Vasopressin v1a receptor antagonists

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

 

The scope of the invention

The present invention was surrounded by the compounds having antagonistic activity against receptor vasopressin V1aand to pharmaceutical compositions comprising such compounds. The present invention also relates to the use of receptor antagonists vasopressin V1afor the treatment of certain psychological disorders, such as illness Rayno and dysmenorrhea (primary dysmenorrhea and secondary dysmenorrhea).

The claimed priority of European patent EP room 04104062 and application for U.S. patent number 60/603557, both of which filed on August 24, 2004.

Prior art

Neurofisiologia hormones vasopressin (VP) and oxytocin (OT) are cyclic nonapeptide that are excreted in the rear lobe of the pituitary gland.

Up to the present time is characterized by only one receptor FROM, while three known receptor VP. They are marked as receptors V1aV1band V2.

Vasopressin acts on blood vessels, where it is a strong vasoconstrictor, and kidney, where it promotes reabsorption of water, the resulting antidiuretic effect.

V1aV1band V2and receptors FROM are members of the superfamily of seven transmembrane receptors, known as receptors, come G-protein. Receptor V1amediate activation of phospholipase C and mobilization of intracellular calcium. Localization of receptors includes platelets, blood vessels, hepatocytes, brain and the uterus is the cervix. Thus, receptor antagonist V1amay have an effect on any of these tissues or all of them. For example, indicate that selective antagonists of the receptor V1ahave clinical utility with dysmenorrhea, premature labor, hypertension, disease Rayno, cerebral oedema, motion sickness in transport, hyperlipidemia, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.

Regarding dysmenorrhea suggested that action on the myometrium is greatly enhanced in women suffering from dysmenorrhea during menstruation. Suggested that myometrial ischemia caused by the increased contractility of the uterus, may explain the menstrual pain. In addition, in the first day of menstruation in women suffering from dysmenorrhea measured higher concentrations of vasopressin in plasma compared with control groups.

In healthy women, not suffering from dysmenorrhea, intravenous infusion of lysine-vasopressin has resulted in uterine bleeding, enlarged reduce the t of the uterus and weak-moderate pain, such pain in dysmenorrhea, and these effects are inhibited by the selective antagonist of the human receptor V1a(Bossmar, T. et al., BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY (1997 Apr), 104(4), 471-7). Furthermore, it is known that vasopressin depending on the dose causes indirect V1athe reduction of the arteries of the uterus of the person.

The above data indicate that receptor antagonist V1ais a suitable and effective for the treatment of dysmenorrhoea (primary dysmenorrhea and secondary dysmenorrhea). Additional proof was obtained in a clinical study conducted with selective receptor antagonist V1aSR49059 ("Effect of SR49059, an orally active V1avasopressin receptor antagonist, in the prevention of dysmenorrhea". Brouard, R. et al., BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY (2000), 107(5), 614-619). Discovered that there is a dose-dependent decrease in pain and a dose-dependent decrease in the number of additional accepted anesthetic compared with patients receiving placebo.

In the international patent application WO 03/016316 A1, published February 27, 2003, disclosed a lot of connections, which, as stated, are aginity oxytocin and are used in the treatment of erectile dysfunction in men. Was not informed about any antagonistic activity against receptor V1a. In the home is at the European patent EP 1449844 A1, published on 25 August 2004, revealed a lot of connections, which, as stated, are antagonists of the receptor V1aand is used in the treatment of primary dysmenorrhea.

There is a need in the treatment of conditions that are associated with the receptor V1a. Also, there remains a need for alternative antagonists V1a. Simple synthesis and availability when administered orally are additional desirable characteristics.

Description of the invention

In accordance with one aspect of the present invention relates to compounds, preferably antagonists VP, and in particular, specific antagonists of the receptor V1aand their pharmaceutically acceptable salts.

In accordance with another aspect of the present invention relates to pharmaceutical compositions comprising these compounds, and such compositions are useful for treating, among other things, dysmenorrhoea (primary dysmenorrhea and secondary dysmenorrhea).

In accordance with another aspect of the present invention relates to the use of the compounds for preparing pharmaceutical compositions for the treatment of dysmenorrhea.

In accordance with other aspects of the present invention relates to medical use and to the use of the above compounds and compositions in the treatment is to therapeutic methods, when using the above-mentioned compounds and compositions.

Detailed description of the invention

In accordance with one aspect of the invention relates to a compound of General formula 1A or connection, representing his tautomer or a pharmaceutically acceptable salt,

where G represents a group selected from General formula 2A, 3A, 4A, 5A and 6A,

where:

And1selected from CH2CH(OH), NH, N-alkyl, O and S;

And2selected from CH2CH(OH), C(=O) and NH;

And3and12independently selected from S, NH, N-alkyl, -C(R8)=CH-, -C(R8)=N-, -N=C(R8)- and-CH=C(R8)-;

And4and13independently selected from C(R9and N;

And5and14independently selected from C(R10and N;

And6selected from CH2, NH, N-alkyl and Oh;

And7and11independently selected from C and N;

And8and9independently selected from CH, N, NH, N(CH2)bR11and S;

And10selected from-CH=CH-, CH, N, NH, N-(CH2)b-R11and S;

where the ring formed And7And8And9And10and11is aromatic;

R1, R2and R3independently selected from H, alkyl, O-alkyl, NO2, F, Cl and Br;

R4selected from H, alkyl, aryl, heteroaryl, -(CH2)c-R12and

R5and R6independently selected from alkyl, aryl, -(CH2)f-aryl and -(CH2)f-heteroaryl;

R7selected from H, alkyl, aryl, heteroaryl and -(CH2)g-R14;

R8, R9and R10independently selected from H, alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, groups, NH(alkyl), N(alkyl)2; provided that when G is a 3A, and R4represents H, alkyl, aryl, heteroaryl or -(CH2)c-R12the ring containing a And3And4and5substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, groups NH(alkyl) or N(alkyl)2; and

when G represents 4A, R4represents H, alkyl, aryl, heteroaryl or

-(CH2)c-R12and8represents NH, NCH3or S, the ring containing a And3And4and5substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, groups NH(alkyl) or N(alkyl)2;

R11and R12independently selected from H, alkyl, aryl, heteroaryl, F, HE, O-alkyl, S-alkyl, O-acyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)acyl, CO2N, CO2-alkyl, CONH2, CONH-alkyl, group SOP(alkyl)2CN and CF3;

R13selected from N, Alki is a, aryl, heteroaryl, -(CH2)h-R15and Z-R16;

R14and R15independently selected from H, alkyl, alkenyl, aryl, heteroaryl, F, HE, O-alkyl, S-alkyl, O-acyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)acyl, CO2N, CO2-alkyl, CO-alkyl, CO-aryl, CONH2, CONH-alkyl, group SOP(alkyl)2alkenyl-CO2-alkyl, alkynylaryl, CN and CF3;

R16selected from H, alkyl, alkenyl, aryl, heteroaryl, O-aryl, -(CH2)i-R17, cyclopropylamine and O-(CH2)i-R17;

R17selected from H, alkyl, aryl, heteroaryl, F, HE, O-alkyl, S-alkyl, O-acyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)acyl, CO2N, CO2-alkyl, CONH2, CONH-alkyl, group SOP(alkyl)2CN and CF3;

W is selected from O and NH;

X is selected from (CH2)mC(=O) and S(=O)j;

Y is selected from O, S, NH and N-alkyl;

Z is selected from-C(=O)- C(=O)-O and-S(=O)k;

and selected from 1 and 2;

b and C are independently selected from 0, 1, 2, and 3;

d, e and f are independently selected from 1 and 2;

g, h and i are independently selected from 1, 2 and 3;

j and k are independently selected from 1 and 2; and

m and n are independently selected from 0, 1 and 2.

In accordance with one aspect of R16it may be additionally selected from O-alkyl and O-alkenyl, and Z is different from-C(=O)-O.

The compounds of formula 1A according to claim 1 are subject to the following limitation is m When G represents 3A and R4represents H, alkyl, aryl, heteroaryl or -(CH2)c-R12the ring containing a And3And4and5substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, groups NH(alkyl) or N(alkyl)2. When G represents 4A, R4represents H, alkyl, aryl, heteroaryl or -(CH2)c-R12and8represents NH, NCH3or S, the ring containing a And3And4and5substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, groups NH(alkyl) or N(alkyl)2. The ring formed A7, A8, A9, a10 and A11 is aromatic, and accordingly, the group must meet certain requirements. When a10 is a-CH=CH-, the ring is a six-membered ring. In itself it may include only the atoms with a type-C(R)=- N=. Therefore, A7 and A11 should both represent C and A8 and A9 should both represent CH or N. When a10 is not a-CH=CH-, the ring is a five-membered ring. In this case, one and only one atom in the ring must be an S or trigonal nitrogen atom. In this context, "trigonal nitrogen atom is a nitrogen atom covalently associated with the tre is I different atoms. Two of these atoms are immediate neighbors of the nitrogen atom in the five-membered ring. The third atom is an atom of hydrogen, carbon or other atom associated with the five-membered ring. Thus, when the a10 is not a-CH=CH-, then one (and only one) of A7, A8, A9, a10 and A11 should be an S or trigonal nitrogen atom. Therefore, the choice A7, A8, A9, a10 and EN is subject to the following restrictions. If a10 is not a-CH=CH-, then one of A8, A9 and a10 represents NH, N-(CH2)b-R11 or S or one of A7 and A11 represents N. No more than one of A8, A9 and a10 may represent NH, N-(CH2)b-R11 or S. A7 and A11 at the same time cannot represent N. Neither A7 nor A11 cannot represent N, if one of A8, A9 and a10 represents NH, N-(CH2)b-R11 or S.

In accordance with aspects of the invention and additional preferred embodiments of the invention are presented below in the description and the claims.

The term "alkyl" includes saturated hydrocarbon residues, including:

linear groups of up to 10 atoms (C1-C10). Examples of such alkyl groups include C1-methyl, C2- ethyl,3- propyl and C4- n-butyl, but are not limited to;

branched groups of 3-10 atoms (C3-C10). Examples of such alkyl groups include3- isopropy is, With4- terbutyl,4- isobutyl,4tert-butyl and C5- neopentyl, but are not limited to;

is a cyclic group of from 3-8 atoms (C3-C8). Examples of such alkyl groups include3- cyclopropyl,4- cyclobutyl, C5- cyclopentyl and C6- cyclohexyl, but are not limited to;

- combinations of linear, branched and cyclic groups. Examples of such groups include

but not limited to.

The term "alkoxy" is used to denote O-alkyl groups.

The term "alkenyl includes monounsaturated hydrocarbon groups, including

linear groups of two to six atoms (C2-C6). Examples of such alkenyl groups include C2- vinyl, With3- 1-propenyl,3- allyl and C4- 2-butenyl, but are not limited to;

branched groups of 3-8 atoms (C3-C8). Examples of such alkenyl groups include4- 2-methyl-2-propenyl and C6- 2,3-dimethyl-2-butenyl, but are not limited to;

is a cyclic group of from 3-8 atoms (C3-C8). Examples of such groups include C5- 3-cyclopentenyl and C6- 1-cyclohexenyl, but are not limited to.

The term "aryl" includes, possibly substituted phenyl, and possibly substituted naphthyl. Examples of such aryl group which include phenyl, 2-tolyl, 3-chlorophenyl, 4-chlorophenyl, 3-forfinal, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,5-differenl, 1-naphthyl and 2-naphthyl, but are not limited to.

The term "heteroaryl" includes, possibly substituted heterocycles. Such heteroaryl groups include pyridyl, 2-chloropyridine, 4-methylpyridyl, thienyl, 3-chloranil, 2,3-dimethylthiophene, furyl, 2-methylphenyl, pyrrole, N-methylpyrrole, oxazole, imidazole, pyrazole and triazole, but are not limited to.

The term "acyl" denotes a group R-C(=O), where R represents H, saturated or unsaturated hydrocarbon group consisting of 0-7 carbon atoms, or, perhaps, substituted phenyl, possibly substituted pyridyloxy or perhaps substituted thienyl group.

Examples of acyl groups include formyl, acetyl, pivaloyl, benzoyl and nicotinoyl, but are not limited to.

Some compounds of the present invention are capable of forming salts with acids or bases. For example, compounds containing one or more than one basic nitrogen atom, may form a salt accession of inorganic and organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, triperoxonane acid, methanesulfonate acid, citric acid and benzoic acid. Compounds containing acidic groups, may make obyvaci salts with bases. Examples of such salts include salts of sodium, potassium, calcium, triethylamine and tetraethylammonium. In addition, compounds having acidic and basic groups can form internal salts (zwitterions). The extent to which these salts are pharmaceutically acceptable, they are included in the scope of the invention.

Some compounds within the scope of the present invention may exist as tautomers. For example, where G1has a General formula 4A (4b, 4C, 4d), and X2represents NH, the resulting imidazole can exist in the form of his tautomer defined G1in the General formula 5A (5b, 5C, 5d) and X2in NH. I believe that all such tautomers are within the scope of the present invention.

Compounds of the present invention can have one or more than one or stereogenic center ("asymmetric carbon atoms and, thus, may exhibit optical isomerism. In the scope of the present invention includes all epimere, enantiomers and diastereoisomers compounds of the present invention, including individual isomers, mixtures and racemates.

In accordance with one aspect it is preferable that G was chosen from:

In accordance with one aspect also predpochtitelno that G was chosen from:

In accordance with one aspect it is preferable that at least one of R1, R2and R3was different from hydrogen; preferably one of R1, R2and R3was selected from methyl, chlorine and fluorine, and the others are hydrogen.

In accordance with various aspects, it is preferable that W was a NH; R4represented alkyl; d represents 2, and e consisted of 2; R13represented alkyl; and/or n was a 0.

In accordance with one aspect preferably, R2was a N, R4was a piperidine, where d is 2 and e is 2, W represents NH, X represents C(=O) and n represents 0, as shown in the formula 18a:

where R1selected from methyl, chlorine and fluorine, and R3represents H; or R1represents N and R3selected from methyl, chlorine and fluorine, and R13represents alkyl.

In accordance with one aspect it is preferable that X was a C(=O)n was represented by a 0 and R4was a piperidine, where d is 2 and e is 2, as shown in the formula 19a:

where G is selected from the General formulas 7a-17A, and R13 represents alkyl.

In accordance with one aspect preferably, R2was a N and W was represented by NH, as shown in the formula 20A:

where R1selected from methyl, chlorine and fluorine, and R3represents H; or R1represents N, and R3selected from methyl, chlorine and fluorine; and G is selected from the General formulas 7a-17A.

In accordance with one aspect preferably, R2was a N, W was represented by NH and X represented the C(=O), as shown in the formula 21A:

where R1selected from methyl, chlorine and fluorine, and R3represents H; or R1represents N, and R3selected from methyl, chlorine and fluorine; and R4represents alkyl.

In accordance with one aspect it is preferable that X was a C(=O), as shown in the formula 22A:

where G is selected from the General formulas 7a-17A, and R4represents alkyl. In accordance with one aspect preferably, R2and R3both were a N, W was a NH, and X represented the C(=O), as shown in the formula 23a:

where G is selected from the General formulas 9a, 10A, 15A, 16A and 17A, R1selected from methyl, chlorine and fluorine and R 4represents alkyl.

In accordance with one aspect preferably, R2and R3both were a N, R4was a piperidine, where d is 2 and e is 2, W represents NH, X represents C(=O) and n represents 0, as shown in the formula 24A:

where G is selected from the General formulas 9a, 10A, 15A, 16A and 17A, R1selected from methyl, chlorine and fluorine, and R13represents alkyl.

In accordance with one aspect of especially preferred compounds proposed 17.

In accordance with one aspect of the present invention relates to compounds according p. In accordance with one aspect of the ring containing A3, A4 and A5 in accordance with the General formula 2b, and 3b, substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, NH(alkyl) or N(alkyl)2.

The compounds of formula 1b by p subject to the following limitations. When the ring formed And7And8And9And10and11is aromatic, the group must meet certain requirements. When And10represents-CH=CH-, the ring is a six-membered ring. In itself it may include only the atoms with a type-C(R)=- N=. Therefore, As7and11, both of whom should be a C and8and9must be a CH or N. When And10does not represent a-CH=CH-, the ring is a five-membered ring. In this case, one and only one atom in the ring must be an S or trigonal nitrogen atom. In this context, "trigonal nitrogen atom is a nitrogen atom covalently associated with three different atoms. Two of these atoms are immediate neighbors of the nitrogen atom in the five-membered ring. The third represents hydrogen, carbon or other atom associated with the five-membered ring. Thus, it follows that, when A10does not represent a-CH=CH-, then one and only one of And7And8And9And10and11must be an S or trigonal nitrogen atom. Therefore, the selection And7And8And9And10and11subject to the following restrictions. If a10does not represent a-CH=CH-, then one of the A8And9and10represents NH, N-(CH2d-R5or S or one of the A7and11represents N. No more than one And8And9and10can represent NH, N-(CH2)d-R5or s And7and11at the same time cannot represent N. No And7nor And11cannot represent N, if Odie is a 8And9and10represents NH, N-(CH2)d-R5or S.

In accordance with one aspect of especially preferred compounds proposed in item 30.

In accordance with one aspect of the present invention relates to compounds according p. The compounds of formula 1C p subject to the following limitations. The ring formed And7And8And9And10and11is aromatic, and accordingly, the group must meet certain requirements. When And10represents-CH=CH-, the ring is a six-membered ring. In itself it may include only the atoms with a type-C(R)=- N=. Therefore, As7and11should both represent C, and a8and9must be a CH or N. When And10does not represent a-CH=CH-, the ring is a five-membered ring. In this case, one and only one atom in the ring must be an S or trigonal nitrogen atom. In this context, "trigonal nitrogen atom is a nitrogen atom covalently associated with three different atoms. Two of these atoms are immediate neighbors of the nitrogen atom in the five-membered ring. The third represents hydrogen, carbon or other atom associated with the five-membered ring. Thus the m it follows that, when A10does not represent a-CH=CH-, then one (and only one) And7And8And9And10and11must be an S or trigonal nitrogen atom. Therefore, the selection And7And8And9And10and11subject to the following restrictions. If a10does not represent a-CH=CH-, then one of the A8And9and10represents NH, N-(CH2)c-R6or S, or one of the A7and11represents N. No more than one And8And9and10can represent NH, N-(CH2)c-R6or s And7and11at the same time cannot represent N. No And7nor And11cannot represent N, if one of the A8And9and10represents NH, N-(CH2)c-R6or S.

In accordance with one aspect of especially preferred compounds proposed in item 45.

In accordance with one aspect of the present invention relates to compounds according to § 46. The compounds of formula 1d on p.46 subject to the following limitations. The ring formed And7And8And9And10and11is aromatic, and accordingly, the group must meet certain requirements. When And10represents-CH=CH-, the ring is a pole who membered ring. In itself it may include only the atoms with a type-C(R)=- N=. Therefore, As7and11should both represent C, and a8and9must be a CH or N. When And10does not represent a-CH=CH-, the ring is a five-membered ring. In this case, one and only one atom in the ring must be an S or trigonal nitrogen atom. In this context, "trigonal nitrogen atom is a nitrogen atom covalently associated with three different atoms. Two of these atoms are immediate neighbors of the nitrogen atom in the five-membered ring. The third represents hydrogen, carbon or other atom associated with the five-membered ring. Thus it follows that, when A10does not represent a-CH=CH-, then one (and only one) And7And8And9And10and11must be an S or trigonal nitrogen atom. Therefore, the selection And7And8And9And10and11subject to the following restrictions. If a10does not represent a-CH=CH-, then one of the A8And9and10represents NH, N-(CH2)c-R11or S, or one of the A7and11represents N. No more than one And8And9and10can represent NH, N-(CH2)c-R 11or s And7and11at the same time cannot represent N. No And7nor And11cannot represent N, if one of the A8And9and10represents NH, N-(CH2)c-R11or S.

In accordance with one aspect of especially preferred compounds proposed p.

Particularly preferred compounds according to the invention are antagonists of the receptor V1athat is highly active.

In accordance with one aspect of at least one of the compounds identified further, it is not part of the present invention: claim 1 and example 286 ([4-(4-Dimethylaminobenzylidene)-phenyl]amide of 3-pyridin-3-yl-4,5-dihydroisoxazole-5-carboxylic acid) in the US 6583141; examples 5 and 6 in WO 02/04403 (amide N-[4-(N-methyl-N-phenylenecarbonyl)phenylmethyl]-3-(4'-triptorelin-2-carbylamine)benzoic acid and amide N-[4-(N-methyl-N-phenylenecarbonyl)phenylmethyl]-3-(biphenyl-2-carbylamine)benzoic acid); abstract, J. Org. Chem. USSR, vol.18, no.6, 1982, str-1119 (para-(N,N-Diethylcarbamoyl)-N,N-diethylbenzamide); 3, 1. 16 - p.4 1. 11, examples 1-4, 11 and 14-19 in WO 01/29005; 3, 1. 9 - 5, 1. 23, examples 11, 28-31, 38 and 71-77 in WO 02/00626; and 3, 1. 1 - 4, 1. 17, examples 12-18 in WO 03/016316.

In accordance with one aspect of the invention relates to pharmaceutical compositions comprising the compound according to izopet the tion as the active agent.

In addition, the invention relates to pharmaceutical compositions comprising the compound according to the invention, which is used as an antagonist of the receptor V1aand such compositions are particularly useful for medical indications such as the treatment of dysmenorrhoea (primary dysmenorrhea and secondary dysmenorrhea), preterm birth, hypertension, disease Rayno, cerebral oedema, motion sickness, hyperlipidemia, small-cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.

The use of any of the excipients will depend on the intended nature of the drug, which, in turn, will depend on the intended route of administration. The administration can be oral, mucous membranes (such as sublingual, transbukkalno, intranasal, vaginal and rectal), transdermal, or by injection (such as subcutaneous, intramuscular and intravenous). As a rule, preferably oral administration. For oral administration of the drug can be a tablet, capsule or sachet. Other drugs include dry powders, solutions, suspensions, suppositories, etc.

In accordance with one aspect of the invention relates to the use of compounds according to the invention for the preparation of drug sredstva treatment of disease, selected from dysmenorrhoea (primary dysmenorrhea and secondary dysmenorrhea), preterm birth, hypertension, disease Rayno, cerebral oedema, motion sickness, hyperlipidemia, small-cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.

Compounds of the present invention may be useful in the treatment of several diseases, disorders or conditions. Used herein, the term "treatment" refers to treatment to cure or relieve symptoms of a disease, disorder or condition and treatment to prevent the development of disease, disorder or condition. The treatment may be performed in an acute or chronic case. The animal or person being treated, i.e. the patient can be a human or any other mammal that is different from the person needing the treatment according to the invention.

The introduction of the compositions of the present invention, as a rule, carried out under the supervision of a physician. The attending physician determines the number of input composition and the regimen of medicines, taking into consideration the physical condition of the patient and therapeutic tasks.

Additional aspects of the invention relate to methods for treating the aforementioned diseases, disorders or conditions. In accordance what about a method according to the invention to a patient, in need of such treatment is administered a therapeutically effective amount of the compound or the above-described pharmaceutical compositions. In accordance with various aspects of the invention relates to a method of treatment of a disorder selected from dysmenorrhoea (primary dysmenorrhea and secondary dysmenorrhea), preterm birth, hypertension, disease Rayno, cerebral oedema, motion sickness, hyperlipidemia, small-cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.

The term "therapeutically effective amount" refers to an amount which lead to the desired therapeutic effect. Therapeutically effective amount determined by the attending physician taking into account all relevant factors. Typically, the single dose comprises from 0.1 mg to 1000 mg, preferably 1 mg to 250 mg of active compounds according to the invention. The dose may be entered one-time or repeated. With the reintroduction of the dose can be introduced at regular intervals, such as once, twice or thrice a day or as needed in accordance with condition that is being treated.

Pharmaceutical compostie of the present invention may be provided in any form known in the art. For example, the drug may be presented in the form of tablets, apali, powder, suppository, cream, solution or suspension, or in more complex forms, such as adhesive plaster. The preparation typically includes one or more than one excipient, such as a diluent, filler, binding agent, dispersing agent, a solvent, a preservative, corrigent etc. Also the drug may include one or more than one additional pharmacologically active molecule. Preferably, the drug does not include any additional active agents.

When the compositions of the present invention are used as therapeutic agents, they can be entered using any appropriate way known in the art. For example, they can be administered orally, transbukkalno, sublingual, rectal, endovaginal, nazalnam, intra-lungs or transdermal means. Alternatively, they may be introduced by injection, including intravenous, subcutaneous and intramuscular injection.

Compounds of the present invention can be obtained using standard chemical manipulations. They are described in detail in WO 03/016316 A1, p.12-17. (Hudson, P.J. et al., "Diazacycloalkanes as Oxytocin Agonists").

The following examples should be considered as giving the opportunity, but not limiting the invention.

Examples

Used the following abbreviations:

AIBN2,2'-Azobisisobutyronitrile
Vostert-Butyl ether carboxylic acid or tert-Butoxycarbonylamino
VIButyl alkyl groups optionally can be denoted as n (normal, i.e. unbranched), i (izo), and t (tertiary)
DIEAN,N-Diisopropylethylamine
DMAP4-(Dimethylamino)pyridine
DMFDimethylformamide
EtEthyl
tOThe ethyl acetate
HOBt1-Hydroxybenzotriazole
HPLCHigh performance liquid chromatography

hhour(s)
Memethyl
minminute(s)
MS Mass spectrum
NMRSpectrum obtained by nuclear magnetic resonance - unless otherwise stated, NMR spectra were recorded in CDCl3with a frequency of 270 MHz
OVAOrnithine-vasotocin similar
PetroleumPetroleum ether, boiling range 60-80°C
ether
PhPhenyl
RPPencil
WGCut
THFTetrahydrofuran
TosToluene-4-sulfonyl
WSCDWater-soluble carbodiimide (hydrochloride (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide)

In the Examples E1-E described the synthesis of intermediates and compounds of the present invention. In the Example As described manner can be analyzed compounds based on their ability to inhibit the cellular effects of stimulation of intact cells in arginine-vasopressin (AVP). In Example B described tab is etki for oral administration, including a connection according to the invention.

Example E1

6-Chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene

Example A

Ethyl ester of 5-(4-chloro-2-nitrophenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid

Sodium hydride (60% dispersion in oil, 7,28 g, 180 mmol) in portions at 0°C was added to a solution of ethyl 5-amino-1-methylpyrazole-4-carboxylate (21.8 g, 148 mmol) in anhydrous THF. The mixture was allowed to warm to room temperature and was stirred for 1 h was added dropwise a solution of 4-chloro-2-peritrabecular (22,6 g, 129 mmol) in anhydrous THF (50 ml). The resulting dark purple solution was stirred at room temperature for 18 h, then poured into a chilled on ice 1 N. hydrochloric acid. The resulting mixture was extracted with dichloromethane (200 ml × 2), and the combined organic extracts were washed with brine and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 60% petroleum ether:40% EtOAc) to obtain specified in the connection header (27.5 g, 62%).

Example A

Ethyl ester of 5-(2-amino-4-chlorpheniramine)-1-methyl-1H-pyrazole-4-carboxylic acid

Zinc powder (26,17 g, 400 mmol) at room temperature was added to a suspension of ethyl ester of 5-(4-chloro-2-nitrophenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid from Example E (26,0 g, 80 the mol) in methanol/acetic acid (10:1, 330 ml). After completion of the exothermic reaction, the resulting suspension was stirred at room temperature for 18 h before filtration through filter agent Celite®. The filtrate was concentrated in vacuum. The residue was dissolved in EtOAc and the solution washed with saturated NaHCO3and brine and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 65% EtOAc:35% petroleum ether up to 80% EtOAc:20% petroleum ether) to obtain specified in the connection header (18,41 g, 78,0%).

Example A

6-Chloro-3-methyl-4,9-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-10-he

(Methylsulfinyl)methane sodium with 53.4 mmol) was obtained from sodium hydride (60% dispersion in oil, 2.14 g, with 53.4 mmol) and anhydrous dimethyl sulfoxide (35 ml) by heating at 65°C until solution. To it was added a solution of ethyl ester 5-(2-amino-4-chlorpheniramine)-1-methyl-1H-pyrazole-4-carboxylic acid from Example E (9,02 g of 30.5 mmol) in anhydrous dimethylsulfoxide (20 ml) and the stirring continued at 65°C for 30 minutes the Mixture was poured into ice (200 ml) and the resulting solid was collected and purified by recrystallization from methanol/EtOAc to obtain specified in the connection header (5,56 g, 73.3 per cent).

Example A

6-Chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene

To a suspension of 6-chloro-3-methyl-4,9-dihydro-3 is -2,3,4,9-tetrazoles-[f]azulene-10-she's from Example E (5,56 g, of 22.4 mmol) in anhydrous THF (200 ml) at 0°C was added alumoweld lithium (4,24 g, 112 mmol) and the resulting suspension was heated under reflux for 18 h, then was allowed to cool to room temperature. Added additional portion of lithium aluminum hydride (4,24 g, 112 mmol) and the mixture is boiled under reflux for 18 hours the Mixture was cooled to 0°C., dropwise within 15 min was added 35% aqueous ammonia (10 ml) and the mixture was stirred at room temperature for 30 minutes the Resulting suspension was filtered through filter agent Celite® and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 0,5% 35% ammonia:5% methanol:dichloromethane) to obtain the specified title compound (3.88 g, 74%).

Example E2

3,6-Dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene

Example A

Ethyl ester of 1-methyl-5-(4-methyl-2-nitrobenzylamine)-1H-pyrazole-4-carboxylic acid

Sodium hydride (60% dispersion in oil, 7,28 g, 180 mmol) in portions at 0°C was added to a solution of ethyl 5-amino-1-methylpyrazole-4-carboxylate (21.8 g, 148 mmol) in anhydrous THF. The mixture was allowed to warm to room temperature and was stirred for 1 h, then was added dropwise a solution of 3-fluoro-4-nitrotoluene (20 g, 129 mmol) in anhydrous THF (50 ml). Resulting in achiev is Tate dark purple solution was stirred at room temperature for 18 h, then poured into a chilled on ice 1 N. hydrochloric acid. The resulting mixture was extracted with dichloromethane (200 ml × 2) and the combined organic extracts were washed with brine and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 60% petroleum ether:40% EtOAc) to obtain specified in the connection header (28,00 g, 61%).

Example A

Ethyl ester of 5-(2-amino-4-methylphenylimino)-1-methyl-1H-pyrazole-4-carboxylic acid

Chloride tin (II) (86,65 g, 457,0 mmol) was added to a solution of ethyl ester of 1-methyl-5-(4-methyl-2-nitrophenylamino)-1H-pyrazole-4-carboxylic acid from Example E (28,00 g, with 91.4 mmol) in methanol and the mixture is boiled under reflux for 3 days. The solvent was removed in vacuum and the residue suspended in EtOAc (400 ml) and cooled to 0°C. 35% ammonia Solution was added to pH 14, and the mixture was stirred for 15 min before filtering through filter agent Celite®. The filtrate is washed with 2M NH3and brine and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; from 6% methanol:94% dichloromethane to 10% methanol:90% dichloromethane) to obtain the specified title compound (12.8 g, 52%).

Example A

3,6-Dimethyl-4,9-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-10-he

(Methylsulfinyl)methane sodium (22.7 mmol) was obtained from sodium hydride (60% dis is the version in oil, 912 mg, 22.7 mmol) and anhydrous dimethyl sulfoxide (5.5 ml) by heating at 65°C until solution. To it was added a solution of ethyl ester 5-(2-amino-4-methylphenylimino)-1-methyl-1H-pyrazole-4-carboxylic acid from Example E (of 3.56 g, 13,0 mmol) in anhydrous dimethyl sulfoxide (10 ml) and the stirring continued at 65°C for 30 minutes the Mixture was then poured into ice (200 ml), the resulting solid was collected and purified by flash chromatography on silica gel (eluent; 10% methanol:90% dichloromethane) to obtain specified in the connection header (1.12 g, 38%).

Example A

3,6-Dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene

To a suspension of 3,6-dimethyl-4,9-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-10-she's from Example E (2.35 g, or 10.3 mmol) in anhydrous THF (100 ml) at 0°C was added alumoweld lithium (1.56 g, 41.2 mmol) and the resulting suspension was heated under reflux for 18 h, then was allowed to cool to room temperature. Added additional portion of lithium aluminum hydride (781 mg, of 20.6 mmol) and the mixture is boiled under reflux for 3 hours the Mixture was cooled to 0°C., dropwise within 15 min was added 35% aqueous ammonia (10 ml) and the mixture was stirred at room temperature for 30 minutes the Resulting suspension was filtered through filter agent Celite® and filtercontrol in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 10% methanol:90% dichloromethane) to obtain the specified title compound (1.60 g, 72%).

Examples Ia-g described in WO 03/016316 A1, (Hudson, P. et al. "Diazacycloalkanes as Oxytocin Agonists"), p.26-31.

Example E2h

4-(tert-Butoxycarbonylamino)-3-methylbenzoic acid

Example E2h.1

Methyl ester of 4-cyano-3-methylbenzoic acid

A mixture of 4-cyano-3-methylbenzoic acid from Example E2d (1.5 g, 9.3 mmol) and thionyl chloride (5 ml, and 68.5 mmol) in dichloromethane (20 ml) was boiled under reflux for 2 h, then the solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in dichloromethane (25 ml). Was added methanol (10 ml) and the solution was stirred at room temperature for 2 h, then concentrated in vacuo. The remainder of pererestorani in EtOAc, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum to obtain specified in the title compound (1.6 g, 100%).

Example 2h.2

Methyl ester of 4-aminomethyl-3-methylbenzoic acid

A solution of methyl ester 4-cyano-3-methylbenzoic acid from Example E2h.1 (1.6 g, 9.3 mmol) in methanol (50 ml) to 0°C was treated with uranyl chloride cobalt (II) (5,1 g of 18.6 mmol). The mixture was stirred for 15 min at room temperature, then portions were added borohydride NAT the Oia (3.5 g, 93 mmol). The reaction mixture was stirred for 90 min, then was added dropwise concentrated NH3(5 ml). The mixture was heated to room temperature for 30 min, filtered through filter agent Celite®, washed with methanol and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 1% 35% ammonia:10% methanol:89% dichloromethane) to obtain the specified title compound (670 mg, 37%).

Example 2h.3

Methyl ester of 4-(tert-butoxycarbonylamino)-3-methylbenzoic acid

Di-tert-butyl dicarbonate (900 mg, 4.1 mmol) at room temperature was added to a solution of methyl ester 4-aminomethyl-3-methylbenzoic acid from Example 2h.2 (670 mg, 3.7 mmol) in dichloromethane (50 ml) and triethylamine (up to pH 9). The mixture was stirred for 1 h, then concentrated in vacuo. The remainder of pererestorani in EtOAc, washed with 0.3 N. KHSO4, then brine, dried and concentrated in vacuum to obtain specified in the title compound (1.04 g, 100%).

Example 2h.4

4-(tert-Butoxycarbonylamino)-3-methylbenzoic acid

Methyl ester of 4-(tert-butoxycarbonylamino)-3-methylbenzoic acid from Example 2h.3 (1.04 g, 3.7 mmol) was dissolved in dioxane (20 ml). Added 1 n NaOH solution (5.6 ml, 5.6 mmol) and the mixture was stirred for 18 h at room temperature, then the end of what was tribali in vacuum. The remainder of pererestorani in EtOAc, washed with 1 N. S4, then brine, dried and concentrated in vacuum to obtain specified in the title compound (800 mg, 81%).

Example E3

4-(tert-Butoxycarbonylamino)-3-Formentera acid

Example A

Methyl ester of 3-fluoro-4-methylbenzoic acid

Thionyl chloride (9,62 g, 81 mmol) was added to a solution of 3-fluoro-4-methylbenzoic acid (5.0 g, 32,4 mmol) in toluene (50 ml). The mixture was stirred at room temperature for 1.5 h and boiled under reflux for 3 hours the Solvent was removed in vacuum and the residue suspended in methanol (30 ml) and CH2Cl2(30 ml) and was stirred for 18 hours the Mixture was evaporated in vacuum and the residue suspended in EtOAc (50 ml), washed with saturated solution of Panso3(3×75 ml), dried and evaporated in vacuum to obtain specified in the title compound (4.5 g, 83%).

Example A

Methyl ester of 4-methyl bromide-3-fermenting acid

Methyl ester of 3-fluoro-4-methylbenzoic acid from Example E (4.5 g, to 26.6 mmol) was dissolved in carbon tetrachloride (150 ml). Added AIBN (457 mg, 2.7 mmol) and N-bromosuccinimide (5,2 g of 29.3 mmol) and the mixture is boiled under reflux for 18 hours the Mixture was allowed to cool and added additional portion of AIBN (457 mg, 2.7 mmol) and N-bromosuccinimide (5,2 g of 29.3 mmol). The mixture was boiled with about the military refrigerator for 56 PM The mixture was allowed to cool and was evaporated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 10% EtOAc:90% petroleum ether) to obtain the specified title compound (2.7 g, 41%).

Example A

Methyl ester of 4-azidomethyl-3-fermenting acid

Sodium azide (609 mg) was added to a solution of methyl ester 4-methyl bromide-3-fermenting acid from Example E (2.1 g, 8.5 mmol) in DMF (30 ml). The mixture was stirred for 18 h, diluted with EtOAc, washed with water and brine and concentrated in vacuo to obtain a colourless oil identified as specified in the title compound (1.8 g, 100%).

Example A

Methyl ester of 4-aminomethyl-3-fermenting acid

Hydrogen for 2 h was passed through degassed solution of methyl ester 4-azidomethyl-3-fermenting acid from Example E (2,11 g, 10 mmol) in methanol containing 10% palladium on carbon. The reaction mixture was filtered through filter agent Celite® and the filtrate was concentrated in vacuo to obtain a colourless oil identified as specified in the title compound (1.51 g, 83%).

Example A

Methyl ester of 4-(tert-butoxycarbonylamino)-3-fermenting acid

To a solution of methyl ester 4-aminomethyl-3-fermenting acid from Example E (1.5 g, 8.2 mmol) in dichloromethane (20 ml) was added di-tributilphosphat (2.3 g, 11 mmol) and triethylamine (1.4 ml, 10 mmol). The mixture was stirred for 18 h, washed with 0.3 m KHSO4and brine and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 10% EtOAc:90% petroleum ether) to give a white solid identified as specified in the title compound (1.4 g, 60%).

Example A

4-(tert-Butoxycarbonylamino)-3-Formentera acid

To a solution of methyl ester 4-(tert-butoxycarbonylamino)-3-fermenting acid from Example E (640 mg, 2.25 mmol) in dioxane (40 ml) was added 1 N. NaOH (4.5 ml, 4.5 mmol). The mixture was stirred for 18 h, diluted with EtOAc, washed with 1 N. S4, water and brine and concentrated in vacuum to obtain a white solid, identified as specified in the title compound (608 mg, 100%).

Example E4

The dihydrochloride of 1-(3,3-dimethylbutyl)piperazine

Example A

tert-Butyl ester 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid

To a solution of 1-BOC-piperazine (8,19 g and 43.9 mmol) in methanol/acetic acid (99:1, vol/about., 100 ml) was added 3,3-dimethylallyl aldehyde (4.0 g, 40.0 mmol) and the resulting mixture was stirred at room temperature for 1 h was Added cyanoborohydride sodium (3,27 g, with 51.9 mmol) and the resulting mixture was stirred at room temperature is for 18 h, then concentrated in vacuo. The residue was dissolved in EtOAc and the resulting solution was washed with saturated Panso3, water and brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 5% methanol: 95% EtOAc) to obtain the specified title compound (9.1 g, 84%).

Example A

The dihydrochloride of 1-(3,3-dimethylbutyl)piperazine

A solution of tert-butyl ester 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid from Example E (9,1 g of 31.8 mmol) in methanol (100 ml) was treated with 4 N. HCl/dioxane (100 ml) and the mixture was stirred at room temperature for 30 min, then concentrated in vacuo. The residue is triturated with diethyl ether and the resulting solid recrystallized from methanol/diethyl ether to obtain the dihydrochloride of 1-(3,3-dimethylbutyl)piperazine (7.4 g, 90%).

Example E5

2-Methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene

Example A

Methyl ester 2-(toluene-4-sulfonylamino)benzoic acid

Methylanthranilate (110 g, 0.73 mol) at 0°C was dissolved in dichloromethane (1 liter) was added triethylamine (115 ml, 0.8 mol). Portions at 0°C was added taillored (133 g, 0,745 mol). The reaction mixture was stirred for 30 min at 0°C and for 64 h at room temperature. The mixture was concentrated in vacuum. The residue was dissolved in EtOAc the organic layer washed with 5% solution of knso 3(aq.), 1 N. HCl solution and brine, dried, filtered and concentrated in vacuum. The residue was led from EtOAc/hexane to obtain specified in the connection header (181 g, 81%).

Example A

Methyl ester 2-[(3-ethoxycarbonylphenyl)-(toluene-4-sulfonyl)amino]benzoic acid

Methyl ester 2-(toluene-4-sulfonylamino)benzoic acid from Example A (100 g) was dissolved in DMF (250 ml). Was added potassium carbonate (125 g) and ethyl 4-bromobutane (60 g) and the mixture was heated at 80°C for 18 hours the Mixture was cooled to room temperature, filtered and concentrated in vacuum. The residue was distributed between chloroform and 1M HCl solution. The aqueous layer was extracted with chloroform. The organic layers were combined, washed with brine, dried, filtered and concentrated in vacuum. Substance led from EtOAc/hexane and dried in a vacuum oven at 60°C for 3 hours to obtain specified in the connection header (98,6 g, 72%).

Example A

Methyl ester of 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepin-4-carboxylic acid and ethyl ester 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepin-4-carboxylic acid

Methyl ester 2-[3-ethoxycarbonylphenyl)-(toluene-4-sulfonyl)amino]benzoic acid from Example E (98,6 g, 0,235 mol) suspended in warm toluene (600 ml) and added dropwise to the mixture is tert-butoxide potassium (40 g) in toluene (1 liter), delegiraj in the conditions of a Dean-stark. The mixture was boiled under reflux in the conditions of a Dean-stark for another 1 h and cooled to room temperature. It was diluted with EtOAc (500 ml) and washed with 1M HCl solution, saturated Panso3(aq.) and brine. The organic layer was dried, filtered and concentrated in vacuum. The residue was besieged from EtOAc/hexane and dried in a vacuum oven to obtain a mixture of methyl ester of 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepin-4-carboxylic acid and ethyl ester 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepin-4-carboxylic acid (53,5 g).

Example A

1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydrobenzo[b]azepin-5-he

A mixture of methyl ester of 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepin-4-carboxylic acid and ethyl ester 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepin-4-carboxylic acid from Example E for 18 h boiled under reflux in a mixture of ethanol (100 ml), acetic acid (300 ml), concentrated HCl (100 ml) and water (50 ml). The mixture was cooled to room temperature, diluted with water (800 ml) and was extracted with chloroform. The combined organic extracts were dried, filtered and concentrated in vacuum. The residue was twice led from methanol to obtain specified in the title compound (44 g, 60% after two studies is).

Example A

1,2,3,4-Tetrahydrobenzo[b]azepin-5-he

Polyphosphoric acid (25 g) was heated at 100°C. in a nitrogen atmosphere, until was not possible to mix. 1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydrobenzo[b]azepin-5-Oh from Example E (2.6 g, compared to 8.26 mmol) was added in portions and the reaction mixture was heated at 100°C for 1.5 h, It was poured into ice and acidified using 2M NaOH (aq.). The aqueous layer was twice extracted with dichloromethane. The organic extracts were combined, washed with brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 40% EtOAc: 60% hexane) to obtain specified in the connection header (1,05 g, 79%).

Example A

1-Benzoyl-1,2,3,4-tetrahydrobenzo[b]azepin-5-he

1,2,3,4-Tetrahydrobenzo[b]azepin-5-Oh from Example A (480 mg, 2,98 mmol) was dissolved in a mixture of dichloromethane (30 ml) and triethylamine (1.3 ml). Added benzoyl chloride (0,46 g of 3.28 mmol) and the reaction mixture is boiled under reflux for 2 hours the Mixture was cooled and concentrated in vacuum. The residue was dissolved in EtOAc and washed with 1M KHSO4(aq.), water and brine. The organic layer was dried, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 50% EtOAc: 50% hexane) to obtain the specified title compound (440 mg, 56%).

Example A

1-Benzoyl-4-bromo-1,2,3,4-those whom rogerebert[b]azepin-5-he

1-Benzoyl-1,2,3,4-tetrahydrobenzo[b]azepin-5-Oh from Example E (54,2 g, 205 mmol), N-bromosuccinimide (3.6 g, of 20.4 mmol) and bromine (11,1 ml, 214,7 mmol) was dissolved in dichloromethane (1.0 liter). Dropwise within 30 minutes was added triethylamine (30 ml, 215 mmol), then the reaction mixture is boiled under reflux for 4 hours. Added additional amount of bromine (1.1 ml, 21.5 mmol) and triethylamine (3.0 ml, 21.5 mmol) and the reaction mixture is boiled under reflux for a further 4 hours. Newly added additional amount of bromine (1.1 ml, 21.5 mmol) and triethylamine (3.0 ml, 21.5 mmol) and the reaction mixture is boiled under reflux for a further 4 hours. After cooling to room temperature the reaction solution washed with 5% aqueous solution of metabisulfite sodium (150 ml) and the aqueous phase was diluted with water (600 ml). The organic phase was separated, washed with saturated Panso3(aq.), was dried over sodium sulfate and filtered. The filtrate was diluted with EtOAc (100 ml), filtered through a layer of silica (eluent; CH2Cl2) and concentrated in vacuum to obtain specified in the connection header (73,6 g)which was used without further purification.

Example A

6-Benzoyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene

1-Benzoyl-4-bromo-1,2,3,4-tetrahydrobenzo[b]azepin-5-he (67,5 g, 200 mmol) from Example E, hydro is lorid of acetamidine (of 92.7 g, 980 mmol) and potassium carbonate (136,0 g, 980 mmol) suspended in acetonitrile (2.0 liters) and boiled under reflux for 17 h under nitrogen atmosphere. Added additional amount of the hydrochloride of acetamidine (18.5 g, 200 mmol) and potassium carbonate (27.7 g, 200 mmol) and the reaction mixture is boiled under reflux for a further 6 hours Again added an additional amount of the hydrochloride of acetamidine (18.5 g, 200 mmol) and potassium carbonate (27.7 g, 200 mmol) and the reaction mixture is boiled under reflux for a further 6 hours After cooling to room temperature the reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue is suspended in dichloromethane (1.4 liters), washed with water (500 ml), dried over sodium sulfate, filtered and concentrated in vacuum. The crude products were purified by flash chromatography on silica gel (eluent; 45% EtOAc: 45% acetonitrile: 10% methanol) to obtain specified in the connection header (26.7 g, 34%) and 6-benzoyl-2-methyl-5,6-dihydro-4H-1-oxa-3,6-database[e]azulene (3,3 g, 4%).

Example A

2-Methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene

6-Benzoyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene from Example E (160 mg, of 0.53 mmol) was dissolved in 6M solution of HCl/dioxane (50 ml) and boiled under reflux for 18 hours, the Reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was distributed between EtOAc and saturated NaHCO3(aq.) and the layers were separated. The organic layer was washed with brine, dried, filtered and concentrated in vacuum to obtain specified in the title compound (69 mg, 66%).

Example EA

1-Benzyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene

Example EA

(1-Benzyl-2-methyl-4.5-dihydro-1H-1,3,6-tratamente]azulene-6-yl)phenylmethanone

Sodium hydride (60% dispersion in oil, 905 mg to 22.5 mmol) was placed in anhydrous THF (200 ml) and cooled to 0°C. was added dropwise 6-benzoyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene from Example E (4.9 g, 16,1 mmol) and the mixture was stirred for 1 h at room temperature. Added benzylbromide (2,31 ml, and 19.3 mmol) and potassium iodide (1,34 g, 8.0 mmol) and the mixture was stirred for 16 hours the Solution was diluted with EtOAC, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc) to obtain the specified title compound (5.73 g, 90%).

Example EA

1-Benzyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene

(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)phenylmethanone Example EA (5.73 g, 14.6 mmol) was placed in methanol (50 ml) was added 6 M aqueous HCl solution (200 ml). The reaction mixture is boiled under reflux for 18 h, the ATEM concentrated in vacuum. The residue was dissolved in dichloromethane, acidified with saturated Panso3, then washed with brine, dried and concentrated in vacuum to obtain specified in the connection header (3,30 g, 78%).

Example E6

2-Methyl-5,6-dihydro-4H-1-oxa-3,6-database[e]azulene

6-Benzoyl-2-methyl-5,6-dihydro-4H-1-oxa-3,6-database[e]azulene from Example E (1.0 g, 3.25 mmol) was brought into reaction with 6M HCl/dioxane (100 ml) using a method similar to that described for Example A, obtaining specified in the title compound (540 mg, 82%).

Example E7

2-Methyl-5,6-dihydro-4H-3-thia-1,6-database[e]azulene

Example A

(2-Methyl-4,5-dihydro-3-thia-1,6-database[e]azulene-6-yl)phenylmethanone

To a solution of 1-benzoyl-4-bromo-1,2,3,4-tetrahydrobenzo[b]azepin-5-she (1.0 g, 2.9 mmol) from Example E in ethanol (50 ml) was added thioacetamide (0.75 g, 10 mmol). The solution was stirred for 16 h the Resulting suspension was reduced in volume by evaporation and cooled. The precipitate was collected by filtration and the solid is washed aclidinium ethanol and dried to obtain specified in the title compound as a white solid (0.65 g, 70%).

Example A

2-Methyl-5,6-dihydro-4H-3-thia-1,6-database[e]azulene

A suspension of (2-methyl-4,5-dihydro-3-thia-1,6-database[e]azulene-6-yl)phenylmethanone Example E (0,42 g, 1.3 mmol) in 6M hydrochloric acid (4 ml) was boiled under reflux for 16 hours The solution was cooled and treated with saturated Panso3(aq.) (100 ml). Added additional amount of solid Panso3up until the solution is basic. The mixture was extracted with dichloromethane and the organic extracts were dried and concentrated in vacuum to obtain specified in the title compound as a yellow oil (0.21 g, 76%).

Example E8

4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-forbindelse 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid

Example A

tert-Butyl ester [4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]carbamino acid

A solution of 4-(tert-butoxycarbonylamino)-3-fermenting acid from Example E (538 mg, 2.0 mmol) and DMAP (220 mg, 1.8 mmol) in dichloromethane (20 ml) at room temperature was treated with DIEA (0,93 ml, 5.4 mmol) and WSCD (460 mg, 2.4 mmol) and the resulting solution was stirred at room temperature for 1 h was Added 3,6-dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E2 (385 mg, 1.8 mmol) and the resulting the resulting solution was boiled under reflux for 20 h and allowed to cool to room temperature. The solution was diluted with dichloromethane, washed with saturated Panso3and brine and concentrated in vacuum. The residue was purified by the reparative HPLC (eluent 10% methanol:90% dichloromethane) to obtain the specified title compound (265 mg, 32%).

Example A

Hydrochloride (4-aminomethyl-3-forfinal)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone

tert-Butyl ester [4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]carbamino acid from Example E (237 mg, 0.51 mmol) was brought into reaction with 4 N. HCl/dioxane using a method similar to that described for Example A, obtaining specified in the title compound (205 mg, 100%).

Example A

4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-forbindelse 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid

DIEA (0.10 ml, of 0.60 mmol) and 1,1'-carbonyldiimidazole (28 mg, 0,17 mmol) was added to a solution of hydrochloride (4-aminomethyl-3-forfinal)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (57 mg, 0.14 mmol) in DMF (5.0 ml) and the mixture was stirred at room temperature for 4 hours. Added the dihydrochloride of 1-(3,3-dimethylbutyl)piperazine from Example E4 (38 mg, 0.16 mmol) and the mixture was stirred at room temperature for 24 h and concentrated in vacuum. The residue was dissolved in EtOAc and the resulting solution was washed with brine and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 10% methanol:90% dichloromethane) to give a white solid identified as specified in the agolove compound (45 mg, 56%).

Example a

4-(tert-Butoxycarbonylamino)cyclohexanecarbonyl acid

To a solution of 4-aminomethylenemalonate acid (20,0 g, 127,39 mmol) in dioxane (400 ml) was added 1 n knso3(300 ml, 300 mmol) and di-tert-butyl dicarbonate (33,3 g, 129,57 mmol). The mixture was stirred for 18 h and concentrated in vacuum. The aqueous residue was washed with a simple ether, then acidified 1 N. KHSO4and was extracted with EtOAc (×3). The combined organic extracts were washed with water and brine and concentrated in vacuum to obtain a white solid, identified as specified in the header connection (31,9 g, 98%).

Example E10

[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide cyclopropanecarbonyl acid

Example A

tert-Butyl ester [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]carbamino acid

A solution of 4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid from Example e (510 mg, 2.0 mmol) in dichloromethane (25 ml) at room temperature was treated with DIEA (to 0.70 ml, 4.0 mmol), bromo-Tris-pyrrolidinone hexaflurophosphate (Rougher) (2,40 g, 5.1 mmol) and 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E1 (422 mg, 1.8 mmol) and the resulting solution boiled with reverse what holodilniki for 20 h and was allowed to cool to room temperature. The solution was diluted with dichloromethane, washed with brine and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent EtOAc) to obtain the specified title compound (775 mg, 91%).

Example A

Hydrochloride (4-Aminoethylthiomethyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone

A solution of tert-butyl ester [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]carbamino acid from Example E (775 mg, and 1.63 mmol) was brought into reaction with 4 N. HCl/dioxane using a method similar to that described for Example A, obtaining specified in the title compound (655 mg, 100%).

Example A

[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide cyclopropanecarbonyl acid

DIEA (0,50 ml, 2,90 mmol) and cyclopropanecarbonyl (0,045 ml, 0.50 mmol) was added to a solution of hydrochloride (4-aminoethylthiomethyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example A (220 mg, of 0.53 mmol) in dichloromethane (5 ml). The mixture was stirred for 2 h, then was diluted with dichloromethane, washed with water and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia/10% methanol/90% dichloromethane) to give a white solid identified the AK specified in the title compound (132 mg, 60%).

Example E11

3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene

Example A

Ethyl ester of 1-methyl-5-(2-nitrophenylamino)-1H-pyrazole-4-carboxylic acid

Sodium hydride (60% dispersion in oil, 7.0 g, 170 mmol) in portions at 0°C was added to a suspension of ethyl ester of 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid (21.1 g, 125 mmol) in anhydrous THF (300 ml). The mixture was allowed to warm to room temperature and was stirred for 0.75 h, then was cooled to 0°Sgabelli 1-fluoro-2-nitrobenzene (17.6 g, 125 mmol) and poluchayuca resulting suspension was stirred at room temperature for 18 hours was Added EtOAc and 0,3M KHSO4and shared. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent 50% hexane/50% ethyl acetate) to obtain specified in the connection header (20,8 g, 58%).

Example A

Ethyl ester of 5-(2-aminophenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid

Ethyl ester of 1-methyl-5-(2-nitrophenylamino)-1H-pyrazole-4-carboxylic acid (20,8 g, 72 mmol) from Example I was dissolved in methanol (330 ml) and was first made over 10% Pd/C catalyst for 4 hours. The mixture was filtered through filter agent Celite® and the filtrate was concentrated in vacuum to obtain a white solid in the society, identified as specified in the title compound (16.2 g, 87%).

Example A

3-Methyl-4,9-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-10-he

(Methylsulfinyl)methane sodium (29.7 mmol) was obtained from sodium hydride (60% dispersion in oil, 1.19 g, 29.7 mmol) and anhydrous dimethyl sulfoxide (7 ml) by heating at 65°C until solution. To it was added a solution of ethyl ester 5-(2-aminophenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid from Example E (3,63 g of 16.9 mmol) in anhydrous dimethyl sulfoxide (10 ml) and the stirring continued at 65°C for 2.5 hours the Mixture was poured into ice (100 ml) and the resulting solid was collected and purified by recrystallization from methanol/EtOAc/60-80 petroleum ether to obtain specified in the connection header (1,46 g, 40%).

Example A

3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene

To a suspension of 3-methyl-4,9-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-10-she's from Example E (3,01 g, 14.1 mmol) in anhydrous THF (100 ml) at 0°C was added alumoweld lithium (2,13 g, 56.2 mmol) and the resulting suspension was heated under reflux for 18 h, then was allowed to cool to room temperature. The mixture was cooled to 0°C., dropwise within 15 min was added 35% aqueous ammonia (10 ml) and the mixture was stirred at room temperature for 30 minutes of Poluchayuca resulting suspension was filtered through filter agent Celite® and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 2% methanol:chloroform to 5% methanol:chloroform) to obtain the specified title compound (1.60 g, 57%).

Example E12

[4-(Isobutylamino)cyclohexyl]-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanon

The solution samalanga aldehyde (0.36 mg, of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) was added to a solution of hydrochloride (4-aminoethylthiomethyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (1,88 mg of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) and DIEA (0,0026 ml). The mixture was stirred at room temperature for 1 h, and then the solution was added triacetoxyborohydride sodium (1,59 mg, 0,0075 mmol) in DMF (0.05 ml). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum to obtain specified in the connection header. (Spray ionization electrons (IRE))+: [M+H]+=396,4.

Example E13

4-Nitrobenzyloxy ester [4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]carbamino acid

A solution of 4-nitrobenzenesulfonate (1.08 mg, of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of hydrochloride (4-aminoethylthiomethyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone (Connection room 149) (1,95 mg of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (00035 ml). The mixture was stirred at room temperature for 1 h, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=533,3

Example E14

(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-(4-exilelifestyle.com)metano

A solution of 1-Bromhexine (0,83 mg of 0.005 mmol) in DMF (0.05 ml) was added to a solution of hydrochloride (4-aminoethylthiomethyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (2,05 mg of 0.005 mmol) in DMF (0.05 ml) and triethylamine (0,0021 ml). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=458,4.

Example E15 motorway

1-(3,3-Dimethylbutyl)piperidine-4-carboxylic acid

Example A

Ethyl ester of 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid 3,3-Dimethylallyl aldehyde (5,26 ml, 42.0 mmol) was added to a solution of utilisedictated (6.6 g, 42.0 mmol) in methanol/acetic acid (99:1, vol/about., 50 ml) and the mixture was stirred at room temperature for 1 h was Added cyanoborohydride sodium (3,43 g of 54.6 mmol) and the mixture was stirred at room temperature for 4 days, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent; 25% EtOAc:75% cyclohexane) to obtain specified in the header Conn is in (7,16 g, 71%).

Example A

1-(3,3-Dimethylbutyl)piperidine-4-carboxylic acid

The monohydrate of lithium hydroxide (1,37 g, a 32.6 mmol) was added to a solution of ethyl ester of 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid from Example E (7,16 g, 29.7 mmol) in THF (50 ml) and water (5 ml). The mixture was stirred at room temperature for 18 h, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel through Isolute (eluent; 90% dichloromethane:9% methanol:1% acetic acid) to obtain specified in the connection header (5,51 g, 87%).

Example EA

1-Cyclopropylmethyl-4-carboxylic acid

Specified in the title compound was obtained from cyclopropanecarboxaldehyde and utilisedictated using methods similar to the methods described for Example E15 motorway.

Example a

[4-(3-Methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid

Example A

[4-(3-Methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-(3,3-dimethylbutyl)piperazine-4-carboxylic acid

2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate (HBTU) (84 mg, 0.22 mmol) was added to a solution of 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid from Example E15 motorway (42 mg, 0,17 mmol) in DMF (5 ml) and DIEA (to pH 9). The mixture was stirred at room is the temperature within 1 hour Added hydrochloride (4-aminoethylthiomethyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone (Connection room 150) (42 mg, 0.11 mmol) and the mixture was stirred at room temperature for 18 hours the Solvent was removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in EtOAc, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 10% methanol:90% dichloromethane) to give a white solid identified as specified in the title compound (34 mg, 57%).

Example E17

The hydrochloride of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]-2-piperidine-4-ylacetamide

A solution of tert-butyl ester 4-({[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]carbarnoyl}methyl)piperidine-1-carboxylic acid (Compound number 228) (259 mg, 0.45 mmol) was brought into reaction with 4 N. HCl/dioxane using a method similar to that described for Example A, obtaining specified in the title compound (230 mg, 93%).

Example E18

N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]methanesulfonamide

The solution methanesulfonanilide (0,57 mg of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (4-aminoet cyclohexyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone (Connection room 149) (1,95 mg, of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0,0035 ml). The mixture was stirred at room temperature for 1 h, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=432,1.

Example E19

N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]-2-(1-methanesulfonamido-4-yl)ndimethylacetamide

The solution methanesulfonanilide (0,57 mg of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of the hydrochloride of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]-2-piperidine-4-ylacetamide Example E17 (to 2.57 mg of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0,0035 ml). The mixture was stirred at room temperature for 1 h, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=557,4.

Example E20

2-(1-Acetylpiperidine-4-yl)-N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]ndimethylacetamide

The solution acetylchloride (0,39 mg, of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of the hydrochloride of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]-2-piperidine-4-ylacetamide Example E17 (to 2.57 mg of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0,0035 ml). The mixture was stirred at room temperature for 1 h, then the solvents UDA the Yali in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=521,5.

Example E21

[4-(3-Methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 1-isobutylpyrazine-4-carboxylic acid

The solution samalanga aldehyde (0.36 mg, of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) was added to a solution of hydrochloride [4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide piperidine-4-carboxylic acid (Compound number 238) (2,43 mg of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) and DIEA (0,0026 ml). The mixture was stirred at room temperature for 1 h, and then the solution was added triacetoxyborohydride sodium (1,59 mg, 0,0075 mmol) in DMF (0.05 ml). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=507,4.

Example E22

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]-3-(1-hexylpyridine-4-yl)propionamide

A solution of 1-Bromhexine (0,83 mg of 0.005 mmol) in DMF (0.05 ml) was added to a solution of the hydrochloride of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]-3-piperidine-4-ylpropionic (Compound No. 237) (to 2.57 mg of 0.005 mmol) in DMF (0.05 ml) and triethylamine (0,0021 ml). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum to obtain specified in the header is the connection. (IRE)+: [M+H]+=597,6/599,6.

Example a

4-Nitrobenzyloxy ester of 4-({[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]carbarnoyl}methyl)-piperidine-1-carboxylic acid

A solution of 4-nitrobenzenesulfonate (1.08 mg, of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of the hydrochloride of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]-2-piperidine-4-ylacetamide Example E17 (2.58 mg, of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0,0035 ml). The mixture was stirred at room temperature for 1 h, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=658,5.

Example a

[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-(3,3-dimethylbutyl)piperazine-1-karbonvansty

DIEA (of 0.30 ml, 1.7 mmol) and 1,1'-carbonyldiimidazole (39 mg, 0.24 mmol) was added to a solution of hydrochloride (4-aminoethylthiomethyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone (Connection room 149) (78 mg, 0.20 mmol) in DMF (4.0 ml) and the mixture was stirred at room temperature for 2 hours was Added to the dihydrochloride of 1-(3,3-dimethylbutyl)piperazine from Example E4 (56 mg, 0,23 mmol) and the mixture was stirred at room temperature for 18 hours the Mixture was diluted with EtOAc, washed with brine, dried and concentrated in Vacu the IU. The residue was purified by preparative HPLC (eluent; 10% methanol:90% dichloromethane) to give a white solid identified as specified in the title compound (32 mg, 29%).

Example E25

3-Chloro-6,7,8,9-tetrahydro-5-oxa-9-athensallowed

Example A

N-(4-Chloro-2-hydroxyphenyl)benzamide

2-Amino-5-chlorophenol (1.45 g, 10 mmol) was dissolved in EtOAc (30 ml) and water (20 ml). Was added sodium bicarbonate (1.25 g, 15 mmol)followed by benzoyl chloride (1.42 g, 10 mmol) and the mixture was stirred at room temperature for 1 h, the Layers were distributed and the organic layer was washed with brine, dried and concentrated in vacuum. The residue is triturated with diethyl ether to obtain specified in the connection header (2,05 g, 82%).

Example A

(3-Chloro-7,8-dihydro-6N-5-oxa-9-athensallowed-9-yl)phenyl-metano

N-(4-Chloro-2-hydroxyphenyl)benzamide Example E (1.0 g, 4 mmol) was dissolved in acetonitrile (10 ml) and dichloromethane (15 ml). Added 1,3-dibromopropane (3,26 g, 16 mmol), aliquat 336 (170 mg, 0.4 mmol) and sodium hydroxide (750 mg, 16 mmol) and the mixture was heated at 60°C for 3 hours, the Solid was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 30% EtOAc:70% hexane) to obtain specified in the connection header (783 mg, 83%).

Example A

3-Chloro-6,7,8,9-tetrahydro-5-oxa-9-azabenzo eclogite (3-Chloro-7,8-dihydro-6N-5-oxa-9-athensallowed-9-yl)phenyl-methanon Example E25,2 (783 mg, 2.7 mmol) was dissolved in dioxane (10 ml) was added 6 M aqueous HCl solution (50 ml). The mixture was boiled under reflux for 20 h, then concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in diethyl ether and water, acidified NaHCO3and the layers were distributed. The organic layer was washed with brine, dried and concentrated in vacuum to obtain specified in the title compound (280 mg, 47%).

Example A

N-Cyclohexyl-N'-methylbenzol-1,2-diamine

Example A

Cyclohexyl-(2-nitrophenyl)amine

A mixture of 2-peritrabecular (5.0 g, of 35.4 mmol), cyclohexylamine (4,5 ml of 39.0 mmol) and potassium carbonate (17.1 g, 124 mmol) in acetonitrile (100 ml) was boiled under reflux for 2 days. The mixture was diluted with EtOAC, washed with water, then brine, dried and partially concentrated in vacuo. The precipitated solid was collected and washed with hexane to obtain specified in the title compound (6.7 g, 86%).

Example A

N-Cyclohexylmethyl-1,2-diamine

Cyclohexyl-(2-nitrophenyl)amine from Example E (3.0 g, to 13.6 mmol) was dissolved in methanol (100 ml) was added tin chloride (II) (12.9 g, 68,1 mmol). The mixture was stirred for 20 h at room temperature, then boiled under reflux for 18 h and concentrated in vacuum. The residue was placed in EtOAC (100 ml), cooled to 0°C and the N brought up to 14 conc. NH3. The precipitate was filtered and washed with EtOAc. The filtrate is washed with 2M NH3, water, then brine, dried and concentrated in vacuum to obtain specified in the title compound (2.25 g, 86%).

Example A

N-Cyclohexyl-N'-methylbenzol-1,2-diamine

Potassium carbonate (2,45 g of 17.7 mmol) and jodean (0,81 ml of 13.0 mmol) was added to a solution of N-Cyclohexylmethyl-1,2-diamine from Example E (2.25 g, and 11.8 mmol) in DMF (10 ml). The mixture was stirred for 6 h at room temperature, then poured into water and was extracted with EtOAc. The organic layer was washed with water, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 5% EtOAc:95% hexane) to obtain the specified title compound (950 mg, 39%).

Example E27

Ethyl ester of 3-fluoro-4-hydroxybenzoic acid

A solution of 3-fluoro-4-hydroxybenzoic acid (5,16 g, up 33.1 mmol) in ethanol (100 ml) was treated with conc. sulfuric acid (5 ml) and the mixture is boiled under reflux for 4 days. Volatiles were removed in vacuum and the aqueous residue was acidified with saturated Panso3and twice was extracted with diethyl ether. The combined organic extracts were dried and concentrated in vacuum to obtain specified in the connection header (5,16 g, 85%).

Example E28

Ethyl ester of 2-chloro-4-hydroxybenzoic acid

3and 4 times was extracted with diethyl ether. The combined organic extracts were dried and concentrated in vacuum to obtain specified in the title compound (2.5 g, 38%).

Example A

Methyl ester of 4-hydroxy-3-methylbenzoic acid Methyl ester 4-amino-3-methylbenzoic acid (5,25 g of 32.0 mmol) was treated with 35% sulfuric acid solution (50 ml) and the mixture was stirred and heated until dissolution, then cooled to 0°C. was added dropwise sodium nitrite (2,82 g of 41.6 mmol) in water (50 ml) and the mixture was stirred for 5 min at 0°C. was Added urea to destroy excess nitrite. Added nitrate copper (121 g, 320 mmol) in water (1 l), then the copper oxide (4,25 g of 32.0 mmol). The mixture was heated to room temperature for 30 min and was extracted with EtOAc (×3). Organic substances were combined, washed with brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 30% EtOAc:70% hexane) to obtain the specified title compound (2.2 g, 42%).

Example E30

Methyl EF the p 4-(3-carboxypropyl)-3-methylbenzoic acid

Example A

Methyl ester of 4-((E)-2-tert-butoxycarbonylamino)-3-methyl-benzoic acid

Tetrakis(triphenylphosphine)palladium (0) (5.0 g, to 4.33 mmol) was added to a stirred solution of methyl 4-bromo-3-methylbenzoate Ltd (9.93 g, a 43.3 mmol), tert-butyl acrylate (50 ml, 341,3 mmol) and sodium acetate (35,8 g, 436,4 mmol) in dimethylacetamide (DMA) (350 ml). The mixture was heated at 140°C for 5 h, filtered through filter agent Celite® and the filtrate was concentrated in vacuum. The remainder of pererestorani in EtOAc, washed with 0.3 m KHSO4, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 15% EtOAc:85% hexane to 20% EtOAc:80% hexane) to obtain specified in the connection header (to 4.81 g, 40%).

Example A

Methyl ester of 4-(2-tert-butoxycarbonylmethyl)-3-methylbenzoic acid

Methyl ester of 4-((E)-2-tert-butoxycarbonylamino)-3-methylbenzoic acid from Example E (4,00 g, 14.5 mmol) was dissolved in methanol (100 ml) and was first made over 10% Pd/C catalyst (480 mg) for 5 h the Mixture was filtered through filter agent Celite® and the filtrate was concentrated in vacuum to obtain specified in the connection header (3,41 g, 84%).

Example A

Methyl ester of 4-{2-carboxyethyl)-3-methylbenzoic acid

Triperoxonane acid (40 ml) at room temperature was slowly added to the mix of rest the ru methyl ester 4-(2-tert-butoxycarbonylmethyl)-3-methylbenzoic acid from Example E (4.9 g, 17.6 mmol) in dichloromethane (80 ml). The mixture was stirred for 2 h, then concentrated in vacuo and subjected to azeotropic distillation with dichloromethane. The residue was recrystallized in EtOAc to obtain specified in the connection header (2,77 g, 71%).

Example A

Methyl ester of 4-(3-carboxypropyl)-3-methylbenzoic acid

Methyl ester of 4-(2-carboxyethyl)-3-methylbenzoic acid from Example E (500 mg, 2.25 mmol) was dissolved in anhydrous dichloromethane (10 ml) and few drops DMF. Was added dropwise oxalicacid (0,393 ml, 4.5 mmol) and the mixture was stirred for 1 h at room temperature. The solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in acetonitrile (20 ml) and cooled to 0°C. was added dropwise a solution of 2M (trimethylsilyl)diazomethane in hexano (2.25 ml, 4.5 mmol) and the reaction mixture was stirred for 5 h at 0°C, then 20 h at room temperature. Added ethyl acetate, then 10% citric acid solution and the layers were distributed. The organic layer was washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 50% ethyl acetate:50% cyclohexane). The obtained product was dissolved in a mixture of acetonitrile and water. Was gradually added a solution of silver benzoate (103 mg, 0.45 mmol) is a triethylamine (1.25 ml, 9 mmol)until the mixture was subjected to ultrasonic treatment in an ultrasonic bath. After 30 min at room temperature the solvents were removed in vacuum. Added ethyl acetate and 10% aqueous citric acid solution, and the layers were distributed. The organic layer was washed with brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 50% EtOAc:50% cyclohexane) to obtain the specified title compound (378 mg, 71%).

Example a

4-(4-Ethoxycarbonylbutyl)-3-methylbenzoic acid

Example A

tert-Butyl ester 4-bromo-3-methylbenzoic acid

4-Bromo-3-methylbenzoic acid (to 2.06 g, 9.6 mmol) and thionyl chloride (2.2 ml, 30.2 mmol) in toluene (50 ml) was boiled under reflux for 2 h, then concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in THF (100 ml) and triethylamine (2.8 ml, of 20.1 mmol), cooled to 0°C and portions were added tert-piperonyl lithium (1.24 g, a 15.5 mmol). The mixture was stirred for 18 h at room temperature, then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M HCl, saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 5% EtOAc;95% petroleum ether) to obtain the specified title compound (1.86 g, 71%).

the example E

tert-Butyl ester 4-((1E,3E)-4-methoxycarbonyl-1,3-dienyl)-3-methylbenzoic acid

Tetrakis(triphenylphosphine)palladium (0) (852 mg, 0.7 mol) was added to a stirred solution of tert-butyl ester 4-bromo-3-methylbenzoic acid from Example E (1.86 g, 6.8 mmol), 1-acetoxy-1,3-butadiene (7.5 ml, at 64.5 mmol) and sodium acetate (5,69 g, to 69.4 mmol) in DMA (75 ml). The mixture was heated at 140°C for 3 h, filtered through filter agent Celite® and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 20% EtOAc:80% petroleum ether) to obtain the specified title compound (1.54 g, 74%).

Example A

tert-Butyl ester 4-(4-ethoxycarbonylbutyl)-3-methylbenzoic acid

tert-Butyl ester 4-((1E,3E)-4-methoxycarbonyl-1,3-dienyl)-3-methylbenzoic acid from Example E (1.54 g, 5.1 mmol) was dissolved in methanol (40 ml) and was first made over 10% Pd/C catalyst (200 mg) for 5 h the Mixture was filtered through filter agent Celite® and the filtrate was concentrated in vacuum to obtain specified in the connection header (1,43 g, 92%).

Example A

4-(4-Ethoxycarbonylbutyl)-3-methylbenzoic acid

Triperoxonane acid (20 ml) was added to a solution of tert-butyl ester 4-(4-ethoxycarbonylbutyl)-3-methylbenzoic acid from Example E (1,43 g, 4.7 mmol) in dichloromethane (40 ml) and the mixture premesis is whether for 2 h at room temperature. The solvent was concentrated in vacuo and subjected to azeotropic distillation with dichloromethane to obtain specified in the title compound (1.07 g, 92%).

Example a

Methyl ester of 4-carboxymethyl-3-methylbenzoic acid

Example A

Methyl ester 4-tert-butoxycarbonylmethyl-3-methylbenzoic acid

Fluoride copper (II) (4,08 g, 40,1 mmol) and dichloride bis-[tri-(ortho-tolyl)phosphine]palladium (473 mg, 0.6 mmol) was added to a solution of methyl 4-bromo-3-methyl benzoate (4,60 g of 20.1 mmol) in THF (30 ml). The mixture was boiled under reflux before adding acetal of silicatein (18,5 g of 80.3 mmol). The mixture was boiled under reflux for 2 days, then diluted with Et2O Added an aqueous solution of NH4Cl (250 ml) and the mixture was stirred for 30 min at room temperature. The layers were distributed, and the aqueous layer was twice extracted with Et2O. the Organic phases were combined, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 5% EtOAc:95% hexane) to obtain specified in the connection header (2,84 g, 53%).

Example A

Methyl ester of 4-carboxymethyl-3-methylbenzoic acid

Triperoxonane acid (15 ml) was added to a solution of methyl ester 4-tert-butoxycarbonylmethyl-3-methylbenzoic acid from Example E (2,84 g of 10.7 mmol) in dichloromethane (15 ml). The mixture peremeci the Ali for 90 min at room temperature, concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was recrystallized from EtOAc and hexane to obtain specified in the connection header (1,81 g, 81%).

Example A

4-[1,3]Dioxolane-2-reprein

Example A

Benzyl ether of 4-hydroxyethylpiperazine-1-carboxylic acid

4-Piperidinemethanol (5.0 g, 43 mmol) was dissolved in dichloromethane (100 ml) and triethylamine (12 ml, 86 mmol) at 0°C. was Added benzylchloride (6.8 ml, of 47.3 mmol) and the mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum. The remainder of pererestorani in EtOAc, washed with 1M KHSO4, water, then brine, dried and concentrated in vacuum to obtain specified in the connection header (8,33 g, 77%).

Example A

Benzyl ever-formylpiperidine-1-carboxylic acid

Reagent dess-Martin (17 g, to 39.6 mmol) in portions at room temperature was added to a solution of benzyl ester 4-hydroxyethylpiperazine-1-carboxylic acid from Example E (8,33 g, 33 mmol) in dichloromethane (100 ml). The mixture was stirred for 3 h in an inert atmosphere, then was diluted with chloroform and water and the layers were distributed. The organic layer was washed with brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 40% EtOAc:60% hexane) to obtain specified in is the head of the compound (5.5 g, 66%).

Example A

Benzyl ether of 4-[1,3]dioxolane-2-reparacin-1-carboxylic acid

Ethylene glycol (5 ml) and a catalytic amount of para-toluensulfonate acid was added to benzilovomu ether 4-formylpiperidine-1-carboxylic acid from Example E (5.6 g, and 22.6 mmol) in toluene (100 ml) and the mixture is boiled under reflux in the conditions of a Dean and stark for 2.5 hours the Solvent was removed in vacuum and the residue pererestorani in EtOAc, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 50% EtOAc:50% petroleum ether) to obtain specified in the connection header (5,14 g, 78%).

Example A

4-[1,3]Dioxolane-2-reprein

Benzyl ether of 4-[1,3]dioxolane-2-reparacin-1-carboxylic acid from Example E (5,14 g of 17.7 mmol) was dissolved in methanol (100 ml) and was first made over 10% Pd/C catalyst (551 mg) for 4 hours. The mixture was filtered through filter agent Celite® and the filtrate was concentrated in vacuum to obtain specified in the connection header (2,84 g, 100%).

Example E34

tert-Butyl ester 4-(3-hydroxypropyl)piperazine-1-carboxylic acid

A solution of tert-butyl methyl ether piperazine-1-carboxylic acid (26.5 g, 142 mmol) in acetone (300 ml) at room temperature was treated with 3-bromopropane-1-I (14,5 ml, 156,2 mmol), carbon is ω potassium (50 g, 361,8 mmol) and potassium iodide (2.4 g, of 14.2 mmol) and the mixture is boiled under reflux for 18 h, then was allowed to cool to room temperature. The suspension was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 5% methanol:95% dichloromethane) to obtain the specified title compound (27.7 g, 80%).

Example A

DATEFORMAT 1 cyclopropylacetylene

Example A

tert-Butyl ether [2-(cyclopropylamino)ethyl]carbamino acid

The potassium bicarbonate (220 mg, 2.2 mmol) and (bromacil)cyclopropane (270 mg, 2.0 mmol) was added to a solution of tert-butyl N-(2-amino-ethyl)carbamate (320 mg, 2.0 mmol) in THF (10 ml). The mixture was heated at 66°C for 20 h and the solvent was concentrated in vacuum. The residue was dissolved in chloroform, washed with water, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 1% triethylamine:4% methanol:95% chloroform) to obtain the specified title compound (130 mg, 30%).

Example A

DATEFORMAT 1 cyclopropylacetylene

Triperoxonane acid (5 ml) was added to a solution of tert-butyl methyl ether [2-(cyclopropylamino)ethyl]carbamino acid from Example A (180 mg, 0.84 mmol) in dichloromethane (3 ml) and the mixture was stirred for 75 min at the room for the Noah temperature. The solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The residue was placed in water (10 ml) was added formaldehyde (37% wt./wt. a solution of 0.10 ml of 1.36 mmol). The mixture was stirred for 6 days at room temperature, concentrated in vacuo, and subjected to azeotropic distillation with toluene and then with petroleum ether to obtain specified in the title compound (255 mg, 86%).

Example E36

The dihydrochloride of 2-piperazine-1-yl-1-pair-of toleration

Example A

tert-Butyl ester 4-(2-oxo-2-para-triletal)piperazine-1-carboxylic acid

2-Bromo-4-methylacetophenone (572 mg, 2.68 mmol) was added to a solution of tert-butyl methyl ether piperazine-1-carboxylic acid (500 mg, 2.68 mmol) in dichloromethane (5 ml) and triethylamine (0.45 ml, up 3.22 mmol). The mixture was stirred for 3 days at room temperature and the solvents were removed in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 40% hexane:60% EtOAc) to obtain specified in the connection header (661 mg, 77%).

Example A

The dihydrochloride of 2-piperazine-1-yl-1-Lara-toleration

tert-Butyl ester 4-(2-oxo-2-para-triletal)piperazine-1-carboxylic acid from Example E (661 mg, of 2.08 mmol) was dissolved in 4M HCl solution in dioxane (25 ml) at 0°C and the mixture was stirred for 45 min at room temperature. The solvent was concentrated in vacuum and the evaluation of the RGALI azeotropic distillation with diethyl ether to obtain specified in the title compound (536 mg, 88%).

Example A

2-Bromo-1-[4-(3,3-dimethylbutyl)piperazine-1-yl]alanon

Bromoacetamide (of 0.52 ml, 6.0 mmol) at 0°C was added to a solution of hydrochloride of 1-(3,3-dimethylbutyl)piperazine from Example E4 (1.5 g, 5.7 mmol) in dichloromethane (20 ml) and triethylamine (3,57 ml, 25.6 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated Panso3, was dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 5% methanol:95% dichloromethane) to obtain the specified title compound (220 mg, 13%).

Example E38

tert-Butyl ether cyclopropylidene-4-ylmethyl-carbamino acid

Example A

Benzyl ether of 4-cyclopropanemethylamine-1-carboxylic acid

Cyclopropylamine (1.4 g, 24.4 mmol) and acetic acid (0.5 ml) was added to a solution of benzyl ester 4-formylpiperidine-1-carboxylic acid from Example E (5.5 g, of 22.2 mmol) in methanol (49.5 ml) and the mixture was stirred for 1 h at room temperature. Added cyanoborohydride sodium (1.84 g, of 28.9 mmol) and the mixture was stirred for 20 h at room temperature in an inert atmosphere. The solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in EtOAC, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by the lash-chromatography on silica gel (eluent; 10% methanol:90% dichloromethane) to obtain the specified title compound (3.0 g, 47%).

Example A

Benzyl ether of 4-[(tert-butoxycarbonylamino)methyl]-piperidine-1-carboxylic acid

DMAP (127 mg, 1.04 mmol) and di-tert-butyl dicarbonate (3.4 g, 12.5 mmol) was added to a solution of benzyl ester 4-cyclopropanemethylamine-1-carboxylic acid from Example E (3.0 g, 10.4 mmol) in dichloromethane (50 ml) and triethylamine (up to pH 9). The mixture was stirred for 20 h at room temperature, then concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 40% EtOAc:60% hexane) to obtain specified in the connection header (3,67 g, 92%).

Example A

tert-Butyl ether cyclopropylidene-4-iletilerinindeki acid

Benzyl ether of 4-[(tert-butoxycarbonylamino)methyl]-piperidine-1-carboxylic acid from Example E (3,67 g, 9.4 mmol) was dissolved in methanol (100 ml) and was first made over 10% Pd/C catalyst (3 g) for 1 h the Mixture was filtered through filter agent Celite® and the filtrate was concentrated in vacuum to obtain specified in the connection header (2,07 g, 87%).

Example E39

tert-Butyl ester 4-[3-(4-carboxy-2-pertenece)propyl]-piperazine-1-carbon is th acid

Example A

tert-Butyl ester 4-[3-(4-etoxycarbonyl-2-pertenece)propyl]-piperazine-1-carboxylic acid

Triphenylphosphorane (loading of 1.0 mmol/g, 11 g, 11.0 mmol) and diethylazodicarboxylate (DEAD) (2,45 g, 11.0 mmol) at 0°C was added to a solution of ethyl ester of 3-fluoro-4-hydroxybenzoic acid from Example E27 (1.3 g, 7.4 mmol) and tert-butyl ester 4-(3-hydroxypropyl)piperazine-1-carboxylic acid from Example E34 (1.8 g, 7.4 mmol) in tetrahydrofuran (100 ml). The suspension was allowed to warm to room temperature and was stirred for 18 hours the Mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAC) to obtain the specified title compound (1.7 g, 57%).

Example A

tert-Butyl ester 4-[3-(4-carboxy-2-pertenece)propyl-piperazine-1-carboxylic acid

A solution of tert-butyl ester 4-[3-(4-etoxycarbonyl-2-pertenece)propyl]piperazine-1-carboxylic acid from Example A (1.7 g, 4.1 mmol) in dioxane (25 ml) was treated with 2 N. NaOH (3 ml) and the mixture was stirred at 50°C for 18 hours Added an additional aliquot of 2 N. NaOH (2 ml) and stirring continued at 50°C for 3 hours

The solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The residue was purified by flash chromatography on silica gel (eluent; 1% acetic acid to the slot:9% methanol:90% chloroform) to obtain the specified title compound (1.45 g, 92%).

Example E40

4-{2-[4-(3,3-Dimethylbutyl)piperazine-1-yl]ethoxy}-3-methylbenzoic acid

Example A

tert-Butyl ester 4-[2-(4-methoxycarbonyl-2-methylphenoxy)ethyl]-piperazine-1-carboxylic acid

tert-Butyl ester 4-(2-hydroxyethyl)piperazine-1-carboxylic acid (500 mg, 2.2 mmol) was dissolved in THF (30 ml) and cooled to 0°C. was Added triphenylphosphine on the polymer (2.2 g, 2.2 mmol), DEAD (378 mg, 2.2 mmol) and methyl ester of 4-hydroxy-3-methylbenzoic acid from Example E (361 mg, 2.2 mmol) and the mixture was stirred for 20 h at room temperature. The resin was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc) to obtain the specified title compound (495 mg, 60%).

Example A

The dihydrochloride methyl ester 3-methyl-4-(2-piperazine-1-ylethoxy)benzoic acid

tert-Butyl ester 4-[2-(4-methoxycarbonyl-2-methylphenoxy)ethyl]piperazine-1-carboxylic acid from Example E (200 mg, of 0.53 mmol) was dissolved in 4M HCl solution in dioxane (5 ml). The mixture was stirred for 30 min at room temperature, concentrated in vacuo and subjected to azeotropic distillation with toluene to obtain specified in the title compound (185 mg, 100%).

Example A

Methyl ester of 4-{2-[4-(3,3-dimethylbutyl)piperazine-1-yl]ethoxy}-3-methylbenzoic acid

3,3-Dimethyl who alany aldehyde (54 mg, of 0.53 mmol) was added to a solution of dihydrochloride methyl ester 3-methyl-4-(2-piperazine-1-ylethoxy)benzoic acid from Example E (146 mg, 0.42 mmol) in methanol/acetic acid (99:1, vol/about., 10 ml) and the mixture was stirred at room temperature for 1 h was Added cyanoborohydride sodium (42 mg, 0.69 mmol) and the mixture was stirred at room temperature for 18 h, then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated Panso3, water, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel through Isolute (eluent; EtOAc) to obtain the specified title compound (64 mg, 34%).

Example A

4-(2-[4-(3,3-Dimethylbutyl)piperazine-1-yl]ethoxy}-3-methylbenzoic acid

Methyl ester of 4-{2-[4-(3,3-dimethylbutyl)piperazine-1-yl]ethoxy}-3-methylbenzoic acid from Example E (42 mg, 0.12 mmol) was dissolved in dioxane (5 ml) was added 1M NaOH (1 ml). The mixture was boiled under reflux for 2 h, then the solvents were concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated Panso3, water, then brine, dried and concentrated in vacuum to obtain specified in the title compound (40 mg, 100%).

Example A

4-{2-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-2-oksidoksi}-3-methylbenzoic acid

Example A

Methyl ester 4-tert-b is oxycarbonate-3-methylbenzoic acid

Potassium carbonate (4.6 g, 33 mmol), potassium iodide (0.25 g, 1.5 mmol) and tert-butylbromide (2.5 ml, 16.5 mmol) was added to a solution of methyl ester 4-hydroxy-3-methylbenzoic acid from Example E (2.5 g, 15 mmol) in acetone (150 ml) and the mixture is boiled under reflux for 20 hours, the Solid was filtered and the filtrate was concentrated in vacuum. The residue was dissolved in EtOAc, washed with 1 N. KHSO4, water, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 15% EtOAc:85% hexane) to obtain the specified title compound (3.8 g, 90%).

Example A

Methyl ester of 4-carboxymethoxy-3-methylbenzoic acid

Triperoxonane acid (20 ml) was added to a solution of methyl ester 4-tert-butoxycarbonylmethyl-3-methylbenzoic acid from Example E (3.8 g, to 13.6 mmol) in dichloromethane (40 ml) and the mixture was stirred for 1 h at room temperature. Volatiles were removed in vacuo and subjected to azeotropic distillation with dichloromethane to obtain specified in the title compound (3.04 from g, 100%).

Example A

Methyl ester of 4-{2-[4-(3,3-dimethylbutyl)piperazine-1-yl]-2-oksidoksi}-3-methylbenzoic acid

WSCD (5,14 g of 27.2 mmol) and DMAP (1.64 g, to 13.6 mmol) was added to a solution of methyl ester 4-carboxymethoxy-3-methylbenzoic acid from Example E (3.04 from g to 13.6 mmol)in dichloromethane (100 ml) and triethylamine (5 ml). The mixture was stirred for 1 h at room temperature, then added the dihydrochloride of 1-(3,3-dimethylbutyl)piperazine from Example E4 (3,67 g, 14.9 mmol). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum. The residue was dissolved in EtOAc, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc) to obtain the specified title compound (2.8 g, 55%).

Example A

4-{2-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-2-oksidoksi}-3-methylbenzoic acid

1M Solution tribromide boron (2.66 ml of 2.66 mmol) at 0°C in an inert atmosphere was added dropwise to a solution of methyl ester 4-{2-[4-(3,3-dimethylbutyl)piperazine-1-yl]-2-oksidoksi}-3-methylbenzoic acid from Example E (500 mg, of 1.33 mmol) in dichloromethane (20 ml). The mixture was stirred for 20 h at room temperature, then was cooled to 0°C. was Added a 1M solution of tribromide boron (1,33 ml of 1.33 mmol) and the mixture was stirred for 2 h at room temperature. The solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The residue was purified by flash chromatography on silica gel (eluent; 1% acetic acid:5% methanol:94% chloroform) to obtain the specified title compound (350 mg, 72%).

Example EA

tert-Butyl ester 4-(2-br is macutil)piperazine-1-carboxylic acid

The solution bromoacetamide (8.5 ml, 97 mmol) in DHM (250 ml) at 0°C was treated dropwise with a solution of 1-BOC-piperazine (15,9, 85,3 mmol) and triethylamine (18,0 ml, 130 mmol) in DHM (150 ml). After complete addition, the mixture was stirred at room temperature for 4 h the Solution was washed with cooled on ice 1M HCl, feast upon. aq. Panso3, was dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 20% EtOAc:80% cyclohexane to 50% EtOAc:50% cyclohexane) to obtain the specified title compound (15.7 g, 60,0%).

Example 41b

Methyl ester 2-chloro-4-hydroxybenzoic acid

Example E41b.1

Methyl ester of 4-amino-2-chlorbenzoyl acid

A solution of 4-amino-2-chlorbenzoyl acid (5.3 g, 31 mmol) in methanol (100 ml) was treated with acetylchloride (5 ml) and then boiled under reflux for 16 hours. The solvent was evaporated in vacuum. The residue was dissolved in EtOAc, washed with saturated sodium bicarbonate, dried and concentrated in vacuum to obtain specified in the title compound as a purple solid, the 5.45 g, 95%.

Example 41b.2

2-Chloro-4-hydroxybenzoic acid

Methyl ester of 4-amino-2-chlorbenzoyl acid from Example 41b.1 (of 5.45 g, 29.4 mmol) was treated with 35% sulfuric acid solution (120 ml) and the mixture was stirred and heated until dissolution, then ohlord is whether to 0°C. Was added dropwise sodium nitrite (4,30 g, 62.5 mmol) in water (25 ml) and the mixture was stirred for 15 min at 0°C. was Added urea to destroy excess nitrite. Added copper nitrate (200 mg, 0.83 mmol) and was heated to 90°C. the Reaction mixture was cooled to room temperature, extracted with ethyl acetate X3, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 30% EtOAc: 70% hexane to 50% EtOAc: 49% hexane: 1% Asón) obtaining specified in the title compound (3.7 g, 73%).

Example 41b.3

Methyl ester 2-chloro-4-hydroxybenzoic acid

A solution of 2-chloro-4-hydroxybenzoic acid (3,70 g, with 21.4 mmol) in methanol (50 ml) was treated dropwise with thionyl chloride (2.4 ml, 32 mmol) and was stirred for 24 hours and the solvents were removed in vacuum. The residue was dissolved with ethyl acetate and washed the feast upon. the sodium bicarbonate, dried and the solvents were removed in vacuum. The residue was purified by column chromatography on silica gel (eluent 30% EtOAc: 70% cyclohexane) to give the desired product as a yellow solid, 3,68 g, 92%.

Example Is

tert-Butyl ester 4-[2-(4-carboxy-3-chlorophenoxy)acetyl]-piperazine-1-carboxylic acid

Example Is

tert-Butyl ester 4-[2-(3-chloro-4-ethoxycarbonylmethoxy)acetyl]-piperazine-1-carboxylic acid

Methyl ester 2-chloro-4-hydroxyben oinoi acid from Example 41b (2.0 g, 10.9 mmol) and tert-butyl ester 4-(2-bromoacetyl)piperazine-1-carboxylic acid from Example Ia (3,68 g, 12,0 mmol) in acetonitrile (30 ml) was treated with potassium carbonate (1.6 g, 11.5 mmol) and the mixture is boiled under reflux for 18 h before removing the solvent in vacuum. The residue was adsorbing on silica gel and purified by flash chromatography on silica gel (eluent; 20% EtOAc:80% cyclohexane to 50% EtOAc:50% cyclohexane to 70% EtOAc:30% cyclohexane) to obtain the specified title compound (4.5 g, 100%).

Example Is

tert-Butyl ester 4-[2-(4-carboxy-3-chlorophenoxy)acetyl]-piperazine-1-carboxylic acid

A solution of tert-butyl ester 4-[2-(3-chloro-4-methoxycarbonyl-phenoxy)acetyl]piperazine-1-carboxylic acid from Example Es (4.5 g, 10.8 mmol) in THF at 0°C was treated with trimethylsilanol potassium (1.6 g, 10.9 mmol) and the mixture was stirred at room temperature for 18 hours were Added to 1.6 g (10.9 mmol) of silanolate potassium and stirring continued at room temperature for 2 hours was Added to 1.6 g (10.9 mmol) of silanolate potassium and the mixture was stirred at 45°C for 2 hours the Mixture then was diluted with water and the THF was removed in vacuum. The residue was washed with a simple ether, cooled in an ice bath and brought to pH 5 solid KHSO4then it was extracted with l3and l3/isopropanol (90:10./vol.). The merged organization the technical substance was dried and the solvent was removed in vacuum to obtain specified in the title compound (3.7 g, 85%).

Example A

4-(3-tert-Butoxycarbonylamino)-3-methylbenzoic acid

Example A

tert-Butyl ether 4-pamakani acid

1M Tribromide boron (39 ml, 39 mmol) was added to a solution of butyrolactone (3 ml, 39 mmol) in dichloromethane (30 ml). The mixture was stirred for 20 h at room temperature, then extinguished by an excess of tert-butyl alcohol. The mixture was stirred for 2 h at room temperature, was diluted with dichloromethane, washed with saturated Panso3saturated PA2S2O3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel through Isolute (eluent; 5% EtOAc:95% hexane) to obtain the specified title compound (3 g, 34%).

Example A

Methyl ester of 4-(3-tert-butoxycarbonylamino)-3-methylbenzoic acid

Potassium carbonate (580 mg, 4.20 mmol) and potassium iodide (72 mg, 0.43 mmol) was added to a solution of methyl ester 4-hydroxy-3-methylbenzoic acid from Example E (293 mg, of 1.76 mmol) and tert-butyl methyl ether 4-pamakani acid from Example E (397 mg, 1.78 mmol) in acetone (50 ml). The mixture was boiled under reflux for 18 h, then the solid was filtered and the filtrate was concentrated in vacuum. The residue was dissolved in EtOAc, washed with water, then brine, dried and concentrated in vacuum. The residue was purified p is the flash-chromatography on silica gel (eluent; 20% EtOAc:80% petroleum ether) to obtain the specified title compound (414 mg, 76%).

Example A

4-(3-tert-Butoxycarbonylamino)-3-methylbenzoic acid

The monohydrate of lithium hydroxide (137 mg, 3,26 mmol) was added to a solution of methyl ester 4-(3-tert-butoxycarbonylamino)-3-methylbenzoic acid from Example E (414 mg, of 1.34 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 48 h at room temperature and concentrated in vacuum. The residue was dissolved in chloroform, acidified by 1M HCl, then washed with brine, dried and concentrated in vacuum to obtain specified in the title compound (275 mg, 70%).

Example E43

4-{4-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-4-oxobutyl}-3-methylbenzoic acid

Example A

Methyl ester of 4-{4-[4-(3,3-dimethylbutyl)piperazine-1-yl]-4-oxobutyl}-3-methylbenzoic acid

2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate (HBTU) (910 mg, 2.4 mmol) was added to a solution of methyl ester 4-(3-carboxypropyl)-3-methylbenzoic acid from Example E30 (378 mg, 1.6 mmol) and the hydrochloride of 1-(3,3-dimethylbutyl)piperazine from Example E4 (467 mg, 1.9 mmol) in dichloromethane (15 ml) and DIEA (0,836 ml, 4.8 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatog is the her on silica gel through Isolute (eluent; 5% methanol:95% dichloromethane) to obtain the specified title compound (582 mg, 94%).

Example A

4-{4-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-4-oxobutyl}-3-methylbenzoic acid

The monohydrate of lithium hydroxide (108 mg, 2.6 mmol) was added to a solution of methyl ester 4-{4-[4-(3,3-dimethylbutyl)piperazine-1-yl]-4-oxobutyl}-3-methylbenzoic acid from Example E (500 mg, 1.3 mmol) in THF (12 ml) and water (6 ml). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 2% acetic acid:4% methanol:94% dichloromethane)and then recrystallized from chloroform and petroleum ether to obtain specified in the title compound (439 mg, 91%).

Example A

4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-3-oxopropyl}-3-methylbenzoic acid

Example A

Methyl ester of 4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]-3-oxopropyl}-3-methylbenzoic acid

Oxalicacid (2.6 ml, 30 mmol) slowly at 0°C was added to a solution of methyl ester 4-(2-carboxyethyl)-3-methylbenzoic acid from Example E (5,33 g, 24 mmol) in dichloromethane (60 ml) and few drops DMF. The mixture was stirred for 2 h at room temperature, then concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in dichloromethane (30 ml) and at 0°Dobavlyali to a solution of hydrochloride of 1-(3,3-dimethylbutyl)piperazine from Example E4 (6.3 g, 26 mmol) in dichloromethane (45 ml) and DIEA (17 ml, 96 mmol). The mixture was stirred for 1 h at room temperature, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent; 5% methanol:95% dichloromethane) to obtain the specified title compound (8.5 g, 96%).

Example A

4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-3-oxopropyl}-3-methylbenzoic acid

The monohydrate of lithium hydroxide (2.4 g, of 56.7 mmol) was added to a solution of methyl ester 4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]-3-oxopropyl}-3-methylbenzoic acid from Example E (8.5 g, 22.7 mmol) in THF (200 ml) and water (100 ml). The mixture was stirred for 24 h at room temperature, then the solvents were removed in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 2% acetic acid:4% methanol:94% dichloromethane) to obtain the specified title compound (8.1 g, 99%).

Example a

3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid

Example A

4-((E)-2-tert-Butoxycarbonylamino)-3-methylbenzoic acid

The monohydrate of lithium hydroxide (384 mg, 9.2 mmol) was added to a solution of methyl ester 4-((E)-2-tert-butoxycarbonylamino)-3-methylbenzoic acid from Example A (1.27 g, 4.6 mmol) in THF (50 ml) and water (20 ml). The mixture was stirred for 20 h at room temperature, sytemrestore was removed in vacuum. The residue was dissolved in EtOAc, washed with 1M KHSO4, water, then brine, dried and concentrated in vacuum to obtain specified in the title compound (1.1 g, 92%).

Example A

tert-Butyl ether (E)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]acrylic acid

4-((E)-2-tert-Butoxycarbonylamino)-3-methylbenzoic acid from Example E (1.1 g, 4.2 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (720 mg, 3.6 mmol) was dissolved in dichloromethane (50 ml) and triethylamine (0.75 ml). Added DMAP (4,45 g, 3.6 mmol) and WSCD (1,36 g, 7.1 mmol) and the mixture is boiled under reflux for 2 days. The solution was diluted with dichloromethane, washed with 0.3 m S4saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc) to obtain the specified title compound (1.35 g, 82%).

Example A

tert-Butyl ester 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid

tert-Butyl ether (E)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]acrylic acid from Example E (436 mg, 0,99 mmol) was dissolved in methanol (40 ml) and was first made over 10% Pd/C catalyst (91 mg) for 5 h the Mixture was filtered through filter agent Celite® and iltram was concentrated in vacuo and subjected to azeotropic distillation with dichloromethane to obtain the specified in the title compound (426 mg, 96%).

Example A

3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid

Triperoxonane acid (5 ml) was added to a solution of tert-butyl ester 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid from Example E (413 mg, of 0.92 mmol) in dichloromethane (10 ml) and the mixture was stirred for 45 min at room temperature. The solvents were removed in vacuo and subjected to azeotropic distillation with dichloromethane. The residue was led with MeOH/Et2O obtaining specified in the title compound (322 mg, 90%).

Example A

(E)-3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]acrylic acid

Triperoxonane acid (5 ml) was added to a solution of tert-butyl methyl ether (E)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles-[f]azulene-9-carbonyl)phenyl]acrylic acid from Example E (338 mg, from 0.76 mmol) in dichloromethane (10 ml) and the mixture was stirred for 45 min at room temperature. The solvents were removed in vacuo and subjected to azeotropic distillation with dichloromethane to obtain specified in the title compound (337 mg, 80%).

Example A

3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-1-piperazine-1-improper-1-he

Example A

tert-Butyl ether 4-{3-[2-methyl-4-(3-methyl-4,10-is ihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)Fenilpropionat}piperazine-1-carboxylic acid

Rouger (1.54 g, 3.3 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid from Example e (850 mg, 2.25 mmol) and DMAP (275 mg, 2.25 mmol) in dichloromethane (20 ml) and DIEA (0,90 ml, 5.2 mmol). The mixture was stirred for 15 minutes at room temperature, then added 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (450 mg, 2.25 mmol). The mixture was boiled under reflux for 18 h, diluted with dichloromethane, washed with 0.3 m solution of KHSO4then saturated Panso3, was dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 5% methanol:95% EtOAc) to obtain specified in the connection header (1,09 g, 87%).

Example A

3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-1-piperazine-1-improper-1-he

tert-Butyl ether 4-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionyl}piperazine-1-carboxylic acid from Example E,1 (1,09 g of 1.95 mmol) was dissolved in methanol (20 ml) and the solution was added 4M HCl/dioxane (20 ml). The mixture was stirred for 3 h at room temperature, concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in methanol (30 ml) and ammonia (5 ml), then concentrated in vacuo. The residue was purified by fluorescence is W-chromatography on silica gel (eluent; 0,5% 35% ammonia:4,5% methanol: 95% dichloromethane to 1% 35% ammonia: 9% methanol: 90% dichloromethane) to obtain the specified title compound (759 mg, 73%).

Example A

{4-[3-(4-Cyclopropylmethyl-1-yl)propoxy]-3-forfinal}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanon

Example A

Ethyl ester of 4-(3-bromopropane)-3-Fermenting acid

1,3-Dibromopropane (2.2 g, 11.0 mmol), potassium carbonate (1.86 g, to 13.6 mmol) and potassium iodide (90 mg, 0.5 mmol) was added to ethyl ether, 3-fluoro-4-hydroxybenzoic acid from Example E27 (1.0 g, 5.4 mmol) in acetone (25 ml) and the mixture is boiled under reflux for 20 hours, the Solid was filtered and washed with EtOAc. The filtrate was concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was purified by flash chromatography on silica gel (eluent; 20% EtOAc: 80% hexane) to obtain the specified title compound (1.18 g, 71%).

Example A

Ethyl ester of 4-[3-(4-cyclopropylmethyl-1-yl)propoxy]-3-fermenting acid

The dihydrochloride of 1-cyclopropylbenzene (642 mg, 3.2 mmol, in accordance with the method described G.S.Poindexter, M.A.Bruce, K.L.Le Boulluec, I.Monkovic, Tet. Lett, 35(44), 7331-7334, 1994), potassium carbonate (2.1 g, of 15.2 mmol) and potassium iodide (50 mg, 0.3 mmol) was added to ethyl ether of 4-(3-bromopropane)-3-fermenting acid from Example E (1.2 g, 3.9 mmol) in acetone (25 ml). The mixture was heated with reverse what holodilniki for 20 hours The solid was filtered off, washed with EtOAc and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc then 1% 35% ammonia:9% methanol:90% dichloromethane) to obtain the specified title compound (1.0 g, 89%).

Example A

4-[3-(4-Cyclopropylmethyl-1-yl)propoxy]-3-Formentera acid

Ethyl ester of 4-[3-(4-cyclopropylmethyl-1-yl)propoxy]-3-fermenting acid from Example E (1.0 g, 2.9 mmol) was dissolved in dioxane (10 ml) was added 2 n NaOH solution (3 ml, 6.0 mmol). The mixture was heated at 60°C for 18 h, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent; 1% 35% ammonia: 19% methanol: 80% dichloromethane) to obtain the specified title compound (920 mg, 100%).

Example A

{4-[3-(4-Cyclopropylmethyl-1-yl)propoxy]-3-forfinal}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanon

HBTU (325 mg, 0.9 mmol) and 4M Hcl in dioxane (0.45 ml, 1.8 mmol) was added to a solution of 4-[3-(4-cyclopropylmethyl-1-yl)propoxy]-3-fermenting acid from Example A (230 mg, 0.7 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes was Added 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E65 (186 mg, 0.9 mmol) and DIEA (pH =9), and the mixture was stirred at room temperature for 18 hours the Mixture was heated at 60°C in ECENA 3 h, then was added HBTU (300 mg, 0.8 mmol). The mixture was heated at 60°C for 2 days, then the solvent was removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in EtOAc, washed with saturated NaHCOs, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to obtain brown solid identified as specified in the title compound (55 mg, 15%).

Example A

The dihydrochloride [3-fluoro-4-(3-piperazine-1-ylpropionic)phenyl]-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone

Example A

tert-Butyl ether 4-{3-[2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]propyl}piperazine-1-carboxylic acid

A solution of tert-butyl ester 4-[3-(4-carboxy-2-pertenece)propyl]piperazine-1-carboxylic acid from Example E39 (865 mg, 2.3 mmol) in dichloromethane (50 ml) was treated with triethylamine (up to pH 9), WSCD (865 mg, 4.5 mmol) and DMAP (276 mg, 2.3 mmol) and the mixture was stirred at room temperature for 10 minutes was Added 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (541 mg, 2.7 mmol). The mixture was boiled under reflux for 18 h, then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3, then brine and koncentrirane and in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 10% methanol:90% dichloromethane) to obtain the specified title compound (615 mg, 48%).

Example A

The dihydrochloride [3-Fluoro-4-(3-piperazine-1-ylpropionic)phenyl]-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone

A solution of tert-butyl ester 4-{3-[2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]propyl}piperazine-1-carboxylic acid from Example E (615 mg, of 1.09 mmol) in methanol (2 ml) at 0°C was treated with 4 N. HCl in dioxane (5 ml). The solution was allowed to warm to room temperature and was stirred for 1 h the Solvent was removed in vacuum to obtain a white foam, identified as specified in the title compound (585 mg, 100%).

Example E50

Bis(triptorelin) (4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}-3-forfinal)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone

3,3-Dimethylallyl aldehyde (120 mg, 1.20 mmol) and triethylamine (up to pH 9) was added to a solution of dihydrochloride [3-fluoro-4-(3-piperazine-1-ylpropionic)phenyl]-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (585 mg, of 1.09 mmol) in methanol/acetic acid (99:1, vol/about., 20 ml) and the mixture was stirred at room temperature for 1 h was Added cyanoborohydride sodium (103 mg, of 1.30 mmol) and the mixture was stirred at room is based temperature for 18 h, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent; 10% methanol:90% dichloromethane) to give (4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}-3-forfinal)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone that liofilizirovanny of water triperoxonane acid to obtain a white solid, identified as specified in the title compound (700 mg, 83%).

Example a

(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-{4-[3-(1-isobutylpyrazine-4-yl)propoxy]-3-were}metano

The solution samalanga aldehyde (0.36 mg, of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) was added to a solution of hydrochloride (3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-[3-methyl-4-(3-piperidine-4-ylpropionic)phenyl]methanone (2.6 mg, of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) and DIEA (0,0026 ml). The mixture was stirred at room temperature for 1 h, and then the solution was added triacetoxyborohydride sodium (1,59 mg, 0,0075 mmol) in DMF (0.05 ml). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=530,5.

Example A

(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-{2-fluoro-4-[3-(4-hexylpyridine-1-yl)propoxy]phenyl}metano

A solution of 1-Bromhexine (0,83 mg of 0.005 mmol) in DMF (0,ml) was added to a solution of dihydrochloride of (6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-[2-fluoro-4-(3-piperazine-1-ylpropionic)phenyl]methanone Example EA (2,85 mg, of 0.005 mmol) in DMF (0.05 ml) and triethylamine (0,0021 ml). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=583,6.

Example a

1-(4-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]propyl}piperazine-1-yl)alanon

The solution acetylchloride (0,39 mg, of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of dihydrochloride of (3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-[3-methyl-4-(3-piperazine-1-ylpropionic)phenyl]metanoia (Connection room 408) or 2.67 mg of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0,0035 ml). The mixture was stirred at room temperature for 1 h, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=503,2.

Example A

{4-[3-(4-Methanesulfonylaminoethyl-1-yl)propoxy]-3-were}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanon

The solution methanesulfonanilide (0,57 mg of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of dihydrochloride of (3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-[3-methyl-4-(3-piperazine-1-ylpropionic)phenyl]methanone (Connection room 408) or 2.67 mg of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0,0035 ml). The mixture was stirred at room temperature for 1 h, then the solvents were removed in vacuum the floor is the group specified in the connection header. (IRE)+: [M+H]+=539,2.

Example E55

1-(4-[1,3]Dioxolane-2-reparacin-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-he

HBTU (327 mg, 0.86 mmol) was added to a solution of 4-[1,3]dioxolane-2-ipipeline Example E (143 mg, of 0.91 mmol) and 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid from Example e (320 mg, 0.82 mmol) in dichloromethane (20 ml) and DIEA (0.7 ml, 4.02 mmol) and the mixture was stirred for 20 h at room temperature. Added dichloromethane and the solution washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 4% methanol:96% dichloromethane to 8% methanol:92% dichloromethane) to give a white solid identified as specified in the title compound (359 mg, 83%).

Example A

1-[4-(Furan-2-carbonyl)piperazine-1-yl]-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-he

A solution of HBTU (1.90 mg, of 0.005 mmol) in DMF (0.05 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid from Example e (1,95 mg of 0.005 mmol) in DMF (0.05 ml) and DIEA (0,0022 ml). The mixture was stirred at room temperature for 30 min, then was added a solution of 1-(2-furoyl)piperazine (0,90 mg of 0.005 mmol) in DMF (0.05 is the l). The mixture was stirred for 18 h at room temperature, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=553,4.

Example A

(E)-3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles-[f]azulene-9-carbonyl)phenyl]-1-[4-(2-piperidine-1-retil)-piperazine-1-yl]propenone

A solution of HBTU (1.90 mg, of 0.005 mmol) in DMF (0.05 ml) was added to a solution of (E)-3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]acrylic acid from Example E (1,95 mg of 0.005 mmol) in DMF (0.05 ml) and DIEA (0,0022 ml). The mixture was stirred at room temperature for 30 min, then was added a solution of 1-(2-piperidine-1-retil)piperazine (0,99 mg of 0.005 mmol) in DMF (0.05 ml). The mixture was stirred for 18 h at room temperature, then the solvents were removed in vacuum to obtain specified in the connection header.

Example a

1-{4-[(Butylmethylamine)methyl]piperidine-1-yl}-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-he

Example A

1-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionyl}piperidine-4-

the carbaldehyde

Pyridine para-toluensulfonate (85 mg, 0.34 mmol) was added to a solution of 1-(4-[1,3]dioxolane-2-reparacin-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-she's from Example E55 (614 mg, 1,16 mm is l) in acetone (20 ml) and water (20 ml). The mixture was boiled under reflux for 7 days, then the solvent was removed in vacuum. The remainder of pererestorani in EtOAc, washed with 0.3 m KHSO4, then brine, dried, concentrated in vacuo, then was led with chloroform and petroleum ether to obtain specified in the title compound (451 mg, 80%).

Example A

1-{4-[(Butylmethylamine)methyl]piperidine-1-yl}-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-he

A solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionyl}piperidine-4-carbaldehyde Example E (2,43 mg of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) was added to a solution of butylmethylamine (0.43 mg, of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) and the mixture was heated at 50°C for 3 h, then stirred at room temperature for 2 days. Solution was added triacetoxyborohydride sodium (1,59 mg, 0,0075 mmol) in DMF (0.05 ml) and the mixture was stirred for 20 h at room temperature. The solvents were removed in vacuum to obtain specified in the connection header. Mass spectrum (MS): (IRE)+:[M+H]+=557,6.

Example A

3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-1-[4-(2-morpholine-4-ylethylamine)piperidine-1-yl]propane-1-he

A solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles-[f]azulene-9-carbonyl)phenyl]propionyl}Pipa is one-4-it (Connection room 701) (2,36 mg, of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) was added to a solution of 2-morpholine-4-ylethylamine (0.65 mg, of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) and the mixture was heated at 50°C for 3 h, then stirred at room temperature for 2 days. Solution was added triacetoxyborohydride sodium (1,59 mg, 0,0075 mmol) in DMF (0.05 ml) and the mixture was stirred for 20 h at room temperature. The solvents were removed in vacuum to obtain specified in the connection header. MS: (IRE)+: [M+H]+=586,6.

Example E60

1-(4-Hexylpyridine-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-he

A solution of 1-Bromhexine (0,83 mg of 0.005 mmol) in DMF (0.05 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles-[f]azulene-9-carbonyl)phenyl]-1-piperazine-1-improper-1-she's from Example E (to 2.29 mg of 0.005 mmol) in DMF (0.05 ml) and triethylamine (0,0021 ml). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=543,4.

Example A

3-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-were]-1-(4-propylpiperazine-1-yl)propane-1-he

The solution Propionaldehyde (0,29 mg of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) was added to a solution of 3-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-were]-1-piperazine-1-improp the n-1-it (2,36 mg, of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) and DIEA (0,0026 ml). The mixture was stirred at room temperature for 1 h, and then the solution was added triacetoxyborohydride sodium (1,59 mg, 0,0075 mmol) in DMF (0.05 ml). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=515,5.

Example A

1-(4-Acetylpiperidine-1-yl)-3-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-were]propane-1-he

The solution acetylchloride (0,39 mg, of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of 3-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-were]-1-piperazine-1-improper-1-it (2,47 mg of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0,0035 ml). The mixture was stirred at room temperature for 20 h, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=535,5.

Example a

3-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-were]-1-(4-methanesulfonylaminoethyl-1-yl)propane-1-he

The solution methanesulfonanilide (0,57 mg of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of 3-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-were]-1-piperazine-1-improper-1-it (2.36 in mg, of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0,0035 ml). The mixture is PE is amasyali at room temperature for 20 h, then the solvent was removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=OF 551.3.

Example A

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]butane-1-he

4-{4-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-4-oxobutyl}-3-methylbenzoic acid from Example E43 (139 mg, and 0.37 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (75 mg, and 0.37 mmol) was dissolved in dichloromethane (5 ml) and DIEA (of € 0.195 ml, 1.11 mmol). Added WSCD (93 mg, 0.48 mmol) and DMAP (9 mg, 0.07 mmol) and the mixture is boiled under reflux for 3 days, then washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give a white powder identified as specified in the title compound (11 mg, 5%).

Example E65

N-Benzyl-3-[4-(2,3,4,5-tetrahydrobenzo[b]azepin-1-carbonyl)phenyl]-propionamide

Example A

4-((E)-2-Methoxycarbonylbenzyl)benzoic acid

Sodium hydride (60% dispersion in oil, of 1.46 g, 36.6 mmol) was added to a solution of 4-formylbenzoate acid (5.0 g, 33.3 mmol) in toluene (200 ml) and the mixture was stirred for 2 h at room temperature. Was added methyl(triphenylphosphonium)acetate (of 11.69 g of 35.0 mmol) and the mixture was heated with reverse Kholodilin the ohms for 20 hours The solvents were removed in vacuum and the residue pererestorani in dichloromethane and 1M Panso3. The layers were distributed and the aqueous layer was acidified using 1M HCl, then was extracted with chloroform. The organic layer was dried and concentrated in vacuum to obtain specified in the connection header (3,65 g, 53%).

Example A

Methyl ester (E)-3-[4-(2,3,4,5-tetrahydrobenzo[b]azepin-1-carbonyl)fenilalanina acid

WSCD (1,17 g, 6,16 mmol) was added to a solution of 4-((E)-2-methoxycarbonylbenzyl)benzoic acid from Example E (740 mg and 3.59 mmol), 2,3,4,5-tetrahydro-1H-benzo[b]azepine (445 mg, to 3.02 mmol) and DMAP (370 mg, to 3.02 mmol) in dichloromethane (40 ml) and triethylamine (0.7 ml, 5,02 mmol). The mixture was boiled under reflux for 42 h, then the solvents were concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M KHSO4, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 30% EtOAc:70% petroleum ether) to obtain the specified title compound (484 mg, 48%).

Example A

Methyl ester of 3-[4-(2,3,4,5-tetrahydrobenzo[b]azepin-1-carbonyl)phenyl]propionic acid

Methyl ester (E)-3-[4-(2,3,4,5-tetrahydrobenzo[b]azepin-1-carbonyl)phenyl]acrylic acid from Example E (485 mg, 1.44 mmol) was dissolved in methanol (60 ml) and was first made over 10% Pd/C catalyst (214 mg) for 2 hours the Mixture Phil is trevali through the filter agent Celite® and the filtrate was concentrated in vacuum to obtain specified in the header of the compound (415 mg, 85%).

Example A

3-[4-(2,3,4,5-Tetrahydrobenzo[b]azepin-1-carbonyl)phenyl]propionic acid

The monohydrate of lithium hydroxide (114 mg, of 2.72 mmol) was added to a solution of methyl ester 3-[4-(2,3,4,5-tetrahydrobenzo[b]azepin-1-carbonyl)phenyl]propionic acid from Example E (415 mg, of 1.23 mmol) in water (5 ml) and dioxane (20 ml). The mixture was stirred for 18 h at room temperature, then concentrated in vacuo. The residue was dissolved in chloroform, washed with 1M HCl solution, then brine, dried and concentrated in vacuum to obtain specified in the title compound (241 mg, 61%).

Example A

N-Benzyl-3-[4-(2,3,4,5-tetrahydrobenzo[b]azepin-1-carbonyl)phenyl]propionamide

A mixture of 3-[4-(2,3,4,5-tetrahydrobenzo[b]azepin-1-carbonyl)phenyl]propionic acid from Example E (57 mg, 0.18 mmol) and thionyl chloride (0.2 ml, is 2.74 mmol) in dichloromethane (6 ml) was boiled under reflux for 2 h, then the volatiles were removed in vacuum.

The residue was dissolved in dichloromethane (8 ml), then added benzylamine (of 0.022 ml, 0.20 mmol) and triethylamine (0.05 ml, 0.36 mmol). The mixture was stirred for 3 h at room temperature, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent; 30% petroleum ether: 70% EtOAc) to obtain the soft white solid, identified as specified in the header with the Association (to 36.5 mg, 50%).

Example A

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-3-[2-methyl-4-(2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)phenyl]propane-1-he

Oxalicacid (0,049 ml, 0.55 mmol) was slowly added to a solution of 4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]-3-oxopropyl}-3-methylbenzoic acid from Example A (100 mg, 0.28 mmol) in dichloromethane (10 ml) and few drops DMF. The mixture was stirred for 1 h at room temperature, then concentrated in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in dichloromethane (10 ml) was added DIEA (0,144 ml, 0.84 mmol) then 2-methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene from Example E5 (55 mg, 0.28 mmol). The mixture was stirred for 20 h at room temperature, then washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to obtain the soft white solid, identified as specified in the title compound (42 mg, 28%).

Example E67

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-3-[2-methyl-4-(6-methyl-3,4-dihydro-2H-quinoline-1-carbonyl)phenyl]propane-1-he

DMAP (51 mg, 0.42 mmol) and WSCD (161 mg, 0.84 mmol) was added to a solution of 4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]-3-oxopropyl}-3-methyl-benzoic acid from Example E (150 mg, 0.42 mmol) in dichloromethane (10 ml) is the triethylamine (0,176 ml, of 1.26 mmol) and the mixture was stirred for 30 min at room temperature. Added 6-methyl-1,2,3,4-tetrahydroquinolin (67 mg, 0.46 mmol) and the mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum. The remainder of pererestorani in EtOAC, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as specified in the title compound (12 mg, 6%).

Example E68

(4-{3-[1-(3,3-Dimethylbutyl)piperidine-4-yl]propoxy}-3-were)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanon

Example A

tert-Butyl ester 4-(3-hydroxypropyl)piperidine-1-carboxylic acid

tert-Butyl ester 4-(2-carboxyethyl)piperidine-1-carboxylic acid (1.0 g, 3.9 mmol, in accordance with the method described in J. Med. Chem., 41(14), 2492, 1998), was dissolved in THF (50 ml) and cooled to 0°C. was Slowly added 2M solution of boron in THF (3.9 ml, 7.8 mmol) and the mixture was stirred for 20 h at room temperature. Added water and the solvent was concentrated in vacuum. The residue was dissolved in EtOAC, acidified Panso3, washed with brine, dried and concentrated in vacuum to obtain specified in the connection header (938 mg, 99%).

Example A

the pet-Butyl ester 4-[3-(4-methoxycarbonyl-2-methylphenoxy)-propyl]piperidine-1-carboxylic acid

tert-Butyl ester 4-(3-hydroxypropyl)piperidine-1-carboxylic acid from Example E (400 mg, of 1.64 mmol) and methyl ester of 4-hydroxy-3-methylbenzoic acid from Example E (274 mg, of 1.64 mmol) was dissolved in THF (30 ml) and cooled to 0°C. was Added triphenylphosphine on the polymer (1.7 g, 2,46 mmol), then DEAD (0,387

ml of 2.46 mmol)and the mixture is boiled under reflux for 20 hours, the Resin was filtered off, washed with EtOAc and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel through Isolute (eluent; 20% EtOAC:80% cyclohexane) to obtain the specified title compound (340 mg, 53%).

Example A

tert-Butyl ester 4-[3-(4-carboxy-2-methylphenoxy)propyl]-piperidine-1-carboxylic acid

2M NaOH Solution (1.25 ml, 2.5 mmol) was added to tert-butyl ether 4-[3-(4-methoxycarbonyl-2-methylphenoxy)propyl]piperidine-1-carboxylic acid from Example E (340 mg, 0.87 mmol) in dioxane (10 ml) and the mixture was heated at 60°C for 20 hours was Added 2M NaOH solution (5 ml, 10 mmol) and the mixture was heated at 60°C for 20 h, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel through Isolute (eluent; 1% acetic acid:9% methanol:90% dichloromethane) to obtain the specified title compound (303 mg, 92%).

Example A

tert-Butyl ether 4-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azule the-9-carbonyl)phenoxy]propyl}piperidine-1-carboxylic acid

Rouger (224 mg, 0.48 mmol) and DMAP (39 mg, 0.32 mmol) was added to a solution of tert-butyl ester 4-[3-(4-carboxy-2-methylphenoxy)propyl]piperidine-1-carboxylic acid from Example E (120 mg, 0.32 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (70 mg, 0.35 mmol) in dichloromethane (5 ml) and DIEA (0,111 ml, 0.64 mmol). The mixture was boiled under reflux for 2 days, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to obtain the specified title compound (71 mg, 40%).

Example A

Hydrochloride (3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-[3-methyl-4-(3-piperidine-4-ylpropionic)phenyl]methanone

4M HCl solution in dioxane (1 ml) was added to a solution of tert-butyl ester 4-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]propyl}piperidine-1-carboxylic acid from Example E (71 mg, 0.13 mmol) in methanol (3 ml). The mixture was stirred for 20 h at room temperature, then the solvent was concentrated in vacuum. The residue is triturated with diethyl ether to obtain specified in the title compound (61 mg, 97%).

Example A

(4-{3-[1-(3,3-Dimethylbutyl)piperidine-4-yl]propoxy}-3-were)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanon

Acetic acid (0.05 ml) and 3,3-dimethylallyl aldehyde (0,024 ml to 0.19 mmol) was added to a solution of hydrochloride (3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-[3-methyl-4-(3-piperidine-4-ylpropionic)phenyl]methanone Example E (60 mg, 0.12 mmol) in methanol (2,45 ml) and triethylamine (0,026 ml to 0.19 mmol). The mixture was stirred at room temperature for 1 h, then was added triacetoxyborohydride sodium (40 mg, 0,19 mmol). The mixture was stirred at room temperature for 18 h, diluted with dichloromethane, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to obtain the soft white solid, identified as specified in the title compound (33 mg, 48%).

Example A

(4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]propoxy}-3-forfinal)-(2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)methanon

Example A

tert-Butyl ether 4-{3-[4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-fervency]propyl}piperazine-1-carboxylic acid

tert-Butyl ester 4-[3-(4-carboxy-2-pertenece)propyl]-piperazine-1-carboxylic acid from Example E39 (130 mg, 0.34 mmol) was dissolved in dichloromethane (5 ml) and few drops DMF. Was slowly added oxalicacid (0,059 ml of 0.68 mmol) and the mixture p is remedial for 30 min at room temperature. The solvent was concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in dichloromethane (5 ml) was added 1-benzyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene from Example Ia (100 mg, 0.34 mmol), then DIEA (0,176 ml of 1.02 mmol). The mixture was stirred for 2 h at room temperature, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to obtain the specified title compound (110 mg, 50%).

Example A

The dihydrochloride (1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]-azulene-6-yl)-[3-fluoro-4-(3-piperazine-1-ylpropionic)phenyl]methanone

tert-Butyl ether 4-{3-[4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-fervency]propyl}piperazine-1-carboxylic acid from Example A (110 mg, 0,17 mmol) was dissolved in methanol (5 ml) was added 4M HCl in dioxane (2 ml). The mixture was stirred for 20 h at room temperature, then concentrated in vacuo to obtain specified in the title compound (105 mg, 100%).

Example A

(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)-(4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}-3-forfinal)metano

The dihydrochloride (1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]-azulene-6-yl)-[3-fluoro-4-(3-piperazine-1-Lai is epoxy)phenyl]methanone Example A (105 mg, 0,17 mmol) was dissolved in methanol (2,45 ml) and triethylamine (of 0.07 ml, 0.50 mmol). Was added acetic acid (0.05 ml), then 3,3-dimethylallyl aldehyde (to 0.032 ml, 0.25 mmol) and the mixture was stirred for 1 h at room temperature. Added cyanoborohydride sodium (16 mg, 0.25 mmol) and the mixture was stirred for 3 h at room temperature, then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 5% methanol:95% dichloromethane) to obtain the specified title compound (102 mg, 95%).

Example A

(4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]propoxy}-3-forfinal)-(2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)methanon

(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)-(4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}-3-forfinal)methanon Example A (90 mg, 0.14 mmol) was dissolved in methanol (5 ml) and acetic acid (1 ml) and was first made over a catalyst 20 wt.% the palladium hydroxide (90 mg) within 8 hours the Mixture was filtered through filter agent Celite® and the filtrate was concentrated in vacuum. The residue was dissolved in dichloromethane, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35%ammonia:9.5% methanol; 90% dichloromethane) to give a white powder identified as specified in the title compound (39 mg, 51%).

Example E70

(4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]propoxy}-3-were)-(2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)methanon

Example A

tert-Butyl ether 4-{3-[4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylphenoxy]propyl}piperazine-1-carboxylic acid

tert-Butyl ester 4-[3-(4-carboxy-2-methylphenoxy)propyl]-piperazine-1-carboxylic acid (350 mg, of 0.92 mmol) was dissolved in dichloromethane (5 ml) and few drops DMF. Was slowly added oxalicacid (rate £ 0.162 ml, of 1.84 mmol) and the mixture was stirred for 30 min at room temperature. The solvent was concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in dichloromethane (10 ml) was added 1-benzyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene from Example Ia (268 mg, of 0.92 mmol) and then DIEA (of 0.48 ml, 2.77 mmol). The mixture was stirred for 2 days at room temperature, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to obtain the specified title compound (230 mg, 38%).

Example A

The dihydrochloride (1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamente]-azulene-6-yl)-[3-methyl-4-(3-piperazine-1-ylpropionic)phenyl]methanone

tert-Butyl ether 4-{3-[4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylphenoxy]propyl}piperazine-1-carboxylic acid from Example A (230 mg, 0.35 mmol) was dissolved in methanol (5 ml) was added 4M HCl in dioxane (2 ml). The mixture was stirred for 2 h at room temperature, then concentrated in vacuo and triturated with diethyl ether to obtain specified in the title compound (215 mg, 98%).

Example A

(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)-(4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy)-3-were)metano

The dihydrochloride (1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]-azulene-6-yl)-[3-methyl-4-(3-piperazine-1-ylpropionic)phenyl]methanone Example A (100 mg, 0.16 mmol) was dissolved in methanol (2,45 ml) and triethylamine (0,068 ml, 0.48 mmol). Was added acetic acid (0.05 ml), then 3,3-dimethylallyl aldehyde (0,031 ml, 0.24 mmol) and the mixture was stirred for 1 h at room temperature. Added cyanoborohydride sodium (16 mg, 0.24 mmol) and the mixture was stirred for 20 h at room temperature, then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated Panso3, then brine, dried and concentrated in vacuum to obtain specified in the title compound (98 mg, 96%).

Example A

(4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]propoxy}-3-ethylphenyl)-(2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)methanon

(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)-(4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}-3-were)methanon Example E (98 mg, 0.15 mmol) was dissolved in methanol (5 ml) and acetic acid (1 ml) and was first made over a catalyst 20 wt.% the palladium hydroxide (98 mg) for 8 hours the Mixture was filtered through glass fiber paper and the filtrate was concentrated in vacuum. The residue was dissolved in dichloromethane, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as specified in the title compound (17 mg, 20%).

Example a

N-(4-Chlorophenyl)-4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}-3-fluoro-N-methylbenzamide

Example A

tert-Butyl ester 4-(3-{4-[(4-chlorophenyl)methylcarbamoyl]-2-fervency}propyl)piperazine-1-carboxylic acid

Rouger (606 mg, 1.3 mmol) was added to a solution of tert-butyl ester 4-[3-(4-carboxy-2-pertenece)propyl]piperazine-1-carboxylic acid from Example E39 (382 mg, 1.0 mmol) in dichloromethane (20 ml) and DIEA (to pH 9). The mixture was stirred for 1 h at room temperature, then was added (4-chlorophenyl)methylamine (156 mg, 1.1 mmol). The mixture was stirred for 2 days at room temperature, then the solvents koncentrira is whether in vacuum. The residue was dissolved in EtOAC, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc) to obtain the specified title compound (210 mg, 41%).

Example A

The dihydrochloride of N-(4-chlorophenyl)-3-Fluoro-N-methyl-4-(3-piperazine-1-ylpropionic)benzamid

tert-Butyl ester 4-(3-{4-[(4-chlorophenyl)methylcarbamoyl]-2-fervency}propyl)piperazine-1-carboxylic acid from Example A (210 mg, 0.4 mmol) was dissolved in 4M HCl in dioxane (5 ml) and was stirred for 1 h at room temperature. The solvent was concentrated in vacuo and subjected to azeotropic distillation with toluene to obtain specified in the title compound (184 mg, 100%).

Example A

N-(4-Chlorophenyl)-4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}-3-fluoro-N-methylbenzamide

The dihydrochloride of N-(4-chlorophenyl)-3-fluoro-N-methyl-4-(3-piperazine-1-ylpropionic)benzamide Example E (184 mg, 0.4 mmol) was dissolved in methanol (4,95 ml) and triethylamine (0,167 ml, 1.2 mmol). Was added acetic acid (0.05 ml), then 3,3-dimethylallyl aldehyde (46 mg, 0.44 mmol) and the mixture was stirred for 1 h at room temperature. Added cyanoborohydride sodium (31 mg, 0.5 mmol) and the mixture was stirred for 20 h at room temperature, then concentrated in vacuo. The residue was purified by flash chromatography on si is imagele (eluent; 10% methanol:90% dichloromethane) to give a white foam, identified as specified in the title compound (77 mg, 37%).

Example E72

(4-{4-[4-(3,3-Dimethylbutyl)piperazine-1-yl]butoxy}-3-forfinal)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanon

Example A

Ethyl ester of 4-(4-bromobutoxy)-3-fermenting acid

1,4-Dibromobutane (2,34 g to 10.8 mmol), potassium carbonate (1.86 g, 13.5 mmol) and potassium iodide (90 mg, 0.5 mmol) was added to a solution of ethyl ester of 3-fluoro-4-hydroxybenzoic acid from Example E27 (1.0 g, 5.4 mmol) in acetone (25 ml) and the mixture is boiled under reflux for 20 hours, the Solid was filtered off, washed with EtOAc and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 15% EtOAc:85% hexane) to obtain specified in the connection header (1,38 g, 80%).

Example A

Ethyl ester of 4-{4-[4-(3,3-dimethylbutyl)piperazine-1-yl]butoxy}-3-fermenting acid

Hydrochloride of 1-(3,3-dimethylbutyl)piperazine from Example E4 (874 mg, 3.7 mmol), potassium carbonate (2.5 g, 18.0 mmol) and potassium iodide (60 mg, 0.4 mmol) was added to a solution of ethyl ester of 4-(4-bromobutoxy)-3-fermenting acid from Example A (1.4 g, 4.4 mmol) in acetone (35 ml) and the mixture is boiled under reflux for 20 hours, the Solid was filtered off, washed with EtOAc and the filtrate was concentrated in vacuum. About what's headed the remainder was purified by flash chromatography on silica gel (eluent; EtOAc to 1% 35% ammonia: 10% methanol:89% EtOAc) to obtain the specified title compound (1.35 g, 90%).

Example A

4-{4-[4-(3,3-Dimethylbutyl)piperazine-1-yl]butoxy}-3-Formentera acid

Sodium hydroxide (0.5 g, 13,2 mmol) and water (5 ml) was added to a solution of ethyl ester of 4-{4-[4-(3,3-dimethylbutyl)piperazine-1-yl]butoxy}-3-fermenting acid from Example E (1.35 g, 3.3 mmol) in dioxane (20 ml). The mixture was stirred for 1 h at room temperature, then was heated at 60°C for 20 hours, the Solvents were concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was purified by flash chromatography on silica gel (eluent; 1% 35% ammonia:19% methanol:80% chloroform) to obtain specified in the connection header (0,85 g, 67%).

Example A

(4-{4-[4-(3,3-Dimethylbutyl)piperazine-1-yl]butoxy}-3-Forfinal)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraethyleneglycol-9-yl)methanon

A mixture of 4-{4-[4-(3,3-dimethylbutyl)piperazine-1-yl]butoxy}-3-fermenting acid from Example E (190 mg, 0.5 mmol) and thionyl chloride (2 ml) in dichloromethane (5 ml) was boiled under reflux for 1 h the Solvent was concentrated in vacuo and the residue was dissolved in dichloromethane (10 ml). Was added 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (110 mg, 0.55 mmol) and DIEA (to pH 9). The mixture was stirred at room temperature for 2 days, concentri is ovale in vacuum. The residue was dissolved in EtOAC, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a colourless oil identified as specified in the title compound (48 mg, 17%).

Example A

(4-{2-[4-(3,3-Dimethylbutyl)piperazine-1-yl]ethoxy}-3-were)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanon

WSCD (58 mg, 0.30 mmol) and DMAP (20 mg, 0.15 mmol) was added to a solution of 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (37 mg, 0.20 mmol) and 4-{2-[4-(3,3-dimethylbutyl)piperazine-1-yl]ethoxy}-3-methylbenzoic acid from Example E40 (53 mg, 0.15 mmol) in dichloromethane (5 ml) and triethylamine (up to pH 9). The mixture was boiled under reflux for 2 days, then concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 10% methanol: 90% chloroform) to obtain the not quite white solid, identified as specified in the title compound (3.5 mg, 4%).

Example A

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-2-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]alanon

Oxalicacid (42 mg, 0.34 mmol) and 2 drops of DMF is ri 0°C was added to a solution of 4-{2-[4-(3,3-dimethylbutyl)piperazine-1-yl]-2-oksidoksi}-3-methylbenzoic acid from Example A (100 mg, 0.28 mmol) in dichloromethane (5 ml). The mixture was stirred for 1 h at room temperature, concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in dichloromethane (5 ml) was added a solution of 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (61 mg, 0.31 mmol) in dichloromethane (1 ml) and triethylamine (up to pH 9). The mixture was stirred for 2 days at room temperature, then concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified twice by flash chromatography on silica gel (eluent; 5% methanol: 95% chloroform to 10% methanol: 90% chloroform, then 5% methanol: 95% EtOAc to 10% methanol: 90% EtOAc) to give a white solid identified as specified in the title compound (25 mg, 17%).

Example E75

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-2-[4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]alanon

Example A

(4-Benzyloxyphenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]-azulene-9-yl)methanon

Oxalicacid (0,41 ml, 4.7 mmol) and few drops of DMF were added to a solution of 4-(benzyloxy)benzoic acid (855 mg, 3.7 mmol) in dichloromethane (15 ml). The mixture was stirred for 2 h at room temperature, concentrated in vacuo and subjected to azeotrope is distilled with toluene. The residue was dissolved in dichloromethane (10 ml) was added a solution of 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (500 mg, 2.5 mmol) in dichloromethane (10 ml) and triethylamine (of 0.87 ml, 6.2 mmol). The mixture was stirred for 20 h at room temperature and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc to 3% methanol:97% EtOAc) to obtain the specified title compound (820 mg, 80%).

Example A

(4-Hydroxyphenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]-azulene-9-yl)methanon

(4-Benzyloxyphenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanon Example E (800 mg, 1,95 mmol) was dissolved in methanol (100 ml) and was first made over 10% Pd/C catalyst (400 mg) for 7 hours the Mixture was filtered through filter agent Celite®, washed with chloroform and methanol and the filtrate was concentrated in vacuum to obtain specified in the title compound (140 mg, 22%).

Example A

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-2-[4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]alanon

Potassium carbonate (104 mg, from 0.76 mmol) was added to a mixture of 2-bromo-1-[4-(3,3-dimethylbutyl)piperazine-1-yl]ethanone Example A (110 mg, 0.38 mmol) and (4-hydroxyphenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example A (90 mg, 0.28 mmol) in acetonitrile (5 ml). The mixture was heated to reverse the m refrigerator for 20 h, then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with 5% solution of knso3, was dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give a white powder identified as specified in the title compound (21 mg, 11%).

Example A

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]butane-1-he

Example A

tert-Butyl ester 4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]butyric acid

WSCD (391 mg, of 2.06 mmol) and DMAP (133 mg, of 1.09 mmol) was added to a solution of 4-(3-tert-butoxycarbonylamino)-3-methylbenzoic acid from Example E (275 mg, of 0.94 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (191 mg, 0.95 mmol) in dichloromethane (30 ml) and triethylamine (0.28 in ml, a 2.01 mmol). The mixture was boiled under reflux for 72 h, washed with 0.3 m KHSO4saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc) to obtain the specified title compound (80 mg, 18%).

Example A

4-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]butyric acid

Triperoxonane acid (5 ml) is obavljale to a solution of tert-butyl ester 4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[Azulen-9-carbonyl)phenoxy]butyric acid of Example A (80 mg, 0,17 mmol) in dichloromethane (10 ml). The mixture was stirred for 2 h at room temperature, concentrated in vacuo and subjected to azeotropic distillation with dichloromethane obtaining specified in the title compound (71 mg, 100%).

Example A

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)Phenoxy]butane-1-he

HBTU (101 mg, 0.27 mmol) was added to a solution of 4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]butyric acid from A (71 mg, 0,17 mmol) dihydrochloride and 1-(3,3-dimethylbutyl)piperazine from Example E4 (54 mg, 0.22 mmol) in dichloromethane (10 ml) and DIEA (0.15 ml, 0.86 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 6% methanol:94% dichloromethane) to give a white powder identified as specified in the title compound (52 mg, 53%).

Example E77

Piperidine-4-ymetray ester of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid

Example A

Benzyl ether of 4-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionyloxy}piperidine-1-carboxylic acid

WSCD (107 mg, 0.54 mmol) and DMAP (33 mg, 0.7 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid from Example e (106 mg, 0.27 mmol) and benzyl ester 4-hydroxyethylpiperazine-1-carboxylic acid (81 mg, 0.32 mmol) in dichloromethane (5 ml) and DIEA (0,095 ml, 0.54 mmol). The mixture was stirred for 3 h at room temperature, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel through Isolute (eluent; EtOAc) to obtain the specified title compound (44 mg, 26%).

Example A

Piperidine-4-ymetray ester of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid

Benzyl ether of 4-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionyloxy}piperidine-1-carboxylic acid from Example E (44 mg, 0.07 mmol) was dissolved in methanol (5 ml) and was first made over 10% Pd/C catalyst (5 mg) for 2 hours the Mixture was filtered through filter agent Celite® and the filtrate was concentrated in vacuum to obtain a white powder, identified as specified in the title compound (34 mg, 98%).

Example A

Methyl(3-chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles-[f]azulene-9-carbonyl)phenoxy)acetate

Diisopropylethylamine (2,1 ml of 12.0 mmol), dimethylaminopyridine (0.74 g, 6.0 mmol), Rouger® (4,20 g, 9.0 mmol) and 3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene from Example E2 (1.28 g, 6.0 mmol) was added to a solution of Tr is t-butyl 4-(2-(4-carboxy-3-chlorophenoxy)acetyl)piperazine-1-carboxylate from Example E (2,39 g, 6.0 mmol) in dichloromethane (50 ml) and the mixture is boiled under reflux for 20 hours the Reaction mixture was cooled, diluted with dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate, dried and concentrated in vacuum. The residue was dissolved in methanol (150 ml) and was treated with a 4M solution of hydrochloride in dioxane (50 ml) with cooling in an ice bath. The solution was stirred at room temperature for 16 hours, the Reaction mixture was evaporated and the residue suspended in water and washed with chloroform. The aqueous solution was treated with solid sodium bicarbonate until basic pH values, were extracted with chloroform, dried and evaporated. The residue was purified by flash chromatography on silica gel (eluent; EtOAc, followed by a gradient from 2% to 10% methanol:98% to 90% EtOAc) to give a white solid identified as specified in the header connection (0,53 g, 20%).

Example E79

1-(4-Hydroxyethylpiperazine-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-he

Sodium borohydride (12 mg, 0.32 mmol) was added to a solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionyl}piperidine-4-carbaldehyde Example E (74 mg, 0.15 mmol) in methanol (6 ml). The mixture was stirred for 1 h at room temperature, was acidified using 1M HCl and conc is listed in the vacuum. The residue was dissolved in EtOAc, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was led from chloroform and petroleum ether to obtain a white powder identified as specified in the title compound (28 mg, 38%).

Example E80

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-were]propane-1-he

Example A

tert-Butyl ester 3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-were]propionic acid

Sodium hydride (14 mg, 0.34 mmol) at 0°C was added to a solution of tert-butyl ester 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid from Example a (125 mg, 0.28 mmol) in DMF (2 ml). The mixture was stirred for 20 min at room temperature, then was cooled to 0°C. was Added methyliodide (0,09 ml, 1.4 mmol) and the mixture was stirred for 20 h at room temperature. Added EtOAc and the mixture is washed with 0.3 m KHSO4, then brine, dried, concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was purified by flash chromatography on silica gel through Isolute (eluent; EtOAc) to obtain the specified title compound (46 mg, 36%).

Example A

3-[4-(3,4-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)2-were]propionic acid

To tert-butyl ether, 3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-were]propionic acid from Example E (46 mg, 0.10 mmol) in dichloromethane (5 ml) was added triperoxonane acid (2 ml). The mixture was stirred for 2 h at room temperature, then concentrated in vacuo to obtain specified in the title compound (40 mg, 100%).

Example A

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-were]propane-1-he

Oxalicacid (0,018 ml, 0.20 mmol) was added to a solution of 3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-were]propionic acid from Example E (40 mg, 0.10 mmol) in dichloromethane (5 ml) and few drops DMF. The mixture was stirred for 1 h at room temperature, concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in dichloromethane (5 ml) was added 1-(3,3-dimethylbutyl)the piperazine dihydrochloride from Example E4 (30 mg, 0.12 mmol) and DIEA (0,052 ml, 0.30 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated NaHC3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give a white powder identified as listed is in the title compound (36 mg, 65%).

Example A

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-4-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-carbonyl)phenyl]butane-1-he

Example A

tert-Butyl ester 1-(4-{4-[4-(3,3-dimethylbutyl)piperazine-1-yl]-4-oxobutyl}-3-methylbenzoyl)-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-carboxylic acid

WSCD (58 mg, 0.30 mmol) and DMAP (18 mg, 0.15 mmol) was added to a solution of 4-{4-[4-(3,3-dimethylbutyl)piperazine-1-yl]-4-oxobutyl}-3-methylbenzoic acid from Example E43 (55 mg, 0.15 mmol) and tert-butyl ether 1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-carboxylic acid (73 mg, 0.30 mmol) in dichloromethane (3 ml) and DIEA (0,052 ml, 0.30 mmol). The mixture was boiled under reflux for 5 days, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to obtain the specified title compound (25 mg, 28%).

Example A

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-4-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-carbonyl)phenyl]butane-1-he

tert-Butyl ester 1-(4-{4-[4-(3,3-dimethylbutyl)piperazine-1-yl]-4-oxobutyl}-3-methylbenzoyl)-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-carboxylic acid from Example E (25 mg, 0.04 mmol) was dissolved in methanol (2 ml) was added 4M HCl in dioxane (2 ml). The mixture was stirred for 1 h at room temperature, then concentri is ovale in vacuum to obtain a white powder, identified as specified in the title compound (6 mg, 28%). (IRE)+: [M+H]+=505,5.

Example A

4-[4-(7,8-Dihydro-6N-5-oxa-9-athensallowed-9-carbonyl)-2-were]-1-[4-(3,3-dimethylbutyl)piperazine-1-yl]butane-1-he

WSCD (58 mg, 0.30 mmol) and DMAP (18 mg, 0.15 mmol) was added to a solution of 4-{4-[4-(3,3-dimethylbutyl)piperazine-1-yl]-4-oxobutyl}-3-methylbenzoic acid from Example E43 (55 mg, 0.15 mmol) and 6,7,8,9-tetrahydro-5-oxa-9-azabenzopyrene (44 mg, 0.30 mmol) in dichloromethane (3 ml) and DIEA (0,052 ml, 0.30 mmol). The mixture was boiled under reflux for 5 days, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia;9.5% methanol:90% dichloromethane) to give a white solid identified as specified in the title compound (6 mg, 10%).

Example a

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]pentane-1-he

Example A

Methyl ester 5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]pentanol acid

WSCD (822 mg, 4.3 mmol) and DMAP (273 mg, 2.2 mmol) was added to a solution of 4-(4-ethoxycarbonylbutyl)-3-methylbenzoic acid from Example e (571 mg, 2.3 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (424 mg, 2.1 mmol) in dihl methane (50 ml) and triethylamine (0.6 ml, 4.3 mmol). The mixture was boiled under reflux for 72 h, diluted with dichloromethane, washed with 0.3 m KHSO4saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc to 5% triethylamine;95% EtOAc) to obtain the specified title compound (424 mg, 46%).

Example A

5-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]pentane acid

The monohydrate of lithium hydroxide (120 mg, of 2.86 mmol) was added to a solution of methyl ester 5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]pentanol acid from Example E (410 mg, 0.95 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 24 h at room temperature and concentrated in vacuum. The residue was acidified using 1M HCl and was extracted with chloroform. The organic layer was washed with brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 3% acetic acid:7% methanol:90% chloroform) to obtain the specified title compound (105 mg, 26%).

Example A

1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]pentane-1-he

HBTU (104 mg, 0.27 mmol) was added to a solution of 5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-ka is bonyl)phenyl]pentanol acid from A (105 mg, 0.25 mmol) dihydrochloride and 1-(3,3-dimethylbutyl)piperazine from Example E4 (69 mg, 0.28 mmol) in DMF (10 ml) and DIEA (0.2 ml, 1.15 mmol). The mixture was stirred for 24 h at room temperature, then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 4% methanol:96% dichloromethane to 8% methanol:92% dichloromethane) to give a white solid identified as specified in the title compound (88 mg, 62%).

Example A

1-(4-Hydroxypiperidine-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-he

Sodium borohydride (4 mg, 0.1 mmol) was added to a solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-propionyl}piperidine-4-it (Connection room 701) (50 mg, 0.11 mmol) in methanol/acetic acid (99:1, vol/about., 100 ml) and the mixture was stirred at room temperature for 1 h the Newly added sodium borohydride (4 mg, 0.11 mmol) and the mixture was stirred for 1 h at room temperature, then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum to obtain a white powder identified as specified the title compound (28 mg, 56%).

Example E85

1-(4-Cyclobutylmethyl-1-yl)-2-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]alanon

Example A

Methyl ester 4-[2-(4-cyclobutylmethyl-1-yl)-2-oxoethyl]-3-methylbenzoic acid

Oxalicacid (0,36 ml, 3.3 mmol) was added to a solution of methyl ester 4-carboxymethyl-3-methylbenzoic acid from Example e (687 mg, 3.3 mmol) in dichloromethane (20 ml) and few drops DMF. The mixture was stirred for 3 h at room temperature, concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in dichloromethane (10 ml) and at 0°C was added to a solution of dihydrochloride of 1-cyclobutanecarbonitrile (750 mg, 3.3 mmol) in dichloromethane (10 ml) and DIEA (1.73 ml, 9.9 mmol). The mixture was stirred for 20 h at room temperature and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 3% methanol:97% dichloromethane) to obtain the specified title compound (528 mg, 46%).

Example A

4-[2-(4-Cyclobutylmethyl-1-yl)-2-oxoethyl]-3-methylbenzoic acid

The monohydrate of lithium hydroxide (122 mg, 2.9 mmol) was added to a solution of methyl ester 4-[2-(4-cyclobutylmethyl-1-yl)-2-oxoethyl]-3-methylbenzoic acid from Example E (500 mg, 1.4 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 20 h at to matnog temperature and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 3% acetic acid:7% methanol:90% chloroform) to obtain the specified title compound (300 mg, 63%).

Example A

1-(4-Cyclobutylmethyl-1-yl)-2-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]alanon

WSCD (76 mg, 0,39 mmol) and DMAP (7 mg, 0.06 mmol) was added to a solution of 4-[2-(4-cyclobutylmethyl-1-yl)-2-oxoethyl]-3-methyl-benzoic acid from Example A (100 mg, 0.30 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[1]azulene from Example E11 (61 mg, 0.30 mmol) in dichloromethane (20 ml) and DIEA (0.16 ml, of 0.91 mmol). The mixture was boiled under reflux for 20 h and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 4% methanol: 96% dichloromethane, 6% methanol: 94% dichloromethane to 1% 35% ammonia: 7% methanol: 92% dichloromethane) to obtain the not quite white solid, identified as specified in the title compound (50 mg, 32%).

Example A

1-(4-Cyclopropanemethylamine-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-he

Example A

Methyl ester of 4-(3-{4-[(tert-butoxycarbonylamino)-methyl]piperidine-1-yl}-3-oxopropyl)-3-methylbenzoic acid

Oxalicacid (1,26 ml, 14.4 mmol) was added to a solution of methyl ester 4-(2-carbox is ethyl)-3-methylbenzoic acid from Example E (1.60 g, 7.2 mmol) in dichloromethane (50 ml) and few drops DMF. The mixture was stirred for 1 h at room temperature, concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in dichloromethane (50 ml) was added DIEA (2.5 ml, 14.4 mmol) and tert-butyl methyl ether cyclopropylidene-4-iletilerinindeki acid from Example E38 (1,83 g, 7.2 mmol) in dichloromethane (5 ml). The mixture was stirred for 2 h at room temperature, was diluted with dichloromethane, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 50% EtOAc:50% cyclohexane) to obtain the specified title compound (1.42 g, 43%).

Example A

4-(3-{4-[(tert-Butoxycarbonylamino)methyl]piperidine-1-yl}-3-oxopropyl)-3-methylbenzoic acid

The monohydrate of lithium hydroxide (142 mg, 3.4 mmol) was added to a solution of methyl ester 4-(3-{4-[(tert-butoxycarbonylamino)-methyl]piperidine-1-yl}-3-oxopropyl)-3-methylbenzoic acid from Example E (1,41 g, 3.1 mmol) in THF (20 ml) and water (2 ml). The mixture was stirred for 16 h at room temperature, then was added 1M NaOH solution (5 ml). The mixture was heated at 60°C for 3 h, then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M HCl, then brine, dried and concentrated in the Aquum obtaining specified in the title compound (1.25 g, 91%).

Example A

tert-Butyl ether cyclopropyl-(1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionyl}-piperidine-4-ylmethyl)carbamino acid

WSCD (1.08 g, 5.6 mmol) and DMAP (343 mg, 2.8 mmol) was added to a solution of 4-(3-{4-[(tert-butoxycarbonylamino)methyl]piperidine-1-yl}-3-oxopropyl)-3-methylbenzoic acid from Example E (1,25 g, 2.8 mmol) in dichloromethane (100 ml) and triethylamine (0,783 ml, 5.6 mmol). The mixture was stirred for 1 h at room temperature, then added 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (676 mg, 3.4 mmol). The mixture was boiled under reflux for 2 days, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 2% methanol:98% EtOAc to 5% methanol:95% EtOAc) to obtain the specified title compound (1.1 g, 62%).

Example A

1-(4-Cyclopropanemethylamine-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-he

tert-Butyl ether cyclopropyl-(1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionyl}-piperidine-4-ylmethyl)carbamino acid from Example A (220 mg, 0.35 mmol) was dissolved in methanol (5 ml) was added 4M solution of HCl in dioxane (5 ml). The mixture peremeci the Ali for 2 h at room temperature, then was concentrated in vacuum to obtain not quite white solid, identified as specified in the title compound (189 mg, 95%).

Example E87

Hydrochloride N-cyclopropyl-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-N-piperidine-4-ylmethylphosphonate

Example A

tert-Butyl ester 4-[(cyclopropyl-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionyl}-amino)methyl]piperidine-1-carboxylic acid

Rouger (238 mg, 0.51 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid from Example e (200 mg, 0.51 mmol) and tert-butyl methyl ether 4-cyclopropanemethylamine-1-carboxylic acid (130 mg, 0.51 mmol) in dichloromethane (10 ml) and DIEA (of 0.18 ml of 1.02 mmol). The mixture was stirred for 4 days at room temperature, diluted with EtOAc, washed with 5% knso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 5% methanol:95% dichloromethane) to obtain the specified title compound (235 mg, 73%).

Example A

Hydrochloride N-cyclopropyl-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-N-piperidine-4-ylmethylphosphonate

tert-Butyl ester 4-[(cyclopropyl-{3-[2-methyl-4-(3-methyl-4,10-d the hydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionyl}-amino)methyl]piperidine-1-carboxylic acid from Example E (235 mg, of 0.37 mmol) was dissolved in 4M HCl in dioxane (5 ml). The mixture was stirred for 1 h at room temperature, concentrated in vacuo and subjected to azeotropic distillation with toluene. The residue was dissolved in 1M HCl, washed twice with dichloromethane and liofilizirovanny with getting not quite white solid, identified as specified in the title compound (82 mg, 39%).

Example A

Ethyl ester of 1-methyl-5-(3-methyl-2-nitrophenylamino)-1H-pyrazole-4-carboxylic acid

The cesium carbonate (35.2 g, 108 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.4 g, 0.7 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.2 g, 0.2 mmol) was added to a solution of ethyl 5-amino-1-methylpyrazole-4-carboxylate (15.3 g, 90 mmol) in dioxane (50 ml) under inert atmosphere. Solution was added 3-bromo-2-nitrotoluene (16.2 g, 75 mmol) in dioxane (10 ml) and the mixture was stirred for 30 min at room temperature, then boiled under reflux for 72 hours, the Suspension was filtered through filter agent Celite®, washed with EtOAc and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 50% EtOAc: 50% petroleum ether, then recrystallized from EtOAc/petroleum ether to obtain specified in the title compound (12.5 g, 45%).

Example A

Ethyl ester of 5-amino-1-ethyl-1H-pyrazole-4-carboxylic acid

Three is Tramin (19.6 ml, 144 mmol) was carefully added to a solution of ethyl (ethoxymethylene)cyanoacetate (10.1 g, 60 mmol) and oxalate acylhydrazone (9,9 g, 66 mmol) in ethanol (200 ml). The mixture was boiled under reflux for 24 h, then concentrated in vacuo. The remainder of pererestorani in EtOAc, washed with 5% solution of knso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 25% petroleum ether: 75% EtOAc) to obtain the specified title compound (8.8 g, 80%).

Example along the E90

3-Fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylated 1-cyclopropylmethyl-4-carboxylic acid

Example A

tert-Butyl ester of [3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]carbamino acid

A mixture of 4-(tert-butoxycarbonylamino)-2-fermenting acid from Example E2 (1.35 g, 5.0 mmol), 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E11 (1.0 g, 5.0 mmol) and Rouger (3.03 g, 6.5 mmol) in dichloromethane (25 ml) and DIEA (1.31 ml, 7.5 mmol) was boiled under reflux for 18 hours, After cooling to room temperature the mixture is washed with 5% knso3, 1M HCl, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc) to obtain the specified title compound (1.5 g, 56%).

Example A

Hydrochloride (4-aminomethyl-2-forfinal)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone

tert-Butyl ester of [3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]carbamino acid from Example E (1,25 g, 2.8 mmol) was brought into reaction with 4 N. HCl/dioxane using a method similar to that described for Example A, obtaining specified in the title compound (1.0 g, 97%).

Example A

3-Fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylated 1-cyclopropylmethyl-4-carboxylic acid

HBTU (227 mg, 0.6 mmol) was added to a solution of 1-cyclopropylmethyl-4-carboxylic acid from Example Ia (99 mg, 0.45 mmol) in DMF (5 ml) and DIEA (to pH 9). The mixture was stirred at room temperature for 1 h were Added hydrochloride (4-aminomethyl-2-forfinal)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (116 mg, 0.3 mmol) and the mixture was stirred at room temperature for 18 hours the Solvent was removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in EtOAc, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 1% 35% ammonia:19% methanol:80% dichloromethane) to obtain white solid washes the VA, identified as specified in the header connection (71,5 mg, 46%).

Example A

The hydrochloride of N-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]-2-piperidine-4-ylacetamide

A solution of tert-butyl ester 4-{[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylcarbamoyl]methyl}piperidine-1-carboxylic acid (Compound number 1067) (156 mg, 0.27 mmol) was brought into reaction with 4 N. HCl/dioxane using a method similar to that described for Example A, obtaining specified in the title compound (135 mg, 97%).

Example A

2-[1-(3,3-Dimethylbutyl)piperidine-4-yl]-N-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]ndimethylacetamide

3,3-Dimethylallyl aldehyde (0,048 ml, 0.38 mmol) was added to a solution of N-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]-2-piperidine-4-ylacetamide Example E (130 mg, 0.25 mmol) in methanol/acetic acid (49:1, vol/about., 2.5 ml) and the mixture was stirred at room temperature for 1 h was Added cyanoborohydride sodium (24 mg, 0.38 mmol) and the mixture was stirred at room temperature for 18 h, then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on forces is the Kagel through Isolute (eluent; 1,5% 35% ammonia: 15% methanol; 83,5% dichloromethane) to give a white solid identified as specified in the title compound (107 mg, 75%).

Example A

2-Chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylated 1-propylpiperidine-4-carboxylic acid

A solution of propionic aldehyde (0,29 mg of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) was added to a solution of the hydrochloride of 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine piperidine-4-carboxylic acid (Compound number 1109) (2.8 mg, of 0.005 mmol) in 1,2-dichlorethane (0.05 ml) and DIEA (0,0026 ml). The mixture was stirred at room temperature for 1 h, and then the solution was added triacetoxyborohydride sodium (1,59 mg, 0,0075 mmol) in DMF (0.05 ml). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=521,4.

Example A

N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]-2-(1-hexylpyridine-4-yl)ndimethylacetamide

A solution of 1-Bromhexine (0,83 mg of 0.005 mmol) in DMF (0.05 ml) was added to a solution of the hydrochloride of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]-2-piperidine-4-ylacetamide (Connection room 1110) (2,82 mg of 0.005 mmol) in DMF (0.05 ml) and triethylamine (0,0021 ml). The mixture was stirred for 20 h p and room temperature, then the solvent was removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=575,7.

Example E95

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzyl]-3-(1-Propionaldehyde-4-yl)propionamide

The solution propionitrile (0,46 mg of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of the hydrochloride of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzyl]-3-piperidine-4-ylpropionic (Connection room 1108) (2,97 mg of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0,0035 ml). The mixture was stirred at room temperature for 1 h, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=577,4.

Example A

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzyl]-3-(1-acanaloniidae-4-yl)propionamide

The solution acanaloniidae (0.64 mg, of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of the hydrochloride of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzyl]-3-piperidine-4-ylpropionic (Connection room 1108) (2,97 mg of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0,0035 ml). The mixture was stirred at room temperature for 1 h then the solvent was removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=613,4.

Example A

4-Nitrobenzyloxy ether 4-{2-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzylamino]-ethyl}piperidine-1-carboxylic acid

A solution of 4-nitrobenzenesulfonate (1.08 mg, of 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of the hydrochloride of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzyl]-3-piperidine-4-ylpropionic (Connection room 1108) (2,97 mg of 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0,0035 ml). The mixture was stirred at room temperature for 1 h, then the solvents were removed in vacuum to obtain specified in the connection header. (IRE)+: [M+H]+=700,5, 702,5.

Example A

4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-forbindelse propane-1-sulfonic acid

Example A

tert-Butyl ester [4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]carbamino acid

A mixture of 4-(tert-butoxycarbonylamino)-3-fermenting acid from Example E3 (1,38 g, 5.1 mmol) and 3,6-dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E2 (1.0 g, 4.7 mmol) in dichloromethane (20 ml) at room temperature was treated with DIEA (2,44 ml, 14.0 mmol), DMAP (627 mg, 5.1 mmol) and WSCD (1,16 g, 6.1 mmol). The solution was boiled under reflux for 2 days, then washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel through Isolute (eluent; EtOAc) to obtain specified in the connection header (129 g, 59%).

Example A

Hydrochloride (4-aminomethyl-3-forfinal)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone

tert-Butyl ester [4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]carbamino acid from Example E (1.29 g, 2.8 mmol) was brought into reaction with 4 N. HCl/dioxane using a method similar to that described for Example A, obtaining specified in the title compound (1.1 g, 99%).

Example A

4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-forbindelse propane-1-sulfonic acid

1-Propanesulfonate (to 0.016 ml, 0.14 mmol) at room temperature was added to a solution of hydrochloride (4-aminomethyl-3-forfinal)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (50 mg, 0.12 mmol) in dichloromethane (2 ml) and triethylamine (of 0.038 ml, 0.27 mmol). The mixture was stirred for 1 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as specified in the title compound (30 mg, 51%).

Example A

N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]formamide

Formic acid (0,85 ml of 22.5 mmol) and acetic anhydride (1.4 ml, 13.5 mmol) were combined and stirred the for 1 h at room temperature. Added hydrochloride (4-aminomethyl-3-forfinal)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (113 mg, 0.3 mmol) and the mixture was stirred for 1 h was Added water (20 ml) and the mixture was stirred for 1 h, It was diluted with chloroform, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum to obtain a white solid, identified as specified in the title compound (48 mg, 40%).

Example E100

4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f|solen-9-carbonyl)-2-forbindelse cyclopropanecarbonyl acid

DIEA (of 0.08 ml, 0.46 mmol) and cyclopropanecarbonyl (of 0.013 ml, 0.14 mmol) at 0°C was added to a solution of hydrochloride (4-aminomethyl-3-forfinal)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (57 mg, 0.14 mmol) in dichloromethane (10 ml). The mixture was stirred for 90 min at room temperature, then was diluted with dichloromethane, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as specified in the title compound (33 mg, 54%).

Example E101

4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine qi is labropoulou acid

Example A

4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzonitrile

A mixture of 4-cyano-3-methylbenzoic acid of Example E6 (753 mg, 4.7 mmol) and thionyl chloride (1,02 ml, 14.0 mmol) in toluene (50 ml) was boiled under reflux for 2 hours After cooling at room temperature the solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in dichloromethane (45 ml) and was slowly added a solution of 3,6-dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E2 (1.0 g, 4.7 mmol) in dichloromethane (5 ml) and triethylamine (1.3 ml, 9.3 mmol). The mixture was stirred at room temperature for 20 h, washed with brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel through Isolute (eluent; EtOAc) to obtain the specified title compound (1.42 g, 85%).

Example A

(4-Aminomethyl-3-were)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanon

A solution of 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzonitrile Example E (1.42 g, 4.0 mmol) in methanol (50 ml) at 0°C was treated with uranyl chloride cobalt (II) (1.90 g, 8.0 mmol). The mixture was stirred for 15 min at room temperature, then portions was added sodium borohydride (1.51 g, 40.0 mmol). The reaction mixture is PE is amasyali for 2 h, then added saturated NH4Cl. The mixture was stirred for 30 min, then the solid was filtered through filter agent Celite® and the filtrate was concentrated in vacuum. The remainder of pererestorani in EtOAc and saturated Panso3. The layers were distributed and the aqueous layer was extracted with additional chloroform. The organic phases were combined, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel through Isolate (eluent; 1% 35% ammonia: 9% methanol: 90% dichloromethane) to obtain the specified title compound (511 mg, 35%).

Example A

4-(3,6-Dimethyl-4.10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine cyclopropanecarbonyl acid

The triethylamine (0,145 ml, 1.04 mmol) and cyclopropanecarbonyl level (0.041 ml, 0.45 mmol) at room temperature was added to a solution of (4-aminomethyl-3-were)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (150 mg, 0.41 mmol) in dichloromethane (10 ml). The mixture was stirred for 20 h, then concentrated in vacuo. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to obtain the not quite white solid, identified as specified in the title compound (91 mg, 51%).

Example E102

4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azule the-9-carbonyl)-2-forbindelse cyclopropanecarbonyl acid

Example A

tert-Butyl ester [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]carbamino acid

A solution of 4-(tert-butoxycarbonylamino)-3-fermenting acid from Example E3 (568 mg, 2.1 mmol) in dichloromethane (25 ml) at room temperature was treated with DMAP (256 mg, 2.1 mmol), DIEA (1.1 ml, 6.3 mmol), then WSCD (520 mg, 2.7 mmol). The mixture was stirred for 3 h then was added 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E1 (450 mg, 1.9 mmol). The mixture was stirred for 4 days, then washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc) to obtain the specified title compound (503 mg, 54%).

Example A

Hydrochloride (4-aminomethyl-3-forfinal)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone

tert-Butyl ester [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]carbamino acid from Example E (503 mg, of 1.03 mmol) was brought into reaction with 4 N. HCl/dioxane using a method similar to that described for Example A, obtaining specified in the title compound (440 mg, 100%).

Example A

4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-forbindelse cyclopropanecarbonyl the howling acid

Cyclopropanecarbonitrile (0,045 ml, 0.5 mmol) at 0°C was added to a solution of hydrochloride (4-aminomethyl-3-forfinal)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example A (210 mg, 0.5 mmol) in dichloromethane (40 ml) and DIEA (of 0.30 ml, 1.7 mmol). The mixture was stirred for 1 h at room temperature, then washed with saturated Panso3, brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as specified in the title compound (134 mg, 59%).

Example A

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]propionamide

DIEA (0,27 ml, 1.56 mmol) and propionyl chloride (0,048 ml, 0.55 mmol) at room temperature was added to a solution of hydrochloride (4-aminomethyl-3-forfinal)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example A (220 mg, 0.52 mmol) in dichloromethane (6 ml). The mixture was stirred for 2 h, washed with saturated NaHC3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give a white powder identified as specified in the title compound (129 mg, 56%).

Example E104

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]butyramide

DIEA (is 0.135 ml, 0.78 mmol) and butyrylcholine (0,027 ml, 0.27 mmol) at room temperature was added to a solution of hydrochloride (4-aminomethyl-3-forfinal)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example A (110 mg, 0.26 mmol) in dichloromethane (3 ml). The mixture was stirred for 1 h, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give a white powder identified as specified in the title compound (77 mg, 65%).

Example E105

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]isobutyramide

DIEA (is 0.135 ml, 0.78 mmol) and isobutylene (0,029 ml, 0.27 mmol) at room temperature was added to a solution of hydrochloride (4-aminomethyl-3-forfinal)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example A (110 mg, 0.26 mmol) in dichloromethane (3 ml). The mixture was stirred for 1 h, washed with saturated NaHC3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give a white powder identified as specified in the title compound (85 mg, 71%).

Example A

2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-Tetra is ebenso[f]azulene-9-carbonyl)benzylated cyclopropanecarbonyl acid

Example A

tert-Butyl ether [2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]carbamino acid

A solution of 4-(tert-butoxycarbonylamino)-3-chlorbenzoyl acid from Example 2b (568 mg, 2.0 mmol) in dichloromethane (25 ml) at room temperature was treated with DMAP (244 mg, 2.0 mmol), DIEA (1.0 ml, 6.0 mmol), then WSCD (500 mg, 2.6 mmol). The mixture was stirred for 3 h, then was added 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetrazoles[f]azulene from Example E1 (430 mg, 1.8 mmol). The mixture was stirred for 4 days, then washed with saturated Panso3, brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; EtOAc) to obtain the specified title compound (570 mg, 63%).

Example A

Hydrochloride (4-aminomethyl-3-chlorophenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone

tert-Butyl ether [2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]carbamino acid from Example E (570 mg, 1.13 mmol) was brought into reaction with 4 N. HCl/dioxane using a method similar to that described for Example A, obtaining specified in the title compound (490 mg, 100%).

Example A

2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylated cyclopropanecarboxylate

Cyclopropanecarbonitrile (0,045 ml, 0.5 mmol) at 0°C was added to a solution of hydrochloride (4-aminomethyl-3-chlorophenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example A (220 mg, 0.5 mmol) in dichloromethane (40 ml) and DIEA (of 0.30 ml, 1.7 mmol). The mixture was stirred for 1 h at room temperature, then washed with saturated Panso3, brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give a white powder identified as specified in the title compound (135 mg, 57%).

Example A

N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]-azulene-9-carbonyl)benzyl]butyramide

Butyrylcholine (46 mg, 0.4 mmol) at room temperature was added to a solution of hydrochloride (4-aminomethyl-3-chlorophenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (161 mg, 0.4 mmol) in dichloromethane (10 ml) and triethylamine (up to pH 9). The mixture was stirred for 20 h, diluted with EtOAc, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give a white solid identified as specified in the title compound (110 mg, 58%).

Example A

N-[2-PI is R-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]-azulene-9-carbonyl)benzyl]isobutyramide

Isobutyramide (46 mg, 0.4 mmol) at room temperature was added to a solution of hydrochloride (4-aminomethyl-3-chlorophenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (161 mg, 0.4 mmol) in dichloromethane (10 ml) and triethylamine (up to pH 9). The mixture was stirred for 18 h, diluted with EtOAc, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as specified in the title compound (75 mg, 40%).

Example A

{4-[(Cyclopropylamino)methyl]-3-were}(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanon

Cyclopropanecarboxaldehyde (26 mg, 0.34 mmol) was added to a solution of (4-aminomethyl-3-were)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone (131 mg, 0.38 mmol) in Meon/Asón (99:1, 5 ml) and the mixture was stirred at room temperature for 30 minutes was Added cyanoborohydride sodium (31 mg, 0.49 mmol) and the mixture was stirred at room temperature for 18 hours the Solvent was removed in vacuo and the residue was dissolved in EtOAc. The solution was washed a feast upon. aq. Panso3and brine, then dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% of methane is: 90% dichloromethane to obtain white solids, identified as specified in the title compound (70 mg, 51%).

Example E110

Methyl ester [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-forbindelsen]acetic acid

and

Example a

Methyl ester {[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]methoxycarbonyl-methylamino}acetic acid

Methylbromide (0,054 ml of 0.58 mmol) was added to a solution of hydrochloride (4-aminomethyl-3-forfinal)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example E (107 mg, 0.28 mmol) and DIEA (0.26 per ml, 1.53 mmol) in THF (25 ml)and the mixture was stirred at room temperature for 2 hours was Added an additional amount of methylpropanoate (0.10 ml, 1.11 mmol) and the mixture was stirred over night at room temperature. The solution is extinguished with water and diluted with EtOAc. The organic layer was washed with brine (×3), dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give two products. More quickly eluruumis the solution was isolated as a white solid and identified as e (68 mg, 46%).

More slowly eluruumis the product was isolated as white solids and identified as E110 (13 mg, 10%).

Example a

(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-t is tratamento[f]azulene-9-yl)-{3-fluoro-4-[(2-hydroxyethylamino)methyl]phenyl}metano

Alumoweld lithium (14,5 mg, 0.38 mmol) was added to a solution of methyl ester [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-forbindelsen]acetic acid from Example E110 (58.5 mg, 0.13 mmol) in THF (5 ml) and the mixture was stirred at room temperature for 30 minutes Extinguished Meon and was extracted with EtOAc. The organic extract was washed with brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 10% methanol: 90% dichloromethane followed by 20% methanol: 80% dichloromethane) to give a pale yellow solid, identified as specified in the title compound (15 mg, 28%).

Example A

tert-Butyl ester {[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-verbesserbar]methyl}-carbamino acid

HBTU (165 mg, 0.44 mmol) was added to a solution of N-(tert-butoxycarbonyl)glycine (65 mg, of 0.37 mmol) in DMF (10 ml) and the mixture was stirred for 30 min at room temperature. Added hydrochloride (4-aminomethyl-3-forfinal)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone Example A (100 mg, 0.22 mmol) and DIEA (0,228 ml of 1.31 mmol) and the mixture was stirred for 24 h at room temperature. The solution was diluted with EtOAc, washed with water, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatogr is the philosophy on silica gel (eluent; 5% methanol:95% dichloromethane followed by 10% methanol:90% dichloromethane) to give a white solid identified as specified in the title compound (123 mg, 100%).

Example A

Hydrochloride of 2-amino-N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]ndimethylacetamide

tert-Butyl ester {[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-verbesserbar]methyl}-carbamino acid from Example E (120 mg, 0.22 mmol) was brought into reaction with 4 N. HCl/dioxane using a method similar to that described for Example A, obtaining specified in the title compound (95 mg, 83%).

Example E115

4-[(3-Chlorobenzylamino)methyl]-N-(4-chlorophenyl)-3,N-dimethyl-benzamide

Example A

N-(4-Chlorophenyl)-4-cyano-3,N-dimethylbenzamide

A mixture of 4-cyano-3-methylbenzoic acid of Example E6 (3.4 g, 21 mmol) and thionyl chloride (10 ml, 137 mmol) in dichloromethane (50 ml) was boiled under reflux for 2 hours After cooling at room temperature the solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in dichloromethane (50 ml). Was added (4-chlorophenyl)methylamine (3.0 g, 21 mmol) and triethylamine (up to pH 9) and the mixture was stirred at room temperature for 20 h, then concentrated in vacuo. The remainder of pererestorani in EtOAc, washed with 1M KHSO4 , water, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 35% EtOAc;65% cyclohexane) to obtain the specified title compound (5.1 g, 85%).

Example A

4-Aminomethyl-N-(4-chlorophenyl)-3,N-dimethylbenzamide

A solution of N-(4-chlorophenyl)-4-cyano-3,N-dimethylbenzamide Example E (5,1 g of 17.9 mmol) in methanol (250 ml) was treated with uranyl chloride cobalt (II) (8,4 g, 35.8 mmol). The mixture was stirred for 15 min at room temperature, then was cooled to 0°C and the portions was added sodium borohydride (6.7 g, 179 mmol). The mixture was stirred for 1 h at room temperature, filtered through filter agent Celite®, washed with methanol and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 1% 35% ammonia: 10% methanol:89% dichloromethane) to obtain the specified title compound (3.6 g, 70%).

Example A

4-[(3-Chlorobenzylamino)methyl]-N-(4-chlorophenyl)-3,N-dimethylbenzamide

3-Chlorobenzylchloride (61 mg, 0.35 mmol) and triethylamine (up to pH 9) at room temperature was added to a solution of 4-aminomethyl-N-(4-chlorophenyl)-3,N-dimethylbenzamide Example A (100 mg, 0.35 mmol) in dichloromethane (5 ml). The mixture was stirred for 1 h, then concentrated in vacuo. The residue was purified by preparative HPLC (eluent; 0,5% 35%ammonia:9,5% met the Nol:90% dichloromethane) to obtain white solids, identified as specified in the title compound (101 mg, 69%).

Example A

4-[(4-Chlorophenyl)methylcarbamoyl]-2-methylbenzene 1-cyclo-propylethylene-4-carboxylic acid

Rouger (212 mg, 0.45 mmol) and 1-cyclopropylmethyl-4-carboxylic acid from Example Ia (76 mg, 0.42 mmol) was added to a solution of 4-aminomethyl-N-(4-chlorophenyl)-3,N-dimethylbenzamide Example A (100 mg, 0.35 mmol) in dichloromethane (5 ml) and DMF (1 ml). The mixture was stirred at room temperature for 18 h, then the solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give a white powder identified as specified in the title compound (34 mg, 22%).

Example A

4-[(4-Chlorophenyl)methylcarbamoyl]-2-methylbenzene 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid

HBTU (296 mg, 0.78 mmol) was added to a solution of 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid from Example E15 motorway (182 mg, 0.73 mmol) in DMF (5 ml) and DIEA (0,272 ml, 1.56 mmol). The mixture was stirred at room temperature for 2 h, and then were added 4-aminomethyl-N-(4-chlorophenyl)-3,N-dimethylbenzamide Example E (150 mg, 0.52 mmol). The mixture was stirred for 2 h at room temperature, then diluted with EtOAc, washed with saturated Panso3, then brine, sushi is whether and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give a white powder identified as specified in the title compound (209 mg, 83%).

Example A

2-Methyl-4-[methyl(4-triptoreline)carbarnoyl]benzylated 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid

Example A

4-Cyano-3-methyl-N-(4-triptoreline)benzamid

A mixture of 4-cyano-3-methylbenzoic acid of Example E6 (750 mg, 4.6 mmol) and thionyl chloride (1,02 ml, 14.0 mmol) in toluene (40 ml) was boiled under reflux for 2 hours After cooling at room temperature the solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in dichloromethane (25 ml), then was added the hydrochloride of 4-triptorelin (1,11 g, 5.6 mmol) in dichloromethane (5 ml) and triethylamine (of 1.95 ml, 14.0 mmol). The mixture was stirred at room temperature for 2 days, washed with brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel through Isolute (eluent; 20% EtOAc:80% cyclohexane) to obtain the specified title compound (1.13 g, 80%).

Example A

4-Cyano-3,N-dimethyl-N-(4-triptoreline)benzamid

4-Cyano-3-methyl-N-(4-triptoreline)benzamide Example E (1.10 g, 3.6 mmol) was dissolved in DMF (10 ml) and cooled to 0°Sgabelli hydride soda is I (60% dispersion in oil, 174 mg, 4.3 mmol) and the mixture was stirred for 30 min at room temperature. Added methyliodide (0,27 ml, 4.3 mmol) and the mixture was stirred for 20 hours, the Solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in EtOAc, washed with brine, dried and concentrated in vacuum to obtain specified in the title compound (1.08 g, 94%).

Example A

4-Aminomethyl-3,N-dimethyl-N-(4-triptoreline)benzamid

A solution of 4-cyano-3,N-dimethyl-N-(4-triptoreline)benzamide from Example E (1.08 g, 3.4 mmol) in methanol (40 ml) at room temperature was treated with uranyl chloride cobalt (II) (1,61 g, 6.8 mmol). The mixture was stirred for 10 min, then portions was added sodium borohydride (1.28 g, 34 mmol). The mixture was stirred for 20 h, then was added a saturated solution of NH4Cl (10 ml). The mixture was stirred for 30 min, filtered through glass fiber paper and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 1% 35% ammonia:9% methanol:90% dichloromethane) to obtain specified in the connection header (863 mg, 79%).

Example A

2-Methyl-4-[methyl-(4-triptoreline)carbarnoyl]benzylated 1-(3.3-dimethylbutyl)piperidine-4-carboxylic acid

Rouger (188 mg, 0.40 mmol) and 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid (82 mg, 0.38 m is ol) was added to a solution of 4-aminomethyl-3,N-dimethyl-N-(4-triptoreline)benzamide from Example A (100 mg, 0.31 mmol) in dichloromethane (5 ml) and DIEA (of 0.081 ml, 0.46 mmol). The mixture was stirred at room temperature for 2 days, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to obtain the not quite white powder, identified as specified in the title compound (22 mg, 14%).

Example E119

2-Methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-database[e]azulene-6-carbonyl)benzylated cyclopropanecarbonyl acid

Example A

tert-Butyl ether [2-methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-database[e]azulene-6-carbonyl)benzyl]carbamino acid

A solution of 4-(tert-butoxycarbonylamino)-3-methylbenzoic acid from Example 2h (400 mg, 1.5 mmol) in dichloromethane (20 ml) and triethylamine (up to pH 9) were treated WSCD (573 mg, 3.0 mmol) and DMAP (183 mg, 1.5 mmol). The solution was stirred for 30 min at room temperature, then added 2-methyl-5,6-dihydro-4H-1-oxa-3,6-database[e]azulene from Example E6 (300 mg, 1.5 mmol) and the mixture is boiled under reflux for 3 days. Added WSCD (287 mg, 1.5 mmol) and the mixture is boiled under reflux for a further 24 h, then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1 N. KHSO4, water, then brine, dried and concentrated in vacuum. The residue was purified is by flash chromatography on silica gel (eluent; EtOAc) to obtain the specified title compound (62 mg, 9%).

Example A

Hydrochloride (4-aminomethyl-3-were)-(2-methyl-4,5-dihydro-1-oxa-3,6-database[e]azulene-6-yl)methanone

tert-Butyl ether [2-methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-database[e]azulene-6-carbonyl)benzyl]carbamino acid from Example A (62 mg, 0.14 mmol) in methanol (0.5 ml) was brought into reaction with 4 N. HCl/dioxane using a method similar to that described for Example A, obtaining specified in the title compound (53 mg, 100%).

Example A

2-Methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-database[e]azulene-6-carbonyl)benzylated cyclopropanecarbonyl acid

Cyclopropanecarbonitrile (26 mg, 0.25 mmol) at room temperature was added to a solution of hydrochloride (4-aminomethyl-3-were)-(2-methyl-4,5-dihydro-1-oxa-3,6-database[e]azulene-6-yl)methanone Example E (85 mg, 0.22 mmol) in dichloromethane (5 ml) and triethylamine (up to pH 9). The mixture was stirred for 1 h, then was purified by flash chromatography on silica gel (eluent; 10% methanol:90% dichloromethane) to give a white solid identified as specified in the title compound (62 mg, 67%).

Example E120

2-Methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-database[e]azulene-6-carbonyl)benzylated 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid

Hydrochloride (4-aminomethyl-3-methyl is enyl)-(2-methyl-4,5-dihydro-1-oxa-3,6-database[e]azulene-6-yl)methanone Example E (89 mg, 0,225 mmol) at room temperature was dissolved in dichloromethane (10 ml) and triethylamine (up to pH 9). Was added 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid (53 mg, 0.25 mmol), DMAP (27 mg, 0,225 mmol) and Rouger (165 mg, 0.36 mmol) and the mixture is boiled under reflux for 18 hours the Solution was diluted with EtOAc, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by slash-chromatography on silica gel (eluent; 1% 35% ammonia: 9% methanol: 90% dichloromethane) to give a white solid identified as specified in the title compound (84 mg, 69%).

Example A

4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylbenzene 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid

Example A

4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylbenzonitrile

A mixture of 4-cyano-3-methylbenzoic acid of Example E6 (557 mg, 3.4 mmol) and thionyl chloride (0,755 ml of 10.3 mmol) in toluene (100 ml) was boiled under reflux for 2 hours After cooling to room temperature the solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in dichloromethane (100 ml) and triethylamine (0,962 ml and 6.9 mmol)was then added 1-benzyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene from Example Ia (1.0 g, 3.4 mmol). The mixture is stirred at room temperature for 2 h, was washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 50% EtOAc: 50% petroleum ether then EtOAc) to obtain specified in the connection header (844 mg, 56%).

Example A

(4-Aminomethyl-3-were)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)methanon

A solution of 4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylbenzonitrile Example E (830 mg, 1.9 mmol) in methanol (10 ml) at room temperature was treated with uranyl chloride cobalt (II) (913 mg, 3.8 mmol). The mixture was stirred for 15 min, then was cooled to 0°Sportime was added sodium borohydride (726 mg, 19 mmol) and the reaction mixture was stirred for 2 h at room temperature. Was added dropwise 35% ammonia (5 ml) and the mixture was stirred for 30 min, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent; 1% 35% ammonia:9% methanol:90% dichloromethane) to obtain the specified title compound (680 mg, 81%).

Example A

4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylbenzene 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid

HBTU (175 mg, 0.46 mmol) was added to a solution of 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid (86 mg, 0.34 mmol) in DMF (5 ml). The mixture is eremetical at room temperature for 2 h, then was added (4-aminomethyl-3-were)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)methanon Example A (100 mg, 0.23 mmol) and DIEA (of 0.12 ml, 0.69 mmol). The mixture was stirred at room temperature for 18 h, then the solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The residue was purified by flash chromatography on silica gel through Isolute (eluent; 5% methanol:95% dichloromethane followed by 10% methanol:90% dichloromethane) to give a yellow foam, identified as specified in the title compound (114 mg, 79%).

Example a

2-Methyl-4-(2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)benzylated 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid

4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylbenzene 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid from Example A (110 mg, 0,17 mmol) was dissolved in absolute ethanol (5 ml) and placed in an inert atmosphere. Was added 10% palladium on carbon (110 mg) and cyclohexene (0,176 ml, 1.7 mmol) and the mixture was heated at 60°C for 3 hours, the Catalyst was filtered through filter agent Celite® and the filtrate was concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia: 9.5% methanol: 90% dichloromethane) to give a white powder identified as specified in the title compound (45 mg, 48%).

Example E12

2-Methyl-4-(2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)benzylated cyclopropanecarbonyl acid

Example A

4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylbenzylamine cyclopropanecarbonyl acid

DIEA (0,176 ml of 1.02 mmol) and cyclopropanecarbonyl (0,033 ml, 0.36 mmol) at room temperature was added to a solution of (4-aminomethyl-3-were)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)methanone Example E (150 mg, 0.34 mmol) in dichloromethane (5 ml). The mixture was stirred for 20 h, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to obtain the specified title compound (155 mg, 90%).

Example A

2-Methyl-4-(2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)benzylated cyclopropanecarbonyl acid

4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylbenzylamine cyclopropanecarbonyl acid from Example E (155 mg, 0.31 mmol) was dissolved in absolute ethanol (10 ml) and placed in an inert atmosphere. Was added 10% palladium on carbon (155 mg) and cyclohexene (0,311 ml, 3.1 mmol) and the mixture was heated at 60°C for 18 hours, the Catalyst was filtered through filter agent Celite® and the filtrate koncentrirane and in vacuum. The residue was purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as specified in the title compound (67 mg, 53%).

Example E124

2-Methyl-4-(2-methyl-4,5-dihydro-3-thia-1,6-database[e]azulene-6-carbonyl)benzylated cyclopropanecarbonyl acid

Example A

2-Methyl-4-(2-methyl-4,5-dihydro-3-thia-1,6-database[e]azulene-6-carbonyl)benzonitrile

A mixture of 4-cyano-3-methylbenzoic acid of Example E6 (147 mg, of 0.91 mmol) was dissolved in dichloromethane (25 ml) and 2 drops DMF and cooled to 0°C. was Slowly added oxalicacid (0.1 ml) and the mixture was stirred for 2 h at room temperature. The solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in dichloromethane (10 ml) and cooled to 0°C. was Added triethylamine (0.5 ml) and 2-methyl-5,6-dihydro-4H-3-thia-1,6-database[e]azulene from Example E7 (165 mg, from 0.76 mmol) in dichloromethane (10 ml) and the mixture was stirred for 2 days at room temperature. Was formed of 0.91 mmol of acid chloride, as previously, and they were added to the mixture. The solution was stirred for 20 h at room temperature, washed with saturated NaHCO3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 10% EtOAc:90% cyclohexane then 20% tOAc: 80% cyclohexane) to obtain the specified title compound (220 mg, 80%).

Example A

(4-Aminomethyl-3-were)-(2-methyl-4,5-dihydro-3-thia-1,6-database[e]azulene-6-yl)methanon

A solution of 2-methyl-4-(2-methyl-4,5-dihydro-3-thia-1,b-database[e]azulene-6-carbonyl)benzonitrile Example E (190 mg, of 0.53 mmol) in methanol (15 ml) at room temperature was treated with uranyl chloride cobalt (II) (275 mg, 1.15 mmol). The mixture was stirred for 20 min, then was cooled to 0°C. Portions was added sodium borohydride (200 mg, 5.3 mmol) and the mixture was stirred for 20 h at room temperature. Was added dropwise saturated NH4Cl (2 ml) and the mixture was stirred for 30 min, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent; 1% 35% ammonia:9% methanol:90% dichloromethane) to obtain the specified title compound (100 mg, 52%).

Example A

2-Methyl-4-(2-methyl-4,5-dihydro-3-thia-1,6-database[e]azulene-6-carbonyl)benzylated cyclopropanecarbonyl acid

DIEA (0,02 ml, 0,115 mmol) and cyclopropanecarbonyl (0,008 ml, 0,088 mmol) at 0°C was added to a solution of (4-aminomethyl-3-were)-(2-methyl-4,5-dihydro-3-thia-1,6-database[e]azulene-6-yl)methanone of E (20 mg, by 0.055 mmol) in dichloromethane (5 ml). The mixture was stirred for 20 h at room temperature, then concentrated in vacuo and purified by preparative HPLC (eluent; 0,5% 35% ammonia:9.5% methanol:90% dichloromethane)to give a white powder, identified as specified in the title compound (11 mg, 46%).

Example A

N-[4-(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylbenzyl]isobutyramide

Example A

4-[1-(4-Cyano-3-methylbenzoyl)-9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl]-2-methylbenzonitrile

A mixture of 4-cyano-3-methylbenzoic acid of Example E6 (262 mg, 1.6 mmol) was dissolved in dichloromethane (20 ml) and 2 drops DMF and cooled to 0°C. was Added oxalicacid (0.6 ml) and the mixture was stirred for 0.5 h at room temperature. The solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The remainder of pererestorani in dichloromethane (10 ml) was added to a solution of 9-chloro-2-methyl-1,4,5,6-tetrahydro-1,3,6-tratamento[e]azulene from Example E7 (190 mg, 0.8 mmol) and DIEA (0.5 ml) in dichloromethane (10 ml) and the mixture was stirred for 20 h at room temperature. The solvents were removed in vacuo and the residue suspended in EtOAc, washed with saturated Panso3, then brine, dried and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 40% EtOAc:60% cyclohexane) to obtain the specified title compound (124 mg, 30%).

Example A

4-(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylbenzonitrile

4-[1-(4-Cyano-3-methylbenzoyl)-9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-three is sebenza[e]azulene-6-carbonyl]-2-methylbenzonitrile of E (124 mg, 0.24 mmol) was dissolved in Meon (5 ml). Added 2M NaOH (2 ml) and the mixture was stirred for 1 h at room temperature. The solvents were removed in vacuo and subjected to azeotropic distillation with toluene. The residue is suspended in EtOAc, washed with saturated Panso3, then brine, dried and concentrated in vacuum to obtain specified in the title compound (80 mg, 89%).

Example A

(4-Aminomethyl-3-were)-(9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)methanon

A solution of 4-(9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylbenzonitrile of E (80 mg, 0.2 mmol) in methanol (5 ml) at room temperature was treated with uranyl chloride cobalt (II) (101 mg, 0.4 mmol). The mixture was cooled to 0°C, then portions was added sodium borohydride (80 mg, 2.1 mmol). The reaction mixture was stirred at 0°C for 30 min, then for 2 h at room temperature, then added saturated NH4Cl. The mixture was stirred for 10 min, then the solid was filtered through filter agent Celite® and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 1% 35% ammonia:9% methanol:90% dichloromethane) to obtain the specified title compound (24 mg, 30%).

Example A

N-[4-(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methyl shall ensil]isobutyramide

Isobutyramide (of 0.07 ml, 0.07 mmol) at 0°C was added to a solution of (4-aminomethyl-3-were)-(9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-yl)methanone Example E (24 mg, 0.07 mmol) in dichloromethane (3 ml) and DIEA (0.10 ml, or 0.57 mmol). The mixture was stirred for 20 h at room temperature, then the solvents were removed in vacuum. The residue was purified by flash chromatography on silica gel (eluent; 5% methanol:95% dichloromethane to 10% methanol:90% dichloromethane) to give a colourless oil identified as specified in the title compound 24 mg, 85%).

Example

Testing in vitro

The compounds were analyzed for their ability to inhibit the cellular effects of stimulation of intact cells in arginine-vasopressin (AVP). In the analysis of the compounds according to the invention cause a significant inhibition of cell activation at concentrations of 30 μm or less. Preferred compounds cause significant inhibition at concentrations of 300 nm.

Example B

Tablet for oral administration

Tablets containing 100 mg of the compound of Example E8 in the form of an active agent, can be prepared from the following:

The compound of Example E8200,0 g
Corn starch 71,0 g
Hydroxypropylcellulose18.0 g
Calcium carboxymethylcellulose13,0 g
Magnesium stearate3.0 g
Lactose195.0 g
Total500.0 g

The materials are mixed and then pressed to obtain 2000 tablets weighing 250 mg each of which contains 100 mg of the compound of Example E8.

All cited sources are included here by reference.

SCHEMES AND PATTERNS

Example E1

Example E2

Examples Ia-g

Example EAExample 2b
tert-Butyl ether 4-amino-methyl-3-chlorbenzoyl acid4-(tert-Butoxycarbonylamino)-3-chlorbenzene acid

/td>
Example EsExample E2d
4-(tert-Butoxycarbonyl-aminomethyl)-3-nitrobenzoic acid4-Cyano-3-methylbenzoic acid
Example EEExample E2f
4-Cyano-2-methylbenzoic acid4-(tert-Butoxycarbonyl-aminomethyl)-2-Formentera acid
Example Ed
4-Cyano-3,5-dimethylbenzoic acid

Example E2h

Example E3

Example E4

Example E5

Example EA

Example E6

Example E7

Example E8

Example a

Example E10

Example E11

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Example E12

Example E13

Example E14

Example E15 motorway

Example EA

Example a

Example E17

Example E18

Example E19

Example E20

Example E21

Example E22

Example a

Example a

Example E25

Example A

Example E27

Example E28

Example A

Example E30

Example a

Example a

Example A

Example E34

Example A

Example E36

Example A

An example is 38

Example E39

Example E40

Example A

Example EA

Example 41b

Example Is

Example A

Example E43

Example A

Example a

Example A

Example A

Example A

Example A

Example E50

Example a

Example A

Example a

Example A

Example E55

Example A

Example A

Example a

Example A

Example E60

Example A

Example A

Example a

Example A

Example E65

Example A

Example E67

Example E68

Example A

Example E70

Example a

Example E72

Example A

Example A

Example E75

Example A

Example E77

Example A

Example E79

Example E80

Example A

Example A

Example a

Example A

Example E85

Example A

Example E87

Example A

Example A

Example along the E90

<> Example A

Example A

Example A

Example A

Example E95

Example A

Example A

Example A

Example A

Example E100

Example E101

Example E102

Example A

Example E104

Example E105

Example A

Example A

Example A

Example A

Example E110 and Example e

Example a

Example A

Example A

Example E115

Example A

Example A

Example A

Example E119

img src="https://img.russianpatents.com/1037/10373912-s.jpg" height="136" width="149" />

Example E120

Example A

Example a

Example A

Example E124

Example A

TABLE EXAMPLES

The following compounds were obtained using methods similar to those described above.

Example E5 and the Connection number 2 have special utility as intermediates.

The connection numberR8MS (IRE)+: [M+H]+=1H NMR: δ (m-1)
1 E5N
2Cl234,0, 236,02.43 (3H, s), 2.98 (2H, d, J=5.2 Hz), 3.34 (2H, t, J=5.2 Hz), 6.59 (2H, d, J=8.4 Hz), 6.90-to 6.95 (1H, m), 7.80-8.10 (1H, m)

Conn-s number R1R4R7MS: [M+H]+
3 E8FMe562,4
4MeMe558,4
5MeMe528,4
6MeMe514,3
7MeMe544,4
8MeMe556,6
9Me Cl578,4,
580,4
10MeCl548,3
550,3
11FMe532,3
12FCl582,4,
584,4
13FCl552,3,
554,3
14FF566,2

Conn-s number R1R4R7MS: [M+H]+
15ClCl598,3,
600,4
16ClCl568,1
17ClMe578,4,
580,4
18ClMe548,3,
550,3
19MeMe532,5
20Me Me622,4
21MeCl576,4,
578,3
22MeCl564,4,
566,4
23MeCl534,3,
536,3
24MeCl564,4,
566,4
25MeCl550,4,
552,4
26MeCl536,4,
538,1
27MeMe544,4

Conn-s numberR1R4R7MS: [M+H]+
28MeMe530,8
29MeMe516,5

R9
The connection numberR1R4R7R8MS: [M+H]+
30MeHMeH558,4
31FMeHH562,4

The connection numberR1R4R7MS: [M+H]+
32MeCl527,1,
529,1
33MeMe507,4

The connection numberR1R4R7MS: [M+H]+
34MeMe493,4
35MeCl513,1

The connection numberR1R4R9MS: [M+H]+
36MeMe491,8
The connection number X2R1R4R10MC: (IRE)+: [M+H]+
37NHMeCl577,4

td align="justify"> 543,4
The connection numberX2R1R4R10MC: (IRE)+: [M+H]+
38NHMeMe557,0
39OMeH544,5
40NHMeH

The connection numberX2R1R4R10ms: [M+H]+
41SMeMe544,2
42SMeH530,4

The connection numberX2R1R4R10MS: [M+H]+
43sMeH560,4

The connection numberR3R4R7MS: [M+H]+
44MeMe558,4
45MeMe528,4
46MeCl578,3,
580,3
47MeCl548,3,
550,3
48FMe562,4

The connection numberR3R4R7MS: [M+H]+49FMe532,450FCl582,4,584,351FCl552,3,554,352ClCl598,3,600,353ClCl568,3 54ClMe578,3,580,355ClMe548,3,550,3The connection number1H NMR: δ (m-1)3 E80.86 (N, s), 1.33-1.39 (2H, m), 2.12 (3H, s), 2.27-2.38 (6H, m), 3.33-3.35 (4H, m), 3.68 (3H, s), 3.92, (1H, d, J=14.3 Hz), 4.25 (2H, d, J=5.4 Hz), 5.45 (1H, t, J=5.4 Hz), 5.79 (1H, d, J=14.3 Hz), 6.43 (1H, d, J=8.0 Hz), 6.53 (1H, d, J=8.0 Hz), 6.79-7.00 (4H, m), 7.17 (1H, s), 7.31 (1H, s)40.88 (N, s), 1.34-1.41 (2H, m), 2.09 (3H, s), 2.18 (3H, s), 2.29-2.36 (2H, m), 2.40 (4H, t, J=4.7 Hz), 3.37 (4H, t, J=4.7 Hz), 3.75 (3H, s), 3.94 (1H, d, J=14.4 Hz), 4.24 (2H, d, J=5.2 Hz), 4.95 (1H, t), 5.85 (1H, d, J=14.4 Hz), 6.53 (1H, q, J=7.9 Hz), 6.76 (1H, d, J=5.7 Hz), 6.90 (1H, s), 7.02-7.11 (3H, m),

The connection number1H NMR: δ (m-1)
7.58 (1H, s)
50.05-0.09 (2H, m), 0.47-0.54 (2H, m), 0.81-0.86 (1H, m), 2.08 (3H, s), 2.16 (3H, s), 2.24 (2H, d, J=6.4 Hz), 2.47-2.49 (4H, m), 3.38-3.44 (4H, m), 3.67 (3H, s), 3.92 (1H, d, J=14.3 Hz), 4.22 (2H, m), 4.92 (1H, m), 5.85 (1H, d, J=14.3 Hz), 6.43-6.56 (2H, m), 6.66-6.85 (3H, m), 7.07-7.24 (3H, m)
60.45-0.47 (4H, m), 1.64 (1H, m), 2.05 (3H, s), 2.13 (3H, s), 2.56 (4H, m), 3.32 (4H, m), 3.65 (3H, s), 3.90 (1H, d, J=14.6 Hz), 4.18 (2H, m), 5.21 (1H, m), 5.82 (1H, d, J=14.6 Hz), 6.43 (1H, d, J=8.0 Hz), 6.53 (1H, d, J=8.0 Hz), 6.80-6.85 (3H, m), 6.93 (1H, s), 7.04 (1H, s), 7.16 (1H, s)
70.84 (3H, s), 0.86 (3H, s), 1.28-1.37 (2H, m), 1.48-1.60 (1H, m), 2.01(3H, s), 2.10 (3H, s), 2.22-2.35 (2H, m), 2.32 (4H, br t), 3.34 (4H, br t), 3.59 (3H, s), 3.90 (1H, d, J=14.6 Hz), 4.16 (2H, d, J=4.9 Hz), 5.15 (1H, t, J=5.2 Hz), 5.81 (1H, d, J=14.6 Hz), 6.40 (1H, d, J=7.9 Hz), 6.51 (1H, d, J=7.9 Hz), 6.69-6.83 (3H, m), 7.01 (1H, s), 7.11 (1H, s), 7.14 (1H, s)
81.06-1.23 (2H, m), 1.38-1.59 (4H, m), 1.63-1.78 (2H, m), 1.98-2.05 (1H, m), 2.07 (3H, s), 2.15 (3H, s), 2.22 (2H, d, J=7.4 Hz), 2.35 (4H, t, J=4.7 Hz), 3.33 (4H, t, J=4.7 Hz), 3.67 (3H, s), 3.91 (1H, d, J=14.6 Hz), 4.22 (2H, d, J=5.2 Hz), 4.84 (1H, br t), 5.84 (1H, d, J=14.6 Hz), 6.43 (1H, d, J=8.2 Hz), 6.54 (1H, d, J=8.2 Hz), 6.67 (1H, s), 6.76 (1H, s), 6.77-6.88 (2H, m), 7.07 (1Hs),7.18(1H, s)
90.88 (9H, s), 1.34-1.41 (2H, m), 2.09 (3H, s), 2.25-2.36 (2H, m), 2.36-2.41 (4H, m), 3.35-3.42 (4H, m), 3.72 (3H, s), 3.93 (1H, d, J=14.6 Hz), 4.24 (2H, d, J=4.45 Hz), 5.02 (1H, br t), 5.83 (1H, d, J=14.6 Hz), 6.59 (1H, s), 6.88 (1H, s), 7.01-7.09 (3H, m), 7.56-7.63 (2H, m)
100.11 (2H, q, J=4.7 Hz), 0.52 (2H, q, J=4.7 Hz), 0.76-0.93 (1H, m), 2.10 (3H, s), 2.31 (2H, d, J=6.4 Hz),2.45-2.62 (4H, m)

The connection number1H NMR δ (m-1)
3.39-3.53 (4H, m), 3.79 (3H, s), 3.93 (1H, d, J=14.6 Hz), 4.23-4.25 (2H, m), 5.27 (1H, s), 5.81 (1H, d, J=14.6 Hz), to 6.58 (2H, s), 6.80-6.90 (2H, m), 7.07 (3H, s), 7.19 (1H, s)
110.05-0.11 (2H, m), 0.47-0.55 (2H, m), 0.75-0.89 (1H, m), 2.18 (3H, s), 2.24 (2H, d, J=6.7 Hz), 2.47 (4H, m), 3.38 (4H, m), 3.75 (3H, s), 3.93 (1H, d, J=14.6 Hz), 4.31 (2H, d, J=5.7 Hz), 5.13 (1H, t, J=5.4 Hz), 5.82 (1H, d, J=14.6 Hz), 6.47-6.58 (2H, m), 6.72-6.80 (2H, m), 6.87-6.95 (2H, m), 7.00-7.04 (1H, m), 7.08-7.17 (1H, m)
120.86 (9H, s), 1.33-1.39 (2H, m), 2.28-2.38 (6H, m), 3.37 (4H, m), 3.66 (3H, m), 3.94 (1H, d, J=14.6 Hz), 4.28 (2H, d, J=5.5 Hz), 5.41 (1H, t, J=5.5 Hz), 5.78 (1H, d, J=14.6 Hz), 6.56 (2H, s), 6.84-6.88 (2H, m), 7.00-7.06 (2H, m), 7.18 (1H, s), 7.98 (1H, s)
130.27-0.29 (2H, m), 0.65-0.67 (2H, m), 0.94-1.10 (1H, m), 1.36-1.56 (2H, m), 2.59 (1H, d, J=6.4 Hz), 2.76-2.89 (4H, m), 3.54-3.70 (4H, m), 3.83 (3H, s), 3.96 (1H, d, J=14.6), 4.31-4.35 (2H, m), 5.81 (1H, d, J=14.6 Hz), 6.63 (1H, s), 6.83-7.00 (1H, m), 7.11 (4H, s), 7.23-7.24 (1H, m), 7.70 (1H, s)
140.89 (9H, s), 1.37-1.43 (2H, m), 2.33-2.43 (6H, m), 3.35-3.39 (4H, m), 3.74 (3H, s), 3.96 (1H, d, J=14.6 Hz), 4.34 (2H, d, J=5.0 Hz), 5.83 (1H, d, J=14.6 Hz), 6.35-6.41 (1H, m), 6.62-6.73 (2H, m), 6.80 (1H, s,), 6.89-6.93 (2H, m), 7.06-7.12 (1H, m)
150.87 (9H, s), 1.33-1.39 (2H, m), 2.28-2.38 (6H, m), 3.37(4H, m), 3.66 (3H, m), 3.94 (1H, d, J=14.6 Hz), 4.31 (2H, d, J=5.5 Hz), 5.45 (1H, t, J=5.5 Hz), 5.78 (1H, d, J=14.6 Hz), 6.91 (1H, m), 7.03 (2H, m), 7.19 (2H, m), 7.84 (1H, s)
16(CD3OD): 0.14-0.18 (2H, m), 0.52-0.59 (2H, m), 0.89 (1H, m), 2.28-2.30 (2H, m), 2.52-2.56 (4H, m), 3.43-3.47 (4H, m), 3.80 (3H, s), 3.97 (1H, d, J=14.6 Hz), 4.34 (2H, d, J=4.5 Hz), 5.73

The connection number1H NMR: δ (m-1)
(1H, d, J=14.6 Hz), 6.64-6.77 (2H, m), 7.08-7.17 (2H, m), 7.23-7.28 (3H, m)
170.87 (9H, s), 1.36 (2H, m), 2.12 (3H, s), 2.32 (6H, m), 3.39 (4H, m), 3.66 (3H, s), 3.92 (1H, d, J=14.3 Hz), 4.28 (2H, m), 5.43 (1H, m), 5.78 (1H, d, J=14.3 Hz), 6.48 (1H, d, J=7.9 Hz), 6.52 (1H, d, J=7.9 Hz), 6.78 (1H, s), 6.88-6.98 (2H, m), 7.05 (1H, s), 7.17 (1H, m)
180.06-0.08 (2H, m), 0.48-0.51 (2H, m), 0.76-0.89 (1H, m), 2.15 (3H, s), 2.21-2.29 (2H, m), 2.44-2.48 (4H, m), 3.36-3.38 (4H, m), 3.68 (3H, s), 3.93 (1H, d, J=14.6 Hz), 4.30 (2H, d, J=6.0 Hz), 5.33 (1H, m), 5.80 (1H, d, J=14.6 Hz), 6.48-6.55 (2H, m), 6.77-7.00 (4H, m), 7.19-7.21 (2H, m)
19CD3OD: 2.18 (3H, s), 2.22 (3H, s), 3.05-3.09 (4H, m), 3.47 (2H, s), 3.58-3.62 (4H, m), 3.79 (3H, s), 3.93 (1H, d, J=14.6 Hz), 4.25 (2H, s), 5.75 (1H, d, J=14.6 Hz), 6.47 (1H, d, J=8.0 Hz), 6.59 (1H, d, J=8.0 Hz), 6.97-7.06 (4H, m), 7.21 (1H, s)
202.02 (3H, s), 2.11 (3H, s), 2.39-2.50 (4H, m), 3.22 (2H, s), 3.32-3.43 (4H, m), 3.60 (3H, s), 3.90 (1H, d, J=14.6 Hz), 4.16 (2H, d, =5.0 Hz), 5.12 (2H, s), 5.25 (1H, t, J=5.0 Hz), 5.80 (1H, d, J=14.6 Hz), 6.41 (1H, d, J=7.9 Hz), 6.51 (1H, d, J=7.9 Hz), 6.76-6.83 (3H, m), 7.02 (1H, s), 7.12-7.14 (2H, m), 7.28-7.31 (5H, m)
211.11-1.18(2H, m), 1.45-1.56 (4H, m), 1.67-1.72 (2H, m), 1.98-2.01, (1H, m), 2.04 (3H, s), 2.22 (2H, d, J=7.2 Hz), 2.29-2.50 (4H, m), 3.30-3.41 (4H, m), 3.62 (3H, s), 3.91 (1H, d, J=14.6 Hz), 4.19-4.21 (2H, m,), 5.04-5.06 (1H, m), 5.80 (1H, d, J=14.6 Hz), 6.53-6.54 (2H, m), 6.80-6.84 (2H, m), 7.01-7.03 (2H, m), 7.16 (1H, s), 7.72 (1H, s)
220.84 (9H, s), 2.05 (2H, s), 2.12 (3H, s), 2.41-2.54 (4H, m), 3.27-3.39 (4H, m), 3.72 (3H, s), 3.92 (1H, d, J=14.6 Hz), 4.26-4.27 (2H, m), 4.66-4.68 (1H, m), 5.85 (1H, d, J=14.6 Hz),

The connection number1H NMR: δ (m-1)
6.58-6.59 (2H, m), 6.88-6.92 (2H, m), 6.98-7.00 (2H, m), 7.09 (1H, s), 7.21 (1H, s)
230.38-0.44 (4H, m), 1.57-1.58 (1H, m), 2.04 (3H, s), 2.53 (4H, m), 3.31 (4H, m), 3.62 (3H, s), 3.91 (1H, d, J=14.6 Hz), 4.20 (2H, m), 5.08 (1H, m), 5.80 (1H, d, J=14.6 Hz), 6.54-6.58 (2H, m), 6.80-6.86 (2H, m,), 7.01-7.03 (2H, m), 7.16 (1H, s), 7.71 (1H, s)
240.85 (6H, d, J=6.4 Hz), 1.23-1.36 (2H, m), 1.49-1.56 (1H, m), 2.01 (3H, s), 2.23-2.35 (6H, m), 3.36 (4H, m), 3.62 (3H, s), 3.91 (1H, d, J=14.6 Hz), 4.18 (2H, m), 5.29 (1H, m), 5.78 (1H, d, J=14.6 Hz), 6.48-6.56 (2H, m), 6.80-6.86 (2H, m), 6.98-7.02 (2H, m), 7.15 (1H, s), 8.12 (1H, s)
250.85 (6H, d, J=6.4 Hz), 1.73 (1H, m), 2.05 (5H, m), 2.26-2.31 4H, m), 3.34 (4H, m), 3.62 (3H, s), 3.91 (1H, d, J=14.6 Hz), 4.21 (2H, m), 5.02 (1H, m), 5.80 (1H, d, J=14.6 Hz), 6.54 (2H, m), 6.84-6.87 (2H, m), 7.02 (2H, m), 7.16 (1H, s), 7.72 (1H, s)
260.85 (3H, t, J=7.2 Hz), 1.40-1.49 (2H, m), 2.01 (3H, s), 2.22-2.28 (2H, m), 2.34 (4H, m), 3.35 (4H, m), 3.58 (3H, s), 3.90 (1H, d, J=14.6 Hz), 4.18 (2H, m), 5.21 (1H, m), 5.77 (1H, d, J=14.6 Hz), 6.51-6.55 (2H,, m), 6.81-6.85 (2H, m), 7.00 (2H, m), 7.13 (1H, s), 7.88 (1H, s)
270.84 (9H, s), 2.04 (2H, s), 2.11 (3H, s), 2.18 (3H, s), 2.45 (4H, t, J=4.7 Hz), 3.30 (4H, t, J=4.7 Hz), 3.71 (3H, s), 3.92 (1H, d, J=14.6 Hz), 4.24 (2H, d, J=5.2 Hz), 4.66 (1H, br t), 5.86 (1H, d, J=14.6 Hz), 6.41 (1H, s), 6.46 (1H, d, J=7.9 Hz), 6.56 (1H, d, J=7.9 Hz), 6.75 (1H, s), 6.88 (2H, s), 7.10 (1H, s), 7.20 (1H, s)
280.86 (6H, d, J=6.7 Hz), 1.68-1.81 (1H, m), 2.05 (2H, d, J=7.4 Hz), 2.09 (3H, s), 2.17 (3H, s), 2.32 (4H, t, J=4.7 Hz), 3.33 (4H, t, J=4.7 Hz), 3.69 (3H, s), 3.92 (1H, d, J=14.6 Hz), 4.23 (2H, d, J=4.9 Hz), 4.78 (1H, t, J=4.9 Hz), 5.85 (1H, d, J=14.6 Hz), 6.46 (1H, d, J=7.9 Hz), 6.55 (1H, d, J=7.9 Hz), 6.57 (1H,

The connection number1H NMR: δ (m-1)
s), 6.76 (1H, s), 6.86 (2H, s), 7.08 (1H, s), 7.19 (1H, s)
290.88 (3H, t, J=7.4 Hz), 1.43-1.54 (2H, m), 2.12 (3H, s), 2.19 (3H, s), 2.28 (2H, t, J=7.4 Hz), 2.38 (4H, t, J=4.9 Hz), 3.35 (4H, t, J=4.9 Hz), 3.73 (3H, s), 3.93 (1H, d, J=14.6 Hz), 4.25 (2H, d, J=5.2 Hz), 4.66 (1H, br t), 5.87 (1H, d, J=14.6 Hz), 6.29 (1H, s), 6.47 (1H, d, J=7.7 Hz), 6.56 (1H, d, J=7.7 Hz), 6.74 (1H, s), 689 (2H, s), 7.11 (1H, s), 7.21 (1H, s)
300.88 (9H, s), 1.32-1.42 (2H, m), 2.02 (3H, s), 2.14 (3H, s), 2.28-2.46 (6H, m), 3.30-3.42 (4H, m), 3.75 (3H, s), 3.94 (1H, d, J=14.4 Hz), 4.26-4.32 (2H, m), 4.48-4.56 (1H, m), 5.87 (1H, d, J=14.4 Hz), 6.07 (1H, s), 6.52 (1H, s), 6.78-6.97 (4H, m), 7.13 (1H, s)
310.88 (9H, s), 1.35-1.41 (2H, m), 2.28-2.42 (8 H, m), 3.27-3.40 (4H, m), 3.82 (3H, s), 3.96 (1H, d, J=14.4 Hz), 4.33 (2H, d, J=5.4 Hz), 4.68-4.79 (1H, m), 5.80 (1H, s), 5.89 (1H, d, J=14.4 Hz), 6.58-6.70 (2H, m), 6.88-6.95 (2H, m), 6.96-7.12 (3H, m), 7.65 (1H, s)
320.88 (9H, s), 1.35-1.41 (2H, m), 2.00-2.18 (2H, m), 2.27-2.35 (2H, m), 2.36-2.43 (4H, m), 3.34-3.41 (4H, m), 3.44 (2H, s), 4.29 (2H, d, J=5.2 Hz), 4.58-4.63 (1H, m), 6.48-6.61 (1H, m), 6.62-6.75 (1H, m), 6.88-7.03 (2H, m), 7.07-7.11 (2H, m)
330.87 (9H, s), 1.35-1.41 (2H, m), 2.16 (3H, s), 2.22 (3H, s), 2.23-2.36 (2H, m), 2.40 (4H, t, J=4.7 Hz), 3.35 (4H, t, J=4.7 Hz), 4.28-4.30 (2H, m), 4.50 (1H, br s), 6.52 (2H, br s), 6.88 (1H, s), 6.95 (2H, s), 7.11 (1H, s)
340.89 (9H, s), 1.36-1.43 (2H, m), 2.23 (3H, s), 2.31 (3H, s), 2.31-2.41 (2H, m), 2.43 (4H, t, J=4.9 Hz), 3.40 (4H, t, J=4.9 Hz), 3.95 (2H, t, J=4.7 Hz), 4.31 (2H, t, J=4.7 Hz), 4.41-4.44 (2H, m), 4.55-4.60 (1H, m), 6.47-6.51 (1H, m), 6.70 (1H, s), 6.81-7.00 (1H, m), 7.21-7.27 (2H, m), 7.34 (1H, s)
350.89 (9H, s), 1.36-1.43 (2H, m), 2.31 (3H, s), 2,32-2.39 (2H,

The connection number1H NMR: δ (m-1)
m), 2.44 (4H, t, J=4.9 Hz), 3.40 (4H, t, J=4.9 Hz), 3.94 (2H, t, J=4.4 Hz), 4.31 (2H, t, J=4.4 Hz), 4.42 (2H, d, J=5.4 Hz), 4.62 (1H, t, J=5.2 Hz), 6.64-6.73 (1H, m), 6.91 (1H, d, J=2.2 Hz), 7.00-7.15 (1H, m), 7.24 (3H, d, J=3.0 Hz)
360.88 (9H, s), 0.89 (3H, s), 1.32-1.42 (2H, m), 1.65-2.20 (4H, m), 2.30-2.45 (7 H, m), 2.49 (2H, t, J=5.2 Hz), 2.80-2.90 (1H, m), 3.36 (4H, br s), 3.60 (2H, t, J=4.9 Hz), 4.25-4.40 (1H, m), 6.80-7.40 (6H,m), 7.84 (1H, s)
370.92 (9H, s), 1.42-1.49 (2H, m), 2.09 (3H, s), 2.48 (3H, s), 2.50-2.58 (4H, m), 2.80-3.03 (2H, m), 3.13-3.33 (1H, m), 3.40-3.53 (4H, m), 4.17-4.33 (2H, m), 4.90-5.08 (1H, m), 5.67-5.78 (1H, m), 6.54-6.58 (2H, m), 6.79-6.90 (2H, m), 7.10 (2H, s), 7.68 (2H, s), 8.13 (1H, d, J=2.0 Hz)
380.89 (9H, s), 1.37-1.43 (2H, m), 2.13 (3H, s), 2.29 (3H, s), 2.30-2.47 (8 H, m), 2.49 (3H, s), 2.76-2.88 (1H, m), 2.90-3.07 (1H, m), 3.31-3.42 (4H, m), 4.26 (2H, d, J=4.2 Hz), 4.70-4.80 (1H, m), 4.96-5.08 (1H, m), 6.51 (1H, d, J=7.9 Hz), 6.65 (2H, d, J=7.4 Hz), 6.85 (1H, d, J=7.7 Hz), 7.06 (1H, s), 7.86-7.97 (1H, m)
390.87 (9H, s), 1.33-1.39 (2H, m), 2.12 (3H, s), 2.27-2.36 (2H, m), 2.36-2.43 (4H, m), 2.54 (3H, s), 2.82-2.91 (1H, m), 2.91-2.98 (1H, m), 3.20-3.27 (1H, m), 3.31-3.35 (4H, m), 4.27 (2H, t, J=4.0 Hz), 4.54 (1H, t, J=4.9 Hz), 5.11-5.16 (1H, m), 6.62-6.72 (2H, m), 6.88-6.98 (2H, m), 6.99 (1H, s), 7.15-7.23 (1H, m), 7.75-7.80 (1H, m)
400.82 (9H, s), 1.31-1.37 (2H, m), 2.20 (3H, s), 2.25-2.42 (6H, m), 3.32-3.42 (4H, m), 3.55 (3H, s), 3.94 (1H, d, J=14.6 Hz), 4.06-4.11 (2H, m), 5.53 (1H, m), 5.77 (1H, d, J=14.6 Hz), 6.49-6.57 (2H, m), 6.64-6.73 (2H, m), to 6.80-6.94, (3H, m), 7.16(1H, s), 7.67 (1H, s)
41 0.07-0.13 (2H, m), 0.49-0.55 (2H, m), 0.83-0.88 (1H, m), 2.17

The connection number1H NMR: δ (m-1)
(3H, s), 2.28 (2H, d, J=6.4 Hz), 2.33 (3H, s), 2.49-2.53 (4H, m), 2.73 (3H, s), 3.02-3.17 (2H, m), 3.36-3.41 (4H, m), 4.27-4.31 (2H, m), 4.51 (1H, s), 5.11-5.18 (1H, m), 6.55 (1H, d, J=7.9 Hz), 6.67 (1H, d, J=7.0 Hz), 6.77 (1H, d, J=7.0 Hz), 6.86 (1H, d, J=7.9 Hz), 7.15 (1H, s), 8.15 (1H, s)
420.07-0.09 (2H, m), 0.46-0.54 (2H, m), 0.80-0.85, (1H, m), 2.15 (3H, s), 2.23-2.27 (2H, m), 2.45-2.49 (4H, m), 2.73 (3H, s), 3.10-3.18 (2H, m), 3.35-3.37 (4H, m), 3.48-3.68 (1H, m), 4.25-4.29 (2H, m), 4.48 (1H, m), 5.16 (1H, m), 6.67 (2H, m), 6.86 (1H, d, J=7.9 Hz), 6.92-6.98 (1H, m), 7.12 (1H, s), 7.20 (1H, m), 8.36 (1H, d, J=7.9 Hz)
430.88 (9H, s), 1.34-1.40 (2H, m), 2.14 (3H, s), 2.29-2.49 (6H, m), 2.72 (3H, s), 3.03-3.18 (2H, m), 3.31-3.35 (4H, m), 3.47-3.67 (1H, m), 4.21-4.31 (2H, m), 4.51-4.54 (1H, m), 5.12-5.19 (1H, m), 6.67 (2H, m), 6.85 (1H, d, J=7.9 Hz), 6.92-6.97 (1H, m), 7.06-7.22 (2H, m), 8.36 (1H, dd, J=1.2, 7.9 Hz)
440.85 (9H, s), 1.31-1.39 (2H, m), 1.99 (3H, s), 2.19 (3H, s), 2.24-2.40 (6H, m), 3.33-3.38 (4H, m), 3.53 (3H, s), 3.90 (1H, d, J=14.6 Hz), 4.10-4.12 (2H, m), 5.56 (1H, m), 5.75 (1H, d, J=14.6 Hz), 6.33-6.35 (1H, m), 6.52-6.56 (2H, m), 6.66-7.11 (3H, m), 7.14 (1H, s), 7.48 (1H, s)
450.01-0.06 (2H, m), 0.42-0.49 (2H, m), 0.75-0.81 (1H, m), 1.98 (3H, s), 2.17-2.25 (5H, m), 2.38-2.48 (4H, m), 3.32-3.41 (4H, m), 3.50 (3H, s), 3.89 (1H, d, J=14.6 Hz), 4.11 (2H, m), 5.54 (1H, m), 5.75 (1H, , J=14.6 Hz), 6.34 (1H, dd, J=1.0, 8.0 Hz), 6.50-6.54 (2H, m), 6.66-7.07 (3H, m), 7.13 (1H, s), 7.37 (1H, s)
460.88 (9H, s), 1.33-1.42 (2H, m), 2.24 (3H, s), 2.27-2.45 (6H, m), 3.35-3.43 (4H, m), 3.68 (3H, s), 3.94 (1H, d, J=14.6 Hz), 4.20 (2H, d, J=5.4 Hz), 5.01-5.07 (1H, m), 5.79 (1H, d, J=14.6 Hz), 6.54 (1H, dd, J=2.2, 8.4 Hz), 6.61-7.02 (5H, m), 7.05 (1H, d, J=1.0 Hz), 7.53 (1H, d, J=4.7 Hz)

The connection number1H NMR: δ (m-1)
470.01-0.06 (2H, m), 0.42-0.47 (2H, m), 0.76-0.80 (1H, m), 2.15-2.23 (5H, m), 2.41-2.46 (4H, m), 3.35-3.48 (4H, m), 3.54 (3H, s), 3.90 (1H, d, J=14.6 Hz), 4.11 (2H, m), 5.46 (1H, m), 5.72 (1H, d, J=14.6 Hz), 6.46 (1H, dd, J=1.5, 8.5 Hz), 6.54-6.61 (2H, m), 6.67-6.73 (1H, m), 6.81-7.09 (2H, m), 7.13 (1H, s), 7.99 (1H, s)
480.84 (9H, s), 1.31-1.37 (2H, m), 1.99 (3H, s), 2.24-2.33 (6H, m), 3.34 (4H, m), 3.57 (3H, s), 3.90 (1H, d, J=14.6 Hz), 4.08 (2H, m), 5.70 (1H, d, J=14.6 Hz), 6.01 (1H, m), 6.34 (1H, m), 6.53-6.60 (2H, m), 6.70 (1H, s), 6.82-6.91 (2H, m), 7.10 (1H, s), 7.49 (1H, s)
490.02-0.08 (2H, m), 0.44-0.51 (2H, m), 0.77-0.82 (1H, m), 2.02 (3H, s), 2.16-2.24 (2H, m), 2.42-2.44 (4H, m), 3.36-3.42 (4H, m), 3.57 (3H, s), 3.92 (1H, d, J=14.6 Hz), 4.11 (2H, m), 5.72 (1H, d, J=14.6 Hz), 5.86 (1H, m), 6.36 (1H, dd, J=1.0, 8.0 Hz), 6.54-6.89 (5H, m), 7.12 (1H, s), 7.27 (1H, s)
500.87 (9H, s), 1.33-1.40 (2H, m), 2.27-2.40 (6H, m), 3.34-3.42 (4H, m), 3.60 (3H, s), 3.94 (1H, d, J=14.6 Hz), 4.16 (2H, d, J=5.2 Hz), 5.72 (1H, d, J=14.6 Hz), 5.81 (1H, t, J=5.4, 11.1 Hz), 6.50 (1H, dd, J=2.2, 8.4 Hz), 6.60-.73 (3H, m), 6.91-7.02 (3H, m), 8.00 (1H, s)
510.02-0.08 (2H, m), 0.44-0.48 (2H, m), 0.77-0.81 (1H, m), 2.20-2.24, (2H, m), 2.43 (4H, m), 3.37-3.47 (4H, m), 3.57 (3H, s), 3.93 (1H, d, J=14.6 Hz), 4.14 (2H, m), 5.70 (1H, d, J=14.6 Hz), 5.82 (1H, m), 6.48 (1H, dd, J=2.0, 8.5 Hz), 6.58-6.72 (3H, m), 6.89-7.00 (2H, m), 7.14 (1H, s), 7.92 (1H, s)
520.89 (9H, s), 1.34-1.42 (2H, m), 2.29-2.46 (6N, m), 3.35-3.44 (4H, m), 3.66 (3H, s), 3.98 (1H, d, J=14.6 Hz), 4.21 (2H, d, J=5.4 Hz), 5.14-5.24 (1H, m), 5.76 (1H, d, J=14.6 Hz), 6.58 (1H, dd, J=2.2, 8.4 Hz), 6.74-7.00 (4H, m), 7,07 (1H, s), 7.22 (1H, s)

The connection number1H NMR: δ (m-1)
530.02-0.07 (2H, m), 0.43-0.48 (2H, m), 0.77-0.81 (1H, m), 2.19-2.24 (2H, m), 2.42-2.47 (4H, m), 3.37-3.41 (4H, m), 3.56 (3H, s), 3.95 (1H, d, J=14.6 Hz), 4.10 (2H, m), 5.68 (1H, d, J=14.6 Hz), 5.89 (1H, m), 6.49 (1H, dd, J=2.0, 8.5 Hz), 6.68-6.96 (5H, m), 7.14 (1H, s), 7.93 (1H, s)
540.82 (9H, s), 1.33-1.41 (2H, m), 1.99 (3H, s), 2.28-2.38 (6H, m), 3.36-3.37 (4H, m), 3.60 (3H, s), 3.95 (1H, d, J=14.6 Hz), 4.07 (2H, m), 5.69 (1H, d, J=14.6 Hz), 6.06 (1H, m), 6.37 (1H, m), 6.61-6.82 (3H, m), 6.94 (2H, m), 7.14 (1H, s), 7.46 (1H, s)
550.02-0.07 (2H, m), 0.43-0.50 (2H, m), 0.76-0.81 (1H, m), 1.97 (3H, s), 2.16-2.23 (2H, m), 2.41-2.45 (4H, m), 3.36-3.44, (4H, m), 3.54 (3H, s), 3.93 (1H, d, J=14.6 Hz), 4.05 (2H, m), 5.68 (1H, d, J=14.6 Hz), 6.00 (1H, m), 6.34 (1H, m), 6.58-6.79 (4H, m), 6.90 (1H, s), 7.11 (1H, s), 7.35 (1H, s)

Conn-s numberR3R11H NMR: δ (m-1)MS
109 E10Cl0.42-0.90 (6H, m), 1.28 (6H, m), 1.78-1.80 (2H, m), 2.08 (1H, m), 2.95-3.01(IRE)+:[M+H]+=442,3, 444,3

(2H, m), 3.66 (3H, s), 3.76 (1H,d, J=14.6 Hz), 5.55 (1H, d, J=14.6 Hz), 5.95 (1H, m), 6.97 (1H, dd, J=8.4, 2.1 Hz), 7.03 (1H, s), 7.07 (1H, d, J=8.4 Hz), 7.09 (1H, d, J=2.1 Hz), 7.14 (1H, s)
110Me0.58-0.90 (6H, m), 1.23-2.13 (M, m), 2.33 (3H, s), 2.95-3.03 (2H, m), 3.68 (3H, s), 3.76 (1H, d, J=14.6 Hz), 5.59 (1H, d, J=14.6 Hz), 5.80 (1H, m), 6.15 (1H, s), 6.81-6.83 (2H, m), 6.97-7.00 (1H, m), 7.14 (1H s)(IRE)+:[M+H]+=422,4
111H0.58-0.81 (6H, m), 1.31-1.74 (6H, m), 1.69-1.80 (2H, m), 2.09-216 (1H, m), 2.89-2.98 (2H, m), 3.64 (3H, s), 3.80 (1H, d, J=14.6 Hz), 5.58 (1H, d, J=14.6 Hz), 6.49 (1H, m), 6.95-7.23 (5H, m), 7.39 (1H, s)Chemical ionization at atmospheric pressure (head)+: [M+H]+=408,3
112MeCH3

113Me(IRE)+:[M+H]+=458,7
114Me(IRE)+:[M+H]+=492,2, 494,2
115Me(IRE)+:[M+H]+=492,6, 494,2
116Me(IRE)+:[M+H]+=492,2, 494,2
117Me (IRE)+:[M+H]+=488,7
118Me(IRE)+:[M+H]+=472,7
119Me(IRE)+:[M+H]+=472,7
120Me(IRE)+:[M+H]+=493,2
121Me(IRE)+:[M+H]+=459,2
122Me(IRE)+:[M+H]+=459,2
123Me(IRE)+:[M+H]+=464,6
124Me
125Me(IRE)+:[M+H]+=464,2
126Me(IRE)+:[M+H]+=476,6
127Me(IRE)+:[M+H]+=448,6
128Me(IRE)+:[M+H]+=449.6 M.
129Me(IRE)+:[M+H]+=to 539.3
130MeCH2CH3(IRE)+:[M+H]+=410,7
131MeCH2CH2CH3 (IRE)+:[M+H]+=424,7
132MeC(CH3)3(IRE)+:[M+H]+=438,3
133Me(IRE)+:[M+H]+=of 464.7
134MeCH2(CH2)3CH3(IRE)+:[M+H]+=452,8
135MeCH(CH2CH3)CH2CH2CH2CH3(IRE)+:[M+H]+=(IRE)+:[M+H]+=480,8
136Me(IRE)+:[M+H]+=532,3
137Me(IRE)+:[M+H]+=472,7

138Me(IRE)+:[M+H]+=486,7
139Me(IRE)+:[M+H]+=498,7
140Me(IRE)+:[M+H]+=478,6
141Me(IRE)+:[M+H]+=488,7
142Me(IRE)+:[M+H]+=502,7
143MeCH2CO2CH2CH3(IRE)+:[M+H]+=468,2
144MeCH2CH2CO2CH3(IRE)+:[M+H]+=468,2
145MeCH2(CH2)2CO2CH2CH3(IRE)+:[M+H]+=496,7

Conn-s numberR1R3XMS (IRE)+: [M+H]+=1H NMR: δ (m-1)
146ClS458,4, 460,40.51-0.98 (6N, m), 1.11-1.99 (7 H, m), 2.30-2.41 (1H, m), 2.67 (3H, s), 2.83-3.08 (4H,
m), 3.42-3.62 (1H, m), 5.55 (1H, s), 7.10 (1H, d, J=8.4 Hz), 7.25 (1H, d, J=2.5, 8.4 Hz), 8.38 (1H, d, J=2.5 Hz)
147Me S438,20.55-0.62 (1H, m), 0.62-0.72 (2H, m), 0.72-0.85 (1H, m), 0.85-1.00 (2H, m), 1.10-1.45 (4H, m), 1.45-1.95 (4H, m), 2.35-2.50 (1H, m), 2.43 (3H, s), 2.68 (3H, s), 2.85-3.10 (4H, m), 3.45-3.65 (1H, m), 4.75-4.85 (1H, m), 5.45-5.65 (1H, m), 7.00-7.15 (2H, m), 8.14 (1H, s)
The connection numberR3MS (IRE)+: [M+H]+=
148 E10.2Cl
149Me354,2
150H340,2

The connection numberR8MS (IRE)+: [M+H]+=
151 E12CH(CH3)2396,4
152CH2CH3396,4
153430,4
154444,4
155436,1
156464,2, 466,2
157rub464.3, 466,3
158CH2CH2CH2CH3410,4
159394,4
160458,4
161CH2CH(CH3)2410,4

162410,3
163 431,1
164472,4
165KZT 446.4
166431,4
167436,3
168CH2CF3436,3
169434,4
170444,4
171444,3
172444,2
173454,2

174454,4
175498,3
176520,4
177488,4

The connection numberR1MC (IRE)+: [M+H]+=
178 E13533,3
179522,2, 524,2

180536,4
181519,7
182 438,2
183504,7
184436,7
185474,7
186to 508.6
187488,7
188454,7
189to 426.2
190556,2, 558,2
191CH3412,2
192424,2
193532,3

Conn-s numberR1MC (IRE)+: [M+H]+=
194 E14CH2CH2CH2CH2CH3458,4
195CH2CH3416,4, 418,4
196(CH2)2CN441,5, 443,5
197484,4, 486,4
198482,4, 484,4
199520,6, is 522.6
200548,5, 550,5
201 is 522.6, 524,6
202464,5, 466,5

203equal to USD 470.5, 472,5
204CH2HE418,3, 420,3
205CO2CH(CH3)2474,4, 476,4
206600,6, 602,6
207CH2CH(CH3)2444,5, 446,5
208CH2CH2HE432,5
209CN413,4, 415,5
210446,5, 448,5
211434,3, 436,3
212 509,5, 511,5
213428,4, 430,4
214514,6, 516,6
215414,4, 416,5
216490,6, 492,6

217540, 6L, 542,6
218472,3, 474,4
219489,4, 491,4
220530,5, 532,5
221SOS(CH3)3472,5, 474,5
222CONH2431,5, 433,5
223 499,5, 501,5
224506,6, to 508.6

Conn-s numberR12MS
264 E19Me(IRE)+: [M+H]+=557,4
265CH(CH3)2(IRE)+: [M+H]+=585,4
266(IRE)+: [M+H]+=633,6

267(IRE)+: [M+H]+=619,5
268(IRE)+: [M+H]+=687,4, 689,4
269(IRE)+: [M+H]+=653,4, 655,4
270(IRE)+: [M+H]+=653,5, 655,5
271(IRE)+: [M+H]+=653,5, 655,5
272(IRE)+: [M+H]+=649,6
273(IRE)+: [M+H]+=633,5
274(IRE)+: [M+H]+=644,5
275(IRE)+: [M+H]+=687,5
276(IRE)+: [M+H]+=676,5
277(IRE)+: [M+H]+=659,4, of 661.4

278(IRE)+: [M+H]+=623,5
279CH2CF3(IRE+: [M+H]+=625,5
280(IRE)+: [M+H]+=732,4, 734,4
281(IRE)+: [M+H]+=667,5
282CH2CH3(IRE)+: [M+H]+=571,4
283CH2CH2CH3(IRE)+: [M+H]+=585,5
284CH2CH2CH2CH3(IRE)+: [M+H]+=599,5

Conn-s numberR12MS
285 E20Me(IRE)+: [M+H]+=521,5
286(IRE)+: [M+H]+=583,4

287(IRE)+: [M+H]+=617,5, 619,5
288(IRE)+: [M+H]+=617,5, 619,5
289(IRE)+: [M+H]+=617,3, 619,3
290(IRE)+: [M+H]+=613,5
291(IRE)+: [M+H]+=597,5
292(IRE)+: [M+H]+=exports, as against 618.5, 620,5
293(IRE)+: [M+H]+=584,4
294(IRE)+: [M+H]+=589,3
295(IRE)+: [M+H]+=623,5, 625,5
296(IRE)+: [M+H]+=589,2

297(IRE)+: [M+H]+=601,5
298(IRE)+: [M+H]+=RUB 573.4
299(IRE)+; [M+H]+=574,4
300(IRE)+: [M+H]+=664,6
301CH2CH3(IRE)+: [M+H]+=535,3
302CH2CH2CH3(IRE)+: [M+H]+=549,4
303(IRE)+: [M+H]+=547,4
304C(CH3)3(IRE)+: [M+H]+=563,5
305(IRE)+: [M+H]+=589,5
306CH2(CH2)3CH3(IRE)+: [M+H]+=577,5
307CH(CH2CH3)CH2CH2CH2CH3(IRE)+: [M+H]+=605,6
308(IRE)+: [M+H]+=657,6
309(IRE)+: [M+H]+=597,4

310(IRE)+: [M+H]+=611,5
311(IRE)+: [M+H]+=623,6
312(IRE)+: [M+H]+=603,5
313(IRE)+: [M+H]+=613,5
314(IRE)+: [M+H]+=627,6
315CH2CH2CO2CH3(IRE)+: [M+H]+=593,4
316CH2(CH2)2CO2CH2CH3(IRE)+: [M+H]+=621,6

Conn-s numberR8MS
317 E21(IRE)+: [M+H]+=507,4
318CH2CH2CH3(IRE)+: [M+H]+=493,5
319(IRE)+: [M+H]+=to 541.5

320(IRE)+: [M+H]+=555,5
321(IRE)+: [M+H]+=547,4
322CH2CH2CH2CH2CH3(IRE)+: [M+H]+=521,5
323(IRE)+: [M+H]+=569,4
324CH2CH2CH(CH3)2(IRE)+: [M+H]+=521,5
325(IRE)+: [is+H]+=542,4
326(IRE)+: [M+H]+=547,4
327CH2CH2CF3(IRE)+: [M+H]+=547,3
328(IRE)+: [M+H]+=545,5
329CH2CH2HE(IRE)+: [M+H]+=495,6
330(IRE)+: [M+H]+=555,5
331(IRE)+: [M+H]+=555,3
332(IRE)+: [M+H]+=566,4
333(IRE)+: [M+H]+=566,4

334(IRE)+: [M+H]+=566,5
335(IRE)+: [M+H]+631,5
336(IRE)+: [M+H]+=609,5
337(IRE)+: [M+H]+=631,6

Conn-s numberR8MS
338 E22(IRE)+: [M+H]+=597,6, 599,6
339CH2CH2CH3(IRE)+: [M+H]+=555,6, 557,6
340CH2(CH2)2CN(IRE)+: [M+H]+=580,7, 582,7

344
341(IRE)+: [M+H]+=631,8, 633,8
342(IRE)+: [M+H]+=623,6, 625,6
343(IRE)+: [M+H]+=621,6, 623,6
(IRE)+: [M+H]+=659,8, 661,8
345(IRE)+: [M+H]+=687,7, 689,7
346(IRE)+: [M+H]+=661,8, 663,8
347(IRE)+: [M+H]+=603,7, 605,7
348CH2CH2HE(IRE)+: [M+H]+=557,5, 559,5
349CH2CO2CH(CH3)2(IRE)+: [M+H]+=613,6, 615,6
350CH2CH2CH(CH3)2(IRE)+: [M+H]+=583,6, 585,6
351CH2CH2CH2HE(IRE)+: [M+H]+=571,6, 573,6
352CH2CN(IRE)+: [M+H]+=552,6, 554,6
353(IRE)+: [M+H]+=648,7, 650,7
354(IRE)+: [M+H]+=567,7, 569,6

355(IRE)+: [M+H]+=653,8, 655,8
356(IRE)+: [M+H]+=553,6, 555,6
357(IRE)+: [M+H]+=629,8, 631,8
358(IRE)+: [M+H]+=679,8, 681,8
359(IRE)+: [M+H]+=611,6, 613,6
360(IRE)+: [M+H]+=628,7, 630,7
361CH2SOS(CH3)3(IRE)+: [M+H]+=611,7, 613,7
362CH2CONH2(IRE)+: [M+H]+=570,6, 572,6
363(IL-IS)+: [M+H]+=638,8, 640,8
364(IRE)+: [M+H]+=645,8, 647,8

Conn-s numberR12MC
365 e(IRE)+: [M+H]+=658,5
366(IRE)+: [M+H]+=647,5
367(IRE)+: [M+H]+=661,7
368(IRE)+: [M+H]+=644,5
369(IRE)+: [M+H]+=563,5
370(IRE)+: [M+H]+=629,6
371(IRE)+: [M+H]+=561,4
372 (IRE)+: [M+H]+=599,4
373(IRE)+: [M+H]+=633,5
374(IRE)+: [M+H]+=613,5
375(IRE)+: [M+H]+=579,5
376(IRE)+: [M+H]+=551,5
377(IRE)+: [M+H]+=683,5
378CH3(IRE)+: [M+H]+=537,4
379(IRE)+: [M+H]+=549,4
380(IRE)+: [M+H]+=657,6

Conn-s numberR1R3R8R12XandMS
443 eMeHMeCH2CH(CH3)2SN3(IRE)+: [M+H]+=530,5
444MeHMeCH2CH2CH3SN3(IRE)+: [M+H]+=516,5
445MeHMeSN3(IRE)+: [M+H]+=564,5
446MeHMe SN3(IRE)+: [M+H]+=570,5
447MeHMeSN3(IRE)+: [M+H]+=578,5

448MeHMeCH3(IRE)+: [M+H]+=570,5
449MeHMeCH3(IRE)+: [M+H]+=598,4
450MeHMeCH3(IRE)+: [M+H]+=598,5
451MeHMe CH3(IRE)+: [M+H]+=598,5
452MeHMeCH2CH2CH2CH2CH3CH3(IRE)+: [M+H]+=544,5
453MeHMeCH3(IRE)+: [M+H]+=528,5
454MeHMeCH3(IRE)+: [M+H]+=592,5
455MeHMeCH2CH2CH(CH3)2CH3(IRE)+: [M+H]+=544,5
456MeH MeCH3(IRE)+: [M+H]+=554,4
457MeHMeCH3(IRE)+: [M+H]+=584,5

458MeHMeCH3(IRE)+: [M+H]+=565,5
459MeHMeCH3(IRE)+: [M+H]+=553,4
460MeHMeCH3(IRE)+: [M+H]+=606,6
461e HMeCH3(IRE)+: [M+H]+=580,5
462MeHMeCH3(IRE)+: [M+H]+=565,4
463MeHMeCH3(IRE)+: [M+H]+=565,4
464MeHMeCH3(IRE)+: [M+H]+=570,4
465MeHMeCH2CH2CF3CH3(IRE)+: [M+H]+=570,4
466Me HMeCH3(IRE)+: [M+H]+=568,5
467MeHMeCH3(IRE)+: [M+H]+=567,5
468MeHMeCH3(IRE)+: [M+H]+=

578,5
469MeHMeSN3(IRE)+: [M+H]+=578,5
470 MeHMeSN3(IRE)+: [M+H]+=578,5
471MeHMeSN3(IRE)+: [M+H]+=589,5
472MeHMeSN3(IRE)+: [M+H]+=589,5
473MeHMeSN3(IRE)+: [M+H]+=589,5
474MeHMeSN3(IRE)+: [M+H]+=632,5
475HMeSN3(IRE)+: [M+H]+=654,6
476MeHMeSN3(IRE)+: [M+H]+=622,6
477MeHMeCH2CH(CH3)2N2(IRE)+: [M+H]+=517,5
478MeHMeCH2CH2CH3N2(IRE)+: [M+H]+=503,5

/tr>
479MeHMeN2(IRE)+: [M+H]+=551,4/td>
480MeHMeN2(IRE)+: [M+H]+=565,5
481MeHMeN2(IRE)+: [M+H]+=557,3
482MeHMeN2(IRE)+: [M+H]+=585,4
483MeHMeN2(IRE)+: [M+H]+=585,4
484MeHMeN2(IRE)+: [M+H]+=585,4
485MeHMeCH2CH2CH2CH2CH3N2(IRE)+: [M+H]+=531,4
486MeHMeN2(IRE)+: [M+H]+=515,5
487MeHMeN2(IRE)+: [M+H]+=579,5
488MeHMeCH2CH2CH(CH3)2N2(IRE)+: [M+H]+=531,5
489MeHMeCH2C(CH3)3N2 (IRE)+: [M+H]+=

531,4
490MeHMeN2(IRE)+: [M+H]+=541,4
491MeHMeN2(IRE)+: [M+H]+=571,5
492MeHMeN2(IRE)+: [M+H]+=552,4
493MeHMeN2 (IRE)+: [M+H]+=540,4
494MeHMeN2(IRE)+: [M+H]+=593,5
495MeHMeN2(IRE)+: [M+H]+=567,4
496MeHMeN2(IRE)+: [M+H]+=552,4
497MeHMeN2(IRE)+: [M+H]+=is 552.5
498MeHMeN2IRE)+: [M+H]+=557,4
499MeHMeCH2CH2CF3N2(IRE)+: [M+H]+=557,4

500MeHMeN2(IRE)+: [M+H]+=555,5
501MeHMeN2(IRE)+: [M+H]+=565,4
502MeHMeN2(IRE)+: [M+H]+=565,4
503MeHMeN 2(IRE)+: [M+H]+=565,4
504MeHMeN2(IRE)+: [M+H]+=576,5
505MeHMeN2(IRE)+: [M+H]+=576,4
506MeHMeN2(IRE)+: [M+H]+=576,4
507MeHMeN2(IRE)+: [M+H]+=619,4
508MeHMeN (IRE)+: [M+H]+=to 641.5
509MeHMeN2(IRE)+: [M+H]+=609,5
510HFHCH2CH(CH3)2N2(IRE)+:

[M+H]+=507,4
511NFNCH2CH2CH3N2(IRE)+: [M+H]+=493,4
512NFNN 2(IRE)+: [M+H]+=541,4
513NFNN2(IRE)+: [M+H]+=555,4
514NFNN2(IRE)+: [M+H]+=547,3
515NFNN2(IRE)+: [M+H]+=575,3
516NFNN2(IRE)+: [M+H]+=575,3
517NFNN (IRE)+: [M+H]+=575,3
518NFNCH2CH2CH2CH2CH3N2(IRE)+: [M+H]+=521,4
519NFNN2(IRE)+: [M+H]+=505,4
520NFNN2(IRE)+: [M+H]+=569,4

521NFNN2(IRE)+: [M+H]+=531,3
522NFN N2(IRE)+: [M+H]+=561,4
523NFNN2(IRE)+: [M+H]+=583,4
524NFNN2(IRE)+: [M+H]+=557,3
525NFNN2(IRE)+: [M+H]+=547,3
526NFNCH2CH2OHN2(IRE)+: [M+H]+=495,3
527NFN N2(IRE)+: [M+H]+=555,3
528NFNN2(IRE)+: [M+H]+=566,3
529NFNN2(IRE)+: [M+H]+=566,4
530NFNN2(IRE)+: [M+H]+=566,3

531NFNN2(IRE)+: [M+H]+=629,4
532NFN N2(IRE)+: [M+H]+=609,3
533NFNN2(IRE)+: [M+H]+=599,4

The connection numberR8R12XMC
534 EClCH2CH2CH2CH2CH2CH3N(IRE)+: [M+H]+=583,6
535ClCH2(CH2)2CH3N(IRE)+: [M+H]+=555,6
536ClCH2(CH2)2CNN(IRE)+: [M+H]+=566,5
537Cl 0N(IRE)+: [M+H]+=617,7

538ClN(IRE)+: [M+H]+=609,8
539ClN(IRE)+: [M+H]+=607,7
540ClN(IRE)+: [M+H]+=645,8
541ClN(IRE)+: [M+H]+=673,7
542ClN(IRE)+: [M+H]+=647,7
543ClN(IRE)+: [M+H]+=589,6
544Cl N(IRE)+: [M+H]+=595,6
545ClCH2CO2CH(CH3)2N(IRE)+: [M+H]+=599,7
546ClCH2CH2CH(CH3)2N(IRE)+: [M+H]+=569,6
547ClCH2CH2CNN(IRE)+: [M+H]+=is 552.5
548ClCH2CH2CH2HEN(IRE)+: [M+H]+=557,6
549ClCH2CNN(IRE)+: [M+H]+=538,5
550ClCH2CH2Och2CH3N(IRE)+: [M+H]+=571,5

551ClWith the 2CH2CH2FN(IRE)+: [M+H]+=byr559.6
552ClN(IRE)+: [M+H]+=634,8
553ClN(IRE)+: [M+H]+=553,5
554ClN(IRE)+: [M+H]+=639,8
555ClN(IRE)+: [M+H]+=539,6
556ClN(IRE)+: [M+H]+=615,7
557ClN(IRE)+: [M+H]+=665,6
558Cl N(IRE)+: [M+H]+=597,6
559ClN(IRE)+: [M+H]+=614,7
560ClCH2SOS(CH3)3N(IRE)+: [M+H]+=597,6
561ClCH2CONH2N(IRE)+: [M+H]+=556,5
562ClN(IRE)+: [M+H]+=624,6

563ClN(IRE)+: [M+H]+=631,6
564NCH2(CH2)4CH3CH(IRE)+: [M+H]+=548,6
565NCH2(CH2)2CH3 SN(IRE)+: [M+H]+=520,6
566NCH2(CH2)3HECH(IRE)+: [M+H]+=536,6
567NSN(IRE)+: [M+H]+=582,5
568NSN(IRE)+: [M+H]+=to 574.6
569NSN(IRE)+: [M+H]+=572,5
570NSN(IRE)+: [M+H]+=610,7
571NSN(IRE)+: [M+H]+=638,7
572NWith the (IRE)+: [M+H]+=612,6
573NSN(IRE)+: [M+H]+=554,5
574NSN(IRE)+: [M+H]+=560,1

575NCH2CO2CH(CH3)2SN(IRE)+: [M+H]+=564,6
576NCH2CH2CH(CH3)2SN(IRE)+: [M+H]+=tune 534.6
577NCH2CH2CNSN(IRE)+: [M+H]+=517,5
578NCH2CNSN(IRE)+: [M+H]+=503,5
579NCH2CH2Och2CH3 SN(IRE)+: [M+H]+=536,6
580NCH2CH2CH2FSN(IRE)+: [M+H]+=524,6
581NSN(IRE)+: [M+H]+=599,6
582NSN(IRE)+: [M+H]+=518,6
583NSN(IRE)+: [M+H]+=604,6
584NSN(IRE)+: [M+H]+=504,5
585NSN(IRE)+: [M+H]+=580,5
586NSN (IRE)+: [M+H]+=630,7
587NSN(IRE)+: [M+H]+=562,5

588NCH(IRE)+: [M+H]+=579,5
589NCH2SOS(CH3)3CH(IRE)+: [M+H]+=562,6
590NCH2CONH2CH(IRE)+: [M+H]+=521,5
591NCH(IRE)+: [M+H]+=589,5
592NCH(IRE)+: [M+H]+=596,6

With the l-e room XR8R19MS
593 eNNMe(IRE)+: [M+H]+=503,2
594NN(IRE)+: [M+H]+=565,3

595NN(IRE)+: [M+H]+=599,3
596NN(IRE)+: [M+H]+=599,3
597NN(IRE)+: [M+H]+=599,3
598NN(IRE)+: [M+H]+=595,3
599N N(IRE)+: [M+H]+=579,3
600NN(IRE)+: [M+H]+=579,3
601NN(IRE)+: [M+H]+=600,3
602NN(IRE)+: [M+H]+=566,3
603NN(IRE)+: [M+H]+=571,3
604NN(IRE)+: [M+H]+=571,3

605NN(IRE)+: [M+H]+=583,3
606N N(IRE)+: [M+H]+=555,3
607NN(IRE)+: [M+H]+=556,3
608NN(IRE)+: [M+H]+=646,4
609NNCH2CH3(IRE)+: [M+H]+=517,3
610NNCH3CH2CH3(IRE)+: [M+H]+=531,3
611NN(IRE)+: [M+H]+=529,3
612NNC(CH3)3(IRE)+: [M+H]+=545,3
613NN/td> (IRE)+: [M+H]+=571,3
614NNCH2(CH2)3CH3(IRE)+: [M+H]+=559,3
615NNCH(CH2CH3)CH2CH2CH2CH3(IRE)+: [M+H]+=for 587.4
616NN(IRE)+: [M+H]+=639,4
617NN(IRE)+: [M+H]+=579,3

618NN(IRE)+: [M+H]+=593,3
619NN(IRE)+: [M+H]+=605,4
620NN (IRE)+: [M+H]+=585,3
621NN(IRE)+: [M+H]+=595,3
622NN(IRE)+: [M+H]+=609,4
623NNCH2CH2CO2CH3(IRE)+: [M+H]+=575,3
624NNCH2CH2CH2CO2CH2CH3(IRE)+: [M+H]+=603,4
625SNMeCH3(IRE)+: [M+H]+=516,4
626SNMe(IRE)+: [M+H]+=578,4
627SNMe (IRE)+: [M+H]+=612,4
628SNMe(IRE)+: [M+H]+=612,4
629SNMe(IRE)+: [M+H]+=612,4
630SNMe(IRE)+: [M+H]+=608,5

631SNMe(IRE)+: [M+H]+=592,4
632SNMe(IRE)+: [M+H]+=592,4
633SNMe(IRE)+: [M+H]+=613,4
634SNMe(IRE)+: [M+H]+=579,4
635SNMe(IRE)+: [M+H]+=579,4
636SNMe(IRE)+: [M+H]+=584,4
637SNMe(IRE)+: [M+H]+=584,4
638SNMe(IRE)+: [M+H]+=596,4
639SNMe(IRE)+: [M+H]+=568,4
640SNMe(IRE)+: [M+H]+=569,4
641SNMe (IRE)+: [M+H]+=659,5

(IRE)+: [M+H]+=600,5
642SNMeCH2CH3CH3(IRE)+: [M+H]+=544,4
643SNMe(IRE)+: [M+H]+=542,4
644SNMeC(CH3)3(IRE)+: [M+H]+=558,4
645SNMe(IRE)+: [M+H]+=584,4
646SNMeCH2(CH2)3CH3(IRE)+: [M+H]+=572,4
647SNMeCH(CH2CH3)CH2CH2CH3CH3
648SNMe(IRE)+: [M+H]+=652,5
649SNMe(IRE)+: [M+H]+=592,5
650SNMe(IRE)+: [M+H]+=606,5
651SNMe(IRE)+: [M+H]+=exports, as against 618.5
652SNMe(IRE)+: [M+H]+=598,4
653SNMe(IRE)+: [M+H]+=608,5
654SNMe(IRE)+: [M+H]+=622,5
655SNMeCH2CH2CH2SON2CH3(IRE)+: [M+H]+=616,5

Conn-s numberXR8R19MC
656 ENNMe(IRE)+: [M+H]+=539,2
657NNCH(CH3)2(IRE)+: [M+H]+=567,3
658NN(IRE)+: [M+H]+=615,3
659NN(IRE)+: [M+H]+=601,3
660NN (IRE)+: [M+H]+=669,3
661NN(IRE)+: [M+H]+=635,3
662NN(IRE)+: [M+H]+=635,3
663NN(IRE)+: [M+H]+=635,3

664NN(IRE)+: [M+H]+=631,3
665NN(IRE)+: [M+H]+=615,3
666NN(IRE)+: [M+H]+=626,3
667NN (IRE)+: [M+H]+=669,3
668NN(IRE)+: [M+H]+=658,4
669NN(IRE)+: [M+H]+=641,3
670NN(IRE)+: [M+H]+=605,3
671NNCH2CF3(IRE)+: [M+H]+=607,3
672NN(IRE)+: [M+H]+=716,2
673NN(IRE)+: [M+H]+=649,3
674NNCH3CH3(IRE)+: [M+H]+=553,3
675 NNCH2CH3CH3(IRE)+: [M+H]+=567,3
676NNCH3CH3CH3CH3(IRE)+: [M+H]+=581,3
677SNMeCH3(IRE)+: [M+H]+=552,3
678SNMeCH(CH3)2(IRE)+: [M+H]+=580,4

679SNMe(IRE)+: [M+H]+=628,5
680SNMe(IRE)+: [M+H]+=614,4
681SNMe(IRE)+: [M+H]+=682,4
682 Me(IRE)+: [M+H]+=648,4
683SNMe(IRE)+: [M+H]+=648,4
684SNMe(IRE)+: [M+H]+=648,4
685SNMe(IRE)+: [M+H]+=644,5
686SNMe(IRE)+: [M+H]+=628,5
687SNMe(IRE)+: [M+H]+=639,5
688SNMe(IRE)+: [M+H]+=682,4
689SNMe (IRE)+: [M+H]+=671,5

690SNMe(IRE)+: [M+H]+=654,4
691SNMe(IRE)+: [M+H]+=exports, as against 618.5
692SNMe(IRE)+: [M+H]+=729,2
693SNMe(IRE)+: [M+H]+=662,4
694SNMeCH2CH3(IRE)+: [M+H]+=566,3
695SNMeCH2CH3CH3(IRE)+: [M+H]+=580,4
696SNMe CH2CH2CH3CH3(IRE)+: [M+H]+=594,4

708(IRE)+: [M+H]+=506,3-
709(IRE)+: [M+H]+=486,4-
710 E(IRE)+: [M+H]+=553,4
711(IRE)+: [M+H]+=458,3-
712(IRE)+: [M+H]+- 472,4-
713(IRE)+: [M+H]+=460,4-
714(IRE)+: [M+H]+=558,4-
71 (IRE)+: [M+H]+=473,3-
716(IRE)+: [M+H]+=512,4-

717(IRE)+: [M+H]+=512,4-
718(IRE)+: [M+H]+=476,3-
719(IRE)+: [M+H]+=462,3-
720(IRE)+: [M+H]+=530,4-
721(IRE)+: [M+H]+=502,4-
722(IRE)+: [M+H]+=502,4-
723 (IRE)+: [M+H]+=487,3-
724(IRE)+: [M+H]+=593,4-
725(IRE)+: [M+H]+=553,4-

726(IRE)+: [M+H]+=530,4-
727(IRE)+: [M+H]+=603,4-
728(IRE)+: [M+H]+=603,4-
729(IRE)+: [M+H]+=565,4-
730(IRE)+: [M+H]+=548,4-
731(IL-IS)+: [M+H]+=527,5 -
732(IRE)+: [M+H]+=550,3-
733(IRE)+: [M+H]+=492,4-

734(IRE)+: [M+H]+=506,4-
735(IRE)+: [M+H]+=508,4-
736(IRE)+: [M+H]+=509,3-
737(IRE)+: [M+H]+=536,4-
738(IRE)+: [M+H]+=515,4-
739(IRE)+: [M+H]+=501,4-
740(IRE)+: [M+H]+=501,4-
741(IRE)+: [M+H]+=557,5-

742(IRE)+: [M+H]+=488,4-
Conn-s numberR15R16MS
743N(IRE)+: [M+H]+=466,1
744N(IRE)+: [M+H]+=494,2
745N(IL-IS)+: [M+H]+=550,3
746N(IRE)+: [M+H]+=510,3
747N(IRE)+: [M+H]+=566,3
748N(IRE)+: [M+H]+=509,3
749N(IRE)+: [M+H]+=467,2
750N(IRE)+: [M+H]+=467,2
751N(IRE)+: [M+H]+=593,3
752N (IRE)+: [M+H]+=549,3
753N(IRE)+: [M+H]+=498,3
754NCH3(IRE)+: [M+H]+=404,2
755NCH2CH3(IRE)+: [M+H]+=418,2
756NCH2CH(CH3)3(IRE)+: [M+H]+=446,2
757NCH2CH2CH3(IRE)+: [M+H]+=432,2
758N(IRE)+: [M+H]+=430,2
759NCH2(CH2)4CH3 (IRE)+: [M+H]+=474,3

760N(IRE)+: [M+H]+=458,2
761N(IRE)+: [M+H]+=486,3
762NC(CH3)2CH2CH3(IRE)+: [M+H]+=460,2
763NCH(CH2CH3)2(IRE)+: [M+H]+=460,3
764NCH2CH2CH(CH3)2(IRE)+: [M+H]+=460,2
765N(IRE)+: [M+H]+=506,3
766N(IRE)+: [M+H]+=506,3
767N (IRE)+: [M+H]+=486,3
768N(IRE)+: [M+H]+=of 480.2
769N(IRE)+: [M+H]+=564,2
770N(IRE)+: [M+H]+=548,2
771N(IRE)+: [M+H]+=510,3

td align="left"> 776
772N(IRE)+: [M+H]+=548,2
773N(IRE)+: [M+H]+=494,3
774N(IRE)+: [M+H]+=528,2
775N(IRE)+: [M+H]+=508,2
N(IRE)+: [M+H]+=524,3
777N(IRE)+: [M+H]+=481,2
778N(IRE)+: [M+H]+=481,2
779N(IRE)+: [M+H]+=495,3
780N(IRE)+: [M+H]+=486,2
781N(IRE)+: [M+H]+=470,2
782NCH2CH2F(IRE)+: [M+H]+=436,2

783NCH2CH2HE(IRE)+: [M+H]+=434,2
784N CH2CH2CH2HE(IRE)+: [M+H]+=USD 448,2
785NCH2(CH2)3HE(IRE)+: [M+H]+=462,2
786NCH2(CH2)4HE(IRE)+: [M+H]+=476,2
787N(IRE)+: [M+H]+=462,2
788N(IRE)+: [M+H]+=502,2
789NCH2(CH2)2S3(IRE)+: [M+H]+=478,2
790N(IRE)+: [M+H]+=503,2
791NCH2CH2N(CH3)2(IRE)+: [M+H]+=461,2
792N (IRE)+: [M+H]+=531,4
793NCH2(CH2)2N(CH3)2(IRE)+: [M+H]+=475,2
794N(IRE)+: [M+H]+=563,3
795NCH2CH2The N3(IRE)+: [M+H]+=475,2
796N(IRE)+: [M+H]+=545,3
797NCH2CO2CH3(IRE)+: [M+H]+=462,2
798N(IRE)+: [M+H]+=558,4
799NCH2CO2CH(CH3)2(IRE)+: [M+H]+=490,3
800N(IRE)+: [M+H]+=590,3

801NCH2CONH2(IRE)+: [M+H]+=447,1
802NCH2CN(IRE)+: [M+H]+=429,2
803NCH2CH2CN(IRE)+: [M+H]+=443,2
804NCH2(CH2)4CN(IRE)+: [M+H]+=485,3
805NCH2CF3(IRE)+: [M+H]+=472,2
806CH3(IRE)+: [M+H]+=494,4
807CH3CH3CH3(IRE)+: [M+H]+=567,4
808CH3CH2CH3(IRE)+: [M+H]+=432,3
809CH2CH3 (IRE)+: [M+H]+=509,4
810CH2CH2CN(IRE)+: [M+H]+=534,3
811CH2CO2CH2CH3(IRE)+: [M+H]+=566,4
812CH3(IRE)+: [M+H]+=544,4
813CH3CH3CH2CH2CH3(IRE)+: [M+H]+=460,3
814CH3CH2(CH3)4CH3(IRE)+: [M+H]+=488,4
815CH(CH3)2(IRE)+: [M+H]+=514,5
816CH2CH3CH2CH3(IRE)+: [M+H]+=446,2
817CH(CH3)2CH(CH3)2(IRE)+: [M+H]+=474,4

818CH3(IRE)+: [M+H]+=509,4
819CH2CH3(IRE)+: [M+H]+=550,4
820CH(CH3)2CH2CH2Och3(IRE)+: [M+H]+=490,4
821CH3(IRE)+: [M+H]+=508,4
822CH2CH3Och3CH3CH2Och3(IRE)+: [M+H]+=506,3
823CH3With6H5(IRE)+: [M+H]+=480,3
824CH3CH3HEWith6 H5(IRE)+: [M+H]+=510,4
825CH3(IRE)+: [M+H]+=514,4
826CH3(IRE)+: [M+H]+=481,4
827CH3(IRE)+: [M+H]+=481,3
828CH3CH3(IRE)+: [M+H]+=502,4
829CH3CH3(IRE)+: [M+H]+=418,3
830CH3(IRE)+: [M+H]+=538,3
831CH3(IRE)+: [M+H]+=484,3

832With the 3CH3CO2N(IRE)+: [M-H]+=460,4
833CH3CH2CH2CH2CO2N(IRE)+: [M+H]+=490,4
834CH3CH2CN(IRE)+: [M+H]+=443,3
835CH3CH2CH2CN(IRE)+: [M+H]+=457,3
836CH2CH2N(CH3)2(IRE)+: [M+H]+=551,5
837CH2CH2OH(IRE)+: [M+H]+=524,4
838CH2CN(IRE)+: [M+H]+=519,4
Connection but the er R4MC
839 E
840
841

Conn-s numberR13R14MS1H NMR
842 eMeCH3CH3CH2CH3(IRE)+: [M+H]+=557,6
843H(IRE)+: [M+H]+=660,7-
844HCH2With6H5-
845HCH2CH2With6H5(IRE)+: [M+H]+=591,7-
846H(IRE)+: [M+H]+=595,7-
847H(IRE)+: [M+H]+=555,6-
848HCH2CH(CH3)2(IRE)+: [M+H]+=543,6-

Conn-s numberR4MS1H NMR
849(IRE)+: [M+H]+=603,7-
850(IRE)+: [M+H]+=573,6-

Conn-s numberR13R14MS1H NMR
851 EN(IRE)+: [M+H]+=586,6
852NCH2With6H5(IRE)+: [M+H]+=563,6-
853N(IRE)+: [M+H]+=569,6-
854N(IRE)+: [M+H]+=to 541.5-
855NCH2CH(CH3)2(IRE)+: [M+H]+=529,8-
856CH2C6H5CH3CH3CH3CH3(IRE)+: [M+H]+=619,6-

857N(IRE)+: [M+H]+=527,6-
858CH3With6H5CH2CH2N(CH3)2(IRE)+: [M+H]+=634,6-
859N(IRE)+: [M+H]+=570,6-
860NCH2CH2HE(IRE)+: [M+H]+=517,6-
861N(IRE)+: [M+H]+=584,6-
862NCH2CH2CH2HE (IRE)+: [M+H]+=531,6-
863N(IRE)+: [M+H]+=581,6-
864NCH2CH2With6H5(IRE)+: [M+H]+=577,6-
865N(IRE)+: [M+H]+=555,6-
866NCH2(CH2)4CH3(IRE)+: [M+H]+=557,6-
867N(IRE)+: [M+H]+=646,6-

Conn-s numberR12MS
868 E60CH3CH3CH3CH2CH3With the 3(IRE)+: [M+H]+=543,4
869CH2CH2CH3(IRE)+: [M+H]+=501,4
870CH2(CH2)3HE(IRE)+: [M+H]+=531,3
871CH2(CH2)2CN(IRE)+: [M+H]+=to 526.4
872(IRE)+: [M+H]+=569,4
873(IRE)+: [M+H]+=567,3
874(IRE)+: [M+H]+=605,5
875(IRE)+: [M+H]+=633,5
876(IRE)+: [M+H]+=607,4
877(IRE)+: [M+H]+=549,4

878CH2/sub> CH2HE(IRE)+: [M+H]+=503,3
879CH2CO2CH(CH3)2(IRE)+: [M+H]+=559,3
880CH2CH2CH(CH3)2(IRE)+: [M+H]+=529.4 M.
881CH2CH2CH2HE(IRE)+: [M+H]+=517,4
882CH2CN(IRE)+: [M+H]+=498,4
883CH2CH2Och2CH3(IRE)+: [M+H]+=531,4
884(IRE)+: [M+H]+=594,4
885(IRE)+: [M+H]+=599,4
886(IRE)+: [M+H]+=499,4
887(IRE)+: [M+H]+=575,4
888 (IRE)+: [M+H]+=625,5
889CH2SOS(CH3)3(IRE)+: [M+H]+=557,4
890CH2CONH2(IRE)+: [M+H]+=516,4
891(IRE)+: [M+H]+=584,4
892(IRE)+: [M+H]+=591,4

Conn-s numberR12MS
893CH3CH3CH3(IRE)+: [M+H]+=515,5
894CH2CH(CH3)2(IRE)+: [M+H]+=529,5
895(IRE)+: [M+H]+=563,4
896(IRE)+: [M+H]+=569,4
897 (IRE)+: [M+H]+=577,5
898(IRE)+: [M+H]+=597,4
899(IRE)+: [M+H]+=597,4
900(IRE)+: [M+H]+=597,5
901CH2CH2CH2CH2CH3(IRE)+: [M+H]+=543,4
902(IRE)+: [M+H]+=527,4

903(IRE)+: [M+H]+=591,5
904CH2CH2CH(CH3)2(IRE)+: [M+H]+=543.5 nm
905(IRE)+: [M+H]+=553,4
906(IRE)+: [M+H]+=583,5
907(IRE)+: [M+H]+=564,4
908(IRE)+: [M+H]+=552,4
909(IRE)+: [M+H]+=605,5
910(IRE)+: [M+H]+=564,4
911(IRE)+: [M+H]+=564,4
912(IRE)+: [M+H]+=569,3
913(IRE)+: [M+H]+=567,5
914CH2CH2OH(IRE)+: [M+H]+=517,4

915(IRE)+: [M+H]+=577,5
916(IRE)+: [M+H]+=577,5
917(IRE)+: [M+H]+=577,4
918(IRE)+: [M+H]+=to 588.5
919(IRE)+: [M+H]+=to 588.5
920(IRE)+: [M+H]+=to 588.5
921(IRE)+: [M+H]+=653,5
922(IRE)+: [M+H]+=631,5
923(IRE)+: [M+H]+=653,6
924(IRE)+: [M+H]+=621,6

Conn-s numberR8R19MS
925 E ClMe(IRE)+: [M+H]+=535,5
926Cl(IRE)+: [M+H]+=597,5
927Cl(IRE)+: [M+H]+=631,5
928Cl(IRE)+: [M+H]+=631,5
929Cl(IRE)+: [M+H]+=631,5
930Cl(IRE)+: [M+H]+=627,6
931Cl(IRE)+: [M+H]+=611,5

932Cl(IRE)+: [M+H]+=611,6
933Cl (IRE)+: [M+H]+=632,5
934Cl(IRE)+: [M+H]+=598,5
935Cl(IRE)+: [M+H]+=598,5
936Cl(IRE)+: [M+H]+=603,5
937Cl(IRE)+: [M+H]+=603,4
938Cl(IRE)+: [M+H]+=615,6
939Cl(IRE)+: [M+H]+=587,5
940Cl(IRE)+: [M+H]+=to 588.5
941Cl(IRE)+: [M+H]+=678,6
942 ClCH2CH3(IRE)+: [M+H]+=549,4

943ClCH2CH2CH3(IRE)+: [M+H]+=563,5
944Cl(IRE)+: [M+H]+=561,5
945ClC(CH3)3(IRE)+: [M+H]+=577,5
946Cl(IRE)+: [M+H]+=603,6
947ClCH2(CH2)3CH3(IRE)+: [M+H]+=591,5
948ClCH(CH2CH3)CH2CH2CH2CH3(IRE)+: [M+H]+=619,6
949Cl(IRE)+: [M+H]+=671,6
Cl(IRE)+: [M+H]+=611,6
951Cl(IRE)+: [M+H]+=625,6
952Cl(IRE)+: [M+H]+=637,6
953Cl(IRE)+: [M+H]+=617,5
954Cl(IRE)+: [M+H]+=627,6

955Cl(IRE)+: [M+H]+=641,6
956ClCH3CH3CH3CO2CH2CH3(IRE)+: [M+H]+=635,6
957Me(IRE)+: [M+H]+=577,4
958Me(IRE)+: [M+H]+=611,3
959Me(IRE)+: [M+H]+=611,3
960Me(IRE)+: [M+H]+=611,3
961Me(IRE)+: [M+H]+=607,4
962Me(IRE)+: [M+H]+=591,4
963Me(IRE)+: [M+H]+=591,3
964Me(IRE)+: [M+H]+=612,3

965Me(IRE)+: [M+H]+=578,3
966 Me(IRE)+: [M+H]+=583,3
967Me(IRE)+: [M+H]+=617,3
968Me(IRE)+: [M+H]+=583,3
969Me(IRE)+: [M+H]+=595,3
970Me(IRE)+: [M+H]+=567,3
971Me(IRE)+: [M+H]+=568,3
972Me(IRE)+: [M+H]+=658,4
973MeCH2CH3(IRE)+: [M+H]+=529,3
974MeCH2CH3CH3IRE)+: [M+H]+=543,4
975Me(IRE)+: [M+H]+=to 541.3
976MeC(CH3)3(IRE)+: [M+H]+=557,3

977Me(IRE)+: [M+H]+=583,4
978MeCH2(CH2)3CH3(IRE)+: [M+H]+=571,4
979MeCH(CH2CH3)CH2CH2CH2CH3(IRE)+: [M+H]+=599,5
980Me(IRE)+: [M+H]+=651,4
981Me(IRE)+: [M+H]+=591,3
982Me(IRE)+: M+H]+=605,4
983Me(IRE)+: [M+H]+=617,4
984Me(IRE)+: [M+H]+=597,3
985Me(IRE)+: [M+H]+=607,4
986Me(IRE)+: [M+H]+=621,4
987MeCH2N(CH3)2(IRE)+: [M+H]+=558,3
988MeCH2CH2CH2CO2CH2CH3(IRE)+: [M+H]+=615,4

Conn-s numberR8R19MC
989 eMee (IRE)+: [M+H]+=of 551.3
990MeCH(CH3)2(IRE)+: [M+H]+=579,4
991Me(IRE)+: [M+H]+=627,4
992Me(IRE)+: [M+H]+=613,3
993Me(IRE)+: [M+H]+=681,3
994Me(IRE)+: [M+H]+=647,3
995Me(IRE)+: [M+H]+=647,3
996Me(IRE)+: [M+H]+=643,3

997Me(IRE)+: M+H]+=627,4
998Me(IRE)+: [M+H]+=638,4
999Me(IRE)+: [M+H]+=681,3
1000Me(IRE)+: [M+H]+=670,4
1001Me(IRE)+: [M+H]+=653,3
1002MeCH2CF3(IRE)+: [M+H]+=619,3
1003Me(IRE)+: [M+H]+=728,3
1004Me(IRE)+: [M+H]+=661,3
1005MeCH3CH3(IRE)+: [M+H]+=565,3
1006MeWith the 3CH3CH3(IRE)+: [M+H]+=579,3
1007MeCH3CH3CH2CH3(IRE)+: [M+H]+=593,3
1008ClCH3(IRE)+: [M+H]+=571,4
1009ClCH(CH3)2(IRE)+: [M+H]+=599,5
1010Cl(IRE)+: [M+H]+=647,6
1011Cl(IRE)+: [M+H]+=633,6

1012Cl(IRE)+: [M+H]+=701,4
1013Cl(IRE)+: [M+H]+=667,5
1014Cl (IRE)+: [M+H]+=667,5
1015Cl(IRE)+: [M+H]+=667,5
1016Cl(IRE)+: [M+H]+=663,6
1017Cl(IRE)+: [M+H]+=647,6
1018Cl(IRE)+: [M+H]+=658,5
1019Cl(IRE)+: [M+H]+=701,5
1020Cl(IRE)+: [M+H]+=690,5
1021Cl(IRE)+: [M+H]+=673,4

1022Cl(IRE)+: [M+H]+=637,5
1023ClCH2CF3(IRE)+: [M+H]+=639,5
1024Cl(IRE)+: [M+H]+=748,5
1025Cl(IRE)+: [M+H]+=687,5
1026ClCH3CH3(IRE)+: [M+H]+=585,4
1027ClCH3CH2CH3(IRE)+: [M+H]+=599,5
1028ClCH3CH2CH3CH3(IRE)+: [M+H]+=613,6

The connection numberR13MS
1117 ECH3CH3CH3(IRE)+: [M+H]+=521,4
1118(IRE)+: [M+H]+=569,3
1119(IRE)+: [M+H]+=583,4
1120(IRE)+: [M+H]+=603,3
1121(IRE)+: [M+H]+=603,4
1122CH3CH3CH3CH3CH3(IRE)+: [M+H]+=549,4
1123(IRE)+: [M+H]+=597,4
1124CH CH2CH(CH3)2(IRE)+: [M+H]+=549,4
1125CH2C(CH3)3(IRE)+: [M+H]+=549,4
1126(IRE)+: [M+H]+=589,4
1127(IRE)+: [M+H]+=570,3
1128(IRE)+: [M+H]+=575,3
1129(IRE)+: [M+H]+=RUB 573.4

td align="left">
1130(IRE)+: [M+H]+=583,3
1131(IRE)+: [M+H]+=583,4
1132(IRE)+: [M+H]+=583,4
1133(IRE)+: [M+H]+=594,4
1134(IRE)+: [M+H]+=594,4
1135(IRE)+: [M+H]+=594,2
1136(IRE)+: [M+H]+=659,4
1137(IRE)+: [M+H]+=659,5

The connection numberR1R8R13nMC
1138 EFMeCH2(CH2)4CH31(IRE)+: [M+H]+=575,7
1139ClHCH2(CH2)4CH30(IRE)+: [M+H]+=563,3
1140ClH/td> CH2(CH2)2CH30(IRE)+: [M+H]+=535,3
1141ClHCH2(CH2)3HE0(IRE)+: [M+H]+=of 551.3
1142ClHCH2(CH2)2CN0(IRE)+: [M+H]+=546,3
1143ClH0(IRE)+: [M+H]+=597,3
1144ClH0(IRE)+: [M+H]+=589,3
1145ClH0(IRE)+: [M+H]+=587,3

1146Cl0(IRE)+: [M+H]+=625,4
1147ClN0(IRE)+: [M+H]+=653,3
1148ClN0(IRE)+: [M+H]+=627,3
1149ClN0(IRE)+: [M+H]+=575,3
1150ClNCH2CO2CH(CH3)20(IRE)+: [M+H]+=579,3
1151ClNCH2CH2SP0(IRE)+: [M+H]+=532,2
1152ClNCH2CH2CH2 OH0(IRE)+: [M+H]+=537,3
1153ClNCH2CN0(IRE)+: [M+H]+=518,2
1154ClN0(IRE)+: [M+H]+=614,3
1155ClN0(IRE)+: [M+H]+=619,3
1156ClN0(IRE)+: [M+H]+=519,2
1157ClN0(IRE)+: [M+H]+=595,3

1165
1158ClN 0(IRE)+: [M+H]+=645,4
1159ClN0(IRE)+: [M+H]+=577,3
1160ClNCH2SOS(CH3)30(IRE)+: [M+H]+=577,3
1161ClNCH2CONH20(IRE)+: [M+H]+=536,2
1162ClN0(IRE)+: [M+H]+=604,3
1163ClN0(IRE)+: [M+H]+=611,3
1164FMeCH2(CH2)2CH31(IRE)+: [M+H]+=547,6
FMeCH2(CH2)3HE1(IRE)+: [M+H]+=563,7
1166FMeCH2(CH2)2CN1(IRE)+: [M+H]+=558,8
1167FMe1(IRE)+: [M+H]+=609,8
1168FMe1(IRE)+: [M+H]+=RUR 601.8
1169FMe1(IRE)+: [M+H]+=599,7

F
1170FMe1(IRE)+: [M+H]+=637,9
1171Me1(IRE)+: [M+H]+=665,7
1172FMe1(IRE)+: [M+H]+=639,8
1173FMe1(IRE)+: [M+H]+=581,7
1174FMe1(IRE)+: [M+H]+=587,8
1175FMeCH2CO2CH(CH3)21(IRE)+: [M+H]+=591,7
1176FMeCH2CH2CH(CH3)21(IRE)+: [M+H]+=561,6
1177FMe CH2CH2CH2HE1(IRE)+: [M+H]+=549,6
1178FMeCH2CH2Och2CH31(IRE)+: [M+H]+=563,5
1179FMeCH2CH2CH2F1(IRE)+: [M+H]+=551,5
1180FMe1(IRE)+: [M+H]+=626,8
1181FMe1(IRE)+: [M+H]+=545,6

1182FMe1(IRE)+: [M+H]+=631,8
1183FMe 1(IRE)+: [M+H]+=607,7
1184FMe1(IRE)+: [M+H]+=657,7
1185FMe1(IRE)+: [M+H]+=byr589.7
1186FMe1(IRE)+: [M+H]+=606,8
1187FMeCH2SOS(CH3)31(IRE)+: [M+H]+=byr589.7
1188FMeCH2CONH21(IRE)+: [M+H]+=548,5
1189FMe1 (IRE)+: [M+H]+=616,7
1190FMe1(IRE)+: [M+H]+=623,6

(IRE)+: [M+H]+=626,3
The connection numberR16MC
1191 E95CH2CH3(IRE)+: [M+H]+=577,4
1192(IRE)+: [M+H]+=660,7
1193(IRE)+: [M+H]+=660,4
1194(IRE)+: [M+H]+=659,5
1195(IRE)+: [M+H]+=655,5
1196(IRE)+: [M+H]+=660,6
1197

1198(IRE)+: [M+H]+=631,4
1199(IRE)+: [M+H]+=643,3
1200CH3CH3CH3(IRE)+: [M+H]+=591,3
1201(IRE)+: [M+H]+=589,4
1202C(CH3)3(IRE)+: [M+H]+=605,2
1203CH2(CH2)3CH3(IRE)+: [M+H]+=619,3
1204CH(CH2CH3)CH3CH2CH2CH3(IRE)+: [M+H]+=648,7
1205(IRE)+: [M+H]+=639,4
1206(IRE)+: [M+H]+=665,5
1207 (IRE)+: [M+H]+=kzt645.3
1208(IRE)+: [M+H]+=655,4
1209CH2CH2CH2CO2CH2CH3(IRE)+: [M+H]+=663,5

The connection numberR16MS
1210 ECH2CH3
1211(IRE)+: [M+H]+=661,2
1212(IRE)+: [M+H]+=686,2
1213(IRE)+: [M+H]+=729,3
1214(IRE)+: [M+H]+=718,4
1215 (IRE)+: [M+H]+=701,2
1216(IRE)+: [M+H]+=776,4
1217CH3CH3CH3CH3(IRE)+: [M+H]+=641,4

The connection numberR16MC
1218 E
1219(IRE)+: [M+H]+=689,4, 691,4
1220(IRE)+: [M+H]+=703,6, 705,6
1221(IRE)+: [M+H]+=686,3, 688,3
1222(IRE)+: [M+H]+=605,4, 607,4
1223(IRE)+: [M+H]+=671,3
1224(IRE)+: [M+H]+=603,4, 605,4
1225(IRE)+: [M+H]+=to 641.5
1226(IRE)+: [M+H]+=675,4, 677,4
1227(IRE)+: [M+H]+=655,5, 657,5

1228(IRE)+: [M+H]+=621,3, 623,3
1229(IRE)+: [M+H]+=593,4
1230(IRE)+: [M+H]+=725,4,
1231CH3(IRE)+: [M+H]+=579,4, 581,4
1232(IRE)+: [M+H]+=to $ 591.1
1233(IRE)+: [M+H]+=699,5, 701,5

Conn-s numberR1R4R8bR11MS
1302FCH3CH3CH3F0(IRE)+: [M+H]+=502,4
1303FCH(CH3)2F0(IRE)+: [M+H]+=502,2
1304FF0 (IRE)+: [M+H]+=500,2
1305FCH3CH3F0(IRE)+: [M+H]+=488,2
1306FCH3CH3CH3F1CH3(IRE)+: [M+H]+=of 454.3
1307FCH(CH3)2F1CH3(IRE)+: [M+H]+=of 454.3
1308FF1CH3(IRE)+: [M+H]+=452,3
1309FCH2CH3F1CH3(IRE)+: [M+H]+=440,3
1310Me CH3CH3CH3F0C(CH3)3(IRE)+: [M+H]+=478,4
1311MeCH3CH3F0C(CH3)3(IRE)+: [M+H]+=464,4
1312MeCH(CH3)2F0C(CH3)3(IRE)+:
[M+H]+=478,4
1313MeF0C(CH3)3(IRE)+: [M+H]+=476,4
1314FCH3CH3CH3F0 (IRE)+: [M+H]+=508,3
1315FCH2CH3F0(IRE)+: [M+H]+=494,2
1316FCH(CH3)2F0(IRE)+: [M+H]+=508,3
1317FF0(IRE)+: [M+H]+=506,2
1318FCH3CH3CH3F0C(CH3)3(IRE)+: [M+H]+=RUB 482.2
1319FCH2CH3F0C(CH3)3(IRE)+: [M+H]+=4682
1320FCH(CH3)2F0C(CH3)3(IRE)+: [M+H]+=RUB 482.2
1321FF0C(CH3)3(IRE)+: [M+H]+=of 480.2
1322FCH(CH3)2Cl1CH3(IRE)+: [M+H]+=436,4
1323FCH3CH3CH3Cl1CH3(IRE)+:

[M+H]+=436,4
1324F CH2CH3Cl1CH3(IRE)+: [M+H]+=422,4
1325FCl1CH3(IRE)+: [M+H]+=434,4
1326MeCH3CH3N2CH2CH3(IRE)+: [M+H]+=446,3
1327MeCH3CH3CH3N2CH2CH3(IRE)+: [M+H]+=460,3
1328MeCH(CH3)2N2CH3CH3(IRE)+: [M+H]+=460,2
1329MeN 2CH2CH3(IRE)+: [M+H]+=458,2
1330FCH2CH3N2CH3CH3(IRE)+: [M+H]+=450,2
1331FCH2CH3CH3N2CH2CH3(IRE)+: [M+H]+=464,2
1332FCH(CH3)2N2CH2CH3(IRE)+: [M+H]+=464,2
1333FN2CH2CH3(IRE)+: [M+H]+=462,4
1334FCl0 (IRE)+: [M+H]+=from 517.2, 519,2
1335FCH(CH3)2Cl0(IRE)+: [M+H]+=519,2, 521,2

1336FCH3CH3CH3Cl0(IRE)+: [M+H]+=519,2, 521,2
1337FCH3CH3Cl0(IRE)+: [M+H]+=505,2, 507,2
1338MeCH(CH3)2N1CH3(IRE)+: [M+H]+=433,2
1339MeCH3CH3CH3N1 CH3(IRE)+: [M+H]+=433,2
1340MeCH3CH3N1CH3(IRE)+: [M+H]+=418,2
1341MeN1CH3(IRE)+: [M+H]+=430,2
1342FCH3CH2CH3Cl0(IRE)+: [M+H]+=524,3, 526,3
1343FCH(CH3)2Cl0(IRE)+: [M+H]+=524,3, 526,3
1344FCl0(IL-IS)+: [M+H]+=522,2, 524,2
1345FSSN3Cl0(IRE)+: [M+H]+=510,3, 512,3
1346FCH3CH3CH3Cl0(IRE)+: [M+H]+=518,3, 520,3
1347FCl0(IRE)+: [M+H]+=530,2, 532,2

1348FCH3CH3Cl0(IRE)+: [M+H]+=504,2, 506,2
1349FCH(CH3)2Cl0 (IRE)+: [M+H]+=518,2, 520,2
1350FCH3CH2CH3Cl0C(CH3)3(IRE)+: [M+H]+=498,2, 500,2
1351FCl0C(CH3)3(IRE)+: [M+H]+=510,4, 512,4
1352FCH2CH3Cl0C(CH3)3(IRE)+: [M+H]+=484,4, 486,4
1353FCH(CH3)2Cl0C(CH3)3(IRE)+: [M+H]+=498,4, 500,4
1354FCH3CH3CH3Cl1CH3(IRE)+: [M+H]+=470,3 472,3
1355FCl1CH3(IRE)+: [M+H]+=482,3, 484,3
1356FCH2CH3Cl1CH3(IRE)+: [M+H]+=456,2, 458,2
1357FCH(CH3)2Cl1CH3(IRE)+: [M+H]+=470,2, 472,2
1358FCH3CH3CH3Cl2CH2CH3(IRE)+: [M+H]+=498,3, 500,3

1359FCl2CH2CH3(IRE)+: [M+H]+=510,3, 512,3
1360FCH2CH3Cl2CH2CH3(IRE)+: [M+H]+=484,3, 486,3
1361FCH(CH3)2Cl2CH2CH3(IRE)+: [M+H]+=498,3, 500,3
1362FCl0(IRE)+: [M+H]+=516,2, 518,2
1363FCl0C(CH3)3(IRE)+: [M+H]+=496,2, 498,2
1364FCl1CH3(IRE)+: [M+H]+=468,1, 470,2
1365F Cl2CH2CH3(IRE)+: [M+H]+=496,3, 498,3

The connection numberR4MS
1366 E(IRE)+: [M+H]+=402,4
1367(Head)+: [M+H]+=522,3

Conn-s numberR12MS
1368 E1The NO2C(CH3)3(IRE)+: [M+H]+=543,2, 545,2
13691N(CH3)2(IRE)+: [M+H]+=471,2
13701 N(CH3)CO2C(CH3)3(IRE)+: [M+H]+=557,1, 559,1
1371 E1NH2(IRE)+: [M+H]+=443,0
13721N3(IRE)+: [M+H]+=457,1

The connection numberR4MS
1373 E115(IRE)+: [M+H]+=427,2
1374(Head)+: [M+H]=357,3, 359,3
1375(Head)+: [M+H]+=413,2, 415,2
1376(Head)+: [M+H]+=399,2, 401,2
1377CH3CH3CH3CH3CH3(Head)+: [M+H]+=387,2, 389,2
1378(Head)+: [M+H]+=427,1, 429,1
1379(Head)+: [M+H]+=427,1, 429,1
1380(Head)+: [M+H]+=393,2, 395,2

The connection numberR1R10R13X2MC
1381MeMeS(IRE)+: [M+H]+=573,3

Conn-s numberR1R16R13X2MC
1382 122 MeHNH(Head)+: [M+H]+=542,4
1383MeClNH(IRE)+: [M+H]+=576,4
1384MeMeNH(IRE)+: [M+H]+=556,4

(IRE)+: [M+H]+=446,2
Conn-s numberR1R4R10X2MC
1385 E124MeHS(Head)+: [M+H]+=432,3
1386ClMeS

Data on the antagonistic activity of the compounds according to the invention receptor VIa obtained in the analysis of Sample A.

1. The compound of General formula 1a or connection, representing his tautomer or pharmaceutically acceptable salt

where G represents a group selected from General formulae 2A, 3A, 4A, 5A and 6A,


where a1selected from CH2, NH,;
And2selected from CH2With(=O);
And3and12independently selected from-C(R8)=CH - and-CH=C(R8)-;
And4and13independently selected from C(R9);
And5 14independently selected from C(R10);
And6selected from CH2, NH and O;
And7and11represent;
And8and9independently selected from CH, N, NH, N(CH2)bR11and S;
And10selected from-CH=CH-, CH, N, NH, N-(CH2)b-R11and S;
where the ring formed And7And8And9And10and11is aromatic;
R1, R2and R3independently selected from H, C1-10of alkyl, F, Cl and Br;
R4selected from H, C1-10of alkyl, C3-8cycloalkyl, possibly substituted aryl and possibly substituted heteroaryl, -(CH2)c-R12and

R5and R6independently selected from C1-10of alkyl, phenyl,-(CH2)f-phenyl, possibly substituted by Cl, Br;
R7selected from C1-10of alkyl;
R8, R9and R10independently selected from H, C1-10of alkyl, C1-10alkoxy, F, Cl, Br;
under conditions that when G represents 3A and R4represents H, C1-10alkyl, C3-8cycloalkyl, aryl, heteroaryl or-(CH2)c-R12the ring containing
And3And4and5substituted at least in one position of C1-10the alkyl, C1-10alkoxy, F, Cl, Br, and
when G represents 4A, R4represents H, C1-10alkyl, C3-8cloaker, aryl, heteroaryl or -(CH2)c-R12and8represents NH, N3or S, the ring containing a And3And4and5substituted at least in one position of C1-10the alkyl, C1-10alkoxy, F, Cl, Br;
R11and R12independently selected from H, C1-10of alkyl, C3-8cycloalkyl, possibly substituted aryl, possibly substituted heteroaryl, NH2, NH-C1-10of alkyl, N(C1-10alkyl)2group CO2-C1-10alkyl;
and R4, R11and R12aryl represents phenyl or naphthyl, heteroaryl represents furyl, pyridyl, thienyl, imidazolyl, isoxazolyl, benzofurazanyl or triazolyl, and aryl and heteroaryl in R4, R11and R12possibly substituted by F, Cl, Br, C1-10the alkyl, CN, O-C1-10the alkyl, O-CF3, CF3SOON3, NO2The N3, phenyl, HE;
R13selected from H, C1-10of alkyl, C3-8alkenyl, aryl, heteroaryl,-(CH2)h-R15and Z-R16;
R15independently selected from H, C1-10of alkyl, C3-8cycloalkyl,2-6alkenyl, cyclic3-8alkenyl, aryl, heteroaryl, F, HE, S-C1-10the alkyl groups CO2-C1-10alkyl, CO-C1-10alkyl, CO-aryl, CONH2, CONH-C1-10alkyl, C2-6alkenyl-CO2-C1-10alkyl, C2-6Ala is melaril, CN and CF3;
R16selected from H, C1-10of alkyl, C3-8cycloalkyl, possibly substituted C1-10the alkyl, C2-6alkenyl, aryl, heteroaryl, O-aryl, cyclopropylamine,
-(CH2)i-R17;
R17selected from H, C1-10of alkyl, C3-8cycloalkyl, possibly substituted C1-10the alkyl, aryl, heteroaryl, F, HE, O-C1-10of alkyl, S-C1-10the alkyl groups, N(C1-10alkyl)2, NH-SOS1-10alkyl, CO2N, CO2-C1-10alkyl, CONH2CN and CF3;
and R13, R15-R17aryl represents phenyl or naphthyl, heteroaryl represents furyl, pyridyl, thienyl or benzofurazanyl, and aryl and heteroaryl in R13, R15-R17possibly substituted by F, Cl, Br, C1-10the alkyl, CN, O-C1-10the alkyl, O-CF3, CF3SOON3, NO2CH2OH, N3, phenyl;
W is selected from O and NH;
X is selected from (CH2)mWith(=O) and S(=O)j;
Y is selected from O, S, NH;
Z is selected from-C(=O)- C(=O)-O and-S(=O)k;
and selected from 1 and 2;
b and C are independently selected from 0, 1, 2, and 3;
d, e and f are independently selected from 1 and 2;
h and i are independently selected from 1, 2 and 3;
j and k equal to 2 and
m and n are independently selected from 0, 1 and 2.

2. The compound according to claim 1, where G is chosen from:

3. The compound according to claim 1, where G is chosen from:

4. The compound according to claim 1, where at least one of R1, R2and R3is other than hydrogen; preferably one of R1, R2and R3selected from methyl, chlorine and fluorine, and the others are hydrogen.

5. The compound according to claim 1, where W represents NH.

6. The compound according to claim 1, where R4represents a C1-10alkyl.

7. The compound according to claim 1, where d is 2 and e is 2.

8. The compound according to claim 1, where R13represents a C1-10alkyl.

9. The compound according to claim 1, where n represents 0.

10. The compound according to claim 1, where R2represents H, R4represents piperidine, where d is 2 and e is 2, W represents NH, X represents C(=O) and n represents 0, as shown in the formula 18a

where R1selected from methyl, chlorine and fluorine, and R3represents N or R1represents N and R3selected from methyl, chlorine and fluorine, and R13represents a C1-10alkyl.

11. The compound according to claim 1, where X represents C(=O), n represents 0 and R4represents piperidine, where d is 2 and e is 2, as shown in the formula 19a

where G is selected from the General formulas 7a-17A and R13present is employed, a C 1-10alkyl.

12. The compound according to claim 1, where R2represents N and W represents NH, as shown in the formula 20A

where R1selected from methyl, chlorine and fluorine, and R3represents N or R1represents N and R3selected from methyl, chlorine and fluorine; and G is selected from the General formulas 7a-17A.

13. The compound according to claim 1, where R2represents N, W represents NH, and X represents C(=O), as shown in the formula 21A

where R1selected from methyl, chlorine and fluorine, and R3represents N or R1represents N and R3selected from methyl, chlorine and fluorine; and R4represents a C1-10alkyl.

14. The compound according to claim 1, where X represents C(=O), as shown in the formula 22A

where G is selected from the General formulas 7a-17A and R4represents a C1-10alkyl.

15. The compound according to claim 1, where R2and R3both represent H, and W represents NH, and X represents C(=O), as shown in the formula 23a

where G is selected from the General formulas 9a, 10A, 15A, 16A and 17A, R1selected from methyl, chlorine and fluorine, and R4represents a C1-10alkyl.

16. The compound according to claim 1, where R2and R3both represent N, R4is own the th piperidine, where d is 2 and e is 2, W represents NH, X represents C(=O) and n represents 0, as shown in the formula 24A

where G is selected from the General formulas 9a, 10A, 15A, 16A and 17A, R1selected from methyl, chlorine and fluorine, and R13represents a C1-10alkyl.

17. The compound according to claim 1, selected from the group consisting of:
2-Chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
2-Chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles-[f]azulene-9-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
2-Fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
2-Methyl-4-(2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
2-Methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-database[e]azulene-6-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
3-Chloro-4-(3,6-dimethyl-4,tigera-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
3-Chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
3-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]-azulene-9-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
3-Fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
3-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-formanilide 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide 1-(3,3-dimethylbutyl)piperidine-4-carbon is howling acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-formanilide 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
4-[(4-Chlorophenyl)methylcarbamoyl]-2-methylbenzylamine 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
2-Chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-cyclopropylmethyl-4-carboxylic acid;
2-Chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-cyclopropylmethyl-4-carboxylic acid;
2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]-azulene-9-carbonyl)benzylamine 1-cyclopropylmethyl-4-carboxylic acid;
2-Fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-cyclopropylmethyl-4-carboxylic acid;
2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-cyclopropylmethyl-4-carboxylic acid;
3-Chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-cyclopropylmethyl-4-carboxylic acid;
3-Chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-cyclopropylmethyl-4-carboxylic acid;
3-Chloro-4-(6-chloro-3-meth is l-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]-azulene-9-carbonyl)benzylamine 1-cyclopropylmethyl-4-carboxylic acid;
3-Fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-cyclopropylmethyl-4-carboxylic acid;
3-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 1-cyclopropylmethyl-4-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 1-cyclopropylmethyl-4-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzene 1-cyclopropylmethyl-4-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide 1-cyclopropylmethyl-4-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-formanilide 1-cyclopropylmethyl-4-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide 1-cyclopropylmethyl-4-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 1-cyclopropylmethyl-4-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzylamine 1-cyclopropylmethyl-4-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-formanilide 1-cyclopropyl ethylpiperidine-4-carboxylic acid;
4-[(4-Chlorophenyl)methylcarbamoyl]-2-methylbenzylamine 1-cyclopropylmethyl-4-carboxylic acid;
2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine cyclobutanecarbonyl acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide cyclobutanecarbonyl acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide cyclobutanecarbonyl acid;
2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine cyclopentanecarbonyl acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide cyclopentanecarbonyl acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide cyclopentanecarbonyl acid;
2-Chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine cyclopropanecarbonyl acid;
2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine cyclopropanecarbonyl acid;
3-Chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine cyclopropanecarbonyl acid;
3-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles [f]-azulene-9-carbonyl)benzylamine cyclopropanecarbonyl acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetr is azabenzo[f]azulene-9-carbonyl)-2-methylbenzylamine cyclopropanecarbonyl acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide cyclopropanecarbonyl acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-formanilide cyclopropanecarbonyl acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzylamine cyclopropanecarbonyl acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine cyclopropanecarbonyl acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-formanilide cyclopropanecarbonyl acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles [f]azulene-9-carbonyl)-2-formanilide cyclopropanecarbonyl acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzylamine cyclopropanecarbonyl acid;
N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]propionamide;
N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]-2,2-dimethylpropanamide;
N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]isobutyramide;
N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]butyramide;
N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]propionamide;
N - [4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]-2,2-dimethylpropanamide;
N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]isobutyramide;
N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]butyramide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]propionamide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]-2,2-dimethylpropanamide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]isobutyramide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]ndimethylacetamide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]butyramide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]formamide;
N-[4-(6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-terbisil]propionamide;
4-(6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide cyclopropanecarbonyl acid;
N-[2-Fluoro-4-(6-fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]propionamide;
N-[2-Fluoro-4-(6-fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzyl]isobutyramide;
2-Fluoro-4-(6-fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine cyclopropanecarbonyl acid and
N-[4-(9-Chloro-2-methyl-4,5-d the hydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)-2-methylbenzyl]isobutyramide.

18. The compound of General formula 1b or connection, representing his tautomer or pharmaceutically acceptable salt

where G1is a bicyclic or tricyclic condensed piperidine or azepino derivative selected from the General formulas 2b, 3b, 4b and 5b


And1selected from CH2, NH and O;
And2selected from CH2With(=O);
And3selected from-C(R7)=CH - and-CH=C(R7)-;
And4selected from C(R8);
And5selected from C(R9);
And6selected from CH2, NH and O;
And7and11represent;
And8and9independently selected from CH, N, N(CH2)dR5;
And10selected from-CH=CH-, CH, N, N-(CH2)d-R5;
And12selected from-C(R10)=CH - and-CH=C(R10)-;
And13selected from C(R11);
And14selected from C(R12);
X1selected from O and NH;
X2selected from O, S, NH;
R1, R2and R3independently selected from H, C1-10of alkyl, F, Cl and Br;
R4selected from H, C1-10of alkyl, -(CH2)e-R6and Y-R15;
R13and R15independently selected from C1-10of alkyl, aryl, heteroaryl and -(CH2)f-R14;
R5, R6and R14independently selected from H, C1-10is Lila, With3-8cycloalkyl, aryl, heteroaryl, F, HE, CO2N, CO2-C1-10of alkyl, CONH2CN;
R7, R8and R9independently selected from H, C1-10of alkyl, C1-10alkoxy, F, Cl, Br;
R10, R11and R12independently selected from H, C1-10of alkyl, C1-10alkoxy, F, Cl, Br;
and R5, R6and R13-R15aryl represents phenyl or naphthyl, heteroaryl represents furyl, pyridyl, thienyl or benzofurazanyl, and aryl and heteroaryl in R5, R6and R13-R15possibly substituted by F, Cl, Br, C1-10the alkyl, CN, O-C1-10the alkyl, O-CF3, CF3SOON3, NO2CH2HE, N3, phenyl;
Y is selected from C=O and S(=O)g;
and selected from 1 and 2;
b is selected from 1, 2 and 3;
selected from 1 and 2;
d is selected from 0, 1, 2, and 3;
e is selected from 1, 2 and 3;
f is selected from 1, 2 and 3;
g is equal to 2; and
provided that the ring contains A3And4and5in accordance with the General formula 2b, and 3b, substituted, at least in one position of C1-10the alkyl, C1-10alkoxy, F, Cl, Br;
and provided that the ring formed And7And8And9And10and11is aromatic.

19. Connection p, where G1chosen from:

20. The connection according to claim 19, where G1selected from the General formulas 6b, 7b, 8b, 9b, 10b, 11b, 12b, 13b, 14b, 15b and 16b 17b:

21. The compound according to any one of p, 19 or 20, where at least one of R1, R2and R3is other than hydrogen.

22. Connection item 21, where one of R1, R2and R3selected from methyl, chlorine and fluorine, and the others are hydrogen.

23. The compound according to any one of p-20, where X1represents NH.

24. The compound according to any one of p-20, where a is a 1 and b is 2.

25. The compound according to any one of p-20, where R4represents a C1-10alkyl.

26. Connection p having the General formula 18b, where R1selected from methyl, chlorine and fluorine, and R4represents a C1-10alkyl

27. Connection claim 20, having the General formula 19b, where R1selected from methyl, chlorine and fluorine:

28. Connection claim 20, having the General formula 20b, where R4represents a C1-10alkyl:

29. Connection claim 20, having the General formula 21b, where R1selected from methyl, chlorine and fluorine; and R4represents a C1-10alkyl:

30. Connection p selected from
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-(2,2-dimethylpropyl)Pieper is Zin-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-(2,2-dimethylpropyl)piperazine-1-carboxylic acid;
2-Chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]-azulene-9-carbonyl)benzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
2-Methyl-4-(2-methyl-4,5-dihydro-1H-1,3,6-tratamento[e]azulene-6-carbonyl)benzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
2-Methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-database[e]azulene-6-carbonyl)benzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
2-Methyl-4-(3-methyl-7,8-dihydro-6H-5-oxa-9-athensallowed-9-carbonyl)benzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
2-Methyl-4-(8-methyl-3,4-dihydro-2H-quinoline-1-carbonyl)benzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
3-Chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
3-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]-azulene-9-carbonyl)benzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
4-3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-formanilide 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
4-(3-Chloro-7,8-dihydro-6H-5-oxa-9-athensallowed-9-carbonyl)-2-methylbenzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-formanilide 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-(3-methylbutyl)piperazine-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-(3-methylbutyl)piperazine-1-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-cyclopentylpropionate-1-carbon is Oh acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-cyclopentylpropionate-1-carboxylic acid;
2-Chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 4-cyclopropylamines-1-carboxylic acid;
2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 4-cyclopropylamines-1-carboxylic acid;
3-Chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)benzylamine 4-cyclopropylamines-1-carboxylic acid;
3-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]-azulene-9-carbonyl)benzylamine 4-cyclopropylmethyl-piperazine-1-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide 4-cyclopropylamines-1-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-cyclopropylamines-1-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-formanilide 4-cyclopropylamines-1-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzylamine 4-cyclopropylamines-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide 4-cyclopropyl reparacin-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-cyclopropylamines-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-formanilide 4-cyclopropylamines-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-3-methylbenzylamine 4-cyclopropylamines-1-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-isobutylpyrazine-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-isobutylpyrazine-1-carboxylic acid;
4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-propylpiperazine-1-carboxylic acid;
4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-propylpiperazine-1-carboxylic acid;
2-Methyl-4-(2-methyl-4,5-dihydro-3-thia-1,6-database[e]azulene-6-carbonyl)benzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
2-Fluoro-4-(6-fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]-azulene-9-carbonyl)benzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
4-(3,7-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-methylbenzylamine 4-(3,3-dimethylbutyl)piperazine-1-carboxylic KIS is the notes; and
4-(3,5-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)-2-formanilide 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid.

31. The compound of General formula 1C or connection, representing his tautomer or pharmaceutically acceptable salt

where G represents a group selected from General formula 2C, 3C, 4C and 5C,

And1selected from CH2, NH,;
And2selected from CH2With(=O);
And3selected from-C(R3)=CH - and-CH=C(R3)-;
And4selected from C(R4);
And5selected from C(R5);
And6selected from CH2, NH and O;
And7and11represent;
And8and9independently selected from CH, N, NH, N(CH2)c-R6;
And10selected from-CH=CH-, CH, N, NH, N-(CH2)c-R6;
where the ring formed And7And8And9And10and11is aromatic; and
R1selected from H, C1-10of alkyl, C3-8cycloalkyl, possibly substituted C1-10the alkyl, C2-6alkenyl, cyclic3-8alkenyl, C1-10alkylaryl,2-6alkynylaryl,3-8cycloalkenyl, aryl, heteroaryl, -(CH2)d-R7,
and
R2selected from C1-10of alkyl;
R3, R4 and R5independently selected from H, C1-10of alkyl, C1-10alkoxy, F, Cl, Br;
R6and R7independently selected from H, C1-10of alkyl, aryl, heteroaryl, F, HE, O-C1-10of alkyl, O-aryl, O-C1-10alkylaryl, NH2, NH-C1-10of alkyl, N(C1-10alkyl)2, CO2-C1-10of alkyl, CONH2CN and CF3;
and R1, R6and R7aryl represents phenyl or naphthyl, heteroaryl represents furyl, pyridyl, thienyl, imidazolyl, isoxazolyl, benzofurazanyl or triazolyl, and aryl and heteroaryl in R1, R6and R7possibly substituted by F, Cl, Br, C1-10the alkyl, CN, a group O-C1-10alkyl, O-CF3, CF3SOON3, NO2, NHCOCH3, phenyl, HE;
R8and R9independently selected from H, C1-10of alkyl, C3-8alkenyl, aryl, heteroaryl, -(CH2)k-R11and Y-R12;
R11independently selected from H, C1-10of alkyl, C3-8cycloalkyl,2-6alkenyl, cyclic3-8alkenyl, aryl, heteroaryl, F, HE, O-C1-10of alkyl, S-C1-10of alkyl, N(C1-10alkyl)2WITH-C1-10of alkyl, CO-aryl, CO2-C1-10of alkyl, CONH2, N-C1-10of alkyl, C2-6alkenyl-CO2-C1-10of alkyl, C2-6alkynylaryl, CN and CF3;
R12selected from H, C1-10of alkyl, C3-8qi is loukili, possibly substituted C1-10the alkyl, C2-6alkenyl, cyclopropylamine, aryl, heteroaryl and (CH2)1-R13;
R13selected from H, C1-10of alkyl, C3-8cycloalkyl, aryl, heteroaryl, F, HE, O-C1-10of alkyl, S-C1-10of alkyl, NH-COC1-10of alkyl, CO2N, CO2-C1-10of alkyl;
and R8, R9and R11-R13aryl represents phenyl or naphthyl, heteroaryl represents furyl, pyridyl, thienyl or benzofurazanyl, and aryl and heteroaryl in R8, R9and R11-R13possibly substituted by F, CL, Br, C1-10the alkyl, CN, a group O-C1-10alkyl, O-CF3, CF3SOON3, NO2CH2HE, N3, phenyl;
W is selected from CH2With(=O) (=O)-O, and S(=O)m;
X is selected from O, S, NH;
Y is selected from C(=O) (=O)-O and-S(=O)n;
b is selected from 1 and 2;
c and d are independently selected from 0, 1, 2, and 3;
e is selected from 0, 1 and 2;
f, g, h and i are independently selected from 1 and 2;
k and l are independently selected from 1, 2 and 3;
m and n are independently selected from 1 and 2.

32. Connection p, where G is chosen from:

33. Connection p, where G is chosen from:

34. Connection p, where R8represents a C1-10alkyl.

35. Connection p, where R9represents a C1-10alkyl.

36. Conn is out on p, where R1chosen from:

37. Connection p, where R1chosen from:

38. Connection p, where W represents C(=O).

39. Connection p, as shown in the formula 18C:

where G is selected from the General formulas 6P-11P and R1selected from the General formulas 12C-15C; preferably R1selected from the 14C and 15C.

40. Connection § 39, where V represents NH.

41. Connection § 39, where a is a 1.

42. Connection § 39, where V is NH, W represents C(=O), and a represents 1; as shown in the formula 16C

where R1selected from the General formulas 12C-15C, preferably R1selected from the 14C and 15C.

43. Connection § 39, where V is NH, W represents C(=O) and a is a 1, as shown in the formula 17c

where G is selected from the General formulas 6P-11P.

44. Connection § 39, as shown in formula 19 (C), where V represents NH, W represents C(=O) and a is a 1:

and where G is selected from the General formulas 6P-11P and R1selected from the General formulas 12C-15C; preferably R1selected from the 14C and 15C.

45. Connection p selected from the group consisting of:
[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazines the[f]azulene-9-carbonyl)cyclohexylmethyl]amide 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
[4-(3-Methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 1-(3,3-dimethylbutyl)piperidine-4-carboxylic acid;
[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 1-cyclopropylmethyl-4-carboxylic acid;
[4-(3-Methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 1-cyclopropylmethyl-4-carboxylic acid;
[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 1-cyclopropylmethyl-4-carboxylic acid;
[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-(2,2-dimethylpropyl)piperazine-1-carboxylic acid;
[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
[4-(3-Methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-(3,3-dimethylbutyl)piperazine-1-carboxylic acid;
[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-CT is of IMT)cyclohexylmethyl]amide 4-(3-methylbutyl)piperazine-1-carboxylic acid;
[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles [f] azulene-9-carbonyl)cyclohexylmethyl]amide 4-(3-methylbutyl)piperazine-1-carboxylic acid;
[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-cyclopentylpropionate-1-carboxylic acid;
[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-cyclopentylpropionate-1-carboxylic acid;
[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-cyclopropylamines-1-carboxylic acid;
[4-(3-Methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-cyclopropylamines-1-carboxylic acid;
[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-cyclopropylamines-1-carboxylic acid;
[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-isobutylpyrazine-1-carboxylic acid;
[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-isobutylpyrazine-1-carboxylic acid;
[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide 4-propylpiperazine-1-carboxylic acid;
[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohe Silmaril]amide 4-propylpiperazine-1-carboxylic acid;
[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide cyclopropanecarbonyl acid;
[4-(3-Methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide cyclopropanecarbonyl acid; and
[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)cyclohexylmethyl]amide cyclopropanecarbonyl acid.

46. The compound of General formula 1d or connection, representing his tautomer or pharmaceutically acceptable salt

where G represents a group selected from General formula 2d, 3d, 4d, 5d and 6d


where a1selected from CH2, NH,;
And2selected from CH2With(=O);
And3selected from-C(R8)=CH - and-CH=C(R8)-;
And4selected from C(R9);
And5selected from C(R10);
And6selected from CH2, NH and O;
And7and11is;
And8and9independently selected from CH, N, NH, N(CH2)cR11;
And10selected from-CH=CH-, CH, N, NH, N-(CH2)c-R11;
where the ring formed And7And8And9And10and11is aromatic, R1, R2and R3independently selected from H, C1-10-alkyl, F, Cl and Br, and at least one of the
R1, R2 and R3is other than hydrogen;
R4selected from

and
R5and R6independently selected from C1-10of alkyl, phenyl,-(CH2)f-phenyl, possibly substituted by CL, Br;
R7selected from C1-10of alkyl;
R8, R9and R10independently selected from H, C1-10of alkyl, C1-10alkoxy, F, CL, Br;
R11selected from C1-10of alkyl;
R12selected from H, C1-10of alkyl, C2-6alkenyl,3-8cycloalkenyl, aryl, heteroaryl, -(CH2)i-R18and Z-R19;
R13and R14independently selected from H, C1-10of alkyl, C3-8cycloalkyl, aryl, heteroaryl and -(CH2)j-R20;
R15, R16independently selected from H, C1-10of alkyl, C3-8cycloalkyl, aryl, heteroaryl, CH(CH2OH)(CH2)k-R21CH(C1-10alkyl)(CH2)k-R21CH(C1-10alkyl)-aryl, CH(CO2-C1-10alkyl)(CH2)k-R21, (CH2)k-CH(aryl)-R21possibly substituted piperidine, indane and -(CH2)k-R21;
R23selected from H, C1-10the alkyl and -(CH2)k-R21;
R18independently select the n of N, With1-10of alkyl, C3-8cycloalkyl,2-6alkenyl, cyclic3-8alkenyl, aryl, heteroaryl, F, HE, O-C1-10of alkyl, S-C1-10of alkyl, N(C1-10alkyl)2, CO2-C1-10of alkyl, CO-C1-10of alkyl, CO-aryl, CONH2,
CONH-C1-10of alkyl, C2-6alkenyl-CO2-C1-10of alkyl, C2-6alkynylaryl, CN and CF3;
R19selected from H, C1-10of alkyl, C3-8cycloalkyl, aryl, heteroaryl, O-aryl, -(CH2)l-R22, cyclopropylamine;
R20, R21and R22independently selected from H, C1-10of alkyl, C3-8cycloalkyl, aryl, heteroaryl, F, HE, O-C1-10of alkyl, S-C1-10of alkyl, N(C1-10alkyl)2,
NH-SOS1-10of alkyl, CO2N, CO2-C1-10of alkyl, CONH2CN and CF3;
R24, R25and R26independently selected from H, C1-10of alkyl, hydroxy-C1-10of alkyl,
CO2-C1-10of alkyl, CONH2, CONH-C1-10the alkyl group SOP(C1-10alkyl)2CH2-phenyl, and
or R24and R25together form a condensed phenyl ring, possibly substituted O-C1-10the alkyl, or together form a condensed tsiklogeksilnogo ring,
or R25and R26together form a condensed phenyl ring, or together form kondensirovannoi tsiklogeksilnogo ring;
and R12-R16, R18-R22aryl represents phenyl or naphthyl, heteroaryl is thiazolyl, imidazolyl, isoxazolyl, pyrrolyl, thiadiazolyl, thiazolyl, furyl, pyridyl, thienyl or benzofurazanyl, and aryl, heteroaryl, piperidine, R12-R16, R18-R22possibly substituted by F, Cl, Br, C1-10the alkyl, CN, O-C1-10the alkyl, O-CF3CH(CH3HE, CF3, SOOS1-4alkyl, N(CH3)2SOON3, NO2CH2HE NHCOCH3, phenyl, CH2the phenyl, HE;
R27and R28independently selected from H and C1-10of alkyl;
U is selected from CH=CH, and CH2;
V is selected from CH2With(=O);
W is selected from O, S, NH;
X is selected from N and CH;
Y is selected from CH-R26, (CH2)n, C=O, O and S;
Z is selected from C=O and S(=O)p;
and selected from 0, 1, 2, and 3;
b is selected from 1 and 2;
selected from 0,1, 2 and 3;
d and e are independently selected from 1 and 2;
f is selected from 0 and 1;
i, j, k and 1 are independently selected from 1, 2 and 3;
n is selected from 0, 1 and 2;
p is selected from 1 and 2.

47. Connection p.46, where G is chosen from:

48. Connection p.46 chosen from:

49. Connection p.46, where one of R1, R2and R3represents methyl, chlorine or fluorine and the others are hydrogen.

50. Connection p.46, where R2 represents a C1-10alkyl.

51. Connection p.46, where R4chosen from:

52. Connection p.46, where R4chosen from:

53. Connection p.46, where U represents O, V is C(=O) and a is a 1.

54. Connection p.46, where U represents CH2V represents C(=O) and a is selected from 1 and 2.

55. Connection p.46, where U represents O, V represents CH2and a is selected from 1 and 2.

56. Connection p.46, where R2and R3both represent H, U represents O, V is C(=O) and a is a 1, as shown in the formula 18d

where R1selected from methyl, chlorine and fluorine, and R4selected from the General formulas 13d, 15d and 16d; preferably R4represents 16d.

57. Connection p.46, where R2and R3both represent H, U represents CH2V represents C(=O) and a is a 1, as shown in the formula 19d:

where R1selected from methyl, chlorine and fluorine; preferably R1represents methyl; R4selected from the General formulas 13d, 15d and 16d; preferably R4represents 16d.

58. Connection p.46, where R2and R3both represent N, U p is ecstasy a and V represents CH 2as shown in the formula 20d

where R1selected from methyl, chlorine and fluorine, and R4selected from the General formulas 13d-17d; preferably R4selected from the General formulas 16d and 17d.

59. Connection p.46, where R2and R3both represent H, U represents O, V represents CH2and a represents 2, as shown in the formula 21d

where R1selected from methyl, chlorine and fluorine, and R4selected from the General formulas 13d-17d; preferably R4selected from 16d and 17d.

60. Connection p.46, where U represents O and V represents CH2as shown in the formula 22d

where G is selected from the General formulas 7d-12d; preferably R4selected from the General formulas 13d-17d, more preferably R4selected from 16d and 17d.

61. Connection p.46, where U represents O, V represents CH2and a represents 2, as shown in the formula 23d

where G is selected from the General formulas 7d-12d; preferably R4selected from the General formulas 13d-17d, more preferably R4selected from 16d-17d.

62. Connection p.46, where U represents CH2V represents C(=O) and a is a 1, as shown in the formula 24d

where G is selected from the General fo the mule 7d-12d; preferably R4selected from the General formulas 13d, 15d and 16d; more preferably R4represents 16d.

63. Connection p.46, where U represents O, V is C(=O) and a is a 1, as shown in the formula 25d

where G is selected from the General formulas 7d-12d; preferably R4selected from the General formulas 13d, 15d and 16d; more preferably R4represents 16d.

64. Connection p.46, where R2and R3both represent H, as shown in the formula 26d

where R1selected from methyl, chlorine and fluorine, and G is selected from the General formulas 7d-12d.

65. Connection p.46, where R2and R3both represent H, U represents O and V represents CH2as shown in the formula 27d

where R1selected from methyl, chlorine and fluorine, and G is selected from the General formulas 7d-12d; preferably R4selected from the General formulas 13d-17d; more preferably R4selected from 16d and 17d.

66. Connection p.46, where R2and R3both represent H, U represents O, V represents CH2and a represents 2, as shown in the formula 28d

where R1selected from methyl, chlorine and fluorine, and G is selected from the General formulas 7d-12d; preferably R4selected from the à bdih formulas 13d-17d, more preferably R4selected from 16d and 17d.

67. Connection p.46, where R2and R3both represent H, U represents CH2V represents C(=O) and a is a 1, as shown in the formula 29d

where R1selected from methyl, chlorine and fluorine; preferably R1represents methyl; G is selected from the General formulas 7d-12d; preferably R4selected from the General formulas 13d, 15d and 16d; more preferably R4represents 16d.

68. Connection p.46, where R2and R3both represent H, U represents O, V is C(=O) and a is a 1, as shown in the formula 30d

where R1selected from methyl, chlorine and fluorine, and G is selected from the General formulas 7d-12d; preferably R4selected from the General formulas 13d, 15d and 16d; more preferably
R4represents 16d.

69. Connection p.46 selected from the group consisting of:
(2-Chloro-4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(2-Chloro-4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(2-Chloro-4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-yl)methanone;
(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-{3-methyl-4-[3-(4-propylpiperazine-1-yl)propoxy]phenyl}methanone;
(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-{4-[3-(4-isobutylpyrazine-1-yl)propoxy]-3-were}methanone;
(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-(3-methyl-4-{3-[4-(3-methylbutyl)piperazine-1-yl]propoxy}phenyl)methanone;
(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-(4-{3-[4-(2,2-dimethylpropyl)piperazine-1-yl]propoxy}-3-were)methanone;
(3-Chloro-4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(3-Chloro-4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(3-Chloro-4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(3-Fluoro-4-{3-[4-(3-methylbutyl)piperazine-1-yl]propoxy}phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(4-{2-[4-(3,3-Dimethylbutyl)piperazine-1-yl]ethoxy}-3-were)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(4-{3-[4-(2,2-Dimethylpropyl)piperazine-1-yl]propoxy}-3-forfinal)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(4-{3-[4-(2-Ethylbutyl)piperazine-1-yl]propoxy}-3-forfinal)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazines the[f]azulene-9-yl)methanone;
(4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]propoxy}-2-forfinal)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]propoxy)-2-forfinal)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]propoxy}-3-forfinal)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]propoxy}-3-forfinal)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]propoxy}-3-were)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(4-{3-[4-(3,3-Dimethylbutyl)piperazine-1-yl]propoxy}-3-were)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-(4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}-3-were)methanone;
(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-(4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}-3-forfinal)methanone;
(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)-(4-{3-[4-(3,3-dimethylbutyl)piperazine-1-yl]propoxy}-2-forfinal)methanone;
{2-Chloro-4-[3-(4-isobutylpyrazine-1-yl)propoxy]phenyl}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
{2-Chloro-4-[3-(4-propylpiperazine-1-yl)propoxy]phenyl}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza is Enzo[f]azulene-9-yl)methanone;
{3-Fluoro-4-[3-(4-isobutylpyrazine-1-yl)propoxy]phenyl}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
{3-Fluoro-4-[3-(4-propylpiperazine-1-yl)propoxy]phenyl}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
{4-[3-(4-Cyclopentylpropionate-1-yl)propoxy]-3-forfinal}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
{4-[3-(4-Cyclopropylamines-1-yl)propoxy]-3-forfinal}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
{4-[3-(4-Cyclopropylamines-1-yl)propoxy]-3-were}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
{4-[3-(4-Cyclopropylmethyl-1-yl)propoxy]-3-forfinal}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-yl)methanone;
1-(4-Benzylaminopurine-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-(4-Cyclobutylmethyl-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-(4-Cyclobutylmethyl-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-(4-Cyclobutylmethyl-1-yl)-4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]butane-1-it;
1-(4-Cyclohexylpiperidine-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]the pan-1-it;
1-(4-Cyclopentenopyridine-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-(4-Cyclopentenopyridine-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-(4-Cyclopentenopyridine-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-(4-Cyclopropanemethylamine-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-(4-Cyclopropylamines-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-(4-Hexylaniline-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-(4-Sibutramineamerican-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-[4-(1-Benzylpiperidine-4-ylamino)piperidine-1-yl]-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl] propane-1-it;
1-[4-(2-Hydroxyethylamino)piperidine-1-yl]-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-2-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]ethanone;
1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-2-[4-(3-methyl-4,10-d the hydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenoxy]ethanone;
1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]butane-1-it;
1-[4-(3,3-Dimethylbutyl)piperazine-1-yl]-5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]pentane-1-it;
1-[4-(3,4-Dihydro-1H-isoquinoline-2-ylmethyl)piperidine-1-yl]-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-propane-1-it;
1-[4-(3-Hydroxypropylamino)piperidine-1-yl]-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-[4-(3-Imidazol-1-ylpropionic)piperidine-1-yl]-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-propane-1-it;
1-[4-(Benzylmethylamine)piperidine-1-yl]-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-[4-(Cyclohexylethylamine)piperidine-1-yl]-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-[4-(Isobutylamino)piperidine-1-yl]-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-{4-[(1-Benzylpiperidine-4-ylamino)methyl]piperidine-1-yl}-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-propane-1-it;
1-{4-[(Butylmethylamine)IU is Il]piperidine-1-yl}-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propane-1-it;
1-{4-[Benzyl-(2-dimethylaminoethyl)amino]piperidine-1-yl}-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-propane-1-it;
3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-1-[4-(2-oxo-2-para-triletal)piperazine-1-yl]propane-1-it;
3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-1-[4-(2-pyrrolidin-1-retil)piperazine-1-yl]propane-1-it;
3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-1-[4-(2-morpholine-4-ylethylamine)piperidine-1-yl]propane-1-it;
3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-1-(4-geneticallymodified-1-yl)propane-1-it;
3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-1-{4-[2-(1-methylpyrrolidine-2-yl)ethylamino]piperidine-1-yl}propane-1-it;
3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-1-[4-(2-pyrrolidin-1 ylethylamine)piperidine-1-yl]propane-1-it;
3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-1-[4-(phenethylamines)piperidine-1-yl]propane-1-it;
3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]-1-(4-thiomorpholine-4-iletilerini-1-yl)propane-1-it; and
Piperidine-4-Eletropaulo ester 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetrazoles[f]azulene-9-carbonyl)phenyl]propionic acid.

70. Pharma is eticeskaja composition, having antagonistic activity against receptor V1acomprising an effective amount of a compound according to any one of claims 1 to 69 and pharmacologically acceptable excipient.

71. The pharmaceutical composition according to item 70, prepared in the form of a preparation for oral administration, preferably in the form of tablets, capsules or sachets.

72. The pharmaceutical composition according to item 70 or 71 for the treatment of a condition selected from dysmenorrhea, premature labor, hypertension, disease Rayno, cerebral oedema, motion sickness, hyperlipidemia, small-cell lung cancer, depression, anxiety, hyponatremia and congestive heart failure.

73. The use of compounds according to any one of claims 1 to 69 for the preparation of drugs for the treatment of a condition selected from dysmenorrhea, premature labor, hypertension, disease Rayno, cerebral oedema, motion sickness, hyperlipidemia, small-cell lung cancer, depression, anxiety, hyponatremia and congestive heart failure.



 

Same patents:

Quinolone analogues // 2349586

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (1): and to their pharmaceutical salts, where B, X, A or V are not present, if Z1, Z2, Z3 or Z4 respectively represent N, and independently H, halogen atom, azido, R2, CH2R2, SR2, OR2 or NR1R2, when Z1, Z2, Z3 or Z4 represent C. In each NR1R2, R1 and R2 together with N there can be formation of an optionally substituted piperidine, pyrrolidine, piperazine or morpholine ring. Z1 represents N and Z2, Z3 and Z4 represent C, or Z1 and Z3 represent N and Z2 and Z4 represent C. W together with N and Z form an optionally substituted thiazole, imidazole or pyrimidine ring, which is condensed with an optionally substituted ring, chosen from a group consisting of: or . U represents NR1R2, NR1-(CR12)n-NR3R4, where in NR3R4, R3 and R4 together with N there can be formation of an optionally substituted piperidine, pyrrolidine, piperazine or morpholine ring. R1 and R3 independently represent H or C1-6alkyl. Each R2 represents H or C1-10alkyl, each optionally substituted with a halogen atom, or C3-6cycloalkyl, aryl, heteroaryl or pyridine, pyrrolidine, piperazine or morpholine ring, where each ring is optionally substituted; or R2 is optionally substituted with piperidine, pyrrolidine, pyridine, piperazine, pyrazine, morpholine or benzimidazole. R2 represents H or C1-10alkyl. Each R5 represents a substitute in any position in ring W, and is H, OR2, amino, alkoxy, amido, halogen atom or cyano; or R5 represents C1-6alkyl, -CONHR1-, each optionally substituted with a halogen atom; or two adjacent R5 are linked with formation of a 5-6-member ring, an optionally substituted heterocyclic ring, chosen piperidine, pyrrolidine, piperazine or morpholine ring. n equals 1-6, and each optionally substituted part can be substituted with one or more halogens, OR2, NR1R2 , carbamate, C1-10alkyl, each optionally substituted with a halogen atom, C=O, cyano, nitro, COR2, NR2COR2, sulphonyl amides, NR2SOOR2; SR2, SOR2, COOR2, CONR22, OCOR2, OCOOR2 or OCONR22. The invention also relates to pharmaceutical compositions, to the method of suppressing proliferation of cells and/or weakening cell proliferative breakdown, to the method of reducing microbe titre and/or weakening microbe infection, to the method of inducing death of cells and/or inducing apoptosis, to compounds, chosen from a group, to pharmaceutical compositions, as well as to the method of producing compounds with formula (1).

EFFECT: obtaining new biologically active compounds, which can suppress proliferation of cells and/or induce apoptosis.

41 cl, 113 ex, 12 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

10 cl, 4 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to an improved process for the preparation of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-f] xanthine of the formula I, causing the induction of microsomal liver enzymes

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to D-proline derivatives of formula I or IA wherein R1 and R2 are independently lower alcoxy, lower alkenyloxy, hydroxy, -OCH(CH3)OC(O)-lower alkyl or -OCH2C(O)N(R3)N(R4), with the proviso, that only one from R1 and R2 represent hydroxy; R3 and R4 are independently hydrogen, lower alkyl? Lower alkenyl, or cycloalkyl; or R1 and R2 together with carbon atom to which they are attached form linkage group X, wherein X represents -O(CH2)nCH=CH(CH2)nO- or -O(CH2)mO-; n = 1, 2 or 3; m = 4-8.

EFFECT: new prodrugs.

14 cl, 1 tbl, 25(29) ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to derivatives of general formula I , wherein R1, R2 and R3 are independently H or C1-C4-alkyl; Ar is condensed thiophene or pyridine ring optionally substituted with one or more substituents selected from C1-C4-alkyl, C1-C4-alkyloxy, C1-C4-alkyloxy(C1-C4)-alkyl, CF3, halogen, nitro, cyano, NR4R5 NR4COR6 and CONR4R5 (R4 and R5 are independently H or C1-C4-alkyl; or R4 and R5 together with adjacent nitrogen atom form 5- or 6-membered saturated heterocyclic ring; R6 is C1-C4-alkyl): A is residue of 4-7-membered saturated heterocyclic ring optionally containing nictogen atom and optiomally substituted with 1-3 substituents selected from C1-C4-alkyl, C1-C4-alkyloxy, hydroxyl, halogen, and alkoxy; and pharmaceutical composition based on the same; with the proviso, that compound of formula I wherein A represents condensed [3,2-f]pyridine ring; each R1, R2 and R3 represents H, and A represents (CH2)3. Also described are application of abovementioned derivatives, pharmaceutical composition enhancing of synaptic response mediated with AMPA receptors in CNS based on the same, and method for treatment of neurological diseases or mental disorders.

EFFECT: new compounds with value biological properties.

7 cl, 1 tbl, 12 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates in particular to derivatives of acylbenzoxazine of the formula: wherein radicals X1 and X2 are taken independently among hydrogen atom, -OR3, -CH2OR3, or taken in common they represent -OCR

42
O-, -OC2R44
O-, -OC2R42
O- wherein in each case R in residue (CR2) represents hydrogen atom, oxy-group, (C1-C6)-alkoxy; R3 represents hydrogen atom, (C1-C6)-alkyl; in each case radical R1 represents hydrogen atom or (C1-C6)-alkyl; in each case radical R4 represents hydrogen atom or (C1-C6)-alkyl; n = 1, 2, 3 or 4. Compounds elicit the higher effect as compared with corresponding benzoylpiperidines for enhancing the synaptic responses mediated by AMPA-receptors. Also, invention relates to methods for their using for treatment of patients suffering with disorders in nervous and intellectual activity as result of insufficiency in function of some excitement synapses or in some AMPA-receptors. Compounds of the present invention can be used for treatment of patients without indicated disorders for enhancing activity associated with sensomotor and cognitive tasks that depend on the brain reticular structure using AMPA-receptors and for improving the memory encoding.

EFFECT: valuable biological and medicinal properties of compounds.

13 cl, 1 tbl, 5 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

--carboline" target="_blank">

The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

-lactams" target="_blank">

-lactams // 2143435
The invention relates to new derivatives-lactam of General formula I given in the description, in which Z denotes a methylene, oxygen or sulfur and R represents hydrogen, optionally substituted, lower alkoxycarbonyl, carbamoyl, lower (cyclo)allylcarbamate, phenylcarbamoyl or hydroxyphenylarsonic lower alkyl, lower alkenylacyl, formyl, optionally substituted with halogen, CYANOGEN, carbarnoyl-lowest alkylthiol, lower alkanoyl, respectively alkylsulfonyl, optionally substituted by lower (cyclo)alkyl, lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl lower alkyl or carboxy-lower alkyl carbarnoyl or ring structure of a General formula

Q-X-CO- (A1),

Q-X-SO2(A2),

where is a five - or six-digit, optionally containing nitrogen, sulfur and/or oxygen ring;

X denotes one of the groups-CH2, -CH2CH2-, -NH-, NHCH2-, -CH2NH-, -CH(NH2)--CH2CH2NH-, -C(=NOCH3)-, -OCH2-, -SCH2-;

A represents lower alkyl, hydroxy-(lower alkyl, vinyl, cianfrini, lower alkoxy, optionally phenylselenenyl lower alkylsulfonate, the remainder is-S-Het or-S- 2-L, where L is a lower alkanoyloxy, respectively carbamoylated, low-alkoxycarbonyl, carboxy, azido, lower alkanolamine, lower alkylsulfonyl, six-membered ring attached to the nitrogen atom, or a residue - or-S-CH2-Het, where Het has the above significance,

and pharmaceutically acceptable, readily hydrolyzable esters and salts of these compounds

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: medicine.

SUBSTANCE: according to the invention there is provided substituted indolequinoxalines of the formula (I), where R1 represents hydrogen or represents one or more similar or different substituent in positions from 7 to 10, selected of the group of halogen, low alkyl/alkoxy, hydroxy, triflouromethyl, trichloromethyl, triflouromethoxy, R2 represents similar or different C1-C4 alkyl substituents, X represents CO or CH2, Y represents OH, NH2, NH-(CH2)n-R3, where R3 represents low alkyl, OH, NH2, NHR4 or NR5R6, where R4, R5 and R6 represent low alkyl or cycloalkyl independently and n represents integer from 2 to 4 provided that X represents CH2, Y represents OH or NH-(CH2)n-OH and its pharmaceutically acceptable salt. There is also provided pharmaceutical composition, containing these compounds, methods of compound producing, formula (I).

EFFECT: compounds are applied as medicine for treatment and prevention of autoimmune diseases.

15 cl, 1 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to antagonists of serotonin 5-HT6 receptors - substituted 4-sulphonylpyrazoles and 3-sulphonyl-pyrazolo[1,5-a]pyrimidines of general formula 1 or general formula 1.2. These compounds can be used for treating and preventing development of different cognitive and neurodegenerative diseases of the central nervous system. In general formulae 1 and 1.2, 1 1.2 respectively, Ar is optionally substituted phenyl or optionally substituted 5-6-member heteroaryl, containing a nitrogen, oxygen or sulphur atom as a heteroatom; R1 is a hydrogen atom, optionally substituted C1-C5 alkyl, lower acyl or optionally substituted phenyl; R2 is an optionally substituted amino group or substituted hydroxy group or R1, together with the nitrogen atom to which it is bonded, and R2, together with the carbon atom to which it is bonded, form a substituted pyrimidine ring; R3 is a hydrogen atom, optionally substituted C1-C5alkyl, substituted hydroxyl group or substituted sulphanyl group, R5 is a hydrogen atom, optionally substituted C1-C5alkyl, substituted hydroxyl group or substituted sulphanyl group, R7 and R9 independently represent a hydrogen atom, C1-C3alkyl or phenyl, R8 is a hydrogen atom.

EFFECT: new compounds have useful biological properties.

13 cl, 2 dwg, 4 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: new derivative of diaminopyrroloquinazolines of formula (I) and their pharmaceutically acceptable salts possess properties of proteintyrosine posphatase PTP1 inhibitors which can be used for treating the diseases mediated by action of the latter, particularly for decreasing glucose content in blood. In formula (I) , A stands for 6-membered aromatic ring, or 5- or 6-membered aromatic ring which contains 1 or 2 heteroatoms chosen from S, N and O; R1 is specified from the group including the following radicals: C1-6alkyl, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl-(C1-6alkyl), benzyloxyC1-6alkyl and phenyl-(C1-6alkoxy)C1-6alkyl; R2 is specified from the group including the following radicals: hydrogen, C1-6alkyl, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl-(C1-6alkyl) and phenyl-(C1-6alkoxy)C1-6alkyl; R3 represents hydrogen or methyl; Ra is specified from the group including the following radicals: hydrogen, C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl(C1-6alkyl), benzyloxyC1-6alkyl or ; R10 represents hydrogen or ; x and y separately stand for integers 0 to 4; Rb and Rc are separately specified from the group including the following radicals: hydrogen, C1-6alkyl, perfluorochemical C1-6alkyl, substituted C1-6alkyl, C1-6alkoxy, phenoxy, halogen, (unsubstituted C1-6alkyl)-(substituted phenyl)-(C1-6alkyl), phenyl-(C1-6alkoxy) or ; R11 represents hydrogen, phenyl or unsubstituted C1-6alkyl; p stands for integer 0 to 1; Rd represents hydrogen, substituted C1-6alkyl or perfluorochemical C1-6alkyl; Re represents hydrogen, halogen, substituted C1-6alkyl and perfluorochemical C1-6alkyl; Rf represents hydrogen or C1-6alkyl; the substitutes found in alkyl groups are independently specified from the following groups: hydroxy, C1-6alkoxy, C1-6alkanoyl; and the substitutes found in substituted phenyl as Rb and Rc, are independently specified from the following groups: C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, hydroxyl, hydroxylC1-6alkoxy, halogen, perfluorC1-6alkyl and C1-6alkanoyl.

EFFECT: improved properties of the derivatives.

29 cl, 2 dwg, 48 ex

FIELD: medicine.

SUBSTANCE: invention covers new pyrrolopyrimidine and pyrrolotriazine derivatives substituted with carbamoyl group of formula [I], characterised as a CRF (corticotrophin release factor) receptor antagonist. The compounds can be effective as a therapeutic or preventive agent for such diseases, as depression, anxiety, Alzheimer's disease, Parkinson's disease, etc. in formula [I]: E means N or CR10; R1 means -OR4, -S(O)1R4 or-NR4R5; R2 means hydrogen, C1-6alkyl; R3 means hydrogen; R4 and R5 are identical or different, and independently mean hydrogen, C1-9alkyl, di(C3-7cycloalkyl)-C1-6alkyl, C1-6alkoxy-C1-6alkyl, di(C1-6alkoxy)-C1-6alkyl, hydroxy-C1-6alkyl, cyano-C1-6alkyl, carbamoyl-C1-6alkyl or di(C1-6alkyl)amino-C2-6alkyl, or R4 and R5 together form (CH2)m-A-(CH2)n where A means CHR9; R9 means hydrogen, hydroxy-C1-6alkyl, or cyano-C1-6alkyl; R10 means hydrogen; I means an integer 0, 1 and 2; m means an integer 1, 2, 3 and 4; n means an integer 0, 1, 2 and 3; Ar means phenyl, and specified phenyl is substituted by one or more substitutes being identical or different, and chosen from the group consisting of halogen, C1-6alkyl, trifluoromethyl; their individual isomers or pharmaceutically acceptable salts.

EFFECT: extended application.

9 cl, 2 dwg, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I where R1 stands for phenyl; G stands for C1-C7-alkylene; Q stands for -NH-; and X stands for C1-C7- alkylene, or to its salts. In addition, the invention concerns a pharmaceutical composition, to application of compound of formula I as defined in claims 1-5 item, as well as the method for making the compound of formula I.

EFFECT: production of the new biologically active compounds inhibiting protein tyrosine kinase.

8 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to new pyridine derivatives or to their pharmaceutically acceptable salts of general formula 1: wherein R1, R2, R3, R4, R5, R6 and R7 are independently chosen from the group including hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino, C4-C9cycloalkylamino, C4-C9heterocycloalkylamino, C1-C10aralkylamino, arylamino, acylamino, saturated heterocyclyl, acyloxy, aryl, heteroaryl, C1-C10aralkyl, aryloxy; X represents oxygen or sulphur atom; Y represents oxygen atom or N-R8, wherein R8 is chosen from the group including hydrogen atom; aforesaid aryl group is chosen from phenyl, naphthyl and condensed phenyl group; aforesaid heteroaryl and saturated heterocyclic groups represent pentagonal or hexagonal heterocyclic ring containing 1 to 2 heteroatoms chosen from oxygen, nitrogen and sulphur atom; or condensed heterocyclic ring; and aforesaid aryl and heteroaryl groups are those that 1 to 4 assistants chosen from group including halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted. And specified compounds or their pharmaceutically acceptable salt of formula 1 are not compounds as follows 6-methyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 5-vinyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 6-methyl-8-furan-2-yl-3,4- dihydropyrano[3,4-c]pyridin-1-one, 3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-8-one and dimethyl ether (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthyridine-3,5-dicarboxylic acids.

EFFECT: compounds possess inhibitory action with respect to formation of cytokines involved in inflammatory reactions, can be used as a therapeutic agent for treatment of inflammatory diseases, immune diseases, chronic inflammations; it provides antiinflammatory and analgesic action.

21 cl, 7 tbl, 144 ex

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