Quinuclidine compounds, medicinal agents comprising thereof and methods for preparing quinuclidine compounds

FIELD: organic chemistry, chemical technology, medicine, biochemistry.

SUBSTANCE: invention relates to quinuclidine compounds of the formula (I) , its salts or their hydrates wherein R1 represents hydroxyl group; W represents: (1) -CH2-CH2-; 2) -CH=CH-, or 3) -C≡C-; HAr represents 5-10-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom that in addition to the group -X-Ar can be substituted with 1-3 groups taken among: (1) halogen atom; (2) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group substituted optionally with: (a) hydroxy-group; (b) (C1-C6)-alkoxycarbonyl; (c) (C1-C6)-alkanoyl optionally substituted with (C1-C6)-alkoxy-group; (d) hydroxylated (C3-C8)-cycloalkyl; (e) (C1-C6)-alkoxy-group; (f) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom, or (g) cyano-group; (3) (C1-C6)-alkoxy-group optionally substituted with: (a) hydroxy-group; (b) (C1-C6)-alkoxy-group optionally substituted with (C1-C6)-alkoxy-group; (c) halogen atom; (d) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (e) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (4) (C1-C6)-alkylthio-group optionally substituted with (C1-C6)-alkoxy-group or hydroxy-group; (5) 5-6-membered heterocyclyloxy-group comprising 1-2 oxygen atoms in heterocycle; (6) amino-group represented by the formula: -N(R3)R4 wherein R3 and R4 are similar or different and each represents hydrogen atom or group taken among: (a) (C1-C6)-alkyl group; (b) (C1-C6)-alkoxy-(C1-C6)-alkyl group; (c) carbonyl substituted with (C6-C14)-aryl; (d) (C6-C14)-arylsulfonyl or (e) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (7) (C3-C8)-cycloalkyl or cycloalkenyl hydrocarbon group optionally substituted with: (a) oxo-group or (b) hydroxy-group; (8) (C6-C14)-aromatic hydrocarbon ring optionally substituted with: (a) (C1-C4)-alkylene dioxy-group or (b) hydroxy-group; (9) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with: (a) cyano-group or (b) (C1-C6)-alkoxy-group; (10) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with one or some groups taken among: (a) hydroxy-group; (b) halogen atom; (c) cyano-group; (d) (C1-C6)-alkoxycarbonyl; (e) (C1-C6)-alkyl; (f) (C1-C6)-alkoxy-group that is optionally substituted with halogen atom or (C1-C6)-alkoxy-group; (g) (C1-C6)-alkanoyl; (h) (C1-C6)-alkoxy-(C1-C6)-alkyl; (i) oxo-group; (j) (C1-C4)-alkylenedioxy-group; (k) (C3-C8)-cycloalkylalkoxy-group or (C3-C8)-cycloalkenylalkoxy-group; (11) carbamoyl of the formula: -CO-N(R5)R6 wherein R5 and R6 can be similar or different and represent hydrogen atom, (C6-C14)-aryl wherein indicated aryl is optionally substituted with halogen atom, or (C3-C8)-cycloalkyl; or R5 and R6 form in common 3-6-membered ring; (12) carbonyl optionally substituted with (C1-C6)-alkoxy-group; X represents: (1) a simple bond; (2) (C1-C6)-alkylene chain; (3) (C1-C6)-alkenylene chain; (4) (C1-C6)-alkynylene chain; or (5) formula: -Q- wherein Q represents oxygen atom or sulfur atom; Ar represents: (1) (C6-C14)-aromatic hydrocarbon ring optionally substituted with one or some groups taken among: (a) halogen atom; (b) (C1-C4)-alkoxy-group or (c) (C1-C6)-alkylthio-group; or (2) 5-6-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom. Compounds of the formula (I) show inhibitory activity with respect to a squalene-synthesizing enzyme. Also, the invention relates to an inhibitor of squalene-synthesizing enzyme and the corresponding medicinal composition based on compound of the invention, a method for prophylaxis and treatment of disease wherein inhibition of squalene-synthesizing enzyme is effective. Also, invention proposes some methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable of medicinal and biochemical properties of com[pounds and composition.

25 cl, 10 tbl, 214 ex

 

This invention relates to a new connection, the method of its production, the inhibitor synthesizing enzyme squalene, an inhibitor of the biosynthesis of cholesterol and inhibitor of the biosynthesis of triglycerides containing such a new connection, as well as to pharmaceutical compositions containing them. More specifically, this connection relates to prophylactic and therapeutic tools for the treatment of hyperlipidemia, including diseases associated with atherosclerosis, and ischemic heart disease.

Prior art

Cholesterol is a Sterol, which is formed in the biosynthesis of all animal cells, except red blood cells, and is a factor that is essential for the preservation of plasma membrane and for the synthesis of steroid hormones. Cholesterol is soluble in fats and exists in the form of hypobaric lipoprotein (LDL=LDL), hyperbaric lipoprotein (HDL=HLD) and the like in the blood. LDL in the blood is included in the cells via the acceptor on the surface of cells and regenerated in free cholesterol after decomposition into constituent parts. This is the main by the inclusion of cholesterol from the outside into the cells. It is also known that the main enzyme involved in the biosynthesis of the acceptor protein for LDL and cholesterol, is subjected to feedback concentration is of Listerine, which is the resulting product. Thus, the level of cholesterol in the cells is maintained and regulated entirely by the mechanism of regulation by feedback akatora LDL and type of the biosynthesis of the enzyme on the basis of the balance between the biosynthesis of the cell itself and the inclusion of LDL outside of the cell.

In recent years it was found that cholesterol is the main cause of hyperlipidemia, and is also the most dangerous factor causing arteriosclerotic disease (e.g., disease with coronary vascular disease with lesions of vascular brain disease with lesions of the aorta and of the disease in peripheral arteries) and coronary heart disease (such as angina and heart attack), creating a serious problem. Hyperlipidemia is defined by any one of the following indicators: blood cholesterol is 220 mg/DL or more neutral lipids are 150 mg/DL or more and hyperbaric urine (HDL)-cholesterol less than 35 mg/DL (Manual Japanese society for atherosclerosis), and a catastrophic disease that causes atherosclerosis, etc. One of the main reasons is the increase of LDL cholesterol in the blood (high cholesterolemia) and the deposition of cholesterol on the inner wall of the blood SOS is Yes. Now suppose that the treatment to reduce serum cholesterol, effectively to prevent the development and progression of arteriosclerosis and the like In recent years, good results have been obtained with the use of an inhibitor of the biosynthesis of cholesterol, especially inhibitor of the enzyme, reducing 3-hydroxy-3-methylglutaryl-COA (HMG-COA), such as pravastatin, instead of conventional medicines fibranova type and nicotinic acid drugs. The inhibitor of the enzyme, reducing HMG-COA, competitive suppresses reduction of HMG-COA enzyme, which enzyme is limiting the rate of cholesterol biosynthesis in the liver, to reduce the speed of the biosynthesis of cholesterol, thereby decreasing the liver's ability to synthesize acceptors LDL cholesterol, decreasing LDL in serum. However, the suppression of the production of avalonbay acid-based suppression of the enzyme, reducing HMG-COA, affects the production of isoprene, including farnesylation acid (FDA). There is therefore a fear as to the effect of, for example, on other metabolic substances such as ubiquinone, dolichol, heme a, isopentyl t-RNA and prenylation received through the isoprene as intermediate compounds. In addition, it was noted the risk of side effects, such cockatrice and myopathy.

Synthesizing enzyme squalene is associated with a membrane enzyme with a molecular mass of 47 kDa and reducirse catalyzes the condensation of head-to-head two molecules FDA for the synthesis of squalene, which is an intermediate compound for the synthesis of cholesterol. In the system of the biosynthesis of cholesterol synthesizing enzyme squalene is in the direction of the system, generating reducing HMG-COA enzyme and isoprene, and therefore the inhibitor synthesizing enzyme squalene, as is almost no effect on the metabolic system other than the system of cholesterol metabolism, and therefore, expected to work like a new depressor cholesterol, which will solve the problems associated with enzyme inhibitor, reducing HMG-COA. Inhibitor synthesizing enzyme squalene, which first reported that it is a connection - analogue FDA and squalene. However, these same compounds have an activity of suppressing the formation of pranipatena and the like in addition to the inhibitory action on the enzyme that synthesizes squalene, and it is difficult to apply these same connections in practice. Meanwhile, it was recently described substituted phenylethanolamine connection and substituted pyridinesulfonamide connection of a particular type, suitable as Inga is itora synthesizing enzyme squalene, in JP-A 7-502283, 8-502731, 8-504803 (U.S. patent 5731323) and 8-509488. However, until now, was not created inhibitor synthesizing enzyme squalene, which can give the effect as a medicinal drug for hyperlipidemia.

Thus, an object of this invention is the search and discovery of a compound that has a stronger suppressive activity on synthesizing enzyme squalene and strong action to reduce cholesterol compared with those connections that are currently in use, and is suitable as a drug for the treatment of hyperlipidemia.

Description of the invention

In view of the foregoing situation, conducted serious research and as a result discovered that specific hinoklidina compounds and their salts possess unprecedented strong suppressive activity against synthesizing enzyme squalene. It was also discovered that these compounds and their salts have a strong activity suppression of cholesterol biosynthesis, activity suppression of the biosynthesis of triglycerides and effect in reducing serum cholesterol and triglycerides-based activity by suppression of the synthesis of squalene. Thus was accomplished the invention. The connection according to this invention is suitable as a drug to treat hyperl is epidemie.

Accordingly, the present invention relates to:

(1) the compound (I)represented by the following formula:

(in which R1represents (1) hydrogen atom or (2) a hydroxyl group; HAr is an aromatic heterocycle which may be substituted by 1-3 groups; Ar represents an optionally substituted aromatic ring; W is a chain, presents (1) -CH2-CH2-that may be substituted, (2) -CH=CH-, which may be substituted, (3)(4) -NH-CO-, (5) -CO-NH-, (6) -NH-CH2-, (7) -CH2-NH-, (8) -CH2-CO-, (9) -CO-CH2-, (10) -NH-S(O)l-, (11) -S(O)l-NH-, (12) -CH2-S(O)lor (13) -S(O)l-CH2- (l is 0, 1 or 2; and X is a chain, presents (1) a single bond, (2) optionally substituted C1-6alkalinous chain, (3) optionally substituted C2-6alkenylamine chain, (4) optionally substituted C2-6alkynylamino chain, (5) the formula-Q- (where Q represents an oxygen atom, a sulfur atom, or N(R2) (where R2is1-6alkyl group or a C1-6alkoxygroup)), (6) -NH-CO-, (7) -CO-NH-, (8) -NH-CH2-, (9) -CH2-NH-, (10) -CH2-CO-, (11) -CO-CH2-, (12) -NH-S(O)m-, (13) -S(O)m-NH-, (14) -CH2-S(O)m-, (15) -S(O)m-CH2- (where m means 0, 1 or 2) or (16) -(CH2)n -O- (where n denotes an integer from 1 to 6), or its salt or hydrate

(2) the compound described in (1), salts thereof or their hydrate, where R1represents (1) hydrogen atom or (2) a hydroxyl group; HAr represents a 5 to 14-membered aromatic heterocycle, which contains 1 to 4 atoms selected from nitrogen atom, sulfur atom, oxygen atom and may be substituted by 1-3 groups selected from (1) halogen atom, (2) hydroxyl group, (3) Tilney group, (4) nitro group, (5) nitrile group, (6) With1-6hydrocarbon group which may be substituted, (7)3-8cyclic hydrocarbon group which may be substituted, (8)6-14aromatic cyclic hydrocarbon group which may be substituted, (9) 5-14-membered aromatic heterocyclic group which may be substituted, (10) 4-10-membered non-aromatic heterocyclic group which may be substituted, (11)1-6alkoxygroup, which may be substituted, (12)3-8cycloalkylcarbonyl, which may be substituted, (14)3-8cyclic uglevodorodnogo, which may be substituted, (15)6-14aromatic uglevodorodakh, which may be substituted, (16) 5-14-membered heterocycle-actigraphy, which may be substituted, (17)6-14aromatic uglevodorodnogo, which may be substituted, (18) 5-1-membered heterocycle-tigraphy, which may be substituted, (19) amino group which may be substituted, (20) azide group, (21) guanidinium, (22) urea group, (23) formyl group, (24)1 - 6midorino group which may be substituted, (25) a substituted carbonyl group, (26) substituted carbonyloxy, (27) carboxyl group which may form a salt, (28) carbamoyl group which may be substituted, (29)1-4alkylenedioxy, which may be substituted, (30) sulfanilic group which may be substituted and (31) sulfonyloxy group which may be substituted; Ar is C6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic heterocycle which may be substituted by one or more groups selected from (1) hydroxyl group, (2) halogen atom, (3)1-6hydrocarbon group which may be substituted, (4)3-8cyclic hydrocarbon group which may be substituted, (5)1-6alkoxygroup, which may be substituted, (6) With3-8cycloalkanes, which may be substituted, (7)1-6uglevodorodnogo, which may be substituted, (8)3-8cyclic uglevodorodnogo, (9)6-14aromatic hydrocarbon cyclic group which may be substituted, (10) 5-14-membered heterocyclic group, which may shall be substituted, (11) an amino group which may be substituted With1-6alkyl group, (12)1-4alkylenedioxy; W is a chain, presents (1) -CH2-CH2-that may be substituted, (2) -CH=CH-, which may be substituted, (3)(4) -NH-CO-, (5) -CO-NH-, (6) -NH-CH2-, (7) -CH2-NH-, (8) -CH2-CO-, (9) -CO-CH2-, (10) -NH-S(O)l-, (11) -S(O)l-NH-, (12) -CH2-S(0)lor (13) -S(O)l-CH2- (l is 0, 1 or 2); X represents a chain, presents (1) a single bond, (2)1-6alkalinous chain which may be substituted, (3)2-6alkenylamine chain which may be substituted, (4)2-6alkynylamino chain which may be substituted, (5) the formula-Q- (where Q represents an oxygen atom, a sulfur atom, or N(R2) (where R2is1-6alkyl group or a C1-6alkoxygroup)), (6) -NH-CO-, (7) -CO-NH-, (8) -NH-CH2-, (9) -CH2-NH-, (10) -CH2-CO-, (11) -CO-CH2-, (12) -NH-S(O)m-, (13) -S(O)m-NH-, (14) -CH2-S(O)m-, (15) -S(O)m-CH2- (where m means 0, 1 or 2) or (16) -(CH2)n-O- (where n is an integer from 1 to 6)

(3) the compound described in (1) or (2), salts thereof or their hydrate, in which R1is a hydroxyl group,

(4) the compound described in (1) or (2), salts thereof or their hydrate, in which W represents-CH2 -CH2-, -CH=CH - or

(5) the compound described in (1) or (2), salts thereof or their hydrate, in which X is a simple bond, -CH2-, -CH2-CH2-, -CH=CH - or-CO-,

(6) the compound described in (1) or (2), salts thereof or their hydrate, where HAr is a 5-14-membered aromatic heterocycle containing 1-4 atoms selected from a nitrogen atom, sulfur atom and oxygen atom and may be substituted by 1-3 groups selected from (1) hydroxyl group, (2) halogen atom, (3) Tilney group, (4) nitro group, (5) nitrile group, (6) With1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be substituted by one or two groups selected from (a) hydroxyl group which may be protected, (b) halogen atom, (C) nitrile group, (d) carboxyl group, (e)3-8cycloalkyl group3-8cycloalkenyl group or3-8cycloalkenyl group, which can be gidroksilirovanii or halogenated, (f)1-6alkoxygroup, which may be substituted by a group selected from a halogen atom, a hydroxyl group, With6-14aryl group, a 5-14-membered heteroaryl group and6-14aryl-C1-6alkoxygroup, (g)3-8cycloalkylcarbonyl, which may be halogenated or hydroxylean is authorized, (h)3-8cycloalkanones, which may be halogenated or gidroksilirovanii, (i) a 5-14-membered alloctype, which may be halogenated or gidroksilirovanii, (j) a 5-14-membered nonaromatic cycle-actigraphy, which may be halogenated or gidroksilirovanii, (k)1-6alkoxycarbonyl group, (l)1-4alkylenedioxy, which may be halogenated, (m)1-6alkanoyloxy group which may be substituted by a group selected from a hydroxyl group, With1-6alkoxygroup and C1-6alkanoyloxy, (n)6-14aryl group which may be substituted by a group selected from a halogen atom, a C1-6calcalkaline group and1-6alkoxygroup, (about) 5 to 14-membered aromatic heterocyclic group which may be substituted by a group selected from a halogen atom, a C1-6alkyl group, a C3-8alkenylphenol group3-8alkenylphenol group and1-6alkoxygroup, (b) 5-10-membered non-aromatic heterocyclic group which may be substituted by a group selected from a halogen atom, a C1-6alkyl group, a C3-8alkenylphenol group3-8alkenylphenol group and1-6alkoxygroup, (q) group (EtO)2RO-, (r) acetyl group (s) sulfonyloxy group which may be substituted group is, selected from C1-6hydrocarbon group, mono-(C1-6hydrocarbon)amino group, (t) an amino group which may be substituted With1-6hydrocarbon group, (u)1-6the hydrocarbon-tigraphy, which can be gidroksilirovanii or halogenated, and (v) carbamoyl group which may be substituted With1-6hydrocarbon group, (7)3-8cycloalkyl group or3-8cycloalkenyl group which may be substituted by one or two groups selected from (a) hydroxyl group, (b) halogen atom, (C) nitrile group, (d) carboxyl group, (e)1-6alkyl group which may be substituted by a group selected from C1-6alkoxygroup, which can be gidroksilirovanii or halogenated,1-6uglevodorodnogo, which may be halogenated, an amino group which may be substituted With1-6hydrocarbon group and1-6alkanoyloxy group, (f)2-6alkenylphenol group which may be substituted by a group selected from C1-6alkoxygroup, which can be gidroksilirovanii or halogenated,1-6uglevodorodnogo, which may be halogenated, an amino group which may be substituted With1-6hydrocarbon group and1-6alkanoyloxy group, (g)2-6alkylamino the group, which may be substituted by a group selected from C1-6alkoxygroup, which can be gidroksilirovanii or halogenated,1-6uglevodorodnogo, which may be halogenated, an amino group which may be substituted With1-6hydrocarbon group and1-6alkanoyloxy group, (h) an amino group which may be substituted by a group selected from C1-6alkoxygroup, which can be gidroksilirovanii or halogenated,1-6uglevodorodnogo, which may be halogenated, a C1-6alkanoyloxy group which may be substituted With1-6hydrocarbon group, (i)1-6alkoxygroup, which may be substituted by a group selected from C1-6alkyl groups, which may be gidroksilirovanii or halogenated,1-6alkoxygroup, which can be gidroksilirovanii or halogenated,1-6uglevodorodnogo, which may be halogenated, an amino group which may be substituted With1-6hydrocarbon group and1-6alkanoyloxy group, (j)1-6uglevodorodnogo, which may be substituted by a group selected from C1-6alkyl groups, which may be gidroksilirovanii or halogenated,2-6alkenylphenol group, which may be halogenide is Anna, With1-6alkoxygroup, which can be gidroksilirovanii or halogenated,1-6uglevodorodnogo, which may be halogenated, an amino group which may be substituted With1-6hydrocarbon group and1-6alkanoyloxy group, (k)1-6alkanoyloxy group which may be substituted by a group selected from a hydroxyl group, With1-6alkoxygroup and C1-6alkanoyloxy, (l)6-14aryl group which may be substituted by a group selected from a halogen atom, a C1-6calcalkaline group and1-6alkoxygroup, (m) 5-14-membered aromatic heterocyclic group which may be substituted by a group selected from a halogen atom, a C1-6alkyl group, a C3-8alkenylphenol group3-8alkenylphenol group and1-6alkoxygroup, (n) non-aromatic heterocyclic group which may be substituted by a group selected from a halogen atom, a C1-6alkyl group, a C3-8alkenylphenol group3-8alkenylphenol group and1-6alkoxygroup, (Oh)1-6alkoxycarbonyl group, (R)1-4alkylenedioxy, which may be halogenated, (q) group (EtO)2PO - and (r) acetyl group, (8)6-14aromatic hydrocarbon group which may be substituted by one or more group and, selected from (a) hydroxyl group, (b) halogen atom, (C)1-6alkylsulfonyl group2-6alkanesulfonyl group and2-6alkylsulfonyl group which may be halogenated, (d)1-4alkylenedioxy, which may be halogenated, (e)1-6alkoxygroup, which may be halogenated, (f)1-6uglevodorodnogo, which may be halogenated, (g)1-6alkoxycarbonyl group, (h)6-14aryl-C1-6alkoxygroup, (i)1-7alkanoyl-amino, (j)1-6alkylcarboxylic group, (k)2-6alkenylamine group, (l)2-6alkylcarboxylic group and (m) an amino group which may be substituted With1-6hydrocarbon group, (9) 5-14-membered aromatic heterocyclic group which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) nitrile group, (d)1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, (e)1-6alkoxygroup, which may be halogenated, (f)1-6allylthiourea,2-6altertekhnogrupp or2-6alinytjara, which may be halogenated, (g)1-6alkoxy-C1-6alkylen the th group, (h) acetyl group (i)1-6alkanoyloxy group, (j) mono-(C1-6hydrocarbon) amino, (k) di(C1-6hydrocarbon) amino and (l) three-(C1-6hydrocarbon) amino group, (10) 4-10-membered non-aromatic heterocyclic group which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) nitrile group, (d)1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, (e)1-6alkoxygroup, which may be halogenated, (f)1-6allylthiourea,2-6altertekhnogrupp or2-6alinytjara, which may be halogenated, (g)1-6alkoxy-C1-6alkyl group, (h) acetyl group, a (i)1-6alkanoyloxy group, (j) mono-(C1-6hydrocarbon) amino, (k) di(C1-6hydrocarbon) amino, (l) three-(C1-6hydrocarbon)amino group, (m)1-4alkylenedioxy and (n) carbonyl group, (11)1-6alkoxygroup, which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C)1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be substituted by a group selected from hydroxyl group, halogen atom, 5-1-membered aromatic heterocyclic group and 4-10-membered non-aromatic heterocyclic group, (d)3-8cycloalkyl group or3-8cycloalkenyl group, which can be gidroksilirovanii or halogenated, (e)1-6alkoxygroup, which can be gidroksilirovanii or halogenated, (f)1-6allylthiourea,2-6altertekhnogrupp or2-6alinytjara, which may be halogenated, (g)3-8cycloalkylcarbonyl or3-8cycloalkanones, which may be halogenated, (h)3-8cycloalkylation or3-8cycloalkenyl, which may be halogenated, (i)6-14aryl group, (j)1-6alkalinising group which may be halogenated, (k) 5-14-membered aromatic heterocyclic group, (12)3-8cycloalkylcarbonyl, which may be substituted by one or two groups selected from (a) hydroxyl group, (b) halogen atom, (C)1-6hydrocarbon group which may be substituted by a group selected from hydroxyl group, halogen atom, With1-6alkoxygroup and C1-6alkanoyloxy group, (d)1-6alkoxygroup, which may be substituted by a group selected from a halogen atom, a C1-6alkoxygroup and C1-6alkanoyloxy group and (e)1-6uglevodorodnogo, which may be substituted by a group selected from the volume of halogen, With1-6alkoxygroup and C1-6alkanoyloxy group, (13) With1-6allylthiourea,2-6altertekhnogrupp or2-6alinytjara, which may be substituted by one or two groups selected from (a) hydroxyl group, (b) halogen atom, (C)1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be substituted by a group selected from hydroxyl group, halogen atom, a 5 to 14-membered aromatic heterocyclic group and 4-10-membered non-aromatic heterocyclic group, (d)3-8cycloalkyl group3-8cycloalkenyl group or3-8cycloalkenyl group, which can be gidroksilirovanii or halogenated, (e)1-6alkoxygroup, which can be gidroksilirovanii or halogenated, (f)1-6allylthiourea,2-6, altertekhnogrupp or2-6alinytjara, which may be halogenated, (g)3-8cycloalkylcarbonyl or3-8cycloalkanones, which may be halogenated, (h)3-8cycloalkylation or3-8cycloalkenyl, which may be halogenated, (i)6-14aryl group, (j)1-6alkanoyloxy group which may be halogenated, (k) 5-14-membered aromatic heterocycle eskay group and (l) 4-10-membered non-aromatic heterocycle, (14)3-8cycloalkylation or3-8cycloalkenyl, which may be substituted by one or two groups selected from (a) hydroxyl group, (b) halogen atom, (C)3-8alkyl group, a C3-8alkenylphenol group or3-8alkenylphenol group which may be halogenated, (d)1-6alkoxygroup, which may be halogenated, (e)1-6uglevodorodnogo, which may be halogenated, and (f)1-6alkalinising group which may be halogenated, (15) an amino group represented by the formula-N(R3R4(where R3and R4are the same or different, and each represents a group selected from (a) aromatic heterocyclic group, (b) non-aromatic heterocyclic group, (C)1-6alkyl group, a C2-6alkenylphenol group or1-6alkenylphenol group which may be substituted by a halogen atom or With1-6alkoxygroup, (d)3-8cycloalkyl group or3-8cycloalkenyl group which may be halogenated, (e) a carbonyl group which may be substituted With1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, a C3-8cycloalkyl group or3-8qi is alkenylphenol group, which may be halogenated, a C6-14aryl group or aromatic heterocyclic group, (f)1-6alkanoyloxy group which may be substituted by a group selected from C6-14aryl group and aromatic heterocyclic group, (g) carbamoyl group which may be substituted With1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group6-14aryl group or aromatic heterocyclic group and (h) sulfonyloxy group which may be substituted With1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group, and (i) R3and R4can be connected and combined with the formation of a 3-10-membered ring, and a cyclic amino group may be substituted by one or more groups selected from hydroxyl group, halogen atom, With1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group, C1-6alkoxygroup, C1-6uglevodorodnogo and C1-4alkylenedioxy, (16)6-14alloctype, which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) C1-6alkylsulfonyl group1-6alkanesulfonyl group or1-6alkylsulfonyl g is uppy, which may be halogenated, (d) C1-4alkylenedioxy, which may be halogenated, (e) C1-6alkoxygroup, which may be halogenated, (f) C1-6uglevodorodnogo, which may be halogenated, (g) C1-6alkoxycarbonyl group, (h)6-14aryl-C1-6alkoxygroup, (i) C1-7alkanolamines, (j) C1-6alkylcarboxylic group, (k) C2-6alkenylamine group, (l)2-6alkylcarboxylic group and (m) an amino group which may be substituted C1-6hydrocarbon group, (17)6-14aristocraty, which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) C1-6alkylsulfonyl group2-6alkanesulfonyl group or2-6alkylsulfonyl group which may be halogenated, (d) C1-4alkylenedioxy, which may be halogenated, (e) C1-6alkoxygroup, which may be halogenated, (f) C1-6uglevodorodnogo, which may be halogenated, (g) C1-6alkoxycarbonyl group, (h)6-14aryl-C1-6alkoxygroup, (i) C1-7alkanolamines, (j) C1-6alkylcarboxylic group, (k) C2-6alkenylamine group, (l)2-6alkynylaryl the ilen group and (m) an amino group, which may be substituted C1-6hydrocarbon group, (18) 5-15 membered aromatic heterocycle-actigraphy, which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) nitrile group, (d) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, (e) C1-6alkoxygroup, which may be halogenated, (f) C1-6allylthiourea,2-6altertekhnogrupp or2-6alinytjara, which may be halogenated, (g) C1-6alkoxy-C1-6alkyl group, (h) acetyl group, (i) C1-6alkanoyloxy group, (j) mono-(C1-6hydrocarbon) amino, (k) di(C1-6hydrocarbon) amino and (l) three(C1-6hydrocarbon) amino group, (19) 5-15 membered aromatic heterocycle-tigraphy, which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) nitrile group, (d) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, (e) C1-6alkoxygroup, which may be halogenated, (f) C1-6allylthiourea,2-6altertekhnogrupp or2-6alinytjara that can be galogenidov the tion, (g) C1-6alkoxy - C1-6alkyl group, (h) acetyl group, (i) C1-6alkanoyloxy group, (j) mono-(C1-6hydrocarbon) amino, (k) di(C1-6hydrocarbon) amino and (l) three(C1-6hydrocarbon) amino group, (20) 4-10-membered nonaromatic a heterocycle-actigraphy, which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) nitrile group, (d) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, (e) C1-6alkoxygroup, which may be halogenated, (f) C1-6allylthiourea,2-6altertekhnogrupp or2-6alinytjara, which may be halogenated, (g) C1-6alkoxy-C1-6alkyl group, (h) acetyl group, (i) C1-6alkanoyloxy group, (j) mono-(C1-6hydrocarbon) amino, (k) di(C1-6hydrocarbon) amino and (l) three(C1-6hydrocarbon)amino group, (21) 4-10-membered nonaromatic a heterocycle-tigraphy, which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) nitrile group, (d) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, (e) C1-6al is actigraphy, which may be halogenated, (f) C1-6allylthiourea,2-6altertekhnogrupp or C2-6alinytjara, which may be halogenated, (g) C1-6alkoxy-C1-6alkyl group, (h) acetyl group, (i) C1-6alkanoyloxy group, (j) mono-(C1-6hydrocarbon) amino, (k) di (C1-6hydrocarbon) amino and (l) three(C1-6hydrocarbon) amino group, (22) azide group, (23) guanidinium, (24) urea group, (25) formyl group, (26) C1-6midorino group which may be substituted, (27) C1-6alkanoyloxy group which may be substituted C1-6alkoxygroup, (28) C1-6alkanoyloxy, which may be substituted C1-6alkoxygroup, (29) carboxyl group which may form a salt, (30) carbonyl group which is substituted by a group selected from (a) C1-6alkoxygroup, (b) (C6-14aryl group, and (C) 5-15 membered aromatic heterocyclic group, (31) carbamoyl group represented by the formula-CO-N(R5R6(where R5and R6are the same or different, and each represents a group selected from (a) hydrogen atom, (b) C1-6alkyl group, (C) C2-6alkenylphenol group, (d) C2-6alkenylphenol group, (e)3-8cycloalkyl group, (f)3-8cycloalkenyl, (g)6-14aryl group, and (h) an aromatic heterocyclic group, or (i) R5and R6can connect and unite with the formation of a 3-8-membered ring, (32) C1-4alkylenedioxy, which may be substituted by (a) a hydroxyl group, or (b) halogen atom, (33) sulfanilic group which may be substituted by a group selected from (a) C1-6hydrocarbon group which may be halogenated, and (b) an amino group which may be monogamist or tizamidine C1-6hydrocarbon group which may be halogenated, and (34) sulfonyloxy group which may be substituted by (a) C1-6hydrocarbon group which may be halogenated, or (b) an amino group which may be monogamist or tizamidine C1-6hydrocarbon group which may be halogenated,

(7) the compound described in (1) or (2), salts thereof or their hydrate, where HAr is a 5-14-membered aromatic heterocycle which may be substituted, in addition to the Deputy-X-Ar, 1-3 groups selected from (1) a 5 - or 6-membered aromatic heterocycles, which can be substituted C1-6alkyl group, (2) a 5-6-membered nonaromatic a heterocycle which may be substituted by one or more groups selected from (a) hydroxyl group, (b) C1-6alkyl groups and(C) C 1-6alkoxygroup, (3) C6-10aromatic hydrocarbon ring which may be substituted by one or more groups selected from (a) halogen atom, (b) C1-6alkoxygroup, (C) C1-4alkylenedioxy and (d) sulfonyloxy group which may be substituted C1-6alkyl group, (4) C1-6alkyl group which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) a 5-6-membered aromatic heterocycle and (d) C1-6alkoxygroup and (5) C1-6alkoxygroup, which may be substituted by a halogen atom or a (b) C1-6alkoxygroup,

(8) the compound described in (1) or (2), salts thereof or their hydrate, where HAr represents a 5-10 membered aromatic heterocycle which may be substituted, in addition to the Deputy-X-Ar, 1-3 groups selected from (1) a benzene ring which may be substituted C1-4alkylenedioxy, (2) a pyridine ring, (3) the pyrimidine ring, (4) pyridazinone rings, (5) pirazinamida rings, (6) thiophene rings, (7) piperidino ring which may be substituted C1-6alkoxygroup, (8) piperazinovogo ring which may be substituted C1-6alkoxygroup, (9) pyrolidine ring which may be substituted C1-6alkoxygroup, (10) piperidino rings, the cat is which may be substituted by a hydroxyl group, and C 1-6alkoxygroup, (11) piperazinovogo ring which may be substituted by a hydroxyl group, and C1-6alkoxygroup, (12) pyrolidine ring which may be substituted by a hydroxyl group, and C1-6alkoxygroup, (13) morpholino ring (14) C1-6alkyl group which may be substituted C1-6alkoxygroup, and (15) C1-6alkoxygroup, which may be substituted by a hydroxyl group, and C1-6alkoxygroup,

(9) the compound described in (1) or (2), salts thereof or their hydrate, in which HAr is pyridine ring, pyrimidine ring, pyridazine ring, pyrazinone ring, indole ring, a quinoline ring, a thiophene ring or benzothiophene ring which may be substituted by 1-3 groups

(10) the compound described in (1) or (2), salts thereof or their hydrate, in which HAr is pyridine ring, pyrimidine ring, pyridazine ring, pyrazinone ring, indole ring, a quinoline ring, a thiophene ring or benzothiophene ring which may be substituted, in addition to the Deputy-X-Ar, 1-3 groups selected from (1) a 5-6-membered aromatic heterocycle which may be substituted C1-6alkyl group, (2) a 5-6-membered aromatic heterocycle which may be substituted by one or more groups selected from (a) hydroxyl group, (b) C1-6alkyl groups and (C) C1-6alkoxygroup, (3) C6-10aromatic hydrocarbon ring which may be substituted by one or more groups selected from (a) halogen atom, (b) C1-6alkoxygroup, (C) C1-6alkylenedioxy and (d) sulfonyloxy group which may be substituted C1-6alkyl group, (4) C1-6alkyl group which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) a 5 - or 6-membered heterocycle and (d) C1-6alkoxygroup, and (5) C1-6alkoxygroup, which may be substituted by a halogen atom and (b) C1-6alkoxygroup,

(11) the compound described in (1) or (2), salts thereof or their hydrate, where Ar represents a C6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic heterocycle, which may have 1-3 substituent selected from (1) halogen atom, (2) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be substituted by one or more groups selected from (a) halogen atom, (b) C1-6alkoxygroup and (C) sulfonyloxy group which may be substituted, (3) C1-6alkoxygroup, which may be halogenated, (4) mono-(C1-6alkyl) amino group, (5) di(C1-6alkyl) amino and (6) C1-4Alki is antioxycaps, which may be halogenated,

(12) the compound described in (1) or (2), salts thereof or their hydrate, in which Ar represents optionally substituted benzene ring or pyridine ring,

(13) the compound described in (1) or (2), salts thereof or their hydrate, in which Ar represents a C6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic heterocycle, which may have 1-3 substituent selected from (1) halogen atom, (2) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be substituted by one or more groups selected from (a) halogen atom, (b) C1-6alkoxygroup and (C) sulfonyloxy group which may be substituted, (3) C1-6alkoxygroup, which may be halogenated, (4) mono-(C1-6alkyl) amino group, (5) di(C1-6alkyl) amino and (6) C1-4alkylenedioxy, which may be halogenated,

(14) the compound described in (1) or (2), salts thereof or their hydrate, in which X represents-CH2-; and Ar is a benzene ring,

(15) the compound described in (1) or (2)with the compound represented by the following formula:

(in which HAr is a 5-10 membered aromatic heterocycle containing 1-4 atoms selected from a nitrogen atom, sulfur atom and atom is oxygen, and it can be substituted by 1-3 groups selected from (1) halogen atom, (2) hydroxyl group, (3) Tilney group, (4) nitro group, (5) nitrile group, (6) C1-6hydrocarbon group, (7)3-8cyclic hydrocarbon group which may be substituted, (8) C6-14aromatic cyclic hydrocarbon group which may be substituted, (9) 5-14-membered aromatic heterocyclic group which may be substituted, (10) 4-10-membered non-aromatic heterocyclic group which may be substituted, (11) C1-6alkoxygroup, which may be substituted, (12) C3-8cycloalkylcarbonyl, which may be substituted, (13) C1-6uglevodorodnogo, which may be substituted, (14)3-8cyclic uglevodorodnogo, which may be substituted, (15) C6-14aromatic uglevodorodakh, which may be substituted, (16) 5-14-membered heterocycle-actigraphy, which may be substituted, (17) C6-14aromatic uglevodorodnogo, which may be substituted, (18) 5-14-membered heterocycle-tigraphy, which may be substituted, (19) amino group which may be substituted, (20) azide group, (21) guanidinium, (22) urea group, (23) formyl group, (24) C1-6midorino group which may be substituted, (25) a substituted carbonyl group, (26) is replaced by the military of carbonyloxy, (27) a carboxyl group which may form a salt, (28) carbamoyl group which may be substituted, (29) C1-4alkylenedioxy, which may be substituted, (30) sulfanilic group which may be substituted, and (31) sulfonyloxy group which may be substituted;

Ar represents C6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic heterocycle which may be substituted by a group selected from (1) hydroxyl group, (2) halogen atom, (3) C1-6hydrocarbon group which may be substituted, (4)3-8cyclic hydrocarbon group which may be substituted, (5) C1-6alkoxygroup, which may be substituted, (6) With3-8cycloalkylcarbonyl, which may be substituted, (7) C1-6uglevodorodnogo, which may be substituted, (8)3-8cyclic uglevodorodnogo, (9)6-14aromatic hydrocarbon cyclic group which may be substituted, (10) 5-14-membered heterocyclic group which may be substituted, (11) amino group which may be substituted C1-6alkyl group, (12) C1-4alkylenedioxy; and

X is a chain, presents (1) a single bond, (2) C1-6alkalinous chain which may be substituted, (3) C2-6alkenylamine chain, which can be the replacement of the s, (4) C2-6alkynylamino chain which may be substituted, (5) the formula-Q- (where Q represents an oxygen atom, a sulfur atom, or N(R2) (where R2represents C1-6alkyl group or a C1-6alkoxygroup)), (6) -NH-CO-, (7) -CO-NH-, (8) -NH-CH2-, (9) -CH2-NH-, (10) -CH2-CO-, (11) -CO-CH2-, (12) -NH-S(O)n-, (13) -S(O)m-NH-, (14) -CH2-S(Oh)m-, (15) -S(O)m-CH2- (where m is 0, 1 or 2) or (16) -(CH2)n-O- (where n denotes an integer from 1 to 6), its salt or hydrate

(16) the compound described in (15), its salt or hydrate, in which HAr is a pyridine ring, pyrazinium ring, pyrimidine ring or pyridazinone ring which may be substituted, in addition to the Deputy-X-Ar, one or more groups selected from (1) a 5 - or 6-membered aromatic heterocycle, (2) a 5 - or 6-membered aromatic heterocycle which may be substituted C1-6alkoxygroup, and (3) C6-10aromatic hydrocarbon ring; Ar is a benzene ring or a pyridine ring which may be halogenated; and X represents-CH2-,

(17) the compound described in (15), its salt or hydrate, in which HAr is a pyridine ring, pyrazinium ring, pyrimidine ring or pyridazinone ring which may be substituted, in addition to the mandated is the tel-X-Ar, group selected from (1) C1-6alkoxygroup, which may be substituted by a hydroxyl group, (2) C1-6alkoxy - C1-6alkoxygroup and (3) C1-6alkoxy - C1-6alkylamino; Ar is optionally halogenated benzene or pyridine ring; and X represents-CH2-,

(18) the compound described in (15), its salt or hydrate, in which HAr is a pyridine ring, pyrazinium ring, pyrimidine ring or pyridazinone ring which may be substituted, in addition to the Deputy-X-Ar, 1-3 groups selected from (1) a benzene ring which may be substituted C1-4alkylenedioxy, (2) a pyridine ring, (3) the pyrimidine ring, (4) pyridazinone rings, (5) pirazinamida rings, (6) thiophene rings, (7) piperidino ring which may be substituted C1-6alkoxygroup, (8) piperazinovogo ring which may be substituted C1-6alkoxygroup, (9) pyrolidine ring which may be substituted C1-6alkoxygroup, (10) piperidino ring which may be substituted by a hydroxyl group, and C1-6alkoxygroup, (11) piperazinovogo ring which may be substituted by a hydroxyl group, and C1-6alkoxygroup, (12) pyrolidine ring which may be substituted by a hydroxyl group, and C1-6 alkoxygroup, (13) morpholino ring (14) C1-6alkyl group which may be substituted C1-6alkoxygroup, and (15) C1-6alkoxygroup, which may be substituted by a hydroxyl group or a C1-6alkoxygroup; Ar is a benzene ring or a pyridine ring which may be halogenated; and X represents-CH2-,

(19) the compound described in (1), salts thereof or their hydrate, and this compound is any compound selected from: 3-(4-benzyl-2-phenyl-5-pyrimidyl)ethinyl-3-hinokitiol; 3-[4-benzyl-2-(2-pyridyl)-5-pyrimidyl]ethinyl-3-hinokitiol; 3-[3-benzyl-5-(2-pyridyl)-2-pyridyl]ethinyl-3-hinokitiol;

3-(3-benzyl-5-phenyl-2-pyridyl)ethinyl-3-hinokitiol; 3-[3-benzyl-5-(3-pyridyl)-2-pyridyl]ethinyl-3-hinokitiol; 3-[3-benzyl-5-(4-pyridyl)-2-pyridyl]ethinyl-3-hinokitiol; 3-(3-benzyl-5-Persil-2-pyridyl)ethinyl-3-hinokitiol; 3-[3-benzyl-5-(2-ethoxycarbonylethyl)-2-pyridyl]ethinyl-3-hinokitiol; 3-[3-benzyl-5-(3-oxobutyl)-2-pyridyl]ethinyl-3-hinokitiol; 3-[3-benzyl-5-(3-hydroxybutyl)-2-pyridyl]ethinyl-3-hinokitiol; 3-[2-benzyl-6-(3-methoxypropylamine)-3-pyridyl]ethinyl-3-hinokitiol; 3-[2-benzyl-6-(2 methoxyethoxy)-3-pyridyl]ethinyl-3-hinokitiol; 3-[2-benzyl-6-(3-methoxyphenoxy)-3-pyridyl]ethinyl-3-hinokitiol; 3-[2-benzyl-6-(4-pyridyl)-3-pyridyl]ethinyl-3-hinokitiol; 3-[2-benzyl-6-(3-feast of the deal)-3-pyridyl]ethinyl-3-hinokitiol; 3-(2-benzyl-6-Persil-3-pyridyl)ethinyl-3-hinokitiol; 3-[2-benzyl-6-(2-pyridyl)-3-pyridyl]ethinyl-3-hinokitiol; 3-[4-benzyl-2-(3-pyridyl)-5-pyrimidyl]ethinyl-3-hinokitiol; 3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyrimidyl]ethinyl-3-hinokitiol; 3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethinyl-3-hinokitiol; 3-[4-benzyl-2-(2-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol; 3-[4-benzyl-2-(3-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol; 3-[4-benzyl-2-Persil-5-pyridyl]ethinyl-3-hinokitiol; 3-[4-benzyl-2-(4-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol; 3-[4-benzyl-2-(2-methoxyethoxy)-5-pyridyl]ethinyl-3-hinokitiol; 3-[2-benzyl-6-(4-ethoxycarbonylpyrimidine)-3-pyridyl]ethinyl-3-hinokitiol; 3-[2-benzyl-6-morpholino-3-pyridyl]ethinyl-3-hinokitiol;

3-[2-benzyl-6-(4-methoxypiperidine)-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-(2-methoxyethyl)oxy-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethinyl-3-hinokitiol; (3S)-3-[2-benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-(3-forproper)oxy-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-(1,3-dioxolane-2-yl)metiloksi-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-(3-hydroxypropyl)oxy-3-pyridyl] ethinyl-3-hinokitiol; 3-[2-benzyl-6-[3-(3-methoxycarbonylpropionyl)propyl]oxy-3-pyridyl]ethinyl-3-hinokitiol; 3-[2-benzyl-6-[3-[N-(tert-butoxycarbonyl)-Alan is loxi]propyl]oxy-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[4-benzyl-2-(3-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[4-benzyl-2-(2-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-[(3S,4R)-3-fluoro-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-[(3R,4R)-3,4-dimethoxypyrimidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-5-chloro-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-5-bromo-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-(3,3-atlantooccipital-1-yl)-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-5-chloro-6-(3,3-atlantooccipital-1-yl)-3-pyridyl]ethinyl-C-hinokitiol; (3R)-3-[2-benzyl-6-(CIS-3,4-dimethoxypyridine-1-yl)-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-(3,3-Ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-[(3R)-3-hydroxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[2-benzyl-6-[(3R)-3-methoxy-2-p is religion-1-yl]-3-pyridyl]ethinyl-3-hinokitiol; (3R)-3-[4-benzyl-2-(1,4-dioxan-2-yl)-5-pyridyl]ethinyl-3-hinokitiol and (3R)-3-[4-benzyl-2-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyrimidyl]ethinyl-3-hinokitiol;

(20) the inhibitor synthesizing enzyme squalene-containing compound described in any of (1) to (19), its salt or hydrate

(21) a pharmaceutical composition containing the compound (I)represented by the following formula:

(in which R1represents (1) hydrogen atom or (2) a hydroxyl group; HAr is an aromatic heterocycle which may be substituted by 1-3 groups; Ar represents an optionally substituted aromatic ring; W is a chain, presents (1) -CH2-CH2-that may be substituted, (2) -CH=CH-, which may be substituted, (3)(4) -NH-CO-, (5) -CO-NH-, (6) -NH-CH2-, (7) -CH2-NH-, (8) -CH2-CO-, (9) -CO-CH2-, (10) -NH-S(O)l-, (11) -S(O)l-NH-, (12) -CH2-S(O)lor (13) -S(O)l-CH2- (l is 0, 1 or 2; and X is a chain, presents (1) a single bond, (2) optionally substituted C1-6alkalinous chain, (3) optionally substituted C2-6alkenylamine chain, (4) optionally substituted C2-6alkynylamino chain, (5) the formula-Q- (where Q represents an oxygen atom, a sulfur atom, or N(R2) (where R2performance, which defaults to C 1-6alkyl group or a C1-6alkoxygroup)), (6) -NH-CO-, (7) -CO-NH-, (8) -NH-CH2-, (9) -CH2-NH-, (10) -CH2-CO-, (11) -CO-CH2-, (12) -NH-S(O)m-, (13) -S(O)m-NH-, (14) -CH2-S(O)m-, (15) -S(O)m-CH2- (where m means 0, 1 or 2) or (16) -(CH2)n-O- (where n denotes an integer from 1 to 6)), or its salt or hydrates,

(22) the medicinal composition described in (21), which is a prophylactic or therapeutic agent against diseases, against which effectively suppressing synthesizing enzyme squalene,

(23) the medicinal composition described in (21), which is an inhibitor of the biosynthesis of cholesterol,

(24) the medicinal composition described in (21), which is an inhibitor of the biosynthesis of triglycerides,

(25) the medicinal composition described in (21), which is an agent for the prophylaxis or treatment of hyperlipidemia,

(26) the medicinal composition described in (21), which is an agent for the prevention or treatment of diseases with arterial sclerosis and ischemic heart disease,

(27) the medicinal composition described in (21), which is an agent for the prophylaxis or treatment of hypertension, diseases of the coronary vessels disease with lesions of the cerebral blood vessels, diseases of the aorta, diseases Sparganium peripheral arteries, angina, acute coronary syndromes or myocardial infarction,

(28) the method of obtaining genociding of the compound (IV)represented by the following formula:

(in which And1And2And3and, b, and R1shall have the same meaning as above), its salts or hydrates, which includes the stage of interaction of aromatic heterocyclic compounds (II)represented by the formula:

(in which And1and3are the same or different, and each represents 1) an optionally substituted carbon atom, or 2) heteroatom; And2means 1) optionally substituted carbon atom, or 2) heteroatom or 3) single bond; L represents a group to delete; and a and b are different, and each represents (1) a group-X-Ar (in which X represents a chain, presents (1) single bond; (2) optionally substituted C1-6alkalinous chain; (3) optionally substituted C2-6alkenylamine chain; (4) optionally substituted C2-6alkynylamino chain; (5) the formula-Q- (where Q represents an oxygen atom, a sulfur atom, or N(R2) (where R2represents C1-6alkyl group or a C1-6alkoxygroup)); (6) -NH-CO-, (7) -CO-NH-, (8) -NH-CH2-, (9) -CH2-NH-, (10) -CH2-CO-, (11) -CO-CH2-, (12) -NH-S(O)m -, (13) -S(O)m-NH-, (14) -CH2-S(O)m-, (15) -S(O)m-CH2- (where m means 0, 1 or 2) or (16) -(CH2)n-O- (where n denotes an integer from 1 to 6; and Ar represents an optionally substituted aromatic ring, respectively), or 2) any one group selected from: (1) halogen atom; (2) a hydroxyl group; (3) Tilney group; (4) nitro; (5) a nitrile group; (6) optionally substituted linear C1-6hydrocarbon group; (7) optionally substituted C3-8cyclic hydrocarbon group; (8) optionally substituted C6-14aromatic hydrocarbon cyclic group; (9) optionally substituted 5 to 14-membered aromatic heterocyclic group; (10) optionally substituted 4-10-membered non-aromatic heterocyclic group; (11) optionally substituted C1-6alkoxygroup; (12) optionally substituted C3-8cycloalkylcarbonyl; (13) optionally substituted linear C1-6uglevodorodnogo; (14) optionally substituted C3-8cyclic uglevodorodnogo; (15) optionally substituted C6-14aromatic hydrocarbon-actigraphy; (16) optionally substituted 5 to 14-membered heterocyclic actigraphy; (17) optionally substituted C6-14aromatic uglevodorodnogo; (18) optionally substituted 5 to 14-membered heterocycle is achieved diography; (19) optionally substituted amino group; (20) azide group; (21) guanidinium; (22) carbamide group; (23) a formyl group; (24) optionally substituted C1-6midorino group; (25) a substituted carbonyl group; (26) substituted carbonyloxy; (27) a carboxyl group which forms a salt; (28) optionally substituted carbamoyl group; (29) optionally substituted C1-4alkylenedioxy; (30) optionally substituted sulfanilic group and (31) optionally substituted sulfonyloxy groups, respectively) and genociding compound (III)represented by the following formula:

(where R1denotes a hydrogen atom or a hydroxyl group) in the presence of a Pd catalyst, a copper salt and grounds

(29) the method of obtaining genociding compound (VI)represented by the following formula:

(in which And1And2And3and Ar and R1shall have the same meaning as above), its salts or hydrates, which includes a step of interaction genociding compound (V)represented by the following formula:

(in which And1and3are the same or different, and each represents 1) an optionally substituted carbon atom or (2) Goethe what oatom; And2means 1) optionally substituted carbon atom, 2) heteroatom or 3) single bond; L represents a group to delete; and a denotes the group-S-Ar (where X and Ar have the same meanings as above); and R1denotes a hydrogen atom or a hydroxyl group, respectively), and an aromatic cyclic compounds represented by the following formula:

Ar-M

(in which Ar denotes an optionally substituted aromatic ring, and M denotes an optionally substituted metal atom, respectively) in the presence of Pd catalyst, and

(30) the method of obtaining genociding compound (VIII)represented by the following formula:

(in which And1And2And3and Ar and R1shall have the same meaning as above), its salts or hydrates, which includes a step of interaction genociding compound (VII)represented by the following formula:

(in which And1and3are the same or different, and each represents 1) an optionally substituted carbon atom, or 2) heteroatom; And2means 1) optionally substituted carbon atom, 2) heteroatom or 3) single bond; M represents optionally substituted metal atom; and a represents 1) a group-X-Ar (where X and Ar have Diakonie values, above); and R1denotes a hydrogen atom or a hydroxyl group, respectively), and an aromatic cyclic compounds represented by the following formula:

Ar-L

(in which Ar denotes an optionally substituted aromatic ring, and L represents a group to delete, respectively) in the presence of a Pd catalyst.

This invention also provides a method of prophylaxis and treatment of diseases in which effectively suppressing synthesizing enzyme squalene, by introducing a compound represented by the above formula (I), its salts or hydrates to a patient a pharmacologically effective amount and use of the compounds represented by the above formula (I), its salts or its hydrates, for the manufacture of a prophylactic and therapeutic agent for treating diseases in which effectively suppressing synthesizing enzyme squalene.

In the description of the present invention is the fact that when the structural formula of the compound represents a specific isomer. However, this invention includes isomers such as geometric isomers, optical isomers derived from asymmetric carbon, stereoisomers and tautomers, and is not limited to the formulae given as illustrations for convenience.

Definition wide-angle the terms used in the description of the present invention will be explained below.

In the description of the present invention, the group represented by R1in the above formula (I), means a hydrogen atom or hydroxyl group, and preferably a hydroxyl group.

In the description of this invention, "aromatic heterocycle which may be substituted by 1 to 3 groups represented by HAr in the above formula (I)is preferably, for example, 5 to 14-membered aromatic heterocycle which has 1 to 4 atoms, optionally selected from nitrogen atom, sulfur atom and oxygen atom and may be substituted by 1, 2 or 3 substituents, and more preferably is an aromatic heterocycle which may be substituted by 1-3 groups selected from (1) halogen atom, (2) hydroxyl group, (3) Tilney group, (4) nitro group, (5) nitrile group, (6) C1-6hydrocarbon group which may be substituted, (7)3-8cyclic hydrocarbon group which may be substituted, (8) C6-14aromatic hydrocarbon cyclic group which may be substituted, (9) 5-14-membered aromatic heterocyclic group which may be substituted, (10) 4-10-membered non-aromatic heterocyclic group which may be substituted, (11) C1-6alkoxygroup, which may be substituted, (12)3-8C is coalcorp, which may be substituted, (13) C1-6uglevodorodnogo, which may be substituted, (14)3-8cyclic uglevodorodnogo, which may be substituted, (15)6-14aromatic uglevodorodakh, which may be substituted, (16) 5-14-membered heterocycle-actigraphy, which may be substituted, (17) C6-14aromatic uglevodorodnogo, which may be substituted, (18) 5-14-membered heterocycle-tigraphy, which may be substituted, (19) amino group which may be substituted, (20) azide group, (21) guanidinium, (22) urea group, (23) formyl group, (24) C1-6midorino group which may be substituted, (25) carbonyl group which may be substituted, (26) carbonyloxy, which may be substituted, (27) carboxypropyl, which may be in the form of salts, (28) carbamoyl group which may be substituted, (29) C1-4alkylenedioxy, which may be substituted, (30) sulfanilic group which may be substituted, and (31) sulfonyloxy group which may be substituted.

In the above definition HAr "aromatic heterocycle" means a monocyclic type, disilicate type or tricyclic type of aromatic heterocycles. Their examples include 5-14-membered aromatic heterocyclic group containing 1-4 atoms selected from and what Ohm nitrogen, the sulfur atom and oxygen atom. Namely, aromatic heterocycles containing two or more different atoms selected from nitrogen atom, sulfur atom and oxygen atom, such as nitrogen-containing aromatic heterocycles, such as pyrrole ring, pyridine ring, Spiridonova ring, pyridazine ring, pyrimidine ring, pyrazinone ring, pyrazol ring, imidazole ring, indole ring, isoindole ring, indolizine ring, purine ring, indazol ring, quinoline ring, isoquinoline ring, chinolinowe ring, phthalazinone ring, naphthyridine ring, hinoksolinov ring, hintline ring, cinnoline ring, pteridine ring, imidazothiazole ring, pyrazinamidase ring, acridine ring, phenanthridinium ring, carbazole ring, carbazoles ring, pyrimidine ring, phenanthroline ring and pearsonvue ring; sulfur-containing aromatic heterocycles such as thiophene ring and benzothiophene ring; oxygen-containing aromatic heterocycles such as furan ring, pernovae ring, cyclopentadiene ring, benzopyrrole ring, isobenzofuranone the ring, thiazole ring, isothiazol ring, benzothiazoline ring, benzothiazoline ring, phenothiazine ring, isoxazol the Noah ring, furazane ring, phenoxazine ring, pyrazoloquinoline ring, imidazothiazole ring, thienopyrrole ring, foraperle ring and pyridoxine ring. As preferred examples of the pyrrole ring, pyridine ring, Spiridonova ring, pyrimidine ring, imidazole ring, indole ring, quinoline ring, isoquinoline ring, chinolinowe ring, phthalazinone ring, naphthyridine ring, hintline ring, acridine ring, pearsonvue ring, thiophene ring, benzothiophene ring, furan ring, pernovae ring, benzopyrrole ring, thiazole ring, benzothiazole ring and phenothiazine ring. As more preferred examples of the pyrrole ring, pyridine ring, thiophene ring, benzothiophene ring, thiazole ring and benzothiazole ring.

In the above definition of "halogen atom" means a halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, preferably fluorine atom, chlorine atom and bromine atom.

"C1-6Hydrocarbon group" in the "C1-6hydrocarbon group which may be substituted"represented as Deputy HAr means "C1-6alkyl group", "C2-6alkenylphenol group" and "C2-6quinil the ing group. As "C1-6alkyl group", for example, preferred are C1-6alkyl group with straight or branched chain, such as methyl group, ethyl group, n-sawn group, isopropyl group, sec-through group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, isopentyl group, sec-pencilina group, tert-pencilina group, n-exilda group, isohexyl group, 1,2-dimethylpropylene group, 2-ethylpropyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1,2-triethylphosphine group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-methylpentyl group and 3-methylpentyl group. As "C2-6alkenylphenol group" preferred2-6alkeneamine group with a straight or branched chain, such as vinyl group, allyl group, isoprenaline group, 1-propene-2-ilen group, 1-butene-1-ilen group, 1-butene-2-ilen group, 1-butene-3-ilen group, 2-butene-1-ilen group and 2-butene-2-ilen group. As "C2-6alkenylphenol groups are preferred etinilnoy group, proponila group, Butyrina group, puntinella group and hexanaldehyde. Moreover, the term "may be substituted" means, which may be substituted by one or two groups selected from, for example, (1) hydroxyl group which may be protected, (2) halogen atom, (3) nitrile group, (4) carboxyl group, (5)3-8cycloalkyl group3-8cycloalkenyl group or3-8cycloalkenyl group, which can be gidroksilirovanii or halogenated, (6) C1-6alkoxygroup, which may be substituted by a group selected from a halogen atom, a hydroxyl group, a C6-14aryl group, a 5-14-membered heteroaryl group and6-14aryl - C1-6alkoxygroup, (7)3-8cycloalkylcarbonyl, which may be halogenated or gidroksilirovanii, (8)3-8cycloalkanones, which may be halogenated or gidroksilirovanii, (9) C1-6alkoxycarbonyl group, (10) C1-4alkylenedioxy, which may be halogenated, (11) C1-6alkanoyloxy group which may be substituted by a group selected from a hydroxyl group, a C1-6alkoxygroup and C1-6alkanoyloxy, (12) C6-14aryl group which may be substituted by a group selected from a halogen atom, a C1-6alkyl groups and C1-6alkoxygroup, (13) 5-14-membered aromatic heterocyclic groups which, which may be substituted by a group selected from a halogen atom, a C1-6alkyl group, a C3-8alkenylphenol group3-8alkenylphenol group and C1-6alkoxygroup, (14) 4-10-membered aromatic heterocyclic group which may be substituted by a group selected from a halogen atom, a C1-6alkyl group, a C3-8alkenylphenol group3-8alkenylphenol group and C1-6alkoxygroup, (15) group (EtO)2PO-, (16) acetyl group, (17) sulfonyloxy group which may be substituted by a group selected from C1-6hydrocarbon group, mono-(C1-6hydrocarbon)amino and di(C1-6hydrocarbon)amino group, (18) amino group which may be substituted C1-6hydrocarbon group, (19) C1-6uglevodorodnogo, which can be gidroksilirovanii or halogenated, and (20) carbamoyl group which may be substituted C1-6hydrocarbon group.

"C1-6Hydrocarbon group which may be substituted" is preferably C1-6hydrocarbon group which may be substituted by one or two groups selected from (1) hydroxyl group, (2) halogen atom, (3) nitrile group, (4) C1-6cycloalkyl group, (5) C1-6alkoxygroup, (6) C1-6alkoxy-C1-6alkoxygroup, (7) C1-4alkilani is a system of groups, (8) C1-6alkoxycarbonyl group, (9) C1-6alkanoyloxy group, (10) C1-6alkoxy-C1-6alkanoyloxy group, (11) C1-6alkanoyloxy, (12) C1-6alkanoyloxy-C1-6alkanoyloxy group, (13) 5-14-membered heterocyclic group, (14) 5-10-membered condensed heterocyclic group which may be substituted C1-6alkoxygroup, (15) carboxyl group, (16) (EtO)2PO and (17) C1-6alkylsulfonyl group, and more preferably, substituted C1-6hydrocarbon group, such as (1) unsubstituted C1-6hydrocarbon group such as ethyl group, through the group and 2-propen-1-ilen group, (2) C1-6hydrocarbon group, substituted C6-14aromatic hydrocarbon group such as phenyl group, (3) C1-6hydrocarbon group, substituted 5 to 14-membered aromatic heterocyclic group, such as Peregrina group, and (4) substituted C1-6hydrocarbon group, such as C1-6alkoxy-C1-6hydrocarbon group.

In the above definition, for example, "C1-6hydrocarbon group which may be halogenated" means any one of the carbon atoms of C1-6the hydrocarbon group may be substituted by a halogen atom. Its specific examples include triptorelin group 2 is ratelow group, 1,2-dichloroethylene group, 2-bromatology group, 3-bromatology group, 3,3,3-triptorelin group, 4-chlorobutanol group, 1,1-dimethyl-3-chloraniline group, 2,2-dimethyl-4-bromatology group and 3-chloro-2-propenyloxy group. Moreover, "C1-6alkoxygroup, which may be halogenated" means any one of the carbon atoms of C1-6alkoxygroup" may be substituted by a halogen atom. Specific examples include cryptometer, 2-chlorethoxyfos, 1,2-declarationthree, 2-pomatocalpa, 3-bromopropylamine, 3,3,3-cryptocomplexity, 4-chlorotyrosine, 1,1-dimethyl-3-choreograph and 2,2-dimethyl-4-brombutylruber.

"C3-8cyclic hydrocarbon group" in the "C3-8cyclic hydrocarbon group which may be substituted", represented as Deputy HAr means "C3-8cycloalkyl group", "C3-8cycloalkenyl group", etc. as "C3-8cycloalkyl group" preferred such 3-8-membered cycloalkyl group, as cyclopropyl group, cyclobutyl group, cyclopentadienyl group, cyclohexadiene group and cycloheptyl group. As "C3-8cycloalkenyl group" preferred such 3-8-membered cycloalkenyl group, as cyclopropylidene group, cyclobutenyl gr is the PAP cyclopentenyl group, cyclohexenyl group and cycloheptenyl group. And the term "may be substituted" means the above "C3-8the cyclic hydrocarbon group may be substituted by one or two groups selected from, for example, (1) hydroxyl group which may be protected, (2) halogen atom, (3) nitrile group, (4) carboxypropyl, (5) C1-6alkyl group which may be substituted by a group selected from hydroxyl group, halogen atom, a C1-6alkoxygroup, which may be halogenated, a C1-6uglevodorodnogo, which may be halogenated, an amino group which may be substituted C1-6hydrocarbon group, and C1-6alkanoyloxy group, (6) C2-6alkenylphenol group which may be substituted by a group selected from hydroxyl group, halogen atom, a C1-6alkoxygroup, which may be halogenated, a C1-6uglevodorodnogo, which may be halogenated, an amino group which may be substituted C1-6hydrocarbon group, and C1-6alkanoyloxy group, (7)2-6alkenylphenol group which may be substituted by a group selected from hydroxyl group, halogen atom, a C1-6alkoxygroup, which may be halogenated, a C1-6uglevodorov is tigraphy, which may be halogenated, an amino group which may be substituted C1-6hydrocarbon group, and C1-6alkanoyloxy group, (8) amino which may be substituted by a group selected from hydroxyl group, halogen atom, a C1-6alkoxygroup, which may be halogenated, a C1-6uglevodorodnogo, which may be halogenated, a C1-6alkanoyloxy group and C1-6hydrocarbon group, (9) C1-6alkoxygroup, which may be substituted by a group selected from hydroxyl group, halogen atom, a C1-6alkyl group which may be halogenated, a C1-6alkoxygroup, which can be gidroksilirovanii or halogenated, C1-6uglevodorodnogo, which may be halogenated, an amino group which may be substituted C1-6hydrocarbon group, and C1-6alkanoyloxy group, (10) C1-6uglevodorodnogo, which may be substituted by a group selected from hydroxyl group, halogen atom, a C1-6alkyl group which may be halogenated, a C2-6alkenylphenol group which may be halogenated, a C2-6alkenylphenol group which may be halogenated, a C1-6alkoxygroup, which may be halogenated, a C1-6Uglevodorody the group, which may be halogenated, an amino group which may be substituted C1-6hydrocarbon group, and C1-6alkanoyloxy group, (11) C1-6alkanoyloxy group which may be substituted by a group selected from hydroxyl group, halogen atom, a C1-6alkoxygroup and C1-6alkanoyloxy, (12)6-14aryl group which may be substituted by a group selected from a halogen atom, a C1-6alkyl groups and C1-6alkoxygroup, (13) 5-14-membered aromatic heterocyclic group which may be substituted by a halogen group, a C1-6alkyl group, a C3-8alkenylphenol group3-8alkenylphenol group and C1-6alkoxygroup, (14) non-aromatic heterocyclic group which may be substituted by a group selected from a halogen atom, a C1-6alkyl group, a C3-8alkenylphenol group3-8alkenylphenol group and C1-6alkoxygroup, (15) C1-6alkoxycarbonyl group, (16) C1-4alkylenedioxy, which may be halogenated, (17) formula (EtO)2PO and (18) acetyl group.

It should be noted that in the description of the present invention "hydrocarbon group"represented in the formula (I), refers to as a "C1-6hydrocarbon group"and "C3-8cyclic hydrocarbon group"to the e have the same definitions as above.

Preferred examples of "C6-14aromatic hydrocarbon cyclic group" in "C6-14aromatic hydrocarbon cyclic group which may be substituted"represented as Deputy HAr, include a phenyl group, pentylaniline group, indenolol group, naftalina group, azulinebloo group, heptylaniline group, benzocyclobutene group and phenanthroline group. Among these groups, more preferably phenyl group and naftalina group. Moreover, the term "may be substituted" means the above "C6-14aromatic hydrocarbon cyclic group" may be substituted by one or more groups selected from, for example, (1) hydroxyl group, (2) halogen atom, (3) C1-6alkylsulfonyl group2-6alkanesulfonyl group2-6alkylsulfonyl group which may be halogenated, (4) C1-4alkylenedioxy, which may be halogenated, (5) C1-6alkoxygroup, which may be halogenated, (6) C1-6uglevodorodnogo, which may be halogenated, (7) C1-6alkoxycarbonyl group, (8)6-14aryl-C1-6alkoxygroup, (9) C1-7alkanolamines, (10) C1-6alkylcarboxylic group, (11)2-6alkenylboronic the Noah group, (12) C2-6alkylcarboxylic group and (13) an amino group which may be substituted C1-6hydrocarbon group. Preferred examples of "C6-14aromatic hydrocarbon cyclic group which may be substituted" include a phenyl group, in turn NITRILES, halogenated phenyl group, phenyl group, substituted C1-6alkyl group, phenyl group, substituted C1-6alkoxygroup, such as a methoxy group, phenyl group, substituted C1-6alkylenedioxy, such as 2,4-methylendioxy, and phenyl group, a substituted di(C1-6alkyl)amino group, such as dimethylaminopropan.

It should be noted that in this invention "6-14the aryl group represented by the formula (I)has the same value as that of the above With6-14aromatic hydrocarbon cyclic group", and excludes aromatic heterocyclic group.

"5 to 14-membered aromatic heterocyclic group" in the "5 to 14-membered aromatic heterocyclic group which may be substituted", represented as Deputy HAr, means an aromatic heterocycle having 1-4 atoms selected from a nitrogen atom, oxygen atom and sulfur atom. Its specific examples include pyrrolidinyl group, pyridinyl group, pyridazinyl groups who, pyrimidinyl group, personilnya group, thiazolino group and oxazoline group. Moreover, the term "may be substituted" means the above "5 to 14-membered aromatic heterocyclic group" may be substituted by one or more groups selected from (1) hydroxyl group, (2) halogen atom, (3) nitrile group, (4) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, (5) C1-6alkoxygroup, which may be halogenated, (6) C1-6allylthiourea,2-6altertekhnogrupp or2-6alinytjara, which may be halogenated, (7) C1-6alkoxy-C1-6alkyl group, (8) acetyl group, (9) C1-6alkanoyloxy group, (10) mono-(C1-6hydrocarbon)amino, (11) di(C1-6hydrocarbon)amino and (12) three(C1-6hydrocarbon) amino group. Preferred examples of substituted 5 to 14-membered aromatic heterocyclic group" include an aromatic heterocycles, converted into NITRILES, aromatic heterocycles, substituted C1-6alkyl group, aromatic heterocycles, substituted C1-6alkoxygroup, aromatic heterocycles, substituted C1-6alkoxy-C1-6alkyl group, aromatic heterocycles, substituted mono-C 1-6hydrocarbon) amino group and an aromatic heterocycles, substituted di(C1-6alkyl)amino group.

In the description of this invention, "C6-14the aryl group represented by the formula (I)has the same value as that for the above "5 to 14-membered aromatic heterocyclic group".

It should be noted that in the description of this invention, "aromatic ring"represented by the formula (I), means all the rings have the same meaning as above With6-14aromatic hydrocarbon ring" and "5 to 14-membered aromatic heterocyclic group".

"4-10-membered non-aromatic heterocyclic group "4-10-membered non-aromatic heterocyclic group which may be substituted", represented as Deputy HAr, means the ring, which has the same meaning as in the above "C3-8the cyclic hydrocarbon group in which a 1-4 carbon atom substituted with an atom selected from a nitrogen atom, oxygen atom and sulfur atom, and also means that it includes unsaturated condensed ring. Preferred specific examples include pyrrolidinyl group, pyrrolidino group, piperidinyl group, piperazinilnom group, imidazolidinyl group, pyrazolidine group, imidazolidinyl group, morpholinyl the ing group, tetrahydropyranyloxy group, azetidinol group, oxetanyl group, oxalylamino group, phthalimide and succinimide. More preferred examples include pyrrolidinyl group, piperidinyl group and morpholinyl group. Moreover, the term "may be substituted" means the above "4-10-membered aromatic heterocyclic group" may be substituted by one or more groups selected from (1) hydroxyl group, (2) halogen atom, (3) nitrile group, (4) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, (5) C1-6alkoxygroup, which may be halogenated, (6) C1-6allylthiourea, C2-6altertekhnogrupp or2-6alinytjara, which may be halogenated, (7) C1-6alkoxy-C1-6alkyl group, (8) acetyl group, (9) C1-6alkanoyloxy group, (10) mono-(C1-6hydrocarbon)amino, (11) di-(C1-6hydrocarbon)amino group, (12) three(C1-6hydrocarbon) amino and (13) the carbonyl group, forming a carbonyl group, an N-oxide group, sulfoxide group or sulfonyloxy group.

It should be noted that in the description of the present invention "heterocycle"represented by the formula (I), refers to as the "5 to 14-membered heterocyclic group"and "4-10-membered non-aromatic heterocyclic group", which have the same definitions as above.

"C1-6alkoxygroup" "C1-6alkoxygroup, which may be substituted"represented as Deputy HAr means "alkoxygroup", corresponding to "C1-6hydrocarbon group" in the above definition. Preferred examples include a C1-6alkyloxy, such as methoxy group, ethoxypropan, n-propoxylate, isopropoxide, second-propoxylate, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, n-phenoxypropan, isobutoxide, second-phenoxypropan, tert-phenoxypropan, n-hexachrome, isohexadecane, 1,2-DIMETHYLPROPANE, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropyl, 1,1,2-trimethylpropyl, 1,1-DIMETHYLPROPANE, 2,2-DIMETHYLPROPANE, 2-itivuttaka, 1,3-dimethyl-butoxypropyl, 2-methylphenoxy and 3-methylphenoxy; C2-6alkenylacyl, such as vinyloxy, alliancegroup, isopropoxy, 1-propenyl-2-oxygraph, 1-butenyl-1-oxygraph, 1-butenyl-2-oxygraph, 1-butenyl-3-oxygraph, 2-butenyl-1-oxygraph, 2-butenyl-1-oxygraph and 2-butenyl-2-oxygraph; and (C2-6alkyloxy, such as atenololviagrawp, propenyloxy, butenyloxy, Pentti, who roxyrama and hexaniacinate. The term "may be substituted" means that it can be substituted by one or more groups selected from, for example, (1) hydroxyl group, (2) halogen atom, (3) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be substituted by a group selected from hydroxyl group, halogen atom, a 5 to 14-membered aromatic heterocyclic group and 4-10-membered non-aromatic heterocyclic group, (4)3-8cycloalkyl group or3-8cycloalkenyl group, which can be gidroksilirovanii or halogenated, (5) C1-6alkyloxy, which can be gidroksilirovanii or halogenated, (6) C1-6allylthiourea,2-6altertekhnogrupp or2-6alinytjara, which may be halogenated, (7)3-8cycloalkylcarbonyl,3-8cycloalkanones or3-8cycloalkanones, which may be halogenated, (8)3-8cycloalkylation,3-8cycloalkenyl or3-8cycloalkylation, which may be halogenated, (9)6-14aryl group, (10) C1-6alkanoyloxy group which may be halogenated, (11) 5-14-membered aromatic heterocyclic group and (12) 4-10-membered non-aromatic heterocycle. Pre is respectful examples, "C 1-6alkoxygroup, which may be substituted" include C1-6alkoxygroup that gidrauxilirovania, C1-6alkoxygroup that galogenirovannami, C1-6alkoxygroup, which is substituted by hydroxy-C3-8cycloalkyl group, C1-6alkoxygroup, replaced the non-aromatic heterocycle-actigraphy, C1-6alkoxy-C1-6alkoxygroup, C1-6alkoxygroup, substituted C1-6alkoxycarbonyl group, C1-6alkoxygroup, substituted non-aromatic heterocyclic group, and C1-6alkoxygroup, which is formelementname.

"C3-8cycloalkylation C3-8cycloalkylation, which may be substituted"represented as Deputy HAr means "cycloalkylation", corresponding to "C1-6cyclic hydrocarbon group" in the above definition. Preferred examples include3-8cycloalkylcarbonyl, such as cyclopropylamino, cyclobutylamine, cyclopentylamine and cyclohexyl-oxygraph, and C3-8cycloalkanones, such as cyclopropylamino, cyclobutylamine, Cyclopentasiloxane and cyclohexasiloxane. Moreover, the term "may be substituted" means that the above3-8cycloalkylation can be samewe is but one or two groups selected from, for example, (1) hydroxyl group, (2) halogen atom, (3) C1-6uglevodorodnogo, which may be substituted by a group selected from hydroxyl group, halogen atom, a C1-6alkoxygroup and C1-6alkanoyloxy group, (4) C1-6alkoxygroup, which may be substituted by a group selected from a halogen atom, a C1-6alkoxygroup and C1-6alkanoyloxy group, and (5) C1-6uglevodorodnogo, which may be substituted by a group selected from a halogen atom, a C1-6alkoxygroup and C1-6alkanoyloxy group. Preferred are3-8cycloalkylation, which may be substituted C1-6alkoxygroup, etc.

"C1-6Uglevodorodnogo" "C1-6uglevodorodnogo, which may be substituted"represented as Deputy HAr means "C1-6uglevodorodnogo", corresponding to "C1-6hydrocarbon group" in the above definition, i.e. "C1-6allylthiourea", "C2-6altertekhnogrupp" and "C2-6alinytjara". Its specific examples include metalcorp, ethylthiourea, n-PropertyGroup, isopropylthio, sec-PropertyGroup, n-butylthiourea, isobutylthiazole, sec-butylthiourea, tert-butylthiourea, 1,2-dimethylpropylene, 2-ethylpropylamine, 1,1-DIMET is butylthiourea, 2,2-dimethylbutylamino, 2-ethylbutyrate, 1,3-dimethylbutylamino, isopropylthio, tinytip and propylthiourea. Moreover, the term "may be substituted" means that it can be substituted by one or two groups selected from, for example, (1) hydroxyl group, (2) halogen atom, (3) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be substituted by a group selected from hydroxyl group, halogen atom, a 5 to 14-membered aromatic heterocyclic group and 4-10-membered non-aromatic heterocyclic group, (4)3-8cycloalkyl group3-8cycloalkenyl group or3-8cycloalkenyl group, which can be gidroksilirovanii or halogenated, (5) C1-6alkyloxy, which can be gidroksilirovanii or halogenated, (6) C1-6allylthiourea, C2-6altertekhnogrupp, C2-6alinytjara, which may be halogenated, (7)3-8cycloalkylcarbonyl,3-8cycloalkanones or3-8cycloalkanones, which may be halogenated, (8)3-8cycloalkylation,3-8cycloalkenyl or3-8cycloalkylation, which may be halogenated, (9)6-14aryl group, (10) 1-6alkanoyloxy group which may be halogenated,

(11) a 5 to 14-membered aromatic heterocyclic group and

(12) 4-10-membered non-aromatic heterocyclic group.

"C1-6Uglevodorodnogo, which may be substituted" is preferably C1-6uglevodorodnogo, which can be gidroksilirovanii, C1-6uglevodorodnogo, which may be substituted C1-6alkoxygroup etc.

"C3-8cyclic uglevodorodnogo C3-8circular uglevodorodnogo, which may be substituted"represented as Deputy HAr means3-8cyclic uglevodorodnogo corresponding "3-8cyclic hydrocarbon group" in the above definition, i.e. "C3-8cycloalkylation" and "C3-8cycloalkenyl". Its specific examples include cyclopropanation, cyclobutenedione, cyclohexanedione, cyclopropanation, cyclobutenedione, cyclopentanedione and cyclohexanedione. "C3-8cyclic uglevodorodnogo, which may be substituted" is preferably "C3-8cyclic uglevodorodnogo", substituted by one or two groups selected from (1) hydroxyl group, (2) halogen atom, (3)3-8 alkyl group, a C3-8alkenylphenol group or3-8alkenylphenol group which may be halogenated, (4) C1-6alkoxygroup, which may be halogenated, (5) C1-6uglevodorodnogo, which may be halogenated, (6) C1-6alkanoyloxy group which may be halogenated.

"C6-14aromatic uglevodorodakh C6-14the aromatic uglevodorodakh, which may be substituted"represented as Deputy HAr means "C6-14cyclic uglevodorodakh", corresponding to "C6-14aromatic hydrocarbon group" in the above definition. For example, preferred are fenoxaprop, pentylaniline and naphthyloxy. As "C6-14aromatic uglevodorodakh, which may be substituted" preferred "C6-14aromatic uglevodorodakh", which is substituted by one or more groups selected from (1) hydroxyl group, (2) halogen atom, (3) C1-6alkylsulfonyl group2-6alkanesulfonyl group or2-6alkylsulfonyl group which may be halogenated, (4) C1-4alkylenedioxy, which may be halogenated, (5) C1-6alkoxygroup, which can be halogenic the bath, (6) C1-6uglevodorodnogo, which may be halogenated, (7) C1-6alkoxycarbonyl group, (8)6-14aryl-C1-6alkoxygroup, (9) C1-7alkanolamines, (10) C1-6alkylcarboxylic group, (11)2-6alkenylamine group, (12)2-6alkylcarboxylic group and (13) an amino group which may be substituted C1-6hydrocarbon group.

It should be noted that in the description of the present invention With6-14alloctype", represented in the formula (I)has the same value as "C6-14aromatic uglevodorodakh" in the above definition.

"5-14-membered heterocycle-oxygraph" in the "5 to 14-membered heterocycle-exigrep, which may be substituted", represented as Deputy HAr means "5-14-membered heterocycle-oxygraph", corresponding to the ring that has the same value as "5 to 14-membered heterocyclic group" and "4-10-membered non-aromatic heterocyclic group" in the above definition. Its specific examples include aromatic heterocycle-oxygraph", such as paralelograma, peridiniaceae, peridiniaceae, pyrimidinylidene, personalantispy and thiazoleacetate; and the non-aromatic heterocycle-oxygraph", such as pyrrolidinyloxy, pyrrol veloxigrup, piperidinyloxy, piperidinyloxy, imidazolylalkyl, imidazolidinone, morpholinopropan and tetrahydropyranyloxy. As a 5-14-membered heterocycle-actigraphy, which may be substituted" preferred "5 to 14-membered heterocycle-oxygraph", which may be substituted by one or more groups selected from (1) hydroxyl group, (2) halogen atom, (3) nitrile group, (4) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, (5) C1-6alkoxygroup, which may be halogenated, (6) C1-6allylthiourea,2-6altertekhnogrupp or C2-6alinytjara, which may be halogenated, (7) C1-6alkoxy-C2-6alkenylphenol group, (8) acetyl group, (9) C1-6alkanoyloxy group, (10) mono-(C1-6hydrocarbon)amino, (11) di(C1-6hydrocarbon)amino and (12) three(C1-6hydrocarbon)amino group.

"C6-14aromatic uglevodorodakh C6-14the aromatic uglevodorodakh, which may be substituted"represented as Deputy HAr means "C6-14cyclic uglevodorodnogo"corresponding "With6-14aromatic hydrocarbon group" in the above definition. Nab is emer, preferred are phenylthiourea, pentylaniline and naphthylthiourea. As "C6-14aromatic uglevodorodakh, which may be substituted" preferred "C6-14aromatic uglevodorodakh", which may be substituted by one or more groups selected from (1) hydroxyl group, (2) halogen atom, (3) C1-6alkylsulfonyl group2-6alkanesulfonyl group or2-6alkylsulfonyl group which may be halogenated, (4) C1-4alkylenedioxy, which may be halogenated, (5) C1-6alkoxygroup, which may be halogenated, (6) C1-6uglevodorodnogo, which may be halogenated, (7) C1-6alkoxycarbonyl group, (8)6-14aryl-C1-6alkoxygroup, (9) C1-7alkanolamines, (10) C1-6alkylcarboxylic group, (11) C2-6alkenylamine group, (12)2-6alkylcarboxylic group and (13) an amino group which may be substituted C1-6hydrocarbon group.

"5-14-membered heterocycle-tighrope" in the "5 to 14-membered heterocycle-tighrope, which may be substituted"represented as Deputy HAr means "5-14-membered heterocycle-togroup", corresponding to the ring that has the same value as "5 to 14-membered aroma is ical heterocyclic group" and "4-10-membered non-aromatic heterocyclic group" in the above definition. Its specific examples include aromatic heterocyclic", such as pyrrolidine, pyridinethione, pyridazinedione, pyrimidinethione, piratininga and thiazolidine; and the non-aromatic heterocyclic", such as pyrrolidinium, pyrrolizidine, piperidinedione, piperazinediones, imidazolinium, imidazolidinethione and morpholinopropan. And as a 5-14-membered heterocycle-tigraphy, which may be substituted", the preferred "5 to 14-membered heterocycle-tighrope", which may be substituted by one or more groups selected from (1) hydroxyl group, (2) halogen atom, (3) nitrile group, (4) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, (5) C1-6alkoxygroup, which may be halogenated, (6) C1-6allylthiourea,2-6altertekhnogrupp or2-6alinytjara, which may be halogenated, (7) C1-6alkoxy-C2-6alkenylphenol group, (8) acetyl group, (9) C1-6alkanoyloxy group, (10) mono-(C1-6hydrocarbon)amino, (11) di(C1-6hydrocarbon)amino group, (12) three(C1-6hydrocarbon)amino and (13) of the carbonyl group.

"Amino group which may be the replacement of the s", presented as Deputy HAr, means an amino group represented by the formula-N(R3R4(where R3and R4are the same or different, and each represents a group selected from (1) aromatic heterocyclic group, (2) non-aromatic heterocyclic group, (3) C1-6alkyl group, a C2-6alkenylphenol group or a C2-6alkenylphenol group which may be substituted by a halogen atom or C1-6alkoxygroup, (4)3-8cycloalkyl group3-8cycloalkenyl group or3-8cycloalkenyl group which may be halogenated, (5) a carbonyl group which is substituted C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group which may be halogenated, a C3-8cycloalkyl group3-8cycloalkenyl group or3-8cycloalkenyl group which may be halogenated, a C1-6alkoxygroup, which may be halogenated, a C6-14aryl group or aromatic heterocyclic group, (6) C1-6alkanoyloxy group which may be substituted by a group selected from C6-14aryl group or aromatic heterocyclic group, (7) carbamoyl group which may be substituted C1-6alkylen the th group, With2-6alkenylphenol group2-6alkenylphenol group6-14aryl group or aromatic heterocyclic group, and (8) sulfonyloxy group which may be substituted C1-6alkyl group, a C2-6alkenylphenol group or2-6alkenylphenol group. Moreover, (9) R3and R4can be connected and combined with the formation of a 3-10-membered ring and the cyclic amino group may be substituted by one or more groups selected from hydroxyl group, halogen atom, a C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group, C1-6alkoxygroup, C1-6uglevodorodnogo and C1-4alkylenedioxy. Amino group, R3and R4are the same or different, and each represents a group selected from C1-6alkyl group, a C1-6alkoxy-C2-6alkyl group, a C1-6alkoxycarbonyl group, C1-6alkanoyloxy group6-14arylcarbamoyl group, heteroarylboronic group, C1-6alkylcarboxylic group, C6-14alkylcarboxylic group6-14arylsulfonyl group, and a 5-14-membered heterocyclic group.

As an example, "C1-6midorino group" "C1-6midorino group which may be substituted"represented as mandated the tel HAr, presents formimidoyl, hexanamide and Succinimidyl. As "C1-6midorino group which may be substituted" preferred C1-6imicola group which may be substituted by a halogen atom.

Examples of the "substituted carbonyl group"represented as Deputy HAr, include a carbonyl group substituted by a group selected from C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group, C1-6alkoxy-C1-6alkyl group, a C1-6alkoxygroup,6-14aryl group, and a 5-14-membered aromatic heterocyclic group.

"Substituted carbonyl group" in the "substituted carbonyloxy"presented as Deputy HAr is a carbonyl, having the same value as the "substituted carbonyl group" in the above definition. Examples of "substituted carbonyloxy" include C1-6alkylcarboxylic,2-6alkenylboronic,2-6alkylcarboxylic, C1-6alkoxy-C2-6alkylcarboxylic, C1-6alkoxycarbonylmethyl,6-14arylcarboxamide and 5-14-membered aromatic heterocycle-carbonyloxy. Preferred examples are C1-6alkylcarboxylic, C2-6alkenylboronic the PAP and C 2-6alkylcarboxylic.

Examples of the "carboxyl group which may form a salt, presents as Deputy HAr include the salts of alkali metals such as lithium, sodium and potassium, salts of alkaline earth metals such as magnesium and calcium, Tetramethylammonium salts, Quaternary ammonium compounds, such as tetraethylammonium salt, salts of amino acids such as alginates, aspartate, glutamate and prolinnova salt, and, in addition, betaines with amino groups in the molecule.

"Carnemolla group which may be substituted"represented as Deputy HAr specifically is carbamoyl group represented by the formula-CO-N(R5R6(where R5and R6are the same or different and each represents a group selected from (1) hydrogen atom, (2) C1-6alkyl group, (3)2-6alkenylphenol group, (4)2-6alkenylphenol group, (5)3-8cycloalkyl group, (6) With3-8cycloalkenyl group, (7)3-8cycloalkenyl group, (8)6-14aryl group, and (9) an aromatic heterocyclic group or (10) R5and R6can be connected and combined with the formation of a 3-8-membered ring. Preferred carnemolla group, where R5and R6are the same or different and each is GRU is sing, selected from C1-6alkyl group, a C3-8cycloalkyl group or6-14aryl group which may be halogenated, etc.

As examples, "C1-4alkylenedioxy" "C1-4alkylenedioxy, which may be substituted"represented as Deputy HAr, presents methylendioxy, atlantoxerus and propyleneoxide. As "C1-4alkylenedioxy, which may be substituted" preferred C1-4alkylenedioxy, which can be gidroksilirovanii or halogenated.

As sulfanilic group which may be substituted"represented as Deputy HAr, preferred sulfonylurea group which may be substituted by a group selected from (1) C1-6hydrocarbon group which may be halogenated, (2) an amino group which may be mono - or tizamidine C1-6hydrocarbon group which may be halogenated.

As sulfonyloxy group which may be substituted, represented as a Deputy HAr, preferred sulfonylurea group which may be substituted by a group selected from (1) C1-6hydrocarbon group which may be halogenated, and (2) an amino group which may be mono - or tizamidine C-6 hydrocarbon group which may be halogenated.

The definition for "aromatic heterocycle which may be substituted"represented as Deputy HAr in the formula (I), is the same as above. Preferred examples of the substituent of the "aromatic heterocycle" include (1) C1-6alkyl group, a C2-6alkenylphenol group or2-6alkylamino group which may be substituted by one or two groups selected from (a) hydroxyl group, (b) halogen atom, (C) 5 to 14-membered heterocyclic group, (d) 4-10-membered non-aromatic heterocyclic group, (e) 5-to 10-membered condensed heterocyclic group which may be substituted C1-6alkoxygroup, and (f) C1-6alkylsulfonyl, (2) C1-6alkoxygroup, which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) 4-10-membered nonaromatic a heterocycle-oxypropyl, (d) C1-6alkoxygroup, (e) C1-6alkoxycarbonyl group and (f) 4-10-membered non-aromatic heterocycle, (3)6-14aromatic hydrocarbon cyclic group which may be substituted by one or more groups selected from (a) halogen atom, (b) C1-6alkoxygroup and (C) C1-4alkylenedioxy, (4) 5-14-membered aroma is ical heterocyclic group, which may be substituted by one or more groups selected from (a) hydroxyl group, (b) nitrile group, (C) C1-6alkyl group, (d) C1-6alkoxygroup, (e) C1-6alkoxy-C1-6alkyl group, (f) C1-6alkanoyloxy group, (g) C1-4alkylenedioxy, (h) mono-(C1-6alkyl) amino and (i) di(C1-6alkyl) amino, and (5) 4-10-membered non-aromatic heterocyclic group which may be substituted by one or more groups selected from (a) hydroxyl group, (b) nitrile group, (C) C1-6alkyl group, (d) C1-6alkoxygroup, (e) C1-6alkoxy-C1-6alkyl group, (f) C1-6alkanoyloxy group, (g) C1-4alkylenedioxy, (h) mono-(C1-6alkyl) amino and (i) di(C1-6alkyl)amino group. More preferred examples include a C1-6alkyl group which may be halogenated, a C2-6alkenylphenol group which may be halogenated, a C1-6alkoxy-C1-6alkyl group, a C1-6alkyl group, substituted C6-14aromatic hydrocarbon cyclic group, a C1-6alkyl group, substituted 5-6-membered aromatic heterocycle, C1-6alkoxygroup, which may be halogenated, a C1-6alkoxy-C1-6alkoxygroup,6-14aromatizes the second hydrocarbon group, 5-6-membered aromatic heterocycle which may be substituted C1-6alkyl group, and 4-10-membered non-aromatic heterocyclic group which may be substituted by one or more groups selected from (a) hydroxyl group, (b) a nitrile group, and (C) C1-6alkoxygroup.

The terms "halogen atom", "C1-6hydrocarbon group", "C1-6alkyl group", "C3-8Alchemilla group", "C3-8Alchemilla group", "C3-8cycloalkenyl group", "C3-8cycloalkenyl group", "C6-14aromatic hydrocarbon group", "C6-14aryl group", "5 to 14-membered aromatic heterocyclic group", "5-14-membered heteroaryl group, 4-10-membered non-aromatic heterocyclic group", "C1-6alkoxygroup", "C3-8cycloalkanes", "C3-8cycloalkylation", "C3-8cycloalkanones", "C1-6uglevodorodnogo", "C1-6allylthiourea", "C2-6alchemistjoshua", "C3-8alinytjara", "C3-8cycloalkylation", "C3-8cycloalkenyl", "C1-6alkoxycarbonyl group", "C1-6alcoolica group", "C1-6alkanoyloxy", "carnemolla group", "C1-6imicola group, carboxyl group which may form a salt","C 1-4alkylenedioxy", "sulfonylurea group" and "sulfonylurea group"), which are all used in the above definitions relating Vice-aromatic heterocycle HAr, shall have the same meaning as above.

In the description of this invention, "aromatic ring" in the "aromatic ring which may be substituted"represented by Ar in the formula (I), means a ring having the same value as the "aromatic ring" in the above definition. Preferred are, for instance, benzene ring, pyridine ring and the like, examples of the "aromatic ring which may be substituted" include an aromatic ring which may be substituted by one or more groups selected from (1) hydroxyl group, (2) halogen atom, (3) C1-6hydrocarbon group which may be substituted, (4)3-8cyclic hydrocarbon group which may be substituted, (5) C1-6alkoxygroup, which may be substituted, (6) With3-8cycloalkanes, which may be substituted, (7) C1-6uglevodorodnogo, which may be substituted, (8)3-8cyclic uglevodorodnogo, (9)6-14aromatic hydrocarbon cyclic group which may be substituted, (10) 5 to 14-membered aromatic heterocyclic group, which may be the substituted, (11) an amino group which may be substituted C1-6alkyl group, and (12) C1-4alkylenedioxy, which may be substituted.

"C1-6Hydrocarbon group which may be substituted"represented as Deputy Ar stands for a group having the same meaning as "C1-6hydrocarbon group which may be substituted"represented in the definition for HAr. As "C1-6hydrocarbon group which may be substituted" preferred C1-6alkyl group which may be halogenated, a C2-6Alchemilla group which may be halogenated, a C2-6Alchemilla group which may be halogenated, etc.

"C3-8cyclic hydrocarbon group which may be substituted"represented as Deputy Ar stands for a group having the same value as "3-8cyclic hydrocarbon group which may be substituted"represented in the definition of HAr. As "C3-8cyclic hydrocarbon group which may be substituted" preferred3-8cycloalkyl group which may be halogenated, a C3-8cycloalkenyl group which may be halogenated, etc.

"C1-6alkoxygroup, which may be substituted"represented as Deputy Ar, means the group having the same meaning as "C1-6alkoxygroup, which may be substituted"represented in the definition of HAr. As "C1-6alkoxygroup, which may be substituted" preferred C1-6alkoxygroup, which may be halogenated, etc.

"C3-8cycloalkanes, which may be substituted"represented as Deputy Ar stands for a group having the same meaning as "C3-8cycloalkanes, which may be substituted"represented in the definition of HAr. As "C3-8cycloalkanes, which may be substituted" preferred3-8cycloalkanes, which may be halogenated, etc.

"C1-6Uglevodorodnogo, which may be substituted"represented as Deputy Ar stands for a group having the same meaning as "C1-6uglevodorodnogo, which may be substituted"represented in the definition of HAr. As "C1-6uglevodorodnogo, which may be substituted" preferred C1-6uglevodorodnogo, which may be halogenated, etc.

"C3-8cyclic uglevodorodnogo"presented as Deputy Ar stands for a group having the same meaning as "C3-8cyclic uglevodorodnogo, to the which may be substituted", presents in determining HAr. As "C3-8cyclic uglevodorodnogo, which may be substituted" preferred3-8cyclic uglevodorodnogo, which may be halogenated, etc.

"C6-14aromatic hydrocarbon cyclic group which may be substituted" and "5 to 14-membered aromatic heterocyclic group which may be substituted"represented as the substituents Ar, mean group having the same meaning and "C6-14aromatic hydrocarbon cyclic group which may be substituted" and "5 to 14-membered aromatic heterocyclic group which may be substituted"represented in the definition of HAr, respectively.

"Amino group which may be substituted C1-6alkyl group"represented as Deputy Ar means an amino group, monosubstituted C1-6alkyl group, such as methylaminopropyl and atramentaria, and disubstituted C1-6alkyl group, such as dimethylaminopropan and diethylaminopropyl. In addition, the nitrogen atom may be trisemester C1-6alkyl group with the formation of ammonium salts.

"C1-4alkylenedioxy, which may be substituted"represented as Deputy Ar stands for a group having the same meaning as "C1-4/sub> alkylenedioxy, which may be substituted"represented in the definition of HAr. For example, the preferred C1-4alkylenedioxy, which may be substituted by a halogen atom, etc.

As defined above, the "aromatic ring which may be substituted"represented by Ar in the formula (I). Preferred examples of Ar include benzene ring, pyridine ring, pyrazinone ring, thiophene ring and a thiazole ring which may be substituted by a group selected from hydroxyl group, halogen atom, a C1-6alkyl group, a C1-6alkoxygroup etc.

In the description of this invention W in the formula (I) means connecting a circuit in which the primary circuit is constructed of two or more atoms. Their examples include, preferably, chain, presents (1) -CH2-CH2-that may be substituted, (2) -CH=CH-, which may be substituted, (3)(4) -NH-CO-, (5) -CO-NH-, (6) -NH-CH2-, (7) -CH2-NH-, (8) -CH2-CO-, (9) -CO-CH2-, (10) -NH-S(O)l, (11) -S(O)l-NH-, (12) -CH2-S(O)l(13) -S(O)l-CH2- (l is 0, 1 or 2), more preferably (1) -CH2-CH2-, (2) -CH=CH - and (3)≡and even more preferably

In the description of this invention, examples of the linking group X in the formula (I) include chain, not only at the nnye (1) single bond, (2) C1-6alkalinous chain which may be substituted, (3)2-6alkenylamine chain which may be substituted, (4)2-6alkynylamino chain which may be substituted, (5) the formula-Q- (where Q represents an oxygen atom, a sulfur atom, or N(R2) (where R2represents C1-6alkyl group or a C1-6alkoxygroup)), (6) -NH-CO-, (7) -CO-NH-, (8) -NH-CH2-, (9) -CH2-NH-, (10) -CH2-CO-, (11) -CO-CH2-, (12) -NH-S(O)m-, (13) -S(O)m-NH-, (14) -CH2-S(O)m-, (15) -S(O)m-CH2- (where m means 0, 1 or 2) or (16) -(CH2)n-O- (where n denotes an integer from 1 to 6). In this case, "C1-6Allenova chain", "C1-6Alcanena chain" and "C1-6akinlana circuit" means a circuit corresponding to C1-6hydrocarbon groups having the same meaning as "C1-6alkyl group", "C2-6Alchemilla group" and "C2-6Alchemilla group" in the above definitions. Connect the circuit X is preferably a single bond, C1-6alkylenes chain, With2-6alkenylamine chain, -CO -, or the like, and more preferably, a simple bond, a methylene chain, ethylene chain or WITH-.

The amino group in the "amino group which may be substituted C1-6alkyl group or acyl group" means an amino group which may be substituted C1-6 alkyl group having the same meaning as the above definition, or acyl group having the same meaning as the above definition. Specific examples include N-formylamino, N-acetylamino, N-Propionaldehyde, N-evaluieringsrapport, N-benzoylamino, N-methyl-N-formylamino, N-methyl-N-benzoylamino, N-methylaminopropyl, N,N-dimethylaminopropyl, N-methyl-N-ethylamino, N-(n-propyl)amino group, N-(isopropyl)amino and N-(tert-butyl)amino group.

"C1-6alkoxycarbonyl group" is alkoxycarbonyl group corresponding to C1-6alkoxygroup in the above definition. Its specific examples include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, sec-propoxycarbonyl group, n-butoxycarbonyl group, isobutoxyethanol group, 1,2-dimethylpropanoyl group and 2-ethylpropylamine group.

Define R1, HAr, Ar, W and X, which must be used in the formula (I)have the meanings as indicated above. For a more precise definition of preferable examples as a-X-Ar - presents benzyl group (X = methylene chain, Ar = benzene ring which may be substituted, and as HAr, in addition to for the escitalo-X-Ar, pyridine ring, pyrimidine ring, pyridazine ring, pyrazinone ring, indole ring, a quinoline ring, a thiophene ring or benzothiophene ring which may be substituted by one or two groups selected from (1) a 5 - or 6-membered aromatic heterocycle which may be substituted C1-6alkyl group, (2) a 5 - or 6-membered non-aromatic heterocycle which may be substituted by one or more groups selected from (a) hydroxyl group, (b) C1-6alkyl groups and (C) C1-6alkoxygroup, (3)6-10aromatic hydrocarbon ring which may be substituted by one or more groups selected from (a) halogen atom, (b) C1-6alkoxygroup, (C) C1-4alkylenedioxy and (d) sulfonyloxy group which may be substituted C1-6alkyl group, (4) C1-6alkyl group which may be substituted by one or more groups selected from (a) hydroxyl group, (b) halogen atom, (C) a 5 - or 6-membered aromatic heterocycle and (d) C1-6alkoxygroup, and (5) C1-6alkoxygroup, which may be substituted by a halogen atom and (b) C1-6alkoxygroup. More preferred examples include HAr pyridine ring, pyrimidine ring, pyridazine ring, pyrazinone ring, indole ring, a quinoline ring is, thiophene ring or benzothiophene ring which may be substituted by one or two groups selected from (1) a benzene ring which may be substituted C1-4alkylenedioxy, (2) a pyridine ring, (3) the pyrimidine ring, (4) pyridazinone rings, (5) pirazinamida rings, (6) thiophene rings, (7) piperidino ring which may be substituted C1-6alkoxygroup, (8) piperazinovogo ring which may be substituted C1-6alkoxygroup, (9) pyrolidine ring which may be substituted C1-6alkoxygroup, (10) piperidino ring which may be substituted by a hydroxyl group, and C1-6alkoxygroup, (11) piperazinovogo ring which may be substituted by a hydroxyl group, and C1-6alkoxygroup, (12) pyrolidine ring, substituted hydroxyl group and C1-6alkoxygroup, (13) morpholino ring (14) C1-6alkyl group which may be substituted C1-6alkoxygroup, and (15) C1-6alkoxygroup, which may be substituted by a hydroxyl group or a C1-6alkoxygroup.

Salt in this invention means usually pharmacologically acceptable salt. Examples of such salts include hydrogenogenic, such as hydrohloride, hydrochloride, hydrobromide and hydroiodide; salts of inorganic acids, so is e as sulfates, nitrates, perchlorates, phosphates, carbonates and hydrogen carbonates; organic carboxylates such as acetates, maleate, tartratami and fumarate; organic sulfonates such as methanesulfonate, triftoratsetata, econsultancy, benzosulfimide and toluensulfonate; Aminata, such as alginates, aspartate and glutamate; salts of amines, such as trimethylamine salt, triethylamine salt, procainamide salt, pyrimidine salt and venetiancasino salts; salts of alkaline metals such as sodium and potassium salts; and salts of alkaline earth metals such as magnesium salts and calcium salts.

A common way to obtain

As a method of obtaining the compound represented by formula (I)according to this invention discussed different ways, and this compound can be obtained in the usual way organic synthesis. For the presentation of typical methods that can be used the following method to get the connection.

The method of obtaining 1

The above method of obtaining is a way of obtaining the compound (IV) in accordance with the invention of this patent application through a combination of aromatic heterocyclic compounds (II) and (III) with each other. In the formula a1And2and3show is by the same or different and each means (1) a carbon atom, which may be substituted, or (2) heteroatom such as nitrogen atom, sulfur atom or oxygen atom, and in this case, And2in addition, means single bond. When And2means a single bond, ring to which we belong And1And2and3is a 5-membered ring. Here, in the case when A1And2and3accordingly, represent a carbon atom which may be substituted", the term "may be substituted" means that it can be replaced by Deputy presented for HAr defined above. In particular, the carbon atom may be substituted by a group selected from (1) halogen atom, (2) hydroxyl group, (3) Tilney group, (4) nitro group, (5) nitrile group, (6) C1-6hydrocarbon group, (7)3-8cyclic hydrocarbon group which may be substituted, (8) C6-14aromatic hydrocarbon cyclic group which may be substituted, (9) 5-14-membered aromatic heterocyclic group which may be substituted, (10) 4-10-membered non-aromatic heterocyclic group which may be substituted, (11) C1-6alkoxygroup, which may be substituted, (12)3-8cycloalkylcarbonyl, which may be substituted, (13) C1-6uglevodorodnogo, which may be substituted, (14)3-8cyclic Uglevodorody the group, which may be substituted, (15)6-14aromatic uglevodorodakh, which may be substituted, (16) 5-14-membered heterocycle-actigraphy, which may be substituted, (17)6-14aromatic uglevodorodnogo, which may be substituted, (18) 5-14-membered heterocycle-actigraphy, which may be substituted, (19) amino group which may be substituted, (20) azide group, (21) guanidinium, (22) urea group, (23) formyl group, (24) C1-6midorino group which may be substituted, (25) carbonyl group which may be substituted, (26) carbonyloxy, which may be substituted, (27) carboxyl group which may be substituted, (28) carbamoyl group which may be substituted, (29) C1-4alkylenedioxy, which may be substituted, (30) sulfanilic group which may be substituted, and (31) sulfonyloxy group which may be substituted. L means the deleted group, and R1means a hydrogen atom or a hydroxyl group, a and b, respectively, indicate the group-X-Ar (where X and Ar have the same meaning as defined above) and Deputy HAr formula (I)described in the above definition, or respectively mean the Deputy HAr and group-X-Ar (where X and Ar have the same meaning as defined above) of the formula (I)described in the above identified is I. Remove the group L may be any group, provided that it is known as the deleted group in organic synthesis, and specific restrictions is not installed. Their examples include halogen atoms such as chlorine atom, bromine atom and iodine atom; a substituted or unsubstituted of acetochlor, such as acetoxygroup and triftoratsetofenona; substituted sulfonyloxy, such as methanesulfonamido, triftormetilfullerenov, benzolsulfonate and p-toluensulfonate, and substituted phosphoryloxy, such as diphenoxyethane. Among these groups, preferred halogen atoms such as chlorine atom, bromine atom and iodine atom, and triftormetilfullerenov. As the palladium catalyst can be used, for example, tetrakis(triphenylphosphine)palladium (0) or chloride bis(triphenylphosphine)palladium (II) in an amount of 0.0001 to 0.1 mol-equivalents. For example, use of 0.0001 to 0.1 mol-equivalents of copper iodide (I) or copper chloride (I) as a salt of copper, for example, you can use 1-5 equivalents of triethylamine or N,N-diisopropylethylamine as a base. The solvent used is N,N-dimethylformamide, N-organic, tetrahydrofuran, methanol or a mixture of these solvents. The reaction temperature preferably ranges from 0° to 40° C.

The method of obtaining 2

The method of obtaining 3

The above methods of obtaining provide the possibility of obtaining compounds (VI) and (VIII) according to this invention. The reaction scheme L and a have the same values as in the above definition. As L, for example, you can use a chlorine atom, a bromine atom, an iodine atom or triftormetilfullerenov. M indicates a metal atom which may have a Deputy. For example, the preferred tri-n-botillo or dihydroxybis. As the palladium catalyst, for example, you can use tetrakis-(triphenylphosphine)palladium (0) or chloride bis(triphenylphosphine)-palladium (II) in an amount of 0.0001 to 0.1 mol-equivalents.

Examples of the solvent include toluene, xylene, N,N-dimethylformamide and N-organic. Allowable reaction temperature in the range from 50°to 150°C. When the metal M is boron, as the Foundation of the used inorganic base such as sodium carbonate, or organic base such as triethylamine. As solvent is also used organic solvent containing water.

Is not set specific limits on the dosage form of the compounds according to this invention and an acceptable or oral administration, or parent the material introduction method which is normally used. The connection can be processed into preparations in the form of tablets, powder, granules, capsules, syrup, cakes, inhalation of the drug, suppositories, injectable preparations, ointments, eye ointments, solutions for eye solution for irrigation of the nasal cavity, ear drops, poultices and lotion and applied in this form. In the manufacture of such dosage forms can be used fillers, binders, sizing, tint substances that improve the taste and smell substances and, if necessary, stabilizers, emulsifiers, substances that improve absorption, surfactants, pH regulators, antiseptics and antioxidants, etc. and the components which are usually used as raw materials of drugs, processed in the usual way. Examples of these components include animal fats and vegetable oils such as soybean oil, beef fat, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; a complex of essential oils, such as octyldodecanol and isopropylmyristate; higher alcohols, such as cetosteatil alcohol and buchenavia alcohol; silicone resins; silicone oils; surfactants such as esters of polyoxyethylene and fatty acids, esters of Sorbi the Ana and fatty acids, esters of glycerol and fatty acids, esters of polyoxyethylenesorbitan and fatty acids, polyoxyethylene, gidrirovannoe castor oil and polyoxyethylene, polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropyleneglycol and sorbitol; sugars such as glucose and sucrose, inorganic powders such as silicic acid anhydride, magnesium aluminum silicate and aluminum silicate; and purified water.

The drug in this invention is administered to an adult patient is usually in a dose of from about 30 μg to 10 g, preferably 100 μg to 5 g, and more preferably from 100 μg to 100 mg in the case of oral administration, and from about 30 μg to 1 g, preferably 100 μg to 500 mg and more preferably from 100 μg to 30 mg in the case of injection one or more times per day, while the dose varies depending on the severity of symptoms, age, sex, weight, dosage form and type of illness.

The biochemical activity of the compounds according to this invention and effects (activity synthesizing enzyme squalene, the inhibitory effect on biosint the C cholesterol and the inhibitory effect on the biosynthesis of cholesterol and triglycerides) connection in the form of drugs can be evaluated by the following methods.

The test example 1

Quantitative determination of activity by suppression of synthesizing enzyme squalene through the use of liver microsomes rat

(I) the Reaction was carried out in a volume of 500 ál. Was mixed with 200 µl of a solution containing 125 mm Tris-hydrochloric acid (pH of 7.3), 2.5 mm magnesium chloride, 5 mm potassium fluoride and 10 mm restorative type nikotinamidadenindinukleotida acid, 100 μl of the sample solution with a 5-fold concentration, 100 μl of distilled water and 50 µl of 0.4-1 mg/ml liver microsomes obtained by the following method.

(II) the above mixture was pre-incubated at 37°C for 10 minutes, and then to the mixture was added 50 μl of 100 μm [3N]-farnesylpyrophosphate acid (30 MCI/mmol, NEN) to start the reaction. The reaction took place at 37°C for 10 minutes. To the mixture was added 1 ml of ethanol to terminate the reaction and then the reaction solution was added 1 ml of distilled water and 3 ml of petroleum ether, which was then shaken for 30 minutes. The aqueous phase was separated from the oil phase, the aqueous phase was frozen at -70°C in a dry ice/methanol and measured the radioactivity of the organic phase using a liquid scintillator. The organic phase is evaporated to dryness using nitrogen gas and the residue was dissolved as a marker in 25 μl of chloroform, containing with the walensee, farnesol and cholesterol. The sample was applied using a spot on the plate for TLC (Merck) and showed, using heptane, for 15-20 minutes. A strip of squalene were cut out of the plate to measure the radioactivity using a liquid scintillation counter. Data were expressed concentration (IC50), which was suppressed by 50% the radioactivity of the control group.

Method of obtaining liver microsomes rat

The following operations were performed on ice, and centrifugation was performed at 4°C. the Liver was dissected from male rats Spraga-doli (Spraugue-Dawly) (hereafter called rats 3D) (8-9 weeks of age) and perfesional 1.15% potassium chloride to remove blood. Then the liver was crushed using scissors and chopped liver homogenized using a Teflon homogenizer. The resulting sample was centrifuged at HD twice within 15 minutes. The supernatant was additionally centrifuged at HD within 60 minutes. The precipitate was defined as the fraction microsomes, which are suspended in 25 mm solution of Tris-hydrochloric acid. The protein concentration was quantified by the method of Bradford and the protein concentration was brought to 20 mg/ml, using the same solution. The resulting solution was kept at 70°C.

The test example 2

Quantitative determination of suppressive activity in relation to the biosynthesis of cholesterol is in

(I) Male rats 3D category SPF (gnotobiotic, 4 weeks of age, SLC = last survey) were bred for more than one week in the room with the change of day-night and subjected to the experiment conducted in the daytime. The compound dissolved in a 2% solution of tween-80 was administered (5 ml/kg) rats using oral probe. Within one hour of intraperitoneally injected sodium salt of [1-14C]acetic acid (1,67-2,22 GBq/mmol, 37 MBq/ml, NEN), prepared by diluting to 1.85 MBq/ml using physiological salt solution (300 μl/animal). After one hour the rats did anesthetic diethyl ether to spend exsanguination through the abdominal aorta. The collected blood was centrifuged at 3000 rpm for 10 minutes to obtain plasma.

(II) To 2 ml of plasma was added to 1 ml of 4N KOH and 1 ml of ethanol, then incubated at 65°C for one hour and then added 3 ml of petroleum ether. Plasma was shaken for 30 minutes. After the aqueous phase was separated from the organic phase by centrifugation, frozen at -80°and measured the radioactivity of the organic phase using a liquid scintillation counter. Or the organic phase is evaporated to dryness using nitrogen gas and the residue was dissolved as a marker in 25 μl of chloroform containing squalene, headlamp shall ESOL and cholesterol. The sample was applied on the plate for TLC (Merck) and showed, using toluene and isopropyl ether (1:1) for 15-20 minutes. The band cholesterol were cut out of the plate to determine the radioactivity using a liquid scintillation counter. Activity suppression of the biosynthesis of cholesterol was expressed by the degree of suppression (%) relative to the control group.

The test example 3

Quantitative determination of activity in the suppression of the biosynthesis of cholesterol and triglycerides in liver cells of rats

Liver cells were isolated from male rats 3D conventional method (a method of perfusion with collagenase) and perform the experiment.

Highlighted the liver cells were sown in the amount of 500 μl in each well of 24-well plate with collagen coating (cell density: 4×105cells/ml). As a solution for cell culture used the environment E. Williams (pH brought to 7.4)containing 10% FCS (FCS), 1 μm insulin, 1 μm dexamethasone, 100 U/ml penicillin and 100 μg/ml streptomycin. Once the liver cells were incubated in CO2thermostat for 2 hours, the damaged cells was removed and cells of the liver additionally incubated overnight.

After the medium was replaced, the sample was diluted with 10% DMSO and 90% solution of cell culture was added to each well in an amount of 5 μl. In the control group, add the Yali DMSO (final concentration of 0.1%). Wednesday was added sodium salt of [1-14C]acetic acid (5 µci/well) in 10 minutes and after 4 hours was added to the sample to measure an overwhelming effect on the synthesis of cholesterol and for measuring an overwhelming effect on the synthesis of triglycerides, respectively, followed by culturing for a further 2 hours.

After the cultivation was completed, the supernatant was removed and cells were washed twice with FBI(-) (phosphate buffered salt solution (without Ca2+and Mg2+)). To the cells was added hexane/isopropyl alcohol (3:2, V/V) and cells were then left to stand for 10 minutes for the extraction vnutrikletochnykh lipids. The extract was transferred to a glass tube and dried in a stream of nitrogen gas. Then the dried extract was washed with petroleum ether containing the following components: 0.01% squalene, 0.3% of free cholesterol, 0.3% acetate cholesterol, 0.1% triolein, 0.01% farnesol and 0.3% of lanosterol.

The resulting solution was applied on the plate for TLC to implement the allocation. The applied solution was shown in the course of 10 minutes, using toluene/isopropyl ether (1:1, V/V) as solvents, and within another 15 minutes, using heptane instead of the above solvent, and then dried using the air.

After the demonstration was over, plasticus TLC was subjected to development with iodine staining. Once confirmed each provision of free cholesterol and triolein, which are used as standards, image plate for TLC transferred to the plate to produce images of BAS 2000 (Fuji Film) by exposure performed for 16 hours. The transferred image is analyzed using the reader BAS 2000 IP and the image analyzer II for measurement of radioactivity contained in fractions of free cholesterol and triglycerides.

Activity by inhibiting the biosynthesis of cholesterol was expressed by the concentration (IC50), which were eliminated 50% of the radioactivity in the control group, and the active suppression of the biosynthesis of triglycerides expressed by the degree of suppression (%) relative to the control group.

The results of the tests according to test example 1 (Quantitative determination of activity by suppression of synthesizing enzyme squalene through the use of liver microsomes rat), test example 2 (Quantitative determination of suppressive activity in relation to the biosynthesis of cholesterol) and test example 3 (Quantitative determination of activity in the suppression of the biosynthesis of cholesterol and triglycerides in liver cells of rats) are shown in table 1-4.

Table 1
Example/td> Activity suppression synthesizing enzyme squalene on IC50(µm)
110
220
934
102
1825
1910
1046,7
1066,9
1102,1
1160,77
1174,5
1182,5
119a 3.9
1241,8
1380,35
1425
1442,6
15311
16615
1806,3
2011,6

tr>
Table 2
ExampleDose (mg/kg)Activity suppression of the biosynthesis of cholesterol suppression (%)
6373
11372
12378
13387
104288
123386
142382
147387
148392
150173
153182
168389
169392
Table 3
ExampleActivity suppression of the biosynthesis of cholesterol by the IC50(µm)
1160,072
1170,079
1180,075
1200,075
124of 0.081
1380,014
1480,16
1490,59
1530,055
1790,13
1860,069

Table 4
ExampleActivity suppression of the biosynthesis of triacylglycerols suppress the 1 micron sample
10681
11084
11885
12080
12479
15080
15385
16682
17674
17984
20185

The connection according to this invention is very useful as an inhibitor of synthesizing enzyme squalene (table 1), and, in fact, as an inhibitor of the biosynthesis of cholesterol (table 2 and table 3). In addition, it is also very useful as an inhibitor of the synthesis of triglycerides as neutral fat (table 4). Accordingly, the connection according to this invention is suitable as a prophylactic and therapeutic agent for the treatment of diseases in which the effective suppression of the synthesis of squalene, the suppression of the biosynthesis of cholesterol or suppression of the biosynthesis of triglycerides. From the above results ledue is, the connection according to this invention is suitable as a prophylactic and therapeutic agent for treatment of hyperlipidemia, as well as prophylactic and therapeutic agents for diseases associated with atherosclerosis or ischemic heart disease.

EXAMPLES

The invention will be explained in more detail and specifically with the following examples, but the invention is not limited to them. Structural formulas of the compounds of these examples are listed in table 5-10 below.

Examples retrieve

An example of a 1: 4-Benzyl-5-bromo-2-pyridylsulfonyl

a) 4-Benzoyl-2-chloropyridin

102 g of 2-chloronicotinic acid suspended in 250 ml of benzene. Added 50 ml of thionyl chloride, followed by boiling under reflux for 7 hours. After cooling, the reaction solution is evaporated. The residue was dissolved in 250 ml of benzene and then adding small portions of 200 g of anhydrous aluminum chloride with stirring on a water bath. After stane reaction solution overnight at room temperature in him small portions was added 2 l of ice water and the mixture was extracted with ethyl acetate. The organic phase was washed with diluted hydrochloric acid, aqueous sodium bicarbonate solution and saturated salt solution, sushi is over anhydrous magnesium sulfate and the solvent was removed to obtain 135 g of the target compound.

1H-NMR (CDCl3) δ ppm: 7,50-7,56 (3H, m), to 7.61 (1H, DD, J=0,8, 1.2 Hz), to 7.68 (1H, t, J=8 Hz), 7,81 (2H, d, J=8 Hz), 8,58 (1H, DD, J=0,8, 5,2 Hz).

b) 4-Benzoyl-2-methoxypyridine

To 28% methanol solution of sodium methoxide boiling under reflux is added dropwise within one hour was added to a mixture of 135 g of 4-benzoyl-2-chloropyridine and 150 ml of methanol, followed by boiling under reflux for 2 hours. After cooling, the reaction solution was filtered to remove undissolved material, and the solvent was removed. To the residue was added aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and then the solvent was removed to obtain 130 g of target compound.

1H-NMR (CDCl3) δ ppm: 4,00 (3H, s), 7,00 (1H, DD, J=0,8, 1.2 Hz), 7,16 (1H, DD, J=1,2, 5,2 Hz), 7,50 (2H, t, J=8 Hz), 7,63 (1H, t, J=8 Hz), 7,83 (2H, d, J=8 Hz), 8,32 (1H, DD, J=0,8, 5,2 Hz)

c) 4-(α-Hydroxybenzyl)-2-methoxypyridine

9.4 g sodium borohydride in small portions was added to a mixture of 130 g of 4-benzoyl-2-methoxypyridine and 300 ml of methanol under stirring in an ice bath. After adding dropwise was completed, the mixture was stirred over night. The reaction solution was added to 1 l of water and then was extracted with ethyl acetate. The organic phase was washed with saturated of rastvorimoi, was dried over anhydrous magnesium sulfate and then the solvent was removed to obtain 104 g of the target compound.

1H-NMR (CDCl3) δ ppm: 2,39 (1H, d, J=3 Hz)to 3.92 (3H, s), 5,74 (1H, d, J=3 Hz), PC 6.82 (1H, s)6,86 (1H, d, J=5 Hz), 7,28 and 7.36 (5H, m), 8,08 (1H, d, J=5 Hz).

d) 4-(α-Acetoxymethyl)-2-methoxypyridine

A mixture of 104 g of 4-(α-hydroxybenzyl)-2-methoxypyridine, 100 ml of acetic anhydride and 100 ml of pyridine was heated under stirring for 5 hours at an oil bath temperature of 110°C. After the reaction solution was evaporated, to the residue was added water and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate and a saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to chromatography on a column of silica gel using 5-20% ethyl acetate/hexane, to obtain 112 g of target compound.

1H-NMR (CDCl3) δ ppm: to 2.18 (3H, s)to 3.92 (3H, s), 6.73 x-6,76 (2H, m), 6,79 (1H, d, J=5 Hz), 7,28-7,38 (5H, m), 8,10 (1H, d, J=5 Hz)

e) 4-Benzyl-2-methoxypyridine

5 g of 10% palladium on coal and 500 ml of methanol was added to 112 g of 4-(α-acetoxymethyl)-2-methoxypyridine followed by hydrocracking in a hydrogen atmosphere. The catalyst was filtered and the filtrate evaporated. Then the residue was neutralized with saturated aqueous sodium bicarbonate solution and the mixture extraheavy is and ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed to obtain 73 g of the target compound.

1H-NMR (CDCl3) δ ppm: 3,90 (5H, s), 6,55 (1H, s)6,70 (1H, d, J=5 Hz), 7,17 (2H, d, J=8 Hz), 7,22 (1H, t, J=8 Hz), 7,30 (2H, t, J=8 Hz), of 8.04 (1H, d, J=5 Hz).

f) 4-Benzyl-5-bromo-2-methoxypyridine

A mixed solution of 22 ml of bromine, 90 g of potassium bromide and 500 ml of water was added dropwise to a mixture of 73 g of 4-benzyl-2-methoxypyridine, 28 g of potassium hydroxide, 1.7 g of the chloride of tetraethylammonium, 90 g of potassium bromide and 500 ml of water with stirring in an ice bath. After stirring overnight was added sodium sulfite and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 5-10% ethyl acetate/hexane, to obtain 62 g of the target compound.

1H-NMR (CDCl3) δ ppm: a 3.87 (3H, s), of 4.00 (2H, s), 6,46 (1H, s), 7,19 (2H, d, J=7 Hz), 7,25 (1H, t, J=7 Hz), 7,32 (2H, t, J=7 Hz), by 8.22 (1H, s).

g) 4-Benzyl-5-bromo-2-hydroxypyridine

250 ml of 47% Hydrobromic acid was added 62 g of 4-benzyl-5-bromo-2-methoxypyridine followed by heating under stirring for 3 hours on an oil bath at a temperature of 100°C. After cooling the reaction solution in small portions was added to the water races is the thief of potassium carbonate and neutralized. The obtained precipitation was filtered to obtain 59 g of target compound.

1H-NMR (CDCl3) δ ppm: a 3.87 (2H, s), of 6.20 (1H, s), 7,21 and 7.36 (5H, m), 7,72 (1H, s).

h) 4-benzyl-5-bromo-2-pyridylsulfonyl

100 g of N-phenyltrichlorosilane was added in small portions to a suspension containing 59 g of 4-benzyl˜5-bromo-2-hydroxypyridine, 100 ml of triethylamine and 8 g of 4-dimethylaminopyridine in 200 ml of dichloromethane. After stirring at room temperature for 7 hours, the reaction solution is evaporated. The residue was subjected to column chromatography on silica gel using 5-10% ethyl acetate/hexane, to obtain 82 g of the target compound.

1H-NMR (CDCl3) δ ppm: 4,11 (2H, s), PC 6.82 (1H, s), 7,18 (2H, d, J=7 Hz), 7,32 (1H, t, J=7 Hz), 7,38 (2H, t, J=7 Hz), 8,46 (1H, s).

Example of getting a 2: 2-benzyl-6-pyridylmethylene

a) 2-Bromo-6-methoxypyridine

250 ml of a 28% methanolic solution of sodium methoxide was added dropwise to a mixture of 200 g of 2,6-dibromopyridine and 150 ml of methanol under heating at 80°and With stirring on an oil bath, followed by stirring under heating for 2 hours. After cooling, the mixture was extracted with a mixture of diethyl ether-water, the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed to obtain 150 g of target compound.

H-NMR (CDCl3) δ ppm: of 3.94 (3H, s), of 6.68 (1H, d, J=7 Hz), 7,06 (1H, d, J=8 Hz), 7,40 (1H, t, J=8 Hz).

b) 2-Benzyl-6-methoxypyridine

The Grignard reagent prepared from 123 ml benzylbromide, 30 g of magnesium and 400 ml of diethyl ether are added slowly dropwise added to a mixture of 150 g of 2-bromo-6-methoxypyridine, 4.3 g of chloride 1,3-bis(diphenylphosphino)-propenies (II) and 500 ml of tetrahydrofuran under stirring in an ice bath. After stirring over night the mixture was extracted with aqueous solution of ammonium chloride and hexane. The organic phase is washed with water and then with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 1% and 1.5% ethyl acetate/hexane, to obtain 150 g of target compound.

1H-NMR (CDCl3) δ ppm: to 3.92 (3H, s), a 4.03 (2H, s), is 6.54 (1H, d, J=8 Hz), of 6.65 (1H, d, J=7 Hz), 7.18 in-to 7.32 (5H, m), 7,44 (1H, DD, J=7, 8 Hz).

c) 2-Benzyl-6-hydroxypyridine

A mixture of 59 g of 2-benzyl-6-methoxypyridine and 200 ml of 47% Hydrobromic acid was heated with stirring for 7 hours at an oil bath at a temperature of 100°C. After cooling was added 250 ml of water and the resulting crystals were filtered off, washed with water and dried in vacuum, obtaining of 38.9 g of target compound.

1H-NMR (CDCl3) δ ppm: of 3.78 (2H, s), 5,96 (1H, d, J=7 Hz), x 6.15 (1H, d, J=9 Hz), 7,20 was 7.36 (6N, m).

d) 2-Benzo is l-6-pyridylmethylene

A mixture of 10 g of 2-benzyl-6-hydroxypyridine, 23 g of N-phenyltrichlorosilane, 0.66 g of 4-dimethylaminopyridine, 23 ml of triethylamine and 100 ml of dichloromethane was stirred at room temperature in a water bath for one hour. The reaction solution is evaporated and the residue was subjected to column chromatography on silica gel using 2-3% ethyl acetate/hexane, and additionally filtered through NH-silica gel (Fuji Silicia Called) and was suirable 3% ethyl acetate/hexane. The eluate is evaporated to obtain 11.7 g of the target compound.

1H-NMR (CDCl3) δ ppm: 4,13 (2H, s), of 6.99 (1H, d, J=8 Hz), 7,16 (1H, d, J=8 Hz), 7,22-7,34 (5H, m), of 7.75 (1H, t, J=8 Hz).

Example of getting 3: 2-Benzyl-Z-bromo-6-pyridylmethylene

a) 2-Benzyl-3-bromo-6-methoxypyridine

A mixed solution of 17 ml of bromine, 90 g of potassium bromide and 450 ml of water was added dropwise to a mixture of 60 g of 2-benzyl-6-methoxypyridine (example getting 2-b), 90 g of potassium bromide, 450 ml of water, 20 g of potassium hydroxide and 2.5 g of tetraammineplatinum for 2 hours with stirring in an ice bath. After stirring overnight was added sodium sulfite and the mixture was extracted with hexane. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel, elwira 0.5 to 1.5% ethyl acetate/hexane, obtaining 72.5 g C is a left join.

1H-NMR (CDCl3) δ ppm: 3,88 (3H, s), 4,20 (2H, s), 6.48 in (1H, d, J=8 Hz), 7,17-7,38 (5H, m), a 7.62 (1H, d, J=8 Hz).

b) 2-Benzyl-3-bromo-6-hydroxypyridine

A mixture of 72.5 g of 2-benzyl-3-bromo-6-methoxypyridine and 300 ml of 47% Hydrobromic acid was heated under stirring for 4 hours on an oil bath at a temperature of 100°C. After cooling, was added 500 ml of water. The obtained crystals were filtered off, washed with water and diethyl ether, dried in air and then dried under heating and reduced pressure to get to 63.8 g of the target compound.

1H-NMR (CDCl3) δ ppm: of 3.97 (2H, s), and 6.25 (1H, d, J=9 Hz), 7,20-to 7.35 (5H, m), 7,58 (1H, d, J=9 Hz).

c) 2-Benzyl-3-bromo-6-pyridylmethylene

A mixture of 1.2 g of 2-benzyl-3-bromo-6-hydroxypyridine, 1.7 g of N-phenyltrichlorosilane, 1.9 ml of triethylamine, 28 mg of 4-dimethylaminopyridine and 15 ml of dichloromethane was stirred at room temperature for 3 hours. To the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 5% ethyl acetate/hexane, to obtain 1.6 g of the target compound.

1H-NMR (CDCl3) δ ppm: 4,28 (2H, s), of 6.29 (1H, d, J=8 Hz), 7,22-7,33 (5H, m), of 7.97 (1H, d, J=8 Hz).

Example 4: 4-Benzyl-5-bromo-2-iterkeys

a) tert-Butyl 2-(dimethylaminomethylene)-3-oxo-4-phenylbutyrate

Phenylacetylene slowly dropwise added to a mixture of 110 g of the acid of Meldrum, 120 ml of pyridine and 500 ml of dichloromethane under stirring in an ice bath. After stirring overnight was added 650 ml of an aqueous solution 1,2N hydrochloric acid. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. To the residue was added 600 ml of tert-butanol, followed by boiling under reflux for 3 hours. After cooling, the solvent was removed and at the same time added to the ethanol. To the residue was added 600 ml of toluene and 110 ml of N,N-dimethylformamidine followed by heating for 2 hours at an oil bath at a temperature of 100°With, at the same time removing the methanol by the apparatus of the Dean-stark. Raccoony the solution is evaporated and the residue was subjected to column chromatography on silica gel, using 50-70% ethyl acetate/hexane, to obtain 93 g of target compound.

1H-NMR (CDCl3) δ ppm: 1,51 (N, C), a 4.03 (2H, s), 7.18 in-7,30 (5H, m), 7,56 (1H, s).

b) 4-benzyl-2-aminopyrimidine

Triperoxonane acid slowly dropwise added to a mixture of 93 g of tert-butyl 2-(dimethylaminomethylene)-3-oxo-4-phenylbutyrate and 400 ml of dichloromethane under stirring in an ice bath. After stirring overnight the solvent was removed and the residue was extracted with aqueous sodium bicarbonate solution, ethyl acetate and tetrahydrofuran. The organic phase is washed with water, saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. To the residue was added 500 ml of ethanol, 110 g of guanidine hydrochloride and 96 g of ethoxide sodium, followed by vigorous boiling under reflux for 20 hours. After cooling, was added 800 ml of water, 150 ml of hexane and 30 ml of diethyl ether. After stirring for 30 minutes at room temperature, the resulting crystals were filtered off, washed with water, dried in air and then in vacuum by heating to obtain 26 g of the target compound.

1H-NMR (CDCl3) δ ppm: 3,91 (2H, s), free 5.01 (2H, s)6,41 (1H, d, J=5 Hz), 7.23 percent-of 7.35 (5H, m), 8,15 (1H, d, J=5 Hz).

C) 4-benzyl-5-bromo-2-iterkeys

60 ml of a methanol solution containing 7.3 ml of bromine slowly dropwise added to a mixture of 26 g of 4-benzyl-2-aminopyrimidine, 24 g of sodium bicarbonate and 150 ml of N,N-dimethylformamide with stirring in an ice bath. After stirring for 10 minutes in an ice bath was added an aqueous solution of sodium thiosulfate. After stirring at room temperature for 30 minutes, insoluble substances were filtered off and dried in vacuo under heating. A mixture of the crude compound, 51 ml of isoamylamine, 51 ml diiodomethane, 24 g of copper iodide and 400 ml of tetrahydrofuran was heated under stirring for 2 hours at an oil bath at 65�B0; C. After cooling, was added 400 ml of ethyl acetate and the insoluble matter was filtered through celite. The filtrate was separated by adding an aqueous sodium thiosulfate solution and an aqueous solution of ammonium chloride. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable 6% ethyl acetate/hexane to obtain 20 g of the target compound.

1H-NMR (CDCl3) δ ppm: 4,20 (2H, s), 7.23 percent-of 7.35 (5H, m), 8,42 (1H, s).

Example of getting a 5: 3-Benzyl-5-bromo-2-pyridylmethylamine

a) 3-Benzyl-2-methoxypyridine

16 g of aluminum chloride was added to a mixture of 8.6 g of 2-chloronicotinic acid and 120 ml of benzene in an ice bath with stirring. After stirring at room temperature for 2 hours was added water and ethyl acetate. Insoluble matter was filtered through celite and the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. To the residue was added 100 ml of methanol and 30 ml of a 28% methanolic solution of sodium methoxide, followed by boiling under reflux overnight. After cooling, the solvent was removed and the mixture was separated by adding water and ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous Sul is an atom of magnesium and the solvent was removed. To the residue was added 90 ml of diethylene glycol, 6.8 g of potassium carbonate and 4.3 ml of hydrazine monohydrate. The mixture was heated with stirring for one hour on an oil bath at 100°and then for 3 hours on an oil bath at 170°C. After cooling, the mixture was separated by adding water and ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable 10% ethyl acetate/hexane to obtain of 4.2 g of the target compound.

1H-NMR (CDCl3) δ ppm: 3,91 (2H, s), of 3.97 (3H, s), 6,79 (1H, DD, J=5.7 Hz), 7.18 in-7,32 (6N, m), 8,03 (1H, DD, J=2, 5 Hz).

b) 3-Benzyl-5-bromo-2-methoxypyridine

0,12 ml of bromine was added to a mixture of 430 mg of 3-benzyl-2-methoxypyridine, 460 mg of sodium bicarbonate and 10 ml of methanol under stirring in an ice bath, followed by stirring at room temperature for 8 hours. The mixture was separated by adding thereto an aqueous solution of sodium thiosulfate and ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable 5% ethyl acetate/hexane to obtain 140 g of target compound.

1H-NMR (CDCl3) δ ppm: a 3.87 (2H, s)to 3.92 (3H, s), 7,17-7,34 (6N, m), with 8.05(1H, d, J=2 Hz).

C) 3-Benzyl-5-bromo-2-pyridylsulfonyl

A mixture of 190 mg of 3-benzyl-5-bromo-2-methoxypyridine and 2 ml of 47% Hydrobromic acid was stirred under heating at an oil bath at a temperature of 70°C, for 2 hours. After cooling, the mixture was separated by adding thereto an aqueous solution of potassium carbonate and ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. To the residue was added 300 mg of N-phenyltrichlorosilane, and 8.4 mg of 4-dimethyl-aminopyridine, 0,29 mg of triethylamine and 2 ml of dichloromethane, followed by stirring at room temperature for one hour. To the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 5% ethyl acetate/hexane, to obtain 220 mg of the target compound.

1H-NMR (CDCl3) δ ppm: 4,01 (2H, s), 7,17-7,20 (2H, m), 7,28-7,39 (3H, m), 7,65-to 7.67 (1H, m), of 8.27 (1H, d, J=2 Hz).

An example of obtaining 6: (3-Pyridyl)tributylamine

of 1.45 ml of a hexane solution containing 1.54 M n-utility was added dropwise in 200 ml diethylamino solution containing 10.0 g 3-bromopyridine at -78°C in nitrogen atmosphere for 10 minutes. After adding dropwise, the mixture was stirred for 10 minutes and then there was added dropwise 20 ml of chloride t is ibotirama for 10 minutes. Then after stirring for 30 minutes to the reaction mixture were added water and then extracted with ethyl acetate. The extract was washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane, then hexane/ethyl acetate (7:1) obtaining of 21.9 g of the target compound.

1H-NMR (CDCl3) δ ppm: 0,87-0,94 (N, m), 1,07-1,11 (6N, m), 1,26-1,38 (6N, m), 1,50-1,58 (6N, m), 7,22 (1H, m), 7,73 (1H, m), and 8.50 (1H, m), 8,59 (1H, s).

An example of obtaining 7: (2-Pyridyl)tributylamine

The target compound was synthesized in the same manner as in the example of a 6.

1H-NMR (CDCl3) δ ppm: 0,87-0,94 (N, m), 1,09-1,14 (6N, m)of 1.28 to 1.37 (6N, m, 1,52-1,58 (6N, m), 7,10 (1H, m), 7,40 (1H, m), of 7.48 (1H, m), 8,73 (1H, m).

An example of obtaining 8: (3,4-Methylenedioxyphenyl)tributylamine

The target compound was synthesized in the same manner as in the example of a 6, except that the solvent for the reaction (diethyl ether) was replaced with tetrahydrofuran.

1H-NMR (CDCl3) δ ppm; of 0.87-0.90 (N, m), 1.00 and was 1.04 (6N, m)of 1.30 to 1.37 (6N, m, 1,49-1,56 (6N, m), 5,61 (2H, s), 6,83-6,93 (3H, m).

An example of obtaining 9: (4-Pyridyl)tributylamine

9,0 ml hexane solution of 2.52 M n-utility was added dropwise in 20 ml of tertrahydrofuran ring solution of 3.2 ml of Diisopropylamine under ice cooling for 10 minutes in nitrogen atmosphere. After premesis the deposits under ice cooling for 20 minutes there was added dropwise 6.3 ml anti-hydrogenated over 10 minutes, followed by stirring under ice cooling for 20 minutes. Then when cooled to -78°there was added dropwise a suspension of 2.0 g of the hydrochloride of 4-bromopyridine and 30 ml of tetrahydrofuran for 10 minutes. After stirring for 2 hours to the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution and the solvent was removed. Then the residue was subjected to column chromatography on NH-silica gel, elwira hexane/ethyl acetate (7:1), and was further subjected to column chromatography on silica and suirable hexane/ethyl acetate (2:1) to give 580 mg (15%) of target compound.

1H-NMR (CDCl3) δ ppm: 0,87-0,91 (N, m), 1,07-1,11 (6N, m), 1.30 and 1.35 (6N, m, 1,49-1,60 (6N, m), 7,35-7,37 (2H, m), of 8.47-8,48 (2H, m).

Example 10: Parasitisation

5.0 g tetranitroaniline (0) were added to 50 ml of a xylene solution containing 8.0 g of chloropyrazine and 200 g of bis(anti), followed by heating under stirring at 140°C for one hour in nitrogen atmosphere. After cooling the reaction mixture to room temperature the solvent was removed. The residue was subjected to column chromatography on silica and suirable hexane, then hexane/ethyl acetate (10:1) to give 9.5 g parasitisation.

1H-NMR (CDCl3) δ ppm: 0,87-0,94 (N, m), 1,15-1,19 (6N, m), 1,26-1,38 (6N, m, 1,53-1,60 (6N, m), at 8.36 (1H, m) 8,54 (1H, m)8,71 (1H, m).

An example of obtaining 11: 2-Benzyl-3-methoxypiperidine-6-carboxyaldehyde

a) 3-Benzyloxy-2-hydroxymethyl-6-methylpyridin

100 g of 3-hydroxy-6-methyl-2-pyridinemethanol and 150 g of potassium carbonate suspended in 400 ml of N,N-dimethylformamide. Under stirring and heated to 60°C in an oil bath was added dropwise 85 ml benzylbromide. Next, after heating with stirring for 30 minutes the insoluble substance was filtered. To the filtrate was added water and the mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was recrystallized from a mixture of ethanol/hexane to obtain 145 g of target compound.

1H-NMR (CDCl3) δ: 2,49 (3H, s), 4,48 (1H, t, J=4 Hz), of 4.77 (2H, d, J=4 Hz), 5,09 (2H, s), 6,98 (1H, d, J=8 Hz), was 7.08 (1H, d, J=8 Hz), 7,28 was 7.45 (5H, m).

b) 3-Benzyloxy-6-methylpyridin-2-carboxyaldehyde

145 g of 3-benzyloxy-2-hydroxymethyl-6-methylpyridine was dissolved in 500 ml of chloroform. Added 400 g of manganese dioxide with stirring and heating at 60°C in an oil bath, followed by heating under stirring for one hour. After cooling, the reaction solution was filtered to remove insoluble substances and the solvent was removed. The obtained crystals were dried in vacuum to obtain 13 g of the target compound.

1H-NMR (CDCl3) δ: to 2.57 (3H, s), with 5.22 (2H, s), 7,25-7,46 (7H, m), 10,41 (1H, s).

C) 3-benzyloxy-2-(α-hydroxybenzyl)-6-methylpyridin

139 g of 3-benzyloxy-6-methylpyridin-2-carboxaldehyde was dissolved in 700 ml of tetrahydrofuran and then cooled to -60°With or below. Under stirring with a mechanical stirrer was added dropwise to 400 ml of cyclohexane/ether solution containing 1.8 mol penility. After stirring for 30 minutes while cooling was added a saturated aqueous solution of ammonium chloride and the temperature was raised to room. Next there was added water and the mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was recrystallized from ethanol under cooling to obtain 116 g of the target compound.

1H-NMR (CDCl3) δ: of 2.53 (3H, s)to 4.92 (1H, d, J=12 Hz), to 4.98 (1H, d, J=12 Hz), 5,80 (1H, d, J=7 HZ), 5,91 (1H, d, J=7 Hz), of 6.99 (1H, d, J=8 Hz),? 7.04 baby mortality (1H, d, J=8 Hz), 7,07-7,14 (2H, m), 7,20 was 7.36 (8H, m).

d) 2-Benzoyl-3-benzyloxy-6-methylpyridin

116 g of 3-benzyloxy-2-(α-hydroxybenzyl)-6-methylpyridine was dissolved in 500 ml of chloroform. With stirring, was added 400 g of manganese dioxide, followed by heating under stirring at 60°C for one hour on an oil bath. After cooling the reaction solution f is literaly to remove insoluble substances and the solvent was removed. The obtained crystals were dried in vacuum to obtain 113 g of target compound.

1H-NMR (CDCl3) δ: of 2.53 (3H, s), is 5.06 (2H, s), 7,13-7,3 0 (7H, m), 7,45 (2H, t, J=8 Hz), 7,58 (1H, t, J=8 Hz), 7,87 (2H, d, J=8 Hz).

e) 6-Hydroxymethyl-2-benzoyl-3-benzyloxypyridine

113 g of 2-benzoyl-3-benzyloxy-6-methylpyridine was dissolved in 600 ml of dichloromethane. Added 96 g of 3-chloroperbenzoic acid, followed by stirring under heating at 50°C in an oil bath. After cooling in a water bath to the reaction solution was added an aqueous solution of sodium sulfite and then saturated aqueous sodium bicarbonate solution. The organic phase was separated, then washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. Then it was dried over anhydrous magnesium sulfate and the solvent was removed. The obtained residue was dissolved in 200 ml of acetic anhydride followed by heating under stirring at 150°C for 3 hours on an oil bath. Then the solvent was removed, was added 400 ml of methanol and 200 ml of 2N aqueous solution of sodium hydroxide followed by heating under stirring at 60°C for 3 hours on an oil bath. To the reaction solution was added activated charcoal. After stirring for some time it was filtered. To the filtrate was added water to precipitate crystals. Received by Italy was filtered and dried in vacuum to obtain 116 g of the target compound.

1H-NMR (CDCl3) δ: 3,18 (1H, t, J=5 Hz), 4,74 (2H, d, J=5 Hz), 5,12 (2H, s), 7,17-7,30 (5H, m), 7,32 (1H, d, J=9 Hz), 7,39 (1H, d, J=9 Hz), 7,46 (2H, t, J=8 Hz), 7,60 (1H, t, J=8 Hz), a 7.85 (2H, d, J=8 Hz).

f) 2-Benzoyl-6-(tert-butyldimethylsilyl)oxymethyl-3-benzyloxypyridine

116 g of 6-hydroxymethyl-2-benzoyl-3-benzyloxypyridine was dissolved in 450 ml of N,N-dimethylformamide. Added 100 g of imidazole and 85 g of tert-butyldimethylsilyloxy, followed by stirring at room temperature over night. The solvent was removed and to the residue was added water and the mixture was extracted with ethyl acetate. Next, the organic phase was washed with diluted hydrochloric acid, water, aqueous saturated sodium bicarbonate solution and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was dried to obtain 141 g of the target compound.

1H-NMR (CDCl3) δ: 0,11 (6N, (C), 0,95 (N, C)4,80 (2H, s), 5,10 (2H, s), 7,15-to 7.32 (5H, m), 7,39 (1H, d, J=9 Hz), 7,44 (2H, t, J=8 Hz), 7,53-to 7.61 (2H, m), a 7.85 (2H, d, J=8 Hz).

g) 2-(α-Acetoxymethyl)-6-(tert-butyldimethylsilyl)oxymethyl-3-benzyloxypyridine

141 g of 2-benzoyl-6-(tert-butyldimethylsilyl)oxymethyl-3-benzyloxypyridine was dissolved in 500 ml of methanol. Under ice cooling was added 4.9 g sodium borohydride, followed by stirring for 2 hours. After increasing the temperature to room was added water and the mixture was extracted with ethylacetate is. Next, the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was dissolved in 200 ml of pyridine was added 100 ml of acetic anhydride followed by heating under stirring for one hour at 150°C in an oil bath. The solvent was removed and to the residue was added water and the mixture was extracted with ethyl acetate. Next, the organic phase was washed with diluted hydrochloric acid, water and saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was dried to obtain 160 g of target compound.

1H-NMR (CDCl3) δ: 0,10 (6N, C)0,94 (N, C)2,17 (3H, s), rate 4.79 (2H, s), 5,04 (1H, d, J=12 HZ), 5,09 (1H, d, J=12 Hz), 7,14-7,46 (13H, m).

h) 2-Benzyl-6-(tert-butyldimethylsilyl)oxymethyl-3-hydroxypyridine

160 g of 2-(α-acetoxymethyl)-6-(tert-butyldimethylsilyl)-oxymethyl-3-benzyloxypyridine was dissolved in a mixed solvent of 200 ml of tetrahydrofuran and 200 ml of methanol. Added 8 g of 10% palladium on coal for conducting hydrocracking. After the atmosphere in the reaction system was replaced with nitrogen, the catalyst was filtered and the filtrate evaporated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous is a Ulfat magnesium and evaporated to obtain 100 g of the target compound.

1H-NMR (CDCl3) δ: 0,11 (6N, (C), 0,95 (N, C)4,19 (2H, s), rate 4.79 (2H, s), to 7.09 (1H, d, J=8 Hz), 7,10-7,34 (6N, m).

i) 2-Benzyl-6-hydroxymethyl-3-methoxyethoxymethyl

To 100 g of 2-benzyl-6-(tert-butyldimethylsilyl)oxymethyl-3-hydroxypyridine was added 63 g of potassium carbonate and 300 ml of N,N-dimethylformamide and the mixture was added dropwise 23 ml chloromethylmethylether ether at room temperature under stirring using a mechanical stirrer. After heating under stirring at 50°C for 2 hours on an oil bath was added water and the mixture was extracted with ethyl acetate. Next, the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The obtained residue was dissolved by adding 400 ml of tetrahydrofuran, was added 300 ml of tertrahydrofuran ring solution containing 1 mol of fluoride, Tetra-n-butylamine while cooling with ice. After stirring under ice cooling was added water and the mixture was extracted with ethyl acetate. Next, the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in a mixture of 50% ethyl acetate/hexane and filtered through silica gel. The filtrate is evaporated and dried to obtain 73 g of the target compound.

1H-NMR (CDCl3) δ: 3,29 (3H, s), 4,17 (2H, s), rate 4.79 (2H, s), 5,12 (2H, s), 7,14 1H, t, J=7 Hz), 7.18 in-to 7.32 (5H, m), 7,37 (1H, d, J=8 Hz).

j) 2-Benzyl-3-methoxypiperidine-6-carboxyaldehyde

73 g of 2-benzyl-6-hydroxymethyl-3-methoxypyridine was dissolved in 300 ml of chloroform followed by the addition of 220 g of manganese dioxide after mixing. Then the mixture was heated under stirring at 50°C for 1.5 hours on an oil bath. After cooling, the reaction solution was filtered to remove insoluble substances and the solvent was removed. The obtained crystals are recrystallized from ether/hexane to obtain 30 g of the target compound. The filtrate obtained in the recrystallization was concentrated. The residue was subjected to column chromatography on silica gel using 5-10% ethyl acetate/hexane as eluent for the separation and purification and recrystallized from a mixture of ether/hexane to obtain 11 g of the target compound.

1H-NMR (CDCl3) δ: 3,29 (3H, s), 4,27 (2H, in), 5.25 (2H, s), 7,18 (1H, t, J=7 Hz), 7,26 (2H, t, J=7 Hz), 7,31 (2H, d, J=7 Hz), was 7.45 (1H, d, J=8 Hz), a 7.85 (1H, d, J=8 Hz), 10,00 (1H, s).

Example 12: 2-Benzyl-3-methoxyethoxy-6-yodellin

a) 2-Bromo-3-methoxyethoxymethyl

50 g of 2-bromo-3-hydroxypyridine suspended in 200 ml of tetrahydrofuran, followed by addition of 33 ml chloromethylmethylether ether. When cooled to -20°and With stirring in small portions was added 17 g of 60% oil suspension Hydra is Yes sodium. After adding sodium hydride cooling medium was removed, followed by stirring at room temperature for 3.5 hours. While cooling in small portions was added ice water and the mixture was extracted with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 10-15% ethyl acetate/hexane as eluent for separation and purification to obtain 35 g of the target compound.

1H-NMR (CDCl3) δ: of 3.53 (3H, s), 5,28 (2H, s), 7,21 (1H, DD, J=4,6, and 8.2 Hz), the 7.43 (1H, DD, J=1,6, 8,2 Hz), with 8.05 (1H, DD, J=1,6, 4.6 Hz).

b) 2-Benzyl-3-methoxyethoxymethyl

The solution benzylbromide magnesium in diethyl ether, prepared from 38 ml benzylbromide, 8 g of magnesium and 250 ml of anhydrous diethyl ether are added slowly dropwise added to a mixture of 35 g of 2-bromo-3-methoxypiperidine, 5 g of chloride 1,3-bis(diphenylphosphino)propenies (II) and 200 ml of tetrahydrofuran under stirring with ice cooling in a nitrogen atmosphere. After stirring for 4.5 hours was added a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to Nochnoi chromatography on silica gel, using 8-20% ethyl acetate/hexane as eluent for separation and purification to obtain 27 g of the target compound.

1H-NMR (CDCl3) δ: to 3.34 (3H, s), is 4.21 (2H, s)to 5.17 (2H, s), 7,11-7,38 (7H, m), to 8.20 (1H, DD, J=1,3, 4,8 Hz).

C) 2-Benzyl-3-hydroxy-6-yodellin

60 ml triperoxonane acid was added to 27 g of 2-benzyl-3-methoxypiperidine, followed by stirring at room temperature for 2 hours and then heated under stirring for one hour at 50°C in an oil bath. The reaction solution was added to aqueous potassium carbonate solution, which was cooled with ice, and the obtained crystals were filtered off. The filtrate is evaporated and to the obtained crystals were added to 19 g of sodium iodide, 5 g of sodium hydroxide and 200 ml of methanol. Under stirring with ice cooling there was added dropwise 158 ml of 5% aqueous sodium hypochlorite solution for 30 minutes. After stirring overnight was added 60 ml of 5N hydrochloric acid and then added saturated aqueous sodium thiosulfate solution, followed by extraction with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The obtained crystals were filtered and dried in vacuum to obtain 17 g of target compound.

d) 2-Benzyl-3-methoxyethoxy-6-yodellin

12 g of 2-Benzyl-3-hydroxy-6-iopidine was dissolved in 50 ml of tetrahydrofuran followed by the addition of 3.8 ml chloromethylmethylether ether. Small portions were added 2 g of 60% oil suspension of sodium hydride with stirring with ice cooling. After adding sodium hydride cooling medium was removed and the mixture was stirred at room temperature for 2.5 hours. Then there is the small portions were added ice-water cooling, followed by extraction with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 15% ethyl acetate/hexane as eluent for separation and purification to obtain 13 g of the target compound.

1H-NMR (CDCl3) δ: of 3.28 (3H, s), 4,14 (2H, s), 5,11 (2H, s),? 7.04 baby mortality (1H, d, J=8,4 Hz), 7,14-7,30 (5H, m), of 7.48 (1H, d, J=8,4 Hz).

Example of getting a 13: 2-(4-Terbisil)-3-bromo-6-hydroxypyridine

Benzylbromide in the example of a 2-b was replaced with 4-tormentilla and one by one carried out the same procedures as in examples for the preparation of 3-a and 3-b for the synthesis of the compound named in the heading.

1H-NMR (CDCl3) δ: 4,15 (2H, s), 6,36 (1H, d, J=9 Hz), 6,99-7,03 (2H, m), 7,33-7,37 (2H, m), 7,51 (1H, d, J=9 Hz).

Example of getting a 14: 2-(3-Terbisil)-3-bromo-6-hydroxypyridine

Ben is libroid in the example of a 2-b was replaced with 3-tormentilla and then performed the same procedure, as in the examples for the preparation of 3-a and 3-b for the synthesis of the compound named in the heading.

1H-NMR (CDCl3) δ: 4,18 (2H, s), 6,37 (1H, d, J=9 Hz), 6,92-6,97 (1H, m), 7,06-7,17 (2H, m), 7,26-7,31 (1H, m), 7,52 (1H, d, J=9 Hz).

An example of obtaining 15: 4-Benzyl-5-bromo-2-chloropyrimidine

The target compound was synthesized in the same manner as in example 4, except that isoamylase was replaced with tert-butylnitrite, diameter and copper iodide was replaced with a copper chloride, and tetrahydrofuran as solvent was changed to acetonitrile.

1H-NMR (CDCl3) δ: of 4.75 (2H, s), 7,25-to 7.35 (5H, m), of 7.70 (1H, s).

Example 16: 2-Benzyl-3-bromo-6-hydroxy-5-yodellin

1.19 g of N-jodatime was added to a mixture of 1.16 g of 2-benzyl-3-bromo-6-hydroxypyridine (example of a 3-b) and 10 ml of N,N-dimethylformamide at room temperature, followed by stirring at the same temperature throughout the night. To the reaction solution were added 50 ml of water and the resulting crystals were filtered off, washed with water and then dried in vacuum to obtain 1.47 g of the target compound.

1H-NMR (CDCl3) δ: was 4.02 (2H, s), 7,30-7,37 (5H, m), 8,11 (1H, s).

An example of obtaining 17: 2-Bromo-6-iodine-3-pyridylsulfonyl

a) 2-Bromo-3-hydroxy-6-yodellin

to 17.6 g of chloramine T was added to a mixture of 10.9 g of 2-bromo-3-hydroxypyridine, 9,35 g of sodium iodide and 110 ml of N,N-dimethylformamide at PE is emisiuni in an ice bath, followed by stirring at the same temperature for 30 minutes, and then at room temperature for 10 minutes. Added water, ethyl acetate and 11 ml of 6N aqueous solution of hydrochloric acid and the organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable 30% ethyl acetate/hexane to obtain 16.5 g of target compound.

1H-NMR (CDCl3) δ: to 5.58 (1H, Sirs), 6,98-7,01 (1H, m), 7,55-7,58 (1H, m).

b) 2-Bromo-6-iodine-3-pyridylsulfonyl

of 19.7 g of N-phenyltrichlorosilane, 336 mg of 4-dimethylaminopyridine and 23.0 ml of triethylamine was added to a mixture of 16.5 g of 2-bromo-3-hydroxy-6-iopidine and 150 ml of dichloromethane at room temperature, followed by stirring at room temperature for 1.5 hours. To the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 5% ethyl acetate/hexane, to obtain 19.9 g of the target compound.

1H-NMR (CDCl3) δ: 7,30 (1H, d, J=9 Hz), 7,78 (1H, d, J=9 Hz).

An example of obtaining 18: (2-Benzyl-3-methoxyethoxy-6-pyridyl)tributylamine

The target compound was synthesized in the same manner as in the example of a 6, except that 3-bromopyridin was replaced with 2-benzyl-6-iodine-3-methoxyethoxymethyl (example 12).

1H-NMR (CDCl3) δ: 0,84-0,89 (N, m), 1,03-1,08 6N, m), 1,28-1,38 (6N, m)and 1.51-1,59 (6N, m)of 3.32 (3H, s), 4,20 (2H, s), 5,12 (1H, s), 7,10 and 7.36 (7H, m).

An example of obtaining 19: Pyrosilicate

a) Piratillacibernetico

to 10.1 g of trimethylsilylacetamide and 28.6 ml of triethylamine was added to a mixture of 6,11 ml chloropyrazine, 653 mg of copper iodide, of 3.96 g of tetrakis(triphenylphosphine)palladium (0) and 100 ml of N,N-dimethylformamide, followed by stirring at 50°C for 3.5 hours. After cooling to room temperature was added celite and hexane, followed by filtering to remove insoluble substances through celite. After evaporation of the solvent the residue was subjected to column chromatography on silica gel and was suirable 10% ethyl acetate/hexane to obtain 9,58 g of target compound.

1H-NMR (CDCl3) δ: 0,31 (N, C)of 8.47 (1H, s), 8,53 (1H, s), 8,68 (1H, s).

b) Pyrosilicate

7.51 g of potassium carbonate was added to the mixture 9,58 g parasitosintestinalesennino and 70 ml of methanol at 0°C, followed by stirring at room temperature for 30 minutes. Added water and diethyl ether and the organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated to obtain 2.50 g of the compound named in the heading.

1H-NMR (CDCl3) δ: 3,20 (1H, s), scored 8.38 (1H, s), to 8.41 (1H, s), to 8.57 (1H, s).

An example of obtaining 20: 2 Methoxyethoxy-1-iadanza

216 mg of 60% oil is a suspension of sodium hydride were added to a mixture of 1.65 g of 2-itfinal and 20 ml of N,N-dimethylformamide under ice cooling, followed by stirring at room temperature for 30 minutes. Added 570 μl chloromethylmethylether ether under ice cooling, followed by stirring for 30 minutes at room temperature. There was added water and ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed to obtain a 2.12 g of the target compound.

1H-NMR (CDCl3) δ: to 3.52 (3H, s), of 5.24 (2H, s)6,76 (1H, dt, J=1.8 Hz), 7,07 (1H, DD, J=1,8 Hz), 7,26-7,30 (1H, m), 7,78 (1H, DD, J=1,8 Hz).

An example of obtaining 21: 2-Methyl-2-propionylthiocholine

1,2-dibromethane (140 μl) and 0.400 ml of 1-chloro-2-methyl-2-propene was added to a mixture of 505 mg of magnesium and 2 ml of tetrahydrofuran, followed by heating. After initiation of the heating was stopped. The reaction solution was diluted in 5 ml of tetrahydrofuran, followed by adding dropwise 8 ml of tertrahydrofuran ring solution of 1.18 ml of 1-chloro-2-methyl-2-propene. After stirring at room temperature for 30 minutes to the reaction solution was added the presence of TBT chloride, followed by stirring at room temperature for 4 hours. Was added an aqueous solution of ammonium chloride and ethyl acetate and the organic phase is washed with saturated sodium bicarbonate solution and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed to obtain 5.29 g of the target compound.

1H-I Is R (CDCl 3) δ: 0,85-0,98 (N, m), 1,25-1,78 (N, m), 4,43-4,48 (2H, m).

An example of obtaining 22: 2-Iodine-1,3,4-thiadiazole

A mixture of 19.2 g of 2-amino-1,3,4-thiadiazole, 35,0 g of copper iodide, 74,0 ml diiodomethane, 74,0 ml isopentylamine and 500 ml of tetrahydrofuran was boiled under reflux for 5 hours. After cooling, to the reaction solution was added 200 ml of ethyl acetate. After filtering off insoluble matters, the filtrate was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (1:2). Then the eluate was led from a mixture of ethyl acetate/methanol/hexane to obtain 15.7 g of the target compound.

1H-NMR (CDCl3) δ ppm: 9,13 (1H, s).

An example of retrieving 23: (2 Pirimidil)tri-n-botillo

3.2 ml hexane solution containing 1.57 mol n-utility, slowly, was added dropwise in 20 ml of tertrahydrofuran ring solution containing 707 μl of Diisopropylamine, while cooling with ice. After stirring at 0°C for 30 minutes slowly, dropwise there was added to 1.4 ml of hydride tri-n-butyanova. After stirring at 0°C for 30 minutes, the mixture was cooled to -78°and slowly dropwise added to the suspension in 30 ml of tetrahydrofuran containing 2-chloropyrimidine. After stirring at -78°C for one hour to the reaction solution at 0°C for 2 hours add the Yali water. The mixture was extracted with ethyl acetate, the organic phase is washed with saturated salt solution and the solvent was removed. Then the residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (10:1), and then hexane/ethyl acetate (7:1) to give 654 mg of target compound.

1H-NMR (CDCl3) δ: 0,86-0,90 (N, m), 1,15-1,20 (6N, m), 1.30 and 1,36 (6N, m), and 1.54-1.61 of the (6N, m), 7,12 (1H, t, J=5 Hz), 8,68 (2H, d, J=5 Hz).

An example of obtaining 24: (5 Pirimidil)tri-n-botillo

The target compound was synthesized in the same manner as in the synthesis of (2-pyrimidyl)tri-n-butyanova.

1H-NMR (CDCl3) δ: 0,87-0,91 (N, m), 1,12-1,16 (6N, m), 1.30 and 1,38 (6N, m), 1,50-1,59 (6N, m), 8,67-8,71 (2H, m), 9,12 (1H, s).

An example of obtaining 25: (4 Pirimidil)tri-n-botillo

5.8 ml of hexane solution containing 2,52 mol n-utility, slowly, was added dropwise in 20 ml of tertrahydrofuran ring of a solution containing 2.5 ml of 2,2,6,6-tetramethylpiperidine. After stirring at 0°C for 30 minutes in there slowly, was added dropwise a mixture of 0.98 ml pyrimidine, 4,6 ml chloride tri-n-butyanova and 20 ml of tetrahydrofuran. After stirring at -78°C for 4 hours to the reaction solution were added water and then extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. Then the residue was subjected to column chromatograph and on silica gel, elwira 15% hexane/ethyl acetate (10:1), with 474 mg of target compound.

1H-NMR (CDCl3) δ: 0,86-0,91 (N, m), 1,14-1,18 (6N, m), 1.30 and 1,38 (6N, m, 1,52-1,60 (6N, m), 7,44 (1H, DD, J=4,8 Hz, 1.6 Hz), of 8.47 (1H, d, J=4,8 Hz), 9,23 (1H, d, J=1.6 Hz).

An example of obtaining 26: (3-Pyridil)tri-n-botillo

11,2 ml hexane solution containing 2,52 mole of n-utility, was slowly added to 30 ml of tertrahydrofuran ring solution containing 4.8 ml 2,2,6,6-tetramethylpiperidine at -30°C, followed by stirring at 0°C for 30 minutes. Then added 7.3 ml of N,N,N',N'-tetramethylethylenediamine and then to the mixture at -78°C was slowly added a mixture of 1.74 ml pyridazine, 10.3 ml chloride tri-n-butyanova and 10 ml of tetrahydrofuran, followed by stirring at -78°C for 3 hours. Then to the reaction solution were added water and then was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. Then the residue was subjected to column chromatography on NH-silica gel (Fuji Silicia), elwira hexane/ethyl acetate (10:1), and then subjected to column chromatography on silica gel, elwira hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (1:1), to obtain 660 mg of the target compound.

1H-NMR (CDCl3) δ: 0,86-0,91 (N, m), 1,14-1,22 (6N, m), 1,24-1,38 (6N, m), and 1.54-1.61 of the (6N, m), 7.24 to 7,28 (1H, m), of 7.48-7,50 (1H, m), 9,03-9,04 (1H, m).

P the emer obtain 27: (4-Pyridil)tri-n-botillo

58,0 ml hexane solution containing 2,52 mol n-utillity slowly dropwise added to 200 ml of tertrahydrofuran ring solution containing 25 mol 2,2,6,6-tetramethylpiperidine, -30°C. After stirring at 0°C for 30 minutes in there slowly, was added dropwise a mixture of 9.1 ml pyridazine, 46,0 ml chloride tri-n-butyanova and 100 ml of tetrahydrofuran at -78°C. After stirring at -78°C for 4 hours to the reaction solution were added water and then were extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. Then the residue was subjected to column chromatography on NH-silica gel (Fuji Silica), elwira hexane/ethyl acetate (10:1). Then was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (1:1) to obtain 6.6 g of the target compound.

1H-NMR (CDCl3) δ: 0,87-0,91 (N, m), 1,13-1,18 (6N, m), 1,31-1,36 (6N, m), 1,50-1,58 (6N, m), 7,53 (1H, d, J=5 Hz), of 9.02 (1H, d, J=5 Hz), 9,17 (1H, s).

An example of retrieving 28: (1,4-Dioxan-2-yl)tri-n-botillo

5.8 ml of pentane solution containing 1,51 mol tert-utility, was slowly added to 30 ml of tertrahydrofuran ring of a solution containing 1.0 g of 1,4-dioxane, -40°C. After stirring at -40°C for one hour there slowly dropwise added to 1.7 ml of tri-n-butyanova at-78° C. After stirring at -78°C for 3 hours to the reaction solution were added water and then extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. Then the residue was filtered through silica gel and the solvent was removed to obtain 1.5 g of the target compound.

1H-NMR (CDCl3) δ: 0,87-1,56 (N, m)4,00-4,11 (4H, m), 5,69 (1H, s).

An example of obtaining 29: (3R)-3-Ethinyl-3-hinokitiol

a) (3R)-3-Ethinyl-3-hinokitiol · L-(+)-tartrate

a 15.1 g of 3-ethinyl-3-hinokitiol and 15 g L-(+)-tartaric acid was dissolved under heating in 300 ml of methanol. After cooling, the resulting crystals were filtered and recrystallized from methanol three times to obtain 2,07 g of compound named in the heading.

1H-NMR (DMSO-d6) δ ppm: 1,45-and 1.54 (1H, m), 1,68-of 1.78 (1H, m), 1,83-2,03 (3H, m), 2,83-a 3.01 (5H, m), 3,21 (1H, DD, J=2,14 Hz), 3,50 (1H, s), of 4.05 (2H, s).

b) (3R)-3-Ethinyl-3-hinokitiol

15.6 g (3R)-3-Ethinyl-3-hinokitiol · L-(+)-tartrate was dissolved in 150 ml of water and small portions were added 20 g of anhydrous potassium carbonate with stirring. The obtained crystals were filtered off, washed with water and then dried with getting to 6.88 g of the compound named in the heading.

1H-NMR (DMSO-d6) δ ppm: 1,20-1,30 (1H, m), 1,47-of 1.55 (1H, m), 1,70-1,90 (3,N, m), 2,54-2,70 (4H, m), of 2.72 (1H, DD, J=2,14 Hz), with 2.93 (1H, d, J=14 Hz), 3,29 (1H, s), vs. 5.47 (1H, s).

[α]589=+58,3 (=1,02, Meon)

(literature: [α]24589=+54,5 (C=0.99, and the Meon); Tetrahedron: Asymmetry, 6, (6), 1393, 1995).

Example 30: (3S)-3-Ethinyl-3-hinokitiol

The target compound was synthesized from 3-ethinyl-3-hinokitiol in the same manner as in example receiving 29, and D-(-)-tartaric acid is used as agent for optical separation.

1H-NMR (DMSO-d6) δ: 1,20-1,30 (1H, m), 1,47-of 1.55 (1H, m), 1,70-1,90 (3H, m), 2,54-2,70 (4H, m), of 2.72 (1H, DD, J=2,14 Hz), with 2.93 (1H, d, J=14 Hz), 3,29 (1H, s), vs. 5.47 (1H, s).

[α]22,5589=-56,9 (C=1.00, the Meon)

(literature: [α]20598=-56,1 (=1,02, Meon); Tetrahedron: Asymmetry, 6 (6), 1393, 1995).

EXAMPLES

Example 1: 3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethinyl-3-hinokitiol

a) 4-Benzyl-5-bromo-2-(3,4-methylenedioxyphenyl)pyridine

A mixture of 400 mg of 4-benzyl-5-bromo-2-pyridylmethylamine, 410 mg (3,4-methylenedioxyphenyl)anti -, 300 mg of tetrabutylammonium chloride, 20 mg of tetrakis(triphenylphosphine)-palladium (0) and 2 ml of xylene was stirred under heating for 3 hours on an oil bath at a temperature of 140°C in nitrogen atmosphere. The reaction solution was subjected to column chromatography on silica gel using 5-10% ethyl acetate/hexane, to obtain 140 g of target compound.

1H-NMR (CDCl3) δ ppm: 4,12 (2H, s)to 6.00 (2H, s), 6,85 (1H, d, J=8 Hz), 7.23 percent (2H, d, J=8 Hz), 7,27 (1H, t, J=7 Hz), 7.3 to 7,41 (5H, m), 8,68 (1H, s).

b) 3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethinyl-3-hinokitiol

A mixture of 140 mg of 4-benzyl-5-bromo-2-(3,4-methylenedioxyphenyl)-pyridine, 70 mg of 3-ethinyl-3-hinokitiol, 10 mg of tetrakis-(triphenylphosphine)palladium (0), 1 mg of copper iodide, 0.5 ml of triethylamine and 1 ml of N,N-dimethylformamide was stirred under heating for 2 hours at an oil bath at a temperature of 100°C in nitrogen atmosphere. After cooling there was added a dilute aqueous solution of ammonia, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was subjected to column chromatography on NH-silica gel using 50% ethyl acetate/hexane and then ethyl acetate to obtain 40 mg of the target compound.

1H-NMR (CDCl3) δ ppm: 1,30-of 1.95 (3H, m), 2.00 in to 2.15 (2H, m), 2,65-2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,23 (1H, d, J=14 Hz), is 4.15 (2H, s), 6,01 (2H, s), 6.87 in (1H, d, J=8 Hz), 7,19 (2H, d, J=8 Hz), 7,22-7,28 (1H, m), 7,32 (2H, t, J=7 Hz), 7,40 (1H, s), 7,42-7,46 (2H, m), 8,65 (1H, s).

Example 2: 3-[4-Benzyl-2-(2-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 1.

1H-NMR (CDCl3) δ ppm: 1,35-1,90 (3H, m), 2.00 in to 2.15 (2H, m), 2,70-2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), is 4.21 (2H, s), 7,20-7,32 (6N, m), 7,81 (1H, dt, J=2, 8 Hz), 8,29 (1H, s), scored 8.38 (1H, d, J=8 Hz), 8,64-8,67 (1H, m), 8,68 (1H, s).

Example 3: 3-[4-Ben the Il-2-(3-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 1.

1H-NMR (CDCl3) δ ppm: 1,38-of 1.92 (3H, m), 2,00-2,11 (2H, m), 2.70 height is 3.00 (4H, m), 3,06 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 4,18 (2H, s), 7,20 (2H, d, J=7 Hz), 7,22-7,2 9 (1H, m), 7,32 (2H, t, J=7 Hz), 7,39 (1H, DD, J=5, 7 Hz), 7,49 (1H, s), by 8.22-of 8.27 (1H, m), 8,63 (1H, DD, J=2, 5 Hz), a total of 8.74 (1H, s), 9,13 (1H, DD, J=1.2 Hz).

Example 4: 3-[4-Benzyl-2-Persil-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 1.

1H-NMR (CDCl3) δ ppm: 1,37-1,90 (3H, m), 2,00-2,11 (2H, m), 2,70-2,96 (4H, m), 3,05 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 4,20 (2H, s), 7.18 in-7,33 (5H, m), to 8.20 (1H, s), 8,56 at 8.60 (2H, m), 8,73 (1H, s), being 9.61 (1H, d, J=2 Hz)

Example 5: 3-[4-Benzyl-2-(4-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 1.

1H-NMR (CDCl3) δ ppm: 1,41 was 1.43 (1H, m), 1,61-to 1.67 (1H, m), 1,84-to 1.87 (1H, m), 2,04 e 2.06 (2H, m), 2.77-to 2,85 (4H, m), 3,05 (1H, DD, J=2, 14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 4,20 (2H, s), 7,19-to 7.35 (5H, m), 7,55 (1H, C), 7,80-of 7.82 (2H, m), 8,69-to 8.70 (2H, m), a total of 8.74 (1H, s).

Example 6: 3-[4-Benzyl-2-(2-methoxyethoxy)-5-pyridyl]-ethinyl-3-hinokitiol

a) 4-(α-Hydroxybenzyl)-2-(2-methoxyethoxy)pyridine

3 g of sodium was added to 50 ml of methoxyethanol and the mixture was stirred under heating at an oil bath at a temperature of 100°C in nitrogen atmosphere for 1 hour. After the sodium had dissolved, there was added dropwise a mixture of 5.6 g of 4-benzoyl-2-chloro what iridin (example obtain 1-a), and 10 ml of methoxyethanol, followed by stirring under heating at an oil bath at a temperature of 100° C in nitrogen atmosphere for 3 hours. The reaction solution is evaporated and there was added an aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated salt solution and subjected to column chromatography on silica gel using 10-50% ethyl acetate/hexane, to obtain 5.9 g of the target compound.

1H-NMR (CDCl3) δ ppm: to 2.55 (1H, Sirs), 3,42 (3H, s), 3,70 of 3.75 (2H, m), 4,40-of 4.45 (2H, m), 5/96 (1H, Sirs), 7,18 (1H, s), 7.24 to 7,40 (6N, m)to 8.12 (1H, s).

b) 4-Benzyl-5-bromo-2-(2-methoxyethoxy)pyridine

to 7.32 g of the compound named in the heading, received from and 11.8 g of 4-(α-hydroxybenzyl)-2-(2-methoxyethoxy)pyridine in the same manner as in examples get (1-d, e and f).

1H-NMR (CDCl3) δ ppm: 3.40 in (3H, s), 3,66-3,70 (2H, m), 3,98 (2H, s), 4,37 was 4.42 (2H, m), 6,50 (1H, s), 7,15-to 7.35 (5H, m), 8,18 (1H, s).

C) 3-[4-Benzyl-2-(2-methoxyethoxy)-5-pyridyl]ethinyl-3-hinokitiol

310 g of compound named in the heading, received from 1,38 g of 4-benzyl-5-bromo-2-(2-methoxyethoxy)pyridine in the same manner as in example 12.

1H-NMR (CDCl3) δ ppm: 1,35-1,90 (3H, m), 1,98-of 2.08 (2H, m), 2,70-2,96 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 3,42 (3H, s), 3,69-to 3.73 (2H, m), Android 4.04 (2H, s), 4,42-to 4.46 (2H, m), 6,55 (1H, s), 7,16 (2H, d, J=7 Hz), 7.23 percent (1H, t, J=7 Hz), 7,30 (2H, t, J=7 Hz), 8,18 (1H, s).

Example 7: 3-[2-Benzyl-6-(4-ethoxycarbonylpyrimidine)-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-(4-ethoxycarbonyl peridine)pyridine

A mixture of 5 g of 2-benzyl-6-pyridylmethylamine, 3.6 ml of ethylisopropylamine, and 3.3 g of potassium carbonate and 15 ml of N-methylpyrrolidone was heated with stirring on an oil bath at 100°C in nitrogen atmosphere. After cooling, the mixture was extracted with a mixture of ethyl acetate/water. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel and was suirable 1-5% ethyl acetate/hexane to obtain 4.7 g of the target compound.

1H-NMR (CDCl3) δ ppm: 1.26 in (3H, t, J=7 Hz), 1.70 to to 1.82 (2H, m), 1,94 is 2.01 (2H, m), of 2.51 (1H, TT, J=4, 11 Hz), 2,88-of 2.97 (2H, m), of 3.97 (2H, s), is 4.15 (2H, q, J=7 Hz), 4,22-the 4.29 (2H, m), 6,38 (1H, d, J=7 Hz), 6,46 (1H, d, J=9 Hz), 7,16-7,22 (1H, m), 7,26-7,31 (4H, m), 7,34 (1H, DD, J=7, 9 Hz),

b) 2-benzyl-3-iodine-6-(4-ethoxycarbonylpyrimidine)pyridine

After stirring in an ice bath to a mixture of 1.2 g of 2-benzyl-6-(4-ethoxycarbonylpyrimidine)of pyridine and 10 ml of N,N-dimethylformamide in small portions was added to 1.25 g of N-jodatime, followed by stirring overnight. Was added sodium sulfite and the mixture was extracted with a mixture of ethyl acetate-water. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel and was suirable 1-5% ethyl acetate/hexane to obtain 1.42 g a the new connection.

1H-NMR (CDCl3) δ MD: of 1.26 (3H, t, J=7 Hz), 1,64 to 1.76 (2H, m), 1,90-to 1.98 (2H, m), 2,50 (1H, TT, J=11 Hz, 4 Hz), 2,87-2,96 (2H, m), 4,10-4,20 (6N, m), 6,27 (1H, d, J=9 Hz), 7,18 (1H, t, J=7 Hz), 7,26 (2H, t, J=7 Hz), 7,32 (2H, d, J=7 Hz), of 7.70 (1H, d, J=9 Hz).

c) 3-[2-Benzyl-6-(4-ethoxycarbonylpyrimidine)-3-pyridyl]-ethinyl-3-hinokitiol

A mixture of 1.42 g of 2-benzyl-3-iodine-6-(4-ethoxycarbonylpyrimidine)pyridine, 520 mg of 3-ethinyl-3-hinokitiol, 110 mg of tetrakis(triphenylphosphine)palladium (0), 3 mg of copper iodide, 1.3 ml of triethylamine and 6 ml of N,N-dimethylformamide was heated with stirring on an oil bath at a temperature of 80°C for 3 hours in nitrogen atmosphere. After cooling, the mixture was extracted with a mixture of ethyl acetate-diluted aqueous solution of ammonia. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on NH-silica gel and was suirable 20-100% ethyl acetate/hexane and then with 2.5% methanol/ethyl acetate to obtain 700 mg of the target compound.

1H-NMR (CDCl3) δ ppm: 1.26 in (3H, t, J=7 Hz), 1,34-of 1.45 (1H, m), 1,53-of 1.78 (3H, m), 1,83-of 2.08 (5H, m), 2,53 (1H, TT, J=4, 11 Hz), 2,69-3.04 from (7H, m), 3,23 (1H, DD, J=2, 14 Hz), 4,10-4,18 (4H, m), 4,22-4,30 (2H, m), to 6.43 (1H, d, J=9 Hz), 7,16 (1H, t, J=7 Hz), 7,25 (2H, t, J=7 Hz), 7,30 (2H, d, J=7 Hz), 7,43 (1H, d, J=9 Hz).

Example 8: 3-(2-Benzyl-6-morpholino-3-pyridyl)ethinyl-3-hinokitiol

The target compound was synthesized in the same way that the example 7.

1H-NMR (CDCl3) δ ppm: 1,35-1,45 (1H, m), 1,54-of 1.64 (1H, m), 1,83-of 1.93 (1H, m), 1,98-of 2.08 (2H, m), 2,68-to 2.94 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 3,52 (4H, t, J=5 Hz), with 3.79 (4H, t, J=5 Hz), to 4.16 (2H, s)6,40 (1H, d, J=8 Hz), 7,14-7,31 (5H, m), 7,47 (1H, d, J=8 Hz).

Example 9: 3-[2-Benzyl-6-(4-methoxypiperidine)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 7.

1H-NMR (CDCl3) δ ppm: 1,35-1,45 (1H, m), 1,52-of 1.65 (3H, m), 1,83 is 1.96 (3H, m), 1,98-of 2.08 (2H, m), 2,70-of 2.93 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,19-of 3.27 (3H, m)to 3.38 (3H, s), 3,39-of 3.46 (1H, m), 3.96 points-Android 4.04 (2H, m), 4,15 (2H, s), 6,44 (1H, d, J=9 Hz), 7,16 (1H, t, J=7 Hz), 7,25 (2H, t, J=7 Hz), 7,30 (2H, d, J=7 Hz), 7,42 (1H, d, J=9 Hz).

Example 10: (3R)-3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine

11 ml of 1,8-diazabicyclo[5,4,0]-7-undecene was added dropwise to a mixture of 11.3 g of 2-benzyl-6-pyridylmethylamine, 11.3 g of (3R,4R)-3,4-dihydroxypyrrolidine (synthesized from D-tartaric acid, as an initial matter, Angew. Chem. Int. Ed. Engl., 23 (6), 435, 1984) and 10 ml of N-methylpyrrolidone on an oil bath at a temperature of 100°C in nitrogen atmosphere, followed by stirring for 6 hours. After cooling, the mixture was extracted with ethyl acetate-water. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to kolonochnoi chromatography on silica gel and was suirable with ethyl acetate to obtain 5.35 g of the target compound.

1H-NMR (CDCl3) δ ppm: 3,47 (2H, DD, J=2, 11 Hz), with 3.79 (2H, DD, J=4, 11 Hz), of 3.97 (2H, s), 4.26 deaths-4,30 (2H, m), 6,17 (1H, d, J=8 Hz), 6,38 (1H, d, J=8 Hz), 7,19 (1H, t, J=7 Hz), 7,26 and 7.36 (5H, m).

b) 2-Benzyl-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine

800 mg oily suspension (60%) sodium hydride was added in small portions to a mixture of 5.35 g of 2-benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine and 40 ml of tetrahydrofuran under stirring, followed by stirring for one hour. Then there was added to 1.24 ml methyliodide, followed by stirring overnight. The mixture was extracted with ethyl acetate-water and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and vaporware. The residue was subjected to column chromatography on silica gel and was suirable 30% ethyl acetate/hexane to obtain 2,18 g of target compound.

1H-NMR (CDCl3) δ ppm: 3,42 (3H, s), 3,47-3,55 (2H, m), 3,69-of 3.78 (2H, m), 3,85-to 3.89 (1H, m), of 3.97 (2H, s), of 4.38 was 4.42 (1H, m), 6,17 (1H, d, J=8 Hz), 6.35mm (1H, d, J=7 Hz), 7,19 (1H, t, J=7 Hz), 7,26-to 7.35 (5H, m).

c) 2-Benzyl-3-iodine-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine

Under stirring in an ice bath to a mixture of 3.11 g of 2-benzyl-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine and 10 ml of N,N-dimethylformamide in small portions was added 2.5 g of N-jodatime, followed by stirring overnight. There was added sodium sulfite and see what camping was extracted with ethyl acetate-water. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel and was suirable 30% ethyl acetate/hexane to obtain 4,19 g of target compound.

1H-NMR (CDCl3) δ ppm: to 3.41 (3H, s), 3,42-3,51 (2H, m), 3,64-3,71 (2H, m), 3,84-a 3.87 (1H, m), 4,19 (2H, s), of 4.38 was 4.42 (1H, m), 5,98 (1H, d, J=8 Hz), 7,18 (1H, t, J=7 Hz), 7,26 (2H, t, J=7 Hz), 7,37 (2H, d, J=7 Hz), 7,69 (1H, d, J=8 Hz).

d) (3R)-3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The mixture 4,19 g of 2-benzyl-3-iodine-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine, 1.7 g (3R)-3-ethinyl-3-hinokitiol, 500 mg of tetrakis(triphenylphosphine)palladium (0), 10 mg of copper iodide and 4.2 ml of triethylamine and 13 ml of N,N-dimethylformamide was heated with stirring on an oil bath at a temperature of 70°C for 3 hours in nitrogen atmosphere. After cooling, the mixture was extracted with a mixture of ethyl acetate-diluted aqueous solution of ammonia. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on NH-silica gel and was suirable 20-100% ethyl acetate/hexane, then 5% methanol/ethyl acetate to obtain 1.54 g of the target compound.

1H-NMR (CDCl3) δ ppm: 1,34-of 1.44 (1H, m), 1,50-1,60 (1H, m), 1,80-1,90 (1H, m), 1,97-of 2.08 (2H, m), 2,60-2,90 (N, m)of 2.97 (1H, d, J=14 Hz), 3,19 (1H, DD, J=2,14 Hz), 3,40 (3H, s), 3,41-of 3.54 (2H, m), 3,62-to 3.73 (2H, m), 3,82-of 3.85 (1H, m), of 4.13 (2H, s), 4,34-4,37 (1H, m)6,09 (1H, d, J=9 Hz), 7,14 (1H, t, J=7 Hz), of 7.23 (2H, t, J=7 Hz), 7,29 (2H, d, J=7 Hz), 7,39 (1H, d, J=9 Hz).

Example 11: 3-[2-Benzyl-6-(3-methoxypropylamine)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 7.

1H-NMR (CDCl3) δ ppm: 1,34-of 1.44 (1H, m), 1,52-of 1.66 (1H, m), 1,81 is 1.91 (3H, m), 1,97-2,07 (2H, m), 2,67-of 2.93 (4H, m), 3,01 (1H, DD, J=2, 14 Hz), 3,21 (1H, DD, J=2, 14 Hz), to 3.34 (3H, s)to 3.36 (2H, q, J=6 Hz), 3,48 (2H, t, J=6 Hz), is 4.93 (1H, t, J=6 Hz), of 6.20 (1H, d, J=8 Hz), 7,16 (1H, t, J=7 Hz), 7,22-7,31 (4H, m), 7,42 (1H, d, J=8 Hz).

Example 12: 3-[2-Benzyl-6-(2-methoxyethoxy)-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-bromo-6-(2-methoxyethoxy)pyridine

A mixture of 5 g of 2-benzyl-3-bromo-6-hydroxypyridine, of 3.9 g of anhydrous potassium carbonate, and 2.7 ml of 2-pomatoleios ether and 20 ml of N,N-dimethylformamide was heated with stirring on an oil bath at a temperature of 80°C for one hour. After cooling, the mixture was extracted with a mixture of ethyl acetate-water. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel and was suirable 1-3% ethyl acetate/hexane to obtain of 4.2 g of the target compound.

1H-NMR (CDCl3) δ ppm: to 3.41 (3H, s), 3,68 (2H, t, J=5 Hz), 4,19 (2H, s)to 4.41 (2H, t, J=5 Hz), 654 (1H, d, J=9 Hz), 7,20 (1H, t, J=7 Hz), 7,27 (2H, t, J=7 Hz), 7,32 (2H, d, J=7 Hz), 7,63 (1H, d, J=9 Hz).

b) 3-[2-Benzyl-6-(2-methoxyethoxy)pyridyl)ethynyl-3-hinokitiol

A mixture of 720 mg of 2-benzyl-3-bromo-6-(2-methoxyethoxy)-pyridine, 340 mg of 3-ethinyl-3-hinokitiol, 130 mg of tetrakis(triphenylphosphine)palladium (0), 42 mg of copper iodide, with 0.93 ml of triethylamine and 3 ml of N,N-dimethylformamide was heated with stirring on an oil bath at a temperature of 80°C for 2 hours in nitrogen atmosphere. After cooling, the mixture was extracted with ethyl acetate-diluted aqueous solution of ammonia. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on NH-silica gel and was suirable 20-100% ethyl acetate/hexane and then with 2.5% methanol/ethyl acetate to obtain 500 mg of the target compound.

1H-NMR (CDCl3) δ ppm: 1,35-1,45 (1H, m), 1,55-1,65 (1H, m), 1,83-of 1.93 (1H, m), 1,98-of 2.08 (2H, m), 2,7-of 2.93 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), to 3.41 (3H, s), of 3.69 (2H, t, J=5 Hz), 4,19 (2N, (C), of 4.45 (2H, t, J=5 Hz), 6,59 (1H, d, J=8 Hz), 7,14-of 7.3 (5H, m), 7,53 (1H, d, J=8 Hz).

Example 13: 3-[2-Benzyl-6-(3-methoxyphenoxy)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 12.

1H-NMR (CDCl3) δ ppm: to 1.38 to 1.48 (1H, m), 1,58 was 1.69 (1H, m), 1,82-of 1.93 (1H, m), from 2.00 (2H, quintet, J=6.4 Hz), 2,72-2,94 (6N, m), 3,03 (1H, DD, J=1,2, 14 Hz), 3,24 (1H, DD, J=,0, 14 Hz), to 3.34 (3H, s), 3,51 (2H, t, J=6.4 Hz), 4,20 (2H, s), 4,37 (2H, t, J=6.4 Hz), 6,53 (1H, d, J=8,4 Hz), 7.18 in-7,31 (5H, m), 7,54 (1H, d, J=8,4 Hz).

Example 14: 3-[2-Benzyl-6-(4-pyridyl)-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-bromo-6-(4-pyridyl)pyridine

A mixture of 298 mg of 2-benzyl-3-bromo-6-pyridylmethylamine, 277 mg (4-pyridyl)presence of TBT, 87 mg of tetrakis-(triphenylphosphine)palladium (0), 209 mg of tetrabutylammonium chloride and 5.0 ml of xylene was heated under stirring on an oil bath at a temperature of 140°C for one hour in nitrogen atmosphere. After cooling, the solvent was removed, the residue was subjected to column chromatography on NH-silica gel and was suirable hexane/ethyl acetate (5:1) to give 196 mg of the target compound.

1H-NMR (CDCl3) δ ppm: was 4.42 (2H, s), 7.23 percent-7,39 (5H, m), 7,54 (1H, d, J=8 Hz), 7,88-of 7.90 (2H, m), to 7.93 (1H, d, J=8 Hz), 8,71-8,72 (2H, m).

b) 3-[2-Benzyl-6-(4-pyridyl)-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 196 mg of 2-benzyl-3-bromo-6-(4-pyridyl)pyridine, 100 mg 3-ethinyl-3-hinokitiol, 70 mg of tetrakis(triphenylphosphine)-palladium (0), 11 mg of copper iodide, 0.25 ml of triethylamine and 3.0 ml of N,N-dimethylformamide was heated with stirring on an oil bath at a temperature of 85°C for one hour in nitrogen atmosphere. After cooling, the mixture was extracted with ethyl acetate-diluted aqueous solution of ammonia. The organic phase is washed with saturated salt solution and the solvent was removed. OS is atok was subjected to column chromatography on NH-silica gel and was suirable hexane/ethyl acetate (1:1) and then with methanol/ethyl acetate (20:1). After removal of solvent the residue was recrystallized from hexane/ethyl acetate to obtain 178 mg of the target compound.

1H-NMR (CDCl3) δ ppm: 1,39-of 1.45 (1H, m), 1,62-to 1.67 (1H, m), 1,83-of 1.88 (1H, m), 2,02 is 2.75 (2H, m), 2,78-2,89 (4H, m), 3,03 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), to 4.41 (2H, s), 7,19-7,33 (5H, m), 7,63 (1H, d, J=8 Hz), 7,78 (1H, d, J=8 Hz), of 7.90-a 7.92 (2H, m), 8,70-8,72 (2H, m).

Example 15: 3-[2-Benzyl-6-(3-pyridyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 14.

1H-NMR (CDCl3) δ ppm: USD 1.43 to 1.47 (1H, m), 1,57-of 1.62 (1H, m), 1,80-of 1.94 (1H, m), 2.05 is-2,07 (2H, m), 2.77-to 2,90 (4H, m), 3,05 (1H, d, J=14 Hz)at 3.25 (1H, d, J=14 Hz), and 4.40 (2H, s), 7.18 in-7,34 (5H, m), 7,39-7,42 (1H, m), 7,56 (1H, d, J=8 Hz), of 7.75 (1H, d, J=8 Hz), 8.34 per-of 8.37 (1H, m), 8,63 (1H, DD, J=2, 5 Hz), of 9.21 (1H, d, J=2 Hz).

Example 16: 3-[2-Benzyl-6-Persil-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 14.

1H-NMR (DMSO-d6) δ ppm: 1,27-of 1.36 (1H, m), 1,52 is 1.60 (1H, m), 1,72-to 1.82 (1H, m), 1,87 is 1.96 (1H, m), 1,99-2,03 (1H, m), 2,56-of 2.72 (4H, m), 2,87 (1H, d, J=14 Hz), of 3.07 (1H, d, J=14 Hz), 4,39 (2H, s)5,80 (1H, s), 7.18 in-7,41 (5H, m), to 7.99 (1H, d, J=8 Hz), to 8.20 (1H, d, J=8 Hz), 8,72 (1H, d, J=3 Hz), the rate of 8.75 (1H, m), of 9.51 (1H, s).

Example 17: 3-[2-Benzyl-6-(2-pyridyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 14.

1H-NMR (CDCl3) δ ppm: 1,40-of 1.93 (3H, m), 2,00-2,11 (2H, m), 2,70-2,95 (4H, m), to 3.02 (1H, d, J=14 Hz), up 3.22 (1H, DD, J=2, 14 Hz), 4,42 (2H, s), 7.18 in-,34 (6N, m), 7,81 (1H, d, J=8 Hz), 7,81 (1H, dt, J=2, 8 Hz), of 8.27 (1H, d, J=8 Hz), 8,46 (1H, d, J=8 Hz), 8,65-8,68 (1H, m).

Example 18: 3-[4-Benzyl-2-(3-pyridyl)-5-pyrimidyl]ethinyl-3-hinokitiol

a) 4-Benzyl-5-bromo-2-(3-pyridyl)pyrimidine

A mixture of 440 mg of 4-benzyl-5-bromo-2-godparenting, 430 mg (3-pyridyl)presence of TBT, 68 mg of tetrakis(triphenylphosphine)-palladium (0) and 5 ml of xylene was heated under reflux for one hour in nitrogen atmosphere. After cooling, to the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable 30% ethyl acetate/hexane to obtain 110 mg of the target compound.

1H-NMR (CDCl3) δ ppm: 4,33 (2H, s), 7,21-7,42 (6N, m), 8,66 (1H, dt, J=2, 8 Hz), 8,71 (1H, DD, J=2, 5 Hz), 8,80 (1H, s), 9,62 (1H, d, J=2 Hz).

b) 3-[4-Benzyl-2-(3-pyridyl)-5-pyrimidyl]ethinyl-3-hinokitiol

A mixture of 110 mg of 4-benzyl-5-bromo-2-(3-pyridyl)pyrimidine, 59 mg of 3-ethinyl-3-hinokitiol, 19 mg of tetrakis-(triphenylphosphine)palladium (0), 10 mg of copper iodide, of 0.14 ml of triethylamine and 1.5 ml of N,N-dimethylformamide was heated with stirring on an oil bath at a temperature of 100°C for 2 hours in nitrogen atmosphere. After cooling, to the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 2.5% methanol/ethyl acetate, to obtain 62 mg of the target compound.

1 H-NMR (CDCl3) δ ppm: 1,42-of 1.92 (3H, m), 2.05 is-a 2.12 (2H, m), was 2.76-to 2.99 (4H, m), 3,10 (1H, d, J=14 Hz), or 3.28 (1H, DD, J=2, 14 Hz), 4,32 (2H, s), 7,21-to 7.35 (5H, m), 7,40-the 7.43 (1H, m), 8,68-to 8.70 (2H, m), a total of 8.74 (1H, s), 9,65-to 9.66 (1H, m).

Example 19: 3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5-pyrimidyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 18.

1H-NMR (CDCl3) δ ppm: 1,40-1,70 (2H, m), 1,84-of 1.92 (1H, m), 2,04-2,12 (2H, m), 2,74-only 2.91 (4H, m), 3,05 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), the 4.29 (2H, s), 6,04 (2H, s)6,91 (1H, d, J=8 Hz), 7,21-7,34 (5N, m), 7,94 (1H, d, J=2 Hz), 8,08 (1H, DD, J=2,8 Hz), 8,66 (1H, s).

Example 20: 3-[4-Benzyl-2-phenyl-5-pyrimidyl)ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 18.

1H-NMR (CDCl3) δ ppm: 1,43 is 1.70 (2H, m), 1,84-of 1.92 (1H, m), 2,02-2,11 (2H, m), 2,75 of 2.92 (4H, m), 3,06 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2, 14 Hz)to 4.33 (2H, s), 7,21 and 7.36 (5H, m), of 7.48-to 7.50 (3H, m), 8,45-8,48 (2H, m), 8,73 (1H, s).

Example 21: 3-[4-Benzyl-2-(2-pyridyl)-5-pyrimidyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 18.

1H-NMR (CDCl3) δ ppm: of 1.40 to 1.48 (1H, m), 1,61-of 1.88 (2H, m), 2.00 in of 2.08 (2H, m), was 2.76-2.95 points (4H, m), 3,06 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), and 4.40 (2H, s), 7,21-7,33 (5H, m), 7,39-7,42 (1H, m), 7,86 (1H, TD, J=2, 8 Hz), 8,54 (1H, d, J=8 Hz), cent to 8.85-8,87 (2H, m).

Example 22: 3-[3-Benzyl-5-(2-pyridyl)-2-pyridyl]ethinyl-3-hinokitiol

a) 3-[3-Benzyl-5-bromo-2-pyridyl]ethinyl-3-hinokitiol

A mixture of 2.2 g of 3-benzyl-5-bromo-2-pericytic methansulfonate, 840 mg of 3-ethinyl-3-hinokitiol, 920 mg of tetrakis-(triphenylphosphine)palladium (0), 170 mg of copper iodide, and 2.3 ml of triethylamine and 25 ml of N,N-dimethylformamide was stirred at room temperature for one hour in nitrogen atmosphere. To the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel, using a 3.5% methanol/ethyl acetate, to obtain 940 mg of the target compound.

1H-NMR (CDCl3) δ ppm: 1,35-of 1.44 (1H, m), 1.56 to of 1.65 (1H, m), 1,80-1,90 (1H, m), 1,98-of 2.09 (2H, m), 2.70 height of 2.92 (4H, m), 3.04 from (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 4,11 (2H, s), 7,14-7,17 (2H, m), 7.23 percent-7,34 (3H, m), EUR 7.57 (1H, d, J=2 Hz)and 8.50 (1H, d, J=2 Hz).

b) 3-[3-Benzyl-5-(2-pyridyl)-2-pyridyl]ethinyl-3-hinokitiol

A mixture of 150 mg of 3-[3-benzyl-5-bromo-2-pyridyl]ethinyl-3-hinokitiol, 150 mg (2-pyridyl)presence of TBT, 86 mg of tetrakis(triphenylphosphine)palladium (0) and 3.5 ml of toluene was heated with stirring on an oil bath at a temperature of 110°C for 2 hours in nitrogen atmosphere. After cooling, to the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 2.5% methanol/ethyl acetate, to obtain 100 mg of the target compound.

1H-NMR (CDCl3) δ ppm: 1,35 was 1.43 (1H, m), 1,54-to 1.63 (1H, m), 1,83-of 1.92 (1H, m), 1,99 is 2.10 (2H, m), 2.71 to to 2.94 (4H, m), of 3.07 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2, 14 Hz), is 4.21 (2H, s), 7,19-7,30 (6N, m), of 7.70 (1H, d, J=8 Hz), 7,76(1H, dt, J=2, 8 Hz), 8,16 (1H, d, J=2 Hz), 8,68-to 8.70 (1H, m), of 9.02 (1H, d, J=2 Hz).

Example 23: 3-(3-Benzyl-5-phenyl-2-pyridyl)ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 22.

1H-NMR (CDCl3) δ ppm: 1,36-of 1.44 (1H, m), 1.56 to of 1.64 (1H, m), 1,86-of 1.95 (1H, m), 1,98-2,11 (2H, m), 2.71 to 2,95 (4H, m), is 3.08 (1H, d, J=14 Hz), or 3.28 (1H, DD, J=2, 14 Hz), is 4.21 (2H, s), 7,19-7,53 (10H, m), of 7.64 (1H, d, J=2 Hz), 8,69 (1H, d, J=2 Hz).

Example 24: 3-[3-Benzyl-5-(3-pyridyl)-2-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 22.

1H-NMR (CDCl3) δ ppm: 1,37-of 1.45 (1H, m), 1.56 to of 1.64 (1H, m), 1,84-of 1.92 (1H, m), 2,04-2,12 (2H, m), 2,73-to 2.94 (4H, m)to 3.09 (1H, d, J=14 Hz), or 3.28 (1H, DD, J=2, 14 Hz), is 4.21 (2H, s), 7.18 in-7,31 (5H, m), 7,38 (1H, DDD, J=l, 5, 8 Hz), to 7.61 (1H, d, J=2 Hz), 7,82 (1H, dt, J=2, 8 Hz), to 8.62 (1H, DD, J=2, 5 Hz), 8,64 (1H, d, J=2 Hz), 8,87 (1H, DD, J=1.2 Hz).

Example 25: 3-[3-Benzyl-5-(4-pyridyl)-2-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 22.

1H-NMR (CDCl3) δ ppm: 1,37-of 1.45 (1H, m), 1,57-of 1.65 (1H, m), 1.85 to of 1.92 (1H, m), 2,00-2,11 (2H, m), 2,73-of 2.93 (4H, m), is 3.08 (1H, d, J=14 Hz), or 3.28 (1H, DD, J=2, 14 Hz), 4,22 (2H, s), 7.18 in-7,34 (5H, m), 7,42-7,44 (2H, m), to 7.67 (1H, d, J=2 Hz), 8,67-8,69 (2H, m), to 8.70 (1H, d, J=2 Hz).

Example 26: 3-(3-Benzyl-5-Persil-2-pyridyl)ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 22.

1H-NMR (CDCl3) δ ppm: 1,36-of 1.44 (1H, m), 1.56 to of 1.64 (1H, m), 1.85 to of 1.93 (1H, m), 2,01-2,11 (2H, m), 273-2,95 (4H, m), is 3.08 (1H, d, J=14 Hz), with 3.27 (1H, DD, J=2, 14 Hz), to 4.23 (2H, s), 7,19-to 7.32 (5H, m), 8,13 (1H, d, J=2 Hz), 8,54 (1H, d, J=2 Hz), 8,64 (1H, DD, J=1.2 Hz), 9,04 (1H, d, J=1 Hz), the remaining 9.08 (1H, d, J=2 Hz).

Example 27: 3-[3-Benzyl-5-(2-ethoxycarbonylethyl)-2-pyridyl]ethinyl-3-hinokitiol

a) 3-Benzyl-5-formyl-2-methoxypyridine

of 4.6 ml of a hexane solution of 1.6 M utility was added dropwise to a mixture of 1.0 g of 3-benzyl-5-bromo-2-methoxypyridine (example obtaining 5b) and 10 ml of diethyl ether at -78°C. After stirring at the same temperature for one hour was added to 0.56 ml of N,N-dimethylformamide, followed by gradual warming to room temperature. The reaction mixture was separated by adding water and ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed.

1H-NMR (CDCl3) δ ppm: 3,94 (2H, s), a 4.03 (3H, s), of 4.00 (3H, s), 7,19-7,33 (5H, m), to 7.77 for 7.78 (1H, m), 8,49 (1H, d, J=4 Hz), for 9.90 (1H, s).

b) 3-Benzyl-5-(2-ethoxycarbonylethyl)-2-methoxypyridine

3-benzyl-5-formyl-2-methoxypyridine added to 0.92 ml triethylphosphate, 11 ml of methanol and 2.9 ml, 21% ethanol solution ethoxide sodium, followed by stirring at room temperature for one hour. The mixture was separated by adding water and ethyl acetate, and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solution is tel removed. The residue was subjected to column chromatography on silica gel and was suirable 5% ethyl acetate/hexane to obtain 950 mg of the target compound.

1H-NMR (CDCl3) δ ppm: to 1.32 (3H, t, J=7 Hz), to 3.92 (2H, s), of 4.00 (3H, s)to 4.23 (2H, q, J=7 Hz), 6,23 (1H, d, J=16 Hz), 7,19-7,34 (5H, m), 7,45 (1H, d, J=2 Hz), EUR 7.57 (1H, d, J=16 Hz), 8,14 (1H, d, J=2 Hz).

c) 3-Benzyl-5-(2-ethoxycarbonylethyl)-2-methoxypyridine

A mixture of 950 mg of Z-benzyl-5-(2-ethoxycarbonylethyl)-2-methoxypyridine, 90 mg of 10% palladium on coal and 10 ml of ethanol was stirred at room temperature for one hour in hydrogen atmosphere. After the atmosphere in the system was replaced with nitrogen, the mixture was filtered through celite. The solvent was removed to obtain 950 mg of the target compound.

1H-NMR (CDCl3) δ ppm: to 1.21 (3H, t, J=7 Hz), 2,52 (2H, t, J=7 HZ), 2,80 (2H, t, J=7 Hz), 3,88 (2H, s), 3,93 (3H, s), 4.09 to (2H, q, J=7 Hz), 7,12 (1H, s), 7.18 in-7,30 (5H, m), 7,86 (1H, s).

d) 3-Benzyl-5-(2-ethoxycarbonylethyl)-2-hydroxypyridine

A mixture of 240 mg of 3-benzyl-5-(2-ethoxycarbonylethyl)-2-methoxypyridine, 2.5 ml of 1,2-dichloromethane and a solution of 1.0 M tribromide boron 0.39 ml of dichloromethane was stirred at 50°C for 8 hours. To the reaction solution were added water and the silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 75% ethyl acetate/hexane, to obtain 86 mg of the target compound.

1H-NMR (CDCl3) δ ppm: 1,21 (3 is, t, J=7 Hz), a 2.45 (2H, t, J=7 Hz), 2,66 (2H, Sirs), the 3.89 (2H, Sirs), 4,08 (2H, q, J=7 Hz), 6,99-7,34 (7H, m).

e) 3-Benzyl-5-(2-ethoxycarbonylethyl)-2-pyridylsulfonyl

A mixture of 86 mg of 3-benzyl-5-(2-ethoxycarbonylethyl)-2-hydroxypyridine, 130 mg N-phenyltrichlorosilane, of 0.13 ml of triethylamine, 3.7 mg of 4-dimethylaminopyridine and 1.5 ml of dichloromethane was stirred at room temperature for one hour. To the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 15% ethyl acetate/hexane, to obtain 130 mg of the target compound.

1H-NMR (CDCl3) δ ppm: to 1.21 (3H, t, J=7 Hz), 2,58 (2H, t, J=7 Hz), of 2.92 (2H, t, J=7 Hz), 4.00 points (2H, s), 4.09 to (2H, q, J=7 Hz), 7,15-7,19 (2H, m), 7,24 and 7.36 (3H, m), 7,42 (1H, d, J=2 Hz), of 8.06 (1H, d, J=2 Hz).

f) 3-[3-Benzyl-5-(2-ethoxycarbonylethyl)-2-pyridyl]ethinyl-3-hinokitiol

A mixture of 180 mg of 3-benzyl-5-(2-ethoxycarbonylethyl)-2-pyridylmethylamine, 66 mg C-ethinyl-3-hinokitiol, 100 mg of tetrakis(triphenylphosphine)palladium (0), 17 mg of copper iodide, of 0.18 ml of triethylamine and 2 ml of N,N-dimethylformamide was heated with stirring at 70°in an oil bath for one hour in nitrogen atmosphere. After cooling there was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 2.5% methanol/ethyl acetate, to obtain 120 mg of zelenog the connection.

1H-NMR (CDCl3) δ ppm: of 1.20 (3H, t, J=7 Hz), 1,33-of 1.42 (1H, m), 1,53-to 1.61 (1H, m), 1,82 is 1.91 (1H, m), 1,98-of 2.08 (2H, m), to 2.57 (2H, t, J=7 Hz), 2,68-2,92 (6N, m), 3,05 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 4,08 (2H, q, J=7 Hz), 7,12-7,16 (2H, m), 7,19-7,31 (4H, m), 8,31 (1H, d, J=2 Hz).

Example 28: 3-[3-Benzyl-5-(3-oxobutyl)-2-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 27.

1H-NMR (CDCl3) δ ppm: of 1.36 to 1.47 (1H, m), 1,55-to 1.63 (1H, m), 1,80-of 1.92 (1H, m), 2.00 in of 2.10 (2H, m), 2,12 (3H, s), 2,68 was 3.05 (8H, m), is 3.08 (1H, DD, J=1,6, 14 Hz)at 3.25 (1H, DD, J=2.0 a, 14 Hz), 4,11 (2H, s), 7,12-7,16 (2H, m), 4,20-to 7.32 (4H, m), 8,30 (1H, d, J=2.2 Hz).

Example 29: 3-[3-Benzyl-5-(3-hydroxybutyl)-2-pyridyl]ethinyl-3-hinokitiol

A mixture of 314 mg of the hydrochloride of 3-[3-benzyl-5-(3-oxobutyl)-2-pyridyl]ethinyl-3-hinokitiol, 129 mg of potassium carbonate, 35 mg of sodium borohydride and 10 ml of methanol was stirred at room temperature for one hour. Added a small amount of water and the mixture evaporated. The residue was subjected to column chromatography on NH-silica gel, using chloroform and then chloroform/methanol/aqueous concentrated ammonia solution (46:1:0,1), with 340 mg of the target compound.

1H-NMR (CDCl3) δ ppm: to 1.21 (3H, d, J=6.0 Hz), 1,33-of 1.41 (1H, m), 1,52-to 1.61 (1H, m)of 1.65 and 1.80 (2H, m), 1,80 is 1.91 (1H, m), 2,00 2,10 (2H, m), 2,58-2,94 (6N, m), 3,06 (1H, DD, J=1,2, 14 Hz), 3,24 (1H, DD, J=2.0 a, 14 Hz), 3,72-3,81 (1H, m), 4,11 (2H, s), 7,13-7,30 (6N, m), 8,30 (1H, d, J=2.2 Hz).

Example 30: 3-[3-(2-Thienylmethyl)--pyridyl]ethinyl-3-hinokitiol

a) 2-Chloro-3-(2-thienylboronic)pyridine

10 g of acid chloride of 2-chloronicotinic acid was added to a mixture of 7.2 g of aluminum chloride and 100 ml of carbon disulfide under ice cooling and then adding back, slowly, drop by drop of 8.8 ml of thiophene. After stirring at room temperature for two days the reaction solution was slowly poured into ice water. The mixture was extracted with ethyl acetate and the organic phase is then washed with a saturated aqueous solution of sodium bicarbonate and a saturated solution of salt. After removal of solvent the residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (3:1) and then with hexane/ethyl acetate (2:1) to give 1.64 g of the target compound.

1H-NMR (CDCl3) δ: 7,15-7,17 (1H, m), 7,37-7,40 (1H, m), 7,42-7,44 (1H, m), 7,78-7,83 (2H, m), 8,54-to 8.57 (1H, m).

b) 2-Methoxy-3-(2-thienylboronic)pyridine

A mixture of 1.64 g of 2-chloro-3-(2-thienylboronic)pyridine and 4.5 ml of a methanol solution of 28% sodium methoxide and 2.0 ml of methanol was heated under stirring for 30 minutes. After cooling, to the reaction solution were added water and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed from the receipt of 1.46 g of the target compound.

1H-NMR (CDCl3) δ: of 3.96 (3H, s), 6.90 to-7,05 (1H, m), 7,11-7,14 (1H m), of 7.48-7,50 (1H, m), 7,72-7,76(2H, m), 8,30-of 8.33 (1H, m).

C) 2-Methoxy-3-[2-thienyl(hydroxy)methyl]pyridine

303 mg of sodium borohydride in small portions was added to the solution containing of 1.46 g of 2-methoxy-3-(2-thienylboronic)-pyridine and 10 ml of ethanol, while cooling with ice. After stirring at room temperature for 2 hours there was slowly added water and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed to obtain 1.47 g of the target compound.

1H-NMR (CDCl3) δ: 3,99 (3H, s), of 6.26 (1H, d), 6,88-of 6.96 (3H, m), 7,25 (1H, m), of 7.64 (1H, DD), to 8.12 (1H, DD).

d) 2-Methoxy-3-(2-thienylmethyl)pyridine

A mixture of 1.47 g of 2-methoxy-3-[2-thienyl(hydroxy)methyl]-pyridine, 3.2 g of zinc iodide, 3.4 g of cyanoborohydride of sodium and 30 ml of 1,2-dichloroethane was stirred at room temperature for two days. The insoluble substance was filtered and to the filtrate was added an aqueous solution of sodium hydroxide. The mixture was extracted with ethyl acetate, the organic phase is washed with saturated salt solution and the solvent evaporated. Then the residue was subjected to column chromatography on silica gel and was suirable hexane, then hexane/ethyl acetate (40:1) to obtain 734 g of target compound.

1H-NMR (CDCl3) δ: 3,99 (3H, s), 4,10 (2H, s), 6,79-6,84 (2H, m), 6,92-to 6.95 (1H, m), 7,13-7,16 (1H, m), of 7.35 and 7.36 (1H, m), of 8.04 (1H, DD).

e) 3-(2-Thienylmethyl)-2-peridicred orleanswhat

10 ml of 47% Hydrobromic acid was added 216 mg of 2-methoxy-3-(2-thienylmethyl)of pyridine followed by heating under stirring for 4 hours on an oil bath at a temperature of 80°C. After cooling, the reaction mixture was neutralized by careful addition there potassium carbonate. There was added water and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed to obtain 140 mg of the crude product. A mixture of 140 mg of the crude product, 314 mg of N-phenyltrichlorosilane, 153 μl of triethylamine, 27 mg of 4-dimethylaminopyridine and 5.0 ml of dichloromethane was stirred at room temperature for 3 hours. To the reaction solution was added water and was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane, then hexane/ethyl acetate (40:1) to give 89 mg of the target compound.

1H-NMR (CDCl3) δ: to 4.23 (2H, s), 6,86-6,89 (1H, m), of 6.96-6,99 (1H m), 7,21-7,24 (1H, m), 7,29-7,33 (1H, m), 7,66-of 7.69 (1H, m), of 8.25 (1H, DD).

f) 3-[3-(2-Thienylmethyl)-2-pyridyl]ethinyl-3-hinokitiol

A mixture of 89 mg of 3-(2-thienylmethyl)-2-pyridylmethylamine, 50 mg of 3-ethinyl-3-hinokitiol, 64 mg tet is Akis(triphenylphosphine)palladium (0), 11 mg of copper iodide, 105 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated with stirring at 70°C for 1.5 hours in a nitrogen atmosphere. The reaction solution was poured in an aqueous dilute solution of ammonia, followed by extraction with ethyl acetate. Then the organic phase is washed with saturated salt solution and the solvent was removed, and the residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (1:1) and then ethyl acetate/methanol (15:1) to give 88 mg of the target compound.

1H-NMR (CDCl3) δ: 1,35-1,45 (1H, m), 1.56 to its 1.68 (1H, m), 1,86 of 1.99 (1H, m), 2,02 and 2.13 (2H, m), 2,73-to 2.94 (4H, m), 3,05-3,10 (1H, m), 3,29-to 3.33 (1H, m), 4,32 (2H, s), 6,76-6,79 (1H, m), 6,92-to 6.95 (1H, m), 7,15-of 7.23 (2H, m)of 7.55 (1H, d), 8,46 (1H, d).

Example 31: 3-(6-Persil-3-benzyl-2-pyridyl)ethinyl-3-hinokitiol

a) 6-Chloro-3-(α-hydroxybenzyl)-2-methoxypyridine

100 ml of a pentane solution containing 1.56 mol of tert-utility slowly dropwise added to 200 ml tetrahydrofurane solution containing 11.9 ml 2-bromoethylene at -78°when cooled. After stirring at the same temperature for one hour there slowly dropwise added to 7.2 ml of 2-chloro-6-methoxypyridine. After stirring under ice cooling for one hour and then at room temperature for one hour there was added to 8.5 ml of benzaldehyde when is hladini ice, followed by stirring at room temperature for another one hour. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane and then hexane/ethyl acetate (7:1) to give 15.0 g of target compound.

1H-NMR (CDCl3) δ: of 3.95 (3H, s), 5,96 (1H, d, J=4 Hz), 6.90 to-6,92 (1H, m), 7,25-7,37 (5H, m), 7,54-EUR 7.57 (1H, m).

b) 6-chloro-3-benzoyl-2-methoxypyridine

36,0 g of manganese oxide (IV) was added to a solution of 3.7 g of 6-chloro-3-(α-hydroxybenzyl)-2-methoxypyridine in 80 ml of tetrahydrofuran, followed by stirring at room temperature for 2 hours. Insoluble substances were filtered off and the solvent is then evaporated to obtain 3.6 g of the compound named in the heading.

1H-NMR (CDCl3) δ: 3,90 (3H, s),? 7.04 baby mortality (1H, DD, J=0.4 Hz, 8 Hz), 7,44-of 7.48 (2H, m), 7,56 to 7.62 (1H, m), of 7.70 (1H, DD, J=0.4 Hz, 8 Hz), 7,76-7,81 (2H, m).

c) (3-Benzoyl-2-methoxy-6-pyridyl)tributylamine

A mixture of 3.6 g of 6-chloro-N-benzoyl-2-methoxypyridine, 42,1 g of bis(anti), 1.7 g tetrakis(triphenylphosphine)palladium (0) and 20 ml of toluene was boiled under reflux for 2 hours. After cooling, the solvent was removed and the residue was subjected to column chromatography on silica gel and was suirable hexane, then hexane/ethyl acetate (2:1) to obtain 5.1 g of the target soy is inane.

1H-NMR (CDCl3) δ: 0,85-1,65 (N, m), 3,90 (3H, s), 7,12-7,14 (1H, m), 7,28-to 7.59 (4H, m), 7,79-of 7.82 (2H, m).

d) 6-Persil-3-benzoyl-2-methoxypyridine

A mixture of 5.1 g of (3-benzoyl-2-methoxy-6-pyridyl)inputs of TBT to 5.4 ml of chloropyrazine, 1.8 g tetrakis(triphenylphosphine)palladium (0) and 30 ml of xylene was heated under reflux for 2 hours. After cooling, the solvent was removed and the residue was subjected to column chromatography on silica gel and was suirable hexane, then hexane/ethyl acetate (1:1) to give 1.3 g of the target compound.

1H-NMR (CDCl3) δ: was 4.02 (3H, s), 7,45 is 7.50 (2H, m), to 7.59-7,63 (1H, m), 7,83-to $ 7.91 (3H, m), 8,10-8,13 (1H, m), 8,63-8,66 (2H, m), to 9.66 (1H, d, J=1.4 Hz).

e) 6-Persil-3-benzyl-2-methoxypyridine

The mixture 806 mg 6-Persil-3-benzoyl-2-methoxypyridine, 177 μl of hydrazine, 421 mg of potassium carbonate and 35 ml of diethylene glycol was heated with stirring at 100°C for one hour, then at 170°C for 3 hours. After cooling, to the reaction solution was added water, followed by extraction with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed, and the residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (5:1), and then hexane/ethyl acetate (4:1) to give 234 mg of the target compound.

1H-NMR (CDCl3) δ: 3,98 (2H, s)4,08 (3H, s), 7,21-7,33 (5H, m), 7,44 (1H, d, J=8 Hz, 7,89 (1H, d, J=8 Hz), 8,53-to 8.57 (2H, m), 9,60 (1H, d, J=1.5 Hz).

f) 6-Persil-3-benzyl-2-hydroxypyridine

5.0 ml of 47% Hydrobromic acid was added to 234 mg 6-Persil-3-benzyl-2-methoxypyridine followed by heating under stirring for one hour on an oil bath at a temperature of 80°C. After cooling, the reaction solution was slowly added to aqueous solution of potassium carbonate. The obtained crystals were filtered and dried to obtain 222 mg of the target compound.

1H-NMR (CDCl3) δ: of 3.95 (2H, s), 6,83 (1H, d, J=7 Hz), 7,12-to 7.15 (1H, m), 7,21 and 7.36 (5H, m), 8,59-8,61 (2H, m), 9,07 (1H, d, J=1.3 Hz).

g) 6-Persil-3-benzyl-2-pyridylsulfonyl

To 222 mg 6-Persil-3-benzyl-2-hydroxypyridine added 365 mg N-phenyltrichlorosilane, 178 μl of triethylamine, 31 mg of 4-dimethylaminopyridine, 10 ml dichloromethane and 3.0 ml of N,N-dimethylformamide, followed by stirring at room temperature for 3 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane, then hexane/ethyl acetate (4:1) to obtain 336 mg of the target compound.

1H-NMR (CDCl3) δ: 4,11 (2H, s), 7,22-7,42 (5H, m), of 7.75 (1H, d, J=8 Hz), at 8.36 (1H, d, J=8 Hz), 8,59-8,63 (2H, m), 9,50 (1H, d, J=1.3 Hz).

h) 3-(6-Persil-3-benzyl-2-pyridyl)ethinyl-3-hinokitiol

A mixture of 336 mg 6-Persil-3-benzyl-2-pyridylmethylamine, 161 mg of 3-ethinyl-3-hinokitiol, 205 mg of tetrakis(triphenylphosphine)palladium (0), 34 mg of copper iodide, 370 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated with stirring at 80°C for 3 hours in nitrogen atmosphere. After cooling, the solvent was removed and the residue was subjected to column chromatography on NH-silica gel (Fuji silicia) and suirable with ethyl acetate/methanol (20:1) to give 204 mg of the target compound.

1H-NMR (CDCl3) δ: 1,39-to 1.79 (2H, m), 1,89 is 1.96 (1H, m), 2.06 to and 2.14 (2H, m), 2,75-to 2.94 (4H, m), of 3.07 (1H, d, J=14 Hz), 3,29 (1H, d, J=14 Hz), to 4.23 (2H, s), 7.18 in-7,34 (5H, m), a 7.62 (1H, d, J=8 Hz), of 8.25 (1H, d, J=8 Hz), 8,59 (2H, s), for 9.64 (1H, s).

Example 32: 3-[3-Benzyl-5-(3-thienyl)-2-pyridyl]ethinyl-3-hinokitiol

A mixture of 127 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethinyl-3-hinokitiol (example 22A), to 61.4 mg 3-tiefenbronn acid, a 55.4 mg of tetrakis(triphenylphosphine)palladium (0), 2 ml of toluene, 0.5 ml of methanol and 1 ml of aqueous 2 M sodium carbonate solution was stirred at 80°C for 2 hours in nitrogen atmosphere. To the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 3% methanol/ethyl acetate, obtaining 83.9 g of target compound.

1H-NMR (CDCl3) δ: 1,35-of 1.42 (1H, m), 1,54-of 1.62 (1H, m), 1,84-1,92 1H, m)2,00 is 2.10 (2H, m), 2,68-and 2.83 (3H, m), 2,87-to 2.94 (1H, m)to 3.09 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2, 14 Hz), 4,18 (2H, s), 7,17-7,33 (6N, m), 7,39-7,42 (1H, m), 7,47-7,49 (1H, m), to 7.61 (1H, s), to 8.70 (1H, d, J=2 Hz).

Example 33: 3-[6-(Methylamino)-3-benzyl-5-Persil-2-pyridyl]ethinyl-3-hinokitiol

a) 6-(Acetoxymethyl)-3-benzoyl-2-methoxypyridine

A mixture of 5 g of 6-methyl-3-benzoyl-2-methoxypyridine, synthesized as in example obtaining 1b, 4.3 g of N-bromosuccinimide and 100 ml of benzene was irradiated with light 200 watt incandescent lamp for 30 minutes and boiled under reflux. After cooling, insoluble materials were filtered off and the filtrate was concentrated. To the residue was added 30 ml of acetic acid and 5 g of sodium acetate, followed by heating on an oil bath at a temperature of 100°With during the night. After concentration of the reaction solution was extracted with ethyl acetate-aqueous saturated sodium bicarbonate solution. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel using 5-10% ethyl acetate/hexane, obtaining of 3.69 g of the target compound.

1H-NMR (CDCl3) δ: of 2.21 (3H, s), a 3.87 (3H, s), 5,20 (2H, s), 7,02 (1H, d, J=8 Hz), 7,45 (2H, t, J=8 Hz), 7,58 (1H, t, J=8 Hz), 7,73 (1H, d, J=8 Hz), 7,79 (2H, d, J=8 Hz).

b) 6-(Acetoxymethyl)-3-benzyl-2-methoxy-5-erazilerden

The mixture 3,93 g of 6-(usetox is methyl)-3-benzoyl-2-methoxypyridine, 8,81 ml of triethylsilane and 30 ml triperoxonane acid was stirred at 60°C for one hour. After cooling the mixture was neutralized by adding an aqueous solution of potassium carbonate. There was added ethyl acetate, the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. After adding to the residue 20 ml of methanol and of 3.48 g of sodium bicarbonate was added 1.07 ml of bromine under ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction solution was added an aqueous solution of sodium thiosulfate and ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. To the residue was added 3,10 g parasitisation, 1,46 tetrakis (triphenylphosphine)palladium (0) and 40 ml of xylene, followed by boiling under reflux for 2.5 hours. To the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 30% ethyl acetate/hexane, obtaining of 2.18 g of the target compound.

1H-NMR (CDCl3) δ: 2,02 (3H, s), of 3.96 (2H, s)to 4.01 (3H, s), from 5.29 (2H, s), 7,21-7,33 (5H, m), 7,46 (1H, s), and 8.50 (1H, d, J=2 Hz), 8,59 at 8.60 (1H, m), 8,66 (1H, d, J=1 Hz).

c) 3-Benzyl-6-(tert-butoxycarbonylamino)-2-methoxy-5-erazilerden

<> 6,24 ml of 1N aqueous sodium hydroxide solution was added to a mixture of 2.18 g of 6-(acetoxymethyl)-3-benzyl-2-methoxy-5-erazilerden and 20 ml of methanol at room temperature, followed by stirring at the same temperature. To the reaction solution were added water and ethyl acetate and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. To a solution of the residue in 20 ml of acetone was added 14.1 ml of the reagent John, followed by stirring at room temperature over night. To the reaction mixture were added 6 ml of 2-propanol, and then was extracted with ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. A mixture of the residue with 25 ml of tert-butanol, 733 μl of triethylamine and 1.13 g diphenylphosphinite was stirred at room temperature for 3 hours. After evaporation of the solvent the residue was subjected to column chromatography on silica gel using 25% ethyl acetate/hexane, to obtain 212 mg of the target compound.

1H-NMR (CDCl3) δ: 1,51 (N, C)3,93 (2H, s)4,08 (3H, s), 7,19-7,31 (5H, m), the 7.65 (1H, s), 8,42 (1H, d, J=2 Hz), charged 8.52-8,54 (1H, m), 8,80 (1H, d, J=1 Hz).

d) 3-[6-(Methylamino)-3-benzyl-5-Persil-2-pyridyl]ethinyl-3-hinokitiol

11,8 mg of 60% oil suspension of sodium hydride was added to the mixture 77,2 m is 3-benzyl-6-(tert-butoxycarbonylamino)-2-methoxy-5-erazilerden and 1 ml of N,N-dimethylformamide under ice cooling. After stirring at the same temperature for 5 minutes there was added to 14.7 μl of methyliodide. After stirring at room temperature for 2 hours there was added water and ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. A mixture of the residue and 2 ml of 48% Hydrobromic acid was stirred at 80°C for 2 hours. After cooling, it was neutralized with an aqueous solution of potassium carbonate. The obtained crystals were filtered and dried in vacuum. Then there was added 3 ml of N,N-dimethylformamide, to 40.4 mg N-phenyltrichlorosilane, 47,2 μl of triethylamine and 1.4 mg of 4-dimethylaminopyridine, followed by stirring at room temperature for 13 hours. The reaction solution was filtered through silica gel and the solvent evaporated. A mixture of the residue, 12,1 mg 3-ethinyl-3-hinokitiol and 16.9 mg of tetrakis(triphenylphosphine)-palladium (0), 2.8 mg of copper iodide, 30,5 μl of triethylamine and 1 ml of N,N-dimethylformamide was stirred at 70°C for one hour in nitrogen atmosphere. To the reaction mixture were added by NH-silica gel, after which the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 3% methanol/ethyl acetate, obtaining of 15.9 mg of the target compound.

1H-NMR (CDCl3) δ: 1,34-of 1.42 (1H, m), 1,52 is 1.60 (1H, m), 1,83-of 1.92 (1H, m), 1,98-2,07 (2H, m), 2,70-2,82 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,11 (3H, d, J=5 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 4.09 to (2N, C), 7,18-7,22 (3H, m), 7,26-7,31 (2H, m), 7,68 (1H, s), 8,44 (1H, d, J=2 Hz), 8,50-8,51 (1H, m), 8,53-8,55 (1H, m), of 8.92 (1H, d, J=1 Hz).

Example 34: 3-[3-Benzyl-5-(1-hydroxycyclopent)ethinyl-2 - pyridyl]ethinyl-3-hinokitiol

100 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethinyl-3-hinokitiol (example 22A), 55 mg of 1-ethynylcyclopentanol, 50 mg tetrakis(triphenylphosphine)palladium (0), 10 mg of copper iodide and 1 ml of triethylamine were mixed in 5 ml of N,N-dimethylformamide, followed by stirring at an oil bath at a temperature of 80°C for 1 hour. Was added an aqueous solution of sodium carbonate, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on NH-silica gel and was suirable 10% methanol/ethyl acetate to obtain 93 g of target compound.

1H-NMR (CDCl3) δ: 1,33 was 1.43 (1H, m), 1,52-of 1.62 (1H, m), 1.70 to of 1.92 (5H, m), 1,95-2,10 (6N, m), 2,69-to 2.94 (4H, m), of 3.07 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2, 14 Hz), a 4.03 (2H, s), 7,12 (2H, d, J=7 Hz), 7,22 (1H, t, J=7 Hz), 7,29 (2H, t, J=7 Hz), 7,43 (1H, d, J=2 Hz)and 8.50 (1H, d, J=2 Hz).

Example 35: 3-[3-Benzyl-5-(N-phenylcarbamoyl)-2-pyridyl]ethinyl-3-hinokitiol

a) 3-Benzyl-2-methoxypyridine-5-carboxylic acid

11.1 g of 3-benzyl-5-bromo-2-methoxypyridine (example obtaining 5b) was dissolved in 70 ml of diethyl ether. There paraply was added 30 ml of hexane solution, containing 1.6 mol n-utility, bath with dry ice-acetone. After one hour the reaction solution was purged with carbon dioxide, then added water. After washing the aqueous phase with diethyl ether there was added 50 ml of 1N hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was led from hexane-ethyl acetate to obtain 7,76 g of target compound.

1H-NMR (CDCl3) 5: 3,93 (2H, s), Android 4.04 (3H, s), 7.18 in-7,33 (5H, m), 7,92 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

b) 3-benzyl-5-(N-phenylcarbamoyl)-2-methoxypyridine

200 mg of 3-benzyl-2-methoxypyridine-5-carboxylic acid and 0.25 ml of pyridine was dissolved in 5 ml dichloromethane. Under ice cooling there was added dropwise 0,073 ml of thionyl chloride. After stirring for 30 minutes was added 0.1 ml of aniline. The temperature was raised to room temperature and the mixture was stirred for 30 minutes. After addition of water the mixture was extracted with ethyl acetate. The extract is washed with 1N hydrochloric acid and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated to obtain 275 mg of the target compound.

1H-NMR (CDCl3) δ: of 3.97 (2H, s), Android 4.04 (3H, s), to 7.15 (1H, t, J=7 Hz), 7,20-7,40 (7H, m), 7,58 (2H, d, J=7 Hz), 7,81 (1H, d, J=2 Hz), 8,55 (1H, d, J=2 Hz).

c) 3-benzyl-5-(N-phenylcarbamoyl)-2-pyridil formeasurement

275 mg of 3-benzyl-5-(N-phenylcarbamoyl)-2-methoxypyridine was dissolved in 5 ml of 1,2-dichloroethane. There was added 0.5 ml of dichloromethane solution containing 1 mol of tribromide boron, followed by stirring at 50°C for 3 hours. Was added an aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution and then evaporated. To the residue was added 360 mg of N-phenyltrichlorosilane, 10 mg of 4-dimethylaminopyridine, 0.4 ml of triethylamine and 5 ml of dichloromethane, followed by stirring at room temperature over night. The reaction solution was subjected to column chromatography on silica gel and was suirable 30% ethyl acetate/hexane to obtain 150 mg of the target compound.

1H-NMR (CDCl3) δ: 4.09 to (2N, C), 7,17-7,42 (8H, m), EUR 7.57 (2H, d, J=8 Hz), 7,69 (1H, Sirs), 8,10 (1H, d, J=2 Hz), 8,65 (1H, d, J=2 Hz).

d) 3-[3-Benzyl-5-(N-phenylcarbamoyl)-2-pyridyl]ethinyl-3-hinokitiol

150 mg of 3-benzyl-5-(N-phenylcarbamoyl)-2-pyridylmethylamine, 60 mg of 3-ethinyl-3-hinokitiol, 50 mg tetrakis(triphenylphosphine)palladium (0), 10 mg of copper iodide and 0.15 ml of triethylamine was added to 2 ml of N,N-dimethylformamide, followed by stirring for 3 hours on an oil bath at a temperature of 50°C. After cooling was added aqueous ammonia and the mixture was extracted with ethyl acetate. The extract was washed n is sasenum salt solution, was dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on NH-silica gel to obtain 90 mg of the target compound.

1H-NMR (CDCl3) δ: 1,35-of 1.92 (3H, m), 1,98 is 2.10 (2H, m), 2,70-2,95 (4H, m), of 3.07 (1H, d, J=14 Hz), with 3.27 (1H, DD, J=2, 14 Hz), 4,20 (2H, s), 7,14-7,19 (3H, m), 7,24 (1H, t, J=7 Hz), 7,31 (2H, t, J=7 Hz), of 7.36 (2H, t, J=8 Hz), 7,58 (2H, d, J=8 Hz), 7,98 (1H, d, J=2 Hz), 8,00 (1H, Sirs), 8,87 (1H, d, J=2 Hz).

Example 36: 3-[3-Benzyl-5-[N-(4-forfinal)carbarnoyl]-2-pyridyl]ethinyl-3-hinokitiol

The compound named in the heading, synthesized as in example 35.

1H-NMR (CDCl3) δ: 1,34-of 1.44 (1H, m), 1,54-of 1.64 (1H, m), 1,78-1,89 (1H, m), 1,99-of 2.09 (2H, m), 2,66-2,95 (4H, m), is 3.08 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), is 4.15 (2H, s), 7,00 (2H, t, J=8 Hz), 7,13 (2H, d, J=7 Hz), 7,22 (1H, t, J=7 Hz), 7,28 (2H, t, J=7 Hz), of 7.48-7,56 (2H, m), to 7.93 (1H, d, J=2 Hz), 8,48 (1H, Sirs), 8,80 (1H, d, J=2 Hz).

Example 37: 3-[3-Benzyl-5-(N-cyclohexylcarbonyl)-2-pyridyl]ethinyl-3-hinokitiol

The compound named in the heading, synthesized as in example 35.

1H-NMR (CDCl3) δ: 1,24-1,90 (11N, m), 1,97 is 2.10 (4H, m), 2,65-2,95 (4H, m), 3,06 (1H, DD, J=2, 14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 3,88-4,00 (1H, m)to 4.16(2H, s), 6,10 (1H, d, J=8 Hz), 7,14 (2H, d, J=7 Hz), 7,22 (1H, t, J=7 Hz), 7,28 (2H, t, J=7 Hz), 7,89 (1H, d, J=2 Hz), 8,72 (1H, d, J=2 Hz).

Example 38: 3-[3-Benzyl-5-(1-pyrrolidinylcarbonyl)-2-pyridyl]ethinyl-3-hinokitiol

The compound named in the heading, synthesized as in example 35.

1H-NMR CDCl 3) δ: 1,35-of 1.65 (2H, m), 1,83 is 2.10 (7H, m), 2,70-2,95 (4H, m), 3.04 from (1H, d, J=14 Hz), with 3.27 (1H, DD, J=2,14 Hz)to 3.38 (2H, t, J=7 Hz), 3,62 (2H, t, J=7 Hz), 4,18 (2H, s), 7,17 (2H, d, J=7 Hz), from 7.24 (1H, t, J=7 Hz), 7,31 (2H, t, J=7 Hz), 7,63 (1H, d, J=2 Hz), to 8.62 (1H, d, J=2 Hz).

Example 39: 3-[3-Benzyl-5-methoxycarbonyl-2-pyridyl]ethinyl-3-hinokitiol

a) 3-Benzyl-2-methoxy-5-ethoxycarbonylpyrimidine

A mixture of 2.1 g of 3-benzyl-2-methoxypyridine-5-carboxylic acid and 2.9 g of potassium carbonate suspended in 40 ml of N,N-dimethylformamide. Was added 1.1 ml of methyliodide at room temperature under stirring. After stirring for 40 minutes, there was added water and was extracted with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was subjected to column chromatography on silica gel using 11-14% ethyl acetate/hexane as eluent for separation and purification to obtain 2.2 g of the target compound.

1H-NMR (CDCl3) δ: a 3.87 (3H, s)to 3.92 (2H, s), was 4.02 (3H, s), 7.18 in-to 7.32 (5H, m), of 7.90 (1H, DD, J=2.3 Hz, 0.7 Hz), to 8.70 (1H, d, J=2.3 Hz).

b) 3-Benzyl-2-hydroxy-5-ethoxycarbonylpyrimidine

2.2 g of 3-benzyl-2-methoxy-5-ethoxycarbonylpyrimidine was dissolved in 40 ml of 1,2-dichloroethane. Was added to 8.5 ml of dichloromethane solution containing 1.0 mol of tribromide boron, nitrogen atmosphere, followed by heating under stirring at 50°oil b is not during the night. After cooling there was added water, and the solvent was removed at low temperature. The residue was subjected to column chromatography on silica gel using 50-60% ethyl acetate/hexane as eluent for separation and purification to obtain 1.2 g of the target compound.

1H-NMR (CDCl3) δ: a 3.83 (3H, s), a 3.87 (2H, s), 7,20-7,34 (5H, m), 7,73 (1H, d, J=2.4 Hz), 8,11 (1H, d, J=2,4 Hz).

c) 3-Benzyl-5-methoxycarbonyl-2-pyridylsulfonyl

1.2 g of 3-benzyl-2-hydroxy-5-ethoxycarbonylpyrimidine was dissolved in 40 ml of 1,2-dichloroethane. Added 2.3 g of N-phenyltrichlorosilane, 202 mg of 4-dimethylaminopyridine and 0.9 ml of triethylamine, followed by stirring at room temperature for 3 hours. Then the solvent was removed and the residue was subjected to column chromatography on silica gel, using 11% ethyl acetate/hexane as eluent for separation and purification to obtain 2.0 g of the target compound.

1H-NMR (CDCl3) δ: 3,93 (3H, s), of 4.05 (2H, s), 7,16-the 7.43 (5H, m), to 8.20 (1H, d, J=2.3 Hz), 8,82 (1H, d, J=2.3 Hz).

d) 3-[3-Benzyl-5-methoxycarbonyl-2-pyridyl]ethinyl-3-hinokitiol

50 ml of N,N-dimethylformamide was added to a mixture of 2.0 g of 3-benzyl-5-methoxycarbonyl-2-pyridylmethylamine, 742 mg of 3-ethinyl-3-hinokitiol, 1.5 g of tetrakis(triphenylphosphine)-palladium (0), 374 mg of copper iodide and 2.7 ml of triethylamine, followed by heating under stirring over their one hour on an oil bath at a temperature of 60° C in nitrogen atmosphere. After cooling there was added ethyl acetate and aqueous ammonia and the mixture was extracted with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using chloroform/methanol/36% aqueous ammonia solution (46:3:0,3) as eluent for separation and purification to obtain 1.1 g of the target compound.

1H-NMR (CDCl3) δ =1,38 is 1.48 (1H, m), 1,58 by 1.68 (1H, m), 1,82-of 1.92 (1H, m), 2.00 in and 2.14 (2H, m), 2,70 are 2.98 (4H, m)to 3.09 (1H, DD, J=14 Hz, 1.8 Hz), with 3.27 (1H, DD, J=14 Hz, 2.0 Hz), to 3.92 (3H, s), 4,19 (2H, s), 7,12-7,74 (5N, m), of 8.09 (1H, d, J=2.0 Hz), 9,04 (1H, d, J=2.0 Hz).

Example 40: 3-[3-Benzyl-5-(N-methylbenzylamino)-2-pyridyl]ethinyl-3-hinokitiol

a) 3-Benzyl-5-tert-butoxycarbonylamino-2-methoxypyridine

7,34 g 3-Benzyl-2-methoxypyridine-5-carboxylic acid (example 35A), and 6.5 ml diphenylphosphinite and 4.2 ml of triethylamine were mixed in 100 ml of tert-butanol, followed by boiling under reflux overnight. After evaporation of the reaction solution was separated by adding water and ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to column chromatography on silica gel with getting 9,37 g of target compound.

1H-NMR (CDCl3) δ: ,48 (N, C)to 3.89 (2H, s)to 3.92 (3H, s), and 6.25 (1H, Sirs), 7,17-7,31 (5H, m), of 7.48 (1H, Sirs), 7,92 (1H, Sirs).

b) 3-Benzyl-5-(N-tert-butoxycarbonylamino)-2-methoxypyridine

970 mg of 3-benzyl-5-tert-butoxycarbonylamino-2-methoxypyridine was dissolved in 10 ml of N,N-dimethylformamide followed by the addition there of 200 mg of 60% oil suspension of sodium hydride. After stirring at room temperature was added 0,192 ml methyliodide in an ice bath. After heating to room temperature was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated to obtain 920 mg of the target compound.

1H-NMR (CDCl3) δ: 1,37 (N, Sirs), 3,17 (3H, s)to 3.89 (2H, s), of 3.96 (3H, s), 7,13 (1H, Sirs), 7,18-of 7.25 (3H, m), 7,30 (2H, d, J=7 Hz), 7,88 (1H, d, J=2 Hz).

c) 3-Benzyl-5-(N-methylbenzylamino)-2-methoxypyridine

920 mg of 3-benzyl-5-(N-tert-butoxycarbonylamino)-2-methoxypyridine was dissolved in 5 ml of ethyl acetate and then adding back the same 10 ml of 4N hydrochloric acid/ethyl acetate. The obtained solid substance was filtered. To solid substance (230 mg) was added 10 ml of ethyl acetate, 150 mg of benzoyl chloride and 0.5 ml of pyridine in an ice bath, followed by stirring. After adding back the water the mixture was extracted with ethyl acetate. The extract is washed with 1N hydrochloric acid, saturated aqueous Hydra is sodium carbonate and a saturated solution of salt, was dried over anhydrous magnesium sulfate and then evaporated to obtain 270 mg of the target compound.

1H-NMR (CDCl3) δ: of 3.42 (3H, in), 3.75 (2H, s), 3,89 (ZN, C), 6,80-to 6.95 (3H, m), 7,15-7,30 (8H, m), 7,80 (1H, Sirs).

d) 3-[3-Benzyl-5-(N-methylbenzylamino)-2-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 35C.

1H-NMR (CDCl3) δ: 1,35 of 1.46 (1H, m), 1,54-of 1.64 (1H, m), 1,75-of 1.85 (1H, m), 2,01-2,12 (2H, m), 2,60-2,90 (4H, m), 2,98 (1H, DD, J=2, 14 Hz)and 3.15 (1H, DD, J=2, 14 HZ), 3,47 (3H, s), of 4.00 (2H, s), 6,85-6,89 (2H, m,),? 7.04 baby mortality (1H, d, J=2 Hz), 7.18 in-7,27 (7H, m), 7,31-to 7.35 (1H, m), 8,19 (1H, d, J=2 Hz).

Example 41: 3-[3-Benzyl-5-(N-methylbenzenesulfonamide)-2-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 40.

1H-NMR (CDCl3) δ: 1,35-of 1.95 (3H, m), 1,98-of 2.08 (2H, m), 2,70-2,95 (4H, m), 3,03 (1H, d, J=14 Hz)and 3.15 (3H, s)of 3.25 (1H, DD, J=2,14 Hz), 4,11 (2H, s), 7,11 (2H, d, J=7 Hz), 7,22-7,33 (4H, m), 7,42 (2H, t, J=7 Hz), to 7.50 (2H, DD, J=2,8 HZ), EUR 7.57 (1H, t, J=7 Hz), 8,16 (1H, d, J=3 Hz).

Example 42: 3-(2-Allyl-6-Persil-3-pyridyl)ethinyl-3-hinokitiol

a) 2-Allyl-6-Persil-3-pyridylsulfonyl

A mixture of 1.22 g of 2-bromo-6-iodine-3-pyridylmethylamine (example getting 17), 1.04 g parasitisation, 326 g of tetrakis(triphenylphosphine)palladium (0) and 10 ml of xylene was stirred at 140°C for 2 hours. After cooling to room temperature the mixture was filtered using silica gel, and the solvent of viparita is I. A mixture of the residue, 868 μl allyltrimethylsilane, 324 mg of tetrakis(triphenylphosphine)-palladium (0) and 10 ml of toluene was boiled under reflux for 1.5 hours. After cooling to room temperature, to the mixture was added silica gel and the solvent evaporated. The residue was subjected to column chromatography on silica gel and was suirable 20% ethyl acetate/hexane to obtain 500 mg of the target compound.

1H-NMR (CDCl3) δ: 3,79 (2H, d, J=6 Hz), 5,20-of 5.26 (2H, m), 6,11-6,21 (1H, m), of 7.75 (1H, d, J=12 Hz), of 8.37 (1H, d, J=12 Hz), 8,60-8,63 (2H, m)9,68 (1H, s).

b) 3-(2-Allyl-6-Persil-3-pyridyl)ethinyl-3-hinokitiol

A mixture of 500 mg of 2-allyl-6-Persil-3-pyridylmethylamine, 203 mg of 3-ethinyl-3-hinokitiol, 155 mg of tetrakis(triphenylphosphine)palladium (0), to 25.5 mg of copper iodide, 0,560 ml of triethylamine and 5 ml of N,N-dimethylformamide was stirred at 65°C for 20 minutes in nitrogen atmosphere. After cooling, to the reaction mixture were added by NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 2.5% methanol/ ethyl acetate, obtaining 428 mg of the target compound.

1H-NMR (CDCl3) δ: 1,42 of 1.50 (1H, m), of 1.66 and 1.75 (1H, m), 1,97 with 2.14 (3H, m), 2,82 are 2.98 (4H, m), 3,11 (1H, d, J=14 Hz), to 3.36 (1H, DD, J=2, 14 Hz), a-3.84 (2H, d, J=6 Hz), 5,14-5,20 (2H, m), 6,13-to 6.22 (1H, m), 7,83 (1H, d, J=12 Hz), 8,19 (1H, d, J=12 Hz), 8,57 at 8.60 (2H, m)9,68 (1H, s).

Example 43: 3-(2-Allyl-6-phenyl-3-pyridyl)ethinyl-3-hinokitiol

Celje is the second compound was synthesized in the same way, as in example 42.

1H-NMR (CDCl3) δ: 1,42-of 2.16 (5H, m), 2,82-2,96 (4H, m), 3,10 (1H, d, J=14 Hz), to 3.34 (1H, DD, J=2, 14 Hz), 3,83 (2H, d, J=6 Hz), 5,14-by 5.18 (2H, m), 6,13-6,23 (1H, m), 7,39-EUR 7.57 (5H, m), 7,73 (1H, d, J=8 Hz), 8,03 (1H, d, J=8 Hz).

Example 44: 3-[2-Allyl-6-(3-pyridyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 42.

1H-NMR (CDCl3) δ: 1,42 of 1.50 (1H, m), 1,65-of 1.74 (1H, m), 1,96 and 2.13 (3H, m), 2,81-2,95 (4H, m), 3,10 (1H, d, J=14 Hz), to 3.34 (1H, DD, J=2, 14 Hz), 3,79-of 3.80 (2H, m), 5,11-5,19 (2H, m), 6,11-6,21 (1H, m), 7,39-7,42 (1H, m), 7,52-7,56(1H, m), 7,72-7,76 (1H, m), 8,35-of 8.37 (1H, m), 8,63-8,64 (1H, m), of 9.21 (1H, s).

Example 45: 3-[2-(2-Methyl-2-propenyl)-6-Persil-3-pyridyl]ethinyl-3-hinokitiol

a) 2-(2-Methyl-2-propenyl)-6-Persil-3-pyridylsulfonyl

A mixture of 220 mg of 2-bromo-6-iodine-3-pyridylmethylamine, 187 mg parasitisation, of 58.7 mg of tetrakis(triphenylphosphine)palladium (0) and 2 ml of xylene was stirred at 140°C for 2 hours. After cooling to room temperature the mixture was filtered through silica gel and the solvent evaporated. To the residue was added 1.20 ml 2-methyl-2-propionylthiocholine (example obtain 21), a 60.2 mg of tetrakis(triphenylphosphine)palladium (0) and 3 ml of xylene, followed by boiling under reflux for 2 hours. After cooling to room temperature there was added silica gel and the solvent evaporated. The residue was subjected to column chromatography on silicagel and was suirable 20% ethyl acetate/hexane to obtain 83,1 g of target compound.

1H-NMR (CDCl3) δ: to 1.83 (3H, s), 3,71 (2H, s), to 4.73 (1H, s)to 4.92 (1H, s), of 7.75 (1H, d, J=8 Hz), at 8.36 (1H, d, J=8 Hz), 8,60-to 8.62 (2H, m), to 9.66 (1H, s).

b) 3-[2-(2-Methyl-2-propenyl)-6-Persil-3-pyridyl]ethinyl-3-hinokitiol

The mixture 83,1 mg of 2-(2-methyl-2-propenyl)-6-Persil-3-pyridylmethylamine, 35,0 mg 3-ethinyl-3-hinokitiol, 13,3 mg tetrakis(triphenylphosphine)palladium (0), 2.2 mg of copper iodide, 96,6 μl of triethylamine and 1 ml of N,N-dimethylformamide was stirred at room temperature for one hour in nitrogen atmosphere. To the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 2.5% methanol/ethyl acetate, to obtain the 71,2 mg of target compound.

1H-NMR (CDCl3) δ: 1,42-1,49 (1H, m), 1,65-of 1.74 (1H, m), of 1.85 (3H, s), 1,97-2,12 (3H, m), 2,78-2,95 (4H, m), 3,10 (1H, d, J=14 Hz), to 3.34 (1H, DD, J=2, M Hz)of 3.78 (2H, s), 4,70 (1H, s), 4,88 (1H, s), 7,83 (1H, d, J=8 Hz), 8,19 (1H, d, J=8 Hz), 8,58 at 8.60 (2H, m), 9,67 (1H, d, J=2 Hz).

Example 46: 3-[2-Benzyl-6-(4-pyridil)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 14.

1H-NMR (CDCl3) δ: of 1.41 to 1.48 (1H, m), 1,63 is 1.91 (2H, m), 2,04-of 2.09 (2H, m), was 2.76 of 2.92 (4H, m), of 3.07 (1H, d, J=14 Hz), 3,26 (1H, d, J=14 Hz), to 4.41 (2H, s), 7,19-7,33 (5H, m), the 7.65 (1H, d, J=8 Hz), 7,80 (1H, d, J=8 Hz), 8,04-of 8.06 (1H, m), 9,27-9,29 (1H, m), 9,78-9,79 (1H, m).

Example 47: (3R)-3-[2-Benzyl-b-(3-pyridil)-3-pyridyl]-ethinyl-3-hinokitiol

The target connection SinTe Aravali as well as in example 14.

1H-NMR (CDCl3) δ: of 1.43 to 1.47 (1H, m), 1.60-to of 1.87 (2H, m), 2.05 is-of 2.08 (2H, m), 2.71 to to 2.99 (4H, m), 3,05 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 4,42 (2H, s), 7,21-7,30 (5H, m), 7,52-of 7.60 (1H, m), 7,87 (1H, d, J=8 Hz), 8,54-8,58 (2H, m), 9,17-9,19 (1H, m).

Example 48: 3-[2-Benzyl-6-(1,4-dioxan-2-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 14.

1H-NMR (CDCl3) δ: 1,39-of 1.41 (1H, m), 1,59-to 1.61 (1H, m), 1,80-to 1.87 (1H, m), 2,01-of 2.05 (2H, m), 2,72-2,87 (4H, m)of 3.00 (1H, d, J=14 Hz), 3,20 (1H, DD, J=2, 14 Hz), 4,16-4,27 (6N, m), 7,16-7,27 (6N, m), 7,34 (1H, ), to 7.61 (1H, d, J=8 Hz).

Example 49: 3-[2-Benzyl-6-(3-oxo-1-cyclohexenyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 14 by using (3-oxo-1-cyclohexenyl)anti synthesized according to the method described in literature (Tetrahedron Letters, Vol.31, No.13, 1837 (1990)).

1H-NMR (CDCl3) δ: 1,42-of 1.44 (1H, m), 1,63 of 1.99 (2H, m), 2.00 in 2,17 (4H, m), 2,49-2,52 (2H, m), 2.77-to 2.91 in (6N, m), 3.04 from (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 4,34 (2H, s), for 6.81 (1H, t, J=1 Hz), 7,19-7,32 (5H, m), 7,44 (1H, d, J=8 Hz), 7,71 (1H, d, J=8 Hz).

Example 50: 3-[2-Benzyl-6-(3,4-dihydro-2H-6-pyranyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 14 by using (3,4-dihydro-2H-6-pyranyl) anti synthesized according to the method described in the literature (Synlett 152 (1994)).

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,66-to 1.82 (2H, m), 1,89-2,04 (4H, m), 2,52-of 2.30 (2H, m), 2,74-to 2.94(4H, m)of 3.00 (1H, d, J=14 Hz), 3,20 (1H, DD, J=2, 14 Hz), 4,17-4,20 (2H, m), 4,32 (2H, s), 6,15-of 6.17 (1H, m), 7,17-7,26 (5H, m), 7,38 (1H, d, J=8 Hz), the 7.65 (1H, d, J=8 Hz).

Example 51: 3-[2-Benzyl-6-(2-hydroxyphenyl)-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-hydroxy-6-(2-hydroxyphenyl)pyridine

The mixture 641 mg (2-benzyl-3-methoxyethoxy-6-pyridyl)anti (example getting 18), 327 mg of 2-ethoxyethylacetate (example receive 20), 71,6 mg tetrakis(triphenylphosphine)palladium (0) and 7 ml of xylene was heated under reflux for one hour in nitrogen atmosphere. After cooling the mixture was filtered through silica gel and the solvent was removed. To the residue was added 2 ml triperoxonane acid, followed by stirring at room temperature over night. The reaction solution was neutralized with an aqueous solution of potassium carbonate. Added ethyl acetate and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography using 30% ethyl acetate/hexane, obtaining of 54.5 mg of target compound.

1H-NMR (CDCl3) δ: 4,24 (2H, s), 6,85-of 6.90 (1H, m), of 6.96-6,99 (1H, m), 7,21-7,27 (3H, m), 7,33-7,34 (4H, m), 7.68 per-of 7.70 (2H, m).

b) 2-Benzyl-6-(2-hydroxyphenyl)-3-pyridylsulfonyl

A mixture of 54.5 mg of 2-benzyl-3-hydroxy-6-(2-hydroxyphenyl)-pyridine, to 70.2 mg N-phenyltrichlorosilane, 824 moltitudine, 1.2 mg of 4-dimethylaminopyridine and 1.5 ml of dichloromethane was stirred at room temperature for 2.5 hours. To the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 12% ethyl acetate/hexane, obtaining and 68.5 mg of target compound.

1H-NMR (CDCl3) δ: the 4.29 (2H, s), 6,88-6,92 (1H, m), 6,95-6,98 (1H, m), 7,28-to 7.32 (4H, m), 7,35-7,39 (2H, m), 7,70-7,76 (2H, m), 7,83 (1H, d, J=8 Hz), 12,81 (1H, s).

C) 3-[2-Benzyl-6-(2-hydroxyphenyl)-3-pyridyl]ethinyl-3-hinokitiol

The mixture 67,0 mg of 2-benzyl-6-(2-hydroxyphenyl)-3-pyridylmethylamine, to 24.7 mg 3-ethinyl-3-hinokitiol, 19,0 mg tetrakis(triphenylphosphine)palladium (0), 0.1 mg of copper iodide, only 68.6 μl of triethylamine and 1.5 ml of N,N-dimethylformamide was heated with stirring at 100°C for 3 hours in nitrogen atmosphere. To the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 3% methanol/ethyl acetate, to obtain the 56,8 mg of target compound.

1H-NMR (CDCl3) δ: of 1.40 to 1.48 (1H, m), 1,52 is 1.60 (1H, m), 1,88 is 2.10 (3H, m), 2,80-2,90 (4H, m), is 3.08 (1H, d, J=14 Hz), or 3.28 (1H, DD, J=2, 14 Hz), 4,36 (2H, s), 6,85-6,89 (1H, m), of 6.96 (1H, d, J=8 Hz), 7.24 to 7,34 (6N, m), to 7.67-7,72 (2H, m), 7,78 (1H, d, J=8 Hz), 13,8 (1H, s).

Example 52: (3R)-3-[2-Benzyl-6-(1,3,4-thiadiazole-2-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same way as the example 51, using 2-iodine-1,3,4-thiadiazole (example getting 22).

1H-NMR (CDCl3) δ: 1,41-of 1.44 (1H, m), 1,62-to 1.98 (2H, m), 2,01-2,07 (2H, m), 2,50-2,95 (4H, m), 3,05 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 4,37 (2H, s), 7,19-7,29 (5H, m), 7,82 (1H, d, J=8 Hz), 8,18 (1H, d, J=8 Hz), 9,16 (1H, s).

Example 53: 3-[2-(4-Methoxybenzyl)-6-methyl-3-pyridyl]ethinyl-3-hinokitiol

a) 3-Benzyloxy-2-[(4-methoxyphenyl)hydroxymethyl]-6-methylpyridin

1.6 M solution of n-utility in hexane was added dropwise to the mixture 2,43 4-bromoanisole and 20 ml of diethyl ether at -50°C, followed by stirring at -20°C for 30 minutes. Next there was added a mixture of 2.27 g of 3-benzyloxy-6-methylpyridin-2-carboxaldehyde (example obtaining 11b) and 50 ml of diethyl ether at -60°C for 15 minutes. After stirring at the same temperature for 30 minutes to the reaction solution was added saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate and the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel using 5-20% ethyl acetate/hexane, obtaining of 1.16 g of the target compound.

1H-NMR (CDCl3) δ: 2,52 (3H, s), of 3.77 (3H, s)to 4.92 (1H, d, J=12 Hz), to 4.98 (1H, d, J=12 Hz), of 5.75 (1H, d, J=6 Hz), by 5.87 (1H, d, J=6 Hz), 6,79 (2H, d, J=9 Hz), 6,98 (1H, d, J=8 Hz), 7,03 (1H, d, J=8 Hz), 7,10-to 7.15 (2H, m), 7.23 percent (2H, d, J=9 Hz), 7,27-7,34 (3H, m).

b) 3-Ki-the Roxy-2-(4-methoxybenzyl)-6-methylpyridin

A mixture of 0.87 g of 3-benzyloxy-2-[(4-methoxyphenyl)hydroxy-methyl]-6-methylpyridine, 2.5 ml of acetic anhydride and 20 ml of pyridine was heated under stirring for 4 hours on an oil bath at a temperature of 120°C. After evaporation of the reaction solution was added water. The mixture was extracted with ethyl acetate and the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. To the residue was added 20 ml of methanol, 10 ml of tetrahydrofuran and a catalytic amount of 10% palladium on coal, followed by stirring for 10 hours in an atmosphere of hydrogen. After the catalyst was filtered, the filtrate was concentrated. Then the crystals were washed with diethyl ether to obtain 320 mg of the target compound.

1H-NMR (CDCl3-DMSO) δ: 2,32 (3H, s), of 3.69 (3H, s)to 3.92 (2H, s), to 6.80 (2H, d, J=8 Hz), 6,92 (1H, d, J=7 Hz), 7,07 (1H, d, J=7 Hz), 7,14 (2H, d, J=8 Hz).

C) 2-(4-Methoxybenzyl)-6-methyl-3-pyridylsulfonyl

A mixture of 160 mg of 3-hydroxy-2-(4-methoxybenzyl)-6-methylpyridine, 300 mg of N-phenyltrichlorosilane, 146 μl of triethylamine, 26 mg of 4-dimethylaminopyridine and 5.0 ml of dichloromethane was stirred at room temperature for 2 hours. To the reaction solution were added water and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. About what's headed the remainder was subjected to column chromatography on NH-silica gel (Fuji silicia), elwira hexane, then hexane/ethyl acetate (2:1), to obtain 230 mg of the target compound.

1H-NMR (CDCl3) δ: to 2.57 (3H, s), of 3.77 (3H, s)to 4.15 (2H, s), 6,80-PC 6.82 (2H, m), was 7.08 (1H, d, J=8 Hz), 7,19-7,21 (2H, m), 7,44 (1H, d, J=8 Hz).

d) 3-[2-(4-Methoxybenzyl)-6-methyl-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 230 mg of 2-(4-methoxybenzyl)-6-methyl-3-pyridyl-triftoratsetata, 116 mg of 3-ethinyl-3-hinokitiol, 147 mg of tetrakis(triphenylphosphine)palladium (0), 24 mg of copper iodide, 266 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated with stirring at 80°C for 3 hours in nitrogen atmosphere. The reaction solution was poured into dilute aqueous ammonia solution and the mixture was extracted with ethyl acetate. Then the organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (1:1)and then ethyl acetate/methanol (20:1), with 192 g of target compound.

1H-NMR (CDCl3) δ: 1,35-of 1.44 (1H, m), 1,54-of 1.65 (1H, m), 1.77 in-1,89 (1H, m), 2,02-2,04 (2H, m), of 2.54 (3H, s), of 2,75 2,95 (4H, m), to 3.02 (1H, DD, J=2, 14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,75 (MN, C)to 4.23 (2H, s), 6,77-to 6.80 (2H, m), 6,97 (1H, d, J=8 Hz), 7,16-7,19 (2H, m), 7,55 (1H, d, J=8 Hz).

Example 54: 3-[6-Methyl-2-(2-pyridylmethyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 53.

1H-NMR (CDCl3) δ: 1,38-of 1.44 (1H, is), 1,53-of 1.84 (2H, m), 1,96 with 2.14 (2H, m), 2,58 (3H, s), of 2,75 2,95 (4H, m), 3,05 (1H, d, J=14 Hz), and 3.16 (1H, DD, J=2, 14 Hz), of 4.49 (2H, s), 7,00 (1H, d, J=8 Hz), 7,11-to 7.15 (1H, m), 7,25-7,30 (1H, m), 7,49 (1H, d, J=8 Hz), 7,55-of 7.60 (1H, m), 7,44-of 8.47 (1H, m).

Example 55: 3-[6-Methyl-2-(3-pyridylmethyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 53.

1H-NMR (CDCl3) δ: 1,31-of 1.39 (1H, m), 1,52-1,7 8 (2H, m), 1.93 and is 2.00 (2H, m), 2,47 (3H, s), 2,63-2,89 (4H, m), 2,98 (1H, DD, J=2, 14 Hz)and 3.15 (1H, DD, J=2, 14 Hz), is 4.21 (2H, s), 6,93 (1H, d, J=8 Hz), 7,09-7,19 (1H, m), 7,51 (1H, d, J=8 Hz), 7,53-7,63 (1H, m), 8.34 per-at 8.36 (1H, m), and 8.50 (1H, d, J=2 Hz).

Example 56: 3-[6-Methyl-2-(4-pyridylmethyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 53.

1H-NMR (CDCl3) δ: 1,36-of 1.45 (1H, m), and 1.54 and 1.80 (2H, m), 1,97-to 2.06 (2H, m)to 2.55 (3H, s), 2,66-2,95 (4H, m), 3,03 (1H, DD, J=2, 14 Hz), 3,19 (1H, DD, J=2, 14 Hz), 4,28 (2H, s),? 7.04 baby mortality (1H, d, J=8 Hz), 7,13-7,15 (2H, m), to 7.61 (1H, d, J=8 Hz), 8,40-8,42 (2H, m).

Example 57: 3-[2-(2-Phenylethyl)-6-methyl-3-pyridyl]ethinyl-3-hinokitiol

a) 3-Benzyloxy-6-methyl-2-sterilely

1.5 g determenirovana was dissolved in 20 ml of tetrahydrofuran followed by the addition of 810 mg of tert-butoxide potassium at room temperature. After stirring for 15 minutes, there was added 10 ml of tertrahydrofuran ring of a solution containing 1.2 g of 3-benzyloxy-6-methylpyridin-2-carboxaldehyde (example obtaining 11b), and then stirred for 1.5 hours. Then there was added water and see what camping was extracted with ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 10% ethyl acetate/hexane as eluent, to obtain 1.2 g of the target compound.

1H-NMR (CDCl3) δ: of 2.53 (3H, s)to 5.13 (2H, s), to 6.95 (1H, d, J=8,4 Hz), 7,12 (1H, d, J=8,4 Hz), 7.24 to of 7.48 (8H, m), to 7.59 (2H, d, J=8,4 Hz), to 7.61 (1H, d, J=16 Hz), 7,80 (1H, d, J=16 Hz).

b) 3-Hydroxy-6-methyl-2-(2-phenylethyl)pyridine

1.2 g of 3-benzyloxy-6-methyl-2-stillpending was dissolved in 20 ml of methanol. There was added 684 mg of 10% palladium on coal and the mixture was first made. The atmosphere in the reaction system was replaced with nitrogen and the catalyst was filtered. The filtrate is evaporated to obtain 695 mg of the target compound.

c) 6-Methyl-2-(2-phenylethyl)pyridylmethylene

The mixture 695 mg of 3-hydroxy-6-methyl-2-(2-phenylethyl)pyridine, 1.5 g of N-phenyltrichlorosilane, 121 mg of 4-dimethylaminopyridine and 0.6 ml of triethylamine were dissolved in 20 ml of dichloromethane, followed by stirring at room temperature for 5 hours. Then the solvent was removed and the residue was subjected to column chromatography on silica gel using 10% ethyl acetate/hexane as eluent, to obtain 1.2 g of the target compound.

1H-NMR (CDCl3) δ: 2,59 (3H, s), 3,02-to 3.09 (2H, m), 3,12-3,19 (2H, m), was 7.08 (1H, d, J=8,4 Hz), 7,20-7,31 (5H, m), 7,44 (1H, d, J8,4 Hz).

d) 3-[2-(2-Phenylethyl)-6-methyl-3-pyridyl]ethinyl-3-hinokitiol

10 ml of N,N-dimethylformamide was added to a mixture of 1.2 g of 6-methyl-2-(2-phenylethyl)pyridylmethylamine, 522 mg of 3-ethinyl-3-hinokitiol, 400 mg of tetrakis(triphenylphosphine)-palladium (0), 217 mg of copper iodide and 1.7 ml of triethylamine, followed by heating under stirring at 50°in an oil bath for one hour in nitrogen atmosphere. After cooling, the reaction solution was sprayed over silica gel and subjected to column chromatography on silica gel using chloroform/methanol/water 36% ammonia solution (46:5:0.5 to) as the eluent for separation and purification, to obtain 490 mg of the target compound.

1H-NMR (CDCl3) δ: 1,42-of 1.52 (1H, m), 1,61-1,72 (1H, m), 1,89-2,02 (1H, m), 2,04-of 2.16 (2H, m), of 2.56 (3H, s), 2,80-2,95 (4H, m), 3,02-3,11 (3H,m), 3,20-of 3.32 (3H, m), 6,97 (1H, d, J=8.0 Hz), 7.18 in-7,28 (5H, m), 7,54 (1H, d, J=8.0 Hz).

Example 58: 3-(2-Styryl-6-methyl-3-pyridyl)ethinyl-3-hinokitiol

a) 3-Hydroxy-6-methyl-2-sterilely

875 mg of 3-benzyloxy-6-methyl-2-stillpending (example 57a) was dissolved in 15 ml of 1,2-dichloroethane and there was added 1.2 ml of dichloromethane solution containing 1.0 mol of tribromide boron, nitrogen atmosphere, followed by heating under stirring at 50°C in an oil bath overnight. After cooling there was added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with 5% methanol the/dichloromethane. The organic phase was further washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was dried in vacuum to obtain 200 mg of the target compound.

b) 3-(2-Styryl-6-methyl-3-pyridyl)ethinyl-3-hinokitiol

The target compound was synthesized as in example 57.

1H-NMR (CDCl3) δ: of 1.40-1.50 (1H, m), 1,66 and 1.80 (1H, m), 2.00 in to 2.18 (3H, m), 2,59 (3H, s), 2,80-3,00 (4H, m), 3,12 (1H, d, J=14 Hz), to 3.38 (1H, DD, J=2, 14 Hz), of 6.96 (1H, d, J=7.9 Hz), 7,30 (1H, d, J=7,3 Hz), 7,37 (2H, DD, J=7.5 Hz, 7,3 Hz)7,565 (1H, d, J=7.9 Hz), 7,572 (1H, d, J=7.5 Hz), 7,60 (1H, d, J=16 Hz), of 7.97 (1H, d, 16 Hz).

Example 59: 3-[2-Benzyl-6-(3-methoxypropyl)-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-(2-ethoxycarbonylethyl)-3-methoxyethoxymethyl

1,3 g ethyldichlorosilane was dissolved in 20 ml of tetrahydrofuran followed by the addition 657 mg of tert-butoxide potassium at room temperature. After stirring for 15 minutes, there was added 10 ml of tertrahydrofuran ring of a solution containing 1.0 g of 2-benzyl-3-methoxypiperidine-6-carboxaldehyde (example receiving 11), followed by stirring for another one hour. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 17% ethyl acetate/hexane as eluent for the separation and isdi, to obtain 1.4 g of the target compound.

b) 2-Benzyl-6-(2-ethoxycarbonylethyl)-3-methoxyethoxymethyl

1.4 g of 2-benzyl-6-(2-ethoxycarbonylethyl)-3-methoxyethoxymethyl was dissolved in 20 ml of ethyl acetate. There was added 457 mg of 10% palladium-on-coal and the mixture was first made. After the atmosphere in the reaction system was replaced with nitrogen, the catalyst was filtered. The filtrate was further filtered through silica gel and the filtrate is evaporated to obtain 1.3 g of the target compound.

1H-NMR (CDCl3) δ: 1,22 (3H, t, J=7,1 Hz), was 2.76 (2H, t, J=7,6 Hz), 3,05 (2H, t, J=7,6 Hz), 3,30 (3H, s), of 4.13 (2H, q, J=7,1 Hz)to 4.15 (2H, s), 5,09 (2H, s), 6,97 (1H, d, J=8,4 Hz), 7,14-7,29 (6N, m).

c) 2-Benzyl-6-(3-hydroxypropyl)-3-methoxyethoxymethyl

205 mg of socialogical suspended in 20 ml of anhydrous ether. Was added dropwise in 10 ml of anhydrous ether solution containing 1.3 g of 2-benzyl-6-(2-ethoxycarbonylethyl)-3-methoxypiperidine, while cooling with ice. After stirring for one hour there was added 0.2 ml of water, then 0.2 ml of 5N aqueous solution of sodium hydroxide and then 0.6 ml of water while cooling with ice. The reaction solution was filtered through filter paper to remove insoluble substances. After washing with ether, the organic phase is evaporated. The residue was subjected to column chromatography on silica gel using 40% ethyl acetate/hexane in ka is este eluent, for separation and purification to obtain 1.0 g of the target compound.

1H-NMR (CDCl3) δ: of 1.94 (2H, TT, J=6,5 Hz, 5.7 Hz), only 2.91 (2H, t, J=6.5 Hz), to 3.34 (3H, s), 3,70 (2H, t, J=5.7 Hz), is 4.15 (2H, s)to 5.13 (2H, s), 6,97 (1H, d, J=8,4 Hz), 7,15-7,31 (6N, m).

d) 2-Benzyl-6-(3-methoxypropyl)-3-methoxyethoxymethyl

527 mg of 2-Benzyl-6-(3-hydroxypropyl)-3-methoxypiperidine was dissolved in 5 ml of N,N-dimethylformamide and added 108 mg of 60% suspension of sodium hydride in oil at room temperature under stirring. After 10 minutes there was added 0.16 ml of methyliodide, followed by stirring for one hour at room temperature. Then there was added water and the mixture was extracted with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 20% ethyl acetate/hexane as eluent for separation and purification, to obtain 389 mg of the target compound.

1H-NMR (CDCl3) δ: to 1.98 (2H, TT, J=7,8 Hz and 6.6 Hz), and 2.79 (2H, t, J=7,8 Hz)and 3.31 (3H, s)to 3.34 (3H, s)to 3.41 (2H, t, J=6.6 Hz), 4,17 (2H, s), 5,09 (2H, s), to 6.95 (1H, d, J=8, 4 Hz), 7,14-7,30 (6N, m).

e) 3-[2-Benzyl-6-(3-methoxypropyl)-3-pyridyl]ethinyl-3-hinokitiol

The compounds obtained as described above, remove protection using triperoxonane acid, and successively held the same procedure is s, as in example 57, for the synthesis of the target compounds.

1H-NMR (CDCl3) δ: 1,35-1,45 (1H, m), 1,53-to 1.63 (1H, m), 1,75-of 1.88 (1H, m), 1,98-of 2.05 (4H, m), 2,67 of 2.92 (4H, m), 2,85 (2H, t, J=7.5 Hz), of 3.00 (1H, DD, J=2, 14 Hz), 3,20 (1H, DD, J=2, 14 Hz), 3,32 (3H, s), 3,40 (2H, t, J=6.4 Hz), or 4.31 (2H, s), of 6.99 (1H, d, J=7.9 Hz), 7,15-7,26 (5H, m), 7,58 (1H, d, J=7.9 Hz).

Example 60; 3-[2-Benzyl-6-(5,6-dihydro-2H-Piran-4-yl)-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-(4-hydroxycitrate-4H-Piran-4-yl)-3-methoxyethoxymethyl

In 10 ml diethylamino solution containing 1,79 g of 2-benzyl-6-iodine-3-methoxypiperidine (example 12)was added dropwise to a mixture of 4.25 ml of a hexane solution of 1.54 mol n-utillity and 10 ml of diethyl ether at -78°C. After stirring at the same temperature for 20 minutes there was added dropwise tetrahydro-4H-Piran-4-one. The temperature of the mixture was raised to room temperature there was added water and diethyl ether. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 30% ethyl acetate/hexane, to obtain 1.39 g of the target compound.

1H-NMR (CDCl3) δ: 1,47-of 1.56 (2H, m), 2.05 is-a 2.12 (2H, m)to 3.38 (3H, s), 3,90-4,01 (4H, m), 4,19 (2H, s), is 5.18 (2H, s), 7,14-7,30 (6N, m), 7,41 (1H, d, J=8 Hz).

b) 2-Benzyl-3-hydroxy-6-(4-hydroxycitrate-4H-Piran-4-yl)pyridine/p>

A mixed solution of 377 mg of 2-benzyl-6-(4-hydroxycitrate-4H-Piran-4-yl)-3-methoxypyridine, 2 ml dichloromethane and 2 ml triperoxonane acid was stirred at room temperature overnight. The reaction solution was neutralized with an aqueous solution of sodium bicarbonate, and there was added ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 60% ethyl acetate/hexane, to obtain 241 mg of the target compound.

1H-NMR (CDCl3) δ: 1,51-of 1.57 (2H, m), 2.05 is-a 2.12 (2H, m), 3,90-4,01 (4H, m), is 4.21 (2H, s)5,00 (1H, s), of 5.39 (1H, s), 7,12 (2H, s), 7,21-7,30 (5H, m).

C) 2-Benzyl-6-(4-hydroxycitrate-4H-Piran-4-yl)-3-pyridylsulfonyl

A mixture of 241 mg of 2-benzyl-3-hydroxy-6-(4-hydroxylate-hydro-4H-Piran-4-yl)pyridine, 302 mg of N-denitrifier-sulfonamide, 353 μl of triethylamine, 5.2 mg of 4-dimethylaminopyridine and 3 ml of dichloromethane was stirred at room temperature for 2 hours. To the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 30% ethyl acetate/hexane, obtaining 332 g of the target compound.

1H-NMR (CDCl3) δ: 1,53-of 1.56 (2H, m), 2,08-2,17 (2H, m), 3,92-of 3.97 (4H, m), 4.26 deaths (2H, s), 4,60 (1H, s), 7.23 percent and 7.36 (6N, m), the 7.65 (1H, d,J=8 Hz).

d) 2-Benzyl-6-(5,6-dihydro-2H-Piran-4-yl)-3-pyridyl-triftorbyenzola

57,9 ál methanesulfonamide was added dropwise to a mixture of 104 mg of 2-benzyl-6-(4-hydroxycitrate-4H-Piran-4-yl)-3-pyridylmethylamine, 139 μl of triethylamine and 2 ml of dichloromethane under ice cooling. After stirring at room temperature for 3 hours there was added water and ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 15% ethyl acetate/hexane, obtaining a total of 60.7 mg of target compound.

1H-NMR (CDCl3) δ: 2,60 (2H, Sirs), to 3.92 (2H, t, J=5 Hz)to 4.23 (2H, s), 4,37 (2H, s), 6,74 (1H, s), 7,21-7,31 (6N, m), 7,53 (1H, d, J=8 Hz).

e) 3-[2-Benzyl-6-(5,6-dihydro-2H-Piran-4-yl)-3-pyridyl]-ethinyl-3-hinokitiol

A mixture of 60.7 g of 2-benzyl-6-(5,6-dihydro-2H-Piran-4-yl)-3-pyridylmethylamine, 23,0 mg 3-ethinyl-3-hinokitiol, 17,6 mg tetrakis(triphenylphosphine)palladium (0), 2,9 mg of copper iodide, 63,6 μl of triethylamine and 1 ml of N,N-dimethylformamide was stirred at 60°C for 1.5 hours in a nitrogen atmosphere. To the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 3% methanol/ethyl acetate, obtaining 40,7 mg of target compound.

1 H-NMR (CDCl3) δ: 1,33-1,44 (1H, m), 1.56 to of 1.64 (1H, m), 1,80-of 1.88 (1H, m), 2.00 in 2,07 (2H, m)2,60 (1H, Sirs), 2,73-is 2.88 (4H, m), to 3.02 (1H, d, J=14 Hz), up 3.22 (1H, DD, J=2, 14 Hz), 3,93 (1H, t, J=5 Hz), or 4.31 (2H, C), 4,36-to 4.38 (2H, m), 6.75 in-6,77 (1H, m), 7,12-7,29 (6N, m)to 7.61 (1H, d, J=8 Hz).

Example 61: 3-[2-Benzyl-6-(4-hydroxy-1-cyclohexenyl)-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-hydroxy-6-(4-oxo-1-hydroxycyclohexyl)-pyridine

The target compound was synthesized as in example 60A and b, except that tetrahydro-4H-Piran-4-one substituted 1,4-cyclohexanedimethanol.

1H-NMR (CDCl3) δ: 2,00 e 2.06 (2H, m), 2,14-2,22 (2H, m), 2,35-to 2.41 (4H, m), 2.95 and totaling 3.04 (2H, m), is 4.21 (2H, s), 7,05-7,31 (7H, m).

b) 2-Benzyl-6-(1,4-dihydroxytoluene)-3-pyridine of 67.4 mg of sodium borohydride was added to the mixture 353 mg of 2-benzyl-3-hydroxy-6-(4-oxo-1-hydroxycyclohexyl)of pyridine and 4 ml of methanol under ice cooling, followed by stirring at the same temperature for one hour. There acetone was added and the solvent was removed. Then the residue was subjected to column chromatography on silica gel using 20% hexane/ethyl acetate, to obtain 193 mg of the target compound.

1H-NMR (CDCl3) δ: 1,30-of 1.95 (8H, m), 3,70 of 3.75 (1H, m), 4,20 (2H, s), 7,06-7,31 (7H, m).

c) 3-[2-Benzyl-6-(4-hydroxy-1-cyclohexenyl)-3-pyridyl]-ethinyl-3-hinokitiol

The target compound was synthesized as in example 60-c, d and e, except that 2-Ben the Il-3-hydroxy-6-(4-hydroxycitrate-4H-Piran-4-yl)pyridine substituted 2-benzyl-6-(1,4-dihydroxytoluene)-3-hydroxypyridine.

1H-NMR (CDCl3) δ: 1,37-of 1.44 (1H, m), 1.56 to of 1.64 (1H, m), 1.77 in-a 1.88 (2H, m), 2.00 in to 2.06 (3H, m), 2,24-2,31 (1H, m), of 2.51-2.91 in (7H, m), 3,01 (1H, d, J=14 Hz), up 3.22 (1H, DD, J=2, 14 Hz), 4.04 the-4,10 (1H, m), or 4.31 (2H, ), 6,69 (1H, s), 7,16-7,28 (6N, m), 7,60 (1H, d, J=8 Hz).

Example 62: 3-[2-Benzyl-6-(tetrahydro-4H-Piran-4-yl)-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-(5,6-dihydro-2H-Piran-4-yl)-3-methoxymethyl-oxypyridine

716 μl of methanesulfonamide was added dropwise to a mixture of 1.02 g of 2-benzyl-6-(4-hydroxycitrate-4H-Piran-4-yl)-3-methoxypiperidine (example 60A), 1,72 ml of triethylamine and 10 ml of dichloromethane under ice cooling. After stirring overnight at room temperature there was added water and ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 20% ethyl acetate/hexane, to obtain 355 mg of the target compound.

1H-NMR (CDCl3) δ: 2,59-2,63 (2H, m)to 3.33 (3H, s), of 3.94 (2H, t, J=5 Hz), 4,19 (2H, s), 4,35-to 4.38 (2H, m), of 5.15 (2H, s), 6,59-6,62 (1H, m), 7,13-7,33 (7H, m).

b) 2-Benzyl-3-methoxyethoxy-6-(tetrahydro-4H-Piran-4-yl)pyridine

20 mg of 10% palladium on coal was added to a mixture of 197 mg of 2-benzyl-6-(5,6-dihydro-2H-Piran-4-yl)-3-methoxypyridine and 3 ml of ethanol, followed by stirring at room temperature overnight in a hydrogen atmosphere. After that is about how the atmosphere in the reaction system was replaced with nitrogen, the reaction solution was filtered through celite. The solvent was removed and then the residue was subjected to column chromatography on silica gel using 20% ethyl acetate/hexane, obtaining 83,7 mg of target compound.

1H-NMR (CDCl3) δ: 1,83-of 1.88 (4H, m), 2,88-2,96 (1H, m), of 3.32 (3H, s), 3,52-to 3.58 (2H, m), 4,06-4,17 (4H, m), 5,10 (2H, s), of 6.96 (1H, d, J=8 Hz), 7,12-7,16 (1H, m), 7,21-7,31 (5H, m).

C) 3-[2-Benzyl-6-(tetrahydro-4H-Piran-4-yl)-3-pyridyl]-ethinyl-3-hinokitiol

The target compound was synthesized as in example 60b, C, and E.

1H-NMR (CDCl3) δ: 1,36-of 1.44 (1H, m), 1,55-to 1.63 (1H, m), 1,79-1,90 (5H, m), 1,98-2,04 (2H, m), 2,68-2,87 (5H, m), 3,01 (1H, d, J=14 Hz), up 3.22 (1H, DD, J=2, 14 Hz), 3,41-to 3.58 (2H, m), 4,07-4,11 (2H, m), 4,30 (2H, ), of 6.99 (1H, d, J=8 Hz), 7,15-7,27 (5H, m), a 7.62 (1H, d, J=8 Hz).

Example 63: 3-[2-Benzyl-6-(3-methoxy-1-PROPYNYL)-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 500 mg of 2-benzyl-3-bromo-6-pyridylmethylamine received in the sample receiving 3, 0,12 ml methylpropanamide ether, 40 mg of tetrakis(triphenylphosphine)-palladium (0), 1.2 mg of copper iodide, of 0.53 ml of triethylamine and 1 ml of N,N-dimethylformamide was stirred at room temperature overnight under nitrogen atmosphere. To the reaction solution were added ethyl acetate and water diluted solution of ammonia to separate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to the column chromatography on silica gel, using 1-10% ethyl acetate/hexane, to obtain 170 mg of 2-benzyl-3-bromo-6-(3-methoxy-1-PROPYNYL)pyridine.

Then a mixture of 170 mg of 2-benzyl-3-bromo-6-(3-methoxy-1-PROPYNYL)pyridine, 90 mg of 3-ethinyl-3-hinokitiol, 30 mg of tetrakis(triphenylphosphine)palladium (0), 1 mg of copper iodide and 0.22 ml of triethylamine and 1 ml of N,N-dimethylformamide was stirred for 2 hours at an oil bath at a temperature of 85°C in nitrogen atmosphere. To the reaction solution were added ethyl acetate and a dilute aqueous solution of ammonia to separate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel, elwira 20-100% ethyl acetate/hexane and then with 2.5% methanol/ethyl acetate, to obtain 120 mg of the target compound.

1H-NMR (CDCl3) δ: 1,35-of 1.84 (3H, m), 1,96 e 2.06 (2H, m), 2,64 of 2.92 (4H, m)to 2.99 (1H, DD, J=2, 14 Hz), 3,17 (1H, DD, J=2, 14 Hz), 3,47 (3H, s)to 4.33 (2H, s), 4,36 (2H, s), 7,15-7,28 (5H, m), 7,30 (1H, d, J=8 Hz), to 7.64 (1H, d, J=8 Hz).

Example 64: 3-[2-Benzyl-6-(4-hydroxy-1-butynyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 63.

1H-NMR (CDCl3) δ: 1,34-of 1.84 (3H, m), 1,96 e 2.06 (2H, m), 2,64 of 2.92 (4H, m), by 2.73 (2H, t, J=6 Hz), 2,99 (1H, DD, J=2, 14 Hz), and 3.16 (1H, DD, J=2, 14 Hz), 3,85 (2H, t, J=6 Hz), or 4.31 (2H, s), 7,14-7,28 (6N, m), 7,60 (1H, d, J=8 Hz).

Example 65: 3-[2-(4-Terbisil)-6-(3-hydroxy-1-butynyl)-3-PIR is DIL]ethinyl-3-hinokitiol

The target compound was synthesized as in example 63.

1H-NMR (CDCl3) δ: 1,35-1,85 (6N, m), 1,95-of 2.08 (2H, m), 2,68-of 2.93 (4H, m), 3,03 (1H, d, J=14 Hz), 3,21 (1H, DD, J=2,14 Hz), 4,28 (2H, s), 4,79 (1H, q, J=7 Hz), 6,94 (2H, t, J=8 Hz), 7,20 (2H, DD, J=6,8 Hz), 7,28 (1H, d, J=8 Hz), the 7.65 (1H, d, J=8 Hz).

Example 66: 3-[2-Benzyl-6-(pyrilamine)-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-bromo-6-(pyrilamine)pyridine

A mixture of 788 mg of 2-benzyl-3-bromo-6-pyridylmethylamine (example obtaining 3), 207 mg of pirazinamide (example getting 19), 230 mg of tetrakis(triphenylphosphine)-palladium (0), to 37.9 mg of copper iodide, 832 μl of triethylamine and 6 ml of N,N-dimethylformamide was stirred at 80°C for one hour in nitrogen atmosphere. To the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 25% ethyl acetate/hexane, obtaining 443 mg of the target compound.

1H-NMR (CDCl3) δ: 4,39 (2H, s), 7,19-7,39 (6N, m), 7,87 (1H, d, J=8 Hz), 8,54-8,56 (1H, m), 8,61-to 8.62 (1H, m), 8,86 (1H, s).

b) 3-[2-Benzyl-6-(pyrilamine)-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 109 mg of 2-benzyl-3-bromo-6-(pyrilamine)pyridine, 47,1 mg 3-ethinyl-3-hinokitiol, 35,9 mg of tetrakis-(triphenylphosphine)palladium (0), 5.9 mg of copper iodide, 130 μl of triethylamine and 1.5 ml of N,N-dimethylformamide was stirred for 5 hours at 70°C in nitrogen atmosphere. To the reaction solution to relax the Lee NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 3% methanol/ethyl acetate, to obtain the 61,0 mg of target compound.

1H-NMR (CDCl3) δ: 1,37 was 1.43 (1H, m), 1.56 to of 1.64 (1H, m), a 1.75-to 1.83 (1H, m), 1,98-2,04 (2H, m), 2,67-is 2.88 (4H, m),3,01 (1H, d, J=14 Hz), 3,19 (1H, DD, J=2, 14 Hz), to 4.38 (2H, s), 7,17-7,28 (5H, m), of 7.48 (1H, d, J=8 Hz), of 7.70 (1H, d, J=8 Hz), 8,53-8,54 (1H, m), 8,61-to 8.62 (1H, m), cent to 8.85-8,86 (1H, m).

Example 67: 3-[2-Benzyl-6-(2-pyrazolate)-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-bromo-6-(2-pyrazolate)pyridine

12 mg of platinum oxide was added to a mixture of 230 mg of 2-benzyl-3-bromo-6-(pyrilamine) pyridine (example getting 66-a), 2.5 ml of ethyl acetate and 2 ml of methanol, followed by stirring at room temperature overnight in a hydrogen atmosphere. After the atmosphere in the reaction system was replaced with nitrogen, the reaction solution was filtered through celite. After removal of solvent the residue was subjected to column chromatography on silica gel using 50% ethyl acetate/hexane, obtaining 85,4 mg of target compound.

1H-NMR (CDCl3) δ: 3,20-3,30 (4H, m), 4,30 (2H, s), at 6.84 (1H, d, J=8 Hz), 7,17-7,28 (5H, m), 7,66 (1H, d, J=8 Hz), a 8.34 (1H, s), scored 8.38 (1H, d, J=2 Hz), of 8.47-8,48 (1H, m).

b) 3-[2-Benzyl-b-(2-pyrazolate)-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 85.4 mg of 2-benzyl-3-bromo-6-(2-pyrazolate)pyridine, 36,4 mg 3-ethinyl-3-hinokitiol, of 27.8 mg of tetrakis-(triphenylphosphine)palladium (0), 4.6 mg of copper iodide, 101 μl of tritium is on and 1.5 ml of N,N-dimethylformamide was stirred for 7 hours at 80° C in nitrogen atmosphere. To the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 3% methanol/ethyl acetate, to obtain the 45,4 mg of target compound.

1H-NMR (CDCl3) δ: 1,36-of 1.44 (1H, m), 1,54-to 1.63 (1H, m), 1,78 is 1.86 (1H, m), 1,98-of 2.05 (2H, m), 2,67-only 2.91 (4H, m), 3,01 (1H, d, J=14 Hz), 3,20 (1H, DD, J=2, 14 Hz), 3.25 to 3.27 to (4H, m), 4,30 (2H, s), 6,92 (1H, d, J=8 Hz), 7,16-7,28 (5H, m), 7,54 (1H, d, J=8 Hz), 8,32 (1H, s), at 8.36 (1H, d, J=2 Hz), of 8.47-8,48 (1H, m).

Example 68: 3-[2-Benzyl-6-(4-methoxy-3-oxobutyl)-3-pyridyl]ethinyl-3-hinokitiol

a) Dimethyl 3-methoxy-2-oxopropionate

108 ml of a hexane solution containing 1,58 mol n-utility, was dissolved in 100 ml of anhydrous tetrahydrofuran. To the mixture was added dropwise a mixture of 15 ml dimethylmethylphosphonate and 50 ml of anhydrous tetrahydrofuran (THF) for 45 minutes in a nitrogen atmosphere, at the same time, the temperature of the mixture was maintained equal to -60°C. Further, after 15 minutes, the reaction solution was added dropwise a mixture of 16.5 ml of methylmetacrylate and 50 ml of anhydrous tetrahydrofuran over 30 minutes. The solution was stirred for 1.5 hours under ice cooling. Then, the cooling medium was removed and the reaction solution was stirred over night at room temperature. Then to the reaction solution was added acetic acid and water, the solvent was removed and was extracted with dichloromethane the m The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and subjected to column chromatography on silica gel using 2% methanol/ethyl acetate as eluent, to obtain 17 g of target compound.

1H-NMR (CDCl3) δ: 3,18 (2H, d, J=23 Hz), 3,44 (3H, s), with 3.79 (3H, s) is 3.82 (3H, s), 4,14 (2H, s).

b) 2-Benzyl-3-methoxyethoxy-6-(4-methoxy-3-oxo-1-butenyl)pyridine

6 g of Dimethyl 3-methoxy-2-oxopropionate was dissolved in 200 ml of tetrahydrofuran, to which was then added 3.2 g of tert-butoxide potassium. After stirring for 15 minutes was added 50 ml of tertrahydrofuran ring solution containing 6 g of 2-benzyl-3-methoxypiperidine-6-carboxaldehyde (example receiving 11), followed by stirring for another one hour. Then add water, the solvent was removed and the mixture was extracted with ethyl acetate. Next, the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 17-33% ethyl acetate/hexane as eluent for separation and purification to obtain 4.6 g of the target compound.

1H-NMR (CDCl3) δ: 3,30 (3H, s), 3,49 (3H, s), is 4.21 (2H, s), 4,32 (2H, s), 5,19 (2H, s), 7,15-to 7.35 (8H, m), of 7.64 (1H, d, J=16 Hz).

C) 2-Benzyl-3-methoxyethoxy-6-(4-methoxy-3-oxobutyl)-pyridine

4.6 g of 2-benzyl-3-methoxyethoxy-6-(4-methoxy-3-oxo-1-butenyl)pyridine was dissolved in 100 ml of ethyl acetate was added 976 mg of 10% palladium on coal and then was first made. After the atmosphere in the reaction system was replaced with nitrogen, the catalyst was filtered and the filtrate evaporated. The obtained residue was subjected to column chromatography on silica gel using 33% ethyl acetate/hexane as eluent for separation and purification to obtain 1.8 g of the target compound.

1H-NMR (CDCl3) δ: of 2.86 (2H, t, J=7.0 Hz), 3,05 (2H, t, J=7,0 Hz)and 3.31 (3H, s), 3,37 (3H, s)to 4.01 (2H, s), 4,14 (2H, s), 5,10 (2H, s), 6,97 (1H, d, J=8,4 Hz), 7,15-7,27 (6N, m).

d) 2-Benzyl-6-(4-methoxy-3-oxobutyl)-3-pyridylsulfonyl

1.8 g of 2-Benzyl-3-methoxyethoxy-6-(4-methoxy-3-oxobutyl)pyridine was dissolved in 50 ml of methanol was added 2 ml of concentrated hydrochloric acid followed by boiling under reflux for 1.5 hours. After cooling the mixture was neutralized with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. Next, the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The obtained residue was dissolved in 50 ml of dichloromethane. Added 2.7 g of N-phenyltrichlorosilane, 209 mg of 4-dimethylaminopyridine and 1 ml of triethylamine, followed by stirring at room is the temperature for 1.5 hours. The solvent was removed, the residue was subjected to column chromatography on silica gel using 25% ethyl acetate/hexane as eluent for separation and purification to obtain 2.3 g of the target compound.

1H-NMR (CDCl3) δ: only 2.91 (2H, t, J=6.8 Hz), of 3.13 (2H, t, J=6.8 Hz), 3,37 (3H, s), of 3.96 (2H, s), 4,19 (2H, s), 7,14 (1H, d, J=8,4 Hz) 7,20-7,29 (5H, m), 7,46 (1H, d, J=8,4 Hz).

e) 3-[2-Benzyl-6-(4-methoxy-3-oxobutyl)-3-pyridyl]ethinyl-3-hinokitiol

10 ml of N,N-dimethylformamide was added to a mixture of 1.9 g of 2-benzyl-6-(4-methoxy-3-oxobutyl)-3-pyridylmethylamine, 773 mg of 3-ethinyl-3-hinokitiol, 525 mg of tetrakis(triphenylphosphine)palladium (0), 267 mg of copper iodide and 2.2 ml of triethylamine, followed by stirring for one hour at 50°C in an oil bath under nitrogen atmosphere. After cooling, was added ethyl acetate. The mixture was filtered through celite followed by washing with water. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using chloroform/methanol/36% aqueous ammonia solution (46:5:0.5 to) as the eluent for separation and purification to obtain 1.3 g of the target compound.

1H-NMR (CDCl3) δ: 1,35-1,45 (1H, m), 1,54-of 1.64 (1H, m), 1,75 is 1.86 (1H, m), 1,95-of 2.05 (2H, m), 2,67-2,90 (4H, m), 2,89 (2H, t, J=7,0 Hz)of 3.00 (1H, DD, J=2, 14 Hz), 3,11 (2H, t, J=7.0 Hz), 3,20 (1H, DD, J=2, 14 Hz), 3,37 (3H, what), of 4.00 (2H, s), 4,27 (2H, s), 7,01 (1H, d, J=7.9 Hz), 7,17-7,26 (5H, m), EUR 7.57 (1H, d, J=7.9 Hz).

Example 69: 3-[2-Benzyl-6-(2-ethoxycarbonylethyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 68.

1H-NMR (CDCl3) δ: of 1.34 (3H, t, J=7,1 Hz), 1,44-of 1.53 (1H, m), 1,62-1,72 (1H, m), 1,80-1,89 (1H, m), 2,08-2,17 (2H, m), 2,75 was 3.05 (4H, m), 3,11 (1H, DD, J=2, 14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 4,28 (2H, q, J=7,1 Hz)to 4.33 (2H, s)6,94 (1H, d, J=16 Hz), 7.18 in-7,30 (6N, m), 7,63 (1H, d, J=16 Hz), 7,66 (1H, d, J=7.9 Hz).

Example 70: 3-[2-Benzyl-6-(2-cyanoethyl)-3-pyridyl]ethinyl-3 - hinokitiol

The target compound was synthesized as in example 68.

1H-NMR (CDCl3) δ: 1,36 of 1.46 (1H, m), 1.56 to of 1.66 (1H, m), 1,76-1,89 (1H, m), 1,98-of 2.08 (2H, m), 2,69-2,95 (4H, m), 2,84 (2H, t, J=7,3 Hz), to 3.02 (1H, DD, J=2, 14 Hz), 3,10 (2H, t, J=7,3 Hz), 3,21 (1H, DD, J=2, 14 Hz), or 4.31 (2H, s),? 7.04 baby mortality (1H, d, J=7.9 Hz), 7.18 in-7,28 (5H, m), of 7.64 (1H, d, J=7.9 Hz).

Example 71: 3-[2-Benzyl-6-(3-oxobutyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 68.

1H-NMR (CDCl3) δ: 1,35-of 1.44 (1H, m), 1,52-of 1.62 (1H, m), a 1.75-to 1.87 (1H, m), 1,98-of 2.08 (2H, m)to 2.13 (3H, s), 2,68-2,95 (4H, m), is 2.88 (2H, t, J=6,9 Hz)of 3.00 (1H, DD, J=2, 14 Hz), 3,03 (2H, t, J=6.9 Hz), 3,19 (1H, DD, J=2, 14 Hz), 4,27 (2H, s), of 6.99 (1H, d, J=7.9 Hz), 7,16-7,28 (5H, m), 7,55 (1H, d, J=7.9 Hz).

Example 72: 3-(2-Phenyl-6-morpholino-3-pyridyl)ethinyl-3-hinokitiol

a) 2-Bromo-6-morpholinopropan

A mixture of 10 g of 2,6-dibromopyridine, 7,4 ml of the research, an 11.7 g of anhydrous potassium carbonate and 30 ml of N-methyl-2-pyrrolidinone under stirring for 5 hours on an oil bath at a temperature of 100° C in nitrogen atmosphere. The mixture was extracted by adding ethyl acetate and water. The extract was washed with water and saturated salt solution and then concentrated. The residue was subjected to column chromatography on silica gel, using 2-10% ethyl acetate/hexane, to obtain 9.8 g of the target compound.

1H-NMR (CDCl3) δ: 3,50 (4H, t, J=5 Hz), 3,80 (4H, t, J=5 Hz), 6,50 (1H, d, J=8 Hz), 6,79 (1H, d, J=8 Hz), 7,31 (1H, t, J=8 Hz).

b) 2-Phenyl-6-morpholinopropan

A mixture of 1 g of 2-bromo-6-morpholinopropan, 110 mg of chloride 1,3-bis(diphenylphosphino)propenies (II) and 4 ml of tetrahydrofuran was stirred in an ice bath under nitrogen atmosphere. To the mixture was added dropwise tertrahydrofuran ring solution phenylmagnesium, which was obtained from 0,65 ml of bromine benzol, 200 mg of magnesium and 5 ml of tetrahydrofuran, followed by stirring at room temperature over night. The reaction solution was extracted with saturated aqueous ammonium chloride and ethyl acetate, and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel, using 2-10% ethyl acetate/hexane, to obtain 750 mg of target compound.

1H-NMR (CDCl3) δ: 3,62 (4H, t, J=5 Hz), 3,86 (4H, t, J=5 Hz), 6,60 (1H, d, J=8 Hz), to 7.15 (1H, d, J=8 Hz), 7,37 (1H, t, J=7 Hz), 7,44 (2H, t, J=7 Hz), 7,58 (1H, t, J=8 Hz), 8,01 (2H, q, j =7 Hz).

C) 2-Phenyl-6-morpholino-3-yodellin

A solution of 750 mg 2-phenyl-6-morpholinopropan and 5 ml of N,N-dimethylformamide was stirred in an ice bath and to the mixture was added 740 mg of N-jodatime, followed by stirring at room temperature over night. In addition, there was added 70 mg of N-jodatime, followed by stirring at room temperature for 5 hours. The reaction mixture was extracted by adding ethyl acetate, water and sodium sulfite and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel using 5-10% ethyl acetate/hexane, to obtain 1.1 g of the target compound.

1H-NMR (CDCl3) δ: to 3.52 (4H, t, J=5 Hz), 3,80 (4H, t, J=5 Hz), 6,37 (1H, d, J=9 Hz), of 7.36 was 7.45 (3H, m), 7,60-the 7.65 (2H, m), to 7.93 (1H, d, J=9 Hz).

d) 3-(2-Phenyl-6-morpholino-3-pyridyl)ethinyl-3-hinokitiol

A mixture of 500 mg of 2-phenyl-6-morpholino-3-iopidine, 230 mg of 3-ethinyl-3-hinokitiol, 79 mg of tetrakis(triphenylphosphine)-palladium (0), 1.3 mg of copper iodide, or 0.57 ml of triethylamine and 1 ml of N,N-dimethylformamide was heated with stirring for 4 hours on an oil bath at a temperature of 75°C in nitrogen atmosphere. The mixture was extracted by addition of dilute aqueous ammonia solution and ethyl acetate and the organic phase is washed with water and saturated rastvorimoi, was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on NH-silica gel and was suirable 50% ethyl acetate/hexane, ethyl acetate and then with 2.5% methanol/ethyl acetate to obtain 296 mg of the target compound.

1H-NMR (CDCl3) δ: 1,32-to 1.82 (3H, m), 1,94-2,03 (2H, m), 2,65-only 2.91 (4H, m), 2,95 (1H, d, J=14 Hz), 3,19 (1H, DD, J=2, 14 Hz), 3,62 (4H, t, J=5 Hz), 3,82 (4H, t, J=5 Hz), is 6.54 (1H, d, J=8 Hz), 7,34-7,44 (3H, m), a 7.62 (1H, d, J=8 Hz), 7,92 (2H, d, J=8 Hz).

Example 73: 3-(2-Vinyloxy-6-morpholino-3-pyridyl)ethinyl-3-hinokitiol

a) 2-Phenyloxy-6-morpholino-3-pyridine

250 mg of 60% oil suspension of sodium hydride were added to a mixture of 1 g of 2-bromo-6-morpholinopropan obtained in example 72 and 580 mg of phenol, 80 mg of copper iodide, 26 mg of copper powder and 3 ml of N-methylpyrrolidine. Once stopped foaming, the mixture was heated with stirring on an oil bath at 150°C for 3 hours in nitrogen atmosphere. Added dilute aqueous ammonia and ethyl acetate and the mixture was extracted. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel, using 5-7% ethyl acetate/hexane, to obtain 1.1 g of the target compound.

1H-NMR (CDCl3) δ: 3,40 (4H, t, J=5 Hz), 3,76 (4H, t, J=5 Hz), 6,11 (1H, d, J=8 Hz), 6,28 (1H, d, J=8 Hz), 15-7,19 (3H, m)of 7.36 (2H, t, J=8 Hz), 7,47 (1H, t, J=8 Hz).

b) 3-(2-Vinyloxy-6-morpholino-3-pyridyl)ethinyl-3-hinokitiol

The target compound was synthesized as in examples 72 C and d.

1H-NMR (CDCl3) δ: 1,34-to 2.06 (5H, m), 2,74-to 2.94 (4H, m)of 3.00 (1H, d, J=14 Hz), with 3.27 (1H, DD, J=2, 14 Hz), to 3.34 (4H, t, J=5 Hz), of 3.69 (4H, t, J=5 Hz), 6,24 (1H, d, J=8 Hz), 7,09-7,17 (3H, m), 7,34 (2H, t, J=4 Hz), 7,56 (1H, d, J=8 Hz).

Example 74: 3-[2-Benzyl-6-(4-piperidino-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,36 is 1.96 (3H, m), 2.00 in of 2.10 (2H, m), the 2.46 (4H, t, J=6 Hz), 2,72-2,96 (4H, m), 3.04 from (1H, d, J=14 Hz), 3,26 (1H, DD, J=2, 14 Hz), to 3.92 (4H, t, J=6 Hz), 4,18 (2H, s), is 6.54 (1H, d, J=8 Hz,), 7,14-to 7.32 (5H, m), 7,52 (1H, d, J=8 Hz).

Example 75: 3-[2-Benzyl-6-(2-methoxyethyl)amino-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,34-of 1.92 (3H, m), 1,98-2,07 (2H, m), 2,68 of 2.92 (4H, m), 3,01 (1H, d, J=14 Hz), up 3.22 (1H, DD, J=2, 14 Hz), 3,37 (3H, s)to 3.49 (2H, q, J=5 Hz), 3,55 (2H, t, J=5 Hz), 4,14 (2H, s), is 4.93 (1H, shirt, J=5 Hz), 6,21 (1H, d, J=8 Hz), 7,13-7,31 (5H, m), 7,40 (1H, d, J=8 Hz).

Example 76: 3-[2-Benzyl-6-(4-acetylpiperidine-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,34-of 1.44 (1H, m), 1,53-to 1.67 (3H, m), 1,83-of 2.08 (5H, m), 2,17 (3H, s)to 2.55 (1H, TT, J=4, 11 Hz), 2,68-2,96 (6N, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), is 4.15 (2H, s), 4,35 (2H, d, J=13 Hz), to 6.43 (1H, d, J=8 Hz), 7,17 (1H, t, J=7 Hz), 7,22-to 7.32 (4H, m), the 7.43 (1H, d, J=8 Hz).

Example 77: 3-[2-Benzyl-6-[(2R)-2-methoxypiperidine-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,36-2,10 (N, m), 2,74-2,95 (4H, m), 3.04 from (1H, d, J=14 Hz), 3,20-3,30 (MN, m)of 3.32 (3H, s), 3,40-to 3.49 (1H, m), 3,53 (1H, DD, J=3, 9 Hz), 4,06-4,30 (3H, m), 6,18 (1H, d, J=9 Hz), 7,16 (1H, t, J=7 Hz), 7,25 (2H, t, J=7 Hz), 7,33 (2H, d, J=7 Hz), 7,40 (1H, d, J=9 Hz).

Example 78: 3-[2-Benzyl-6-(thiomorpholine)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 191 using 2-benzyl-3-bromo-6-pyridinedicarboxylate (example obtaining 3) as the source.

1H-NMR (CDCl3) δ: 1,36-of 1.95 (3H, m), 1,97-of 2.08 (2H, m), 2,58-2,63 (4H, m), 2,70-2,95 (4H, m), 3,03 (1H, d, J=14 Hz)at 3.25 (1H, d, J=14 Hz), 3,94-3,99 (4H, m), is 4.15 (2H, s)6,40 (1H, d, J=9 Hz), 7,14-to 7.32 (5H, m), was 7.45 (1H, d, J=9 Hz).

Example 79: 3-[2-Benzyl-6-(3-hydroxypiperidine)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,36-to 1.98 (7H, m), 1,98-of 2.08 (2H, m), 2,70-2,95 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, d, J=14 Hz), 3,40-3,90 (5H, m), 4,14 (2H, s), 6,47 (1H, d, J=9 Hz), 7,12-to 7.32 (5H, m), 7,42 (1H, d, J=9 Hz).

Example 80: 3-[2-Benzyl-6-(4-cyanopiperidine)-3-pyridyl]-ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ =1,36-2,10 (N, m), 2,70-2,95 (5H, m), 3,03 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 3,47-,55 (2H, m), 3,81-to 3.89 (2H, m)to 4.16 (2H, s), of 6.45 (1H, d, J=9 Hz), 7,15-7,31 (5H, m), 7,47 (1H, d, J=9 Hz).

Example 81: 3-(2-Benzyl-6-piperidino-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,35-1,45 (1H, m), 1,52-to 1.82 (7H, m), 1.85 to 1,95 (1H, m), 2.00 in 2,07 (2H, m), 2,72-2,96 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), of 3.56 (4H, DD, J=5.6 Hz, 4.8 Hz), is 4.15 (2H, s), 6,41 (1H, d, J=8,8 Hz), 7,14-7,33 (5H, m), 7,41 (1H, d, J=8,8 Hz).

Example 82: 3-[2-Benzyl-6-(N-morpholino)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,35-of 1.95 (3H, m), 1,98-of 2.08 (2H, m), 2,70-of 2.93 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,53 (4H, t, J=5 Hz), with 3.79 (4H, t, J=5 Hz), 4,17 (2H, s)6,41 (1H, d, J=9 Hz), 7,14-to 7.32 (5H, m), 7,47 (1H, d, J=9 Hz)

Example 83: 3-[2-Benzyl-6-(4-tetrahydropyranyl)amino-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,35-of 1.95 (5H, m), 1,96-of 2.08 (4H, m), 2,70-of 2.93 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,50 (2H, dt, J=2, 12 Hz), 3.75 to of 3.85 (1H, m), 3,98 (2H, TD, J=4, 12 Hz), 4,14 (2H, C)a 4.53 (1H, d, J=8 Hz), 6,18 (1H, d, J=8 Hz), 7,14-to 7.32 (5H, m), 7,41 (1H, d, J= Hz).

Example 84; 3-[2-Benzyl-6-(1-pyrrolidinyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,57-to 1.67 (1H, m), 1,89-of 1.95 (1H, m)to 1.98 (4H, t, J=6.2 Hz), 2,01 is 2.10 (2H, m), 2,72 are 2.98 (4H, m), 3,05 (1H, d, J=14 Hz) of 3.25 (1H, d, J=14 Hz), of 3.45 (4H, t, J=6.2 Hz), 4,16 (2H, s), 6,14 (1H, d, J=8.6 Hz), 7,16-to 7.35 (5H, m), 7,40 (1H, d, J=8.6 Hz).

Example 85: 3-[2-Benzyl-6-(3-hydroxypyrrolidine-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,35-of 1.95 (3H, m), 1,98-of 2.20 (4H, m), 2,70-2,95 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, d, J=14 Hz), 3,50-the 3.65 (4H, m)to 4.16 (2H, s), 4,57-br4.61 (1H, m), 6,16 (1H, d, J=9 Hz), 7,16 (1H, t, J=7 Hz), 7,24 (2H, t, J=7 Hz), 7,32 (2H, d, J=7 Hz), 7,42 (1H, d, J=9 Hz).

Example 86: (3R)-3-[2-Benzyl-6-[(3R)-3-hydroxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,35-1,95 (MN, m), 1,98-of 2.20 (4H, m), 2,70-2,95 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, d, J=14 Hz), 3,50-the 3.65 (4H, m)to 4.16 (2H, s), 4,57-br4.61 (1H, m), 6,16 (1H, d, J=9 Hz), 7,16 (1H, t, J=7 Hz), 7,24 (2H, t, J=7 Hz), 7,32 (2H, d, J=7 Hz), 7,42 (1H, d, J=9 Hz).

Example 87: (3R)-3-[2-Benzyl-6-[(3S)-3-hydroxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,35-of 1.95 (3H, m), 1,98-of 2.20 (4H, m), 2,70-2,95 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, d, J=14 Hz), 3,50-the 3.65 (4H, m)to 4.16 (2H, s), 4,57-br4.61 (1H, m), 6,16 (1H, d, J=9 Hz), 7,16 (1H, t, J=7 Hz), 7,24 (2H, t, J=7 Hz), 7,32 (2H, d, J=7 Hz), 7,42 (1H, d, J=9 Hz).

Example 88: 3-[2-Benzyl-6-(1-azetidine)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,37-of 1.42 (1H, m), 1,52-of 1.62 (1H, m, 1,78 is 1.86 (1H, m), 1,98-2,07 (2H, m), is 2.37 (2H, quintet, J=7.4 Hz), 2.70 height of 2.92 (4H, m)of 3.00 (1H, d, J=14 Hz), 3,21 (1H, DD, J=2, 14 Hz), a 4.03 (4H, t, J=7.4 Hz), 4,16 (2H, s), equal to 6.05 (1H, d, J=8.5 Hz), 7,14-7,32 (5H, m), 7,40 (1H, d, J=8,5 Hz).

Example 89: (3R)-3-[2-Benzyl-6-(1-azetidine)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,37-of 1.42 (1H, m), 1,52-of 1.62 (1H, m), 1,78 is 1.86(1H, m), 1,98-2,07 (2H, m), is 2.37 (2H, quintet, J=7.4 Hz), 2.70 height of 2.92 (4H, m)of 3.00 (1H, d, J=14 Hz), 3,21 (1H, DD, J=2, 14 Hz), a 4.03 (4H, t, J=7,4 Hz), to 4.16 (2H, s), equal to 6.05 (1H, d, J=8.5 Hz), 7,14-to 7.32 (5H, m), 7,40 (1H, d, J=8,5 Hz).

Example 90: (3R)-3-[2-Benzyl-6-(3-hydroxyazetidine-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,40-of 1.95 (3H, m), 2.05 is-of 2.15 (2H, m), 2,65-2,95 (4H, m), 2,98-up 3.22 (2H, m), 3,88 (2H, DD, J=5, 10 Hz), 4,17 (2H, s), 4.26 deaths (2H, DD, 3=6, 10 Hz), the 4.65-of 4.75 (1H, m), 6,13 (1H, d, J=9 Hz), 7,10-then 7.20 (1H, m), 7,20-7,30 (4H, m), 7,44 (1H, d, J=9 Hz).

Example 91: 3-[2-Benzyl-6-(3-ethoxypyrrolidine-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 10.

1H-NMR (CDCl3) δ: 1,37-of 1.42 (1H, m), 1,52-of 1.62 (1H, m), 1,84-of 1.94 (1H, m), 1,98-of 2.20 (4H, m), 2,72-to 2.94 (4H, m), 3,01 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,36 (ZN, s), 3.46 in-to 3.64 (4H, m), as 4.02-4,08 (1H, m,), is 4.15 (2H, s), 6,13 (1H, d, J=8.6 Hz), 7,13-7,34 (5H, m), 7,40 (1H, d, J=8.6 Hz).

Example 92: (3R)-3-[2-Benzyl-6-[(3S)-3-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same way as the example 10.

1H-NMR (CDCl3) δ: 1,37-of 1.42 (1H, m), 1,52-of 1.62 (1H, m), 1,84-of 1.94 (1H, m), 1,98-of 2.20 (4H, m), 2,72-to 2.94 (4H, m), 3,01 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), to 3.36 (3H, s), 3.46 in-to 3.64 (4H, m), as 4.02-4,08 (1H, m,), is 4.15 (2H, s), 6,13 (1H, d, J=8.6 Hz), 7,13-7,34 (5H, m), 7,40 (1H, d, J=8.6 Hz).

Example 93: (3R)-3-[2-Benzyl-6-[(3R)-3-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 10.

1H-NMR (CDCl3) δ: 1,37-of 1.42 (1H, m), 1,52-of 1.62 (1H, m), 1,84-of 1.94 (1H, m), 1,98-of 2.20 (4H, m), 2,72-to 2.94 (4H, m), 3,01 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), to 3.36 (3H, s), 3.46 in-to 3.64 (4H, m), as 4.02-4,08 (1H, m,), is 4.15 (2H, s), 6,13 (1H, d, J=8.6 Hz), 7,13-7,34 (5H, m), 7,40 (1H, d, J=8.6 Hz).

Example 94: 3-[2-Benzyl-6-(3-ethoxypyrrolidine-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 10.

1H-NMR (CDCl3) δ: to 1.21 (3H, t, J=7.0 Hz), 1,35-1,45 (1H, m), 1,54-of 1.62 (1H, m), 1.85 to 1,95 (1H, m), 1,98-of 2.15 (4H, m), 2,72-to 2.94 (4H, m), 3,01 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,48-3,62 (6N, m), 4,12-4,20 (3H, m), 6,13 (1H, d, J=8.6 Hz), 7,13-7,34 (5H, m), 7,40 (1H, d, J=8.6 Hz).

Example 95: (3R)-3-[2-Benzyl-6-[(3R)-3-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 10.

1H-NMR (CDCl3) δ: to 1.21 (3H, t, J=7.0 Hz), 1,35-1,45 (1H, m), 1,54-of 1.62 (1H, m), 1.85 to 1,95 (1H, m), 1,98-of 2.15 (4H, m), 2,72-to 2.94 (4H, m), 3,01 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,48-3,62 (6N, m), 4,12-4,20 (3H, m), 6,13 (1H, d, J=8.6 HZ), 7,13-7,34 (5H, m), 7,40 (1H, d, J=8.6 Hz).

Example 96: (3R)-3-[2-Benzyl-6-[(3S)-3-ethoxypyrrolidine-1-yl]-3-pyridyl]this is Neil-3-hinokitiol

The target compound was synthesized as in example 10.

1H-NMR (CDCl3) δ: to 1.21 (3H, t, J=7 Hz), 1,35-1,45 (1H, m), 1,54-of 1.62 (1H, m), 1.85 to 1,95 (1H, m), 1,98-of 2.15 (4H, m), 2,72-to 2.94 (4H, m), 3,01 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,48-3,62 (6N, m), 4,12-4,20 (3H, m), 6,13 (1H, d, J=8.6 Hz), 7,13-7,34 (5H, m), 7,40 (1H, d, J=8.6 Hz).

Example 97: (3R)-3-[2-Benzyl-6-(ethoxypyridine)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7 using (3R)-3-ethinyl-3-hinokitiol.

1H-NMR (CDCl3) δ: 1,22 (3H, t, J=7 Hz), 1,35-of 1.44 (1H, m)and 1.51-of 1.62 (3H, m), 1,73 is 1.96 (3H, m), 1,97-of 2.08 (2H, m), 2,70-2,95 (4H, m), 3,01 (1H, d, J=14 Hz), 3,14-3,26 (3H, m), 3,48-to 3.58 (3H, m), EUR 4.00-4.09 to (2N, m), is 4.15 (2H, s), to 6.43 (1H, d, J=9 Hz), 7,16 (1H, t, J=7 Hz), 7,24 (2H, t, J=7 Hz), 7,30 (2H, d, J=7 Hz), 7,42 (1H, d, J=9 Hz).

Example 98: 3-[2-Benzyl-6-(3-methoxyisatin-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 10.

1H-NMR (CDCl3) δ: 1,35-1,90 (3H, m), 1,97-of 2.08 (2H, m), 2,70-2,95 (4H, m), 3,01 (1H, d, J=14 Hz), 3,21 (1H, DD, J=2, 14 Hz), to 3.34 (3H, s), 3,90 (2H, DD, J=4, 10 Hz)to 4.16 (2H, s), is 4.21 (2H, DD, J=6, 10 Hz), 4,30 is 4.35 (1H, m), 6,10 (1H, d, J=9 Hz), 7,16 (1H, t, J=7 Hz), 7,22-to 7.32 (4H, m), 7,42 (1H, d, J=9 Hz).

Example 99: (3R)-3-[2-Benzyl-6-(3-methoxyisatin-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 10, using (3R)-3-ethinyl-3-hinokitiol.

1H-NMR (CDCl3) δ: 1,35-1,90 (3H, m), 1,97-of 2.08 (2H, m), 2,70-2,95 (4H, m), 3,01 (1H, d, J=14 Hz), 3,21 (1H, DD, J=2 14 Hz), to 3.34 (3H, s), 3,90 (2H, DD, J=5, 10 Hz)to 4.16 (2H, s), is 4.21 (2H, DD, J=6, 10 Hz), 4,30 is 4.35 (1H, m), 6,10 (1H, d, J=9 Hz), 7,16 (1H, t, J=7 Hz), 7,22-to 7.32 (4H, m), 7,42 (1H, d, J=9 Hz).

Example 100: (3R)-3-[2-Benzyl-6-(3-ethoxyacetylene-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 10, using (3R)-3-ethinyl-3-hinokitiol.

1H-NMR (CDCl3) δ: of 1.24 (3H, t, J=7 Hz), 1,34-1,4 3 (1H, m)and 1.51-of 1.64 (1H, m), 1,80-1,90 (1H, m), 1,97-of 2.08 (2H, m), 2,66-of 2.93 (4H, m)of 3.00 (1H, d, J=14 Hz), 3,21 (1H, DD, J=2, 14 Hz), 3,49 (2H, q, J=7 Hz), 3,90 (2H, DD, J=4, 10 Hz)to 4.16 (2H, s), is 4.21 (2H, DD, J=6, 10 Hz), 4,37-of 4.44 (1H, m)6,09 (1H, d, J=8 Hz), 7,16 (1H, t, J=7 Hz), 7,24 (2H, t, J=7 Hz), 7,29 (2H, d, J=7 Hz), 7,41 (1H, d, J=8 Hz).

Example 101: (3R)-3-[2-Benzyl-6-(3-ethoxymethyleneamino-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 7.

1H-NMR (CDCl3) δ: 1,35-1,90 (3H, m), 1,97-of 2.08 (2H, m), 2,68-of 2.93 (4H, m)of 3.00 (1H, d, J=14 Hz), 3,21 (1H, DD, J=2, 14 Hz), to 3.41 (3H, s), of 3.94 (2H, DD, J=5, 10 Hz)to 4.16 (2H, s), 4.26 deaths (2H, DD, J=7, 10 Hz), 4,55-br4.61 (1H, m), of 4.67 (2H, s), 6,10 (1H, d, J=8 Hz), 7,16 (1H,T,J=7 Hz), 7,22-to 7.32 (4H, m), 7,42 (1H, d, J=9 Hz).

Example 102: 3-[4-Benzyl-2-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 10, except that methyliodide replaced by ethyliodide.

1H-NMR (CDCl3) δ: of 1.26 (3H, t, J=7 Hz), 1,38-to 1.63 (2H, m), 1,84-of 1.93 (1H, m), 2.00 in 2,07 (2H, m), 2,74-of 2.93 (4H, m), 3.00 and totaling 3.04 (1H, m), 3,21-of 3.25 (1H, m), 3,48-to 3.52 (2H, m), 3,61 (2H, q, J=7 G is), 3,71-of 3.77 (2H, m), 3,94-of 3.96 (1H, m), is 4.15 (2H, s), 4,37-and 4.40 (1H, m), x 6.15 (1H, d, J=8 Hz), 7,16-7,33 (5H, m), 7,42 (1H, d, J=8 Hz).

Example 103: (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 10.

1H-NMR (CDCl3) δ: 1,30-1,32 (1H, m), of 1.52 (1H, m), 1.77 in-1,99 (MN, m), 2,56-of 2.72 (4H, m), 2,82 (1H, d, J= Hz), 3,01 (1H, d, J=14 Hz), 3,50-of 3.53 (2H, m), 4,01-4,11 (4H, m), 5,10-5,11 (2H, m), of 6.26 (1H, d, J=8 Hz,), 7,14-7,34 (5H, m), 7,42 (1H, d, J=8 Hz).

Example 104: (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-dimethoxypyrimidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-[(3R,4R)-3,4-dimethoxypyrimidine-1-yl] pyridine

700 mg of 60% oil suspension of sodium hydride and 1 ml of methyliodide was added to a mixture of 1.78 g of 2-benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine (example 10A), 10 ml of tetrahydrofuran and 10 ml of N,N-dimethylformamide. The mixture was extracted with ethyl acetate-water. The organic layer was washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel and was suirable 15% ethyl acetate/hexane to obtain 1.0 g of the target compound.

1H-NMR (CDCl3) δ: 3,42 (6N, (C), 3,55 (2H, DD, J=2, 11 Hz), to 3.67 (2H, DD, J=4, 11 Hz), 3,92-of 3.96 (2H, m), of 3.97 (2H, s), 6,16 (1H, d, J=9 Hz), 6,33 (1H, d, J=7 Hz), 7,18 (1H, t, J=7 Hz), 7.24 to 7,34 (5H, m).

b) (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-dimethoxypyrimidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

Target connection is out synthesized in the same way, as in example 10.

1H-NMR (CDCl3) δ: 1,34-of 1.44 (1H, m), 1,52-of 1.62 (1H, m), 1,82-of 1.92 (1H, m), 1,97-of 2.08 (2H, m), 2,70-2,95 (4H, m), 3,01 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,41 (6N, (C), 3,53-to 3.67 (4H, m), 3,92-of 3.96 (2H, m,), to 4.16 (2H, s), 6,14 (1H, d, J=9 Hz), to 7.15 (1H, t, J=7 Hz), 7,24 (2H, t, J=7 Hz), 7,31 (2H, d, J=7 Hz), 7,40 (1H, d, J=9 Hz).

Example 105: (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-detoxification-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 104, using (3R)-3-ethinyl-3-hinokitiol.

1H-NMR (CDCl3) δ: 1,20 (6N, t, J=7 Hz), 1,35-of 1.95 (3H, m), 1,98-of 2.09 (2H, m), 2,70-2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 3,50 of 3.56 (2H, m)and 3.59 (4H, q, J=7 Hz), to 3.67 (2H, DD, J=4, 12 Hz), was 4.02 (2H, DD, J=2, 4 Hz), is 4.15 (2H, s), 6,14 (1H, d, J=9 Hz), to 7.15 (1H, t, J=7 Hz), 7,24 (2H, t, J=7 Hz), 7,32 (2H, d, J=7 Hz), 7,40 (1H, d, J=9 Hz).

Example 106: (3R)-3-[2-Benzyl-6-[(3R,4S)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-iodine-6-[(3S,4S)-3-(3-nitrobenzenesulfonyl)hydroxy-4-ethoxypyrrolidine-1-yl]pyridine

300 mg of 4-Dimethylaminopyridine, 10 ml of triethylamine and 9.7 g of 3-nitrobenzenesulfonamide was added to a solution of 10.0 g of 2-benzyl-3-iodine-6-[(3S,4S)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine obtained in the same manner as in example 10C, in 150 ml of ethyl acetate, followed by stirring at room temperature for 3 days. The reaction solution was first filtered through 50 g of silica gel and washed with ethyl acetate. Next, the filtrate passes the through 50 g of NH-silica gel and washed with ethyl acetate. The filtrate was concentrated to obtain 14.6 g of the target compound.

1H-NMR (CDCl3) δ: to 3.38 (3H, s), 3,48 (1H, d, J=12 Hz), to 3.58-to 3.73 (3H, m), 4,08-4,20 (3H, m), 5,10-5,14 (1H, m), of 5.92 (1H, d, J=8 Hz), 7,18 (1H, t, J=7 Hz), 7,25 (2H, t, J=7 Hz), 7,32 (2H, d, J=7 Hz), of 7.69 (1H, d, J=8 Hz), 7,73 (1H, t, J=8 Hz), 8,21 (1H, d, J=8 Hz), 8,49 (1H, d, J=8 Hz), is 8.75 (1H, s).

b) 2-Benzyl-3-iodine-6-[(3R,4S)-3-acetoxy-4-ethoxypyrrolidine-1-yl]pyridine

4,2 ml of Acetic acid was added to a mixture of 7.9 g of cesium carbonate and 15 ml of dimethyl sulfoxide. After foaming ceased, was added a mixture of 14.4 G. of 2-benzyl-3-iodine-6-[(3S,4S)-3-(3-nitrobenzenesulfonyl)hydroxy-4-ethoxypyrrolidine-1-yl]pyridine and 35 ml of dimethylsulfoxide, followed by heating under stirring for 6 hours at an oil bath at a temperature of 70°C in nitrogen atmosphere. The reaction solution was cooled and then subjected to extraction with ethyl acetate-water. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel using 10-15% ethyl acetate/hexane, to obtain 7.5 g of the target compound.

1H-NMR (CDCl3) δ: 2,12 (3H, s), 3,42 (3H, s), 3,37-3,7 3 (4H, m), Android 4.04 (1H, dt, J=4, 6 Hz), 4,19 (2H, s), 5,42-vs. 5.47 (1H, m), 5,96 (1H, d, J=8 Hz), 7,19 (1H, t, J=7 Hz), 7,27 (2H, t, J=7 Hz), 7,38 (2H, d, J=7 Hz), of 7.70 (1H, d, J=8 Hz).

C) 2-Benzyl-3-iodine-6-[(3R,4S)-3-hydroxy-4-ethoxypyrrolidine-yl]pyridine

28% solution of sodium methoxide in 0.33 ml of methanol was added to a mixture of 7.5 g of 2-benzyl-3-iodine-6-[(3R,4S)-3-acetoxy-4-ethoxypyrrolidine-1-yl]pyridine and 30 ml of methanol, followed by stirring at room temperature for 30 minutes in nitrogen atmosphere. Added water and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel using 20-50% ethyl acetate, to obtain 6.7 g of the target compound.

1H-NMR (CDCl3) δ: 2,63 (1H, d, J=5 Hz), 3,38-to 3.67 (4H, m), 3,47 (3H, s), 3,93 (1H, q, J=5 Hz), 4,18 (2H, s)to 4.41 (1H, Quint., J=5 Hz), 5,96 (1H, d, J=9 Hz), 7,18 (1H, t, J=7 Hz), 7,26 (2H, t, J=7 Hz), 7,37 (2H, d, J=7 Hz), 7,69 (1H, d, J=9 Hz).

d) (3R)-3-[2-Benzyl-6-[(3R,4S)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 4.6 g of 2-benzyl-3-iodine-6-[(3R,4S)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine, 1.7 g (3R)-3-ethinyl-3-hinokitiol, 130 mg of tetrakis(triphenylphosphine)palladium (0), 110 mg of copper iodide and 3.1 ml of triethylamine was stirred for 5 hours at room temperature in a nitrogen atmosphere. The reaction solution was extracted with dilute aqueous solution of ammonia-ethyl acetate and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to the Lee column chromatography on NH-silica gel, using 0-5% methanol/ethyl acetate, to obtain 4.0 g of the target compound.

1H-NMR (CDCl3) δ: 1,34-of 1.93 (3H, m), 1,97-2,07 (2H, m), 2,63-to 2.94 (5H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,41 is 3.57 (2H, m), of 3.48 (3H, s), 3,60-to 3.73 (2H, m), of 3.94 (1H, q, J=5 Hz)to 4.41 (1H, kV, J=5 Hz), 6,12 (1H, d, J=9 Hz), 7,16 (1H, t, J=7 Hz), 7,24 (2H, t, J=7 Hz), 7,31 (2H, d, J=7 Hz), 7,41 (1H, d, J=9 Hz).

Example 107: (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-debtorprovidian-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-[(3R,4R)-3,4-debtorprovidian-1-yl]pyridine

3.0 ml of dichloromethane solution containing 481 mg of 2-benzyl-6-[(3S,4S)-3,4-dihydroxypyrrolidine-1-yl)-3-pyridine, slowly, was added dropwise in 5 ml of dichloromethane solution containing 235 μl of the TRIFLUORIDE diethylaminoethyl at -78°C. After stirring under heating for 30 minutes at room temperature, the mixture was further stirred for one hour at 40°C. After cooling, to the reaction solution were added water and the mixture was then extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (5:1), and then hexane/ethyl acetate (2:1) to give 104 mg of the target compound.

1H-NMR (CDCl3) δ: 3,71-3,93 (4H, m)to 3.99 (2H, s), 5,19-of 5.34 (2H, m), to 6.19 (1H, d, J=8 Hz), 6.42 per (1H, d, J=7 Hz), 7,21-7,38 (6N, m).

b) 2-Benzyl-6-[(3R,4R)-3,4-deftoner ridin-1-yl]-3-yodellin

94 mg of imide N-jocantaro acid in small portions was added to 5 ml of N,N-dimethylformamide solution containing 104 mg of 2-benzyl-6-[(3R,4R)-3,4-debtorprovidian-1-yl]pyridine under ice cooling, followed by stirring overnight. To the reaction solution were added water and the mixture was extracted with ethyl acetate. The organic phase is washed with aqueous sodium thiosulfate solution, water and saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (10:1) to give 152 mg of the target compound.

1H-NMR (CDCl3) δ: 3,66-3,86 (4H, m), 4,20 (2H, s), 5,18-5,33 (2H, m), 6,01 (1H, d, J=9 Hz), 7.18 in-7,38 (5H, m), 7,74 (1H, d, J=9 Hz).

(C) (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-debtorprovidian-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 152 mg of 2-benzyl-6-[(3R,4R)-3,4-debtorprovidian-1-yl]-3-iopidine, 60 mg of (3R)-3-ethinyl-3-hinokitiol, 22 mg of tetrakis(triphenylphosphine)palladium (0), 7 mg of copper iodide, 106 μl of triethylamine and 1.5 ml of methanol was heated under stirring for 3 hours at 75°C in nitrogen atmosphere. The reaction solution was poured into dilute aqueous ammonia solution and then was extracted with ethyl acetate. The extract was washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia), was suirable hexane/et is lacerata (1:1), and then ethyl acetate/methanol (15:1) and was led from a mixture of hexane/ethyl acetate to obtain 65 mg of the target compound.

1H-NMR (CDCl3) δ: 1,37-of 1.44 (1H, m), 1,58 (1H, m), 1,88-1,89 (1H, m), 2,02-of 2.05 (2H, m), 2,75-is 2.88 (4H, m), 3,03 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 3.75 to 3,93 (4H, m), 4,18 (2H, s), 5,19-of 5.34 (2H, m), to 6.19 (1H, d, J=9 Hz), 7,16-7,33 (5H, m), 7,47 (1H, d, J=9 Hz).

Example 108: (3R)-3-[2-Benzyl-6-[(3R)-3-ftorpirimidinu-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized from (3S)-1-benzyl-3-pyrrolidinone the same way as in example 107.

1H-NMR (CDCl3) δ: 1,37-to 1.61 (2H, m), 1,86-of 1.94 (1H, m), 2.00 in 2,19 (3H, m), 2,33-to 2.42 (1H, m), 2,75-2,90 (4H, m), 3,03 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 3,52-are 3.90 (4H, m), 4,17 (2H, s), from 5.29-5,43 (1H, m,), 6,18 (1H, d, J=8 Hz), 7,15-7,34 (5H, m), 7,44 (1H, d, J=8 Hz).

Example 109: (3R)-3-[2-Benzyl-6-[(3S)-3-ftorpirimidinu-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized from (3R)-1-benzyl-3-pyrrolidinone the same way as in example 107.

1H-NMR (CDCl3) δ: 1,37-to 1.60 (2H, m), 1,86-of 1.93 (1H, m), 1,99-2,19 (3H, m), 2,32-to 2.42 (1H, m), 2,75-2,90 (4H, m), 3,03 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 3,52-are 3.90 (4H, m), 4,17 (2H, s), from 5.29-5,43 (1H, m,), 6,18 (1H, d, J=8 Hz), 7,15-7,34 (5H, m), 7,44 (1H, d, J=8 Hz).

Example 110: (3R)-3-[2-Benzyl-6-[(3S,4R)-3-fluoro-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized using 2-benzyl-3-iodine-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine (example 10) as in example 107.

1 H-NMR (CDCl3) δ: 1,39-of 1.44 (1H, m), 1,57-to 1.63 (1H, m), 1,87-of 1.93 (1H, m), 2,02-to 2.06 (2H, m), 2,75-2,89 (4H, m), 3,03 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 3.43 points (3H, s), 3,66-of 3.80 (4H, m), 4,06-4.09 to (1H, m,), to 4.16 (2H, s), 5.08 to a total of 5.21 (1H, m), 6,16 (1H, d, J=9 Hz), 7,14-to 7.32 (5H, m), the 7.43 (1H, d, J=9 Hz).

Example 111: (3R)-3-[2-Benzyl-6-[(3R,4S)-3-hydroxy-4-ftorpirimidinu-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Bromo-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine

A mixture of 12.8 g of 2,6-dibromopyridine, 8,87 g of (3R,4R)-3,4-dihydroxypyrrolidine, 10 ml of 1,8-diazabicyclo[5,4,0]-7-undecene and 20 ml of 1-methyl-2-pyrrolidinone was heated with stirring for 2 hours at an oil bath at 70°C. After cooling was added water and the mixture was extracted with ethyl acetate five times. The organic layers were combined, washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel using 10-100% ethyl acetate/hexane, to obtain 10.1 g of the target compound.

1H-NMR (CDCl3) δ: to 1.86 (2H, Sirs), 3,49 (2H, d, J=11 Hz), 3,80 (2H, DD, J=4, 11 Hz), 4,34 (2H, Sirs), of 6.26 (1H, d, J=8 Hz), of 6.71 (1H, d, J=8 Hz), 7,26 (1H, t, J=8 Hz).

b) 2-Bromo-6-[(3R,4R)-3-methoxyethoxy-4-hydroxypyrrolidine-1-yl]pyridine

To a mixture of 10 g of 2-bromo-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine and 100 ml of tetrahydrofuran at room temperature was added under stirring 1.54 g of 60% oil suspension of sodium hydride, and then the 3.0 is l chloromethylmethylether ether, followed by stirring at the same temperature for one hour. The reaction solution was extracted with ethyl acetate-water and the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel using 10-100% ethyl acetate/hexane, to obtain 7.6 g of the target compound.

1H-NMR (CDCl3) δ: 2,95 (1H, d, J=4 Hz), 3,36-3,50 (2H, m), 3,44 (3H, s), 3,78-3,88 (2H, m), 4,06-of 4.12 (1H, m), 4,32-to 4.38 (1H, m), 4.72 in (1H, d, J=7 Hz), was 4.76 (1H, d, J=7 Hz), 6,24 (1H, d, J=8 Hz), 6,70 (1H, d, J=8 Hz), 7,25 (1H, t, J=8 Hz).

c) 2-Benzyl-6-[(3R,4R)-3-methoxyethoxy-4-hydroxypyrrolidine-1-yl]pyridine

46,7 ml tertrahydrofuran ring solution containing 1.07 mol benzylaniline was added dropwise in 50 ml of tertrahydrofuran ring solution containing 5.1 g of 2-bromo-6-[(3R,4R)-3-methoxyethoxy-4-hydroxypyrrolidine-1-yl] pyridine and 451 mg chloride 1,3-bis(diphenylphosphino) propenies (II) for 10 minutes in an ice bath. After cooling overnight, the reaction solution was poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (10:1), and then hexane/ethyl acetate (1:1) to obtain 5.2 g of the target compound.

1H-NMR (CDCl3) δ: of 3.45 (3H, what), 3,36-3,47 (2H, m), 3,85-3,91 (2H, m), of 3.97 (2H, s), 4,05-4,11 (1H, m), 4,32 is 4.35 (1H, m), 4,73-rate 4.79 (2H, m), 6,16 (1H, d, J=8 Hz), 6,37 (1H, d, J=8 Hz), 7,17-7,38 (6N, m).

d) 2-Benzyl-6-[(3R,4S)-3-methoxyethoxy-4-ftorpirimidinu-1-yl]pyridine and 2-benzyl-6-[(3R,4S)-3-formatosi-4-ethoxypyrrolidine-1-yl]pyridine

5.0 ml dichloromethane solution of 2-benzyl-6-[(3R,4R)-3-methoxyethoxy-4-hydroxypyrrolidine-1-yl]pyridine was added dropwise in 10 ml of dichloromethane solution containing 278 μl of the TRIFLUORIDE diethylaminoethyl at -78°C for 10 minutes. After stirring at room temperature for one hour the mixture was heated under stirring at 40°C for one hour. After cooling, the reaction solution was poured into water. The mixture was extracted with ethyl acetate, the organic phase is washed with saturated salt solution and the solvent was removed. Then the residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (10:1), and then hexane/ethyl acetate (2:1) obtaining of 56.7 mg of 2-benzyl-6-[(3R,4S)-3-methoxyethoxy-4-ftorpirimidinu-1-yl]pyridine (1H-NMR (CDCl3) δ: to 3.38 (3H, s), 3,65-3,82 (4H, m), of 3.97 (2H, s), to 4.41-4,43 (1H, m), 4,69-of 4.75 (2H, m), is 5.18 (1H, sird, J=49 Hz), 6,18 (1H, d, J=8 Hz), 6,38 (1H, d, J=7 Hz), 7,01 and 7.36 (6N, m)) and 294 mg of a crude product of 2-benzyl-6-[(3R,4S)-3-formatosi-4-ethoxypyrrolidine-1-yl]pyridine. The crude product was purified by thin-layer chromatography (threefold manifestation, ISOE is isua hexane/ethyl acetate (5/1) and three times using hexane/ethyl acetate (4/1)) with the receipt of 47.8 g of 2-benzyl-6-[(3R,4S)-3-(formatosi)-4-ethoxypyrrolidine-1-yl]pyridine ( 1H-NMR (CDCl3) δ: of 3.48 (3H, s), 3,54-to 3.73 (4H, m), of 3.97 (2H, s), 4,00-Android 4.04 (1H, m), to 4.41-to 4.46 (1H, m), 5,41 (2H, d, J=56 Hz), x 6.15 (1H, d, J=8 Hz), 6,37 (1H, d, J=7 Hz), 7,17-7,35 (6N, m)).

e) 2-Benzyl-6-[(3R,4S)-3-methoxyethoxy-4-ftorpirimidinu-1-yl]-3-yodellin

44,4 mg imide N-jocantaro acid was added in small portions to a solution containing of 56.7 mg of 2-benzyl-6-[(3R,4S)-3-methoxyethoxy-4-ftorpirimidinu-1-yl]pyridine and 3.0 ml of N,N-dimethylformamide, with stirring under ice cooling, followed by stirring overnight. To the reaction solution were added water and then extracted with ethyl acetate. The organic phase is successively washed with aqueous sodium thiosulfate solution, water and saturated salt solution and the solvent was removed. The residue was suirable with ethyl acetate through NH-silica gel (Fuji Silicia) obtaining 73,4 mg of target compound.

1H-NMR (CDCl3) δ: to 3.36 (3H, s), to 3.58 is 3.76 (4H, m), 4,19 (2H, s), 4,37-to 4.41 (1H, m), 4,70 (2H, s), 5,09 with 5.22 (1H, m)6,00 (1H, d, J=9 Hz), 7,16-7,38 (5H, m), of 7.70 (1H, d, J=9 Hz).

f) 2-Benzyl-6-[(3R,4S)-3-hydroxy-4-ftorpirimidinu-1-yl]-3-yodellin

The mixture 73,4 mg of 2-benzyl-6-[(3R,4S)-3-methoxyethoxy-4-ftorpirimidinu-1-yl]-3-iopidine and 5.0 ml triperoxonane acid was heated with stirring for 2 hours at 45°C. After cooling, it was poured into aqueous potassium carbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated dissolve the Ohm salt and the solvent was removed. Then the residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (5:1), and then hexane/ethyl acetate (1:1) to obtain 50 mg of the target compound.

1H-NMR (CDCl3) δ: 3.46 in-3,82 (4H, m), 4,19 (2H, s), 4,48-4,51 (1H, m), 5,04 (1H, sird, J=52 Hz), 6,00 (1H, d, J=9 Hz), 7,16-7,38 (5H, m), 7,71 (1H, d, J=9 Hz).

g), (3R)-3-[2-Benzyl-6-[(3R,4S)-3-hydroxy-4-ftorpirimidinu-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 50 mg of 2-benzyl-6-[(3R,4S)-3-hydroxy-4-ftorpirimidinu-1-yl]-3-iopidine, 21 mg of (3R)-3-ethinyl-3-hinokitiol, 15 mg of tetrakis(triphenylphosphine)palladium (0), 1 mg of copper iodide, 53 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated with stirring for 3 hours at 75°C in nitrogen atmosphere. The reaction solution was poured into diluted aqueous ammonia, then extracted with ethyl acetate. Then the organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (1:1)and then ethyl acetate/methanol (15:1) to give 37 mg of the target compound.

1H-NMR (CDCl3) δ: 1,35 was 1.43 (1H, m), 1.56 to was 1.58 (1H, m), 1,85-1,90 (1H, m), 2,01-of 2.16 (2H, m), 2,73-of 2.86 (4H, m), 2,97-of 3.00 (1H, m), 3.15 and 3.21-in (1H, m), 3,57-3,86 (4H, m), is 4.15 (2H, s), 4,47-of 4.49 (1H, m), 5,04 (1H, shirt, J=52 Hz), 6,14 (1H, d, J=9 Hz), 7,15-to 7.32 (5H, m), 7,42 (1H, d, J=9 Hz).

Example 112: (3R)-3-[2-Benzyl-6-[(3R,4S)-3-(formatosi)-4-methoxime ridin-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-[(3R,4S)-3-(formatosi)-4-ethoxypyrrolidine-1-yl]-3-yodellin

37,4 mg N-jodatime small portions was added to the solution containing of 47.8 mg of 2-benzyl-6-[(3R,4S)-3-(formatosi)-4-ethoxypyrrolidine-1-yl]pyridine obtained in example 111, and 4.0 ml of N,N-dimethylformamide, with stirring in an ice bath, followed by stirring overnight. To the reaction solution were added water and the mixture was extracted with ethyl acetate. The organic phase is successively washed with aqueous sodium thiosulfate solution, water and saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (5:1), and then hexane/ethyl acetate (3:1) to obtain 43,9 mg of target compound.

1H-NMR (CDCl3) δ: 3,47 (H, C), 3,48-of 3.64 (4H, m), 3,97-a 4.03 (1H, m), 4,19 (2H, s), to 4.41 was 4.42 (1H, m), of 5.40 (2H, d, J=56 Hz), 5,97 (1H, d, J=9 Hz), 7,17-7,38 (5H, m), of 7.70 (1H, d, J=9 Hz).

b) (3R)-3-[2-Benzyl-6-[(3R,4S)-3-(formatosi)-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The mixture 43,9 mg of 2-benzyl-6-[(3R,4S)-3-(formatosi)-4-ethoxypyrrolidine-1-yl]-3-iopidine, 16,5 mg (3R)-3-ethinyl-3-hinokitiol, and 11.5 mg of tetrakis(triphenylphosphine)palladium (0), 0.9 mg of copper iodide, 42 μl of triethylamine and 3.0 ml of MM-dimethylformamide was heated with stirring for 1 hour at 75°C in nitrogen atmosphere. The reaction solution was crying with the Ali in dilute aqueous ammonia solution and then the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (1:1)and then ethyl acetate/methanol (15:1) to give 33 mg of the target compound.

1H-NMR (CDCl3) δ: 1,34-of 1.42 (1H, m), 1,54-of 1.62 (1H, m), 1,85-1,90 (1H, m), 1,99-2,07 (2H, m), 2,73-only 2.91 (4H, m), 3,01 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,48 (3H, s), 3,54-to 3.58 (1H, m), 3,65 at 3.69 (3H, m), 3,99-a 4.03 (1H, m), is 4.15 (2H, s), to 4.41 is 4.45 (1H, m), of 5.40 (2H, d, J=56 Hz), 6,13 (1H, d, J=9 Hz), 7,13-7,40 (5H, m), 7,42 (1H, d, J=9 Hz).

Example 113: (3R)-3-[2-Benzyl-6-[(3S,4R)-3-chloro-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-[(3S,4R)-3-(3-nitrobenzenesulfonyl)hydroxy-4-ethoxypyrrolidine-1-yl]-3-yodellin

A mixture of 1.0 g of 2-benzyl-3-iodine-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine (example 10C), 1.0 g of 3-nitrobenzenesulfonamide, 0.1 g of 4-dimethylaminopyridine and 5 ml of pyridine was stirred at room temperature overnight. To the reaction solution were added water and the mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (5:1), and then hexane/ethyl acetate (2:1) to give 1.23 g of the target compound.

1H-ANR (CDCl3) δ: to 3.38 (3H, s), 3,47-3,51 (1H, m), 3,61-3,3 (3H, m), 4,11-4,16 (3H, m), 5,11-5,12 (1H, m)5,94 (1H, d, J=9 Hz), 7.18 in-7,33 (5H, m), 7.68 per-7,76 (2H, m), 8,20 is 8.22 (1H, m), 8,48-8,51 (1H, m), is 8.75 (1H, s).

b) 2-Benzyl-6-[(3S,4R)-3-chloro-4-ethoxypyrrolidine-1-yl]-3-yodellin

The mixture 553 g of 2-benzyl-6-[(3S,4R)-3-(3-nitrobenzenesulfonyl)hydroxy-4-ethoxypyrrolidine-1-yl]-3-iopidine, 79 mg of lithium chloride and 5.0 ml of N,N-dimethylformamide was heated with stirring at 75°C for 9 hours. After cooling, to the reaction mixture were added water and the mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (10:1), and then hexane/ethyl acetate (5:1) to give 391 mg of the target compound.

1H-NMR (CDCl3) δ: of 3.48 (3H, s), 3,48-3,51 (1H, m), 3,65 at 3.69 (1H, m), 3,83-of 3.85 (2H, m), of 4.05-4.09 to (1H, m), 4,19 (2H, s), 4,55-4,58 (1H, m), 5,97 (1H, d, J=9 Hz), 7.18 in-7,38 (5H, m), 7,72 (1H, d, J=9 Hz).

c) (3R)-3-[2-Benzyl-6-[(3S,4R)-3-(3-chloro-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 391 mg of 2-benzyl-6-[(3S,4R)-3-chloro-4-ethoxypyrrolidine-1-yl]-3-iopidine, 152 mg of (3R)-3-ethinyl-3-hinokitiol, 105 mg of tetrakis(triphenylphosphine)palladium (0), 9 mg of copper iodide, of 0.38 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated with stirring for 4 hours at 75°C in an atmosphere of nitrogen with subsequent removal of solvent. The residue was subjected to column items is matography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (1:1), and then ethyl acetate/methanol (20:1) and then was led from a mixture of hexane/ethyl acetate to obtain 150 mg of the target compound.

1H-NMR (CDCl3) δ: 1,46-of 1.53 (1H, m), 1,64-of 1.92 (2H, m), 2,04-2,12 (2H, m), 2,82-of 2.97 (4H, m), 3,11 (1H, d, J=14 Hz), 3,29 (1H, DD, J=2, 14 Hz), 3,49 (3H, s), 3,52 of 3.56 (1H, m), 3,70 of 3.75 (1H, m), 3,85-3,91 (2H, m,), 4,06-4,11 (1H, m), is 4.15 (2H, s), 4,57-4,60 (1H, m), x 6.15 (1H, d, J=9 Hz), 7,17-7,30 (5H, m), 7,44 (1H, d, J=9 Hz).

Example 114: (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-atlantooccipital-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Bromo-6-[(3R,4R)-3-methoxyethoxy-4-[2-(tetrahydro-2H-2-pyranyloxy)ethyl]oxopyrrolidin-1-yl]pyridine

3.88 g of 60% oil suspension of sodium hydride in small portions was added to a solution of 50 ml of N,N-dimethylformamide, containing of 14.7 g of 2-bromo-6-[(3R,4R)-3-methoxyethoxy-4-hydroxypyrrolidine-1-yl]pyridine (example 111b), with stirring in an ice bath. The mixture was stirred for 10 minutes in an ice bath, and then for 20 minutes at room temperature. Then gradually dropwise added 14.7 ml 2-(2-bromacil)oxythyrea-2H-Piran in an ice bath. The reaction solution was stirred at room temperature for 20 minutes and then at 60°C for 20 minutes. Further at room temperature was added 7.4 ml of 2-(2-bromacil)oxythyrea-2H-Piran followed by heating under stirring at 60°C for 30 minutes. After cooling, the reaction solution was poured into the ode and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (3:1) and then with hexane/ethyl acetate (2:1) to obtain the 17,58 g g target compound.

1H-NMR (CDCl3) δ: 1,50-to 1.59 (4H, m), 1,67 of-1.83 (2H, m), 3,39 (3H, s), 3,48-3,61 (4H, m), 3,67 of 3.75 (4H, m), 3,82-3,88 (2H, m), 4,13-to 4.14 (1H, m), or 4.31-4,34 (1H, m), br4.61-4,63 (1H, m), 4,70-4,74 (2H, m), and 6.25 (1H, d, J=8 Hz), 6,69 (1H, d, J=7 Hz), 7,22-7,27 (1H, m).

b) 2-Bromo-6-[(3R,4R)-3-methoxyethoxy-4-[2-(hydroabietyl)oxopyrrolidin-1-yl]pyridine

of 2.26 g of the monohydrate of p-toluensulfonate acid was added dropwise 60 ml of a methanol solution containing 17,09 g of 2-bromo-6-[(3R,4R)-3-methoxyethoxy-4-[2-(tetrahydro-2H-2-pyranyloxy)ethyl]oxopyrrolidin-1-yl]pyridine, in an ice bath. After stirring for 30 minutes under ice cooling and the mixture was stirred at room temperature for 2 hours. Next was added 377 mg of the monohydrate of p-toluensulfonate acid, followed by stirring for 2 hours. Then the reaction solution was poured into aqueous saturated sodium bicarbonate solution and was extracted twice with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was filtered through silica gel with getting 13,14 g of target compound.

1H-NMR (CDCl3) δ: 3,39 (3H, s) 3,53 of 3.56 (2H, m), 3,66-3,75 (6N, m), 4,10-4,13 (1H, m), 4,30-or 4.31 (1H, m), 4,70-4,74 (2H, m), and 6.25 (1H, d, J=8 Hz), 6,70 (1H, d, J=8 Hz), 7.24 to 7,28 (1H, m).

C) 2-Bromo-6-[(3R,4R)-3-methoxyethoxy-4-[2-(methanesulfonate)ethyl]oxopyrrolidin-1-yl]pyridine

7.9 ml of triethylamine was slowly added to a solution of 70 ml of dichloromethane containing 13,14 g of 2-bromo-6-[(3R,4R)-3-methoxyethoxy-4-[2-(hydroabietyl)oxopyrrolidin-1-yl]-pyridine, in an ice bath. Then slowly added to 3.2 ml of methanesulfonanilide, followed by stirring for 15 minutes. Then the reaction solution was poured into water and was extracted twice with dichloromethane. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was filtered through NH-silica gel with getting 15,66 g of target compound.

1H-NMR (CDCl3) δ: of 3.00 (3H, s)to 3.38 (3H, s), 3,52-3,59 (2H, m), 3,66-and 3.72 (2H, m), 3,82-a-3.84 (2H, m), 4,10-to 4.15 (1H, m), 4,28-4,30 (1H, m), 4,33 is 4.35 (2H, m), 4,71 (2H, s), and 6.25 (1H, d, J=8 Hz), of 6.71 (1H, d, J=8 Hz), 7.24 to 7,28 (1H, m).

d) 2-Bromo-6-[(3R,4R)-3-hydroxy-4-[2-(methanesulfonylaminoethyl)oxopyrrolidin-1-yl]pyridine

2.0 ml of concentrated sulfuric acid slowly dropwise added to 160 ml of a methanol solution containing 15,66 g of 2-bromo-6-[(3R,4R)-3-methoxyethoxy-4-(2-methanol-phenylacetyl)oxopyrrolidin-1-yl]pyridine, with stirring in an ice bath. The reaction solution was stirred at room temperature for 10 minutes and then at 50°in ECENA 45 minutes. Next, after adding back dropwise 1.0 ml of concentrated sulfuric acid and the mixture was stirred at 50°C for one hour. After cooling, the reaction mixture was poured into aqueous potassium carbonate solution and was extracted twice with ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was filtered through silica gel with getting 11,82 g of target compound.

1H-NMR (CDCl3) δ: a 3.01 (3H, s), 3,44 of 3.56 (2H, m), 3,69-a 3.87 (4H, m), 4,01-Android 4.04 (1H, m), 4,34-4,37 (2H, m), of 4.44 is 4.45 (1H, m), and 6.25 (1H, d, J=8 Hz), 6,72 (1H, d, J=7 Hz), 7.24 to 7,28 (1H, m).

e) 2-Bromo-6-[(3R,4R)-3,4-atlantooccipital-1-yl]-pyridine

1,49 g of 60% oil suspension of sodium hydride in small portions was added to 150 ml of N,N-dimethylformamide solution containing 11,82 g of 2-bromo-6-[(3R,4R)-3-hydroxy-4-(2-methanesulfonylaminoethyl)oxopyrrolidin-1-yl]pyridine, with stirring in an ice bath. Then after stirring at room temperature for one hour was added to 372 mg of 60% oil suspension of sodium hydride. After stirring for a further 45 minutes the reaction mixture was poured into water and was extracted twice with ethyl acetate. The organic phase is washed with water and saturated salt solution and the solvent was removed. The residue was led from a mixture of ethyl acetate/hexane to obtain 5.35 g of the target compound.

p> 1H-NMR (CDCl3) δ: 3,20-of 3.25 (2H, m), of 3.73-to 3.92 (8H, m), 6,23 (1H, d, J=8 Hz), 6.73 x (1H, d, J=8 Hz), 7,25-7,29 (1H, m).

f) 2-Benzyl-6-[(3R,4R)-3,4-atlantooccipital-1-yl]-pyridine

26,6 mol tertrahydrofuran ring solution containing 1.06 mol benzylaniline was added dropwise 100 ml of tertrahydrofuran ring solution containing 5.3 g of 2-bromo-6-[(3R,4R)-3,4-atlantooccipital-1-yl]pyridine and 509 mg chloride 1,3-bis(diphenylphosphino)propenies (II), for 10 minutes under ice cooling. After stirring at room temperature overnight, the reaction solution was poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (10:1), and then hexane/ethyl acetate (1:2). The resulting crude product was led from a mixture of hexane/ethyl acetate to obtain 4,84 g of target compound.

1H-NMR (CDCl3) δ: 3,20-of 3.25 (2H, m), 3.72 points-3,91 (8H, m), of 3.96 (2H, s), 6,13 (1H, d, J=8 Hz), to 6.39 (1H, d, J=7 Hz), 7,17 and 7.36 (6N, m).

g) 2-Benzyl-6-[(3R,4R)-3,4-atlantooccipital-1-yl]-3-yodellin

of 4.04 g of N-jodatime small portions was added to 40 ml of N,N-dimethylformamide solution containing 4,84 g of 2-benzyl-6-[(3R,4R)-3,4-atlantooccipital-1-yl]pyridine, with stirring at legano the bath, followed by stirring overnight. The reaction solution was poured into water and was extracted with ethyl acetate. The organic phase is then washed with an aqueous solution of sodium sulfite, water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to filtration using silica gel, and was led from a mixture of hexane/ethyl acetate to obtain 5,12 g of target compound.

1H-NMR (CDCl3) δ: 3,15-3,18 (2H, m), 3,7 1-3,91 (8H, m), 4,14-4,22 (2H, m), 5,95 (1H, d, J=9 Hz), 7.18 in-7,39 (5H, m), of 7.70 (1H, d, J=9 Hz).

h) (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-atlantooccipital-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The mixture 5,12 g of 2-benzyl-6-[(3R,4R)-3,4-atlantooccipital-1-yl]-3-iopidine and 1.83 g of (3R)-3-ethinyl-3-hinokitiol, 140 mg of tetrakis(triphenylphosphine)palladium (0), 115 mg of copper iodide, 3.4 ml of triethylamine and 12 ml of methanol was stirred at room temperature overnight under nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia solution and the mixture was extracted with ethyl acetate/tetrahydrofuran (1:1). The organic phase is washed with saturated salt solution and the solvent was removed. The residue was led from a mixture of tetrahydrofuran/methanol/ethyl acetate to obtain 3,59 g of target compound.

1H-NMR (CDCl3) δ: 1,37-of 1.44 (1H, m), 1,55-of 1.64 (1H, m), 1,87 is 1.91 (1H, m), 2,04-of 2.05 (2H, m), 2,75-2,89 (4H, m), 3.04 from (1H, d, J=14 Hz), 3,18 of 3.28 (3H, m), of 3.73-3,91 (8H, m), 4,11-is 4.21 (2H, is), 6,12 (1H, d, J=9 Hz), 7,14-7,34 (5H, m), 7,44 (1H, d, J=9 Hz).

Example 115: (3R)-3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-cyclopropylacetylene-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-[(3R,4R)-3-methoxyethoxy-4-vinylacetylene-1-yl]pyridine

145 mg of 60% oil suspension of sodium hydride were added to a mixture of 906 mg of 2-benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine (example 10 (a) and 10 ml of tetrahydrofuran under ice cooling, followed by stirring for one hour at the same temperature. There was added 0,252 ml chloromethylmethylether ether, followed by stirring at room temperature for 1.5 hours. To the reaction solution were added water and ethyl acetate and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. To the residue was added 4 ml of etilenovogo ether and 238 mg of the acetate of mercury with subsequent stirring for two nights at room temperature. To the reaction solution was added aqueous saturated sodium bicarbonate solution and diethyl ether. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 15% ethyl acetate/hexane, obtaining 229 g of target compound.

1H-NMR (CDCl3) δ : 3,39 (3H, s), 3,51-3,61 (4H, m), of 3.97 (2H, s), of 4.12 (1H, DD, J=2, 7 Hz), 4,42-to 4.46 (2H, m), 4,54-4,55 (1H, m), 4,71 was 4.76 (2H, m), 6,17 (1H, d, J=8 Hz), 6,34-6.42 per (2H, m), 7,16-7,34 (6N, m).

b) 2-Benzyl-6-[(3R,4R)-3-methoxyethoxy-4-cyclopropylacetylene-1-yl]pyridine

The mixture 229 mg of 2-benzyl-6-[(3R,4R)-3-methoxyethoxy-4-vinylacetylene-1-yl]pyridine, 217 μl diiodomethane, of 1.35 ml of a hexane solution containing 1.0 mol of diethylzinc, and 3 ml of toluene was stirred at 80°C for 3 hours. To the reaction solution were added ammonium chloride, and the mixture was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 15% ethyl acetate/hexane, obtaining of 47.8 mg of target compound.

1H-NMR (CDCl3) δ: from 0.50 to 0.63 (4H, m), 3,38-of 3.42 (4H, m), 3,52-of 3.60 (2H, m), 3,69 of 3.75 (2H, m), of 3.97 (2H, s), 4,18-is 4.21 (1H, m), 4,30-to 4.33 (1H, m), 4,70-4,74 (2H, m), 6,16 (1H, d, J=8 Hz), 6,33 (1H, d, J=8 Hz), 7,17-7,33 (6N, m).

(C) (3R)-3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-cyclopropylacetylene-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 47.8 mg of 2-benzyl-6-[(3R,4R)-3-methoxyethoxy-4-cyclopropylacetylene-1-yl]pyridine, 1.5 ml dichloromethane and 0,156 ml triperoxonane acid was stirred overnight at room temperature. To the reaction solution was added aqueous saturated sodium bicarbonate solution and ethyl acetate and the organic phase is washed with water and feast upon the s ' solution of salt, was dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to the same reaction as in example 10, to synthesize the target compound.

1H-NMR (CDCl3) δ: from 0.50 to 0.62 (4H, m), 1,35 was 1.43 (1H, m), 1,53-to 1.61 (1H, m), 1,82-1,90 (1H, m), 1,99 e 2.06 (2H, m), 2.71 to only 2.91 (4H, m), 2,98 (1H, d, J=14 Hz), 3,20 (1H, DD, J=2, 14 Hz), 3,36-to 3.41 (1H, m), 3,43-3,47 (1H, m), 3,55-to 3.58 (1H, m), 3,68 (1H, DD, J=5, 11 Hz in), 3.75 (1H, DD, J=5, 12 Hz), 4,06-to 4.15 (3H, m), 4,39 was 4.42 (1H, m), 6,12 (1H, d, J=8 Hz), 7,13-to 7.32 (5H, m), 7,40 (1H, d, J=8 Hz).

Example 116: (3R)-3-[2-Benzyl-5-chloro-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-5-chloro-3-iodine-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine

100 mg of N-chlorosuccinimide small portions was added to a mixture of 256 mg of 2-benzyl-3-iodine-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine (example 10C) and 3 ml of N,N-dimethylformamide, followed by stirring at 70°C for 2 hours. After cooling, were added water and ethyl acetate and the mixture was extracted. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 25% ethyl acetate/hexane, to obtain 132 mg of the target compound.

1H-NMR (CDCl3) δ: 3,39 (3H, s), 3,64 at 3.69 (2H, m), 3,76-with 3.79 (1H, m), 3,86-are 3.90 (1H, m), 3,94-of 3.97 (1H, m), 4,14 (2H, s), 4,30-to 4.33 (1H, m), 7.18 in-7,33 (5H, m), 7,74 (1H, s).

b) (3R)-3-[2-Benzyl-5-chloro-6-[(3R,4R)-3-is hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 132 mg of 2-benzyl-5-chloro-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine, 49,4 mg (3R)-3-ethinyl-3-hinokitiol, 17,2 mg tetrakis(triphenylphosphine)palladium (0), 11.3 mg of copper iodide, 124 μl of triethylamine and 1.5 ml of methanol was heated under reflux for one hour in nitrogen atmosphere. After cooling, to the reaction mixture were added water and ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 3% methanol/ethyl acetate, to obtain 125 mg of the target compound.

1H-NMR (CDCl3) δ: 1,36-of 1.44 (1H, m), 1.56 to and 1.63 (1H, m), 1,82-1,89 (1H, m), 1,99-of 2.05 (2H, m), 2,50-is 2.88 (4H, m)of 3.00 (1H, d, J=14 Hz), 3,20 (1H, DD, J=2, 14 Hz), 3,40 (3H, s), 3,71-of 3.78 (3H, m), 3,92-of 3.97 (1H, m,), 4,00-Android 4.04 (1H, m), 4.09 to (2N, C), 4,30-4,32 (1H, m), 7,17-7,29 (5H, m), 7,45 (1H, s).

Example 117: (3R)-3-[2-Benzyl-5-bromo-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 116, except that N-chlorosuccinimide was replaced with N-bromosuccinimide.

1H-NMR (CDCl3) δ: 1,36-of 1.44 (1H, m), 1,58-of 1.64 (1H, m), 1,82 is 1.91 (1H, m), 1,99 e 2.06 (2H, m), 2,72-of 2.93 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,40 (ZN, s), 3.72 points-of 3.80 (3H, m), 3,92-of 3.97 (1H, m,), 4,01-4,06 (1H, m), 4.09 to (2N, C), 4,30-4,32 (1H, m), 7,16-7,30 (5H, m), to 7.67 (1H, s).

Example 118: (3R)-3-[2-Benzyl-6-[3,3-Ethylenedioxy pyrrolidin-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Bromo-6-[3,3-atlantooccipital-1-yl]-3-pyridine

A mixture of 5.7 g of 2,6-dibromopyridine, 2.5 g of 3-hydroxypyrrolidine, 3.6 ml of 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) and 20 ml of tetrahydrofuran was heated with stirring for 11 hours on an oil bath at a temperature of 70°C. the Mixture was distributed between ethyl acetate-water and the organic layer was washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel, using 10-30% ethyl acetate/hexane, to obtain 5.9 g of 2-bromo-6-(3-hydroxypyrrolidine-1-yl)pyridine.

Then 4.6 ml of dimethyl sulfoxide was added dropwise 100 ml of a dichloromethane solution containing 2.8 ml of oxalicacid, with stirring in a bath of dry ice-acetone. Then was added dropwise 50 ml of dichloromethane solution containing 5.9 g of the obtained 2-bromo-6-(3-hydroxypyrrolidine-1-yl)pyridine. Finally, was added dropwise 17 ml of triethylamine and the temperature of the mixture was raised to room temperature over one hour. The reaction solution was washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. To the residue was added 50 ml of toluene, 7 ml of ethylene glycol and a catalytic amount of monohydrate p-toluensulfonate acid followed by boiling with inverse x is Hladilnika for 3 hours with distillation of water. After cooling, the mixture was washed with saturated aqueous sodium bicarbonate solution and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel, using 5-7% ethyl acetate/hexane, to obtain 6.3 g of the target compound.

1H-NMR (CDCl3) δ: 2,30 (2H, t, J=7 Hz), of 3.54 (2H, s)to 3.58 (2H, t, J=7 Hz), 3.96 points-Android 4.04 (4H, m), from 6.22 (1H, d, J=8 Hz), 6,70 (1H, d, J=8 Hz), 7,24 (1H, t, J=8 Hz).

b) 2-Benzyl-6-[3,3-atlantooccipital-1-yl]pyridine

A mixture of 6.3 g of 2-bromo-6-[3,3-atlantooccipital-1-yl]pyridine, 240 mg of chloride 1,3-bis(diphenylphosphino)propenies (II) and 20 ml of tetrahydrofuran was stirred in an ice bath under nitrogen atmosphere. To the mixture was added dropwise a solution of benzylacrylamide in diethyl ether, prepared from 3,4 ml benzylbromide, 0.8 g of magnesium and 15 ml of diethyl ether, followed by stirring at room temperature over night. The reaction solution was distributed between aqueous saturated solution of ammonium chloride and ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel using 5-10% ethyl acetate/hexane, to obtain 6.6 g of the target compound.

1H-NMR (CDCl3) δ: 2,19 (2H, t, J=7 Hz), of 3.57 (2H, s)and 3.59 (2 is, t, J=7 Hz), of 3.97 (2H, s)to 4.01 (4H, s), 6,14 (1H, d, J=8 Hz), 6,34 (1H, d, J=7 Hz), 7,16-7,35 (6N, m).

C) 2-Benzyl-3-iodine-6-[3,3-atlantooccipital-1-yl]-pyridine

A mixture of 6.6 g of 2-benzyl-6-[3,3-atlantooccipital-1-yl]pyridine and 60 ml of N,N-dimethylformamide was stirred in an ice bath. To the mixture was added dropwise 5.5 g N-jodatime, followed by stirring at room temperature over night. Added 10 ml of an aqueous solution containing one mole of sodium thiosulfate, and the mixture was distributed between ethyl acetate and water. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel using 5-10% ethyl acetate/hexane, to obtain 6.7 g of the target compound.

1H-NMR (CDCl3) δ: 2,17 (2H, t, J=7 Hz), 3,50 (2H, s), of 3.54 (2H, t, J=7 Hz), of 4.00 (4H, s), 4,18 (2H, s), 5,95 (1H, d, J=8 Hz), 7,18 (1H, t, J=7 Hz), 7,26 (2H, t, J=7 Hz), 7,37 (2H, d, J=7 Hz), 7.68 per (1H, d, J=8 Hz).

d) (3R)-3-[2-Benzyl-6-[3,3-atlantooccipital-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 3.0 g of 2-benzyl-3-iodine-6-[3,3-atlantooccipital-1-yl]pyridine, 1.07 g (3R)-3-ethinyl-3-hinokitiol, 82 mg of tetrakis(triphenylphosphine)palladium (0), 68 mg of copper iodide, 2.0 ml of triethylamine and 7 ml of methanol was stirred at room temperature overnight under nitrogen atmosphere. The reaction solution was distributed between water once allonym solution of ammonia-acetic acid ethyl ester washed with water, dried over anhydrous magnesium sulfate and then concentrated. To the residue was added 10 ml of tetrahydrofuran to dissolve when heated and to the mixture was added 15 ml of ethyl acetate. The mixture was filtered through 10 g of NH-silica gel, washed with ethyl acetate and concentrated. The residue was led from ethyl acetate to obtain and 2.79 g of the target compound.

1H-NMR (CDCl3) δ: 1,34-of 1.94 (3H, m), 1,98-2/06 (2H, m)to 2.18 (2H, t, J=8 Hz), 2,70-to 2.94 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,55 (2H, s), of 3.60 (2H, t, J=8 Hz), to 4.01 (4H, s), 4,15 (2N with), 6,12 (1H, d, J=8 Hz), 7,12-7,34 (5H, m), 7,41 (1H, d, J=8 Hz).

Example 119: (3R)-3-[2-Benzyl-5-chloro-6-[3,3-atlantooccipital-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 500 mg of 2-benzyl-3-iodine-6-(3,3-atlantooccipital-1-yl)pyridine obtained in example s, 174 mg of N-chlorosuccinimide and 5 ml of N,N-dimethylformamide was stirred under heating for 5 hours on an oil bath at a temperature of 60°C. To the reaction solution was added 1 ml of an aqueous solution containing 1 mol of sodium thiosulfate, and the mixture was distributed between ethyl acetate and water. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel using 5-10% ethyl acetate/hexane, to obtain 320 mg of 2-benzyl-3-iodine-5-chloro-6-(3,3-atlantooccipital--yl)pyridine and then got the connection, named in the title, by the same methods as in example 118d.

1H-NMR (CDCl3) δ: 1,35-of 1.92 (3H, m), 1,98-of 2.05 (2H, m), is 2.09 (2H, t, J=7 Hz), 2,70-to 2.94 (4H, m), 3,03 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,80 (2H, s), a-3.84 (2H, t, J=7 Hz), of 4.00 (4H, s), 4,10 (2H with), 7,14-to 7.32 (5H, m), 7,44 (1H, s).

Example 120: (3R)-3-[2-Benzyl-6-[CIS-3,4-dimethoxypyridine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Bromo-6-(3-pyrrolin-1-yl)pyridine

A mixture of 12.4 g of 2,6-dibromopyridine, 7.2 g of 3-pyrroline (purity: 65%, Aldrich), 14.5 g of potassium carbonate and 100 ml of 1-methyl-2-pyrrolidinone was heated with stirring at 125°C for 4 hours. After cooling, the reaction mixture was poured into water and was extracted with ethyl acetate. The organic phase is washed with water and saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane, then hexane/ethyl acetate (10:1) to give 11.6 g of the target compound and 2-bromo-6-(pyrrolidin-1-yl)pyridine.

b) 2-Benzyl-6-(3-pyrrolin-1-yl)pyridine

72,3 ml tertrahydrofuran ring solution containing 1.07 mol benzylaniline was added dropwise to a mixture of 11.6 g of a mixture of 2-bromo-6-(3-pyrrolidin-1-yl)pyridine and 2-bromo-6'-(pyrrolidin-1-yl)pyridine and 20 ml of tetrahydrofuran containing 1.4 g of chloride 1,3-bis(diphenylphosphino)-propenies (II), for 10 minutes in an ice bath. After cooling at room temperature over night, auktsionnyi the solution was poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane and then hexane/ethyl acetate (20:1) to give 11.8 g of the target compound in the form of a mixture with 2-benzyl-6-(pyrrolidin-1-yl)pyridine.

c) 2-Benzyl-6-(CIS-3,4-dihydroxypyrrolidine-1-yl)pyridine

2,3 ml of 2-methyl-2-propanolol solution containing 2.5% tetroxide osmium, slowly dropwise added to a mixture of 11.8 g of a mixture of 2-benzyl-6-(3-pyrrolin-1-yl)pyridine and 2-benzyl-6-(pyrrolidin-1-yl)pyridine, with 23.5 g of aqueous 50% solution of N-methylmorpholin-N-oxide, 50 ml of acetone and 10 ml of water in an ice bath. After stirring for 2 hours in an ice bath, the mixture was further stirred at room temperature overnight. An aqueous solution of sodium thiosulfate was added to the reaction solution, followed by stirring at room temperature for 30 minutes. Then the mixture was extracted with ethyl acetate, the organic phase is washed with water and saturated salt solution and the solvent was removed. Then the residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (5:1)and then ethyl acetate to obtain of 4.2 g of the target compound.

1H-NMR (CDCl3) δ: 3,47-3,50 (2H, m), 3,71 of 3.75 (2H, m), of 3.97 (2H, s), 4,37-4,39 (2H, m), x 6.15 (1H, d, J=8 Hz), 6,37 (1H, d, J7 Hz), 7,17-7,35 (6N, m).

d) 2-Benzyl-6-(CIS-3,4-dimethoxypyridine-1-yl)pyridine

347 mg of 60% oil suspension of sodium hydride in small portions was added to the mixture 781 mg of 2-benzyl-6-(CIS-3,4-dihydroxypyrrolidine-1-yl)pyridine, 536 μl of methyliodide and 6.0 ml of N,N-dimethylformamide in an ice bath. After stirring at room temperature for 2 hours to the reaction solution in small portions was added water and the mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated salt solution and the solvent was removed.

Then the residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (5:1), and then hexane/ethyl acetate (1:1) to obtain 783 mg of target compound.

1H-NMR (CDCl3) δ: 3,47 (6N, (C), 3,60-the 3.65 (4H, m), 3,97-was 4.02 (4H, m), 6,16 (1H, d, J=8 Hz), 6,34 (1H, d, J=7 Hz), 7.18 in-7,34 (6N, m).

e) 2-Benzyl-6-(CIS-3,4-dimethoxypyridine-1-yl)-3-yodellin

708 mg N-jodatime small portions was added to the mixture 783 mg of 2-benzyl-6-(CIS-3,4-dimethoxypyridine-1-yl)pyridine and 7.0 ml of N,N-dimethylformamide under ice cooling, followed by stirring overnight. The reaction solution was poured into water and was extracted with ethyl acetate. The organic phase is washed with sodium thiosulfate, water and saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fui Silicia) and suirable hexane/ethyl acetate (5:1), and then hexane/ethyl acetate (3:1) to obtain 995 mg of target compound.

1H-NMR (CDCl3) δ: 3.46 in (6N, (C), 3,54-3,55 (4H, m), 3,97-4,01 (2H, m), 4,19 (2H, s), 5,97 (1H, d, J=9 Hz), 7,16-7,38 (5H, m), of 7.69 (1H, d, J=9 Hz).

f) (3R)-3-[2-Benzyl-6-[CIS-3,4-dimethoxypyridine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 510 mg of 2-benzyl-6-(CIS-3,4-dimethoxypyridine-1-yl)-3-iopidine, 200 mg of (3R)-3-ethinyl-3-hinokitiol, 139 mg of tetrakis(triphenylphosphine)palladium (0), 11 mg of copper iodide, and 0.50 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated at 75°C for 2 hours in nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia solution and extracted with ethyl acetate. The extract was washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (1:1)and then ethyl acetate/methanol (15:1) to obtain 281 mg of the target compound.

1H-NMR (CDCl3) δ: 1,38-of 1.40 (1H, m), 1,57 by 1.68 (1H, m), 1,87-of 1.92 (1H, m), 2,02-2,04 (2H, m), 2,74-2,87 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, d, J=14 Hz), 3,47 (6N, (C), of 3.60 (4H, m)to 3.99 (2H, m)to 4.16 (2H, C), 6,13-x 6.15 (1H, m), 7,14-7,33 (5H, m), 7,42 (1H, d, J=9 Hz).

Example 121: (3R)-3-[2-Benzyl-6-[CIS-3,4-methylenedioxypyrovalerone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-[CIS-3,4-methylenedioxypyrovalerone-1-yl] pyridine

A mixture of 300 mg of 2-benzyl-6-[CIS-3,4-dihydroxypyrrolidine-1-yl]-3-pyridine, 376 mhara-formaldehyde, 0.7 ml of concentrated sulfuric acid and 5.0 ml of acetic acid was heated under stirring at 90°C for 2 hours. After cooling, the reaction solution was slowly added to aqueous solution of potassium carbonate. The mixture was extracted with ethyl acetate, the organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (5:1), and then hexane/ethyl acetate (3:1) to give 221 mg of the target compound.

1H-NMR (CDCl3) δ: 3,37-to 3.41 (2H, m), 3,90-3,93 (2H, m), of 3.97 (2H, s), 4,81-4,82 (2H, m), equal to 4.97 (1H, s), 5,11 (1H, s), of 6.26 (1H, d, J=8 Hz), to 6.43 (1H, d, J=7 Hz), 7,17-7,37 (6N, m).

b) 2-Benzyl-6-[CIS-3,4-methylenedioxypyrovalerone-1-yl]-3-yodellin

143 mg of imide N-jocantaro acid in small portions was added to a mixture of 150 mg of 2-benzyl-6-(CIS-3,4-methylenedioxypyrovalerone-1-yl)pyridine and 5.0 ml of N,N-dimethylformamide under ice cooling, followed by stirring overnight. The reaction solution was poured into water and then extracted with ethyl acetate. The organic phase is washed with sodium thiosulfate, water and saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane and then hexane/ethyl acetate (4:1) to give 116 mg of the target compound.

1H-NMR (CDCl3) δ: 3,34-to 3.38 (2H, m),3,82-3,86 (2H, m), 4,19 (2H, s), 4,79-4,89 (2H, m), of 4.95 (1H, s), 5,09 (1H, s), the 6.06 (1H, d, J=9 Hz), 7,07-7,38 (5H, m), 7,72 (1H, d, J= Hz).

c) (3R)-3-[2-Benzyl-6-[CIS-3,4-methylenedioxypyrovalerone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 116 mg of 2-benzyl-6-[CIS-3,4-methylenedioxypyrovalerone-1-yl]-3-iopidine, 47 mg of (3R)-3-ethinyl-3-hinokitiol, 33 mg of tetrakis(triphenylphosphine)palladium (0), 3 mg of copper iodide, of 0.12 ml of triethylamine and 3.0 ml of N,N-dimethylformamide was heated with stirring at 75°C for 4 hours in nitrogen atmosphere. The reaction solution was poured into dilute aqueous ammonia solution and then was extracted with ethyl acetate. The extract was washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (1:1)and then ethyl acetate/methanol (20:1) to give 38 mg of the target compound.

1H-NMR (CDCl3) δ: 1,40 was 1.43 (1H, m), and 1.63 (1H, m), 1,80-of 1.88 (1H, m), 2.00 in a 2.12 (2H, m), 2,72-to 2.85 (4H, m), 3,03 (1H, d, J=14 Hz), 3,11-of 3.23 (1H, m), 3,41-3,44 (2H, m), 3,88-3,91 (2H, m)to 4.16 (2H, s), 4,81-4,82 (2N, m), 4,96 (1H, s), 5,10 (1H, s), 6,23 (1H, d, J=9 Hz), 7,17-to 7.32 (5H, m), 7,45 (1H, d, J=9 Hz).

Example 122: (3R)-3-[2-Benzyl-6-[CIS-3-isopropoxy-4-hydroxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-[CIS-3,4-(dimethylmethylene)pyrrolidin-1-yl]pyridine

A mixture of 2.5 g of 2-benzyl-6-[CIS-3,4-dihydroxypyrrolidine-1-yl]pyridine, 2,3 g of dl-10-camphorsulfonic acid, 20 ml of 2-dimethoxypropane and 5.0 ml of N,N-dimethylformamide was stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated salt solution and the solvent was removed. Then the residue was filtered through silica gel and was suirable with ethyl acetate to obtain 2,87 g of target compound.

1H-NMR (CDCl3) δ: of 1.37 (3H, s)to 1.48 (3H, s), 3.33 and is 3.40 (2H, m), 3,85-3,88 (2H, m), of 3.97 (2H, s), a 4.86-to 4.87 (2H, m), 6,24 (1H, d, J=8 Hz), to 6.39 (1H, d, J=7 Hz), 7,17-7,35 (6N, m).

b) 2-Benzyl-6-[CIS-3-isopropoxy-4-hydroxypyrrolidine-1-yl]pyridine

Hexane solution containing 1.5 mol of diisobutylaluminium small portions was added to a solution of 5.0 ml of diethyl ether containing 460 mg of 2-benzyl-6-[CIS-3,4-(dimethylmethylene)pyrrolidin-1-yl]pyridine, at -20°C. After stirring at room temperature overnight, the reaction solution was poured into an aqueous solution of ammonium chloride, the mixture was filtered through celite and extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. Then the residue was filtered through silica gel and was suirable with ethyl acetate to obtain 369 mg of the target compound.

1H-NMR (CDCl3) δ: 1,22-1.27mm (6N, m), 3,44-3,50 (2H, m), 3,63-a-3.84 (3H, m), of 3.97 (2H, s), 4.09 to to 4.15 (1H, m), 4,33-4,37 (1H, m), 6,13-x 6.15 (1H, m), 6,34 (1H, d, J=7 Hz), 7,17-7,32 (6N, m).

c) 2-Benzyl-6-(CIS-3-isopropoxy-4-hydroximino is lidin-1-yl)-3-yodellin

342 mg of N-jodatime small portions was added to a mixture of 396 mg of 2-benzyl-6-(CIS-3-isopropoxy-4-hydroxy-pyrrolidin-1-yl)pyridine and 5.0 ml of N,N-dimethylformamide under ice cooling, followed by stirring overnight. The reaction solution was poured into water and then extracted with ethyl acetate. The organic phase is washed with sodium thiosulfate, water and saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane and then hexane/ethyl acetate (3:1) to give 464 mg of the target compound.

1H-NMR (CDCl3) δ: 1,21-1.27mm (6N, m), 3,40-of 3.46 (2H, m), 3,56-3,82 (3H, m), 4.09 to 4,19 (3H, m), or 4.31-4,34 (1H, m), 5,96 (1H, d, J=8 Hz), 7,16-7,38 (5H, m), 7,68 (1H, d, J=8 Hz).

d) (3R)-3-[2-Benzyl-6-(CIS-3-isopropoxy-4-hydroxypyrrolidine-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 464 mg of 2-benzyl-6-(CIS-3-isopropoxy-4-hydroxypyrrolidine-1-yl)-3-iopidine, 176 mg (3R)-3-ethinyl-3-hinokitiol, 122 mg of tetrakis(triphenylphosphine)-palladium (0), 10 mg of copper iodide, of 0.44 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated with stirring for 2 hours at 75°C in nitrogen atmosphere. The reaction solution was poured into dilute aqueous ammonia solution and then was extracted with ethyl acetate. The extract was washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography n the NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (1:1), and then ethyl acetate/methanol (20:1) to give 168 mg of the target compound.

1H-NMR (CDCl3) δ: 1,21-1.27mm (6N, m), 1,50-of 1.97 (3H, m), 2,04-2,17 (2H, m), 2,75 are 2.98 (4H, m), 3,12 (1H, d, J=14 Hz), 3,28-of 3.31 (1H, m), 3,41-of 3.64 (3H, m), of 3.73-3,81 (2H, m), 4,11-to 4.14 (3H, m), 4,36 (1H, Sirs), 6,14 (1H, d, J=9 Hz), 7,16-7,29 (5H, m), 7,41 (1H, d, J=9 Hz).

Example 123: (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-methoxyethoxy-6-[(3R,4R)-3,4-dimethylethylenediamine-2-pyrrolidinone-1-yl]pyridine

3.6 g of 2-benzyl-3-methoxyethoxy-6-iopidine (example 12), 1.5 g of (3R,4R)-3,4-dimethylethylenediamine-2-pyrrolidinone synthesized according to the method known from the literature (J. Org. Chem., 1969, 34, 675), 1,1 g of copper iodide and 3.3 g of potassium carbonate suspended in 20 ml of 1-methyl-2-pyrrolidinone, followed by stirring at 140°C for 20 minutes in an oil bath under nitrogen atmosphere. After cooling there was added ethyl acetate and aqueous ammonia and the mixture was extracted with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 20-50% ethyl acetate/hexane as eluent for separation and purification to obtain 2 g of the target compound.

1H-NMR (CDCl3) δ: of 1.42 (3H, s)of 1.46 (3H, s), 3,37 (3H, s), 4,08 is 4.13 (3H, m), 4.26 deaths (1H, d, J=3 Hz), 4,80 (2H, s), 5,14 (2H, DD, J=6,8, 10 Hz), 7,17-7,31 (5H, m), 7,42 (1H, d, J=9.0 Hz), by 8.22 (1H, d, J=9.0 Hz).

b) 2-Benzyl-6-[(3R,4R)-3,4-dimethylethylenediamine-2-pyrrolidinone-1-yl]-3-pyridylsulfonyl

5 ml triperoxonane acid was added to 2 g of 2-benzyl-3-methoxyethoxy-6-[(3R,4R)-3,4-dimethylethylenediamine-2-pyrrolidinone-1-yl]pyridine, followed by stirring at room temperature for 6 hours. The mixture is then neutralized with an aqueous solution of potassium carbonate and was extracted with ethyl acetate. Next, the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. After dissolving the obtained residue in 30 ml of dichloromethane was added 2.1 g of N-phenyltrichlorosilane, 192 mg of 4-dimethylaminopyridine and 0.8 ml of triethylamine. After stirring at room temperature for one hour the solvent was removed and the residue was subjected to column chromatography on silica gel using 25% ethyl acetate/hexane as eluent for separation and purification to obtain 2.2 g of the target compound.

1H-NMR (CDCl3) δ: of 1.42 (3H, s)of 1.46 (3H, s), a 4.03 (1H, DD, J=4,0, 13 Hz), 4,18 (2H, s)to 4.23 (1H, d, J=13 Hz), 4,79 of 4.83 (2H, m), 7,20-7,42 (5H, m), 7,60 (1H, d, J=9,2 Hz), 8,44 (1H, d, J=9,2 Hz).

C) 2-Benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinone-1-yl]-3-pyridylsulfonyl (a) and 2-benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinone-1-yl]-3-Piri is intraformational (In)

2.2 g of 2-benzyl-6-[(3R,4R)-3,4-dimethylethylenediamine-2-pyrrolidinone-1-yl]-3-pyridylsulfonyl was dissolved in 20 ml of methanol was added 5 ml of 5N hydrochloric acid, followed by stirring at room temperature for 1.5 hours and at 50°C in oil bath for 2 hours. After cooling the mixture was neutralized with an aqueous solution of potassium carbonate and was extracted with ethyl acetate. Next, the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The obtained residue was dissolved in 20 ml of acetonitrile was added 1.5 ml of methyliodide and 5.6 g of silver oxide (I), followed by heating under stirring at 60°C in an oil bath for 1.5 hours. Insoluble matter was filtered through celite and the filtrate evaporated. The residue was subjected to column chromatography on silica gel, using approximately 33-50% ethyl acetate/hexane as eluent for the separation and purification of obtaining 685 mg of target compound (a) and 599 mg of target compound (B).

Connection (A):1H-NMR (CDCl3) δ: 3,47 (3H, s), of 3.69 (3H, s), 3,80 (1H, DD, J=3,8, 12 Hz), 4,07-is 4.21 (5H, m), 7,22-7,29 (5H, m), 7,58 (1H, d, J=9,2 Hz), scored 8.38 (1H, d, J=9,2 Hz).

Connection (In):1H-NMR (CDCl3) δ: 3,48 (1H, d, J=4.6 Hz), 3,74 (3H, s), 3,86 (1H, DD, J=13 Hz, 4.0 Hz), 4,06-4,18 (4H, m), 4,54-of 4.57 (1H, m), 7.24 to 7,30 (5H, m), to 7.59 (1H, d, J=9.0 Hz), of 8.37 (1H, d, J=9.0 Hz).

d) (3R)-3-[2-Benzyl-6-[(3R,4R)-3,-dimethoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

5 ml of N,N-dimethylformamide was added to the mixture 685 mg of 2-benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinone-1-yl]-3-pyridylmethylamine, 293 mg of 16.5 mg (3R)-3-ethinyl-3-hinokitiol, 107 mg of tetrakis(triphenylphosphine)palladium (0), 22 mg of copper iodide and 0.7 ml of triethylamine, followed by heating under stirring at 60°C in oil bath for 1.3 hours in nitrogen atmosphere. After cooling there was added ethyl acetate and aqueous ammonia and extracted with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel, using 66% ethyl acetate/hexane and 2% methanol/ethyl acetate as eluents, for separation and purification to obtain 361 mg of the intended compound.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,57-to 1.67 (1H, m), 1,68-of 1.92 (1H, m), 2.00 in 2,19 (2H, m), 2,70-2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,24 (1H, DD, J=1,6, 14 Hz), 3,48 (3H, s), 3,70 (3H, s), a-3.84 (1H, DD, J=2,0, 13 Hz), 4.09 to (1H, d, J=2,8 Hz), 4,15-4,17 (1H, m), 4,23-of 4.25 (3H, m), 7,09-7,29 (5H, m), to 7.67 (1H, d, J=8,8 Hz), 8,24 (1H, d, J=8,8 Hz).

Example 124: (3R)-3-[2-Benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same manner as in example 123, using 2-benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridylmethylamine (example 123 is).

1H-NMR (CDCl3) δ: of 1.36 to 1.47 (1H, m), 1,58 by 1.68 (1H, m), 1,82-of 1.93 (1H, m), 2,00-2,09 (2H, m), 2,70-2,95 (4H, m), 3,03 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2.0 a, 14 Hz), 3,74 (3H, s), 3,90 (1H, DD, J=4,0, 13 Hz), 4,07 (1H, d, J=3.6 Hz), is 4.21 (1H, d, J=13 Hz), 4,24 (2H, s)4,55 (1H, DD, J=3,6, 4.0 Hz), 7,08-7,28 (5H, m), 7,66 (1H, d, J=8,4 Hz), 8,21 (1H, d, J=8,4 Hz).

Example 125: (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-dimethylethylenediamine-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: 1,35-1,45 (1H, m)of 1.42 (3H, s)of 1.47 (3H, s), 1,58-1,72 (1H, m), 1,82-of 1.92 (1H, m), 2.00 in of 2.08 (2H, m), 2.71 to 2,95 (4H, m), 3,05 (1H, d, J=14 Hz), 3,26 (1H, DD, J=1,8, 14 Hz), 4,07 (1H, DD, J=4,0, 13 Hz), 4,25 (2H, s), the 4.29 (1H, d, J=13 Hz), 4,78 of 4.83 (2H, m), 7.18 in-7,28 (5H, m), of 7.69 (1H, d, J=8.6 Hz), 8,29 (1H, d, J=8.6 Hz).

Example 126: 3-[2-Benzyl-6-(2-oxo-1,3-oxazolidin-3-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ =1,38 is 1.48 (1H, m), 1,60-1,70 (1H, m), 1.85 to 1,95 (1H, m), 2.00 in to 2.13 (2H, m), 2,74 are 2.98 (4H, m), 3.04 from (1H, d, J=14 Hz)at 3.25 (1H, d, J=14 Hz), to 4.23 (2H, t, J=8.1 Hz), 4,24 (2H, s), 4,47 (2H, t, J=8.1 Hz), 7,17-7,28 (5H, m), 7,66 (1H, d, J=8.7 Hz), 8,02 (1H, d, J=8.7 Hz).

Example 127: 3-[2-Benzyl-6-(2-pyrrolidino-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: to 1.38 to 1.47 (1H, m), 1,58 is 1.70 (1H, m), 1.85 to 1,95 (1H, m), 2,03-of 2.15 (2H, m), is 2.09 (2H, TT, J=7,2, 8,1 Hz)to 2.65 (2H, t, J=8.1 Hz), 2,73-2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2.0 a, 14 Hz), 4,07 (2H, t, J=7.2 G is), 4,24 (2H, s), 7.18 in-7,27 (5H, m), 7,66 (1H, d, J=8.7 Hz), 8,24 (1H, d, J=8.7 Hz).

Example 128: (3R)-3-[2-Benzyl-6-(2-pyrrolidino-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: to 1.38 to 1.47 (1H, m), 1,58 is 1.70 (1H, m), 1.85 to 1,95 (1H, m), 2,03-of 2.15 (2H, m), is 2.09 (2H, TT, J=7,2, 8,1 Hz)to 2.65 (2H, t, J=8.1 Hz), 2,73-2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2.0 a, 14 Hz), 4,07 (2H, t, J=7.2 Hz), 4,24 (2H, s), 7.18 in-7,27 (5H, m), 7,66 (1H, d, J=8.7 Hz), 8,24 (1H, d, J=8.7 Hz).

Example 129: 3-[2-Benzyl-6-(2-piperidino-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3)δ: to 1.38 to 1.48 (1H, m), 1,58-of 1.65 (1H, m), 1.70 to of 1.97 (5H, m), 1,98-of 2.08 (2H, m)at 2.59 (2H, t, J=6.4 Hz), 2,69-to 2.94 (4H, m), to 3.02 (1H, DD, J=1,5, 14 Hz), up 3.22 (1H, DD, J=2.0 a, 14 Hz), 3,93 (2H, t, J=5,7 Hz), 4,25 (2H, s), 7,17-7,27 (5H, m), 7,63 (1H, d, J=8.5 Hz), 7,74 (1H, d, J=8,5 Hz).

Example 130: (3R)-3-[2-Benzyl-6-(2-piperidino-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,58-of 1.65 (1H, m), 1.70 to of 1.97 (5H, m), 1,98-of 2.08 (2H, m)at 2.59 (2H, t, J=6.4 Hz), 2,69-to 2.94 (4H, m), to 3.02 (1H, DD, J=1,5, 14 Hz), up 3.22 (1H, DD, J=2.0 a, 14 Hz), 3,93 (2H, t, J=5,7 Hz), 4,25 (2H, s), 7,17-7,27 (5H, m), 7,63 (1H, d, J=8.5 Hz), 7,74 (1H, d, J=8,5 Hz).

Example 131: (3R)-3-[2-Benzyl-6-[(4R)-4-hydroxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: of 1.35 to 1.47 (1H, m), 53-1,63 (1H, m), 1,78-1,89 (1H, m), 2,00-2,09 (2H, m), 2.63 in (1H, DD, J=2.0 a, 18 Hz), 2,68-to 2.94 (4H, m), with 2.93 (1H, DD, J=6,2, 18 Hz), 2,99 (1H, DD, J=1,6, 14 Hz), 3,20 (1H, DD, J=2.0 a, 14 Hz), 4.09 to 4,18 (2H, m), 4,20 (2H, ), 4,50-4,56 (1H, m), 7,15-7,28 (5H, m), 7,53 (1H, d, J=8.6 Hz), to 8.12 (1H, d, J=8.6 Hz).

Example 132: (3R)-3-[2-Benzyl-6-[(4S)-4-hydroxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: of 1.35 to 1.47 (1H, m), 1,53-to 1.63 (1H, m), 1,78-1,89 (1H, m), 2,00-2,09 (2H, m), 2.63 in (1H, DD, J=2.0 a, 18 Hz), 2,68-to 2.94 (4H, m), with 2.93 (1H, DD, J=6,2, 18 Hz), 2,99 (1H, DD, J=1, 6, 14 Hz), 3,20 (1H, DD, J=2.0 a, 14 Hz), 4.09 to 4,18 (2H, m), 4,20 (2H, s), 4,50-4,56 (1H, m), 7,15-7,28 (5H, m), 7,53 (1H, d, J=8.6 Hz), to 8.12 (1H, d, J=8.6 Hz).

Example 133: 3-[2-Benzyl-6-(2-oxo-2,5-dihydropyrrol-1-yl)-3 - pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123, using 2-benzyl-6-(2-oxo-2,5-dihydropyrrol-1-yl)-3-pyridylmethylamine, which was a side obtained when synthesized the compound of example 131.

1H-NMR (CDCl3) δ: of 1.35 to 1.47 (1H, m), 1.56 to to 1.67 (1H, m), 1,83 is 2.10 (3H, m), 2,72-2,95 (4H, m), 3.04 from (1H, d, J=14 Hz)at 3.25 (1H, DD, J=14 Hz and 2.1 Hz), 4,24 (2H, s), with 4.64 (2H, t, J=1,8 Hz), 6,23 (2H, dt, J=6.0 Hz, 1,8 Hz), 7.18 in-7,29 (6N, m), to 7.67 (1H, d, J=8.6 Hz), compared to 8.26 (1H, d, J=8.6 Hz).

Example 134: (3R)-3-[2-Benzyl-6-[(4S)-4-methoxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: 1,35-1,49 (1H, m), 1,57 by 1.68 (1H, m), 1,78-of 1.92 (1H, m), 1,98-210 (2H, m), 2,70 are 2.98 (5H, m), 3.04 from (1H, d, J=14 Hz)at 3.25 (1H, d, J=14 Hz), to 3.38 (3H, s), 4,07-4,22 (4H, m), 4,25 (2H, s), 7,08-7,29 (5H, m), to 7.67 (1H, d, J=8.6 Hz), 8,23 (1H, d, J=8.6 Hz).

Example 135: 3-[2-Benzyl-6-(1-imidazolyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: 1,39-1,49 (1H, m), 1,58-1,72 (1H, m), 1,82-of 1.92 (1H, m), 2.00 in of 2.10 (2H, m), 2,75 are 2.98 (4H, m), of 3.07 (1H, d, J=14 Hz), with 3.27 (1H, DD, J=1,9, 14 Hz), 4,32 (2H, s), 7,14 (1H, d, J=8,2 Hz), 7.18 in-7,30 (7H, m), 7,78 (1H, d, J=8,2 Hz), a 8.34 (1H, s).

Example 136: 3-[2-Benzyl-6-(2-oxo-1,2-dihydropyrimidin-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,58 by 1.68 (1H, m), 1,75-1,90 (1H, m), 2,00-2,09 (2H, m), 2,69-2,95 (4H, m), 3.04 from (1H, d, J=14 Hz)at 3.25 (1H, DD, J=1,8, 14 Hz), 4,34 (2H, s), of 6.29 (1H, DD, J=6,5, 7,2 Hz), 6,63 (1H, d, J=9,2 Hz), 7,16-7,34 (5H, m), 7,37 (1H, DDD, J=2,1, 6,5, 9,2 Hz), 7,79 (1H, d, J=8,4), 7,89 (1H, d, J=8,4 Hz), 7,92 (1H, DD, J=2,1, 7,2 Hz).

Example 137: 3-[2-Benzyl-6-(1-pyrazolyl)-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,58 by 1.68 (1H, m), 1,79-of 1.93 (1H, m), 2.00 in of 2.10 (2H, m), 2,70-2,95 (4H, m), 3.04 from (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2.0 a, 14 Hz), or 4.31 (2H, s), 6,44 (1H, DD, J=1,0, and 1.6 Hz), 7,19-to 7.32 (5H, m), 7,72-7,81 (3H, m), 8,54 (1H, DD, J=1,0 2,7 Hz).

Example 138: (3R)-3-[2-Benzyl-3-(3,3-Ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-methoxyethoxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-yl]pyridine

14.3 g of 2-benzyl-3-methoxyethoxy-6-yodellin (example 12) and 4.1 g of (3S)-3-hydroxy-2-pyrrolidinone synthesized according to the method well known from the literature (Synthesis, 1978, 614), 4.6 g of copper iodide and 13.7 g of potassium carbonate suspended in 30 ml of 1-methyl-2-pyrrolidinone followed by heating under stirring at 140°C in oil bath for 20 minutes in nitrogen atmosphere. After cooling there was added ethyl acetate and aqueous ammonia. The mixture was extracted with ethyl acetate, the organic phase is then washed with a saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 50-60% ethyl acetate as eluent for separation and purification to obtain 9.7 g of target compound.

1H-NMR (CDCl3) δ: 1,95-of 2.08 (1H, m), 2,53-of 2.58 (1H, m)to 3.09 (1H, Sirs), 3,37 (3H, s), 3,76 (1H, TD, J=10 Hz and 6.6 Hz), of 4.12 (2H, s), 4,19 (1H, t, J=9,2 Hz), 4,48 (1H, t, J=10 Hz), 5,14 (2H, s), 7,17-7,30 (5H, m), 7,42 (1H, d, J=9.0 Hz), 8,14 (1H, d, J=9.0 Hz).

b) 2-Benzyl-6-(3,3-Ethylenedioxy-2-pyrrolidinone-1-yl)-3-hydroxypyridine

1.1 g of 2-benzyl-3-methoxyethoxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine was dissolved in 20 ml of acetone was added 1 ml of reagent John, followed by stirring at room temperature for 1.5 hours. Was added 2-propanol and water and then was extracted with ethyl acetate. Organizes the phase was further washed with a saturated solution of salt, was dried over anhydrous magnesium sulfate and the solvent was removed. The obtained residue was dissolved in 20 ml of toluene. Added 1 ml of ethylene glycol and 198 mg p-toluensulfonate acid followed by boiling under reflux for 2 hours while removing water using the apparatus of Dean-stark. After cooling, was added water and the mixture was extracted with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 30-40% ethyl acetate/hexane as eluent for separation and purification to obtain 398 mg of the target compound.

1H-NMR (CDCl3) δ: of 2.34 (2H, t, J=6.9 Hz), to 4.01 (2H, t, J=6.9 Hz), of 4.12 (4H, s), 4,39 (2H, s), 5,28 (1H, Sirs), 7,13 (1H, d, J=8.6 Hz), 7.18 in-7,30 (5H, m), 8,11 (1H, d, J=8.6 Hz).

C) 2-Benzyl-6-(3,3-Ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridylsulfonyl

505 mg of 2-Benzyl-6-(3,3-Ethylenedioxy-2-pyrrolidinone-1-yl)-3-hydroxypyridine was dissolved in 10 ml of dichloromethane there was added 757 mg N-phenyltrichlorosilane, 61 mg of 4-dimethylaminopyridine and 0.3 ml of triethylamine, followed by stirring at room temperature over night. Then the solvent was removed and the residue was subjected to column chromatography on silica gel using 17% ethyl acetate/hexane as eluent, the La separation and purification to obtain 1.1 g of the target compound.

1H-NMR (CDCl3) δ: of 2.34 (2H, t, J=7.0 Hz), of 3.96 (2H, t, J=7.0 Hz), 4,10-is 4.21 (4H, m), 4,34 was 4.42 (2H, m), 7,20-7,42 (5H, m), to 7.59 (1H, d, J=9,2 Hz), a 8.34 (1H, d, J=9,2 Hz).

d) (3R)-3-[2-Benzyl-6-(3,3-Ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethinyl-3-hinokitiol

7 ml of N,N-dimethylformamide was added to a mixture of 1.1 g of 2-benzyl-6-(3,3-Ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridylmethylamine, 437 mg (3R)-3-ethinyl-3-hinokitiol, 168 mg of tetrakis(triphenylphosphine)palladium (0), 24 mg of copper iodide and 1.1 ml of triethylamine and heated under stirring at 60°C in oil bath for 1.3 hours in nitrogen atmosphere. After cooling, was added ethyl acetate and aqueous ammonia and the mixture was extracted with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel, using 66% ethyl acetate/hexane and 2% methanol/ethyl acetate as eluents, for separation and purification to obtain 669 mg of target compound.

1H-NMR (CDCl3) δ: 1,35-1,45 (1H, m), 1,58-of 1.66 (1H, m), 1,82-of 1.92 (1H, m), 1,95-of 2.09 (2H, m), of 2.34 (2H, t, J=6.8 Hz), 2.71 to 2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2.0 a, 14 Hz), of 4.00 (2H, t, J=6,8 Hz), 4.09 to 4,18 (2H, m), 4,24 (2H, s), 4,34 was 4.42 (2H, m), 7,08-7,28 (5H, m), to 7.67 (1H, d, J=8,4 Hz), by 8.22 (1H, d, J=8,4 Hz).

Example 139: (3R)-3-[2-Benzyl-6-[(3S)-3-fluoro-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-label is imetrix-6-[(3S)-3-(3-nitrobenzenesulfonyl)-2-pyrrolidinone-1-yl]pyridine

2.2 g of 2-Benzyl-3-methoxyethoxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine (example a) was dissolved in 20 ml of ethyl acetate was added 2.3 g of 3-nitrobenzenesulfonamide, 183 mg of 4-dimethylaminopyridine and 3 ml of triethylamine, followed by stirring at room temperature over night. Then added water and the mixture was extracted with ethyl acetate. Next, the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 25-33% ethyl acetate/hexane as eluent, to obtain 3.5 g of the target compound.

1H-NMR (CDCl3) δ: 2,30-to 2.42 (1H, m), 2,68 was 2.76 (1H, m)to 3.35 (3H, s), a 3.87-of 3.94 (1H, m), 4,10 (2H, s), is 4.21 (1H, DDD, J=2,4, 9,2, 12 Hz), 5,14 (2H, s), 5,32 (1H, t, J=8,2 Hz), 7,15-7,27 (5H, m), 7,38 (1H, d, J=9,0 Hz), 7,81 (1H, t, J=7.9 Hz), of 7.97 (1H, d, J=9.0 Hz), scored 8.38 (1H, d, J=7.9 Hz), 8,53 (1H, d, J=7.9 Hz), 8,88 (1H, s).

b) 2-Benzyl-3-methoxyethoxy-6-[(3R)-3-acetoxy-2-pyrrolidinone-1-yl]pyridine

2.7 g of cesium carbonate suspended in 20 ml of DMSO, followed by addition of 1.2 ml of acetic acid. Under stirring at room temperature was added 20 ml dimethylsulfoxide solution containing 3.5 g of 2-benzyl-3-methoxyethoxy-6-[(3S)-3-(3-nitrobenzenesulfonyl)-2-pyrrolidinone-1-yl]pyridine, followed by heating under stirring at 70°C in an oil bath in which Uchenie 3 hours in nitrogen atmosphere. After cooling, was added water and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to separation and purification using column chromatography on silica gel using 33% ethyl acetate/hexane as eluent, to obtain 2.2 g of the target compound.

1H-NMR (CDCl3) δ: 2,00-to 2.18 (1H, m)to 2.18 (3H, s), 2,60 of 2.68 (1H, m), 3,37 (3H, s), 3,84-3,91 (1H, m), 4,11 (2H, s), 4,20 (1H, DDD, J=2,4, 9,2, 12 Hz), further 5.15 (2H, s), the 5.51 (1H, t, J=8.7 Hz), 7.18 in-7,29 (5H, m), the 7.43 (1H, d, J=9.0 Hz), 8,17 (1H, d, J=9.0 Hz).

C) 2-Benzyl-3-methoxyethoxy-6-[(3R)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine

453 mg of 2-benzyl-3-methoxyethoxy-6-[(3R)-3-acetoxy-2-pyrrolidinone-1-yl]pyridine was dissolved in 5 ml of methanol there was added two drops of 28% methanolic solution of sodium methoxide under stirring at room temperature, followed by stirring for 30 minutes. Then added water and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to separation and purification using column chromatography on silica gel, using 66% ethyl acetate/hexane as eluent, to obtain 371 mg of the target compound.

1H-NMR (CDCl3) δ: 1,95-of 2.08 (1H, m), 2,53-of 2.58 (1H, m)3,0 (1H, Sirs), 3,37 (3H, s), 3,76 (1H, TD, J=10 Hz and 6.6 Hz), of 4.12 (2H, s), 4,19 (1H, t, J=9,2 Hz), 4,48 (1H, t, J=10 Hz), 5,14 (2H, s), 7,17-7,30 (5H, m), 7,42 (1H, d, J=9.0 Hz), 8,14 (1H, d, J=9.0 Hz).

d) 2-Benzyl-3-methoxyethoxy-6-[(3S)-3-fluoro-2-pyrrolidinone-1-yl]pyridine

3 ml of dichloromethane was added to the 0.18 ml of the TRIFLUORIDE diethylaminoethyl. To the mixture was added dropwise a solution of 3 ml of dichloromethane containing 371 mg of 2-benzyl-3-methoxyethoxy-6-[(3R)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine while cooling in a bath with ethanol/dry ice. The mixture was heated to room temperature and was stirred for 2 hours. Then there was added water and the mixture was extracted with ethyl acetate. Next, the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 17-20% ethyl acetate/hexane as eluent for separation and purification to obtain 116 mg of the target compound.

1H-NMR (CDCl3) δ: 2,20-2/36 (1H, m), 2,52-of 2.64 (1H, m), 3,37 (3H, s), a 3.87-of 3.95 (1H, m), of 4.12 (2H, s), 4,17-4,22 (1H, m), of 5.15 (2H, s), 5,23 (1H, dt, J=53, 7,2 Hz), 7,17-7,29 (5H, m), 7,44 (1H, d, J=9.0 Hz), 8,19 (1H, d, J=9.0 Hz).

(e) (3R)-3-[2-Benzyl-6-[(3S)-3-fluoro-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 138.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1.56 to about 1.75 (1H, m), 1,82-of 1.92 (1H, m), 2.00 in of 2.08 (2H, m), 2.21 are of 2.38 (1H, m), 2,55 of 2.68 (1H, m), 2,72-2,95 (4H, m),3,05 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2.0 a, 14 Hz), 3,85-3,93 (1H, m), 4,19-to 4.28 (1H, m), 4.26 deaths (2H, s), 5,23 (1H, dt, J=7,9, and 7.6 Hz), 7,08-7,28 (5H, m), 7,71 (1H, d, J=8.6 Hz), of 8.27 (1H, d, J=8.6 Hz).

Example 140: (3R)-3-[2-Benzyl-6-[(3R)-3-fluoro-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example C using 2-benzyl-3-methoxyethoxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine (example a).

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1.56 to about 1.75 (1H, m), 1,82-of 1.92 (1H, m), 2.00 in of 2.08 (2H, m), 2.21 are of 2.38 (1H, m), 2,55 of 2.68 (1H, m), 2,72-2,95 (4H, m), 3,05 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2.0 a, 14 Hz), 3,85-3,93 (1H, m), 4,19-to 4.28 (1H, m), 4.26 deaths (2H, s), 5,23 (1H, dt, J=7,9, and 7.6 Hz), 7,08-7,28 (5H, m), 7,71 (1H, d, J=8.6 Hz), of 8.27 (1H, d, J=8.6 Hz).

Example 141: (3R)-3-[2-Benzyl-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: 1,39-1,49 (1H, m), 1,50-of 1.78 (1H, m), 1,82-of 1.92 (1H, m), 1,98-of 2.09 (2H, m), 2,52-2,61 (1H, m), 2,73-to 2.94 (4H, m), 3,05 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2.0 a, 14 Hz), 3.72 points-with 3.79 (1H, m), of 4.12 (1H, DD, J=7,2, 14 Hz), 4,20-of 4.25 (1H, m), 4,25 (2H, s), of 4.49 (1H, DD, J=8,0, 10 Hz), 7,08-7,28 (5H, m), of 7.69 (1H, d, J=8,8 Hz), by 8.22 (1H, d, J=8,8 Hz).

Example 142: (3R)-3-[2-Benzyl-6-[(3R)-3-hydroxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123 except that drew the configuration of the hydroxyl group by the method of example 139.

1H-NMR (CDCl3) δ: 1,39-1,49 (1H, m), 1,50-of 1.78 (1H, m), 1,82-of 1.92 (1H, m), 1,98-2,0 (2H, m), 2,52-2,61 (1H, m), 2,73-to 2.94 (4H, m), 3,05 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2.0 a, 14 Hz), 3.72 points-with 3.79 (1H, m), of 4.12 (1H, DD, J=7,2, 14 Hz), 4,20-of 4.25 (1H, m), 4,25 (2H, s), of 4.49 (1H, DD, J=8,0, 10 Hz), 7,08-7,28 (5H, m), of 7.69 (1H, d, J=8,8 Hz), by 8.22 (1H, d, J=8,8 Hz).

Example 143: (3R)-3-[2-Benzyl-6-[(3S)-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,58 by 1.68 (1H, m), 1.85 to 2,10 (4H, m), 2,41-2,52 (1H, m), 2.70 height of 2.92 (4H, m), 3.04 from (1H, DD, J=2.0 a, 14 Hz)at 3.25 (1H, DD, J=2.0 a, 14 Hz), 3,61 (3H, s), 3,80-a 3.87 (1H, m), 4,10-4,18 (2N, m), 4,24 (2H, s), 7,08-7,27 (5H, m), 7,68 (1H, d, J=8,8 Hz), compared to 8.26 (1H, d, J=8,8 Hz).

Example 144: (3R)-3-[2-Benzyl-6-[(3R)-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 123 except that drew the configuration of the hydroxyl group by the method of example 139.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,58 by 1.68 (1H, m), 1.85 to 2,10 (4H, m), 2,41-2,52 (1H, m), 2.70 height of 2.92 (4H, m), 3.04 from (1H, DD, J=2.0 a, 14 Hz)at 3.25 (1H, DD, J=2.0 a, 14 Hz), 3,61 (ZN, C), 3,80-a 3.87 (1H, m), 4,10-4,18 (2N, m), 4,24 (2H, s), 7,08-7,27 (5H, m), 7,68 (1H, d, J=8,8 Hz), compared to 8.26 (1H, d, J=8,8 Hz).

Example 145: (3S)-3-[2-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethyl-3-hinokitiol

180 mg of target compound was obtained using 200 mg (3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol (example 10) in 2 ml of methanol at normal pressure in an atmosphere of hydrogen using 10 mg of the oxide of the platinum (IV) as catalyst for catalytic reduction.

1H-NMR (CDCl3) δ: 1,15-2,03 (7H, m), 2,37-2.91 in (8H, m), 3,42 (3H, s), 3,45-3,55 (2H, m), 3,66-of 3.77 (2H, m), 3,85-3,88 (1H, m), of 4.05 (2H, s), 4,35-4,39 (1H, m), from 6.22 (1H, d, J=8 Hz), 7,13-to 7.18 (1H, m), 7,20 (1H, d, J=8 Hz), 7,22-7,28 (4H, m).

Example 146: (3R)-3-[(E)-2-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-hinokitiol

270 mg of (3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol (example 10) was dissolved in 10 ml of ethyl ether. Added 300 mg of lithium aluminum hydride, followed by boiling under reflux for 6 hours. Under stirring in an ice bath was added 0.3 ml of water, 0.3 ml of 5N aqueous solution of sodium hydroxide, 1 ml of water and 10 ml of tetrahydrofuran. The mixture was filtered and the filtrate was concentrated. The residue was subjected to column chromatography on NH-silica gel and was suirable 10% methanol/ethyl acetate to obtain 165 mg of the target compound.

1H-NMR (CDCl3) δ: 1,31-of 1.55 (3H, m), 1,72-to 1.77 (1H, m), 2,00-2,10 (1H, m), 2,55-to 2.65 (1H, m), 2,67-and 2.83 (3H, m), 2,85-of 2.97 (2H, m), 3,42 (3H, s), 3,47-3,59 (2H, m), 3,68-with 3.79 (2H, m), 3,84-to 3.89 (1H, m), 4.09 to (2N, C), 4,37-and 4.40 (1H, m), 5,97 (1H, J=16 Hz), 6,24 (1H, d, J=9 Hz), of 6.65 (1H, d, J=16 Hz), 7,11-to 7.18 (1H, m), 7,19-of 7.25 (4H, m), 7,51 (1H, d, J=9 Hz).

Example 147: (3R)-3-[2-Benzyl-6-(2-methoxyethyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 12.

1H-NMR (CDCl3) δ: 1,35-1,45 (1H, m), 1,55-1,65 (1H, m), 1,83-of 1.93 (1H, m), 1,98-of 2.08 (2H, m), 2,7-of 2.93 (4H, m), 3,02 (H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), to 3.41 (3H, s), of 3.69 (2H, t, J=5 Hz), 4,19 (2H, s), of 4.45 (2H, t, J=5 Hz), 6,59 (1H, d, J=8 Hz), 7,14-7,30 (5H, m), 7,53 (1H, d, J=8 Hz).

Example 148: (3R)-3-[2-Benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 12.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,58 was 1.69 (1H, m), 1,82-of 1.93 (1H, m), from 2.00 (2H, quintet, J=6.4 Hz), 2,72-2,94 (6N, m), 3,03 (1H, DD, J=1,2, 14 Hz), 3,24 (1H, DD, J=2.0 a, 14 Hz), to 3.34 (3H, s), 3,51 (2H, t, J=6,4 Hz), 4,20 (2H, s), 4,37 (2H, t, J=6.4 Hz), 6,53 (1H, d, J=8,4 Hz), 7.18 in-7,31 (5H, m), 7,54 (1H, d, J=8,4 Hz).

Example 149: (3S)-3-[2-Benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 12.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,58 was 1.69 (1H, m), 1,82-of 1.93 (1H, m), from 2.00 (2H, quintet, J=6.4 Hz), 2,72-2,94 (6N, m), 3,03 (1H, DD, J=1,2, 14 Hz), 3,24 (1H, DD, J=2.0 a, 14 Hz), to 3.34 (3H, s), 3,51 (2H, t, J=6,4 Hz), 4,20 (2H, s), 4,37 (2H, t, J=6.4 HZ), 6,53 (1H, d, J=8,4 Hz), 7.18 in-7,31 (5H, m), 7,54 (1H, d, J=8,4 Hz).

Example 150: (3R)-3-[2-Benzyl-6-(3-forproper)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 12.

1H-NMR (CDCl3) δ: 1,36-of 1.44 (1H, m), 1,58-of 1.65 (1H, m), 1.85 to of 1.93 (1H, m), 1,99-2,17 (4H, m), 2,74 of 2.92 (4H, m), 3.04 from (1H, d, J=14 Hz)at 3.25 (1H, d, J=14 Hz), 4,20 (2H, s), 4,42 (2H, t, J=6 Hz), 4,58 (2H, dt, J=6, 47 Hz), 6,53 (1H, d, J=8 Hz), 7,16-7,31 (5H, m), 7,55 (1H, d, J=8 Hz).

Example 151: (3R)-3-[2-Benzyl-6-(4-terbutyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized in the same way, the AK in example 12.

1H-NMR (CDCl3) δ: 1,38 of 1.46 (1H, m), of 1.57-1.93 and (6N, m), 2,00-2,09 (2H, m), 2.71 to to 2.94 (4H, m), 3.04 from (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 4,20 (2H, s), or 4.31-4,34 (2H, m), to 4.41-4,55 (2H, m), of 6.52 (1H, d, J=8 Hz), 7,17-7,31 (5H, m), 7,54 (1H, d, J=8 Hz).

Example 152: (3R)-3-[2-Benzyl-6-(4-chlorobutyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 12.

1H-NMR (CDCl3) δ: 1,38 of 1.46 (1H, m), 1,58-1,94 (6N, m), 2,00-2,09 (2H, m), 2,72-to 2.94 (4H, m), 3.04 from (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), is 4.21 (2H, s), or 4.31-4,34 (2H, m), to 4.41-4,55 (2H, m), 6,53 (1H, d, J=8 Hz), 7,17-7,34 (5H, m), 7,55 (1H, d, J=8 Hz).

Example 153: (3R)-3-[2-Benzyl-6-(1,3-dioxolane-2-yl)metiloksi-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 12.

1H-NMR (CDCl3) δ: 1,38 of 1.46 (1H, m), 1,57-of 1.66 (1H, m), 1.85 to of 1.92 (1H, m), 2.00 in 2,07 (2H, m), 2,75-to 2.94 (4H, m), 3,03 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 3,92-of 4.05 (4H, m), 4,20 (2H, s), to 4.38 (2H, d, J=4 Hz), 5,27 (1H, t, J=4 Hz), 6,62 (1H, d, J=8 Hz), 7,17-7,30 (5H, m), 7,56 (1H, d, J=8 Hz).

Example 154: (3R)-3-[2-Benzyl-6-(2-pyridylmethyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 12.

1H-NMR (CDCl3) δ: 1,38 of 1.46 (1H, m), 1,58-of 1.66 (1H, m), 1,86-of 1.94 (1H, m), 2.00 in 2,07 (2H, m), 2,75-to 2.94 (4H, m), 3,05 (1H, d, J=14 Hz), with 3.27 (1H, DD, J=2, 14 Hz), 4,17 (2H, s), of 5.50 (2H, s), to 6.67 (1H, d, J=8 Hz), 7,15-7,22 (6N, m), 7,33 (1H, d, J=8 Hz), 7,58 (1H, d, J=8 Hz), a 7.62 (1H, dt, J=2, 8 Hz), 8,59 at 8.60 (1H, m).

Example 155: (3R)-3-[2-(4-Terbisil)-6-(3-forproposals)-3-pyridyl]ethinyl-3-hinokitiol

A is the first compound was synthesized in the same way, as in example 12, except that 2-benzyl-3-bromo-6-hydroxypyridine substituted 2-(4-terbisil)-3-bromo-6-hydroxypyridine.

1H-NMR (CDCl3) δ: 1,39 of 1.46 (1H, m), 1,58-of 1.94 (2H, m), 2.00 in to 2.18 (4H, m), 2,72-to 2.94 (4H, m), 3,06 (1H, d, J=14 Hz), with 3.27 (1H, DD, J=2, 14 Hz), 4,16 (2H, s)to 4.41 (2H, t, J=6 Hz), 4,59 (2H, dt, J=6, 47 Hz)that is 6.54 (1H, d, J=8 Hz), 6,93-6,97 (2H, m), 7.24 to 7,28 (2H, m), 7,56 (1H, d, J=8 Hz).

Example 156: (3R)-3-[2-(3-Terbisil)-6-(3-forproper)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 12, except that 2-benzyl-3-bromo-6-hydroxypyridine substituted 2-(3-terbisil)-3-bromo-6-hydroxypyridine.

1H-NMR (CDCl3) δ: 1,39 of 1.46 (1H, m), 1,58-of 1.94 (2H, m), 2.00 in to 2.18 (4H, m), 2,72-to 2.94 (4H, m), 3,06 (1H, d, J=14 Hz), with 3.27 (1H, DD, J=2, 14 Hz), 4,19 (2H, s), 4,40-of 4.44 (2H, m), to 4.52 with 4.64 (2H, m), 6,56 (1H, d, J=8 Hz), 6,86-6,91 (1H, m), 6,98-to 7.09 (2H, m), 7,20-7,28 (1H, m), 7,56 (1H, d, J=8 Hz).

Example 157: (3R)-3-[2-(4-Terbisil)-6-(2-methoxyethyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 12, except that 2-benzyl-3-bromo-6-hydroxypyridine substituted 2-(4-terbisil)-3-bromo-6-hydroxypyridine.

1H-NMR (CDCl3) δ: 1,37-of 1.94 (3H, m), 1,98-of 2.09 (2H, m), 2,70-of 3.95 (4H, m), 3,06 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2, 14 Hz), 3,42 (3H, s), of 3.69 (2H, t, J=5 Hz)to 4.16 (2H, s), 4,43 (2H, t, J=5 Hz), is 6.61 (d, J=8 Hz), 6,94 (2H, t, J=9 Hz), 7,25 (2H, DD, J=6, 9 Hz), 7,55 (1H, d, J=8 Hz).

Example 158: 3-[2-Benzyl-6-(2-ethoxyethyl)oxy-3-pyridyl]ethinyl-3-Hinoki is dinol

a) 2-Bromo-6-(2-ethoxyethyl)oxypyridine

1.7 g of 60% oil suspension of sodium hydride suspended in 20 ml of N,N-dimethylformamide, followed by adding 10 ml of N,N-dimethylformamide solution containing a 4.1 ml of 2-ethoxyethanol, with stirring under ice cooling. After stirring for 20 minutes was added in 10 ml of N,N-dimethylformamide solution containing 5 g of 2,6-dibromopyridine, and then the mixture was stirred at room temperature for one hour. Then added water and the mixture was extracted with ethyl acetate. The organic phase was further washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 5% ethyl acetate/hexane as eluent for separation and purification to obtain 4.8 g of the target compound.

1H-NMR (CDCl3) δ: of 1.24 (3H, t, J=7,0 Hz)and 3.59 (2H, q, J=7.0 Hz), of 3.78 (2H, t, J=4,8 Hz), 4,47 (2H, t, J=4,8 Hz), to 6.75 (1H, DD, J=8.0 Hz, 0.7 Hz), 7,05 (1H, DD, J=7.5 Hz, 0.7 Hz), 7,41 (1H, DD, J=8.0 Hz, 7.5 Hz).

b) 2-Benzyl-6-(2-ethoxyethyl)oxypyridine

1,09 mol. tertrahydrofuran ring solution containing benzylaniline slowly dropwise added to a mixture of 1 g of 2-bromo-6-(2-ethoxyethyl)oksipiridina, 145 mg of chloride 1,3-bis(diphenylphosphino)propenies (II) and 5 ml of tetrahydrofuran with stirring under ice cooling in a nitrogen atmosphere. PEFC is stirring for 2.5 hours was added a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. Next, the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 5% ethyl acetate/hexane as eluent for separation and purification to obtain 1 g of the target compound.

1H-NMR (CDCl3) δ: of 1.23 (3H, t, J=7.0 Hz), of 3.57 (2H, q, J=7.0 Hz), 3,76(2H, t, J=4.9 Hz), of 4.00 (2H, s), 4,47 (2H, t, J=4.9 Hz), 6,59 (1H, d, J=8,2 Hz), of 6.65 (1H, d, J=7,2 Hz), 7,19-7,30 (5H, m), 7,44 (1H, DD, J=8,2 Hz, 7.2 Hz).

c) 2-Benzyl-3-bromo-6-(2-ethoxyethyl)oxypyridine

A mixture of 1 g of 2-benzyl-6-(2-ethoxyethyl)oksipiridina, 125 mg tetraethylammonium and 279 mg of potassium hydroxide suspended in 5 ml of an aqueous solution of potassium bromide (2.5 g of potassium bromide was dissolved in 10 ml of water). To the suspension was added dropwise a mixture of 0.23 ml of bromine and 5 ml of the above aqueous solution of potassium bromide through the addition funnel with stirring under ice cooling for 10 minutes. The mixture was heated to room temperature and was stirred overnight. Then added an aqueous solution of sodium sulfite and the mixture was extracted with ethyl acetate. Next, the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 5% ethyl acetate/hexane as eluent for the separation and isdi obtaining 1.2 g of the target compound.

1H-NMR (CDCl3) δ: 1,22 (3H, t, J=7.0 Hz), 3,55 (2H, q, J=7.0 Hz), and 3.72 (2H, t, J=4,8 Hz), 4,18 (2H, s)to 4.41 (2H, t, J=4,8 Hz), 6,53 (1H, d, J=8.6 Hz), 7,19-7,34 (5H, m), 7,30 (1H, d, J=8.6 Hz).

d) 3-[2-Benzyl-3-(2-ethoxyethyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

7 ml of N,N-dimethylformamide was added to a mixture of 2-benzyl-3-bromo-6-(2-ethoxyethyl)oksipiridina, 601 mg 3-ethinyl-3-hinokitiol, 406 mg of tetrakis(triphenylphosphine)palladium (0), 220 mg of copper iodide and 1.7 ml of triethylamine, followed by heating under stirring at 80°in an oil bath for one hour in nitrogen atmosphere. After cooling, was added ethyl acetate. The mixture was filtered through celite and washed with an aqueous solution of ammonia. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel, using ethyl acetate/hexane as eluent for separation and purification to obtain 247 mg of the target compound.

1H-NMR (CDCl3) δ: 1,22 (3H, t, J=7,1 Hz), to 1.38 to 1.48 (1H, m), 1,57-to 1.67 (1H, m), 1,82-of 1.92 (1H, m), 1,98-of 2.08 (2H, m), 2.71 to 2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2.0 a, 14 Hz), of 3.56 (2H, q, J=7,1 Hz), 3,74 (2H, t, J=4,8 Hz), 4,20 (2H, s), to 4.46 (2H, t, J=4,8 Hz), 6,60 (1H, d, J=8.5 Hz), 7.18 in-7,30 (5H, m), 7,54 (1H, d, J=8,5 Hz).

Example 159: 3-[2-Benzyl-6-(2-ethoxypropan)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 158.

1 H-NMR (CDCl3) δ: of 1.20 (3H, t, J=6.9 Hz), of 1.37 to 1.47 (1H, m), 1,5,7-of 1.65 (1H, m), 1,83-of 1.93 (1H, m), a 2.01 (2H, quintet, J=6.4 Hz), 2.00 in of 2.08 (2H, m), 2,72-to 2.94 (4H, m), 3,05 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2.0 a, 14 Hz), of 3.48 (2H, q, J=6, 9 Hz), 3,55 (2H, t, J=6.4 Hz), 4,20 (2H, s), 4,37 (2H, t, J=6.4 Hz), of 6.52 (1H, d, J=8.6 Hz), 7.18 in-7,31 (5H, m), 7,53 (1H, d, J=8.6 Hz).

Example 160: 3-[2-(4-Terbisil)-6-[(3-tetrahydrofuranyl)-metiloksi-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 158.

1H-NMR (CDCl3) δ: of 1.37 to 1.47 (1H, m), 1,58-of 1.92 (3H, m), 1,98-2,12 (2H, m), 2,62-2,95 (4H, m), 3,05 (1H, DD, J=1,6, 14 Hz)at 3.25 (1H, DD, J=2.0 a, 14 Hz), the 3.65 (2H, DD, J=5,2, 8,8 Hz), 3.72 points-of 3.96 (3H, m), 4.09 to 4,18 (3H, m), 4,27 (1H, DD, J=6,4, 11 Hz), 6,53 (1H, d, J=8,4 Hz), to 6.95 (2H, t, J=8,8 Hz), 7,24 (2H, DD, J=5,5, 8,8 Hz), 7,55 (1H, d, J=8,4 Hz).

Example 161: 3-[2-Benzyl-6-[(3-tetrahydrofuranyl)metiloksi-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 158.

1H-NMR (CDCl3) δ: 1,35-1,45 (1H, m), 1,55-of 1.64 (1H, m), rate of 1.67 and 1.75 (1H, m), 1,83-of 1.95 (1H, m), 1,98 is 2.10 (2H, m), 2,62 of 2.92 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2.0 a, 14 Hz), the 3.65 (2H, DD, J=5,7, and 8.8 Hz), to 3.73-to 3.92 (3H, m), 4,10-is 4.21 (3H, m), 4,28 (1H, DD, J=6,6, 11 Hz), of 6.52 (1H, d, J=8.6 Hz), 7,15-to 7.32 (5H, m), 7,54 (1H, d, J=8.6 Hz)

Example 162: 3-[2-(3-Terbisil)-6-(3-methoxypropyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 158.

1H-NMR (CDCl3) δ: 1,35-1,45 (1H, m), 1,58 by 1.68 (1H, m), 1,82-of 1.92 (1H, m), from 2.00 (2H, quintet, J=6.4 Hz), 2,00-2,10 (2H, m), 2,72-2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,23 (1H, is d, J=2,0, 14 Hz), to 3.34 (3H, s), 3,51 (2H, t, J=6.4 Hz), 4,17 (2H, s), 4,36 (2H, t, J=6.4 Hz), 6,53 (1H, d, J=8,4 Hz), 6,82-of 7.25 (4H, m), 7,53 (1H, d, J=8,4 Hz).

Example 163: 3-[2-Benzyl-6-(3-tetrahydropyranyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 158.

1H-NMR (CDCl3) δ: 1,38-of 1.97 (3H, m), 2,00-2,25 (4H, m), 2,70-2,95 (4H, m), 3,05 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2, 14 Hz), of 3.80-4.00 points (4H, m), 4,19 (2H, s), the 5.45 5,52 (1H, m), is 6.54 (1H, d, J=8 Hz), 7,14-7,30 (5H, m), 7,55 (1H, d, J=8 Hz).

Example 164: 3-[2-Benzyl-6-[2-(2-methoxyethyl)oxyethyl]oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 158.

1H-NMR (CDCl3) δ: 1,35-of 1.95 (3H, m), 1,98-of 2.08 (2H, m), 2,70-of 2.93 (4H, m), 3.04 from (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 3,38 (ZN, C), 3,54 is 3.57 (2H, m), 3,65 at 3.69 (2H, m), 3,81 (2H, t, J=5 Hz), 4,19 (2H, C)4,48 (2H, t, J=5 Hz), 6,59 (1H, d, J=8 Hz), 7,14-7,30 (5H, m), 7,55 (1H, d, J=8 Hz).

Example 165: 3-[2-Benzyl-6-(3-hydroxypropyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-bromo-6-(3-hydroxypropyl)oxypyridine

A mixture of 1.0 g of 2-benzyl-3-bromo-6-hydroxypyridine obtained in example 3b, of 0.44 ml 3-bromopropane, 780 mg of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was heated with stirring on an oil bath at a temperature of 80°C for one hour in nitrogen atmosphere. The reaction solution was distributed between ethyl acetate-water and the organic phase is washed with water and saturated salt solution, dried over betwedn the m magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel using 10-20% ethyl acetate/hexane, to obtain 860 mg of the target compound.

1H-NMR (CDCl3) δ: of 1.94 (2H, quintet, J=6 Hz), 2,47 (1H, Sirs), of 3.69 (2H, shirt, J=6 Hz), 4,20 (2H, s), 4,43 (2H, t, J=6 Hz), of 6.49 (1H, d, J=8 Hz), 7.18 in-7,34 (5H, m), 7,66 (1H, d, J=8 Hz).

b) 3-[2-Benzyl-6-(3-hydroxypropyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 860 mg of 2-benzyl-3-bromo-6-(3-hydroxypropyl)-oksipiridina, 400 mg of 3-ethinyl-3-hinokitiol, 150 mg of tetrakis(triphenylphosphine)palladium (0), 10 mg of copper iodide, 1.1 ml of triethylamine and 4 ml of N,N-dimethylformamide was heated with stirring on an oil bath at a temperature of 85°C for 3 hours in nitrogen atmosphere. The reaction solution was distributed between ethyl acetate-water-ammonia solution and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography using NH-silica gel, and was suirable 50-100% ethyl acetate/hexane, and then a 2.5-5% methanol/ethyl acetate to obtain 470 mg of the target compound.

1H-NMR (CDCl3) δ: 1,36 of 1.46 (1H, m), 1,55-of 1.66 (1H, m), 1,83-of 2.08 (5H, m), 2,68-2,96 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 3,68 (2H, t, J=6 Hz), 4.00 points (2H, s), 4,47 (2H, t, J=6 Hz), 6,55 (1H, d, J=9 Hz), 7,16-7,30 (5H, m), EUR 7.57 (1H, d, J=9 Hz).

Example 166: (3R)-3-[2-Benzyl-6-(3-hydroxypropyl)oxy-3-pyridyl]ethinyl-3-Hinkle the Nol

The target compound was synthesized as in example 165.

1H-NMR (CDCl3) δ: 1,36 of 1.46 (1H, m), 1,55-of 1.66 (1H, m), 1,83-of 2.08 (5H, m), 2,68-2,96 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), 3,68 (2H, t, J=6 Hz), 4.00 points (2H, s), 4,47 (2H, t, J=6 Hz), 6,55 (1H, d, J=9 Hz), 7,16-7,30 (5H, m), EUR 7.57 (1H, d, J=9 Hz).

Example 167: 3-[2-Benzyl-6-(2-hydroxyethyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 165.

1H-NMR (CDCl3) δ: 1,37-of 1.93 (3H, m), 1,98-of 2.08 (2H, m), 2,70-2,95 (4H, m), 3.04 from (1H, d, J=14 Hz), 3,26 (1H, DD, J=2, 14 Hz), a 3.87-to 3.92 (2H, m), is 4.21 (2H, s), 4,42-4,47 (2H, m), is 6.61 (1H, d, J=8 Hz), 7,16-7,32 (5H, m), to 7.59 (1H, d, J=8 Hz).

Example 168: 3-[2-Benzyl-6-[3-(3-methoxycarbonylpropionyl)propyl]oxy-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-3-bromo-6-[3-(3-methoxycarbonylpropionyl)-propyl]oxypyridine

509 mg of 2-benzyl-3-bromo-6-(3-hydroxypropyl)oksipiridina (example a) was dissolved in 5 ml dichloromethane. Under stirring with ice cooling was added 0.33 ml of triethylamine and 0,29 ml 3-methoxycarbonylpropionyl. After the temperature of the reaction solution was increased to room temperature, the reaction solution was stirred for 30 minutes, to the reaction solution were added water. The mixture was extracted with ethyl acetate and then the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column is cromatografia on silica gel, using 20% ethyl acetate/hexane as eluent for the separation and purification of obtaining 643 mg of the target compound.

1H-NMR (CDCl3) δ: 2,04 (2H, TT, J=6,2, 6.4 Hz), 2.63 in (4H, s), 3,68 (3H, s), 4,19 (2H, s)to 4.23 (2H, t, J=6.4 Hz), 4,32 (2H, t, J=6.2 Hz), 6,46 (1H, d, J=8.6 Hz), 7,20 and 7.36 (5H, m), 7,63 (1H, d, J=8.6 Hz)

b) 3-[2-Benzyl-6-[3-(3-methoxycarbonylpropionyl) propyl]oxy-3-pyridyl]ethinyl-3-hinokitiol

5 ml of N,N-dimethylformamide was added to the mixture 643 mg of 2-benzyl-3-bromo-6-[3-(3-methoxycarbonylpropionyl)propyl]-oksipiridina, 245 mg of 3-ethinyl-3-hinokitiol, 84 mg of tetrakis(triphenylphosphine)palladium (0), 10 mg of copper iodide and 0.72 ml of triethylamine, followed by heating under stirring at 80°C in an oil bath for two hours in nitrogen atmosphere. After cooling, was added ethyl acetate, and the mixture was washed with an aqueous solution of ammonia. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 50% ethyl acetate/hexane and 2% methanol/ethyl acetate as eluents, for separation and purification to obtain 223 mg of the intended compound.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,57-to 1.67 (1H, m), 1,82-of 1.92 (1H, m), 1,97-of 2.15 (4H, m), 2,61 (4H, s), 2,70-to 2.94 (4H, m), 3.04 from (1H, d, J=14 Hz), 3,24 (1H, DD, J=2.0 a, 14 Hz), 3,68 (3H, s), 4,20 (2H, s), 4,23 (2H, t, J=6.4 Hz), 4,36 (2H, t, J=6.2 Hz), 6,53 (1H, d, J=8,4 Hz), 7.18 in-7,30(5H, m), 7,54 (1H, d, J=8,4 Hz).

Example 169: 3-[2-Benzyl-6-[3-[N-(tert-butoxycarbonyl)-arimidexe]propyl]oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 168.

1H-NMR (CDCl3) δ: of 1.27 (3H, d, J=7,1 Hz), to 1.38 to 1.48 (1H, m), 1,44 (N, C), 1,58 by 1.68 (1H, m), 1,82-of 1.94 (1H, m), 2.00 in of 2.10 (2H, m), of 2.08 (2H, TT, J=6,2, 6.4 Hz), 2,72-2,95 (4H, m), 3,03 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2.0 a, 14 Hz), 4,20 (2H, s), 4,22 is 4.35 (3H, m), 4,36 (2H, t, J=6.2 Hz), 5,04 (1H, Sirs), 6,53 (1H, d, J=8,4 Hz), 7.18 in-7,30 (5H, m), 7,55 (1H, d, J=8,4 Hz).

Example 170: 3-[2-Benzyl-6-[3-[N-(benzyloxycarbonyl)-glycolate]propyl]oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 168.

1H-NMR (CDCl3) δ: 1,35-1,45 (1H, m), 1,55-1,65 (1H, m), 1,82-of 1.92 (1H, m), 1,98 is 2.10 (4H, m), 2,70-2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2.0 a, 14 Hz), of 3.96 (2H, d, J=5.5 Hz), 4,19 (2H, s), the 4.29 (2H, t, J=6.4 Hz), 4,35 (2H, t, J=6.2 Hz), 5,12 (2H, s), 5,28 (1H, Sirs), 6,51 (1H, d, J=8,4 Hz), 7,15-7,24 (10H, m), 7,53 (1H, d, J=8,4 Hz).

Example 171: 3-[2-Benzyl-6-[3-(pivaloyloxy)propyl]oxy-3-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 168.

1H-NMR (CDCl3) δ: 1,18 (N, C), 1,35-1,45 (1H, m), 1,55-1,65 (1H, m), 1.85 to a 2.12 (5H, m), 2.70 height of 2.92 (4H, m), 3,03 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2.0 a, 14 Hz), 4,19 (2H, t, J=6.2 Hz), 4,20 (2H, s), 4,37 (2H, t, J=6.4 Hz), of 6.52 (1H, d, J=8,4 Hz), 7.18 in-7,30 (5H, m), 7,54 (1H, d, J=8,4 Hz).

Example 172: (3R)-3-[2-Benzyl-6-[(tetrahydro-4H-Piran-2-yl)metiloksi]-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6[(tetrahydro-4H-Piran-2-yl)metiloksi]-3-(methoxyethoxy)pyridine

Sodium hydride was added to a mixture of 456 mg of 2-benzyl-6-iodine-3-(methoxyethoxy)pyridine, 122 mg of copper iodide and 3 ml tetrahydropyran-2-methanol, followed by stirring at 90°C for 3 hours. To the reaction solution was added an aqueous solution of ammonium chloride and ethyl acetate, followed by stirring at room temperature for one hour. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 15% ethyl acetate/hexane, obtaining 383 mg of the target compound.

1H-NMR (CDCl3) δ: 1,36-of 1.64 (5H, m), 1,84-1,90 (1H, m), 3,40 (3H, s), 3.43 points-to 3.49 (1H, m), 3,62-3,68 (1H, m), as 4.02-4,07 (3H, m), 4,15-the 4.29 (2H, m), of 5.03 (2H, s), 6,59 (1H, d, J=8 Hz), 7,14-7,34 (6N, m).

b) 2-Benzyl-6-[(tetrahydro-4H-Piran-2-yl)metiloksi]-3-pyridylsulfonyl

2 ml Triperoxonane acid was added to a mixture of 378 mg of 2-benzyl-6-[(tetrahydro-4H-Piran-2-yl)metiloksi]-3-(methoxyethoxy)pyridine and 3 ml of dichloromethane at room temperature, followed by stirring at the same temperature throughout the night. Was added a saturated aqueous solution of sodium bicarbonate and diethyl ether for extraction. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. To 5 ml of d is klimatologi solution, contains the residue was added 424 mg N-phenyltrichlorosilane, 301 μl of triethylamine and 1.3 mg of 4-dimethylaminopyridine, followed by stirring at room temperature for 2 hours. To the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 10% ethyl acetate/hexane, obtaining 428 mg of the target compound.

1H-NMR (CDCl3) δ: 1,36-of 1.64 (5H, m), 1,84-1,90 (1H, m), 3,41-of 3.48 (1H, m), to 3.58-of 3.64 (1H, m), 4,01-4,06 (1H, m), 4,10 (2H, s), 4,18-4,30 (2H, m), 6,70 (1H, d, J=8 Hz), 7,20-7,29 (5H, m), 7,44 (1H, d, J=8 Hz).

(C) (3R)-3-[2-Benzyl-6-[(tetrahydro-4H-Piran-2-yl)metiloksi]-3-pyridyl]ethinyl-3-hinokitiol

A mixture of 428 mg of 2-benzyl-6-[(tetrahydro-4H-Piran-2-yl)metiloksi]-3-pyridylmethylamine, 180 mg of (3R)-3-ethinyl-3-hinokitiol, 57,3 mg tetrakis(triphenylphosphine)-palladium (0), 1.9 mg of copper iodide, 415 μl of triethylamine and 5 ml of N,N-dimethylformamide was stirred at 90°C for 3 hours in nitrogen atmosphere. To the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 3% methanol/ethyl acetate, to obtain 305 mg of the target compound.

1H-NMR (CDCl3) δ: 1,34-of 1.65 (7H, m), 1.85 to 1.91 a (2H, m), 1,98-2,07 (2H, m), 2,75-2,90 (4H, m), 3,03 (1H, d, J=14 Hz), 3,24 (1H, d, J=14 Hz), 3,42-to 3.49 (1H, m), 3,61-3,68 (1H, m), as 4.02-4,07 (1H, m), 4,18-4,34 (4H, m), 6,62 (1H, d, J=8 Hz), 7,14-7,29 (5H, m),7,54 (1H, d, J=8 Hz).

Example 173: 3-[2-Benzyl-6-(2-hydroxy-3-butenyl)oxy-3-pyridyl]ethinyl-3-hinokitiol

a) 2-Benzyl-6-(2-hydroxyethyl)oxy-3-pyridylsulfonyl

The target compound was synthesized as in example 172 a and b, except that tetrahydropyran-2-methanol was replaced by ethylene glycol.

1H-NMR (CDCl3) δ: a 3.87-to 3.89 (2H, m), of 4.12 (2H, s), 4,39 was 4.42 (2H, m), of 6.68 (1H, d, J=8 Hz), 7,21-to 7.32 (5H, m), 7,49 (1H, d, J=8 Hz).

b) 2-Benzyl-6-(2-hydroxy-3-butenyl)hydroxy-3-pyridylsulfonyl

473 mg pyridinediamine was added to the mixture 395 mg of 2-benzyl-6-(2-hydroxyethyl)oxy-3-pyridylmethylamine, 1.4 g of molecular sieves 4A, and 5 ml of dichloromethane at room temperature, followed by stirring for 3 hours. The mixture was filtered through celite and the solvent was removed. To 5 ml diethylamino solution containing the residue at 0°With added 236 μl of tertrahydrofuran ring solution containing 1.1 mol vinylmania, followed by stirring at the same temperature for 40 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride and diethyl ether, the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 30% ethyl acetate/hexane, the floor is rising 46,5 mg of target compound.

1H-NMR (CDCl3) δ: 2,67 of 2.68 (1H, m), of 4.13 (2H, s), 4,19-4,24 (1H, m), 4,37-to 4.41 (1H, m), 4,46 (1H, Sirs), 5,23 at 5.27 (1H, m), are 5.36-5,41 (1H, m), of 5.84-to 5.93 (1H, m), 6,70 (1H, d, J=8 Hz), 7,21-to 7.32 (5H, m), 7,49 (1H, d, J=8 Hz).

c) 3-[2-Benzyl-6-(2-hydroxy-Z-butenyl)oxy-3-pyridyl]-ethinyl-3-hinokitiol

The mixture 46,5 mg of 2-Benzyl-6-(2-hydroxy-3-butenyl)hydroxy-3-pyridylmethylamine, or 22.7 mg 3-ethinyl-3-hinokitiol, 6.6 mg tetrakis(triphenylphosphine)palladium (0), 0.1 mg of copper iodide, 60,1 ál diisopropylethylamine and 1 ml of N,N-dimethylformamide was stirred at 80°C for 3 hours in nitrogen atmosphere. To the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 5% methanol/ethyl acetate, obtaining of 10.7 mg of the target compound.

1H-NMR (CDCl3) δ: 1,38 of 1.46 (1H, m), 1,58-of 1.66 (1H, m), 1,84-of 1.93 (1H, m), 1,99-of 2.08 (2H, m), a 2.75-2.91 in (4H, m), 3.04 from (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), is 4.21 (2H, s), 4,24-to 4.28 (1H, m), 4,39-4,48 (2H, m,), to 5.21-5,24 (1H, m), are 5.36-5,41 (1H, m), 5,85-5,94 (1H, m), 6,60 (1H, d, J=8 Hz), 7,27-7,31 (5H, m), 7,58 (1H, d, J=8 Hz).

Example 174: 3-[2-Benzyl-6-(3-methoxypropyl)thio-3-pyridyl]-ethinyl-3-hinokitiol

a) 2-Benzyl-3-bromo-6-mercaptopyridine

A mixture of 5.0 g of 2-benzyl-3-bromo-6-hydroxypyridine received in the sample receiving 3b, 5.7 g of reagent Losson and 50 ml of toluene was heated under stirring for 6 hours at an oil bath at a temperature of 100°C. To the reaction solution to relax is whether chloroform and silica gel and the mixture was concentrated to dryness. The residue was subjected to column chromatography on silica gel using 10% ethyl acetate/toluene, to obtain 3.5 g of the target compound.

1H-NMR (CDCl3) δ: 4,15 (2H, S), 7,21-7,27 (3H, m), 7,30-7,42 (4H, m).

b) 2-Benzyl-3-bromo-6-(3-methoxypropyl)dipyridine

A mixture of 500 mg of 2-benzyl-3-bromo-6-mercaptopyridine, 360 mg of 3-methoxypropylacetate, 370 mg of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was stirred at room temperature for one hour in nitrogen atmosphere. The reaction solution was distributed between ethyl acetate-water and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel using 1-2% ethyl acetate/hexane, to obtain 425 mg of the target compound.

1H-NMR (CDCl3) δ: of 1.85 (2H, quintet, J=7 Hz), of 3.13 (2H, t, J=7 Hz), 3,32 (3H, s)to 3.41 (2H, t, J=7 Hz), 4,25 (2H, s), to 6.88 (1H, d, J=8 Hz), 7,17-7,34 (5H, m), 7,56 (1H, d, J=8 Hz).

C) 3-[2-Benzyl-6-(3-methoxypropyl)thio-3-pyridyl]ethinyl-3-hinokitiol

Blend 425 mg of 2-benzyl-3-bromo-6-(3-methoxypropyl)-dipyridine, 200 mg of 3-ethinyl-3-hinokitiol, 70 mg of tetrakis(triphenylphosphine)palladium (0), 4.6 mg of copper iodide, 0.5 ml of triethylamine and 2.0 ml of N,N-dimethylformamide was heated with stirring on an oil bath at a temperature of 85°C for 4 hours in nitrogen atmosphere. React the solution was distributed between ethyl acetate-water solution of ammonia, the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography using NH-silica gel, and was suirable 20-100% ethyl acetate/hexane, and then with 2.5% methanol/ethyl acetate to obtain 300 mg of the intended compound.

1H-NMR (CDCl3) δ: 1,36-of 1.93 (5H, m), 1,98-of 2.08 (2H, m), 2,70-to 2.94 (4H, m), 3,03 (1H, d, J=14 Hz), 3,18 (2H, t, J=7 Hz), 3,24 (1H, DD, J=2, 14 Hz), 3,32 (3H, s), 3,42 (2H, t, J=7 Hz), 4.26 deaths (2H, s), 6,97 (1H, d, J=8 Hz), 7,16-7,31 (5H, m), the 7.43 (1H, d, J=8 Hz).

Example 175: 3-[2-Benzyl-6-(3-hydroxypropyl)thio-3 - pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 174.

1H-NMR (CDCl3) δ: 1,36-1,90 (5H, m), 1,98 e 2.06 (2H, m), 2,68-to 2.94 (4H, m), to 3.02 (1H, d, J=14 Hz), up 3.22 (1H, DD, J=2, 14 Hz), or 3.28 (2H, t, J=6 Hz), to 3.67 (2H, t, J=6 Hz), 4,27 (2H, s),? 7.04 baby mortality (1H, d, J=8 Hz,), 7,16-7,31 (5H, m), 7,47 (1H, d, J=8 Hz).

Example 176: (3R)-3-[4-Benzyl-2-(3-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 1.

1H-NMR (CDCl3) δ: 1,38-of 1.92 (3H, m), 2,00-2,11 (2H, m), 2.70 height is 3.00 (4H, m), 3,06 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 4,18 (2H, s), 7,20 (2H, d, J=7 Hz), 7,22-7,29 (1H, m), 7,32 (2H, t, J=7 Hz), 7,39 (1H, DD, J=5, 7 Hz), 7,49 (1H, s), by 8.22-of 8.27 (1H, m), 8,63 (1H, DD, J=2, 5 Hz), a total of 8.74 (1H, s), 9,13 (1H, DD, J=1, 2 Hz).

Example 177: 3-[4-Benzyl-2-(1-methyl-2-oxo-1,2-dihydropyridines-5-yl)-5-pyridyl]ethinyl-3-hinokitiol

The target connection synthesisof what is it as in example 1.

1H-NMR (CDCl3) δ: 1,36 of 1.46 (1H, m), 1.56 to 1,89 (2H, m), 1,99 is 2.10 (2H, m), 2,68-2,96 (4H, m), 3,05 (1H, DD, J=2,14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,63 (3H, s), of 4.12 (2H, s), is 6.61 (1H, d, J=10 Hz), 7,15-7,22 (3H, m), 7,26 (1H, t, J=7 Hz), 7,32 (2H, t, J=7 Hz), 7,76(1H, DD, J=2, 10 Hz), 8,15 (1H, d, J=2 Hz), 8,54 (1H, s).

Example 178: 3-[4-Benzyl-2-(2-cyano-5-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 1.

1H-NMR (CDCl3) δ: 1,38-of 1.92 (3H, m), 2.00 in 2,17 (2H, m), 2.70 height is 3.00 (4H, m), 3,06 (1H, DD, J=2, 14 Hz), 3,26 (1H, DD, J=2, 14 Hz), is 4.21 (2H, s), 7,20 (2H, d, J=7 Hz), 7,28 (1H, t, J=7 Hz), 7,34 (2H, t, J=7 Hz), 7,53 (1H, s), to 7.77 (1H, DD, J=1, 8 Hz), to 8.41 (1H, DD, J=2, 8 Hz), total of 8.74 (1H, s), which 9.22 (1H, DD, J=1, 2 Hz).

Example 179: (3R)-3-[4-Benzyl-2-(2-pyridyl)-5-pyridyl]ethinyl - 3-hinokitiol

The target compound was synthesized as in example 1.

1H-NMR (CDCl3) δ: 1,35-1,90 (3H, m), 2.00 in to 2.15 (2H, m), 2,70-2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), is 4.21 (2H, s), 7,20-7,32 (6N, m), 7,81 (1H, dt, J=2, 8 Hz), 8,29 (1H, s), scored 8.38 (1H, d, J=8 Hz), 8,64-8,67 (1H, m), 8,68 (1H, s).

Example 180: (3R)-3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5 - pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 1.

1H-NMR (CDCl3) δ: 1,30-of 1.95 (3H, m), 2.00 in to 2.15 (2H, m), 2,65-2,95 (4H, m), 3,03 (1H, d, J=14 Hz), 3,23 (1H, d, J=14 Hz), is 4.15 (2H, s), 6,01 (2H, s), 6.87 in (1H, d, J=8 Hz), 7,19 (2H, d, J=8 Hz), 7,22-7,28 (1H, m), 7,32 (2H, t, J=7 Hz), 7,40 (1H, s), 7,42-7,46 (2H, m), 8,65 (1H, s).

Example 181: 3-[4-Benzyl-2-(2-pyrimidyl)-5-pyridyl]ethinyl-3 - hin clininal

The target compound was synthesized as in example 1.

1H-NMR (CDCl3) δ: 1,32-of 1.44 (1H, m), 1,61-to 1.63 (1H, m), 1,84 of 1.99 (1H, m), 2.05 is-is 2.09 (2H, m), 2,75 of 2.92 (4H, m), is 3.08 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), to 4.23 (2H, s), 7,19-7,32 (6N, m), scored 8.38 (1H, s), 8,84 (1H, s), of 8.90 (2H, d, J=5 Hz).

Example 182: 3-[4-Benzyl-2-(5-pyrimidyl)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 1.

1H-NMR (CDCl3) δ: 1,42 of 1.46 (1H, m), 1,64-of 1.88 (2H, m), 2.05 is-of 2.08 (2H, m), 2,75-2,89 (4H, m), 3,06 (1H, d, J=14 Hz), 3,26 (1H, DD, J=2, 14 Hz), of 4.12 (2H, s), 7.18 in-7,3 6 (5H, m), of 7.48 (1H, s), a total of 8.74 (1H, s), 9,23 (1H, s), 9,26 (2H, s).

Example 183: 3-[4-Benzyl-2-(4-pyrimidyl)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 1.

1H-NMR (CDCl3) δ: of 1.42 to 1.47 (1H, m), 1,62 is 1.86 (2H, m), 2.05 is e 2.06 (2H, m), 2,74-only 2.91 (4H, m), 3,05 (1H, DD, J=2, 14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), to 4.23 (2H, s), 7,21-7,33 (5H, m), 8,33-8,35 (2H, m), 8,71 (1H, ), cent to 8.85 (1H, d, J=5 Hz), the 9.25 (1H, d, J=1 Hz).

Example 184: 3-[4-Benzyl-2-(3-pyridil)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 1.

1H-NMR (CDCl3) δ: of 1.42 to 1.47 (1H, m), 1,64-to 1.87 (2H, m), 2.00 in 2,07 (2H, m), 2.77-to is 2.88 (4H, m), 3,06 (1H, d, J=14 HZ), 3,26 (1H, DD, J=2, 14 Hz), to 4.23 (2H, s), 7,22-to 7.32 (5H, m), EUR 7.57-to 7.61 (1H, m), 8,53 (1H, DD, J=1,6, 8.6 Hz), 8,58 (1H, s), to 8.70 (1H, s), 9,18 (1H, DD, J=1,6, 4,9 Hz).

Example 185: 3-[4-Benzyl-2-(4-pyridil)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 1.

1 H-NMR (CDCl3) δ: of 1.40 to 1.47 (1H, m), 1,62-of 1.88 (2H, m), 2.05 is-is 2.09 (2H, m), 2,75 of 2.92 (4H, m), of 3.07 (1H, DD, J=2, 14 Hz), 3,26 (1H, DD, J=2, 14 Hz), 4,20 (2H, s), 7,18 and 7.36 (5H, m), EUR 7.57 (1H, s), 7,98 (1H, DD, J=2, 5 Hz), 8,76 (1H, s), 9,26 (1H, DD, J=1, 5 Hz), 9,71 (1H, DD, J=1, 2 Hz).

Example 186: (3R)-3-[4-Benzyl-2-(1,4-dioxan-2-yl)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 1.

1H-NMR (CDCl3) δ: 1,31-1,49 (1H, m), 1,57-1,90 (2H, m), 2,02-of 2.08 (2H, m), 2,73-2,87 (4H, m), 3,01 (1H, d, J=14 Hz), 3,20 (1H, DD, J=2, 14 Hz), 4.09 to (2N, C), 4,15-4,24 (4H, m), 7,15-7,31 (7H, m), of 8.47 (1H, s).

Example 187: 3-[4-Benzyl-2-(3-oxo-1-cyclohexenyl)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 1, using (3-oxo-1-cyclohexenyl)tributylamine synthesized according to the method described in literature (Tetrahedron Letters, Vol.31, No.13, 1837 (1990)).

1H-NMR (CDCl3) δ: 1,42-of 1.44 (1H, m), 1,62-1,89 (2H, m), 2,02-of 2.16 (4H, m), 2,47-of 2.50 (2H, m), was 2.76-2,87 (6N, m), 3,05 (1H, d, J=14 Hz), 3,24 (1H, d, J=14 Hz), 4,14 (2H, s), 6,63 (1H, s), 7,15-7,43 (6N, m), 8,66 (1H, s).

Example 188: 3-[4-Benzyl-2-(3,4-dihydro-2H-6-pyranyl)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 1, using (3,4-dihydro-2H-6-pyranyl)tributylamine synthesized according to the method described in the literature (Synlett 152 (1994)).

1H-NMR (CDCl3) δ: 1,37-of 1.40 (1H, m), 1,52-1,89 (2H, m), 1,89 is 1.96 (2H, m), 2,01-of 2.05 (2H, m), 2,24-of 2.28 (2H, m), of 2.51 vs. 2.94 (4H, m), 3,01 (1H, m), 3,19 (1H, d, J=14 Hz), 4,10 (2H, s), 4,13-4,18 (2H, m), 6,04-6,06 (N, m), 7,14-7,30 (5H, m), 7,38 (1H, s), 8,55 (1H, s).

Example 189: 3-[4-Benzyl-2-(3-hydroxy-1-butynyl)-5-pyridyl]ethinyl-3-hinokitiol

a) 4-Benzyl-5-bromo-2-(3-hydroxy-1-butenyl)pyridine

650 mg of 4-benzyl-5-bromo-2-pyridylmethylamine (example obtain 1), 115 mg of 1-butyn-3-ol, 100 mg of tetrakis(triphenylphosphine)palladium (0), 30 mg of copper iodide and 1 ml of triethylamine was mixed with 5 ml of N,N-dimethylformamide, followed by stirring for one hour on an oil bath at a temperature of 60°C. After cooling was added aqueous ammonia and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution and then evaporated. The residue was subjected to column chromatography on silica gel and was suirable 30% ethyl acetate/hexane to obtain 410 mg of the target compound.

1H-NMR (CDCl3) δ: and 1.54 (3H, d, J=7 Hz), a 2.01 (1H, d, J=5 Hz), of 4.05 (2H, s), 4,67-of 4.77 (1H, m), 7,12 (1H, s), 7,18 (2H, d, J=7 Hz), 7,29 (1H, t, J=7 Hz), 7,35 (2H, t, J=7 Hz), 8,63 (1H, s).

b) 3-[4-Benzyl-2-(3-hydroxy-1-butynyl)-5-pyridyl]ethinyl-3-hinokitiol

110 mg of 4-benzyl-5-bromo-2-(3-hydroxy-1-butenyl)pyridine, 53 mg of 3-ethinyl-3-hinokitiol, 50 mg of tetrakis-(triphenylphosphine)palladium (0), 7 mg of copper iodide and 0.5 ml of triethylamine was added to 2 ml of 1-methyl-2-pyrrolidinone, followed by stirring for 1 hour on an oil bath at a temperature of 100°C. After cooling, the mixture is evaporated. The residue was subjected to Colo the internal chromatography on NH-silica gel and was suirable 5% methanol/ethyl acetate to obtain 32 mg of the target compound.

1H-NMR (CDCl3) δ: 1,35-1,88 (6N, m), 2,01-2,12 (2H, m), 2,69-to 2.94 (4H, m)to 3.09 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), Android 4.04 (2H, s), 4.72 in (1H, q, J=7 Hz), 7,12-7,16 (MN, m), 7,22-7,33 (3H, m), 8,55 (1H, d, J=2 Hz).

Example 190: 3-[4-Benzyl-2-(3-hydroxybutyl)-5-pyridyl]ethinyl-3-hinokitiol

a) 4-Benzyl-5-bromo-2-(3-hydroxybutyl)pyridine

200 mg of 4-benzyl-5-bromo-2-(3-hydroxy-1-butenyl)pyridine (example a) and 10 mg of platinum oxide (IV) was added to 10 ml methanol, 10 ml of tetrahydrofuran and 10 ml of ethyl acetate, followed by stirring at room temperature under normal pressure in an atmosphere of hydrogen overnight. The catalyst was filtered and the filtrate evaporated to obtain 50 mg of the target compound.

1H-NMR (CDCl3) δ: of 1.20 (3H, d, J=6 Hz), 1.70 to 1,89 (2H, m), 2.77-to 2,89 (2H, m), 3.25 to to 3.38 (1H, Sirs), 3,76-of 3.85 (1H, m), of 4.05 (2H, s), make 6.90 (1H, s), 7,18 (2H, d, J=7 Hz), 7,27 (1H, t, J=7 Hz), 7,33 (2H, t, J=7 Hz), 8,56 (1H, s).

b) 3-[4-Benzyl-2-(3-hydroxybutyl)-5-pyridyl]ethinyl-3-hinokitiol

50 mg of 4-benzyl-5-bromo-2-(3-hydroxybutyl)of pyridine, 20 mg of 3-ethinyl-3-hinokitiol, 20 mg of tetrakis(triphenylphosphine)-palladium (0), 5 mg of copper iodide and 0.5 ml of triethylamine was added to 2 ml of 1-methyl-2-pyrrolidinone, followed by stirring for 1 hour on an oil bath at a temperature of 100°C. After cooling, the mixture is evaporated. The residue was subjected to column chromatography on NH-silica gel and was suirable 5% methanol/ethyl acetate to obtain 3 mg of the target compound.

1H-NMR (CDCl3) δ: of 1.20 (3H, d, J=6 Hz), 1,35-1,90 (5H, m), 1,99-of 2.09 (2H, m), 2,68-2,95 (6N, m), 3.04 from (1H, DD, J=2, 14 Hz), up 3.22 (1H, DD, J=2, 14 Hz), 3,76-of 3.85 (1H, m), 4.09 to (2N, C)6,94 (1H, s), to 7.15 (2H, d, J=7 Hz), 7,24 (1H, t, J=7 Hz), 7,31 (2H, t, J=7 Hz), 8,56 (1H, s).

Example 191: 3-[4-Benzyl-2-(4-hydroxypiperidine)-5-pyridyl]ethinyl-3-hinokitiol

a) 4-Benzyl-5-bromo-2-(3-hydroxypiperidine)pyridine

A mixture of 550 mg of 4-benzyl-5-bromo-2-pyridylcarbonyl-sulfonate (example obtain 1), 600 mg of the hydrochloride of 4-hydroxypiperidine, 1 ml of triethylamine and 2 ml of N,N-dimethylformamide was heated with stirring for 3 hours on an oil bath at a temperature of 100°C in nitrogen atmosphere. After cooling, the mixture was extracted with ethyl acetate/water. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel and was suirable 50% ethyl acetate/hexane to obtain 270 mg of the target compound.

1H-NMR (CDCl3) δ: 1,44-to 1.60 (2H, m), 1,88-of 1.97 (2H, m), 3,03-of 3.12 (2H, m), 3.75 to of 3.96 (3H, m)to 3.99 (2H, s)6,41 (1H, s), 7,19 (2H, d, J=7 Hz), 7,25 (1H, t, J=7 Hz), 7,32 (2H, t, J=7 Hz), to 8.20 (1H, s).

b) 3-[4-Benzyl-2-(4-hydroxypiperidine)-5-pyridyl]ethinyl-3-hinokitiol

A mixture of 270 mg of 4-benzyl-5-bromo-2-(4-hydroxypiperidine)-pyridine, 16,5 mg 3-ethinyl-3-hinokitiol, 50 mg tetrakis(triphenylphosphine)palladium (0), 2 mg of copper iodide, 0.35 ml of triethylamine and 2.0 ml of N,N-dimetilformamida was stirred at 100° C for 3 hours in nitrogen atmosphere. After cooling, the reaction solution was extracted with ethyl acetate-diluted aqueous solution of ammonia. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on NH-silica gel and was suirable 20-100% ethyl acetate/hexane, then 5% methanol/ethyl acetate to obtain 120 mg of the intended compound.

1H-NMR (CDCl3) δ: 1,33-to 1.87 (5H, m), 1,90-of 2.05 (4H, m), 2,65-to 2.94 (4H, m), 2,98 (1H, DD, J=2,14 Hz), 3,12-3,20 (3H, m), 3,88-of 3.96 (1H, m), 3,98-4,07 (4H, m), 6,41 (1H, s), 7,14-to 7.32 (5H, m), by 8.22 (1H, s).

Example 192: 3-[4-Benzyl-2-(morpholino)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 191.

1H-NMR (CDCl3) δ: 1,34-1,87 (MN, m), 1,95-2,07 (2H, m), 2,64 of 2.92 (4H, m), 3.04 from (1H, d, J=14 Hz), 3,18 (1H, DD, J=2, 14 Hz), of 3.48 (4H, t, J=5 Hz), of 3.78 (4H, t, J=5 Hz), a 4.03 (2H, s), 6,36 (1H, s), 7,17 (2N, d, J=8 Hz), 7,22 (1H, t, J=8 Hz), 7,30 (2H, t, J=8 Hz), 8,24 (1H, s).

Example 193: 3-[4-Benzyl-2-(3-methoxypropylamine)-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 191.

1H-NMR (CDCl3) δ: 1,33-1,89 (5H, m), 1,97-2,07 (2H, m), 2,65-of 2.93 (4H, m)to 2.99 (1H, DD, J=2, 14 Hz), 3,18 (1H, DD, J=2, 14 Hz), 3,32 (3H, s)to 3.35 (2H, q, J=6 Hz), 3,47 (2H, t, J=6 Hz), 3,99 (2H, s), 4.92 in (1H, t, J=6 Hz), 6,11 (1H, s), 7,14-to 7.32 (5H, m), 8,16 (1H, s).

Example 194: 3-[4-Benzyl-2-(thiomorpholine)-5-pyridyl]ethinyl-3-Chinook Idina

The target compound was synthesized as in example 191.

1H-NMR (CDCl3) δ: 1,34 is 1.86 (3H, m), 1,95 e 2.06 (2H, m), 2,58-2,94 (8H, m)to 2.99 (1H, DD, J=2,14 Hz), 3,17 (1H, DD, J=2,14 Hz), 3,89-of 3.94 (4H, m), was 4.02 (2H, s), 6.35mm (1H, s), 7,14-to 7.32 (5H, m), by 8.22 (1H, s).

Example 195: (3R)-3-[4-Benzyl-2-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-5-pyridyl]ethinyl-3-hinokitiol

a) 4-Benzyl-5-bromo-2-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine

A mixture of 4.0 g of 4-benzyl-5-bromo-2-pyridylmethylamine, 1.8 g of (3R,4R)-3,4-dihydroxypyrrolidine, 3 ml of 1,8-diazabicyclo[5,4,0]-7-undecene and 5 ml of tetrahydrofuran was heated under stirring for 3 hours on an oil bath at a temperature of 70°C in nitrogen atmosphere. After cooling, the reaction mixture was extracted with a mixture of ethyl acetate-water. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel and was suirable 10% methanol/ethyl acetate to obtain a rate of 1.67 g of the target compound.

1H-NMR (CDCl3) δ: 3,27-to 3.33 (2H, m), 3,61-to 3.67 (2H, m)to 3.99 (2H, s), 4,17-is 4.21 (2H, m), 6,14 (1H, s), 7,20 (2H, d, J=7 Hz), 7,24 (1H, t, J=7 Hz), 7,31 (2H, t, J=7 Hz), of 8.09 (1H, s).

b) 4-Benzyl-5-bromo-2-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]pyridine

190 mg of 60% oil suspension of sodium hydride and 0.3 ml of methyliodide was added to the solution to 1.67 g of 4-benzyl-5-bromo-2-[(3R,4R)-3,4-dihydroxypyrrolidine-yl]pyridine in tetrahydrofuran, followed by stirring for 6 hours. Then the reaction solution was extracted with a mixture of ethyl acetate-water, the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel and was suirable 50% ethyl acetate to obtain 560 mg of the target compound.

1H-NMR (CDCl3) δ: 3,34-3,47 (2H, m), 3,40 (3H, s), to 3.58-to 3.67 (2H, m), 3,82-3,86 (1H, m)to 3.99 (2H, s), 4,37-to 4.41 (1H, m), between 6.08 (1H, s), 7,19 (2H, d, J=7 Hz), 7,24 (1H, t, J=7 Hz), 7,31 (2H, t, J=7 Hz), 8,18 (1H, s).

c) (3R)-3-[4-Benzyl-2-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 191 using (3R)-3-ethinyl-3-hinokitiol.

1H-NMR (CDCl3+CD3OD) δ: 1,35-1,45 (1H, m), 1,52-of 1.62 (1H, m), 1,78-of 1.88 (1H, m), 1,97-of 2.08 (2H, m), 2,60-2,90 (4H, m), 2,95 (1H, d, J=14 Hz), of 3.13 (1H, DD, J=2, 14 Hz), 3,40 (3H, s), 3,40-3,50 (2H, m), to 3.58-3,68 (2H, m), 3,82-3,86 (1H, m), was 4.02 (2H, s), 4,32 is 4.36 (1H, m), 6,13 (1H, s), 7,17 (2H, d, J=7 HZ), 7,21 (1H, t, J=7 Hz), 7,29 (2H, d, J=7 Hz), 8,13 (1H, s).

Example 196: (3R)-3-[4-Benzyl-2-[(3R,4R)-3,4-dimethoxypyrimidine-1-yl]-5-pyridyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 195 using two equivalent methyliodide and sodium hydride in relation to 4-benzyl-5-bromo-2-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine (example a).

1H-NMR (CDCl3) δ: 1,30-of 1.88 (3H, m), 1,95-of 2.08 (2H, m), 2,60-2,90 (4H, m), 2,99 (1H, d, J=14 Hz), 3,17 (1H, d, J=14 Hz), 3,40 (6 is, C)3,50-the 3.65 (4H, m)to 3.92 (2H, Sirs), was 4.02 (2H, s), 6,10 (1H, s), 7,15-to 7.32 (5H, m), by 8.22 (1H, s).

Example 197: 3-[4-Benzyl-2-(2-thiazolyl)-5-pyrimidyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 18.

1H-NMR (CDCl3) δ: of 1.40 to 1.48 (1H, m), 1,61 was 1.69 (1H, m), 1,79-to 1.87 (1H, m), 2,00-2,09 (2H, m), 2,75-to 2.94 (4H, m), 3,05 (1H, DD, J=1, 14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 4,37 (2H, s), 7,21-7,34 (5H, m), 7,56 (1H, d, J=3 Hz), of 8.06 (1H, d, J=3 Hz), the rate of 8.75 (1H, s).

Example 198: 3-[4-Benzyl-2-(2-thienyl)-5-pyrimidyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 18.

1H-NMR (CDCl3) δ: of 1.40 to 1.48 (1H, m), 1,61 by 1.68 (1H, m), 1,81-1,89 (1H, m), 2,01-of 2.08 (2H, m), 2,73-2,95 (4H, m), 3,06 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 4,27 (2H, s), to 7.15 (1H, DD, J=4, 5 Hz), 7,20-7,34 (5H, m)to 7.50 (1H, DD, J=1, 5 Hz), 8,01 (1H, DD, J=1, 4 Hz), 8,61 (1H, s).

Example 199: 3-[4-Benzyl-2-(2-furyl)-5-pyrimidyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 18.

1H-NMR (CDCl3) δ: of 1.39 to 1.47 (1H, m), 1,60 by 1.68 (1H, m), 1,78 is 1.86 (1H, m), 2,01-of 2.08 (2H, m), 2,70-to 2.94 (4H, m), 3.04 from (1H, DD, J=1, 14 Hz), up 3.22 (1H, DD, J=2, 14 Hz), 4,30 (2H, s), to 6.58 (1H, DD, J=2, 3 Hz), 7,20-7,31 (5H, m), of 7.36 (1H, d, J=3 Hz), the 7.65 (1H, d, J=2 Hz), 8,67 (1H, s).

Example 200; 3-[4-Benzyl-2-(2-methoxypyridine-5-yl)-5-pyrimidyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 18, except that (3-pyridyl)tributylamine substituted (2-methoxypyridine-5-yl)tributiloltin.

1H-NMR (CDCl3) δ: 1,401,48 (1H, m), 1,61 by 1.68 (1H, m), 1,83-of 1.92 (1H, m), 2,01 is 2.10 (2H, m), 2,78-to 2.94 (4H, m), of 3.07 (1H, d, J=14 Hz), or 3.28 (1H, DD, J=2, 14 Hz), was 4.02 (3H, s), the 4.29 (2H, s), PC 6.82 (1H, d, J=9 Hz), 7,20 and 7.36 (5H, m), to 8.57 (1H, DD, J=2, 9 Hz), 8,68 (1H, s), a 9.25 (1H, d, J=2 Hz).

Example 201: (3R)-3-[4-Benzyl-2-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl)-3-pyrimidyl]ethinyl-3-hinokitiol

a) 4-Benzyl-5-bromo-2-(3R,4R)-3,4-dihydroxypyrrolidine-1-yl)-3-pyrimidine

644 μl of 1,8-diazabicyclo[5,4,0]-7-undecene was added to the mixture 509 mg of 4-benzyl-5-bromo-2-chloropyrimidine (example receive 15), 351 mg (3R,4R)-3,4-dihydroxypyrrolidine and 5 ml of 1-methyl-2-pyrrolidinone at room temperature, followed by stirring at 70°C for one hour.

Added water and ethyl acetate and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 20% hexane/ethyl acetate, obtaining 766 mg of target compound.

1H-NMR (CDCl3) δ: of 3.60 (2H, d, J=12 Hz), 3,85 (2H, DD, J=4, 12 Hz), 4,08 (2H, s), or 4.31 (2H, Sirs), 7,20-7,37 (5H, m), compared to 8.26 (1H, s).

b) (3R)-3-[4-Benzyl-2-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl)-3-pyrimidyl]ethinyl-3-hinokitiol

70.0 mg of 60% oil suspension of sodium hydride were added to a mixture of 766 mg of 4-benzyl-5-bromo-2-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]-3-pyrimidine and 10 ml of tetrahydrofuran while cooling with ice and then adding back 99,6 MK is methyliodide. After stirring at room temperature for 6 hours to the reaction solution were added water and ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. A mixture of the residue, 4.5 mg of tetrakis(triphenylphosphine)palladium (0), 0.1 mg of copper iodide, a 32.6 μl of triethylamine and 1 ml of N,N-dimethylformamide was stirred at 90°C for 3 hours in nitrogen atmosphere. To the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel, using 5% ethanol/ethyl acetate, obtaining of 22.0 mg of target compound.

1H-NMR (CDCl3) δ: 1,36 was 1.43 (1H, m), 1,55-of 1.62 (1H, m), 1,78-of 1.85 (1H, m), 2,01-of 2.08 (2H, m), 2,67-2,90 (4H, m), 2.95 and 3.00 for (1H, m), 3,13-3,18 (1H, m)to 3.41 (3H, s), 3,64-a-3.84 (5H, m)4,06 (2H, s), 4,37 (1H, Sirs), 7,18-7,30 (5H, m), 8,29 (1H, s).

Example 202: (3R)-3-[4-Benzyl-2-(2-FuelMAX)-5-pyrimidyl]ethinyl-3-hinokitiol

a) 4-Benzyl-2-(2-FuelMAX)-5-bromopyrimidine

a 14.1 mg of 60% oil suspension of sodium hydride was added to the mixture 73,3 mg of 4-benzyl-5-bromo-2-chloropyrimidine (example receive 15), 1 ml of furfuryl alcohol and 14.8 mg of copper iodide at room temperature, followed by stirring at 90°C for 2 hours. To the reaction solution was added diethyl ether and the organic phase is washed with water and saturated salt solution, dried on the anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 10% ethyl acetate/hexane, obtaining 50.9 mg of target compound.

1H-NMR (CDCl3) δ: 4,19 (2H, s), 5,33 (2H, s), 6,32-6,37 (2H, m), 7,22-7,41 (6N, m), 8,48 (1H, s).

b) (3R)-3-[4-Benzyl-2-(2-FuelMAX)-5-pyrimidyl]ethinyl-3-hinokitiol

A mixture of 50.9 mg of 4-benzyl-2-(2-FuelMAX)-5-bromopyrimidine, and 26.8 mg of (3R)-3-ethinyl-3-hinokitiol, 8.5 mg tetrakis(triphenylphosphine)palladium (0), 0.3 mg of copper iodide, 61,5 μl of triethylamine and 1 ml of N,N-dimethylformamide was stirred at 90°C for 4 hours in nitrogen atmosphere. To the reaction solution was added NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel using 3% methanol/ethyl acetate, to obtain 29.0 mg of target compound.

1H-NMR (CDCl3) δ: 1,38 of 1.46 (1H, m), 1.60-to 1,89 (2H, m), 2.00 in 2,07 (2H, m), 2,73-of 2.93 (4H, m), 3,05 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=2, 14 Hz), 4,19 (2H, s)5,38 (2H, s), 6,32-to 6.39 (2H, m), 7,21-7,30 (5H, m), 7,40-7,41 (1H, m), 8,48 (1H, s).

Example 203: (3R)-3-[4-Benzyl-2-(3-hydroxypropoxy)-5-pyrimidyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 202, except that furfuryl alcohol was replaced with 1,3-propane diol.

1H-NMR (CDCl3) δ: 1,38 of 1.46 (1H, m), 1,58-to 1.67 (1H, m), 1,79-1,89 (1H, m), 1,99-2,07 (4H, m), 2.71 to at 2.93 (4H, m), 3.04 from (1H, d, J=14 Hz), up 3.22 (1H, d, J=14 Hz), of 3.77 (2H, t, J=6 Hz), 4,17 (2H, s)to 4.52 (2H, t, J=6 Hz), 7,20-7,29 (5H, m), to 8.45 (1H,s).

Example 204: 3-(3-Phenyl-5-benzyl-6-pyridazin]ethinyl-3-hinokitiol

a) 3-Phenyl-6-methoxypyridazine

A mixture of 3.0 g of 3-chloro-6-methoxypyridazine, 3.8 g of phenylboric acid, 2.4 g tetrakis(triphenylphosphine)-palladium (0), 160 ml of toluene, 40 ml of methanol, 80 ml of 2 M aqueous solution of sodium carbonate and 30 ml of tetrahydrofuran was stirred while heating at 85°C for one hour. After cooling, the reaction solution was extracted with ethyl acetate. The organic phase was washed with a saturated solution of salt and suirable with ethyl acetate through NH-silica gel (Fiji Silicia). After removal of solvent the residue was led by obtaining 1.8 g of the target compound.

1H-NMR (CDCl3) δ: 4,20 (3H, s), 7,06 (1H, d, J=9 Hz), 7,44-7,52 (3H, m), 7,79 (1H, d, J=9 Hz), 7,99-8,03 (2H, m).

b) 5-(α-Hydroxybenzyl)-3-phenyl-6-methoxypyridazine of 7.7 ml of a hexane solution containing of 1.52 mol n-utility, slowly, was added dropwise in 50 ml of tertrahydrofuran ring solution containing 2.0 ml 2,2,6,6-tetramethylpiperidine, while cooling with ice. After stirring for one hour while cooling with ice, the mixture was cooled to -78°and slowly dropwise added 10 ml of tertrahydrofuran ring solution containing 1.68 g of 3-phenyl-6-methoxypyridazine. After stirring at -78°C for 2 hours slowly dropwise added benzaldehyde. After stirring at -78°there for another 30 minutes, the mixture was stirred at room temperature overnight. To the reaction solution was added ice water, extracted with ethyl acetate and the organic phase was washed with a saturated solution of salt. After removal of solvent the residue was subjected to chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (3:1), and then hexane/ethyl acetate (1:1) to give 1.39 g of the target compound.

1H-NMR (CDCl3) δ: 4,15 (3H, s), of 5.99 (1H, s), 7,17-7,69 (N, m), 7,99-of 8.04 (2H, m).

c) 5-(α-Acetoxymethyl)-3-phenyl-6-methoxypyridazine

5.0 ml of acetic anhydride slowly was added dropwise to a solution of 1.39 g of 5-(α-hydroxybenzyl)-3-phenyl-6-methoxypyridazine, 174 mg of 4-dimethylaminopyridine and 1.0 of triethylamine in 10 ml of dichloromethane under ice cooling. After stirring at room temperature for one hour to the reaction solution were added water. After extraction with dichloromethane the organic phase was washed with a saturated solution of salt. After removal of solvent the residue was subjected to chromatography on NH-silica gel (Fuji Silicia) and suirable with ethyl acetate to obtain 1,58 g of target compound.

1H-NMR (CDCl3) δ: of 2.20 (3H, s)to 4.16 (3H, s), 7,02 (1H, s), 7,34-7,54 (N, m), 8,00-8,02 (2H, m).

d) 3-Phenyl-5-benzyl-6-methoxypyridazine

600 mg of 10% palladium on coal was added to the mixture 1,58 g of 5-(α-acetoxymethyl)-3-phenyl-6-methoxypyridazine, 2.0 ml of triethylamine and 10 ml of ethanol and the mixture was subjected to is whether the hydrocracking hydrogen atmosphere. The catalyst was filtered and the solvent was removed. Then the residue was subjected to chromatography on NH-silica gel (Fuji Silicia) and suirable with ethyl acetate to obtain 1.31 g of the target compound.

1H-NMR (CDCl3) δ: 3,98 (2H, s), 4,22 (3H, s), 7.23 percent-7,73 (N, m), 7,89-to 7.93 (2H, m).

e) 3-Phenyl-5-benzyl-6-pyridasinylmethane

10 ml of 47% Hydrobromic acid was added to 1.31 g of 3-phenyl-5-benzyl-6-methoxypyridazine followed by heating under stirring on an oil bath at a temperature of 90°C for 3 hours. After cooling the reaction solution in small portions was added to aqueous solution of potassium carbonate for neutralization. After extraction with ethyl acetate the organic phase is washed with saturated salt solution and the solvent was removed to obtain 1.18 g of the crude product. A mixture of 1.18 g of the crude product of 1.93 g of N-phenyltrichlorosilane, 165 mg of 4-dimethylaminopyridine, 943 μl of triethylamine and 10 ml of dichloromethane was stirred at room temperature overnight. After the reaction solution was concentrated, the residue was subjected to chromatography on silica gel with elution with hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (7:1) to give 484 mg of the target compound.

1H-NMR (CDCl3) δ: 4,12 (2H, s), 7.23 percent-of 7.64 (N, m), 7,94-of 7.96 (2H, m).

f) 3-(3-Phenyl-5-benzyl-6-pyridazin)ethinyl-3-Hina is liminal

A mixture of 484 mg of 3-phenyl-5-benzyl-6-pyridasinylmethane, 223 mg of 3-ethinyl-3-hinokitiol, 284 mg of tetrakis(triphenylphosphine)palladium (0), 47 mg of copper iodide, 513 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated with stirring at 80°C for 2 hours in nitrogen atmosphere. The reaction solution was poured into dilute aqueous ammonia solution and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (1:1), then ethyl acetate/methanol (20:1) and was led from a mixture of hexane/ethyl acetate to obtain 413 mg of the target compound.

1H-NMR (CDCl3) δ: 1,25-1,99 (3H, m), 2,02-of 2.15 (2H, m), 2,78-2,95 (4H, m), is 3.08 (1H, d, J=14 Hz), 3,30 (1H, d, J=14 Hz), 4,18 (2H, s), 7,07-7,38 (5H, m), of 7.48-7,52 (4H, m), 7,99-8,02 (2H, m).

Example 205: 3-[3-(3-Pyridyl)-5-benzyl-6-pyridazin]ethinyl-3-hinokitiol

The target compound was synthesized as in example 204.

1H-NMR (CDCl3) δ: 1,38 is 1.96 (3H, m), 2,03-2,17 (2H, m), 2,81 are 2.98 (4H, m), 3,11 (1H, d, J=14 Hz), 3,32 (1H, DD, J=2, 14 Hz), 4,19 (2H, s), 7,19-7,38 (5H, m), 7,43-7,46 (1H, m), 7,53 (1H, s), 8,39-8,42 (1H, m), 8,70-8,71 (1H, m), 9,14 (1H, d, J=2 Hz).

Example 206: 3-(2-Benzyl-3-thienyl)ethinyl-3-hinokitiol

a) 2-Methoxycarbonyl-3-tjenesteproduksjon

A mixture of 4.12 g of 3-hydroxy-2-methoxycarbonylamino, 9,76 g N is entreperneurship, 5,44 ml of triethylamine, 318 4-dimethylaminopyridine and 70 ml of dichloromethane was stirred at room temperature overnight. To the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 10% ethyl acetate/hexane, obtaining 6,21 mg of target compound.

1H-NMR (CDCl3) δ: to 3.92 (3H, s), 7,01 (1H, d, J=5 Hz), 7,55 (1H, d, J=5 Hz).

b) 2-Methoxycarbonyl-3-(trimethylsilylethynyl)thiophene

The mixture 2,07 g 2-methoxycarbonyl-3-tjenesteproduksjon, 2,02 ml trimethylsilylacetamide, of 1.57 g of tetrakis(triphenylphosphine)palladium (0), 272 mg of copper iodide, 2,98 ml of triethylamine and 30 ml of N,N-dimethylformamide was stirred at 65°C for 3 hours in nitrogen atmosphere. To the reaction solution was added silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel using 6% ethyl acetate/hexane, to obtain 1.78 g of the target compound.

1H-NMR (CDCl3) δ: 0,29 (N, C), 3,90 (3H, s), 7,14 (1H, d, J=5 Hz), 7,41 (1H, d, J=5 Hz).

c) 3-Ethinyl-2-(α-hydroxybenzyl)thiophene

131 mg of socialogical was added to the mixture 821 mg 2-methoxycarbonyl-3-(trimethylsilylethynyl)of thiophene and 10 ml of tetrahydrofuran, followed by boiling under reflux for 1.5 hours. After cooling sequentially added 131 μl water, 131 ál of 1N aqueous solution is hydroxide sodium and 393 μl of water followed by filtration through celite. After removal of solvent the 5.25 g of manganese dioxide was added to 10 ml of a dichloromethane solution containing the residue, followed by stirring at room temperature over night. The mixture was filtered through celite and the solvent was removed. 3.5 ml cyclohexanedimethanol solution containing 1.8 mol finelite was added dropwise to a mixture of the residue and 5 ml of diethyl ether at -78°C, followed by stirring at the same temperature for 20 minutes. To the reaction solution was added an aqueous solution of ammonium chloride and the temperature of the system was raised to room temperature. Added ethyl acetate and the organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 10% ethyl acetate/hexane, obtaining of 85.7 mg of target compound.

1H-NMR (CDCl3) δ: 2,59 (1H, d, J=3 Hz), 3,26 (1H, s)6,34 (1H, d, J=3 Hz), 7,02 (1H, d, J=5 Hz), 7,17 (1H, d, J=5 Hz), 7,22-7,38 (3H, m), 7,49-7,51 (3H, m).

d) 2-Benzyl-3-idenitifed

201 mg Centripetality sodium was added to a mixture of 85.7 mg 3-ethinyl-2-(α-hydroxybenzyl)thiophene, 192 mg of zinc iodide and 1.5 ml 1,2-dichloroethane at room temperature over night. To the reaction solution was added 5 ml of diethyl ether, followed by filtration through celite. After TRG is how the solvent was removed, the residue was subjected to column chromatography on silica gel using 2% ethyl acetate/hexane, obtaining of 45.2 mg of target compound.

1H-NMR (CDCl3) δ: 3,21 (1H, s), 4,25 (2H, s), 7,02 (1H, d, J=5 Hz), 7,05 (1H, d, J=5 Hz), 7,21-to 7.32 (5H, m).

e) 3-(2-Benzyl-3-thienyl)ethinyl-3-hinokitiol

0,200 ml Hexane solution containing 1.8 mol of utility was added dropwise to a mixture of 45.2 mg of 2-benzyl-3-idenitify and 1 ml of tetrahydrofuran at -78°C, followed by stirring at the same temperature for 20 hours. To the reaction solution was added dropwise 0.5 ml of tertrahydrofuran ring solution containing 39.9 mg 3 binucleation, at the same temperature, followed by stirring and then at room temperature for 4 hours. To the reaction solution was added 0.5 ml of water and NH-silica gel and the solvent was removed. The residue was subjected to column chromatography on silica gel, using ethyl acetate, obtaining of 39.5 mg of target compound.

1H-NMR (CDCl3) δ: 1,36-of 1.44 (1H, m), 1.56 to of 1.64 (1H, m), 1,86-of 1.95 (1H, m), 1,98-2,07 (2H, m), 2,72 of 2.92 (4H, m), to 3.02 (1H, d, J=14 Hz), 3,24 (1H, DD, J=2, 14 Hz), is 4.21 (2H, s), 6,98 (1H, d, J=5 Hz), 7,06 (1H, d, J=5 Hz), 7,20 (5H, m).

Example 207: 3-(3-Benzyl-5-Persil-2-thienyl)ethinyl-3-hinokitiol

a) 1-Phenyl-1-(3-thienyl)methanol

10 ml of 3-Thiophenecarboxaldehyde was dissolved in 50 ml of tetrahydrofuran. To the mixture was added dropwise 64 ml of hexane/cyclohexane the second solution, containing 1.8 mol finelite, bath with dry ice/acetone. After adding to the mixture an aqueous solution of ammonium chloride was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel and was suirable 10% ethyl acetate/hexane to obtain the target compounds.

1H-NMR (CDCl3) δ: 2,20 (1H, d, J=4 Hz), 5,90 (1H, d, J=4 Hz), 7,00 (1H, DD, J=1.5 Hz), 7,17-7,21 (1H, m), 7,26-7,42 (6N, m).

b) 3-Benzoylthiophene

6.2 g of 1-phenyl-1-(3-thienyl)methanol was dissolved in 50 ml of chloroform. To the mixture was added 30 g of manganese dioxide, followed by stirring overnight. Manganese dioxide was filtered and the filtrate evaporated to obtain between 6.08 g of the target compound.

1H-NMR (CDCl3) δ: 7,39 (1H, DD, J=3.5 Hz), 7,49 (2H, t, J=7 Hz), 7,56 to 7.62 (2H, m), 7,84-7,87 (2H, m), 7,94 (1H, DD, J=1.3 Hz).

c) 3-Benzoyl-5-bromothiophene

3.0 g of 3-benzoylthiophene was dissolved in 10 ml of N,N-dimethylacetamide was added 1 ml of acetic acid and 2.83 g of N-bromosuccinimide, followed by stirring overnight. To the reaction solution was added water, followed by extraction with diethyl ether. The extract is washed with aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to column chromatography on si is imagele and suirable 10% ethyl acetate/hexane to obtain 2.7 g of the target compound.

1H-NMR (CDCl3) δ: 7,50 (2H, t, J=8 Hz), 7,55 (2H, d, J=2 Hz), 7,60 (1H, t, J=8 Hz) 7,79-to 7.84 (3H, m).

d) 3-(3-Benzyl-5-Persil-2-thienyl)ethinyl-3-hinokitiol

2.7 g of 3-benzoyl-5-bromothiophene, 3.0 g parasitisation and 1.0 g of tetrakis(triphenylphosphine)palladium (0) was stirred with 30 ml of xylene, followed by boiling with reverse holodilnik in a stream of nitrogen. The reaction solution was subjected to column chromatography on NH-silica gel and was suirable 10% ethyl acetate/hexane to obtain 1.23 g of the product. 500 mg of the Product was dissolved in 5 ml of tetrahydrofuran and 20 ml of methanol. Added 60 mg of sodium borohydride, followed by stirring at room temperature. To the reaction solution were added water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated. To the residue was added 1 ml of triethylsilane and 10 ml triperoxonane acid, followed by stirring in an ice bath. After the mixture was neutralized with a saturated aqueous solution of sodium carbonate, was extracted with ethyl acetate and evaporated. To the residue was added 10 ml of N,N-dimethylformamide and then to the mixture was added 40 mg of N-bromosuccinimide in an ice bath followed by stirring for one hour. Was added water, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous Sul is blockhead magnesium and then evaporated. To the residue was added 300 mg of 3-ethinyl-3-hinokitiol, 100 mg of tetrakis(triphenylphosphine)palladium (0), 50 mg of copper iodide, 1 ml of triethylamine and 10 ml of N,N-dimethylformamide and then was heated with stirring on an oil bath at a temperature of 100°C. the Reaction solution is evaporated and the residue was subjected to chromatography on NH-silica gel to obtain 225 mg of the target compound.

1H-NMR (CDCl3) δ: 1,37 by 1.68 (2H, m), 1,86 is 1.96 (1H, m), 1,98 is 2.10 (2H, m), was 2.76-2,96 (4H, m), 3,06 (1H, d, J=14 Hz), 3,29 (1H, DD, J=2, 14 Hz), of 4.05 (2H, s), 7,21-7,34 (5H, m), of 7.36 (1H, s), 8,39 (1H, d, J=3 Hz), of 8.47 (1H, DD, J=1, 3 Hz), 8,83 (1H, d, J=1 Hz).

Example 208: 3-[3-Benzyl-6-(hydroxymethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl]ethinyl-3-hinokitiol

a) Ethyl-4-oxo-1-cyclohexanecarboxylate

120 ml of reagent John was added dropwise to 800 ml of acetone solution containing 81,1 g of ethyl 4-hydroxycyclohexanecarboxylate, for 30 minutes in an ice bath. After stirring at the same temperature for 20 minutes was added 2-propanol. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed to obtain 80,0 g of target compound.

1H-NMR (CDCl3) δ: 1,28 (ZN, t, J=7 Hz), 1,98 is 2.10 (2H, m), 2,18 was 2.25 (2H, m), 2,31-2,39 (2H, m), 2,45 is 2.51 (2H, m), 2.71 to 2,77 (1H, m), 4,18 (2H, q, J=7 Hz)

b) 2-Amino-3-benzoyl-6-oxycarbonyl-4,5,6,7-tetrahydro-benzo[b]thiophene

A mixture of 25.2 g of ethyl-4-oxo-1-cyclohexanecarboxylate, 21,4 g benzoylacetonitrile, 25,2 ml diethylamine and 250 ml of ethanol was boiled under reflux for 45 minutes. To the mixture was added 4.7 g of sulfur while boiling under reflux, followed by boiling under reflux for a further 2 hours. After cooling, the solvent was removed and the residue was led from methanol to obtain a 13.4 g of target compound.

1H-NMR (CDCl3) δ: of 1.24 (3H, t, J=7 Hz), 1,52-to 1.61 (1H, m), 1,82 of 1.99 (3H, m), 2.05 is-and 2.79 (3H, m), 4,10-4,18 (2H, m), 6,66 (2H, Sirs), 7,37-of 7.48 (5H, m).

c) 3-(α-Hydroxybenzyl)-6-etoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene

A mixture of 21.5 g of 2-amino-3-benzoyl-6-etoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene, 12.5 g of copper iodide, 26,3 ml diiodomethane, 26,3 ml isopentylamine and 250 ml of tetrahydrofuran was heated under reflux for 1.5 hours. After cooling, to the reaction solution was added 500 ml of ethyl acetate. Insoluble substances were filtered off, the mixture was subjected to column chromatography on silica gel and was suirable hexane, then hexane/ethyl acetate (10:1) obtaining of 17.4 g of the crude product. To 200 ml of an ethanol solution containing of 17.4 g of the crude product in small portions was added 1.5 g of sodium borohydride under ice cooling. After stirring at room temperature for ar is th hour the solvent was removed. To the residue was added ethyl acetate and water, followed by extraction with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane, then hexane/ethyl acetate (4:1) to give 11.2 g of the target compound.

1H-NMR (CDCl3) δ: 1,23 of 1.28 (3H, m), 1,72-of 1.85 (1H, m), 2,09-of 2.28 (2H, m), 2,47 was 2.76 (2H, m), 2.93 which is a 3.06 (2H, m), 4,13-4,18 (2H, m), 5,75-USD 5.76 (1H, m), 7,27-7,38 (6N, m).

d) 3-Benzyl-6-etoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene

A mixture of 8.3 g of 3-(α-hydroxybenzyl)-6-etoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene, 12.5 g of zinc iodide, 2.0 g of cyanoborohydride sodium and 150 ml of dichloromethane was stirred at room temperature for 3 hours. After adding methanol to the reaction solution, the insoluble matter was filtered. The solvent was removed and the residue was subjected to column chromatography on silica gel and was suirable hexane, then hexane/ethyl acetate (10:1) to obtain 5.9 g of the target compound.

1H-NMR (CDCl3) δ: of 1.26 (3H, t, J=7 Hz), 1.77 in-to 1.87 (1H, m), 2,16-2,22 (1H, m), 2,33-to 2.42 (1H, m), 2,54 is 2.75 (2H, m), 2.93 which is a 3.06 (2H, m), 3.75 to 3,86 (2H, m)to 4.16 (2H, q, J=7 Hz), only 6.64 (1H, s), 7,16-7,30 (5H, m).

e) 3-Benzyl-6-(hydroxymethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene

A solution of 10 ml of diethyl ether containing 2.8 g of 3-benzyl-6-etoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene,slowly dropwise added to the suspension in 100 ml of diethyl ether, contains 421 mg socialogical, while cooling with ice. After stirring for 30 minutes to the reaction solution was sequentially added with 0.4 of water, 0.4 ml of 1N aqueous sodium hydroxide solution and 0.4 ml of water and the mixture was dried over anhydrous magnesium sulfate. After filtration the solvent was removed to obtain 2.5 g of the target compound.

1H-NMR (CDCl3) δ: 1,39 of 1.50 (1H, m), 1,94-of 2.09 (2H, m), 2,32 at 2.59 (3H, m), 2,88-to 2.94 (1H, m), 3,63-of 3.64 (2H, m), of 3.77-3,86 (2H m), 6,62 (1H, s), 7,16-7,31 (5H, m).

f) 2-Bromo-3-benzyl-6-hydroxymethyl-4,5,6,7-tetrahydrobenzo[b]thiophene

103 mg of N-bromosuccinimide small portions was added to 5.0 ml of N,N-dimethylformamide solution containing 136 mg of 3-benzyl-6-(hydroxymethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene, while cooling with ice. After stirring for one hour to the reaction solution were added water and the mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. Then the residue was subjected to column chromatography on silica gel and was suirable hexane, then hexane/ethyl acetate (2:1) to give 164 mg of the target compound.

1H-NMR (CDCl3) δ: 1,34-of 1.44 (1H, m), 1,87 of 1.99 (2H, m), 2.23 to-2,8 (MN, m), 2,78-and 2.83 (1H, m), 3,59-of 3.60 (2H, m), 3,81-to 3.92 (2H, m), 7,13-7,28 (5H, m).

g) 3-[3-Benzyl-6-(hydroxymethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl]ethinyl-hinokitiol

A mixture of 164 mg of 2-bromo-3-benzyl-6-hydroxymethyl-4,5,6,7-tetrahydrobenzo[b]thiophene, 88 mg of 3-ethinyl-3-hinokitiol, 112 mg of tetrakis(triphenylphosphine)palladium (0), 19 mg of copper iodide, 203 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated with stirring at 80°C for 1 hour in nitrogen atmosphere. After cooling, the solvent was removed and the residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (1:1)and then ethyl acetate/methanol (20:1) to give 113 mg of the intended compound.

1H-NMR (CDCl3) δ: 1,33-1,44 (2H, m), 1,52 is 1.60 (1H, m), 1,84 is 2.01 (5H, m), 2.23 to-2,31 (1H, m), 2,39 at 2.45 (2H, m), 2.71 to-2,90 (5H, m), 2,99 (1H, d, J=14 Hz), 3,23 (1H, DD, J=2, 14 Hz), 3,57-3,59 (2H, m), 3,86-3,98 (2N, m), 7,14-7,34 (5H, m).

Example 209: 3-(2-Benzyl-7-Persil-3-chinolin]ethinyl-3-hinokitiol

a) 1-Methoxy-3-phenyl-2-propanol

35 ml of a 28% Methanolic solution of sodium methoxide was added to 100 ml of a methanol solution containing 14.0 g of benzylacetone, followed by heating under stirring for 2 hours at an oil bath at a temperature of 80°C. After cooling, the solvent was removed. Was added water, followed by extraction with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed to obtain 17.3 g of target compound.

1H-NMR (CDCl3) δ: 2,75-2,84 (2H, m), 3,28-of 3.32 (1H, m)to 3.38 (3H, s), 3,39-of 3.43 (1H, m), 4,01-a 4.03 (1H, m) 7,22-7,33 (5H, m).

b) 1-Methoxy-3-phenylacetone

20.4 ml of the reagent John slowly dropwise added to 200 ml of acetone solution containing 5.1 g of 1-methoxy-3-phenyl-2-propanol. After stirring for 30 minutes at room temperature to the reaction solution was slowly added 30 ml of 2-propanol. After removal of the solvent there was added water and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (6:1) to obtain 3.7 g of the target compound.

1H-NMR (CDCl3) δ: 3,39 (3H, s), 3,76 (2H, s)4,06 (2H, s), 7,22 and 7.36 (5H, m).

c) 2-Amino-4-bromobenzaldehyde

16,1 ml of water 29% ammonia solution was added to a mixture of 5.0 g of 2-nitro-4-bromobenzaldehyde, 60,4 g of iron sulfate heptahydrate (II), 200 ml of methanol, 100 ml of water and 335 μl of concentrated hydrochloric acid in the oil bath at a temperature of 90°followed by heating under stirring for 10 minutes. After cooling, the insoluble matter was filtered through celite and the filtrate was extracted with ethyl acetate. The organic phase is washed with saturated salt solution and the solvent was removed to obtain 3.9 g of the target compound.

1H-NMR (CDCl3) δ: 6,17 (2H, Sirs), at 6.84-6.89 in (2H, m), 7,33 (1H, d, J=8 Hz), 9,82 (1H, s).

d) 2 Be the ZIL-7-bromo-3-methoxyquinoline

A mixture of 3.3 g of 2-amino-4-bromobenzaldehyde, and 3.3 g of 1-methoxy-3-phenylacetone, an aqueous solution of potassium hydroxide (10 g of potassium hydroxide was dissolved in 10 ml of water) and 20 ml of ethanol was heated under stirring at 100°C for 4 hours in a sealed tube. After cooling, the reaction solution was poured into water and the mixture was extracted with diethyl ether. The organic phase is washed with saturated salt solution and the solvent was removed. The residue was led from a mixture of hexane/ethyl acetate to obtain 3.7 g of the target compound.

1H-NMR (CDCl3) δ: 3,90 (3H, s), 4,34 (2H, s), 7,15-7,27 (4H, m), 7,32-to 7.35 (2H, m), 7,51-7,56 (2H, m), 8,20-8,21 (1H, m).

e) 2-Benzyl-7-Persil-3-methoxyaniline

A mixture of 200 mg of 2-benzyl-7-bromo-3-methoxyaniline, 337 mg parasitisation, 141 mg of tetrakis(triphenylphosphine)palladium (0) and 10 ml of xylene was heated under stirring for 3 hours on an oil bath at a temperature of 150°C in nitrogen atmosphere. After cooling, the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (5:1) and then with hexane/ethyl acetate (1:1) to give 126 mg of the target compound.

1H-NMR (CDCl3) δ: of 3.95 (3H, s), 4,39 (2H, s), 7,16-7,28 (3H, s), 7,35-7,39 (3H, m), 7,83 (1H, d, J=8 Hz), 8,20-8,23 (1H, m), 8,53 (1H, d, J=3 Hz), 8,66-8,68 (2H, m), which 9.22 (1H, m).

f) 2-Benzyl-7-Persil-3-chinainternational

A mixture of 127 mg of 2-benzyl-7-irail-3-methoxyaniline, 40 mg of n-hexadecyl-tri-n-butylphosphonium and 10 ml of 47% Hydrobromic acid was heated under stirring for 48 hours at an oil bath at a temperature of 120°C. the Reaction solution was slowly poured into an aqueous solution of potassium carbonate, the mixture was extracted with diethyl ether and the solvent was removed. To the residue was added 274 mg N-phenyltrichlorosilane, 133 μl of triethylamine, 23 mg of 4-dimethylaminopyridine, 10 ml dichloromethane and 3.0 ml of N,N-dimethylformamide, followed by stirring at room temperature over night. After removal of solvent the residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (4:1) and then with hexane/ethyl acetate (2:1) to give 134 mg of the target compound.

1H-NMR (CDCl3) δ: to 4.46 (2H, s), 7,25-7,40 (5H, m), to 7.77 (1H, d, J=8 Hz), of 8.09 (1H, s), 8.34 per-of 8.37 (1H, m), 8,61 (1H, d, J=2 Hz), 8,72-8,76 (2H, m), a 9.25 (1H, m).

g) 3-(2-Benzyl-7-Persil-3-chinolin)ethynyl-3-hinokitiol

A mixture of 134 mg of 2-benzyl-7-Persil-3-chinainternational, 55 mg of 3-ethinyl-3-hinokitiol, 70 mg of tetrakis(triphenylphosphine)palladium (0), 11 mg of copper iodide, 126 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated with stirring at 85°C for 30 minutes in nitrogen atmosphere. The reaction solution was poured into dilute aqueous ammonia solution and the mixture was extracted with ethyl acetate. Then organic is such a phase was washed with saturated salt solution and the solvent was removed to obtain 76 mg of the target compound.

1H-NMR (CDCl3) δ: 1,41 of 1.46 (1H, m), 1.60-to of 1.93 (2H, m), 2.05 is e 2.06 (2H, m), 2.77-to 2,89 (4H, m), 3.04 from (1H, d, J=14 Hz), 3,21-of 3.25 (1H, m), 4,55 (2H, s), 7,20 and 7.36 (5H, m), 7,89 (1H, d, J=9 Hz), of 8.25 (1H, s), 8,27-8,29 (1H, m), 8,58 (1H, d, J=3 Hz), 8,69-8,71 (2H, m), 9,24 (1H, d, J=1 Hz).

Example 210; 3-(2-Benzyl-7-etoxycarbonyl-3-chinolin)ethinyl-3-hinokitiol

a) 2-Benzyl-7-bromo-3-hydroxyquinolin

A mixture of 1.28 g of 2-benzyl-7-bromo-3-methoxyquinoline obtained in example 209d, 990 mg of n-hexadecyl-tri-n-butylphosphonium, 12 ml of 47% Hydrobromic acid and 10 ml acetic acid was heated under reflux for 12 hours. After cooling, the reaction solution was slowly poured into an aqueous potassium carbonate solution and the mixture was extracted with diethyl ether. The organic phase is washed with saturated salt solution and the solvent was removed to obtain 1.8 g of target compound (containing n-hexadecyl-tri-n-butylphosphonium) in the form of a crude product.

b) 2-Benzyl-7-cyano-3-hydroxyquinolin

A mixture of 370 mg of 2-benzyl-7-bromo-3-hydroxyquinoline solution (containing n-hexadecyl-tri-n-butylphosphonium), 208 mg of cyanide zinc, 272 mg of tetrakis(triphenylphosphine)palladium (0) and 10 ml of N,N-dimethylformamide was heated with stirring for 7 hours at an oil bath at a temperature of 90°C. After cooling, the insoluble matter was filtered through celite and to the filtrate was added an aqueous solution of carbonate kalimas were extracted with ethyl acetate and the organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (3:1) and then with hexane/ethyl acetate (2:1) to give 203 mg of the target compound.

1H-NMR (CDCl3) δ: to 4.28 (2H, s), 7,15-7,30 (5H, m), 7,54 (1H, s), 7,71-7,74 (1H, m), 7,95 (1H, d, J=9 Hz), of 8.37 (1H, s).

c) 2-Benzyl-7-etoxycarbonyl-3-hydroxyquinolin

A mixture of 203 mg of 2-benzyl-7-cyano-3-hydroxyquinoline solution, 2.6 g of potassium hydroxide, and 5.5 ml of water and 20 ml of ethanol was boiled under reflux for 2 hours. After cooling, was added diluted hydrochloric acid. The mixture was extracted with diethyl ether and the solvent was removed. To the residue was added 30 ml of ethanol and 3.0 ml of concentrated sulfuric acid followed by boiling under reflux for one hour. After cooling, the solvent was removed. Added diethyl ether and aqueous potassium carbonate solution, followed by extraction with diethyl ether. The organic phase is washed with saturated salt solution and the solvent was removed to obtain 204 mg of the target compound.

1H-NMR (CDCl3) δ: 1,43 (3H, m), 4,40-of 4.45 (4H, m), 7,20-7,38 (6N, m), to 7.67 (1H, d, J=8 Hz), 8,05-8,08 (1H, m), 8,79 (1H, s).

d) 2-Benzyl-7-etoxycarbonyl-3-chinainternational

204 mg of 2-benzyl-7-etoxycarbonyl-3-hydroxyquinoline solution, 285 mg of N-phenyltrichlorosilane, 134 μl of triethylamine, 24 mg of 4-dimethylaminopyridine the 20 ml of dichloromethane were mixed, followed by stirring at room temperature for 2 hours. After removal of solvent the residue was subjected to column chromatography on silica gel and was suirable hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (5:1) to obtain 220 mg of the target compound.

1H-NMR (CDCl3) δ: of 1.46 (3H, m), of 4.44-4,50 (4H, m), 7,21-7,34 (5H, m), 7,87 (1H, d, J=8 Hz), 8,08 (1H, s), 8,19 is 8.22 (1H, m), 8,84 (1H, d, J=1 Hz).

e) 3-(2-Benzyl-7-etoxycarbonyl-3-chinolin)ethinyl-3-hinokitiol

A mixture of 220 mg of 2-benzyl-7-etoxycarbonyl-3-chinainternational, 83 mg of 3-ethinyl-3-hinokitiol, 116 mg of tetrakis(triphenylphosphine)palladium (0), 19 mg of copper iodide, 209 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was stirred at room temperature for 45 minutes under nitrogen atmosphere. The reaction solution was poured into diluted aqueous solution of ammonia, followed by extraction with ethyl acetate. Then the organic phase is washed with saturated salt solution and the solvent was removed. The residue was subjected to column chromatography on NH-silica gel (Fuji Silicia) and suirable hexane/ethyl acetate (1:1)and then ethyl acetate/methanol (15:1) to obtain 220 mg of the target compound.

1H-NMR (CDCl3) δ: 1,41 by 1.68 (5H, m), 1,81-of 1.88 (1H, m), 2,01-of 2.09 (2H, m), 2,73 of 2.92 (4H, m), 3,02-of 3.06 (1H, m), 3,19-3,24 (1H, m), to 4.46 (2H, q), of 4.54 (2H, s), 7,20-7,58 (5H, m), 7,80 (1H, d, J=8 Hz), 8,21-8,49 (1H, m)8,23 (1H, s), 8,79-8,81 (1H, m).

Example 211: 3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5-thiazolyl)ethinyl-3-hinokitiol

p> a) Benzylchloride

100 ml of Anhydrous diethyl ether was added 12.4 g of magnesium (used to obtain Grignard reagent), then was added dropwise a mixture of 45 ml of benzylbromide and 50 ml of anhydrous ether, using an addition funnel over 30 minutes in a nitrogen atmosphere so that the solution was weakly delegirovali. The solution benzylacrylamide in diethyl ether was added dropwise to a mixture of 40 ml of chloroacetanilide, 778 mg of copper iodide and 100 ml of tetrahydrofuran, using an addition funnel over 2 hours in a nitrogen atmosphere so that the temperature of the system was kept at -60°C. After the addition was completed, the mixture was additionally stirred for 2.5 hours. Then was added a saturated aqueous solution of ammonia and the mixture was extracted with ethyl acetate. Next, the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel, using 1-3% ethyl acetate/hexane as eluent for separation and purification to obtain 20.4 g of the target compound.

1H-NMR (CDCl3) δ: to 3.89 (2H, s), of 4.12 (2H, s), 7,22-7,38 (5H, m).

(b) 3,4-Methylenedioxybenzene

882 mg of 3,4-Methylenedioxyphenethylamine was dissolved in 20 ml of acetone, to which was then added 1 ml of 36% aqueous ammonia solution and the mixture p is remedial at room temperature for 20 minutes. Then added water and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The obtained residue was dissolved in 20 ml of tetrahydrofuran, then added to 1.9 g of reagent Losson and the mixture is boiled under reflux for 3 hours. After cooling, the solvent was removed and the residue was subjected to column chromatography on silica gel using 25% ethyl acetate/hexane as eluent for the separation and purification of obtaining 637 mg of the target compound.

c) 4-Benzyl-2-(3,4-methylenedioxyphenyl)thiazole

A mixture of 372 mg of 3,4-methylenedioxybenzene and 343 mg of baselcommittee was dissolved in 20 ml of ethanol, followed by boiling under reflux for 3 hours. After cooling, the solvent was removed and the obtained crystals were filtered off to obtain 367 mg of the target compound.

1H-NMR (CDCl3) δ: a 4.53 (2H, s), 6,11 (2H, s), of 6.73 (1H, s), of 6.99 (1H, d, J=8,2 Hz), 7,27-7,40 (5H, m), 7,80 (1H, d, J=1.9 Hz), 8,03 (1H, DD, J=1,9, 8,2 Hz).

d) 4-Benzyl-5-bromo-2-(3,4-methylenedioxyphenyl)thiazole

367 mg of 4-benzyl-2-(3,4-methylenedioxyphenyl)thiazole was dissolved in 2 ml N,N-dimethylformamide. Added 244 mg of N-bromosuccinimide under ice cooling, followed by stirring overnight. Then to the reaction solution was added ethyl acetate, followed about what ywaniem water. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to column chromatography on silica gel using 3% ethyl acetate/hexane as eluent for the separation and purification of obtaining 377 mg of the target compound.

1H-NMR (CDCl3) δ: 4,12 (2H, s), 6,01 (2H, s), PC 6.82 (1H, d, J=8.1 Hz), 7,19-7,37 (7H, m).

e) 3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5-thiazolyl]-ethinyl-3-hinokitiol

5 ml of N,N-dimethylformamide was added to a mixture of 377 mg of 4-benzyl-5-bromo-2-(3,4-methylenedioxyphenyl)thiazole, 178 mg of 3-ethinyl-3-hinokitiol, 68 mg of tetrakis(triphenylphosphine)palladium (0), 18 mg of copper iodide and 0.5 ml of triethylamine, followed by heating under stirring at 100°C in oil bath for 15 minutes in nitrogen atmosphere. After cooling, was added ethyl acetate and aqueous ammonia and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. The obtained crystals were filtered off with getting 253 mg of the target compound.

1H-NMR (CDCl3) δ: to 1.38 to 1.48 (1H, m), 1,59 was 1.69 (1H, m), 1.85 to to 1.98 (1H, m), 2.00 in a 2.12 (2H, m), 2.77-to 2,98 (4H, m), 3,03 (1H, d, J=14 Hz)at 3.25 (1H, DD, J=1,9, 14 Hz), 4,18 (2H, s), 6,01 (2H, s), for 6.81 (1H, d, J=8,0 Hz), 7,19-7,40 (7H, m).

Example 212: 3-[4-Benzyl-2-(2-pyridyl)-5-thiazolyl]ethinyl-3-hinokitiol

a) 4-Benzyl-2(2-pyridyl)thiazole

532 mg of 2-Cyanopyridine was dissolved in 2 ml of 1,3-dimethyl-2-imidazolidinone. Was added a mixture of 474 mg of sodium methoxide, 2.2 ml of bis(trimethylsilyl)sulfide and 4 ml of 1,3-dimethyl-2-imidazolidinone followed by heating under stirring at 40°C in an oil bath overnight. After cooling, was added water and the mixture was extracted with ether. Next, the organic phase is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed. To the obtained residue was added 560 mg baselcommittee (example 211A) and 20 ml of ethanol, followed by boiling under reflux for 5 hours. After cooling, the solvent was removed and the residue was subjected to column chromatography on silica gel, using 11% ethyl acetate/hexane as eluent for separation and purification to obtain 302 mg of the target compound.

1H-NMR (CDCl3) δ: is 4.21 (2H, s), 6.89 in (1H, s), 7,21-7,38 (6N, m), 7,78 (1H, DD, J=7,7, and 9.3 Hz), 8,18 (1H, d, J=7,7 Hz), at 8.60 (1H, d, J=4,9 Hz).

b) 3-[4-Benzyl-2-(2-pyridyl)-5-thiazolyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 211.

1H-NMR (CDCl3) δ: of 1.40-1.50 (1H, m), 1,62-1,72 (1H, m), 1.85 to 1,95 (1H, m), 2,02 is 2.10 (2H, m), 2,78-2,95 (4H, m), 3.04 from (1H, d, J=14 Hz), 3,26 (1H, DD, J=2.0 a, 14 Hz), 4,24 (2H, s), 7,20-7,35 (6N, m), 7,76 (1H, DD, J=7,7, and 9.3 Hz), 8,14 (1H, d, J=7,7 Hz), to 8.57 (1H, d, J=4.0 Hz)

Example 213: 3-[4-Benzyl-2-(4-pyridyl)-5-thiazolyl]ethinyl-3-Hinoki is dinol

a) 4-Benzyl-2-(4-pyridyl)thiazole

1 g of 4-Cyanopyridine and 2 ml of triethylamine were dissolved in 20 ml of pyridine. Gaseous hydrogen sulfide was passed through the solution for 30 minutes, and the reaction solution was stirred under heating at 50°C in an oil bath. After cooling the gaseous hydrogen sulfide in the system was replaced with nitrogen gas and the solvent was removed. To the obtained residue was added 619 mg baselcommittee (example 211A) and 20 ml of ethanol, followed by boiling under reflux for 3 hours. After cooling, the solvent was removed and the residue was subjected to column chromatography on silica gel using 20% ethyl acetate/hexane as eluent for separation and purification to obtain 215 mg of the target compound.

1H-NMR (CDCl3) δ: is 4.21 (2H, s)6,91 (1H, s), 7,22-7,40 (5H, m), 7,80 (2H, DD, J=4,6 Hz, 1.6 Hz), 8,69 (2H, DD, J=4,6 Hz, 1.6 Hz).

b) 3-[4-Benzyl-2-(4-pyridyl)-5-thiazolyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 211.

1H-NMR (CDCl3) δ: of 1.40-1.50 (1H, m), 1,62-1,72 (1H, m), 1,82-of 1.92 (1H, m), 2.00 in of 2.10 (2H, m), 2,78-2,95 (4H, m), 3,06 (1H, d, J=14 Hz), 3,26 (1H, DD, J=14 Hz, 2.0 Hz), to 4.23 (2H, s), 7,20-to 7.35 (5H, m), 7,71 (2H, DD, J=1,6, 4,4 Hz), 8,66 (2H, DD, J=1,6, 4,4 Hz).

Example 214: 3-[4-Benzyl-2-(3-pyridyl)-5-thiazolyl]ethinyl-3-hinokitiol

a) 2-Amino-4-benzilate

5.0 g of benzylchloride (example 211A) was dissolved in 20 ml etano is and was added 2.3 g of thiourea, followed by boiling under reflux for 3 hours. After cooling, the solvent was removed and the residue was subjected to column chromatography on silica gel using 50% ethyl acetate/hexane and ethyl acetate as eluent for separation and purification to obtain 1.7 g of the target compound.

1H-NMR (CDCl3) δ: 3,86 (2H, s), is 5.06 (2H, Sirs), 6,01 (1H, s), 7,21-to 7.32 (5H, m).

b) 4-Benzyl-2-jadesola

A mixture of 504 mg of 2-amino-4-benzilate, 520 mg of copper iodide, 1.1 ml diiodomethane and 1.1 ml of isoamylamine suspended in 10 ml of tetrahydrofuran, followed by heating under stirring on an oil bath at 80°C for one hour in nitrogen atmosphere. After cooling, the insoluble matter was filtered through celite. The filtrate was washed with tetrahydrofuran and the solvent was removed. The obtained residue was subjected to column chromatography on silica gel, using 2-4% ethyl acetate/hexane as eluent for separation and purification to obtain 468 mg of the target compound.

1H-NMR (CDCl3) δ: 4,15 (2H, s), of 6.73 (1H, s), 7.24 to to 7.35 (5H, m).

c) 4-benzyl-2-(3-pyridyl)thiazole

5 ml of Xylene was added to a mixture of 468 mg of 4-benzyl-2-jadesola, 580 mg (3-pyridyl)anti-and 90 mg of tetrakis(triphenylphosphine)palladium (0) followed by heating with stirring on an oil bath at 150°C for 2.5 hours. After cooling, the insoluble matter was filtered through celite and the solvent UDA is yiali. The residue was subjected to column chromatography on silica gel, using 20-25% ethyl acetate/hexane as eluent for separation and purification to obtain 101 mg of the target compound.

1H-NMR (CDCl3) δ: is 4.21 (2H, s), at 6.84 (1H, s), 7,33-7,40 (6N, m), 8,24 (1H, DD, J=1,7, 8.1 Hz), 8,64 (1H, DD, J=1,7, 4,9 Hz)to 9.15 (1H, s).

d) 3-[4-Benzyl-2-(3-pyridyl)-5-thiazolyl]ethinyl-3-hinokitiol

The target compound was synthesized as in example 211.

1H-NMR (CDCl3) δ: 1,48 is 1.58 (1H, m), 1,60-1,70 (1H, m), 1.85 to 1,95 (1H, m), 2,03-2,12 (2H, m), 2,75 are 2.98 (4H, m), 3,06 (1H, d, J=14 Hz), with 3.27 (1H, DD, J=2.0 a, 14 Hz), 4,20 (2H, s), 7,19-7,38 (6N, m)to 8.12 (1H, DD, J=1,7, 8.0 Hz), 8,61 (1H, DD, J=1,7, 4,8 Hz), 9,06 (1H, s).

The structural formulas of the examples given in table 5-10.

Table 5

1. Hinkley the new compound (I), represented by the following formula, its salt or hydrate

in which R1represents a hydroxyl group;

W represents (1) -CH2-CH2-, (2) -CH=CH-, or (3)≡ -;

HAr represents a 5-10 membered aromatic heterocycle which has 1 to 2 heteroatoms selected from a nitrogen atom and sulfur atom, which in addition to the group-X-Ar may be substituted by 1-3 groups selected from the

(1) halogen atom;

(2) C1-6alkyl, C2-6alkenylphenol or C2-6alkenylphenol group, optionally substituted

(a) hydroxy;

(b) (C1-6alkoxycarbonyl;

(c)1-6alkanoyl, optionally substituted C1-6alkoxy;

(d) gidroksilirovanii3-8cycloalkyl;

(e)1-6alkoxy;

(f) a 5-6-membered aromatic heterocycle which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, or

(g) cyano;

(3) (C1-6alkoxy, optionally substituted

(a) hydroxy;

(b) (C1-6alkoxy, optionally substituted C1-6alkoxy;

(c) a halogen atom;

(d) 4-6-membered nonaromatic a heterocycle, which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and atom color is Yes;

(e) a 5-6-membered aromatic heterocycle which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom;

(4)1-6allylthiourea, optionally substituted C1-6alkoxy or hydroxy;

(5) 5-6-membered geterotsiklicheskikh, which has a 1-2 oxygen atom in the heterocycle;

(6) an amino group represented by the formula-N(R3R4where

R3and R4are the same or different, and each represents a hydrogen atom or a group selected from the

(a)1-6alkyl groups;

(b) (C1-6alkoxy-C1-6alkyl groups;

(c) carbonyl, substituted C6-14by aryl;

(d)6-14arylsulfonyl or

(e) 4-6-membered non-aromatic heterocycle, which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom;

(7)3-8cycloalkyl or cycloalkenyl hydrocarbon group, optionally substituted

(a) oxopropoxy or

(b) hydroxy;

(8)6-14aromatic hydrocarbon ring, optionally substituted

(a)1-4alkylenedioxy or

(b) hydroxy;

(9) a 5-6-membered aromatic heterocycle which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and ate what and oxygen, optionally substituted

(a) cyano, or

(b) (C1-6alkoxy;

(10) 4-6-membered non-aromatic heterocycle, which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, optionally substituted by one or more groups selected from the

(a) hydroxy;

(b) halogen atom;

(c) cyano;

(d)1-6alkoxycarbonyl;

(e)1-6of alkyl;

(f)1-6alkoxy, which is optionally substituted by a halogen atom or C1-6alkoxy;

(g)1-6alkanoyl;

(h)1-6alkoxy-C1-6of alkyl;

(i) the carbonyl group;

(j)1-4alkylenedioxy;

(k)3-8cycloalkylcarbonyl or3-8cycloalkenyl;

(11) carbamoyl formula-CO-N(R5R6where R5and R6may be the same or different and represent a hydrogen atom, a C6-14aryl, where the specified aryl optionally substituted by a halogen atom, or With3-8cycloalkyl, or R5and R6together form a 3-6-membered ring, and

(12) carbonyl, optionally substituted C1-6alkoxy;

X represents

(1) single bond;

(2)1-6alkylenes chain;

(3) (C1-6alkenylamine chain;

(4)1-6the quinil the new chain or

(5) the formula-Q-, where Q represents an oxygen atom or a sulfur atom, and Ar represents

(1) C6-14aromatic hydrocarbon ring, optionally substituted by one or more groups selected from the

(a) a halogen atom,

(b) (C1-4alkoxy or

(c)1-6allylthiourea, or

(2) a 5-6-membered aromatic heterocycle which has 1 to 2 heteroatoms,

selected from a nitrogen atom and sulfur atom.

2. The compound according to claim 1, its salt or its hydrate, in which

HAr represents a 5-10 membered aromatic heterocycle which has 1 to 2 heteroatoms selected from a nitrogen atom and sulfur atom, which in addition to the group - X-Ar may be substituted by 1-3 groups selected from the

(1) a 5-6-membered aromatic heterocycle, as defined above;

(2) a 5-6-membered non-aromatic heterocycle, as defined above, which may be substituted by one or more groups selected from the

(a) hydroxy;

(b) (C1-6of alkyl and (f)1-6alkoxy;

(3) a benzene ring which may be substituted by one or more groups selected from the

(a) hydroxy, and

(b) (C1-4alkylenedioxy.

3. The compound according to claim 1 or 2, its salt, or a hydrate, in which HAr is a 5-10-membered aromatic heterocycle, which may be the substitute in addition to the Deputy-X-Ar 1-3 groups selected from the

(1) a benzene ring which may be substituted With1-4alkylenedioxy;

(2) a pyridine ring;

(3) the pyrimidine ring;

(4) pyridazinone ring;

(5) pirazinamida ring;

(6) thiophene rings;

(7) piperidino ring which may be substituted With1-6alkoxygroup;

(8) piperazinovogo ring which may be substituted With1-6alkoxygroup;

(9) pyrolidine ring which may be substituted With1-6alkoxygroup;

(10) morpholino ring;

(11)1-6alkyl group which may be substituted With1-6alkoxygroup, and

(12)1-6alkoxygroup, which may be substituted by a hydroxyl group or a C1-6alkoxygroup.

4. The compound according to claim 1 or 2, its salt, or a hydrate, in which HAr is pyridine ring, pyrimidine ring, pyridazine ring, quinoline ring, thiophene ring or tetrahydrobenzene ring which may be substituted in addition to the Deputy-X-Ar 1-3 groups selected from the

(1) a 5-6-membered aromatic heterocycle, as defined above, which may be substituted by one or more1-6alkoxygroup;

(2) the benzene ring, which may be the substituted C 1-4alkylenedioxy;

(3) (C1-6alkyl group which may be substituted by one or more groups selected from the

(a) a hydroxy-group and

(b) (C1-6alkoxygroup, and

(4)1-6alkoxygroup, which may be substituted With1-6alkoxygroup.

5. The compound according to claim 1 or 2, its salt, or a hydrate, in which Ar represents a pyridine ring or a benzene ring, optionally substituted by one or more groups selected from the

(a) a halogen atom,

(b) (C1-4alkoxy or

(c)1-6ancilliary.

6. The compound according to claim 1 or 2, its salt, or a hydrate, in which Ar represents

(1) a benzene ring or a pyridine ring which may have 1-3 substituent selected from the

(a) a halogen atom, and

(b) (C1-4alkoxygroup.

7. The compound according to claim 1 or 2, its salt, or a hydrate, in which X represents-CH2and Ar is a benzene ring.

8. The compound according to claim 1 or 2, its salt, or a hydrate, where the compound represented by the following formula:

in which HAr is a 5-10 membered aromatic heterocycle containing 1-2 heteroatoms selected from a nitrogen atom and sulfur atom, which in addition to the group - X-Ar may be substituted by 1-3 groups selected from

(1) halogen atom,

(2)1-6alkyl, C2-6alkenylphenol or2-6alkenylphenol group, optionally substituted

(a) hydroxy;

(b) (C1-6alkoxycarbonyl;

(c)1-6alkanoyl, optionally substituted C1-6alkoxy;

(d) gidroksilirovanii3-8cycloalkyl;

(e)1-6alkoxy;

(f) a 5-6-membered aromatic heterocycle which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom;

(g) cyano;

(3) (C1-6alkoxy, optionally substituted

(a) hydroxy;

(b) (C1-6alkoxy, optionally substituted C1-6alkoxy;

(c) a halogen atom;

(d) 4-6-membered nonaromatic a heterocycle, which has 1-3 atoms selected from nitrogen atom, sulfur atom and oxygen atom;

(e) a 5-6-membered aromatic heterocycle which has 1-3 atoms selected from nitrogen atom, sulfur atom and oxygen atom;

(4)1-6allylthiourea, optionally substituted C1-6alkoxy or hydroxy;

(5) 5-6-membered geterotsiklicheskikh, which has a 1-2 oxygen atom in the heterocycle;

(6) an amino group represented by the formula-N(R3R4where R3and R4are the same or different, and K is jdy represents a hydrogen atom or a group selected from the

(a)1-6alkyl groups;

(b) (C1-6alkoxy-C1-6alkyl groups;

(c) carbonyl, substituted C6-14by aryl;

(d)6-14arylsulfonyl or

(e) 4-6-membered non-aromatic heterocycle, which has 1-3 atoms selected from nitrogen atom, sulfur atom and oxygen atom;

(7)3-8cycloalkyl or cycloalkenyl hydrocarbon group, optionally substituted

(a) oxopropoxy or

(b) hydroxy;

(8)6-14aromatic hydrocarbon ring, optionally substituted

(a)1-4alkylenedioxy or

(b) hydroxy;

(9) a 5-6-membered aromatic heterocycle which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, optionally substituted

(a) cyano, or

(b) (C1-6alkoxy;

(10) 4-6-membered non-aromatic heterocycle, which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, optionally substituted by one or more groups selected from the

(a) hydroxy;

(b) halogen atom;

(c) cyano;

(d)1-6alkoxycarbonyl;

(e)1-6of alkyl;

(f)1-6alkoxy, which is optionally substituted by a halo atom is s or 1-6alkoxy;

(g)1-6alkanoyl;

(h)1-6alkoxy-C1-6of alkyl;

(i) the carbonyl group;

(j)1-4alkylenedioxy;

(k)3-8cycloalkylcarbonyl or3-8cycloalkenyl;

(11) carbamoyl formula-CO-N(R5R6where R5and R6may be the same or different and represent a hydrogen atom, a C6-14aryl, where the specified aryl optionally substituted by a halogen atom, or With3-8cycloalkyl, or R5and R6together form a 3-8-membered ring;

(12) carbonyl, optionally substituted C1-6alkoxy, X represents

(1) single bond;

(2)1-6alkylenes chain;

(3) (C1-6alkenylamine chain;

(4)1-6alkynylamino chain or

(5) the formula-Q-, where Q represents an oxygen atom or a sulfur atom, and Ar represents

(1) C6-14aromatic hydrocarbon ring, optionally substituted by one or more groups selected from the

(a) a halogen atom,

(b) (C1-4alkoxy or

(c)1-6allylthiourea, or

(2) a 5-6-membered aromatic heterocycle which has 1 to 2 atoms selected from a nitrogen atom and sulfur atom.

9. The connection of claim 8, its salt, or a hydrate, in which HAr is pyridines the ring, pyrimidine ring, pyridazine ring, quinoline ring, thiophene ring or tetrahydrobenzene ring which may be substituted in addition to the Deputy-X-Ar 1-3 groups selected from the

(1) a 5-6-membered aromatic heterocycle, as defined above, which may be substituted by one or more1-6alkoxygroup;

(2) a benzene ring which may be substituted With1-4alkylenedioxy;

(3) (C1-6alkyl group which may be substituted by one or more groups selected from the

(a) hydroxy, and

(b) (C1-6alkoxygroup, and

(4)1-6alkoxygroup, which may be substituted With1-6alkoxygroup;

Ar is optionally halogenated benzene ring or pyridine ring, and X represents-CH2-.

10. The connection of claim 8, its salt, or a hydrate, in which HAr is a pyridine ring, pyrimidine ring or pyridazinone ring which may be substituted in addition to the Deputy-X-Ar 1-31-6alkoxygroup, which may be substituted With1-6alkoxygroup;

Ar is optionally halogenated benzene ring or pyridine ring, and X represents-CH2-.

11. The connection of claim 8, its salt, or a hydrate, in which HAr is is a pyridine ring, pyrimidine ring or pyridazinone ring which may be substituted in addition to the Deputy-X-Ar 1-3 groups selected from the

(1) a benzene ring which may be substituted With1-4alkylenedioxy;

(2) a pyridine ring;

(3) the pyrimidine ring;

(4) pyridazinone ring;

(5) pirazinamida ring;

(6) thiophene rings;

(7) piperidino ring which may be substituted With1-6alkoxygroup;

(8) piperazinovogo ring which may be substituted With1-6alkoxygroup;

(9) pyrolidine ring which may be substituted With1-6alkoxygroup;

(10) morpholino ring;

(11)1-6alkyl group which may be substituted With1-6alkoxygroup, and

(12)1-6alkoxygroup, which may be substituted by a hydroxy-group or1-6alkoxygroup;

Ar is a benzene ring which may be halogenated or pyridine ring, and X represents-CH2-.

12. The compound according to claim 1, its salt or its hydrate, and the connection is any selected from the

3-(4-benzyl-2-phenyl-5-pyrimidyl)ethinyl-3-hinokitiol;

3-[4-benzyl-2-(2-pyridyl)-5-pyrimidyl]ethinyl-3-hinokitiol;

3-[3-benzyl-5-(pyridyl)-2-pyridyl]ethinyl-3-hinokitiol;

3-(3-benzyl-5-phenyl-2-pyridyl)ethinyl-3-hinokitiol;

3-[3-benzyl-5-(3-pyridyl)-2-pyridyl]ethinyl-3-hinokitiol;

3-[3-benzyl-5-(4-pyridyl)-2-pyridyl]ethinyl-3-hinokitiol;

3-(3-benzyl-5-Persil-2-pyridyl)ethinyl-3-hinokitiol;

3-[3-benzyl-5-(2-ethoxycarbonylethyl)-2-pyridyl]ethinyl-3-hinokitiol;

3-[3-benzyl-5-(3-oxobutyl)-2-pyridyl]ethinyl-3-hinokitiol;

3-[3-benzyl-5-(3-hydroxybutyl)-2-pyridyl]ethinyl-3-hinokitiol;

3-[2-benzyl-6-(3-methoxypropylamine)-3-pyridyl]ethinyl-3-hinokitiol;

3-[2-benzyl-6-(2-methoxyethoxy)-3-pyridyl]ethinyl-3-hinokitiol;

3-[2-benzyl-6-(3-methoxyphenoxy)-3-pyridyl]ethinyl-3-hinokitiol;

3-[2-benzyl-6-(4-pyridyl)-3-pyridyl]ethinyl-3-hinokitiol;

3-[2-benzyl-6-(3-pyridyl)-3-pyridyl]ethinyl-3-hinokitiol;

3-(2-benzyl-6-Persil-3-pyridyl)ethinyl-3-hinokitiol;

3-[2-benzyl-6-(2-pyridyl)-3-pyridyl]ethinyl-3-hinokitiol;

3-[4-benzyl-2-(3-pyridyl)-5-pyrimidyl]ethinyl-3-hinokitiol;

3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyrimidyl]ethinyl-3-hinokitiol;

3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethinyl-3-hinokitiol;

3-[4-benzyl-2-(2-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol;

3-[4-benzyl-2-(3-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol;

3-4-benzyl-2-Persil-5-pyridyl]ethinyl-3-hinokitiol;

3-[4-benzyl-2-(4-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol;

3-[4-benzyl-2-(2-methoxyethoxy)-5-pyridyl]ethinyl-3-hinokitiol;

3-[2-benzyl-6-(4-ethoxycarbonylpyrimidine)-3-pyridyl]ethinyl-3-hinokitiol;

3-[2-benzyl-6-morpholino-3-pyridyl]ethinyl-3-hinokitiol;

3-[2-benzyl-6-(4-methoxypiperidine)-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-(2-methoxyethyl)oxy-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethinyl-3-hinokitiol;

(3S)-3-[2-benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-(3-forproper)oxy-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-(1,3-dioxolane-2-yl)metiloksi-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-(3-hydroxypropyl)oxy-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[4-benzyl-2-(3-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[4-benzyl-2-(2-pyridyl)-5-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-[(3R,4S)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-[(3S,4R)-3-fluoro-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]Atin the l-3-hinokitiol;

(3R)-3-[2-benzyl-6-[(3R,4R)-3,4-dimethoxypyrimidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-5-chloro-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-5-bromo-6-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-(3,3-atlantooccipital-1-yl)-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-5-chloro-6-(3,3-atlantooccipital-1-yl)-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-(CIS-3,4-dimethoxypyridine-1-yl)-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-(3,3-Ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-[(3R)-3-hydroxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[2-benzyl-6-[(3R)-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethinyl-3-hinokitiol;

(3R)-3-[4-benzyl-2-(1,4-dioxan-2-yl)-5-pyridyl]ethinyl-3-hinokitiol and

(3R)-3-[4-benzyl-2-[(3R,4R)-3-hydroxy-4-ethoxypyrrolidine-1-yl]-5-pyrimidyl]ethinyl-3-hinokitiol.

13. Inhibitor synthesizing enzyme squalene-containing compound according to any one of claims 1 to 12, its salt or its hydrate.

14. Pharmaceutical composition for suppression of synthesizing enzyme squalene and inhibition of the biosynthesis of cholesterol and triglycerides containing compound (I) according to claim 1, its salt or their is iDRAC.

15. A pharmaceutical composition according to 14, which is a prophylactic or therapeutic agent against diseases for which effective suppression of synthesizing enzyme squalene.

16. A pharmaceutical composition according to 14, which is an inhibitor of the biosynthesis of cholesterol.

17. A pharmaceutical composition according to 14, which is an inhibitor of the biosynthesis of triglycerides.

18. A pharmaceutical composition according to 14, which is an agent for the prophylaxis or treatment of hyperlipidemia.

19. A pharmaceutical composition according to 14, which is an agent for the prevention or treatment of diseases associated with atherosclerosis or ischemic heart disease.

20. A pharmaceutical composition according to 14, which is an agent for the prophylaxis or treatment of hypertension, coronary disease, cerebrovascular diseases, diseases of the aorta, diseases with peripheral artery disease, angina, acute coronary syndromes or myocardial infarction.

21. The method of obtaining genociding of the compound (IV)represented by the following formula:

in which And1and3are the same or different, and each represents

1) a carbon atom optionally substituted by a substitute, specific for a group Hr in item 8, or

2) heteroatom selected from a nitrogen atom and sulfur atom;

And2means

1) carbon atom, optionally substituted Deputy defined for the group HAr in item 8,

2) heteroatom selected from a nitrogen atom, or

3) single bond;

a and b are different and each denotes

1) a group-X-Ar (in which X represents

(1) single bond;

(2)1-6alkylenes chain;

(3) (C1-6alkenylamine chain;

(4)1-6alkynylamino chain or

(5) the formula-Q-, where Q represents an oxygen atom or a sulfur atom, and Ar represents

(1) C6-14aromatic hydrocarbon ring, optionally substituted by one or more groups selected from the

(a) a halogen atom;

(b) (C1-4alkoxy or

(c)1-6allylthiourea, or

(2) a 5-6-membered aromatic heterocycle which has 1 to 2 heteroatoms selected from a nitrogen atom, or sulfur atom, or

optional Deputy, a certain group HAr in item 8; and

R1represents a hydroxyl group, its salt or hydrates, which includes the stage of interaction of aromatic heterocyclic compounds (II)represented by the formula

in which And1And2And3and b are defined above;

L denotes the group that you want,

and genociding compound (III)represented by the following formula:

where R1denotes a hydroxyl group,

in the presence of Pd catalyst, salts

copper and base.

22. The method of obtaining genociding compound (VI)represented by the following formula:

in which And1And2And3and R1have the same values, which are listed below,

Ar represents C6-14aromatic hydrocarbon ring, optionally substituted

(a)1-4alkylenedioxy or

(b) hydroxy, or

5-6-membered aromatic heterocycle which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom and which is optionally substituted

(a) cyano, or

(b) alkoxy,

its salts or their hydrates, which includes a step of interaction genociding compound (V)represented by the following formula:

in which And1and3are the same or different, and each represents

1) carbon atom, optionally substituted at what estealam, defined for the group HAr in item 8, or

2) heteroatom selected from a nitrogen atom and sulfur atom;

And2means

1) carbon atom, optionally substituted Deputy defined for the group HAr in item 8,

2) heteroatom selected from a nitrogen atom, or

3) single bond;

and denotes the group-S-Ar, in which X represents

(1) single bond;

(2)1-6alkylenes chain;

(3) (C1-6alkenylamine chain;

(4)1-6alkynylamino chain or

(5) the formula-Q-, where Q represents an oxygen atom or a sulfur atom, and Ar represents

(1) C6-14aromatic hydrocarbon ring, optionally substituted by one or more groups selected from the

(a) a halogen atom,

(b) (C1-4alkoxy or

(c)1-6allylthiourea, or

(2) a 5-6-membered aromatic heterocycle which has 1 to 2 heteroatoms selected from a nitrogen atom and sulfur atom, and

R1represents a hydroxyl group,

and aromatic cyclic compounds represented by the following formula:

Ar-M

in which Ar denotes a6-14aromatic hydrocarbon ring, optionally substituted

(a)1-4alkylenedioxy or

(b) hydroxy, what do

5-6-membered aromatic heterocycle which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom and which is optionally substituted

(a) cyano, or

(b) (C1-6alkoxy, and

M denotes tri-n-botillo or dihydroxybis,

in the presence of a Pd catalyst.

23. The method of obtaining genociding compound (VIII)represented by the following formula:

in which And1And2And3and R1have the same values, which are listed below,

Ar represents C6-14aromatic hydrocarbon ring, optionally substituted

(a)1-4alkylenedioxy or

(b) hydroxy,

or 5-6-membered aromatic heterocycle which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom and which is optionally substituted

(a) cyano, or

(b) alkoxy,

its salts or their hydrates, which includes a step of interaction genociding compound (VII)represented by the following formula:

in which And1and3are the same or different, and each represents

1) a carbon atom optionally substituted by a Deputy, a certain group for the s HAr in item 8,

2) heteroatom selected from a nitrogen atom and sulfur atom, or

3) single bond;

And2means

1) carbon atom, optionally substituted Deputy opredelennim group HAr in item 8,

2) heteroatom selected from a nitrogen atom, or

3) single bond;

and means

1) a group-X-Ar, in which X represents

(1) single bond;

(2)1-6alkylenes chain;

(3) (C1-6alkenylamine chain;

(4)1-6alkynylamino chain or

(5) the formula-Q-, where Q represents an oxygen atom or a sulfur atom, and Ar represents

(1) C6-14aromatic hydrocarbon ring, optionally substituted by one or more groups selected from the

(a) a halogen atom,

(b) (C1-4alkoxy or

(c)1-6allylthiourea, or

(2) a 5-6-membered aromatic heterocycle which has 1 to 2 atoms selected from a nitrogen atom, or sulfur atom, and

R1represents a hydroxyl group,

M denotes tri-n-botillo or dihydroxybis,

and aromatic cyclic compounds represented by the following formula:

Ar-L

in which Ar denotes a6-14aromatic hydrocarbon ring, optionally substituted

(a)1-4alkylenedioxy or

(b) hydroxy,or

5-6-membered aromatic heterocycle which has 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom and which is optionally substituted

(a) cyano, or

(b) (C1-6alkoxy; and

L denotes the group that you want,

in the presence of a Pd catalyst.

24. A method of preventing or treating diseases in which effectively suppressing synthesizing enzyme squalene, by introducing the patient a pharmacologically effective amount of a compound according to claim 1, its salt or its hydrate.

25. The compound according to claim 1, its salt or hydrate for the production of tools for the prevention and treatment of diseases in which effectively suppressing synthesizing enzyme squalene.

Priority items:

28.09.1999 according to claims 1-20, 25;

15.06.2000 on p-23;

27.09.2000 on PP and 24.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinuclidine of the general formula (I):

wherein © represents phenyl ring, (C4-C9)-heteroaromatic group comprising one or some heteroatoms, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R1, R2 and R3 represent hydrogen halogen atom, phenyl and others; n represents a whole number from 0 to 4; A represents group -CH=CR6-, -CR6=CH-, -CR6R7 and others; R6 and R7 represent hydrogen atom, alkyl and others; m represents a whole number from 0 to 8; p represents a whole number from 1 to 2; and a substitute in azoniabicyclic ring can be at position 2, 3 or 4 including all possible configurations of asymmetric carbon atoms; B represents the group of the formula i) or ii) wherein R10 represents hydrogen atom, hydroxyl group or methyl; each R8 and R9 represents: wherein R11 represents hydrogen, halogen atom, alkyl; Q represents a single bond, -CH2- and others; X represents pharmaceutically acceptable anion of mono- or polyvalent acid. Compounds of the formula (I) possess antagonistic activity with respect to muscarinic M3-receptors and can be used in medicine for treatment of diseases wherein muscarinic M3-receptors are implicated.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

36 cl, 164 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new biarylcarboxamides of the general formula (I): wherein A means compound of the formula (II): ; D means oxygen atom (O) or sulfur atom (S); E means a simple bond, oxygen atom, sulfur atom or NH; Ar1 means 5-membered heteroaromatic ring comprising one nitrogen atom (N) and one sulfur atom (S) or one oxygen atom (O), or one S atom, or one N atom; or 6-membered aromatic ring, or heteroaromatic ring comprising one N atom; Ar2 means 5-membered heteroaromatic ring comprising one S atom or on O atom, or one N atom and one O atom, or one N atom; or 6-membered aromatic ring or heteroaromatic ring comprising one N atom; or 9-membered condensed heteroaromatic ring system comprising one O atom, or 10-membered condensed aromatic ring system, or heteroaromatic ring system comprising one N atom wherein aromatic ring Ar2 is possibly substituted with one or two substitutes taken among halogen atom, (C1-C4)-alkyl, cyano-group (-CN), nitro group (-NO2), NR1R2, OR3, trihalogen-(C1-C4)-alkyl, (C1-C4)-acylamino-, hydroxy-, morpholino-, amino-, methylamino-group, amino-(C1-C4)-alkyl and hydroxymethyl but if Ar1-phenyl and Ar2 represent quinolinyl group then Ar2 is substituted with one or two (C1-C4)-alkyls, -CN, -NO2, NR1R2, OR3 wherein R1, R2 and R3 mean (C1-C4)-alkyl and compound of the formula (III) doesn't represent .

EFFECT: improved preparing and treatment methods.

33 cl, 69 ex

The invention relates to therapeutic active usacycling or azabicyclic compounds, method of their preparation and to pharmaceutical compositions comprising these compounds

The invention relates to new compounds, methods for their preparation, containing compositions and their use in the treatment of

The invention relates to a method for separating 1 - azabicyclo[2.2.2]Octan-3-amine, 2- (diphenylmethyl) -N- [[2-methoxy - 5-(1-methylethyl)phenyl]methyl]

FIELD: medicine.

SUBSTANCE: method involves administering a combination of an agent reducing cholesterol content in blood and reduced coenzyme Q10 of general formula .

EFFECT: enhanced effectiveness of treatment.

8 cl, 2 tbl

FIELD: medicine, cardiology.

SUBSTANCE: the present innovation deals with introducing nitrates, heparin, beta-blocking agents, calcium antagonists, aspirin. Additionally, one should intravenously inject dalargin once daily at the rate of about 5-7 mcg/kg/h at the dosage of 25-30 mcg/kg daily per 100 ml sodium chloride physiological solution for about 5-6 d against the onset of hospitalization period. The innovation provides favorable impact upon diastolic function of left ventricle by decreasing the risk of dangerous arrhythmias and coronary lethality.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, cardiology.

SUBSTANCE: one should introduce the suspension of autologous mononuclear medullary cells without preliminary cultivation in to the mouth of coronary artery nourishing infarction area. Cell suspension should be introduced at the quantity of 100-150 mln. cells immediately after stenting coronary artery due to technique of passive passage. The procedure should be performed on the 14th - 21st d against the onset of the disease mentioned. The method provides efficient counterbalance of cardiomyocytes due to applying valuable stem cells at excluding complications induced by arterial occlusion.

EFFECT: higher efficiency of therapy.

1 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 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: medicine, pharmacy.

SUBSTANCE: invention concerns a new oral formulation of the galenic preparation molsidomine with prolonged releasing an active substance and designated in treatment of stenocardia attack in all its variations (stress stenocardia, spastic stenocardia, nonstable stenocardia). This novel formulation of galenic preparation comprises the therapeutically effective dose of molsidomine or one of its active metabolites and shows the following dissolving rate values in vitro [measured by spectrophotometry method at wavelength 286 or 311 nm according to a method reported in Pharmacopee Europeene, 3-d edition (or U. S. P. XXIV) at 50 rev./min in 500 ml of medium consisting of 0.1 N HCl at 37°C]: 15-25% of molsidomine released in 1 h; 20-35% of molsidomine released in 2 h; 50-65% of molsidomine released in 6 h; 75-95% of molsidomine released in 12 h; >85% of molsidomine released in 18 h, and >90% of molsidomine released in 24 h wherein the maximal blood plasma concentration of molsidomine in vivo appears in 2.5-5 h but preferably in 3-4 h after intake of abovementioned formulation and has value from 25 to 50 ng/ml of blood plasma. Invention provides reducing amount of doses of drug per a day that is more suitable for a patient.

EFFECT: improved and valuable pharmaceutical properties of preparation.

14 cl, 5 dwg, 2 tbl, 7 ex

FIELD: medicine, phytotherapy, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to using Belamcanda chinensis extract for preparing organ-selective medicinal preparation without uterotropic effect or with minimal such effect that is used as estrogen-like preparation. This preparation is used in selective treatment and/or prophylaxis of cardiovascular diseases, in particular, atherosclerosis and osteoporosis, climacteric disturbances, especially for prophylaxis or softening congestions of blood. Extract is used in manufacturing a medicinal preparation in ready formulation for selective treatment and/or prophylaxis of cardiovascular diseases, in particular atherosclerosis, and for selective treatment and/or prophylaxis of osteoporosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood. Extract promotes to effective prophylaxis and/or treatment of cardiovascular diseases, in particular, atherosclerosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood.

EFFECT: valuable medicinal properties of extract.

4 cl, 4 ex

FIELD: medicine, neurology.

SUBSTANCE: the present innovation deals with treating cerebral vascular diseases accompanied with psychic disorders. For this purpose one should introduce homeopathic preparations named Cerebrum compositum and Hepar compositum per 2.2 ml every other day for 20 d intramuscularly, and beginning since the 11th d one should additionally prescribe Vertigohel preparation per 10 drops thrice daily for 10 d. The innovation suggested provides decreased different psychotic and unpsychotic depressive syndromes that considerably improves quality of life in this category of patients.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention proposes applying moxonidine as an active component in preparing pharmaceutical compositions designated for treatment of injuries of heart muscle caused by infarction. Indicated compositions promote to prophylaxis in the infarction progression and to treatment of its complications also.

EFFECT: valuable medicinal properties of composition.

3 cl, 1 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

FIELD: organic chemistry, biochemistry, biotechnology, pharmacy.

SUBSTANCE: invention relates to a compound named perciquinnine of the molecular formula C12H16O3 that can be prepared by culturing fungus ST 001837 (DSM 13303) belonging to basidiomycetes Stereum complicatum and to its pharmaceutically acceptable salts used as inhibitors of lipase. Perciquinnine is prepared by a method involving culturing basidiomycetes of species ST 001837 (DSM 13303) belonging to class of basidiomycetes Stereum complicatum under aerobic conditions in nutrient medium containing carbon and nitrogen sources followed by its isolation and purification. Invention provides the development of pharmaceutical composition possessing ability to inhibit activity of lipase.

EFFECT: improved preparing method, valuable biochemical property of agent.

7 cl, 2 tbl, 6 ex

Up!