Indole-2-carboxamides as inhibitors of factor xa and/or viia, medicinal agent based on thereof and method for their preparing

FIELD: organic chemistry, medicine, hematology, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): in all their stereoisomeric forms and their mixtures taken in any ratio and their physiologically acceptable salts possessing properties of inhibitors of factor Xa and/or factor VIIa, and to a medicinal agent based on thereof. Also, invention relates to a method for synthesis of these compounds and their using for preparing pharmaceutical agents for inhibition of activity of factor Xa and/or factor VIIa or for their effect on blood coagulation or fibrinolysis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 276 ex

 

The present invention relates to compounds of formula I

in which R0; R1; R2; R3; R4; R5; R6; R7; 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, in the treatment and prevention of cardiovascular disorders such as thromboembolic diseases or restenoses. They are reversible inhibitors of factor XA (Fxa) and/or factor VIIa (FVIIa), enzymes, blood clotting, and can in General be applied in conditions in which there is undesired activity of factor XA and/or factor VIla, or for the treatment or prevention of which intend to carry out the inhibition of factor XA and/or factor VIla. The invention also relates to methods of preparing compounds of the formula I, their use especially as active ingredients in pharmaceuticals and including pharmaceuticals.

Normal hemostasis is the result of a complex balance between the processes of initiation of coagulation, the formation and dissolution of clots. The complex interaction between blood cells, specific plasma proteins and the surface of soudo who maintain the fluidity of blood, while there is no damage and the loss of blood (EP-A-987274). Many significant painful conditions attributed to an abnormal hemostasis. For example, the local formation of a blood clot due to a rupture of atherosclerotic plaques is a major cause of acute myocardial infarction and unstable angina. Treatment of occlusal coronary thrombus by either thrombolytic treatment or percutaneous angioplasty may be accompanied by acute thrombolytic occlusion of the affected vessel.

There remains a need for safe and effective therapeutic anticoagulants to limit or prevent the formation of thrombus. The most desirable development tools that inhibit coagulation without direct inhibition of thrombin, but the inhibition of other steps in the coagulation cascade, such as the activity of factor XA and/or factor VIIa. Now suppose that inhibitors of factor XA lead to a lower risk of bleeding than thrombin inhibitors (AER Adang & J.B.M. Rewinkel, Drugs of the Future 2000, 25, 369-383).

Low molecular weight, specific for factor XA inhibitors of blood coagulation, which are effective, but do not cause unwanted side effects described for example in WO-A-95/29189. However, introducing an effective specific in relation to the fact that the ru Ha inhibitor of blood coagulation, in addition, it is desirable that such inhibitors also had a further preferred properties, such as stability in plasma and liver and selectivity against other serine proteases, inhibition of which is not understood, such as thrombin. There is a continuing need for further specific towards 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 with 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 highly effective means of controlling formation of a blood clot, caused by acute arterial damage or thrombotic complications related to bacterial septicemia. 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 angioplasty. Of bleeding studies were conducted on baboons and showed that inhibition of the complex of factor VIIa/tissue factor has the most wide window security in relation to therapeutic efficacy and risk of CR is bleeding skills tested any anticoagulant approach including the inhibition of thrombin, platelets and factor XA. Some inhibitors of factor VIIa already described. EP-A-987274, for example, discloses compounds containing tripeptides block that inhibits the factor VIIa. However, the personal profile of these compounds is still not perfect and there is a continuing need for further low-molecular inhibiting factor VIIa inhibitors of blood coagulation. WO-A-99/33800 discloses indole derivatives, which inhibit the activity of factor XA.

The present invention satisfies the above requirements by providing new compounds of formula I, which are the best inhibitory activity against factor XA and/or factor VIIa and represent favorable funds with high bioavailability.

Thus, the present invention relates to compounds of formula I

where R0represents a

1. monocyclic or bicyclic 6-14-membered aryl, where aryl is mono-, di - or triamese independently of one another a radical R8,

2. monocyclic or bicyclic 4-14-membered heteroaryl from the group consisting of pyridyl, pyrimidinyl, indolyl, isoindolyl, indazole, phthalazine, chinoline, izochinolina, benzothiophene, heatline and phenylpyridine where specified heteroaryl one is camping unsubstituted or mono-, di - or triamese independently of one another a radical R8or

3. monocyclic or bicyclic 4-14-membered heteroaryl containing one, two, three or four heteroatoms chosen from nitrogen, sulphur or oxygen, where indicated heteroaryl is unsubstituted or mono-, di - or triamese independently of one another a radical R8and which is optionally substituted monocyclic or bicyclic 4-14-membered heteroaryl containing one, two, three or four heteroatoms chosen from nitrogen, sulphur or oxygen, where heteroaryl is unsubstituted or mono-, di - or triamese independently of one another a radical R8,

R8represents a

1. halogen,

2. -NO2,

3. -CN

4. -C(O)-NH2,

5. HE

6. -NH2,

7. -OCF3,

8. monocyclic or bicyclic 4-14-membered aryl, where aryl is mono-, di - or triamese independently of one another by halogen or-O-(C1-C8)alkyl,

9. -(C1-C8) alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen, NH2HE or balance methoxy, or

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

provided that R8before the hat is, at least one halogen, -C(O)-NH2or a residue-O-(C1-C8) alkyl, where R0represents a monocyclic or bicyclic 6-14-membered aryl,

Q represents a direct bond, -C(O)-, -(C0-C2)alkylen-C(O)-NR10-, -NR10-C(O)-NR10-, -NR10-C(O)-, -SO2-, -(C1-C6)alkylen where alkylene is unsubstituted or mono-, di - or triamese 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 the radical R13or monocyclic or bicyclic 4-14-membered heteroaryl where specified heteroaryl is unsubstituted or mono-, di - or triamese independently of one another a radical R14,

R2represents a direct bond or -(C1-C4)alkylene, or R1and R7together with the atoms to which they are linked, may form a 4-7-membered cyclic group, containing up to 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic group is unsubstituted or mono-, di - or tizamidine ezavisimo from one another radical R 14,

R1-N-R2-V can form a 4-7-membered cyclic group, containing up to 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 one another a radical R14,

R14represents a halogen, -HE, =O, -(C1-C8)alkyl, -(C1-C4)alkoxy, -NO2-C(O)-OH, -CN, -NH2-C(O)-O-(C1-C4) alkyl, -(C1-C8)alkylsulfonyl, SO2-C(O)-NH-(C1-C8) alkyl, -C(O)-N[(C1-C8)alkyl]2, -NR10-C(O)-NH-(C1-C8)alkyl, -C(O)-NH2, -SR10or-NR10-C(O)-NH-[(C1-C8)alkyl]2,

where R10represents a hydrogen atom, -(C1-C3)perfluoroalkyl or -(C1-C6)alkyl,

V represents

1. 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 one another a radical R14,

2. 6-14-membered aryl, where aryl is unsubstituted or mono-, di - or triamese independently of one another a radical R14or

3. monocyclic or bicyclic 4-14-membered heteroaryl where specified heteroaryl is nezam the seal or mono-, di - or triamese independently of one another a radical R14,

G represents a direct bond, - (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 independently of one another are identical or different and represent integers 0, 1, 2, 3, 4, 5 or 6,

R10represents a hydrogen atom, -(C1-C3)perfluoroalkyl or -(C1-C6) alkyl,

M represents

1. a hydrogen atom,

2. -(C1-C8)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of one another a radical R14,

3. -C(O)-NR11R12,

4. -(CH2)m-N(R10)2,

5. -(C6-C14)aryl, where aryl is unsubstituted or mono-, di - or triamese independently of one another a radical R14,

6. - (C4-C14)heteroaryl where heteroaryl is unsubstituted or mono-, di - or triamese independently of one another a radical R14,

7. (C3-C7)cycloalkyl where specified cycloalkyl is unsubstituted or mono-, di - or triamese independently of one another a radical R14or

8. 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 one another a radical R14where R14such as defined above,

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 one another a radical R13,

3. -(C6-C14)aryl(C1-C4)alkyl-, where the alkyl and aryl independently from one another are unsubstituted or mono-, di - or tizamidine radical R13,

4. -(C6-C14)aryl-, where aryl is unsubstituted or mono-, di - or triamese independently of one another a radical is m R 13,

5. -(C4-C14) heteroaryl where heteroaryl is unsubstituted or mono-, di - or triamese independently of one another a radical R13or

6. (C4-C14)heteroaryl(C1-C4)alkyl-, where the alkyl and heteroaryl independently of one another are unsubstituted or mono-, di -, or three substituted by the radical R13,

R11and R12together with the nitrogen atom to which they are bound, may form a saturated 5-7 membered monocyclic heterocyclic ring which in addition to the nitrogen atom can contain one or two identical or different ring heteroatoms selected from oxygen, sulfur or nitrogen, where the aforementioned heterocyclic ring is unsubstituted or mono-, di - or tizamidine independently one from the other radical R13,

R13represents a halogen, -NO2, -CN, =O, -OH, -(C1-C8)alkyl, -(C1-C8)alkoxy, -CF3, phenyl, phenyloxy, -C(O)-O-R11, phenyl (C1-C4)alkoxy-, -C(O)-N-R11R12, -NR11R12, -NR10-SO2-R10, -S-R10, -SOn-R10where n is 1 or 2, -SO2-NR11R12or-C(O)-R10, -(C0-C4)alkyl-C(O)-O-C(R15R16)-O-C(O)-R17, -(C0-C4)alkyl-C(O)-O-C(R15R16)-O-C(O)O-R17or a residue of formula Va

where R10, R11, R12such as defined above, and R15, R16or R17such as defined below,

R15and R16represent independently of one another hydrogen, -(C1-C6)alkyl or together with the carbon atom to which they are bound, may form a 3-6-membered carbocyclic ring which is unsubstituted or substituted one to three times the radical R10,

R17represents -(C1-C6)alkyl, -(C1-C8)cycloalkyl, -(C1-C6)alkyl(C1-C8)cycloalkyl where specified cycloalkyl is unsubstituted or substituted one to three times the radical R10and

R3, R4, R5, R6and R7independently of one another are identical or different and represent

(a) a hydrogen atom,

b) halogen,

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

d) -(C1-C3)perfluoroalkyl,

e) phenyl, where phenyl is unsubstituted or substituted one to three times the radical R13,

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

g) -NO2,

h) -CN,

i) HE,

j) phenyloxy-where phenyloxy is asamese the major or substituted one to three times the radical R 13,

jj) benzyloxy-where benzyloxy is unsubstituted or substituted one to three times the radical R13,

k) -C(O)-O-R11,

l) -C(O)-N-R11R12,

m) -NR11R12,

n) -NR10-SO2-R10,

o) -S-R10,

p) -SOn-R10where n is 1 or 2,

q) -SO2-NR11R12,

r) -C(O)-R10where R10such as defined above,

s) -C(O)-O-C(R15R16)-O-C(O)O-R17where R15, R16and R17such as defined above,

t) -C(O)-O-C(R15R16)-O-C(O)O-R17where R15, R16and R17such as defined above,

u) a residue of formula Va

where R10such as defined above,

v) a residue of formula Vb or Vc

w) -NR10-(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times the radical R13,

x) -OCF3or

y) residue from the following list:

where R10, R11, R12and R13such as defined above,

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

The present invention also relates to compounds of formula I, where

R0represents a

1. phenyl, where phenyl is a Ki is unsubstituted or mono-, di - or triamese independently of one another a radical R8,

2. bicyclic 5 to 14-membered heteroaryl selected from the group consisting of indolyl, isoindolyl, benzofuranyl, benzothiophene, 1,3-benzodioxolyl, indazole, benzimidazole, benzoxazole, benzothiazole, chinoline, izochinolina, Romania, isopropanyl, cinnoline, heatline, khinoksalinona, phthalazine, predominately, pyridopyrimidines, pyridopyrimidines, purine and pteridine where specified heteroaryl is unsubstituted or mono-, di - or triamese independently of one another a radical R8,

and additionally substituted by a residue selected from the group consisting of pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil; tanila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, isothiazoline, thiadiazolyl, tetrazolyl, pyrimidinyl, pyridazinyl and pyrazinyl, where the specified residue is unsubstituted or mono-, di - or triamese independently of one another a radical R8,

3. monocyclic 5 to 14-membered heteroaryl from the group consisting of pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil; tanila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazole is a, isoxazolyl, thiazolyl, thiadiazolyl, isothiazoline, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl where specified heteroaryl is unsubstituted or mono-, di - or triamese independently of one another a radical R8,

and additionally substituted by a residue selected from the group consisting of pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil; tanila, 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 one another a radical R8,

R8represents a

1. halogen, such as F, Cl, Br or I,

2. -C(O)-NH2,

3. -(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or triamese independently of one another by halogen, HE or balance methoxy, or

4. -O-(C1-C4)alkyl, where the 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-C8)alkyl, where R0represents a monocyclic or bicyclic 6-14-membered and the sludge

Q represents a direct bond, -C(O)-, -SO2- or - (C1-C6)alkylene -(C0-C2)alkylen-C(O)-NR10-,

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

R2represents a direct bond or -(C1-C2)alkylen or

R1-N-R2-V can form a 5-7-membered cyclic group, containing 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, cefoperazon, oxazol, isoxazol, isoxazolidine, 2-isoxazoline, morpholine, thiazole, isothiazol, thiadiazole or thiomorpholine where the specified cyclic group is unsubstituted or mono-, di - or tizamidine independently of one another radical R14,

R14represents a halogen, -(C1-C4)alkyl or-NH2,

V represents

1. 3-7-membered cyclic residue from the group consisting of compounds that are derivatives of aziridine, azirine, azetidine, 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, PI is uridine, piperazine, pyrrolidinone, cefoperazone, furan, Piran, dioxole, oxazole, isoxazol, 2-isoxazoline, isoxazolidine, research, oxirane, oxaziridine, 1,3-dioxolane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxaziridine, thiophene, thiopyran, Titan, thiazole, isothiazole, isothiazoline, isothiazolinone, 1,2-oxathiolane, 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 one another a radical R14,

2. phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of one another a radical R14or

3. bicyclic 5 to 14-membered heteroaryl, from the group consisting of chinosol, ethanolic and honokalani where specified heteroaryl is unsubstituted or mono-, di - or triamese independently of one another a radical R14,

G represents a direct bond, -(CH2)m- or -(CH2)m-NR10-,

m represents the integer 0, 1, 2, 3,or 4

R10represents a hydrogen atom, -(C1-C3)perfluoroalkyl or -(C1-C4)alkyl,

M represents

1. a hydrogen atom,

2. -(C6-C14)heteroaryl where heteroaryl represents the balance of the group, which can be derived PI is uridine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, pyridinyl, imidazole, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,1,3-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, thiadiazole or thiomorpholine where specified heteroaryl is unsubstituted or mono-, di - or triamese independently of one another a radical R14,

3. -(C1-C6)alkyl, where the specified alkyl is unsubstituted or mono-, di - or triamese independently of one another a radical R14or

4. (C3-C6)cycloalkyl,

R3, R4, R5, R6and R7independently of one another are identical or different and represent

(a) a hydrogen atom,

b) F, Cl, Br,

c) -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted by a radical R13,

d) -CF3,

(e) phenyl, where phenyl is unsubstituted or substituted one to three times the radical R13,

f) -O-(C1-C4)alkyl, where the alkyl is unsubstituted or substituted by a radical R13,

g) -NO2,

h) -CN,

i) HE,

j) phenyloxy-where phenyloxy is unsubstituted or substituted by a radical R13,

p> jj) benzyloxy-where benzyloxy is unsubstituted or substituted by a radical R13,

k) -C(O)-O-R11,

l) -C(O)-N-R11R12,

m) -NR11R12,

n) -NR10-SO2-R10,

o) -SOn-R10where n is 1 or 2,

p) -SO2-NR11R12,

q) -C(O)-R10,

r) -C(O)-O-C(R15R16)-O-C(O)-R17where R15, R16and R17such as defined above,

s) -C(O)-O-C(R15R16)-O-C(O)O-R17where R15, R16and R17such as defined above

t) residue of formula Va

u) residue of formula Vb or Vc

v) -OCF3or

w) residue from the following list:

R13represents a halogen, -NO2, -CN,=O, -OH, -(C1-C8)alkoxy, -CF3, -C(O)-O-R11-C(O)-N-R11R12, -NR11R12, -NR10-SO2-R10, SOn-R10where n is 1 or 2, -SO2-NR11R12, -C(O)-R10, -(C0-C4)alkyl-C(O)-O-C(R15R16)-O-C(O)-R17, -(C0-C4)alkyl-C(O)-O-C(R15R16)-O-C(O)O-R17or a residue of formula Va

where R10, R11, R12, R15, R16or R17such as defined above,

in all its stereoisomeric forms and the x mixtures in any ratio, and its physiologically tolerated salt.

The present invention also relates to compounds of formula I, where

R0represents a

1. phenyl, where phenyl is unsubstituted or mono-, di - or triamese independently of one another a radical R8,

2. monocyclic 4-14-membered heteroaryl selected from the group consisting of tanila, thiadiazolyl, isoxazolyl and thiazolyl where specified heteroaryl 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 one another a radical R8,

R8represents F, Cl, Br, -och3-C(O)-NH2or-OCF3, Q represents a direct bond, -C(O)-, -SO2-, methylene or ethylene,

R1represents a hydrogen atom, R2represents a direct bond or methylene, or

R1-N-R2-V can form a 5-7-membered cyclic group, containing pyrrolidine, piperidine and piperazine,

R13represents-C(O)-O-R11-C(O)-N-R11R12, -NR11R12, -NR10-SO2-R10, -SOn-R10where n is 1 or 2, -SO2-NR11R12-C(O)-R10-(C0-C4)alkyl-C(O)-OC(R15R16)-O-C(O)-R17-(C0-C4)alkyl-C(O)-OC(R15R16)-O-C(O)O-R17or a residue of formula Va

where R10, R11, R12, R15, R16or R17such as defined above,

R14represents halogen, methyl, ethyl, or-NH2,

V represents

1. the rest of the group containing compounds that are derivatives of isoquinoline, quinoline, heatline, piperidine, azetidine, pyrrolidine, tetrahydropyran, piperazine and isoxazol where the specified cyclic residue is unsubstituted or mono - or Disaese independently of one another a radical R14or

2. phenyl, where phenyl is unsubstituted or mono - or Disaese independently of one another a radical R14or

G represents a direct bond, -(CH2)m- or -(CH2)m-NR10-,

m represents the integer 0, 1 or 2, R10represents a hydrogen atom or -(C1-C4)alkyl,

M represents a hydrogen atom, -(C2-C4)alkyl, imidazolyl, pyrazolyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl or (C3-C6)cycloalkyl, where the above cyclic residues are unsubstituted or mono - or tizamidine independently of one another a radical R14,

R3, R4, R5, R6and R7independently of one another are identical or different the mi and represent

(a) a hydrogen atom,

b) F, Cl,

c) (C1-C4)alkyl, where the alkyl is unsubstituted or substituted by a radical R13,

d) phenyl, where phenyl is unsubstituted or substituted one to three times the radical R13,

e) -O-(C1-C4)alkyl, where the alkyl is unsubstituted or substituted by a radical R13,

f) -C(O)-O-R11,

g) -C(O)-N-R11R12,

h) -NR11R12,

i) -NR10-SO2-R10,

j) -SO2-NR11R12,

k) -C(O)-R10,

l) -C(O)-O-C(R15R16)-O-C(O)-R17where R15, R16and R17such as defined above,

m) -C(O)-O-C(R15R16)-O-C(O)O-R17where R15, R16and R17such as defined above,

n) residue of formula Va

on balance formula Vb or Vc

R) residue from the following list:

in all its stereoisomeric forms and mixtures in any ratio, and its physiologically tolerated salt.

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-methanesulfonyl-1H-indole-2-arbonboy acid,

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-6-methoxy-1H-indole-2-carboxylic acid,

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,6-dimethoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5,6-dimethoxy-1H-indole-2-carboxylic acid,

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

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

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

(1-isopropylpiperazine is n-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-(2,2-dimethylpropylene)-1H-indole-2-carboxylic acid,

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-6-hydroxy-5-methoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,6-debtor-1H-indole-2-carboxylic acid,

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

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

(1-isopropylpiperazine-4-yl)amide 6-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-yl is ethyl]-5,7-debtor-1H-indole-2-carboxylic acid,

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

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic acid,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-isopropylpiperazine-1-yl)methanon,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indol-2-yl}-(4-isopropylpiperazine-1-yl)methanon,

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

(1-ethylpiperazin-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-pyrrolidin-1-reparacin-1-yl)methanon,

[1,4']beeper dinil-1'-yl{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}mechanon,

(3-pyridin-4-yl-4,5-dihydroisoxazole-5-ylmethyl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-pyridin-4-iletileri-1-yl)methanon,

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

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

[1-(tetrahydropyran-4-yl)piperidine-4-yl)]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-ylmethyl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(4-isopropylpiperazine-1-yl)-[1-(3-methoxybenzyl)-1H-indol-2-yl]metano,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(3-methoxybenzyl)-1H-ind the l-2-carboxylic acid,

[1-(3-methoxybenzyl)-1H-indol-2-yl]-[4-(pyridine-4-ylamino)piperidine-1-yl]metano,

(1-isopropylpiperazine-4-yl)amide of 4-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-chloro-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 6-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-5-methyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-benzyloxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-5-nitro-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzoyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzenesulfonyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid,

(4-isopropylpiperazine-4-yl)-[1-(4-methoxyphenyl)-1H-indol-2-yl]metano,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxyphenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-those whom rehydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-ylmethyl)amide 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3,5-dichlorophenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(4-chlorophenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(6-chlorobenzo[b]thiophene-2-ylmethyl)-1H-indole-2-carboxylic acid,

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-(4-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(4-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(2,4-dichlorobenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(4-methoxybenzyl)-1H-indole-2-carboxylic acid,

(4-isopropylpiperazine-1-yl)-[1-(4-methoxybenzyl)-1H-indol-2-yl]metano,

(1-isopropylpiperazine-4-yl)amide 1-(4-cryptomaterial)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(2-x is orbenin)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(2-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-(2-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3,5-dichlorobenzyl)-1H-indole-2-carboxylic acid,

[1-(3,5-dichlorobenzyl)-1H-indol-2-yl]-(4-isopropylpiperazine-1-yl)methanon,

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-7-methyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-Chlorobenzyl)-1H-indole-2-carboxylic acid,

[1-(3-Chlorobenzyl)-1H-indol-2-yl]-(4-isopropylpiperazine-1-yl)methanon,

(1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(2,4-dichlorophenyl)ethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(3-methoxyphenyl)ethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-methoxy-1H-indole-2-carboxylic acid,

(1 isopropyle uridin-4-yl)amide of 4-bromo-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

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

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

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

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

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

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

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

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

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H and the Dol-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[(1-(1-ethylpropyl)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

[(1-(2,2,2-triptorelin)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

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

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

[1-(2-chloropyrimidine-4-yl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-[4-(pyridine-4-yloxy)piperidine-1-yl]metano,

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

(4-pyridin-3-yl)thiazol-2-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

[3-(pyrrolidin-1-carbonyl)-4,5-dihydroisoxazole-ylmethyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

methyl ester of 4-({1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}amino)piperidine-1-carboxylic acid,

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

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

pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-dead-4-methoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-dicyano-4-methoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)thiazol-4-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(1,7-dichlorethylene-ylmethyl)-1H-indole-2-carboxylic acid,

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

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

(1-isopropylpiperazine-4-yl)amide 1-[3-(4-chlorophenyl)-[1,2,4]oxadiazol-5-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-methanesulfonyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-5-methanesulfonyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-chloro-1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-fluoro-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5,7-debtor-1H-indole-2-carboxylic acid,

(1-ethylpyrrolidin-3-yl)amide S-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

(1-ethylpyrrolidin-3-yl)amide R-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpyrimidine-3-yl)amide R-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpyrimidine-3-yl)amide S-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)from xazal-3-ylmethyl]-4-trifluoromethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester [{4,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester [{5,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester [{4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-trifluoromethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

[{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{4,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{5,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic KIS the PTA,

[{4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

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

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

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

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

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

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

isopropyl ester 1-[5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole-2-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid,

1-[5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole-2-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid,

isopropyl ester 1-[(4-chlorpheniramol)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid,

1-[(4-chlorpheniramol)methyl]-2-(1-isopropylpiperazine-4-carbamoyl)-1H-indole-5-carboxylic acid,

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-chlorothiophene-2-ylcarbonyl)methyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[4-chloro-2-tortenelmebol)methyl]-1H-indole-2-carboxylic acid,

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

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid,

N-(4-chlorophenyl)-2-{2-[4-(pyridine-4-ylamino)piperidine-1-carbonyl]indole-1-yl}acetamide", she

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

N-(4-chlorophenyl)-2-[2-(4-pyrrolidin-1-reparacin-1-carbonyl]indole-1-yl}acetamide", she

(1-isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-5-nitro-1H-indole-2-carbon is th acid,

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

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

[1-(2-hydroxyethyl)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

[1-(2-methoxyethyl)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

[1-(1H-imidazol-2-iletilerini-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

[1-(2-dimethylaminoacetyl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

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

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

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

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

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

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

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

In General, the value of any group, residue, heteroatom, rooms, etc. that can occur more than once in the compounds of the formula I is independent of the values of this group, residue, heteroatom, rooms, etc. in any other case. All groups, residues, heteroatoms, rooms, etc. that can occur more than once in the compounds of formula I, may be the same or different.

As IP is alzavano in this description, the term alkyl should be understood in its broadest sense to denote a hydrocarbon residue which may be linear, i.e. straight-chain or branched, and which may represent an acyclic or cyclic residues of or include any combination of acyclic and cyclic subunits. In addition, the term alkyl, as used herein, includes exactly saturated group, as well as unsaturated groups, the latter group contain 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 in such a way that leads to the creation of an aromatic system. All these statements are also applicable, if the alkyl group used as a substituent with another residue, for example in the remainder of alkyloxy, allyloxycarbonyl residue or arylalkyl residue. Examples of alkyl residues containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl, n-isomers of all data residues, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl, tert-pentyl, sec-butyl, tert-butyl or tert-pentyl.

Unsaturated alkyl residues represent the a, 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 replaced.

Examples of cyclic alkyl residues are cycloalkyl residues containing 3, 4, 5 or 6 ring carbon atoms, as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, 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.

Of course, a cyclic alkyl group should contain at least three carbon atoms, and unsaturated alkyl group should contain at least two carbon atoms. Thus, it should be understood that a group such as (C1-C8)alkyl includes, among others, saturated acyclic (C1-C8)alkyl, (C3-C6)cycloalkyl and unsaturated (C2-C8)alkyl, such (C2-C8)alkenyl or (C2-C8)quinil. Similarly, it should be understood that a group such as (C1-C4)alkyl, VK is uchet, among others, saturated acyclic (C1-C4)and unsaturated alkyl (C2-C4)alkyl, such (C2-C4)alkenyl or (C2-C4)quinil.

Unless specified otherwise, the term alkyl preferably includes acyclic saturated hydrocarbon residues, which contain from one to six carbon atoms and which may be linear or branched. A specific group of saturated acyclic alkyl residues formed (C1-C4)alkyl residues such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

Unless stated otherwise, and irrespective of any specific substituents associated with the alkyl groups listed in the definition of compounds of formula I, the alkyl groups in the General case can be unsubstituted or substituted by one or more, for example one, two or three identical or different substituents. Any type of substituents present in the substituted alkyl residues may be present in any desired position, provided that the substitution does not lead to an unstable molecule. Examples of substituted alkyl residues are alkyl residues in which one or more, e.g. 1, 2 or 3 hydrogen atoms replaced by halogen atoms, in particular fluorine atoms.

Those who min. mono - or bicyclic 4-14-membered heteroaryl" refers to (C 4-C14)aryl, in which one or more from 5-14 ring atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur. Examples are asocial, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzothiazole, benzotriazole, betterall, benzisoxazole, benzisothiazole, benzimidazolinyl, carbazole, 4H-carbazolyl, carbolines, bromanil, bromanil, cinnoline, decahydroquinoline, 2N,6N-1,5,2-detainer, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furutani, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isopropanol, isoindolyl, isoindolines, isoindolyl, ethenolysis (benzimidazolyl), isothiazolin, isoxazolyl morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridines, phenanthrolines, phenazines, phenothiazines, phenoxathiin, phenoxazines, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, pyridoxal, predominate, peridotite, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl 2N-pyrrolyl, pyrrolyl, hintline, chinoline, 4H-hemolysins, hinokio the sludge, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 6N-1,2,5-thiadiazine, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl and xantinol. Preferred are pyridyl, such as 2-pyridyl, 3-pyridyl or 4-pyridyl; pyrrolyl, such as 2-pyrrolyl and 3-pyrrolyl; furyl, such as 2-furyl and 3-furyl; thienyl, such as 2-thienyl and 3-thienyl; imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, tetrazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzothiophene, 1,3-benzodioxolyl, indazoles, benzimidazoles, benzoxazoles, benzothiazoles, chinoline, ethenolysis, bromanil, isopropanol, cinnoline, hintline, honokalani, phthalazine, predominately, pyridopyrimidines, pyridopyrimidines, purines and pteridines.

The expression "R1and R2together with the nitrogen atom and V, with which they are linked, form a 5-7-membered cyclic structure" refers to structures of heterocycles which can be derived from compounds such as 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, cefoperazon, oxazol, isoxazol, isoxazolidine, 2-isoxazoline, morpholine, thiazole, isothiazol, the thiadiazole or calm surroundings is Holin.

The expression "3-7-membered cyclic residue, containing up to 1, 2, 3 or 4 heteroatoms" refers to structures of heterocycles which can be derived compounds, such as aziridine, asirin, azetidine, pyrrole, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyrimidine, pyrazin, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, tetrazine, tetrazole, azepine, diasorin, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, pyridazine, piperidine, piperazine, pyrrolidine, cefoperazon, furan, Piran, dioxole, oxazol, isoxazol, 2-isoxazolin, isoxazolidine, morpholine, oxiran, oxaziridine, 1,3-dioxolan, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxaziridine, thiophene, thiopyran, Titan, thiazole, isothiazol, isothiazolin, isothiazolin, 1,2-oxathiolan, thiopyran, 1,2-thiazin, 1,3-thiazole, 1,3-thiazin, 1,4-thiazin, thiadiazin or thiomorpholine.

The expression "R11and R12together with the nitrogen atom to which they are linked, form a saturated or unsaturated 5-7-membered monocyclic heterocyclic ring" refers to residues that may be derivatives of compounds such as 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, cefoperazon, oxazol, isoxazol, isoxazolidine, 2-isoxazoline, mo the folin, the thiazole, isothiazol, thiadiazole or thiomorpholine.

The fact that many of the above names heterocycles represent chemical names unsaturated or aromatic cyclic systems, does not mean that the 4-15 membered mono - or polycyclic group can be derived only from the corresponding cyclic system. The names in this case serve only to describe the cyclic system in relation to the ring size and the number of heteroatoms and their relative positions. As explained above, 4-15 membered mono - or polycyclic group may be saturated or partly unsaturated or aromatic, and may, therefore, be derived not only themselves above heterocycles, but also their partially or completely hydrogenated analogs, as well as their more highly unsaturated analogues, if this is applicable. As examples of fully or partially hydrogenated analogues of the above heterocycles, from which this group can occur, can be the following: 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), purged the on-1,4-thiazin (=thiomorpholine), peligrosas, indolin, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline etc.

4-15 membered mono - or polycyclic group can be connected through any carbon atom of the ring and, in the case of nitrogen-containing heterocycles, through any suitable nitrogen atom of the ring. Thus, for example, the balance pyrrolyl can be a 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl, the rest of pyrrolidinyl can be pyrrolidin-1-yl(=pyrrolidino), pyrrolidin-2-yl or pyrrolidin-3-yl, the rest of pyridinyl can be a pyridine-2-yl, pyridin-3-yl or pyridin-4-yl, the rest of piperidinyl can represent piperidine-1-yl (=piperidino), piperidine-2-yl, piperidine-3-yl piperidine or-4-yl. Furyl can be a 2-furyl or 3-furyl, thienyl can be a 2-thienyl or 3-thienyl, imidazolyl can represent imidazol-1-yl, imidazol-2-yl, imidazol-4-yl or imidazol-5-yl, 1,3-oxazolyl can be a 1,3-oxazol-2-yl, 1,3-oxazol-4-yl or 1,3-oxazol-5-yl, 1,3-thiazolyl can be a 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl, pyrimidinyl can be a pyrimidine-2-yl, pyrimidine-4-yl (=6-pyrimidinyl) or 5-pyrimidinyl, piperazinil can represent piperazine-1-yl (=piperazine-4-yl-piperazine derivatives) or piperazine-2-yl. Indolyl may be indol-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl. Similarly benzimidazolinyl, benzoxazolyl and benzothiazolyl residues can be linked via position 2 and through any of the positions 4, 5, 6 and 7. Chinoline may be a quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, quinoline-5-yl, quinoline-6-yl, quinoline-7-yl or quinoline-8-yl, ethenolysis can represent isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, isoquinoline-5-yl, isoquinoline-6-yl, isoquinoline-7-yl or isoquinoline-8-yl. In addition to related through any of the provisions specified for chinoline and izochinolina, 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinolines can also be linked through the nitrogen atoms in position 1 and position 2, respectively.

Unless stated otherwise, and irrespective of any specific substituents associated with the 4-15 membered mono - or polycyclic group or any other heterocyclic groups which are indicated in the definition of compounds of formula I, 4-15 membered mono - or polycyclic group can be unsubstituted or substituted on the carbon atoms of the ring by one or more, for example one, two, three, four, or five, identical or different substituents, such as (C1-C8)alkyl, in particular (C1-C4)alkyl, (C1-C8)alkoxy, in particular (C1 -C4)alkoxy, (C1-C4)alkylthio, halogen, nitro, amino, ((C1-C4)alkyl)carbylamine like acetylamino, trifluoromethyl, triptoreline, hydroxy, oxo, hydroxy(C1-C4)alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, Ethylenedioxy, formyl, acetyl, cyano, aminosulfonyl, methylsulphonyl, hydroxycarbonyl, aminocarbonyl, (C1-C4)allyloxycarbonyl, optionally substituted phenyl, optionally substituted, phenoxy, benzyl, optionally substituted on the phenyl group, etc. Substituents may be present in any desired position, provided that this leads to a stable molecule. Of course, oxoprop may not be present in the aromatic ring. Each suitable nitrogen atom of the ring in the 4-15 membered mono - or polycyclic group may independently from each other be unsubstituted, i.e. to bear a hydrogen atom, or can be substituted, i.e. to carry Deputy, like (C1-C8)alkyl such as (C1-C4)alkyl, such as methyl or ethyl, optionally substituted phenyl, phenyl(C1-C4)alkyl, for example benzyl, optionally substituted on the phenyl group, hydroxy(C2-C4)alkyl, such as, for example, 2-hydroxyethyl, acetyl or another acyl group, methylsulphonyl or the other is th sulfonylurea group, aminocarbonyl, (C1-C4)allyloxycarbonyl etc. In General, in compounds of formula I of nitrogen-containing heterocycles can also be present as N-oxides or Quaternary salts. The sulfur atoms in the ring may be oxidized to a sulfoxide or to the sulfone. Thus, for example, the balance tetrahydrothieno may be present as a residue S,S-dioxotetrahydrofuran or the rest of thiomorpholine, like thiomorpholine-4-DRS, may be present as 1-Osotimehin-4-yl or 1,1-diocletianopolis-4-yl. Substituted 4 to 15-membered mono - or polycyclic group which may be present in a specific position of the compounds of formula I can independently of other groups to be substituted by substituents selected from any desired subgroup of the substituents listed above and/or in the definition of this group.

3-7-membered monocyclic group may be connected through any carbon atom of the ring and, in the case of nitrogen-containing heterocycles, through any suitable nitrogen atom of the ring. Thus, for example, the balance pyrrolyl can be a 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl, the rest of pyrrolidinyl can be pyrrolidin-1-yl (=pyrrolidino), pyrrolidin-2-yl or pyrrolidin-3-yl, the rest of pyridinyl can be a pyridine-2-yl, pyridin-3-yl or pyridin-4-yl, the remainder of the PIP is reinila can represent piperidine-1-yl (=piperidino), piperidine-2-yl, piperidine-3-yl or piperidine-4-yl. Furyl can be a 2-furyl or 3-furyl, thienyl can be a 2-thienyl or 3-thienyl, imidazolyl can represent imidazol-1-yl, imidazol-2-yl, imidazol-4-yl or imidazol-5-yl, 1,3-oxazolyl can be a 1,3-oxazol-2-yl, 1,3-oxazol-4-yl or 1,3-oxazol-5-yl, 1,3-thiazolyl can be a 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl, pyrimidinyl can be a pyrimidine-2-yl, pyrimidine-4-yl (=6-pyrimidinyl) or 5-pyrimidinyl, piperazinil can represent piperazine-1-yl (=piperazine-4-yl-piperazine derivatives) or piperazine-2-yl. Unless stated otherwise, and irrespective of any specific substituents associated with a 3-7-membered mono - or polycyclic group or any other heterocyclic groups which are indicated in the definition of compounds of formula I can be unsubstituted or substituted on the carbon atoms of the ring by one or more, for example one, two, three, four, or five, identical or different substituents, such as (C1-C8)alkyl, in particular (C1-C4)alkyl, (C1-C8)alkoxy, in particular (C1-C4)alkoxy, (C1-C4)alkylthio, halogen, nitro, amino, ((C1-C4)alkyl)carbylamine like acetylamino, trifluoromethyl, triptoreline, hydroxy, oxo, is hydroxy-(C 1-C4)alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, Ethylenedioxy, formyl, acetyl, cyano, aminosulfonyl, methylsulphonyl, hydroxycarbonyl, aminocarbonyl, (C1-C4)allyloxycarbonyl, optionally substituted phenyl, optionally substituted, phenoxy, benzyl, optionally substituted on the phenyl group, etc. Substituents may be present in any desired position, provided that this leads to a stable molecule. Of course, oxoprop may not be present in the aromatic ring. Each suitable nitrogen atom of the ring of 3-7-membered monocyclic group may independently from each other be unsubstituted, i.e. to bear a hydrogen atom, or can be substituted, i.e. to carry Deputy, such as (C1-C8)alkyl such as (C1-C4)alkyl, such as methyl or ethyl, optionally substituted phenyl, phenyl(C1-C4)alkyl, for example benzyl, optionally substituted on the phenyl group, hydroxy(C2-C4)alkyl, such as, for example, 2-hydroxyethyl, acetyl or another acyl group, methylsulphonyl or other sulfonylurea group, aminocarbonyl, (C1-C4)allyloxycarbonyl etc. In General in compounds of formula I of nitrogen-containing heterocycles can also be present as N-oxides or che is vertacnik salts. The sulfur atoms in the ring may be oxidized to a sulfoxide or to the sulfone. Thus, for example, the balance tetrahydrothieno may be present as a residue of 3,3-dioxotetrahydrofuran or the rest of thiomorpholine, like thiomorpholine-4-DRS, may be present in the form of 1-Osotimehin-4-yl or 1,1-diocletianopolis-4-yl. Substituted 3-7-membered monocyclic group which may be present in a specific position of the compounds of formula I can independently of other groups to be substituted by substituents selected from any desired subgroup of the substituents listed above and/or in the definition of this group.

Halogen represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, particularly preferably chlorine or bromine.

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

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

Physiologically tolerated salts of the compounds of formula I are non-toxic salts which are physiologically acceptable, in particular pharmaceutically salt used. Such salts of compounds of formula I containing an acid group such as carboxyl group COOH, represents, 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 tolerated and Quaternary ammonium ions, such as Tetramethylammonium or tetraethylammonium, and salt accession acids 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 salts accession acids, 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, 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 represented in the form zwitterions (betaines), which is also included in the present invention.

Salts of compounds of formula I can be obtained by conventional methods known to experts in this field, such as the Association is soedineniya formula I with an inorganic or organic acid or base in a solvent or dispersing medium, or from other salts by cation or anion exchange. 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 pharmaceuticals, 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.

The present invention also includes all of the solvate of the compounds of the formula I, for example hydrates or adducts with alcohols.

The invention also includes derivatives and modifications of the compounds of the formula I, for example, prodrugs, protected form or other physiologically tolerated derivatives, as well as active metabolites of compounds of formula I. This invention also 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 the properties that are improved in the desired direction, for example, with respect to solubility, bioavailability or duration of the action is s, are known to specialists in this field. More detailed information relating to prodrugs can be found in the standard literature, as, for example, in Design of Prodrugs, H. Bungaard (ed.), Elsevier, 1985, Fleisher et al. Advanced Drug Delivery Reviews 19 (1996), 115-130, or H. Bungaard, Drugs of the Future 16 (1991) 443, which are all included in the present 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 and guanidinium and ester prodrugs and amide prodrugs of carboxylic acid groups which may be represented as compounds of the formula I. In the acyl prodrugs and urethane the prodrugs of one or more, for example one or two hydrogen atoms at the nitrogen atoms in such groups substituted acyl group, or a carbamate, preferably (C1-C6)alkoxycarbonyl group. Suitable acyl groups and urethane groups to acyl 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-C 4)alkyl-, in which Rp2matter listed for Rp1with the exception of hydrogen.

Especially preferred compounds of formula I are those compounds in which two or more residues are defined as indicated above for the preferred compounds of formula I, or residues may have one or some of the specific designations of residue data in their General definitions or definitions of preferred compounds of the above. All possible combinations of the definitions for the preferred definitions or specific designations residues, clearly represent an object of the present invention.

Also in respect to all preferred compounds of formula I, all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts are definitely the subject of the present invention, as well as their prodrugs. Similarly, in all the preferred compounds of formula I, all the residues, which represented more than once in the molecule, are independent of each other and can be identical or different.

The compounds of formula I can be obtained using techniques and methods which are in themselves well known and recognized an ordinary person skilled in the art. The source of the substance or bildi the g-blocks for use in the General synthetic methods, which can be applied to obtain the compounds of formula I are readily accessible to the ordinary 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 by analogy with the methods described in the literature or by methods or analogously to the methods described in this application.

In General, compounds of formula I can be obtained in the course of a convergent synthesis, by linking two or more fragments which can be retrosynthetic formed from the formula I. More specifically, suitably substituted the original indole derivatives are used as building blocks in the formation of compounds of formula I. In the case of commercial unavailability of such indole derivatives can be obtained in accordance with well known standard methods for the formation of indole cyclic systems, such as indole synthesis, Fischer indole synthesis of Madelung, indole synthesis, coming from the N-Chloroaniline and 3-ketosulfones described by Gassman et al., indole synthesis Bichler, indole synthesis Reisert or indole synthesis Nenitzescu. By selecting a suitable precursor molecules data indole syntheses allow introduction the diversity of substituents in different positions indole system, which can then be chemically modified, in order, ultimately, to form a molecule of formula I having the desired circuit deputies. As one of the comprehensive reviews where you can find many details and references on the chemistry of indoles and synthetic methods for their production, the authors refer to WJ Hoolihan (ed.), "Indoles, Part One", volume 25, 1972, from the series "The Chemistry of Heterocyclic Compounds", A. Weissberger and E.C. Taylor (ed.), John Wiley & Sons.

Examples of many commercially available indole derivatives that are suitable as starting compounds for preparing compounds of formula I are the following : (these acids are commercially available in the form of free acid as such and/or in the form of methyl or ethyl esters): indole-2-carboxylic acid, indole-3-carboxylic acid, indole-3-acetic acid, 3-(3-indolyl)propionic acid, indole-2,3-dicarboxylic acid, 3-ethoxycarbonylmethylene-2-carboxylic acid, C-methylindol-2-carboxylic acid, 5-Florinda-2-carboxylic acid, 5-Clorinda-2-carboxylic acid, 5-bromoindole-2-carboxylic acid, 5-methoxyindole-2-carboxylic acid, 5-hydroxyindole-2-carboxylic acid, 5,6-dimethoxyindole-2-carboxylic acid, 4-benzyloxyindole-2-carboxylic acid, 5-benzyloxyindole-2-carboxylic acid, 6-benzyloxy-5-methoxyindol-2-carbon is I acid, 5-methylindol-2-carboxylic acid, 5-ethylindole-2-carboxylic acid, 7-methylindole-2-carboxylic acid, 4-methoxyindol-2-carboxylic acid, 6-methoxyindol-2-carboxylic acid, 4,6-dimethoxyindole-2-carboxylic acid, 4,6-disorienta-2-carboxylic acid, 5-nitroindole-2-carboxylic acid, 5-methylsulfonylbenzoyl-2-carboxylic acid, 7-nitroindole-2-carboxylic acid, 7-tert-butylcarbamoyl-2-carboxylic acid, 7-(3-triphtalocyaninine)indole-2-carboxylic acid, 7-(4-methoxyphenylacetylene)indole-2-carboxylic acid, 5-bromo-3-methylindol-2-carboxylic acid, 3-(2-carboxyethyl)-6-Clorinda-2-carboxylic acid.

If the original indole derivatives need to synthesize this can be accomplished, for example, in accordance with well-known syntheses of indoles, above. Below they are briefly explained, however, they are standard techniques, discussed in the literature and well known specialist in this field.

Indole synthesis, Fischer includes acid cyclization of phenylhydrazones, for example, General formula 2

which can be obtained in various ways, and where R30, R31and R32and n can have a great variety of values. In addition to hydrogen and alkyl, R31and R32may, in particular, to mean complex is aeternae group or a methyl or ethyl group, or 2,2,2-triptoreline group, bearing ester group, as Deputy, making it possible, therefore, the introduction indole molecule fragment (CH2)p-Found in groups of R2and/or R3in the compounds of formula I. as examples of many literary references describing the synthesis of indole derivatives in accordance with the synthesis Fischer, in addition to the above books edited by Houlihan, referred to the following articles: F.G. Salituro et al., J. Med. Chem. 33 (1990) 2944; N.M. Gray et al., J. Med. Chem. 34 (1991) 1283; J.Sh. Chikvaidze et al., Khim. Geterotsikl. Soedin. (1991) 1508; S.P. Hiremath et al., Indian J. Chem. 19 (1980) 770; J. Bornstein, J. Amer. Chem. Soc. 79 (1957) 1745; S. Wagaw, C. Yang and S. Buchwald, J. Am. Chem. Soc. 121 (1999), 10251, or Y. Murakami, Y. Yokoyama, T. Miura, H. Hirasawa Y. Kamimura and M. Izaki, Heterocycles 22 (1984) 1211.

Indole synthesis Reissert includes reductive cyclization of o-nitrophenylpyruvic acids or their esters, for example, General formula 3

in which groups R30can have a great variety of meanings and can be represented in all positions of the benzene ring. Indole synthesis Reissert leads to a derivative of indole-2-carboxylic acid. Derivatives of pyruvic acid of formula 3 can be obtained by condensation of esters Savelievich acids with substituted o-nitrotoluene. As a literary references, in addition to the above vysokyy edited by Houlihan and mentioned in her literary articles, given, for example, articles H.G.Lindwall and G.J.Mantell, J. Org Chem. 18 (1953), 345, or .Burton and J.L.Stoves, J. Chem. Soc. (1937), 1726, or W. Noland, F. Buude, Org. Synth Coll. Vol. V. J. Wiley, New York, (1973) 567.

Another way to achieve regioselective access to the indole structure includes palladium catalysis, for example o-halogenation (X=Cl, Br, I) or o-triftoratsetilatsetonom (X=OTf) of General formula 4 can be cyklinowanie in indoles using some alkynes on adapted techniques described J. Ezquerra, S. Pedegral. C. Lamas, J. Barluenga, M. Perez, M. Garcia-Martin, J. Gonzalez, J. Org. Chem. 61 (1996), 5805, or F. Ujjainwalla, D. Warner, Tetrahedron Lett. 39 (1998) 5355 and, in addition, A. Rodriguez, S. Koradin, W. Dohle, P. Knochel, Angew. Chem. 112 (2000) 2607; or R. Larock, E. Yum, M. Refvik, J. Org. Chem. 63 (1998) 7653; R. Larock, E. Yum, J. Am. Chem. Soc. 113 (1991) 6689; R. Larock, J. Org. Chem. 66 (2001) 412.

Alternative indole structure can be built using diversity ketones in terms of palladium catalysis by adapting and modifying the techniques described S. Chen, D. Liebermann, R. Larsen, T. Verhoeven and P. Reider J. Org. Chem. 62 (1997) 2676, as described below.

In accordance with indole synthesis Bichler-anilinomethyl, for example, the General formula 10

can be cyklinowanie in derivatives of indole.

Indole synthesis Nenitzescu provides a valuable path derived in the ol-3-carboxylic acid, bearing the hydroxy-group in position 5. It includes the interaction of parabenzoquinone with ∃-aminocrotonate, for example, compounds of formula 11 and 12

A further way to specifically substituted indole derivative passes through 2,3-dihydroindole (indoline), which can be easily obtained by reduction of indoles, for example, by hydrogenation or by cyclization of an appropriate derivative of phenethylamine. Indoline can undergo a variety of reactions electrophilic aromatic substitution, which allows the introduction of different substituents in the benzene nucleus of the molecule indole. Indoline can continue to be digidrirovanny in the corresponding indoles, for example, reagents such as chloranil, or palladium together with acceptor hydrogen. Again the details of these syntheses can be found in the above book edited by Houlihan.

In addition, indoles can be converted into the corresponding carboxylic acids or esters of carboxylic acids by otherovarian position 2 of the indoles of General formula 13 and the subsequent interaction with carbon dioxide or alkylchlorosilanes in accordance with I. Hasan, E. Marinelli, L. Lin, F. Fowler, A. Levy, J. Org. Chem. 46 (1981) 157; T. Kline J. Heterocycl. Chem. 22 (1985) 505; J. R. Dormoy, A. Heymes, Tetrahedron 49, (1993) 2885; E. Desarbre, S. Coudret, C. Meheust, J.-Y. Merour, Tetrahedron 53 (1997) 3637, as follows:

R45means hydrogen or a protective group, like, for example, benzosulfimide or tert-butoxycarbonyl.

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

Next, to obtain the desired substituents in the benzene nucleus and a heterocyclic nucleus of the cyclic system of indole in the formula I, the functional group introduced in the cyclic system in the process of indole synthesis can be chemically modified. For example, indoles bearing a hydrogen atom in position 2 or position 3, can also be obtained by saponification and subsequent decarboxylation of indoles bearing ester group in the corresponding position. Groups, carboxylic acid groups and acetic acid in position 2 or position 3 can be converted to their homologues in the usual reactions for chain elongation of carboxylic acids. The halogen atoms can be introduced in position 2 or position 3, for example, the interaction of the corresponding indolinone with a halogenation agent such as pentachloride phosphorus, similar to the method described J.C. Powers, J. Org. Chem. 31 (1966) 2627. Source indolinone for such synthesis can be obtained from 2-aminophen luxusni acids. Source derivatives of indole to produce compounds of formula I bearing a halogen substituent in position 3, can also be obtained in accordance with the methods described in the literature such as the following. For fluorination derivatives ethyl ester 1H-indole-2-carboxylic acid in position 3 is selected reagent is triplet N-fluoro-2,4,6-trimethylpyridine (T. Umemoto, S. Fukami, G. Tomizawa, K. Harazawa, K. Kawada, K. Tomita J. Am. Chem. Soc. 112 (1990) 8563 in order). Chlorination derivatives ethyl ester 1H-indole-2-carboxylic acid in position 3 by reaction with sulfurylchloride in benzene leads to the production of ethyl ester of 3-chloro-1H-indole-2-carboxylic acid (Chem. Abstr. 1962, 344i-3442b); the same result can be obtained by NCS (D. Comins, M. Killpack, Tetrahedron Lett. 33 (1989) 4337; M. Brennan, K. Erickson, F. Szmlac, M. Tansey, J. Thornton, Heterocycles 24 (1986) 2879). Bromination derivatives ethyl ester 1H-indole-2-carboxylic acid in position 3 can be achieved by reaction with NBS (M. Tani, H. Ikegami, M. Tashiro, T. Hiura, H. Tsukioka, Heterocycles 34 (1992) 2349). Similar to the techniques described above, NIS can be used effectively to salt derivatives ethyl ester 1H-indole-2-carboxylic acid in position 3. In addition, to salt derivatives ethyl ester 1H-indole-2-carboxylic acid in position 3 effective is the use of iodine (T. Sakamoto, T. Nagano, Y. Kondo, H. Yamanaka Chem. Pharm. Bull. 36 (1988) 2248).

In particular g is uppy, presents cyclical indole, can be modified by a number of reactions and, thus, can be obtained the required residues R1a, R1b, R1c, R1dand R1e. For example, the nitro group can be restored to the amino group of various reducing agents, such as sulfides, dithionite, a complex hydride, or by catalytic hydrogenation. The restoration of the nitro group can also be carried out at a late stage of the synthesis of the compounds of formula I, and the restoration of the nitro group to the amino group can also take place simultaneously with the reaction carried out according to another functional group, for example, when interacting groups, such as cyano, hydrogen sulfide or by hydrogenation of the group. To enter or create the residues R1a-ethe amino group can be further modified in accordance with the standard methods of alkylation, for example, by interaction with the (substituted) alkylhalogenide, or by reductive amination of carbonyl compounds in accordance with the standard methods of acylation, for example, by interaction with activated derivatives of carboxylic acids, such as anhydrides of the acids, anhydrides, activated esters or other, or by reaction with carboxylic acids in the presence of antiviruse what about the agent, or in accordance with standard techniques sulfonylamine, for example, by reaction with sulphonylchloride. Carboxylic acid chlorides of carboxylic acids or esters of carboxylic acids can be introduced according to the methods described by F. Santangelo, C. Casagrande, G. Norchini, F. Gerii, Synth. Commun. 23 (1993) 2717; P. Beswick, C. Greenwood, T. Mowlem, G. Nechvatal, D. Widdowson, Tetrahedron 44 (1988) 7325; V. Collot, M. Schmitt, P. Marwah, J. Bourguignon, Heterocycles 51 (1999) 2823. Halogen or hydroxy-group through triplet or nonflat, or primary amines via their salt, page, or after interconversion in the appropriate stannane, or baronova acid represented in the structure of indole, can be converted into a variety of other functional groups, such as-CN, -CF3, ethers, acids, esters, amides, amines, alkyl or aryl groups, mediated by transition metals, namely palladievye or Nickel catalysts or copper salts and reagents are, for example, refer below (F. Diederich, P. Stang, Metal-catalyzed Cross-coupling Reactions, Wiley-VCH, 1998; or M. Beller, C. Bolm, Transition Metals for Organic Synthesis, Wiley-VCH, 1998; J. Tsuji, Palladium Reagents and Catalysts, Wiley, 1996; J. Hartwig, Angew. Chem. 110 (1998) 2154; B. Yang, S. Buchwald, J. Were Obtained. Chem. 576 (1999) 125; T. Sakamoto, K. Ohsawa, J. Chem. Soc. Perkin Trans I, (1999), 2323; D. Nichols, S. Freskas, D. Marona-Lewicka, X. Huang, B. Roth, Gudelsky G., J. Nash, J. Med. Chem, 37 (1994), 4347; P. Lam, S. dark, S. Saubern, J. Adams, M. Winters, D. Chan, A. Combs, Tetrahedron Lett., 39 (1998) 2941; D. Chan, K. Monaco, R. Wang, M. Winters, Tetrahedron Lett., 39 (998) 2933; V. Farina, V. Krishnamurthy, W. Scott, The Stille Reaction, Wiley, 1994; A. Klaspars, X. Huang, S. Buchwald, J. Am. Chem. Soc. 124 (2002) 7421; F. Kwong, A. Klapars, S. Buchwald, Org. Lett. 4 (2002) 581; M. Wolter, G. Nordmann, G. Job, S. Buchwald, 4 (2002) 973).

Ester groups represented in the benzene nucleus, can be hydrolyzed to the corresponding carboxylic acids, which after activation can further interact with amines or alcohols under standard conditions. Simple ester groups represented in the benzene nucleus, such as benzyloxy or other easily otsepleniya ester group, can be derived from the receipt of the hydroxy groups, which can further interact with the various agents, for example, by esterification agents or activating agents, which allows the replacement of the hydroxy-group in other groups. Sulfur-containing groups may interact similarly.

In the course of the synthesis to modify the groups R50or R8'attached to the cyclic system of the indole applying the methodology of parallel synthesis, in addition to a variety of reactions, it may be useful to catalysis by palladium or copper salt. Such reactions are described, for example, F. Diederich, P. Stang, Metal-catalyzed Cross-coupling Reactions, Wiley-VCH, 1998; or M. Beller, C. Bolm, Transition Metals for Organic Synthesis, Wiley-VCH, 1998; J. Tsuji, Palladium Reagents and Catalysts, Wiley, 1996; J. Hartwig, Angew. Chem. 110 (1998) 2154; B. Yang, S. Buchwald, J. Were Obtained. Chem. 576 (1999) 125; P. Lam, C. Clark, S. Saubern, J. Adams, M. Winters, D. Chan, A. Combs, Tetahedron Lett., 39 (1998) 2941; D. Chan, K. Monaco, R. Wang, M. Winters, Tetrahedron Lett., 39 (1998) 2933; J. Wolfe, H. Tomori, J. Sadight, J. Yin, S. Buchwald, J. Org. Chem. 65 (2000) 1158; V. Farina, V. Krishnamurthy, W. Scott, The Stille Reaction, Wiley, 1994; A. Klaspars, X. Huang, S. Buchwald, J. Am. Chem. Soc. 124 (2002) 7421; F. Kwong, A. Klapars, S. Buchwald, Org. Lett. 4 (2002) 581; M. Wolter, G. Nordmann, G. Job, S. Buchwald, 4 (2002) 973.

The above reaction for the conversion of functional groups, in addition, in General, is extensively described in textbooks of organic chemistry, such as M. Smith, J. March, March's Advanced Organic Chemistry, Wiley-VCH, 2001, and in scientific works, such as Houben-Weyl, "Methods der Organischen Chemie" (Methods of Organic Chemistry), Georg Thieme 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 Heterocyclic Chemistry II, Elsenier Science, 1996), in which you can find details of the reactions and primary literary source. Due to the fact that in the present case the functional group attached to the indole ring, in some cases it may be necessary to specifically adapt reaction conditions or to choose specific reagents from a variety of reagents that can in principle be used in the reaction for the conversion or otherwise to take specific measures for achieving a desired conversion, for example, to use the methods with protective groups. However, finding a suitable reaction variants and p the offer conditions in such cases does not cause any problems for professionals in this field.

Structural elements presented in the residues in position 1 of the indole ring in the compounds of the formula I and in group COR8in position 2 and/or in position 3 of the indole ring can be entered in the source indole derivative, obtained as described above, sequential reaction stages using methodologies parallel synthesis, as shown below, using techniques that are well known specialist in this field.

The remains of R8'that can be entered into the formula 14, for example, by condensation of the corresponding carboxylic acid of formula 14 with a compound of formula HR8', i.e. with an amine of the formula HN(R1')R2'-V-G-M, to obtain the compounds of formula 15. The compound of formula 15, thus obtained, may already contain the desired final groups, i.e. groups of R8' and R50may represent a group-N(R1R2-V-G-M and R0-Q-as defined in the formula I, or optionally in the compound of formula 15, thus obtained, consistently residue or residues R8' and the remainder R50converted to residues-N(R1R2-V-G-M and R0-Q -, respectively, to give the desired compounds of formula I.

Thus, the residues R8'and the remains of R1'and R2'-V-G-M, sod is rasciesa in the structure, can 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 presented in the form of groups that can consistently be transformed into a nite group, R1and R2-V-G-M, i.e., functional groups can be represented as groups of precursors or derivatives, for example in protected form. In the course of obtaining the compounds of formula I in General can be beneficial 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 to temporarily block functional groups by using the strategy of protective groups suitable for the solution of the problem of synthesis. Such strategies are well known to specialists in this field (see for example, Greene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991, or P. Kocienski, Protecting Groups, Thieme 1994). As examples of groups precursor can be converted nitro and ceanography that at a later stage can be transformed into derivatives of carboxylic acids or restored in the aminomethyl group or nitro group, which can be transformed what to restore, such as catalytic hydrogenation, in the amino group. Protective groups can also be set to a solid phase, and cleavage from the solid phase means the removal of the protective group. The use of such methods known to experts in this area (Burgess, K. (Ed.) Solid Phase Organic Synthesis, New York: Wiley, 2000). For example, the phenolic hydroxy-group can be attached to triticosecale the resin, which serves as a protective group, and the molecule is cleaved from the resin by treatment TFUK at a late stage of the synthesis.

The remainder R50in the compounds of formulas 14 and 15 can mean the group-Q-R0as defined above, which must ultimately be presented in the desired target molecule of formula I, or it can mean a group that can consistently be transformed into the group-Q-R0for example, the group-precursor or derivative of the group-Q-R0in which functional groups are represented in protected form, or R50can mean a hydrogen atom or a protective group for the nitrogen atom of indole ring. Similarly, the residues R1e, R1a, R1b, R1cand R1din formulas 14 and 15 have corresponding definitions R7, R6, R5, R4and R3in the formula I, as defined above, however, for the synthesis of compounds of formula I, these balances can also be, in principle, before which taulani at the stage of condensation of the compounds of formula 14 with a compound of formula HR 8'giving the compound of formula 15 in the form of groups of precursors or in a protected form.

The remains of R49in compounds of formula 14, which may be the same or different, can represent, for example, hydroxy or (C1-C4)alkoxy, that is, the group COR49presented in compounds of formula 14 can be, for example, the free carboxylic acids or their esters, such as alkalemia esters, which can be a group COR8in the compounds of the formula I. the Group COR49can also be any other activated carboxylic acid derivative, which allows for the amide formation, the formation of ester or the formation of complex tiefer with the compound of the formula HR8'. The group COR49may also represent, for example, the acid chloride acid, activated ester, such substituted phenyl ether, asolid, such imidazoline, azide or a mixed anhydride, for example a mixed anhydride of ester of carboxylic acid or sulfonic acid derivatives which can be obtained from the carboxylic acids by standard methods and can interact with an amine, alcohol or mercaptan of the formula HR8'under standard conditions. The group COOH carboxylic acid, representing COR49in soy is ininii formula 14, can be obtained, for example, ester groups introduced into the indole system in the process of indole synthesis by standard methods of hydrolysis.

The compounds of formula I in which the group COR8is an ester group can also be obtained from compounds of formula 14 in which COR49represents a group of the carboxylic acid, by conventional esterification reactions, as, for example, the interaction of the acid with an alcohol under conditions of acid catalysis, or alkylation of salts of carboxylic acid electrophile, such as alkylhalogenide, or by transesterification from another of ester. The compounds of formula I in which the group COR8is the amide group can be obtained from amines and compounds of formula 14 in which COR49is a carboxylic acid group or its ether complex, through the conventional amination reactions. Especially for amides, compounds of formula 14 in which COR49is a carboxylic acid group, can be condensed under standard conditions with compounds HR8'who are amines, using a conventional condensing agent used in peptide synthesis. Such condensing reagents are, for example, carbodiimide as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, urbanistically, such as 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-R0presented in the indole of the formula I or the residue R50presented in the indole of formula 14, or a residue in which functional groups of the residue-Q-R0or R50represented in protected form or in the form of group-predecessor, not introduced during the previous stage, for example in the synthesis of indole nucleus, these residues can be, for example, is entered in position 1 of the indole system by conventional literature procedures well known to the person skilled in the art for N-alkylation, reductive amination, N-arilirovaniya, N-acylation or N-sulfonylamine ring atoms of nitrogen heterocycles. Source indole derivative for use in this reaction is the hydrogen atom in position 1. N-Alkylation of the ring nitrogen atom may, for example, be carried out under standard conditions, preferably in the presence of a base, using alkylating the compounds of formula LG-Q-R0or of the formula R50-LG, where the atom in the group Q or R50associated with the group LG, Yes the nom case represents an aliphatic carbon atom alkyl fragment and LG is a leaving group, for example a halogen, such as chlorine, bromine or iodine, or sulfonyloxy, such as tosyloxy, mesilate or tripterocalyx. LG may, for example, also be a hydroxy-group, which is to achieve the alkylation reaction is activated with conventional activating agent. To obtain the compounds for which a represents a direct bond and the aromatic group is directly related to the position 1 of the indole system, can be used generally accepted methods of arilirovaniya. For example, as the progress of the agents can be used aristorod, such as alkalicarbonate or 4-performativity. Such methods are described, for example, in S. Stabler, Jahangir, Synth. Commun. 24 (1994) 123; I. Khanna, R. Weier, Y. Yu, X. Xu. F. Koszyk, J. Med. Chem. 40 (1997) 1634. Alternatively, a large variety of substituted arisitide, the approach formulated above or aritifical can serve as progress agents on position 1 of the indole system mediated salt of copper or palladium reaction in accordance with R. Sarges, H. Howard, K. KOe, A. Wessmann, J. Med. Chem, 32 (1989) 437; P. Unangst, D. Connor, R. Stabler, R. Weikert, J. Hettrocecl. Chem, 24 (1987) 811; G. Tokmakov, I. Grandberg, Tetrahedron 51 (1995) 2091; Odd D., M. Harris, S. Buchwald, Org. Lett. 2 (2000) 1403, G. Mann, J. Hartwig, M. Driver, C. Fernandez-Rivas, J. Am. Chem. Soc. 120 (1998) 824; J. Hartwig, M. Kawatsura, S. Hauk, K. Shaughnessy, L. J. Org. Chem. 64 (1999) 5575. In addition, such arilirovaniya can also be terminated by reaction with a wide range of substituted arylboronic Ki the lot, as shown, for example, W. Mederski, M. Lefort, M. Germann, D. Kux, Tetrahedron 55 (1999) 12757.

During synthesis, the use of microwave equipment to expedite, facilitate or support reactions can be beneficial or even required in many cases. Some of the reactions, for example, described J.L. Krstenansky, I. Cotteril, Curr. Opin. Drug. Disc. & Development., 4 (2000), 454; P. Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron, 57 (2001, 9225; M. Larhed, A. Hallberg, Drug Discovery Today, 8 (2001) 406; S. Caddick, Tetrahedron, 51 (1995) 10403.

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

Compounds of the present invention are inhibitors of serine proteases that inhibit the activity of the enzymes of the blood coagulation factors XA and/or factor VIIa. In particular, they are highly active inhibitors of factor XA. They are specific inhibitors of serine proteases, insofar as they do not inhibit significantly 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 to specialists in this field. With respect to inhibition of factor XA preferred embodiment of the present invention includes compounds that have Ki 1 μm for the inhibition of factor XA, as defined in the analysis, description is nnom below, with a concomitant inhibition of factor VIIa or without him, and which preferably inhibits essentially the activity of other proteases that are included in coagulation and fibrinolysis, inhibition which is not desirable (when using the same concentration of the inhibitor). The compounds of this invention inhibit the catalytic activity of factor XA or directly in prothrombinase complex or in the form of a soluble subunit, or not directly inhibiting the embedding factor Ha prothrombinase complex.

The present invention also relates 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 the production of 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, for the production of pharmaceuticals for the treatment and prevention of heart cardiovascular disorders, thromboembolic diseases or restenoses. This invention also relates to the use of compounds of the formula I is/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 and prevention of cardiovascular disorders, thromboembolic diseases or restenoses, and to methods of treatment aimed at such problems, including methods for the specified treatment and prevention. The present invention also relates to pharmaceutical preparations (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 a conventional pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable substance-carrier or excipients and/or auxiliary substances or additives.

This invention also relates to the treatment of painful conditions such as abnormal thrombus formation, acute myocardial infarction, unstable angina, thromboembolism, acute occlusion of the vessel associated with thrombolytic therapy or percutaneous transluminal coronary angioplasty, transient ischemic attacks, stroke, pathologic thrombus formation occurring in the veins nor is their extremities after abdominal, knee and hip surgery, a risk of pulmonary thromboembolism, or diffuse systemic intravascular coagulopathy occurring in vascular systems during septic shock, certain viral infections or cancer.

The compounds of formula I and their physiologically tolerated salts and their prodrugs can be administered to animals, preferably mammals, and in particular, people in the form of pharmaceutical preparations for treatment or prevention. They can be administered by themselves or in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral administration.

The pharmaceutical agents can be administered orally, for example in the form of pills, tablets, lacquered 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 injection solutions or infusion solutions, microcapsules, implants or rods, or transdermally, or topically, e.g. in the form of ointments, solutions or mixtures, or in other ways, for example in the form of aerosols or nasal sprays.

Pharmaceutical preparations in accordance with the laws the AI with the invention are methods, known as such and familiar to a person skilled in the art, pharmaceutically suitable inert inorganic and/or organic media used in addition to the compound (compounds) of the formula I and/or its (their) physiologically acceptable salts and/or its (their) prodrugs. For the manufacture of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for example, lactose, corn starch or derivatives thereof, 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 hardened oils, etc. Suitable carriers for the production of solutions, for example injection solutions, or emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oil 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% by weight of 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 E. what about the prodrugs in the pharmaceutical preparations normally is from about 0.5 to 1000 mg, preferably from about 1 to 500 mg

In addition to the active ingredients of the formula I and/or their physiologically acceptable salts and/or prodrugs and substances media pharmaceutical preparations can contain additives such as, for example, excipients, disintegrators, binders, lubricants, moisturizing agents, stabilizers, emulsifiers, preservatives, sweeteners, pigments, perfumes, fragrances, thickeners, diluents, buffer substances, solvents, soljubilizatory, agents for achieving a depositing effect, salts for modifying the osmotic pressure, covering agents or antioxidants. They can also contain two or more compounds of formula I. when the pharmaceutical preparation contains one or more compounds of the formula I and/or physiologically-tolerated salts and/or prodrugs, the choice of individual connections can be routed to specific General pharmacological profile of a pharmaceutical product. For example, highly active connection with a shorter duration of action may be combined with a long acting compound with a lower activity. The flexibility permitted with respect to the choice of substituents in the compounds of formula I, makes possible a high degree of control over the biological and physico-chemical properties of the mi connections and thus, allowing selection of such desired connections. Furthermore, in addition to at least one compound of the formula I and/or its physiologically tolerable salts and/or prodrugs, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.

As inhibitors of factor XA and/or factor VIIa compounds of the formula I and/or their physiologically tolerated salts and/or 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 effect or which can favorably be influenced by inhibiting factor XA and/or factor VIIa, or if the reduction of their activities it is advisable for therapist. 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 blood coagulation plays a role or has an undesired extent, or which can favorably be influenced by reducing blood clotting, or for the prevention, mitigation or treatment which reduced asset is the awn system of blood coagulation is desirable for therapist. A specific object of the present invention, therefore, is the reduction or inhibition of unwanted blood clotting, particularly in a patient by introducing an effective amount of compound I or its physiologically tolerable salts, or prodrugs, as well as pharmaceutical products for these purposes.

The condition in which the compound of the formula I can favorably be used include, for example, cardiovascular disorders, thromboembolic diseases or complications associated with, for example, infection or surgical intervention. Compounds of the present invention can also be used to reduce the inflammatory response. Examples of specific disorders, for the treatment or prevention of which can be used the compounds of formula I, are coronary heart disease, myocardial infarction, angina pectoris, vascular restenosis, for example restenosis after angioplasty, such as RTS, respiratory distress syndrome of adults, multiple organ damage, bump and diffuse intravascular any bleeding disorder. Examples of related complications associated with surgery are thrombosis, such as thrombosis of deep veins and thrombosis in the proximal veins, which can occur after surgery. From the point C the value of their pharmacological activity of the compounds of this invention can replace or Supplement other anticoagulant funds such as heparin. The use of compounds of the invention may, for example, to save money compared with other anticoagulants. When using compounds of formula I dose may vary within a wide range and, as is usual and well known physician, its fit to the individual conditions in each individual case. It depends on your specific applicable compounds from nature and severity of the disease to be treated, the mode and schedule for the implementation or whether the condition for the treatment of acute or chronic or prevention is conducted. The appropriate dosage 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 for adult, having a weight of approximately 75 kg, is from 0.01 to 100 mg/kg, preferably from 0.1 to 50 mg/kg, in particular from 0.1 to 10 mg/kg (in each case in mg per 1 kg of body weight). The daily dose may be divided, in particular, in the case of the introduction of relatively large quantities for several, for example 2, 3 or 4, partial injections. As usual, depending on individual behaviour, it may be necessary to make a deviation up or down from a specified daily dose.

The compound of the formula I can also favorably be used is as an anticoagulant outside of the patient. For example, the effective amount of the compounds of the invention may come in contact with vegetarianism a sample of blood to prevent coagulation of the blood sample. Further, the compounds of formula I and salts thereof can be used for diagnostic purposes, for example for diagnosing in vitro, and as an aid in biochemical research. For example, the compound of the formula I can be used in the analysis for the identification of factor XA and/or factor VIIa or for selection of factor XA and/or factor VIIa in a substantially purified form. The compound of the invention may be labeled, for example, a radioactive isotope, and the labeled compound associated with factor XA and/or factor VIIa, further detects, using the common method used for detection of specific labels. Thus, the compound of formula I or its salt can be used as a probe to detect the location or magnitude 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 intermediate products of 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 is practical sequence for producing compounds applicable in the present invention, highlighted in the examples below. As explanation and valid methodology for the various aspects of the present invention are described where necessary. Assume that the following examples merely serve to illustrate the present invention and not limit it either by volume or entity. Specialists in this field will readily understand that known variations of the conditions and methods described in the examples can be used to synthesize compounds of the present invention.

It should be understood that changes that do not influence essentially on the activity of various embodiments of the present invention, included in the invention disclosed in the present description. Thus, assume that the following examples illustrate but do not limit the present invention.

Examples

When at the final stage of synthesis of the compounds used acid, such as triperoxonane acid or acetic acid, for example, when triperoxonane acid is used to remove the tert-butilkoi group or when the connection is purified by chromatography using an eluent which contains an acid, in some cases, depending on the method of processing, for example parts of freeze-drying, the connection get partially or completely in the form of salt used acid is, for example, as a salt of acetic acid or salt triperoxonane acid, or salts of hydrochloric acid. Abbreviations:

Tert-butylt-Bu
2,2'-Bis(diphenylphosphino-1,1'-binaphthylBinap
Bis-(oxo-3-oxazolidinyl)phosphorylchlorideBOP-Cl
Dibenzylideneacetonedba
DicyclohexylcarbodiimideDEPC
DichloromethaneDCC
DiethylphosphoramiditeDHM
4-DimethylaminopyridineDMAP
N,N-DimethylformamideDMF
The sulfoxideDMSO
EthyldiethanolamineDIPEA
1,1'-Bis(diphenylphosphino)ferroceneDPPE
Hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylureaHATU
N-BromosuccinimideNBC
N-ChlorosuccinimideNCS
N-JodatimeNIS
N-EthylmorpholineNEM
MethanolMeOH
Room temperatureKT
Tetrahydrofuran THF
Triperoxonane acidTFUK
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-indole-2-carboxylic acid

(i) tert-Butyl methyl ether (1-isopropylpiperazine-4-yl)carbamino 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 hours at room temperature 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 to obtain product as a white solid. The output of 4.8, MC(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 methanolic hydrochloric acid (8 M) and the mixture is stirred for casul. Removal of solvent under reduced pressure, followed by removal of residual volatile products joint evaporation twice with toluene receive the product. Output 5,42, MC(ES+): m/e=143.

(iii) Methyl ester 1H-indole-2-carboxylic acid

2 g of 1H-indole-2-carboxylic acid are dissolved in 15 ml of methanolic hydrochloric acid (8 M) and the mixture is stirred for 16 hours. After removal of the solvent under reduced pressure the residual volatile products are removed by joint distillation twice with 10 ml of toluene. The remaining solid is slightly yellow subjected to subsequent interaction without further purification. Output 2.3 g

(iv) Methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 244,2 mg methyl ester 1H-indole-2-carboxylic acid in 2 ml DMF at room temperature add 52,2 mg of sodium hydride (60% in oil). After stirring for 30 min add 500 mg of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol [obtained by adaptation of the method described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Puuls, 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.; Poll, Gregory C.; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] and the mixture is heated for 1 hour at 80°C. After further cooling reactio the Noah mixture to CT and add 5 ml of water the mixture is filtered through a cartridge chem elut® , elwira with ethyl acetate. After concentration under reduced pressure the residue is directly subjected to the subsequent saponification reaction without further purification. Yield 288 mg MC(ES+): m/e=373.

(v) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 288 mg of methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 10 ml of THF, add 3 ml of water and to 57.0 mg of the monohydrate of lithium hydroxide. After stirring for 2 h at 60°the reaction mixture is cooled to CT. The mixture is acidified policecontributing hydrochloric acid. The precipitate is collected by filtration and washed with 3 ml of water. The product is obtained in the form of a white solid, which is dried under reduced pressure.

Yield 253 mg of MC(ES+): m/e=359, the isotopic distribution of the chlorine atoms.

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

To a solution of 117 mg of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 1 ml DHM and 0.17 ml NEt3add 76 mg THIEF-Cl at RT and the mixture is stirred for 30 minutes After adding 81 mg of the hydrochloride of 1-isopropylpiperazine-4-ylamine the mixture is stirred over night. After removal of the solvent under reduced pressure the residue is purified preparative HPLC (C18 column with education the military phase, elution with a gradient mixture of H2O/MeCN with 0.1% TFUC). The fractions containing the product is evaporated and lyophilizers obtaining a white solid. The product is obtained in the form of its triptoreline salt.

Yield 93 mg MS (ES+): m/e=483, the isotopic distribution of the chlorine atoms.

A similar method of example 1 to obtain the following compounds.

ExampleStructureMC(ESI+)
2561, the isotopic distribution of the chlorine atoms
3528, the isotopic distribution of the chlorine atoms
4589, the isotopic distribution of the chlorine atoms
5517, the isotopic distribution of the chlorine atoms
6513, the isotopic distribution of the chlorine atoms
7513, the isotopic distribution of the chlorine atoms
8497, the isotopic distribution of the chlorine atoms
543, the isotopic distribution of the chlorine atoms
10543, the isotopic distribution of the chlorine atoms
11528, the isotopic distribution of the chlorine atoms
12567, the isotopic distribution of the chlorine atoms
13497, the isotopic distribution of the chlorine atoms
14582, the isotopic distribution of the chlorine atoms
15513, the isotopic distribution of the chlorine atoms
16559, the isotopic distribution of the chlorine atoms
17529, isotopic distribution of chlorine atoms
18519, the isotopic distribution of the chlorine atoms
19589, the isotopic distribution of the chlorine atoms
20517, the isotopic distribution of the chlorine atoms
21517, the isotopic distribution of the chlorine atoms
22511, the isotopic distribution of the chlorine atoms
23501, the isotopic distribution of the chlorine atoms
24604, the isotopic distribution of the chlorine atoms
25593, the isotopic distribution of the chlorine atoms
26519, the isotopic distribution of the chlorine atoms
27573, isotopic distribution of chlorine atoms

Example 28: (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

(i) tert-Butyl ether (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)carbamino acid

A solution of 3 g of tert-butyl methyl ether piperidine-4-icarb mirovoi acid and 2.5 g of 4-chloropyridine in 9 ml of a mixture n-butanol/water/Net 3(1:1:1) is heated at 100°C for 48 hours. The solution is cooled to CT, diluted DHM and washed with a solution of NaHCO3and then water. The organic layer is dried over Na2SO4and the solvent is removed under reduced pressure. Chromatographic purification of the residue on silica gel with DHM as eluent, after evaporation of the fractions containing the product, receive a white foam. The output of 1.7,

(ii) 3,4,5,6-Tetrahydro-2H-[1,4']bipyridinyl-4-ylamine

To a solution of 4 g of tert-butyl methyl ether (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)carbamino acid in 4 ml DHM at RT add 12 ml TFUCK. After stirring for 20 h the solution was diluted with 20 ml of toluene and evaporated under reduced pressure. The remainder together is distilled twice with toluene and used in subsequent reactions without further purification. The product is obtained in the form of its triptoreline salt.

Output 2.1 g

(iii) (3,4,5,6-Tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylicacid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use 3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylamine.

MS (ESI+): m/e=518, the isotopic distribution of the chlorine atoms.

Example 29: (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)am the d 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 28 with the difference that instead of 1H-indole-2-carboxylic acid using 7-methyl-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=532, the isotopic distribution of the chlorine atoms.

Example 30: (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 28 with the difference that instead of 1H-indole-2-carboxylic acid using 5-nitro-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=563, the isotopic distribution of the chlorine atoms.

Example 31: {1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano

(i) tert-Butyl ether 4-(pyridine-4-ylamino)piperidine-1-carboxylic acid

A solution of 2.5 g of tert-butyl methyl ether 4-aminopiperidin-1-carboxylic acid and 2.5 g of 4-chloropyridine in 9 ml of a mixture n-butanol/water/NEt3(1:1:1) is heated at 100°With over 85 hours. Then, the solution is cooled to CT, diluted DHM and washed with a solution of NaHCO3and then water. The organic layer is dried over Na2SO4and the solvent is removed under reduced pressure. Chromate is a graphical purification of the residue on silica gel with DHM as eluent, after evaporation of the fractions containing the product, receive a white foam. Yield 1.7 g

(ii) piperidine-4-espiridion-4-ylamine

To a solution of 1.7 g of tert-butyl ester 4-(pyridine-4-ylamino)piperidine-1-carboxylic acid in 4 ml DHM at RT add 12 ml TFUCK. After stirring for 20 h the solution was diluted with 20 ml of toluene and evaporated under reduced pressure. The remainder together is distilled twice with toluene and used in subsequent reactions without further purification. The product is obtained in the form of its triptoreline salt. The output of 4.0,

(iii) {1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use piperidine-4-espiridion-4-ylamine.

MS (ESI+): m/e=518, the isotopic distribution of the chlorine atoms.

Example 32: {1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano

Specified in the header of the connection will receive is similar to the method of example 31, with the difference that instead of 1H-indole-2-1H-indole-2-carboxylic acid using 5-nitro-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=563, the isotopic distribution of the chlorine atoms.

Example 33: {1-[5-(5-what cortifen-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano

Specified in the header of the connection will receive is similar to the method of example 31, with the difference that instead of 1H-indole-2-carboxylic acid using 7-methyl-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=532, the isotopic distribution of the chlorine atoms.

Example 34: {1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-isopropylpiperazine-1-yl)methanon

(i) tert-Butyl ether 4-isopropylpiperazine-1-carboxylic acid

To a solution of 1.5 g of tert-butyl methyl ether 4-aminopiperidin-1-carboxylic acid in 20 ml of acetonitrile added to 2.6 ml of acetone, 0,94 g Na(CN)BH3and 0.3 ml of acetic acid. After stirring for 16 h at RT 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 dried over Na2SO4. Removal of solvent under reduced pressure to obtain white solid.

The output of 2.8, MS (ESI+): m/e=243.

(ii) Isopropylpiperazine-4-ylamine

To a solution of 2.8 g of tert-butyl methyl ether 4-isopropylpiperazine-1-carboxylic acid in 8 ml DHM at RT add 4 ml TFUCK. After stirring for 20 h the solution was diluted with 20 ml of Tolu is La and evaporated under reduced pressure. The remainder together is distilled twice with toluene and used in subsequent reactions without further purification. The product is obtained in the form of its triptoreline salt.

The output of 4.4 g MS (ESI+): m/e=143.

(iii) {1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-isopropylpiperazine-1-yl)methanon

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use isopropylpiperazine-4-ylamine.

MS (ESI+): m/e=483, the isotopic distribution of the chlorine atoms.

Example 35: {1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indol-2-yl}-(4-isopropylpiperazine-1-yl)methanon

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1H-indole-2-carboxylic acid using 7-methyl-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=497, the isotopic distribution of the chlorine atoms.

Example 36: (1 ethylpiperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

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

To a solution of 5 g of tert-butyl methyl ether piperidine-4-ylcarbamate acid in 20 ml of methanol, add 5.6 ml of acetaldehyde, 3.2 g of Na(CN)BH3and 3.2 ml of acetic key is lots. After stirring for 16 h at RT the solvent is removed under reduced pressure and the residue partitioned between 30 ml of water and 200 ml of ethyl acetate. The organic layer was washed with a saturated solution of Na2CO3, water and dried over Na2SO4. Removal of solvent under reduced pressure to obtain white solid. The output of 4.4,

(ii) 1-Ethylpiperidine-4-ylamine

To 4.4 g of tert-butyl methyl ether (1-ethylpiperazin-4-yl)carbamino acid in 15 ml of methanol are added 20 ml of methanolic hydrochloric acid (8 M) and the mixture is stirred for 16 hours Removal of solvent under reduced pressure to obtain white solid, which together evaporated twice with toluene. The product is obtained in the form of its hydrochloride.

The output of 4.3,

(iii) (1-Ethylpiperazin-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use 1-ethylpiperidine-4-ylamine.

MS (ESI+): m/e=469, the isotopic distribution of the chlorine atoms.

Example 37: (1 ethylpiperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 36 with the difference, instead of 1H-indole-2-carboxylic acid using 7-methyl-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=483, the isotopic distribution of the chlorine atoms.

Example 38: {1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-pyrrolidin-1-reparacin-1-yl)methanon

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use 4-pyrrolidin-1-reprein.

MS (ESI+): m/e=509, the isotopic distribution of the chlorine atoms.

Example 39: {1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-[4-(1-methylpiperidin-4-yl)piperazine-1-yl]metano

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine using 1-(1-methylpiperidin-4-yl)piperazine.

MS (ESI+): m/e=524, the isotopic distribution of the chlorine atoms.

Example 40: [1,4']bipyridinyl-1'-yl-{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}metano

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use [1,4']bipyridinyl.

MS (ESI+): m/e=523, the isotopic distribution of the chlorine atoms.

Example 41: (3-pyridin-4-yl-4,5-dihydroisoxazole-5-ilma who yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use S-(3-pyridin-4-yl-4,5-dihydroisoxazole-5-yl)methylamine.

MS (ESI+): m/e=518, the isotopic distribution of the chlorine atoms.

Example 42: (4-aminoquinazolin-7-ylmethyl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use 7-aminomethylbenzoic-4-ylamine [Ewing, William R. PCT Int. Appl. (2001), 466 pp. WO 0107436 A2].

MC (ESI+): m/e=518, the isotopic distribution of the chlorine atoms.

Example 43: {1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-pyridin-4-iletileri-1-yl)methanon

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine using 1-pyridin-4-iletileri

MC (ESI+): m/e=518, the isotopic distribution of the chlorine atoms.

Example 44: 3,5-dichloraniline 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive the same methodology applied is as 1 with the difference, instead of 1-isopropylpiperazine-4-ylamine use a 3.5-dichlorbenzene.

MC (ESI+): m/e=516, the isotopic distribution of the chlorine atoms.

Example 45: (4-tert-butylphenyl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use 4-tert-butylbenzylamine.

MS (ESI+): m/e=490, the isotopic distribution of the chlorine atoms.

Example 46: (1 isopropylpiperazine-4-ylmethyl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

(i) tert-Butyl methyl ether (1-isopropylpiperazine-4-ylmethyl)carbamino acid

To a solution of 1 g of tert-butyl methyl ether piperidine-4-ylcarbamate acid in 20 ml of acetonitrile added to 2.6 ml of acetone and 586 mg Na(CN)BH3. After stirring for 16 h at RT 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 dried over Na2SO4. Removal of solvent under reduced pressure to obtain white solid.

The output 802 mg

(ii)-(1-Isopropylpiperazine-4-yl)methylamine

To a solution of 802 mg of tert-butyl methyl ether (1-isopropylpiperazine-4-ylmethyl)carbamino acid in 5 ml DHM added at room temperature 4 ml TFUCK. After stirring for 20 h the solution was diluted with 20 ml of toluene and evaporated under reduced pressure. The remainder together is distilled twice with toluene and used in subsequent reactions without further purification. The product is obtained in the form of its triptoreline salt. The output of 1.7,

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

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use-(1-isopropylpiperazine-4-yl)methylamine.

MS (ESI+): m/e=496, the isotopic distribution of the chlorine atoms.

Example 47: (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide indole-2-carboxylic acid

(i) tert-Butyl ether (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)carbamino acid

A suspension of 5 g (23,3 mmol) tert-butyl ether piperidine-4-iletilerinindeki acid and 3.85 g (of 25.7 mmol) of the hydrochloride of 4-chloropyridine in 15 ml of a mixture of n-BuOH/H2O/NEt3(1:1:1) is refluxed for 3 days. After removal of the solvent under reduced pressure the AI residue purified by chromatography on silica gel with a mixture DHM/Meon (100:1→ 50:1→10:1-5:1). The product is obtained in the form of a white solid.

The output of 4.3,

(ii) C-(3,4,5,6-Tetrahydro-2H-[1,4']bipyridinyl-4-yl)methylamine

To a solution 4,58 g tert-butyl ether (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)carbamino acid in 12 ml DHM added at room temperature, 12 ml TFUCK. After stirring for 30 min the solution was diluted with 20 ml of toluene and evaporated under reduced pressure. The residue is distilled twice together with toluene and used in subsequent reactions without further purification. The product is obtained in the form of its triptoreline salt.

Output 3.3V,

(iii) (3,4,5,6-Tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use of C-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)methylamine.

MS (ESI+): m/e=532, the isotopic distribution of the chlorine atoms.

Example 48: (1 cyclopropylidene-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

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

To a suspension of 1 g of tert-butyl methyl ether piperidine-iletilerinindeki acid, 2 g svezheasfaltirovannaya molecular sieves 3A, 1 ml of acetic acid, 6 ml of 1-amoxicillinprescription in 25 ml of methanol add 22.5 ml of Na(CN)BH3(1 M in THF) and refluxed for 2 hours. The reaction mixture was filtered through a layer of celite, concentrated under reduced pressure and the residue is transferred into ethyl acetate. The organic layer was washed with 1 M NaOH and saturated NaCl solution and finally dried over Na2SO4. The evaporation of the solvents under reduced pressure to obtain a clear oil. The output of 1.44,

(ii) 1-Cyclopropylidene-4-ylamine

The solution to 0.72 g of tert-butyl methyl ether (1-cyclopropylidene-4-yl)carbamino acid in 5 ml DHM CT add 3 ml TFUCK. After stirring for 20 h the solution was diluted with 20 ml of toluene and evaporated under reduced pressure. The residue is distilled twice together with toluene and used in subsequent reactions without further purification. The product is obtained in the form of its triptoreline salt.

Yield 870 mg

(iii) (1-Cyclopropylidene-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use 1-cyclopropylidene-4-ylamine.

MS ESI+): m/e=481, the isotopic distribution of the chlorine atoms.

Example 49: [1-(tetrahydropyran-4-yl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

(i) tert-Butyl ether 4-({1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}amino)piperidine-1-carboxylic acid

To a solution of 1 g of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid and 1.4 ml of NEM in 5 ml DHM add 0.9 g TOTU and the mixture is stirred for 30 min at RT. Next, add 0.7 g of tert-butyl methyl ether 4-aminopiperidin-1-carboxylic acid and the reaction mixture is stirred for 16 hours. After removal of the solvent under reduced pressure the residue is purified by chromatography on silica gel using a mixture of ethyl acetate/heptane (4:1) as eluent. The fractions containing the product evaporated to obtain a white foam. Output 1,

(ii) piperidine-4-alamid 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To 1 g of tert-butyl ester 4-({1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}amino)piperidine-1-carboxylic acid, add 10 ml of methanolic hydrochloric acid (8 M) and the mixture is stirred at RT for 2 hours. After removal of the solvent under reduced pressure OST the current is distilled twice with 10 ml of toluene. The obtained solid is slightly yellow color used in subsequent reactions without further purification.

The output of 0.85,

(iii) [1-(Tetrahydropyran-4-yl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

In a solution of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid and 35 mg tetrahydropyran-4-it is in 2 ml of acetonitrile enter 14 mg Na(CN)BH3. After stirring at RT for 16 h, the reaction mixture was concentrated under reduced pressure and purified preparative HPLC (C 18 column with reversed phase elution with a gradient mixture of H2O/MeCN with 0.5% TFUC). The fractions containing the product, evaporated and lyophilizers. The product is obtained in the form of its triptoreline salt.

Exit 14 mg MS (ESI+): m/e=525, the isotopic distribution of the chlorine atoms.

Similar to the method of example 49 receive the following connections.

ExampleStructureMC(ESI+)
50495, the isotopic distribution of the chlorine atoms
51509, the isotopic distribution of the chlorine atoms

Example 52: (1 isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-1H-indole--carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 1-methyl bromide-3-methoxybenzoyl. MS (ESI+): m/e=406.

ExampleStructureMS(ESI+)
53441
54420
55455
56441
57441
58427
59439, the isotopic distribution of the chlorine atoms
60438
61405
62441
63413
64 420

Example 65: (4-pyridin-4-ylphenyl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid

(i) (4-Itfinal)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid

To a solution of 500 mg of 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid in 8 ml DHM and 0.9 ml NEt3when the CT type 452 mg THIEF-Cl and the mixture is stirred for 30 minutes After adding 583 mg of 4-idfamilia the mixture is stirred for 16 hours. Next, the solvent is removed under reduced pressure to obtain a white precipitate, which is washed with 1 ml of a mixture of Meon/GHM (1:1). Exit 380 mg.

(ii) (4-Pyridine-4-ylphenyl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid

A solution of 100 mg (4-itfinal)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid, 31 mg of 4-pyridylamino acid and 200 μl of an aqueous solution of Na2CO3(2 M) in 5 ml of dimethoxyethane (DME) is blown with argon for 15 minutes Then add 20 mg of Pd(PPh3)4and the mixture is heated at 80°C for 16 hours. Finally add 3 ml of a saturated solution of NaHCO3and the mixture is filtered through a cartridge chem elut® with elution by ethyl acetate. After subsequent removal of the solvent under reduced pressure the residue is purified preparative HPLC (C18 column with reversed phase elution what radianta mixture of H 2O/MeCN with 0.1% TFUC). The fractions containing the product, evaporated and lyophilizers obtaining a white solid. The product is obtained in the form of its triptoreline salt. Output 15 mg

MC(ESI+): m/e=434.

Example 66: (1 isopropylpiperazine-4-yl)amide of 4-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 52 with the difference that instead of 1H-indole-2-carboxylic acid using 4-methoxy-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=436.

Example 67: (1 isopropylpiperazine-4-yl)amide 5-chloro-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 57 with the difference that instead of 1H-indole-2-carboxylic acid using 5-chloro-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=440, the isotopic distribution of the chlorine atoms.

Example 68: (1 isopropylpiperazine-4-yl) amide 6-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 52 with the difference that instead of 1H-indole-2-carboxylic acid using 6-methoxy-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=436.

Example 69: (1 isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-methyl-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 52 with the difference that instead of 1H-indole-2-carboxylic acid using 5-methyl-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=420.

Example 70: (1 isopropylpiperazine-4-yl)amide 5-benzyloxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 52 with the difference that instead of 1H-indole-2-carboxylic acid using 5-benzyloxy-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=512.

Example 71: (1 isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-5-nitro-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 52 with the difference that instead of 1H-indole-2-carboxylic acid using 5-nitro-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=451.

Example 72: (1 isopropylpiperazine-4-yl)amide 5-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 52 with the difference that instead of 1H-indole-2-carboxylic acid using 5-methoxy-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=436.

Example 73: (1 isopropylpiperazine-4-yl)amide 1-(3-methods Dibenzoyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol use 3-methoxybenzoate.

MS (ESI+): m/e=420.

Example 74: (1 isopropylpiperazine-4-yl)amide 1-(3-methoxybenzenesulfonyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol use 3-methoxybenzenesulfonamide.

MS (ESI+): m/e=456.

Example 75: (1 isopropylpiperazine-4-yl)amide 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid

(i) Methyl ester 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid

To a suspension of 2 g of methyl ester 1H-indole-2-carboxylic acid, 3.2 g of 4-methoxyphenylacetic acid, 2 g of molecular sieves (4Å), 1.7 ml of pyridine, 3 ml NEt3in 40 ml DHM type of 3.9 g of Cu(SLA)2. The suspension is stirred for 3 days at RT and for 2 days at 50°With, then add 3 ml of a saturated solution of NaHCO3and the mixture is filtered through a cartridge chem elut® with elution by ethyl acetate. After concentration under reduced pressure and chromatographic purification on silica gel with a mixture of ethyl acetate/heptane (4:1) fraction, the soda is containing product, evaporated. Exit 3,

(ii) 1-(4-Methoxyphenyl)-1H-indole-2-carboxylic acid

To a solution of 3 g of methyl ester 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid in 50 ml of THF, add 10 ml of water and of 0.58 g of the monohydrate of lithium hydroxide. After stirring for 2 h at 60°the reaction mixture is cooled to CT. The mixture is acidified policecontributing hydrochloric acid, the precipitate is collected by filtration and washed with 10 ml of water. The product is obtained in the form of a white solid, which is dried under reduced pressure. The output of 520 mg.

(vi) (1-Isopropylpiperazine-4-yl)amide 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid

To a solution of 36 mg of 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid in 1 ml DHM and 0.17 ml NEt3CT added 34 mg THIEF-Cl and the mixture is stirred for 30 minutes After adding 57 mg of the hydrochloride of 1-isopropylpiperazine-4-ylamine the mixture is stirred over night. Next, the solvent is removed under reduced pressure and the residue purified preparative HPLC (C18 column with reversed phase elution with a gradient mixture of H2O/MeCN with 0.1% TFUC). The fractions containing the product, evaporated and lyophilizers obtaining a white solid. The product is obtained in the form of its triptoreline salt.

Exit 14 mg MC (ESI+): m/e=329.

Similar to the method of example 75 receive the following connections.

ExampleStructureMC (ESI+)
76427
77391
78424
79405
80424
81441
82425, the isotopic distribution of the chlorine atoms
83413
84427
85427

Example 86: 4-pyridine-4-ylbenzene 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid

(i) tert-Butyl ether (4-bromobenzyl)carbamino acid

To a solution of 5 g of 4-bromobenzylamine and 7 ml NEt3in 30 ml DHM type of 5.4 g of Boc2O. After stirring for 16 h at RT, the reaction mixture was concentrated and the precipitate collected by filtration. T is erdy the product is dried under reduced pressure and used in subsequent reactions without further purification. The output of 6.5,

(ii) tert-Butyl ether (4-pyridin-4-ylbenzyl)carbamino acid

A solution of 500 mg of tert-butyl methyl ether (4-bromobenzyl)carbamino acid, 213 mg of 4-pyridylamino acid and 500 μl of an aqueous solution of Na2CO3(2 M) in 5 ml of dimethoxyethane rinsed with argon for 15 minutes Then add 60 mg of Pd(PPh3)4and the mixture is heated at 100°C for 16 hours. Finally, add 10 ml of a saturated solution of NaHCO3and the mixture is filtered through a cartridge chem elut® with elution by ethyl acetate. After subsequent removal of the solvent under reduced pressure the residue is purified by chromatography on silica gel with ethyl acetate as eluent. The fractions containing the product evaporated to obtain white solids. The output 490 mg.

(iii) 4-Pyridine-4-eventelement

To a solution of 490 mg of tert-butyl methyl ether (4-pyridin-4-ylbenzyl)carbamino acid in 2 ml of DHM CT add 3 ml TFUCK. After stirring for 12 hours the reaction mixture was diluted with 10 ml toluene and evaporated under reduced pressure to obtain a brown foam. The product is obtained in the form of its triptoreline salt. The output 330 mg

(iv) 4-Pyridine-4-ylbenzene 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid

To a solution of 50 mg 1-(4-methoxyphenyl)-1H-indole-2-carbon is howling acid and 100 µl of the NEt 3in 2 ml of DHM CT added 47 mg THIEF-Cl. After 1 hour, add 51 mg of 4-pyridine-4-ivesiana and the reaction mixture is stirred for 16 hours. After removal of the solvent under reduced pressure the residue is purified preparative HPLC (C18 column with reversed phase elution with a gradient mixture of H2O/MeCN with 0.1% TFUC). The fractions containing the product, evaporated and lyophilizers obtaining a white solid. The product is obtained in the form of its triptoreline salt.

Yield 27 mg of MC (ESI+): m/e=434.

Example 87: (1 isopropylpiperazine-4-yl)amide 1-(3-methoxyphenyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 75 with the difference that instead of 4-methoxyphenylacetic acid using 3-methoxyphenylalanine acid.

MC (ESI+): m/e=392.

Example 88: (1 isopropylpiperazine-4-yl)amide 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 75 with the difference that instead of 4-methoxyphenylacetic acid using 3-Chlorfenvinphos acid.

MC (ESI+): m/e=396, the isotopic distribution of the chlorine atoms.

Similar to the method of example 88 receive the following connections.

Example StructureMC (ESI+)
89431, the isotopic distribution of the chlorine atoms
90396, the isotopic distribution of the chlorine atoms
91409, the isotopic distribution of the chlorine atoms
92417, the isotopic distribution of the chlorine atoms
93431, the isotopic distribution of the chlorine atoms
94431, the isotopic distribution of the chlorine atoms
95428, the isotopic distribution of the chlorine atoms
96445, the isotopic distribution of the chlorine atoms
97429, the isotopic distribution of the chlorine atoms

Example 98: 4-pyridine-4-ylbenzene 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid

Specified in the header connection receive similar is offered by the method of example 86 with the difference, instead of 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid using 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=438, the isotopic distribution of the chlorine atoms.

Example 99: (1 isopropylpiperazine-4-yl)amide 1-(3,5-dichlorophenyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 75 with the difference that instead of 4-methoxyphenylacetic acid use a 3.5-dichlorophenylamino acid.

MC (ESI+): m/e=430, the isotopic distribution of the chlorine atoms.

A similar method of example 99 receive the following connections.

ExampleStructureMC (ESI+)
100430, the isotopic distribution of the chlorine atoms
101465, the isotopic distribution of the chlorine atoms
102479, the isotopic distribution of the chlorine atoms
103465, the isotopic distribution of the chlorine atoms
104451, isotopic distribution automobilia
105465, the isotopic distribution of the chlorine atoms

Example 106: (1 isopropylpiperazine-4-yl)amide 1-(4-chlorophenyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 75 with the difference that instead of 4-methoxyphenylacetic acid using 4-Chlorfenvinphos acid.

MC (ESI+): m/e=396, the isotopic distribution of the chlorine atoms.

Similar to the method of example 107 receive the following connections.

108428, the isotopic distribution of the chlorine atoms
109415, the isotopic distribution of the chlorine atoms
110429, the isotopic distribution of the chlorine atoms
111410, the isotopic distribution of the chlorine atoms
112445, the isotopic distribution of the chlorine atoms
113431, isotopic distribution is of the chlorine atoms
114431, the isotopic distribution of the chlorine atoms
115431, the isotopic distribution of the chlorine atoms
116396, the isotopic distribution of the chlorine atoms

Example 117: 4-pyridine-4-ylbenzene 1-(4-chlorophenyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 86, with the difference that instead of 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid using 1-(4-chlorophenyl)-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=438, the isotopic distribution of the chlorine atoms.

Example 118: (1 isopropylpiperazine-4-yl)amide 1-(4-aminoquinazolin-7-ylmethyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol use 7-bromethalin-4-ylamine [obtained by adaptation of the method described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Puuls, 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 C.; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2].

MC (ESI+): me=443.

Example 119: (1 isopropylpiperazine-4-yl)amide 1-(6-chlorobenzo[b]thiophene-2-ylmethyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 2-methyl bromide-6-chloro-benzo[b]thiophene [obtained by adaptation of the method described by Ewing, William R. et al. in PCT Int. Appl. (1999), 300 pp. WO 9937304 Al, and Ewing, William R. et al. PCT Int. Appl. (2001), 460 pp. WO 0107436 A2].

MC(ESI+): m/e=466, the isotopic distribution of the chlorine atoms.

Example 120: (1 isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole-2-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 2-methyl bromide-5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole [obtained by adaptation of the method described by Ewing, William R. et al. PCT Int. Appl. (2001), 460 pp. WO 0107436 A2].

MC (ESI+): m/e=500, the isotopic distribution of the chlorine atoms.

Example 121: (1 isopropylpiperazine-4-yl)amide 1-[3-(5-chlorothiophene-2-yl)isoxazol-5-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazolines 5-methyl bromide-3-(5-chlorothiophene-2-yl)isoxazol [Ewing, William R. et al. PCT Int. Appl. (2001), 460 pp. WO 0107436 A2].

MC (ESI+): m/e=483, the isotopic distribution of the chlorine atoms.

Example 122: (1 isopropylpiperazine-4-yl)amide 3-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 40 mg of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid type (1-isopropylpiperazine-4-yl)amide in 1 ml DHM, 17 mg NCS and the mixture is stirred at RT for 16 hours. Finally, the reaction mixture was directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt.

Output 15 mg MC (ESI+): m/e=517, the isotopic distribution of the chlorine atoms.

Example 123: (1 isopropylpiperazine-4-yl)amide 3-bromo-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 40 mg of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid type (1-isopropylpiperazine-4-yl)amide in 1 ml DHM, 22 mg of NBS and the mixture is stirred at RT over night. Finally, the reaction mixture was directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt.

Example 124: (1 isopropylpiperazine-4-yl)amide 1-(4-Chlorobenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 1-chloromethyl-4-chlorobenzene.

MC (ESI+): m/e=410, the isotopic distribution of the chlorine atoms.

Similar to the method of example 124 receive the following connections.

ExampleStructureMC (ESI+)
125445, the isotopic distribution of the chlorine atoms
126409, the isotopic distribution of the chlorine atoms
127423, the isotopic distribution of the chlorine atoms
128431, the isotopic distribution of the chlorine atoms
129443, the isotopic distribution of the chlorine atoms
130445, the isotopic distribution of the ATO is s chlorine
131442, the isotopic distribution of the chlorine atoms
132445, the isotopic distribution of the chlorine atoms
133445, the isotopic distribution of the chlorine atoms
134459, the isotopic distribution of the chlorine atoms

Example 135: (1 isopropylpiperazine-4-yl)amide 1-(2,4-dichlorobenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 1-chloromethyl-2,4-dichlorobenzene.

MC (ESI+): m/e=444, the isotopic distribution of the chlorine atoms.

Similar to the method of example 135 receive the following connections.

ExampleStructureMC (ESI+)
136465, the isotopic distribution of the chlorine atoms
137493, the isotopic distribution of the chlorine atoms
138 479, the isotopic distribution of the chlorine atoms
139457, isotopic distribution of chlorine atoms
140479, the isotopic distribution of the chlorine atoms
141479, the isotopic distribution of the chlorine atoms
142476, the isotopic distribution of the chlorine atoms
143478, the isotopic distribution of the chlorine atoms

Example 144: (1 isopropylpiperazine-4-yl)amide 1-(4-methoxybenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 1-chloromethyl-4-methoxybenzoyl.

MC (ESI+): m/e=406.

Example 145: (4-isopropylpiperazine-1-yl)-[1-(4-methoxybenzyl)-1H-indol-2-yl]metano

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use 4-isopr preparedin-1-ylamine.

MC (ESI+): m/e=406.

Example 146: (1 isopropylpiperazine-4-yl)amide 1-(4-cryptomaterial)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 1-methyl bromide-4-cryptomaterial.

MC (ESI+): m/e=459.

Example 147: (4-isopropylpiperazine-1-yl)-[1-(4-cryptomaterial)-1H-indol-2-yl]metano

Specified in the header of the connection will receive is similar to the method of example 146, with the difference that instead of 1-isopropylpiperazine-4-ylamine use isopropylpiperazine-4-ylamine.

MC (ESI+): m/e=459.

Example 148: (1 isopropylpiperazine-4-yl)amide 1-(2-Chlorobenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 1-methyl bromide-2-chlorobenzene.

MC (ESI+): m/e=410, the isotopic distribution of the chlorine atoms.

Similar to the method of example 148 receive the following connections.

ExampleStructureMC (ESI+)
149410, from Topsoe distribution of chlorine atoms
150459, the isotopic distribution of the chlorine atoms
151409, the isotopic distribution of the chlorine atoms
152443, the isotopic distribution of the chlorine atoms
153431, the isotopic distribution of the chlorine atoms
154423, the isotopic distribution of the chlorine atoms
155445, the isotopic distribution of the chlorine atoms
156445, the isotopic distribution of the chlorine atoms

Example 157: (1 isopropylpiperazine-4-yl)amide 1-(3,5-dichlorobenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 1-chloromethyl-3,5-dichlorobenzene.

MC (ESI+): m/e=444, the isotopic distribution of the chlorine atoms.

Example 158: [1-(3,5-dichlorobenzyl)-1H-indol-2-yl]-(4-isopropylpiperazine-1-yl)methane is

Specified in the header of the connection will receive is similar to the method of example 157 with the difference that instead of 1-isopropylpiperazine-4-ylamine use isopropylpiperazine-4-ylamine.

MC (ESI+): m/e=443, the isotopic distribution of the chlorine atoms.

Example 159: (1 isopropylpiperazine-4-yl)amide 3-fluoro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 40 mg (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 1 ml DHM add 22 mg of the triflate N-herperidin and the mixture is stirred at RT for 4 days. Finally, the reaction mixture was directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt.

Yield 22 mg MC (ESI+): m/e=501, the isotopic distribution of the chlorine atoms.

Example 160: (1 isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-1H-indole-2-carboxylic acid

(i) Methyl ester of 3-iodine-1H-indole-2-carboxylic acid

To a solution of 2 g of methyl ester 1H-indole-2-carboxylic acid and 2.1 g of KOH in 20 ml of DMF is added dropwise at RT add a solution of 2.7 g 12 in 10 ml of DMF. After 30 min the reaction speciesbased solution of 2.5 G. of NaHSO 3in 100 ml of water. The product is collected as a white precipitate by filtration and washed with 10 ml of water. Exit 3,

(ii) Methyl ether 3-cyano-1H-indole-2-carboxylic acid

To a solution of 2 g of methyl ester of 3-iodine-1H-indole-2-carboxylic acid in 10 ml of DMF and 20 ml of THF added 1.5 g of CuCN, 434 mg Et4NCN and 461 mg DPPF and the mixture is blown with argon for 15 minutes Then injected 254 mg Pd2(dba)3and the reaction mixture is heated at 80°C for 5 hours. Finally, add 10 ml of a saturated solution of NaHCO3and the mixture is filtered through a cartridge chem elut® elution DHM. After further removal of the solvent under reduced pressure the residue is purified by chromatography on silica gel with ethyl acetate as eluent. The fractions containing the product evaporated to obtain white solids. Output 1,2,

(iii) Methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-1H-indole-2-carboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 1 (iv)using methyl ester of 3-cyano-1H-indole-2-carboxylic acid as the starting material.

(iv) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-1H-indole-2-carboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 1 (v), using metrowater 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-1H-indole-2-carboxylic acid as the starting material.

(v) (1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-1H-indole-2-carboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 1 (vi), using 1-[5- (5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-1H-indole-2-carboxylic acid as the starting material.

MS (ESI+): m/e=508, the isotopic distribution of the chlorine atoms.

Example 161: (1 isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-7-methyl-1H-indole-2-carboxylic acid

This connection will receive is similar to the method of example 86, with the difference that instead of the methyl ester 1H-indole-2-carboxylic acid using methyl ester 7-methyl-1H-indole-2-carboxylic acid.

MS (ESI+): m/e=522, the isotopic distribution of the chlorine atoms.

Example 162: (1 isopropylpiperazine-4-yl)amide 1-[2-(5-chlorothiophene-2-yl)isoxazol-5-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 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].

MC (ESI+): m/e=499, the isotopic distribution of the chlorine atoms.

Example 163: (1 isopropylpiperazine-4-yl)amide 1-(3-Chlorobenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 1-methyl bromide-3-chlorobenzene.

MC (ESI+): m/e=410, the isotopic distribution of the chlorine atoms.

Example 164: [1-(3-Chlorobenzyl)-1H-indol-2-yl]-(4-isopropylpiperazine-1-yl)methanon

Specified in the header of the connection will receive is similar to the method of example 163 with the difference that instead of 1-isopropylpiperazine-4-ylamine use isopropylpiperazine-4-ylamine.

MC (ESI+): m/e=409, the isotopic distribution of the chlorine atoms.

Example 165: (1 isopropylpiperazine-4-yl)amide 1-(3-carbamoylmethyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol use 3-bromocinnamic.

MC (ESI+): m/e=419.

Example 166: 3-[2-(4-isopropylpiperazine-1-carbonyl)indole-1-ylmethyl]benzamide

Specified in the header of the connection will receive is similar to the method of example 165 with the difference that instead of 1-isopropylpiperazine-4-ylamine use isopropy the piperidine-4-ylamine.

MC (ESI+): m/e=419.

Example 167: (1 isopropylpiperazine-4-yl)amide 1-(3,5-dimethoxybenzyl)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol using 1-chloromethyl-3,5-dimethoxybenzene.

MC (ESI+): m/e=435.

Example 168: [1-(3,5-dimethoxybenzyl)-1H-indol-2-yl]-(4-isopropylpiperazine-1-yl)methanon

Specified in the header of the connection will receive is similar to the method of example 167 with the difference that instead of 1-isopropylpiperazine-4-ylamine use isopropylpiperazine-4-ylamine.

MC (ESI+): m/e=435.

Example 169: (1 isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-1H-indole-2-carboxylic acid

(i) 2-(4-Chlorophenyl)ethyl ester toluene-4-sulfonic acid

5 g (31.9 per mmol) of 2-(4-chlorophenyl)ethanol was dissolved in 100 ml of pyridine and the solution cooled to 0°C. To the solution was added 6,09 g (31.9 per mmol) para-toluensulfonate and the reaction mixture stirred at 0°C for 2 h, then at room temperature for 16 hours. The solvent is removed under reduced pressure, the residue is transferred into ethyl acetate and the solution washed once with saturated aqueous sodium bicarbonate solution, once with water and is continuously saturated aqueous sodium chloride. The organic phase is dried with sodium sulfate, filter and remove the solvent under reduced pressure. The compound is recrystallized from a mixture of n-heptane/ethyl acetate.

Output 6,23, MS (CI+): m/e=311, the isotopic distribution of the chlorine atoms.

(ii) Ethyl ester 1-[2-(4-chlorophenyl)ethyl]-1H-indole-2-carboxylic acid

0.5 g (2.6 mmol) of ethyl ester 1H-indole-2-carboxylic acid is dissolved in DMF and added 116 mg (2.9 mmol) of sodium hydride (60% dispersion in mineral oil). The solution is stirred for 30 min at room temperature, then cooled to -78°C. To this chilled solution was added a solution of 0.82 g (2.6 mmol) of 2-(4-chlorophenyl)ethyl ester toluene-4-sulfonic acid in DMF. The solution is heated to CT and stirred for 16 hours. The solvent is removed under reduced pressure, the residue is transferred into ethyl acetate and the solution washed once with saturated aqueous sodium bicarbonate solution, once with water and once with saturated aqueous solution of sodium chloride. The organic phase is dried with magnesium sulfate, filter and remove the solvent under reduced pressure. The remainder chromatographic on silica gel with elution with a gradient mixture of n-heptane/ethyl acetate.

The output of 480 mg. MS (CI+): m/e=328, the isotopic distribution of the chlorine atoms.

(iii) 1-[2-(4-Chlorophenyl)ethyl]-1H-indole-2-carboxylic acid

Mg (1.5 mmol) of ethyl ester 1-[2-(4-chlorophenyl)ethyl]-1H-indole-2-carboxylic acid are dissolved in 5 ml of dioxane and add 5 ml of 2 N. an aqueous solution of sodium hydroxide. The reaction mixture is heated at 60°C for 2 h, then cooled to 0°C. the Solution was diluted with 10 ml of water and bring the solution pH to a value from 2 to 3 by addition of concentrated aqueous HCl until precipitation of the product. The product is filtered and dried under reduced pressure.

The output 390 mg MS (CI+): m/e=300, the isotopic distribution of the chlorine atoms.

(iv) (1-Isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-1H-indole-2-carboxylic acid

50 mg (0.2 mmol) of ethyl ester 1-[2-(4-chlorophenyl)ethyl]-1H-indole-2-carboxylic acid are dissolved in 2 ml of DMF and add 54,7 mg (0.2 mmol) of TOTU and 0.21 ml (1.7 mmol) of NEM. This solution was stirred at room temperature for 30 minutes Add up 35.9 mg (0.2 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine and the resulting solution was stirred at room temperature for 16 hours. The product was then purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt.

Output 46,9 mg MS (TOF-ESI+): m/e=424, the isotopic distribution of the chlorine atoms.

Example 170: (1 isopropylpiperazine-4-yl)amide 1-[2-(2,4-dichlorophenyl)ethyl]-1H-indole-2-carboxylic acid

(i) 2-(2,4-Dichlorophenyl)ethyl ester toluene-4-sulfon the howling acid

This connection receive, using a technique similar to that described for obtaining the compound of example 169 (i)using 2-(2,4-dichlorophenyl)ethanol as the starting material. This compound is recrystallized from a mixture of n-heptane/ethyl acetate.

Output 7,12, MS (CI+): m/e=345, the isotopic distribution of the chlorine atoms.

(ii) Ethyl ester 1-[2-(2,4-dichlorophenyl)ethyl]-1H-indole-2-carboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 169 (ii)using 2-(2,4-dichlorophenyl)ethyl ester toluene-4-sulfonic acid as the starting material.

Yield 91 mg MS (LC-MS-ESI+): m/e=362, the isotopic distribution of the chlorine atoms.

(iii) 1-[2-(2,4-Dichlorophenyl)ethyl]-1H-indole-2-carboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 169 (iii)using ethyl ester 1-[2-(2,4-dichlorophenyl)ethyl]-1H-indole-2-carboxylic acid as the starting material.

Yield 69 mg MS (CI+): m/e=334, the isotopic distribution of the chlorine atoms.

(iv) (1-Isopropylpiperazine-4-yl)amide 1-[2-(2,4-dichlorophenyl)ethyl]-1H-indole-2-carboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 169 (iv), using 1-[2-(2,4-dichlorophenyl)ethyl]-1H-indole-2-carboxylic acid in quality is TBE source of the substance.

Yield 69 mg MS (CI+): m/e=334, the isotopic distribution of the chlorine atoms.

Example 171: (1 isopropylpiperazine-4-yl)amide 1-[2-(3-methoxyphenyl)ethyl]-1H-indole-2-carboxylic acid

(i) 2- (3-Methoxyphenyl)ethyl ester toluene-4-sulfonic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 169 (i)using 2-(3-methoxyphenyl)ethanol as the starting material. This connection chromatographic on silica gel with elution with a mixture of n-heptane/ethyl acetate (4:1).

Output 5,13, MS (CI+): m/e=306 (M+).

(ii) Ethyl ester 1-[2-(3-methoxyphenyl)ethyl]-1H-indole-2-carboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 169 (ii)using 2-(3-methoxyphenyl)ethyl ester toluene-4-sulfonic acid as the starting material.

The output 554 mg. MS (LC-MS-ESI+): m/e=324 (M+N+).

(iii) 1-[2-(3-Methoxyphenyl)ethyl]-1H-indole-2-carboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 169 (iii)using ethyl ester 1-[2-(3-methoxyphenyl)ethyl]-1H-indole-2-carboxylic acid as the starting material.

Exit 384 mg MS (CI+): m/e=296 (M+N+).

(iv) (1-Isopropylpiperazine-4-yl)amide 1-[2-(3-methoxy who enyl)ethyl]-1H-indole-2-carboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 169 (iv), using 1-[2-(3-methoxyphenyl)ethyl]-1H-indole-2-carboxylic acid as the starting material.

Yield 44 mg MS(LC-MS-ESI): m/e=419 (M+).

Example 172: (1 isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-methoxy-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 169 with the difference that it is used as the starting material methyl ester 4-methoxy-1H-indole-2-carboxylic acid.

Yield 67 mg of MC(ES+): m/e=454 (M+), the isotopic distribution of the chlorine atoms.

Example 173: (1 isopropylpiperazine-4-yl)amide of 4-bromo-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1H-indole-2-carboxylic acid using 4-bromo-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=562, the isotopic distribution of the chlorine atoms.

Example 174: (1 isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-methyl-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of the fact 1H-indole-2-carboxylic acid using 4-methyl-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=497, the isotopic distribution of the chlorine atoms.

Example 175: (1 isopropylpiperazine-4-yl)amide 5-bromo-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1H-indole-2-carboxylic acid using 5-bromo-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=562, the isotopic distribution of the chlorine atoms.

Example 176: (1 isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-cyano-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1H-indole-2-carboxylic acid using 5-cyano-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=508, the isotopic distribution of the chlorine atoms.

Example 177: (1 isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-trifluoromethyl-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1H-indole-2-carboxylic acid using 4-trifluoromethyl-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=551, the isotopic distribution of the chlorine atoms.

Example 178: (1 isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene--yl)isoxazol-3-ylmethyl]-4,7-dimethyl-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1H-indole-2-carboxylic acid using 4,7-dimethyl-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=511, the isotopic distribution of the chlorine atoms.

Example 179: (1 isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1H-indole-2-carboxylic acid using 4,7-dimethoxy-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=543, the isotopic distribution of the chlorine atoms.

Example 180: (1 isopropylpiperazine-4-yl)amide 4,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1H-indole-2-carboxylic acid using 4,7-dichloro-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=551, the isotopic distribution of the chlorine atoms.

Example 181: (1 isopropylpiperazine-4-yl)amide 5,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header connection receive similar metadisciplinary 1 with the difference, instead of 1H-indole-2-carboxylic acid using 5,7-dichloro-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=551, the isotopic distribution of the chlorine atoms.

Example 182: (1 isopropylpiperazine-4-yl)amide of 4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1H-indole-2-carboxylic acid using 4-chloro-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=517, the isotopic distribution of the chlorine atoms.

Example 183: (4-metapopulation-1-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that instead of 1-isopropylpiperazine-4-ylamine use 4-methylpiperazin-1-ylamine.

MC (ESI+): m/e=456, the isotopic distribution of the chlorine atoms.

Example 184: ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}- (1-isopropylpiperazine-4-yl)amino]acetic acid

(i) Ethyl ester (1-isopropylpiperazine-4-ylamino)acetic acid

To a solution of 1 g of the hydrochloride of 1-isopropylpiperazine-4-ylamine in 10 ml of DMF added 1.2 g of ethyl ester of 2-bromoxynil acid, 2.3 g Cs2CO3the 2 ml NEt 3and the reaction mixture is stirred for 2 hours at RT. Finally, add 10 ml of a saturated solution of NaHCO3and the mixture is filtered through a cartridge chem elut® elution DHM. After evaporation of the solvent under reduced pressure the product is obtained as white foam and used in subsequent reactions without further purification. The output of 1.3,

(ii) Ethyl ester [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

To a solution of 70 mg of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid in 1 ml DMF add 0.1 ml NEt3, 47 mg THIEF-Cl and 81 mg of ethyl ether (1-isopropylpiperazine-4-ylamino)acetic acid and the mixture is stirred for 16 hours. After removal of the solvent under reduced pressure the residue is filtered through a cartridge chem elut® elution with ethyl acetate and further purified preparative HPLC (C18 column with reversed phase elution with a gradient mixture of H2O/MeCN with 0.1% TFUC). The fractions containing the product, evaporated and lyophilizers obtaining a white solid. The product is obtained in the form of its triptoreline salt.

The output of 9.3 mg MS (ES+): m/e=583, the isotopic distribution of the chlorine atoms.

Example 185: [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amine is]acetic acid

To a solution of 15 mg of ethyl ether [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid in 2 ml of a mixture of water/THF (1:2) add 25 ál of an aqueous solution of NaOH (2 M) and the reaction mixture stirred for 16 h at RT. The reaction mixture is acidified by adding hydrochloric acid (5 ml), concentrated under reduced pressure and the residue is transferred in DHM. Inorganic salts are filtered off, the filtrate is concentrated under reduced pressure, transferred into 1 ml of water and lyophilizers obtaining a white solid. The product is obtained in the form of its HCl salt.

Output 5 mg MS (ES+): m/e=555, the isotopic distribution of the chlorine atoms.

Example 186: [1-(1-ethylpropyl)piperidine-4-yl)]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 49 with the difference that instead of tetrahydropyran-4-she is using pentane-3-one.

MC (ESI+): m/e=511, the isotopic distribution of the chlorine atoms.

Example 187: (1 methylpiperidin-4-yl)]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole--carboxylic acid in 1 ml DMF and 40 ál NEt 3CT added 24 mg of methyliodide and the reaction mixture is stirred for 4 hours. After removal of the solvent under reduced pressure the residue directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt.

Yield 32 mg of MC (ES+): m/e=455, the isotopic distribution of the chlorine atoms.

Example 188: [1-(2,2,2-triptorelin)piperidine-4-yl)]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 187, with the difference that 2-iodine-1,1,1-trifluoroethane is used instead of methyliodide.

MC (ESI+): m/e=523, the isotopic distribution of the chlorine atoms.

Example 189: (1 formylpiperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

A solution of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 2 ml of formic acid is heated at 100°C for 5 hours. After removal of the solvent under reduced pressure the residue directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization, the product is obtained as a white solid.

Exit 14 mg MC (ES+): m/e=469, the isotopic distribution of the chlorine atoms.

Example 190: (1 carbamoylbiphenyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 2 ml of acetic acid added 14 mg KOCN at RT and stirred over night. After removal of the solvent under reduced pressure the residue directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of a white solid.

Yield 31 mg of MC (ES+): m/e=484, the isotopic distribution of the chlorine atoms.

Example 191: (1 methanesulfonanilide-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 2 ml of DHM at RT add 0.3 ml NEt3and 20 mg of methanesulfonamide and stirred for 16 hours. After removal of the solvent under reduced pressure the residue directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization receive in the form of a white solid.

Yield 23 mg of MC (ES+): m/e=519, the isotopic distribution of the chlorine atoms.

Example 192: (1 acetylpiperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 2 ml of DHM at RT add 0.3 ml NEt3and 11 mg of acetic anhydride and stirred overnight. After removal of the solvent under reduced pressure the residue directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of a white solid.

Yield 24 mg of MC (ES+): m/e=483, the isotopic distribution of the chlorine atoms.

Example 193: [1-(2-chloropyrimidine-4-yl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

(i) tert-Butyl ether [1-(2-chloropyrimidine-4-yl)piperidine-4-yl]carbamino acid

To a solution of 500 mg of tert-butyl methyl ether piperidine-4-ylcarbamate acid in 6 ml of a mixture of n-BuOH/water/NEt3(1:1:1) add 557 mg of 2,4-dichloropyrimidine and the reaction mixture is heated at 100°With during the night. After cooling the reaction mixture to CT the solvent is evaporated under reduced pressure and the mod is to endure in ethyl acetate, washed twice with water and then a saturated solution of salt. The organic layer is dried over Na2SO4and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel with elution with a mixture of ethyl acetate/heptane 2:1. The fractions containing the product, evaporated under reduced pressure to obtain white solid. Yield 630 mg

(ii) 1-(2-Chloropyrimidine-4-yl)piperidine-4-ylamine

To a solution of 250 mg of tert-butyl methyl ether [1-(2-chloropyrimidine-4-yl)piperidine-4-yl]carbamino acid in 1 ml DHM add 1 ml TFUK and the mixture is stirred for 2 hours at RT. Next, add 10 ml of toluene and the solvents removed under reduced pressure. The residue is distilled twice with toluene to obtain a yellow oil. The product is obtained in the form of its triptoreline salt. Yield 367 mg

(iii) [1-(2-Chloropyrimidine-4-yl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 100 mg 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 3 ml DHM add 91 mg TOTU and 0.13 ml of NEM. This solution was stirred at room temperature for 30 minutes Then add 148 mg trifenatate 1-(2-chloropyrimidine-4-yl)piperidine-4-ylamine and the resulting solution was stirred at room temperature for 16 hours. The product was then purified preparative RP-HPLC with elution Grady is Tom 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt.

Yield 71 mg of MC (ES+): m/e=553, the isotopic distribution of the chlorine atoms.

Example 194: (1-pyrimidine-4-reparacin-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-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, add 20 mg of Pd/C (10%) and the mixture is blown with argon for 10 minutes Then the flask contents are stirred in hydrogen atmosphere for 5 h at RT. After adding 10 ml of ethyl acetate, the reaction mixture was filtered through a layer of celite. The solvent is evaporated under reduced pressure and the residue is distilled twice with toluene to obtain the product as a white solid. The output of 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 DHM add 2 ml TFUK and the mixture is stirred for 2 hours at RT. Next, add 10 ml of toluene and the solvents removed under reduced pressure. The residue is distilled twice with toluene to obtain a yellow oil. The product is obtained in the form of its triptoreline salt. Output 703 mg

(iii) (1-P is rimidine-4-reparacin-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 100 mg 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 3 ml DHM add 91 mg TOTU and 0.13 ml of NEM. This solution was stirred at room temperature for 30 minutes Then add 135 mg trifenatate 1-pyrimidine-4-reparacin-4-ylamine and the resulting solution was stirred at room temperature for 16 hours. The product was then purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt.

Yield 52 mg of MC (ES+): m/e=519, the isotopic distribution of the chlorine atoms.

Example 195: {1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-[4-(pyridine-4-yloxy)piperidine-1-yl]metano

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that the use of 4-(piperidine-4-yloxy)pyridine [obtained by the adapted method described Baxter, Andrew Douglas; Owen, David Alan; Montana, John Gary; Robert John PCT Int. Appi. (1999), 44 pp. WO 9924399 Al] instead of 1-isopropylpiperazine-4-ylamine.

MC (ESI+): m/e=519, the isotopic distribution of the chlorine atoms.

Example 196: [4-(1H-imidazol-4-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header connection receive similar is yodice of example 1 with the difference, using 4-(1H-imidazol-4-yl)phenylamine instead of 1-isopropylpiperazine-4-ylamine.

MC (ESI+): m/e=500, the isotopic distribution of the chlorine atoms.

Example 197: (4-pyridine-3-iltiazem-2-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that use 4-pyridine-3-iltiazem-2-ylamine instead of 1-isopropylpiperazine-4-ylamine.

MC (ESI+): m/e=518, the isotopic distribution of the chlorine atoms.

Example 198: [3-(pyrrolidin-1-carbonyl)-4,5-dihydroisoxazole-5-ylmethyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that they use (5-aminomethyl-4,5-dihydroisoxazole-3-yl)pyrrolidin-1-ylmethanone instead of 1-isopropylpiperazine-4-ylamine.

MC (ESI+): m/e=538, the isotopic distribution of the chlorine atoms.

Example 199: (1 isobutylparaben-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 187, with the difference that 1-iodine-2-methylpropan used instead of methyliodide.

MC (ESI+): m/e=497, the isotopic distribution of the chlorine atoms./p>

Example 200: (1 propylpiperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 187, with the difference that 1-iodopropane used instead of methyliodide.

MC (ESI+): m/e=483, the isotopic distribution of the chlorine atoms.

Example 201: methyl ester of 4-({1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}amino)piperidine-1-carboxylic acid

To a solution of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 2 ml of DHM at RT add 0.3 ml NEt3and 20 mg of methylchloroform and stirred over night. After removal of the solvent under reduced pressure the residue directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt as a white solid.

Yield 24 mg of MC (ES+): m/e=499, the isotopic distribution of the chlorine atoms.

Example 202: (4-isopropylpiperazine-1-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

(i) tert-Butyl ether 4-aminopiperidin-1-carboxylic acid

To a solution of piperazine-1-silts is in 20 ml of THF and to 1.37 ml NEt 3when 0°With added dropwise 2.2 g Vos2About 5 ml of THF. The reaction mixture was stirred for 16 h at RT, then add 50 ml of ethyl acetate and 20 ml of water. The organic layer is separated, washed with saturated salt solution and dried over Na2SO4. After removal of the solvent under reduced pressure the product is obtained in the form of a white solid. Output 1,53,

(ii) tert-Butyl ether 4-({1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}amino)piperazine-1-carboxylic acid

To a solution of 1 g of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid and 1.3 ml of NEM in 8 ml DHM add 914 mg TOTU and the mixture is stirred for 30 min at RT. Next add 673 mg of tert-butyl methyl ether 4-aminopiperidin-1-carboxylic acid and the reaction mixture was stirred over night. After removal of the solvent under reduced pressure the residue directly purified by chromatography on silica gel with elution with a gradient mixture of ethyl acetate/heptane. The output of 1.1,

(iv) Piperazine-1-alamid 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To 1.1 g of tert-butyl ester 4-({1-[5-(5-chlorothiophene-2-yl) isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}amino)piperazine-1-carboxylic acid in 5 ml of Meon add 20 ml of a saturated methanolic solution of HCl and the reaction mixture is stirred for 5 h p and CT. Next, add 70 ml of toluene and the solvent is evaporated under reduced pressure to obtain yellow solid. The product is obtained in the form of its triptoreline salt. Output 941 mg

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

To 100 mg piperazine-1-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 2 ml methanol and 2 ml of DMF and 0.2 ml of acetone add 0,42 ml of Na(CN)NR3in THF (1 M) and the mixture is heated at 80°C for 30 minutes After cooling the reaction mixture to CT the solvent is removed under reduced pressure and the residue directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt.

Yield 39 mg of MC(ESI+): m/e=484, the isotopic distribution of the chlorine atoms.

Example 203: (4-ethylpiperazin-1-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 202 with the difference that acetaldehyde is used instead of acetone in the recovery stage amination.

MC(ESI+): m/e=470, the isotopic distribution of the chlorine atoms.

Example 204: pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']BP is idini-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

(i) tert-Butyl ether pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)carbamino acid

A solution of 5 g of tert-butyl methyl ether piperidine-4-ylcarbamate acid and 8 g of the hydrochloride of 4-chloropyridine in 9 ml of a mixture n-butanol/water/NEt3(1:1:1) is heated at 100°C for 48 hours. Next, the reaction mixture is cooled to CT, concentrated under reduced pressure and directly purified by chromatography on silica gel with elution DHM. The fractions containing the product, evaporated under reduced pressure to obtain a white foam. Exit 7,

(ii) Pyridinyl-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)Amin

To 2 g of tert-butyl methyl ether pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)carbamino acid in 10 ml of Meon add 30 ml of a saturated methanolic solution of HCl and stirred for 5 hours at RT. Next, add 70 ml of toluene and the solvent is evaporated under reduced pressure to obtain yellow solid. The product is obtained in the form of its triptoreline salt. The output of 1.6,

(iii) Pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a solution of 200 mg 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid and 0.3 ml of NEM in 2 ml DHM add 182 mg TOTU and the mixture is stirred for 30 m is h at RT. Next, add 170 mg of pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amine and the reaction mixture is stirred for 16 hours. After removal of the solvent under reduced pressure the residue directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt.

Yield 39 mg of MC(ESI+): m/e=595, the isotopic distribution of the chlorine atoms.

Example 205: pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic acid

Specified in the header connection receive analogous to the methods of example 204, with the difference that using 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic carboxylic acid instead of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=642, the isotopic distribution of the chlorine atoms.

Example 206: (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 160 with the difference that use 3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylamine instead of 1-isopropylate the one-4-ylamine.

MC (ESI+): m/e=543, the isotopic distribution of the chlorine atoms.

Example 207: (1 isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-dead-4-methoxy-1H-indole-2-carboxylic acid

(i) Methyl ester of 3,7-dead-4-methoxy-1H-indole-2-carboxylic acid

To a solution of 1 g of methyl ester 4-methoxy-1H-indole-2-carboxylic acid in 15 ml DHM CT add to 5.4 g tetrafluoroborate bis(pyridine)iodone (I) and the reaction mixture was stirred over night. Next, the reaction mixture was diluted with 20 ml DHM and washed with saturated solution of Na2S2O3and water. The organic layer is separated, dried over Na2SO4and the solvent is removed under reduced pressure. The rest is used in subsequent reactions without further purification. The output of 1.6,

(ii) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-dead-4-methoxy-1H-indole-2-carboxylic acid.

To a solution of 200 mg of methyl ester of 3, 7-dead-4-methoxy-1H-indole-2-carboxylic acid in 2 ml DMF at room temperature, add 20 mg of sodium hydride (60% in oil). After stirring for 30 min add 121 mg of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol [obtained by adaptation of the method described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Puuls, 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, regory C.; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] and the mixture is heated for 1 hour at 60°C. After further cooling the reaction mixture to CT and add 5 ml of water the mixture is filtered through a cartridge chem elut®, elwira with ethyl acetate. After concentration under reduced pressure the residue is treated with 30 mg of the monohydrate of lithium hydroxide in a mixture of THF/water (2:1). After stirring for 2 h at 60°the reaction mixture is cooled to CT. The mixture is acidified policecontributing hydrochloric acid to pH 2, the precipitate is collected by filtration and washed with 3 ml of water. The product is obtained in the form of a white solid, which is dried under reduced pressure. Yield 200 mg.

(vi) (1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-dead-4-methoxy-1H-indole-2-carboxylic acid

To a solution of 100 mg 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-dead-4-methoxy-1H-indole-2-carboxylic acid and 0.1 ml of NEM in 2 ml DHM add 63 mg TOTU and the mixture is stirred for 30 min at RT. Next, add 41 mg of the hydrochloride of 1-isopropylpiperazine-4-ylamine and the reaction mixture is stirred for 2 hours. After removal of the solvent under reduced pressure the residue directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of e is about triptoreline salt.

Yield 67 mg of MC (ESI+): m/e=765, the isotopic distribution of the chlorine atoms.

Example 208: (1 isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-dicyano-4-methoxy-1H-indole-2-carboxylic acid

To a solution of 20 mg (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-dead-4-methoxy-1H-indole-2-carboxylic acid in 1 ml DMF and 1 ml of THF added mg CuCN, 4 mg Et4NCN, 5 mg of DPPE and the mixture is blown with argon for 15 minutes Then administered 3 mg Pd2(dba)3and the reaction mixture is heated for 5 min at 120°under microwave irradiation (150 W, the device Discover THISTM). Finally, add 10 ml of a saturated solution of NaHCO3and the mixture is filtered through a cartridge chem elut® elution DHM. After removal of the solvent under reduced pressure the residue directly purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt.

Output 3 mg MC (ESI+): m/e=563, the isotopic distribution of the chlorine atoms.

Example 209: (1 isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)thiazol-4-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1, however the one, that being alkylation using 4-chloromethyl-2-(4-chlorophenyl)thiazole instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol.

MC (ESI+): m/e=493, the isotopic distribution of the chlorine atoms.

Example 210: (1 isopropylpiperazine-4-yl)amide 1-(1,7-dichlorethylene-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that at the stage of alkylation using 3-methyl bromide-1,7-dichlorethylene [obtained by adaptation of the method described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Puuls, 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 C.; PCT Int. Appi. (1999), 300 pp.WO 9937304 A1] instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol.

MC (ESI+): m/e=495, the isotopic distribution of the chlorine atoms.

Example 211: (1 isopropylpiperazine-4-yl)amide 1-[3-(4-chlorophenyl)isoxazol-5-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that at the stage of alkylation using 5-chloromethyl-3-(4-chlorophenyl)isoxazol instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol.

MC (ESI+): m/e=477, the isotopic distribution of the chlorine atoms.

Example 212: (1 isopropylpiperazine-4-yl)amide 1-[5-(4-chlorophenyl)isoxazol-3-ylmethyl]-1H-Indo) - Rev.-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that at the stage of alkylation using 3-chloromethyl-5-(4-chlorophenyl)isoxazol instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol.

MC (ESI+): m/e=477, the isotopic distribution of the chlorine atoms.

Example 213: (1 isopropylpiperazine-4-yl)amide 1-[3-(4-chlorophenyl)-[1,2,4]oxadiazol-5-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that at the stage of alkylation using 5-chloromethyl-3-(4-chlorophenyl)-[1,2,4]oxadiazol instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol.

MC (ESI+): m/e=478, the isotopic distribution of the chlorine atoms.

Example 214: (1 isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-methanesulfonyl-1H-indole-2-carboxylic acid

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

To a solution of 5 g of 5-chloropyridin-2-ylamine and 1.5 ml of pyridine in 30 ml of toluene is added dropwise while cooling with ice, add 8 g of bromoacetamide in 10 ml of toluene. After 2 hours the precipitate are filtered and recrystallized from toluene to obtain a white solid. Exit 12,

(ii) 1-[(5-Chloropyridin-2-ylcarbonyl)methyl]-5-methanesulfonyl-1H-indole-2-carboxylic acid.

To a solution of 1 g of methyl ester of 5-methanesulfonyl-1H-indole-2-carboxylic acid in 10 ml of DMF at RT add 158 mg of sodium hydride (60% in oil). After stirring for 10 min add 985 mg of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide and the mixture is stirred for 2 hours. After adding 7 ml of water the mixture is filtered through a cartridge chem elut® elution with ethyl acetate and concentrated under reduced pressure. The residue is transferred into 10 ml of a mixture of water/THF (1:2) and treated with 2 ml of an aqueous solution of KOH (10%). After stirring for 16 h at RT the reaction mixture is acidified with hydrochloric acid (5 M). The precipitate is collected by filtration and dried in vacuum to obtain the product as a yellow solid. The output of 1.1,

(iii) (1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-methanesulfonyl-1H-indole-2-carboxylic acid

To a solution of 500 mg of 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-methanesulfonyl-1H-indole-2-carboxylic acid in 5 ml of DMF and 0.7 ml NEt3when the CT type 312 mg THIEF-Cl and 264 mg of the hydrochloride of 1-isopropylpiperazine-4-ylamine and the mixture is stirred for 16 hours. Next, the solvent is removed under reduced pressure and the residue purified preparative HPLC (C18 column with reversed phase elution with a gradient mixture of H2O/MeCN with 0.1% TFUC). The fractions containing the product, evaporated and lyophilizers obtaining a white solid. The product is obtained in the form of its triptoreline salt.

The output 364 mg MS (ES+): m/e=532, isotopic distribution is their chlorine atoms.

Example 215: (1 isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-5-methanesulfonyl-1H-indole-2-karbonvansty

Specified in the header of the connection will receive is similar to the method of example 214 with the difference that at the stage of alkylation using 2-bromo-N-(4-chlorophenyl)ndimethylacetamide instead of 2-bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide.

MC (ESI+): m/e=531, the isotopic distribution of the chlorine atoms.

Example 216: (1 isopropylpiperazine-4-yl)amide 5-chloro-1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 214 with the difference that use methyl ester 5-chloro-1H-indole-2-carboxylic acid instead of methyl ester 5-methanesulfonyl-1H-indole-2-carboxylic acid.

MC (ESI+) m/e=488, the isotopic distribution of the chlorine atoms.

Example 217: (1 isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-fluoro-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 214 with the difference that use methyl ester 5-fluoro-1H-indole-2-carboxylic acid instead of methyl ester 5-methanesulfonyl-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=472, the isotopic distribution of the chlorine atoms.

Example 218: (-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5,7-debtor-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 214 with the difference that use methyl ether 5,7-debtor-1H-indole-2-carboxylic acid instead of methyl ester 5-methanesulfonyl-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=490, the isotopic distribution of the chlorine atoms.

Example 219: (1 ethylpyrrolidin-3-yl)amide S-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 36 with the difference that at the stage of reductive amination using 3S-3-tert-butoxycarbonylamino instead of tert-butyl methyl ether (1-isopropylpiperazine-4-yl)carbamino acid.

MC (ESI+): m/e=455, the isotopic distribution of the chlorine atoms.

Example 220: (1 ethylpyrrolidin-3-yl)amide R-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 36 with the difference that at the stage of reductive amination using 3R-3-tert - butoxycarbonylamino instead of tert-butyl methyl ether (1-isopropylpiperazine-4-yl)carbamino acid.

MC (ESI+): m/e=455, the isotopic distribution of the chlorine atoms.

Example 221: (1 isopropylpyrimidine-3-yl)amide R1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that at the stage of reductive amination using 3R-3-tert-butoxycarbonylamino instead of tert-butyl methyl ether (1-isopropylpiperazine-4-yl)carbamino acid.

MC (ESI+): m/e=469, the isotopic distribution of the chlorine atoms.

Example 222: (1 isopropylpyrimidine-3-yl)amide S-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 1 with the difference that at the stage of reductive amination using 3S-3-tert-butoxycarbonylamino instead of tert-butyl methyl ether (1-isopropylpiperazine-4-yl)carbamino acid.

MC(ESI+): m/e=469, the isotopic distribution of the chlorine atoms.

Example 223: ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-trifluoromethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

Specified in the header of the connection will receive is similar to the method of example 184 with the difference that using 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-trifluoromethyl-1H-indole-2-carboxylic acid instead of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=37, the isotopic distribution of the chlorine atoms.

Example 224: ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

Specified in the header of the connection will receive is similar to the method of example 184 with the difference that using 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethyl-1H-indole-2-carboxylic acid instead of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=597, the isotopic distribution of the chlorine atoms.

Example 225: ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

Specified in the header of the connection will receive is similar to the method of example 184 with the difference that using 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carboxylic acid instead of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=629, the isotopic distribution of the chlorine atoms.

Example 226: ethyl ester [{4,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

Specified in the header connection receive similar the th procedure of example 184 with the difference, using 4,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid instead of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl] -7-methyl-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=638, the isotopic distribution of the chlorine atoms.

Example 227: ethyl ester [{5,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

Specified in the header of the connection will receive is similar to the method of example 184 with the difference that using 5,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid instead of ylmethyl]-7-methyl-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=638, the isotopic distribution of the chlorine atoms.

Example 228: ethyl ester [{4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

Specified in the header of the connection will receive is similar to the method of example 184 with the difference that use 4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid instead of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid.

MC (ESI+): m/e=603, the isotopic distribution of the chlorine atoms.

Example 229: [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-trifluoromethyl-1H-indole-2-carbonyl}-(1-isop oilpipeline-4-yl)amino]acetic acid

Specified in the header of the connection will receive is similar to the method of example 185 with the difference that they use ethyl ester [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-trifluoromethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid instead of the ethyl ester [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid.

MC (ESI+): m/e=609, the isotopic distribution of the chlorine atoms.

Example 230: [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

Specified in the header of the connection will receive is similar to the method of example 185 with the difference that they use ethyl ester [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid instead of the ethyl ester [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indol-2-carbonyl}- (1-isopropylpiperazine-4-yl)amino]acetic acid.

MC (ESI+): m/e=601, the isotopic distribution of the chlorine atoms.

Example 231: [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]- 4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

Specified in the header connection receive is about similar to the method of example 185 with the difference, using the ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid instead of the ethyl ester [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid.

MC (ESI+): m/e=601, the isotopic distribution of the chlorine atoms.

Example 232: [{4,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

Specified in the header of the connection will receive is similar to the method of example 185 with the difference that they use ethyl ester [{4,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid instead of the ethyl ester [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}- (1-isopropylpiperazine-4-yl)amino]acetic acid.

MC (ESI+): m/e=609, the isotopic distribution of the chlorine atoms.

Example 233: [{5,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

Specified in the header of the connection will receive is similar to the method of example 185 with the difference that they use ethyl ester [{5,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-ronil}-(1-isopropylpiperazine-4-yl)amino]acetic acid instead of the ethyl ester [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid.

MC (ESI+): m/e=609, the isotopic distribution of the chlorine atoms.

Example 234: [{4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid

Specified in the header of the connection will receive is similar to the method of example 185 with the difference that they use ethyl ester [{4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid instead of the ethyl ester [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}- (1-isopropylpiperazine-4-yl)amino]acetic acid. MC (ESI+): m/e=575, the isotopic distribution of the chlorine atoms.

Example 235: isopropyl ether, 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl]-1H-indole-5-carboxylic acid

(i) 5-Isopropyl ester 2-ethyl ester 1H-indole-2,5-dicarboxylic acid

To a solution of 15.5 g AlCl3400 ml DHM added dropwise 10 ml of oxalicacid. Then after 30 min add 10 g of ethyl ester 1H-indole-2-carboxylic acid in 100 ml DHM and the reaction mixture is stirred for 2 hours. The reaction mixture is poured on crushed ice and extracted with twice 500 ml DHM. The organic layer is dried over MgSO4and the solvent is removed under reduced pressure. The residue is transferred at 00 ml of propan-2-ol and stirred for 4 h at room temperature. After concentrating the reaction mixture under reduced pressure the residue is purified by chromatography on silica gel with elution with a gradient mixture of ethyl acetate/heptane (1:10→4:1). Output 2,71,

(ii) 5-Isopropyl ester 2-ethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 1 (iv)using 5-isopropyl ester 2-ethyl ester 1H-indole-2,5-dicarboxylic acid as the starting material. Connection purified by chromatography on silica gel with elution with a mixture of n-heptane/ethyl acetate (6:1).

The output of 6.3, MC (ESI+): m/e=473 (M+) isotopic distribution of the chlorine atoms.

(iii) 5-Isopropyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid

To a solution 6,21 g of 5-isopropyl ester 2-ethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid in 100 ml of THF and 40 ml Meon added 52 ml of an aqueous solution of 1 M LiOH and stirred for 2 hours. Organic solvents are removed under reduced pressure and the residue acidified with 2 M hydrochloric acid to pH 2. The precipitated product is collected by filtration and dried over P2O5in vacuum to obtain a white solid. Output 5,77,

(iv) Isopropyl ester of 1-[5-(5-chart is open-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl]-1H-indole-5-carboxylic acid

To a solution 5,77 g of 5-isopropyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid and 2.79 g of the hydrochloride of 1-isopropylpiperazine-4-ylamine in 100 ml of DMF type of 4.25 g of TOTU and 6.6 ml of DIPEA and the mixture is stirred for 3 hours at room temperature. After removal of the solvent under reduced pressure the residue is dissolved in 200 ml ethyl acetate and washed with saturated solution of NaHCO3. The organic layer is dried over MgSO4. After removal of the solvent under reduced pressure the residue is purified by chromatography on silica gel with elution with a mixture DHM/Meon/Asón/N2About(95:5:0,5:0,5). The fractions containing the product are collected and the solvent is evaporated under reduced pressure. The product is obtained in the form of its triptoreline salt.

Output 6,13, MS (ES+): m/e=569, the isotopic distribution of the chlorine atoms.

Example 236: 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

To a solution of 6,13 g of isopropyl ether, 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid in 200 ml Meon add 54 ml of 1 M aqueous LiOH solution and heated for 24 hours at 60°C. the Reaction mixture was concentrated under reduced pressure and acidified with 2 M hydrochloric acid to p is 3. The mixture is extracted with ethyl acetate (2×200 ml) and the organic layer is dried over MgSO4that results after evaporation of the solvent under reduced pressure to obtain 5.3 g of the crude acid as a yellow solid. 600 mg of this acid purified preparative HPLC (C18 column with reversed phase elution with a gradient mixture of N2O/MeCN with 0.1% TFUC). The fractions containing the product, evaporated and lyophilizers after adding 2 M hydrochloric acid to obtain a white solid. The product is obtained in the form of its hydrochloride.

The output of 280 mg. MS (ES+): m/e=527, the isotopic distribution of the chlorine atoms.

Example 237: (1 isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-hydroxymethyl-1H-indole-2-carboxylic acid

To a solution of 100 mg 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid and 50 µl NEt3in 4 ml of THF at -7°add 17 ál ethylchloride. After stirring for 2 h at -7°the reaction mixture is filtered, the filtrate is treated with 24 mg NaBH4and warmed to room temperature. After 2 hours add an additional 24 mg NaBH4and the reaction mixture is stirred for 16 hours. During the next 2 hours add 110 ál of the Meon in 4 ml THF and the reaction see what camping is stirred for additional 4 h at room temperature. After removal of the solvents under reduced pressure the residue is purified by chromatography on silica gel with elution with a mixture DHM/Meon (8:2). The fractions containing the product are collected and evaporated under reduced pressure.

Yield 39 mg of MC(ES+): m/e=513, the isotopic distribution of the chlorine atoms.

Example 238: ethyl ester of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

To a solution of 0.6 g of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid in 10 ml of DMF successively added 0.4 ml of EtOH, 110 mg of DMAP and 256 mg of DCC, and the reaction mixture stirred for 16 h at room temperature. The precipitate then filtered off, the filtrate concentrated and purified by chromatography on silica gel with elution with a mixture DHM/Meon/Asón/N2About(95:3:0,5:0,5). The fractions containing the product are collected and the solvent is evaporated under reduced pressure.

The output 418 mg, MS (ES+): m/e=555, the isotopic distribution of the chlorine atoms.

Example 239: methyl ether of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 238 with the difference that at the point the esterification using methanol instead of ethanol.

MC (ES+): m/e=541, the isotopic distribution of the chlorine atoms.

An alternative is specified in the title compound can be obtained by the following method.

(i) 5-Methyl ester 1H-indole-2,5-dicarboxylic acid

A solution of 25 g of methyl ester 4-amno-3-identies acid, 19 ml of 2-oxopropanoic acid, 30,4 g of 1,4-diazabicyclo[2.2.2]octane and 1 g of Pd(OAc)2heated in an argon atmosphere at 100°C. After 5 hours the reaction mixture was concentrated under reduced pressure and the residue partitioned between 300 ml of ethyl acetate and 200 ml of 1 M hydrochloric acid. The organic layer is dried over MgSO4and the solvent is removed under reduced pressure to obtain yellow solid (6.4 g). From the aqueous layer with additional product slowly precipitates as a white solid (7.9 g), which is collected by filtration. Both factions unite, dried in vacuum and used in the next reaction without further purification.

The output of 14.3, MC (ES+): m/e=220.

(ii) 5-Methyl ester 2-tert-butyl ester 1H-indole-2,5-dicarboxylic acid

To 13 g of 5-methyl ester 1H-indole-2,5-dicarboxylic acid in 300 ml of toluene at 80°With added dropwise 59 ml di-tert-butoxydiethylene. Next, the reaction mixture is heated to boiling under reflux for an additional 6 hours. After removal of the solvents when the pony is hinnon pressure, the residue is dissolved in 300 ml DHM and washed with saturated aqueous NaHCO 3(2×100 ml). The organic layer is dried over MgSO4and concentrate under reduced pressure. The residue is purified by chromatography on silica gel with elution with a gradient mixture of n-heptane/ethyl acetate. The fractions containing the product are collected and concentrated under reduced pressure.

The output of 8.3, MC (ES+): m/e=276.

(iii) 5-Methyl ester 2-tert-butyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 1 (iv)using 5-methyl ether tert-butyl ester 1H-indole-2,5-dicarboxylic acid as the starting material. Connection chromatographic on silica gel with elution with a mixture of n-heptane/ethyl acetate (6:1).

The output of 9.6, MC (ESI+): m/e=417, the isotopic distribution of the chlorine atoms.

(iv) 5-Methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid

9.5 g of 5-methyl ester 2-tert-butyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid are dissolved in 300 ml triperoxonane acid and stirred for 1 hour at RT. Next, add 200 ml of toluene and the solvents removed under reduced pressure. This technique is repeated three times, then the residue is dried in vacuum. The output of 8.4,

(v) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxa the ol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 1 (vi), using 5-methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid as the starting material. Connection chromatographic on silica gel with elution with a mixture DHM/Meon/Asón/N2About(95:3:0,5:0,5).

Output 10, MC (ESI+): m/e=541, the isotopic distribution of the chlorine atoms.

Example 240: 2,2-dimethylphenylacetate ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

To a solution of 1.2 g of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid in 30 ml of DMF add 0,641 g chlormethiazole ether of 2,2-dimethylpropionic acid and 885 μl NEt3and the reaction mixture is stirred for 5 hours at 60°C. Next add an additional 0.32 g chlormethiazole ether of 2,2-dimethylpropionic acid and 295 ál NEt3and the reaction mixture is stirred for 6 hours at 60°C. After removal of the solvent under reduced pressure the residue is dissolved in CH2Cl2and the solution washed with water. The phases are separated and the organic phase after drying over Na2SO4) was concentrated in vacuo. The residue is purified preparative RP-HPLC with elwira what W a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After adding 1 M hydrochloric acid and freeze-drying in a mixture of acetonitrile/water, the product is obtained in the form of its hydrochloride.

The output of 1.17 g MC (ESI+): m/e=641, the isotopic distribution of the chlorine atoms.

Example 241: isopropyl ether, 1-[5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole-2-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 235 with the difference that the use of 2-methyl bromide-5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole [obtained for adapted the method described by Ewing, William R. et al. PCT Int. Appl. (2001), 460 pp.WO 0107436 A2] instead of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol.

MC (ESI+): m/e=586, the isotopic distribution of the chlorine atoms.

Example 242: 1-[5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole-2-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 236 with the difference that use isopropyl ester 1-[5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole-2-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid instead of isopropyl ether, 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid.

MC (ESI+): m/e=544, the isotopic distribution of the atoms is Laura.

Example 243: isopropyl ether, 1-[(4-chlorpheniramol)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

(i) 5-Isopropyl ester 1H-indole-2,5-dicarboxylic acid

To a solution of 855 mg 5-isopropyl ester 2-ethyl ester 1H-indole-2,5-dicarboxylic acid in 50 ml of Meon type of 12.4 ml of 1 M aqueous LiOH solution. After heating the reaction mixture at 50°C for 1 hour and the organic solvents removed under reduced pressure and the residue is acidified to pH 2 1 M hydrochloric acid. The precipitated product is collected by filtration and dried in vacuum. Output 673 mg

(ii) Isopropyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

To a solution of 673 mg 5-isopropyl ester 1H-indole-2,5-dicarboxylic acid and 702 mg of the hydrochloride of 1-isopropylpiperazine-4-ylamine in 20 ml of DMF added 1.07 g TOTU and 1.67 ml of DIPEA and the mixture is stirred for 1 hour at room temperature. After removal of the solvent under reduced pressure the residue is dissolved in 100 ml DHM and washed with saturated solution of NaHCO3. The organic layer is dried over MgSO4. After removal of the solvent under reduced pressure the residue is purified by chromatography on silica gel with elution with a mixture DHM/Meon/Asón/N2About(95:5:0,5:0,5). The fractions containing the product are collected and races is oritel is evaporated under reduced pressure. The product is obtained in the form of its acetate salt. Exit 698 mg

(iii) 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 hours the precipitate are filtered and recrystallized from toluene to obtain a white solid. Output 10,

(iv) Isopropyl ester 1-[(4-chlorpheniramol)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylicacid

To a solution of 100 mg of isopropyl ether 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid in 2 ml DMF at RT add 8 mg of sodium hydride (60% in oil). After 30 minutes add 67 mg of 2-bromo-N-(4-chlorophenyl)ndimethylacetamide and the reaction mixture is stirred for 3 hours. After removal of the solvent under reduced pressure the residue is purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of its triptoreline salt.

Yield 66 mg MS (ESI+): m/e=539, the isotopic distribution of the chlorine atoms.

Example 244: 1-[(4-chlorpheniramol)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

To a solution of 1.2 g of isopropyl ether, 1-[(4-chlorpheniramol)methyl]-2-(1-isop oilpipeline-4-ylcarbonyl)-1H-indole-5-carboxylic acid in 150 ml of Meon add 11 ml of 1 M aqueous solution of LiOH and the reaction mixture is heated at 60° C for 24 hours. After concentration under reduced pressure the residue is acidified to pH 2 with 2 M hydrochloric acid. The precipitated product is collected by filtration and purified by chromatography on silica gel with elution with a mixture DHM/Meon/Asón/N2About(95:3:0,5:0,5). The fractions containing the product are collected and concentrated under reduced pressure. After adding 3 ml of 2 M hydrochloric acid and freeze-drying the product is obtained in the form of its hydrochloride.

Exit 499 mg MS (ESI+): m/e=497, the isotopic distribution of the chlorine atoms.

Example 245: methyl ether of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid

(i) tert-Butyl ether 4-bromo-1H-indole-2-carboxylic acid

To 7 g of 4-bromo-1H-indole-2-carboxylic acid in 150 ml of toluene at 80°With added dropwise 28 ml of di-tert-butoxydiethylene. The reaction mixture is heated to boiling under reflux for an additional 12 caspase removal of the solvents under reduced pressure the residue is dissolved in 200 ml DHM and washed with saturated aqueous NaHCO3(2×50 ml). The organic layer is dried over MgSO4and concentrate under reduced pressure. The residue is purified by chromatography on silica gel with elution with a mixture of n-heptane/ethyl acetate (9:1). F. the shares, containing the product are collected and concentrated under reduced pressure.

The output of 6.5, MS (ESI+): m/e=297.

(ii) 4-Methyl ester 2-tert-butyl ester 1H-indole-2,4-dicarboxylic acid

To a solution of 7.3 g of tert-butyl ester 4-bromo-1H-indole-2-carboxylic acid in 100 ml of DMF added 6.8 ml NEt3, 276 mg of Pd(OAc)2, 128 mg of 1,1'-bis(diphenylphosphino)ferrocene and 12 ml Meon and rinsed with argon for 15 minutes This solution was then rinsed with carbon monoxide and heated at 70°C for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue is dissolved in 200 ml DHM and washed with 100 ml of water. The organic layer is dried over MgSO4and after removal of the solvent under reduced pressure the residue is purified by chromatography on silica gel with elution with a mixture of n-heptane/ethyl acetate (9:1). The fractions containing the product are collected and concentrated under reduced pressure.

The output of 3.8, MS (ESI+): m/e=276.

(iii) 4-Methyl ester 2-tert-butyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,4-dicarboxylic acid

This connection receive, using a technique similar to that described for obtaining the compound of example 1 (iv)using 4-methyl ester 2-tert-butyl ester 1H-indole-2,4-dicarboxylic acid as the starting material. Connection chromatographic on silica gel with elution with a mixture of n-heptane/tracecut (6:1).

The output of 4.1, MS (ESI+): m/e=473 (M+), the isotopic distribution of the chlorine atoms.

(iv) 4-Methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,4-dicarboxylic acid

4.1 g of 4-methyl ester 2-tert-butyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,4-dicarboxylic acid are dissolved in 100 ml triperoxonane acid and stirred for 1 hour at RT. Next, add 100 ml of toluene and the solvents removed under reduced pressure. This technique is repeated three times, then the residue is dried in vacuum.

The output of 3.4, MS (ESI+): m/e=416, the isotopic distribution of the chlorine atoms.

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

This connection receive, using a technique similar to that described for obtaining the compound of example 235 (iv)using 4-methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2,4-dicarboxylic acid as the starting material. Connection chromatographic on silica gel with elution with a mixture DHM/Meon/Asón/N2O(95:3:0,5:0,5).

The output of 4.2, MS (ESI+): m/e=541, the isotopic distribution of the chlorine atoms.

Example 246: 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylicacid

This connection get rimasta technique similar to that described to obtain the compound of example 236 using methyl ester of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid as a starting material. Connection chromatographic on silica gel with elution with a mixture DHM/Meon/Asón/N2O(95:3:0,5:0,5).

MS (ESI+): m/e=527 (M+), the isotopic distribution of the chlorine atoms.

Example 247: 2-[(1-isopropylpiperazine-4-yl)amide] 5-amide 1-[5- (5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-4-carboxylic acid

Specified in the title compound isolated as a side product in example 176.

MS (ES+): m/e=526, the isotopic distribution of the chlorine atoms.

Example 248: (1 isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid

(i) Benzyl ester 1H-indole-2-carboxylic acid

To a solution of 10,32 g 1H-indole-2-carboxylic acid in 100 ml of tetrahydrofuran, add 10,38 g diimidazole-1 ylmethanone and the mixture is stirred for 20 min at room temperature. To this mixture 7,29 ml phenylmethanol and the reaction mixture is refluxed for 10 hours. The mixture is allowed to cool to ambient temperature and then partitioned between 200 ml of water and 200 ml of dichloromethane. The organic layer was washed with updat the additional amount of water and then dried over sodium sulfate. After filtration the solvent is removed under reduced pressure to obtain white solid. The residue is directly subjected to the subsequent reaction without further purification.

Output 18,8, MS (ES+): m/e=252, the isotopic distribution of the chlorine atoms.

1H-NMR (400 MHz, DMSO/TMS): δ=the 7.65 (d, 1H); 7,40 (m, 7H); to 7.25 (t, 1H); 7,20 (s, 1H); 7,07 (t, 1H); of 5.39 (s,2H).

(ii) Benzyl ester 1-tert-butoxycarbonylmethyl-1H-indole-2-carboxylic acid

To a solution of 18,80 g benzyl ester 1H-indole-2-carboxylic acid in 70 ml of N,N-dimethylformamide at 0°add 1.98 g of sodium hydride. After stirring for 1 hour to the mixture 15,91 ml tert-butyl methyl ether bromoxynil acid and the reaction mixture is stirred for 2 hours at room temperature. After removal of the solvent under reduced pressure the residue is partitioned between 300 ml of water and 300 ml of dichloromethane. The aqueous layer was washed twice more with 200 ml of dichloromethane. Next, the combined organic phases are washed with saturated aqueous sodium chloride. After filtration the solvent is removed under reduced pressure and the residue is crystallized from a mixture of ethoxyethane/heptane. The product is obtained in the form of a white solid.

1H-NMR (400 MHz, DMSO/TMS): δ=of 7.70 (d, 1H); a 7.62 (d, 1H); 7,46 (d, 2H); 7,38 (m, 5H); to 7.15 (t, 1H); to 5.35 (s, 2H); 5,28 (s, 2H); 1.39 in (C, N).

(iii) 1-tert-Butoxide arylmethyl-1H-indole-2-carboxylic acid

To a solution of 3.0 g of benzyl ester 1-tert-butoxycarbonylmethyl-1H-indole-2-carboxylic acid in a mixture of 10 ml of N,N-dimethylformamide and 10 ml of ethanol is added 0.5 g of palladium, 5% on carbon. The reaction mixture is stirred for 2 hours in hydrogen atmosphere. The mixture is filtered through a cartridge chem elut® and the connection elute ethanol. After concentration under reduced pressure the residue is directly subjected to the subsequent reaction without further purification. The output of 2.2,

1H-NMR (400 MHz, DMSO/TMS): δ=12,50 (s, 1H); to 7.68 (d, 1H); to 7.59 (d, 1H); 7,31 (m, 1H); to 7.25 (s, 1H); 7,13 (t, 1H); of 5.26 (s, 2H); of 1.40 (s, N).

(iv) tert-Butyl[2-(1-isopropylpiperazine-4-ylcarbonyl)indol-1-yl]acetate

To a solution of 0.5 g of 1-tert-butoxycarbonylmethyl-1H-indole-2-carboxylic acid and of 0.91 ml of N-ethylmorpholine in 3 ml of dichloromethane added 0.6 g of tetrafluoroborate O-[(etoxycarbonyl)cyanomethylene]-N,N,N',N'-tetramethylurea and the mixture is stirred for 30 min at room temperature. To the mixture of 0.39 g of 1-isopropylpiperazine-4-ylamine and the reaction mixture is further stirred for 1 hour. After removal of the solvent under reduced pressure the residue partitioned between 15 ml of water and 15 ml of dichloromethane. The organic layer was washed with additional water and then dried over sodium sulfate. After filtration the solvent is removed under reduced pressure and produces the t white solid. The residue is directly subjected to the subsequent reaction without further purification.

The output of 0.51, MS (ES+): m/e=400.

1H-NMR (400 MHz, DMSO/TMS): δ=scored 8.38 (d, 1H); 7,63 (d, 1H); 7,51 (d, 1H); to 7.25 (t, 1H); 7,20 (s, 1H); 7,11 (t, 1H); at 5.27 (s, 2H); 3,55 (m, 1H); 2,82 (m, 2H); 2,30 (m, 1H), 2,18 (m, 2H); 1.77 in (m, 2H); of 1.55 (m, 2H); 1.39 in (C, N); and 0.98 (d, 6N).

(v) [2-(1-Isopropylpiperazine-4-ylcarbonyl)indol-1-yl]acetic acid

To 0.51 g of tert-butyl[2-(1-isopropylpiperazine-4-ylcarbonyl)indol-1-yl]acetate in 5 ml of dichloromethane was added 1 ml of triperoxonane acid and the mixture is stirred for 16 hours. Removal of solvent under reduced pressure to obtain white solid, which is distilled twice with 15 ml of toluene. The product is obtained in the form of its triptoreline salt.

The output of 0.43, MS (ES+): m/e=344.

1H-NMR (400 MHz, DMSO/TMS): δ=12,6 (1H); 9,17 (s, 1H); 8,56 (d, 1H); 7,66 (d, 1H); 7,53 (d, 1H); 7,27 (t, 1H); to 7.25 (s, 1H); 7,11 (t, 1H); and 5.30 (s, 2H); was 4.02 (m, 1H); 3.43 points (m, 2H); 3,10 (m, 2H), 2.06 to (m, MN); to 1.83 (m, 2H); 1,25 (d, 6N).

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

To a suspension of 50 mg of [2-(1-isopropylpiperazine-4-ylcarbonyl)indol-1-yl]acetic acid at room temperature add 22 mg of 4-chlorpheniramine and 37 mg of bis(2-oxo-3-oxazolidinyl)hasfinished in 1 ml dichloromethane and 0.08 ml of N-ethylmorpholine and the mixture is stirred for 16 hours. After removal of the solvent at igenom pressure the residue is purified preparative HPLC (C18 column with reversed phase, elution with a gradient mixture of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product, evaporated and lyophilizers obtaining a white solid. The product is obtained in the form of its triptoreline salt.

The output of 12.6 mg MS (ES+): m/e=453, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=10,44 (s, 1H); of 8.95 (s, 1H); 8,58 (d, 1H); to 7.67 (d, 1H); of 7.60 (d, 2H); 7,58 (d, 1H); to 7.35 (d, 2H); 7,28 (m, 1H); to 7.25 (s, 1H); 7,13 (t, 1H); of 5.45 (s, 2H); 4,03 (s, 1H); of 3.43 (m, 2H); is 3.08 (m, 2H), 2.05 is (m, 3H); of 1.80 (m, 2H); of 1.23 (d, 6N).

Example 249: (1 isopropylpiperazine-4-yl)amide 1-[(5-chlorothiophene-2-ylcarbonyl)methyl]-1H-indole-2-carboxylic acid

Specified in the header connection receive analogous to the methods of example 248 with the difference that using 5-chlorothiophene-2-ylamine [obtained by the method published in Synth. Comm. 1977, 255-256] instead of 4-chlorpheniramine.

MS (ESI+): m/e=459, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=11,72 (s, 1H); of 8.90 (s, 1H); to 8.57 (d, 1H); to 7.68 (d, 1H); 7,58 (d, 1H); 7,27 (t, 1H); to 7.25 (s, 1H); 7,14 (t, 1H); to 6.88 (d, 1H); 6,53 (d, 1H); 5,46 (s, 2H); 4,00 (s, 1H); of 3.43 (m, 2H); is 3.08 (m, 2H), 2,03 (m, 3H); of 1.80 (m, 2H); of 1.23 (d, 6N).

Example 250: (1 isopropylpiperazine-4-yl)amide 1-[(4-chloro-2-tortenelmebol)methyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 28 with the difference, using 4-chloro-2-forfinally instead of 4-chlorpheniramine.

MS (ESI+): m/e=471, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=10,24 (s, 1H); 8,93 (s, 1H); at 8.60 (d, 1H); to 7.95 (t, 1H); to 7.68 (d, 1H); at 7.55 (d, 1H); 7,50 (d, 1H); 7,26 (d, 1H); from 7.24 (s, 1H); 7,22 (s, 1H); 7,13 (t, 1H); of 5.48 (s, 2H); Android 4.04 (s, 1H); 3.43 points (m, 2H); 3,10 (m, 2H); of 2.08 (m, 3H); of 1.80 (m, 2H); 1,25 (d, 6N).

Example 251: (1 isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-indole-2-carboxylic acid

Specified in the header connection receive analogous to the methods of example 248 with the difference that using 5-chloropyridin-2-ylamine instead of 4-chlorpheniramine.

MS (ESI+): m/e=454, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=10,99 (s, 1H); of 8.90 (s, 1H); 8,58 (d, 1H); 8,39 (d, 1H); of 7.97 (d, 1H); 7,87 (DD, 1H); to 7.68 (d, 1H); 7,56 (d, 1H); 7,27 (t, 1H); to 7.25 (s, 1H); 7,13 (t, 1H); of 5.45 (s, 2H); was 4.02 (s, 1H); 3.43 points (m, 2H); is 3.08 (m, 2H); 2,03 (m, 3H); of 1.80 (m, 2H); of 1.23 (d, 6N).

Example 252: (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid

(i) Ethyl ester 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid

To a solution of 1.0 g of ethyl ester 1H-indole-2-carboxylic acid in 10 ml of N,N-dimethylformamide at 0°With added 0.14 g of sodium hydride. After stirring for 30 min add 1,58 g of 2-bromo-N-(4-chlorophenylacetic and the mixture is stirred for 2 hours at room temperature. After diluting 15 ml of water the mixture is filtered through a cartridge chem elut® and the connection elute with ethyl acetate. After concentration under reduced pressure the residue is directly subjected to the subsequent saponification reaction without further purification.

The output of 1.45, MS (ESI+): m/e=357, the isotopic distribution of the chlorine atoms.

(ii) 1-[(4-Chlorpheniramol)methyl]-1H-indole-2-carboxylic acid

To a solution of 1.45 g of ethyl ester 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid in 100 ml of tetrahydrofuran, add 30 ml of water and 0.59 g of potassium hydroxide. After stirring for 2 hours at room temperature, the reaction mixture was acidified with 6 N. hydrochloric acid. The precipitate is collected by filtration and washed with 20 ml of water. The product is obtained as a white solid and dried under reduced pressure.

The output of 1.37, MS (ESI+): m/e=329, the isotopic distribution of the chlorine atoms.

1H-NMR (400 MHz, DMSO/TMS): δ=10,50 (s, 1H); of 7.70 (d, 1H); to 7.61 (d, 2H); 7,58 (d, 1H); 7,37 (d, 2H); to 7.32 (t, 1H); to 7.25 (s, 1H); 7,14 (t, 1H); 5,44 (s, 2H).

(iii) (3,4,5,6-Tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid

To a suspension of 50 mg 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid type 97 mg (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)methylamine and of 38.7 mg bis(2-oxo-3-oxazolidinyl)hasfinished in 1 ml N,N-dime Informatica and of 61.7 μl of triethylamine. After stirring at room temperature for 16 hours the solvent is removed under reduced pressure and the residue purified preparative HPLC (C18 column with reversed phase elution with a gradient mixture of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product, evaporated and lyophilizers obtaining a white solid. The product is obtained in the form of its triptoreline salt.

The output of 6.9 mg MS (ES+): m/e=502, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=13,14 (s, 1H); 10,45 (s, 1H), 8,63 (t, 1H); 8.17 and (d, 2H); to 7.64 (d, 1H); to 7.61 (d, 2H); 7,56 (d, 1H); 7,38 (d, 2H); 7,26 (t, 1H); 7,17 (s, 1H); for 7.12 (m, 3H); 5,43 (s, 2H); 4,13 (d, 2H); of 3.13 (m, 4H); of 1.80 (m, 2H); to 1.21 (m, 3H).

Example 253: (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 252, with the difference that use 3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylamine instead of (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)methylamine.

MS (ES+): m/e=488, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=13,23 (s, 1H); 10,44 (s, 1H); 8,43 (d, 1H); 8,23 (d, 2H); the 7.65 (d, 1H); to 7.61 (d, 2H); 7,56 (d, 1H); to 7.35 (d, 2H); 7.23 percent (m, 4H); for 7.12 (t, 1H); 5,44 (s, 2H); 4,20 (m, 3H); of 3.32 (m, 2H); 1,95 (m, 2H); was 1.58 (m, 2H).

Example 254 N-(4-chlorophenyl)-2-{2-[4-(pyridine-4-ylamino)PIP is ridin-1-carbonyl]indole-1-yl}ndimethylacetamide

Specified in the header of the connection will receive is similar to the method of example 252, using piperidine-4-ilerideki-4-ylamine instead of (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)methylamine.

MS (ES+): m/e=488, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=13,24 (s, 1H); 10,45 (s, 1H); 8,43 (d, 1H); 8,23 (d, 2H); to 7.64 (d, 1H); of 7.60 (d, 2H); at 7.55 (d, 1H); to 7.35 (d, 2H); 7,22 (m, 4H); 7,11 (t, 1H); 5,44 (s, 2H); 4,20 (m, 3H); to 3.33 (m, 2H); 1,95 (m, 2H); 1.57 in (m, 2H).

Example 255: (1 cyclopropylidene-4-yl)amide 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 252, with the difference that using 1-cyclopropylidene-4-ylamine instead of (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)methylamine.

MS (ES+): m/e=451, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=10,44 (s, 1H); 8,78 (s, 1H);to 8.57 (d, 1H); to 7.68 (d, 1H); of 7.60 (d, 2H); EUR 7.57 (d, 1H); of 7.36 (d, 2H); 7,27 (t, 1H); 7.23 percent (s, 1H); for 7.12 (t, 1H); 5,44 (s, 2H); 3,44 (m, 2H); of 3.25 (m, 2H); 2,03 (m, 3H); at 1.73 (m, 2H); 0,84 (m, 5H).

Example 256 N-(4-chlorophenyl)-2-[2-(4-pyrrolidin-1-reparacin-1-carbonyl)indole-1-yl]ndimethylacetamide

Specified in the header of the connection will receive is similar to the method of example 252, using 4-pyrrolidin-1-reprein instead (3,4,5,6-tetrahydro-2H-[1,4 bipyridinyl-4-yl)methylamine.

MS (ES+): m/e=465, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=10,53 (s, 1H); for 9.64 (s, 1H); to 7.64 (d, 1H); EUR 7.57 (m, 3H); of 7.36 (d, 2H); 7,26 (t, 1H); 7,13 (t, 1H); 6,76 (s, 1H); 5,20 (s, 2H); of 4.45 (s, 2H); to 3.45 (m, 3H); to 3.06 (m, 3H); of 1.97 (m, 7H); of 1.55 (s, 2H).

Example 257: (1 isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-5-nitro-1H-indole-2-carboxylic acid

Specified in the header connection receive analogous to the methods of example 248 with the difference that the use of ethyl ester of 5-nitro-1H-indole-2-carboxylic acid instead of the ethyl ester of unsubstituted 1H-indole-2-carboxylic acid.

MS (ES+): m/e=498, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=10,53 (s, 1H); 8,98 (s, 1H); 8,83 (d, 1H); total of 8.74 (s, 1H); to 8.14 (d, 1H); a 7.85 (d, 1H); to 7.59 (d, 2H); to 7.50 (s, 1H); 7,38 (d, 2H); 5,52 (s, 2H); was 4.02 (m, 1H); to 3.45 (m, 2H); of 3.07 (m, 2H); 2,03 (m, 3H); is 1.81 (m, 2H); 1,25 (d, 6N).

Example 258: (1 isopropylpiperazine-4-yl)amide 5-amino-4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

is 24.4 mg (1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic acid are added to a solution of 58.5 mg of the dihydrate of tin chloride in 1 ml of ethanol. Add 0.5 ml of 12 N. aqueous hydrochloric acid and the mixture is stirred at room temperature for 16 hours. After the hladiny her reaction mixture is alkalinized to pH 12 with a saturated aqueous solution of sodium hydroxide and the product produce by filtration. The product is obtained in the form of a white solid, which is dried under reduced pressure.

The output of 10.0 mg MS (ES+): m/e=532, the isotopic distribution ofchlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=to 8.40 (d, 1H); 7,56 (d, 1H); 7,28 (d, 1H); from 7.24 (d, 1H); 7,07 (s, 1H); 6,86 (d, 1H); is 6.54 (s, 1H); of 5.83 (s, 2H); equal to 4.97 (s, 2H); 3,70 (m, 1H); 2,78 (m, 2H); in 2.68 (m, 1H); and 2.14 (m, 2H); of 1.78 (m, 2H); 1,53 (m, 2H); to 0.96 (d, 6N).

Example 259: (1 cinematelevision-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

To a suspension of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 1 ml ethanol add to 43.5 mg of potassium carbonate, to 14.5 μl of triethylamine and 7.3 μl of bromoacetonitrile. After stirring at room temperature for 16 hours the solvent is removed under reduced pressure and the residue purified preparative HPLC (C 18 column with reversed phase elution with a gradient mixture of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product, evaporated and lyophilizers obtaining a white solid. The product is obtained in the form of its triptoreline salt.

The output of 13.8 mg MS (ES+): m/e=480, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=8,49 (d, 1H); to 7.67 (d, 1H); 7,58 (d, 1H); at 7.55 (d, 1H); 7,28 (m, 1H); to 7.25 (d, 1H); 7,22 (s, 1H); 7,13 (t, 1H); 6,59 (s, 1H); 5,90 (s, 2H); a 3.87 (who, 3H); 3,00 (m, 2H); 2,48 (m, 2H); 1.91 a (m, 2H); to 1.67 (m, 2H).

Example 260: [1-(2-hydroxyethyl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 259, with the difference that use 2-bromoethanol instead of bromoacetonitrile.

MS (ES+): m/e=485, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): 5=a 9.35 (s, 1H); 8,63 (m, 1H); to 7.68 (d, 1H); to 7.61 (d, 1H); at 7.55 (d, 1H); 7,30 (m, 1H); 7,25 (m, 2H); 7,14 (t, 1H); 6,59 (s, 1H); 5,90 (s, 2H); 5,33 (s, 1H); Android 4.04 (m, 1H); 3,76 (m, 2H); of 3.56 (m, 2H); to 3.33 (m, 2H); of 3.12 (m, 2H); 2,02 (m, 2H); to 1.87 (m, 1H); at 1.73 (m, 1H).

Example 261: [1-(2-methoxyethyl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 259, with the difference that using 1-bromo-2-methoxyethane instead of bromoacetonitrile and acetonitrile as solvent.

MS (ES+): m/e=499, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=of 9.30 (s, 1H); 8,65 (d, 1H); to 7.68 (d, 1H); of 7.60 (d, 1H); rate of 7.54 (d, 1H); 7,30 (m, 1H); 7,25 (m, 2H); to 7.15 (t, 1H); to 6.58 (s, 1H); 5,90 (s, 2H); was 4.02 (m, 1H); to 3.67 (t, 2H); of 3.54 (m, 2H); to 3.33 (s, 3H); or 3.28 (t, 2H); 3,10 (m, 2H); 2,04 (m, 2H); to 1.83 (m, 2H).

Example 262: (1 carbamoylbiphenyl-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-shall ndol-2-carboxylic acid

To a suspension of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 1 ml of acetonitrile add 42,4 ál ethyldiethanolamine and 29.4 mg of 2-chloracetamide. The reaction mixture was stirred at 80°C for 3 hours. After removal of the solvent under reduced pressure the residue is purified preparative HPLC (C 18 column with reversed phase elution with a gradient mixture of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product, evaporated and lyophilizers obtaining a white solid. The product is obtained in the form of its triptoreline salt.

MC (ES+): m/e=498, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=9,62 (s, 1H); 8,65 (d, 1H); 7,94 (s, 1H); to 7.68 (m, 2H); of 7.60 (d, 1H); rate of 7.54 (d, 1H); 7,28 (m, 1H); 7,25 (m, 2H); to 7.15 (t, 1H); to 6.58 (s, 1H); 5,90 (s, 2H); 4,00 (m, 1H); 3,88 (m, 2H); of 3.53 (m, 2H); and 3.16 (m, 2H); 2,00 (m, 4H).

Example 263: (1 methylcarbamoylmethyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 262 with the difference that the use of 2-chloro-N-methylacetamide instead of 2-chloracetamide.

MC (ES+): m/e=512, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=9,74 (s, 1H); 8,65 (d, 1H); 8,5 (s, 1H); to 7.68 (d, 1H); of 7.60 (d, 1H); 7,53 (d, 1H); 7,29 (m, 1H); 7,25 (m, 2H); 7,14 (t, 1H); 6,56 (s, 1H); 5,90 (s, 2H); 4,00 (m, 1H); 3,88 (m, 2H); of 3.53 (m, 2H); and 3.16 (m, 2H); 2,69 (d, 3H); 2,04 (m, 2H); of 1.92 (m, 2H).

Example 264: [1-(1H-imidazol-2-ylmethyl)piperidine-4-yl]amide 1- [5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

A solution of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 1.5 ml 1,2-dichloroethane is treated 66,76 mg triacetoxyborohydride sodium, 18 mg icy acid and 11.1 mg of 1H-imidazole-2-carbaldehyde. After stirring the reaction mixture for 16 hours at room temperature the solvent is removed under reduced pressure. The residue is purified preparative HPLC (C18 column with reversed phase elution with a gradient mixture of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product, evaporated and lyophilizers obtaining a white solid. The product is obtained in the form of its triptoreline salt.

MS (ES+): m/e=521, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=8,54 (d, 1H); to 7.68 (d, 1H); 7,58 (d, 1H); 7,53 (d, 1H); 7,45 (s, 2H); 7,29 (m, 1H); to 7.25 (d, 1H); 7,22 (s, 1H); 7,14 (t, 1H); to 6.57 (s, 1H); 5,90 (s, 2H); 4,13 (m, Shir.); a 3.87 (m, W); 3,18 (m, 2H); 1,95 (m, 2H); to 1.75 (m, 2H).

Example 265: [1-(1-methyl-1H-imidazol-2-ylmethyl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-carboxylic acid

Specified in the header of the connection will receive is similar to the method of example 264 with the difference that using 1-methyl-1H-imidazole-2-carbaldehyde instead of 1H-imidazole-2-carbaldehyde.

MS (ES+): m/e=535, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=8,54 (d, 1H); to 7.68 (d, 1H); to 7.59 (d, 1H); at 7.55 (d, 1H); 7.50 for (s, 1H); 7,29 (m, 1H); to 7.25 (d, 1H); 7,22 (s, 1H); 7,14 (t, 1H); to 6.57 (s, 1H); 5,90 (s, 2H); 4,13 (m, Shir.); 3,93 (m, W); of 3.78 (s, 3H); 3,23 (m, W); of 1.95 (m, 2H); to 1.75 (m, 2H).

Example 266: [1-(2-dimethylaminoacetyl)piperidine-4-yl]amide 1-[5- (5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

A solution of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid in 1 ml of N,N-dimethylformamide is treated 29.0 mg of potassium carbonate, to 187.5 μl of ethyldiethanolamine and 16.7 ál chloroacetanilide. After stirring the reaction mixture for 15 min at room temperature add 19.5 mg of dimethylamine hydrochloride and the mixture is further stirred at room temperature for 16 hours. The solvent is removed under reduced pressure and the residue purified preparative HPLC (C18 column with reversed phase elution with a gradient mixture of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product, evaporated and lyophilizers floor with the rising white solid. The product is obtained in the form of its triptoreline salt.

MS (ES+): m/e=526, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS), characteristic for aromatic protons and amide fragments: 9,50 (s, 1H); 8,53 (d, 1H); to 7.68 (d, 1H); of 7.60 (d, 1H); at 7.55 (d, 1H); 7,28 (m, 1H); to 7.25 (d, 1H); 7,20 (s, 1H); to 7.15 (t, 1H); 6,59 (s,1H).

Example 267: [1-(2-aminoacetyl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid

(i) tert-Butyl ether {2-[4-({1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}amino)piperidine-1-yl]-2-oxoethyl}carbamino acid

To a solution of 50 mg of piperidine-4-ylamide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid and 44.1 μl of N-ethylmorpholine in 1 ml dichloromethane added to 28.5 mg tetrafluoroborate O-[(etoxycarbonyl)cyanomethylene]-N, N, N',N'-tetramethylurea and the mixture is stirred for 1 hour at room temperature. To the mixture of 15.2 mg of tert-butoxycarbonylamino acid and the reaction mixture is further stirred for 1 hour. After removal of the solvent under reduced pressure the residue is purified preparative HPLC (C18 column with reversed phase elution with a gradient mixture of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product, evaporated and lyophilizers with getting the white t is ejogo substances. The product is obtained in the form of its triptoreline salt.

The output of 22.0 mg MS (ES+): m/e=598.

(ii) [1-(2-Aminoacetyl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid.

A solution of 22.0 mg of tert-butyl methyl ether (2-[4-({1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}amino)piperidine-1-yl]-2-oxoethyl}carbamino acid in 5 ml of a 8 n solution of hydrochloric acid in methanol is stirred at room temperature for 16 hours. To the reaction mixture add 10 ml of water and the resulting mixture lyophilizer obtaining a white solid. The product is obtained in the form of cleaners containing hydrochloride salt.

MS (ES+): m/e=498, the isotopic distribution of the chlorine atoms.

1H-NMR (300 MHz, DMSO/TMS): δ=8,54 (d, 1H); 8,03 (m, 2H); to 7.68 (d, 1H); to 7.59 (d, 1H); at 7.55 (d, 1H); 7,28 (m, 1H); to 7.25 (d, 1H); 7,22 (s, 1H); 7,13 (t, 1H); 6,59 (s, 1H); 5,90 (s, 2H); of 4.35 (m, 1H); 4,07 (m, 1H); 3,95 (m, 1H); a 3.87 (m, 1H); to 3.73 (m, 1H); and 3.16 (m, 1H); of 2.86 (m, 1H); 1,90 (m, 2H); and 1.54 (m, 1H); of 1.44 (m, 1H).

Example 268: 1-ethoxycarbonylmethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

To a solution of 0.39 g of the hydrochloride of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid in 15 ml of DMF added to 0.23 g KI, 0,383 g2CO3 and 0.37 ml of 1-chloritisation and the reaction mixture is stirred for 3 hours at 60° C in argon atmosphere. After filtration and removal of solvent under reduced pressure the residue directly purified preparative HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After adding 1 M hydrochloric acid and freeze-drying in a mixture of acetonitrile/water, the product is obtained in the form of its hydrochloride.

The output of 0.33, MS (ESI+): m/e=643, the isotopic distribution of the chlorine atoms.

Example 269: 1-ethoxycarbonylmethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid

To a solution of 0.6 g of the hydrochloride of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid in 20 ml of DMF add 0,679 g KI, 1.13 g2CO3and 1,094 ml of 1-chloritisation and the reaction mixture is stirred for 3 hours at 60°C in argon atmosphere. After filtration and removal of solvent under reduced pressure the residue directly purified preparative HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After adding 1 M hydrochloric acid and freeze-drying in a mixture of acetonitrile/water, the product is obtained in the form of its hydrochloride.

The output of 0.56, MS (ESI+): m/e=643, the isotopic distribution of the atoms is Laura.

Example 270: 2,2-dimethylphenylacetate ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid

To a solution of 0.6 g of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid in 20 ml of DMF add 0,319 g chlormethiazole ether of 2,2-dimethylpropionic acid and 441 μl NEt3and the reaction mixture is stirred for 5 hours at 60°C. Next add an additional 0.16 g chlormethiazole ether of 2,2-dimethylpropionic acid and 147 μl NEt3and the reaction mixture is stirred for 6 hours at 60°C. After removal of the solvent under reduced pressure the residue is dissolved in CH2Cl2and the solution washed with water. The phases are separated and the organic phase after drying over Na2SO4) was concentrated in vacuo. The residue is purified preparative HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After adding 1 M hydrochloric acid and freeze-drying in a mixture of acetonitrile/water, the product is obtained in the form of its hydrochloride.

The output of 0.5, MS (ESI+): m/e=641, the isotopic distribution of the chlorine atoms.

Example 271: 1-(2,2-dimethylpropionic)ethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-ind the l-5-carboxylic acid

To a suspension of 0.5 g of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid in 30 ml of acetone add 531 μl DBU and the mixture is stirred for 15 min at room temperature. To this solution add 0,556 g 1 bromatologia ether of 2,2-dimethylpropionic acid (obtained as described E. Defossa et al., Liebigs Ann. 1996, 1743-1749) and the reaction mixture stirred for 4 h at room temperature. Next add an additional 266 μl DBU and 0,185 g 1 bromatologia ether of 2,2-dimethylpropionic acid. After 16 hours at room temperature the mixture was concentrated in vacuo and the residue purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After adding 1 M hydrochloric acid and freeze-drying in a mixture of acetonitrile/water, the product is obtained in the form of its hydrochloride.

The output of 0.48, MS (ESI+): m/e=655, the isotopic distribution of the chlorine atoms.

Example 272: 1-(2,2-dimethylpropionic)ethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid

To a suspension 0,427 g of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid in 30 ml of acetone add the 453 μl DBU and the mixture is stirred for 15 min at room temperature. To this solution add value (0.475) g 1-bromatologia ether of 2,2-dimethylpropionic acid (obtained as described E. Defossa et al., Liebigs Ann. 1996, 1743-1749) and the reaction mixture stirred for 4 h at room temperature. Next add an additional 227 μl DBU and 0,158 g 1 bromatologia ether of 2,2-dimethylpropionic acid. After 16 hours at room temperature the mixture was concentrated in vacuo and the residue purified preparative RP-HPLC with elution with a gradient of 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After adding 1 M hydrochloric acid and freeze-drying in a mixture of acetonitrile/water, the product is obtained in the form of its hydrochloride.

The output of 0.4, MS (ESI+): m/e=655, the isotopic distribution of the chlorine atoms.

Example 273: 5-methyl-2-oxo[1,3]dioxol-4-ymetray ester 1-[5- (5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

can be obtained from 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid and 4-chloromethyl-5-methyl[1,3]dioxol-2-it according to the method described by N. Yanagisawa et al., J. Med. Chem. 1996, 39, 323-338.

Example 274: 5-methyl-2-oxo[1,3]dioxol-4-ymetray ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid

can be obtained from 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid and 4-chloromethyl-5-methyl[1,3]dioxol-2-it according to the method described by N. Yanagisawa et al., J. Med. Chem. 1996, 39, 323-338.

Example 275: 1-cyclohexyloxycarbonyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid

can be obtained from 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid cyclohexyl-1-charitycardonate according to the method described by K. Kubo et al., J. Med. Chem. 1993, 36, 2343-2349.

Example 276: 1-cyclohexyloxycarbonyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid

can be obtained from 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-4-carboxylic acid cyclohexyl-1-charitycardonate according to the method described by K. Kubo et al., J. Med. Chem. 1993, 36, 2343-2349.

Pharmacological testing

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 evaluated by determining the concentration of the compounds of formula I, Kotor is inhibited enzyme activity by 50%, i.e. the values of the IC50that are related to the inhibition constant Ki. In chromogenic assays using purified enzymes. The concentration of inhibitor that causes a 50% reduction in the rate of hydrolysis of the substrate, determined by linear regression after building the graphical dependence of relative velocities of hydrolysis (compared to eingeborenen control) from the logarithm of the concentration of the compound of formula I. To calculate the inhibition constants Ki value IC50adjust to competition with the substrate, using the formula

Ki=IC50/{1+(the substrate concentration/Km)},

where Km is a constant Michaelis-Menten (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 of the definition of inhibiting the activity of factor XA using TBS-PEG buffer (50 mm Tris-HCl, pH of 7.8, 200 mm NaCl, 0,05% (wt./about.) PEG-8000, 0,02% (wt./about.) NaN3). 1050 determined by combining in appropriate wells of microtiter tablets Costar separated wells, 25 μl human factor XA (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 test compounds dissolved in 10% (vol./about.) DMSO in TBS-PEG, and the substrate S-2765 (N(a)-benzyloxycarbonyl-D-Arg-GlyL-Arg-p-nitroanilide; Kabi Pharmacia, Inc.; Franklin, Ohio) in TBS-PEG. The analysis is carried out at pre-incubation of the compounds of formula I plus the enzyme for 10 minutes Further analysis initiated by adding substrate to obtain a final volume of 100 μl. The initial rate of hydrolysis of a chromogenic substrate is determined by the change in absorption at 405 nm using a kinetic reader tablets Bio-tek Instruments (Ceres UV900HD1) at 25°linear plot of the time dependence (usually 1.5 min after substrate addition). The concentration of the enzyme is 0.5 nm and the substrate concentration is equal to 140 microns.

b) Analysis of factor VIIa

Inhibitory activity against factor VIIa/tissue factor determined using chromogenic analysis, essentially as described previously (J.A. Ostrem et al. Biochemistry 37 (1998) 1053-1059, which is incorporated in this description by reference). Kinetic tests conducted at 25°in microtiter tablets separated by wells (Costar Corp., Cambridge, Massachusets), using the kinetic reader tablet (Molecular Devices Spectramax 250). Typical analysis consists of 25 μl human factor VIIa and TF (5 nm and 10 nm, relative to the final concentration)combined with 40 μl of a dilution of the inhibitor in a 10% mixture of DMSO/TBS-PEG buffer (50 mm Tris, 15 mm NaCl, 5 mm CaCl2, 0,05% PEG-8000, pH 8,15). After a 15 minute period prior incubations initiate 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) in the table.

1. The compound of the formula I

where R0represents a

1. phenyl, mono-, di - or tizamidine independently of one another a radical R8;

2. monocyclic or bicyclic 6-, 9-, 10-membered heteroaryl selected from the group consisting of pyridyl, benzothiophene and hintline where specified heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R8; or

3. monocyclic 5-membered heteroaryl containing two or three heteroatoms selected from nitrogen, sulfur or oxygen, where indicated heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R8and which is optionally substituted monocyclic 5-membered heteroaryl containing one sulfur atom, where heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R8,

provided that R0is not phenyl when Q represents a direct bond,

R8is a halogen; -C(O)-NH2; -NH2; -OCF3; phenyl, mono-, di - or TRIZ is substituted by halogen; -O-(C1-C8)alkyl, where the alkyl is unsubstituted or mono-, di - or tizamidine halogen,

provided that R8represents at least one halogen-free, residue-C(O)-NH2or-O-(C1-C8)alkyl, where R0represents phenyl;

Q represents a direct bond, -C(O)-, -(C0-C2)alkylen-C(O)-NR10-, -SO2-, -(C1-C6)alkylen;

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

R2represents a direct bond or -(C1-C4)alkylene; or

R1-N-R2-V can form a 6-membered cyclic residue, containing 1 or 2 nitrogen atom;

R10represents a hydrogen atom;

V represents

1. 5 - or 6-membered cyclic residue, containing 1 nitrogen atom, where the specified cyclic residue is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;

2. 6-membered aryl, where aryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14; or

3. monocyclic 5-membered heteroaryl containing 2 heteroatoms selected from nitrogen, sour what kind or sulfur, or bicyclic 10-membered heteroaryl containing 1 or 2 nitrogen atom, where these heteroaryl are unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;

G represents a direct bond, -(CH2)m-, -(CH2)-SO2-(CH2)n-, -(CH2)m-NR10-, (CH2)m-C(O)-(CH2)n-, -(CH2)n, -O-(CH2)n-,

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

R14represents a halogen, -OH, -(C1-C8)alkyl, -(C1-C4)alkoxy, -CN,-NH2-C(O)-O-(C1-C4)alkyl, -C(O)-NH2;

R10represents a hydrogen atom or -(C1-C6)alkyl;

M represents a hydrogen atom; -(C1-C8)alkyl, where the alkyl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;-C(O)-NR11NR12; -(CH2)m-NR10; C5- or6-heteroaryl containing one or two nitrogen atom, where heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;3-C5- or6-cycloalkyl where specified cycloalkyl is asamese the major or mono-, di - or tizamidine independently of one another a radical R14; or 6-membered cyclic residue, containing up to 1 or 2 heteroatoms selected from nitrogen or oxygen, where indicated cyclic residue is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;

R11and R12are independently of one another identical or different and represent a hydrogen atom; -(C1-C6)alkyl; or

R11and R12together with the nitrogen atom to which they are bound, may form a saturated 5-membered monocyclic heterocyclic ring;

R13is a halogen; =O; -IT; -(C1-C8)alkyl; -(C1-C8)alkoxy; phenyl; -C(O)-O-R11;

R3, R4, R5, R6and R7independently of one another are identical or different and represent a hydrogen atom; halogen; -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times the radical R13; -(C1-C3)perfluoroalkyl; phenyl; -O-(C1-C4)alkyl; -NO2; -CN; -HE; benzyloxy-; -C(O)-R10; -C(O)-N-R11R12; -NR11R12; -SOn-R10where n is 1 or 2; -C(O)-O-C(R15R16)-O-C(O)CO-R17; -C(O)-O-C(R15R16)-O-C(O)-R17; -NR -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times the radical R13;

R15and R16represent independently of one another hydrogen, -(C1-C6)alkyl;

R17represents -(C1-C6)alkyl,

in all its stereoisomeric forms and mixtures in any ratio, and its physiologically tolerated salt.

2. The compound of formula I according to claim 1, where

R0represents a

1. phenyl, where phenyl is mono-, di - or triamese independently of one another a radical R8;

2. bicyclic 9 - or 10-membered heteroaryl selected from the group consisting of benzothiophene or hintline where specified heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R8;

3. monocyclic 5-membered heteroaryl from the group consisting of imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazole or triazolyl where specified heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R8,

and additionally substituted by a residue selected from the group consisting of tanila, 2-thienyl or 3-tanila, where the specified residue is unsubstituted or mono-, di - or triamese the tion independently of one another a radical R 8,

R8represents a halogen such as F, Cl, Br or I; -C(O)-NH2or-O-(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or tizamidine halogen,

provided that R8represents at least one halogen-free, residue-C(O)-NH2or-O-(C1-C8)alkyl, where R0represents phenyl,

Q represents a direct bond, -C(O)-, -SO2- or -(C1-C6)alkylene -(C0-C2)alkylen-C(O)-NR10-;

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

R2represents a direct bond or-(C1-C2)alkylene; or

R1-N-R2-V can form a 6-membered cyclic group containing piperidine, piperazine, pyridine or pyrimidine;

R14represents a halogen, -(C1-C4)alkyl or-NH2;

V represents

1. 5 - or 6-membered cyclic residue selected from the residue of pyrrole, pyrrolidine, pyridine or piperidine, where the specified cyclic residue is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;

2. phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14; or

. bicyclic 10-membered heteroaryl selected from the group consisting of chinosol, ethanolic and honokalani where specified heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;

G represents a direct bond, -(CH2)m- or -(CH2)m-NR10-;

m represents the integer 0, 1, 2, 3 or 4;

R1represents a hydrogen atom or-(C1-C4)alkyl;

M represents a hydrogen atom; C5-or6-heteroaryl where heteroaryl represents a residue selected from the group, which may be a derivative of piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, imidazole, pyridazine or pyrazine where specified heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14; -(C1-C6)alkyl, where the specified alkyl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14or3-With5- or6-cycloalkyl;

R3, R4, R5, R6and R7independently of one another are identical or different and represent a hydrogen atom; F, Cl or Br; -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted glad the faeces R 13; -CF3; phenyl; -O-(C1-C4)alkyl; -NO2; -CN; -HE; benzyloxy-; -C(O)-R10; -C(O)-N-R11R12; -NR1R12; -SOn-R10where n is 1 or 2; -C(O)-O-C(R15R16)-O-C(O)-R17; -C(O)-O-C(R15R16)-O-C(O)O-R17;

R13represents halogen, =O, -OH, -(C1-C8)alkoxy, -C(O)-O-R11,

in all its stereoisomeric forms and mixtures in any ratio, and its physiologically tolerated salt.

3. The compound of formula I according to claim 1 or 2, where

R0represents a

phenyl, where phenyl is mono-, di - or triamese independently of one another a radical R8,

monocyclic 5-membered heteroaryl selected from the group consisting of thiadiazolyl, isoxazolyl and thiazolyl where specified heteroaryl substituted by a residue selected from the group of tanila, 2-thienyl or 3-tanila, where the specified residue is unsubstituted or mono - or disubstituted independently of one another a radical R8,

R8represents F, Cl, Br, -och3-C(O)-NH2or-OCF3;

Q represents a direct bond, -C(O)-, -SO2is methylene or ethylene;

R1represents a hydrogen atom;

R2represents a direct bond or methylene; or

R1-N-R2-V arr is its 6-membered cyclic group, include piperidine and piperazine;

R13represents-C(O)-O-R11;

R14represents halogen, methyl, ethyl, or-NH2;

V represents the balance of the group, which includes the balance of isoquinoline, quinoline, heatline, piperidine and isoxazol where the specified cyclic residue is unsubstituted or mono - or Disaese independently of one another a radical R14; or phenyl, where phenyl is unsubstituted or mono - or Disaese independently of one another a radical R14;

G represents a direct bond, -(CH2)m- or-(CH2)m-NR10-;

m represents the integer 0, 1 or 2;

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

M represents a hydrogen atom, -(C2-C4)alkyl, imidazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl; or (C3-With5- or6-cycloalkyl, where the above cyclic residues are unsubstituted or mono - or tizamidine independently of one another a radical R14;

R3, R4, R5, R6and R7independently of one another are identical or different and represent a hydrogen atom; F, Cl; -(C1-C )alkyl, where the alkyl is unsubstituted or substituted by a radical R13; phenyl; -O-(C1-C4)alkyl; -C(O)-R10-C(O)-N-R11R12; -NR11R12; -C(O)-O-C(R15R16)-O-C(O)-R17; -C(O)-O-C(R15R16)-O-C(O)-R17,

in all its stereoisomeric forms and mixtures in any ratio, and its physiologically tolerated salt.

4. The compound of formula I according to claim 1, where the compound of formula I is a

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

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

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-6-methoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-what cortifen-2-yl)isoxazol-3-ylmethyl]-5-methyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,6-dimethoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5,6-dimethoxy-1H-indole-2-carboxylic acid,

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

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

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-6-hydroxy-5-methoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,6-debtor-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide of 4-benzyloxy-1-[5-(5-chlorothiophene-2-yl)isoxa the ol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

(1-isopropylpiperazine-4-yl)amide 6-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

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

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

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

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

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-ind the l-2-carboxylic acid,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-isopropylpiperazine-1-yl)methanon,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indol-2-yl}-(4-isopropylpiperazine-1-yl)methanon,

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

(1-ethylpiperazin-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-pyrrolidin-1-reparacin-1-yl)methanon,

[1,4']bipyridinyl-1'-yl{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}mechanon,

(3-pyridin-4-yl-4,5-dihydroisoxazole-5-ylmethyl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-pyridin-4-iletileri-1-yl)methanon,

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

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

[1-(tetrahydropyran-4-yl)piperidine-4-yl)]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-ylmethyl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(4-isopropylpiperazine-1-yl)-[1-(3-methoxybenzyl)-1H-indol-2-yl]metano,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

[1-(3-methoxybenzyl)-1H-indol-2-yl]-[4-(pyridine-4-ylamino)piperidine-1-yl]metano,

(1-isopropylpiperazine-4-yl)amide of 4-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-chloro-1-(3-methoxybenzyl)-1H-indole-2-Carbo the OIC acid,

(1-isopropylpiperazine-4-yl)amide 6-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-5-methyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-benzyloxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-5-nitro-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzoyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzenesulfonyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid,

(4-isopropylpiperazine-4-yl)-[1-(4-methoxyphenyl)-1H-indol-2-yl]metano,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxyphenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-ylmethyl)amide 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid,

(Isopropylpiperazine-4-yl)amide 1-(3,5-dichlorophenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(4-chlorophenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(6-chlorobenzo [b]thiophene-2-ylmethyl)-1H-indole-2-carboxylic acid,

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-(4-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(4-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(2,4-dichlorobenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(4-methoxybenzyl)-1H-indole-2-carboxylic acid,

(4-isopropylpiperazine-1-yl)-[1-(4-methoxybenzyl)-1H-indol-2-yl]metano,

(1-isopropylpiperazine-4-yl)amide 1-(4-cryptomaterial)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(2-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-yl)amide 1-(2-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-(2-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3,5-dichlorobenzyl)-1H-indole-2-carboxylic acid,

[1-(3,5-dichlorobenzyl)-1H-indol-2-yl]-(4-isopropylpiperazine-1-yl)methanon,

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-7-methyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-Chlorobenzyl)-1H-indole-2-carboxylic acid,

[1-(3-Chlorobenzyl)-1H-indol-2-yl]-(4-isopropylpiperazine-1-yl)methanon,

(1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(2,4-dichlorophenyl)ethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(3-methoxyphenyl)ethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-methoxy-1H-indole-2-carboxylic acid,

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

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

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

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

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

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

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

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

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

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

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

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid is acid,

[{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[(1-(1-ethylpropyl)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

[(1-(2,2,2-triptorelin)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

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

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

[1-(2-chloropyrimidine-4-yl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-[4-(pyridine-4-yloxy)piperidine-1-yl]metano,

[4-(1H-imidazol-4-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol the-3-ylmethyl]-1H-indole-2-carboxylic acid,

(4-pyridin-3-yl)thiazol-2-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

[3-(pyrrolidin-1-carbonyl)-4,5-dihydroisoxazole-5-ylmethyl] amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

methyl ester of 4-({1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}amino)piperidine-1-carboxylic acid,

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

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

pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-dead-4-methoxy-1H-in the ol-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-dicyano-4-methoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)thiazol-4-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(1,7-dichlorethylene-3-ylmethyl)-1H-indole-2-carboxylic acid,

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

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

(1-isopropylpiperazine-4-yl)amide 1-[3-(4-chlorophenyl)-[1,2,4]oxadiazol-5-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-methanesulfonyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-5-methanesulfonyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-chloro-1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-fluoro-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5,7-debtor-1H-indole-2-carboxylic acid,

(1-ethylpyrrolidin-3-yl)amide S-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-elmet the l]-1H-indole-2-carboxylic acid,

(1-ethylpyrrolidin-3-yl)amide R-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpyrimidine-3-yl)amide R-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpyrimidine-3-yl)amide S-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-trifluoromethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester [{4,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester [{5,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester [{4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-trifluoromethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4 and is)amino]acetic acid,

[{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{4,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{5,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

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

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

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

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

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

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

isopropyl ester 1-[5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole-2-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid,

1-[5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole-2-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid,

isopropyl ester 1-[4-chlorpheniramol)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid,

1-[4-chlorpheniramol)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid,

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-chlorothiophene-2-ylcarbonyl)methyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[4-chloro-2-fluoro-phenylcarbamoyl)methyl]-1H-indole-2-carboxylic acid,

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

(3,4,5,6-tetrahydro-2 is-[1,4']bipyridinyl-4-ylmethyl)amide 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid,

N-(4-chlorophenyl)-2-{2-[4-(pyridine-4-ylamino)piperidine-1-carbonyl]indole-1-yl}acetamide", she

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

N-(4-chlorophenyl)-2-[2-(4-pyrrolidin-1-reparacin-1-carbonyl]indole-1-yl}acetamide", she

(1-isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-5-nitro-1H-indole-2-carboxylic acid,

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

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

[1-(2-hydroxyethyl)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

[1-(2-methoxyethyl)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

[1-(1H-imidazol-2-iletilerini-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic KIS is the notes,

[1-(2-dimethylaminoacetyl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

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

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

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

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

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

1-cyclohexyloxycarbonyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-carbamoyl)-1H-indole-5-carboxylic acid, or

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

5. The method of obtaining the compounds of formula I according to one or more of claims 1 to 4, which involves the condensation of compounds of formula 14 with a compound of formula HR8'obtaining the compounds of formula 15, and optionally converting the compounds of formula 15 in the compound of formula I by esterification, replacement, recovery, catalytic hydrogenation, alkylation, arilirovaniya, acylation, hydrolysis, amination, reductive amination, removing the protective groups

where the remainder R8is a donor-N(R1)-R2-V-G-M, as specified in claims 1 to 4, but where R8'functional groups may also be present in the form of groups that are subsequently transformed into the final functional group represented by-N(R1)-R2-V-G-M, where the group-C(O)-R49can be a carboxylic acid group or its derivatives, where the remainder R50means the group-Q-R0and where the group R1e, R1a, R1b, R1cand R1din formulas 14 and 15 have corresponding definitions R7, R6, R5, R4and R3in the formula I, as defined in claims 1 to 4, or the functionality is global groups can also be represented in a protected form.

6. Drug, possessing properties of inhibitors of factor XA and/or VIIa, comprising at least one compound of formula I according to one or more of claims 1 to 4, in all its stereoisomeric forms and mixtures thereof in any ratio and/or its physiologically tolerated salts and pharmaceutically acceptable carrier.

7. The use of the compounds of formula I

in all its stereoisomeric forms and mixtures thereof in any ratio and/or its physiologically-tolerated salts to obtain pharmaceuticals for inhibition of factor XA and/or factor VIIa or for influencing blood coagulation or fibrinolysis, where

R0represents a

1. phenyl, mono-, di - or tizamidine independently of one another a radical R8;

2. monocyclic or bicyclic 6-, 9-, 10-membered heteroaryl selected from the group consisting of pyridyl, benzothiophene and hintline where specified heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R8; or

3. monocyclic 5-membered heteroaryl containing two or three heteroatoms selected from nitrogen, sulfur or oxygen, where indicated heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R8and which is optionally substituted monocyclic 5-membered heteroaryl, containing one sulfur atom, where heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R8,

provided that R0is not phenyl when Q represents a direct bond,

R8is a halogen; -C(O)-NH2; -NH2; -OCF3; phenyl, mono-, di - or triamese halogen; -O-(C1-C8)alkyl, where the alkyl is unsubstituted or mono-, di - or tizamidine halogen;

provided that R represents at least one halogen-free, residue-C(O)-NH2or-O-(C1-C8)alkyl, where R0represents phenyl;

Q represents a direct bond, -C(O)-, -(C0-C2)alkylen-C(O)-NR10-, -SO2-, -(C1-C6)alkylen;

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

R2represents a direct bond or -(C1-C4)alkylene; or

R1-N-R2-V can form a 6-membered cyclic residue, containing 1 or 2 nitrogen atom;

R10represents a hydrogen atom;

V represents

1. 5 - or 6-membered cyclic residue, containing 1 nitrogen atom, where the decree is hydrated cyclic residue is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;

2. 6-membered aryl, where aryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14; or

3. monocyclic 5-membered heteroaryl containing 2 heteroatoms selected from nitrogen, oxygen, or sulfur, or a bicyclic 10-membered heteroaryl containing 1 or 2 nitrogen atom, where these heteroaryl are unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;

G represents a direct bond, -(CH2)m-, (CH2)-SO2-(CH2)n-, -(CH2)m-NR10-, (CH2)m-C(O)-(CH2)n-, -(CH2)n, -O-(CH2)n-,

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

R14represents a halogen, -OH, -(C1-C8)alkyl, -(C1-C4)alkoxy, -CN, -NH2-C(O)-O-(C1-C4)alkyl, -C(O)-NH2;

R10represents a hydrogen atom or-(C1-C6)alkyl;

M represents a hydrogen atom; -(C1-C8)alkyl, where the alkyl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14; -C(O)NR11R2 ; -(CH2)m-NR10; C5- or6-heteroaryl containing one or two nitrogen atom, where heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;3-With5- or6-cycloalkyl where specified cycloalkyl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14; or 6-membered cyclic residue, containing up to 1 or 2 heteroatoms selected from nitrogen or oxygen, where indicated cyclic residue is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;

R11and R12are independently of one another identical or different and represent a hydrogen atom; -(C1-C6)alkyl, or

R11and R12together with the nitrogen atom to which they are bound, may form a saturated 5-membered monocyclic heterocyclic ring;

R13is a halogen; =O; -IT; -(C1-C8)alkyl; -(C1-C8)alkoxy; phenyl; -C(O)-O-R11;

R3, R4, R5, R6and R7independently of one another are identical or different and represent a hydrogen atom; halogen; -(C1-C4)alkyl, where the alkyl is unsubstituted or is emenim from one to three times the radical R 13; -(C1-C3)perfluoroalkyl; phenyl; -O-(C1-C4)alkyl; -NO2; -CN; -HE; benzyloxy-; -C(O)-R10;-C(O)-N-R11R12; -NR11R12; -SOn-R10where n is 1 or 2; -C(O)-O-C(R15R16)-O-C(O)-R17; -C(O)-O-C(R15R16)-O-C(O)O-R17; -NRl0-(C1-C4)alkyl, where the alkyl is unsubstituted or substituted one to three times the radical R13;

R15and R16represent independently of one another hydrogen, -(C1-C6)alkyl;

R17represents -(C1-C6)alkyl.

8. The use according to claim 7, where

R0represents a

1. phenyl, where phenyl is mono-, di - or triamese independently of one another a radical R8;

2. bicyclic 9 - or 10-membered heteroaryl selected from the group consisting of benzothiophene or hintline where specified heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R8;

3. monocyclic 5-membered heteroaryl from the group consisting of imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazole or triazolyl where specified heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R8,

and additionally is substituted by the residue selected from the group consisting of tanila, 2-thienyl or 3-tanila, where the specified residue is unsubstituted or mono-, di - or tizamidine independently of one another a radical R8,

R8represents a halogen such as F, Cl, Br or I; -C(O)-NH2or-O-(C1-C4)alkyl, where the alkyl is unsubstituted or mono-, di - or tizamidine halogen,

provided that R8represents at least one halogen-free, residue-C(O)-NH2or-O-(C1-C8)alkyl, where R0represents phenyl,

Q represents a direct bond, -C(O)-, -SO2- or -(C1-C6)alkylene -(C0-C2)alkylen-C(O)-NR10-;

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

R2represents a direct bond or -(C1-C2)alkylene; or

R1-N-R2-V can form a 6-membered cyclic group containing piperidine, piperazine, pyridine or pyrimidine;

R14represents a halogen, -(C1-C4)alkyl or-NH2;

V represents

1. 5 - or 6-membered cyclic residue selected from the residue of pyrrole, pyrrolidine, pyridine or piperidine, where the specified cyclic residue is unsubstituted or mono-, di - or triamese is output independently of one another a radical R 14;

2. phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14; or

3. bicyclic 10-membered heteroaryl selected from the group consisting of chinosol, ethanolic and honokalani where specified heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14;

G represents a direct bond, -(CH2)m- or -(CH2)m-NR10-;

m represents the integer 0, 1, 2, 3 or 4;

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

M represents a hydrogen atom; C5- or6-heteroaryl where heteroaryl represents a residue selected from the group, which may be a derivative of piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, imidazole, pyridazine or pyrazine where specified heteroaryl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14; -(C1-C6)alkyl, where the specified alkyl is unsubstituted or mono-, di - or tizamidine independently of one another a radical R14or3-With5-or6-cycloalkyl;

R3, R4, R5, R6and R7independently of one another are Odinak is new or different and represent a hydrogen atom; F, Cl or Br; -(C1-C4)alkyl, where the alkyl is unsubstituted or substituted by a radical R13; -CF3; phenyl; -O-(C1-C4)alkyl; -NO2; -CN; -HE; benzyloxy-; -C(O)-R10; -C(O)-N-R11R2; -NR11R12; -SOn-R10where n is 1 or 2; -C(O)-O-C(R15R16)-O-C(O)-R17; -C(O)-O-C(R15R16)-O-C(O)O-R17;

R13represents halogen, =O, -OH, -(C1-C8)alkoxy, -C(O)-O-R11.

9. The use according to claim 7 or 8, where

R0represents a

phenyl, where phenyl is mono-, di - or triamese independently of one another a radical R8,

monocyclic 5-membered heteroaryl selected from the group consisting of thiadiazolyl, isoxazolyl and thiazolyl where specified heteroaryl substituted by a residue selected from the group of tanila, 2-thienyl or 3-tanila, where the specified residue is unsubstituted or mono - or disubstituted independently of one another a radical R8,

R8represents F, Cl, Br, -och3, -C(O)-NH2or-OCF3;

Q represents a direct bond, -C(O)-, -SO2is methylene or ethylene;

R1represents a hydrogen atom;

R2represents a direct bond or methylene; or

R1-N-R2-V can form a 6-membered cyclizes the th group, include piperidine and piperazine;

R13represents-C(O)-O-R11;

R14represents halogen, methyl, ethyl, or-NH2;

V represents the balance of the group, which includes the balance of isoquinoline, quinoline, heatline, piperidine and isoxazol where the specified cyclic residue is unsubstituted or mono - or Disaese independently of one another a radical R14; or phenyl, where phenyl is unsubstituted or mono - or Disaese independently of one another a radical R14;

G represents a direct bond, -(CH2)m- or -(CH2)m-NR10-;

m represents the integer 0, 1 or 2;

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

M represents a hydrogen atom, -(C2-C4)alkyl, imidazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl; or (C3-With5- or6-cycloalkyl, where the above cyclic residues are unsubstituted or mono - or tizamidine independently of one another a radical R14;

R3, R4, R5, R6and R7independently of one another are identical or different and represent a hydrogen atom; F, Cl; -(C1- 4)alkyl, where the alkyl is unsubstituted or substituted by a radical R13; phenyl; -O-(C1-C4)alkyl; -C(O)-R10-C(O)-N-R11R12; -NR11R12; -C(O)-O-C(R15R16)-O-C(O)-R17; -C(O)-O-C(R15R16)-O-C(O)-R17.

10. The use according to claim 7 where the compound of formula I is a

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

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

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-6-methoxy-1H-indole-2-carboxylic acid,

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorine is thiophene-2-yl)isoxazol-3-ylmethyl]-4,6-dimethoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5,6-dimethoxy-1H-indole-2-carboxylic acid,

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

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

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-6-hydroxy-5-methoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,6-debtor-1H-indole-2-carboxylic acid,

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

(1-isopropylpiperazine-4-yl)amide 7-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-and the methyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 6-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

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

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

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

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

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic acid,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperid the n-1-yl]metano,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indol-2-yl}-[4-(pyridine-4-ylamino)piperidine-1-yl]metano,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-isopropylpiperazine-1-yl)methanon,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indol-2-yl}-(4-isopropylpiperazine-1-yl)methanon,

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

(1-ethylpiperazin-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carboxylic acid,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-pyrrolidin-1-reparacin-1-yl)methanon,

[1,4']bipyridinyl-1'-yl{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl} mechanon,

(3-pyridin-4-yl-4,5-dihydroisoxazole-5-ylmethyl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-(4-pyridin-4-iletileri-1-yl)methanon,

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

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-CA is oil acid,

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

[1-(tetrahydropyran-4-yl)piperidine-4-yl)]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-ylmethyl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylmethyl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(4-isopropylpiperazine-1-yl)-[1-(3-methoxybenzyl)-1H-indol-2-yl]metano,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

[1-(3-methoxybenzyl)-1H-indol-2-yl]-[4-(pyridine-4-ylamino)piperidine-1-yl]metano,

(1-isopropylpiperazine-4-yl)amide of 4-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-chloro-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 6-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-5-methyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-benzyloxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzyl)-5-nitro-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-methoxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzoyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxybenzenesulfonyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(4-methoxyphenyl)-1H-indole-2-carboxylic acid,

(4-isopropylpiperazine-4-yl)-[1-(4-methoxyphenyl)-1H-indol-2-yl]metano,

(1-isopropylpiperazine-4-yl)amide 1-(3-methoxyphenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-ylmethyl)amide 1-(3-chlorophenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3,5-dichlorophenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine the-4-yl) amide 1-(4-chlorophenyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(6-chlorobenzo[b]thiophene-2-ylmethyl)-1H-indole-2-carboxylic acid,

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-(4-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(4-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(2,4-dichlorobenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(4-methoxybenzyl)-1H-indole-2-carboxylic acid,

(4-isopropylpiperazine-1-yl)-[1-(4-methoxybenzyl)-1H-indol-2-yl]metano,

(1-isopropylpiperazine-4-yl)amide 1-(4-cryptomaterial)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(2-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-(2-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']is piperidinyl-4-ylmethyl)amide 1-(2-Chlorobenzyl)-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3,5-dichlorobenzyl)-1H-indole-2-carboxylic acid,

[1-(3,5-dichlorobenzyl)-1H-indol-2-yl]-(4-isopropylpiperazine-1-yl)methanon,

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-7-methyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(5-chlorothiophene-2-yl)thiazole-5-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(3-Chlorobenzyl)-1H-indole-2-carboxylic acid,

[1-(3-Chlorobenzyl)-1H-indol-2-yl]-(4-isopropylpiperazine-1-yl)methanon,

(1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(2,4-dichlorophenyl)ethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(3-methoxyphenyl)ethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)ethyl]-4-methoxy-1H-indole-2-carboxylic acid,

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

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

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

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

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

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

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

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

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

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

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

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-7-methyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)AMI is about]acetic acid,

[(1-(1-ethylpropyl)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

[(1-(2,2,2-triptorelin)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

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

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

[1-(2-chloropyrimidine-4-yl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indol-2-yl}-[4-(pyridine-4-yloxy)piperidine-1-yl]metano,

[4-(1H˜imidazol-4-yl)phenyl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

(4-pyridin-3-yl)thiazol-2-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-shall ndol-2-carboxylic acid,

[3-(pyrrolidin-1-carbonyl)-4,5-dihydroisoxazole-5-ylmethyl] amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

methyl ester of 4-({1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}amino)piperidine-1-carboxylic acid,

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

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

pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

pyridine-4-yl(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-3-cyano-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-dead-4-methoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]was 3.7-d is cyano-4-methoxy-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[2-(4-chlorophenyl)thiazol-4-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-(1,7-dichlorethylene-3-ylmethyl)-1H-indole-2-carboxylic acid,

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

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

(1-isopropylpiperazine-4-yl)amide 1-[3-(4-chlorophenyl)-[1,2,4]oxadiazol-5-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-methanesulfonyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-5-methanesulfonyl-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 5-chloro-1-[(5-chloropyridin-2-ylcarbonyl)methyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-fluoro-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5,7-debtor-1H-indole-2-carboxylic acid,

(1-ethylpyrrolidin-3-yl)amide S-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

(1-ethylpyrrolidin-3-yl)amide R-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbon is acid,

(1-isopropylpyrimidine-3-yl)amide R-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

(1-isopropylpyrimidine-3-yl)amide S-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-trifluoromethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester of [{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester [{4,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester [{5,7-dichloro-1-[5-(5-chlorothiophene-2˜ yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

ethyl ester [{4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-trifluoromethyl-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{1-[5-(3-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethyl-1H-indole-2-Carbo is Il}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4,7-dimethoxy-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{4,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{5,7-dichloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

[{4-chloro-1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-(1-isopropylpiperazine-4-yl)amino]acetic acid,

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

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

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

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

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

2,2-dimethylphenylacetate ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid is you,

isopropyl ester 1-[5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole-2-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid,

1-[5-(5-chlorothiophene-2-yl)-[1,3,4]thiadiazole-2-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid,

isopropyl ester 1-[4-chlorpheniramol)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid,

1-[4-chlorpheniramol)methyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-indole-5-carboxylic acid,

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

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

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

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

(1-isopropylpiperazine-4-yl)amide 1-[5-chlorothiophene-2-ylcarbonyl)methyl]-1H-indole-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[4-chloro-2-fluoro-phenylcarbamoyl)methyl]-1H-indole-2-carboxylic acid,

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

(3,4,5,6-tetrahydro-2 is-[1,4']bipyridinyl-4-ylmethyl)amide 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid,

(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)amide 1-[(4-chlorpheniramol)methyl]-1H-indole-2-carboxylic acid,

N-(4-chlorophenyl)-2-{2-[4-(pyridine-4-ylamino)piperidine-1-carbonyl]indole-1-yl}acetamide", she

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

N-(4-chlorophenyl)-2-[2-(4-pyrrolidin-1-reparacin-1-carbonyl]indole-1-yl}acetamide", she

(1-isopropylpiperazine-4-yl)amide 1-[(4-chlorpheniramol)methyl]-5-nitro-1H-indole-2-carboxylic acid,

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

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

[1-(2-hydroxyethyl)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

[1-(2-methoxyethyl)piperidine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

[1-(1H-imidazol-2-iletilerini-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic KIS is the notes,

[1-(2-dimethylaminoacetyl)piperidine-4-yl]amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid,

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

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

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

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

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

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

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

1-cyclohexyloxycarbonyloxy ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-carbamoyl)-1H-indole-5-carboxylic acid, or

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



 

Same patents:

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of bipiperidine of the formula (I): , wherein X means a direct bond, -CH2-, -CH2-CH2- or -CHR9-; R1 means optionally R10- and/or R11-substituted phenyl, optionally R10- and/or R11-substituted heteroaryl, N-oxide of optionally R10- and/or R11-substituted heteroaryl or optionally R10- and/or R11-substituted naphthyl; R2 has one of values given for R1, or it means optionally R10-substituted (C1-C6)-alkyl, optionally R10-substituted (C3-C6)-cycloalkyl, optionally R10-substituted adamantyl; R3 has one of values given for R1; each radical among R4, R5, R6 and R7 means hydrogen atom; R8 means hydrogen atom or (C1-C6)-alkyl; R9 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; R10 represents from 1 to 4 substitutes chosen independently from (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C2-C6)-alkoxyalkyl, (C1-C6)-halidealkyl, (C3-C6)-cycloalkyl, phenyl, heteroaryl, heteroaryl N-oxide, fluorine, chlorine, bromine, iodine atoms, hydroxyl, groups -OR9, -CONH2, -CONHR9, -CONR9R9, -COOH, -CF3, -CHF2, -CN, -NH2, -NHR9, -NHC(O)R9, -NR9C(O)R9; R11 represents two adjacent substitutes that form anellated 4-7-membered nonaromatic ring optionally comprising up to two heteroatoms chosen independently from nitrogen oxygen and sulfur atoms; Y means a direct bond, -C(O)-, -S(O2)-, -CH2-. Proposed compounds can be in free form as a salt. Compounds of the formula (I) and their salts possess antagonistic activity with respect to CCR5-receptors and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 6 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinone of the general formula (VI): wherein R1, R2, R3 and R4 are chosen independently from group consisting of hydrogen atom (H) and halogen atom; each R5 means independently (C1-C12)-alkyl; R6 means -NR8-(CH2)mR9, -NR10R11 under condition that from 1 to 4 groups -CH2- can be substituted optionally with -OH; R8 means H; R9 means -NR10R11 wherein R10 and R11 mean (C1-C12)-alkyl, or R10 and R11 in common with nitrogen atom to which they are bound can form a heterocyclic group chosen from morpholinyl, pyrrolidinyl and piperidinyl under condition that the heterocyclic group can be substituted optionally with morpholino-group; J means -NH; L means carbon atom (C), and group -C(O)R6 is bound with L; K and M means -CR5; m = 1, 2, 3 or 4; p = 2. Method for synthesis of these compounds involves the addition reaction of compound of the general formula (III): wherein R* means R with compound of the formula (IV): wherein values R1, R2, R3 and R4 are given above with amine of the general formula (V): HR6 (V) wherein R6 is given above to form indolinone of the general formula (VI). Method provides synthesis of indolinone derivatives with the yield 25-85%.

EFFECT: improved method of synthesis.

20 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved method of inhibition, improved method of synthesis of compounds.

15 cl, 2 sch, 133 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II): wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R1, R2 or R3; Ar means naphthyl; X means (C5-C8)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C1-C4)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C1-C6)-alkyls or group -CONH2, (C1-C6)-alkyl, nitrile, hydroxy-group, (C1-C6)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C1-C3)-alkyl or (C1-C5)-alkoxyalkyl, tetrahydrofuranyl-(C1-C3)-alkyl, nitrile-(C1-C3)-alkyl, carboxamide-(C1-C3)-alkyl; R1 means independently in each case (C1-C10)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C3-C6)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R2 means branched or unbranched (C1-C6)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C1-C4)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C1-C6)-alkoxy-group, hydroxy-group, mono- or di-(C1-C4)-alkyl-amino-group, group -OR6, nitro-group or group mono- or di-(C1-C4)-alkyl-amino-S(O)2 that is optionally partially or completely halogenated, or group -H2NSO2; R3 in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C1-C4)-alkynyl group or branched or unbranched (C1-C6)-alkoxy-group wherein each of them is optionally partially halogenated, -OR18 or (C1-C6)-alkyl optionally substituted with group -OR18, amino-group or mono- either di-(C1-C5)-alkyl-amino-group, (C2-C6)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R6 means (C1-C4)-alkyl that is optionally partially or completely halogenated; in each case R18 means independently hydrogen atom, (C1-C4)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

12 cl, 1 tbl, 38 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes compound of the formula (I): wherein B represents oxygen atom (O) or -NR1; J represents 5-membered heteroaromatic ring representing group of the formula (J-1): optionally substituted with 1-2 radicals R5 wherein Q represents -NR5; each X, Y and Z represents independently nitrogen atom (N), -CH or - CR5; B1 represents O; R2 represents hydrogen atom (H) or (C1-C6)-alkyl optionally substituted with one halogen atom, or (C2-C6)-alkynyl; or R1 and R2 taken in common form a binding chain consisting of 2-3 members and comprising at least one carbon atom, optionally comprising one carbon atom as -C(=O), optionally substituted with R3 wherein R3 represents (C1-C2)-alkyl; each R represents independently H, (C1-C6)-alkyl, halogen atom or -CN; each R5 represents independently (C1-C6)-halogenalkyl or halogen atom, or each ring is substituted with one R6; each R6 represents independently halogen atom; n represents a whole number 1 or 2. Also, invention describes a composition used for control of insects and comprising the biologically effective dose of compound of the formula (I) and at least one additional component chosen from group comprising surface-active substances, solid and liquid diluting agents, and methods for control of insects with using compositions based on compounds of the formula (I) and compounds of the formula (I). Proposed compounds of the formula (I) possess insecticide activity and can be used in agriculture.

EFFECT: valuable insecticide properties of compounds and compositions.

11 cl, 26 tbl, 4 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel oxazolidinones of the general formula (I): , their pharmaceutically acceptable salts, hydrates and salt hydrates that inhibit factor Xa selectively and possess anti-thrombosis effect. Also, invention relates to a method for synthesis of these compounds (variants) and using the known substituted oxazolidinones of the general formula (A): as agent inhibiting factor Xa selectively and possessing anti-thrombosis effect, and to a medicinal agent based on at least one compound of the formula (I) or at least one compound of the general formula (A). Values of substitutes R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are given in the invention claim.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and agent.

10 cl, 2 tbl, 252 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, chemical technology, insecticides.

SUBSTANCE: invention relates to derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide represented by the general formula (I): wherein R represents (C1-C6)-alkyl group that can be substituted with one or some halogen atoms; R1 represents hydrogen atom, (C1-C6)-alkyl group that can be substituted with one or some substituted chosen from group of substitutes A, (C2-C6)-alkenyl group or acyl group; X represents group of the formula -C-R2 or nitrogen atom; each among R2 and R3 represents independently hydrogen atom, halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from group of substitutes A, (C3-C7)-cycloalkyl group, (C2-C6)-alkenyl group, (C3-C7)-cycloalkenyl group, formyl group, group of the formula: -CH=NOR4 (wherein R4 represents hydrogen atom or (C1-C6)-alkyl group, cyano-group, phenyl group that can be substituted with one or some substitutes chosen from group of substitutes B, 5- or 6-membered heterocyclic group (heterocycle comprising 1-2 heteroatoms that are similar and chosen from nitrogen atom), (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or phenoxy-group. The group of substitutes A represents group consisting of halogen atom, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group, cyano-group and phenyl group. The group of substitutes B represents group consisting of halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from above given group of substitutes A, (C1-C6)-alkoxy-group that can be substituted with one or some substitutes chosen from above given group of substitutes A, or its salt. Also, invention relates to insecticide comprising a derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide or its salt as an active component and a carrier optionally. Also, invention relates to a method for synthesis of derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide. Invention provides synthesis of derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide possessing the high insecticide activity.

EFFECT: improved method of synthesis, valuable properties of derivatives.

18 cl, 3 tbl, 91 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to anthranylamidepyridine amides of selective effect as inhibitors of VEGFR-2 and VEGFR-3. Invention describes compounds of the general formula (I): wherein A, B and D represent independently of one another nitrogen atom or carbon atom wherein at least one nitrogen atom is in a ring; E represents aryl comprising 6-12 ring carbon atoms or heteroaryl comprising 5 or 6 ring atoms and comprising in ring instead carbon atom similar or different heteroatoms chosen from nitrogen or sulfur atoms, or represents group -COOR8, -CONR2R3 or -C≡C-R9; G represents nitrogen atom or group -C-X; L represents nitrogen atom or group -C-X; M represents nitrogen atom or group -C-X; Q represents nitrogen atom or group -C-X and wherein a ring comprises maximally one nitrogen atom; X represents hydrogen atom; W represents hydrogen or halogen atom; R1 represents aryl similarly or differently optionally mono- or multi-substituted with halogen atom, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl or group =O and wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 16 ring atoms and comprising in ring instead carbon one or more similar or different heteroatoms, such as oxygen, nitrogen or sulfur and it can be mono-, bi- or tricyclic and condensed additionally condensed with benzene ring; R2 and R3 represent independently of one another hydrogen atom or aryl similarly or differently mono- or multi-substituted with halogen atom, cyano-group, (C1-C6)-alkyl, phenyl, hydroxy-(C1-C6)-alkyl, halogen-(C1-C6)-alkyl or group -NR6R7, -OR5, (C1-C6)-alkyl-OR5-(C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkenyl wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 6 ring atoms and comprising in ring instead carbon one or more heteroatoms, such as nitrogen or sulfur; or R2 and R3 in common with nitrogen atom form (C3-C8)-ring that can comprise optionally one more nitrogen or oxygen atom or it can comprise group -N(R10); R5 represents hydrogen atom; R6 and R7 represent independently of one another hydrogen atom or (C1-C6)-alkyl; R8 represents (C1-C6)-alkyl mono- or multi-substituted optionally with halogen atom or benzyl; R9 represents hydrogen atom or tri-(C1-C6)-alkylsilyl; R10 represents hydrogen atom or (C1-C6)-alkyl, and their isomers, enantiomers and salts also. Also, invention describes a medicinal agent based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 162 ex

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