Nitrogen containing heterocyclic derivative showing type i 11β -hydroxysteroiddehydrogenase inhibitory activity

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (II)

or to its pharmaceutically acceptable salt wherein the ring A represents a group presented by formula 2 R1 represents hydrogen or C1-6alkyl; R2 represents -SR5, halogen, halogenated C1-6alkyl, etc., R3 represents a group presented by formula: -CH=CH-C(RaRb)-Rc-Rd, or a group presented by formula: -(CReRf)m-C(RaRb)-Rc-Rd wherein radicals and symbols have the values presented in the patent claim, R4 represents -OR6, -CONR7R8, -NR9CONR7R8, -(CR10R11)POH, -(CR10R11)pOCONR7R8, -NR9COR12, -(CR10R11)pNR9COR12, -C(=O)NR9OR12, -CONR9CONR7R8, -CN, halogen or NR9(C=O)OR12; R5 represents C1-6alkyl; R6 represents -CONR7R8; each of R7 and R8 independently represents hydrogen or etc., R10 and R11 independently represents hydrogen; R12 represents C1-6alkyl; each of m and p independently represents an integer 1 to 3. This compound is applicable as a type 1 11β-hydroxysteroiddehydrogenase inhibitor.

EFFECT: invention also refers to single compounds, pharmaceutical compositions on the basis of the declared compounds, to a method for preventing and treating diabetes and the use of the compound of formula (II).

21 cl, 289 ex

 

The present invention relates to pharmaceutically suitable compound having inhibitory activity against 11β-hydroxysteroiddehydrogenase type 1 (hereinafter in this description referred to as 11β-HSD-1).

11β-HSD-1 is an enzyme that converts 11β-dehydrothermal, which is inactive steroid, steroid, and it is considered to be very important mainly biological metabolism (non-patent document 1). In addition, knocked out 11β-HSD-1 mouse has resistance to hyperglycemia-induced obesity and stress (non-patent document 2). In addition, people of a similar phenomenon was observed when injected carbenoxolone, which is an inhibitor of 11β-HSD-1 (non-patent document 3).

These facts suggest the possibility of selective inhibitor of this enzyme as a therapeutic agent in non-insulin-dependent diabetes and obesity (non-patent document 4).

In patent document 1 is disclosed a compound that has inhibitory activity against 11β-HSD-1, but it is limited isoxazol derivative, and this connection has not been disclosed.

In patent documents 2, 3 and 4 revealed adamantane derivatives having inhibitory activity against 11β-HSD-1, but heteroaryl derivative, which is substituted by alkyloxy, this ka is present connection, was not disclosed.

In patent document 5 revealed pyrazole derivative having inhibitory activity against 11β-HSD-1, but this connection has not been disclosed.

In patent document 6 revealed pyrazole derivative having inhibitory activity against 11β-HSD-1, but the substituent in position 3 of the pyrazole is limited carbamoyl, and this connection has not been disclosed.

In patent document 7 open pyrazole derivative, useful as a herbicide, but the substituent in position 1 of the pyrazole is limited to hydrogen, alkyl or aralkyl, and this connection has not been disclosed.

In patent document 8 revealed pyrazole derivative having the activity of a receptor agonist SW, but the substituent in position 2 of the pyrazole is limited to 2-(4-morpholino)ethoxypropanol, 2-(diallylamine)ethoxypropanol, 2-, 3 - or 4-pyridylmethyl, 2-(diethylamino)ethoxypropane, 1-methylpiperidine-2-methoxy group, benzyloxycarbonyl and 4-substituted benzyloxycarbonyl, and this connection has not been disclosed.

In patent document 9 disclosed pyrazole derivative having the activity of a modulator of the receptor NK-3, but the Deputy carbamoyl group in position 4 of the pyrazole is limited arylalkyl, heteroallyl or tenoxicam and this connection has not been disclosed.

In a patent document is 10 disclosed derivative of pyrazole, possessing inhibitory activity against 11β-HSD-1, but the substituent in position 1 of the pyrazole is limited to alkyl, hydroxy-group, hydroxyalkyl or the like, and optionally substituted of alkenyl", such as the present compound has not been disclosed.

[Patent document 1] WO2006/132197

[Patent document 2] WO2006/074330

[Patent document 3] WO2006/024627

[Patent document 4] WO2005/016877

[Patent document 5] WO2007/058346

[Patent document 6] WO2005/016877

[Patent document 7] WO2001/023358

[Patent document 8] WO98/41519

[Patent document 9] WO2005/061462

[Patent document 10] WO2007/107470

[Non-patent document 1] Clin. Endocrinol, 1996, vol. 44, p. 493

[Non-patent document 2] Proc. Nat. Acad. Sci. USA, 1997, vol. 94, p. 14924

[Non-patent document 3] J. Clin. Endocrinol. Metab., 1995, vol. 80, p. 3155

[Non-patent document 4] Lancet, 1997, vol. 349, p. 1210.

The problems solved by the present invention.

The present invention provides a useful inhibitor of 11β-hydroxysteroiddehydrogenase type 1.

The present invention provides:

(1) the Compound represented by formula (I):

Formula 1

,

its pharmaceutically acceptable salt or MES,

where ring a is a group represented by the formula:

Formula 2

or

The ring represents n is necessarily substituted heteroaryl provided what is excluded optionally substituted isoxazolyl or optionally substituted heterocycle,

R1represents hydrogen or optionally substituted alkyl,

R2represents-OR5, -SR5, halogen, halogenated alkyl, halogenated alkoxygroup, the hydroxy-group, a cyano, a nitro-group, carboxypropyl, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocycle,

the group represented by formula: -NR5AR6A,

where R5Aand R6Aeach independently represents hydrogen, a hydroxy-group, alkoxygroup, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted carbarnoyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle, or R5Aand R6Ataken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring,

the group represented by the formula: -S(=O)x-R7A,

g the e x is an integer 1 or 2 ,R7Arepresents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle,

the group represented by formula: -C(=O)NR5AR6A,

where R5Aand R6Aare as defined above, or

the group represented by formula: -(CR8AR9A)y-O-(CR10AR11A)z-CR12AR13AR14A,

where y and z, each independently, is an integer from 0 to 5,

R8A, R9A, R10A, R11A, R12A, R13Aand R14Aeach independently represents hydrogen, a hydroxy-group, halogen, halogenated alkyl, halogenated alkoxygroup, alkoxygroup, cyano, carboxylate, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle,

R3represents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optional samisen the th cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle,

the group represented by the formula: -CH=CH-C(RaRb)-Rc-Rdor a group represented by the formula: -(CReRf)m-C(RaRb)-Rc-Rd,

where Raand Rbeach independently represents hydrogen, optionally substituted alkyl or halogen, or Raand Rbtaken together with the neighboring carbon atom to which they are attached, can form an optionally substituted ring,

Rcrepresents -(CH2)n-where n is an integer from 0 to 3,

Rdrepresents hydrogen, halogen, a hydroxy-group, carboxypropyl, cyano, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle,

the group represented by formula: -C(=O)-NRgRhor

the group represented by formula: -NRiRj,

Reand Rfeach independently represents hydrogen, halogen or optionally substituted alkyl,

Rgand Rh, each independently, represent the possessing a hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity, optionally substituted by alkyloxy, optionally substituted carbarnoyl, or Rgand Rhtaken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring,

Riand Rjeach independently represents hydrogen, carboxypropyl, the hydroxy-group, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbarnoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally Sames the config cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity, optionally substituted allyloxycarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted aryloxyalkyl, optionally substituted heteroarylboronic, optionally substituted heterocyclisation, optionally substituted alkylaryl, optionally substituted cycloalkylcarbonyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic, optionally substituted heterocyclicamines, optionally substituted sulfamoyl, or Riand Rjtaken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring,

R4represents an optionally substituted alkyl, optionally substituted of alkenyl, -OR6, -CONR7R8, -NR9CONR7R8, -NR9SO2NR7R8, -(CR10R11)pOH, -(CR10R11)pOCONR7R8, -NR9COR12, -NR9C(=O)OR12, -(CR10R11)pNR9COR12, -C(=O)NR9OR12, -CONR9CONR7R8, -CN, -COOH, halogen, or-NR7R8,

R5represents an optionally substituted alkyl, it is certainly replaced alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

R6represents hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, -SO2R5, -SO2NR7R8or-CONR7R8,

R7and R8each independently represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle or-SO2R5or R7and R8taken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring,

R9represents hydrogen or optionally substituted alkyl,

R10and R11each independently represents hydrogen, halogen or optionally substituted alkyl,

R12represents an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

m and p is each independently is an integer from 1 to 3,

provided that when ring b is pyrazolyl, and R2represents halogen, halogenated alkyl, optionally substituted alkyl, optionally substituted heteroaryl,

the group represented by formula: -NR5AR6Awhere R5Aand R6Aare as defined above, or

the group represented by formula: -(CR8AR9A)y-O-(CR10AR11A)z-CR12AR13AR14Awhere R8A-R14A, y and z are as defined above,

R3represents an optionally substituted of alkenyl or a group represented by the formula: -CH=CH-C(RaRb)-Rc-Rd,

provided that when the ring is piperidyl or pyrrolidinyl, and R2represents an optionally substituted alkyl, R3represents an optionally substituted of alkenyl or a group represented by the formula: -CH=CH-C(RaRb)-Rc-Rdand

provided that excluded the following shows the connections

Formula 3

Formula 4

Formula 5

Formula 6

and.

(2) the Compound according to above item(1), its pharmaceutically acceptable salt or MES, where R2represents-OR5or-SR5where R5is the same as defined in the above item (1).

(3) the Compound according to the above item (2), its pharmaceutically acceptable salt or MES, where the compound represented by formula (I)is a compound represented by the formula (II):

Formula 7

,

where ring A, R1, R2and R3are as defined in the above item (1),

(4) the Compound according to any of the above items (1)to(3), its pharmaceutically acceptable salt or MES, where R6represents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle or-CONR7R8where R7and R8are as defined in the above item (1).

(5) the Compound according to any of the above items (1)to(4), its pharmaceutically acceptable salt or MES, where the ring And represents a group represented by the formula (III):

Formula 8

,

where R4is the same as defined in the you the e paragraph (1), R6represents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle or-CONR7R8where R7and R8are as defined in the above item (1).

(6) the Compound according to the above points(1), (2), (4) or (5), its pharmaceutically acceptable salt or MES, where the ring is an optionally substituted heteroaryl, provided that excluded optionally substituted isoxazol.

(7) the Compound according to any of the above items (1)to(6), its pharmaceutically acceptable salt or MES, where R1represents hydrogen.

(8) the Compound according to any of the above items (1)to(7), its pharmaceutically acceptable salt or MES, where R2represents-OR5where R5is the same as defined in the above item (1).

(9) the Compound according to any of the above items (1)to(7), its pharmaceutically acceptable salt or MES, where R2represents-SR5where R5is the same as defined in the above item (1).

(10) the Compound according to any of the above items (1)to(9), it formats whitesky acceptable salt or MES, where R5represents an optionally substituted alkyl.

(11) the Compound according to any of the above items (1)to(10), its pharmaceutically acceptable salt or MES, where R3represents an optionally substituted alkyl or optionally substituted of alkenyl.

(12) the Compound according to the above item (11), its pharmaceutically acceptable salt or MES, where R3represents a group represented by the formula: -CH=CH-C(RaRb)-Rc-Rdor a group represented by the formula: -(CReRf)m-C(RaRb)-Rc-Rdwhere Ra-Rfand m are as defined in the above item (1).

(13) the Compound according to the above item (12), its pharmaceutically acceptable salt or MES, where Raand Rbeach independently represents an optionally substituted alkyl.

(14) the Compound according to the above item (12) or (13), its pharmaceutically acceptable salt or MES, where Rcrepresents -(CH2)n-where n is an integer of 0 or 1.

(15) the Compound according to any of the above items (12)-(14), its pharmaceutically acceptable salt or MES, where Rdrepresents a halogen, a hydroxy-group, cyano, not necessarily zamestnavatelia or optionally substituted heterocycle.

(16) the Compound according to any of the above items (12)-(14), its pharmaceutically acceptable salt or MES, where Rdrepresents a group represented by the formula: -C(=O)-NRgRhwhere Rgand Rheach independently represents hydrogen, optionally substituted alkyl, optionally substituted by alkyloxy or optionally substituted carbarnoyl.

(17) the Compound according to any of the above items (12)-(14), its pharmaceutically acceptable salt or MES, where Rdrepresents a group represented by the formula: -NRiRjwhere Riand Rjeach independently represents hydrogen, optionally substituted alkylsulfonyl, optionally substituted allyloxycarbonyl, optionally substituted alkylaryl or optionally substituted heterocyclicamines.

(18) the Compound according to any of the above items (1)to(17), its pharmaceutically acceptable salt or MES, where R4represents-OR6, -CONR7R8, -NR9CONR7R8, -(CR10R11)pOH, -(CR10R11)pOCONR7R8, -NR9COR12, -NR9C(=O)OR12, -(CR10R11)pNR9COR12, -C(=O)NR9OR12, -CONR9CONR7R8or-CN, where R6-R12and p are such as defined in the above item (1).

(19) the Compound according to above item (18), its pharmaceutically acceptable salt or MES, where R7and R8each independently represents hydrogen or optionally substituted alkyl.

(20) the Compound according to above item (18) or (19), its pharmaceutically acceptable salt or MES, where R9represents hydrogen.

(21) the Compound according to any of the above items (18)to(20), its pharmaceutically acceptable salt or MES, where R10and R11each independently represents hydrogen.

(22) the Compound according to any of the above items (18)to(21), its pharmaceutically acceptable salt or MES, where R12represents an optionally substituted alkyl.

(23) the Compound defined below, its pharmaceutically acceptable salt or MES,

Formula 9

Formula 10

Formula 11

Formula 12

Formula 13

Formula 14

Formula 15

or

(24) a Pharmaceutical composition comprising a connection is giving according to any of the above items (1)to(23), its pharmaceutically acceptable salt or MES.

(25) the Pharmaceutical composition according to above item (24), which has inhibitory activity against 11β-hydroxysteroiddehydrogenase type 1.

In addition, the present invention includes:

(26) a Method of preventing or treating diabetes, comprising introducing the compound according to any of the above items (1)to(23), its pharmaceutically acceptable salt or MES.

(27) the Use of compounds according to any of the above items (1)to(23), its pharmaceutically acceptable salt or MES for the manufacture of medicinal products for the treatment and/or prevention of diabetes.

In addition, the present invention includes:

(28) the Compound according to any of the above items(1), (4)-(22), its pharmaceutically acceptable salt or MES, where R2represents halogen, halogenated alkyl, halogenated alkoxygroup, the hydroxy-group, a cyano, a nitro-group, carboxypropyl, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocycle,

group, PR is dostavlenny formula: -NR 5AR6A,

where R5Aand R6Aeach independently represents hydrogen, a hydroxy-group, alkoxygroup, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted carbarnoyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle, or R5Aand R6Ataken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring,

the group represented by the formula: -S(=O)x-R7A,

where x is an integer 1 or 2, R7Arepresents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle,

the group represented by formula: -C(=O)NR5AR6A,

where R5Aand R6Aare as defined above, or represents a group represented by the formula: -(CR8AR9A)y-O-(CR10AR11A)z-CR12AR13AR14A,

where y and z, each independently, is an integer from 0 to 5,

R8A, R9A, R10A, R11A , R12A, R13Aand R14Aeach independently represents hydrogen, a hydroxy-group, halogen, halogenated alkyl, halogenated alkoxygroup, alkoxygroup, cyano, carboxylate, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle.

(29) a Pharmaceutical composition comprising the compound according to above item (28), its pharmaceutically acceptable salt or MES.

(30) the Pharmaceutical composition according to above item (29), which has inhibitory activity against 11β-hydroxysteroiddehydrogenase type 1.

(31) a Method of preventing or treating diabetes, comprising introducing the compound according to above item (28), its pharmaceutically acceptable salt or MES.

(32) the Use of the compounds according to the above item (28), its pharmaceutically acceptable salt or MES for the manufacture of medicinal products for the treatment and/or prevention of diabetes.

(A1) a Compound represented by the formula (I):

Formula 16

,

its pharmaceutically acceptable salt or Olivet, where ring A is a group of the formula:

Formula 17

or,

the ring is an optionally substituted heteroaryl, provided that excluded optionally substituted isoxazol or optionally substituted heterocycle,

R1represents hydrogen or optionally substituted alkyl,

R2represents-OR5or-SR5,

R3represents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle,

the group represented by the formula: -CH=CH-C(RaRb)-Rc-Rdor

the group represented by formula: -(CReRf)m-C(RaRb)-Rc-Rd,

where Raand Rbeach independently represents hydrogen, optionally substituted alkyl or halogen, or Raand Rbtaken together with the neighboring carbon atom to which they are attached, can form an optionally substituted ring,

Rcrepresents -(CH2)n-where n is an integer from 0 to 3,

Rdbefore the hat is hydrogen, halogen, a hydroxy-group, carboxypropyl, cyano, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

the group represented by formula: -C(=O)-NRgRhor

the group represented by formula: -NRiRj,

Reand Rfeach independently represents hydrogen, halogen or optionally substituted alkyl,

Rgand Rheach independently represents hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity, optionally substituted by alkyloxy, optionally substituted carbarnoyl, or Rgand Rhtaken together with the neighboring atom is zhota, to which they are attached, can form an optionally substituted ring,

Riand Rjeach independently represents hydrogen, carboxypropyl, the hydroxy-group, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbarnoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity, optionally substituted allyloxycarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted aryloxyalkyl, optionally substituted heteroarylboronic, optionally substituted heterocyclisation, optionally substituted alkylsulphonyl, optionally substituted cycloalkylcarbonyl, optionally substituted aryl carbonyl, optionally substituted heteroarylboronic, optionally substituted heterocyclicamines, optionally substituted who sulfamoyl, or Riand Rjtaken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring,

R4represents an optionally substituted alkyl, optionally substituted of alkenyl, -OR6, -CONR7R8, -NR9CONR7R8, -NR9SO2NR7R8, -(CR10R11)pOH, -(CR10R11)pOCONR7R8, -NR9COR12, -NR9C(=O)OR12, -(CR10R11)pNR9COR12, -C(=O)NR9OR12, -CONR9CONR7R8, -CN, -COOH, halogen, or-NR7R8

R5represents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

R6represents hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, -SO2R5, -SO2NR7R8or-CONR7R8,

R7and R8each independently represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle or-SO2R5,

R9represents hydrogen or optionally substituted alkyl,

R10and R11each independently represents hydrogen, halogen or optionally substituted alkyl,

R12represents an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

m and p each independently is an integer from 1 to 3,

provided that excluded the following shows the connections

Formula 18

Formula 19

Formula 20

Formula 21

and

(A2) a Compound according to the above item (A1), its pharmaceutically acceptable salt or MES, where R6represents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle or-CONR7R8where R7and R8are as defined in the above item (1).

(A3) the Compound according to above item (A1) or (A2), its pharmaceutically acceptable salt or MES, where the ring And represents a group represented by the formula:

Formula 22

,

where R4is the same as defined in the above item (A1), R6represents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle or-CONR7R8where R7and R8are as defined in the above item (A1).

(A4) a Compound according to any of the above paragraphs (A1)-(A3), its pharmaceutically acceptable salt or MES, where the ring is an optionally substituted heteroaryl, provided that excluded optionally substituted isoxazol.

(A5) the Compound according to any of the above paragraphs (A1)-(A4), its pharmaceutically acceptable salt or MES, where R1represents hydrogen.

(A6) the Compound according to any of the above paragraphs (A1)-(A5), its pharmaceutically acceptable salt or MES, where R2represents-OR5where R5is the same as defined in the above item (A1).

(A7) the Compound according to any of the above paragraphs (A1)-(A6), its pharmaceutically acceptable salt or MES, where R5represents an optionally substituted alkyl.

(A8) the Compound according to any of the above (A1)to(A7), its pharmaceutically acceptable salt or MES, where R3represents an optionally substituted alkyl or optionally substituted of alkenyl.

(A9) the Compound according to above item (A8), its pharmaceutically acceptable salt or MES, where R3represents a group represented by the formula: -CH=CH-C(RaRb)-Rc-Rdor a group represented by the formula: -(CReRf)m-C(RaRb)-Rc-Rdwhere Ra-Rfare as defined in the above item (A1).

(A10) the Compound according to above item (A9), its pharmaceutically acceptable salt or MES, where Raand Rbeach independently represents an optionally substituted alkyl.

(A11) the Compound according to above item (A9) or (A10), its pharmaceutically acceptable salt or MES, where Rcrepresents -(CH2)n-where n is an integer of 0 or 1.

(A12) the Compound according to any of the above paragraphs (A9)-(A11), its pharmaceutically acceptable whom I Sol or MES, where Rdrepresents a halogen, a hydroxy-group, cyano, optionally substituted heteroaryl or optionally substituted heterocycle.

(A13) the Compound according to any of the above paragraphs (A9)-(A11), its pharmaceutically acceptable salt or MES, where Rdrepresents a group represented by the formula: -C(=O)-NRgRhwhere Rgand Rheach independently represents hydrogen, optionally substituted alkyl, optionally substituted by alkyloxy or optionally substituted carbarnoyl.

(A14) the Compound according to any of the above paragraphs (A9)-(A11), its pharmaceutically acceptable salt or MES, where Rdrepresents a group represented by the formula: -NRiRjwhere Riand Rjeach independently represents hydrogen, optionally substituted alkylsulfonyl, optionally substituted allyloxycarbonyl, optionally substituted alkylaryl or optionally substituted heterocyclicamines.

(A15) the Compound according to any of the above (A1)to(A14), its pharmaceutically acceptable salt or MES, where R4represents-OR6, -CONR7R8, -NR9CONR7R8, -(CR10R11)nOH, -(CR10R11)nOCONR7R8, -NR9COR , -NR9C(=O)OR12, -(CR10R11)nNR9COR12, -C(=O)NOR12, -CONR9CONR7R8or-CN, where R6-R12are as defined in the above item (A1).

(A16) the Compound according to above item (A15), its pharmaceutically acceptable salt or MES, where R7and R8each independently represents hydrogen or optionally substituted alkyl.

(A17) the Compound according to above item (A15) and (A16), its pharmaceutically acceptable salt or MES, where R9represents hydrogen.

(A18) the Compound according to any of the above paragraphs (A15)-(A17), its pharmaceutically acceptable salt or MES, where R10and R11each independently represents hydrogen.

(A19) the Compound according to any of the above paragraphs (A15)-(A18), its pharmaceutically acceptable salt or MES, where R12represents an optionally substituted alkyl.

(A20) the Connection specified below, its pharmaceutically acceptable salt or MES,

Formula 23

Formula 24

Formula 25

Formula 26

Formula 27

Formula 28

Formula 29

or

(A21) a Pharmaceutical composition comprising a compound according to any of the above (A1)to(A20), its pharmaceutically acceptable salt or MES.

(A22) the Pharmaceutical composition according to above item (A21), which is an inhibitor of 11β-hydroxysteroiddehydrogenase type 1.

(A23) a Method of preventing or treating diabetes, comprising introducing the compound according to any of the above (A1)to(A20), its pharmaceutically acceptable salt or MES.

(A24) the Use of compounds according to any of the above (A1)to(A20), its pharmaceutically acceptable salt or MES for the manufacture of medicinal products for the treatment and/or prevention of diabetes.

The effect of the present invention

Since the present compound has inhibitory activity against 11β-hydroxysteroiddehydrogenase type 1, pharmaceutical compositions containing this compound is very useful as medicines, especially as medicines for the treatment and/or prevention of hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis, hyperglycemia and/or syndrome X. moreover, the present compound selectively inhibit is no 11β-hydroxysteroiddehydrogenase type 1 and represents a connection, possessing and other useful properties as a medicinal product. In this case such useful properties as a medicinal product include high metabolic stability, a weak induction of the enzyme metabolizing the medicine, weak inhibition of the metabolizing enzyme, which metabolizes another medication, high oral absorption, low clearance, prolonged half-life, sufficient to reveal the effectiveness of drugs, etc.

Best mode for carrying out the present invention

The following discussion will explain the meaning of terms used in this description. Each term has the same meaning when used separately or in combination with another term in the present description.

"Halogen" includes fluorine, chlorine, bromine or iodine. Especially preferred fluorine, chlorine and bromine.

"Alkyl" means a straight or branched C1-Sal group, and the example includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl or the like, Preferred is C1-c6alkyl or C1-Salkil, and the example includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-antil, isopentyl, neopentyl, n-hexyl or isohexyl.

"Alkenyl" means a straight or branched C2-Calcaneal having one or more double bonds in the above "alkyl", and the example includes vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl or similar

"Quinil" means a straight or branched C2-Calciner having one or more triple bonds in the above "alkyl", and the example includes ethinyl, PROPYNYL, butynyl or similar

"Cycloalkyl" means a cyclic saturated C3-C15 hydrocarbon group, and an example includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, a Spiro hydrocarbon group or the like is Preferable cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bridged cyclic hydrocarbon group.

"Spiropentane group" includes a group which formed by removing one hydrogen from a ring, which consists of two hydrocarbon rings that have one common carbon atom. The sample includes Spiro[3.4]octyl or similar

"Bridged cyclic hydrocarbon group" includes a group which formed by removing one hydrogen from C5-C8 aliphatic cycle, which consists of two or more rings having at least DV is x total atoms

The sample includes bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,

tricyclo[2.2.1.0]heptyl, the following groups or the like:

Formula 30

"Cycloalkenyl" means a cyclic unsaturated aliphatic C3-C15 hydrocarbon group, and the sample includes cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or the like is Preferable cyclopropyl, cyclobutyl, cyclopentenyl or cyclohexenyl. Cycloalkenyl also includes bridged cyclic hydrocarbon group which has an unsaturated bond in the ring. The example includes a group having one or two double bonds in the ring bridged cyclic hydrocarbon groups listed above as examples of "cycloalkyl".

"Aryl" means a monocyclic aromatic hydrocarbon group (e.g. phenyl) and polycyclic aromatic hydrocarbon group (for example, 1-naphthyl, 2-naphthyl, 1-antrel, 2-antrel, 9-antrel, 1-phenanthrol, 2-phenanthrol, 3-phenanthrol, 4-phenanthrol or 9-phenanthrol). Preferred is phenyl or naphthyl (1-naphthyl or 2-naphthyl).

"Heteroaryl" means a monocyclic aromatic heterocyclic group or condensed aromatic heterocyclic group. Monocyclic aromatic heterocyclic group SN which denotes the group formed from 5-8-membered aromatic ring which may contain 1 to 4 oxygen atom, sulfur and/or nitrogen in the ring and may have a bond at an arbitrary substitutable position.

Condensed aromatic heterocyclic group means a group in which a 5-8-membered aromatic ring, optionally containing 1 to 4 oxygen atom, sulfur and/or nitrogen in the ring is condensed with 1-4 5-8-membered aromatic carbocycle or other 5-8-membered aromatic heterocycle which may have a connection at an arbitrary substitutable position.

Example of "heteroaryl" include furyl (e.g. 2-furyl or 3-furyl), thienyl (for example: 2-thienyl or 3-thienyl), pyrrolyl (for example: 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl), imidazolyl (for example: 1-imidazolyl, 2-imidazolyl or 4-imidazolyl), pyrazolyl (for example: 1-pyrazolyl, 3-pyrazolyl or 4-pyrazolyl), triazolyl (for example: 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl or 1,2,4-triazole-4-yl), tetrazolyl (for example: 1-tetrazolyl, 2-tetrazolyl or 5-tetrazolyl), oxazolyl (for example: 2-oxazolyl, 4-oxazolyl or 5-oxazolyl), isoxazolyl (for example: 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl), thiazolyl (for example: 2-thiazolyl, 4-thiazolyl or 5-thiazolyl), thiadiazolyl, isothiazolin (for example: 3-isothiazole, 4-isothiazole or 5-isothiazolin), pyridyl (for example: 2-pyridyl, 3-pyridyl or 4-PI is ideal), pyridazinyl (for example: 3-pyridazinyl or 4-pyridazinyl), pyrimidinyl (for example: 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl), furutani (for example: 3-furutani), pyrazinyl (for example: 2-pyrazinyl), oxadiazolyl (for example: 1,3,4-oxadiazol-2-yl), benzofuran (for example: 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl or 7-benzo[b]furyl), sensational (for example: 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl or 7-benzo[b]thienyl), benzimidazolyl (for example: 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl or 5-benzimidazolyl), benzothiazolyl, dibenzofuran, benzoxazolyl, honokalani (for example: 2-honokalani, 5-honokalani or 6-honokalani), indolinyl (for example: 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl or 8-indolinyl), hintline (for example: 2-hintline, 4-hintline, 5-hintline, 6-hintline, 7-hintline or 8-hintline), chinolin (for example: 2-chinolin, 3-chinolin, 4-chinolin, 5-chinolin, 6-chinolin, 7-chinolin or 8-chinolin), phthalazine (for example: 1-phthalazine, 5-phthalazine or 6-phthalazine), ethanolic (for example: 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, 6-ethanolic, 7-ethanolic or 8-ethanolic), peril, pteridinyl (for example: 2-pteridinyl, 4-pteridinyl, 6-pteridinyl or 7-pteridinyl), carbazolyl, phenanthridines, acridines (for example, 1-acridines, 2-acridines, 3-acridines, 4-acridine or 9-acridine), indolyl (for example: 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl or 7-indolyl), isoindolyl, fentanil (for example: 1-fenadine or 2-fenadine), phenothiazines (for example: 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl or 4-phenothiazinyl) or similar

"Heterocycle" means a non-aromatic heterocyclic group which may contain 1 to 4 oxygen atom, sulfur and/or nitrogen in the ring and may have a bond at an arbitrary substitutable position. Moreover, non-aromatic heterocyclic group may have a bridge in the form of C1-Salcininky chain or may be condensed with cycloalkanes (preferred is a 5-6-membered ring or benzene ring. The heterocycle may be saturated or unsaturated, remaining non-aromatic. Preferred is a 5-8-membered ring. The example includes : 1-pyrrolidyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrazolidone, 3-pyrazolidone, 4-pyrazolidine, piperidine, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholinopropan, tetrahydropyranyl, the following groups or the like:

p> Formula 31

The alkyl part of the "alkyloxy", "alkylsulfonyl", "allyloxycarbonyl", "alkylcarboxylic" and "alkoxygroup" means the above "alkyl".

Cycloalkyl part cycloalkylcarbonyl", "cycloalkylcarbonyl" and "cycloalkylcarbonyl" means the above "cycloalkyl".

Aryl part arylsulfonyl", "aryloxyalkyl" and "arylcarbamoyl" means the above "aryl".

Heteroaryl part heteroarylboronic", "heteroarylboronic" and "heteroarylboronic" means the above "heteroaryl".

Heterocyclyl part heterozygosity", "geterotsiklicheskikh" and "geterotsiklicheskikh" means the above "heterocycle."

"The ring formed by Raand Rbtaken together with the neighboring carbon atom to which they are attached, means 3-15 membered saturated or unsaturated hydrocarbon ring or a 3 to 15-membered saturated or unsaturated heterocyclic ring containing 1 to 4 oxygen atom, sulfur and/or nitrogen in the specified hydrocarbon ring.

Preferred is a non-aromatic ring, the sample includes cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, saturated or unsaturated, heterocycle the mini-ring, containing 1 to 4 oxygen atom, sulfur and/or nitrogen in the above-mentioned hydrocarbon ring.

For example, as a group of the formula: -C(RaRb)-, where Raand Rbtaken together with the neighboring carbon atom to which they are attached, can form an optionally substituted ring, called the following groups.

Formula 32

"The ring formed by Rgand Rhtaken together with the neighboring nitrogen atom to which they are attached, and the ring formed by Riand Rjtaken together with the neighboring nitrogen atom to which they are attached"mean 3-15 membered non-aromatic heterocyclic ring which may contain 1 to 4 oxygen atom, sulfur and/or nitrogen along with the above nitrogen atom in the ring. Moreover, non-aromatic heterocyclic ring may have a bridge in the form of C1-Salcininky chain or may be condensed with cycloalkanes (preferred is a 5-6-membered ring or benzene ring. The ring may be saturated or unsaturated, remaining non-aromatic. Preferred is a 5-8-membered ring. For example, as a group of the formula: -C(=O)-NRgRhwhere Rgand Rhtaken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring, and GRU the dust of the formula: -NR iRjwhere Riand Rjtaken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring, call 1-pyrrolidyl, 1-pyrrolidinyl, 1-imidazolyl, 1-imidazolidinyl, 1-pyrazolyl, 1-pyrazolidine, piperidine, morpholinopropan and the following groups.

Formula 33

"The ring formed by R5Aand R6Ataken together with the neighboring nitrogen atom to which they are attached, and the ring formed by R7and R8taken together with the neighboring nitrogen atom to which they are attached"mean 3-15 membered aromatic heterocyclic ring or non-aromatic heterocyclic ring which may contain 1 to 4 oxygen atom, sulfur and/or nitrogen along with the above nitrogen atom in the ring. "Ring" means a monocyclic or condensed ring, for example, it can be condensed with cycloalkanes (preferred is a 5-6-membered ring or benzene ring. Moreover, non-aromatic heterocyclic ring may have a bridge in the form of C1-Salcininky chain. Preferred is a 5-8-membered ring. For example, the following examples are included:

Formula 34

"optionally substituted alkyl", "optionally substituted of alkenyl", "optional is entrusted substituted quinil", "optionally substituted cycloalkyl", “optionally substituted cycloalkenyl", "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted heterocycle", optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity, optionally substituted alkyloxy, optionally substituted acyl, optionally substituted allyloxycarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted aryloxyalkyl, optionally substituted heteroarylboronic, optionally substituted heterocyclisation, optionally substituted alkylaryl, optionally substituted cycloalkylcarbonyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic, optionally substituted heterocyclicamines, "ring formed Raand Rbtaken together with the neighboring carbon atom to which they are attached", "a ring formed by Rgand Rhtaken together with the neighboring nitrogen atom to which they are attached", "a ring formed by Riand Rjtaken together with the neighboring nitrogen atom to which they are attached", "ring, obrazovanie R 5Aand R6Ataken together with the neighboring nitrogen atom to which they are attached, and the ring formed by R7and R8taken together with the neighboring nitrogen atom to which they are attached may be substituted by 1-4 substituents, selected from the group including, for example,

the hydroxy-group, carboxypropyl, halogen, halogenated alkyl (e.g.- CF3, -CH2CF3or-CH2Cl3), a nitrogroup, nitrosolobus, cyano,

alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl),

alkenyl (e.g. vinyl), quinil (for example: ethinyl),

cycloalkyl (for example: cyclopropyl or substituted), hydroxyalkyl (e.g. hydroxymethyl),

cycloalkenyl (for example: cyclohexylmethyl or adamantylamine),

cycloalkenyl (for example: cyclopropyl), aryl (e.g. phenyl or naphthyl),

arylalkyl (e.g. benzyl or phenethyl), heteroaryl (e.g. pyridyl or furyl),

heteroallyl (for example: pyridylmethyl), heterocycle (for example: piperidyl), heterocyclyl (for example: morpholinomethyl), alkyloxy (for example, methoxy group, ethoxypropan, propoxylate or butoxypropyl), a halogenated alkyloxy (for example: OCF3), alkenylacyl (for example: vinyloxy or alliancegroup), alloctype (for example: fenoxaprop), allyloxycarbonyl (example is: methoxycarbonyl, etoxycarbonyl or tert-butoxycarbonyl), arylalkylamine (for example: benzyloxy), amino group (for example: alkylamino (for example: methylaminopropyl, ethylamino or dimethylaminopropyl), alluminare (for example: acetaminoph or benzoylamino), arylalkylamines (for example: benzylamino or trilaminar), hydroxyamino, acylaminoalkyl (for example: diethylaminomethyl), sulfamoyl etc.

The alkyl part of the "hydroxyalkyl" means the above "alkyl".

Alchemilla part alkenylacyl" means the above "alkenyl".

Kilakila part arylalkylamine" means the above "arylalkyl".

Aryl part alloctype" means the above "aryl".

Alkyl part and halogen part of the "halogenated alkyl", "halogenated alkyloxy" and "halogenated alkoxygroup" are the same as above.

Example of the substituent of the "optionally substituted amino", "optionally substituted of carbamoyl", "optionally substituted of thiocarbamoyl” and "optionally substituted sulfamoyl" includes alkyl, alkenyl, aryl, heteroaryl, alkylaryl, arylcarbamoyl, heteroarylboronic, heterocyclicamines, allyloxycarbonyl, aryloxyalkyl, heteroarylboronic, heterocyclisation, Sul is Tamoil, alkylsulfonyl, carbarnoyl, cycloalkylcarbonyl, arylsulfonyl, heteroarylboronic, heterozygosity, acyl, hydroxy-group, sulfonyl, sulfinil, the amino group or the like

Among the compounds according to the present invention, preferred are the following options for implementation.

Ring A is a group represented by the formula:

Formula 35

or.

Ring A preferably represents a group represented by the formula:

Formula 36

or.

Particularly preferably, if the ring A is a group represented by the formula:

Formula 37

Ring A includes each of the SYN - and anisomerous.

The ring is an optionally substituted heteroaryl, provided that excluded optionally substituted isoxazolyl, or optionally substituted heterocycle.

Preferred is furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isothiazolin, pyridyl, morpholinopropan, morpholinyl, piperidyl, piperidino, piperazinyl, pyrrolidinyl or tetrahydrothieno.

Particularly preferably, the ring is pyrazolyl.

Moreover, the ring may have replaced the Fort worth, other than R2and R3.

R1represents hydrogen or optionally substituted alkyl. Preferred is hydrogen, methyl, ethyl, n-propyl or isopropyl. Especially preferred is hydrogen.

R2represents-OR5, -SR5, halogen, halogenated alkyl, halogenated alkoxygroup, the hydroxy-group, a cyano, a nitro-group, carboxypropyl, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocycle,

the group represented by formula: -NR5AR6A,

where R5Aand R6Aeach independently represents hydrogen, a hydroxy-group, alkoxygroup, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted carbarnoyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle, or R5Aand R6Ataken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring,

groups who, represented by the formula: -S(=O)x-R7A,

where x is an integer 1 or 2, R7Arepresents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle,

the group represented by formula: -C(=O)NR5AR6A,

where R5Aand R6Aare as defined above, or

the group represented by formula: -(CR8AR9A)y-O-(CR10AR11A)z-CR12AR13AR14A,

where y and z, each independently, is an integer from 0 to 5,

R8A, R9A, R10A, R11A, R12A, R13Aand R14Aeach independently represents hydrogen, a hydroxy-group, halogen, halogenated alkyl, halogenated alkoxygroup, alkoxygroup, cyano, carboxylate, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle.

R2preferably represents-OR5, -SR5, halogenated alkyl, cyano, long is correctly substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl,

the group represented by formula: -NR5AR6Aor

the group represented by formula: -(CR8AR9A)y-O-(CR10AR11A)z-CR12AR13AR14A.

More preferred are-OR5or-SR5.

Especially preferred is-OR5.

R5Aand R6Aeach independently represents hydrogen, a hydroxy-group, alkoxygroup, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted carbarnoyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle, or R5Aand R6Ataken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring.

Preferred is hydrogen, optionally substituted alkyl or optionally substituted carbarnoyl, or optionally substituted ring formed R5Aand R6Ataken together with the neighboring nitrogen atom to which they are attached.

x is an integer 1 or 2.

R7Arepresents an optionally substituted alkyl, optionally substituted of alkenyl, long is correctly substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle.

R8A, R9A, R10A, R11A, R12A, R13Aand R14Aeach independently represents hydrogen, a hydroxy-group, halogen, halogenated alkyl, halogenated alkoxygroup, alkoxygroup, cyano, carboxylate, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl or optionally substituted heterocycle.

Preferred is hydrogen, the hydroxy-group, halogen, optionally substituted alkyl.

More preferred is hydrogen.

y is an integer from 0 to 5.

Preferred is an integer from 0 to 3. More preferred is 1.

z is an integer from 0 to 5.

Preferred is an integer of 0 to 3. More preferred is 0.

R3represents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optional the nutrient substituted heteroaryl, optionally substituted heterocycle,

the group represented by the formula: -CH=CH-C(RaRb)-Rc-Rdor

the group represented by formula: - (CReRf)m-C(RaRb)-Rc-Rd,

where Raand Rbeach independently represents hydrogen, optionally substituted alkyl or halogen, or Raand Rbtaken together with the neighboring carbon atom to which they are attached, can form an optionally substituted ring,

Rcrepresents -(CH2)n-where n is an integer from 0 to 3,

Rdrepresents hydrogen, halogen, a hydroxy-group, carboxypropyl, cyano, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle,

the group represented by formula: -C(=O)-NRgRhor

the group represented by formula: -NRiRj,

Reand Rfeach independently represents hydrogen, halogen or optionally substituted alkyl,

Rgand Rheach independently represents hydrogen, optionally substituted alkyl, long is Ino replaced alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity, optionally substituted by alkyloxy, optionally substituted carbarnoyl, or Rgand Rhtaken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring,

Riand Rjeach independently represents hydrogen, carboxypropyl, the hydroxy-group, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbarnoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylsulfonyl optionally substituted heteroarylboronic, optionally substituted heterozygosity, optionally substituted allyloxycarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted aryloxyalkyl, optionally substituted heteroarylboronic, optionally substituted heterocyclisation, optionally substituted alkylaryl, optionally substituted cycloalkylcarbonyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic, optionally substituted heterocyclicamines, optionally substituted sulfamoyl, or Riand Rjtaken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring.

R3preferably represents a group represented by the formula: -CH=CH-C(RaRb)-Rc-Rdor a group represented by the formula: -(CReRf)m-C(RaRb)-Rc-Rd.

More preferably, R3represents a group represented by the formula: -CH=CH-C(RaRb)-Rc-Rd.

Raand Rbeach independently represents hydrogen, optionally substituted alkyl or halogen, or Raand Rbtaken together with the neighboring carbon atom to which they are attached, can form an optionally Samusenko the ring.

Preferred is hydrogen, optionally substituted alkyl or halogen.

Particularly preferably, Raand Rbrepresent optionally substituted alkyl.

Rcrepresents -(CH2)n-where n is an integer from 0 to 3.

Preferably, n is 0 or 1.

Rdrepresents hydrogen, halogen, a hydroxy-group, carboxypropyl, cyano, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle,

the group represented by formula: -C(=O)-NRgRhor

the group represented by formula: -NRiRj,

where Rgand Rheach independently represents hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylsulfonyl, not battelino substituted heteroarylboronic, optionally substituted heterozygosity, optionally substituted by alkyloxy, optionally substituted carbarnoyl, or Rgand Rhtaken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring,

Riand Rjeach independently represents hydrogen, carboxypropyl, the hydroxy-group, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbarnoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity, optionally substituted allyloxycarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted aryloxyalkyl, optionally substituted heteroarylboronic, optionally substituted heterocyclisation, optionally substituted alkylsulphonyl, optional for ewenny cycloalkylcarbonyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic, optionally substituted heterocyclicamines, optionally substituted sulfamoyl, or Riand Rjtaken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring.

Preferably, Rdrepresents a halogen, a hydroxy-group, cyano, optionally substituted heteroaryl,

the group represented by formula: -C(=O)-NRgRhor

the group represented by formula: -NRiRj.

Particularly preferred is a group represented by the formula: -C(=O)-NRgRhor a group represented by the formula: -NRiRj.

Rgand Rheach independently represents hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity, neo is Astelin replaced alkyloxy, optionally substituted carbarnoyl, or Rgand Rhtaken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring.

Preferred is hydrogen, optionally substituted carbarnoyl, optionally substituted alkyl or optionally substituted alkyloxy.

Riand Rjeach independently represents hydrogen, carboxypropyl, the hydroxy-group, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbarnoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity, optionally substituted allyloxycarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted aryloxyalkyl, optionally substituted heteroarylboronic, optionally substituted heterosiloxanes the Nile, optionally substituted alkylaryl, optionally substituted cycloalkylcarbonyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic, optionally substituted heterocyclicamines, optionally substituted sulfamoyl, or Riand Rjtaken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring.

Preferred is hydrogen, optionally substituted allyloxycarbonyl, optionally substituted alkylaryl, optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optionally substituted alkyl, optionally substituted heterocyclicamines.

Reand Rfeach independently represents hydrogen, halogen or optionally substituted alkyl.

Preferred is hydrogen or halogen. Especially preferred is hydrogen.

R4represents an optionally substituted alkyl, optionally substituted of alkenyl, -OR6, -CONR7R8, -NR9CONR7R8, -NR9SO2NR7R8, -(CR10R11)pOH, -(CR10R11)pOCONR7R8, -NR9COR12, -NR9C(=O)OR12, -(CR10R11)pNR9COR12, -C(=O)NR9OR12, -CONR9 CONR7R8, -CN, -COOH, halogen, or-NR7R8.

Preferred is-OR6, -CONR7R8, -NR9CONR7R8, -(CR10R11)pOH, -(CR10R11)pOCONR7R8, -NR9COR12, -CN, -NR9C(=O)OR12, -(CR10R11)pNR9COR12, -C(=O)NR9OR12, -CONR9CONR7R8.

Especially preferred is-OR6or -(CR10R11)pOCONR7R8.

R5represents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle.

Preferred is an optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle.

Especially preferred is optionally substituted alkyl.

R6represents hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, -SO2R5, -SO2NR7R8or-CONR7R8.

Predpochtitel the s ' is hydrogen or-CONR 7R8.

R7and R8each independently represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle or-SO2R5or R7and R8taken together with the neighboring nitrogen atom to which they are attached, can form an optionally substituted ring.

Preferred is hydrogen or optionally substituted alkyl.

Especially preferred is hydrogen.

R9represents hydrogen or optionally substituted alkyl. Preferred is hydrogen.

R10and R11each independently represents hydrogen, halogen or optionally substituted alkyl.

Preferred is hydrogen.

R12represents an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle.

Preferred is optionally substituted alkyl.

m and p each independently is an integer from 1 to 3. Preferably, m is 1 or 2. Preferably, p is 1.

As pharmaceutically acceptable salts of the compounds according to the present izaberete the Oia can be included the following salt.

As the main salt sample includes a salt of an alkali metal such as sodium salt or potassium salt; alkali earth metal salt such as calcium salt or magnesium salt; ammonium salt; salts of aliphatic amine, such as salt, trimethylamine salt of triethylamine, salt dicyclohexylamine, ethanolamine salt, diethanolamine salt, triethanolamine salt, salt of procaine, salt meglumine, diethanolamine salt or salt of ethylene diamine; salt aralkylamines, such as salt N,N-dibenziletilendiaminom or salt benyamina; salt heterocyclic aromatic amine, such as salt of pyridine, picoline salt, salt of quinoline or salt of isoquinoline; salt of Quaternary ammonium, such as salt Tetramethylammonium, salt tetraethylammonium, salt designed, salt benzyltriethylammonium, salt benzyltrimethylammonium, salt methyltrioctylammonium or tetrabutylammonium salt; salt of the basic amino acids, such as salt of arginine or lysine salt or the like

As the acid salt example includes a salt of an inorganic acid such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate or ammonium salt of organic acid such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate or ascorbate; a sulfonate such as methanesulfonate, isetionate, bansilalpet or p-toluensulfonate; salt sour is Noah amino acids, such as aspartate or glutamate or other

The term "MES" means the MES compounds according to the present invention or its pharmaceutically acceptable salts, and the example includes an alcohol (e.g. ethanol) MES, hydrate or the like, an example of a hydrate includes monohydrate, dihydrate or the like

General method for obtaining compounds according to the present invention are presented below.

Extraction, purification, etc. can also be carried out according to the method used in the usual experiment of organic chemistry.

Compounds where R2means-OR5

Formula 38

where each symbol in the above scheme is the same as described above, and as the compound (II-A) can be used a known compound or can be used a compound derived from a known compound in the usual way. Pro represents a protective group. As a protective group sample includes alkyl group or the like

Stage 1

Stage 1 represents a method of obtaining a compound represented by formula (II-B), which includes the interaction of the compounds represented by formula (II-B), with hydrazine.

As a solvent, the sample includes N-dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons (e.g. toluene, benzene, xylene or the like), on yennie hydrocarbons (for example, cyclohexane, hexane or the like), halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane or the like), ethers (e.g. tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane or the like), esters (e.g. methyl acetate, ethyl acetate or the like), ketones (e.g. acetone, methyl ethyl ketone or the like), NITRILES (e.g. acetonitrile or the like), alcohols (e.g. methanol, ethanol, tert-butanol or the like), water, a mixed solvent or the like, Preferably, you can use alcohols (e.g. methanol, ethanol, tert-butanol or the like). More preferably, it is possible to use Pro-OH. The reaction can be conducted at a temperature in the range from room temperature to the boiling point of the used solvent under reflux, for 0.5 to 48 hours.

Stage 2

Stage 2 represents a method of obtaining a compound represented by formula (II-C), which includes the interaction of the compounds represented by formula (II-B) with the compound represented by the formula, R5X, in the presence of a base. As a solvent it is possible to use a solvent described in stage 1. Preferably, you can use ketones (e.g. acetone, methyl ethyl ketone or the like) or N-dimethylformamide.

As the base sample includes metal hydrides (e.g. sodium hydride or the like), GI is rockside metals (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or the like), metal carbonates (e.g. sodium carbonate, calcium carbonate, potassium carbonate, cesium carbonate or the like), alkoxides of metals (e.g. sodium methoxide, ethoxide sodium tert-piperonyl potassium or the like), sodium bicarbonate, sodium metal, organic amines (e.g. triethylamine, diisopropylethylamine, DBU, 2,6-lutidine or the like), pyridine, alkality (n-BuLi, sec-BuLi, tert-BuLi or the like) or the like, Preferably you can use metal carbonates (e.g. sodium carbonate, calcium carbonate, potassium carbonate, cesium carbonate or the like). The reaction can be conducted at a temperature in the range from room temperature to the boiling point of the used solvent under reflux, for 0.5 to 48 hours.

Stage 3

Stage 3 represents a method of obtaining a compound represented by formula (II-D), which includes hydrolysis of the compounds represented by formula (II-C).

As a solvent it is possible to use a solvent described in stage 1. Preferably, you can use ethers (e.g. tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane or the like), alcohols (e.g. methanol, ethanol, tert-butanol or the like), water, a mixed solvent or the like as a base, you can use the core is a cation, described in stage 2. Preferably, you can use metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or the like). The reaction can be performed at 20-40°C for 0.5-24 hours.

Stage 4

Stage 4 represents a method of obtaining a compound represented by formula (I-A), which includes the interaction of the compounds represented by formula (II-D), with the compound represented by formula (ring A-NH-R1).

As a solvent it is possible to use a solvent described in stage 1. Preferably, you can use ethers (e.g. tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane or the like) or N-dimethylformamide. As a basis you can use the basis described in stage 2. Preferably, it is possible to use organic amines (e.g. triethylamine, diisopropylethylamine, DBU, 2,6-lutidine or the like). As the condensing means you can use 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (WSCI) or 1,3-dicyclohexylcarbodiimide (into). As an additive it is possible to use N-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu). The reaction can be conducted at a temperature in the range from -20°C to the boiling point of the used solvent under reflux, for 0.5-24 hours.

Connection, where the R 2means-SR5

Formula 39

Stage 5

Stage 5 represents a method of obtaining a compound represented by formula (II-E), which includes the conversion of the hydroxy-group in the compound represented by formula (II-B), chlorine.

As a solvent, you can use phosphorylchloride (POCl3). The reaction can be conducted at a temperature in the range from -20°C to the boiling point of phosphorylchloride under reflux, for 0.5-24 hours.

Stage 6

Stage 6 represents a method of obtaining a compound represented by formula (II-F), which includes the interaction of the compounds represented by formula (II-E), with the compound represented by the formula, R5SH, in the presence of a base.

As a solvent it is possible to use a solvent described in stage 1. Preferably, you can use ketones (e.g. acetone, methyl ethyl ketone or the like) or N-dimethylformamide. As a basis you can use the basis described in stage 2. Preferably, it is possible to use metal hydrides (e.g. sodium hydride or the like), metal carbonates (e.g. sodium carbonate, calcium carbonate, potassium carbonate, cesium carbonate or the like) or the like

The reaction can be conducted at a temperature in d is apatone from room temperature to the boiling point of the used solvent under reflux, for 0.5-48 hours.

Stage 7

Stage 7 is the method of obtaining the compound represented by formula (II-F), which includes hydrolysis of the compounds represented by formula (II-E).

The reaction can be conducted under conditions similar to the above in stage 3.

Stage 8

Stage 8 is a method of obtaining a compound represented by formula (I-B), which includes the interaction of the compounds represented by formula (II-F), with the compound represented by formula (ring A-NH-R1).

The reaction can be conducted under conditions similar to the above in stage 4.

Formula 40

where each symbol in the above scheme is the same as described above, and as the compound (II-G) you can use the well-known compound or can be used a compound obtained from known compounds in the usual way.

Stage 9

Stage 9 is a method of obtaining a compound represented by formula (I-C), which includes the interaction of the compounds represented by formula (II-G), with the compound represented by formula (ring A-NH-R1).

The reaction can be conducted under conditions similar to the above in stage 4.

Formula 41

where each symbol in the above scheme has the same as indicated above, and as the compound (II-H) you can use the well-known compound or can be used a compound obtained from known compounds in the usual way. Pro and Pro' represents a protective group. As a Pro, and Pro' example includes methyl group, ethyl group, benzyl group, benzoyloxy group, tert-boutelou group or the like Hal represents halogen.

Stage 10

Stage 10 is the method of obtaining the compound represented by formula (II-I), which includes the interaction of the compounds represented by formula (II-H), with hydrazine.

The reaction can be conducted under conditions similar to the above in stage 1.

Stage 11

Stage 11 is a method of obtaining a compound represented by formula (II-J), which involves the oxidation of the compounds represented by formula (II-I).

As the oxidizing agent can be used IBX (2-iodoxybenzoic acid), salts or oxides of such metals as chromium, manganese, silver or the like, or organic oxidizing agent.

As a solvent it is possible to use a solvent described in stage 1. Preferably, you can use acetonitrile or esters (e.g. methyl acetate, ethyl acetate or the like).

The reaction can be conducted at a temperature in the range from room temperature to the temperature of the andsinging used solvent under reflux, for 0.5-24 hours.

The oxidation reaction can be conducted under oxidizing conditions in Turn, oxidation with the use or TEMPO etc.

Stage 12

Stage 12 is a method of obtaining a compound represented by formula (II-L), in which the compound represented by formula (II-J), and the compound represented by formula (II-K), is subjected to the Wittig reaction.

As a solvent it is possible to use a solvent described in stage 1. Preferably, it is possible to use esters (e.g. methyl acetate, ethyl acetate or the like) or ethers (e.g. tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane or the like).

As a basis you can use the basis described in stage 2. Preferably, it is possible to use organic amines (e.g. triethylamine, diisopropylethylamine, DBU, 2,6-lutidine or the like). The reaction can be performed at 20-40°C for 0.5-48 hours.

Stage 13

Stage 13 is the method of obtaining the compound represented by formula (II-M), which includes the interaction of the compounds represented by formula (II-L), with the compound represented by the formula, Rb-Hal, in the presence of a base.

As a solvent it is possible to use a solvent described in stage 1. Preferably, you can use ethers (e.g. tetrahydrofuran, etilogy ether, dioxane, 1,2-dimethoxyethane or the like).

As a basis you can use the basis described in stage 2. Preferably, you can use the alkoxides of metals (e.g. sodium methoxide, ethoxide sodium tert-piperonyl potassium or the like) or LDA. The reaction can be conducted at-78-40°C for 0.5-24 hours.

Stage 14

Stage 14 is a method of obtaining a compound represented by formula (II-N), which includes removing protection from a compound represented by formula (II-M), in strongly acidic conditions.

For example, as a strong acid can be used triperoxonane acid or sulfuric acid.

As a solvent it is possible to use a solvent described in stage 1. Preferably, it is possible to use halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane or the like). The reaction can be conducted at-78-40°C for 0.5-24 hours.

Stage 15

Stage 15 is a method of obtaining a compound represented by formula (II-O), which includes the interaction of the compounds represented by formula (II-N), with the amine.

The reaction can be conducted under conditions similar to the above in stage 4.

Stage 16

Stage 16 is a method of obtaining a compound represented by formula (II-P), which includes the removal of protection connection data is built by the formula (II-O).

The reaction can be conducted under conditions similar to the above in stage 3.

Stage 17

Stage 17 is a method of obtaining a compound represented by formula (I-D), which includes the interaction of the compounds represented by formula (II-P), with the compound represented by formula (II-Q).

The reaction can be conducted under conditions similar to the above in stage 4.

Stage 18

Stage 18 is a method of obtaining a compound represented by formula (I-E), which includes the restoration of the compounds represented by formula (I-D).

The reaction can be carried out by catalytic hydrogenation using a catalyst of a transition metal.

As the transition metal catalyst can be used platinum, palladium, rhodium, ruthenium, Nickel or the like

As a solvent it is possible to use a solvent described in stage 1. Preferably, it is possible to use alcohols (e.g. methanol, ethanol, tert-butanol or the like), ethers (e.g. tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane or the like), water, a mixed solvent or the like, the Reaction can be carried out in the presence of hydrogen and of a catalyst of a transition metal at 20-50°C. for 0.5 to 48 hours.

Formula 42

where each character on preveden the th above scheme is such as indicated above, and as the compound (II-R) you can use the well-known compound or can be used a compound obtained from known compounds in the usual way. Pro represents a protective group. As a protective group example includes methyl group, ethyl group, benzyl group, benzoyloxy group, tert-boutelou group or the like

Stage 19

Stage 19 is a method of obtaining a compound represented by formula (II-S), in which the compound represented by formula (II-R), is subjected to acid hydrolysis.

As a solvent it is possible to use a solvent described in stage 1. Preferably, you can use water. As the acid, you can use a strong acid such as sulfuric acid, nitric acid, hydrochloric acid or the like, the Reaction can be conducted at 20-100°C for 0.5-48 hours.

Stage 20

Stage 20 is a way of converting the compound represented by formula (II-S), the compound represented by formula (II-T).

This method is a process of interaction, when one of Riand Rjrepresents hydrogen and the other Riand Rjrepresents an optionally substituted alkylsulfonyl, optionally substituted cycloalkylcarbonyl, optional replacement of the military arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity, optionally substituted alkylaryl, optionally substituted cycloalkylcarbonyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic or optionally substituted heterocyclicamines. This reaction can be conducted by reacting the compound represented by formula (II-S), with a corresponding acid chloride of the acid, acid anhydride or sulphonylchloride.

As a solvent it is possible to use a solvent described in stage 1. Preferably, you can use ethers (e.g. tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane or the like), N-dimethylformamide, or a halogenated hydrocarbon (e.g. dichloromethane, chloroform, 1,2-dichloroethane or the like).

As a basis you can use the basis described in stage 2. Preferably, it is possible to use organic amines (e.g. triethylamine, diisopropylethylamine, DBU, 2,6-lutidine or the like) or pyridine.

The reaction can be conducted at a temperature in the range from -20°C to the boiling point of the used solvent under reflux, for 0.5-24 hours.

Stage 21

This stage represents a method of obtaining a compound represented forms the Loy (II-U), which includes removing protection from a compound represented by formula (II-T).

The reaction can be conducted under conditions similar to the above in stage 3.

Stage 22

This stage represents a method of obtaining a compound represented by formula (I-F), which includes the interaction of the compounds represented by formula (II-U) with the compound represented by formula (II-Q).

The reaction can be conducted under conditions similar to the above in stage 4.

Stage 23

This stage represents a method of obtaining a compound represented by formula (I-G), which includes the restoration of the compounds represented by formula (I-F).

The reaction can be conducted under conditions similar to the preceding stage 18.

Formula 43

where each symbol in the above scheme is the same as described above, and as the compound (II-R) you can use the well-known compound or can be used a compound obtained from known compounds in the usual way. Pro represents a protective group. As a protective group example includes methyl group, ethyl group, benzyl group, benzoyloxy group, tert-boutelou group or the like

Stage 24

Stage 24 is a way of converting the compound represented by f is rmulas (II-R), in the compound represented by formula (II-T).

This method is a process of interaction, when one of Riand Rjrepresents hydrogen and the other Riand Rjrepresents an optionally substituted carbarnoyl, optionally substituted allyloxycarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted aryloxyalkyl, optionally substituted heteroarylboronic, optionally substituted heterocyclizations. This reaction can be conducted by reacting the compound represented by formula (II-R), with the corresponding alcohol or amine.

As a solvent it is possible to use a solvent described in stage 1. Preferably, it is possible to use aromatic hydrocarbons (e.g. toluene, benzene, xylene or the like) or ethers (e.g. tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane or the like).

The reaction can be conducted at a temperature in the range from -20°C to the boiling point of the used solvent under reflux, for 0.5-24 hours,

Formula 44

where each symbol in the above scheme is the same as described above, and as the compound (II-N) can be used a known compound or can be used to connect the group of obtained from known compounds in the usual way. Pro represents a protective group. As a protective group example includes methyl group, ethyl group, benzyl group, benzoyloxy group, tert-boutelou group or the like Hal represents halogen.

Stage 25

Stage 25 is a method of obtaining a compound represented by formula (II-V), which includes the restoration of the compounds represented by formula (II-N). This reaction can be conducted by reacting the compound represented by formula (II-N), with atilglukuronida to get active complex ether, followed by reaction with a reducing agent.

As a solvent it is possible to use a solvent described in stage 1. Preferably, you can use ethers (e.g. tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane or the like).

As a reducing agent can be used createcachetable sodium, sodium borohydride, tetrahydroborate lithium, pyridine-bananowy complex, tetrahydrofuran-bananowy complex, dimethylsulfoxide-bananowy complex sulfide bananowy complex or 2-picoline-bananowy complex. Preferably, you can use sodium borohydride.

The reaction can be conducted at-20-50°C for 0.5-24 hours.

Stage 26

Stage 26 depict the defaults to a method for obtaining compounds, represented by formula (II-W), which includes removing protection from a compound represented by formula (II-V).

The reaction can be conducted under conditions similar to the above in stage 3.

Stage 27

Stage 27 is a method of obtaining a compound represented by formula (I-H), which includes the interaction of the compounds represented by formula (II-W), with the compound represented by formula (II-Q).

The reaction can be conducted under conditions similar to the above in stage 4.

Stage 28

Stage 28 is a method of obtaining a compound represented by formula (I-J), which includes the restoration of the compounds represented by formula (I-H).

The reaction can be conducted under conditions similar to the preceding stage 18.

Stage 29

Stage 29 is a method of obtaining a compound represented by formula (I-K), which includes halogenoalkane compounds represented by formula (I-H).

As a solvent it is possible to use a solvent described in stage 1. Preferably, it is possible to use halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane or the like).

As halogenation means you can use DAST (TRIFLUORIDE (diethylamino)sulfur), NCS (N-chlorosuccinimide), NBS (N-bromosuccinimide), CBr4, PBr3or PBr 5.

The reaction can be conducted at temperatures ranging from -78°C to the boiling point of the used solvent under reflux, for 0.5-24 hours.

Stage 30

Stage 30 is a method of obtaining a compound represented by formula (I-L), which includes halogenoalkane compounds represented by formula (I-J).

The reaction can be conducted under conditions similar to the preceding stage 29.

Formula 45

Compounds where Rdmeans-CN

where Rgand Rhrepresent hydrogen, each of the other symbols in the diagram above is the same as described above, and as the compound (II-O) can be used a known compound or can be used a compound obtained from known compounds in the usual way. Pro represents a protective group. As a protective group example includes methyl group, ethyl group, benzyl group, benzoyloxy group, tert-boutelou group or the like

Stage 31

Stage 31 is a method of obtaining a compound represented by formula (II-X), which involves the dehydration of the compounds represented by formula (II-O).

The reaction can be conducted by reacting the compound represented by formula (II-O), with dry trifero ssnoi acid and pyridine in halogenated hydrocarbons (for example, dichloromethane, chloroform, 1,2-dichloroethane or the like) at 20-40°C for 0.5-10 hours.

Stage 32

Stage 32 is a method of obtaining a compound represented by formula (II-Y), which includes removing protection from a compound represented by formula (II-X).

The reaction can be conducted under conditions similar to the preceding stage 18.

Stage 33

Stage 33 is a method of obtaining a compound represented by formula (I-M), which includes the interaction of the compounds represented by formula (II-Y), with the compound represented by formula (II-Q).

The reaction can be conducted under conditions similar to the above in stage 4.

Stage 34

Stage 34 is a method of obtaining a compound represented by formula (I-N), which includes the restoration of the compounds represented by formula (I-M).

The reaction can be conducted under conditions similar to the preceding stage 18.

Formula 46

where each symbol in the above scheme is the same as described above, and as the compound (II-A) can be used a known compound or can be used a compound derived from a known compound in the usual way. Pro represents a protective group. As a protective group example includes methyl group, ethyl g is the SCP, benzyl group, benzoyloxy group, tert-boutelou group or other Pro represents a protective group. As a protective group sample includes tert-boutelou group, trityloxy group, benzyl group, p-methoxybenzyloxy group, silyl group, methanesulfonyl group, acyl group or the like

Stage 35

Stage 35 is a method of obtaining a compound represented by formula (II-AA), which includes the interaction of the compounds represented by formula (II-A), with the compound represented by formula (II-Z).

The reaction can be conducted under conditions similar to the above in stage 1.

Stage 36

Stage 36 is a method of obtaining a compound represented by formula (II-AB), which includes halogenoalkane compounds represented by formula (II-AA).

For example, halogenoalkane can be performed according to example 3 in W02007/058346.

The chlorination can be carried out with phosphorylchloride at a temperature in the range from -20°C to the boiling point of phosphorylchloride under reflux, for 0.5-24 hours. This reaction can be carried out in a solvent described in stage 1, or without solvent.

Bromination can be carried out with PBr3in conditions similar to the above. Ftoroproizvodnykh can be obtained by interaction of the corresponding chlorprom is underwater with potassium fluoride.

Stage 37

Stage 37 is a method of obtaining a compound represented by formula (I-O), of the compounds represented by formula (II-AB).

The reaction can be performed according to the General method described in this specification.

Formula 47

where each symbol in the above scheme is the same as described above, and as the compound (II-AB), you can use the well-known compound or can be used a compound obtained from known compounds in the usual way. Pro represents a protective group. As a protective group example includes methyl group, ethyl group, benzyl group, benzoyloxy group, tert-boutelou group or other Pro represents a protective group. As a protective group sample includes tert-boutelou group, trityloxy group, benzyl group, p-methoxybenzyloxy group, silyl group, methanesulfonyl group, acyl group or the like Hal represents halogen. As X', the sample includes =N - or =CRY-where RYrepresents hydrogen, C1-Salkil or halogen.

Stage 38

Stage 38 is a method of obtaining a compound represented by formula (II-AD), which includes the interaction of the compounds represented by formula (II-AB), with whom the Association, represented by formula (II-AC) in the presence of a base.

As a basis you can use the basis described in stage 2. Preferably, it is possible to use metal hydrides (e.g. sodium hydride or the like) or LDA.

As a solvent it is possible to use a solvent described in stage 1. Preferably, you can use ethers (e.g. tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane or the like).

The reaction can be conducted at-78-50°C for 0.5-24 hours.

Stage 39

Stage 39 is a method of obtaining a compound represented by formula (I-P), from the compound represented by formula (II-AD).

The reaction can be performed according to the General method described in this specification.

Stage 40

Stage 40 is a method of obtaining a compound represented by formula (II-AF), which includes the interaction of the compounds represented by formula (II-AB), with the compound represented by formula (II-AE).

As a solvent it is possible to use a solvent described in stage 1. The reaction can also be carried out without solvent.

The reaction can be conducted at 80-150°C for 0.5-48 hours. For this reaction can also use a microwave.

Stage 41

Stage 41 is a method of obtaining compounds, predstavlennoj the formula (I-Q), of the compounds represented by formula (II-AF).

The reaction can be performed according to the General method described in this specification.

Formula 48

where each symbol in the above scheme is the same as described above, and as the compound (II-AG) can be used a known compound or can be used a compound derived from a known compound in the usual way.

Stage 42

Stage 42 is a method of obtaining a compound represented by formula (II-AH), which includes the interaction of the compounds represented by formula (II-AG), with hydrazine.

The reaction can be conducted under conditions similar to the above in stage 1.

Stage 43

Stage 43 is a method of obtaining a compound represented by formula (II-AI), which includes halogenoalkane compounds represented by formula (II-AH).

For example, halogenoalkane can be performed by the reaction of Sandmeyer. Bromination can be carried out with CuBr at a temperature in the range from -20°C to the boiling point of the used solvent under reflux, for 0.5-24 hours.

The chlorination can be carried out with CuCl in conditions similar to the above. In addition, in conditions similar to the above, can be iodized with potassium iodide and can be tonirovanie with tetrafluoroborate silver.

Stage 44

Stage 44 is a method of obtaining a compound represented by formula (II-AJ) or (II-AK), of the compounds represented by formula (II-AI).

The reaction can be performed according to the General method described in this specification.

The compound in which the halogen group of compounds represented by the above formula (II-AJ) or (II-AK), substituted by various substituents, can be obtained by reacting compounds represented by the above formula (II-AJ) or (II-AK), in conditions similar to the above in stage 6, stage 38 and stage 40.

In this connection it is possible to introduce different substituents according to the references of publication: (1) Alan R.Katriszly et al., Comprehensive Heterocyclic Chemistry (2) Alan R.Katriszly et al., Comprehensive Heterocyclic Chemistry II (3) RODD''S CHEMISTRY OF CARBON COMPOUNDS VOLUME IV HETEROCYCLIC COMPOUNDS or the like

The present compound has an excellent inhibitory activity against 11β-hydroxysteroiddehydrogenase type 1. So it can be used for treating or preventing diseases related to 11β-hydroxysteroiddehydrogenase type 1, especially diseases such as hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis, hyperglycemia and/or syndrome X. It is particularly useful for the treatment or prevention of diabetes.

The compound used in the present invention, can enter the be oral or parenteral. In the case of oral administration, the compound used in the present invention can be applied in any dosage form, including normal drugs, for example, solid preparations such as tablet, powder, granule, capsule and the like; water products; oil suspension; or such liquid preparations, as a syrup or elixir. In the case of parenteral administration, the compound used in the present invention can be applied in the form of aqueous or oily suspension for injection or intranasal solution.

In the manufacture of such preparations can optionally use the traditional excipient, binder, lubricant, water, solvent, oil, solvent, emulsifier, suspendisse agent, preservative, stabilizer and the like are Particularly preferably used in the form of oral medication.

Dosage form of the compounds used in the present invention, can be formed by combining (e.g., mixing) a therapeutically effective amount of the compounds used in the present invention, with the pharmaceutically acceptable carrier or diluent. Drug form of the compounds used in the present invention, can be obtained by a known method, using well-known readily available ingredient.

Dose with the organisations, used in the present invention is different depending on the route of administration, age, body mass, condition and disease of the patient; it is usually from about 0.05 mg to 3000 mg, preferably from about 0.1 mg to 1000 mg per day per adult human in the case of oral administration, and if necessary, you can enter it in divided doses. In the case of parenteral administration can be entered from about 0.01 mg to 1000 mg and preferably from about 0.05 mg to 500 mg per day for an adult. In the introduction it can be used in conjunction with other therapeutic means.

The following summary of the present invention will be described in more detail by way of examples, which are not intended limit the scope of the present invention.

In addition, the group represented by formula (III'):

Formula 49

equivalent to the following groups:

Formula 50

Example 1

Formula 51

To a solution of compound (II-1) (diethylethylenediamine, 10 g) in N,N-dimethylformamide (50 ml) was added dropwise 80% Gidrodinamika (4.4 g) in N,N-dimethylformamide (50 ml) for 15 minutes To the resulting solution was added potassium carbonate (6.4 g) and the reaction mixture paramashiva and at 80°C for 2 hours. To the mixture was added isobutyramide (7,6 ml) and the resulting mixture was stirred at 120°C for 1.5 hours. After the reaction, the reaction mixture was poured into 0,5M aqueous HCl solution and was extracted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous NaHCO3and salt solution, dried over sodium sulfate and concentrated. The residue was dissolved in a small amount of ethyl acetate and the resulting solution was added hexane under ice cooling, to obtain a crystalline substance. The crystalline substance was separated by filtration and dried, obtaining the compound II-2 (4.6 g).

To a solution of compound II-2 (5.7 g) in ethyl acetate (160 ml) was added IBX (7.5 g), then the resulting mixture was boiled under reflux for 6 hours. After the reaction, the insoluble substance was removed by filtration and the filtrate was concentrated, obtaining the compound II-3 (5.6 g). The obtained product was used in next reaction without further purification.

To a solution of compound II-3 (5.6 g) in tetrahydrofuran (40 ml) was added phosphonium salt (13.5 g). To the solution is added dropwise within 20 min was added triethylamine (3.4 g), then the resulting mixture for 3 hours, stirred at room temperature. After the reaction, to the mixture was added water (40 ml), then was extracted with ethyl acetate. The organic layer was washed concrete is salt, was dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving compound II-4 (5,2 g).

The solution Diisopropylamine (1.3 ml) in tetrahydrofuran (60 ml) was cooled to -78°C, then to the solution was added dropwise n-utility (of 3.25 ml, 2,8 M in hexane). After stirring at -78°C for 30 min, to the solution was added compound II-4 (2.8 g) in tetrahydrofuran (40 ml) and the resulting mixture was stirred for 30 minutes To the mixture was added logmean (1,4 ml), then the resulting mixture gave the opportunity to gradually warm to 0°C. After 3 hours the mixture was diluted with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic layer was washed with salt solution, dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving compound II-5 (2,42 g).

To a solution of compound II-5 (19,4 g) in dichloromethane (100 ml) was added triperoxonane acid (50 ml), then the reaction mixture for 3 hours, stirred at room temperature. After the reaction the solvent was removed, the residue was diluted with H2O (100 ml) and was extracted with ethyl acetate. The organic layer was washed with salt solution, dried over magnesium sulfate and concentrated, obtaining compound II-6 (16.6 g).

To a solution of compound II-6 (237 mg) in tetrahydrofuran (3 ml) at 0°C gobblelization (152 μl) and ethylchloride (84 μl), then the reaction mixture was stirred at room temperature for one hour. At 0°C to the mixture was added sodium borohydride (69 mg) and water (1 ml) and the resulting mixture was stirred for 20 minutes After completion of the reaction, to the mixture was added an aqueous solution of HCl. Carried out the extraction with ethyl acetate. The organic layer was washed with salt solution, dried over sodium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving II-7 (185 mg).

To a solution of compound II-7 (185 mg) in dichloromethane (5 ml) at -78°C was added DAST (102 μl), then the reaction mixture was stirred at the same temperature for 30 minutes After completion of the reaction, to the mixture was added saturated aqueous solution of NH4Cl. Carried out the extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving compound II-8 (62 mg).

To a solution of compound II-8 (of 61.6 mg) in tetrahydrofuran (1 ml) with methanol (1 ml) was added 2n. aqueous NaOH solution (1 ml) and then the reaction mixture was stirred at room temperature for 14 hours. After the reaction mixture was acidified using 2n. aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed with salt solution, dried over sodium sulfate and concentrated, obtaining compound II-9 (60.1 mg). The floor is this product used in the next reaction without further purification.

To a solution of compound II-9 (60.1 mg) in dimethylformamide (3 ml) was added hydroxyadamantane (38,8 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (48,5 mg), 1-hydroxybenzotriazole (8.5 mg) and triethylamine (50 μl) and then the reaction mixture was stirred at room temperature for 18 hours. After the reaction mixture was acidified using 2n. aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous NaHCO3and the salt solution and dried over sodium sulfate. The residue was purified column chromatography on silica gel, receiving compound II-10 (62 mg).

To a solution of compound II-10 (54 mg) in tetrahydrofuran (1.2 ml) at -45°C was added chlorosulfonylisocyanate (22 μl) and then the reaction mixture was stirred at -30°C for 2 hours. To the solution was added solid NaHCO3(74 mg) and water (24 ml) and the resulting mixture was stirred at room temperature for 2 hours. After the reaction, to the mixture was added water, then was extracted with ethyl acetate. The organic layer was washed with salt solution and dried over sodium sulfate. The residue was purified column chromatography on silica gel, receiving compound I-1 (51 mg).

(Compound I-1) NMR (DMSO-d6): δ (ppm) of 0.95 (d, J=6.6 Hz, 6H), of 1.30 (s, 3H), of 1.36 (s, 3H), of 1.41 (d, J=12,4 Hz, 2H), 1,94 is 2.10 (m, 12H), 2,46 of $ 2.53 (m, 2H), 3,94 (s, 1H), 4,10 (d, J=6.3 Hz, 2H), between 6.08-6,16 (m, 1H), 6,20 (the Il, 2H), 6,92 (d, J=14,2 Hz, 1H), 7,50 (d, J=6,6 Hz, 1H), 7,94 (s, 1H).

The compounds below were synthesized in a similar manner.

For each connection the results of the measurements of NMR or log k'.

log k' is a value that indicates the degree of lipophilic in nature and which are calculated according to the following formula.

log k'=log (tR-t0)/t0

tR: the retention time of compounds in terms of the gradient

t0: the retention time of standard material not held in the column.

To measure the used column XTerra MS C18 5 μm, and 2.1×100 mm (manufactured by Waters). Elution was carried out at the straight gradient mixture of acetonitrile/buffer pH 6.8 (from 5:95 to 95:5 in 20 min) at a flow rate of 0.25 ml/min

Example 2

Formula 52

(compound I-2) log k'=1,014 registered

Example 3

Formula 53

(Compound I-3) log k'=1,066

Example 4

Formula 54

(Compound I-4) NMR (CDCl3): δ (ppm) of 1.10 (d, J=6,7 Hz, 6H), 1,36-of 1.84 (m, 8H), and 1.54 (s, 6H), of 1.95 (s, 3H), of 2.10 to 2.35 (m, 5H), 2,64 was 2.76 (m, 1H), 3,98 (d, J=6,8 Hz, 2H), 4,23-to 4.28 (m, 1H), 5,32 (W, 1H), vs. 5.47 (s, 1H), 5,50 (W, 1H), 6,38 (d, J=14.1 Hz, 1H), 6,46 (d, J=8.0 Hz, 1H), 6,86 (d, J=14.1 Hz, 1H), 7,83 (s, 1H).

Example 5

Formula 55

(Compound I-5) log k'=0,795.

Example 6

Formula 56

<> (Compound I-6) NMR (DMSO-d6): δ (ppm) to 0.96 (t, J=7.5 Hz, 3H), of 0.97 (d, J=6.6 Hz, 6H), 1.32 to about 1.36 (m, 2H), 1,40 (s, 6H), 1,58 is 1.75 (m, 6H), 1,89-2,11 (m, 8H), 3,86-3,91 (m, 1H), 4,07 (d, J=6.3 Hz, 2H), 4,42 (s, 1H), 6.35mm (d, J=14.1 Hz, 1H), 6,76 (d, J=14.1 Hz, 1H), 7,38 (d, J=6,9 Hz, 1H), to 7.67 (s, 1H), 7,95 (s, 1H).

Example 7

Formula 57

(Compound I-7) NMR (DMSO-d6): δ (ppm) to 0.98 (d, J=6.8 Hz, 6H), of 1.42 (d, J=13.1 Hz, 2H), of 1.52 (s, 6H), 1,95-2,11 (m, 12H), of 3.96 (s, 1H), 4,15 (d, J=6.3 Hz, 2H), 6,20 (W, 2H), 6,24 (d, J=14,2 Hz, 1H), 7,10 (d, J=14,2 Hz, 1H), 7,55 (d, J=6,1 Hz, 1H), 8,04 (s, 1H).

Example 8

Formula 58

(Compound I-8) log k'=0,883.

Example 9

Formula 59

(Compound I-9) NMR (DMSO-d6): δ (ppm) to 0.97 (d, J=6.6 Hz, 6H), 1,40-of 1.44 (m, 8H), 1,94 is 2.10 (m, 12H), 2,90 (s, 3H), 3,94-of 3.96 (m, 1H), 4,11 (d, J=6.3 Hz, 2H), 6,20 (W, 2H), 6,33 (d, J=14.4 Hz, 1H), 6,92 (d, J=14.4 Hz, 1H), 7,24 (s, 1H), to 7.50 (d, J=6,8 Hz, 1H), 7,98 (s, 1H).

Example 10

Formula 60

(Junction I-10) log k'=0,798.

Example 11

Formula 61

(Compound I-11) log k'=0,831.

Example 12

Formula 62

(Compound I-12) log k'=0,763.

Example 13

Formula 63

(Compound I-13) log k'=0,822.

Example 14

Formula 64

(Compound I-14) log k'=0,981.

Example 15

Formula 65

(Compound I-15) NMR (CDCl3): is (ppm) of 1.08 (d, J=6.8 Hz, 6H)and 1.51 (s, 6H), 1,58-of 1.85 (m, 6H), 2,02-2,11 (m, 6H), 2,12 (m, 1H), 2,92 totaling 3.04 (m, 1H), 3,62 (s, 3H), of 3.97 (d, J=7,0 Hz, 2H), 4,07-4,10 (m, 1H), a 4.83 (s, 1H), 5,35 (W, 1H), 5,51 (W, 1H), 6,37 (d, J=14.1 Hz, 1H), 6,46 (d, J=7,6 Hz, 1H), 6.87 in (d, J=14.1 Hz, 1H))7,83 (s, 1H).

Example 16

Formula 66

(Compound I-16) log k'=0,842.

Example 17

Formula 67

(Compound I-17) log k'=0,916.

Example 18

Formula 68

(Compound I-18) log k'=0,866.

Example 19

Formula 69

(Compound I-19) log k'=0,907.

Example 20

Formula 70

(Compound I-20) log k'=0,845.

Example 21

Formula 71

(Compound I-21) log k'=0,909.

Example 22

Formula 72

(Compound I-22) log k'=0,879.

Example 23

Formula 73

(Compound I-23) log k'=0,864.

Example 24

Formula 74

(Compound I-24) log k'=0,876.

Example 25

Formula 75

(Compound I-25) log k'=0,87.

Example 26

Formula 76

(Compound I-26) log k'=0,895.

Example 27

Formula 77

(Compound I-27) log k'=of 0.903.

Example 28

Formula 78

(Compound I-28) log k'=0,927.

Example 29

Formula 79

(Compound I-29) NMR (CDCl3); δ (ppm) of 1.39 (d, J=6.3 Hz, 6H)and 1.51 (s, 6H), 1,55-2,11 (m, 13H), 3,62 (s, 3H), of 3.73 (s, 2H), 4,14-4,16 (m, 1H), br4.61 (W, 2H), 4,67-of 4.75 (m, 1H), a 4.83 (m, 1H), 6,36 (d, J=14,2 Hz, 1H), 6,53 (d, J=7,3 Hz, 1H), 6,83 (d, J=14,2 Hz, 1H), 7,86 (s, 1H).

Example 30

Formula 80

(Compound I-30) NMR (CDCl3): δ (ppm) of 1.39 (d, J=6.3 Hz, 6H), and 1.54 (s, 6H), 1,59-of 1.78 (m, 4H), to 1.96 (s, 3H), 2,13-to 2.29 (m, 9H), 4,20-to 4.23 (m, 1H), 4,43 (W, 2H), 4,67-of 4.75 (m, 1H), 5,46 (s, 1H), 6,36 (d, J=14,2 Hz, 1H), 6,47 (d, J=and 7.6 Hz, 1H), for 6.81 (d, J=14,2 Hz, 1H), a 7.85 (s, 1H).

Example 31

Formula 81

(Compound I-31) log k'=0,819.

Example 32

Formula 82

(Compound I-32) NMR (CDCl3): δ (ppm) of 1.39 (d, J=6.3 Hz, 6H), and 1.54 (s, 6H), 1.56 to 2,10 (m, 13H), a 1.96 (s, 3H), of 3.73 (s, 2H), 4,14-4,16 (m, 1H), 4,63 (W, 2H), 4,67-of 4.75 (m, 1H), 5,48 (s, 1H), 6,36 (d, J=14,2 Hz, 1H), 6,56 (d, J=7,8 Hz, 1H), PC 6.82 (d, J=14,2 Hz, 1H), 7,86 (s, 1H).

Example 33

Formula 83

(Compound I-33) log k'=0,955.

Example 34

Formula 84

(Compound I-34) log k'=0,877.

Example 35

Formula 85

(Compound I-35) log k'=0,921.

Example 36

Formula 86

(Compound I-36) NMR (DMSO-d6): δ (ppm) of 1.08 (d, J=6.6 Hz, 6H), 1,47-of 1.74 (m, 19H), and 1.54 (s, 3H), of 1.64 (s, 3H), 1,89-to 1.98 (m, 2H), 2,10-of 2.24 (m, 6H), 3,98 (d, J=6,9 Hz, 2H), 4,14-4,20 (m, 1H), 5,42 (s, 1H), 6,38 (d, J=14.4 Hz, 1H), 6,38 (1H), 6,86 (d, J=14.4 Hz, 1H), 7,80 (s, 1H).

Example 37

Formula 87

(Compound I-37)

Example 38

Formula 88

(Compound I-38)

Example 39

Formula 89

(Compound I-39)

Example 40

Formula 90

(Compound I-40)

Example 41

Formula 91

(Compound I-41)

Example 42

Formula 92

(Compound I-42) log k'=0,805

Example 43

Formula 93

(Compound I-43) log k'=0,851.

Example 44

Formula 94

(Compound I-44) NMR (CDCl3); δ (ppm) of 1.08 (d, J=6,7 Hz, 6H)and 1.51 (s, 6H), 1,58-to 2.06 (m, 13H), 2,07-of 2.20 (m, 1H), 2,24-of 2.36 (m, 1H), 3,41 (d, J=6.2 Hz, 2H), 3,62 (s, 3H), 3,98 (d, J=6,7 Hz, 2H), 3,99-was 4.02 (m, 1H), 4,82 (s, 1H), 6,37 (d, J=14,2 Hz, 1H), of 6.49 (d, J=7,6 Hz, 1H), 6.87 in (d, J=14,2 Hz, 1H), 7,82 (s, 1H).

Example 45

Formula 95

(Compound I-45) log k'=0,865.

Example 46

Formula 96

(Compound I-46) log k'=0,913.

Example 47

Formula 97

(Compound I-47) NMR (CDCl3): δ (ppm) of 1.08 (d, J=6.6 Hz, 6H), 1,51-of 1.84 (m, 8H), was 1.58 (s, 3H), of 1.66 (s, 3H), 1,88-to 1.98 (m, 2H), 2.06 to 2,24 (m, 4H), to 3.41 (s, 3H), 3,80 (s, 2H), 3,98 (d, J=6.6 Hz, 2H), 4,14-4,20 (m, 1H), 6.35mm (d, J=8,1 Hz, 1H), 6,41 (d, J=14.1 Hz, 1H), of 6.52 (s, 1H), 6.87 in (d, J=14.1 Hz, 1H), 7,81 (s, 1H).

Por the measures 48

Formula 98

(Compound I-48) NMR (DMSO-d6): δ (ppm) of 0.85 (t, J=7.2 Hz, 3H), of 0.96 (d, J=6.6 Hz, 6H), 1,35-of 1.56 (m, 4H), of 1.40 (s, 6H), 1,90-of 2.16 (m, 14H), 3,91-3,98 (m, 1H), 4,07 (d, J=6.3 Hz, 2H), 6,21 (W, 2H), 6.35mm (d, J=14.4 Hz, 1H), 6,76 (d, J=14.4 Hz, 1H), 7,47 (d, J=6.3 Hz, 1H), 7,72 (s, 1H).

Example 49

Formula 99

(Compound I-49) log k'=0,945.

Example 50

Formula 100

(Compound I-50) log k'=0,989.

Example 51

Formula 101

(Compound I-51) log k'=0,882.

Example 52

Formula 102

(Compound I-52) NMR (CDCl3): δ (ppm) of 1.07 (d, J=6.6 Hz, 6H), 1,51-of 1.84 (m, 8H), to 1.60 (s, 3H), of 1.62 (s, 3H), 1,88-to 1.98 (m, 2H), 2.05 is amounts to 2.24 (m, 4H), 3,99 (d, J=6.6 Hz, 2H), 4,14-4,20 (m, 1H), 4,39 (s, 2H), 6,36 (d, J=7.5 Hz, 1H), 6,44 (d, J=14.4 Hz, 1H), return of 6.58 (s, 1H), 6,86-of 6.96 (m, 3H), 7,00-7,06 (m, 1H), 7,28 and 7.36 (m, 2H), 7,81 (s, 1H).

Example 53

Formula 103

(Compound I-53) NMR (CDCl3): δ (ppm) of 1.09 (d, J=6.9 Hz, 6H), 1,38-of 1.84 (m, 8H), of 1.47 (s, 3H), and 1.63 (s, 3H), 1,88 is 2.00 (m, 2H), 2,08-of 2.26 (m, 4H), 2,42 (t, J=7.5 Hz, 2H), 2,93 (t, J=7.5 Hz, 2H), 3,99 (d, J=6,9 Hz, 2H), 4,12-4,20 (m, 1H), from 5.29 (s, 1H), 6,33 (d, J=14.1 Hz, 1H), to 6.39 (s, 1H), at 6.84 (d, J=14.1 Hz, 1H), 7,14-to 7.32 (m, 5H), of 7.82 (s, 1H).

Example 54

Formula 104

(Compound I-54) log k'=0,886.

Example 55

Formula 105

(Compound I-55) NMR (DMSO-d6): δ (ppm) to 0.97 (d, J=6.6 Hz, 6H), of 1.27 (s, 6H), of 1.35 (d, J=12.1 Hz, 2H), 1,61-1,72 (m, 6H), 1,9-2,04 (m, 6H), to 2.57 (d, J=4.3 Hz, 3H), a 3.87-3,91 (m, 1H), 4,10 (d, J=6.3 Hz, 2H), of 4.44 (s, 1H), 6,33 (d, J=14,2 Hz, 1H), 6,78 (d, J=14,7 Hz, 1H), 7,39 (d, J=6,1 Hz, 1H), 7,52-7,56 (m, 1H), 7,98 (s, 1H).

Example 56

Formula 106

(Compound I-56) log k'=0,838.

Example 57

Formula 107

(Compound I-57) log k'=0,852.

Example 58

Formula 108

(Compound I-58) log k'=0,899.

Example 59

Formula 109

(Compound I-59) log k'=0,833.

Example 60

Formula 110

(Compound I-60) log k'=0,813.

Example 61

Formula 111

(Compound I-61) log k'=0,841.

Example 62

Formula 112

(Compound I-62) log k'=0,794.

Example 63

Formula 113

(Compound I-63) NMR (DMSO-d6): δ (ppm) to 0.98 (d, J=6.8 Hz, 6H), of 1.27 (s, 6H), 1,39-is 1.51 (m, 8H), 1,87-2,03 (m, 6H), of 3.00 (d, J=5.6 Hz, 2H), 3,88 (s, 1H), 4,10 (d, J=6.3 Hz, 2H),4,37 (t, J=5.6 Hz, 1H), 6,37 (d, J=14.4 Hz, 1H), for 6.81 (d, J=14.4 Hz, 1H), 6,95 (s, 1H), 7,15 (s, 1H), 7,41 (d, J=7,1 Hz, 1H), 7,98 (s, 1H).

Example 64

Formula 114

(Compound I-64) log k'=0,814.

Example 65

Formula 115

(Compound I-65) log k'=0,838.

Example 66

Formula 116

(Compound I-66) log k'=0,886.

Example 67

Formula 117

(Compound I-67) log k'=0,82.

Example 68

Formula 118

(Compound I-68) log k'=0,85.

Example 69

Formula 119

(Compound I-69) log k'=0,866.

Example 70

Formula 120

(Compound I-70) log k'=0,882.

Example 71

Formula 121

(Compound I-71) log k'=0,868.

Example 72

Formula 122

(Compound I-72) NMR (DMSO-d6): δ (ppm) 0,96-1,01. (m, 9H), of 1.27 (s, 6H), of 1.34 (d, J=12.1 Hz, 2H), 1,61-1,72 (m, 6H), 1,89-2,04 (m, 6H), 3,03-is 3.08 (m, 2H), 3,89 (s, 1H), 4,10 (d, J=6.6 Hz, 2H), of 4.44 (s, 1H), 6,34 (d, J=14.4 Hz, 1H), 6,78 (d, J=14.4 Hz, 1H), 7,39 (d, J=6,6 Hz, 1H), EUR 7.57 (t, J=5.4 Hz, 1H), 7,98 (s, 1H).

Example 73

Formula 123

(Compound I-73) log k'=0,876.

Example 74

Formula 124

(Compound I-74) log k'=0,896.

Example 75

Formula 125

(Compound I-75) log k'=0,95.

Example 76

Formula 126

(Compound I-76) log k'=0,946.

Example 77

Formula 127

(Compound I-77) log k'=0,926.

Example 78

Formula 128

(Compound I-78) log k'=0,955

Example 79

Formula 129

(Compound I-79) log k'=0,818.

Example 80

Formula 130

(Compound I-80) log k'=0,852.

Example 81

Formula 131

(Compound I-81) log k'=0,813.

Example 82

Formula 132

(Compound I-82) log k'=0,682.

Example 83

Formula 133

(Compound I-83) log k'=0,87.

Example 84

Formula 134

To a solution of compound II-11 (ethyl-3-(dimethylamino)acrylate, 6,9 g) in toluene (100 ml) at -11°C for 20 min was added dropwise anhydrous triperoxonane acid (6,7 ml), then the reaction mixture was stirred at room temperature for 4 hours. After the reaction, to the mixture was added dichloromethane and H2O and the resulting mixture was stirred for 20 min, then separated. The aqueous layer was extracted with dichloromethane. The organic layer was combined, dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving compound II-12 (10.1 g).

To a solution of compound II-12 (10.1 g) in acetonitrile (100 ml) was added dropwise 80% Gidrodinamika (3,72 ml) and the reaction mixture was stirred at 50°C for one hour. After the reaction solvent was removed, the residue was added H2O and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and koncentrirovalisb was purified column chromatography on silica gel, receiving compound II-13 (at 8.36 g).

To a solution of compound II-13 (of 7.82 g) in ethyl acetate (156 ml) was added TEMPO (242 mg), potassium bromide (738 mg), solid NaHCO3(6,51 g) and (H2O (15.6 ml). To the resulting mixture at -7°C for 8 min was added dropwise a 5% aqueous solution of NaClO (48,5 ml), then the reaction mixture was stirred at the same temperature for one hour. After confirming the formation of the aldehyde to the mixture was added phosphonium salt (14,62 g) and triethylamine (5.2 ml), and then the resulting mixture was stirred at room temperature for 30 minutes After the reaction to the reaction mixture was added H2O, then extracted with ethyl acetate. The organic layer was washed with salt solution, dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving compound II-14 (9.2 grams),

To a solution of compound II-14 (of 9.2 g) in tetrahydrofuran (92 ml) was added logmean (1.9 ml) and the resulting solution was cooled to -30°C. To the solution was added ethoxide sodium (1.9 grams), then the reaction mixture was stirred at -25°C for 2 hours. After the reaction, the reaction mixture was acidified using 1N. aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed successively with 10% aqueous solution of Na2S2O3and the salt solution and dried over magnesium sulfate. Solvent was removed, getting the unity II-15 (9.4 g). The obtained product was used in next reaction without further purification.

To a solution of compound II-15 (9.4 g) in formic acid (14.1 ml) at 0°C was added H2SO4(1,41 ml). After stirring for one hour at 0°C the reaction mixture was stirred for one hour at room temperature. After the reaction, the reaction mixture was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with salt solution and solvent was removed. To the residue was added an aqueous solution of NaHCO3and the mixture is washed with diisopropyl ether. The organic layer was extracted with aqueous solution of NaHCO3and combined with the aqueous layer. The resulting mixture was acidified with an aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed with salt solution, dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving compound II-16 (? 7.04 baby mortality g).

To a solution of compound II-16 (1.5 g) in toluene (7.5 ml) was added triethylamine (718 μl) and diphenylphosphoryl (1,06 ml), then the reaction mixture for 3 hours was stirred at 80°C. After confirming the disappearance of the original substance to the mixture was added methanol (285 μl) at 0°C and the resulting mixture was stirred at 80°C for one hour. After the reaction, to the mixture was added 2n. an aqueous solution of NOH and were extracted with ethyl acetate. The organic layer was washed with salt solution, dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving compound II-17 (1.13 g).

To a solution of compound II-17 (1.13 g) in methanol (4.5 ml) with H2O (2.3 ml) was added 4n. an aqueous solution of LiOH (1,62 ml), then the reaction mixture was stirred at room temperature for 1.5 hours. After the reaction mixture was acidified using 2n. aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed with salt solution, dried over magnesium sulfate and concentrated. Crystallization was carried out from a mixture of ethyl acetate-hexane, obtaining compound II-18 (677 mg).

To a solution of compound II-18 (100 mg) in dimethylformamide (1.5 ml) was added the hydrochloride of hydroxyadamantane (76 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (78 mg), 1-hydroxybenzotriazole (12.6 mg) and triethylamine (108 μl), then the reaction mixture was stirred at room temperature for 6 hours. After the reaction, the mixture was acidified using 2n. aqueous solution of HCI and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO3and the salt solution and dried over sodium sulfate. The residue was purified column chromatography on silica gel, receiving compound I-84 (139 mg).

(Compound I-84) NMR (d6-DMSO); δ (ppm) 1,2-1,35 (m, 2H), 1,40 (s, 6H), 1,58-2,03 (m, 11H), 3,50 (s, 3H), a 3.87-to 3.92 (m, 1H), 4,43 (s, 1H), to 6.57 (d, J=13,6 Hz, 1H), to 6.88 (d, J=13,6 Hz, 1H), 7,35 (s, 1H), 7,95 (s, 1H), 8,28 (d, J=6,8 Hz, 1H).

To a solution of compound I-84 (117 mg) in tetrahydrofuran (4,7 ml) at -30°C was added chlorosulfonylisocyanate (33 μl), then the resulting solution for 2 hours, stirred at -30°C. To the solution was added solid NaHCO3(104 mg) and H2O (157 μl) and the resulting mixture was stirred at room temperature for 2 hours. After the reaction, to the mixture was added H2O and was extracted with ethyl acetate. The organic layer was washed with salt solution, dried over sodium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving compound I-85 (116 mg).

(Compound I-85) NMR (d6-DMSO); δ (ppm) of 1.40 (s, 8H), of 1.88 and 2.13 (m, 11H), 3,50 (s, 3H), 3,94-to 3.99 (m, 1H), 6,05 to 6.35 (s, 2H), return of 6.58 (d, J=13,6 Hz, 1H), to 6.88 (d, J=13,6 Hz, 1H), 7,35 (s, 1H), of 7.96 (s, 1H), with 8.33 (d, J=6,8 Hz, 1H).

The compounds below were synthesized in a similar manner.

Example 85

Formula 135

(Compound I-86) NMR (d6-DMSO); δ (ppm) of 1.40 (s, 8H), 1,72-2,03 (m, 14H), 3,50 (s, 3H), 3,91-of 3.97 (m, 1H), return of 6.58 (d, J=13,6 Hz, 1H), to 6.88 (d, J=13,6 Hz, 1H), 7,31-7,39 (m, 2H), 7,95 (s, 1H), with 8.33 (d, J=7.2 Hz, 1H).

Example 86

Formula 136

To a solution of compound II-16 (1.5 g) in toluene (7.5 ml) was added triethylamine (718 μl), diphenylphosphoryl (1,06 ml), then reacts the traditional mixture for 30 min was stirred at 80°C. After confirming the disappearance of the original substance to the mixture at 0°C was added sulfuric acid (374 μl), then the resulting mixture was stirred at 80°C for one hour. After the reaction mixture was podslushivaet 2n. aqueous solution of NaOH and was extracted with ethyl acetate. The organic layer was washed with salt solution, dried over magnesium sulfate and concentrated. The obtained product was used in next reaction without further purification.

According to the above method, the obtained residue was dissolved in dichloromethane (14 ml) and the resulting solution was added triethylamine (1,74 ml) and acetic anhydride (0,59 ml). The reaction mixture was stirred at room temperature for 3 hours. After the reaction, to the mixture was added 1N. an aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO3and salt solution, dried over magnesium sulfate and concentrated. The obtained product was used in next reaction without further purification.

According to the above method, the obtained residue was dissolved in methanol (5.5 ml) with H2O (2,8 ml) and the resulting solution was added 4n. an aqueous solution of LiOH (2,08 ml). The reaction mixture was stirred at room temperature for 1.5 hours. After the reaction the mixture was acidified using 2n. water RA is tworoom HCl and was extracted with ethyl acetate. The organic layer was washed with salt solution, dried over magnesium sulfate and concentrated. Crystallization was carried out from chloroform, receiving compound II-21 (1,09 g).

The compound below was synthesized from compound II-21 according to the above example.

Example 87

Formula 137

(Compound I-87) NMR (d6-DMSO); δ (ppm) of 1.28 and 1.35 (m, 2H), of 1.42 (s, 6H), 1,58-2,03 (m, 14H), a 3.87-3,91 (m, 1H), 4,43 (s, 1H), only 6.64 (d, J=13,6 Hz, 1H), 6,86 (d, J=13,6 Hz, 1H), a 7.85 (s, 1H), 7,94 (s, 1H), 8,27 (d, J=7.2 Hz, 1H).

Example 88

Formula 138

(Compound I-88) NMR (d6-DMSO); δ (ppm) of 1.37 was 1.43 (m, 8H), 1,78-2,11 (m, 14H), 3,93-3,98 (m, 1H), 6,05 to 6.35 (s, 2H), only 6.64 (d, J=13,6 Hz, 1H), 6,86 (d, J=13,6 Hz, 1H), a 7.85 (s, 1H), 7,95 (s, 1H), 8,32 (d, J=6.0 Hz, 1H).

Example 89

Formula 139

(Compound I-89) NMR (d6-DMSO); δ (ppm) 1,34-of 1.45 (m, 8H), 1,72-2,02 (m, 17H), 3,90-of 3.97 (m, 1H), only 6.64 (d, J=13,6 Hz, 1H), 6,86 (d, J=13,6 Hz, 1H), 7,37 (s, 1H), a 7.85 (s, 1H), 7,95 (s, 1H), 8,31 (d, J=7.2 Hz, 1H).

Example 90

Formula 140

To a solution of compound II-16 (1 g) in tetrahydrofuran (10 ml) under ice cooling was added dimethylformamide (24 ml) and oxacillin (396 μl), then the resulting mixture was stirred at room temperature for one hour. The resulting acid chloride with ice cooling was added dropwise to a 40% aqueous solution of methylamine (2,42 g), then the reaction is second mixture for 3 hours, stirred at room temperature. After the reaction, to the mixture was added H2O and was extracted with ethyl acetate. The organic layer was washed with salt solution, dried over magnesium sulfate and concentrated. The obtained product was used in next reaction without further purification.

According to the above method, the obtained residue was dissolved in methanol (4,1 ml) with H2O (2 ml) and the resulting solution was added 4n. an aqueous solution of LiOH (1,54 ml). The reaction mixture for 30 min was stirred at room temperature. After the reaction the mixture was diluted with water and washed with ethyl acetate. The aqueous layer was acidified aqueous HCl solution was extracted with ethyl acetate and dried over magnesium sulfate. Solvent was removed, obtaining the compound II-23 (929 mg).

The compound below was synthesized from compound II-23 according to the above example.

Example 91

Formula 141

(Compound I-90) NMR (d6-DMSO); δ (ppm) of 1.25 to 1.37 (m, 8H), 1,57-to 2.06 (m, 11H), 2,58 (d, J=4.4 Hz, 3H), 3,85-3,91 (m, 1H), of 4.44 (s, 1H), 6,62 (d, J=13,6 Hz, 1H), 6.87 in (d, J=13,6 Hz, 1H), to 7.61 (d, J=4.4 Hz, 1H), of 7.97 (s, 1H), 8,27 (d, J=6,8 Hz, 1H).

Example 92

Formula 142

(Compound I-91) NMR (d6-DMSO); δ (ppm) of 1.30 (s, 6H), 1,35 of 1.46 (m, 2H), 1,87 and 2.13 (m, 11H), 2,55-2,61 (m, 3H), 3,92-3,98 (m, 1H), 6,00 to 6.35 (s, 2H), 6,62 (d, J=14,0 Hz, 1H), to 6.88 (d, J=14,0 Hz, 1H), to 7.61 (s, 1H), 7,98 (s, 1H), 8,32 (d, J=6,4 Hz, 1H).

Example 93/p>

Formula 143

(Compound I-92) NMR (d6-DMSO); δ (ppm) of 1.30 (s, 6H), 1,34 was 1.43 (m, 2H), 1,80-of 2.21 (m, 11H), 2,58 (d, J=4.4 Hz, 3H), 3,91-3,98 (m, 1H), 6,62 (d, J=13,6 Hz, 1H), to 6.88 (d, J=13,6 Hz, 1H), 7,58-7,66 (m, 1H), to 7.99 (s, 1H), with 8.33 (d, J=6,4 Hz, 1H).

Example 94

Formula 144

(Compound I-93) NMR (d6-DMSO); δ (ppm) of 1.30 (s, 6H), 1,35 was 1.43 (m, 2H), 1,72-2,03 (m, 14H), 2,58 (d, J=4.4 Hz, 3H), 3,91-of 3.97 (m, 1H), 6,62 (d, J=13,6 Hz, 1H), to 6.88 (d, J=13,6 Hz, 1H), 7,37 (s, 1H), to 7.61 (d, J=4.0 Hz, 1H), 7,97 (, 1H), 8,31 (d, J=7.2 Hz, 1H).

Example 95

Formula 145

(Compound I-94) NMR (d6-DMSO); δ (ppm) to 1.00 (t, J=7.2 Hz, 3H), of 1.23 and 1.35 (m, 8H), 1,55-of 2.05 (m, 11H), 3.04 from-of 3.12 (m, 2H), a 3.87-was 4.02 (m, 1H), of 4.44 (s, 1H), 6,62 (d, J=13,6 Hz, 1H), 6.87 in (d, J=13,6 Hz, 1H), 7,62-of 7.69 (m, 1H), 7,97 (s, 1H), 8,28 (d, J=7.2 Hz, 1H).

Example 96

Formula 146

(Compound I-95) NMR (d6-DMSO); δ (ppm) to 1.00 (t, J=6.8 Hz, 3H), of 1.30 (s, 6H), 1,36-of 1.44 (m, 2H), 1,87 and 2.13 (m, 11H), 3.04 from-of 3.12 (m, 2H), 3,93-to 3.99 (m, 1H), 6,00-6,40 (s, 2H), 6,63 (d, J=13,6 Hz, 1H), 6.87 in (d, J=13,6 Hz, 1H), 7,62-7,69 (m, 1H), 7,98 (s, 1H), with 8.33 (d, J=6,8 Hz, 1H).

Example 97

Formula 147

(Compound I-96) NMR (d6-DMSO); δ (ppm) to 1.00 (t, J=7.2 Hz, 3H), of 1.30 (s, 6H), 1,35 was 1.43 (m, 2H), 1,72-2,03 (m, 14H), 3,03-3,13 (m, 2H), 3,90-of 3.96 (m, 1H), 6,62 (d, J=13,6 Hz, 1H), 6.87 in (d, J=13,6 Hz, 1H), 7,37 (s, 1H), 7,62-of 7.69 (m, 1H), of 7.97 (s, 1H), 8,32 (d, J=6,8 Hz, 1H).

Example 98

Formula 148

To a solution of compound II-24 (methyl ester of 4-methoxy-3-oxobutanoic the th acid, 9,87 g) in toluene (99 ml) for 10 min was added dropwise 1,1-dimethoxy-N,N-dimethylethanamine (26,9 ml), then the reaction mixture for 2 hours boiled under reflux. After the reaction mixture was concentrated. The obtained product was used in the next reaction.

According to the above method, the obtained residue was dissolved in a solution of acetonitrile (136 ml) and the resulting solution was added 80% Gidrodinamika (6,58 g). The reaction mixture for one hour and stirred at 50°C. After the reaction mixture was concentrated. To the residue was added 1N. an aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO3and salt solution, dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving compound II-26 (9,74 g).

The compound below was synthesized from compound II-26 according to the above example.

Example 99

Formula 149

(Compound I-97) NMR (d6-DMSO); δ (ppm) 1,28 was 1.43 (m, 8H), 1,58-of 2.09 (m, 11H), 3,26 (s, 3H), 3,50 (s, 3H), 3,86-to 3.92 (m, 1H), to 4.41 (s, 1H), 4,82 (s, 2H), 6.48 in (d, J=14,0 Hz, 1H), 6,99 (d, J=14,0 Hz, 1H), 7,24 (s, 1H), to 7.59 (d, J=6,4 Hz, 1H), 8,14 (s, 1H).

Example 100

Formula 150

(Compound I-98) NMR (d6-DMSO); δ (ppm) of 1.35 to 1.48 (m, 8H), 1,90-to 2.18 (m, 11H), 3,26 (who, 3H), 3,50 (s, 3H), 3.95 to 4,01 (m, 1H), a 4.83 (s, 2H), 6,00 to 6.35 (s, 2H), of 6.49 (d, J=14,0 Hz, 1H), 7,00 (d, J=14,0 Hz, 1H), 7,26 (s, 1H), 7,65 (d, J=6,8 Hz. 1H), 8,15 (s, 1H).

Example 101

Formula 151

(Compound I-99) NMR (d6-DMSO); δ (ppm) of 1.30 to 1.47 (m, 8H), 1.56 to 2,09 (m, 14H), 3,26 (s, 3H), 3,88-3,95 (m, 1H), to 4.41 (s, 1H), 4,82 (s, 2H), 6,55 (d, J=14,0 Hz, 1H), 6,98 (d, J=14,0 Hz, 1H), to 7.59 (d, J=6,4 Hz, 1H), to 7.77 (s, 1H), 8,13 (s, 1H).

Example 102

Formula 152

(Compound I-100) NMR (d6-DMSO); δ (ppm) 1,35-of 1.56 (m, 8H), 1.77 in-2,05 (m, 14H), 3,01 (d, J=5.6 Hz, 2H), 3.27 to (s, 3H), 3,88-3,95 (m, 1H), 4,36 (t, J=5.6 Hz, 1H), a 4.83 (s, 2H), 6,55 (d, J=14,0 Hz, 1H), 6,98 (d, J=14,0 Hz, 1H), 7,63 (d, J=6,8 Hz, 1H), 7,78 (s, 1H), 8,14 (s, 1H).

Example 103

Formula 153

(Compound I-101) NMR (d6-DMSO); δ (ppm) 1,35-of 1.56 (m, 8H), 1.77 in-2,05 (m, 14H), 3,01 (d, J=5.6 Hz, 2H), 3.27 to (s, 3H), 3,88-3,95 (m, 1H), 4,36 (t, J=5.6 Hz, 1H), a 4.83 (s, 2H), 6,55 (d, J=14,0 Hz, 1H), 6,98 (d, J=14,0 Hz, 1H), 7,63 (d, J=6,8 Hz, 1H), 7,78 (s, 1H), 8,14 (s, 1H).

The compounds below were synthesized in a similar manner.

Example 104

Formula 154

(Compound I-102) NMR (DMSO-d6): δ (ppm) to 1.00 (t, J=7,1 Hz, 3H), 1,27-2,03 (m, 28H), 3,05-3,11 (m, 2H), 3,70-of 3.77 (m, 1H), 3,93 (Sirs, 1H), 6.42 per (d, J=a 13.9 Hz, 1H), 6,94 (d, J=a 13.9 Hz, 1H), was 7.36 (s, 1H), 7,56-to 7.61 (m, 2H), to 7.93 (s, 1H).

Example 105

Formula 155

(Compound I-103) NMR (DMSO-d6): δ (ppm) of 1.27 (d, J-7,3 Hz, 6H), 1.32 to-2,05 (m, 19H), 3,50 (s, 3H), 3,76-a 3.83 (m, 1H), 3,88 (Sirs, 1H), to 4.41 (s, 1H), 6,38 (d, J=a 13.9 Hz, 1H), of 6.96 d, J=a 13.9 Hz, 1H), 7,27 (s, 1H), 7,56 (d, J=6.3 Hz, 1H), to 7.93 (s, 1H).

Example 106

Formula 156

(Compound I-104.) NMR (DMSO-d6): δ (ppm) of 1.27 (d, J=7,1 Hz, 6H), 1,38 and 2.13 (m, 19H), 3,50 (s, 3H), 3,76-a 3.83 (m, 1H), 3,95 (Sirs, 1H), 6,18 (Sirs, 2H), 6,38 (d, J=a 13.9 Hz, 1H), of 6.96 (d, J=a 13.9 Hz, 1H), 7,26 (s, 1H), 7.62mm (d, J=6,1 Hz, 1H), 7,94 (s, 1H).

Example 107

Formula 157

(Compound I-105) NMR (DMSO-d6): δ (ppm) of 1.28 (d, J=71 Hz, 6H), 1,36-2,05 (m, 19H), 3,01 (d, J=5.6 Hz, 2H), 3,50 (s, 3H), of 3.77-a-3.84 (m, 1H), 3,88 (Sirs, 1H), 4,35 (t, J=5.6 Hz, 1H), 6,38 (d, J=13,6 Hz, 1H), of 6.96 (d, J=13,6 Hz, 1H), 7,25 (s, 1H), EUR 7.57 (d, J=6.6 Hz, 2H), 7,94 (s, 1H).

Example 108

Formula 158

(Compound I-106) NMR (DMSO-d6): δ (ppm) of 1.28 (d, J=7,1 Hz, 6H), 1,38-to 2.06 (m, 19H), 3,50 (s, 3H), of 3.56 (s, 2H), of 3.77-a-3.84 (m, 1H), 3,90 (Sirs, 1H), 6,38 (d, J=13,6 Hz, 1H), 6,40 (Sirs, 2H), of 6.96 (d, J=13,6 Hz, 1H), 7,25 (s, 1H), to 7.61 (d, J=6.3 Hz, 1H), 7,94 (s, 1H).

Example 109

Formula 159

(Compound I-107) NMR (DMSO-d6): δ (ppm) of 1.27 (d, J=7,1 Hz, 6H), 1,38-2,03 (m, 22H), 3,49 (s, 3H), 3,76-a-3.84 (m, 1H), 3,92 (Sirs, 1H), 6,38 (d, J=a 13.9 Hz, 1H), of 6.96 (d, J=a 13.9 Hz, 1H), 7,27 (s, 1H), was 7.36 (s, 1H), 7,60 (d, J=6,6 Hz, 1H), 7,94 (s, 1H).

Example 110

Formula 160

(Compound I-108) NMR (DMSO-d6): δ (ppm) 1.26 in-2,08 (m, 28H), 3,74-3,81 (m, 1H), 3,88 (Sirs, 1H), to 4.41 (s, 1H), 6,44 (d, J=13,6 Hz, 1H), 6,94 (d, J=13,6 Hz, 1H), 7,56 (d, J=6.3 Hz, 1H), to 7.77 (s, 1H), to 7.93 (s, 1H).

Example 111

Formula 161

(Compound I-109) YAM who (DMSO-d 6): δ (ppm) of 1.27 (d, J=7,1 Hz, 6H), 1,38-2,12 (m, 22H), 3,74-3,81 (m, 1H), 3,94 (Sirs, 1H), to 6.19 (Sirs, 2H), 6,44 (d, J=a 13.9 Hz, 1H), 6,94 (d, J=a 13.9 Hz, 1H), to 7.61 (d, J=5.8 Hz, 1H), to 7.77 (s, 1H), to 7.93 (s, 1H).

Example 112

Formula 162

(Compound I-110) NMR (DMSO-d6): δ (ppm) of 1.27 (d, J=7,1 Hz, 6H), 1,35-2,05 (m, 22H), of 3.00 (d, J=6.3 Hz, 2H), 3.75 to 3,82 (m, 1H), a 3.87 (Sirs, 1H), 4,36 (t, J=5.3 Hz, 1H), 6,44 (d, J=a 13.9 Hz, 1H), 6,94 (d, J=a 13.9 Hz, 1H), 7,58 (d, J=6.3 Hz, 1H), 7,78 (s, 1H), to 7.93 (s, 1H).

Example 113

Formula 163

(Compound I-111) NMR (DMSO-d6): δ (ppm) of 1.27 (d, J=7,1 Hz, 6H), 1,37-of 2.08 (m, 22H), of 3.56 (s, 2H), 3.75 to a 3.83 (m, 1H), 3,89 (Sirs, 1H), 6.42 per (Sirs, 2H), 6,44 (d, J=a 13.9 Hz, 1H), 6,94 (d, J=a 13.9 Hz, 1H), to 7.61 (d, J=7,1 Hz, 1H), 7,78 (s, 1H), 7,94 (s, 1H).

Example 114

Formula 164

(Compound I-112) NMR (DMSO-d6): δ (ppm) of 1.27 (d, J=7,1 Hz, 6H), 1,38-2,02 (m, 25H), 3.75 to 3,82 (m, 1H), 3,93 (Sirs, 1H), 6,44 (d, J=13,6 Hz, 1H), 6,95 (d, J=13,6 Hz, 1H), was 7.36 (s, 1H), 7,60 (d, J=6.3 Hz, 1H), 7,78 (s, 1H), to 7.93 (s, 1H).

Example 115

Formula 165

(Compound I-113) NMR (DMSO-d6): δ (ppm..) 0,84 (d, J=6.6 Hz, 6H), and 1.00 (t, J=7,1 Hz, 3H), 1,29-2,04 (m, 20H), 2,95 (d, J=7,1 Hz, 2H), 3,05-3,11 (m, 2H), 3,90 (Sirs, 1H), and 4.40 (s, 1H), 6,46 (d, J=14,2 Hz, 1H), to 6.88 (d, J=a 13.9 Hz, 1H), 7,41 (d, J=6,6 Hz, 1H), 7,54 (Sirs, 1H), 8,15 (s, 1H).

Example 116

Formula 166

(Compound I-114) NMR (DMSO-d6): δ (ppm) of 0.85 (d, J=6.6 Hz, 6H), and 1.00 (t, J=7.2 Hz, 3H), of 1.30 (s, 6H), 1,38 is 2.10 (m, 14H), 2,95 (d, J=7,1 Hz, 2H), 3.04 from-3,11 (m, 2H), 3,97 (Sirs, 1H), 6,17 (Sirs, 2), 6,47 (d, J=a 13.9 Hz, 1H), to 6.88 (d, J=a 13.9 Hz, 1H), 7,46 (d, J=6,6 Hz, 1H), 7,54 (Sirs, 1H), 8,15 (s, 1H).

Example 117

Formula 167

(Compound I-115) NMR (DMSO-d6): δ (ppm) 0,84 (d, J=6.6 Hz, 6H), 1.32 to-2,04 (m, 20H), of 2.92 (d, J=7,3 Hz, 2H), 3,50 (s, 3H), 3,90 (Sirs, 1H), to 4.41 (s, 1H), gold 6.43 (d, J=a 13.9 Hz, 1H), to 6.88 (d, J=a 13.9 Hz, 1H), 7,24 (s, 1H), 7,42 (d, J=6.3 Hz, 1H), 8,14 (s, 1H).

Example 118

Formula 168

(Compound I-116) NMR (DMSO-d6): δ (ppm) 0,84 (d, J=6.6 Hz, 6H), 1.41 to 2,10 (m, 20H), with 2.93 (d, J=6,8 Hz, 2H), 3,50 (s, 3H), 3.96 points (Sirs, 1H), 6,17 (Sirs, 2H), to 6.43 (d, J=a 13.9 Hz, 1H), 6.89 in (d, J=a 13.9 Hz, 1H), 7.23 percent (s, 1H), 7,46 (d, J=6.3 Hz, 1H), 8,14 (s, 1H).

Example 119

Formula 169

(Compound I-117) NMR (DMSO-d6): δ (ppm) 0,84 (d, J=6.6 Hz, 6H), 1,37-of 2.20 (m, 20H), with 2.93 (d, J=6,8 Hz, 2H), 3,50 (s, 3H), 3.96 points (Sirs, 1H), 6,44 (d, J=14.4 Hz, 1H), 6.89 in (d, J=14.4 Hz, 1H), 7.23 percent (s, 1H), of 7.48 (d, J=6.3 Hz, 1H), 8,14. (s, 1H).

Example 120

Formula 170

(Compound I-118) NMR (DMSO-d6): δ (ppm) 0,84 (d, J=6.6 Hz, 6H), 1.41 to a 2.01 (m, 23H), with 2.93 (d, J=7,1 Hz, 2H), 3,50 (s, 3H), 3,94 (Sirs, 1H), gold 6.43 (d, J=a 13.9 Hz, 1H), 6.89 in (d, J=a 13.9 Hz, 1H), 7,24 (s, 1H), was 7.36 (s, 1H), 7,45 (d, J=6,8 Hz, 1H), 8,14 (s, 1H).

Example 121

Formula 171

(Compound I-119) NMR (CDCl3): δ (ppm) of 0.95 (d, J=6.6 Hz, 6H), 1,55-of 2.21 (m, 23H), to 2.94 (d, J=7,1 Hz, 2H), 4,15 (Sirs, 1H), vs. 5.47 (s, 1H), of 5.89 (d, J=7.8 Hz, 1H), 6,50 (d, J=a 13.9 Hz, 1H), to 6.88 (d, J=a 13.9 Hz, 1H), to 7.67 (s, 1H).

Example 122

Formula 172

(Connection I120) NMR (DMSO-d6): δ (ppm) 0,84 (d, J=6.6 Hz, 6H), 1,38 is 2.10 (m, 23H), with 2.93 (d, J=6,8 Hz, 2H), 3.96 points (Sirs, 1H), to 6.19 (Sirs, 2H), 6,50 (d, J=13,6 Hz, 1H), 6.87 in (d, J=13,6 Hz, 1H), 7,46 (d, J=6.3 Hz, 1H), 7,76 (s, 1H), 8,14 (s, 1H).

Example 123

Formula 173

(Compound I-121) NMR (DMSO-d6): δ (ppm) 0,84 (d, J=6.6 Hz, 6H), 1,36-2,05 (m, 23H), with 2.93 (d, J=7,3 Hz, 2H), 3,01 (d, J=5,1 Hz, 2H), 3,89 (Sirs, 1H), 4,35 (t, J=5,1 Hz, 1H), of 6.49 (d, J=a 13.9 Hz, 1H), 6.87 in (d, J=a 13.9 Hz, 1H), 7,43 (d, J=6,8 Hz, 1H), of 7.75 (s, 1H), 8,14 (s, 1H).

Example 124

Formula 174

(Compound I-122) NMR (DMSO-d6): δ (ppm) 0,84 (d, J=6.6 Hz, 6H), 1,37-2,07 (m, 23H), with 2.93 (d, J=7,1 Hz, 2H), of 3.56 (s, 2H), 3,91 (Sirs, 1H), 6.42 per (Sirs, 2H), of 6.49 (d, J=14,2 Hz, 1H), 6.87 in (d, J=14,2 Hz, 1H), 7,47 (d, J=6,8 Hz, 1H), 7,76 (s, 1H), 8,14 (s, 1H).

Example 125

Formula 175

(Compound I-123) NMR (CDCl3): δ (ppm) of 0.95 (d, J=6.6 Hz, 6H), 1,55-to 2.29 (m, 23H), with 2.93 (d, J=7,1 Hz, 2H), 4,18 (Sirs, 1H), 5,61 (s, 1H), 5,91 (d, J=7,3 Hz, 1H), 6,51 (d, J=a 13.9 Hz, 1H), to 6.88 (d, J=a 13.9 Hz, 1H), 7,68 (s, 1H).

Example 126

Formula 176

(Compound I-124) NMR (DMSO-d6): δ (ppm) 0,84 (d, J=6.6 Hz, 6H), 1.32 to-2,04 (m, 20H), with 2.93 (d, J=7,1 Hz, 2H), and 3.31 (s, 3H), 3,76 (s, 2H), 3,90 (Sirs, 1H), and 4.40 (s, 1H), 6,51 (d, J=14,2 Hz, 1H), 6,91 (d, J=14,2 Hz, 1H), was 7.36 (s, 1H), 7,41 (d, J=6.3 Hz, 1H), 8,14 (s, 1H).

Example 127

Formula 177

(Compound I-125) NMR (DMSO-d6): δ (ppm) 0,84 (d, J=6.6 Hz, 6H), 1,38 is 2.10 (m, 20H), with 2.93 (d, J=6.6 Hz, 2H), 3,32 (s, 3H), 3,76 (s, 2H), 3.96 points (s, 1H), to 6.19 (Sirs, 2H), 6,51 (d, J=14.4 Hz, 1H), 6,91 (d, J=14.4 Hz, 1H), was 7.36 (s, 1H), 7,46 (d, J=6,1 Hz, 1H), 8,14 (s, 1H).

Example 128

Formula 178

(Compound I-126) NMR (d6-DMSO); δ (ppm) 1,14-1,89 (m, 19H), of 3.43 (s, 3H), 3,76-3,81 (m, 1H), 4,37 (s, 1H), to 6.39 (d, J=14,0 Hz, 1H), 6,46 (d, J=14,0 Hz, 1H), 6,69 (d, J=6,4 Hz, 1H), 7,15 (s, 1H), 7,40-of 7.60 (m, 5H), 8,08 (s, 1H).

Example 129

Formula 179

(Compound I-127) NMR (d6-DMSO); δ (ppm) 1,20-1,49 (m, 10H), 1,85-2,08 (s, 9H), 3,44 (s, 3H), 3,82-to 3.89 (m, 1H), 6,00-6,30 (s, 2H), to 6.39 (d, J=14,0 Hz, 1H), 6,47 (d, J=14,0 Hz, 1H), 6,79 (d, J=6,8 Hz, 1H), 7,15 (s, 1H), 7,39-to 7.59 (m, 5H), 8,10 (s, 1H).

Example 130

Formula 180

(Compound I-128) NMR (d6-DMSO); δ (ppm) 1,20-1,50 (m, 10H), 1.70 to 2,04 (m, 9H), of 3.43 (s, 3H), 3,81-3,88 (m, 1H), to 6.39 (d, J=14,0 Hz, 1H), 6,47 (d, J=14,0 Hz, 1H), at 6.84 (d, J=6,4 Hz, 1H), 7,15 (s, 1H), 7,39-to 7.59 (m, 5H), of 8.09 (s, 1H).

Example 131

Formula 181

(Compound I-129 NMR (d6-DMSO); δ (ppm) 1,15-1,89 (m, 22H), 3,76-3,81 (m, 1H), 4,37 (s, 1H), 6,44 (s, 2H), of 6.71 (d, J=6,4 Hz, 1H), 7,40-of 7.69 (m, 6H), 8,08 (s, 1H).

Example 132

Formula 182

(Compound I-130) NMR (d6-DMSO); δ (ppm) 1,20-1,50 (m, 10H), to 1.70 (s, 3H), 1.85 to 2,07 (m, 9H), 3,81-to 3.89 (m, 1H), 6,00-6,30 (s, 2H), 6,45 (s, 2H), PC 6.82 (d, J=6,8 Hz, 1H), 7,40-of 7.70 (m, 6H), 8,10 (s, 1H).

Example 133

Formula 183

(Compound I-131) NMR (d6-DMSO); δ (ppm) 1,19 and 1.80 (m, 22H), 2,95 (d, J=4,8 Hz, 2H), 3.75 to of 3.80 (m, 1H), 4,34 (t, J=5,2 Hz, 1H), 6,44 (s, 2H), 6,70 (d, J=6,4 Hz, 1H), 7,42-7,71 (m, 6H), of 8.09 (s, 1H).

Example 134

Formula 184

(Compound I-132) NMR (d6-DMSO); δ (ppm) 1,21-to 1.82 (m, 22H), 3,51 (s, 2H), of 3.77-3,82 (m, 1H), 6,20-6,50 (m, 4H), 6,76 (d, J=6,8 Hz, 1H), 7,42-of 7.69 (m, 6H), of 8.09 (s, 1H).

Example 135

To a solution of compound II-27 (ethyl ether ethoxymethylenemalonic acid, 50,75 g) in ethanol (100 ml) was added dropwise 80% Gidrodinamika (28,54 g), then the reaction mixture for 3.5 hours was stirred at 125°C. After the reaction mixture was concentrated. The residue was purified column chromatography on silica gel, receiving compound II-28 (54,73 g).

To compound II-28 (32,42 g) was added 48% aqueous solution of Hydrobromic acid (130 ml), and then to the resulting mixture at -11°C for 5 min was added dropwise sodium nitrite (16,91 g) in H2O cases (33.8 ml). The mixture for 2 hours, stirred at -3°C, getting salt page. According to the above method obtained Sol, page at room temperature was added dropwise to a solution of CuBr-HBr, then the mixture for 1 hour and 40 minutes was stirred at 50°C. After the reaction to the mixture was added H2O and was extracted with chloroform. The organic layer was washed with salt solution and dried over sodium sulfate. Solvent was removed, obtaining the compound II-29 (33,54 g).

* Obtaining a solution of CuBr-HBr: H2O (270 ml) was added pentahydrate of copper sulfate (52,67 g) and sodium bromide (51,45 g). To the resulting mixture at 60 the C for 5 min was added sodium sulfite (21,43 g) in H 2O (33 ml), then the mixture for 10 min was stirred at the same temperature. The mixture was cooled to room temperature, one hour later, supernatant was removed, obtaining a white precipitate CuBr.

The obtained white precipitate was twice washed H2O (100 ml). The white precipitate was added 48%aqueous solution of Hydrobromic acid (130 ml), then the mixture used for the reaction.

Compound II-30 was synthesized from compound II-29, similarly to the above example. The following compounds were synthesized using compound II-30 as a common intermediate.

Example 136

Formula 186

To a solution of pyrazole (378 mg) in dimethylformamide (2 ml) under ice cooling was added 60% sodium hydride (211 mg), and then the resulting mixture for one hour, and stirred at 40°C. To the mixture was added dropwise a solution of compound II-30 (1 g) in dimethylformamide (6 ml), then the mixture for 35 min was stirred at 80°C. After the reaction, the reaction mixture was poured into 2n. an aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed with salt solution, dried over sodium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving compound II-31 (416 mg).

Compound I-133 was synthesized from compound II-31 analog is a rule of the above example.

(Compound I-133) NMR (d6-DMSO); δ (ppm) of 1.29 (s, 6H), 1.30 and a 2.00 (m, 13H), of 3.45 (s, 3H), 3,80-a 3.87 (m, 1H), 4,43 (s, 1H), 6,36 (s, 2H), 6,66 (t, J=2.1 Hz, 1H), 7.23 percent (s, 1H), 7,37 (d, J=7.2 Hz, 1H), 7,98 (d, J=2.1 Hz, 1H), 8,19 (, 1H), 8,23 (d, J=2.1 Hz, 1H).

The compounds below were synthesized in a similar manner.

Example 137

Formula 187

(Compound I-134) NMR (CDCl3): δ (ppm) of 1.10 (t, J=7.2 Hz, 3H), of 1.30 (s, 6H), 1,40-of 2.09 (m, 13H), 3,19 of 3.28 (m, 2H), 4,05-4,10 (m, 1H), 5,58 (W, 1H), to 6.39 (d, J=14.1 Hz, 1H), 6,46 (d, J=14.1 Hz, 1H), 6,67 (t, J=2.1 Hz, 1H), 6,80 (d, J=7.5 Hz, 1H), to 7.77 (d, J=2.1 Hz, 1H), 7,94 (d, J=2.1 Hz, 1H), 8,12 (s, 1H).

Example 138

Formula 188

(Compound I-135) NMR (CDCl3): δ (ppm) of 1.10 (t, J=7.5 Hz, 3H), of 1.30 (s, 6H), 1,45-of 2.23 (m, 13H), 3,20 to be 3.29 (m, 2H), 4.09 to to 4.17 (m, 1H), to 4.41 (W, 2H), 5,58 (W, 1H), to 6.39 (d, J=14.1 Hz, 1H), 6,46 (d, J=14.1 Hz, 1H), 6,67 (t, J=2.1 Hz, 1H), PC 6.82 (d, J=7.2 Hz, 1H), to 7.77 (d, J=2.1 Hz, 1H), 7,94 (d, J=2.1 Hz, 1H), 8,12 (s, 1H).

Example 139

Formula 189

(Compound I-136) NMR (CDCl3): δ (ppm) of 1.10 (t, 0=7.2 Hz, 3H), of 1.30 (s, 6H), 1,46-2,17 (m, 16H), 3,19-3,29 (m, 2H), 4,08-to 4.15 (m, 1H), 5,13 (W, 1H), 5,59 (W, 1H), to 6.39 (d, J=14.1 Hz, 1H), 6,45 (d, J=14.1 Hz, 1H), 6,67 (t, J=2.1 Hz, 1H), 6,83 (d, J=7.2 Hz, 1H), to 7.77 (d, J=2.1 Hz, 1H), 7,94 (d, J=2.1 Hz, 1H), 8,12 (s, 1H).

Example 140

Formula 190

(Compound I-137) NMR (CDCl3): δ (ppm) of 1.42 (s, 6H), 1,48-of 2.23 (m, 13H), 3,61 (s, 3H), 4,11-4,17 (m, 1H), to 4.41 (W, 2H), 4,77 (s, 1H), of 6.31 (d, J=14.1 Hz, 1H), 6,44 (d, J=14.1 Hz, 1H), 6,63 (t, J=2.1 Hz, 1H), was 7.36 (W, 1H), a 7.85 (d, J=2.1 Hz, 1H), to $ 7.91 (d, J=2.1 a is C, 1H), 8,12 (s, 1H).

Example 141

Formula 191

(Compound I-138) NMR (CDCl3): δ (ppm) of 1.42 (s, 6H), 1,46 is 1.96 (m, 13H), up 3.22 (d, J=3,6 Hz, 2H), 3,61 (s, 3H), 4,05-4,08 (m, 1H), 4,77 (s, 1H), of 6.31 (d, J=14.1 Hz, 1H), 6,44 (d, J=14.1 Hz, 1H), 6,63 (t, J=2.1 Hz, 1H), was 7.36 (W, 1H), the 7.85 (d, J=2.1 Hz, 1H), to $ 7.91 (d, J=2.1 Hz, 1H), 8,13 (s, 1H).

Example 142

Formula 192

(Compound I-139) NMR (CDCl3): δ (ppm) of 1.42 (s, 6H), 1,45 is 1.96 (m, 13H), 3,61 (s, 3H), of 3.69 (s, 2H), 4,03-4,10 (m, 1H), 4,58 (W, 2H), amounts to 4.76 (s, 1H), of 6.31 (d, J=14.1 Hz, 1H), 6,44 (d, J=14.1 Hz, 1H), 6,63 (t, J=2.1 Hz, 1H), 7,37 (Shir, 1H), 7,8,5 (d, J=2.1 Hz, 1H), to $ 7.91 (d, J=2.1 Hz, 1H), 8,12 (s, 1H).

Example 143

Formula 193

(Compound I-140) NMR (d6-DMSO); δ (ppm) to 1.31 (s, 6H), 1,54-to 1.98 (m, 16H), 3,80-a 3.87 (m, 1H), 4,43 (s, 1H), 6.35mm (d, J=14.1 Hz, 1H), gold 6.43 (d, J=14.1 Hz, 1H), 6,67 (t, J=2.4 Hz, 1H), 7,38 (d, J=6,9 Hz, 1H), of 7.75 (s, 1H), 7,98 (d, J=2.4 Hz, 1H), 8,19 (s, 1H), 8,23 (d, J=2.4 Hz, 1H).

Example 144

Formula 194

(Compound I-141) NMR (CDCl3): δ (ppm) of 1.45 (s, 6H), 1,48-of 2.23 (m, 16H), 4,10-4,17 (m, 1H), to 4.41 (W, 2H), 5,42 (s, 1H), of 6.31 (d, J=14.1 Hz), 6.42 per (d, J=14.1 Hz, 1H), only 6.64 (t, J=2.4 Hz, 1H), 7,45 (d, J=7.8 Hz), of 7.90 (d, J=2.4 Hz, 2H), to 8.12 (s, 1H).

Example 145

Formula 195

(Compound I-142) NMR (CDCl3): δ (ppm) of 1.45 (s, 6H), 1,51-of 2.20 (m, 16H), 4,08-to 4.14 (m, 1H), 5,41 (W, 1H), 6,32 (d, J=a 13.8 Hz, 1H), gold 6.43 (d, J=a 13.8 Hz, 1H), 6,65 (t, J=2.1 Hz, 1H), of 7.48 (d, J=7.2 Hz, 1H), of 7.90 (d, J=2.1 Hz, 1H), to $ 7.91 (d, J=2.1 Hz, 1H), 8,13 (s, 1H).

Example 146

Formula 196

(Compound I-143) NMR (CDCl3): δ (ppm) of 1.45 (s, 6H), 1,51-of 2.16 (m, 19H), 4,10-4,16 (m, 1H), 5,17 (s, 1H), 5,46 (s, 1H), of 6.31 (d, J=14.1 Hz, 1H), gold 6.43 (d, J=14.1 Hz, 1H), only 6.64 (t, J=2.1 Hz, 1H), of 7.48 (d, J=7.8 Hz, 1H), of 7.90 (d, J=2.1 and Hz, 2H), 8,12 (s, 1H).

Example 147

Formula 197

To compound II-30 (300 mg) was added methoxyethylamine (2 ml), then the reaction mixture for 16 hours was stirred at 80°C. After the reaction to the reaction mixture was added 2n. an aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed with salt solution and concentrated. The residue was purified column chromatography on silica gel, receiving compound II-32 (257 mg).

Compound I-144 was synthesized from compound II-32 same as above.

(Compound I-144) NMR (CDCl3): δ (ppm) of 1.52 (s, 6H), 1,54 was 2.25 (m, 13H), to 2.94 (s, 3H), of 3.25 (s, 3H), 3,32 (t, J=4,8 Hz, 2H), 3,41 (t, J=4,8 Hz, 2H), 3,62 (s, 3H), 4,12-4,19 (m, 1H), 4,84 (s, 1H), 6,38 (d, J=14.1 Hz, 1H), 6,93 (d, J=14.1 Hz, 1H), 7,43 (d, J=7.2 Hz, 1H), 7,89 (s, 1H).

The compounds shown below were synthesized in a similar manner.

Example 148

Formula 198

(Compound I-145) NMR (CDCl3): δ (ppm) to 1.11 (t, J=7.2 Hz, 3H), 1,21 (d, J=6.3 Hz, 6H), of 1.40 (s, 6H), 1,45-2,3 (m, 13H), 3,26 (m, 2H), 3,50 (m, 1H), 4,14 (sird, J=7.5 Hz, 1H), 5,74 (Sirs, 1H), of 5.83 (d, J=7.5 Hz, 1H), 5,95 (d, J=9.9 Hz, 1H), 6,38 (d, J=14.1 Hz, 1H), at 6.84 (d, J=14.1 Hz, 1H), 7,58 (s, 1H).

Example 149

Formula 199

(Link the I-146) NMR (CDCl 3): δ (ppm) to 1.22 (t, J=7.2 Hz, 3H), of 1.41 (s, 6H), of 1.57 (s, 6H), 1,6-and 2.14 (m, 13H), with 3.27 (m, 2H), to 3.67 (s, 3H), 4,19 (m, 1H), 5,65 (m, 1H), 5,97 (d, J=7.5 Hz, 1H), 6,37 (d, J=14,7 Hz, 1H), 6,93 (d, J=14,1 Hz, 1H), 7,82 (s, 1H), 8,02 (s, 1H).

Example 150

Formula 200

(Compound I-147) NMR (CDCl3): δ (ppm) to 1.11 (t, J=7.2 Hz, 3H), of 1.40 (s, 6H), is 1.81 (d, J=6.6 Hz, 6H), 1.93 and (s, 6H), 1,61-2,3 (m, 13H), 3,26 (m, 2H), 3,49 (m, 1H), 4,17 (sird, J=7.2 Hz, 1H), 5,16 (s, 1H), 5,71 (s, 1H), 5,86 (d, J=7,5 Hz, 1H), 5,94 (d, J=10,2 Hz, 1H), 6,38 (d, J=14.1 Hz, 1H), at 6.84 (d, J=a 13.8 Hz, 1H), EUR 7.57 (s, 1H).

Example 151

Formula 201

(Compound I-148) NMR (DMSO-d6): δ (ppm) of 1.08 (d, J=6.3 Hz, 6H), 1.32 to-2,03 (m, 19H), 3,42-to 3.49 (m, 4H), 3,91 (Sirs, 1H), 4,42 (s, 1H), 6,04 (d, J=9.1 Hz, 1H), and 6.25 (d, J=a 13.9 Hz, 1H), 6.75 in (d, J=a 13.9 Hz, 1H), 7,25 (s, 1H), 7,40 (d, J=6,6 Hz, 1H), of 8.09 (s, 1H).

Example 152

Formula 202

(Compound I-149) NMR (DMSO-d6): δ (ppm) of 1.09 (d, J=6.3 Hz, 6H), 1,38 is 2.10 (m, 19H), of 3.46-3.49 points (m, 4H), 3,97 (Sirs, 1H), 6,04 (d, J=6,4 Hz, 1H), to 6.19 (Sirs, 2H), and 6.25 (d, J=14.4 Hz, 1H), 6.75 in (d, J=14.4 Hz, 1H), 7,25 (s, 1H), 7,44 (d, J=6,1 Hz, 1H), 8,10 (s, 1H).

Example 153

Formula 203

(Compound I-150) NMR (CDCl3): δ (ppm) 1,21-1,89 (d, J=6.6 Hz, 6H), 1,38-2,19 (m, 13H), of 1.55 (s, 3H), of 1.57 (s, 3H), of 3.56 (m, 1H), 4,13 (m, 1H), 5,44 (s, 1H), of 5.82 (m, 1H), to 5.85 (s, 1H), 6,32 (d, J=14.1 Hz, 1H), for 6.81 (d, J=14.1 Hz, 1H), at 7.55 (s, 1H).

Example 154

Formula 204

(Compound I-151) NMR (CDCl3): δ (ppm) of 1.13 (t, J=7.2 Hz, 3H), of 1.42 (s, 6H), 1,48-to 2.29 (m, 13H), 3,20 (t, J=4.5 Hz, 4H), 3,24-to 3.33 (m, 2H), 3,84 t, J=4.5 Hz, 4H), 4,15-is 4.21 (m, 1H), 5,70 (W, 1H), 6.48 in (d, J=7.5 Hz, 1H), of 6.49 (d, J=14.4 Hz, 1H), 7,12 (d, J=14.4 Hz, 1H), 7,76 (s, 1H).

Example 155

Formula 205

(Compound I-152) NMR (CDCl3): δ (ppm) of 1.13 (t, J=7.2 Hz, 3H), of 1.42 (s, 6H), 1,62-2,31 (m, 13H), 3,20 (t, J=4.5 Hz, 4H), 3,24-to 3.33 (m, 2H), 3,83 (t, J=4.5 Hz, 4H), 4,20-4,27 (m, 1H), 4,46 (W, 2H), 5,70 (W, 1H), of 6.49 (d, J=14.1 Hz, 1H), of 6.50 (d, J=7.8 Hz, 1H), 7,12 (d, J=14.1 Hz, 1H), 7,76 (s, 1H).

Example 156

Formula 206

(Compound I-153) NMR (CDCl3): δ (ppm) of 1.53 (s, 6H), 1.56 to of 2.27 (m, 13H), 3,20 (t, J=4.5 Hz, 4H), to 3.64 (s, 3H), 3,83 (t, J=4.5 Hz, 4H), 4,14-is 4.21 (m, 1H), 4,84 (s, 1H), 6,38 (d, J=14.1 Hz, 1H), return of 6.58 (d, J=7.5 Hz, 1H), was 7.08 (d, J=14,1 Hz, 1H), of 7.75 (s, 1H).

Example 157

Formula 207

(Compound I-154) NMR (CDCl3): δ (ppm) of 1.53 (s, 6H), 1.60-to 2,31 (m, 13H), 3,20 (t, J=4.5 Hz, 4H), to 3.64 (s, 3H), 3,83 (t, J=4.5 Hz, 4H), 4,19-of 4.25 (m, 1H), of 4.44 (Sirs, 2H), around 4.85 (s, 1H), 6,38 (d, J=14.1 Hz, 1H), 6,60 (d, J=7.8 Hz, 1H), 7,07 (d, J=14.1 Hz, 1H), of 7.75 (s, 1H).

Example 158

Formula 208

(Compound I-155) NMR (CDCl3): δ (ppm) of 1.56 (s, 6H), 1,55-2,4 (m, 13H), to 1.98 (s, 3H), 3,21 (m, 4H), of 3.84 (m, 4H), 4,17 (sird, J=7.2 Hz, 1H), of 5.53 (s, 1H), to 6.39 (d, J=14.1 Hz, 1H), 6,63 (d, J=7.2 Hz, 1H), 7,07 (d, J=14.1 Hz, 1H), 7,75 (s, 1H).

Example 159

Formula 209

(Compound I-156) NMR (CDCl3): δ (ppm) of 1.55 (s, 6H), 1,55-of 2.15 (m, 13H), of 1.97 (s, 3H), 3,21 (Sirs, 4H), of 3.25 (s, 2H), 3,83 (Sirs, 4H), of 4.13 (m, 1H), to 5.66 (s, 1H), 6,38 (d, J=14.1 Hz, 1H), 6,77 (sird, J=7.2 Hz, 1H), 7,06 (d, J=14.1 Hz, 1H), 7,76 (s, 1H).

Example 160

Formula 210

(Compound I-157) NMR (CDCl3): δ (ppm) of 1.55 (s, 6H), 1,6-of 1.85 (m, 8H), of 1.92 (s, 3H), 1,9-of 2.25 (m, 6H), of 1.97 (s, 3H), 3,19 (m, 4H), 3,49 (s, 1H), 3,83 (m, 4H), 4,20 (sird, J=6,6 Hz, 1H), total of 5.21 (Sirs, 1H), 5,52 (Sirs, 1H), 6,38 (d, J=14.1 Hz, 1H), to 6.67 (d, J=7.5 Hz, 1H), 7,06 (d, J=14.1 Hz, 1H), of 7.75 (s, 1H).

Example 161

Formula 211

(Compound I-158) NMR (CDCl3): δ (ppm) is 1.51 (s, 6H), 1,58-of 2.23 (m, 13H), 3,34-3,44 (m, 2H), 3,39 (s, SH), 3,52 (t, J=4,8 Hz, 2H), 3,61 (s, 3H), 4,12-4,18 (m, 1H), around 4.85 (s, 1H), 5,96 (d, J=7.5 Hz, 1H), to 6.19 (t, J=6,6 Hz, 1H), 6.30-in (l, J=14.1 Hz, 1H), 6,98 (d, J=14.1 Hz, 1H), EUR 7.57 (s, 1H).

Example 162

Formula 212

(Compound I-159) NMR (DMSO-d6): δ (ppm) 0,90-to 0.96 (m, 6H), 1,36 is 2.10 (m, 19H), of 3.48 (s, 3H), 3,97 (Sirs, 1H), 4,33-and 4.40 (m, 1H), 6,21 (Sirs, 2H), 6,40-6.42 per (m, 3H), of 6.66 (d, J=13,6 Hz, 1H), 7,24 (d, J=8,1 Hz, 1H), 7,31 (s, 1H), of 7.96 (s, 1H).

Example 163

Formula 213

To a solution of propane-2-thiol (413 μl) in dimethylformamide (8 ml) under ice cooling was added 60% sodium hydride (169 mg), and then the resulting mixture for one hour, and stirred at room temperature. To the mixture was added dropwise a solution of compound II-30 (800 mg) in dimethylformamide (8 ml), then the resulting mixture was stirred for 2 hours. After the reaction, the reaction mixture was poured into 1N. an aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO3/sub> and salt solution, dried over sodium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving compound II-33 (738 mg).

Compound I-160 was synthesized from compound II-33 same as above.

(Compound I-160) NMR (CDCl3): δ (ppm) of 1.28 (d, J=6.8 Hz, 6H), 1,53-of 2.20 (m, 19H), 3,30-3,37 (m, 1H), 3,63 (s, 3H), 4,25 (d, J=7,3 Hz, 1H), 4,91 (s, 1H), 6,56 (d, J=14,2 Hz, 1H), 7,40 (d, J=14,2 Hz, 1H), of 7.96 (d, J=7,6 Hz, 1H), 8,20 (s, 1H).

The compounds below were synthesized in a similar manner.

Example 164

Formula 214

(Compound I-161) NMR (CDCl3): δ (ppm) of 1.12 (t, J=7.2 Hz, 3H), of 1.29 (d, J=6.8 Hz, 6H), USD 1.43 (s, 6H), 1,58-2,22 (m, 13H), 3,24-to 3.34 (m, 3H), 4.26 deaths (Sirs, 1H), 5,76 (Sirs, 1H), only 6.64 (d, J=14,2 Hz, 1H), 7,42 (d, J=14,2 Hz, 1H), 7,92 (d, J=7,8 Hz, 1H), they were 8.22 (s, 1H).

Example 165

Formula 215

(Compound I-162) NMR (CDCl3): δ (ppm) of 1.12 (t, J=7.2 Hz, 3H), of 1.29 (d, J=6.6 Hz, 6H), USD 1.43 (s, 6H), 1,64-of 2.28 (m, 13H), 3,24-to 3.34 (m, 3H), 4,30 (Sirs, 1H), 4,55 (s, 2H), 5,74 (s, 1H), only 6.64 (d, J=a 13.9 Hz, 1H), 7,42 (d, J=a 13.9 Hz, 1H), a 7.92 (d, J=7,6 Hz, 1H), they were 8.22 (s, 1H).

Example 166

Formula 216

(Compound I-163) NMR (CDCl3): δ (ppm) of 1.12 (t, J=7.2 Hz, 3H), of 1.29 (d, J=6.6 Hz, 6H), USD 1.43 (s, 6H), 1,66-2,22 (m, 16H), 3,24-of 3.32 (m, 3H), 4,29 (Sirs, 1H), 5,26 (s, 1H), 5,70 (Sirs, 1H), only 6.64 (d, J=14.4 Hz, 1H), 7,42 (d, J=14.4 Hz, 1H), of 7.95 (d, J=8,3 Hz, 1H), 8,21 (s, 1H).

Example 167

Formula 217

(Compound I-164) NMR (CDCl3): is (ppm) of 1.28 (d, J=6.6 Hz, 6H), and 1.54 (s, 6H), 1,64-of 2.28 (m, 13H), 3,30-3,37 (m, 1H), 3,63 (s, 3H), 4,30 (d, J=7,1 Hz, 1H), 4,57 (s, 2H), 4,96 (s, 1H), 6,56 (d, J=a 13.9 Hz, 1H), 7,39 (d, J=a 13.9 Hz, 1H), 7,95 (d, J=7.8 Hz, 1H), to 8.20 (s, 1H).

Example 168

Formula 218

(Compound I-165) NMR (d6-DMSO); δ (ppm) of 1.17 (d, J=6.4 Hz, 6H), 1,38-of 1.56 (m, 8H), 1.77 in-to 2.18 (m, 14H), 3,32 is 3.40 (m, 1H), 4,00-4,07 (m, 1H), 6,00-6,40 (s, 2H), 6,55 (d, J=14,0 Hz, 1H), 7,29 (d, J=14,0 Hz, 1H), 7,79-of 7.90 (m, 2H), 8,07 (s, 1H).

Example 169

Formula 219

(Compound I-166) NMR (d6-DMSO); δ (ppm) of 1.18 (d, J=6.8 Hz, 6H), 1,38 is 1.58 (m, 8H), 1.77 in-to 2.18 (m, 14H), to 3.02 (d, J=5.6 Hz, 2H), 3,32 is 3.40 (m, 1H),,3,93-4,00 (m, 1H), 4,39 (t, J=5.6 Hz, 1H), 6,55 (d, J=14,0 Hz, 1H), 7,29 (d, J=14,0 Hz, 1H), to 7.84 (s, 1H), to $ 7.91 (d, J=7.2 Hz, 1H), 8,07 (s, 1H).

Example 170

The formula 220

(Compound I-167) NMR (d6-DMSO); δ (ppm) of 1.18 (d, J=5.6 Hz, 6H), of 1.44 (s, 6H), 1,50-2,07 (m, 16H), 3,32 is 3.40 (m, 1H), 3,98-4,10 (m, 3H), 6,55 (d, J=14,0 Hz, 1H), to 7.09 (s, 1H), 7,29 (d, J=14,0 Hz, 1H), 7,66 (s, 1H), a 7.85 (s, 1H), 7,92 (d, J=6.0 Hz, 1H), 8,08 (s, 1H), with 8.33 (s, 1H).

Example 171

Formula 221

(Compound I-168) NMR (CDCl3): δ (ppm) of 1.29 (d, J=6.6 Hz, 6H), 1,57-of 2.20 (m, 22H), 3,31-to 3.38 (m, 1H), 4,25 (d, J=6,6 Hz, 1H), 5,59 (s, 1H), 6,55 (d, J=14,2 Hz, 1H), 7,39 (d, J=14,2 Hz, 1H), of 7.96 (d, J=7.8 Hz, 1H), 8,19 (s, 1H).

The compounds below were synthesized according to the above example.

Example 172

Formula 222

(Compound I-169) NMR (DMSO-d6): δ (ppm) 1,25-2,03 (m, 25H), 2,58 (d, J=4.3 Hz, 3H), 3,90 (Sirs, 1), was 4.42 (s, 1H), 4,88-4,94 (m, 1H), 6.35mm (d, J=14,2 Hz, 1H), 6,77 (d, J=14,2 Hz, 1H), 7,30 (d, J=6,8 Hz, 1H), 7,52 (Sirs, 1H), 8,03 (s, 1H).

Example 173

Formula 223

(Compound I-170) NMR (DMSO-d6): δ (ppm) to 1.00 (t, J=7,1 Hz, 3H), 1,25-2,03 (m, 25H), 3.04 from-3,10 (m, 2H), 3,89 (Sirs, 1H), 4,42 (s, 1H), 4,89-4,94 (m, 1H), 6.35mm (d, J=14.4 Hz, 1H), 6,77 (d, J=14.4 Hz, 1H), 7,31 (d, J=6,8 Hz, 1H), EUR 7.57 (t, J=5,2 Hz, 1H), 8,02 (s, 1H).

Example 174

Formula 224

(Compound I-171) NMR (DMSO-d6): δ (ppm) 1.26 in-2,10 (m, 25H), 2,58 (d, J=4,6 Hz, 3H), 3,97 (Sirs, 1H), 4,89-4,96 (m, 1H), to 6.19 (Sirs, 2H), 6.35mm (d, J=14.4 Hz, 1H), 6,77 (d, J=14.4 Hz, 1H), 7,38 (d, J=6.3 Hz, 1H), 7,53 (Sirs, 1H), 8,04 (s, 1H).

Example 175

Formula 225

(Compound I-172) NMR (DMSO-d6): δ (ppm) to 1.00 (t, J=7.2 Hz, 3H), 1,25-2,10 (m, 25H), 3.04 from-3,11 (m, 2H), 3.96 points (Sirs, 1H), 4,90 is equal to 4.97 (m, 1H), 6,20 (Sirs, 2H), 6.35mm (d, J=14.4 Hz, 1H), 6,77 (d, J=14.4 Hz, 1H), 7,38 (d, J=7,1 Hz, 1H), EUR 7.57 (t, J=5.4 Hz, 1H), 8,04 (s, 1H).

Example 176

The formula is 226

(Compound I-173) NMR (DMSO-d6): δ (ppm) of 0.87 (t, J=7,3 Hz, 3H), 1,24 (d, J=6,1 Hz, 6H), 1,33-2,07 (m, 23H), 3,88 (Sirs, 1H), 4,42 (s, 1H), 4,87-is 4.93 (m, 1H), 6.35mm (d, J=14.4 Hz, 1H), 6.75 in (d, J=14.4 Hz, 1H), 7,31 (d, J=7,3 Hz, 1H), 7,69 (s, 1H), 8,00 (s, 1H).

Example 177

Formula 227

(Compound I-174) NMR (DMSO-d6): δ (ppm) of 0.87 (t, J=7,3 Hz, 3H), 1,24 (d, J=6,1 Hz, 6H), 1,40-2,10 (m, 23H), 3,96 (Sirs, 1H), 4,89-of 4.95 (m, 1H), 6,20 (Sirs, 2H), 6,36 (d, J=14.4 Hz, 1H), 6.75 in (d, J=14.4 Hz, 1H), 7,38 (d, J=6,6 Hz, 1H), 7,69 (s, 1H), 8,01 (s, 1H).

Example 178

Formula 228

(Compound I-175) NMR (d6-DMSO); δ (ppm) was 1.43 (s, 6H), is 1.81 (s, 6H), 1,86-of 2.21 (m, 13H), 2,17 (m, 1H), 3.96 points (Sirs, 1H), 6,59 (d, J=10,8 Hz, 1H), 7,00 (d, J=10.5 Hz, 1H), to 7.64 (sird, J=4.5 Hz, 1H), 7,83 (s, 1H), 8,21 (s, 1H), 8,31 (Sirs, 1H).

Example 179

Formula 229

(Compound I-176) NMR (d6-DMSO); δ (ppm) of 1.34 is 2.10 (m, 13H), USD 1.43 (s, 3H), of 1.44 (s, 3H), of 1.81 (s, 3H), 3,92 (m, 1H), of 4.44 (m, 1H), 6,72 (d, J=10.5 Hz, 1H), 6,99 (d, J=10.5 Hz, 1H), 7,89 (s, 1H), 8,21 (s, 1H), of 8.47 (s, 1H).

Example 180

Formula 230

(Compound I-177) NMR (CDCl3): δ (ppm) of 1.55 (s, 6H), 1,61-of 2.20 (m, 13H), a 1.96 (s, 3H), 3,1 (m, 1H), 3,29 (Sirs, 1H), 4,19 (m, 1H), 6,59 (d, J=14.1 Hz, 1H), 6,72 (sird, J=6,9 Hz, 1H), 7,03 (d, J=a 13.8 Hz, 1H), of 8.06 (s, 1H).

Example 181

Formula 231

(Compound I-178) NMR (CDCl3): δ (ppm) 1,6-2,3 (m, 13H), of 1.97 (s, 3H), 4,27 (sird, J=7.8 Hz, 1H), to 4.41 (Sirs, 2H), 5,46 (s, 1H), 6,50 (d, J=7.2 Hz, 1H), 6,60 (d, J=13,2 Hz, 1H),? 7.04 baby mortality (d, J=a 13.8 Hz, 1H), 8,07 (s, 1H).

Example 182

Formula 232

(Compound I-179) NMR (DMSO-d6): δ (ppm) to 1.25 (d, J=6,1 Hz, 6H), 1,35-2,03 (m, 19H), and 3.31 (s, 3H), 3,76 (s, 2H), 3,89 (Sirs, 1H), 4,43 (s, 1H), 4,86-is 4.93 (m, 1H), to 6.39 (d, J=14.4 Hz, 1H), 6,79 (d, J=14,4 Hz; 1H), 7,31 (d, J=7,1 Hz, 1H), 7,40 (s, 1H), 8,01 (s, 1H).

Example 183

Formula 233

(Compound I-180) NMR (DMSO-d6): δ (ppm) to 1.25 (d, J=6,1 Hz, 6H), 1.41 to of 2.10 (m, 19H), and 3.31 (s, 3H), 3,76 (s, 2H), 3,95 (Sirs, 1H), 4,87-4,94 (m, 1H), to 6.19 (Sirs, 2H), to 6.39 (d, J=14.4 Hz, 1H), 6,79 (d, J=144 Hz, 1H), was 7.36-7,40 (m, 2H), 8,02 (s, 1H).

The following compounds can be synthesized as this connection is similar to the above example.

The formula 234

Formula 235

Formula 236

Formula 237

Formula 238

Formula 239

Formula 240

In addition, as the present compounds can be synthesized following the connection.

Specifically provides compounds defined by formula (IV).

Formula 241

Abbreviations used for ring a in the formula (IV)represent the following groups.

Formula 242

Abbreviations used for R3in the formula (IV)represent the following groups.

Formula 243

Abbreviations used for R2in the formula (IV)represent the following groups.

Formula 244

Test example 1

Method of assessment inhibitor of 11β-HSD1 (assessment Conn is tion against human 11β-HSD1)

After pre-incubation of the inhibitor in the reaction solution consisting of 50 mm sodium phosphate buffer (pH 7.5), bovine serum albumin (1 mg/ml), NADPH (0,42 mg/ml), glucose-6-phosphate (1,26 mg/ml), glucose-6-phosphate dehydrogenase and the enzyme at room temperature for 30 minutes was added cortisone (5 μm) as a substrate (total 10 ml). After the interaction at 37°C for 2 hours was added to the solution of cortisol labelled XL-665 (5 μl), and anticortisol antibodies labeled with Cryptocom (Cryptate). The reaction was carried out at room temperature for 2 hours and measured the intensity of fluorescence (HTRF method). The concentration of cortisol was calculated by the standard curve obtained using known concentrations of cortisol for each analysis.

Taking the concentration of cortisol formed in the absence of inhibitor, as a reference value, the concentration of 50%inhibition (IC value50) inhibitor against 11β-HSD1 was calculated by the inhibition curve, which shows the degree of inhibition relative to control values at each concentration of inhibitor.

Test example 2

Method of assessment inhibitor of 11β-HSD1 (evaluation of compounds against mouse 11β-HSD1)

After pre-incubation of the inhibitor in the reaction solution consisting of 50 mm in the atrium-phosphate buffer (pH 7.5), bovine serum albumin (1 mg/ml), NADPH (0,42 mg/ml), glucose-6-phosphate (1,26 mg/ml), glucose-6-phosphate dehydrogenase and the enzyme at room temperature for 30 minutes was added 11-dehydrocorticosterone (2 μm) as a substrate (total 10 ml). After the interaction at 37°C for 2 hours was added to the solution of cortisol labelled XL-665 (5 μl), and anticortisol antibodies labeled with Cryptocom. The reaction was carried out at room temperature for 2 hours and measured the intensity of fluorescence (HTRF method).

The concentration of corticosterone was calculated by the standard curve obtained using known concentrations of corticosterone for each analysis.

Taking the concentration of corticosterone formed in the absence of inhibitor, as a reference value, the concentration of 50%inhibition (IC value50) inhibitor against 11β-HSD1 was calculated by the inhibition curve, which shows the degree of inhibition relative to control values at each concentration of inhibitor.

The results of test examples 1 and 2 shown below.

td align="left"> Compound I-133
Compound I-7:Human IC50=3.4 nm,Mouse IC50=0,41 nm
Connect the imposition of the I-9: Human IC50=11 nm,Mouse IC50=1,7 nm
Compound I-36:Human IC50=1.2 nm,Mouse IC50=1 nm
Compound I-63:Human IC50=1,4 nmMouse IC50=0,21 nm
Compound I-77:Human IC50=0,62 nmMouse IC50=0,23 nm
Compound I-105Human IC50=147,8 nmMouse IC50=3,6 nm
Compound I-121Human IC50=154,3 nmMouse IC50=4,9 nm
Compound I-127Human IC50=88,1 nmMouse IC50=3,0 nm
Compound I-128Human IC50=62,4 nmMouse IC50=5,5 nm
Compound I-131Human IC50=20,8 nmMouse IC50=1,4 nm
Human IC50=75,6 nmMouse IC50=0.52 nm
Compound I-138Human IC50=35,1 nmMouse IC50=0,28 nm
Compound I-139Human IC50=64,4 nmMouse IC50=0,37 nm

Test example 3

Materials and methods oral absorption inhibitor of 11β-HSD1 against diabetes

(1) Animals: male rats orl:CD(SD)B aged 6 weeks were purchased from CHARLES RIVER LABORATORIES Japan, Inc. and used for the experiment at the age of 7 weeks after the initial detention for 1 week.

(2) Conditions: the Rats were kept under the following conditions; temperature 23±2°C, humidity 55±10%cycle: light time from 8:00 to 20:00, dark time from 20:00 until 8:00. During pre-trial detention and experimental periods, the rats were given free access to solid feed (CRF-1, ORIENTAL YEAST co., Ltd.) and sterilized tap water.

(3) Identification of individual animals and cells: Individual rooms were painted with oil paint on the tail of the rat to provide identification. The cage was attached a label with the name of the head of the study, the date the settlement is upline, line, sex and name of the supplier; during the preliminary period, the rats were kept in 5 individuals in the cell. After the start of the experiment the rats were kept for 1 individuals in the cell.

(4) Install the dose and the division into groups: Established the following groups according to the dosage amounts when taken orally or intravenously.

Oral administration2 mg/kg (n=3)
Intravenous0.5 mg/kg (n=3)

(5) Preparation of liquid doses: Method of preparation is shown below. The suspension was prepared using 0.5% methylcellulose (1500 CPS) as filler for oral administration. Solubilizing solution was prepared using N,N-dimethylacetamide with polyethylene glycol (=1/2) as a filler for intravenous injection.

(6) route of administration: oral introduction dosed suspension was injected forcibly into the stomach using an oral probe, at a dose of 5 ml/kg When intravenously dosed solution was injected into the tail vein at a dose of 1 ml/kg using a glass syringe.

(7) the Analyzed sample: Blood was collected in a certain time from the jugular vein through a cannula inserted into a vein for three days before the injection, and the concentration of Les is artenova funds in plasma was measured, using HPLC or LC/MS/MS.

(8) Statistical analysis: For the concentration profile in the plasma area under the curve plasma concentrations (AUC) was calculated using nonlinear least WinNonlin (registered trade name), the bioavailability was calculated as the AUC values in the group of oral administration and in the group of intravenous injection.

ConnectionRat VA (%)
1-2911,5
1-3251,4
1,4736,3
1,4820,3
1,5538,1
1-7266,8

The method of evaluation of inhibitory activity against HSD1 using isecheno adipose tissue

In the experiment used male mice ob/ob at the age of 9-10 weeks. Animal oral was administered the test compound at a dose of 30-50 mg/kg After 8 and 16 hours was dissected abdominal adipose tissue during anaesthesia with chloral hydrate and measured HSD1 activity. Inhibitory activity of the test compounds against HSD1 was measured, COI is lsua as a reference value (100%) HSD1 activity in adipose tissue of the animal, which oral introduced a 0.5% solution of methylcellulose and which were subjected to the same treatment.

Three-time equivalent volume of phosphate buffer solution (50 mm sodium phosphate (pH 7.5) with bovine serum albumin (1 mg/ml)) were added to about 200 mg isecheno adipose tissue and preparing the solution of the homogenate, which was used to measure the enzymatic activity HSD1. To measure the enzymatic activity HSD1 was mixed with 60 μl of reaction solution (50 mm sodium phosphate buffer (pH 7.5), bovine serum albumin (1 mg/ml), NADPH (0,42 mg/ml), glucose-6-phosphate (1,26 mg/ml), glucose-6-phosphatedehydrogenase) and 20 μl of a solution of fat homogenate and initiated the reaction by adding 20 μl of a 10 μm solution of 11-DHC as a substrate. The reaction was carried out at 37°C for 60 minutes and for stopping the reaction was added to 200 μl of ethyl acetate. After adding 10 μl of a solution of dexamethasone (20 pmol/µl)was used for analysis as an internal standard, the mixture was centrifuged (15000 rpm × 3 min, room temperature) and collected 150 μl of the supernatant. After drying the supernatant under reduced pressure the residue was dissolved in 60 μl of water-methanol solution (H2O:methanol = 45:55) and by HPLC was determined by the concentration of corticosterone.

The concentration of corticosterone was calculated by a calibration curve with use the of dexamethasone as an internal standard.

Connection% inhibition (16 hours)
1-2961%
1-3274%
1-4867%

The following examples of formulations 1-8 are only examples and are not intended to limit the present invention. The term "active ingredient" means the present compound, its pharmaceutically acceptable salt or hydrate.

Example formulations 1

Hard gelatin capsule is prepared using the following ingredients:

Dose (mg / capsule)
The active ingredient250
Starch (dry)200
Magnesium stearate10
The total mass460 mg

Example recipe 2

The tablet is obtained using the following ingredients:

Dose (the g on the pill)
The active ingredient250
Cellulose (microcrystalline)400
Silicon dioxide (fuming)10
Stearic acid5
The total mass665 mg

The ingredients are mixed and pressed, receiving tablets weighing 665 mg each.

Example formulation 3

Prepare a spray solution containing the following ingredients.

Weight
The active ingredient0,25
Ethanol25,75
The propellant 22 (Chlorodifluoromethane)74,00
The total mass100,00

Mix the active ingredient and ethanol, the mixture was added to a portion of the propellant 22, cooled to -20°C and transferred to a packing machine. Then the required number placed in a stainless steel container and diluted with the remaining propellant. To the container attached with the lo-spray (bubble unit, the sprinklers).

Example recipe 4

Tablet containing 50 mg of active ingredient, was prepared as follows:

The active ingredient60 mg
Starch45 mg
Microcrystalline cellulose36 mg
Polyvinylpyrrolidone (10% solution in water)4 mg
Natrocarbonatite4.5 mg
Magnesium stearate0.5 mg
Talc1 mg
The total mass150 mg

The active ingredient, starch and cellulose are passed through sieve No. 45 mesh U.S. and thoroughly mix. An aqueous solution containing polyvinylpyrrolidone, mixed with the obtained powder and the mixture is then passed through sieve No. 14 mesh U.S. dollars. The granules thus obtained, dried at 50°C and passed through sieve No. 18 mesh U.S. dollars. Natrocarbonatite, magnesium stearate and talc, previously passed through sieve No. 60 mesh U.S. add to the pellet, mixed and then pressed N. the tablet press machine receiving tablets weighing 150 mg each.

An example of the formulation 5

Capsule containing 80 mg of the active ingredient, was prepared as follows:

The active ingredient80 mg
Starch59 mg
Microcrystalline cellulose59 mg
Magnesium stearate2 mg
The total mass200 mg

The active ingredient, starch, cellulose and magnesium stearate are mixed and passed through sieve No. 45 mesh U.S. and the mixture fill hard gelatin capsule with 200 mg

Example formulations 6

Suppository containing 225 mg of active ingredient, was prepared as follows:

The active ingredient225 mg
The glycerides of saturated fatty acids2000 mg
The total mass2225 mg

The active ingredient is passed through sieve No. 60 mesh U.S. and suspended in the glycerides of saturated fatty acid, to which were pre-melted by heating, if it is necessary. Then the mixture is placed in a mold about 2 g and cool.

Example formulations 7

The suspension containing 50 mg of active ingredient, was prepared as follows:

The active ingredient50 mg
The sodium carboxymethyl cellulose50 mg
Syrup1.25 ml
A solution of benzoic acid0.10 ml
Perfumeq.v.
Pigmentq.v.
Purified water to total amount5 ml

The active ingredient is passed through a sieve No. 45 mesh U.S. and mixed with the sodium carboxymethyl cellulose and syrup, getting a smooth paste. Add a solution of benzoic acid and the odorant diluted part of water, and mix. Then add water in sufficient quantity to achieve the required volume.

Example recipe 8

An intravenous drug is produced as follows:

The active ingredient 100 mg
The glycerides of saturated fatty acids1000 ml

The solution of the above ingredients is injected to the patient, usually at the rate of 1 ml per minute.

Industrial applicability

As can be seen from the above test examples, the compounds according to the present invention show inhibitory activity against 11β-hydroxysteroiddehydrogenase type 1. Therefore, the compounds according to the present invention is very useful as therapeutic agents for diabetes.

1. The compound represented by formula (II):
formula 1

its pharmaceutically acceptable salt, where the ring And represents a group represented by the formula:
formula 2

where R1represents hydrogen or C1-6alkyl;
R2represents-SR5, halogen, halogenated1-6alkyl, cyano, C1-6alkyl, optionally substituted C1-6alkoxygroup, phenyl, pyrazolyl,
the group represented by formula: -NR5AR6A,
where R5Aand R6Arepresent hydrogen, C1-6alkyl, carbarnoyl, or R5Aand R6Ataken together with the neighboring nitrogen atom to which they are attached, may form morpholino ring,
g is the SCP, represented by the formula: -O-(CR10AR11A)z-CR12AR13AR14A,
where z is an integer from 0 to 5,
R10Aand R11Arepresent hydrogen,
R12A, R13Aand R14Aeach independently represent hydrogen or C1-6alkyl;
R3represents a group represented by the formula:
-CH=CH-C(RaRb)-Rc-Rdor
the group represented by formula: -(CReRf)m-C(RaRb)-Rc-Rd,
where Raand Rbrepresent1-6alkyl,
Rcrepresents -(CH2)nwhere n is an integer from 0 to 3,
Rdrepresents a halogen, a hydroxy-group, cyano, C3-8cycloalkyl, oxadiazolyl, optionally substituted C1-6the alkyl, oxazolidinyl, replaced by exography,
the group represented by the formula: -S(=O)-NRgRhor
the group represented by formula: -NRiRj;
Reand Rfrepresent hydrogen;
Rgand Rheach independently represent hydrogen, C1-6alkyl, C1-6alkylsulfonyl, C1-6alkoxygroup, carbarnoyl;
Riand Rjeach independently represent hydrogen, (C1-6alkoxy)carbonyl, C1-6alkylsulfonyl, (C1-6alkyl)carbonyl, optionally substituted C1-6 alkoxygroup, phenyl, phenyloxy,3-8cycloalkyl and benzyloxy,3-8cycloalkylcarbonyl, heterocalixarenes where heterocyclyl is tetrahydropyranyl or morpholinyl;
R4represents-OR6, -CONR7R8, -NR9CONR7R8, -(CR10R11)pOH, -(CR10R11)pOCONR7R8, -NR9COR12, -(CR10R11)pNR9COR12-C(=O)NR9OR12, -CONR9CONR7R8, -CN, halogen or NR9(C=O)OR12;
R5represents a C1-6alkyl;
R6is a-CONR7R8;
R7and R8each independently represent hydrogen, C1-6alkyl, or R7and R8taken together with the neighboring nitrogen atom to which they are attached, can form an imidazole ring;
R9represents hydrogen or C1-6alkyl;
R10and R11represent hydrogen;
R12represents a C1-6alkyl;
m and R, each independently, is an integer from 1 to 3, and
provided that excluded the following below the connection
formula 3

formula 4


formula 5

formula 6

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where R6is a-CONR7R8where R7and R8are as defined in claim 1.

3. The compound according to claim 1 or its pharmaceutically acceptable salt, where the ring And represents a group represented by the formula (III):
formula 8

where R4is such as defined in claim 1, R6is a-CONR7R8where R7and R8are as defined in claim 1.

4. The compound according to claim 1 or its pharmaceutically acceptable salt, where R1represents hydrogen.

5. The compound according to claim 1 or its pharmaceutically acceptable salt, where Rcrepresents -(CH2)n-where n is an integer of 0 or 1.

6. The compound according to claim 1 or its pharmaceutically acceptable salt, where Rdrepresents a group represented by the formula: -C(=O)-NRgRhwhere Rgand Rheach independently represent hydrogen, C1-6alkyl, C1-6alkyloxy or carbarnoyl.

7. The compound according to claim 1 or its pharmaceutically acceptable salt, where Rdrepresents a group represented by the formula: -NRiRjwhere Riand Rjeach independently represent hydrogen, (C1-6alkoxy)carbonyl, C1-6alcalali the Nile, C1-6alkylsulphonyl, optionally substituted C1-6alkoxygroup, phenyl, phenyloxy,3-8cycloalkyl or benzyloxy, With3-8cycloalkylcarbonyl or heterocyclicamines where heterocyclyl is tetrahydrofuranyl or morpholinyl.

8. The compound according to claim 1 or its pharmaceutically acceptable salt, where R4represents-OR6, -CONR7R8, -NR9CONR7R8, -(CR10R11)pOH, -(CR10R11)pOCONR7R8, -NR9COR12, -NR9C(=O)OR12, -(CR10R11)pNR9COR12, -C(=O)NR9OR12, -CONR9CONR7R8or-CN, where R6-R12and p are as defined in claim 1.

9. The compound of claim 8 or its pharmaceutically acceptable salt, where R7and R8each independently represent hydrogen or C1-6alkyl.

10. The compound of claim 8 or its pharmaceutically acceptable salt, where R9represents hydrogen.

11. The connection, as defined below, or its pharmaceutically acceptable salt
formula 9

formula 10

formula 11

formula 12

formula 13

formula 14

12. Pharmaceutical composition having inhibitory activity against 11β-hydroxysteroiddehydrogenase type 1, containing a compound according to any one of claims 1 to 11, or its pharmaceutically acceptable salt.

13. A method of preventing or treating diabetes, comprising introducing the compound according to any one of claims 1 to 11, or its pharmaceutically acceptable salt.

14. The use of compounds according to any one of claims 1 to 11, or its pharmaceutically acceptable salt for a medicinal product for the treatment and/or prevention of diabetes.

15. The connection, as defined below, or its pharmaceutically acceptable salt:

16. The connection, as defined below, or its pharmaceutically acceptable salt:

17. The connection, as defined below, or its pharmaceutically acceptable salt:

18. The connection, as defined below, or its pharmaceutically acceptable salt:

19. The connection, as defined below, or its pharmaceutically acceptable salt:

20. The connection, as defined below, or its pharmaceutically acceptable salt:

21. Pharmaceutical composition having inhibitory activity against 11β-hydroxyether is degidrogenazy type 1, containing the compound according to any one of p-20 or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a novel clathrate complex of β-cyclodextrin with 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine of formula : with molar ratio 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine: β-cyclodextrin from 1:1 to 1:10, synthesis method and use thereof as an antiviral agent for treating influenza. The disclosed method involves mixing solutions of β-cyclodextrin and 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine in molar ratio from 1:1 to 1:10 while stirring and heating to temperature not higher than 70°C and then maintaining said conditions until a homogeneous solution is obtained and extraction of the obtained complex.

EFFECT: clathrate complex is a novel effective anti-influenza virus agent which is obtained using a novel efficient method.

13 cl, 2 ex, 3 tbl, 11 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of 2-substituted azole

compounds of formula , (a) reaction of an aldehyde of formula

with an azole of formula in the presence of a carbonylating agent of formula to obtain an oxazolidone of formula , reaction of the oxazolidone of formula (Ia) so as to perform hydrolysis of a triarylmethyl group, splitting the O-(C=Q) bond and opening the oxazolidone, followed by reaction of the obtained intermediate compound with Prot-Z, where Prot-Z is an agent which protects an amino group, to obtain an azole-containing intermediate compound of formula (lb) and and oxidation of the intermediate compound of formula (Ib) to obtain a 2-substituted azole derivative of formula (I). The invention also relates to azole compounds of formulae (I), (la), (lb), (Ic) and (II).

EFFECT: novel method of obtaining azoles of formula (I), as well as obtaining novel compounds of formulae (I), (la), (lb), (Ic) and (II), having useful biological properties.

41 cl, 5 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), in which (i) R1 denotes C1-C6-alkyl or hydrogen; and R2 denotes hydrogen or a -R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C(O)O-R7 or -Z-C(O)-R7 group; and R3 denotes an undefined pair or C1-C6-alkyl; or (ii) R1 and R3 together with a nitrogen atom with which they are bonded form a 5-6-member heterocycloalkyl ring; and R2 denotes an undefined pair or a -R7 , -Z-Y-R7 group; or (iii) R1 and R2 together with a nitrogen atom with which they are bonded form a 6-member heterocycloalkyl ring, where said ring is substituted with a -Y-R7 group, and R3 denotes an undefined pair or C1-C6-alkyl; R4 and R5 are independently selected from a group consisting of phenyl, C3-C6-cycloalkyl; R6 denotes -OH, C1-C6-alkyl, C1-C6-alkoxy or a hydrogen atom; A denotes an oxygen or sulphur atom; X denotes a C1-C6-alkylene group; R7 denotes C1-C6-alkyl, phenyl, phenyl(C1-C6-alkyl)-, dihydrobenzofuran or pyridine, where any phenyl in group R7 can be optionally substituted with one or two groups independently selected from halogen, aminoacyl, C1-C6-alkoxycarbonyl, aminosulphonyl, C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl, -COOH; and any pyridine in group R7 can be optionaly substituted with C1-C6-alkyl; R8 denotes C1-C6-alkyl or a hydrogen atom; Z denotes a C1-C10-alkylene or C2-C10-alkenylene group; Y denotes a bond or an oxygen atom; R9 and R10 independently denote a hydrogen atom, C1-C6-alkyl group, isoxazole or 8-hydroxy-1H-quinolin-2-one-(C1-C6-hydroxyalkyl); and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition having activity with respect to M3 muscarinic receptor; use of the compounds of formula (I) to produce a medicinal agent for treating and a method of treating diseases or conditions in which M3 muscarinic receptor activity is involved.

EFFECT: compounds of given formula have activity with respect to M3 muscarinic receptor.

26 cl, 8 dwg, 91 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxazole derivatives of general formula I. The disclosed compounds have affinity to the µ-opioid receptor. In general formula I

, n equals 0, 1 or 2, R1 denotes a phenyl residue bonded through a C1-C3alkyl chain, R2 denotes phenyl or thienyl, each of which is unsubstituted or mono-substituted with F or Cl, R3 and R4 independently denote a saturated, branched or straight C1-C6alkyl, phenyl or a phenyl residue bonded through a C1-C3akyl chain, or R3 and R4 together form an unsubstituted five-, six- or seven-member saturated ring which can optionally contain an extra heteroatom selected from a group comprising O or NR9, where R9 denotes phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which is unsubstituted or mono-substituted with a substitute selected from a group comprising F, Cl, Br, I and O-C1-C6alkyl, where the ring can be optionally condensed with a phenyl ring, R5 and R6 independently denote a saturated, branched or straight C1-C6alkyl, R7 and R8 independently denote a saturated, branched or straight unsubstituted C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, or R7 and R8 together form an unsubstituted or mono- or disubstituted five-, six- or seven-member saturated ring, where the substitutes are selected from a group comprising C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, where the ring can optionally contain an extra heteroatom selected from a group comprising S, O and NR10, where R10 denotes a phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which can be unsubstituted or mono-substituted with O-C1-C6alkyl. The invention also relates to methods of producing the disclosed compounds, a medicinal agent containing at least one substituted oxazole derivative of formula I, use of the compounds to prepare a medicinal agent.

EFFECT: improved properties.

13 cl, 1 tbl, 150 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new piperazine amide derivatives of formula wherein X represents N or CH; Y represents N or CH; R1 represents lower alkyl, phenyl, phenyl-lower alkyl wherein phenyl can be optionally substituted by 1-2 substitutes independently specified in a group consisting of halogen, lower alkyl; R2 represents lower alkyl, phenyl, naphthyl or heteroaryl specified in dimethylisoxazolyl, quinolinyl, thiophenyl or pyridinyl wherein phenyl or heteroaryl are optionally substituted by 1 substitute optionally specified in a group consisting of halogen, lower alkoxy group, fluor-lower alkyl, lower alkoxy-carbonyl and phenyl; R3 represents phenyl, pyridinyl or pyrazinyl wherein phenyl, pyridinyl or pyrazinyl are substituted by 1-2 substituted optionally specified in a group consisting of halogen, lower alkyl and fluor-lower alkyl; R4, R5, R6, R7, R8, R9, R10 and R11 independently represent hydrogen, as well as to their physiologically acceptable salts. These compounds are bound with LXR alpha and LXR beta, and are applicable as therapeutic agents for treatment and/or prevention of high lipid levels, high cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non insulin dependent diabetes mellitus, metabolic syndrome, dislipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, etc.

EFFECT: preparing new piperazine amide derivatives.

15 cl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to quinoline derivatives of formula I

, or to its pharmaceutically acceptable salts, wherein X1 represents O; p represents 0, 1 or 2; each group R1 which can be identical or different and which can be located only in positions of 6- and/or 7-quinoline ring, specified in halogen, cyano, carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, or in a group of formula: Q1-X2-, wherein X2 represents CO and Q1 represents pyrrolidine, q represents 0 or 1; R2 represents (1-6C)alkoxy; R3 represents hydrogen or (1-6C)alkyl; R4 represents hydrogen; R5 represents hydrogen, methyl, ethyl, propyl, allyl, 2-propynyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-cyanoethyl or 3-cyanopropyl; the ring A represents a 5-membor monocyclic heteroaryl ring with up to three ring heteroatoms specified in oxygen, nitrogen and sulphur; r represents 0, 1 or 2; and each group R6 which can be identical or different is specified in amino, (1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, or in a group of formula: -X6-R15 wherein X6 represents a single link and R15 represents (1-6C)alkoxy-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or in a group of formula: -X7-Q3 wherein X7 represents C(R17)2N(R17) wherein each R17 represents hydrogen and Q3 represents (3-8C)cycloalkyl, and wherein any CH2 group within the R6 group optionally carries a hydroxy group on each said group. Also, the invention refers to methods for making the compound of formula I, to a pharmaceutical composition on the basis of the compound of formula I, to applying the compound of formula I and the combinations on the basis of the compound of formula I and additional anticancer drugs.

EFFECT: there are produced new quinoline derivatives effective in treating diabetic retinopathy and disturbed cell proliferation.

15 cl, 6 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing piperazinophenols, involving reaction of piperazine, N-(β-aminoethyl)piperazine, N-(β-benzylaminoethyl)piperazine or N,N1-bis-(piperazinoethyl)ethylenediamine with a Mannich base in an aqueous medium at temperature 90-110°C in molar ratio of piperazine, N-(β-aminoethyl)piperazine, N-(β-benzylaminoethyl)piperzine:Mannich base equal to 1:0,8-2, N,N1-bis-(piperazinoethyl)ethylenediamine:Mannich base equal to 1:2 or 1:4 until release of dimethylamine stops; as well as aminomethylation of piperazine or N-(β-aminoethyl) piperazine with diphenylol propane (DPP) in the presence of formaldehyde (FA) in an aqueous medium with molar ratio piperazine: FA: DPP equal to 1:1:1 or 1:2:2 at temperature 50-90°C for 4-10 hours. Reactants react in the presence of a surfactant in amount of 2-6% of the weight of the starting piperazine, and the surfactant used is neonol, OP-7, OP-10.

EFFECT: ensuring fire safety of the process, high output of the end product which can be used as antioxidant phenol stabilisers.

1 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula 1c

, where A, B, R1, R2 and n have values given in the description, and pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions based on compounds of formula 1c, which are used as modulators of ATP-binding cassette ("ABC") transporters or fragments thereof, including cystic fibrosis transmembrane conductance regulator ("CFTR"). The present invention also relates to a method of modulating ABC-transporter activity and methods of treating ABC-transporter mediated diseases using compounds of formula 1c.

EFFECT: improved method.

32 cl, 3 tbl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of 1,2,4-triazole derivatives of formula I:

, where R1, R2 and R3 independently denote hydrogen or halogen; R4 denotes C1-C6 alkyl; R5 and R6 independently denote C1-C6 alkyl or, together with a nitrogen atom to which they are bonded, form a 5-7-member heterocyclyl group, in which the 6-member heterocyclyl can further contain one oxygen or nitrogen atom and can be substituted with acetyl, C1-C6 alkyl or phyenyl; X-S-, -SO-, -SO2- or O; and n is a whole number selected from 1-8; or pharmaceutically acceptable salts, stereoisomers or solvates thereof, when producing a drug for treating or preventing sigma-1 receptor-mediated diseases or conditions, methods of producing said compounds, intermediate compounds and pharmaceutical compositions which contain compounds of formula 1.

EFFECT: improved compounds.

19 cl, 49 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

SUBSTANCE: invention relates to specific derivatives of bicyclic amides disclosed in the claim, as well as a pharmaceutical composition.

EFFECT: compounds having protein kinase inhibiting activity, meant for use in treating protein kinase-dependant diseases, preferably proliferative diseases such as tumorous diseases.

13 cl, 115 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (IB) or to their pharmaceutically acceptable salts:

, wherein R means formula: R1 means -C(O)NR3R4, -C(O)R3 and -C(O)OR3; each R3 and R4 independently means H, C1-10 alkyl, wherein alkyl is optionally substituted by one -OH; R3 and R4 are bound together with N atoms to form a 5-6-member heterocyclic ring which additionally contains one O heteroatom; R5 means H; R6 means CN; R7 means H; W means C. What is described is a method for producing both them and intermediate compounds of formula (1-1c): , wherein: R1 means -C(O)NR3R4; R3 and R4 are specified above.

EFFECT: compounds (IB) shows DPP-IV inhibitory activity that allows them being used in a pharmaceutical composition.

9 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula I

and/or to all isomer forms of a compound of formula I and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula I, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents aminomethylene, 2) Het-Z, wherein Z represents amino group, and wherein Het is unsubstituted or additionally monosubstituted by group T, R2 represents 1) -(C0)-alkylene-(C6-C14)aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T or 2) -(C0)-alkylene-Het, wherein Het is unsubstituted or monosubstituted by group T, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T, 2) -O-(C6-C14)-alkylene(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 3) -(C0)-alkylene-Het, wherein Het is unsubstituted or mono-, di- or trisubstituted by group T, 4) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryl radicals are unsubstituted, 5) -(C0)-alkylene-(C6-C14)-aryl-Q)-Het, wherein aryl and Het in each case are independently unsubstituted or disubstituted by group T, 6) -(C0)-alkylene-Het-Q-Het, wherein both radicals Het are unsubstituted, Q represents a covalent bond, -(C1-C4)-alkylene, -N((C1-C4)-alkyl)- or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl, wherein alkyl is unsubstituted disubstituted by group -(C1-C3)-fluoralkyl or -N-C(O)-(C1-C4)-alkyl, 3) -(C1-C3)-fluoralkyl, 4) -(C3-C8)-cycloalkyl, 5) -O-(C1-C4)-alkyl, 6) -O-(C1-C3)-fluoralkyl, 7) -N(R10)(R11), wherein R(10) and R(11) independently represent hydrogen atom or -(C1-C6)-alkyl, 8) -C(O)-NH-R10, 9) -SO2-(C1-C4)-alkyl, 10) -SO2-(C1-C3)-fluoralkyl, R4 and R5 are identical and represent hydrogen atom, and R6 represent hydrogen atom with said Het being 5-10-member ring system consisting of 1 or 2 coupled ring systems, and wherein one or two identical or different heteroatoms are selected from oxygen, nitrogen and sulphur. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds exhibiting antithrombotic activity, which particularly inhibit blood coagulation factor lXa.

6 cl, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of formula

as well as their pharmaceutically acceptable salts where the substitutes are those as described in the patent claim. The compounds of formula (I) are 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme inhibitors.

EFFECT: making the compounds effective for treating and preventing the diseases, such as insulin-independent diabetes and metabolic syndrome, particularly obesity, eating disorders or dislipidemia.

15 cl, 1 tbl, 28 ex

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