Derivatives of benzimidazol inhibiting factor xa

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

 

The present invention relates to compounds of formula I

in which R0, R1, R2, Q, V, G and M have the meanings specified below. The compounds of formula I are valuable pharmacologically active compounds. They have a strong antithrombotic effect and are suitable, for example, for the treatment and prevention of cardiovascular disorders, such thromboembolic diseases or restenoses. They are reversible inhibitors of the enzyme factor XA (FXa) and/or factor VIIa (FVIIa) blood clotting, and can in General be applied in conditions in which there is undesired activity of factor XA and/or factor VIIa or for the treatment or prevention of which is expected inhibition of factor XA and/or factor VIIa. In addition, the invention relates to a method for producing compounds of the formula I, their use, in particular as active ingredients in pharmaceutical preparations containing pharmaceuticals.

Normal hemostasis is the result of a complex balance between the processes of stimulation, the formation of a clot of blood and dissolving the blood clot. The complex interaction between blood cells, specific plasma proteins and vascular surface supports the fluidity of blood, unless you have the t location of the damage and the loss of blood (EP-A-987274). Many significant pathological condition related to abnormal hemostasis. For example, the local formation of a blood clot is the result of the rupture of atherosclerotic plaque, a major cause of acute myocardial infarction and unstable angina. Treatment alterimage coronary thrombus either thrombolytic therapy or subcutaneous plastic surgery on the blood vessels may be accompanied by acute thrombolytic re-closure of the affected vessel.

Continues to be a need for safe and effective therapeutic anticoagulants to limit or prevent blood clots. The most desirable is to develop agents that inhibit coagulation without direct inhibition of thrombin, but through inhibition of other stages in the coagulation cascade, similar to the inhibition of the activity of factor XA and/or factor VIIa. Currently, it is believed that inhibitors of factor XA lead to a lower risk of bleeding than thrombin inhibitors (A. E. P. Adang & J. B. M. Rewinkel, Drugs of the Future 2000, 25, 369-383).

In WO-A-95/29189 described, for example, having a low molecular weight, specific for factor XA inhibitors of blood coagulation, which are effective, but do not cause unwanted side effects. However, besides the fact that they are inhibitorresistant blood, specific for factor XA, it is desirable that such inhibitors also had more favorable properties, for example, showed stability in plasma and liver and selectivity against other semiprotect, the inhibition of which is not anticipated, such as thrombin. Currently, there is a need for having a low molecular weight, specific for factor XA inhibitors, blood coagulation, which are effective and also have the aforementioned advantages.

Specific inhibition of the catalytic complex of factor VIIa/tissue factor using monoclonal antibodies (WO-A-92/06711) or protein, such as an inactivated by chloromethylketone factor VIIa (WO-A-96/12800, WO-A-97/47651), is a very effective way of dealing with the formation of a blood clot, caused by acute arterial damage or thrombotic complications related to bacterial sepsis. There is also experimental evidence to suggest that the inhibition of the activity of a complex of factor VIIa/tissue factor inhibits restenosis after balloon plastic surgery on the blood vessels. The study bleeding conducted on baboons and this study showed that inhibition of the complex of factor VIIa/tissue factor has the widest window security agains therapeutic efficacy and the risk of bleeding for any anticoagulant tested approach including the inhibition of thrombin, platelets and factor XA. Some inhibitors of factor VIIa already described. In EP-A-987274, for example, described containing Tripeptide link compounds that inhibit factor VIIa. However, the profile of properties of the above compounds is not perfect, and at present there is a need for additional low molecular weight inhibitory factor VIIa inhibitors of blood coagulation.

The present invention satisfies the above needs by providing novel compounds of the formula I, which are the best inhibitory activity against factor VIIa and/or tissue factor and are suitable agents with high biological availability.

1. Thus, the present invention relates to compounds of formula I

in which

R0represents a

1) monocyclic or bicyclic 6-14-membered aryl, where aryl is mono-, di - or triamese independently of each R8,

2) monocyclic or bicyclic 4 to 15-membered heterocyclyl from the group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophene, cinnoline, Romania, indazole, indoline, isopropanyl, isoindolyl, izochinolina, phenylpyridine, phthalazine, pteridine, purinol is, pyridyl, predominately, pyridopyrimidines, pyridopyrimidines, pyrimidinyl, heatline, chinoline, khinoksalinona or 1,4,5,6-tetrahydropyridine where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8or

3) a monocyclic or bicyclic 4 to 15-membered heterocyclyl containing one, two, three or four heteroatoms chosen from nitrogen, sulphur or oxygen, where indicated heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8and which is optionally substituted monocyclic or bicyclic 4 to 15-membered heterocyclyl containing one, two, three or four heteroatoms chosen from nitrogen, sulphur or oxygen, where heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8,

R8represents a

1) halogen,

2) -NO2,

3) -CN,

4) -C(O)-NH2,

5) -OH,

6) -NH2,

7) -O-CF3,

8) a monocyclic or bicyclic 6-14-membered aryl, where aryl is mono-, di - or triamese independently of one another by halogen or-O-(C1-C8)alkyl,

9) -(C1-C8alkyl), where alkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen, NH2HE or balance methoxy,

10) -O-(C1-C8/sub> alkyl), where alkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen, NH2HE or balance methoxy,

11) -SO2-CH3or

12) -SO2-CF3,

provided that R8represents at least one halogen atom, -C(O)-NH2or-O-(C1-C8)alkyl residue, if R0represents a monocyclic or bicyclic 6-14-membered aryl,

provided that R8is not-O-(C1-C8)alkyl residue, if R0and V represents a monocyclic or bicyclic 6-14-membered aryl,

substructure

in the formula I represents a 4-8 membered saturated, partially unsaturated or aromatic cyclic group containing 0, 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, and is unsubstituted or substituted 1, 2, 3, 4, 5 or 6 times R3or substituted 1 or 2 times =O,

Q represents a direct bond, -(C0-C2)alkylen-C(O)NR10-,

-NR10-C(O)NR10-, -NR10-C(O)-, -SO2-, methylene,

-(CH2)m-NR10-C(O)-NR10-(CH2)n-, -(CH2)m-NR10-C(O)-(CH2)n-,

-(CH2)m-S-(CH2)n-, -(CH2)m-C(O)-(CH2)n-, -(CH2)m-SO2-NR10 -(CH2)n-,

-(CH2)m-NR10-SO2-(CH2)n-, -(CH2)m-NR10-SO2-NR10-(CH2)n-,

-(CH2)m-CH(OH)-(CH2)n-, -(CH2)m-O-C(O)-NR10-(CH2)n-,

-(C2-C3)alkylen-O-(C0-C3)alkylene-, -(C2-C3)alkylen-S(O)-,

-(C2-C3)alkylen-S(Oh)2-, -(CH2)m-NR10-C(O)-O-(CH2)n-,

-(C2-C3)alkylen-S(Oh)2-NH-(R10)-, -(C2-C3)alkylene-N(R10)- or

-(C0-C3)alkylen-C(O)-O-(CH2)m-,

where R10has the values listed below, and where n and m are independently of one another identical or different and are equal to integers 0, 1, 2, 3, 4, 5 or 6, where alkylene residues, which are formed by -(CH2)m- or -(CH2)n-are unsubstituted or mono-, di - or tizamidine independently of one another by halogen, -NH2or is HE; or

-(C3-C6)cycloalkyl where cycloalkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen, -NH2or is HE;

R1represents a hydrogen atom, -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times R13; -(C1-C3)alkylen-C(O)-NH-R0-(C1-C3 10, monocyclic or bicyclic 6-14-membered aryl, where aryl is mono-, di - or triamese independently of each R8where R8has the values listed above; monocyclic or bicyclic 4 to 15-membered heterocyclyl containing one, two, three or four heteroatoms selected from nitrogen, sulfur or oxygen; -(C1-C3)perforation -(C1-C3alkylene)-S(O)-(C1-C4)alkyl, -(C1-C3alkylene)-S(O)2-(C1-C4)alkyl, -(C1-C3alkylene)-S(O)2-N(R4'R5'-(C1-C3alkylene)-O-(C1-C4)alkyl, -(C0-C3alkylen)-(C3-C8)cycloalkyl or -(C0-C3alkylen)-het, where het represents a 3-7-membered cyclic residue, containing up to 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic residue is unsubstituted or mono-, di - or triamese independently of each R14,

R4'and R5'are independently of one another identical or different and represent a hydrogen atom or -(C1-C4)alkyl,

R2represents a direct bond,

R1-N-R2-V can form a 4-to 8-membered cyclic group, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic GRU the PA is unsubstituted or mono-, di - or tizamidine independently of each R14,

R14represents a halogen, -HE, =O, -(C1-C8)alkyl,

-(C1-C4)alkoxy, -NO2, -C(O)OH, -CN, -NH2, -C(O)-O-(C1-C4)alkyl,

-(C0-C8)alkyl-SO2-(C1-C4)alkyl-,

-(C0-C8)alkyl-SO2-(C1-C3)perfluoroalkyl, -(C0-C8)alkyl-SO2-N(R18)-R21,

-C(O)-NH-(C1-C8)alkyl-, -C(O)-N-[(C1-C8)alkyl]2,

-NR18-C(O)-NH-(C1-C8)alkyl-, -C(O)-NH2, -S-R18or

-NR18-C(O)-NH-[(C1-C8)alkyl]2,

where R18and R21represent, independently from each other hydrogen atom, -(C1-C3)perfluoroalkyl or -(C1-C6)alkyl,

V represents

1) 6-14-membered aryl, where aryl is unsubstituted or mono-, di - or triamese independently of each R14or

2) heterocyclyl group acridine, 8-azabicyclo[3.2.1]Oct-3-yl, azaindole (1H-pyrrolopyridine), asianshemale, azaspirodecanedione, azepine, azetidine, aziridine, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, benzatropine, benzisoxazole, benzisothiazole, carbazole, 4H-carbazolyl, carboline, Romania, x is Manila, cinnoline, decahydroquinoline, 1,4-diazepine, 4,5-dihydroquinoline, dioxazine, dioxazine, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 6N-1,5,2-detainee, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazane, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizine, indolyl, 3H-indolyl, isobenzofuranyl, isopropanyl, isoindolyl, isoindoline, isoindolyl, izochinolina, isothiazoline, isothiazolinone, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, phenanthridine, phenanthroline, phenazine, phenothiazine, femoxetine, phenoxazine, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxically, predominately, peridotite, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinone, pyrroline 2N-pyrrolyl, pyrrolyl, heatline, chinoline, 4H-chinoiserie, khinoksalinona, hinokitiol, tetrahydrofuranyl, then it is carbonated is rothenaigner, tetrahydroquinoline, 1,4,5,6-tetrahydropyridine, tetrahydropyridine, tetrahydrothiophene, tetrazine, tetrazole, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, 1,2-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, teinila, tatania, tiantianriri, cyanoacetyl, tenomodulin, tatania, thiomorpholine, 1λ6-thiomorpholine, thiophenyl, dipiradol, 1,2,3-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanterra where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R14,

G represents a direct link,

-(CH2)m-NR10-SO2-NR10-(CH2)n-, -(CH2)m-CH(OH)-(CH2)n-, -(CH2)m-,

-(CH2)m-O-(CH2)n-, -(CH2)m-C(O)-NR10-(CH2)n-, -(CH2)-SO2-(CH2)n-,

-(CH2)m-NR10-C(O)-NR10-(CH2)n-, -(CH2)m-NR10-C(O)-(CH2)n-,

-(CH2)m-C(O)-(CH2)n-, -(CH2)-S-(CH2)n-, -(CH2)m-SO2-NR10-(CH2)n-,

-(CH2)m-NR10-SO2-(CH2)n-, -(CH2)m-NR10 -, -(CH2)m-O-C(O)-NR10-(CH2)n-

or -(CH2)m-NR10-C(O)-O-(CH2)n-,

n and m are independently of one another identical or different and are equal to integers 0, 1, 2, 3, 4, 5 or 6,

M represents

1) a hydrogen atom,

2) -(C1-C8)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R14,

3) -C(O)-N(R11)-R12,

4) -(CH2)m-NR10,

5) 6-14-membered aryl, where aryl is unsubstituted or mono-, di - or triamese independently of each R14,

6) a monocyclic or bicyclic 4 to 15-membered heterocyclyl where heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R14,

7) -(C3-C8)cycloalkyl where specified cycloalkyl is unsubstituted or mono-, di - or triamese independently of each R14or

8) 3-7-membered cyclic residue, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic residue is unsubstituted or mono-, di - or triamese independently of each R14where R14has the values listed above,

R3represents a

1) a hydrogen atom,

2) a halogen atom,

3) -(C1-C4)alkyl, where alkyl is illegal is displaced or mono-, di - or triamese independently of each R13,

4) -(C1-C3)perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

6) -(C0-C4)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13or

(C) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

d) -CF3or

e) -CHF2,

7) -NO2,

8) -CN,

9) -SOs-R11where s is 1 or 2,

10) -SOt-N(R11)-R12where t is 1 or 2,

11) -(C0-C4)alkylen-C(O)-R11,

12) -(C0-C4)alkylen-C(O)-O-R11,

13) -(C0-C4)alkylen-C(O)-N(R11)-R12,

14) -(C0-C4)alkylene-N(R11)-R12,

15) -NR10-SO2-R10,

16) -S-R10,

17) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-(C1-C4)alkyl,

18) -C(O)-O-C(R15,R16)-O-C(O)-R17,

19) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-O-(C1-C6)alkyl,

20) -C(O)-O-C(R15,R16)-O-C(O)-O-R17,

21) -(C0-C4)alkylene-(C6-C14)aryl, where aryl is mono-, di - or triamese independently of each R13,

22) -(C0-C4)alkylene-(C4-C15)heterocyclyl where heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R13,

23) -(C0-C4)alkylene-(C3-C8)cycloalkyl where cycloalkyl is unsubstituted or mono-, di - or triamese independently of each R13,

24) -(C0-C4)alkylene-het where het is unsubstituted or mono-, di - or triamese independently of each R13,

25) -(C0-C4)alkylen-O-CH2-(C1-C3)perforation-CH2-O-(C0-C4)alkyl,

26) -SOW-N(R11)-R13where w is 1 or 2,

27) -(C0-C4)alkylen-C(O)-N(R11)-R13,

28) -(C0-C4)alkylene-N(R11)-R13or

29) a residue from the following list of balances:

,

where Me represents methyl or,

if the two balance-OR19attached to adjacent atoms they can form with the atoms to which they are attached, a 5 - or 6-membered ring which is unsubstituted or mono-, di - or tizamidine independently of each R13,

R11and R12are independently of one another identical or different and represent

1) and the om hydrogen

2) -(C1-C6)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

3) -(C0-C6)alkyl-(C3-C8)cycloalkyl,

4) -SOt-R10where t is 1 or 2,

5) -(C0-C6)alkyl-(C6-C14)-aryl, where alkyl and aryl independently from one another are unsubstituted or mono-, di - or tizamidine R13,

6) -(C1-C3)perfluoroalkyl,

7) -O-R17or

8) -(C0-C6)alkyl-(C4-C15)heterocyclyl, where the alkyl and heterocyclyl, independently of one another are unsubstituted or mono-, di - or tizamidine R13or

R11and R12together with the nitrogen atom to which they are linked, may form a 4-8-membered monocyclic heterocyclic ring which in addition to the nitrogen atom can contain one or two identical or different heteroatoms in the ring selected from oxygen, sulfur and nitrogen; where the specified heterocyclic ring is unsubstituted or mono-, di - or tizamidine independently of each R13,

R13represents a halogen, -NO2, -CN, =O, -OH, -CF3, -C(O)-O-R10, -C(O)N(R10)-R20, -N(R10)-R20-(C3-C8)cycloalkyl -(C0-C3)alkylen-O-R10, -Si(CH3)3, -N(R10)-S(O)u-R10, is de u is 1 or 2, -S-R10, -SOr-R10where r is 1 or 2, -S(O)v-N(R10)-R20where v is 1 or 2, -C(O)-R10-(C1-C8)alkyl, -(C1-C8)alkoxy, phenyl, phenyloxy-, -O-CF3, -(C0-C4)alkyl-C(O)-O-C(R15,R16)-O-C(O)-R17-(C1-C4)alkoxyphenyl -(C0-C4)alkyl-C(O)-O-C(R15,R16)-O-C(O)-O-R17-(C1-C3)perfluoroalkyl, -O-R15, -NH-C(O)-NH-R10, -NH-C(O)-O-R10or a residue from the following list of balances:

and,

where Me represents methyl, or

R10and R20represent, independently from each other hydrogen, -(C1-C6)alkyl, -(C0-C4)alkyl-HE,

-(C0-C4)alkyl-O-(C0-C4)alkyl or -(C1-C3)perfluoroalkyl,

R15and R16represent, independently from each other hydrogen, -(C1-C6)alkyl or together with the carbon atom to which they are attached, they form a 3-6-membered carbocyclic ring which is unsubstituted or substituted one to three times R10and

R17represents -(C1-C6)alkyl, -(C1-C6)alkyl-HE,

-(C1-C6)alkyl-O-(C1-C6)alkyl, -(C3-C8)cycloalkyl,

-(C1-C6)alkyl-O-(is 1-C8)alkyl-(C3-C8)cycloalkyl,

-(C1-C6)alkyl-(C3-C8)cycloalkyl, where the specified cycloalkyl ring is unsubstituted or substituted one, two or three times by-OH, -O-(C1-C4)alkyl, or R10,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerable salts.

2. Also, the present invention relates to compounds of the formula I, in which

R0represents a

1) monocyclic or bicyclic 6-14 membered aryl group phenyl, naphthyl, biphenyl, antila or fluorenyl, where aryl is mono-, di - or triamese independently of each R8,

2) heterocyclyl from the group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophene, cinnoline, Romania, indazole, indoline, isopropanyl, isoindolyl, izochinolina, phenylpyridine, phthalazine, pteridine, purine, pyridyl, predominately, pyridopyrimidines, pyridopyrimidines, pyrimidinyl, heatline, chinoline, khinoksalinona or 1,4,5,6-tetrahydropyridine where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8or

3) heterocyclyl where heterocyclyl selected from the group of acridine, asianshemale, azaspirodecanedione,azepine, azetidine, aziridine, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, benzatropine, benzisoxazole, benzisothiazole, carbazole, 4H-carbazolyl, carboline, Romania, chromene, cinnoline, decahydroquinoline, 4,5-dihydroquinoline, dioxazine, dioxazine, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 6N-1,5,2-detainee, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazane, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizine, indolyl, 3H-indolyl, isobenzofuranyl, isopropanyl, isoindolyl, isoindoline, isoindolyl, izochinolina, isothiazoline, isothiazolinone, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, phenanthridine, phenanthroline, phenazine, phenothiazine, femoxetine, phenoxazine, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, Piri is oxazolyl, predominately, peridotite, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinone, pyrroline 2N-pyrrolyl, pyrrolyl, heatline, chinoline, 4H-chinoiserie, khinoksalinona, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 1,4,5,6-tetrahydropyridine, tetrahydropyridine, tetrahydrothiophene, tetrazine, tetrazole, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, 1,2-teinila, 1,3-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, teinila, tatania, tiantianriri, cyanoacetyl, tenomodulin, tatania, thiomorpholine, thiophenolate, thiophenyl, dipiradol, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanterra,

where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8and optionally substituted heterocycle selected from the group of acridine, asianshemale, azaspirodecanedione, azepine, azetidine, aziridine, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, benzatropine, benzisoxazole, benzisothiazole, carbazole, 4H-carbazolyl, carboline, Romani is a, chromene, cinnoline, decahydroquinoline, 4,5-dihydroquinoline, dioxazine, dioxazine, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 6N-1,5,2-detainee, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazane, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizine, indolyl, 3H-indolyl, isobenzofuranyl, isopropanyl, isoindolyl, isoindoline, isoindolyl, izochinolina, isothiazoline, isothiazolinone, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, phenanthridine, phenanthroline, phenazine, phenothiazine, femoxetine, phenoxazine, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxically, predominately, peridotite, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinone, pyrroline 2N-pyrrolyl, pyrrolyl, hintline, chinoline, 4H-chinoiserie, khinoksalinona, hinokitiol, tetrahydrofuranyl, tetrahydro what thinline, tetrahydroquinoline, 1,4,5,6-tetrahydropyridine, tetrahydropyridine, tetrahydrothiophene, tetrazine, tetrazole, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, 1,2-teinila, 1,3-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, teinila, tatania, tiantianriri, cyanoacetyl, tenomodulin, tatania, thiomorpholine, thiophenolate, thiophenyl, dipiradol, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanterra where heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8,

R8represents a

1) halogen,

2) -NO2,

3) -CN,

4) -C(O)-NH2,

5) -OH,

6) -NH2,

7) -O-CF3,

8) a monocyclic or bicyclic 6-14-membered aryl, where aryl has the above values and where the aryl is mono-, di - or triamese independently of one another by halogen or-O-(C1-C8)alkyl,

9) -(C1-C8alkyl), where alkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen, NH2HE or balance methoxy, or

10) -O-(C1-C8alkyl), where alkyl is unsubstituted or mono-, di - or triamese independently from each other halogen is m, NH2HE or balance methoxy,

11) -SO2-CH3or

12) -SO2-CF3,

provided that R8represents at least one halogen atom, -C(O)-NH2or-O-(C1-C8)alkyl residue, if R0represents a monocyclic or bicyclic 6-14-membered aryl, where aryl has the values listed above,

provided that R8is not-O-(C1-C8)alkyl residue, if R0and V represents a monocyclic or bicyclic 6-14-membered aryl,

substructure D is a residue selected from the group of azetidine, asatina, asokan, asokan-2-it, cyclobutyl, cyclooctane, cyclooctene, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, [1,4]diatkine, [1,2]diadakan-3-one, [1,3]diadakan-2-it, dioxazine, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, 1,2-oxathiane, 1,2-oxathiolane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, [1,4]oxazoline, [1,3]oxazolin-2-it, oxetane, oxolane, oxolan-2-it, piperazine, piperidine, phenyl, Piran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine is, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, 5,6,7,8-tetrahydro-1H-Asotin-2-it, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, thiadiazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazoline, Tatana, Ciocana, 1,1-dioxide tikana, 1-oxide tikana, Ciocan-2-it, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole and unsubstituted or substituted 1, 2, 3, 4, 5 or 6 times R3or substituted 1 or 2 times =O,

Q represents a direct bond,

-(C0-C2)alkylen-C(O)NR10-, -NR10-C(O)NR10-, -NR10-C(O)-, -SO2-,

methylene, -(CH2)m-NR10-C(O)-NR10-(CH2)n-, -(CH2)m-NR10-C(O)-(CH2)n-,

-(CH2)m-S-(CH2)n-, -(CH2)m-C(O)-(CH2)n-, -(CH2)m-SO2-NR10-(CH2)n-,

-(CH2)m-NR10-SO2-(CH2)n-, -(CH2)m-NR10-SO2-NR10-(CH2)n-,

-(CH2)m-CH(OH)-(CH2)n-, -(CH2)m-O-C(O)-NR10-(CH2)n-,

-(C2-C3)alkylen-O-(C0-C3)alkylene-, -(C2-C3)alkylen-S(O)-,

-(C2-C3)alkylen-S(Oh)2-, -(CH2)m-NR10-CO)-O-(CH 2)n-,

-(C2-C3)alkylen-S(Oh)2-NH-(R10)-, -(C2-C3)alkylene-N(R10)- or

-(C0-C3)alkylen-C(O)-O-(CH2)m-,

where R10has the values listed below, and where n and m are independently of one another identical or different and are equal to integers 0, 1, 2, 3, 4, 5 or 6, where alkylene residues, which are formed by -(CH2)m- or -(CH2)n-are unsubstituted or mono-, di - or tizamidine independently of one another by halogen, -NH2or is HE; or -(C3-C6)cycloalkyl where cycloalkyl is unsubstituted or mono-, di - or triamese independently of one another, halogen, -NH2or is HE;

R1represents a hydrogen atom, -(C1-C4)alkyl, where the alkyl are unsubstituted or substituted one to three times R13; -(C1-C3)alkylen-C(O)-NH-R0-(C1-C3)alkylen-C(O)-O-R15the aryl group phenyl, naphthyl, biphenyl, antila or fluorenyl, where aryl is mono-, di - or triamese independently of each R8where R8has the values listed above;

monocyclic or bicyclic 4 to 15-membered heterocyclyl, which has the values listed above, -(C1-C3)perforation -(C1-C3alkylene)-S(O)-(C1-C4)alkyl, -(C1-C3alkylen)-SO) 2-(C1-C3)alkyl, -(C1-C3alkylene)-S(O)2-N(R4'R5'-(C1-C3alkylene)-O-(C1-C4)alkyl, -(C0-C3alkylen)-(C3-C8)cycloalkyl or -(C0-C3alkylen)-het, where het is a residue selected from the group of azepine, azetidine, aziridine, azirine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dioxazine, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, 1,4-oxazepine, 1,2-oxathiane, 1,2-oxathiolane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxazolidine, oxirane, piperazine, piperidine, Piran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 2,3-thiazole, thiazole, thiazolidine, thiazoline, teinila, Tatana, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where het is unsubstituted or mono-, di - or triamese independently of each R14,

R4'and R5'are independently al the g from each other, equal or different and represent a hydrogen atom or -(C 1-C4)alkyl,

R2represents a direct bond,

R1-N-R2-V can form a 4-to 8-membered cyclic group, selected from azepine, azetidine, dioxazine, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where this cyclic group is unsubstituted or mono-, di - or tizamidine independently of each R14,

R14represents fluorine, chlorine, bromine, iodine, -HE, =O,

-(C1-C8)alkyl, -(C1-C4)alkoxy, -NO2, -C(O)OH, -CN, -NH2,

-C(O)-O-(C1-C4)alkyl, -(C0-C8)alkyl-SO2-(C1-C4)alkyl-,

-(C0-C8)alkyl-SO2-(C1-C3)perfluoroalkyl,

-(C0-C8)alkyl-SO2-N(R18)-R21, -C(O)-NH-(C1-C8)alkyl-,

-C(O)-N[(C1-C8)alkyl]2, -NR -C(O)-NH-(C1-C8)alkyl, -C(O)-NH2,

-S-R18or-NR18-C(O)-NH-[(C1-C8)alkyl]2,

where R18and R21represent independently from each other hydrogen atom, -(C1-C3)perfluoroalkyl or -(C1-C6)alkyl,

V represents

1) monocyclic or bicyclic 6-14 membered aryl group phenyl, naphthyl, biphenyl, antila or fluorenyl, where aryl is mono-, di - or triamese independently from each other R14,

2) heterocyclyl group acridine, 8-azabicyclo[3.2.1]Oct-3-yl, azaindole (1H-pyrrolopyridine), asianshemale, azaspirodecanedione, azepine, azetidine, aziridine, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, benzatropine, benzisoxazole, benzisothiazole, carbazole, 4H-carbazolyl, carboline, Romania, chromene, cinnoline, decahydroquinoline, 1,4-diazepine, 4,5-dihydroquinoline, dioxazine, dioxazine, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 6N-1,5,2-detainee, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazane, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizine, indolyl, 3H-indolyl, isobenzofuranyl, isopropanol, isoindolyl, isoindoline, isoindolyl, izochinolina, isothiazoline, izote is tolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, phenanthridine, phenanthroline, phenazine, phenothiazine, femoxetine, phenoxazine, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxically, predominately, peridotite, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinone, pyrroline 2N-pyrrolyl, pyrrolyl, heatline, chinoline, 4H-chinoiserie, khinoksalinona, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 1,4,5,6-tetrahydropyridine, tetrahydropyridine, tetrahydrothiophene, tetrazine, tetrazole, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, 1,2-teinila, 1,3-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, tanila, tatania, tiantianriri, cyanoacetyl, tenomodulin, tatania, thiomorpholine, 1λ6-t is morpholinyl, thiophenyl, dipiradol, 1,2,3-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanterra where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R14,

G represents a direct link,

-(CH2)m-NR10-SO2-NR10-(CH2)n-, -(CH2)m-CH(OH)-(CH2)n-, -(CH2)m-,

-(CH2)m-O-(CH2)n-, -(CH2)m-C(O)-NR10-(CH2)n-, -(CH2)-SO2-(CH2)n-,

-(CH2)m-NR10-C(O)-NR10-(CH2)n-, -(CH2)m-NR10-C(O)-(CH2)n-,

-(CH2)m-C(O)-(CH2)n-, -(CH2)-S-(CH2)n-, -(CH2)m-SO2-NR10-(CH2)n-,

-(CH2)m-NR10-SO2-(CH2)n-,-(CH2)m-NR10-, -(CH2)m-O-C(O)-NR10-(CH2)n-

or -(CH2)m-NR10-C(O)-O-(CH2)n-,

n and m are independently of one another identical or different and are equal to integers 0, 1, 2, 3, 4, 5 or 6,

M represents

1) a hydrogen atom,

2) -(C1-C8)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R14,

3) -C(O)-N(R11)-R12 ,

4) -(CH2)m-NR10,

5) -(C6-C14)-aryl, where aryl has the above values and where the aryl is unsubstituted or mono-, di - or triamese independently of each R14,

6) (C4-C15)heterocyclyl where heterocyclyl has the values indicated above and is unsubstituted or mono-, di - or triamese independently of each R14or

7) -(C3-C8)cycloalkyl where specified cycloalkyl is unsubstituted or mono-, di - or triamese independently of each R14,

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

4) -(C1-C3)perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

6) -(C0-C4)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13or

(C) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

d) -CF3or

e) -CHF2,

7) -NO2,

8) -CN,

9) -SOs-R11, s is 1 or 2,

10) -SOt-N(R11)-R12where t is 1 or 2,

11) -(C0-C4)alkylen-C(O)-R11,

12) -(C0-C4)alkylen-C(O)-O-R11,

13) -(C0-C4)alkylen-C(O)-N(R11)-R12,

14) -(C0-C4)alkylene-N(R11)-R12,

15) -NR10-SO2-R10,

16) -S-R10,

17) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-(C1-C4)alkyl,

18) -C(O)-O-C(R15,R16)-O-C(O)-R17,

19) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-O-(C1-C6)alkyl,

20) -C(O)-O-C(R15,R16)-O-C(O)-O-R17,

21) -(C0-C4)alkylene-(C6-C14)aryl, where aryl is mono-, di - or triamese independently of each R13,

22) -(C0-C4)alkylene-(C4-C15)heterocyclyl where heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R13,

23) -(C0-C4)alkylene-(C3-C8)cycloalkyl where cycloalkyl is unsubstituted or mono-, di - or triamese independently of each R13,

24) -(C0-C4)alkylene-het where het is unsubstituted or mono-, di - or triamese independently of each R13,

25) -(C0-C3)alkylen-O-CH2-(C1-C3)perforation-CH2-O-(C0-C3

26) -SOW-N(R11)-R13where w is 1 or 2,

27) -(C0-C4)alkylen-C(O)-N(R11)-R13,

28) -(C0-C4)alkylene-N(R11)-R13or

29) a residue from the following list of balances:

and,

where Me represents methyl, or,

if the two balance-OR19attached to adjacent atoms they can form together with the atoms to which they are attached, a ring 1,3-dioxole or ring 2,3-dihydro[1,4]dioxin, which is substituted one, two, three or four times R13,

R11and R12are independently of one another identical or different and represent

1) a hydrogen atom,

2) -(C1-C6)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

3) -(C0-C6)alkyl-(C3-C8)cycloalkyl,

4) -SOt-R10where t is 1 or 2,

5) -(C0-C6)alkyl-(C6-C14)-aryl, where alkyl and aryl independently from one another are unsubstituted or mono-, di - or tizamidine R13,

6) -(C1-C3)perfluoroalkyl,

7) -O-R17or

8) -(C0-C6)alkyl-(C4-C15)heterocyclyl, where the alkyl and heterocyclyl have the values listed is use, and are independently from each other unsubstituted or mono-, di - or tizamidine R13or

R11and R12together with the nitrogen atom to which they are linked, form a heterocyclic ring from the group of azepine, azetidine, dioxazine, dioxazine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, [1,4]oxazepan, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, thiophene, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where the aforementioned heterocyclic ring is unsubstituted or mono-, di - or tizamidine independently of each R13,

R13represents a halogen, -NO2, -CN, =O, -OH, -CF3, -C(O)-O-R10, -C(O)N(R10)-R20, -N(R10)-R20-(C3-C8)cycloalkyl -(C0-C3)alkylen-O-R10, -Si(CH3)3, -N(R10)-S(O)u-R10where u is 1 or 2, -S-R10, -SOr-R10where r is 1 or 2, -S(O)v-N(R10)-R20where v is avno 1 or 2, -C(O)-R10-(C1-C8)alkyl, -(C1-C8)alkoxy, phenyl, phenyloxy-, -O-CF3, -(C0-C4)alkyl-C(O)-O-C(R15,R16)-O-C(O)-R17-(C1-C4)alkoxyphenyl -(C0-C4)alkyl-C(O)-O-C(R15,R16)-O-C(O)-O-R17-(C1-C3)perfluoroalkyl, -O-R15, -NH-C(O)-NH-R10, -NH-C(O)-O-R10or a residue from the following list of balances:

and,

where Me represents methyl,

R10and R20represent independently from each other hydrogen, -(C1-C6)alkyl, -(C0-C4)alkyl-OH, -(C0-C4)alkyl-O-(C0-C4)alkyl or -(C1-C3)perfluoroalkyl,

R15and R16represent independently from each other hydrogen, -(C1-C6)alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, where each ring is unsubstituted or substituted one to three times R10and

R17represents -(C1-C6)alkyl, -(C1-C6)alkyl-HE,

-(C1-C6)alkyl-O-(C1-C6)alkyl, -(C3-C8)cycloalkyl,

-(C1-C6)alkyl-O-(C1-C8)alkyl-(C3-C8)cycloalkyl,

-(C1-C6)alkyl-(C3-C8)cycloalkyl, where the specified cycloalkyl the ring is unsubstituted or substituted one, two, three times-OH, -O-(C1-C4)alkyl, or R10,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerable salts.

3. The present invention also relates to compounds of the formula I, in which

R0represents a

1) monocyclic or bicyclic 6-14 membered aryl group phenyl, naphthyl, biphenyl, antila or fluorenyl, where aryl is mono-, di - or triamese independently of each R8,

2) heterocyclyl from the group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophene, cinnoline, Romania, indazole, indoline, isopropanyl, isoindolyl, izochinolina, phenylpyridine, phthalazine, pteridine, purine, pyridyl, predominately, pyridopyrimidines, pyridopyrimidines, pyrimidinyl, heatline, chinoline, izochinolina or 1,4,5,6-tetrahydropyridine where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8or

3) heterocyclyl from the group asianshemale, benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzothiazolyl, benzothiophene, benzoxazole, Romania, indolinyl, 2-furil, 3-furil, imidazolyl, indolyl, indazole, isopropanyl, isoindolyl, izochinolina, isothiazoline, isoxazole, about cazalilla, phthalazine, pteridine, purine, pyrazine, pyrazolyl, pyridazinyl, predominately, pyridopyrimidines, pyridopyrimidines, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, chinoline, heatline, khinoksalinona, tetrazolyl, thiadiazolyl, thiazolyl, 2-tanila or 3-tanila,

which is optionally substituted by heterocyclyl selected from the group of acridine, asianshemale, azaspirodecanedione, azepine, azetidine, aziridine, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, benzatropine, benzisoxazole, benzisothiazole, carbazole, 4H-carbazolyl, carboline, Romania, chromene, cinnoline, decahydroquinoline, 4,5-dihydroquinoline, dioxazine, dioxazine, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 6N-1,5,2-detainee, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazane, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isopropanyl, isoindolyl, isoindoline, isoindolyl, izochinolina (benzimidazolyl), isothiazoline, isothiazolinone, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, morpholinyl, naphthyridine, octahydronaphthalene the La, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, phenanthridine, phenanthroline, phenazine, phenothiazine, femoxetine, phenoxazine, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxically, predominately, peridotite, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinone, pyrroline, 2N-pyrrolyl, pyrrolyl, heatline, chinoline, 4H-chinoiserie, khinoksalinona, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 1,4,5,6-tetrahydropyridine, tetrahydropyridine, tetrahydrothiophene, tetrazine, tetrazole, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, 1,2-teinila, 1,3-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, teinila, tatania, tiantianriri, cyanoacetyl, tenomodulin, tatania, thiomorpholine, thiophenyl, dipiradol, 1,2,3-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanterra,

where heterocyclyl is nezam the seal or mono-, di - or triamese independently of each R8,

R8represents a

1) fluorine, chlorine or bromine,

2) -NO2,

3) -CN,

4) -C(O)-NH2,

5) -OH,

6) -NH2,

7) -OCF3,

8) a monocyclic or bicyclic 6-14-membered aryl, where aryl has the above values and mono-, di - or triamese independently of one another by halogen or-O-(C1-C8)alkyl,

9) -(C1-C8alkyl), where alkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen, NH2HE or balance methoxy, or

10) -O-(C1-C8alkyl), where alkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen, NH2HE or balance methoxy,

11) -SO2CH3or

12) -SO2CF3,

provided that R8represents at least one halogen, -C(O)-NH2or-O-(C1-C8)alkyl residue, if R0represents aryl or heterocyclyl that have values above

provided that R8is not-O-(C1-C8)alkyl residue, if R0and V represent phenyl,

substructure D is a residue selected from the group of phenyl, pyridyl, N-oxide pyridyl, pyrrolyl, furil, teinila, imidazolyl, pyrazolyl, oxazolyl, from cazalilla, thiazolyl, triazolyl, isothiazoline, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, and is unsubstituted or substituted 1, 2, 3 or 4 times R3or substituted 1 or 2 times =O,

Q represents a direct bond, -(C0-C2)alkylen-C(O)NR10-, -NR10-C(O)NR10-, -NR10-C(O)-, -SO2-, methylene or -(C0-C3)alkylen-C(O)-O-(C0-C2)alkylene-,

R1represents a hydrogen atom, -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times R13;

-(C1-C3)alkylen-C(O)-NH-R0-(C1-C3)alkylen-C(O)-O-R15,

-(C1-C3)perforation -(C1-C3)alkylen-S(O)-(C1-C4)alkyl,

-(C1-C3)alkylen-S(Oh)2-(C1-C3)alkyl,

-(C1-C3)alkylen-S(Oh)2-N(R4')-R5'-(C1-C3)alkylen-O-(C1-C4)alkyl,

-(C0-C3)alkylene-(C3-C8)cycloalkyl or -(C0-C3)alkylene-het, where het is a residue selected from the group of azepine, azetidine, aziridine, azirine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dioxazine, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazole is a, the isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxazolidine, oxirane, piperazine, piperidine, Piran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazoline, teinila, Tatana, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where het is unsubstituted or mono-, di - or triamese independently of each R14,

R4'and R5'are independently of one another identical or different and represent a hydrogen atom or -(C1-C4)alkyl,

R2represents a direct bond,

R1-N-R2-V form a 4-8-membered cyclic group, selected from azepine, azetidine, 1,4-diazepine, dioxazine, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, 1,4-oxazepine, oxazole, piperazine, piperidine, pyrazine, the pyrazole is, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where this cyclic group is unsubstituted or mono-, di - or tizamidine independently of each R14,

R14represents fluorine, chlorine, bromine, iodine, -HE, =O,

-(C1-C8)alkyl, -(C1-C4)alkoxy, -NO2, -C(O)OH, -CN, -NH2,

-C(O)-O-(C1-C4)alkyl, -(C0-C8)alkyl-SO2-(C1-C4)alkyl-,

-(C0-C8)alkyl-SO2-(C1-C3)perfluoroalkyl,

-(C0-C8)alkyl-SO2-N(R18)-R21, -C(O)-NH-(C1-C8)alkyl,

-C(O)-N[(C1-C8)alkyl]2, -NR18-C(O)-NH-(C1-C8)alkyl, -C(O)-NH2,

-S-R18or-NR18-C(O)-NH-[(C1-C8)alkyl]2,

where R18and R21represent independently from each other hydrogen atom, -(C1-C3)perfluoroalkyl or -(C1-C6)alkyl,

V represents

1) the remainder of the het group 8-azabicyclo[3.2.1]Oct-3-yl, azaindole (1H-pyrrolopyridine), azepine, azetidine, aziridine, azirine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-di is Espina, diaziridine, diazirine, dioxazine, dioxazine, dicosola, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxazolidine, oxirane, piperazine, piperidine, Piran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazoline, teinila, Tatana, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,3,5-triazole or 1,2,4-triazole, where het is unsubstituted or mono-, di - or triamese independently of each R14or

2) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R14,

G represents a direct link,

-(CH2)m-NR10-SO2-NR10-(CH2)n-, -(CH2)m-CH(OH)-(CH2)n-, -(CH2)m-,

-(CH2)m-O-(CH2)n-, -(CH2)m-C(O)-NR10-(CH2)n-, -(CH2)-SO2-(CH2)n-,

-(CH2)m-NR10-C(O)-NR10-(CH2)n-, -(CH2)m-NR10-C(O)-(CH2)n-,

-(CH2)m-C(O)-(CH2)n-, -(CH2)m-S-(CH2)n-, -(CH2)m-SO2-NR10-(CH2)n-,

-(CH2)m-NR10-SO2-(CH2)n-, -(CH2)m-NR10-, -(CH2)m-O-C(O)-NR10-(CH2)n-

or -(CH2)m-NR10-C(O)-O-(CH2)n-,

n and m are independently of one another identical or different and are equal to integers 0, 1, 2, 3, 4, 5 or 6,

M represents

1) a hydrogen atom,

2) -(C1-C8)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R14,

3) -C(O)-N(R11)-R12,

4) -(CH2)m-NR10,

5) phenyl or naphthyl, where phenyl and naphthyl are unsubstituted or mono-, di - or tizamidine independently of each R14,

6) heterocyclyl where heterocyclyl is the remainder of the group, which may be selected from azepine, azepine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, isothiazole, isoxazol, isoxazolidine, 2-isoxazoline, metamorphosen, cefoperazone, research, oxazole, [1,4]oxazepan, piperazine, piperazinone, piperidine, piperidine, pyrazine, peridas is on, pyridazinone, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydropyridine, tetrazine, tetrazole, thiadiazole, thiazole, thiomorpholine, 1λ6-thiomorpholine, thiophene, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R14, or

7) -(C3-C8)cycloalkyl where specified cycloalkyl is unsubstituted or mono-, di - or triamese independently of each R14,

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

4) -(C1-C3)perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

6) -(C0-C4)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or tizamidine independently of each R13or

(C) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

d) -CF3or

e) -CHF2,

7) -CN,

8) -(C0-C4)alkylene-(C -C15)heterocyclyl where heterocyclyl matter above and is unsubstituted or mono-, di - or triamese independently of each R13,

9) -SOs-R11where s is 1 or 2,

10) -SOt-N(R11)-R12where t is 1 or 2,

11) -(C0-C4)alkylen-C(O)-R11,

12) -(C0-C4)alkylen-C(O)-O-R11,

13) -(C0-C4)alkylen-C(O)-N(R11)-R12,

14) -(C0-C4)alkylene-N(R11)-R12,

15) -NR10-SO2-R10,

16) -(C0-C4)alkylene-het, where het has the meanings indicated above and is unsubstituted or mono-, di - or triamese independently of each R13,

17) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-(C1-C4)alkyl,

18) -C(O)-O-C(R15,R16)-O-C(O)-R17,

19) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-O-(C1-C6)alkyl,

20) -C(O)-O-C(R15,R16)-O-C(O)-O-R17,

21) -(C0-C4)alkylene-(C6-C14)aryl, where aryl has the values listed above, and mono-, di - or triamese independently of each R13,

22) -(C0-C4)alkylene-(C3-C8)cycloalkyl where cycloalkyl is unsubstituted or mono-, di - or triamese independently of each R13,

23) -(C0-C3alkylen-O-CH 2-CF2-CH2-O-(C0-C3)alkyl,

24) -(C0-C3)alkylen-O-CH2-CF2-CF2-CH2-O-(C0-C3)alkyl,

25) -(C0-C3)alkylen-O-CH2-(C1-C3)perforation-CH2HE

26) -SOW-N(R11)-R13where w is 1 or 2,

27) -(C0-C4)alkylen-C(O)-N(R11)-R13,

28) -(C0-C4)alkylene-N(R11)-R13or

29) a residue from the following list of balances:

and,

where Me represents methyl,

if the two balance-OR19attached to adjacent atoms they can form together with the atoms to which they are attached, a ring 1,3-dioxole or ring 2,3-dihydro[1,4]dioxin, which is substituted one, two, three or four times R13,

R11and R12are independently of one another identical or different and represent

1) a hydrogen atom,

2) -(C1-C6)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

3) -(C0-C6)alkyl-(C6-C14)-aryl, where aryl has the values listed above, and where alkyl and aryl are independently of one another, unsubstituted or mono-, di - or tizamidine R13,

4) -O-R17or

5) -(C0-sub> 6)alkyl-(C4-C15)heterocyclyl, where the alkyl and heterocyclyl have the meanings indicated above, and independently of one another are unsubstituted or mono-, di - or tizamidine R13or

R11and R12together with the nitrogen atom to which they are bound, may form a ring selected from the group of azepine, azetidine, 1,4-diazepine, dioxazine, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, [1,4]oxazepan, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, that is unsubstituted or mono-, di - or triamese independently of each R13,

R13represents fluorine, chlorine, bromine, iodine, -NO2, -CN, =O,

-OH, -CF3, -C(O)-O-R10, -C(O)N(R10)-R20, -N(R10)-R20,

-(C0-C3)alkylen-O-R10, -Si(CH3)3, -N(R10)-S(O)2-R10, -S-R10,

-SO2-R10, -S(O)2-N(R10/sup> )-R20, -C(O)-R10-(C1-C8)alkyl,

-(C1-C8)alkoxy, phenyl, phenyloxy-, -O-CF3,

-(C1-C3)perfluoroalkyl, -(C0-C4)alkyl-C(O)-O-C(R15,R16)-O-C(O)-R17,

-(C1-C4)alkoxyphenyl,

-(C0-C4)alkyl-C(O)-O-C(R15,R16)-O-C(O)-O-R17, -O-R15,

-NH-C(O)-NH-R10, -NH-C(O)-O-R10or a residue from the following list of balances:

and,

where Me represents methyl,

R10and R20represent independently from each other hydrogen, -(C1-C6)alkyl, -(C0-C4)alkyl-OH, -(C0-C4)alkyl-O-(C0-C4)alkyl or -(C1-C3)perfluoroalkyl,

R15and R16represent independently from each other hydrogen, -(C1-C6)alkyl or together form a ring group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, where each ring is unsubstituted or substituted one to three times R10and

R17represents -(C1-C6)alkyl, -(C1-C6)alkyl-HE,

-(C1-C6)alkyl-O-(C1-C6)alkyl, -(C3-C8)cycloalkyl,

-(C1-C6)alkyl-O-(C1-C8)alkyl-(C3-C8)cycloalkyl,

-(C1-the 6)alkyl-(C3-C8)cycloalkyl, where the specified cycloalkyl ring is unsubstituted or substituted one, two, three times-OH, -O-(C1-C4)alkyl, or R10,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerable salts.

4. The present invention relates to compounds of the formula I, in which

R0represents a

1) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R8,

2) heterocyclyl from the group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophene, cinnoline, Romania, indazole, indoline, isopropanyl, isoindolyl, izochinolina, phenylpyridine, phthalazine, pteridine, purine, pyridyl, predominately, pyridopyrimidines, pyridopyrimidines, pyrimidinyl, heatline, chinoline, khinoksalinona or 1,4,5,6-tetrahydropyridine where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8or

3) heterocyclyl group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil, teinila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazoline, triazolyl,tetrazolyl, pyridazinyl and pyrazinyl where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8and additionally substituted by a residue selected from the group of pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil, teinila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazoline, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl, where the specified residue is unsubstituted or mono-, di - or triamese independently of each R8,

R8represents a

1) F, Cl, Br or I,

2) -C(O)-NH2,

3) -(C1-C4alkyl), where alkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen, -HE or balance methoxy,

4) -O-(C1-C4alkyl), where alkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen or a residue methoxy,

provided that R8represents at least one halogen, -C(O)-NH2or a residue-O-(C1-C8alkyl), if R0represents aryl or heterocyclyl that have values above

provided that R8does not represent a residue-O-(C1-With8alkyl), if R0and V are phenyl,

p is structure D represents the balance, selected from the group of phenyl, pyridyl, N-oxide pyridyl, pyrrolyl, furil, teinila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, isothiazoline, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl or thiophenyl, and is unsubstituted or substituted 1, 2, 3 or 4 times R3or substituted 1 or 2 times =O,

Q represents a direct bond, -C(O)-, -SO2-, methylene, -(C0-C2)alkylen-C(O)-NR10- or -(C0-C3)alkylen-C(O)-O-(C0-C2)alkylene-,

R1represents a hydrogen atom, -(C1-C2)alkyl, -(C1-C3)alkylen-C(O)-NH-R0-(C1-C3)perforation -(C1-C3)alkylen-C(O)-O-R15-(C1-C3)alkylen-S(Oh)2-(C1-C3)alkyl or -(C1-C3)alkylen-S(Oh)2-N(R4')-R5'where R4'and R5'are independently of one another identical or different and represent a hydrogen atom or -(C1-C4)alkyl,

R2represents a direct bond,

R1-N-R2-V can form a 4-7-membered cyclic group out of a group of azetidine, azetidinone, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,4-diazepine, 1,2-diazepine, 13-diazepine, 1,4-diazepine, azepine, cefoperazone, 1,4-oxazepine, oxazole, isoxazol, isoxazolidine, 2-isoxazoline, research, thiazole, isothiazole, thiadiazole or thiomorpholine where the specified cyclic group is unsubstituted or mono-, di - or tizamidine independently of each R14,

R14represents fluorine, chlorine, -HE, =O, -(C1-C8)alkyl,

-C(O)OH, -CN, -NH2, -C(O)-O-(C1-C4)alkyl, -C(O)-NH-(C1-C8)alkyl,

-C(O)-N-[(C1-C8)alkyl]2, -C(O)-NH2or-N(R18)-R21,

where R18and R21represent independently from each other hydrogen atom, -(C1-C3)perfluoroalkyl or -(C1-C6)alkyl,

V represents

1) cyclic residue from the group consisting of compounds that are selected from 8-azabicyclo[3.2.1]Oct-3-yl, azaindole (1H-pyrrolopyridine), aziridine, azirine, azetidine, azetidinone, 1,4-diazepine, pyrrole, pyrrolidine, pyridinyl, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, tetrazine, tetrazole, azepine, diazirine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, pyridazine, piperidine, piperazine, pyrrolidinone, cefoperazone, furan, Piran, dioxolan, 1,4-oxazepine, oxazole, isoxazol, 2-isoxazoline, isoxazolidine, research,oxirane, oxaziridine, 1,3-dioxolene, 1,3-dioxolane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxaziridine, thiophene, thiopyran, Tatana, thiazole, isothiazole, isothiazoline, isothiazolinone, 1,2-oxathiolane, thiadiazole, thiopyran, 1,2-thiazine, 1,3-thiazole, 1,3-thiazine, 1,4-thiazine, thiadiazine or thiomorpholine,

where the specified cyclic residue is unsubstituted or mono-, di - or triamese independently of each R14or

2) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R14or

G represents a direct bond, -(CH2)m-or -(CH2)mNR10-,

m is an integer 0, 1, 2, 3,or 4

M represents

1) a hydrogen atom,

2) heterocyclyl where heterocyclyl is the remainder of the group, which may be selected from azepine, azepine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, isothiazole, isoxazol, isoxazolidine, 2-isoxazoline, metamorphosen, cefoperazone, research, oxazole, [1,4]oxazepan, piperazine, piperazinone, piperidine, piperidine, pyrazine, pyridazine, pyridazine, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydropyridine, tetrazine, tetrazole, thiadiazole, thiazole, thiomorpholine, 1λ6-thiomorpholine, thiophene, 1,2,3-triazine, 1,2,4-triazine is, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R14,

3) -(C1-C6)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R14,

4) (C3-C6)cycloalkyl or

5) -C(O)-NR11)-R12,

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

4) -(C1-C3)perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

6) -(C0-C4)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13or

(C) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

d) -CF3or

e) -CHF2,

7) -CN,

8) -NR10-SO2-R10,

9) -SOs-R11where s is 1 or 2,

10) -SOt-N(R11)-R12where t is 1 or 2,

11) -(C0-C4)alkylen-C(O)-R11,

12) -(C0-C4)alkylen-C(O)-O-R 11,

13) -(C0-C4)alkylen-C(O)-N(R11)-R12,

14) -(C0-C4)alkylene-N(R11)-R12,

15) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-(C1-C4)alkyl,

16) -C(O)-O-C(R15,R16)-O-C(O)-R17,

17) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-O-(C1-C6)alkyl,

18) -C(O)-O-C(R15,R16)-O-C(O)-O-R17,

19) -(C0-C3)alkylen-O-CH2-CF2-CH2-O-(C0-C3)alkyl,

20) -(C0-C3)alkylen-O-CH2-CF2-CF2-CH2-O-(C0-C3)alkyl,

21) -(C0-C3)alkylen-O-CH2-(C1-C3)perforation-CH2HE

22) -SOW-N(R11)-R13where w is 1 or 2,

23) -(C0-C4)alkylen-C(O)-N(R11)-R13,

24) -(C0-C4)alkylene-N(R11)-R13or

25) a residue from the following list of balances:

where Me represents methyl,

if the two balance-OR19attached to adjacent atoms they can form together with the atoms to which they are attached, a ring 1,3-dioxole or ring 2,3-dihydro[1,4]dioxin, which is substituted one, two, three or four times R13,

R11and R12together with the nitrogen atom to which they relate, can obrazovawe the b ring, selected from the group of azepine, azetidine, 1,4-diazepine, dioxazine, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, [1,4]oxazepan, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, thiophene, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where the specified ring is unsubstituted or mono-, di - or tizamidine independently of each R13,

R13represents fluorine, chlorine, -NO2, -CN, =O, -OH, -CF3,

-C(O)-O-R10, -C(O)N(R10)-R20, -N(R10)-R20-(C0-C3)alkylen-O-R10,

-Si(CH3)3, -N(R10)-S(O)2-R10, -S-R10, -SO2-R10, -S(O)2-N(R10)-R20,

-C(O)-R10-(C1-C8)alkyl, -(C1-C8)alkoxy, phenyl, phenyloxy-,

-O-CF3-(C1-C3)perfluoroalkyl, -NH-C(O)-NH-R10,

-(C0-C4)alkyl-C(O)-O-C(R15,R16)-O-C(O)-R17-(C1-C4)alkoxyphenyl,

-(C0 -C4)alkyl-C(O)-O-C(R15,R16)-O-C(O)-O-R17, -O-R15,

-NH-C(O)-O-R10or a residue from the following list of balances:

where Me represents methyl,

R10and R20represent, independently from each other hydrogen, -(C1-C6)alkyl, -(C0-C4)alkyl-OH, -(C0-C4)alkyl-O-(C0-C4)alkyl or -(C1-C3)perfluoroalkyl,

R15and R16represent independently from each other hydrogen, -(C1-C6)alkyl or together form a ring group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, where each ring is unsubstituted or substituted one to three times R10and

R17represents -(C1-C6)alkyl, -(C1-C6)alkyl-HE,

-(C1-C6)alkyl-O-(C1-C6)alkyl, -(C3-C8)cycloalkyl,

-(C1-C6)alkyl-O-(C1-C8)alkyl-(C3-C8)cycloalkyl,

-(C1-C6)alkyl-(C3-C8)cycloalkyl, where the specified cycloalkyl ring is unsubstituted or substituted one, two, three times-OH, -O-(C1-C4)alkyl, or R10,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerable salts.

5. Now izaberete the s refers to compounds of the formula I, in which

R0represents a

1) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R8,

2) heterocyclyl selected from the group of indolyl, isoindolyl, benzofuranyl, benzothiophene, 1,3-benzodioxolyl, indazole, benzimidazole, benzoxazole, benzothiazole, chinoline, izochinolina, Romania, isopropanyl, cinnoline, heatline, khinoksalinona, phthalazine, predominately, pyridopyrimidines, pyridopyrimidines, pyridyl, purine and pteridine where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8,

3) heterocyclyl group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil, teinila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazoline, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8and additionally substituted by a residue selected from the group of pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil, teinila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, TIA is Azolla, isothiazoline, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl, where the specified residue is unsubstituted or mono-, di - or triamese independently of each R8,

R8represents a

1) F, Cl, Br, I,

2) -C(O)-NH2,

3) -(C1-C4alkyl), where alkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen, -HE or balance methoxy, or

4) -O-(C1-C4alkyl), where alkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen or a residue methoxy,

provided that R8represents at least one halogen, -C(O)-NH2or-O-(C1-C8)alkyl residue, if R0represents aryl or heterocyclyl that have values above

provided that R8is not-O-(C1-C8)alkyl residue, if R0and V represent phenyl,

substructure D is a residue selected from the group of phenyl, pyridyl, N-oxide pyridyl, pyrrolyl, furil, teinila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, isothiazoline, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, and is unsubstituted or substituted 1, 2, 3 or 4 times R3or substituted 1 or 2 times =O,

Q represents a direct bond, -C(O), -SO2-, -C(O)-O-methylene, methylene or -(C0-C2)alkylen-C(O)-NR10-,

R1represents a hydrogen atom or -(C1-C2)alkyl,

R2represents a direct bond,

R1-N-R2-V can form a 4-7-membered cyclic group, selected from piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, cefoperazone, oxazole, isoxazol, isoxazolidine, 2-isoxazoline, research, thiazole, isothiazole, thiadiazole or thiomorpholine where the specified cyclic group is unsubstituted or mono-, di - or tizamidine independently other R14,

R14represents fluorine, chlorine, -(C1-C4)alkyl or-NH2,

V represents

1) cyclic residue from the group consisting of compounds that are selected from 8-azabicyclo[3.2.1]Oct-3-yl, azaindole (1H-pyrrolopyridine), azetidine, azepine, aziridine, azirine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, 1,3-dioxolane, dioxazine, furan, imidazole, isoquinoline, isothiazole, isothiazoline, isothiazoline, isoxazol, 2-isoxazoline, isoxazolidine, cefoperazone, research, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, about the casola, 1,2-oxathiolane, piperidine, Piran of pyrazine, pyrazole, pyridazine, piperazine, pyridine, pyridone, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, heatline, quinoline, tetrazine, tetrazole, thiadiazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, Tatana, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where the specified cyclic residue is unsubstituted or mono-, di - or triamese independently from each other R14or

2) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R14,

G represents a direct bond, -(CH2)m- or -(CH2)mNR10-,

m is an integer 0, 1, 2, 3,or 4

M represents

1) a hydrogen atom,

2) heterocyclyl where heterocyclyl is a residue that can be formed from 1,4-diazepan, metamorphine, thiophene, pyridazine, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, pyridinyl, imidazole, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, cefoperazone, oxazole, isoxazol, isoxazolidine, 2-isoxazoline, research, thiazole, isothiazole, tetrahydropyran, 1,4,5,6-tetrahydropyridine, tiadi the ash, 1λ6-thiomorpholine or thiomorpholine where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R14,

3) -(C1-C6)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R14or

4) (C3-C6)cycloalkyl,

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

4) -(C1-C3)perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

6) -(C0-C4)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13or

(C) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

d) -CF3or

e) -CHF2,

7) -CN,

8) -NR10-SO2-R10,

9) -SOs-R11where s is 1 or 2,

10) -SOt-N(R11)-R12where t is 1 or 2,

11) -(C0-C4)alkylen-C(O)-R11,

12) -(C0-C4)alkylen-C(O)-O-R11,

13) -(C0-C4 11)-R12,

14) -(C0-C4)alkylene-N(R11)-R12,

15) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-(C1-C4)alkyl,

16) -C(O)-O-C(R15,R16)-O-C(O)-R17,

17) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-O-(C1-C6)alkyl,

18) -C(O)-O-C(R15,R16)-O-C(O)-O-R17or

19) a residue from the following list of balances:

,

where Me represents methyl,

R11and R12are independently of one another identical or different and represent

1) a hydrogen atom,

2) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

3) -(C0-C6)alkyl-(C3-C6)cycloalkyl,

4) -O-R17or

5) -(C0-C6)alkyl-(C4-C15)heterocyclyl, where the alkyl and heterocyclyl independently of one another are unsubstituted or mono-, di - or tizamidine R13and where heterocyclyl selected from the group of azetidine, cyclopropyl, cyclobutyl, 4,5-dihydrooxazolo, imidazolidine, research, (1,4)-oxazepine, oxazolidine, piperidine, piperazine, pyrrolidine, tetrahydrothiophene, thiazolidine or thiomorpholine, or

R11and R12together with the nitrogen atom to which it is connected, form a heterocyclic ring which is selected from the group of azetidine, cyclopropyl, cyclobutyl, 4,5-dihydrooxazolo, imidazolidine, research, (1,4)-oxazepine, oxazolidine, piperidine, piperazine, pyrrolidine, tetrahydrothiophene, thiazolidine or thiomorpholine, where the specified ring is unsubstituted or mono-, di - or tizamidine R13,

R13represents a fluorine, -CN, =O, -OH, -CF3, -C(O)-O-R10, -C(O)N(R10)-R20, -N(R10)-R20-(C3-C6)cycloalkyl -(C0-C3)alkylen-O-R10-, Si(CH3)3, -S-R10, -SO2-R10-(C1-C3)perfluoroalkyl, or a residue from the following list of balances:

where Me represents methyl,

R10and R20represent independently from each other hydrogen, -(C1-C4)alkyl or -(C1-C3)perfluoroalkyl,

R15and R16represent, independently from each other hydrogen, -(C1-C4)alkyl or together form a ring group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, where each ring is unsubstituted or substituted one to three times R10and

R17represents -(C1-C6)alkyl, -(C1-C6)alkyl-HE,

-(C1-C6)alkyl-O-(C1-C8)alkyl-(C3-C 8)cycloalkyl,

-(C1-C6)alkyl-O-(C1-C6)alkyl, or

-(C0-C6)alkyl-(C3-C8)cycloalkyl, where the specified cycloalkyl ring is unsubstituted or substituted one, two, three times-OH, -O-(C1-C4)alkyl, or R10,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerable salts.

6. The present invention relates to compounds of the formula I, in which

R0represents a

1) phenyl, where phenyl is unsubstituted or mono - or Disaese independently of each R8,

2) pyridyl or 1H-indazole where pyridyl or 1H-indazoles are unsubstituted or mono - or tizamidine independently of each R8or

3) heterocyclyl group tanila, thiadiazolyl, isoxazolyl and thiazolyl where specified heterocyclyl substituted by a residue selected from the group of tanila, 2-tanila and 3-tanila, where the specified residue is unsubstituted or mono - or Disaese independently of each R8,

R8represents F, Cl, Br, -O-CH3or-C(O)-NH2,

provided that R8is not-O-(C1-C8)alkyl residue, if R0and V represent phenyl,

substructure D is a residue selected from the group of phenyl, pyridyl, N-oxide PI is idela, pyrrolyl, teinila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, thiadiazolyl, pyrimidinyl, pyridazinyl or pyrazinyl, and is unsubstituted or substituted 1, 2, 3 or 4 times R3or substituted 1 or 2 times =O,

Q represents a direct bond, -C(O)-, -SO2-, -C(O)-O-methylene, -CH2-C(O)-NH -, or a methylene,

R1represents a hydrogen atom,

R2represents a direct bond,

R1-N-R2-V can form a 4-to 8-membered cyclic group out of a group of azetidine, pyrrolidine, piperidine and piperazine,

R14represents fluorine, chlorine, methyl, ethyl, =O, -SO2-CH3or-NH2,

V represents

1) the rest of the group containing compounds that are selected from 8-azabicyclo[3.2.1]Oct-3-yl, azaindole (1H-pyrrolopyridine), azetidine, 1,4-diazepine, isoxazol, isoquinoline, piperazine, piperidine, pyrazine, pyridazine, pyrimidine, pyrrolidine, heatline, quinoline or tetrahydropyrane where the specified cyclic residue is unsubstituted or mono - or Disaese independently of each R14or

2) phenyl, where phenyl is unsubstituted or mono - Disaese independently of each R14,

G represents a direct bond, -(CH2)m-, -C(O)- or -(CH2)mNR10-,

m is a Chi is Lu 0, 1 or 2,

M represents a hydrogen atom, (C2-C4)alkyl, azepane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, geomorphology, morpholinyl, [1,4]oxazepan, piperazinil, piperidinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolidinyl, 1λ6-thiomorpholine, 1,4,5,6-tetrahydropyridine or tetrahydropyranyl, where the residues are unsubstituted or mono - or tizamidine independently of each R14,

R3represents a

1) a hydrogen atom,

2) fluorine, chlorine,

3) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

4) -(C1-C3)perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

6) -(C0-C2)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

(C) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R13,

d) -CF3or

e) -CHF2,

7) -CN,

8) -NR10-SO2-R10,

9) -SOs-R11where s is 1 or 2,

10) -SOt-N(R11)-R12

11) -(C0-C4)alkylen-C(O)-R11,

12) -(C0-C4)alkylen-C(O)-O-R11,

13) -(C0-C4)alkylen-C(O)-N(R11)-R12,

14) -(C0-C4)alkylene-N(R11)-R12,

15) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-(C1-C4)alkyl,

16) -C(O)-O-C(R15,R16)-O-C(O)-R17,

17) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-O-(C1-C6)alkyl, or

(18) -C(O)-O-C(R15,R16)-O-C(O)-O-R17or

R11and R12are independently of one another identical or different and represent

1) a hydrogen atom,

2) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

3) -(C0-C6)alkyl-(C3-C6)alkyl,

4) -O-R17or

5) -(C0-C6)alkylglycerol, where the alkyl and heterocyclyl are independently from each other unsubstituted or mono-, di - or tizamidine R13and where heterocyclyl selected from the group of azetidine, imidazolidine, research, (1,4)-oxazepine or pyrrolidine, or

R11and R12together with the nitrogen atom to which they are bound, may form a ring which is selected from the group of azetidine, imidazolidine, research, [1,4]oxazepan, Pieper is Zina, piperidine, pyrrolidine or thiomorpholine, where the specified ring is unsubstituted or mono-, di - or tizamidine R13,

R13represents a fluorine, -CN, =O, -OH, -CF3, -C(O)-O-R10, -C(O)N(R10)-R20, -N(R10)-R20-(C1-C3)alkyl, -(C3-C6)cycloalkyl -(C0-C3)alkylen-O-R10, -Si-(CH3)3, -S-R10, -SO2-R10, -SO2-NH or -(C1-C3)perfluoroalkyl,

R10and R20represent independently from each other hydrogen, -(C1-C4)alkyl or -(C1-C3)perfluoroalkyl,

R15and R16represent independently from each other hydrogen, -(C1-C4)alkyl or together form a ring group cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, where each ring is unsubstituted or substituted one to three times R10and

R17represents -(C1-C6)alkyl, -(C1-C6)alkyl-HE,

-(C1-C6)alkyl-O-(C1-C8)alkyl-(C3-C8)cycloalkyl,

-(C1-C6)alkyl-O-(C1-C6)alkyl, or

-(C0-C4)alkyl-(C3-C8)cycloalkyl, where the specified cycloalkyl ring is unsubstituted or substituted one, two or three times by-OH, -O-(C1-C4)alkyl, or R10,

in everything of their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerable salts.

7. The present invention relates also to compounds of the formula I, in which

R0represents a

1) phenyl, where phenyl is unsubstituted or mono - or Disaese independently of each R8,

2) pyridyl or 1H-indazole where pyridyl and 1H-indazoles are unsubstituted or mono - or tizamidine independently of each R8or

3) heterocyclyl from the group thiadiazolyl, oxazolyl and thiazolyl where specified heterocyclyl substituted by a residue selected from the group of tanila, 2-tanila and 3-tanila, where the specified residue is unsubstituted or mono - or Disaese independently of each R8,

R8represents Cl or-O-CH3,

provided that R8is not-O-(C1-C8)alkyl residue, if R0and V represent phenyl,

substructure D is a residue selected from the group of phenyl, pyridyl, tanila or pyrimidinyl, and is unsubstituted or substituted 1, 2, 3 or 4 times R3or substituted 1 or 2 times =O,

Q represents-CH2-C(O)-NH -, or a methylene,

R1represents a hydrogen atom,

R2represents a direct bond,

R14represents fluorine or =O,

V represents piperidinyl or phenyl, where phenyl is unsubstituted or mono - or Disaese independently of the other the other R 14,

G represents a direct bond or-C(O)-,

M represents a hydrogen atom, (C2-C4)alkyl, isopropyl, cyclopropyl, morpholinyl, piperazinil, piperidinyl, pyrazinyl, pyridyl, pyrimidyl, pyrrolidinyl or 1λ6-thiomorpholine, where the residues are unsubstituted or mono - or tizamidine independently of each R14,

R3represents a

1) a hydrogen atom,

2) fluorine, chlorine,

3) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13,

4) -(C0-C2)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13or

C) -CF3,

5) -SO2-R11,

6) -(C0-C4)alkylen-C(O)-O-R11,

7) -(C0-C4)alkylen-C(O)-N(R11)-R12,

8) -(C0-C2)alkylen-C(O)-O-(C2-C4)alkylen-O-C(O)-O-(C1-C6)alkyl, or

9) -C(O)-O-C(R15,R16)-O-C(O)-O-R17,

R11and R12are independently of one another identical or different and represent

1) a hydrogen atom,

2) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently the Rog from each other R 13or

3) -(C0-C6)alkyl-(C3-C6)cycloalkyl, or

R11and R12together with the nitrogen atom to which they are bound, may form a ring which is selected from the group of azetidine, research, (1,4)-oxazepine or piperidine, where the specified ring is unsubstituted or mono-, di - or tizamidine R13,

R13represents fluorine, =O, -OH, -CF3, -C(O)-O-R10-(C1-C3)alkyl, -(C3-C6)cycloalkyl or -(C0-C3)alkylen-O-R10,

R10represents a hydrogen atom or -(C1-C4)alkyl,

R15and R16represent independently each other a hydrogen atom or -(C1-C4)alkyl and

R17represents -(C1-C6)alkyl, -(C1-C6)alkyl-IT or -(C0-C4)alkyl-(C3-C8)cycloalkyl,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerable salts.

8. The present invention relates also to compounds of formula I, which are

1) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

2) (1-isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-1H-benzoimidazol-2-carboxylic acid,

3) (1-isopropylpiperazine-4-yl)amide 1-[(chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

4) (1-pyrimidine-4-reparacin-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

5) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

6) methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

7) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

8) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

9) methyl ester 1-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

10) methyl ester of 3-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

11) 1-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

12) 3-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

13) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

14) methyl ester of 3-[5-(5-chlorothiophene-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid,

15) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

16) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid,

17) (1-isopropylpiperazine-4-yl)amide 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid,

18) methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

19) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

20) methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

21) methyl ether 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

22) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

23) 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

24) 1-ethoxycarbonylmethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

25) 1-cyclohexyloxycarbonyloxy the silt ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

26) 4-[(2-hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazole-2,4-dicarboxylic acid,

27) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

28) 4-[(2-hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazole-2,4-dicarboxylic acid,

29) 5-[(2-hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazole-2,5-dicarboxylic acid,

30) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

31) 1-ethoxycarbonylmethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

32) 1-cyclohexyloxycarbonyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

33) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid,

34) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-6-(2-hydroxyethanesulfonic)-1H-benzo idazole-2-carboxylic acid,

35) 4-[(2-hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,4-dicarboxylic acid,

36) 4-[(2-hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,4-dicarboxylic acid,

37) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

38) 1-ethoxycarbonylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

39) 1-cyclohexyloxycarbonyloxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

40) [4-(3-exmortis-4-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

41) methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid,

42) [4-(4-oxo-4H-pyridin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

43) [4-(4-oxo-4H-pyridin-1-yl)phenyl]amide 1-(3-methoxybenzyl)-1H-benzoimidazol-2-carboxylic acid,

44) [4-(4-oxo-4H-pyridin-1-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic KIS is the notes,

45) (8-methyl-8-azabicyclo[3.2.1]Oct-3-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

46) [4-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

47) [4-(2-oxoacridine-3-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

38) [4-(2-oxoacridine-3-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

49) [4-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

50) [4-(4-oxopiperidin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

51) [4-(1,1-dioxo-1λ6-thiomorpholine-4-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzimidazole-2-carboxylic acid,

52) [4-(1,1-dioxo-1λ6-thiomorpholine-4-yl)phenyl]amide 1-[(5-chloropyridin-2-yl)carbarnoyl)methyl]-1H-benzimidazole-2-carboxylic acid,

53) [4-(2-oxo-2H-pyrazin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

54) [4-(2-oxo-2H-pyrazin-1-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

55) [4-(2-oxopiperidin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzo idazole-2-carboxylic acid,

56) [4-(2-oxopiperidin-1-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

57) [4-(3-exmortis-4-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid,

58) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid,

59) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

60) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

61) 5-[(2-hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,5-dicarboxylic acid,

62) 5-[(2-hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-3H-benzoimidazole-2,5-dicarboxylic acid,

63) 5-[(2-hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,5-dicarboxylic acid,

64) 5-[(2-hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-3H-benzoimidazole-2,5-dicarboxylic acid,

65) 1-cyclohexyloxycarbonyloxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isop oilpipeline-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

66) 1-cyclohexyloxycarbonyloxy ester of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

67) 1-ethoxycarbonylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

68) 1-ethoxycarbonylmethyl ester of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

69) 2-hydroxyethyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

70) 2-hydroxyethyloxy ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

71) carboxymethylate ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

72) 1-(3-methoxybenzyl)-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid,

73) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid,

74) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid,

75) cyclopropylmethoxy the fir 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

76) 2-methoxyethoxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

77) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-hydroxymethyl-1H-benzoimidazol-2-carboxylic acid,

78) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-carboxylic acid,

79) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(morpholine-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

80) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-([1,4]oxazepan-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

81) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2,6-dimethylpiperidin-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

82) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(4,4-deformability-1-carbonyl)-1H-benzimidazole-2-carboxylic acid,

83) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-([1,4]oxazepan-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

84) 2-hydroxyethyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

85) carboxymethylate ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

86) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-methoxyisatin-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

87) 2-(1-isopropylpiperazine-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-4-carboxylic acid,

88) 2-(1-isopropylpiperazine-4-ylcarbonyl)-3-(3-methoxybenzyl)-3H-benzoimidazol-4-carboxylic acid,

89) 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

90) 3-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid,

91) (1-isopropylpiperazine-4-yl)amide of 4-(3-hydroxyazetidine-1-carbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-2-carboxylic acid,

92) (1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

93) (1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-(3-methoxyisatin-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

94) methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-5-carboxylic acid,

95) methyl ester of 2-(1-isopropylpiperazine-4-carbarnoyl)-3-(3-methoxybenzyl)-3H-benzoimidazol-5-carboxylic acid,

96) methyl ester 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

97) methyl ester of 3-[2-(4-chlorophenyl)e is Il]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

98) 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

99) 1-(5-chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

100) 3-(5-chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid,

101) 1-(5-chloro-1H-indazol-3-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

102) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(4-hydroxypiperidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

103) (1-isopropylpiperazine-4-yl)amide 7-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid,

104) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

105) methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

106) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

107) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

108) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-CEC is propylpiperidine-4-ylcarbonyl)-1H-benzimidazole-4-carboxylic acid,

109) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzimidazole-4-carboxylic acid,

110) methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzimidazole-4-carboxylic acid,

111) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzimidazole-4-carboxylic acid,

112) cyclopropylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzimidazole-4-carboxylic acid,

113) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid,

114) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid,

115) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid,

116) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid,

117) 6-[(2-hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-thieno[3,4-d]imidazol-2,6-dicarboxylic acid,

118) 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid,

119) 3-[5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid,

120) (1-isopropylpiperazine-4-yl)amide 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-([1,4]oxazepan-4-carbonyl)-3H-thieno[3,4-d]imidazole-2-carboxylic acid,

121) methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-6-(2,2,2-triptoreline)-3H-thieno[3,4-d]imidazole-4-carboxylic acid,

122) 1-[3-(5-chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzimidazole-5-carboxylic acid,

123) 3-[3-(5-chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzimidazole-5-carboxylic acid,

124) 1-[5-(5-chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzimidazole-5-carboxylic acid,

125) 3-[5-(5-chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-5H-benzimidazole-5-carboxylic acid,

126) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid,

127) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-ethoxyethoxy)-1H-benzoimidazol-2-carboxylic acid,

128) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-hydroxyethoxy)-1H-benzoimidazol-2-carboxylic acid,

129) methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[2-fluoro-4-(pyrrolidin-1-carbonyl)phenylcarbamoyl]-1H-benzamid the evil-4-carboxylic acid,

130) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid,

131) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-3H-benzoimidazol-5-carboxylic acid,

132) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-fluoro-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

133) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-5-carboxylic acid, or

134) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-hydroxyazetidine-1-carbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-2-carboxylic acid.

In General, the value of any group, residue, heteroatom, numbers, etc. that may occur in the compounds of formula I, more than once, does not depend on the values of this group, residue, heteroatom, numbers, etc. in any other case. All groups, residues, heteroatoms, numbers, etc. that can occur more than once in the compounds of formula I, may be the same or different.

Used in this description, the term "alkyl" should be understood in its broadest sense to denote a hydrocarbon residue which may be linear, for example have a non-branched chain or branched, and is the quiet can be acyclic or cyclic residues or contain any combination of acyclic and cyclic subunits. In addition, the term "alkyl"used in this description, explicitly includes saturated group and an unsaturated group, the last group contains one or more, for example one, two or three double bonds and/or triple bond, provided that the double bond is not located in cyclic alkyl group such that the formed aromatic system. All these statements are true, if an alkyl group is present as a substituent in another residue, for example in alkylacrylate, allyloxycarbonyl residue or arylalkyl residue. Examples of "-(C1-C8)alkyl or-(C1-C8)alkylene" are alkyl residues containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as methyl, methylene, ethyl, ethylene, propyl, propylene, butyl, butylene, pentyl, pentile, hexyl, heptyl or octyl, n-isomers of all these residues, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl, tert-pentyl, Deut-butyl, tert-butyl or tert-pentyl. The term "-(C1-C8)alkyl or-(C1-C8)alkylene" means a hydrocarbon residue containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. The term "-C0alkyl or C0kilen" is defined covalent bond. Unsaturated alkyl residues are, for example, alkeline residues such as vinyl, 1-propenyl, 2-propenyl, (= allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl, or alkyline residues, such as ethinyl, 1-PROPYNYL, 2-PROPYNYL, (= propargyl) or 2-butynyl. Alkyl residues may also be unsaturated when they are replaced. Examples -(C3-C8)cycloalkyl cyclic alkyl residues are cycloalkyl residues containing 3, 4, 5, 6, 7 or 8 carbon atoms of the ring-like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, which can also be substituted and/or unsaturated. Unsaturated cyclic alkyl groups and unsaturated cycloalkyl group, such, for example, cyclopentenyl or cyclohexenyl can be connected through any carbon atom.

The terms "monocyclic or bicyclic 6-14-membered aryl or-(C6-C14)-aryl" means an aromatic hydrocarbon radicals containing from 6 to 14 carbon atoms in the ring. Examples (C6-C14)-aryl radicals are phenyl, naphthyl, for example 1-naphthyl and 2-naphthyl, biphenyl, for example, 2-biphenyl, 3-biphenyl, and 4-biphenyl, antrel or fluorenyl. Biphenylene radicals, raftiline radicals, especially phenyl, R is dicale are the preferred aryl radicals.

The term "mono - or bicyclic 4-15 membered heterocyclyl or-(C4-C15)heterocyclyl" refers to a heterocycle in which one or more of 4-15 carbon atoms of the ring are replaced by heteroatoms such as nitrogen, oxygen or sulfur. Examples are acridines, 8-azabicyclo[3.2.1]Oct-3-yl, azaindole (1H-pyrrolopyridine), asianshemales, azaspiracid, azepine, azetidine, aziridine, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, asterisell, benzisoxazole, benzisothiazole, carbazole, 4H-carbazolyl, carbolines, bromanil, bromanil, cinnoline, decahydroquinoline, 4,5-dihydrooxazolo, doxazosin, dioxazines, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 3,3-dioxo[1,3,4]oxadiazine, 6N-1,5,2-detainer, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furutani, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isopropanol, isoindolyl, isoindolines, isoindolyl, ethenolysis (benzimidazolyl), isothiazolin, isothiazolinones, isothiazolines, isoxazolyl, isoxazolyl, isoxazolidine, 2-isoxazoline, cefoperazone, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,2-what Catalani, 1,4-oxazepan, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, oxetanyl, axokine, phenanthridines, phenanthrolines, phenazines, phenothiazines, phenoxathiin, pennacchini, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxicaly, predominately, peridotites, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinone, pyrroline 2N-pyrrolyl, pyrrolyl, hintline, chinoline, 4H-hemolysins, honokalani, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridine, tetrahydrothiophene, tetrazines, tetrazolyl, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, 1,2-thiazines, 1,3-thiazines, 1,4-thiazines, 1,3-thiazolyl, thiazolyl, diazolidinyl, thiazolyl, thienyl, titanyl, theNational, cyanoacetyl, tenomodulin, titanyl, thiomorpholine, thiophenols, thiophenyl, tiopronin, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xantinol.

Preferred are such compounds as benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzothiazolyl, benzothiophene, benzoxazole, bromanil, cinnoline is, 2-furyl, 3-furyl, imidazolyl, indolyl, indazoles, isopropanol, isoindolyl, ethenolysis, isothiazolin, isoxazolyl, oxazolyl, phthalazine, pteridine, purinol, pyrazinyl, pyrazolyl, pyridazinyl, predominately, pyridopyrimidines, pyridopyrimidines, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, chinoline, hintline, honokalani, tetrazolyl, thiazolyl, 2-thienyl and 3-thienyl.

Preferred are also

The term "het" or "3-7-membered cyclic residue, containing up to 1, 2, 3 or 4 heteroatoms" refer to structures of heterocycles which can be formed from such compounds as azepin, azetidin, aziridine, asirin, 1,4-diazepan, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dixital, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazol, isothiazolin, isothiazolin, isoxazol, isoxazolin, isoxazolidine, 2-isoxazolin, metamorphosen, cefoperazon, morpholine, 1,2-exatape, 1,2-oxathiolan, 1,4-oxazepan, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxazol, oxaziridine, oxetan, oxiran, piperazine, piperidine, Piran, pyrazin, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrrolin, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tet is asin, tetrazol, thiadiazine, thiadiazole, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 1,3-thiazole, thiazole, thiazolidine, thiazoline, thienyl, tieton, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole.

The term "R1-N-R2-V can form a 4-to 8-membered cyclic group, or R11and R12together with the nitrogen atom to which they are bound, may form a 4-8-membered monocyclic heterocyclic ring which in addition to the nitrogen atom can contain one or two identical or different heteroatoms in the ring selected from oxygen, sulfur and nitrogen" refers to structures of heterocycles which can be formed from such compounds as ASEAN, azepin, azetidin, dixital, dioxazine, 1,4-diazepan, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 2,3-dihydroindol, imidazole, imidazoline, imidazolidine, indole, isothiazol, isothiazolin, isothiazolin, isoxazol, isoxazolin, isoxazolidine, 2-isoxazoline, cefoperazon, morpholine, [1,4]oxazepan, oxazole, piperazine, piperidine, pyrazin, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrrolin, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole.

The term "R15and R16together with the carbon atom, with the cat is the ring they are attached, may form a 3-6-membered carbocyclic ring" refers to structures that can be formed from compounds such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "substructure

in the formula I" or "structure D is 4-to 8-membered saturated, partially unsaturated or aromatic cyclic group containing 0, 1, 2, 3 or 4 heteroatoms selected from nitrogen atom, sulfur or oxygen" refers to structures that can be formed from such compounds as ASEAN, azetidin, azatin, asokan, asokan-2-it, cyclobutyl, cyclooctyl, cyclooctene, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1,2-diazepan, 1,4-diazepin, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, [1,4]diadakan, [1,2]diadakan-3-one, [1,3]diadakan-2-it, dixital, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazol, isothiazolin, isothiazolin, isoxazol, isoxazolin, isoxazolidine, 2-isoxazoline, cefoperazon, morpholine, 1,4-oxazepan, 1,2-exatape, 1,2-oxathiolan, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxazol, [1,4]oxytocin, [1,3]oxazolin-2-it, oxetan, oxacin, oxolan-2-it, piperazine, piperidine, phenyl, Piran, pyrazin, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrrolin, 5,6,7,8-tetrahydro-1H-Asotin-2-the n, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, thiadiazine, thiadiazole, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 1,3-thiazole, thiazole, thiazolidine, thiazoline, tieton, Ciocan, 1,1-dioxide tikana, 1-oxide tikana, Ciocan-2-it, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,3,5-triazole or 1,2,4-triazole.

The term "substructure D is a 5-6-membered saturated, partially unsaturated or aromatic cyclic group containing 0, 1, 2, 3 or 4 heteroatoms selected from nitrogen atom, sulfur or oxygen" refers to structures that can be formed from compounds such as cyclopentyl, cyclohexyl, dixital, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazol, isothiazolin, isothiazolin, isoxazol, isoxazolin, isoxazolidine, 2-isoxazoline, metamorphosen, cefoperazon, morpholine, 1,2-oxathiolan, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxazole, piperazine, piperidine, phenyl, Piran, pyrazin, pyrazole, pyrazoline, pyrazolidine, pyrazin, pyrazine, pyridazine, pyridate, pyridine, pyridone, pyrimidine, pyrimidone, pyrrole, pyrrolidine, pyrrolidinone, pyrrolin, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 1,3-thiazole, thiazole, thiazolidine, thiazoline, thiomorpholine, thiophene, thiopyran, terasi the, tetrazole, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole.

The term "R1and R3together with the atoms to which they are linked, can form a 6-8 membered cyclic group, containing up to 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, sulfur or oxygen" refers to structures of heterocycles which can be selected from such compounds as asokan, asokan-2-it, cycloheptyl, cyclohexyl, cyclooctyl, cyclooctene, 1,4-diazepan, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, [1,4]diadakan, [1,2]diadakan-3-one, [1,3]diadakan-2-it, dioxazine, [1,4]dioxin, dioxole, cefoperazon, morpholine, 1,2-exatape, 1,4-oxazepan, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, [1,4]oxytocin, [1,3]oxazolin-2-it, oxacin, oxolan-2-it, phenyl, piperazine, piperidine, Piran, pyrazin, pyridazine, pyrimidine, 5,6,7,8-tetrahydro-1H-Asotin-2-he or thiomorpholine. The term "residue oxo" or "=O" refers to such balances as carbonyl (-C(O)-) or nitroso (-N=O).

The fact that many of the above names heterocycles are chemical names unsaturated or aromatic cyclic systems, does not mean that the 4-15 membered mono - or polycyclic group can only be selected from the corresponding unsaturated cyclic system. Names serve only to describe the cyclic system with respect to ring size and number of the heteroatom is in and their relative positions. As explained above, 4-15 membered mono - or polycyclic group may be saturated or partly unsaturated or aromatic, and, thus, can be selected not only of the above-mentioned heterocycles, but also, if appropriate, from all their partially or completely hydrogenated analogs, as well as from their more unsaturated analogues. As examples of fully or partially hydrogenated analogues of the above heterocycles from which the group can be selected can be specified following analogs: pyrrolin, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydropyridines, tetrahydropyridine, piperidine, 1,3-dioxolane, 2-imidazolin, imidazolidin, 4,5-dihydro-1,3-oxazole, 1,3-oxazolidin, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazin (= morpholine), perhydro-1,4-thiazin (= thiomorpholine)peligrosas, indolin, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline etc.

The term "-(C1-C3)perfluoroalkyl" means a partially or fully fluorinated alkyl residue, which can be selected from such residues, CF3, -CHF2, -CH2F, -CHF-CF3, -CHF,-CH2F, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CF2-CF3, -CF2-CHF2, -CF2-CH2F, -CH2-CHF-CF 3, -CH2-CHF-CHF2, -CH2-CHF-CH2F, -CH2-CH2-CF3, -CH2-CH2-CHF2, -CH2-CH2-CH2F, -CH2-CF2-CF3, -CH2-CF2-CHF2, -CH2-CF2-CH2F, -CHF-CHF-CF3, -CHF-CHF-CHF2, -CHF-CHF-CH2F, -CHF,-CH2-CF3, -CHF,-CH2-CHF2, -CHF,-CH2-CH2F, -CHF-CF2-CF3, -CHF-CF2-CHF2, -CHF-CF2-CH2F, -CF2-CHF-CF3, -CF2-CHF-CHF2, -CF2-CHF-CH2F, -CF2-CH2-CF3, -CF2-CH2-CHF2, -CF2-CH2-CH2F, -CF2-CF2-CF3, -CF2-CF2-CHF2or-CF2-CF2-CH2F.

The term "-(C1-C3)perforation" means a partially or fully fluorinated alkalinity residue, which may be selected from such residues, CF2-, -CHF-, -CHF-CHF2-, CHF-CHF-, -CH2-CF2-, -CH2-CHF-, -CF2-CF2-, -CF2-CHF-, -CH2-CHF-CF2-, -CH2-CHF-CHF-, -CH2-CH2-CF2-, -CH2-CH2-CHF-, -CH2-CF2-CF2-, -CH2-CF2-CHF-, -CHF-CHF-CF2-, -CHF-CHF-CHF-, -CHF-CH2-CF2-, -CHF-CH2-CHF-, -CHF-CF2-CF2-, -CHF-CF2-CHF-, -CF2-CHF-CF2-, -CF2-CHF-CHF-, -CF2-CH2-CF2-, -CF2-CH2-CHF-, -CF2-CF2-CF2- or-CF2-CF2-CHF-,

G the lågen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, particularly preferably chlorine or bromine.

Optically active carbon atoms present in the compounds of formula I can independently of each other to have the R-configuration or S-configuration. The compounds of formula I may be present in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers and/or diastereomers, for example in the form of racemates. The present invention relates to the pure enantiomers and mixtures of enantiomers, as well as pure diastereomers and mixtures of diastereomers. The invention contains a mixture of two or more than two stereoisomers of the formula I and contains all ratios of the stereoisomers in the mixtures. When the compounds of formula I can be present as E isomers or Z isomers (or CIS isomers or TRANS isomers), the invention relates both to the pure S-isomers and the pure Z-isomers, mixtures of E/Z in all relationships. The invention also includes all tautomeric forms of compounds of formula I.

The diastereomers, including E/Z-isomers, can be separated into the individual isomers, for example, chromatography. The racemates can be separated into two enantiomers by conventional means, such as chromatography on chiral phases or by separation, for example by crystallization of the diastereomeric salts obtained with optical AK is active acids or bases. Stereochemical homogeneous compounds of formula I can also be obtained by the application of stereochemical homogeneous initial substances or by using stereoselective reactions.

Physiologically tolerated salts of the compounds of formula I are non-toxic salts which are physiologically acceptable, in particular, pharmaceutically salts used. Such salts of compounds of formula I containing an acid group such as carboxyl group COOH, are, for example, alkali metal salts or salts of alkaline-earth metals such as sodium, potassium salts, magnesium salts and calcium salts, and also salts with physiologically tolerable Quaternary ammonium ions, such as Tetramethylammonium or tetraethylammonium, and acid additive salts with ammonia and physiologically tolerable organic amines, such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or Tris-(2-hydroxyethyl)amine. Basic groups contained in the compounds of the formula I, for example amino groups or guanidinium form an acid additive salt, for example, with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids is mi, such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate acid or p-toluensulfonate acid.

The compounds of formula I, which simultaneously contain a basic group and an acidic group, such as guanidinium and carboxyl groups can also be present in the form of zwitterions (betaines), which are likewise included in the present invention.

Salts of compounds of formula I can be obtained by conventional methods known to the person skilled in the art, for example by mixing the compounds of formula I with an inorganic or organic acid or base in a solvent or dispersant or from other salts by cautionable or aminoalkenes. The present invention also includes all salts of the compounds of the formula I which, owing to low physiological tolerability, are not directly suitable for use in pharmaceutical preparations, but are suitable, for example, as intermediates for further chemical modifications of the compounds of formula I or as starting materials for the production of physiologically-tolerated salts.

Us is Aasee the invention, in addition, includes all the solvate of the compounds of the formula I, for example hydrates or adducts with alcohols.

The invention also includes derivatives and products of modifications of the compounds of the formula I, for example, prodrugs, protected forms and other physiologically tolerated derivatives, as well as active metabolites of compounds of formula I. the Invention relates in particular to prodrugs and protected forms of the compounds of formula I which may be converted into compounds of formula I under physiological conditions. Suitable prodrugs for the compounds of formula I, i.e. chemically modified derivatives of the compounds of formula I, having properties that enhance the desired manner, for example with respect to solubility, bioavailability or duration of action known to the person skilled in the art. More detailed information relating to prodrugs can be found in the usual literature, such, for example, publications, Design of Prodrugs, H. Bundaard (ed.), Elsevier, 1985; Fleisher et al, Advanced Drug Delivery Reviews 19 (1996) 111-130; or H. Bundgaard, Drugs of the Future 16 (1991) 443, which are all included in this description by reference. Suitable prodrugs for the compounds of formula I are especially acyl prodrugs and urethane prodrugs alleluiah nitrogen-containing groups such as amino groups and guanidinium and ester Ave the medicine and amide prodrugs groups of carboxylic acids, which may be present in compounds of the formula I. In the acyl prodrugs and urethane the prodrugs of one or more, for example one or two hydrogen atoms on the nitrogen atoms in such groups substituted acyl group, or a carbamate, preferably (C1-C6)allyloxycarbonyl group. Suitable acyl groups and urethane groups to acyl prodrugs and urethane prodrugs are, for example, the group Rp1-CO - and Rp2-O-CO-, in which Rp1represents hydrogen, (C1-C18)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl-(C1-C4)alkyl, (C6-C14)aryl, Het-, (C6-C14)aryl-(C1-C4)alkyl - or Het-(C1-C4)alkyl -, and in which Rp2matter listed for Rp1with the exception of hydrogen.

Especially preferred compounds of formula I are compounds that have two or more residues have the values specified above for the preferred compounds of formula I, or residues may have one or more specific values of the residues mentioned above in their General definitions or definitions of preferred compounds. All possible combinations of the definitions specified in detail for the preferred definitions and specific values of the residues, Aleuts is the subject of the present invention.

In addition, with respect to all preferred compounds of the formula I, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts and their prodrugs are definitely the subject of the present invention. Similarly, in all the preferred compounds of formula I, all the residues, which are present in the molecule more than once, also do not depend on each other and can be identical or different.

The compounds of formula I can be obtained using techniques and methods, which per se are well known and recognized by the average person skilled in the art. Source materials or building blocks for" for use in the General methods of synthesis, which can be used for obtaining the compounds of formula I are easily accessible to the average person skilled in the art. In many cases, they are commercially available or described in the literature. Otherwise they can be obtained from readily available compounds, the precursors similar to the techniques described in the literature, or by the techniques described in this application, or similar such methods.

In General, the compounds of formula I can be obtained, for example, in the course of a convergent synthesis, by linking two or more fragments which can be defined retrace the Tethyan follows from the formula I. More specifically, upon receipt of the compounds of formula I as blocks for building use appropriately substituted derivatives of the original benzoimidazole. If such derivatives are not commercially available, they can be obtained by well-known standard methods of education circular system benzoimidazole. By selecting a suitable precursor molecules syntheses of these benzoimidazole enable the introduction of different substituents at different positions of the system benzoimidazole, which can be chemically modified, in order finally to obtain a molecule of formula I having the desired structure replacement. As one of the full review, where you can find various details and references on the chemistry of benzoimidazole and synthetic methods of obtaining them, you can specify J. Backes, B. Heinz, G. W. Ried in Houben-Weyl, "Methods der Organischen Chemie" (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, Germany, 1994, Vol. E8c Hetarene.

If the original derivatives benzoimidazole are not commercially available and must be synthesized, it can be done, for example, in accordance with well-known syntheses of benzoimidazole mentioned above. The following methods are listed and briefly described techniques are particularly interesting option for carrying out this invention, but they assumesthat techniques, widely discussed in the literature and well known to the person skilled in the art. Although not always shown exactly, in some cases, during the synthesis of the following reactions can take place with the formation of positional isomers. However, such mixtures of positional isomers can be separated modern methods of separation, such, for example, preparative HPLC.

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e) E. L Samuel et al., J. Chem. Soc. C, 1967, 25.

7) P.A. Petyunin et al., Khim. Geterosikl Soedin 1982, 5, 684.

8) CT Brain et al., Tetrahedron Lett., 2002, 43, 1893.

9) E.L. Samuel et al., J. Chem. Soc. C, 1967, 25.

10) E.L. Samuel et al., J. Chem. Soc. C, 1967, 25.

11) G. Dannhardt et al., Arch. Pharm. 2000, 333, 23.

12) A. Orjales et al., Eur. J. Med. Chem. 1999, 34, 415.

13) H. Goker et al., Arch. Pharm. Pharm. Med. Chem. 2001, 334, 148.

14) a) R.B. Baudy et al., J. Med. Chem. 2001, 44, 1516.

b) Y.K. Yun et al., Synlett 2002, No. 5, 739.

15) N. Nabulsi, R. Gandour, J. Org. Chem. 1991, 56, 2260.

Depending on the substituents in the original substances in some syntheses of benzoimidazole can be obtained mixture of positional isomers, which, however, can be separated modern methods of separation, such, for example, preparative HPLC.

In addition, to obtain the desired substituents in the cyclic system benzoimidazole in the formula I of the functional group introduced in the cyclic system during the synthesis of benzoimidazole, can be chemically modified. Especially groups present in the cyclic system benzoimidazole, can be modified in many reactions, and thus, can be obtained the required residues R30. For example, benzoimidazol containing a hydrogen atom in position 2 can also be obtained by saponification and subsequent decarboxylation of benzoimidazole with complex ester group in the corresponding position. Groups, carboxylic acid groups and acetic acid in position , position 4, position 5, position 6 and position 7 can be converted into their homologues conventional reactions for chain elongation of carboxylic acids. The halogen atoms can be introduced, for example, by the techniques described in the literature, similar to the following. For fluorination of benzoimidazole selected reagent is triplet N-fluoro-2,4,6-trimethylpyridine (T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada, K. Tomita, J. Am. Chem. Soc. 1990, 112, 8563 in order), but the choice is not limited to this reagent. Chlorination, bromination or iodination of benzoimidazole can be done by interaction with elemental halogen or using NCS, NBS or NIS and many other reagents well known to the person skilled in the art. These techniques see, for example, in Y. Shi et al., Synth. Commun. 1993, 23, 2623; H. Rapoport et at., Synthesis 1988, 767; R. Jones et al., J. Org. Chem. 1999, 64, 6575; J. Sessler et al., Chem. Eur. J. 2001, 7, 721. Depending on the reaction conditions, reagent stoichiometry and pattern of substitution of the halogen is introduced in position 2 and/or position 4 and/or position 5 and/or 6 position, and/or position 7. Selective exchange of the halogen/metal or metallation of selective exchange of hydrogen/metal and the subsequent interaction with a wide range of electrophiles in the heterocyclic ring can be entered in different substituents (R. Breslow et al., J. Am. Chem. Soc. 1983, 105, 5337; P. Knochel et al., J. Org. Chem. 2000, 65, 4618; S. Ohta et al., Chem. Pharm. Bull. 196, 44, 1831). Halogen or hydroxy-group - through triplet or nonflat or primary amines via their diazonium salt or after interconversion to the corresponding stannane or Bronevoy acid present in the structure of benzoimidazole, can be converted into various other functional groups, such, for example, -CN, -CF3, -C2F5, ethers, acids, amides, amines, alkyl or aryl groups, reactions mediated by transition metals, namely by using palladium or Nickel catalysts or copper salts and reagents, the following (F. Diederich, P. Stang, Metal-catalyzed Cross-coupling Reactions, Wiley-VCH, 1998; or M. Belier, C. Bolm, Transition Metals for Organic Synthesis, Wiley-VCH, 1998; J. Tsuji, Palladium Reagents and Catalysts, Wiley, 1996; J. Hartwig, Angew. Chem. 1998, 110, 2154; B. Yang, S. Buchwald, J. Were Obtained. Chem. 1999, 576, 125; T. Sakamoto, K. Ohsawa, J. Chem. Soc. Perkin Trans I, 1999, 2323; D. Nichols, S. Frescas, D. Marona-Lewicka, X. Huang, B. Roth, Gudelsky G., J. Nash, J. Med. Chem, 1994, 37, 4347; P. Lam, C. Clark, S. Saubern, J. Adams, M. Winters, D. Chan, A. Combs, Tetrahedron Lett, 1998, 39, 2941; D. Chan, K. Monaco, R. Wang, M. Winters, Tetrahedron Lett. 1998, 39, 2933; V. Farina, V. Krishnamurthy, W. Scott, The Stille Reaction, Wiley, 1994; F. Qing et al. J. Chem. Soc. Perkin Trans. 11997, 3053; S. Buchwald et al. J. Am. Chem Soc. 2001, 123, 7727; S. Kang et al. Synlett 2002, 3, 427; S. Buchwald et al. Organic Lett. 2002, 4, 581; T. Fuchikami et al. Tetrahedron Lett. 1991, 32, 91; Q. Chen et al. Tetrahedron Lett. 1991, 32, 7689). For example, the nitro group can be restored in amino various reducing agents, such as sulfides, dithionite, complex hydrides, and catalytic hydrogenation. The restoration of the nitro group can be carried out at a later stage of the synthesis of the compounds of formula I and the restoration of the nitro group to the amino group can also be carried out simultaneously with the reaction performed by another functional group, for example by reaction group such as cyano, hydrogen sulfide or by hydrogenation of the group. For the introduction of the residue R30amino groups can then be modified by standard methods for alkylation, for example by interaction with (substituted) alkylhalogenide or by reductive amination of carbonyl compounds by standard methods of acylation, for example by interaction with activated derivatives of carboxylic acids, such as acid chlorides, anhydrides, activated esters or other derivatives of the acids, or by interaction with carboxylic acids in the presence of an activating agent, or standard methods sulfonylamine, such as the interaction with sulphonylchloride.

Ester groups present in the ring benzoimidazole, can be hydrolyzed to the corresponding carboxylic acid, which after activation can then be subjected to interaction with amines or alcohols under standard conditions. In addition, these ester or acid groups can be restored in accordance with the laws the corresponding alcohols by many standard techniques. Simple ester groups present in benzoimidazole ring, such as benzyloxy or other easily degradable group, can be split with getting hydroxyl groups, which can then be subjected to interaction with various agents, for example agents for the formation of ethers or activating agents, allowing to replace the hydroxy-group to other groups. Similarly can interact sulfur group.

In the synthesis process for the modification of the groups R62or R8'attached to the cyclic system benzoimidazole, using the methodology of parallel synthesis in addition to the various reactions are extremely applicable may be the catalysis with palladium, Nickel or copper. Such reactions are described, for example, F. Diederich, P. Stang, Metal-catalyzed Cross-coupling Reactions, Wiley-VCH, 1998; or M. Seller, C. Bolm, Transition Metals for Organic Synthesis, Wiley-VCH, 1998; J. Tsuji, Palladium Reagents and Catalysts, Wiley, 1996; J. Hartwig, Angew. Chem. 1998, 110, 2154; B. Yang, S. Buchwald, J. Were Obtained. Chem. 1999, 576, 125; P. Lam, C. Clark, S. Saubern, J. Adams, M. Winters, D. Chan, A. Combs, Tetrahedron Lett. 1998, 39, 2941; D. Chan, K. Monaco, R. Wang, M. Winters, Tetrahedron Lett. 1998, 39, 2933; J. Wolfe, H. Tomori, J. Sadight, J. Yin, S. Buchwald, J. Org. Chem. 2000, 65, 1158; V. Farina, V. Krishnamurthy, W. Scott, The Stille Reaction, Wiley, 1994; S. Buchwald et al., J. Am. Chem Soc. 2001, 123, 7727; S. Kang et al., Synlett 2002, 3, 427; S. Buchwald et al., Org. Lett. 2002, 4, 581.

In addition, the above reaction for the conversion of functional groups, in General, are widely described in the textbooks of organic chemistry, like M. Smith, J. March, March's Advanced Organic Chemistry, Wiley-VCH, 2001 and in the monographs, such Houben-Weyl, "Methods der Organischen Chemie" (Methods of Organic Chemistry), GeorgThieme Verlag, Stuttgart, Germany, or "Organic Reactions", John Wiley & Sons, New York, or R.C. Larock, "Comprehensive Organic Transformations", Wiley-VCH, 2nded (1999), B. Trost, I. Fleming (eds.) Comprehensive Organic Synthesis, Pergamon, 1991; A. Katritzky, C. Rees, E. Scriven Comprehensive Heterocvdic Chemistry II, Elsevier Science, 1996), where you can find the details of the reactions and primary literature sources. Due to the fact that in the present case the functional groups attached to the ring benzoimidazole, in some cases it may be necessary to specifically adapt reaction conditions or to choose specific reagents from a number of reagents, which, in principle, can be used in the reaction conversion, or otherwise, to use specific activities to achieve the desired conversion, for example to use the methods of protective groups. Whatever the case, finding suitable options of reactions and reaction conditions in such cases does not create any problems for professionals in this field. The structural elements present in the residues in position 1 of the ring benzoimidazole in the compounds of the formula I and in group COR8'present in position 2 of the ring benzoimidazole can be entered in the source derived benzoimidazole available, as described above, the serial stud is s reaction using the methods of parallel synthesis, similar to the methods described below, using techniques that are per se well known specialist in this field.

The remains of R8'can be introduced into the compound of formula 2, for example, by condensation of the corresponding carboxylic acid of formula 2 with the compound of the formula HR8', i.e. with an amine of the formula HN(R1'R2'-V-G-M, to obtain the compounds of formula 3. Thus obtained compound of formula 3 can already contain the desired final groups, i.e. groups of R8'and R62can be a group-N(R1'R2'-V-G-M and R0Q-values are indicated in the formula I, or, optionally, in the thus obtained compound of formula 3 residue or residues R8'and the remainder R62transform remains in N(R1R2-V-G-M and R0-Q, respectively, to obtain the desired compounds of formula I.

Thus, the residues R8'and the remains of R1'and R2'-V-G-M contained herein may have values of R1and R2-V-G-M, respectively, above, or in addition to the residues R1'and R2'-V-G-M functional groups can also be present in the form of groups, which can then be converted to a finite group R1and R2-V-G-M, i.e., functional groups can be present in the form of groups precursor or derivative is, for example in a protected group. In the process of producing compounds of the formula I is usually advantageous or necessary to introduce functional groups that reduce or prevent undesired reactions or side reactions in the respective synthesis step, in the form of groups of precursors which are later converted into the desired functional groups or temporarily block functional groups by a strategy of protective groups suitable for problems of synthesis. Such strategies are well known to the person skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991, or P. Kocienski, Protecting Groups, Thieme 1994). Examples of groups predecessors are ceanography and nitro. Cyano can be later converted to derivatives of carboxylic acids or restored aminomethyl group, or nitro group can be converted by the recovery similar to catalytic hydrogenation, in the amino group. The protective group may also have the appearance of a solid phase, and cleavage from the solid phase means the removal of the protective group. The use of such methods known to the person skilled in the art (Burgess K (Ed.) Solid Phase Organic Synthesis, New York, Wiley, 2000). For example, the phenolic hydroxy-group can be attached to trichlorethylene the resin, which serves as a protective group, and the molecule otscheplaut from annoymously processing TFA at a later stage of the synthesis.

The remainder R62in the compounds of formulas 2 and 3 can mean the group-Q-R0, the value of which is indicated above, which in the end must be present in the desired target molecule of formula I, or it can mean a group that can then be transformed into the group-Q-R0for example a group of the precursor or derivative of the group-Q-R0in which functional groups are present in protected form, or R62can mean a hydrogen atom or a protective group for the nitrogen atom of the ring benzoimidazole. Similarly, the residues R30have the appropriate definition of R3in the formula I, as described above, however, for the synthesis of compounds of formula I, these residues can also in principle be present at the stage of condensation of the compounds of formula 2 with the compound of the formula HR8'to obtain the compounds of formula 3 in the form of groups of precursors or in a protected form.

Residues R63in the compounds of formula 2, which may be identical or different, can be, for example, hydroxy or (C1-C4)alkoxy, that is, the group COR63present in the compounds of formula 2 can be, for example, the free carboxylic acids or their esters, like alkilany esters, as can be group COR8'in the compounds of formula I. the Groups COR63can also be any other assets the new carboxylic acid derivative, which allows to obtain amide, to obtain an ester or get complicated tiefer when interacting with the compound of the formula HR8'. Group COR63may be, for example, the acid chloride acid, activated ester, such substituted difficult phenyl ether, asolid like imidazolyl, azide or a mixed anhydride, for example a mixed anhydride with an ester of carbonic acid or sulfuric acid, all of these derivatives can be obtained from the carboxylic acids by standard methods and can be subjected to interaction with an amine, alcohol or mercaptan of the formula HR8'under standard conditions. The carboxylic acid group COOH, representing COR63in the compound of formula 2 can be obtained, for example, ester groups introduced into the system benzoimidazole during synthesis benzoimidazole standard methods of hydrolysis.

The compounds of formula I in which the group COR8' is a group of ester can also be obtained from compounds of formula 2, in which COR63represents a group of the carboxylic acid, the usual reactions of esterification, like, for example, the reaction of the acid with an alcohol under conditions of acid catalysis, or alkylation of salts of carboxylic acid electrophile, such alkylhalogenide, or interesterification of others the Gogo of ester. The compounds of formula I in which the group COR8'represents an amide group can be obtained from amines and compounds of formula 2, which COR63represents a group of the carboxylic acid or its ester, conventional amination reactions. Especially for amides, compounds of formula 2, in which COR63represents a group of the carboxylic acid can be condensed under standard conditions with compounds of the formula HR8'who are amines, using a standard combination of reagents used in the synthesis of peptides. Such reagents combinations are, for example, carbodiimide like dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, carbonylcyanide like carbonyldiimidazole (CDI) and similar reagents, propylphosphonic anhydride, tetrafluoroborate O-((cyano(etoxycarbonyl)methylene)amino)-N,N,N',N'-tetramethylurea (TOTU), diethylphosphoramidite (DEPC) or bis-(2-oxo-3-oxazolidinyl)phosphorylchloride (THIEF-Cl) and many others.

If the residue-Q-R0present in benzoimidazole formula I, or a residue R63present in benzoimidazole formula 2, or a residue in which functional groups within the residue-Q-R0or R63present in protected form or in the form of group-predecessor, not introduced during the previous stage, for example at the time when NASA ring benzoimidazole, these residues can be, for example, is entered in position 1 system benzoimidazole common literary methods, well known to the person skilled in the art for N-alkylation, reductive amination, N-arilirovaniya, N-acylation or N-sulfonylamine atoms of the nitrogen ring heterocycles. Source derived benzoimidazole which should be used in such a reaction is the hydrogen atom in position 1. N-alkylation of the nitrogen atom of the ring may be, for example, carried out under standard conditions, preferably in the presence of a base, similar To2CO3Cs2CO3, NaH or KO-t-Bu, using alkylating the compounds of formula LG-Q-R0or of the formula R62-LG, in which the atom in the group Q or R62associated with the group LG in this case is an aliphatic carbon atom in the alkyl part and LG represents a leaving group, for example halogen, like chlorine, bromine or iodine, or sulfonyloxy, such tosyloxy, mesilate or tripterocalyx. IG may be, for example, hydroxy-group, which for the reaction of alkylation activate conventional activating agent. To obtain compounds in which a represents a direct bond and the aromatic group is directly related to the position 1 of the system be the of tinidazole, you can apply the conventional techniques arilirovaniya. As progress reagents can be used, for example, aristorod like alkalicarbonate, or 4-performativity. Such methods are described, for example, M. Yamada et al. J. Med. Chem. 1996, 39, 596; J. Ohmori et al. J. Med. Chem. 1996, 39, 3971. Alternatively, a large number of substituted arisitide, the approach formulated above or aritifical can serve as progress agents in position 1 of the nitrogen atom of the heterocycle in mediated salt of copper or palladium reaction in accordance with, for example, P. Cozzi et at. Farmaco 1987, 42, 205; P. Unangst, D. Connor, R. Stabler, R. Weikert, J. Heterocyd. Chem. 1987, 24, 811; G. Tokmakov, I. Grandberg, Tetrahedron 1995, 51, 2091; D. Old, M. Harris, S. Buchwald, Org. Lett. 2000, 2, 1403, G. Mann, J. Hartwig, M., Driver, S. Fernandez-Rivas, J. Am. Chem. Soc. 1998, 120, 827; J. Hartwig, M. Kawatsura, S. Hauk, K. Shaughnessy, L J. Org. Chem. 1999, 64, 5575; S. Buchwald et al., J. Am. Chem. Soc. 2001, 123, 7727. In addition, such arilirovaniya can also be carried out by the interaction of a large number of substituted arylboronic acids, as shown, for example, Mederski, M. Lefort, M. Germann, D. Kux, Tetrahedron 1999, 55, 12757; J. Collman et al., J. Org. Chem. 2001, 66, 7892. During the above transformations may be the formation of positional isomers, however, these mixtures of positional isomers can be separated modern methods of separation, such, for example, preparative HPLC.

The invention relates also to a method for obtaining compounds of formula IV.

The method according to the teachings derived benzoimidazolyl described in DE 3708292. These compounds were obtained in strongly acidic conditions with yields of approximately 50%. Similar methods are also described in DE 4304650 or in the Journal of Medicinal Chemistry (1984, Vol. 27, No. 2, pages 121-125), in which compounds were obtained in the presence of sodium bicarbonate. These conditions provide products only with low yields. Another objective of the present invention is to find ways amination of compounds of formula V with high yields and purity.

The invention therefore relates to a method for obtaining compounds of formula IV.

,

in which

x is an integer of 0 or 1,

R21and R24are the same or different and independently from each other represent

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times R13,

(C) -(C1-C3)alkylen-C(O)-NH-R0,

d) -(C1-C3)alkylen-C(O)-O-R10,

(e) -(C0-C4)alkylaryl, where the aryl is a monocyclic or bicyclic 6-14-membered aryl or mono-, di - or triamese independently of each R8,

f) -(C0-C4)alkylglycerol where heteroaryl is a monocyclic or bicyclic 4 to 15-membered heterocyclyl containing one, two, three or four heteroatoms selected from azo is a, sulfur or oxygen, and mono-, di - or triamese independently of each R8,

g) -(C1-C4)alkylglycerol where heterocyclyl is a monocyclic or bicyclic 4 to 15-membered heterocyclyl containing one, two, three or four heteroatoms chosen from nitrogen, sulphur or oxygen, where indicated heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8and optionally substituted monocyclic or bicyclic 4 to 15-membered heterocyclyl containing one, two, three or four heteroatoms chosen from nitrogen, sulphur or oxygen, where heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8,

h) -(C1-C3)perforation,

i) -(C1-C3)alkylen-S(O)-(C1-C4)alkyl,

j) -(C1-C3)alkylen-S(O)2-(C1-C3)alkyl,

k) -(C1-C3)alkylen-S(O)2-N(R4')-R5',

l) -(C1-C3)alkylen-O-(C1-C4)alkyl,

m) -(C0-C3)alkylene-(C3-C8)cycloalkyl or

n) -(C0-C3)alkyl-het, where het represents a 3-7-membered cyclic residue, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic residue is unsubstituted or mono-, di - or triseme the Yong independently of each R 14,

where R0, R4', R5', R8, R10, R13and R14have the meanings indicated in formula I,

R22represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times R13,

(C) -(C1-C3)alkylen-C(O)-NH-R0,

d) -(C1-C3)alkylen-C(O)-O-R10,

(e) -(C0-C4)alkylaryl, where the aryl is a monocyclic or bicyclic 6-14-membered aryl or mono-, di - or triamese independently of each R8,

f) -(C0-C4)alkylglycerol where heteroaryl is a monocyclic or bicyclic 4 to 15-membered heterocyclyl containing one, two, three or four heteroatoms chosen from nitrogen, sulphur or oxygen, and mono-, di - or triamese independently of each R8,

g) -(C0-C4)alkylglycerol where heterocyclyl is a monocyclic or bicyclic 4 to 15-membered heterocyclyl containing one, two, three or four heteroatoms chosen from nitrogen, sulphur or oxygen, where indicated heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8and optionally substituted monocyclic or bicyclic 4 to 15-membered heterocyclyl containing one, two, three or four heteroatoms selected from azo is a, sulfur or oxygen, where heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8,

h) -(C1-C3)perforation,

i) -(C0-C3)alkylen-S(O)-(C1-C4)alkyl,

j) -(C0-C3)alkylen-S(O)2-(C1-C3)alkyl,

k) -(C0-C3)alkylen-S(O)2-N(R4')-R5',

l) -(C1-C3)alkylen-O-(C1-C4)alkyl,

m) -(C0-C3)alkylene-(C3-C8)cycloalkyl,

n) -(C0-C3)alkylene-het, where het represents a 3-7-membered cyclic residue, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic residue is unsubstituted or mono-, di - or triamese independently of each R14or

o) R2-V-G-M,

where R0, R2, R4', R5', R8, R10, R13, R14, V, G and M have the meanings indicated in formula I, or a substructure of R21-N-R2-V in the formula IV may form a 4-8-membered cyclic group, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic group is unsubstituted or mono-, di - or tizamidine independently of each R14where the remainder R14matter specified in formula I,

R23represents the FDS is th

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times R13,

(C) -(C1-C3)alkylen-C(O)-NH-R0,

d) -(C1-C3)alkylen-C(O)-O-R10,

e) a monocyclic or bicyclic 6-14-membered aryl, where aryl is mono-, di - or triamese independently of each R8,

f) a monocyclic or bicyclic 4 to 15-membered heterocyclyl containing one, two, three or four heteroatoms chosen from nitrogen, sulphur or oxygen,

g) -(C1-C3)perforation,

h) -(C1-C3)alkylen-S(O)-(C1-C4)alkyl,

j) -(C1-C3)alkylen-S(O)2-(C1-C3)alkyl,

k) -(C1-C3)alkylen-S(O)2-N(R4')-R5',

l) -(C1-C3)alkylen-O-(C1-C4)alkyl,

m) -(C0-C3)alkylene-(C3-C8)cycloalkyl,

n) -(C0-C3)alkyl-het, where het represents a 3-7-membered cyclic residue, containing up to 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic residue is unsubstituted or mono-, di - or triamese independently of each R14or

o) -Q-R0,

where R0, R2, R4', R5', R8, R10, R13, R14, Q, V, G and M have the meanings indicated in formula I, and substructure

in formula IV represents a 4-8 membered saturated, partially unsaturated or aromatic cyclic group containing 0, 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, and is unsubstituted or substituted 1, 2, 3, 4, 5 or 6 times R3where R3matter specified in formula I,

which includes the interaction of the compounds of formula V

where R23matter specified in the formula IV, and substructure

in the formula V has the values specified in the formula IV, with a primary amine or a secondary amine in the presence of water, at least one base and at least one miscible with water and organic solvent.

Another objective of the present invention is a method of obtaining the compounds of formula IV, in which the primary amine is a

a) NH2-R21where R21matter specified in the formula IV,

b) NH2-R2-V-G-M, where R2, V, G and M have the meanings indicated in formula IV,

C) NH2-N(R21)-R22where R21and R22have the meanings indicated in formula IV, or

d) compound of formula VI

where R2, R21, V, G and M have the meanings indicated in formula IV.

Another objective of the present invention javljaetsja obtain compound IV,

where the secondary amine is

a) compound

where R21and R22have the meanings indicated in formula IV,

b) the compound of formula VII

where R21, R2, V, G and M have the meanings indicated in formula IV, or

C) the compound of formula VIII

where R2, R21, R24, V, G and M have the meanings indicated in formula IV.

With the introduction of a primary or secondary amine in a mixture of water and miscible with water, an organic solvent begins obtaining the compounds of formula IV. Then add the base, in particular sodium bicarbonate and the resulting solution or suspension is stirred or shaken at K.T. Finally, add the compound of the formula V are either in solid form or dissolved in a suitable organic solvent. The resulting reaction mixture is then stirred or shaken under temperature control. After a suitable reaction time, the compound of formula IV allocate deposition, for example by removal of organic solvent by evaporation. Alternatively, the compound of formula IV can be extracted using an organic solvent, such as dichloromethane, ethyl acetate, toluene, tert-butyl methyl ether or diethyl ether.

The term ")is the range of water-organic solvent" is used to denote, for example, organic solvents such as tetrahydrofuran, acetonitrile, dimethylsulfoxide, dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N-organic, acetone, or sulfolan.

The term "base" is used to denote carbonates of alkali metals such as sodium bicarbonate or potassium bicarbonate, in solid form or in the form of solutions of different concentrations. Essentially all inorganic salts, especially bicarbonate, which have a basicity comparable to the basicity of sodium bicarbonate, can be used for the above-described method. In addition, the term "base" is also used to refer to tertiary amines, such as triethylamine or diisopropylethylamine.

The term "primary amine" is used to refer to an amine, which is substituted by one residue at the nitrogen atom. The term "secondary amine" is used to refer to an amine, which is replaced by two residues at the nitrogen atom.

The term

in the formula IV is a covalent bond, and when x is 1, represents the balance N(R24).

For the reaction of the invention is preferably used from 2 to 12 moles of moles of base per 1 mol of compound of formula V.

For the reaction of the invention is preferably used from 1 mole to 1.5 mole of a primary amine or a secondary amine to 1 mol of compound fo the mules V.

The number of used mixed with water, an organic solvent is usually from 5 g to 300 g per 1 g of compound of formula V, preferably from 10 to 200,

The reaction time is usually from several minutes to 24 hours, preferably 1-5 hours, depending on the composition of the mixture and the chosen temperature range.

The reaction temperature is from 5°to 120°C, preferably from 10°to 35°With, in particular 25°C. In the case of 1-substituted derivatives of imidazole (compound where R23is not a hydrogen atom), the reaction temperature is from 50°to 120°C, preferably from 70°to 100°With, in particular 90°C.

The residual contents of the source substrate, the compounds of formula V is reduced to the content in the selected compound of formula IV below 0.5%.

The predominant features of the process of the invention are very short reaction time, no additional stages of purification, high yields and high purity of the products obtained.

Additional preferred features of the process of the invention are:

easy availability variously substituted amides imidazol-2-carboxylic acids, particularly the amides benzoimidazol-2-carboxylic acid. Getting these structural classes is difficult when using standard techniques, such as with the combination of benzoimidazol-2-carboxylic acids with amines. Very that the synthesis of substituted benzoimidazol-2-carboxylic acid is difficult. In addition, benzoimidazol-2-carboxylic acid, especially 1-substituted benzoimidazol-2-carboxylic acid, tend to decarboxylates during their synthesis, as well as typical combination of conditions for obtaining amides;

easy availability is still completely unexplored structural classes, such as amides thieno[3,4]imidazole-2-carboxylic acid.

Amines with a very low reactivity, such as amines, which do not react even with anhydrides corresponding benzoimidazol-2-carboxylic acids, such as (4-amino-3-forfinal)pyrrolidin-1-ylmethanone (example 165) or methyl ether 2-amino-3-nitrobenzoic acid (example 167), react smoothly (in a very mild conditions)that can synthesize a special anilide the imidazole-2-carboxylic acids, which are difficult to synthesize by other existing methods. For example, acylation of methyl ester 2-amino-3-nitrobenzoic acid even with sterically unhindered by the acid chloride of the acid, such as acetylchloride, requires a large excess of the appropriate carboxylic acid and elevated temperatures (100°With toluene as solvent).

Preferred methods include, but are not limited to, the methods described in the examples.

Connected to the I of the present invention are inhibitors of semipretioase, which inhibit the enzyme activity of factor XA and/or enzyme factor VIIa coagulation. In particular, they are highly active inhibitors of factor XA. They are specific inhibitors of semipretioase, because they essentially do not inhibit the activity of other proteases, inhibition which is not desirable.

The activity of the compounds of formula I can be determined, for example, in the analysis described below, or other assays known in this field. With regard to the inhibition of factor XA, the preferred embodiment of the invention contains compounds that have Ki<1 mm for the inhibition of factor XA, as defined in the following analysis, with a concomitant inhibition of factor VIIa or without him, and which preferably essentially does not inhibit the activity of other proteases involved in coagulation and fibrinolysis, inhibition of which is undesirable (using the same concentration of the inhibitor). Compounds of the invention inhibit the catalytic activity of factor XA or directly in prothrombinase complex or in the form of a soluble subunit, or indirectly by inhibiting the Assembly of factor XA in prothrombinase complex.

As inhibitors of factor XA and/or factor VIIa the compounds of formula I, and the physical is logically portable salt, and their prodrugs are generally suitable for the treatment and prophylaxis of conditions in which the activity of factor XA and/or factor VIIa plays a role or has an undesired value, or which has a favorable impact of the inhibition of factor XA and/or factor VIIa or reduce their activities, or for the prevention, mitigation or treatment which is desirable inhibition of factor XA and/or factor VIIa doctor. Because the inhibition of factor XA and/or factor VIIa affects blood coagulation and fibrinolysis, the compounds of formula I and their physiologically tolerated salts and their prodrugs are generally suitable for reducing blood clotting, or for the treatment and prophylaxis of conditions in which the activity of the blood coagulation system plays a role or has an undesired value, or for which a favorable influence may decrease blood clotting, or for the prevention, mitigation or treatment which is desirable reduction in the activity of the blood coagulation system doctor. The specific objective of the present invention, therefore, is the reduction or inhibition of unwanted blood clotting, in particular, the individual, the introduction of an effective amount of compound I or its physiologically tolerable salts, or prodrugs, as well as their pharmaceutical is x drugs.

The present invention relates also to compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for use as pharmaceuticals (or drugs), to the use of compounds of the formula I and/or their physiologically-tolerated salts and/or their prodrugs for obtaining pharmaceuticals for inhibition of factor XA and/or factor VIIa or for influencing blood coagulation, inflammatory response or fibrinolysis or for therapy or prophylaxis of the diseases mentioned above or below, for example, to obtain pharmaceutical preparations for the treatment and prevention of cardiovascular disorders, thromboembolic diseases or restenoses. The invention relates also to the use of compounds of the formula I and/or their physiologically-tolerated salts and/or their prodrugs for the inhibition of factor XA and/or factor VIIa or for influencing blood coagulation or fibrinolysis or for therapy or prophylaxis of the diseases mentioned above or below, for example for use in the treatment or prevention of cardiovascular disorders, thromboembolic diseases or restenoses, and to methods of treatment with such purposes, including methods for the specified treatment and prevention. The present invention relates also to a pharmaceutical preparation is (or pharmaceutical compositions), which contain an effective amount of at least one of the compounds of formula I and/or physiologically-tolerated salts and/or its prodrugs in addition to customary pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable compounds, carriers, or excipients and/or auxiliary substances or additives.

The invention relates also to the treatment of pathological conditions such as abnormal blood clot, acute myocardial infarction, unstable angina, thromboembolism, acute occlusion of the vessel associated with thrombolytic therapy or subcutaneous transluminal surgery coronary vessels (RTSA), transient episodes of ischemia, stroke, intermittent claudication or bypass vascular bypass grafting of the coronary or peripheral arteries, luminale the narrowing of blood vessels, restenosis after plastic surgery on the coronary arteries and venous vessels, maintaining access to the opened vessel with long-term hemodialysis patients, pathologic thrombus formation occurring in the veins of the lower extremities after surgery in the abdominal cavity, knee or thigh, pathologic thrombus formation occurring in the veins of the lower extremities after surgery in the abdominal cavity, the knee or the hip, the risk of pulmonary embolism or dissemina is consistent systemic intravascular coagulopathy, occurring in vascular systems during septic shock, certain viral infections or cancer. Compounds of the present invention can also be applied to attenuate the inflammatory response. Examples of specific disorders, for the treatment or prevention of which it is possible to apply the compounds of formula I are coronary heart disease, myocardial infarction, angina pectoris, vascular restenosis, for example restenosis after plastic surgery on vessels, such RTSA, respiratory distress syndrome of adults, multiple failure and disseminated intravascular coagulation disorder blood. Examples of related complications associated with surgical operations are thrombosis such as deep vein thrombosis and thrombosis of superficial veins, which can occur after surgery.

The compounds of formula I, and their physiologically tolerated salts and their prodrugs can be introduced animal, preferably a mammal, and in particular to humans as pharmaceuticals for therapy or prophylaxis. They can be administered as such or in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral administration.

The pharmaceutical preparations can be administered orally, e.g. is in the form of pills, tablets, tablets is a tablets, coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. The introduction, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously in the form of solutions for injection or solution for infusion, microcapsules, implants or rods, or subcutaneously, or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention is produced by way known per se and familiar to the person skilled in the art, with the addition of the compound(s) of formula I and/or its (their) physiologically-tolerated salts and/or its (their) prodrugs used pharmaceutically acceptable inert inorganic and/or organic carriers. For more pills, tablets, coated tablets and hard gelatin capsules can be applied, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hydrogenated oils, etc. Appropriate media to obtain solutions, such as rest the ditch for injection, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain about 0.5-90% of the mass. compounds of the formula I and/or their physiologically-tolerated salts and/or their prodrugs. The amount of the active ingredient of the formula I and/or physiologically-tolerated salts and/or its prodrugs in the pharmaceutical preparations normally is from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg

In addition to the active ingredients of the formula I and/or their physiologically acceptable salts and/or their prodrugs and substances, carriers of the pharmaceutical preparations can contain additives such as, for example, fillers, dezintegriruetsja agents, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, corrigentov, aromatizers, thickeners, diluents, buffer substances, solvents, soljubilizatory, agents for achieving depot effect, salts for modifying the osmotic pressure, agents for receipt of the coatings or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically-tolerated salts and/or their prodrugs. If the content of a pharmaceutical preparation of two or more compounds of formula I the choice of the individual compounds can be aimed at a particular General pharmacological profile of a pharmaceutical product. For example, a very potent compound with a shorter duration of action may be a combination of long-acting connection with lower activity. The flexibility allowed in the choice of substituents in the compounds of formula I, can significantly regulate biological and physico-chemical properties of compounds and, thus, allows selecting the required connections. In addition, in addition, at least one of the compounds of formula I and/or physiologically tolerable salts and/or its prodrugs in the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.

When using compounds of formula I dose can vary within wide limits and that is conventional and well-known physician, must be adapted to the individual conditions in each particular case. It depends on your specific applicable connection of nature and is Aresti disease, being treated that way and regimens medicines, or do you treat acute or chronic condition or prevention is conducted. A suitable dose can be set using clinical approaches that are well known in the field of medicine. In General, the daily dose to achieve the desired results in an adult patient weighing approximately 75 kg is from 0.01 mg/kg to 100 mg/kg, preferably from 0.1 mg/kg to 50 mg/kg, in particular from 0.1 mg/kg to 10 mg/kg (in each case in mg per kg of body weight). The daily dose may be divided, especially in the case of the introduction of relatively large amounts, in several parts, for example, for 2, 3 or 4 injections. As usual, depending on the behavior of the individual may be necessary to change the daily dose indicated in the direction of increase or decrease.

The compound of the formula I can also suitably be used as anticoagulant outside the body of the individual. For example, the effective amount of the compounds of the invention may be subjected to contact with vegetarianism a sample of blood to prevent coagulation of the blood sample. In addition, the compound of formula I or its salt can be used for diagnostic purposes, for example when establishing diagnoses in vitro, and as an aid in biochemical research. For example, with the Association of the formula I can be used in the analysis to identify the presence of factor XA and/or factor VIIa or for selection of factor XA and/or factor VIIa essentially in purified form. The compound of the invention can also be marked, for example, a radioactive isotope, and the labeled compound associated with factor XA and/or factor VIIa, then you can detect using conventional method, applicable for the detection of a specific label. Thus, the compound of formula I or its salt can be used as a probe to detect the location or quantity of the activity of factor XA and/or factor VIIa in vivo, in vitro or ex vivo.

In addition, the compounds of formula I can be used as intermediates synthesis for the preparation of other compounds, in particular other pharmaceutically active ingredients that can be obtained from compounds of the formula I, for example, the introduction of substituents or modification of functional groups.

General synthetic sequence for producing compounds used in the present invention, are described in the following examples. If necessary, describe how explanations and valid methods of various aspects of the present invention. The following examples are intended merely to illustrate the present invention and not limit it either by volume or on the merits. The person skilled in the art it will be obvious that for the synthesis of compounds of the present invention can be used known variations of the conditions and way is, described in the examples.

It is clear that the changes that essentially no effect on the activity of various embodiments of the present invention, included in the described invention. Thus, the following examples are intended to illustrate and not to limit the present invention.

EXAMPLES

When in the final stage of synthesis of the compounds used acid, such as triperoxonane acid or acetic acid, for example when triperoxonane acid used for the removal of the tBu group or when the compound was purified by chromatography using eluent containing such an acid, in some cases, depending on the processing method, for example details of the method of freeze drying, the compound was obtained partially or completely in the form of an acid salt used, for example in the form of a salt of acetic acid or salt triperoxonane acid, or salts of hydrochloric acid.

Used abbreviations:

tert-ButyltBu
2,2'-Bis(diphenylphosphino)-1,1'-binaphthylBinap
Bis(oxo-3-oxazolidinyl)phosphorylchlorideBOP-Cl
Dibenzylideneacetonedba
DichloromethaneDHM
DicyclohexylcarbodiimideDCC
DiethylphosphoramiditeDEPC
DephosphorylationDIPEA
4-DimethylaminopyridineDMAP
N,N-DimethylformamideDMF
The sulfoxideDMSO
1,1'-Bis(diphenylphosphino)ferroceneDPPF
Hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylureaHATU
N-BromosuccinimideNBS
N-ChlorosuccinimideNCS
N-IodosuccinimideNIS
N-EthylmorpholineNEM
MethanolMeOH
Room temperature, 20°25°K.T.
Richthe feast upon.
TetrahydrofuranTHF
Triperoxonane acidTFA
Tetrafluoroborate O-((etoxycarbonyl)cyanomethylene)-N,N,N',N'-tetramethylureaTOTU

Example 1: (1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

(i) tert-Butyl methyl ether (1-isopropylpiperazine-4-yl)ka is benovoy acid

To a solution of 5.0 g of tert-butyl methyl ether piperidine-4-ylcarbamate acid in 15 ml of methanol add 7,34 ml of acetone, 3,14 g Na(CN)BH3and 0.3 ml of acetic acid. After stirring for 16 h at K.T. the solvent is removed under reduced pressure and the residue partitioned between 30 ml of water and 30 ml of ethyl acetate. The organic layer was washed with a saturated solution of Na2CO3, water and then dried over Na2SO4. The solvent is removed under reduced pressure, thus obtaining the product as a white solid.

Output: 4,8, MS(ES+): m/e=243.

(ii) 1-Isopropylpiperazine-4-ylamine

To 4.8 g of tert-butyl methyl ether (1-isopropylpiperazine-4-yl)carbamino acid in 15 ml of methanol are added 20 ml of a solution of hydrochloric acid in methanol (8M) and the mixture is stirred for 16 hours the solvent under reduced pressure, followed by removal of residual volatile components twice by evaporation together with toluene gives the product.

Output: 5,42, MS(ES+): m/e=143.

(iii) (1-Isopropylpiperazine-4-yl)amide 1H-benzoimidazol-2-carboxylic acid

To a solution of 300 mg of 1H-benzoimidazol-2-carboxylic acid in 3 ml DMF and 1 ml NEt3add 398 mg of the hydrochloride of 1-isopropylpiperazine-4-ylamine and 470 mg THIEF-Cl and the mixture is stirred for 3 hours Finally, add 3 ml of a saturated solution of NaHCO3and the mixture is filtered through a cartridge chem elut® , elwira with ethyl acetate. After removal of the solvent under reduced pressure the crude product is subjected to the next reaction stage without further purification.

Output: 604 mg

(iv) (1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

To a solution of 200 mg (1-isopropylpiperazine-4-yl)amide 1H-benzoimidazol-2-carboxylic acid in 2 ml of DMF at K.T. added 227 mg Cs2CO3and 194 mg of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol [obtained for adapted the method described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] and the mixture is stirred for 16 hours After addition of 5 ml water the mixture is filtered through a cartridge chem elut®, elwira with ethyl acetate. After removal of the solvent under reduced pressure the residue is purified preparative HPLC (column reversed-phase C18, elution with a gradient mixture of N2O/MeCN with 0.1% TFA). The fractions containing the product, evaporated and lyophilized, while receiving white solid. The product is obtained in the form of its triptoreline salt.

Yield: 29 mg MS(ES+): m/e=484, range chlorinated.

Example 2: (1-Isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-1H-benzoimidazol-2-carbon is acid

(i) 2-Bromo-N-(4-chlorophenyl)ndimethylacetamide

To a solution of 5 g of 4-chlorpheniramine and 1.5 ml of pyridine in 30 ml of toluene under ice cooling are added dropwise 8 g bromoacetamide dissolved in 10 ml of toluene. After 2 cha precipitate are filtered and recrystallized from toluene, thus obtaining a white solid.

Output: 10,

(ii) (1-Isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-1H-benzoimidazol-2-carboxylic acid

To a solution of 200 mg (1-isopropylpiperazine-4-yl)amide 1H-benzoimidazol-2-carboxylic acid in 2 ml of DMF at K.T. added 227 mg Cs2CO3and 173 mg of 2-bromo-N-(4-chlorophenyl)ndimethylacetamide and the mixture is stirred for 16 hours After addition of 5 ml water the mixture is filtered through a cartridge chem elut®, elwira with ethyl acetate. After removal of the solvent under reduced pressure the residue is purified preparative HPLC (column reversed-phase C18, elution with a gradient mixture of N2O/MeCN+0.1% of TFA). The fractions containing the product, evaporated and lyophilized, while receiving white solid. The product is obtained in the form of its triptoreline salt.

Yield: 63 mg MS(ES+): m/e=454, range chlorinated.

Example 3: (1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid

(i) 2-Bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide

To a solution of 5 g of 5-chloropyridin-2-yl is mine and 1.5 ml of pyridine in 30 ml of toluene is added dropwise under ice cooling 8 g bromoacetamide, dissolved in 10 ml of toluene. After 2 h the precipitate are filtered and recrystallized from toluene, thus obtaining a white solid.

Output: 12,

(ii) (1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid

To a solution of 200 mg (1-isopropylpiperazine-4-yl)amide 1H-benzoimidazol-2-carboxylic acid in 2 ml of DMF at K.T. added 227 mg Cs2CO3and 174 mg of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide and the mixture is stirred for 16 hours After addition of 5 ml water the mixture is filtered through a cartridge chem elut®, elwira with ethyl acetate. After removal of the solvent under reduced pressure the residue is purified preparative HPLC (column reversed-phase C18, elution with a gradient mixture of N2O/MeCN+0.1% of TFA). The fractions containing the product, evaporated and lyophilized, while receiving white solid. The product is obtained in the form of its triptoreline salt.

Yield: 34 mg MS(ES+): m/e=455, the spectrum of the chlorinated.

Example 4: (1-Pyrimidine-4-reparacin-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

(i) tert-Butyl methyl ether (1-pyrimidine-4-reparacin-4-yl)carbamino acid

To a solution of 395 mg of tert-butyl methyl ether [1-(2-chloropyrimidine-4-yl)piperidine-4-yl]carbamino acid in 10 ml of ethanol and 0.3 ml of acetic acid DOB is given 20 mg of Pd/C (10%) and the mixture is blown with argon for 10 minutes Then the mixture is stirred in hydrogen atmosphere for 5 h at K.T. After adding 10 ml of ethyl acetate, the reaction mixture was filtered through a loose layer of celite. The solvent is evaporated under reduced pressure and the residue double-distilled with toluene, thus obtaining the product as a white solid.

Output: 468 mg

(ii) 1-Pyrimidine-4-reparacin-4-ylamine

To a solution of 468 mg of tert-butyl methyl ether (1-pyrimidine-4-reparacin-4-yl)carbamino acid in 2 ml of DCM is added 2 ml of TFA and the mixture is stirred for 2 h at K.T. Then add 10 ml of toluene and the solvents removed under reduced pressure. The remainder of double-distilled with toluene, thus obtaining a yellow oil. The product is obtained in the form of its triptoreline salt.

Output: 703,

(iii) (1-Pyrimidine-4-reparacin-4-yl)amide 1H-benzoimidazol-2-carboxylic acid

To a solution of 80 mg of 1H-benzoimidazol-2-carboxylic acid in 1 ml DMF and 0.2 ml NEt3add 200 mg of triptoreline 1-pyrimidine-4-reparacin-4-ylamine and 125 mg THIEF-Cl and the mixture is stirred for 3 hours Finally, add 3 ml of saturated NaHCO3and the mixture is filtered through a cartridge chem elut®, elwira with ethyl acetate. After removal of the solvent under reduced pressure the crude product is subjected to the next reaction stage without further purification.

Yield: 160 mg

(iv) (1-is eremein-4-reparacin-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

To a solution of 160 mg (1-pyrimidine-4-reparacin-4-yl)amide 1H-benzoimidazol-2-carboxylic acid in 2 ml of DMF at K.T. add 161 mg Cs2CO3and 138 mg of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol and the mixture is stirred for 16 hours After addition of 5 ml water the mixture is filtered through a cartridge chem elut®, elwira with ethyl acetate. After removal of the solvent under reduced pressure the residue is purified preparative HPLC (column reversed-phase C18, elution with a gradient mixture of N2O/MeCN+0.1% of TFA). The fractions containing the product, evaporated and lyophilized, while receiving white solid. The product is obtained in the form of its triptoreline salt.

Yield: 114 mg MS(ES+): m/e 520, the spectrum of the chlorinated.

Example 5: a) Methyl ester of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

b) Methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

(i) Methyl-2-trichloromethyl-1H-benzoimidazol-5-carboxylate

a 2.00 g (12,0 mmol) methyl-3,4-diaminobenzoate dissolved in 50 ml of concentrated acetic acid. Then slowly add 2,09 ml (1.4 EQ.) methyl-2,2,2-trichloroacetimidate and the resulting mixture was stirred at K.T. within 2 hours the Mixture is diluted with 100 ml of toluene and the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane and washed once with saturated solution of NaHCO3and once with a saturated solution of salt. The organic layer is dried over MgSO4and the solvent is removed under reduced pressure, thus obtaining pure methyl-2-trichloromethyl-1H-benzoimidazol-5-carboxylate as a pale brown amorphous solid.

Output: 3,64, MS(ES+): m/e 293, range chlorinated.

(ii) Methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

500 mg (1.7 mmol) of methyl 2-trichloromethyl-1H-benzoimidazol-5-carboxylate are added to a mixture of 548 mg (1.8 EQ.) dihydrochloride 1-isopropylpiperazine-4-ylamine and 1.43 g (10 EQ.) NaHCO3in 15 ml of THF and 7.5 ml of N2Oh and the mixture is vigorously stirred for 4 h at K.T. Reaction mixture is diluted with dichloromethane and washed with saturated solution of NaHCO3and a saturated solution of salt. The organic layer is dried over MgSO4and concentrate. Preparative HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives pure methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid as a white solid.

Yield: 300 mg MS(ES+): m/e=345.

(iii) a) Methyl ester of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid is you

b) Methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

115 mg (0.33 mmol) of the methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid are dissolved in 10 ml of DMF. Then add 69,2 mg (1.5 EQ.) To2CO3and 111,6 mg (1.2 EQ.) 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol and the resulting mixture is stirred for 2 h at 80°C. the Reaction mixture is diluted with toluene and washed twice with saturated solution of NaHCO3and once with saturated salt solution, dried over anhydrous MgSO4and concentrate under reduced pressure. Preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives a mixture of 6:4 of the two mentioned in the title of the isomers. These isomers can be separated by RP-HPLC using a chiral stationary phase and a mixture of heptane, ethanol, methanol and diethylamine as solvent. Structural assignment of both isomers reach NOE spectroscopy.

The yield of methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid: 52 mg; MS (ES+): m/e=542, the spectrum of the chlorinated.

The yield of methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoyl Gasol-5-carboxylic acid: 34 mg; MS (ES+): m/e=542, the spectrum of the chlorinated.

Example 6: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

To the suspension was 43.6 mg (0,080 mmol) of methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid in 4 ml of Meon add 0.4 ml of 1M aqueous LiOH solution and the resulting mixture was stirred at 60°C for 5 hours the Mixture is acidified by addition of 1M HCl solution (pH≈2-3) and concentrate under reduced pressure. Final purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) to give pure 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid. The corresponding dihydrochloride is obtained by treatment of the product in 0.1m HCl solution followed by lyophilization.

Yield: 43 mg MS (ES+): m/e=528, the spectrum of the chlorinated.

Example 7: 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid will receive, as described in example 6, 20 mg (0,037 mmol) of methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isoprop piperidin-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic the acid.

Yield: 18 mg MS (ES+): m/e=528, the spectrum of the chlorinated.

Example 8: a) Methyl ester of 1-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

b) Methyl ester of 3-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

To a solution of 80.0 mg (0.23 mmol) of the methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid in 5 ml of DMF added to 9.3 mg of sodium hydride (60% suspension in mineral oil). The mixture is stirred for 30 min at K.T. and then add to 68.4 mg (0.23 mmol) of 5-methyl bromide-2-(5-chlorothiophene-2-yl)thiazole [obtained for adapted the method described by Ewing, William R. et al.; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2]. After 1 h, add more of 17.1 mg (0.25 EQ.) 5-methyl bromide-2-(5-chlorothiophene-2-yl)thiazole and the reaction mixture stirred for an additional 2 hours the Reaction is stopped by careful addition of Meon and water. The solvent is removed under reduced pressure and the residue purified preparative RP-HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid). Two isomers are then separated using RP-HPLC on chiral stationary phase and a mixture of heptane, ethanol, methanol and diethylamine as solvent. Structural assignment of both isomers reach NOE-spectroscopy is th.

The yield of methyl ester 1-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid: 40 mg; MS (ES+): m/e=558, the spectrum of the chlorinated.

The yield of methyl ester of 3-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid: 26 mg; MS (ES+): m/e=558, the spectrum of the chlorinated.

Example 9: 1-[2-(5-Chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

1-[2-(5-Chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid is obtained according to the method of example 6, on the basis of 40 mg (0,072 mmol) of methyl ester 1-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid. Specified in the header connection receive in the form of its dihydrochloride.

Yield: 23 mg MS (ES+): m/e=544, the spectrum of the chlorinated.

Example 10: 3-[2-(5-Chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

3-[2-(5-Chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid is obtained according to the method of example 6, from 26 mg (0,047 mmol) of methyl ester of 3-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylidene the DIN-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid. Specified in the header connection receive in the form of its dihydrochloride.

Yield: 19 mg MS (ES+): m/e=544, the spectrum of the chlorinated.

Example 11: (a) Methyl ester of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

b) Methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid

(i) Methyl-2,3-diaminobenzoate

3.0 g of 15.3 mmol) of methyl 2-amino-3-nitrobenzoate was dissolved in 200 ml of abs. Meon. From a flask with a solution pump out the air and the flask with the solution, rinsed several times with argon. Add 300 mg of palladium on coal (10%)of the flask with the solution again pull vacuum and the flask is rinsed several times with argon. Finally, the argon is replaced by hydrogen (balloon, filled with hydrogen and the mixture is stirred for 4 h at K.T., the Reaction mixture was filtered through celite and the filter residue is washed with 150 ml of methanol. The filtrate is concentrated under reduced pressure, thus obtaining methyl-2,3-diaminobenzoate in the form of a brown oil.

Output: 2,53, MS (ES+): m/e=167.

(ii) Methyl-2-trichloromethyl-1H-benzoimidazol-4-carboxylate

Methyl-2-trichlorophenyl-1H-benzoimidazol-4-carboxylate get similarly obtaining methyl-2-trichloromethyl-1H-benzoimidazol-5-carboxylate as described in example 5 (i), and is walking out of 2.53 g (15.1 mmol) of methyl-2,3-diaminobenzoate.

Output: 4,15, MS (ES+): m/e=293, range chlorinated.

(iii) Methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

Methyl ester 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid is obtained from 1,82 g (6.2 mmol) of methyl 2-trichlorophenyl-1H-benzoimidazol-4-carboxylate as described in example 5 (ii).

Output: 1,10, MS (ES+): m/e 345.

iv) a) Methyl ester of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

b) Methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid

Both isomers receive according to the method similar to that described in example 5 (iii), based on 150,0 mg (0.44 mmol) of the methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 145,6 mg (1.2 EQ.) 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol. In this case, the ratio of the two isomers is 3:1. As described in example 5 (iii), isomers shared by RP-HPLC using a chiral stationary phase and a mixture of heptane, ethanol, methanol and diethylamine. And in this case, the structural assignment of both isomers spend NOE spectroscopy.

The yield of methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzo idazole-4-carboxylic acid: 105 mg; MS (ES+): m/e=542, the spectrum of the chlorinated.

The yield of methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid: 45 mg; MS (ES+): m/e=542, the spectrum of the chlorinated.

Example 12: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid is obtained from 60 mg (0,111 mmol) of methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid as described in example 6. Specified in the header connection receive in the form of its dihydrochloride.

Yield: 34 mg MS (ES+): m/e=528, the spectrum of the chlorinated.

Example 13: 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid

3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid is obtained from 20 mg (0,037 mmol) of methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid as described in example 6. Specified in the header connection receive in the form of its dihydrochloride.

+): m/e=528, the spectrum of the chlorinated.

Example 14: (1 Isopropylpiperazine-4-yl)amide 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid

(i) Methyl ester 3H-imidazo[4,5-b]pyridine-2-carboxylic acid

1,76 g (9,16 mmol) methyldichlorosilane added to a solution of 1.00 g (9,16 mmol) of 2,3-diaminopyridine in 40 ml of methanol and the solution stirred at K.T. added dropwise 1.85 g (18,32 mmol) of triethylamine. After complete addition, the reaction mixture is stirred for 15 h at 80°C. the Reaction is not completed, which requires the addition of another 1,76 g methyldichlorosilane and 1.85 g of triethylamine. The reaction mixture is again stirred for 8 h at 80°C. the Mixture is concentrated under reduced pressure and the residue is treated sequentially with diethyl ether and a saturated solution of NaHCO3and then washed with water, while receiving almost pure methyl ester 3H-imidazo[4,5-b]pyridine-2-carboxylic acid.

Yield: 210 mg MS (ES+): m/e=178.

(ii) Methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid

100 mg high (0.56 mmol) of the methyl ester 3H-imidazo[4,5-b]pyridine-2-carboxylic acid is dissolved in 3 ml of DMF. Add to 22.6 mg high (0.56 mmol) of sodium hydride (60% in mineral oil) and the mixture is stirred for 30 min at K.T. Add 157,2 mg high (0.56 mmol) 3-b is amatil-5-(5-chlorothiophene-2-yl)isoxazol and the resulting mixture is stirred for 1 h at 80° C. the Reaction mixture is cooled to K.T. and after adding a few drops of water concentrated under reduced pressure. HPLC-MS analysis shows the presence of another isomer (ratio of isomers≈7:1). Final purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) to give methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid as a brown amorphous solid.

Yield: 203 mg) MS (ES+): m/e=375, range chlorinated.

(iii) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid

175,0 mg (0.46 mmol) of methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid are added to a solution of 19.6 mg (0.82 mmol) LiOH in 6 ml of THF and 2 ml of N2O. the Reaction mixture was stirred for 2 h at 60°C, cooled to K.T. and acidified (pH 2) by adding policecontributing HCl solution. The precipitate is filtered off and washed with water, thus obtaining pure 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid as a brown crystalline solid.

Yield: 150 mg MS (ES+): m/e=361, range chlorinated.

(iv) (1-Isopropylpiperazine-4-yl)amide 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-Carbo the OIC acid

150,0 mg (0.41 mmol) of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid are dissolved in 4 ml of DMF. Then add 142 μl DIPEA and to 151.8 mg (0.41 mmol) of HATU, and the mixture is stirred for 20 min at K.T. Type of 74.3 mg (0.41 mmol) of the hydrochloride of 1-isopropylpiperazine-4-ylamine and another 71 μl DIPEA and the resulting mixture is stirred for 3 h at K.T. Concentration under reduced pressure, and the final purification RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) to give pure (1-isopropylpiperazine-4-yl)amide 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid as a pale brown amorphous solid. Specified in the title compound obtained as its hydrochloride.

Yield: 17 mg MS (ES+): m/e=485, range chlorinated.

Example 15: Methyl ether of 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

to 100.8 mg (0.29 mmol) of the methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid are dissolved in 6 ml DMF. Then add to 60.6 mg (0.44 mmol) To a2CO3and 87.5 mg (0.35 mmol) of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide and the resulting mixture is stirred for 3 h at 80°C. the Reaction mixture is diluted with 60 ml of toluene and washed with a saturated solution NaCO 3and a saturated solution of salt. The organic layer is dried over MgSO4and the solvent is removed under reduced pressure. The residue is purified preparative HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid), while receiving methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid as white amorphous solids. The product is obtained in the form of his hydrotreat.

Yield: 106 mg MS (ES+): m/e=513, the spectrum of the chlorinated.

Example 16: 1-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

30 mg (0,058 mmol) of methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid are dissolved in 3 ml dichloromethane and cooled to 0°C. Carefully add 234 μl of 1M solution of BBr3(4 equiv.) in dichloromethane and the resulting mixture was stirred at K.T. for 16 hours Under cooling added dropwise 3 ml of water followed by the addition of 0.7 ml of 1M NaOH solution. The mixture is concentrated under reduced pressure. Purification preparative HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) to give pure 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic sour is. The corresponding dihydrochloride is obtained by treatment of the product in 0.1m HCl solution and subsequent lyophilization.

Yield: 26 mg MS (ES+): m/e=499, the spectrum of the chlorinated.

Example 17: (a) Methyl ester of 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

b) Methyl ester of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

to 102.3 mg (0,297 mmol) methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid are dissolved in 6 ml DMF. Then add of 61.6 mg (0,446 mmol) To a2CO3and 88.9 mg (0,356 mmol) of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide and the resulting mixture is stirred for 2 h at 80°C. the Reaction mixture is diluted with 60 ml of toluene and washed with saturated solution of NaHCO3and a saturated solution of salt. The organic layer is dried over MgSO4and the solvent is removed under reduced pressure. The residue is purified preparative HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid), while receiving both isomers described in the header, in the ratio of 1.3:1. Both isomers can be separated by RP-HPLC using a chiral stationary phase and a mixture of heptane, ethanol and methanol as solvent. Structural assignment of both isomers to thaut NOE spectroscopy. Both isomers convert them dihydrochloride by treatment with 0,1M HCl solution and subsequent lyophilization.

The yield of methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid: 50 mg) MS (ES+): m/e=513, the spectrum of the chlorinated.

The yield of methyl ester of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid: 51 mg. MS (ES+): m/e=513, the spectrum of the chlorinated.

Example 18: 1-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

1-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid is obtained according to the method of example 16, from 27.8 mg (0,047 mmol) of methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid. Specified in the header connection receive in the form of its dihydrochloride.

Yield: 15 mg MS (ES+): m/e=499, the spectrum of the chlorinated.

Example 19: 3-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

3-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid is obtained by the method of example is 16, on the basis of 28 mg (0,048 mmol) of methyl ester of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid. Specified in the header connection receive in the form of its dihydrochloride.

Yield: 22 mg MS (ES+): m/e=499, the spectrum of the chlorinated.

Example 20: 1-Ethoxycarbonylmethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

50 mg (0.08 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid are dissolved in 3 ml of DMF. Then add a 27.6 mg (0.16 mmol) of KI, 46 mg (0.33 mmol) To a2CO3and 45 μl (0.32 mmol) of 1-chloritisation and the reaction mixture stirred at 60°C for 4 h, the Reaction mixture was concentrated and the resulting residue purified preparative HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid), while receiving 1-ethoxycarbonylmethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid as white amorphous solids. The corresponding dihydrochloride is obtained by processing in 0.1m HCl solution and subsequent lyophilization.

Yield: 46 mg MS (ES+): m/e=644, the spectrum of the chlorinated.

Example 21: 1-Cycle is hexyloxyethoxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

1-Cyclohexyloxycarbonyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid get adapted to the method described for example 20, on the basis of 50 mg (0.08 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 61 μl (0.32 mmol) cyclohexyl-1-charitycardonate. Specified in the header connection receive in the form of its dihydrochloride.

Yield: 47 mg MS (ES+): m/e=698, range chlorinated.

Example 22: 4-[(2-Hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazole-2,4-dicarboxylic acid

30 mg (0,057 mmol) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid are dissolved in 3 ml of DMF. Then add 29 μl (0,171 mmol) DIPEA and 21.6 mg (0,057 mmol) of HATU. After 30 minutes add the 3.5 ál (0,057 mmol) of 2-aminoethanol and 10 μl of DIPEA and the resulting mixture was stirred at K.T. for 16 hours, the Reaction mixture was concentrated and the residue purified preparative HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid). Specified in the title compound obtained as its hydroformed in the form of a white amorphous solid.

Yield: 29 mg MS (ES+): m/e571, range chlorinated.

Example 23: (1 Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzimidazole-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzimidazole-2-carboxylic acid get by the method of example 22, from 50 mg (0.08 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-the benzimidazole-4-carboxylic acid and 6.7 mg (0.09 mmol) of 3-hydroxyazetidine. Specified in the title compound obtained as its hydroformed in the form of a white amorphous solid.

Yield: 51 mg MS (ES+): m/e=583, range chlorinated.

Example 24: 4-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazole-2,4-dicarboxylic acid

4-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazole-2,4-dicarboxylic acid get by the method of example 22, from 40 mg (0,067 mmol) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 5.6 mg (0,075 mmol) N-methyl-2-aminoethanol. Specified in the title compound obtained as its hydroformed in the form of a white Amorin the th solid.

Yield: 35 mg MS (ES+): m/e=585, range chlorinated.

Example 25: 5-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazole-2,5-dicarboxylic acid

5-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazole-2,5-dicarboxylic acid get by the method of example 22, from 50 mg (0.08 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 6.8 mg (0.09 mmol) of N-methyl-2-aminoethanol. Specified in the title compound obtained as its hydroformed in the form of a white amorphous solid.

Yield: 43 mg MS (ES+): m/e=585, range chlorinated.

Example 26: (1 Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, from 50 mg (0.08 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 6.7 mg (0.09 mmol) of 3-hydroxyazetidine. Specified in the header connection receive in the form of g is of toformat in the form of a white amorphous solid.

Yield: 37 mg MS (ES+): m/e=583, range chlorinated.

Example 27: 1-Ethoxycarbonylmethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

1-Ethoxycarbonylmethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid get adapted to the method described for example 20, on the basis of 50 mg (0.08 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 45 μl (0.32 mmol) of 1-chloramination. Specified in the header connection receive in the form of its dihydrochloride.

Yield: 57 mg MS (ES+): m/e=644, the spectrum of the chlorinated.

Example 28: 1-Cyclohexyloxycarbonyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

1-Cyclohexyloxycarbonyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid get adapted to the method described for example 20, on the basis of 50 mg (0.08 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 61 μl (0,32 IMO the ü) cyclohexyl-1-charitycardonate. Specified in the header connection receive in the form of its dihydrochloride.

Yield: 59 mg MS (ES+): m/e=698, range chlorinated.

Example 29: (a) (1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid

b) (1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-6-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid

(i) 2-(2-Trichloromethyl-1H-benzoimidazol-5-sulfonyl)ethanol

500 mg (2,31 mmol) 3,4-diaminobenzanilide-2-ol is dissolved in 10 ml of concentrated acetic acid. Slowly add 0.4 ml (1.4 EQ.) methyl-2,2,2-trichloroacetimidate and the resulting mixture was stirred at K.T. within 4 hours the Mixture is diluted with 100 ml of toluene and the solvent is removed under reduced pressure. The residue is washed with toluene, filtered and dried in vacuum, obtaining a brown crystalline solid, pure enough for all of the following reactions.

Output: 680 mg MS (ES+): m/e=345, the spectrum of the chlorinated.

(ii) (1-Isopropylpiperazine-4-yl)amide 5-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid

360 mg (1.05 mmol) of 2-(2-trichloromethyl-1H-benzimidazole-5-sulfonyl)ethanol is added to the mixture 225,4 mg (of 1.05 equiv.) dihydrochloride 1-isopropylpiperazine-4-ylamine and 880 mg (10 EQ.) NaHCO3in 6 ml Thfi 3 ml of N 2Oh and the mixture is vigorously stirred for 2 h at K.T. Reaction mixture is diluted with dichloromethane and washed with saturated solution of NaHCO3and a saturated solution of salt. The organic layer is dried over MgSO4and concentrate. The resulting product is pure enough for the following reactions.

Output: 207 mg) MS (ES+): m/e=395.

(iii) (a) (1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid

b) (1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-6-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid

126,2 mg (0.32 mmol) (1-isopropylpiperazine-4-yl)amide 5-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid are dissolved in 10 ml of DMF. Then add to 48.6 mg (1.1 EQ.) To2CO3and 89,0 mg (1.0 EQ.) 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol and the resulting mixture is stirred for 3 h at 55°C. the Reaction mixture is diluted with toluene and washed twice with saturated solution of NaHCO3and once with saturated salt solution, dried over anhydrous MgSO4and concentrate under reduced pressure. Preparative RP-HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid) gives a mixture of 6:4 of the two mentioned in the title of the isomers. These isomers can be divided RP-HPLC with the use the of the chiral stationary phase and a mixture of heptane, ethanol, methanol and diethylamine as solvent. Structural assignment of both isomers reach NOE spectroscopy.

Output (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid: 79 mg MS (ES+): m/e=391, range chlorinated.

Output (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-6-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid: 59 mg. MS (ES+): m/e=391, range chlorinated.

Example 30: 4-[(2-Hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,4-dicarboxylic acid

4-[(2-Hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,4-dicarboxylic acid get by the method of example 22, from 40 mg (0.08 mmol) of 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 5.4 mg (0,088 mmol) of 2-aminoethanol. Specified in the title compound obtained as its hydroformed in the form of a white amorphous solid.

Yield: 34 mg MS (ES+): m/e=542, the spectrum of the chlorinated.

Example 31: 4-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,4-dick is Borovoy acid

4-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,4-dicarboxylic acid get by the method of example 22, from 50 mg (0.10 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 8.3 mg (0.11 mmol) N-methyl-2-aminoethanol. Specified in the title compound obtained as its hydroformed in the form of a white amorphous solid.

Output: 30 mg MS (ES+): m/e=556, range chlorinated.

Example 32: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, from 50 mg (0.10 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 8.1 mg (0.11 mmol) 3-hydroxyazetidine. Specified in the title compound obtained as its hydroformed in the form of a white amorphous solid.

Yield: 28 mg MS (ES+): m/e=554, range chlorinated.

Example 33: 1-Ethoxycarbonylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-elkarra the oil)-1H-benzoimidazol-4-carboxylic acid

1-Ethoxycarbonylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid get by the method of example 20, from 50 mg (0.10 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and to 61.2 mg (0,401 mmol) of 1-chloramination. Specified in the title compound obtained as its hydroformed in the form of a white amorphous solid.

Yield: 38 mg MS (ES+): m/e=615, the spectrum of the chlorinated.

Example 34: 1-Cyclohexyloxycarbonyloxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

1-Cyclohexyloxycarbonyloxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid get by the method of example 20, from 50 mg (0.10 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 82.8 mg (0,401 mmol) cyclohexyl-1-charitycardonate. Specified in the title compound obtained as its hydroformed in the form of a white amorphous solid.

Yield: 46 mg MS (ES+): m/e=669, range chlorinated.

Example 35: [4-(3-Exmortis-4-yl)phenyl]amide 1-[(5-chlorine is pyridine-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid

(i) 4-(4-Nitrophenyl)morpholine

A mixture of 24.5 g of the research and 13.3 g of 1-fluoro-4-nitrobenzene in 30 ml of DMSO is heated to 100°C for 4 h the resulting solution was poured into 300 ml of water and the resulting precipitate was separated by filtration, thus obtaining a bright yellow crystalline product, which is dried under reduced pressure. Output: 19,7,

(ii) 4-(4-Nitrophenyl)morpholine-3-one

To a solution of 10 g of 4-(4-nitrophenyl)the research in 200 ml DCM carefully add when K.T. 32 mg of chloride of benzyltriethylammonium and 22.7 g of potassium permanganate (325 mesh). After stirring for 1 h at K.T. the reaction mixture is heated at the boil under reflux for 10 hours and Then cooling and vigorous stirring, 95 g of Na2SO3in 450 ml of water. The mixture is filtered through a loose layer of celite and the filtrate concentrated under reduced pressure. The yellow solid is stirred with 250 ml of water and the precipitated product is separated by filtration. The crude product is purified by chromatography on silica gel with elution with a gradient mixture of DCM/Meon 100%→50%. The fractions containing the product are pooled and the solvent is evaporated under reduced pressure. Output: 2,6,

(iii) 4-(4-AMINOPHENYL)morpholine-3-one

To a solution of 2.6 g of 4-(4-nitrophenyl)morpholine-3-one in 350 ml of ethyl acetate and 17 ml of ethanol added to 13.2 g of dihydrate SnCl2and the reaction mixture is heated when the pile is AI under reflux for 2 hours Then, after cooling to K.T., the mixture is stirred for 16 hours the Precipitated product is separated by filtration, it is sufficiently pure for the next reaction stage. Output: 2,07,

(iv) [4-(3-Exmortis-4-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid

To a solution of 100 mg of 1H-benzoimidazol-2-carboxylic acid and 118 mg of 4-(4-AMINOPHENYL)morpholine-3-one in 2 ml of DCM added 157 mg THIEF-Cl and 0.3 ml NEt3and the mixture is stirred for 16 h at K.T. Then, after dilution of the reaction mixture, 20 ml of water, the precipitated product is separated by filtration. The crude product is subjected to the next reaction stage without further purification. Yield: 122 mg

(v) [4-(3-Exmortis-4-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid

To a solution of 50 mg of [4-(3-exmortis-4-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid in 2 ml of DMF at K.T. added 49 mg Cs2CO3and 37 mg of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide and the reaction mixture is stirred for 2 hours Then when K.T. add an additional 20 mg Cs2CO3and 30 mg of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide and the reaction mixture stirred for additional 2 hours, the Reaction mixture was diluted with 20 ml water and the precipitated product is separated by filtration. The product is dissolved in 3 ml of diluted HCl and lyophilized, while receiving white firmly the substance. The product is obtained in the form of its hydrochloride.

Yield: 128 mg MS (ES+): m/e=505, the spectrum of the chlorinated.

Example 36: Methyl ether of 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid

(1) Methyl ester 2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid

The solution is 69.4 mg (0,236 mmol) methyl-2-trichloromethyl-1H-benzoimidazol-4-carboxylate in 2 ml of THF is added slowly to a mixture containing 50 mg (0.26 mmol) of 4-(4-AMINOPHENYL)morpholine-3-one, 220 mg (2,62 mmol) and NaHCO3, 8 ml of THF and 3 ml of N2O. the Mixture is vigorously stirred for 3 h at K.T., diluted with 50 ml of CH2Cl2and washed with 30 ml of a saturated solution of NaHCO3. The aqueous solution is extracted with 50 ml of CH2Cl2combined organic layers dried over MgSO4and concentrate under reduced pressure, thus obtaining a brown solid, which is pure enough for further reactions.

Yield: 72 mg MS (ES+): m/e=395.

(ii) Methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid

72,0 mg (0,183 mmol) methyl ester 2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid are dissolved in 7 ml of DMF. Consistently add of 37.8 mg (0,274 mmol) To a2 CO3and 54.6 mg (0,219 mmol) of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide and the resulting mixture is stirred for 4 h at 80°C. the Mixture is diluted with 200 ml of toluene and washed with 50 ml of a saturated solution of NaHCO3. The product is not completely soluble in toluene, so you need to add the ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and concentrate under reduced pressure. The residue is purified preparative HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid), while receiving methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid as a pale brown amorphous solid.

Yield: 46 mg MS (ES+): m/e=563, range chlorinated.

Example 37: [4-(4-Oxo-4H-pyridin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

(i) 1-(4-Nitrophenyl)-1H-pyridin-4-one

A mixture of 10.1 g of pyridine-4-ol and 10 g of 1-fluoro-4-nitrobenzene and 46,1 g Cs2CO3in 30 ml of DMF was stirred at K.T. within 2 hours the resulting solution was poured into 300 ml of water and the resulting precipitates are filtered, thus obtaining a bright yellow crystalline product, which is dried under reduced pressure. Output: 11,2,

(ii) 1-(4-AMINOPHENYL)-1H-pyridin-4-one

To rest is PN 10 g of 1-(4-nitrophenyl)-1H-pyridine-4-she's in 510 ml of ethyl acetate and 26 ml of ethanol added to 52.1 g of dihydrate SnCl 2and the reaction mixture is heated at boiling under reflux for 6 hours Then, after cooling to K.T., solvents are removed under reduced pressure. The residue is dissolved in 100 ml aqueous solution of NaHCO3and add 200 ml of ethyl acetate. The inorganic precipitate is filtered and the solids washed with ethyl acetate. After separation of the organic layer the aqueous layer of the filtrate is extracted with ethyl acetate (2×100 Il) and DCM (3×150 ml). The combined organic layers dried over Na2SO4and the solvents removed under reduced pressure. The remaining product is sufficiently pure for the next reaction stage. Output: 6,

(iii) 2-Trichloromethyl-1H-benzoimidazol

To a solution of 10 g of benzene-1,2-diamine in 250 ml of acetic acid at K.T. added dropwise to 22.8 g of methyl ester 2,2,2-trichloroacetimidate acid. After 2 h adds 500 ml of toluene and the solvents removed under reduced pressure. The residue is optionally together is distilled twice with toluene. After drying under reduced pressure the product is sufficiently pure for the next reaction stage. Output: 25,

(iv) [4-(4-Oxo-4H-pyridin-1-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid

The solution 769 mg 2 trichloromethyl-1H-benzoimidazole in 10 ml of THF is added slowly to the mixture containing 304 mg of 1-(4-AMINOPHENYL)-1H-pyridine-4-it, 1.3 g NaHCO3, 40 ml of THF and 15 ml of N2O. the Mixture is vigorously stirred for 3 h at K.T., diluted with 200 ml of CH2Cl2and washed with 40 ml of a saturated solution of NaHCO3. The aqueous solution is extracted with CH2Cl2(3×200 ml), the combined organic layers dried over MgSO4and concentrate under reduced pressure, thus obtaining a brown solid, which is pure enough for further reactions. Output: 598 mg

(v) [4-(4-Oxo-4H-pyridin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

To a solution of 192 mg of [4-(4-oxo-4H-pyridin-1-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid in 10 ml of DMF at K.T. add 120 mg2CO3and 194 mg of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol and the mixture is heated for 2 h at 70°C. After adding 30 ml of water the mixture is extracted with ethyl acetate (3×100 ml). After drying the combined organic phases over Na2SO4the solvents are removed under reduced pressure and the residue purified preparative HPLC (column reversed-phase C18, elution with a gradient mixture of N2O/MeCN with 0.1% TFA). The fractions containing the product is evaporated and lyophilized, while receiving white solid. The product is obtained in the form of its triptoreline salt.

Yield: 70 mg MS (ES+): m/e=528, the spectrum of the chlorinated.

Example 38 [4-[4-Oxo-4H-pyridin-1-yl)phenyl]amide 1-(3-methoxybenzyl)-1H-benzoimidazol-2-carboxylic acid

Specified in the header of the connection get analogously to example 37, with the difference that 1-methyl bromide-3-methoxybenzoyl used instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol-stage alkylation. MS (ES+): m/e=451.

Example 39: [4-[4-Oxo-4H-pyridin-1-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header of the connection get analogously to example 37, with the difference that 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide used instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol-stage alkylation. MS (ES+): m/e=499 range chlorinated.

Example 40: (8-Methyl-8-azabicyclo[3.2.1]Oct-3-yl)amide 1-[5-[5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header of the connection get analogously to example 37 except that the hydrochloride of 8-methyl-8-azabicyclo[3.2.1]Oct-3-ylamine used instead of 1-(4-AMINOPHENYL)-1H-pyridine-4-she's on stage (iv). MS (ES+): m/e=482, the spectrum of the chlorinated.

Example 41: [4-(2,4-Dioxo-3,4-dihydro-2H-pyrimidine-1-yl)phenyl]amide 1-[5-[5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

(i) 1-(4-Nitrophenyl)-1H-pyrimidine-2,4-dione

A mixture of 3.5 g of 1H-pyrimidine-2,4-dione and 3 g of 1-fluoro-4-nitrobenzene and 13.8 g Cs2CO3in 60 ml of DMF is heated to 80°C for 12 hours pouring the resulting solution is between 200 ml of water and the resulting precipitate was separated by filtration, while receiving a bright yellow crystalline product, which is dried under reduced pressure. Yield: 2.6 g

(ii) 1-(4-AMINOPHENYL)-1H-pyrimidine-2,4-dione

Into a solution of 1.4 g of 1-(4-nitrophenyl)-1H-pyrimidine-2,4-dione in 120 ml Meon enter 15 g of Raney Nickel (washed three times Meon) in nitrogen atmosphere. Then add 15 ml of a 7M solution of NH3in the Meon. The nitrogen atmosphere is replaced by an atmosphere of hydrogen and the mixture hydronaut at normal pressure when K.T. After 2 h, the reaction mixture was filtered through a loose layer of celite. The solvents are removed under reduced pressure and the residue is subjected to the next reaction stage without further purification. Output: 502 mg

(iii) [4-(2,4-Dioxo-3,4-dihydro-2H-pyrimidine-1-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid

Specified in the header connection receive similar stage (iv) of example 37 with the difference that 1-(4-AMINOPHENYL)-1H-pyrimidine-2,4-dione is used instead of 1-(4-AMINOPHENYL)-1H-pyridine-4-it. MS (ES+): m/e=348.

(iv) [4-(2,4-Dioxo-3,4-dihydro-2H-pyrimidine-1-yl)phenyl]amide 1-[5-[5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header connection receive similar stage (iv) of example 37 except that [4-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid is used instead of [4-(4-oxo-4H-pyridin-1-yl)phenyl]amide of 1H-benzoimidazol-2-carbon is th acid. MS (ES+): m/e=545, the spectrum of the chlorinated.

Example 42: [4-(2-Oxoacridine-3-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header of the connection get analogously to example 41 with the exception that oxazolidin-2-he used instead of 1H-pyrimidine-2,4-Dion on stage (i). MS (ES+): m/e=520, range chlorinated.

Example 43: [4-(2-Oxoacridine-3-yl)phenyl]amide 1-[[5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header of the connection get analogously to example 41 with the exception that oxazolidin-2 he and 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide used instead of 1H-pyrimidine-2,4-dione (stage (i)) and 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol (stage (iv)). MS (ES+): m/e=490, the spectrum of the chlorinated.

Example 44: [4-(2,4-Dioxo-3,4-dihydro-2H-pyrimidine-1-yl)phenyl]amide 1-[[5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header of the connection get analogously to example 41 with the difference that 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide used instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol-stage alkylation. MS (ES+): m/e=516, the spectrum of the chlorinated.

Example 45: [4-(4-Oxopiperidin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header of the connection get analogously to example 41 except that the hydrochloride piperidine-4-it is used instead of 1H-pyrimidine-2,4-Dion on stage (i). MS (ES+): m/e=532, the spectrum of the chlorinated.

Example 46: [4-(1,1-Dioxo-1λ6-thiomorpholine-4-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

(i) tert-Butyl ester [4-(1,1-dioxo-1λ6-thiomorpholine-4-yl)phenyl]carbamino acid

A solution of 408 mg of tert-butyl methyl ether (4-AMINOPHENYL)carbamino acid and 254 mg idealhumidity in 4 ml of EtOH is heated for 30 min at 140°under microwave irradiation (100 W, the device CEM Discover). Then, after cooling to K.T., solvents are removed under reduced pressure and the residue is dried in vacuum. The crude product is subjected to the next reaction stage. Output: 0,64,

(ii) 4-(1,1-Dioxo-1λ6-thiomorpholine-4-yl)phenylamine

To a solution of 640 mg of tert-butyl ester [4-(1,1-dioxo-1λ6-thiomorpholine-4-yl)phenyl]carbamino acid in 30 ml of DCM and 30 ml of TFA allow to stand for 16 h at K.T. Then, after adding 100 ml of toluene, the solvent is removed under reduced pressure and the residue is dried in vacuum. The product is obtained in the form of his trifenatate. Output: 0,44,

(iii) [4-(1,1-Dioxo-1λ6-thiomorpholine-4-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid

Specified in the title is information connection receive similar stage (iv) of example 37 with the difference, 14-(1,1-dioxo-1λ6-thiomorpholine-4-yl)phenylamine used instead of 1-(4-AMINOPHENYL)-1H-pyridine-4-it.

(iv) [4-(1,1-Dioxo-1λ6-thiomorpholine-4-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header connection receive similar stage (v) of example 37 with the difference that [4-(1,1-dioxo-1λ6-thiomorpholine-4-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid is used instead of [4-(4-oxo-4H-pyridin-1-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid. MS (ES+): m/e=568, the spectrum of the chlorinated.

Example 47: [4-(1,1-Dioxo-1λ6-thiomorpholine-4-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header of the connection get analogously to example 46, with the difference that 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide used instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol (stage (iv)). MS (ES+): m/e=500, range chlorinated.

Example 48: [4-(2-Oxo-2H-pyrazin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

(1) 1-(4-Nitrophenyl)-1H-pyrazin-2-he

A mixture of 632 mg pyrazin-2-olate sodium and 720 mg of 1-fluoro-4-nitrobenzene and 3.3 g Cs2CO3in 13 ml of DMF is heated to 35°C for 6 hours the resulting solution was poured into 300 ml of water and the resulting precipitate was separated by filtration, is the learn with this bright yellow crystalline product, which is dried under reduced pressure. Output: 545 mg

(ii) 1-(4-AMINOPHENYL)-1H-pyrazin-2-he

To a solution of 520 mg of 1-(4-nitrophenyl)-1H-Pirin-2-it in 26 ml of ethyl acetate and 1.3 ml of ethanol is added 2.7 g of dihydrate SnCl2and the reaction mixture is heated at boiling under reflux for 6 hours Then, after cooling to K.T., the mixture is stirred for 16 hours the Precipitated product is separated by filtration, it is sufficiently pure for the next reaction stage. Yield: 450 mg

(iii) [4-(2-Oxo-2H-pyrazin-1-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid

Specified in the header connection receive similar stage (iv) of example 37 with the difference that 1-(4-AMINOPHENYL)-1H-pyrazin-2-it is used instead of 1-(4-AMINOPHENYL)-1H-pyridine-4-it. Output: 513 mg

(iv) [4-(2-Oxo-2H-pyrazin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header connection receive similar stage (v) of example 37 with the difference that [4-(2-oxo-2H-pyrazin-1-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid is used instead of [4-(4-oxo-4H-pyridin-1-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid. MS (ES+): m/e=529, range chlorinated.

Example 49: [4-(2-Oxo-2H-pyrazin-1-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header with the unity gain analogously to example 48 with the difference, 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide used instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol. MS (ES+): m/e=500, range chlorinated.

Example 50: [4-(2-Oxopiperidin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

(i) 1-(4-AMINOPHENYL)piperazine-2-he

To a solution of 670 mg of 1-(4-nitrophenyl)-1H-pyrazin-2-it in 100 ml Meon add 8 g of Raney Nickel (washed three times Meon) in nitrogen atmosphere. Then add 10 ml of a 7M solution of NH3in the Meon. The nitrogen atmosphere is replaced by an atmosphere of hydrogen and the mixture hydronaut at normal pressure when K.T. After 2 h, the reaction mixture was filtered through a loose layer of celite. The solvents are removed under reduced pressure and the residue is subjected to the next reaction stage without further purification. Output: 464 mg

(ii) tert-Butyl ether 4-(4-AMINOPHENYL)-3-oxopiperidin-1-carboxylic acid

To a solution of 464 mg of 1-(4-AMINOPHENYL)piperazine-2-she and 30 mg DMAP in 15 ml of acetonitrile at K.T. add 794 mg of di-tert-BUTYLCARBAMATE. After 2 h the solvents are removed under reduced pressure and the residue is dissolved in 200 ml of ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over Na2SO4and the solvent is removed under reduced pressure. Output: 547 mg

(iii) tert-Butyl ether 4-{4-[(1H-benzoimidazol-2-carbonyl)amino]phenyl}-3-oxo is piperazin-1-carboxylic acid

Specified in the header connection receive similar stage (iv) of example 37 with the exception that tert-butyl ester 4-(4-AMINOPHENYL)-3-oxopiperidin-1-carboxylic acid is used instead of 1-(4-AMINOPHENYL)-1H-pyridine-4-it. Yield: 160 mg

(iv) tert-Butyl ether 4-[4-({1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carbonyl}amino)phenyl]-3-oxopiperidin-1-carboxylic acid

Specified in the header connection receive similar stage (v) of example 37 with the exception that tert-butyl ester 4-{4-[(1H-benzoimidazol-2-carbonyl)amino]phenyl}-3-oxopiperidin-1-carboxylic acid is used instead of [4-(4-oxo-4H-pyridin-1-yl)phenyl]amide of 1H-benzoimidazol-2-carboxylic acid. MS (ES+): m/e=633, the spectrum of the chlorinated.

(v) [4-(2-Oxopiperidin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid

To a solution of 150 mg of tert-butyl ester 4-[4-({1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carbonyl}amino)phenyl]-3-oxopiperidin-1-carboxylic acid in 30 ml of DCM and 10 ml of TFA allow to stand for 16 h at K.T. Then, after adding 100 ml of toluene, the solvent is removed under reduced pressure and the residue purified preparative HPLC (column reversed-phase C18, elution gradient a mixture of N2O/MeCN with 0.1% TFA). The fractions containing the product is evaporated and lyophilized, the floor is friends with this white solid. The product is obtained in the form of its triptoreline salt.

Yield: 84 mg MS (ES+): m/e=533, range chlorinated.

Example 51: [4-(2-Oxo-2H-piperazine-1-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid

Specified in the header of the connection get analogously to example 50 except that 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide used instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol. MS (ES+): m/e=504, the spectrum of the chlorinated.

Example 52: [4-(3-Exmortis-4-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid

(i) 2-(2-Methoxyethoxy)-6-nitroaniline

A solution of 5 g of 2-amino-3-NITROPHENOL, 4.5 g of 1-bromo-2-methoxyethane, 4.4 g2CO3in 50 ml of DMF is heated to 60°C for 16 hours Then add 50 ml of water and the mixture extracted with ethyl acetate (3×100 ml). The combined organic layers dried over MgSO4and the solvents removed under reduced pressure. The remaining product is sufficiently pure for the next reaction stage. Output: 5,8,

(ii) 3-(2-Methoxyethoxy)benzene-1,2-diamine

To a solution of 1 g of 2-(2-methoxyethoxy)-6-nitroaniline in 10 ml of ethyl acetate and 3 ml of ethanol is added 4.4 g of dihydrate SnCl2and the reaction mixture is heated at boiling under reflux for 6 hours Then, after cooling, to ablaut 50 ml of 2M NaOH and inorganic residue is filtered off and rinsed with ethyl acetate. The filtrate is extracted with ethyl acetate (3×100 ml), the combined organic layers dried over MgSO4and the solvents removed under reduced pressure. The remaining product is sufficiently pure for the next reaction stage. Output: 640 mg.

(iii) 4-(2-Methoxyethoxy)-2-trichloromethyl-1H-benzoimidazol

Specified in the header connection receive similar stage (iii) of example 37 with the exception that 3-(2-methoxyethoxy)benzene-1,2-diamine is used instead of benzene-1,2-diamine.

(iv) [4-(3-Exmortis-4-yl)phenyl]amide 4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid

Specified in the header connection receive similar stage (iv) of example 37 with the difference that 4-(2-methoxyethoxy)-2-trichloromethyl-1H-benzoimidazol used instead of 2-trichloromethyl-1H-benzoimidazole. MS (ES+): m/e=411.

(v) [4-(3-Exmortis-4-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid

specified in the header connection receive similar stage (v) of example 35 except that [4-(3-exmortis-4-yl)phenyl]amide 4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid is used instead of [4-(3-exmortis-4-yl)phenyl]amide of 1H-benzimidazole-2-carboxylic acid. MS (ES+): m/e=579, range chlorinated.

Example 53: 1-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-[4-(3-exmortis-4-yl)forcarbon the yl]-1H-benzoimidazol-4-carboxylic acid

127 mg (0.20 mmol) of methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid are dissolved in 15 ml of CH2Cl2. When 0°add 1.8 ml (1.8 mmol) of 1M solution of BBr3. The reaction mixture was stirred for 24 h at K.T. Due to incomplete conversion add an additional 0.9 ml (0.9 mmol) of 1M solution of BBr3. After stirring for 24 h at K.T., the reaction mixture was concentrated and purified preparative HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid). 1-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid is obtained as a pale brown amorphous solid.

Yield: 73 mg MS (ES+): m/e=549, range chlorinated.

Example 54: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, from 50 mg (0.10 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 8.1 mg (0.11 mmol) 3-hydroxyazetidine. Specified in C is the cylinder connection receive in the form of formate in the form of a white amorphous solid.

Yield: 10 mg MS (ES+): m/e=552, the spectrum of the chlorinated.

Example 55: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, from 50 mg (0.10 mmol) of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid and 8.1 mg (0.11 mmol) 3-hydroxyazetidine. Specified in the title compound obtained as its formate in the form of a white amorphous solid.

Yield: 27 mg MS (ES+): m/e=552, the spectrum of the chlorinated.

Example 56: 5-[(2-Hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,5-dicarboxylic acid

5-[(2-Hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,5-dicarboxylic acid get by the method of example 22, from 50 mg (0.10 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 6.8 mg (0.11 mmol) 2-aminoethanol. Specified in the title compound obtained as its formate in the form of a white amorphous solid substances is STV.

Output: 4 mg MS (ES+): m/e=542, the spectrum of the chlorinated.

Example 57: 5-[(2-Hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-3H-benzoimidazole-2,5-dicarboxylic acid

5-[(2-Hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-3H-benzoimidazole-2,5-dicarboxylic acid get by the method of example 22, from 50 mg (0.10 mmol) of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid and 6,7 mg (0.11 mmol) 2-aminoethanol. Specified in the title compound obtained as its formate in the form of a white amorphous solid.

Yield: 18 mg MS (ES+): m/e=542, the spectrum of the chlorinated.

Example 58: 5-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,5-dicarboxylic acid

5-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,5-dicarboxylic acid get by the method of example 22, from 50 mg (0.10 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 8.3 mg (0.11 mmol) N-methyl-2-aminoethanol. Specified in the title compound obtained as its formate in the form of white amorphous Targovishte.

Yield: 23 mg MS (ES+): m/e=556, range chlorinated.

Example 59: 5-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-3H-benzoimidazole-2,5-dicarboxylic acid

5-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-3H-benzoimidazole-2,5-dicarboxylic acid get by the method of example 22, from 50 mg (0.10 mmol) of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid and 8.3 mg (0.11 mmol) N-methyl-2-aminoethanol. Specified in the title compound obtained as its formate in the form of a white amorphous solid.

Yield: 32 mg MS (ES+): m/e=556, range chlorinated.

Example 60: 1-Cyclohexyloxycarbonyloxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

1-Cyclohexyloxycarbonyloxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid get by the method of example 20, from 50 mg (0.10 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 82.8 mg (0.40 mmol) of cyclohexyl-1-charitycardonate. Specified in the header of the compounds is their gain in the form of its dihydrochloride in the form of a white amorphous solid.

Yield: 27 mg MS (ES+): m/e=669, range chlorinated.

Example 61: 1-Cyclohexyloxycarbonyloxy ester of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

1-Cyclohexyloxycarbonyloxy ester of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid get by the method of example 20, from 50 mg (0.10 mmol) of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid and 82.8 mg (0.40 mmol) of cyclohexyl-1-charitycardonate. Specified in the header connection receive in the form of its dihydrochloride in the form of a white amorphous solid.

Yield: 49 mg MS (ES+): m/e=669, range chlorinated.

Example 62: 1-Ethoxycarbonylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

1-Ethoxycarbonylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid get by the method of example 20, from 50 mg (0.10 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and to 61.2 mg (0.40 mmol) of 1-chloramination. The decree of the TES in the header connection receive in the form of its dihydrochloride in the form of a white amorphous solid.

Yield: 21 mg MS (ES+): m/e=615, the spectrum of the chlorinated.

Example 63: 1-Ethoxycarbonylmethyl ester of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

1-Ethoxycarbonylmethyl ester of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid get by the method of example 20, from 50 mg (0.10 mmol) of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid and to 61.2 mg (0.40 mmol) of 1-chloramination. Specified in the title compound obtained as dihydrochloride in the form of a white amorphous solid.

Yield: 42 mg MS (ES+): m/e=615, the spectrum of the chlorinated.

Example 64: 2-Hydroxyethyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

50 mg (0.08 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid are dissolved in 4 ml of DMF. Then add 20 mg of DMAP, to 34.3 mg (0.16 mmol) of DCC and 46 μl (0.83 mmol) of ethylene glycol. The resulting mixture is stirred for 8 h at 60°and then concentrate under reduced pressure. The remaining residue is purified preparative HPLC (gradient mixture sub> 3CN/H2O+0.05% of formic acid)to give the pure 2-hydroxyethyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid as white amorphous solids. The corresponding dihydrochloride is obtained by processing in 0.1m HCl solution and subsequent lyophilization.

Yield: 22 mg, MS (ES+): m/e=572, the spectrum of the chlorinated.

Example 65: 2-Hydroxyethyloxy ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

50 mg (0.08 mmol) of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid are dissolved in 10 ml of CH2Cl2. Then add 3 mg of DMAP, 23 mg (0.11 mmol) of DCC and 46 μl (0.83 mmol) of ethylene glycol. The resulting mixture was stirred at K.T. for 16 h and then concentrated under reduced pressure. The remaining residue is purified preparative HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid)to give the pure 2-hydroxyethyloxy ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid as white amorphous solids. The corresponding dihydrochloride is obtained by processing in 0.1m HCl solution and subsequent leofiles the tution.

Yield: 44 mg, MS (ES+): m/e=572, the spectrum of the chlorinated.

Example 66: Carboxymethylate ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

50 mg (0.08 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid are dissolved in 5 ml of DMF. Then add a 27.6 mg KI, 126,5 mg (0.88 mmol) To a2CO3and 62.8 mg (0.64 mmol) of Chloroacetic acid. The resulting mixture is stirred for 8 h at 60°C. Then added 92 mg2CO3and 62.8 mg (0.64 mmol) of Chloroacetic acid. After keeping an additional 8 h at 60°the reaction mixture is concentrated under reduced pressure. The remaining residue is purified preparative HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid), while receiving clean carboxymethylate ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid as white amorphous solids. The corresponding dihydrochloride is obtained by processing in 0.1m HCl solution and subsequent lyophilization.

Yield: 21 mg, MS (ES+): m/e=586, range chlorinated.

Example 67: 1-(3-Methoxybenzyl)-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid

(i) Met Lowy ether 1-(3-methoxybenzyl)-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid

366,50 mg (0,929 mmol) methyl ester 2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid are dissolved in 15 ml of DMF. Then add 192,6 mg (KZT 1,394 mmol) To a2CO3and 156,1 ál (KZT 1,394 mmol) 1-methyl bromide-3-methoxybenzene and the resulting mixture is stirred for 4 h at 80°C. the Mixture is diluted with 300 ml of toluene and washed with 50 ml of a saturated solution of NaHCO3. The product is completely in toluene does not dissolve, so you need to add the ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and concentrate under reduced pressure. The residue is purified preparative HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid (separation of isomers), while receiving methyl ester 1-(3-methoxybenzyl)-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid as a pale brown amorphous solid.

Yield: 150 mg MS (ES+): m/e=515.

(ii) 1-(3-Methoxybenzyl)-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid

20 mg (0.04 mmol) of methyl ester 1-(3-methoxybenzyl)-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid are suspended in 5 ml of Meon. Add 194 ál (0,19 mmol) of 1M aqueous LiOH solution and the resulting mixture is stirred for 8 h at 60°C. After acidification 1M solution of HC mixture of concentrate. The resulting residue is purified preparative HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid)to give the pure 1-(3-methoxybenzyl)-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid as a colorless amorphous solid.

Yield: 44 mg MS (ES+): m/e=501.

Example 68: (a) (1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-hydroxyethanesulfonic]-1H-benzoimidazol-2-carboxylic acid

b) (1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-hydroxyethanesulfonic]-1H-benzoimidazol-2-carboxylic acid and (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid get by the method of example 29, from 1 g (2.5 mmol) of the crude (1-isopropylpiperazine-4-yl)amide 5-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid and 758,9 mg (3.04 from mmol) of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide. Preparative RP-HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid) gives a mixture of 1:1 both listed in the header of the isomers. These isomers can be separated by NP-HPLC using a chiral NEPAD is mportant phase and a mixture of heptane, ethanol, methanol and diethylamine as solvent. Structural assignment of both isomers reach NOE spectroscopy.

Output (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-hydroxyethanesulfonic]-1H-benzoimidazol-2-carboxylic acid: 79 mg MS (ES+): m/e=563, range chlorinated.

Output (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-(2-hydroxyethanesulfonic]-1H-benzoimidazol-2-carboxylic acid: 44 mg. MS (ES+): m/e=563, range chlorinated.

Example 69: Cyclopropylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

325,1 mg (or 0.57 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid was dissolved in 20 ml of CH2Cl2. Then add 470 ml (5.7 mmol) of cyclopropylmethanol, 152,2 mg (0,74 mmol) DCC and 6.9 mg of DMAP. The resulting mixture was stirred at K.T. for 16 hours the next day, add an additional 100 ml (2.28 mmol) of cyclopropylmethanol, to 58.6 mg (0.29 mmol) of DCC and 20 mg of DMAP and the reaction mixture is stirred for 48 hours the Solvent is removed in vacuum. Final purification preparative RP-HPLC (gradient mixture of CH3CN/N2O+0,05 formic acid) gives cyclopropylmethyl ester 1-[(5-chloropyrid is n-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid as white amorphous solids. The corresponding acetate receive the following method. The above matter is dissolved in CH2Cl2and washed with saturated solution of NaHCO3. The organic layer is dried over anhydrous MgSO4and concentrate. The resulting residue was diluted with 20 ml of water containing 4 EQ. Asón and lyophilized.

Output: 231 mg) MS (ES+): m/e=553, the spectrum of the chlorinated.

Example 70: 2-Methoxyethoxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

2-Methoxyethoxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid get by the method of example 69, on the basis of 112 mg (0.22 mmol) of 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 177 μl (2.2 mmol) of 2-methoxyethanol. Specified in the header connection receive in the form of its dihydrochloride in the form of a white amorphous solid.

Yield: 66 mg MS (ES+): m/e=557, range chlorinated.

Example 71: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-hydroxymethyl-1H-benzoimidazol-2-carboxylic acid

85,0 mg (0,166 mmol) of methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carbon is acid are dissolved in 3 ml of abs. THF. In argon atmosphere, add 0.25 ml (0,497 mmol) of a 2M solution of LiBH4in THF. After stirring for 1.5 h at K.T. add 0.5 ml water and the reaction mixture is concentrated. The residue is purified preparative RP-HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid), get (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-hydroxymethyl-1H-benzoimidazol-2-carboxylic acid as white amorphous solids. Specified in the title compound obtained as its formate.

Yield: 20 mg MS (ES+): m/e=485, range chlorinated.

Example 72: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-carboxylic acid

81,6 mg (0,065 mmol) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-hydroxymethyl-1H-benzoimidazol-2-carboxylic acid are dissolved in 5 ml of abs. DMF. When 0°add to 21.9 mg (of € 0.195 mmol) of potassium tert-butylate. After 5 min add 12 μl (0.13 mmol) 1-bromo-2-methoxyethane and the reaction mixture was allow to warm to K.T. After 3 hours add an additional 12 μl (0.13 mmol) 1-bromo-2-methoxyethane and the reaction mixture is stirred for 16 hours the Solvent is distilled off and the resulting residue purified preparative RP-HPLC (gradient mixture of CH3CN/N2O+0.05% Murav the other acid), while receiving (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-carboxylic acid as a pale brown amorphous solid. Specified in the title compound obtained as its formate.

Yield: 12 mg MS (ES+): m/e=543, range chlorinated.

Example 73: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(morpholine-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(morpholine-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, from 450 mg (0.90 mmol) of 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 87 μl (2,70 mmol) of the research. Specified in the title compound obtained as its formate. Subsequent conversion to the corresponding acetate gives white amorphous solid.

Output: 456 mg) MS (ES+): m/e=568, the spectrum of the chlorinated.

Example 74: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-([1,4]oxazepan-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-([1,4]oxazepan-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid get method the ke of example 22, on the basis of 423 mg (0.85 mmol) of 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 128,3 mg (0,94 mmol) of the hydrochloride homomorpholine. Specified in the title compound obtained as its formate. Subsequent conversion to the corresponding acetate gives white amorphous solid.

Yield: 370 mg MS (ES+): m/e=582, range chlorinated.

Example 75: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2,6-dimethylpiperidin-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2,6-dimethylpiperidin-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, on the basis of 100 mg (0.20 mmol) of 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 50.0 μl (0.40 mmol) 2,6-dimethylpiperidine. Specified in the title compound obtained as its formate in the form of a white amorphous solid.

Yield: 72 mg MS (ES+): m/e=594, range chlorinated.

Example 76: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(4,4-deformability-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4,4-diporeia the Jn-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, on the basis of 870 mg (1.70 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 302,3 mg (of 1.87 mmol) of the hydrochloride 4,4-deformability. Specified in the title compound obtained as its formate. Subsequent conversion to the corresponding acetate gives white amorphous solid.

Yield: 700 mg MS (ES+): m/e=602, the spectrum of the chlorinated.

Example 77: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-([1,4]oxazepan-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-([1,4]oxazepan-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, from 147,8 mg (0,296 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 44.8 mg (0,326 mmol) of hydrochloride homomorpholine. Specified in the title compound obtained as its formate. Subsequent conversion to the corresponding acetate gives white amorphous solid.

Yield: 113 mg MS (ES+): m/e=582, range chlorinated.

Example 78: 2-Hydroxyethyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

2-Hydroxyethyloxy ester 1-[5-(5-CHL is reopen-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid get by the method of example 65, on the basis of 100 mg (0,17 mmol) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 93 μl (1.7 mmol) of ethylene glycol. Specified in the header connection receive in the form of its dihydrochloride in the form of a white amorphous solid.

Yield: 86 mg MS (ES+): m/e=572, the spectrum of the chlorinated.

Example 79: Carboxymethylate ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

Carboxymethylate ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid get by the method of example 66, from 100 mg (0,17 mmol) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 62.9 mg (of 0.68 mmol) Chloroacetic acid. Specified in the header connection receive in the form of its dihydrochloride in the form of a white amorphous solid.

Yield: 44 mg MS (ES+): m/e=586, range chlorinated.

Example 80: (1 Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-methoxyisatin-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-methoxyisatin-1-carbonyl)-1H-benzoimidazol-2-to benovoy acid get by the method of example 22, on the basis of 205 mg (0.34 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 46.6 g (of 0.37 mmol) of the hydrochloride of 3-methoxyacridine. Specified in the title compound obtained as its formate. Subsequent conversion to the corresponding acetate gives white amorphous solid.

Yield: 190 mg MS (ES+): m/e=597, range chlorinated.

Example 81: a) 2-(1-Isopropylpiperazine-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-4-carboxylic acid

b) 2-(1-Isopropylpiperazine-4-ylcarbonyl)-3-(3-methoxybenzyl)-3H-benzoimidazol-4-carboxylic acid

1.45 g (4,21 mmol) methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid are dissolved in 45 ml of DMF. Then add 698,2 mg (of 5.05 mmol) To a2CO3and 888,8 mg (4,42 mmol) 1-methyl bromide-3-methoxybenzene and the resulting mixture is stirred for 2 h at 60°C. the Solvent is distilled off. The residue is dissolved in 300 ml ethyl acetate and washed once with saturated solution of NaHCO3and a saturated solution of salt. The organic layer is dried over anhydrous MgSO4concentrate under reduced pressure and purified flash chromatography on silica gel using a mixture of ethyl acetate : methanol as the eluent, thus obtaining 1.19 g of a mixture of 4:1 methyl ester of 2-(1-isop oilpipeline-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-4-carboxylic acid and methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-3-(3-methoxybenzyl)-3H-benzoimidazol-4-carboxylic acid. This mixture of isomers is dissolved in 100 ml of the Meon. Add to 12.8 ml (12.8 mmol) of 1M aqueous LiOH solution and the resulting suspension is stirred for 3 h at 60°C. the Mixture is acidified by addition of 1M HCl solution and concentrated under reduced pressure. Final purification preparative RP-HPLC (CH3CN/N2O+0.05% of formic acid) gives both isomers: (a) 2-(1-isopropylpiperazine-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-4-carboxylic acid and (b) 2-(1-isopropylpiperazine-4-ylcarbonyl)-3-(3-methoxybenzyl)-3H-benzoimidazol-4-carboxylic acid as white amorphous solids. Both isomer is converted into the corresponding dihydrochloride.

The yield of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-4-carboxylic acid: 890 mg MS (ES+): m/e=451.

The yield of 2-(1-isopropylpiperazine-4-ylcarbonyl)-3-(3-methoxybenzyl)-3H-benzoimidazol-4-carboxylic acid: 250 mg. MS (ES+): m/e=451.

Example 82: (a) 1-[2-(4-Chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

b) 3-[2-(4-Chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid

1.45 g (4,21 mmol) methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid are dissolved in 45 ml of DMF. Then add 989,1 mg (7,16 mmol) To a2CO3and 11 g (6,32 mmol) 1-chloro-4-(2-chloroethyl)benzene and the resulting mixture is stirred for 24 h at 80° C. the Solvent is distilled off. The residue is dissolved in 300 ml ethyl acetate and washed once with saturated solution of NaHCO3and a saturated solution of salt. The organic layer is dried over anhydrous MgSO4, concentrated and purified flash chromatography using a mixture of ethyl acetate : methanol as the eluent, thus obtaining of 1.30 g of a mixture of 3:1 methyl ester 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and methyl ester of 3-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid. This mixture of isomers is dissolved in 100 ml of the Meon. Type of 16.2 ml (16.2 mmol) of 1M aqueous LiOH solution and the resulting suspension is stirred for 3 h at 60°C. the Mixture is acidified by addition of 1M HCl solution and concentrated under reduced pressure. Final purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives both isomers: (a) 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and (b) 3-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-karbonova acid as white amorphous solids. Both isomer is isolated in the form of formate.

Output 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic sour the s: 800 mg MS (ES+): m/e=468, range chlorinated.

Output 3-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid: 250 mg. MS (ES+): m/e=468, range chlorinated.

Example 83: (1 Isopropylpiperazine-4-yl)amide of 4-(3-hydroxyazetidine-1-carbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide of 4-(3-hydroxyazetidine-1-carbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, from 150 mg (0,287 mmol) 2-(1-isopropylpiperazine-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-4-carboxylic acid and 23.0 mg (0,315 mmol) 3-hydroxyazetidine. Specified in the title compound obtained as its formate in the form of a white amorphous solid.

Yield: 62 mg MS (ES+): m/e=506.

Example 84: (1 Isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, from 150 mg (0.29 mmol) of 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 23.4 mg (0.32 mmol) of 3-hydroxyazetidine. Specified in the title compound obtained as its formate in the form of logo amorphous substance.

Yield: 62 mg MS (ES+): m/e=524, the spectrum of the chlorinated.

Example 85: (1 Isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-(3-methoxyisatin-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-(3-methoxyisatin-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, from 50 mg (0,097 mmol) 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-2-carboxylic acid and 13.5 mg (0.015 mmol) of 3-methoxyacridine. Specified in the title compound obtained as its formate in the form of a white amorphous solid.

Yield: 35 mg MS (ES+): m/e=538, the spectrum of the chlorinated.

Example 86 (a) Methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-5-carboxylic acid

b) Methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-3-(3-methoxybenzyl)-3H-benzoimidazol-5-carboxylic acid

Methyl ester 2-(1-isopropylpiperazine-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-5-carboxylic acid and methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-3-(3-methoxybenzyl)-3H-benzoimidazol-5-carboxylic acid get by the method of example 5 (iii), starting from 300 mg (0.87 mmol) of the methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 210,2 mg (0.04 mmol who) 1-methyl bromide-3-methoxybenzene. Preparative RP-HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid) gives a mixture of 1:1 both listed in the header of the isomers. These isomers can be separated by NP-HPLC using a chiral stationary phase and a mixture of heptane, ethanol, methanol and diethylamine as solvent. Structural assignment of both isomers can be achieved NOE spectroscopy.

Output: methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-5-carboxylic acid: 65 mg MS (ES+): m/e=465.

Output: methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-3-(3-methoxybenzyl)-3H-benzoimidazol-5-carboxylic acid: 70 mg MS (ES+): m/e=465.

Example 87: (a) Methyl ester of 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

b) Methyl ester of 3-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

Methyl ether of 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and methyl ester of 3-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid get by the method of example 5 (iii), starting from 300 mg (0.87 mmol) of the methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and RUB 365.9 mg (2.0 mmol) 1-chloro-4-(2-chloroethyl)benzene. Since 1-chloro-4-(2-chloroethyl)benzene is less reactive, the reaction time should be extended until 10 o'clock preparative RP-HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid) gives a mixture of 4:3 are both listed in the header of the isomers. These isomers can be separated by NP-HPLC using a chiral stationary phase and a mixture of heptane, ethanol and methanol as solvent. Structural assignment of both isomers can be achieved NOE spectroscopy.

The yield of methyl ester 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid: 102 mg MS (ES+): m/e=483, range chlorinated.

The yield of methyl ester of 3-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid: 74 mg MS (ES+): m/e=483, range chlorinated.

Example 88: 1-[2-(4-Chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

1-[2-(4-Chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid is obtained according to the method of example 6, on the basis of 100 mg (0.21 mmol) of methyl ester 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 1.04 ml (1.04 mmol) of 1M LiOH solution. Specified in the header connection receive in the form of its dihydrochloride is white, amorphous solids.

Yield: 54 mg MS (ES+): m/e=469, range chlorinated.

Example 89: (a) 1-(5-Chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

b) 3-(5-Chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid

1-(5-Chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 3-(5-chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid is obtained according to the method of example 81, from 200 mg (of 0.58 mmol) of the methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 151,9 mg (of 0.58 mmol) 2-methyl bromide-5-chlorobenzo[b]thiophene. Hydrolysis of the resulting ester and purification preparative RP-HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid) gives specified in the connection header in the form of formate in the form of a white amorphous solids.

Output 1-(5-chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid: 134 mg MS (ES+): m/e=511, the spectrum of the chlorinated.

Exit 3-(5-chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid: 49 mg. MS (ES+): m/e=511, the spectrum of the chlorinated.

u> Example 90: 1-(5-Chloro-1H-indazol-3-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

1-(5-Chloro-1H-indazol-3-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid is obtained according to the method of example 81, from 200 mg (of 0.58 mmol) of the methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and of 116.8 mg (of 0.58 mmol) 5-chloro-3-chloromethyl-1H-indazole. Hydrolysis of the resulting ester and purification preparative RP-HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid) gives specified in the title compound in the form of formate in the form of a white amorphous solid.

Yield: 20 mg MS (ES+): m/e=495, the spectrum of the chlorinated.

Example 91: (1 Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(4-hydroxypiperidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(4-hydroxypiperidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, from 670 mg (1.10 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 124,0 mg (1,21 mmol) piperidine-4-ol. Specified in the title compound obtained as its formate. Subsequent transformation into with testwuide acetate gives white amorphous solid.

Output: 538 mg. MS (ES+): m/e=611, range chlorinated.

Example 92: (1 Isopropylpiperazine-4-yl)amide 7-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-Pirin-8-carboxylic acid

(i) 1,3-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid

to 5.00 g (24,0 mmol) of 8-hydroxymethyl-1,3-dimethyl-3,7-dihydropyran-2,6-dione are suspended in 15 ml of water. Add to 16.8 ml (33.6 mmol) of 2 n NaOH solution. The resulting mixture is cooled to 5°C. At this temperature, add a solution of 5.05 g (32,2 mmol) KMnO4in 86 ml of water. After stirring at K.T. for 4 h, the reaction mixture was filtered through celite. After adding activated charcoal, the filtrate is again filtered through celite. The filtrate is concentrated to a volume of 200 ml and add 5 ml conc. HCl solution. After standing at 4°C for 16 h crystalline product is filtered off, washed twice with cold water and acetone and dried under reduced pressure at 40°C.

Output: 5,18, MS (ES+): m/e=225.

(ii) (1-Isopropylpiperazine-4-yl)amide 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid

100 mg (0.45 mmol) of 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid are dissolved in 5 ml of DMF. Then add 227 μl (1.35 mmol) and DIPEA 186,5 mg (0,495 mmol) of HATU. After 1 h, add 105,6 mg (0,495 mmol) of the dihydrochloride of 1-isopropylpiperazine the-4-ylamine and 227 μl (1.35 mmol) PIPEA and the resulting mixture was stirred at K.T. within 4 hours the Reaction mixture was concentrated and purified preparative RP-HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid), get (1-isopropylpiperazine-4-yl)amide 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid as its formate.

(iii) (1-Isopropylpiperazine-4-yl)amide 7-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-Pirin-8-carboxylic acid

155 mg (0.45 mmol) (1-isopropylpiperazine-4-yl)amide 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid are dissolved in 5 ml of DMF. Then add 184,4 mg (1.35 mmol) To a2CO3and 111,5 mg (0,405 mmol) 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol and the resulting mixture was stirred at 80°C for 1 h the Mixture was concentrated and purified preparative RP-HPLC (gradient mixture of CH3CN/N2O+0.05% of formic acid), get (1-isopropylpiperazine-4-yl)amide 7-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid. The corresponding dihydrochloride is obtained by treatment of the product in 0.1m HCl solution and subsequent lyophilization.

Yield: 55 mg MS (ES+): m/e=546, the spectrum of the chlorinated.

Example 93: (a) Methyl ester of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

b) Methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

(i) tert-Butyl methyl ether (1-cyclopropylidene-4-yl)carbamino acid

To a solution of 14.0 g (0,0699 mol) tert-butyl ether piperidine-4-ylcarbamate acid in 500 ml of abs. Meon add 250 g of dried molecular sieves 3 that is, In an argon atmosphere add to 39.9 ml (0,699 mol) of acetic acid and of 52.5 ml (0,262 mol) (1-amoxilcompare)trimethylsilane. Finally, added dropwise 314,5 ml (0,3145 mol) of 1M solution of NaCNBH3in THF. After incubation for 20 min at K.T. reaction mixture is stirred for 6 h at 60°C. the Mixture is filtered through celite. The filtrate is concentrated under reduced pressure. The resulting residue is dissolved in 700 ml ethyl acetate and washed with 250 ml of 1M NaOH solution. The aqueous layer was extracted with 300 ml of ethyl acetate. The combined organic layers washed with saturated salt solution, dried over MgSO4and concentrate under vacuum, thus obtaining the crude tert-butyl methyl ether (1-cyclopropylidene-4-yl)carbamino acid as colorless solid.

Output: 23,0, MS (ES+): m/e=241.

(ii) the Dihydrochloride of 1-cyclopropylidene-4-ylamine

23,0 g of the above crude tert-butyl methyl ether (1-cyclopropylidene-4-yl)carbamino acid R is straut in 350 ml of TFA and the solution is stirred for 45 minutes at K.T. The reaction mixture was concentrated under reduced pressure and the resulting residue is dissolved in water. After addition of 23.1 ml conc. HCl solution, the mixture lyophilized, thus obtaining a white amorphous solid. Specified, the solid is suspended in 300 ml of ethyl acetate and incubated for 45 minutes in the conditions of ultrasonic influence. This procedure was repeated twice. Finally, the filtered crystalline solid is dried at 45°With under reduced pressure.

Yield: 15.9 g MS (ES+): m/e=141.

(iii) Methyl ether 2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid

To a solution of 10.0 g (to 0.060 mol) of the methyl ester of 3,4-diaminobenzoic acid in 260 ml of acetic acid add 10,47 ml (0,084 mol) methyl ester 2,2,2-trichloroacetimidate acid. After stirring for 2 h at K.T. acetic acid is evaporated. The residue is dissolved in CH2Cl2, washed with saturated salt solution, dried over MgSO4and concentrate under reduced pressure, thus obtaining the crude methyl ester 2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid as a brown resinous substance.

Output: 20,5 mg MS (ES+): m/e=293, range chlorinated.

(iv) Methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

To the mixture 7,53 g (35,3 mmol) Digi is rochloride 1-cyclopropylidene-4-ylamine and 32,39 g (0,386 mol NaHCO 3in 1300 ml of THF and 370 ml of water, add the solution to 11.79 g (32.1 mmol) of methyl ester of 2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid in 360 ml of THF. The reaction mixture was vigorously stirred for 2 h at K.T. THF is evaporated. The precipitate is filtered off and twice treated with approximately 300 ml of a saturated solution of NaHCO3in the conditions of ultrasonic influence. After filtration of the resulting solid is washed twice with 150 ml of water and dried in vacuum at 45°thus the pure methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid in the form of a light brown crystalline substance.

Output: 9,9, MS (ES+): m/e=343.

(v) Methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzimidazole-5-carboxylic acid

17.3 g (50,52 mmol) methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid are dissolved in 800 ml of DMF. Then add of 10.47 g (to 75.8 mmol) To a2CO3and 14,84 g (50,52 mmol) 5-(5-chlorothiophene-2-yl)isoxazol-3-Eletropaulo ether methanesulfonate acid and the resulting mixture is stirred for 2 h at 80°C. the Mixture is concentrated under reduced pressure. The residue is suspended in 800 ml of ethyl acetate. The next day the precipitate is filtered off and washed with the 100 ml of ethyl acetate, thus the methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzimidazole-5-carboxylic acid. The filtrate is concentrated to a volume of approximately 100 ml Again the precipitate is filtered off. This procedure is repeated one more time. The remaining filtrate is concentrated under reduced pressure and finally purified flash chromatography on silica gel using ethyl acetate as eluent. Containing the product fractions are concentrated under vacuum, thus obtaining pure (>98%) of methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzimidazole-5-carboxylic acid as a light brown crystalline solid.

Output: 7,9, MS (ES+): m/e=540, range chlorinated.

(vi) Methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

1.0 g of the crude methyl ester 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid is recrystallized from ethyl acetate.

Yield: 500 mg MS (ES+): m/e=540, range chlorinated.

Example 94: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic who Isleta

to 7.84 g (14,52 mmol) of methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid are dissolved in 400 ml of Meon. Add 72,59 ml (72,59 mmol) of 1M aqueous LiOH solution and the resulting mixture is stirred for 7 h at 60°C. the Solution is concentrated to a volume of approximately 200 ml) and acidified by addition of 4M aqueous HCl to achieve pH≈1. After 30 minutes the precipitate is filtered and washed several times with cold Meon. Recrystallization from Meon gives 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid in the form of a colorless crystalline solid. Specified in the title compound obtained as its monohydrochloride.

Output: 7,3, MS (ES+): m/e=526, the spectrum of the chlorinated.

4.0 g (7,11 mmol) of the above product is converted into its sodium salt by suspendirovanie in 10 ml of water, add 100,15 ml of 0.2m aqueous solution of NaOH, followed by extraction with 100 ml of n-butanol (2×). Merged layers butanol again extracted with 20 ml of water (3×) and distilled together with 200 ml of water (3×). The resulting solution lyophilized, while receiving specified in the title compound in the form of its sodium salt in the form of white amorphous substance. Output: 3,49 is.

1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid also get selective synthesis:

(i)-[5-(5-Chlorothiophene-2-yl)isoxazol-3-yl]methylamine

to 1.00 g (3,59 mmol) 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol and 503,3 mg (3,59 mmol) hexamine dissolved in 40 ml of EtOH. The reaction mixture was stirred at K.T. for 16 hours the next day, add 3 ml conc. HCl solution and the resulting mixture is refluxed for 45 minutes. After cooling, the precipitate is filtered off and washed with water. The white crystalline substance is dried under reduced pressure at 40°C. Output: 806 mg

(ii) Methyl ester of 4-{[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]amino}-3-nitrobenzoic acid

To a solution of 634,4 mg (3,19 mmol) of methyl ester of 4-fluoro-3-nitrobenzoic acid in 12 ml of DMF type of 800.0 mg (3,19 mmol) of s-[5-(5-chlorothiophene-2-yl)isoxazol-3-yl]methylamine and 0.88 ml (6,37 mmol) of triethylamine. The reaction mixture was stirred at K.T. for 16 hours Add 12 ml of water. The precipitate is filtered off and washed with water. A yellow crystalline substance is dried under reduced pressure at 42°C.

Output: 1,03, MS (ES+): m/e=394, range chlorinated.

(iii) Methyl ester 3-amino-4-{[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]amino}benzoic acid

to 97.1 mg (0.41 mmol) NiCl2 6H2O dissolved in 10 ml Meon and treated in an ultrasonic conditions. Add to 46.4 g (1,24 mmol) NaBH4. After 15 minutes add 214,0 mg (0.54 mmol) of methyl ester of 4-{[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]amino}-3-nitrobenzoic acid in 20 ml of CH2Cl2. After another 15 minutes in the form of three portions add 55,6 mg (1.48 mmol) NaBH4. The reaction mixture was treated in an ultrasonic conditions for 2 hours Adding NaBH4(55,6 mg each time) and the processing in ultrasonic conditions should be repeated three times to achieve full conversion. The reaction mixture is filtered on celite and the filtrate concentrated under reduced pressure. The residue is suspended in 30 ml of Meon. After filtration, the filtrate was concentrated in vacuo and the residue is dissolved in 100 ml of CH2Cl2. The organic layer is washed four times with water, dried over anhydrous MgSO4and concentrate under reduced pressure, thus obtaining the crude methyl ester of 3-amino-4-{[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]amino}benzoic acid as a brown oil.

Yield: 83 mg MS (ES+): m/e=364, the spectrum of the chlorinated.

(iv) Methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid

to 36.0 mg (0,098 mmol) of methyl ester of 3-amino-4-{[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]amino}benzoi the Oh of the acid dissolved in 3 ml of acetic acid, add to 17.4 μl (0.14 mmol) of the methyl ester 2,2,2-trichloroacetimidate acid and the resulting mixture was stirred at K.T. within 3 hours, the Reaction mixture was concentrated under reduced pressure and the residue is distilled twice with 15 ml of toluene, thus obtaining the crude methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid as a brown solid.

Yield: 49 mg MS (ES+): m/e=491, range chlorinated.

(v) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

21,0 mg (0,098 mmol) dihydrochloride (1-cyclopropylidene-4-ylamine) dissolved in 3 ml of CH3CN and 3 ml of water. Add to 82.3 mg (0.98 mmol, 10 EQ.) NaHCO3. Finally, add a solution of 48.1 mg (0,098 mmol) of methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid in 2 ml of CH3CN and the resulting mixture is stirred vigorously for 3 hours at the boil under reflux. The mixture is concentrated under reduced pressure. The residue is purified preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid)to give the pure 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid in the form b is izvetnogo amorphous solid.

Yield: 26 mg (50%). MS (ES+): m/e=526, the spectrum of the chlorinated. (Under these conditions simultaneously hydrolyzing methyl ether).

Example 95: 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid is obtained according to the method of example 94, on the basis of 250.0 mg (0.46 mmol) of methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid. Specified in the title compound is isolated in the form of his monohydrochloride in the form of a colorless crystalline substance.

Yield: 135 mg MS (ES+): m/e=526, the spectrum of the chlorinated.

Example 96: a) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

b) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid

i) Methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

Methyl ester 2-(1-cyclopropylidene-4-yl)carbarnoyl)-1H-benzoimidazol-4-carboxylic acid get by the method of example 93 (iv)on the basis of of 1.62 g (5,52 mmol) methyl ester 2-trichloromethyl-1H-b is isoimidazole-4-carboxylic acid and 1.29 g (6,07 mmol) of the dihydrochloride of cyclopropylidene-4-ylamine.

Output: 1,62, MS (ES+): m/e=343.

(ii) a) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

b) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid

1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid is obtained according to the method of example 81, on the basis of 248,0 mg (0,72 mmol) methyl ester 2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 221,9 mg (0,79 mmol) 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol. Hydrolysis of the resulting ester and purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives specified in the connection header in the form of formate in the form of a white amorphous solids. Appropriate hydrochloride receive treatment both 0,1M HCl solution and subsequent lyophilization.

Output 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid: 119 mg MS (ES+): m/e=526, the spectrum of the chlorinated.

Output 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropyl piperidin-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid: 39 mg. MS (ES+): m/e=526, the spectrum of the chlorinated.

Example 97: Methyl ether of 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

Methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid get by the method of example 15, on the basis of 1.40 g (4.09 to mmol) methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and of 1.02 g (4.09 to mmol) of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide.

Output: 1,90, MS (ES+): m/e=511, the spectrum of the chlorinated.

Example 98: 1-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

1-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid is obtained according to the method of example 16, on the basis of 1.89 g (3,70 mmol) of methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid.

Output: 1,90, MS (ES+): m/e=497, range chlorinated.

Example 99: Cyclopropylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

Cyclopropylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid get by the method of example 69, based on 589,0 mg (1,19 mmol) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 1.92 ml (23,8 mmol) cyclopropylmethanol.

Output: 362 mg MS (ES+): m/e=551, range chlorinated.

Example 100: a) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid

b) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid

i) Methyl ester 2-trichloromethyl-3H-thieno[3,4-d]imidazole-6-carboxylic acid

To a solution of 2.00 g (11.6 mmol) of the methyl ester of 3,4-diminutive-2-carboxylic acid in 50 ml acetic acid is added to 2.06 ml (16,24 mmol) methyl ester 2,2,2-trichloroacetimidate acid. After stirring for 2 h at 95°the mixture is concentrated and distilled together twice with 100 ml of toluene. The residue is dried in vacuum, obtaining a brown resinous substance.

Output: 4.2V, MS (ES+): m/e=300, range chlorinated.

(ii) Methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid

Methyl ester 2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid get by the method of example 93 (iv)on the basis of 3,48 g (11.6 mmol) of methyl ester of 2-trichloromethyl-3H-is ieno[3,4-d]imidazole-6-carboxylic acid and 2.50 g (11.6 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine.

Output: 3.7V, MS (ES+): m/e=351.

(iii) (a) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid

b) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid

3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid is obtained according to the method of example 81 on the basis of 500 mg (1,40 mmol) methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl]-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 397,4 mg (1,40 mmol) 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol. Hydrolysis of the resulting esters and purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives specified in the connection header in the form of formate in the form of a white amorphous solids. Structural classification of both isomers reach NOE spectroscopy.

Output 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid: 113 mg MS (ES+): m/e=534, the spectrum of the chlorinated.

Output 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-Tien is[3,4-d]imidazole-4-carboxylic acid: 146 mg. MS (ES+): m/e=534, the spectrum of the chlorinated.

Example 101: a) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid

b) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid

i) Methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid

Methyl ester 2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid get by the method of example 93 (iv)on the basis of 203,7 mg (of 0.68 mmol) methyl ester 2-trichloromethyl-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 158,7 mg (0.75 mmol) of the dihydrochloride of 1-cyclopropylidene-4-ylamine.

Output: 309 mg MS (ES+): m/e=349.

(ii): a) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid

b) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid

3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid is obtained according to the method of example 81 based on 236,0 mg (0,mol) methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and amounts to 188.7 mg (of 0.68 mmol) 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol. Hydrolysis of the resulting esters and purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives specified in the connection header in the form of formate in the form of a white amorphous solids. Structural classification of both isomers reach NOE spectroscopy.

Output 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid: 46 mg. MS (ES+): m/e=531. range chlorinated.

Output 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid: 78 mg MS (ES+): m/e=531. range chlorinated.

Example 102: 6-[(2-Hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-thieno[3,4-d]imidazol-2,6-dicarboxylic acid

6-[(2-Hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-thieno[3,4-d]imidazol-2,6-dicarboxylic acid get by the method of example 22, from 96 mg (0.18 mmol) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 11.0 μl (0.18 mmol) of 2-aminoethanol. Specified in the title compound obtained as its formate in the form of a white amorphous solid.

Yield: 55 mg MS (ES+): m/e577, range chlorinated.

Example 103: a) 3-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid

(b) 3-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid

3-[(5-Chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid is obtained according to the method of example 81, on the basis of 500 mg (1,40 mmol) methyl ester 2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 356,0 mg (1,40 mmol) of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide. Hydrolysis of the resulting esters processing BBr3in example 16 and purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives specified in the connection header in the form of formate in the form of a white amorphous solids. Structural classification of both isomers reach NOE spectroscopy.

Output 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid: 142 mg) MS (ES+): m/e=505, the spectrum of the chlorinated.

Output 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ilk who rebamol)-3H-thieno[3,4-d]imidazole-4-carboxylic acid: 58 mg. MS (ES+): m/e=505, the spectrum of the chlorinated.

Example 104: 1-(Isopropylpiperazine-4-yl)amide 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-([1,4]oxazepan-4-carbonyl)-3H-thieno[3,4-d]imidazole-2-carboxylic acid

1-(Isopropylpiperazine-4-yl)amide 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-([1,4]oxazepan-4-carbonyl)-3H-thieno[3,4-d]imidazole-2-carboxylic acid get by the method of example 22, from 80 mg (0,158 mmol) 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 21.8 mg (0,158 mmol) of the hydrochloride homomorpholine. Specified in the title compound obtained as its formate in the form of a white amorphous solid.

Yield: 70 mg MS (ES+): m/e=588, range chlorinated.

Example 105: Methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-6-(2,2,2-triptoreline)-3H-thieno[3,4-d]imidazole-4-carboxylic acid

(i) Methyl ester 2-trichloromethyl-6-(2,2,2-triptoreline)-3H-thieno[3,4-d]imidazole-4-carboxylic acid

Methyl ester 2-trichloromethyl-6-(2,2,2-triptoreline)-3H-thieno[3,4-d]imidazole-4-carboxylic acid get by the method of example 100 (i) of 500 mg (of 1.85 mmol) of the methyl ester of 3,4-diamino-5-(2,2,2-triptoreline)thiophene-2-carboxylic acid and 328,0 ál (at 2.59 mmol) methyl ester 2,2,2-trichloroacetimidate acid.

Output: 735 mg MS (ES+

(ii) Methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-6-(2,2,2-triptoreline)-3H-thieno[3,4-d]imidazo-4-carboxylic acid

Methyl ester 2-(1-isopropylpiperazine-4-ylcarbonyl)-6-(2,2,2-triptoreline)-3H-thieno[3,4-d]imidazo-4-carboxylic acid get by the method of example 93 (iv)on the basis of 725,0 mg (of 1.85 mmol) methyl ester 2-trichloromethyl-6-(2,2,2-triptoreline)-3H-thieno[3,4-d]imidazo-4-carboxylic acid and 397,8 mg (of 1.85 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine.

Yield: 71 mg MS (ES+): m/e=449.

(iii) Methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-6-(2,2,2-triptoreline)-3H-thieno[3,4-d]imidazole-4-carboxylic acid

Methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-6-(2,2,2-triptoreline)-3H-thieno[3,4-d]imidazole-4-carboxylic acid get by the method of example 81, according to 68.0 mg (0.15 mmol) of the methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-6-(2,2,2-triptoreline)-3H-thieno[3,4-d]imidazo-4-carboxylic acid and 42.2 mg (0.15 mmol) 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol. Purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives specified in the title compound in the form of formate in the form of a white amorphous solid. Structural classification of both isomers reach NOE-what artroscopia.

Yield: 19 mg MS (ES+): m/e=646, the spectrum of the chlorinated.

Example 106: a) 1-[3-(5-Chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

b) 3-[3-(5-Chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

1-[3-(5-Chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 3-[3-(5-chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid is obtained according to the method of example 81, on the basis of 240 mg (0.70 mmol) of methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 201,3 mg (0.70 mmol) of 5-methyl bromide-3-(5-chlorothiophene-2-yl)isoxazol. Hydrolysis of the resulting ester and purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives specified in the connection header in the form of formate in the form of a white amorphous solids. Structural classification of both isomers reach NOE spectroscopy.

Output 1-[3-(5-chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid: 93 mg MS (ES+): m/e=526, the spectrum of the chlorinated.

Output 3-[3-(5-chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene is n-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid: 60 mg MS (ES+): m/e=526, the spectrum of the chlorinated.

Example 107: a) 1-[5-(5-Chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

b) 3-[5-(5-Chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid

1-[5-(5-Chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 3-[5-(5-Chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid is obtained according to the method of example 81, from 200 mg (of 0.58 mmol) of the methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid and 181,8 mg (of 0.58 mmol) 2-methyl bromide-5-(5-chlorothiophene-2-yl)[1,3,4]thiadiazole. Hydrolysis of the resulting ester and purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives specified in the connection header in the form of formate in the form of a white amorphous solids. Structural classification of both isomers reach NOE spectroscopy.

Output 1-[5-(5-chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid: 18 mg; MS (ES+): m/e=543, range chlorinated.

Output 3-[5-(5-chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cycle is propylpiperidine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid: 6 mg; MS (ES+): m/e=543, range chlorinated.

Example 108: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid

(i) 1-(2-Methoxyethoxy)-2,3-dinitrobenzene

1.50 g (8,15 mmol) of 2,3-dinitrophenol dissolved in 75 ml of acetone. Then add 1,69 g (12,22 mol)2CO3, 135,3 mg KI (0.81 mmol) and of 0.93 ml (9,77 mmol) 1-bromo-2-methoxyethane. The reaction mixture is refluxed for 8 hours then add additional 1,69 g (12,22 mol)2CO3400 mg of KI and of 0.93 ml (9,77 mmol) 1-bromo-2-methoxyethane. The resulting mixture is refluxed for 16 h and then concentrated under reduced pressure. The residue is dissolved in hot ethyl acetate and purified flash chromatography on silica gel using a mixture of ethyl acetate/heptane as the eluent, thus obtaining 1-(2-methoxyethoxy)-2,3-dinitrobenzene as an orange crystalline substance.

Output: 1,35, MS (ES+): m/e=243.

ii) 3-(2-Methoxyethoxy)benzene-1,2-diamine

of 1.80 g (7,43 mmol) 1-(2-methoxyethoxy)-2,3-dinitrobenzene dissolved in 250 ml of Meon. The air from the flask with the solution pump and the flask with the contents rinsed several times with argon. Add 250 mg of palladium on coal (10%), the mixture is again pumped the air and rinsed several times with argon. Finally, argon replacement shall comply with hydrogen (balloon, filled with hydrogen and the mixture is stirred for 2 h at K.T., the Reaction mixture was filtered through celite and the filter residue is washed with 100 ml of the Meon. The filtrate was concentrated in vacuo, thus obtaining pure 3-(2-methoxyethoxy)benzene-1,2-diamine as a brown oil.

Output: 1,33, MS (ES+): m/e=183.

(iii) 4-(2-Methoxyethoxy)-2-trichloromethyl-1H-benzoimidazol

1,33 g (7,30 mmol) 3-(2-methoxyethoxy)benzene-1,2-diamine are dissolved in 35 ml of acetic acid. Add 1.25 ml (10,22 mmol) methyl ester 2,2,2-trichloroacetimidate acid and the resulting mixture is stirred for 2 h at K.T. Mixture is concentrated under reduced pressure and the residue is twice distilled together with 20 ml of toluene, thus obtaining the crude 4-(2-methoxyethoxy)-2-trichloromethyl-1H-benzoimidazol in the form of a brown solid.

Output: 2,25, MS (ES+): m/e=309, the spectrum of the chlorinated.

(iv) (1-Isopropylpiperazine-4-yl)amide of 4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide of 4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid get by the method of example 5(ii)on the basis of 1,91 g (6,18 mmol) of 4-(2-methoxyethoxy)-2-trichloromethyl-1H-benzoimidazole and of 1.46 g (6,79 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine. Final cleaning is performed flash chromatography on silica gel using as eluent see the sea ethyl acetate/Meon.

Output: 660 mg MS (ES+): m/e=361.

(v) (1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid get by the method of example 5(iii)on the basis of 650,0 mg (1,80 mmol) (1-isopropylpiperazine-4-yl)amide of 4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid and 449,9 mg (1,80 mmol) of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide. Purification with flash chromatography on silica gel using as eluent a mixture of ethyl acetate/heptane gives a mixture of 9:1 (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid and (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-7-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acids. These isomers shared by RP-HPLC using a chiral stationary phase and a mixture of heptane, ethanol, methanol and diethylamine as solvent. Specified in the title compound is converted into its acetate, thus obtaining a colorless amorphous substance.

Output (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid is 500 mg, MS (ES+): m/e=529, range of chlorinated the O.

Example 109: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-ethoxyethoxy)-1H-benzoimidazol-2-carboxylic acid

(i) 1-(2-Ethoxyethoxy)-2,3-dinitrobenzene

1-(2-Ethoxyethoxy)-2,3-dinitrobenzene receive according to the method of example 108(i), starting from 500 mg (2,72 mmol) of 2,3-dinitrophenol and 0.72 ml (of 6.52 mmol) 1-chloro-2-ethoxyethane.

Yield: 450 mg MS (ES+): m/e=257.

(ii) 3-(2-Ethoxyethoxy)benzene-1,2-diamine

3-(2-Ethoxyethoxy)benzene-1,2-diamine receive according to the method of example 108(ii)on the basis of 450 mg (1,76 mmol) 1-(2-ethoxyethoxy)-2,3-dinitrobenzene.

Output: 345 mg MS (ES+): m/e=197.

(iii) 4-(2-Ethoxyethoxy)-2-trichloromethyl-1H-benzoimidazol

4-(2-Ethoxyethoxy)-2-trichloromethyl-1H-benzoimidazol receive according to the method of example 108(iii)on the basis of 345 mg (1,76 mmol) 3-(2-ethoxyethoxy)benzene-1,2-diamine and 0.30 ml (2,46 mmol) methyl ester 2,2,2-trichloroacetimidate acid.

Output: 568 mg MS (ES+): m/e=323, the spectrum of the chlorinated.

(iv) (1-Isopropylpiperazine-4-yl)amide of 4-(2-ethoxyethoxy)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide of 4-(2-ethoxyethoxy)-1H-benzoimidazol-2-carboxylic acid get by the method of example 108 (iv)on the basis of 569,6 mg (1,76 mmol) of 4-(2-ethoxyethoxy)-2-trichloromethyl-1H-benzoimidazole and 454,4 mg (2,11 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine.

Yield: 540 mg MS (ES+): m/e=375.

(v) (1-Isopropy the piperidine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-ethoxyethoxy)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-ethoxyethoxy)-1H-benzoimidazol-2-carboxylic acid get by the method of example 108 (v)on the basis of 540,0 mg (1.44 mmol) (1-isopropylpiperazine-4-yl)amide of 4-(2-ethoxyethoxy)-1H-benzoimidazol-2-carboxylic acid and 359,8 mg (1.44 mmol) of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide. Specified in the title compound is converted into its acetate, thus obtaining a colorless amorphous substance.

Output (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-ethoxyethoxy)-1H-benzoimidazol-2-carboxylic acid: 201 mg MS (ES+): m/e=543, range chlorinated.

Example 110: (1 Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-hydroxyethoxy)-1H-benzoimidazol-2-carboxylic acid

(i) tert-Butyl[2-(2,3-dinitrophenoxy)ethoxy]dimethylsilane

tert-Butyl[2-(2,3-dinitrophenoxy)ethoxy]dimethylsilane receive according to the method of example 108 (i), starting from 500 mg (2,72 mmol) of 2,3-dinitrophenol and 1.00 g (4,18 mmol) (2-bromoethoxy)-tert-butyldimethylsiloxy.

Yield: 610 mg) MS (ES+): m/e=343.

(ii) 3-[2-(tert-Butyldimethylsilyloxy)ethoxy]benzene-1,2-diamine

3-[2-(tert-Butyldimethylsilyloxy)ethoxy]benzene-1,2-diamine receive according to the method of example 108 (ii)on the basis of 610 mg (1.78 mmol) of tert-butyl[2-(2,3-dinitrophenoxy)ethoxy]dimethylsilane.

Output: 503 mg) MS (ES+): m/e=283.

(iii) 4-[2-tert-Butyldimethylsilyloxy)ethoxy]-2-trichloromethyl-1H-benzoimidazol

4-[2-tert-Butyldimethylsilyloxy)ethoxy]-2-trichloromethyl-1H-benzoimidazol receive according to the method of example 108 (iii)on the basis of 503 mg (1.78 mmol) of 3-[2-(tert-butyldimethylsilyloxy)ethoxy]benzene-1,2-diamine and 0.31 ml (2.49 mmol) of the methyl ester 2,2,2-trichloroacetimidate acid.

Output: 680 mg MS (ES+): m/e=409, the spectrum of the chlorinated.

(iv) (1-Isopropylpiperazine-4-yl)amide of 4-[2-(tert-butyldimethylsilyloxy)ethoxy]-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide of 4-[2-tert-butyldimethylsilyloxy)ethoxy]-1H-benzoimidazol-2-carboxylic acid get by the method of example 108 (iv), according to 680.0 mg (from 1.66 mmol) 4-[2-tert-butyldimethylsilyloxy)ethoxy]-2-trichloromethyl-1H-benzoimidazole and 428,4 mg (1,99 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine.

Yield: 670 mg MS (ES+): m/e=461.

(v) (1-Isopropylpiperazine-4-yl)amide of 4-[2-(tert-butyldimethylsilyloxy)ethoxy]-1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide of 4-[2-(tert-butyldimethylsilyloxy)ethoxy]-1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid get by the method of example 108 (v)on the basis of 670,0 mg (1,45 mmol) (1-isopropylpiperazine-4-yl)amide of 4-[2-(tert-butyldimethylsilyloxy)ethoxy]-1H-benzoyl Gasol-2-carboxylic acid and 362,8 mg (1,45 mmol) of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide. Final purification with flash chromatography on silica gel using ethyl acetate as eluent gives specified in the title compound as a brown oil.

Yield: 350 mg MS (ES+): m/e=629, range chlorinated.

(vi) (1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-hydroxyethoxy)-1H-benzoimidazol-2-carboxylic acid

250 mg (0.40 mmol) (1-isopropylpiperazine-4-yl)amide of 4-[2-(tert-butyldimethylsilyloxy)ethoxy]-1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid are dissolved in 15 ml of THF. Add 435 μl of 1M solution of TBAF in THF and added 26 μl of acetic acid. The resulting mixture is stirred for 48 h at K.T., the Reaction mixture was concentrated under reduced pressure. The residue is dissolved in 50 ml of CH2Cl2and washed once with saturated solution of NaHCO3and five times with water. The organic layer is dried over anhydrous MgSO4and concentrated in vacuo. Final purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) to give pure (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-hydroxyethoxy)-1H-benzoimidazol-2-carboxylic acid in the form of formate in the form of a colorless amorphous substance. Specified in the title compound is converted into its acetate.

Output: 132 mg MS (ES +): m/e=515, the spectrum of the chlorinated.

Example 111: Methyl ether of 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[2-fluoro-4-(pyrrolidin-1-carbonyl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid

(i) (3-Fluoro-4-nitrophenyl)pyrrolidin-1-ylmethanone

to 1.00 g (5.40 mmol) of 3-fluoro-4-nitrobenzoic acid are suspended in 55 ml of benzene. Add 1 ml of tinylolita and 7 drops of DMF. The resulting mixture is stirred for 5 h at 70°and then concentrate under reduced pressure. The residue is dissolved in 40 ml of CH2Cl2. Then add 75 ml (5.40 mmol) of triethylamine and 0.45 ml (540 mmol) of pyrrolidine and the resulting solution stirred for 1 h at K.T. Mixture is diluted with CH2Cl2and washed successively with 0.1 N. HCl solution, a saturated solution of NaHCO3and a saturated solution of salt. The organic layer is dried over anhydrous MgSO4and concentrate under vacuum, thus obtaining the crude (3-fluoro-4-nitrophenyl)pyrrolidin-1-ylmethanone as an orange solid.

Output: 1,35 g (ES+): m/e=239.

(ii) (4-Amino-3-forfinal)pyrrolidin-1-ylmethanone

515,0 mg (2,16 mmol) (3-fluoro-4-nitrophenyl)pyrrolidin-1 ylmethanone dissolved in 20 ml of Meon. The air from the flask with the solution pump and the flask with the contents rinsed several times with argon. Add 150 mg of palladium on coal (10%) and the flask with the mixture again pumped and blow n is the number of times with argon. Finally, the argon is replaced by hydrogen (balloon, filled with hydrogen and the mixture is stirred for 2 h at K.T., the Reaction mixture was filtered through celite and the filter residue is washed with 30 ml of the Meon. The filtrate was concentrated in vacuo, thus obtaining pure (4-amino-3-forfinal)pyrrolidin-1-ylmethanone in the form of a colorless oil.

Output: 448 mg (ES+): m/e=209.

(iii) Methyl ester 2-[2-fluoro-4-(pyrrolidin-1-carbonyl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid

59,0 mg (0.28 mol) of (4-amino-3-forfinal)pyrrolidin-1 ylmethanone dissolved in 6 ml of THF and 3 ml of water. Add 238,0 mg and 2.83 mmol) and NaHCO3. Finally, add to 75.6 mg (0.26 mmol) of the methyl ester of 2-trichloromethyl-1H-benzoimidazole-4-carboxylic acid and the resulting mixture vigorously stirred for 3 h at K.T. Mixture is diluted with CH2Cl2and washed with saturated solution of NaHCO3and a saturated solution of salt. The organic layer is dried over anhydrous MgSO4and concentrate under reduced pressure. Final purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives pure methyl ester 2-[2-fluoro-4-(pyrrolidin-1-carbonyl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid in the form of colorless amorphous solid.

Yield: 69 mg (ES+): m/e=411.

(iv) Methyl ester 1-[(5-chloropyridin-2-ylcarbonyl]-2-[2-fluoro-4-(pyrrolidin-1-carbonyl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid

Methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[2-fluoro-4-(pyrrolidin-1-carbonyl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid get by the method of example 36 (ii), based on 40,0 mg (0.10 mmol) of the methyl ester 2-[2-fluoro-4-(pyrrolidin-1-carbonyl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid and 29.2 mg (0.12 mmol) of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide. Final purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives pure methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[2-fluoro-4-(pyrrolidin-1-carbonyl)phenylcarbamoyl)-1H-benzoimidazol-4-carboxylic acid as a colorless amorphous solid.

Yield: 13 mg MS (ES+): m/e=579, range chlorinated.

Example 112: a) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid

b) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-3H-benzoimidazol-5-carboxylic acid

(i) 4-Amino-3-methyl-5-nitrobenzoic acid

4-Amino-3-methyl-5-nitrobenzoic acid is obtained as described Bolhofer et al. in U.S. patent 5369166.

(ii) Methyl ester of 4-amino-3-methyl-5-nitrobenzoic acid

500 mg (2,50 mmol) 4-amino-3-methyl-5-nitrobenzoic acid dissolved in a mixture of 8 ml of CH2Cl2and 2 ml of the Meon. P and 0° To add 1.3 ml of a 2M solution trimethylsilyldiazomethane in hexane. After incubation for 1 h at 0°the reaction mixture is allowed the opportunity to reach K.T. the next day, add 1.3 ml of 2M solution trimethylsilyldiazomethane in hexane. After stirring for 3 h at K.T. added dropwise a solution to 0.22 ml of acetic acid, 1.8 ml of CH2Cl2to destruction the excess trimethylsilyldiazomethane. The reaction mixture was concentrated under reduced pressure. The residue is treated with heptane and crystalline substance is filtered, thus obtaining the pure methyl ester of 4-amino-3-methyl-5-nitrobenzoic acid.

Output: 496 mg. MS (ES+): m/e=211.

(iii) Methyl ester of 3,4-diamino-5-methylbenzoic acid

Methyl ester of 3,4-diamino-5-methylbenzoic acid get by the method of example 11 (i)on the basis of 495,0 mg (2.36 mmol) of methyl ester of 4-amino-3-methyl-5-nitrobenzoic acid.

Output: 404 mg) MS (ES+): m/e=181.

(iv) Methyl ester 7-methyl-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid

Methyl ester 7-methyl-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid get by the method of example 5 (i)on the basis of 404,0 mg (2,20 mmol) of the methyl ester of 3,4-diamino-5-methylbenzoic acid and 0.39 ml (is 3.08 mmol) methyl ester 2,2,2-trichloroacetimidate acid.

Output: 869 mg) MS (ES+): m/e=307, the spectrum of CHL is proizvodnjo.

(v) Methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid

Methyl ester 2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid get by the method of example 93 (iv)on the basis of 685,0 mg (2,20 mmol) methyl ester 7-methyl-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid and 474,4 mg (2,20 mmol) of the dihydrochloride

1-cyclopropylidene-4-ylamine.

Output: 730 mg) MS (ES+): m/e=357.

(vi) (a) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid

b) 3-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-3H-benzoimidazol-5-carboxylic acid

1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid and 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-3H-benzoimidazol-5-carboxylic acid is obtained according to the method of example 81, on the basis of 200 mg high (0.56 mmol) of the methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid and 164, 8mm mg high (0.56 mmol) of 5-(5-chlorothiophene-2-yl)isoxazol-3-Eletropaulo ether methanesulfonate acid. Hydrolysis of the resulting esters processing LiOH and purification preparative RP-HPLC (gradient, see the si CH 3CN/H2O+0.05% of formic acid) gives specified in the connection header in the form of formate in the form of a white amorphous solids. Structural assignment of both isomers was achieved NOF-spectroscopy.

Output 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid is 7 mg; MS (ES+): m/e=540, range chlorinated.

Output 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-3H-benzoimidazol-5-carboxylic acid is 111 mg; MS (ES+): m/e=540, range chlorinated.

Example 113: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-fluoro-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

(i) Ethyl ester of 2,3-diamino-6-fermenting acid

Ethyl ester of 2,3-diamino-6-fermenting acid get by the method of example 11(i)on the basis of 200.0 mg (0.88 mmol) of ethyl ester of 2-amino-6-fluoro-3-nitrobenzoic acid.

Output: 157 mg) MS (ES+): m/e=229.

(ii) Ethyl ester 5-fluoro-2-trichloromethyl-1H-benzoimidazole-4-carboxylic acid

Ethyl ester of 5-fluoro-2-trichloromethyl-1H-benzoimidazole-4-carboxylic acid get by the method of example 5(i), based on 150,0 mg (from 0.76 mmol) of the ethyl ester of 2,3-diamino-6-fermenting acid and 133 μl (1.06 mmol) of the methyl ester 2,2,2-trichloroacetate the OIC acid.

Yield: 280 mg MS (ES+): m/e=325, the spectrum of the chlorinated.

(iii) Ethyl ester 5-fluoro-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

Ethyl ester of 5-fluoro-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid get by the method of example 93(iv)on the basis of 240,0 mg (0,74 mmol) ethyl ester 5-fluoro-2-trichloromethyl-1H-benzoimidazole-4-carboxylic acid and 158,6 mg (0,74 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine.

Output: 232 mg MS (ES+): m/e=377.

(iv) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-fluoro-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-fluoro-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid is obtained according to the method of example 81, on the basis of 230 mg (0,60 mmol) ethyl ester 5-fluoro-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid and 179,5 mg (0,60 mmol) 5-(5-chlorothiophene-2-yl)isoxazol-2-Eletropaulo ether methanesulfonate acid. Hydrolysis of the resulting ethyl ester processing LiOH and purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) gives specified in the title compound in the form of formate in the form of a white amorphous solid.

Yield: 87 mg MS (ES+): m/e=546, the spectrum of the chlorinated.

u> Example 114: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-4-carboxylic acid

(i) Ethyl ester of 2-amino-3-nitro-6-(2,2,2-trichloroethane)benzoic acid

420 mg of NaH (60% suspension in oil) are added to a solution of 2.16 ml (29,8 mmol) 2,2,2-treattramadol in 5 ml of THF. When gas evolution ceases, add 1.0 g (of 4.38 mmol) ethyl ester 2-amino-6-fluoro-3-nitrobenzoic acid. The resulting mixture was stirred at 0°C for 30 minutes and K.T. for an additional 30 minutes. To the mixture add 2 ml of 6M aqueous HCl and the main part of the solvent is removed under reduced pressure. The residue is mixed with 20 ml of water and the resulting solid is isolated and washed with water and then hexane. The yellow crystalline substance is dried under reduced pressure at 35°C.

Output: 1,22,

(ii) Ethyl ester of 2,3-diamino-6-(2,2,2-triptoreline)benzoic acid

Ethyl ester of 2,3-diamino-6-(2,2,2-triptoreline)benzoic acid get by the method of example 11(i)on the basis of 1.22 g (of 3.96 mmol) ethyl ester 2-amino-3-nitro-6-(2,2,2-triptoreline)benzoic acid.

Output: 1,07, MS (ES+): m/e=279.

(iii) Ethyl ester 2-trichloromethyl-5-(2,2,2-triptoreline)-1H-benzoimidazol-4-carboxylic acid

Ethyl ester of 2-trichloromethyl-5-(2,2,2-triptoreline)-1H-b is isoimidazole-4-carboxylic acid get by the method of example 5(i), on the basis of 200.0 mg (0,72 mmol) ethyl ester of 2,3-diamino-6-fermenting acid and 128 μl (1.01 mmol) of the methyl ester 2,2,2-trichloroacetimidate acid.

Yield: 340 mg MS (ES+): m/e=405, range chlorinated.

(iv) Ethyl ester 2-(1-isopropylpiperazine-4-ylcarbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-4-carboxylic acid

Ethyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-4-carboxylic acid get by the method of example 93(iv)on the basis of 290,0 mg (0,72 mmol) ethyl ester 2-trichloromethyl-5-(2,2,2-triptoreline)-1H-benzoimidazol-4-carboxylic acid and 153,8 mg (to 0.72 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine.

Output: 299 mg) MS (ES+): m/e=457.

(v) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-4-carboxylic acid

1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-4-carboxylic acid is obtained according to the method of example 81, on the basis of 299,0 mg (0.66 mmol) of ethyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-4-carboxylic acid and 192,4 mg (0.66 mmol) 5-(5-chlorothiophene-2-yl)isoxazol-3-Eletropaulo ether methanesulfonate acid. Hydrolysis of the resulting ethyl ester processing LiOH and Meon and cleaning preparative the Oh RP-HPLC (gradient mixture of CH 3CN/H2O+0.05% of formic acid) gives specified in the title compound in the form of formate in the form of a white amorphous solid.

Yield: 90 mg MS (ES+): m/e=626, the spectrum of the chlorinated.

Example 115: (1 Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-hydroxyazetidine-1-carbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-2-carboxylic acid

(1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-hydroxyazetidine-1-carbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-2-carboxylic acid get by the method of example 22, on the basis of 50.0 mg (0.08 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-4-carboxylic acid and 8.7 mg (0.12 mmol) of azetidin-3-ol. Specified in the title compound obtained as its formate in the form of a white amorphous solid.

Yield: 18 mg MS (ES+): m/e=681, range chlorinated.

Example 116: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-fluoro-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 117: 7-Chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic KIS the PTA

Specified in the title compound can be obtained by adapting the above-described methods.

Example 118: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-cyclopropyl-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 119: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-ethyl-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 120: 1-[3-(5-Chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 121: 1-[3-(5-Chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-fluoro-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 122: 7-Chloro-1-[3-(5-chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods is IKI.

Example 123: 1-[3-(5-Chlorothiophene-2-yl)isoxazol-5-ylmethyl]-7-cyclopropyl-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 124: 1-[3-(5-Chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-ethyl-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 125: 1-[5-(5-Chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 126: 1-[5-(5-Chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-fluoro-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 127: 7-Chloro-1-[5-(5-chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 128: 1-[5-(5-Chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene--ylcarbonyl)-7-ethyl-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 129: 1-[5-(5-Chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-7-cyclopropyl-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 130: 1-(6-Chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 131: 7-Chloro-1-(6-chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 132: 1-(6-Chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-cyclopropylidene-4-ylcarbonyl)-7-fluoro-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 133: 1-(6-Chlorobenzo[b]thiophene-2-ylmethyl)-7-cyclopropyl-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 134: 1-(chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-cyclopropylidene-4-ylcarbonyl)-7-ethyl-1H-benzoimidazol-5-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 135: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-4-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 136: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-fluoro-1H-benzoimidazol-4-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 137: 7-Chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 138: 1-[3-(5-Chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-4-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 139: 1-[3-(5-Chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-fluoro-1H-benzoimidazol-4-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 140: 7-Chloro-1-[3-(5-chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 141: 1-[5-(5-Chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-4-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 142: 7-Chloro-1-[5-(5-chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 143: 1-[5-(5-Chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-7-fluoro-1H-benzoimidazol-4-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 144: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-fluoro-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 145: 4-[(2-Hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-metil]-5-fluoro-1H-benzoimidazole-2,4-dicarboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 146: 4-Amide-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2,2,2-triptoreline)-1H-benzoimidazole-2,4-dicarboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 147: 4-[(2-Hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2,2,2-triptoreline)-1H-benzoimidazole-2,4-dicarboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 148: 4-Dimethylamide-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2,2,2-triptoreline)-1H-benzoimidazole-2,4-dicarboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 149: 2-[(1-Isopropylpiperazine-4-yl)amide]-4-(methylpropanamide) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2,2,2-triptoreline)-1H-benzoimidazole-2,4-dicarboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 150: 4-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-fluoro-7-methyl-1H-benzoni the azole-2,4-dicarboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 151: (1 Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-fluoro-4-(3-hydroxyazetidine-1-carbonyl)-7-methyl-1H-benzoimidazol-2-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 152: 4-[(2-Hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-5-fluoro-7-methyl-1H-benzoimidazole-2,4-dicarboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 153: (1 Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-5-fluoro-4-(3-hydroxyazetidine-1-carbonyl)-7-methyl-1H-benzoimidazol-2-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 154: (1 Isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-(2-hydroxyethoxy)-1H-benzoimidazol-2-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 155: (1 Isopropylpiperazine-4-yl)amide 1-(6-chlorobenzo[b]thiophene-2-ylmethyl)-4-(2-hydroxyethoxy)-1H-benzoimidazol-2-carboxylic acid

Specified in sagola the COC connection can be obtained by adapting the above-described methods.

Example 156: (1 Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-thieno[3,4-d]imidazole-2-carboxylic acid

Specified in the title compound can be obtained by adapting the above-described methods.

Example 157: Benzylated 5-chloro-1H-benzoimidazol-2-carboxylic acid

The solution to 120.0 mg (0.45 mmol) of 5-chloro-2-trichloromethyl-1H-benzoimidazole in 2 ml of tetrahydrofuran (THF) is added slowly to a mixture of 53.5 μl (0.49 mmol) of benzylamine and 373,8 mg (of 4.45 mmol, 10 EQ.) NaHCO3in 8 ml of THF and 4 ml of water. The reaction mixture was stirred for 2 h at K.T. (20°to 25°With, in the future K.T.). The suspension is filtered and the filtrate concentrated under reduced pressure. After purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) net benzylated 5-chloro-1H-benzoimidazol-2-carboxylic acid obtained as a white amorphous solid.

Yield: 84 mg MS (ES+): m/e=286, range chlorinated.

Example 158: Methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid

A solution of 3.99 g (to 13.6 mmol) methyl ester 2-trichloromethyl-1H-benzoimidazole-4-carboxylic acid in 40 ml THF is added slowly to a mixture of 2.9 g (to 13.6 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine and 13.7 g (0,163 mol, 12 equivalents)NaHCO 3in 200 ml of THF and 120 ml of water. The reaction mixture was stirred for 2 h at K.T. THF is distilled off. The resulting aqueous suspension was diluted with 200 ml of CH2Cl2and extracted with twice 150 ml of water. The organic layer is concentrated under reduced pressure and the resulting residue purified flash chromatography on silica gel using a mixture of ethyl acetate/methanol (4:1) as eluent. Specified in the title compound obtained as a light brown crystalline substance.

Output: 3,20, MS (ES+): m/e=345.

Example 159: Methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

To the mixture 7,53 g (to 35.3 mmol) of the dihydrochloride of 1-cyclopropylidene-4-ylamine and 32,39 g (0,386 mol NaHCO3in 1300 ml of THF and 370 ml of water, add the solution to 11.79 g (32.1 mmol) of methyl ester of 2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid in 360 ml of THF. The reaction mixture was vigorously stirred for 2 h at K.T. THF is evaporated. The precipitate is filtered off and treated twice about 300 ml of a saturated solution of NaHCO3in ultrasonic conditions. After filtration of the resulting solid is washed twice with 150 ml of water and dried under reduced pressure at 45°thus the methyl ester of 2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid in the Orme light brown crystalline substance.

Output: 9,9 g (90%). MS (ES+): m/e=343.

Example 160: Diisopropylamide 5-chloro-1H-benzoimidazol-2-carboxylic acid

A solution of 500.0 mg (of 1.85 mmol) 5-chloro-2-trichloromethyl-1H-benzoimidazole in 20 ml of THF is added slowly to a mixture of 286 ml (2.04 mmol) of Diisopropylamine and 1.55 g (18.5 mmol, 10 equivalents) NaHCO3in 70 ml of THF and 20 ml of water. The reaction mixture was stirred for 2 h at K.T. Organic solvent is evaporated. The resulting crystalline precipitate is filtered off and treated once approximately 50 ml of a saturated solution of NaHCO3in ultrasonic conditions. The crystalline residue is again filtered off and washed twice with 20 ml water. Drying under reduced pressure at 35°network net diisopropylamide 5-chloro-1H-benzoimidazol-2-carboxylic acid in the form of a light brown crystalline solid.

Output: 321 mg) MS (ES+): m/e=280, range chlorinated.

Example 161: (5-Chloro-1H-benzoimidazol-2-yl)morpholine-4-ylmethanol

(5-Chloro-1H-benzoimidazol-2-yl)morpholine-4-ylmethanol receive according to the method of example 157, according to 120.0 mg (0.45 mmol) of 5-chloro-2-trichloromethyl-1H-benzoimidazole and 42.6 μl (0.49 mmol) of the research. Specified in the title compound is isolated in the form of colorless amorphous solid.

Yield: 95 mg (80%). MS (ES+): m/e=266, the spectrum of the chlorinated.

Example 162: (4-Methyl who piperazin-1-yl)amide 5-chloro-1H-benzoimidazol-2-carboxylic acid

(4-Methylpiperazin-1-yl)amide 5-chloro-1H-benzoimidazol-2-carboxylic acid get by the method of example 157, according to 120.0 mg (0.45 mmol) of 5-chloro-2-trichloromethyl-1H-benzoimidazole and 58.9 μl (0.49 mmol) of 4-methylpiperazin-1-ylamine. Specified in the title compound is isolated in the form of colorless amorphous solid.

Yield: 89 mg MS (ES+): m/e=294, range chlorinated.

Example 163: (4-Cyanophenyl)amide 5-chloro-1H-benzoimidazol-2-carboxylic acid

(4-Cyanophenyl)amide 5-chloro-1H-benzoimidazol-2-carboxylic acid get by the method of example 160, on the basis of 500.0 mg (of 1.85 mmol) 5-chloro-2-trichloromethyl-1H-benzoimidazole and 229,8 mg (1,95 mmol) of 4-aminobenzonitrile. Specified in the title compound is isolated in the form of a light brown crystalline solid.

Output: 475 mg (86%). MS (ES+): m/e=297, range chlorinated.

Example 164: Methyl ester of 2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid

Methyl ester 2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid get by the method of example 160, based on 1,32 g (4,49 mmol) methyl ester 2-trichloromethyl-1H-benzoimidazole-4-carboxylic acid and 950,0 mg (4,94 mmol) of 4-(4-AMINOPHENYL)morpholine-3-one. Specified in the title compound is isolated in the form of a light brown crystalline solid.

In the move: 1,44 mg (81%). MS (ES+): m/e=395.

Example 165: Methyl ester 2-[2-Fluoro-4-(pyrrolidin-1-carbonyl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid

59,0 mg (0.28 mmol) of (4-amino-3-forfinal)pyrrolidin-1 ylmethanone dissolved in 6 ml of THF and 3 ml of water. Add 238,0 mg and 2.83 mmol) and NaHCO3. Finally, add to 75.6 mg (0.26 mmol) of the methyl ester of 2-trichloromethyl-1H-benzoimidazole-4-carboxylic acid and the resulting mixture vigorously stirred for 3 h at K.T. Mixture is diluted with 25 ml of CH2Cl2and washed with saturated solution of NaHCO3and a saturated solution of salt. The organic layer is dried over anhydrous MgSO4and concentrate under reduced pressure. After purification preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid) pure methyl ester 2-[2-Fluoro-4-(pyrrolidin-1-carbonyl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid in the form of colorless amorphous solid.

Yield: 69 mg (65%). MS (ES+): m/e=411.

Example 166: Isoquinoline-4-alamid 5-chloro-1H-benzoimidazol-2-carboxylic acid

Isoquinoline-4-alamid 5-chloro-1H-benzoimidazol-2-carboxylic acid get by the method of example 160, on the basis of 100.0 mg (from 0.37 mmol) 5-chloro-2-trichloromethyl-1H-benzoimidazole and 56.1 mg (0,39 mmol) of isoquinoline-4-ylamine. Specified in the title compound is isolated in the form of a light brown crystal is practical solid.

Yield: 113 mg (94%). MS (ES+): m/e=323, the spectrum of the chlorinated.

Example 167: Methyl ester of 2-[(5-chloro-1H-benzoimidazol-2-carbonyl)amino]-3-nitrobenzoic acid

Methyl ester 2-[(5-chloro-1H-benzoimidazol-2-carbonyl)amino]-3-nitrobenzoic acid get by the method of example 160, on the basis of 200.0 mg (0,74 mmol) 5-chloro-2-trichloromethyl-1H-benzoimidazole and 152,6 mg (0.78 mmol) of the methyl ester 2-amino-3-nitrobenzoic acid. Specified in the title compound is isolated in the form of a yellow crystalline solid.

Output: 218 mg (79%).

Example 168: Methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-thieno[3,4-d]imidazole-4-carboxylic acid

Methyl ester 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-thieno[3,4-d]imidazole-4-carboxylic acid get by the method of example 158, based on 1,74 g (5,80 mmol) methyl ester 2-trichloromethyl-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 1.25 g (5,80 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine. Specified in the title compound is isolated in the form of a light brown solid.

Yield: 1.75 g (86%). MS (ES+): m/e=351.

Example 169: 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid

21,0 mg (0,098 mmol) dihydrochloride (1-cyclopropyl)piperidine-4-ylamine dissolved in 3 ml of CH3CN and 3 ml of water. Add recipients who have to 82.3 mg (0.98 mmol, 10 equivalents) NaHCO3. Then add a solution of 48.1 mg (0,098 mmol) of methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid in 2 ml of CH3CN and the resulting mixture vigorously stirred for 3 hours at the boil under reflux. The mixture is concentrated under reduced pressure. The residue is purified preparative RP-HPLC (gradient mixture of CH3CN/H2O+0.05% of formic acid)to give the pure 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid in the form of colorless amorphous solid. (Under these conditions simultaneously hydrolyzing methyl ether).

Yield: 26 mg (50%). MS (ES+): m/e=526, the spectrum of the chlorinated.

Pharmacological test

The ability of the compounds of formula I to inhibit factor Xa or factor VIIa, or other enzymes such as thrombin, plasmin, or trypsin, can be analyzed by determining the concentration of the compounds of formula I that inhibits enzyme activity by 50%, i.e. the IC50 value, which correlates with the inhibition constant Ki. In chromogenic assays used purified enzymes. The concentration of inhibitor which causes 50% reduction in the rate of hydrolysis of the substrate was determined by linear regression after applying the gr is fixed relative velocities of hydrolysis (compared to eingeborenen control) depending on the log concentration of the compound of formula I. To calculate the inhibition constants Ki were introduced IC50 value for amendments to the competition with the substrate using the formula

Ki=IC50/{1+(the substrate concentration/Km)},

where Km is a constant Michaelis-Menten (publications Chen and Prusoff, Biochem. Pharmacol. 22 (1973) 3099-3108; I.H. Segal, Enzyme Kinetics, 1975, John Wiley & Sons, New York, 100-125; which are incorporated in this description by reference).

A) analysis of the factor Ha

In the analysis to determine the inhibition of the activity of factor XA was used buffer TBS-PEG (50 mm Tris-HCl, pH of 7.8, 200 mm NaCl, 0,05% (wt./about.) PEG-8000, 0,02% (wt./about.) NaN3). IC50 was determined by mixing in suitable holes half square tiralongo Costar microplate 25 ál of factor XA person (Enzyme Research Laboratories, Inc.; South Bend, Indiana) in TBS-PEG; 40 ál of 10% (vol./about.) DMSO in TBS-PEG (neighbourly control) or various concentrations of the test compounds, dissolved in 10% (vol./about.) DMSO in TBS-PEG and substrate S-2765 (N(α)-benzyloxycarbonyl-D-Arg-Gly-L-Arg-p-nitroanilide; Kabi Pharmacia, Inc.; Franklin, Ohio) in TBS-PEG. The analysis was carried out preliminary incubation of the compounds of formula I plus enzyme for 10 minutes Then the analysis was initiated by addition of substrate to obtain a final volume of 100 μl. The initial rate of hydrolysis of a chromogenic substrate was measured by the change in absorption at 405 nm using a BiO-Tek, kinetic spectrophotometer for PR is reading tablets (Ceres UV900HDi) at 25° With on interval linear dependence on time (usually 1.5 min after substrate addition). The concentration of the enzyme was 0.5 nm and the substrate concentration was 140 μm.

b) Analysis of factor VIIa

Inhibitory activity relative to the activity of factor VIIa/tissue factor was determined using a chromogenic analysis carried out essentially as described previously (publication J.A. Ostem et al., Biochemistry 37 (1998) 1053-1059, which is incorporated herein by reference). Kinetic analyses were carried out at 25°With half square titration microplate (Costar Corp., Cambridge, Massachusetts) using a kinetic spectrophotometer for reading tablets (Molecular Devices Spectramax 250). A typical mixture for analysis consists of 25 μl of factor VIIa person and TF (5 nm and 10 nm, the corresponding final concentration) combined with 40 μl of the product of the dilution of the inhibitor in a mixture of 10% DMSO/buffer TBS-PEG (50 mm Tris, 15 mm NaCl, 5 mm CaCl2, 0.05% PEG 8000, pH 8,15). After a 15 minute period prior incubation analysis initiated by the addition of 35 μl of chromogenic substrate S-2288 (D-Ile-Pro-Arg-p-nitroanilide, Pharmacia Hepar Inc., the final concentration of 500 μm). The results of the inhibition constants Ki (FXa) inhibition of factor XA) are shown in table 1.

Table 1
ExampleKi(FX)

[µm]
ExampleKi(FXa

[µm]
ExampleKi(FXa)

[µm]
10,000729b0,011568A)0,070
20,0031300,009068b)0,226
30,0014310,0155690,015
40,0592320,0105700,015
5A0,002533of 0.0125710,007
5b0,1750340,019572of 0.0125
60,0030350,041730,019
70,0165360,0315740,0105
90,0940370,012750,0026
101,357390,047760,0085
11a0,004400,020770,0525
11b0,00141 0,006780,0035
120,0030420,462790,001
130,2990430,840800,007
142,3900440,028A)0,558
150,0115450,210A)0,064
160,0110480,002910,021
17A0,0195490,015920,0225
17b0,3710500,141940,0245
180,0225510,51096A)0,0305
190,0235520,014100A)0,005
200,0085530,0401020,0025
210,0310540,031103A)0,022
220,000755of 1.30 μm103b)0,0885
230,0080570,5851040,020
240,0260600,0351050,0545
250,0650610,867A)0,022
260,0185620,019106b)0,188
27of 0.0125630,6871080,0065
280,0480640,0021090,0035
29A0,0255650,1211100,004
660,003A)0,0008

1. The compound of the formula I

in which R0represents a

1) monocyclic 6-14-membered aryl, where aryl is mono-, di - or triamese independently of each R8,

2) heterocyclyl from the group benzothiazolyl, indazole, pyridyl where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8or

3) monocyclic 4 to 15-membered Goethe is iillil, containing two or three heteroatoms selected from nitrogen, sulfur or oxygen, where indicated heterocyclyl is unsubstituted or substituted monocyclic 4 to 15-membered heterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur or oxygen, where heterocyclyl is unsubstituted or monogamist R8;

R8is a halogen;

provided that R8represents at least one halogen atom, if R0represents a monocyclic 6-14-membered aryl;

substructure

in the formula I represents a 4-8 membered saturated, partially unsaturated or aromatic cyclic group containing 0, 1 heteroatom selected from nitrogen or sulfur and is unsubstituted or substituted 1, 2, 3 times R3;

Q represents -(C0-C2)alkylen-C(O)NR10-, methylene;

R1represents a hydrogen atom, -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times R13;

R2represents a direct bond;

R1-N-R2-V can form a 4-to 8-membered cyclic group, selected from the group of the piperazine or piperidine;

R14represents halogen, =O, -(C1-C8)Ala is l, -CN;

V represents

1) 6-14-membered aryl, where aryl is unsubstituted or mono-, di - or triamese independently of each R14or

2) heterocyclyl from group 8-azabicyclo[3.2.1]Oct-3-yl, izochinolina, piperidinyl where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R14;

G represents a direct link,

-(CH2)m-NR10where m is 0 and R10is hydrogen,

-(CH2)m-C(O)-(CH2)n-where m is 0 or 1, and n is About,

-(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 represents

1) a hydrogen atom,

2) 6-14-membered aryl,

3) monocyclic 4 to 15-membered heterocyclyl where heterocyclyl is unsubstituted or mono-, disamament independently of each R14,

4) -(C3-C8)cycloalkyl where specified cycloalkyl is unsubstituted,

5) 3-7-membered cyclic residue, containing 1 or 2 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic residue is unsubstituted or mono-, disamament independently of each R14where R14matter of the criminal code is mentioned above;

R3represents a

1) a hydrogen atom,

2) a halogen atom,

3) -(C1-C4)alkyl, where alkyl is unsubstituted,

4) -(C0-C4)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13or

c) -CF3,

5) -SOs-R11where s is 1 or 2,

6) -(C0-C4)alkylen-C(O)-R11,

7) -(C0-C4)alkylen-C(O)-O-R11,

8) -(C0-C4)alkylen-C(O)-N(R11)-R12,

9) -C(O)-O-C(R15,R16)-O-C(O)-O-R17,

10) -(C0-C4)alkylene-(C4-C15)heterocyclyl where heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R13;

R11and R12are independently of one another identical or different and represent

1) a hydrogen atom,

2) -(C1-C6)alkyl, where the alkyl is unsubstituted or monogamist R13,

3) -(C0-C6)alkyl-(C3-C8)cycloalkyl,

4) -(C0-C6)alkyl-(C6-C14)-aryl, where alkyl and aryl independently from each other are illegal is displaced,

5) -O-R17or

6) -(C0-C6)alkyl-(C4-C15)heterocyclyl, where the alkyl and heterocyclyl, independently of one another, are unsubstituted or monogamist R13or

R11and R12together with the nitrogen atom to which they are linked, may form a 4-8-membered monocyclic heterocyclic ring which in addition to the nitrogen atom can contain one or two identical or different heteroatoms in the ring selected from oxygen, sulfur and nitrogen; where the specified heterocyclic ring is unsubstituted or mono-, tizamidine independently of each R13;

R13represents halogen, =O, -OH, -CF3-(C3-C8)cycloalkyl -(C0-C3)alkylen-O-R10;

R10represents hydrogen, -(C1-C6)alkyl;

R15and R16represent, independently from each other hydrogen, -(C1-C6)alkyl;

R17represents -(C1-C6)alkyl, -(C3-C8)cycloalkyl;

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerated salts.

2. The compound of the formula according to claim 1, in which

R0represents a

1) monocyclic 6-14 membered aryl group phenyl, where the aryl is mono-, the and - or triamese independently of each R 8,

2) heterocyclyl from the group benzothiazolyl, indazole, pyridyl where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8or

3) heterocyclyl where heterocyclyl selected from the group 4,5-dihydroquinoline, dioxazine, dioxazine, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 6N-1,5,2-detainee, furazane, imidazolidinyl, imidazolyl, imidazolyl, isothiazoline, isothiazolinone, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, morpholine, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, piperazinil, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, pyrimidinyl, 1,4,5,6-tetrahydropyridine, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2-teinila, 1,3-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, tatania, thiomorpholine, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,

where specified heterocyclyl is unsubstituted or additionally substituted by heterocyclyl, select the major from the group azepine, azetidine, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, imidazolidinyl, imidazolyl, imidazolyl, isothiazoline, isothiazolinone, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, morpholine, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, piperazinil, piperidinyl, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrroline 2N-pyrrolyl, pyrrolyl, tetrahydrofuranyl, 1,4,5,6-tetrahydropyridine, tetrahydropyridine, tetrahydrothiophene, 1,2-teinila, 1,3-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, teinila, tatania, thiomorpholine, thiophenolate, thiophenyl, dipiradol where heterocyclyl is unsubstituted or monogamist independently of each R8,

R8represents halogen,

provided that R8represents at least one halogen atom, if R0represents a monocyclic 6-14-membered aryl;

substructure D is a residue selected from the group of azetidine, asatina, asokan, cyclobutyl, cyclooctane, cyclooctene, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, piperidine, Hairdryer is La, of pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, Tatana, Ciocana, thiophene, thiopyran, and is unsubstituted or substituted by 1,2, 3 times R3,

Q represents -(C0-C2)alkylen-C(O)NR10-, methylene;

R1represents a hydrogen atom, -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times R13;

R2represents a direct bond,

R1-N-R2-V can form a 4-to 8-membered cyclic group selected from piperazine or piperidine;

R14represents fluorine, chlorine, bromine, iodine, =O, -(C1-C8)alkyl, -CN;

V represents

1) 6-14 membered aryl group phenyl, where the aryl is mono-, di - or triamese independently of each R14,

2) heterocyclyl from group 8-azabicyclo[3.2.1]Oct-3-yl, izochinolina, piperidinyl where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R14,

G represents a direct link,

-(CH2)m-NR10where m is 0 and R10is 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 javljaetsja, 1 or 2,

-(CH2)m-where t is 1;

M represents

1) a hydrogen atom,

2) 6-14-membered aryl,

3) monocyclic 4 to 15-membered heterocyclyl where heterocyclyl is unsubstituted or mono-, disamament independently of each R14,

4) -(C3-C8)cycloalkyl where specified cycloalkyl is unsubstituted,

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)alkyl, where alkyl is unsubstituted,

4) -(C0-C4)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13or

c) -CF3,

5) -SOs-R11where s is 1 or 2,

6) -(C0-C4)alkylen-C(O)-R11,

7) -(C0-C4)alkylen-C(O)-O-R11,

8) -(C0-C4)alkylen-C(O)-N(R11)-R12,

9) -C(O)-O-C(R15,R16)-O-C(O)-O-R17,

10) -(C0-C4)alkylene-(C4-C15)heterocyclyl where heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R13,

R11and R12are independent the one from another identical or different and represent

1) a hydrogen atom,

2) -(C1-C6)alkyl, where the alkyl is unsubstituted or monogamist R13,

3) -(C0-C6)alkyl-(C3-C8)cycloalkyl,

4) -(C0-C6)alkyl-(C6-C14)-aryl, where alkyl and aryl independently from one another are unsubstituted,

5) -O-R17or

6) -(C0-C6)alkyl-(C4-C15)heterocyclyl, where the alkyl and heterocyclyl, independently of one another, are unsubstituted or monogamist R13or

R11and R12together with the nitrogen atom to which they are linked, form a heterocyclic ring from the group of azepine, azetidine, dioxazine, dioxazine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, [1,4]oxazepan, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, thiophene, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where the aforementioned heterocyclic ring is unsubstituted or is it, tizamidine independently of each R13,

R13represents halogen, =O, -OH, -CF3-(C3-C8)cycloalkyl -(C0-C3)alkylen-O-R10;

R10represents hydrogen, -(C1-C6)alkyl;

R15and R16represent, independently from each other hydrogen, -(C1-C6)alkyl;

R17represents -(C1-C6)alkyl, -(C3-C8)cycloalkyl,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerated salts.

3. The compound of formula I according to claims 1 and 2,

where R0represents a

1) monocyclic 6-14 membered aryl group phenyl, where the aryl is mono-, di - or triamese independently of each R8,

2) heterocyclyl from the group benzothiazolyl, indazole, pyridyl where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8or

3) heterocyclyl from a group of imidazolyl, isothiazoline, isoxazole, oxazoline, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, thiadiazolyl, thiazolyl,

which is optionally substituted by heterocyclyl selected from the group of azepine, azetidine, 4,5-dihydroquinoline, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, imide is olidine, imidazoline, imidazole, isothiazole, isothiazoline, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, morpholine, 1,2-oxathiane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, piperazinil, piperidinyl, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrroline 2N-pyrrolyl, pyrrolyl, tetrahydrofuranyl, 1,4,5,6-tetrahydropyridine, tetrahydropyridine, tetrahydrothiophene, 1,2-teinila, 1,3-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, teinila, tatania, thiomorpholine, thiophenyl, dipiradol where heterocyclyl is unsubstituted or monogamist R8,

R8represents a fluorine, chlorine or bromine,

provided that R represents at least one halogen, if R0is a 6-14-membered aryl;

substructure D is a residue selected from the group of phenyl, pyridyl, pyrrolyl, tatania or thiophenyl and unsubstituted or substituted 1, 2, 3 times R3;

Q represents -(C0-C2)alkylen-C(O)NR10-, methylene;

R1represents a hydrogen atom, -(C1-C4)alkyl, where alkyl is what I'm unsubstituted or substituted one to three times R 13;

R2represents a direct bond,

R1-N-R2-V form a 4-8-membered cyclic group selected from piperazine or piperidine;

R14represents fluorine, chlorine, bromine, iodine, =O, -(C1-C8)alkyl, -CN;

V represents

1) heterocyclyl from group 8-azabicyclo[3.2.1]Oct-3-yl, izochinolina, piperidine, where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R14or

2) phenyl, where phenyl (aryl is unsubstituted or mono-, di - or triamese independently of each R14,

G represents a direct link,

-(CH2)m-NR10, m is 0 and R10is 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 represents

1) a hydrogen atom,

2) phenyl,

3) heterocyclyl where heterocyclyl is the remainder of the group, which may be selected from azepine, azepine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, isothiazole, isoxazol, isoxazolidine, 2-isoxazoline, metamorphosen, ket is piperazine, the research, oxazole, [1,4]oxazepan, piperazine, piperazinone, piperidine, piperidine, pyrazine, pyridazine, pyridazine, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydropyridine, tetrazine, tetrazole, thiadiazole, thiazole, thiophene, thiomorpholine, 1λ,6-thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where specified heterocyclyl is unsubstituted or mono - or Disaese independently of each R14or

4) -(C3-C8)cycloalkyl where specified cycloalkyl is unsubstituted,

R3represents a

1) a hydrogen atom,

2) a halogen atom,

3) -(C1-C4)alkyl, where alkyl is unsubstituted,

4) -(C0-C4)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13or

c) -CF3,

5) -SOs-Rnwhere s is 1 or 2,

6) -(C0-C4)alkylen-C(O)-R11,

7) -(C0-C4)alkylen-C(O)-O-R11,

8) -(C0-C4)alkylen-C(O)-N(R11)-R12,

9) -C(O)-O-C(R15,R16)-O-C(O)-O-R17,

11and R12are independently of one another identical or different and represent

1) a hydrogen atom,

2) -(C1-C6)alkyl, where the alkyl is unsubstituted or monogamist R13,

3) -(C0-C6)alkyl-(C6-C14)-aryl, where alkyl and aryl are independently from each other unsubstituted,

4) -O-R17or

5) -(C0-C6)alkyl-(C4-C15)heterocyclyl, where the alkyl and heterocyclyl independently of one another are unsubstituted or monogamist R13or

R11and R12together with the nitrogen atom to which they are bound, may form a ring selected from the group of azepine, azetidine, 1,4-diazepine, dioxazine, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, [1,4]oxazepan, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, that is unsubstituted or mono-, d is substituted independently from each other R 13,

R13represents fluorine, chlorine, bromine, iodine, =O, -OH, -CF3, -(C0-C3)alkylen-O-R10,

R10represents hydrogen, -(C1-C6)alkyl,

R15and R16represent, independently from each other hydrogen, -(C1-C6)alkyl; and

R17represents -(C1-C6)alkyl, -(C3-C8)cycloalkyl,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerated salts.

4. The compound according to claim 1,

where R0represents a

1) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R8,

2) heterocyclyl from the group benzothiazolyl, indazole, pyridyl where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8or

3) heterocyclyl from a group of imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazoline, triazolyl, pyridazinyl and pyrazinyl where specified heterocyclyl is unsubstituted or additionally substituted by a residue selected from the group of pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, teinila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazolyl, from cazalilla, thiazolyl, isothiazoline, pyridazinyl and pyrazinyl, where the specified residue is unsubstituted or mono-, di - or triamese independently of each R8,

R8represents F, Cl, Br or I,

provided that R8represents at least one halogen atom, if R0represents a monocyclic 6-14-membered aryl;

substructure D is a residue selected from the group of phenyl, pyridyl, pyrrolyl, tanila or thiophenyl, and is unsubstituted or substituted 1, 2, 3 times R3,

Q represents a methylene, -(C0-C2)alkylen-C(O)-NR10-,

R1represents a hydrogen atom, -(C1-C2)alkyl,

R2represents a direct bond,

R1-N-R2-V can form a 4-to 8-membered cyclic group out of the group of the piperidine or piperazine,

R14represents fluorine, chlorine, =O, -(C1-C8)alkyl, -CN,

V represents

1) cyclic residue from the group consisting of compounds that are selected from 8-azabicyclo[3.2.1]Oct-3-yl, piperidine, where the specified cyclic residue is unsubstituted or mono-, di - or triamese independently of each R14or

2) phenyl, where phenyl is unsubstituted or mono-, di - or t is izlesen independently of each R 14or

G represents a direct link,

-(CH2)m-where m is an integer 1,

-(CH2)mNR10-, m is an integer 0 and R10is hydrogen,

M represents

1) a hydrogen atom,

2) heterocyclyl where heterocyclyl is the remainder of the group, which may be selected from azepine, azepine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, isothiazole, isoxazol, isoxazolidine, 2-isoxazoline, metamorphosen, cefoperazone, research, oxazole, [1,4]oxazepan, piperazine, piperazinone, piperidine, piperidine, pyrazine, pyridazine, pyridazine, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydropyridine, thiadiazole, thiazole, thiomorpholine, 1λ6-thiomorpholine, thiophene, tetrazine, tetrazole, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where specified heterocyclyl is unsubstituted or mono-, disamament independently of each R14,

3) -(C3-C6)cycloalkyl;

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)alkyl, where alkyl is unsubstituted,

4) -(C0-C4)alkylen-O-R19where R19represents the FDS is th

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13or

c) -CF3or

5) -SOs-R11where s is 1 or 2,

6) -(C0-C4)alkylen-C(O)-R11,

7) -(C0-C4)alkylen-C(O)-O-R11,

8) -(C0-C4)alkylen-C(O)-N(R11)-R12,

9) -C(O)-O-C(R15,R16)-O-C(O)-R17,

R11and R12together with the nitrogen atom to which they are bound, may form a ring selected from the group of azepine, azetidine, 1,4-diazepine, dioxazine, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, [1,4]oxazepan, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, thiophene, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where the specified ring is unsubstituted or mono-, tizamidine independently of each R13,

R13the submitted is a fluorine, chlorine, =O, -OH, -CF3-(C0-C3)alkylen-O-R10,

R10represents hydrogen, -(C1-C6)alkyl,

R15and R16represent, independently from each other hydrogen, -(C1-C6)alkyl;

R17represents -(C1-C6)alkyl, -(C3-C8)cycloalkyl,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerated salts.

5. The compound of formula I according to claim 1,

where R0represents a

1) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R8,

2) heterocyclyl selected from the group indazole, benzothiazole, pyridyl where specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8,

3) heterocyclyl from a group of imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazoline, triazolyl, pyridazinyl and pyrazinyl where specified heterocyclyl is unsubstituted or additionally substituted by a residue selected from the group of pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, teinila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, pyridate the silt and pyrazinyl, where the specified residue is unsubstituted or monogamist R8,

R8represents F, Cl, Br, I,

provided that R8represents at least one halogen, if R0represents aryl, which has the values listed above,

substructure D is a residue selected from the group of phenyl, pyridyl, pyrrolyl or thiophenyl, and is unsubstituted or substituted 1, 2, 3 or 4 times R3,

Q represents a methylene or -(C0-C2)alkylen-C(O)-NR10-,

R1represents a hydrogen atom or -(C1-C2)alkyl,

R2represents a direct bond;

R1-N-R2-V can form a 4-7-membered cyclic group out of the group of the piperidine or piperazine,

R14represents fluorine, chlorine, -(C1-C4)alkyl;

V represents

1) cyclic residue from the group consisting of compounds that are selected from 8-azabicyclo[3.2.1]Oct-3-yl, isoquinoline, piperidine, where the specified cyclic residue is unsubstituted or mono-, di - or triamese independently of each R14or

2) phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of each R14,

G represents the nternet connection,

-(CH2)m-where m is an integer 1,

-(CH2)m-NR10-, m is an integer 0 and R10is hydrogen,

M represents

1) a hydrogen atom,

2) heterocyclyl where heterocyclyl is a residue that can be selected from the group 1,4-diazepan, metamorphosen, thiophene, pyridazine, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, pyridinyl, imidazole, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, cefoperazone, oxazole, isoxazol, isoxazolidine, 2-isoxazoline, research, thiazole, isothiazole, tetrahydropyran, 1,4,5,6-tetrahydropyrimidine, 1λ6-thiomorpholine, thiadiazole or thiomorpholine where specified heterocyclyl is unsubstituted or mono-, disamament independently of each R14,

3) -(C3-C6)cycloalkyl,

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)alkyl, where alkyl is unsubstituted,

4) -(C0-C4)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - and triamese independently of each R 13or

c) -CF3or

5) -SOs-R11where s is 1 or 2,

6) -(C0-C4)alkylen-C(O)-R11,

7) -(C0-C4)alkylen-C(O)-R11,

8) -(C0-C4)alkylen-C(O)-O-R11,

9) -C(O)-O-C(R15,R16)-O-C(O)-R17,

R11and R12are independently of one another identical or different and represent

1) a hydrogen atom,

2) -(C1-C4)alkyl, where the alkyl is unsubstituted or monogamist R13,

3) -(C0-C6)alkyl-(C3-C6)cycloalkyl,

4) -O-R17or

5) -(C0-C6)alkyl-(C4-C15)heterocyclyl, where the alkyl and heterocyclyl independently of one another are unsubstituted or monogamist R13and where heterocyclyl selected from the group of azetidine, cyclopropyl, cyclobutyl, 4,5-dihydrooxazolo, imidazolidine, research, [1,4]-oxazepan, oxazolidine, piperidine, piperazine, pyrrolidine, tetrahydrothiophene, thiazolidine or thiomorpholine, or

R11and R12together with the nitrogen atom to which they are linked, form a heterocyclic ring which is selected from the group of azetidine, cyclopropyl, cyclobutyl, 4,5-dihydrooxazolo, imidazolidine, research, [1,4]-oxazepan, oxazolidine, piperidine, PIP is Razin, pyrrolidine, tetrahydrothiophene, thiazolidine or thiomorpholine, where the specified ring is unsubstituted or mono-, tizamidine R13,

R13represents fluorine, =O, -OH, -CF3-(C3-C6)cycloalkyl -(C0-C3)alkylen-O-R10-,

R10represents hydrogen, -(C1-C4)alkyl,

R15and R16represent hydrogen, -(C1-C4)alkyl,

R17represents -(C1-C6)alkyl,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerated salts.

6. The compound of formula I according to claim 1,

where R0represents a

1) phenyl, where phenyl is unsubstituted or mono - or Disaese independently of each R8,

2) pyridyl, where pyridyl is unsubstituted or mono - or Disaese independently of each R8or

3) heterocyclyl from the group thiadiazolyl, isoxazolyl and thiazolyl where specified heterocyclyl substituted by a residue selected from the group of tanila, 2 - tanila and 3-tanila, where the specified residue is unsubstituted or monosubstituted R8,

R8represents F, Cl, Br;

substructure D is a residue selected from the group of phenyl, pyridyl, pyrrolyl, Tien is La, thiophene and is unsubstituted or substituted 1, 2, 3 times R3,

Q represents-CH2-C(O)-NH-, methylene,

R1represents a hydrogen atom,

R2represents a direct bond,

R1-N-R2-V can form a 4-to 8-membered cyclic group, selected from piperidine and piperazine,

R14represents fluorine, chlorine, methyl, ethyl, =O,

V represents

1) residue selected from the group including 8-Aza-bicyclo[3.2.1]Oct-3-yl, isoquinoline, piperidine, where the specified cyclic residue is unsubstituted or mono - or Disaese independently of each R14or

2) phenyl, where phenyl is unsubstituted or mono - or Disaese independently of each R14,

G represents a direct link,

-(CH2)mwhere m is an integer 1,

-(CH2)m-NR10, m is an integer 0 and R10is hydrogen,

M represents a hydrogen atom, azepane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, geomorphology, morpholinyl, [1,4]oxazepan, piperazinil, piperidinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolidinyl, 1,4,5,6-tetrahydropyrimidine, 1λ6-thiomorpholine or tetrahydropyranyl, geostate are unsubstituted or mono - or tizamidine independently of each R 14,

R3represents a

1) a hydrogen atom,

2) fluorine, chlorine,

3) -(C1-C4)alkyl, where alkyl is unsubstituted,

4) -(C0-C2)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13or

c) -CF3or

5) -SOs-R11where s is 1 or 2,

6) -(C0-C4)alkylen-C(O)-R11,

7) -(C0-C4)alkylen-C(O)-O-R11,

8) -(C0-C4)alkylen-C(O)-N(R11)-R12,

9) -C(O)-O-C(R15,R16)-O-C(O)-O-R17,

R11and R12are, independently of one another, identical or different and represent

1) a hydrogen atom,

2) -(C1-C4)alkyl, where the alkyl is unsubstituted or monogamist R13or

3) -O-R17or

4) -(C0-C6)alkyl-(C4-C15)heterocyclyl, where the alkyl and heterocyclyl independently of one another are unsubstituted or monogamist R13and where heterocyclyl selected from the group of azetidine, imidazolidine, research, [1,4]oxazepan or pyrrolidine, or

R11and R12along with the atom and the PTA, with which they are linked, can form a ring which is selected from the group of azetidine, imidazolidine, research, [1,4]oxazepan, piperazine, piperidine, pyrrolidine or thiomorpholine, where the specified ring is unsubstituted or mono-, tizamidine R13,

R13represents fluorine, =O, -OH, -CF3-(C3-C6)cycloalkyl or -(C0-C3)alkylen-O-R10,

R10represents hydrogen, -(C1-C4)alkyl,

R15and R16represent, independently from each other hydrogen, -(C1-C4)alkyl, and

R17represents -(C1-C6)alkyl,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically tolerated salts.

7. The compound of formula I according to claim 1,

where R0represents a

1) phenyl, where phenyl is unsubstituted or mono - or Disaese independently of each R8,

2) pyridyl, where pyridyl is unsubstituted or mono - or Disaese independently of each R8or

3) heterocyclyl from the group thiadiazolyl, isoxazolyl and thiazolyl where specified heterocyclyl substituted by a residue selected from the group of tanila, 2-tanila and 3-tanila, where the specified residue is unsubstituted or mono - or Disaese independently researched the mo from each other, R 8,

R8represents Cl,

substructure D is a residue selected from the group of phenyl, pyridyl, thiophenyl, tanila and is unsubstituted or substituted 1, 2, 3 times R3,

Q represents-CH2-C(O)-NH -, or a methylene,

R1represents a hydrogen atom,

R2represents a direct bond,

R14represents fluorine or =O,

V represents piperidinyl or phenyl, where phenyl is unsubstituted or mono - or Disaese independently of each R14,

G represents a direct bond or-C(O)-,

M represents a hydrogen atom, cyclopropyl, morpholinyl, piperazinil, piperidinyl, pyrazinyl, pyridyl, pyrimidyl, pyrrolidinyl or 1λ6-thiomorpholine, where the residues are unsubstituted or mono - or tizamidine independently of each R14,

R3represents a

1) a hydrogen atom,

2) fluorine, chlorine,

3) -(C1-C4)alkyl, where alkyl is unsubstituted,

4) -(C0-C2)alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of each R13or

c) -CF 3,

5)-SO2-R11,

6) -(C0-C4)alkylen-C(O)-O-R11,

7) -(C0-C4)alkylen-C(O)-N(R11)-R12,

or

8) -C(O)-O-C(R15,R16)-O-C(O)-O-R17,

R11and R12are, independently of one another, identical or different and represent

1) a hydrogen atom,

2) -(C1-C4)alkyl, where the alkyl is unsubstituted or monogamist independently of each R13or

3) -(C0-C6)alkyl-(C3-C6)cycloalkyl, or

R11and R12together with the nitrogen atom to which they are bound, may form a ring which is selected from the group of azetidine, research, [1,4]-oxazepan or piperidine, where the specified ring is unsubstituted or monogamist R13,

R13represents fluorine, =O, -OH, -CF3-(C3-C6)cycloalkyl or -(C0-C3)alkylen-O-R10,

R10represents a hydrogen atom or -(C1-C4)alkyl,

R15and R16represent, independently from each other, hydrogen atom or -(C1-C4)alkyl and

R17represents -(C1-C6)alkyl,

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically the portable ski salt.

8. The compound of formula I according to claim 1, where the compound of formula I is a

1) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

2) (1-isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-1H-benzoimidazol-2-carboxylic acid,

3) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

4) (1-pyrimidine-4-reparacin-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

5) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

6) methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

7) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

8) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

9) methyl ester 1-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

10) methyl ester of 3-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropylpiperazine is n-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

11) 1-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropyl-piperidine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

12) 3-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-2-(1-isopropyl-piperidine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

13) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

14) methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid,

15) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

16) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid,

17) (1-isopropylpiperazine-4-yl)amide 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid,

18) methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

19) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

20) methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic to the slots,

21) methyl ether 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

22) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

23) 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

24) 1-ethoxycarbonylmethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

25) 1-cyclohexyloxycarbonyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

26) 4-[(2-hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide]1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazole-2,4-dicarboxylic acid,

27) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

28) 4-[(2-hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazole-2,4-dicarboxylic acid,

29) 5-[(2-hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazole-2,5-dick is Borovoy acid,

30) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

31) 1-ethoxycarbonylmethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

32) 1-cyclohexyloxycarbonyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

33) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid,

34) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-6-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid,

35) 4-[(2-hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,4-dicarboxylic acid,

36) 4-[(2-hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,4-dicarboxylic acid,

37) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

38) 1-ethoxycarbonylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-is isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

39) 1-cyclohexyloxycarbonyloxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

40) [4-(3-exmortis-4-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

41) methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid,

42) [4-(4-oxo-4H-pyridin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

43) [4-(4-oxo-4H-pyridin-1-yl)phenyl]amide 1-(3-methoxybenzyl)-1H-benzoimidazol-2-carboxylic acid,

44) [4-(4-oxo-4H-pyridin-1-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

45) (8-methyl-8-azabicyclo[3.2.1]Oct-3-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

46) [4-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

47) [4-(2-oxoacridine-3-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

48) [4-(2-oxoacridine-3-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

49) [4-(2,4-dioxo-3,4-di is Idro-2H-pyrimidine-1-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

50) [4-(4-oxopiperidin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

51) [4-(1,1-dioxo-1λ6-thiomorpholine-4-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzimidazole-2-carboxylic acid,

52) [4-(1,1-dioxo-1λ6-thiomorpholine-4-yl)phenyl]amide 1-[(5-chloropyridin-2-yl)carbarnoyl)methyl]-1H-benzimidazole-2-carboxylic acid,

53) [4-(2-oxo-2H-pyrazin-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

54) [4-(2-oxo-2H-pyrazin-1-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

55) [4-(2-oxo-2H-piperazine-1-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-benzoimidazol-2-carboxylic acid,

56) [4-(2-oxo-2H-piperazine-1-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazol-2-carboxylic acid,

57) [4-(3-exmortis-4-yl)phenyl]amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid,

58) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid,

59) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

60) (1-isopropyl shall piperidin-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

61) 5-[(2-hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,5-dicarboxylic acid,

62) 5-[(2-hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide]3-[(5-chloropyridin-2-ylcarbonyl)methyl]-3H-benzoimidazole-2,5-dicarboxylic acid,

63) 5-[(2-hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-benzoimidazole-2,5-dicarboxylic acid,

64) 5-[(2-hydroxyethyl)methylamide]-2-[(1-isopropylpiperazine-4-yl)amide] 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-3H-biyokimyasal-2,5-dicarboxylic acid,

65) 1-cyclohexyloxycarbonyloxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

66) 1-cyclohexyloxycarbonyloxy ester of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

67) 1-ethoxycarbonylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

68) 1-ethoxycarbonylmethyl ester of 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

69) 2-hydroxyethyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-metil]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

70) 2-hydroxyethyloxy ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

71) carboxymethylate ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

72) 1-(3-methoxybenzyl)-2-[4-(3-exmortis-4-yl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid,

73) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid,

74) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-(2-hydroxyethanesulfonic)-1H-benzoimidazol-2-carboxylic acid,

75) cyclopropylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

76) 2-methoxyethoxy ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

77) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-hydroxymethyl-1H-benzoimidazol-2-carboxylic acid,

78) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-carboxylic acid,

79) (1-isopropylpiperazine-4-yl)amide 1[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(morpholine-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

80) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-([1,4]oxazepan-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

81) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2,6-dimethylpiperidin-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

82) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(4,4-deformability-1-carbonyl)-1H-benzimidazole-2-carboxylic acid,

83) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-([1,4]oxazepan-4-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

84) 2-hydroxyethyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

85) carboxymethylate ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

86) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-methoxyisatin-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

87) 2-(1-isopropylpiperazine-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-4-carboxylic acid,

88) 2-(1-isopropylpiperazine-4-ylcarbonyl)-3-(3-methoxybenzyl)-3H-benzoimidazol-4-carboxylic acid,

89) 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-icarb mail)-1H-benzoimidazol-4-carboxylic acid,

90) 3-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid,

91) (1-isopropylpiperazine-4-yl)amide of 4-(3-hydroxyazetidine-1-carbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-2-carboxylic acid,

92) (1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-(3-hydroxyazetidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

93) (1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-(3-methoxyisatin-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

94) methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1-(3-methoxybenzyl)-1H-benzoimidazol-5-carboxylic acid,

95) methyl ester of 2-(1-isopropylpiperazine-4-carbarnoyl)-3-(3-methoxybenzyl)-3H-benzoimidazol-5-carboxylic acid,

96) methyl ester 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

97) methyl ester of 3-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

98) 1-[2-(4-chlorophenyl)ethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

99) 1-(5-chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

100) 3-(5-chlorobenzo[b]thiophene-2-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-3H-benzoimidazol the-4-carboxylic acid,

101) 1-(5-chloro-1H-indazol-3-ylmethyl)-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

102) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(4-hydroxypiperidine-1-carbonyl)-1H-benzoimidazol-2-carboxylic acid,

103) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

104) methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

105) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

106) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

107) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidine-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

108) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidine-4-ylcarbonyl)-3H-benzoimidazol-4-carboxylic acid,

109) methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzoimidazol-4-carboxylic acid,

110) 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropyl-piperidine-4-ylcarbamate is)-1H-benzoimidazol-4-carboxylic acid,

111) cyclopropylmethyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-cyclopropylidene-4-ylcarbonyl)-1H-benzimidazole-4-carboxylic acid,

112) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid,

113) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid,

114) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid,

115) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid,

116) 6-[(2-hydroxyethyl)amide]-2-[(1-isopropylpiperazine-4-yl)amide] 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3H-thieno[3,4-d]imidazol-2,6-dicarboxylic acid,

117) 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropyl-piperidine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid,

118) 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-(1-isopropyl-piperidine-4-ylcarbonyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid,

119) (1-isopropylpiperazine-4-yl)amide 3-[(5-chloropyridin-2-ylcarbonyl)methyl]-6-([1,4]oxazepan-4-carbonyl)-3H-thieno[3,4-d]imidazole-2-carboxylic acid,

120) methyl ester of 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ileti the]-2-(1-isopropylpiperazine-4-ylcarbonyl)-6-(2,2,2-triptoreline)-3H-thieno[3,4-d]imidazole-4-carboxylic acid,

121) 1-[3-(5-chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropyl-piperidine-4-ylcarbonyl)-1H-benzimidazole-5-carboxylic acid,

122) 3-[3-(5-chlorothiophene-2-yl)isoxazol-5-ylmethyl]-2-(1-cyclopropyl-piperidine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

123) 1-[5-(5-chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclo-propylpiperidine-4-ylcarbonyl)-1H-benzoimidazol-5-carboxylic acid,

124) 3-[5-(5-chlorothiophene-2-yl)[1,3,4]thiadiazole-2-ylmethyl]-2-(1-cyclo-propylpiperidine-4-ylcarbonyl)-3H-benzoimidazol-5-carboxylic acid,

125) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-methoxyethoxy)-1H-benzoimidazol-2-carboxylic acid,

126) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-ethoxyethoxy)-1H-benzoimidazol-2-carboxylic acid,

127) (1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-4-(2-hydroxyethoxy)-1H-benzoimidazol-2-carboxylic acid,

128) methyl ester 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-2-[2-fluoro-4-(pyrrolidin-1-carbonyl)phenylcarbamoyl]-1H-benzoimidazol-4-carboxylic acid,

129) 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidine-4-ylcarbonyl)-7-methyl-1H-benzoimidazol-5-carboxylic acid,

130) 3-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidine-4-icarbon who yl)-7-methyl-3H-benzoimidazol-5-carboxylic acid,

or

131) (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-(3-hydroxyazetidine-1-carbonyl)-5-(2,2,2-triptoreline)-1H-benzoimidazol-2-carboxylic acid.

9. Pharmaceutical preparation containing at least one compound of formula I according to one or more of claims 1 to 8, in all its stereoisomeric forms and mixtures in any ratio and/or its physiologically tolerated salts and pharmaceutically acceptable carrier, which is a reversible inhibitor of the enzyme factor XA and/or factor VIIa coagulation.

10. The use of the compounds of formula I according to one or more of claims 1 to 8, in all its stereoisomeric forms and mixtures in any ratio and/or its physiologically-tolerated salts to obtain pharmaceuticals for inhibition of factor XA and/or factor VIIa and for influencing blood coagulation or fibrinolysis.

11. The use of claim 10 for cases of abnormal formation of thrombus, acute myocardial infarction, cardio-vascular disorders, unstable angina, thromboembolism, acute vessel occlusion associated with thrombolytic therapy or subcutaneous transluminal surgery vessels (RTSA), transient cerebral attacks, stroke, intermittent claudication, vascular bypass grafting of the coronary or peripheral and the clear, luminale stenosis, restenosis after plastic surgery on the coronary or venous vessels, maintaining access to the opened condition of the vessel in continuous hemodialysis patients, pathologic blood clots in the veins of the lower extremities after surgery in the abdominal cavity, the knee or the hip, the risk of pulmonary thromboembolism, or disseminated systemic intravascular coagulation occurring in vascular systems during septic shock, viral infections or cancer, or attenuation of the inflammatory response, fibrinolysis, or treatment of coronary heart disease, myocardial infarction, angina pectoris, restenosis of blood vessels, for example, restenosis after plastic surgery on vessels, this RTSA, respiratory distress syndrome in adults, multiple failure and disseminated intravascular coagulation disorders, deep vein thrombosis and thrombosis of superficial veins, which can occur after surgery.

12. The method of obtaining the compounds of formula IV

in which R21represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times R13,

c) -(C0With 4)alkylglycerol where heteroaryl is a monocyclic 4 to 15-membered heterocyclyl containing one heteroatom selected from nitrogen, sulfur or oxygen, and mono-, disamament independently of each R8,

d) -(C1-C4)alkylglycerol where heterocyclyl is a monocyclic 4 to 15-membered heterocyclyl containing one, two, heteroatoms selected from nitrogen, sulfur or oxygen, where indicated heterocyclyl is unsubstituted or mono-, disamament independently of each R8or optionally substituted monocyclic 4 to 15-membered heterocyclyl containing one or two heteroatoms selected from nitrogen or oxygen, where heterocyclyl is unsubstituted or mono-, disamament independently of each R8,

where R8and R13have the meanings indicated in claim 1 for compounds of formula I,

R22represents a

(a) a hydrogen atom,

b) -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times R13,

c) -(C0-C4)alkylglycerol where heteroaryl is a monocyclic or bicyclic 4 to 15-membered heterocyclyl containing one or two heteroatoms selected from nitrogen, and mono - or Disaese independently of each R8,

d) -(C0-C4)alkylglycerol, DG is heterocyclyl is a monocyclic 4 to 15-membered heterocyclyl, containing one or two heteroatoms selected from nitrogen, where the specified heterocyclyl is unsubstituted or mono-, di - or triamese independently of each R8or optionally substituted monocyclic 4 to 15-membered heterocyclyl containing one or two heteroatoms selected from nitrogen or oxygen, where heterocyclyl is unsubstituted or mono-, disamament independently of each R8,

f) R2-V-G-M,

where R2, R8, R13, V, G and M have the meanings indicated in claim 1 for compounds of formula I, or substructure R21-N-R2-V in the formula IV may form a 4-8-membered cyclic group, containing 1, 2 heteroatoms selected from nitrogen, where the specified cyclic group is unsubstituted or mono-, di - or tizamidine independently of each R14where the remainder R14matter specified in claim 1 for compounds of formula I,

R23represents a hydrogen atom,

and substructure in the formula IV

represents a 4-to 8-membered saturated or aromatic cyclic group containing 0, 1 heteroatom selected from nitrogen and sulfur and is unsubstituted or substituted 1, 2, 3 times R3where R3matter specified in claim 1 for compounds of formula I,

which includes inter the step the compounds of formula V

where R has the meanings specified for formula IV, and substructure

in the formula V has the values specified for formula IV, with a primary amine, where the primary amine selected from the group

a) NH2-R21where R21has the values specified for formula IV, or

b) NH2-R2-V-G-M, where R2, V, G and M have the meanings specified for formula IV,

or secondary amine, the secondary amine selected from the group

a) connection

where R21and R22have the meanings specified for formula IV, or

b) compounds of the formula VII

where R21, R2, V, G and M have the meanings specified for formula IV,

provided that R21is not 8-azabicyclo[3.2.1]octane, or

provided that R21-N-R2-V does not form a piperazine residue, or [1,4]diazepan,

in the presence of water, at least one base and at least one miscible with water, an organic solvent, where it is mixed with water, an organic solvent selected from the group of tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, dimethyl sulfoxide, dioxane, N,N-dimethylformamide, N-methylp is rolidone, acetone or sulfolane.

13. The method of obtaining the compounds of formula IV indicated in paragraph 12, where the base is a carbonate of an alkali metal, sodium bicarbonate, potassium bicarbonate, tertiary amine, triethylamine or diisopropylethylamine.

14. The method of obtaining the compounds of formula IV indicated in paragraph 12, where the amount used is mixed with water to solvent is from 5 to 300 g per 1 g of compound of formula V, preferably from 10 to 200,

15. The method of obtaining the compounds of formula IV indicated in paragraph 12, where the reaction temperature is from 5 to 120°C, preferably from 10 to 35°With, in particular 25°C.

16. The method of obtaining the compounds of formula IX

in which x is the integer 1,

R24identical to R21whose values are specified for formula IV in item 12, and

R22has the values specified for formula IV,

including the interaction of the compounds of formula X

where substructure

in the formula X has the meanings specified for formula IV, with a primary amine, where the primary amine selected from the group

a) NH2-N(R21)-R22where R21and R22have the meanings specified for formula IV, or

b) compounds of the formula VI

where R2, R21, V, G and M have the meanings specified for formula IV, or

secondary amine, where the secondary amine is a compound of formula VIII

where R2, R21, R24, V, G and M have the meanings specified for formula IV,

in the presence of water, at least one base and at least one miscible with water, an organic solvent, where it is mixed with water, an organic solvent selected from the group of tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, dimethyl sulfoxide, dioxane, N,N-dimethylformamide, N-methylpyrrolidone, acetone or sulfolane.

17. The method of obtaining the compounds of formula IX according to clause 16, where the base is a carbonate of an alkali metal, sodium bicarbonate, potassium bicarbonate, tertiary amine, triethylamine or diisopropylethylamine.

18. The method of obtaining the compounds of formula IX according to clause 16, where the amount used is mixed with water to organic solvent is from 5 to 300 g per 1 g of compound of formula V, preferably from 10 to 200,

19. The method of obtaining the compounds of formula IX according to clause 16, where the reaction temperature is from 5 to 120°C, preferably from 10 to 35°With, in particular 25°C.



 

Same patents:

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: invention relates to 2,2'-di(3,4-alkylenedioxythiophene)s of general formula (I) , where A, R and x have given in description values, which are intended for obtaining electroconducting or semiconducting compounds and valuable semi-products for π-conjugated polymers. Also described is method of their obtaining and method of obtaining poly(3,4-alkylenedioxythophene)s based on them. Claimed method allows to obtain novel 2,2'-di(3,4-alkylenedioxythiophene)s by simplified techniques and extend possibilities of their application.

EFFECT: obtaining agents by simplified techniques and extension of possibilities of their application.

12 cl, 4 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to novel azaheterocycles of general formula 1.1-13 and 2, as well as their pharmaceutically acceptable salts, which possess anti-carcinogenic activity, pharmaceutical composition with their application and combinatorial and focused libraries including novel azaheterocycles. In general formulae 1.1-1.3 and 2.

.

For compounds 1.1-1.3 each of R1a R2a independently on each other represent possibly substituted C1-C6alkyl; each of R1d, R2d, R3d, R4d, R5d, R6d and R7d independently on each other represent substitutes of cyclic system, preferably hydrogen atom, or for compounds 1.1 and 1.3 independently R1d and R2d, R3d and R4d, R5d and R6d together with atoms with which they are bound can form through R1d and R2d, R3d and R4d, R5d and R6d respectively, possibly substituted aromatic cycle, such as benzole, 5-6-member heterocycle which includes, at least, one of heteroatoms, selected from S; or for compounds 1.2 independently R1d and R2d, R3d and R4d, R4d and R5d, R6d and R7d together with atoms with which they are bound can form through R1d and R2d, R3d and R4d, R4d and R5d, R6d and R7d respectively, possibly substituted aromatic cycle, such as benzole, 5-6-member heterocycle which includes, at least, one of heteroatoms, selected from S; for compound 2 R1a represents amino group substitute, excluding hydrogen atom, such as possibly substituted C1-C6alkyl, possibly substituted phenyl; R2a represents possibly substituted C1-C6alkyl; R3a represents amino group substitute, such as hydrogen atom, possibly substituted C1-C6alkyl; Rnd represents one or two substitutes of cyclic system, preferably hydrogen atom, solid line with accompanying it dotted line represent single or double bond.

EFFECT: obtaining novel azaheterocycles and their pharmaceutically acceptable salts, which possess anti-carcinogenic activity.

9 cl, 4 dwg, 3 tbl, 7 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining 4-amino-3-quinolinecarbonitryl, which includes: a) combining aminocompound with cyanoacetic acid and acid catalyst obtaining cyanoacetomide; b) condensing cyanoacetomide from stage a with aniline, alcohol solvent and trialkylorthoformiate obtaining 3-amino-2-cyanoakrylamide; and c) combining 3-amino-2-cyanoakrylamide with phosphorus oxychloride in acetonitryl, butyronitrile, toluol or xylol, optionally in presence of catalyst, obtaining 4-amino-3-quinolinecarbonitryl. Also described is method (version) of obtaining 4-amino-3-quinolinecarbonitryl, method of obtaining 7-aminothieno[3,2-b]pyridine-6-carbonitrile and method of obtaining cyanoacetamide.

EFFECT: creation of efficient method of obtaining 4-amino-3-quinolinecarbonitryl.

24 cl, 50 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new annelated asaheterocycles include pyrimidine fragment of general formula I in the form of free bases or pharmaceutically acceptable salts. Compounds of this invention possess properties of PI3 kinase inhibitors. In general formula I X represents oxygen atom or sulphur atom; Z represents oxygen atom, R1 represents hydrogen atom or optionally substituted C1-C6alkyl, or Z represents nitrogen atom together with bound carbon atom forming through Z and R1 optionally substituted annelated imidazoline cycle; R2 represents optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, possibly annelated with 5-6-term heterocyclyl containing heteroatoms chosen from oxygen and nitrogen, optionally substituted 5-6-term heterocyclyl containing heteroatoms chosen from nitrogen, oxygen and/or sulphur, possibly annelated with phenyl ring. Invention also concerns method of production of compounds, pharmaceutical compositions and medical products.

EFFECT: effective application for preparation of medical products for oncologic therapy.

14 cl, 3 dwg, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new derivatives of hydrochloride 8-amino-7-(2-hydroxypropyl-1)-1,3-dimethylxanthine of general formula: where . Compounds under this invention display haemorheological activity surpassing that of common pentoxifylline compound. Compounds represent hydrochloride 1,3-dimethy-7-(2-hydroxy-3- piperidinopropyl-1)-8-phenylaminoxanthine or hydrochloride 1,3- dimethy-7-[2-hydroxy-3-(2- chlorophenoxy)-propyl-1]-8- piperazinoxanthine.

EFFECT: production of compounds displaying haemorheological activity.

4 cl, 2 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to application as ligands of 5-NT6 receptor azaheterocyclic compositions of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and/or hydrates , where R2 and R3 independently represent substitute of amides chosen from hydrogen; substituted carbonyl; substituted aminocarbonyl; substituted aminothiocarbonyl; substituted sulphonyl; C1-C5-alkyl, optionally substituted with C6-C10-aryl, optionally substituted with heterocyclil, C6-C10-arylaminocarbonyl, C6-C10- arylaminothiocarbonyl, C5-C10-azaheteroaryl, optionally substituted with carboxyl, nitrile group; optionally substituted with aryl; R1k are 1 to 3 independent substitutes to cyclic system chosen from hydrogen, optionally substituted C1-C5-alkyl, C1-C5-alkyloxy, C1-C5-alkenyl, C1-C5- alkenyl, halogen, trifluoromathyl, nitrile, carboxyl, optionally substituted heterocyclil, substituted sulphonyl, optionally substituted carboxyl; dashed line with accompanying continuous line () corresponds to single or double bond; n=1.2 or 3. Invention also concerns a pharmaceutical formulation, production method and tabletted, capsulated or injection medical product in pharmaceutically acceptable package.

EFFECT: agent has improved efficiency.

17 cl, 8 tbl, 5 ex, 1 dwg

The invention relates to new chemical substances suitable for use as medicaments, in particular to the xanthine derivative of General formula I

R3where R1and R2lower alkyl;

R3the rest of the group, including tetrahydrofurane, thiophene, dithiolane, dithienyl, furan, optionally substituted by a group: -CH2OH, CHO, COOH,

-CH=where Alk denotes alkyl with 1-4 carbon atoms,

-CH=CH-CO-NO,

-CONHN-CH< / BR>
-CH=C< / BR>
-CH=C< / BR>
-CONH-(CH2)2N(Alk)2where Alk has the specified value, tetrahydrofuran, optionally substituted lower alkyl or the group-CH2CH2-CO-NO, or furan or thiophene, substituted lower alkyl or nitro-group or the unsubstituted cycloalkyl with 6-8 carbon atoms, cycloalkane or ticlea, alseny of Gruppman2,N,NH-phenyl, whereby phenyl may be substituted,NOH, -OCONH-phenyl, and phenyl may be samisens-COOCH3, -CH2COOCH3, -CH2CH2NH2, -OC(C6H5)3, -OALK, where Alk has the specified value, ОСОR4where R4matter: the rest campanulas acid, lower alkyl, phenyl, substituted lower alkoxyl, phenyl, methoxymethyl, six-membered nitrogen-containing heterocycle; cyclohexane, substituted cyanomethylene or oxyalkyl1-C4or hydroxy-group, or cyclopentane, substituted lower alkyl or phenyl, which may have as a second Deputy in genialnom position relative to the first hydroxyl group or ketal formula

or R3residue selected from the group:

(CH2)1,2< / BR>
ororin VI

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: description is given of a lactam-containing compound-derivative of tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide with formula I , its pharmaceutical salt and pharmaceutical compositions, their content, and their use as Xa factor inhibitors. The given compound can be used for treating thromboembolic diseases.

EFFECT: obtaining a lactam-containing compound, which can be used for treating thromobembolic diseases.

42 cl, 9 tbl, 140 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to novel azaheterocycles of general formula 1.1-13 and 2, as well as their pharmaceutically acceptable salts, which possess anti-carcinogenic activity, pharmaceutical composition with their application and combinatorial and focused libraries including novel azaheterocycles. In general formulae 1.1-1.3 and 2.

.

For compounds 1.1-1.3 each of R1a R2a independently on each other represent possibly substituted C1-C6alkyl; each of R1d, R2d, R3d, R4d, R5d, R6d and R7d independently on each other represent substitutes of cyclic system, preferably hydrogen atom, or for compounds 1.1 and 1.3 independently R1d and R2d, R3d and R4d, R5d and R6d together with atoms with which they are bound can form through R1d and R2d, R3d and R4d, R5d and R6d respectively, possibly substituted aromatic cycle, such as benzole, 5-6-member heterocycle which includes, at least, one of heteroatoms, selected from S; or for compounds 1.2 independently R1d and R2d, R3d and R4d, R4d and R5d, R6d and R7d together with atoms with which they are bound can form through R1d and R2d, R3d and R4d, R4d and R5d, R6d and R7d respectively, possibly substituted aromatic cycle, such as benzole, 5-6-member heterocycle which includes, at least, one of heteroatoms, selected from S; for compound 2 R1a represents amino group substitute, excluding hydrogen atom, such as possibly substituted C1-C6alkyl, possibly substituted phenyl; R2a represents possibly substituted C1-C6alkyl; R3a represents amino group substitute, such as hydrogen atom, possibly substituted C1-C6alkyl; Rnd represents one or two substitutes of cyclic system, preferably hydrogen atom, solid line with accompanying it dotted line represent single or double bond.

EFFECT: obtaining novel azaheterocycles and their pharmaceutically acceptable salts, which possess anti-carcinogenic activity.

9 cl, 4 dwg, 3 tbl, 7 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of pyridine [2,3-d] pyrimidine of general formula (I) and their pharmaceutically acceptable salts, which possess properties of KDR and FGFR inhibitors. Compounds can be applied to produce medications for treatment of cancer, for instance, of mammary gland, large intestine, lungs and prostate gland. In general formula (I) , Ar and Ar' independently on each other are selected from group that includes phenyl; phenyl substituted with 1-3 substituents selected from group C1-C4alkyl, hydroxy, halogen, halogen-substituted C1-C4alkyl, C1-C4alkoxy; 6-member nitrogen-containing heteroaryl and 6-member nitrogen-containing heteroaryl substituted with C1-C4alkoxygroup, on condition that Ar standing for heteroaryl does not represent 2-pyridyl, and standing for substituted heteroaryl does not represent substituted 2-pyridyl, R1 is selected from group including phenyl, C1-C10alkyl, C1-C10alkyl independently containing substituents selected from group that includes phenyl, C3-C6cycloalkyl. Invention also relates to intermediate compounds for compounds of general formula (I) and to pharmaceutical compositions.

EFFECT: obtaining derivatives and their pharmaceutically acceptable salts which possess properties of selective KDR and FGFR inhibitors.

21 cl, 2 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: described is obtaining and pharmaceutical application of substituted derivatives of arylalkane acid of formula I , where ring A, ring B, R1, R2, R3, R4, R5, X, Alk1, Alk2, Ar1 and Ar2 are such as determined in said description. Said compounds, as selective agonists activating (RAPPs) receptors, activated by peroximal proliferator, in particular, RXRs/RAPPs-alfa, RXRs/RAPPs-gamma and RXRs/RAPPs-delta heterodimers, are applied in treatment and/or prevention of type 2 diabetes and connected with it metabolic syndrome, such as hypertension, obesity, insulin-resistence, hyperlipidemia, hyperglycemia, hyperolesterinemia, artheriaslerosis, coronary artery disease, and other cardio-vascular disorders, and possess improved profile of side effects, connected with common RAPPs-gamma agonists.

EFFECT: obtaining compunds, which possess improved profile of side effects, connected with common RAPPs-gamma agonists.

22 cl, 38 ex, 2 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: novel compounds are selected from group, consisting of: 4-(2-cyclopropyl-ethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-(2-hydroxymethyl-cyclopropylmethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopentylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-chlorine-4-(3-methyl- 4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-(2-cyclopropyl-ethyl)-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-fluorine-4-(3-methyl-4,10-dihudro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 2-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4;9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-ethyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 2-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide and 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-methoxy-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-benzylamide. Invention also relates to pharmaceutical composition and to application of compounds of general formula 1.

EFFECT: obtaining novel biologically active compounds and based on them pharmaceutical composition, possessing antagonistic activity with respect to vasopressin receptors.

60 cl, 153 ex

FIELD: chemistry.

SUBSTANCE: in general formula I

R1 is phenyl or 5-6-member heterocycle, containing one N atom and/or one O atom; R2 is imidazole or annelated imidazole, selected from group, including a), b), c), d) and e); and R3 stands for hydrogen, phenyl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, benzo[b]thiophen-3-yl, 3-methylbenzo[b] thiophen-2-yl, thiophen-2-yl or thiophen-2-ylmethyl, R4 is hydrogen or lower alkyl, R5 is hydrogen, lower alkyl, halogen, morpholinyl, -NR'R", piperydinyl, optionally substituted with hydroxy-group, or is pyrrolidin-1-yl; R6 is hydrogen or -(CH2)nO-lower alkyl, R7 is hydrogen, -C(O)O-lower alkyl, -C(O)-C6H4-halogen, -C(O)-C6H4-lower alkyl, -C(O)-lower alkyl, -C(O)-cycloalkyl, -C(O)-NR'R", -C(O)-(CH2)nO-lower alkyl, -S(O)2-lower alkyl, -(CH2)nO-lower alkyl, -C(O)-pyridin-4-yl, whose ring can contain as substituents lower alkyl, halogen-lower alkyl or pyrrolidin-1-ylmethyl or is -(CH2)n-C(O)-NR'R"; R'/R" independently on each other stand for hydrogen, lower alkyl or -(CH2)n-tetrahydropyran-4-yl, X is -CH2-, -NR'''- or -O-; R''' is hydrogen, -C(O)-lower alkyl, -C(O)O-lower alkyl, -C(O)-C6H4CH3 or benzyl; n is 1 or 2.

EFFECT: increase of composition and treatment method efficiency.

14 cl, 56 ex

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