Ethylenediamine derivatives and fxa inhibitor and anticoagulant comprising thereof

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to new compounds which inhibit activated factor X coagulation (hereinafter commonly referred to as "FXa"), showing a strong anticoagulant effect and can be administered orally, and anticoagulants or means for preventing and/or treating thrombosis or embolism, which contain this new compound as the active component.

BACKGROUND of INVENTION

In unstable angina, myocardial infarction cerebral embolism cerebral, myocardial infarction, heart lung, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation, thrombus formation after valve replacement, reocclusion after angioplasty and the formation of blood clots in the extracorporeal circulation, the main factor is the hypercoagulable state. Therefore, there is a need to create a very good anticoagulants with good pharmacological response to a change of dosage, excellent duration, low risk of bleeding and low side effects and rapid onset sufficient desired effects even when administered orally (Thrombosis Research, Vol.68, pp.507-512, 1992).

Based on research and is decoagulant with different mechanism of action arose assumption, the Fxa inhibitors are promising anticoagulants. The system of blood coagulation involves a series of reactions leading to the formation of large amounts of thrombin due to the amplification process is sequential enzymatic reactions with formation of insoluble fibrin. In the endogenous system activated factor IX, activated factor X on phospholipid membrane in the presence of activated factor VIII and calcium ions after multistage reactions after activating factor of the contact. In the exogenous system activated factor VII activates factor X in the presence of tissue factor. In particular, the activation of factor X to Fxa in the coagulation system is a crucial reaction in the formation of thrombin. Activated factor X (FXa) limited decomposes prothrombin to form thrombin in both systems. Since the generated thrombin activates coagulation factors in the upper reaches, the formation of thrombin is further enhanced. As described above, since the coagulation system in the upper reaches of FXa is divided into endogenous system and exogenous system, production of FXa may not be sufficiently ingibirovany any abscopal enzymes in the coagulation in the upper reaches of Fxa, which leads to the production of thrombin. Because of the coagulation system includes reaction with samozrejme, inhib is the formation of the coagulation system can be more effectively achieved by inhibition of FXa in the upper reaches of thrombin, than by inhibiting thrombin (Thrombosis Research, Vol.15, pp.612-629, 1979).

Another excellent quality of FXa inhibitors is a big difference between an effective dose in the model of thrombosis and dose, prolong bleeding time in experimental hemorrhagic model. Based on the results of this experiment, inhibitors of FXa consider anticoagulation with low risk of bleeding.

Already there were reports of various compounds that serve as inhibitors of Fxa. It is known that antithrombin III and antithrombin III-dependent pentasaccharide essentially does not inhibit prothrombinase complexes, which play an important role in thrombus formation in vivo (Thrombosis Research, Vol.68, pp.507-512, 1992; Journal of Clinical Investigation Vol.71, pp.1383-1389, 1983; Mebio, Vol.14, the August number, pp.92-97). In addition, they are not effective when administered orally. Tick anticoagulant peptide (TAP) (Science, Vol.248, pp.593-596, 1990) and antistain (AST) (Journal of Biological Chemisry, Vol.263, pp.10162-10167, 1988), isolated from ticks or leeches, which are blood-sucking also have antithrombotic effect. However, these compounds are high molecular weight peptides and unsuitable for oral administration. As described above, was already carried out work on creation of the antithrombin III-independent low-molecular weight FXa inhibitors, directly inhibiting coagulation factors.

Thus, the present invention is the creation of new compounds with strong FXa-inhibiting effect and offering a prompt, adequate and sustained antithrombotic effect by oral administration.

Description of the INVENTION

The creators of the present invention investigated the synthesis and the pharmacological effects of new inhibitors of FXa. The results were found Ethylenediamine derivatives, their salts and solvate and N-oxides, which exhibit strong FXa-inhibiting effect and anticoagulation effect. It was also found that these compounds quickly, consistently and strongly inhibit FXa and have a strong anticoagulant and antithrombotic effects and therefore useful as a prophylactic and therapeutic drug for various diseases caused by embolism, which led to the creation of the present invention.

In accordance with the present invention features a compound represented by the General formula (1):

where

R1and R2independently from each other represent a hydrogen atom, hydroxyl group, alkyl group, or alkoxygroup;

Q1represents a saturated or unsaturated 5 - or 6-membered cyclic hydrocarbon group which may be substituted, n is Simandou or unsaturated 5 - or 6-membered heterocyclic group, which may be substituted, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may be substituted;

Q2represents a single bond, an unbranched or branched alkylenes group having 1-6 carbon atoms, unbranched or branched alkynylamino group having 2-6 carbon atoms, unbranched or branched alkynylamino group having 2-6 carbon atoms, a group-N(R3)-, where R3means a hydrogen atom or alkyl group, a group-N(R4)-(CH2)m-where R4means a hydrogen atom or alkyl group and m is an integer from 1 to 6, saturated or unsaturated 5 - or 6-membered divalent cyclic hydrocarbon group which may be substituted, saturated or unsaturated 5 - or 6-membered divalent heterocyclic group which may be substituted, saturated or unsaturated divalent bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated divalent bicyclic or tricyclic condensed g is teracycline group, which may be substituted;

Q3represents a group:

in which R5, R6, R7and R8independently from each other mean a hydrogen atom, hydroxyl group, halogen atom, halogenation group, cyano, lanakila group, acyl group, arylalkyl group, alkyl group, alkenylphenol group, alkylamino group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxialkilnuyu group, alkoxycarbonyl group, alkoxycarbonyl group, karbamoilnuyu group, N-alkylcarboxylic group, N,N-dialkylamino group, carbamoylethyl group, N-alkylcarboxylic group, N,N-dialkylanilines group, aryl group, aracelio group, heteroaryl group, or heteroallyl group or following group:

in which Q5means alkylenes group having 1-8 carbon atoms, or alkynylamino group having 2-8 carbon atoms, and R9and R10are substituents at the carbon atom(s) of the ring containing Q5and independently from each other represent a hydrogen atom, hydroxyl group, alkyl group, alkenylphenol group, alkylamino group, halogen atom, halogenate is inuu group, the cyano, lanakila group, amino group, aminoalkyl group, N-acylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, arylalkyl group, allmenalp, which may be substituted, alkoxyimino, hydroxyimino, acylaminoalkyl group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxialkilnuyu group, alkoxycarbonyl group, alkoxycarbonyl group, alkoxycarbonylmethyl, carboxymethylamino, alkoxycarbonylmethyl, alkoxycarbonylmethyl group, karbamoilnuyu group, N-alkylcarboxylic group which may have a substituent in the alkyl group, N,N-dialkylamino group which may have a substituent in the alkyl group, N-alkenylamine group, N-alkenylboronic group, N-alkenyl-N-alkylcarboxylic group, N-alkenyl-N-alkylcarboxylic group, N-alkoxycarbonyl group, N-alkyl-N-alkoxycarbonyl group, N-alkoxycarbonylmethyl group, N-alkyl-N-alkoxycarbonylmethyl group, carbazoyl group which may be substituted by 1-3 alkyl groups, alkylsulfonyl group, alkylsulfonyl group, 3-6-membered nitrogen-containing heterocyclic carbonyl group which the can is to be substituted, 3-6-membered nitrogen-containing heterocyclic carbonylethyl group which may be substituted, carbamoylethyl group, N-alkylcarboxylic group which may have a substituent in the alkyl group, N,N-dialkylanilines group which may have a substituent in the alkyl group, carbamoylmethyl group, N-alkylcarboxylic group, N,N-dialkylimidazolium group, 3-6-membered nitrogen-containing heterocyclic carboncillo group which may be substituted, aryl group, aracelio group, heteroaryl group, heteroallyl group, alkylsulfonamides, arylsulfonamides, alkylsulfonyl group, arylsulfonyl group, alkylsulfonamides group, arylsulfonamides group, alkylsulfonylpyridines group, arylsulfonamides group, oxoprop, carbamoyloximes, aralkylated, carboxymethyloxime, alloctype or aryloxyalkyl group, or R9and R10together with each other means alkylenes group having 1-5 carbon atoms, alkynylamino group having 2-5 carbon atoms, alkylenedioxy having 1-5 carbon atoms, or carbondioxide;

Q4represents the t aryl group, which may be substituted, arylalkyl group which may be substituted, a heteroaryl group which may be substituted, heteroallyl group which may be substituted, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may be substituted; and

T1represents carbonyl or sulfonyloxy group;

his salt, MES or N-oxide.

In accordance with the present invention it is also proposed medicinal product containing the above compound, its salt, MES or N-oxide as the active component.

In addition, we offer pharmaceutical composition comprising the compound described above, its salt, MES or N-oxide and a pharmaceutically acceptable carrier.

Further, in accordance with the present invention features the use of compounds described above, its salts, MES or N-oxide for the manufacture of a medicinal product.

In accordance with this invention features a method of treating thrombosis or embolism, which includes the introduction of the above-described compounds, its salts, MES or N-oxide.

And the school in accordance with the present invention features a method of treating a heart attack brain embolism cerebral, myocardial infarction, angina, heart attack, lung, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation, thrombus formation after valve replacement or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory syndrome response (SIRS), syndrome diseases of many organs (MODS), blood clots in the extracorporeal circulation, or blood clotting in its collection, which includes the introduction of compounds described above, its salts, MES or N-oxide. In addition, in accordance with the present invention offers an intermediate connection suitable for connection (1) according to the present invention.

PREFERRED embodiments of the INVENTIONS

The following describes the substituents in the derivatives of ethylene diamine of the present invention represented by the General formula (1).

<group Q4>

Group Q4means aryl group which may be substituted, arylalkyl group which may be substituted, a heteroaryl group which may be substituted, heteroallyl group which may be substituted, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may be the ü substituted, or saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may be substituted.

In the group of Q4the aryl group may include aryl groups having 6-14 carbon atoms, such as phenyl, naftalina, untilnow and phenanthroline group.

Arylalkylamine group means a group formed aryl group having 6-14 carbon atoms, and alkynylamino group having 2-6 carbon atoms, and its examples may include stielow group.

Heteroaryl group means a monovalent aromatic group having at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, and its examples include 5 - or 6-membered heteroaryl group, for example, pyridyloxy, follow, thienyl, pyrimidinyl and tetrazolyl group.

Heteroarylboronic group means a group formed of the above-described heteroaryl group and alkynylamino group having 2-6 carbon atoms, and its examples may include titilatingly and pyridylamino group.

Saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group means a monovalent group derived saturated or unsaturated bicyclic or tricyclic condensed Ugledar the ne group. Saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon means a bicyclic or tricyclic condensed hydrocarbon formed by the condensation of 2 or 3 saturated or unsaturated 5 - or 6-membered cyclic hydrocarbons, equal or different from each other. In this case, examples of the saturated or unsaturated 5 - or 6-membered cyclic hydrocarbons may include cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, and benzene. Specific examples of the saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group may include indenolol, indenolol and tetrahydronaphthalene group. Moreover, the position of the saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group attached to the T1in the General formula (1)is not particularly limited.

Saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group means a monovalent group derived saturated or unsaturated bicyclic or tricyclic condensed heterocyclic ring. Saturated or unsaturated bicyclic or tricyclic condensed heterocyclic ring means following geterotsiklicheskikh the ring ,or:

bicyclic or tricyclic condensed heterocyclic ring formed by condensation of 2 or 3 saturated or unsaturated 5 - or 6-membered heterocyclic ring, the same or different from each other;

bicyclic or tricyclic condensed heterocyclic ring formed by condensation of saturated or unsaturated 5 - or 6-membered heterocyclic ring with 1 or 2 saturated or unsaturated 5 - or 6-membered cyclic hydrocarbons;

or

tricyclic condensed heterocyclic ring formed by condensation of 2 saturated or unsaturated 5 - or 6-membered heterocyclic rings with a saturated or unsaturated 5 - or 6-membered cyclic hydrocarbon.

The position of the saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group attached to the T1in the General formula (1)is not particularly limited.

Saturated or unsaturated 5 - or 6-membered heterocyclic ring means a heterocyclic ring having at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, and its particular at the minimum level may include furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, oxazolidine, thiazole, thiadiazole, furazan, Piran, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, oxazin, oxadiazine, morpholine, teasin, thiadiazin, thiomorpholine, tetrazole, triazole and triazine. Saturated or unsaturated 5 - or 6-membered cyclic hydrocarbon means the same saturated or unsaturated 5 - or 6-membered cyclic hydrocarbon, as specified in the description of saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group. Specific examples of the saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group may include benzofuranol, benzothiazoline, indolenine, indolinyl, isoindolyl, indazolinone, pinolillo, tetrahydroquinoline, izohinolinove, tetrahydroisoquinoline, chinadaily, dihydroquinazolin, tetrahydroquinazoline, khinoksalinona, tetrahydroquinoxaline, cinnoline, tetrahydrocannabinol, indolizinyl, tetrahydroisoquinoline, benzothiazolyl, tetrahydroaminoacridine, naphthyridinone, tetrahydronaphthalene, thienopyridine tetrahydrocannabinol, triazolopyridine, tetrahydroisoquinoline, triazolopyridazines, tetrahydroisoquinoline, pyrrolo iridology, tetrahydroprotoberberine, pyrrolopyrimidine, dihydropyrimidines, digidroizokhinolin, pyridopyrimidines, tetrahydropyrimidines, paranoiacally, dihydropyrazolo, properidine, tetrahydrofurfurylamine, oxazolopyridine, tetrahydroaminoacridine, oxazolopyridine, tetrahydroaminoacridine, pyrolitically, dihydropyrazolo, pyrroloquinoline and dihydropyrazolo group. There are no particular restrictions on the type of condensation condensed heterocyclic group. For example, naphthyridinone group can be any of the 1,5-, 1,6-, 1,7-, 1,8-, 2,6- and 2.7-naphthyridinone groups, thienopyridine group may be any of thieno[2,3-b]peredelnoj, thieno[2,3-C]peredelnoj, thieno[3,2-b]peredelnoj, thieno[3,2-C]peredelnoj, thieno[3,4-b]peredelnoj and thieno[3,4-C]peredelnoj groups, triazolopyrimidine group can be any of thiazolo[4,5-b]peredelnoj, thiazolo[4,5-with]peredelnoj, thiazolo[5,4-b]peredelnoj, thiazolo[5,4-C]peredelnoj, thiazolo[3,4-a]peredelnoj and thiazolo[3,2-a]peredelnoj groups, triazolopyridazines group can be any of thiazolo [4,5-C] pyridazinyl, triazolo [4,5-d]pyridazinyl, triazolo[5,4-C]pyridazinyl and thiazolo[3,2-b]pyridazinyl groups, pyrrolopyridine group can be any of the feast of the olo[2,3-b]peredelnoj, pyrrolo[2,3-C]peredelnoj, pyrrolo[3,2-b]peredelnoj, pyrrolo[3,2-C]peredelnoj, pyrrolo[3,4-b]peredelnoj and pyrrolo[3,4-C]peredelnoj groups, pyridopyrimidines group can be any of the pyrido[2,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[1,2-C]pyrimidinyl and pyrido[1,2-a]pyrimidinyl groups, paranoiacally group can be any of pyrano[2,3-d]thiazoline, pyrano[4,3-d]thiazoline, pyrano[3,4-d]thiazoline and pyrano[3,2-d]thiazoline groups, properidine group can be any of the furo[2,3-b]peredelnoj, furo[2,3-C]peredelnoj, furo[3,2-b]peredelnoj, furo[3,2-C]peredelnoj, furo[3,4-b]peredelnoj and furo[3,4-C]peredelnoj groups, oxazolopyridine group can be any of oxazolo[4,5-b]peredelnoj, oxazolo[4,5-C]peredelnoj, oxazolo[5,4-b]peredelnoj, oxazolo[5,4-C]peredelnoj, oxazolo[3,4-a]peredelnoj and oxazolo[3,2-a]peredelnoj groups, oxazolopyridine group can be any of oxazolo[4,5-C]pyridazinyl, oxazolo[4,5-d]pyridazinyl, oxazolo[5,4-C]pyridazinyl and oxazolo[3,4-b]pyridazinyl groups, pyrolitically group can be any of pyrrolo[2,1-b]thiazoline, pyrrole[1,2-C]thiazolidine, pyrrolo[2,3-d]thiazoline, pyrrole[3,2-d]thiazoline and pyrrolo[3,4-d]thiazoline groups and pyrroloquinoline group can be any the th of pyrrolo[2,1-b]oxazoline, pyrrolo[1,2-C]oxazolidine, pyrrolo[2,3-d]oxazoline, pyrrolo[3,2-d]oxazoline and pyrrolo[3,4-d]oxazoline groups. Valid and different from these types of condensation.

Each of the above aryl groups, heteroaryl groups, arylalkyl groups, heteroarylboronic groups, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon groups and saturated or unsaturated bicyclic or tricyclic condensed heterocyclic groups may have 1-3 substituent. Examples of the substituents may include a hydroxyl group, halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, halogenoalkane group having 1-6 carbon atoms and 1-3 halogen as substituents, amino, cyano, aminoalkyl group, a nitrogroup, a hydroxyalkyl group (for example, hydroxymethylene group, 2-hydroxyethyloxy group, and so on), alkoxyalkyl group (for example, methoxymethyl group, 2-methoxyaniline group, and so on), a carboxyl group, carboxialkilnuyu group (for example, carboxymethyl group, 2-carboxyaniline group, and so on), alkoxycarbonylmethyl group (for example, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, and so on), acyl groups (for example, acetyl group, propionyl group, and so is.), amidinopropane, hydroxyamides, unbranched, branched or cyclic alkyl group (e.g. methyl group, ethyl group etc)having 1-6 carbon atoms, an unbranched, branched or cyclic alkoxygroup (for example, a methoxy group, ethoxypropan etc.)having 1-6 carbon atoms, amidinopropane (for example, methoxycarbonylamino, ethoxycarbonylmethoxy etc), substituted unbranched, branched or cyclic alkoxycarbonyl group having 2-7 carbon atoms, an unbranched, branched or cyclic alkeneamine group (for example, vinyl group, allyl group, etc), having 2-6 carbon atoms, unbranched or extensive alkyline group (for example, etinilnoy group, propenyloxy group, and so on)having 2-6 carbon atoms, an unbranched, branched or cyclic alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, and so on)having 2-6 carbon atoms, karbamoilnuyu group, mono - or dialkylamino (for example, ethylamino, dimethylamino methylaminopropyl), substituted by 1 or two unbranched, branched or cyclic alkyl groups having 1-6 carbon atoms, and 5-or 6-membered nitrogen-containing heterocyclic group (e.g. the measures pyrrolidinone, piperidine, piperazinone, morpholinopropan etc).

As a group, Q4of the above groups, the following 5 groups are preferred. Namely:

where R11and R12independently from each other represent a hydrogen atom, cyano, halogen atom, alkyl group, hydroxyalkyl group, alkoxygroup, alkoxyalkyl group, carboxyl group, carboxialkilnuyu group, acyl group, alkoxycarbonyl group, alkoxycarbonyl group or a phenyl group which may be substituted by cyano, hydroxyl group, halogen atom, alkyl group or alkoxygroup, and R13and R14independently from each other represent a hydrogen atom, a hydroxyl group, a nitrogroup, cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group, halogenation group, hydroxyalkyl group, alkoxygroup, alkoxyalkyl group, carboxyl group, carboxialkilnuyu group, karbamoilnuyu group, alkoxycarbonyl group, amidinopropane or alkoxycarbonylmethyl group;

where R15, R16and R17independently from each other represent a hydrogen atom, a hydroxyl group, a nitrogroup, ziang is the SCP, halogen atom, alkyl group, alkenylphenol group, alkylamino group, halogenation group, hydroxyalkyl group, alkoxygroup, alkoxyalkyl group, carboxyl group, carboxialkilnuyu group, acyl group, karbamoilnuyu group, alkoxycarbonyl group, amidinopropane or alkoxycarbonylmethyl group;

where X1is CH2, CH, NH, NOH, N, O or S and R18, R19and R20independently from each other represent a hydrogen atom, a hydroxyl group, a nitrogroup, cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group, halogenation group, hydroxyalkyl group, alkoxygroup, alkoxyalkyl group, carboxyl group, carboxialkilnuyu group, acyl group, karbamoilnuyu group, alkoxycarbonyl group, amidinopropane or alkoxycarbonylmethyl group;

where X2represents NH, N, O or S, X3represents N, C or CH, X4represents N, C or CH and R21and R22independently from each other represent a hydrogen atom, a hydroxyl group, a nitrogroup, cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group, halogenation group, hydroxyalkyl group, alkoxygroup, Ala calcilo group, carboxyl group, carboxialkilnuyu group, acyl group, karbamoilnuyu group, alkoxycarbonyl group, amidinopropane or alkoxycarbonylmethyl group; and

where N indicates that any one of carbon atoms of the ring substituted by a group R23that has already been substituted by a nitrogen atom, and R23, R24and R25independently from each other represent a hydrogen atom, a hydroxyl group, a nitrogroup, cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group, halogenation group, hydroxyalkyl group, alkoxygroup, alkoxyalkyl group, carboxyl group, carboxialkilnuyu group, acyl group, karbamoilnuyu group, alkoxycarbonyl group, amidinopropane or alkoxycarbonylmethyl group.

These groups will be described below.

In the description of R11-R25the halogen atom is a fluorine atom, chlorine, bromine or iodine, an alkyl group is unbranched, branched or cyclic alkyl group having 1-6 carbon atoms, Alchemilla group is unbranched, branched or cyclic alkenylphenol group having 2-6 carbon atoms, Alchemilla group is unbranched or branched alkenylphenol group having 2-6 carbon atoms, Hydra is kalkilya group means the above-described alkyl group, substituted hydroxyl group, alkoxygroup is unbranched, branched or cyclic alkoxygroup having 1-6 carbon atoms, alkoxyalkyl group means the above-described alkyl group described above substituted by alkoxygroup, carboxialkilnuyu group means the above-described alkyl group, substituted carboxyl group, acyl group is alkanoyloxy group having 1-6 carbon atoms, arilou group, such as benzoline or napolina group, or arylalkylamine group with the above-described aryl group substituted by the above alkanoyloxy group, alkoxycarbonyl group is a group consisting of the above-described alkoxygroup and carbonyl group, alkoxycarbonyl group means the above-described the alkyl group described above substituted alkoxycarbonyl group, and halogenation group means the above-described alkyl group substituted by 1-3 halogen atoms. Incidentally, in the above description are not imposed special restrictions on the position of substitution.

In the following group:

where R11, R12, R13and R14have the same meanings as defined above, and numerals 1 to 6 indicate positions, R11and R12preferably predstavlyayte hydrogen or alkyl groups. In the case of alkyl group, preferred is a methyl group. R13and R14preferably represent, independently from each other, a hydrogen atom, cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group or halogenation group. It is preferred that one of R13and R14represented a hydrogen atom and the other cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group or halogenation group. Especially preferred is that the other team was a halogen atom or alkylamino group. In this case, the halogen atom is preferably fluorine atom, chlorine or bromine. If alkenylphenol groups are especially preferred is etinilnoy group. As specific preferable examples of the group represented by the above formula can be called chlorostyrene, fertirelin, posterino and etinilestradiol group. Especially preferred position substituted by a halogen atom or alkenylphenol group in the formula is position 4. As specific preferred examples of this can be called 4-chlorostyrene, 4-Portillo, 4-posterino and 4-etinilestradiol group.

In the following group:

where R15 , R16and R17have the same meanings as defined above, and numerals 1 to 8 indicate positions, R15, R16and R17preferably represent, independently from each other, a hydrogen atom, cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group or halogenation group. R15preferably represents a hydrogen atom, alkyl group, halogen atom or hydroxyl group, and particularly preferred is a hydrogen atom. It is preferred that one of R16and R17represented a hydrogen atom and the other cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group or halogenation group. Especially preferred is that the other team was a halogen atom or alkylamino group. In this case, the halogen atom is preferably fluorine atom, chlorine or bromine. If alkenylphenol group is preferred etinilnoy group. If naftilos group 2-naftalina group is more preferable than 1-naftalina group. In the case of 2-naftilos group's most preferred position substituted by a halogen atom or alkenylphenol group in the formula is the position 6 or 1, and most preferred is position 6. The decree is installed raftiline groups are preferably substituted by a chlorine atom, fluorine or bromine, alkenylphenol group or the like, and particularly preferred is a group having substituents such as chlorine atom, fluorine or bromine, Alchemilla group or the like in the above position in the formula. As specific preferable examples of 6-chloro-2-naftalina, 6-fluoro-2-naftalina, 6-bromo-2-naftalina, 6-ethinyl-2-naftalina, 7-chloro-2-naftalina, 7-fluoro-2-naftalina, 7-bromo-2-naftalina and 7-ethinyl-2-naftalina group.

In the following group:

where X1, R18, R19and R20have the same meanings as defined above, and figures 4-7 show the position, X1is preferably NH, NOH, N, O or S, particularly preferably NH, O or S. R18preferably represents a hydrogen atom, and R19and R20preferably represent, independently from each other, a hydrogen atom, cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group or halogenation group. It is preferred that one of R19and R20represented a hydrogen atom or a halogen atom, preferably a fluorine atom, and the other cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group or halogenation group. Especially preferred is out, to the other group consisted of a halogen atom, alkyl or alkylamino group. In this case, the halogen atom is preferably fluorine atom, chlorine or bromine. In the case of alkyl group, preferred is a methyl group. If alkenylphenol group is preferred etinilnoy group. The preferred position is substituted by a halogen atom, alkyl group or alkenylphenol group in the formula is the position 5 or 6. As specific preferable examples of the group represented by the above formula can be called groups such as 5-floridalma, 5-farindola, 5-bromoindoline, 5-itinerantly, 5-methylindoline, 5-chloro-4-farindola, 6-floridalma, 6-farindola, 6-bromoindoline, 6-itinerantly, 6-methylindoline, 5-chlorobenzothiazole, 5-fermentatively, 5-bromobenzonitrile, 5-ethynylbenzene, 5-methylbenzothiazole, 5-chloro-4-fermentatively, 6-chlorobenzothiazole, 6-fermentatively, 6-pomescheniya, 6-ethynylbenzene, 6-methylbenzothiazole, 5-chlorobenzophenone, 5-Formentera, 5-bromobenzophenone, 5-ethenylbenzene, 5-methylbenzofuran, 5-chloro-4-Formentera, 6-chlorobenzophenone, 6-Formentera, 6-brombenzene, 6-ethenylbenzene and 6-methylbenzo the strong group. The situation described above replacement group attached to the T1not particularly limited. More preferred are 5-Clorinda-2-ilen, 5-Florinda-2-ilen, 5-bromoindole-2-ilen, 5-atenilol-2-ilen, 5-methylindol-2-ilen, 5-chloro-4-Florinda-2-ilen, 6-Clorinda-2-ilen, 6-Florinda-2-ilen, 6-bromoindole-2-ilen, 6-atenilol-2-ilen, 6-methylindol-2-ilen, 5-Clorinda-3-ilen, 5-Florinda-3-ilen, 5-bromoindole-3-ilen, 5-atenilol-3-ilen, 5-methylindol-3-ilen, 5-chloro-4-Florinda-3-ilen, 6-Clorinda-3-ilen, 6-Florinda-3-ilen, 6-bromoindole-3-ilen, 6-atenilol-3-ilen, 6-methylindol-3-ilen, 5-chlorobenzamide-2-ilen, 5-fermentative-2-ilen, 5-bromobenzoate-2-ilen, 5-ethynylbenzoate-2-ilen, 5-methylbenzofuran-2-ilen, 5-chloro-4-fermentative-2-ilen, 6-chlorobenzamide-2-ilen, 6-fermentation-2-ilen, 6-bromination-2-ilen, 6-ethynylbenzoate-2-ilen, 6-methylbenzofuran-2-ilen, 5-chlorobenzamide-3-ilen, 5-fermentation-3-ilen, 5-bromobenzoate-3-ilen, 5-ethynylbenzoate-3-ilen, 5-methylbenzofuran-3-ilen, 5-chloro-4-fermentative-3-ilen, 6-chlorobenzamide-3-ilen, 6-fermentation-3-ilen, 6-bromination-3-ilen, 6-ethynylbenzoate-3-ilen, 6-methylbenzofuran-3-ilen, 5-chlorobenzophenone-2-ilen, 5-perbendaharaan-2-ilen, 5-bromobenzophenone-2-ilen, 5-ethynylbenzene-ilen, 5-methylbenzofuran-2-ilen, 5-chloro-4-perbendaharaan-2-ilen, 6-chlorobenzophenone-2-ilen, 6-perbendaharaan-2-ilen, 6-bromobenzophenone-2-ilen, 6-ethynylbenzoate-2-ilen, 6-methylbenzofuran-2-ilen, 5-chlorobenzophenone-3-ilen, 5-perbendaharaan-3-ilen, 5-bromobenzophenone-3-ilen, 5-ethynylbenzene-3-ilen, 5-methylbenzofuran-3-ilen, 5-chloro-4-perbendaharaan-3-ilen, 6-chlorobenzophenone-3-ilen, 6-perbendaharaan-3-ilen, 6-bromobenzophenone-3-ilen, 6-ethynylbenzoate-3-ilen and 6-methylbenzofuran-3-ilen group, and particularly preferred are 5-Clorinda-2-ilen, 5-Florinda-2-ilen, 5-bromoindole-2-ilen, 5-atenilol-2-ilen, 5-methylindol-2-ilen, 5-chloro-4-Florinda-2-ilen, 6-Clorinda-2-ilen, 6-Florinda-2-ilen, 6-bromoindole-2-ilen, 6-atenilol-2-ilen, 6-methylindol-2-ilen, 5-chlorobenzamide-2-ilen, 5-fermentative-2-ilen, 5-bromobenzoate-2-ilen, 5-ethynylbenzoate-2-ilen, 5-methylbenzofuran-2-ilen, 5-chloro-4-fermentative-2-ilen 6-chlorobenzamide-2-ilen, 6-heroisation-2-ilen, 6-bromination-2-ilen, 6-ethynylbenzoate-2-ilen, 6-methylbenzofuran-2-ilen, 5-chlorobenzophenone-2-ilen, 5-perbendaharaan-2-ilen, 5-bromobenzophenone-2-ilen, 5-ethynylbenzene-2-ilen, 5-methylbenzofuran-2-ilen, 5-chloro-4-perbendaharaan-2-ilen, 6-chlorobenzophenone-2-ilen 6-perbendaharaan-2-ilen, 6-bromobenzophenone-2-Il is th, 6-ethynylbenzoate-2-ilen and 6-methylbenzofuran-2-ilen group.

In the following group:

where X2X3X4, R21and R22have the same meanings as defined above, and figures 4-7 indicate positions, any one of X3and X4is preferably CH or s, and particularly preferably s R21and R22preferably represent, independently from each other, a hydrogen atom, cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group or halogenation group. It is preferred that one of R21and R22represented a hydrogen atom and the other cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group or halogenation group. Especially preferred is that the other team was a halogen atom or alkylamino group. In this case, the halogen atom is preferably fluorine atom, chlorine or bromine. If alkenylphenol group is preferred etinilnoy group. The preferred position is substituted by a halogen atom or alkenylphenol group in the formula is the position 5 or 6. As specific preferable examples of the group represented by the above formula include such groups as

5-chlorite is cazalilla, 5-perindoprilat,

5-prominately, 5-ethynylnaphthalene,

6-chlorination, 6-perindoprilat, 6-prominately,

6-ethynylnaphthalene, 5-chlorobenzimidazole,

5-foranimation, 5-bromobenzimidazole,

5-ethynylbenzaldehyde, 6-chlorobenzimidazole,

6-foranimation, 6-bromobenzimidazole,

6-ethynylbenzaldehyde, 5-chlorobenzothiazole,

5-fermentatively, 5-bromobenzonitrile,

5-etinilestradiolo, 6-chlorobenzothiazole,

6-fermentatively, 6-bromobenzonitrile,

6-etinilestradiolo, 5-chlorobenzoxazole,

5-fermentatively, 5-bromobenzonitrile,

5-ethynylbenzoate, 6-chlorobenzoxazole,

6-fermentatively, 6-bromobenzonitrile,

6-ethynylbenzoate, 5-chlorobenzothiazole,

5-fermentatively, 5-bromobenzenediazonium,

5-etinilestradiolo, 6-chlorobenzothiazole,

6-fermentatively, 6-bromobenzenediazonium,

6-etinilestradiolo, 5-chlorobenzotriazole,

5-fermentatively, 5-bromantically,

5-etinilestradiolo, 6-chlorobenzothiazole,

6-fermentatively, 6-bromantically and 6-ethynylbenzoate the other group. The situation described above replacement group attached to the T1not particularly limited. More preferred are 5-chlorinator-3-ilen, 5-Florinda-3-ilen, 5-brominated-3-ilen, 5-etinilestradiol-3-ilen, 6-chlorinator-3-ilen, 6-Florinda-3-ilen, 6-etinilestradiol-3-ilen, 5-forbesides-2-ilen, 5-ethynylbenzene-2-ilen, 6-forbesides-2-ilen, 6-ethynylbenzoate-2-ilen, 5-fermentational-2-ilen, 5-ethynylbenzoate-2-ilen, 6-fermentation-2-ilen, 6-ethynylbenzoate-2-ilen, 5-perbenzoate-2-ilen, 5-ethynylbenzoate-2-ilen, 6-perbenzoate-2-ilen, 6-ethynylbenzoate-2-ilen, 5-ferberization-3-ilen, 6-brominated-3-ilen, 5-chlorobenzimidazole-2-ilen, 5-bromobenzimidazole-2-ilen, 6-chlorobenzimidazole-2-ilen, 6-bromobenzimidazole-2-ilen, 5-chlorobenzothiazole-2-ilen, 5-bromobenzoate-2-ilen, 6-chlorobenzothiazole-2-ilen, 6-bromobenzimidazole-2-ilen, 5-chlorobenzoxazol-2-ilen, 5-bromobenzoate-2-ilen, 6-chlorobenzoxazol-2-ilen, 6-bromobenzimidazole-2-ilen, 5-chlorobenzotriazol-3-ilen, 5-bromonicotinate-3-ilen, 5-ethinylestradiol-3-ilen, 6-chlorobenzotriazol-3-ilen, 6-ferberization-3-ilen, 6-bromonicotinate-3-ilen, 6-ethinylestradiol-3-ilen, 5-chlorobenzotriazol-3-ilen, 5-forbusinesses-3-ilen, 5-BROKBUSINESS-3-ilen, 5-ethinyl isoxazol-3-ilen, 6-chlorobenzotriazol-3-ilen, 6-forbusinesses-3-ilen, 6-BROKBUSINESS-3-ilen and 6-ethinylestradiol-3-ilen group, and particularly preferred are 5-chlorobenzimidazole-2-ilen, 5-forbesides-2-ilen, 5-bromobenzimidazole-2-ilen, 5-ethynylbenzene-2-ilen, 6-chlorobenzimidazole-2-ilen, 6-forbesides-2-ilen, 6-bromobenzimidazole-2-ilen, 6-ethynylbenzoate-2-ilen A 5-chlorobenzotriazol-2-ilen, 5-fermentational-2-ilen, 5-bromobenzoate-2-ilen, 5-ethynylbenzoate-2-ilen, 6-chlorobenzothiazole-2-ilen, 6-fermentation-2-ilen, 6-bromobenzimidazole-2-ilen, 6-ethynylbenzoate-2-ilen, 5-chlorobenzoxazol-2-ilen, 5-perbenzoate-2-ilen, 5-bromobenzoate-2-ilen, 5-ethynylbenzoate-2-ilen, 6-chlorobenzoxazol-2-ilen, 6-perbenzoate-2-ilen, 6-bromobenzimidazole-2-ilen and 6-ethynylbenzoate-2-ilen group.

In the following group:

where N indicates that any one of carbon atoms of the ring substituted by a group R23that has already been substituted by a nitrogen atom, R23, R24and R25have the same meanings as defined above, and figures 5-8 show the position, R23, R24and R25preferably represent, independently from each other, a hydrogen atom, cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group is at or halogenation group. R23especially preferably represents a hydrogen atom. It is preferred that one of R24and R25represented a hydrogen atom, and the other cyano, halogen atom, alkyl group, alkenylphenol group, alkylamino group or halogenation group. Especially preferred is that the other team was a halogen atom or alkylamino group. In this case, the halogen atom is preferably fluorine atom, chlorine or bromine. If alkenylphenol group is preferred etinilnoy group. The preferred position is substituted by a halogen atom or alkenylphenol group in the formula is the position 6 or 7. As specific preferable examples of the specified group can be called hyalinella and athinodorou group. More preferred are 6-hlorhinaldola, 6-verginella, 6-branchinella, 6-ethynylpyridine, 6-chloroisoquinoline, 6-verizononline, 6-bromoisoquinoline and 6-etinilestradiolo group, and particularly preferred are 6-chlorhydrin-2-ilen, 6-ftorhinolon-2-ilen, 6-bronchioles-2-ilen, 6-ethynylphenyl-2-ilen, 6-chlorhydrin-3-ilen, 6-ftorhinolon-3-ilen, 6-bronchioles-3-ilen, 6-ethynylphenyl-3-ilen, 7-chlorhydrin-2-ilen, 7-ftorhinolon-2-ilen, 7-bronchioli the-2-ilen, 7-ethynylphenyl-2-ilen, 7-chlorhydrin-3-ilen, 7-ftorhinolon-3-ilen, 7-bronchioles-3-ilen, 7-ethynylphenyl-3-ilen, 6-chloroisoquinoline-3-ilen, 6-forsakenly-3-ilen, 6-bromoisoquinoline-6-ilen, 6-ethynylation-3-ilen, 7-chloroisoquinoline-3-ilen, 7-forsakenly-3-ilen, 7-bromoisoquinoline-3-ilen and 7-ethynylation-3-strong group.

<group Q1>

In the present invention Q1means a saturated or unsaturated 5 - or 6-membered cyclic hydrocarbon group which may be substituted, saturated or unsaturated 5 - or 6-membered heterocyclic group which may be substituted, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may be substituted.

As examples of saturated or unsaturated 5 - or 6-membered cyclic hydrocarbon group can be called cyclopentyloxy, cyclopentenyl, tsiklogeksilnogo, cyclohexenyl and phenyl groups. Preferred are cyclopentene, tsiklogeksilnogo and phenyl groups, of which particularly preferred is a phenyl group.

Saturated or unsaturated 5 - or 6-membered Goethe is acyclically group means a monovalent heterocyclic group, having at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, and specific examples may include follow, pyrrolidinyl, thienyl, pyrazolidine, imidazolidine, pyrazolidine, oxazolidine, oxazolidinone, thiazolidine, thiazolidinone thiadiazolidine, foratenolol, pyranyloxy, pyridyloxy, pyramidalnou, pyridazinyl, pyrrolidinyl, piperazinilnom, piperidinyloxy, oxazinyl, oxydianiline, morpholinyl, teasingly, thiodianiline, thiomorpholine, tetrazolyl, triazolyl and triazinyl group. Preferred are pyrazolidine, imidazolidine, oxazolidine, thiazolidine, thiadiazolidine, furazolidine, perederina, piramidalnaya, pyridinoline, pyrrolidinyl, piperazinilnom, piperidinyl, morpholinyl, thiodianiline and thiazolidine group, of which particularly preferred are pyrazolidine, imidazolidine, perederina, piramidalnaya, pyridinoline, pyrrolidinyl, piperazinilnom and piperidinyl group. Of these heterocyclic groups are nitrogen-containing heterocyclic group may be in the form of N-oxide.

Saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group means the same saturated or unsaturated, bizi the symbolic or tricyclic condensed hydrocarbon group, as described in the description of Q4in the General formula (1). As its specific examples are indenolol, indenolol, naftalina, tetrahydronaphthalene, untilnow and phenanthroline group, of which preferred are angenlina, indayla, naftalina and tetrahydronaphthalene group.

Saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group means the same saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group, as described in the description of Q4in the General formula (1). As its specific examples are benzofuranol, benzothiazoline, indolenine, indolinyl, isoindolyl, indazolinone, pinolillo, tetrahydroquinoline, izohinolinove, tetrahydroisoquinoline, chinadaily, dihydroquinazolin, tetrahydroquinazoline, khinoksalinona, tetrahydroquinoxaline, cinnoline, tetrahydrocannabinol, indolizinyl, tetrahydroisoquinoline, benzothiazolyl, tetrahydroaminoacridine, naphthyridinone, thienopyridine, tetrahydrocannabinol, triazolopyridine, tetrahydroisoquinoline, tetrahydronaphthalene, triazolopyridazines, tetrahydroisoquinoline, pyrrolopyridine, dihydropyrrolo rigelnuyu, tetrahydroprotoberberine, pyrrolopyrimidine, dihydropyrimidines, digidroizokhinolin, pyridopyrimidines, tetrahydropyrimidines, paranoiacally, dihydropyrazolo, properidine, tetrahydrofurfurylamine, oxazolopyridine, tetrahydroaminoacridine, oxazolopyridine, tetrahydroaminoacridine, pyrolitically, dihydropyrazolo, pyrroloquinoline, dihydropyrazolo, pyrazoloacridine, tetrahydroprotoberberine and hexahydromethylseverely group. Preferred are benzothiazolinone, tetrahydroaminoacridine, thienopyridine, tetrahydroaminoacridine, triazolopyridine, tetrahydroisoquinoline, triazolopyridazines, tetrahydroisoquinoline, pyrrolopyrimidine, dihydropyrimidine, paranoiacally, dihydroergotamine, properidine, tetrahydrofurfurylamine, oxazolopyridine, tetrahydroaminoacridine, pyrrolopyridine, dihydropyrimidine, tetrahydropyrimidine, oxazolopyridine, tetrahydroaminoacridine, pyrolitically, dehydroaromatization, pyrroloquinoline, dihydropyrrol oxazolidine, 4,5,6,7-tetrahydro-5,6-tetramethylethylenediamine and 5,6-trimethylene-4,5,6,7-tetrahydroisoquinoline group, of which particularly preferred are tetrahydroaminoacridine, tetrahydroaminoacridine, tetrahydroisoquinoline, tetrahydroisoquinoline, dihydropyrimidine, dihydroergotamine, tetrahydroaminoacridine, dehydroaromatization, 4,5,6,7-tetrahydro-5,6-tetramethylethylenediamine and 5,6-trimethylene-4,5,6,7-tetrahydroisoquinoline group. Imposed special restrictions on the type of condensation condensed heterocyclic group. For example, thienopyridine may be any of thieno[2,3-b]pyridine, thieno[2,3-C]pyridine, thieno[3,2-b]pyridine, thieno[3,2-C]pyridine, thieno[3,4-b]pyridine and thieno[3,4-C]pyridine, which are preferred thieno[2,3-C]pyridine and thieno[3,2-C]pyridine; triazolopyridine may be any of thiazolo[4,5-b]pyridine, thiazolo[4,5-C]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-C]pyridine, thiazolo[3,4-a]pyridine and thiazolo[3,2-a]pyridine, of which preferred are thiazolo[4,5-C]pyridine and thiazolo[5,4-C]pyridine; triazolopyridine may be any of thiazolo[4,5-C]pyridazine, thiazolo [4,5-d]pyridazine, thiazolo [5,4-C] pyridazine and thiazolo[3,2-b]pyridazine, of which preferred is thiazolo [4,5-d]PI is easin; pyrrolopyridine may be any of pyrrolo[2,3-b]pyridine, pyrrolo[2,3-C]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[3,2-C]pyridine, pyrrolo[3,4-b]pyridine and pyrrolo[3,4-C]pyridine, which are preferred pyrrolo[2,3-C]pyridine and pyrrolo[3,2-C]pyridine; pyrrolopyrimidine may be any of pyrrolo[3,4-d]pyrimidine, pyrrolo[3,2-d]pyrimidine and pyrrolo[2,3-d]pyrimidine, of which preferred is pyrrolo[3,4-d]pyrimidine; pyridopyrimidines can be any of the pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido[1,2-C]pyrimidine and pyrido[1,2-a]pyrimidine, of which preferred are pyrido[3,4-d]pyrimidine and pyrido[4,3-d]pyrimidine; pernetiana may be any of pyrano [2,3-d]thiazole, pyrano[4,3-d]thiazole, pyrano [3,4-d]thiazole and pyrano[3,2-d]thiazole, of which preferred are pyrano[4,3-d]thiazole and pyrano[3,4-d]thiazole; properidine can be any Isfara[2,3-b]pyridine, furo[2,3-C]pyridine, furo[3,2-b]pyridine, furo[3,2-C]pyridine, furo[3,4-b]pyridine and furo[3,4-C]pyridine, which are preferred furo[2,3-C]pyridine and furo[3,2-C]pyridine; oxazolopyridine may be any of oxazolo[4,5-b]pyridine, oxazolo[4,5-C]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-C]pyridine, oxazolo[3,4-a]pyridine and oxazolo[3,2-a]pyridine, of which preferred are oxazolo[4,5-C]feast the Dean and oxazolo[5,4-C]pyridine; oxazolopyridine may be any of oxazolo[4,5-C]pyridazine, oxazolo[4,5-d]pyridazine, oxazolo[5,4-C]pyridazine and oxazolo[3,4-b]pyridazine, of which preferred is oxazolo[4,5-d]pyridazin; petrolatina may be any of pyrrolo[2,1-b]thiazole, pyrrolo[1,2-C]thiazole, pyrrolo[2,3-d]thiazole, pyrrolo[3,2-d]thiazole and pyrrolo[3,4-d]thiazole, of which preferred is pyrrolo[3,4-d]thiazole; and pyrroleacetic may be any of pyrrolo[2,1-b]oxazole, pyrrolo[1,2-C]oxazole, pyrrolo[2,3-d]oxazole, pyrrolo[3,2-d]oxazole and pyrrolo[3,4-d]oxazole, of which preferred is pyrrolo[3,4-d]oxazol.

Of these heterocyclic groups are nitrogen-containing heterocyclic group may be in the form of N-oxide. Moreover, the position above the replacement group attached to Q2not particularly limited.

Each of the above-described saturated or unsaturated 5 - or 6-membered cyclic hydrocarbon groups, saturated or unsaturated 5 - or 6-membered cyclic heterocyclic group, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon groups and saturated or unsaturated bicyclic or tricyclic condensed heterocyclic groups may have 1-3 substituent. Examples of the substituents may include a hydroxyl group; the atoms of g is lagena, such as fluorine atom, chlorine atom, bromine atom and iodine atom; halogenmethyl group having 1-3 halogen substituent; an amino group; a cyano; amidinopropane; hydroxyamides; an unbranched, branched or cyclic alkyl group having 1-6 carbon atoms (hereinafter referred to as C1-C6alkyl groups, which means an unbranched, branched or cyclic alkyl group, for example, unbranched or branched C1-C6alkyl groups such as methyl, ethyl, isopropyl and tert-butyl; C3-C6cycloalkyl groups, such as cyclopropyl group, cyclobutyl group, cyclopentenone group and 1-methylcyclopropyl group; and (C3-C6cycloalkyl-C1-C6alkyl groups, such as cyclopropylmethyl group), hydroxy-C1-C6alkyl groups (such as hydroxyethylene and 1,1-dimethyl-2-hydroxyethylene group); C1-C6alkoxygroup (for example, a methoxy group, ethoxypropan and the like); C1-C6alkoxy-C1-C6alkyl group; a carboxyl group;1-C6carboxialkilnuyu group (for example, carboxymethyl group and the like); C2-C6alkoxycarbonyl-C1-C6alkyl groups (for example, methoxycarbonylmethyl group,tert-butoxycarbonylmethyl group and the like); amidinopropane, substituted C2-C6alkoxycarbonyl group; C2-C6alkeneamine group (for example, vinyl group, allyl group and the like); (C2-C6alkyline group (for example, etinilnoy group, propenyloxy group and the like); (C1-C6alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group and the like); amino-C1-C6alkyl groups (for example, aminomethyl group, aminoethyl group and the like); C1-C6alkylamino-C1-C6alkyl groups (for example, N-methylaminomethyl group, N-ethylaminoethanol group and the like); C1-C6dialkylamino-C1-C6alkyl groups (for example, N,N-dimethylaminomethylene group, N,N-diethylaminomethyl group and the like); (C1-C6alkoxycarbonyl-C1-C6alkyl groups (for example, methoxycarbonylmethyl group, tert-butoxycarbonylmethyl group and the like); C1-C6alcoholnye group (for example, formyl group, acetyl group, methylpropionyl group, cyclopentanecarbonyl group and the like); C1-C6alkanolamine-C1-C6alkyl groups (for example, acetylamino lilou group and the like); C1-C6alkylsulfonyl group (for example, methanesulfonyl group and the like); C1-C6alkylsulfonamides-C1-C6alkyl groups (for example, methanesulfonylaminoethyl group and the like); karbamoilnuyu group; C1-C6alkylcarboxylic group (for example, methylcarbamoyl group, ethylcarbitol group, isopropylcarbamate group, tert-butylcarbamoyl group and the like); N,N-di(C1-C6alkyl)carbamoyl group (for example, dimethylcarbamoyl group, diethylcarbamoyl group, methylethylcarbinol group and the like); C1-C6alkylamino (for example, N-methylaminopropyl, N-ethylamino and the like); C1-C6dialkylamino (for example, N,N-dimethylaminopropyl, N,N-diethylaminopropyl, N-methyl-N-ethylamino and the like); 5 - or 6-membered heterocyclic group containing one atom of nitrogen, oxygen and sulfur, or two identical or different atom (for example, pyrrolidinyl group, piperidinyl group, piperazinilnom group, morpholinyl group, pyridyloxy group, pyrimidinyl group, tetrahydropyranyloxy group and the like); and the group consisting of the above 5 - or 6-membered heterocyclic group, and C1-C4alkyl groups (for example, mo is polinomialnoi group and the like). As specific examples of Q1you can call bicyclic heterocyclic groups such as 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-ilen, 4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-ilen, 5-cyclopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-ilen, 5-carboxymethyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-ilen, 5-butyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-ilen, 5-(4-pyridyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-ilen, 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-ilen, 6-methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine-2-ilen, 5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine-2-ilen, 5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-2-ilen, 5,7-dihydro-6-methylpyrazolo[3,4-d]pyrimidine-2-ilen, 5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,5-d]pyridazin-2-ilen, 5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[4,5-d]pyridazin-2-ilen, 5-dimethylamino-4,5,6,7-tetrahydrobenzo[d]thiazol-2-ilen, 5-(4-pyridyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-ilen and 6,7-dihydro-4H-pyrano[4,3-d]thiazole-2-ilen group and 4-(4-pyridyl)phenyl group. By the way, Q1not limited to these examples.

<group Q2>

Group Q2means a single bond, an unbranched or branched alkylenes group having 1-6 carbon atoms, unbranched or branched alkynylamino group having 2-6 carbon atoms, unbranched or Razvitie the ing alkynylamino group, having 2-6 carbon atoms, a group-N(R3)-, where R3means a hydrogen atom or alkyl group, a group-N(R4) (CH2)m-where R4means a hydrogen atom or alkyl group and m is an integer from 1 to 6, saturated or unsaturated 5 - or 6-membered divalent cyclic hydrocarbon group which may be substituted, saturated or unsaturated 5 - or 6-membered divalent heterocyclic group which may be substituted, saturated or unsaturated divalent bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated divalent bicyclic or tricyclic condensed heterocyclic group which may be substituted.

As examples of unbranched or branched alkalinous group having 1-6 carbon atoms in the group Q2you can call methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene and hexamethylene group.

As examples of unbranched or branched alkynylamino group having 2-6 carbon atoms, can be called vanilinovoi, propenylidene, butenylamine and pentesilea group. Imposed special restrictions on the location of its double bonds.

In the when asked examples of unbranched or branched alkynylamino group, having 2-6 carbon atoms, can be called atenololbuy, propylene, butilyenov, pentylindol and hexylamino group. Imposed special restrictions on the location of its triple bond.

R3in the group-N(R3is a hydrogen atom or alkyl group. Alkyl group represents an unbranched, branched or cyclic alkyl group having 1-6 carbon atoms, and its examples may include methyl, ethyl, ISO-propyl and cyclopropyl group.

R4in the group-N(R4)-(CH2)mrepresents a hydrogen atom or alkyl group. Alkyl group represents an unbranched, branched or cyclic alkyl group having 1-6 carbon atoms, and its examples may include methyl, ethyl, ISO-propyl and cyclopropyl group, m is an integer from 1 to 6, preferably is an integer from 1 to 3.

Saturated or unsaturated 5 - or 6-membered divalent cyclic hydrocarbon group means a divalent group derived saturated or unsaturated 5 - or 6-membered cyclic hydrocarbon, described in the description of Q4in the General formula (1). As its specific examples are cyclohexylamino, cyclohexadienone and fenelonov group, of which predpochtite lname are cyclohexylurea and fenelonov group.

Saturated or unsaturated 5 - or 6-membered divalent heterocyclic group means a divalent group derived saturated or unsaturated 5 - or 6-membered heterocyclic ring described in the description of Q4in the General formula (1). As its specific examples of the divalent group derived from furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, oxazolidine, thiazole, thiadiazole, furazane, Piran, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, oxazine, oxadiazine, research, thiazine, thiadiazine, thiomorpholine, tetrazole, triazole and triazine. As the preferred examples are, in particular, the divalent group - derivatives of pyrazole, imidazole, oxazole, thiazole, thiadiazole, furazane, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine derivatives, triazole and triazine.

Saturated or unsaturated divalent bicyclic or tricyclic condensed hydrocarbon group means a divalent group derived saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon, described in the description of Q4in the General formula (1). As its specific examples include divalent groups derived from indene, indane, naphthalene, tetrahedr is naphthalene, anthracene, phenanthrene and the like. As preferred examples of the divalent group derived indane and naphthalene.

Saturated or unsaturated divalent bicyclic or tricyclic condensed heterocyclic group means a divalent group derived saturated or unsaturated bicyclic or tricyclic condensed heterocyclic rings described in the description of Q4in the General formula (1). As specific examples include divalent groups derived benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, heatline, dihydroquinazolin, tetrahydroquinazoline, cinoxacin, tetrahydroquinoxaline, cinnoline, tetrahydroquinoline, indoline, tetrahydroquinoline, benzothiazole, tetrahydroindazole, naphthiridine, tetrahydronaphthalene, thienopyridine, tetrahydroaminoacridine, triazolopyridine, tetrahydropyridine, triazolopyridine, tetrahydropyridine, pyrrolopyridine, dihydropyrimidine, tetrahydropyrimidine, pyrrolopyrimidine, dihydropyrimidine, digidroizokhinolin, pornotesao, dihydrofarnesol, properidine, tetrahydropyrimidine, oxazolopyridine, tetrahedron is azolopyrimidine, oxazolopyridine, tetrahydroaminoacridine, pyrrolotriazine, dihydropyrazolo, pyrroleacetic and dihydroperoxide. As preferred examples of the divalent group derived benzofuran, benzothiophene, indole, indazole, quinoline, isoquinoline, tetrahydroisoquinoline, benzothiazole, naphthiridine, thienopyridine, triazolopyridine, tetrahydropyridine, triazolopyridine, pyrrolopyridine, tetrahydropyrimidine, pyridopyrimidines, pornotesao, dihydrofarnesol, properidine, oxazolopyridine, oxazolopyridine, pyrrolotriazine, dihydropyrazolo, pyrroleacetic and dihydroperoxide. Imposed special restrictions on the type of condensation condensed heterocyclic group. For example, naphthiridine can be any of the 1,5-, 1,6-, 1,7-, 1,8-, 2,6-and 2.7-naphthiridine, thienopyridine may be any of thieno[2,3-b]pyridine, thieno[2,3-C]pyridine, thieno[3,2-b]pyridine, thieno[3,2-C]pyridine, thieno[3,4-b]pyridine and thieno[3,4-C]pyridine, triazolopyridine may be any of thiazolo[4,5-b]pyridine, thiazolo[4,5-C] pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-C]pyridine, thiazolo[3,4-a]pyridine and thiazolo[3,2-a]pyridine, triazolopyridine may be any of thiazolo[4,5-C]pyridazine, thiazolo[4,5-d]pyridazine, thiazolo[5,4-C]pyridazine and thiazolo[3,2-b]pyridazine, pyrrolopyridine can b the th any of pyrrolo[2,3-b]pyridine, pyrrolo[2,3-C]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[3,2-C]pyridine, pyrrolo[3,4-b]pyridine and pyrrolo[3,4-C]pyridine, pyrrolopyrimidine may be any of pyrrolo[3,4-d]pyrimidine, pyrrolo[3,2-d]pyrimidine and pyrrolo[2,3-d]pyrimidine, pyridopyrimidines can be any of the pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine and pyrido[3,4-d]pyrimidine, pernetiana can to be any of pyrano[2, 3-d]thiazole, pyrano[4,3-d]thiazole, pyrano[3,4-d]thiazole and pyrano[3,2-d]thiazole, properidine can be any of the furo[2,3-b]pyridine, furo[2,3-C]pyridine, furo[3,2-b]pyridine, furo[3,2-C]pyridine, furo[3,4-b]pyridine and furo[3,4-C]pyridine, oxazolopyridine may be any of oxazolo[4,5-b]pyridine, oxazolo[4,5-C]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-C]pyridine, oxazolo[3,4-a]pyridine and oxazolo[3,2-a]pyridine, oxazolopyridine may be any of oxazolo[4,5-C]pyridazine, oxazolo[4,5-d]pyridazine, oxazolo[5,4-C]pyridazine and oxazolo[3,4-b]pyridazine, petrolatina may be any of pyrrolo[2,1-b]thiazole, pyrrolo[1,2-C]thiazole, pyrrolo[3,2-d]thiazole and pyrrolo[3,4-d]thiazole and pyrroleacetic may be any of pyrrolo[2,1-b]oxazole, pyrrolo[1,2-C]oxazole, pyrrolo[2,3-d]oxazole, pyrrolo[3,2-d]oxazole and pyrrolo[3,4-d]oxazole. Valid other than these types of condensation.

Each of the above-described saturated or unsaturated 5 - or 6-membered divalent cyclic pleva orodnik groups, saturated or unsaturated 5 - or 6-membered divalent heterocyclic group, saturated or unsaturated divalent bicyclic or tricyclic condensed hydrocarbon groups and saturated or unsaturated divalent bicyclic or tricyclic condensed heterocyclic groups may have 1-3 substituent. Examples of the substituents may include gidroksilnyh group, halogen atoms such as fluorine atoms, chlorine, bromine and iodine, halogenoalkane group having 1-3 halogen substituent, an amino group, cyano, aminoalkyl group, amidinopropane, hydroxyamides, unbranched, branched or cyclic alkyl group having 1-6 carbon atoms (e.g. methyl group, ethyl group etc), unbranched, branched or cyclic alkoxygroup having 1-6 carbon atoms (for example, a methoxy group, ethoxypropan etc), amidinopropane, substituted unbranched, branched or cyclic alkoxycarbonyl groups having 2-7 carbon atoms (for example, methoxycarbonylamino, ethoxycarbonylmethoxy etc), unbranched, branched or cyclic alkeneamine group having 2-6 carbon atoms (for example, vinyl group, allyl group, etc), unbranched or razvetvlenno the e alkyline group, having 2-6 carbon atoms (for example, etinilnoy group, propenyloxy group, and so on), an unbranched, branched or cyclic alkoxycarbonyl group having 2-6 carbon atoms (for example, methoxycarbonyl group, ethoxycarbonyl group, and so on), and karbamoilnuyu group.

The preferred groups described above, Q2are single bond, Allenova group having 1 or 2 carbon atoms, alkenylamine group having 2 carbon atoms, akinlana group having 2 carbon atoms, the group-NH-, group-N(R4)-(CH2)2-saturated or unsaturated 5 - or 6-membered divalent cyclic hydrocarbon group which may be substituted, a saturated or unsaturated 5 - or 6-membered divalent heterocyclic group which may be substituted, saturated or unsaturated divalent bicyclic or tricyclic condensed heterocyclic group which may be substituted. Especially preferred are a single bond, a saturated or unsaturated divalent 5 - or 6-membered cyclic hydrocarbon group, such as cyclohexylurea group and fenelonov group, and divalent groups derived condensed heterocyclic rings such as thiazole and piperidine.

When Q1PR is dstanley saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group, which may be substituted, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may be substituted, the group Q2preferably is a single bond. The fact that Q2represents a single bond, means the General formula (1):

where R1, R2, Q1, Q2, Q3, Q4and T1have the same meanings as defined above, takes the form of the following General formula (1'):

where Q1represents the specified bicyclic or tricyclic condensed hydrocarbon group or a bicyclic or tricyclic condensed heterocyclic group, and R1, R2, Q3, Q4and T1have the same meanings as defined above.

In particular, preferred are those compounds in which the group Q1is thienopyridine group which may be substituted, tetrahydrocannabinol group which may be substituted, triazolopyrimidine group which may be substituted, tetrahydroisoquinoline group which may be substituted, triazolopyridazines group which may be substituted, tetrahydroisoquinoline group, the cat heaven may be substituted, paranoiacally group which may be substituted, dihydropyrazolo group which may be substituted, properidine group which may be substituted, tetrahydropyrimidine group which may be substituted, oxazolopyridine group which may be substituted, tetrahydrooxazolo group which may be substituted, pyrrolopyridine group which may be substituted, dihydropyrimidine group which may be substituted, tetrahydroprotoberberine group which may be substituted, pyrrolopyrimidine group which may be substituted, dihydropyrimidine group which may be substituted, oxazolopyridine group which may be substituted, tetrahydroaminoacridine group, which may be substituted, pyrrolidinyloxy group which may be substituted, dihydropyrazolo group which may be substituted, pyrroloquinoline group which may be substituted, dihydropyrazolo group which may be substituted, benzothiazolyl group which may be substituted, tetrahydroaminoacridine group which may be substituted,

4,5,6,7-tetrahydro-5,6-tetramethylpiperidinyloxy group, which can the be replaced, or 5,6-trimethylene-4,5,6,7-tetrahydroisoquinoline group which may be substituted, and Q2represents a single bond.

When Q1represents a saturated or unsaturated 5 - or 6-membered cyclic hydrocarbon group which may be substituted, or a saturated or unsaturated 5 - or 6-membered heterocyclic group which may be substituted, the group Q2preferably represents a saturated or unsaturated 5 - or 6-membered divalent cyclic hydrocarbon group which may be substituted, or a saturated or unsaturated 5 - or 6-membered divalent heterocyclic group which may be substituted. In the group of Q1-Q2preferred are 5-(4-pyridyl)thiazolidine group and the like.

<group Q3>

Group Q3represents a group:

in which R5, R6, R7and R8independently from each other mean a hydrogen atom, hydroxyl group, halogen atom, halogenation group, cyano, lanakila group, acyl group, arylalkyl group, alkyl group, alkenylphenol group, alkylamino group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxialkilnuyu group, alcox the carbonyl group, alkoxycarbonylmethyl group, karbamoilnuyu group, N-alkylcarboxylic group, N,N-dialkylamino group, carbamoylethyl group, N-alkylcarboxylic group, N,N-dialkylanilines group, aryl group, aracelio group, heteroaryl group, or heteroallyl group, or the following group:

in which Q5means alkylenes group having 1-8 carbon atoms, or alkynylamino group having 2-8 carbon atoms, and R9and R10are, independently from each other, the substituents at the carbon atom of the ring containing Q5and represent a hydrogen atom, hydroxyl group, alkyl group, alkenylphenol group, alkylamino group, halogen atom, halogenation group, cyano, lanakila group, amino group, aminoalkyl group, N-acylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, arylalkyl group, allmenalp, which may be substituted, alkoxyimino, hydroxyimino, acylaminoalkyl group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxialkilnuyu group, alkoxycarbonyl group, alkoxycarbonyl group, alkoxycarbonylmethyl, carboxymethylamino the PU, alkoxycarbonylmethyl, alkoxycarbonylmethyl group, karbamoilnuyu group, N-alkylcarboxylic group which may have a substituent in the alkyl group, N,N-dialkylamino group which may have a substituent in the alkyl group, N-alkenylamine group, N-alkenylboronic group, N-alkenyl-N-alkylcarboxylic group, N-alkenyl-N-alkylcarboxylic group, N-alkoxycarbonyl group, N-alkyl-N-alkoxycarbonyl group, N-alkoxycarbonylmethyl group, N-alkyl-N-alkoxycarbonylmethyl group, carbazolyl group, which may be sameena 1-3 alkyl groups, alkylsulfonyl group, alkylsulfonyl group, 3-6-membered nitrogen-containing heterocyclic carbonyl group which may be substituted, carbamoylethyl group, N-alkylcarboxylic group which may have a substituent in the alkyl group, N,N-dialkylanilines group which may have a substituent in the alkyl group, carbamoylmethyl group, N-alkylcarboxylic group, N,N-dialkylimidazolium group, 3-6-membered nitrogen-containing heterocyclic carbonylethyl group which may be substituted, 3-6-membered nitrogen-containing heterocyclic carboncillo group, which may be for esenkoy, aryl group, aracelio group, heteroaryl group, heteroallyl group, alkylsulfonamides, arylsulfonamides, alkylsulfonyl group, arylsulfonyl group, alkylsulfonamides group, arylsulfonamides group, alkylsulfonylpyridines group, arylsulfonamides group, oxoprop, carbamoyloximes, aralkylated, carboxymethyloxime, alloctype or aryloxyalkyl group, or R9and R10together with each other means alkylenes group having 1-5 carbon atoms, alkynylamino group having 2-5 carbon atoms, alkylenedioxy having 1-5 carbon atoms, or carbondioxide.

Further, the substituents R5, R6, R7and R8described in detail. The halogen atom means a fluorine atom, chlorine, bromine or iodine. Examples of alkyl groups include unbranched, branched or cyclic C1-C6alkyl group (e.g. methyl group, cyclopropyl group, isobutylene group and the like). Examples halogenoalkanes groups include alkyl groups substituted by 1-3 Halogens (e.g., chloromethylene group, 1-bromatology group, triptorelin group and the like). Examples lanakila gr is PPI include C 1-C6alkyl group substituted by a cyano (for example, cyanomethylene group, 1-zenatello group and the like). Examples alkenylphenol groups include unbranched or branched alkeneamine group having 2-6 carbon atoms and a double bond (for example, vinyl group, allyl group and the like). Examples alkenylphenol groups include unbranched or branched alkeneamine group having 2-6 carbon atoms and a triple bond (e.g., etinilnoy group, propenyloxy group and the like). Examples of acyl groups include C1-C6alcoholnye group (for example, formyl group, acetyl group and the like), C7-C15aroline groups, such as benzoline group and napolina group, and arylalkylamine groups that are C1-C6alkanolamine groups, substituted C6-C14aryl group (for example, Venizelou group and the like). Examples acidalkaline groups include C1-C6alkyl group, a substituted acyl group (for example, acetylamino group and the like).

Examples of alkoxygroup include unbranched, branched or cyclic C1-C6alkoxygroup (for example, a methoxy group, cyclopropane, isopropoxy and the like). Examples of Ala is cialiles groups include C 1-C6alkyl groups, substituted C1-C6alkoxygroup (for example, methoxymethyl group, ethoxymethyl group and the like). Examples of hydroxyalkyl groups include C1-C6alkyl groups, substituted hydroxyl group (for example, hydroxymethylene group, 1-hydroxyethylene group and the like). Examples carboxialkilnuyu groups include C1-C6alkyl group, substituted carboxyl group (for example, carboxymethyl group, 1-carboxyaniline group and the like). Examples alkoxycarbonyl groups include the group consisting of C1-C6alkoxygroup and carbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group and the like). Examples alkoxycarbonylmethyl groups include C1-C6alkyl groups, substituted C1-C6alkoxycarbonyl group (for example, methoxycarbonylamino group, ethoxycarbonylethyl group and the like). Examples carbamylcholine groups include C1-C6alkyl groups, substituted carbamoyl group (for example, carbamoylmethyl group, carbamoylethyl group and the like). Examples of N-alkylcarboxylic groups include carbamoyl group, substituted C1-C6alkyl group (for example, N-IU is elkabakalova group, N-isopropylcarbamate group, N-cyclopropylamino group and the like). Examples of N,N-dialkylanilines groups include carbamoyl group, substituted two C1-C6alkyl groups are the same or different from each other (for example, N,N-dimethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group and the like). Examples of N-alkylcarboxylic groups include1-C6alkyl groups, substituted N-alkylcarboxylic group (for example, N-methylcarbamoylmethyl group, N-methylcarbamoylmethyl group and the like). Examples of N,N-dialkylanilines groups include C1-C6alkyl groups, substituted N,N-dialkylanilines group (for example, N,N-dimethylcarbamoyl group, N,N-dimethylcarbamoyl group and the like). Examples of heteroaryl groups include the same heteroaryl group as described in the description of Q4in the General formula (1). Examples heteroarylboronic groups include C1-C6alkyl group, substituted heteroaryl group (for example, thienylmethyl group, pyridylamino group and the like). Examples of aryl groups include aryl groups having 6-14 carbon atoms, such as phenyl group and naftalina group. Aryl groups can have 1-3 substituent, selected the C 1-C6alkyl groups, C1-C6alkanoyl groups, hydroxyl group, nitro group, ceanography, atoms, halogen, C1-C6alkenyl groups2-C6etkinlik groups, halogenating groups, alkoxygroup, carboxypropyl, carbamoyl group, alkoxycarbonyl groups and the like. Examples Uralkalij groups include C1-C6alkyl groups, substituted C6-C14aryl groups (for example, benzyl group, fenetylline group and the like). Incidentally, in the above description are not imposed special restrictions on the position of substitution.

Next is described the following group:

where Q5, R9and R10have the same meanings as defined above, and numerals 1 and 2 indicate positions.

Part of a cyclic structure containing the group Q5is a 3-10-membered divalent cyclic hydrocarbon group which may have a double bond, preferably 3-8-membered divalent cyclic hydrocarbon group, and more preferably 5 to 7-membered divalent cyclic hydrocarbon group. Of them, preferred is a group in which Q3is alkalinous group. The specified cyclic hydrocarbon group can have when ructure as CIS-, and TRANS-forms in relation to the position 1 and position 2. But in the case of 5-membered ring is preferred TRANS-form, and in the case of a 6-or 7-membered rings are preferred, and CIS-form and TRANS-form.

Described in detail below, the substituents R9and R10.

Alkyl group, Alchemilla group, Alchemilla group, halogen atom, halogenation group, lanakila group, acyl group, acidalkaline group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, carboxialkilnuyu group, alkoxycarbonyl group, alkoxycarbonyl group, aryl group, kalkilya group, heteroaryl group and heteroallyl group are the same as those described above in the description of the substituents R5, R6, R7and R8. Examples of alluminare, which may be substituted include an amino group, a substituted acyl group (for example, formylamino, acetylamino and the like), and acyl groups having 1 or more substituents selected from halogen atoms, hydroxyl groups, C1-C6alkoxygroup, amino, N-C1-C6alkylamino, N,N-di-C1-C6alkylamino, a carboxyl group, a C2-C6alkoxycarbonyl groups and the like (e.g. the, 2-methoxyethylamine, 3-aminodiphenylamine and the like). Examples acylaminoalkyl groups include C1-C6alkyl groups, substituted allmineral (for example, tormilainetel group, acetamidomethyl group and the like). Examples aminoalkyl groups include C1-C6alkyl group, a substituted amino group (for example, aminomethyl group, 1-aminoethyl group and the like). Examples of N-acylaminoalkyl groups include amino-C1-C6alkyl groups, substituted C1-C6alkyl group at the nitrogen atom (for example, N-methylaminomethyl group, N-methylaminoethanol group and the like). Examples of N,N-dialkylaminoalkyl groups include amino-C1-C6alkyl group, respectively, substituted with two C1-C6alkyl groups at the nitrogen atoms (for example, N,N-dimethylaminomethylene group, N-ethyl-N-methylaminoethanol group and the like). Examples of N-alkenylamine groups include carbamoyl group, substituted unbranched or branched C2-C6alkenylphenol group (for example, arylcarbamoyl group and the like). Examples of N-alkenylboronic groups include C1-C6alkyl groups, substituted N-alkenylamine group (for example, as likability group and the like). Examples of N-alkenyl-N-alkylcarboxylic groups include N-alkenylamine group, substituted unbranched or branched C1-C6alkyl group at the nitrogen atom (for example, N-allyl-N-methylcarbamoyl group and the like). Examples of N-alkenyl-N-alkylcarboxylic groups include N-alkenylboronic group, substituted unbranched or branched C1-C6alkyl group at the nitrogen atom (for example, N-allyl-N-methylcarbamoylmethyl group and the like). Examples of N-alkoxycarbonyl groups include carbamoyl group, substituted unbranched or branched C1-C6alkoxygroup (for example, methoxycarbonylamino group and the like). Examples of N-alkoxycarbonylmethyl groups include unbranched or branched C1-C6alkyl groups, substituted N-alkoxycarbonyl group (for example, methoxycarbonylamino group and the like). Examples of N-alkyl-N-alkoxycarbonyl groups include carbamoyl group, substituted unbranched or branched C1-C6alkoxygroup and C1-C6alkyl group (for example, N-ethyl-N-methoxycarbonylamino group and the like). Examples of N-alkyl-N-alkoxycarbonylmethyl groups include unbranched or branched C1 -C6alkyl groups, substituted N-alkyl-N-alkoxycarbonyl group (for example, N-ethyl-N-methoxycarbonylamino group and the like). Examples carbazole group which may be substituted by 1-3 alkyl groups include carbazolyl group, and carbazole group, substituted 1-3 unbranched or branched C1-C6alkyl groups (for example, 1-methylcarbazole group, 1,2-dimethylcarbamoyl group and the like). Examples alkylsulfonyl groups include unbranched or branched C1-C6alkylsulfonyl group (for example, methanesulfonyl group and the like). Examples alkylsulfonyl groups include unbranched or branched C1-C6alkyl groups, substituted alkylsulfonyl group (for example, methanesulfonyl group and the like). Examples of alkoxyimino include C1-C6alkoxyimino (for example, methoxyimino, toksikologiya and the like). Examples of alkoxycarbonylmethyl include amino, substituted alkoxycarbonyl group (for example, methoxycarbonylmethylene, ethoxycarbonylpyrimidine and the like). Examples of carboxylterminated include amino, substituted carboxialkilnuyu what Ruppel (for example, carboxymethylamino, carboxymethylamino and the like). Examples of alkoxycarbonylmethyl include amino, substituted alkoxycarbonyl group (for example, methoxycarbonylamino, tert-butoxycarbonylamino and the like). Examples alkoxycarbonylmethyl groups include alkyl groups, substituted alkoxycarbonylmethyl (for example, methoxycarbonylamino group, tert-butoxycarbonylmethyl group and the like). N-alkylcarboxylic group which may have a substituent in the alkyl group, means karbamoilnuyu group, substituted unbranched, branched or cyclic C1-C6alkyl group which may be substituted with hydroxyl group, amino group, N-C1-C6alkylaminocarbonyl, amidinopropane, halogen atom, carboxyl group, cyano, carbamoyl group3-C6alkoxygroup, C1-C6alkanoyloxy group, C1-C6alkanolamines, C1-C6alkylsulfonamides or the like, and examples include N-methylcarbamoyl group, N-ethylcarbazole group, N-isopropylcarbamate group, N-cyclopropylamino group, N-(2-hydroxyethyl)karbamoilnuyu group, N-(2-foradil)karbamoilnuyu group, N-(2-Tianeti is)karbamoilnuyu group, N-(2-methoxyethyl)karbamoilnuyu group, N-carboximetilkrahmala group, N-(2-amino-ethyl)karbamoilnuyu group, N-(2-amidaniel)karbamoilnuyu group and the like. N,N-dialkylanilines group which may have a substituent in the alkyl group, means karbamoilnuyu group, substituted 2 unbranched, branched or cyclic C1-C6alkyl groups which may be substituted with hydroxyl group, amino group, N-C1-C6alkylaminocarbonyl, amidinopropane, halogen atom, carboxyl group, cyano, carbamoyl group, C1-C6alkoxygroup, C1-C6alkanoyloxy group, C1-C6alkanolamines, C1-C6alkylsulfonamides or the like, and examples include N,N-dimethylcarbamoyl group, N,N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl group, N-(2-hydroxyethyl)-N-methylcarbamoyl group, N,N-bis(2-hydroxyethyl)karbamoilnuyu group, N,N-bis(2-foradil)karbamoilnuyu group, N-(2-Tianeti)-N-methylcarbamoyl group, N-(2-methoxyethyl)-N-methylcarbamoyl group, N-carboxymethyl-N-methylcarbamoyl group, N,N-bis(2-amino-ethyl)karbamoilnuyu group and the like. N-alquilerbarcelona group which may have a substituent in and Kilroy group, includes unbranched or branched C1-C6alkyl group, substituted N-alkylcarboxylic group which may have a substituent in the alkyl group (for example, N-methylcarbamoylmethyl group, N-(2-hydroxyethyl)carbamoylmethyl group and the like). Examples of N,N-dialkylanilines group which may have a substituent in the alkyl group include an unbranched or branched C1-C6alkyl groups, substituted N,N-dialkylanilines group which may have a substituent in the alkyl group (such as N,N-dimethylcarbamoyl group, N-(2-hydroxyethyl)-N-methylethylenediamine group and the like).

3-6-Membered nitrogen-containing heterocyclic carbonyl group which may be substituted, represents the group consisting of saturated or unsaturated nitrogen-containing heterocyclic ring and a carbonyl group. Nitrogen-containing heterocyclic ring means a 3-6-membered heterocyclic ring which contains at least 1-3 nitrogen atom and may contain an oxygen atom or a sulfur atom. Heterocyclic ring may have a Deputy, such as a hydroxy-group, halogen atom, amino group or C1-C6an alkyl group. As its specific examples, azetidin carbonyloxy group, azetidinol group, 3-hydroxyacetylamino group, 3-methoxyaminomethyl group, pyrrolidinylcarbonyl group, 3-hydroxypropionitrile group, 3-perpersonperbooking group, piperidinylcarbonyl group, piperazinylcarbonyl group and morpholinylcarbonyl group.

Examples 3-6-membered nitrogen-containing heterocyclic carbonylation group which may be substituted, include a C1-C6alkyl groups, substituted 3-6-membered nitrogen-containing heterocyclic carbonyl group which may be substituted (for example, setidentityproviderid group, pyrrolidinylcarbonyl group and the like).

Examples 3-6-membered nitrogen-containing heterocyclic carbonylcyanide group which may be substituted, include a C1-C6alkyl groups, substituted 3-6-membered nitrogen-containing heterocyclic carbonyloxy, which consists of a 3-6-membered nitrogen-containing heterocyclic group which may be substituted, and oxygen atom (for example, piperidinecarbonitrile group, morpholinylcarbonyl group and the like).

Example carbamylcholine group includes C1-C6alkyl groups, substituted carbamoyl group (e.g. the, carbamoylmethyl group, carbamoylethyl group and the like).

Examples carbamoyloximes groups include C1-C6alkyl groups, substituted carbamoyloximes consisting of carbamoyl group and oxygen atom (for example, carbamoylmethyl group, carbamoylmethyl group and the like).

Examples of N-alkylcarboxylic groups include C1-C6alkyl groups, substituted N-alkylcarboxylic consisting of N-alkylcarboxylic group which may have a substituent in the alkyl group and oxygen atom (for example, N-methylcarbamoylmethyl group, N-methylcarbamoylmethyl group and the like).

Examples of N,N-dialkylanilines groups include C1-C6alkyl groups, substituted N,N-dialkylanilines consisting of N,N-dialkylanilines group which may have a substituent in the alkyl group and oxygen atom (for example, N,N-dimethylcarbamoyl group, N-ethyl-N-methylcarbamoylmethyl group and the like).

Examples of alkylsulfonamides include amino, substituted alkylsulfonyl group having C1-C6alkyl group (for example, methylsulfonylamino, isopropylbenzylamine and the like).

Examples of what resultonline include amino groups, substituted arylsulfonyl group having aryl group (for example, phenylcarbonylamino, naphtylcontaining and the like).

Examples alkylsulfonamides groups include C1-C6alkyl groups, substituted C1-C6alkylsulfonamides (for example, methylsulfonylamino group, methylsulfonylamino group and the like).

Examples arylsulfonamides groups include C1-C6alkyl groups, substituted arylsulfonamides (for example, vinylsulfonylacetamido group, afternoonfortunately group and the like).

Examples alkylsulfonamides groups include the group consisting of C1-C6alkylsulfonamides and carbonyl group (for example, methylsulfonylmethyl group, isopropylaminocarbonyl group and the like).

Examples arylsulfonamides group include groups composed of arylsulfonamides and carbonyl group (for example, vinylsulfonylacetamido group, afternoonfortunately group and the like).

Examples alkylsulfonylpyridines groups include C1-C6alkyl groups, substituted C1-C6alkylsulfonyl the carbonyl group (for example, methylsulfonylmethyl group, isopropylaminocarbonyl group and the like).

Examples arylsulfonylglycines groups include C1-C6alkyl groups, substituted arylsulfonamides group (for example, phenylcarbonylamino group, mattercollaboration group and the like).

Alloctype means group consisting of the acyl group and oxygen atom (for example, formyloxy, acetyloxy and the like).

Examples aryloxyalkyl groups include C1-C6alkyl groups, substituted alloctype (for example, formyloxyethyl group, acetylocholine group and the like).

Examples of aralkylated include alkoxygroup, substituted aryl group (for example, benzyloxy, naphthylmethyl and the like).

Examples of carboxymethyloxime include alkoxygroup, substituted carboxyl group (for example, carboxymethoxy, carboxitherapy and the like).

Allenova group means an unbranched or branched alkylenes group having 1-5 carbon atoms, and its examples include methylene group, ethylene group, propylene group and the like.

Alkenylamine group pre who is alkynylamino group, having 2-5 carbon atoms and a double bond, and examples include vanilinovoi group, propenylidene group and the like. Examples of alkylenedioxy include alkylenedioxy having 1-5 carbon atoms, such as methylendioxy, atlantoxerus and propyleneoxide.

Carbondioxide is a group represented by formula-O-C(=O)-O-. Incidentally, in the above description are not imposed special restrictions on the position of substitution.

Among these substituents, represented by the symbols R9and R10preferred are a hydrogen atom, a hydroxyl group, an alkyl group, Alchemilla group, Alchemilla group, halogen atom, halogenation group, amino group, hydroxyimino, alkoxyimino, aminoalkyl group, N-acylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acidalkaline group, alluminare, which may be substituted, acylaminoalkyl group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxialkilnuyu group, alkoxycarbonyl group, alkoxycarbonyl group, alkoxycarbonylmethyl, alkoxycarbonylmethyl group, carnemolla group, N-alkylcarboxylic group which may have mandated the tel in the alkyl group, N,N-dialkylanilines group which may have a substituent in the alkyl groups, N-alkenylamine group, N-alkenylboronic group, N-alkenyl-N-alkylcarboxylic group, N-alkenyl-N-alquilerbarcelona group, N-alkoxycarbonyl group, N-alkyl-N-alkoxycarbonyl group, N-alkoxycarbonylmethyl group, N-alkyl-N-alkoxycarbonylmethyl group, carbazole group which may be substituted by 1-3 alkyl groups, alkylsulfonyl group, alkylsulfonyl group, 3-6-membered nitrogen-containing heterocyclic carbonyl group which may be substituted, 3-6-membered nitrogen-containing heterocyclic carbonylcyanide group which may be substituted, carbamylcholine group, carbamoylmethyl group, N-alkylcarboxylic group, N,N-dialkylcarbocyanine group, N-alquilerbarcelona group which may have a substituent in the alkyl group, N,N-dialkylanilines group which may have a substituent in the alkyl groups, alkylsulfonamides, alkylsulfonamides group, oxoprop, alloctype and aryloxyalkyl group. Also are the preferred Allenova group, alkenylamine group, alkylenedioxy and carbondioxide formed by mixing what italiani R 9and R10together with each other.

It is preferred that R9was the hydrogen atom, and R10one of the above preferred substituents. In this case, examples of the group is more preferable as R10include a hydrogen atom, hydroxyl group, alkyl group, halogen atom, hydroxyimino, N-acylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, allmenalp, which may be substituted, acylaminoalkyl group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, alkoxycarbonyl group, alkoxycarbonyl group, alkoxycarbonylmethyl, karbamoilnuyu group, N-alkylcarboxylic group which may have a substituent in the alkyl group, N,N-dialkylamino group which may have a substituent in the alkyl groups, N-alkenylamine group, N-alkenylboronic group N-alkenyl-N-alkylcarboxylic group, N-alkenyl-N-alkylcarboxylic group, N-alkoxycarbonyl group, N-alkyl-N-alkoxycarbonyl group, N-alkyl-N-alkoxycarbonylmethyl group, carbazoyl group which may be substituted by 1-3 alkyl groups, alkylsulfonyl group, alkylsulfonyl group, 3-6-membered nitrogen-containing heterotic the practical carbonyl group, which may be substituted, 3-6-membered nitrogen-containing heterocyclic carboncillo group which may be substituted, carbamoylethyl group, N,N-dialkylimidazolium group, N-alkylcarboxylic group which may have a substituent in the alkyl group, N,N-dialkylanilines group which may have a substituent in the alkyl groups, alkylsulfonamides, alkylsulfonyl group and alloctype.

Of them, particularly preferred examples of R10include a hydrogen atom, hydroxyl group, alkyl group, N,N-dialkylaminoalkyl group, allmenalp, which may be substituted, acylaminoalkyl group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, alkoxycarbonyl group, alkoxycarbonylmethyl, karbamoilnuyu group, N-alkylcarboxylic group which may have a substituent in the alkyl group, N,N-dialkylamino group which may have a substituent in the alkyl groups, N-alkenylamine group, N-alkenylboronic group, N-alkenyl-N-alkylcarboxylic group, N-alkenyl-N-alkylcarboxylic group, N-alkyl-N-alkoxycarbonyl group, carbazoyl group which may be substituted by 1-3 alkyl groups, alkylsulfonyl group, ALK is sulfonylamino group, 3-6-membered nitrogen-containing heterocyclic carbonyl group which may be substituted, N,N-dialkylimidazolium group, N-alkylcarboxylic group which may have a substituent in the alkyl group, N,N-dialkylanilines group which may have a substituent in the alkyl groups, alkylsulfonamides, alkylsulfonyl group and alloctype.

As specific preferred examples of R9and R10you can call a hydrogen atom, hydroxyl group, methyl group, ethyl group, isopropyl group, N,N-dimethylaminomethylene group, N,N-dimethylaminomethylene group, N,N-diethylaminoethyl group, acetylamino, methoxyacetophenone acetamidomethyl group, acetylaminophenol group, a methoxy group, ethoxypropan, methoxymethyl group, methoxyamino group, hydroxymethylene group, 2-hydroxyethylene group, 1-hydroxy-1-methylamino group, methoxycarbonyl group, ethoxycarbonyl group, methoxycarbonylamino, ethoxycarbonylmethyl, N-arylcarbamoyl group, N-arylcarbamoyl group, N-allyl-N-methylcarbamoyl group, N-allyl-N-methylcarbamoylmethyl group, N-methoxy-N-methylcarbamoyl group, N,N-dimethylcarbamoyl group, N,N,N'-trimethylquinoline gr the PPU, methanesulfonyl group, methysulfonylmethane group, econsultation group, N-methylcarbamoyl group, N-ethylcarbazole group, N-profilirovannuju group, N-isopropylcarbamate group, N-tert-butylcarbamoyl group, N-cyclopropylamino group, N-cyclopropanecarbonyl group, N-(1-ethoxycarbonylethyl)karbamoilnuyu group, N-(2-hydroxyethyl)karbamoilnuyu group, N-(2-foradil)karbamoilnuyu group, N-(2-methoxyethyl)karbamoilnuyu group, N-(carboxymethyl)karbamoilnuyu group, N-(2-amino-ethyl)karbamoilnuyu group, N-(2-amidaniel)karbamoilnuyu group, N,N-dimethylcarbamoyl group, N,N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl group, N-methyl-N-profilirovannuju group, N-(2-hydroxyethyl)-N-methylcarbamoyl group, N-(2-foradil)-N-methylcarbamoyl group, N,N-bis(2-hydroxyethyl)karbamoilnuyu group, N,N-bis(2-foradil)karbamoilnuyu group, N-(2-methoxyethyl)-N-methylcarbamoyl group, N-carboxymethyl-N-methylcarbamoyl group, N,N-bis(2-amino-ethyl)karbamoilnuyu group, azetidinol group,

3-methoxyaminomethyl group,

3-hydroxylaseadenocarcinoma group,

pyrrolidinecarbonyl group,

3-hydroxypyrrolidine group,

3-ftorpirimidinov the ing group,

3,4-dimethoxypyrimidine group,

piperidinylcarbonyl group, piperazinylcarbonyl group,

morpholinosydnonimine group, N-methylcarbamoylmethyl

group, N-methylcarbamoylmethyl group,

N-ethylcarbodiimide group,

N-(2-foradil)carbamoylmethyl group,

N-(2-methoxyethyl)carbamoylmethyl group,

N,N-dimethylcarbamoyl group,

N,N-dimethylcarbamoyl group,

N-(2-foradil)-N-methylcarbamoylmethyl group,

N-(2-methoxyethyl)-N-methylcarbamoylmethyl group,

N,N-dimethylcarbamoyl group, 2-(N-ethyl-N-methylcarbamoyl)ethyl group, methylsulfonylamino, ethylsulfonylimidazo, methylsulfonylamino group and methylsulfonylmethyl group. As described above, it is preferable that R9was a hydrogen atom, a R10one of these specific substituents. But, generally speaking, R9and R10not limited to these specific substituents.

The T1represents a carbonyl group or sulfonyloxy group, preferably a carbonyl group, when the group Q1is a bicyclic or tricyclic condensed hydrocarbon group or a bicyclic or tricyclic condensed heterocyclic the mini group and the group Q 2is a single bond.

R1and R2represent, independently from each other, a hydrogen atom, hydroxyl group, alkyl group, or alkoxygroup, preferably a hydrogen atom or alkyl group, and more preferably a hydrogen atom.

In the compounds of the present invention represented by the General formula (1)may be present stereoisomers or optical isomers are possible because of the presence of asymmetric carbon atom. But all of these stereoisomers, optical isomers and their mixtures are included in the scope of the present invention.

Imposed special restrictions on salt compounds of the present invention represented by the General formula (1), as long as they are pharmaceutically acceptable salts. However, their specific examples include salts of mineral acids, such as hydrochloride, hydrobromide, hydroiodide, phosphates, nitrates and sulfates; benzoate; organic sulfonates such as methanesulfonate, 2-hydroxyethanesulfonic and p-toluensulfonate; and organic carboxylates such as acetates, propanoate, oxalates, malonate, succinate, glutarate, adipate, tartratami, maleate, malate and mandelate. When compounds represented by the General formula (1)have an acidic group, they may be salts of alkali metal ions or alkaline earth ions metalone imposed special restrictions on their solvate, if only they were a pharmaceutically acceptable solvate. But as their specific examples the hydrate and solvate with ethanol. When in the General formula (1) is a nitrogen atom, such compounds can be converted into their N-oxides.

The following describes methods of obtaining derivatives (1) Ethylenediamine according to the present invention.

[Method 1 retrieve]

A derivative of ethylene diamine represented by General formula (1), its salt, MES or N-oxide can be obtained, for example, in the following way:

where Q1, Q2, Q3, Q4, R1and R2have the same meanings as defined above, and T1represents a carbonyl group.

A mixed acid anhydride, halogenmethyl, activated ester or the like, being derived carboxylic acid (3), when interacting with the diamine (2) to give compound (4). The obtained compound (4) may interact with carboxylic acid (5), to give the compound (1) according to the present invention. In the above stages, you can use the reagents and conditions used in the synthesis of peptides. The mixed acid anhydride can be obtained, for example, the interaction of chloroformate such as ethylchloride or isobutylparaben, with carboxylic acid (3) in the presence of the basis of the Oia. Gelegenheid can be obtained by treatment of carboxylic acid (3) galogenangidridy, such as thionyl chloride or oxalicacid. Activated ester includes various types of esters. This ester can be obtained, for example, the interaction of phenol, such as p-NITROPHENOL, N-hydroxybenzotriazole or N-hydroxysuccinimide, with carboxylic acid (3) using a condensing agent such as N,N'-dicyclohexylcarbodiimide or hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide. The activated ester can also be obtained by the interaction of the carboxylic acid (3) with pentacarbonylchlororhenium or the like, by the interaction of the carboxylic acid (3) with hexaphosphate 1-benzothiazolylsulfenamide, the interaction of carboxylic acid (3) with diethylthiophosphate (method Shioiri), the interaction of carboxylic acid (3) with triphenylphosphine and 2,2'-dipyridylium (Mukaiyama method) or the like. Collected in this way a mixed acid anhydride, halogenmethyl or activated ester of carboxylic acid (3) can, by interacting with the diamine (2) at (-78° (C)-(150° (C) in the presence of a suitable base in an inert solvent, to give compound (4). The obtained compound (4) can interact with the mixed anhydride, galogenangidridy the house or activated complex ether carboxylic acid (5) under the same conditions, giving the compound (1) according to the present invention. Reagents and reaction conditions in the interaction of the compound (4) with carboxylic acid (5) are the same as in the interaction of the diamine (2) with carboxylic acid (3).

As specific examples of the base used in each stage can be called the carbonates of alkaline or alkaline earth metals such as sodium carbonate and potassium carbonate, alkoxides of alkali metals, such as ethoxide sodium and piperonyl potassium, hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide, and hydrides of alkali or alkaline earth metals, such as sodium hydride and potassium hydride; organic metal bases, examples of which are alkality, such as n-utility, and dialkylaminomethyl, such as diisopropylamide lithium; organic metal bases such as bis(silyl)amine such as bis(trimethylsilyl)amide and lithium; and organic bases such as pyridine, 2,6-lutidine, kallidin, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).

Examples of the inert solvent used in this reaction include solvents of the type alkylhalogenide, such as dichloromethane, chloroform and carbon tetrachloride, a solvent type, a simple ester, such as tetrahydrofuran is, 1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene and toluene, amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidine-2-it. In addition to these solvents, in some cases, you can use sulfoxide solvent, such as dimethylsulfoxide or sulfolane, a ketone solvent such as acetone or methyl ethyl ketone, or the like.

[Way 2 get]

Connection (1) according to the present invention can also be obtained in the following way:

where Q1, Q2, Q3, Q4, R1and R2have the same meanings as defined above, T1represents a carbonyl group. The BOC is tert-butoxycarbonyl group and Boc-ON is 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile.

As described above, the diamine (2) process, using Boc-ON (6) to obtain the compound (7)in which one of the 2 amino groups protected with tert-butoxycarbonyl group. The obtained compound (7) interacts with carboxylic acid (5), gives compound (8). Compound (8) is then treated with acid to obtain compound (9). Further, the compound (9), interacting with a carboxylic acid (3), gives compound (1) according to the present invention. Compound (7) can be obtained in the following conditions is the third. The reaction is carried out at (-10° (C)-(40° (C) in the presence of triethylamine in a solvent such as dichloromethane. The interaction of the compound (7) with the mixed anhydride, galogenangidridy and the activated ester of carboxylic acid (5) is carried out using the same reagents and reaction conditions as those described in method 1 to obtain the result in can be obtained compound (8). The obtained compound (8) is treated triperoxonane acid or the like at (-20° (C)-(70°C), which may be obtained amine (9). In the reaction between the obtained amine (9) and carboxylic acid (3) can be used the same reagents and conditions as described in method 1 is received.

In addition, tert-butoxycarbonyl group of compound (7) can be replaced by other aminosidine groups. In this case, the reagent (6) also be replaced by other reagents, it is necessary to use the appropriate reagents, reaction conditions and the like. As other examples of protective groups for amino groups can be called conventional protective groups are acyl type, namely alcoholnye groups such as acetyl group, alkoxycarbonyl groups, such as methoxycarbonyl and ethoxycarbonyl group, arylethoxysilanes groups, such as benzyloxycarbonyl, p-methoxybenzyloxy Bonilla and p - or o-nitrobenzisoxazole group, arylmethyl groups such as benzyl and triphenylmethyl group, aroline groups, such as benzoline group, and arylsulfonyl groups, such as 2,4-dinitrobenzenesulfonyl and on-nitrobenzenesulfonyl group. These protective groups can be selected for use in accordance with the nature and the like compounds, amino group which you want to protect. When removing such protective groups can be used reagents and conditions suitable protective group.

[Method 3 get]

Connection (1) according to the present invention can be obtained by the interaction of the diamine (2) sulphonylchloride (10):

where Q1, Q2, Q3, Q4, R1and R2have the same meanings as defined above, T1is sulfonyloxy group and X represents a halogen atom.

The diamine (2) interacts with sulphonylchloride (10) at (-10° (C)-(30° (C) in the presence of a base, such as triethylamine, in an inert solvent and in the network connection (4). Inert solvent and base may be appropriately selected for use from those described in method 1 is received. The obtained compound (4) is condensed with carboxylic acid (5)using the reagents and conditions described in method 1 to obtain, in the cut is ltate which can be obtained compound (1) according to the present invention. Sulfonylmethane (10) can be synthesized in a suitable basis of a known method (WO 96/10022, WO 00/09480) or the corresponding method.

[Method 4 getting]

Connection (1) according to the present invention can also be obtained in the following way:

where Q1, Q2, Q3, Q4, R1, R2and X have the same meanings as defined above. T1is sulfonyloxy group.

In particular, the amine (9) can interact with sulphonylchloride (10) at (-10° (C)-(30° (C) in the presence of a base in an inert solvent, giving the compound (1). Inert solvent and base may be appropriately selected for use from those described in method 1 is received.

[Method 5 retrieve]

In compounds (1) according to the present invention are geometric isomers of TRANS-form and CIS-form in relation to the position 1 and position 2, when Q3represents the following group:

where R9, R10and Q5have the same meanings as defined above, and numerals 1 and 2 indicate positions.

Methods for obtaining compounds (1)having TRANS-form and CIS-form of Q3described below.

<a Method of obtaining TRANS-form>

where Q5, R9 and R10have the same meanings as defined above.

As an example of obtaining the TRANS-diol (12A) of the cyclic alkene (11) is known transformation, for example, cyclohexene in the TRANS-cyclohexanediol (Organic Synthesis, 1995, Vol.III, p.217). As an example of obtaining the TRANS-diamine (2A) of the TRANS-diol (12A) is known for the transformation of the TRANS-cyclopentanediol in TRANS-cyclopentadien (WO 98/30574). In accordance with the specified message TRANS-diamine (2A) can be obtained from the cyclic alkene (11).

TRANS-diamine (2A), obtained as described above can be converted into the TRANS-compound (1) any of the above methods 1-4.

<a method of obtaining a CIS-form>

where Q5, R9and R10have the same meanings as defined above.

As an example obtain CIS-diol (12b) of the cyclic alkene (11) is known transformation, for example, cyclohexene in CIS-cyclohexanediol (J.Org. Chem., 1998, Vol.63, R). As an example obtain CIS-diamine (2b) of the CIS-diol (12A) is known for the conversion of CIS-cyclopentanediol in CIS-cyclopentadien (WO 98/30574). In accordance with the specified messages CIS-diamine (2b) can be obtained from the cyclic alkene (11).

CIS-diamine (2b), obtained as described above can be converted into the CIS-compound (1) any of the above methods 1-4.

[Method 6 receive]

As opisanie, in compounds (1) according to the present invention may be either CIS-form or TRANS-form, formed in Q3and therefore, there are geometrical isomers. In addition, the corresponding geometric isomers may be present optical isomers. A method of obtaining optically active compounds described below:

where Q5, R1, R2, R9and R10have the same meanings as defined above, and R50represents a protective group for amino group.

As for the method of obtaining optically active aminopyrrolo derivative (15) 1,2-TRANS-forms, known, for example, a method of obtaining optically active 1,2-TRANS-2-aminocyclopentane from Cyclopentanone or a method of obtaining optically active 1,2-TRANS-2-aminocyclohexanol from cyclohexanone (Tetrahedron: Asymmetry, 1996, Vol.7, R; J.Org. Chem., 1985, Vol.50, p.4154; J. Med. Chem., 1998, Vol.41, p.38). When the interaction between the amino group of the optically active amerosport (15), already obtained in a known manner or by application of the above method, with suitable protective reagent can be obtained compound (16). As a protective group corresponding to R50in the compound (16), from the usual protective groups are acyl type is preferred alkoxycarbonyl group, such as IU oxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, armletaccessory group, such as benzyloxycarbonyl, p-methoxybenzylideneamino or p - or o-nitrobenzisoxazole group, or arylsulfonyl group, such as 2,4-dinitrobenzenesulfonyl or on-nitrobenzenesulfonyl. When the protection of the amino group, for example, tert-butoxycarbonyl group, amerosport (15) can interact with di-tert-BUTYLCARBAMATE at (-78° (C)-(50° (C) in an inert solvent with the formation of compound (16). Suitable inert solvent can be selected for use from those described in method 1 is received.

Compound (16) can interact with methanesulfonamido at (-78° (C)-(50° (C) in the presence of a base in an inert solvent with the formation of compound (17). Suitable inert solvent can be selected for use from those described in method 1 is received. As a preferred base is an organic base, such as pyridine, 2,6-lutidine, kallidin, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine or diazabicyclo[5.4.0]undec-7-ene (DBU).

The compound (17) can interact with sodium azide at (-10° (C)-(150° (C) in a suitable solvent with the formation of compound (18). Suitable solvents are the two which is the amide solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidine-2-it, an alcohol solvent such as methanol or ethanol, a solvent type simple ether, such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane, an aromatic solvent such as toluene, halide carbon, such as dichloromethane, chloroform or carbon tetrachloride, acetone, dimethyl sulfoxide or a mixed solvent obtained from the specified solvent mixed with water.

There are many ways suitable for the conversion of the derivative (18) azide in the compound (7a), such as hydrogenation using palladium catalyst, Raney Nickel or platinum catalyst, the reaction using a reducing agent such as alumalite lithium, sodium borohydride or zinc borohydride, the reaction using zinc in the presence of Nickel chloride or cobalt chloride and the reaction using triphenylphosphine. Suitable reaction conditions may be selected in accordance with the nature of the connections. For example, the derivative (18) azide hydronaut at a temperature of (-10° (C)-(70° (C) using 1-20% palladium on carbon as catalyst in a suitable solvent, which may be obtained compound (7a). The hydrogen pressure may be above atmospheric pressure. The solvent is eligible who is an alcoholic solvent, such as methanol or ethanol, a solvent type simple ether, such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane, an amide solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidine-2-he, solvent type of ester, such as ethyl acetate, acetic acid, hydrochloric acid, water or a mixed solvent of these solvents.

Optically active amine (7a)obtained as described above can be converted into optically active compound (1) in accordance with the above-described method 2 is received. The same method can be also obtained antipode (1) optically active substance (1), obtained from the optically active amine (7a).

Optically active compound (1) can be obtained by separation of racemic compounds (1) by passing through a column of optically active carrier. You can also split the intermediate connection(2), (4), (7), (8) or (9) to obtain racemic compounds (1) by passing through a column of optically active media for separation of optically active intermediate compounds(2), (4), (7), (8) or (9) and then for obtaining optically active compounds (1) any means of obtaining 1-4. As a way of marking the active intermediate compounds(1), (2), (4), (7), (8) or (9) you can use the method of fractionalisation salts with optically active carboxylic acid or on the contrary, the method of fractional crystallization of salts with optically active base.

Suitable compounds from the point of view of intermediates for preparing compounds (1) according to the present invention are the following amines (4)used in the above-described methods 1-4 obtain:

where R1, R2, Q3, Q4and T1have the same meanings as defined above, or the following amines (9):

where R1, R2, Q1That Q and Q have the same meanings as defined above.

Appropriate intermediate compounds are also optically active amines (7a). In particular, as described below, the following amine (7b) can be converted into the specified optically active compound (1A) as described above 2 are received. The compound (1A) can then be transformed into a derivative having a carboxyl group, amide group or the like, by converting the ester group in the cyclohexane ring connection.

where Boc has the same meaning as defined above.

The following describes specific methods of obtaining and FXa-inhibiting effects of derivatives of ethylene diamine according to the present invention.

EXAMPLES

In this embodiment, derivatives of ethylene diamine for us is oasea the invention are named as substituted alkadiene. For example, the following connection:

call (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine.

[Reference example 1]

4-[(tert-Butoxycarbonyl)amino]pyridine:

4-Aminopyridine (10 g) was dissolved in tetrahydrofuran (500 ml), to the solution was added di-tert-BUTYLCARBAMATE (25,5 g) and the mixture was stirred at room temperature for 10 minutes. The resulting reaction mixture was concentrated under reduced pressure and precipitated in the sludge solids were washed with hexane to obtain specified in the connection header (16,9 g) as a colourless solid.

1H-NMR (CDCl3) δ: 1,53 (N, C)6,86 (1H, sh), 7,30 (2H, DD, J=1,5, a 4.9 Hz), 8,44 (2H, DD, J=1,5, 4,9 Hz).

MS (FAB) m/z: 195 (M+H)+.

[Referential example 2]

4-[(tert-Butoxycarbonyl)amino]-3-mercaptopyridine:

4-[(tert-Butoxycarbonyl)amino]pyridine (of 61.6 g) was dissolved in tetrahydrofuran (2000 ml) and the solution was stirred at -78°C for 10 minutes. To the solution was added dropwise hexane solution (1,59 mol/l, 500 ml) n-utility and the mixture was stirred 10 minutes and then 2 hours under ice cooling. After the reaction mixture was cooled to -78°With added poroshkoobraz the Yu sulfur (12.2 g) and the resulting mixture was heated to room temperature and was stirred for 1 hour. In the reaction mixture were added water (1000 ml) to separate the aqueous layer. Once added to the water layer 3 N. hydrochloric acid to bring the pH of the aqueous layer to 3-4 was added dichloromethane to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (dichloromethane:methanol=50:1) to obtain specified in the connection header (33,2 g) as a pale yellow foamy substance.

1H-NMR (DMSO-d6) δ: 1.52m (N, C), 7,89 (1H, d, J=6.4 Hz), to 7.99 (1H, d, J=6.4 Hz), to 8.20 (1H, s), to 9.91 (1H, sh),

MS (FAB) m/z: 227 (M+H)+

[Referential example 3]

Thiazolo[5,4-C]pyridine:

4-[(tert-Butoxycarbonyl)amino]-3-mercaptopyridine (33/2 g) was dissolved in formic acid (250 ml) and the solution boiled under reflux for 3 days. The reaction mixture was concentrated under reduced pressure and to the residue was added 5 N. aqueous solution (100 ml) of potassium hydroxide and ether to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and then drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (dichloromethane:methanol=25:1) to obtain specified in the connection header (9,03 g) as a colourless TV is Gogo substances.

1H-NMR (CDCl3) δ: with 8.05 (1H, d, J=5.4 Hz), to 8.70 (1H, D, J=5.4 Hz), 9,23 (1H, s), 9,34 (1H, s).

MS (FAB) m/z 137 (M+H)+.

[Reference example 4]

5-Methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

Thiazolo[5,4-C]pyridine (1,61 g) was dissolved in N,N-dimethylformamide (50 ml), the solution was added methyliodide (1.50 ml) and the resulting mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol (100 ml)was added sodium borohydride (1,53 g) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and to the residue was added an aqueous solution of potassium carbonate and ether to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (dichloromethane:methanol=25:1) to obtain the specified title compound (1.28 g) as a pale yellow oil.

1H-NMR (CDCl3) δ: 2,52 (3H, s), and 2.83 (2H, t, J=5,9 Hz), 2,98 (2H, t, J=5,9 Hz), 3,70 (2H, s), 8,63 (1H, s).

MS (FAB) m/z: 155 (M+N)+.

[Reference example 5]

5-Methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium:

5-Methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine (6.3 g) was dissolved in absolute tetrahydrofuran (200 ml), to the solution was added dropwise at -78°With n-utility (1,47 N. hexane solution, 34,0 ml) and the resulting mixture was stirred for 40 minutes. After filing in the reaction mixture of gaseous carbon dioxide at -78°C for 1 hour, the reaction mixture was heated to room temperature and then concentrated under reduced pressure to obtain specified in the connection header (9,42 g) as a pale brown foamy solid.

1H-NMR (DMSO-d6) δ: is 2.37 (3H, s), 2,64-2,77 (4H, m), of 3.54 (2H, s).

MS (FAB) m/z: 199 (M+N)+.

[Reference example 6]

5-Etoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

Pentasulfide phosphorus (500 g) suspended in formamide

(3000 ml) under ice cooling, and the suspension was stirred over night. To the reaction mixture were added water and diethyl ether and the organic layer was separated and dried over anhydrous magnesium sulfate, and then drove the solvent to obtain a yellow oil. Then the oil was dissolved in n-butanol (350 ml), to the solution was added 3-chloro-1-ethoxycarbonylpyrimidine-4-one (150 g)synthesized by a method described in literature (Tetrahedron, 1983, Vol.39, R), and the resulting mixture was stirred at 100°C for 2.5 hours. The reaction mixture was filtered through Celite. The obtained filtrate was washed with saturated aqueous RA is tworoom of sodium bicarbonate and a saturated salt solution and then dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane-ethyl acetate:hexane=1:2) to obtain specified in the connection header (79,0 g) as a brown oil.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7,3 Hz), 2,96 (2H, sh), 3,82 (2H, sh), 4,19 (2H, q, J=7,3 Hz), to 4.73 (2H, sh), 8,68 (1H, s).

[Referential example 7]

5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

To 5-etoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine (33,5 g) was added 3,5 N. aqueous solution (250 ml) of sodium hydroxide and the mixture is boiled under reflux during the night. After cooling the reaction mixture to room temperature was added di-tert-BUTYLCARBAMATE (103 g) under ice cooling and the mixture was stirred at room temperature overnight. Adding to the reaction mixture of 3 N. hydrochloric acid to bring the pH to 1-2, was added dichloromethane. After separation of organic layer, the organic layer was washed sequentially with an aqueous solution of sodium bicarbonate and a saturated salt solution and then dried over anhydrous sodium sulfate. Then the organic layer was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the specified header is compound (21.1 g) as pale brown oil.

1H-NMR (CDCl3) δ: 1,49 (N, C)to 2.94 (2H, sh), 3,76 (2H, sh), and 4.68 (2H, s), 8,67 (1H, s).

[Referential example 8]

5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylic acid:

To a solution of 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine (845 mg) in absolute tetrahydrofuran (20 ml) was added dropwise at -78°With n-utility (1,65 N. hexane solution of 2.13 ml) and the mixture was stirred for 30 minutes under ice cooling. After passing gaseous carbon dioxide through the reaction mixture at -78°C for 1 hour, the reaction mixture was heated to room temperature. Was added to the reaction mixture 5 N. aqueous sodium hydroxide solution and diethyl ether to separate the water layer. In aqueous solution was added 6 N. hydrochloric acid to bring its pH to 1-2. After adding dichloromethane separated organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent is obtaining specified in the title compound (562 mg) as a pale yellow foamy substance.

1H-NMR (CDCl3) δ: 1,50 (N, C)of 3.00 (2H, sh), of 3.78 (2H, sh), 4,74 (2H, sh).

MS (FAB) m/z: 241 (M+N)+.

[Referential example 9]

2-Amino-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

1-tert-Butoxycarbonyl-4-piperidone (40,0 g) was dissolved in cyclohexane (80 ml) and to the solution was added monohydrate p-toluensulfonate acid (191 mg) and pyrrolidine (17.6 ml). The mixture was boiled under reflux for 2 hours, removing the water by means of traps Dean-stark. Then the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (60 ml) was added powdered sulfur (6.42 per g). Was slowly added dropwise a methanolic solution (10 ml) of cyanamide (8,44 g) under ice cooling and the mixture was stirred at room temperature for 5 hours. Precipitated precipitated solid was filtered to obtain specified in the title compound (31.0 g) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,42 (N, s), 2.40 a is 2.46 (2H, m), of 3.57 (2H, t, J=5.6 Hz), the 4.29 (2H, s), 6,79 (2H, s).

MS (FAB) m/z: 255 (M)+.

[Referential example 10]

2-Bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

The copper bromide(II) (1/05 g) suspended in N,N-dimethylformamide and the suspension was added tert-butylnitrite (0,696 ml). Then added 2-amino-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine (1,00 g) under ice cooling and the reaction mixture was heated and stirred at 40°C for 30 minutes. The reaction mixture was concentrated under reduced is the t and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:5) to obtain the specified title compound (568 mg) as a yellow solid.

1H-NMR (CDCl3) δ: 1,48 (N, C), 2,85 (2H, sh), and 3.72 (2H, t, J=5.6 Hz), 4,56 (2H, sh).

MS (FAB) m/z: 319 (M+N)+.

[Reference example 11]

Triptorelin 2-bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

2-Bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine (890 mg) was dissolved in dichloromethane (2 ml), to the solution was added triperoxonane acid (15 ml) and the mixture was stirred at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure and to the residue was added diethyl ether. Precipitated precipitated solid was filtered to obtain specified in the title compound (867 mg) as colorless solids.

1H-NMR (DMSO-d6) δ: 2,98 (2H, t, J=6,1 Hz) and 3.72 (2H, t, J=6,1 Hz), 4,35 (2H, s), at 9.53 (2H, sh).

MS (FAB) m/z: 219 (M+N)+.

[Reference example 12]

2-Bromo-5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

Triptorelin 2-bromo-4,5,6,7-tetrahydrothieno[5,4-C]pyridine (422 mg) suspended in dichloromethane (10 ml), was added triethylamine (0,356 ml) and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added acetic acid (0,216 ml) and aqueous solution (35% solution, 0,202 ml) of formaldehyde and the resulting mixture was stirred at room temperature for 2 minutes. In the reaction mixture was added triacetoxyborohydride sodium (428 mg) and the resulting mixture was stirred at room temperature for 1 hour. Was added to the reaction mixture 1 N. aqueous solution (10 ml) of sodium hydroxide and separated the organic layer. Then the organic layer was dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (dichloromethane:methanol=100:1) to obtain the specified title compound (286 mg) as pale brown oil.

1H-NMR (CDCl3) δ: 2,49 (3H, s), and 2.79 (2H, t, J=5.8 Hz), 2,88-of 2.93 (2H, m)to 3.58 (2H, s).

MS (FAB) m/z: 233 (M+N)+.

[Reference example 13]

5-Methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium:

2-Bromo-5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine (531 mg) was dissolved in absolute diethyl ether (20 ml)was added dropwise at -78°With n-utility (1,54 N. hexane solution of 1.63 ml) and the mixture was stirred for 30 minutes under ice cooling. After passing the carbon dioxide through the reaction mixture at -78°C for 1 hour the mixture was heated to room temperature. The reaction mixture was concentrated under reduced pressure to obtain specified in the title compound (523 mg) as a pale brown solid.

1H-NMR (DMSO-d 6) δ: is 2.37 (3H, s), 2,64-2,77 (4H, m), of 3.54 (2H, s).

MS (FAB) m/z: 199 (M+N)+.

[Referential example 14]

4-Etoxycarbonyl-2-(TRANS-styryl)oxazol:

Carried out the synthesis in accordance with the message (J. Org. Chem., 1996, Vol.61, R) Headed and others (Panek et al). Was added sodium bicarbonate (22,8 g) and ethylbromide (10.5 ml) to a solution of cinnamamide (10.0 g) in tetrahydrofuran (250 ml) at room temperature and the mixture is boiled under reflux for 48 hours. The reaction mixture was allowed to cool to room temperature, filtered through Celite and then concentrated under reduced pressure to obtain a residue. Added triperoxonane anhydride (30 ml) to a solution of the specified residue in tetrahydrofuran (30 ml) at 0°and the mixture was gradually heated to room temperature. After stirring the mixture for 63 hours, the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (500 ml) and ethyl acetate (150 ml) and the separated organic layer. The aqueous layer was extracted with ethyl acetate (150 ml). The organic layers were combined, washed with saturated salt solution (150 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=5:1→3:1) to obtain specified in the header connect the deposits (up 10.9 g) as a colourless solid.

1H-NMR (CDCl3) δ: of 1.41 (3H, t, J=7.0 Hz), 4,42 (2H, q, J=7.0 Hz), of 6.96 (1H, D, J=16.6 Hz), 7,30-7,40 (3H, m), 7,53 (2H, d, J=6.8 Hz), 7,63 (1H, d, J=16.6 Hz), 8,2-0 (1H, s).

[Referential example 15]

4-Formyl-2-(TRANS-styryl)oxazol:

Diisobutylaluminium (1,0 N. hexane solution, 66 ml) was added dropwise to a solution of 4-etoxycarbonyl-2-(TRANS-styryl)oxazol (to 8.57 g) in dichloromethane (80 ml) at -78°C. After 15 minutes, was added dropwise methanol (11 ml) and the mixture was heated to room temperature within 1 hour. The reaction mixture was filtered through Celite, and the obtained paste-like substance was dissolved in ethyl acetate (200 ml)was added a saturated aqueous solution (200 ml) of ammonium chloride and separated the organic layer. Then the aqueous layer was extracted with dichloromethane (2×100 ml). The obtained organic layers were collected and washed with a saturated aqueous solution (100 ml) of sodium bicarbonate and a saturated salt solution (100 ml)was combined with the filtrate obtained from the filtration through Celite, and then dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (dichloromethane:ethyl acetate=5:1→dichloromethane: methanol=10:1) to obtain specified in the connection header (5,86 g) as colorless needle crystals.

1H-NMR (CDCl3δ : of 6.96 (1H, d, J=16.6 Hz), 7,35-7,45 (3H, m), 7,56 (2H, d, J=6.4 Hz), to 7.67 (1H, d, J=16.6 Hz), compared to 8.26 (1H, s), 9,98 (1H, s).

MS (FAB) m/z: 200 (M+H)+.

[Referential example 16]

2-(TRANS-Styryl)-4-vinyloxy:

n-Utility (1,54 N. hexane solution of 14.2 ml) was added dropwise to a solution of methyltriphenylphosphonium (8,16 g) in tetrahydrofuran (80 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was again cooled to 0°C, was added a solution of 4-formyl-2-(TRANS-styryl)oxazol (of 3.64 g) in tetrahydrofuran (20 ml) and the mixture was heated to room temperature. After stirring for 2 hours was added water (200 ml) and ethyl acetate (100 ml) and separated the organic layer. The aqueous layer was extracted with ethyl acetate (50 ml). Then the organic layers were combined, washed with saturated salt solution (100 ml) and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=4:1→3:1) to obtain specified in the connection header (2,84 g) as a pale yellow oil.

1H-NMR (CDCl3) δ: 5,33 (1H, DD, J=1,5 and 10.7 Hz), 5,98 (1H, DD, J=1,5, and 17.6 Hz), 6,56 (1H, DD, J=10,7, and 17.6 Hz), to 6.95 (1H, d, J=16.6 Hz), 7,31-7,42 (3H, m), 7,49-7,56 (4H, m).

MS (FAB) m/z: 198 (M+N)+.

[Reference example 17]

4-(2-Hydroxyethyl)-2-(TRANS-styryl)on Sasol:

9-Borabicyclo[3.3.1]nonan (0,5 N. tertrahydrofuran ring solution, 158 ml) was added to a solution of 2-(TRANS-styryl)-4-vinylacetal (13,0 g) in tetrahydrofuran (500 ml) at 0°and the mixture was stirred at room temperature for 15 hours. In the reaction mixture at 0°sequentially added dropwise water (10 ml), 3 N. aqueous solution (80 ml) of sodium hydroxide and aqueous hydrogen peroxide (80 ml) and the mixture was stirred at room temperature for 6 hours. After adding to the resulting reaction mixture water (600 ml) and ethyl acetate (200 ml) to separate an organic layer, the aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were collected, washed with saturated salt solution (200 ml) and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=2:1→only ethyl acetate) to obtain the specified title compound (14.1 g) as a colourless solid.

1H-NMR (CDCl3) δ: 2,69 (1H, sh), 2,80 (2H, t, J=5.6 Hz), 3,90-of 3.97 (2H, m)6,91 (1H, d, J=16.6 Hz), 7,30-7,42 (4H, m), 7,43-7,56 (3H, m).

MS (FAB) m/z: 216 (M+H)+.

[Referential example 18]

N-[2-[2-(TRANS-Styryl)oxazol-4-yl]ethyl]phthalimide:

Phthalimide (200 mg), triphenylphosphine (357 mg) and titilated carboxylate (0,214 ml) was added to a solution of 4-(2-hydroxyethyl)-2-(TRANS-styryl)oxazol (292 mg) in tetrahydrofuran (15 ml) at room temperature and the mixture was stirred for 4 hours. From the reaction mixture kept under reduced pressure the solvent. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (447 mg)as colorless solids.

1H-NMR (CDCl3) δ: 2,98 (2H, t, J=7.2 Hz), a 4.03 (2H, t, J=7.2 Hz), to 6.88 (1H, d, J=16.6 Hz), 7,28 was 7.45 (5H, m), of 7.48 (2H, d, J=7,3 Hz), 7,71 (2H, DD, J=2,9, a 5.4 Hz), to 7.84 (2H, DD, J=2,9, 5,4 Hz).

MS (FAB) m/z: 345 (M+N)+.

[Reference example 19]

4-[2-(tert-Butoxycarbonylamino)ethyl]-2-(TRANS-styryl)oxazol:

After adding hydrazine monohydrate (1.50 ml) to a solution of N-[2-[2-(TRANS-styryl)oxazol-4-yl]ethyl]phthalimide (6,40 g) in ethanol (150 ml) at room temperature and stirring the mixture for 1 hour again was added hydrazine monohydrate (0,500 ml) at room temperature and the mixture was stirred for 2 hours. To the reaction mixture at room temperature was added dichloromethane (150 ml), a saturated solution (150 ml) of sodium bicarbonate and di-tert-BUTYLCARBAMATE (13,4 g). After stirring for 30 minutes the aqueous layer was separated and was extracted with dichloromethane (50 ml). The obtained organic layers were combined and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=2:1→:1) to obtain specified in the connection header (of 5.06 g) as a colourless solid.

1H-NMR (CDCl3) δ: 1,45 (N, C)of 2.75 (2H, t, J=6.6 Hz), of 3.46 (2H, dt, J=5,9, and 6.6 Hz), to 4.92 (1H, sh), 6,91 (1H, d, J=16.6 Hz), 7.29 trend was 7.45 (4H, m), of 7.48 (1H, d, J=16.6 Hz), 7,52 (2H, d, J=7,3 Hz).

MS (FAB) m/z: 315 (M+N)+, 259 (M-isobutene+N)+, 315 (M-BOC+H)+.

[Referential example 20]

5-(tert-Butoxycarbonyl)-2-(TRANS-styryl)-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine:

Paraformaldehyde (54,5 mg) and p-toluensulfonate acid (7.2 mg) was added to a solution of 4-[2-(tert-butoxycarbonylamino)ethyl]-2-(TRANS-styryl)oxazol (190 mg) in toluene (15 ml) at room temperature. After boiling under reflux for 1 hour, the reaction mixture was allowed to cool and added to it in ethyl acetate (15 ml) and saturated aqueous solution (15 ml) of sodium bicarbonate to separate the organic layer. After the aqueous layer was extracted with ethyl acetate (10 ml), the organic layers were combined and dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:1→2:1) to obtain the specified title compound (153 mg) as a colourless oil.

1H-NMR (CDCl3) δ: 1,50 (N, C)to 2.67 (2H, sh), to 3.73 (2H, sh), 4,55 (2H, s), make 6.90 (1H, d, J=16.1 Hz), 7,29-7,42 (3H, m), 7,46 (1H, d, J=16.1 Hz), 7,52 (2H, d, J=7,3 Hz)

MS (FAB) m/z: 327 (M+N)+, 271 (M-isobutene+N)+, 227 M-BOC+H) +.

[Referential example 21]

5-(tert-Butoxycarbonyl)-2-formyl-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine:

Acetone (8.0 ml), water (4.0 ml), N-methylmorpholine (577 mg) and osmium tetroxide (0,039 M 3,20 ml) was added to a solution of 5-(tert-butoxycarbonyl)-2-(TRANS-styryl)-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine (803 mg) in tetrahydrofuran (16 ml) at room temperature and the mixture was stirred over night. Was added to the reaction mixture in ethyl acetate (50 ml) and 10% aqueous solution (50 ml) of sodium thiosulfate solution to separate the organic layer. Then the aqueous layer was extracted with ethyl acetate (30 ml). The obtained organic layers were combined and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. To a solution of the residue in tetrahydrofuran (16 ml) was added methanol (8.0 ml), water (8.0 ml) and metaperiodate sodium (790 mg). After stirring for 3 hours the reaction mixture was added ethyl acetate (30 ml) and water (50 ml)to separate an organic layer. The aqueous layer was extracted with ethyl acetate (20 ml). The obtained organic layers were combined, washed with saturated solution (50 ml) of sodium bicarbonate and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=4;1#x02192; 2:1) to obtain the specified title compound (234 mg) as a colorless amorphous substance. Because the obtained aldehyde was unstable, he was immediately used in the next reaction.

1H-NMR (CDCl3) δ: 1,49 (N, C)2,77 (2H, sh), of 3.77 (2H, sh), to 4.62 (2H, s)to 9.70 (1H, s).

[Referential example 22]

5-(tert-Butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine:

Cyanide sodium (220 mg) and manganese dioxide (780 mg) was added to a solution of 5-(tert-butoxycarbonyl)-2-formyl-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine (225 mg) in methanol (9.0 ml) at room temperature. After stirring for 30 minutes the reaction mixture was filtered through Celite with ethyl acetate. The filtrate was washed with water (50 ml) and saturated salt solution (50 ml) and dried over anhydrous sodium sulfate. Then drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:2→1:1) to obtain the specified title compound (120 mg) as a colorless amorphous substance.

1H-NMR (CDCl3) δ: 1,49 (N, (C), by 2.73 (2H, sh), 3,74 (2H, sh), to 4.01 (3H, s), 4,59 (2H, s).

MS (FAB) m/z: 283 (M+N)+.

[Reference example 23]

2-Methoxycarbonyl-5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine:

Triperoxonane acid 15 ml) was added to a solution of 5-(tert-butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine (500 mg) in dichloromethane (15 ml) at room temperature and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure and to the residue at room temperature was added dichloromethane (20 ml), triethylamine (0,495 ml), acetic acid (205 ml), formalin (0,230 ml) and triacetoxyborohydride sodium (570 mg). After stirring for 15 minutes was added dichloromethane (20 ml) and saturated aqueous solution (50 ml) of sodium bicarbonate, to separate the organic layer. The aqueous layer was extracted with dichloromethane (3×20 ml). The obtained organic layers were combined and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (chloroform:methanol=20:1→10:1) to obtain the specified title compound (257 mg) as a colourless oil.

1H-NMR (CDCl3) δ: 2,52 (3H, s), 2,72-2,78 (2H, m), 2,78-and 2.83 (2H, m), 3,61 (2H, t, J=1.7 Hz), of 4.00 (3H, s).

MS (FAB) m/z: 197 (M+N)+, 165 (M-och3).

[Reference example 24]

5-Methyl-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine-2-carboxylate lithium:

Water (6.0 ml) and lithium hydroxide (99,7 mg) was added to a solution of 2-methoxycarbonyl-5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine (800 mg) in tetrahydrofuran (24 ml) at room temperature and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain decree of the frame in the title compound (825 mg).

1H-NMR (DMSO-d6) δ: is 2.37 (3H, s), 2,47 (2H, t, J=5.6 Hz), of 2.54 (2H, t, J=5.6 Hz), 3.43 points (2N, C).

[Reference example 25]

5-Chlorobenzo[b]thiophene-2-carboxylic acid:

After dissolving 5-chlorobenzo[b]thiophene (2,53 g) in absolute ether (40 ml) and purge the vessel with argon, the solution was cooled to -78°C. was Added to the solution dropwise tert-utility (1,54 N. hexane solution, 9,74 ml) and the mixture was stirred at the same temperature in General within 1 hour. The reaction mixture was heated to 0°C and stirred for 1.5 hours. Again cooled the reaction mixture to -78°C and stirred for 1.5 hours, feeding at the same time, the internal volume of the vessel carbon dioxide. Bringing to room temperature, was added to the reaction mixture of 0.3 N. hydrochloric acid (100 ml) and ethyl acetate to separate an organic layer. Drove away under reduced pressure, the solvent and to the residue was added ether. Precipitation was filtered, to deliver specified in the title compound (2.67 g) as a colourless solid.

1H-NMR (DMSO-d6) δ: 7,53 (1H, DD, J=85 and 2.2 Hz), 8.07-a 8,11 (3H, m), 13,65 (1H, sh).

MS (FAB) m/z 213 (M+H)+.

[Referential example 26]

Methyl 5-chloro-6-Florinda-2-carboxylate:

A mixture of methyl 3-chloro-4-fluoro-α-azidocillin (published application No. 149723/1995 patent Japan) (185 g) and xylene (140 ml) was boiled under reflux for 1 hour, then drove the solvent. The residue was purified column chromatography on silica gel (dichloromethane) to obtain the specified title compound (491 mg) as colorless powder.

1H-NMR (CDCl3) δ: of 3.95 (3H, s), 7,13-to 7.15 (1H, m), 7,20 (1H, DD, J=9,3, 0,49 Hz), 7,71 (1H, d, J=7,3 Hz), 8,93 (1H, sh).

MS (FAB) m/z 227 (M)+.

[Referential example 27]

5-Chloro-6-Florinda-2-carboxylic acid:

Methyl 5-chloro-6-Florinda-2-carboxylate (461 mg) was dissolved in a mixed solvent consisting of tetrahydrofuran (15 ml), methanol (10 ml) and water (10 ml)was added at room temperature, lithium hydroxide (283 mg) and the mixture was stirred for 4 hours. Drove away under reduced pressure, the solvent and to the residue was added 1 n chlorotoluron acid to weak its acidification. The resulting powder was filtered and dried to obtain specified in the title compound (422 mg) as colorless powder.

1H-NMR (CDCl3) δ: 7,08-7,10 (1H, m), 7,34 (1H, d, J=9.5 Hz), 7,88 (1H, d, J=7,6 Hz), 12,04 (1H, s), 13,16 (1H, s).

MS (FAB) m/z: 217 (M)+.

[Reference example 28]

5-(4-Pyridyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

Triperoxonane acid (25 ml) was added to a solution of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine (5,00 g) in dichloromethane (25 ml) at room temperature After stirring the mixture for 10 minutes, the reaction mixture was concentrated under reduced pressure and to the residue at room temperature was added 4-bromopyridine (5.20 g), N,N-dimethylformamide (30 ml) and triethylamine (15,5 ml) and the mixture was stirred at 150°C for 2 days, then allowed it to cool to room temperature. Colorless precipitates were separated by filtration and the filtrate was concentrated under reduced pressure. Then to the residue was added dichloromethane (50 ml) and saturated aqueous solution (100 ml) of sodium bicarbonate and the resulting aqueous layer was saturated with sodium chloride. After separation of the organic layer of the resulting aqueous layer was extracted with dichloromethane (5×30 ml). The obtained organic layers were combined and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (dichloromethane:methanol=20:1→8:1) to obtain specified in the connection header (2,97 g) as a brown solid.

1H-NMR (CDCl3) δ: of 3.07 (2H, t, J=5,9 Hz), 3,81 (2H, t, J=5,9 Hz), br4.61 (2H, s), 6,74 (2H, t, J=6.5 Hz), 8,30 (2H, t, J=6.5 Hz), to 8.70 (1H, s).

MS (FAB) m/z: 218 (M+H)+.

[Referential example 29]

Methyl 5-(4-pyridyl)thiazole-2-carboxylate:

The monohydrate of 1-hydroxybenzotriazole (805 mg) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1,71 g) was added to a solution of 5-(4-pyridyl)thiazole-2-carboxylate lithium (632 mg) in methanol (5.0 ml) at room temperature. After stirring in ECENA 4 days the reaction mixture was concentrated under reduced pressure and to the residue was added dichloromethane (20 ml), a saturated aqueous solution (100 ml) of sodium bicarbonate and water (100 ml)to separate an organic layer. Then the aqueous layer was extracted with dichloromethane (2×20 ml). The obtained organic layers were combined and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. Then the residue was purified column chromatography on silica gel (dichloromethane:acetone=5:1→2:1) to obtain the specified title compound (353 mg) as colorless solids.

1H-NMR (CDCl3) δ: of 4.05 (3H, s), 7,51 (2H, d, J=6,1 Hz), 8,32 (1H, s)8,71 (2H, d, J=6,1 Hz).

MS (ESI) m/z: 221 (M+H)+.

[Reference example 30]

(±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopropylamine:

The monohydrate of 1-hydroxybenzotriazole (377 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (642 mg) and diisopropylethylamine (1,95 ml) was added to the hydrochloride CIS-1,2-cyclopropylamine (J. Med. Chem., 1998, Vol.41, pp.4723-4732) (405 mg) and a solution of 5-Clorinda-2-carboxylic acid (546 mg) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred at 50 hours. The reaction mixture was concentrated under reduced pressure, after which was added dichloromethane (50 ml) and saturated aqueous solution (200 ml) of sodium bicarbonate in order to separate the precipitated precipitated colorless solid by filtration. the content of inorganic fillers layer of the filtrate was separated and the aqueous layer was extracted with dichloromethane. The obtained organic layers were combined and dried over anhydrous sodium sulfate, and then drove away under reduced pressure, the solvent to obtain a residue. The residue was purified column flash chromatography (medium pressure silica gel (dichloromethane:methanol=100:7→10:1) to obtain the specified title compound (110 mg) as a colorless solid.

1H-NMR (DMSO-d6) δ: 0,44 (1H, DD, J=10,7, 4,4 Hz), 1,11 (1H, DD, J=14,0, 7.4 Hz), 2.63 in-2,70 (1H, m), 3,07-and 3.16 (1H, m), 6,77 (1H, s), 6,97 (1H, sh), of 7.23 (1H, DD, J=8,9, 1.8 Hz), was 7.36 (1H, D, J=8,9 Hz), 7,60 (1H, s), to 9.32 (1H, s).

MS (FAB) m/z: 250 (M+H)+.

[Reference example 31]

2-Chloro-6,7-dihydro-4H-pyrano[4,3-d]thiazole:

1) Tetrahydro-4H-Piran-4-one (5.0 g) was dissolved in cyclohexane (20 ml) and to the solution was added pyrrolidine (4,35 ml) and the monohydrate p-toluensulfonate acid (48 mg), after which the mixture was boiled under reflux for 70 minutes, thereby removing the water by means of traps Dean-stark. The reaction mixture was cooled to room temperature, decantation of the solvent and the obtained solvent was concentrated under reduced pressure. The residue was dissolved in methanol (15 ml) and to the solution was added with ice cooling powdered sulfur (1.60 g). After 15 minutes, was added dropwise within 20 minutes, a methanol solution (10 ml) of cyanamide (2.10 g) and the mixture is displaced is ivali 3 days. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=20:1→10:1→4:1) to give 2-amino-6,7-dihydro-4H-pyrano [4,3-d]thiazole (of 3.97 g) as a brown amorphous substance.

1H-NMR (CDCl3) δ: 2,66-2,70 (2H, m), of 3.97 (2H, t, J=5.6 Hz), 4,63 (2H, s), 4,94 (2H, sh).

MS (FAB) m/z 157 (M+N)+.

2) Chloride copper(II) (4,10 g) was dissolved in acetonitrile (50 ml) and to the solution was added tert-butylnitrite (3,93 g) in one portion under ice cooling. After 10 minutes, to the mixture was added over about 1 hour connection (of 3.97 g)obtained in the above reaction, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was heated to 65°C and continuously stirred for 2 hours. After addition, the reaction mixture on silica gel (20 g) drove under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (1.78 g) as a yellow oil.

1H-NMR (CDCl3) δ: 2,85-2,89 (2H, m), was 4.02 (2H, t, J=5.6 Hz), to 4.73 (2H, s).

MS (FAB) m/z: 175 (M+H)+.

[Referential example 32]

6,7-dihydro-4H-pyrano[4,3-d]thiazole-2-carboxylate lithium:

1) 2-Chloro-6,7-dihydro-4H-pyrano[4,3-d]thiazole (1.78 g)was dissolved in methanol (30 ml) and the solution is obavljale 10% palladium on carbon (300 mg) and sodium acetate (830 mg). The mixture was stirred for 5 days in a stream of hydrogen at 5 bar. After separation of the catalyst by filtration, the filtrate was concentrated and the residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 6,7-dihydro-4H-pyrano[4,3-d]thiazole (1,14 g) as a colourless oil.

1H-NMR (CDCl3) δ: 2,97-a 3.01 (2H, m), Android 4.04 (2H, t, J=5.6 Hz), to 4.87 (2H, s), 8,69 (1H, S).

MS (FAB) m/z 142 (M+N)+.

2) After dissolution of the product (1,14 g), obtained as described above, in diethyl ether (30 ml) and cool to -78° (C) was added to a solution of 1.6 M utility (6.6 ml) and the mixture was stirred. After 20 minutes was barbotirovany carbon dioxide for 15 minutes. The reaction mixture was heated to room temperature and concentrated under reduced pressure to obtain specified in the title compound (1.65 g) as a colorless amorphous substance.

1H-NMR (DMSO-d6) δ: and 2.83 (2H, t, J=5.6 Hz), to 3.92 (2H, t, J=5.6 Hz), to 4.73 (2H, s).

[Referential example 33]

(±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclobutadiene:

Specified in the title compound was obtained from hydrochloride of the CIS-1,2-cyclobutylamine (J. Am. Chem. Soc., 1942, Vol.64, pp.2696-2700) in a manner similar to the method of reference example 30.

1H-NMR (DMSO-d6) δ: 1,55-of 2.20 (4H, m), 3,52-3,62 (1H, m), 4,35-4,50 (1H, m), 7,16 (1H, DD, J=8,7, 2,1 Hz), 7,19 (1H, s), 7,42 (1H, d, J=8.7 Hz), of 7.70 (1H, D, J=2.1 Hz), at 8.36 (1H, d, J=7.8 Hz), 11,77 (1H, sh).

MS (ESI) m/z: 264 (M+H)+.

[Referential example 34]

(±)-CIS-N-tert-Butoxycarbonyl-1,2-cyclopentanedione;

CIS-1,2-Cyclopentanedione (W098/30574) (692 mg) was dissolved in dichloromethane (10 ml), was added triethylamine (1.1 ml) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) and the mixture was stirred at 0°C for 1 hour. After that I added 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) and the mixture was stirred at room temperature for 7 hours. To the reaction mixture were added water to separate the organic layer. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The residue was purified column flash chromatography on silica gel (dichloromethane:methanol=9:1) to obtain the specified title compound (395 mg) as a pale yellow oil.

1H-NMR (CDCl3) δ: 1,46 (N, C), 1,55-2,00 (6N, m), 3.45 points-to 3.52 (1H, m), 3,83-are 3.90 (1H, m), 5,27 (1H, sh).

MS (ESI) m/z: 201 (M+H)+.

[Referential example 35]

Hydrochloride of TRANS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene:

TRANS-N-tert-Butoxycarbonyl-1,2-cyclopentanedione (1.40 g) was dissolved in N,N-dimethylformamide (15 ml) and to the solution was added 5-Clorinda-2-carboxylic acid (1.64 g), the hydrochloride of 1-(3-dimethylaminopropyl who yl)-3-ethylcarbodiimide (2,68 g) and the monohydrate of 1-hydroxybenzotriazole (473 mg). The mixture was stirred at room temperature for 23 hours. The solvent is kept under reduced pressure and to the residue was added dichloromethane and a saturated solution of sodium bicarbonate, to filter sediments. Precipitation was washed with ethyl acetate, dichloromethane and methanol. On the other hand, the filtrate was separated to obtain an organic layer was separated and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column flash chromatography (medium pressure silica gel (dichloromethane:methanol=19:1) to obtain a pale yellow solid. Specified pale yellow solid was combined with precipitation, obtained by filtration, and dissolved in dichloromethane (10 ml), then added triperoxonane acid (10 ml) and the mixture was stirred at room temperature for 3 hours. Drove away under reduced pressure, the solvent and to the residue was added dichloromethane and 1 N. aqueous sodium hydroxide solution, to filter sediment. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate. To the resulting solution was added precipitation, obtained by filtration, and was additionally added 4 N. dioxane solution (20 ml) of hydrochloric acid. Drove away under reduced pressure, the solvent and the residue doba is Lyali dichloromethane (10 ml), and 4 N. dioxane solution (10 ml) of hydrochloric acid. Again drove under reduced pressure the solvent. To the residue was added ethyl acetate, to filter sediments, resulting in the received specified in the header connection (1,83 g) as a gray solid.

1H-NMR (DMSO-d6) δ: 1,60-1,75 (4H, m), 2.05 is is 2.10 (2H, m), 3,49 (1H, q, J=7,6 Hz), 4,27 (4H, quintet, J=7,6 Hz), 7,17 (1H, d, J=8.6 Hz), 7,19 (1H, s), 7,42 (1H, d, J=8.6 Hz), of 7.70 (1H, s), 8,24 (3H, sh), cent to 8.85 (1H, d, J=7,3 Hz), 11,91 (1H, s).

MS (ESI) m/z: 278 (M+H)+.

[Referential example 36]

(±)-TRANS-N-tert-Butoxycarbonyl-1,2-cyclopentanedione:

Specified in the title compound was obtained from TRANS-1,2-cyclopentadiene (WO 98/30574) in a manner similar to the method of reference example 34.

1H-NMR (CDCl3) δ: 1,25-1,40 (2H, m), 1,49 (N, C), 1,59-to 1.77 (2H, m), 1,92-of 2.08 (1H, m), 2,10-2,17 (1H, m), 2,98 (1H, q, J=7.2 Hz), 3,48-of 3.53 (1H, m), 4,49 (1H, sh).

MS (ESI) m/z: 201 (M+H)+.

[Referential example 37]

Hydrochloride (±)-TRANS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene:

(±)-TRANS-N-tert-Butoxycarbonyl-1,2-cyclopentanedione (175 mg) was dissolved in N,N-dimethylformamide (3 ml) and to the solution was added 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (purity 90%, 258 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbonate the IDA (252 mg) and the monohydrate of 1-hydroxybenzotriazole (60 mg). The mixture was stirred at room temperature for 2 days. The solvent is kept at reduced pressure using a pump, and to the residue was added dichloromethane and saturated sodium hydrogen carbonate solution to separate the organic layer. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column flash chromatography (medium pressure silica gel (dichloromethane:methanol=47:3). The obtained pale-yellow oil was dissolved in a saturated ethanol solution (5 ml) of hydrochloric acid and the solution was stirred at room temperature for 1 hour. Then added ethyl acetate and drove away under reduced pressure the solvent. To the residue was added ethyl acetate to precipitate by filtration and the result has been specified in the title compound (120 mg) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,63-of 1.73 (4H, m), 1,99 e 2.06 (2H, m), 2.91 in (3H, s), 3,09-3,14 (1H, m), 3.25 to 3,70 (4H, m), 4,27-4,32 (1H, m), 4,42-to 4.46 (1H, m), 4,68-4,71 (1H, m), 8,20-8,23 (3H, m), which is 9.09 (1H, d, J=8,3 Hz), 11,82-12,01 (1H, m).

MS (ESI) m/z: 281 (M+H)+.

[Reference example 38]

(±)-CIS-N-(5-Chloro-1-phenylsulfonyl-2-sulfonyl)-1,2-cyclopentadien:

CIS-1,2-Cyclopentanedione (WO 98/30574) (38 mg) was dissolved in dichloromethane (10 ml) and to the solution was added triethylamine (1 ml) and 5-chloro-1-phenylsulfonyl-2-sulphonylchloride (390 mg) under stirring at 0° C. After 15 minutes and after 1 hour was added 5-chloro-1-phenylsulfonyl-2-sulphonylchloride (156 mg). After stirring for 15 minutes added 5-chloro-1-phenylsulfonyl-2-sulphonylchloride (78 mg) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added water to separate the organic layer. The obtained organic layer was washed with a saturated solution of sodium bicarbonate and dried over anhydrous sodium sulfate. The residue was purified column flash chromatography on silica gel (chloroform:methanol=23:2) to obtain specified in the connection header (739 mg) as a pale yellow solid.

1H-NMR (CDCl3) δ: 1,38 is 1.91 (8H, m), 3.27 to and 3.31 (1H, m), 3,41 is-3.45 (1H, m), 7,42-to 7.50 (4H, m), 7,58-to 7.61 (2H, m), 8,11-8, 15 (3H, m).

MS (ESI) m/z: 454 (M+H)+.

[Referential example 39]

(±)-TRANS-N-tert-Butoxycarbonyl-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-TRANS-1,2-cyclohexanediamine a manner similar to the method of reference example 34.

TPL 79-81°

1H-NMR (CDCl3) δ: of 1.05 to 1.34 (4H, m), 1,45 (N, C), 1,68 is 1.75 (2H, m), 1,92-2,02 (2H, m), 2,32 (1H, dt, J=10, 3, 3,GC), is 3.08-3,20 (1H, m), 4,50 (1H, sh).

MS (FAB) m/z: 215 (M+H)+.

[Referential example 40]

Triptorelin (±)-TRANS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carb the Nile]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-TRANS-N-tert-butoxycarbonyl-1,2-cyclohexanediamine a manner similar to the method of reference example 37.

1H-NMR (DMSO-d6) δ: 1,10-of 1.80 (7H, m), 1,95-2,05 (1H, m), of 2.97 (3H, s)3,00-3,20 (3H, m), 3,63 (2H, sh), and 3.72-3,88 (1H, m), br4.61 (2H, sh), 7,98 (3H, s)8,89 (1H, d, J=9,2 Hz).

MS (FAB) m/z: 295 (M+N)+.

[Referential example 41]

(±)-CIS-N-tert-Butoxycarbonyl-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-CIS-1,2-cyclohexanediamine a manner similar to the method of reference example 34.

1H-NMR (CDCl3) δ: 1,30-1,70 (17H, m), 2,98 was 3.05 (1H, m), 3,60 (1H, sh), to 4.98 (1H, sh).

MS (FAB) m/z: 215 (M+H)+.

[Referential example 42]

Triptorelin (±)-TRANS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(±)-TRANS-N-tert-Butoxycarbonyl-1,2-cyclohexanediamine (642 mg) was dissolved in N,N-dimethylformamide (20 ml) and to the solution was added 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (795 mg), monohydrate, 1-hydroxybenzotriazole (46 mg), and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.30 g) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and to which the STATCOM was added dichloromethane and water, then the organic layer was separated and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=100:3) to give a pale yellow foamy substance. The resulting material was dissolved in dichloromethane (5 ml), was added triperoxonane acid (30 ml) and the mixture was stirred at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure to obtain specified in the connection header (731 mg) as a pale brown foamy substance.

1H-NMR (DMSO-d6) δ: 1,10-of 1.80 (7H, m), 1,95-2,05 (1H, m), of 2.97 (3H, s)3,00-3,20 (3H, m), 3,63 (2H, sh), and 3.72-3,88 (1H, m), br4.61 (2H, sh), 7,98 (3H, s)8,89 (1H, d, J=9,2 Hz).

MS (FAB) m/z: 295 (M+N)+.

[Referential example 43]

The allocation of optically active substances (±)-CIS-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(±)-CIS-N-[(5-Methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine˜2-yl)carbonyl]-1,2-cyclohexanediamine (900 mg) was dissolved in isopropyl alcohol (6 ml) and the solution was purified portions 11 by HPLC. For carrying out elution with a volumetric flow of 6 ml/min using as solvent a mixture of hexane:isopropyl alcohol:diethylamine=68;32:0,5 used column CHIRALPAK AD (Daicel Chemical Industries, Ltd.; 2.0 (diameter) × 25 cm). Faction, erwerbende through 24.8 minutes and 33.4 minutes, collected separately and concentrated under reduced pressure to obtain isomer A (320 mg) and isomer B (390 mg) as a brown amorphous substance.

Isomer A:

1H-NMR (CDCl3) δ: 1,30-1,90 (8H, m), of 2.51 (3H, s), 2,82 (2H, t, J=5,9 Hz), 2,90-of 3.00 (2H, m), 3,10-3,15 (1H, m), 3,71 (2H, s), 4,00-4,20 (1H, m), 7,55 to 7.75 (1H, m).

MS (FD+) m/z 295 (M+N)+.

The isomer In:

1H-NMR (CDCl3) δ: 1,30-1,90 (8H, m), of 2.51 (3H, s), 2,82 (2H, t, J=5,9 Hz), 2,90-of 3.00 (2H, m), 3,10-3,15 (1H, m), 3,71 (2H, s), 4,00-4,20 (1H, m), 7,55 to 7.75 (1H, m).

MS (FD+) m/z: 295 (M+H)+.

In the reference example 49, which will be described below, the isomer In identified as (1R,2S)-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and isomer And (1S,2R)-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine.

[Reference example 44]

(1S, 2S)-2-tert-Butoxycarbonylamino-1-cyclohexanol:

(1S,2S)-2-Amino-1-cyclohexanol (J. Med. Chem., 1998, Vol.41, R) (0,83 g) was dissolved in dichloromethane (10 ml), to the solution was added di-tert-BUTYLCARBAMATE (1.64 g) and the mixture was stirred at room temperature for 2 hours. Drove away under reduced pressure, the solvent and the resulting solids recrystallized from a mixture of hexane:ethyl acetate=20:1 with obtaining the specified reception in the e connection (1,33 g) as colorless needle crystals.

TPL: 103-105°C.

[α]D-5,48° (19,8°s=1,01, CHCl3).

1H-NMR (CDCl3) δ: of 1.05 to 1.50 (4H, m), 1,45 (N, C)of 1.65 and 1.75 (2H, m), 1,90-2,10 (2H, m), 3,10-3,30 (3H, m), 4,51 (1H, sh).

[Referential example 45]

(1S,2S)-1-tert-Butoxycarbonylamino-2-methanesulfonylaminoethyl:

(1S,2S)-2-tert-Butoxycarbonylamino-1-cyclohexanol (646 mg) was dissolved in pyridine (4 ml), was added under cooling with ice methanesulfonanilide (378 mg) and the mixture was stirred for 5 hours. After addition the reaction mixture of diethyl ether and 5-fold washing with water the organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent is obtaining specified in the title compound (630 mg) as colorless crystals.

TPL 123-124°C.

[α]D+7,16° (19,8°s=1,01, CHCl3).

1H-NMR (CDCl3) δ: 1,20-1,40 (3H, m), 1,44 (N, C), 1,55-1,70 (2H, m), 1,70-1,80 (1H, m), 2,03-of 2.23 (2H, m), 3,03 (3H, s)to 3.58 (1H, sh), of 4.44 (1H, TD, J=9,8, 4,2 Hz), of 4.67 (1H, sh).

[Referential example 46]

(1R,2S)-1-Azido-2-(tert-butoxycarbonylamino)cyclohexane:

(1S,2S)-1-(tert-Butoxycarbonylamino)-2-methanesulfonylaminoethyl (475 mg) was dissolved in N,N-dimethylformamide (6 ml), was added sodium azide (156 mg) and the mixture was stirred 2 hours at 60°and then 24 hours at 80°C. After doba is ing in the reaction mixture of diethyl ether obtained organic layer, washed with water, dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane) to obtain the specified title compound (184 g) as a colourless solid.

TPL 69-70°C. [α]D- 105,14° (19,8°C=1,01, CHCl3).

MS (FAB) m/z: 241 (M+N)+.

1H-NMR (CDCl3) δ: 1,20-1,80 (7H, m), 1,45 (N, C), 1,90-2,00 (1H, m), 3,61 (1H, sh), of 3.95 (1H, sh), 4,70 (1H, sh).

[Referential example 47]

(1S,2R)-N1-tert-Butoxycarbonyl-1,2-cyclohexanediamine:

(1R,2S)-1-Azido-2-(tert-butoxycarbonylamino)cyclohexane (174 mg) was dissolved in methanol (10 ml) and to the solution was added 10% palladium on carbon (120 mg) for carrying out catalytic reduction at atmospheric pressure. The catalyst was separated by filtration and the filtrate was concentrated to obtain the crude specified in the title compound (145 mg) as a colorless amorphous substance. The compound obtained was used in the next reaction without purification.

[Referential example 48]

(1S,2R)-N1-tert-Butoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

The crude (1S, 2R)-N1-tert-butoxycarbonyl-1,2-cyclohexanediamine (145 mg) solution of the Li in N,N-dimethylformamide (3 ml), was added 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (180 mg), monohydrate, 1-hydroxybenzotriazole (13 mg) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (770 mg) and the mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added dichloromethane and water to separate the liquids, then the obtained organic layer was dried over anhydrous potassium carbonate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=40:1) to obtain a pale yellow foamy substance (126 mg).

[α]D-19,964° (19,7°C=0,51, CHCl3).

1H-NMR (CDCl3) δ: 1,20-1,90 (7H, m), and 1.56 (N, C)of 2.50 (3H, s), of 2,75 2,85 (2H, m), 2,85-2,95 (2H, m), 3,71 (2H, s), 3,88-4,00 (1H, m), 4,22 (1H, sh), 4,91 (1H, sh), of 7.48 (1H, sh).

[Referential example 49]

(1R,2S)-N1-[(5-Methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1S,2R)-N1-tert-Butoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (120 mg) was dissolved in methanol (1 ml), was added 1 N. ethanolic hydrochloric acid solution (3 ml) and the mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under PON the leaders introduce pressure and to the residue was added diethyl ether, resulting in the formed powder. The powder was filtered, obtaining hydrochloride (106 mg) specified in the title compounds as pale yellow powder.

1H-NMR (DMSO-d6) δ: 1,30-1,90 (8H, m), of 2.92 (3H, s), 3,05-3,79 (5H, m), 4,24 (1H, sh), 4,34-rate 4.79 (2H, m), a 7.85-to 8.20 (3H, m), 8.30 to-8,49 (1H, m), 11,50-12,10 (1H, m).

MS (FAB) m/z: 295 (M+N)+.

Part of hydrochloride specified in the title compounds were added dichloromethane and a saturated aqueous solution of sodium bicarbonate for the separation of liquids. The obtained organic layer was dried over anhydrous sodium sulfate and then drove away under reduced pressure the solvent. The residue was analyzed by HPLC (solvent: hexane:isopropyl alcohol:diethylamine=80:20:0.5; the volumetric flow rate: 2 ml/min) using a column CHIRALPAK AD (Daicel Chemical Industries, Ltd.; 0,46 (diameter) ×25 cm. As a result, over 9.5 minutes was suirable specified in the header connection. Isomer a and isomer B, shown in reference example 43, was suirable for 7.2 minutes and 9.5 minutes, respectively, under the same conditions. Therefore, the isomer In identified as (1R,2S)-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine.

1H-NMR (CDCl3) δ: 1,30-1,90 (8H, m), of 2.51 (3H, s), 2,82 (2H, t, J=5.6 Hz), with 2.93 (2H, t, J=5.6 Hz), 3,10-3,15 (1H, m), 3,70 (2H, s), 4,00-4,20 (1H, m), 7,63 (1H, d, J=8,1 Hz).

[Referential example 50]

Hydrochloride (±)-TRANS--(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-TRANS-N-tert-butoxycarbonyl-1,2-cyclohexanediamine a manner similar to the method of reference example 37.

1H-NMR (DMSO-d6) δ: 1,10-2,17 (8H, m), of 2.92 (3H, s), 3.00 and-3,93 (6N, m), of 4.38-4,60 (1H, m), with 4.64-of 4.77 (1H, m), 8,00-8,19 (3H, m), 8,82-8,96 (1H, m), 11,95-11,30 (1H, m).

MS (FAB) m/z: 295 (M+H)+.

[Referential example 51]

Hydrochloride (±)-CIS-N-(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-CIS-N-tert-butoxycarbonyl-1,2-cyclohexanediamine a manner similar to the method of reference example 37.

1H-NMR (DMSO-d6) δ: 1,30-1,90 (8H, m), of 2.92 (3H, s), 3,05-3,79 (5H, m)to 4.23 (1H, sh), 4,34-rate 4.79 (2H, m), 8,01-to 8.34 (3H, m), 8.30 to-8,49 (1H, m), 11,90-12,30 (1H, m).

MS (FAB) m/z: 295 (M+N)+.

[Referential example 52]

(±)-TRANS-N1-(tert-Butoxycarbonyl)-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

5-Clorinda-2-carboxylic acid (2,88 g), monohydrate, 1-hydroxybenzotriazole (2,08 g) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2,95 g) was added to a solution of (±)-TRANS-N-tert-butoxycarbonyl-1,2-cyclohexanediamine (3.00 g) in N,N-dimethylformamide (10 ml) at room temperature. After stirring for 3 days react the mixture was concentrated under reduced pressure and to the residue was added dichloromethane (30 ml), a saturated aqueous solution (150 ml) of sodium bicarbonate and water (150 ml). Filtering the resulting colorless precipitate and drying it got mentioned in the title compound (total of 5.21 g) as a colourless solid.

1H-NMR (DMSO-d6) δ: 1,10-of 1.45 (4H, m), 1,21 (N, C)1,68 (2H, d, J=8.1 Hz), to 1.86 (2H, t, J=16.2 Hz), 3,22-of 3.42 (1H, m), of 3.69 (1H, sh), of 6.66 (1H, d, J=8.5 Hz), 7,02 (1H, s), to 7.15 (1H, DD, J=8,5, 2.0 Hz), 7,41 (1H, d, J=8.5 Hz), to 7.67 (1H, d, J=2.0 Hz), 8,15 (1H, d, J=8.1 Hz), 11,73 (1H, sh).

MS (ESI) m/z: 392 (M+H)+.

[Referential example 53]

(±)-CIS-N1-(tert-Butoxycarbonyl)-N2[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-CIS-N-(tert-butoxycarbonyl)-1,2-cyclopentylamine a manner similar to the method of reference example 52.

1H-NMR (DMSO-d6) δ: 1,20-1,45 (11N, m), 1,45 is 1.70 (4H, m), 1.70 to of 1.85 (2H, m), 3,76 (1H, sh), 4,08 (1H, sh), only 6.64 (1H, d, J=7,6 Hz), 7,12 (1H, s), 7,16 (1H, DD, J=8,8, 2.0 Hz), the 7.43 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=2.0 Hz), the 7.85 (1H, d, J=6.9 Hz), RS 11.80 (1H, sh).

MS (ESI) m/z: 392 (M+N)+.

[Referential example 54]

Hydrochloride (±)-TRANS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine

Saturated ethanol solution (100 ml) of hydrochloric acid was added to a solution of (±)-TRANS-N1-(tert-butoxycarbonyl)-N2-[(5-Clorinda-2-yl) carbonyl]-1,2-cyclohexane is yamina (5,18 g) in dichloromethane (100 ml) at room temperature. After stirring for 2 days the reaction mixture was concentrated under reduced pressure, the obtained residue was added diethyl ether (300 ml) and the resulting colorless precipitate was filtered and dried, to deliver specified in the header connection (4,30 g) as a colourless solid.

1H-NMR (DMSO-d6) δ: 1,20-of 1.36 (2H, m), 1,36 of 1.50 (2H, m), 1,60 (2H, sh), 1,90 (1H, d, J=13,0 Hz)2,07 (1H, d, J=13,7 Hz), 3,06 (1H, sh), 3,83-of 3.96 (1H, m), 7,15-7,24 (2H, m), 7,45 (1H, d, J=8.6 Hz), 7,73 (1H, s), 8,00 (3H, sh), at 8.60 (1H, d, J=8,3 Hz), up 11,86 (1H, s).

MS (ESI) m/z: 292 (M+N)+.

[Referential example 55]

(±)-CIS-N-(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-CIS-N1-(tert-butoxycarbonyl)-N2[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine a manner similar to the method of reference example 54.

1H-NMR (DMSO-d6) δ: 1,30-1,50 (2H, m), 1,55-1,95 (6N, m)to 3.41 (1H, sh), 4,32 (1H, sh), 7,19 (1H, DD, J=8,7, 2.0 Hz), 7,33 (1H, s), 7,45 (1H, D, J=8.7 Hz), 7,60-of 7.90 (4H, m), 8,17 (1H, d, J=7,1 Hz), 11,91 (1H, s).

MS (FAB) m/z 292 (M+H)+.

[Reference example 56]

(±)-CIS-N1-Benzyl-N2-tert-butoxycarbonyl-1,2-cyclohexanediamine:

(±)-CIS-N-Tert-Butoxycarbonyl-1,2-cyclohexanediamine

(of 3.78 g) was dissolved in acetonitrile (80 ml)was added to a solution of treat the Lamin (2,44 ml) and benzylbromide (2.10 ml) and the mixture was stirred at room temperature for 13 hours. Drove away under reduced pressure, the solvent and to the residue was added dichloromethane and water to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column flash chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain specified in the connection header (is 3.08 g) as a pale orange oil.

1H-NMR (CDCl3) δ: 1,35-1,63 (17H, m), 2,75-and 2.79 (1H, m), 3,71-a 3.83 (3H, m)to 5.17 (1H, sh), 7,22-7,33 (5H, m).

MS (FAB) m/z: 305 (M+N)+.

[Referential example 57]

(±)-CIS-N1-Benzyl-N2-tert-butoxycarbonyl-N1-methyl-1,2-cyclohexanediamine:

(±)-CIS-N1-Benzyl-N2-tert-butoxycarbonyl-1,2-cyclohexanediamine (3,24 g) was dissolved in methanol (30 ml), to the solution was added an aqueous solution (35%, 0,909 ml) of formaldehyde and the mixture was stirred at room temperature for 10 minutes. To the mixture was added Lamborghini sodium (666 mg) and the mixture was stirred at room temperature for 6 hours. Then was added a saturated aqueous solution of sodium bicarbonate and drove away under reduced pressure the solvent. To the residue was added dichloromethane to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and kept at low d is in relation to the solvent. The residue was purified column flash chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (1.98 g) as a yellow oil.

1H-NMR (CDCl3) δ: 1,24-1,50 (14N, m), 1,76-to 1.79 (1H, m), 1.93 and-to 1.98 (1H, m), of 2.15 (3H, s), 2,16-of 2.21 (1H, m), is 2.30 to 2.35 (1H, m)to 3.34 (1H, d, J=13,4 Hz), of 3.78 (1H, d, J=13,4 Hz), 4,08 (1H, sh), 5,09 (1H, sh), 7,20-7,32 (5H, m).

MS (ESI) m/z: 319 (M+N)+.

[Referential example 58]

(±)-CIS-N1-tert-Butoxycarbonyl-N2-methyl-1,2-cyclohexanediamine:

(±)-CIS-N1-Benzyl-N2-tert-butoxycarbonyl-N1-methyl-1,2-cyclohexanediamine (1.92 g) was added to methanol (50 ml)was added 10% palladium on carbon (containing 50% water, 900 mg) and the mixture was stirred for 20 hours in a hydrogen atmosphere. After separation of the catalyst by filtration, the filtrate was concentrated to obtain specified in the title compound (1.27 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,37-1,60 (17H, m), 2,39 (3H, s), 2,58 at 2.59 (1H, m), 3,48-to 3.49 (1H, m), and 3.72 (1H, sh), 5,10 (1H, sh).

MS (ESI) m/z: 229 (M+H)+.

[Referential example 59]

Triptorelin (±)-CIS-N1[(5-Clorinda-2-yl)carbonyl]-N1-methyl-1,2-cyclohexanediamine:

(±)-CIS-N1-tert-Butoxycarbonyl-N2-methyl-1,2-cyclohexanediamine (629 mg), 5-Clorinda-2-carboxylic acid (647 mg), the hydrochloride of 1-(3-dime alminoprofen)-3-ethylcarbodiimide (792 mg) and the monohydrate of 1-hydroxybenzotriazole (186 mg) was dissolved in N,N-dimethylformamide (20 ml) and the solution was stirred at room temperature for 4 days. The solvent is kept at reduced pressure using a pump and to the residue was added dichloromethane and saturated sodium hydrogen carbonate solution to separate the organic layer. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column flash chromatography on silica gel (hexane:ethyl acetate=1:1). The obtained pale yellow solid was dissolved in a mixed solvent comprising dichloromethane (5 ml) and triperoxonane acid (5 ml)and the solution was stirred at room temperature for 1 hour. Drove away under reduced pressure, the solvent was added dichloromethane and saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was concentrated under reduced pressure and to the residue was added ethyl acetate. The precipitate was filtered, to deliver specified in the header connection (786 mg) as a pale yellow solid.

1H-NMR (CDCl3) δ: 1,37-of 1.55 (3H, m), 1,72 is 1.96 (4H, m), 2,09-2,19 (1H, m), 3,23 (3H, s), 3,76 (1H, sh), 4,34-4,39 (1H, m), 6,92 (1H, d, J=1.7 Hz), 7,20 (1H, DD, J=8,8, 2.0 Hz), 7,46 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=2.0 Hz), 8,08 (3H, sh), 11,74 (1H, sh).

MS (ESI) m/z: 306 (M+N)+.

[Referential example 60]

(±)-CIS-N 1-(tert-Butoxycarbonyl)-N2N-methyl-N2[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (613 mg) suspended in dichloromethane (10 ml), was added 1 N. ethanol solution (3.0 ml) of hydrochloric acid and the mixture was stirred at room temperature for several minutes. Drove away under reduced pressure, the solvent, to the residue was added chloroform (15 ml), N,N-dimethylformamide (one drop) and thionyl chloride (5 ml) and the mixture was stirred at 60°C for 4 hours. Drove away under reduced pressure, the solvent, to the residue were added pyridine (10 ml) and dichloromethane (10 ml) and then was added a solution (5 ml) (±)-CIS-N1-(tert-butoxycarbonyl)-N2-methyl-1,2-cyclohexanediamine (455 mg) in dichloromethane (5 ml). After stirring the mixture at room temperature for 2 hours was added water to separate the organic layer. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column flash chromatography on silica gel (dichloromethane:methanol=47:3) to obtain the specified title compound (324 mg) as a pale brown solid fuel is Dogo substances.

MS (ESI) m/z: 409 (M+H)+.

[Referential example 61]

(±)-TRANS-1,2-Cycloheptenyl:

Cyclohepten (of 3.85 g) was added in portions to a 30% aqueous solution of hydrogen peroxide (45 ml) and 88% formic acid (180 ml) and the mixture was stirred at 40-50°C for 1 hour and then at room temperature overnight. Drove away under reduced pressure, the solvent and the remainder for its alkalizing was added 35% aqueous sodium hydroxide solution. After mixing the specified amount at 40-50°C for 10 minutes was added ethyl acetate to separate liquids. The resulting aqueous layer was extracted 4 times with ethyl acetate. The obtained organic layers were collected and dried over anhydrous sodium sulfate, and then drove away under reduced pressure, the solvent is obtaining specified in the connection header (4,56 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,44-1,56 (6N, m), 1,63 is 1.70 (2H, m), 1,83 is 1.91 (2H, m), 2.91 in (2H, sh), 3,40-3,44 (2H, m).

MS (FAB) m/z: 131 (M+N)+.

[Reference example 62]

Hydrochloride (±)-TRANS-1,2-cycloheptadiene:

(±)-TRANS-1,2-Cycloheptanol (4,56 g) was dissolved in dichloromethane (35 ml), was added triethylamine (29 ml) and the mixture was cooled to -78°C. was Added thereto dropwise methanesulfonanilide (8,13 ml). Because the resulting OS the dock complicated mixing, was slowly added dichloromethane (10 ml) and the mixture was stirred for 20 minutes at the same temperature and then for 1.5 hours at 0°C. In the reaction mixture were added water for the separation of liquids and the resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Drove under reduced pressure the solvent to obtain a brown oil.

The resulting oil was dissolved in N,N-dimethylformamide (90 ml), was added sodium azide (13,65 g) and the mixture was stirred at 65°C for 18 hours. In the reaction mixture was added ether and water to separate liquids. The obtained ether layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous sodium sulfate. Drove under reduced pressure the solvent to obtain a yellow oil.

The resulting oil was dissolved in ethanol (70 ml), was added 10% palladium on carbon (containing 50% water, 4 g) and the mixture was stirred for 4 days in an atmosphere of hydrogen (3.5 ATM). After separation of palladium on carbon filtration, to the filtrate was added 1 N. ethanol solution (70 ml) of hydrochloric acid and kept under reduced pressure the solvent. The residue was dissolved in methanol, was added ethyl acetate and again drove under reduced pressure the solvent. The formed precipitate Otti triviali, receiving the result mentioned in the title compound (3.57 g) as a colourless solid.

1H-NMR (DMSO-d6) δ: of 1.44 (4H, sh), 1,73-1,81 (6N, m), 3.43 points (2H, sh), 8,63 (6N, sh).

MS (ESI) m/z: 129 (M+H)+.

[Referential example 63]

(±)-TRANS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cycloheptadiene:

Specified in the title compound was obtained from (±)-TRANS-1,2-cycloheptadiene a manner similar to the method of reference example 30.

1H-NMR (DMSO-d6) δ: 1,49-of 1.52 (4H, m), 1,72 is 1.91 (6N, m), 4.04 the-4,10 (1H, m), 7,17-of 7.23 (2H, m), 7,44 (1H, d, J=8,8 Hz), 7,72 (1H, d, J=2.0 Hz), of 7.96 (2H, sh), is 8.75 (1H, d, J=8.5 Hz), 11,89 (1H, sh).

MS (ESI) m/z: 306 (M+H)+.

[Referential example 64]

CIS-1,2-Cycloheptenyl

Cyclohepten (of 3.85 g) was dissolved in acetonitrile (45 ml) and water (15 ml), to the solution was added N-oxide N-methylmorpholine (5,15 g) and microencapsulated osmium tetroxide (1 g, containing 10% osmium tetroxide) and the mixture was stirred at 40-50°C for 21 hours. Insoluble microencapsulated osmium tetroxide was removed by filtration, and the insoluble substance was washed with acetonitrile, and the filtrate was concentrated under reduced pressure. The residue was purified column flash chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the specified title compound (4.77 g) in the form bessfetovornoe substances.

1H-NMR (CDCl3) δ: 1,34-1,84 (10H, m), 2,31 (2H, m), 3,86 (2H, d, J=7,1 Hz).

MS (FAB) m/z: 131 (M+H)+.

[Referential example 65]

CIS-1,2-Cycloheptadiene

The triethylamine (30 ml) was added to a solution of CIS-1,2-cycloheptadiene (4,76 g) in dichloromethane (50 ml), after which the vessel was purged with argon, the mixture was cooled to -78°and added thereto dropwise methanesulfonanilide (8.5 ml). The mixture was stirred 1 hour at the same temperature and then for 2 hours at 0°C. In the reaction mixture were added water for the separation of liquids and the resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was dissolved in N,N-dimethylformamide (90 ml), was added sodium azide (of 14.28 g) and the mixture was stirred at 65°C for 21 hours. In the reaction mixture was added ether and water to separate liquids. The obtained ether layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column flash chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the specified title compound (3.57 g) as a colourless oil.

1H-NMR (DMSO-d6) &x003B4; : 1,46-of 1.80 (8H, m), 1,89-to 1.98 (2H, m), 3,71 (2H, DD, J=6,7, and 2.3 Hz).

[Reference example 66]

Hydrochlorides-1,2-cycloheptadiene:

CIS-1,2-Cycloheptadiene (6,35 g) was dissolved in ethanol (75 ml)was added 10% palladium on carbon (containing 50% water and 4.2 g) and the mixture was stirred for 3 days in a hydrogen atmosphere (3.5 ATM). After separation by filtration of 10% palladium on carbon, to the filtrate was added 1 N. ethanol solution (70,5 ml) of hydrochloric acid and kept under reduced pressure the solvent. To the residue was added ethyl acetate and again drove under reduced pressure the solvent. The precipitate was filtered and washed with ethyl acetate to obtain specified in the connection header (5,28 g) as a colourless solid.

1H-NMR (DMSO-d6) δ: 1,44-1,68 (6N, m), 1,79-of 1.93 (4H, m), 3,68 (2H, DD, J=6,8, 3,GC), 8,62 (6N, sh).

MS (FAB) m/z: 129 (M+N)+.

[Reference example 67]

(±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cycloheptadiene:

Specified in the title compound was obtained from (±)-CIS-1,2-cycloheptadiene a manner similar to the method of reference example 30.

MS (ESI) m/z: 306 (M+H)+.

[Referential example 68]

CIS-1,2-Cyclooctanol

Cycloocten (to 4.41 g) was dissolved in acetonitrile (45 ml) and water (15 ml)to dissolve the at was added N-oxide N-methylmorpholine (5,15 g) and microencapsulated osmium tetroxide (1 g, containing 10% osmium tetroxide) and the mixture was stirred at 40-50°C for 21 hours. Insoluble microencapsulated osmium tetroxide was removed by filtration and washed with acetonitrile, and the filtrate was concentrated under reduced pressure. The residue was purified column flash chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain specified in the connection header (equal to 4.97 g) as a colourless solid.

1H-NMR (CDCl3) δ: 1,48-1,58 (6N, m)of 1.64 and 1.75 (4H, m), 1,86 is 1.96 (2H, m), 2,28 (2H, d, J=2,9 Hz), 3,90 (2H, d, J=8,3 Hz).

MS (FAB) m/z: 145 (M+H)+.

[Referential example 69]

CIS-1,2-Cyclooctadiene

CIS-1,2-Cyclooctanol (4,82 g) was dissolved in dichloromethane (60 ml) and to the solution was added triethylamine (27.7 ml). The vessel was purged with argon, after which the mixture was cooled to -78°and added thereto dropwise methanesulfonanilide (7.7 ml, 100 mmol). The mixture was stirred 1 hour at the same temperature and then for 1 hour at 0°C. In the reaction mixture were added water for the separation of liquids and the resulting organic layer was washed with water, 0,5 N. hydrochloric acid, water and saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was dissolved in N,N-dimethylformamide (80 ml), was added sodium azide (13,0 g) and the mixture is stirred at 65° C for 19 hours. In the reaction mixture was added ether and water to separate liquids. The obtained ether layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column flash chromatography on silica gel (hexane:ethyl acetate=6:1) to obtain specified in the connection header (4,85 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,49-1,64 (6N, m), 1,67-of 1.78 (2H, m), 1,81-of 1.97 (4H, m), 3,74 is 3.76 (2H, m).

[Referential example 70]

Hydrochloride CIS-1,2-cyclooctadiene:

CIS-1,2-Cyclooctadiene (4,85 g) was dissolved in ethanol (55 ml), to the solution was added 10% palladium on carbon (containing 50% water, 3.0 g) and the mixture was stirred for 21 hours in an atmosphere of hydrogen (4.5 ATM). After separation of the catalyst by filtration the filtrate was added 1 N. ethanol solution (50 ml) of hydrochloric acid and kept under reduced pressure the solvent. To the residue was added ethyl acetate and the resulting precipitate was filtered to obtain specified in the connection header (4,14 g) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,51 (6N, sh), was 1.69 (2H, sh), 1,79 of 1.99 (4H, m), 3,68-3,70 (2H, m), 8,66 (6N, sh).

MS (ESI) m/z: 143 (M+N)+.

[Referential example 71]

(±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclooctadiene:

Specified in the title compound was obtained from (±)-CIS-1,2-cyclooctadiene a manner similar to the method of reference example 30.

MS (ESI) m/z: 320 (M+N)+.

[Reference example 72]

N1-tert-Butoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-Ethylenediamine:

tert-Butyl N-(2-amino-ethyl)carbamate (1.0 g) was dissolved in N,N-dimethylformamide and to the solution was added 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (purity 90%, 1.13 g), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1,79 g) and the monohydrate of 1-hydroxybenzotriazole (422 mg) and the mixture was stirred at room temperature for 23 hours. Using a vacuum pump, drove away under reduced pressure, the solvent and to the residue was added dichloromethane and saturated sodium hydrogen carbonate solution, to separate the liquid. The resulting aqueous layer was extracted with dichloromethane, the organic layers were collected and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column flash chromatography on silica gel (dichloromethane:methanol=91:9) to obtain the specified title compound (1.26 g) as a pale-altago solids.

1H-NMR (CDCl3) δ: 1,43 (N, C)of 2.51 (3H, m), 2,81-2,84 (2H, m), 2.91 in-2,95 (2H, m), 3,35 is 3.40 (2H, m), 3,53 is 3.57 (2H, m), 3,71 (2H, s), and 5.30 (1H, sh), 7,47 (1H, sh).

MS (FAB) m/z: 341 (M+N)+.

[Reference example 73]

N1-tert-Butoxycarbonyl-N2-[(1-phenylsulfonyl-5-Clorinda-2-yl)sulfonyl]-1,2-Ethylenediamine:

tert-Butyl N-(2-amino-ethyl)carbamate (1.0 g) was dissolved in dichloromethane (10 ml), to the solution was added 5-chloro-1-phenylsulfonyl-2-sulphonylchloride (2,44 g) and triethylamine (1.73 ml) and the mixture was stirred over night at room temperature. In the reaction mixture were added water for the separation of liquids and the resulting aqueous layer was extracted with dichloromethane. The obtained organic layers were collected and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column flash chromatography on silica gel (hexane:ethyl acetate=4:1→3:2) to obtain the specified title compound (2.83 g) as a colourless solid.

1H-NMR (CDCl3) δ: 1,43 (N, C), 3,17-is 3.21 (2H, m), 3,28-and 3.31 (2H, m), 4,89 (1H, sh), 5,97-6,00 (1H, m), 7,42-7,51 (4H, m), to 7.59-the 7.65 (2H, m), 8,11-8,16 (3H, m).

MS (FAB) m/z: 514 (M+H)+.

[Reference example 74]

N1-tert-Butoxycarbonyl-N1-methyl-1,2-Ethylenediamine:

Carried out the synthesis in accordance with the liter is dependent on the (J. Med. Chem., 1990, Vol.33, R). N-methyl-1,2-Ethylenediamine (5,57 ml) was dissolved in dichloromethane (80 ml) was added at 0°With a solution of di-tert-BUTYLCARBAMATE (4,37 g) in dichloromethane (20 ml). The mixture was stirred at room temperature overnight. For the separation of liquids in the reaction mixture was added a saturated solution of salt. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The obtained product was purified column chromatography on silica gel (chloroform:methanol=9:1→4:1) to obtain specified in the connection header (2,96 g) as a pale-yellow oil from the initial eluate.

1H-NMR (DMSO-d6) δ: 1,37 (N, C)2,63 (2H, t, J=6,7 Hz), 2,77 (3H, s), of 3.12 (2H, t, J=6,7 Hz).

MS (FAB) m/z: 175 (M+H)+.

In addition, from the following eluate was obtained N1-tert-butoxycarbonyl-N2-methyl-1,2-Ethylenediamine (339 mg) as a pale yellow oil.

1H-NMR (DMSO-d6) δ: 1,36 (N, C), 2,24 (3H, s)to 2.46 (2H, t, J=6.5 Hz), of 2.97 (2H, q, J=6.5 Hz), of 6.68 (1H, sh).

MS (ESI) m/z: 175 (M+H)+.

[Reference example 75]

The hydrochloride of N1N-methyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-Ethylenediamine:

Nl-tert-Butoxycarbonyl-Nl-methyl-1,2-Ethylenediamine (of 1.05 g) was dissolved in N,N-dimethylformamide (30 ml), to the solution was added 5-IU the Il-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (157 mg), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (181 mg) and the monohydrate of 1-hydroxybenzotriazole (42 mg) and the mixture was stirred at room temperature overnight. Using a vacuum pump, drove away under reduced pressure, the solvent and to the residue was added dichloromethane and saturated sodium hydrogen carbonate solution, to separate the liquid. The resulting aqueous layer was extracted with dichloromethane, the organic layers were collected and dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The residue was purified column flash chromatography on silica gel (dichloromethane:methanol=23:2) and the compound obtained was dissolved in a small amount of dichloromethane, to the solution was added a saturated ethanol solution (8 ml) of hydrochloric acid and the mixture was stirred at room temperature for 1 hour. After distillation under reduced pressure of the solvent was added ethyl acetate and the resulting precipitate was filtered to obtain specified in the title compound (697 mg) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: of 2.54 (3H, s), 2,89 (3H, s), 3,02 of 3.28 (4H, m), 3,43-3,74 (4H, sh), of 4.45 (1H, sh), of 4.66 (1H, sh), 8,79 (2H, sh), 9,04 (1H, t, J=5,9 Hz), 11,88 (1H, sh).

MS (FAB) m/z: 255 (M+H)+.

[Referential example 76]

The hydrochloride of N1-[(5-Clorinda-2-yl)carbonyl]-N2-methyl-12-Ethylenediamine:

N1-tert-Butoxycarbonyl-N1-methyl-1,2-Ethylenediamine (348 mg) was dissolved in N,N-dimethylformamide (5 ml), to the solution was added 5-Clorinda-2-carboxylic acid (391 mg), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (575 mg) and the monohydrate of 1-hydroxybenzotriazole (135 mg) and the mixture was stirred at room temperature for 3 days. Drove away under reduced pressure, the solvent and to the residue was added dichloromethane and saturated sodium hydrogen carbonate solution, to separate the liquid. The obtained organic layer was dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The residue was purified column flash chromatography on silica gel (dichloromethane:methanol=47:3) and the resulting pale yellow solid was dissolved in dichloromethane (10 ml) and methanol (10 ml), to the solution was added a saturated ethanol solution (10 ml) of hydrochloric acid and the mixture was stirred at room temperature for 1 hour. After distillation under reduced pressure of the solvent was added ethyl acetate and the resulting precipitate was filtered to obtain specified in the title compound (288 mg) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 2,59 (3H, t, J=5,4 Hz), 3,11 (2H, Quint, J=5,9 Hz), 3,61 (2H, q, J=5,9 Hz), 7,19 (1H, DD, J=8,8, 2.2 Hz), 7,22 (1H, d, 0=1.2 Hz), and 44 (1H, d, J=8,8 Hz), 7,71 (1H, d, J=2.2 Hz), of 9.00 (1H, t, J=5, 9 Hz), 9,03 (2H, sh), 11,89 (1H, sh).

MS (ESI) m/z: 252 (M+H)+.

[Reference example 77]

N1-tert-Butoxycarbonyl-N1N2-dimethyl-1,2-Ethylenediamine:

N,N'-Dimethyl-1,2-Ethylenediamine (1.07 ml) was dissolved in dichloromethane, to the solution was added at room temperature, di-tert-BUTYLCARBAMATE (2,18 g) and the mixture was stirred over night. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=4:1) to obtain the specified title compound (678 mg) as a yellow oil.

1H-NMR (CDCl3) δ: 1,46 (N, C)2,48 (3H, sh), 2,78 (2H, sh), 2,89 (3H, s), 3,37 (2H, sh).

MS (ESI) m/z: 189 (M+N)+.

[Reference example 78]

4-(2-Pyridyl)benzoic acid:

2-(p-Toluene)pyridine (17,2 g) suspended in water (200 ml) and to the suspension was added potassium permanganate (21,0 g). The mixture was boiled under reflux for 18 hours. Allowing the reaction mixture to cool, removed by filtration of the insoluble matter, the filtrate was added dichloromethane and the resulting aqueous layer was separated and acidified 2 N. hydrochloric acid. The solution was concentrated and the precipitate was filtered, to deliver specified in the header connection (7,07 g) as a white solid prophetic is STV.

1H-NMR (DMSO-d6) δ: of 7.60 (1H, t, J=5,9 Hz), 8,08 (2H, d, J=7.8 Hz), 8,17 (2H, m), 8,21 (2H, d, J=7.8 Hz), 8,78 (1H, d, J=4,9 Hz).

MS (El) m/z: 199 (M)+.

[Referential example 79]

Thiazolo[4,5-C]pyridine:

3-(tert-Butoxycarbonylamino)-4-mercaptopyridine (published application No. 321691/1992 patent Japan) (9,20 g) was dissolved in formic acid (60 ml) and the solution boiled under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added 4 N. aqueous solution (100 ml) of potassium hydroxide and ether to separate liquids. The obtained organic layer was dried over anhydrous sodium sulfate and then drove away under reduced pressure the solvent. To the residue was added ether and precipitated precipitated solids were filtered to obtain specified in the connection header (of 3.97 g) as a colourless solid.

1H-NMR (CDCl3) δ: to 7.93 (1H, d, J=5.4 Hz), at 8.60 (1H, d, J=5.4 Hz), 9,07 (1H, s), 9,46 (1H, s).

[Referential example 80]

5-Methyl-4,5,6,7-tetrahydropyrazolo[4,5-C]pyridine:

Specified in the title compound was obtained from thiazolo[4,5-C]pyridine in a manner similar to the method of reference example 4.

1H-NMR (CDCl3) δ: 2,52 (3H, s), 2,77 (2H, t, J=5.4 Hz), 2,92-of 3.00 (2H, m), of 3.69 (2H, t, J=2.0 Hz), 8,61 (1H, s).

MS (FAB) m/z: 155 (M+N)+.

[Reference the example 81]

5-Methyl-4,5,6,7-tetrahydropyrazolo[4,5-C]pyridine-2-carboxylate lithium:

Specified in the title compound was obtained from 5-methyl-4, 5, 6, 7-tetrahydropyrazolo[4,5-C]pyridine in a manner similar to the method of reference example 5.

1H-NMR (DMSO-d6) δ: of 2.38 (3H, s)of 2.64 (2H, sh), 2,80 (2H, sh), 3,44 (2H, sh).

MS (FD) m/z: 199 (M+N)+.

[Referential example 82]

6-Methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine:

35% Aqueous solution (6 ml) of formaldehyde was added to 3-[(2-amino)ethyl]thiophene (Arkiv for kemi, 1971, Vol.32, R) under ice cooling and the mixture was heated and stirred at 90°C for 3 hours. The reaction mixture was again cooled to room temperature and was extracted with benzene. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and to the residue was added 7 N. chloride in portly acid, stirring the mixture overnight at room temperature. The reaction mixture was concentrated under reduced pressure and to separate the liquids were added 3 N. aqueous solution (100 ml) hydroxide Natrii dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate and drove away under reduced pressure, the solvent, after which the residue was dissolved in dichloromethane (200 ml) and RA is Toru was added 35% aqueous solution (2 ml) of formaldehyde, acetic acid (2 ml) and triacetoxyborohydride sodium (11,24 g) with stirring the mixture at room temperature for 1 hour. In the reaction mixture were added 3 N. aqueous solution (100 ml) of sodium hydroxide and the organic layer was separated and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was distilled under reduced pressure (0.3 mm RT. post, 45-47° (C) obtaining specified in the connection header (1,82 g) as a colourless oil.

1H-NMR (CDCl3) δ: 2,49 (3H, s), 2.70 height is 2.80 (4H, m)to 3.64 (2H, s), is 6.78 (1H, d, J=4.9 Hz), to 7.09 (1H, d, J=4,9 Hz).

MS (FAB) m/z 154 (M+N)+.

[Referential example 83]

6-Methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine-2-carboxylate lithium:

Specified in the title compound was obtained from 6-methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine in a manner similar to the method of reference example 5.

1H-NMR (DMSO-d6) δ: 2,48-2,70 (4H, m), 3,30-3,50 (3H, m), 3,61 (1H, s), 7,01 (1H, s).

MS (FD) m/z: 198 (M+H)+.

[Referential example 84]

2-Chloro-5-(N,N-dimethylamino)-4,5,6,7-tetrahydrobenzo[d]thiazole:

2-Chloro-5-oxo-4,5,6,7-tetrahydrobenzo[d]thiazole (Helv. Chim. Acta, 1994, Vol.77, R) (2.0 g) was dissolved in methanol (100 ml), the solution was added ammonium acetate (8.2 g) and cyanoborohydride sodium (4.0 g) and the mixture is boiled under reflux. Ceres hours the reaction was stopped, added hydrochloric acid to decompose the excess cyanoborohydride sodium, and then drove away under reduced pressure the solvent. The residue was podslushivaet 1 N. a sodium hydroxide solution and then was extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate and drove away under reduced pressure, the solvent to obtain a pale yellow oil. The resulting oil was dissolved in methanol (50 ml) and to the solution was added an aqueous solution (4,29 g) formaldehyde and Lamborghini sodium (3,49 g) under stirring the mixture for 12 hours at room temperature. Drove away under reduced pressure, the solvent and to the residue was added methylene chloride, then the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=10:1) to obtain the specified title compound (740 mg) as a pale yellow oil.

1H-NMR (CDCl3) δ: 1,71-of 1.78 (1H, m), 2,10-2,19 (1H, m), 2,35 (6N, (C), 2,66-to 2.94 (5H, m).

MS (FAB) m/z: 217 (M+H)+.

[Referential example 85]

[5-(N,N-Dimethylamino)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]carboxylate lithium:

2-Chloro-5-(N,N-dimethylamino)-4,5,6,7-tetrahedron is zo[d]thiazole (750 mg) was dissolved in ether (15 ml) and the solution was cooled to -78° With, after which was added to 1.5 N. tetrabutyrate (3.5 ml) and the mixture was stirred. After 20 minutes was barbotirovany carbon dioxide and stopped bubbling after about 15 minutes. The reaction mixture was heated to room temperature and concentrated under reduced pressure to obtain specified in the title compound as a yellow amorphous substance.

1H-NMR (DMSO-d6) δ: 1,75-of 1.78 (1H, m), 1,98-2,07 (1H, m), 2,50 (6N, (C), 2,64-is 2.88 (5H, m)

[Reference example 86]

4-(Morpholinomethyl)thiazol:

4-Methylthiazole (1.98 g), N-bromosuccinimide (of 3.56 g) and α,α'-azobisisobutyronitrile (164 mg) was dissolved in carbon tetrachloride (200 ml) and the solution boiled under reflux for 2 hours. Upon completion of the reaction was removed by filtration of the insoluble matter, the filtrate was added N,N-dimethylformamide (20 ml) and kept under reduced pressure carbon tetrachloride to obtain N,N-dimethylformamide solution (about 20 ml) of 4-(methyl bromide)thiazole. To the obtained N,N-dimethylformamide solution (about 10 ml) of 4-(methyl bromide)thiazol sequentially added morpholine (871 μl), triethylamine (2,79 ml) and N,N-dimethylformamide (10 ml) and the mixture was stirred over night at room temperature. Drove away under reduced pressure, the solvent, to the residue were added dichloromethane and saturated aqueous Rast is the PR of sodium bicarbonate and separated the organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:19) to obtain the specified title compound (700 mg) as a yellow oil.

1H-NMR (CDCl3) δ: 2,45-2,60 (4H, sh), the 3.65-3,90 (6N, sh), 7,21 (1H, s), 8,79 (1H, s).

MS (ESI) m/z 185 (M+N)+.

[Reference example 87]

5-[(N,N-Dimethylamino)methyl]thiazole:

Using a 5-methylthiazole (of 5.00 g), N-bromosuccinimide (8,97 g) and α,α'-azobisisobutyronitrile (414 mg)was obtained N,N-dimethylformamide a solution of 5-(methyl bromide)thiazol a manner similar to the method of reference example 86, and the resulting solution was subjected to interaction with morpholine (2,20 ml) and triethylamine (7,02 ml), to deliver specified in the header connection (1,76 g) as a yellow oil.

1H-NMR (CDCl3) δ: 2,27 (6N, (C), 3,68 (2H, s), of 7.70 (1H, S), IS 8.75 (1H, s).

MS (ESI) m/z: 143 (M+H)+.

[Reference example 88]

4-(Morpholinomethyl)thiazol-2-carboxylate lithium:

4-(Morpholinomethyl)thiazol (640 mg) was dissolved in diethyl ether (5 ml) in an argon atmosphere and the solution was added dropwise at -78°With n-utility (1,54 N. hexane solution of 2.50 ml). The reaction mixture was stirred for 10 minutes under ice cooling and was again cooled on the -78° C. After purging the reaction mixture with carbon dioxide for 20 minutes, it was heated to room temperature. The reaction mixture was concentrated under reduced pressure to obtain specified in the connection header (873 mg) as a crude yellow powder.

1H-NMR (DMSO-d6) δ: 2,40 (4H, sh), 3,50-3,70 (6N, m), 7,34 (1H, s).

[Referential example 89]

5-[(N,N-Dimethylamino)methyl]thiazole-2-carboxylate lithium:

Specified in the header connection (2,34 g) was obtained as a violet powder of 5-[(N,N-dimethylamino)methyl]thiazole (1,81 g) in a manner similar to the method of reference example 5.

1H-NMR (DMSO-d6) δ: 2,14 (6N, sh), of 3.56 (2H, sh), 7,51 (1H, s).

[Referential example 90]

2-Amino-5-tert-butoxycarbonyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole:

1-tert-Butoxycarbonyl-3-pyrrolidone (1,58 g) was dissolved in cyclohexane (10 ml), to the solution was added monohydrate p-toluensulfonate acid (8,12 mg) and pyrrolidine (607 mg) and the mixture is boiled under reflux for 1.5 hours, removing water by using traps Dean-stark. The supernatant was collected and concentrated under reduced pressure, then the residue was dissolved in methanol (5 ml) and to the solution was added powdered sulfur (274 mg). The mixture was stirred for 15 minutes under ice cooling. Was slowly added is in the reaction mixture of a methanol solution (2 ml) of cyanamide (377 mg) and the mixture was stirred overnight at room temperature. The mixture is then boiled under reflux for 2 hours, the reaction mixture was concentrated and added to her dichloromethane and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:39) to obtain the specified title compound (248 mg) as a yellow oil.

1H-NMR (CDCl3) δ: 1,50 (N, C), 4,34-4,37 (1H, m), 4,40-of 4.45 (1H, m), 4,49-4,55 (2H, m), 4,99 (2H, m).

[Referential example 91]

2-Bromo-5-tert-butoxycarbonyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole:

The copper bromide (II) (445 mg) suspended in N,N-dimethylformamide was added dropwise tert-butylnitrite (256 mg) at room temperature. Was added under ice cooling, N,N-dimethylformamide solution (1 ml) of 2-amino-5-tert-butoxycarbonyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (400 mg), after which the reaction mixture was heated and stirred at 60°C for 1.5 hours. In the reaction mixture were added diethyl ether and a saturated salt solution, and the obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the decree of the frame in the title compound (174 mg) as a pale yellow powder.

1H-NMR (CDCl3) δ: 1,51 (N, C)to 4.52-4,55 (1H, m), 4,57-of 4.67 (3H, m).

MS (FAB) m/z: 305 (M+N)+.

[Reference example 92]

5-(Benzazolyl)-4,6-dihydro-5H-pyrrolo [3,4-d]thiazole:

1) 4,5-Dimethylthiazol (of 5.00 g), N-bromosuccinimide (15.7 g) and α,α'-azobisisobutyronitrile (362 mg) was dissolved in dichloroethane (500 ml) at room temperature and the solution was boiled under reflux for 1 hour. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:diethyl ether=1:4) to give 4,5-bis(methyl bromide)thiazole (5,24 g) as a pale yellow oil.

1H-NMR (CDCl3) δ: with 4.64 (2H, s), 4,74 (2H, s), is 8.75 (1H, c).

2) Benzosulfimide (638 mg) and 4,5-bis(methyl bromide)thiazole (1.10 g) was dissolved in dimethylformamide (10 ml)was added in one 60% sodium hydride in oil (357 mg) and the mixture was stirred at room temperature for 3 hours. Added water and dichloromethane to separate liquids. The resulting oil layer was dried over anhydrous sodium sulfate, and then drove the solvent and the residue was purified column chromatography on silica gel (dichloromethane:ethyl acetate=9:1) to obtain the specified title compound (173 mg) as colorless powder.

1H-NMR (CDCl3) δ: 4,60-4,63 (2H, m), 4,70-to 4.73 (2H, m), 7,52-to 7.64 (3H, m), 7,88-a 7.92 (2H, m), 8,71 (1 is, C).

MS (FAB) m/z: 267 (M+N)+.

[Reference example 93]

The hydrobromide of 4,6-Dihydro-5H-pyrrolo[3,4-d]thiazole:

A mixture of 5-(benzazolyl)-4,6-dihydro-5H-pyrrolo [3,4-d] thiazole (800 mg), phenol (800 μl) and 47% Hydrobromic acid (5,00 ml) was boiled under reflux for 2 hours. Cooled the reaction mixture to room temperature, was added ethyl acetate and water to separate liquids. The resulting aqueous layer was concentrated under reduced pressure. To the residue was added ethyl acetate and filtering the precipitated precipitated colorless powder was obtained is listed in the title compound (521 mg).

1H-NMR (DMSO-d6) δ: was 4.42 (2H, sh), 4,56 (2H, sh), 9,14 (1H, s).

MS (FAB) m/z: 127 (M+N)+.

[Referential example 94]

5-Methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole:

Specified in the title compound was obtained from hydrobromide 4,6-dihydro-5H-pyrrolo[3,4-d]thiazole and formalin in a manner similar to the method of reference example 12.

1H-NMR (CDCl3) δ: to 2.67 (3H, s), 3.95 to 3,99 (2H, m), 4,01-of 4.05 (2H, m), 8,69 (1H, s).

MS (ESI) m/z: 141 (M+N)+.

[Reference example 95]

5-Methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-2-carboxylate lithium:

5-Methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (771 mg) was dissolved in tetrahydrofuran (10 ml) in an argon atmosphere and races who the thief was cooled to -78° C. To the resulting reaction mixture was added tert-utility (1,54 N. pentane solution, 3,93 ml). The reaction mixture was stirred for 1 hour under ice cooling and was again cooled to -78°C. After purging the reaction mixture with carbon dioxide for 20 minutes, it was heated to room temperature. The reaction mixture was concentrated under reduced pressure to obtain specified in the title compound (1.08 g) as a crude brown powder.

1H-NMR (DMSO-d6) δ: 2,52 (3H, s), of 3.73 (2H, t, J=3.2 Hz), a 3.87 (2H, t, J=3.2 Hz).

[Referential example 96]

2-Bromo-5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

Triptorelin 2-bromo-4,5,6,7-tetrahydrothieno[5,4-C]pyridine (5,00 g) suspended in dichloromethane (200 ml), to the suspension was added triethylamine (4,16 ml) and the mixture was stirred at room temperature to obtain a solution. To the reaction mixture was added acetic acid (2.55 ml) and acetone (17 ml) and the resulting mixture was stirred at room temperature for 2 minutes. In the reaction mixture was added triacetoxyborohydride sodium (19,1 g) and the resulting mixture was stirred at room temperature for 5 hours. Was added to the reaction mixture 3 N. aqueous solution (200 ml) of sodium hydroxide and separated the organic layer. The organic layer was dried over anhydrous sodium sulfate, and C is the drove under reduced pressure the solvent. The residue was purified column chromatography on silica gel (dichloromethane:methanol=100:1) to obtain specified in the connection header (of 3.45 g) as a yellow oil.

1H-NMR (CDCl3) δ: 1,13 (6N, d, J=6.6 Hz), of 2.86 (4H, s), 2,92-a 3.01 (1H, m), 3,70 (2H, s).

MS (FAB) m/z: 261 (M)+.

[Referential example 97]

5-Isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium:

Specified in the title compound was obtained from 2-bromo-5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine in a manner similar to the method of reference example 13.

1H-NMR (DMSO-d6) δ: 0,90-1,20 (6N, m), 2,60-3,03 (5H, m), to 3.58-4,00 (2H, m).

[Reference example 98]

5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium:

Specified in the title compound was obtained from 2-bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine in a manner similar to the method of reference example 13.

1H-NMR (DMSO-d6) δ: 1,42 (N, C), 2,69-2,77 (2H, m), 3,60-3,68 (2H, m), 4,51-4,58 (2H, m).

MS (FAB) m/z: 285 (M+H)+.

[Referential example 99]

Methyl 2-bromo-5-methoxycarbonylmethyl-4-acetate:

Chloride copper(II) (26,8 g) was added to a solution of tert-butylnitrite (15.5 g) in acetonitrile (500 ml) at once while cooling with ice. A solution of methyl 2-amino-5-methoxycarbonyl the ol-4-acetate (Yakugaku Zasshi, 1966, Vol.86, R) (23,0 g) in acetonitrile (500 ml) was added dropwise over 45 minutes and the mixture was stirred for 1 hour under ice cooling and for 30 minutes at room temperature. The solvent was concentrated and to the residue was added to separate the organic layer with 10% hydrochloric acid and diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain specified in the connection header (25,9 g) as a yellow solid.

1H-NMR (CDCl3) δ: of 3.73 (3H, s), a 3.87 (3H, s), is 4.21 (2H, s).

[Reference example 100]

4-(2-Hydroxyethyl)-5-hydroxymethylimidazole:

A solution of methyl 2-bromo-5-methoxycarbonylmethyl-4-acetate (23,4 g) in tetrahydrofuran (500 ml) was added dropwise during 1 hour to a suspension of lithium aluminum hydride (9,03 g) in tetrahydrofuran (500 ml) under cooling with ice. After stirring for another 1 hour under ice cooling, were added successively water (9 ml), 35% aqueous solution (9 ml) of sodium hydroxide and water (27 ml) and the mixture was stirred at room temperature for 1 hour. After addition, the reaction mixture anhydrous magnesium sulfate and stirring the obtained mixture, insoluble materials were removed by filtration through C is lit and the filtrate was concentrated. The residue was purified column chromatography on silica gel (methanol:dichloromethane=7:93) to obtain specified in the connection header (8,64 g) as a yellow oil.

1H-NMR (CDCl3) δ: a 3.01 (2H, t, J=5.5 Hz), 3,30 (1H, sh), 3,57 (1H, sh), 3,90 (2H, sh), and 4.75 (2H, sh), 8,66 (1H, s).

MS (ESI) m/z: 160 (M+H)+.

[Referential example 101]

4-(2-Methanesulfonylaminoethyl)-5-(methanesulfonylaminoethyl)thiazole:

The dichloromethane solution methanesulfonanilide (of 12.6 ml) was added dropwise to a solution of 4-(2-hydroxyethyl)-5-(hydroxymethyl)thiazole (8,64 g) and triethylamine (45,4 ml)dissolved in dichloromethane (500 ml)for 20 minutes at -78°C. After stirring the reaction mixture for 15 minutes at -78°and 1 hour at 0°With added water to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent is obtaining specified in the connection header (13,4 g) as a crude pale yellow oil.

1H-NMR (CDCl3) δ: of 2.93 (3H, s), 3,03 (3H, s), or 3.28 (2H, t, J=6.3 Hz), br4.61 (2H, t, J=6.3 Hz), 5,44 (2H, s), 8,84 (1H, s).

[Referential example 102]

5-(1-Methylcyclopropyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

Hydrochloride of 1-methylcyclopropene (J. Org. Chem., 1989, Vol.54, R) (1.89 g) was added to dichloromethane (20 ml)containing 4(2-methanesulfonylaminoethyl)-5-methanesulfonylaminoethyl (4,46 g), under ice cooling, and the mixture was stirred over night at room temperature. Added the hydrochloride of 1-methylcyclopropene (1.89 g) and the mixture was stirred for 20 hours at room temperature and 5 hours at the boil under reflux. In the reaction mixture were added dichloromethane and water to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:49) to obtain specified in the connection header (944 mg) as a pale yellow oil.

1H-NMR (CDCl3) δ: 0,40-0,50 (2H, m), 0,68-to 0.73 (2H, m)of 1.16 (3H, s), 2,88-to 2.94 (2H, m), 3,03 (2H, t, J=5.7 Hz), with 3.89 (2H, sh), at 8.60 (1H, s).

MS (ESI) m/z: 195 (M+H)+.

[Reference example 103]

5-(1-Methylcyclopropyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium:

Specified in the title compound was obtained from 5-(1-methyl-cyclopropyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine in a manner similar to the method of reference example 5.

1H-NMR (DMSO-d6) δ: 0,39 (2H, sh), of 0.56 (2H, sh), 1,10 (3H, sh), to 2.66 (2H, sh), 2,89 (2H, sh in), 3.75 (2H, sh).

[Reference example 104]

5-tert-Butyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

Specified in the title compound was obtained from 4-(2-meta is sulfonyloxy)-5-(methanesulfonylaminoethyl)thiazole and tert-butylamine way similar to the method of reference example 102.

1H-NMR (CDCl3) δ: 1,20 (N, C), 2,87-2,96 (4H, m), a 3.87 (2H, s), 8,59 (1H, s).

MS (ESI) m/z: 197 (M+H)+.

[Referential example 105]

5-tert-Butyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium:

Specified in the title compound was obtained from 5-tert-butyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine in a manner similar to the method of reference example 5.

1H-NMR (DMSO-d6) δ: 1,09 (M, sh), 2,65 (2H, sh), of 2,75 2,85 (2H, m), 3,71 (2H, sh).

[Referential example 106]

5-(1,1-Dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

Specified in the title compound was obtained from 4-(2-methanesulfonylaminoethyl)-5-(methanesulfonylaminoethyl)thiazole and 2-amino-2-methyl-1-propanol in a manner similar to the method of reference example 102.

1H-NMR (CDCl3) δ: 1,15 (6N, (C), only 2.91 (4H, s), of 3.45 (2H, s), a 3.87 (2H, s), 8,63 (1H, s).

[Reference example 107]

5-[2-(tert-Butyldiphenylsilyl)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine:

tert-Butylchloroformate (1,93 g) and imidazole (994 mg) was added to a solution of 5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine (1.24 g) in N,N-dimethylformamide (5 ml) at room temperature and the mixture was stirred over night. In the reaction mixture was added to the TAC and diethyl ether, to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=1:2) to obtain specified in the connection header (2,46 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,07 (N,) and 1.15 (6N, (C), 2,83-2,90 (2H, m), 2.93 which is 3.00 (2H, m), 3,63 (2H, s), of 3.97 (2H, s), 7,35-of 7.48 (6N, m), 7,63-of 7.70 (4H, m), 8,58 (1H, s).

MS (ESI) m/z 451 (M+N)+.

[Reference example 108]

5-[2-(tert-Butyldiphenylsilyl)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium:

Specified in the title compound was obtained from 5-[2-(tert-butyldiphenylsilyl)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine in a manner similar to the method of reference example 5.

1H-NMR (DMSO-d6) δ: 1,01 (N, C); 1,11 (6N, (C), 2,55-to 2.65 (2H, m), 2,80-2,90 (2H, m), of 3.57 (2H, s), 3,80 (2H, sh), 7,40-7,52 (6N, m), 7,60-the 7.65 (4H, m).

[Referential example 109]

4,5,6,7-Tetrahydro-5,6-trimethylthiazole [4,5-d]pyridazin:

1) 4,5-Dimethylthiazol (of 5.00 g), N-bromosuccinimide (15.7 g) and α,α'-azobisisobutyronitrile (362 mg) was dissolved in ethylene dichloride (500 ml) at room temperature and the solution was boiled under reflux for 1 hour. Drove away under reduced pressure, the solvent and the OST is OK purified column chromatography on silica gel (hexane:diethyl ether=1:4) to give 4,5-bis(methyl bromide)thiazole (5,24 g) as a pale yellow oil.

1H-NMR (CDCl3) δ: with 4.64 (2H, s), 4,74 (2H, s), is 8.75 (1H, s).

2) 4,5-Bis(methyl bromide)thiazole (1,37 g) hydrochloride and 1,2-trimethylhydrazine (WO 95/32965) (732 mg) suspended in ethanol (15 ml) under ice cooling, and to the suspension was added dropwise over 5 minutes, triethylamine (2,82 ml). After stirring at room temperature for 2 hours, drove the solvent and to the residue was added dichloromethane and saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=3:47) obtaining specified in the title compound (358 mg) as a yellow powder.

1H-NMR (CDCl3) δ: 2,10-of 2.25 (2H, m), 3,01 (4H, sh), of 3.95 (2H, s)to 3.99 (2H, sh), 8,64 (1H, s).

MS (FAB) m/z: 182 (M+N)+.

[Reference example 110]

4,5,6,7-Tetrahydro-5,6-tetramethylenebis[4,5-d]pyridazin:

Specified in the title compound was obtained from 4,5-bis(methyl bromide)thiazole (2.20 g) and hydrochloride 1,2-tetramethylpyrazine (US 5726126) in a manner similar to the method of reference example 109.

1H-NMR (CDCl3) δ: or 1.77 (4H, sh), 2,20-3,50 (4H, sh), to 3.92 (4H, sh), 8,65 (1H, s).

MS (FAB) m/z: 196 (M+H)+.

[Reference example 111]

4,5,6,7-Tetrahydro-5,6-trimethylthiazole the[4,5-d]pyridazin-2-carboxylate lithium:

Specified in the title compound was obtained from 4,5,6,7-tetrahydro-5,6-trimethylthiazole[4,5-d]pyridazine a manner similar to the method of reference example 5.

1H-NMR (DMSO-d6) δ: 1,90-2,10 (2H, m), 2,60-3,10 (4H, sh), 3,65-4,00 (4H, m).

[Reference example 112]

4,5,6,7-Tetrahydro-5,6-tetramethylenebis [4,5-d]pyridazin-2-carboxylate lithium:

Specified in the title compound was obtained from 4,5,6,7-tetrahydro-5,6-tetramethylenebis[4,5-d]pyridazine a manner similar to the method of reference example 5.

[Reference example 113]

6-(tert-Butoxycarbonyl)-5,7-dihydro-2-methylthiopurine[3,4-d]pyrimidine:

1-tert-Butoxycarbonyl-Z-pyrrolidone (of 4.57 g) was added to dimethylacetal N,N-dimethylformamide (30 ml) at room temperature and the mixture was heated 1 hour at 140°C. Allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure. To the residue was added hexane and precipitated precipitated yellow powder was filtered. The obtained powder was dissolved in ethanol (100 ml)to the resulting solution at room temperature was added sulphate methylisothiazoline (9/24 g) and ethoxide sodium (4.52 g) and the mixture is boiled under reflux for 24 hours. In the reaction mixture was added a saturated solution of salt, stabitlity the organic layer. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:99) to obtain the specified title compound (1.10 g) as a yellow powder.

1H-NMR (CDCl3) δ: 1,51 (N, (C), to 2.57 (3H, m), 4,15-of 4.45 (4H, m), 8,39 (1/2H, s), 8,43 (1/2H, s).

MS (FAB) m/z: 268 (M+N)+.

[Reference example 114]

6-(tert-Butoxycarbonyl)-5,7-dihydro-2-methylsulfonylbenzoyl[3,4-d]pyrimidine:

m-Chlorbenzoyl acid (1,99 mg) was added to a dichloromethane solution (20 ml) of 6-(tert-butoxycarbonyl)-5,7-dihydro-2-methylthiopurine[3,4-d]pyrimidine (1.08 g) under ice cooling and the mixture was stirred for 5 hours. To separate the organic layer was added saturated aqueous solution of sodium sulfite, saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent, to the residue was added hexane and precipitated precipitated powder was filtered to obtain specified in the connection header (1,09 g) as colorless powder.

1H-NMR (CDCl3) δ: 1,53 (N, C)to 3.36 (3H, m), 4,77-of 4.90 (4H, m), 8,77 (1/2H, s), 8,81 (1/2H, s).

MS (FAB) m/z: 300 (M+N)+.

[Reference example 115]

6-(tert-Butoxycarbonyl)-2-cyano-5,7-dihydropyrrolo is[3,4-d]pyrimidine:

Tetrabutylammonium cyanide (1.04 g) was added to a solution of 6-(tert-butoxycarbonyl)-5,7-dihydro-2-methylsulfonylbenzoyl[3,4-d]pyrimidine (1,05 g) in dichloromethane (30 ml) at room temperature and the mixture was stirred at room temperature for 1 hour. In the reaction mixture was added 1 n sodium hydroxide to separate the organic layer, and the obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:acetone=20:1) to obtain the specified title compound (776 mg) as colorless powder.

1H-NMR (CDCl3) δ: 1.52m (N, C), 4,70-4,85 (4H, m), 8,68-8,77 (1H, m).

MS (FAB) m/z: 247 (M+H)+.

[Referential example 116]

6-(tert-Butoxycarbonyl)-5,7-dihydro-2-methoxycarbonylamino[3,4-d]pyrimidine:

Concentrated hydrochloric acid (5 ml) was added to a solution of 6-(tert-butoxycarbonyl)-2-cyano-5,7-dihydropyrrolo[3,4-d]pyrimidine (776 mg) in methanol (10 ml) at room temperature and the mixture was stirred at 100°C for 1 hour. Allowing the reaction mixture to cool, it was concentrated under reduced pressure and the residue was dissolved in methanol (10 ml). To the solution at room temperature was added triethylamine (2.20 ml) and di-Tr is t-BUTYLCARBAMATE (1,37 g) and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue were added dichloromethane and a saturated salt solution to separate the organic layer, and the obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=3:97) to obtain the specified title compound (317 mg) as colorless powder.

1H-NMR (CDCl3) δ: 1,53 (N, s), 4.09 to (3H, s), 4.75 V-4,85 (4H, m), 8,81 (1/2H, s), cent to 8.85 (1/2H, s).

MS (FAB) m/z: 280 (M+N)+.

[Reference example 117]

1-Isopropylpiperazine-4-carboxylate lithium:

Ethyl 1-isopropylpiperazine-4-carboxylate (Farmaco., 1993, Vol.48, R) (3,43 g) was dissolved in tetrahydrofuran (60 ml) and water (15 ml)was added at room temperature, lithium hydroxide (421 mg) and the mixture was stirred over night. The reaction mixture was concentrated under reduced pressure to obtain specified in the connection header (3,05 g) as a white solid.

1H-NMR (DMSO-d6) δ: 1,05 (6N, d, J=6.6 Hz), 1,65-of 1.78 (2H, m), 1,83-of 1.94 (2H, m)2,07 (1H, TT, J=11,4, 3,9 Hz), measuring 2.20 (2H, dt, J=2.7, and an 11.6 Hz), 2,60-of 2.72 (1H, m), 2,84-2,95 (2H, m).

[Reference example 118]

p-Nitrophenyl 5-Clorinda-2-carboxylate:

After suspension of 5-Clorinda-2-carboxylic key is lots (20 g) in dichloromethane (1500 ml) and add N,N-dimethylformamide (2 ml) was added dropwise at room temperature thionyl chloride (11 ml). The reaction mixture is boiled under reflux overnight and then concentrated under reduced. pressure. The residue was dissolved in dichloromethane (1000 ml), the solution was added triethylamine (84,7 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and to the residue was added ethyl acetate and 0.2 N. hydrochloric acid, to separate the organic layer. The organic layer was sequentially washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent is obtaining specified in the connection header (29,9 g) as a pale brown solid.

1H-NMR (CDCl3) δ: to 7.35 (1H, DD, J=9,0, 1.7 Hz), 7,39-7,42 (2H, m), 7,45 (2H, DD, J=7,3, 1.7 Hz), 7,73 (1H, d, J=1.0 Hz), 8,35 (2H, DD, J=7,3, 1.7 Hz), which is 9.09 (1H, sh).

MS (FD) m/z: 316 (M)+.

[Referential example 119]

6-Chloro-4-hydroxynaphthalene-2-carboxylic acid:

6-Chloro-4-hydroxy-2-methoxycarbonylmethyl (J. Chem. Research (S), 1995, R) (473 mg) was dissolved in ethanol (10 ml), to the solution was added 1 N. aqueous solution (4.0 ml) of sodium hydroxide and the mixture was stirred at room temperature for 24 hours. Then the reaction mixture was stirred 1 hour at 60°and 6 hours at 0° With and drove away under reduced pressure the solvent. Added 1 N. aqueous solution of hydrochloric acid and ethyl acetate to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate and drove away under reduced pressure, the solvent is obtaining specified in the title compound (442 mg) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: the 7.43 (1H, d, J=1.2 Hz), 7,58 (1H, DD, J=8,8, 2.2 Hz), 8.07-a of 8.09 (2H, m), 8,13 (1H, d, J=2.2 Hz), 10,69 (1H, s), 12,99 (1H, sh).

MS (ESI) m/z: 223 (M+H)+.

[Reference example 120]

The allocation of optically active substances (±)-TRANS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene:

(±)-TRANS-N-[(5-Methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadien (1,83 g) was dissolved in 2-propanol (15 ml) and the solution was purified by HPLC. For carrying out elution with a volumetric flow of 6 ml/min using as solvent a mixture of hexane:2-propanol:diethylamine=75:25:0.5 to used column CHIRALPAK AD. Faction, erwerbende through 32 minutes and 45 minutes, was collected separately to obtain (1S,2S)-form (675 mg) as an orange oil and (1R,2R)-form (673 mg) as a brown oil.

[Reference example 121]

1,2-Epoxy-4-methoxycarbonylamino:

3-Cycle is PENTACARBONYL acid (J. Org. Chem., 1984, Vol.49, R) (2,42 g) was dissolved in methanol (8 ml) and 2,2-dimethoxypropane, was added dropwise trimethylsilane (253 μl) and the mixture was stirred at room temperature for 6.5 hours. Drove away under reduced pressure, the solvent, the residue was dissolved in dichloromethane (50 ml) and to the solution was added m-chlorbenzoyl acid (70%, is 4.93 g) under cooling with ice. After heating the mixture to room temperature and stirring for 5 hours was added saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain specified in the connection header (1,59 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,86-of 1.92 (2H, m), 2,32-of 2.38 (2H, m), 2,61-2,70 (1H, m), 3,53 (2H, s), 3,68 (3H, s).

[Reference example 122]

(1R*That 2R*)-1,2-Dihydroxy-4-methoxycarbonylamino:

1,2-Epoxy-4-methoxycarbonylamino (37,7 g) was dissolved in a mixed solvent consisting of tetrahydrofuran (500 ml) and water (500 ml), to the solution was added dropwise while cooling with ice sulfuric acid (1.3 ml) and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added sodium carbonate and sodium bicarbonate to make the mixture neutral or slightly alkaline, and drove away under reduced pressure the solvent. The residue was extracted with dichloromethane and ethyl acetate were removed by filtration of the insoluble matter and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (35.5 g) as a pale yellow oil.

1H-NMR (CDCl3) δ: 1,81-of 1.93 (2H, m), 2,20-is 2.37 (2H, m), 2,84 (1H, sh), 2,99-of 3.07 (1H, m), 3,70 (3H, s), 3,97-4,01 (1H, s), 4,08-of 4.12 (1H, m), 4,56 (1H, sh).

[Reference example 123]

(1R*That 2R*)-1,2-Bis(methanesulfonate)-4-methoxycarbonylamino:

(1R*That 2R*)-1,2-Dihydroxy-4-methoxycarbonylamino (700 mg) was dissolved in dichloromethane (10 ml) and to the solution was added triethylamine (3,63 ml). After purging with argon, the mixture was cooled to -78°and added thereto dropwise methanesulfonanilide (1,01 ml). After heating the mixture to 0°and With stirring for 2 hours, adding water to separate liquids. The organic layer was separated and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column flash chromatography on silica gel (ethyl acetate:hexane=1:1) to obtain specified in the header connect the FL (521 mg) as a pale yellow oil.

1H-NMR (CDCl3) δ: 2,21-to 2.29 (2H, m), 2,42-2,63 (2H, m), 3,02-3,14 (7H, m), and 3.72 (3H, s), 5,07-4,11 (1H, m), 5,13-5,17 (1H, m).

MS (FAB) m/z: 317 (M+N)+.

[Reference example 124]

(1R*That 2R*)-1,2-Diazido-4-methoxycarbonylamino:

(1R*That 2R*)-1,2-Bis(methanesulfonate)-4-methoxycarbonylamino cases (27.3 g) was dissolved in N,N-dimethylformamide (200 ml), to the solution was added sodium azide (33,7 g) and the mixture was stirred at 75°C for 16 hours. Allowing the reaction mixture to cool, add water and the reaction mixture was extracted with ether. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain specified in the connection header (11,53 g) as a pale yellow oil.

1H-NMR (CDCl3) δ: 1,92-2,02 (2H, m), 2,34 is 2.43 (2H, m), 2,96 totaling 3.04 (1H, m), and 3.72 (3H, s), 3.75 to of 3.80 (1H, m), 3,85-are 3.90 (1H, m).

[Referential example 125]

(1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-methoxycarbonyl-1,2-cyclopentanedione (mixture of stereoisomers):

TRANS-1,2-Diazido-4-methoxycarbonylamino (10.6 g) was dissolved is in tetrahydrofuran (200 ml), was added 10% palladium on carbon (3 g) and the mixture was stirred at room temperature for 13 hours in an atmosphere of hydrogen. The catalyst was removed by filtration and drove away under reduced pressure the solvent. To the residue was added dropwise under ice cooling a solution of p-nitrophenyl 5-Clorinda-2-carboxylate (13,6 g) in N,N-dimethylformamide (100 ml). The mixture was stirred 2 hours at 0°and then 11 hours at room temperature. Was added to the reaction mixture, a saturated aqueous solution of sodium bicarbonate to conduct extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=19:1→9:1) to obtain specified in the connection header (4,22 g) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,51-of 1.81 (2H, m), 2.05 is-of 2.34 (2H, m), 2,93 totaling 3.04 (1H, m), 3,15-up 3.22 (1H, m), 3,62, 3,63 (3H, each s), a 3.87-of 3.94 (1H, m), 7,15-7,19 (2H, m), the 7.43 (1H, d, J=8,8 Hz), of 7.70 (1H, d, J=2.0 Hz), of 8.37-8,42 (1H, m), 11,74 (1H, sh).

MS (FAB) m/z: 336 (M+H)+.

[Reference example 126]

(1R*That 2R*)-1,2-Dihydroxy-4-methoxycinnamate:

60% sodium Hydride (800 mg) was added in portions to a solution of 3-CEC is apentin-1-ol (1.68 g) and under the conditions (1.25 ml) in tetrahydrofuran (20 ml) under ice cooling and the mixture was stirred over night at room temperature. In the reaction mixture were added water and diethyl ether to separate the organic layer, the organic layer was dried over anhydrous magnesium sulfate and drove away under reduced pressure, the solvent, after receiving cooling with ice crude 4-methoxy-1-cyclopenten.

To the obtained 4-methoxy-1-cyclopentene added 88% formic acid (90 ml) and 30% hydrogen peroxide (3,17 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and to the residue was added 35% aqueous sodium hydroxide solution for alkalizing the reaction mixture, after which it was stirred at 50°C for 10 minutes. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=5:95) to obtain specified in the connection header (1,21 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,65-of 1.85 (2H, m), 2,15-of 2.30 (2H, m), or 3.28 (3H, s), 3,90-4,00 (2H, m), 4.26 deaths (1H, sh).

[Reference example 127]

(1R*That 2R*)-1,2-Diazido-4-methoxycinnamate:

(1R*That 2R*)-1,2-Dihydroxy-4-methoxycinnamate (1,21 g) and triethylamine (7,66 ml was dissolved in dichloromethane (20 ml) and to the solution was added dropwise over 20 minutes at -78° With methanesulfonanilide (2,13 ml). Upon completion of the drop addition, the mixture was heated to 0°and was stirred for 80 minutes to obtain crude (1R*That 2R*)-1,2-bis(methanesulfonate)-4-methoxycyclohexanone. The obtained product was dissolved in N,N-dimethylformamide (20 ml) was added sodium azide (3.57 g). The mixture was stirred at 65°C for 22 hours. Added sodium azide (3.57 g) and the mixture was stirred at 70°C for 2 days. The reaction mixture was allowed to cool and added to her water and diethyl ether to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate. Drove the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the specified title compound (584 mg) as colorless liquid.

1H-NMR (CDCl3) δ: of 1.65 and 1.80 (2H, m), 2.05 is-to 2.18 (1H, m), 2,25-to 2.40 (1H, m), 3,21 (3H, s), 3,55-the 3.65 (1H, m), 3.75 to 3,90 (2H, m).

[Reference example 128]

Hydrochloride (1R*That 2R*)-4-methoxythiophene-1,2-diamine:

(1R*That 2R*)-1,2-Diazido-4-methoxycinnamate (584 mg) was dissolved in ethanol, was added 10% palladium on carbon (321 mg) and carried out the hydrogenation at normal temperature and normal pressure for 2 days. After removal of catalyst by filtration of reaction the second mixture was concentrated and to the residue was added 1 N. ethanolic hydrochloric acid solution and ethyl acetate. The mixture was concentrated to obtain specified in the title compound (488 mg).

1H-NMR (CDCl3) δ: 1,72 of-1.83 (1H, m), 1.91 a-2,03 (1H, m), 2,07-to 2.18 (1H, m), 2,37-of 2.50 (1H, m), 3,19 (3H, s), 3,55 of 3.75 (2H, sh), 3,85-of 3.95 (1H, m), 8,60-8,90 (6N, W.).

MS (ESI) m/z: 261 (2M+N)+.

[Reference example 129]

TRANS-4-Benzyloxy-1,2-dihydrocyclopenta:

Specified in the title compound was obtained by benzylalkonium 3-cyclopenten-1-ol by benzylbromide and then processing the product of formic acid and hydrogen peroxide in a manner similar to the method of reference example 126.

1H-NMR (CDCl3) δ: of 1.62 (1H, sh), a 1.75-of 1.95 (2H, m), of 2.21 (1H, dt, J=14.2 and 5,9 Hz), 2,33 (1H, DD, J=14,7 and 6.9 Hz), to 2.57 (1H, sh), of 3.96 (1H, s), 4,15 (1H, s), 4,30 (1H, s), 4,48 (2H, s), 7,20-7,40 (5H, m).

[Reference example 130]

TRANS-4-Benzyloxy-1,2-diazodinitrophenol:

Specified in the title compound was obtained from TRANS-4-benzyloxy-1,2-dihydrocyclopenta a manner similar to the method of reference example 127.

1H-NMR (CDCl3) δ: 1,75-1,90 (2H, m), 2,15-of 2.30 (1H, m), 2,35-of 2.50 (1H, m)to 3.67 (1H, DD, J=14,9 and 6.8 Hz), of 3.96 (1H, DD, J=of 15.2 and 6.8 Hz), 4,00-4,10 (1H, m), of 4.44 (1H, DD, J=11.8 Hz), 4,48 (1H, DD, J=11.8 Hz), 7,20-7,40 (5H, m).

[Reference example 131]

TRANS-4-Benzyloxy-1,2-cyclopentanedione:

Glamorized lithium (2.0 g) suspended in tetrahydrofuran (50 ml) and to the suspension was added dropwise over 70 minutes in an argon atmosphere tertrahydrofuran ring solution (30 ml) of TRANS-1,2-diazido-4-benzyloxyacetophenone (6,74 g). After 1 hour the reaction mixture was cooled with ice and was slowly added thereto dropwise water (2 ml), 15% aqueous solution (2 ml) of sodium hydroxide and water (3 ml). After stirring the mixture at room temperature for 2 hours was removed by filtration of the insoluble matter and the filtrate was concentrated to obtain specified in the connection header (lower than the 5.37 g) as a crude pale yellow oil.

1H-NMR (CDCl3) δ: 1,20-1,80 (6N, m)to 2.18 (1H, DD, J=13,9 and 7.1 Hz), 2,41 (1H, dt, J=13.5 and a 7.1 Hz), 2,71 (1H, q, J=7,6 Hz), 3.04 from (1H, q, J=7,6 Hz), 3.95 to of 4.05 (1H, m), of 4.45 (2H, s), 7,20-7,40 (5H, m).

MS (ESI) m/z: 207 (M+N)+.

[Reference example 132]

A mixture of (1R*That 2R*,4R*)-4-benzyloxy-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene and (1R*That 2R*4S*)-4-benzyloxy-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene:

Specified in the title compound was obtained from (±)-TRANS-4-benzyloxy-1,2-cyclopentadiene and 5-Clorinda-2-carboxylic acid in a manner similar to the method of reference example 30.

1H-NMR (CDCl3) δ: 1,60-of 2.20 (4H, m), 3,3-of 3.60 (3H, m), 3,95 is 4.45 (2H, m), 4,43, 4,45 (total 2H, each s), 7,10-to 7.50 (8H, m), 7,68, 7,70 (total 1H, each s), 8,67, 8,69 (total 1H, d, J=8,3 Hz), 11.87 per (1H, sh).

MS (ESI) m/z: 384 (M+H)+.

[Reference example 133]

(1R*That 2R*)-4-Benzoyloxymethyl-1,2-cyclopentanediol:

Specified in the title compound was obtained by benzylalkonium (1R*That 2R*)-4-hydroxymethyl-1-cyclopentene (J. Heterocycl. Chem., 1989, Vol.26, R) benzylbromide and then the interaction of the product with formic acid and hydrogen peroxide in a manner similar to the method of reference example 126.

1H-NMR (CDCl3) δ: 1,44-of 1.52 (1H, m), 1.77 in-of 1.85 (1H, m), 1,89-of 1.97 (1H, m), of 2.25 to 2.35 (1H, m), 2,46-of 2.58 (1H, m), 3,40-3,50 (2H, m)to 3.89 (1H, sh), 4,08 (1H, sh), of 4.54 (2H, s), 7,27-7,39 (5H, m).

MS (FAB) m/z: 223 (M+H)+.

[Reference example 134]

(1R*That 2R*)-4-Benzoyloxymethyl-1,2-cyclopentanedione:

(1R*That 2R*)-4-Benzoyloxymethyl-1,2-diazodinitrophenol was obtained from (1R*That 2R*)-4-benzoyloxymethyl-1,2-cyclopentanediol a manner similar to the method of reference example 127. Specified in the title compound was obtained in a manner similar to the method of reference example 128 without purification of the obtained product.

[Reference example 135]

(1R*That 2R*)-4-Benzoyloxymethyl-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopen Indiamen:

Specified in the title compound was obtained from (1R*,2R*)-4-benzoyloxymethyl-1,2-cyclopentadiene a manner similar to the method of reference example 125.

1H-NMR (DMSO-d6) δ: 1,07-1,15 (0,5H, m), 1,26-1,35 (0,5H, m), 1,47-1.55V (0,5H, m), 1,61-to 1.79 (1H, m), 1,83-1,92 (0,5H, m), 1,99-2,10 (0,5H, m), 2,12-2,20 (0,5H, m), 2,27-to 2.40 (1H, m), of 3.10-3.20 (1H, m), 3.33 and-3,39 (2H, m), 3,81-to 3.92 (1H, m), 4,48 (2H, s), 7,13-7,20 (2H, m), 7,22-7,39 (5H, m), the 7.43 (1H, d, J=8.5 Hz), 7,69 (1H, d, J=2.2 Hz), a 8.34 (1H, t, J=7,1 Hz).

MS (FAB) m/z: 398 (M+H)+.

[Reference example 136]

(±)-TRANS-4,4-Bis(methoxymethyl)-1,2-dihydrocyclopenta:

Specified in the title compound was obtained from 1,1-bis(hydroxymethyl)-3-cyclopentene (J. Med. Chem., 1991, Vol.34, R) in a manner similar to the method of reference example 126.

1H-NMR (CDCl3) δ: of 1.57 (2H, d, J=14,7 Hz)of 2.16 (2H, DD, J=14,7, a 4.9 Hz), 3,23 (4H, s), 3,40 (6N, (C), 3,90-3,98 (1H, m).

MS (FAB) m/z: 191 (M+N)+.

[Reference example 137]

(±)-TRANS-4,4-Bis(methoxymethyl)-1,2-cyclopentadien:

(±)-TRANS-4,4-Bis(methoxymethyl)-1,2-diazodinitrophenol received from (±)-TRANS-4,4-bis(methoxymethyl)-1,2-dihydrocyclopenta a manner similar to the method of reference example 127. Specified in the title compound was obtained in a manner similar to the method of reference example 128 without purification of the obtained product.

1H-NMR (CDCl3/sub> ) δ: 1,19-1,25 (2H, m), 1,89 (2H, DD, J=13,2, 6,GC), 2,70-2,77 (2H, m), 3,20 (4H, s), 3.33 and (6N, C).

MS (FAB) m/z: 189 (M+N)+.

[Reference example 138]

(±)-TRANS-4,4-Bis(methoxymethyl)-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadien:

Specified in the title compound was obtained from (±)-TRANS-4,4-bis(methoxymethyl)-1,2-cyclopentylamine a manner similar to the method of reference example 125.

1H-NMR (CDCl3) δ: of 1.42 (1H, DD, J=14,0, 3.5 Hz), 1,58 (1H, DD, J=14,0, 3.5 Hz), was 2.05 (1H, DD, J=14,0, 6,9 Hz)and 3.31 (1H, DD, J=14,0, 6.9 Hz), 3.25 to 3,55 (11N, m), 4,16-to 4.23 (1H, m), 6,69 (1H, s), 7,19 (1H, DD, J=8,8, 1.7 Hz)that was 7.36 (1H, d, J=8,8 Hz), 7,58 (1H, s), the 7.65 (1H, d, J=7,6 Hz).

MS (FAB) m/z: 366 (M+H)+.

[Referential example 139]

(±)-TRANS-4,4-Bis(benzoyloxymethyl)-1,2-cyclopentanediol:

Specified in the title compound was obtained by benzylalkonium 1,1-bis(hydroxymethyl)-3-cyclopentene (J. Med. Chem., 1991, Vol.34, R) benzylbromide and then processing the product of formic acid and hydrogen peroxide in a manner similar to the method of reference example 126.

1H-NMR (CDCl3) δ: 1,58-of 1.65 (2H, m), of 2.21 (2H, DD, J=14,5, a 4.9 Hz), 3.27 to to 3.34 (4H, m), 3,93 (2H, DD, J=7,5, a 4.9 Hz), 4,55 (4H, s), 7,27-7,39 (10H, m).

MS (FAB) m/z: 343 (M+N)+.

[Reference example 140]

(±)-TRANS-4,4-Bis(benzoyloxymethyl)-1,2-cyclopentadien:

(±)-TRANS-4,4-Bis(benzyloxy the l)-1,2-diazodinitrophenol received from (± )-TRANS-4,4-bis(benzoyloxymethyl)-1,2-cyclopentanediol a manner similar to the method of reference example 127. Specified in the title compound was obtained in a manner similar to the method of reference example 128.

1H-NMR (CDCl3) δ: 1,20 of 1.28 (2H, m), a 1.96 (2H, DD, J=13,2, 6,GC), 2,69-2,78 (2H, m), 3,32 (4H, s), 4,50 (4H, s), 7,27-7,38 (10H, m).

MS (FAB) m/z: 341 (M+N)+.

[Referential example 141]

(±)-TRANS-4,4-Bis(benzoyloxymethyl)-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadien:

Specified in the title compound was obtained from (±)-TRANS-4,4-bis(benzoyloxymethyl)-1,2-cyclopentadiene and 5-Clorinda-2-carboxylic acid in a manner similar to the method of reference example 30.

1H-NMR (DMSO-d6) δ: 1,33-of 1.41 (1H, m), 1,45-and 1.54 (1H, m), 1,86 is 2.00 (2H, m), 3.15 and is 3.23 (1H, m), 3,26-to 3.38 (4H, m), 3,98-4,07 (1H, m), 4,51 (2H, d, J=4, 2 Hz), 7,14 (1H, s), 7,17 (1H, DD, J=8,8, 2.0 Hz), 7,25-7,39 (11H, m), the 7.43 (1H, d, J=8.5 Hz), of 7.70 (1H, d, J=2.0 Hz), to 8.41 (1H, d, J=7.5 Hz).

MS (FAB) m/z: 518 (M+H)+.

[Referential example 142]

5,6-Dimethyl-4,5,6,7-tetrahydropyrazolo[4,5-d]pyridazin-2-carboxylate lithium:

1) After dissolving 4,5-bis(methyl bromide)thiazole (600 mg)synthesized in 1) reference example 109, in ethanol (20 ml) and adding hydrochloride 1,2-dimethylhydrazine (294 mg) under ice cooling was added at once triethylamine (1.23 ml) and the mixture was stirred for 30 minutes at room t is mperature and 30 minutes at 50° C. Drove the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:19) to give 5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,5-d]pyridazine (90 mg) as a colourless oil.

1H-NMR (CDCl3) δ: 2,43 (3H, s), of 2.56 (3H, s)to 3.92 (2H, s)4,06 (2H, sh), 8,68 (1H, s).

MS (FAB) m/z: 170 (M+H)+.

2) is listed in the title compound was obtained from 5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,5-d]pyridazine a manner similar to the method of reference example 5.

1H-NMR (DMSO-d6) δ: of 2.28 (3H, s), 2,39 (3H, s), 3,66 (2H, sh), 3,88 (2H, sh)

[Referential example 143]

5-tert-Butyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-2-carboxylate lithium:

1) 4,5-Bis(methyl bromide)thiazole (1.50 g)synthesized in 1) reference example 109, was dissolved in dioxane (30 ml) and to the solution was added dropwise over 1 hour dioxane solution (10 ml) at room temperature. After stirring at room temperature for 5 hours the reaction mixture was concentrated and to the residue was added dichloromethane and saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:19) to give 5-tert-butyl-4,6-dihydro-5H-PI is Rolo[3,4-d]thiazole (407 mg) as a pale yellow oil.

1H-NMR (CDCl3) δ: 1,19 (N, C), 4,05-4,07 (2H, m), 4,10-to 4.14 (2H, sh), 8,68 (1H, s).

MS (ESI) m/z: 183 (M+H)+.

2) the product Obtained (407 mg) was dissolved in diethyl ether (3 ml), to the solution was added dropwise at -78°With n-utility (1,53 N. hexane solution of 1.60 ml) in an argon atmosphere and the mixture was stirred for 30 minutes under ice cooling. The reaction mixture was again cooled to -78°C. After purging the reaction mixture with carbon dioxide for 20 minutes, it was heated to room temperature. The reaction mixture was concentrated under reduced pressure to obtain specified in the title compound (580 mg) as a crude brown powder.

[Referential example 144]

1-(tert-Butoxycarbonyl)-4-(methoxycarbonylmethyl)piperidine:

n-Utility (1,57 N. hexane solution, 3,11 ml) was added dropwise to a solution of 1-(tert-butoxycarbonyl)-4-(2,2-dibromovinyl)piperidine (WO 98/06720) (900 mg) in tetrahydrofuran (16 ml) at -78°and the mixture was stirred for 1 hour. To the reaction mixture was added methylcarbonate (377 μl) and the mixture was heated for 1 hour to room temperature. Was added to the reaction mixture diethyl ether (30 ml) and saturated aqueous solution (50 ml) of ammonium chloride and separated the organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove under reduced giving the situation the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the specified title compound (634 mg) as a colorless transparent oil.

1H-NMR (CDCl3) δ: 1,45 (N, C), 1,58 is 1.70 (2H, m), 1,78-of 1.88 (2H, m), 2,68 was 2.76 (1H, m), 3,14 is 3.23 (2H, m), 3,67-of 3.77 (2H, m), of 3.77 (3H, s).

MS (ESI) m/z: 268 (M+N)+.

[Reference example 145]

1-(tert-Butoxycarbonyl)-4-hydroxy-4-(methoxycarbonylmethyl)piperidine:

n-Utility (1,57 N. hexane solution of 6.4 ml) was added dropwise to a solution of methylpropionate (893 μl) in tetrahydrofuran (50 ml) at -78°C. After stirring the mixture for 30 minutes was added a solution of 1-(tert-butoxycarbonyl)-4-piperidone (2.0 g) in tetrahydrofuran (10 ml) and the mixture was gradually heated to room temperature and was stirred overnight. Was added to the reaction mixture, a saturated aqueous solution (50 ml) of ammonium chloride and ethyl acetate (50 ml) and separated the organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain specified in the connection header (1/78 g) as a pale yellow caramelising substances.

1H-NMR (CDCl3) δ: 1,46 (N, C), 1,72-to 1.82 (2H, m), 1,90-2,00 (2H, m), 2,39 (1H, sh), 3,30-to 3.38 (2H, m), 3,67-of 3.77 (2H, m), with 3.79 (3H, s).

MS (ESI) m/z: 284 (M+H)+.

[Referential example 146]

1-(tert-Butoxycarbonyl)-4-(methoxycarbonylethyl)-1,2,3,6-tetrahydropyridine:

Pyridine (1,12 ml) and triftormetilfullerenov anhydride (875 ml) was added dropwise to a solution of 1-(tert-butoxycarbonyl)-4-hydroxy-4-(methoxycarbonylmethyl)piperidine (490 mg) in dichloromethane (15 ml) at -78°C. After heating the mixture to room temperature within 1 hour to the reaction mixture were added saturated aqueous solution (50 ml) of sodium bicarbonate and dichloromethane (10 ml) and the separated organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=5:1→2:1) to obtain the specified title compound (249 mg) as a pale yellow oil.

1H-NMR (CDCl3) δ: 1,48 (N, s), 2.26 and is 2.33 (2H, m), 3,51 (2H, t, J=5.6 Hz), with 3.79 (3H, s), 4,00-of 4.05 (2H, m), 6,36 (1H, sh).

[Reference example 147]

CIS-N1N2Bis(tert-butoxycarbonyl)-1,2-cyclohexanediamine:

CIS-1,2-Cyclohexanediamine (4,79 ml) was dissolved in dichloromethane (200 ml), to the solution was added di-tert-BUTYLCARBAMATE (18.3 g) and 1 N. aqueous solution (100 ml) of sodium hydroxide and the mixture was stirred at room temperature for 2 hours. The organic layer was separated, washed with saturated salt solution and then dried over anhydrous sodium sulfate. Drove under reduced pressure the solvent from the floor is the group specified in the connection header (17,2 g) as a white solid.

1H-NMR (CDCl3) δ: 1,40-1,71 (N, m), with 3.79 (2H, sh), 4,84-a 4.86 (2H, m).

MS (ESI) m/z: 315 (M+N)+.

[Reference example 148]

CIS-N1N2Bis(tert-butoxycarbonyl)-N1N2-dimethyl-1,2-cyclohexanediamine:

N,N-dimethylformamide (20 ml) was cooled to 0°and was added 60% sodium hydride (800 mg). To the reaction mixture was added CIS-N1N2bis(tert-butoxycarbonyl)-1,2-cyclohexanediamine (3,14 g) and the mixture was stirred for 30 minutes at the same temperature and then for 4 hours at room temperature. Was added to the reaction mixture, a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with hexane. The obtained extract was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent is obtaining specified in the title compound (2.16 g) as a pale yellow solid.

1H-NMR (CDCl3) δ: 1,43-1,83 (N, m), 2,89 (6N, sh), 4,35 (2H, sh).

MS (ESI) m/z: 343 (M+N)+.

[Reference example 149]

Hydrochloride CIS-N1N2-dimethyl-1,2-cyclohexanediamine:

CIS-N1N2Bis(tert-butoxycarbonyl)-N1N2-dimethyl-1,2-cyclohexanediamine (2.15 g) was dissolved in a saturated ethanol solution of hydrochloric acid and the solution was stirred at room temperature during the course the e 30 minutes. Drove away under reduced pressure, the solvent, to the residue was added ethyl acetate and the solids were filtered off to obtain specified in the title compound (1.19 g) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,40-of 1.41 (2H, m), 1,71-1,92 (6N, m), 2,65 (6N, (C), 3,61 (2H, sh).

MS (ESI) m/z: 143 (M+N)+.

[Reference example 150]

CIS-N1-[(1-Benzazolyl-5-Clorinda-2-yl)carbonyl]-N1N2-dimethyl-1,2-cyclohexanediamine:

1-Benzazolyl-5-Clorinda-2-carboxylic acid (890 mg) was dissolved in chloroform (20 ml), was added thionyl chloride (2 ml) and N, N-dimethylformamide (one drop) and the mixture was stirred at 65°C for 45 minutes. Drove away under reduced pressure, the solvent and to the residue was added dichloromethane (10 ml) and pyridine (10 ml). In the reaction mixture was added a solution of hydrochloride CIS-N1N2-dimethyl-1,2-cyclohexanediamine (855 mg) in a mixed solvent (10 ml), consisting of (1:1) of dichloromethane and pyridine, and the mixture was stirred at room temperature for 3 days. The reaction mixture was heated and stirred at 55°With a further 4 hours, after which was added water, and separated the organic layer. The organic layer was washed with water and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified colonoscopy because it allows the Noah flash chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the specified title compound (738 mg) as a solid ochre.

MS (ESI) m/z: 460 (M+N)+

[Reference example 151]

(1R,2S)-N1-tert-Butoxycarbonyl-1,2-cyclohexanediamine:

Specified in the title compound was synthesized from (1R,2S)-2-amino-1-cyclohexanol (J. Org. Chem., 1985, Vol.50, R) methods similar to the methods of reference examples 44-47.

1H-NMR (CDCl3) δ: 1,00 is 1.70 (8H, m), 1,45 (N, s), 2.95 and was 3.05 (1H, m), 3,60 (1H, sh), 5,00 (1H, sh).

MS (FAB) m/z: 215 (M+H)+.

[Reference example 152]

Hydrochloride, (1S,2R)-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R,2S)-N1(tert-Butoxycarbonyl)-N2[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine was obtained from (1R, 2S)-N1-(tert-butoxycarbonyl)-1,2-cyclohexanediamine a manner similar to the method of reference example 52, after which he rented the protection of saturated ethanolic hydrochloric acid in a manner similar to the method of reference example 54, obtaining specified in the connection header.

1H-NMR (DMSO-d6) δ: 1,30-1,50 (2H, m), 1,55-1,95 (6N, m), to 3.02 (1H, sh), 3,90-of 3.97 (1H, sh), 7,15-7,19 (2H, m), the 7.43 (1H, d,J=8,8 Hz), to 7.68 (1H, d, J=2.0 Hz), of 7.90 (1H, d, J=8,1 Hz).

[Reference example 153]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-4-cyclohexen-1,2-diamine:

Specified in the title compound was obtained from hydrochloride of the CIS-4-cyclohex the ene-1,2-diamine (EP 154788) and 5-Clorinda-2-carboxylic acid method, similar to the method of reference example 30.

1H-NMR (DMSO-d6) δ: of 1.93 (m, 1H), 2.05 is(m, 1H), a 2.36 (m, 2H), 2.91 in (dt, 1H, J=5,6, or 10.3 Hz), 3,82 (m, 1H), ceiling of 5.60 (s, 2H), 7,17 (m, 2H), 7,43 (d, 1H, J=8,8 Hz), 7,69 (d, 1H, J=1.7 Hz), 8,32 (d, 1H, J=8.6 Hz).

[Reference example 154]

Ethyl (1R*,3R*4S*)-3,4-epoxycyclohexane-1-carboxylate:

(1R*,4R*,5R*)-4-Iodine-6-oxabicyclo[3.2.1]Octan-7-he (J. Org. Chem., 1996, Vol.61, p.8687) (14.3 g) was dissolved in ethanol (130 Il), was added 2 N. aqueous solution (34,5 ml) of sodium hydroxide under ice cooling and then the mixture was stirred at room temperature for 7 hours. Drove away under reduced pressure, the solvent and to the residue was added water, then the mixture was extracted with dichloromethane and the extract was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=83:17) to obtain specified in the connection header (6,54 g) as a colourless oil.

1H-NMR (CDCl3) δ: of 1.25 (3H, t, J=7,1 Hz), 1,50-1,70 (2H, m), 1,71-to 1.82 (1H, m), 2,08-of 2.28 (4H, m), and 3.16 (2H, s), of 4.12 (2H, q, J=7,1 Hz).

[Reference example 155]

Ethyl (1R*,3S*4S*)-3-azido-4-hydroxycyclohexane-1-carboxylate:

Ethyl (1R*,3R*4S* )-3,4-epoxycyclohexane-1-carboxylate (13,6 g) was dissolved in N,N-dimethylformamide (100 ml)was sequentially added at room temperature, ammonium chloride (6,45 g) and sodium azide (7.8 g) and the mixture is then stirred at 75°C for 12 hours. The solvent was concentrated to about 1/3, the residue was diluted with water and ethyl acetate and the mixture was stirred for 3 minutes. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain specified in the connection header (15,8 g) as a colourless oil.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=7,1 Hz), 1,37-to 1.67 (2H, m), 1,86-of 1.95 (1H, m), 2,04-to 2.18 (2H, m), 2,32 is 2.43 (1H, m), 2,68-2,78 (1H, m), 3,40-of 3.60 (2H, m)to 4.17 (2H, q, J=7,1 Hz).

[Reference example 156]

Ethyl (1R*,3S*4S*)-3-(tert-butoxycarbonylamino)-4-hydroxycyclohexane-1-carboxylate:

Ethyl (1R*,3S*4S*)-3-azido-4-hydroxycyclohexane-1-carboxylate (100 mg) and di-tert-BUTYLCARBAMATE (133 mg) was dissolved in ethyl acetate (12 ml)was added catalytic amount of 10% palladium on carbon and the mixture was stirred at room temperature for 12 hours in an atmosphere of hydrogen. After AHP crystal growth is mitrofania insoluble substances drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (145 mg) in the form of a colorless solid.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=7,1 Hz), 1,45 (N, C), 1,38-of 1.57 (2H, m), 1,86-of 1.95 (1H, m), 2.05 is-2,17 (1H, m), 2,29-2,39 (2H, m), 2,61 of 2.68 (1H, m), 3.25 to 3,66 (3H, m)to 4.17 (2H, q, J=7,1 Hz), a 4.53 (1H, sh).

[Reference example 157]

Ethyl (1R*,3S*,4R*)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate and ethyl (1R*,3S*4S*)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate:

Ethyl (1R*,3S*,4S*)-3-tert-butoxycarbonylamino-4-hydroxycyclohexane-1-carboxylate (16 g) and triethylamine (38 ml) was dissolved in dichloromethane (150 ml) and the solution was cooled to -78°C, after which was added dropwise at the same temperature methanesulfonanilide (13 ml). After stirring for 15 minutes at the same temperature and the mixture was heated to 0°C and stirred for 30 minutes, and then 2 hours at room temperature. Was added 0.1 G. of hydrochloric acid and the mixture was diluted with dichloromethane, then the organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous magnesium sulfate. Drove under reduced pressure the solvent to obtain crude ethyl (1R*,3S*4S* )-3-(tert-butoxycarbonylamino)-4-methanesulfonylaminoethyl-1-carboxylate.

The obtained product was dissolved in N,N-dimethylformamide (100 ml) was added at room temperature sodium azide (18 g). The mixture was heated to 75°C and stirred for 12 hours. The solvent was concentrated to about 1/3, the residue was diluted with water and ethyl acetate and the mixture was stirred for 3 minutes. The obtained organic layer was separated, washed with saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain specified in the header of the compounds [(1R*,3S*,4R*)-form (6,74 g) and (1R*,3S*4S*)-form (1,32 g)] as colorless solids.

(1R*,3S*,4R*-form:

1H-NMR (CDCl3) δ: of 1.26 (3H, t, J=7,1 Hz), 1,45 (N, C), 1,38-2,33 (6N, m), 2.57 m) of 2.68 (1H, m), of 3.77-4,20 (4H, m), 4,63 (1H, sh).

(1R*,3S*4S*-form:

1H-NMR (CDCl3) δ: of 1.27 (3H, t, J=7,1 Hz), 1,46 (N, C),1,53-2,30 (6N, m), 2,50-to 2.65 (1H, m), 3,42-and 3.72 (2H, m), is 4.15 (2H, q, J=7,1Hz), of 4.67 (1H, sh).

[Reference example 158]

(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-4-etoxycarbonyl-1,2-cyclohexanediamine:

Ethyl (1R*,3S*,4R*)-4-Azi is about-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate (5.4 g) was dissolved in a mixed solvent, consisting of ethanol (10 ml) and ethyl acetate (10 ml)was added catalytic amount of 10% palladium on carbon and the mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere. After removal by filtration of the insoluble substances drove away under reduced pressure, the solvent is obtaining specified in the title compound (4.7 g) as a pale yellow oil.

[Reference example 159]

(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-N1[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine:

(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-4-etoxycarbonyl-1,2-cyclohexanediamine (4,62 g) was dissolved in dichloromethane (50 ml)was added at room temperature 5-Clorinda-2-carboxylic acid (3,63 g), monohydrate, 1-hydroxybenzotriazole (2,43 g) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3,45 g) and the mixture was stirred for 12 hours. After adding 0.1 G. of hydrochloric acid and extracting the mixture with dichloromethane the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column of chromatography her Seeley is agile (ethyl acetate:hexane=2:3) to obtain the specified title compound (5.3 g) as a colourless solid.

1H-NMR (CDCl3) δ: of 1.26 (3H, t, J=7,1 Hz), 1,43 (N, C), 1,35-2,46 (7H, m), 3,91-was 4.02 (1H, m), 4,10-4,22 (2H, m), 4,79 (1H, sh), 6,79 (1H, s), 7.18 in-7,40 (2H, m), to 7.59 (1H, s), 8,00 (1H, sh), 9,13 (1H, sh).

[Reference example 160]

(1R*That 2R*4S*)-N2-tert-Butoxycarbonyl-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine:

1) (1R*That 2R*4S*)-N2-tert-Butoxycarbonyl-4-etoxycarbonyl-1,2-cyclohexanediamine was obtained from ethyl (1R*,3S*4S*)-4-azido(tert-butoxycarbonylamino)cyclohexane-1-carboxylate obtained in reference example 157, in a manner similar to the method of reference example 158.

2) is listed in the title compound was obtained from the product described above, in a manner similar to the method of reference example 159.

1H-NMR (CDCl3) δ: 1,22-1,72 (6N, m), 1,34 (N, C), 2,15-of 2.28 (2H, m), 2,41-2,49 (1H, m), 2,85 (1H, sh), 3,62 of 3.75 (1H, m), 3,78-to 3.92 (1H, m), 4,12-to 4.28 (2H, m), 4,56-4,63 (1H, m), to 6.88 (1H, sh), 7,20 (1H, DD, J=8.8 and 2.0 Hz), 7,33 (1H, d, J=8,8 Hz), 7,52-EUR 7.57 (1H, m), to 7.59 (1H, d, J=2.0 Hz), 9,24 (1H, s).

MS (ESI) m/z: 464 (M+H)+.

[Reference example 161]

Ethyl (1S,3S,4R)-3,4-epoxycyclohexane-1-carboxylate:

(1S,4S,5S)-4-Iodine-6-oxabicyclo[3.2.1]Octan-7-he (J. Org. Chem., 1996, Vol.61, p.8687) (89,3 g) was dissolved in ethanol (810 ml), was added 2 N. aqueous solution (213 ml) of sodium hydroxide and then the mixture was stirred at anatoy temperature for 3 hours. Drove away under reduced pressure, the solvent and to the residue was added water, then the mixture was extracted with dichloromethane and the extract was dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=17:3) to obtain specified in the connection header (41,2 g) as a pale yellow oil.

[α]D-58°(C=1.0, chloroform).

[Reference example 162]

Ethyl (1S,3R,4R)-3-azido-4-hydroxycyclohexane-1-carboxylate:

Ethyl (1S,3S,4R)-3,4-epoxycyclohexane-1-carboxylate (41 g) was dissolved in N,N-dimethylformamide (300 ml)was sequentially added at room temperature, ammonium chloride (19.3 g) and sodium azide (23,5 g) and the mixture is then stirred at 75°C for 13 hours. The reaction mixture was filtered, the filtrate was concentrated by distillation 400 ml of solvent, the product on the filter is formed residue was added water to dissolve the collected product. The solution was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent is obtaining specified in the connection header (51,5 g) in the form of oil.

[α]D+8°(C=1.0, chloroform)

[Reference example 163]

Ethyl (1S,3R,4R)-3-(tert-butoxycarbonyl is ylamino)-4-hydroxycyclohexane-1-carboxylate:

Ethyl (1S,3R,4R)-3-azido-4-hydroxycyclohexane-1-carboxylate (51,2 g) and di-tert-BUTYLCARBAMATE (68,1 g) was dissolved in ethyl acetate (1000 ml), was added 5% palladium on carbon and the mixture was stirred at room temperature for 16 hours under hydrogen pressure of 5 kg/cm2. After filtering off insoluble substances drove away under reduced pressure, the solvent, the residue was purified column chromatography on silica gel (hexane:ethyl acetate=4:1) and for his cure were added hexane to obtain specified in the connection header (53,6 g) as colorless crystals.

[α]D+25°(C=1.0, chloroform).

[Reference example 164]

Ethyl (1S,3R,4S)-4-azido-3-(tert-

butoxycarbonylamino)cyclohexane-1-carboxylate and ethyl (1S,3R,4R)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate:

Ethyl (1S,3R,4R)-3-tert-butoxycarbonylamino-4-

hydroxycyclohexane-1-carboxylate (53,5 g) and triethylamine (130 ml) was dissolved in dichloromethane (500 ml) and was added dropwise methanesulfonanilide (42 ml), cooling the solution to a temperature in the range from -10°-15°C. After stirring for 20 minutes at the same temperature, the mixture was heated to room temperature over 30 minutes and stirred for another 2 hours.

The reaction mixture was cooled to 0°C, was added dropwise to 0.5 N. hydrochloric acid (800 ml) and the mixture was extracted with the dichloromethane. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous magnesium sulfate. Drove under reduced pressure the solvent to obtain crude ethyl (1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-(methanesulfonate)cyclohexane-1-carboxylate.

The crude (1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-(methanesulfonate)cyclohexane-1-carboxylate was dissolved in N,N-dimethylformamide (335 ml)was added sodium azide (60,5 g) and the mixture was stirred at 68-73°C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated by distillation of 250 ml of the solvent, the product on the filter was formed by the remainder of the collected product was dissolved in water and was extracted with ethyl acetate. The obtained organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain specified in the header of the compounds [(1S,3R,4S)-form (18,4 g) and (1S,3R,4R)-form (3.3 grams)] as colorless solids.

(1S,3R,4S) - form: [α]D+62° (C=1.0, chloroform)

(1S,3R,4R) - form: [α]D-19° (C=1.0, chloroform)

[Reference example 165]

(1S,2R,4S)-N2-tert-Butoxycarbonyl-4-etoxycarbonyl-1,2-cyclo is essentialin:

Ethyl (1S,3R,4S)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate (4.0 g) was dissolved in a mixed solvent consisting of ethanol (150 ml) and ethyl acetate (150 ml), was added 5% palladium on carbon and the mixture was stirred at room temperature for 17 hours in an atmosphere of hydrogen. After removal by filtration of the insoluble substances drove away under reduced pressure, the solvent is obtaining specified in the connection header (4,2 g) as a pale yellow oil.

[Reference example 166]

(1S,2R,4S)-N2-tert-Butoxycarbonyl-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine:

(1S,3R,4S)-N2-tert-Butoxycarbonyl-4-etoxycarbonyl-l,2-cyclohexanediamine of 4.2 g) was dissolved in dichloromethane (50 ml)was added at room temperature 5˜chlorinda-2-carboxylic acid (3.33 g), monohydrate, 1-hydroxybenzotriazole (2,52 g) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3,15 g) and the mixture was stirred for 12 hours. After adding to the reaction mixture of 0.1 G. of hydrochloric acid and extracting the mixture with dichloromethane the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column of chromatographie the on silica gel (ethyl acetate:hexane=1:1) to obtain specified in the connection header (4,36 g) as a colourless solid.

[α]D-27°(C=1.0, chloroform)

[Reference example 167]

(1S,2R,4S)-N2-tert-Butoxycarbonyl-4-etoxycarbonyl-N1-[(5-Florinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

Ethyl (1S,3R,4R)-4-azido-3-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (500 mg) was dissolved in methanol (10 ml), was added 10% palladium on carbon (50 mg) and the mixture was stirred in hydrogen atmosphere. After 3 hours the reaction was stopped, the catalyst was removed by filtration and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 ml) and N,N-dimethylformamide (10 ml), was added 5-Florinda-2-carboxylic acid (345 mg), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (460 mg), monohydrate, 1-hydroxybenzotriazole (325 mg) and N-methylmorpholin (485 mg) and the mixture was stirred at room temperature for 15 hours. Drove away under reduced pressure, the solvent was added dichloromethane and the resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:50) to obtain the specified title compound (740 mg) as a pale yellow amorphous substance.

1H-NMR (CDCl3) δ : of 1.26 (3H, t, J=7,1 Hz), 1,52 (N, C), 1,67-2,41 (7H, m), of 3.97 (1H, sh), is 4.15 (2H, q, J=7,1 Hz), 4,08-4,22 (1H, m), 6,83 (1H, s), 7,00-7,05 (1H, m), to 7.32 and 7.36 (1H, m), 8,02 (1H, s), of 9.51 (1H, s).

MS (FAB) m/z: 448 (M+H)+.

[Referential example 168]

(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-4-etoxycarbonyl-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R*,2S*,4R*)-N2-tert-butoxycarbonyl-4-etoxycarbonyl-1,2-cyclohexanediamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of reference example 48.

[Reference example 169]

Benzyl (±)-3-cyclohexen-1-caboxylate:

(±)-3-Cyclohexen-1-carboxylic acid (50 g) was dissolved in N,N-dimethylformamide (550 ml)was added under cooling with ice, triethylamine (170 ml) and benzylbromide (61 ml) and the mixture was stirred at room temperature for 12 hours. Added water, the mixture was extracted with ethyl acetate and the resulting organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the MC is connected in the connection header (70,8 g) as a reddish brown oil.

1H-NMR (CDCl3) δ: from 1.66 to 1.76 (1H, m), 2.00 in to 2.13 (3H, m), 2,27-to 2.29 (2H, m), 2,58-to 2.65 (1H, m)to 5.13 (2H, s), to 5.66 (2H, sh), 7,29-7,38 (5H, m).

[Reference example 170]

Benzyl (1R*,33*,4R*)-3,4-epoxycyclohexane-1-carboxylate:

Benzyl (±)-3-cyclohexen-1-carboxylate (40 g) was dissolved in dichloromethane (500 ml)was added under ice cooling m-chloroperbenzoic acid (86 g) and the mixture was stirred for 2 hours. After adding 10% aqueous sodium thiosulfate solution and stirring for 20 minutes the organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:9) to obtain specified in the connection header (23,4 g) and benzyl (1R*,3R*4S*)-3,4-epoxycyclohexane-1-carboxylate (12.1 g) as colourless oils.

1H-NMR (CDCl3) δ: 1,39-1,49 (1H, m), a 1.75-to 1.82 (1H, m), 1,90-2,04 (3H, m), 2,30 (1H, DD, J=14,9, a 4.9 Hz), 2,54-2,61 (1H, m), 3,12-3,14 (1H, m), 3,22-3,24 (1H, m), 5,12 (2H, s), 7,30-7,39 (5H, m).

MS (FAB) m/z: 233 (M+H)+.

[Reference example 171]

Benzyl (1R*,3S*4S*)-4-azido-3-hydroxycyclohexane-1-carboxylate:

Benzyl (1R*,3S*,4R*)-3,4-epoxycyclohexane-1-carboxylate (52,3 g) was dissolved in N,N-dimethylformamide (1000 ml)was added ammonium chloride (21,9 g) and sodium azide (18,1 g) and the mixture was heated to 70°C and stirred for 24 hours. Drove away under reduced pressure, the solvent was added water and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent is obtaining specified in the connection header (61,8 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,51-of 1.66 (2H, m), 1.91 a-to 1.98 (1H, m), 2,07-2,10 (1H, m), 2,27 of-2.32 (1H, m), of 2.51-2,52 (1H, m), 2,81-of 2.86 (1H, m), 3,30-to 3.36 (1H, m), 3,70 of 3.75 (1H, m)to 5.13 (2H, s), 7,30-7,39 (5H, m).

[Referential example 172]

Benzyl (1R*,3S*4S*)-4-(N-tert-butoxycarbonyl)amino-3-hydroxycyclohexane-1-carboxylate:

Benzyl (1R*,3S*4S*)-4-azido-3-hydroxycyclohexane-1-carboxylate (5,27 g) was dissolved in tetrahydrofuran (25 ml), was added triphenylphosphine (5.53 g) and water (0,55 ml) and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added di-tert-BUTYLCARBAMATE (4,82 g), continuing to stir for another 2 hours. Drove away under reduced pressure, the solvent and the balance of cleansing and column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain specified in the connection header (6,22 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,44 (N, C), 1,59-of 1.66 (2H, m), 1,88 is 2.00 (2H, m), 2,29 of-2.32 (1H, m), 2,80-to 2.85 (1H, m), to 3.02 (1H, sh), 3,42 (1H, sh), 3,59-the 3.65 (1H, m), 4,56 (1H, sh), 5,12 (2H, q, J=12,5 Hz), 7,30-7,38 (5H, m).

MS (FAB) m/z: 350 (M+H)+.

[Reference example 173]

Methyl (1R*,3S*4S*)-4-N-(tert-butoxycarbonylamino)-3-hydroxycyclohexane-1-carboxylate:

Benzyl (1R*,3S*4S*)-4-N-(tert-butoxycarbonylamino)-3-hydroxycyclohexane-1-carboxylate (2,54 g) was dissolved in ethyl acetate (15 ml) and to the solution was added a catalytic amount of 10% palladium on charcoal. The mixture was stirred in a stream of hydrogen at room temperature for 20 hours. The catalyst was filtered and the filtrate was concentrated under reduced pressure to obtain (1R*,3S*4S*)-4-N-(tert-butoxycarbonylamino)-3-hydroxycyclohexane-1-carboxylic acid as colorless oil. The oil was dissolved in a mixture of methanol (8 ml) and toluene (15 ml), to the solution was added a 2 n solution trimethylsilyldiazomethane (10 ml) and the resulting mixture was stirred for 30 minutes at room temperature. After removal under reduced pressure of the solvent, the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain specified in the connection header (1,82 g) in VI is e a colorless oil.

1H-NMR (CDCl3) δ: 1,44 (N, C), 1,36-2,32 (7H, m), 2,74-2,82 (1H, m), 3.04 from (1H, sh), 3,33-3,47 (1H, m), 3,55-the 3.65 (1H, m), 3,68 (3H, s), 4,56 (1H, sh).

MS (FAB) m/z: 274 (M+H)+.

[Reference example 174]

Methyl (1R*,3R*4S*)-3-azido-4-N-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate and methyl (1R*,3R*,4R*)-3-azido-4-N-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate:

Methyl (1R*,3S*4S*)-4-(N-tert-butoxycarbonylamino)-3-hydroxycyclohexane-1-carboxylate (1,81 g) was dissolved in dichloromethane (36 ml) was added at -78°With triethylamine (4.6 ml) and methanesulfonamide (1,63 ml). After 30 minutes the mixture was heated to 0°and was stirred for 30 minutes. Added 1 N. hydrochloric acid, the mixture was extracted with dichloromethane and the resulting organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Drove under reduced pressure the solvent to obtain crude methyl (1R*,3S*4S*)-4-N-tert-butoxycarbonylamino-3-methanesulfonylaminoethyl-1-carboxylate.

The crude methyl (1R*,3S*4S*)-4-N-Tert-butoxycarbonylamino-3-methanesulfonylaminoethyl-1-carboxylate was dissolved in N,N (23 ml), was added sodium azide (1.29 g) and the mixture was heated to 70°C and stirred for 12 hours. In the reaction mixture was added ice water, extracted with ethyl acetate and the resulting organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column flash chromatography on silica gel (ethyl acetate:hexane=3:17) to obtain methyl (1R*,3R*,4R*)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (85 mg) and methyl (1R*,3R*4S*)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (590 mg) as colorless oils.

(1R*,3R*4S*-form:1H-NMR (CDCl3) δ: 1,45 (N, C)of 1.35 to 2.35 (7H, m), 2,45 is 2.55 (1H, m), of 3.73 (3H, s), 3,67-a-3.84 (2H, m), 4,70 (1H, sh).

MS (FAB) m/z: 299 (M+H)+.

(1R*,3R*,4R*-form:1H-NMR (CDCl3) δ: 1,45 (N, s), 1.56 to to 2.25 (7H, m), 2,68 is 2.80 (1H, m), 3,70 (3H, s), 3,48-3,68 (2H, m), 4,56 (1H, sh).

MS (FAB) m/z: 299 (M+H)+.

[Reference example 175]

(1R*,2S*4S*)-N1-tert-Butoxycarbonyl-4-methoxycarbonyl-1,2-cyclohexanediamine:

Methyl (1R*,3R*4S*)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (230 mg) rest rely in ethyl acetate (8 ml), added catalytic amount of 10% palladium on carbon and the mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere. Was removed by filtration of the insoluble matter and the filtrate was concentrated under reduced pressure to obtain specified in the title compound (220 mg) as a pale yellow oil.

[Reference example 176]

(1R*,2S*4S*)-N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R*,2S*4S*)-N1-tert-butoxycarbonyl-4-methoxycarbonyl-1,2-cyclohexanediamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate in a manner similar to the method of reference example 48.

1H-NMR (CDCl3) δ: 1,46 (N, C), 1,53-of 1.95 (5H, m), 2,17-of 2.24 (1H, m)of 2.50 (3H, s), 2,50 of $ 2.53 (1H, m), 2,80-2,96 (4H, m)to 3.67 (3H, s), 3,69-3,74 (1H, m), 4,10 (2H, sh), 4,88 (1H, sh).

MS (FAB) m/z: 453 (M+H)+.

[Reference example 177]

(1R*,2S*4S*)-N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R*,2S*4S*)-N1 -tert-butoxycarbonyl-4-methoxycarbonyl-1,2-cyclohexanediamine and 5-Clorinda-2-carboxylic acid in a manner similar to the method of reference example 159.

1H-NMR (CDCl3) δ: 1,33 (N, C), 1,42-2,47 (6N, m), 2,78-is 2.88 (1H, m), 3,70 (3H, s), 3,86-to 4.15 (2H, m), 4,65-of 4.75 (1H, m)6,86 (1H, sh), 7,18-7,38 (2H, m), EUR 7.57-to 7.61 (1H, m), 8,32 (1H, sh).

MS (ESI) m/z: 450 (M+N)+.

[Reference example 178]

Benzyl (1R,3S,4R)-3,4-epoxycyclohexane-1-carboxylate:

1) Benzyl (1R)-3-cyclohexen-1-carboxylate was obtained from (1R)-3-cyclohexen-1-carboxylic acid (J. Am. Chem. Soc., 1978, Vol.100, R) in a manner similar to the method of reference example 169.

2) is listed in the title compound was obtained from the above of the product in a manner similar to the method of reference example 170.

MS (FAB) m/z: 233 (M+H)+.

[Referential example 179]

Benzyl (1R,3S,4S)-4-(N-tert-butoxycarbonylamino)-3-hydroxycyclohexane-1-carboxylate:

1) Benzyl (1R,3S,4S)-4-azido-3-hydroxycyclohexane-1-carboxylate was obtained from benzyl (1R,3S,4R)-3,4-epoxycyclohexane-1-carboxylate in a manner similar to the method of reference example 171.

2) is listed in the title compound was obtained from the above of the product in a manner similar to the method of reference example 172.

MS (FAB) m/z: 350 (M+H)+.

[Reference example 180]

Benzyl (1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate:

Specified in the title is information compound was obtained from benzyl (1R,3S,4S)-4-(N-tert-butoxycarbonylamino)-3-hydroxycyclohexane-1-carboxylate way similar to the method of reference example 174.

1H-NMR (CDCl3) δ: 1,45 (N, C), 1,52-of 1.66 (2H, m), 1,83 is 2.01 (3H, m), 2,20-of 2.28 (1H, m), of 2.51-of 2.54 (1H, m), of 3.77 (2H, sh), 4,70 (1H, sh), of 5.15 (2H, Avkw, J=and 12.2 Hz), 7,33-7,38 (5H, m).

MS (FAB) m/z: 375 (M+N)+.

[Reference example 181]

Methyl (1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate:

Benzyl (1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (3.5 g) was dissolved in tetrahydrofuran (130 ml) and to the solution was added under cooling with ice water (16 ml) and lithium hydroxide (291 mg). After 10 minutes the mixture was heated to room temperature while continuing the stirring. After 20 minutes the reaction was stopped, drove away under reduced pressure, the solvent and the obtained residue was subjected to column chromatography on silica gel (methanol:dichloromethane=1:20) to obtain (1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylic acid (3,34 g) as a pale yellow oil. The obtained product was dissolved in methanol (18 ml) and toluene (64 ml)was added under ice cooling trimethylsilyldiazomethane (2 M solution of 6.1 ml) and the mixture was heated to room temperature and stirred. After 2 hours the reaction was stopped, drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the decree is spent in the connection header (at 3.35 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,45 (N, C), 1,57-to 1.63 (2H, m), 1,82-of 1.85 (1H, m), 1,95 of 1.99 (2H, m), 2,20-of 2.28 (1H, m), 2,48 is 2.51 (1H, m), of 3.73 (3H, s), of 3.78 (2H, sh), 4,70-4,72 (1H, m).

MS (FAB) m/z: 299 (M+H)+.

[Reference example 182]

(1S,2R,4R)-N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

1) (1S,2R,4R)-N1-tert-Butoxycarbonyl-4-methoxycarbonyl-1,2-cyclohexanediamine was obtained from methyl (1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate in a manner similar to the method of reference example 175.

2) is listed in the title compound was obtained from the above-described product and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]-pyridine-2-carboxylate lithium in a manner similar to the method of reference example 176.

MS (FAB) m/z: 453 (M+H)+.

[Reference example 183]

A mixture of dimethyl (1R*,2S*4S*,5R*)-4,5-dihydroxy-1,2-cyclohexanedicarboxylate and dimethyl (1R*,2S*,4R*,5S*)-4,5-dihydroxy-1,2-cyclohexanedicarboxylate:

Dimethyl (±)-CIS-4-cyclohexene-1,2, in primary forms (20 g) was dissolved in a mixed solvent consisting of water (30 ml) and acetonitrile (90 ml), was added N-oxide N-methylmorpholine (18 g) and microencapsulated osmium (1.0 g) and the mixture was stirred at room tempera what ur in for 17 hours. After heating the reaction mixture to 40°and With stirring for 5 hours was added N-oxide N-methylmorpholine (11 g) and the mixture was stirred at 40°C for 41 hours. Microencapsulated osmium was filtered and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=1:4), and provided the parent compound (5 g), to deliver specified in the title compound (6.2 g) as a colourless oil.

1H-NMR (CDCl3) δ: of 2.09 and 2.13 (4H, sh), of 3.13 (2H, sh), 3,68 (6N, (C), 3,90 (2H, sh).

MS (FAB) m/z: 233 (M+N)+.

[Reference example 184]

Dimethyl (1R*,2S*,4R*,5S*or 1R*,2S*4S*,5R*)-4,5-diazido-1,2-cyclohexanedicarboxylate:

Specified in the title compound was obtained as a main product from a mixture of dimethyl (1R*,2S*4S*,5R*)-4,5-dihydroxy-1,2-cyclohexanedicarboxylate and dimethyl (1R*,2S*,4R*,5S*)-4,5-dihydroxy-1,2-cyclohexanedicarboxylate a manner similar to the method of reference example 127.

1H-NMR (CDCl3) δ: 1,81-3,13 (6N, m), 3,64-3,71 (2H, m), of 3.73 (6N, C).

[Reference example 185]

Dimethyl (1R*,2S*,4R*,5S* or (1R*,2S*4S*,5R*)-4,5-bis(tert-butoxycarbonylamino)-1,2-cyclohexanedicarboxylic:

Dimethyl (1R*,2S*,4R*,5S*or 1R*,2S*4S*,5R*)-4,5-diazido-1,2-cyclohexanedicarboxylate (900 mg) was dissolved in tetrahydrofuran (100 ml)was added di-tert-BUTYLCARBAMATE (3 g) and 10% palladium on carbon (180 mg) and the mixture was stirred for 22 hours in an atmosphere of hydrogen. After removal by filtration of the catalyst the filtrate was added di-tert-BUTYLCARBAMATE (1.5 g) and the reaction was performed for 5 hours in an atmosphere of hydrogen. Was removed by filtering the catalyst, the filtrate was concentrated and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=1:1 (2:3) to obtain the specified title compound (570 mg) as a white powder.

1H-NMR (CDCl3) δ: 1,44 (N, C)of 2.08 (4H, sh), 2,87 (2H, sh), 3,69 (6N, (C)a 3.83 (2H, sh), to 4.98 (2H, sh).

MS (FAB) m/z: 432 (M+N)+.

[Reference example 186]

(1R*,2S*,4R*)-N2(tert-Butoxycarbonyl)-4-carbarnoyl-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R*,2S*,4R*)-N2-(tert-Butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-this is xianbei-1,2-cyclohexanediamine (590 mg) was dissolved in a mixed solvent, consisting of ethanol (3 ml) and tetrahydrofuran (6 ml)was added at room temperature 1 N. aqueous solution (2.5 ml) of sodium hydroxide and the mixture was stirred for 12 hours. Drove the solvent to obtain sodium salt of (1R*,2S*,4R*)-N2-(tert-butoxycarbonyl)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine. The resulting product is suspended in N,N-dimethylformamide (4 ml)was added at room temperature, di-tert-BUTYLCARBAMATE (654 mg) and ammonium bicarbonate (1 g) and the mixture was stirred 18 hours. Drove away under reduced pressure, the solvent was added water and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methylene chloride:methanol=47:3) to obtain the specified title compound (82 mg) as a colorless solid.

MS (ESI) m/z: 435 (M+H)+.

[Reference example 187]

(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine:

(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(etoxycarbonyl)-1,2-cyclohexanediamine (1.5 g) Rast is oral in tetrahydrofuran (10 ml) and ethanol (10 ml), added 5 N. aqueous solution (1,29 ml) of sodium hydroxide and the mixture was stirred at room temperature for 18 hours. In the reaction mixture for its weak acidification was added 10% aqueous citric acid solution. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate and the resulting organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was dissolved in N,N-dimethylformamide (20 ml), to the solution was added dimethylamine hydrochloride (791 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (806 mg), monohydrate, 1-hydroxybenzotriazole (644 mg) and triethylamine (2,24 ml) and the mixture was stirred at room temperature for 7 hours. Added dimethylamine hydrochloride (527 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (620 mg), monohydrate, 1-hydroxybenzotriazole (495 mg) and triethylamine (896 ml) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, added an aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate and the resulting organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on si is imagele (dichloromethane:methanol=95:5) to obtain specified in the connection header (1,49 g) as a pale yellow amorphous solid.

1H-NMR (CDCl3) δ: 1.52m (N, C)1,71 (1H, m), 1,89 (2H, m)to 2.13 (1H, m), is 2.30 (1H, m), 2,65 (1H, s), 2,89 (3H, s), of 3.07 (3H, s)to 4.01 (1H, sh), 4,20 (1H, s), 4,82 (1H, sh), 6,79 (1H, d, J=2.0 Hz), 7.23 percent (1H, DD, J=8,5, 2.0 Hz), 7,35 (1H, d, J=8.5 Hz), to 7.59 (1H, s), 8,02 (1H, s), 9,54 (1H, s).

MS (ESI) m/z: 462 (M+H)+.

[Reference example 188]

(1S,2R,4S)-1-Azido-2-(N-tert-butoxycarbonylamino)-4-[N-(tert-butyl)carbarnoyl]cyclohexane:

(1S,2R,4S)-1-Azido-2-(N-tert-butoxycarbonylamino)-4-methoxycarbonylamino (509 mg) was dissolved in tetrahydrofuran (40,0 ml)was sequentially added under ice cooling, the lithium hydroxide (111 mg) and water (5.0 ml) and the mixture was stirred at room temperature for a period of 36.5 hours. Drove away under reduced pressure, the solvent, to the residue was added water and 1 N. hydrochloric acid (with 4.64 ml) and again drove away under reduced pressure, the solvent to obtain (1S,2R,4S)-1-azido-2-(N-tert-butoxycarbonylamino)-4-carboxylicacid. To the obtained crude product was added dichloromethane (25 ml) and N,N-dimethylformamide (260 ml) and the mixture was stirred under ice cooling. Then add oxalicacid (216 μl) and the mixture was continuously stirred at room temperature for 1 hour. In the reaction mixture was added with ice cooling tert-butylamine (1130 ml) and the mixture was stirred at room temperature for 14 hours. After addition the reaction is ionic mixture of water and dichloromethane for the separation of liquids was dried over anhydrous sodium sulfate the organic layer and drove away under reduced pressure the solvent. The residue was purified column flash chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the specified title compound (197 mg) as a pale yellow amorphous substance.

1H-NMR (CDCl3) δ: 1,25-1,35 (N, m), 1,35-1,45 (N, m, 1,55-2,00 (6N, m), 2,20-of 2.30 (1H, m), 3,70-4,80 (3H, m), and 5.30-of 5.45 (1H, m).

MS (FAB) m/z: 340 (M+H)+.

[Reference example 189]

(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-4-[N-(tert-butyl)carbarnoyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-1-azido-2-(tert-butoxycarbonylamino)-4-[N-(tert-butyl)carbarnoyl]cyclohexane in a manner similar to the method of reference example 47.

1H-NMR (CDCl3) δ: 1,20-1,35 (N, m), 1,44 (N, C), 1,50-2,20 (N, m), 2,90-of 3.00 (1H, m), a-3.84 (1H, sh), 4,94 (1H, sh), of 5.34 (1H, sh).

[Reference example 190]

(1S,2R,4S)-N2(tert-Butoxycarbonyl)-4[N - (tert-butyl)carbarnoyl]-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine;

Specified in the title compound was obtained from (1S,2R,4S)-N2-(tert-butoxycarbonyl)-4-[N-(tert-butyl)carbarnoyl]-1,2-cyclohexanediamine and 5-Clorinda-2-carboxylic acid in a manner similar to the method of reference example 159.

1H-NMR (CDCl3) δ: 1,33 (N, C), 1,352,30 (N, m), 3,90-of 4.05 (1H, m), 4,15-of 4.25 (1H, m), 5,04 (1H, sh), 5,42 (1H, sh), 6,65-of 6.90 (1H, m), 7,19 (1H, DD, J=8,8, 1.7 Hz), 7,37 (1H, d, J=8,8 Hz), to 7.59 (1H, sh), 8,13 (1H, sh), 10,51 (1H, s).

MS (ESI) m/z: 491 (M+H)+.

[Reference example 191]

(3R)-1-Benzyl-3-(tert-butyldiphenylsilyl)pyrrolidin:

(3R)-1-Benzyl-3-hydroxypyrrolidine (500 ml) and imidazole (466 mg) was dissolved in N,N-dimethylformamide (15 ml)was added under ice cooling tert-butyldiphenylsilyl (1,57 ml) and the mixture was stirred at room temperature for 9 days. Drove away under reduced pressure, the solvent, to the residue were added dichloromethane and water to separate liquids obtained organic layer was dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The residue was subjected to column flash chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (1.27 g) as a yellow oil.

1H-NMR (CDCl3) δ: 1,05 (N, s), 1.70 to of 1.85 (1H, m), 1,90-2,00 (1H, m), 2,45-to 2.65 (3H, m), 2.70 height is 2.80 (1H, m), 3,50-3,70 (2H, m), 4,35 is 4.45 (1H, m), 7,20 was 7.45 (11H, m), 7,60-of 7.70 (4H, m).

MS (ESI) m/z: 416 (M+H)+.

[Reference example 192]

1-Benzhydryl-3-(tert-butyldiphenylsilyl)azetidin:

Specified in the title compound was obtained from hydrochloride of 1-benzhydryl-3-hydroxyazetidine a manner similar to the method of reference example 191.

p> 1H-NMR (CDCl3) δ: 1,01 (N, C), 2,90-of 3.00 (2H, m), 3,40-3,50 (2H, m), 4,36 (1H, s), 4,40-4,50 (1H, m), 7,10-7,20 (2H, m), 7,20-7,30 (4H, m), 7,30-7,40 (10H, m), 7,55-the 7.65 (4H, m).

MS (ESI) m/z: 478 (M+N)+.

[Reference example 193]

CIS-N1N2Bis (benzyloxycarbonyl)-4-cyclohexen-1,2-diamine:

Hydrochloride 4-cyclohexen-1,2-diamine (4.0 g) was dissolved in a mixed solvent consisting of water (20 ml) and acetonitrile (20 ml), was added benzylchloride (7,66 ml) and potassium carbonate (14.9 g) and the mixture was stirred at room temperature for 3 days. In the reaction mixture is poured into water, the mixture was extracted with methylene chloride and the organic layer was washed with a saturated solution of salt. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane) to obtain specified in the connection header (by 8.22 g) as a colourless solid.

1H-NMR (CDCl3) δ: 2,03 (2H, m), 2,53 (2H, d, J=17,1 Hz), of 3.77 (2H, m), of 5.03 (2H, q, J=12.3 Hz), 5,09 (2H, q, J=12.3 Hz), 5,59 (2H, s), 7,32 (10H, m).

MS (ESI) m/z: 381 (M+H)+.

[Reference example 194]

(1R*,2S*)-N1N2Bis(benzyloxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine:

CIS-N1N2Bis(benzyloxycarbonyl)-4-cyclohexen-1,2-diamine (10 g) was dissolved in absolute is tetrahydrofurane (70 ml), was added at 0°With borane-dimethylsulfide complex (7,4 ml) and the mixture was gradually heated to room temperature and was stirred for 14 hours. In the reaction mixture were added ice to decompose the excess borane was added 1 N. aqueous solution (80 ml) of sodium hydroxide and 30% aqueous hydrogen peroxide (80 ml) and the mixture was stirred for 1 hour. The reaction mixture was extracted with ethyl acetate and the resulting organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=2:1) to obtain specified in the connection header (9.2 grams) as a colorless wax.

1H-NMR (CDCl3) δ: to 1.98 (1H, m), of 2.08 (1H, m), is 2.30 (1H, m), 3.43 points (2H, m), of 3.73 (1H, m), 5,06 (6N, m)to 7.32 (10H, s).

MS (ESI) m/z: 399 (M+H)+.

[Reference example 195]

(±)-CIS-N1N2Bis(benzyloxycarbonyl)-4-oxo-1,2-cyclohexanediamine:

Dimethyl sulfoxide (8.2 ml) was added to a solution of oxalicacid (9,9 ml) in dichloromethane (90 ml) at -60°and to the mixture was added in one portion a solution of (1R*,2S*)-N,N2bis(benzyloxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine (9.2 grams) in tetrahydrofuran (90 ml). After 1 hour, raised the temperature of the mixture to -40°and added the one portion of triethylamine (26 ml). The mixture was heated to room temperature and stirred 3 hours. The reaction mixture was poured into water and was extracted with methylene chloride. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromium that grafy her on silica gel (ethyl acetate:hexane=1:1) to obtain the specified title compound (8.0 g) as a pale yellow solid.

1H-NMR (CDCl3) δ: 2,27 is 2.43 (4H, m), 2,78 (1H, DD, J=14,4, 3,9 Hz), 3,86 (2H, m)5,08 (4H, m), with 5.22 (2H, m), 7,32 (10H, m).

MS (ESI) m/z: 397 (M+H)+.

[Reference medalist 196]

(±)-CIS-N1N2Bis(benzyloxycarbonyl)-4,4-dimethoxy-1,2-cyclohexanediamine:

(±)-CIS-N1N2Bis(benzyloxycarbonyl)-4-oxo-1,2-cyclohexanediamine (to 3.89 g) was dissolved in a mixed solvent consisting of methanol (15 ml) and tetrahydrofuran (15 ml)was added 2,2-dimethoxypropane (10,7 ml) and p-toluensulfonate acid (187 mg) and the mixture was stirred at room temperature for 3 hours. The solution was concentrated, added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate, after which the distillate is whether under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain specified in the connection header (3,54 g) as a colorless amorphous solid.

1H-NMR (CDCl3) δ: 1,30-of 1.41 (4H, m)of 1.93 (1H, m), of 2.38 (1H, m), 3,19 (6N, (C), of 3.46 (1H, m)and 3.59 (1H, m), of 5.03 (2H, q, J=12,5 Hz), 5,09 (2H, q, J=12,5 Hz), to 7.32 (10H, s).

[Reference example 197]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamine and (±)-CIS-N2-[(5-Clorinda-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamine:

(±)-CIS-N1N2Bis(benzyloxycarbonyl)-4,4-dimethoxy-1,2-cyclohexanediamine (1.45 g) was dissolved in methanol (12 ml), was added 10% palladium on carbon (290 mg) and the mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere. Added 10% palladium on carbon (290 mg) and methanol (10 ml) and the mixture was stirred for 8 hours. The reaction mixture was filtered through Celite, and the mother liquor was concentrated and the residue was dissolved in N,N-dimethylformamide (10 ml). Added 5-chlorinda˜2-carboxylic acid (320 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (377 mg), monohydrate, 1-hydroxybenzotriazole (301 mg) and N-methylmorpholin (360 ml) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into aqueous sodium hydrogen carbonate solution and was extracted with ethyl acetate. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate, and then drove away under reduced is the making of the solvent and the residue was isolated and purified preparative thin-layer chromatography on silica gel (dichloromethane:methanol 93:7) to give (± )-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamine (98 mg) and (±)-CIS-N2(or N1)-[(5-Clorinda-2-yl) carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamine (105 mg).

(±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamine:

1H-NMR (CDCl3)δ: to 1.48 (2H, m), of 2.08 (2H, m), 2,34 (1H, d, J=13.1 Hz), 2,78 (1H, dt, J=2,9, 13.1 Hz), 3,18 (3H, s), 3,23 (3H, s), 3,76 (1H, m), 6,24 (1H, d, J=8,3 Hz), 6,79 (1H, s), 7.23 percent (1H, DD, J=8,8, 2.0 Hz), 7,35 (1H, d, J=8,8 Hz), 7,60 (1H, d, J=8,8 Hz), at 9.53 (1H, sh).

MS (ESI) m/z: 352 (M+H)+.

(±)-CIS-N2(or N1)-[(5-Clorinda-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamine:

1H-NMR (CDCl3) δ: of 1.85 (1H, m), 1,99 (1H, m), 2,39 (1H, sh. J=13.2hz), is 2.88 (1H, m), 3,26 (10H, m)4,00 (1H, m), 6,77 (1H, s), 7.23 percent (1H, d, J=8.5 Hz), 7,37 (1H, d, J=8.5 Hz), to 7.61 (1H, s), 9,49 (1H, sh).

MS (ESI) m/z: 352 (M+N)+.

[Reference example 198]

(±)-CIS-N1N2Bis(benzyloxycarbonyl)-4,4(1,2-Ethylenedioxy)-1,2-cyclohexanediamine:

(±)-CIS-N1N2Bis(benzyloxycarbonyl)-4-oxo-1,2-cyclohexanediamine (4.0 g) was dissolved in absolute tetrahydrofuran (30 ml)was added ethylene glycol (5.6 ml) and p-toluensulfonate acid (192 mg) and the mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and was extracted with what acetate. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate, and then drove away under reduced pressure, the solvent and the residue was purified column chrome cografya on silica gel (ethyl acetate:hexane=1:1) to obtain specified in the connection header (to 4.23 g) as a pale yellow solid.

1H-NMR (CDCl3) δ: 1,65-1,71 (4H, m), from 2.00 (1H, m), 2,11 (1H, m), 3,49 (1H, m), of 3.73 (1H, m), 3,93 (4H, s)of 5.03 (2H, q, J=and 12.2 Hz), to 5.08 (2H, q, J=and 12.2 Hz), to 7.32 (10H, s).

MS (ESI) m/z: 441 (M+N)+.

[Reference example 199]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-4,4(1,2-Ethylenedioxy)-1,2-cyclohexanediamine and (±)-CIS-N2-[(5-Clorinda-2-yl)carbonyl]-4,4-(1,2-Ethylenedioxy)-1,2-cyclohexanediamine:

(±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4,4-(1,2-Ethylenedioxy)-1,2-cyclohexanediamine and (±)-CIS-N2(or N1)-[(5-Clorinda-2-yl)carbonyl]-4,4-(1,2-Ethylenedioxy)-1,2-cyclohexanediamine received from (±)-CIS-N1N2bis(benzyloxycarbonyl)-4,4-(1,2-Ethylenedioxy)-1,2-cyclohexanediamine a manner similar to the method of reference example 197.

(±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4,4-(1,2-Ethylenedioxy)-1,2-cyclohexanediamine:

1H-NMR (CDCl3) δ: 1,68-of 1.81 (4H, m), 2,11 (2H, m), 2,87 (1H, TD, J=3,9, 11.2 Hz), of 3.77 (1H, m), of 3.97 (4H, s), 6,27 (1H, d, J=7,6 Hz, to 6.80 (1H, s), 7,24 (1H, d, J=9.0 Hz), 7,35 (1H, d, J=9.0 Hz), to 7.61 (1H, s), for 9.47 (sh, 1H).

MS (ESI) m/z: 350 (M+H)+.

(±)-CIS-N2(or N1)-[(5-Clorinda-2-yl)carbonyl]-4,4-(1,2-Ethylenedioxy)-1,2-cyclohexanediamine:

1H-NMR (CDCl3) δ: of 1.65 (2H, m), a 1.88 (1H, m), a 1.96 (1H, m), 2,31 (1H, DD, J=12,9, and 3.2 Hz), 2,96 (1H, m), 3,98 (1H, m), was 4.02 (4H, s), of 4.12 (1H, m), 6,77 (1H, s), 7,06 (1H, sh), of 7.23 (1H, DD, J=8,8, 2.0 Hz), 7,37 (1H,d, J=8,8 Hz), a 7.62 (1H, d, J=2.0 Hz), 9,49 (1H, sh).

MS (ESI) m/z: 350 (M+H)+.

[Reference example 200]

CIS-N1N2Bis(tert-butoxycarbonyl)-4-cyclohexen-1,2-diamine:

Hydrochloride CIS-4-cyclohexene-1,2-diamine (4.0 g) was dissolved in a mixed solvent consisting of water (40 ml) and acetonitrile (40 ml), was added di-tert-butoxycarbonyl (11.8 g) and triethylamine (12 ml) and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was poured into water, the mixture was extracted with dichloromethane and the obtained dichloromethane layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain specified in the connection header (6,12 g) as a colourless solid.

1H-NMR (CDCl3) δ: 1,44 (N, C)to 1.98 (2H, DD, J=9,3, or 15.9 Hz), 2,48 (2H, CHD, J=15,9 Hz), 3,66 (2H, sh), 4,88 (2H, sh), to 5.58 (2H, d, J=2 Hz).

[Reference example 201]

(1R*,2S*)-N1N2Bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine (mixture of stereoisomers):

CIS-N1N2Bis(tert-butoxycarbonyl)-4-cyclohexen-1,2-diamine (6,1 g) was dissolved in absolute tetrahydrofuran (40 ml)was added by syringe under ice cooling borane-dimethylsulfide complex (2,22 ml). The mixture was stirred 16 hours, gradually warming to room temperature. In the reaction mixture were added ice, was added 1 N. aqueous sodium hydroxide solution and 30% aqueous hydrogen peroxide (50 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate and the resulting organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:2→2:1) to obtain specified in the connection header (6,1 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,42 (N, C)1,43 (N,) and 1.83-to 1.67 (5H, m)to 2.15 (1H, m), 2,22 (1H, s)to 3.34 (1H, m), of 3.78 (1H, m), 4,15 (1H, s), to 4.98 (1H, q, J=9.0 Hz), 5,02 (1H, q, J=9,0 Hz).

MS (ESI) m/z: 331 (M+H)+.

[Reference example 202]

CIS-N1N2Bis (tert-butoxycarbonyl)-4-oxo-1,2-cyclohexanediamine:

Dimethyl sulfoxide (6.8 ml) was added to a solution of oxalicacid (8.2 ml) in dichloromethane (100 ml) at -60°and to the mixture was added at once a solution of (1R*,2S*)-N1N2bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine (mixture of stereoisomers) (6,32 g) in tetrahydrofuran (80 ml) and the mixture was stirred for 1 hour. The temperature of the mixture was raised to -40°and added to a mixture of triethylamine (21 ml). The mixture was heated to room temperature. After 3 hours the reaction mixture was poured into water and was extracted with dichloromethane. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:1) to obtain the specified title compound (3.8 g) as a pale yellow solid.

1H-NMR (CDCl3) δ: 1,43 (N, C), 1,44 (N, C), a 2.36-of 2.24 (3H, m), 2,39 is 2.44 (2H, m)of 2.75 (1H, DD, J=14,6, 2,9 Hz), 3,66-3,81 (2H, m), 4.95 points-of 4.90 (1H, m), equal to 4.97-to 5.03 (1H, m).

MS (ESI) m/z: 329 (M+H)+.

[Reference example 203]

(±)-CIS-N1N2Bis(tert-butoxycarbonyl)-4-methoxyimino-1,2-cyclohexanediamine:

CIS-N1N2Bis (tert-butoxycarbonyl)-4-oxo-1,2-cyclohexanediamine (1.5 g) was dissolved in methanol (30 ml), was added g is drochloric O-methylhydroxylamine (572 mg) and pyridine (737 ml) and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, added water and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the specified title compound (1.52 g) as a colourless solid.

1H-NMR (CDCl3) δ: 1,44 (N, C)of 1.64 (1H, m)of 2.16 (2H, m)2,44 (1H, m), 3,45-3,63 (3H, m), 3,82 (3H, s), is 4.93 (1H, m).

MS (ESI) m/z: 358 (M+N)+.

[Reference example 204]

(1R*,2S*,4R*(or 4S*)-NlN2Bis(tert-butoxycarbonyl)-4-tert-butyldiphenylsilyl-1,2-cyclohexanediamine (stereoisomer A):

Specified in the title compound was obtained from (1R*,2S*)-N1N2bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine (mixture of stereoisomers) in a manner similar to the method of reference example 191.

1H-NMR (CDCl3) δ: 1,03 (N, C)1,39 (N, C), 1,40 (N, C)1,72 (1H, m)to 1.86 (1H, m)to 2.13 (1H, m), 3,24 (2H, m), the 3.65 (1H, m), a 4.83 (1H, m), 7,37 (10H, m).

[Reference example 205]

(1R*,2S*)-4-Acetoxy-N1N2bis(tert-butoxycarbonyl)-1,2-cyclohexanediamine (stereoisomer is R):

(1R*,2S*)-N1N2Bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine (stereoisomer B) (1,74 g) was dissolved in pyridine (15 ml), was added acetic anhydride (5 ml) and the mixture was stirred at room temperature for 4 days. To the reaction mixture were added 1 N. hydrochloric acid, the mixture was extracted with ethyl acetate and the resulting organic layer was washed successively 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:3) to obtain specified in the connection header (1,96 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,43 (N, C)1,89 (2H, m), 2,10 (3H, s), 2,19 (1H, m)to 3.35 (1H, m), of 3.69 (1H, m), a 4.86 (1H, d, J=8,3 Hz)to 5.00 (1H, d, J=8,3 Hz), 5,11 (1H, s).

MS (ESI) m/z: 373 (M+H)+.

[Reference example 206]

(1R*,2S*)-N1N2Bis(benzyloxycarbonyl)-4-hydroxy-4-methyl-1,2-cyclohexanediamine:

Anhydrous cerium chloride (6.4 g) suspended in tetrahydrofuran (50 ml) and the suspension was cooled to -78°C in argon atmosphere. To the suspension was added a solution metallici the (1,14 N. solution in diethyl ether, 22.5 ml) and the mixture was stirred at -78°C for 30 minutes. Was added dropwise at -78°tertrahydrofuran ring solution (50 ml) (±)-CIS-N1N2bis (benzyloxycarbonyl)-4-oxo-1,2-cyclohexanediamine (3.0 g) and the mixture was stirred for 30 minutes. The reaction mixture was poured into 3% aqueous solution (100 ml) of acetic acid, was added diethyl ether (50 ml) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was extracted with ethyl acetate and the resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified double-column chromatography (medium pressure silica gel (methanol:chloroform=0:100→1:19) to obtain the specified title compound (stereoisomer A) (780 mg) as colorless foamy connection and specified in the title compound (stereoisomer B) (1.1 g) as a white powder.

Stereoisomer A:

1H-NMR (CDCl3) δ: of 1.26 (3H, s), 1,27-2,08 (6N, m), 3,48 (1H, sh)and 3.59 (1H, sh), 5,02-5,09 (5H, m), 5,33 (1H, sh), 7,30-to 7.32 (10H, s)

MS (FAB) m/z: 413 (M+H)+.

Stereoisomer In:

1H-NMR (CDCl3) δ: 1,25 (3H, s), 1,29-2,07 (6N, m), 3,39 (1H, sh), 3,82 (1H, sh), 5,02-5,23 (6N, m), 7,30 (10H, s)

MS (FAB) m/z: 413 (M+N)+.

[With Ilony example 207]

(1R*,2S*)-4-Hydroxy-4-methyl-1,2-cyclohexanediamine

(stereoisomer A):

10% Palladium on carbon (350 mg) suspended in methanol solution (100 ml) of (1R*,2S*)-N1N2bis(benzyloxycarbonyl)-4-hydroxy-4-methyl-1,2-cyclohexanediamine (stereoisomer A) (780 mg) and the suspension was stirred for 5 hours in an atmosphere of hydrogen. Was removed by filtration of the catalyst and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 ml) and then the solution was dried over anhydrous sodium sulfate and drove the solvent to obtain specified in the title compound (stereoisomer A) (190 mg) as a colourless oil.

1H-NMR (CDCl3) δ: 1,22 (3H, S), 1,25-2,48 (11N, m), 2,62 (1H, sh), 2,78 (1H, sh).

[Reference example 208]

(1R*,2S*)4-Hydroxy-4-methyl-1,2-cyclohexanediamine (stereoisomer):

Specified in the title compound was obtained from (1R*,2S*)-N1N2bis(benzyloxycarbonyl)-4-hydroxy-4-methyl-1,2-cyclohexanediamine (stereoisomer B) in a manner similar to the method of reference example 207.

1H-NMR (CDCl3) δ: 1,17 (3H, s), 1,39-1,79 (11N, m), 2,10-to 2.18 (1H, m), 2,55-2,61 (1H, m)

[Reference example 209]

A mixture of (1R*,2S*)-N1-[(5-chlorinda--yl)carbonyl]-4-hydroxy-4-methyl-1,2-cyclohexanediamine (stereoisomer a) and (1R *,2S*)-N2-[(5-Clorinda-2-yl)carbonyl]-4-hydroxy-4-methyl-1,2-cyclohexanediamine (stereoisomer A):

Specified in the title compound was obtained from (1R*,2S*)-4-hydroxy-4-methyl-1,2-cyclohexanediamine (stereoisomer A) in a manner similar to the method of reference example 30.

1H-NMR (CDCl3) δ: of 1.32 (3H, s), 1,34-2,29 (6N, m), 4,42-4,70 (4H, sh), 7,13 (2H, s), 7,50 (2H, s), of 8.00(1H, s), and 11.0 (1H, sh).

[Reference example 210]

(1R*,2S*)-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4-hydroxy-4-methyl-1,2-cyclohexanediamine (stereoisomer):

Specified in the title compound was obtained from (1R*,2S*)-4-hydroxy-4-methyl-1,2-cyclohexanediamine (stereoisomer B) in a manner similar to the method of reference example 125.

1H-NMR (DMSO-d6) δ: of 1.18 (3H, s), 1,23-1,96 (6N, m), 4,12-the ceiling of 5.60 (4H, sh), 7,11-8,59 (5H, m), and 11.8(1H, sh)

MS (FAB) m/z: 322 (M+N)+.

[Reference example 211]

(1R*,2S*)-4-(tert-Butyldiphenylsilyl)-1,2-cyclohexanediol:

1) 3-Cyclohexen-1-methanol (5.0 g) was dissolved in N,N-dimethylformamide (50 ml), the solution was added imidazole (3,93 g) and tert-butylchloroformate (14 ml) and the mixture was stirred for 22 hours. Adding methanol, kept at reduced pressure, the solvent, to the residue was added water and the mixture was extracted with ethylacetate is. The extract was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=30:1) to give (±)-4-(tert-butyldiphenylsilyl)-1-cyclohexene (16,1 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,05 (N, C)of 1.20 and 1.35 (2H, m), 1,70-1,90 (3H, m), 2.05 is-of 2.20 (2H, m), 3,55 (2H, d, J=5,9 Hz), 5,67 (2H, s), 7,35-7,50 (6N, m), the 7.65 to 7.75 (4H, m).

MS (FAB) m/z: 351 (M+N)+.

2) is listed in the title compound was obtained from (±)-4-(tert-butyldiphenylsilyl)-1-cyclohexene in a manner similar to the method of reference example 183.

1H-NMR (CDCl3) δ: 1,04, 1,05 (General N, each s), 1,29-2,09 (7H, m), is 2.05 (2H, s), 3,44-3,51 (2H, m), 3,52-to 3.67 (1H, m), 4,00, 3,96 (total 1H, each sh), 7,35-7,44 (6N, m), 7,63-7,66 (4H, m).

MS (FAB) m/z: 385 (M+N)+.

[Referential example 212]

(1R*,2S*)-4-(tert-Butyldiphenylsilyl)-1,2-bis(methanesulfonate)cyclohexane:

Methanesulfonanilide (2.5 ml) was added dropwise to a dichloromethane solution (300 ml) of (1R*,2S*)-4-(tert-butyldiphenylsilyl)-1,2-cyclohexanediol (4,2 g) and triethylamine (9.1 ml) at 0°and the mixture was stirred for 1.5 hours. Added water and the mixture was extracted with dichloromethane, then the organic layer was washed with a saturated aqueous solution is of hydrocarbonate sodium and saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography (medium pressure silica gel (hexane:ethyl acetate=3:2) to obtain the specified title compound (4.9 g) as a pale yellow oil.

1H-NMR (CDCl3) δ: 1,04, 1,05 (General N, each s), 1,31-2,29 (7H, m), 3,07, is 3.08 (total 3H, each s), 3,09, 3,10 (total 3H, each s), 4,11 (2H, dt, J=7,1, 0,73 Hz)and 4.65-4.72 in (1H, m), 5,11, 5,08 (total 1H, each sh), 7,39-7,43 (6N, m)to 7.61-to 7.64 (4H, m).

[Reference example 213]

(1R*,2S*)-4-(tert-Butyldiphenylsilyl)-1,2-deesidecollege (stereoisomer a and stereoisomer B):

Relevant specified in the title compound (stereoisomer a and stereoisomer B) was obtained from (1R*,2S*)-4-(tert-butyldiphenylsilyl)-1,2-bis(methanesulfonate)cyclohexane in a manner similar to the method of reference example 127.

Stereoisomer A:

1H-NMR (CDCl3) δ: 0,88 (1H, m), 1.06 a (N, C), 1,24-of 1.30 (2H, m), 1,63-of 1.66 (1H, m), 1,89-of 1.92 (2H, m), 2.00 in was 2.05 (1H, m), 3,37-of 3.42 (1H, m), 3,52 (2H, S.T., J=6.0 Hz), 3,92 (1H, sh), 7,37 was 7.45 (6N, m), 7,63-the 7.65 (4H, m).

Stereoisomer In:

1H-NMR (CDCl3) δ: 0,88 (1H, m), 1,05 (N, C), 1,13 was 1.43 (2H, m), 1,79-of 1.84 (3H, m), 2,02-to 2.06 (1H, m), 3,34-to 3.38 (1H, m), 3,47-3,51 (2H, m), of 3.94 (1H, CHD, J=2,9 Hz), 7,37 was 7.45 (6N, m), 7,62-to 7.64 (4H, m).

[Referential example 214]

(1R*,2S*)-4-(tert-Butyldiphenylsilyl)-1,cyclohexanediamine (stereoisomer A):

Specified in the title compound was obtained from (1R*,2S*)-4-(tert-butyldiphenylsilyl)-1,2-vasiliymorgansage (stereoisomer A) in a manner similar to the method of reference example 128.

1H-NMR (CDCl3) δ: 1,05 (N, C)of 1.09 to 1.76 (7H, m), was 2.76-and 2.79 (1H, m), 2,98 (1H, sh), 3,48-to 3.49 (2H, m), of 7.36-7,41 (6N, m)of 7.64-7,66 (4H, m).

[Reference example 215]

(1R*,2S*)-4-tert-Butyldiphenylsilyl-1,2-cyclohexanediamine (stereoisomer):

Specified in the title compound was obtained from (1R*,2S*)-4-(tert-butyldiphenylsilyl)-1,2-vasiliymorgansage (stereoisomer B) in a manner similar to the method of reference example 128.

1H-NMR (CDCl3) δ: 1,05 (N, C), 1,42-1,79 (7H, m), 2,70-by 2.73 (1H, m), 3,01-3,03 (1H, m), 3,44-to 3.49 (2H, m), 7,37-7,42 (6N, m)of 7.64-7,66 (4H, m).

[Reference example 216]

(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylic acid:

Benzyl (1R,3S,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (4.4 g) was dissolved in tetrahydrofuran (160 ml) and to the solution was added under cooling with ice water (20 ml) and lithium hydroxide (366 mg). After 10 minutes the mixture was heated to room temperature while continuing the stirring. After 20 minutes, drove away under reduced pressure, the solvent and the OST is OK purified column chromatography on silica gel (methanol:dichloromethane=1:10) to obtain the specified title compound (1.86 g) as a pale yellow oil.

1H-NMR (CDCl3) δ: 1,47 (N, C), 1,72-of 1.73 (2H, m), 1,82-1,90 (3H, m), 2.05 is-2,10 (1H, m), 2.77-to 2,80 (1H, m), 3,49-the 3.65 (2H, m).

MS (FAB) m/z: 285 (M+H)+.

[Reference example 217]

(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonylamino)-1-(hydroxymethyl)cyclohexane:

(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylic acid (1.86 g) was dissolved in dichloromethane (20 ml) and to the solution was added at -15°With isobutylparaben (1,02 ml) and N-methylmorpholin (860 mg). The mixture was stirred 10 minutes at the same temperature. Precipitated precipitated hydrochloride N-the research was separated by filtration, to the filtrate was added an aqueous solution (4 ml), sodium borohydride (370 mg) and the mixture was stirred for 10 minutes. Adding water, kept under reduced pressure, the solvent and the residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:1) to obtain the specified title compound (1.35 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,46 (N, C), 1,33-of 2.20 (7H, m), 3,52-3,55 (2H, m), 3,64-3,81 (2H, m).

MS (FAB) m/z: 271 (M+N)+.

[Reference example 218]

(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonylamino)-1-(tert-butyldiphenylsilyl)cyclohexane:

Listed in the agolove compound was obtained from (1R,3S,4S)-3-azido-4-(N-tert-butoxycarbonylamino)-1-hydroxymethyl)cyclohexane way similar to the method of reference example 107.

1H-NMR (CDCl3) δ: 1,06 (N, C), 1,45 (N, C), 1,53-2,16 (7H, m), 3,51 (2H, d, J=6.4 Hz), 3,61 (2H, sh), was 7.36-7,46 (6N, m), 7,63-7,66 (4H, m).

MS (FAB) m/z: 509 (M+N)+.

[Reference example 219]

(1S,2S,4R)-N1-tert-Butoxycarbonyl-4(tert-butyldiphenylsilyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

1) (1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonylamino)-1-(tert-butyldiphenylsilyl)cyclohexane (2,59 g) was dissolved in methanol (50 ml)was added 10% palladium on carbon (200 mg) and the mixture was stirred for 20 hours in a hydrogen atmosphere. Removing by filtration the catalyst that drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:20→1:10) to obtain (1S, 2S, 4R)-N1-tert-butoxycarbonyl-4-(tert-butyldiphenylsilyl)-1,2-cyclohexanediamine (1.66 g) as a pale yellow oil.

2) is listed in the title compound was obtained from (1S, 2S, 4R)-N1-tert-butoxycarbonyl-4-(tert-butyldiphenylsilyl)-1,2-cyclohexanediamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of reference example 48.

1H-NMR (CDCl3) δ: 1,05 (N, C)1,29 (N, s), 1.56 to was 1.58 (3H, m), 1,80-of 1.84 (2H, m), 2.00 in was 2.05 (2H, m), 2.49 USD (3H, s), 2,80-of 2.81 (2H, m),2,90-of 3.00 (2H, m)of 3.48 (1H, sh), to 3.58 at 3.69 (4H, m), a-3.84 (1H, sh), 7,35-7,44 (6N, m), 7,63-the 7.65 (4H, m).

MS (FAB) m/z 663 (M+N)+.

[Referential example 220]

(1S,2S,4R)-N1-tert-Butoxycarbonyl-4-hydroxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1S,2S,4R)-N1-tert-Butoxycarbonyl-4-(tert-butyldiphenylsilyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (1.25 g) was dissolved in tetrahydrofuran (30 ml), was added tetrabutylammonium (1 M solution, 2.5 ml) and the mixture was stirred at room temperature for 3 days. Away under reduced pressure, the solvent was added dichloromethane, the reaction mixture was washed with water and the resulting organic layer was dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:20→1:10) to obtain the specified title compound (540 mg) as a pale yellow amorphous substance.

1H-NMR (CDCl3) δ: 1,31 (N, C), 1,37-2,37 (7H, m)of 2.50 (3H, s), was 2.76-2,82 (2H, m), 2,89 are 2.98 (2H, m), 3,56 of 3.75 (5H, m), 3,91-of 3.94 (1H, m), 4.80 to 4,82 (1H, m).

MS (FAB) m/z: 425 (M+N)+.

[Reference example 221]

(1R*That 2R*4S*)-N2(tert-Butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]4-hydroxymethyl-1,2-cyclohexanediamine:

(1R*That 2R*4S*)-N2-(tert-Butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine (735 mg) was dissolved in dichloromethane (10 ml)was added at -78°1 N. hexane solution (5 ml) hydride isobutyrate and the mixture was stirred for 3 hours and then 30 minutes at 0°C. was Added at -78°With a saturated aqueous solution of ammonium chloride, the mixture was extracted with dichloromethane and the resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then was dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=19:1) to obtain the specified title compound (480 mg) as a colorless solid.

1H-NMR (CDCl3) δ: 1,20-of 2.30 (7H, m), 3,60-3,86 (4H, m), with 4.64 (1H, sh), 6,87 (1H, s), 7,20-of 7.48 (3H, m)to 9.15 (1H, sh).

MS (ESI) m/z: 422 (M+N)+.

[Reference example 222]

(1R,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine with the special similar to the method of reference example 221.

MS (ESI) m/z: 422 (M+N)+.

[Reference example 223]

(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-N1-[(5-Clorinda-2-yl)carbonyl]-4-(1-hydroxy-1-methylethyl)-1,2-cyclohexanediamine:

Motility (1,14 N. a solution of 2.27 ml) was added to tertrahydrofuran ring solution (10 ml) of (1R*,2S*,4R*)-N2-tert-butoxycarbonyl-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine (200 mg) at -78°and the mixture was stirred 1 hour and then 2 hours under ice cooling. In the reaction mixture was added an aqueous solution of ammonium chloride, the mixture was extracted with chloroform and the organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=1:3) to obtain the specified title compound (115 mg) as a colorless solid.

1H-NMR (DMSO-d6) δ: 1,04 (6N, (C), 1,33 (N, C)0,97-2,05 (7H, m), 3,80-was 4.02 (2H, m), to 6.43 (1H, m), 7,01 (1H, sh), 7,16 (1H, CHD, J=8,8 Hz), 7,41 (1H, d, J=8,8 Hz), 7,68 (1H, s), 8,03-to 8.14 (2H, m).

MS (ESI) m/z: 450 (M+H)+.

[Reference example 224]

Hydrochloride (1R*,2S*,4R*)-N1-[(5-chlorinda the-2-yl)carbonyl]-4-(1-hydroxy-1-methylethyl)-1,2-cyclohexanediamine:

To an ethanol solution (5 ml) of (1R*,2S*,4R*)-N2-tert-butoxycarbonyl-N1-[(5-Clorinda-2-yl)carbonyl]-4-(1-hydroxy-1-methylethyl)-1,2-cyclohexanediamine was added a 4 n solution of hydrogen chloride in dioxane (10 ml) and the mixture was stirred at room temperature for 12 hours. Drove away under reduced pressure, the solvent is obtaining specified in the title compound (100 mg) as a colourless oil.

1H-NMR (DMSO-d6) δwith 1.07 (3H, s)a 1.08 (3H, s), 1,10-2,08 (7H, s), 3,60-4,06 (2H, m), 7,19 (1H, DD, J=8.8 and 1.6 Hz), 7,27 (1H, sh), 7,44 (1H, d, J=8,8 Hz), 7,72 (1H, sh), 7,92 (1H, sh), 8,43 (1H, d, J=6,8 Hz).

MS (ESI) m/z: 350 (M+H)+.

[Reference example 225]

(1R*,2S*4S*)-1,2-Epoxy-4-methoxymethylethoxy:

1) (1R*,3R*,4R*)-4-Iodine-6-oxabicyclo[3.2.1]Octan-7-he (2.8 g) was dissolved in a mixed solvent consisting of tetrahydrofuran (27 ml) and water (3 ml)was added concentrated hydrochloric acid (0.1 ml) and the mixture is boiled under reflux for 1 hour. Drove under reduced pressure the solvent to obtain (1R*,3R*,4R*)-3-hydroxy-4-idzikowski-1-carboxylic acid (3,23 g) as a colourless solid.

2) the Product (3,22 g), receiving the hydrated in the above reactions, was dissolved in tetrahydrofuran (50 ml)was added under ice cooling borane-dimethylsulfide complex (2 M tertrahydrofuran ring solution (47 ml) and the mixture was stirred at room temperature for 12 hours. Drove away under reduced pressure, the solvent, the residue was dissolved in isopropanol (10 ml), was added 1 N. aqueous solution (12 ml) of sodium hydroxide and the mixture was stirred for 12 hours. After concentration of the solvent to about 1/5 the reaction mixture was diluted with water and dichloromethane and stirred for 10 minutes. The organic layer was separated, sequentially washed with saturated aqueous ammonium chloride and saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:2) to give (1R*,2S*4S*)-1,2-epoxy-4-hydroxymethylcytosine (1.25 g) as a colourless oil.

3) the Product (4,63 g)obtained in the above reaction, was dissolved in tetrahydrofuran (50 ml) was added bis(gramatically)amide potassium (0,5 N. toluene solution, 80 ml) and then methyliodide (2,93 ml). After heating the mixture to 0°With was stirred for 1 hour, reduce saturated aqueous ammonium chloride and then diluted with diethyl ether. The organic layer was separated, the industry is Ali saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the specified title compound (3.7 g) as a colourless oil.

1H-NMR (CDCl3) δ: 0,89-to 1.63 (5H, m), 1,80-of 2.05 (2H, m), 1,89-of 3.06 (4H, m), and 3.16 (3H, s).

[Reference example 226]

(1R*That 2R*4S*)-2-Azido-4-methoxymethyl-1-cyclohexanol:

Specified in the title compound was obtained from (1R*,2S*4S*)-1,2-epoxy-4-methoxymethylethoxy a manner similar to the method of reference example 155.

1H-NMR (CDCl3) δ: 1,45 is 1.70 (5H, m), 1.77 in-1,95 (2H, m), 1,98-of 2.08 (1H, m), 3,30 (2H, d, J=6.8 Hz), the 3.35 (3H, s), 3.45 points-of 3.65 (2H, m).

[Reference example 227]

(1R*That 2R*4S*)-2-(tert-Butoxycarbonylamino)-4-methoxymethyl-1-cyclohexanol:

Specified in the title compound was obtained from (1R*That 2R*4S*)-2-azido-4-methoxymethyl-1-cyclohexanol in a manner similar to the method of reference example 156.

1H-NMR (CDCl3) δ: 1,35-2,01 (N, m), 3,05 (1H, sh), 3,32 (2H, d, J=7,1 Hz)to 3.34 (3H, s), 3,44-3,62 (2H, m), 4,59 (1H, sh).

[Reference example 228]

(1R*,2S*,4R*)-1-Azido-2-(tert-butoxycarbonylamino)-4-methoxymethylethoxy:

Specified in the title compound was obtained from (1R*That 2R*4S*)-2-(tert-butoxycarbonylamino)-4-methoxymethyl-1-cyclohexanol in a manner similar to the method of reference example 157.

1H-NMR (CDCl3) δ: 1,31-1,93 (N, m), with 3.27 (2H, d, J=6.4 Hz), 3,32 (3H, s), 3,57-3,70 (1H, m)to 3.67(1H, sh), of 3.95 (1H, sh).

[Reference example 229]

(1R*,2S*,4R*)-N2-(tert-Butoxycarbonyl)-4-methoxymethyl-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R*,2S*,4R*)-1-azido-2-(tert-butoxycarbonylamino)-4-methoxymethylethoxy a manner similar to the method of reference example 47.

[Reference example 230]

(1R*,2S*,4R*)-N2-(tert-Butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-methoxymethyl-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R*,2S*,4R*)-N2-(tert-butoxycarbonyl)-4-methoxymethyl-1,2-cyclohexanediamine and 5-Clorinda-2-carboxylic acid in a manner similar to the method of reference example 159.

1H-NMR (CDCl3) δ: 1,12-2,31 (N, m), 3,14-3,30 (2H, m)to 3.34 (3H, s)to 3.92 (1H, sh), 4,13 (1H, sh), 4,88 (1H, sh), PC 6.82 (1H, s), 7,21 (1H, CHD, J=8,8 Hz), 7,33 (1H, d, J=8,8 Hz), 7,60 (1H, s), of 8.09 (1H, sh), 9,42 (1H, SHS).

MS (ESI) m/z: 436 (M+H)+.

[Reference example 231]

A mixture of (1R*,2S*,4R*,5S*)-N1N2bis(benzyloxycarbonyl)-4,5-dihydroxy-1,2-cyclohexanediamine and (1R*,2S*4S*,5R*)-N1N2bis(benzyloxycarbonyl)-4,5-dihydroxy-1,2-cyclohexanediamine:

Specified in the title compound was obtained from CIS-N1N2bis (benzyloxycarbonyl)-4-cyclohexen-1,2-diamine in a manner similar to the method of reference example 183.

[Reference example 232]

A mixture of (1R*,2S*,4R*,5S*)-N1N2bis(benzyloxycarbonyl)-4,5-isopropylidenedioxy-1,2-cyclohexanediamine and (1R*,2S*4S*,5R*)-N1N2bis(benzyloxycarbonyl)-4,5-isopropylidenedioxy-1,2-cyclohexanediamine:

A mixture (1.0 g) (1R*,2S*,4R*,5S*)-N1N2bis(benzyloxycarbonyl)-4,5-dihydroxy-1,2-cyclohexanediamine and (1R*,2S*4S*,5R*)-NlN2bis(benzyloxycarbonyl)-4,5-dihydroxy-1,2-cyclohexanediamine was dissolved in tetrahydrofuran (20 ml)was added 2,2-dimethoxypropane (443 ml) and p-toluensulfonate pyridinium (61 mg) and the mixture stirred the ri room temperature for 2 hours. Added 1,2-dimethoxypropane (2 ml), the reaction mixture was stirred for 16 hours, was added a saturated salt solution and was extracted with a mixture of ethyl acetate. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate, and then drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:2→1:1) to obtain the specified title compound (1.10 g) as a colorless amorphous solid.

1H-NMR (CDCl3) δ: 1,50 (3H, s), 1,54-of 1.64 (2H, m)of 1.66 (3H, s), 2,16-2,19 (1H, m), 2,39 (1H, CHD, J=14,2 Hz), 3,47-to 3.49 (1H, m), 3,80-3,82 (1H, m), 4,16-4,19 (1H, m), 4,25 (1H, s), of 4.95 (1H, d, J=8.1 Hz), to 5.03 (2H, d, J=12.0 Hz), to 5.08 (2H, D, J=12.0 Hz), to 5.21 (1H, d, J=8.1 Hz), 7,31 (10H, s).

[Reference example 233]

A mixture of (1R*,2S*,4R*,5S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-isopropylidenedioxy-1,2-cyclohexanediamine and (1R*,2S*4S*,5R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-isopropylidenedioxy-1,2-cyclohexanediamine:

Specified in the title compound was obtained from a mixture of (1R*,2S*,4R*,5S*)-NlN2bis(benzyloxycarbonyl)-4,5-isopropylidenedioxy-1,2-cyclohexanediamine and (1R*,2S*4S*,5R )-NlN2bis(benzyloxycarbonyl)-4,5-isopropylidenedioxy-1,2-cyclohexanediamine a manner similar to the method of reference example 197.

1H-NMR(DMSO-d6) δ: of 1.44 (3H, s)of 1.47 (3H, s), 1,59-1,72 (2H, m), 1.93 and is 1.96 (1H, m), 2,23-of 2.26 (2H, m), 2,66-2,69 (1H, m), 2,93-2,95 (1H, m), 3,60-3,62 (1H, m), 4,15-4,16 (1H, m), 4,22 (1H, s), to 7.15(1H, s), 7,17 (1H, DD, J=8,5, 2.0 Hz), the 7.43 (1H, d, J=8.5 Hz), of 7.70 (1H, s), of 8.27 (1H, s), 11,76 (1H, s).

[Reference example 234]

A mixture of dimethyl (1R*,2S*,4R*,5S*)-4,5-dimethoxytoluene-1,2-in primary forms and dimethyl (1R*,2S*4S*,5R*)-4,5-dimethoxytoluene-1,2-in primary forms:

In the atmosphere of argon methyliodide (2.00 ml) and sodium hydride (60% oil suspension, 1.29 g) was sequentially added to tertrahydrofuran ring solution (25 ml) mixture (3,74 g) (1R*,2S*,4R*,5S*)-4,5-dihydrocyclopenta-1,2-dicarboxylic acid and (1R*,2S*4S*,5R*)-4,5-dihydrocyclopenta-1,2-dicarboxylic acid under ice cooling and the mixture was stirred at room temperature overnight. To the reaction mixture were added diethyl ether and water to separate liquids. The resulting oil layer was dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified Colo is face-to-face chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the specified title compound (2.64 g) as a colourless oil.

1H-NMR (CDCl3) δ: 1,35-1,45 (1H, m), 1,80-1,90 (1H, m), 2,10-of 2.16 (1H, m), 2,34-to 2.40 (1H, m), 2,65 is 2.75 (1H, m), 2,93-a 3.01 (1H, m), 3,20-3,26 (1H, m), 3,35 is-3.45 (7H, s), 3,69 (6N, C).

MS (ESI) m/z: 261 (M+H)+.

[Reference example 235]

A mixture of (1R*,2S*,4R*,5S*)-4,5-dimethoxytoluene-1,2-dicarboxylicacid and (1R*,2S*4S*,5R*)-4,5-dimethoxytoluene-1,2-dicarboxylicacid:

Hydrazine monohydrate (1.97 ml) was added dropwise to an ethanol solution (10 ml) mixture (2.64 g) dimethyl (1R*,2S*,4R*,5S*)-4,5-dimethoxytoluene-1,2-in primary forms and dimethyl (1R*,2S*4S*,5R*)-4,5-dimethoxytoluene-1,2-in primary forms and the resulting mixture was boiled under reflux overnight. After cooling the reaction mixture to room temperature it was concentrated and to the residue was added for curing diethyl ether, to deliver specified in the title compound (1.07 g).

1H-NMR (DMSO-d6) δ: 1,25-1,35 (1H, m), 1,55-1,70 (2H, m), 1.91 a is 2.00 (1H, m), 2.40 a-2,50 (1H, m), 2,55-2,70 (1H, m), 3,12-3,20 (1H, m), 3,20-3,40 (6N, m)to 3.64 (1H, sh), 4,06 (4H, sh), cent to 8.85 (1H, sh), 8,97 (1H, sh).

MS (FAB) m/z: 261 (M+H)+.

[Reference example 236]

The mixture hydrochloride (1R*,2S*,4R*,5S*)-4,5-di is ethoxy-1,2-cyclohexanediamine hydrochloride and (1R *,2S*4S*,5R*)-4,5-dimethoxy-1,2-cyclohexanediamine:

Ice (3.7 g), concentrated hydrochloric acid (1.9 ml) and diethyl ether (4,1 ml) was sequentially added to the mixture (1.07 g) (1R*,2S*,4R*,5S*)-4,5-dimethoxytoluene-1,2-dicarboxylicacid and (1R*,2S*4S*,5R*)-4,5-dimethoxytoluene-1,2-dicarboxylicacid. Was added dropwise over 10 minutes with stirring under cooling with ice water (1.6 ml)containing sodium nitrite (709 mg). The mixture was stirred for 5 minutes under ice cooling and the ether layer was separated and dried over calcium chloride. Was added to a solution of toluene (10 ml), carefully drove away under reduced pressure only diethyl ether and the resulting toluene solution was heated at 120°C for 1 hour. The reaction mixture was added dropwise to concentrated hydrochloric acid (3 ml), heated to 60°and the mixture was stirred at 60°C for 1 hour. After cooling the reaction mixture to room temperature, concentrated and to the residue was added ethanol. The mixture was concentrated. Added ethyl acetate and precipitated precipitated powder was filtered, to deliver specified in the title compound (745 mg).

1H-NMR (DMSO-d6) 4 : 1,50-1,60 (1H, m), a 1.75-to 1.87 (1H, m), 2.05 is-to 2.15 (1H, m), 2,31-to 2.40 (1H, m), 3,20-3,40 (N, m in), 3.75 (1H, sh), 8,67 (6N, sh).

MS (FAB) m/z: 175 (M+H)+.

[Reference example 237]

(1R*,2S*,4R*)-N2-(tert-Butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R*,2S*,4R*)-N2-(tert-butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine a manner similar to the method of reference example 221.

1H-NMR (CDCl3) δ: 0,78-2,30 (N, m), 3,41-3,59 (3H, m), 3,86-of 3.95 (1H, m), 4,12-4,20 (1H, m), 4,82-4,91 (1H, m), for 6.81 (1H, s), 7,17-7,40 (2H, m), 7,60 (1H, s), 8,03 (1H, sh), 9,18 (1H, sh).

MS (ESI) m/z: 422 (M+N)+.

[Reference example 238]

(1R*,2S*,4R*)-4-Azidomethyl-N2-(tert-butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R*,2S*,4R*)-N2-(tert-butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclohexanediamine a manner similar to the method of reference example 127.

[Reference example 239]

(1R*,2S*)-N,N-Bis(tert-butoxycarbonyl)-4-[(1-etoxycarbonyl)cyclopropane-1-yl]amino-1-cyclohexanediamine (stereoisomer a and stereoisomer B):

Hydrochloride ethyl 1-aminocyclohexanecarboxylic (1.63 g) was dissolved in dichloromethane (60 ml)was added (1R*,2S*)-N,N-bis(tert-butoxycarbonyl)-4-oxo-1,2-cyclohexanediamine (3.0 g) and triacetoxyborohydride sodium (of 2.51 g) and the mixture was stirred at room temperature for 3 hours. Was added aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:1→1:1) to obtain specified in the title compound (stereoisomer A: 1,43 g stereoisomer In: 2.17 g) as colorless amorphous solids.

Stereoisomer A:

1H-NMR (CDCl3) δ: 0,90-1,00 (1H, m), 1,05-1,15 (1H, m), 1,20-1,85 (29N, m), 2.00 in the 2.1 (1H, m), 3,20-to 3.35 (2H, m), 3,65 of 3.75 (1H, m), 4,11 (2H, q, J=7,1 Hz), 4.75 V-4,95 (2H, m).

MS (FAB) m/z: 442 (M+H)+.

Stereoisomer In:

1H-NMR (CDCl3) δ: 0,90-1,70 (28N, m), 1.85 to 1,95 (1H, m), 1,95-2,10 (1H, m), 2,20-of 2.30 (1H, m), 2,85-2,95 (1H, m), 3,20-of 3.45 (2H, m), of 4.13 (2H, q, J=7,1 Hz), 4.80 to 4,94 (2H, m).

MS (FAB) m/z: 442 (M+H)+.

[Reference example 240]

(1R*,2S*)-N2-[(5-Clorinda-2-yl)carbonyl]-4-[(1-etoxycarbonyl)cyclopropane-1-yl]amino-1,2-cyclohexanediamine (stereoisomer a) and (1R*,2S*)-N1-[(5-chloring the l-2-yl)carbonyl]-4-[(1-etoxycarbonyl)cyclopropane-1-yl]amino-1/2-cyclohexanediamine (stereoisomer A):

(1R*,2S*)-N,N-Bis(tert-butoxycarbonyl)-4-[(1-etoxycarbonyl)cyclopropane-1-yl]amino-1,2-cyclohexanediamine (stereoisomer A) (1,34 g) was dissolved in dichloromethane (20 ml)was added a saturated ethanolic solution (20 ml) of hydrochloric acid and the mixture was stirred for 90 minutes. Drove away under reduced pressure, the solvent is obtaining hydrochloride (1R*,2S*)-4-[(1-etoxycarbonyl)cyclopropane-1-yl]amino-1,2-cyclohexanediamine (stereoisomer A) (1.07 g) as a colourless solid.

Obtained as described above, the product was treated in a manner similar to the method of reference example 125, obtaining specified in the connection header.

The one specified in the header connection:

1H-NMR (CDCl3+CD3OD) δ: 0,95-1,05 (2H, m), 1,20-1,35 (6N, m)of 1.45 (1H, m), 1,50-1,90 (4H, m), 2,00-2,10 (1H, m), 3,05 (1H, m), 3,30 (1H, m), 3,76 (1H, m), of 4.13 (2H, q, J=7,1 Hz), 6,98 (1H, d, J=2.2 Hz), 7,21 (1H, DD, J=8,8, 2.2 Hz), 7,35 (1H, d, J=8,8 Hz), 7,60 (1H, d, J=1.5 Hz).

MS (FAB) m/z: 419 (M+H)+.

Another is specified in the header connection:

1H-NMR (CDCl3+CD3OD) δ: 0,99 (1H, m), 1,20-1,35 (6N, m), 1,35-1,90 (6N, m), 2,15 was 2.25 (1H, m), 2,61 (1H, m)to 3.36 (1H, m), 4,05-4,20 (3H, m), to 6.88 (1H, s), 7,22 (1H, DD, J=8,8, 2.0 Hz), 7,35 (1H, d, J=8,8 Hz), 7,60 (1H, d, J=2.0 Hz).

MS (FAB) m/z: 419 (M+H)+.

[Reference example 241]

4-(tert-Butoxycarbonylamino)-1-cyclohexen:

3-Cyclohexa the-1-carboxylic acid (25,3 g) was dissolved in tert-butanol (250 ml), was added triethylamine (28 ml) and diphenylphosphoryl (43,0 ml) and the mixture was stirred 1 hour at room temperature and 2 days at 90°C. drove Away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane), and then was purified column chromatography on silica gel (hexane:ethyl acetate=20:1) to obtain specified in the connection header (24,9 g) as colorless crystals.

1H-NMR (CDCl3) δ: 1,45 (N, C), 1,45-to 1.60 (1H, m), 1,80-1,90 (2H, m), 2.05 is-of 2.20 (2H, m), 2,35 at 2.45 (1H, m), of 3.78 (1H, sh), 4,56 (1H, sh), 5,55-the 5.65 (1H, m), 5,65-of 5.75 (1H, m).

[Referential example 242]

(1R*,2S*)-4-(tert-Butoxycarbonylamino)-1,2-dihydrocyclopenta:

Specified in the title compound was obtained from 4-(tert-butoxycarbonylamino)-1-cyclohexene in a manner similar to the method of reference example 183.

1H-NMR (CDCl3) δ: 1,15-1,30 (1,2H, m), 1,35-2,00 (15 NM, m), 2,15-2,30 (3,2N, m), 2,40-2,60 (1H, m)to 3.64 (1H, sh), 3,75-3,90 (3/2H, m)4,00 (1/2H, sh).

MS (FAB) m/z: 232 (M+H)+.

[Referential example 243]

(1R*,2S*)-4-(tert-Butoxycarbonylamino)-1,2-diazodioxocyclopentanes (stereoisomer a and stereoisomer B):

Relevant specified in the title compound was obtained from (1R*,2S*)-4-(tert-butoxycarbonylamino)-1,2-dihydrooxazolo the Xan way similar to the method of reference example 127.

Stereoisomer A:

1H-NMR (CDCl3) δ: 1,45 (N, C), 1,40-of 1.55 (1H, m), 1.55V and 1.80 (3H, m), 1,95-2,15 (2H, m), 3,53 (1H, m)and 3.59 (1H, sh), of 3.80 (1H, m), 4,70 (1H, sh).

Stereoisomer In:

1H-NMR (CDCl3) δ: of 1.27 (1H, m), 1,44 (N, C), 1,40-of 1.55 (1H, m), 1,80-2,00 (2H, m), 2.00 in to 2.15 (1H, m), of 2.21 (1H, m), of 3.48 (1H, m), of 3.77 (1H, sh), the 3.89 (1H, sh), 4,34 (1H, sh).

[Reference example 244]

The hydrochloride of 4-(4-pyridyl)benzoic acid:

Hydrochloride 4-bromopyridine (11,7 g) and 4-carboxyphenylazo acid (10.0 g) was dissolved in a mixed solvent consisting of toluene (250 ml) and water (250 ml), the solution was added sequentially tetrakis(triphenylphosphine)palladium(0) (5.0 g) and anhydrous sodium carbonate (25.4 g) and the mixture was heated under reflux at 120°C for 19 hours. The reaction mixture was cooled to room temperature, was added ethyl acetate and was extracted with water. In the water layer to acidification was added concentrated hydrochloric acid. The aqueous layer was washed with ethyl acetate and then concentrated and separated precipitated in the sludge solids, to deliver specified in the header of the connection (of 8.37 g) as a colourless solid.

1H-NMR (DMSO-d6) δ: 8,11 (2H, d, J=8,8 Hz)to 8.14 (2H, d, J=8,8 Hz), 8,35 (2H, d, J=6.6 Hz), 8,97 (2H, d, J=6,6 Hz).

MS (FAB) m/z 200 (M+H)+.

[Reference item is emer 245]

Methyl 4-(pyridyl)benzoate:

The hydrochloride of 4-(4-pyridyl)benzoic acid (12.4 g) was dissolved in methanol (200 ml)was added at room temperature, concentrated sulfuric acid (5 ml) and the mixture is boiled under reflux for 3 hours. Upon completion of the reaction drove the solvent and to the residue was added a saturated aqueous solution of sodium bicarbonate and was extracted with him ethyl acetate. The extract was dried over anhydrous sodium sulfate, drove the solvent and to the residue for solidification was added hexane, to deliver specified in the header connection (9,86 g) as colorless powder.

1H-NMR (CDCl3) δ: of 3.96 (3H, s), 7,54 (2H, d, J=5,9 Hz), 7,71 (2H, d, J=8,3 Hz), 8,16 (2H, d, J=8,3 Hz), 8,71 (2H, d, J=5,9 Hz).

[Reference example 246]

N-Oxide of 4-(4-ethoxycarbonylphenyl)pyridine:

Methyl 4-(4-pyridyl)benzoate (1,49 g) was dissolved in dichloromethane (30 ml)was added 70% m-chloroperbenzoic acid (of 3.46 g) and the mixture was stirred at room temperature for 1 hour. Was added an aqueous solution of sodium sulfite for the separation of liquids. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous sodium sulfate. Drove the solvent to obtain specified in the title compound (1.3 g) as a white powder.

1H-NMR (DMSO-d6) δ: 3,88 (3H, s), 7,86 (2H, d, J=7,2 Hz), 7,94 (2H, d, J=8,3 Hz), with 8.05 (2H, d, J=8,3 Hz), 8,30 (2H, d, J=7,2 Hz).

MS (FAB) m/z: 230 (M+H)+.

[Reference example 247]

N-Oxide of 4-(4-carboxyphenyl)pyridine:

N-Oxide of 4-(4-ethoxycarbonylphenyl)pyridine (802 mg) was dissolved in dioxane (20 ml), was added 1 N. aqueous solution (5 ml) of sodium hydroxide and the mixture is boiled under reflux for 1 hour and then stirred at room temperature for 2 hours. To neutralize the mixture was added 1 N. hydrochloric acid (5 ml). Then added water (5 ml) and the precipitate was filtered, to deliver specified in the title compound (627 mg) as a white solid.

1H-NMR (DMSO-d6) δ: a 7.85 (2H, d, J=7,2 Hz), to $ 7.91 (2H, d, J=8,3 Hz), 8,03 (2H, d, J=8,3 Hz), 8,30 (2H, d, J=7,2 Hz).

[Reference example 248]

N-Oxide 2-(4-carboxyphenyl)pyridine:

N-Oxide 2-(4-ethoxycarbonylphenyl)pyridine (260 mg), synthesized from 4-(2-pyridyl)benzoic acid in a manner similar to the method of the reference example described above, was dissolved in 1,4-dioxane (10 ml), was added 1 N. aqueous solution (2.00 ml) of sodium hydroxide and the mixture is boiled under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, to the residue was added N. hydrochloric acid (6 ml) and the precipitate was filtered, to deliver specified in the title compound (202 mg) as a colorless amorphous solid.

1H-NMR (DMSO-d6) δ: 7,41 was 7.45 (2H, m), 7,65-of 7.69 (1H, m), 7,94 (2H, d, J=8,3 Hz), 8,02 (2H, d, J=8,3 Hz), 8.34 per is 8.38 (1H, m), to 13.09 (1H, s).

MS (FAB) m/z: 216 (M+H)+.

[Reference example 249]

(1R,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-(5-Clorinda-2-yl)carbonyl-4-etoxycarbonyl-1,2-cyclohexanediamine:

1) (1R,2R,4S)-N2-tert-Butoxycarbonyl-4-etoxycarbonyl-1,2-cyclohexanediamine was obtained as a pale-brown oil from ethyl (1S,3R,4R)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate in a manner similar to the method of reference example 158.

2) is listed in the title compound was obtained as a colorless solid of the above product in a manner similar to the method of reference example 159.

1H-NMR (CDCl3) δ: 1,22-1,72 (5H, m), 2,15-of 2.28 (2H, m), 2,41-2,49 (1H, m), 2,85 (1H, sh), 3,62 of 3.75 (1H, m), 3,78-to 3.92 (1H, m), 4,12-to 4.28 (2H, m), 4,56-4,63 (1H, m), to 6.88 (1H, sh), 7,20 (1H, DD, J=8.8 and 2.0 Hz), 7,33 (1H, d, J=8,8 Hz), 7,52-EUR 7.57 (1H, m), to 7.59 (1H, d, J=2.0 Hz), 9,24 (1H, s).

MS (ESI) m/z: 464 (M+N)+.

[Reference example 250]

6-Chloro-2-cyanhydrin:

6-Chlorhydrin (2.50 g) was dissolved in dichloromethane (25 ml)was added under ice cooling is-chlorbenzoyl acid (3,71 g) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane, diluted mixture was washed with an aqueous solution of sodium thiosulfate and aqueous solution of sodium hydroxide and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was dissolved in dichloromethane (40 ml), was added trimethylsilylacetamide (2.0 ml) and N,N-dimethylcarbamoyl (1.50 ml) and the resulting mixture was boiled under reflux for 9 hours. Added trimethylsilylacetamide (2.0 ml) and N,N-dimethylcarbamoyl (1.50 ml) and the mixture is boiled under reflux for 16 hours after which the reaction mixture was diluted with dichloromethane, was added 10% aqueous solution (40 ml) of potassium carbonate and the mixture was stirred for 30 minutes. The organic layer was separated and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. To the residue was added dichloromethane and precipitated precipitated crystals were filtered to obtain specified in the title compound (1.77 g) as colorless crystals. Then the mother liquor was purified column chromatography on silica gel (dichloromethane) to obtain specified in the connection header (0,80 g) as pale yellow crystals.

1H-NMR (DMSO-d6) δ: 7,94 (1H, DD, J=9,0, 2.2 Hz), of 8.09 (1H, d, J=8.5 Hz), 8,15 (1H, d, J=9.0 Hz), 8,29 (1H, d, J=2.2 Hz), 8,63 (1H, d, J=8,5 Hz).

MS (FAB) m/z: 189 (M+H)+.

[Reference ol the measures 251]

6-Chlorhydrin-2-carboxylic acid:

6-Chloro-2-cyanhydrin (1.73 g) was dissolved in concentrated hydrochloric acid (40 ml) and the solution boiled under reflux for 19 hours. The reaction mixture was cooled to room temperature and amount of precipitation was filtered and then washed with water, to deliver specified in the header connection (1,81 g) as a colourless solid.

1H-NMR (DMSO-d6) δ: 7,87 (1H, DD, J=9,0, 2.4 Hz), 8,10-to 8.20 (2H, m), 8,24 (1H, d, J=2.2 Hz), charged 8.52 (1H, d, J=8,5 Hz).

MS (FAB) m/z: 208 (M+H)+.

[Referential example 252]

(1S,2R,4S)-N1-Benzyloxycarbonyl-N2-(tert-butoxycarbonyl)-4-ethoxycarbonylmethylene:

(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-4-ethoxycarbonylmethylene (3,10 g) was dissolved in tetrahydrofuran (50 ml) and to the solution was added a saturated aqueous solution (50 ml) of sodium bicarbonate. In the reaction mixture was added dropwise while cooling with ice benzyloxycarbonylamino (1,71 ml), after which the mixture was stirred at room temperature for 3 days. For the separation of liquids in the reaction mixture were added ethyl acetate (200 ml) and water (200 ml). The obtained organic layer was dried over anhydrous sodium sulfate and then drove away under reduced pressure, dissolve the ü. Precipitated precipitated solids were filtered to obtain specified in the connection header (3,24 g) as a colourless solid.

1H-NMR (CDCl3) δ: of 1.24 (3H, t, J=7,1 Hz), 1,29-of 1.44 (1H, m)and 1.51-of 1.64 (1H, m), 1,72-2,02 (4H, m), 2,27-to 2.40 (1H, m), 3,60-to 3.73 (1H, m), 4,00-to 4.15 (3H, m), 4,59 (1H, sh), 5,01-5,13 (2H, m), of 5.26 (1H, sh), 7,27-7,38 (5N, m).

[Referential example 253]

(1S,2R,4S)-4-Carboxy-N1-benzyloxycarbonyl-N2-(tert-butoxycarbonyl)-1,2-cyclohexanediamine:

(1S,2R,4S)-N1-Benzyloxycarbonyl-N2-(tert-butoxycarbonyl)-4-etoxycarbonyl-1,2-cyclohexanediamine (620 mg) was dissolved in tetrahydrofuran (10 ml), was added an aqueous solution (5.0 ml) of the monohydrate of lithium hydroxide (93 mg) and the mixture was stirred at room temperature for 16 hours. Another was added to the reaction mixture of the monohydrate of lithium hydroxide (221 mg) and the mixture was stirred at room temperature for 2 hours, after which the reaction mixture is neutralized 1 N. hydrochloric acid and was extracted with methylene chloride. The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent is obtaining specified in the title compound (580 mg) as a colorless foamy substance.

1H-NMR (CDCl3) δ: 1,22-2,02 (6N, m), 1,44 (N, C), 2,27 at 2.45 (1H, sh), 3,71 is 3.76 (1H, sh),4.09 to (1H, W.), 4, 66-4,71 (1H, sh), at 5.10 (2H, s), of 5.26 (1H, sh), x 6.15 (1H, sh), to 7.35 (5H, s).

MS (FAB) m/z: 393 (M+N)+.

[Reference example 254]

(1S,2R,4S)-N1-Benzyloxycarbonyl-N2-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine:

(1S,2R,4S)-4-Carboxy-N1-benzyloxycarbonyl-N2-(tert-butoxycarbonyl)-1,2-cyclohexanediamine was dissolved in dichloromethane (50 ml)was added dimethylamine hydrochloride (240 mg), triethylamine (0,41 ml), hydrochloride 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide (420 mg) and the monohydrate of 1-hydroxybenzotriazole (340 mg) and the mixture was stirred at room temperature for 1 hour. Another was added to the reaction mixture of dimethylamine hydrochloride (480 mg) and triethylamine (0,82 ml) and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was poured into water to separate the organic layer. Then the organic layer washed with 1 N. hydrochloric acid and saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:methylene chloride=3:47→2:23) to obtain the specified title compound (620 mg) as a colorless foamy substance.

1H-NMR (CDCl3) δ: 1,26-1,98 (6N, m), 1,44 (N, (C), to 2.57 2.63 in (1H, m), with 2.93 (3H, s), to 3.02 (3H, s), 3,70 (1H, sh), 4,14 (1 is, sh)and 4.65 (1H, sh), 5,10 (2H, s), of 5.05-5,13 (1H, sh), to 7.35 (5H, s).

MS (FAB) m/z: 420 (M+H)+.

[Reference example 255]

(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-4(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine:

(1S,2S,4R)-N1-Benzyloxycarbonyl-N2-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine (560 mg) was dissolved in tetrahydrofuran (100 ml)was added 10% palladium on carbon (220 mg) and the mixture was stirred for 17 hours in an atmosphere of hydrogen. Removing by filtration the catalyst, the filtrate was concentrated to obtain specified in the title compound (370 mg) as a colourless oil.

1H-NMR (CDCl3) δ: 1,21-1,87 (6N, m), 1,45 (N, C), 2,64 is 2.75 (1H, m), of 2.92 (3H, s), to 3.02 (3H, s), of 3.73-of 3.78 (2H, sh), is 4.93 (1H, sh).

MS (FAB) m/z: 286 (M+N)+.

[Reference example 256]

(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(6-chlorhydrin-2-yl) carbonyl]-4(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S) N2-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine and 6-chlorhydrin-2-carboxylic acid in a manner similar to the method of reference example 159.

1H-NMR (CDCl3) δ: 1,41 (M, sh), 1,50-1,70 (1H, m), 1,75-of 1.95 (2H, m), 1,95 was 2.25 (3H, m), 2,65 is 2.80 (1H, m), 2,96 (3H, s), of 3.07 (3H, s), 4,15-4,30 (1H, m), 4,30-and 4.40 (1H, m), of 4.95 (1H, sh), 7,66 (1H, d, J=8,8 Hz), to 7.84 (1H, s), of 8.00 (1H,d, J=8,8 Hz), 8,19 (1H, d, J=8.6 Hz), 8,30 (1H, d, J=8.6 Hz).

MS (FAB) m/z: 475 (M+H)+.

[Reference example 257]

Methyl ether (±)-N-formyl-(4-chlorophenyl)alanine:

Hydrochloride methyl ester (±)-(4-chlorophenyl)alanine (2.00 g) suspended in dichloromethane (20 ml)were added hydrochloride 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide (1.60 g), monohydrate, 1-hydroxybenzotriazole (1,23 g), N-methylmorpholin (1.90 ml) and formic acid (0,30 ml) and the mixture was stirred for 15 minutes. After three additional formic acid (0,30 ml) with stirring for 15 minutes the reaction mixture was diluted with dichloromethane. The organic layer was washed with water and dried over anhydrous sodium sulfate, and then drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (dichloromethane:methanol=40:1) to obtain specified in the connection header (1,21 g) as a yellow oil.

1H-NMR (CDCl3) δ: 3,10 (1H, DD, J=13,9, 5.6 Hz), 3,18 (1H, DD, J=13,9, 5,9 Hz in), 3.75 (3H, s), of 4.95 (1H, m), 6,07 (1H, sh), 7,05 (2H, d, J=8,3 Hz), 7,27 (2H, d, J=8,3 Hz), 8,18 (1H, s).

MS (FAB) m/z: 242 (M+H)+.

[Reference example 258]

Methyl 7-chloroisoquinoline-3-carboxylate:

Methyl ether (±)-N-formyl-(4-chlorophenyl)alanine was dissolved in dichloromethane (40 ml) was added dropwise oxalicacid of 0.57 ml). After stirring the mixture at room temperature for 30 minutes, was added iron chloride (3) (1,17 g) at ambient temperature of about -10°and the mixture was stirred at room temperature for 4 days. Added 1 N. hydrochloric acid and the resulting mixture was diluted with dichloromethane to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was dissolved in methanol (38 ml)was added concentrated sulfuric acid (2 ml) and the mixture is boiled under reflux for 20 hours. In the reaction mixture was added an aqueous solution of sodium bicarbonate, the mixture was extracted with dichloromethane and the extract was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=2:1→ethyl acetate) to obtain the specified title compound (0.25 g) as colorless crystals.

1H-NMR (CDCl3) δ: 4,07 (3H, s), 7,74 (1H, DD, J=8,8, 2.0 Hz), 7,94 (1H, d, J=8,8 Hz), of 8.06 (1H, d, J=2.0 Hz), 8,59 (1H, s), 9.28 are (1H, s).

[Reference example 259]

Hydrochloride 7-chloroisoquinoline-3-carboxylic acid:

Methyl 7-chloroisoquinoline-3-carboxylate (0,23 g) was dissolved in concentrated chloridometer the ne acid (10 ml) and the mixture is boiled under reflux for 18 hours. The temperature of the reaction mixture was lowered to room and precipitation was filtered and washed with water to obtain specified in the title compound (0.21 g) as a colourless solid.

1H-NMR (DMSO-d6) δ: of 7.96 (1H, m), 8,29 (1H, d, J=8.5 Hz), 8,44 (1H, s), 8,72 (1H, s), to 9.45 (1H, d, J=6,6 Hz).

MS (FAB) m/z: 208 (M+H)+.

[Reference example 260]

(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(7-chloroisoquinoline-3-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine

Specified in the title compound was obtained from (1S,2R,4S)-N2-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine hydrochloride and 7-chloroisoquinoline-2-carboxylic acid in a manner similar to the method of reference example 159.

1H-NMR (CDCl3) δ: 1,30-1,65 (10H, sh), a 1.75-1,90 (2H, m), 1,90 was 2.25 (3H, m), 2,65-2,90 (1H, sh), 2,96 (3H, s), is 3.08 (3H, s), 4,20-4,30 (1H, m), 4,30-and 4.40 (1H, m), is 4.93 (1H, sh), to 7.68 (1H, m), of 7.90 (1H, sh), to 7.99 (1H, s), 8,35-to 8.70 (2H, m), 9,01 (1H, sh).

MS (FAB) m/z 475 (M+N)+.

[Example 1]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopropylamino:

The monohydrate of 1-hydroxybenzotriazole (71 mg) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (100 mg) was added to a solution of (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclepro is antamina (108 mg) and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (124 mg) in N,N-dimethylformamide (3 ml) at room temperature and the mixture was stirred for 8 days. After concentrating the reaction mixture under reduced pressure using a vacuum pump to the residue was added water (50 ml) and saturated aqueous solution (50 ml) of sodium bicarbonate and the mixture was extracted with dichloromethane. The obtained organic layers were collected and dried over anhydrous sodium sulfate, and then drove away under reduced pressure, the solvent and the residue was purified preparative thin-layer chromatography on silica gel (dichloromethane:methanol=10:1). Adding to the above matter 1 N. hydrochloric acid, dichloromethane and methanol, the mixture was concentrated to obtain specified in the title compound (72 mg) as a colorless solid.

1H-NMR (DMSO-d6) δ: 1,15-1,35 (2H, m), is 2.88 (3H, s), 2.95 and is 3.25 (4H, m), 3,35 of 3.75 (2H, m), 4,32 is 4.45 (1H, m), and 4.68 (1H, sh. J=to 15.4 Hz), was 7.08 (1H, s), 7,17 (1H, DD, J=8,6, and 2.1 Hz), 7,41 (1H, d, J=8.6 Hz), of 7.70 (1H, s), and 8.50 (1H, sh. J=to 11.0 Hz), 8,56 (1H, sh), to 11.56 (1H, sh. J=19.3 Hz), up 11,86 (1H, s).

MS (FAB) m/z: 430 (M+H)+.

[Example 2]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclobutadiene:

5-Methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (136 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (255 mg) and the monohydrate of 1-hydroxybenzotriazole (90 mg) was added to a solution of (±)CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclobutylamine (117 mg) in N,N-dimethylformamide (5 ml) and the mixture was stirred over night at room temperature. Then drove away under reduced pressure, the solvent using a vacuum pump, and to the residue was added dichloromethane and a saturated aqueous solution of sodium bicarbonate for the separation of liquids. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate, and then drove away under reduced pressure, the solvent and the residue was purified column flash chromatography on silica gel (methanol:dichloromethane=7:93). Adding to the above connection of ethyl acetate and 1 N. ethanolic solution of hydrochloric acid for acidification, drove under reduced pressure the solvent. Newly added ethyl acetate and the precipitate was filtered and dried to obtain specified in the title compound (56 mg) as colorless powder.

1H-NMR (DMSO-d6) δ: from 2.00 to 2.35 (4H, m), is 2.88 (3H, m), 3,10 (2H, sh), 3,20 of 3.75 (3H, m), 4,20-4,85 (3H, m), to 7.09 (1H, s), 7,16 (1H, d, J=8,8 Hz), 7,38 (1H, d, J=8,8 Hz), 7,71 (1H, s), 8,63 (1H, d, J=8,3 Hz), cent to 8.85 (1H, d, J=8.6 Hz), 10,85-11,20 (1H, sh), 11,81 (1H, s).

MS (FAB) m/z: 444 (M+H)+.

[Example 3]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene:

5-Clorinda-2-carboxylic acid (80 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (98 mg), manage the rat 1-hydroxybenzotriazole (23 mg) and triethylamine (141 μl) was added to a solution of hydrochloride (± )-TRANS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (120 mg) in N,N-dimethylformamide (5 ml) and the mixture was stirred at room temperature for 3 days. Then drove away under reduced pressure, the solvent and to the residue was added dichloromethane and a saturated aqueous solution of sodium bicarbonate for the separation of liquids. The obtained organic layer was dried over anhydrous sodium sulfate, drove away under reduced pressure, the solvent and the residue was purified column flash chromatography on silica gel (dichloromethane:methanol=93:7). To the obtained in this way pale-yellow solid substance was added dichloromethane (5 ml) and 1 N. ethanol solution (282 μl) of hydrochloric acid. Added ethyl acetate, kept under reduced pressure, the solvent and the formed precipitate was filtered to obtain specified in the title compound (109 mg) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,64-of 1.74 (4H, m), 1,98-2,02 (2H, m), 2,89 (3H, s), 3,14 (2H, sh), 3,47-the 3.65 (2H, m), 4,29-4,63 (4H, m), 7,10 (1H, d, J=1.5 Hz), 7,14 (1H, DD, J=8,5, 2.0 Hz), 7,38 (1H, d, J=8.5 Hz), to 7.68 (1H, d, J=2.0 Hz), 8,55 (1H, d, J=8.5 Hz), 8,91 (1H, d, J=8.5 Hz), 11,49(1H, sh), 11,76 (1H, s).

MS (ESI) m/z: 458 (M+H)+.

[Example 4]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)sulfonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentan the amine:

Specified in the title compound (182 mg) was obtained as a pale yellow solid, dissolving (±)-CIS-N-[(5-chloro-1-phenylsulfonyl-2-yl)sulfonyl]-1,2-cyclopentadien (409 mg), 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (250 mg) and the monohydrate of 1-hydroxybenzotriazole (61 mg) in N,N-dimethylformamide (7 ml) and acting hydrochloride 1(3-dimethylaminopropyl)-3-ethylcarbodiimide (259 mg) as a condensing agent, in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,43-1,85 (6N, m)to 2.94 (3H, s)and 3.15 (2H, sh), 3,49-a-3.84 (3H, m)to 4.23 (1H, t, J=7.5 Hz), 4,35-4,63 (2H, sh), is 6.78 (1H, s), 7,22 (1H, DD, J=8,8, 2.0 Hz), 7,30 (1H, sh), 7,54 (1H, sh), 7,88, of 7.90 (1H, each)of 8.15 (1H, sh. J=8,3 Hz), 11,55-of 11.75 (1H, sh), 12,01 (1H, sh).

MS (ESI) m/z: 494 (M+H)+.

[Example 5]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)sulfonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Triptorelin (±)-CIS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (400 mg) suspended in dichloromethane (10 ml), was added triethylamine (0,514 ml) and 5-chloro-1-phenylsulfonyl-2-sulphonylchloride (published application No. 2000-119253 patent Japan) (319 mg) and the mixture was stirred at room temperature for 15 minutes. Adding in the reaction mixtures is ü water for the separation of liquids the obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane: methanol=100:3) to give a pale yellow foamy substance. The resulting substance was dissolved in tetrahydrofuran (3 ml), was added methanol (2 ml) and 1 N. aqueous solution (1.5 ml) of sodium hydroxide and the mixture is boiled under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added dichloromethane and 1 N. hydrochloric acid for the separation of liquids. The obtained organic layer was dried over anhydrous sodium sulfate, drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=100:3) to give a pale yellow foamy substance. The obtained substance was added to 1 N. hydrochloric acid (1 ml) and the mixture was concentrated under reduced pressure to obtain specified in the title compound (108 mg) as a pale yellow foamy substance.

1H-NMR (DMSO-d6) δ: 1,20-of 1.78 (8H, m)to 2.94 (3H, s), of 3.13 (2H, sh), 3,22 is 3.40 (1H, m), 3,44-3,70 (3H, m), 3,83-of 3.95 (1H, m), 4,20-4,70 (1H, m), 6,78 (1H, s), 7.18 in-7,30 (2H, m), 7,44 (1H, s), 7,69 (1H, sh), of 8.09 (1H, sh), 11,92 (1H, s).

MS (FAB) m/z: 508 (M+H)+

[Example 6]

Hydrochloride (±)-TRANS-N1-[(5-chlorine is indol-2-yl)carbonyl]-N 2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

5-Clorinda-2-carboxylic acid (109 mg), monohydrate, 1-hydroxybenzotriazole (9 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (321 mg) and triethylamine (0,232 ml) was added to a solution of triptoreline (±)-TRANS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (300 mg) in N,N-dimethylformamide (20 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure using a vacuum pump and to the residue was added dichloromethane and water for the separation of liquids. The obtained organic layer was dried over anhydrous sodium sulfate, drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=25:1) to obtain colorless foamy substance. To the obtained substance was added 1 N. hydrochloric acid (1 ml) and kept under reduced pressure, the solvent is obtaining specified in the title compound (203 mg) as a pale brown foamy substance.

1H-NMR (DMSO-d6) δ: 1,25-1,40 (2H, m), 1,46-of 1.81 (4H, m), 1,88-to 1.98 (2H, m), 2,89 (3H, s), 3.00 and is 3.76 (5H, mg, 3,86-of 3.97 (1H, m), 4,00-4,10 (1H, m), 4,25-4,72 (1H, m), 7,03 (1H, s), 7,12 (1H, DD, J=8,5, 1.2 Hz), 7,38 (1H, d, J=8 Hz), to 7.64 (1H, s), of 8.28 (1H, d, J=8.5 Hz), 8,54 (1H, d, J=8.5 Hz), 11,70 (1H, s).

MS (FAB) m/z: 472 (M+H)+.

[Example 7]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from trifenatate (±)-CIS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine a manner similar to the method of example 6.

1H-NMR (DMSO-d6) δ: 1,35-1,70 (6N, m), 1,80 e 2.06 (2H, m), 2,89 (3H, s), 3.00 and-of 3.27 (2H, m), 3,35-3,51 (1H, m), 3,57-3,82 (1H, m), 4,15-4,30 (2H, m), 4,32-4,48 (1H, m), 4,60-4,74 (1H, m), to 7.15 (1H, s), 7,17 (1H, DD, J=8,8, 2,z), 7,41 (1H, d, J=8.6 Hz), of 7.70 (1H, d, J=2.0 Hz), 8,14 (1H, sh), at 8.36-8,48 (1H, m), 11,51 (1H, sh), up 11,86 (1H, s).

MS (FAB) m/z: 472 (M+H)+.

[Example 8]

(1S,2R)-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R,2S)-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (isomer B) in a manner similar to the method of example 6.

[α]D-128,7°(20,8°s=0,5, CHCl3).

1H-NMR (DMSO-d6) δ: 1,38-of 1.52 (2H, m), 1,55-1,70 (4H, m), 1,89-2,07 (2H, m), of 2.38 (3H, s), 2,70-2,77 (2H, m), 2,78-2,87 (2H, m), 3,63 (2H, s), 4,20-4,30 (2H, m), 7,12 (1H, s), 7,14 (1H, d, J=8,8 Hz), 7,41 (1H, d, J=8,8 Hz), and 7.7 (1H, C), 8,10 (1H, d, J=6.9 Hz), 8,30 (1H, d, J=8.1 Hz), 11,77 (1H, s).

MS (FAB) m/z: 472 (M+H)+.

[Example 9]

(1R,2S)-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R)-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (isomer A) in a manner similar to the method of example 6.

[α]D+125,7°(20,8°s=0,5, CHCl3).

1H-NMR (DMSO-d6) δ: 1,38-of 1.52 (2H, m), 1,55-1,70 (4H, m), 1,89-2,07 (2H, m), is 2.37 (3H, s), 2,70 was 2.76 (2H, m), 2,78-of 2.86 (2H, m), 3,63 (2H, s), 4,20-4,30 (2H, m), 7,13 (1H, s), to 7.15 (1H, d, J=8,8 Hz), 7,41 (1H, d, J=8,8 Hz), to 7.67 (1H, s), 8,10 (1H, d, J=6.9 Hz), 8,30 (1H, d, J=8.1 Hz), 11,78 (1H, s).

MS (FAB) m/z: 472 (M+H)+.

[Example 10]

Hydrochloride (±)-CIS-N1-[(6-chloronaphthalene-2-yl) carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound (186 mg) was obtained as a pale brown foamy substance, dissolving the hydrochloride (±)-CIS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (275 mg), 6-chloronaphthalene-2-carboxylic acid (Eur. J. Chem.-Chim. Ther., 1984, Vol.19, pp.205-214) (148 mg), triethylamine (0,298 ml) and the monohydrate of 1-hydroxybenzotriazole (11 mg) in N,N-dimethylformamide (20 m is) and acting hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (412 mg) as a condensing agent, in a manner similar to the method of example 6.

1H-NMR (DMSO-d6) δ: 1,40-of 1.56 (2H, m), of 1.57-1.77 in (4H, m), 1,90-2,10 (2H, m), 2,90 (3H, s), of 3.13 (2H, sh), 3,28-3,74 (2H, m), 4.26 deaths (2H, sh), 4,30-4,74 (2H, m), to 7.59 (1H, d, J=8.6 Hz), of 7.90 (1H, d, J=8.6 Hz), 7,98 (1H, d, J=8,3 Hz), 8,03-8,11 (2H, m), 8,25-8,58 (3H, m), to 11.52 (1H, sh).

MS (FAB) m/z: 483 (M+H)+.

[Example 11]

Hydrochloride (±)-TRANS-N1-[(6-chlorobenzo[b]thiophene-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound (239 mg) was obtained as a pale brown foamy substance, dissolving the hydrochloride (±)-TRANS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (255 mg, 0,665 mmol), 6-chlorobenzo[b]thiophene-2-carboxylic acid (published application No. 2000-119253 patent Japan) (141 mg), triethylamine (0,276 ml) and the monohydrate of 1-hydroxybenzotriazole (10 mg) in N,N-dimethylformamide (20 ml) and acting hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (382 mg) as a condensing agent, in a manner similar to the method of example 6.

1H-NMR (DMSO-d6) δ: 1,20-to 1.98 (8H, m), is 2.88 (3H, s), 3.00 and-and 3.72 (4H, m), a-3.84-4.09 to (2H, m), 4,20-of 4.75 (2H, m), 7,41 (1H, DD, J=8,6) and 1.7 Hz), to $ 7.91 (1H, d, J=8.6 Hz), to 7.99 (1H, s)to 8.12 (1H, s), 8,54-8,67 (2H, m), 11,53 (1H, sh).

MS (FAB) m/z 489 (M+H)+.

[Example 12]

Hydrochloride (±)-TRANS-N1-[(5-Florinda-2-yl)carbonyl]-N2[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-TRANS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and 5-Florinda-2-carboxylic acid in a manner similar to the method of example 6.

1H-NMR (DMSO-d6) δ: 1,20-to 1.38 (2H, m), 1,40-of 1.57 (1H, m), 1,54 by 1.68 (1H, m), 1,71 (2H, d, J=7,3 Hz), a 1.88 (2H, d, J=12.0 Hz), of 2.86 (3H, s), 2.95 and-3,24 (2H, m), 3,40 (1H, sh), 3,63 (1H, sh), 3,90 (1H, sh), 3,97-4,10 (1H, m), 4,20-of 4.44 (1H, m), 4.53-in-4,70 (1H, m), 6,98 (1H, DD, J=9,2, 2.3 Hz), 7,01 (1H, s), 7,31-7,39 (2H, m), compared to 8.26 (1H, D, J=8,Hz), 8,59 (1H, d, J=8,4 Hz), 11,21 (1,2H, sh), 11,42 (1,2H, sh), 11,60 (1H, s).

MS (FAB) m/z: 456 (M+H)+.

[Example 13]

Hydrochloride (±)-CIS-N1-[(5-Florinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and 5-Florinda-2-carboxylic acid in a manner similar to the method of example 6.

1H-NMR (DMSO-d6) δ: 1,43 (2H, sh), to 1.61 (4H, sh), 1,82-of 2.08 (2H, m), 2,89 (3H, s), 3.00 and is 3.23 (2H, m), 3,44 (1H, sh), the 3.65 (1H, sh), to 4.23 (1H, d, J=16.2 Hz), 4.26 deaths (1H, sh), to 4.41 (1H, sh), and 4.68 (1H, d, J=16.2 Hz), 6,98-7,07 (1H, m), 7,14 (1H, s), 7,37-the 7.43 (2H, m), 8,01 (1H, sh), 8,35-charged 8.52 (1H, sh), 11,37 (1H, sh), 11,74 (1H, s).

MS (FAB) m/z: 456 (M+H)+.

[Example 14]

Hydrochloride (±)-TRANS-N1-[(5-chlorine is-6-Florinda-2-yl)carbonyl]-N 2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-TRANS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and 5-chloro-6-Florinda-2-carboxylic acid in a manner similar to the method of example 6.

1H-NMR (DMSO-d6) δ: 1,20-1,40 (2H, m), of 1.40 and 1.80 (4H, m), 1,80-2,00 (2H, m), 2,87 (3H, s), 3,01 (2H, sh), 3,30-of 3.80 (2H, m), 3,81-of 3.97 (2H, m), 4,20-4,80 (2H, m), 7,06 (1H, s), 7,28 (1H, d, J=10.0 Hz), 7,86 (1H, d, J=7,3 Hz), 8,32 (1H, d, J=8.5 Hz), 8,59 (1H, d, J=8.5 Hz), 11,77 (1H, s).

MS (FAB) m/z: 490 (M+H)+.

[Example 15]

Hydrochloride (±)-CIS-N1-[(5-bromoindole-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and 5-bromoindole-2-carboxylic acid in a manner similar to the method of example 6.

1H-NMR (DMSO-d6) δ: 1,43 (2H, sh), to 1.61 (4H, sh), 1,80-2,10 (2H, m), is 2.88 (3H, s), 3.00 and-3,26 (2H, m), 3,40 (1H, sh), the 3.65 (1H, sh), 4,22 (1H, sh), 4.26 deaths (1H, sh), to 4.41 (1H, sh), of 4.67 (1H, d, J=15.6 Hz), 7,14 (1H, s), 7,28 (1H, d, J=8.7 Hz), 7,37 (1H, d, J=8.7 Hz), to 7.84 (1H, s), 8,13 (1H, sh), 8,33-charged 8.52 (1H, m), 11,51 (1H, sh), up 11,86 (1H, s).

MS (ESI) m/z: 515 (M)+.

[Example 16]

(±)-CIS-N -[(5-atenilol-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

The triethylamine (6 ml), N,N-dimethylformamide (5 ml), trimethylsilylacetamide (0,250 ml) and palladium acetate (20 mg) was added to tertrahydrofuran ring solution (2 ml) (±)-CIS-N1-[(5-bromoindole-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (300 mg) and triphenylphosphine (70 mg) at room temperature. After stirring at 90°C for 2 hours the reaction mixture was allowed to cool to room temperature and was added a saturated aqueous solution (30 ml) of sodium bicarbonate for the separation of liquids. The resulting aqueous layer was extracted with dichloromethane (3×10 ml), the organic layers were collected and dried over anhydrous sodium sulfate and drove away under reduced pressure, the solvent to obtain a residue. The obtained residue was purified preparative thin-layer chromatography on silica gel (dichloromethane:acetone:methanol=10:10:1) to obtain a mixture, mainly containing (±)-CIS-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-N2-[[5-(trimethylsilylethynyl)indol-2-yl]carbonyl]-1,2-cyclohexanediamine in the form of a colorless solid. The obtained product was dissolved in methanol (6 ml), was added to the potassium carbonate (120 mg) and the mixture was stirred for 1 hour. To the reaction mixture was added dichloromethane (20 ml) and water (20 ml) to separate the liquids. The resulting aqueous layer was extracted with dichloromethane (2×15 ml), the organic layers were collected and dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The obtained residue was purified preparative thin-layer chromatography on silica gel (dichloromethane:acetone:methanol=10:10:1) and was dissolved in a mixture of water-methanol-dichloromethane. Then the resulting solution was concentrated to obtain specified in the title compound (72 mg) as a pale yellow solid.

1H-NMR (CDCl3) δ: 1,50 was 2.25 (8H, m), of 2.53 (3H, s), 2,85 (2H, sh), with 2.93 (2H, sh), 3,01 (1H, s), 3,74 (1H, d, J=14.1 Hz), of 3.77 (1H, D, J=14.1 Hz), is 4.21 (1H, sh), of 4.45 (1H, sh), 6,91 (1H, s), 7,25-7,42 (2H, m), to 7.61 (1H, sh), 7,80-of 7.97 (2H, m), 9,72 (1H, s).

MS (FAB) m/z: 462 (M+H)+.

[Example 17]

Hydrochloride (±)-CIS-N1-[(6-does not depend-2-yl) carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and 6 does not depend-2-carboxylic acid in a manner similar to the method of example 6.

1H-NMR (DMSO-d6) δ: to 1.45 (2H, sh), of 1.62 (4H, sh), a 1.96 (2H, sh), is 2.88 (3H, s), 2.93 which is 3.25 (2H, m), 3,40 1H, sh), to 3.64 (1H, sh), 4,25 (2H, sh), to 4.41 (1H, sh), of 4.66 (1H, sh), 7,72 (1H, sh), of 7.90 (1H, sh), to 7.99 (2H, sh), 8,20-8,55 (4H, m), 11,46 (1H, sh).

MS (ESI) m/z: 526 (M+, Br79), 528 M+, Br81).

[Example 18]

(±)-CIS-N1-[(6-Ethynylnaphthalene-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine;

Specified in the title compound was obtained from (±)-CIS-N1-[(6-does not depend-2-yl) carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine a manner similar to the method of example 16.

1H-NMR (CDCl3) δ: 1,53 by 1.68 (3H, m), 1,72 (1H, sh), of 1.80 (1H, sh), of 1.93 (2H, sh), 2,17 (1H, sh), at 2.59 (3H, s)to 2.94 (2H, sh), 2,96 totaling 3.04 (2H, m), 3,19 (1H, s), 3,78-are 3.90 (2H, m), 4,27 (1H, sh), 4,48 (1H, d, J=3,7 Hz), at 7.55 (1H, DD, J=8,4, 1.3 Hz), a 7.62 (1H, d, J=7.8 Hz), 7,71 (1H, d, J=5,9 Hz), 7,83 (1H, d, J=8.5 Hz), 7,87 (1H, d, J=8,4 Hz), 7,89 (1H, DD, J=8,5) and 1.7 Hz), 8,02 (1H, s), 8,31 (1H, s).

MS (FAB) m/z: 473 (M+H)+.

[Example 19]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,5-d]pyridazin-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopropylamine and 5,6-dimethyl-4,5,6,7-tetrahydropyrazolo [4,5-d]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1 6) δ: 1,35 of 1.50 (2H, m), 1,50-1,75 (4H, m), 1,80-2,10 (2H, m), 2,70 (3H, sh), and 2.79 (3H, sh), 4,10-4,70 (6N, m), 7,10-7,27 (2H, m), 7,41 (1H, d, J=8,8 Hz), of 7.70 (1H, s)to 8.12 (1H, d, J=6.8 Hz), of 8.47 (1H, d, J=7,6 Hz), 11,85 (1H, s).

MS (FAB) m/z: 487 (M+H)+.

[Example 20]

(±)-CIS-N1-[(5-Clorinda-2-yl) carbonyl]-N2-[(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopropylamine and 6,7-dihydro-4H-pyrano[4,3-d]thiazole-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,36-1,72 (6N, m), 1,90-2,10 (2H, m), 2,80-2,87 (2H, m), 3,93 (2H, t, J=5.6 Hz), 4,20-4,32 (2H, m), to 4.81 (2H, s), 7,12 (1H, s), to 7.15 (1H, DD, J=8,8, 2.0 Hz), 7,41 (1H, d, J=8,8 Hz), to 7.67 (1H, d, J=1.7 Hz), 8,11 (1H, d, J=6.6 Hz), at 8.36 (1H, d, J=8,3 Hz), 11,78 (1H, s).

MS (FAB) m/z: 459 (M+H)+.

[Example 21]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopropylamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,32-1,74 (6N, m), 1,82 is 2.10 (2H, m), of 2.92 (3H, s), 3,12-3,50 (3H, m), of 3.69 (1H, sh), 4,13-4,39 (3H, what), 4,51 (1H, sh), 7,10-7,19 (2H, m), 7,41 (1H, d, J=8,Hz), to 7.68 (1H, s), 8,10 (1H, sh), 8,40 (1H, sh), 11,41 (1H, sh), 11.87 per (1H, s).

MS (FAB) m/z: 472 (M+H)+.

[Example 22]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-TRANS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopropylamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,23-of 1.39 (2H, m), 1,40-of 1.81 (4H, m), 1,82-to 1.98 (2H, m), 2,60-of 3.00 (5H, m), 3,20-3,70 (2H, m), a 3.87-of 3.96 (1H, m), 3,98-4,10 (1H, m), 4,12-4,70 (2H, m),? 7.04 baby mortality (1H, d, J=1.5 Hz), 7,12 (1H, DD, J=8,8, 2.0 Hz), 7,38 (1H, d, J=8,8 Hz), the 7.65 (1H, d, J=2.0 Hz), with 8.33 (1H, d, J=8.6 Hz), 8,72 (1H, d, J=8.6 Hz), to 11.61 (1H, sh), 11,72 (1H, s).

MS (FAB) m/z: 456 (M+H)+.

[Example 23]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopropylamine and 5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,33-1,72 (6N, m), 1,86 e 2.06 (2H, m), 2,70 was 3.05 (5H, m), 3,303,77 (2H, m), 4,17-4,32 (2H, m), 4,33-4,70 (2H, m), 7,12-7,20 (2H, m), 7,41 (1H, d, J=8,8gts), to 7.68 (1H, s), 8,08 (1H, d, J=6,GC), 8,54 (1H, sh), to 11.61 (1H, sh), 11,85 (1H, s).

MS (FAB) m/z: 456 (M+H)+.

[Example 24]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(6-methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopropylamine and 6-methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: of 1.41 (2H, sh)and 1.51-of 1.74 (4H, m), 1,99 (2H, sh), 2,85-3,10 (5H, m), 3,25-3,50 (1H, m), 3,60 (1H, sh), 4,10-4,37 (3H, m), 4.53-in-of 4.67 (1H, m), to 7.15 (1H, DD, J=8,6, 2.0 Hz), 7.23 percent (1H, s), 7,41 (1H, d, J=8.6 Hz), the 7.65 (1H, s), 7,80 (1H, s), 8,10-8,30 (2H, m), 10,84 (1H, sh), 11,90 (1H, s).

MS (FAB) m/z: 471 (M+H)+.

[Example 25]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[2,3-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained by dissolving the hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopropylamine (164 mg), 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-carboxylic acid (WO 94/21599) (140 mg) and the monohydrate of 1-hydroxybenzotriazole (76 mg) in N,N-dimethylformamide (20 ml), acting hydrochloride 1-(-dimethylaminopropyl)-3-ethylcarbodiimide (192 mg) as a condensing agent, and then by processing hydrochloric acid to remove the protection, in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: of 1.42 (2H, sh), and 1.56 to 1.76 (4H, m), 1,98-2,11 (2H, m), 3.04 from (2H, sh), 3,32 is-3.45 (2H, m), 4,15 (3H, sh), 4.26 deaths (1H, sh), 7,14 (1H, DD, J=8,8, 2.0 Hz), 7.23 percent (1H, s), 7,41 (1H, d, J=8,8 Hz), a 7.62 (1H, s), to 7.77 (1H, s), 8,18-8,30 (2H, m), 9,42 (2H, sh), 11,92 (1H, s).

MS (FAB) m/z: 457(M+H)+.

[Example 26]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (171 mg) suspended in dichloromethane (10 ml), was added triethylamine (0.104 g ml) and the mixture was stirred at room temperature for 10 minutes. After addition the reaction mixture of acetic acid (0,059 ml) was added 35% aqueous solution of formaldehyde (0,070 ml) and triacetoxyborohydride sodium (118 mg) and the mixture was stirred at room temperature for 30 minutes. In the reaction mixture was added n aqueous solution (3 ml) of sodium hydroxide and then water, to separate the liquid. The obtained organic layer was dried over anhydrous sodium sulfate, and then drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=50:3) to give a colorless foamy prophetic is TBA. The resulting substance suspended in 1 N. hydrochloric acid and the suspension was concentrated under reduced pressure to obtain specified in the title compound (85 mg) as a colorless foamy substance.

1H-NMR (DMSO-d6) δ: of 1.40 (2H, sh), 1,50-1,71 (4H, m), 1,97-of 2.05 (2H, m), 2,87 (3H, s), 2,98-3,20 (1H, m), 3,30-to 3.38 (2H, m), 3,54-3,70 (1H, m), 4,05 was 4.42 (4H, m), 7,14 (1H, d, J=8.6 Hz), 7.23 percent (1H, s), 7,40 (1H, d, J=8.6 Hz), 7,63 (1H, s), to 7.77 (1H, s), 8.17-a of 8.27 (2H, m), 10,83 (1H, sh), 11,92 (1H, s).

MS (FAB) m/z: 471 (M+H)+.

[Example 27]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5-(N,N-dimethylamino)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl]carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and [5-(N,N-dimethylamino)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: of 1.44 (2H, sh), 1,52 by 1.68 (4H, m), 1,87-of 2.08 (3H, m), 2,30-to 2.40 (1H, m), 2,65 is 2.75 (1H, m), 2,77 (6N, s), 2.95 and-3,17 (2H, m), 3,30-3,70 (2H, m), 4,15-4,30 (2H, m), 7,10-7,20 (2H, m), 7,41 (1H, d, J=8.6 Hz), 7,69 (1H, s), 8,11 (1H, d, J=5,1 Hz), a 8.34 (1H, d, J=8.1 Hz), 10,95 (1H, sh), 11,83 (1H, s).

MS (FAB) m/z: 500 (M+H)+.

[Example 28]

Hydrochloride (±)-CIS-N1-[(6-Clorinda-2-yl)carbonyl]-N2-[[5-(4-pyridyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

n-Utility (1,60 N. hexane solution, 0,704 ml) was added dropwise to a solution of 5-(4-pyridyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine (204 mg) in tetrahydrofuran (3 ml) at -78°and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was again cooled to -78°and then was heated for 20 minutes to room temperature by blowing with carbon dioxide, after which the reaction mixture was concentrated under reduced pressure. To a solution of the obtained residue in N,N-dimethylformamide (6 ml) at room temperature was added the hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (400 mg), monohydrate, 1-hydroxybenzotriazole (254 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (360 mg) and Diisopropylamine (0,491 ml). After stirring for 3 days the reaction mixture was concentrated under reduced pressure, to the residue was added dichloromethane (30 ml), saturated aqueous solution (100 ml) of sodium bicarbonate and water (100 ml) to separate the liquids. The resulting aqueous layer was extracted with dichloromethane (4 x 15 ml), the organic layers were collected and dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The obtained residue was purified column chromatography on silica gel (dichloromethane: methanol=20:1→10:1) and was dissolved in a mixture of 1 N. hydrochloric acid-methanol di is Loretan. Then the resulting solution was concentrated to obtain specified in the title compound (245 mg) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: of 1.42 (2H, sh), to 1.60 (4H, sh), 1,84-of 1.94 (1H, m), 1,94-of 2.08 (1H, m), of 2.97 (2H, sh), 3,97 is 4.13 (2H, m), 4,19 (1H, sh), 4,27 (1H, sh), to 5.03 (2H, s), 7,13 (1H, sh), 7,16 (1H, DD, J=8,8, 2.0 Hz), 7,32 (2H, sh), 7,40 (1H, d, J=8,8 Hz), to 7.68 (1H, d, J=2.0 Hz), 8,15 (1H, sh. J=7,3 Hz), 8,31 (2H, d, J=5,9 Hz), 8,39 (1H, d, J=8.1 Hz), 11,90 (1H, s), 14,03 (1H, sh).

MS (ESI) m/z: 535 (M+H)+.

[Example 29]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2[4-(4-pyridyl)benzoyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and 4-(4-pyridyl)benzoic acid in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,40-of 1.52 (2H, m), 1,60-1,80 (4H, m), 1,96 is 2.10 (2H, m), 4,24-4,39 (2H, m), to 7.15 (1H, DD, J=8,8, 2.0 Hz), 7,21 (1H, s), 7,40 (1H, d, J=8,8 Hz), to 7.64 (1H, d, J=2.0 Hz), of 8.06 (4H, s), 8,18 (1H, J=the 7.3 Hz), 8.34 per-8,42 (3H, m), to 8.94 (2H, d, J=6.9 Hz), 11,91 (1H, s).

MS (FAB) m/z: 473 (M+H)+.

[Example 30]

N-oxide (±)-4-[4-[N-[CIS-2-[[(5-Clorinda-2-yl)carbonyl]amino]cyclohexyl]carbarnoyl]phenyl]pyridine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and N-oxide of 4-(4-carboxyphenyl)the feast of the Dean way similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,40-of 1.52 (2H, m), 1,60-1,80 (4H, m), 1,88 is 2.00 (2H, m), 4,21 is 4.36 (2H, m), 7,12-to 7.18 (2H, m), 7,41 (1H, d, J=8.6 Hz), 7,66 (1H, s), 7,80-7,87 (4H, m), to $ 7.91 (2H, D, J=8,3 Hz), 8,01 (1H, d, J=7,6 Hz), of 8.09 (1H, D, J=7,3 Hz), of 8.27 (2H, d, J=6.6 Hz), to 11.79 (1H, s).

MS (FAB) m/z 489 (M+H)+.

[Example 31]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[4-(2-pyridyl)benzoyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and 4-(2-pyridyl)benzoic acid (published application No. 2000-119253 patent Japan) in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,39-is 1.51 (2H, m), 1,60-1,80 (4H, m), 1,89 is 2.00 (2H, m), 4,24-to 4.38 (2H, m), 7,12-7,16 (2H, m), of 7.36-7,39 (1H, m), 7,42 (1H, d, J=8,8 Hz), 7,66 (1H, d, J=2.0 Hz), 7,87-of 7.90 (1H, m), 7,92 (2H, d, J=8,3 Hz), 7,98-8,11 (3H, m), 8,15 (2H, d, J=8,3 Hz), 8,69 (1H, d, J=4.6 Hz), RS 11.80 (1H, s).

MS (FAB) m/z: 473 (M+H)+.

[Example 32]

N-oxide (±)-2-[4-[N-[CIS-2-[[(5-Clorinda-2-yl)carbonyl]amino]cyclohexyl]carbarnoyl]phenyl]pyridine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and N-oxide 2-(4-carboxyphenyl)pyridine in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,39-is 1.51 (2H, m), 1.60-to to 1.79 (4H, m), 1,89 is 2.00 (2H, m), 23-4,37 (2H, m), 7,12-7,17 (2H, m), 7,39-the 7.43 (3H, m), to 7.61-to 7.64 (1H, m), to 7.67 (1H, d, J=2.0 Hz), 7,89 (4H, s), 8,00-of 8.06 (1H, m), 8,08-8,02 (1H, m), 8,32-8,35 (1H, m), to 11.79 (1H, s).

MS (FAB) m/z: 489 (M+N)+.

[Example 33]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5-(4-pyridyl)thiazol-2-yl]carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-TRANS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and 5-(4-pyridyl)thiazole-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: of 1.44 (2H, sh), of 1.65 (4H, sh), 1.85 to to 2.06 (2H, m)to 4.23 (1H, sh), 4,30 (1H, sh), 7,14-of 7.23 (2H, m), 7,41 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,04-8,13 (2H, m), 8,13 (1H, d, J=8,8 Hz), 8,59 (1H, d, J=8.0 Hz), 8,75-8,87 (3H, m), 11,83 (1H, s).

MS (FAB) m/z: 480 (M+H)+.

[Example 34]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N1N-methyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N1-methyl-l,2-cyclohexanediamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,42-1,90 (7H, m), 2,23 of-2.32 (1H, m), 2,90 (3H, s), 3,11 (3H, sh), 3,19 (2H, sh), 3,45-to 3.67 (2H, sh), to 4.41-4,72 (4H, m), 6,76 (1H, s), 7,17 (1H, DD, J=8,8, 2.0 Hz), the 7.43 (1H, d, J=8,8 Hz), to 7.64 (1H, sh), charged 8.52 (1H, sh. J=8.5 Hz), 11,46 (1H, sh), 11,71 (1H, s).

MS (ESI) m/z: 500 (M+H)+

[Example 35]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2N-methyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Saturated ethanol solution (5 ml) of hydrochloric acid was added to (±)-CIS-N1-(tert-butoxycarbonyl)-N2N-methyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (324 mg), the mixture was stirred at room temperature for 30 minutes and drove away under reduced pressure the solvent. The residue was dissolved in N,N-dimethylformamide (5 ml) and to the solution was added triethylamine (1 ml), 5-Clorinda-2-carboxylic acid (279 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (458 mg) and the monohydrate of 1-hydroxybenzotriazole (108 mg). The resulting mixture was stirred at room temperature for 7 days. Drove away under reduced pressure, the solvent, using a pump, and to the residue was added dichloromethane and a saturated aqueous solution of sodium bicarbonate for the separation of liquids. The obtained organic layer was dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The obtained residue was column purified flash chromatography on silica gel (who harmatan:methanol=93:7) to give a pale yellow solid (176 mg). After dissolving the resulting product in methanol (5 ml) and add 1 N. ethanol solution (362 ml) of hydrochloric acid kept at reduced pressure, the solvent and to the residue was added ethyl acetate. The resulting precipitate was filtered to obtain specified in the title compound (164 mg) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,43-1,90 (7H, m), 2.26 and of-2.32 (1H, m), 2,90 (3H, s), 3,11-3,19 (5H, m), 3,48-3,68 (2H, m), 4,42-4,72 (4H, m), 6,76 (1H, d, J=1.5 Hz), 7,17 (1H, DD, J=8,8, 2,1 Hz), the 7.43 (1H, d, J=8,8 Hz), to 7.64 (1H, sh), charged 8.52 (1H, sh. J=7,6 Hz), of 11.45 (1H, sh), 11,71 (1H, sh).

MS (ESI) m/z: 486 (M+H)+.

[Example 36]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cycloheptadiene:

Specified in the title compound was obtained from (±)-TRANS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cycloheptadiene and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,51-of 1.55 (4H, m), 1,75-1,80 (6N, m), is 2.88 (3H, s), 3,12 (1H, sh), 3,35-3,63 (4H, m), 4,10-4,13 (1H, m), 4,29-br4.61 (2H, m), 7,06 (1H, s), 7,14 (1H, DD, J=8,8, 2.0 Hz), 7,39 (1H, d, J=8,8 Hz), to 7.67 (1H, d, J=2.0 Hz), 8,46 (1H, q, j=8,3 Hz), 8,77 (1H, d, J=8,3 Hz), 11,21-11,35 (1H, m), 11,71 (1H, s).

MS (ESI) m/z: 486 (M+H)+.

[Example 37]

Hydrochloride (±)-CIS-N1-[(5-chlorinda the-2-yl)carbonyl]-N 2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclooctadiene:

Specified in the title compound was obtained from (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclooctadiene and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,61-to 2.06 (N, m), 2,90 (3H, s), is 3.08-3,17 (2H, m), 3.43-3.45 points (1H, m)to 3.67 (1H, sh), 4,43 (3H, sh), of 4.67 (1H, sh), 7,16-to 7.18 (2H, m), 7,42 (1H, d, J=8,8 Hz), of 7.70 (1H, s), 8,24 (1H, sh), 8,58 (1H, d, J=8,3 Hz), 11,43, 11,63 (1H, each sh), RS 11.80 (1H, s).

MS (ESI) m/z 500 (M+H)+.

[Example 38]

The hydrochloride of N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-Ethylenediamine:

Specified in the title compound was obtained from N1-tert-butoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-Ethylenediamine in a manner similar to the method of example 35.

1H-NMR (DMSO-d6) δ: only 2.91 (3H, s), 3,17 (2H, sh), 3,47 (4H, sh), of 3.56 (2H, sh), a 4.53 (2H, sh), was 7.08 (1H, d, J=1.7 Hz), 7,17 (1H, DD, J=8,8, 2.0 Hz), 7,42 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=2.0 Hz), 8,69 (1H, sh), 9,00 (1H, sh), are 11.62 (1H, sh), to 11.79 (1H, sh).

MS (FAB) m/z: 418 (M+H)+.

[Example 39]

The hydrochloride of N1-[(5-Clorinda-2-yl)carbonyl]-N1N-methyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-12-Ethylenediamine:

Specified in the title compound was obtained from N1N-methyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-Ethylenediamine and 5-Clorinda-2-carboxylic acid in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: only 2.91 (3H, s), 3,15-to 3.73 (11N, m), 4,46-br4.61 (2H, m)6,86 (1H, d, J=2.0 Hz), 7,18 (1H, DD, J=8,8, 2.0 Hz), 7,41 (1H, d, J=8,8 Hz), the 7.65 (1H, sh), 9,06 (1H, t, J=5.7 Hz), of $ 11.48 (1H, sh), 11,72 (1H, sh).

MS (ESI) m/z: 432 (M+H)+.

[Example 40]

The hydrochloride of N1-[(5-Clorinda-2-yl)sulfonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-Ethylenediamine:

Specified in the title compound was obtained by elimination of tert-butoxypropyl N1-[(5-chloro-1-phenylsulfonyl-2-yl)sulfonyl]-N2-(tert-butoxycarbonyl)-1,2-Ethylenediamine, followed by its interaction with 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 35.

1H-NMR (DMSO-d6) δ: 2,92 (3H, m), 3,06-of 3.12 (4H, m), 3,31-3,37 (2H, m), 3,44-3,74 (2H, m), of 4.38-of 4.75 (2H, m), 6,92 (1H, d, J=1.2 Hz), 7,27 (1H, DD, J=8,8, 1.7 Hz), the 7.43 (1H, d, J=8,8 Hz), of 7.70 (1H, d, J=1.7 Hz), of 7.90 (1H, t, J=5.8 Hz), 8,81 (1H, t, J=5.8 Hz), 11,25 (1H, sh), 12,14 (1H, sh).

MS (FAB) m/z: 454 (M+H)+.

[Example 41]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole--yl)carbonyl]-1,2-cyclohexanediamine:

5-Methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (155 mg) was dissolved in tetrahydrofuran (7 ml) in an argon atmosphere, the solution was cooled to -78°and added thereto dropwise tert-utility (1,54 N. pentane solution, 0,792 ml). The reaction mixture was stirred for 1 hour under ice cooling and was again cooled to -78°C. After purging the reaction mixture with carbon dioxide for 20 minutes, it was heated to room temperature. The reaction mixture was concentrated under reduced pressure to obtain crude 5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-2-carboxylate lithium. The obtained product was dissolved in N.N-dimethylformamide (20 ml) and to the solution was added the hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (364 mg), monohydrate, 1-hydroxybenzotriazole (150 mg) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (426 mg). The resulting mixture was stirred overnight, the solution was concentrated and to the residue was added dichloromethane and a saturated aqueous solution of sodium bicarbonate for the separation of liquids. The obtained organic layer was dried over anhydrous sodium sulfate and then drove away under reduced pressure the solvent. The obtained residue was purified column chromatography on silica gel (methanol:dichloromethane=7:93). To the resulting product were added 1 N. ethanol races is the thief of hydrochloric acid and ethyl acetate and precipitated precipitated powder was filtered to obtain specified in the title compound (343 mg) as colorless powder.

1H-NMR (DMSO-d6) δ: 1,35-of 1.53 (2H, m)of 1.64 (4H, sh), 1,82-of 2.05 (2H, m), 3,03 (3H, sh), 4,15-5,00 (6N, m), to 7.15 (1H, d, J=1.9 Hz), 7,18 (1H, DD, J=8,7, 1.9 Hz), 7,42 (1H, d, J=8.7 Hz), 7,71 (1H, d, J=1.9 Hz), 8,11 (1H, d, J=7,6 Hz), 8,46 (1H, d, J=7,1 Hz), 11,85 (1H, sh), of 12.26 (1H, sh).

MS (FAB) m/z: 458 (M+N)+.

[Example 42]

Hydrochloride (1R,2R)-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene:

Specified in the title compound was obtained from hydrochloride of (1R, 2R)-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine a manner similar to the method of example 6. The absolute configuration was determined by x-ray analysis.

MS (ESI) m/z: 458 (M+N)+.

[α]D-181,59° (C=1,02, dimethylsulfoxide).

[Example 43]

Hydrochloride (±)-TRANS-N1-[(5-bromoindole-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene:

Specified in the title compound was obtained from hydrochloride (±)-TRANS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene and 5-bromoindole-2-carboxylic acid in a manner similar to the method of example 6.

1H-NMR (DMSO-d6) δ: of 1.65 to 1.76 (4H, m), 2.00 in 2,03 (2H, m), 2.91 in (3H, s), 3,13-3,19 (2H, sh), 3,47 (1H, sh), 3,68 (1H, sh), 4,30-of 4.67 (4H, m), 7,11 (N, d, J=1.5 Hz), 7,27 (1H, DD, J=8,8, 2.0 Hz), 7,35 (1H, d, J=8,8 Hz), to 7.84 (1H, d, J=1.5 Hz),8,56 (1H, d, J=8.5 Hz), 8,93 (1H, d, J=8,8 Hz), 11,44 (1H, sh), 11,78 (1H, sh).

MS (ESI) m/z: 502 (M+H)+.

[Example 44]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene:

Specified in the title compound was obtained, subjecting the product obtained by the interaction (±)-TRANS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium treatment for removing protection in a manner similar to the method of example 2

1H-NMR (DMSO-d6) δ: 1,60-to 1.82 (4H, m), 1,91-of 2.15 (2H, m), is 3.08 (2H, s), 3,37-to 3.49 (2H, m), 4,28-4,56 (4H, m), 7,13 (1H, s), to 7.15 (1H, d, J=8,8 Hz), 7,40 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,61 (1H, d, J=8,3 Hz), 8,88 (1H, d, J=8,3 Hz), of 10.05 (2H, sh), 11,82 (1H, s).

MS (FAB) m/z: 444 (M+N)+.

[Example 45]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene:

Hydrochloride(±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (30 mg) suspended in dichloromethane (20 ml), was added triethylamine (260 μl) and the mixture was stirred at room t is mperature within 15 minutes. In the reaction mixture was added acetic acid (179 μl) and acetone (920 μl) and the resulting mixture was stirred at room temperature for 2 minutes. In the reaction mixture was added triacetoxyborohydride sodium (796 mg) and the mixture was stirred at room temperature for 5 hours. In the reaction mixture were added 1 N. aqueous solution (10 ml) of sodium hydroxide to separate the liquids. The obtained organic layer was dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The residue was purified column chromatography on silica gel (dichloromethane:methanol=100:3) to give a colorless foamy substance. The obtained product was dissolved in dichloromethane and added 1 N. ethanolic hydrochloric acid. The solution was concentrated under reduced pressure to obtain specified in the title compound (205 mg) as a pale yellow foamy substance.

1H-NMR (DMSO-d6) δ: 1,27-1,39 (6N, m), 1,58 and 1.80 (4H, m), 1,95 is 2.10 (2H, m), 3.00 and-of 3.12 (1H, m), of 3.25 to 3.45 (2H, m), 3,59-of 3.77 (2H, m), 4,25-4,39 (1H, m), 4,40-4,55 (2H, m), 4,57 with 4.65 (1H, m), 7,10 (1H, s), 7,14 (1H, d, J=8,8 Hz), 7,38 (1H, d, J=8,8 Hz), 7,68 (1H, s), 8,56 (1H, d, J=8,8 Hz), of 8.90 (1H, d, J=8,8 Hz), is 11.39 (1H, sh), 11,76 (0,5H, C)11,80 (0,5H, s).

MS (FAB) m/z: 486 (M+N)+.

[Example 46]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5(2,3,5,6-tetrahydro-4H-Piran-4-yl)-4,5,6,7-tetrahydropyrazolo[5,4-C]pyridine-2-yl]carbon is l]-1,2-cyclopentadiene:

Specified in the title compound was obtained from hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene using tetrahydro-4H-Piran-4-it instead of acetone of example 45.

1H-NMR (DMSO-d6) δ: 1,60-of 2.20 (10H, m), is 3.08-3,18 (1H, m), 3,21-3,70 (5H, m), 3.72 points-3,91 (1H, m), 3,93-Android 4.04 (2H, m), 4,27 was 4.42 (1H, m), 4,45-4,60 (2H, m), 4,62-of 4.77 (1H, m), 7,12 (1H, s), to 7.15 (1H, DD, J=8,8, 2.0 Hz), 7,39 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=1.7 Hz), 8,56 (1H, d, J=8,3 Hz), 8,91 (1H, d, J=8,3 Hz), 11,77 (1H, s), to 11.79 (1H, s).

MS (FAB) m/z: 528 (M+H)+.

[Example 47]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-cyclopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene:

Acetic acid (0.1 ml), powdered molecular sieves 4A (1 g) and [(1-amoxicilpin)oxy]trimethylsilane (0,173 ml) and then lansberger sodium (to 43.2 mg) was added to a solution of hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl) carbonyl]-N2-[(4,5,6,7-tetrahydrothieno [5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (82,8 mg) in methanol (30 ml) and the mixture is boiled under reflux in a period of 18.5 hours. Allowing the reaction mixture to cool, it was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and dissolve the washed 2 N. aqueous sodium hydroxide solution and saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=3:97) to give a pale yellow amorphous substance (52 mg). To the obtained product was added a mixture of ethanol and hydrochloric acid, and then was added methanol and dichloromethane, to deliver specified in the title compound in the form of solids.

1H-NMR (DMSO-d6) δ: 0,86 (2H, D, J=6.8 Hz), 1,16-of 1.23 (3H, m), 1,62 to 1.76 (4H, m), 2,01-2,04 (2H, m)of 3.00 (1H, sh), 3,19 (2H, sh), 3,68 (2H, sh), 4,30-4,34 (1H, m), 4,47-4,51 (1H, m), with 4.64 (1H, sh), 7,10 (1H, d, J=1.4 Hz), 7,14 (1H, DD, J=8,7, and 2.1 Hz), 7,39 (1H, d, J=8.7 Hz), to 7.67 (1H, d, J=1.9 Hz), 8,53 (1H, d, J=8,3 Hz), 8,89 (1H, d, J=8.5 Hz), 11,74 (1H, s).

MS (FAB) m/z: 484 (M+N)+.

[Example 48]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-1,2-cyclopentadiene:

Specified in the title compound was obtained from hydrochloride (±)-TRANS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene and 5-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 0,81 (2H, sh), 1,20-of 1.55 (5H, s.), 1.55V and 1.80 (4H, m), 1,95-2,12 (2H, m), 305-3,40 (2H, W.), 3,60-of 3.80 (2H, sh), 4,25-4,80 (4H, m), 7,10 (1H, s), 7,16 (1H, d, J=8,8 Hz), 7,39 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,53 (1H, d, J=8.6 Hz), cent to 8.85-8,95 (1H, m), or 10.60-10,90 (1H, sh), 11,73 (1H, sh).

MS (FAB) m/z: 498 (M+H)+.

[Example 49]

Hydrochloride (±)-TRANS-N1-[[5-(tert-butyl)-4,6-dihydro-5H. pyrrolo[3,4-d]thiazol-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene:

Specified in the title compound was obtained from hydrochloride (±)-TRANS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene and 5-(tert-butyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,40 (N, C), 1,60-1,80 (4H, m), 1,95 is 2.10 (2H, m), 4,25-and 4.40 (1H, m), 4,40-4,55 (2H, m), 4,60-4,85 (3H, m), 7,11 (1H, s), 7,16 (1H, d, J=8,8 Hz), 7,39 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,54 (1H, d, J=8.5 Hz), 8,95-9,05 (1H, m), 11,70-RS 11.80 (1H, m), 12,45-12,65 (1H, m).

MS (FAB) m/z: 486 (M+H)+.

[Example 50]

Hydrochloride (±)-TRANS-N1-[[5-(tert-butyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene:

Specified in the title compound was obtained from hydrochloride (±)-TRANS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene and 5-(tert-butyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,43 (N, C), 1,55-of 1.85 (4H, m), 195-2,10 (2H, m), 3,05 is 3.40 (3H, m), 3,85-of 3.95 (1H, m), 4,25-and 4.40 (1H, m), 4,40-4,55 (2H, m), 4,70-is 4.85 (1H, m), 7,11 (1H, s), 7,16 (1H, DD, J=8,8, 2.0 Hz), 7,39 (1H, d, J=8,8 Hz), of 7.70 (1H, d, J=2.0 Hz), 8,50-8,58 (1H, m,), of 8.92 (1H, d, J=8.5 Hz), 10,78 (1H, sh), 11,73-to 11.79 (1H, m).

MS (FAB) m/z: 500 (M+H)+.

[Example 51]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-1,2-cyclopentadiene:

1 M tertrahydrofuran ring solution (5.0 ml) tetrabutylammonium was added to (±)-TRANS-N1-[[5-[2-(tert-butyldiphenylsilyl)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentylamine (757 mg)obtained by the interaction hydrochloride (±)-TRANS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentylamine (393 mg) with 5-[2-(tert-butyldiphenylsilyl)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (812 mg) in a manner similar to the method of example 2, and the mixture was stirred over night at room temperature. To the reaction mixture were added dichloromethane and a saturated salt solution to separate the organic layer, and the obtained organic layer was dried over anhydrous magnesium sulfate. Drove the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:19) to obtain the yellow on Oska. The obtained product was dissolved in dichloromethane and to the solution was added 1 N. ethanolic hydrochloric acid solution and ethyl acetate. The mixture was concentrated, and then added ethyl acetate for curing residue, to deliver specified in the title compound (328 mg) as colorless powder.

1H-NMR (DMSO-d6) δ: of 1.30 (3H, s)of 1.39 (3H, s), 1.55V and 1.80 (4H, m), 1,95 is 2.10 (2H, m), 3,05-3,95 (6N, m), 4.75 V-of 4.25 (4H, m), 5,80 (1H, sh), 7,10 (1H, s), 7,16 (1H, d, J=8.6 Hz), 7,39 (1H, d, J=8.6 Hz), 7,69 (1H, s), charged 8.52 (1H, d, J=8,3 Hz), of 8.90 (1H, d, J=8,3 Hz), 9,92 (1H, sh), 11,72 (1H, sh).

MS (FAB) m/z: 516 (M+H)+.

[Example 52]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl) carbonyl]-N2-[(5-ethyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene:

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (500 mg) was dissolved in N,N-dimethylformamide (10 ml), was added triethylamine (576 μl) and ethyliodide (329 μl) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, to the residue was added water and was filtered, the insoluble substance. The obtained product was purified column chromatography on silica gel (dichloromethane:methanol=100:3) to give pale brown penisdog the matter. The resulting substance suspended in 1 N. hydrochloric acid (2 ml) and the suspension was concentrated under reduced pressure to obtain specified in the title compound (180 mg) as a pale yellow foamy substance.

1H-NMR (DMSO-d6) δ: of 1.32 (3H, t, J=7,1 Hz), 1,60-1,80 (4H, m), 1,96 is 2.10 (2H, m), 3,20-3,39 (5H, m), 3,70-of 3.80 (1H, m), 4.26 deaths-4,58 (3H, m), 4,68-rate 4.79 (1H, m), 7,11 (1H, s), to 7.15 (1H, DD, J=8,8, 2.0 Hz), 7,39 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=1.5 Hz), 8,55 (1H, d, J=8.5 Hz), of 8.92 (1H, d, J=8.5 Hz), 11,38 (1H, sh), 11,70-RS 11.80 (1H, m).

MS (FAB) m/z: 472 (M+H)+.

[Example 53]

Hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5(2-methoxyethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-1,2-cyclopentadiene:

Specified in the title compound was obtained from hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno [5,4-C]pyridine-2-yl)carbonyl]-!,2-cyclopentadiene and 2-methoxyethylamine a manner similar to the method of example 52.

1H-NMR (DMSO-d6) δ: 1,58-of 1.80 (4H, m), 1,96-of 2.09 (2H, m), 3,05 of 3.28 (2H, m), and 3.31 (3H, s), 3,41 is 3.57 (3H, m), 3,70-of 3.85 (3H, m), 4.26 deaths-of 4.38 (1H, m), 4,40-of 4.57 (2H, m), 4,66-4,80 (1H, m), 7,10 (1H, s), to 7.15 (1H, d, J=8,8 Hz), 7,38 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,56 (1H, d, J=8,3 Hz), 8,93 (1H, d, J=8,3 Hz), 11,20 (1H, sh), or 1.77 (1H, s).

MS (FAB) m/z: 502 (M+H)+.

[Example 54]

(±)-TRANS-N1-[[5(tert-Butoxycarbonylmethyl)-4,5,6,7-tetrahydrothieno[5,4-C]Piri is in-2-yl]carbonyl]-N 2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadien:

Specified in the title compound was obtained from hydrochloride (±)-TRANS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene and tert-butylbromide a manner similar to the method of example 52.

1H-NMR (CDCl3) δ: 1,47 (N, s), 1.60-to of 1.95 (4H, m), 2,19-of 2.28 (1H, m), 2,45 is 2.55 (1H, m), 2,87-of 3.07 (4H, m)to 3.36 (2H, s), 3,88 (1H, d, J=15,4 Hz), of 3.97 (1H, d, J=15,4 Hz), 4.09 to 4,18 (1H, m), of 4.38 figure-4.49 (1H, m), 6.90 to (1H, d, J=2.0 Hz), 7,18 (1H, DD, J=8,8, 2.0 Hz), 7,31 (1H, d, J=8,8 Hz), 7,49 (1H, d, J=7.8 Hz), to 7.61 (1H, s), 7,71 (1H, d, J=5.6 Hz), to 9.57 (1H, s).

MS (FAB) m/z: 558 (M+H)+.

[Example 55]

(±)-TRANS-N1-[[5 - (Carboxymethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadien:

The compound (170 mg)obtained in example 54 was dissolved in dichloromethane (1 ml), was added triperoxonane acid (5 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, to the residue was added diethyl ether and the precipitated residue was filtered to obtain specified in the title compound (127 mg) as a colorless foamy substance.

1H-NMR (DMSO-d6) 6: of 1.65 and 1.80 (4H, m), 2.00 in a 2.12 (2H, m), 3,02-3,10 (2H, m), 3,40-3,55 (2H, m), 3,98-4,08 (2N, is), 4,30-4,59 (4H, m), 7,10 (1H, s), 7,17 (1H, DD, J=8,6, 2.0 Hz), 7,39 (1H, d, J=8.6 Hz), 7,69 (1H, s), 8,53 (1H, d, J=8.6 Hz), 8,99 (1H, d, J=9.0 Hz), 11,73 (1H, s).

MS (FAB) m/z: 502 (M+H)+.

[Example 56]

Hydrochloride (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer a and stereoisomer B):

(1R*That 2R*)-N1-[(5-Clorinda-2-yl) carbonyl]-4-methoxycarbonyl-1,2-cyclopentanedione (mixture of stereoisomers) (3.42 g) was dissolved in N,N-dimethylformamide (20 ml), was added 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (3.12 g), monohydrate, 1-hydroxybenzotriazole (689 mg), and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4,89 g) and the mixture was stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate solution and dichloromethane and separated liquid. The resulting aqueous layer was extracted with dichloromethane. The obtained organic layers were collected and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column flash chromatography on silica gel (dichloromethane:methanol=97:3→19:1) to obtain the stereoisomer (585 mg) and stereos the measure In (1.31). Each stereoisomer was dissolved in methanol and to the solution was added 1 N. ethanolic hydrochloric acid. Drove away under reduced pressure, the solvent and to the residue was added ethyl acetate. The precipitate was filtered with getting listed in the title compounds [stereoisomer A (573 mg) and stereoisomer B (1.26 g] as pale yellow solids.

Hydrochloride stereoisomer A:

1H-NMR (DMSO-d6) δ: 1,91-2,02 (2H, m), 2,23-of 2.27 (2H, m), 2,90 (3H, s), 3,06-3,14 (3H, m), 3.46 in-to 3.64 (5H, m), of 4.38 with 4.64 (4H, m), 7,10 (1H, d, J=1.5 Hz), 7,16 (1H, DD, J=8,7, 2.0 Hz), 7,39 (1H, d, J=8.7 Hz), of 7.70 (1H, d, J=2.0 Hz), 8,64 (1H, d, J=8,3 Hz), of 9.02 (1H, d, J=8.6 Hz), 11,41 (1H, sh), to 11.79 (1H, sh).

MS (FAB) m/z: 516 (M+H)+.

Hydrochloride stereoisomer In:

1H-NMR (DMSO-d6) δ: 1,91-2,02 (2H, m), 2,19 is 2.33 (2H, m), 2,90 (3H, s), 3,05-3,17 (3H, m), 3.46 in-3,68 (5H, m), 4,39 with 4.64 (4H, m), 7,11 (1H, d, J=1.5 Hz), to 7.15 (1H, DD, J=8,8, 2.0 Hz), 7,38 (1H, d, J=8,8 Hz), of 7.70 (1H, d, J=2.0 Hz), 8,63 (1H, d, J=8.6 Hz), 9,01 (1H, d, J=8,8 Hz), 11,42 (1H, sh), 11,78 (1H, sh).

MS (FAB) m/z: 516 (M+H)+.

[Example 57]

(1R*That 2R*)-4-Carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadien (stereoisomer):

Stereoisomer (900 mg)obtained in example 56 was dissolved in methanol (10 ml) and water (3 ml), was added lithium hydroxide (84 mg) and the mixture was stirred at room is temperature for 3 hours. The reaction mixture is neutralized, drove away under reduced pressure, the solvent and to the residue was added water. The insoluble substance was filtered to obtain specified in the connection header (of 1.03 g) as a crude pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,86 of 1.99 (2H, m), 2,20-of 2.30 (2H, m), of 2.38 (3H, s), was 2.76 (2H, sh), 2,84 (2H, sh), 2,95-3,03 (1H, m), 3,66 (2H, sh), 4,37 was 4.42 (1H, m), 4,56-4,60 (1H, m), 7,11 (1H, s), 7,16 (1H, d, J=8.5 Hz), 7,40 (1H, d, J=8.5 Hz), of 7.70 (1H, s), 8,58 (1H, d, J=8.1 Hz), 8,81 (1H, d, J=8,3 Hz), 11,73 (1H, sh).

MS (FAB) m/z: 502 (M+H)+.

[Example 58]

Hydrochloride (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N-methylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer):

Stereoisomer (195 mg)obtained in example 57 was dissolved in N,N-dimethylformamide (5 ml), was added monohydrate, 1-hydroxybenzotriazole (26 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (149 mg), methylamine hydrochloride (52 mg) and triethylamine (107 μl) and the mixture was stirred at room temperature for 24 hours. Drove away under reduced pressure, the solvent, to the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate, Otho the Yali under reduced pressure the solvent. The residue was purified column flash chromatography on silica gel (dichloromethane:methanol=9:1).

The obtained pale yellow solid was dissolved in methanol, was added 1 N. ethanol solution (276 μl) hydrochloric acid, concentrated under reduced pressure, the solvent and to the residue was added ethyl acetate. The resulting precipitate was filtered to obtain specified in the title compound (140 mg) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,83 is 1.91 (2H, m), 2,09-2,19 (2H, m), 2,59, 2,60 (3H, each s), 2,82-2,90 (4H, m)and 3.15 (2H, sh), 3,44-to 3.67 (2H, sh), 4,34-4,63 (4H, m), 7,12 (1H, d, J=1.2 Hz), 7,16 (1H, DD, J=8,8, 2,1 Hz), 7,39 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=2.1 Hz), 7,88, 7,89 (1H, each s), 8,81 (1H, d, J=8.6 Hz), 8,97 (1H, d, J=8.6 Hz), 11,37 (1H, sh), 11,76 (1H, sh).

MS (ESI) m/z: 515 (M+H)+.

[Example 59]

Hydrochloride (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]-pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer):

Specified in the title compound was obtained from a stereoisomer, obtained in example 57, in a manner similar to the method of example 58.

1H-NMR (DMSO-d6) δ: 1,84-of 1.95 (2H, m), 2,12-2,22 (2H, m), 2,85 (3H, s), is 2.88 (3H, s), a 3.01 (3H, s), 3,05-3,10 (1H, m)and 3.15 (2H, sh), 3,29-of 3.53 (2H, m), 4,34-4,63 (4H, m), 7,11 (1H, s), to 7.15 (1H, DD, J=8,7, 1.7 Hz), 7,38 (1H, d, J=8.7 Hz), 7,69 (1 is, d, J=1.7 Hz), 8,64 (1H, d, J=8.6 Hz), 8,97 (1H, d, J=8,8 Hz), is 11.39 (1H, sh), 11,76.(1H, s).

MS (ESI) m/z: 529 (M+N)+.

[Example 60]

Hydrochloride (1R*That 2R*)-4-methoxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer a and stereoisomer B):

1) Hydrochloride (1R*That 2R*)-4-methoxy-1,2-cyclopentadiene (470 mg) suspended in N,N-dimethylformamide (5 ml), was added triethylamine (0,966 ml) and p-nitrophenyl 5-Clorinda-2-carboxylate (805 mg) and the mixture was stirred at room temperature for 4 days. Drove away under reduced pressure, the solvent and to the residue was added saturated aqueous sodium hydrogen carbonate solution and dichloromethane to separate liquids. The obtained organic layers were dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:9) to give (1R*That 2R*)-4-methoxy-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentylamine (mixture of stereoisomers at position 4) (268 mg) as a yellow powder.

2) a Mixture of stereoisomers a and b indicated in the title compound was synthesized from the product obtained above, in a manner similar to the method of example 2, and the isomers is delali column chromatography on silica gel in the same way, as in example 56, and then turned in hydrochloride with getting listed in the title compounds [stereoisomer A (75 mg) and stereoisomer B (70 mg)].

Stereoisomer A:

1H-NMR (DMSO-d6) δ: 1,70-of 2.15 (4H, m), 2,90 (3H, s), 3.00 and-are 3.90 (8H, m), 4,10-4,80 (4H, m), was 7.08 (1H, s), 7,16 (1H, d, J=8,8 Hz), 7,38 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,56 (1H, d, J=8,8 Hz), 8,88 (1H, d, J=8,3 Hz), 10,96 (1H, sh), 11,75 (1H, sh).

MS (FAB) m/z: 488 (M+H)+.

Stereoisomer In:

1H-NMR (DMSO-d6) δ: 1,60-2,10 (4H, m), 2,89 (3H, s), 3.00 and-3,70 (7H, m), 3,70-are 3.90 (1H, m), 4,20-4,80 (4H, m), 7,05-7,20 (2H, m), 7,38 (1H, d, J=8,8 Hz), 7,68 (1H, s), 8,59 (1H, d, J=8,3 Hz), of 8.90 (1H, d, J=8,5 Hz), of 11.26 (1H, sh), 11,74 (1H, sh).

MS (FAB) m/z: 488 (M+H)+.

[Example 61]

(1R*That 2R*)-4-Benzyloxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadien (stereoisomer a and stereoisomer B):

Stereoisomers a and b indicated in the title compounds were obtained from a mixture of (1R*That 2R*,4R*)and (1R*That 2R*4S*)-4-benzyloxy-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadienes and their respectively allocated column chromatography on silica gel with getting listed in the header of the compounds, stereoisomers a and B.

Stereoisomer A:

1H-NMR (CDCl3) δ: 1,75-of 1.95 (2H, m)of 2.50 (3H, s), 2,60-2,70 (1H, m), 2,70-2,90 (5H, m),the 3.65 (1H, d, J=15,4 Hz), 3,74 (1H, d, J=15.6 Hz), 4,10-4,20 (1H, m), 4,30-4,45 (2H, m), 4,47 (1H, d, J=11.7 Hz), 4,58 (1H, d, J=12.0 Hz), to 6.88 (1H, d, J=2.2 Hz), 7,20 (1H, DD, J=8.6 and 2.0 Hz), 7,30-7,40 (6N, m)to 7.50 (1H, d, J=5.4 Hz), 7,58 (1H, d, J=7,3 Hz), 7,63 (1H, d, J=2.0 Hz), 9,19 (1H, sh).

MS (FAB) m/z: 564 (M+H)+.

Stereoisomer In:

1H-NMR (CDCl3) δ: 1,80-2,00 (2H, m), 2,45 is 2.55 (1H, m), 2.49 USD (3H, s), 2,70-2,90 (5H, m), the 3.65 (1H, d, J=15,8 Hz), and 3.72 (1H, d, J=15.2 Hz), 4,15-4,30 (2H, m), 4,48 (1H, d, J=11.3 Hz), to 4.52 (1H, d, J=11.5 Hz), 4,55-4,70 (1H, m), of 6.68 (1H, d, J=1.7 Hz), 7,18 (1H, DD, J=8.7 and 2.0 Hz), 7,20-7,35 (6N, m), 7,42 (1H, d, J=7.8 Hz), 7,56 (1H, D, J=1.7 Hz), 7,60 (1H, d, J=6.4 Hz), 9,31 (1H, sh).

MS (FAB) m/z: 564 (M+H)+.

[Example 62]

Hydrochloride (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxy-N2-[(5-methyl-4,5,6,7-tetrahydrothieno [5,4-C] pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer):

Dimethyl sulphide (8 ml) and anhydrous aluminium chloride (2.0 g) was dissolved in dichloromethane (100 ml)was added stereoisomer In (1.20 g)obtained in example 61, and the mixture was stirred at room temperature for 8.5 hours. The reaction mixture was concentrated under reduced pressure and to the residue to acidification was added diluted hydrochloric acid. The resulting solution was podslushivaet saturated aqueous sodium bicarbonate and was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and then drove propanganda pressure of the solvent. The residue was purified column chromatography on silica gel (dichloromethane:methanol=9:1) to give yellow powder (0,93 g). To the obtained powder (100 mg) was added 1 N. ethanolic solution of hydrochloric acid and the solution was concentrated under reduced pressure to obtain specified in the title compound (84 mg) as a pale yellow powder.

1H-NMR (DMSO-d6) δ: 1,55-1,70 (1H, m), 1.85 to 1,95 (2H, m), of 2.25 to 2.35 (1H, m), with 2.93 (3H, s)3,00-3,20 (2H, m), 3,35-3,70 (2H, m), 4,15-of 4.25 (1H, m), 4,30-of 4.75 (3H, m), 7,13 (1H, d, J=2.2 Hz), to 7.15 (1H, DD, J=8.8 and 2.2 Hz), 7,38 (1H, d, J=9.3 Hz), to 7.67 (1H, s), to 8.57 (1H, D, J=8.1 Hz), 8,88 (1H, d, J=8,3 Hz), 10,79 (1H, sh), 11,72 (1H, s).

MS (FAB) m/z: 474 (M+H)+.

[Example 63]

(1R*That 2R*)-4-Acetoxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadien (stereoisomer):

Stereoisomer (208 mg)obtained in example 62 was dissolved in pyridine (3 ml)was added at room temperature acetylchloride (35,5 μl) and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was podslushivaet saturated aqueous sodium bicarbonate and was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and then drove away under reduced pressure restoreselection was purified column chromatography on silica gel (dichloromethane:methanol=1:1) to obtain the specified title compound (180 mg) in powder form.

1H-NMR (CDCl3) δ: 1,70-of 1.85 (1H, m), 2.00 in to 2.15 (1H, m)to 2.06 (3H, s), of 2.20 to 2.35 (1H, m)of 2.50 (3H, s), 2,70-3,10 (5H, m), 3,66 (1H, d, J=15.1 Hz), to 3.73 (1H, d, J=15,4 Hz), 4,05-4,20 (1H, m), 4,60-of 4.75 (1H, m), 5,15-and 5.30 (1H, m), 6.90 to (1H, d, J=1.2 Hz), 7,21 (1H, DD, J=8.8 and 2.0 Hz), 7,31 (1H, d, J=8.5 Hz), of 7.48 (1H, d, J=7.8 Hz), 7,63 (1H, d, J=2.0 Hz), to 7.67 (1H, d, J=5.4 Hz), of 9.30 (1H, sh).

MS (FAB) m/z: 516 (M+H)+.

[Example 64]

Hydrochloride (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer A):

1) (1R*That 2R*)-4-Benzoyloxymethyl-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadien (794 mg) was dissolved in N,N-dimethylformamide (150 ml), was added 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (694 mg), monohydrate, 1-hydroxybenzotriazole (61 mg) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1,15 g) and the mixture was stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure, to the residue was added water and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified preparative thin-layer chromatography (dichloromethane:acetone=2:1) to obtain the stereoisomer A (378 mg) and ground is of isomer In (354 mg), (1R *That 2R*)-4-benzoyloxymethyl-N1-[(5-Clorinda-2-yl) carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene.

Stereoisomer A:

1H-NMR (CDCl3) δ: 1,50-of 1.53 (1H, m), 1,76-of 1.84 (1H, m), 2,31-to 2.40 (2H, m), 2.49 USD (3H, s), of 2.51 at 2.59 (1H, m), 2,72-of 2.93 (4H, m), 3,38-3,50 (2H, m), 3,66 (1H, d, J=15,4 Hz), to 3.73 (1H, d, J=15,4 Hz), 4,10-4,19 (1H, m), to 4.38-4,47 (1H, m), 4,55 (2H, s), to 6.88 (1H, s), 7,20 (1H, DD, J=8,8, 1.5 Hz), 7,25-7,37 (6N, m), 7,55 (1H, d, J=6.3 Hz), to 7.64 (1H, s), 9,16 (1H, s).

MS (FAB) m/z 578 (M+H)+.

Stereoisomer In:

1H-NMR (CDCl3) δ: 1,40-is 1.51 (1H, m), 1,83-of 1.92 (1H, m), 2,10-to 2.18 (1H, m), 2.49 USD (3H, s), of 2.51 of 2.68 (2H, m), 2,73-to 2.94 (4H, m), 3,39-to 3.49 (2H, m), 3,63 (1H, d, J=15,4 Hz), and 3.72 (1H, d, J=15,4 Hz), 4,14-to 4.23 (1H, m), to 4.41-4,50 (2H, m), of 4.54 (2H, s), 6,72 (1H, d, J=1.7 Hz), 7,17 (1H, DD, J=8,8, 2.0 Hz), 7,27-7,42 (6N, m), EUR 7.57 (1H, d, J=1.7 Hz), 7,66 (1H, d, J=6,1 Hz), 9,41 (1H, s).

MS (FAB) m/z 578 (M+H)+.

2) Benzyl group obtained above stereoisomer And eliminated in a manner similar to the method of example 62, obtaining specified in the title compound (269 mg).

1H-NMR (DMSO-d6) δ: 1,41-of 1.52 (1H, m), 1,69-1,90 (2H, m), 2,03-of 2.30 (2H, m), 2,90 (3H, s), 3,09-3,19 (2H, m), 3,40-to 3.73 (5H, m), 4,40-4,74 (4H, m), 7,11 (1H, s), to 7.15 (1H, DD, J=8,6, 2.0 Hz), 7,38 (1H, d, J=8.6 Hz), of 7.69 (1H, J=1.7 Hz), charged 8.52 (1H, J=8.6 Hz), 8,88 (1H, J=8.6 Hz), 11,07 (1H, sh), 11,74 (1H, s).

MS (FAB) m/z: 488 (M+H)+.

[Example 65]

Hydrochloride (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer):

Specified in the title compound was obtained from a stereoisomer, obtained in stage 1) of example 64, in a manner similar to step 2) of example 64.

1H-NMR (DMSO-d6) δ: 1,35-1,40 (1H, m), of 1.78-1.90 (2H, m), 2,01-2,11 (1H, m), 2,19-of 2.30 (1H, m), 2.91 in (3H, s), 3,10-of 3.77 (7H, m), 4,27-4,78 (4H, m), to 7.09 (1H, s), to 7.15 (1H, d, J=8,8 Hz), 7,38 (1H, d, J=8,8 Hz), 7,69 (1H, s), charged 8.52 (1H, d, J=8,3 Hz), of 8.90 (1H, d, J=8,3 Hz), 10,97 (1H, sh), 11,73 (1H, s).

MS (FAB) m/z: 488 (M+H)+.

[Example 66]

The allocation of optically active compounds (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer A):

Stereoisomer a, obtained in example 64, separated into optically active compounds by HPLC (hexane:isopropyl alcohol:diethylamine=80:20:0.5; the volumetric flow rate: 12 ml/min)using CHIRALPAK AD (Daicel Chemical Industries Ltd.), obtaining optically active compounds A1, lirovannomu for 45 minutes, and optically active compounds A2, lirovannomu for 62 minutes. Into the corresponding optically active compounds to be suspended them, added 1 N. hydrochloric acid and then each suspension was concentrated under reduced pressure to obtain hydrochloride (92 mg) optically active compounds A1 and hydrochloride (74 mg) optically active compound A2 in the IDA pale brown foamy substance.

Hydrochloride optically active compounds A1:

1H-NMR (DMSO-d6) δ: 1,41-of 1.52 (1H, m), 1,69-1,90 (2H, m), 2,03-of 2.30 (2H, m), 2,90 (3H, s), 3,09-3,19 (2H, m), 3,40-to 3.73 (5H, m), 4,40-4,74 (4H, m), 7,11 (1H, s), to 7.15 (1H, DD, J=8,6, 2.0 Hz), 7,38 (1H, d, J=8.6 Hz), of 7.69 (1H, J=1.7 Hz), charged 8.52 (1H, J=8.6 Hz), 8,88 (1H, J=8.6 Hz), 11,07 (1H, sh), 11,74 (1H, s).

MS (FAB) m/z: 488 (M+H)+.

Hydrochloride optically active compounds A2:

1H-NMR (DMSO-d6) δ: 1,41-of 1.52 (1H, m), 1,69-1,90 (2H, m), 2,03-of 2.30 (2H, m), 2,90 (3H, s), 3,09-3,19 (2H, m), 3,40-to 3.73 (5H, m), 4,40-4,74 (4H, m), 7,11 (1H, s), to 7.15 (1H, DD, J=8,6, 2.0 Hz), 7,38 (1H, d, J=8.6 Hz), of 7.69 (1H, J=1.7 Hz), charged 8.52 (1H, J=8.6 Hz), 8,88 (1H, J=8.6 Hz), 11,07 (1H, sh), 11,74 (1H, s).

MS (FAB) m/z: 488 (M+H)+.

[Example 67]

Hydrochloride (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer A):

1) Stereoisomers a and b (1R*That 2R*)-4-benzoyloxymethyl-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene was obtained from (1R*That 2R*)-4-benzoyloxymethyl-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene and 5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to stage 1) of example 64.

Stereoisomer A:

1H-I Is R (CDCl 3) δ: 1,12 (6N, d, J=6.4 Hz), 1,53-to 1.63 (1H, m), 1,75-of 1.85 (1H, m), 2,29-2,39 (2H, m), 2,47-of 2.58 (1H, m), 2,78-to 3.02 (5H, m), 3,37-to 3.49 (2H, m), 3,76 (1H, d, J=15.1 Hz), 3,83 (1H, d, J=15.1 Hz), 4,15-to 4.23 (1H, m), 4,40-4,50 (1H, m), of 4.54 (2H, s), to 6.88 (1H, d, J=1.7 Hz), 7,16 (1H, DD, J was 8.8, 2.0 Hz), 7,27-7,38 (6N, m), 7,58 (1H, d, J=7,3 Hz), 7,60 (1H, S), to 7.64 (1H, d, J=5.6 Hz), of 9.56 (1H, s).

MS (FAB) m/z: 606 (M+H)+.

Stereoisomer In:

1H-NMR (CDCl3) δ: 1,12 (1H, d, J=6.6 Hz), 1,42-of 1.52 (1H, m), 1,82-of 1.92 (1H, m), 2,10-of 2.20 (1H, m), 2,48 of 2.68 (2H, m), 2,80-to 3.02 (5H, m), 3,40-to 3.49 (2H, m), of 3.77 (1H, d, J=15,5 Hz), 3,83 (1H, d, J=15,5 Hz), 4,15-4,25 (1H, m), 4,42-to 4.52 (1H, m), a 4.53 (1H, d, J=1.0 Hz), 6,74 (1H, d, J=1.5 Hz), 7,17 (1H, DD, J=8,8, 2.0 Hz), 7,27-7,37 (6N, m), 7,41 (1H, d, J=7.8 Hz), EUR 7.57 (1H, d, J=2.0 Hz), to 7.68 (1H, d, J=6,1 Hz), 9,51 (1H with).

MS (FAB) m/z: 606 (M+H)+.

2) is listed in the title compound was obtained from the above stereoisomer And in a manner similar to step 2) of example 64.

1H-NMR (DMSO-d6) δ: 1,30-1,40 (6N, m), USD 1.43-of 1.53 (1H, m), 1,71 is 1.91 (2H, m), 2,09-of 2.16 (1H, m), 2,19-2,31 (1H, m), 3.04 from is 3.15 (1H, m), 3,34-of 3.77 (7H, m), 4,30-of 4.67 (4H, m), 7,12 (1H, S), 7,16 (1H, d, J=8,8 Hz), 7,40 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,56 (1H, d, J=8,3 Hz), cent to 8.85 (1H, d, J=8,3 Hz), 11,42 (1H, sh), 11,77 (0,5H, C)11,80 (0,5H, s).

MS (FAB) m/z: 516 (M+N)+.

[Example 68]

Hydrochloride (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer):

Specified in the title compound was obtained from a stereoisomer, recip is spent in stage 1) of example 67, in a manner similar to step 2) of example 67.

1H-NMR (DMSO-d6) δ: 1,30-1,39 (6N, m), 1,40-and 1.54 (1H, m), 1,75-1,90 (2H, m), 2,02-2,11 (1H, m), 2,18-of 2.30 (1H, m), 3,05 is 3.15 (1H, m), 3,30-3,55 (5H, m), 3,60-with 3.79 (2H, m), 4,29-to 4.38 (1H, m), to 4.41-of 4.67 (3H, m), 7,10 (1H, C)to 7.15 (1H, d, J=8,8 Hz), 7,39 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,54 (1H, d, J=8.5 Hz), 8,87 (1H, d, J=8.5 Hz), of 11.29 (1H, sh), 11,75 (0,5H, s), 11,78 (0,5H, s).

MS (FAB) m/z: 516 (M+N)+.

[Example 69]

Hydrochloride (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclopentadiene (stereoisomer A):

1) Stereoisomers a and b (1R*That 2R*)-4-benzoyloxymethyl-N1-[[5[2(tert-butyldiphenylsilyl)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene was obtained from (1R*That 2R*)-4-benzoyloxymethyl-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene and 5-[2-(tert-butyldiphenylsilyl)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

Stereoisomer A:

1H-NMR (CDCl3) δ: 1,05 (N, C), 1,168, 1,171 (6N, each s), 1,53-to 1.61 (1H, m), 1,76-of 1.88 (1H, m), 2,30-is 2.37 (2H, m), 2,78-and 2.79 (2H, m), 2,87-2,90 (1H, m), 2,96-of 3.00 (1H, m), 3,37-3,47 (2H, m)to 3.58 (2H, s), of 3.96 (1H, q, J=13.1 Hz), to 4.41 is 4.45 (1H, m), 4,51-of 4.57 (2H, m), to 6.88 (1H, d, J=1,5 is C), 7,17 (1H, DD, J=8,8, 2.0 Hz), 7.23 percent-7,43 (N, m), 7,52 (1H, d, J=7,6 Hz), 9,37 (1H, sh).

Stereoisomer In:

1H-NMR (CDCl3) δ: 1,05 (N, C)1,17 (6N, (C), of 1.43 to 1.47 (1H, m), 1.85 to a 1.88 (1H, m), 2,09 with 2.14 (1H, m), 2,58-2,63 (1H, m), 2,78-and 2.79 (2H, m), 2,86-2,90 (1H, m), 2,96-of 3.00 (1H, m), 3,38-of 3.46 (2H, m)and 3.59 (2H, s), 3.95 to (1H, q, J=13.3 Hz), 4,15-4,20 (1H, m), 4,45-4,56 (3H, m), 6,74 (1H, d, J=2.0 Hz), 7,16 (1H, DD, J=8,8, 2.0 Hz), 7,27-7,43 (N, m), EUR 7.57 (1H, d, J=2.0 Hz), 9,48 (1H, sh).

2) the above stereoisomer A (288 mg) suspended in dichloromethane (20 ml), was added dimethyl sulfide (1,15 ml) and anhydrous aluminium chloride (350 mg) and the mixture was stirred at room temperature for 1 hour. In the reaction mixture were added 1 N. aqueous solution (10 ml) of sodium hydroxide and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column flash chromatography on silica gel (dichloromethane:methanol=9:1) to give (1R*That 2R*)-N1-[[5-[2-(tert-butyldiphenylsilyl)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl) carbonyl]-4-hydroxymethyl-1,2-cyclopentadiene (stereoisomer A) (184 mg) as a pale yellow solid.

1H-NMR (CDCl3) δ: 1,04 (N,) and 1.15 (6N, (C), and 1.54-of 1.62 (1H, m), 1,73-of 1.81 (1H, m), 1,99 was 2.25 (2H, m), 2,34-of 2.38 (2H, m), 2,67-to 2.85 (3H, m), 2,92-of 2.97 (1H, m), 3,48-3,62 (4H, m), 3,93 (1H, q, J=15.6 Hz), 4,20-to 4.28 (1H, m), 4,47-,56 (1H, m), 6,89 (1H, s), 7,11-to 7.18 (1H, m), 7.24 to 7,27 (1H, m), 7,32-7,43 (6N, m), 7,54 (1H, d, J=1.7 Hz), 7,63 (4H, DD, J=7,8, 1.5 Hz), of 7.90-a 7.92 (2H, m), 10,13 (1H, sh).

MS (FAB) m/z: 784 (M+H)+.

3) Stereoisomer A (180 mg)obtained in stage 2), described above, was dissolved in 1 N. tertrahydrofuran ring solution (2 ml) tetrabutylammonium and the solution was stirred over night at room temperature. To the reaction mixture was added dichloromethane, 1 N. aqueous solution of sodium hydroxide and sodium chloride for the separation of liquids. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column flash chromatography on silica gel (dichloromethane:methanol=19:1). The obtained powder was dissolved in methanol and added 1 N. ethanol solution (229 μl) of hydrochloric acid to which was added ethyl acetate. Drove away under reduced pressure, the solvent is obtaining specified in the title compound (63 mg) as a pale brown solid.

1H-NMR (DMSO-d6) δ: 1,33 of 1.50 (8H, m), 1.70 to at 1.91 (2H, m), 2,07 with 2.14 (1H, m), 2,23-of 2.24 (1H, m), 3.04 from-3,10 (1H, m), 3.27 to 3,44 (4H, m), 3,57-3,70 (2H, m), 3,92-of 3.95 (1H, m), 4,29-4,72 (4H, m), of 5.81 (1H, sh), 7,11 (1H, s), to 7.15 (1H, DD, J=8,6, 2.0 Hz), 7,39 (1H, d, J=8.6 Hz), to 7.68 (1H, d, J=2.0 Hz), 8,53-8,56 (1H, m), 8,83 (1H, d, J=8,3 Hz), 10,36 (1H, sh), 11,75, 11,77 (1H, each s).

MS (ESI) m/z: 546 (M+H)+.

[Example 70]

Hydrochloride (1R*That 2R*)-N 1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclopentadiene (stereoisomer):

Specified in the title compound was obtained by elimination of the benzyl group (1R*That 2R*)-4-benzoyloxymethyl-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[5-[2-(tert-butyldiphenylsilyl)hydroxy-1,1-dimethylethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-1,2-cyclopentylamine (stereoisomer B), obtained in stage 1) of example 69 and then the elimination of tert-butyldiphenylsilyl group in a manner similar to stage 3) of example 69.

1H-NMR (DMSO-d6) δ: 1,32 of 1.46 (8H, m), 1,78 is 1.91 (2H, m), 2,03-2,10 (1H, m), 2,24 (1H, m), 3,05-3,11 (1H, m), 3,26-3,37 (3H, m), to 3.58 at 3.69 (2H, m), 3,92 (1H, sh), 4,29 is 4.36 (1H, m), to 4.52-4.72 in (4H, m), 5,80-of 5.81 (1H, m), 7,10 (1H, s), to 7.15 (1H, d, J=8,8 Hz), 7,39 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,53 (1H, d, J=7,6 Hz), 8,86 (1H, d, J=8.1 Hz), 10,28 (1H, sh), 11,75, 11,76 (1H, each s).

MS (ESI) m/z: 546 (M+H)+.

[Example 71]

(1R*That 2R*)-4-Carbamoyloxymethyl-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadien (stereoisomer A):

(1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadien (stereoisomer A) (200 mg) suspended in tetrahydrofuran (80 ml), was added pyridine (100 μl) and then phenylcarbamate (156 μl) and the mixture was stirred at room temperature for 10 minutes. In the reaction mixture were added a saturated methanol solution (10 ml) of ammonia and the mixture was left to stand overnight at room temperature. The reaction mixture was concentrated under reduced pressure and to the residue was added a mixed solution (100 ml) of methanol and dichloromethane (1:9) and 1 N. aqueous solution (50 ml) of sodium hydroxide to separate the liquids. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=10:1). The obtained colorless amorphous solid is suspended in 1 N. hydrochloric acid (1 ml) and the suspension was concentrated under reduced pressure to obtain specified in the title compound (151 mg) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,44-of 1.56 (1H, m), 1,70-1,90 (2H, m), 2.05 is-to 2.15 (1H, m), 2,35 at 2.45 (1H, m), 3,02-3,26 (2H, m), 3,39-and 3.72 (2H, m), 3,80-to 3.92 (2H, m), 4,30 was 4.42 (2H, m), 4,49-4,59 (1H, m), 4,60-4,70 (1H, m), 6,46 (2H, sh), 7,10 (1H, s), 7,14 (1H, DD, J=8,8, 2.0 Hz), 7,38 (1H, d, J=8,8 Hz), 7,68 (1H, s), to 8.57 (1H, J=8,3 Hz), 8,91 (1H, J=8,3 Hz), of $ 11.48 (1H, sh), 11,75 (1H, s).

MS (FAB) m/z: 531 (M+H)+.

[Example 72]

(1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4(N,N-dimethylcarbamoyl) is kemetyl-N 2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadien (stereoisomer A):

Specified in the title compound was obtained from (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-N1-hydroxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer A) in a manner similar to the method of example 71.

1H-NMR (DMSO-d6) δ: 1,50-1,60 (1H, m), 1,76-1,90 (2H, m), 2.06 to to 2.15 (1H, m), 2,39 is 2.46 (1H, m), 2,75-2,93 (N, m), 3,14 (2H, sh), 3,38-to 3.73 (2H, m), 3,89-are 3.90 (1H, m), 4,28-4,71 (4H, m), to 7.09 (1H, s), to 7.15 (1H, DD, J=the 8.6, 2.0 Hz), 7,37 (1H, d, J=8.6 Hz), 7,68 (1H, s), to 8.57 (1H, d, J=8,3 Hz), to 8.94 (1H, d, J=8,3 Hz), 11,42 (1H, sh), 11,74 (1H, s).

MS (FAB) m/z: 559 (M+H)+.

[Example 73]

(1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-4-morpholinosydnonimine-1,2-cyclopentanedione (stereoisomer):

Specified in the title compound was obtained from (1R*That 2R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentylamine (stereoisomer B) in a manner similar to the method of example 71.

1H-NMR (DMSO-d6) δ: 1,43-of 1.52 (1H, m), 1,80-1,90 (2H, m), 2,07-2,17 (2H, m), 2,85 (3H, s), of 3.12 (2H, sh), 3.25 to the 3.65 (10H, m), 3,91-4,04 (2 is, m), 4,32-4,65 (6N, m), was 7.08 (1H, s), 7,14 (1H, d, J=8,8 Hz), 7,37 (1H, d, J=8,8 Hz), 7,68 (1H, s), 8,54 (1H, d, J=8.6 Hz), 8,93 (1H, d, J=8.6 Hz), 11,40 (1H, sh), 11,75 (1H, s).

MS (FAB) m/z: 601 (M+H)+.

[Example 74]

Hydrochloride (±)-TRANS-4,4-bis(methoxymethyl)-N1-[(5-Clorinda-2-yl) carbonyl]-N2-[(5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadiene:

Specified in the title compound (300 mg) was obtained as a pale yellow foamy substance, dissolving (±)-TRANS-4,4-bis(methoxymethyl)-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadien (365 mg), 5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (395 mg) and the monohydrate of 1-hydroxybenzotriazole (31 mg) in N,N-dimethylformamide (50 ml) and acting hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (575 mg) as a condensing agent, in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,33 (6N, sh), 1,59-1,72 (1H, m), 1,80-of 1.95 (1H, m), 3,01-3,14 (1H, m), 3,18 is-3.45 (M, m), 3,60-of 3.80 (2H, m), 4,30-4,69 (4H, m), 7,11 (1H, s), to 7.15 (1H, DD, J=8,5, 2.0 Hz), 7,39 (1H, D, J=8.5 Hz), of 7.69 (1H, d, J=2.0 Hz), 8,49 (1H, d, J=8,3 Hz), 8,80 (1H, d, J=8,3 Hz)to 11.11 (1H, sh), of 11.69-RS 11.80 (1H, m).

MS (FAB) m/z 574 (M+H)+.

[Example 75]

(±)-TRANS-4,4-Bis(hydroxymethyl)-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]-pyridine-2-yl)carbonyl]-1,2-cyclopentadien:

1)(± )-TRANS-4,4-Bis(benzoyloxymethyl)-N1-[(5-Clorinda-2-yl) carbonyl]-N2-[(5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclopentadien received from (±)-TRANS-4,4-bis (benzoyloxymethyl)-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclopentadiene and 5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,01 (6N, d, J=6.6 Hz), 1.60-to 1,72 (2H, m), 1,89 of 1.99 (2H, m), was 2.76 (4H, sh), 2,85-2,95 (1H, m), 3,32-of 3.43 (4H, m), 3,69-3,74 (2H, m), 4,32-of 4.44 (1H, m), 4,48-4,60 (5H, m), 7,07 (1H, s), 7,13 (1H, DD, J=8,8, 2.0 Hz), 7.23 percent-7,40 (11N, m), to 7.67 (1H, d, J=1.7 Hz), to 8.45 (1H, d, J=8.6 Hz), 8,65 (1H, d, J=8.6 Hz), of 11.69 (1H, s).

MS (FAB) m/z: 726 (M+H)+.

2) is listed in the title compound was obtained by elimination of the benzyl group of the product obtained above, in a manner similar to the method of example 62.

1H-NMR (DMSO-d6) δ: 1,22-1,39 (6N, m), 1,44 is 1.60 (2H, m), 1.85 to 1,98, (2H, m), 3.00 and-3,78 (N, m), 4,25-4,80 (4H, m), to 7.09 (1H, s), 7,14 (1H, d, J=8,8 Hz), 7,37 (1H, d, J=8,8 Hz), to 7.67 (1H, s), 8,48 (1H, d, J=8,5 Hz), 8,73 (1H, d, J=8.5 Hz), was 10.82 (1H, sh), 11,72 (1H, s).

MS (FAB) m/z: 546 (M+H)+.

[Example 76]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(thiophene-2-yl)sulfonyl]-1,2-cyclohexanediamine:

Hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (200 mg) was dissolved in N,N-dimethylformamide (1 ml), was added triethylamine (0,28 ml) and 2-tiof sulphonylchloride (111 mg) and the mixture was stirred for 75 minutes. In the reaction mixture was added water and the precipitate was filtered and recrystallized from methanol to obtain specified in the title compound (198 mg) as colorless crystals.

1H-NMR (DMSO-d6) δ: 1,20-1,80 (8H, m), 3,52 (1H, sh), of 3.97 (1H, sh), 6,86 (1H, t, J=4.5 Hz), 7,01 (1H, s), 7,17 (1H, DD, J=8,3, 2.2 Hz), the 7.43 (1H, d, J=8.6 Hz), 7,51 (1H, s), 7,60-of 7.70 (2H, m), 7,73 (1H, s), 7,80 (1H, d, J=8,3 Hz), 11,71 (1H, s).

MS (FAB) m/z: 437 (M+N)+.

[Example 77]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2(2-butanol)-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and tetralogy acid in a manner similar to the method of example 2.

1H-NMR (CDCl3) δ: 1,40-1,81 (6N, m), 1,81-of 1.92 (1H, m)to 1.99 (3H, s), 2,08-2,17 (1H, m), 4,11 (1H, sh), the 4.29 (1H, sh), from 6.22 (1H, sh. J=6.8 Hz), 6.87 in (1H, d, J=2.0 Hz), 7,22 (1H, DD, J=8,8, 2.0 Hz), 7,34 (1H, d, J=8,8 Hz), to 7.61 (1H, s), of 7.70 (1H, sh), 9,31 (1H, s).

MS (ESI) m/z: 358 (M+H)+.

[Example 78]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-phenylpropionyl-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and phenylpropiolic acid in a manner similar to the method of example 2.

1H-NMR (CDCl3) δ: 1,40-2,00 (7H, m), 2,09-2,10 (1H, is), to 4.17 (1H, sh), 4,36 (1H, sh), of 6.45 (1H, sh. J=5.6 Hz), make 6.90 (1H, d, J=2.0 Hz), 7,10-73 (N, m)9,50 (1H, s).

MS (ESI) m/z: 420 (M+H)+.

[Example 79]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(pyridine-4-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and isonicotinic acid in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,04 (2H, sh), of 1.62 (2H, d, J=10,2 Hz), 1,74 (2H, sh), 1,99 (2H, d, J=4.6 Hz), 4,23-of 4.35 (2H, m), 7,16 (2H, DD, J=8,8, 1.8 Hz), 7.23 percent (1H, s), 7,40 (1H, d, J=8,8 Hz), 7,63 (1H, d, J=1,8 Hz), 8,25 (2H, d, J=6,1 Hz), with 8.33 (1H, sh. J=7,3 Hz), 8,88 (1H, sh. J=6.6 Hz), to 8.94 (2H, d, J=6,1 Hz), 11,93 (1H, s).

MS (ESI) m/z: 397 (M+H)+.

[Example 80]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-(4-dimethylaminobenzoyl)-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and 4-dimethylaminobenzoyl acid in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: of 1.40 (2H, sh), to 1.61 (4H, sh), of 1.97 (2H, sh), 2,96 (6N, (C), 4,13-of 4.25 (2H, m), to 6.88 (2H, d, J=8.5 Hz), 7,16 (1H, DD, J=8,8, 2.0 Hz), 7,17 (1H, s), 7,40 (1H, d, J=8,8 Hz), the 7.65 (1H, d, J=2.0 Hz), to 7.77 (2H, d, J=8.5 Hz), of 7.90 (1H, sh. J=6.8 Hz), 8,18 (1H, sh. J=6.8 Hz), 11,91 (1H, s).

MS (ESI) m/z: 439 (M+H)+.

p> [Example 81]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[3-(4-pyridyl)acryloyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and 3-(4-pyridyl)acrylic acid in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,21 (2H, sh), 1,50-to 1.67 (3H, m), 1,67 and 1.80 (1H, m), 1,80 is 1.96 (2H, m), 4,11-4,30 (2H, m), to 7.15 (1H, DD, J=8,8, 1.7 Hz), 7,21 (1H, s), 7,40 (1H, d, J=8,8 Hz), 7,42 (1H, d, J=16.0 Hz), 7,53 (1H, d, J=16.0 Hz), a 7.62 (1H, d, J=1.7 Hz), of 8.06 (2H, d, J=6.0 Hz), of 8.27 (1H, sh. J=7,6 Hz)and 8.50 (1H, sh. J=7,6 Hz), 8,87 (2H, d, J=6.0 Hz), up 11,86 (1H, s).

MS (ESI) m/z: 423 (M+N)+.

[Example 82]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(1-isopropylpiperazine-4-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and 1-isopropylpiperazine-4-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 0,94 is 2.10 (10H, m), 1,22 (6N, d, J=6,1 Hz), 2,60-to 2.94 (4H, m), 2,98-to 3.50 (4H, m)to 4.01 (1H, sh), of 4.12 (1H, sh), 7,16 (1H, d, J=8,4 Hz), 7,20 (1H, s), 7,42 (1H, d, J=8,4 Hz), the 7.65 (1H, s), to 7.93 (1H, W., J=7,1 Hz), 8,17 (1H, sh. J=7.8 Hz), 9,59 (1H, sh), 11,91 (1H, s).

MS (ESI) m/z: 445 (M+H)+.

[Example 83]

Hydrochloride (±)-CIS-N1-[(5-chloring the l-2-yl)carbonyl]-N 2-[[(E)-3-(1-methylpiperidin-4-yl)acryloyl]-1,2-cyclohexanediamine:

1) Water (1 ml) and lithium hydride (10 mg) was added to a solution of 1-(tert-butoxycarbonyl)-4-[(E)-2-(methoxycarbonyl)ethynyl]piperidine (J. Med. Chem., 1998, Vol.41, R) (110 mg) in tetrahydrofuran (4.0 ml) at room temperature and the mixture was stirred 3 days. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in N,N-dimethylformamide (3 ml), to the solution was added at room temperature hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (134 mg), monohydrate, 1-hydroxybenzotriazole (111 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (157 mg) and diisopropylethylamine (286 μl) and the mixture was stirred for 7 days. The reaction mixture was concentrated under reduced pressure, to the residue was added dichloromethane (20 ml), water (50 ml) and saturated aqueous solution (50 ml) of sodium bicarbonate and separated the organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:acetone=10:1→2:1) to give (±)-CIS-N1-[[(E)-3-[1-(tert-butoxycarbonyl)piperidine-4-yl]acryloyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (215 mg) as a white solid.

<> 1H-NMR (CDCl3) δ: 1,24 and 1.80 (10H, m), 1,47 (N, s), 1.85 to of 1.97 (1H, m), 2,10-of 2.20 (1H, m), 2,22-of 2.36 (1H, m), 2,68-to 2.74 (2H, m), 4,12 (3H, sh), the 4.29 (1H, sh), of 5.84 (1H, d, J=15.2 Hz), the 6.06 (1H, sh), 6,89 (1H, s), 6,92 (1H, DD, J=15,2, 6.4 Hz), 7.23 percent (1H, DD, J=8,8, 1.7 Hz), 7,35 (1H, d, J=8,8 Hz), to 7.64 (1H, d, J=1.7 Hz), of 8.04 (1H, sh), 9,41 (1H, s).

MS (ESI) m/z: 529 (M+N)+.

2) Triperoxonane acid (1 ml) was added to a solution of the product (210 mg)obtained above in dichloromethane (1 ml) at room temperature and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in dichloromethane (5 ml) and to the solution was added at room temperature triethylamine (111 μl), acetic acid (68 ml), 35% formalin (51 μl) and triacetoxyborohydride sodium (126 mg). The resulting mixture was stirred for 4 hours. In the reaction mixture was added dichloromethane (10 ml) and saturated aqueous solution (10 ml) of sodium bicarbonate and separated the organic layer. The organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified by reversed-phase HPLC (system an aqueous solution of formic acid-acetonitrile). Resulting solids were dissolved in system 1 N. hydrochloric acid-dichloromethane and the solution was concentrated to obtain specified in the title compound (12 mg) as a white solid.

1H-NMR (DMSO-d6) δ: 130-1,93 (N, m), 2,25-of 2.38 (1H, m), 2,70 (3H, d, J=4.9 Hz), 2,87-2,-3,00 (2H, m), 3,34-3,44 (2H, m), 4,13 (2H, sh), of 6.20 (1H, d, J=15,5 Hz), 6,55 (1H, DD, J=15,5, 5,9 Hz), 7,18 (1H, DD, J=8,8, 2,1 Hz), 7,20 (1H, d, J=1,5 Hz), the 7.43 (1H, d, J=8,8 Hz), to 7.67 (1H, d, J=2.1 Hz), 8,01 (1H, sh. J=7,6 Hz), 8,29 (1H, sh. J=7,1 Hz), the 10.40 (1H, sh), 11,89 (1H, s).

MS (ESI) m/z: 443 (M+H)+.

[Example 84]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[3-(1-methylpiperidin-4-yl)propionyl]-1,2-cyclohexanediamine:

1) (±)-CIS-N1-[3-[1-(tert-Butoxycarbonyl)piperidine-4-yl]propionyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine was obtained from 1-(tert-butoxycarbonyl)-4-[2-(methoxycarbonyl)ethyl]piperidine (J. Med. Chem., 1998, Vol.41, R) in a manner similar to stage 1) of example 83.

1H-NMR (CDCl3) δ: 1,00-1,17 (2H, m), of 1.30 and 1.80 (11N, m), 1,44 (N, C), 1,80-of 1.95 (1H, m), 2,10-of 2.23 (1H, m)to 2.29 (2H, t, J=7.8 Hz), 2,50-2,70 (2H, m), 3,90-4,18 (3H, m)to 4.23 (1H, sh), equal to 6.05 (1H, sh. J=6.0 Hz), 6,85 (1H, d, J=2.0 Hz), 7,22 (1H, DD, J=8,8, 1.8 Hz), 7,37 (1H, d, J=8,8 Hz), a 7.62 (1H, d, J=1,8 Hz), 7,89 (1H, sh), 9,59 (1H, s).

MS (ESI) m/z: 531 (M+H)+.

2) is listed in the title compound was obtained from the product described above, in a manner similar to step 2) of example 83.

1H-NMR (DMSO-d6) δ: 1,20-1,90 (15 NM, m), 2,10-of 2.26 (1H, m)to 2.55 (3H, s), 2,55-2,70 (2H, m), 3,21 (2H, t, J=12.0 Hz), 4,00-4,16 (2H, m), 7,18 (1H, DD, J=8,8, 2.2 Hz), 7,21 (1H, s), 7,44 (1H, d, J=8,8 Hz), of 7.70 (1H, d, J=2.2 Hz), 7,82 (1H, sh. J=6.9 Hz), 8,11 (1H, sh. J=7,6 Hz), 10,02 (1H, sh), 11,94 (1H, s).

MS (ESI) m/z: 445 (M+H)+.

[Example 85]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(1-methylpiperidin-4-yl)propiolic]-1,2-cyclohexanediamine:

1) (±)-CIS-N1-[[1-(tert-Butoxycarbonyl) piperidine-4-yl] propiolic]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine was obtained from 1-(tert-butoxycarbonyl)-4-(methoxycarbonylmethyl)piperidine in a manner similar to stage 1) of example 83.

1H-NMR (DMSO-d6) δ: 1,30-1,82 (N, m), 1,38 (N, C), 2,68-2,78 (1H, m), 2,96-3,10 (2H, m), 3,56-3,66 (2H, m), 4,00-4,20 (2H, m), 7,16 (1H, s), 7,18 (1H, DD, J=8,6, 2.0 Hz), the 7.43 (1H, d, J=8.6 Hz), of 7.70 (1H, d, J=2,0 Hz), to $ 7.91 (1H, sh. J=7,3 Hz), of 8.25 (1H, sh. J=7.8 Hz), 11,81 (1H, s).

2) is listed in the title compound was obtained from the product described above, in a manner similar to step 2) of example 83.

1H-NMR (DMSO-d6) δ: 1,30-1,45 (2H, m), 1,45-1,70 (6N, s), 1.70 to to 1.82 (4H, m), 1,90-2,03 (2H, m), 2,10 (3H, s), 2.40 a-2,52 (1H, m), 2,52-2,62 (2H, m), 4.04 the-4,18 (2H, m), to 7.15 (1H, s), 7,18 (1H, DD, J=8,8, 2.0 Hz), the 7.43 (1H, d, J=8,8 Hz), 7,71 (1H, d, J=2.0 Hz), 7,92 (1H, sh. J=7,3 Hz), of 8.25 (1H, sh. J=7.8 Hz), 11,83 (1H, s).

MS (FAB) m/z: 441 (M+H)+.

[Example 86]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)propiolic]-1,2-cyclohexanediamine:

1) (±)-CIS-Nl-[[1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-yl]propiolic]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine was obtained from 1-(tert-butoxycarbonyl who yl)-4-(methoxycarbonylethyl)-1,2,3,6-tetrahydropyridine way similar to stage 1) of example 83.

1H-NMR (DMSO-d6) δ: 1,35-to 1.82 (8H, m), 1.39 in (N, C), 2,15-of 2.23 (2H, m), 3,40 (2H, t, J=5.4 Hz), 3,92 (2H, sh), 4,14 (2H, sh), of 6.29 (1H, sh), 7,16 (1H, s), 7,18 (1H, DD, J=8,7, and 2.1 Hz), the 7.43 (1H, d, J=8.7 Hz), 7,71 (1H, d, J=2.1 Hz), 7,92 (1H, sh. J=7,3 Hz), 8,40 (1H, sh. J=8,3 Hz), RS 11.80 (1H, s).

MS (ESI) m/z: 525 (M+H)+.

2) is listed in the title compound was obtained from the product described above, in a manner similar to step 2) of example 83.

1H-NMR (DMSO-d6) δ: 1,30-of 1.46 (2H, m), 1,46-1,84 (6N, (C), 2,15 was 2.25 (2H, m), of 2.21 (3H, s), 2,42 (2H, t, J=5.6 Hz), 2,89-of 2.97 (2H, m), 4,13 (2H, sh), and 6.25 (1H, sh), to 7.15 (1H, s), 7,17 (1H, d, J=8.6 Hz), the 7.43 (1H, d, J=8.6 Hz), of 7.70 (1H, s), of 7.97 (1H, sh. J=7.8 Hz), to 8.41 (1H, sh. J=7.8 Hz), 11,84 (1H, s).

MS (FAB) m/z: 439 (M+H)+.

[Example 87]

Hydrochloride (±)-CIS-N1[(5-Clorinda-2-yl)carbonyl]-N2-[[1-(4-pyridyl)piperidine-4-yl]carbonyl]-1,2-cyclohexanediamine:

1-(4-Pyridyl)piperidine-4-carboxylic acid (Tetrahedron, 1998, Vol.44, R) (206 mg) suspended in dichloromethane (50 ml)was added under ice cooling thionyl chloride (144 μl) and the mixture was stirred for 30 minutes. Adding to the reaction mixture triethylamine (969 μl)were added hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (328 mg) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and to the residue was added water, then ristorantedilovero under reduced pressure and the precipitated residue was filtered to obtain specified in the title compound (310 mg) as a pale brown solid.

1H-NMR (DMSO-d6) δ: 1,30 is 2.00 (10H, m), is 2.74 (1H, sh), 3,18 (2H, q, J=12.3 Hz), a 4.03 (1H, sh), 4,10-of 4.25 (3H, m), 7,15-of 7.55 (4H, m), 7,42 (1H, d, J=8,8 Hz), the 7.65 (1H, s), to $ 7.91 (1H, d, J=8,8 Hz), 8,20-8,35 (3H, m), 11,91 (1H, s), 13,47 (1H, sh).

MS (FAB) m/z: 480 (M+H)+.

[Example 88]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[4-(morpholinomethyl)thiazol-2-yl]carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and 4-(morpholinomethyl)thiazol-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,35-of 1.55 (2H, m), 1.55V and 1.80 (4H, m), 1,95-2,15 (2H, m), 3.00 and-of 3.60 (4H, m), 3,85-4,00 (4H, m), 4,15-of 4.35 (2H, m), 4,40 with 4.65 (2H, m), 7,18 (1H, DD, J=8,8, 2,1 Hz), 7,30 (1H, s), 7,41 (1H, d, J=8,8 Hz), the 7.65 (1H, d, J=2.1 Hz), 8,19 (1H, s), 8,35-of 8.50 (2H, m), br11.01 (1H, sh), 11,94 (1H, sh).

MS (FAB) m/z: 502 (M+H)+.

[Example 89]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5-[(N,N-dimethylamino)methyl]thiazol-2-yl]carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and 5-[(N,N-dimethylamino)methyl]thiazole-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,35-of 1.55 (2H, m), 1.55V and 1.80 (4H, m), 1.85 to 2,10 (2H, m), 72 (6N, sh), 4,17 is 4.35 (2H, m), to 4.62 (2H, sh), 7,16-7,10 (2H, m), the 7.43 (1H, d, J=8,8 Hz), 7,71 (1H, d, J=1.7 Hz), 8,10 (1H, s), 8,15 (1H, d, J=7.8 Hz), charged 8.52 (1H, d, J=7.8 Hz), 10,70-10,80 (1H, sh), up 11,86 (1H, sh).

MS (FAB) m/z: 460 (M+H)+.

[Example 90]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydro-5,6-trimethylthiazole[4,5-d]pyridazin-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and 4,5,6,7-tetrahydro-5,6-trimethylthiazole[4,5-d]pyridazin-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,35 of 1.50 (2H, m)to 1.61 (4H, sh), 1,80-2,00 (2H, m), and 2.27 (2H, sh), 2,80-4,80 (10H, m), 7,14 (1H, d, J=1.5 Hz), 7,17 (1H, DD, J=8,5, 2.0 Hz), 7,41 (1H, d, J=8.5 Hz), of 7.70 (1H, d, J=2.0 Hz), of 8.09 (1H, d, J=7,3 Hz), 8,44 (1H, sh), 11,81 (1H, sh).

MS (FAB) m/z: 499 (M+H)+.

[Example 91]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydro-5,6-tetramethylenebis[4,5-d]pyridazin-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from 4,5,6,7-tetrahydro-5,6-tetramethylenebis[4,5-d]pyridazin-2-carboxylate lithium hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,35-of 1.55 (2H, m) 1.55V is 2.10 (10H, m), 2,80-4,80 (10H, m), 7,10-of 7.25 (2H, m), 7,42 (1H, d, J=8,8 Hz), 7,72 (1H, d, J=1.7 Hz), 8,12 (1H, sh), to 8.41 (1H, sh), 11,83 (1H, sh).

MS (FAB) m/z: 513 (M+H)+.

[Example 92]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]-1,2-cyclohexanediamine:

2-Bromo-5-tert-butoxycarbonyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (171 mg) was dissolved in diethyl ether (5 ml) in an argon atmosphere and the solution was cooled to -78°and added thereto dropwise n-utility (1,60 N. hexane solution, 385 μl). The reaction mixture was stirred 10 minutes at -78°With, blew within 20 minutes with carbon dioxide and then was allowed to warm to room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in N,N-dimethylformamide (10 ml). To the solution was added the hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (184 mg), monohydrate, 1-hydroxybenzotriazole (76 mg) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (215 mg). The resulting mixture was stirred 3 days. The reaction mixture was concentrated, to the residue were added dichloromethane and a saturated aqueous solution of sodium bicarbonate and separated the organic layer. The organic layer was dried over anhydrous sodium sulfate and then drove away under reduced pressure the solvent. Received the STATCOM was purified column chromatography on silica gel (methanol:dichloromethane=3:97) to obtain (± )-CIS-N1-[(5-tert-butoxycarbonyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (44 mg). To the thus obtained product was added a saturated ethanol solution (5 ml) of hydrochloric acid, the mixture was stirred at room temperature for 1 hour and then the reaction mixture was concentrated and to the residue for solidification was added ethyl acetate. The resulting powder was filtered to obtain specified in the title compound (31 mg) as colorless powder.

1H-NMR (DMSO-d6) δ: 1,35-of 1.52 (2H, m), 1.55V and 1.80 (4H, m), 1,82-of 2.05 (2H, m), 4,22 (1H, sh), 4,28 (1H, sh), to 4.38 (2H, s), 4,56 (2H, s), 7,14-7,20 (2H, m), 7,42 (1H, d, J=8.6 Hz), 7,71 (1H, d, J=1.7 Hz), 8,10 (1H, d, J=7,1 Hz), to 8.45 (1H, d, J=7.8 Hz), 10,10-10,50 (2H, sh), 11,83 (1H, sh).

MS (FAB) m/z: 444 (M+H)+.

[Example 93]

Hydrochloride, (1S,2R)-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R)-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and 5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-2-carboxylate lithium in a manner similar to the method of example 2.

[α]D+to 110.7° (24,8°s=1,20, DMSO).

1H-NMR (DMSO-d6) δ: 1,35 of 1.50 (2H, m), and 1.63 (4H, sh), 1,85 is 2.10 (2H, m), to 3.02 (3H, sh), 4,15-4,80 (6N, m), 7,10-7,22 (2H, m), 7,2 (1H, d, J=8,8 Hz), 7,71 (1H, d, J=1.7 Hz), 8,10 (1H, d, J=6.8 Hz), 8,46 (1H, d, J=7.8 Hz), 11,83 (1H, sh), of $ 11.97 (1H, sh).

MS (FAB) m/z: 458 (M+H)+.

[Example 94]

(±)-CIS-N1-[[6-(tert-Butoxycarbonyl)-5,7-dihydropyrrolo[3,4-d]pyrimidine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

6-(tert-Butoxycarbonyl)-5,7-dihydro-2-methoxycarbonylamino[3,4-d]pyrimidine hydrolyzed with lithium hydroxide and then subjected to interaction with hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine a manner similar to the method of example 2, obtaining specified in the connection header.

1H-NMR (CDCl3) δ: 1,54 (N, C), 1,55-of 2.30 (8H, m)to 4.23 (1H, sh), a 4.53 (1H, sh), 4,74 of 4.83 (4H, m), of 6.99 (1H, d, J=1.5 Hz), 7,19 (1H, DD, J=8,8, 2,1 Hz), 7,34 (1H, d, J=8,8 Hz), a 7.62 (1H, d, J=2.1 Hz), 8,11 (1H, sh), 8,48 are 8.53 (1H, sh), 8,70-8,76 (1H, sh), 9,60-to 9.70 (1H, sh)

MS (ESI) m/z: 539 (M+H)+.

[Example 95]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5,7-dihydro-6-methylpyrazolo[3,4-d]pyrimidine-2-yl]carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-CIS-N1-[[6-(tert-butoxycarbonyl)-5,7-dihydropyrrolo[3,4-d]pyrimidine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine a manner similar to the method of example 83.

1H-NMR (DMSO-d6) δ: 1,40-of 1.55 (2H,m), 1,55-1,75 (4H, m), 1,80-of 2.05 (2H, m), 2,98 (3H, sh), 4,28 (2H, sh)and 4.65 (4H, sh), 7,14-7,20 (2H, m), 7,41 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=2.0 Hz), 8,17 (1H, d, J=6.9 Hz), 8,65 (1H, d, J=8,3 Hz), 8,93 (1H, C)11,73 (1H, sh), 11,82 (1H, sh).

MS (FAB) m/z: 453 (M+H)+.

[Example 96]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N1N2-dimethyl-N2-[[5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-1,2-cyclohexanediamine:

5-Methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (653 mg) suspended in dichloromethane (10 ml), was added 1 N. ethanol solution (3.2 ml) of hydrochloric acid and the mixture was stirred for a few minutes. Then drove under reduced pressure the solvent. To the residue was added chloroform (15 ml), then was added thionyl chloride (7 ml) and N,N-dimethylformamide (one drop) and the mixture was stirred at 65°C for 4 hours. Drove away under reduced pressure, the solvent, to the residue was added to the solution (14 ml) (±)-CIS-N1-[(1-benzazolyl-5-Clorinda-2-yl)carbonyl]-N1N2-dimethyl-1,2-cyclohexanediamine (847 mg) in a mixed solvent (14 ml), consisting of dichloromethane and pyridine (1:1) and the mixture was stirred overnight at room temperature. To the reaction mixture were added water and the separated organic layer. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Drove the ri reduced pressure, the solvent and the residue was purified column flash chromatography on silica gel (dichloromethane:methanol=47:3). The obtained pale yellow solid was dissolved in methanol (10 ml), was added potassium hydroxide (98 mg) and the mixture was stirred at room temperature for 10 hours. Drove away under reduced pressure, the solvent, to the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate. The residue was purified column flash chromatography on silica gel (dichloromethane:methanol=47:3), the obtained pale yellow solid was dissolved in dichloromethane (5 ml) was added 1 N. ethanol solution (528 ml) of hydrochloric acid. Added ethyl acetate and drove away under reduced pressure, the solvent is obtaining specified in the title compound (267 mg) as a white solid.

1H-NMR (DMSO-d6) δ: 1,59-2,07 (8H, m), 2,82 (3H, m), 3,07-3,48 (10H, m), 4.26 deaths ñ 4.50 (2H, m), 4,94 (1H, s), 5,27 (1H, sh), is 6.61 (1H, s), 7,13 (1H, d, J=8.6 Hz), the 7.43 (1H, sh), EUR 7.57 (1H, s), 11,25 (1H, sh), 12,90 (1H, sh).

MS (ESI) m/z: 500 (M+H)+.

[Example 97]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine and 5-tert-butoxy arbonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium method, similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,39-of 1.52 (2H, m)of 1.62 (4H, sh), 1,86-of 2.09 (2H, m), 3,03 (2H, sh), 3,40-3,47 (2H, m), 4,17-4,32 (2H, m), of 4.44 (2H, s), to 7.15 (1H, s), 7,17 (1H, DD, J=8,6, 2.0 Hz), 7,41 (1H, d, J=8.6 Hz), 7,71 (1H, C), 8,10-of 8.15 (1H, m), 8,40-of 8.47 (1H, m), RS 9.69 (2H, sh), 11,85 (1H, s).

MS (FAB) m/z: 458 (M+H)+.

[Example 98]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-ethyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained by metilirovaniem hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine ethyliodide a manner similar to the method of example 52.

1H-NMR (DMSO-d6) δ: of 1.31 (3H, t, J=7,1 Hz)to 1.45 (2H, sh), of 1.62 (4H, sh), 1,82 is 2.10 (2H, m), 3.00 and-to 3.52 (5H, m), 3,71 (1H, sh), 4,15-4,50 (3H, m), 4,68-4,82 (1H, m), to 7.15 (1H, s), 7,17 (1H, DD, J=8,8, 2.0 Hz), 7,41 (1H, d, J=8,8 Hz), 7,71 (1H, d, J=2.0 Hz), 8,14 (1H, sh), at 8.36-8,55 (1H, m), made 11.32 (1H, sh), up 11,86 (1H, s).

MS (FAB) m/z: 486 (M+H)+.

[Example 99]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5-(2-methoxyethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydro Asolo[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and 2-methoxyethylamine way similar to the method of example 52.

1H-NMR (DMSO-d6) δ: of 1.44 (2H, sh), of 1.62 (4H, sh), 1,85 is 2.10 (2H, m), was 2.76 3.21-in (6N, m), or 3.28 (3H, s)to 3.64 (2H, sh), 4,00-to 4.52 (4H, m), 7,14 (1H, s), 7,17 (1H, DD, J=8,8, 2.0 Hz), 7,41 (1H, d, J=8,8 Hz), of 7.70 (1H, d, J=2.0 Hz), 8,08-to 8.20 (1H, m), at 8.36-8,48 (1H, m), 11,84 (1H, s).

MS (FAB) m/z: 516 (M+H)+.

[Example 100]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methoxycarbonylmethyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±) -CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and methylpropanoate a manner similar to the method of example 52.

1H-NMR (CDCl3) δ: 1,52-to 1.98 (7H, m), 2,17 (1H, sh), 2,87-3,10 (4H, m), 3,49 (2H, s), 3,76 (3H, s), 3,93 (1H, d, J=15,4 Hz), 3,99 (1H, d, J=15,4 Hz), 4,22 (1H, sh), of 4.45 (1H, Sh.S.), 6,86 (1H, d, J=1.2 Hz), 7,18 (1H, DD, J=8,8, 2.0 Hz), 7,33 (1H, d, J=8,8 Hz), 7,58-7,63 (2H, m), 7,87 (1H, sh), 9,88 (1H, sh).

MS (FAB) m/z: 530 (M+H)+.

[Example 101]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-isopropyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-yl)carbonyl]-1,2-cyclohexanediamine and acetone way similar to the method of example 45.

1H-NMR (DMSO-d6) δ: 1,18-of 1.73 (8H, m), 1,81 is 2.10 (2H, m), 2,97-and 3.16 (1H, m), 3,20-to 3.41 (2H, m), 3,52-of 3.80 (2H, m), 4,19-or 4.31 (2H, m), 4,34-of 4.77 (2H, m), 7,17 (1H, s), 7,18 (1H, DD, J=8,8, 2.0 Hz), 7,42 (1H, d, J=8,8 Hz), 7,71 (1H, d, J=2.0 Hz), 8,15 (1H, sh), 8,28-8,51 (1H, m), to 11.31 (1H, sh), up 11,86 (1H, s).

MS (FAB) m/z 500 (M+H)+.

[Example 102]

Hydrochloride (±)-CIS-N1[(5-Clorinda-2-yl) carbonyl]-N2-[[5-(2,3,5,6-tetrahydro-4H-Piran-4-yl)-4,5,6,7-tetrahydropyrazolo[5,4-C]pyridine-2-yl]carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and tetrahydro-4H-Piran-4-it is a manner similar to the method of example 45.

1H-NMR (DMSO-d6) δ: 1,30-3,56 (N, m), 3,70-4,01 (3H, m), 4,17-4,30 (2H, m), 4,32-4,80 (1H, m), to 7.15 (1H, s), 7,17 (1H, DD, J=8,6, 2.0 Hz), 7,41 (1H, d, J=8.6 Hz), 7,71 (1H, d, J=2.0 Hz), 8,14 (1H, sh), 8,39 (1H, sh), 11,84 (1H, s).

MS (FAB) m/z: 542 (M+H)+.

[Example 103]

(±)-CIS-N1-[[5[2(tert-Butoxycarbonylamino)ethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]is iridin-2-yl)carbonyl]-1,2-cyclohexanediamine and N-(tert-butoxycarbonyl)aminoacetaldehyde (J. Org. Chem., 1988, Vol.53, R) in a manner similar to the method of example 45.

1H-NMR (CDCl3) δ: 1,44 (N, C), 1,54-to 1.98 (7H, m), 2,10-of 2.20 (1H, m), is 2.74 (2H, sh), of 2.92 (4H, sh), to 3.34 (2H, sh), a-3.84 (2H, sh), is 4.21 (1H, sh), of 4.45 (1H, sh), 6,86 (1H, s), 7,19 (1H, DD, J=8,8, 2.0 Hz), 7,33 (1H, d, J=8,8 Hz), EUR 7.57-7,63 (2H, m), 7,81 (1H, sh), to 9.66 (1H, sh).

MS (FAB) m/z: 601 (M+N)+.

[Example 104]

Hydrochloride (±)-CIS-N1-[[5-(2-(aminoethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

(±)-CIS-N1-[[5-[2(tert-Butoxycarbonylamino)ethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (450 mg) was dissolved in dichloromethane (5 ml), was added nasypany ethanol solution (30 ml) of hydrochloric acid and the mixture was stirred at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure, to the residue was added ethyl acetate and precipitated precipitated solids were filtered to obtain specified in the title compound (367 mg) as a pale yellow amorphous solid.

1H-NMR (DMSO-d6) δ: 1,38 of 1.50 (2H, m)to 1.61 (4H, sh), 1,85-of 2.08 (2H, m), 3.00 and-4,62 (N, m), 7,14 (1H, s), 7,16 (1H, DD, J=8,8, 2.0 Hz), 7,41 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=2.0 Hz), to 8.12 (1H, d, J=6.6 Hz), 8,15-8,68 (4H, m), 11,85 (1H, s).

MS (FAB) m/z: 501 (M+H)+.

[Example 105]

Hydra is chloride (± )-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5-[2-(methanesulfonamido)ethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-1,2-cyclohexanediamine:

(±)-CIS-N1-[[5-(2(Aminoethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (110 mg) was dissolved in pyridine (3 ml), was added methanesulfonamide (30 μl) and the mixture was stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure and added to a mixed solvent consisting of dichloromethane and methanol (85:15), and water for the separation of liquids. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=100:3) to give a pale yellow foamy substance. The resulting product is suspended in 1 N. hydrochloric acid (0.3 ml) and the suspension was concentrated under reduced pressure to obtain specified in the title compound (63 mg) as a pale yellow foamy substance.

1H-NMR (DMSO-d6) δ: 1,38 of 1.50 (2H, m), 1,55-1,70 (4H, m), 1,86-of 2.05 (2H, m), of 2.97 (3H, s), 3,02-of 3.25 (2H, m), 3,30-of 3.60 (5H, m), of 3.78 (1H, sh), 4,18-4,30 (2H, m), 4,45-a 4.86 (2H, m), 7,14 (1H, s), 7,16 (1H, DD, J=8,8, 2.0 Hz), 7,40 (1H, d, J=8,8 Hz), 7,41 (1H, sh), of 7.69 (1H, D, J=2.0 Hz), of 8.09 (1H, sh), 8,43 (1H, sh), 11,18 (1H, sh), 11,82 (1H, s).

MS (FAB) m/z 579 (M+N)+.

[Example 106]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[[5-[2-(methoxycarbonylamino)ethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-1,2-cyclohexanediamine:

Hydrochloride (±)-CIS-N1-[[5-(2-(aminoethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (144 mg) was dissolved in pyridine (3 ml), was added triethylamine (138 μl) and the mixture was stirred at room temperature for 5 minutes. To the resulting solution was added dropwise a solution obtained by adding triphosgene (49 mg) to tetrahydrofuran (1 ml)containing methanol (20 µl). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure and the residue was dissolved in a mixed solvent consisting of dichloromethane and methanol (9:1). To the solution was added water for the separation of liquids. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=100:3) to give a colorless foamy substance. The resulting product is suspended in 1 N. hydrochloric acid is the (0.2 ml) and the suspension was concentrated under reduced pressure to obtain specified in the title compound (60 mg) as a pale yellow foamy substance.

1H-NMR (DMSO-d6) δ: 1,38 of 1.50 (2H, m)to 1.61 (4H, sh), 1.85 to 2,04 (2H, m), 2,80-to 3.49 (8H, m), 3,52 (3H, s), 3,62-4,91 (4H, m), 7,14 (1H, s), 7,16 (1H, DD, J=8,8, 2.0 Hz), 7,37 (1H, SH), 7,40 (1H, d, J=8,8 Hz), of 7.70 (1H, C), 8,11 (1H, d, J=6.8 Hz), 8,40 (1H, sh), 11,05 (1H, sh), 11,82 (1H, sh).

MS (FAB) m/z: 559 (M+H)+

[Example 107]

Hydrochloride (±)-CIS-N1-[[5-2(acetylamino)ethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

Hydrochloride (±)-CIS-N1-[[5-(2-(aminoethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-N2[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (90 mg) was dissolved in N,N-dimethylformamide (3 ml), was added triethylamine (65 μl) and acetic anhydride (22 ml) and the mixture was stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure and to the residue was added dichloromethane and 0.3 N. aqueous sodium hydroxide solution to separate liquids. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=100:3) to give a colorless foamy substance. The resulting product is suspended in 1 N. hydrochloric acid (0.3 ml) and the suspension was concentrated under reduced pressure with the teachings specified in the title compound (73 mg) as a pale yellow foamy substance.

1H-NMR (DMSO-d6) δ: 1,39-of 1.52 (2H, m), 1,54 is 1.70 (4H, m)and 1.83 (3H, s), 1,84 e 2.06 (2H, m), 3,02-a 3.87 (8H, m), 4,16-4,32 (2H, m), 4,40-to 4.52 (1H, m), 4,78-4,88 (1H, m), 7,14 (1H, s), 7,16 (1H, d, J=8.6 Hz), 7,40 (1H, d, J=8.6 Hz), of 7.70 (1H, s), 8.07-a 8,17 (1H, m), by 8.22-8,30 (1H, m), 8/38-charged 8.52 (1H, m), 11,14 (1H, sh), 11,83 (1H, s).

MS (FAB) m/z: 543 (M+N)+.

[Example 108]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2[[5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N1[(5-Clorinda-2-yl)carbonyl]-N2[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and 2-bromoethanol a manner similar to the method of example 52.

1H-NMR (DMSO-d6) δ: 1,37-1.69 in (6N, m), 1,86-2,03 (2H, m), 2,54-2,61 (2H, m), 2,75-of 2.86 (4H, m), 3,52-3,59 (2H, m in), 3.75 (2H, s), 4,47 (1H, t, J=5.4 Hz), 7,12 (1H, s), 7,16 (1H, DD, J=8,8, 2.0 Hz), 7,40 (1H, d, J=8,8 Hz), of 7.70 (1H, s), 8,05-8,13 (1H, m), 8,28-8,35 (1H, m), 11,78 (1H, s).

MS (FAB) m/z: 502 (M+N)+

[Example 109]

Hydrochloride (±)-CIS-N1[(5-Clorinda-2-yl)carbonyl]-N2-[[5-(3-hydroxypropyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl]carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N1[(5-Clorinda-2-yl)carbonyl]-N2[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohex is antamina and 3-bromopropane way similar to the method of example 52.

1H-NMR (DMSO-d6) δ: to 1.45 (2H, sh), 1.56 to 1,71 (4H, m), 1,87 is 2.10 (4H, m), 3,05-3,55 (7H, m), 3,70-of 3.80 (1H, m), 4,19-4,32 (2H, m), 4,40-4,50 (1H, m), 4,74-4,84 (1H, m), 7,12-7,20 (2H, m), 7,41 (1H, d, J=8,8 Hz), of 7.70 (1H with), 8,08-8,16 (1H, m), 8,40-8,51 (1H, m), 10,98 (1H, sh), 11,82 (1H, s).

MS (FAB) m/z: 516 (M+H)+

[Example 110]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-butyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N1[(5-Clorinda-2-yl)carbonyl]-N2[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and n-butylbromide in a manner similar to the method of example 52.

1H-NMR (DMSO-d6) δ: to 0.88 (3H, t, J=7.2 Hz), 1,20-1,70 (10 H, m), 1,87-of 2.05 (2H, m), 2,55 is 3.40 (8H, m), 4,16-4,30 (2H, m), 7,13 (1H, s), 7,16 (1H, d, J=8,8 Hz), 7,40 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,05-to 8.14 (1H, m,), 8,35 (1H, sh), 11,81 (1H, s).

MS (FAB) m/z: 514 (M+H)+

[Example 111]

Hydrochloride (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-isobutyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N1[(5-Clorinda-2-yl)carbonyl]-N2[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and Isobe is elided way similar to the method of example 52.

1H-NMR (DMSO-d6) δ: 0,80-1,05 (7H, m), 1,38 of 1.50 (2H, m), 1,54 is 1.70 (4H, m), 1,89-2,02 (2H, m), 2,52-of 3.77 (8H, m), 4,18-or 4.31 (2H, m), 7,17 (1H, DD, J=8,8, 2.0 Hz), 7,40 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,05-8,13 (1H, m,), 8,27 are 8.53 (1H, m), 11,81 (1H, s).

MS (FAB) m/z: 514 (M+H)+

[Example 112]

(±)-CIS-N1-[(5-Acetyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-N2-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine:

Hydrochloride (±)-CIS-N1[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (100 mg) was dissolved in N,N-dimethylformamide (3 ml), was added triethylamine (84 μl) and acetic anhydride (29 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added dichloromethane and 1 N. hydrochloric acid for the separation of liquids. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain the specified title compound (86 mg) as a pale yellow foamy substance.

1H-NMR (CDCl3) δ: 1,52-of 1.85 (5H, m), at 1.91 (2H, sh), 2,10-of 2.28 (4H, m), 2.77-to of 3.00 (2H, m), 3,70-4,00 (2H, m), 4,19-to 4.38 (1H, m), of 4.45 (1H, sh), 4,68-4,99 (2H, m), 6,85(1H, C), 7,17-7,22 (1H, m), 7,30-7,39 (1H, m), 7,50-to 7.84 (3H, m), 9,72 of 10.05 (1H, m).

MS (FAB) m/z: 500 (M+H)+

[Example 113]

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methanesulfonyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Hydrochloride (±)-CIS-N1[(5-Clorinda-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (100 mg) was dissolved in pyridine (3 ml), was added triethylamine (168 μl) and methanesulfonamide (48 μl) and the mixture was stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure and to the residue was added dichloromethane and 1 N. hydrochloric acid to separate an organic layer. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=100:1) to obtain the specified title compound (79 mg) as a pale yellow foamy substance.

1H-NMR (CDCl3) δ: 1,50-1,82 (5H, m), 1,90 (2H, sh)by 2.13 (1H, sh), 2,89 (3H, s), 2.91 in are 2.98 (2H, m), 3,60-3,70 (2H, m), 4,30 (1H, sh), of 4.44 (1H, sh), 4,58 (2H, s), 6.87 in (1H, s), 7,19 (1H, d, J=8,8 Hz), 7,34 (1H, d, J=8,8 Hz), to 7.61 (MN, sh), to 9.91 (1H, sh).

MS (FAB) m/z: 536 (M+H)+

[Example 114]

Hydrochloride (±)-CIS-N1[(5-methylindol-2-the l)carbonyl]-N 2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and 5-methylindol-2-carboxylic acid in a manner similar to the method of example 6.

1H-NMR (DMSO-d6) δ: 1,35 of 1.50 (2H, m), 1,50-1,80 (4H, m), 1.85 to 2,07 (2H, m), a 2.36 (3H, s), is 2.88 (3H, s), of 3.12 (2H, sh), 3,53 (2H, sh), 4,15-4,30 (2H, m), 4,30-4,80 (2H, sh), of 7.00 (1H, DD, J=8,4, 1.5 Hz), 7,05 (1H, d, J=1.5 Hz), 7,30 (1H, d, J=8,4 Hz), 7,38 (1H, s), of 8.00 (1H, d, J=7,3 Hz), 8,43 (1H, sh), of 11.45 (1H, sh), 11,49 (1H, sh).

MS (FAB) m/z: 452 (M+H)+

[Example 115]

Hydrochloride (±)-CIS-N1[(6-chloro-4-hydroxynaphthalene-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (±)-CIS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and 6-chloro-4-hydroxynaphthalene-2-carboxylic acid in a manner similar to the method of example 6.

1H-NMR (DMSO-d6) δ: 1,44-1,63 (6N, m), 1,98 of 1.99 (2H, m), 2,87 (3H, s), is 3.08 (2H, sh), 3,52 (2H, sh), 4,22 (2H, sh), 4,74 (2H, sh), 7,26 (1H, s), 7,55-EUR 7.57 (1H, m), 7,82 (1H, s), to 7.99 (1H, d, J=9.0 Hz), 8,10 (1H, s), by 8.22 (1H, d, J=5, 9 Hz), 8,49 (1H, sh), 10,65 (1H, s), 11,33 (1H, sh).

MS (FAB) m/z: 485 (M+H)+

[Example 16]

Hydrochloride (±)-CIS-N1[(6-chloroimidazo[1,2-a]pyridine-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Ethyl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (published application No. 11-500123 on the Japan patent under the PCT) (150 mg) was dissolved in tetrahydrofuran (4 ml), was added water (1 ml) and lithium hydroxide (18 mg) at room temperature and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude 6-chloroimidazo[1,2-a]pyridine-2-carboxylate lithium. The obtained product was dissolved in N,N-dimethylformamide (4.0 ml), to the solution was added the hydrochloride (±)-CIS-N-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (232 mg), monohydrate, 1-hydroxybenzotriazole (180 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (256 mg) and triethylamine (371 μl) and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, to the residue were added water and saturated aqueous solution of sodium bicarbonate and the mixture was extracted with dichloromethane. Then the obtained organic layer was dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The obtained residue was purified column is a chromatography on silica gel (dichloromethane:acetone=1:1→ dichloromethane:acetone: methanol=5:5:1) to obtain white solid. To the obtained solid substance was added dichloromethane, methanol and 1 N. hydrochloric acid and the resulting mixture was concentrated to obtain specified in the title compound (224 mg) as a pale brown solid.

1H-NMR (DMSO-d6) δ: 1,35-is 1.51 (2H, m)and 1.51 is 1.70 (4H, m), 1,86-of 2.05 (2H, m), 2,87 (3H, s), 3.00 and is 3.15 (1H, m), 3,15-3,30 (1H, m), 3,35-3,50 (1H, m), 3,44 (1H, sh), the 3.65 (1H, sh), 4,10-4,32 (2H, m), 4,32 is 4.45 (1H, m), 4,58-4,70 (1H, m), 7,60-of 7.70 (1H, m), of 7.75 (1H, d, J=9.5 Hz), 8,50 at 8.60 (2H, m), 8,60-to 8.70 (1H, m), the remaining 9.08 (1H, d, J=15,9 Hz), 11,75-11,98 (1H, sh).

MS (FAB) m/z: 473 (M+H)+

[Example 117]

Hydrochloride (±)-CIS-N1[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-4-cyclohexen-1,2-diamine:

Specified in the title compound was obtained from (±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-4-cyclohexen-1,2-diamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 2,43-of 2.34 (m, 4H), of 2.50 (s, 3H), 3,11 (m, 2H), 3,42 (m, 1H), 3,65 (m, 1H), 4,20 (m, 1H), 4,30 (m, 2H), with 4.64 (m, 1H), to 5.66 (s, 2H), 7,02 (s, 1H) 7.15m (DD, 1H, J=1,5, 8,8 Hz), 7,39 (d, 1H, J=8,5 HZ), 7,68 (s, 1H), 8.34 per (d, 1H, J=8.5 Hz), 8,69 (d, 1H, J=8,8 Hz), 11,72 (s, 1H).

MS (ESI) m/z: 470 (M+H)+

[Example 118]

Hydrochloride (1R*,2S*,4R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-e is oxycarbonyl-N 2[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine (1.40 g) suspended in ethanol (8 ml)was added at room temperature a saturated ethanol solution (10 ml) of hydrochloric acid and the mixture was stirred for 12 hours. Drove away under reduced pressure, the solvent is obtaining hydrochloride (1R*,2S*,4R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine (1.25 g) as a colourless solid.

Specified in the title compound was obtained from the above-described product and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7,1 Hz), 1,52 and 1.80 (2H, m), 2,03-is 2.37 (4H, m), of 2.53 (3H, s), 2.57 m-a 2.71 (1H, m), of 3.73 and of 3.78 (each 1H, each d, J=14.4 Hz), 4,08-4,17 (1H, m), 4,18 (2H, q, J=7.2 Hz), 4;55-4,65 (1H, m), 6,85 (1H, sh), 7,21 (1H, DD, J=8,8, 2.0 Hz), 7,33 (1H, d, J=8,8 Hz), of 7.48 (1H, d, J=7,6 Hz), 7,63 (1H, d, J=2.0 Hz), 7,98 (1H, d, J=7,6ru), of 9.30 (1H, s).

MS (ESI) m/z: 544 (M+H)+

[Example 119]

(1S,2R,43)-N1[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine;

(1S,2R,4S-N 2-tert-Butoxycarbonyl-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine (4,2 g) suspended in ethanol (25 ml)was added at room temperature a saturated ethanol solution (55 ml) of hydrochloric acid and the mixture was stirred for 11 hours. Drove away under reduced pressure, the solvent is obtaining hydrochloride (1S,3R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine (4.15 g) as a colourless solid.

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine (4.15 g) was dissolved in N,N-dimethylformamide (40 ml)to the resulting solution at room temperature was added 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (2.86 g), monohydrate, 1-hydroxybenzotriazole (1,72 g) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.15 g) and the mixture was stirred for 39 hours. The reaction mixture was concentrated under reduced pressure, to the residue was added water and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the obtained residue was purified column chromatography on silica gel (chloroform:methanol=100:1) to obtain specified in the connection header (1,71 g) in view of the colorless amorphous substance.

[α]D- 94° (C=1.0, chloroform).

[Example 120]

(1R*That 2R*4S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R*That 2R*4S*)-N2-tert-Butoxycarbonyl-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-1,2-cyclohexanediamine was treated with saturated ethanolic hydrochloric acid and then are condensed with 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 118, with obtaining specified in the connection header.

1H-NMR (CDCl3) δ: (3H, t, J=7,10 Hz), 1,4.3-1,86 (3H, m), 2,19 to 2.35 (2H, m), the 2.46 (3H, s), 2,45-2,60 (1H, m), 2,67 is 2.80 (1H, m), 2,80 are 2.98 (4H, m), 3.58 and 3,71 (each 1H, each d, J=15.2 Hz), 3,80-of 3.95 (1H, m), 4,10-and 4.40 (3H, m)6,86 (1H, sh), 7,14-7,22(1H, m,), 7,22-7,34 (2H, m), 7,47 (1H, d, J=6.8 Hz), 7,60 (1H, s), a 9.35 (1H, s).

MS (ESI) m/z: 544 (M+H)+.

[Example 121]

(1R*the 23*4S*)-N2-[(5-Clorinda-2-yl)carbonyl]-4-methoxycarbonyl-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R*the 23*4S*)-N1-tert-Butoxycarbonyl-N2-[(5-Clorinda-2-yl)carbonyl]-4-methoxycarbonyl-1,cyclohexanediamine was treated with saturated ethanolic hydrochloric acid and then are condensed with 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium method, similar to the method of example 118, with obtaining specified in the connection header.

1H-NMR (DMSO-d6) δ: 1.55V and 1.80 (3H, m), 1,80-2,20 (3H, m), 2,60-of 2.75 (1H, m), of 2.92 (3H, s), 3,15-3,30 (1H, m), 3,30-to 3.50 (4H, m), of 3.57 (3H, s), 3,55-3,70 (1H, m), 4,20-4,30 (1H, m), 4,30-and 4.40 (1H, m), 7,02 (1H, s), 7,17 (1H, DD, J=8,5, 2.0 Hz), 7,41 (1H, d, J=8.5 Hz), 7,71 (1H, s), 8,20-8,35 (1H, m), 8,35-to 8.45 (1H, m), 11,82 (1H, sh).

MS (FAB) m/z: 530 (M+N)+

[Example 122]

(1R*,2S*,4R*)-N2-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-4-etoxycarbonyl-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with saturated ethanolic hydrochloric acid and then are condensed with 5-Clorinda-2-carboxylic acid in a manner similar to the method of example 118, with obtaining specified in the connection header.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7,1 Hz), 1,82-2,30 (6N, m), 2.49 USD (3H, s), 2,62-by 2.73 (1H, m), 3,74-of 3.85 (2H, m), 3,85-3,93 (2H, m), 3,71 (2H, s), 4,12-the 4.29 (3H, m), 4,49-4,59 (1H, m), 6.89 in (1H, sh), 7,21 (1H, DD, J=8.8 and 2.0 Hz), 7,32 (1H, d, J=8,8 Hz), 7,33 (1H, sh), 7,41 (1H, sh), a 7.62 (1H, sh), 9,37 (1H, S).

MS (ESI) m/z: 544 (M+H)+

[Example 123]

Hydrochloride (1R*,2S*4S*)-N1-[(5-Clorinda-yl)carbonyl]-4-methoxycarbonyl-N 2[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R*,2S*4S*)-N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with 4 N. dioxane solution of hydrochloric acid and then are condensed with 5-Clorinda-2-carboxylic acid in a manner similar to the method of example 118, with obtaining specified in the connection header.

1H-NMR (DMSO-d6) δ: of 1.65 and 1.80 (3H, m), 1,80-2,10 (2H, m), 2,15 was 2.25 (1H, m), 2,55-2,70 (1H, m), 2,89 (3H, s), 3,05-3,20 (1H, m), 3,30-to 3.50 (4H, m), 3,55-the 3.65 (1H, m), 3,62 (3H, s), 4,20-4,30 (1H, m), 4,35 is 4.45 (1H, m), 7,19 (1H, DD, J=8,8, 1.2 Hz), 7.23 percent (1H, s), the 7.43 (1H, d, J=8,8 Hz), 7,73 (1H, s), 8,03 (1H, d, J=6.8 Hz), 8,73 (1H, d, J=8.5 Hz), 11,85 (1H, s).

MS (FAB) m/z: 530 (M+H)+

[Example 124]

Hydrochloride, (1S,2R,4R)-N1-[(5-Clorinda-2-yl)carbonyl]-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1S,2R,4R)-N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with 4 N. dioxane solution of hydrochloric acid and then are condensed with 5-Clorinda-2-carboxylic acid in a manner similar to the way note the RA 118, obtaining specified in the connection header.

1H-NMR (DMSO-d6) δ: 1,67 to 1.76 (3H, m), 1,88 is 1.91 (1H, m), a 2.01 (1H, sh), 2,13-2,22 (1H, m), 2,52-to 2.67 (4H, m), of 2.86 (2H, sh), totaling 3.04 (2H, sh), 3,33-to 3.41 (1H, m), 3,61 (3H, s), 4,22 is 4.36 (3H, m), 7,17-7,22 (2H, m), 7,42 (1H, d, J=8,8 Hz), 7,72 (1H, s), of 8.00 (1H, d, J=6.9 Hz), 8,68 (1H, d, J=8.6 Hz), RS 11.80 (1H, s).

MS (FAB) m/z: 530 (M+H)+

[Example 125]

Hydrochloride, (1S,2R,4R)-N1[(5-Florinda-2-yl)carbonyl]-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1S,2R,4R)-N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with 4 N. dioxane solution of hydrochloric acid and then are condensed with 5-Florinda-2-carboxylic acid in a manner similar to the method of example 118, with obtaining specified in the connection header.

1H-NMR (CD3OD) δ: 1,81-1,90 (3H, m), 2,09-2,17 (3H, m), 2,61 (3H, s), 2,60-2,63 (1H, m), 2,95 (2H, sh), 3,10-of 3.12 (2H, m), 3.45 points-to 3.49 (1H, m), of 3.69 (3H, s), 4,28-4,69 (3H, m), 6,99? 7.04 baby mortality (1H, m), 7,16 (1H, s), 7,29 (1H, DD, J=9,8, 2,5 Hz), 7,41 (1H, DD, J=8,8, 4.6 Hz).

MS (FAB) m/z: 514 (M+N)+

[Example 126]

(1S,2R,4S)-4-Etoxycarbonyl-N1-[(5-Florinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1S,2R,4S)-N2-tert-B is oxycarbonyl-4-etoxycarbonyl-N 1-[(5-Florinda-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with 4 N. dioxane solution of hydrochloric acid and then are condensed with 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 118, with obtaining specified in the connection header.

1H-NMR (CD3OD) δ: of 1.29 (3H, t, J=7,1 Hz), 1.60-to 2,34 (6N, m)of 2.53 (3H, s), 2,61 of 2.68 (1H, m), 2,80-is 2.88 (2H, m), 2,96-to 2.99 (2H, m in), 3.75 (2H, s), 4,12-to 4.14 (1H, m), 4,18 (2H, q, J=7,1 Hz), 4,59-4,60 (1H, m), 6,86 (1H, s), 6,99? 7.04 baby mortality (1H, m), 7,27-7,34 (2H, m), 7,47 (1H, d, J=7,1 Hz), 7,92 (1H, d, J=5.6 Hz), 9,13 (1H, s).

MS (FAB) m/z: 528 (M+H)+

[Example 127]

(1R*,2S*,4R*,5S*or 1R*,2S*4S*,5R*)-4,5-Bis(methoxycarbonyl)-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-N2(or N1)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Dimethyl (1R*,2S*,4R*,5S*or 1R*,2S*4S*,5R*)-4,5-bis (tert-butoxycarbonylamino)-1,2-cyclohexanedicarboxylic (350 mg) was dissolved in methanol (30 ml)was added a saturated methanolic hydrochloric acid solution and the mixture was stirred at room temperature for 9 hours. Drove away under reduced pressure, the solvent receiving neo is imennogo dimethyl 4,5-diamino-1,2-cyclohexanedicarboxylate. The obtained product was dissolved in N,N-dimethylformamide (50 ml), the solution was added 5-Clorinda-2-carboxylic acid (120 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (120 mg), monohydrate, 1-hydroxybenzotriazole (140 mg) and N-methylmorpholin (0,13 ml) and the mixture was stirred at room temperature for 17 hours. Drove away under reduced pressure, the solvent, to the residue was added water and the mixture was extracted with dichloromethane. The obtained organic layer was washed saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the obtained residue was purified column chromatography on silica gel (methanol:dichloromethane=1:9) to give crude (1R*,2S*,4R*,5S*or 1R*,2S*4S*,5R*)-4,5-bis(methoxycarbonyl)-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (190 mg). The obtained product was dissolved in N,N-dimethylformamide (50 ml), was added 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (280 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (130 mg) and the monohydrate of 1-hydroxybenzotriazole (210 mg) and the mixture was stirred at room temperature for 17 hours. Drove away under reduced pressure, the solvent, to the residue was added to the water, and the mixture was extracted with dichloromethane. The obtained organic layer was washed saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the obtained residue was purified column chromatography on silica gel (methanol:dichloromethane=1:9) and preparative chromatography to obtain specified in the title compound (22 mg) as a white powder.

1H-NMR (DMSO-d6) δ: 1,97 of 1.99 (2H, m), 2,33-of 2.36 (2H, m), 2,39 (3H, s), 2,68 at 3.69 (8H, m), 3,88 (3H, s)to 3.89 (3H, s), 4,18 (1H, sh), to 4.28 (1H, sh), 7,01 (1H, s), 7,16-7,19 (2H, m), 7,40-7,42 (2H, m), 7,74 (1H, s), 11,81 (1H, s).

MS (FAB) m/z: 588 (M+N)+

[Example 128]

(1R*,2S*,4R*)-4-Carboxy-N1[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R*,2S*,4R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (916 mg) suspended in a mixed solvent consisting of ethanol (10 ml) and tetrahydrofuran (8 ml)was added at room temperature 1 N. aqueous solution (3.3 ml) of sodium hydroxide and the mixture was stirred 12 hours at the same temperature. After addition of 1 N. hydrochloric acid (3.3 ml) kept under reduced pressure Rast is oritel and the residue was washed with water and ether to obtain specified in the title compound (712 mg) as colorless solids.

[Example 129]

(1R,2R,4S)-4-Carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R,2R,4S)-N1[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (1.6 g) suspended in a mixed solvent consisting of ethanol (20 ml) and tetrahydrofuran (15 ml)was added at room temperature 1 N. aqueous solution (5,9 ml) of sodium hydroxide and the mixture was stirred 12 hours at the same temperature. After addition of 1 N. hydrochloric acid (5,9 ml) kept under reduced pressure, the solvent and the residue was washed with water and ether to obtain specified in the title compound (1.19 g) as a colourless solid. TPL 234-236°C.

[α]D- 57° (C=1.0, methanol).

[Example 130]

Hydrochloride (1R*,2S*4S*)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R*,2S*4S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (180 mg) was dissolved in cm is Shannon solvent, consisting of tetrahydrofuran (8 ml) and water (2 ml), was added lithium hydroxide (17 mg) and the mixture was stirred at room temperature for 45 minutes. After addition of 1 N. hydrochloric acid, the reaction mixture was concentrated under reduced pressure, to the residue was added a small amount of water and the amount of precipitation was filtered to obtain specified in the title compound (140 mg) as a pale yellow solid.

1H-NMR (DMSO-d6) δ: 1,60-1,80 (3H, m), 1,80-of 1.95 (1H, m), 1,95-of 2.20 (2H, m), is 2.41 (3H, s), 2,70-2,90 (4H, m), 3,70-of 3.85 (2H, m), 4,15-4,30 (1H, m), 4,30-and 4.40 (1H, m), 7,19 (1H, DD, J=8,8, 2.2 Hz), 7,22 (1H, d, J=1.5 Hz), the 7.43 (1H, d, J=8,8 Hz), 7,72 (1H, d, J=2.2 Hz), 8,00 (1H, d, J=6.8 Hz), 8,64 (1H, d, J=8.5 Hz), 11,82 (1H, s).

MS (FAB) m/z: 516 (M+H)+.

[Example 131]

(1R*That 2R*4S*)-4-Carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R*That 2R*,4R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-etoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (244 mg) were suspended in a mixed solvent consisting of ethanol (8 ml) and tetrahydrofuran (5 ml)was added at room temperature 1 N. aqueous solution (0.9 ml) of sodium hydroxide and the mixture was stirred 12 h the century After addition of 1 N. hydrochloric acid (0.9 ml) kept under reduced pressure, the solvent and the residue was washed with water and ether to obtain specified in the title compound (152 mg) as a colorless solid.

1H-NMR (DMSO-d6) δ: 1,44-2,23 (6N, m)of 2.34 (3H, s), 2,60-2,90 (5H, m), 3,53 and 3,62 (each 1H, each d, J=5,65 Hz), 3.95 to of 4.25 (2H, m), 7,02 (1H, s), 7,12 (1H, sh. J=8,8 Hz), was 7.36 (1H, d, J=8,8 Hz), 8,29 (1H, d, J=8,8 Hz), 8,40 (1H, d, J=8,8 Hz), 11,65 (1H, s).

MS (ESI) m/z: 516 (M+H)+.

[Example 132]

Lithium salt of (1R*,2S*4S*)-4-carboxy-N2-[(5-Clorinda-2-yl)carbonyl]-N1-[(5-methyl-4,5,6,7-tetrahydrothieno [5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R*,2S*4S*)-N2-[(5-Clorinda-2-yl)carbonyl]-4-methoxycarbonyl-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (1.2 g) was dissolved in tetrahydrofuran (32 ml)were added successively under ice cooling, the lithium hydroxide (of 60.8 mg) and water (4 ml) and the mixture was stirred at room temperature for 14 hours. Drove away under reduced pressure, the solvent is obtaining specified in the title compound (1.12 g).

1H-NMR (DMSO-d6) δ: 1,55-1,70 (2H, m), 1.70 to was 2.05 (4H, m), 2,10-of 2.20 (1H, m), 2,25-to 2.40 (4H, m), 2,50 is 2.80 (4H, m), 3.45 points-of 3.65 (3H, m), 4,10-4,30 (2H, m), 7,00-7,20 (2H, m), 7,50 and 7.6 (2H, m).

[Example 133]

(1R*,2S*,4R*)-4-Carbarnoyl-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1R*,2S*,4R*)-N2(tert-Butoxycarbonyl)-4-carbarnoyl-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with 4 N. dioxane solution of hydrochloric acid and then are condensed with 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 118, with obtaining specified in the connection header.

1H-NMR (CDCl3) δ: 0,78-to 2.40 (7H, m), of 2.53 (3H, s), 2,80-2,89 (1H, m), 2.91 in-3,00 (1H, m), 3,68 is 3.76 (2H, m), 4,08-4,19 (1H, m), 4,54 with 4.65 (1H, m), to 6.80 (1H, sh), 7,21 (1H, DD, J=8.4 and 1.6 Hz), 7,33 (1H, d, J=8,4 Hz), 7,38-the 7.43 (1H, m), 7,49-of 7.55 (1H, m), 7,63 (1H, sh), 9,14 (1H, sh).

MS (ESI) m/z: 515 (M+H)+.

[Example 134]

Hydrochloride (1R*,2S*,4R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

The triethylamine (0.25 ml), hydrochloride diethylamine (133 mg), monohydrate, 1-hydroxybenzotriazole (53 mg), and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (75 mg) was added to a chloroform suspension (10 ml) of (1R ,2S*,4R*)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4, 5,6,7-tetrahydropyrazolo[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (168 mg) and the mixture was stirred for 72 hours. Drove away under reduced pressure, the solvent, to the residue was added water and the mixture was extracted with chloroform. The obtained organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the obtained residue was purified column chromatography on silica gel (dichloromethane:methanol=93:7). Collected in this way colourless solid (135 mg) suspended in ethanol and the suspension was added 1 N. hydrochloric acid (0.5 ml). The mixture was stirred for 2 hours and drove the solvent to obtain specified in the title compound (112 mg) as colorless powder.

1H-NMR (DMSO-d6) δ: 1,42-2,07 (6N, m), 2,73-3,70 (10 H, m), is 2.88 (3H, s), of 2.97 (3 H, s), a 4.03-4,20 (1H, m), 4,51-of 4.67 (1H, m),? 7.04 baby mortality (1H, sh), 7,16 (1H, sh. J=8,8 Hz), 7,41 (1K, d, J=8,8 Hz), 7,68 (1H, sh), 8,32-of 8.47 (2H, m), of 10.76 (1H, sh).

MS (ESI) m/z: 543 (M+H)+

[Example 135]

Hydrochloride (1R*That 2R*4S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N.N-dimethylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R*That 2R*4S*)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and dimethylamine hydrochloride in a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,00-2,05 (7H, m)of 2.50 (3H, s), of 2.81 (3H, s), 2,92-3,65 (N, m), 3.95 to-4,10 (1H, m), 4,50-and 4.68 (1H, m), was 7.08 (1H, s), 7,13 (1H, DD, J=8,8, 2.0 Hz), 7,37 (1H, d, J=8,8 Hz), 7,66 (1H, sh), 8,31 (1H, d, J=8,4 Hz)and 8.50 (1H, d, J=9,2 Hz), 11,67 (1H, s).

MS (ESI) m/z: 543 (M+H)+

[Example 136]

Hydrochloride (1R*,2S*4S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4(N,N-dimethylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R*,2S*4S*)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and dimethylamine hydrochloride in a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,42-of 2.25 (7H, m), 2,80-of 3.12 (4H, m), 2,82 (3H, s), is 2.88 (3H, s), 3.04 from (3H, s), 3,32-3,68 (2H, m), 4,29-br4.61 (2H, m), 7,16-7,24 (2H, m), 7,42 (1H, d, J=8,8 Hz), 7,74 (1H, s), 8,01 (1H, d, J=5,6 Hz), 8,91 (1H, d, J=8,4 Hz), 11,85 (1H, sh).

MS (ESI) m/z: 543 (M+H)+.

[Example 137]

Hydrochloride (1R* ,2S*,4R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N-methylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R*,2S*,4R*)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and methylamine hydrochloride in a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,50-2,70 (7H, m), 2,90 (3H, s), 3,05-3,75 (N, m), 4,05-4,20 (1H, m), of 4.38-a 4.53 (1H, m), 7,03 (1H, sh), 7,16 (1H, sh. J=8,8 Hz), 7,41 (1H, d, J=8,8 Hz), 7,69 (1H, sh), 8,11 (1H, sh), 8,39 (1H, d, J=7,6 Hz), 11,78 (1H, sh).

MS (ESI) m/z: 529 (M+H)+

[Example 138]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N-isopropylcarbamate)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and Isopropylamine a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,02 (6N, DD, J=6,5, 2,5 Hz), 1,50-2,10 (6N, m), 2,30 (1H, t, J=12.0 Hz), only 2.91 (3H, s), 3,10-of 3.75 (4H, m), 3.75 to 3,90 (1H, m), 4,07-4,20 (1H, m), 4,30-of 4.57 (2H, sh) 4,57 of 4.83 (1H, sh), 7,03 (1H, d, J=1.5 Hz), 7,16 (1H, DD, J=8,8, 2,1 Hz), 7,41 (1H, d, J=8,8 Hz), 7,60 to 7.75 (2H, m), with 8.05 (1H, sh), 8,43 (1H, sh. J=7.8 Hz), 11,63 (1H, sh), to 11.79 (1H, s).

MS (FAB) m/z: 557 (M+H)+.

[Example 139]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N-cyclopropanecarbonyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-4-carboxy-N1[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and cyclopropylamine a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 0,32-0,40 (2H, m), of 0.53 to 0.63 (2H, m), 1,50-2/10 (6N, m), 2,25-to 2.40 (1H, m), 2,45-2,70 (2H, m), 2.91 in (3H, s), 3,05-of 3.80 (3H, m), 4,05-4,17 (1H, m), 4,30-4,55 (2H, m), 4,55-4,80 (1H, m), 7,03 (1H, d, J=1.5 Hz), 7,16 (1H, DD, J=8,8, 2.0 Hz), 7,41 (1H, d, J=8,8 Hz), to 7.68 (1H, d, J=2.0 Hz), 7,86 (1H, sh. J=3,4 Hz), of 8.06 (1H, sh), 8,40 (1H, sh. J=7,6 Hz), 11,20-11,60 (1H, W.), to 11.79 (1H, s).

MS (FAB) m/z: 555 (M+H)+

[Example 140]

Hydrochloride, (1S,2R,43)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N-ethyl-N-methylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexane is Amina and ethylmethylamine way similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 0,93-of 1.13 (3H, m), 1,40-of 1.64 (1H, m), 1,64-of 1.88 (3H, m), 1,88 is 2.10 (2H, m), was 2.76 (1/2 of 3H, s), 2,90 (3H, s), 2,93 (1/2 of 3H, s), 3,10-of 3.80 (7H, m), 4,05-4,17 (1H,m), 4,30-4,85 (3H, m),? 7.04 baby mortality (1H, s), to 7.15 (1H, DD, J=8,8, 1.7 Hz), 7,40 (1H, d, J=8,8 Hz), to 7.67 (1H, s), 8.30 to-8,50 (2H, m), of 11.29 (1H, sh), 11,77 (1H, s).

MS (FAB) m/z: 557 (M+H)+

Example 141]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-4-(pyrrolidinecarbonyl)-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and pyrrolidine a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,45-2,10 (10H, m), 2/75-2,90 (2H, m), 2,90 (3H, s), 3,10-3,70 (N, m), 4,05-4,20 (1H, m), 4,25-4,80 (3H, m), 7,05 (1H, s), 7,17 (1H, d, J=8.7 Hz), 7,41 (1H, D, J=8.7 Hz), 7,69 (1H, s), 8,32 (1H, W., J=7,6 HZ), scored 8.38 (1H, sh. D=7,1 Hz), 11,22 (1H, sh), 11,78 (1H, s).

MS (FAB) m/z: 569 (M+H)+

[Example 142]

Hydrochloride (1R*,2S*,4R*)-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-4-(4-morpholinoethyl)-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1R*,2S*,4R *)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and research in a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,40-2,05 (6N, m), 2,75-3,70(N, m), as 4.02-4,17 (1H, m), 4,55-4,69 (1H, m), 7,05 (1H, sh), 7,17 (1H, sh. J=8,8 Hz), 7,41 (1H, d, J=8,8 Hz), to 7.67 (1H, sh), 8,35 (1H, d, J=7,6 Hz), 8,40 (1H, d, J=7,6 Hz), 10,79 (1H, sh).

MS (ESI) m/z: 585 (M+H)+

[Example 143]

Hydrochloride, (1S,2R,4S)-N1-(5-Clorinda-2-yl)carbonyl]-4-(N-ethylcarbazole)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1S,2R,4S)-4-Carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (150 mg) was dissolved in N,N-dimethylformamide (3 ml), to the solution was added the hydrochloride of N-ethylamine (119 mg), monohydrate, 1-hydroxybenzotriazole (79 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (112 mg) and triethylamine (326 μl) and the mixture was stirred at room temperature for 4 days. Drove away under reduced pressure, the solvent, to the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent poluchenii the residue was purified column flash chromatography on silica gel (dichloromethane:methanol=47:3). Resulting white solid was dissolved in dichloromethane and to the solution was added 1 N. ethanol solution (171 μl) of hydrochloric acid. Drove away under reduced pressure, the solvent, to the residue was added methanol and diethyl ether and the resulting precipitate was filtered, to deliver specified in the title compound (74 mg) as a white solid.

1H-NMR (DMSO-d6) δ: 0,99 (3H, t, J=7.2 Hz), 1.57 in-2,02 (6N, m), 2,33-of 2.38 (1H, m), of 2.92 (3H, s), 3,01-is 3.08 (2H, m), 3,17-3,20 (2H, s), 3,45-3,70 (2H, m), 4,10-4,17 (1H, m), 4,40-4,69 (3H, m),? 7.04 baby mortality (1H, d, J=2.0 Hz), 7,17 (1H, DD, J=8,8, 2.0 Hz), 7,41 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=2.0 Hz), 7,78-7,81 (1H, m), 8,08-to 8.12 (1H, m), 8,40 (1H, d, J=8.1 Hz), 11,23 (1H, sh), to 11.79 (1H, sh).

MS (FAB) m/z: 543 (M+H)+

[Example 144]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1S,2R,4S)-4-Carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (900 mg) was dissolved in N,N-dimethylformamide (50 ml), the solution was added dimethylamine hydrochloride (304 mg), monohydrate, 1-hydroxybenzotriazole (262 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (369 mg) and diisopropylethylamine (1,83 ml) and the mixture was stirred at room temperature is within 12 hours. Drove away under reduced pressure, the solvent, to the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the obtained residue was column purified flash chromatography on silica gel (dichloromethane:methanol=47:3). Resulting white solid was dissolved in dichloromethane and to the solution was added 1 N. ethanol solution (1,49 ml) of hydrochloric acid. Drove away under reduced pressure, the solvent, to the residue was added methanol and diethyl ether and the resulting precipitate was filtered, to deliver specified in the title compound (777 mg) as a white solid.

[α]D- 53,9° (18°s=worn : 0.505, methanol).

1H-NMR (DMSO-d6) δ: 1,45-to 1.60 (1H, m), 1.70 to of 1.85 (3H, m), 2,80 (3H, s), 2.91 in (3H, s), 2.95 and-3,10 (1H, m), of 2.97 (3H, s), 3,10-of 3.75 (4H, m), 4,05-to 4.15 (1H, m), 4,35-of 4.75 (3H, m), 7,05 (1H, s), 7,16 (1H, DD, J=8,7, 2,1 Hz), 7,41 (1H, d, J=8.6 Hz), to 7.67 (1H, s), 8,30-to 8.45 (2H, m), 11,63 (1H, sh), 11,78 (1H, s).

MS (FAB) m/z: 543 (M+H)+

[Example 145]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N.N-diethylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the header connection recip is of (1S,2R,4S)-4-carboxy-N 1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and diethylamine a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 0,99, 1,05 (6N, each t, J=7 Hz), 1,53-to 1.61 (1H, m), 1,74 and 1.80 (3H, m), 1,96-of 2.05 (2H, m), 2,88-2,95 (4H, m), 3,17-to 3.67 (8H, m), 4,11-4,16 (1H, m) of 4.45 (1H, sh), 4,55-4,58 (1H, m), of 4.66 (1H, sh), 7,06 (1H, d, J=2.0 Hz), 7,16 (1H, DD, J=8,9, 1.9 Hz), 7,42 (1H, d, J=8,9 Hz), 7,69 (1H, d, J=l,9 Hz), to 8.41 (2H, D, J=7.8 Hz), 11,65 (1H, sh), 11,81 (1H, sh).

MS (FAB) m/z: 571 (M+H)+.

[Example 146]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N-methyl-N-propellerblades)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and N-methyl-N-Propylamine in a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 0,71, of 0.79 (3H, each t, J=7,3 Hz), 1.41 to 1,75 (6N, m)to 1.99 (2H, sh), 2,67-3,02 (7H, m), 3,11 is 3.40 (4H, m), 3,47 (1H, sh), to 3.67 (1H, sh), of 4.12 (1H, sh), of 4.44-and 4.68 (3H, m), 7,05 (1H, s), 7,16 (1H, DD, J=of 8.8, 1.7 Hz), 7,41 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=1.7 Hz), 8,35-8,42 (2H, m), of 11.45 (1H, sh), to 11.79, 11,81 (1H, each s).

MS (FAB) m/z: 571 (M+H)+

[Example 147]

Hydrochloride, (1S,2R,43)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N,N-dipropylamino)N 2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)-carbonyl]-1,2-cyclohexanediamine and dipropylamine a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 0,69 (3, t, J=7,3 Hz)of 0.79 (3H, t, J=7,3 Hz), to 1.38 to 1.47 (4H, m), 1,57-of 1.78 (4H, m), 1,98 is 2.01 (2H, m), 2,80 (1H, t, J=11.5 Hz), 3,01-3,39 (6N, m), 3,48 (1H, sh), 3,68 (1H, sh), 4,13-4,16 (1H, m), 4,43 (1H, sh), 4,48-4,50 (1H, m), and 4.68 (1H, sh),? 7.04 baby mortality (1H, d, J=2.0 Hz), 7,16 (1H, DD, J=8,8, 2.2 Hz), 7,41 (1H, d, J=8,8 Hz), of 7.70 (1H, d, J=2.2 Hz), with 8.33 (1H, d, J=7,6 Hz), 11,27-11,40 (1H, m), RS 11.80 (1H, sh).

MS (FAB) m/z: 599 (M+H)+

[Example 148]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N-isopropyl-N-methylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and N-isopropyl-N-methylamine in a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 0,99-1,15 (6N, m), 1,50-1,99 (6N, m), 2,64, 2,78 (3H, each s)of 2.92 (3H, s), 2,96-3,39 (4H, m), 3,47 (1H, sh), 3,68 (1H, sh), 4,12-4,13 (1H, m), of 4.45 (1H, sh), 458-4,70 (2H, m), 7,05 (1H, s), 7,16 (1H, DD, J=8,8, 2.0 Hz), 7,41 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=2.0 Hz), scored 8.38-8,46 (2H,m), 11,27 (1H, sh), to 11.79 (1H, sh).

MS (FAB) m/z: 571 (M+H)+

[Example 149]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-[N-(2-methoxyethyl)-N-methylcarbamoyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and N-(2-methoxyethyl)-N-methylamine in a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,50-1,99 (6N, m), 2,80, a 3.01 (3H, each s), only 2.91 (3H, s), 3,03 (1H, sh), and 3.16 (2H, s), 3,23 (3H, s), 3,35-3,67 (6N, m), 4.09 to to 4.16 (1H, m), 4,43-of 4.67 (3H, m),? 7.04 baby mortality-7,06 (1H, m), 7,16 (1H, DD, J=8,8, 2,0 Hz), 7,42 (1H, d, J=8,8 Hz), 7,69 (1H, sh), 8,29-to 8.41 (2H, m), 11,59 (1H, sh), RS 11.80 (1H, sh).

MS (FAB) m/z: 587 (M+H)+

[150]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-[N-(2-hydroxyethyl)-N-methylcarbamoyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and N-(2-hydroxyethyl)-N-mate the amine way similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,50-1,55 (1H, m), 1,74-of 1.84 (3H, m), 1,94-of 1.97 (2H, m), 2,67, to 3.02 (3H, each s), only 2.91 (3H, s), 3,10-3,68 (N, m), 4,11-4,13 (1H, m), 4,43-of 4.66 (4H, m), 7,05 (1H, s), 7,16 (1H, DD, J=8,7, 2.0 Hz), 7,41 (1H, d, J=8.7 Hz), 7-,68 (1H, s), 8.34 per-of 8.40 (2H, m), 11,47 (1H, sh), to 11.79 (1H, s).

MS (FAB) m/z: 573 (M+H)+

[Example 151]

Hydrochloride, (1S,2R,4S)-4-[(azetidin-1-yl)carbonyl]-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and hydrochloride of azetidine a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,47-of 1.55 (1H, m), 1,65-to 1.82 (3H, m), 1,88 is 2.01 (2H, m)of 2.16 (2H, Quint., J=7,6 Hz), 3,17-to 3.67 (5H, m), 3,82 (2H, t, J=7,6 Hz), was 4.02-to 4.14 (3H, m), 4,43-of 4.67 (3H, m), 7,06 (1H, s), 7,17 (1H, DD, J for 8.7 and 1.7 Hz), 7,41 (1H, d, J=8.7 Hz), 7,69 (1H, sh), 8,31 (1H, d, J=7,6 Hz), scored 8.38 (1H, d, J=7,6 Hz), 11,41 (1H, sh), RS 11.80 (1H, s).

MS (FAB) m/z: 555 (M+H)+

[Example 152]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-[[(3S)-3-ftorpirimidinu-1-yl]carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (1S,2R,4S)-4-carbon and-N 1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and (S)-3-terpinolene (Synlett., 1995, p. 55) in a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,23-of 3.77 (22N, m), 4,11-4,16 (1H, m), 4,58-4,51 (1H, m), 5,23-5,42 (1H, m), 7,05 (1H, s), 7,16 (1H, d, J=8,3 Hz), 7,42 (1H, d, J=8,3 Hz), 7,68 (1H, s), 8.34 per-of 8.37 (2H, m), 11,78 (1H, s).

MS (FAB) m/z: 587 (M+N)+

[Example 153]

(1R*,2S*4S*)-N2-[(5-Clorinda-2-yl)carbonyl]-4-(N-methylcarbamoyl)-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from the lithium salt of (1R*,2S*4S*)-4-carboxy-N2-[(5-Clorinda-2-yl)carbonyl]-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and methylamine in a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,50-1,80 (4H, m), 1,90-of 2.05 (2H, m), 2,35 at 2.45 (4H, m), 2,59 (3H, d, J=4.4 Hz), 2.70 height is 2.80 (2H, m), 2,85-2,95 (2H, m)to 3.64 (2H, s), 4,20 is 4.35 (2H, m), 7,02 (1H, s), 7,16 (1H, d, J=8.6 Hz), 7,41 (1H, d, J=8,8 Hz), 7,68 (1H, s), a 7.85 (1H, d, J=4.4 Hz), 7,98 (1H, d, J=7,6 Hz), 8,67 (1H, d, J=7,6 Hz), 11,76 (1H, s).

MS (FAB) m/z: 529 (M+H)+

[Example 154]

Hydrochloride (1R*,2S*4S*)-N2-[(5-Clorinda-2-yl)carbonyl]-4-[N-(2-methoxyethyl)carbarnoyl]-N1-[(5-methyl-,5,6,7-tetrahydropyrazolo[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from the lithium salt of (1R*,2S*4S*)-4-carboxy-N2-[(5-Clorinda-2-yl)carbonyl]-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and 2-methoxyethylamine a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,50-1,80 (4H, m), 1,95-of 2.05 (2H, m), 2,85-2,95 (4H, m), 3,10 is 3.40 (10H, m), 3,40-3,70 (2H, m), 4,15-4,70 (4H, m), 7,02 (1H, s), 7,16 (1H, d, J=8,8 Hz), 7,41 (1H, d, J=8,8 Hz), 7,69 (1H, s), 7.95 is-with 8.05 (1H, m), 8,08 (1H, d, J=7,6 Hz), 8,67 (1H, d, J=7.8 Hz), 11,20-11,90 (2H, m).

MS (FAB) m/z: 573 (M+N)+.

[Example 155]

Hydrochloride (1R*,2S*4S*)-N2-[(5-Clorinda-2-yl)carbonyl]-4-(N-isopropylcarbamate)-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from the lithium salt of (1R*,2S*4S*)-4-Carboxy-N2-[(5-Clorinda-2-yl)carbonyl]-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and Isopropylamine a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,00-1,10 (6N, m), 1,50-1,80 (4H, m), 1,95-of 2.05 (2H, m), 2,35 at 2.45 (1H, m), 2.91 in (3H, s), 3.15 and is 3.25 (2H, m), 3,45-3,70 (2H, m), 3,80-are 3.90 (1H, m), 4,20-4,70 (4H, m), 7,02 (1H, d, J=l,5 Hz), 7,16 (1H, DD, J=8,8, 2.2 Hz), 7,41 (1H, d, J=8,8 Hz), 7,-8 (1H, d, J=1.7 Hz), 7,76 (1H, d, J=7,6 Hz), of 8.04 (1H, d, J=8,8 Hz), 8,68 (1H, d, J=7.8 Hz), is 11.39 (1H, sh), 11,76 (1H, s).

MS (FAB) m/z: 557 (M+H)+

[Example 156]

Hydrochloride (1R*,2S*4S*)-N2-[(5-Clorinda-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from the lithium salt of (1R*,2S*4S*)-4-carboxy-N2-[(5-Clorinda-2-yl)carbonyl]-N1-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and dimethylamine hydrochloride in a manner similar to the method of example 134.

1H-NMR (DMSO-d6) δ: 1,40-1,60 (2H, m)of 1.65 and 1.80 (2H, m), 1,95 is 2.10 (2H, m), 2,84 (3H, s), 2,90 was 3.05 (1H, m), of 2.92 (3H, s), 3,06 (3H, s), 3,15-of 3.75 (4H, m), 4,25-of 4.75 (4H, m), 7,02 (1H, d, J=1.5 Hz), to 7.15 (1H, DD, J=to 8.8, 2.1 Hz), 7,41 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=2.1 Hz), with 8.05 (1H, d, J=7,7 Hz), 8,63 (1H, d, J=7,7 Hz), 11,20 (1H, sh), to 11.79 (1H, s).

MS (FAB) m/z: 543 (M+H)+

[Example 157]

Hydrochloride, (1S,2R,4R)-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-4-(piperidine-1-yl)carbonyl-1,2-cyclohexanediamine:

(1S,2R,4R)-N1-[(5-Clorinda-2-yl)carbonyl]-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (200 mg) races shall varali in tetrahydrofuran (5 ml) and water (0.6 ml), was added lithium hydroxide (12 mg) and the mixture was stirred at room temperature. After 3 hours the reaction was stopped, drove away under reduced pressure, the solvent and then the residue was dissolved in N,N-dimethylformamide (10 ml), to the solution was added piperidine (65 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (110 mg), 1-hydroxybenzotriazole (77 mg) and diisopropylethylamine (390 mg) and the mixture was stirred at room temperature for 3 days. Drove away under reduced pressure, the solvent, to the residue was added dichloromethane and the resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the obtained residue was purified column chromatography on silica gel (methanol:dichloromethane=1:10) to give the product (132 mg) in free form. The obtained product was dissolved in methanol and to the solution was added 1 N. ethanol solution (230 ml) of hydrochloric acid. The mixture was dried to obtain a solid substance. To the residue for solidification was added ether. The obtained solid was filtered to obtain specified in the title compound (127 mg) as a colorless solid.

1H-NMR (CD3OD) δ: 1,55-2,10 (N, m), 3,06 (3H, s), 3,07-3,16 (MN, m), 3,59-3,70 (7H, m), 4,35 (1H, sh), br4.61 (2N sh), 7,13-7,21 (2H, m), 7,41 (1H, d, J=8,8 Hz) of 7.60 (1H, s), 7,86 (0,5H, d, J=7,6 Hz), 8,84 (0,5H, d, J=7,6 Hz).

MS (FAB) m/z: 583 (M+H)+

[Example 158]

Hydrochloride, (1S,2R,4S)-N1-[(5-Florinda-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1S,2R,4S)-4-Etoxycarbonyl-N1-(5-Florinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine hydrolyzed and then subjected to the condensation reaction with dimethylamine hydrochloride in a manner similar to the method of example 157, obtaining specified in the connection header.

1H-NMR (DMSO-d6) δ: 1,48-2,00 (6N, m), 2,60-3,30 (5H, m), 2,80 (3H, s), 2.91 in (3H, s), 2,98 (3H, s), 3,70-and 4.68 (4H, m), 7,00-7,06 (2H, m), 7,37-7,42 (2H, m), at 8.36-to 8.41 (2H, m), of 11.69 (1H, s).

MS (FAB) m/z: 527 (M+N)+

[Example 159]

Hydrochloride, (1S,2R,4S)-N1-[(5-Florinda-2-yl)carbonyl]-4-(N-methylcarbamoyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1S,2R,4S)-4-Etoxycarbonyl-N1-[(5-Florinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine hydrolyzed and then subjected to the condensation reaction with hydrochloride monomethylamine a manner similar to the method of example 157, obtaining the decree is spent in the connection header.

1H-NMR (DMSO-d6) δ: 1,57-2,04 (6N, m), 2,33-to 2.41 (1H, m)to 2.55 (3H, s), of 2.92 (3H, s), 3,17-3,71 (4H, m), 4,13-to 4.14 (1H, m), 4,46 (2H, sh), 4,69-to 4.73 (1H, m), 7,00-7,05 (2H, m), 7,38-7,42 (2H, m), to 7.77 (1H, s), 8,09-8,15 (1H, m), 8,39 (1H, d, J=7,6 Hz), 11,70 (1H, s).

MS (FAB) m/z: 513 (M+H)+

[Example 160]

Hydrochloride, (1S,2R,43)-4-[N-(tert-butyl)carbarnoyl]-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(1S,2R,4S)-N2-tert-Butoxycarbonyl-4-[N - (tert-butyl)carbarnoyl]-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with 4 N. dioxane solution of hydrochloric acid and then are condensed with 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 118, with obtaining specified in the connection header

1H-NMR (DMSO-d6) δ: 1,23 (N, C), 1,50-2,00 (6N, m), 2,30-of 2.50 (1H, m), with 2.93 (3H, s), 3,10-of 3.80 (4H, m), 4,05-4,80 (4H, m), 7,03 (1H, d, J=1.5 Hz), 7,16 (1H, DD, J=8,8, 2.0 Hz), 7,35-7,45 (2H, m), 7,68 (1H, d, J=2,0 Hz), of 7.90-8,10 (1H, m), 8,42 (1H, d, J=8.1 Hz), 11,30-of 11.45 (1H, m), to 11.79 (1H, s).

MS (FAB) m/z: 571 (M+H)+

[Example 161]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-[[(3R)-3-hydroxypyrrolidine-1-yl]carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

1) (3R)-1-Benzyl-3-(tert-butylbiphenyl is relaxi)pyrrolidin (1.18 g) was dissolved in methanol (12 ml), added 1 N. hydrochloric acid (240 μl) and palladium hydride (221 mg)was injected hydrogen and a spent catalytic reduction at normal pressure and room temperature for 4.5 hours. Was removed by filtration of the catalyst and the filtrate was concentrated under reduced pressure to a solid state to obtain the crude hydrochloride (3R)-3-(tert-butyldiphenylsilyl)pyrrolidine (984 mg).

Thus obtained product (249 mg), (1S,2R,4S)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (295 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (126 mg) and 1-hydroxybenzotriazole (87 mg) was dissolved in N,N-dimethylformamide (10 ml). To the solution was added dropwise under ice cooling diisopropylethylamine (450 μl) and the mixture was stirred at room temperature for 12 hours. Drove away under reduced pressure, the solvent and to the residue was added dichloromethane and a saturated aqueous solution of sodium bicarbonate for the separation of liquids. The obtained organic layer was dried over anhydrous sodium sulfate and drove away under reduced pressure the solvent. The residue was subjected to column flash chromatography on silica gel (methanol:dichloromethane=3:97) to obtain (1S,2R,4S)-4-[[(3R)-3-(tert-butyldiphenylsilyl)pyrrolidin-1-yl]rbony]-N 1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (248 mg) as a pale yellow amorphous substance.

1H-NMR (CDCl3) δ: 1,06(N, C), 1,50-1,60 (1H, m), 1,75-2,10 (5H, m), 2,20-of 2.50 (2H, m), of 2.54 (3H, d, J=2,8 Hz), 2,60-of 3.00 (5H, m), 3,30-3,80 (6N, m), 4,10-4,20 (1H, m), 4,40-4,70 (2H, m), 6,85 (1H, s), 7,15-of 7.25 (1H, m), 7,30 is 7.50 (8H, m), 7,60-of 7.70 (5H, m), of 7.90-8,00 (1H, m), 9,38 (1H, s).

MS (FAB) m/z: 823 (M+N)+

2) the above product (240 mg) was dissolved in pyridine (10 ml)was added dropwise while cooling with ice complex (3.0 ml) hydrogen fluoride-pyridine and the mixture was stirred at 0°C for 4.5 hours. In the reaction mixture for dilution was added under ice cooling, the ethyl acetate (80 ml). Diluted the reaction mixture was poured on ice. To the obtained solution for alkalizing was added sodium bicarbonate and separated liquid. The obtained organic layer was dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (methanol:dichloromethane=1:19→1:9). The obtained purified product was dissolved in dichloromethane and methanol, to the solution was added 1 N. ethanol solution (225 ml) of hydrochloric acid and then dried it once. To the residue for solidification was added methanol and ether to obtain the hydrochloride (114 mg) indicated what about the title compound as a colorless powder.

1H-NMR (DMSO-d6) δ: 1,50-1,60 (1H, m), 1.70 to 2,10 (6N, m), of 2,75 2,85 (1H, m), of 2.92 (3H, s), 3,10-of 3.80 (8H, m), 4,10-5,10 (6N, m), 7,05 (1H, d, J=1.7 Hz), 7,16 (1H, DD, J=8,8, 1.7 Hz), 7,42 (1H, d, J=8,8 Hz), 7,68 (1H, C)8,30-to 8.45 (2H, m), 11,10-11,40 (1H, m), 11,78 (1H, s).

MS (FAB) m/z: 585 (M+H)+

[Example 162]

Hydrochloride, (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-[(3-hydroxyazetidine-1-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

1) After catalytic reduction of 1-benzhydryl-3-(tert-butyldiphenylsilyl)azetidine in a manner similar to stage 1) of example 161, to obtain the hydrochloride of 3-(tert-butyldiphenylsilyl)azetidine obtained product are condensed with (1S,2R,4S)-4-carboxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine, resulting in the (1S,2R,4S)-4-[[3-(tert-butyldiphenylsilyl)azetidin-1-yl]carbonyl]-N1[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine.

1H-NMR (CDCl3) δ: 1,07 (N, C), 1,50-2,50 (5H, m)to 2.55 (3H, d, J=2.0 Hz), 2,80-3,00 (6N, m), 3,70-of 3.80 (2H, m), 3,90-4,30 (5H, m), 4,55 with 4.65 (2H, m), at 6.84 (1H, sh), 7,15-of 7.25 (1H, m), 7,30 is 7.50 (8H, m), 7,60-of 7.70 (5H, m), of 7.90-8,10 (1H, m), of 9.30 (1H, sh).

MS (FAB) m/z: 809 (M+N)+

2) is listed in the title compound was obtained from described to enter the product way similar to stage 2) of example 161.

1H-NMR (DMSO-d6) δ: 1,45-1,55 (1H, m), 1.60-to 2,10 (5H, m), 2,55-to 2.65 (1H, m), 2.91 in (3H, s), 3,10-3,90 (6N, m)4,00-4,30 (3H, m), 4,40-5,80 (5H, m), 7,06 (1H, d, J=1.5 Hz), 7,16 (1H, DD, J=8,8, 2.2 Hz), 7,42 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=1.7 Hz), 8,30-to 8.45 (2H, m), 11,40-11,60 (1H, m), RS 11.80 (1H, s).

MS (FAB) m/z: 571 (M+N)+

[Example 163]

(1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4(N,N-dimethylcarbamoyl)-N2-[[5(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

1) (1S,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine (200 mg) was dissolved in dichloromethane (6 ml), was added triperoxonane acid (2 ml) and the mixture was stirred at room temperature for 2.5 hours. Drove away under reduced pressure, the solvent is getting trifenatate (1S,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine.

Triptorelin, 5-[1,1-dimethyl-2-(tert-butyldiphenylsilyl)ethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium (324 mg), N-methylmorpholin (143 μl) and the monohydrate of 1-hydroxybenzotriazole (86 mg) was dissolved in N.N-dimethylformamide (5 ml) and the solution was subjected to interaction with the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (108 mg) as a condensing agent, resulting in the (1S,2R43)-N 1-[(5-Clorinda-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N2-5-[1,1-dimethyl-2-(tert-butyldiphenylsilyl)ethyl]-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (363 mg) as amorphous solids.

1H-NMR (DMSO-d6) δwith 1.07 (s, N), of 1.66 (m, 2H), 1.77 in (m, 1H), of 1.84 (m, 1H), 2,04 (m, 1H), 2,23 (m, 1H), 2,34 (m, 1H), 2,84-3,06 (8H), of 2.97 (s, 3H), 3,10 (s, 3H), to 3.58 (m, 1H), 3,62 (s, 2H), 3,98 (s, 1H), 4,03 (, 2H), 4,17 (m, 1H), 4,63 (m, 1H), 6,84 (s, 1H), 7,20 (DD, 1H, J=8,8, 2.0 Hz), 7,33 (d, 1H, J=8,8 Hz), 7,39-7,66 (N), 7,89 (1H, d, J=5, 9 Hz), 9,34 (1H, c).

2) is listed in the title compound was obtained from the above of the product in a manner similar to stage 3) of example 69.

1H-NMR (DMSO-d6) δ: and 1.54 (1H, m), of 1.74 (3H, m)of 1.97 (2H, m), was 2.76 (1H, m), 2,80 (3H, s), 2.91 in (3H, s), 2,98 (3H, s), 3.00 and is 3.76 (3H), 3.04 FROM (2H, m), 3,18 (2H, m), 3,49 (1H, m), 3,68 (1H, m), of 4.12 (1H, sh. J=3.6 Hz), 4,43 (1H, m), 4,59 (1H, d, J=3.6 Hz), of 4.67 (1H, m), 7,05 (1H, s), 7,17 (1H, d, J=8,8 Hz), 7,41 (1H, d, J=8,8 Hz), 11,78 (1H, s), to 7.68 (1H, s), scored 8.38 (1H, s), 8,40 (1H, s), 11,35 (1H, sh).

MS (ESI) m/g: 601 (M+N)+

[Example 164]

(±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4,4-dimethoxy-N2(or N1)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4-4-dimethoxy-1,2-cyclohexanediamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (CDCl3) δ: 2,13 (1H, m), of 2.23 (1H, m), 2,42 (1H, m), the 2.46 (3H, s), of 2.72 (1H, m), 2,84 (1H, m), 3,21 (3H, s), 3,24 (3H, s), 3,49 (1H, s)to 3.58 (1H, d, J=15.6 Hz), 3,71 (1H, d, J=15.6 Hz), with 3.89 (1H, m), to 4.28 (1H, m), 6,85 (1H, d, J=2.0 Hz), 7,19 (1H, DD, J=8,5, 2.0 Hz), 7,30 (1H, d, J=8.5 Hz), a 7.62 (1H, s), of 9.21 (1H, s).

[Example 165]

(±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-N2(or N1)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-4-oxo-l,2-cyclohexanediamine:

(±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4,4-dimethoxy-N2(or N1)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (100 mg) was dissolved in chloroform (2 ml), was added triperoxonane acid (0.5 ml) and water (0.5 ml) and the mixture was stirred at room temperature for 3.5 hours. In the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the obtained residue was purified preparative thin-layer chromatography on silica gel (dichloromethane:methanol=19:1). Resulting solid was dissolved in methanol (4 ml) and to the solution was added 1 N. ethanolic solution of 0.38 ml) of hydrochloric acid. Drove under reduced pressure Rast is oritel obtaining specified in the title compound (35 mg) as a white powder.

1H-NMR (DMSO-d6) δ: of 1.86 (1H, m), is 2.09 (1H, m), is 2.30 (1H, m), of 2.54 (1H, m), 2,87 (3H, s), 2,96 (1H, t, J=13,0 Hz), is 3.08 (2H, m)to 3.35 (3H, m), a 4.03 (2H, m), 4,56 (2H, m), 7,03 (1H, s), to 7.15 (1H, d, J=8,8 Hz), 7,38 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,43 (1H, d, J=8,8 Hz), 8,91 (1H, d, J=8,8 Hz), 11,75 (1H, s).

[Example 166]

(±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4-hydroxyimino-N2(or N1)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine;

(±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-N2(or N1)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-4-oxo-l,2-cyclohexanediamine (133 mg) was dissolved in a mixed solvent consisting of pyridine (8 ml) and methanol (8 ml), was added hydroxylamine hydrochloride (30 mg) and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, to the residue was added water and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the obtained residue was purified column chromatography on silica gel (dichloromethane: methanol=97:3→17:3) to obtain the specified title compound (131 mg) as a colorless solid.

1H-NMR (CDCl3) δ: 1,43 is 1.86 (3H), A 2.01 (1H, m), 2,28 (1H, m), of 2.45 (3H, s), of 2.51 (1H, m), 2,69 (1H, is), 2,82 (3H, m), 3,86-of 3.43 (2H, m), 4,20 (2H, m), 6,85 (1H, s), 7,16-7,13 (1H, m), 7,22 (1H, m), 7,46, 7,50 (total 1H, s), 7,56-to 7.64 (2H), 9,59, 9,62 (total 1H, s).

[Example 167]

(±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4,4(1,2-Ethylenedioxy)-N2(or N1)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4,4-(1,2-Ethylenedioxy)-1,2-cyclohexanediamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (CDCl3) δ: 1,69-1,87 (6N, m), 2,31 (1H, m), 2,47 (3H, s), 2,73 (1H, m), of 2.86 (2H, m)to 3.58 (1H, d, J=15,4 Ru), and 3.72 (1H, d, J=15,4 Hz), 3,91 (1H, m)to 3.99 (4H, s), to 4.38 (1H, m)6,86 (1H, d, J=2.0 Hz), 7,19 (1H, DD, J=8,8, 2.0 Hz), 7,30 (1H, d, J=8,8 Hz), 7,38 (1H, d, J=7,3 Hz), a 7.62 (1H, d, J=2.0 Hz), to 9.15 (1H, s).

[Example 168]

(±)-CIS-N2(or N1)-[(5-Clorinda-2-yl)carbonyl]-4,4-(1,2-Ethylenedioxy)-N1(or N2)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from (±)-CIS-N2(or N1)-[(5-Clorinda-2-yl)carbonyl]-4,4-(1,2-Ethylenedioxy)-1,2-cyclohexanediamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (CDCl3) δ: 1,71-of 1.93 (5H, m)2,07 (1H, m), of 2.45 (1H, m), 2,47 (3H, s), of 2.72 (1H, m), 2,86 (2 is, m)and 3.59 (1H, d, J=15,4 Hz), and 3.72 (1H, d, J=15,4 Hz), 3,98 (4H, s), of 4.05 (1H, m)to 4.16 (1H, m), 4,25 (1H, m), 6,85 (1H, s), 7,18 (1H, DD, J=8,8, 2.0 Hz), 7,34 (1H, D, J=8,8 Hz), 7,39 (1H, d, J=7,1 Hz), to 7.61 (1H, s), for 9.47 (1H, s).

[Example 169]

(±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4-methoxyimino-N2(or N1)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

1) (±) -CIS-N1N2bis (tert-Butoxycarbonyl)-4-methoxyimino-1,2-cyclohexanediamine (of 2.21 g) was dissolved in dichloromethane (30 ml), was added triperoxonane acid (6 ml) and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, dried using a vacuum pump and then was dissolved in N.N-dimethylformamide (20 ml) and to the solution was added 5-Clorinda-2-carboxylic acid (500 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (593 mg), monohydrate, 1-hydroxybenzotriazole (473 mg) and N-methylmorpholine (2.8 ml). The mixture was stirred at room temperature for 10 hours. Added 5-Clorinda-2-carboxylic acid (242 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (237 mg) and the monohydrate of 1-hydroxybenzotriazole (189 mg) and the mixture was stirred for 4 hours. In the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate, and a mixed solvent consisting of ethyl acetate of tetrahydrofuran. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the obtained residue was purified column chromatography on silica gel (dichloromethane:methanol=97:3→4:1) to give (±)-CIS-N1(or N2)-[(5-Clorinda-2-yl) carbonyl]-4-methoxyimino-1,2-cyclohexanediamine (368 mg) and (±)-CIS-N2(or N1)-[(5-Clorinda-2-yl)carbonyl]-4-methoxyimino-1,2-cyclohexanediamine (300 mg).

2) is listed in the title compound (mixture of SYN - and anisomerous in part that contains methoxyimino) was obtained from obtained above (±)-CIS-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4-methoxyimino-1,2-cyclohexanediamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (CDCl3) δ: 1,84 is 2.00 (3H, m), 2.26 and-of 2.56 (3H, m), the 2.46 (3H, s), of 2.81 (4H, m), of 3.57 (1H, q, J=15,4 Hz), 3,70 (1H, q, J=15,4 Hz), 3,84, 3,85(total 3H, s), 4,11 (1H, m), 4,28 (1H, m), at 6.84 (1H, s), 7,17 (1H, d, J=8,8 Hz), 7,27 (1H, d, J=8,8 Hz.), 7,46 (2H, m), 7,56 (1H, m), 9,42, of 9.55 (total 1H, s).

[Example 170]

(1R*,2S*)-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4-hydroxy-N2(or N1)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer A):

1) (1R*,2S*)-NlN2bis(t is et-Butoxycarbonyl)-4(tert-butyldiphenylsilyl)-1,2-cyclohexanediamine (stereoisomer A) were subjected to de(tert-butoxycarbonylamino) method, similar to stage 1) of example 169, and interaction with 5-Clorinda-2-carboxylic acid to obtain (1R*,2S*)-4-(tert-butyldiphenylsilyl)-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer a) and (1R*,2S*)-4-(tert-butyldiphenylsilyl)-N2(or N1)-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer A).

2) (1R*,2S*)-4-(tert-Butyldiphenylsilyl)-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-N2(or N1)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer A) was obtained from (1R*That 2R*)-4-(tert-butyldiphenylsilyl)-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer A)obtained in the reaction described above, and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (CDCl3) δ: 1,06 (N, C)was 1.58 (1H, m)to 1.87 (1H, m), of 2.21 (1H, m), the 2.46 (3H, s), of 2.51 (2H, d, J=7,Hz), of 2.72 (1H, m), of 3.56 (1H, s), 3,57 (1H, d, J=15.3 Hz), and 3.72 (1H, d, J=15.3 Hz), 3,76 (1H, m), 3,92 (1H, m), 6,78 (1H, s), 7,17 (1H, DD, J=2.0 a, 8,8 Hz), 7,40 (7H, m), to 7.59 (1H, s), 7,66 (6N, m), of 9.30 (1H, s).

3) is listed in the title compound was obtained from the compound obtained in the reaction described above, in a manner similar to stage 1) of example 69.

1H-NMR (DMSO-d6 ) δ: of 1.28 (2H, m), 1,45-of 1.64 (2H, m)to 1.86 (1H, d, J=9.0 Hz), 2,02 (1H, m), of 2.33 (3H, s), 2,69 (2H, m), 2,77 (2H, m), of 3.54 (1H, d, J=15.6 Hz), 3,62 (1H, d, J=15.6 Hz), 3,99 (2H, M), 4,78 (1H, d, J=4,2 Hz), 7,00 (1H, s), 7,14 (1H, DD, J=2.0 a, 8,8 Hz), 7,38 (1H, d, 8,8 Hz), 7,66 (1H, s), to 8.20 (1H, D, J=7.8 Hz), 8,54 (1H, d, J=7.8 Hz), of 11.69 (1H, s).

[Example 171]

(1R*,2S*)-N2(or N1)-[(5-Clorinda-2-yl)carbonyl]-4-hydroxy-N1(or N2)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer):

1) (1R*,2S*)-4-Acetoxy-N1N2bis (tert-butoxycarbonyl)-1,2-cyclohexanediamine (stereoisomer B) were subjected to de(tert-butoxycarbonylamino) in a manner similar to stage 1) of example 169, and interaction with 5-Clorinda-2-carboxylic acid. The reaction mixture was subjected to chromatography on silica gel to obtain (1R*,2S*)-4-acetoxy-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer b) and (1R*,2S*)-4-acetoxy-N2(or N1)-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer B).

2) (1R*,2S*)-4-Acetoxy-N2(or N1)-[(5-Clorinda-2-yl)carbonyl]-N1(or N2)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]-pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer B) was obtained from (1R*,2S*)-4-acetoxy-N2(or N )-[(5-Clorinda-2-yl)-carbonyl]-1,2-cyclohexanediamine (stereoisomer B)obtained in the reaction described above, and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (CDCl3) δ: of 1.74 (2H, m), is 2.09 (2H, m), 2,11 (3H, s)to 2.29 (2H, m), 2,47 (3H, s), 2,73 (1H, m), 2,84 (3H, m)and 3.59 (1H, d, J=15,4 Hz), and 3.72 (1H, d, J=15,4 Hz)to 3.89 (1H, m)to 4.41 (1H, m), of 5.24 (1H, s), 6,87 (1H, s), 7,20 (1H, DD, J=8,8, 2.0 Hz), 7,26 (1H), 7,30 (1H, d, J=8,8 Hz), the 7.43 (1H, d, J=6.8 Hz), to 7.64 (1H, s), 9,13 (1H, s).

MS (ESI) m/z: 530 (M+H)+

3) the above product (82 mg) was dissolved in a mixture of tetrahydrofuran (2 ml)-methanol (2 ml), to the solution was added 1 n lithium hydroxide (232 mg) and the mixture was stirred at room temperature for 4 hours. In the reaction mixture was added water and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the obtained residue was purified preparative thin-layer chromatography (dichloromethane:methanol=47:3) to obtain the specified title compound (53 mg) as a pale yellow solid.

1H-NMR (CDCl3) δof 1.75 (4H, m), with 1.92 (3H, m)to 2.15 (1H, m), of 2.23 (1H, m), the 2.46 (3H, s), of 2.72 (1H, m), 2,85 (2H, m)to 3.58 (1H, d, J=15.6 Hz), 3,70 (1H, d, J=15.6 Hz), 4,33 (1H, s), 3,93 (1H, m), 4,56 (1H, m), 6,89 (1H, d, J=2.0 Hz), 7,18 (1H, DD, J=8,8, 2.0 Hz), 7,27 (1H), 7,31 (1H, d, J=8,8 Hz), 7,46 (1H, d, J=,1 Hz), 7,58 (1H, s), 9,16 (1H, s).

[Example 172]

(1R*,2S*)-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4-hydroxy-4-methyl-N2(or N1)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer A1) and (1R*,2S*)-N2(or N1)-[(5-Clorinda-2-yl)carbonyl]-4-hydroxy-4-methyl-N1(or N2)-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer A2):

Specified in the title compound was obtained by interaction of a mixture of (1R*,2S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxy-4-methyl-1,2-yclohexanol (stereoisomer a) and (1R*,2S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxy-4-methyl-1,2-cyclohexanediamine (stereoisomer a) 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

Stereoisomer A1:

1H-NMR (DMSO-d6) δ: 1,24 (3H, s), 1,33-to 1.82 (4H, m), of 2.34 (3H, s), 2,67-of 3.64 (8H, m)4,06 (2H, sh), of 4.67 (1H, sh), 7,02 (1H, s), 7,13 (1H, d, J=8.6 Hz), 7,38 (1H, d, J=8.6 Hz), 7,66 (1H, d, J=2.0 HZ), 8,23 (1H, sh), 8,59 (1H, d, J=8.1 Hz), 11,73 (1H, sh)

MS (FAB) m/z: 502 (M+H)+

Stereoisomer A2:

1H-NMR (DMSO-d6) δ: 1,25 (3H, s), 1,33-to 1.79 (4H, m), of 2.33 (3H, s), 2,65-3,63 (8H, m), 3,88-of 3.94 (1H, m)to 4.23 (1H, m), 4,59 (1H, sh), 7,01 (1H, s), 7,13 (1H, d, J=7.8 Hz), 7,38 (1H, d, J=8.6 Hz), to 7.67 (1H, s), 8,29 (1H, sh), 8,43 (1H, d, J=9.3 Hz), 11,67 (1H, sh)

MS (FAB) m/z: 502 (M+H)+

[Example 173]

(1R*,2S*)-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4-hydroxy-4-methyl-N2(or N1) [(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer):

Specified in the title compound was obtained from (1R*,2S*)-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4-hydroxy-4-methyl-1,2-cyclohexanediamine (stereoisomer b) and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: of 1.16 (3H, s), 1,24 (1H, sh), 1,39-of 1.42 (1H, m), 1,57-to 1.79 (3H, m), 1,92-of 1.94 (1H, m), of 2.33 (3H, s), 2,66-2,78 (4H, m), 3,53 (1H, d, J=15.7 Hz), 3,60 (1H, d, J=15.7 Hz), 4,01 (1H, sh), 4,32 (1H, sh), ? 7.04 baby mortality (1H, s), 7,13 (1H, DD, J=8,8, 2.0 Hz), 7,37 (1H, d, J=8,8 Hz), 7,65.(1H, d, J=2.0 Hz), 8,24 (1H, d, J=8,8 Hz), of 8.28 (1H, d, J=9.0 Hz), 11,65 (1H, sh)

MS (FAB) m/z: 502 (M+H)+

[Example 174]

(1R*,2S*)-N1(or N2)-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)-carbonyl]-1,2-cyclohexanediamine (stereoisomer A):

1) (1R*,2S*)-4-(tert-butyldiphenylsilyl)-N1-[(5-Clorinda-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer A) was obtained from (1R*,2S*)-4-(tert-butyldiphenylsilyl)-1,2-cyclohexanediamine the (stereoisomer a) and 5-Clorinda-2-carboxylic acid method, similar to the method of reference example 30.

2) Hydrochloride (1R*,2S*)-4-(tert-butyldiphenylsilyl)-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine (stereoisomer A) was obtained from the compound obtained above, and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (DMSO-d6) δ: 1,04 (N, C), 1,23-2,07 (7H, m)to 2.35 (3H, s), 2,73-2,89 (4H, m), to 3.58-3,59 (2H, m), 3,63 (2H, sh), 4,20 (1H, m), or 4.31 (1H, sh), 7,16 (1H, s), 7,19 (1H, DD, J=8,8, 1.2 Hz), 7,42-7,46 (6N, m), 7,63-the 7.65 (4H, m), 7,69 (1H, sh), 7,88 (1H, d, 0=6,6 Hz), 7,95 (1H, s)8,71 (.1H, d, J=8.5 Hz), 11,82 (1H, s).

MS (FAB) m/z: 741 (M+H)+

Specified in the title compound was obtained by treatment of the product obtained above, in a manner similar to the way in stage 3) of example 69.

1H-NMR (DMSO-d6) δ: 1,21-of 1.23 (1H, m), 1,49-1,72 (5H, m), 2.00 in 2,04 (1H, m), of 2.34 (3H, s), 2,67-2,69 (2H, m), 2,74 is 2.75 (2H, m), 3,62 (2H, s), 4,10-4,13 (2H, m), or 4.31 (1H, sh), a 4.53 (1H, m), 7,17-7,20 (2H, m), the 7.43 (1H, d, J=8.6 Hz), 7,73 (1H, d, J=2.0 Hz), to $ 7.91 (1H, d, J=6,9 Hz), 8,64 (1H, d, J=8.6 Hz), 11,83 (1H, s).

MS (FAB) m/z: 502 (M+H)+

[Example 175]

(1R*That 2R*4S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the header is connected to the e was obtained by treatment of (1R *That 2R*4S*)-N2-(tert-butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclohexanediamine saturated ethanolic hydrochloric acid and then by the condensation of 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 118.

1H-NMR (DMSO-d6) δ: 1,42-1,90 (5H, m), 2,07-of 2.26 (3H, m), the 2.46 (3H, s), 2,67-2,95 (4H, m), 3,55-of 3.80 (4H, m), 3,80-of 3.95 (1H, m), 4,13-of 4.25 (1H, m), at 6.84 (1H, sh), 7,17 (1H, DD, J=8,8, 2.0 Hz), 7.23 percent-of 7.35 (2H, m), the 7.43 (1H, d, J=7,2 Hz), 7,58 (1H, sh), 9,29 (1H, s).

MS (ESI) m/z: 502 (M+H)+

[Example 176]

(1R,2R,4S)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained by treatment of (1R,2R,4S)-N2-(tert-butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclohexanediamine saturated ethanolic hydrochloric acid and then by the condensation of 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 118.

1H-NMR (DMSO-d6) δ: 1,42-1,90 (5H, m), 2,07-of 2.26 (3H, m), the 2.46 (3H, s), 2,67-2,95 (4H, m), 3,55-of 3.80 (4H, m), 3,80-of 3.95 (1H, m), 4,13-of 4.25 (1H, m), at 6.84 (1H, sh), 7,17 (1H, DD, J=8,8, 2.0 Hz), 7.23 percent-of 7.35 (2H, m), the 7.43 (1H, d, J=7,2 Hz), 7,58 (1H, sh), 9,29 (1H, s).

MS (ESI) m/z: 502 (M+H) +

[Example 177]

Hydrochloride (1R*,2S*,4R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4(1-hydroxy-1-methylethyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained from hydrochloride (1R*,2S*,4R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4(1-hydroxy-1-methylethyl)-1,2-cyclohexanediamine and 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

1H-NMR (CD3OD3) δ: 1,17 (3H, s), 1,20 (ZN, C), 1,24-2,22 (7H, m), to 3.02 (3H, s), 3,18-to 3.41 (4H, m), 3,52-3,68 (2H, m), 4,08-is 4.21 (1H, m), 4,50 with 4.65 (1H, m), 6,92 (1H, sh), 7,13-7,19 (1H, m), 7,39 (1H, sh. J=8.0 HZ), 7,84-to 7.93 (1H, m), by 8.22-8,32 (1H, m).

MS (FAB) m/z: 530 (M+H)+

[Example 178]

(1R*,2S*,4R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4-methoxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound was obtained by treatment of (1R*,2S*,4R*)-N2-(tert-butoxycarbonyl)-N1-[(5-Clorinda-2-yl)carbonyl]-4-methoxymethyl-1,2-cyclohexanediamine saturated ethanolic hydrochloric acid and then by the condensation of 5-methyl-4,5,6,7-tetrahydrothieno what about[5,4-C]pyridine-2-carboxylate lithium method, similar to the method of example 118.

1H-NMR (CDCl3) δ: 1,20-to 1.38 (1H, m), 1,50-to 1.67 (2H, m), 1,88-2,03 (2H, m), 2,03 with 2.14 (1H, m), 2,21 of-2.32 (1H, m), of 2.53 (3H, s), of 2,75 2,95 (2H, m), 3,20-to 3.35 (2H, m), 3,37 (3H, s), 3,71 and of 3.78 (each 1H, each d, J=11.2 Hz), 4.04 the is 4.13 (1H, m), 4.53-in-to 4.62 (1H, m), 6,85 (1H, d, J=2.0 Hz), 7,19 (1H, DD, J=8,8, 2.0 Hz), 7,33 (1H, d, J=8,8 Hz), 7,54 (1H, d, J=7,2 Hz), 7,63 (1H, d, J=2.0 Hz), 8,07 (1H, d, J=5.6 Hz), 9,49 (1H, sh).

[Example 179]

The mixture hydrochloride (1R*,2S*,4R*,5S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-dihydroxy-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride and (1R*,2S*4S*,5R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-dihydroxy-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

(±)-CIS-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-4-cyclohexen-1,2-diamine (2.85 g) was dissolved in a mixed solvent consisting of tetrahydrofuran (10 ml), acetone (10 ml) and water (10 ml)was added osmium tetroxide (31 mg) and N-methylmorpholin-N-oxide (1.23 g) and the mixture was stirred at room temperature for 14 hours. Another was added osmium tetroxide (16 mg) and N-methylmorpholin-N-oxide (613 mg) and the mixture was stirred at 40°C for 5 days. The reaction mixture vlive and 10% aqueous sodium thiosulfate solution and extracted with ethyl acetate. The obtained organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Drove away under reduced pressure, the solvent and the residue was purified column chromatography on silica gel (dichloromethane:methanol=49:1→17:3) to give the crude delovogo derived (811 mg). Part of it (200 mg) was purified preparative thin-layer chromatography (dichloromethane:methanol=93:7) and then dissolved in methanol. To the solution was added 1 N. ethanolic hydrochloric acid solution to obtain specified in the connection header (811 mg).

1H-NMR (DMSO-d6) δ: 2,02-to 1.79 (3H, m), of 2.33 (3H, s), was 2.76-of 2.64 (4H, m), of 3.57 (4H, m), 3,82 (1H, sh), 3,96, of 4.13 (1H, m), 4,32 (1H, m), 4,49, to 4.52 (1H, each d, J=16.4 Hz), 4,66, of 4.67 (1H, each d, J=17,4 Hz), 7,02, 7,06 (1H, each s), 7,14 (1H, m), 7,37, 7,39 (1H, each s), 7,66, to 7.67 (1H, each d, J=2.4 Hz), 8,18, of 8.28 (1H, each d, J=8.5 Hz), 8,33, to 8.41 (1H, each d, J=8,8 Hz), 11,67, 11,71 (1H, each s).

[180]

A mixture of (1R*,2S*,4R*,5S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-diacetoxy-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pirigyi-2-yl)carbonyl]-1,2-cyclohexanediamine and (1R*,2S*4S*,5R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-diacetoxy-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

With the ect (200 mg), (1R *,2S*,4R*,5S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-dihydroxy-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and (1R*,2S*4S*,5R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-dihydroxy-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine was dissolved in pyridine (8 ml), was added acetic anhydride (745 μl) and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated and was purified preparative thin-layer chromatography (dichloromethane:methanol=97:3) to obtain the specified title compound (132 mg) as a pale yellow solid. To the solution was added 1 N. ethanol solution (1 ml) of hydrochloric acid and the mixture was concentrated under reduced pressure with the conversion of the compounds obtained in hydrochloride.

1H-NMR (DMSO-d6) δ: a 1.96 (4H, m), of 2.08 (3H, s), is 2.09 (3H, s), and 2.14 (3H, s), of 2.33 (3H, s), 2.70 (4H, m), or 4.31 (1H, m), 4,84 (1H, m), of 5.26 (1H, s), 7,05 (1H, s), to 7.15 (1H, d, J=8.5 Hz), 7,38 (1H, d, J=8.5 Hz), to 7.68 (1H, s), 8,49(1H, d, J=8,8 Hz), 8,54 (1H, d, J=8,8 Hz), 11,71 (1H, s).

[Example 181]

Hydrochloride (1R*,2S*,4R*,5S*)-4,5-carbonyloxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl-1-cyclohexanediamine hydrochloride and (1R *,2S*4S*,5R*)-4,5-carbonyloxy-N1-[(5-Clorinda-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Compound (253 mg), (1R*,2S*,4R*,5S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-dihydroxy-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and (1R*,2S*,4R*,5R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-dihydroxy-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and N,N'-carbonyldiimidazole (122 mg) was dissolved in tetrahydrofuran (6 ml) and the solution was stirred at room temperature overnight. Then another was added N,N'-carbonyldiimidazole (122 mg) and the mixture was stirred at 60°C for 10 hours. Added N,N'-carbonyldiimidazole (81 mg) and the mixture was stirred over night. The reaction mixture was concentrated, to the residue was added water and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the residue was purified preparative thin-layer chromatography (dichloromethane:methanol=19:1) split stereoisomer the RC. The products were respectively dissolved in methanol and tetrahydrofuran and the solution was added 1 N. ethanolic solution of hydrochloric acid, producing one specified in the header of the compound (stereoisomer A) (91 mg), and other specified title compound (stereoisomer B) (93 mg) as colorless powder.

Stereoisomer A:

1H-NMR (DMSO-d6) δ: of 2.08 (2H, m), 2,34 (2H, m), is 2.88 (3H, s), 3,11 (2H, m), 3,68 (1H, m), of 3.73 (1H, d, J=16,7 Hz), was 4.02 (1H, m), 4,37 (1H, m), 5,02 (1H, s)5,08 (1H, m), 7,01 (1H, s), to 7.15 (1H, DD, J=8,8, 2,0 Hz), 7,38 (1H, d, J=8,8 Hz), 7,69 (1H, d, J=1.7 Hz), to 8.41 (1H, d, J=8.6 Hz), 8,83 (1H, d, J=8,8 Hz), 11,75 (1H, s).

Stereoisomer In:

1H-NMR (DMSO-d6) δ: of 1.85 (1H, m), 2,22 (1H, m), 2,33 (2H, m), 2,87 (3H, s), 3,10 (2H, m), 3,53 (2H, m), and 3.72 (1H, d, J=17,9 Hz)to 4.23 (1H, m), of 4.49 (1H, m), of 5.03 (1H, sh), to 5.08 (1H, m), 7,00 (1H, s), to 7.15 (1H, DD J was 8.8, 2.0 Hz), 7,37 (1H, d, J=8,8 Hz), 7,69 (1H, s), 8,42 (1H, d, J=7.8 Hz), cent to 8.85 (1H, d, J=8,3 Hz), 11,74 (1H, s).

[Example 182]

(1R*,2S*,4R*,5S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-isopropylidenedioxy-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine and (1R*,2S*4S*,5R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-isopropylidenedioxy-N2-[(5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-yl)carbonyl]-1,2-cyclohexanediamine:

Specified in the title compound which was alocale interaction of a mixture of (1R *,2S*,4R*,5S*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-isopropylidenedioxy-1,2-cyclohexanediamine and (1R*,2S*4S*,5R*)-N1-[(5-Clorinda-2-yl)carbonyl]-4,5-isopropylidenedioxy-1,2-cyclohexanediamine 5-methyl-4,5,6,7-tetrahydrothieno[5,4-C]pyridine-2-carboxylate lithium in a manner similar to the method of example 2.

One connection:

1H-NMR (DMSO-d6) δ: of 1.39 (3H, s), 1,58 (3H, s)of 1.78 (1H, m), 1,90 (1H, m), and 2.27 (1H, m), the 2.46 (3H, s), 2,84-2,69 (5H, m)