol], 7,07 (d, J=2 Hz, 1H) [H-4 indol], 6,74 (DD, J=8,5, 2 Hz, 1H) [H-6 indol], 6,56 (width d, J=1.5 Hz, 1H) [H-3 of the indole], of 3.96 (t, J=6 Hz, 2H) [-OCH2-], of 2.50 (m, 6H), 1.91 a (m, 2H), 1,53 (m, 4H), of 1.40 (m, 3H).

The following examples 6-22 prepared in accordance with the methods of the AMI, similar to the one described in the previous examples.

Example 6

1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}piperidine-4-ol

LC/MS: RT=2,17 min, observed M+H=397,18

Example 7

6-(3-piperidine-1-ylpropionic)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole

LC/MS: RT=2,35 min, observed M+H=381,18

Example 8

1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}piperidine-3-ol

LC/MS: RT=2,45 min, observed M+H=397,4

Example 9

(1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}piperidine-3-yl)methanol

LC/MS: RT=2,49 min, observed M+H=411,2

Example 10

6-[3-(4-Ethylpiperazin-1-yl)-propoxy]-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole

LC/MS: RT=2,27 min, observed M+H=410,4

Example 11

Dimethyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}amine

LC/MS: RT=2,23 min, observed M+H=341,16

Example 12

Diethyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}amine

LC/MS: RT=2,35 min, observed M+H=369,19

Example 13

Diallyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}amine

LC/MS: RT=2,48 min, observed M+H393,14

Example 14

1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}pyrrolidin-3-ol

LC/MS: RT=2,2 min, observed M+H=383,17

Example 15

2-(Methyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}amino)-ethanol

LC/MS: RT=2.13 minutes, observed M+H=371,25

Example 16

1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yloxy]propyl}piperidine-4-ol

LC/MS: RT=2,03 min, observed M+H=397,17

Example 17

1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yloxy]propyl}piperidine-3-ol

LC/MS: RT=1,87 min, observed M+H=397,2

Example 18

(1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yloxy]propyl}piperidine-3-yl)methanol

LC/MS: RT=2,07 min, observed M+H=411,18

Example 19

1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yloxy]propyl}pyrrolidin-3-ol

LC/MS: RT=2,48 min, observed M+H=383,2

Example 20

3-(5-(3-piperidine-1-ylpropionic)-1H-benzoimidazol-2-yl)-1H-benzo[4,5]thieno[3,2-c]pyrazole hydrochloride

LC/MS: RT=2,49 min, observed M+H=432,18

Example 21

(2-Thiophene-2-retil)amide 2-{1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-5-carboxylic acid

LC/MS: RT=3,22 min, abodeely M+H=393,2

Example 22

1-{3-[2-(5-Dimethylaminoethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]propyl}piperidine-4-ol

LC/MS: RT=1,87 min, observed M+H=454

Example 23

[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]methanol

Stage 1. A mixture of tert-butyl ester 5-(tert-butyldimethylsilyloxy)-1H-indole-2-boronic 1-carboxylic acid [3,82 g, 9,42 mmol, intermediate compound (8), prepared as described in example 1-4 publication of international patent application no WO 02/32861], tert-butyl ester 3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid [4.0 g, 11,42 mmol, example 5B above], tetrakis(triphenylphosphine)palladium (0) (544 mg, 0,470 mmol), potassium carbonate (2 M aqueous solution, 12 ml) in tetrahydrofuran (60 ml) is purged with N2within 10 minutes, and then heated to 55-60°C for 7.5 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (20 ml). The aqueous layer was subjected to back extraction with ethyl acetate (50 ml). United an ethyl acetate phase is dried over sodium sulfate. The remainder chromatographic 35 g column of silica gel (5 to 30% gradient of ethyl acetate in heptane)to obtain tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [3.8 g, 69%, intermediate compound (9)];1H NMR[(D 3)2SO)]: δ 8,08 (2H, m), of 7.64 (1H, s), 7,38 (2H, m), 7,14 (1H, s), to 4.81 (2H, s, -OCH2), of 1.65 (9H, s)of 1.32 (9H, s)to 0.92 (9H, s, Si(CH3)3), of 0.10 (6H, s, Si(CH2)); LC/MS: 584 (M+H).

Stage 2. A solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [3.8 g, 6,51 mmol, intermediate compound (9)]) in anhydrous tetrahydrofuran (40 ml) cooled to 0°C. To the solution is added dropwise tetrabutylammonium fluoride (1 M in tetrahydrofuran, 10 ml). Stirred at 0°C for 20 minutes and then at room temperature for 20 minutes. Add water (20 ml) and the solution extracted three times with ethyl acetate (30 ml). United an ethyl acetate phases are washed with brine and dried over sodium sulfate. The remainder chromatographic 35 g column of silica gel (10-50% ethyl acetate in heptane) and receive tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-hydroxymethylene-1-carboxylic acid. [2,63 g, 85%, intermediate compound (10)] in the form of a white solid;1H NMR [(CD3)2SO)]: δ with 8.05 (2H, m), a 7.62 (1H, s), 7,38 (2H, m), 7,02 (1H, s), a total of 5.21 (1H, t), and 4.6 (2H, d), of 1.64 (9H, s), 1,25 (9H, s); LC/MS: 470 (M+H).

Stage 3. To a solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-hydroxymethylene-1-carboxylic acid [200 mg, 0,426 mmol, intermediate compounds is s (10)] in tetrahydrofuran (5 ml) is added KOH (1M aqueous solution, 2.5 ml) and heated to 60°C for 20 hours. Then remove the solvent and the residue is dissolved in water. The water layer is neutralized 3N hydrochloric acid and extracted twice with ethyl acetate (20 ml). United an ethyl acetate phase is washed twice with saline and dried over sodium sulfate. Purification by chromatography using a 10 g column of silica gel (50% ethyl acetate in heptane, then ethyl acetate) to give 2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-methanol (84 mg, 74%, example 23) in the form of light yellow solids;1H NMR [(CD3)2SO)]: δ 13,22 (1H, s)11,43 (1H, s), to 7.77 (1H), 7,56 (1H), 7,38 (1H), 7,20 (1H),? 7.04 baby mortality (1H), is 6.61 (1H), 5,02 (1H, OH), of 4.57 (2H, -CH2OH); LC/MS: 270 (M + H).

Example 24

Phenyl-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]methanol

Stage 1. To a solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-hydroxymethylene-1-carboxylic acid [373 mg, 0,794 mmol, intermediate compound (10)] in dichloromethane (20 ml) add reagent dess-Martin (407 mg, 0,959 mmol). Stirred at room temperature for 30 minutes. Then add water (10 ml) and stirred for 30 minutes at room temperature. The reaction mixture was diluted with ethyl acetate (30 ml) and washed twice with a mixture of 10% Na2S2O3/saturated NaHCO3(4 ml) solution. An ethyl acetate phase is washed with water, NaHCO3 , brine and dried over sodium sulfate. The remainder chromatographic on a 10 g column of silica gel, elwira 30-40% of an ethyl acetate gradient) to obtain tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-formylindole-1-carboxylic acid [300 mg, 81%, intermediate compound (11)] in the form of a white solid.1H NMR [(CD3)2SO)]: δ 10,079 there (1H, s, CHO), 8,323 (1H, s)8,318 (1H, d), 8,017 (1H, s)7,978 (1H, d), 7,391 (1H, d), 7,345 (1H, s), 1,660 (9H, s), 1,341 (9H, s); data TLC: Rf=0,37 (30% ethyl acetate in heptane).

Stage 2. To a solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-formylindole-1-carboxylic acid [100 mg, 0,214 mmol, intermediate compound (11)] in anhydrous tetrahydrofuran (5 ml) add phenylmagnesium (1 M in tetrahydrofuran, 1 ml) at -78°C. the Reaction mixture was stirred at the same temperature for 1 hour and then quenched by addition of water at 0°C (4 ml). The reaction mixture is extracted three times with ethyl acetate (30 ml). United an ethyl acetate phases are washed with saline, dried over sodium sulfate and filtered. Evaporation of the solvent in vacuo gives tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(hydroxyphenylethyl)-indole-1-carboxylic acid [99 mg, 85%, intermediate compound (12)] as a white foam; LC/MS: (M+H, 546).

Stage 3. A mixture of tert-butyl methyl ether 2-(1-TPE is-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(hydroxyphenylethyl)-indole-1-carboxylic acid [99 mg, 0,181 mmol, intermediate compound (12)] in tetrahydrofuran (2 ml) and KOH (1M aqueous solution, 1 ml) was stirred at 60°C in nitrogen atmosphere for 2 hours. The solvent is removed under vacuum. To the resulting suspension add water (2 ml) and adjusted pH to 6 by the addition of 2N hydrochloric acid. The product is extracted three times with dichloromethane (20 ml) and the combined extracts washed with brine and dried over sodium sulfate. The remainder chromatographic on a 10 g column of silica gel, elwira 50-100% gradient of ethyl acetate in heptane, to obtain phenyl-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]methanol [56 mg, 89%, example 24] in the form of a whitish solid; LC/MS: 346 (M+H), 328(M-18)+H]; data TLC: Rf=0,14 (50% ethyl acetate in heptane).

Example 25

Phenyl-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]metano

Stage 1. To a solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(hydroxyphenylethyl)-indole-1-carboxylic acid [640 mg, 1,17 mmol, intermediate compound (12)] in dichloromethane (25 ml) add reagent dess-Martin (677 mg, was 1.69 mmol) and stirred at room temperature. After 30 minutes, add water (5 ml) and stirred for 10 minutes. The reaction mixture was diluted with dichloromethane (50 ml) and washed twice with a mixture of 10% Na2S2O3/saturated NaHCO3(5 ml), NaHCO3(10 ml), in the s (10 ml), brine and dried over sodium sulfate. The remainder chromatographic 35 g column of silica gel, elwira with 30% ethyl acetate in heptane, to obtain tert-butyl ester 5-benzoyl-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid [440 mg, 69%, intermediate compound (13)] in the form of a white solid, LC/MS: 544 (M+H).

Stage 2. A mixture of tert-butyl ester 5-benzoyl-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid [122 mg, 0,224 mmol, intermediate compound (13)] in tetrahydrofuran (9 ml) and 1M KOH (aqueous solution, 2 ml) heated to 60oC in an oil bath overnight. Remove the solvent and water is added (5 ml). The water layer is neutralized 3N hydrochloric acid and extracted three times with ethyl acetate (20 ml). United an ethyl acetate phases are washed with brine and dried over sodium sulfate. The remainder chromatographic on a 10 g column of silica gel, elwira 50-100% of an ethyl acetate gradient in heptane, to obtain phenyl-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]metano (58 mg, 75%, example 25) in the form of a pale yellow solid.1H NMR [(CD3)2SO)]: δ 13,38 (1H, s), 12,09 (1H, s), with 8.05 (1H), 7,78 (8H, m), 7.23 percent (1H, d, J=5,2 Hz), 6.87 in (1H); LC/MS: 344 (M+H).

Example 26

1-Phenyl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]ethanol

To a solution of tert-butyl ester 5-benzo is Il-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid [intermediate compound (13)] in anhydrous tetrahydrofuran (5 ml) add methylanisole (1M in tetrahydrofuran, 0.8 ml) at -78°C. Stirred in nitrogen atmosphere for 30 minutes. Add to 0.88 ml methylacrylamide and leave to gradually warm to room temperature. The next morning the solution add a mixture of water and saturated ammonium chloride (2 ml) at 0°C and twice extracted with a mixture of ethyl acetate (25 ml). The combined ethyl acetate phase was washed with brine and dried over sodium sulfate. The remainder chromatographic on 10 g of silica gel, elwira 30-50% gradient of ethyl acetate in heptane, to obtain 1-phenyl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]ethanol (56 mg, 71%, example 26) in the form of a beige solid; LC/MS: 360 (M+H);1H NMR [(CD3)2SO)]: δ 13,20 (1H, s), of 11.45 (1H, s), 7,73 (1H, d), a 7.62 (1H, s), the 7.43 (2H, m), 7,25 (6H, m), 6,59 (1H, s), of 5.53 (1H, s)to 1.86 (3H, s).

Example 27

(S)-1-Phenyl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]ethanol

Racemic 1-phenyl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]ethanol (45 mg, example 26) is cleared chiral HPLC (column: chiralcel EXT. dia. 4.6 mm ID × 250 mm, 10 micron. Mobile phase: 55% ethanol with 1 mmol of triptoreline ammonium and 45% heptane with 1 mmol of triptoreline ammonium) and the required fractions of eluent concentrate and sublimate, to obtain one of the enantiomers of 1-phenyl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]ethanol (11 mg) as white solid residue; retention time chiral HPLC 10,96 mi is at 215 nm.

Example 28

1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propane-1-he

Stage 1. Performing a sequence of operations similar to that described in stage 2 of example 24, but replacing phenylmagnesium ethylmagnesium receive tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(1-hydroxypropyl)-indole-1-carboxylic acid [73%, intermediate compound (14)] in the form of a white solid

Stage 2. Performing a sequence of operations similar to that described in stage 1 of example 25, but replacing tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(1-hydroxypropyl)-indole-1-carboxylic acid [intermediate compound (14)] tert-butyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(hydroxyphenylethyl)-indole-1-carboxylic acid [intermediate compound (12)], receive tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-propionamido-1-carboxylic acid [73%, intermediate compound (15)] in the form of a white solid.

Stage 3. Performing a sequence of operations similar to that described in stage 2 of example 25, but replacing tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-propionamido-1-carboxylic acid [intermediate compound (15)] tert-butyl ether 5-benzoyl-2-(1-tert-BU is oxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid [intermediate the compound (13)], get 1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-propane-1-[94%example 28]allocated in the form of a white solid residue;1H NMR [(CD3)2SO)]: δ 13,34 (1H, s), 11,98 (1H, s), 8,31 (1H, s), to 7.77 (2H, m), 7,47 (1H, d, J=8.5 Hz), 7,21 (1H, d, J=5,2 Hz), 6,79 (1H, s), of 3.07 (2H, square, -CH2CH3), of 1.13 (3H, t, -CH3); LC/MS: 296 (M + H).

Example 29

1-Cyclohexyl-1-[2-(1H-thieno [3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol

A solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)-5-propionamido-1-carboxylic acid [400 mg, 0,807 mmol, intermediate compound (15)] in anhydrous tetrahydrofuran (20 ml) cooled to -78°C in a stream of nitrogen. To it add cyclohexylmaleimide (2M in tetrahydrofuran, 1 ml). After stirring for 20 minutes the cooling bath is removed and within 20 minutes raise the reaction temperature to room. The reaction mixture is cooled to 0°C and extinguished by adding a saturated solution of ammonium chloride (6 ml)and then water (20 ml). The aqueous layer was extracted three times with ethyl acetate (40 ml). The combined extracts washed with brine and dried over sodium sulfate and fillout through a column of 5 g of silica gel and washed through the column with ethyl acetate (20 ml). The filtrate is removed in vacuo to obtain the alcohol (520 mg) as an orange foam.

Orange foam (520 mg, 0,862 mmol) dissolved tetrahydrofurane (15 ml) and treated 1M KOH (water, 15 ml), and then maintained overnight at a temperature of 70°C in an oil bath. The solvent is removed, water is added and neutralized 3N hydrochloric acid. The product is extracted three times with ethyl acetate (20 ml). The combined ethyl acetate phase was washed with brine and dried over sodium sulfate. Purification by chromatography (10 g column of silica gel, 50% ethyl acetate/heptane) to give 1-cyclohexyl-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol (150 mg, 46%, example 29) in the form of a cream powder;1H NMR [(CD3)2SO)]: δ 13,21 (1H, s), 11,41 (1H, s), of 7.75 (1H, d), 7,53 (1H), 7,29 (1H), 7,20 (1H), 7,11 (1H), 6,59 (1H), is 4.21 (1H, OH), at 1.91 (3H, Shir. m)of 1.78 (1H, Shir., d), by 1.68 (3H, Shir. t)of 1.39 (1H, Shir. d), 1,25-0,87 (5H, m)to 0.63 (3H, t); LC/MS: 380 (M+H).

Example 30

1-Cyclohexyl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol, enantiomer 1

The racemic mixture of 1-cyclohexyl-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol (145 mg, example 29) purified chiral HPLC (column: chiralcel OJ. Mobile phase: 40% heptane/60% ethanol/0,05% deja), and the desired fractions of eluent was concentrated and liofilizirovanny to obtain chiral alcohol 1-cyclohexyl-1-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol, enantiomer 1 [51 mg, 30] in the form of a white powder; chiral HPLC retention time 12,57 minutes at 215 nm;1H NMR [(CD3)2SO)]: δ 13,22 (1H, s), is 11.39 (1H, s), of 7.75 (1H, d, J=5 Hz), 7,53 (1H, s), 7,32 (1H, J=8.7 Hz), 7,20 (1H, d, J=5,2 Hz), 7,11 (1H, DD), and 6.6 (1H, C)is 4.21 (1H, s, OH), to 1.87 (3H, Shir. m)1,71 (1H, Shir. d)to 1.59 (3H, Shir. t)of 1.18 (1H, Shir. d), 1,18-0,87 (5H, m)to 0.63 (3H, t); LC/MS: 380 (M+H).

Example 31

1-Pyridin-2-yl-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol

To a solution of 2-bromopyridine (224 mg, of 1.42 mmol) in anhydrous tetrahydrofuran (2 ml) is added n-BuLi (1.6 M in hexane, 0.95 ml of 1.52 mmol) at -78°C in a stream of nitrogen. After stirring for 20 minutes, to the mixture are added dropwise a solution of 1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl)-propane-1-she (140 mg, 0,473 mmol, example 28) in anhydrous tetrahydrofuran (4 ml). After 30 minutes the cooling bath is removed and continue to stir at room temperature for 30 minutes. The reaction is stopped by adding a saturated solution of ammonium chloride (4 ml)and then water (4 ml). The reaction mixture was extracted with ethyl acetate (120 ml). An ethyl acetate phase is washed with water, brine and dried over sodium sulfate. Purification by chromatography (10 g column of silica gel, 30 to 60%gradient of ethyl acetate in heptane) to receive the final product. He was then dissolved in minimum quantity of methanol and triturated with water to obtain 1-pyridin-2-yl-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol (171 mg, 31%, example 31) in the form of a beige solid;1H NMR [(CD3)2SO)]: δ 13,195 (1H, s)11,417 (1H, s)8,472 (1H, d), 7,742-7,661 (4H, m) 7,259-7,166 (4H, m), 6,59 1H, C)5,697 (1H, s, OH), 2,361 (2H, m), 0,785 (3H, t); LC/MS: 375 (M+H).

Example 32

2-[2-(1H-Thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol

To a solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)-5-propionamido-1-carboxylic acid [450 mg, 0,908 mmol, intermediate compound (15)] in anhydrous tetrahydrofuran (25 ml), cooled to -78°C in a stream of nitrogen via syringe add methylanisole (1M in tetrahydrofuran, 3 ml). After stirring for 30 minutes the cooling bath is removed, and within 30 minutes raise the reaction temperature to room. The reaction mixture was cooled to -78°C, then add another 5 ml of methylacrylamide. After 30 minutes the cooling bath is removed and adjusting the temperature of the reaction mixture to room. After 4 hours, the mixture is quenched by adding a saturated solution of ammonium chloride (6 ml). After stirring for 10 minutes, add water (20 ml) and extracted three times with ethyl acetate (40 ml). The combined ethyl acetate phase was washed with brine and dried over sodium sulfate. Purification by chromatography (35 g column of silica gel, 1:1 ethyl acetate/heptane) gave 2-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol [148 mg, 52%, example 32] in the form of a white powder;1H NMR [(CD3)2SO)]: δ 13,204 (1H, s)11,402 (1H, s)7,743 (1H, d), 7,595 (1H, s), 7,333-7,192 (3H, m), 6,598 (1H, s)4,658 (1H, s, OH), 1,728 (2H, HF), 1,461(3H, C), 0,702 (3H, t); LC/MS: 312 (M+H).

Example 33A and the Example 33B

(R)-2-[2-(1H-Thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol and (S)-2-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol

and

Example 33AExample 33B

The racemic mixture of 2-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol [example 32] purify chiral HPLC (Column: chiralcel OJ. Mobile phase: 40% heptane/60% ethanol/0,05% deja), and the desired fractions of eluent was concentrated and liofilizirovanny to get isomers (R)-2-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol and (S)-2-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol. One isomer has a retention time of chiral HPLC to 11.52 minutes at 254 nm;1H NMR [(CD3)2SO)]: δ 13,21 (1H, s), 11,40 (1H, s), 7,73 (1H, d, J=5,2 Hz), 7,58 (1H, s), 7,32 (1H, d, J=8.5 Hz), 7,18 (2H, m), 6,59 (1H, s)and 4.65 (1H, s)of 1.73 (2H, HF), the 1.44 (3H, s)to 0.70 (3H, t); LC/MS 312 (M+H)], and the other isomer has a retention time of chiral HPLC 14,35 minutes at 254 nm;1H NMR [(CD3)2SO)]: ∆ 13,23 (1H, s), 11,41 (1H, s), of 7.75 (1H, d, J=5,2 Hz), 7,60 (1H, s), 7,34 (1H, d, J=8.5 Hz), 7,20 (2H, m), is 6.61 (1H, s), of 4.67 (1H, s), 1.77 in (2H, kV)of 1.46 (3H, s)to 0.72 (3H, t); LC/MS 312 (M+H)].

Example 34

1-(2-Pyrrolidin-1-ylmethylene)-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol

To a cooled (-40°C) R is the target 1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propane-1-she (110 mg, 0,372 mmol, example 28) in anhydrous tetrahydrofuran (2 ml) is added (2-(1-pyrrolidinyl)phenyl)minibrain (0.25 M in tetrahydrofuran) in a stream of nitrogen. After 1 hour, the cooling bath is removed and the temperature of the reaction mixture is brought to room temperature. After a night of maturation, the solution is quenched by adding a saturated solution of ammonium chloride (2 ml). The precipitate is dissolved with water and extracted three times with ethyl acetate (2 ml). The combined extracts washed with brine and dried over sodium sulfate. Purification by chromatography (10 column of silica gel, 1:1 ethyl acetate/heptane) gave 1-(2-pyrrolidin-1-ylmethylene)-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol (50 mg, example 34) in the form of a white solid;1H NMR [(CD3)2SO)]: δ 13,22 (1H, s), of $ 11.48 (1H, s), 8,73 (1H, s), 7,74 (2H, m), 7,45 (1H, s), 7,41 (1H, t), 7,39-of 7.25 (4H, m), 6,93 (1H, d), 6,59 (1H, s), 2,68 (1H, d), a 2.45 (2H, in), 2.25 (4H), 2,08 (1H), 1,74 (4H, m), 0.75 in (3H, t); LC/MS: 457 (M+H).

Example 35

1-Tert-butyl-5-methyl ether 3-(5-acetyl-1-tert-butoxycarbonyl-1H-indol-2-yl)thieno[3,2-C]pyrazole-1,5-

dicarboxylic acids

Stage 1. To a solution of indole-5-carboxylic acid [10 g, 62,05 mmol, intermediate compound (16)] in anhydrous tetrahydrofuran (1000 ml) added dropwise motility (a 1.6 M in diethyl ether, 150 ml) for 60 minutes. The precipitate is stirred for 40 hours at room te is the temperature.

The reaction mixture was cooled to 0°C and quenched by careful addition of water (5 ml) to stop the boiling. The solvent is removed in vacuum and the suspension is divided between phases dichloromethane (500 ml) and water (100 ml). The dichloromethane layer was washed with 1N hydrochloric acid (20 ml), saturated NaHCO3(20 ml), brine and dried over sodium sulfate. The remainder chromatographic 110 g column of silica gel (30-50%gradient of ethyl acetate in heptane)to obtain 1-(1H-indol-5-yl)-Etalon [5.0 g, 50.6%respectively, the intermediate compound (17)] as a colorless oily liquid. When standing oily liquid hardens;1H NMR (CDCl3): δ 8,846 (1H, Shir. C)8,356 (1H, s), of 7.917 (1H, d), 7,449-7,297 (2H, m), 6,690 (1H), 2,713 (3H, s); LC/MS: 160 (M+H).

Stage 2. To a solution of 1-(1H-indol-5-yl)-ethanone [5 g, 31,41 mmol, intermediate compound (17)] and 4-(dimethylamino)pyridine (39,4 mg) in tetrahydrofuran (60 ml) was added dropwise di-tert-BUTYLCARBAMATE (1M in tetrahydrofuran, 32 ml) at 0°C for 55 minutes. Stirred for 10 minutes, then add water (30 ml) and thrice extracted the product with ethyl acetate (50 ml). The combined ethyl acetate phase was washed with brine and dried over sodium sulfate. The remainder chromatographic 110 g column of silica gel (15-20%gradient of ethyl acetate in heptane)to obtain tert-butyl ester 5-acetylindole-1-carboxylic acid [1.28 g, 81%, intermediate compound (18) in the form of a colorless oily liquid. When standing oily liquid hardens;1H NMR (CDCl3): δ 8,201 (2H), 7,966 (1H), 7,657 (1H), 6,661 (1H), 2,672 (3H), 1,701 (9H); LC/MS: 260 (M+H).

Stage 3. A mixture of tert-butyl ester 5-acetylindole-1-carboxylic acid [4,85 g, 18,70 mmol, intermediate compound (18)], ethylene glycol (5.0 g), p-toluensulfonate pyridinium (100 mg) in benzene (35 ml) is subjected to inverse distilled under N2within 24 hours trapped in a Dean-stark. To the resulting dark reaction mixture was added solid NaHCO3(2.5 g). After stirring for 15 minutes the mixture is filtered under vacuum and washed three times with ethyl acetate (30 ml). The filtrate is washed twice with water (10 ml) and dried over sodium sulfate. The crude product chromatografic on a 10 g column of silica gel (heptane, then 10% ethyl acetate in heptane)to obtain tert-butyl ester 5-(2-methyl-[1,3]dioxolane-2-yl)-indole-1-carboxylic acid [intermediate compound (19)] as a colorless oily liquid;1H NMR (CDCl3): δ 8,128 (1H, d), 7,706 (1H, s)7,625 (1H), 7,475 (1H, DD), 6,591 (1H, d), 4,106 (2H, m)3,843 (2H, m)1,742 (3H, s), 1,703 (9H, s); LC/MS: 304 (M+H).

Stage 4. To a solution of tert-butyl ester 5-(2-methyl-[1,3]dioxolane-2-yl)-indole-1-carboxylic acid [4,96 g, 16,35 mmol, intermediate compound (19)] in anhydrous tetrahydrofuran (20 ml) add triisopropylsilyl (4.61 in) 24,51 mmol) and cooled to 0°C under N2. To the mixture are added dropwise di is isopropylated lithium (1.8 M) in a mixture of heptane/tetrahydrofuran/ethylbenzene, 14 ml) at 0°C for 40 minutes. After 35 minutes the reaction is quenched by addition of aqueous 2N hydrochloric acid at 0°C. the Precipitated white precipitate slowly acidified with 3N hydrochloric acid to pH 3. The mixture turned into a solution, which is twice extracted with ethyl acetate (100 ml). The combined ethyl acetate phase is dried over sodium sulfate and filtered. The solid crude product is triturated with acetonitrile and water, to obtain tert-butyl ester 5-acetyl-2-methylindol-1-carboxylic acid (4,76 g, 96%, intermediate compound (20)] as a pale yellow solid residue;1H NMR (CDCl3): δ 8.30 to (or 2.67, 3H), 8,18 (1H, d), of 7.90 (1H, d), is 6.78 (1H, s), 2,61 (3H, s)of 1.62 (9H, s); LC/MS: IER + 304 (M+H).

Alternatively, the crude product can be cleaned by chromatography on silica gel with elution by ethyl acetate in heptane.

Stage 5. In the apparatus Smith (with a capacity of 10-20 ml) was placed tert-butyl ester 5-acetyl-2-methylindol-1-carboxylic acid (436 mg, 1.44 mmol, intermediate compound (20)], 1-tert-butyl-5-methyl ether 3-Otieno[3,2-C]pyrazole-1,5-dicarboxylic acid [392 mg, 0,960 mmol, intermediate compound (21)], the adduct [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium with dichloromethane (78 mg, 0,0955 mmol), cesium carbonate (938 mg, is 2.88 mmol) and a mixture of 1,4-dioxane/water(10:2 ml). The reaction tube is filled with N2and is sealed using a sealing device. The reaction mixture was naked eveda up to 90°C in a microwave (Personal chemistry optimizer) for 10 minutes. Water is taken with a pipette and add solid sodium sulfate. The organic phase is directly loaded into a 10 g column of silica gel and chromatographic 35 g column of silica gel (20-30%gradient of ethyl acetate in heptane)to obtain 1-tert-butyl-5-methyl ether 3-(5-acetyl-1-tert-butoxycarbonyl-1H-indol-2-yl)thieno[3,2-C]pyrazole-1,5-

dicarboxylic acid (230 mg, example 35) as white solids;1H NMR [(CD3)2SO)]: δ 8,388 (1H, s)8,199 (1H), 8,055 (1H), 7,901 (1H, s)7,339 (1H, s)3,914 (3H, s)2,662 (3H, s)1,671 (9H, s)1,365 (9H, s); LC/MS: 540 (M+H).

The intermediate compound (21)

1-Tert-butyl-5-methyl ether 3-Otieno[3,2-C]pyrazole-1,5-dicarboxylic acid used in stage 5 of example 35 was obtained in the following way:

Stage 1. 5-Methyl-4-nitrothiophen-2-carboxylic acid obtained according to Snider et al. (H. R. Snider and L. A. Carpino, J. F. Zack, Jr., J. F. Mills, J. Am. Chem. Soc., 1951, 79, 2556-2559) from commercially available 5-methylthiophene-2-carboxylic acid and tarifitsiruetsya in accordance with known methods (P. Cogolli, F. Maiolo, L. Testaferri, M. Tiecco, M. Tingoli, J.Chem. Soc., Perkin I, 1980, 1331-1335; V.M. Colburn, B. Iddon, H. Shuschitzky, J. Chem. Soc., Perkin I, 1977, 2436-2441)in order to obtain the methyl ester of 5-methyl-4-nitrothiophen-2-carboxylic acid [intermediate compound (23)].

Stage 2. Methyl ester 5-methyl-4-nitrothiophen-2-carboxylic acid [15,09 g, 75.0 mm, the intermediate compound (23)] R is storaetsa in ethyl acetate (200 ml), to the resulting solution was added 10% palladium on charcoal (1,03 g) and the mixture shaken under hydrogen pressure of 50 psig. The catalyst was removed by filtration and the solvent is removed, highlighting the methyl ester of 4-amino-5-methylthiophene-2-carboxylic acid [12,82 g, 99.8 per cent, intermediate compound (24)] as a yellow solid residue; MS 171,9 (100%, M+1).

Stage 3. Stir on a magnetic stirrer, a mixture of potassium acetate (4.52 g, 46,1 mm) in toluene (100 ml)containing methyl ester of 4-amino-5-methylthiophene-2-carboxylic acid [12.8 g, 74,7 mm, the intermediate compound (24)], heated to dissolve the amine. To the mixture is added acetic anhydride (13,8 ml, was 124.9 mm) and heat it in the oil bath. For 30 minutes add soliditet (9,73 ml, 72.4 mm). Heating at 93°C continue throughout the night. The cooled mixture is diluted with etiracetam (100 ml), filtered and the filtrate is concentrated to obtain a black powder, which is purified by chromatography, elwira mixtures of heptane-25% ethyl acetate, heptane-35% ethyl acetate, heptane-40% ethyl acetate, heptane-50% ethyl acetate, heptane-60% ethyl acetate. The fractions containing pure product are combined and concentrated to obtain methyl ester of 1-acetyl-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [9,74 g, 49,3%, intermediate compound (25)].

Stage 4. To a suspension of methyl ether of 1-acetyl-1H-thieno[3,2-C]pyrazole-5-ka is oil acid [1,3 g, 5,79 mmol, intermediate compound (25)] in methanol (30 ml) is added sodium methoxide (25 wt%. in methanol). The obtained mixture solution was stirred at 60°C in an oil bath for 20 minutes. The oil bath is removed and stirred the solution for 5 minutes. To it add a solution of iodine (1,76 g, 6,93 mmol) in dimethylformamide (2 ml). Then the reaction mixture is heated to 60°C for 1 hour. The solvent is removed under vacuum. The crude product is separated between ethyl acetate (100 ml) and water (100 ml) and the aqueous layer was further extracted twice with ethyl acetate (25 ml). The combined ethyl acetate phase was washed with brine, dried over sodium sulfate and filtered. The solvent is removed under vacuum to obtain the methyl ester of 3-iodine-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [1,58 g, 89%, intermediate compound (26)] as a pale yellow solid residue;1H NMR [(CD3)2SO)]: δ 13,80 (1H, Shir. s, NH), 7,947 (1H, s)3,870 (3H, s).

Stage 5. To a mixture of methyl ester of 3-iodine-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [1.5 g, to 4.87 mmol, intermediate compound (26)] in tetrahydrofuran (120 ml) was added dropwise 4-(dimethylamino)pyridine (8 mg) and di-tert-BUTYLCARBAMATE (1M in tetrahydrofuran, 5,3 ml) at room temperature. After stirring for 30 minutes the solvent was removed under vacuum. The solid is suspended in a mixture of ethyl acetate, heptane the methanol and some time was stirred. The solid precipitate was filtered and dried under vacuum to obtain 1-tert-butyl-5-methyl ether 3-Otieno[3,2-C]pyrazole-1,5-dicarboxylic acid [1,72 g, 87%, intermediate compound (21)] as off-white solids;1H NMR [(CD3)2SO)]: δ 6,880 (1H, s), 3,900 (3H, s)1,633 (9H, s); LC/MS: 409 (M+H).

Example 36

Methyl ester 3-(5-acetyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid

A solution of 1-tert-butyl 5-methyl ester 3-(5-acetyl-1-tert-butoxycarbonyl-1H-indol-2-yl)thieno[3,2-C]pyrazole-1,5-

dicarboxylic acid (115 mg, 0,213 mmol, example 35) in tetrahydrofuran (5 ml) was treated with 2N hydrochloric acid (aqueous solution, 3 ml) and heated at 70°C for 17 hours. The reaction mixture was cooled to room temperature and neutralized Na2CO3(aqueous solution). The aqueous phase is shaken out three times with ether (10 ml). The combined ether phases are washed with brine and dried over sodium sulfate. Purification by chromatography on a 10 g column of silica gel (50 to 70%gradient of ethyl acetate in heptane) leads to methyl ether 3-(5-acetyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid (15 mg, example 36) in the form of a white solid;1H NMR [(CD3)2SO)]: δ 13,82 (1H, s), 12,13 (1H, s), a 8.34 (1H, s), of 7.97 (1H, s), 7,78 (1H, d), to 7.50 (1H, d), of 6.90 (1H, s), 3,91 (3H, s), 2,61 (3H, s); LC/MS: 340 (M+H).

Example 37

3-(5-Hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid

Stage 1. In two separate apparatuses Smith (with a capacity of 10-20 ml) is mixed with methyl ester of 3-iodine-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [420 mg of 1.36 mmol, intermediate compound (26)], tert-butyl ester 5-(tert-butyldimethylsilyloxy)-1H-indole-2-boronic 1-carboxylic acid [912 mg, 2.25 mmol, intermediate compound (8), prepared as described in example 1-4 of the publication of international patent application no WO 02/32861], carbonate potassium (2M, water, 2,25 ml), tetrakis(triphenylphosphine)palladium (0) (87 mg, 0,0752 mmol) and the mixture of toluene/ethanol (9:3 ml). The reaction tube is filled with N2and is sealed using a sealing device. The reaction mixture is heated to 120°C using a microwave (Personal chemistry optimizer) for 900 seconds. After completion of the reaction mixtures are combined in a single vessel, diluted with ethyl acetate (50 ml) and washed twice with water (10 ml), brine and dried over sodium sulfate. Purification by chromatography on 35 g column of silica gel (30-50%gradient of ethyl acetate in heptane) allowed us to identify two main factions. Fractions with higher Rf were combined, the solvent was evaporated under vacuum to obtain tert-butyl ester 5-(tert-butyldimethylsilyloxy)-2-(5-methoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)-indole-1-carboxylic acid [653 mg, intermediate connection of the tell (27)] as a pale yellow powder. LC/MS: 542 (M+H). Fractions with lower Rf were combined and evaporated under vacuum to obtain the product methyl ester 3-[5-(tert-butyldimethylsilyloxy)-1H-indol-2-yl]-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [253 mg, intermediate compound (28)] as a pale yellow solid; LC/MS: 442 (M+H).

Stage 2. To a solution of methyl ester of 3-[5-(tert-butyldimethylsilyloxy)-1H-indol-2-yl]-1H-thieno[3,2-C]pyrazole-5-carboxylic acid (1.0 g, of 2.26 mmol, intermediate compound 28) in tetrahydrofuran (20 ml) is added sodium hydroxide (500 mg) and water (7 ml) and heated on an oil bath at 60°C for 16 hours. Add water to the mixture and adjusted to pH 4 2N hydrochloric acid. The product is extracted three times with ethyl acetate (50 ml). The combined ethyl acetate phase was washed with brine and dried over sodium sulfate. Purification by chromatography on silica gel (ethyl acetate, then 10%methanol in ethyl acetate) gives oily liquid. Oily liquid was dissolved in methanol and shaken with water to obtain 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid (286 mg, 91%, example 37) in the form of a beige solid;1H NMR [(CD3)2SO)]: δ 13,572 (2H, Shir. C)11,570 (1H, s)7,817 (1H), 7,509 (1H, s)7,381 (1H, d), 7,104 (1H, d), 6,677 (1H, s)5,004 (1H, OH), 4,550 (2H, CH2OH); LC/MS: 313 (M+H).

Example 38

[4-(4-Forfinal)-piperazine-1-yl]-[3-(5-hydroxymet the l-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-yl]-methanon

To a solution of 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [124 mg, 0,396 mmol, example (37)] in dimethylformamide (5 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (91 mg, 0,474 mmol) and 1-hydroxybenzotriazole (54 mg, 0,399 mmol). After stirring for 10 minutes added diisopropylethylamine (was 0.138 ml) and 1-(4-forfinal)piperazine (79 mg, 0,438 mmol). The yellow mixture solution was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with water (3×10 ml), brine and dried over sodium sulfate. Purification by chromatography on silica gel (50%ethyl acetate/heptane, then ethyl acetate) allows to obtain a solid substance. The substance is re-dissolved in methanol and shaken out with water, to obtain [4-(4-forfinal)-piperazine-1-yl]-[3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-yl]-methanon [110 mg, 56%of the sample (38)] in the form of a cream solid, so pl.=156-158°C;1H NMR [(CD3)2SO)]: δ 13,490 (1H, s), 11,59 (1H, s)7,563 (2H), 7,356 (1H), 7,109-6,985 (5H, m)6,648 (1H), 5,004 (1H, t, OH), 4,553 (2H, d, OCH2), 3,856 (4H, Shir. C)3,208 (4H, Shir. peak); LC/MS: 476 (M+H).

Example 39

(3 Ethoxy-propyl)amide of 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid

A mixture of 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-what ieno[3,2-C]pyrazole-5-carboxylic acid [159 mg, 0,507 mmol, example 37], 1-hydroxybenzotriazole (116 mg, 0,858 mmol), carbodiimide on a polymer substrate (1.2 mmol/g, 845 mg) in dichloromethane (8 ml) and dimethylformamide (2 ml) is stirred at room temperature for 25 minutes before adding 3-ethoxypropylamine (45 mg, 0,436 mmol). After 4 h add trisamin on the polymer (a 4.03 mmol/g, 500 mg) and stirred for 6 hours. The reaction mixture was filtered and the resin washed by water jet pump dichloromethane (3×15 ml). The filtrate is evaporated under vacuum. The crude product is purified by chromatography on a 10 g column of silica gel (ethyl acetate, then 1%methanol in ethyl acetate)to obtain a thick slurry. It re-dissolved in methanol and shaken out with water, to obtain (3-ethoxypropan)amide 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [30 mg, example 39] in the form of a pale yellow solid;1H NMR [(CD3)2SO)]: δ 13,490 (1H, s, NH), to 11.56 (1H, NH, C)to 8.70 (1H, t), 7,88 (1H, s), 7,51 (1H, s), 7,38 (1H, d), 7,10 (1H, s), of 6.66 (1H, s), free 5.01 (1H, t, OH), 4,55 (2H, HOCH2-), 3,44 (6H, m), of 1.80 (2H), 1,12 (3H, t); LC/MS: 399 (M+H).

Example 40

Methyl ester 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid

A solution of methyl ester of 3-[5-(tert-butyldimethylsilyloxy)-1H-indol-2-yl]-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [192 mg, 0,435 mmol, intermediate EDINENIE (28)] is dissolved in tetrahydrofuran (10 ml) and treated with tetrabutylammonium (1.0 M in tetrahydrofuran, of 0.52 ml) and stirred over night. The reaction mixture was diluted with ethyl acetate and washed with water, brine and dried over sodium sulfate. The residue was chromatographically on a 10 g column of silica gel (50%ethyl acetate in heptane, then ethyl acetate) to obtain a solid substance. Recrystallization from ethyl acetate and heptane gave the methyl ester of 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [90 mg, 73%, example 40] in the form of a beige solid;1H NMR [(CD3)2SO)]: δ 13,66 (1H, s), 11,60 (1H, s), 7,92 (1H, s), 7,51 (1H, s), 7,38 (1H, d, J=8,2 Hz), 7,10 (1H, d, J=8,2 Hz), of 6.68 (1H, s), of 5.75 (1H, Shir. s, OH), of 4.54 (2H, s, -CH2OH), 3,90 (3H, s, -CO2CH3); LC/MS 328 (M+ H).

Example 41

(Pyridine-2-ylmethyl)amide 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid

Stage 1. To a solution of methyl ester of 3-iodine-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [4,5 g, 14,60 mmol, intermediate compound (26)] in tetrahydrofuran (90 ml) is added potassium hydroxide (2.83 g, 50,44 mmol) and water (20 ml). The resulting reaction mixture is heated at 60°C in an oil bath for 2 hours. The solvent is removed under vacuum and dissolve the crude product in water (20 ml). The aqueous layer was acidified with 2N hydrochloric acid to pH 5. The precipitated white powder was collected and washed with water. The filtrate is shaken out three times utilized the volume (50 ml). The combined ethyl acetate phase was washed with brine and dried over magnesium sulfate, then filtered. Combine solids and shake them in heptane, filtered to obtain 3-iodine-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [2.15 g, 50%intermediate, compound (29)] as white solids;1H NMR [(CD3)2SO)]: δ 13,711 (1H, s)7,832 (1H, s); LC/MS: 294 (M+H).

Stage 2. A mixture of 3-iodine-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [of 1.05 g of 3.57 mmol, intermediate compound (29)], 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (821 mg, 4,28 mmol), 1-hydroxybenzotriazole (482 mg, of 3.57 mmol) in diethylformamide (45 ml) was stirred at room temperature for 10 minutes. To the mixture add diisopropylethylamine (1.3 ml, 7,46 mmol), then a solution of 2-(aminomethyl)pyridine (425 mg, 3.93 mmol) in dimethylformamide (2 ml). After stirring over night the reaction mixture was diluted with ethyl acetate (200 ml) and washed with water, brine and dried over sodium sulfate. The remainder chromatographic 35 g column of silica gel (ethyl acetate and 10%methanol in ethyl acetate)to obtain (pyridine-2-ylmethyl)amide 3-iodine-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [1,08 g, 79%, intermediate compound (30)] as a pale yellow solid; LC/MS: 385 (M+H);1H NMR [(CD3)2SO)]: δ 13,67 (1H, s), 9,35 (1H, t), 8,53 (1H), 8,01 (1H), 7,80 (1H), was 7.36 (1H, d), 7,28 (1H), 4,58 (2H, d)

Stage 3. In the apparatus Smith (capacity 10-20 ml) is mixed (pyridine-2-ylmethyl)amide 3-iodine-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [255 mg, 0,664 mmol,intermediate compound (30)], tert-butyl ester 5-(tert-butyldimethylsilyloxy)-1H-indole-2-boronic 1-carboxylic acid [404 mg, 0,997 mmol, intermediate compound (8), prepared in accordance with examples 1-4 of the publication of international patent application no WO 02/32861], tetrakis(triphenylphosphine)palladium(0) (77 mg, 0,0666 mmol), potassium carbonate (2M in water, 1 ml) and toluene/ethanol (6:3 ml). The reaction tube is filled with N2and is sealed using a sealing device. The resulting reaction mixture is heated to 120°C using a microwave (Personal chemistry optimizer) for 1020 C. the Reaction mixture was diluted with ethyl acetate (50 ml), washed twice with water (10 ml), brine and dried over sodium sulfate. Purification by chromatography using a 10 g column of silica gel (50% ethyl acetate in heptane, ethyl acetate, then 10%methanol in ethyl acetate) gave (pyridine-2-ylmethyl)amide 3-[5-(tert-butyldimethylsilyloxy)-1H-indol-2-yl]-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [397 mg, intermediate compound (31)] as a yellow oily liquid.

Stage 4. To a solution of (pyridine-2-ylmethyl)amide 3-[5-(tert-butyldimethylsilyloxy)-1H-indol-2-yl]-1H-thieno[3,2-C]pyrazole-5-carboxylic to the slots [258 mg, 0,498 mmol, intermediate compound (31)] in tetrahydrofuran (10 ml) add tetrabutylammonium (1.0 M in tetrahydrofuran, 0.6 ml) and stirred at room temperature for 16 hours. Add water and extracted three times with ethyl acetate (30 ml). The combined ethyl acetate phase was washed with brine and dried over sodium sulfate. Purification by chromatography on a 10 g column of silica gel (9:1 ethyl acetate in methylene chloride, then 8:1:1 ethyl acetate/methylene chloride/methanol) gave (pyridine-2-ylmethyl)amide 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid [85 mg, 43%, example 41] in the form of a white solid;1H NMR [(CD3)2SO)]: δ 13,51 (1H, s, NH), 11,545 (1H, s, NH), 9,358 (1H, C(O)NH, t, J=5.7 Hz), 8,533 (1H, d, J=4.5 Hz), 7,990 (1H, s)7,808 (1H, m)7,503 (1H, s), 7,387-7,266 (3H, m)7,097 (1H, d, J=8.1 Hz ), 6,663 (1H, ), 5,021 (1H, OH, t, J=5.7 Hz), 4,612 (2H, d, J=6 Hz), 4,551 (2H, d, J=5.7 Hz); LC/MS: 404 (M+H).

Example 42

5-Bromo-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole

In the apparatus Smith (capacity 10-20 ml) was placed tert-butyl ester 5-bromo-2-methylindol-1-carboxylic acid [290 mg, 1.11 mmol, intermediate compound (32)received in accordance with J. Org. Chem 2002, 67, 7551], tert-butyl ester 3-Otieno[3,2-C]pyrazole-1-carboxylic acid [250 mg, 0,714 mmol, example 5B above], the adduct [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium with dichloromethane (58 mg, 0,0710 mmol), sodium carbonate CAS is I (698 mg, 2.14 mmol) and the mixture 1,4-dioxane/water(13:2 ml). The reaction tube is filled with nitrogen and sealed using a sealing device. The reaction mixture is heated at 90°C using a microwave (Personal chemistry optimizer) for 20 minutes at high heat output. The contents transferred into a separating funnel using ethyl acetate (60 ml). The ethyl acetate layer washed with water (20 ml), brine and then dried over sodium sulfate. The crude product is purified using 35 g column of silica gel (5-15%gradient of ethyl acetate in heptane)to obtain the product (280 mg, 49%) as a beige solid. Compound (90 mg, 0,174 mmol) is placed in the apparatus Smith (with a capacity of 10-20 ml). Added potassium carbonate (90 mg) and tetrahydrofuran/methanol/H2O (10:5:3 ml). The reaction tube is sealed using a sealing device and heated at 70°C for 10 minutes under normal heating power. The reaction mixture was diluted with ethyl acetate and washed with water, brine and dried over sodium sulfate. The crude product is purified using a 10 g column of silica gel (50%ethyl acetate in heptane)to obtain 5-bromo-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole [44 mg, 80%, example 42] as a pale yellow solid;1H NMR [(CD3)2SO)]: δ 13,33 (1H, s), RS 11.80 (1H, s), 7,76 (2H), 7,38 (1H), 7,21 (2H), only 6.64 (1H, s); LC/MS: 317 (M+H).

Example 43

Mate the new ester 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid

Stage 1. To a solution of methyl ester 1H-indole-6-carboxylic acid [26,65 g, 146 mmol, intermediate compound (33)] and 4-(dimethylamino)pyridine (230 mg) in anhydrous tetrahydrofuran (490 ml) is added di-tert-BUTYLCARBAMATE (1M in tetrahydrofuran (THF, 150 ml) dropwise over a 40 minute periods. Stirred at room temperature for 100 minutes. The solvent is removed under vacuum and the mixture was re-dissolved in ethyl acetate (400 ml). The ethyl acetate layer washed with water (20 ml), 0.5 N hydrochloric acid (20 ml), 10%NaHCO3(20 ml), water (20 ml), brine and dried over sodium sulfate, then filtered through 5 g column of silica gel. The filtrate is evaporated in vacuum to dryness. Solid material is recrystallized from a mixture of ethyl acetate and heptane to obtain 1-tert-butyl 6-methyl ether indole-1,6-dicarboxylic acid as a white solid (18,53 g). Phase recrystallization is repeated to obtain a second portion of 1-tert-butyl 6-methyl ester indole-1,6-dicarboxylic acid as a white solid (16.3 g). The third portion (of 5.17 g) 1-tert-butyl 6-methyl ester indole-1,6-dicarboxylic acid is obtained from the mother liquor by chromatography on silica gel; the total yield 1-tert-butyl 6-methyl ester indole-1,6-dicarboxylic acid [40 g, 100%, intermediate compound (34)];1H NMR (CDCl 3): δ 8,886 (1H, s)7,937 (1H, d), 7,764 (1H), 7,621 (1H, d), 6,636 (1H), 3,972 (3H, s)1,734 (9H, s); LC/MS: 276 (M+H).

Stage 2. A solution of 1-tert-butyl 6-methyl ester indole-1,6-dicarboxylic acid [13,32 g, 48.38 per mmol, intermediate compound (34)] and triisopropylsilane (13,65 g, 72,58 mmol) in anhydrous tetrahydrofuran (200 ml) cooled to 0°C in a stream of nitrogen. To it add diisopropylamide lithium (1.8 M in heptane/tetrahydrofuran/ethylbenzene, 35 ml) dropwise over a 40 minute periods. Stirred at 0°C for 1.5 hours. The reaction is quenched by addition of 3N hydrochloric acid to pH~4 on the indicator paper. After stirring at 0°C for 5 minutes, the mixture was separated between ethyl acetate (200 ml) and water (50 ml). The ethyl acetate layer was washed with brine and dried over sodium sulfate. The residue is purified on 300 g column of silica gel (30-50%gradient of ethyl acetate in heptane, then 100%ethyl acetate). The fractions containing the spot with higher Rf, are combined and the solvent is removed under vacuum to obtain a whitish solid (2,32 g).1H NMR and MS confirmed that this regenerando starting material, 1-tert-butyl 6-methyl ether indole-1,6-dicarboxylic acid. The fractions containing spots with lower Rf, are combined and the solvent is removed under vacuum. The solid residue (14.2 g) triturated with acetonitrile and water to obtain 6-methoxycarbonyl-1-tert-bout xcarmenelectr-2-boric acid [11,8 g, 76,5%, intermediate compound (35)] in the form of a beige solid;1H NMR [(CD3)2SO)]: δ 8,764 (1H, s)8,311 (2H, s, B(OH)2), 7,795 (1H, d), 7,675 (1H, d), 6,713 (1H, s)3,876 (3H, s), 1,621 (9H, s).

Stage 3. Prepare a mixture of 6-methoxycarbonyl-1-tert-butoxycarbonylamino-2-boric acid (3,24 g, 10,15 mmol, intermediate compound (35)], tert-butyl ester 3-Otieno[3,2-C]pyrazole-1-carboxylic acid [2,37 g, 6,77 mmol, example 5B above], adduct [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium with dikhloretana (552 mg, 0,676 mmol), cesium carbonate (6,61 g, 20,29 mmol) in a mixture of 1,4-dioxane/water (40:10 ml). The resulting mixture was heated at 82°C in an oil bath for 3 hours under nitrogen. The reaction mixture was poured into ethyl acetate (300 ml). The ethyl acetate layer is washed twice with water (20 ml), brine and then dried over sodium sulfate. The crude reaction product is purified on 110 g column of silica gel (3% mixture of ethyl acetate in methylene chloride and 97% heptane)to obtain 1-tert-butyl 6-methyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)-indole-1,6-dicarboxylic acid [1.68 g, 50%intermediate, compound (36)] as a white foam;1H NMR

[(CD3)2SO)]: δ 8,975 (1H, s)8,017 (1H), 7,669 (1H), 7,583 (1H), 7,379 (1H), 7,048 (1H, s)3,986 (3H, s), 1,736 (9H, s), 1,440 (9H, s); LC/MS: 498 (M+H). There are also a mixture of 1-tert-butyl 6-methyl ester 1H-thieno[3,2-c]pyrazole-3-yl)-indole-1,6-dicarboxylic acid sludge is 6-methyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)-indole-1,6-dicarboxylic acid 1-tert-butyl 6-methyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)-indole-1,6-dicarboxylic acid (340 mg). 1-Tert-butyl 6-methyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)-indole-1,6-dicarboxylic acid [intermediate compound (36)] dissolved in a mixture of methanol/tetrahydrofuran/water (20 ml, 10:5:3) and treated with potassium carbonate (300 mg). The resulting mixture is stirred over night at room temperature. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water, brine and dried over sodium sulfate. The crude product is distilled at 35 g column of silica gel (50%ethyl acetate in heptane, then ethyl acetate)to obtain methyl ester of 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid [136 mg, example 43] in the form of a white powder;1H NMR [(CD3)2SO)]: δ 13,434 (1H, s)12,044 (1H, s)8,093 (1H, s), 7,789-7,631 (3H, m)7,231 (1H, d, J=5.4 Hz), 6,752 (1H, s)3,855 (3H, s); LC/MS: 298 (M+H).

Example 44

Dicyclopropyl-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]methanol

To a mixture of methyl ester of 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid (180 mg, 0,605 mmol, example 43) in anhydrous tetrahydrofuran (8 ml) add cyclopropylmagnesium (6,0 ml, 0.5 M in tetrahydrofuran) at 0°C. the Ice bath is removed and the reaction mixture was stirred at room temperature for 4 hours. It adds another cyclopropylmagnesium (6 ml, 0.5 M in tetrahydrofuran) and stirred at room temperature during the night. The reaction has ended (TLC), add cyclopropylmagnesium (6,0 ml). Then the solution of the reaction mixture is stirred over night. The reaction is stopped at 0°C by addition of saturated solution of ammonium chloride. The reaction mixture is divided between diethyl ether and water. A layer of diethyl ether was washed with brine and dried over magnesium sulfate. The crude product chromatografic on a 10 g column of silica gel (30-50%gradient of ethyl acetate in heptane)to yield the final product (120 mg). Recrystallization of the resulting product is as follows: in the office of Smith, a mixture of solid product (120 mg) and ethyl acetate (2 ml) is heated at 70°C using a microwave (Personal chemistry optimizer) for 240 seconds at normal heating power. After cooling, dicyclopropyl-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]methanol crystallizes in the form of a white solid substance so pl. 110-112°C;1H NMR [(CD3)2SO)]: δ 13,189 (1H, s)11,440 (1H, s)7,747 (1H, d, J=5,1 Hz)7,631 (1H, s)7,467 (1H, d, J=8,4 Hz), 7,249 (2H, m)6,579 (1H, s)4,304 (1H, s), 1,225 (2H), 0,581 (2H, m), 0,387 (4H, m), of € 0.195 (2H, m); LC/MS: 350 (M+H).

Example 45

(4-Benzo[1,3]dioxo-5-iletileri-1-yl)-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]metano

Stage 1. The solution diisopropylamide lithium (1.8 M), and 50.5 ml, 90,9 mmol, 2.5 EQ.) added to a solution of 1-tert-butyl 6-m is delovogo ether indole-1,6-dicarboxylic acid [10 g, 38.4 mmol, intermediate compound (34)] in tetrahydrofuran (160 ml) at -78°C. the Resulting mixture was mixed for 2 hours at -78°C before adding a solution of trimethylacetylchloride in tetrahydrofuran (1 M, 145,5 ml, 4 EQ.). The resulting solution was heated to 0°C for 15 minutes and twice was divided between ethyl acetate (150 ml) and water polysystem solution of ammonium chloride (200 ml). The organic layers were combined and dried over magnesium sulfate and concentrated. The residue was purified column flash chromatography (10%ethyl acetate in heptane)to obtain trimethyl(indole-1,6-dicarboxylic acid 1-tert-butyl -, 6-methyl ether)tin [8.7 g, the intermediate compound (37)] LC/MS: 440 (M+H); RT=2.5 minutes;1H NMR [(CD3)2SO)]: δ 8,8 (1H, t), and 7.8 (1H, d), 6,8 (1H, t), of 3.9 (3H, s), and 1.7 (9H, s).

Stage 2. A solution of trimethyl(indole-1,6-dicarboxylic acid 1-tert-butyl -, 6-methyl ether)tin [7.5 g, 17,1 mmol, 2 EQ., the intermediate compound (37)] in dioxane (30 ml) in two equal portions over 2 hours was added to a solution of tert-butyl methyl ether 3-Otieno[3,2-C]pyrazole-1-carboxylic acid [3 g, 8.6 mmol, 1 EQ., example 5B above], copper iodide (171 mg, 0.43 mmol, 0.1 EQ.) and tetrakis(triphenylphosphine)palladium (497 mg, 0.43 mmol, of 0.05 EQ.) in dioxane. The mixture was heated to 90°C and stirred for 24 hours. Then the solution was cooled to room temperature and Tr is GDI was divided between ethyl acetate (150 ml) and the mixture of aqueous saturated solution of NaHCO 3and a salt solution of 3:1 (300 ml). The combined organic layers were washed brine (250 ml) and dried over magnesium sulfate and concentrated. The residue was subjected to column flash chromatography (20%ethyl acetate in heptane) and a solution of crude product (of 5.45 g, a mixture of methyl ester of 2-(1H-Tien [3,2-c] pyrazole-3-yl)-1H-indole-6-carboxylic acid, 1-tert-butyl 6-methyl ester 1H-thieno[3,2-C]pyrazole-3-yl)indole-1,6-dicarboxylic acid 6-methyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)indole-1,6-dicarboxylic acid 1-tert-butyl 6-methyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)indole-1,6-dicarboxylic acid) in a mixture of tetrahydrofuran and water (50 ml, 1:1) was treated with potassium hydroxide (1.1 g, 19 mmol, 2 EQ.) at 60°C. the Reaction mixture was stirred overnight, and then cooled to room temperature. To the solution was added 1N hydrochloric acid to bring the pH to approximately 6. The solid was filtered, washed with water and heptane and dried to obtain 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid [3,18 g of the intermediate compound (38)], which was used without further purification. LC/MS: 282 (M-H, negative mode).

Stage 3. A mixture of 2-(1H-thieno[3,2-c] pyrazole-3-yl)-1H-indole-6-carboxylic acid [100 mg, 1.5 EQ., the intermediate compound (38)], dicyclohexylcarbodiimide on poly is ore (2 EQ.) and 1-hydroxybenzotriazole (1.7 EQ.) in dichloromethane (5 ml) was shaken for 15 minutes. Then added 1-benzo[1,3] dioxol-5-iletileri and the reaction mixture was shaken at room temperature overnight. Added trisamin on the polymer (4 equiv.) and the mixture is stirred at room temperature overnight. The resin was filtered, washed with dichloromethane and the filtrate was concentrated. The residue was purified column chromatography (20%ethyl acetate in heptane) and received (4-benzo[1,3]dioxol-5-iletileri-1-yl)-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-methanon [example 45]. LC/MS: 486 (M+H); RT=2.35 minutes;1H NMR

[(CD3)2SO)]: δ 11.8 in (1H, s), and 8.0 (1H, s), and 7.8 (1H, d), and 7.6 (d, 1H), and 7.4 (1H, s), 7,2 (1H, d), a 7.0 (d, 1H), 6,8 (2H, m), and 6.6 (2H, m).

The following examples 46-51 based on methods similar to the one used in the previous example.

Example 46

[4-(2-Cyclohexylethyl)-piperazine-1-yl]-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]metano

This compound [LC/MS: 462 (M+H); RT=8,7 min;1H NMR [(CD3)2SO)]: δ 13,4 (1H, s), and 11.8 (1H, s), and 7.8 (1H, d), and 7.6 (1H, d), and 7.4 (1H, s), 7,2 (1H, d), 7,0 (1H, d), 6,7 (1H, d), and 2.8 (6H, m), 1,6 (4H, m), 0,9-1,3 (13H, m)] is obtained based on methods similar to example 45, using 1-(2-cyclohexylethyl)-piperazine instead of 1-benzo[1,3]dioxol-5-iletilerini at stage 3.

Example 47

(2-Hydroxy-2-phenylethyl)amide 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid

This compound [LC/MS: 403 (M+H); RT=2,72 minutes;1H NMR [(CD3)2SO)]: δ 13,4 (1H, s), and 11.8 (1H, s), and 8.4 (1H, t), of 7.96 (1H, m), 7,89 (1H, m), 7,78 (1H, m), 7,2-7,6 (11H, m), 6,8 (1H, s), 5,6 (1H, d), 4,8 (1H, d), 3,6 (2H, m)] is obtained based on methods similar to example 45, using 2-amino-1-phenylethanol instead of 1-benzo[1,3]dioxol-5-iletilerini at stage 3.

Example 48

(2-Cyclohex-1-teletel)amide 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid

This compound [LC/MS: 391 (M+H); RT=3.3 minutes;1H NMR [(CD3)2SO)]: δ 13,4 (1H, s), and 11.8 (1H,s), and 8.2 (1H, t), and 7.9(1H, s), and 7.7 (1H, d), and 7.6 (1H,m), and 7.4 (1H,m), 7,2 (1H, d), and 6.6 (1H, d), 5,4 (1H, d), 2,2 (1H, m), and 2.0 (4H,m), 1,2-1,4 (1H, m)] is obtained by using methods similar to example 45, using 2-cyclohex-1-unilaterally instead of 1-benzo[1,3]dioxol-5-iletilerini at stage 3.

Example 49

(2-Thiophene-2-retil) amide 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid

This compound [LC/MS: 393 (M+H); RT=2,98 minutes;1H NMR [(CD3)2SO)]: δ 13,4 (1H, d), and 11.8 (1H, d), and 8.6 (1H, t), and 8.0 (1H, s), and 7.8 (1H, d), and 7.5 (1H, d), and 7.4 (1H, m), and 7.3 (1H, d), 7,2 (1H, m), 7,0 (1H, m), 6,8 (1H, s), 3,6 (2H, s), and 3.0 (2H, m)] is obtained based on the methods similar to the shown in example 45, using 2-thiophene-2-ylethylamine instead of 1-benzo[1,3]dioxol-5-iletilerini at stage 3.

Example 50

(4-Pyridine-2-reparation-yl)-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]metano

This compound [LC/MS: 428 (M+H), RT=1,99 minutes] based on methods similar to example 45, using 1-pyridin-2-reparation instead of 1-benzo[1,3]dioxol-5-iletilerini at stage 3.

Example 51

(2-Pyridin-3-retil)amide 2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-carboxylic acid

This compound [LC/MS: 387 (M+H), RT=1.89 minutes] based on methods similar to example 45, using 2-pyridin-3-ylethylamine instead of 1-benzo[1,3]dioxol-5-iletilerini at stage 3.

Example 52

Cyclohexylmethyl-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-ylmethyl]Amin

A mixture of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-formylindole-1-carboxylic acid [200 mg, 1 EQ., the intermediate compound (11)obtained as described for stage 1 of example 24], aminomethylation (1.1 equiv.) MP-cyanoborohydride (macroporous triethylammonium metropolitical cyanoborohydride, 1.5 EQ.) and acetic acid (0.5 ml) in dimethylformamide (10 ml) was shaken at room temperature overnight. The resin was filtered and the filtrate poured into water. The mixture was twice extracted with ethyl acetate; the extract was dried over magnesium sulfate and concentrated. The residue was purified on a column of silica gel (Elya is believed 20%methanol in etilatsetate), to obtain a mixture of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)-5-[(cyclohexylethylamine)methyl]-indole-1-carboxylic acid [main product, LC/MS: 565 (M+H), RT=3.5 minutes], tert-butyl ester 5-[(cyclohexylethylamine)methyl]-2-(1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid tert-butyl ester 3-{5-[(cyclohexylethylamine)methyl]-1H-indol-2-yl}-thieno[3,2-c]pyrazole-1-carboxylic acid. This mixture was treated triperoxonane acid in dichloromethane (10 ml, 1:1) at room temperature for 2 hours and the reaction mixture was passed through SCX column with elution 7N ammonia in methanol, giving cyclohexylmethyl-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-ylmethyl]Amin [example 52]. LC/MS: 365 (M+H); RT=2.5 minutes;1H NMR [(CD3)2SO)]: δ 11,4 (1H, s), and 7.8 (d, 2H), 7,5 (1H, s, 7,4 (1H, d), 7,2 (1H, d), 7,0 (1H, d), and 6.6 (1H, s), 3,8 (2H, s) of 2.2 (2H, d), of 1.8-2.0 (4H, m), 1,0-1,2 (4H, m), of 0.8-1.0 (3H, m).

Example 53

5-[4-(4-Chlorobenzyl)-piperazine-1-ylmethyl]-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole

Example 53

This compound [LC/MS: 462 (M+H);1H NMR [(CD3)2SO)]: δ 13,2 (1H, s), and 11.6 (1H, s), and 7.8 (d, 1H), 7,45 (1H), 7.3 to 7.4 (6H, m), 7,2 (1H, m), and 6.6 (1H, s), 3,5 (4H, m), 3,3-3,4 (6H, m), and 3.3 (1H, m), 2,9 (1H, m)] is obtained on the basis of methods such as those shown in example 52, using 1-(4 Chlorobenzyl)piperazine instead of cyclohexylethylamine in stage 1.

Primer

[2-(4-Phenoxyphenyl)-ethyl]-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-ylmethyl]-Amin

Example 54

This compound [LC/MS: 465 (M+H); δ 13,2 (1H, s), and 11.4 (1H, s), and 7.8 (1H, d), and 7.5(1H, s), and 7.4 (3H, m), and 7.3 (3H, m), 7,2 (2H, m), 6,8 (4H, m), and 6.6 (1H, d), 3,8 (2H, s), 2,6-2,8 (4H, m)] is obtained on the basis of methods, such shown in example 52 using 2-(4-phenoxyphenyl)ethylamine instead of aminometilbensana in stage 1.

Example 55

3-[6-(3-piperidine-1-ylpropionic)-1H-benzoimidazol-2-yl]-1H-benzo[4,5]thieno[3,2-c]pyrazole hydrochloride

Stage 1. To a solution of 3,4-dinitrophenol (2 g, 10.9 mmol, 1 EQ.) in dimethylformamide (40 ml) under stirring was added chlorpropramide hydrochloride (2.8 g, of 14.2 mmol, 1.3 EQ.) and potassium carbonate (3.2 g, is 22.9 mmol, 2.1 EQ.). The mixture was heated to 100°C for 4 hours and the reaction mixture was cooled to room temperature. The mixture was passed through a column of strongly acidic cation exchange resin and suirable 7N ammonia in methanol eluent was concentrated and the residue was chromatographically on silica gel (100 g)to obtain 1-[3-(3,4-dinitrophenoxy)propyl]-piperidine [3,45 g] as a yellow oily liquid.

Stage 2. 1-[3-(3,4-Dinitrophenoxy)propyl]-piperidine [3.2 g] was dissolved in methanol (20 ml) was added palladium on charcoal (1.12 g, 10%) and formic acid (2 ml). The mixture was hydrogenosomal at 50 psi in accordance with the s 3 hours and the mixture filtered through celite. The filtrate was concentrated to remove the product 4-(3-piperidine-1-ylpropionic)benzene-1,2-diamine [of 2.45 g of the intermediate compound (39)] as a dark oily liquid. LC/MS: 250 (M+H).

Stage 3. A mixture of 4-(3-piperidine-1-ylpropionic)benzene-1,2-diamine [2,2 g of the intermediate compound (39)] and formic acid (20 ml) at 100°C was stirred for 3 hours and then cooled to room temperature and passed through a column of strongly acidic cation exchanger. The column was suirable 7N ammonia in methanol to obtain 6-(3-piperidine-1-ylpropionic)-1H-benzoimidazol [of 3.45 g of the intermediate compound (40)] in the form of a dark oily liquid; LC/MS: 260 (M+H).

Stage 4. To a solution of 6-(3-piperidine-1-ylpropionic)-1H-benzimidazole [2.6 g, the intermediate compound (40)] in dimethylformamide (20 ml) was added with stirring sodium hydride (0,44 g, 60%suspension in oil) in two portions under nitrogen and then poured dropwise benzylcarbamoyl ester (1.89 g) in dimethylformamide (5 ml). The reaction mixture was stirred at room temperature overnight, then poured into water (150 ml) and then was extracted three times with ethyl acetate (50 ml). The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel allows to obtain 1-benzoyloxymethyl-6-(3-piperidine-1-ylpropionic)-1H-benzoimidazol the l [5.7 g, the intermediate compound (41)]. LC/MS: 380 (M+H).

Stage 5. 1-Benzoyloxymethyl-6-(3-piperidine-1-ylpropionic)-1H-benzoimidazol [460 mg, intermediate compound (41)] was dissolved in tetrahydrofuran (15 ml, dry) under nitrogen and the solution was cooled to 0°C. was Added n-utility (2 ml, 1.3 mmol, 2.4 EQ.) and the solution was stirred for 0.5 hour. Then the mixture was heated to room temperature and was added to the second portion of n-utility (1 ml, 1.2 EQ.), then the stirring was continued for 0.5 hours. Then add methoxyethylamine 3 bromobenzo[b]thiophene-2-carboxylic acid (401 mg, 1.1 EQ.) and the resulting solution was stirred at room temperature overnight. The solution was passed through a column of strongly acidic cation exchange resin and the residue was chromatographically to obtain [1-benzoyloxymethyl-6-(3-piperidine-1-yl-propoxy)-1H-benzoimidazol-2-yl]-(3-bromobenzo[b]thiophene-2-yl)methanon [40 mg, intermediate compound (42)].

Stage 6. A mixture of [1-benzoyloxymethyl-6-(3-piperidine-1-ylpropionic)-1H-benzoimidazol-2-yl]-(3-bromobenzo[b]thiophene-2-yl)methanone [40 mg, intermediate compound (42)], benzophenone hydrazone (18 mg, 1.4 EQ.), Pd(OAc) (0.9 mg, of 0.05 equiv.) diphenylphosphinite (3.8 mg, 0,equ.) and cesium carbonate (33,7 mg, 1.6 EQ.) in 5 ml of toluene under nitrogen was heated at 90°C during the night. The reaction mixture was cooled to room temperature and was passed through a column selenocysteines the cation exchanger and suirable 7N ammonia in methanol, to obtain [3-(N'-benzhydrylpiperazine)benzo[b]thiophene-2-yl]-[1-benzoyloxymethyl-6-(3-piperidine-1-ylpropionic)-1H-benzoimidazol-2-yl]metano [200 mg, intermediate compound (43)].

Stage 7. A mixture of [3-(N'-benzhydrylpiperazine)benzo[b]thiophene-2-yl]-[1-benzoyloxymethyl-6-(3-piperidine-1-ylpropionic)-1H-benzoimidazol-2-yl]methanone [200 mg, intermediate compound (43)] and concentrated HBr (2 ml) in ethanol (4 ml) was heated at 90°C during the night. The solution was cooled to room temperature and the mixture was passed through a column of strongly acidic cation exchange resin. Elution 7N ammonia in methanol leads to 3-[6-(3-piperidine-1-ylpropionic)-1H-benzoimidazol-2-yl]-1H-benzo[4,5]thieno[3,2-c]pyrazole (72,1 mg). The resulting substance was dissolved in a mixture of HCl/1,4-dioxane (2 ml, 4 M) and methanol (0.05 ml) and the mixture was concentrated and dried to obtain 3-[6-(3-piperidine-1-ylpropionic)-1H-benzoimidazol-2-yl]-1H-benzo[4,5]thieno[3,2-c]pyrazole hydrochloride [85,1 mg, example 55]. LC/MS: 432 (M+H); RT=2,49 minutes;1H NMR [(CD3)2SO)]: δ and 9.6 (1H, s), and 8.0 (1H, t), and 7.4 (2H, m), and 7.3 (1H, s), 7,2 (1H, m), 6,9 (1H, m), 6,8 (1H, m), 4.2V (2H, t), up 3.6-3.7 (4H, m), 3,5-3,6 (2H, m), 3,4 (1H, m), and 3.2 (1H, m), 2,8 (2H, m), of 2.2 (2H, m), 1.8 m (1H, m), 1,4 (1H, m).

Example 56

1-{3-[2-(5-Phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-3-ol

Stage 1. 1-(5-phenyl-thieno[3,2-c]pyrazole-1-yl)Etalon [intermediate compound (44), LC/MS: 243,1 (M+H), RT =3.45 minutes;1H NMR (300 MHz, CDCl3): δ to 7.84 (s, 1H), 7,78 (s, 1H), to 7.64 (m, 2H), 7,43-7,31 (m, 3H), of 2.75 (s, 3H)] obtained using methods similar to those described above for the intermediate (25) using 2-phenyl-5-methylthiophene instead of 5-methylthiophene-2-carboxylic acid in stage 1.

Stage 2. To a mixture of 1-(5-phenyl-thieno[3,2-c]pyrazole-1-yl)-ethanone [3,82 g, 15.8 mmol, intermediate compound (44)] and ethanol (50 ml) in one portion was added 6N hydrochloric acid (50,0 ml, 300 mmol) and the resulting mixture was heated at 70°C. After 18 hours the reaction mixture was cooled to room temperature and neutralized with 25% aqueous potassium carbonate. The mixture was diluted with water (200 ml) and kept at 0°C for 1 hour. The resulting solid was collected, washed three times with water (50 ml)and then dried under vacuum, after which turned out to be 5-phenyl-1H-thieno[3,2-c]pyrazole [of 2.93 g, 92%, intermediate compound (45)] in the form of a powder beige. LC/MS: 201,0 (M+H), RT=3.15 minutes).

Stage 3. Pulverized KOH (1,09 g of 6.49 mmol) was added in one portion to a stirred mixture of 5-phenyl-1H-thieno[3,2-c]pyrazole [1,30 g of 6.49 mmol, intermediate compound (45)], iodine (2,47 g, 9.73 mmol) and dimethylformamide (15 ml) under nitrogen atmosphere at room temperature and the dark reaction mixture was stirred at room temperature. After 3 hours was added with stirring 10% aqueous NaHSO (40 ml). The resulting suspension was diluted with water (40 ml) and the mixture was stirred at room temperature for 5 minutes. The solid is collected by filtration, washed three times with water (20 ml)and then dried under high vacuum at 40°C, after which turned out to be 3-iodine-5-phenyl-1H-thieno[3,2-c]pyrazole [1,94 g 91%, intermediate compound (46)] in the form of a yellowish-brown powder. TLC Rf value of 0.52 (silica, 70% ethyl acetate/heptane); LC/MS: 326,94 (M+H), RT=3.38 minutes;1H NMR [600 MHz, (CD3)2SO]: δ 13,51 (ush. s, 1H), 7,73 (m, 2H), 7,69 (ush. s, 1H), 7,46 (m, 2H), 7,38 (m, 1 Hz).

Stage 4. 4-Dimethylaminopyridine (195 mg, 1,60 mmol) was added to a mixture of 3-iodine-5-phenyl-1H-thieno[3,2-c]pyrazole [2,60 g of 7.97 mmol, intermediate compound (46)], di-tert-butylboronic (2,78 g, 12.7 mmol) and anhydrous dichloromethane (30 ml) at room temperature under stirring. The resulting solution was stirred at room temperature. After 16 hours the reaction mixture was diluted with dichloromethane (20 ml), then washed with water (50 ml) and brine (40 ml), dried over magnesium sulfate and concentrated under reduced pressure to obtain oily liquid amber. The crude product was chromatographically on silica with elution with dichloromethane, then turned tert-butyl ether 3-iodine-5-phenyl-thieno[3,2-c]pyrazole-1-carboxylic acid [2,6 g, 75%, intermediate compound (47)] in the form of a cream solid color. TLC Rf of 0.41 (silica, dichloromethane); LC/MS: 449,0 (M+Na), RT=4,23 minutes).

Stage 5. A mixture of 5-(tert-butyldimethylsilyloxy)-1H-indole-2-boronic acid tert-butyl ester 1-carboxylic acid [2,39 g, 6,11 mmol, intermediate compound (8), prepared as described in examples 1-4 publication of international patent application no WO 02/32861], tert-butyl ester 3-iodine-5-phenyl-thieno[3,2-c]pyrazole-1-carboxylic acid [2.00 city, 4,69 mmol, intermediate compound (47)], cesium carbonate (6.11 g, 17,0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (230 mg, 0,282 mmol), 1,4-dioxane (40 ml) and water (10 ml) was purged with nitrogen, and then heated at 90°C under stirring in nitrogen atmosphere. After 1.5 hours the reaction mixture was cooled to room temperature, diluted with ethyl acetate (125 ml) and then washed twice with water (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure, then formed a dark residue. The residue was chromatographically on silica with elution with dichloromethane, after which there was obtained tert-butyl ester 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(tert-butyl-dimethylsiloxy)-indole-1-carboxylic acid [255 g 84%, intermediate compound (48)] in the form of foam yellow-brown color. TLC Rf 0.31 in (silica, dichloromethane); LC/MS: 646,2 (M+H), RT=3,05 minutes).

Stage 6. To a solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [2,44 g of 3.78 mmol, intermediate compound (48)] in tetrahydrofuran (25 ml) at 0°C was added tetrabutylammonium fluoride (4,20 ml concentration of 1 M in tetrahydrofuran, 4.20 mmol) in one portion under stirring. After 40 minutes the reaction mixture was divided into ethyl acetate (75 ml) and 10% aqueous ammonium chloride (50 ml) and the layers were separated. Organic matter then washed with water (50 ml) and brine (50 ml), dried over magnesium sulfate and the solvent was removed under reduced pressure. After what happened foam amber color. The crude product was chromatographically on silica with elution with a mixture of 10% ethyl acetate/dichloromethane, to obtain tert-butyl ester 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-hydroxyindole-1-carboxylic acid [1,99 g, 99%, intermediate compound (49)] in the form of foam yellow-brown color. TLC Rf 0.31 in (silica, 10% ethyl acetate/dichloromethane); LC/MS: 532,2 (M+H ), RT=or 4.31 minutes;1H NMR [300 MHz, (CD3)2SO]: δ 9,73 (s, 1H), 7,84-7,81 (m, 2H), 7,76 (s, 1H), to 7.61 (d, J=2 Hz, 1H), 7,56-7,44 (m, 4H), 7,07 (s, 1H), at 6.84 (DD, J=2,8 Hz, 1H), 1,71 (s, 9H), of 1.40 (s, 9H).

Stage 7. A mixture of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-hydroxyindole-1-carboxylic acid [950 mg, to 1.79 mmol, intermediate compound (49)], cesium carbonate (1.75 g, 5.37 mmol) and 1,3-dibromopropane (6,0 ml) was heated at 90°C in nitrogen atmosphere. After 1.5 hours the mixture was cooled to room temperature, was filtered and the insoluble substance was twice washed with dichloromethane (10 ml). The filtrate was concentrated in vacuum with the formation of a turbid oil. The crude product was chromatographically on silica with elution first with a mixture of 80% dichloromethane/heptane and then with 100% dichloromethane to obtain tert-butyl ester 6-(3-bromopropane)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid [760 mg, 65%, intermediate compound (50)] in the form of a white foam. TLC Rf of 0.37 (silica, dichloromethane); LC/MS: 674 (M+Na), RT=2,60 minutes.

Stage 8. A mixture of tert-butyl ester 6-(3-bromopropane)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid [300 mg, 0,460 mmol, intermediate compound (50)], 3-hydroxypiperidine (73,0 mg, 0,722 mmol), potassium carbonate (191 mg, 1.38 mmol), potassium iodide (39,0 mg, 0,235 mmol) and anhydrous acetonitrile (5 ml) was heated at 70°C under stirring speed of 200 rpm in 20 hours Rea is operating and the mixture was cooled to room temperature, was filtered, the insoluble matter was washed with a mixture of dichloromethane/methanol (5:1) and the filtrate was concentrated under reduced pressure with the formation of a dark residue. The residue was chromatographically on silica with elution with a mixture of 20% methanol/dichloromethane (20 ml), and then a solution of 1 M ammonia in methanol/dichloromethane 1:9 (30 ml)to obtain tert-butyl ester 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-[3-(3-hydroxypiperidine-1-yl)-propoxy]-indole-1-carboxylic acid (329 mg) in the form fragile foam green color. LC/MS: 673,3 (M+H), 74% UV purity). To a solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-[3-(3-hydroxypiperidine-1-yl)-propoxy]-indole-1-carboxylic acid (326 mg), anisole (1.0 ml) and dichloromethane (1.0 ml) at room temperature was added triperoxonane acid (1.0 ml) and the resulting amber solution was heated at 45°C. After 2 hours the reaction mixture was cooled to room temperature and added to a column Varian Mega Bond Elut of strongly acidic cation exchange resin (5 g), treated with methanol. The product was washed with methanol (30 ml) and was suirable a solution of 1 M ammonia in methanol. Fractions with product were mixed and concentrated under reduced pressure with the formation of white solids. Rubbing this solid from a mixture of methanol/ether (1:4) gave 1-{3-[2-(5-phenyl-1H-ti is but[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-3-ol [163 mg, 75%, example 56] in the form of powder off-white color. TLC Rf of 0.55 (silica, 20% 1 M NH3in methanol/80% dichloromethane); TPL: 213-216°C; LC/MS: 473,2 (M+H), RT=2,67 minutes;1H NMR [300 MHz, (CD3)2SO]: δ 13,31 (ush. s, 1H), is 11.39 (ush. s, 1H), 7,79 (m, 2H), 7,66 (s, 1H), 7,51 and 7.36 (m, 4H), 6,93 (d, J=2 Hz, 1H), to 6.67 (DD, J=2, 8.5 Hz, 1H), 6,60 (d, J=1.5 Hz, 1H), 4,58 (d, J=5 Hz, 1H), 3,99 (t, J=6.5 Hz, 2H), 3,47 (m, 1H), 2,85 (EBM, J=11 Hz, 1H), 2,68 (DM, J=11 Hz, 1H), 2,45 (m, 2H), 1,95-to 1.67 (m, 5H), 1,62 (DM, J=13.5 Hz, 1H), 1,40 (m, 1H), 1,07 (m, 1H).

Example 57

1-{3-[2-(5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-4-ol

This connection [TLC Rf of 0.44 (silica, 20% 1 M ammonia in methanol/80% dichloromethane); TPL: 239-242°C; LC/MS: 473,2 (M+H), RT=2.94 minutes;1H NMR [600 MHz, (CD3)2SO]: δ 13,30 (ush. s, 1H), 11,37 (ush. s, 1H), 7,80 (d, J=7.7 Hz, 2H), 7,65 (s, 1H), 7,50-7,44 (m, 3H), 7,39 (m, 1H), 6,94 (d, J=1.3 Hz, 1H), to 6.67 (DD, J=2, 8.6 Hz, 1H), is 6.61 (s, 1H), to 4.52 (d, J=4,2 Hz, 1H), 3,99 (t, J=6.4 Hz, 2H), 3,44 (m, 1H), 2,72 (m, 2H), 2,42 (m, 2H), 2,01 (m, 2H), of 1.88 (m, 2H), 1,71 (m, 2H), 1,42-of 1.36 (m, 2H)] prepared using methods similar to those described in example 56 using 4-hydroxypiperidine instead of 3 hydroxypiperidine on stage 8.

Example 58

2-(5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(3-piperidine-1-yl-propoxy)-1H-indole

A mixture of tert-butyl ester 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid [300 mg, 0,460 IMO the e l e C intermediate compound 50)], piperidine (60,2 mg, 0,707 mmol), potassium carbonate (191 mg, 1.38 mmol), potassium iodide (40,0 mg, 0,241 mmol) and anhydrous acetonitrile (5.0 ml) was heated at 70°C with shaking at 200 rpm After 20 hours the reaction mixture was cooled to room temperature, was filtered, the insoluble substance was thrice washed with dichloromethane (5 ml) and the filtrate was concentrated under reduced pressure with the formation of a dark residue. The residue was chromatographically on silica with elution with a solution of 10% - 1 M ammonia in methanol/90% dichloromethane to obtain tert-butyl ester 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-[3-(piperidine-1-yl)-propoxy]-indole-1-carboxylic acid (310 mg) in the form of fragile green foam: LC/MS: 657,3, (M+H), RT=3,92 minutes, 50% UV purity). A mixture of this material (300 mg), 4 M aqueous potassium carbonate (5.0 ml), tetrahydrofuran (5.0 ml) and methanol (5.0 ml) was heated at 60°C for 2 hours. After cooling to room temperature the solvent was removed under vacuum, and then turned solid. The crude solid is suspended in water (25 ml) and the mixture was stirred at room temperature for 0.5 hours. The solid was collected by filtration and dried, after which turned to a solid grey color. Rubbing solids is about a mixture of 20% methanol/ether gave 2-(5-phenyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(3-piperidine-1-ylpropionic)-1H-indole [90,0 mg, 43%, example 58] in a solid gray color. TLC Rf of 0.37 (silica, 14% - 1 M ammonia in methanol/86% dichloromethane); LC/MS: 457,3 (M+H), RT=2.93 min;1H NMR [300 MHz, (CD3)2SO]: δ 13,30 (ush. s, 1H), is 11.39 (ush. s, 1H), 7,78 (d, J=7 Hz, 2H), to 7.64 (s, 1H), 7,49-7,35 (m, 4H), 6,92 (s, 1H), 6,65 (d, J=8.5 Hz, 1H), 6,59 (s, 1H), 3,98 (t, J=6 Hz, 2H), 2,43 is 2.33 (m, 6H), of 1.88 (m, 2H), 1,50-of 1.39 (m, 6H).

Example 59

1-(3-{2-[5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole-3-yl]-1H-indole-6-yloxy}-propyl)-piperidine-4-ol

Stage 1. A mixture of 1-(thieno[3,2-c]pyrazole-1-yl)ethanone (5,00 g, to 30.1 mmol), N-bromosuccinimide (16,1 g, 90,4 mmol) and chloroform (100 ml) was heated at 50°C in nitrogen atmosphere for 5 hours. This mixture of orange color was stirred at room temperature for 17 hours. The resulting red-orange mixture was filtered and the insoluble substance was twice washed with dichloromethane (60 ml). The filtrate is washed with 10% aqueous NaHSO3(60 ml)and then twice washed with water (60 ml), then dried over calcium sulfate and concentrated under reduced pressure. The residue was purified in a chromatography column of silica gel with elution with a mixture of 30% ethyl acetate/heptane to 50% ethyl acetate/heptane, to obtain 1-(5-bromo-thieno[3,2-c]pyrazole-1-yl)-Etalon [6,21 g, 84%, intermediate compound (51)] in the form of a solid off-white color. TLC Rf of 0.50 (silica, 40% of etelaat the/heptane). LC/MS: 244,93 (M+H), RT=3,10 minutes;1H NMR [300 MHz, (CD3)2SO]: δ to 8.12 (s, 1H), to 7.67 (s, 1H), to 2.67 (s, 3H).

Stage 2. A mixture of 1-(5-bromo-thieno[3,2-c]pyrazole-1-yl)-ethanone [12.0 g, 49,0 mmol of intermediate compound (51)], 1,4-dioxane (120 ml) and 2 M aqueous potassium carbonate (80,0 ml) was stirred at 95°C in nitrogen atmosphere. After 20 hours the reaction mixture was cooled to room temperature and then was diluted with ethyl acetate (200 ml). The resulting mixture was twice washed with water (100 ml) and brine (100 ml), successively dried over magnesium sulfate and concentrated in vacuum. The product was dried under vacuum to obtain 5-bromo-1H-thieno[3,2-c]pyrazole [9,48 g, 95%, intermediate compound (52)] in the form of a solid off-white color. TLC Rf 0.26 (silica, 1:1 ethyl acetate/heptane); LC/MS: 202,93 (M+H), RT=2,79 minutes;1H NMR (300 MHz, CDCl3) δ 10,8 (ush. s, 1H), of 7.70 (s, 1 H), 7,12 (s, 1H).

Stage 3. A solution of 5-bromo-1H-thieno[3,2-c]pyrazole [8.00 g, to 39.4 mmol, intermediate compound (52)] in dimethylformamide (50 ml) was added dropwise to a mixture of sodium hydride (1,74 g, 60% dispersion in oil, to 43.5 mmol) and dimethylformamide (10 ml) at room temperature for 5 minutes and the resulting mixture was stirred at room temperature for 30 minutes. Was added dropwise 2-(trimethylsilyl)ethoxymethylene (9,85 g, 5,91 mmol) and the resulting white suspension was stirred p. and room temperature for 21 hours. The reaction mixture was diluted with water (300 ml) and was extracted twice with ethyl acetate (125 ml). The combined extracts are then washed with water (100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated. The resulting crude product was chromatographically on silica with elution first with a mixture of 30% ethyl acetate/heptane, and then with a mixture of 40% ethyl acetate/heptane, to obtain a mixture of 5-bromo-1-(2-trimethylsilylethynyl)-1H-thieno[3,2-c]pyrazole and 5-bromo-2-(2-trimethylsilylethynyl)-2H-thieno[3,2-c]pyrazole [12,1 g (92%)]. LC/MS: 333,0 (M+H), RT=3,97 minutes and 333,0 (M+H), RT=a 3.87 minutes.

Part of this mixture of 5-bromo-1-(2-trimethylsilylethynyl)-1H-thieno[3,2-c]pyrazole and 5-bromo-2-(2-trimethylsilylethynyl)-2H-thieno[3,2-c]pyrazole (5,51 g, 16.5 mmol), 3-methoxyflavones acid (3.77 g, 24,8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.35 g, of 1.65 mmol), 4 M aqueous potassium carbonate (16.5 ml, 66,0 mmol) and 1,4-dioxane (66,0 ml) was purged with nitrogen for 5 minutes, then was heated at 75°C for 2.5 hours. This dark mixture was cooled to room temperature, diluted with ethyl acetate (250 ml) and then washed twice with water (100 ml) and brine (100 ml). Organic matter was dried over magnesium sulfate and concentrated with the formation of oily liquid amber CEE is and. This liquid was chromatographically on silica with elution first with a mixture of 5% ethyl acetate/dichloromethane and then a mixture of 10% ethyl acetate/dichloromethane, to obtain a mixture of 5-(3-methoxyphenyl)-1-(2-trimethylsilylethynyl)-1H-thieno[3,2-c]pyrazole and 5-(3-methoxyphenyl)-2-(2-trimethylsilylethynyl)-2H-thieno[3,2-c]pyrazole [4,58 g, 77%] in the form of a turbid oily liquid amber. TLC Rf 0,41 main and 0.35 additional (silica, 5% ethyl acetate/dichloromethane); LC/MS: 361,2 (M+H), RT=4,14 minutes and 361,2 (M+H), RT=4,05 minutes.

Part of this mixture of 5-(3-methoxyphenyl)-1-(2-trimethylsilylethynyl)-1H-thieno[3,2-c]pyrazole and 5-(3-methoxyphenyl)-2-(2-trimethylsilylethynyl)-2H-thieno[3,2-c]pyrazole (to 4.41 g, 12.2 mmol) and Ethylenediamine (2,50 ml, 37,0 mmol) at room temperature under nitrogen atmosphere was added in tetrabutylammonium fluoride (61,0 ml solution of 1 M in tetrahydrofuran, 61,0 mmol) and the resulting solution was heated at 70°C. After 21.5 hours, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. To the residue was added water (150 ml)and the resulting aqueous mixture was extracted twice with ethyl acetate (100 ml). Mixed extracted substance is then washed with water (75 ml) and brine (75 ml), dried over magnesium sulfate and concentrated to obtain 5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole [2,47 g, 87, the intermediate compound (53)] in the form of a solid off-white color: TLC Rf of 0.45 (silica, ethyl acetate); LC/MS: 231,0 (M+H), RT=3,20 minutes;1H NMR (300 MHz, CDCl3): δ 10,65 (ush. s, 1H), 7,78 (s, 1H), 7,32 (m, 1H), 7,25-7,21 (m, 2H), 7,16 (m, 1H), 6.89 in (m, 1H), 3,86 (s, 3H).

Stage 4. Powdered potassium hydroxide (1.35 g, 24,1 mmol) was added in one portion to a solution of 5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole [1.85 g, 8,03 mmol, intermediate compound (53)] and of dimethylformamide at 0°C under stirring. After 10 minutes, was added iodine (3,05 g, 12,0 mmol) in one portion and the resulting dark reaction mixture was stirred at 0°C for 30 minutes and then at room temperature for 5 hours. This reaction mixture was extinguished 10% aqueous NaHSO3(100 ml), the resulting white mixture was diluted with water (100 ml) and the mixture was kept at 5°C during the night. The solid is collected by filtration, washed with water (3×30 ml) and dried under vacuum at 40°C, to obtain 3-iodine-5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole [2,61 g, 91%, intermediate compound (54)] in the form of powder yellow-brown color. TPL: 159-163°C; TLC Rf of 0.54 (silica, 80% ethyl acetate/heptane); LC/MS: 357,0 (M+H), RT=3,60 minutes; NMR1H (300 MHz, CDCl3): δ 11,3 (ush. s, 1H), 7,33 (m, 1H), 7,28-7,20 (m, 2H), 7,14 (m, 1H), 6,91 (m, 1H), a 3.87 (s, 3H).

Stage 5. Appendix 4-dimethylaminopyridine (102 mg, 0,835 mmol) to a mixture of 3-iodine-5-(3-methoxyphenyl)-1H-thieno[3,2c]pyrazole [1.50 g, is 4.21 mmol, intermediate compound (54)], di-tert-BUTYLCARBAMATE (1,38 g, 6,32 mmol) and anhydrous dichloromethane (40 ml) at room temperature under stirring. The resulting solution was mixed at room temperature. After 20 hours the reaction mixture was washed with water (2×30 ml), dried over magnesium sulfate and concentrated under reduced pressure with the formation of solid yellow-brown color. The crude product was chromatographically on silica with elution with dichloromethane to obtain tert-butyl ether 3-iodine-5-(3-methoxyphenyl)thieno[3,2-c]pyrazole-1-carboxylic acid [1.68 g, 87%, intermediate compound (55)] in the form of a cream solid color: TLC Rf of 0.27 (silica, dichloromethane); LC/MS: (M+H 457,0, RT4,08 minutes);1H NMR (300 MHz, DMSO-d6): δ of 7.75 (s, 1H), 7,40 (DD, J=7,5, 8,5 Hz, 1H), 7,32 (DDD, J=1, 1.5 and 7.5 Hz, 1H), 7,28 (DD, J=1,5, 2,5 Hz, 1H), 7,01 (DDD, J=1, 2.5 and 8.5 Hz), of 3.84 (s, 3H), of 1.65 (s, 9H).

Stage 6. A mixture of tert-butyl ester 5-(tert-butyldimethylsilyloxy)-1H-indole-2-boronic 1-carboxylic acid [1,67 g, 4,27 mmol, intermediate compound (8), prepared as described in examples 1-4 publication of international patent application no WO 02/32861], tert-butyl ester 3-iodine-5-(3-methoxyphenyl)thieno[3,2-c]pyrazole-1-carboxylic acid (1.50 g, 3,29 mmol, intermediate compound (55)], cesium carbonate (4,29 g, 13,2 mmol), [1,1'-bis(WPPT is itsfine)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (268 mg, 0,328 mmol), 1,4-dioxane (35 ml) and water (7.0 ml) was flushed with nitrogen, and then heated at 75°C under stirring in nitrogen atmosphere. After 70 minutes, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 ml) and twice washed sequentially with water (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure with the formation of oily liquid black. This liquid was cromatografierea on silica with elution with dichloromethane to obtain tert-butyl ester 2-[1-tert-butoxycarbonyl-5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole-3-yl]-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [1,80 g, 81%, intermediate compound (56)] in the form of a beige foam. TLC Rf of 0.25 (silica, dichloromethane); LC/MS: 676,3 (M+H), RT=3,82 minutes.

Stage 7. To a solution of tert-butyl methyl ether 2-[1-tert-butoxycarbonyl-5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole-3-yl]-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [1.70 g, 2,52 mmol, intermediate compound (56)] in tetrahydrofuran (20 ml) at 0°C was added in one portion with stirring tetrabutylammonium fluoride (2,80 ml solution of 1 M in tetrahydrofuran, 2,80 mmol). After 40 minutes, this reaction mixture is orange was divided between ethyl what Etat (80 ml) and 10% aqueous ammonium chloride (40 ml), and the layers were separated. The organic phases were sequentially washed with water (40 ml) and brine (40 ml), dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product was chromatographically on silica with elution first with a mixture of 10% ethyl acetate/dichloromethane and then a mixture of 20% ethyl acetate/dichloromethane, to obtain 1.54 g of a yellow-brown foam. Rubbing with a mixture of ether/heptane gave tert-butyl ester 2-[1-tert-butoxycarbonyl-5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole-3-yl]-6-hydroxyindole-1-carboxylic acid [1,25 g, 88%, intermediate compound (57)] in the form of a white powder; TLC Rf of 0.23 (silica, 10% ethyl acetate/dichloromethane); LC/MS: 562,2 (M+H), RT=2,80 minutes.

Stage 8. A mixture of tert-butyl methyl ether 2-[1-tert-butoxycarbonyl-5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole-3-yl]-6-hydroxyindole-1-carboxylic acid [1.19 g, 2,12 mmol, intermediate compound (57)], cesium carbonate (2,07 g 6,35 mmol) and 1,3-dibromopropane (8.0 ml) was heated at 75°C in nitrogen atmosphere. After 6 hours the mixture was cooled to room temperature and left overnight. The mixture was filtered, and the insoluble substances were washed twice with dichloromethane (10 ml). The filtrate was concentrated under vacuum, the result of which was obtained oily liquid Golden. The crude product was chromatographically ncremental with elution with a mixture of 30% ethyl acetate/heptane to 50% ethyl acetate/heptane, to obtain tert-butyl ester 6-(3-bromo-propoxy)-2-[1-tert-butoxycarbonyl-5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole-3-yl]-indole-1-carboxylic acid [1,11 g, 76%, intermediate compound (58)] in the form of a white foam. TLC Rf and 0.46 (silica, 40% ethyl acetate/heptane); LC/MS: 682,2 (M+H), RT=3,23 minutes.

Stage 9. A mixture of tert-butyl ester 6-(3-bromo-propoxy)-2-[1-tert-butoxycarbonyl-5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole-3-yl]-indole-1-carboxylic acid [250 mg, 0,366 mmol, intermediate compound (58)], 4-hydroxypiperidine (90,0 mg, 0,889 mmol), potassium carbonate (245 mg, 1.77 mmol), potassium iodide (45.0 mg, 0,271 mmol) and anhydrous acetonitrile (4 ml) was heated at 70°C under stirring speed of 200 rpm After 18 hours the reaction mixture was cooled to room temperature for 30 minutes. In the reaction mixture was added 4 M aqueous potassium carbonate (4.0 ml)and the mixture was heated at 70°C with shaking at 200 rpm for 30 minutes. After cooling to room temperature the solvent was removed under vacuum, and the mixture was diluted with ethyl acetate (40 ml). The organic phases were sequentially washed with water (20 ml) and brine (20 ml), dried over magnesium sulfate and concentrated to precipitate a dark color. The residue was chromatographically on silica with elution first with a solution of 10% - 1 M ammonia in methanol/ 90% of harmatan, and then with a solution of 20%/1 M ammonia in methanol/80% dichloromethane to obtain 125 mg solid purple color. Rubbing of the powder with a mixture of 20% methanol/ether gave 1-(3-{2-[5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole-3-yl]-1H-indole-6-yloxy}-propyl)-piperidine-4-ol [94,1 mg, 51%, example 59] in the form of a powder pale purple. TLC Rf of 0.40 (silica, the solution 20% - 1 M ammonia in methanol/80% dichloromethane); TPL: 205-207°C; LC/MS: 503,3 (M+H), RT=2,22 minutes;1H NMR [300 MHz, (CD3)2SO]: δ 13,30 (USS, 1H), 11,37(ush. s, 1H), to 7.67 (2, 1H), 7,43 (d, J=8.5 Hz, 1H), 7,38-to 7.32 (m, 3H), 6,97-6,91 (m, 2H), 6,65 (DD, J=2, 8.5 Hz, 1H), 6,59 (s, 1H), 4,51 (d, 4 Hz, 1H), 3,98 (t, J=6 Hz, 2H), 3,85 (s, 3H), 3,41 (m, 1H), 2,72 (m, 2H), 2,42 (m, 2H), 2,01 (m, 2H) 1,92 of-1.83 (m, 2H), 1,71 (m, 2H), 1,44-of 1.32 (m, 2H).

Example 60

5-Methoxy-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-pyrrolo[3,2-b]pyridine

Stage 1. 4-Dimethylaminopyridine (102 mg, 0,835 mmol) was added under stirring at room temperature to a mixture of 5-methoxyphenol[3,2-b]pyridine (4,50 g, 30.4 mmol, prepared according to the methods described in Liebigs Ann. Chem. 1988, 203-208), di-tert-BUTYLCARBAMATE (10.7 g, is 49.0 mmol) and anhydrous dichloromethane (100 ml). The resulting solution was mixed at room temperature over night. The reaction mixture was sequentially washed with water (75 ml) and brine (75 ml), dried over magnesium sulfate and concentrated under reduced pressure, the Institute of obtaining oily liquid amber. The crude product was chromatographically on silica with elution first with dichloromethane and then a mixture of 10% ethyl acetate/dichloromethane, to obtain tert-butyl ester 5-methoxyphenol[3,2-b]pyridine-1-carboxylic acid [7,06 g, 94%, intermediate compound (60)] in the form of a viscous oily liquid amber. TLC Rf of 0.27 (silica, dichloromethane); LC/MS: 249,1 (M+H), RT=3,60 minutes);1H NMR [300 MHz, (CD3)2SO]: δ 8,21 (d, J=9 Hz, 1H), a 7.85 (d, J=4 Hz, 1H), 6,76 (d, J=9 Hz, 1H), 6,70 (d, J=4 Hz, 1 H), the 3.89 (s, 3H), and 1.63 (s, 9H).

Stage 2. A solution of tert-utility (15.0 ml of a solution of 1.5 M in pentane, to 22.5 mmol) was added to a solution of tert-butyl ester 5-methoxyphenol[3,2-b]pyridine-1-carboxylic acid [of 4.66 g of 18.8 mmol, intermediate compound (60)] in anhydrous tetrahydrofuran (85 ml) in a nitrogen atmosphere at -78°C for 4 minutes. The resulting reaction mixture is red mixed at -78°C for 41 minutes. Within 2 minutes was added triisopropylsilyl (8,70 ml of 37.7 mmol)and the resulting red-brown reaction mixture is stirred at -78°C for 20 minutes. The reaction mixture was heated to 0°C, stirred for 2.5 hours and then was added water (50 ml). After stirring at room temperature for 1 hour the solvent was removed under reduced pressure. The basicity of this aqueous mixture was raised 5N-vodnymir.com sodium to pH 14. The mixture was twice extracted with ethyl acetate (30 ml). The aqueous layer was cooled to 0°C, acidified with 10% aqueous KHSO4to pH 4, and the resulting slurry was aged at 0°C for 15 minutes. The solid was collected, washed with water and dried, resulting in a was obtained tert-butyl ester 5-methoxy-1H-indole-2-boronic 1-carboxylic acid [2,48 g, 45%intermediate compound (61)] in the form of a white powder. LC/MS: 293,16 (M+H), RT=2,43 minutes;1H NMR [300 MHz, (CD3)2SO]: δ of 8.28 (s, 2H), 8,23 (d, J=9 Hz, 1H), 6,70 (d, J=9 Hz, 1H), return of 6.58 (s, 1H), a 3.87 (s, 3H), 1,60 (s, 9H).

Stage 3. A mixture of tert-butyl ester 5-methoxy-1H-indole-2-boronic 1-carboxylic acid [600 mg, 2.05 mmol, intermediate compound (61)], tert-butyl ester 3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid [600 g, 1,71 mmol, example 5B], cesium carbonate (2,23 g, at 6.84 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) with dichloromethane (1:1) (93 mg, 0,114 mmol), 1,4-dioxane (12 ml) and water (3.0 ml) was flushed with nitrogen, and then heated at 90°C under stirring in nitrogen atmosphere. After 105 minutes, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 ml) and twice washed sequentially with water (25 ml) and brine (25 ml). The organic layer was dried over magnesium sulfate, the solvent was removed under reduced pressure, the resulting PE is a brown color. The crude product was chromatographically on silica with elution first with a mixture of 5% ethyl acetate/dichloromethane and then a mixture of 10% ethyl acetate/dichloromethane, the result of which was obtained tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-methoxyphenol[3,2-b]pyridine-1-carboxylic acid [470 mg (58%, the intermediate compound (62)] in the form of foam yellow-brown color. TLC Rf and 0.46 (silica, 10% ethyl acetate/dichloromethane); LC/MS: 471,19 (M+H), RT=as 4.02 minutes;1H NMR [300 MHz, (CD3)2SO]: δ 8,32 (d, J=9 Hz, 1H), 8,00 (d, J=5 Hz, 1H), was 7.36 (d, J=5 Hz, 1H), 7,07 (s, 1 H), to 6.88 (d, J=9 Hz, 1H), 3,92 (s, 3H), of 1.65 (s, 9H), of 1.33 (s, 9H).

Stage 4. To a solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-methoxyphenol[3,2-b]pyridine-1-carboxylic acid [250 mg, mean HDI of 0.531 mmol, intermediate compound (62)], anisole (1.0 ml) and dichloromethane (1.0 ml) at room temperature was added triperoxonane acid (1.0 ml)and the resulting solution was heated at 45°C. After 1 hour, the resulting reaction mixture green was cooled to at room temperature, its basicity was increased 5% aqueous potassium carbonate (30 ml)and the resulting mixture was extracted twice with ethyl acetate (20 ml). The combined extracts were sequentially washed with water (20 ml) and brine (20 ml), dried over magnesium sulfate and concentrated in vacuum, is the result of what happened oily mixture. Rubbing with a mixture of ether/heptane (1:1) gave 5-methoxy-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-pyrrolo[3,2-b]pyridine [107 mg, 74%, example 60] in the form of powder yellow-brown color. TLC Rf value of 0.52 (silica, ethyl acetate); TPL: 234-236°C; LC/MS: 271,02 (M+H), RT=2,03 minutes;1H NMR [300 MHz, (CD3)2SO]: δ 13,32 (ush. s, 1H), 11,67 (ush. s, 1H), 7,74 (d, J=5 Hz, 1H), 7,66 (d, J=9 Hz, 1H), 7,18 (d, J=5 Hz, 1H), 6,58-6,53 (m, 2H), 3,85 (s, 3H).

Example 61

3-Bromo-6-(3-piperidine-1-ylpropionic)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole.

Stage 1. Tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [intermediate compound (63), LC-MS: 570 (M+H), RT=4.2 minutes ;1H NMR [(CD3)2SO]: δ 7,98 (d, 1H), 7,56 (DD, 2H), 7,35 (d, 1H), 7,06 (s, 1H), 6,86 (DD, 1H), 1,65 (s, 9H), of 1.33 (s, 3H), 0,99 (s, 9H), of 0.23 (s, 6H)] was prepared with a yield of 46% using methods similar to those described in example 5C, using 6-(tert-butyldimethylsilyloxy)-1H-indole-2-boronic acid [intermediate compound (74), prepared according to the method described in examples 4-6 publication of international patent application no WO 02/32861] instead of 5-(tert-butyldimethylsilyloxy)-1H-indole-2-boronic acid.

Stage 2. To a solution of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [0.87 g and 1.51 mmol, Prohm is filling compound (63)] in chloroform (15 ml) was added bromine (95 μl, is 1.81 mmol). The reaction mixture was stirred at room temperature overnight. Was added potassium bisulfite, while the orange mixture turned pale yellow. The mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 95/5, and then 80/20), resulting in 0,49 g of the product with one missing protective group, tert-butyl ester 3-[3-bromo-6-(tert-butyldimethylsilyloxy)-1H-indol-2-yl]thieno[3,2-c]pyrazole-1-carboxylic acid or tert-butyl ester 3-bromo-6-(tert-butyldimethylsilyloxy)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid in powder form. This substance was dissolved in dichloromethane (5 ml). Then were added di-tert-butylboronic (0.28 g, 1.10 mmol), triethylamine (0.15 ml, 0.98 mmol) and DMAP (dimethylaminopyridine) (0.03 g, 0.18 mmol). The mixture is stirred at room temperature for 30 minutes. The solvent was removed. The residue was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 96:4)to obtain tert-butyl ester 3-bromo-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [0.33 g, 33%, intermediate compound (64)] in the form of a white powder. LC/MS: 648,1 (M+H)

RT=3,82 min is you.

Stage 3. To a solution of tert-butyl ester 3-bromo-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [0.32 g, 49 mmol, intermediate compound (64)] in tetrahydrofuran at 0°C was added a solution of 1.0 M TBAF (tetrabutylammonium fluoride) in tetrahydrofuran (0.51 ml, 0.51 mmol). The resulting solution is stirred at 0°C for 30 minutes. The solvent was removed. The residue was chromatographically on silica gel (eluent is a mixture of dichloromethane/ethyl acetate 95/05)to obtain tert-butyl ester 3-bromo-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-hydroxy-indole-1-carboxylic acid [0,22 g, 83%, intermediate compound (65)] in the form of an orange foam.

Stage 4. In tert-butyl ester 3-bromo-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-hydroxyindole-1-carboxylic acid [0,22 g, 0.40 mmol, intermediate compound (65)] 1,3-dibromopropane (4 ml) was added cesium carbonate (0.33 g, 1.0 mmol). The resulting suspension stirred at 75°C for 1 hour and then was filtered. The insoluble substance was removed by filtration. The filtrate was concentrated. The residue was chromatographically on silica gel (n-heptane/ethyl acetate 100/0, then 90/10)to obtain tert-butyl ester 3-bromo-6-(3-bromopropane)-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid [0,19 is, 72%, the intermediate compound (66)] in the form of a white foam. LC/MS: 654,0 (M+H), RT=4,71 minutes.

Stage 5. To tert-butyl ether, 3-bromo-6-(3-bromopropane)-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid [0.17 g, 0.26 mmol, intermediate compound (66)] in acetonitrile (4 ml) were added DIEA (N,N-diisopropylethylamine) on a polymer basis (0.14 mg, 0.52 mmol) and 4-hydroxypiperidine (53 mg, 0.52 mmol). This mixture is gently stirred at 70°C for 4 hours. Then it was filtered and concentrated. The residue was dissolved in dichloromethane (2 ml) and anisole (0.5 ml). Was added triperoxonane acid (0.5 ml). The resulting bright yellow solution was stirred at 40°C overnight, after which it acquired a greenish hue. He was placed directly in cationic ion-exchange column (strongly acidic cation exchanger mega bond elut production VARIAN, 5 g), washed with methanol and blueraven solution of 1.0 M ammonia in methanol. The desired fractions were mixed and concentrated. The residue was twice chromatographia on silica gel (eluent is a mixture of dichloromethane/1,0 M ammonia in methanol 85/15)to obtain 3-bromo-6-(3-piperidine-1-ylpropionic)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole [29 mg, 23%, example 61] in the form of a powder purple. LC/MS: 475,08 (M+H), RT=2,55 minutes;1H NMR [300 MHz, (CD3)2SO]: δ 13,45 (s, 1H), 11,59 (s, 1H), 7,69 (d, J=5,2 is C, 1H), 7,27 (d, J=8,3 Hz, 1H), 7,15 (d, J=5,2 Hz, 1H), 6,91 (s, 1H), 6.75 in (d, J=8.0 Hz, 1H), 4,60 (USS, 1H), 3,99 (m, 2 H), 3,47 (m, 1H), 2,80 (m, 2H), 2,11 (m, 2H), 1,92 (m, 2H), 1,73 (m, 2H), 1,42 (m, 2H), 1,13 (m, 2H).

Example 62

{3-[6-(3-piperidine-1-ylpropionic)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-yl}-methanol

Stage 1. To a solution of (4-bromothiophene-2-yl)methanol (25 g, 130 mmol) in dichloromethane was added imidazole (9.7 g, 142 mmol)and then tert-butyldimethylsilyl (23,4 g, 156 mmol). The resulting white suspension stirred at room temperature for 30 minutes. The insoluble substance was filtered. The filtrate was concentrated. The residual oily liquid was cromatografierea on silica gel (eluent is a mixture of n-heptane/dichloromethane 90/10)to obtain (4-bromothiophene-2-ylethoxy)-tert-butyldimethylsilyl [34,6 g of the intermediate compound (67)] in the form of a yellowish oily liquid. LC/MS: 307,0 (M+H), RT=to 4.38 minutes.

Stage 2. To a solution of (4-bromothiophene-2-ylethoxy)-tert-butyldimethylsilyl [34,6 g, 112,6 mmol, intermediate compound (67)] in tetrahydrofuran (100 ml) at 0°C under nitrogen atmosphere was added a solution of 1.8 M DIAL (diisopropylamide lithium) in a mixture tetrahydrofuran/heptane/ethylbenzene (68,8 ml, 123,9 mmol). Then was added N-formylpiperidine (15 ml, 135,1 mmol). This dark green mixture was stirred at room temperature over night and was extinguished saturated the output of aqueous ammonium chloride. Then it was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 90/10)to obtain 3-bromo-5-(tert-butyl-dimethylsiloxane)thiophene-2-carbaldehyde [30,1 g, 80%, intermediate compound (68)].

Stage 3. To a solution of 3-bromo-5-(tert-butyldimethylsilyloxy)thiophene-2-carbaldehyde [to 30.1 g of 89.7 mmol, intermediate compound (68)] in ethanol (350 ml) was added benzophenone hydrazone (20 g, 104,7 mmol). The resulting yellow solution stirred under reflux for 6 hours. Then the solvent was removed, and the residue was chromatographically on silica gel (eluent is a mixture of n-heptane/dichloromethane, 20/80)to obtain N-benzhydrylidene-N'-[1-[3-bromo-5-(tert-butyl-dimetilglioximatul)thiophene-2-yl]-methylidene]-hydrazine [41,3 g of the intermediate compound (69)]. LC/MS: 515,1 (M+H) (found 2 isomer) RT=4,17 minutes and 4.34 minutes.

Stage 4. To a solution of N-benzhydrylidene-N'-[1-[3-bromo-5-(tert-butyldimethylsilyloxy)thiophene-2-yl]-methylidene]-hydrazine [41,2 g, 80.2 mmol, intermediate compound (69)] in toluene (500 ml) was added benzophenone hydrazone (18,9 g of 96.2 mmol), cesium carbonate (44,3 g, 136,3 mmol)and then 1,1'-diphenylphosphinite (6,66 g, 12 mmol) and palladium acetate (1.35 g, 6 mmol). This orange mixture peremeci is alas at 90°C for 20 hours. The insoluble substance was filtered, and the filtrate was concentrated. The residue was chromatographically (n-heptane/ethyl acetate, 90/10). The resulting oily substance is dark orange (of 45.7 g) was dissolved in methanol (400 ml)was then added concentrated hydrochloric acid (150 ml). The resulting dark red mixture was stirred at 75°C during the night. Was added a 2.5 N solution of sodium hydroxide in water to neutralize the pH. Then the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 50/50, then 20/80)to obtain (1H-thieno[3,2-c]pyrazole-5-yl)-methanol [3,3 g, 27%, intermediate compound (70)] in the form of a powder orange color.

Stage 5. In solution (1H-thieno[3,2-c]pyrazole-5-yl)-methanol [3,2 g of 20.8 mmol, intermediate compound (70)] in dimethylformamide (40 ml) were added potassium hydroxide (3.5 g, of 62.3 mmol) and iodine (7.9 g, and 31.1 mmol). This mixture was mixed at room temperature for 5 hours. Was added a concentrated solution of sodium bisulfite in water until disappearance of the orange color. The resulting mixture was extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The residue is triturated in dihl methane, to obtain (3-iodine-1H-thieno[3,2-c]pyrazole-5-yl)-methanol [5,3 g, 91%, intermediate compound (71)]. LC/MS: 280,91 (M+H), RT=1,93 minutes;1H NMR [300 MHz, (CD3)2SO]: ∆ 13,23 (s, 1H), 7,12 (s, 1H), 5,64 (t, J=6,6 Hz, 1H), 4,63 (d, J=6,5 Hz, 1H).

Stage 6. To (3-iodine-1H-thieno[3,2-c]pyrazole-5-yl)-methanol [2,89 g of 10.3 mmol, intermediate compound (71)] in dimethylformamide (20 ml) were added imidazole (1.4 g, to 20.6 mmol) and tert-butyldimethylsilyl (2,63 g, 17.5 mmol). The resulting solution was mixed at room temperature for 5 minutes. Then it was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 100/0, then 90/10, then 70/30)to obtain 5-(tert-butyldimethylsilyloxy)-3-iodine-1H-thieno[3,2-c]pyrazole [3.5 g, 85%, intermediate compound (72)] in the form of a white powder. LC/MS: 395,0 (M+H)

RT=3,95 minutes.

Stage 7. 5-(tert-butyldimethylsilyloxy)-3-iodine-1H-thieno[3,2-c]pyrazole [3,40 g, to 8.62 mmol, intermediate compound (72)] in dichloromethane (80 ml) were added DMAP (dimethylaminopyridine) (0,22 g, 1,72 mmol) and di-tert-butylboronic (of 2.26 g, 10,34 mmol). This mixture was mixed at room temperature for 30 minutes. Then the solvent was removed. The residue was chromatographically C is imagele (eluent - dichloromethane)to obtain tert-butyl ester 5-(tert-butyldimethylsilyloxy)-3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid [3.57 g, 84%, intermediate compound (73)]. LC/MS: 495,07 (M+H), RT=4,37 minutes.

Stage 8. To a solution of 6-(tert-butyldimethylsilyloxy)-1H-indole-2-boronic acid [3.57 g, 9,13 mmol, intermediate compound (74), prepared according to the method described in examples 4-6 publication of international patent application no WO 02/32861] and tert-butyl ester 5-(tert-butyldimethylsilyloxy)-3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid [3,47 g, 7,02 mmol, intermediate compound (73)] in 1,4-dioxane (60 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (complex with dichloromethane (1:1)) (385 mg, of 0.53 mmol). Was added an aqueous solution (25 ml), cesium carbonate (9,14 g, 28,08 mmol). This mixture was mixed at 80°C for 1 hour. It was cooled to room temperature, after which it was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (n-heptane/ethyl acetate 95/05, then 90/10)to obtain tert-butyl ester 2-[1-tert-butoxycarbonyl-5-(tert-butyldimethylsilyloxy)-1H-thieno[3,2-c]pyrazole-3-yl]-6-(tert-butyl-dimethylsiloxy)-indole-1-carboxylic acid [3.8 g, 76%, intermediate compound (75)]. LC/MS: 714,38 (M+H), RT=3.2 minutes.

Stage 9. To a solution of tert-butyl methyl ether 2-[1-tert-butoxycarbonyl-5-(tert-butyl-dimetilglioximatul)-1H-thieno[3,2-c]pyrazole-3-yl]-6-(tert-butyl-dimethylsiloxy)-indole-1-carboxylic acid [3.2 g, 4.5 mmol, intermediate compound (75)] in tetrahydrofuran (30 ml) at 0°C was added a solution of 1.0 M TBAF (tetrabutylammonium) in tetrahydrofuran. Received green solution stirred at 0°C to complete the reaction, after which it was diluted with water. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of dichloromethane/ethyl acetate 90/10)to obtain tert-butyl ester 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-hydroxy-indole-1-carboxylic acid [1.5 g (66%, the intermediate compound (76)]. LC/MS: 486,2 (M+H), RT=3,30 minutes.

Stage 10. To a suspension of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-hydroxyindole-1-carboxylic acid [1.45 g, 2,99 mmol, intermediate compound (76)] 1,3-dibromopropane (5 ml) was added cesium carbonate (2,43 g of 7.48 mmol). The suspension was mixed at 80°C for 3 hours. It was cooled to room temperature. The insoluble substance was filtered. The filtrate was applied onto a silica gel is cromatografia (n-heptane/ethyl acetate 100/0, then gradually up to 65/35)to obtain tert-butyl ester 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid [990 mg, 55%, the intermediate compound (77)]. LC/MS: 606,1 (M+H), RT=3,22 minutes.

Stage 11. To tert-butyl ether, 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carbolic acid [160 mg, 0.26 mmol, intermediate compound (77)] in acetonitrile (4 ml) were added DIEA on a polymer basis (3,86 mmol/g, 135 mg, 0.52 mmol) and piperidine (52 μl, 0.52 mmol). This mixture is gently stirred at 75°C for 3 hours. DIA on the polymeric base was filtered, and the solvent was removed. The residue was chromatographically on silica gel (eluent is a mixture of dichloromethane/1,0M ammonia in methanol 90/10)to obtain an oily yellow substance. It was dissolved in dichloromethane (1 ml). Were added anisole (0.5 ml), and then triperoxonane acid (0.5 ml). The resulting yellow solution stirred at 45°C overnight, and then was placed directly in cationic ion-exchange column (VARIAN mega bond elut, 5 g), washed with methanol and blueraven solution of 1.0 M ammonia in methanol. The desired fractions were mixed and concentrated. The residue is triturated in dichloromethane to obtain {3-[6-(3-piperidine-1-yl-propoxy)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazol-yl}-methanol [91 mg, 84%, example 62] in the form of a white powder. LC/MS: 411,3 (M+H), RT=2,42 minutes;1H NMR [300 MHz, (CD3)2SO]: δ of 13.05 (s, 1H), 11,33 (s, 1H), 7,42 (d, J=8.5 Hz, 1H), 7,05 (s, 1H), 6,91 (s, 1H), 6,65 (DD, J1=8,5 Hz, J2=1.7 Hz, 1H), of 6.52 (s, 1H), 5,65 (t, J=5.7 Hz, 1H), 4,70 (d, J=5.5 Hz, 2H), 3,99 (t, J=6.2 Hz, 2H), 2,45-of 2.36 (m, 6H), 1,89 (quintet, J=6,7 Hz, 2H), 1,49 (d, J=5.0 Hz, 4H), of 1.39 (d, J=5,2 Hz, 2H).

Example 63

1-{3-[6-(3-piperidine-1-yl-propoxy)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-ylmethyl}-piperidine-4-ol

Stage 1. To tert-butyl ether, 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1-carboxylic acid [990 mg, and 1.63 mmol, intermediate compound (77)] in acetonitrile (20 ml) were added DIEA based on polymers (a 3.83 mmol/g, 850 mg, 3,26 mmol) and piperidine (0,32 ml, 3,26 mmol). This mixture is gently stirred at 60°C for 4 hours. DIA on the polymeric base was filtered, and the solvent was removed. The residue was chromatographically on silica gel (dichloromethane/1,0M ammonia in methanol 95/05)to obtain tert-butyl ester 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(3-piperidine-1-ylpropionic)-indole-1-carboxylic acid [730 mg, 74%, intermediate compound (78)] in the form of a white foam. LC/MS: 611,2 (M+H), RT=3,05 minutes.

Stage 2. To tert-butyl ether, 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]PI is the azole-3-yl)-6-(3-piperidine-1-ylpropionic)-indole-1-carboxylic acid [1,21 g, to 1.98 mmol, intermediate compound (78)] in dichloromethane (25 ml) at 0°C was added triethylamine (0,29 ml, 2.28 mmol) and methanesulfonamide (0,34 ml, 4.40 mmol). This mixture stirred at 0°C for 30 minutes and then at room temperature for 4 hours. She was diluted with dichloromethane, and then washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of dichloromethane/methanol 90/10)to obtain tert-butyl ester 2-(1-tert-butoxycarbonyl-5-methanesulfonylaminoethyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(3-piperidine-1-yl-propoxy)-indole-1-carboxylic acid [0,85 g, 62%, the intermediate compound (79)] in the form of a yellow foam. LC/MS: 689,3 (M+H), RT=2,58 minutes.

Stage 3. To tert-butyl ether, 2-(1-tert-butoxycarbonyl-5-methanesulfonylaminoethyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(3-piperidine-1-ylpropionic)-indole-1-carboxylic acid [150 mg, 0.26 mmol, intermediate compound (79)] in dichloromethane (5 ml) were added triethylamine (40 μl, 0.31 mmol) and 4-hydroxypiperidine (55 mg, 0.52 mmol). This mixture was mixed at 45°C for 15 hours. It was concentrated. The residue was chromatographically on silica gel (dichloromethane/1.0 M ammonia in methanol, 90/10). The desired fractions were mixed and concentrated. The residue was dissolved in dichloromethane (2 ml) and anisole (0.5 ml). Was added triperoxonane acid (0.5 ml). This solution was stirred at 45°C for 3 hours. Then it was placed directly in cationic ion-exchange column (Varian Mega Bond Elut strongly acidic cation exchanger, 5 g), washed with methanol and loireau solution of 1.0 M ammonia in methanol. The desired fractions were mixed and concentrated. The residue is triturated in dichloromethane, and then chromatographically on silica gel (eluent is a mixture of dichloromethane/methanol 90/10)to obtain 1-{3-[6-(3-piperidine-1-ylpropionic)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-ylmethyl}-piperidine-4-ol [19 mg, example 63]. LC/MS: 494,3 (M+H), RT=1,77 minutes;1H NMR [300 MHz, (CD3)2SO]: δ 13,01 (s, 1H), 11,30 (s, 1H), 7,40 (d, J=8.5 Hz, 1H),? 7.04 baby mortality (s, 1H), 6.90 to (s, 1H), only 6.64 (DD, J1=8.6 Hz, J2=2.1 Hz, 1H), 4,54 (d, J=4 Hz, 1H), 3,98 (t, J=6.2 Hz, 2H), 3,71 (s, 2H), 3.46 in (m, 1H), 2,77 (m, 2H), 2.49 USD to 2.35 (m, 6H), of 2.15 (t, J=9.7 Hz, 2H), 1,90 (t, J=6,7 Hz, 2H), 1,73 (m, 2H), 1,55-of 1.30 (m, 8H).

Example 64

2-{5-[4-(4-Forfinal)-piperazine-1-ylmethyl]-1H-thieno[3,2-c]pyrazole-3-yl}-6-(3-piperidine-1-ylpropionic)-1H-indole

This compound [LC/MS: 573,3 (M+H), RT=2,17 minutes;1H NMR [300 MHz,

(CD3)2SO]: δ 13,07 (s, 1H), 11,30 (s, 1H), 7,39 (d, J=8.5 Hz, 1H), 7,11 (s, 1H), 6,99 (m, 1H), 6,92 (m, 1H), 6,63 (d, J=8.5 Hz, 1H), 6,53 (s, 1H), 6,98 (t, J=6.2 Hz, 2H), 3,82 (s, 2H), 3,11 (ush. s, 2H), 2,64 (ush. s, 2H), 2.49 USD is 2.33 (m, 6H), of 1.88 (t, J=6,7 Hz, 2H), 1,49 (m, 4H), to 1.38 (m, 2H)] was obtained with a yield of 46% using methods similar to those described in the application of the e 63, using 1-(4-forfinal)-piperazine instead of 4-hydroxypiperidine in stage 3 of example 63.

Example 65

Methyl-{3-[6-(3-piperidine-1-ylpropionic)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-ylmethyl}-pyridine-2-yl-amine

This compound [LC/MS: 501,3 (M+H), RT=1,93 minutes;1H NMR [300 MHz,

(CD3)2SO]: δ 13,01 (s, 1H), 11,31 (s, 1H), 8,49 (d, J=4,5Hz, 1H), to 7.77 (m, 1H), 7,47 (d, J=8 Hz, 1H), 7,40 (d, J=8.5 Hz, 1H), 7,26 (t, J=6,1 Hz, 1H), 7,06 (s, 1H), 6.90 to (s, 1H), only 6.64 (d, J=8,7H, 1H), of 6.52 (s, 1H), 3,99(s, 3H), of 3.97 (m, 2H), a 3.87 (s, 2H), 2,43 (m, 6H), 1.91 a (t, J=6.4 Hz, 2H), 1,53 (m, 4H), of 1.40 (m, 2H)] was obtained with a yield of 6% using methods similar to those described in example 63, using methyl-pyridine-2-yl-amine instead of 4-hydroxypiperidine in stage 3 of example 63.

Example 66

Benzyl-{3-[6-(3-piperidine-1-ylpropionic)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-ylmethyl}-amine

This compound [LC/MS: 500,3 (M+H), RT=1.68 minutes;1H NMR [300 MHz,

(CD3)2SO]: δ 13,00 (s, 1H), of 11.29 (s, 1H), 7,42-7,20 (m, 6H),? 7.04 baby mortality (s, 1H), make 6.90 (d, J=2 Hz, 1H), only 6.64 (DD, J1=2.2 Hz, J2=8.5 Hz, 1H), 6,53 (s, 1H), 3,98 (t, J=6.5 Hz, 2H), 3,93 (s, 2H), 3,76 (s, 1H), 2,94 (ush. s, 1H), 2,41 (t, J=1.9 Hz, 2H), 2,34 (m, 4H), of 1.88 (m, 2H), 1,50 (m, 4H), to 1.38 (m, 2H)] was obtained with a yield of 37% using methods similar to those described in example 63, using benzylamine instead of 4-hydroxypiperidine in stage 3 of example 63.

Example 67

6-(3-piperidine-1-ylpropionic)-2-[5-(4-trifter ethylpiperidine-1-ylmethyl)-1H-thieno[3,2-c]pyrazole-3-yl]-1H-indole

This compound [LC/MS: 546,3 (M+H), RT=1.66 minutes;1H NMR [300 MHz, (CD3)2SO]: δ 13,03 (s, 1H), of 11.29 (s, 1H), 7,39 (d, J=8.5 Hz, 1H), 7,07 (s, 1H), 6.89 in (s, 1H), 6,63 (m, 1H), of 6.52 (s, 1H), 3,98 (t, J=6.3 Hz, 2H), of 3.77 (s, 2H), 3,01 (d, J=11 Hz, 2H), 2,43-of 2.27 (m, 7H), 2,07 (t, J=10,8 Hz), 1,92-of 1.78 (m, 4H), 1,50 (m, 6H), to 1.37 (m, 2H)] was obtained with a yield of 36% using methods similar to those described in example 63 using 4-triftormetilfullerenov instead of 4-hydroxypiperidine in stage 3 of example 63.

Example 68

[2-(5-piperidine-1-ylmethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]methanol

Stage 1. To tert-butyl ether, 5-(tert-butyldimethylsilyloxy)-3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid [410 mg, 0.83 mmol, intermediate compound (73)] in tetrahydrofuran (5 ml) was added a solution of 1.0 M TBAF in tetrahydrofuran (0,92 ml of 0.92 mmol) at 0°C. the resulting solution was stirred at 0°C for 1 hour. The solvent was removed and the residue was chromatographically on silica gel (eluent is a mixture of dichloromethane/ethyl acetate 90/10)to obtain tert-butyl ester 5-hydroxymethyl-3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid [230 mg, 73%, intermediate compound (80)] in the form of a white powder. LC/MS: 380,97 (M+H), RT=2.8 minutes.

Stage 2. To tert-butyl ether, 5-hydroxymethyl-3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid [220 mg of 0.58 mmol, Prohm is filling connection (80)] in dichloromethane (5 ml) were added triethylamine (85 μl, 0.67 mmol) and methanesulfonamide (50 μl, 0.67 mmol). The mixture is stirred at 0°C for 15 minutes and then at room temperature for 30 minutes. The resulting solution was washed with saturated potassium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to obtain tert-butyl ether 3-iodine-5-methanesulfonylaminoethyl-thieno[3,2-c]pyrazole-1-carboxylic acid [220 mg, 79%, intermediate compound (81)] in the form of a white foam. LC/MS: up KZT 458,97 (M+H), RT=3,39 minutes.

Stage 3. To tert-butyl ether, 3-iodine-5-methanesulfonylaminoethyl-thieno[3,2-c]pyrazole-1-carboxylic acid [210 mg, 0.46 mmol, intermediate compound (81)] in dichloromethane (3 ml) were added triethylamine (70 μl, 0.55 mmol) and piperidine (55 μl, 0.55 mmol). The mixture is stirred at room temperature for 1 hour. The solvent was removed, and the residue was chromatographically on silica gel (eluent is a mixture of dichloromethane/ethyl acetate 95/05)to obtain tert-butyl ether 3-iodine-5-piperidine-1-ylmethyl-thieno[3,2-c]pyrazole-1-carboxylic acid [110 mg, 53%, intermediate compound (82)] in the form of a white foam. LC/MS: 448,0 (M+H), RT=2,55 minutes.

Stage 4. To tert-butyl ether, 3-iodine-5-piperidine-1-ylmethyl-thieno[3,2-c]pyrazole-1-carboxylic acid [390 mg, 0.87 mmol, intermediate compound (82)] in 1,4-dioxane (8 ml) were added tert-butyl ester 5-(tert-butyl-is metilsalicilata)-1H-indole-2-boronic 1-carboxylic acid (450 mg, 1.13 mmol, intermediate compound (8), prepared as described in examples 1-4 publication of international patent application no WO 02/32861], and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (complex with dichloromethane (1:1)) (50 mg, 0.07 mmol), and then cesium carbonate (1.13 g, of 3.48 mmol) and water (3 ml). This mixture was mixed at 80°C for 3 hours. It was then extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residual oily substance was chromatographically on silica gel (eluent is a mixture of dichloromethane/methanol 95/05)to obtain tert-butyl ester 2-(1-tert-butoxycarbonyl-5-piperidine-1-ylmethyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [310 mg, 53%, intermediate compound (83)] in the form of a white powder. LC/MS: 681,33 (M+H), RT=3,88 minutes.

Stage 5. To tert-butyl ether, 2-(1-tert-butoxycarbonyl-5-piperidine-1-ylmethyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [530 mg, 0.78 mmol, intermediate compound (83)] in tetrahydrofuran (10 ml) at 0°C was added a solution of 1 M TBAF in tetrahydrofuran (0,86, 0.86 mmol). The mixture is stirred at 0°C for 2 hours. She was diluted with ethyl acetate and washed with aqueous ammonium chloride. The organic layer was dried over magnesium sulfate is concentrated. The residue was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 80/20)to obtain tert-butyl ester 2-(1-tert-butoxycarbonyl-5-piperidine-1-ylmethyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-hydroxymethylene-1-carboxylic acid [305 mg, 70%, intermediate compound (84)] in the form of a white foam. LC/MS: 567,3 (M+H), RT=2,89 minutes.

Stage 6. To tert-butyl ether, 2-(1-tert-butoxycarbonyl-5-piperidine-1-ylmethyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-hydroxymethylene-1-carboxylic acid [280 mg, 0.50 mmol, intermediate compound (84)] in a mixture of tetrahydrofuran (5 ml) and water (1 ml) was added sodium hydroxide (150 mg, 3.75 mmol). The mixture was mixed at 65°C over night. She was diluted with ethyl acetate. The mixture was washed with saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of dichloromethane/1.0 M ammonia in methanol 95/05, then 50/50)to obtain [2-(5-piperidine-1-ylmethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yl]-methanol [10 mg, 5%, example 68] in the form of a white powder. LC/MS: 367,1 (M+H), RT=2,22 minutes;1H NMR [300 MHz, (CD3)2SO]: δ 13,08 (s, 1H), of 11.45 (s, 1H), 7,47 (s, 1H), 7,34 (d, J=8,2 Hz, 1H), 7,07 (s, 1H), 7,05 (s, 1H), to 6.57 (s, 1H), to 4.98 (m, 1H), 4,53 (d, J= 5.8 Hz, 2H), 3,71 (s, 2H), 2,44 (m, 4H), of 1.53 (m, 4H), 1,42 (m, 2H).

Primer

1-{3-[2-(5-Benzoyloxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}piperidine-4-ol

Stage 1. To (4-bromothiophene-2-yl)methanol (18,8 g of 97.4 mmol, intermediate compound (85)] in tetrahydrofuran (200 ml) was added sodium hydride (3.9 g, of 97.4 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. Was added tetrabutylammonium iodide (3.6 g, 9.7 mmol), and then benzylbromide (of 11.6 ml of 97.4 mmol). The mixture is stirred at room temperature for 1 hour. Was added water. The resulting mixture was extracted with diethyl ether. The ether layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 90/10)to obtain 2-benzoyloxymethyl-4-bromothiophene [29,2 g of the intermediate compound (86)] (quantitatively) as an oily yellow substance. LC/MS: 282,96 (M+H), RT=3,68 minutes.

Stage 2. 2-benzoyloxymethyl-4-bromothiophene (29,2 g, 103 mmol, intermediate compound (86)] in tetrahydrofuran (100 ml) was dropwise added a solution of 1.8 M DIAL in tetrahydrofuran (63 ml, 113 mmol) at 0°C under nitrogen atmosphere. This solution was stirred at 0°C for 30 minutes. Then was added N-formylpiperidine (of 13.75 ml, 127 mmol)and the resulting reaction mixture was stirred at 0°C in those who begins 45 minutes and then at room temperature for 15 minutes and was extinguished with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The remaining oily substance was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 90/10)to obtain 5-benzoyloxymethyl-3-bromothiophene-2-carbaldehyde [23.3 g, the intermediate compound (87)] in the form of oily substances orange color.

Stage 3. To (5-benzoyloxymethyl-3-bromothiophene-2-carbaldehyde (23,2 g, 74,6 mmol, intermediate compound (87)] in ethanol was added benzophenone hydrazone (16,1 g, 82 mmol). The mixture was mixed at 80°C during the night. The solvent was removed. The residual oily substance was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 60/40, then 0/100)to obtain N-benzhydrylidene-N'-[1-(5-benzoyloxymethyl-3-bromothiophene-2-yl)-methylidene]hydrazine [34,1 g, 68%, stage 2, the intermediate compound (88)] in the form of a waxy yellow substance. LC/MS: 489,0 (M+H), RT=1.48 minutes and 1,84 minutes.

Stage 4. To N-benzhydrylidene-N'-[1-(5-benzoyloxymethyl-3-bromothiophene-2-yl)-methylidene]hydrazine (34 g, 69,5 mmol, intermediate compound (88)] in toluene (500 ml) was added benzophenone hydrazone (16,4, of 83.4 mmol), cesium carbonate (38,4 g, 118,2 mmol), 1,1'-diphenylphosphinite (5.8 g, 10,4 mm is l) and palladium (II) acetate (1,17 g, 5.2 mmol). The suspension was mixed at 90°C under nitrogen atmosphere until completion of the reaction. The solvent was removed. The residual oily substance was chromatographically (eluent is a mixture of ethyl acetate/n-heptane 10/90) with the formation of oily substances orange. It was dissolved in ethanol (350 ml). Was added concentrated hydrochloric acid (100 ml). The obtained dark mixture was mixed at 80°C for 15 hours and then was diluted with water. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 80/20, then 50/50)to obtain 5-benzoyloxymethyl-1H-thieno[3,2-c]pyrazole [5,2 g, 37%, intermediate compound (89)] in the form of a powder orange. LC/MS: 245,1 (M+H), RT=2,83 minutes.1H NMR [300 MHz, (CD3)2SO]: tautomer 1: δ 12,97 (s, 1H), 7,73 (s, 1H), 7,40-7,25 (m, 5H), 7,15-7,05 (m,1H), 4,71 (s, 2H), 4,55 (s, 2H) tautomer 2: δ of 13.27 (ush. s, 1H), 7,98 (s, 1H), 7,40-7,25 (m, 5H), 7,15-7,05 (m,1H), 4,71 (s, 2H), 4,55 (s, 2H).

Stage 5. 5-Benzoyloxymethyl-3-iodine-1H-thieno[3,2-c]pyrazole [intermediate compound (90), LC/MS: 371,0 (M+H), RT=3,49 minutes] was prepared with a yield of 77% using methods similar to those described in example 5A using 5-benzoyloxymethyl-1H-thieno[3,2-c]pyrazole [intermediate compound (89)] instead of 1H-thieno[3,2-c]pyrazole.

Stage 6. Tert-BU is silt ether 5-benzoyloxymethyl-3-Otieno[3,2-c]pyrazole-1-carboxylic acid [intermediate compound (91)] was prepared with a yield of 100% by using methods described in example 5B, using 5-benzoyloxymethyl-3-iodine-1H-thieno[3,2-c]pyrazole [intermediate compound (90)] instead of 3-iodine-1H-thieno[3,2-c]pyrazole.

Stage 7. Tert-butyl ester 2-(5-benzoyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid [intermediate compound (92)] was prepared with a yield of 39% using methods similar to those described in example 5C, using tert-butyl ester 5-benzoyloxymethyl-3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid [intermediate compound (91)] instead of the tert-butyl ester 3-iodine-thieno[3,2c]pyrazole-1-carboxylic acid and 6-(tert-butyl-dimethylsiloxy)-1-(tert-butoxycarbonyl)-1H-indole-2-Bronevoy acid [intermediate compound (74), prepared according to the method described in examples 4-6 publication of international patent application no WO 02/32861] instead of 5-(tert-butyl-dimethylsiloxy)-1-(tert-butoxycarbonyl)-1H-indole-2-Bronevoy acid.

Stage 8. Tert-butyl ester 2-(5-benzoyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-hydroxyindole-1-carboxylic acid [intermediate compound (93), LC/MS: 576,2 (M+H), RT=4.0 minutes] was prepared with a yield of 33% using methods similar to those described in example 5D, using tert-butyl ester 2-(5-benzoyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-yl)-6-(tert-butyl-dimethylsiloxy)-indole-1-carboxylic acid [intermediate compound (92)] instead of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2c]pyrazole-3-yl)-5-(tert-butyl-dimethylsiloxy)-indole-1-carboxylic the acid.

Stage 9. Tert-butyl ester 2-(5-benzoyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(3-bromopropane)-indole-1-carboxylic acid [intermediate compound (94), LC/MS: 696,0 (M+H), RT=4,82 minutes] was prepared with a yield of 72% using methods similar to those described in example 5E, using tert-butyl ester 2-(5-benzoyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-hydroxy-indole-1-carboxylic acid [intermediate compound (93)] instead of tert-butyl methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2c]pyrazole-3-yl)-5-hydroxy-indole-1-carboxylic acid.

Stage 10. 1-{3-[2-(5-benzoyloxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-4-ol [example 69, LC/MS: 517,1 (M+H), RT=3,02 minutes;1H NMR [300 MHz, (CD3)2SO]: δ 13,17 (ush. s, 1H), 11,35 (ush. s, 1H), 7,45-7,25 (m, 6H), 7,20 (s, 1H), 6,91 (d, J=1.7 Hz, 1H), 6,65 (DD, J1=8.6 Hz, J2=2.1 Hz, 1H), 6,55 (s, 1H), 4,78 (s, 2H), 4,59 (s, 2H), 4.53-in (m, 1H), 3,98 (t, J= 6.4 Hz, 2H), 3,44 (m, 1H), 2,72 (m, 2H), 2,50 (m, 2H), 2,01 (m, 2H), 1,89 (m, 2H), 1,71 (m, 2H), 1,32 (m, 2H)] was prepared with a yield of 52% using methods similar to those described in stage 6 of example 5 using tert-butyl ester 2-(5-benzoyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(3-bromo-propoxy)-indole-1-carboxylic acid [intermediate compound (94)] instead of the tert-butyl ester 5-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]feast the evil-3-yl)-indole-1-carboxylic acid and 4-hydroxypiperidine instead of piperidine.

Example 70

3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol

To 1-tert-butyl 6-methyl ether 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1,6-dicarboxylic acid [250 mg, 0.5 mmol, intermediate compound (36)] in tetrahydrofuran (5 ml) was added a solution of 1.0 M of ethylacetamide in tetrahydrofuran (2.5 ml, 2.5 mmol) at -45°C in nitrogen atmosphere. The mixture was left to warm to room temperature and then was stirred for 3 hours. Were added 2 ml of 1.0 M ethylmagnesium. The resulting solution was mixed at room temperature over night. Then the reaction mixture was extinguished with a mixture of brine and saturated ammonium chloride and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 50/50)to obtain 3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol [137 mg, 92%, example 70] in the form of a white powder. LC/MS: 326,2 (M+H), RT=3,07 minutes;1H NMR [300 MHz, (CD3)2SO]: δ of 13.18 (s, 1H), 11,43 (s, 1H), 7,73 (d, J=5,2 Hz, 1H), 7,50 (s, 1H), 7,44 (d, J=8,2 Hz, 1H), 7,18 (d, J= 5,2 Hz, 1H), 6,94 (DD, J1=1.1 Hz, J2=8,4 Hz, 1H), 6,56 (d, J=1.5 Hz, 1H), to 4.41 (s, 1H), 1,76 (m, 4H), to 0.66 (t, J=6.2 Hz, 6H).

Example 71

3-[2-(5-Benzoyloxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol

Stage 1. To tert-butyl ether 5-benzoyloxymethyl-3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid (1.78 g, of 3.78 mmol, intermediate compound (91)] in 1,4-dioxane are successively added copper iodide (0.07 g, 0.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (complex with dichloromethane (1:1)) (0.14 g, 0,19 mmol) and trimethyl(1-tert-butyl-6-methyl ether indole-1,6-dicarboxylic acid)tin [4.1 g, to 9.45 mmol, intermediate compound (37)]. The mixture is stirred at 90°C for 5 hours and then at room temperature for 2 hours. She was diluted with diethylacetal and washed with saturated aqueous sodium bicarbonate and saline. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of n-heptane/ethyl acetate 80/20, then 0/100)to obtain 1-tert-butyl 6-methyl ester 2-(5-benzoyloxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1,6-dicarboxylic acid [1.66 g, 71%, intermediate compound (96), LC/MS: 618,3 (M+H), RT=4,57 minutes] in the form of a yellow powder, and 1-tert-butyl 6-methyl ester 2-(5-benzoyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1,6-dicarboxylic acid [0,37 g, 19%, intermediate compound (95), LC/MS: 518,2 (M+H), RT=a 3.87 minutes] in the form of a green powder.

Stage 2. To 1-tert-butyl 6-methyl ether 2-(5-gasoline oxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1,6-dicarboxylic acid [0.35 g, of 0.68 mmol, intermediate compound (95)] in tetrahydrofuran (5 ml) at -78°C under nitrogen atmosphere was added a solution of 1.0 M of ethylacetamide in tetrahydrofuran (1.7 ml, 1.7 mmol). The mixture is stirred at -78°C for 1 hour. Was added 1.7 ml of a solution of 1.0 M ethylmagnesium. The temperature was raised to -45°C, and the mixture is stirred for 1 hour. Then it was left to warm to room temperature over night. The reaction mixture was extinguished saturated aqueous ammonium chloride and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent - dichloromethane/ethyl acetate 50/50)to obtain 3-[2-(5-benzoyloxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol [95 mg, 61%, example 71] in the form of a powder beige. LC/MS: 446,3 (M+H), RT=3,19 minutes.1H NMR [300 MHz, (CD3)2SO]: δ of 13.18 (s, 1H), 11,44 (s, 1H), 7,50 (s, 1H), 7,45 (s, 1H), 7,43 (d, J=8,3 Hz, 1H), was 7.36 (m, 5H), 7,21 (s, 1H), 6,93 (m, 1H), 6,55 (d, J=1.2 Hz, 1H), 4,78 (s, 2H), 4,59 (s, 2H), 4,43 (s, 1H), 1,75 (m, 4H), 0,66 (m, 6H).

Example 72

[2-(5-Benzoyloxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-piperidin-2-ylmethanol

2-bromopyridin (305 mg, 1.9 mmol) in anhydrous tetrahydrofuran (2 ml) at -78°C under nitrogen atmosphere was added a solution of 2.5 M n-utility in tetrahydrofuran (0,76 ml, 1.9 mmol). Added rest the p 1-tert-butyl 6-methyl ester 2-(5-benzoyloxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-indole-1,6-dicarboxylic acid [160 mg, 0.38 mmol, intermediate compound (96)] in tetrahydrofuran (5 ml). The dark mixture was slowly warmed to room temperature. The mixture was suppressed saturated aqueous ammonium chloride and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was twice chromatographia on silica gel (eluent is a mixture of dichloromethane/ethyl acetate 70/30, then 50/50)to obtain [2-(5-benzoyloxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-piperidin-2-ylmethanol [60 mg, 33%, example 72] in the form of a white powder. LC/MS: 544,2 (M+H), RT=2,65 minutes. NMR1H [300 MHz, (CD3)2SO]: δ 13,19 (ush. s, 1H), of 11.45 (ush. s, 1H), 8,49 (m, 2H), to 7.77 (m, 2H), 7,63 (d, J=7.8 Hz, 2H), 7,43-7,26 (m, 9H), 7,19 (s, 1H), 7,94 (d, J=8.6 Hz, 1H), 6.73 x (d, J=3,7 Hz, 1H), to 6.57 (s, 1H), of 4.77 (s, 2H), 4,58 (s, 2H).

Using the methods described above, it is possible to prepare the following compounds.

Example 73

1-{3-[6-(1-Ethyl-1-hydroxypropyl)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-ylmethyl}-piperidine-4-ol

Example 74

3-[2-(5-Dimethylaminomethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol

Example 75

3-(2-{5-[4-(Pyridine-4-yloxy)-piperidine-1-ylmethyl]-1H-thieno[3,2-c]pyrazole-3-yl}-1H-indol-6-yl)-pentane-3-ol

Example 76

3-[2-(5-Piperazine-1-ylmethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol

Example 77

3-[2-(5-Piperazine-1-yl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol

Example 78

3-{2-[5-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-1H-thieno[3,2-c]pyrazole-3-yl]-1H-indol-6-yl}-pentane-3-ol

Example 79

3-[2-(5-Pyridin-4-yl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol

Example 80

Bis-(1-Methylpiperidin-4-yl)-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-methanol

Example 81

3-[2-(5-Deformity-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol

Example 82

4-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-piperidine-4-ol

Example 83

6-(4-Foreperiod-4-yl)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole

Example 84

2-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-butane-2-ol

Example 85

1-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-alanon

Example 86

3-[3-piperidine-4-yl-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol

Example 87

3-[3-Pyridin-4-yl-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol

Example 88

3-[3-(4-Methylpiperazin-1-yl)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane--ol

Example 89

3-[3-Morpholine-4-ylmethyl-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol

Example 90

4-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-tetrahydro-Piran-4-ol

Example 91

3-{2-[5-(1-Hydroxy-1-methylethyl)-1H-thieno[3,2-c]pyrazole-3-yl]-1H-indol-6-yl}-pentane-3-ol

Example 92

3-[2-(5-Methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-3-pyridin-4-yl-1H-indol-6-yl]-pentane-3-ol

Example 93

4-[2-(5-Methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-6-yl]-tetrahydro-Piran-4-ol

Example 94

3-[2-(5-Methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-3-piperazine-1-yl-1H-indol-6-yl]-pentane-3-ol

Example 95

3-[2-(5-Methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-3-morpholine-4-ylmethyl-1H-indol-6-yl]-pentane-3-ol

Example 96

2-{3-[6-(1-Ethyl-1-hydroxypropyl)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-yl}-tetrahydro-furan-3-carbonitril

Example 97

3-[2-(5-Methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-3-methyl-1H-indol-6-yl]-pentane-3-ol

Example 98

3-[2-(5-Methoxymethyl-1H-thieno[3,2-c]pyrazole-3-yl)-3-piperidine-4-yl-1H-indol-6-yl]-pentane-3-ol

Stage synthetic is for example 22 are described in detail below and shown in Fig. 1:

In Fig. 1, the following intermediate compounds(1), (2), (3), (4), (5), (6) and (7):

The intermediate compound (1)

(4-bromothiophene-2-ylmethyl)dimethylamine

To a solution of 4-bromo-2-thiophene-carboxaldehyde (5 g, to 26.2 mmol) in 1,2-dichloroethane (50 ml) add triacetoxyborohydride sodium (8,3 g, or 39.3 mmol) and dimethylamine (14,5 ml, 28.8 mmol)and then acetic acid (1,55 ml, or 39.3 mmol). This mixture is stirred at room temperature for 2 hours. The insoluble substance was filtered and washed with diethyl ether. The mother liquor is concentrated. The resulting thick oily substance chromatographic on silica gel (eluent - dichloromethane/1.0 M ammonia in methanol, 95:05 90:10) and get oily substance orange. It is dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer is dried over magnesium sulfate, concentrated and receive (4-bromothiophene-2-ylmethyl)-dimethylamine [4,08 g, 71%, intermediate compound (1)] in the form of oily substances orange. LC/MS: RT=0,63 minutes, 219,99 m/e (M+H).

The intermediate compound (2)

3-bromo-5-dimethylaminomethylene-2-carbaldehyde

To (4-bromothiophene-2-ylmethyl)dimethylamine [4,08 g, 18.5 mmol, intermediate compound (1)] in tetrahydrofuran (40 ml) at 0°C in the atmosphere is nitrogen add liedeseplein (2.0 M in a mixture of tetrahydrofuran-pentane production Aldrich Chemicals, to 20.4 mmol). Received the orange solution was stirred at 0°C for 30 minutes. Then add N-formylpiperidine (2.5 ml, of 22.2 mmol). The mixture is stirred at 0°C for 1 hour. The mixture is diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated. The remaining oily substance orange was chromatographically on silica gel (eluent is a mixture of dichloromethane/1.0 M ammonia in methanol, 95:05)to obtain 3-bromo-5-dimethylaminomethylene-2-carbaldehyde [4.4 g, the intermediate compound (2)] in the form of oily substances orange. LC/MS: RT=0,47 minutes, 247,98 m/e (M+H).

The intermediate compound (3)

[5-(Benzhydrylpiperazine)-4-bromothiophene-2-ylmethyl]dimethylamine

To 3-bromo-5-dimethylaminomethylene-2-carbaldehyde [4,30 g, 17.3 mmol, intermediate compound (2)] in ethanol (40 ml) was added benzophenone hydrazone (3.75 g, 19.0 mmol). The solution was heated at 65°C for 5 hours. The solvent was removed under reduced pressure. The residue was chromatographically on silica gel (eluent n-heptane/ethyl acetate 90:10)to obtain [5-(benzhydrylpiperazine)-4-bromothiophene-2-ylmethyl]dimethylamine [5,57 g, 75%, intermediate compound (3)] in the form of oily substances orange. LC/MS: RT=2,72 minutes, 426,05 m/e (M+H).

The intermediate compound (4)

[4-(N'-Ben is gidroliticaskie)-5-(benzhydrylpiperazine)thiophene-2-ylmethyl]-dimethylamine

(4)

To the compound (3) (5.5 g, 12.9 mmol) in solution in toluene (100 ml) was added benzophenone hydrazone (3.03 g, 14.4 mmol), cesium carbonate (7,15 g, 21.9 mmol), palladium diacetate (0,22 g, 2,80 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (1.07 g, 1.94 mmol). The resulting suspension was heated at 100°C for 4 1/2 hours. The solvent is then removed under reduced pressure. The residual oily substance was chromatographically on silica gel (eluent - dichloromethane/methanol 100:0 to 90:10)to obtain [4-(N'-benzhydrylpiperazine)-5-(benzhydrylpiperazine)thiophene-2-ylmethyl]dimethylamine [6,98 g, 100%, intermediate compound (4)] in the form of an orange foam. LC/MS: RT=3,38 minutes, 542,21 m/e (M+H).

The intermediate compound (5)

Dimethyl-(1H-thieno[3,2-c]pyrazole-5-ylmethyl)-Amin

In [4-(N'-benzhydrylpiperazine)-5-(benzhydrylidene-hydrazinophenyl)thiophene-2-ylmethyl]-dimethylamine [intermediate compound (4)] in ethanol (100 ml) was added 50 ml of concentrated hydrochloric acid. The obtained dark red mixture was stirred at 85°C for 2 hours. Was added water, and then was added solid sodium carbonate until the pH was not slightly basic. Then the reaction mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated the Residue was chromatographically (eluent - a mixture of ethyl acetate/1.0 M ammonia in methanol, 90:10)to obtain dimethyl-(1H-thieno[3,2-c]pyrazole-5-ylmethyl)-amine [1.06 g, 45% intermediate compound (5)] in the form of a solid brown color. LC/MS: RT=0.4 minutes, 182,09 m/e (M+H).

The intermediate compound (6)

(3-Iodine-1H-thieno[3,2-c]pyrazole-5-ylmethyl)-dimethylamine

It dimethyl-(1H-thieno[3,2-c]pyrazole-5-ylmethyl)-amine [1 g, 5.51 mmol, intermediate compound (5)] in solution in dimethylformamide (10 ml) was added iodine (2.1 g, 8.3 mmol) and potassium hydrochloride (0.930 g, 16.5 mmol). The dark solution is stirred at room temperature for 5 hours. Was added sodium bisulfite (1.5 g) in aqueous solution. The resulting suspension was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (eluent is a mixture of ethyl acetate/1.0 M ammonia in methanol 90:10)to obtain (3-iodine-1H-thieno[3,2-c]pyrazole-5-ylmethyl)-dimethylamine [0.87 g, 51%, the intermediate compound (6)] in the form of a powder beige. LC/MS: RT=1,20 minutes, 307,98 m/e (M+H).

The intermediate compound (7)

Tert-butyl ester 5-dimethylaminomethyl-3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid

To (3-iodine-1H-thieno[3,2-c]pyrazole-5-ylmethyl)-dimethylamine [0,77 g of 2.50 mmol, intermediate compound (6)] WM is ansii in dichloromethane (10 ml) were added triethylamine (0,36 ml, a 2.75 mmol), tert-BUTYLCARBAMATE (0.66 g, 3.00 mmol) and 4-dimethylaminopyridine (60 mg, 0.2 mmol). The suspension quickly turned into a solution. After that, the solvent was removed. The residue was chromatographically on silica gel (eluent - ethyl acetate)to obtain tert-butyl ester 5-dimethylaminomethyl-3-iodine-thieno[3,2-c]pyrazole-1-carboxylic acid [960 mg, 94%, intermediate compound (7)] in a solid yellow color. LC/MS: RT=2,07 minutes, 408,01 m/e (M+H).

PROTOCOL ANALYSIS IN VITRO FOR TIC

Analysis of mouse splenocytes in IL-4-stimulated with anti-CD3.

Introduction

Tyrosinekinase ITC participates in intracellular signaling events induced by surface receptors of lymphocytes. Since mice that lack TIC decreases the production of IL-4 (interleukin-4) T-cells, using the cell analysis of the production of IL-4 measured the intracellular efficacy of ITK inhibitors of the present invention. In this analysis, the level of IL-4 measured in the environment of murine splenocytes stimulated with anti-CD3, and is determined by the ability of the compounds of the present invention to inhibit this reaction.

Conditions analysis

The spleen of mice of BALB/c are separated, and from preparing a mixed suspension of splenocytes. Spleen homogenized using a cell filter (Falcon, cat. No. 352350 and 5 ml syringe) in the environment RPMI. centrifuged and the pellets suspended in 3 ml of buffer for lysis of red blood cells (Red Blood Cell Lysing Buffer, Sigma, cat. No. 7757) and leave on for 10 minutes at room temperature. The cells are again centrifuged and re-suspended in RPMI medium containing 10% ETS, and passed through a cell filter. The total number of cells is determined by hemocytometer.

The number of cells of splenocytes is chosen equal to 10 million per milliliter of RPMI medium containing 10% fetal calf serum (ETS), and 100 ál of this suspension is placed in wells of 96-well plate with a round bottom. 50 μl of RPMI medium containing 4-fold the final concentration of the analyzed compounds, is added to each cell. To determine IC50 use the following concentration of the compound. The initial concentration of 10 μm, followed by 7 dilutions 1:3, and in each concentration of the compound is placed in three wells. Added to 50 μl of 4-fold concentration. Then cell cultures stimulated by adding 50 μl solution of 4 μg/ml anti-CD3 antibodies (BD Bioscience, cat. No. 553166)prepared in RPMI medium containing 10% ETS, and incubated at 37oC CO2-the incubator for 3 days. At the end of the 3-day incubation, the culture medium was removed and 50 ál of solution are injected on the subject of education IL-4 by the method of enzyme-linked immunosorbent assay (ELISA kit IL-4 ELISA production R&D Systems, Inc., cat. No. M4000 standard conditions described by the manufacturer.

UB is neither IL-4 lay on the graph as a function of the concentration of the compound. The resulting curve to determine the concentration of compound causing 50% inhibition of IL-4, which is called the IC50 (IL-4).

Order analysis

1. Add 100 µl of 1×107/ml murine splenocytes in RPMI medium containing 10% ETS, in 96-well tablets with a round bottom.

2. Add 50 μl of the compounds of TIC (4-fold final concentration) in RPMI medium containing 10% ETS.

3. Add 50 ál solution of 4 μg/ml anti-CD3 antibody in RPMI medium containing 10% ETS.

4. Incubate at 37°C in CO2-the incubator for 3 days.

5. Transfer 150 ál of culture medium in a fresh tablet.

6. 50 ál of medium to use for ELISA analysis (set R&D, cat. No. M4000).

The Protocol definition inhibition of ITK with tablet FlashPlate

ITK kinase is produced with N-terminal tagged maltose-binding protein (MW=~114 kDa) using baculovirus expression system. The transfer of radioactive [γ-33P] phosphate from [γ-33P]ATP at ITC in the process of autophosphorylation ITC is measured by the method of counting scintillations. 384-well microplates FlashPlate PlusTMcoated with streptavidin (PerkinElmer Life Sciences) are designed to perform radiometric analysis inside the tablet. The inner surface of each hole is constantly covered with a thin layer of scintillator and covalently-linked layer of streptavidin. ITC is arsiwala

[γ-33P]ATP, biotinylated anti-exchange rate antibody (Cell Signaling TechnologyTM) and analyzed compounds in 384-well streptavidin coated tablet FlashPlate. Biotinylated anti-exchange rate tightly associated with exchange rate-tagged ITK and knits her with streptavidin on the surface of the tablet. Unreacted33P-ATP, washed, and measured33P-phosphorylated TIC, with built-in TIC [γ33P] passes the excitation of the scintillator on the surface of the holes to the light emission. Radioactivity is recorded using a scintillation counter Packard TopCount. The reagents are metered and dispensed using robotic equipment manufactured by Beckman Biomek. Test compounds (2 ál per well) pre-diluted from solutions of 1 mm in 100% dimethyl sulfoxide in a 30% solution of DMSO in water, to obtain the dose dependence curves (curves of 10 points from the final concentration of 30 ám to ~1 nm); all tests are performed twice. Background binding is analyzed by replacing the enzyme inhibitor EDTA (ethylenediaminetetraacetate, final concentration 25 mm) during the connection, and the maximum binding is analyzed to enable analytical buffer instead of connecting. The first hole is added to the analyzed compound (2 MKS), and then 10 μl of an enzyme solution analyte in the logical buffer. After a 30-minute pre-incubation, add all the other reagents in a volume of 10 µl. The final concentration of reagents in the well as follows: 20 nm enzyme of 0.25 µci

[γ-33P]ATP, analytical buffer: 20 mm HEPES (N-2-hydroxyethylpiperazine-N-2-econsultancy acid) (pH 7.5), 0.15 M NaCl, 3 mm MgCl2, 3 mm MnCl20.01% of Triton X-100, 1 mm DDT, 5% glycerol and 0.01% γ-globulin. The plate is incubated at room temperature for 60 minutes, to pass the kinase reaction. The reaction is stopped using 20 μl of a solution of 50 mm EDTA (ethylenediaminetetraacetate), and biotinylation anti-exchange rate is allowed to communicate with the ICT streptavidin in the next 60 minutes at room temperature. Unbound reagents are washed with saline phosphate buffer, 2×100 μl. Radioactivity is measured for 45 s in each hole.

The results of these analyses for the compounds of this invention are shown in table I.

Table I
The MOLECULAR STRUCTURE AND the name of the SUBSTANCEMolecular weightThe observed M+HHPLC, retention timeIC50
(enzyme inhibition), nm
IC50 Analysis of the inhibition of the release of IL-4, nm

2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-benzoimidazol
240,05241,041,82167264

6-Methoxy-2-(1-H-thieno[3,2-c]pyrazole-3-yl)-1-H-benzoimidazol
270,06271,051,9157164

3-(6-Methoxy-1H-benzoimidazol-2-yl)-1H-benzo[4,5]thieno[3,2-c]pyrazole
320,07321,052,43862900

Tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-5-(tert-butyl-dimethylsiloxy)-indole-1-carboxylic acid
569,24570,14,29

5-(3-piperidine-1-yl-propoxy)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole
380,52381,182,1816,6153

1-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-4-ol
396,16397,182,17the 3.65180

6-(3-piperidine-1-yl-propoxy)-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole
380,17381,182,321,89163

1-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-3-ol
396,16397,42,451,6211,3

(1-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-3-yl)-methanol
410,18411,292,492,08129

6-[3-(4-This is l-piperazine-1-yl)-propoxy]-2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole
409,19410,32,272,94289

Diethyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-amine
368,17369,192,355,22

Diallyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-amine
392,17393,142,4812,3

1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-pyrrolidin-3-ol
382,15383,172,215,1

Dimethyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-amine
340,14341,132,1824,2

2-(Methyl-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-amino)-ethanol
370,14371,252,133,26

5-(Methoxy-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-pyrrolo[3,2-b]pyridine
270,05271,022,03224

1-{3-[2-(1H-thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yloxy]-propyl}-piperidine-4-ol
396,16397,172,03of 40.9

1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yloxy]-propyl}-piperidine-3-ol
396,16397,21,8776,3

(1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yloxy]-propyl}-piperidine-3-yl)-methanol
410,17411,182,0741

1-{3-[2-(1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indol-5-yloxy]-propyl}-pyrrolidin-3-ol
382,14383,22,48of 45.7

3-(5-(3-piperidine-1-yl-propoxy)-1H-benzoimidazol-2-yl)-1H-benzo[4,5]thieno[3,2-c]pyrazole hydrochloride
431,18432,182,49112

2-{1H-Thieno[3,2-c]pyrazole-3-yl)-1H-indole-5-carboxylic acid (2-thiophene-2-yl-ethyl)-amide
392,07393,23,22
1
Tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(tert-butyl-dimethylsiloxy)-indole-1-carboxylic acid
569,24570,24,22

Tert-butyl ester 2-(1-tert-butoxycarbonyl the-5-dimethylaminomethyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-(tert-butyl-dimethylsiloxy)-indole-1-carboxylic acid
626,29627,28to 3.73

Tert-butyl ester 2-(1-tert-butoxycarbonyl-5-dimethylaminomethyl-1H-thieno[3,2-c]pyrazole-3-yl)-6-hydroxy-indole-1-carboxylic acid
512,2513,22,47
1-{3-[2-(5-Dimethylaminoethyl-1H-thieno[3,2-c]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-4-ol453,24541,87

1. Theoperator formula I

where:
X represents N or C-R7;
X1denotes N or C-R1;
R1, R2, R3, R4, R5and R6independently selected from the group comprising hydrogen, possibly substituted acyl, possibly substituted alkyl, possibly substituted alkoxygroup, possibly substituted alluminare, possibly substituted alkoxyalkyl, (Y1)(Y2)NC(=O)-, possibly substituted alkoxycarbonyl, possibly substituted aryl, halogen, carboxy is the SCP; or
R5and R6together with the two carbon atoms with a double bond to which they are connected, form a possibly substituted benzene ring;
R7is a hydrogen atom, halogen or possibly substituted alkyl; and
Y1and Y2independently represent a hydrogen atom, possibly substituted alkyl, possibly substituted aryl or possibly substituted heteroaryl or Y1and
Y2together with the nitrogen atom to which they are connected, form a possibly substituted heteroaryl group or a possibly substituted geterotsyklicescoe group, or its pharmaceutically acceptable salt or ester.

2. Pharmaceutically acceptable salt or ester of canoperate according to claim 1.

3. The compound according to claim 1, in which R1, R2, R3, R4, R5, R6independently selected from the group comprising hydrogen, possibly substituted acyl, possibly substituted alkoxygroup, possibly substituted alkoxycarbonyl, possibly substituted alkyl, possibly substituted aryl, carboxy, halogen or (Y1)(Y2)NC(=O)-, where Y1and Y2independently represent a hydrogen atom, possibly substituted alkyl, possibly substituted aryl or possibly substituted heteroaryl or Y1and Y2together with the nitrogen atom to which they are connected, form a possibly substituted, heteroaryl the second group or perhaps substituted geterotsyklicescoe group.

4. The compound according to claim 3, in which X and X1independently represent N, C-N or C-halogen; one of R2and R3is a hydrogen atom, and R6- the hydrogen atom.

5. The compound according to claim 3, in which X1represents the C-H; X is N, C-Br or C-H.

6. The compound according to claim 5, in which one of R2and R3is an atom of hydrogen and one of R2and R3selected from the group comprising a hydrogen atom,,,,,,,,,,,,,,,,,,,,,,,,,,, halogen,,,,,, and.

7. The compound according to claim 5, in which R4is a hydrogen atom or its pharmaceutically acceptable salt or ester.

8. The connection according to claim 6, in which R5is selected from the group comprising a hydrogen atom,,,,,,,,,,,carboxypropyl,,and.

9. Pharmaceutically acceptable salt or ester of canoperate according to claim 7.

10. The connection according to claim 7, which is selected from the group which includes:
2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-benzoimidazol,
6-methoxy-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-benzoimidazol,
3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-benzo[4,5]thieno[3,2-C]pyrazole,
6-(3-piperidine-1-ylpropionic)-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-benzoimidazol,
5-(3-piperidine-1-ylpropionic)-2-(1H-thieno[3,2-C]pyrazole-3-yl)-indole,
1-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-4-ol,
6-(3-piperidine-1-yl-propoxy)-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole,
1-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-yloxy]-propyl}-piperidine-3-ol,
(1-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-3-yl)-methanol,
6-[3-(4-ethyl-piperazine-1-yl)-propoxy]-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole,
dimethyl-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}amine,
diethyl-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}amine,
diallyl-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}amine,
1-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}pyrrolidin-3-ol,
2-(methyl-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-amino)-ethanol,
1-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yloxy]-propyl}piperidine-4-ol,
1-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yloxy]-propyl}piperidine-3-ol,
(1-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yloxy]-propyl}piperidine-3-yl)-methanol,
1-{3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yloxy]-propyl}-pyrrolidin-3-ol,
3-(5-(3-piperidine-1-ylpropionic)-1H-benzoimidazol-2-yl)-1H-benzo[4,5]thieno[3,2-C]pyrazole,
(2-thiophene-2-yl-ethyl)-amide 2-{1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-5-carboxylic acid,
1-{3-[2-(5-dimethylaminoethyl-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-4-ol,
tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)-5-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid;
tert-butyl ester 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-C]pyrazole-3-yl)-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic key is lots;
tert-butyl ester 2-(1-tert-butoxycarbonyl-5-dimethylaminomethyl-1H-thieno[3,2-C]pyrazole-3-yl)-6-(tert-butyldimethylsilyloxy)-indole-1-carboxylic acid; and
tert-butyl ester 2-(1-tert-butoxycarbonyl-5-dimethylaminomethyl-1H-thieno[3,2-C]pyrazole-3-yl)-6-hydroxyindole-1-carboxylic acid;
[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-methanol,
phenyl-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-methanol,
phenyl-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-methanon,
1-phenyl-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-ethanol,
(S)-1-phenyl-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-ethanol,
1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propane-1-he,
1-cyclohexyl-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol,
1-cyclohexyl-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol, enantiomer 1,
1-pyridin-2-yl-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol,
2-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol,
(R)-2-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-butane-2-ol,
1-(2-pyrrolidin-1-ylmethylene)-1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]-propan-1-ol,
1-tert-butyl-5-methyl ether 3-(5-acetyl-1-tert-butoxycarbonyl-1H-indol-2-yl)thieno[3,2-C]pyrazole-1,5-dicarboxylic acid,
methyl ester 3-(5-acetyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid,
3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid,br/> [4-(4-forfinal)-piperazine-1-yl]-[3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-yl]-methanon,
3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid (3-ethoxy-propyl)-amide,
methyl ester 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid,
3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-C]pyrazole-5-carboxylic acid (pyridine-2-ylmethyl)-amide,
5-bromo-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole,
methyl ester of 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid,
dicyclopropyl-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-methanol,
(4-benzo[1,3]dioxol-5-iletileri-1-yl)-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-methanon,
[4-(2-cyclohexylethyl)-piperazine-1-yl]-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-methanon,
(2-hydroxy-2-phenyl-ethyl) - amide 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid,
(2-cyclohex-1-teletel)-amide 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid,
(2-thiophene-2-yl-ethyl)-amide 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid,
(4-pyridin-2-yl-piperazine-1-yl)-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-methanon,
(2-pyridin-3-yl-ethyl)-amide 2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-carboxylic acid,
cyclohexylmethyl-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-ylmethyl]Amin,
5-[4-(4-Chlorobenzyl)-piperazine-1-ylmethyl]-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole,
[2-(4-phenoxy enyl)-ethyl]-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-ylmethyl]-amine,
3-[6-(3-piperidine-1-yl-propoxy)-1H-benzoimidazol-2-yl]-1H-benzo[4,5]thieno[3,2-C]pyrazole,
1-{3-[2-(5-phenyl-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-3-ol,
1-{3-[2-(5-phenyl-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-4-ol,
2-(5-phenyl-1H-thieno[3,2-C]pyrazole-3-yl)-6-(3-piperidine-1-yl-propoxy)-1H-indole,
1-(3-{2-[5-(3-methoxyphenyl)-1H-thieno[3,2-C]pyrazole-3-yl]-1H-indole-6-yloxy}-propyl)-piperidine-4-ol,
5-methoxy-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-pyrrolo[3,2-b]pyridine,
3-bromo-6-(3-piperidine-1-yl-propoxy)-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole,
{3-[6-(3-piperidine-1-yl-propoxy)-1H-indol-2-yl]-1H-thieno[3,2-C]pyrazole-5-yl}-methanol,
1-{3-[6-(3-piperidine-1-yl-propoxy)-1H-indol-2-yl]-1H-thieno[3,2-C]pyrazole-5-ylmethyl}-piperidine-4-ol,
2-{5-[4-(4-forfinal)-piperazine-1-ylmethyl]-1H-thieno[3,2-C]pyrazole-3-yl}-6-(3-piperidine-1-yl-propoxy)-1H-indole,
methyl-{3-[6-(3-piperidine-1-yl-propoxy)-1H-indol-2-yl]-1H-thieno[3,2-C]pyrazole-5-ylmethyl}-pyridine-2-yl-amine,
benzyl-{3-[6-(3-piperidine-1-yl-propoxy)-1H-indol-2-yl]-1H-thieno[3,2-C]pyrazole-5-ylmethyl}-amine,
6-(3-piperidine-1-yl-propoxy)-2-[5-(4-triftormetilfosfinov-1-ylmethyl)-1H-thieno[3,2-C]pyrazole-3-yl]-1H-indole,
[2-(5-piperidine-1-ylmethyl-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-5-yl]methanol,
1-{3-[2-(5-benzoyloxymethyl-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole-6-yloxy]-propyl}-piperidine-4-ol,
3-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]pentane-3-ol,
3-[2-(5-benzilic imethyl-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol, and
[2-(5-benzoyloxymethyl-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-di-pyridin-2-yl-methanol.

11. The compound according to claim 1, which is selected from the group which includes:
1-{3-[6-(1-ethyl-1-hydroxypropyl)-1H-indol-2-yl]-1H-thieno[3,2-C]pyrazole-5-ylmethyl}-piperidine-4-ol,
3-[2-(5-dimethylaminomethyl-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol,
3-(2-{5-[4-(pyridine-4-yloxy)-piperidine-1-ylmethyl]-1H-thieno[3,2-C]pyrazole-3-yl}-1H-indol-6-yl)-pentane-3-ol,
3-[2-(5-piperazine-1-ylmethyl-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol,
3-[2-(5-piperazine-1-yl-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol,
3-{2-[5-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-1H-thieno[3,2-C]pyrazole-3-yl]-1H-indol-6-yl}-pentane-3-ol,
3-[2-(5-pyridin-4-yl-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol,
bis-(1-methylpiperidin-4-yl)-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-methanol,
3-[2-(5-deformity-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol,
4-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-piperidine-4-ol,
6-(4-foreperiod-4-yl)-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indole,
2-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-butane-2-ol,
1-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-Etalon,
3-[3-morpholine-4-ylmethyl-2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-pentane-3-ol,
4-[2-(1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-tetrahydro-Piran-4-ol,
3-{2-[5-(1-hydroxy-1-methyl-ethyl)-1H-thieno[3,2-C]pyrazole-3-yl]-1H-indol-6-yl}-pentane-3-ol,
4-[2-(5-m is taximeter-1H-thieno[3,2-C]pyrazole-3-yl)-1H-indol-6-yl]-tetrahydro-Piran-4-ol,
3-[2-(5-methoxymethyl-1H-thieno[3,2-C]pyrazole-3-yl)-3-morpholine-4-ylmethyl-1H-indol-6-yl]-pentane-3-ol,
2-{3-[6-(1-ethyl-1-hydroxypropyl)-1H-indol-2-yl]-1H-thieno[3,2-C]pyrazole-5-yl}-tetrahydro-furan-3-carbonitril,
3-[2-(5-methoxymethyl-1H-thieno[3,2-C]pyrazole-3-yl)-3-methyl-1H-indol-6-yl]-pentane-3-ol.

12. Pharmaceutically acceptable salt or ester of canoperate on any of PP or 11.

13. Pharmaceutical product which is able to inhibit the protein kinase ITK, which includes an active ingredient and pharmaceutically acceptable excipient where the above-mentioned active ingredient is a compound according to claim 1.

14. Pharmaceutical product according to item 13, in which the aforementioned active ingredient is a compound according to claim 9.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention refers to Clopidogrel process by optical separation of its racemic form with using optically active amine of formula V to make optically active form of compound of formula III or its acid-additive salt followed with methylation of compound III or its salts. The intermediate product of formula resulted from reaction of racemic form of Clopidogrel and amine V.

EFFECT: possibility to make a high-yield end product.

22 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new spirocyclic cyclohexane derivatives of general formula I , where: R1-R3, R5-R10, W, X are disclosed in the claim 1 of formula.

EFFECT: compounds exhibit analgesic activity to be applied for making a medical product for pain therapy.

20 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention concerns development of method of obtaining furylhetarylmethane derivatives of the general formula I applicable as semiproducts for obtainment of new polycyclic derivatives of thieno[2,3-b]pyridine. Method of obtaining furylhetarylmethanes with thieno[2,3-b]pyridine fragment of the general formula I involves forming furylhetarylmethane structure by alkylation of furane ring catalysed by acids; reaction is performed by boiling alcohols of 3-amino[2,3-b]pyridine and 2-methylfurane range in dioxane in the presence of 0.2-0.4 ml of acid catalyst, which is a mix of 70% perchloric acid, acetic anhydride and glacial acetic acid at the ratio of HClO4:(CH3CO2)O:CH3COOH=0.056:0.033:0.052 mol for 1.5-8 hours. It allows forming new heterocyclic system of furylhetarylmethanes with thieno[2,3-b]pyridine fragment by alkylation of 2-methylfurane by 2-hydroxy(phenyl)methyl-4,6-disubstituted-3-substituted carboxamidothieno[2,3-b]pyridines.

EFFECT: obtaining compounds applicable as semiproducts for obtainment of new polycyclic derivatives.

2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of obtaining heterocycles of formula I , where X, A, R10-R17 are as defined in point 1 of the claim, while a) isothiocyanate of formula II is transformed into thiourea of formula IV by interaction with primary amine of formula III, and b) thiourea of formula IV is transformed into compound of formula I by interaction with sulfochloride R6SO2Cl in the presence of a base, where A, X, n, m and R10 to R17 in compounds of formulae II, III and IV are as defined in formula I, and R6 is (C1-C4)-alkyl, trifluoromethyl or phenyl non-sustituted or substituted by methyl, trifluoromethyl, F, CI, Br or polymer carreir. The transportation is shown by combination formulae

EFFECT: new multipurpose synthesis technique for heterocyclic compounds of the general formula I.

8 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new photochromic monomers

Alk=CH3-C10H21 X=Cl, Br, I, F, NH2, CH2OH, CH2Cl, CH2Br, CHO, CO2H, method of obtaining them, photochromic polymers- polyazomethines, which are reversibly photocontrolled due to introduction into their structure, of dihetarylenthane class photochromic fragments.

EFFECT: obtaining new photochromic photocontrolled polymers for designing new information technologies.

8 cl, 25 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new photochromic monomers and new polymers based on such monomers, intended for use in making two-photon photochromic recording media for three dimensional optical memory and photoswitches of optical signals. Description is given of monomers

Q=; ; ;

Alk=CH3-C10H21 X=Cl, Br, I, F, NH2, CH2OH, CH2Cl, CH2Br, CHO, CO2H and X=CH2, O, S, NAlk; Y=O, S, NAlk; n=0-6; Q=; ; ; ; ;

Alk=CH3-C10H21, methods of obtaining them, photochromic polymers based on them, method of obtaining photochromic monomers and their application. The proposed materials exhibit thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

EFFECT: obtaining materials with thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

15 cl, 46 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of obtaining derivatives of 8-thieno[2,3-b]indole of general formula I and can be used for obtaining biologically active substances. Method is characterised by the fact that derivatives of 2-alkyl-5-(2-isothiocyanoaryl)furanes are mixed in 1,2-dichloroethane in presence of aluminium chloride with molar ratio of initial substance and aluminium chloride 1:1÷1:2 at temperature from room temperature to temperature of 1,2-dichloroethane boiling for from 30 min to 48 hours. I a-e, Ia R1 = H, R2 = CH3, b R1 = H, R2 = CH2CH3, c R1 = CI, R2 = CH3, d R1 = CH3, R2 = CH3, e R1 = OCH3, R2 = CH3.

EFFECT: extension of series of potentially biologically active derivatives of the said agent.

1 cl, 6 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: described are new derivatives of imidazo-pyridine with general formula I in racemic, enantiomeric form or in combination of these forms, and their pharmaceutically used salts. Radicals R1-R4 are described in the description.

EFFECT: these compounds have affinity to melanocortin receptor; possibility of using them in making medicinal agents for treating disorders, related to body weight, mental disorders, pain, sexual activity disorders.

21 cl, 5 ex, 1 tbl

Kinase inhibitors // 2348635

FIELD: chemistry; pharmacy.

SUBSTANCE: invention concerns new compounds of formula I: , where W is , X is N or C-R1; R is C1-C7alkyl, C3-C7cycloalkyl, (C1-C7alkylene)-(C3-C7cycloalkyl), -SO2-(C1-C7alkyl) or -SO2-NR5R6; R1 is hydrogen, amino, methyl or -N=CH(NMe)2; R is phenyl optionally substituted by one or more substitutes selected independently out of halogen; R3 is hydrogen, C1-C7alkyl, C3-C7cycloalkyl or phenyl optionally substituted by one or more substitutes selected independently out of halogen and trifluoromethyl; R4 is hydrogen or C1-C7alkyl; R5 and R6 are independently selected out of group including C1-C7alkyl; and its pharmaceutically acceptable salts. Also invention concerns pharmaceutical composition and application.

EFFECT: obtaining new bioactive compounds with inhibition effect on kinase p-38.

10 cl, 114 ex

FIELD: medicine; pharmacology.

SUBSTANCE: apply 7-bromomidazo[4,5-b]indole-2-thyone, possessing antihypoxic action against hypobaric hypoxia at the level of reference antihypoxic agent and exceeding standard action on models of hypercapnic and hemic hypoxias.

EFFECT: expansion of an arsenal of medical products for control of hypobaric, hypercapnic and hemic hypoxias.

1 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutical industry, in particular the structure for stimulation of hair growth. The structure for stimulation of hair growth in the form of a composition of the local application, containing active substances: melatonin or its derivative; Gingko Biloba and biotin. Application of the above described compound for enhancement of hair growth.

EFFECT: provision of effective stimulation of hair growth.

17 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to the field of pharmacology and medicine and concerns the application of 4-acetyl-7-bromine-8b-hydroxy-3a,8b-dihydroimizado[4,5-b]indole-2-thione for protection of organism against hypobaric and gemic hypoxia.

EFFECT: increase of efficiency of organism protection against impact of hypobaric and gemic hypoxia.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to the field of pharmacology and medicine and concerns the application of 7-bromine-4-acetylmidazo[4,5-b]indole-2-thione for protection against hypobaric and hypercapnic hypoxia.

EFFECT: increase of efficiency of protection against hypobaric and hypercapnic hypoxia.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: medical product for hemic hypoxia prevention is offered. Product represents imidazo[4,5-b]indole-2-thione. It is shown, that substance saves life of 16.7% of mice suffering from hemic hypoxia while reference preparation Amthizole solely increases life expectancy and does not prevents death. Invention presupposes possibility of composition application for prevention of harmful toxic agent activity, blocking haemoglobin production within chemical production conditions and in emergency cases.

EFFECT: product has improved efficiency.

1 tbl

FIELD: medicine; cosmetic substances.

SUBSTANCE: invention refers to medicine agents and concerns mineral complex with vitamins added for dry skin containing beta-carotene, vitamin B5, vitamin E, vitamin PP, zinc, biotin, selenium, characterised by the following component proportions (mg per 1 dose): beta-carotene 1.0-5.0; vitamin B5 7.5-22.5; vitamin E 15.0-45.0; vitamin PP 15.0-45.0; biotin 35.0-105.0; zinc 6.0-18.0; selenium 0.0275-0.0775.

EFFECT: improving of dry skin health.

1 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to pharmaceutical agents and applied to composition with local anesthetic activity, with the following formulation: 0.0125-0.05% dihydrochloride 1-(3-pyrrolidine propyl)-2-phenylimidazol[1,2-а]-benzimidazole, the rest amount is constituted by 1% Visiton-PEG.

EFFECT: composition increases and prolongs the local anesthetic activity.

3 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a system for controlled release of temosolomide that comprises 10 wt.-% of temosolomide and biodegradable polymeric material representing polyanhydride. This polyanhydride is synthesized by condensation of 3,4-bis-(p-carboxyphenoxy)propane with sebacic acid in their ratio = 20:80, respectively. The system for controlled release of temosolomide represents implanted tablets. Implants are able to release anticancer preparation temosolomide by the controlled manner in vivo for prolonged time from 1 h to 4 weeks.

EFFECT: improved and valuable medicinal and pharmaceutical properties of system.

13 cl, 1 tbl, 2 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones with general formula (I), including all their enantiomeric and diastereomeric forms, as well as their pharmaceutically used salts, which inhibit undesirable or excessive excretion of cells of phlogistic cytokines, chosen from "ФНО-α" and "ИЛ-1β" and can be used for treating congestive heart failure, for example. In formula (I): R is: a) -O[CH2]kR3, where k=0; or b) -NR4aR4b; R3 is substituted or unsubstituted with phenyl, in which substitutes are chosen from halogen, C1-C4 alkyl; one of R4a and R4b is a independently a hydrogen atom; and the other of R4a and R4b is b) -[C(R5aR5b)]mR6; R5a and R5b each is independently a hydrogen atom, straight, or branched alkyl C1-C4, R6 is substituted or unsubstituted with alkyl C1-C4, in which substitutes are chosen from -OR7, cyano, phenyl, 6-member saturated heterocycle, containing a heteroatom in form of nitrogen, unsubstituted 5-6-member heteroaryl, containing 1-2 heteroatoms, chosen from nitrogen and oxygen; group R7 is a hydrogen atom, water soluble cation, alkyl C1-C4, index m assumes values from 0 to 5; R1 is: a) unsubstituted or substituted by 1-2 substitutes, chosen from halogen or C1-6alkyl, phenyl; L is a bridge group, chosen from: 1) -[C(R12)2]n-, where each R12 denotes hydrogen or together with two R12 groups form a carbonyl group, n= 1-2 ; 2) -[C(R12)2]nNR12[C(R12)2]n-, chosen from -[CH2]nNHC(O)- group, where n=1-2; and 3)-[C(R12)2]nO[C(R12)2]n-, where n=0; each R2 fragment is independently chosen from hydrogen; Z is O.

EFFECT: agents are highly effective.

24 cl, 4 dwg, 10 tbl, 4 ex

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