Benzofuran derivatives

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

 

The scope of the invention

The present invention relates to a derivative of benzofuran, which may find application as a medicine, particularly as an inhibitor of activated factor X in the coagulation of blood or its pharmaceutically acceptable salt.

The level of technology

In recent years, as the Westernization of the life and habits of an aging population, growing year by year the number of thromboembolic diseases such as myocardial infarction, cerebral infarction and peripheral arterial thrombosis, and therefore the social importance of treating such diseases becomes increasingly more likely.

Among the methods of treatment of thromboembolic diseases anticoagula therapy, as well as fibrinolytic therapy and antithrombotics therapy, are included in a medical therapy for the treatment and prevention of thrombosis (Sogorinsho 41: 2141-2145, 1989). In particular, it is essential to prevent thrombosis are permanent security with a long introduction and a reliable and adequate expression antikoaguliruyuschey activity. Around the world often use a derivative of coumarin, especially warfarin potassium, as only anticoagulative tools available for oral administration. However, based on the characteristics of the resulting mechanism of action, takes a long time on what I manifestations of the effectiveness of this medication, because it has a very long half-life in the blood, although the range of concentrations for the manifestation of efficacy of a drug is relatively narrow, and it demonstrates the significant differences in terms of effective doses among individuals. For these reasons, the ability anticoagulative tools can be controlled with difficulty (Journal of Clinical Pharmacology, 1992, vol.32, pp.196-209; NEW ENGLAND JOURNAL OF MEDICINE, 1991, vol.324, no.26, pp.1865-1875). Additionally, there may be adverse side effects from drugs, such as the risk of bleeding, nausea, vomiting, diarrhea, hair loss, etc. and, therefore, clinical application it is very difficult and it is necessary to organize search antikoaguliruyuschee tools that are useful and easily carried.

In addition, increasing the ability to clot blood represents one of the significant causal factors unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation, thrombogenesis after the offset of the artificial heart valve, parekklisia after the reconstruction of circulation and thrombogenesis during artificial blood circulation, and so Therefore would be desirable to develop action the public anticoagulative means, which acts quickly after the administered dose and has a lower risk of call of bleeding with few side effects, this could be quite effective when administered orally (Thrombosis Research, 1992, vol.68, pp.507-512). Thrombin is involved not only in the transformation of fibrinogen into fibrin, which is the final stage of the cascade of coagulation, but also and mainly in the activation and aggregation of platelets in the blood (Matsuo, O., t-PA and Pro-UK"Gakusaikikaku, 1986, pp.5-40), and its inhibitor in a long time was in the center of the search anticoagulants in the development of new drugs. However, thrombin inhibitor shows a low bioprosthetic oral and also has drawbacks in terms of safety, such as a tendency to bleeding, as one of the side effects (Biomedica Biochimica Acta, 1985, Vol.44, R-1210), when it previously was not known to any of the available inhibitors of thrombin, which could be administered orally.

Activated factor X in the coagulation of blood is a key enzyme that is localized in a position in the General direction both - both external and internal reactions of the coagulation cascade. Factor XA localized upstream of thrombin in the coagulation cascade. Therefore, the inhibition of factor XA is probably more effective and specification the figures in the inhibition of the coagulation system in comparison with the inhibition of thrombin (Thrombosis Research, 1980, Vol.19, pp.339-349).

Thus, among the inhibitors of activated factor X in the coagulation of blood is a substance that inhibits factor XA in the coagulation of blood and shows excellent enzymatic selectivity, and high bioavailability, as expected, will provide control of his antikoaguliruyuschey activity for a long period of time and will allow you to achieve a higher therapeutic effect when administered orally compared with existing anticoagulants. Accordingly, it is strongly required to make a search of a new inhibitor of activated factor X in the coagulation of blood (FXa inhibitor), which can be administered orally.

Examples of known compounds that have inhibitory effect on activated factor X in the coagulation of blood, include derivatives thiobenzamide that are useful in the prevention or treatment of thrombosis (WO 99/42439).

The following derivatives of benzofuran were also known (Indian Journal of Heterocyclic Chemistry, 1994, Vol.3, pp.3247-3252), but the specified source does not mention the inhibitory effect of compounds on activated factor X in the coagulation of blood.

Also known condensed bicyclic amide compound of the formula:

who have active is here, which consists in suppressing the growth of activated lymphocytes and are useful as drugs for prevention or treatment of autoimmune diseases (WO 02/12189). In WO 02/12189 not to mention the inhibitory effect on activated factor X in the coagulation of blood. In the brochure are disclosed compounds having condensed rings of pyridine and furan, where amide and carnemolla group is disubstituted; however, all of these compounds are benzene ring by the nitrogen atom carbamoyl group and specified the benzene ring is substituted by X and Y simultaneously.

The invention

The present invention provides a new derived benzofuran, which has an excellent inhibitory effect on activated factor X in the coagulation of blood, or its pharmaceutically acceptable salt.

Was studied and found that the derived benzofuran the formula shown below, has a strong inhibitory effect on activated factor X in the coagulation of blood, which solves the problem of the present invention.

That is, the present invention is as follows:

(i) Derived benzofuran formula [1]:

where X represents a group of the formula:or the formula:;

Y before the hat is optionally substituted by an amino group, optionally substituted cycloalkyl group or optionally substituted saturated heterocyclic group;

Rather it represents a simple bond, the carbon chain optionally having a double bond within or at the end(s) of a circuit or an oxygen atom;

R1represents a hydrogen atom, halogen atom, lower alkyl group, lower alkoxygroup, cyano or amino group, optionally substituted with lower alkyl groups;

Ring In the formula:

represents an optionally substituted benzene ring; and

R3represents a hydrogen atom or a lower alkyl group,

or its pharmaceutically acceptable salt.

(ii) Compound in accordance with (i), where the ring is a benzene ring, optionally substituted by group(s)independently selected from a halogen atom, optionally substituted lower alkyl group, a hydroxy-group, optionally substituted lower alkoxygroup, actigraphy, substituted optionally substituted saturated heterocyclic group, substituted carbonyl group, optionally substituted amino, nitro, ceanography, 4,5-dihydroquinoline group or groups of the formula:

and

"optionally substituted recloak is supplemented flax group" for Y is cycloalkyl group, optionally substituted with a group selected from optionally substituted amino, optionally substituted group of the formula selected from:

and optionally substituted lower alkyl group.

(iii) Connection in accordance with (ii), where the "optionally substituted saturated heterocyclic group" for Y is a saturated heterocyclic group optionally substituted with a group selected from the following:

(1) lower alkyl groups,

(2) a lower alkyl group substituted with peredelnoj group,

(3) piperidino group substituted with a lower alkyl group,

(4) piperidino group,

(5) piperidino group substituted with a lower alkoxycarbonyl group,

(6) an unsaturated heterocyclic group selected from peredelnoj group, pyrimidines group, 4,5-dihydroquinoline group and thiazolidine group,

(7) lower alkanoyloxy group,

(8) lower alkanoyloxy group substituted with di-lower alkylamino,

(9) a carbonyl group substituted with peredelnoj group,

(10) lower alkylsulfonyl group,

(11) lower alkoxycarbonyl group,

(12) a lower alkyl group substituted with di-lower alkylamino, and

(13) the carbonyl group:

"optionally substituted amino group" for Y is an amino group, optionally substituted with a group selected from the following:

(1) piperidino group substituted with a lower alkyl group,

(2) a lower alkyl group, and

(3) lower alkoxycarbonyl group;

"optionally substituted amino group" as a substituent on cycloalkyl group Y is an amino group, optionally substituted with a group selected from the following:

(1) lower alkyl groups,

(2) cycloalkyl group,

(3) hydroxy-lower alkyl group,

(4) 1,3-dioxanone group substituted with a lower alkyl group,

(5) a lower alkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkanoyloxy group, (C) lower alkanoyloxy group substituted by an amino group substituted with a lower alkyl group, and (d) lower alkoxycarbonyl group,

(6) a lower alkyl group substituted with ceanography,

(7) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(8) a lower alkyl group substituted with carboxyl group,

(9) a lower alkyl group substituted with carbamoyl g is uppy, optionally substituted with lower alkyl groups,

(10) a lower alkyl group substituted with aryl group,

(11) a lower alkyl group substituted with peredelnoj group,

(12) lower alkoxycarbonyl group,

(13) lower alkanoyloxy group substituted with di-lower alkyl amino group,

(14) lower alkanoyloxy group,

(15) pyrimidinyl group,

(16) lower alkanoyloxy group substituted with morpholinyl group,

(17) lower alkylsulfonyl group,

(18) carbamoyl group substituted with a lower alkyl group,

(19) a carbonyl group substituted with aryl group,

(20) lower alkanoyloxy group substituted with lower alkoxygroup,

(21) the lower alkanoyloxy group substituted with lower alkanoyloxy,

(22) aryl group substituted with hydroxyl group, and

(23) a hydroxy-lower alkanoyloxy group;

"optionally substituted group of the formula selected from:

as Deputy to cycloalkyl group for Y is a group chosen from:

which is optionally substituted by carbonyl group;

"optionally substituted lower alkyl group" as for what estates on cycloalkyl group for Y is a lower alkyl group, optionally substituted with a group selected from the following groups:

(1) oxopyrrolidin group,

(2) ecomorphological group, and

(3) amino groups, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group;

"optionally substituted lower alkyl group" as a substituent for ring b is a lower alkyl group, optionally substituted with a group chosen from:

(1) lower alkoxycarbonyl group,

(2) carboxyl group,

(3) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) low alkoxygroup,

(4) a carbonyl group substituted with morpholinyl group,

(5) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(6) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(7) a carbonyl group substituted with hydroxyl group, substituted with piperidine group and

(8) a hydroxyl group;

"optionally substituted lower alkoxygroup" as the e substituent for ring b is a lower alkoxygroup, optionally substituted with a group chosen from:

(1) carboxyl group,

(2) the lower alkoxycarbonyl group,

(3) low alkoxygroup,

(4) a hydroxyl group,

(5) aminochrome, optionally substituted with lower alkoxycarbonyl group,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) a carbonyl group substituted with morpholinyl group, piperidino group or pyrrolidinyl group,

(8) a carbonyl group substituted with hydroxypiperidine group,

(9) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(10) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(11) a carbonyl group substituted with a lower alkylpiperidines group,

(12) amino group, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group,

(13) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) a lower alkyl group substituted with di-lower alkylamino; and

(14) GRU is dust formula: ;

"oxygraph, substituted optionally substituted with saturated heterocyclic group" as a substituent for ring b is oxygraph, substituted heterocyclic group, optionally substituted with aryl groups;

"substituted carbonyl group" as a substituent for ring b is a carbonyl group substituted by a group selected from:

(1) low alkoxygroup,

(2) a hydroxyl group,

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) low alkoxygroup, (C) lower alkoxy-lower alkyl group, (d) hydroxy-lower alkyl group, (e) a lower alkyl group substituted with amino group, optionally substituted with lower alkyl groups, (f) a lower alkyl group substituted with aryl group, and (g) a lower alkyl group substituted with peredelnoj group,

(4) morpholinyl group, pyrrolidinyl group, piperidino group or thiomorpholine group,

(5) hydroxypiperidine group,

(6) piperidino group, substituted with hydroxy-lower alkyl group,

(7) pyrrolidinyloxy group, substituted with hydroxy-lower alkyl group, and

(8) lower alkylpiperidines group;

"neovasularization amino group" as a substituent for ring b is an amino group, optionally substituted with a group chosen from:

(1) lower alkyl groups,

(2) a lower alkoxy-lower alkyl group,

(3) hydroxy-lower alkyl group,

(4) lower alkanoyloxy group,

(5) a lower alkoxy-lower alkanoyloxy group,

(6) hydroxy-lower alkanoyloxy group,

(7) lower alkanoyloxy group substituted with lower alkanoyloxy,

(8) lower alkanoyloxy group substituted with amino group, optionally substituted with a group selected from (a) a lower alkyl group and (b) lower alkanoyloxy group,

(9) lower alkoxycarbonyl group,

(10) lower alkoxycarbonyl group substituted with aryl group,

(11) carbamoyl group substituted with a lower alkyl group,

(12) lower alkylsulfonyl group and

(13) lower alkylsulfonyl group substituted with morpholinyl group.

(iv) the Compound according to (iii), where a is an unsaturated benzene ring; and

Y is a saturated heterocyclic group optionally substituted with a group chosen from:

(1) lower alkyl groups,

(2) a lower alkyl group substituted with peredelnoj group,

(3) piperidino group substituted with a lower alkyl group,

() piperidino group,

(5) piperidino group substituted with a lower alkoxycarbonyl group,

(6) an unsaturated heterocyclic group selected from peredelnoj group, pyrimidinyl group, 4,5-dihydroquinoline group and thiazolidine group,

(7) lower alkanoyloxy group,

(8) lower alkanoyloxy group substituted with di-lower alkylamino,

(9) a carbonyl group substituted with peredelnoj group,

(10) lower alkylsulfonyl group,

(11) lower alkoxycarbonyl group,

(12) a lower alkyl group substituted with di-lower alkylamino and

(13) the carbonyl group.

(v) the Compound according to (iii), where a is an unsaturated benzene ring; and

Y represents an amino group, optionally substituted with a group chosen from:

(1) piperidino group substituted with a lower alkyl group,

(2) a lower alkyl group, and

(3) lower alkoxycarbonyl group.

(vi) the Compound according to (iii), where a is an unsaturated benzene ring; and

Y represents cycloalkyl group optionally substituted by the following groups:

(A) amino group, optionally substituted with the following groups:

(1) lower alkyl groups,

(2) cycloalkyl group,

(3) hydroxy-what Issa alkyl groups,

(4) 1,3-dioxanone group substituted with a lower alkyl group,

(5) a lower alkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkanoyloxy group, (C) lower alkanoyloxy group substituted by an amino group substituted with a lower alkyl group, and (d) lower alkoxycarbonyl group,

(6) a lower alkyl group substituted with ceanography,

(7) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(8) a lower alkyl group substituted with carboxyl group,

(9) a lower alkyl group substituted with carbamoyl group, optionally substituted with lower alkyl groups,

(10) a lower alkyl group substituted with aryl group,

(11) a lower alkyl group substituted with peredelnoj group,

(12) lower alkoxycarbonyl group,

(13) lower alkanoyloxy group substituted with di-lower alkyl amino group,

(14) lower alkanoyloxy group,

(15) pyrimidinyl group,

(16) lower alkanoyloxy group substituted with morpholinyl group,

(17) lower alkylsulfonyl group,

(18) carbamoyl group substituted with a lower alkyl the group,

(19) a carbonyl group substituted with aryl group,

(20) lower alkanoyloxy group substituted with lower alkoxygroup,

(21) the lower alkanoyloxy group substituted with lower alkanoyloxy,

(22) aryl groups substituted with hydroxy-group and

(23) a hydroxy-lower alkanoyloxy group;

C) a group of the formula selected from the structures:

which is optionally substituted by carbonyl group; or

C) a lower alkyl group optionally substituted by a group selected from:

(1) oxopyrrolidin group,

(2) ecomorphological group and

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group.

(vii) the Compound according to (iii), where the ring is a benzene ring substituted with a lower alkyl group optionally substituted with a group chosen from:

(1) lower alkoxycarbonyl group,

(2) carboxyl group,

(3) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) the lower alcohol is a system of groups,

(4) a carbonyl group substituted with morpholinyl group,

(5) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(6) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(7) a carbonyl group substituted with hydroxyl group, substituted with piperidine group and

(8) a hydroxyl group; and

Y is a saturated heterocyclic group optionally substituted with a group chosen from:

(1) lower alkyl groups,

(2) a lower alkyl group substituted with peredelnoj group,

(3) piperidino group substituted with a lower alkyl group,

(4) piperidino group,

(5) piperidino group substituted with a lower alkoxycarbonyl group,

(6) an unsaturated heterocyclic group selected from peredelnoj group, pyrimidinyl group, 4,5-dihydroxialumini group and thiazolidine group,

(7) lower alkanoyloxy group,

(8) lower alkanoyloxy group substituted with di-lower alkylamino,

(9) a carbonyl group substituted with peredelnoj group,

(10) lower alkylsulfonyl group,

(11) lower alkoxycarbonyl group,

(12) a lower alkyl group substituted with d is the lowest of alkylamino and

(13) the carbonyl group.

(viii) the Compound according to (iii), where the ring is a benzene ring substituted with a lower alkyl group optionally substituted with a group chosen from:

(1) lower alkoxycarbonyl group,

(2) carboxyl group,

(3) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) low alkoxygroup,

(4) a carbonyl group substituted with morpholinyl group,

(5) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(6) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(7) a carbonyl group substituted with hydroxyl group, substituted with piperidine group and

(8) a hydroxyl group; and

Y represents an amino group, optionally substituted with a group chosen from:

(1) piperidino group substituted with a lower alkyl group,

(2) a lower alkyl group, and

(3) lower alkoxycarbonyl group.

(ix) the Compound according to (iii), where the ring is a benzene ring substituted with ness the th alkyl group, optionally substituted with a group chosen from:

(1) lower alkoxycarbonyl group,

(2) carboxyl group,

(3) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) low alkoxygroup,

(4) a carbonyl group substituted with morpholinyl group,

(5) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(6) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(7) a carbonyl group substituted with hydroxyl group, substituted piperidine group and

(8) a hydroxyl group; and

Y represents cycloalkyl group optionally substituted with the following groups:

(A) amino group, optionally substituted with the following groups:

(1) lower alkyl groups,

(2) cycloalkyl group,

(3) hydroxy-lower alkyl group,

(4) 1,3-dioxanone group substituted with a lower alkyl group,

(5) a lower alkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkanoyloxy the group, (C) lower alkanoyloxy group substituted by an amino group substituted with a lower alkyl group, and (d) lower alkoxycarbonyl group,

(6) a lower alkyl group substituted with ceanography,

(7) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(8) a lower alkyl group substituted with carboxyl group,

(9) a lower alkyl group substituted with carbamoyl group, optionally substituted with lower alkyl groups,

(10) a lower alkyl group substituted with aryl group,

(11) a lower alkyl group substituted with peredelnoj group,

(12) lower alkoxycarbonyl group,

(13) lower alkanoyloxy group substituted with di-lower alkyl amino group,

(14) lower alkanoyloxy group,

(15) pyrimidinyl group,

(16) lower alkanoyloxy group substituted with morpholinyl group,

(17) lower alkylsulfonyl group,

(18) carbamoyl group substituted with a lower alkyl group,

(19) a carbonyl group substituted with aryl group,

(20) lower alkanoyloxy group substituted with lower alkoxygroup,

(21) the lower alkanoyloxy group substituted with lower alkanoyloxy,

(22) aryl gr is PPI, substituted with hydroxy-group and

(23) a hydroxy-lower alkanoyloxy group;

C) groups of the formula selected from the structures:

which is optionally substituted by carbonyl group; or

C) a lower alkyl group optionally substituted with a group selected from the following groups:

(1) oxopyrrolidin group,

(2) ecomorphological group and

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group.

(x) the Compound according to (iii), where the ring is a benzene ring substituted with lower alkoxygroup, optionally substituted with a group chosen from:

(1) carboxyl group,

(2) the lower alkoxycarbonyl group,

(3) low alkoxygroup,

(4) a hydroxyl group,

(5) aminochrome, optionally substituted with lower alkoxycarbonyl group,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) a carbonyl group substituted with morpholinyl group, piperidino group or pyrrolidinyl group,

(8) a carbonyl group substituted with hydroxypiperidine group,

(9) piperidinylcarbonyl group substituted by the Oh with hydroxy-lower alkyl group,

(10) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(11) a carbonyl group substituted with a lower alkylpiperidines group,

(12) amino group, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group,

(13) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) a lower alkyl group substituted with di-lower alkylamino; and

(14) a group of the formula:; and

Y is a saturated heterocyclic group optionally substituted with a group chosen from:

(1) lower alkyl groups,

(2) a lower alkyl group substituted with peredelnoj group,

(3) piperidino group substituted with a lower alkyl group,

(4) piperidino group,

(5) piperidino group substituted with a lower alkoxycarbonyl group,

(6) an unsaturated heterocyclic group selected from peredelnoj group, pyrimidinyl group, 4,5-dihydroxialumini group and thiazolidine group,

(7) lower alkanoyloxy group,

p> (8) lower alkanoyloxy group substituted with di-lower alkylamino,

(9) a carbonyl group substituted with peredelnoj group,

(10) lower alkylsulfonyl group,

(11) lower alkoxycarbonyl group,

(12) a lower alkyl group substituted with di-lower alkylamino and

(13) the carbonyl group.

(xi) the Compound according to (iii), where the ring is a benzene ring substituted with lower alkoxygroup, optionally substituted with a group chosen from:

(1) carboxyl group,

(2) the lower alkoxycarbonyl group,

(3) low alkoxygroup,

(4) a hydroxyl group,

(5) aminochrome, optionally substituted with lower alkoxycarbonyl group,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) a carbonyl group substituted with morpholinyl group, piperidino group or pyrrolidinyl group,

(8) a carbonyl group substituted with hydroxypiperidine group,

(9) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(10) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(11) a carbonyl group substituted with a lower alkylpiperidines group,

p> (12) amino group, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group,

(13) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) a lower alkyl group substituted with di-lower alkylamino; and

(14) a group of the formula:; and

Y represents an amino group, optionally substituted with a group chosen from:

(1) piperidino group substituted with a lower alkyl group,

(2) a lower alkyl group, and

(3) lower alkoxycarbonyl group.

(xii) the Compound according to (iii), where the ring is a benzene ring substituted with lower alkoxygroup, optionally substituted with a group chosen from:

(1) carboxyl group,

(2) the lower alkoxycarbonyl group,

(3) low alkoxygroup,

(4) a hydroxyl group,

(5) aminochrome, optionally substituted with lower alkoxycarbonyl group,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) a carbonyl group substituted with morpholinyl the Noah group, piperidino group or pyrrolidinyl group,

(8) a carbonyl group substituted with hydroxypiperidine group,

(9) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(10) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(11) a carbonyl group substituted with a lower alkylpiperidines group,

(12) amino group, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group,

(13) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) a lower alkyl group substituted with di-lower alkylamino; and

(14) a group of the formula:; and

Y represents cycloalkyl group optionally substituted with the following groups:

(A) amino group, optionally substituted with the following groups:

(1) lower alkyl groups,

(2) cycloalkyl group,

(3) hydroxy-lower alkyl group,

(4) 1,3-dioxanone group substituted with a lower alkyl group,

(5) lower alkyl groups, is, substituted with amino, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkanoyloxy group, (C) lower alkanoyloxy group substituted by an amino group substituted with a lower alkyl group, and (d) lower alkoxycarbonyl group,

(6) a lower alkyl group substituted with ceanography,

(7) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(8) a lower alkyl group substituted with carboxyl group,

(9) a lower alkyl group substituted with carbamoyl group, optionally substituted with lower alkyl groups,

(10) a lower alkyl group substituted with aryl group,

(11) a lower alkyl group substituted with peredelnoj group,

(12) lower alkoxycarbonyl group,

(13) lower alkanoyloxy group substituted with di-lower alkyl amino group,

(14) lower alkanoyloxy group,

(15) pyrimidinyl group,

(16) lower alkanoyloxy group substituted with morpholinyl group,

(17) lower alkylsulfonyl group,

(18) carbamoyl group substituted with a lower alkyl group,

(19) a carbonyl group substituted with aryl group,

(20) lower alkanoyloxy groups who, substituted with lower alkoxygroup,

(21) the lower alkanoyloxy group substituted with lower alkanoyloxy,

(22) aryl groups substituted with hydroxy-group and

(23) a hydroxy-lower alkanoyloxy group;

C) groups of the formula selected from the structures:

which is optionally substituted by carbonyl group; or

C) a lower alkyl group optionally substituted with a group chosen from:

(1) oxopyrrolidin group,

(2) ecomorphological group and

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group.

(xiii) the Compound according to (iii), where the ring is a benzene ring substituted with a carbonyl group substituted by a group selected from:

(1) low alkoxygroup,

(2) a hydroxyl group,

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) low alkoxygroup, (C) lower alkoxy-lower alkyl group, (d) hydroxy-lower alkyl group, (e) a lower alkyl group substituted with amino group, optionally substituted with lower alkyl groups, (f) a lower alkyl group substituted with airlinegroup and (g) a lower alkyl group, substituted with peredelnoj group,

(4) morpholinyl group, pyrrolidinyl group, piperidino group or thiomorpholine group,

(5) hydroxypiperidine group,

(6) piperidino group, substituted with hydroxy-lower alkyl group,

(7) pyrrolidinyloxy group, substituted with hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinilnom group; and

Y is a saturated heterocyclic group optionally substituted with a group chosen from:

(1) lower alkyl groups,

(2) a lower alkyl group substituted with peredelnoj group,

(3) piperidino group substituted with a lower alkyl group,

(4) piperidino group,

(5) piperidino group substituted with a lower alkoxycarbonyl group,

(6) an unsaturated heterocyclic group selected from peredelnoj group, pyrimidinyl group, 4,5-dihydroxialumini group and thiazolidine group,

(7) lower alkanoyloxy group,

(8) lower alkanoyloxy group substituted with di-lower alkylamino,

(9) a carbonyl group substituted with peredelnoj group,

(10) lower alkylsulfonyl group,

(11) lower alkoxycarbonyl group,

(12) a lower alkyl group substituted with di-Issa alkylamino and

(13) the carbonyl group.

(xiv) the Compound according to (iii), where the ring is a benzene ring substituted with a carbonyl group substituted by a group selected from:

(1) low alkoxygroup,

(2) a hydroxyl group,

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) low alkoxygroup, (C) lower alkoxy-lower alkyl group, (d) hydroxy-lower alkyl group, (e) a lower alkyl group substituted with amino group, optionally substituted with lower alkyl groups, (f) a lower alkyl group substituted with aryl group, and (g) a lower alkyl group substituted with peredelnoj group,

(4) morpholinyl group, pyrrolidinyl group, piperidino group or thiomorpholine group,

(5) hydroxypiperidine group,

(6) piperidino group, substituted with hydroxy-lower alkyl group,

(7) pyrrolidinyloxy group, substituted with hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinilnom group; and

Y represents an amino group, optionally substituted with a group chosen from:

(1) piperidino group substituted with a lower alkyl group,

(2) a lower alkyl group, and

(3) lower alkoxycarbonyl group.

(xv) the Compound according to (iii), where the ring is a benzene ring substituted with a carbonyl group substituted by a group selected from:

(1) low alkoxygroup,

(2) a hydroxyl group,

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) low alkoxygroup, (C) lower alkoxy-lower alkyl group, (d) hydroxy-lower alkyl group, (e) a lower alkyl group substituted with amino group, optionally substituted with lower alkyl groups, (f) a lower alkyl group substituted with aryl group, and (g) a lower alkyl group substituted with peredelnoj group,

(4) morpholinyl group, pyrrolidinyl group, piperidino group or thiomorpholine group,

(5) hydroxypiperidine group,

(6) piperidino group, substituted with hydroxy-lower alkyl group,

(7) pyrrolidinyloxy group, substituted with hydroxy-lower alkyl group, and

(8) lower alkylpiperidines group; and

Y represents cycloalkyl group optionally substituted with the following groups:

(A) amino group, optionally substituted with the following groups:

(1) lower alkyl groups,

(2) cycloalkyl group,

(3) hydroxy-lower alkylen the th group,

(4) 1,3-dioxanone group substituted with a lower alkyl group,

(5) a lower alkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkanoyloxy group, (C) lower alkanoyloxy group substituted by an amino group substituted with a lower alkyl group, and (d) lower alkoxycarbonyl group,

(6) a lower alkyl group substituted with ceanography,

(7) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(8) a lower alkyl group substituted with carboxyl group,

(9) a lower alkyl group substituted with carbamoyl group, optionally substituted with lower alkyl groups,

(10) a lower alkyl group substituted with aryl group,

(11) a lower alkyl group substituted with peredelnoj group,

(12) lower alkoxycarbonyl group,

(13) lower alkanoyloxy group substituted with di-lower alkyl amino group,

(14) lower alkanoyloxy group,

(15) pyrimidinyl group,

(16) lower alkanoyloxy group substituted with morpholinyl group,

(17) lower alkylsulfonyl group,

(18) carbamoyl group substituted with a lower alkyl the group,

(19) a carbonyl group substituted with aryl group,

(20) lower alkanoyloxy group substituted with lower alkoxygroup,

(21) the lower alkanoyloxy group substituted with lower alkanoyloxy,

(22) aryl groups substituted with hydroxy-group and

(23) a hydroxy-lower alkanoyloxy group;

C) groups of the formula selected from the structures:

which is optionally substituted by carbonyl group; or

C) a lower alkyl group optionally substituted with a group chosen from:

(1) oxopyrrolidin group,

(2) ecomorphological group and

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group.

(xvi) a Compound in accordance with (i), (ii), (iii), (iv), (vii), (x) or (xiii), where the saturated heterocyclic ring is a saturated 4-7 membered heterocyclic group containing from 1 to 4 heteroatoms, independently selected from the group consisting of nitrogen atom, oxygen and sulphur.

(xvii) a Compound in accordance with (i), (ii), (iii), (iv), (vii), (x) or (xiii), where the saturated heterocyclic group is imidazolidinyl, piperidinyl, piperidyl, piperazinil, morpholinyl, thiomorpholine, Homoptera inil, homopiperazin, pyrrolidinyl, oxazolidinyl or 1,3-dioxane.

(xviii) the Compound according to (iii), where a group of the formula:

represents a group of the formula:

and a group of the formula:

represents a group of the formula:

or

R1represents a halogen atom or a lower alkyl group;

R2represents a group selected from the following groups:

(A) a hydrogen atom,

B) a lower alkyl group optionally substituted with a group chosen from:

(1) lower alkoxycarbonyl group,

(2) carboxyl group,

(3) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) low alkoxygroup,

(4) a carbonyl group substituted with morpholinyl group,

(5) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(6) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(7) a carbonyl group substituted with a hydroxyl GRU is dust, substituted piperidine group and

(8) a hydroxyl group;

C) the lowest alkoxygroup, optionally substituted with a group chosen from:

(1) carboxyl group,

(2) the lower alkoxycarbonyl group,

(3) low alkoxygroup,

(4) a hydroxyl group,

(5) aminochrome, optionally substituted with lower alkoxycarbonyl group,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) a carbonyl group substituted with morpholinyl group, piperidino group or pyrrolidinyl group,

(8) a carbonyl group substituted with hydroxypiperidine group,

(9) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(10) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(11) a carbonyl group substituted with a lower alkylpiperidines group,

(12) amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group,

(13) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) lower alkyl groups substituted with hydroximino group, and (d) a lower alkyl group, substituted with di-lower alkylamino and

(14) a group of the formula:; or

D) a carbonyl group substituted by a group selected from:

(1) low alkoxygroup,

(2) a hydroxyl group,

(3) amino groups, optionally substituted with a group selected from (a) lower alkyl groups, (b) low alkoxygroup, (C) lower alkoxy-lower alkyl group, (d) hydroxy-lower alkyl group, (e) a lower alkyl group substituted with amino group, optionally substituted with lower alkyl groups, (f) a lower alkyl group substituted with aryl group, and (g) a lower alkyl group substituted with peredelnoj group,

(4) morpholinyl group, pyrrolidinyl group, piperidino group or thiomorpholine group,

(5) hydroxypiperidine group,

(6) piperidino group, substituted with hydroxy-lower alkyl group,

(7) pyrrolidinyloxy group, substituted with hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinilnom group;

Rather it represents a simple bond; and

R3represents a hydrogen atom.

(xix) the Compound according to (xviii), where Y is a group selected from the following groups:

(1) piperidino group, substituted with Issa alkyl groups,

(2) cycloalkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group,

(3) cycloalkyl group, substituted by groups of the formulae selected from the structure:

which is optionally substituted by carbonyl group,

(4) cycloalkyl group substituted by an amino group substituted with a lower alkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkanoyloxy group and (b) lower alkoxycarbonyl group and

(5) cycloalkyl group substituted with a lower alkyl group substituted with amino group, optionally substituted with lower alkyl group; and

R2represents a group chosen from:

(1) a hydrogen atom,

(2) ceanography,

(3) amino groups, optionally substituted with lower alkyl groups,

(4) a hydroxyl group,

(5) low alkoxygroup,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) low alkoxygroup substituted with hydroxyl group,

(8) low alkoxygroup, substituted with amino, neoba is consequently substituted with lower alkyl groups,

(9) lower alkoxycarbonyl group,

(10) a carboxyl group,

(11) aminocarbonyl group, optionally substituted with a group selected from (a) lower alkyl groups, and (b) a hydroxy-lower alkyl group,

(12) morpholinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group or dimorpholinyldiethyl group,

(13) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group or pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(14) a lower alkyl group,

(15) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(16) carboxy-lower alkyl group,

(17) a lower alkyl group substituted with carbamoyl group, optionally substituted with a group selected from (a) a lower alkyl group and (b) a hydroxy-lower alkyl group,

(18) a lower alkyl group substituted with morpholinylcarbonyl group,

(19) a lower alkyl group substituted with piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group or a lower alkyl group substituted with pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group, or

(20) hydroxy-Nisse the alkyl group.

(XX) the Compound according to (xviii), where Y represents cycloalkyl group, substituted by groups of the formulae selected from the structure:

which is optionally substituted by carbonyl group or cycloalkyl group substituted with amino group, optionally substituted with a group selected from (a) a lower alkyl group and (b) lower alkanoyloxy group; and R2represents a group chosen from:

(1) a hydrogen atom,

(2) amino group, a substituted carbonyl group, optionally substituted with a group selected from (a) a lower alkyl group and (b) a lower alkoxy-lower alkyl group,

(3) lower alkoxycarbonyl group,

(4) morpholinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group or dimorpholinyldiethyl group,

(5) a lower alkyl group substituted with a lower alkyl group, a substituted carbamoyl group,

(6) carboxy-lower alkyl group,

(7) a lower alkyl group substituted with morpholinylcarbonyl group and

(8) hydroxy-lower alkyl group.

(xxi) the Compound according to (xviii), where Y represents cycloalkyl group substituted with oxopyrrolidin group, cycloalkyl GRU is PU, substituted with ecomorphological group or cycloalkyl group substituted with amino group, optionally substituted with a group selected from (a) a lower alkyl group and (b) lower alkanoyloxy group; and

R2represents a group chosen from:

(1) a hydrogen atom,

(2) hydroxy-lower alkyl group,

(3) carboxy-lower alkyl group,

(4) low alkoxygroup substituted with lower alkoxygroup or

(5) a carbonyl group substituted by a group selected from (a) amino group, optionally substituted with lower alkyl groups and (b) morpholinyl group.

(xxii) the Compound according to (xviii), where Y represents a group chosen from:

(1) cycloalkyl group substituted by an amino group substituted with a lower alkyl group having from 1 to 3 carbon atoms,

(2) cycloalkyl group substituted by an amino group substituted with lower alkanoyloxy group having 1 to 2 carbon atoms,

(3) cycloalkyl group substituted with pyrrolidin-1-ilen group, optionally substituted by carbonyl group,

(4) cycloalkyl group substituted with piperidine-1-ilen group, optionally substituted by carbonyl group,

(5) cycloalkyl group substituted with p the power morpholine-4-ilen group, optionally substituted by carbonyl group,

(6) cycloalkyl group substituted with a lower alkyl group substituted with amino group, substituted with lower alkyl groups having from 1 to 3 carbon atoms or

(7) cycloalkyl group substituted with a lower alkyl group substituted with amino group, substituted with lower alkanoyloxy group having 1 to 2 carbon atoms.

(xxiii) a Compound selected from the

TRANS-5-dimethylaminoethyl-3-[4-(N-formyl-N-methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide;

TRANS-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl]-5-(2-hydroxyethyl)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide;

TRANS-5-(mohlin-4-ylcarbonyl)-3-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide; and

TRANS-3-(4-dimethylaminopropylamine)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide or its pharmaceutically acceptable salt.

(xxiv) Derived benzofuran having a partial structure of the formula [1-1]:

where the symbols are the same as defined above, or its pharmaceutically acceptable salt.

(xxv) Derived benzofuran formula [2]:

where the characters I have are the same, as defined above, or its salt.

(xxvi) a Pharmaceutical composition which contains as active ingredient a compound according to any one of paragraph (i) to (xxiv)above or its pharmaceutically acceptable salt.

(xxvii) a Method of treating thrombosis, which includes the introduction of an effective amount of a compound according to any one of paragraph (i) to (xxiv)above or its pharmaceutically acceptable salt to a patient in need of it.

(xxviii) the Use of compounds in accordance with any one item (i) to (xxiv)above or its pharmaceutically acceptable salts in the treatment of patients suffering from thrombosis.

(xxix) a Drug for the treatment of thrombosis, significantly reducing phospholipids containing as active ingredient an inhibitor of factor XA (FXa), showing the size distribution of 0.1-3.0 l/kg and an FXa inhibitory effects with the size of the IC50of 100 nm or below.

(xxx) a Drug for the treatment of thrombosis, essentially non-hepatotoxicity, which comprises as an active ingredient an FXa inhibitor having a size distribution of 0.1-3.0 l/kg or below, and the inhibiting effect of FXa with the value of the IC50of 100 nm or below.

(xxxi) a Drug for oral administration for treatment of thrombosis substantially with ijoumee phospholipids, which contains as active ingredient an inhibitor of Ha factor (FXa), which has the largest distribution of 0.1-3.0 l/kg and an FXa inhibitory effects with the size of the IC50of 100 nm or below.

(xxxii) a Drug for oral administration for treatment of thrombosis, essentially non-hepatotoxicity, which comprises as an active ingredient an FXa inhibitor having a size distribution of 0.1-3.0 l/kg or below, and the inhibiting effect of FXa with the value of the IC50of 100 nm or below.

(xxxiii) a Drug for the treatment of thrombosis, significantly reducing phospholipids, which contains as active ingredient an FXa inhibitor having a partial structure of the formula:

and having a size distribution of 0.1-3.0 l/kg and an FXa inhibitory effects with the size of the IC50of 100 nm or below.

(xxxiv) Drug for the treatment of thrombosis, essentially non-hepatotoxicity, which comprises as an active ingredient an FXa inhibitor having a partial structure of the formula:

and having a size distribution of 0.1-3.0 l/kg and an FXa inhibitory effects with the value of the IC50of 100 nm or below.

(xxxv) a Drug for oral administration for treatment of thrombosis substantially reduce phospholipids, which is contains as active ingredient an FXa inhibitor, having a partial structure of the formula:

and having a size distribution of 0.1-3.0 l/kg and an FXa inhibitory effects with the value of the IC50of 100 nm or below.

(xxxvi) a Drug for oral administration for treatment of thrombosis, essentially non-hepatoxicity, which contains as active ingredient an FXa inhibitor having a partial structure of the formula:

and having a size distribution of 0.1-3.0 l/kg and an FXa inhibitory effects with the size of the IC50of 100 nm or below.

The preferred method of carrying out the invention

Further, the compound [1] of the present invention in more detail.

The term "lower"used in the definitions of formulas in the present invention, means, unless otherwise noted, a straight or branched carbon chain having from 1 to 6 carbon atoms.

Accordingly, the examples of "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, ,2.2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and so on. Among them, alkyl groups having from 1 to 4 carbon atoms, are preferred, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are particularly preferred.

The term "lower alkoxygroup" means the Deputy, in which the oxygen atom is attached to the above-mentioned alkyl group. Among them, alkoxy groups having from 1 to 4 carbon atoms, are preferred, and methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy group, are particularly preferred.

Examples of the carbon chain, optionally having a double bond within or at the end(Ah) chain" include "lower alkylenes group", "lower alkynylamino group" and "lower alkynylamino group.

Examples of "lower alkalinous group" include a straight or branched chain alkalinous group having from 1 to 6 carbon atoms, in particular methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and so on. Among them Allenova group having from 1 to 5 carbon atoms, is preferred.

Examples of "lower alkynylamino group" include a straight or branched chain alkenylamine group having from 2 to 6 carbon atoms, in particular vinile, propylen, butylen, pen is enilan and so on. Among them alkenylamine group having from 2 to 5 carbon atoms, is preferred.

Examples of "lower alkynylamino group" include alkanolamine having from 2 to 6 carbon atoms, in particular vinyliden, propenylidene, butenolide, pentanolide, and so on.

Examples of "lower alkanoyloxy group" include alcoholnye group formed by removing the "IT" group of the carboxyl group of the lower carboxylic acids, in particular formyl, acetyl, propionyl, butyryl, and so on.

The term "saturated heterocyclic group" means a saturated heterocyclic group containing 1 to 4 heteroatoms, independently selected from the group consisting of nitrogen atom, oxygen and sulfur, preferably a 4-7-membered heterocyclic group containing from 1 to 4 heteroatoms, independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Condensed heterocyclic ring included. Specific examples include imidazolidinyl, pyrazolidine, piperidyl, piperazinil, morpholinyl, thiomorpholine, homopiperazine, homopiperazin, pyrrolidinyl, oxazolidinyl, 1,3-dioxane, and so on. Among all piperidyl, piperazinil, homopiperazine and pyrrolidinyl are preferred.

The term "unsaturated heterocyclic group" means an unsaturated, heterocy the symbolic group, containing from 1 to 4 heteroatoms, independently selected from the group consisting of nitrogen atom, oxygen and sulfur, preferably a 4-7-membered heterocyclic group containing from 1 to 4 heteroatoms, independently selected from the group consisting of nitrogen atom, oxygen and sulfur. Condensed heterocyclic ring included. Specific examples include pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 4,5-dihydrooxazolo, thiazolyl, isothiazole and so on. Among all pyridyl, pyrimidinyl, pyrazinyl, thienyl, oxazolyl, 4,5-dihydro-oxazolyl and thiazolyl are preferred.

Examples of the "halogen atom " include fluorine atom, chlorine, bromine or iodine. Among all the atoms fluorine, chlorine or bromine, which are preferred.

The term "cycloalkyl group" means a cyclic lower alkyl group, preferably tsiklogeksilnogo group.

The term "aryl group" means a phenyl or naftalina group, preferably phenyl group.

The symbol "Y"when a and Y are connected via a double bond, refers to the corresponding divalent group.

Pharmaceutically acceptable salt of the compound [1] includes a salt with an inorganic acid, such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, and the now acid, phosphoric acid and the like; salt with organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, etc.; salt with acidic amino acid such as aspartic acid, glutamic acid and the like; salt with a metal such as sodium, potassium, magnesium, calcium, aluminum and the like; salt with organic base, such as methylamine, ethylamine, ethanolamine, and so forth; or a salt with basic amino acid such as lysine, ornithine, and so on.

The compound [1] of the present invention may be in the form of Quaternary ammonium salts, and such Quaternary ammonium salts are within the boundaries of the present compounds [1].

Moreover, the compound [1] of the present invention includes an intramolecular salt, hydrate, MES or crystalline polymorphism, and so on.

In addition, when the compound [1] has the double bond(s), it may exist as geometric isomers (CIS, TRANS), when the compound [1] has an unsaturated bond such as carbonyl, it may exist as tautomers, when the compound [1] is asymmetric at the m(s) carbon, it can exist as optical isomers, and the present invention covers all of these isomers and mixtures thereof.

In addition, compound [1] of the present invention includes prodrugs of the compounds as mentioned above. Examples of prodrugs include those obtained by protecting the functional group such as amino or carboxypropyl compounds, using a conventional protecting group.

The compound of the present invention can be obtained by the following processes.

[Process]

Among the compounds [1] of the present invention the connection, where a represents a simple bond or a carbon chain optionally having a double bond within or at the end(s) of the chain, i.e. the compound which has the formula [1-a]:

where a1represents a simple bond or a carbon chain optionally having a double bond within or at the end(Ah) chain, and the other symbols are the same as defined above, can be obtained by reaction of amino compounds having the formula [2]:

where the symbols are the same as defined above, with a compound of carboxylic acid having the formula [3-a]:

where the symbols are the same as defined above, or goregrindcore the derivative of the carboxyl group.

[Process]

Among the compounds [1] of the present invention the connection, where a represents an oxygen atom or a represents a simple bond and Y represents optionally substituted by an amino group, i.e. a compound which has the formula [1]:

where a represents an oxygen atom, and other symbols have the same meanings as defined above, or when A2represents a simple bond or other symbols have the same meanings as defined above, it can be obtained by reaction of compound [2] above with a compound that has the formula [3-B1]:

where the symbols have the same meanings as defined above, with a compound which has the formula [3-B2]:

where L1and L2have the same values or different and each group goes back.

The compound [1] can also be obtained, if necessary, through a total transformation when the rest of Y and/or Deputy ring (R2) of the obtained compound [1] or [1] adequately converted into the compound [1] by the total conversion by alkylation, reductive alkylation, amidation, sulfonylmethane, amidinotransferase, arilirovaniya, restored the I, dealkylation, hydrolysis, Quaternary amination, formirovanie, pyrrolidone, protection of the amino or carboxyl group and remove protection and so on.

[The process of obtaining the source of materials: Obtain compounds [2]]

The compound [2] can be obtained by using a method including:

the transformation of the aldehyde group of compounds of formula [10]:

where the symbols have the same meanings as defined above, cyano, that gives compound which has the formula [9]:

where the symbols have the same meanings as defined above, the reaction of the compound [9] with a compound that has the formula [8]:

where L3represents a leaving group, and R1is a protective group for the carboxyl group, which gives a compound which has the formula [7]:

where the symbols have the same meanings as defined above, removing protection with a protective group, R1connections [7] gives a compound which has the formula [6]:

where the symbols have the same meanings as defined above,

the interaction of compounds [6], if necessary, after transformation into reactionsare the derivative of its carboxyl group to connect the discharge [5]:

where the symbols have the same meanings as defined above, which gives a compound which has the formula [4]:

and implementation of the cyclization of compounds [4].

In addition, compound [4] can be also obtained by the reaction of a compound that has the formula [9], with a compound which has the formula [12]:

where L4represents a leaving group and other symbols have the same meanings as defined above.

Compound [4] can also be obtained through reaction of a compound that has the formula [13]:

where L5represents a leaving group and other symbols have the same meanings as defined above, with a compound which has the formula [14]:

where the symbols have the same meanings as defined above.

In addition, the compound which has the formula [10]can be obtained by using formirovaniya compound that has the formula [11]:

where the symbols have the same meanings as defined above.

The processes [A] and [V]described above can be performed as follows.

[Process]

A reaction in which the compound [1-a] gain, using with the Association [2] and the compound [3-a], can be performed by usual methods of amidation process. The reaction can be performed by reacting the compound [2] with the compound [3-a], its reactive derivative or its salt in the presence or in the absence of a condensing agent and, if necessary, in the presence of an acid acceptor in an appropriate solvent.

The condensing agent includes conventional agents, such as N,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or its hydrochloride, carbonyldiimidazole (CDI), diphenylphosphoryl (DPPA), diethyl cyanophosphonate (DEPC) and so on. Among all DCC, EDC or its hydrochloride are preferred.

Examples reaktsionnosposobnykh derived compounds [3-a] include conventional compounds such as galoyanized, mixed anhydride, reactionary ether and so on. Examples of the activator, which can be used to convert a compound [3-a] in its reactive derivative include chloride thionyl, bromide tional, the acid chloride oxalic acid, N-hydroxylamine, such as 1-hydroxysuccinimide, 1-hydroxybenzotriazole, and so forth, and phenols, such as p-NITROPHENOL, and so forth. Among all chloride thionyl, the acid chloride oxalic acid, 1-hydroxysuccinimide and 1-hydroxybenzotriazole preferred. Method and with the use of carboxylic acid is particularly preferred.

Examples of salts of compounds [3-a] or reaktsionnosposobnykh derived compounds [3-a] include a salt of an inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid and so on. The acid acceptor is also suitable depending on the method used, which includes inorganic or organic bases.

The course specified reaction can be facilitated when it is conducted in the presence of a base, or use basis, are solvent. Examples of inorganic bases include inorganic bases such as alkali metal carbonates (sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkaline earth metal carbonates (calcium carbonate, and so forth), acid carbonates of alkali metals (sodium bicarbonate, potassium bicarbonate, etc.), gidroksidy alkali metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, and so forth). Examples of organic bases include three lower bonds alkylamines (triethylamine, tributylamine, diisopropylethylamine and so on), tertiary amines (1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), amines (N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine and so on), pyridine, dimethylpyridine, arylmethylidene and so on. Among neither is preferred to conduct the reaction, the triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine. This reaction can be carried out in the presence or absence of a solvent, preferably in the presence of solvent.

Examples of the solvent include any inert solvent which does not interrupt the reaction, such as halogenated hydrocarbons (chloroform, dichloromethane, dichloroethane etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and so on), esters (ethyl acetate, etc.), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone and so on), NITRILES (acetonitrile and so on), dimethylsulfoxide, pyridine, 2,6-lutidine, and so forth, a mixed solvent comprising two or more of these solvents, if necessary, and any mixture(s) of these solvents and water. It is preferable to select a suitable solvent depending on the method used. Among them, dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidine, pyridine and the like are preferable, and dichloromethane, chloroform, N,N-dimethylformamide and pyridine are particularly preferred. This reaction can be conducted in a wide range of temperatures, the t temperature of the cooling to the heating temperature. For example, the reaction may be preferably conducted at a temperature of from -10°C to the boiling point of the reaction mixture, particularly the temperature of the ice up to 60°C.

[Process]

The process where the connection [1] are obtained by reaction of compound [2] with compounds of the formulas [3-B1] and [3-B2], respectively, can be performed in accordance with the usual method of carbonylation in the presence of an appropriate acid acceptor in an appropriate solvent.

Examples of the leaving group to the compound that has the formula [3-B2], include halogen atom. Examples of compounds [3-B2] include phosgene, triphosgene, CDI, and so forth, and triphosgene is preferable.

Examples of the acid acceptor used in the reaction include inorganic and organic bases. Examples of inorganic bases include alkali metal carbonates (sodium carbonate, potassium carbonate, cesium carbonate, and so forth) bicarbonates of the alkali metal (sodium bicarbonate, potassium bicarbonate, etc.). Examples of organic bases include trinessa alkyl amines (triethylamine, tributylamine, diisopropylethylamine and so on), tertiary amines (1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]-undec-7-ene, etc.), amines (N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine and so the alley), pyridine, lutidine, kallidin and so on. They include triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and pyridine are preferred.

Examples of the solvent include any inert solvent which does not terminate the reaction, such as halogenated hydrocarbons (chloroform, dichloromethane, dichloroethane etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and so on), esters (ethyl acetate, etc.), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone and so on), NITRILES (acetonitrile etc.), pyridine, 2,6-lutidine, and so forth, and solvent mixtures containing two or more of these solvents, if necessary. It is preferable to choose any appropriate solvent depending on the method used. Among them, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidine, pyridine and the like are preferable, and dichloromethane and N,N-dimethylformamide are particularly preferred. This reaction can be performed in a wide temperature range from -78°C to the boiling point of the reaction mixture. For example, the reaction may be preferably performed at a temperature of from -10°C to the boiling point of the reaction mixture, especially from t is mperature ice to room temperature.

In addition, after the implementation of the processes [A] and [In] the target compound [1] can also be obtained, if necessary, through a total transformation by the following reaction(s), provided that the compounds of the formula [1-a] and/or [1] have one or more residues, capable of further reaction(s) with substituent(s) for group Y and/or rings (mainly with regard to, for example, a protective group for an amine, alcohol or phenolic HE, of ester, carboxylic acid, nitro, halogen, and so on)

The reaction of alkylation, reductive alkylation, amidation, sulfonyl-amidation, amidinotransferase, arilirovaniya, reduction, dealkylation, hydrolysis, Quaternary amination, pyrrolidone, protect and unprotect amino or carboxyl group, which meets when necessary, can be performed as follows.

The alkylation can be performed in the usual way when necessary. For example, this reaction can be carried out using the reaction of compound [1] with alkylhalides, such as alkylchloride, allylbromide, alkylated and so forth, in the presence or in the absence of a base in an appropriate solvent.

Examples of suitable bases include inorganic and organic bases. Inorganic base the cation include alkali metal carbonates (sodium carbonate, potassium carbonate, cesium carbonate, and so forth), alkali metal bicarbonates (sodium bicarbonate, potassium bicarbonate, etc.), hydroxide of alkaline metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, and so forth). Examples of organic bases include tenessee alkyl amines (triethylamine, tributylamine, diisopropylethylamine and so on), tertiary amines (1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), pyridine, lutidine, kallidin and so on. Among them, the alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, triethylamine, diisopropylethylamine, pyridine and so forth are preferred.

The alkali metal iodide such as lithium iodide, sodium iodide, potassium iodide, and so forth may also be added, since they can facilitate the reaction.

Any inert solvents which do not disturb the reaction can be used without limitation, and examples include ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone and so on), NITRILES (acetonitrile etc.), alcohols (methanol, ethanol, propanol, etc.), dimethylsulfoxide, pyridine, 2,6-lutidine,and so forth, and mixtures of solvents, containing two or more of these solvents, if necessary. It is preferable to choose any appropriate solvent depending on the method used. Among them, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, ethanol, dimethylsulfoxide, and so forth, are preferred, and N,N-dimethylformamide, acetonitrile, ethanol and mixtures of these solvents are particularly preferred.

This reaction can be performed in a wide temperature range from the temperature of the cooling to the heating temperature, preferably from -10°C to the boiling point of the reaction mixture.

Reductive alkylation can be performed in the usual way, if you want. For example, this reaction can be performed using the reaction of compound [1] with the corresponding carbonyl compound in the presence of an appropriate recovery agent, such as a metal hydride, or in the conditions of catalytic reduction in the presence of an appropriate metal catalyst in an appropriate solvent.

In this reaction, any conventional recovery agents such as metal hydrides, can be used without restrictions; however, the recovery agent, which has no effect on the amide bond, and so forth, is such as sodium borohydride, borderedrectangle sodium borohydride renontre and so forth are preferred.

In addition, organic acids such as acetic acid, etc., or inorganic acids such as hydrochloric acid and so forth may also be added to the present reaction, which can facilitate the reaction.

In addition, when the compound [1] is an amine as a salt with inorganic acid, such as hydrochloric acid and so on suitable neutralizing agent, such as an organic base (e.g. triethylamine) or an alkali metal acetate (e.g. sodium acetate) can be added to the reaction, which may facilitate the reaction.

Any inert solvent which does not disturb the reaction can be used without limitation, and examples include halogenated hydrocarbons (chloroform, dichloromethane, dichloroethane, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone and so on), NITRILES (acetonitrile etc.), aromatic hydrocarbons (benzene, toluene, xylene, and so forth), alcohols (methanol, ethanol, propanol, etc.), water and solvent mixture containing two or more of these solvents, if necessary odimo. It is preferable to choose any appropriate solvent depending on the method used. Among them, dichloromethane, dichloroethane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, propanol and so on are preferable, and dichloromethane, dichloroethane and tetrahydrofuran are particularly preferred.

The reaction can be performed in a wide temperature range from the temperature of the cooling to the heating temperature. For example, the reaction may be preferably performed at a temperature of from -10°C to the boiling point of the reaction mixture, particularly the temperature of the ice to the boiling point of the mixture.

This reaction can likewise be carried out in accordance with the process of catalytic hydrogenation in the presence of a metal catalyst. Examples of the metal catalyst include palladium on charcoal, platinum on charcoal, platinum oxide, Raney Nickel, and so forth.

In addition, organic acids such as acetic acid, etc., or inorganic acids such as hydrochloric acid and so forth may also be added to the present reaction, which may facilitate its flow.

In addition, when the compound [1] is an amine as a salt of an inorganic acid, such as hydrochloric acid and so on, corresponding not tralize agent, such as an organic base (e.g. triethylamine) or an alkali metal acetate (e.g. sodium acetate) can be added to the reaction, which can facilitate its flow.

Any inert solvent which does not disturb the reaction can be used without limitation, and examples include ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone and so on), aromatic hydrocarbons (benzene, toluene, xylene, and so forth), alcohols (methanol, ethanol, propanol, etc.), water and solvent mixture containing two or more of these solvents, if necessary. It is preferable to choose any appropriate solvent depending on the method used. Among them, tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol and so forth are preferable, and tetrahydrofuran, methanol, ethanol and so forth are particularly preferred.

The reaction can be performed in a wide temperature range from the temperature of the cooling to the heating temperature. For example, the reaction may be preferably performed at a temperature of from -10°C to the boiling point of the reaction mixture, particularly the temperature of the ice to room tempera is URS.

The amidation can be performed in a similar way by the above-mentioned reaction between the compound [2] and the compound [3-a], when it is necessary.

Sulfanilamidnaya can be made in the usual way when necessary. For example, this reaction can be performed using the reaction of compound [1] with optionally substituted by halogen alkylsulfonic acid in the presence or in the absence of a base in an appropriate solvent. For the reaction can be used similar to an acid absorber, a solvent and the reaction temperature, such as that used in the amidation reaction between the compound [2] and the compound [3-a], above.

Amidinotransferase can be made in the usual way when necessary. For example, the reaction can be performed using the reaction of compound [1] with 2-bromadiolone or 2-chlorotriazine in the presence or in the absence of acceptor acid in an appropriate solvent.

Examples of suitable bases include inorganic and organic bases. Inorganic bases include alkali metal carbonates (sodium carbonate, potassium carbonate, cesium carbonate, and so forth), alkali metal bicarbonates (sodium bicarbonate, potassium bicarbonate, and so on and so forth. Examples of the organic base which requirements include trinessa alkyl amines (triethylamine, tributylamine, diisopropylethylamine and so on), tert-amines (1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), amines (N,N-dimethylaniline, N,N-diethylaniline, 4-dimethyl-aminopyridine, and so on), pyridine, lutidine, kallidin, and so on. Among them, triethylamine and diisopropylethylamine are preferred.

This reaction can be performed in the presence or in the absence of a solvent, preferably in the presence of a solvent.

Any inert solvent which does not disturb the reaction can be used without limitation, and examples include halogenated hydrocarbons (chloroform, dichloromethane, dichloroethane etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone and so on), NITRILES (acetonitrile etc.), dimethyl sulfoxide, pyridine, 2,6-lutidine, and so forth, and mixtures of solvents containing two or more of these solvents, if necessary. Among them, dichloromethane, tetrahydrofuran, N,N-dimethylformamide and so on are preferable, and tetrahydrofuran is preferred.

The reaction can be performed in a wide d is apatone temperature the temperature of the cooling to the heating temperature. For example, the reaction may be preferably performed at a temperature of from -10°C to the boiling point of the reaction mixture, particularly the temperature of the ice to room temperature.

Atilirovanie can be made in the usual way when necessary. For example, the reaction can be performed using the reaction of compound [1] with a halogenated compound of aryl in the presence or in the absence of an appropriate base in an appropriate solvent.

Examples of suitable bases include inorganic and organic bases. Inorganic bases include alkali metal carbonates (sodium carbonate, potassium carbonate, cesium carbonate, and so forth), alkali metal bicarbonates (sodium bicarbonate, potassium bicarbonate, and so on and so forth. Examples of organic bases include trinessa alkyl amines (triethylamine, tributylamine, diisopropylethylamine and so on), tert-amines (1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), amines (N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine and so on), pyridine, lutidine, kallidin and so on. They include triethylamine, diisopropylethylamine, potassium carbonate and so forth, are preferred.

This reaction can be performed in the presence or in the absence of a process is Italia, preferably in the presence of a solvent.

Any inert solvent which does not disturb the reaction can be used without limitation, and examples include aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and so on), NITRILES (acetonitrile etc.), alcohols (methanol, ethanol, propanol, 2-butanol, and so etc.), dimethylsulfoxide, pyridine, 2,6-lutidine, and so forth, and mixtures of solvents containing two or more of these solvents, if necessary. Among them, xylene, tetrahydrofuran, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, ethanol, 2-butanol, and so forth are preferable, and tetrahydrofuran, N,N-dimethylacetamide and 2-butanol are particularly preferred.

The reaction can be performed in a wide temperature range from the temperature of the cooling to the heating temperature. For example, the reaction may be preferably performed at a temperature of from -10°C to the boiling point of the reaction mixture, especially from room temperature to the boiling point of the reaction mixture.

Recovery may be made in the usual way when necessary. For example, the reaction can be accomplished is through the reaction of compound [1] with the corresponding recovery agent or with hydrogen in the presence of a metal catalyst in an appropriate solvent.

In the reaction, any conventional recovery agents can be used without restrictions; however, recovery agents, such as metal hydrides, namely lithium alumoweld lithium, lithium borohydride, sodium borohydride, and so forth, metals such as zinc, iron, tin, and so forth, and a metal salt, such as chloride of tin, and so forth, are preferred, and metals such as tin, and so forth, and a metal salt, such as chloride of tin, and so forth, are especially preferred. When catalytic hydrogenation any conventional metal catalyst can be used without restrictions; however, palladium on charcoal, Raney Nickel, Raney cobalt, platinum oxide, and so forth are preferred, and metals, such as Raney Nickel, and so forth, are especially preferred. In addition, depending on the method used, the reaction can sometimes better to leak when it is carried out in acidic conditions in the presence of inorganic acids such as hydrochloric acid, and so forth.

In the reaction using the recovery agent, such as a metal hydride, any inert solvent which does not disturb the reaction can be used without limitation, and examples include ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and so is her), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and so on), aromatic hydrocarbons (benzene, toluene, xylene, and so forth), alcohols (methanol, ethanol, propanol, etc.), water, and so forth, and mixtures of solvents containing two or more of these solvents, if necessary. It is preferable to choose any appropriate solvent depending on the method used.

In the reaction using a metal, such as zinc, iron, tin, and so forth, or salt of a metal, such as tin chloride, and so forth, any inert solvents which do not disturb the reaction can be used without limitation, and examples include water, alcohols (methanol, ethanol, propanol, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and so on), amides (N,N-dimethylformamide N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and so on), NITRILES (acetonitrile, etc.), aromatic hydrocarbons (benzene, toluene, xylene, and so forth), and a mixture of solvents containing two or more of these solvents, if necessary. It is preferable to choose any appropriate solvent depending on the method used. Among them, ethyl acetate, water or a mixture of solvents, provided the water and alcohol, ester, amide, nitrile, and so forth, which is preferred.

In the reaction, where the hydrogenation is performed in the presence of a metal catalyst, any inert solvent which does not disturb the reaction can be used without limitation, and examples include alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, esters (ethyl acetate, etc.), organic cyclotomy (formic acid, acetic acid, propionic acid, triperoxonane acid, and so forth), and a mixture of solvents containing two or more of these solvents, if necessary. It is preferable to choose any appropriate solvent depending on the method used.

This reaction can be performed in a wide temperature range from the temperature of the cooling to the heating temperature. For example, the reaction may be preferably performed at a temperature of from -10°C to the boiling point of the reaction mixture.

The pressure of hydrogen used in the reaction of catalytic hydrogenation is typically about 1-100 atmospheres.

The reaction time for this reaction varies depending on species recovery agent or activity of the used catalyst; however, it is usually in the range from about 10 minutes to 24 hours.

Dialkyl the Finance can be made in the usual way, when it is necessary. For example, this reaction can be performed using the reaction of compound [1] with the corresponding dealkylation agent in an appropriate solvent or without solvent.

Any conventional agents dealkylation can be used without limitation, and preferred examples include tribromide boron, trichloride boron, attributively, aluminum chloride(III), pyridinium chloride, and so forth, and tribromide boron, attributively, and so forth are preferred.

Any inert solvent which does not disturb the reaction can be used without limitation, and examples include halogenated hydrocarbons (chloroform, dichloromethane, dichloroethane, etc.), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and so on), NITRILES (acetonitrile, etc.) and the mixture of solvents containing two or more of these solvents, if necessary. It is preferable to choose any appropriate solvent depending on the method used.

The reaction can be performed in a wide temperature range from the temperature of the cooling to the heating temperature, preferably from -78°C to the boiling point of the reaction mixture.

The hydrolysis can be performed in the usual way, when necessary.

Quaternary amination can the t to be made in the usual way, when it is necessary. This reaction can be carried out in a similar way to the above-mentioned alkylation.

Pyrrolidinone can be performed by, for example, reaction of compounds having the amino group, tetrahydro-2,5-dimethoxyfuran in the presence of an acid in an appropriate solvent.

Examples of the acid include organic acids such as formic acid, acetic acid, propionic acid, triperoxonane acid, and so forth, and inorganic acids such as hydrochloric acid, and so forth, which can also be used as a solvent.

Any inert solvents in addition to the above-mentioned organic acids and inorganic acids, which does not disturb the reaction can be used without limitation, and examples include halogenated hydrocarbons (chloroform, dichloromethane, dichloroethane, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and so on), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and so on), NITRILES (acetonitrile, etc.), and so forth, and organic acids are preferred.

The reaction can be performed in a wide temperature range from temperature ohla the Denia to the heating temperature, preferably from -78°C to the boiling point of the reaction mixture.

Protection of the amino - or carboxypropyl or unprotect a protected group can be performed, when necessary, in accordance with any known methods.

[The process of obtaining the source of materials: Obtain compound [2]

(1) the Reaction conversion of the aldehyde group of compound [10] the cyano to obtain the compound [9] can be performed using the reaction of compound [10] with hydroxylamine or its hydrochloride in the presence or in the absence of sodium formate in an appropriate solvent. Can be added dehydrating agent. Available organic solvent of lower fatty acid, such as formic acid; however, preferred is the choice of an appropriate solvent depending on the method used.

This reaction can be performed in a wide temperature range from the temperature of the cooling to the heating temperature. For example, the reaction can be preferably performed with the temperature of the ice to the boiling point of the reaction mixture, especially at the boiling point of the reaction mixture.

(2) Following the reaction between the obtained compound [9] and the compound [8] to obtain the compound [7] can be made in the usual way for O-alkylation of phenol is connected to the I. This reaction can be performed using the reaction of compound [9] with the compound [8] in an appropriate solvent in the presence of base or by the use of such a base as a solvent.

Leaving group in the compound [8] can be preferred, for example, in the form of a halogen atom. Examples of preferred protective groups for the carboxyl group of compound [8] include a lower alkyl group and a phenyl-lower alkyl group.

Examples of suitable bases include inorganic and organic bases, such as alkali metal carbonates (sodium carbonate, potassium carbonate, and so forth), alkali metal bicarbonates (sodium bicarbonate, potassium bicarbonate, etc.), hydroxide of alkaline metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, and so forth), alkali metal hydrides (sodium hydride, and so on), alkali metal alkoxides (sodium methoxide, tert-piperonyl potassium, and so forth), trinessa the bonds alkylamines (triethylamine, tributylamine, diisopropylethylamine, and so etc.), tertiary amines (1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), amines (N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine, and so on), pyridine, lutidine, kallidin, and so on. Among them, carbonate of alkaline metal, diisopropylethylamine, is iridin, and so forth are preferred.

Examples of the solvent include any inert solvent which does not disturb the reaction, such as ketones (e.g. acetone, metaliteracy ketone, and so on), aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and so on), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and so on), NITRILES (acetonitrile, etc.), alcohols (methanol, ethanol, propanol, 2-butanol, and so forth), dimethylsulfoxide, pyridine, 2,6-lutidine, and so forth, and mixtures of solvents containing two or more of these solvents, if necessary. Among them, ketones, such as acetone, metaliteracy ketone, and so forth, and amides such as N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and so forth, are preferred.

This reaction can be performed in a wide temperature range from the temperature of the cooling to the heating temperature. For example, the reaction may be preferably performed at a temperature from the temperature of the ice to the boiling point of the reaction mixture.

The alkali metal iodide such as lithium iodide, sodium iodide, potassium iodide, and so forth, may also be added to facilitate the reaction.

(3) the Reaction of removing the protective group from the compound [7] to obtain compounds [6] can be performed, usually with the help of the method used for removing the protection of the carboxyl group.

(4) the condensation Reaction of compound [5] with the compound [6] to obtain the compound [4] can be performed in a similar way, such as for the reaction of compound [2] with the compound [3-a].

(5) the cyclization Reaction of compound [4], to obtain the compound [2]can be performed by treating the compound [4] a base in an appropriate solvent.

Examples of suitable bases include inorganic and organic bases, such as alkali metal carbonates (sodium carbonate, potassium carbonate, etc.), hydroxide of alkaline metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, and so forth), alkali metal hydrides (sodium hydride, and so on), alkali metal alkoxides (sodium methoxide, tert-piperonyl potassium, and so forth), trinessa alkyl amines (triethylamine, tributylamine, diisopropylethylamine, and so on), tert-amines (1,4-diazabicyclo[2.2.2]octane, 1, 5-diazabicyclo[4.3.0]-non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), amines (N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine, and so on), pyridine, lutidine, kallidin, and so on. Among them, carbonate of alkaline metal alkoxides saloon the first metal, diisopropylethylamine, pyridine, and so forth, are preferred.

This reaction can be performed in the presence or in the absence of a solvent, preferably in the presence of a solvent. Examples of the solvent include any inert solvent which does not disturb the reaction, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and so on), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and so on), NITRILES (acetonitrile, etc.), alcohols (methanol, ethanol, propanol, 2-butanol, and so forth), dimethylsulfoxide, pyridine, 2,6-lutidine, and so forth, and mixtures of solvents containing two or more of these solvents, if necessary. Among them, xylene, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, methanol, pyridine, and so forth are preferred, and N,N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone are particularly preferred.

This reaction can be performed in a wide temperature range from the temperature of the cooling to the heating temperature, preferably the temperature of the ice to the boiling point of the reaction mixture.

(6) the Reaction of the compound [9] and the compound [12] DL is receiving the compound [4] can be carried out in the presence of a base in an appropriate solvent, if you want to. The leaving group in the compound [12] can be preferably, for example, halogen atom.

Examples of suitable bases in this reaction include inorganic and organic bases. Inorganic bases include alkali metal carbonates (sodium carbonate, potassium carbonate, and so forth), alkali metal bicarbonates (acidic sodium carbonate, acidic potassium carbonate, and so forth), hydroxide of alkaline metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, and so forth), alkali metal hydrides (sodium hydride, and so on). A mixture of cesium carbonate and sodium iodide may also be used. Organic bases include alkali metal alkoxides (sodium methoxide, tert-piperonyl potassium, and so forth), trinessa the bonds alkylamines (triethylamine, tributylamine, diisopropylethylamine, and so on), tert-amines (1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]-undec-7-ene, etc.), amines (N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine, and so on), pyridine, lutidine and kallidin, and so on. Among them, the alkali metal carbonates, diisopropylethylamine, pyridine, and so forth are preferred. In this reaction the reasons indicated above may also be used as a solvent.

Examples of solvents usable in the us is oasa reaction, include any inert solvent which does not disturb the reaction, such as ketones (e.g. acetone, metaliteracy ketone, and so on), aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and so on), amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and so on), NITRILES (acetonitrile, etc.), alcohols (methanol, ethanol, propanol, 2-butanol, and so forth), dimethylsulfoxide, pyridine, 2,6-lutidine, and so on. A mixture of solvents containing two or more of these solvents may also be used. Among them, ketones and amides are preferred.

This reaction may usually be carried out with the temperature of the ice to the boiling point of the solvent.

The reaction time for this reaction is generally between 30 minutes and 24 hours; however long or short the appropriate reaction time can be selected, if necessary. Moreover, the alkali metal iodide such as lithium iodide, sodium iodide, potassium iodide, and so forth, may also be added to facilitate the reaction.

The reaction of the compound [13] and the compound [14] can be performed in the presence of a base in an appropriate solvent, if necessary in the IMO. The leaving group in the compound [13] can be preferably, for example, a halogen atom or a nitro-group.

Examples of suitable bases in this reaction include alkali metal carbonates (sodium carbonate, potassium carbonate, cesium carbonate, and so forth), alkali metal hydrides (sodium hydride, and so on) and alkali metal alkoxides (sodium methoxide, tert-piperonyl potassium, and so forth). Among them, sodium hydride is preferred.

Examples of solvents usable in this reaction include amides (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and so on), and ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and so forth) and N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and so forth are preferred.

The reaction formirovaniya compounds [11] to obtain the compound [10] can be made in the usual way, if you want. For example, the reaction may be performed using a reaction agent formirovaniya in accordance with the method for the reaction Duffy, the reaction Katterman-Koch reaction to Valmiera, and so on in an appropriate solvent.

Any ordinary agent formirovaniya can be used without limitation, and hexamethylenetetramine, and so forth are preferred.

This reaction can be performed in a wide temperature range from the temperature of the cooling to the heating temperature, preferably from -78°C to the boiling point of the reaction mixture.

Thus obtained compounds of the present invention can be isolated and purified using techniques well known in the field of organic chemistry, such as recrystallization, chromatography on a column, and so on.

The present compound [1] or its pharmaceutically p is Jemima salt have a strong inhibitory effect on activated factor X in the coagulation of blood and therefore, applicable to the prevention and treatment of various diseases caused by thrombus and embolus in mammals (e.g. human, monkey, rabbit, dog, cat, pig, horse, bull, mice, rats, Guinea pigs, and so forth), such diseases include, for example, stable angina, unstable angina, cerebral thrombosis, cerebral infarction, cerebral embolism, transient ischemic stroke (TIA), ischemic cerebrovascular disease, such as cerebrovascular spasm after subarachnoid hemorrhage, ischemic heart disease caused by coronary thrombogenesis arteries, congestive chronic heart failure, myocardial infarction, acute myocardial infarction, pulmonary infarction, pulmonary embolism, pulmonary vascular disorders, economy class syndrome, kidney disease (diabetic renal disease, chronic glomerulonephritis, IgA nephropathy, and so on), thromboxanes with atherosclerosis, peripheral arterial occlusion, peripheral venous occlusion disease Bugger, deep vein thrombosis, disseminated intravascular coagulation (DIC), thrombogenesis after implantation of synthetic vascular prosthesis or replacement artificial heart valve or joint, intermittent claudication, thrombogenesis and Proclus the I after reconstruction circulation, such as percutaneous transluminal coronary angioplasty (RTSA) or percutaneous transluminal restoration of patency of the coronary artery (PTCR), the system inflammatory response syndrome (SIRS), multiple organ failure (MODS), thromboxanes in artificial circulation of the blood, coagulation of blood if the blood is drawn, diabetic circulatory disturbance regime, transplant rejection, protection of the authority and functions of recovery in the case of transplantation, and so on

This connection is characterized by the fact that it has a strong inhibitory effect on activated factor X in the coagulation of blood, reduces the toxicity and causes only minor side effects (selection condensate fractions, and so on), which is noted for existing antikoaguliruyuschee funds.

When the FXa inhibitor has a small volume of distribution (therapy/blood concentrations), he basically has no side effects such as phospholipids, hepatotoxicity, and so on. Accordingly, the FXa inhibitors, especially those that have a size distribution of 0.1-3.0 l/kg and an FXa inhibitory effect with the value of the IC50equal to 100 nm or below, generally do not have side effects, such as phospholipids, hepatotoxicity, and so forth, and is useful as a drug for Thu is able to treat thrombosis. For example, TRANS-5-dimethylaminoethyl-3-[4-(N-formyl-N-methylamino)-cyclohexylcarbodiimide]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide has a volumetric distribution of 0.8 l/kg and an FXa inhibitory effects with the size of the IC50equal to a value, less than 100 nm, and can be an excellent drug mainly not having side effect, such as phospholipids, hepatotoxicity, and so on.

The FXa inhibitors with low volume of distribution, preferably have the following partial structure:

and more preferably the following partial structure:

The present compound (1) or its pharmaceutically acceptable salt can be introduced into a pharmaceutical composition comprising a therapeutically effective amount of the compound (1) and its pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include diluents, binding agents (e.g. syrup, Arabian gum, gelatin, sorbitol, tragakant, polyvinylpyrrolidone), inert fillers (e.g. lactose, sucrose, corn starch, potassium phosphate, sorbitol, aminouksusnoy acid), lubricants (e.g. magnesium stearate, talc, polyethylene glycol, silica), leavening agents (e.g., potato starch) and wetting the substances (for example, sulphate of lauryl sodium), and so on

The compound [1] of the present invention or its pharmaceutically acceptable salt can be administered orally or parenterally and be used as appropriate pharmaceuticals. Examples of appropriate medications for oral administration include obtaining solids (tablets, granules, capsules, powders, and so forth), solutions, suspensions and emulsions. Examples of appropriate medications for parenteral administration include suppositories, injections or drugs for the continuous extraction obtained using distilled water for injection, physiological salt solution or an aqueous solution of glucose, and so forth, or inhaler.

The dose of a compound [1] or its pharmaceutically acceptable salt of the present invention may vary depending on route of administration, age, weight and condition of the patient or the type or severity of disease, but it is usually in the range from approximately 0.1 to 50 mg/kg/day, preferably from about 0.1 to 30 mg/kg/day.

EXAMPLES

The present invention further discloses use of examples and comparative examples, which should not be construed as limiting the bounds of the specified inventions

Example 1: TRANS-5-methoxycarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl the Mino]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide

TRANS-4-(2-oxopyrrolidin-1-yl)cyclohexanecarbonyl acid (634 mg)obtained in example of preparation 113, dissolved in thionyl chloride (10 ml) and the mixture is stirred at room temperature for 4 hours. The reaction solution is concentrated under reduced pressure and the residue dissolved in chloroform (5 ml). The mixture is added dropwise to a suspension of 3-amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (691 mg)obtained in example of preparation 72, in pyridine (15 ml) under cooling with ice. After adding the reaction solution warmed to room temperature and then stirred for 17 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: chloroform), which gives the named compound (785 mg). APCI-MS M/E: 539/541 [M+H]+.

Example 2: TRANS-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl]-5-methoxycarbonylmethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-(N-acetyl-N-methylamino)cyclohexanecarbonyl acid (1.80 g)obtained in which the Rimera cooking 114, dissolved in thionyl chloride (20 ml) and the mixture is stirred at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure and the residue dissolved in chloroform (70 ml) and add 3-amino-5-methoxycarbonylmethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.20 g)obtained in example of preparation 73, while cooling with ice. To the mixture add additional pyridine (4,95 ml) and the reaction solution is heated to room temperature and stirred for 3 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: n-hexane/ethyl acetate =1/1, then ethyl acetate), giving a named connection (2,97 g). APCI-MS M/E: 541/543 [M+H]+.

Example 3: 3-[2-(1-Isopropylpiperazine-4-yl)acetylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

Hydrochloride (1-isopropylpiperazine-4-yl)acetic acid (432 mg)obtained in example of preparation 129, dissolved in thionyl chloride (5 ml) and the mixture is stirred at room temperature for 3 hours. T is oneshare is evaporated under reduced pressure and the obtained residue was dissolved in dichloromethane (10 ml) and cooled with ice. To this solution was added 3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (374 mg)obtained in example of preparation 74, and pyridine (420 μl) and the reaction solution is heated to room temperature and stirred for 3 hours. In the reaction solution is added water and a saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: chloroform, then chloroform/methanol =10/1, then 6/1), which gives 3-[2-(1-isopropylpiperazine-4-yl)acetylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (489 mg), which is then dissolved in dichloromethane (10 ml) and added dropwise 4N hydrogen chloride in dioxane (5 ml) and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure and the resulting residue suspended in a mixture of methanol-chloroform. Precipitation is collected by filtration, giving the named compound (423 mg). APCI-MS M/E: 455/457 [M+H]+.

Examples 4-75

The corresponding amino compounds and compounds of carboxylic acid is treated with a method similar to that described in example 1, example 2 or example 3, which gives further connections to free the nom, which is then treated with hydrogen chloride, which leads to the formation of their hydrochloride.

Example 76: 3-[(1-Isopropylpiperazine-4-yl)carbylamine]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-Amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (201 mg)obtained in example of preparation 74, dissolved in N,N-dimethylformamide (6 ml) and successively added hydrochloride (1-isopropylpiperazine-4-yl) carboxylic acid (199 mg)obtained in example of preparation 130, 4-dimethylaminopyridine (137 mg) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (203 mg), after which the mixture is stirred at a temperature 60°C for 4 hours. The reaction solution was diluted with ethyl acetate and water and poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is raybaut water and saturated brine, dried over sodium sulfate and passed through a bed of NH-silica gel. The solvent is evaporated under reduced pressure and the resulting residue purified HPLC recycle and suspended in a mixture of diethyl ether/n-hexane. Precipitation is collected by filtration, giving the named compound (174 mg). APCI-MS M/E: 441 [M+H]+.

Example 77: TRANS-5-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-5-methoxycarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (710 mg)obtained in example 1 are suspended in a mixture of tetrahydrofuran-methanol (1:1, 10 ml) and added 4N aqueous sodium hydroxide solution (2 ml) under cooling with ice. The mixture is heated to room temperature and stirred for 18 hours. The reaction solution is concentrated under reduced pressure and poured onto ice water and the mixture is neutralized with 10% hydrochloric acid. Precipitation is collected by filtration, washed with water and dried, giving a named connection (655 mg).

ESI-MS M/E: 523/525 [M-N]-.

Examples 78-86

The corresponding esters of carboxylic acid is treated in a manner analogous manner as in example 77, which provides the following compounds in a free form, which is then treated with hydrogen chloride, which gives g is drochloride.

Example 87: TRANS-5-(morpholine-4-ylcarbonyl)-3-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-5-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (830 mg)obtained in example 77, suspended in N,N-dimethylformamidine (1:1, 30 ml) and added dropwise sequentially morpholine (196 mg), 1-hydroxybenzotriazole (406 mg) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (576 mg) under cooling ice, after which the mixture was stirred at room temperature for 17 hours. In the reaction solution is poured onto ice water and saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over sodium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of NH-silica gel (eluent: chloroform). The precipitate is suspended in a mixture of ethyl acetate-n-hexane and the precipitates are collected by filtration and dried, giving the named compound (805 mg). APCI-MS M/E: 594/596 [M+H]+.

Examples 88-143

Appropriate connections are treated the way analogichnymi in example 87, that gives the following compounds in a free form, which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 144: TRANS-5-(4,5-dihydrooxazolo-2-yl)-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-5-carboxy-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (220 mg)obtained in example 78, suspended in pyridine (3 ml) and added sequentially 2-bromide of bromadiolone (125 mg), a solution of 1.0 M 1-hydroxy-benzotriazole-N,N-dimethyl-formamide (600 μl) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (115 mg) under ice cooling, and the mixture is stirred at room temperature for 2.5 days. The reaction solution was poured into ice water and saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica compound is El (eluent: chloroform, then chloroform/ethyl acetate =4/1) and the resulting residue is suspended in diisopropyl ether. Precipitation is collected by filtration and dried, giving the named compound (117 mg). APCI-MS M/E: 510/512 [M+H]+.

Example 145: TRANS-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl]-5-(2-hydroxyethyl)-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide

TRANS-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl]-5-methoxycarbonylmethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2,95 g)obtained in example 2, are suspended in tetrahydrofuran (65 ml) and add lithium borohydride (238 mg), then the mixture is stirred at room temperature for 12 hours. In the reaction solution pour in 10% hydrochloric acid under ice cooling and the mixture is stirred at room temperature for 15 minutes. Then the reaction solution is neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: ethyl acetate and then chloroform/methanol =40/1) and the precipitate is suspended in diethyl ether. Precipitation is collected by filtration, giving a named connection (2.24 g) APCI-MS M/E: 513/515 [M+H] +.

Examples 146-149

The corresponding compounds are treated in a manner analogous to the one described in example 145, which gives further compounds in free form, which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 150: TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-hydroxymethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride

TRANS-5-carboxy-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (243 mg)obtained in example 78, suspended in thionyl chloride (2.5 ml) and the mixture is stirred at room temperature for 10 minutes, then stirred at a temperature of 50°C for 10 minutes. The mixture is cooled to room temperature and again stirred for one hour. The reaction solution is concentrated to dryness under reduced pressure. The precipitate is suspended in a mixture of tetrahydrofuran/chloroform (2:1, 15 ml), add sodium borohydride (150 mg) and the mixture is stirred at room temperature overnight. Then, the reaction solution is poured onto 1N hydrochloric acid under ice cooling and the mixture is stirred for 0.5 hour. Then poured onto saturated aqueous sodium hydrogen carbonate solution, whereupon the mixture is extracted with chloroform. Organicheskikh washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: chloroform and then a mixture of chloroform/methanol =200/1), which gives TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-hydroxymethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (46 mg). This product is dissolved in chloroform (1 ml) and added 2N hydrogen chloride in methanol (0.1 ml) and the reaction solution was concentrated under reduced pressure. The precipitate is suspended in a mixture of ethyl acetate-methanol, and the precipitates are collected by filtration and dried, giving the named compound (45 mg). APCI-MS M/E: 471/473 [M+H]+.

Example 151: TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-6-hydroxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride

To a suspension of TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-6-methoxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (473 mg)obtained in example 23, in dichloromethane (20 ml) is added dropwise tribromide boron (3.5 g) for 2 minutes at a temperature of -78°C. the Mixture is stirred at room temperature for 4 days and the reaction solution was poured into ice water, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with a mixture solvent of the ethyl acetate-tetrahydro is furan. The organic layer was washed with saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The precipitate is suspended in a mixture of chloroform/diethyl ether and the precipitates are collected by filtration and dried, giving TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-6-hydroxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (335 mg). This product (48 mg) is suspended in methanol and treated with 4N hydrogen chloride in dioxane, which gives the named compound (54 mg).

APCI-MS M/E: 457/459 [M+H]+.

Example 152: TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-hydroxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride

TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-metiloksi-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (473 mg)obtained in example 19 is treated with a method similar to that described in example 151, which gives the named compound (33 mg). APCI-MS M/E: 457/459 [M+H]+.

Example 153: TRANS-6-tert-butoxycarbonylmethyl-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-6-hydroxy-N-(5-chloro-pyridine-2-yl)benzofuran-2-carboxamide (90 mg)obtained in example 151, dissolved in N,N-dimethylformamide (2 ml) and add a carb is NAT cesium (110 mg) and bromoacetic tert-butyl (35,5 µl). The mixture is stirred at room temperature for 12 hours and then stirred at a temperature of 50°C for 2.5 hours. The reaction solution allow to stand to cool, and then diluted with water and extracted with ethyl acetate. The organic layer is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of NH-silica gel (eluent: hexane/ethyl acetate =1/1, then ethyl acetate), giving the named compound (21 mg). APCI-MS M/E: 571/573 [M+H]+.

Examples 154-155

TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-6-hydroxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide obtained in example 151, and the corresponding starting compound is treated with a method similar to that described in example 153, which gives further compounds in free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 156: TRANS-6-carboxymethoxy-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride

TRANS-6-tert-butoxycarbonylmethylene-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (21 mg)obtained in example 153, suspended in a mixture of 4N hydrogen chloride in dioxane is (8 ml) and the mixture is stirred at room temperature for 28 hours. The reaction solution was diluted with diethyl ether and the precipitates are collected by filtration, washed several times with diethyl ether and dried, giving the named compound (17 mg). APCI-MS M/E: 515/517 [M+H]+.

Example 157: TRANS-5-carboxymethoxy-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride

TRANS-5-tert-butoxycarbonylmethyl-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (1.92 g)obtained in example 31, was dissolved in 6N hydrochloric acid (40 ml) and the mixture is stirred at room temperature for 2 hours. In the reaction solution is added isopropanol (100 ml) and precipitated precipitated solid is collected by filtration, washed with isopropanol and diethyl ether and dried under reduced pressure, giving the named compound (1.86 g). APCI-MS M/E: 515/517 [M+H]+.

Examples 158-179

TRANS-5-carboxymethoxy-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride obtained in example 157, and the corresponding starting compound, is treated with a method similar to that described in example 87, which gives further compounds in free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 180: TRANS-5-amino-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-nitro-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (3.00 g)obtained in example 18, is suspended in ethanol (100 ml) and added tin chloride(II) (anhydrous) (7,02 g) and water (1.0 ml). The mixture is heated at the boiling point under reflux for 7 hours and allow to stand to cool. In the reaction solution was added 10% aqueous sodium hydroxide solution (30 ml) and tetrahydrofuran (200 ml) and the mixture is stirred at room temperature for one hour. Insoluble products is filtered through celite, the filtrate concentrated under reduced pressure and purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate =1/1, then chloroform/ethyl acetate =1/1). The precipitate is suspended in a mixture of ethyl acetate/n-hexane and the precipitates are collected by filtration and dried, giving TRANS-5-amino-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (1,43 g). This product (35 mg) is dissolved in ethanol and treated with 4N hydrogen chloride/ethyl acetate, giving called EDINENIE (43 mg). APCI-MS M/E: 456/458 [M+H]+.

Example 181: TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-methylamino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

In TRANS-5-[N-(benzyloxycarbonyl)-N-methylamino]-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg)obtained in example 22, add 30% hydrogen bromide in acetic acid (2 ml) and the mixture is stirred at room temperature for 2 hours. In the reaction solution was added diethyl ether (20 ml) and the precipitates are collected by filtration and suspended in a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure, which gives TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-methylamino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide. Then this product is dissolved in ethanol and treated with 4N hydrogen chloride in ethyl acetate, which gives the named compound (88 mg). APCI-MS M/E: 470/472 [M+H]+.

Example 182: TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-(2-methylamino-ethoxy)-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide trihydrochloride

TRANS-5-[2-(N-tert-butoxycarbonyl-N-methylamino)ethoxy]-3-[4-(is metilamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (300 mg), obtained in example 36, was dissolved in dioxane (5 ml) and added dropwise 4N hydrogen chloride in dioxane (10 ml) and the mixture is stirred at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is suspended in diethyl ether. Precipitation is collected by filtration and dried, giving the named compound (301 mg). APCI-MS M/E: 514/516 [M+H]+.

Example 183: TRANS-5-(2-aminoketone)-3-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

TRANS-5-[2-(tert-butoxycarbonylamino)ethoxy]-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (250 mg)obtained in example 10, is treated with a method similar to that described in example 182, which gives the named compound (334 mg). APCI-MS M/E: 556/558 [M+H]+.

Example 184: TRANS-5-methoxyethylamine-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide hydrochloride

TRANS-5-amino-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg)obtained in example 180, suspended in N,N-dimethylformamide (6 ml) and add sequentially methoxybutanol acid (23 mg), 1-hydroxybenzotriazole (39 mg) and 1-the Teal-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (55 mg) under ice cooling and the mixture is stirred at room temperature for 17 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of NH-silica gel (eluent: chloroform, then chloroform/methanol =30/1), which gives TRANS-5-methoxyethylamine-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide. Then this product is dissolved in ethanol and treated with 4N hydrogen chloride in ethyl acetate, which gives the named compound (84 mg).

APCI-MS WE: 528/530 [M+H]+.

Examples 185-188

TRANS-5-amino-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide obtained in example 180, and the corresponding starting compound is treated in a manner analogous to the one described in example 184, the compounds in free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 189: TRANS-5-acetoxyacetyl-3-[4-(dimethylamino)-cyclohexylcarbodiimide]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide hydrochloride

TRANS-5-amino-3-[4-(dimethylamino)cyclohexyl is Beniamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg), obtained in example 180, dissolved in dichloromethane (8 ml) and add acetoxyacetyl (36 mg) and pyridine (36 μl) under ice cooling, after which the mixture was stirred at room temperature for 17 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: chloroform, then chloroform/methanol =50/1), which gives TRANS-5-acetoxyacetyl-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (110 mg). Part of this product is dissolved in ethanol and treated with 4N hydrogen chloride in ethyl acetate, which gives titled compound (16 mg). APCI-MS M/E: 556/558 [M+H]+.

Examples 190-196

The corresponding compounds are treated in a manner analogous to the one described in example 189, which gives further compounds in free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 197: TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-hydroxyacyl-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxyhemoglobin

TRANS-5-acetoxyacetyl-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (70 mg)obtained in example 189, dissolved in a mixture of tetrahydrofuran/methanol (1:1.8 ml) and add potassium carbonate (5 mg) and the mixture is stirred at room temperature for 48 hours. The reaction solution is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: chloroform/methanol =30/1). The resulting TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-hydroxyacyl-amino-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide dissolved in ethanol and treated with 4N hydrogen chloride in ethyl acetate, which gives the named compound (46 mg). APCI-MS M/E: 514 [M+H]+.

Example 198: TRANS-5-dimethylamino-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

TRANS-5-amino-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (50 mg)obtained in example 180, suspended in dichloromethane (3 ml) and add sequentially 35% aqueous formaldehyde solution (82 ml) and triacetoxyborohydride sodium (70 mg) under ice cooling. The reaction solution is heated to room temperature and stirred at Uchenie 11.5 hours. In the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution under ice cooling and the mixture is extracted with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: ethyl acetate), giving TRANS-5-dimethylamino-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (44 mg). This product is suspended in methanol and treated with 4N hydrogen chloride in ethyl acetate, which gives the named compound (49 mg). APCI-MS M/E: 528/530 [M+H]+.

Examples 199-200

TRANS-5-amino-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide obtained in example 180, and the corresponding starting compound is treated in a manner analogous to the one described in example 198, which gives further compounds in free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 201: TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-(2-hydroxy-1-hydroxyethyloxy)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-(2-FeNi is-[1,3]dioxane-5-yloxy)-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (200 mg), obtained in example 35, was dissolved in tetrahydrofuran (5 ml) and added 2N hydrochloric acid (5 ml), after which the mixture was stirred at room temperature for 3 hours. The reaction solution is alkalinized with a saturated aqueous solution of sodium bicarbonate and potassium carbonate and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: methanol/ethyl acetate =1/20 → methanol/ethyl acetate =1/5), which gives TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-5-(2-hydroxy-1-hydroxyethyloxy)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (162 mg). This product is dissolved in methanol and added dropwise 4N hydrogen chloride in ethyl acetate (1 ml). The solvent is evaporated under reduced pressure and the resulting residue is suspended in diethyl ether and the precipitates are collected by filtration, giving the named compound (141 mg).

APCI-MS M/E: 531/533 [M+H]+.

Example 202: TRANS-3-[4-(N-tert-butoxycarbonyl-N-methylamino)-cyclohexylcarbodiimide]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-(N-tert-butoxycarbonyl-N-methylamino)-cyclohexane-carboxylic acid (4.12 g)obtained in example the cooking is 115, dissolved in dichloromethane (80 ml) and added dropwise pyridine (7.9 ml). Then the mixture was added dropwise thionyl chloride (1,04 ml) under ice cooling and the mixture is stirred at room temperature for 3 hours. The reaction solution is concentrated and to the resulting precipitate added sequentially pyridine (80 ml), 3-amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.76 g)obtained in example of preparation 72, and 4-dimethylaminopyridine (195 mg) under ice cooling. The reaction solution is heated to room temperature and stirred for 17 hours. In the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution and precipitates are collected by filtration, washed successively with water and diethyl ether and dried, giving a named connection (4,63 g). APCI-MS M/E: 585 [M+H]+.

Example 203: TRANS-3-[4-(tert-butoxycarbonylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-(tert-butoxycarbonylamino)cyclohexanecarbonyl acid (2,54 g)obtained in example of preparation 116, dissolved in dichloromethane (50 ml) and added dropwise pyridine (4,22 ml) and the mixture is cooled with ice. To the mixture is added dropwise thionyl chloride (0,76 ml), after which the mixture was stirred at room temperature for 5 hours. The reaction solution was again cooled l is ω and add 3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.00 g), obtained in example of preparation 74, and dichloromethane (20 ml) and the mixture is stirred at room temperature for 15 hours. In the reaction solution is poured onto water and the mixture extracted with chloroform. The organic layer is washed successively with water, 5% aqueous solution of citric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: chloroform) and suspended in diethyl ether. Precipitation is collected by filtration, giving a named connection (2,94 g). APCI-MS M/E: 513/515 [M+H]+.

Examples 204-217

The corresponding starting compound is treated in a similar way to example 202 or example 203, which provides the following connections.

Example 218: TRANS-5-methoxycarbonyl-3-[4-(methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride

TRANS-3-[4-(N-tert-butoxycarbonyl-N-methylamino)cyclohexylcarbonyl]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (4,60 g)obtained in example 202, dissolved in dioxane (20 ml) and add recipients who have 4N hydrogen chloride in dioxane (10 ml), then the mixture is stirred at room temperature for 48 hours. The reaction solution was diluted with diethyl ether and the precipitates are collected by filtration, washed several times with diethyl ether and dried, giving a named connection (as 4.02 g). APCI-MS M/E: 485/487 [M+H]+.

Example 219: TRANS-3-(4-aminocyclohexanecarboxylic)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

TRANS-3-[4-(tert-butoxycarbonylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (10,70 g)obtained in example 203, dissolved in dioxane (150 ml) and added dropwise 4N hydrogen chloride in dioxane (150 ml). The mixture is stirred at room temperature for 12 hours and concentrated under reduced pressure. The precipitate is ground up in diethyl ether and collected by filtration, giving a named connection (9.80 g). APCI-MS M/E: 412/414 [M+H]+.

Example 220: 3-[2-(piperidine-4-yl)acetylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-[2-(1-tert-Butoxycarbonylamino-4-yl)acetylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2,34 g)obtained in example 212, suspended in ethyl acetate (30 ml) and add 2,6N hydrogen chloride in ethyl acetate (30 ml) and the mixture is stirred at room temperature for 5 hours. The reaction solution concentration is irout under reduced pressure and the obtained residue add chloroform and an aqueous solution of sodium bicarbonate. Precipitation is collected by filtration, giving the named compound (1.47 g). APCI-MS M/E: 413/415 [M+H]+.

Examples 221-233

The corresponding starting compound is treated in a manner analogous to the one described in example 218, the example 219 or in example 220, that gives further compounds in free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 234: TRANS-3-[4-(N-formyl-N-methylamino)cyclohexylcarbonyl]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

To a solution of imidazole (783 mg) and triethylamine (2,41 ml) in chloroform (80 ml) is added dropwise formic acid (709 ml) with stirring under ice cooling. Then add oxalicacid (1,00 ml) in chloroform (10 ml) and the mixture is stirred at room temperature for 0.5 hours. The reaction solution was again cooled with ice and add TRANS-5-methoxycarbonyl-3-[4-(methylamino)-cyclohexylcarbodiimide]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride (1.50 g)obtained in example 218. The mixture is heated to room temperature and stirred for 3 hours. In the reaction solution is poured onto ice water and saturated aqueous solution of sodium bicarbonate and CME is ü extracted with chloroform. The extract was washed with saturated brine and dried over sodium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of NH-silica gel (eluent: chloroform), which gives the named compound (1.45 g). APCI-MS M/E: 513/515 [M+H]+.

Examples 235-238

The corresponding starting compound is treated with a method similar to that described in example 234, which provides the following connections.

Example 239: TRANS-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-5-methoxycarbonyl-3-[4-(methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride (1.50 g)obtained in example 218, suspended in dichloromethane (80 ml) and add acetylchloride (307 μl) and triethylamine (1.60 ml) under cooling with ice. The mixture is heated to room temperature and stirred for 2 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform, washed with water and saturated brine and dried over sodium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of NH-silica gel (eluent: chloroform),which gives the named compound (1.51 g). APCI-MS M/E: 527/529 [M+H]+.

Example 240: 3-[(1-Acetylpiperidine-4-yl)carbylamine]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-[(piperidine-4-yl)carbylamine]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (140 mg)obtained in example 228, suspended in dichloromethane (10 ml) and add acetylchloride (30 μl) and triethylamine (74 Il) under ice cooling and the mixture is stirred at room temperature for 6 hours. The reaction solution was diluted with chloroform, washed successively with water, 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine and dried over sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate and treated with activated carbon. The precipitate is recrystallized from ethyl acetate, giving the named compound (38 mg). APCI-MS M/E: 441/443 [M+H]+.

Examples 241-245

The corresponding starting compound is treated in a manner analogous to the one described in example 239 or in example 240, which gives further compounds in free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 246: TRANS-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl]-5-(2-methoxyethoxy)-N-(5-chloro what iridin-2-yl)benzofuran-2-carboxamide

TRANS-5-(2-methoxyethoxy)-3-[4-(methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride (110 mg)obtained in example 223, suspended in N,N-dimethylformamide (5 ml) and added sequentially acetic acid (13,2 μl), 1-hydroxybenzotriazole (31 mg), triethylamine (80 μl) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg) and the mixture is stirred at room temperature for 15 hours. In the reaction solution is added acetic acid (8,2 μl), 1-hydroxybenzotriazole (20 mg), triethylamine (67 μl) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28 mg) and the mixture is then stirred at room temperature for 20 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: n-hexane/ethyl acetate =1/1, then ethyl acetate). The obtained solid is suspended in a mixture of n-hexane/diisopropyl ether and collected by filtration, giving the named compound (42 mg). APCI-MS M/E: 543/545 [M+H]+.

Example 247: 3-[1-((Pyridin-3-yl)carbonyl)piperidine-4-yl-CARBONYLS is but]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

3-[(piperidine-4-yl)carbylamine]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg)obtained in example 228, dissolved in N,N-dimethylformamide (3 ml) and add sequentially nicotinic acid (34 mg), 1-hydroxybenzotriazole (37 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg) and the mixture is stirred at room temperature for 4 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and water and precipitates are collected by filtration, washed with chloroform and dried, giving 3-[1-((pyridin-3-yl)carbonyl)piperidine-4-ylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (103 mg). This product is treated with hydrogen chloride in dioxane, which gives the named compound (115 mg). APCI-MS M/E: 504/506 [M+H]+.

Examples 248-257

The corresponding starting compound is treated in a manner analogous to the one described in example 246 or in example 247, which provides the following compounds in a free form, or which is treated with hydrogen chloride, which gives them hydrochloride.

Example 258: TRANS-5-carboxy-3-[4-(N-formyl-N-methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-3-[4-(N-formyl-N-methylamino)cycle is paxilonline]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (1,90 g), obtained in example 234, suspended in a mixture of tetrahydrofuran/methanol (1:1, 50 ml) and added 4N aqueous sodium hydroxide solution (5 ml) under cooling with ice. The mixture is heated to room temperature and stirred for 17 hours. The reaction solution is concentrated under reduced pressure and the residue poured onto ice water and the mixture is neutralized with 10% hydrochloric acid solution. Precipitation is collected by filtration, washed successively with water and tetrahydrofuran, and dried, giving a named connection (1,59 g). ESI-MS M/E: 497/499 [M-N]-.

Examples 259-260

The corresponding starting compound is treated in a manner analogous to the one described in example 258, which gives further compounds in free form, or which is treated with hydrogen chloride, which gives them hydrochloride.

Example 261: TRANS-5-dimethylaminoethyl-3-[4-(N-formyl-N-methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-5-carboxy-3-[4-(N-formyl-N-methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (196 mg)obtained in example 258, suspended in a mixture of N,N-dimethylformamide/pyridine (1:1, 8 ml) and added dropwise successively dimethylaminohydrolase (49 mg), 1-hydroxybenzotriazole (108 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbody the MFA hydrochloride (153 mg) under ice cooling and the mixture is stirred at room temperature for 48 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The extract is washed with water and saturated brine, dried over sodium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of NH-silica gel (eluent: ethyl acetate). The precipitate is suspended in a mixture of diethyl ether/n-hexane and the precipitates are collected by filtration, giving the named compound (141 mg). APCI-MS M/E: 526/528 [M+H]+.

Examples 262-275

The corresponding starting compound is treated in a manner analogous to the one described in example 261, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Examples 276-277

The corresponding starting compound is treated in a manner analogous to the one described in example 145, which provides the following connections.

Example 278: TRANS-3-[4-(N-(2-hydroxyethyl)-N-methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

TRANS-3-[4-(methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carbox the amide (125 mg), obtained in example 221 is suspended in ethanol (5 ml) and add 2-ionatana (105 μl) and sodium carbonate (57 mg) and the mixture is stirred at a temperature of 50°C for 15 hours. To the mixture add additional 2-iodine-ethanol (53 ml) and the mixture is then stirred at a temperature of 80°C for 6 hours. In the mix again add 2-ionatana (53 μl) and the mixture is stirred at a temperature of 80°C for 24 hours. The reaction solution is concentrated under reduced pressure and the residue is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is washed with water, saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: a mixture of n-hexane/ethyl acetate =1/2, then ethyl acetate), which gives TRANS-3-[4-(N-(2-hydroxyethyl)-N-methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (53 mg). Then this product is dissolved in a mixture of chloroform/methanol (5/1, 6 ml) and added dropwise 4N hydrogen chloride in ethyl acetate (1 ml). The solvent is evaporated under reduced pressure. The precipitate is suspended in diethyl ether and collected by filtration, giving the named compound (55 mg). APCI-MS M/E: 471/473 [M+H]+.

Example 279: 3-[[1-((Pyridin-4-yl)methyl)piperidine-4-yl]it is Beniamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-(piperidine-4-yl)carbylamine)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg)obtained in example 228, suspended in N,N-dimethylacetamide (3 ml) and add the hydrochloride of 4-(chloromethyl)pyridine (45 mg), sodium carbonate (80 mg) and sodium iodide (41 mg), after which the mixture was stirred at room temperature for 12 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated brine and dried over sodium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of NH-silica gel (eluent: a mixture of n-hexane/ethyl acetate =2/1 then 1/1), which gives the named compound (109 mg). APCI-MS M/E: 490/492 [M+H]+.

Examples 280-289

The corresponding starting compound is treated in a manner analogous to the one described in example 278, or in the example 279, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 290: TRANS-3-[4-(2-hydroxyethylamino)cyclohexylcarbonyl]-N-(4-chlorophenyl)benzofuran-2-carboxamide hydrochloride

TRANS-3-[4-aminotic is hexylcaine]-N-(4-chlorophenyl)benzofuran-2-carboxamide hydrochloride (150 mg), obtained in example 225, suspended in a mixture of acetonitrile/methanol (5/1, 6 ml) and add triethylamine (93 μl), after which the mixture was stirred at room temperature for a few minutes. The reaction solution is cooled with ice and add 2-ionatana (29 μl) and the mixture is stirred at a temperature of 50°C for 3 hours. Then add another portion of 2-idechannel (58 μl) and the mixture is stirred at a temperature of 50°C for 3 hours. Again to the reaction mass is added 2-ionatana (58 μl) and the mixture is then stirred at a temperature of 50°C for 15 hours. The reaction solution is concentrated under reduced pressure and the residue poured water and a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is washed with water and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: ethyl acetate, then ethyl acetate/methanol =20/1), which gives TRANS-3-[4-(2-hydroxyethylamino)cyclohexylcarbonyl]-N-(4-chlorophenyl)benzofuran-2-carboxamide (104 mg). This product (104 mg) dissolved in a mixture of chloroform/methanol (5/1, 6 ml) and added dropwise 4N hydrogen chloride in ethyl acetate (1 ml). The solvent is evaporated under reduced pressure and the resulting residue is suspended in Diatlov the m ether and collected by filtration, that gives the named compound (95 mg).

APCI-MS M/E: 456/458 [M+H]+.

Examples 291-296

The corresponding starting compound is treated in a manner analogous to the one described in example 290, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 297: TRANS-3-[4-(morpholine-4-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

TRANS-3-[4-aminocyclohexanecarboxylic]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride (200 mg)obtained in example 219, suspended in N,N-dimethylacetamide (10 ml) and added dropwise bis(2-chloroethyl)ether (73 μl), sodium iodide (185 mg) and sodium carbonate (131 mg) and the mixture is stirred at a temperature of 50°C for 5 hours and then stirred at a temperature of 89°C for 3 hours. Then add bis(2-chloroethyl)ether (73 μl) and the mixture is stirred at a temperature of 80°C for 15 hours. The reaction solution is concentrated under reduced pressure and the residue is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is washed with water and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. Received wasp is OK purified using chromatography on a column of NH-silica gel (eluent: a mixture of n-hexane/ethyl acetate =5/1, then 1/1), which gives TRANS-3-[4-(morpholine-4-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (70 mg). Then this product is dissolved in a mixture of chloroform/methanol (5/1, 6 ml) and added dropwise 4N hydrogen chloride in ethyl acetate (1 ml) and the solvent is evaporated under reduced pressure. The precipitate is suspended in diethyl ether and collected by filtration, giving the named compound (65 mg). APCI-MS M/E: 483/485 [M+H]+.

Examples 298-301

The corresponding starting compound is treated in a manner analogous to the one described in example 297, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 302: TRANS-3-[4-(N-carboxymethyl-N-methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

TRANS-3-[4-(N-tert-butoxycarbonylmethyl-N-methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (820 mg)obtained in example 293, process, method, similar to that described in example 156, which gives the named compound (778 mg). ESI-MS M/E: 507/509 [M+Na]+.

Examples 303-305

TRANS-3-[4-(N-carboxymethyl-N-methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride, receiving the hydrated in example 302, process method, similar to that described in example 87, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 306: TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride

TRANS-3-(4-aminocyclohexanecarboxylic)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride (of 9.30 g)obtained in example 219, suspended in dichloromethane (430 ml) and add triethylamine (7,99 ml) under ice cooling and the mixture is stirred for several minutes. Then to the reaction mixture are added 35% aqueous formaldehyde solution (to 7.59 ml) and triacetoxyborohydride sodium (12,10 g) and the reaction solution is heated to room temperature and stirred for 12 hours. In the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution under ice cooling and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue purified by chromatography on a column of NH-silica gel (eluent: a mixture of n-hexane/ethyl acetate =3/1, then ethyl acetate), which gives TRANS-3-[4-(Dima is ylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (6,92 g). This product is dissolved in a mixture of chloroform/methanol (5/1, 60 ml) and added dropwise 4N hydrogen chloride in ethyl acetate (50 ml) under cooling with ice. The reaction solution is concentrated under reduced pressure and the resulting residue is suspended in diethyl ether and collected by filtration, giving a named connection (7,83 g). APCI-MS M/E: 441/443 [M+H]+.

Example 307: TRANS-3-[4-[N-[3-(tert-butoxycarbonylamino)propyl]-N-methylamino]cyclohexylcarbodiimide]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-3-[4-(methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (250 mg)obtained in example 221, suspended in dichloromethane (8 ml) and added to the mixture of 3-tert-butoxycarbonylamino (198 mg) and triethylamine (160 μl) under ice cooling and the mixture is stirred for several minutes. Then add triacetoxyborohydride sodium (243 mg) and the reaction solution is heated to room temperature and stirred for 4 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate under ice cooling and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The precipitate is cleaned by chromatography is on a column of NH-silica gel (eluent: a mixture of n-hexane/ethyl acetate =3/1, then 1/1), which gives the named compound (312 mg).

APCI-MS M/E: 584/586 [M+H]+.

Examples 308-326

The corresponding starting compound is treated in a manner analogous to the one described in example 306, or in example 307, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 327: TRANS-3-[4-[N-[3-(dimethylamino)propyl]-N-methylamino]cyclohexylcarbodiimide]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide trihydrochloride

(1) 3-Aminopropionitrile diethylacetal (5,00 g) dissolved in dichloromethane (70 ml) and added to the mixture sequentially 35% aqueous formaldehyde solution (13.5 ml) and triacetoxyborohydride sodium (18.0 g) under ice cooling and the reaction solution is heated to room temperature and stirred for 6 hours. In the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution under ice cooling and then add the potassium carbonate. The mixture is extracted with chloroform and the organic layer was washed with saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure, giving crude 3-(dimethylamino)Propionaldehyde diethylacetal (5.31g).

(2)3-(dimethylamino)Propionaldehyde diethylacetal (284 mg), obtained in example 327-(1), dissolved in tetrahydrofuran (3 ml) and to the solution was added concentrated hydrochloric acid (3 ml), after which the mixture was stirred at room temperature for 15 hours. The reaction solution is concentrated to dryness under reduced pressure and the obtained residue was dissolved in dichloromethane (7 ml). Add TRANS-3-[4-(methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (150 mg)obtained in example 221, and triethylamine (226 μl) and the mixture is stirred for several minutes. Then to the mixture add triacetoxyborohydride sodium (137 mg) and the reaction solution is heated to room temperature and stirred for 15 hours. In the reaction solution was added saturated aqueous sodium hydrogen carbonate solution under ice cooling and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: ethyl acetate and then a mixture of ethyl acetate/methanol =20/1), which gives TRANS-3-[4-[N-[3-(dimethylamino)propyl]-N-methylamino]cyclohexylcarbodiimide]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (99 mg). Then this product is dissolved in a mixture of chloroform/methanol (5/1, 6 ml) and add the 4N hydrogen chloride in ethyl acetate (1 ml), then the solvent is evaporated under reduced pressure. The precipitate is suspended in diethyl ether and collected by filtration, giving the named compound (106 mg). APCI-MS M/E: 512/514 [M+H]+.

Examples 328-332

The corresponding starting compound is treated in a manner analogous to the one described in example 327, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 333: TRANS-3-[4-(piperidine-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

TRANS-3-(4-aminocyclohexanecarboxylic)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride (125 mg)obtained in example 219, suspended in dichloromethane (10 ml) and the mixture added triethylamine (102 μl) under ice cooling, after which the mixture is stirred for several minutes. Then add about 25% aqueous solution of glutaraldehyde (150 mg) and triacetoxyborohydride sodium (155 mg), the mixture is stirred under ice cooling for 2 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over Sul is the sodium atom and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: n-hexane/ethyl acetate =3/1, then 1/1), which gives TRANS-3-[4-(piperidine-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (106 mg). Then this product is dissolved in a mixture of chloroform/methanol (5/1, 6 ml) and added dropwise 4N hydrogen chloride in ethyl acetate (5 ml) under cooling with ice. The reaction solution is concentrated under reduced pressure and the resulting residue is suspended in diethyl ether and collected by filtration, giving the named compound (107 mg).

APCI-MS M/E: 481/483 [M+H]+.

Example 334: TRANS-3-[4-(N-acetyl-N-isopropylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-3-[4-(isopropylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg)obtained in example 310, and triethylamine (61 μl) dissolved in chloroform (5 ml) and the mixture was added acetylchloride (24 μl). The mixture is stirred at room temperature for one hour and poured onto saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The precipitate is cleaned by chromatography is on a column of silica gel (eluent: a mixture of n-hexane/ethyl acetate =1/1, then ethyl acetate). The precipitate is suspended in n-hexane and collected by filtration, giving the named compound (60 mg). APCI-MS M/E: 497/499 [M+H]+.

Example 335: TRANS-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-3-(4-aminocyclohexanecarboxylic)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride (150 mg)obtained in example 219, suspended in dichloromethane (5 ml) and add triethylamine (129 μl) under ice cooling and the mixture is stirred for several minutes. Then add a 15% aqueous solution of amber tolualdehyde (290 μl) and triacetoxyborohydride sodium (131 mg) and under ice cooling, the mixture is stirred for 0.5 hour. Then successively added 1-hydroxybenzotriazole (63 mg), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (118 mg) and N,N-dimethylformamide (3 ml) and the mixture is stirred at room temperature for 15 hours. The reaction solution is concentrated under reduced pressure and poured the chloroform. The mixture is washed successively with a saturated aqueous solution of sodium bicarbonate, water and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of N-silica gel (eluent: a mixture of n-hexane/ethyl acetate =1/1, then ethyl acetate) and the resulting residue is suspended in n-hexane and collected by filtration, giving the named compound (29 mg). APCI-MS M/E: 481/483 [MH-H]+.

Example 336: TRANS-3-[4-(tert-butoxycarbonylamino)cyclohexylcarbonyl]-5-carboxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-3-[4-(tert-butoxycarbonylamino)cyclohexylcarbonyl]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (540 mg)obtained in example 209, process, method, similar to that described in example 77, which gives the named compound (475 mg). ESI-MS M/E: 555/557 [M-N]-.

Example 337: TRANS-3-[4-(N-tert-butoxycarbonyl-N-methylamino)cyclohexylcarbonyl]-5-carboxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-3-[4-(N-tert-butoxycarbonyl-N-methylamino)cyclohexylcarbonyl]-5-methoxycarbonyl-N-5-chloropyridin-2-yl)benzofuran-2-carboxamide (3,52 g)obtained in example 202, process, method, similar to that described in example 77, which gives a named connection (3,19 g). ESI-MS M/E: 569/571 [M-N]-.

Examples 338-340

The corresponding starting compound is treated in a manner analogous to the one described in example 87, which provides the following connections.

Examples 341-344

The corresponding source connecting the handle means, similar to that described in example 218, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 345: TRANS-5-dimethylaminoethyl-3-[4-(isopropylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide hydrochloride

TRANS-3-(4-aminocyclohexanecarboxylic)-5-dimethylaminoethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride (160 mg)obtained in example 344, suspended in dichloromethane (8 ml) and added successively triethylamine (129 ml), acetone (113 μl) and triacetoxyborohydride sodium (130 mg) under ice cooling and the reaction solution is heated to room temperature and stirred for 17 hours. Under ice cooling to the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: ethyl acetate and then chloroform/methanol =30/1). The precipitate is dissolved in ethanol and added dropwise 4N hydrogen chloride in ethyl acetate. The reaction solution is concentrated and receive the config residue is suspended in diethyl ether. Precipitation is collected by filtration, giving the named compound (94 mg). APCI-MS M/E: 526/528 [M+H]+.

Example 346: TRANS-5-carboxy-3-[4-(isopropylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-3-[4-(isopropylamino)cyclohexylcarbonyl]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (690 mg)obtained in example 311, suspended in a mixture of tetrahydrofuran/methanol (1:1, 10 ml) and cooled with ice added 4N aqueous sodium hydroxide solution (3 ml). The mixture is heated to room temperature and stirred for 18 hours. The reaction solution is concentrated under reduced pressure and poured into ice water. The mixture is neutralized with 10% hydrochloric acid and the precipitates are collected by filtration, washed successively with water, tetrahydrofuran and diethyl ether and dried, giving a named connection (702 mg). ESI-MS M/E: 497/499 [M-N]-.

Examples 347-349

TRANS-5-carboxy-3-[4-(isopropylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide obtained in example 346, process, method, similar to that described in example 87, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Examples 350-354

the Corresponding starting compound is treated with a way similar to that described in example 218, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Examples 355-362

The corresponding starting compound is treated in a manner analogous to the one described in example 239 or in example 246, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Examples 363-364

The corresponding starting compound is treated in a manner analogous to the one described in example 306, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Examples 365-366

The corresponding starting compound is treated with a method similar to that described in example 201, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 367:

Iodide [4-[2-(4-chlorpheniramol)benzofuran-3-ylcarbonyl]cyclohexyl]trimethylammonium

TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(4-chlorophenyl)benzofuran-2-carboxamide (106 mg), polucen the th in example 308, dissolved in dichloromethane (5 ml) and added dropwise methyl iodide (30 μl), after which the mixture was stirred at room temperature for 5 hours. In the reaction solution is poured dichloromethylsilane ether (1/5, 25 ml) and the precipitates are collected by filtration, giving the named compound (126 mg). ESI-MS M/E: 454/456 [M-I]+.

Example 368: Iodide [4-[2-(5-chloropyridin-2-ylcarbonyl)benzofuran-3-ylcarbonyl]cyclohexyl]trimethylammonium

TRANS-3-[4-(dimethylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (150 mg)obtained in example 306, and methyl iodide (21 μl) is treated with a method similar to that described in example 367, which gives the named compound (137 mg). ESI-MS M/E: 455/457 [M-I]+.

Example 369: 3-[2-[1-(4,5-Digitoxose-2-yl)piperidine-4-yl]acetylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-[2-(piperidine-4-yl)acetylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (103 mg)obtained in example 220, suspended in tetrahydrofuran (5 ml) and added dropwise to the isocyanate-2-bromacil (27 μl), after which the mixture was stirred at room temperature for one hour add triethylamine (280 μl) and the mixture is then stirred at room temperature for 6 hours. In the reaction solution is poured onto water and ethyl acetate and precipitation collected by filtration, p is washed with ethyl acetate and dried, that gives titled compound (50 mg). APCI-MS M/E: 482/484 [M+H]+.

Examples 370-372

The corresponding starting compound is treated in a manner analogous to the one described in example 369, which provides the following connections.

Example 373: 3-[[1-(2-Thiazolyl)piperidine-4-yl]carbylamine]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride

3-[(piperidine-4-yl)carbylamine]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg)obtained in example 228, suspended in 2-butanol (5 ml) and add 2-bromothiazole (113 μl) and N,N-diisopropylethylamine (131 μl) and the mixture is heated at boiling temperature under reflux for 24 hours. In the reaction solution was added 2-bromothiazole (57 μl) and N,N-dimethylacetamide (2 ml) and the mixture is again heated at boiling temperature under reflux for 24 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is washed with water and saturated brine and dried over sodium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: a mixture of n-hexane/ethyl acetate =3/1, then ethyl acetate), giving 3-[[1-(2-thiazolyl)piperidine-4-yl]-carbylamine]-N-(5-habiri the Jn-2-yl)benzofuran-2-carboxamide (38 mg). This product is then treated with hydrogen chloride in dioxane, which gives titled compound (25 mg). APCI-MS M/E: 482/484 [M+H]+.

Example 374: TRANS-3-[4-(pyrimidine-2-yl)amino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

TRANS-3-[4-aminocyclohexanecarboxylic]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride (350 mg)obtained in example 219 and 2-chloropyrimidine (99 mg) is treated with a method similar to that described in example 373, which gives titled compound (65 mg). APCI-MS M/E: 491/493 [M+H]+.

Example 375: TRANS-3-[4-(pyrrol-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-3-(4-aminocyclohexanecarboxylic)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride (200 mg)obtained in example 219, tetrahydro-2,5-dimethoxyfuran (53 μl), sodium acetate (68 mg) is stirred at a temperature of 80°C for 2 hours in acetic acid (3 ml). The mixture was added tetrahydro-2,5-dimethoxyfuran (26 μl) and the mixture is then stirred at a temperature of 80°C for 2 hours. After cooling, the reaction solution was poured into ice water and the mixture extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate, saturated brine and dry the t over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: ethyl acetate/hexane =1/5 → ethyl acetate/hexane =1/3), which gives the named compound (96 mg). APCI-MS M/E: 463/465 [M+H]+.

Example 376: 3-[(1-tert-Butoxycarbonylamino-4-yl)oxycarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

tert-Butyl-4-hydroxy-1-piperidinecarboxylate (175 mg) and triphosgene (90 mg) was dissolved in dichloromethane (5 ml) and added dropwise with stirring, pyridine (77 μl) under ice cooling. The reaction solution was stirred at room temperature for 3 hours and then cooled with ice. To the mixture is added 3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (250 mg)obtained in example of preparation 74, and the mixture is stirred for several minutes. Then to the mixture is added pyridine (105 μl) and the mixture is stirred at room temperature for 3 hours. The reaction solution was poured into water and the mixture extracted with chloroform. The organic layer is washed successively with 5% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: a mixture of n-Gex is n/ethyl acetate =10/1, then 5/1), which gives the named compound (406 mg).

APCI-MS M/E: 515/517 [M+H]+.

Example 377: TRANS-3-[4-(tert-butoxycarbonylamino)cyclohexyloxycarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-Amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (500 mg)obtained in example of preparation 74, and tert-butyl TRANS-(4-hydroxycyclohexyl)carbamate (375 mg) is treated with a method similar to that described in example 376, which gives the named compound (680 mg). APCI-MS M/E: 529/531 [MN-N]+.

Examples 378-379

The compound obtained in example 376 or example 377, process, method, similar to that described in example 220, which provides the following connections.

Examples 380-381

The compound obtained in example 378 or example 379, process, method, similar to that described in example 345, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 382: 3-[3-(1-Isopropylpiperazine-4-yl)ureido]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

(1) Hydrochloride 1-isopropylpiperazine-4-carboxylic acid (3.00 g)obtained in example 130, suspended in toluene (180 ml) and the mixture added triethylamine (5 ml) and diphenylphosphoryl (4,0 ml), then, it is heated at a temperature of 100°C for 2 hours. After cooling, the reaction solution was added benzyl alcohol (4.5 ml) at room temperature and the mixture is heated at boiling temperature under reflux for 4 hours. The reaction solution is concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The product is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue purified by chromatography on a column of NH-silica gel (eluent: n-hexane/diethyl ether =2/1, then n-hexane/ethyl acetate =2/1), which gives a crude product (6,32 g)containing benzyl (1-isopropylpiperazine-4-yl)carbamate. APCI-MS M/E: 277 [M+H]+.

(2) the Crude product (6,32 g)containing benzyl(1-isopropylpiperazine-4-yl)carbamate obtained in example 382-(1), dissolved in ethanol (100 ml) and add 10% palladium on coal (600 mg), after which the mixture was stirred at ambient temperature in an atmosphere of hydrogen overnight. Insoluble products are removed by filtration and the filtrate concentrated under reduced pressure and subjected to azeotropic distillation with toluene. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: a mixture of n-Huck is an/ethyl acetate =1/1, then chloroform/methanol =20/1 and then 10/1), which gives 4-amino-1-isopropylpiperazine (1.90 g). The obtained 4-amino-1-isopropylpiperazine treated with 4N hydrogen chloride in dioxane, which gives 4-amino-1-isopropylpiperazine the dihydrochloride. APCI-MS M/E: 143 [M+H]+.

(3) 4-Amino-1-isopropylpiperazine the dihydrochloride (112 mg)obtained in example 382-(2), and triphosgene (54 mg) is suspended in dichloromethane (3 ml) and add pyridine (253 μl) with stirring under ice cooling. The reaction solution was stirred at room temperature for 3 hours and add 3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (150 mg)obtained in example of preparation 74, and the mixture is stirred at room temperature for 12 hours, then heated at boiling temperature under reflux for 15 hours. In the reaction solution is poured onto water and a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: n-hexane/ethyl acetate =4/1, then 2/1), which gives 3-[3-(1-isopropylpiperazine-4-yl)ureido]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (112 mg). Then this product is treated with 4N hydrogen chloride in those who acetate (2 ml), that gives the named compound (114 mg). APCI-MS M/E: 456/458 [M+H]+.

Example 383: TRANS-3-(4-methylhomopiperazine-1 ylcarbonyl)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

3-Amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (200 mg)obtained in example of preparation 74, and 1-methylhomopiperazine (86 μl) is treated with a method similar to that described in example 382-(3), which gives titled compound (110 mg). APCI-MS M/E: 428/430 [M+H]+.

Example 384: TRANS-3-[4-(2-oxopiperidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

(1) TRANS-3-(4-aminocyclohexanecarboxylic)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride (300 mg)obtained in example 219, suspended in N,N-dimethylacetamide (5 ml) and added dropwise methyl-5-bromovalerate (106 μl), N,N-diisopropylethylamine (537 μl) and potassium iodide (111 mg) and the mixture is stirred at a temperature of 100°C for 24 hours. Then add methyl - 5-bromovalerate (106 μl), N,N-diisopropylethylamine (537 μl) and potassium iodide (111 mg) and the mixture is again stirred at a temperature of 100°C for 12 hours. The reaction solution was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water, saturated brine and dried over sodium sulfate. Dissolve the spruce is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of NH-silica gel (eluent: n-hexane/ethyl acetate =1/1, then ethyl acetate), which gives TRANS-3-[4-(4-methoxycarbonylmethylene)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (101 mg). APCI-MS M/E: 527/529 [M+H]+.

(2) TRANS-3-[4-(4-methoxycarbonylmethylene)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (95 mg)obtained above (1), dissolved in tetrahydrofuran (3 ml) and add 1N aqueous solution of sodium hydroxide (216 μl) and the mixture is stirred at room temperature for 4 hours. The mixture was added 1N aqueous sodium hydroxide solution (684 μl) and the mixture is then stirred for 2 days. The reaction solution is concentrated to dryness under reduced pressure and the obtained residue type N,N-dimethylformamide (3 ml), 1-hydroxybenzotriazole (73 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104 mg). The mixture is stirred at room temperature for one day and then was added 1-hydroxybenzotriazole (73 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104 mg) and the mixture is then stirred for one day. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated brine and dried over sodium sulfate and the solvent is evaporated under reduced pressure. The precipitate is cleaned by the chromate is graphy on a column of silica gel (eluent: ethyl acetate), that gives the named compound (40 mg). APCI-MS M/E: 495/497 [M+H]+.

Example 385: TRANS-5-(N2-hydroxy)amidino-3-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-5-cyano-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (107 mg)obtained in example 6, is suspended in dimethyl sulfoxide (2 ml) and add chloride of hydroxyamine (36 mg) and 28% solution of sodium methoxide in methanol (100 ml). The mixture is heated at a temperature of 50°C for 2 hours and then at a temperature of 80°C for 2 hours. The reaction solution was poured into ice-water and the precipitates are collected by filtration and purified by using HPLC with recycling, which gives titled compound (25 mg; APCI-MS M/E: 539/541 [M+H]+) and TRANS-5-aminocarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (18 mg; APCI-MS M/E: 524/526 [M+H]+).

Example 386: TRANS-5-[2-(guanidinate)ethoxy]-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

(1) TRANS-5-(2-aminoketone)-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride (90 mg)obtained in example 183, dissolve Aut in N,N-dimethylformamide (3 ml) and add N,N-diisopropylethylamine (38 μl) and N,N-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (57 mg) and the mixture is stirred at room temperature for one day. The reaction solution is concentrated under reduced pressure and the residue poured into water and extracted with chloroform. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: n-hexane/ethyl acetate =1/1, then ethyl acetate), giving TRANS-5-{2-[N,N'-bis(tert-butoxycarbonyl)guanidino]ethoxy}-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (82 mg). ESI-MS M/E: 820/822 [M+Na]+, 798/800 [M+H]+.

(2) TRANS-5-{2-[N,N'-bis(tert-butoxycarbonyl)guadanucci]ethoxy}-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (73 mg)obtained above (1), add triperoxonane acid (2 ml) and the mixture is stirred at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure and the residue is neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue purified by chromatography on a column of NH-silica gel (eluent: chloroform and then a mixture of chloroform/methanol =97/3), which gives TRANS-5-[2-(guanidinate)ethoxy]-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-what lipiridy-2-yl)benzofuran-2-carboxamide (15 mg). Then the product (15 mg) is suspended in methanol (0.5 ml) and added dropwise 4N hydrogen chloride in dioxane (25 ml). The mixture was poured diethyl ether and the precipitates washed with diethyl ether and dried, giving the named compound (17 mg). ESI-MS M/E: 598/600 [M+H]+.

Examples 387-391

TRANS-5-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide obtained in example 77, and the corresponding starting compound is treated in a manner analogous to the one described in example 87, which provides the following connections.

Examples 392-393

TRANS-5-carboxy-3-[4-(N-formyl-N-methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide obtained in example 258, and amino compounds are treated in a manner analogous to the one described in example 261, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Examples 394-399

TRANS-5-dimethylaminoethyl-3-[4-(methylamino)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride obtained in example 343, and the anhydrides of the acids is treated in a manner analogous to the one described in example 239, that gives the following connection.

Example 400: TRANS-5-dimethylaminoethyl-3-[4-(N-hydroxyacetic-N-methylamino)-cyclohexylcarbodiimide]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-3-[4-(N-acetoxyacetyl-N-methylamino)cyclohexylcarbonyl]-5-dimethylaminoethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (91 mg)obtained in example 398, dissolved in a mixture of tetrahydrofuran/methanol (2:3, 5 ml) and added dropwise at room temperature 2N aqueous sodium hydroxide solution (300 μl) and the mixture is stirred for 4 hours. The reaction solution is acidified with diluted hydrochloric acid, and then diluted with chloroform. The mixture is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue purified by using HPLC with recycling, which gives the named compound (44 mg). APCI-MS M/E: 556/558 [M+H]+.

Examples 401-403

The compound obtained in example 345, 347 or 348, and acetylchloride treated in a manner analogous to the one described in example 334, which provides the following connections.

Examples 404-405

3-Amino-5-nitro-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide obtained in example of preparation 86, and a carboxylic acid is treated in a manner similar to OPI is anomo in example 1 or in example 2, that gives the following connection.

Example 406: TRANS-5-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride

TRANS-5-nitro-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.50 g)obtained in example 404, suspended in a mixture of ethanol/tetrahydrofuran (1:1, 400 ml) and added Raney Nickel, after which the mixture was stirred at room temperature under atmospheric pressure of hydrogen for 12 hours. In the resulting yellow suspension was poured chloroform (200 ml) and the mixture is stirred at room temperature for 0.5 hours. Insoluble products are removed by filtration and the filtrate concentrated under reduced pressure. The residue purified by chromatography on a column of silica gel (eluent: chloroform to chloroform/methanol =4/1), suspended in a mixture of ethyl acetate/diethyl ether. Precipitation is collected by filtration, washed with diethyl ether and dried, giving TRANS-5-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (1,94 g). This product (150 mg) is suspended in methanol and the mixture is treated with 4N hydrogen chloride in dioxane, which gives the named compound (158 mg). APCI-MS M/E: 496/498 [M+H]+

Example 407: TRANS-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl]-5-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride

TRANS-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl]-5-nitro-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide of 2.27 g)obtained in example 405, process, method, similar to that described in example 406, which gives TRANS-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl]-5-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (of 1.62 g). Obtained free compound (150 mg) is suspended in methanol and treated with 4N hydrogen chloride in dioxane, which gives the named compound (158 mg). APCI-MS M/E: 484/486 [M+H]+.

Examples 408-409

TRANS-5-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride obtained in example 406, or TRANS-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl]-5-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride obtained in example 407, process, method, similar to that described in example 198, which provides the following compounds in a free form, or which is then treated with hydrogen chloride, which gives them hydrochloride.

Example 410: TRANS-5-dimethylaminoethyl-3-[4-(3-exmortis-4-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-(3-exmortis-4-yl)cyclohexanecarbonyl acid (5 mg), obtained in example of preparation 141, dissolved in chloroform (3 ml) and added dropwise thionyl chloride (30 ml) and added dropwise N,N-dimethylformamide and the mixture is stirred at room temperature for 15 hours. In the resulting reaction solution was added 3-amino-5-dimethylaminoethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (96 mg)obtained in example of preparation 156, and pyridine (2 ml) and the mixture is stirred at room temperature for 2 hours. In the reaction solution is poured a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: n-hexane/ethyl acetate =2/1, then ethyl acetate) and then purified using HPLC with recycling, which gives the named compound (28 mg). APCI-MS M/E: 568/570 [M+H]+.

Examples 411-417

The amino compounds obtained in preparation examples 156-158, and appropriate carbolic acid is treated with a method similar to that described in example 410, which provides the following connections.

Example 418: TRANS-4-methoxycarbonyl-3-[4-(2-oxoacridine-3-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-Amino-4-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (351 mg)obtained in example of preparation 152, and TRANS-4-(2-oxoacridine-3-yl)cyclohexanecarbonyl acid (432 mg)obtained in example of preparation 142, process, method, similar to that described in example 1, giving a named connection (129 mg). APCI-MS M/E: 541/543 [M+H]+.

Example 419: TRANS-4-carboxy-3-[4-(2-oxoacridine-3-yl)-cyclohexylcarbodiimide]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-methoxycarbonyl-3-[4-(2-oxo-oxazolidin-3-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (107 mg)obtained in example 418, process, method, similar to that described in example 77, which gives a named connection (80.4 mg). ESI-MS M/E: 525/527 [M-N]-.

Example 420: TRANS-4-dimethylaminoethyl-3-[4-(2-oxoacridine-3-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-carboxy-3-[4-(2-oxoacridine-3-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (50 mg)obtained in example 419, process, method, similar to that described in example 87, which gives a named connection (36,4 mg). APCI-MS M/E: 554/556 [M+H]+.

Example 421: TRANS-4-methoxycarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohex is carbonylative]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-Amino-4-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2,33 g)obtained in example of preparation 152, and TRANS-4-(2-oxopyrrolidin-1-yl)cyclohexanecarbonyl acid (to 2.06 g)obtained in example of preparation 142, process, method, similar to that described in example 1, which gives the named compound (1.90 g). APCI-MS M/E: 539/541 [M+H]+.

Example 422: TRANS-4-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-methoxycarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (880 mg)obtained in example 421, process, method, similar to that described in example 77, which gives the named compound (623 mg).

ESI-MS M/E: 523/525 [M-N]-.

Example 423: TRANS-4-hydroxymethyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-methoxycarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (350 mg)obtained in example 421, process, method, similar to that described in example 145, which gives a named connection (of 40.9 mg). ESI-MS M/E: 511/513 [M+H]+.

Example 424: TRANS-4-[N-(2-dimethylaminoethyl)-N-me is Il]aminocarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide the dihydrochloride

TRANS-4-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (70 mg)obtained in example 422, process, method, similar to that described in example 87, which gives TRANS-4-[N-(2-dimethylaminoethyl)-N-methyl]aminocarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (40,7 mg). This product is dissolved in methanol and treated with 4N hydrogen chloride in dioxane (50 ml), giving a named connection (35,7 mg). APCI-MS M/E: 609/611 [M+H]+.

Example 425: TRANS-4-tert-butoxycarbonylamino-3-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (325 mg)obtained in example 422, dissolved in tert-butanol (8 ml) and added at room temperature triethylamine (91 μl) and diphenylphosphoryl (140 Il) and the mixture is stirred at a temperature of 60°C for 1.5 hours and then heated at boiling temperature under reflux for 5.5 hours. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with saturated Rasso the Ohm, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: a mixture of chloroform/methanol =100/1, then 10/1), which gives a named connection (141,7 mg). ESI-MS M/E: 596/598 [M+H]+.

Example 426: TRANS-4-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-tert-butoxycarbonylamino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (108 mg)obtained in example 425, dissolved in triperoxonane acid (2 ml) and the mixture is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: a mixture of n-hexane/ethyl acetate =1/1, then ethyl acetate), giving a named connection (85,4 mg). ESI-MS M/E: 496/498 [M+H]+.

Example 427: TRANS-4-dimethylamino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (41.7 mg)obtained in example 426, process, method, similar to that described in example 198, which gives the named compound (8.0 mg).

APCI-MS M/E: 524/526 [M+H]+.

Example 428: TRANS-4-methanesulfonamido-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

TRANS-4-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (27 mg)obtained in example 426, dissolved in pyridine (2 ml) and add methanesulfonanilide (7 μl) under ice cooling. The mixture is stirred at room temperature over night and then re-add pyridine (3 ml) and methanesulfonamide (500 μl) under ice cooling. The mixture is stirred at room temperature for 6 hours. In the reaction solution is added water and the mixture extracted with chloroform. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: chloroform, then chloroform/methanol =9/1), which gives the named compound (21.2 mg). APCI-MS M/E: 574/576 [M+H]+.

Example 429: TRANS-3-[4-(3-oxo-morpholine-4-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-CT is the oksamid

3-Amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (66 mg)obtained in example of preparation 74, and TRANS-4-(3-oxo-morpholine-4-yl)cyclohexanecarbonyl acid (68 mg)obtained in example of preparation 141, process, method, similar to that described in example 410, which gives the named compound (74 mg). APCI-MS M/E: 497/499 [M+H]+.

Sample preparation 1: Methyl 3-formyl-4-hydroxybenzoate

Methyl-4-hydroxybenzoate (1.52 g) was dissolved in triperoxonane acid (20 ml), added hexamethylenetetramine (700 mg) and the mixture is heated at boiling temperature under reflux for 2 hours. The reaction solution is concentrated under reduced pressure, poured onto ice water and the mixture is then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The precipitate is dissolved in chloroform and then filtered to remove insoluble products. The filtrate is concentrated under reduced pressure and then purified using chromatography on a column of silica gel (eluent: a mixture of n-hexane/ethyl acetate =4/1), which gives the named compound (540 mg).

ESI-MS M/e - 179 [M-N]-.

Example of preparation is ia 2: Methyl (3-formyl-4-hydroxyphenyl)acetate

Methyl-(4-hydroxyphenyl)acetate (1.66 g) was dissolved in triperoxonane acid (20 ml), added hexamethylenetetramine (700 mg) and the mixture is heated at boiling temperature under reflux for 2 hours. The reaction solution is concentrated under reduced pressure, poured onto ice water and the mixture is then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate =9/1, then =4/1), which gives the named compound (1.08 g).

ESI-MS M/E: 193 [M-N]-.

Examples of cooking 3-4

The corresponding compounds are treated in a manner analogous to the one described in example of preparation 1 or in example of preparation 2, which gives further connections.

Sample preparation 5: Methyl 3-cyano-4-hydroxybenzoate

Methyl-3-formyl-4-hydroxybenzoate (28,60 g)obtained in example of preparation 1, was dissolved in formic acid (120 ml), add chloride of hydroxylamine (14,30 g) and the mixture is heated at the boiling point under reflux in the course is the development of 15 hours. The reaction solution is concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure, giving a named connection (24,25 g). ESI-MS M/E: 176 [M-N]-.

Example 6 preparation: Methyl(3-cyano-4-hydroxyphenyl)acetate

Methyl(3-formyl-4-hydroxyphenyl)acetate (1,05 g)obtained in example of preparation 2, was dissolved in formic acid (15 ml) and add chloride of hydroxylamine (0,49 g) and sodium formate (0,81 g) and the mixture is heated at boiling temperature under reflux for 8 hours. The reaction solution is concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate and the solvent is evaporated under reduced pressure, giving the named compound (520 mg). ESI-MS M/E: 190 [M-N]-.

Examples preparation 7-19

The corresponding compounds are treated in a manner analogous to the one described in example of preparation 5 or example 6 preparation that provides the following connections.

Sample preparation 20: 2-(4-Methoxycarbonyl-2-cianfrocca)-N-(5-chloropyridin-2-yl)ndimethylacetamide

(1) Chlorocatechol (95,5 ml) dissolved in dichloromethane (500 ml) and added dropwise a suspension of 2-amino-5-chloropyridine (of 128.6 g) and triethylamine (169 ml) in dichloromethane (1000 ml) under ice cooling and the reaction solution is heated to room temperature and stirred for 0.5 hour. Then the reaction solution is concentrated under reduced pressure, poured ice-cold water and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and treated with activated charcoal. After filtration to remove insoluble products, the filtrate is concentrated under reduced pressure and the resulting residue is suspended in diisopropyl ether. Precipitation is collected by filtration, washed with diisopropyl ether and dried, giving 2-chloro-N-(5-chloropyridin-2-yl)ndimethylacetamide (153,4 g). APCI-MS M/E: 205/207 [M+H]+.

(2) Methyl-3-cyano-4-hydroxybenzoate (500 mg)obtained in example of preparation 5, is dissolved in acetone (25 ml)is added 2-chloro-N-(5-chloropyridin-2-yl)ndimethylacetamide (695 mg)obtained in example of preparation 20(1), potassium carbonate (546 mg) and sodium iodide (550 mg) and the mixture is heated at boiling temperature under reflux for 2 hours. After cooling, insoluble products are removed by filtration and nerastvorimaya washed with acetone several times. The filtrate and washing are combined and concentrated under reduced pressure and then purified using chromatography on a column of silica gel (eluent: chloroform, then chloroform/ethyl acetate =4/1). The precipitate is suspended in diethyl ether and then precipitates are collected by filtration, giving the named compound (660 mg). APCI-MS M/E: 346/348 [M+H]+.

Sample preparation 21: 2-[2-Cyano-4-(methoxycarbonylmethyl)phenoxy]-N-(5-chloropyridin-2-yl)ndimethylacetamide

Methyl-(3-cyano-4-hydroxyphenyl)acetate (500 mg)obtained in example 6 preparation, dissolved in acetone (25 ml)is added 2-chloro-N-(5-chloropyridin-2-yl)ndimethylacetamide (640 mg)obtained in example of preparation 20(1), cesium carbonate (1.20 g) and sodium iodide (510 mg) and the mixture is heated at boiling temperature under reflux for 5 hours. After cooling, insoluble products are removed by filtration and then washed with acetone several times. The filtrate and washing are combined to a concentrated under reduced pressure, the residue poured onto water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: a mixture of n-hexane/ethyl acetate/chloroform =3/1/1). the received residue suspended in a mixture of diethyl ether-n-hexane, and then the precipitates are collected by filtration, that gives the named compound (570 mg). APCI-MS M/E: 360/362 [M+H]+.

Examples preparation 22-23

The corresponding compounds are treated in a manner analogous to the one described in example of preparation of 20 or in the example of preparation 21, which provides the following connections.

Example of preparation 24: tert-Butyl(2-cianfrocca)acetate

2-Cyanoprop (107,1 g) dissolved in acetone (1000 ml) and added dropwise tert-butyl bromoacetate (200,0 g). Then add potassium carbonate (141,6 g), and then the reaction solution is heated at the boiling point under reflux for 2 hours. After cooling, insoluble products are removed by filtration, and then washed with acetone several times. The filtrate and washing are combined to a concentrated under reduced pressure and treated with diisopropyl ether azeotrope. The precipitate is crystallized from a mixture of n-hexane-Diisopropylamine ether (5/1) (600 ml) and then stirred under ice cooling. Precipitation is collected by filtration, washed several times with cold mixture of n-hexane-diisopropyl ether (10/1) (600 ml) and dried, giving the above mentioned compounds (194,5 g). APCI-MS M/E: 251 [M+NH4]+.

Examples preparation 25-36

The corresponding compounds are treated in a manner analogous to the one described in example of preparation 4, that gives the following connection.

Sample preparation 37: (2 Cianfrocca)acetic acid

tert-Butyl(2-cianfrocca)acetate (300,0 g)obtained in example of preparation 24, dissolved in dichloromethane (400 ml) and add triperoxonane acid (990 ml) and the mixture is stirred at room temperature for 4 hours. The reaction solution is concentrated under reduced pressure, the obtained residue is suspended in diethyl ether (100 ml) and poured into the obtained mixture of diisopropyl ether (500 ml). Precipitation is collected by filtration, washed with diisopropyl ether several times and dried, giving a named connection (198.4 g). ESI-MS M/E: 176 [M-N]-.

Examples preparation 38-49

The corresponding compounds are treated in a manner analogous to the one described in example of preparation 37, which provides the following connections.

Sample preparation 50: [4-(N-Benzyloxycarbonyl-N-methylamino)-2-cianfrocca]acetic acid

(1) tert-Butyl 2-(4-nitro-2-cianfrocca)acetate (500 mg)obtained in example of preparation 29, dissolved in tetrahydrofuran (20 ml), add 10% palladium on coal (100 mg) and the mixture is stirred is for 2 hours under atmospheric pressure of hydrogen. Insoluble products are removed by filtration and then the filtrate is concentrated under reduced pressure, giving tert-butyl(4-amino-2-cianfrocca)acetate (440 mg). APCI-MS M/E: 249 [M+H]+.

(2) tert-Butyl(4-amino-2-cianfrocca)acetate (430 mg)obtained in example of preparation 50(1), dissolved in tetrahydrofuran (10 ml), add a saturated solution of sodium bicarbonate (10 ml) and then add benzylchloride (355 mg) under ice cooling. Next, while cooling with ice, the reaction solution is stirred for one hour and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate =9/1, then 3/1), which gives tert-butyl(4-benzyloxycarbonylamino-2-cianfrocca)acetate (540 mg). APCI-MS M/E: 383 [M+H]+.

(3) tert-Butyl(4-benzyloxycarbonylamino-2-cianfrocca)acetate (100 mg)obtained in example of preparation 50(2), dissolved in N,N-dimethylformamide (3 ml) and added 60% oily sodium hydride (12.5 mg). The mixture is then stirred for 20 minutes at room temperature, is added dropwise methyl iodide (24,4 μl) and the mixture is then stirred for one hour. In the reaction solution is poured a saturated aqueous restorelite ammonium and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent. The obtained residue purified by chromatography on a column of silica gel (eluent: a mixture of n-hexane/ethyl acetate =9/1, then 3/1), which gives tert-butyl[4-(N-benzyloxycarbonyl-N-methylamino)-2-cianfrocca]acetate (91 mg). APCI-MS M/E): 414 [M+NH4]+.

(4) tert-Butyl[4-(N-benzyloxycarbonyl-N-methylamino)-2-cianfrocca]acetate (2,42 g)obtained in example of preparation 50(3), is treated with a method similar to that described in example of preparation 37, which gives a named connection (to 2.06 g). ESI-MS M/E: 339 [M-N]-.

Sample preparation 51: (2 Cianfrocca)-N-(5-chloropyridin-2-yl)ndimethylacetamide

(2 Cianfrocca)acetic acid (48,63 g)obtained in example of preparation 37, dissolved in dichloromethane (1000 ml), add oxalicacid (26,34 ml) and N,N-dimethylformamide (10 drops) and the mixture is stirred at room temperature for 3.5 hours. The reaction solution is cooled in a bath with ice, add 2-amino-5-chloropyridin (32,08 g) and then added pyridine (they accounted for 60,54 ml). After 5 minutes the reaction solution is heated to room temperature and stirred over night. In the reaction solution was added ice water and the pH value of the solution was adjusted to 4 with 10% solution is olaney acid and then extracted with chloroform. The organic layer is washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate and evaporated to remove the solvent. The precipitate is suspended in a mixture of chloroform-ethyl acetate and collected by filtration, which gives (2-cianfrocca)-N-(5-chloropyridin-2-yl)ndimethylacetamide (51,58 g). Then the filtrate is concentrated under reduced pressure and then purified using chromatography on a column of silica gel (eluent: chloroform), giving a named connection (11,50 g). APCI-MS M/E: 288/290 [M+H]+.

Examples preparation 52-66

The corresponding compounds are treated in a manner analogous to the one described in example of preparation 51, which provides the following connections.

Example of preparation 67: (2 Cianfrocca)-N-(4-chlorophenyl)ndimethylacetamide

(2 Cianfrocca)acetic acid (30,00 g)obtained in example of preparation 37, dissolved in N,N-dimethylformamide (300 ml), successively added 4-Chloroaniline (25,9 g), 4-dimethylaminopyridine (22,7 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (35,6 g) and the mixture is stirred for 3 hours at room temperature. The reaction solution is concentrated under reduced pressure and p the obtained residue was diluted with a mixture of ethyl acetate-tetrahydrofuran, washed successively with water, 5% hydrochloric acid, water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent. The precipitate is suspended in diisopropyl ether and then precipitates are collected by filtration, giving a named connection (44,00 g). APCI-MS M/E: 287/289 [M+H]+.

Examples preparation 68-71

The corresponding compounds are treated in a manner analogous to the one described in example of preparation 67, which provides the following connections.

Example of preparation 72: 3-Amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

2-(4-Methoxycarbonyl-2-cianfrocca)-N-(5-chloropyridin-2-yl)ndimethylacetamide (1.73 g)obtained in example of preparation 20, dissolved in N,N-dimethylacetamide (15 ml), add sodium carbonate (160 mg) and the mixture is stirred at a temperature of 100°C for 2 hours. After cooling, the reaction solution is poured onto ice water and the resulting precipitates are collected by filtration, washed successively with water, tetrahydrofuran and diethyl ether and dried, giving the named compound (1.20 g). APCI-MS M/E: 346/348 [M+H]+.

Example of preparation 73: 3-Amino-5-methoxycarbonylmethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

2-[2-Cyano-4-(is ethoxycarbonylmethyl)phenoxy]-N-(5-chloropyridin-2-yl)ndimethylacetamide (500 mg), obtained in example of preparation 21, dissolved in N,N-dimethylacetamide (15 ml), add sodium carbonate (74 mg) and the mixture is stirred at a temperature of 100°C for 16 hours. After cooling, the reaction solution is poured onto ice water and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent. The obtained residue purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate/chloroform =3/1/1), suspended in diethyl ether-n-hexane, and then the precipitates are collected by filtration, giving the named compound (180 mg). APCI-MS M/E: 360/362 [MN-N]+.

Example of preparation 74: 3-Amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

(2 Cianfrocca)-N-(5-chloropyridin-2-yl)ndimethylacetamide (150,00 g)obtained in example of preparation 51, dissolved in N,N-dimethylacetamide (1500 ml), add sodium carbonate (60,8 g) and the mixture is stirred at a temperature of 70°C for 7 hours. After cooling, the reaction solution was poured into ice water and the resulting precipitates are collected by filtration and washed several times with water. Precipitation was dissolved in ethyl acetate, washed with water and saturated brine, dried over sodium sulfate and the organic layer is treated with activated Dre the forest carbon. Insoluble products are filtered and then the filtrate is concentrated under reduced pressure and the resulting residue suspended in a mixture of diethyl ether-ethyl acetate. Precipitation is collected by filtration, washed with diethyl ether and dried, giving a named connection (119,33 g).

APCI-MS M/E: 288/290 [M+H]+.

Sample preparation 75-96

The corresponding compounds are treated in a manner analogous to the one described in example of preparation 72, 73 or 74, which provides the following connections.

Example of preparation 97: (2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)-ndimethylacetamide

To a suspension of (2-cyano-4-methoxyphenoxy)-N-(5-chloropyridin-2-yl)ndimethylacetamide (40,0 g)obtained in example of preparation 59, in dichloromethane (2000 ml) is added dropwise at a temperature of -58°C for 40 minutes tribromide boron (173 g). The reaction solution is stirred for 26 hours with maintaining the internal temperature between -20°s and 0°and then poured into ice water. The precipitated solid is collected by filtration, washed with water and then dried under reduced pressure. Part of the obtained solid (37,2 g), that is, 24,3 g, purified using chromatography on a column of silica gel (eluent: chlorine is of the form/methanol =50/1-10/1), that gives the named compound (17.0 g). APCI-MS M/E: 304/306 [M+H]+.

Example of preparation 98: 3-Amino-5-hydroxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

(2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)ndimethylacetamide (321 mg)obtained in example of preparation 97, process, method, similar to that described in example of preparation 73, which gives the named compound (274 mg). APCI-MS M/E: 304/306 [M+H]+.

Example of preparation 99: (4-tert-Butoxycarbonylmethyl-2-cianfrocca)-N-(5-chloropyridin-2-yl)ndimethylacetamide

(2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)ndimethylacetamide (5.75 g)obtained in example of preparation 97, dissolved in acetone (160 ml) and the solution was added cesium carbonate (8,08 g), tert-butylbromide (4,58 g) and sodium iodide (of 3.64 g). The reaction solution is heated at the boiling point under reflux for 8 hours, add another portion of cesium carbonate (1.89 g), tert-butylbromide (840 μl) and sodium iodide (875 mg) and the mixture is heated at boiling temperature under reflux for an additional 14 hours. After cooling, the reaction solution was poured into ice water, adjusted the pH value to a value of 1-2 with 10% hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and evaporated, which is advised to remove the solvent. The obtained residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate =3/1, 2/1 then 1/1) and then purified using chromatography on a column of NH-silica gel (eluent: hexane/ethyl acetate =2/1 then 1/1), giving a named connection (as 4.02 g). APCI-MS M/E: 418/420 [M+H]+.

Sample preparation 100: 3-Amino-5-tert-butoxycarbonylmethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

(4-tert-Butoxycarbonylmethyl-2-cianfrocca)-N-(5-chloropyridin-2-yl)ndimethylacetamide (8,18 g)obtained in example 99 cooking, process, method, similar to that described in example of preparation 73, which gives a named connection (5,72 g). APCI-MS M/E: 418/420 [M+H]+.

Example cooking 101: 3-Amino-5-(2-methoxyethoxy)-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide

(1) (2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)ndimethylacetamide (100 mg)obtained in example of preparation 97, dissolved in tetrahydrofuran and add 2-methoxyethanol (of 9.30 ml) and triphenylphosphine (31.0 g), and then added dropwise under ice cooling diethylazodicarboxylate (22,2 ml). The reaction solution is heated to room temperature, stirred for 17 hours and concentrated under reduced pressure. In the obtained residue was poured diisopropyl ether and insoluble products UDA is EUT by filtration and then the filtrate is concentrated under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: chloroform/ethyl acetate =10/1), which gives [4-(2-methoxyethoxy)-2-cianfrocca]-N-(5-chloropyridin-2-yl)ndimethylacetamide (71,48 g) as a crude product, which is used in the next stage without further purification. APCI-MS M/E: 362/364 [M+H]+.

(2) the Crude product containing [4-(2-methoxyethoxy)-2-cianfrocca]-N-(5-chloropyridin-2-yl)ndimethylacetamide (71,48 g)obtained in example of preparation 101(1), is treated in a manner analogous to the one described in example of preparation 72, giving a named connection (24,40 g). APCI-MS M/E: 362/364 [M+H]+.

Examples of preparation 102 to 106

(2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide", she obtained in example of preparation 97, and the corresponding alcohol is treated with a method similar to that described in example cooking 101, which provides the following connections.

Example of preparation 107: (2,4-Dicyanobenzene)-N-(5-chloropyridin-2-yl)ndimethylacetamide

4-Nitrobenzonitrile (3,02 g) and potassium cyanide (2,02 g) dissolved in dimethyl sulfoxide (100 ml) and stirred at a temperature of 100°within hours. The reaction the solution is allowed to cool down to room temperature and is added potassium carbonate (1,49 g), 2-chloro-N-(5-chloropyridin-2-yl)ndimethylacetamide (10,42 g)obtained in example sentence is the service 20(1), and sodium iodide (8,76 g) and the mixture is stirred at a temperature of 60°C for 4.5 hours. The reaction solution was poured into water and the precipitated precipitated solids are collected by filtration, washed with water and dried in air. The obtained solid substance was dissolved in ethyl acetate, dried over sodium sulfate, evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate =5/1 to 1/1), and then the precipitate is suspended in a mixture of ethyl acetate-diisopropyl ether. Precipitation is collected by filtration and dried, giving a named connection (2,81 g). APCI-MS M/E: 313/315 [M+H]+.

Example of preparation 108: 3-Amino-5-cyano-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

(2,4-Dicyanobenzene)-N-(5-chloropyridin-2-yl)ndimethylacetamide (1,02 g)obtained in example of preparation 107, process, method, similar to that described in example of preparation 73, which gives the named compound (0.96 g).

APCI-MS M/E: 313/315 [M+H]+.

Example of preparation 109: (3-Chloro-2-cianfrocca)-N-(5-chloropyridin-2-yl)ndimethylacetamide

(1) 2-Chloro-N-(5-chloropyridin-2-yl)ndimethylacetamide (30,68 g)obtained in example of preparation 20(1), dissolved in N,N-dimethylformamide (500 ml), add sodium acetate (RUB 24.55 g) and the mixture paramashiva the t at a temperature of 60° C for 5 hours. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine. The solution is dried over magnesium sulfate, treated with activated charcoal and the filtrate is concentrated under reduced pressure. The precipitate is suspended in n-hexane and the resulting crystals are collected by filtration, washed with n-hexane and dried, giving N-(5-chloropyridin-2-yl)-2-acetoxyacetyl (30,58 g). APCI-MS M/E: 229/231 [M+H]+.

(2) 2-Acetoxy-N-(5-chloropyridin-2-yl)ndimethylacetamide (30,36 g)obtained in example of preparation 109(1), suspended in methanol (1200 ml) and add potassium carbonate (22,0 g) under cooling with ice. The reaction solution is heated to room temperature, stirred for 0.5 hour and concentrated under reduced pressure. In the obtained residue was poured in ethyl acetate (1500 ml) and ice water (1000 ml) and the mixture is then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The precipitate is suspended in a small amount of ethyl acetate, added diisopropyl ether and precipitated precipitated crystals are collected by filtration, washed with diisopropyl ether and dried, giving 2-hydroxy-N-(5-chloropyridin-2-yl)ndimethylacetamide (22,85 g). APCI-MS M/E: 187/189 [M+H]+.

(3) 2-Chloro-6-NITR benzonitrile (187 mg) and 2-hydroxy-N-(5-chloropyridin-2-yl)ndimethylacetamide (183 mg), obtained in example of preparation 109(2), dissolved in N,N-dimethylformamide (2 ml) and added 60% oily sodium hydride (80 mg) under ice cooling. After stirring for 6 hours with cooling, the reaction solution is poured a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The precipitate is suspended in n-hexane-diisopropyl ether, the resulting product is collected by filtration and dried, giving a named connection (286 mg). APCI-MS M/E: 322/324 [M+H]+.

Sample preparation 110: 3-Amino-4-chloro-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

(3-Chloro-2-cianfrocca)-N-(5-chloropyridin-2-yl)ndimethylacetamide (274 mg)obtained in example of preparation 109, dissolved in N,N-dimethylacetamide (10 ml), add cesium carbonate (333 mg) and the mixture is stirred at a temperature of 100°C for 8 hours. After cooling, the reaction solution was added ice water, precipitates are collected by filtration and washed with water. Precipitation was dissolved in hot ethyl acetate, washed with saturated brine and dried over sodium sulfate. The organic layer add activated charcoal and NH-silica gel (5 g) and the mixture is filtered to remove insoluble products. The filtrate is concentrated under reduced pressure, the precipitate is suspended in a mixture of ethyl acetate-diethyl ether and the resulting product is collected by filtration, giving the named compound (112 mg). APCI-MS M/E: 322/324 [M+H]+.

Example of preparation 111: 3-Amino-4-methoxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

2-Methoxy-6-nitrobenzonitrile (589 mg) and 2-hydroxy-N-(5-chloropyridin-2-yl)ndimethylacetamide (560 mg)obtained in example of preparation 109(2), dissolved in N,N-dimethylacetamide (10 ml) and add potassium carbonate (810 mg). The reaction solution is stirred at a temperature of 60°during the night, add another portion of potassium carbonate (810 mg) and the mixture is stirred at a temperature of 100°C for 4 hours. After cooling, the reaction solution is poured onto ice water and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate and treated with activated charcoal. Insoluble products are removed by filtration, washed with a mixture of chloroform-methanol and the filtrate and washing are combined and concentrated under reduced pressure. The precipitate is suspended in diisopropyl ether, and then the resulting product is collected by filtration, giving the named compound (104 mg). APCI-MS M/E: 317/319 [M+H]+.

Example of preparation 112: ethyl-TRANS-4-(tert-butoxycarbonylamino)cyclohexane-carboxylate

(1) thionyl chloride (254 ml) is added dropwise to methanol (1500 ml) under cooling to a temperature of -30°C for about an hour. After the addition the reaction mixture was stirred at room temperature for 0.5 hour, add TRANS-cyclohexane-1,4-dicarboxylic acid (500.0 g) and the mixture is stirred at room temperature for 17 hours. The reaction solution is concentrated under reduced pressure, the residue is diluted with chloroform and then washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer is dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The precipitate is crystallized from n-hexane, the resulting product is collected by filtration, dried, giving dimethyl TRANS-cyclohexane-1,4 -, in primary forms (545,0 g). APCI-MS M/E: 201 [M+H]+.

(2) Dimethyl-TRANS-cyclohexane-1,4 -, in primary forms (150,0 g)obtained in example of preparation 112(1), dissolved in tetrahydrofuran (1500 ml) and the solution is added dropwise a mixture of 28% sodium methoxide in methanol (149 g) and water (13,2 g) under cooling with ice. The reaction solution is heated to room temperature, stirred for 3.5 hours, add n-hexane (1500 ml) and the mixture is filtered and the collected precipitation. The obtained solid is added to a mixture of concentrated the Anna hydrochloric acid (50 ml), water (450 ml) and chloroform (1000 ml) under cooling with ice and stirred at room temperature for 20 minutes. The chloroform layer is separated and the aqueous layer was extracted with chloroform. The organic layers are combined, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The precipitate is crystallized from n-hexane, and the resulting product is collected by filtration and dried, giving monomethyl-TRANS-cyclohexane-1,4 -, in primary forms (to 106.0 g). ESI-MSM/E: 185[M-N]-.

(3) Monomethyl-TRANS-cyclohexane-1,4 -, in primary forms (100.0 g)obtained in example of preparation 112(2), dissolved in tert-butanol (1000 ml), add diphenylphosphinite (155 g) and triethylamine (78,6 ml). The mixture is heated at a temperature of about 60°C for one hour and then heated at boiling temperature under reflux for a further 17 hours. After cooling, the reaction solution was added ice water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The precipitate is dissolved in methanol (250 ml), add water (750 ml) and the mixture is stirred under ice cooling. After 0.5 hour precipitation collected by filtration, washed successively cm is sue water-methanol (3:1, 1000 ml) and n-hexane and dried, giving a named connection (117,0 g). APCI-MS M/E: 275 [M+H]+.

Example of preparation 113: TRANS-4-(2-oxopyrrolidin-1-yl)cyclohexanecarbonyl acid

(1) Methyl-TRANS-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (234,0 g)obtained in example of preparation 112, dissolved in dioxane (500 ml) and added 4N solution of hydrogen chloride in dioxane (500 ml) and the mixture is stirred at room temperature for 19 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is suspended in diethyl ether and then precipitates are collected by filtration, giving the hydrochloride of methyl TRANS-4-aminocyclohexanecarboxylic (121,9 g).

APCI-MS M/E: 158 [M+H]+.

(2) Hydrochloride methyl-TRANS-4-aminocyclohexanecarboxylic (45,31 g) is suspended in dichloromethane (1000 ml), add 4-chlorobutyrate (31.5 ml) under ice cooling and the mixture was added dropwise a solution of triethylamine (81,5 ml) in dichloromethane (80 ml). The reaction solution is heated to room temperature, stirred for 3 hours and then concentrated under reduced pressure. In the obtained residue was poured in ethyl acetate and 5% hydrochloric acid solution and the organic layer is separated, washed with saturated aqueous sodium hydrogen carbonate and saturated brine. Organicheskikh dried over sodium sulfate and treated with activated charcoal and the filtrate is concentrated under reduced pressure. The precipitate is suspended in diisopropyl ether, filtered to collect precipitation, dried, giving methyl-TRANS-4-(4-chloroethylamino)-cyclohexanecarboxylate (38,81 g). APCI-MS M/E: 262/264 [M+H]+.

(3) 60% sodium Hydride in oil (9.60 g) is suspended in N,N-dematiaceae (500 ml), the mixture gradually add methyl-TRANS-4-(4-chloroethylamino)-cyclohexanecarboxylate (52,32 g)obtained in example of preparation 113(2), while cooling with ice. The reaction solution is heated to room temperature, stirred for 24 hours and poured onto saturated aqueous solution of ammonium chloride and ice water and the mixture extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: ethyl acetate) and the resulting solid is suspended in a mixture of n-hexane-diisopropyl ether. The resulting crystals are collected by filtration and dried, giving methyl-TRANS-4-(2-oxo-pyrrolidin-1-yl)cyclohexanecarboxylate (39,20 g). APCI-MS M/E: 226 [M+H]+.

(4) Methyl-TRANS-4-(2-oxo-pyrrolidin-1-yl)cyclohexanecarboxylate (39,15 g)obtained in example of preparation 113(3), dissolved in methanol (400 ml) and added 2N aqueous sodium hydroxide solution (60 ml) and the mixture paramesh what happens at room temperature for 3 hours. The pH value of the reaction solution was adjusted to 1-2 using infusion of 10% hydrochloric acid under ice cooling, saturated sodium chloride and then extracted with chloroform. The organic layer is dried over sodium sulfate and then evaporated to remove the solvent under reduced pressure. The precipitate is suspended in a small amount of ethyl acetate and poured diisopropyl ether and the resulting crystals are collected by filtration. The crystals are washed with diisopropyl ether several times and dried, giving a named connection (35,94 g). ESI-MS M/E: 210 [M-N]-.

Sample preparation 114: TRANS-4-(N-acetyl-N-methylamino)cyclohexanecarbonyl acid

(1) Methyl-TRANS-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (30,00 g) dissolved in N,N-dimethylformamide (150 ml) and added 60% sodium hydride in oil (the ceiling of 5.60 g) under cooling with ice. After stirring for 0.5 hours when it is cooled reaction solution was successively added methyl iodide (14,5 ml) and methanol (0.15 ml) and the reaction solution is heated to room temperature and stirred for 4 hours. Under ice cooling to the reaction solution is poured onto a saturated ammonium chloride and ice water and the mixture extracted with ethyl acetate. The organic layer is successively washed with water and saturated Russ is scrap, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate =10/1, then 7/1), which gives methyl TRANS-4-(N-tert-butoxycarbonyl-N-methylamino)cyclohexanecarboxylate (26,33 g).

APCI-MS M/E: 272 [M+H]+.

(2) Methyl TRANS-4-(N-tert-butoxycarbonyl-N-methylamino)cyclohexanecarboxylate (26,32 g)obtained in example of preparation 114(1), dissolved in dioxane (100 ml) and added 4N solution of hydrogen chloride-dioxane (100 ml). The reaction solution was stirred at room temperature for 4 hours and the resulting solution was poured diisopropyl ether (500 ml). Precipitation is collected by filtration, washed with diisopropyl ether and dried, giving the hydrochloride of methyl TRANS-4-(methylamino)cyclohexanecarboxylate (19.01 in g). APCI-MS M/E: 172 [M+H]+.

(3) the Hydrochloride of methyl TRANS-4-(methylamino)cyclohexanecarboxylate (18,93 g)obtained in example of preparation 114(2), is suspended in dichloromethane (400 ml) and the resulting solution add acetylchloride (8,42 ml) under cooling with ice and then add dropwise a solution of triethylamine (38,1 ml) in dichloromethane (40 ml). The reaction solution is heated to room temperature, stirred for 2 hours, add 5% solution of hydrochloric acid and the mixture extracted with dihl what Rotana. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: ethyl acetate), giving methyl-TRANS-4-(N-acetyl-N-methylamino)cyclohexanecarboxylate (19,05 g). APCI-MS M/E: 214 [M+H]+.

(4) Methyl-TRANS-4-(N-acetyl-N-methylamino)-cyclohexanecarboxylate (19,00 g)obtained in example of preparation 114(3), dissolved in methanol (200 ml), added 2N aqueous solution of sodium hydroxide (60 ml) and the mixture is stirred at room temperature for 3 hours. Under ice cooling, the pH of the reaction solution was adjusted to 1-2 with 10% hydrochloric acid, saturated sodium chloride and then extracted with chloroform. The organic layer is dried over sodium sulfate and then evaporated to remove the solvent under reduced pressure. The precipitate is suspended in a small amount of ethyl acetate, the mixture was poured diisopropyl ether and the crystals are collected by filtration. The crystals are washed with diisopropyl ether several times and dried, giving a named connection (to 16.31 g). ESI-MS M/E: 198 [M-N]-.

Example of preparation 115: TRANS-4-(N-tert-butoxycarbonyl-N-methylamino)-cyclohexanecarbonyl acid

Methyl-TRANS-4-(N-Tr is t-butoxycarbonyl-N-methylamino)cyclohexanecarboxylate (44,78 g), obtained in example of preparation 114(1), dissolved in methanol (300 ml), added 2N aqueous solution of sodium hydroxide (100 ml) and the mixture is stirred at room temperature for 6 hours. The reaction solution is concentrated under reduced pressure, the residue add ice water, ethyl acetate and 10% hydrochloric acid under ice cooling and then the mixture is extracted with ethyl acetate. The organic layer is successively washed with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The precipitate is suspended in a small amount of ethyl acetate, the mixture was poured n-hexane and the crystals are collected by filtration. The crystals are washed several times with a mixture of n-hexane-diisopropyl ether and dried, giving a named connection (39,20 g). ESI-MS M/E: 256 [M-N]-.

Example of preparation 116: TRANS-4-(tert-butoxycarbonylamino)cyclohexanecarbonyl acid

Methyl-TRANS-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (44,78 g)obtained in example of preparation 112, process, method, similar to that described in example of preparation 115, which gives a named connection (24,04 g), ESI-MS M/E: 242 [M-N]-.

Example of preparation 117: Hydrochloride, TRANS-4-dietilaminoetoksietanola acid

(1) Hydrochloride methyl-TRANS-4-aminocyclohexanecarboxylic (93.0 g)obtained in example of preparation 113(1), dissolved in methanol (1000 ml), add aqueous 35% formaldehyde solution (95,4 ml), sodium acetate (39,4 g) and 10% solution of palladium on coal (10 g) and the mixture is stirred for 3.5 hours in an atmosphere of hydrogen pressure. Insoluble products are removed by filtration, the filtrate is concentrated under reduced pressure, the resulting residue add aqueous 20% potassium carbonate solution (500 ml) and the reaction mixture is extracted with chloroform. The organic layer is dried over sodium sulfate and potassium carbonate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: n-hexane/ethyl acetate =2/1), which gives methyl TRANS-4-dimethylaminoethylmethacrylate (of 87.3 g). APCI-MS M/E: 186 [M+H]+.

(2) Methyl TRANS-4-dimethylaminoethoxy-carboxylate (27,6 g)obtained in example of preparation 117(1), dissolved in dioxane (300 ml) and water (100 ml), added 6N hydrochloric acid (50 ml) and the mixture is heated at boiling temperature under reflux for 4 hours. To the mixture add 6N hydrochloric acid (50 ml) and the reaction mixture is heated at boiling temperature under reflux for another hour. The reaction solution concentrate at eigendom pressure, subjected to azeotropic distillation with toluene, and then the obtained residue is suspended in diisopropyl ether. Precipitation is collected by filtration, washed with diisopropyl ether and dried, giving a named connection (27.5 g). APCI-MS M/E: 172 [M+H]+.

Example of preparation 118: Hydrochloride, TRANS-4-(pyrrolidin-1-yl)cyclohexanecarbonyl acid

(1) Hydrochloride methyl-TRANS-4-aminocyclohexanecarboxylic (10 g)obtained in example of preparation 113(1), 1,4-diiodobutane (19.2 g), sodium carbonate (16.4 g) is suspended in a mixture of tetrahydrofuran (300 ml) and N,N-dimethylacetamide (60 ml) and the mixture is stirred at a temperature of 70°C for 20 hours. The reaction solution is concentrated under reduced pressure, the residue dissolved in a mixture of ethyl acetate-water and the organic layer separated. The organic layer is washed with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: ethyl acetate/hexane =1/5), which gives methyl TRANS-4-(pyrrolidin-1-yl)cyclohexanecarboxylate (10,9 g). APCI-MS M/E: 212 [M+H]+.

(2) In a solution of methyl TRANS-4-(pyrrolidin-1-yl)cyclohexanecarboxylate (10,9 g)obtained in example of preparation 118(1), in dioxane (150 ml), added 2N hydrochloric acid is (80 ml) and the mixture is stirred at a temperature of 110° C for 3 hours when evaporation to remove the methanol. The reaction solution is concentrated under reduced pressure, the obtained residue is suspended in diethyl ether and then collected by filtration, giving the named compound (11.1 g). APCI-MS M/E: 198 [M+H]+.

Sample preparation 119: Hydrochloride, TRANS-4-(morpholine-4-yl)cyclohexanecarbonyl acid

(1) Hydrochloride methyl-TRANS-4-aminocyclohexanecarboxylic (47,5 g)obtained in example of preparation 113(1), bis(2-chloroethyl)ether (34,5 ml), sodium carbonate (77.9 g) and sodium iodide (88 g) is suspended in a mixture of tetrahydrofuran (1400 ml) and N,N-dimethylacetamide (280 ml) and the mixture is heated at boiling temperature under reflux for 18 hours. In the reaction solution was added bis(2-chloroethyl) ether (23 ml) and sodium iodide (22 g) and the mixture is heated to boiling point under reflux for a further 6 hours. The reaction solution is concentrated under reduced pressure and the residue dissolved in a mixture of ethyl acetate-water and the organic layer separated. The organic layer is washed with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: a mixture of ethyl acetate/hexane =1/30, then etelaat the/hexane =1/5 and then 1/3), that gives methyl TRANS-4-(morpholine-4-yl)cyclohexanecarboxylate (53,9 g).

APCI-MS M/E: 228 [M+H]+.

(2) In a solution of methyl TRANS-4-(morpholine-4-yl)cyclohexanecarboxylate (53,8 g)obtained in example of preparation 119(1), in dioxane (750 ml), added 2N hydrochloric acid (400 ml) and the mixture is stirred at a temperature of 110°C for 4 hours when evaporation to remove the methanol. The reaction solution is concentrated and the resulting residue is suspended in diethyl ether and then the resulting product is collected by filtration, giving a named connection (of 54.8 g).

APCI-MS M/E: 214 [M+H]+.

Example of preparation 120: Hydrochloride of TRANS-[4-(dimethylamino)cyclohexyl]acetic acid

(1) potassium Hydroxide (12.8 g) was dissolved in water (30 ml) and add diethyl ether (45 ml). While cooling with ice to the mixture is added N-nitroso-N-metalmachine (5,07 g). The reaction solution is stirred for 10 minutes while cooling and the organic layer separated and dried over potassium hydroxide, which gives the solution diazomethane in diethyl ether.

(2) In an argon atmosphere TRANS-4-(tert-butoxycarbonylamino)-cyclohexanecarbonyl acid (3.0 g)obtained in example of preparation 116, suspended in diethyl ether (40 ml), add triethylamine (1.89 ml) at -10 ° °and then the mixture was added dropwise to Isobe is alchoholic (1.75 ml). The reaction solution is stirred at a temperature of -10°C for 30 minutes and the reaction solution at a temperature of -10°With added dropwise a solution of diazomethane in diethyl ether obtained in example of preparation 120(1) and the mixture is heated to room temperature and stirred for 15 hours. While cooling with ice and 10% aqueous citric acid solution was poured into the solution and the organic layer separated. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: a mixture of ethyl acetate/hexane =1/3, then a mixture of ethyl acetate/hexane =1/2), which gives tert-butyl TRANS-[4-(2-diazoacetic)cyclohexyl]carbamate (1.86 g). APCI-MS M/E: 285 [M+NH4]+.

(3) tert-Butyl TRANS-[4-(2-diazoacetic)cyclohexyl]-carbamate (1,62 g)obtained in example of preparation 120(2), dissolved in methanol (30 ml) in the light, shielding the reaction vessel in an argon atmosphere, and the mixture is cooled to a temperature of -25°C. In the reaction solution is added a solution of silver benzoate (153 mg) in triethylamine (2.4 ml) and the mixture is heated to room temperature and stirred for 3 hours. The reaction solution is concentrated under reduced d is the pressure, the precipitate is dissolved in ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride and saturated brine, dried over sodium sulfate and evaporated to remove the solvent, which ensures obtaining methyl-TRANS-4-(tert-butoxycarbonylamino)cyclohexyl]acetate (1.25 g).

APCI-MS M/E: 289 [M+NH4]+.

(4) a solution of methyl TRANS-[4-(tert-butoxycarbonylamino)cyclohexyl]acetate (1.23 g)obtained in example of preparation 120(3), in 1,4-dioxane (8 ml), added 4N solution of hydrogen chloride-dioxane (8 ml) and the mixture is stirred at room temperature for 5 hours. The reaction solution is concentrated to dryness under reduced pressure, giving methyl-TRANS-(4-aminocyclohexane)acetate hydrochloride (898 mg). APCI-MS M/E: 172 [M+H]+.

(5) Under ice cooling to a suspension of the hydrochloride of methyl TRANS-(4-aminocyclohexane)acetate (895 mg)obtained in example of preparation 120(4), in dichloromethane (30 ml), add triethylamine (1.2 ml) and the mixture is stirred. Successively added under ice cooling aqueous 35% formaldehyde solution (1,71 ml) and triacetoxyborohydride sodium (2,74 g). The reaction solution is heated to room temperature and stirred for 6 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into zespri ice cooling and the mixture is extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and then the solvent is removed under reduced pressure, giving methyl-TRANS-[4-(dimethylamino)cyclohexyl]acetate (771 mg). APCI-MS M/E: 200 [M+H]+.

(6) In a solution of methyl TRANS-[4-(dimethylamino)cyclohexyl] acetate (760 mg)obtained in example of preparation 120(5), in dioxane (25 ml)and add 1N hydrochloric acid (15 ml) and the mixture is heated at boiling temperature under reflux for 3 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is suspended in diethyl ether. Precipitation is collected by filtration and dried, giving a named connection (795 mg).

APCI-MS M/E: 186 [M+H]+.

Sample preparation 121: Hydrochloride, TRANS-4-(dimethylaminomethyl)cyclohexanecarbonyl acid

(1) TRANS-4-(aminomethyl)cyclohexanecarbonyl acid (6,29 g) is suspended in methanol (32 ml) and the suspension is added dropwise thionyl chloride (6 ml) under cooling with ice. The reaction solution is heated to room temperature, stirred overnight and concentrated to dryness under reduced pressure, which ensures hydrochloride methyl-TRANS-4-(aminomethyl)-cyclohexanecarboxylate (8.69 g).

APCI-MS M/E: 172 [M+H]+.

(2) Hydrochloride methyl-TRANS-4-(aminomethyl)cyclohexanone the power (8.69 g), obtained in example of preparation 121(1), is suspended in dichloromethane (400 ml), add triethylamine (11.2 ml) and the mixture is stirred at room temperature for several minutes and added 35% aqueous solution of formaldehyde (15,9 ml) and triacetoxyborohydride sodium (25,43 g) under cooling with ice. The reaction solution is heated to room temperature, stirred for 2 hours, the solution is poured a saturated aqueous solution of sodium bicarbonate and the solution extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent, giving methyl-TRANS-4-(dimethylaminomethyl)cyclohexanecarboxylate (7,42 g). APCI-MS M/E: 200 [M+H]+.

(3) Methyl-TRANS-4-(dimethylaminomethyl)-cyclohexanecarboxylate (7,41 g)obtained in example of preparation 121(2), dissolved in dioxane (140 ml), added 2N hydrochloric acid (70 ml) and the mixture is heated at boiling temperature under reflux for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure, the obtained residue is subjected to azeotropic distillation with toluene, and then the obtained product is dried, giving a named connection (8,45 g). APCI-MS M/E: 186 [M+H]+.

Sample preparation 122: TRANS-4-(tert-butoxycarbonylamino)cyclohexylcarbamate the acid

TRANS-4-(aminomethyl)cyclohexanecarbonyl acid (8,35 g) is suspended in dioxane (100 ml), add water (50 ml) and 1N aqueous sodium hydroxide solution (50 ml) and then added dropwise under ice cooling di-tert-butyl dicarbonate (12.7 g). The reaction solution is heated to room temperature, stirred for 4 hours and the reaction solution was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, the pH adjusted to 3-4 by addition of aqueous citric acid and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The precipitate is suspended in n-hexane and the resulting product is collected by filtration and dried, giving a named connection (13,30 g). ESI-MS M/E: 256 [M-N]-.

Sample preparation 123: Hydrochloride ethyl-3-(piperidine-4-yl)propionate

(1) 60% sodium hydride in oil (33,6 g) is suspended in tetrahydrofuran (600 ml) and added dropwise under ice cooling a solution of triethylphosphate (188.4 g) in tetrahydrofuran (100 ml). The mixture is stirred for 0.5 hour under cooling with ice and add dropwise a solution of pyridine-4-carbaldehyde (75,00 g) in tetrahydrofuran (10 ml) and the mixture is stirred for one hour. In the reaction solution is poured onto ice water (1000 ml) under cooling with ice and the mixture extracted with ethyl acetate. The organic layer is washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The precipitate is suspended in a small amount of diisopropyl ether under ice cooling, and the precipitates are collected by filtration. Precipitation is washed successively with a small amount of diisopropyl ether and n-hexane and dried, giving ethyl 3-(pyridin-4-yl)acrylate (77,53 g). APCI-MS M/E: 178 [M+H]+.

(2) Ethyl-3-(pyridin-4-yl)acrylate (28,00 g)obtained in example of preparation 123(1), dissolved in acetic acid (280 ml), added platinum oxide (1.80 g) and the mixture shaken under an atmosphere pressure of hydrogen 55 psi at room temperature for 24 hours. Insoluble products are removed by filtration and the filtrate concentrated under reduced pressure. The precipitate is dissolved in dioxane (200 ml), add 4N hydrogen chloride-dioxane (200 ml) and the mixture is evaporated to remove the solvent under reduced pressure. The precipitate is suspended in a mixture of diethyl ether-diisopropyl ether, precipitates are collected by filtration, washed with diisopropyl ether and dried, giving the name the TES connection (33,50 g). APCI-MS M/E: 186 [M+H]+.

Example of preparation 124: Hydrochloride ethyl (piperidine-4-yl) acetate

Ethyl-(pyridin-4-yl)acetate (50,00 g) dissolved in acetic acid (500 ml), added platinum oxide (3,44 g) and the mixture is shaken under pressure atmosphere of hydrogen 55 psi at room temperature for 20 hours. Insoluble products are removed by filtration, and the filtrate concentrated under reduced pressure. The precipitate is dissolved in dioxane (200 ml), add 4N hydrogen chloride-dioxane (400 ml) and the mixture is then evaporated to remove the solvent under reduced pressure. The precipitate is suspended in a mixture of diethyl ether-diisopropyl ether and the precipitates are collected by filtration, washed with diisopropyl ether and then dried, giving a named connection (61,80 g). APCI-MS M/E: 172 [M+H]+.

Example of preparation 125: Ethyl-3-(1-isopropylpiperazine-4-yl)propionate

Hydrochloride ethyl-3-(piperidine-4-yl)propionate (70,83 g)obtained in example of preparation 123, dissolved in ethanol (700 ml), add 2-iodopropane (38,2 ml) and potassium carbonate (132.3 g) and the mixture is heated at the boiling point under reflux for 6 hours. Insoluble products are removed by filtration and the filtrate concentrated under reduced pressure. The precipitate of Rabba is given by ethyl acetate (800 ml), washed successively with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: a mixture of n-hexane/ethyl acetate =20/1, then 9/1), which gives a named connection (57,13 g). APCI-MS M/E: 228 [M+H]+.

Examples preparation 126-127:

The corresponding compounds are treated in a manner analogous to the one described in example of preparation 125, which provides the following connections.

Example of preparation 128: Hydrochloride 3-(1-isopropylpiperazine-4-yl)propanoic acid

Ethyl-3-(1-isopropylpiperazine-4-yl)propionate (57,12 g)obtained in example of preparation 125, dissolved in dioxane (1200 ml), added 2N hydrochloric acid (600 ml) and the mixture is heated at boiling temperature under reflux for 3 hours. The reaction solution is concentrated under reduced pressure, subjected to azeotropic distillation with dioxane and the resulting residue suspended in a mixture of diethyl ether-diisopropyl ether (1:1, 500 ml). Precipitation is collected by filtration, washed with diisopropyl ether and dried, giving a named connection (55,36 g). APCI-MS M/E: 200 [M+H]+.

Examples preparation 129-130

Appropriate connections amrabat who live way similar to that described in example of preparation 128, which provides the following connections.

Example of preparation 131: 1-(Pyridine-4-yl)piperidine-4-carboxylic acid

Hydrochloride 4-chloropyridine (of 9.55 g) and triethylamine (26,0 ml) dissolved in ethanol (10 ml) and water (30 ml), add utilitarianist (10,00 g) and then the reaction solution is heated at a temperature of 150°C for 96 hours in a sealed flask. After cooling the reaction solution add ethanol and insoluble products are removed by filtration. The filtrate is concentrated under reduced pressure, the obtained residue is suspended in chloroform, precipitation collected by filtration and recrystallized from a mixture of water-N,N-dimethylformamide, giving a named connection (10,34 g). APCI-MS M/E: 207 [M+H]+.

Example of preparation 132: Hydrochloride [1-(pyridine-4-yl)piperidine-4-yl]acetic acid

(1) Hydrochloride ethyl-(piperidine-4-yl)acetate (5,00 g)obtained in example of preparation 124, hydrochloride 4-chloropyridine (3,62 g) and triethylamine (10.1 ml) suspended in xylene (130 ml) and heated at boiling temperature under reflux for 20 hours. The reaction solution is cooled with water and the insoluble products are removed by filtration. The filtrate is concentrated at bonigen the m pressure, the obtained residue was diluted with chloroform, washed with water, dried over magnesium sulfate and then evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: a mixture of chloroform/ethyl acetate =4/1), which gives ethyl-[1-(pyridine-4-yl)piperidine-4-yl]acetate (4.15 g). APCI-MS M/E: 249 [M+H]+.

(2) Ethyl-[1-(pyridine-4-yl)piperidine-4-yl]acetate (4.15 g)obtained in example of preparation 132(1), dissolved in dioxane (200 ml)and add 1N hydrochloric acid (70 ml) and the mixture is heated at boiling temperature under reflux for 4 hours. The reaction solution is concentrated under reduced pressure and the obtained residue lyophilized that gives a named connection (3,90 g). APCI-MS M/E: 221 [M+H]+.

Sample preparation 133: Hydrochloride 3-[1-(pyrimidine-4-yl)piperidine-4-yl]-propanoic acid

(1) Hydrochloride ethyl-3-(piperidine-4-yl)propionate (of 5.00 g)obtained in example of preparation 123, suspended in tetrahydrofuran (50 ml) and added 4,6-dichloropyrimidine (2,80 g) and diisopropylethylamine (13.1 ml) at room temperature. The reaction solution is stirred for 3 hours at room temperature, water is added and the mixture extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, the tub over sodium sulfate and evaporated, to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: a mixture of n-hexane/ethyl acetate =5/1, then 3/1), which gives ethyl-3-[1-(6-chloropyrimidine-4-yl)piperidine-4-yl]propionate (to 5.58 g). APCI-MS M/E: 298/300 [M+H]+.

(2) Ethyl-3-[1-(6-chloropyrimidine-4-yl)piperidine-4-yl]propionate (5,54 g)obtained in example of preparation 133(1), dissolved in ethanol (100 ml), add 10% solution of palladium on coal (0.55 g) and the mixture is stirred for 4 hours in hydrogen atmosphere at normal pressure. Insoluble products are removed by filtration and the filtrate concentrated under reduced pressure. The ethyl acetate and saturated aqueous sodium hydrogen carbonate solution was poured into the obtained residue, the organic layer was separated, washed successively with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure, giving ethyl-3-[1-(pyrimidine-4-yl)piperidine-4-yl]propionate (3.57 g). APCI-MS M/E: 264 [M+H]+.

(3) Ethyl-3-[1-(pyrimidine-4-yl)piperidine-4-yl]-propionate (3,54 g)obtained in example of preparation 133(2), dissolved in dioxane (140 ml)and add 1N hydrochloric acid (70 ml) and the mixture is heated at boiling temperature under reflux for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure and will overhaul diazotrophy distillation with dioxane. The precipitate is suspended in diethyl ether and the resulting product is collected by filtration, washed with diethyl ether and then dried, giving a named connection (3,63 g).

ESI-MS M/E: 234 [M-N]-.

Example of preparation 134: Hydrochloride 3-(1-isopropylpiperazine-4-yl)acrylic acid

(1) Aluminiumhydride lithium (1.10 g) is suspended in tetrahydrofuran (80 ml) and added dropwise under ice cooling a solution of ethyl-1-isopropylpiperazine-4-carboxylate (of 5.00 g)obtained in example of preparation 127, in tetrahydrofuran (30 ml). The reaction solution is stirred for 2 hours while cooling with ice and water (1.1 ml), successively added dropwise 15% aqueous sodium hydroxide solution (1.1 ml) and water (3.3 ml) and stirred for another 10 minutes. In the resulting reaction solution was added potassium carbonate and the mixture is stirred for 20 minutes and then removed by filtration. The filtrate is concentrated under reduced pressure and then the residue purified by chromatography on a column of NH-silica gel (eluent: a mixture of chloroform/ethyl acetate =1/1), giving (1-isopropylpiperazine-4-yl)methanol (4,29 g). APCI-MS M/E: 158 [M+H]+.

(2) Oxalicacid (2.0 ml) dissolved in dichloromethane (120 ml) and added dropwise a solution of DMSO (3.3 ml) in dichloromethane (15 ml) under cooling dry the ice-acetone. After stirring for 10 minutes under ice cooling are added dropwise within 15 minutes to a solution of (1-isopropylpiperazine-4-yl)methanol (3.00 g)obtained in example of preparation 134(1), in dichloromethane (30 ml). After adding the reaction solution is stirred for 2 hours while cooling with ice and added dropwise the triethylamine (13.3 ml) for 10 minutes. The reaction solution is stirred for one hour, until it warms up to room temperature, and then the solution was poured in a saturated aqueous solution of sodium bicarbonate. The mixture is extracted with dichloromethane and evaporated to remove the solvent under reduced pressure. The aqueous layer was extracted with ethyl acetate and the extract was combined with the residue obtained by removing the solvent from the above extract, dichloromethane, washed with water and saturated brine and dried over sodium sulfate. The solvent is evaporated under reduced pressure, giving crude 1-isopropylpiperazine-4-carbaldehyde (1,96 g). APCI-MS M/E: 156 [M+H]+.

(3) Triethylphosphate (of 7.96 g) dissolved in tetrahydrofuran (50 ml) and added gradually 60% sodium hydride in oil (1.45 g) under cooling with ice. After stirring for 20 minutes under ice cooling to the mixture was added 1-isopropylpiperazine-4-carbaldehyde (5,03 g)obtained in example of preparation 134(2), in tetrahydrofuran(25 ml). The reaction solution is stirred for 3 hours, diluted with diethyl ether, water is added and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of NH-silica gel (eluent: a mixture of n-hexane/ethyl acetate =9/1), which gives ethyl 3-(1-isopropylpiperazine-4-yl)acrylate (6,87 g). APCI-MS M/E: 226 [M+H]+.

(4) Ethyl-3-(1-isopropylpiperazine-4-yl)acrylate (1.01 g)obtained in example of preparation 134(3), dissolved in ethanol (20 ml), added 2N aqueous sodium hydroxide solution (4.5 ml) and the mixture is stirred at room temperature for 24 hours. In the reaction solution was added 2N hydrochloric acid (9 ml) and the mixture is concentrated under reduced pressure and then the precipitate lyophilised that gives a named connection (1,43 g). APCI-MS M/E: 198 [M+H]+.

Example of preparation 135: (1-tert-Butoxycarbonylamino-4-yl)acetic acid

(1) Hydrochloride ethyl-(piperidine-4-yl)acetate obtained in example of preparation 124 (10,00 g), suspended in tetrahydrofuran (95 ml) and added dropwise while cooling with ice, add sodium bicarbonate (12,14 g) and water (150 ml) and then add a solution of di-tert-BUTYLCARBAMATE (11,60 g) is tetrahydrofurane (55 ml). The reaction solution was stirred at room temperature for 20 hours, an aqueous solution of potassium carbonate was poured into the solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate =5/1), which gives ethyl-(1-tert-butoxycarbonylamino-4-yl)acetate (13,06 g). APCI-MS M/E: 272 [M+H]+.

(2) Ethyl-(1-tert-butoxycarbonylamino-4-yl)acetate (13,00 g)obtained in example of preparation 135(1), dissolved in a mixture of tetrahydrofuran-ethanol (2:1, 180 ml) and add sodium hydroxide solution (4,80 g) in water (60 ml). The reaction solution was stirred at room temperature overnight, concentrated under reduced pressure and the resulting aqueous layer washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid under ice cooling and then extracted with ethyl acetate. The organic layer is washed with water and saturated brine and then dried with magnesium sulfate. The solvent is evaporated under reduced pressure, giving a named connection (11,10 g). ESI-MS M/E: 242 [M-N]-.

Examples preparation 136-137

The corresponding compounds are treated in a manner analogous to the one described in example th is increasing 135, that gives the following connection.

Example of preparation 138: tert-Butyl 4-carboxymethyl-1-piperidinecarboxylate

(1) tert-Butoxylate (4,49 g) is suspended in N,N-dimethylformamide in an argon atmosphere and the mixture was added dropwise triethylphosphate (of 5.83 g) under cooling with ice. After stirring for 0.5 hour under ice cooling to the reaction solution is added dropwise tert-butyl-4-oxo-1-piperidinecarboxylate (4,07 g) and the mixture is heated to room temperature and stirred for 1.5 hours. In the reaction solution was added ice water with ice cooling, and the precipitates are collected by filtration and dried, giving tert-butyl-4-ethoxycarbonylmethyl-1-piperidinecarboxylate (3,02 g). APCI-MS M/E: 287 [M+NH4]+.

(2) tert-Butyl-4-ethoxycarbonylmethyl-1-piperidinecarboxylate (1.08 g)obtained in example of preparation 138(1), dissolved in dioxane (12 ml)and add 1N aqueous sodium hydroxide solution (8 ml) and the mixture is stirred at room temperature overnight. The reaction solution is acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. Received wasp is OK purified using chromatography on a column of silica gel (eluent: chloroform/methanol =50/1), that gives a named connection (0,72 g). ESI-MS M/E): 240 [M-N]-.

Sample preparation 139: (4-Isopropylpiperazine-1-yl)acetic acid

(1) 1-Isopropylpiperazine (1,21 g) dissolved in acetonitrile (12 ml), add potassium carbonate (3.15 g) and then added dropwise a solution of benzylbromide (2,08 g) in acetonitrile (2 ml). The reaction solution is heated at the boiling point under reflux for one hour, after cooling, insoluble products are removed by filtration and the filtrate concentrated under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: chloroform/methanol =50/1, then 9/1)benzyl(4-isopropylpiperazine-1-yl)acetate (2,84 g).

APCI-MS M/E: 277 [M+H]+.

(2) Benzyl-(4-isopropylpiperazine-1-yl)acetate (2.83 g)obtained in example of preparation 139(1), dissolved in methanol (40 ml), add 10% solution of palladium on coal (0.31 g) and the mixture is then stirred for 7 hours in a hydrogen atmosphere at normal pressure. Insoluble products are removed by filtration, the filtrate is concentrated under reduced pressure, giving a named connection (1,82 g). APCI-MS M/E: 187 [M+H]+.

Example of preparation 140: the Dihydrochloride of 3-(4-isopropylpiperazine-1-yl)propanoic acid

(1) 1-Isopropylate asin (650 mg) was dissolved in acetonitrile (7 ml) and added dropwise tert-butyl acrylate (743 μl) under ice cooling. The reaction solution is heated to room temperature and stirred for 4 hours and add another portion of tert-butyl acrylate (148 μl) and the mixture is then stirred at room temperature for another 10 hours. In the reaction solution further added tert-butyl acrylate (222 μl) and the mixture is stirred for 6 hours, then poured onto water and the solution extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: chloroform/methanol =20/1, then 10/1), which gives tert-butyl 3-(4-isopropylpiperazine-1-yl)propionate (1.18 g). APCI-MS M/E: 257 [M+H]+.

(2) tert-Butyl 3-(4-isopropylpiperazine-1-yl)propionate (1,15 g)obtained in example of preparation 140(1), dissolved in dioxane (10 ml) and added dropwise 4N hydrogen chloride-dioxane (25 ml) and the reaction solution was stirred at room temperature for 48 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is suspended in diethyl ether. Precipitation is collected and dried, giving a named connection (1.06 g). APCI-MS M/E: 201 [M+H]+.

Example of preparation 141: TRANS-4-(3-oxo-morpholine-4-yl)cyclohexanecarbonyl acid

6% sodium Hydride in oil (6,80 g) is suspended in N,N-dimethylacetamide (80 ml) and the mixture was added dropwise over 10 minutes under ice cooling a solution of 2-benzyloxyethanol (12.9 g) in N,N-dimethylacetamide (50 ml). After stirring at room temperature for 15 minutes the reaction solution is cooled with ice, gradually add Chloroacetic acid (8,13 g) and the mixture is stirred at room temperature for 11 hours. The reaction solution is concentrated under reduced pressure, the resulting residue add an aqueous solution of sodium bicarbonate and the mixture was washed with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure, which gives (2-benzyloxyethyl)acetic acid (18,24 g). ESI-MS M/E: 209 [M-N]-.

(2 Benzylacetone)acetic acid (6,51 g)obtained in (1), the hydrochloride of methyl TRANS-4-aminocyclohexanecarboxylic (5,27 g)obtained in example of preparation 113(1), and 1-hydroxybenzotriazole (of 5.06 g) was dissolved in N,N-dimethylformamide (100 ml). To the mixture successively added the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (7,10 g) and triethylamine (4,50 ml) under ice cooling and the mixture is stirred at room temperature for 3 days. The reaction solution is concentrated under reduced pressure, the resulting residue add an aqueous solution of sodium bicarbonate and sesamstraat with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate =1:1, then ethyl acetate), giving methyl-TRANS-4-[2-(2-benzyl-acetoxy)acetylamino]cyclohexanecarboxylate (8,24 g). APCI-MS M/E: 350 [M+H]+.

Methyl-TRANS-4-[2-(2-benzyloxyethyl)acetylamino]cyclohexanecarboxylate (5,09 g)obtained in (2), dissolved in acetic acid (150 ml) and add 5% solution of palladium on coal (1.01 g) and the mixture is stirred for 2,4 hours in hydrogen atmosphere at normal pressure. The reaction solution is filtered to remove the catalyst and then the filtrate is concentrated under reduced pressure. The precipitate is dissolved in chloroform, washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated to remove the solvent, giving methyl-TRANS-4-[2-(2-hydroxyethoxy)acetylamino]cyclohexanecarboxylate (of 3.32 g). APCI-MS M/E: - 260 [M+H]+.

Methyl-TRANS-4-[2-(2-hydroxyethoxy)acetylamino]-cyclohexanecarboxylate (1,37 g)obtained in (3), dissolved in chloroform (15 ml) and add triethylamine (890 μl) under ice cooling. Then add paraply at the same temperature methanesulfonanilide (450 μl). The reaction solution is stirred for 3 hours while cooling with ice, diluted with water and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and remove the solvent by evaporation under reduced pressure, which gives methyl TRANS-4-[2-(2-methanesulfonylaminoethyl)acetylamino]cyclohexanecarboxylate (1,83 g). APCI-MS M/E: 338 [M+H]+.

Methyl-TRANS-4-[2-(2-methanesulfonylaminoethyl)acetylamino]cyclohexanecarboxylate (1.08 g)obtained in (4), dissolved in N,N-dimethylacetamide (15 ml), added 60% sodium hydride in oil (135 mg) under ice cooling and the mixture is stirred for 16 hours at room temperature. In the residue obtained by concentrating the reaction solution under reduced pressure, water is added and the excess of sodium chloride and the mixture extracted with chloroform. The organic layer is dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate =1:1, then ethyl acetate), giving methyl-TRANS-4-(3-oxo-morpholine-4-yl)cyclohexanecarboxylate (715 mg). APCI-MS M/E: 242 [M+H]+.

Methyl-TRANS-4-(3-oxo-morpholine-4-yl)cyclohexanecarboxylate (500 mg)obtained is in (5), treated similarly as in example of preparation 113(4), which gives the named compound (322 mg). ESI-MS M/E: 226 [M-N]-.

Example of preparation 142: TRANS-4-(2-oxo-oxazolidin-3-yl)cyclohexanecarbonyl acid

(1) Hydrochloride methyl-TRANS-4-aminocyclohexanecarboxylic (of 5.00 g)obtained in example of preparation 113(1), dissolved in chloroform (60 ml), add triethylamine (11 ml) under cooling with ice and then add dropwise a solution of 2-chloroethylphosphonic (3.3 ml) in chloroform (10 ml). After stirring at room temperature for 2.5 hours, the reaction solution was added 5% hydrochloric acid and the mixture is then extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and then evaporated to remove the solvent under reduced pressure. The precipitate is suspended in a mixture of chloroform-diisopropyl ether, precipitates are collected by filtration and dried, giving methyl-TRANS-4-(2-chloro-ethoxycarbonylethyl)cyclohexanecarboxylate (5,11 g). APCI-MS M/E: 264/266 [M+H]+.

(2) Methyl TRANS-4-(2-chloroethylamino)cyclohexanecarboxylate (3,70 g)obtained in (1), dissolved in N,N-dimethylacetamide (50 ml), add 60% solution of sodium hydride in oil (630 mg) under ice cooling and the mixture is stirred at room temperature t is the increase of 16.5 hours. In the reaction solution, water is added, the mixture extracted with ethyl acetate, the organic layer washed with water and saturated brine and then dried over sodium sulfate. The solvent is removed by evaporation under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate =1/1, then ethyl acetate), which gives methyl TRANS-4-(2-oxo-oxazolidin-3-yl)cyclohexanecarboxylate (1,83 g). APCI-MS M/E: 228 [M+H]+.

(3) Methyl-TRANS-4-(2-oxo-oxazolidin-3-yl)cyclohexanecarboxylate (1.84 g)obtained in (2), is treated with a method similar to that described in example of preparation 113(4), which gives the named compound (1.75 g). ESI-MS M/E: 212 [M-N]-.

Example of preparation 143: TRANS-4-(2-oxo-pyrrolidin-1-ylmethyl)cyclohexanecarbonyl acid

(1) Hydrochloride methyl-TRANS-4-(aminomethyl)cyclohexanecarboxylate (4,57 g)obtained in example of preparation 121(1), is treated with a method similar to that described in example of preparation 113(2), which gives methyl TRANS-4-(4-chlorobutyrophenone)cyclohexanecarboxylate (5.35 g). APCI-MS M/E: 276/278 [M+H]+.

(2) Methyl TRANS-4-(4-chlorobutyrophenone)cyclohexanecarboxylate (3.75 g)obtained in (1), is treated with a method similar to that described in example of preparation 113(3), which gives methyl TRANS-4-(2-oxo-pyrrolidin-ylmethyl)-cyclohexanecarboxylate (2,07 g). APCI-MS M/E): 240 [M+H]+.

(3) Methyl-TRANS-4-(2-oxo-pyrrolidin-1-ylmethyl)cyclohexanecarboxylate (2,04 g)obtained in (2), is treated with a method similar to that described in example of preparation 113(4), which gives TRANS-4-(2-oxo-pyrrolidin-1-ylmethyl)-cyclohexanecarbonyl acid (2,41 g).

ESI-MS M/E: 224 [M-N]-.

Example of preparation 144: TRANS-4-[(N-acetyl-N-methylamino)methyl]cyclohexanecarbonyl acid

(1) Hydrochloride methyl-TRANS-4-(aminomethyl)cyclohexanecarboxylate (5,86 g)obtained in example of preparation 121(1), dissolved in chloroform (100 ml), add triethylamine (12 ml) under cooling with ice and then add acetylchloride (2,69 g). The mixture is stirred at room temperature for one hour and 40 minutes and the reaction solution was added water and the mixture extracted with chloroform. The organic layer is washed successively with 10% hydrochloric acid, saturated brine, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate =1/1, then ethyl acetate), giving methyl-TRANS-4-(acetamidomethyl)cyclohexanecarboxylate (of 5.92 g). APCI-MS M/E: 214 [M+H]+.

(2) Methyl-Tran is-4-(acetamidomethyl)cyclohexanecarboxylate (4,32 g), obtained in (1), dissolved in N,N-dimethylformamide (50 ml) and added dropwise sequentially 60% solution of sodium hydride in oil (of 1.00 g), methyl iodide (5,91 g) and methanol (5 drops) under cooling with ice. After stirring for 8 hours at room temperature, add sodium hydride (430 mg), methyl iodide (1.5 ml) and methanol (2 drops) and the mixture is stirred for 2 hours. In the reaction solution is added water and the mixture extracted with ethyl acetate. The organic layer is washed with water and dried over sodium sulfate. The solvent is removed by evaporation and the resulting residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate =1/2, then ethyl acetate), giving methyl-TRANS-4-[(N-acetyl-N-methylamino)methyl]cyclohexanecarboxylate (totaling 3.04 g). APCI-MS M/E: 228 [M+H]+.

(3) Methyl-TRANS-4-[(N-acetyl-N-methylamino)-methyl]cyclohexanecarboxylate (3.03 g)obtained in (2), is treated with a method similar to that described in example of preparation 113(4), which gives the named compound (2.67 g).

ESI-MS M/E: 212 [M-N]-.

Example of preparation 145: 5-(2-Oxo-pyrrolidin-1-yl)pentane acid

(1) 5-Aminovaleric acid (7,35 g) dissolved in methanol (50 ml)is added dropwise thionyl chloride (4.9 ml) under ice cooling and the reaction solution is heated to room temperature and ne is amerivault for 17 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is suspended in diethyl ether and the precipitates are collected by filtration, giving the hydrochloride of methyl-5-aminovaleric Ltd (9.93 g). APCI-MS M/E: 132 [M+H]+.

(2) Hydrochloride methyl-5-aminovaleric (1.68 g)obtained in (1), suspended in chloroform (20 ml). In the suspension is added under ice cooling, the triethylamine (2,54 g) and then added dropwise 4-chlorobutyrate (1.55 g). The reaction solution is heated to room temperature, stirred for 2 hours, ice water was poured into the reaction solution and the mixture extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous bicarbonate sodium and saturated brine and then dried over sodium sulfate. The residue is evaporated to remove the solvent under reduced pressure, giving methyl-5-(4-chloroethylamino)pentanoate (2,34 g). APCI-MS M/E: 236/238 [M+H]+.

(3) Methyl-5-(4-chloroethylamino)pentanoate (2,33 g)obtained in (2), dissolved in N,N-dimethylacetamide (20 ml) and slowly added under ice cooling to 60% solution of sodium hydride in oil (0.47 in). The reaction solution is heated to room temperature, stirred for 20 hours and evaporated to remove the solvent under reduced pressure. The obtained residue purified via chromatography on the column of silica gel (eluent: chloroform, then chloroform/ethyl acetate =20/1), which gives methyl 5-(2-oxo-pyrrolidin-1-yl)pentanoate (2.15 g). APCI-MS M/E: 200 [M+H]+.

(4) Methyl-5-(2-oxo-pyrrolidin-1-yl)pentanoate (1,00 g)obtained in (3) is dissolved in methanol (20 ml), added 4N aqueous sodium hydroxide solution (2.5 ml), the reaction solution is heated to room temperature and stirred for 18 hours. The reaction solution was washed with diethyl ether, added 2N hydrochloric acid (5.0 ml) and then concentrated under reduced pressure. The precipitate is extracted with chloroform and dried over sodium sulfate. The product is evaporated to remove the solvent under reduced pressure, giving a named connection (0,90 g). ESI-MS M/E: 184 [M-N]-

Example of preparation 146: Methyl-2-formyl-3-hydroxybenzoate and methyl-4-formyl-3-hydroxybenzoate

Methyl-3-hydroxybenzoate (75,5 g) dissolved in triperoxonane acid (2 l), add at room temperature hexamethylenetetramine (141,4 g) and the mixture is heated at boiling temperature under reflux for 3 hours. The reaction solution is concentrated under reduced pressure, the resulting residue water is added, the pH value of the mixture was adjusted to 8 with potassium carbonate and sodium bicarbonate, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated Rasso the Ohm, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate =8/1, 5/1, then 2/1), which gives methyl 2-formyl-3-hydroxybenzoate (54.6 g) (ESI-MS m/z: 179 [M-N]-) and methyl-4-formyl-3-hydroxybenzoate (4.4 g).

(ESI-MS m/z: 179 [M-N]-).

Example of preparation 147: Methyl 4-cyano-3-hydroxybenzoic

Methyl-4-formyl-3-hydroxybenzoate (1,96 g)obtained in example of preparation 146, dissolved in formic acid (50 ml), add chloride of hydroxylamine (0.85 grams) and sodium formate (0.85 grams) and the mixture is heated at boiling temperature under reflux for 14 hours. The reaction solution is concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The precipitate is suspended in a mixture of chloroform/diisopropyl ether and then precipitates are collected by filtration, giving the named compound (0.66 g). Then the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate =3/2), which gives a named connection (1,08 is). ESI-MS M/E: 176 [M-N]-.

Sample preparation 148: 2-(2-Cyano-5-ethoxycarbonylmethoxy)-N-(5-chloropyridin-2-yl)ndimethylacetamide

Methyl-4-cyano-3-hydroxybenzoate (655 mg)obtained in example of preparation 147, dissolved in acetone (20 ml)is added 2-chloro-N-(5-chloropyridin-2-yl)ndimethylacetamide (897 mg)obtained in example of preparation 20(1), potassium carbonate (773 mg) and sodium iodide (657 mg) and the mixture is heated at boiling temperature under reflux for 40 minutes. The reaction solution is concentrated under reduced pressure, water is added and the mixture extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The precipitate is suspended in a mixture of chloroform-diisopropyl ether and the precipitates are collected by filtration, giving a named connection (1,16 g).

APCI-MS M/E: 346/348 [M+H]+.

Sample preparation 149: 3-Amino-6-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

2-(2-Cyano-5-ethoxycarbonylmethoxy)-N-(5-chloropyridin-2-yl)ndimethylacetamide (1,03 g)obtained in example of preparation 148, dissolved in N,N-dimethylacetamide (10 ml), add sodium carbonate (97 mg) and the mixture is stirred at a temperature of 100°C for 4 hours. React the solution was poured into water (50 ml), precipitation is collected by filtration, washed with water and ethanol and dried, giving a named connection (839 mg). APCI-MS M/E: 346/348 [M+H]+.

Sample preparation 150: Methyl 2-cyano-3-hydroxybenzoic

(1) Methyl-2-formyl-3-hydroxybenzoate (9,23 g)obtained in example of preparation 146, suspended in methanol (150 ml) and aqueous solution (15 ml) of the chloride of hydroxylamine (of 3.56 g) and the suspension is added under ice cooling an aqueous solution (15 ml) sodium acetate (4,36 g). The mixture is heated to room temperature, stirred for 2 hours and then evaporated to remove the methanol. The obtained residue was diluted with water and extracted with chloroform. The organic layer is dried over sodium sulfate and evaporated to remove the solvent under reduced pressure, giving methyl-2-gidroksilaminami-3-hydroxybenzoate (9,89 g). APCI-MS M/E: 196 [M+H]+.

(2) Methyl-2-gidroksilaminami-3-hydroxybenzoate (10,57 g)obtained in (1), suspended in chloroform (100 ml) and add triethylamine (19,35 g) under cooling with ice. At the same temperature in the resulting solution is added dropwise triperoxonane anhydride (25,40 g) for 30 minutes. The reaction solution was stirred at room temperature for 3 days, add saturated aqueous solution of sodium bicarbonate and extracted with chloroform. Organic with the Oh is dried over magnesium sulfate and evaporated, to remove the solvent under reduced pressure. The precipitate is dissolved in methanol (150 ml), add potassium carbonate (15.6 g) and the mixture is stirred at room temperature for 50 minutes. The reaction solution was diluted with water, acidified with concentrated hydrochloric acid and then extracted with chloroform. The organic layer is dried over magnesium sulfate, the solvent is removed by evaporation and the resulting residue suspended in a mixture of ethyl acetate-diisopropyl ether. Precipitation is collected by filtration, giving a named connection (8,71 g). ESI-MS M/E: 176 [M-N]-.

Example of preparation 151: 2-(2-Cyano-3-ethoxycarbonylmethoxy)-N-(5-chloropyridin-2-yl)ndimethylacetamide

Methyl-2-cyano-3-hydroxybenzoate (1.70 g)obtained in example of preparation 150, process, method, similar to that described in example of preparation 148 that provides a named connection (2,69 g). APCI-MS M/E: 346/348 [M+H]+.

Sample preparation 152: 3-Amino-4-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

2-(2-Cyano-3-ethoxycarbonylmethoxy)-N-(5-chloropyridin-2-yl)ndimethylacetamide (1.51 g)obtained in example of preparation 151, is treated in an analogous way to example cooking 149, which gives the named compound (335 mg). APCI-MS M/E: 346/348 [M+H]+.

The sample prepared with the I 153: 3-Amino-5-carboxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-Amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2,01 g) is suspended in tetrahydrofuran (20 ml) - methanol, added 4N aqueous sodium hydroxide solution (5 ml) under ice cooling and the reaction solution was stirred at room temperature for 13 hours. The reaction solution is concentrated under reduced pressure, the obtained residue was diluted with water and the pH value of the mixture was adjusted to approximately 3 with an injection of 10% hydrochloric acid. Precipitation is collected by filtration, washed successively with water and ethanol and dried, giving a named connection (1,87 g). ESI-MS M/E: 330 [M-N]-.

Examples preparation 154-155

Ester obtained in example of preparation 149 or sample preparation 152, process, method, similar to that described in example of preparation 153, which provides the following connections.

Sample preparation 156: 3-Amino-5-dimethylaminoethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-Amino-5-carboxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (1.51 g)obtained in example of preparation 153, suspended in pyridine (15 ml), successively added dimethylamine hydrochloride (0,77 g), 1-hydroxy-benzotriazole (1,37 g) and the hydrochloride of 1-ethyl-3-(3-dimethy the aminopropyl)carbodiimide (1,79 g) under ice cooling and the mixture is stirred at room temperature for 14 hours. The reaction solution was diluted with water (100 ml) and add saturated aqueous sodium hydrogen carbonate solution, bringing the pH to 8-9. Precipitation is collected by filtration, washed successively with water and ethanol and then dried, giving a named connection (1.50 g). APCI-MS M/E: 359/361 [M+H]+.

Examples preparation 157-158

Carboxylic acid, obtained in example of preparation 154 or the sample preparation 155, process, method, similar to that described in example of preparation 156, which provides the following connections.

Industrial application

The compound which has the formula [1]or its pharmaceutically acceptable salt, are less toxic and are safe and possess a strong inhibitory effect on activated factor X in the coagulation of blood. Accordingly, the specified connection [1], it is useful as a drug for the prevention and treatment of diseases caused by thrombus or embolus.

Appendix 1

Experimental example 1

Inhibitory effect on activated factor X (FXa) clotting (coagulation)

blood.

Prepare the substrate solution, the dissolution of S-2222 (chromogenic substrate) to a final concentration of 0.625 mm in 100 mm Tris buffer (pH 8,4)containing 200 mm sodium chloride and 0.1% bovine serum albumin (cow serum, and the solution under test connect the Oia in the buffer, containing 10% dimethyl sulfoxide. 25 μl of the test solution add 200 µl of substrate solution. In the control instead of the solution of test compound in the substrate solution add 25 μl of buffer containing 10% dimethyl sulfoxide.

After a preheating for 3 minutes at 37°in the control and experimental sample add 25 ál of human FXa (Enzyme Research Laboratories, I), dissolved in buffer at a concentration of 0.5 u/ml to initiate the reaction (final concentration of FXa: Of 0.05 u/ml). After 5 minutes of interaction at 37°To continuously measure the absorption at 405 nm using a counter 96 well plates (Spectra MAH, Molecular Devices) and the increase of absorption is used as an index of FXa activity. To determine FXa activity of test compounds is compared to the concentration of the test compounds, FXa inhibitory 50% with the control sample (IC50using analytical method (GraphPad Prism, GraphPad Software, Inc.). Examples of results are shown in table 1.

Table 1
N exampleIC50(nm)
76,4
1310,6
163,3
257,0
5910,5
819,3
967,3
1035,6
1166,8
1466,0
1635,3
1845,2
1957,0
33310,6
3555,0
41411,1
42010,4
4263,6

Experimental example 2.

Antidromically effect with arterial thrombosis in rats

Model animal with thrombosis of arteries is carried out according to the method described in JP.J.PharmacoL. 68.397 (1995); short - induce combinatoria in the descending abdominal aorta 7-8 weeks rats male Wistar rats (Charles River Japan, Inc.). This method provides a rush of blood and hypercoagulation, which leads to the blockage of blood vessels.

The test compound dissolved or suspended in a 0.1% aqueous solution Nikkol PCO-60 (Nikko chemicals), and introduce experimental animal (oral) dose of 10 ml/kg. animal Control receives a 0.1% aqueous solution Nikkol PCO-60 in the same conditions as experienced. After administration of the tested compounds induce the formation of thrombin in the blood. When the level of the tested compounds reaches a peak, 15 minutes after the introduction of the formed thrombin removed and weighed after drying the deposits. Antithrombotic activity estimated using the following formula, where a is the weight of thrombin in test group; In - weight thrombin in the control group. Weight reduction of thrombin (%)=(1-a/b)×100.

Next, calculate the magnitude of the dose, which reduces the weight of thrombin at 50% ED50with using the software GraphPad Prism (GraphPad Software, Inc.). The results are presented in table 2.

Table 2
Test the connection (N sample)ED50(mg/kg, per/oc) (Vienna)ED50(mg/kg, per/OS) (artery)
871,22,5
3061,51,7

Antithrombotic effect on arterial thrombosis in rats

Model animal with thrombosis is carried out according to the method described in Eur.J.PharmacoL, 330,151 (1997); short - induce combinatoria in the descending abdominal aorta 9-10 weeks rats male Wistar rats (Charles River Japan, Inc.) by 4 hours of electrification. The test compound dissolved or suspended in a 0.1% aqueous solution Nikkol PCO-60 (Nikko chemicals), and introduce experimental animal (oral) dose of 10 ml/kg animal. Control animal receives a 0.1% aqueous solution Nikkol PCO-60 in the same conditions as experienced. After the introduction of the test is about connections carry out the electrification of the animal for 4 hours. The test compound is introduced in such a way as to reach the peak concentration in plasma during the process of electrification. Electrification induces the formation of thrombin in the blood. When the test compound reaches its peak, the formed thrombin removed and weighed (wet weight). Antithrombotic activity estimated using the following formula, where a is the weight of thrombin in test group; In - weight thrombin in the control group. Weight reduction of thrombin (%)=(1-A/B)×100.

Next, calculate the magnitude of the dose, which reduces the weight of thrombin at 50% ED50with using the software GraphPad Prism (GraphPad Software, Inc.). The results are presented in table 2.

1. Derived benzofuran formula [1]

where x represents a group of formula-N= or of formula-CH=;

Y represents optionally substituted by an amino group, optionally substituted cycloalkyl group or optionally substituted saturated heterocyclic group;

Rather it represents a simple bond, the carbon chain optionally having a double bond within or at the end(s) of a circuit or an oxygen atom;

R1represents a hydrogen atom, halogen atom, lower alkyl group, lower alkoxygroup, cyano or aminogroup the PU, optionally substituted with lower alkyl groups;

Ring In the formula

represents an optionally substituted benzene ring; and

R3represents a hydrogen atom or a lower alkyl group,

or its pharmaceutically acceptable salt.

2. The compound according to claim 1 in which the ring represents a benzene ring, optionally substituted by group(s)independently selected from a halogen atom, optionally substituted lower alkyl group, a hydroxy-group, optionally substituted lower alkoxygroup, actigraphy, substituted optionally substituted saturated heterocyclic group, substituted carbonyl group, optionally substituted amino, nitro, ceanography, 4,5-dihydroquinoline group or groups of the formula

and optionally substituted cycloalkyl group for Y is cycloalkyl group, optionally substituted with a group selected from optionally substituted amino, optionally substituted by a group of the formula selected from the

and optionally substituted lower alkyl group.

3. The compound according to claim 2, where it is not necessary sameena the saturated heterocyclic group, Y represents a saturated heterocyclic group, optionally substituted with a group selected from the

(1) lower alkyl groups,

(2) a lower alkyl group substituted with peredelnoj group,

(3) piperidino group substituted with a lower alkyl group,

(4) piperidino group,

(5) piperidino group substituted with a lower alkoxycarbonyl group,

(6) an unsaturated heterocyclic group selected from peredelnoj group, pyrimidines group, 4,5-dihydroquinoline group and thiazolidine group,

(7) lower alkanoyloxy group,

(8) lower alkanoyloxy group substituted with di-lower alkylamino,

(9) a carbonyl group substituted with peredelnoj group,

(10) lower alkylsulfonyl group,

(11) lower alkoxycarbonyl group,

(12) a lower alkyl group substituted with di-lower alkylamino, and

(13) the carbonyl group;

optionally substituted amino group Y is an amino group,

optionally substituted with a group selected from the

(1) piperidino group substituted with a lower alkyl group,

(2) a lower alkyl group, and

(3) lower alkoxycarbonyl group;

neovasularization amino group as a substituent on cycloalkyl group Y is an amino group, optionally substituted with a group selected from the

(1) lower alkyl groups,

(2) cycloalkyl group,

(3) hydroxy-lower alkyl group,

(4) 1,3-dioxanone group substituted with a lower alkyl group,

(5) a lower alkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkanoyloxy group, (C) lower alkanoyloxy group substituted by an amino group substituted with a lower alkyl group, and (d) lower alkoxycarbonyl group,

(6) a lower alkyl group substituted with ceanography,

(7) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(8) a lower alkyl group substituted with carboxyl group,

(9) a lower alkyl group substituted with carbamoyl group, optionally substituted with lower alkyl groups,

(10) a lower alkyl group substituted with aryl group,

(11) a lower alkyl group substituted with peredelnoj group,

(12) lower alkoxycarbonyl group,

(13) lower alkanoyloxy group substituted with di-lower alkyl amino group,

(14) ness the th alkanoyloxy group,

(15) pyrimidinyl group,

(16) lower alkanoyloxy group substituted with morpholinyl group,

(17) lower alkylsulfonyl group,

(18) carbamoyl group substituted with a lower alkyl group,

(19) a carbonyl group substituted with aryl group,

(20) lower alkanoyloxy group substituted with lower alkoxygroup,

(21) the lower alkanoyloxy group substituted with lower alkanoyloxy,

(22) aryl group substituted with hydroxyl group, and

(23) a hydroxy-lower alkanoyloxy group;

optionally substituted group of the formula selected from structures

and as Deputy to cycloalkyl group for Y is a group selected from the group patterns

and which is optionally substituted by carbonyl group;

optionally substituted lower alkyl group as a substituent on cycloalkyl group for Y is a lower alkyl group, optionally substituted with a group selected from the

(1) oxopyrrolidin group,

(2) ecomorphological group and

(3) amino groups, optional the nutrient substituted with group, selected from (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group;

optionally substituted lower alkyl group as a substituent for ring b is a lower alkyl group, optionally substituted with a group selected from the

(1) lower alkoxycarbonyl group,

(2) carboxyl group,

(3) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) low alkoxygroup,

(4) a carbonyl group substituted with morpholinyl group,

(5) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(6) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(7) a carbonyl group substituted with hydroxyl group, substituted with piperidine group and

(8) a hydroxyl group;

optionally substituted lower alkoxygroup as a substituent for ring b is a lower alkoxygroup, optionally substituted with a group selected from the

(1) carboxyl the group,

(2) the lower alkoxycarbonyl group,

(3) low alkoxygroup,

(4) a hydroxyl group,

(5) aminochrome, optionally substituted with lower alkoxycarbonyl group,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) a carbonyl group substituted with morpholinyl group, piperidino group or pyrrolidinyl group,

(8) a carbonyl group substituted with hydroxypiperidine group,

(9) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(10) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(11) a carbonyl group substituted with a lower alkylpiperidines group,

(12) amino group, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group,

(13) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) a lower alkyl group substituted with di-lower alkylamino; and

(14) the group of formulas is-O-NH-C (=NH) NH 2;

oxygraph, substituted optionally substituted with saturated heterocyclic group as a substituent for ring b is oxygraph, substituted heterocyclic group, optionally substituted with aryl groups;

substituted carbonyl group as a substituent for ring b is a carbonyl group substituted by a group selected from the following groups:

(1) low alkoxygroup,

(2) a hydroxyl group,

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) low alkoxygroup, (C) lower alkoxy-lower alkyl group, (d) hydroxy-lower alkyl group, (e) a lower alkyl group substituted with amino group, optionally substituted with lower alkyl groups, (f) a lower alkyl group substituted with aryl group, and (g) a lower alkyl group substituted with peredelnoj group,

(4) morpholinyl group, pyrrolidinyl group, piperidino group or thiomorpholine group,

(5) hydroxypiperidine group,

(6) piperidino group, substituted with hydroxy-lower alkyl group,

(7) pyrrolidinyloxy group, substituted with hydroxy-lower alkyl, y is uppy and

(8) lower alkylpiperidines group;

optionally substituted amino group as a substituent for ring b is an amino group, optionally substituted with a group selected from the

(1) lower alkyl groups,

(2) a lower alkoxy-lower alkyl group,

(3) hydroxy-lower alkyl group,

(4) lower alkanoyloxy group,

(5) a lower alkoxy-lower alkanoyloxy group,

(6) hydroxy-lower alkanoyloxy group,

(7) lower alkanoyloxy group substituted with lower alkanoyloxy,

(8) lower alkanoyloxy group substituted with amino group, optionally substituted with a group selected from (a) a lower alkyl group and (b) lower alkanoyloxy group,

(9) lower alkoxycarbonyl group,

(10) lower alkoxycarbonyl group substituted with aryl group,

(11) carbamoyl group substituted with a lower alkyl group,

(12) lower alkylsulfonyl group and

(13) lower alkylsulfonyl group substituted with morpholinyl group.

4. The compound according to claim 3, where In represents an unsaturated benzene ring;

Y is a saturated heterocyclic group, long is Ino substituted with group, selected from the following groups:

(1) lower alkyl groups,

(2) a lower alkyl group substituted with peredelnoj group,

(3) piperidino group substituted with a lower alkyl group,

(4) piperidino group,

(5) piperidino group substituted with a lower alkoxycarbonyl group,

(6) an unsaturated heterocyclic group selected from peredelnoj group, pyrimidinyl group, 4,5-dihydroquinoline group and thiazolidine group,

(7) lower alkanoyloxy group,

(8) lower alkanoyloxy group substituted with di-lower alkylamino,

(9) a carbonyl group substituted with peredelnoj group,

(10) lower alkylsulfonyl group,

(11) lower alkoxycarbonyl group,

(12) a lower alkyl group substituted with di-lower alkylamino and

(13) the carbonyl group.

5. The compound according to claim 3, where In represents an unsaturated benzene ring;

Y represents an amino group, optionally substituted with a group selected from the

(1) piperidino group substituted with a lower alkyl group,

(2) a lower alkyl group, and

(3) lower alkoxycarbonyl group.

6. The connection P3, where In represents an unsaturated benzene ring;

Y represents cycloalkyl group, optionally substituted slodowski groups:

(A) amino group, optionally substituted with the following groups:

(1) lower alkyl groups,

(2) cycloalkyl group,

(3) hydroxy-lower alkyl group,

(4) 1,3-dioxanone group substituted with a lower alkyl group,

(5) a lower alkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkanoyloxy group, (C) lower alkanoyloxy group substituted by an amino group substituted with a lower alkyl group, and (d) lower alkoxycarbonyl group,

(6) a lower alkyl group substituted with ceanography,

(7) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(8) a lower alkyl group substituted with carboxyl group,

(9) a lower alkyl group substituted with carbamoyl group, optionally substituted with lower alkyl groups,

(10) a lower alkyl group substituted with aryl group,

(11) a lower alkyl group substituted with the help peredelnoj group,

(12) lower alkoxycarbonyl group,

(13) lower alkanoyloxy group substituted with di-lower alkyl amino group,

(14) lower alkanoyloxy group,

(15) pyrimidinyl group,

(16) lower alkanoyloxy group substituted with morpholinyl group,

(17) lower alkylsulfonyl group,

(18) carbamoyl group substituted with a lower alkyl group,

(19) a carbonyl group substituted with aryl group,

(20) lower alkanoyloxy group substituted with lower alkoxygroup,

(21) the lower alkanoyloxy group substituted with lower alkanoyloxy,

(22) aryl groups substituted with hydroxy-group and

(23) a hydroxy-lower alkanoyloxy group;

C) a group of the formula selected from structures

which is optionally substituted by carbonyl group; or

C) a lower alkyl group optionally substituted by a group selected from the

(1) oxopyrrolidin group,

(2) ecomorphological group and

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy groups is.

7. The compound according to claim 3 in which the ring represents a benzene ring substituted with a lower alkyl group optionally substituted with a group selected from the

(1) lower alkoxycarbonyl group,

(2) carboxyl group,

(3) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) low alkoxygroup,

(4) a carbonyl group substituted with morpholinyl group,

(5) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(6) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(7) a carbonyl group substituted with hydroxyl group, substituted with piperidine group, and

(8) a hydroxyl group; and

Y is a saturated heterocyclic group optionally substituted with a group selected from the

(1) lower alkyl groups,

(2) a lower alkyl group substituted with peredelnoj group,

(3) piperidino group substituted with a lower alkyl group,

(4) piperidinium,

(5) piperidino group substituted with a lower alkoxycarbonyl group,

(6) an unsaturated heterocyclic group selected from peredelnoj group, pyrimidinyl group, 4,5-dihydroxialumini group and thiazolidine group,

(7) lower alkanoyloxy group,

(8) lower alkanoyloxy group substituted with di-lower alkylamino,

(9) a carbonyl group substituted with peredelnoj group,

(10) lower alkylsulfonyl group,

(11) lower alkoxycarbonyl group,

(12) a lower alkyl group substituted with di-lower alkylamino and

(13)the carbonyl group.

8. The compound according to claim 3 in which the ring represents a benzene ring substituted with a lower alkyl group optionally substituted with a group selected from the

(1) lower alkoxycarbonyl group,

(2) carboxyl group,

(3) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) low alkoxygroup,

(4) a carbonyl group substituted with morpholinyl group,

(5) piperidinylcarbonyl GRU is dust, substituted with hydroxy-lower alkyl group,

(6) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(7) a carbonyl group substituted with hydroxyl group, substituted with piperidine group, and

(8) a hydroxyl group; and

Y represents an amino group, optionally substituted with a group selected from the

(1) piperidino group substituted with a lower alkyl group,

(2) a lower alkyl group, and

(3) lower alkoxycarbonyl group.

9. The compound according to claim 3 in which the ring represents a benzene ring substituted with a lower alkyl group optionally substituted with a group selected from the

(1) lower alkoxycarbonyl group,

(2) carboxyl group,

(3) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) low alkoxygroup,

(4) a carbonyl group substituted with morpholinyl group,

(5) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(6) pyrrolidin karbonilnoj group, substituted with hydroxy-lower alkyl group,

(7) a carbonyl group substituted with hydroxyl group, substituted piperidine group, and

(8) a hydroxyl group; and

Y represents cycloalkyl group, optionally substituted with

of the following groups:

(A) amino group, optionally substituted with the following groups:

(1) lower alkyl groups,

(2) cycloalkyl group,

(3) hydroxy-lower alkyl group,

(4) 1,3-dioxanone group substituted with a lower alkyl group,

(5) a lower alkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkanoyloxy group, (C) lower alkanoyloxy group substituted by an amino group substituted with a lower alkyl group, and (d) lower alkoxycarbonyl group,

(6) a lower alkyl group substituted with ceanography,

(7) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(8) a lower alkyl group substituted with carboxyl group,

(9) a lower alkyl group substituted with carbamoyl group, optionally substituted using Issa alkyl groups,

(10) a lower alkyl group substituted with aryl group,

(11) a lower alkyl group substituted with peredelnoj group,

(12) lower alkoxycarbonyl group,

(13) lower alkanoyloxy group substituted with di-lower alkyl amino group,

(14) lower alkanoyloxy group,

(15) pyrimidinyl group,

(16) lower alkanoyloxy group substituted with morpholinyl group,

(17) lower alkylsulfonyl group,

(18) carbamoyl group substituted with a lower alkyl group,

(19) a carbonyl group substituted with aryl group,

(20) lower alkanoyloxy group substituted with lower alkoxygroup,

(21) the lower alkanoyloxy group substituted with lower alkanoyloxy,

(22) aryl groups substituted with hydroxy-group, and

(23) a hydroxy-lower alkanoyloxy group;

C) groups of the formula selected from structures

which is optionally substituted by carbonyl group; or

C) a lower alkyl group optionally substituted with a group selected from the following groups:

(1) oxopyrrolidin group,

(2) accomo polinelli group and

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group.

10. The compound according to claim 3 in which the ring represents a benzene ring substituted with lower alkoxygroup, optionally substituted with a group selected from the

(1) carboxyl group,

(2) the lower alkoxycarbonyl group,

(3) low alkoxygroup,

(4) a hydroxyl group,

(5) aminochrome, optionally substituted with lower alkoxycarbonyl group,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) a carbonyl group substituted with morpholinyl group, piperidino group or pyrrolidinyl group,

(8) a carbonyl group substituted with hydroxypiperidine group,

(9) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(10) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(11) a carbonyl group substituted with a lower alkylpiperidines group,

(12) amino group, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (the) lower alkanoyloxy group,

(13) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) a lower alkyl group substituted with di-lower alkylamino; and

(14) a group of the formula-O-NH-C(=NH)NH2; and

Y is a saturated heterocyclic group optionally substituted with a group selected from the

(1) lower alkyl groups,

(2) a lower alkyl group substituted with peredelnoj group,

(3) piperidino group substituted with a lower alkyl group,

(4) piperidino group,

(5) piperidino group substituted with a lower alkoxycarbonyl group,

(6) an unsaturated heterocyclic group selected from peredelnoj group, pyrimidinyl group, 4,5-dihydroxialumini group and thiazolidine group,

(7) lower alkanoyloxy group,

(8) lower alkanoyloxy group substituted with di-lower alkylamino,

(9) a carbonyl group substituted with peredelnoj group,

(10) lower alkylsulfonyl group,

(11) lower alkoxycarbonyl group,

(12) lower alkyl gr is PPI, substituted with di-lower alkylamino, and

(13) the carbonyl group.

11. The compound according to claim 3 in which the ring represents a benzene ring substituted with lower alkoxygroup, optionally substituted with a group selected from the

(1) carboxyl group,

(2) the lower alkoxycarbonyl group,

(3) low alkoxygroup,

(4) a hydroxyl group,

(5) aminochrome, optionally substituted with lower alkoxycarbonyl group,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) a carbonyl group substituted with morpholinyl group, piperidino group or pyrrolidinyl group,

(8) a carbonyl group substituted with hydroxypiperidine group,

(9) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(10) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(11) a carbonyl group substituted with a lower alkylpiperidines group,

(12) amino group, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group,

(13) carbamoyl group, optional C is displaced with the help of the group, selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) a lower alkyl group substituted with di-lower alkylamino; and

(14) a group of the formula-O-NH-C(=NH)NH2; and

Y represents an amino group, optionally substituted with a group selected from the

(1) piperidino group substituted with a lower alkyl group,

(2) a lower alkyl group, and

(3) lower alkoxycarbonyl group.

12. The compound according to claim 3 in which the ring represents a benzene ring substituted with lower alkoxygroup, optionally substituted with a group selected from the

(1) carboxyl group,

(2) the lower alkoxycarbonyl group,

(3) low alkoxygroup,

(4) a hydroxyl group,

(5) aminochrome, optionally substituted with lower alkoxycarbonyl group,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) a carbonyl group substituted with morpholinyl group, piperidino group or pyrrolidinyl group,

(8) a carbonyl group substituted with hydroxypiperidine group,

(9) piperidinylcarbonyl the th group, substituted with hydroxy-lower alkyl group,

(10) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(11) a carbonyl group substituted with a lower alkylpiperidines group,

(12) amino group, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group,

(13) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) a lower alkyl group substituted with di-lower alkylamino; and

(14) a group of the formula-O-NH-C(=NH)NH2; and

Y represents cycloalkyl group, optionally substituted with

A) amino group, optionally substituted with the following groups:

(1) lower alkyl groups,

(2) cycloalkyl group,

(3) hydroxy-lower alkyl group,

(4) 1,3-dioxanone group substituted with a lower alkyl group,

(5) a lower alkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) Nisse alkanoyloxy group, (C) lower alkanoyloxy group substituted by an amino group substituted with a lower alkyl group, and (d) lower alkoxycarbonyl group,

(6) a lower alkyl group substituted with ceanography,

(7) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(8) a lower alkyl group substituted with carboxyl group,

(9) a lower alkyl group substituted with carbamoyl group, optionally substituted with lower alkyl groups,

(10) a lower alkyl group substituted with aryl group,

(11) a lower alkyl group substituted with peredelnoj group,

(12) lower alkoxycarbonyl group,

(13) lower alkanoyloxy group substituted with di-lower alkyl amino group,

(14) lower alkanoyloxy group,

(15) pyrimidinyl group,

(16) lower alkanoyloxy group substituted with morpholinyl group,

(17) lower alkylsulfonyl group,

(18) carbamoyl group substituted with a lower alkyl group,

(19) a carbonyl group substituted with aryl group,

(20) lower alkanoyloxy group substituted with lower alkoxygroup,

(21) Issa alkanoyloxy group, substituted with lower alkanoyloxy,

(22) aryl groups substituted with hydroxy-group, and

(23) a hydroxy-lower alkanoyloxy group;

B) groups of the formula selected from structures

which is optionally substituted by carbonyl group; or

C) a lower alkyl group optionally substituted with a group selected from the following groups:

(1) oxopyrrolidin group,

(2) ecomorphological group and

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group.

13. The compound according to claim 3 in which the ring represents a benzene ring substituted with a carbonyl group substituted by a group selected from the

(1) low alkoxygroup,

(2) a hydroxyl group,

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) low alkoxygroup, (C) lower alkoxy-lower alkyl group, (d) hydroxy-lower alkyl group, (e) a lower alkyl group substituted with amino group, optionally substituted with lower alkyl groups, (f) a lower alkyl group substituted with aryl group is (g) a lower alkyl group, substituted with peredelnoj group,

(4) morpholinyl group, pyrrolidinyl group, piperidino group or thiomorpholine group,

(5) hydroxypiperidine group,

(6) piperidino group, substituted with hydroxy-lower alkyl group,

(7) pyrrolidinyloxy group, substituted with hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinilnom group; and

Y is a saturated heterocyclic group optionally substituted with a group chosen from:

(1) lower alkyl groups,

(2) a lower alkyl group substituted with peredelnoj group

(3) piperidino group substituted with a lower alkyl group,

(4) piperidino group,

(5) piperidino group substituted with a lower alkoxycarbonyl group,

(6) an unsaturated heterocyclic group selected from peredelnoj group, pyrimidinyl group, 4,5-dihydroxialumini group and thiazolidine group,

(7) lower alkanoyloxy group,

(8) lower alkanoyloxy group substituted with di-lower alkylamino,

(9) a carbonyl group substituted with peredelnoj group,

(10) lower alkylsulfonyl group,

(11) lower alkoxycarbonyl group,

(12) a lower alkyl group substituted with di-lower alkylamino, and

(13) the carbonyl group.

14. The compound according to claim 3 in which the ring represents a benzene ring substituted with a carbonyl group substituted by a group selected from the

(1) low alkoxygroup,

(2) a hydroxyl group,

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) low alkoxygroup, (C) lower alkoxy-lower alkyl group, (d) hydroxy-lower alkyl group, (e) a lower alkyl group substituted with amino group, optionally substituted with lower alkyl groups, (f) a lower alkyl group substituted with aryl group, and (g) a lower alkyl group substituted with peredelnoj group,

(4) morpholinyl group, pyrrolidinyl group, piperidino group or thiomorpholine group,

(5) hydroxypiperidine group,

(6) piperidino group, substituted with hydroxy-lower alkyl group,

(7) pyrrolidinyloxy group, substituted with hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinilnom group; and

Y represents an amino group, optionally substituted with the group selected from the following groups:

(1) piperidino group substituted with a lower alkyl group,

(2) a lower alkyl group, and

(3) lower alkoxycarbonyl group.

15. The compound according to claim 3 in which the ring represents a benzene ring substituted with a carbonyl group substituted by a group selected from the

(1) low alkoxygroup,

(2) a hydroxyl group,

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) low alkoxygroup, (C) lower alkoxy-lower alkyl group, (d) hydroxy-lower alkyl group, (e) a lower alkyl group substituted with amino group, optionally substituted with lower alkyl groups, (f) a lower alkyl group substituted with aryl group, and (g) a lower alkyl group substituted with peredelnoj group,

(4) morpholinyl group, pyrrolidinyl group, piperidino group or thiomorpholine group,

(5) hydroxypiperidine group,

(6) piperidino group, substituted with hydroxy-lower alkyl group,

(7) pyrrolidinyloxy group, substituted with hydroxy-lower alkyl group, and

(8) lower alkylpiperidines group; and

Y represents qi is alkiline group, optionally substituted with

of the following groups:

(A) amino group, optionally substituted with the following groups:

(1) lower alkyl groups,

(2) cycloalkyl group,

(3) hydroxy-lower alkyl group,

(4) 1,3-dioxanone group substituted with a lower alkyl group,

(5) a lower alkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkanoyloxy group, (C) lower alkanoyloxy group substituted by an amino group substituted with a lower alkyl group, and (d) lower alkoxycarbonyl group,

(6) a lower alkyl group substituted with ceanography,

(7) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(8) a lower alkyl group substituted with carboxyl group,

(9) a lower alkyl group substituted with carbamoyl group, optionally substituted with lower alkyl groups,

(10) a lower alkyl group substituted with aryl group,

(11) a lower alkyl group substituted with peredelnoj group,

(12) lower alkoxycarbonyl group,

(13) lower alkanoyl the Noah group, substituted with di-lower alkyl amino group,

(14) lower alkanoyloxy group,

(15) pyrimidinyl group,

(16) lower alkanoyloxy group substituted with morpholinyl group,

(17) lower alkylsulfonyl group,

(18) carbamoyl group substituted with a lower alkyl group,

(19) a carbonyl group substituted with aryl group,

(20) lower alkanoyloxy group substituted with lower alkoxygroup,

(21) the lower alkanoyloxy group substituted with lower alkanoyloxy,

(22) aryl groups substituted with hydroxy-group, and

(23) a hydroxy-lower alkanoyloxy group;

C) groups of the formula selected from structures

which is optionally substituted by carbonyl group; or

C) a lower alkyl group optionally substituted with a group selected from the

(1) oxopyrrolidin group,

(2) ecomorphological group and

(3) amino groups, optionally substituted with (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group.

16. The compound according to any one of claims 1 to 4, 7, 10 and 13, where rich g is teracycline ring represents a saturated 4-7 membered heterocyclic group, containing from 1 to 4 heteroatoms, independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom.

17. The compound according to any one of claims 1 to 4, 7, 10 and 13, where the saturated heterocyclic group is imidazolidinyl, piperidinyl, piperidyl, piperazinil, morpholinyl, thiomorpholine, homopiperazine, homopiperazin, pyrrolidinyl, oxazolidinyl or 1,3-dioxane.

18. The compound according to claim 3, where a group of the formula

represents a group of the formula

and a group of the formula

represents a group of the formula

or

or R1represents a halogen atom or a lower alkyl group;

R2represents a group selected from the following groups:

(A) a hydrogen atom,

B) a lower alkyl group optionally substituted with a group chosen from:

(1) lower alkoxycarbonyl group,

(2) carboxyl group,

(3) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) lower al the ilen group, substituted with a hydroxyl group and (d) low alkoxygroup,

(4) a carbonyl group substituted with morpholinyl group,

(5) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(6) pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(7) a carbonyl group substituted with hydroxyl group, substituted piperidine group and

(8) a hydroxyl group;

C) the lowest alkoxygroup, optionally substituted with a group chosen from:

(1) carboxyl group,

(2) the lower alkoxycarbonyl group,

(3) low alkoxygroup,

(4) a hydroxyl group,

(5) aminochrome, optionally substituted with lower alkoxycarbonyl group,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) a carbonyl group substituted with morpholinyl group, piperidino group or pyrrolidinyl group,

(8) a carbonyl group substituted with hydroxypiperidine group,

(9) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group,

(10) pyrrolidinylcarbonyl group substituted with Ki-the Roxy-lower alkyl group,

(11) a carbonyl group substituted with a lower alkylpiperidines group,

(12) amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group,

(13) carbamoyl group, optionally substituted with a group selected from (a) lower alkyl groups, (b) a lower alkoxy-lower alkyl group, (C) a lower alkyl group substituted with hydroxyl group, and (d) a lower alkyl group substituted with di-lower alkylamino, and

(14) a group of the formula-O-NH-C(=NH)NH2; or

D) a carbonyl group substituted by a group selected from the

(1) low alkoxygroup,

(2) a hydroxyl group,

(3) amino groups, optionally substituted with a group selected from (a) lower alkyl groups, (b) low alkoxygroup, (C) lower alkoxy-lower alkyl group, (d) hydroxy-lower alkyl group, (e) a lower alkyl group substituted with amino group, optionally substituted with lower alkyl groups, (f) a lower alkyl group substituted with aryl group, and (g) a lower alkyl group substituted with peredelnoj group,

(4) morpholinyl group, pyrrolidinyl gr is PPI, piperidino group or thiomorpholine group,

(5) hydroxypiperidine group,

(6) piperidino group, substituted with hydroxy-lower alkyl group,

(7) pyrrolidinyloxy group, substituted with hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinilnom group;

Rather it represents a simple bond; and

R3represents a hydrogen atom.

19. Connection p, where Y is a group selected from the following groups:

(1) piperidino group substituted with a lower alkyl group,

(2) cycloalkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkyl groups, (b) lower alkoxycarbonyl group and (C) lower alkanoyloxy group, (3) cycloalkyl group, substituted with groups of the formula selected from structures

which is optionally substituted by carbonyl group,

(4) cycloalkyl group substituted by an amino group substituted with a lower alkyl group substituted with amino group, optionally substituted with a group selected from (a) lower alkanoyloxy group and (b) lower alkoxycarbonyl group and

(5) cycloalkyl group substituted with a lower alkyl group substituted with amino group, optionally substituted with lower alkyl group; and

R2represents a group selected from the

(1) a hydrogen atom,

(2) ceanography,

(3) amino groups, optionally substituted with lower alkyl groups,

(4) a hydroxyl group,

(5) low alkoxygroup,

(6) low alkoxygroup substituted with lower alkoxygroup,

(7) low alkoxygroup substituted with hydroxyl group,

(8) low alkoxygroup, substituted with amino, optionally substituted with lower alkyl groups,

(9) lower alkoxycarbonyl group,

(10) a carboxyl group,

(11) aminocarbonyl group, optionally substituted with a group selected from (a) lower alkyl groups, and (b) a hydroxy-lower alkyl group,

(12) morpholinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group or dimorpholinyldiethyl group,

(13) piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group or pyrrolidinylcarbonyl group, substituted with hydroxy-lower ALK is through group

(14) a lower alkyl group,

(15) a lower alkyl group substituted with a lower alkoxycarbonyl group,

(16) carboxy-lower alkyl group,

(17) a lower alkyl group substituted with carbamoyl group, optionally substituted with a group selected from (a) a lower alkyl group and (b) a hydroxy-lower alkyl group,

(18) a lower alkyl group substituted with morpholinylcarbonyl group,

(19) a lower alkyl group substituted with piperidinylcarbonyl group, substituted with hydroxy-lower alkyl group or a lower alkyl group substituted with pyrrolidinylcarbonyl group, substituted with hydroxy-lower alkyl group, or

(20) hydroxy-lower alkyl group.

20. Connection p, where Y represents cycloalkyl group, substituted with groups of the formula selected from structures

which is optionally substituted by carbonyl group or cycloalkyl group substituted with amino group, optionally substituted with a group selected from (a) a lower alkyl group and (b) lower alkanoyloxy group; and

R2represents a group selected from the following the groups:

(1) a hydrogen atom,

(2) amino group, a substituted carbonyl group, optionally substituted with a group selected from (a) a lower alkyl group and (b) a lower alkoxy-lower alkyl group,

(3) lower alkoxycarbonyl group,

(4) morpholinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group or dimorpholinyldiethyl group,

(5) a lower alkyl group substituted with a lower alkyl group, a substituted carbamoyl group,

(6) carboxy-lower alkyl group,

(7) a lower alkyl group substituted with morpholinylcarbonyl group, and

(8) hydroxy-lower alkyl group.

21. Connection p, where Y represents cycloalkyl group substituted with oxopyrrolidin group, cycloalkyl group substituted with ecomorphological group or cycloalkyl group substituted with amino group, optionally substituted with a group selected from (a) a lower alkyl group and (b) lower alkanoyloxy group; and

R2represents a group selected from the

(1) a hydrogen atom,

(2) hydroxy-lower alkyl group,

(3) carboxy-lower alkyl group,

(4) low alkoxygroup, for esenkoy using low alkoxygroup or

(5) a carbonyl group substituted by a group selected from (a) amino group, optionally substituted with lower alkyl groups and (b) morpholinyl group.

22. Connection p, where Y is a group selected from the

(1) cycloalkyl group substituted by an amino group substituted with a lower alkyl group having from 1 to 3 carbon atoms,

(2) cycloalkyl group substituted by an amino group substituted with lower alkanoyloxy group having 1 to 2 carbon atoms,

(3) cycloalkyl group substituted with pyrrolidin-1-ilen group, optionally substituted by carbonyl group,

(4) cycloalkyl group substituted with piperidine-1-ilen group, optionally substituted by carbonyl group,

(5) cycloalkyl group substituted with morpholine-4-ilen group, optionally substituted by carbonyl group,

(6) cycloalkyl group substituted with a lower alkyl group substituted with amino group, substituted with lower alkyl groups having from 1 to 3 carbon atoms, or

(7) cycloalkyl group substituted with a lower alkyl group substituted with amino group, substituted with lower alkanoyloxy group having 1 to 2 carbon atoms.

23. A compound selected from

TRANS-5-dimethylaminoethyl-3-[4-(N-formyl-N-methylamino) cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide;

TRANS-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl]-5-(2-hydroxyethyl)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide;

TRANS-5-(mohlin-4-ylcarbonyl)-3-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylcarbonyl]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide; and

TRANS-3-(4-dimethylaminopropylamine)-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide or its pharmaceutically acceptable salt.

24. Derived benzofuran having the formula [1-1]

where the symbols have the same meanings as defined above,

or its pharmaceutically acceptable salt.

25. Pharmaceutical composition for treating thrombosis, which contains as active ingredient a compound according to any one of claims 1 to 24, above, or its pharmaceutically acceptable salt.

26. A method of treating thrombosis, which includes the introduction of an effective amount of a compound according to any one from (1) to (24)above, or its pharmaceutically acceptable salt to a patient in need of it.

27. The use of compounds according to any one of claims 1 to 24, Kazanovich, or its pharmaceutically acceptable salts for the treatment of patients suffering from thrombosis.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

EFFECT: improved method for treatment, valuable medicinal properties of compounds and composition.

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide of the formula: and to its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition inhibiting activity of protein-tyrosine kinases and comprising the indicated compound, a method for treatment of disorders associated with protein-tyrosine kinases, such as an immune disorder, and oncology disease, and a method for cancer treatment.

EFFECT: valuable biochemical and medicinal properties of compounds and composition.

5 cl, 2 tbl, 581 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of amide of the general formula (I)

wherein X means -CH; Y means -CH or nitrogen atom (N); m = 1 or 2; R1 means (C1-C6)-alkyl, (C1-C)-alkoxy-group, N,N-di-[(C1-C6)-alkyl]-amino-group, heterocyclyl-(C1-C6)-alkyl wherein heterocyclyl represents piperazinyl or homopiperazinyl; n = 3; R2 means halogen atom, (C1-C6)-alkyl; R3 means hydrogen atom; Q means phenyl optionally substituted with cyano-group, or pyridyl optionally substituted with morpholino-group, or their pharmaceutically acceptable salts, to methods for synthesis of indicated compounds, pharmaceutical compositions containing thereof and their using in treatment of diseases or states mediated by cytokines.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and pharmaceutical compositions.

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to anthranylamide derivative selected from compound of formula I or N-oxides thereof, wherein R1 represents methyl, F, Cl, Br; R2 represents F, Cl, Br, I, CF3; R3 represents CF3, Cl, Br, OCH2CF3; R4a represents C1-C4-alkyl; R4b represents H, CH3; and R5 represents Cl, Br, and agriculturally acceptable salt thereof. Also disclosed are composition for pest controlling containing biologically effective amount of formula I and at least one additional component selected from group comprising surfactants, solid and liquid diluents; composition for invertebrate insect controlling containing biologically effective amount of formula I and at least one additional biologically active compound or agent. Also disclosed are method for insect controlling as well as intermediates such as benzoxazinone and parasolocarboxylic acid derivatives.

EFFECT: compounds with insecticide activity, useful in insect controlling.

20 cl, 16 tbl, 33 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new sulfonamide derivatives possessing anti-tumor activity, namely to compounds of the formula (I): wherein R6 means hydroxyl; R7 means methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl; R8 means hydrogen atom; R9 means phenylene; R10 means thienyl, furyl or pyridyl optionally substituted with lower alkyl or halogen atom. Also, invention relates to their derivatives or pharmaceutically acceptable salts or solvates. Invention describes medicinal agents used in treatment or prophylaxis of cancer and for prophylaxis of metastasis. Also, invention describes a case for treatment of cancer in mammal.

EFFECT: improved treatment method, valuable medicinal properties of agent.

5 cl, 17 tbl, 112 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes using 2-morpholyl-6-piperidyl-4-[(4'-(ethoxycarbonyl-5'-1',2',3'-triazol)-1'-yl]-1,3,5-triazine of the formula: as an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on sunflower germinated seeds. The proposed substance allows significant increasing roots and hypocotyls length of seedlings and to expand assortment of the known antidotes.

EFFECT: improved and valuable properties of antidote.

2 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

EFFECT: improved method for treatment, valuable medicinal properties of compounds and composition.

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention describes a new compound 4,6-bis-(morpholyl)-2-[(2'-ethoxyacetyltetrazolyl)-5'-yl]-1,3,5-triazine of the formula: that represents an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on germinating sunflower seeds and seedlings.

EFFECT: valuable properties of compound.

2 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

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